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"abstract": "Obstetrical antiphospholipid syndrome (APS) is associated with maternal and fetal morbidity and mortality. Standard treatment with low-dose acetylsalicylic acid and unfractionated heparin has achieved up to a 70 to 80% likelihood of success. Conversely, up to 30% of women with APS will have further pregnancy losses, despite treatment. Intravenous immunoglobulin (IVIG) may be a promising adjuvant when standard treatment fails. We present a case of a 35-year-old woman with obstetrical APS and maternal floor infarction in prior pregnancy losses who continued to have further unsuccessful pregnancies despite standard treatment with acetylsalicylic acid and unfractionated heparin. On an investigational basis, she was prescribed concomitant IVIG and had two subsequent healthy newborns. IVIG appears to be promising in obstetrical patients with APS who are refractory to standard treatment. Prior history of maternal floor infarction may be a prognostic indicator for triple therapy for obstetrical APS.",
"affiliations": "Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois 60637, USA.",
"authors": "Chang|Phyllis|P|;Millar|Debra|D|;Tsang|Peter|P|;Lim|Kenneth|K|;Houlihan|Edwina|E|;Stephenson|Mary|M|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": "10.1055/s-2006-931805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1631",
"issue": "23(2)",
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D000328:Adult; D016736:Antiphospholipid Syndrome; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005865:Gestational Age; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007238:Infarction; D008423:Maternal Age; D010298:Parity; D017773:Pelvic Floor; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011295:Prenatal Care; D018570:Risk Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "125-9",
"pmc": null,
"pmid": "16506120",
"pubdate": "2006-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Intravenous immunoglobulin in antiphospholipid syndrome and maternal floor infarction when standard treatment fails: a case report.",
"title_normalized": "intravenous immunoglobulin in antiphospholipid syndrome and maternal floor infarction when standard treatment fails a case report"
} | [
{
"companynumb": "AU-BAYER-2016-222114",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "ASPIRIN"
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"abstract": "OBJECTIVE\nHypercoagulability, resulting in thromboembolic events, can be a life-threatening complication of nephrotic syndrome (NS). Conventional anticoagulants, such as warfarin, have been the standard of care for more than 50 years; however, the availability of target-specific oral anticoagulants (TSOACs) have provided additional options for the treatment and prevention of thromboembolic events. Documented use of the TSOACs in patients with NS and hypercoagulability is currently limited.\n\n\nMETHODS\nWe present the case of an 18-year-old young woman with NS and renal vein thrombosis who was readmitted with bilateral pulmonary emboli on therapeutic doses of warfarin, with a goal international normalized ratio of 2.0 to 3.0. The decision was made to transition the patient from warfarin to rivaroxaban, an oral factor Xa inhibitor.\n\n\nCONCLUSIONS\nRivaroxaban was the first of the emerging TSOACs to be FDA approved for both prevention and treatment of venous thromboembolism. With favorable safety and efficacy data compared with warfarin in addition to a predictable pharmacokinetic profile and the lack of requirement of routine monitoring, rivaroxaban provides a useful alternative in this patient population.\n\n\nCONCLUSIONS\nWhile on therapeutic anticoagulation, a patient previously diagnosed with NS and renal vein thrombosis experienced pulmonary emboli on a conventional anticoagulant and was switched to a target-specific oral anticoagulant with documented completion of 6 months of therapy without recurrent thromboembolism.",
"affiliations": "University of Florida College of Pharmacy, Jacksonville, FL, USA ldupree@cop.ufl.edu.;University of Florida, Jacksonville, FL, USA.",
"authors": "Dupree|Lori H|LH|;Reddy|Pramod|P|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D014859:Warfarin; D000069552:Rivaroxaban",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014549349",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "48(12)",
"journal": "The Annals of pharmacotherapy",
"keywords": "anticoagulants; disease management; hematology; internal medicine; nephrology",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D009025:Morpholines; D009404:Nephrotic Syndrome; D011655:Pulmonary Embolism; D000069552:Rivaroxaban; D013876:Thiophenes; D019851:Thrombophilia; D054556:Venous Thromboembolism; D014859:Warfarin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1655-8",
"pmc": null,
"pmid": "25169250",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of rivaroxaban in a patient with history of nephrotic syndrome and hypercoagulability.",
"title_normalized": "use of rivaroxaban in a patient with history of nephrotic syndrome and hypercoagulability"
} | [
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"companynumb": "US-TEVA-605158USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
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"abstract": "We report a case of rapid pleural effusion after discontinuation of lenvatinib. A 73-year-old woman was diagnosed with poorly differentiated thyroid cancer with right pleural metastasis. Weekly paclitaxel treatment was performed for 18 weeks, but it was not effective. Oral administration of lenvatinib, a multi-target tyrosine kinase inhibitor, reduced the size of cervical and thoracic tumors and lowered serum thyroglobulin levels. Lenvatinib was discontinued on day 28 because of Grade 2 thrombocytopenia and Grade 3 petechiae. Seven days after discontinuation of lenvatinib, the patient was hospitalized because of dyspnea and right pleural effusion. Pleural effusion rapidly improved with drainage and re-initiation of lenvatinib and did not recur. Anorexia caused by lenvatinib led to undernutrition, which resulted in death 13 months after initiation of lenvatinib. Autopsy revealed extensive necrosis with primary and metastatic lesions, suggesting that the patient responded to lenvatinib. Physicians should be aware of the possibility of flare-up in patients with thyroid cancer treated with lenvatinib. Learning points: Autopsy findings revealed that lenvatinib was efficacious in treating poorly differentiated thyroid cancer without primary lesion resection. Flare-up phenomenon may occur in thyroid cancer treated with lenvatinib. Attention should be paid to flare-up phenomenon within a few days of discontinuing lenvatinib.",
"affiliations": "Department of Neurology, Respirology, Endocrinology and Metabolism, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Neurology, Respirology, Endocrinology and Metabolism, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Neurology, Respirology, Endocrinology and Metabolism, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Neurology, Respirology, Endocrinology and Metabolism, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Diagnostic Pathology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Clinical Oncology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Division of the Gastrointestinal, Endocrine and Pediatric Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Diagnostic Pathology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Neurology, Respirology, Endocrinology and Metabolism, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.",
"authors": "Uchida|Taisuke|T|;Yamaguchi|Hideki|H|;Nagamine|Kazuhiro|K|;Yonekawa|Tadato|T|;Nakamura|Eriko|E|;Shibata|Nobuhiro|N|;Kawano|Fumiaki|F|;Asada|Yujiro|Y|;Nakazato|Masamitsu|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-18-0158EDM180158Unusual Effects of Medical TreatmentRapid pleural effusion after discontinuation of lenvatinib in a patient with pleural metastasis from thyroid cancer T Uchida and othersFlare up after discontinuation of lenvatinibUchida Taisuke 1Yamaguchi Hideki 1Nagamine Kazuhiro 1Yonekawa Tadato 1Nakamura Eriko 2Shibata Nobuhiro 3Kawano Fumiaki 4Asada Yujiro 2Nakazato Masamitsu 11 Department of Neurology, Respirology, Endocrinology and Metabolism, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan2 Department of Diagnostic Pathology, University of Miyazaki Hospital, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan3 Department of Clinical Oncology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan4 Division of the Gastrointestinal, Endocrine and Pediatric Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, JapanCorrespondence should be addressed to M Nakazato; Email: nakazato@med.miyazaki-u.ac.jp18 3 2019 2019 2019 18-015804 2 2019 26 2 2019 © 2019 The authors2019The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..Summary\nWe report a case of rapid pleural effusion after discontinuation of lenvatinib. A 73-year-old woman was diagnosed with poorly differentiated thyroid cancer with right pleural metastasis. Weekly paclitaxel treatment was performed for 18 weeks, but it was not effective. Oral administration of lenvatinib, a multi-target tyrosine kinase inhibitor, reduced the size of cervical and thoracic tumors and lowered serum thyroglobulin levels. Lenvatinib was discontinued on day 28 because of Grade 2 thrombocytopenia and Grade 3 petechiae. Seven days after discontinuation of lenvatinib, the patient was hospitalized because of dyspnea and right pleural effusion. Pleural effusion rapidly improved with drainage and re-initiation of lenvatinib and did not recur. Anorexia caused by lenvatinib led to undernutrition, which resulted in death 13 months after initiation of lenvatinib. Autopsy revealed extensive necrosis with primary and metastatic lesions, suggesting that the patient responded to lenvatinib. Physicians should be aware of the possibility of flare-up in patients with thyroid cancer treated with lenvatinib.\n\nLearning points:\nAutopsy findings revealed that lenvatinib was efficacious in treating poorly differentiated thyroid cancer without primary lesion resection.\n\nFlare-up phenomenon may occur in thyroid cancer treated with lenvatinib.\n\nAttention should be paid to flare-up phenomenon within a few days of discontinuing lenvatinib.\n==== Body\nBackground\nPoorly differentiated or anaplastic thyroid cancer has aggressive behavior and poor prognosis (1). In 2015, the SELECT study showed that lenvatinib, a multi-tyrosine kinase inhibitor (TKI), prolonged progression-free survival (PFS) of radioiodine-refractory differentiated thyroid cancer with primary tumor resection compared to placebo (2). The efficacy of lenvatinib was also confirmed in patients with poorly differentiated or anaplastic thyroid cancer (3). In some cases, rapid disease progression after TKI discontinuation was observed, which was called the flare-up phenomenon (4). No cases of flare-up phenomenon after discontinuation of lenvatinib in thyroid cancer have been reported. Here, we report rapid development of pleural effusion after discontinuation of lenvatinib in a patient with poorly differentiated thyroid cancer without primary tumor resection.\n\nCase presentation\nA 73-year-old woman was referred to our hospital because of abnormal shadows on chest X-ray (Fig. 1A). Computed tomography (CT) revealed solid tumors in the right anterior cervix, lungs and right pleura. Fine-needle aspiration biopsy of the thyroid and CT-guided biopsy of the pleural tumor showed thyroid tumor cells with limited evidence of follicular cell differentiation with an insular pattern and convoluted nuclei. The diagnosis was poorly differentiated thyroid cancer. The patient underwent weekly paclitaxel therapy (80 mg/m2) for 18 weeks. However, cervical tumors grew from 4.8 to 6.4 cm and serum thyroglobulin (Tg) levels increased from 2330 to 18 800 ng/mL. We chose to administer lenvatinib because of the multiple lung and pleural metastases and the lack of any emergent condition that would cause obstructive complications. Two weeks following treatment with daily oral lenvatinib (24 mg/day), cervical and pleural tumors decreased in size. Lenvatinib was discontinued for 1 week on day 28 because of Grade 2 thrombocytopenia (52 000/μL) and Grade 3 petechiae according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). The patient was admitted to the hospital because of dyspnea 7 days after discontinuation of lenvatinib.Figure 1 Chest X-ray before and after re-starting lenvatinib. (A) Before discontinuation of lenvatinib. (B) Massive right pleural effusion 7 days after discontinuation of lenvatinib. (C) Smaller pleural effusion and lung shadows 6 months after re-starting lenvatinib.\n\n\n\n\nInvestigation\nOn examination, height was 151.7 cm and weight was 41.7 kg. Temperature was 37.7°C, blood pressure was 140/90 mmHg, heart rate was 110 beats per minute and respiratory rate was 36 breaths per minute. Arterial blood analysis showed hypoxia. We palpated thyroid tumors, but heard no sounds indicating airway obstruction. Auscultation revealed no breath sounds in the right lung field. Chest X-ray showed massive right pleural effusion (Fig. 1B). The pleural fluid was exudative with pleural Tg levels of 21 800 ng/mL, suggesting malignant pleural effusion from thyroid cancer.\n\nTreatment\nA chest tube was inserted to drain the pleural effusion and lenvatinib (20 mg/day) was re-started. Chest tube was removed shortly afterwards, with no pleural effusion recurrence after lenvatinib therapy was re-started (Fig. 1C).\n\nOutcome and follow-up\nAt 12 months after re-starting lenvatinib treatment, serum Tg levels decreased from 18 800 to 450 ng/mL. Simultaneous CT and positron emission tomography (PET-CT) revealed that the cervical tumor regressed from 6.4 to 4.0 cm with no evidence of new metastases (Fig. 2). Partial response based on the Response Evaluation Criteria in Solid Tumors (RECIST) was achieved. Thyroid function testing results before administration of lenvatinib were as follows: TSH 0.59 μU/mL, FT3 3.96 pg/mL and FT4 0.46 ng/dL. Hypothyroidism developed gradually during lenvatinib treatment. We prescribed levothyroxine, which was increased up to 150 μg per day. Cervical CT revealed shrinkage of thyroid tumors, which was consistent with hypothyroidism. Severe anorexia occurred as an adverse effect of lenvatinib. Neither dose reduction of lenvatinib (14 mg/day) nor administration of dexamethasone improved anorexia. Undernutrition and aspiration pneumonia led to poor systemic condition. Thirteen months after lenvatinib therapy began, the patient died because of respiratory and circulatory failure. Histopathology obtained during autopsy showed extensive necrosis in the primary lesion (80%) and metastatic lesions in the anterior mediastinum lymph nodes (60%) and the pleura (40%), consistent with effective treatment of thyroid cancer with pleural metastasis (Fig. 3).Figure 2 Computed tomography imaging before and after lenvatinib treatment. (A) Cervical tumor before administration of lenvatinib. (B) Shrinkage of cervical tumor 12 months after administration of lenvatinib. (C) Pleural metastases before administration of lenvatinib. (D) Size reduction of pleural metastases at 12 months after administration of lenvatinib.\n\n\nFigure 3 Histopathology of the pleural metastatic tumor obtained during autopsy showed tumor cells (*1) and extensive necrosis (*2). Hematoxylin-eosin staining, original magnification: ×20 (A), ×200 (B).\n\n\n\n\nDiscussion\nLenvatinib is a multi-TKI that targets vascular endothelial growth factor (VEGF) receptors 1–3, fibroblast growth factor receptors (FGFR) 1–4, RET, c-kit and platelet-derived growth factor receptor-alpha (PDGFRα). It inhibits tumor growth and angiogenesis. Lenvatinib was approved for the treatment of unresectable hepatocellular carcinoma and radioiodine-refractory differentiated thyroid cancer. Lenvatinib was shown to prolong progression-free survival (PFS) compared to sorafenib in patients with unresectable hepatocellular carcinoma (7.4 vs 3.7 months) in the REFLECT trial (5). Lenvatinib significantly prolonged PFS in patients with radioiodine-refractory differentiated thyroid cancer without primary lesion resection compared to placebo (18.3 vs 3.6 months) in the SELECT trial (2). Lenvatinib has also been prescribed for patients with poorly differentiated or anaplastic thyroid cancer. In patients with renal cell carcinoma with metastasis to the lung and pleura, rapid development of pleural effusion after discontinuation of sunitinib or sorafenib has been reported (6). Rapid disease progression after discontinuation of TKI is called the flare-up phenomenon (4); its mechanism is poorly understood. Tumor cells with hypersensitivity to TKI may proliferate rapidly after TKI discontinuation (6, 7). Experiments in mouse models of lung cancer suggest that VEGF plays an important role in the proliferation of pleural dissemination and formation of pleural effusion (8). Discontinuation of TKI enhances VEGF effects and increases angiogenesis, blood flow and vascular permeability in tumors (6). One report on the flare-up phenomenon in thyroid cancer is available (9); however, it has never been reported after discontinuation of lenvatinib. In lung cancer, the flare-up phenomenon occurs more commonly in patients with pleural lesions compared to patients without pleural lesions (7). In our case, right pleural effusion rapidly increased within 7 days after discontinuation of lenvatinib, but improved with re-starting lenvatinib, suggesting that thyroid cancer cells remained susceptible to lenvatinib. Autopsy findings showed that pleural lesions had widespread necrosis, consistent with the flare-up phenomenon induced by discontinuation of lenvatinib.\n\nAdverse effects of lenvatinib include diarrhea (22.6%), hypertension (19.9%), proteinuria (18.8%) and decreased appetite (18.0%). It might reduce the quality of life. Temporary withholding, dose reduction or permanent discontinuation due to adverse effects of lenvatinib has been reported in 82.4, 67.8 and 14.2% of patients, respectively. In the middle of discontinuation, increases in tumor size and pleural effusion have been reported (4). In metastatic renal cell carcinoma, short-term intermittent administration of TKI was recommended (10). In our case, Grade 3 weight loss (−30%; 48 to 34 kg) secondary to anorexia occurred 5 months after administration of lenvatinib. Anorexia occurred not only due to the adverse effects of lenvatinib but also due to varicella zoster virus infection and post-herpetic neuralgia. We could not stop lenvatinib due to concerns about the flare-up phenomenon; thus, we continued lenvatinib at a lower dose (14 mg/day) over the next 8 months despite anorexia. Switching the TKI from lenvatinib to sorafenib was a therapeutic choice in our case, but we continued administration of lenvatinib because of its effectiveness against the patient’s tumors.\n\nWe described a patient with rapid accumulation of pleural effusion after discontinuation of lenvatinib. In TKI-responsive, poorly differentiated thyroid cancer with pleural metastasis, more attention should be paid to the flare-up phenomenon within a few days after discontinuation of lenvatinib.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.\n\nPatient consent\nWritten informed consent was obtained from the patient’s husband.\n\nAuthor contribution statement\nT Uchida and H Yamaguchi wrote the case report. E Nakamura and Y Asada prepared and commented on the pathological findings. K Nagamine, T Yonekawa, N Shibata (oncologists), F Kawano (surgeon), and M Nakazato contributed to the clinical management of this patient.\n==== Refs\nReferences\n1 Kepal N Ashok R. \nPoorly differentiated and anaplastic thyroid cancer . Cancer Control \n2006 \n13 \n119 –128 . (10.1177/107327480601300206 )16735986 \n2 Schlumberger M Tahara M Wirth LJ Robinson B Brose MS Elisei R Habra MA Newbold K Shah MH Hoff AO. \nLenvatinib versus placebo in radioiodine-refractory thyroid cancer . New England Journal of Medicine \n2015 \n372 \n621 –630 . (10.1056/NEJMoa1406470 )25671254 \n3 Tahara M Kiyota N Yamazaki T Chayahara N Nakano K Inagaki L Toda K Enokida T Minami H Imamura Y , et al\nLenvatinib for anaplastic thyroid cancer . Frontiers in Oncology \n2017 \n7 \n1 –7 . (10.3389/fonc.2017.00025 )28168163 \n4 Wolter P Beuselinck B Pans S Schöffski P. \nFlare up: an often unreported phenomenon nevertheless familiar to oncologists prescribing tyrosine kinase inhibitors . Acta Oncologica \n2009 \n4 \n621 –624 . (10.1080/02841860802609574 )\n5 Kudo M Finn RS Qin S Han KH Ikeda K Piscaglia F Baron A Park JW Han G Jassem J , et al\nLenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial . Lancet \n2018 \n391 \n1163 –1173 . (10.1016/S0140-6736(18)30207-1 )29433850 \n6 Desar IM Mulder SF Stillebroer AB van Spronsen DJ van der Graaf WT Mulders PF van Herpen CM. \nThe reverse side of the victory: flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. A report of three cases . Acta Oncologica \n2009 \n48 \n927 –931 . (10.1080/02841860902974167 )19452305 \n7 Chaft JE Oxnard GR Sima CS Kris MG Miller VA Riely GJ. \nDisease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design . Clinical Cancer Reserch \n2011 \n17 \n6298 –6303 . (10.1158/1078-0432.CCR-11-1468 )\n8 Ishii H Yazawa T Sato H Suzuki T Ikeda M Hayashi Y Takanashi Y Kitamura H. \nEnhancement of pleural dissemination and lymph node metastasis of intrathoracic lung cancer cells by vascular endothelial growth factors (VEGFs) . Lung Cancer \n2004 \n45 \n325 –337 . (10.1016/j.lungcan.2004.02.021 )15301873 \n9 Yun KJ Kim W Kim EH Kim MH Lim DJ Kang MI Cha BY. \nAccelerated disease progression after discontinuation of sorafenib in a patient with metastatic papillary thyroid cancer . Endocrinology and Metabolism \n2014 \n29 \n388 –393 . (10.3803/EnM.2014.29.3.388 )25309799 \n10 Grünwald V Merseburger AS. \nThe progression free survival-plateau with vascular endothelial growth factor receptor inhibitors – is there more to come . European Journal of Cancer \n2013 \n49 \n2504 –2511 . (10.1016/j.ejca.2013.03.022 )23601669\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2019()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2019; Anaplastic thyroid cancer; Anorexia; Asian - Japanese; CT scan; Dexamethasone; Dyspnoea; FT3; FT4; Female; Geriatric; Glucocorticoids; Histopathology; Hypothyroidism; Hypoxia; Japan; Levatinib; Levothyroxine; Lung metastases; March; Oncology; PET scan; Paclitaxel; Petechiae; Pneumonia; TSH; Thrombocytopenia; Thyroglobulin; Thyroid; Thyroid function; Thyroxine (T4); Triiodothyronine (T3); Tyrosine-kinase inhibitors; Unusual effects of medical treatment; Weight loss; X-ray",
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101618943",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30884464",
"pubdate": "2019-03-18",
"publication_types": "D016428:Journal Article",
"references": "15301873;16735986;19107622;19452305;21856766;23601669;25309799;25671254;28299283;29433850",
"title": "Rapid pleural effusion after discontinuation of lenvatinib in a patient with pleural metastasis from thyroid cancer.",
"title_normalized": "rapid pleural effusion after discontinuation of lenvatinib in a patient with pleural metastasis from thyroid cancer"
} | [
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"companynumb": "JP-EISAI MEDICAL RESEARCH-EC-2016-018024",
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"activesubstancename": "LENVATINIB"
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"abstract": "We report the case of a 63-year-old male patient admitted to our emergency department for dyspnoea, peripheral oedema, severe diarrhoea and asthenia. History revealed Crohn's disease (CD) submitted to several intestinal surgical resections in the previous years. He recently started a treatment with adalimumab for the control of CD. Laboratory tests at the admission revealed severe haemolytic anaemia and thrombocytopaenia. Haptoglobin levels were low, schistocyte count was markedly increased. In the suspect of thrombotic microangiopathy, he was admitted to our internal medicine department where we urgently started plasma exchange (PEX). We observed normal ADAMTS-13 activity in absence of Shiga toxin or enterotoxic Escherichia c oli at stool tests. Despite a diagnosis of atypical haemolytic-uraemic syndrome, we observed full platelet count recovery and schistocytes normalisation after the fourth PEX. We then put a diagnosis of adalimumab-induced thrombocytopaenic microangiopathy. Adalimumab was withdrawn. We did not observe relapses in the following 3 months.",
"affiliations": "Medicina Interna Subintensiva, Ospedali Riuniti, Ancona, Marche, Italy drfalsetti@yahoo.it.;Scuola di Specializzazione di Medicina d'Urgenza, Università Politecnica delle Marche, Ancona, Marche, Italy.;Scuola di Specializzazione di Medicina d'Urgenza, Università Politecnica delle Marche, Ancona, Marche, Italy.;Medicina Interna Subintensiva, Ospedali Riuniti, Ancona, Marche, Italy.",
"authors": "Falsetti|Lorenzo|L|http://orcid.org/0000-0003-3411-2388;Sampaolesi|Mattia|M|;Riccomi|Francesca|F|;Nitti|Cinzia|C|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-233526",
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"issn_linking": "1757-790X",
"issue": "13(3)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; haematology (incl blood transfusion)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000068879:Adalimumab; D000893:Anti-Inflammatory Agents; D003424:Crohn Disease; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008875:Middle Aged; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "101526291",
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"pmid": "32139450",
"pubdate": "2020-03-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adalimumab as a potential cause of drug-induced thrombocytopaenic microangiopathy.",
"title_normalized": "adalimumab as a potential cause of drug induced thrombocytopaenic microangiopathy"
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"companynumb": "IT-AMGEN-ITASP2020042081",
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"abstract": "We describe the case of an elderly woman with an episode of ambulatory de novo absence status epilepticus of late onset (DNASLO) after oral treatment with cefuroxime. A high level of suspicion of DNASLO in cases of unexplained confusion in adults or elderly subjects taking cephalosporins is essential to prompt an emergency EEG and, in turn, rapidly achieve an appropriate diagnosis and enable optimal treatment.",
"affiliations": "Department of Clinical Neurophysiology, Marqués de Valdecilla University Hospital, Santander, Cantabria, Department of Physiology and Pharmacology, University of Cantabria (UNICAN), Santander, Cantabria, Biomedical Research Institute (IDIVAL), Santander.;Department of Clinical Neurophysiology, Marqués de Valdecilla University Hospital, Santander, Cantabria.;Department of Clinical Neurophysiology, Marqués de Valdecilla University Hospital, Santander, Cantabria.;Department of Clinical Neurophysiology, Marqués de Valdecilla University Hospital, Santander, Cantabria.;Biomedical Research Institute (IDIVAL), Santander, Department of Neurology, Marqués de Valdecilla University Hospital, Santander, Cantabria.;Biomedical Research Institute (IDIVAL), Santander, Department of Intensive Medicine, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain.",
"authors": "Fernández-Torre|José L|JL|;Paramio-Paz|Alicia|A|;López-Delgado|Anjana|A|;Martín-García|María|M|;González-Aramburu|Isabel|I|;Hernández-Hernández|Miguel A|MA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D002444:Cefuroxime",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2017.0938",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "20(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "cefuroxime; de novo absence status epilepticus; emergency EEG; non-convulsive status epilepticus",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D017668:Age of Onset; D000368:Aged; D000900:Anti-Bacterial Agents; D002444:Cefuroxime; D002511:Cephalosporins; D004832:Epilepsy, Absence; D005260:Female; D006801:Humans; D010033:Otitis Media; D013226:Status Epilepticus",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "73-76",
"pmc": null,
"pmid": "29160209",
"pubdate": "2018-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "De novo absence status epilepticus of late onset (DNASLO) precipitated by oral treatment with cefuroxime: description of an ambulatory case.",
"title_normalized": "de novo absence status epilepticus of late onset dnaslo precipitated by oral treatment with cefuroxime description of an ambulatory case"
} | [
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"companynumb": "ES-ALKEM LABORATORIES LIMITED-ES-ALKEM-2018-01720",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFUROXIME AXETIL"
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... |
{
"abstract": "Monoclonal antibodies bevacizumab and cetuximab both improve overall survival (OS), progression free survival (PFS) and overall response rate (ORR) when combined with irinotecan-containing regimens. The optimal sequence of these monoclonal antibodies in combination with chemotherapy is controversial. This study analysed the efficacy of cetuximab plus Folfiri after progression with the same regimen plus bevacizumab in patients with metastatic colorectal cancer (mCRC). Patients are eligible if progressive disease (PD) after Folfiri-bevacizumab; ECOG PS 0-1. Primary endpoint is the disease control rate (DCR:ORR plus stable disease > 6 months); secondary endpoints: ORR, PFS, duration of response, OS and toxicity. ORR and DCR were reported with their confidence interval at 95%. Kaplan-Meier method was used for PFS and OS evaluation.\n\n\nRESULTS\n54 patients were enrolled to receive Folfiri-cetuximab after PD to Folfiri-bevacizumab treatment. Median age was 65 (43-80), M/F 31/23, ECOG PS 0/1 was 36/ 18, WT Kras 33(61%). The DCR was 64.8% (CI 95% 52.1-77.5). Among the group of patients with stable or progressive disease at first line treatment, 13.3% of them obtained a response at second line. For second line treatment median duration of response was 6 months and clinical benefit 7 months. The ORR was 22.2% (CI 95% 11.1-33.3). The median progression-free survival was 7 months (CI 95% 6-8). The median overall survival for second line treatment was 14 months (CI 95% 11-17). No grade 4 toxicity was observed. Data suggest that this sequential combination therapy is active and well tolerated. At disease progression to first line chemotherapy treatment the maintenance of the same chemotherapy regimen and the change of the monoclonal antibody showed efficacy in response and survival in patients with mCRC.",
"affiliations": "Medical Oncology Unit, ASL Frosinone, Kragujevac, Italy.",
"authors": "Grande|Roberta|R|;Gemma|Donatello|D|;Sperduti|Isabella|I|;Gelibter|Alain|A|;Giampaolo|Maria Anna|MA|;Trombetta|Giorgio|G|;Nelli|Fabrizio|F|;Gamucci|Teresa|T|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1186/2193-1801-2-185",
"fulltext": "\n==== Front\nSpringerplusSpringerplusSpringerPlus2193-1801Springer International Publishing AG Cham 24210.1186/2193-1801-2-185ResearchChanging monoclonal antibody keeping unaltered the chemotherapy regimen in metastatic colorectal cancer patients: is efficacy maintained? Grande Roberta robertagrande@virgilio.it 1Gemma Donatello donatello.gemma@gmail.com 1Sperduti Isabella isperduti@yahoo.it 2Gelibter Alain agelibter@yahoo.it 3Giampaolo Maria Anna magiampi53@virgilio.it 1Trombetta Giorgio giorgiotrombetta@virgilio.it 1Nelli Fabrizio f.nelli@asl.vt.it 4Gamucci Teresa t.gamucci@libero.it 11 Medical Oncology Unit, ASL Frosinone, Kragujevac, Italy 2 Bio-Statistics Unit Regina Elena National Cancer Institute, Rome, Italy 3 Medical Oncology Unit Regina Elena National Cancer Institute, Rome, Italy 4 Medical Oncology Unit Belcolle Hospital, Viterbo, Italy 25 4 2013 25 4 2013 2013 2 18520 12 2012 16 4 2013 © Grande et al.; licensee Springer. 2013This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Monoclonal antibodies bevacizumab and cetuximab both improve overall survival (OS), progression free survival (PFS) and overall response rate (ORR) when combined with irinotecan-containing regimens. The optimal sequence of these monoclonal antibodies in combination with chemotherapy is controversial. This study analysed the efficacy of cetuximab plus Folfiri after progression with the same regimen plus bevacizumab in patients with metastatic colorectal cancer (mCRC). Patients are eligible if progressive disease (PD) after Folfiri-bevacizumab; ECOG PS 0–1. Primary endpoint is the disease control rate (DCR:ORR plus stable disease > 6 months); secondary endpoints: ORR, PFS, duration of response, OS and toxicity. ORR and DCR were reported with their confidence interval at 95%. Kaplan-Meier method was used for PFS and OS evaluation. Results: 54 patients were enrolled to receive Folfiri-cetuximab after PD to Folfiri-bevacizumab treatment. Median age was 65 (43–80), M/F 31/23, ECOG PS 0/1 was 36/ 18, WT Kras 33(61%). The DCR was 64.8% (CI 95% 52.1-77.5). Among the group of patients with stable or progressive disease at first line treatment, 13.3% of them obtained a response at second line. For second line treatment median duration of response was 6 months and clinical benefit 7 months. The ORR was 22.2% (CI 95% 11.1-33.3). The median progression-free survival was 7 months (CI 95% 6–8). The median overall survival for second line treatment was 14 months (CI 95% 11–17). No grade 4 toxicity was observed. Data suggest that this sequential combination therapy is active and well tolerated. At disease progression to first line chemotherapy treatment the maintenance of the same chemotherapy regimen and the change of the monoclonal antibody showed efficacy in response and survival in patients with mCRC.\n\nKeywords\nMetastatic colorectal cancerBevacizumabCetuximabChemotherapyMonoclonal antibodyissue-copyright-statement© The Author(s) 2013\n==== Body\nIntroduction\nColorectal cancer is a major cause of morbidity and mortality worldwide. Nowadays the median duration of survival among patients with advanced colorectal cancer has been increased through the introduction of new drugs. Survival has reached about twenty-four months (Van Cutsem et al. 2009).\n\nThese significant improvements are the result of new combinations of standard drugs, such as fluorouracil, irinotecan and oxaliplatin, in association with new therapeutic agents, namely bevacizumab and cetuximab (De Gramont et al. 2000; Douillard et al. 2000a; Giacchetti et al. 2000; Goldberg et al. 2004a; Saltz et al. 2000a; Cunningham et al. 1998; Rougier et al. 1998; Cunningham et al. 2004a).\n\nThese monoclonal antibodies target molecular regions involved in colorectal carcinogenesis. Bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor A (VEGF-A), improves response rate (RR), progression-free survival (PFS) and overall survival (OS) in combination with irinotecan when compared with patients treated with chemotherapy treatment alone (Hurwitz et al. 2004). Similar benefits in OS, PFS and RR were also shown in second line treatment , where adding bevacizumab to standard chemotherapy (Giantonio et al. 2007).\n\nMoreover, cetuximab, a human-murine chimeric monoclonal antibody that targets epidermal growth factor receptors (EGFR), has shown antitumor activity both alone and in combination with irinotecan (Cunningham et al. 2004b; Saltz et al. 2001; Saltz et al. 2004; Lenz et al. 2006).\n\nUntil last year standard first-line chemotherapy included fluorouracil with leucovorin and irinotecan or oxaliplatin, alone or combined with bevacizumab (Douillard et al. 2000b; Saltz et al. 2000b; Goldberg et al. 2004b\n; Van Cutsem & Geboes 2007).\n\nRecently, CRYSTAL and OPUS studies have shown the activity of cetuximab in first line chemotherapy treatment in wild-type KRAS gene status. This gene is predictor for resistance to epidermal growth factor receptor (EGFR) monoclonal antibody therapies (Van Cutsem et al. 2009; Bokemeyer et al. 2009; McLellan et al. 1993; Arber et al. 2000; De Roock et al. 2008; Di Fiore et al. 2007b; Lièvre et al. 2008; Lièvre et al. 2006; Cervantes et al. 2008).\n\nHowever, the optimal sequence of these monoclonal antibodies in combination with chemotherapy is controversial and there are no studies suggesting what the most effective sequence of these drugs is.\n\nTherefore this study aims to evaluate the feasibility of a sequential chemotherapy regimen. In particular it aims to explore the efficacy of cetuximab in association with irinotecan-based chemotherapy (Folfiri) after disease progression with the same chemotherapy regimen plus bevacizumab in patients with metastatic colorectal cancer.\n\nMaterials and methods\nPatients were considered eligible if they had pathologically confirmed colorectal cancer, metastatic disease, positive EGFR immunostaining. To be eligible, patients must have received at least six months of first line chemotherapy with Folfiri plus bevacizumab. Eligibility criteria also included: age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status of ≤1; normal hematopoietic function (haemoglobin, at least 9 g per decilitre [5.6 mmol per liter]; neutrophil count, at least 1500 per cubic millimeter; and platelet count, at least 100,000 per cubic millimeter), renal function (serum creatinine, less than 1.5 times the upper limit of normal), and liver function (bilirubin, not more than 1.5 times the upper limit of normal; aspartate aminotransferase and alanine aminotransferase, not more than 5 times the upper limit of normal); no coexisting medical problem of sufficient severity to limit study compliance.\n\nDosage and drug administration\nEGFR status of the tumor was determined by immunoistochemical analysis of a paraffin-embedded tumor specimen with the use of an EGFR diagnostic kit (Dako Cytomation). Since 2006 attention has been focused on intracellular mediators involved in the transduction of EGFR signal to predict the efficacy of the treatment and KRAS pathways have been investigated. (Lievre et al. 2006; De Roock et al. 2007; Di Fiore et al. 2007a; Khambata-Ford et al. 2007\n; Lievre et al. 2008). From November 2008 we had the opportunity to analyse KRAS oncogene status by the PCR/sequencing technique.\n\nAfter screening, patients were enrolled to receive first line chemotherapy with Folfiri (irinotecan 180 mg/m2 IV over 90 minutes, day 1, concurrently with folinic acid 100 mg/m2 day 1–2 IV over 120 minutes followed by fluorouracil 400 mg/m2 IV bolus, days 1,2, then fluorouracil 1200 mg/m2/die intravenous infusion over 46 hours) plus bevacizumab 5 mg/Kg day1. Treatment was administered every 2 weeks. If patients maintained at least stable disease after 6 months of treatment they continued therapy with bevacizumab 7.5 mg/Kg every 3 weeks as maintenance.\n\nPatients showing disease progression underwent to second line treatment with the same chemotherapy schedule, but replacing monoclonal antibody with cetuximab (first dose 400 mg/mq then 250 mg/mq weekly). If stable disease was maintained after 6 months, patients continued therapy with cetuximab alone with a dosage of 250 mg/mq weekly until intolerable toxicity or progressive disease.\n\nDisease progression was documented by computed tomography (CT), magnetic resonance imaging (MRI) or Positron Emission Tomography (PET).\n\nToxic effects were assessed according to the National Cancer Institute Common Toxicity Criteria, version 3. Modifications of the dose were made in cases of hematologic or non-hematologic toxic effects.\n\nThe primary endpoint was the disease control rate (DCR) defined as ORR plus stable disease ≥6 months. The secondary endpoints included the overall response rate (ORR), the progression-free survival (PFS), the duration of response, the overall survival (OS) and the toxicities.\n\nAll patients signed a consent form. The study was approved by the institutional ethic committee.\n\nStatistical analysis\nThe endpoint of this study is the disease control rate (DRC defined as ORR plus stable disease ≥6 months).\n\nThis phase II trial is planned as a single-stage design as described by A’Hern. A sample of 53 patients is considered sufficient to give an 80% probability of rejecting a baseline disease control rate (DCR) of 35% with an exact 5% one-sided significance test when the true DCR is 55%. The drug regimen will be rejected if less than 25 DCR (as previously defined) are observed.\n\nAll patients enrolled were considered the intention-to-treat population (ITT). This population was evaluated for the efficacy and safety analysis.\n\nThe standard summary statistics were used for both continuous and discrete variables. The DCR and the objective response rate were reported with its 95% confidence interval.\n\nThe time to event analysis was performed according the Kaplan-Meier product-limit method. The log-rank test was used to assess differences between subgroups. Significance was defined at the p<0.05 level.\n\nResults\nBetween January 2008 to January 2010, 54 patients with positive EGFR status after progression of the disease at first line with Folfiri plus bevacizumab were enrolled to receive second line combination treatment with Folfiri plus cetuximab (FC) followed by cetuximab (C) alone if stable disease was maintained. The analysis of Kras status was feasible and performed for 33 (61%) tumor specimens. Patient’s characteristics are shown in Table 1.Table 1 Baseline patient’s characteristics\n\nCharacteristics (N=54)\tN° of patients (%)\t\nMedian age (range)\t65 (43–80)\t\nMedian follow-up from 1st line, months (range)\t26 (8–65)\t\nMedian follow-up from 2nd line, months (range)\t13 (3–51)\t\nSex Men\t31 (57)\t\n Women\t23 (43)\t\nECOG performance status\t\t\n 0/1\t36 (67)/18 (33)\t\nPrimary diagnosis\t\t\n Colon cancer\t42 (78)\t\n Rectal cancer\t12 (22)\t\nMetastasis Site\t\t\n Single\t41 (76)\t\n Multiple\t13 (24)\t\nKRAS status\t\t\n Wild type (%)\t31 (57)\t\n Mutant Kras (%)\t2 (4)\t\n Unknown\t21 (39)\t\n\n\nMedian cycles of first line treatment were 12 (range 4–16) for 35 patients and 8 (1–23) cycles of bevacizumab alone for 32 patients with at least stable disease.\n\nMedian cycles of second line chemotherapy with Folfiri plus cetuximab were 9 (range 1–14) for 19 patients and 7 (range 2–15) for 12 patients that continued treatment with cetuximab alone for maintenance.\n\nThe Disease Control Rate was achieved in 64.8 percent (CI 95% 52.1-77.5) of the patients who received second line treatment with Folfiri plus cetuximab (Figure 1 and Table 2).Figure 1 DCR survival curve for second line treatment (Kaplan Maier Method).\n\n\n\nTable 2 Kaplan Maier estimate for overall response rate (ORR) and disease control rate (DCR)\n\n\tOverall survival\t\n\t6 months\t12 months\t24 months\tMedian (CI 95%)\tp value\t\nORR\t\t\t\t\t0.02\t\n No\t78.6\t49.7\t11.8\t12(9–15)\t\t\n Yes\t100\t91.7\t55.0\t27(11–43)\t\t\nDCR\t\t\t\t\t\t\n No\t52.3\t5.3\t-\t7(5–9)\t<0.0001\t\n Yes\t100\t88.2\t33.8\t20(15–24)\t\t\nThe overall response rate (the rate of complete response plus the rate of partial response, ORR) was 22.2 percent (95% confidence interval, 11.1 to 33.3 percent) (Table 3).Table 3 Overall response rate\n\n\tFirst line\tSecond line\t\n\tN. (%)\tN. (%)\t\nBest Overall Response\t22 (44.5)\t12 (22.2)*\t\n Complete Response\t5 (9.3)\t0 (0)\t\n Partial Response\t19 (35.2)\t12 (22.2)\t\n Stable Disease\t22(40.7)\t23 (46.2)\t\n Progressive Disease\t8 (14.8)\t19 (35.2)\t\nDisease Control Rate\t44 (81.5)\t35 (64.8)**\t\n* CI 95% 11.1-33.3\t\t\t\n**CI 95% 52.1-77.5\t\t\t\n\n\nAt first line chemotherapy 44.5% of the patients had a complete or partial response; 33.3% of them continued to be responsive to second line with the same chemotherapy regimen plus cetuximab. Of special interest is the finding that 13.3% of patients with stable or progressive disease obtained a response.\n\nFor second line treatment the median duration of response was 6 months (CI 95% 4–8). The clinical benefit was 7 months (range 1–21).\n\nThe median progression-free survival was 7 months (CI 95% 6–8). The percentage of patients free of progression at year one was 15.9%. The median overall survival for second line treatment was 14 months (CI 95% 11–17). At year one 58.9 percent of patients were alive and 21.8 percent at years two (Figure 2 and Table 2).Figure 2 Responder survival curve for second line therapy (Kaplan Maier Method).\n\n\n\nThe median OS of all patients from first line chemotherapy with Folfiri plus bevacizumab was twenty-seven months (CI 95% 25–29). The overall survival for 32 (59.3%) patients that had DCR at first and second line treatment was 33 months (CI95% 26.4-39.6).\n\nIn Table 4 and 5 toxicities were shown. The majority of patients presented grade 1–2 side effects.Table 4 Main adverse events at first line chemotherapy\n\n\tGrading\t\n\t0\t1\t2\t3\t4\t\nNeutropenia\t25\t11\t6\t9\t3\t\nAnaemia\t41\t13\t0\t0\t0\t\nSkin toxicity\t0\t1\t0\t0\t0\t\nFatigue\t29\t10\t13\t2\t0\t\nNausea/Vomiting\t40\t13\t1\t0\t0\t\nHypertension\t43\t10\t1\t0\t0\t\nBleeding\t41\t13\t0\t0\t0\t\nProteinuria\t49\t3\t2\t0\t0\t\nDiarrhea\t29\t12\t11\t2\t0\t\nStomatitis\t37\t6\t11\t0\t0\t\nTable 5 Main adverse events at second line chemotherapy\n\n\tGrading\t\n\t0\t1\t2\t3\t4\t\nNeutropenia\t39\t7\t6\t2\t0\t\nAnaemia\t40\t12\t1\t1\t0\t\nSkin toxicity\t16\t17\t17\t4\t0\t\nFatigue\t37\t8\t8\t1\t0\t\nNausea/vomiting\t46\t8\t0\t0\t0\t\nHypertension\t54\t0\t0\t0\t0\t\nBleeding\t54\t0\t0\t0\t0\t\nProteinuria\t54\t0\t0\t0\t0\t\nDiarrhea\t28\t14\t11\t1\t0\t\nStomatitis\t34\t10\t12\t0\t0\t\n\n\nData showed that no increasing of toxicities was noted moving from first line to second line treatment although patients restarted the same chemotherapy regimen.\n\nFirst line chemotherapy with Folfiri plus bevacizumab was well tolerated. Only 3 patients had grade 4 neutropenia. No other grade 4 toxicities were presented. No bleeding, thromboembolism or severe hypertension were shown. Dose reduction of irinotecan was made for only three patients for side effects reasons.\n\nIn the group of patients treated with cetuximab acne-like rash occurred in 70% of patients (39% grade ≥2; no grade 4 toxicity was observed). No severe gastrointestinal side effects were shown.\n\n57 percent of patients reached and made it to third line chemotherapy. Due to acceptable performance status 15 patients were administered to FOLFOX4 chemotherapy regimen (standard dose or adjusted dose if necessary). For eight patients only monotherapy regimen with fluoropyrimidines was possible.\n\nTo date nine patients are alive and two of them are still in treatment with chemotherapy.\n\nDiscussion\nThe analysis of literature shows that metastatic colorectal cancer patients, who have received chemotherapy may survive for about twenty-four months. If the effective drugs have failed, there are no other options (Cunningham et al. 2004a; Hurwitz et al. 2004).\n\nThis study analysed a feasible sequence of monoclonal antibodies maintaining the same chemotherapy regimen. The results confirmed the feasibility and efficacy of treatment.\n\nIn accordance with the outcome of phase III trials the response rate in first line treatment reached about 44% and second line showed about 22% (Cunningham et al. 2004a; Hurwitz et al. 2004).\n\nThe changing of bevacizumab after progression of disease with cetuximab produced an interesting survival rate in this sample of patients without resulting in an increase of toxicities.\n\nIndeed, the median overall survival from first line treatment was 27 months, that reached 33 months for patients that maintained DCR at first and second line therapy.\n\nFrom first line treatment 8 (14.8%) patients had progressive disease at six months of chemotherapy and started second line chemotherapy. Among them, 6 patients had progressive disease at Folfiri plus cetuximab and the resulting overall survival was 14 months for these patients. The other two patients had clinical benefit (DCR) at second line treatment of 14 and 15 months respectively and the overall survival was 21 and 23 months respectively. The clinical benefit was 7 months (range 1–21).\n\nThe achievement of a new responsiveness in these progressive patients had an impact on survival. This result was allowed by the changing monoclonal antibody.\n\nDespite the use of the same chemotherapy for about twelve consecutive months, the regimen was well tolerated and there was no evidence of increase of the frequency or severity of the characteristic toxicities associated with treatment.\n\nMoreover, it is very important to emphasize that the population included also older patients with 21.5% of them being older than 70. This characteristic did not influence the results concerning toxicities and survival rates.\n\nIn this study the number of patients receiving third line chemotherapy is encouraging (57 percent) and it underlines the feasibility of this sequence, which helps an acceptable quality of life for patients.\n\nThese data suggest that this sequential combination therapy is active, however, due to the small number of patients this study is limited and the KRAS mutation status was not available for all patients.\n\nFurthermore, it should also be noted that at the beginning of the study a high percentage of patients (76%) had only a single distant metastatic site.\n\nWhen the study started no data were available for the efficacy of cetuximab plus chemotherapy in the first line treatment of metastatic colorecatal cancer.\n\nRecently, first line treatment with cetuximab has been approved in combination with chemotherapy and the benefits of cetuximab was limited to patients with KRAS wild-type tumors, reducing the risk of progression of metastatic colorectal cancer.\n\nIn this study for only 33 patients the analysis of KRAS status was performed; an adequate selection of patients could improve survival.\n\nIn conclusion, this research underlines the need for more information about a better sequence of chemotherapy regimens for this kind of patients.\n\nIt would be interesting to evaluate in a larger randomized trial what is the better sequence of drugs that can allow patients to obtain better responses and consequently a longer survival along with an acceptable quality of life.\n\nCompeting interest\n\nWe declare that we have no conflict of interest.\n\nAuthors’ contributions\n\nRG, DC and IS carried out the molecular genetic studies, participated in the sequence alignment and drafted the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgment\nThe authors would like to acknowledge the financial support of IRIS PCR – OG ONLUS, Sora-Frosinone.\n==== Refs\nReferences\nArber N Activation of c-K-ras mutations in human gastrointestinal tumors Gastroenterology 2000 118 1045 1050 10.1016/S0016-5085(00)70357-X 10833479 \nBokemeyer C Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer J Clin Oncol 2009 27 663 667 10.1200/JCO.2008.20.8397 19114683 \nCervantes A Correlation of KRAS status (wild type [wt] vs. mutant [mt]) with efficacy to first-line cetuximab in a study of cetuximab single agent followed by cetuximab + FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) J Clin Oncol 2008 26 Suppl: 210s 4129 \nCunningham D Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer 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\nHurwitz H Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N Engl J Med 2004 350 2335 2342 10.1056/NEJMoa032691 15175435 \nKhambata-Ford S Expression of epiregulin and amphiregulin and K -Ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab J Clin Oncol 2007 25 3230 3237 10.1200/JCO.2006.10.5437 17664471 \nLenz HJ Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines J Clin Oncol 2006 24 4914 4921 10.1200/JCO.2006.06.7595 17050875 \nLievre A Kras mutation status is predictive of response to cetuximab therapy in colorectal cancer Cancer Res 2006 66 3992 3995 10.1158/0008-5472.CAN-06-0191 16618717 \nLièvre A KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer Cancer Res 2006 66 3992 3995 10.1158/0008-5472.CAN-06-0191 16618717 \nLievre A Kras mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab J Clin Oncol 2008 26 374 379 10.1200/JCO.2007.12.5906 18202412 \nLièvre A KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab J Clin Oncol 2008 26 374 379 10.1200/JCO.2007.12.5906 18202412 \nMcLellan EA High frequency of K-ras mutations in sporadic colorectal adenomas Gut 1993 34 392 396 10.1136/gut.34.3.392 8472989 \nRougier P Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer Lancet 1998 352 1407 1412 10.1016/S0140-6736(98)03085-2 9807986 \nSaltz LB Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer N Engl J Med 2000 343 905 914 10.1056/NEJM200009283431302 11006366 \nSaltz L Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR) Proc Am Soc Clin Oncol 2001 20 abstr 7 3a \nSaltz LB Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor J Clin Oncol 2004 22 1201 1208 10.1200/JCO.2004.10.182 14993230 \nVan Cutsem E Geboes K The multidisciplinary management of gastrointestinal cancer. The integration of cytotoxics and biologicals in the treatment of metastatic colorectal cancer Best Pract Res Clin Gastroenterol 2007 21 1089 1108 10.1016/j.bpg.2007.10.020 18070705 \nVan Cutsem E Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer N Engl J Med 2009 360 1408 1417 10.1056/NEJMoa0805019 19339720\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2193-1801",
"issue": "2(1)",
"journal": "SpringerPlus",
"keywords": "Bevacizumab; Cetuximab; Chemotherapy; Metastatic colorectal cancer; Monoclonal antibody",
"medline_ta": "Springerplus",
"mesh_terms": null,
"nlm_unique_id": "101597967",
"other_id": null,
"pages": "185",
"pmc": null,
"pmid": "23667824",
"pubdate": "2013-12",
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"title": "Changing monoclonal antibody keeping unaltered the chemotherapy regimen in metastatic colorectal cancer patients: is efficacy maintained?",
"title_normalized": "changing monoclonal antibody keeping unaltered the chemotherapy regimen in metastatic colorectal cancer patients is efficacy maintained"
} | [
{
"companynumb": "IT-CIPLA LTD.-2016IT17070",
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"abstract": "OBJECTIVE\nEpilepsy is the most common neurological disorder requiring medical treatment during pregnancy. However, very few studies are specially dedicated to pregnant women with refractory epilepsy. This study was carried out with the aim of describing obstetrical and neurological outcomes of pregnant women with refractory epilepsy in Brazil.\n\n\nMETHODS\nPregnant women with refractory epilepsy were enrolled in longitudinal cohort study between January 2005 and January 2018. They were regularly followed by a neurologist until the end of pregnancy. Neurological outcomes included seizure control, status epilepticus and adherence to antiepileptic medications. Obstetrical outcomes included major congenital malformations and obstetrical complications.\n\n\nRESULTS\nA total of eighty two patients with a mean age of 24.5 ± 5.5 were included in our study. A significant number of women experienced an increase in seizure frequency and the prevalence of status epilepticus was 8.5%. More than half were non-adherent to antiepileptic drugs. Most of patients required treatment changes during pregnancy, in dose and/or in number of antiepileptic drugs. Cesarean section was the preferred way of delivery and five cases of major congenital malformations were detected. Obstetrical complications were significantly associated with polytherapy, multiple comorbidities, poor adherence to treatment and seizure deterioration during pregnancy (p < 0.05).\n\n\nCONCLUSIONS\nWomen with refractory epilepsy can have a significant risk of obstetric and neurological complications during pregnancy. Treatment of refractory epilepsy in pregnancy is a real challenge for neurologists.",
"affiliations": "Department of Neurology, Santa Casa de São Paulo School of Medical Sciences, Dr. Cesário Motta Júnior Street 112, 01221-020, São Paulo, Brazil. Electronic address: z_azul@hotmail.com.;Department of Neurology, Santa Casa de São Paulo School of Medical Sciences, Dr. Cesário Motta Júnior Street 112, 01221-020, São Paulo, Brazil.;Department of Neurology, Santa Casa de São Paulo School of Medical Sciences, Dr. Cesário Motta Júnior Street 112, 01221-020, São Paulo, Brazil.",
"authors": "Kusznir Vitturi|Bruno|B|;Barreto Cabral|Fábio|F|;Mella Cukiert|Cristine|C|",
"chemical_list": "D000927:Anticonvulsants",
"country": "England",
"delete": false,
"doi": "10.1016/j.seizure.2019.05.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "69()",
"journal": "Seizure",
"keywords": "Antiepileptic drugs; Drug resistant epilepsy; Epilepsy; Pregnancy; Seizures",
"medline_ta": "Seizure",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001938:Brazil; D015897:Comorbidity; D000069279:Drug Resistant Epilepsy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D055118:Medication Adherence; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011446:Prospective Studies; D012307:Risk Factors; D012640:Seizures; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "251-257",
"pmc": null,
"pmid": "31128468",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of pregnant women with refractory epilepsy.",
"title_normalized": "outcomes of pregnant women with refractory epilepsy"
} | [
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"companynumb": "BR-JNJFOC-20190705974",
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{
"abstract": "This cross-sectional study compared the effects of treatment with atypical antipsychotic drugs on quality of life (QoL) and side effects in 218 patients with schizophrenia attending the ambulatory services of psychiatric in Rio Grande do Norte, Brazil. Socio-economic variables were compared. The five-dimension EuroQoL (EQ-5D) was used to evaluate QoL, and side effects were assessed using the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale and the Simpson-Angus Scale. Data were analysed using the χ (2) test and Student's t test, with a significance level of 5 %. Average monthly household incomes in the medication groups were 1.1-2.1 minimum wages ($339-$678). UKU Scale scores showed significant differences in side effects, mainly, clozapine, quetiapine and ziprasidone (p < 0.05). EQ-5D scores showed that all drugs except olanzapine significantly impacted mobility (p < 0.05), and proportions of individuals reporting problems in other dimensions were high: 63.6 % of clozapine users reported mobility problems, 63.7 and 56.3 % of clozapine and ziprasidone users, respectively, had difficulties with usual activities, 68.8 and 54.5 % of ziprasidone and clozapine users, respectively, experienced pain and/or discomfort, and 72.8 % of clozapine users reported anxiety and/or depression. Psychiatric, neurological, and autonomous adverse effects, as well as other side effects, were prevalent in users of atypical antipsychotic drugs, especially clozapine and ziprasidone. Olanzapine had the least side effects. QoL was impacted by side effects and economic conditions in all groups. Thus, the effects of these antipsychotic agents appear to have been masked by aggravating social and economic situations.",
"affiliations": "Department of Biophysical and Pharmacology, Universidade Federal do Rio Grande do Norte (UFRN), Natal, RN, Brazil, aurigena@ufrnet.br.",
"authors": "de Araújo|Aurigena Antunes|AA|;de Araújo Dantas|Diego|D|;do Nascimento|Gemma Galgani|GG|;Ribeiro|Susana Barbosa|SB|;Chaves|Katarina Melo|KM|;de Lima Silva|Vanessa|V|;de Araújo|Raimundo Fernandes|RF|;de Souza|Dyego Leandro Bezerra|DL|;de Medeiros|Caroline Addison Carvalho Xavier|CA|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1007/s11126-014-9290-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2720",
"issue": "85(3)",
"journal": "The Psychiatric quarterly",
"keywords": null,
"medline_ta": "Psychiatr Q",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001938:Brazil; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011788:Quality of Life; D018967:Risperidone; D012559:Schizophrenia; D012923:Social Class",
"nlm_unique_id": "0376465",
"other_id": null,
"pages": "357-67",
"pmc": null,
"pmid": "24789610",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "20805913;10087570;20135234;2887090;23452754;23137171;22615901;21169888;19779255;22806578;16224604;18034373;22587635;19840592;21625758;16298428;22788567;14728110;15774006;16647796;15118477;8883573;20422824;11213134;19717224;18828933;15521791;21310400;22516268",
"title": "Quality of life in patients with schizophrenia: the impact of socio-economic factors and adverse effects of atypical antipsychotics drugs.",
"title_normalized": "quality of life in patients with schizophrenia the impact of socio economic factors and adverse effects of atypical antipsychotics drugs"
} | [
{
"companynumb": "BR-JNJFOC-20140909943",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
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... |
{
"abstract": "BACKGROUND\nNecrotizing soft tissue infections can affect various tissue planes. Although predisposing etiologies are many, they mostly center on impaired immunity occurring directly or indirectly and loss of integrity of protective barriers which predispose to infection. The nonspecific presentation may delay diagnosis and favor high mortality.\n\n\nMETHODS\nTwo case vignettes are presented. The first patient, a 44-year-old healthy South Asian man with a history of repeated minor traumatic injury presented to a primary health care center with a swollen left lower limb. He was treated with antibiotics with an initial diagnosis of cellulitis. Because he deteriorated rapidly and additionally developed intestinal obstruction, he was transferred to our hospital which is a tertiary health care center for further evaluation and management. Prompt clinical diagnosis of necrotizing soft tissue infection was made and confirmed on magnetic resonance imaging as necrotizing fasciitis. Urgent debridement was done, but the already spread infection resulted in rapid clinical deterioration with resultant mortality. The second patient was a 35-year-old South Asian woman with systemic lupus erythematous receiving immunosuppressive therapy who developed left lower limb pain and fever. Medical attention was sought late as she came to the hospital after 4 days. Her condition deteriorated rapidly as she developed septic shock and died within 2 days.\n\n\nCONCLUSIONS\nNecrotizing fasciitis can be fatal when not recognized and without early intervention. Clinicians and surgeons alike should have a greater level of suspicion and appreciation for this uncommon yet lethal infection.",
"affiliations": "National Hospital of Sri Lanka, Regent Street, Colombo 10, Sri Lanka. rayno.navinan@gmail.com.",
"authors": "Navinan|Mitrakrishnan Rayno|MR|;Yudhishdran|Jevon|J|;Kandeepan|Thambyaiah|T|;Kulatunga|Aruna|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-8-229",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-2292496538210.1186/1752-1947-8-229Case ReportNecrotizing fasciitis – a diagnostic dilemma: two case reports Navinan Mitrakrishnan Rayno 1rayno.navinan@gmail.comYudhishdran Jevon 1yudhishdran@yahoo.comKandeepan Thambyaiah 1kathambyaiah@yahoo.comKulatunga Aruna 1kulatunga.aruna@yahoo.com1 National Hospital of Sri Lanka, Regent Street, Colombo 10, Sri Lanka2014 25 6 2014 8 229 229 26 2 2014 22 4 2014 Copyright © 2014 Navinan et al.; licensee BioMed Central Ltd.2014Navinan et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/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.Introduction\nNecrotizing soft tissue infections can affect various tissue planes. Although predisposing etiologies are many, they mostly center on impaired immunity occurring directly or indirectly and loss of integrity of protective barriers which predispose to infection. The nonspecific presentation may delay diagnosis and favor high mortality.\n\nCase presentation\nTwo case vignettes are presented. The first patient, a 44-year-old healthy South Asian man with a history of repeated minor traumatic injury presented to a primary health care center with a swollen left lower limb. He was treated with antibiotics with an initial diagnosis of cellulitis. Because he deteriorated rapidly and additionally developed intestinal obstruction, he was transferred to our hospital which is a tertiary health care center for further evaluation and management. Prompt clinical diagnosis of necrotizing soft tissue infection was made and confirmed on magnetic resonance imaging as necrotizing fasciitis. Urgent debridement was done, but the already spread infection resulted in rapid clinical deterioration with resultant mortality. The second patient was a 35-year-old South Asian woman with systemic lupus erythematous receiving immunosuppressive therapy who developed left lower limb pain and fever. Medical attention was sought late as she came to the hospital after 4 days. Her condition deteriorated rapidly as she developed septic shock and died within 2 days.\n\nConclusions\nNecrotizing fasciitis can be fatal when not recognized and without early intervention. Clinicians and surgeons alike should have a greater level of suspicion and appreciation for this uncommon yet lethal infection.\n\nNecrotizing fasciitisNecrotizing soft tissue infectionsSystemic lupus erythematosus\n==== Body\nIntroduction\nNecrotizing soft tissue infection (NSTI) targets skin, subcutaneous tissue, muscle or fascia and the infection may spread to involve adjacent tissue planes [1]. Classification systems vary based on tissue plane level or that of the microorganisms involved [2]. Based on the causative organism it is commonly categorized as type I or II necrotizing fasciitis (NF) [3] but some authors choose to extend this up to type III and IV when atypical organisms are included [4,5]. Multiple risk factors favor development of NF, which include loss of integrity of barrier mechanisms and conditions eventually predisposing to impaired immunity [2,6] among others. Few cases are diagnosed early due to the absence of specific symptoms; this predisposes to increased mortality because it can delay definitive surgical intervention and delay in diagnosis has been shown to be a major contributing factor for death [7]. NF is considered a rare and potentially fatal condition [4] and two cases are described here.\n\nCase presentation\nCase 1\nA previously healthy 44-year-old South Asian man who worked as a groundskeeper and caretaker presented with left lower limb pain of 3 days’ duration with fever. The pain was significant enough to cause subjective weakness and his limb was found to be warm to touch and swollen. A preliminary clinical diagnosis of cellulitis was made and he was started on low-dose intravenous cloxacillin. The clinical situation worsened rapidly with progressive limb swelling and he became more septic. He developed absolute constipation and his abdominal girth increased during this timeframe and intestinal obstruction was suspected. He was transferred to our tertiary care center for further evaluation and management. An examination revealed multiple superficial wounds and healed injuries over his torso and legs (Figure 1). He appeared ill and was febrile. His left leg was noted to be kept in a laterally rotated position and the whole leg was swollen. It was also warm and tender to touch but did not exhibit any obvious superficial skin changes (Figure 1). There were crepitations on auscultation in both lung bases. His abdomen was distended but soft and percussion note was tympanic. Auscultation revealed diminished bowel sounds. Cardiovascular and neurological systems were normal on examination.\n\nFigure 1 Initial clinical presentation and surgical intervention. The two top images depict the various healed and recent injuries sustained by the patient. The image in the middle shows a laterally rotated swollen left thigh and lower limb. The bottom image depicts necrotic muscle on surgical debridement of the left thigh.\n\nWhole blood analysis revealed an elevated leucocyte count of 25.87 × 109μ/L (normal: 4 to 10) which was predominantly neutrophilic (83%; normal: 50 to 70) with preserved hemoglobin and platelets. Inflammatory markers were elevated with an erythrocyte sedimentation rate (ESR) of 51mm for the first hour (normal: < 15). His renal functions were within reference range and remained normal throughout. An X-ray of his abdomen revealed dilated gaseous bowel loops (Figure 2) while an X-ray of his left thigh failed to demonstrate any abnormality or gas (Figure 2). An urgent magnetic resonance imaging (MRI) of his thigh revealed marked edema of the muscle of the adductor compartment of his left thigh with numerous cystic areas of peripheral enhancement and gas. Fascial involvement was seen extending to involve his hip and there was a concomitant large left-side knee joint effusion. Appearances were that of a NSTI with muscle and fascial involvement (Figure 3). Based on the clinical picture and MRI interpretation a diagnosis of NF was made. Surgical debridement was carried out urgently and intravenous cloxacillin was continued in high dosage together with intravenous metronidazole. During debridement, a copious quantity of necrotic material and fluid was cleared (Figure 1). Deep tissue culture taken at surgery revealed methicillin-resistant Staphylococcus aureus (MRSA) and intravenous vancomycin was added to the antibiotic regimen. Blood cultures were persistently negative. The intestinal obstruction resolved spontaneously with passage of stools and flatus. Although follow-through debridement and intervention were planned the patient became hemodynamically unstable and unsuitable for general anesthesia and induction as he remained inotrope dependent in septic shock. The unavoidable delay resulted in the infection rapidly spreading to involve his upper trunk and further ascending to involve his left upper limb as well over 48 hours (Figure 4). His clinical condition was reflected in our investigations because his leucocyte levels rose to 33.92 × 109/L (normal: 4 to 10) although his blood cultures remained negative. He developed deteriorating liver functions with an elevated international normalized ratio of 1.43, an aspartate amino transferase of 97U/L (normal: 10 to 35) an alanine amino transferase of 74U/L (normal: 10 to 40) and an alkaline phosphatase value of 1091U/L (normal: 100 to 360). Arterial blood gas revealed a compensated metabolic acidosis, with a pH of 7.41, bicarbonate (HCO3−) of 17.1mmol/L (normal: 22 to 26) and a partial pressure of carbon dioxide of 27mmHg (normal: 35 to 45). However, his renal functions remained normal. His creatinine kinase was elevated with a value of 776U/L (normal: 25 to 174). Human immunodeficiency virus screening was negative as was hepatitis C antibodies. On day 7, he died.\n\nFigure 2 X-ray imaging of left thigh and abdomen. Image on the left is an X-ray of the left thigh; it failed to demonstrate presence of gas. Image on the right is an X-ray of the abdomen in supine position which demonstrates dilated large bowel loops favoring the clinical picture of intestinal obstruction.\n\nFigure 3 Magnetic resonance imaging of the left lower limb. Row 1: T2-weighted sagittal and axial view magnetic resonance imaging cuts of the left thigh demonstrate loss of normal architecture and edema of the muscle of the adductor compartment and numerous cystic areas. Row 2: Fat-suppressed T1-weighted image on the left, and T2-weighted image on the right, both axial magnetic resonance imaging cuts at the knee level demonstrate presence of gas with knee joint effusion.\n\nFigure 4 Clinical deterioration and progression of necrotizing fasciitis. Image depicts necrotizing fasciitis ascending to involve the chest and left upper limb.\n\nCase 2\nA 35-year-old South Asian woman who was previously diagnosed with systemic lupus erythematosus (SLE) and was on immunosuppressive therapy consisting of prednisolone and azathioprine presented with a 4-day history of fever and left lower limb pain. On examination she was febrile with a tender left leg was which was mildly erythematous and warm to touch and initially without any obvious skin manifestations such as bullae or blisters. Systemic examination was normal including preserved hemodynamic parameters. Blood cultures were taken and she was started on empirical antibiotics of intravenous cloxacillin. However, within 12 hours she developed bullae (Figure 5) on the medial aspect of her left calf and thigh. She deteriorated rapidly soon afterwards with hemodynamic compromise. Urgent debridement was undertaken.\n\nFigure 5 Superficial skin manifestations of necrotizing fasciitis. Image on the left shows early skin involvement of the left medial aspect of the thigh and bullae formation of the calf, which is more clearly demonstrated on the image on the right.\n\nWhole blood analysis demonstrated neutrophilic predominant (90%) leucopenia of 3.87 × 109/L (4 to 11) and a mild anemia with hemoglobin of 9.9g/dL (normal: 11 to 18) which was normocytic and normochromic. Her preliminary renal profile was unaltered. Her international normalized ratio was mildly deranged at 1.42 (normal: 0.9 to 1.1), aspartate transaminase was elevated at 55U/L (normal: 10 to 35) but alkaline phosphatase and proteins were normal. Her ESR was elevated at 110mm for the first hour. Arterial blood gas demonstrated partially compensated metabolic acidosis with a pH of 7.35 (normal: 7.5 to 7.45) and a HCO3− of 13.2mm/L (normal: 22 to 26). On admission she had normal serum sodium of 144mmol/L (normal: 135 to 148) and serum potassium of 3.8mmol/L (normal: 3.5 to 5.1) and a serum creatinine of 69μmol/L (normal: 60 to 120). Random blood sugar was 85mg/dL (normal: 79 to 140). Blood cultures and deep tissue cultures failed to reveal any organisms. Following surgery she remained in intensive care but she rapidly deteriorated and became inotrope dependent. She died 34 hours into hospital admission.\n\nDiscussion\nThe first patient had NF and muscle necrosis of the adductor compartment of his thigh from the outset, but failure of the primary care center to realize the masked signs of NF led to the infection moving up to involve his upper trunk and arm. The delay in definitive management resulted in spread of infection with eventual sepsis and death. Case 2 was an immunocompromised patient who presented late. The inability of her body to mount an effective immune response resulted in rapid progression of NF with sepsis and septic shock despite urgent surgical and medical intervention.\n\nDiagnosis of NF is a challenge to a clinician because it is a rare entity and there may be no obvious pointers favoring its diagnosis [8]. Expected manifestations like skin necrosis are not always obvious, and care should be taken to search for suggestive local (severe spontaneous pain that is disproportional to the degree of inflammation, indurated edema, bullae, cyanosis, skin pallor, absence of lymphangitis, skin hypoesthesia, crepitation, muscle weakness) and systemic signs of ongoing sepsis [2,6]. Furthermore the classic bronze or reddish discoloration of skin due to clostridial infections may not be commonly visualized due to the already tanned skin complexion of Asians, although Case 2 demonstrated typical skin manifestations with bullae formation. In Case 1 the possible missed sign was the out of proportion pain with a sense of weakness and heaviness which are nonspecific presenting features of gas-forming NF [9]. These were mistaken for a milder form of infection, cellulitis, with absence of superficial skin manifestations.\n\nRisk factors include compromised integrity of skin or mucous membranes, diabetes, arteriopathy, alcoholism, obesity, immunosuppression, malnutrition, renal failure, and age > 60 years. Non-steroidal anti-inflammatory drugs have been suggested as possible risk factors for NF [2,6]. Both our patients had predisposing factors. The patient in Case 1 suffered multiple injuries secondary to his occupation as a laborer, but none were recent. However, Clostridium spores may remain dormant for many years before germination and resultant NF [10]. NF in SLE is uncommon [11] and Kamran et al. state that only 13 cases were reported up to 2008 [12]. A dampened immune system due to immunosuppressive (azathioprine with prednisolone in our patient) therapy, the disease process per se [12] or skin fragility secondary to prednisolone [13] could be additional predisposing factors for patients with SLE to get NF.\n\nAlthough any part of the body may be involved, the lower limbs are the most commonly affected sites for infection (28%) [14]. The absence of fibrous attachments in the limbs and trunk lead to widespread infection and tissue destruction. Infection can also spread to venous and lymphatic channels with resultant edema and thrombosis of blood vessels which cause ischemia and gangrene of subcutaneous fat and dermis [2]. The involvement of the trunk carries a poorer prognosis compared with the extremities in isolation [15]. The rapidity at which the infection spread up the lower limbs in both our patients and the involvement of the trunk and upper limb in Case 1 can thus be explained.\n\nPolymicrobial NF infections are poorly demonstrated on blood cultures which are found positive only in 20 to 27% [3,7] of patients. Neither of our patients’ blood cultures became positive. However, Case 1 had MRSA present on deep tissue culture. But the presence of gas in MRI suggested presence of an additional gas-forming organism, possibly a clostridial species. Although NF is commonly classified into type I and II, some extend the classification further and identify Gram negative or clostridial induced as type III and fungal-induced NF as type IV [4,5,16]. Type III due to clostridial species with muscle involvement is also considered clostridial myonecrosis. Clostridial sepsis can be secondary to trauma due to penetrating injuries, underlying intestinal pathology or even occur spontaneously. The patient in Case 1 most probably had type III NF as gas was present with muscle necrosis. In Case 2 neither blood nor deep tissue culture yielded growth, in keeping with culture patterns observed in polymicrobial NF or it may also be due to the immunocompromised state which may result in atypical organisms causing NF in SLE, for example Pseudomonas aeruginosa, and Serratia marcescens[17,18].\n\nImaging aids diagnosis. X-rays can show gas, although only in a minority (13%) of cases, and show increased soft tissue thickness. Ultrasound can help identify fascial edema and gas and fluid collection, having a sensitivity of 88.2% and a higher specificity of 93.3%, although user limitations may affect interpretation. Contrast-enhanced computed tomography can reveal soft tissue air and fluid and abscess collection, but its use may be limited by concomitant renal failure. MRI has been found to have a sensitivity of 100% and specificity of 86%. It can demonstrate gas bubbles as signal voids, and identify fascial fluid secondary to necrosis and inflammatory edema because it causes variation in signal intensity. When not enhanced the severity may be overestimated due to its inability to differentiate affected tissue from that of non-affected, and underestimated when gadolinium enhanced because tissue hypoperfusion may limit uptake [19-22]. Overall, MRI is considered the investigation of choice, but none of the imaging modalities should delay definitive surgical intervention [23]. Case 1 demonstrated typical imaging changes on MRI with presence of gas with fascial and adjacent muscle compartment involvement as NSTI has been known to cross and involve neighboring tissue planes [1].\n\nA Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score of 6 or above (parameters made of total white cell count, hemoglobin, sodium, glucose, serum creatinine, and C-reactive protein) introduced by Wong et al. in their retrospective analysis [24] was found to be useful in detecting NF early. Although our patients’ ESR was elevated and available it is not included in the scoring system and, unfortunately, C-reactive protein is not available in the free health-care system offered in our country, thus limiting initial assessment using the LRINEC scoring system, but clinical sense should take precedence when other parameters are unavailable and when the LRINEC score contradicts diagnosis of NF on clinical grounds [25].\n\nTreatment is mainly surgical with relevant early radical debridement of devitalized tissue. Being too judicious and attempting to conserve tissue may in fact be detrimental in the long run as it has been shown to worsen mortality [26]. In addition, supportive measures should be implemented with broad spectrum antibiotic treatment to target the spectrum of causative microorganisms (Streptococcus pyogenes, Staphylococcus aureus including MRSA, and Gram-negative aerobes and anaerobes) until cultures are available [2]. Other novel treatment options and adjuncts have been tried and suggested, for example intravenous immunoglobulin to counteract systemic toxicity produced by beta-hemolytic Streptococci [27] and hyperbaric oxygen as an effective adjunct in reducing morbidity and mortality [28], although it remains disputed [29]. Vacuum-assisted closing as a postsurgical adjunct to expedite healing [30] also has been tried.\n\nNF without treatment has a mortality of 100% [2] but with medical and mainly surgical intervention it now has an overall mortality of 16 to 20% [15,31]. Type I NF was found to have a mortality of 21% by Wong et al.[7] but mortality in type III NF due to clostridial species can range from 25 to 80% [32]. Female gender, presence of malignant disease, and diabetes mellitus were found to be independent factors associated with increased mortality in the idiopathic variants [33]. However time plays the most significant role as a delay of no greater than 24 hours can literally double the mortality rate [27]. The primary focus in the first patient was shifted to the intestinal obstruction which was due to two possible mechanisms. One was that he developed paralytic ileus, an observed complication of an abdominal abscess [34] which could occur with infection tracking up to involve the psoas. The second possibility is of an occult intestinal malignancy, which is known to have an association with type III NF due to Clostridium species [35,36], which in turn could track through fascial and muscle planes to involve the lower limb and upper trunk. However, since lower limb features were predominant in the absence of any abdominal involvement at the outset and the transient intestinal obstruction resolved, the former is more likely. The urgency of time in managing NF is reinforced as there is little doubt that mortality was due to failure in identifying and curtailing the disease in time in Case 1 and delay in seeking management in Case 2.\n\nConclusions\nNSTIs are a poorly recognized group of lethal conditions. Clinicians and surgeons should have a high index of suspicion when symptomology is out of proportion to the clinical presentation. Failing to identify classical risk factors and not clinching the diagnosis early, non-aggressive treatment and delayed definitive surgical intervention favor mortality.\n\nConsent\nWritten informed consent was obtained from the patients’ next of kin for the publication of this case report and accompanying images. Copies of the written consent are available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nESR: Erythrocyte sedimentation rate; HCO3−: Bicarbonate; LRINEC: Laboratory Risk Indicator for Necrotizing Fasciitis; MRI: Magnetic resonance imaging; MRSA: Methicillin-resistant Staphylococcus aureus; NF: Necrotizing fasciitis; NSTI: Necrotizing soft tissue infection; SLE: Systemic lupus erythematosus.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nAK, MRN, JY, and TK diagnosed the clinical scenario. MRN and AK researched and drafted the document. All authors provided care for the patient. All authors read and approved the final manuscript.\n\nAuthors’ information\nMRN is a registrar of medicine at the National Hospital of Sri Lanka, Colombo. JY is a senior registrar in medicine at the National Hospital of Sri Lanka, Colombo. TK is a senior registrar in medicine at the National Hospital of Sri Lanka, Colombo. AK is a consultant physician in acute medicine at the National Hospital of Sri Lanka, Colombo.\n\nAcknowledgments\nWe would like to acknowledge the patients’ families for allowing these cases to be published. No funding was utilized for this report.\n==== Refs\nSmith GH Huntley JS Keenan GF Necrotising myositis: a surgical emergency that may have minimal changes in the skin Emerg Med J 2007 24 e8 17251603 \nPuvanendran R Huey JC Pasupathy S Necrotizing fasciitis Can Fam Physician 2009 55 981 987 19826154 \nElliott D Kufera JA Myers RA The microbiology of necrotizing soft tissue infections Am J Surg 2000 179 361 366 10930480 \nDavoudian P Flint NJ Necrotizing fasciitis 2012 Critical Care & Pain: Continuing Education in Anaesthesia doi:10.1093/bjaceaccp/mks033 \nNecrotizing Fasciitis http://www.nycpm.edu/surgclub/necrotizing.pdf \nRoujeau JC Necrotizing fasciitis. Clinical criteria and risk factors Ann Dermatol Venereol 2001 128 376 381 11319368 \nWong CH Chang HC Pasupathy S Khin LW Tan JL Low CO Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality J Bone Joint Surg Am 2003 85-A 1454 1460 12925624 \nAnaya DA Dellinger EP Necrotizing soft-tissue infection: diagnosis and management Clin Infect Dis 2007 44 705 710 17278065 \nWiersema BM Scheid DK Psaradellis T A rare trifocal presentation of Clostridium septicum myonecrosis Orthopedics 2008 31 274 19292235 \nClostridial myonecrosis http://www.uptodate.com/contents/clostridial-myonecrosis \nMendez EA Espinoza LM Harris M Angulo J Sanders CV Espinoza LR Systemic lupus erythematosus complicated by necrotizing fasciitis Lupus 1999 8 157 159 10192511 \nKamran M Wachs J Putterman C Necrotizing fasciitis in systemic lupus erythematosus Semin Arthritis Rheum 2008 37 236 242 17570472 \nHashimoto N Sugiyama H Asagoe K Hara K Yamasaki O Yamasaki Y Makino H Fulminant necrotising fasciitis developing during long term corticosteroid treatment of systemic lupus erythematosus Ann Rheum Dis 2002 61 848 849 12176816 \nGolger A Ching S Goldsmith CH Pennie RA Bain JR Mortality in patients with necrotizing fasciitis Plast Reconstr Surg 2007 119 1803 1807 17440360 \nSerinken M Erdur B Sener S Kabay B Cevik A A Case of Mortal Necrotizing Fasciitis of the Trunk Resulting From a Centipede (Scolopendra moritans) Bite Internet J Emerg Med 2004 2 2 \nNecrotising fasciitis http://www.dermnetnz.org/bacterial/necrotising-fasciitis.html \nHuang JW Fang CT Hung KY Hsueh PR Chang SC Tsai TJ Necrotizing fasciitis caused by Serratia marcescens in two patients receiving corticosteroid therapy J Formos Med Assoc 1999 98 851 854 10634026 \nNimesh KP Laura M A Rare Cause of Necrotizing Fasciitis in a Patient With Systemic Lupus Erythematosus C56 PULMONARY AND NON-PULMONARY CRITICAL CARE: GREAT CASES!: American Thoracic Society: A4596: American Thoracic Society International Conference Abstracts \nFugitt JB Puckett ML Quigley MM Kerr SM Necrotizing fasciitis Radiographics 2004 24 1472 1476 15371620 \nAngoules AG Kontakis G Drakoulakis E Vrentzos G Granick MS Giannoudis PV Necrotising fasciitis of upper and lower limb: a systematic review Injury 2007 38 Suppl 5 S19 S26 18048033 \nYen ZS Wang HP Ma HM Chen SC Chen WJ Ultrasonographic screening of clinically-suspected necrotizing fasciitis Acad Emerg Med 2002 9 1448 1451 12460854 \nSchmid MR Kossmann T Duewell S Differentiation of necrotizing fasciitis and cellulitis using MR imaging AJR Am J Roentgenol 1998 170 615 620 9490940 \nStoneback JW Hak DJ Diagnosis and management of necrotizing fasciitis Orthopedics 2011 34 196 21410101 \nWong CH Khin LW Heng KS Tan KC Low CO The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections Crit Care Med 2004 32 1535 1541 15241098 \nWilson MP Schneir AB A case of necrotizing fasciitis with a LRINEC score of zero: clinical suspicion should trump scoring systems J Emerg Med 2013 44 928 931 23287745 \nFreischlag JA Ajalat G Busuttil RW Treatment of necrotizing soft tissue infections. The need for a new approach Am J Surg 1985 149 751 755 4014552 \nSeal DV Necrotizing fasciitis Curr Opin Infect Dis 2001 14 127 132 11979121 \nRiseman JA Zamboni WA Curtis A Graham DR Konrad HR Ross DS Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements Surgery 1990 108 847 850 2237764 \nHassan Z Mullins RF Friedman BC Shaver JR Brandigi C Alam B Mian MA Treating necrotizing fasciitis with or without hyperbaric oxygen therapy Undersea Hyperb Med 2010 37 115 123 20462144 \nAl-Subhi F Zuker R Cole W Vacuum-assisted closure as a surgical assistant in life-threatening necrotizing fasciitis in children Can J Plast Surg 2010 18 139 142 22131841 \nFrazee BW Fee C Lynn J Wang R Bostrom A Hargis C Moore P Community-acquired necrotizing soft tissue infections: a review of 122 cases presenting to a single emergency department over 12 years J Emerg Med 2008 34 139 146 17976799 \nBretzke ML Bubrick MP Hitchcock CR Diffuse spreading Clostridium septicum infection, malignant disease and immune suppression Surg Gynecol Obstet 1988 166 197 199 3344448 \nTaviloglu K Cabioglu N Cagatay A Yanar H Ertekin C Baspinar I Ozsut H Guloglu R Idiopathic necrotizing fasciitis: risk factors and strategies for management Am Surg 2005 71 315 320 15943405 \nManagement of intra-abdominal abscesses http://www.ncbi.nlm.nih.gov/books/NBK6937/ \nGibson MA Avgerinos DV Llaguna OH Sheth ND Myonecrosis secondary to Clostridium septicum in a patient with occult colon malignancy: a case report Cases J 2008 1 300 18992141 \nLarson CM Bubrick MP Jacobs DM West MA Malignancy, mortality, and medicosurgical management of Clostridium septicum infection Surgery 1995 118 592 597 discussion 597–598 7570310\n\n",
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"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D002481:Cellulitis; D003646:Debridement; D018450:Disease Progression; D042241:Early Diagnosis; D061345:Early Medical Intervention; D019115:Fasciitis, Necrotizing; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D018805:Sepsis; D013203:Staphylococcal Infections",
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"references": "19826154;17278065;10634026;2237764;17251603;12460854;15241098;10192511;21410101;3344448;20462144;15943405;15371620;12176816;9490940;19292235;23287745;10930480;18992141;7570310;11319368;22131841;11979121;17570472;18048033;12925624;4014552;17440360;17976799",
"title": "Necrotizing fasciitis--a diagnostic dilemma: two case reports.",
"title_normalized": "necrotizing fasciitis a diagnostic dilemma two case reports"
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"abstract": "Actinic keratosis (AK) is considered as superficial squamous cell carcinoma. Chronic sun exposure plays a central role in its pathogenesis. In particular, ultraviolet B radiation causes direct damage to the DNA, producing pyrimidine dimers that suppress the protective role of p53. Other risk factors include advanced age, male sex, and fair skin type. Even some drugs used for treating blood hypertension, such as thiazide diuretics, can increase the risk of developing AK. Their photosensitizing action seems to be connected with reactive oxygen species production. We report our experience with ten patients affected by multiple AK, in therapy with thiazide diuretics, treated by ingenol mebutate gel. AK was clinically and dermoscopically evaluated at baseline and after 30 days from the beginning of the treatment. Moreover, patients were screened for vitamin D3 values and reported a general hypovitaminosis status. To our knowledge, we report for the first time the efficacy of ingenol mebutate gel in this group of patients, particularly at risk of developing AK.",
"affiliations": "Department of Dermatology.;Department of Dermatology.;Department of Dermatology.;Department of Dermatology.;Department of Pathology, University of Rome Tor Vergata, Rome, Italy.",
"authors": "Campione|Elena|E|;Di Prete|Monia|M|;Diluvio|Laura|L|;Bianchi|Luca|L|;Orlandi|Augusto|A|",
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"fulltext": "\n==== Front\nClin Cosmet Investig DermatolClin Cosmet Investig DermatolClinical, Cosmetic and Investigational DermatologyClinical, Cosmetic and Investigational Dermatology1178-7015Dove Medical Press 10.2147/CCID.S111305ccid-9-405Original ResearchEfficacy of ingenol mebutate gel for actinic keratosis in patients treated by thiazide diuretics Campione Elena 1Di Prete Monia 1Diluvio Laura 1Bianchi Luca 1Orlandi Augusto 21 Department of Dermatology2 Department of Pathology, University of Rome Tor Vergata, Rome, ItalyCorrespondence: Elena Campione, Department of Dermatology, University of Rome Tor, Viale Oxford, 81, 00133, Rome, Italy, Tel +39 6 2090 0252, Fax +39 6 2090 2742, Email campioneelena@hotmail.com2016 07 11 2016 9 405 409 © 2016 Campione et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Actinic keratosis (AK) is considered as superficial squamous cell carcinoma. Chronic sun exposure plays a central role in its pathogenesis. In particular, ultraviolet B radiation causes direct damage to the DNA, producing pyrimidine dimers that suppress the protective role of p53. Other risk factors include advanced age, male sex, and fair skin type. Even some drugs used for treating blood hypertension, such as thiazide diuretics, can increase the risk of developing AK. Their photosensitizing action seems to be connected with reactive oxygen species production. We report our experience with ten patients affected by multiple AK, in therapy with thiazide diuretics, treated by ingenol mebutate gel. AK was clinically and dermoscopically evaluated at baseline and after 30 days from the beginning of the treatment. Moreover, patients were screened for vitamin D3 values and reported a general hypovitaminosis status. To our knowledge, we report for the first time the efficacy of ingenol mebutate gel in this group of patients, particularly at risk of developing AK.\n\nKeywords\nanticancer agentsantitumor activitycancer cellsskin precancerous lesion\n==== Body\nIntroduction\nActinic keratosis (AK) is an intradermal proliferation of atypical keratinocytes. AKs are considered as superficial squamous cell carcinoma (SCC), because they are fundamentally indistinguishable in terms of cytology and are similar for molecular biology.1 Clinically, AKs mostly present as squamous or hyperkeratotic papules on an erythematous background, but they can also present as pigmented, lichenoid, or cutaneous horn. A sandpaper-like texture is revealed by palpation and surrounding skin generally shows the chronic sun damage signs.2 Based on their features, people can have single or multiple AKs: patients with single lesions usually are young or old people with fair skin type. Immunosuppressed people who spend a lot of time outdoors or in photosensitization treatment have generally multiple lesions.3,4 A central role in the pathogenesis of the lesions is played by the chronic ultraviolet (UV) radiation exposure. In particular, UVB can cause direct DNA damage, producing pyrimidine dimers. It can lead to suppression of p53 function which seems to be the most important pathway in the development of both AKs and SCCs, with the consequence of clonal expansion of keratinocytes.5 On the other hand, UVA, absorbed by skin chromophores, can generate reactive oxygen species that are mutagenic for DNA.6,7 Human papilloma virus seems to play a marginal role and acts as a cofactor of UV radiation-induced DNA alterations in the development of AKs.8 The main risk factors include advanced age, male sex, cumulative sun exposure, and fair skin type. Organ transplant recipients, as well as people treated with chemotherapy, antibiotics, nonsteroidal anti-inflammatory drugs, and diuretics have higher risk than the general population for developing AKs.9 Diuretics are a class of antihypertensive drugs and thiazide diuretics, in particular, are significantly associated with increased risk of SCC. Their photosensitizing action may be due to conversion to electrophiles or production of reactive oxygen species.3 There are two different and effective treatments for AKs: lesion-directed and field-directed therapies. The lesion-directed treatments aim to destroy or remove atypical keratinocytes, whereas the field-directed therapies not only act against the lesion, but also against areas with subclinical atypical keratinocytes within a field of chronic sun exposed and damaged skin, the so-called field of cancerization.10–12 Among the latter novel therapies, ingenol mebutate gel, an extract from the plant Euphorbia peplus, induces swelling of mitochondria of dysplastic keratinocytes and cell death by primary necrosis. Its topical application generates a neutrophil infiltration, due to protein-kinase C activation, causing effective wound healing.13–15 Phase 3 studies have revealed the efficacy of ingenol mebutate gel at concentrations of 0.015% (for the face/scalp) and 0.05% (for the trunk/extremities) in clearing AKs, with remission over 12 months.16 We report cases of ten patients affected by multiple AKs, undergoing therapy with thiazide diuretics for hypertension, treated using ingenol mebutate gel in different concentrations depending on the region to treat.\n\nMaterial and methods\nPatients with AKs received ingenol mebutate gel in different concentrations on the basis of localization of their lesions, 0.015% for face and scalp and 0.05% for trunk and extremities, for 3 and 2 consecutive days, respectively. Eligibility criteria included an age of at least 18 years, presence of one or more AKs, and current treatment with thiazide diuretics for hypertension. The main exclusion criterion was other concomitant therapies for AKs. Females included in the study were not pregnant or breast-feeding. Ten patients (five females and five males), mean age 64.2 years (from 55 to 75 years), in good blood pressure control, were involved in the study (Table 1). No other dermatological disorders were referred. All patients signed a written consent before starting the therapy, and the study was conducted following the ethical guidelines of the Helsinki Declaration. As ingenol mebutate is approved for the treatment of actinic keratosis there was no formal ethical review board approval sought. Enrolled patients were affected by multiple AKs (a total of 24 lesions from 3.2 to 15 mm diameter) localized all over the body surface. All patients were educated to self-apply the medical device on the target lesion and perilesional field of cancerization (25 cm2). Short-distance lesions were treated at the same time if they were in a 25 cm2 diameter area, otherwise in two different times. Patients were also informed of the normal important skin reaction that would have been expected in the days following the topical application and they were asked to communicate any side effects that lay outside this one (eg, infections, allergy, and swelling). AKs were clinically and dermoscopically evaluated at baseline and at 1 month from the beginning of the treatment. From a clinical point of view, AKs were recognized by their typical sandpaper-like texture revealed by palpation. Surrounding skin generally showed chronic sun damage signs. Dermoscopy features defining AKs were erythematous pseudo-network for facial lesions and erythematous background for the ones localized elsewhere, and white-yellowish surface scales and atrophic hypopigmented areas for everywhere placed lesions. The end-point was the complete, clinical, and dermoscopic clearance of AKs after the treatment. Afterwards, the patients were followed for approximately a year with no evidence of recurrence of the disease.\n\nResults\nWe enrolled ten patients (five females and five males; mean age 64.2 years) affected by multiple AKs (24 total lesions, from 3.2 to 15 mm diameter, localized on face, scalp, trunk, and upper and lower extremities) that consecutively referred to the Dermatological Unit of our Hospital for a general skin examination (Table 1). They were on treatment with thiazide diuretics for their hypertension. The mean duration of the treatment with hydrochlorothiazide was 6.9 years (from 4 to 10 years). AKs were clinically and dermoscopically evaluated (their images were archived in our database) at baseline and after 1 month. It was prescribed ingenol mebutate gel at concentrations of 0.015% for lesions of face and scalp and 0.05% for those of trunk and extremities. In the first case, the drug was topically applied for three consecutive nights and in the latter for two consecutive nights. None of them reported particular side effect (eg, infections of the treated areas and allergy). Everyone had an important erythematous reaction at the site of application with vesicles and crusts that began within the first day of application and peaked during the following week, and totally resolved in <2 months. Despite the important sun damage that could result in lower treatment effectiveness, these patients’ response was excellent, leaving the underlying skin completely clear from lesions after only one cycle of therapy (Figures 1–3). Afterwards, patients were followed for approximately a year with no evidence of recurrence of the disease. Before the beginning of the treatment, all patients were screened for vitamin D3 values and reported a general hypovitaminosis status (mean value 14.55 ng/mL, normal range 30–80 ng/mL).\n\nDiscussion\nWe analyzed a cohort of ten patients and found a general hypovitaminosis D status (mean value 14.55 ng/mL, values from 10.20 to 22.00 ng/mL). Many investigations have indicated that vitamin D3 action reduces risk of nonmelanoma skin cancers, maybe modulating p53 response to DNA damage in SCC.17,18 The association between plasma 25-hydroxy-vitamin D (25(OH)D) levels and the incident risk of SCC has been recognized, and could be, together with photoprotection, one of the parameters based on which patients having major risk factors for the development of SCC can be treated. Patients treated with thiazide diuretics show, in our experience, greater photo- and chrono-aging (xerosis, thin skin, fine wrinkles, and loss of elasticity) compared with the general population based on clinical and dermoscopic evaluations. As the epidermis is the major source of vitamin D3 and aged skin has less capacity to synthesize this component, it is conceivable that the hypovitaminosis status, typical of this group of patients, is ascribable to their treatment with thiazide diuretics. Therefore, the accelerated skin aging found in this group of patients might be both the cause and effect of the severe vitamin D deficiency. A population-based case–control study in 2008 in Denmark by Jensen showed association between diuretics usage, especially hydrochlorothiazide, and SCC development. Moreover, the study found an increase in the risk of tumor with an increase in the dosage of drug. The pathogenic mechanism is considered to be an interaction with UV radiation as demonstrated for another diuretic molecule, amiloride.19 Recently, a further case–control study was published and found an increased, yet imprecise, risk of SCC among Americans on treatment with diuretics.20 Thiazide diuretics are used to lower hypertension and reduce the risk of cardiovascular disease. They act on the luminal membrane of the distal convoluted tubule of the ascending loop of Henle. After being secreted into the tubular lumen, they inhibit the sodium chloride cotransporter and cause natriuresis. Moreover, they increase the secretion of potassium and hydrogen ions, increase the expression of sodium–calcium exchange channel, and promote the reabsorption of calcium.21,22 The diuresis and blood volume reduction are the early causes of pressure decreasing. The exact mechanism on long-term period response is not yet known. The most common side effect described is electrolyte disturbance, in particular hypokalemia, followed by hypochloremic alkalosis, hyponatremia, and hypercalcemia.23 Ingenol mebutate has demonstrated its extraordinary effectiveness in a group of patients particularly at risk of nonmelanoma skin cancers. The induction of necrosis in dysplastic keratinocytes is a winning strategy in these skin tumors.13–15 On one hand, ingenol mebutate permits to treat AKs and avoids their evolution into SCC, and on the other hand, it also makes it possible to heal the cancerization field. Nowadays, it is understood that the field of cancerization has the same importance as lesions, as it represents a large area of chronic sun damage, whence new precancerous and tumor lesions can develop in the future.24\n\nConclusion\nOur clinical observation is useful for patients who have to perform this specific diuretic photosensitization therapy to suggest strategies that try to prevent nonmelanoma skin cancer development. Assuring good plasma 25(OH)D levels and investigating other factors that may influence its action (receptor status, binding protein levels, synthesis and catabolism mechanisms) could be the first step in this direction. Further studies are needed to determine the real photosensitizing mechanism of thiazide diuretics. To the best of our knowledge, we report for the first time the extraordinary efficacy of ingenol mebutate gel in this peculiar group of patients particularly at risk of developing nonmelanoma skin cancers.\n\nAcknowledgments\nIn memory of our Professor Sergio Chimenti, recently passed away, who was a guide and a mentor for us.\n\nAll the patients gave their consent to use their photos for the publication.\n\nAuthor contributions\n\nAll authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 A 75-year-old woman affected by actinic keratosis of the left cheek.\n\nNotes: (A) Diameter before therapy approximately 11 mm. (B) Reaction after 3 consecutive days application of ingenol mebutate gel 0.015%. (C) Complete clearance after 1 month from the end of treatment.\n\nFigure 2 A 59-year-old woman affected by actinic keratosis of the left side of the nose.\n\nNotes: (A) Diameter before therapy approximately 6 mm. (B) Important inflammatory reaction after 3 consecutive days application of ingenol mebutate gel 0.015%. (C) Complete clearance after 1 month from the end of treatment.\n\nFigure 3 A 60-year-old woman affected by actinic keratosis of the nose.\n\nNotes: (A) Diameter before therapy approximately 13 mm. (B) Complete clearance after 1 month from the end of treatment with ingenol mebutate gel 0.015% applied for 3 consecutive days.\n\nTable 1 General information about patients involved in the study\n\nSex\tAge (years)\tLocalization\tVitamin D3 (ng/mL)\tTherapy\t\nM\t58\tBack, left forearm\t12.40\tHCT (5 years)\t\nM\t69\tBack (2#), right forearm, right hand\t10.20\tHCT (8 years)\t\nF\t75\tLeft cheek*, forehead\t11.50\tHCT (10 years)\t\nM\t56\tNose, chin\t22.00\tHCT (5 years)\t\nF\t59\tNose*, left leg\t13.10\tHCT (4 years)\t\nM\t67\tLeft forearm, left hand\t12.00\tHCT (7 years)\t\nM\t68\tBack, right arm\t11.80\tHCT (10 years)\t\nF\t55\tRight cheek, left forearm\t20.50\tHCT (4 years)\t\nF\t60\tNose*, neckline (2#)\t17.60\tHCT (8 years)\t\nF\t75\tNose, neckline, forehead\t14.40\tHCT (8 years)\t\nNote:\n\n* Lesions in figures.\n\n# The number of the lesions localized in that place.\n\nAbbreviations: F, female; HCT, hydrochlorothiazide; M, male.\n==== Refs\nReferences\n1 Ackerman AB Mones JM Solar (actinic) keratosis is squamous cell carcinoma Br J Dermatol 2006 155 1 9 22 16792746 \n2 Schmitt JV Miot HA Actinic keratosis: a clinical and epidemiological revision An Bras Dermatol 2012 87 3 425 434 22714759 \n3 de Vries E Trakatelli M Kalabalikis D Known and potential new risk factors for skin cancer in European populations: a multicentre case–control study Br J Dermatol 2012 167 Suppl 2 1 13 \n4 Gould JW Mercurio MG Elmets CA Cutaneous photosensitivity diseases induced by exogenous agents J Am Acad Dermatol 1995 33 4 551 573 7673488 \n5 Nomura T Nakajima H Hongyo T Induction of cancer, actinic keratosis, and specific p53 mutations by UVB light in human skin maintained in severe combined immunodeficient mice Cancer Res 1997 57 11 2081 2084 9187098 \n6 Garland CF Garland FC Gorham ED Epidemiologic evidence for different roles of ultraviolet A and B radiation in melanoma mortality rates Ann Epidemiol 2003 13 6 395 404 12875796 \n7 Rinnerthaler M Bischof J Streubel MK Trost A Richter K Oxidative stress in aging human skin Biomolecules 2015 5 2 545 589 25906193 \n8 Queille S Luron L Spatz A Analysis of skin cancer risk factors in immunosuppressed renal transplant patients shows high levels of UV-specific tandem CC to TT mutations of the p53 gene Carcinogenesis 2007 28 3 724 731 17065198 \n9 Tessari G Girolomoni G Nonmelanoma skin cancer in solid organ transplant recipients: update on epidemiology, risk factors, and management Dermatol Surg 2012 38 10 1622 1630 22805312 \n10 Babino G Diluvio L Bianchi L Long-term use of a new topical formulation containing piroxicam 0.8% and sunscreen: efficacy and tolerability on actinic keratosis. A proof of concept study Curr Med Res Opin 2016 32 8 1345 1349 27046744 \n11 Campione E Paternò EJ Candi E The relevance of piroxicam for the prevention and treatment of nonmelanoma skin cancer and its precursors Drug Des Devel Ther 2015 9 5843 5850 \n12 Bianchi L Campione E Marulli GC Costanzo A Chimenti S Actinic keratosis treated with an immune response modifier: a case report of six patients Clin Exp Dermatol 2003 28 Suppl 1 39 41 \n13 Ogbourne SM Suhrbier A Jones B Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death Cancer Res 2004 64 8 2833 2839 15087400 \n14 Cozzi SJ Le TT Ogbourne SM James C Suhrbier A Effective treatment of squamous cell carcinomas with ingenol mebutate gel in immunologically intact SKH1 mice Arch Dermatol Res 2013 305 1 79 83 22871992 \n15 Cozzi SJ Ogbourne SM James C Ingenol mebutate field-direct treatment of UVB-damaged skin reduces lesion formation and removes mutant p53 patches J Invest Dermatol 2012 132 4 1263 1271 22189786 \n16 Lebwohl M Shumack S Stein Gold L Long-term follow-up study of ingenol mebutate gel for the treatment of actinic keratoses JAMA Dermatol 2013 149 666 670 23553119 \n17 Reichrath J Reichrath S The relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of nonmelanoma skin cancer (NMSC): present concepts and future perspectives Dermatoendocrinol 2013 5 1 38 50 24494041 \n18 Caini S Boniol M Tosti G Vitamin D and melanoma and nonmelanoma skin cancer risk and prognosis: a comprehensive review and meta-analysis Eur J Cancer 2014 50 15 2649 2658 25087185 \n19 Jensen AØ Thomsen HF Engebjerg MC Olesen AB Sørensen HT Karagas MR Use of photosensitising diuretics and risk of skin cancer: a population-based case–control study Br J Cancer 2008 99 1522 1528 18813314 \n20 Robinson SN Zens MS Perry AE Spencer SK Duell EJ Karagas MR Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case-control study J Invest Dermatol 2013 133 8 1950 1955 23344461 \n21 Eladari D Chambrey R Identification of a novel target of thiazide diuretics J Nephrol 2011 24 4 391 394 21667455 \n22 Cooney D Milfred-LaForest S Rahman M Diuretics for hypertension: hydrochlorothiazide or chlorthalidone? Cleve Clin J Med 2015 82 8 527 533 26270432 \n23 Palmer BF Metabolic complications associated with use of diuretics Semin Nephrol 2011 31 6 542 552 22099511 \n24 Costa C Scalvenzi M Ayala F Fabbrocini G Monfrecola G How to treat actinic keratosis? an update J Dermatol Case Rep 2015 9 2 29 35 26236409\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7015",
"issue": "9()",
"journal": "Clinical, cosmetic and investigational dermatology",
"keywords": "anticancer agents; antitumor activity; cancer cells; skin precancerous lesion",
"medline_ta": "Clin Cosmet Investig Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101543449",
"other_id": null,
"pages": "405-409",
"pmc": null,
"pmid": "27853385",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "26270432;16792746;23344461;24494041;26604686;22805312;15087400;18813314;14616813;17065198;22714759;26236409;7673488;23553119;9187098;12875796;27046744;25906193;22871992;22881582;22099511;21667455;25087185;22189786",
"title": "Efficacy of ingenol mebutate gel for actinic keratosis in patients treated by thiazide diuretics.",
"title_normalized": "efficacy of ingenol mebutate gel for actinic keratosis in patients treated by thiazide diuretics"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-132271",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
... |
{
"abstract": "OBJECTIVE\nDetection and reporting of drug-induced life-threatening potassium disturbances and the study of associated factors under a Pharmacovigilance Program using Laboratory Signals at a Hospital (PPLSH) during a 2-year period.\n\n\nMETHODS\nAll serum potassium levels <2 mmol/l or >7 mmol/l detected at admission to the hospital, including those of patients who died in the emergency ward or during hospitalization, were monitored prospectively from January 2009 through to December 2010. The incidence rate of each etiology of potassium disturbances was calculated. Factors associated with drug-induced potassium disturbances were detected using a multiple logistic regression model.\n\n\nRESULTS\nThe incidence of true life-threatening drug-induced hyper- and hypokalemia events was 3 and 4.32 (Poisson 95 % confidence interval 1.62-10.24), respectively, per 10,000 admissions. Of the severe potassium disturbances, 32.3 % were drug-induced, and 23 % were lethal. We identified previously undescribed pharmacological causes of hyperkalemia (risedronate, doxazosin) and hypokalemia (acyclovir, teicoplanin, cefepime, meropenem, dexketoprofen colistimethate). Significant predictor factors associated with drug-induced hyperkalemia were the use of polypharmacy (>5 drugs), age (>74 years), sex (female) and kidney disease (glomerular filtration rate <60 ml/min) with the presence of ≥4 comorbid conditions. The only predictor of drug-induced hypokalemia was the use of >5 drugs. The triggering factor associated with drug-induced hyperkalemia and hypokalemia was azotemia and hypoalbuminemia, respectively.\n\n\nCONCLUSIONS\nDrug-induced life-threatening potassium disturbances remain a relevant problem. Potential strategies for prevention are to avoid polypharmacy, early discontinuation of treatment of drugs causing hyperkalemia or nephrotoxicity in cases of various clinical situations (cardiac descompensation, infection, hypovolemia) or obstructive causes, and insistence on albumin control during hospitalization.",
"affiliations": "Clinical Pharmacology Deparment, Hospital Universitario La Paz (IdiPaz), School of Medicine, Universidad Autónoma de Madrid, Arzobispo Morcillo s/n, 28029 Madrid, Spain. elena.ramirez@uam.es",
"authors": "Ramírez|Elena|E|;Rossignoli|Tomás|T|;Campos|Armando J|AJ|;Muñoz|Raúl|R|;Zegarra|Claudia|C|;Tong|Hoi|H|;Medrano|Nicolás|N|;Borobia|Alberto M|AM|;Carcas|Antonio J|AJ|;Frías|Jesús|J|",
"chemical_list": "D011188:Potassium",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-012-1303-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "69(1)",
"journal": "European journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006785:Hospitals, University; D006801:Humans; D006947:Hyperkalemia; D007008:Hypokalemia; D007223:Infant; D007753:Laboratories; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D011188:Potassium; D013030:Spain",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "97-110",
"pmc": null,
"pmid": "22648277",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "4424028;7629896;15680458;16600469;9570179;20935343;8601645;10471241;1604881;16694129;14418577;12880547;8231040;21270925;21885259;16996842;11229629;19738369;17848395;21438068;6496556;2255809;19830061;7950162;2251604;17722968;18235147;1462021;7662755;19890254;7091169;16553;11723313;15295051;9700180;8384030;3714603;16145218;1335467;8386930;21880197;10996582",
"title": "Drug-induced life-threatening potassium disturbances detected by a pharmacovigilance program from laboratory signals.",
"title_normalized": "drug induced life threatening potassium disturbances detected by a pharmacovigilance program from laboratory signals"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-10899",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
... |
{
"abstract": "Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are increasingly used for the treatment of type 2 diabetes (T2D) and can improve glucose control also in type 1 diabetes (T1D). In May 2015, regulatory agencies issued a warning that SGLT2is may cause diabetic ketoacidosis (DKA). We report details on 2 new cases of SGLT2i-associated DKA and review the literature for similar cases within randomized controlled trials (RCTs), cohort studies and single reports. We searched the medical literature for reports of SGLT2i-associated DKA cases. A quantitative analysis of frequency and clinical characteristics is reported. The 2 narrative cases illustrate that SGLT2i-associated DKA can occur in patients with T1D incorrectly diagnosed as T2D, perhaps without the presence of obvious DKA precipitating factors. The incidence of SGLT2i-associated DKA was less than 1/1000 in randomized controlled trials and 1.6/1000 person-years in cohort studies. We retrieved detailed data on 105 SGLT2i-associated DKA case reports, wherein 35% showed glucose levels of less than 200 mg/dL and 22% were not associated with typical triggers. In case reports and in pharmacovigilance databases, duration of SGLT2i treatment before DKA onset was extremely variable. Fatal SGLT2i-associated DKA episodes were found only in pharmacovigilance databases and represented 1.6% of all reported cases. DKA is a rare adverse event during SGLT2i therapy. Predisposing and precipitating factors are still incompletely understood, although a minority of cases lacked typical DKA triggers. More narrative case series and cohort studies are needed to better understand the true risk and the spectrum of this adverse event.",
"affiliations": "Department of Medicine, University of Padova, Padova, Italy.;Department of Medicine, University of Padova, Padova, Italy.;Department of Medicine, University of Padova, Padova, Italy.",
"authors": "Bonora|Benedetta Maria|BM|;Avogaro|Angelo|A|;Fadini|Gian Paolo|GP|0000-0002-6510-2097",
"chemical_list": "D007004:Hypoglycemic Agents; D049990:Membrane Transport Modulators; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1111/dom.13012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-8902",
"issue": "20(1)",
"journal": "Diabetes, obesity & metabolism",
"keywords": "acute complications; case reports; clinical trials; glucose-lowering drugs; pharmacovigilance",
"medline_ta": "Diabetes Obes Metab",
"mesh_terms": "D003922:Diabetes Mellitus, Type 1; D003924:Diabetes Mellitus, Type 2; D016883:Diabetic Ketoacidosis; D003951:Diagnostic Errors; D006801:Humans; D006943:Hyperglycemia; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D049990:Membrane Transport Modulators; D060735:Pharmacovigilance; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
"nlm_unique_id": "100883645",
"other_id": null,
"pages": "25-33",
"pmc": null,
"pmid": "28517913",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Sodium-glucose co-transporter-2 inhibitors and diabetic ketoacidosis: An updated review of the literature.",
"title_normalized": "sodium glucose co transporter 2 inhibitors and diabetic ketoacidosis an updated review of the literature"
} | [
{
"companynumb": "IT-JNJFOC-20170100378",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "INSULIN DETEMIR"
},
"drugadditional": null,
... |
{
"abstract": "Hypophysitis is rarely reported in patients receiving pembrolizumab-only immunotherapies. Since the clinical presentation is usually as isolated adrenocorticotrophic hormone (ACTH) deficiency, patients may be misjudged as having clinical symptoms due to cancer or chemotherapy. A 49-year-old male with laryngeal cancer applied to our clinic just after the tenth cycle of his pembrolizumab treatment, with weakness and nausea/vomiting. Serum morning cortisol and ACTH were 0.47 mcg/dl and 10.1 pg/ml, respectively; the remaining anterior pituitary hormone levels were normal. Pituitary MRI revealed mild glandular enlargement and loss of posterior pituitary bright-spot. All symptoms and signs improved with low-dose prednisolone. This is the second reported case of pembolizumab-associated isolated ACTH deficiency having abnormal pituitary MRI findings as we have reviewed all reported cases in the literature.",
"affiliations": "Department of Internal Medicine, Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey.;Department of Internal Medicine, Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey.;Department of Internal Medicine, Division of Medical Oncology, Hacettepe University School of Medicine, Ankara, Turkey.;Department of Internal Medicine, Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey.",
"authors": "Oğuz|Seda Hanife|SH|0000-0002-7781-944X;Ünlütürk|Uğur|U|0000-0002-5054-1396;Aksoy|Sercan|S|0000-0003-4984-1049;Erbas|Tomris|T|0000-0003-1377-9394",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/imt-2021-0061",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "13(14)",
"journal": "Immunotherapy",
"keywords": "adrenocorticotropic hormone; cancer immunotherapy; endocrinopathy; hypophysitis; pancreatitis; pembrolizumab",
"medline_ta": "Immunotherapy",
"mesh_terms": null,
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "1157-1163",
"pmc": null,
"pmid": "34387129",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical course and management of pembrolizumab-associated isolated adrenocorticotrophic hormone deficiency: a new case and literature review.",
"title_normalized": "clinical course and management of pembrolizumab associated isolated adrenocorticotrophic hormone deficiency a new case and literature review"
} | [
{
"companynumb": "TR-009507513-2109TUR002168",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAutologous stem cell transplantation (auto-SCT) is a treatment approach in non-Hodgkin lymphoma (NHL) patients. The options for mobilization of CD34+ cells to support high-dose therapy are granulocyte-colony stimulating factors (G-CSFs) alone or after chemotherapy. Limited data exist on the efficacy of lipegfilgrastim (LIPEG) in the mobilization field.\n\n\nMETHODS\nThe present prospective nonrandomized study compared LIPEG 6 mg (n = 40) with pegfilgrastim (PEG) 6 mg (n = 37) in the mobilization of blood CD34+ cells after chemotherapy in NHL patients with comparable mobilizing chemotherapy and disease status before auto-SCT.\n\n\nRESULTS\nSignificantly higher blood CD34+ cell (B-CD34+ ) counts were observed in the LIPEG group at the start of the first apheresis (44 vs 23 × 106 /L, P = .009), in line with a higher collection yield of the first apheresis (3.3 vs 2.1 × 106 /kg, P = .086) and total yield of CD34+ cells (4.7 vs 2.9 × 106 /kg, P = .004). LIPEG proved to be a more effective G-CSF, resulting in a higher B-CD34+ cell peak (60 vs 32 × 106 /L, P = .030) and higher proportion of excellent mobilizers (33% vs 8%, P = .008). The superiority of LIPEG was confirmed in the multivarite analysis concerning the CD34+ cell yield of the first apheresis day (P = .010) and the total yield (P = .001).\n\n\nCONCLUSIONS\nThe mobilization of blood grafts with LIPEG added to chemotherapy was associated with higher CD34+ cell apheresis yields than with PEG. A randomized study is warranted to verify these findings.",
"affiliations": "Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Oncology, Central Hospital of Central Finland, Jyväskylä, Finland.;Siunsote-Department of Medicine, Hospital District of North Karelia, Joensuu, Finland.;Department of Medicine, Central Hospital of Savonlinna, Savonlinna, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Eastern Finland Laboratory Centre, Kuopio, Finland.;Eastern Finland Laboratory Centre, Kuopio, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Medicine, Kymenlaakso Central Hospital, Kotka, Finland.",
"authors": "Partanen|Anu|A|https://orcid.org/0000-0002-5634-2582;Turunen|Antti|A|;Valtola|Jaakko|J|;Vasala|Kaija|K|;Ågren|Lasse|L|;Penttilä|Karri|K|;Pyörälä|Marja|M|;Kuittinen|Taru|T|;Mäntymaa|Pentti|P|;Pelkonen|Jukka|J|;Jantunen|Esa|E|;Varmavuo|Ville|V|https://orcid.org/0000-0001-5070-6018",
"chemical_list": "D018952:Antigens, CD34; D000970:Antineoplastic Agents; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21785",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "35(4)",
"journal": "Journal of clinical apheresis",
"keywords": "CD34+ cell mobilization; hematological recovery; lipegfilgrastim; non-Hodgkin lymphoma; pegfilgrastim",
"medline_ta": "J Clin Apher",
"mesh_terms": "D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001781:Blood Component Removal; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011092:Polyethylene Glycols; D011446:Prospective Studies; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "255-263",
"pmc": null,
"pmid": "32311780",
"pubdate": "2020-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "A prospective comparison of pegfilgrastim and lipegfilgrastim combined with chemotherapy in the mobilization of CD34+ cells in NHL patients.",
"title_normalized": "a prospective comparison of pegfilgrastim and lipegfilgrastim combined with chemotherapy in the mobilization of cd34 cells in nhl patients"
} | [
{
"companynumb": "FI-AMGEN-FINSP2021124839",
"fulfillexpeditecriteria": "2",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Imatinib, a BCR-ABL tyrosine kinase inhibitor, is known to cause mild to moderate cutaneous reactions in up to approximately 20% of patients. It rarely causes severe reactions, such as Stevens-Johnson syndrome, which can be life threatening. Typically, these rashes occur within two months of initiating therapy. We report a case of Stevens-Johnson syndrome induced by imatinib after several years of therapy, but later successfully was treated with nilotinib therapy.",
"affiliations": "Rite Aid, Waterville, ME, USA.;Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA lisa.holle@uconn.edu.;Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA.",
"authors": "Bois|Evan|E|;Holle|Lisa M|LM|;Farooq|Umar|U|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1177/1078155213518226",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "20(6)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Imatinib; Stevens–Johnson syndrome; rash",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000970:Antineoplastic Agents; D001549:Benzamides; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines; D011743:Pyrimidines; D013262:Stevens-Johnson Syndrome; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "476-8",
"pmc": null,
"pmid": "24399835",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late onset imatinib-induced Stevens-Johnson syndrome.",
"title_normalized": "late onset imatinib induced stevens johnson syndrome"
} | [
{
"companynumb": "US-ACTAVIS-2015-14685",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "Establishment of a preferential liver allocation rule for simultaneous liver and kidney transplantation (SLK) and revisions of laws regarding organ transplants from deceased donors have paved the way for SLK in Japan. Very few cases of SLK have been attempted in Japan, and no such recipients have survived for longer than 40 days. The present report describes a case of a 50-year-old woman who had undergone living donor liver transplantation at the age of 38 years for management of post-partum liver failure. After the first transplant surgery, she developed hepatic vein stenosis and severe hypersplenism requiring splenectomy. She was then initiated on hemodialysis (HD) due to the deterioration of renal function after insertion of a hepatic vein stent. She was listed as a candidate for SLK in 2011 because she required frequent plasma exchange for hepatic coma. When her Model for End-stage Liver Disease score reached 46, the new liver was donated 46 days after registration. The reduced trisegment liver and the kidney grafts were simultaneously transplanted under veno-venous bypass and intraoperative HD. The hepatic artery was reconstructed prior to portal reconstruction in order to shorten anhepatic time. Although she developed subcapsular bleeding caused by hepatic contusion on the next day, subsequent hemostasis was obtained by transcatheter embolization. Thereafter, her recovery was uneventful, except for mild rejection and renal tubular acidosis of the kidney graft. This case highlights the need to establish Japanese criteria for SLK.",
"affiliations": "Hepato-Biliary and Pancreatic Surgery, Okayama University Hospital, Okayama, Japan.",
"authors": "Yagi|Takahito|T|;Nobuoka|Daisuke|D|;Shinoura|Susumu|S|;Umeda|Yuzo|Y|;Sato|Daisuke|D|;Yoshida|Ryuichi|R|;Utsumi|Masashi|M|;Fuji|Tomokazu|T|;Sadamori|Hiroshi|H|;Fujiwara|Toshiyoshi|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.12122",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "44(3)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "deceased donor; kidney transplantation; liver transplantation; living donor; retransplantation; simultaneous",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "358-63",
"pmc": null,
"pmid": "23607507",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "First successful case of simultaneous liver and kidney transplantation for patients with chronic liver and renal failure in Japan.",
"title_normalized": "first successful case of simultaneous liver and kidney transplantation for patients with chronic liver and renal failure in japan"
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"abstract": "BACKGROUND\nAzithromycin has been associated with abnormalities of cardiac repolarization and development of torsades de pointes. Observational data suggest that the risk of death from cardiovascular causes is increased in patients taking azithromycin. Little is known regarding the risk of ventricular arrhythmia in patients with prolongation of the corrected QT interval who receive azithromycin.\n\n\nOBJECTIVE\nThe purpose of this study was to determine the incidence of sustained ventricular tachycardia in patients with prolonged corrected QT (QTc) who subsequently received azithromycin.\n\n\nMETHODS\nWe performed a retrospective cohort analysis of the incidence of sustained ventricular tachycardia in patients with prolonged QTc (greater than 450 ms) who successively received intravenous (IV) and/or oral azithromycin. Patients hospitalized in a tertiary care teaching hospital between November 2009 and June 2012 were included in the study. The primary outcome was sustained ventricular tachycardia documented in patients on telemetry.\n\n\nRESULTS\nOf the 103 patients enrolled in the study, only one patient experienced the primary outcome (0.97 %). The event occurred 1 day after the administration of a single dose of 500 mg IV azithromycin.\n\n\nCONCLUSIONS\nThe risk of sustained ventricular tachycardia was 0.97 % in our cohort of patients with prolonged QTc who subsequently received azithromycin. Given the small size of this study, additional research is needed to determine the true incidence of arrhythmia in the population.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA. sears.steven@mayo.edu.;CRISP Investigative Research Program, Mayo Clinic, Jacksonville, FL, USA.;Department of Cardiology, Mayo Clinic, Jacksonville, FL, USA.;Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA.;CRISP Investigative Research Program, Mayo Clinic, Jacksonville, FL, USA.;Department of Internal Medicine, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA.",
"authors": "Sears|Steven P|SP|http://orcid.org/0000-0001-7257-1599;Getz|Trevor W|TW|;Austin|Christopher O|CO|;Palmer|William C|WC|;Boyd|Evelyn A|EA|;Stancampiano|Fernando F|FF|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40801-016-0062-9",
"fulltext": "\n==== Front\nDrugs Real World OutcomesDrugs Real World OutcomesDrugs - Real World Outcomes2199-11542198-9788Springer International Publishing Cham 270737626210.1007/s40801-016-0062-9Original Research ArticleIncidence of Sustained Ventricular Tachycardia in Patients with Prolonged QTc After the Administration of Azithromycin: A Retrospective Study http://orcid.org/0000-0001-7257-1599Sears Steven P. 650.515.0292sears.steven@mayo.edu 1Getz Trevor W. 2Austin Christopher O. 3Palmer William C. 4Boyd Evelyn A. 2Stancampiano Fernando F. 11 Department of Internal Medicine, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL 32224 USA 2 CRISP Investigative Research Program, Mayo Clinic, Jacksonville, FL USA 3 Department of Cardiology, Mayo Clinic, Jacksonville, FL USA 4 Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL USA 14 3 2016 14 3 2016 3 2016 3 1 99 105 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nAzithromycin has been associated with abnormalities of cardiac repolarization and development of torsades de pointes. Observational data suggest that the risk of death from cardiovascular causes is increased in patients taking azithromycin. Little is known regarding the risk of ventricular arrhythmia in patients with prolongation of the corrected QT interval who receive azithromycin.\n\nObjective\nThe purpose of this study was to determine the incidence of sustained ventricular tachycardia in patients with prolonged corrected QT (QTc) who subsequently received azithromycin.\n\nMethods\nWe performed a retrospective cohort analysis of the incidence of sustained ventricular tachycardia in patients with prolonged QTc (greater than 450 ms) who successively received intravenous (IV) and/or oral azithromycin. Patients hospitalized in a tertiary care teaching hospital between November 2009 and June 2012 were included in the study. The primary outcome was sustained ventricular tachycardia documented in patients on telemetry.\n\nResults\nOf the 103 patients enrolled in the study, only one patient experienced the primary outcome (0.97 %). The event occurred 1 day after the administration of a single dose of 500 mg IV azithromycin.\n\nConclusion\nThe risk of sustained ventricular tachycardia was 0.97 % in our cohort of patients with prolonged QTc who subsequently received azithromycin. Given the small size of this study, additional research is needed to determine the true incidence of arrhythmia in the population.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nKey Points\nAzithromycin has been associated with prolongation of the QTc interval and development of torsades de pointes.\t\nPreviously, there were no data detailing the incidence of sustained ventricular tachycardia in patients with known prolonged QTc who were subsequently given azithromycin.\t\nIn a small cohort of patients admitted to a tertiary referral medical center, the risk of sustained ventricular tachycardia was less than 1 % in patients with prolonged QTc who subsequently received azithromycin.\t\n\n\nIntroduction\nMacrolides are commonly used and effective antibiotics for conditions such as respiratory infections and certain sexually transmitted diseases. Early generation macrolides such as erythromycin were found to prolong cardiac repolarization and were associated with torsades de pointes (TdP), a potentially fatal ventricular arrhythmia [1]. Newer macrolides were developed for the treatment of atypical organisms in respiratory tract infections. Post-marketing surveillance demonstrated an improved safety profile compared to erythromycin and clarithromycin [2]. Further, azithromycin may provide a survival benefit in older adults with pneumonia when compared with fluoroquinolones [3]. However, as use of the drug became more prevalent, case reports emerged linking azithromycin to prolongation of the QT interval, TdP, and polymorphic ventricular tachycardia. The US Food and Drug Administration’s (FDA’s) Adverse Event Reporting System has documented over 20 cases of TdP in patients taking azithromycin [4].\n\nA large retrospective cohort study in 2012 showed the risk of both cardiovascular and all-cause mortality in patients who received azithromycin was increased when compared with patients who took amoxicillin [5]. Despite some limitations, this study prompted further investigation, and in 2013 the FDA revised product labels to advise against using azithromycin in patients with prolonged QTc, risk factors for prolonged QTc, and in persons who concomitantly take medications that delay cardiac repolarization. However, no data are available regarding the incidence of ventricular arrhythmias in such populations when they receive azithromycin. In this retrospective study, we evaluated the incidence of sustained ventricular tachycardia in hospitalized patients with prolonged corrected QT interval (QTc), who subsequently received azithromycin (Fig. 1).Fig. 1 \na Rhythm strip of torsades de pointes in a 91-year-old male with prolonged QTc. b Ventricular tachycardia documented 27 h following a 500 mg IV dose of azithromycin\n\n\n\nMethods\nStudy Cohort\nBetween November 2009 and June 2012, 266 patients at Mayo Clinic in Florida with prolonged QTc greater than 450 ms (ms) who subsequently received azithromycin were evaluated for inclusion in this retrospective study [6]. Data were collected by retrospective chart review performed by interrogation of our electronic medical record for patients with prolonged QTc, cross-referenced by administration of azithromycin. The resultant database was subsequently manually reviewed and validated by the study authors. Patients were excluded if they were younger than 18 years of age, had a history of sustained ventricular tachycardia (defined as ventricular tachycardia for greater than 30 s or requiring termination in less than 30 s due to hemodynamic compromise), had an implanted defibrillator, were using antiarrhythmic medications, or had received azithromycin or another antibiotic within 72 h prior to admission. The study protocol was approved by the Mayo Clinic Institutional Review Board IRB# 14-005155. The primary outcome was sustained ventricular tachycardia. Secondary outcomes included cardiac death, all-cause mortality, and length of hospital stay. Baseline characteristics and co-morbidities were collected along with concomitant use of QTc prolonging medications. All EKGs were read automatically and reviewed by a staff cardiologist. Bazett’s formula was used to correct the QT interval.\n\nStatistical Analysis\nContinuous variables were summarized using the sample median. Categorical variables were summarized with number and percentage. The proportion of patients who experienced sustained ventricular tachycardia following the start of azithromycin was estimated along with a 95 % confidence interval (CI). Statistical analysis was performed using JMP (version 9.01; SAS Institute, Inc., Cary, NC, USA).\n\nResults\nA total of 103 patients were included in the final analysis. Subjects may have been excluded for more than one reason. Five patients were excluded due to a history of ventricular tachycardia, 16 due to prior AICD placement, 16 due to concomitant treatment with an antiarrhythmic, 102 excluded for treatment with another antibiotic within 72 h of admission, 17 were treated with azithromycin prior to admission, and 16 developed prolonged QTc only after a dose of azithromycin. Information on mean age, gender, race, diagnosis at admission, and co-morbid conditions is represented in Table 1. The most common reasons for admission were pulmonary (60 %), cardiovascular (19 %), and renal failure (7 %). A history of hypertension was noted in 62 % of patients, coronary artery disease in 45 %, diabetes mellitus in 31 %, and heart failure with reduced ejection fraction in 14 % of patients.Table 1 Characteristics and co-morbidities of patients with pre-existing QT prolongation admitted to a US tertiary-care hospital between November 2009 and June 2012\n\nVariable\tSummary (N = 103)\t\nAge\t76 (26, 58, 89, 98)\t\nGender (Male)\t65 (63 %)\t\nRace\t\n Caucasian\t93 (91 %)\t\n African American\t4 (4 %)\t\n Asian\t3 (3 %)\t\n Other\t2 (2 %)\t\nBody mass index\t27 (16, 23, 31, 49)\t\nAdmission diagnosis\t\n Pulmonary\t60 (58 %)\t\n Chronic obstructive pulmonary disease\t12 (12 %)\t\n Pneumonia\t33 (32 %)\t\n Other\t15 (15 %)\t\n Cardiovascular\t19 (18 %)\t\n Congestive heart failure\t12 (12 %)\t\n Coronary\t4 (4 %)\t\n Arrhythmia\t3 (3 %)\t\n Renal failure\t7 (7 %)\t\n Neurologic\t5 (5 %)\t\n Vascular\t3 (3 %)\t\n Non-vascular\t2 (2 %)\t\n Gastrointestinal\t4 (4 %)\t\n Liver\t2 (2 %)\t\n Other\t2 (2 %)\t\n Infectious\t4 (4 %)\t\n Oncologic\t3 (3 %)\t\n Hematologic\t1 (1 %)\t\nSerum potassium (mEq/L)\t4.0 (2.7, 3.6, 4.3, 6.2)\t\nSerum calcium (mg/dL)\t8.8 (7.4, 8.4, 9.4, 12.5)\t\nSerum creatinine (mg/dL)\t1.0 (0.4, 0.7, 1.9, 15.4)\t\nSerum sodium (mmol/L)\t138 (127, 135, 140, 159)\t\nGlomerular filtration rate\t60 (3.4, 35, 60, 60)\t\nEjection fraction\t58 (22, 47, 66, 73)\t\nTelemetry\t94 (92 %)\t\nDiabetes\t32 (31 %)\t\nHypertension\t64 (62 %)\t\nCoronary artery disease\t46 (45 %)\t\nCongestive heart failure\t14 (14 %)\t\nThe sample median and descriptive statistics (minimum, 25th percentile, 75th percentile, maximum) are given for continuous variables\n\nSerum calcium (N = 13), and cardiac ejection fraction (N = 43)\n\n\n\nThe use of beta-blockers (50 %) and antidepressants was common (36 %), whereas antifungal (2 %) and antipsychotic (6 %) use was not (Table 2). Indications for azithromycin often differed from initial admission diagnosis and included sexually transmitted infection (0.9 %), bronchitis (6.7 %), respiratory failure (9.7 %), chronic obstructive pulmonary disease exacerbation (16.5 %), and pneumonia (66.0 %). The initial dose of azithromycin was 250 mg in nine patients (9 %), 500 mg in 92 patients (89 %), 1,000 mg in one patient (0.9 %), and 1,200 mg in one patient (0.9 %). Intravenous (IV) administration of azithromycin (41 %) was preferred to oral dosing (38 %), and 22 patients received the medication by both routes (22 %). The median duration of treatment was 2 days, (range 1–36 days). The median total dose of azithromycin was 1000 mg (range 250–9000 mg). The median duration of the QTc interval at time of admission was 474 ms (range 423–583 ms), while the longest median QTc was 485 ms (range 451–583 ms). Ninety-four of the 103 patients were monitored on telemetry (91 %).Table 2 Medications present on admission along with route and dosing of azithromycin administration with median and maximum duration of the QTc, and length of hospital stay in patients with pre-existing QT prolongation admitted to a US tertiary-care hospital between November 2009 and June 2012\n\nVariable\tSummary (N = 103)\t\nBeta blocker at admission\t52 (50 %)\t\n Type of beta blocker\t\n Metoprolol\t34 (33 %)\t\n Carvedilol\t12 (12 %)\t\n Atenolol\t4 (4 %)\t\n Other\t2 (2 %)\t\nAntidepressant at admission\t37 (36 %)\t\n Type of antidepressant\t\n Sertraline\t16 (16 %)\t\n Citalopram\t7 (7 %)\t\n Paroxetine\t7 (7 %)\t\n Other\t7 (7 %)\t\nAntifungal at admission\t2 (2 %)\t\n Type of antifungal\t\n Fluconazole\t2 (2 %)\t\nAntipsychotic at admission\t6 (6 %)\t\n Type of antipsychotic\t\n Quetiapine\t4 (4 %)\t\n Other\t2 (2 %)\t\nInitial azithromycin dose\t\n 250 mg\t9 (9 %)\t\n 500 mg\t92 (89 %)\t\n Other\t2 (2 %)\t\nRoute of azithromycin administration\t\n IV\t42 (41 %)\t\n PO\t39 (38 %)\t\n Both\t22 (22 %)\t\nDays of azithromycin\t2 (1, 1, 4, 36)\t\nTotal dose of azithromycin (mg)\t1000 (250, 500, 2000, 9000)\t\nQTc at admission (ms)\t474 (423, 460, 495, 583)\t\nLongest QTc during admission (ms)\t485 (451, 464, 510, 583)\t\nLength of stay (days)\t3.2 (0.5, 2.1, 7.0, 148)\t\nThe sample median and descriptive statistics (minimum, 25th percentile, 75th percentile, maximum) are given for continuous variables\n\n\n\nOnly one patient with prolonged QTc developed sustained ventricular tachycardia following administration of azithromycin (0.97 %), and subsequently expired from the arrhythmia. This patient was critically ill with multiple co-morbidities including atrial fibrillation, dementia, severe aortic stenosis, and NYHA class IV congestive heart failure with systolic ejection fraction of 47 %. Prior to admission, he took no medications known to prolong the QTc interval but regularly consumed tea containing Zhi Gan Cao, or licorice root. This Chinese herb has been associated with cases of hypokalemia and even ventricular tachycardia and TdP [7]. The primary diagnoses at admission were altered mental status and sepsis, but during the hospitalization, the patient developed stress-related myocardial infarction. On admission the patient’s QTc was 486 ms but later increased to 550 ms. The EKG with QTc interval in excess of 500 ms was obtained after the patient developed self-terminating TdP. He received one 500 mg IV dose of azithromycin after the index arrhythmia and documentation of prolonged QTc. Recurrent ventricular tachycardia followed by asystolic arrest occurred the following day, 27 h after the IV dose of azithromycin (half-life of azithromycin is 68 h). Additionally, seven patients died from all-cause mortality (6.79 %) including one from pneumonia, one from renal failure, one from septic shock, and four from respiratory failure . The median time from first dose of azithromycin to the advent of all-cause mortality was 3 days (range 1–37). In all patients who died, the dose of azithromycin was 500 mg. Median length of hospitalization for the cohort was 3.2 days (range 0.5–148 days).\n\nDiscussion\nEach year in the USA, between 300,000 and 400,000 people experience sudden cardiac death (SCD) [8], which exceeds the combined mortality of breast cancer, prostate cancer, traffic accidents, firearms, and AIDS [9]. While most cases of SCD are related to underlying structural heart abnormalities or coronary artery disease, a substantial portion is due to arrhythmias [10, 11]. In the inpatient setting, four of every 1000 patients develop cardiac arrest, of which only 20–50 % are successfully resuscitated [12]. It has been reported that TdP, an insidious polymorphic ventricular arrhythmia, represents 6 % of in-hospital cardiac arrests [13], but the incidence may be higher, as fatal ventricular arrhythmias eventually degrade into pulseless electrical activity or asystole prior to documentation of the instigating dysrhythmia [14].\n\nTorsades de pointes can result from prolongation of the electrocardiographic QTc interval, which represents the period of both cardiac depolarization and repolarization [8, 15, 16]. Prolongation of the QTc interval is caused by extension of the myocyte action potential due to increased intracellular current or impairment of phase 3 Ik resulting in accumulation of intracellular potassium [17, 18]. The reduced outward current also imparts a risk for the development of early after-depolarization, in which an extrasystole during the prolonged QT may trigger TdP by re-entry [19]. The length of the QTc interval is dependent upon gender and normally less than 460 ms in women, and 450 ms in men [20]. Prolongation of the QTc interval beyond 500 ms substantially increases the risk of TdP. QTc prolongation may occur as a familial variant of long QT syndrome, but more is more often acquired [21].\n\nCommonly cited risk factors for acquired QTc prolongation include female gender, bradycardia, advanced age, electrolyte disturbances such as hypokalemia and hypomagnesemia, heart failure, and conditions that reduce the hepatic metabolism of medications [17, 19]. Medication-induced QTc prolongation is more common, with a myriad of agents having been implicated [21]. The risk of medication-induced TdP may be additive with polypharmacy, as the mechanism of QTc prolongation differs between drug classes [17]. As the population ages, polypharmacy is more abundant and hospitalizations become more frequent. In prior studies, 25 % of patients admitted to the hospital had QTc prolongation at time of admission, and nearly 20 % of those were admitted with a QTc greater than 500 ms [22]. A study showed the prevalence of prolonged QTc to be even higher in an acute geriatric ward [23]. Forty percent of hospitalized patients with a QTc greater than 500 ms have been observed to receive drugs associated with further prolongation of the QTc.\n\nThe most common agents that predispose to TdP are class I and III antiarrhythmics. These drugs are associated with TdP in more than 8 % of cases [15]. Of the non-cardiac drugs, it has been proposed that macrolides are the antibiotics with the greatest QTc prolonging potential [24]. This effect is multifactorial as macrolides not only block Ik channels, but are also metabolized by CYP3A4, an isoenzyme responsible for the metabolism of over 60 % of medications whose function is inhibited by many commonly prescribed drugs [25]. Macrolides are therefore more dangerous for those who simultaneously take CYP3A4 inhibitors or another QTc prolonging medication metabolized by this isoenzyme [17, 26]. For example, use of clarithromycin alone increases the QTc by 6 ms, but co-administration with cisapride, a prokinetic agent associated with QTc prolongation and also metabolized by CYP3A4, increases the QTc by 25 ms [27, 28].\n\nAzithromycin has been shown to have less effect on CYP3A4 and is more widely used than other macrolides [27, 29]. Between January 2002 and December 2011, azithromycin was mentioned 69,790,000 times during outpatient office visits in connection with bronchitis. This represented 40.6 % of all drugs cited for this diagnosis. During this time, azithromycin was second only to amoxicillin for treatment of sinusitis, and was mentioned 34,077,000 times [30]. In 2012, 40.3 million people were prescribed azithromycin [30]. Interestingly, the risk of sudden cardiac death observed with azithromycin occurred only within a typical 5-day course [5]. The rate of drug-induced TdP varies by medication class. In a population-based study of 605,127 people taking fluoroquinolone antibiotics, ventricular arrhythmias were detected in 180 patients and cardiac arrest occurred in 555 patients that had prior exposure to a quinolone. However, this study had an extensive immeasurable time bias between drug exposure and event rate and did not take into account the incidence of sustained ventricular tachycardia in patients with known prolonged QT who subsequently received the medication [31]. However, in our previous work of 1,004 patients evaluating the incidence of TdP in patients with prolonged QTc who subsequently received levofloxicin, 0.2 % of patients experienced sustained ventricular tachycardia [32]. This is in contrast to our current study noting an event rate of 0.97 %. The rate of ventricular arrhythmia in our study was far too small to speculate about potential risk factors that contribute to the development of ventricular tachycardia in patients with prolonged QTc who are given azithromycin. However, consistent with the risk noted by Ray et al. [5], our lone case of ventricular tachycardia occurred during a 5-day course of therapy.\n\nOur study included subjects with prolonged QTc, though we are uncertain if any patients within the cohort had a prior history of long QT syndrome. Although 43 % of patients in this study were taking antidepressants, antifungals or antipsychotics, we did not account for a number of other commonly prescribed drug classes such as antiemetics and prokinetics that also prolong the QTc. To fully account for all medications that influence cardiac repolarization would be a monumental undertaking [17, 33].\n\nAlthough the reasons why physicians in this study chose to use azithromycin in the presence of a prolonged QTc were not analyzed, the high degree of complexity and acuity of illness may have justified it. Furthermore, 58 % of patients in the cohort were admitted with a primary diagnosis of respiratory illness and 66 % of patients treated with azithromycin had pneumonia. Current guidelines for patients hospitalized with pneumonia recommend combination therapy with macrolides as first-line treatment [34] and emerging data suggest that azithromycin is associated with a reduction in 90-day mortality in patients with pneumonia [3]. However, this study was intended to provide new information on only the risk of sustained ventricular tachycardia in patients with prolonged QTc, not to partition the global risks and benefits of azithromycin which will vary by indication.\n\nOur study has several limitations. First, the size of the study may not be large enough to detect the true incidence of antibiotic-instigated TdP. Second, the retrospective nature of the study may introduce bias as it relies on accurate charting. Third, the incidence of antibiotic-induced Tdp is difficult to estimate, and the arrhythmia is often self-limited, and thus may be missed. Two-thirds of cases of SCD or syncope have no record of a preceding arrhythmia [15]. However, a high percentage of our patients were monitored on telemetry, which may have aided in the identification of ventricular tachycardia. In addition, all QTc values were measured by computer-based analysis. Well-designed algorithms can accurately assess the QTc 95 % of the time, and it has been suggested that the detection of drug-induced effects on ECG intervals is markedly enhanced by the use of computer-based analysis [35]. Fourth, patients with bundle branch blocks or implantable pacemakers were not analyzed independently. This may have led to an overestimation of subjects with prolonged QTc due to repolarization abnormalities. Fifth, as 91 % of our cohort was Caucasian, the results of this study may not be generalizable to all populations. Finally, only short-term, in-hospital outcomes were observed. The long-term occurrence of sustained ventricular tachycardia following administration of azithromycin in patients with prolonged QT is unknown. However, prior studies noted the risk of cardiac death associated with azithromycin is present only during a course of treatment [5].\n\nTo our knowledge, this is the first study that examined the incidence of ventricular tachycardia in patients with prolonged QTc who were subsequently given azithromycin. Although there is no consensus on the degree of QTc prolongation that is clinically significant, caution should be exercised when prescribing medications that further prolong the QTc interval [36]. The Mayo Clinic has adopted an institution-wide QTc alert system to notify providers when a patient has prolonged QTc. This system has determined that a QTc greater than 500 ms is a strong predictor of all-cause, inpatient mortality, as seen in the one event in this cohort. In fact, mortality rates in patients with critically long QTc intervals are greater with increasing numbers of modifiable risk factors for TdP (electrolyte disturbances, polypharmacy) [37]. There is evidence that these risk factors contribute to greater mortality than do non-modifiable factors such as age and gender. Institutional alert systems may help providers mitigate modifiable risk factors, or minimize unnecessary drug-drug interactions [37, 38]. Other drugs that prolong the QTc require providers to monitor the patient for ECG changes. For example, the antiarrhythmic dofetilide should only be started in the hospital setting with serial monitoring of the QTc and electrolytes [39]. A similar strategy could be useful when prescribing other QTc-prolonging medications in patients with a QTc greater than 500 ms.\n\nConclusion\nBased on the study results capturing patients treated with multiple doses of azithromycin in the setting of QTc prolongation over a 3-year period, we observed that the occurrence of sustained ventricular tachycardia in patients with prolonged QTc interval who subsequently received azithromycin may be less than 1 %. As azithromycin is widely prescribed and polypharmacy becomes more prevalent in the aging population, larger studies are needed to fully understand the implications of using macrolides in patients with prolonged QTc.\n\nCompliance with Ethical Standards\nAuthor contributions\nSteven Sears had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. Steven Sears, Trevor Getz, Christopher Austin, William Palmer, Evelyn Boyd, and Fernando Stancampiano contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript.\n\nEthical approval\nThe study was approved by the Mayo Clinic Institutional Review Board, study ID 14-005155. It has been performed in accordance with the ethical standards of the declaration of Helsinki.\n\nFunding\nNo sources of funding were used to assist in the preparation of this study.\n\nConflicts of interest\nSteven P. Sears, Trevor W. Getz, Christopher O. Austin, William C. Palmer, Evelyn A. Boyd, and Fernando F. Stancampiano have no conflicts of interest and nothing to disclose.\n==== Refs\nReferences\n1. Ray WA Murray KT Meredith S Narasimhulu SS Hall K Stein CM Oral erythromycin and the risk of sudden death from cardiac causes N Engl J Med 2004 351 11 1089 1096 10.1056/NEJMoa040582 15356306 \n2. Inserts P. Zithromax (azithromycin for oral and injection) Package Inserts 4763, 5179.5191.\n3. Ray WA Azithromycin associated with a reduction in 90-day mortality among older pneumonia patients, although a true clinical benefit is uncertain Evid Based Med. 2014 19 6 226 227 10.1136/ebmed-2014-110061 25121563 \n4. Poluzzi E Raschi E Moretti U De Ponti F Drug-induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS) Pharmacoepidemiol Drug Saf 2009 18 6 512 518 10.1002/pds.1746 19358226 \n5. Ray WA Murray KT Hall K Arbogast PG Stein CM Azithromycin and the risk of cardiovascular death N Engl J Med 2012 366 20 1881 1890 10.1056/NEJMoa1003833 22591294 \n6. Rautaharju PM Surawicz B Gettes LS Bailey JJ Childers R Deal BJ AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology J Am Coll Cardiol 2009 53 11 982 991 10.1016/j.jacc.2008.12.014 19281931 \n7. Eriksson JW Carlberg B Hillorn V Life-threatening ventricular tachycardia due to liquorice-induced hypokalaemia J Intern Med 1999 245 3 307 310 10.1046/j.1365-2796.1999.00476.x 10205594 \n8. Elming H Brendorp B Kober L Sahebzadah N Torp-Petersen C QTc interval in the assessment of cardiac risk Card Electrophysiol Rev. 2002 6 3 289 294 10.1023/A:1016345412555 12114854 \n9. Rakic D Rumboldt Z Carevic V Bagatin J Polic S Pivac N In-hospital cardiac arrest and resuscitation outcomes: rationale for sudden cardiac death approach Croat Med J. 2005 46 6 907 912 16342343 \n10. Myerburg RJ Kessler KM Castellanos A Sudden cardiac death: epidemiology, transient risk, and intervention assessment Ann Intern Med 1993 119 12 1187 1197 10.7326/0003-4819-119-12-199312150-00006 8239250 \n11. Zipes DP Wellens HJ Sudden cardiac death Circulation 1998 98 21 2334 2351 10.1161/01.CIR.98.21.2334 9826323 \n12. Zheng ZJ Croft JB Giles WH Mensah GA Sudden cardiac death in the United States, 1989 to 1998 Circulation 2001 104 18 2158 2163 10.1161/hc4301.098254 11684624 \n13. Pickham D Helfenbein E Shinn JA Chan G Funk M Weinacker A High prevalence of corrected QT interval prolongation in acutely ill patients is associated with mortality: results of the QT in Practice (QTIP) Study Crit Care Med 2012 40 2 394 399 10.1097/CCM.0b013e318232db4a 22001585 \n14. Anderson KP The changing epidemiology of ventricular arrhythmias Cardiol Clin. 2008 26 3 321 333 10.1016/j.ccl.2008.03.007 18538182 \n15. Shaffer D Singer S Korvick J Honig P Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System Clin Infect Dis 2002 35 2 197 200 10.1086/340861 12087527 \n16. Beitland S Platou ES Sunde K Drug-induced long QT syndrome and fatal arrhythmias in the intensive care unit Acta Anaesthesiol Scand 2014 58 3 266 272 10.1111/aas.12257 24397608 \n17. Gupta A Lawrence AT Krishnan K Kavinsky CJ Trohman RG Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes Am Heart J 2007 153 6 891 899 10.1016/j.ahj.2007.01.040 17540188 \n18. Owens RC Jr QT prolongation with antimicrobial agents: understanding the significance Drugs. 2004 64 10 1091 1124 10.2165/00003495-200464100-00005 15139788 \n19. Haverkamp W Breithardt G Camm AJ Janse MJ Rosen MR Antzelevitch C The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology Eur Heart J 2000 21 15 1216 1231 10.1053/euhj.2000.2249 10924311 \n20. Al-Khatib SM LaPointe NM Kramer JM Califf RM What clinicians should know about the QT interval JAMA. 2003 289 16 2120 2127 10.1001/jama.289.16.2120 12709470 \n21. Armahizer MJ Seybert AL Smithburger PL Kane-Gill SL Drug-drug interactions contributing to QT prolongation in cardiac intensive care units J Crit Care 2013 28 3 243 249 10.1016/j.jcrc.2012.10.014 23312127 \n22. Tisdale JE Wroblewski HA Overholser BR Kingery JR Trujillo TN Kovacs RJ Prevalence of QT interval prolongation in patients admitted to cardiac care units and frequency of subsequent administration of QT interval-prolonging drugs: a prospective, observational study in a large urban academic medical center in the US Drug Saf 2012 35 6 459 470 10.2165/11598160-000000000-00000 22612851 \n23. Lubart E Segal R Yearovoi A Fridenson A Baumoehl Y Leibovitz A QT interval disturbances in hospitalized elderly patients Isr Med Assoc J. 2009 11 3 147 150 19544703 \n24. Owens RC Jr Risk assessment for antimicrobial agent-induced QTc interval prolongation and torsades de pointes Pharmacotherapy. 2001 21 3 301 319 10.1592/phco.21.3.301.34206 11253855 \n25. Dresser GK Spence JD Bailey DG Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition Clin Pharmacokinet 2000 38 1 41 57 10.2165/00003088-200038010-00003 10668858 \n26. Stanat SJ Carlton CG Crumb WJ Jr Agrawal KC Clarkson CW Characterization of the inhibitory effects of erythromycin and clarithromycin on the HERG potassium channel Mol Cell Biochem 2003 254 1–2 1 7 10.1023/A:1027309703313 14674677 \n27. Owens RC Jr Nolin TD Antimicrobial-associated QT interval prolongation: pointes of interest Clin Infect Dis 2006 43 12 1603 1611 10.1086/508873 17109296 \n28. Desta Z Kerbusch T Flockhart DA Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6) Clin Pharmacol Ther 1999 65 1 10 20 10.1016/S0009-9236(99)70117-7 9951426 \n29. Harris S Hilligoss DM Colangelo PM Eller M Okerholm R Azithromycin and terfenadine: lack of drug interaction Clin Pharmacol Ther 1995 58 3 310 315 10.1016/0009-9236(95)90247-3 7554704 \n30. Mosholder AD Mathew J Alexander JJ Smith H Nambiar S Cardiovascular risks with azithromycin and other antibacterial drugs N Engl J Med 2013 368 18 1665 1668 10.1056/NEJMp1302726 23635046 \n31. Lapi F Wilchesky M Kezouh A Benisty JI Ernst P Suissa S Fluoroquinolones and the risk of serious arrhythmia: a population-based study Clin Infect Dis 2012 55 11 1457 1465 10.1093/cid/cis664 22865870 \n32. Stancampiano FF Palmer WC Getz TW Serra-Valentin NA Sears SP Seeger KM Rare Incidence of Ventricular Tachycardia and Torsades de Pointes in Hospitalized Patients With Prolonged QT Who Later Received Levofloxacin: a Retrospective Study Mayo Clin Proc 2015 90 5 606 612 10.1016/j.mayocp.2015.02.011 25863416 \n33. Kallergis EM Goudis CA Simantirakis EN Kochiadakis GE Vardas PE Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review Sci World J 2012 2012 212178 10.1100/2012/212178 \n34. Mandell LA Wunderink RG Anzueto A Bartlett JG Campbell GD Dean NC Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults Clin Infect Dis 2007 1 44 Suppl 2 S27 S72 10.1086/511159 17278083 \n35. Guth BD Bass AS Briscoe R Chivers S Markert M Siegl PK Comparison of electrocardiographic analysis for risk of QT interval prolongation using safety pharmacology and toxicological studies J Pharmacol Toxicol Methods. 2009 60 2 107 116 10.1016/j.vascn.2009.05.006 19470407 \n36. Malik M Camm AJ Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling Drug Saf 2001 24 5 323 351 10.2165/00002018-200124050-00001 11419561 \n37. Haugaa KH Bos JM Tarrell RF Morlan BW Caraballo PJ Ackerman MJ Institution-wide QT alert system identifies patients with a high risk of mortality Mayo Clin Proc 2013 88 4 315 325 10.1016/j.mayocp.2013.01.013 23541006 \n38. Giudicessi JR Ackerman MJ Azithromycin and risk of sudden cardiac death: guilty as charged or falsely accused? Cleve Clin J Med. 2013 80 9 539 544 10.3949/ccjm.80a.13077 24001961 \n39. Friedman L Alexander E Update of the clinical impact and issues surrounding Dofetilide (Tikosyn) therapy AACN Adv Crit Care. 2006 17 2 102 108 10.1097/01256961-200604000-00002 16767008\n\n",
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"title": "Incidence of Sustained Ventricular Tachycardia in Patients with Prolonged QTc After the Administration of Azithromycin: A Retrospective Study.",
"title_normalized": "incidence of sustained ventricular tachycardia in patients with prolonged qtc after the administration of azithromycin a retrospective study"
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"abstract": "Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud's Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance of myocardial fibrosis after sudden interruption of sildenafil treatment.",
"affiliations": "Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Firenze. cosimobruni85@gmail.com.",
"authors": "Bruni|C|C|;Bellando-Randone|S|S|;Gargani|L|L|;Picano|E|E|;Pingitore|A|A|;Matucci-Cerinic|M|M|;Guiducci|S|S|",
"chemical_list": "D018501:Antirheumatic Agents; D000068677:Sildenafil Citrate",
"country": "Italy",
"delete": false,
"doi": "10.4081/reumatismo.2016.889",
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"issue": "68(2)",
"journal": "Reumatismo",
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"mesh_terms": "D018501:Antirheumatic Agents; D009202:Cardiomyopathies; D005385:Fingers; D006801:Humans; D007511:Ischemia; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D011928:Raynaud Disease; D012307:Risk Factors; D012595:Scleroderma, Systemic; D000068677:Sildenafil Citrate; D013375:Substance Withdrawal Syndrome; D013997:Time Factors",
"nlm_unique_id": "0401302",
"other_id": null,
"pages": "109-11",
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"pmid": "27608801",
"pubdate": "2016-09-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Critical finger ischemia and myocardial fibrosis development after sudden interruption of sildenafil treatment in a systemic sclerosis patient.",
"title_normalized": "critical finger ischemia and myocardial fibrosis development after sudden interruption of sildenafil treatment in a systemic sclerosis patient"
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"abstract": "BACKGROUND\nAlveolar echinococcosis is a potentially lethal zoonosis caused by larval forms of the tapeworm Echinococcus multilocularis. Humans are aberrant intermediate hosts who become infected by ingestion of egg-contaminated food or water or via physical contact with domestic or wild animals that carry the parasite in their small intestine. In humans, the disease usually affects the liver and can spread to other organs causing metastatic infiltration. In this report, we describe an advanced presentation of human alveolar echinococcosis mimicking metastatic malignancy.\n\n\nMETHODS\nA 62-year-old white woman was evaluated for fever, jaundice, and abdominal pain, associated with significant weight loss. She lived in a rural area in Switzerland and used to eat wild forest fruits and mushrooms. She owned cats that used to hunt rodents. On physical examination, she appeared severely ill with cachexia, altered mental status, jaundice, and massive hepatomegaly. Laboratory tests showed cholestasis with preserved liver function. An abdominal computed tomography scan showed an enlarged liver with a huge cystic mass in the right lobe extending into the left lobe, infiltrating her hepatic hilum, causing intrahepatic bile duct dilation and occlusion of her right portal vein. A chest computed tomography scan showed multiple calcified bilateral pulmonary nodules. Her clinical and radiological presentation resembled an advanced neoplastic disease. Serologic tests for Echinococcus multilocularis were positive. The diagnosis of alveolar echinococcosis was established on her past history of exposure, imaging, and serology results.\n\n\nCONCLUSIONS\nClinical presentation and radiologic imaging findings of disseminated alveolar echinococcosis can mimic metastatic malignancy, and diagnosis can be challenging in atypically advanced cases. As the incidence of human alveolar echinococcosis appears to be increasing in Europe and Switzerland, physicians should be aware of alveolar echinococcosis, its epidemiology, and its clinical features.",
"affiliations": "Service de médecine interne générale, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Service de médecine interne générale, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland. doctoreche@hotmail.com.;Service de médecine tropicale et humanitaire, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Service de médecine interne générale, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Service de pathologie clinique, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Service de pathologie clinique, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.;Service de médecine tropicale et humanitaire, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.",
"authors": "Caire Nail|Laura|L|;Rodríguez Reimundes|Ezequiel|E|;Weibel Galluzzo|Christelle|C|;Lebowitz|Dan|D|;Ibrahim|Yasmine Lucile|YL|;Lobrinus|Johannes Alexander|JA|;Chappuis|François|F|",
"chemical_list": "D000871:Anthelmintics; D015766:Albendazole",
"country": "England",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 127910.1186/s13256-017-1279-2Case ReportDisseminated alveolar echinococcosis resembling metastatic malignancy: a case report Caire Nail Laura laura.nail@hcuge.ch 1Rodríguez Reimundes Ezequiel doctoreche@hotmail.com 1Weibel Galluzzo Christelle chrisweibel4@gmail.com 2Lebowitz Dan dan.lebowitz@hcuge.ch 1Ibrahim Yasmine Lucile yasminelucile.ibrahim@hcuge.ch 3Lobrinus Johannes Alexander johannes.a.lobrinus@hcuge.ch 3Chappuis François francois.chappuis@hcuge.ch 21 grid.150338.cService de médecine interne générale, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland 2 grid.150338.cService de médecine tropicale et humanitaire, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland 3 grid.150338.cService de pathologie clinique, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland 18 4 2017 18 4 2017 2017 11 11324 4 2016 12 12 2016 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAlveolar echinococcosis is a potentially lethal zoonosis caused by larval forms of the tapeworm Echinococcus multilocularis.\n\nHumans are aberrant intermediate hosts who become infected by ingestion of egg-contaminated food or water or via physical contact with domestic or wild animals that carry the parasite in their small intestine. In humans, the disease usually affects the liver and can spread to other organs causing metastatic infiltration. In this report, we describe an advanced presentation of human alveolar echinococcosis mimicking metastatic malignancy.\n\nCase presentation\nA 62-year-old white woman was evaluated for fever, jaundice, and abdominal pain, associated with significant weight loss. She lived in a rural area in Switzerland and used to eat wild forest fruits and mushrooms. She owned cats that used to hunt rodents.\n\nOn physical examination, she appeared severely ill with cachexia, altered mental status, jaundice, and massive hepatomegaly. Laboratory tests showed cholestasis with preserved liver function.\n\nAn abdominal computed tomography scan showed an enlarged liver with a huge cystic mass in the right lobe extending into the left lobe, infiltrating her hepatic hilum, causing intrahepatic bile duct dilation and occlusion of her right portal vein. A chest computed tomography scan showed multiple calcified bilateral pulmonary nodules. Her clinical and radiological presentation resembled an advanced neoplastic disease. Serologic tests for Echinococcus multilocularis were positive.\n\nThe diagnosis of alveolar echinococcosis was established on her past history of exposure, imaging, and serology results.\n\nConclusions\nClinical presentation and radiologic imaging findings of disseminated alveolar echinococcosis can mimic metastatic malignancy, and diagnosis can be challenging in atypically advanced cases. As the incidence of human alveolar echinococcosis appears to be increasing in Europe and Switzerland, physicians should be aware of alveolar echinococcosis, its epidemiology, and its clinical features.\n\nKeywords\nAlveolar echinococcosisEchinococcus multilocularisZoonosisMalignant mimicsissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nAlveolar echinococcosis (AE) is a potentially lethal zoonosis of the northern hemisphere caused by larval forms (metacestodes) of the tapeworm Echinococcus multilocularis.\n\nThe parasite resides in the small intestine of the definitive hosts, either carnivorous wild animals, such as foxes, or domestic animals, such as dogs and cats, which excrete eggs in their stools. They become infected while eating contaminated wild rodents, the natural intermediate host. After ingestion by the intermediate host, the eggs hatch in the small intestine and release oncospheres that migrate to the tissues where they develop cysts. Humans are aberrant hosts that replace the natural intermediate host in the parasite life cycle. In humans, E. multilocularis cysts grow very slowly, resulting in an incubation period of 5 to 15 years. The disease usually affects the liver producing an alveolar-like pattern of microvesicles. The parasite can spread from the liver to other organs causing metastatic infiltration [1–4].\n\nHumans are infected by ingestion of egg-contaminated food or water or via physical contact with domestic or wild animals that have eaten infected animals. The role of foxes in the zoonotic transmission of AE appears to be important, as demonstrated by the increase of AE incidence in humans and natural intermediate hosts following an increase in the population of foxes in some regions of Europe over the last 20 years [5].\n\nCase presentation\nA 62-year-old white woman was evaluated in a Swiss regional hospital for fever, itching, jaundice, and abdominal pain, associated with significant weight loss (15% of total body weight in the last 3 months). Progressive right upper quadrant discomfort had been present for the last 5 years but she did not seek medical advice.\n\nShe had no past medical history and did not take any medication. She lived in a rural area in Switzerland and used to eat wild forest fruits and mushrooms. She owned cats that used to hunt rodents. She had no known underlying immunosuppression and declared no risk factors for human immunodeficiency virus (HIV) infection.\n\nOn physical examination, she appeared severely ill with cachexia, altered mental status, skin and mucous jaundice, and massive hepatomegaly. Laboratory tests showed lymphopenia (0.77 G/l; normal range 1 to 4.5) with normal eosinophil count, as well as cholestasis with preserved liver function: total bilirubin 135 μmol/L (reference value 7 to 25), direct bilirubin 64 μmol/L (0 to 10), aspartate aminotransferase 40 U/L (11 to 42), alanine aminotransferase 49 U/L (9 to 42), alkaline phosphatase 802 U/L (25 to 102), gamma glutamyl transferase 376 U/L (9 to 35), prothrombin time 43% (>70%), and factor V >100% (>70%). A HIV test was not done.\n\nAn abdominal computed tomography (CT) scan showed an enlarged liver with a 15 cm cystic mass in the right lobe with finely lobulated contours, and perilesional calcifications. The lesion extended into the left lobe, infiltrating her hepatic hilum, causing intrahepatic bile duct dilation, compression of her inferior vena cava and left branch of her portal vein, and occlusion of her right portal vein. Ascites was also present (Fig. 1). A chest CT scan showed multiple calcified pulmonary nodules up to 50 mm in diameter, some of which were cavitated (Fig. 2). An enzyme-linked immunosorbent assay (ELISA) and Western blot for E. multilocularis (EgP, EgHF and Em18 antigens) were positive. ELISA for Echinococcus granulosus was also positive but this was considered a cross-reaction. No other serological test was done. She was referred to our center for bile duct drainage, surgical evaluation, and initiation of anti-parasitic treatment.Fig. 1 Abdominal computed tomography scan showing hepatomegaly with a 15 cm cystic mass in the right lobe with finely lobulated contours, and perilesional calcifications. The lesion extended into the left lobe of the liver, infiltrating the hepatic hilum, and provoking intrahepatic bile ducts dilatation, compression of the inferior cava vein and the left branch of the portal vein, and occlusion of the right portal vein\n\n\nFig. 2 Thorax computed tomography scan showing multiple calcified pulmonary nodules up to 50 mm in diameter, some of which were cavitated\n\n\n\n\nThe diagnosis of AE was established on her past history of exposure, imaging, and serology results. Treatment with albendazole was started at a dose of 10 mg/kg per day with close follow-up of her liver function and blood count. The disease was classified as PNM stage IV (P4, N1, M1) according to the World Health Organization (WHO) classification. The extent of the disease and her bad general condition precluded liver transplantation. She benefited from an endoscopic drainage of her bile ducts with a bile stent placement leading to partial relief of pain and itching. Disease activity was assessed using an 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan, showing multiple hypermetabolic lesions affecting both lungs, and a voluminous heterogeneous right hepatic lesion composed of tissue, liquid, and calcified elements with intense hypermetabolism of its circumference (Fig. 3).Fig. 3 \n18F-fluorodeoxyglucose-positron emission tomography scanning showing multiple hypermetabolic lesions affecting both lungs, and a voluminous heterogeneous right hepatic lesion composed of tissue, liquid, and calcified elements surrounded by a ring of intense hypermetabolism\n\n\n\n\nShe developed agranulocytosis due to supratherapeutic plasma levels of albendazole sulfoxide and had severe oropharyngeal candidiasis. She then developed fever and abdominal pain. An abdominal CT scan showed gas bubbles within the cyst, evoking a bile duct bacterial infection.\n\nA percutaneous drain was placed in the cyst. The procedure was complicated by Escherichia coli bacteremia associated with septic shock. She was admitted in the intensive care unit and her clinical course was further complicated by acute hepatic and kidney failure, encephalopathy, coagulopathy, and pulmonary embolism. Palliative care was provided and she died in the following days.\n\nAn autopsy was performed. Macroscopic and microscopic examination confirmed AE and showed no evidence of neoplasia. At the pulmonary level, the autopsy found AE with cystic, necrotic, and focally calcified lesions of the three lobes of her right lung and the upper lobe of her left lung, measuring up to 4.5 cm in diameter (Fig. 4). Examination of her liver showed cystic AE partially necrotic in the right lobe measuring 18.5 × 18 × 13 cm (Fig. 5). No other organ involvement was identified at autopsy.Fig. 4 Sagittal section of the right lung showing cystic, necrotic, and focally calcified lesions of the three lobes measuring up to 4.5 cm in diameter\n\n\nFig. 5 Liver section showing a cystic, partially necrotic lesion of the right lobe measuring 18.5 × 18 × 13 cm\n\n\n\n\nOn histological examination of the pulmonary and hepatic lesions, irregular cysts containing periodic acid–Schiff (PAS)-positive laminated membranes were seen. These cysts were surrounded by an extensive peripheral fibrosis with fibroblasts, inflammatory cells, focal calcifications, and necrosis (Figs. 6, 7). Some of the cavitary pulmonary lesions were colonized by Aspergillus species.Fig. 6 Histological examination of pulmonary cystic lesions (hematoxylin eosin) shows extensive fibrosis with inflammatory cells and necrosis surrounding alveolar echinococcosis cysts that contain laminated membranes\n\n\nFig. 7 Histological examination of pulmonary cystic lesions shows laminated membranes in alveolar echinococcosis cysts delineated by periodic acid–Schiff stain\n\n\n\n\nDiscussion\nThis case illustrates the cancer-like presentation of E. multilocularis with infiltrative growth and metastatic spread.\n\nIn a case-control study performed in Germany the following risk factors for acquiring AE were identified: working as a farmer, living in a farmhouse, owning dogs that kill game, owning dogs and cats that roam outdoors unattended, collecting wood, chewing grass, living close to fields, walking in the woods for recreational reasons, growing leaf or root vegetables, and eating unwashed strawberries [6]. Some of these risk factors were present in our patient.\n\nAn initial asymptomatic incubation period of 5 to 15 years and a subsequent chronic course are typical of AE. E. multilocularis larvae proliferate like a slow-growing liver tumor, with a high mortality rate (about 90% at 10 years of diagnosis) in the absence of curative surgery and anti-helminthic treatment. Numerous local complications can occur, including biliary obstruction, cholangitis, sepsis, portal hypertension, and Budd–Chiari syndrome. Extrahepatic locations are rare [7].\n\nDiagnosis of AE is based on clinical findings and epidemiological data, imaging studies, histopathology, nucleic acid detection, and serology. FDG-PET scanning demarcates areas of parasitic activity and is useful to assess the response to treatment. It is noteworthy that FDG-PET indicates suppressed inflammatory activity rather than parasite eradication [4]. In our patient, FDG-PET showed intense metabolic activity in pulmonary and hepatic lesions.\n\nThe WHO Informal Working Group on Echinococcosis (IWGE) PNM classification system, based on imaging findings, has been established to standardize diagnostic and therapeutic measures. It denotes the parasitic mass in the liver (P), the involvement of neighboring organs (N), and metastases (M), thus highlighting the malignant nature of AE.\n\nTreatment should be planned within a multidisciplinary team that should include at least a surgeon, radiologist, hepatologist, and infectious-diseases physician with extensive experience in clinical parasitology. Radical surgery is the treatment of choice. However, surgery is reserved for early-stage disease when lesions can be completely resected with a safe (≥2 cm) margin of unaffected tissue and no distant metastases. Complete surgical resection of the parasite at an early stage of infection provides favorable prospects for cure, but since most cases are detected at an advanced stage, curative surgery can be performed in only 35% of patients. Non-radical liver surgery, previously regarded as beneficial for reducing the parasitic mass, does not appear to offer advantages over conservative treatment. Palliative surgery is almost always contraindicated [4].\n\nLiver transplantation has been performed in patients with inoperable lesions and/or chronic liver failure. However, immunosuppression may favor growth of larval remnants and metastases [8, 9]. Our patient was neither eligible for radical resection nor for liver transplantation due to the disseminated disease and her altered general condition associated with incurable biliary tract infection.\n\nLong-term benzimidazole (preferably with albendazole) treatment is mandatory in all inoperable patients as well as following radical surgery. Frequent adverse effects include alopecia, hepatotoxicity, and neutropenia, as observed in our patient. Screening for adverse reactions such as liver tests alterations and leukopenia is recommended every 2 weeks during the first 3 months of treatment, then monthly during the first year, then every 3 months [4]. Albendazole is metabolized in the liver to albendazole sulfoxide. Blood levels of this active metabolite should be monitored in all patients, especially in the case of hepatocellular dysfunction and/or cholestasis. Albendazole is parasitostatic and rarely eliminates E. multilocularis. Lifelong treatment is thus generally required to inhibit or at least suppress parasite growth in patients who cannot benefit from radical surgery. For the latter, albendazole treatment can be stopped after 2 years. Despite its limited efficacy, long-term albendazole therapy has improved the life expectancy of patients with AE to a near-normal level [10].\n\nPatients undergoing radical surgery have a better outcome, whereas older patients have a poorer prognosis than younger patients [10]. One study showed that the presence of metastasis is not an independent prognostic factor for AE-related mortality [11]. Two recent studies performed in Switzerland and France showed a drastic improvement of AE prognosis in the last years [10, 11].\n\nConclusions\nClinical presentation and radiologic imaging findings of disseminated AE can mimic metastatic malignancy, as described in our patient. As the incidence of human AE appears to be increasing in Europe and Switzerland [5, 12] and as diagnosis can be challenging in atypically advanced cases, physicians should be aware of AE, its epidemiology, and its clinical features. Treatment consists of chemotherapy with albendazole and/or hepatic surgery based on a multidisciplinary decision.\n\nAbbreviations\nAEAlveolar echinococcosis\n\nCTComputed tomography\n\nELISAEnzyme-linked immunosorbent assay\n\nFDG-PETFluorodeoxyglucose-positron emission tomography\n\nIWGEInformal Working Group on Echinococcosis\n\nPASPeriodic acid–Schiff\n\nWHOWorld Health Organization\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nOriginal medical imaging will not be shared because it is not fully anonymous.\n\nAuthors’ contributions\nLCN, ERR, CWG, DL, and FC managed the patient. YLI and JAL performed the autopsy as well as the macroscopic and histological examinations. All authors have been involved in drafting the manuscript and revising it critically. All authors approved the final version to be published.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent for publication could not be obtained from our deceased patient’s next-of-kin despite all reasonable attempts. Every effort has been made to protect the identity of our patient and there is no reason to believe that our patient would have objected to publication.\n\nEthics approval and consent to participate\nApproval from our local ethics committee for publication was obtained.\n==== Refs\nReferences\n1. Moro P Schantz PM Echinococcosis: a review Int J Infect Dis 2009 13 125 33 10.1016/j.ijid.2008.03.037 18938096 \n2. Chappuis F Echinococcosis: the threat of the urban fox Rev Med Suisse 2012 8 989 93 22662627 \n3. McManus DP Zhang W Li J Barthley PB Echinococcosis Lancet 2003 362 1295 304 10.1016/S0140-6736(03)14573-4 14575976 \n4. Brunetti E Kern P Vuiton DM Writing Panel for the WHO-IWGE Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans Acta Trop 2010 114 1 16 10.1016/j.actatropica.2009.11.001 19931502 \n5. Schweiger A Ammann RW Candinas D Clavien PA Eckert J Gottstein B Halkic N Muellhaupt B Prinz BM Reichen J Tarr PE Torgerson PR Deplazes P Human alveolar echinococcosis after fox population increase, Switzerland Emerg Infect Dis 2007 13 6 878 82 10.3201/eid1306.061074 17553227 \n6. Kern P Ammon A Kron M Sinn G Sander S Petersen LR Gaus W Kern P Risk factors for alveolar echinococcosis in humans Emerg Infect Dis 2004 10 12 2088 93 15663843 \n7. Bresson-Hadni S Vuitton DA Bartholomot B Heyd B Godart D Meyer JP Hrusovsky S Becker MC Mantion G Lenys D Miguet JP A twenty-year history of alveolar echinococcosis: Analysis of a series of 117 patients from eastern France Eur J Gastroenterol Hepatol 2000 12 327 36 10.1097/00042737-200012030-00011 10750654 \n8. Bresson-Hadni S Blagosklonov O Knapp J Should possible recurrence of disease contraindicate liver transplantation in patients with end-stage alveolar echinococcosis? A 20-year follow-up study Liver Transpl 2011 17 855 65 10.1002/lt.22299 21455928 \n9. Koch S Bresson-Hadni S Miguet JP Experience of liver transplantation for incurable alveolar echinococcosis: a 45-case European collaborative report Transplantation 2003 75 856 63 10.1097/01.TP.0000054230.63568.79 12660515 \n10. Torgerson PR Schweiger A Deplazes P Pohar M Reichen J Ammann RW Tarr PE Halkik N Müllhaupt B Alveolar echinococcosis: from a deadly disease to a well-controlled infection. Relative survival and economic analysis in Switzerland over the last 35 years J Hepatol 2008 49 1 72 7 10.1016/j.jhep.2008.03.023 18485517 \n11. Piarroux M Piarroux R Giorgi R Knapp J Bardonnet K Sudre B Watelet J Dumortier J Gérard A Beytout J Abergel A Mantion G Vuitton DA Bresson-Hadni S Clinical features and evolution of alveolar echinococcosis in France from 1982 to 2007: results of a survey in 387 patients J Hepatol 2011 55 5 1025 33 10.1016/j.jhep.2011.02.018 21354448 \n12. Gottstein B Stojkovic M Vuitton DA Millon L Marcinkute A Deplazes P Threat of alveolar echinococcosis to public health – a challenge for Europe Trends Parasitol 2015 31 9 407 12 10.1016/j.pt.2015.06.001 26115902\n\n",
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"keywords": "Alveolar echinococcosis; Echinococcus multilocularis; Malignant mimics; Zoonosis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D015766:Albendazole; D000818:Animals; D000871:Anthelmintics; D001652:Bile Ducts; D002415:Cats; D003937:Diagnosis, Differential; D004322:Drainage; D004443:Echinococcosis; D019353:Endemic Diseases; D017809:Fatal Outcome; D005247:Feeding Behavior; D005260:Female; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D008875:Middle Aged; D009102:Multiple Organ Failure; D016609:Neoplasms, Second Primary; D012772:Shock, Septic; D013557:Switzerland",
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"title": "Disseminated alveolar echinococcosis resembling metastatic malignancy: a case report.",
"title_normalized": "disseminated alveolar echinococcosis resembling metastatic malignancy a case report"
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"abstract": "Small-cell lung cancer (SCLC) is highly sensitive to platinum-based chemotherapy. However, its indication in patients with a poor performance status (PS) at initial diagnosis is controversial. We retrospectively reviewed all clinical courses of pathologically diagnosed SCLC patients with poor PS, Eastern Cooperative Oncology Group PS 3 and 4. Among 18 patients, 12 were treated with chemotherapy and 6 with supportive care alone. During the chemotherapy courses, PS improved in 7 (58.3%, including the PS 4 cases), remained stable in 2 (16.7%), and deteriorated in 3 (25%) patients. Moreover, 5 patients showed partial responses to chemotherapy (response rate of 41.7%). Grade 3-4 neutropenia developed in 10 (83.3%) patients and grade 3 febrile neutropenia occurred in 5 (41.7%) patients, but no grade 4 non-hematological toxicity was noted. Mortality associated with lung toxicity (grade 5) due to treatment occurred in a 77-year-old-male patient with PS 3. No substantial difference in survival was observed between patients with PS 3 and 4, even when including those treated with supportive care alone. Treatment had a positive effect on survival: after chemotherapy, the 6-month survival rate of PS 3 and 4 patients was 66.7%. In contrast, all patients treated with supportive care alone died within 5 months. These findings suggest that chemotherapy is indicated in selected SCLC patients not only with PS 3, but also with PS 4.",
"affiliations": "Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.",
"authors": "Aida|Yuka|Y|;Nakazawa|Kensuke|K|;Shiozawa|Toshihiro|T|;Ogawa|Ryoko|R|;Kiwamoto|Takumi|T|;Morishima|Yuko|Y|;Sakamoto|Toru|T|;Sekine|Ikuo|I|;Hizawa|Nobuyuki|N|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000501548cro-0012-0613Case ReportSmall-Cell Lung Cancer Treatment of Newly Diagnosed Patients with Poor Performance Status Aida Yuka abNakazawa Kensuke aShiozawa Toshihiro aOgawa Ryoko aKiwamoto Takumi aMorishima Yuko aSakamoto Toru aSekine Ikuo b*Hizawa Nobuyuki aaDepartment of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, JapanbDepartment of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan*Ikuo Sekine, MD, PhD, Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575 (Japan), E-Mail isekine@md.tsukuba.ac.jpMay-Aug 2019 6 8 2019 6 8 2019 12 2 613 620 15 6 2019 18 6 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This 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.Small-cell lung cancer (SCLC) is highly sensitive to platinum-based chemotherapy. However, its indication in patients with a poor performance status (PS) at initial diagnosis is controversial. We retrospectively reviewed all clinical courses of pathologically diagnosed SCLC patients with poor PS, Eastern Cooperative Oncology Group PS 3 and 4. Among 18 patients, 12 were treated with chemotherapy and 6 with supportive care alone. During the chemotherapy courses, PS improved in 7 (58.3%, including the PS 4 cases), remained stable in 2 (16.7%), and deteriorated in 3 (25%) patients. Moreover, 5 patients showed partial responses to chemotherapy (response rate of 41.7%). Grade 3–4 neutropenia developed in 10 (83.3%) patients and grade 3 febrile neutropenia occurred in 5 (41.7%) patients, but no grade 4 non-hematological toxicity was noted. Mortality associated with lung toxicity (grade 5) due to treatment occurred in a 77-year-old-male patient with PS 3. No substantial difference in survival was observed between patients with PS 3 and 4, even when including those treated with supportive care alone. Treatment had a positive effect on survival: after chemotherapy, the 6-month survival rate of PS 3 and 4 patients was 66.7%. In contrast, all patients treated with supportive care alone died within 5 months. These findings suggest that chemotherapy is indicated in selected SCLC patients not only with PS 3, but also with PS 4.\n\nKeywords\nSmall-cell lung cancerPoor performance statusPlatinumChemotherapySupportive care\n==== Body\nIntroduction\nSmall-cell lung cancer (SCLC) accounts for about 13% of all lung cancers in Japan, although its incidence has been gradually declining [1]. As it spreads rapidly to other body parts, more than 60% of newly diagnosed SCLC patients present extensive disease [2]. Moreover, the prognosis of these patients is very poor with a median survival of only 1–2 months on supportive care alone [3].\n\nEver since a significant survival benefit with cyclophosphamide monotherapy was shown in a randomized trial in 1960s [4], chemotherapy has been universally used to treat SCLC patients in a good general condition. Although SCLC is highly sensitive to platinum-based chemotherapy, its indication in patients with a poor performance status (PS, Eastern Cooperative Oncology Group [ECOG] PS 3 and 4) at initial diagnosis is still controversial, due to high treatment-related mortality risk of such patients [5, 6].\n\nThere has been only one randomized trial that evaluated platinum-based chemotherapy for poor-risk SCLC treatment in PS 3 patients <70 years of age) and PS 0–2 (ECOG, good PS) patients ≥70 years of age. In this study, a subgroup analysis showed a median overall survival of 7.1 months in the patients with PS 3 treated with carboplatin and etoposide, and of 6.9 months in those treated with cisplatin and etoposide, without death occurrence due to toxicity of either treatment [7]. Regarding the results of a retrospective case series, the objective response rate to combined platinum and etoposide chemotherapy was 67% and the median overall survival was 2.1 months in patients with PS 3, which corresponded to 20% and 7 days, respectively, in those with PS 4. Additionally, 20% of PS 3 patients and 60% of PS 4 patients died shortly after the first chemotherapy cycle [8]. Moreover, in another case series study of the effect of chemotherapy on poor-risk SCLC, the objective response rate and median overall survival were 75% and 8.4 months, respectively, in patients with PS 3, in contrast to 40% and 4.8 months, respectively, in those with PS 4 [9]. In addition, one patient with each PS died due to chemotherapy-related toxicity [9]. All these studies show discrepant results, which may be attributable to differences in patients' characteristics between clinical trials and clinical practice. Nonetheless, this issue should be addressed carefully to achieve a standard clinical treatment for such debilitated patients. Furthermore, only patients who received chemotherapy were included in these studies, however, best supportive care in clinical settings is also an alternative treatment to consider.\n\nTherefore, the main objective of our retrospective case series study was to evaluate the clinical courses of extensive SCLC patients with poor PS at initial diagnosis in order to identify optimal treatment options.\n\nPatients and Methods\nWe conducted a retrospective review of the clinical data of 18 pathologically diagnosed SCLC patients with poor PS, ECOG PS 3 and 4, treated at University of Tsukuba Hospital between April 2000 and May 2017.\n\nThe data collected from medical records of our hospital were as follows: medical history, physical examination on admission, pathological diagnosis, laboratorial and radiological findings, treatment regimen and respective adverse events/toxicity, ECOG PS grade variation (before and during chemotherapy), and patient's clinical course.\n\nFurthermore, tumor responses to treatment were evaluated according to World Health Organization response criteria [10]. Treatment toxicities were evaluated according to Common Terminology Criteria for Adverse Events version 4.0.\n\nThe overall survival was determined from the pathological diagnosis to patient's death or last follow-up.\n\nStatistical analyses were performed with Statistical Package for Social Sciences Soft Ware version 25.0. Survival curves were estimated by the Kaplan-Meier method and compared by the log rank test.\n\nResults\nPatient Characteristics\nAmong 142 patients diagnosed with SCLC by cytological or histological examination at out hospital, 12 had a PS 3 and 6 had a PS 4 at initial diagnosis. Table 1 summarizes the characteristics of the patients considered for study. Overall, 14 males and 4 females were included, with a median age of 73 years. There were no large differences in age, gender, or tumor-related factors between patients with PS 3 and 4.\n\nTreatment\nTwelve patients, with both PS3 and 4, were treated with chemotherapy and 6 patients with best supportive care alone (Table 1). Chemotherapy was not administered in 2 patients with PS3 due to severe comorbidities and mental disease. The chemotherapeutic regimen was a combination of carboplatin and etoposide in 11 out of those 12 patients. Of these, 7 patients received the standard dose, carboplatin area under the curve (AUC) of 5 intravenously on day 1 and etoposide 80–100 mg/m2 intravenously on days 1–3. In the remaining 4 patients, the doses of carboplatin and etoposide were reduced to AUC of 4 and 50–80 mg/m2, respectively. One patient was only treated with carboplatin AUC of 5 because the serum total bilirubin level was high (>5 mg/dL) and he presented hepatic metastases. The number of chemotherapy cycles in the first-line chemotherapy ranged from 1 to 4 (50% of patients underwent 4 cycles; 8.3%, 3; 8.3%, 2; 33.3%, 1). Second-line chemotherapy was administered to 5 patients.\n\nWhole brain radiation therapy was administered to 4 patients before chemotherapy and stereotactic radiotherapy for brain metastasis was administered to 1 patient. Additionally, 1 patient underwent palliative thoracic radiotherapy at a dose of 30.6 Gy in 17 fractions.\n\nImprovement of PS\nDuring chemotherapy, PS improved in 7 (58.3%) patients. This was observed in the 2 patients with PS 4 (Table 1): 1 patient shifted to PS 2, and the other shifted to PS 1. In addition, PS remained unchanged in 2 (16.7%) patients, while it deteriorated in 3 (25%) patients (Fig. 1).\n\nToxicity\nGrade 3–4 neutropenia developed in 10 (83%), and grade 3 febrile neutropenia in 5 (42%) patients (Table 2). Treatment-related mortality associated with lung toxicity occurred in a 77-year-old male patient with PS 3. There were 3 early deaths within 4 weeks of treatment; these patients were all treated with supportive care alone and died of lung cancer progression.\n\nObjective Response and Overall Survival\nConsidering all 18 patients studied, the median overall survival and 6-month survival rate were 4.9 months and 47.9%, respectively. The overall survival of the patients with PS 4 was comparable to that of the patients with PS 3; the 6-month survival rate was 50% in both groups (log rank p = 0.31, Fig. 2).\n\nDuring chemotherapy, there were 5 partial responses (objective response rate of 41.7%), 3 stable disease (25%), and 4 progressive disease (33.3%). Treatment significantly affected survival: the 6-month survival rate was 66.7% in those patients treated with chemotherapy, while all patients treated with supportive care alone died within the first 5 months (logrank p = 0.037, Fig. 3).\n\nDiscussion\nIt is difficult to select the best treatment option in SCLC patients with a poor PS because occasionally chemotherapy is too toxic to be administered to patients in such a poor general condition. In this study, one patient (aged 77 years) with PS 3 died of chemotherapy, which might be explained by the patient's advanced age. Although toxicity was tolerable in the other patients studied (Table 2), it was reported that both poor PS and advanced age are significant factors associated with toxic death in patients with SCLC [5], as well as in those with breast and non-small-cell lung cancers [6].\n\nOn the contrary, patient's general condition may actually take a turn for the better when active systemic chemotherapy is administered. Indeed, in this study, a considerable improvement in PS after chemotherapy was observed in 7 of 12 (58%) patients. This is comparable to the response rate to carboplatin and etoposide in elderly patients with extensive SCLC reported in a phase III trial [7]. Thus, it is reasonable to expect a PS improvement with systemic chemotherapy in SCLC having a poor PS.\n\nThe current Japanese lung cancer guidelines provide the treatment options for SCLC patients with PS 3 and 4 separately [11]. According to those, platinum doublets are recommended for patients with PS 3. However, this is based on only one phase III trial, which included 18 patients with PS 3. In addition, this study excluded elderly patients >70 years of age, but currently this group corresponds to about half of the patients with a poor PS. Regarding patients with PS 4, the guidelines do not recommend chemotherapy because there are no available supportive data. However, we report on two patients with PS 4 in whom carboplatin and etoposide combined chemotherapy was so effective that their PS improved significantly. Accordingly, they were able to receive a total of four cycles of chemotherapy without life-threatening toxicity. Although our number of patients was limited, overall survival did not differ between patients with PS 3 and 4, even when the patients treated with supportive care alone were included in the analysis. Importantly, the American guidelines for the treatment of SCLC do not consider patients with PS 3 and 4 separately, and recommend chemotherapy for all if the poor PS is a result of the SCLC itself [12, 13, 14]. Therefore, our findings strongly suggest that chemotherapy is indicated in selected SCLC patients with both PS 3 and 4 if the poor PS is mostly due SCLC rather than by comorbidities, as an improvement of PS due to treatment is expected.\n\nIn conclusion, the poor PS was improved significantly in about 58% of patients with aggressive systemic chemotherapy, strongly suggesting that chemotherapy is indicated in selected SCLC patients with both PS 3 and 4.\n\nStatement of Ethics\nThis study was approved by the Ethical Committee of University of Tsukuba Hospital.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFig. 1 Performance status (PS) variation during chemotherapy courses. As a result of treatment, PS improved in 7 (58.3%), remained stable in 2 (16.7%), and deteriorated in 3 (25%) patients. Solid lines: patients who received standard chemotherapy; Dashed lines: patients who received chemotherapy at low doses; PS is categorized as 1–4.\n\nFig. 2 Patients' overall survival according to performance status (PS). Solid line: patients with PS 3 (n = 12); Dotted line: patients with PS 4 (n = 6).\n\nFig. 3 Patients' overall survival according to treatment type. Solid line: patients treated with chemotherapy (n = 12); Dotted line: patients treated with supportive care alone (n = 6).\n\nTable 1 Patients' characteristics\n\n\tPS 3 (n = 12)\tPS 4 (n = 6)\tTotal(n = 18)\t\nAge, years\t\n Median (range)\t74.5 (51–85)\t70.5 (64–77)\t73 (51–85)\t\nGender,n (%)\t\n Male\t8 (66.7)\t6 (100)\t14 (77.8)\t\n Female\t4 (33.3)\t0\t4 (22.2)\t\nSuperior vena cava syndrome,n (%)\t\n Yes\t2 (16.7)\t1 (16.7)\t3 (16.7)\t\n No\t10 (83.3)\t5 (83.3)\t15 (83.3)\t\nBrain metastases,n (%)\t\n Yes\t6 (50)\t3 (50)\t9 (50)\t\n No\t6 (50)\t2 (33.3)\t8 (44.4)\t\n Unknown\t0\t1 (16.7)\t1 (5.6)\t\nSerum LDH, IU/L\t\n Median (range)\t263 (170–877)\t597.5 (205–5,739)\t352 (170–5,739)\t\nTreatment,n (%)\t\n Chemotherapy\t10 (83.3)\t2 (33.3)\t12 (66.7)\t\n Supportive care alone\t2 (16.7)\t4 (66.7)\t6 (33.3)\t\nTable 2 Toxicity of first-line chemotherapy (Grade 3–5)\n\n\tToxicity,n (%)\t\n\tgrade 3\tgrade 4\tgrade 5\tgrade 3–5 (total)\t\nNeutropenia\t4 (33.3)\t6 (50)\t0\t10 (83.3)\t\nAnemia\t4 (33.3)\t1 (8.3)\t0\t5 (41.7)\t\nThrombocytopenia\t5 (41.7)\t1 (8.3)\t0\t6 (50)\t\nFebrile neutropenia\t4 (33.3)\t0\t0\t4 (33.3)\t\nDyspnea\t0\t0\t1 (8.3)\t1 (8.3)\t\nn, number of patients.\n==== Refs\nReferences\n1 Toyoda Y Nakayama T Ioka A Tsukuma H Trends in lung cancer incidence by histological type in Osaka, Japan Jpn J Clin Oncol 2008 8 38 (8) 534 9 18689853 \n2 Shepherd FA Crowley J Van Houtte P The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 2 2007 1067 1077 \n3 Zelen M Keynote address on biostatistics and data retrieval Cancer Chemother Rep 3 1973 3 4 (2) 31 42 \n4 Green RA Humphrey E Close H Patno ME Alkylating agents in bronchogenic carcinoma Am J Med 1969 4 46 (4) 516 25 5791000 \n5 Lassen UN Osterlind K Hirsch FR Bergman B Dombernowsky P Hansen HH Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression Br J Cancer 1999 2 79 (3-4) 515 9 10027322 \n6 Wallington M Saxon EB Bomb M Smittenaar R Wickenden M McPhail S 30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study Lancet Oncol 2016 9 17 (9) 1203 16 27599138 \n7 Okamoto H Watanabe K Kunikane H Yokoyama A Kudoh S Asakawa T Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702 Br J Cancer 2007 7 97 (2) 162 9 17579629 \n8 Baldotto CS Cronemberger EH de Biasi P Palliative care in poor-performance status small cell lung cancer patients: is there a mandatory role for chemotherapy? Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer 2012 20 2721 2727 22322592 \n9 Sakuragi T Oshita F Nagashima S Kasai T Kurata T Fukuda M Retrospective analysis of the treatment of patients with small cell lung cancer showing poor performance status Jpn J Clin Oncol 1996 6 26 (3) 128 33 8656551 \n10 World Health Organization WHO Handbook for Reporting Results of Cancer Treatment. WHO Publication 1979 No. 48 ed Geneva \n11 The Japan Lung Cancer Society Guidelines for Diagnosis and Treatment of the Lung Cancer 2018 2018 ed. Tokyo KANEHARA & CO., LTD (in Japanese) \n12 Jett JR Schild SE Kesler KA Treatment of small cell lung cancer: Diagnosis and management of lung cancer American College of Chest Physicians evidence-based clinical practice guidelines Chest 2013 143 3rd ed e400S e419S 23649448 \n13 Rudin CM Ismaila N Hann CL Malhotra N Movsas B Norris K Treatment of Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American College of Chest Physicians Guideline J Clin Oncol 2015 12 33 (34) 4106 11 26351333 \n14 NCCN Clinical Practice Guidelines in Oncology Small Cell Lung Cancer. 2018 available at: https://www.nccn.org/professionals/physician_gls/.ed\n\n",
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"title": "Small-Cell Lung Cancer Treatment of Newly Diagnosed Patients with Poor Performance Status.",
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"abstract": "Pathological gambling behaviour is a side effect of dopaminergic drugs used in Parkinson's disease, but has seldom been reported with selective serotonin reuptake inhibitors. A 58-years-old woman with somatisation disorder since the age of 20 and recent-onset major depression (at 54 years) received 40 mg/day intravenous citalopram, thereafter switching to the same dose of oral citalopram to treat her comorbid psychiatric disorders after showing poor response to paroxetine for one year. Her anxious and depressive symptoms were moderately reduced after 7 months of oral citalopram, but simultaneously, the patient admitted gambling. We gradually discontinued citalopram and introduced pregabalin and alprazolam; this was followed by a reduction of gambling compulsions, but the somatisation and depressive symptoms did not further improve. Pathological gambling may be mediated by an interplay of 5-HT1A serotonergic and D2 dopaminergic mechanisms. Citalopram affects both these mechanisms in areas that were shown to be involved in gambling behaviour, but while dopaminergic effects of citalopram appear to be consistent with the induction of gambling, its serotonergic mechanisms are rather inconsistent. In our patient, mood destabilisation induced by citalopram may have contributed to the first onset of pathological gambling.",
"affiliations": "NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), Unit of Psychiatry, School of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University, Via di Grottarossa 1035-1039, 00189, Rome, Italy, ilaria.cuomo@uniroma1.it.",
"authors": "Cuomo|Ilaria|I|;Kotzalidis|Georgios D|GD|;Caccia|Federica|F|;Danese|Emanuela|E|;Manfredi|Giovanni|G|;Girardi|Paolo|P|",
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"mesh_terms": "D015283:Citalopram; D015897:Comorbidity; D003865:Depressive Disorder, Major; D005260:Female; D005715:Gambling; D006801:Humans; D008875:Middle Aged; D017367:Serotonin Uptake Inhibitors; D013001:Somatoform Disorders; D016896:Treatment Outcome",
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"title": "Citalopram-associated gambling: a case report.",
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"abstract": "The aim was to present our experience of managing six cases of anti-melanoma differentiation-associated gene 5 (anti-MDA-5) DM with associated interstitial lung disease (ILD), presenting between June 2017 and October 2020.\nThe electronic notes were reviewed for six patients being followed up by the Rheumatology service at Auckland District Health Board. Three patients were initially diagnosed and treated in neighbouring Counties Manukau District Health Board and later transferred to Auckland District Health Board. All had different initial treating clinicians at a time before any predefined treatment algorithm. Emphasis was placed on initial diagnosis and treatment, subsequent disease activity and changes in management. Local management was compared retrospectively with existing evidence relating to the treatment of anti-MDA-5 DM with ILD. Ethical approval was not obtained, according to the New Zealand Health and Disability Ethics Committee exemption for audits and related activities.\nSix patients with a variety of clinical presentations were identified appropriately as having anti-MDA-5 DM with ILD. They were commenced on different immunosuppressive regimens, with treatment adjusted according to response and on-going disease activity. Four have achieved clinical and biochemical remission, a fifth has improving active disease, and the sixth is in the early stages of their illness.\nAnti-MDA-5 DM is commonly associated with ILD. This can be rapidly progressive, with a poor prognosis in spite of treatment, particularly among Asian patients. Disease activity can seemingly be monitored with serum ferritin. The most effective management of this condition remains poorly researched; however, increasing retrospective evidence favours early aggressive multi-agent immunosuppression and a low threshold for escalation of therapy.",
"affiliations": "Department of Medicine.;Department of Rheumatology, Auckland District Health Board, Auckland, New Zealand.;Department of Rheumatology, Auckland District Health Board, Auckland, New Zealand.",
"authors": "Dick|Michael|M|https://orcid.org/0000-0002-8601-5662;Martin|Julia|J|;Tugnet|Nicola|N|",
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"doi": "10.1093/rap/rkab024",
"fulltext": "\n==== Front\nRheumatol Adv Pract\nRheumatol Adv Pract\nrheumap\nRheumatology Advances in Practice\n2514-1775\nOxford University Press\n\n10.1093/rap/rkab024\nrkab024\nConcise Report\nAcademicSubjects/MED00010\nManagement of MDA-5 antibody-positive dermatomyositis with interstitial lung disease—an Auckland case series\nhttps://orcid.org/0000-0002-8601-5662\nDick Michael 1\nMartin Julia 2\nTugnet Nicola 2\n1 Department of Medicine\n2 Department of Rheumatology, Auckland District Health Board, Auckland, New Zealand\nCorrespondence to: Michael Dick, Auckland City Hospital, Park Road, Grafton, Auckland 1023, New Zealand. E-mail: mdick@adhb.govt.nz\n2021\n07 4 2021\n07 4 2021\n5 1 rkab02419 9 2020\n08 3 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nObjective\n\nThe aim was to present our experience of managing six cases of anti-melanoma differentiation-associated gene 5 (anti-MDA-5) DM with associated interstitial lung disease (ILD), presenting between June 2017 and October 2020.\n\nMethods\n\nThe electronic notes were reviewed for six patients being followed up by the Rheumatology service at Auckland District Health Board. Three patients were initially diagnosed and treated in neighbouring Counties Manukau District Health Board and later transferred to Auckland District Health Board. All had different initial treating clinicians at a time before any predefined treatment algorithm. Emphasis was placed on initial diagnosis and treatment, subsequent disease activity and changes in management. Local management was compared retrospectively with existing evidence relating to the treatment of anti-MDA-5 DM with ILD. Ethical approval was not obtained, according to the New Zealand Health and Disability Ethics Committee exemption for audits and related activities.\n\nResults\n\nSix patients with a variety of clinical presentations were identified appropriately as having anti-MDA-5 DM with ILD. They were commenced on different immunosuppressive regimens, with treatment adjusted according to response and on-going disease activity. Four have achieved clinical and biochemical remission, a fifth has improving active disease, and the sixth is in the early stages of their illness.\n\nConclusion\n\nAnti-MDA-5 DM is commonly associated with ILD. This can be rapidly progressive, with a poor prognosis in spite of treatment, particularly among Asian patients. Disease activity can seemingly be monitored with serum ferritin. The most effective management of this condition remains poorly researched; however, increasing retrospective evidence favours early aggressive multi-agent immunosuppression and a low threshold for escalation of therapy.\n\nanti-MDA-5\ndermatomyositis\ninterstitial lung disease\nimmunosuppression\n==== Body\nKey messages\n\nAnti-MDA-5 DM is associated with interstitial lung disease, which can be rapidly progressive with poor prognosis.\n\nEarly, aggressive, combined immunosuppression seems to be the most effective treatment.\n\nFerritin may be a useful biomarker of disease activity.\n\nIntroduction\n\nDM is an idiopathic inflammatory myopathy characterized by proximal weakness, associated with muscle inflammation and numerous skin manifestations. It is a multisystem disease, manifesting with interstitial lung disease (ILD), dysphagia, polyarthritis, malignancy and other features that may overlap with several systemic rheumatic diseases. Consistent laboratory findings include elevated muscle enzymes (creatine kinase, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase) and positive autoantibodies (ANA and myositis-specific antibodies). One autoantibody is the anti-melanoma differentiation-associated gene 5 (anti-MDA-5), which was first reported in Japanese patients in 2005 [1]. Histopathological, electromyographical and MRI findings also aid diagnosis.\n\nThe MDA-5 gene encodes the clinically amyopathic DM-140 protein. Generally, anti-MDA-5 DM patients have a lower incidence of myositis, although anti-MDA-5 can be detected in clinically amyopathic, hypomyopathic or classic DM [2]. It is highly specific for DM, strongly associated with rapidly progressive ILD (rp-ILD), confers poor prognosis, and is associated with the lowest survival rates for all DM patients, even when compared with those with malignancy-associated DM [1, 2]. Many recommend serum ferritin as a marker of disease activity to assess treatment response and guide treatment intensification [3].\n\nClassical DM is treated with oral glucocorticoids, preceded by pulse i.v. methylprednisolone in severe cases, with a prolonged taper over 9–12 months according to response [4, 5]. Owing to the poor overall prognosis of anti-MDA-5 DM, additional immunosuppressive agents are commonly commenced from the time of diagnosis, even when ILD is initially mild. A recent prospective study showed efficacy of early aggressive combined immunosuppressive therapy with improved prognosis compared with step-up therapy of initial high-dose glucocorticoid and gradual intensification [6]. This involved a tapering course of oral glucocorticoid, i.v. CYC and tacrolimus, with plasmapheresis added if patients deteriorated. This study also reported improvements in anti-MDA-5 titre, serum ferritin and respiratory function after treatment [6]. Pre-treatment CRP, ferritin and the presence of skin ulcers were poor prognostic factors [6]. More recently, recommendations, largely based on poor-quality evidence and expert opinion, have been published for the treatment of rp-ILD in anti-MDA-5 DM [7]. This evidence was not available when our paper was first written in 2019. An overall recommendation is given for initial multi-agent immunosuppression combining high-dose glucocorticoids and calcineurin antagonists, with or without CYC, with scope for individualized changes to the regimen based on contraindications or treatment failure [7].\n\nHere, we present six cases demonstrating the spectrum of clinical features associated with anti-MDA-5 DM, emphasizing the immunosuppressive agents used and the response to therapy. We highlight the association with ILD, including four cases with definite or possible rp-ILD, requiring a regimen of potent, multi-agent immunosuppression to achieve remission.\n\nCases\n\nDemographic details, relevant initial investigations and a summary of the treatment agents used and current disease status is provided in Table 1. Anti-MDA-5 testing was positive in all cases. Assessment of anti-MDA-5 status was performed as part of a myositis antibody panel by an external laboratory using a multi-parameter line blot test (EUROLINE by EUROIMMUN, Lübeck, Germany). Although the manufacturer reports the ability to quantify positive signal intensity and correlate this with antibody titre, our laboratory reported only a positive or negative result, with no information on the anti-MDA-5 titre [8]. Remission was defined by improvements in clinical and functional outcomes, including ferritin level, appearance of skin lesions, diffusing capacity of the lungs for carbon monoxide (DLCO), high-resolution CT (HRCT) appearance and patient-reported modified HAQ-2 scores.\n\nTable 1 Demographics, relevant initial investigations, treatment agents and outcomes\n\nParameter\tPatient A\tPatient B\tPatient C\tPatient D\tPatient E\tPatient F\t\nAge, years\t36\t27\t72\t39\t47\t48\t\nSex\tFemale\tFemale\tFemale\tFemale\tMale\tMale\t\nEthnicity\tTongan\tTongan\tNew Zealand–European\tMāori\tFilipino\tIndian\t\nPhenotype\tBreathlessness, rash, myopathy\tBreathlessness, rash, myopathy\tBreathlessness, rash, amyopathic\tBreathlessness, rash, amyopathic\tBreathlessness, rash, myopathy\tBreathlessness, rash, amyopathic\t\nCK, U/l\n\n(normal range 60–220 U/l)\n\n\t1010\t910\t75\t192\t375\t52\t\nPeak CK, U/l\n\n(normal range 60–220 U/l)\n\n\t1010\t910\t75\t192\t1002\t52\t\nFerritin, μg/l\n\n(normal range 20–450 μg/l)\n\n\t1474\t942\t161\t784\t1553\t607\t\nPeak ferritin, μg/l\n\n(normal range 20–450 μg/l)\n\n\t3198\t2404\t798\t2283\t4545\t860\t\nALT, U/l\n\n(normal range 0–45 U/l)\n\n\t100\t47\t50\t40\t45\t55\t\nAST, U/l\n\n(normal range 0–45 U/l)\n\n\tNP\t71\t33\tNP\t64\t28\t\nCRP, mg/l\n\n(normal range 0–5 mg/l)\n\n\t8\t19\t7\t33\t4\t7\t\nANA\t1:640\tNegative\tNegative\tNegative\tNegative\t1:1280\t\nAnti-MDA-5\tPositive\tPositive\tPositive\tPositive\tPositive\tPositive\t\nHRCT findings\tScattered areas of peripheral ground-glass change\tPeribronchovascular and subpleural patchy ground-glass opacities and nodularities\tInflammatory changes in both upper lobes, with ground-glass peripheral infiltrates and mild centrilobular emphysema bilaterally\tSmall upper lobe foci of ground-glass change\tBilateral patchy, peripheral and peribronchial areas of consolidation\tSubtle bibasal traction bronchiectasis, right > left; peripheral irregular densities in middle lobe and lingula\t\nILD\tRapidly progressive\tNot rapidly progressive\tPossible rapidly progressive\tPossible rapidly progressive\tRapidly progressive\tNot rapidly progressive\t\nInitial treatment agents\ti.v. methylprednisolone; CSA; CYC\tPrednisone; CSA\tHCQ; MTX; prednisone\tPrednisone; MMF\tPrednisone\tPrednisone\t\nOther agents used\tRituximab\tIVIG; AZA\tIVIG; CYC\ti.v. methylprednisolone; CYC\ti.v. methylprednisolone; MMF; CYC\ti.v. methylprednisolone\t\nCurrent treatment agents\tPrednisone; tacrolimus; MMF\tNil\tMTX; CSA\tPrednisone; CSA\tPrednisone; CSA\tPrednisone; CSA; CYC\t\nDisease status\tRemission\tRemission\tRemission\tRemission\tActive; improving\tActive; early disease\t\nALT: alanine aminotransferase; AST: aspartate aminotransferase; CK: creatine kinase; HRCT: high-resolution CT; ILD: interstitial lung disease; NP: not performed.\n\nPatient A\n\nPatient A presented with 6 weeks of itchy rash, 3 weeks of progressive exertional breathlessness and mild weakness when raising her arms. Spirometry showed restriction with reduced DLCO (50%), and HRCT showed evidence of ILD. MRI demonstrated muscle oedema. Skin and muscle biopsies were consistent with DM, confirming the diagnosis of anti-MDA-5 DM with predominant ILD, skin involvement and mild myositis.\n\nTwo days of i.v. methylprednisolone was given, followed by 80 mg prednisone. A 15 mg/kg fortnightly i.v. CYC (total 6 g) and 100 mg twice a day CSA were started, with initial clinical improvement. CSA was stopped and prednisone reduced to 40 mg within 1 month owing to worsening liver function tests, although investigations concluded that this was likely to be related to non-alcoholic fatty liver disease. Subsequently, the existing rash worsened, a new heliotrope rash developed, hyperferritinaemia persisted, and breathlessness rapidly worsened. Prednisone was increased to 80 mg, CSA re-started and MMF added (maximum dose 3 g). HRCT revealed progressive organizing pneumonia, dictating further escalation of immunosuppression. Tacrolimus replaced CSA (dose titrated to 3 milligrams (mg) twice a day, to maintain trough concentrations between 10 and 15 ng/ml). A few weeks later, characteristic new painful digital ulcerations appeared, and ferritin worsened (1030 μg/l). Given the progressive disease activity and marked disability despite CYC, tacrolimus, MMF and glucocorticoids, rituximab infusions were commenced.\n\nSince rituximab was added, the patient’s 6 min walk test and DLCO (75%) have improved. No new digital ulcerations or rash lesions have developed, and the heliotrope rash has resolved. Ferritin has normalized (106 μg/l). She remains prednisone dependent and has developed CS-induced diabetes, but anti-MDA-5 DM is in remission.\n\nPatient B\n\nPatient B presented with 2 months of exertional breathlessness and 4 weeks of progressive proximal muscle weakness, myalgias, arthralgias and rash. Spirometry showed restriction (DLCO not measured); HRCT demonstrated evidence of ILD, and muscle biopsy was consistent with DM. Diagnosis of anti-MDA-5 DM with ILD, skin involvement and myositis was made. Concern regarding cardiac function prompted cardiac MRI, suggestive of myocarditis/cardiomyopathy related to DM.\n\nProgressive skin involvement and carpal tunnel syndrome related to left wrist swelling occurred despite commencing CSA 4 mg/kg and prednisone 80 mg. Ferritin did not improve. IVIG 1 g/kg over 2 days was added, with monthly doses given for 6 months. CS-induced psychosis prompted prednisone dose reduction and taper. Muscle strength improved, while respiratory and cardiac function stabilized. Ferritin decreased at 6 months (270 μg/l). She remained well at 12 months, returning to work part time. All medications were stopped at 14 months (ferritin 15 μg/l), mainly owing to the large size of CSA tablets and mild derangement of liver function tests (probably related to either CSA or steatosis). She became pregnant and remained well off all medications for 2 months. Subsequent worsening of cough and breathlessness was deemed inconsistent with recurrent ILD, based on normal spirometry and chest X-ray. Recurrent abdominal rash and pustular lesions on her fingers and soles were thought to be related to recurrent disease, although ferritin remained normal (50 μg/l). She was commenced on AZA (maximum dose 150 mg once a day), with improvement in the rash and cough. Respiratory opinion suggested that late-onset asthma might be contributing, with flixotide markedly improving her breathlessness.\n\nPatient B successfully carried her pregnancy to term and remained stable on AZA, with ferritin improved (108 μg/l), before ceasing this of her own volition. Recent HRCT shows no on-going evidence of ILD; she is anti-MDA-5 antibody negative and remains asymptomatic off all treatment.\n\nPatient C\n\nPatient C presented with 3 months of breathlessness and typical rash, with severe digital ulceration and features of DM on skin biopsy (Fig. 1a). There was no muscle weakness. Spirometry showed no restriction but reduced DLCO (52%). HRCT revealed changes reflecting possible ILD or aspiration pneumonitis, with emphysema from previous smoking. Diagnosis of anti-MDA-5 DM sine myositis, with predominant skin involvement and evidence of ILD, was made.\n\nFig. 1 Skin changes in patients C and F\n\n(A) Patient C at presentation. (B) Patient C in remission. (C) Patient F at presentation.\n\nHCQ 400 mg once a day, MTX 10 mg weekly and prednisone 20 mg were started without improvement. Digital ulcerations caused major disability: loss of functional grip, with inability to dress, wash or drive, necessitating hospital admission. Prednisone was increased to 60 mg and MTX to 20 mg weekly, and CSA 100 mg twice a day was added. Digital ulcerations proved refractory to treatment; therefore, HCQ was stopped, and two doses of IVIG (1 g/kg) were given. Investigation of progressive breathlessness within 2 months showed stable spirometry (DLCO 48%), but progressive ILD on HRCT. Intravenous CYC was added (15 mg/kg for six cycles), leading to complete resolution of digital ulcerations (Fig. 1b). Worsening flexor tenosynovitis improved with increased MTX (25 mg weekly).\n\n \n\nPatient C weaned off prednisone and remains on MTX 25 mg weekly and CSA 100 mg once a day. The digital ulcerations have resolved, and ferritin has normalized (82 μg/l). Breathing has improved (DLCO 63%) such that she is independent with daily activities and exercising regularly. Recent HRCT showed non-progressive fibrosis.\n\nPatient D\n\nPatient D presented with 2 months of a photo-distributive, erythematous rash, with associated arthralgias and alopecia. Co-morbidities included brittle asthma, morbid obesity, hypertension and valvular heart disease from previous rheumatic fever. She had no muscle weakness. Skin biopsy was consistent with DM or SLE. HCQ 400 mg once a day and 10 mg prednisone were initiated for possible ANA-negative SLE while awaiting myositis panel results. Progressive breathlessness and rash with Gottron’s papules developed within 2 months following patient-initiated cessation of prednisone. HRCT was suspicious for early ILD or reflux. Coronavirus disease 2019 pandemic restrictions prevented spirometric assessment. Echocardiogram revealed indirect signs of possible pulmonary hypertension. Diagnosis of anti-MDA-5 DM sine myositis with predominant skin involvement was inferred. Breathlessness was probably multifactorial.\n\nPrednisone 40 mg and MMF 1 g twice a day were commenced, with more aggressive immunosuppression withheld, given the lack of significant ILD. Repeat HRCT 2 weeks later confirmed mild DM-related ILD. Ferritin was increasing (peak 2283 μg/l). Spirometry revealed normal lung volumes with reduced DLCO (56%). Right-heart catheter detailed normal pulmonary arterial pressures. She was admitted for 3 days of pulse i.v. methylprednisolone followed by 100 mg prednisone. One gram of i.v. CYC fortnightly (6 g total) and CSA 150 mg twice a day were commenced; MMF was stopped.\n\nPatient D responded well to treatment and remains on prednisone 5 mg (weaning) and CSA200 mg twice a day. Ferritin has normalized (195 μg/l). The rash improved markedly, with resolution of active erythematous areas, but with evidence of scarring present. Breathlessness still limits activity but has improved subjectively and objectively, with near resolution of HRCT findings and DLCO 72%.\n\nPatient E\n\nPatient E presented with 4 weeks of progressive exertional breathlessness, fatigue, weakness, myalgia and rash. Examination revealed Gottron’s papules, heliotrope rash, digital ulceration, proximal muscle weakness and bibasal crepitation. HRCT was in keeping with organizing pneumonia. Skin biopsy was consistent with DM. Coronavirus disease 2019 pandemic restrictions prevented spirometric assessment. Diagnosis of DM with ILD, skin involvement and myositis was made.\n\nHe initially improved with 60 mg prednisone, pending myositis panel results. Subsequent rapid clinical and radiological progression necessitated treatment escalation with i.v. methylprednisolone, CSA 400 mg once a day and i.v. CYC 1 g monthly, resulting in clinical stabilization. Spirometry at this time demonstrated restriction, with impaired gas transfer (DLCO 54%). Further subsequent deterioration in breathlessness was associated with fever, cough and sputum production. Repeat HRCT demonstrated progressive ILD and a new cavitating pneumonic process. Bronchoalveolar lavage and sputum PCR were positive for Mycobacteriumtuberculosis, probably representing reactivation of latent infection following immunosuppression. CYC was withheld, CSA stopped and prednisone reduced to 30 mg to allow for treatment of M. tuberculosis. MMF 1 g twice a day was commenced. Increasing disease activity prompted gradual prednisone re-intensification to 80 mg once a day, cessation of MMF and re-introduction of CSA 400 mg twice a day with uptitration (higher dose owing to interaction with rifampicin). Screening also revealed re-activation of CMV with immunosuppression, prompting treatment.\n\nHis condition stabilized and subsequently continues to improve (ferritin 811 μg/l). The rash has resolved, and breathlessness no longer limits activity. He remains on outpatient treatment for his pulmonary M. tuberculosis. Immunosuppression consists of prednisone 10 mg twice a day (weaning) and CSA 400 mg twice a day, with oral CYC ceased owing to leucopoenia.\n\nPatient F\n\nPatient F presented with 2 months of progressive malar rash, alopecia, additional rash over his hands, elbows and knees and increasingly swollen hands and wrists with arthralgia. Examination revealed the rash as above, Gottron’s papules, bibasal crepitation and evidence of symmetrical synovitis affecting multiple hand joints (Fig. 1c). There was no muscle weakness. Breathlessness on exertion developed while awaiting outpatient investigations, prompting admission to hospital. Spirometry showed mild restriction with moderately reduced DLCO (65%), and HRCT was consistent with ILD. Skin biopsy was consistent with DM. Diagnosis of anti-MDA-5 DM sine myositis with predominant skin involvement and evidence of ILD was made.\n\nPrednisone 5 mg was commenced and rapidly escalated with pulse i.v. methylprednisolone (1000 mg/day for 3 days), fortnightly 1000 mg i.v. CYC (six doses), prednisone 60 mg (weaning), and CSA 100 mg twice a day on recognition of ILD. He remained well during a brief admission.\n\nCurrently, he is stable as an outpatient, with evidence of on-going active disease, early in his disease course, on prednisone 30 mg, CSA 100 mg twice a day and fortnightly CYC infusions. Ferritin is 740 μg/l. The rash and hand swelling are improving, while breathlessness limits his activity to climbing two flights of stairs.\n\nDiscussion\n\nAnti-MDA-5 DM is increasingly recognized and is strongly associated with rp-ILD and non-rp-ILD [2]. rp-ILD is observed more frequently among patients of Asian/Japanese descent compared with patients from European or American populations, probably representing a combination of genetic susceptibility and environmental factors [6]. Distant Asian ancestry and the associated greater propensity for anti-MDA-5 DM might explain the ethnicities of our patients despite the predominantly European population of New Zealand.\n\nTo identify existing evidence relating to the treatment of anti-MDA-5 DM with ILD, a literature search was performed in PubMed (MEDLINE) using a strategy to identify publications current up to August 2019 relating to any combination of ‘interstitial lung disease’ or synonyms, ‘MDA-5’ or synonyms and ‘dermatomyositis’. Two significant studies were subsequently identified and ultimately included before publication [6, 7]. Numerous case reports and case series have reported efficacy for various immunosuppressive agents; however, comparative studies have not been performed. Additionally, most reports include all DM patients with associated ILD, with little evidence specific to anti-MDA-5 DM. Recent data suggest that patients with ILD associated with anti-MDA-5 DM have lower mortality and better outcomes with aggressive early combination therapies involving CYC, calcineurin antagonists and glucocorticoids [6, 7]. This builds on previous evidence demonstrating the efficacy of early combined therapy among DM patients complicated by respiratory involvement [9].\n\nInitial treatments varied widely among all patients in our cohort, probably reflecting the different initial treating clinicians, varying disease severity at presentation and prior lack of consensus opinion regarding the most effective treatment strategy. From our experience, we have found multi-agent immunosuppression involving glucocorticoids, a calcineurin antagonist and CYC to be effective for inducing remission in patients with both rp-ILD and non-rp-ILD, and our experience with patient A supports the notion of adjusting the treatment approach when first-line therapy is insufficient. It is often difficult to differentiate those patients who will develop rp-ILD from those who might have non-rp-ILD at initial presentation. As such, we recommend aggressive multi-agent immunosuppression in all patients with anti-MDA5-associated ILD, even when ILD is initially mild, because delayed treatment for the most severe cases can be life threatening. On this basis, we would largely support the recent consensus recommendations [7]. It is important to consider that immunosuppression, particularly when intensive, predisposes patients to various infections, as seen in patient E. Another important consideration in younger patients is the infertility that might result from CYC therapy, requiring balance against treatment efficacy. As such, judicious use of CYC is encouraged, especially if the initial disease is less severe.\n\nAlthough we have no available data relating to ferritin levels in patients with other conditions, in our experience ferritin seems to be an effective biomarker for monitoring disease activity in patients with anti-MDA-5 DM. It might also be useful in identifying patients more likely to experience rp-ILD, as demonstrated by patients A and E having high initial and peak ferritin levels.\n\nConclusion\n\nMyositis-specific autoantibodies are becoming increasingly important in guiding management. Here, we have presented our experience with six patients with anti-MDA-5 DM with associated ILD. Increasing poor-quality evidence suggests that the greatest likelihood of disease suppression and survival can be achieved through an early multi-agent immunosuppressive regimen. Also, ferritin appears to be a useful biomarker for monitoring disease activity and severity. Further prospective studies focused on anti-MDA-5 DM treatment regimens and monitoring of biomarkers such as ferritin are required to improve existing management algorithms based upon this pattern of myositis-specific autoantibodies.\n\nFunding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.\n\nDisclosure statement: The authors have declared no conflicts of interest.\n\nData availability statement\n\nThe data that support the findings of this study are available on request from the corresponding author.\n==== Refs\nReferences\n\n1 Sato S , HirakataM, KuwanaM et al Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum 2005;52 :1571–6.15880816\n2 Moghadam-Kia S , OddisCV, SatoS, KuwanaM, AggarwalR. Antimelanoma differentiation-associated gene 5 antibody: expanding the clinical spectrum in North American patients with dermatomyositis. J Rheumatol 2017;44 :319–25.28089977\n3 Gono T , KawaguchiY, OzekiE et al Serum ferritin correlates with activity of anti-MDA5 antibody-associated acute interstitial lung disease as a complication of dermatomyositis. Mod Rheumatol 2011;21 :223–7.21052763\n4 Schwarz MI , MatthayRA, SahnSA et al Interstitial lung disease in polymyositis and dermatomyositis: analysis of six cases and review of the literature. Medicine (Baltimore) 1976;55 :89–104.1246203\n5 Marie I , HachullaE, ChérinP et al Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum 2002;47 :614–22.12522835\n6 Tsuji H , NakashimaR, HosonoY et al Multicenter prospective study of the efficacy and safety of combined immunosuppressive therapy with high-dose glucocorticoid, tacrolimus, and cyclophosphamide in interstitial lung diseases accompanied by anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Arthritis Rheumatol 2020;72 :488–98.31524333\n7 Romero-Bueno F , Diaz del CampoP, Trallero-ArguásE et al .; MEDRA5 (Spanish MDA5 Register) group (listed contributors at the end of the article). Recommendations for the treatment of anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated rapidly progressive interstitial lung disease. Semin Arthritis Rheum 2020;50 :776–90.32534273\n8 EUROIMMUN. Product Catalogue 2021 [Internet]. Lübeck (Germany): EUROIMMUN; 2020. https://www.euroimmun.com/documents/Catalogue/EUROIMMUN-Product-Catalogue.pdf (22 December 2020, date last accessed).\n9 Kameda H , NagasawaH, OgawaH et al Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis. J Rheumatol 2005;32 :1719–26.16142867\n\n",
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"issn_linking": "2514-1775",
"issue": "5(1)",
"journal": "Rheumatology advances in practice",
"keywords": "anti-MDA-5; dermatomyositis; immunosuppression; interstitial lung disease",
"medline_ta": "Rheumatol Adv Pract",
"mesh_terms": null,
"nlm_unique_id": "101736676",
"other_id": null,
"pages": "rkab024",
"pmc": null,
"pmid": "33898921",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "12522835;21052763;31524333;16142867;15880816;1246203;28089977;32534273",
"title": "Management of MDA-5 antibody-positive dermatomyositis with interstitial lung disease-an Auckland case series.",
"title_normalized": "management of mda 5 antibody positive dermatomyositis with interstitial lung disease an auckland case series"
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"abstract": "Although data on the prevalence of anticholinergic misuse is scarce, it has been reported among psychiatric patients. Anticholinergic drugs can act as potent indirect dopamine agonists in the limbic system, a mechanism that has been hypothesized to explain their misuse potential among patients. In psychiatric practice settings, the use of typical antipsychotics in conjunction with anticholinergics is common, with the latter mainly used to manage extrapyramidal side effects of the former. Haloperidol is a first-generation (typical) antipsychotic with weak anticholinergic properties that may sometimes be potentiated when it is used in combination with other anticholinergic medications. This combination can induce significant gastrointestinal hypomotility, constipation, and rarely even paralytic ileus. We present the case of a 67-year-old African American male with a history of schizophrenia, benign prostatic hyperplasia, and essential hypertension, who abruptly started misusing benztropine, without any prior history of a substance use disorder. This case highlights the importance of obtaining a detailed history when previously stable psychiatric patients develop acute physical symptoms. It also illustrates the importance of care coordination among care providers and the central role of the psychiatrist in the care of patients with medical comorbidities.",
"affiliations": "Psychiatry, Clarion Psychiatric Center, Clarion, USA.;Psychiatry and Behavioral Sciences, Nassau University Medical Center, East Meadow, USA.;Psychiatry and Behavioral Sciences, American University of the Caribbean School of Medicine, Cupecoy, SXM.;Psychiatry and Behavioral Sciences, American University of the Caribbean School of Medicine, Cupecoy, SXM.;Psychiatry and Behavioral Sciences, American University of the Caribbean School of Medicine, Cupecoy, SXM.",
"authors": "Esang|Michael|M|;Person|Ulziibat S|US|;Izekor|Odeyuwa O|OO|;Le|Thien Kim|TK|;Ahmadian|Donya|D|",
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"doi": "10.7759/cureus.13434",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13434\nMedical Education\nPsychiatry\nGastroenterology\nAn Unlikely Case of Benztropine Misuse in an Elderly Schizophrenic\nMuacevic Alexander\nAdler John R\nEsang Michael 1\nPerson Ulziibat S 2\nIzekor Odeyuwa O 3\nLe Thien Kim 3\nAhmadian Donya 3\n1 Psychiatry, Clarion Psychiatric Center, Clarion, USA\n2 Psychiatry and Behavioral Sciences, Nassau University Medical Center, East Meadow, USA\n3 Psychiatry and Behavioral Sciences, American University of the Caribbean School of Medicine, Cupecoy, SXM\nMichael Esang silversensorium@gmail.com\n18 2 2021\n2 2021\n13 2 e1343418 2 2021\nCopyright © 2021, Esang et al.\n2021\nEsang et al.\nThis 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/51438-an-unlikely-case-of-benztropine-misuse-in-an-elderly-schizophrenic\nAlthough data on the prevalence of anticholinergic misuse is scarce, it has been reported among psychiatric patients. Anticholinergic drugs can act as potent indirect dopamine agonists in the limbic system, a mechanism that has been hypothesized to explain their misuse potential among patients. In psychiatric practice settings, the use of typical antipsychotics in conjunction with anticholinergics is common, with the latter mainly used to manage extrapyramidal side effects of the former. Haloperidol is a first-generation (typical) antipsychotic with weak anticholinergic properties that may sometimes be potentiated when it is used in combination with other anticholinergic medications. This combination can induce significant gastrointestinal hypomotility, constipation, and rarely even paralytic ileus. We present the case of a 67-year-old African American male with a history of schizophrenia, benign prostatic hyperplasia, and essential hypertension, who abruptly started misusing benztropine, without any prior history of a substance use disorder. This case highlights the importance of obtaining a detailed history when previously stable psychiatric patients develop acute physical symptoms. It also illustrates the importance of care coordination among care providers and the central role of the psychiatrist in the care of patients with medical comorbidities.\n\nbenztropine\nhaloperidol\nschizophrenia\nanticholinergic misuse\ngeriatric\ndopamine\nmuscarinic\ngastrointestinal\nurologic\ncomplications\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nIn psychiatry, anticholinergics have been used to manage extrapyramidal symptoms arising from the strong D2 receptor antagonism caused by antipsychotic medications. The extrapyramidal symptoms are believed to be due to dopamine antagonism in the nigrostriatal pathway of the brain. This pathway connects the substantia nigra pars compacta in the midbrain with the dorsal striatum in the forebrain. Anticholinergic medications help alleviate the neurologic effects of blocking D2 receptor activity in this pathway. These agents, however, can cause a variety of distressing peripheral and central adverse effects such as dry mouth, urinary disturbances, constipation, cognitive impairment, and in severe cases, delirium. The prevalence of anticholinergic misuse has been reported as 34% and occurs most commonly in psychiatric patients [1,2]. Benztropine, a medication often prescribed to treat Parkinson’s disease, is also utilized for the management of the extrapyramidal side effects of antipsychotic medications [3]. It has both anticholinergic and antihistaminic properties. It also binds the dopamine transporter (DAT) and inhibits the reuptake of dopamine (DA), resulting in increased dopaminergic neurotransmission in the mesolimbic (nucleus accumbens) and mesocortical systems. This is the critical element in mediating the reinforcing and psychostimulant effects of benztropine misuse [4]. Furthermore, benztropine has been found to improve some of the social and affective dysfunction seen in schizophrenia, perhaps providing additional incentives for its misuse [4]. Overuse of this medication subsequently increases the likelihood of anticholinergic side effects, which include constipation, urinary retention (M3 receptor blockade), decreased appetite, dry mouth, and dry skin, as well as drowsiness, confusion, delirium, and hallucinations [5]. Each anticholinergic medication that a patient takes may increase the risk of cognitive impairment by 46% over six years [6]. This review aims to shed light on the possibility of benztropine misuse, even in a stable elderly schizophrenic with no significant prior history of problems related to substance use. The authors highlight benztropine’s pharmacological and clinical profile and the most prominent drawbacks from its misuse, especially in the geriatric patient population.\n\nCase presentation\n\nThe patient was a 67-year-old African American male who had a psychiatric history of schizophrenia as well as a history of benign prostatic hyperplasia and essential hypertension. He had been receiving care for over 10 years at our ambulatory psychiatric center while on a monthly intramuscular injection of 50 mg of haloperidol decanoate. He had a past history of muscle stiffness from the haloperidol injection and this extrapyramidal symptom had been controlled with oral benztropine at 0.5 mg two times a day on an as-needed basis. During the course of his treatment, he developed hematochezia along with lower abdominal pain, constipation, and difficulty with urination, which was initially attributed to his enlarged prostate. However, a careful history by his psychiatrist subsequently revealed that he had been using Benztropine more than he was being prescribed. He admitted to taking more than double his prescribed dose per day as well as increasing doses over a period of months, as he had also been receiving this prescription from his gastroenterologist (up to a total of 5-8 mg per day in divided doses). He did not give any clear reason for taking higher doses of the benztropine and only stated that he was just taking his \"side effect medication\" as needed. The psychiatrist contacted his outpatient gastroenterologist and urologist, coordinating his care with these specialists. Extensive psychoeducation, over a period of multiple clinic visits, was provided to him focusing on his increased susceptibility to the anticholinergic effects of benztropine. It was explained that his advanced age and history of benign prostatic hyperplasia placed him at an elevated risk of anticholinergic complications. The benztropine dose was reduced and shorter duration prescriptions were provided to allow for increased monitoring and he began to use the medication as prescribed. His gastroenterologist and urologist had both ruled out a malignant neoplasm as the etiology of his presentation. These symptoms gradually resolved and he continued to receive psychiatric care regularly at our clinic without any further incidents.\n\nDiscussion\n\nAnticholinergic drugs bind to muscarinic receptors and block acetylcholine neurotransmission, which is involved in many major body functions including central nervous system (CNS) functions such as attention, learning, and memory mechanisms. Cholinergic transmission in the peripheral nervous system (PNS) is also involved in the basal functioning of humans such as urination, intestinal transit, or heart rhythm regulation [7].\n\nWhen considering this patient, it should be noted that constipation is a minor side effect of haloperidol therapy because of its weak anticholinergic effect. In combination with anticholinergics such as benztropine, however, it can induce significant gastrointestinal hypomotility, constipation, and rarely, paralytic ileus [8]. In elderly patients with chronic medical comorbidities, iatrogenic anticholinergic effects can be overlooked as the potential culprit of these symptoms. Among the currently available antiparkinsonian anticholinergics, benztropine has the highest affinity for muscarinic acetylcholine receptors (mAChRs) [9]. Anticholinergic drugs can also act as potent indirect dopamine agonists in the limbic system [4]. Through the blockade of the muscarinic receptors, anticholinergic drugs inhibit dopamine reuptake and storage, accounting for the euphoric and hallucinogenic effects sometimes encountered with their use [10]. Although anticholinergics can exacerbate psychosis, they can also modestly improve negative symptoms of schizophrenia [9]. In accordance with these findings, patients with schizophrenia often report an activating effect at higher doses of anticholinergics, which sometimes can result in misuse [9]. This is an important clinical point and warrants further investigation, considering the limitations of existing therapies in combating the negative symptoms of schizophrenia spectrum disorders.\n\nWe reviewed relevant literature in order to explore clinical trends in the use of anticholinergic medications in treatment settings, and Table 1 summarizes our findings. Although our review was not systematic and was of limited scope, the cognitive burden of chronic anticholinergic use was immediately apparent and deserves to be mentioned.\n\nTable 1 Summary of literature review findings on risks associated with anticholinergic use.\n\nSources\tSummary of findings\tLimitations\t\nOgino et al. (2014) [9]\tPatients with schizophrenia often report an activating effect of higher doses of anticholinergics, which sometimes results in anticholinergic misuse.\tThis is the first study in its field to examine the effects of anticholinergic drug use with long‐acting injectable antipsychotics on cognitive function and safety in patients with schizophrenia.\t\nNaja and Halaby (2017) [10]\tShifting, when possible, to second-generation antipsychotics could contribute to fewer extrapyramidal side effects, thereby limiting the need for anticholinergic drugs.\tThe majority of the data was related to trihexyphenidyl abuse although benztropine was noted as a drug that has significant abuse potential.\t\nLopez et al. (2019) [7]\tGiven the potential risk of irreversible cognitive effects in prolonged treatments, the efficacy and risks of anticholinergic drugs should be re-evaluated with longer treatment periods.\tDrug scales used in this study did not account for drug interactions and comorbidities. The anticholinergic load was also underestimated. Furthermore, the results are not translatable worldwide as the scales had drugs that are not approved or commercialized in specific countries.\t\nAng et al. (2017) [11]\tThere was an inverse relationship between cumulative anticholinergic activity and cognition; those with higher medication anticholinergic burden had a deficit in their performance on cognitive tasks.\tMedication adherence was not assessed in this study. Medication dose and frequency were un-adjusted for.\t\nO’Reily et al. (2016) [12]\tAnticholinergic burden significantly impacted reasoning and perception, which further weakened the ability of patients suffering from schizophrenia and schizoaffective disorder to benefit from psychosocial treatment programs.\tCross-sectional study, a limited sample size, and a limited duration in which patients were followed and assessed (three years).\t\nEum et al. (2017) [13]\tAnticholinergic burden was inversely related to cognitive performance. This study explored the impact of cognitive impairment on a patient's ability to live and operate independently, their potential for occupational success, and other psychosocial factors. \tAs a cross-sectional study, the ability to establish causal relationships was therefore limited. The severity of disease/medication dose and duration of exposure were unaccounted for.\t\n\nIt is well established that chronic use of anticholinergic medications can increase the risk of cognitive impairment, particularly in geriatric patients. Ang et al. investigated the impact of anticholinergic use among individuals with schizophrenia [11]. The results of this study suggested an inverse relationship between cumulative anticholinergic activity and cognition, indicating that those with a higher medication anticholinergic burden had cognitive deficits [11]. In another study, the anticholinergic burden significantly impacted reasoning and perception in patients with schizophrenia, schizoaffective disorder, and psychotic bipolar illness [12,13]. Investigators were able to demonstrate the relationship between anticholinergic burden and negative outcomes of psychosocial treatment programs for patients with schizophrenia and schizoaffective disorder [12].\n\nIn spite of these drawbacks, geriatric prescriptions of anticholinergic drugs cannot always be avoided in clinical practice. For instance, a patient may be quite reluctant to switch to a different antipsychotic medication after multiple treatment failures with dire consequences. Where these medications remain crucial to keeping patients in remission, priority should be given to those with a mild anticholinergic load and those with more selectivity for receptors at their site of action. In addition, possible medication management problems should be addressed in view of the increased anticholinergic load associated with multiple anticholinergic agents [11]. Given the potential risk of irreversible cognitive effects in prolonged treatments, the efficacy and risks of anticholinergic drugs should be re-evaluated when treatment periods longer than three months are considered or anticipated [14]. When possible, switching to a second-generation antipsychotic could contribute to less extrapyramidal side effects, hence potentially obviating the need for anticholinergics. Although they may be safe to use over an extended period, anticholinergic effectiveness may diminish over time, and side effects such as sedation and cognitive impairment may worsen. Periodic trials of discontinuation could therefore be useful in justifying the need for continued use, especially in institutional settings where they are prescribed as adjuncts to antipsychotics [10].\n\nConclusions\n\nThis case highlights the importance of obtaining a detailed history when previously stable psychiatric patients develop acute physical complaints. It also illustrates the importance of coordination among different care providers and specialists involved in the care of a patient. The central role of the psychiatrist in this regard cannot be overemphasized, especially in the management of patients with chronic and severe psychiatric illnesses. Even in elderly patients with no apparent prior history of a substance use disorder, anticholinergic medications can be misused leading to adverse health outcomes. Our review is limited in scope as we have reported only on a single individual. We, however, believe that the complex interrelationship among extra-pyramidal side effects of antipsychotics, anticholinergic use and their abuse potential, negative symptoms of schizophrenia spectrum disorders, and the negative effects of anticholinergics, deserves further investigation.\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 Misuse of anticholinergic drugs by people with serious mental illness Psychiatr Serv Buhrich N Weller A Kevans P 928 929 51 2000 10875961\n2 Mood elevation and medications Dis Nerv Syst Dugas JE 958 38 1977 https://pubmed.ncbi.nlm.nih.gov/21060/ 21060\n3 Comparative structure-activity relationships of benztropine analogues at the dopamine transporter and histamine H1 receptors Bioorg Med Chem Kulkarni SS Kopajtic TA Katz JL Newman AH 3625 3634 14 2006 16460947\n4 Applicability of the dopamine and rate hypotheses in explaining the differences in behavioral pharmacology of the chloro-benztropine analogs: Studies conducted using intracerebral microdialysis and population pharmacodynamic modeling J Pharmacol Exp Ther Othman AA Newman AH Eddington ND 760 769 322 2007 17519385\n5 Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol Urology Moro C Uchiyama J Chess-Williams R 0 1442 78 2011\n6 Use of anticholinergics and the risk of cognitive impairment in an African American population Neurology Campbell NL Boustani MA Lane KA 152 159 75 2010 20625168\n7 Anticholinergic Drugs in Geriatric Psychopharmacology. Front Neurosci López-Álvarez J Sevilla-Llewellyn-Jones J Agüera-Ortiz L 1309 13 2019 31866817\n8 Haloperidol and benztropine interaction presenting as acute intestinal pseudo-obstruction Am J Gastroenterol Sheikh RA Prindiville T Yasmeen S 934 935 96 2001 11280595\n9 Benefits and limits of anticholinergic use in schizophrenia: focusing on its effect on cognitive function Psychiatry Clin Neurosci Ogino S Miyamoto S Miyake N Yamaguchi N 37 49 68 2014 24102938\n10 Anticholinergic use and misuse in psychiatry: a comprehensive and critical review J Alcohol Drug Depend Naja WJ Halaby A 263 5 2017\n11 The impact of medication anticholinergic burden on cognitive performance in people with schizophrenia J Clin Psychopharmacol Ang MS Rashid NA Lam M 651 656 37 2017 29016375\n12 Anticholinergic burden in schizophrenia and ability to benefit from psychosocial treatment programmes: A 3-year prospective cohort study Psychol Med O'reilly K O'connell P Donohoe G 3199 3211 46 2016 27576609\n13 Cognitive burden of anticholinergic medications in psychotic disorders Schizophrenia Res Eum S Hill SK Rubin LH 129 135 190 2017\n14 Book review: Stahl’s essential psychopharmacology, prescriber’s guide, antipsychotics Can J Psychiatry Awad G 584 64 2019\n\n",
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"keywords": "anticholinergic misuse; benztropine; complications; dopamine; gastrointestinal; geriatric; haloperidol; muscarinic; schizophrenia; urologic",
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"title": "An Unlikely Case of Benztropine Misuse in an Elderly Schizophrenic.",
"title_normalized": "an unlikely case of benztropine misuse in an elderly schizophrenic"
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"abstract": "Despite the various parenchymal presentation of coronavirus disease 2019 (COVID-19) pneumonia, the involvement of the vascular component, the reduction of perfusion in noninjured part of the lung and secondary right to left shunt play an important role in the genesis of the respiratory insufficiency. We present the case of a 72-year-old woman admitted to Livorno Hospital for severe respiratory insufficiency due to SARS-CoV-2 infection unresponsive to noninvasive in whom administration of nebulized phosphodiesterase 3 (PDE3) inhibitor enoximone was able to improve oxygenation avoiding tracheal intubation. Intravenous infusions of phosphodiesterase inhibitors are commonly used as pulmonary vasodilators in the management of pulmonary hypertension. This is the first case showing that inhaled route administration of PDE3 inhibitor enoximone could be important in the management of COVID-19 hypoxemia, to restore perfusion in noninjured part of the lung, improving oxygenation and avoiding risks of systemic infusion.",
"affiliations": "Department of Anesthesia and Critical Care, and Spedali Riuniti Livorno Estav Nordovest, Livorno, Italy.;Department of Infectious Disease, Spedali Riuniti Livorno Estav Nordovest, Livorno, Italy.;Department of Anesthesia and Critical Care, and Spedali Riuniti Livorno Estav Nordovest, Livorno, Italy.;Department of Pharmacy, University of Pisa, Pisa, Italy.;Department of Anesthesia and Critical Care, and Spedali Riuniti Livorno Estav Nordovest, Livorno, Italy.",
"authors": "Ferro|Baldassare|B|0000-0001-9718-9943;Cinelli|Roberta|R|;Vegnuti|Lara|L|;Piras|Anna Maria|AM|0000-0002-4082-6400;Roncucci|Paolo|P|",
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"title": "The Potential Role of Aerosolized Phosphodiesterase 3 Inhibitor Enoximone in the Management of Coronavirus Disease 2019 Hypoxemia: A Case Report.",
"title_normalized": "the potential role of aerosolized phosphodiesterase 3 inhibitor enoximone in the management of coronavirus disease 2019 hypoxemia a case report"
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"companynumb": "IT-PFM-2021-08993",
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"abstract": "Drug-induced liver injury is one of the main reasons for acute liver failure. We report the case of a young patient who experienced a drug-induced liver injury resulting in life-threatening acute liver failure after treatment with different antibiotics (amoxicillin, ciprofloxacin, cefazolin, clindamycin) and acetaminophen, or a combination of these drugs. Moreover, we provide an overview of the hepatotoxic potential of these drugs.",
"affiliations": "Department of Oncology and Hematology, Paracelsus Medical University, Nürnberg,, Germany.",
"authors": "Munz|Martin|M|;Grummich|Hans|H|;Birkmann|Josef|J|;Wilhelm|Martin|M|;Holzgrabe|Ulrike|U|;Sörgel|Fritz|F|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000658:Amoxicillin; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002437:Cefazolin",
"country": "Switzerland",
"delete": false,
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"issue": "62(6)",
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"keywords": "Acetaminophen; Acute liver failure; Amoxicillin; Antibiotics; Cefazolin; Ciprofloxacin; Clindamycin; Drug-induced liver injury",
"medline_ta": "Chemotherapy",
"mesh_terms": "D000410:Alanine Transaminase; D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D001219:Aspartate Aminotransferases; D002437:Cefazolin; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D008199:Lymphadenitis; D055815:Young Adult; D005723:gamma-Glutamyltransferase",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "367-373",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Drug-Induced Liver Injury as an Adverse Drug Event of Antibiotics: A Case Report and Review of the Literature.",
"title_normalized": "severe drug induced liver injury as an adverse drug event of antibiotics a case report and review of the literature"
} | [
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"companynumb": "DE-LANNETT COMPANY, INC.-DE-2018LAN000011",
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"abstract": "BACKGROUND\nRecently, a new enteropathy has been described: olmesartan-associated enteropathy. However, the association has been questioned: a phase 3 trial and a cohort study found no association between gastrointestinal events and olmesartan.\n\n\nOBJECTIVE\nTo collect French cases of sartan-associated enteropathy to describe further this entity, confirm or refute causality, and determine if the association exists with other sartans.\n\n\nMETHODS\nFrench gastroenterologists were invited to report cases of sartan-associated enteropathy and collect clinical, biological and histological data. Patients with diarrhoea and histological duodenal abnormalities were included.\n\n\nRESULTS\nThirty-six patients with olmesartan-associated enteropathy were reported, including 32 with villous atrophy and four without. There was only one patient with irbesartan-associated enteropathy. None of the patients died. Patients with villous atrophy had diarrhoea, vomiting, renal failure, hypokalaemia, body weight loss and hypoalbuminaemia. Thirty-one patients were hospitalised; four required intensive care. Anti-transglutaminase and anti-enterocyte antibodies were negative; anti-nuclear antibodies were positive (9/11). Endoscopic duodenal biopsies showed villous atrophy (32/32) and polyclonal intra-epithelial CD3+CD8+ lymphocytosis (11/11). Exactly, 14/15 patients responded to steroids and/or immunosuppressants, prescribed because of suspected autoimmune enteropathy. Ten olmesartan interruptions were followed by reintroductions before steroids or immunosuppressants. Interruptions were followed by remissions (9/10), but reintroductions were followed by relapses (9/9). Twenty-nine patients were in remission since olmesartan interruption, including 26 without immunosuppressants. Patients with normal villi had similar clinical characteristics, but mild histological abnormalities (intra-epithelial lymphocytosis and lamina propria lymphocytic infiltration).\n\n\nCONCLUSIONS\nOlmesartan causes a severe and immune-mediated enteropathy, with or without villous atrophy. Enteropathy associated with other sartans seems to be very rare.",
"affiliations": "Kremlin Bicêtre University Hospital, Assistance Publique-Hopitaux de Paris (AP-HP), Paris-Sud University, Le Kremlin Bicêtre; Antoine Béclère University Hospital, AP-HP, Paris-Sud University, Clamart, France.",
"authors": "Marthey|L|L|;Cadiot|G|G|;Seksik|P|P|;Pouderoux|P|P|;Lacroute|J|J|;Skinazi|F|F|;Mesnard|B|B|;Chayvialle|J A|JA|;Savoye|G|G|;Druez|A|A|;Parlier|D|D|;Abitbol|V|V|;Gompel|M|M|;Eoche|M|M|;Poncin|E|E|;Bobichon|R|R|;Colardelle|P|P|;Wils|P|P|;Salloum|H|H|;Peschard|S|S|;Zerbib|F|F|;Méresse|B|B|;Cerf-Bensussan|N|N|;Malamut|G|G|;Carbonnel|F|F|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan",
"country": "England",
"delete": false,
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D047228:Angiotensin II Type 1 Receptor Blockers; D015331:Cohort Studies; D003625:Data Collection; D003967:Diarrhea; D005260:Female; D005602:France; D005767:Gastrointestinal Diseases; D006801:Humans; D007093:Imidazoles; D007413:Intestinal Mucosa; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles",
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"pubdate": "2014-11",
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"references": null,
"title": "Olmesartan-associated enteropathy: results of a national survey.",
"title_normalized": "olmesartan associated enteropathy results of a national survey"
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"activesubstancename": "IRBESARTAN"
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... |
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"abstract": "BACKGROUND\nIncidence of gastric perforation following cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) is not widely reported.\n\n\nMETHODS\nSuitable patients were identified from our database of 1028 procedures. Relevant information was then gathered via medical records and operation reports for these patients.\n\n\nRESULTS\nSix patients suffered early postoperative gastric perforation following the procedure (0.58%), all of whom received heated intraoperative intraperitoneal chemotherapy (HIPEC). Surgical exploration revealed protrusion of nasogastric (NG) tube through stomach wall defects which were either located at or near the greater curvature of stomach. These patients were managed successfully with operation, and no mortality was recorded.\n\n\nCONCLUSIONS\nGastric perforation following CRS and PIC is most likely the result of a multifactorial process. To reduce the risk of such complication, avoiding nasogastric suction in these patients may prove helpful. Any suspected perforated viscus must be addressed promptly to avoid unwanted morbidity and mortality from the procedure. To our knowledge, conservative management has not been documented to work in this subgroup and surgery remains the mainstay of treatment.",
"affiliations": "Department of Surgery, St. George Hospital, University of New South Wales, Sydney, New South Wales, Australia. frank.ls01@hotmail.com.;Department of Surgery, St. George Hospital, University of New South Wales, Sydney, New South Wales, Australia.;Department of Surgery, St. George Hospital, University of New South Wales, Sydney, New South Wales, Australia.;Department of Surgery, St. George Hospital, University of New South Wales, Sydney, New South Wales, Australia.",
"authors": "Kyang|Lee S|LS|;Alzahrani|Nayef A|NA|;Zhao|Jing|J|;Morris|David L|DL|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s12957-017-1114-7",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 111410.1186/s12957-017-1114-7ResearchGastric perforation following cytoreductive surgery and perioperative intraperitoneal chemotherapy: a case series of six Kyang Lee S. frank.ls01@hotmail.com 1Alzahrani Nayef A. nayefalhariri@hotmail.com 12Zhao Jing jing.zhao@health.nsw.gov.au 1Morris David L. david.morris@unsw.edu.au 11 0000 0004 4902 0432grid.1005.4Department of Surgery, St. George Hospital, University of New South Wales, Sydney, New South Wales Australia 2 0000 0001 2243 1790grid.440750.2Imam Muhammad ibn Saud Islamic University College of Medicine, Riyadh, Saudi Arabia 10 2 2017 10 2 2017 2017 15 445 10 2016 1 2 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIncidence of gastric perforation following cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) is not widely reported.\n\nMethods\nSuitable patients were identified from our database of 1028 procedures. Relevant information was then gathered via medical records and operation reports for these patients.\n\nResults\nSix patients suffered early postoperative gastric perforation following the procedure (0.58%), all of whom received heated intraoperative intraperitoneal chemotherapy (HIPEC). Surgical exploration revealed protrusion of nasogastric (NG) tube through stomach wall defects which were either located at or near the greater curvature of stomach. These patients were managed successfully with operation, and no mortality was recorded.\n\nConclusions\nGastric perforation following CRS and PIC is most likely the result of a multifactorial process. To reduce the risk of such complication, avoiding nasogastric suction in these patients may prove helpful. Any suspected perforated viscus must be addressed promptly to avoid unwanted morbidity and mortality from the procedure. To our knowledge, conservative management has not been documented to work in this subgroup and surgery remains the mainstay of treatment.\n\nKeywords\nPeritonectomyNasogastric tubeSuctionHeated intraoperative intraperitoneal chemotherapyHIPECAppendiceal cancerGastric perforationStomachissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nHistorically, the prognosis of peritoneal dissemination of neoplasms (primary or metastatic), also known as peritoneal carcinomatosis (PC), was poor. Over the past few decades, the introduction of cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) has significantly altered the treatment landscape for PC and, owing to its promising survival benefits [1–3], the combination treatment has gained popularity. Essentially, there are two major components to the procedure: first, CRS involves removal of macroscopic tumour off the peritoneum and/or visceral organs; then, intraoperative chemotherapy (HIPEC) or postoperative chemotherapy (EPIC) allows a high concentration of cytotoxic drug to destroy microscopic residual disease [4].\n\nDespite well-documented survival results, perception towards the therapeutical approach remains sceptical due partly to its high toxicity [5]. However, clinical experience has allowed surgeons to improve the outcomes. A study at St. George Hospital in Sydney, which prospectively studied 140 patients who underwent CRS and PIC, demonstrated a significant reduction in morbidity from 30 to 10% and mortality from 7 to 1% when the former 70 patients were compared to latter 70 patients [6]. This data suggests a learning curve effect associated with the procedure. We have now done 1000 procedures and have a mortality of approximately 1% in the last 4 years.\n\nThe high morbidity and mortality rates of such intervention can be largely attributed to the surgery and/or chemotherapy [7]. Multiple body systems can be impacted and gastrointestinal complications are the most prevalent including abscess (0–37%), fistula (0–23%), ileus (0–86%), anastomotic leak (0–9%) and bowel perforation (0–10%) [4]. To our knowledge, there are, however, only a few reports of gastric perforation in these patients. Here we outline and evaluate our experience with six patients complicated by gastric perforation following CRS and PIC.\n\nMethods\nWe retrospectively explore a prospectively maintained database of 843 patients, amounting to 1028 procedures, who underwent CRS and perioperative chemotherapy for intraperitoneal dissemination of primary cancers at St. George Hospital (Sydney) from 1996 to June 2016 to identify patients with postoperative gastric perforation. Medical records and operation reports for the identified patients were then reviewed to gather relevant information for this case series. All our patients are preoperatively consented to have information stored in our database for research purposes (by South Eastern Sydney Local Health District Human Research Ethics Committee).\n\nResults\nAll the procedures were done by one surgical team. These patients were reviewed by a multidisciplinary team of surgical oncologists, medical oncologists, anaesthetist, radiologists, nurses and allied health members. So far, six incidents of postoperative gastric perforations were reported following CRS and perioperative chemotherapy. The patients consisted of two men and four women with a mean age of 50.7 (41–62 years old), representing an incidence of 0.58% (6/1028) from our database. The initial CRS were performed to remove pseudomyxoma peritoneii (appendiceal neoplasm) in three patients, peritoneal mesothelioma in one patient and ovarian cancer in the remaining two. During the surgeries, variable procedures were done (Table 1), determined by the distribution, volume and invasion of PC. Mean peritoneal cancer index (PCI), as defined by Jacquet and Sugarbaker [8], was 27.5 in these patients. A mean time of 9.6 h was required to operate on these patients.Table 1 Characteristics of patients with gastric perforation following CRS and PIC at a tertiary referral centre (St. George Hospital) in Sydney\n\nPatient number; age; gender\tDiagnosis\tProcedures performed\tPCIa\n\tHIPECb (chemotherapy)\tEPICc\n\tLength of surgery (hours)\t\n1; 62; M\tPseudomyxoma peritoneii (redo)\tPeritonectomy, small bowel resection\t17\tYes (MMCd)\tNo\t8.5\t\n2; 58; F\tOvarian cancer\tPeritonectomy, splenectomy, cholecystectomy, partial gastrectomy with Roux-En-Y anastomosis, small bowel resection, bilateral diaphragm strip\t32\tYes (CDDPe)\tNo\t10.5\t\n3; 41; F\tPseudomyxoma peritoneii\tPeritonectomy, splenectomy, cholecystectomy, omentectomy, right hemicolectomy\t14\tYes (MMC)\tYes\t10.0\t\n4; 51; F\tPeritoneal mesothelioma\tPeritonectomy, bilateral diaphgram stripping, splenectomy, right hemicolectomy, cholecystectomy, segment II liver resection, pelvic stripping, omentectomy\t33\tYes (CDDP)\tNo\t9.0\t\n5; 44; M\tPseudomyxoma peritoneii\tPeritonectomy, bilateral diaphragmatic stripping, splenectomy, pancreas stripping, liver surface stripping, cholecystectomy, Billroth I gastrectomy, right hemicolectomy, anterior resection\t39\tYes (OXf)\tNo\t12.0\t\n6; 48; F\tOvarian cancer\tPeritonectomy, oophorectomy, salpingectomy, salpingooophorectomy, removal of ligaments (ovarian, paraovarian, fimbrial or broad ligaments), hysterectomy with rectum, bilateral diaphragm stripping, splenectomy, partial gastrectomy, left hepatectomy and creation of colostoma\t30\tYes (OX)\tNo\t7.8\t\n\naPeritoneal cancer index\n\n\nbHyperthermic intraperitoneal chemotherapy\n\n\ncEarly postoperative intraperitoneal chemotherapy\n\n\ndMitomycin C\n\n\neCisplatin\n\n\nfOxaliplatin\n\n\n\n\nHyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) was introduced in all six patients. Hyperthermic mitomycin C was given to patients 1 and 3, hyperthermic cisplatin was given to patients 2 and 4 and hyperthermic oxaliplatin was used in patients 5 and 6. In contrast, only one patient received early postoperative intraperitoneal 5-fluorouracil (patient 3) for a total of 5 days. Following the procedure, proton pump inhibitor (PPI) was prescribed for these patients till they are mobilised or discharged from hospital.\n\nDiagnosis of gastric perforation was confirmed by direct visualisation of stomach wall defect. It took us a mean time of 6 days postoperatively to diagnose possible perforated viscus in these patients based on signs of peritonitis, fluid content in drain and CT abdomen (Table 2). These patients were brought to theatre for exploration and closure of perforation. We tried conservative management on one patient (patient 3), however, with no clinical improvement. Ultimately, she underwent surgical exploration to fix the perforation.Table 2 Operative and post-operative characteristics of the same set of patients\n\nPatient number; age; gender\tTime from initial CRS to perforation diagnosis (days)\tIndications of perforated viscus\tSurgery or conservative\tLocation of stomach perforation\tHow was it fixed?\tLength of hospital stay (days)\t\n1; 62; M\t2\tBrown fluid in drain\tSurgery\t5 mm adjacent to liver edge\tOversewn with vicryl\t24\t\n2; 58; F\t9\tOngoing peritonism with brownish discharge from abdominal wound despite unremarkable CT\tSurgery\tAbove gastroenterostomy\tOversewn then with diaphragm patch\t55\t\n3; 41; F\t7\tPeritonism, green billous fluid in drain\tConservative then surgery\tStomach body\tOversewn with vicryl\t44\t\n4; 51; F\t10\tPeritonism, CT abdomen, green billous fluid in drain\tSurgery\t3 mm, greater curvature of stomach\tOversewn with menseteric fat\t26\t\n5; 44; M\t6\tPeritonism, CT abdomen\tSurgery\t5 mm, greater curvature of proximal stomach\tOversewn with vicryl and plication\t34\t\n6; 48; F\t3\tGreen billous fluid in drain\tSurgery\t5 mm, posterior gastric wall 1 cm away from greater curvature\tOversewn with vicryl and plication\t35\t\n\n\n\nAll gastric perforations were either located at or near the greater curvature of stomach (Fig. 1). The sizes of the defects were no more than 0.5 cm in diameter and NG tube was seen protruding through the stomach, causing bile peritonitis in all cases. The defects were repaired by suturing the perforation on two layers. The outcome for these patients was positive with no mortality. The mean length of hospital stay for these patients was 36 days. Patient 2 had the longest in-hospital admission (55 days) due to concurrent complications of gastrointestinal bleeding and intra-abdominal abscess.Fig. 1 Postoperative nasogastric tube perforation (arrow), through the greater curvature of stomach, leading to bile peritonitis in patients who underwent CRS and HIPEC\n\n\n\n\nDiscussion\nWe retrospectively explored the incidence of gastric perforation following CRS and PIC from our prospective database. In our institution, out of the 1028 procedures performed in the last two decades, six patients (0.58%) had postoperative recovery complicated by gastric perforation. These patients were taken back to theatre for emergency repair of perforated viscus. All gastric perforations were either at or near the greater curvature of stomach. Fortunately, all of them achieved complete resolution and the mean length of hospital stay for these patients was 36 days. In contrast to bowel perforation, postoperative gastric perforation associated with CRS and PIC is a relatively rare surgical complication. To our knowledge, this has not been widely reported in the literature. So far, only eight patients were described to have gastric perforation following CRS and PIC (Table 3).Table 3 Available literature documenting incidence of gastric perforation following CRS and PIC\n\nReference\tStudy type\tAim\tNumber\tEarly or delayed complication\tOrigin\tHIPEC\tMortality from complication\tManagement\tSuggested possible mechanism\t\nKusamura et. al. [12]\tRetrospective observational study\tTo analyse morbidity and mortality of CRS and intraoperative hyperthermic infusion in treatment of peritoneal malignancies\t1/209 procedures\tUCa\n\tUC\tYes (UC)\tNo\tSurgical\t• Partial thickness mechanical and/or thermal damage to visceral surface (aggravated by heated chemotherapy) • Focal heat injury at tip of inflow catheter • Mechanical trauma due to suctioning effect of outflow catheter • Post-operative shrinking of infiltrating metastatic nodules on visceral wall from antiblastic effect of heated chemotherapy\t\nCeelen et. al. [20]\tProspective study\tTo analyse safety and efficacy of HIPEC using high dose oxaliplatin in CRS\t1/52 patients\tUC\tUC\tYes (OX)\tNo\tSurgical\tThermal damage during omentectomy using ultrasonic shears\t\nZappa et. al. [9]\tRetrospective observational study\tTo explore the cause and management of gastric perforation following CRS and HIPEC\t4/1251 patients\tEarly\t• 3 appendiceal cancer • 1 ovarian cancer\tYes (1—MMC; 2—MMC + DOXc; 1—CDDP\tNo\tSurgical\t• Local seromuscular trauma to the greater curvature as a result of traction on the ligated blood vessel and vascular compromise • Damage of stomach wall from direct effects of chemotherapy, which is further amplified by poor perfusion • Nasogastric trauma secondary to suction during postoperative phase\t\nBhagwandin et. al. [13]\tRetrospective observational study\tTo analyse incidence of delayed major complications of CRS and HIPEC post-discharge\t1/140 procedures\tDelayed\tMesothelioma\tYes (cisplatin, DOX)\tNo\tEndoscopic clipping\tNRb\n\t\nMunoz-Casares et. al. [14]\tRetrospective observational study\tTo analyse long-term outcomes of CRS plus HIPEC\t1/218 patients\tDelayed\tOvarian cancer\tYes (paclitaxel)\tNo\tSurgical\tNR\t\nMartin et. al. [15]\tRetrospective observational study\tTo identify variables associated with readmission rates following CRS and HIPEC\tNR\tDelayed\tUC\tYes (NR)\tYes (1 sepsis)\tNR\tNR\t\n\naUnclear\n\n\nbNot reported\n\n\ncDoxorubicin\n\n\n\n\nThe location of stomach defect at or near the greater curvature indicates possible pathology at that area. All our patients, except patient 1, had either omentectomy, splenectomy or both done during the procedure. During the procedure, ligations of right and left gastroepiploic vessels (greater omentectomy) and splenic vessels (splenectomy) reduce perfusion of greater curvature, resulting in seromuscular trauma at site of ligation due to traction [9]. We also strongly believe that the injury may be associated with nasogastric tube based on the visualisation of tube protrusion through the stomach defects during exploratory laparotomy. Perhaps it was related to pressure ischemia exerted on stomach mucosa by nasogastric tube suction and by relatively rigid nasogastric tubes [10]. Other proposed mechanisms include direct effect of intraperitoneal chemotherapy [11] and thermal injury caused by inflow and outflow catheters during infusion of HIPEC [12]. All these factors, ultimately, lead to friability of stomach wall making it susceptible to perforation.\n\nPostoperative monitoring for any indication of perforated viscus is paramount. Signs of peritonitis, fluid content in intraperitoneal drain and CT abdomen can be useful to guide our suspicion. We would like to highlight, though, that false negative is still possible on CT abdomen and complete clinical presentation must be taken into account to establish index of suspicion, in addition to imaging. For instance, in patient 2, we decided to perform surgical exploration due to continuous sepsis (temperature >40 °C) and feculent discharge from abdominal wound despite unremarkable CT finding. In contrast, the delayed diagnosis in patient 4 was rather unfortunate. Spiked temperature postoperatively was initially thought to result from hospital-acquired pneumonia (Pseudomonas-positive on sputum culture). Because of unresolved fever despite being on optimal antibiotic therapy, an abdominal CT imaging was performed, which showed a defect in lateral wall of stomach, and an urgent surgical intervention was conducted. Surprisingly, the patient’s recovery was unremarkable and had a relatively short postsurgical stay.\n\nAll six gastric perforations were diagnosed in the early postoperative phase (mean of 6 days). However, there were at least three incidents of gastric perforation described in the literature that manifested as a long-term complication of CRS and PIC [13–15]. The documented events occurred following discharge of patients from hospital. At our institution, all patients are monitored monthly for the first 3 months after discharge and six monthly thereafter, during which clinical examination and review of pertinent tumour markers are conducted. Thus far, we have not encountered a single case of gastric perforation throughout follow-up period following discharge for patients with CRS and PIC. However, we acknowledge and concur with Bhagwandi et al. [13] that possible occurrence of such life-threatening complication while patients are no longer monitored by the treating surgeon could lead to unnecessarily high morbidity and mortality. Therefore, follow-up schedule should be well established in each peritonectomy institution to track patients’ postoperative progress.\n\nNonoperative management of gastric perforation was proven to be viable by Crofts et al. [16] in managing patients with perforated gastric ulcer, dating back to 1989. It has been studied extensively in patients with perforated peptic ulcers, and the results have been promising when compared to operative management [17, 18]. This alternative can be executed by keeping the stomach empty through a strict nil-by-mouth regime and nasogastric aspiration, in adjunct with close monitoring of patient’s clinical status and administration of antibiotic and PPI [19]. We tried conservative management on one patient (patient 3). A lack of clinical improvement prompted immediate surgical intervention. Similarly, as outlined in Table 3, none of the patients were managed conservatively in the literature. As the nonoperative management hinges on allowing the perforated site to heal and seal by itself [19], the impact of HIPEC on this is currently not clear. Regardless of the mechanism, CRS and HIPEC are suggested to result in a weaker stomach wall, at least in the immediate postoperative phase. It would be sensible to refrain exerting more pressure on the stomach mucosa. Therefore, we propose to avoid suction on NG tubes following the procedure.\n\nConclusions\nGastric perforation is a rare surgical complication following CRS and PIC, and it is most likely the result of a multifactorial process. To reduce the risk of such complication, avoiding nasogastric suction in these patients may prove helpful. Nevertheless, any suspected perforated viscus must be addressed promptly to avoid unwanted morbidity and mortality from the procedure. To our knowledge, conservative management has not been documented to work in this subgroup and surgery remains the mainstay of treatment.\n\nAbbreviations\nCRSCytoreductive surgery\n\nHIPECHeated intraoperative intraperitoneal chemotherapy\n\nPCPeritoneal carcinomatosis\n\nPCIMean peritoneal cancer index\n\nPPIProton pump inhibitor\n\nAcknowledgement\nNot applicable.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.\n\nAvailability of data and materials\nAll data will be provided in the submitted tables.\n\nAuthors’ contributions\nLK is the main author. NA and JZ were involved in the editing of the paper and data collection. DLM was involved in the study design and patient recruitment. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nAll patient data was consented for use in publication.\n\nEthics approval and consent to participate\nAll our patients are preoperatively consented to have information stored in our database for research purposes (by South Eastern Sydney Local Health District Human Research Ethics Committee).\n==== Refs\nReferences\n1. Franko J Ibrahim Z Gusani NJ Holtzman MP Bartlett DL Zeh HJ III Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis Cancer 2010 116 3756 62 10.1002/cncr.25116 20564081 \n2. Glehen O Gilly FN Arvieux C Cotte E Boutitie F Mansvelt B Bereder JM Lorimier G Quenet F Elias D Association Francaise de Chirurgie Peritoneal carcinomatosis from gastric cancer: a multi-institutional study of 159 patients treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy Ann Surg Oncol 2010 17 2370 7 10.1245/s10434-010-1039-7 20336386 \n3. Verwaal VJ Ruth S Bree E Slooten GW Tinteren H Boot H Zoetmulder FAN Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer J Clin Oncol 2003 21 3737 43 10.1200/JCO.2003.04.187 14551293 \n4. Chua TC Yan TD Saxena A Morris DL Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure? A systematic review of morbidity and mortality Ann Surg 2009 249 900 7 10.1097/SLA.0b013e3181a45d86 19474692 \n5. Mehta SS Gelli M Agarwal D Goere D Complications of cytoreductive surgery and HIPEC in the treatment of peritoneal metastases Indian Assoc Surg Oncol 2016 7 225 9 10.1007/s13193-016-0504-6 \n6. Yan TD Links M Fransi S Jacques T Black D Saunders V Morris DL Learning curve for cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal surface malignancy—a journey to becoming a nationally funded peritonectomy center Ann Surg Oncol 2007 14 2270 80 10.1245/s10434-007-9406-8 17464543 \n7. Baratti D Kusamura S Laterza B Balestra MR Deraco M Early and long-term postoperative management following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy World J Gastrointest Oncol 2010 2 36 43 10.4251/wjgo.v2.i1.36 21160815 \n8. Jacquet P Sugarbaker PH Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis Cancer Treat Res 1996 82 359 74 10.1007/978-1-4613-1247-5_23 8849962 \n9. Zappa L Savady R Sugarbaker PH Gastric perforation following cytoreductive surgery with perioperative intraperitoneal chemotherapy J Surg Oncol 2010 101 634 6 10.1002/jso.21546 20461773 \n10. Daliya P White TJ Makhdoomi KR Gastric perforation in an adult male following nasogastric intubation Ann R Coll Surg Engl 2012 94 e210 2 10.1308/003588412X13171221502347 23031751 \n11. Carter J Durfee J A case of bowel perforation after neoadjuvant chemotherapy for advanced epithelial ovarian cancer Gynecol Oncol 2007 107 586 9 10.1016/j.ygyno.2007.09.008 17949798 \n12. Kusamura S Younan R Baratti D Costanzo P Favaro M Gavazzi C Deraco M Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique Am Cancer Soc 2006 106 1144 53 \n13. Bhagwandin SB Naffouje S Salti G Delayed presentation of major complications in patients undergoing cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy following hospital discharge J Surg Oncol 2015 111 324 7 10.1002/jso.23834 25557653 \n14. Munoz-Casares FC Medina-Fernandez FJ Arjona-Sanchez A Casado-Adam A Sanchez-Hidalgo JM Rubio MJ Ortega-Salas R Munoz-Villanueva MC Rufian-Pena S Briceno FJ Peritonectomy procedures and HIPEC in the treatment of peritoneal carcinomatosis from ovarian cancer: long-term outcomes and perspectives from a high-volume center Eur J Surg Oncol 2015 42 224 33 10.1016/j.ejso.2015.11.006 26673283 \n15. Martin AS Abbott DE Hanseman D Sussman JE Kenkel A Greiwe P Saeed N Ahmad SH Sussman JJ Ahmad SA Factors associated with readmission after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis Ann Surg Oncol 2016 23 1941 7 10.1245/s10434-016-5109-3 26842489 \n16. Crofts TJ Park KGM Steele RJC Chung SC Li AKC A randomized trial of nonoperative treatment for perforated peptic ulcer New Engl J Med 1989 320 15 10.1056/NEJM198904133201504 \n17. Cao F Li J Li A Fang Y Wang Y-J Li F Nonoperative management for perforated peptic ulcer: who can benefit? Asian J Surg 2014 37 148 53 10.1016/j.asjsur.2013.10.002 24393814 \n18. Dascalescu C Andriescu L Bulat C Danilla R Dodu L Acornicesei M Radulescu C Taylor’s method: a therapeutic alternative for perforated gastroduodenal ulcer Hepatogastroenterology 2006 53 543 6 16995458 \n19. Hanumanthappa MB Gopinathan S Rai DG Dsouza N A non-operative treatment of perforated peptic ulcer: a prospective study with 50 cases J Clin Diagn Res 2012 6 696 9 \n20. Ceelen WP Peeters M Houtmeyers P Breusegem FD Pattyn P Safety and efficacy of hyperthermic intraperitoneal chemoperfusion with high-dose oxaliplatin in patients with peritoneal carcinomatosis J Clin Diagn Res 2008 15 535 41\n\n",
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"keywords": "Appendiceal cancer; Gastric perforation; HIPEC; Heated intraoperative intraperitoneal chemotherapy; Nasogastric tube; Peritonectomy; Stomach; Suction",
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"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007036:Hypothermia, Induced; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D013275:Stomach Rupture",
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"abstract": "BACKGROUND\nAs the use of anti-angiogenic treatments is gaining scope in the treatment of various malignancies, there are increasing reports of laryngeal side effects. We report two cases of laryngeal necrosis and dysphonia.\n\n\nMETHODS\nTwo patients with gynecological malignancies presented with severe dysphonia 11-24 months after initiation of bevacizumab therapy. Videostroboscopic examination of the larynx revealed bilateral ulcerations and eschar of the superior surface with absent mucosal waves.\n\n\nRESULTS\nPatients were treated with discontinuation of the bevacizumab, vocal rest, and proton pump inhibitors. Both had improvement in voice and resolution of the eschar and ulceration. Shallow sulci and mild breathiness persisted in one patient.\n\n\nCONCLUSIONS\nWith increasing use of potent systemic anti-angiogenic compounds, clinicians should be vigilant of this important complication of therapy. Time to onset of symptoms and reversibility of symptoms vary by patient and require further study. There may be long-term voice sequelae.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Temple University Hospital.;Department of Surgical Oncology, Fox Chase Cancer Center.;Department of Speech Therapy, Fox Chase Cancer Center.;Department of Otolaryngology-Head and Neck Surgery, Temple University Hospital; Department of Surgical Oncology, Fox Chase Cancer Center. Electronic address: asoliman@temple.edu.",
"authors": "Sulibhavi|Anita|A|;Tharmalingam|Senthuran|S|;McCarroll|Liane|L|;Soliman|Ahmed M S|AMS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvoice.2020.11.028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0892-1997",
"issue": null,
"journal": "Journal of voice : official journal of the Voice Foundation",
"keywords": "Vocal fold necrosis—Dysphonia—Bevacizumab",
"medline_ta": "J Voice",
"mesh_terms": null,
"nlm_unique_id": "8712262",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33358072",
"pubdate": "2020-12-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reversible Bevacizumab Induced Vocal Fold Necrosis.",
"title_normalized": "reversible bevacizumab induced vocal fold necrosis"
} | [
{
"companynumb": "US-PFIZER INC-2021005220",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Celiac disease is a risk factor for lymphoma. Previously, we reported a case of diffuse large B-cell lymphoma (DLBCL) associated with celiac disease in a Japanese patient. Without any signs of DLBCL recurrence, he suddenly developed gastrointestinal symptoms and subcutaneous masses after resuming a gluten-containing diet. Peripheral T-cell lymphoma (PTCL) was diagnosed. Although a complete response was seen for 8 months, he was later admitted again with pleural and pericardial effusion due to PTCL. Expression of cytotoxic molecules, CCR4 and CXCR4 were all confirmed in PTCL cells, and the patient died soon afterwards. Clinically speaking, even though no gastrointestinal symptoms were seen, a gluten-free diet should have been strongly recommended for this patient.",
"affiliations": "Department of Internal Medicine, Division of Hematology, Shinshu University School of Medicine, Matsumoto, Japan. mhideki@hsp.md.shinshu-u.ac.jp",
"authors": "Makishima|Hideki|H|;Komiyama|Yuichi|Y|;Asano|Naoko|N|;Momose|Kayoko|K|;Nakamura|Shigeo|S|;Ishida|Fumihiro|F|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.47.0500",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "47(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D002446:Celiac Disease; D006801:Humans; D016393:Lymphoma, B-Cell; D016403:Lymphoma, Large B-Cell, Diffuse; D016411:Lymphoma, T-Cell, Peripheral; D008297:Male",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "295-8",
"pmc": null,
"pmid": "18277033",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Peripheral T-cell lymphoma following diffuse large B-cell lymphoma associated with celiac disease.",
"title_normalized": "peripheral t cell lymphoma following diffuse large b cell lymphoma associated with celiac disease"
} | [
{
"companynumb": "JP-ROCHE-2984189",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nTo analyse the clinical and computed tomography (CT) findings related to reactive thymic hyperplasia in order to improve the recognition of this phenomenon and avert over-treatment.\n\n\nMETHODS\nFifty-two children with pathologically proven lymphoma developed reactive thymic hyperplasia following chemotherapy, which was confirmed with long-term review and follow-up. The clinical and CT findings of these 52 children were retrospectively analysed.\n\n\nRESULTS\nThe median follow-up period for the whole study group was 32.9 months. Fifty-one children survived free of disease; 23 of these had been with tumour invasion and the remaining 29 without. The median period from complete remission (CR) of the mediastinal lesions to the date of recurrent mediastinal masses was 8.6 months, which was not statistically significantly different from that of 9.5 months from commencement of treatment to the date of newly developed mediastinal masses (P = 0.495). The median maximal diameters of the recurrent and newly developed mediastinal masses were not significantly different (P = 0.091). All of the 52 cases presented with a single mediastinal mass; 42 masses (42/52, 81%) of those showed trapezoidal or triangular shapes and were well-circumscribed; 10 masses (10/52, 19%) manifested diffuse shapes and were ill-circumscribed. Forty-two masses (42/52, 81%) showed homogeneous density. All of the masses revealed mild enhancement after contrast administration. Forty-two masses (42/52, 81%) slightly displaced and 10 masses (10/52, 19%) partly surrounded adjacent vessels. After long-term follow-up, 42 masses (42/52, 81%) shrank naturally, and 10 (10/52, 19%) remained unchanged.\n\n\nCONCLUSIONS\nReactive thymic hyperplasia can, and often does, occur in children receiving regular chemotherapy for lymphoma, regardless of whether the tumour initially invades the mediastinum. Knowing the characteristic CT findings of this benign entity is helpful in differentiating it from residual or recurrent lymphoma and averting unnecessary treatment.",
"affiliations": "Imaging Diagnosis and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou, China State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Imaging Diagnosis and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou, China State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Imaging Diagnosis and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou, China State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Imaging Diagnosis and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou, China State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China.;Imaging Diagnosis and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou, China State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China fanwei_9798@163.com.",
"authors": "Tian|Li|L|;Cai|Pei-Qiang|PQ|;Cui|Chun-Yan|CY|;Mo|Yun-Xian|YX|;Gong|Xiao|X|;Fan|Wei|W|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1093/ejcts/ezu303",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-7940",
"issue": "47(5)",
"journal": "European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery",
"keywords": "Chemotherapy; Children; Computed tomography; Hyperplasia; Lymphoma; Thymus",
"medline_ta": "Eur J Cardiothorac Surg",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008223:Lymphoma; D008297:Male; D008479:Mediastinal Neoplasms; D000069342:Medical Overuse; D012074:Remission Induction; D012189:Retrospective Studies; D013952:Thymus Hyperplasia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8804069",
"other_id": null,
"pages": "883-9",
"pmc": null,
"pmid": "25079775",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reactive thymic hyperplasia following chemotherapy for children with lymphoma: computed tomography may be able to provide valuable information to avoid over-treatment.",
"title_normalized": "reactive thymic hyperplasia following chemotherapy for children with lymphoma computed tomography may be able to provide valuable information to avoid over treatment"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-107898",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"dru... |
{
"abstract": "A middle-aged woman with a history of leiomyosarcoma of the uterus treated with surgery and adjuvant chemotherapy suffered a bulky metastatic recurrence 1 year later. She elected treatment with palliative eribulin, presenting with acute renal failure and electrolyte abnormalities consistent with tumour lysis syndrome on cycle 1 day 8. Despite aggressive supportive care and treatment including intravenous hydration, bicarbonate and rasburicase, she continued to decline, ultimately foregoing haemodialysis in favour of palliative care and passed away in the hospital.",
"affiliations": "College of Medicine, University of Florida, Gainesville, Florida, USA.;Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Department of Hematology and Oncology, University of Florida, Gainesville, Florida, USA.",
"authors": "Pabon|Cindy|C|;Esnakula|Ashwini K|AK|;Daily|Karen|K|",
"chemical_list": "D050256:Antimitotic Agents; D005663:Furans; D007659:Ketones; C490954:eribulin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-224576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "chemotherapy; gynecological cancer; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D050256:Antimitotic Agents; D017809:Fatal Outcome; D005260:Female; D005663:Furans; D006801:Humans; D007659:Ketones; D007890:Leiomyosarcoma; D008113:Liver Neoplasms; D008875:Middle Aged; D015275:Tumor Lysis Syndrome; D014594:Uterine Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30573532",
"pubdate": "2018-12-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7977169;12655435;26903338;28478879;23335221;29130003;28173193;21937277;21410837;24359983;16336296;28621163;22000653;21561350;8430709;11680837;18274611;25938028;9375703",
"title": "Tumour lysis syndrome following eribulin for metastatic uterine leiomyosarcoma.",
"title_normalized": "tumour lysis syndrome following eribulin for metastatic uterine leiomyosarcoma"
} | [
{
"companynumb": "GB-EISAI MEDICAL RESEARCH-EC-2019-049946",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERIBULIN"
},
"drugadditional":... |
{
"abstract": "This case report presents an adult patient with decreased levels of consciousness and bizarre behavior. A silent delirium was first suspected however, symptoms did not improve and further examination revealed elevated ammonia levels. A hepatic cause and portosystemic shunting were excluded and eventually a diagnosis of ornithine transcarbamylase deficiency was made. After treatment with high carbohydrate intake, a low protein diet and supplementation with arginine and sodium benzoate, the patient recovered.",
"affiliations": "Red Cross Hospital, Beverwijk, the Netherlands.",
"authors": "van Son|J|J|;Rietbroek|R C|RC|;Vaz|F M|FM|;Hollak|C E M|CEM|",
"chemical_list": "D004040:Dietary Carbohydrates",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "77(1)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D003244:Consciousness Disorders; D004040:Dietary Carbohydrates; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D008875:Middle Aged; D020163:Ornithine Carbamoyltransferase Deficiency Disease",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "25-28",
"pmc": null,
"pmid": "30774101",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bizarre behavior and decreased level of consciousness in an adult patient.",
"title_normalized": "bizarre behavior and decreased level of consciousness in an adult patient"
} | [
{
"companynumb": "NL-MYLANLABS-2019M1107704",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": "1",
... |
{
"abstract": "Sedation can be challenging in critically ill children. Inhaled anesthetics such as sevoflurane have proved to be useful in difficult or long-term sedation. However, its use in children out of the operating room is still limited and little is yet known about its use in patients undergoing ECMO with no previous reports in children. The objective is to assess the effectiveness and safety of sevoflurane during ECMO in two pediatric patients. Sedation was successfully achieved in both patients, and patients' contribution to breathing was possible even with deep sedation. There were not any side effects during sevoflurane treatment or after withdrawal.",
"affiliations": "Pediatric Intensive Care Unit, Gregorio Marañón University Hospital, Madrid, Spain.;Emergency Pediatric Department, Institute for Research and Health Care (IRCCS), Bambino Gesù Children's Hospital, Rome, Italy.;Pediatric Intensive Care Unit, Gregorio Marañón University Hospital, Madrid, Spain.;Pediatric Intensive Care Unit, Gregorio Marañón University Hospital, Madrid, Spain.",
"authors": "Butragueño Laiseca|Laura|L|0000-0001-5430-0488;Murciano|Manuel|M|;López-Herce|Jesús|J|;Mencía|Santiago|S|",
"chemical_list": "D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D000077149:Sevoflurane",
"country": "France",
"delete": false,
"doi": "10.1111/pan.14046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "31(2)",
"journal": "Paediatric anaesthesia",
"keywords": "ECMO; anesthetic conserving device (AnaConDa); critical care; difficult sedation; inhaled anesthetics; pediatric; sevoflurane",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation; D002648:Child; D016638:Critical Illness; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D008738:Methyl Ethers; D000077149:Sevoflurane",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "230-233",
"pmc": null,
"pmid": "33112440",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Inhaled sedation with sevoflurane in critically ill children during extracorporeal membrane oxygenation.",
"title_normalized": "inhaled sedation with sevoflurane in critically ill children during extracorporeal membrane oxygenation"
} | [
{
"companynumb": "ES-BBM-202100996",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "REMIFENTANIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nThe aim is to evaluate the role of diazepam concentrations in development of low-concentration-methadone-associated QTc prolongation in patients with opioid use disorder during methadone maintenance treatment (MMT) induction.\n\n\nMETHODS\nIndividuals with addiction disorder on MMT were studied before the beginning of MMT and after one and six months of MMT. Serum concentrations of methadone, diazepam, electrolytes and ECG were analyzed.\n\n\nRESULTS\nThirty patients were enrolled. The mean methadone concentration at time points was 177 ± 119 ng/ml and 343 ± 182 ng/ml, while the mean diazepam concentration was 561 ± 437 ng/ml and 1045 ± 933 ng/ml. The QTc interval before the introduction of MMT, after 1 and 6 months of MMT were 412 ± 27 ms, 425 ± 18 ms and 424 ± 15 ms, respectively, showing statistically significant increase in the length of QTc interval after 1 and 6 months of MMT. Statistically significant correlation between the concentration of methadone and QTc interval length at observed time points (R2 = 0.239, p = 0.018; R2 = 0.513, p = 0.006) was shown, and it remained so if the concentration of diazepam was included (R2 = 0.347, p = 0.026, R2 = 0.513, p = 0.009).\n\n\nCONCLUSIONS\nThe prolongation of QTc below the risk threshold in low methadone therapeutic doses has been recorded and concomitant use of diazepam could be a co-factor in such issue.",
"affiliations": "a Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia.;a Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia.;b Department of Forensic Medicine, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia.;a Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia.;c Department of Anesthesia and Perioperative Medicine, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia.;d Department of Psychiatry, Faculty of Medicine , University of Novi Sad , Novi Sad , Serbia.",
"authors": "Mijatović|Vesna|V|;Samojlik|Isidora|I|;Petković|Stojan|S|;Vukmirović|Saša|S|;Uvelin|Arsen|A|;Dickov|Aleksandra|A|",
"chemical_list": "D006993:Hypnotics and Sedatives; D003975:Diazepam; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1080/14740338.2017.1382470",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "16(12)",
"journal": "Expert opinion on drug safety",
"keywords": "Concentration; diazepam; heart; methadone; safety",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000328:Adult; D003975:Diazepam; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004562:Electrocardiography; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008133:Long QT Syndrome; D008297:Male; D008691:Methadone; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D010865:Pilot Projects; D011446:Prospective Studies; D013997:Time Factors",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "1323-1328",
"pmc": null,
"pmid": "28934555",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cardiovascular effects of methadone and concomitant use of diazepam during methadone maintenance treatment induction: low concentration risk.",
"title_normalized": "cardiovascular effects of methadone and concomitant use of diazepam during methadone maintenance treatment induction low concentration risk"
} | [
{
"companynumb": "RS-ALKEM LABORATORIES LIMITED-RS-ALKEM-2017-01306",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadd... |
{
"abstract": "We report a case of ileo-colonic Histoplasmosis without apparent respiratory involvement in a patient who had previously undergone an orthotopic liver transplant (OLT) for primary biliary cholangitis 15 years earlier. The recipient lived in the United Kingdom, a non-endemic region for Histoplasmosis. However, she had previously lived in rural southern Africa prior to her OLT. The patient presented with iron deficiency anaemia, diarrhoea, abdominal pain and progressive weight loss. She reported no previous foreign travel, however, it later became known that following her OLT she had been on holiday to rural southern Africa. On investigation, a mild granulomatous colitis primarily affecting the right colon was identified, that initially improved with mesalazine. Her symptoms worsened after 18 mo with progressive ulceration of her distal small bowel and right colon. Mycobacterial, Yersinia, cytomegalovirus and human immunodeficiency virus infections were excluded and the patient was treated with prednisolone for a working diagnosis of Crohn's disease. Despite some early symptom improvement following steroids, there was subsequent deterioration with the patient developing gram-negative sepsis and multi-organ failure, leading to her death. Post-mortem examination revealed that her ileo-colonic inflammation was caused by Histoplasmosis.",
"affiliations": "Department of Gastroenterology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United Kingdom.;Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE7 7DN, United Kingdom.;Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE7 7DN, United Kingdom.;Department of Radiology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United Kingdom.;Department of Histopathology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United Kingdom.;Department of Histopathology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United Kingdom.;Department of Gastroenterology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United Kingdom. nick.thompson@nuth.nhs.uk.",
"authors": "Agrawal|Nikita|N|;Jones|David Ej|DE|;Dyson|Jessica K|JK|;Hoare|Tim|T|;Melmore|Sharon A|SA|;Needham|Stephanie|S|;Thompson|Nick P|NP|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v23.i43.7807",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v23.i43.pg780710.3748/wjg.v23.i43.7807Case ReportFatal gastrointestinal histoplasmosis 15 years after orthotopic liver transplantation Agrawal Nikita Department of Gastroenterology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United KingdomJones David EJ Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE7 7DN, United KingdomDyson Jessica K Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE7 7DN, United KingdomHoare Tim Department of Radiology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United KingdomMelmore Sharon A Department of Histopathology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United KingdomNeedham Stephanie Department of Histopathology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United KingdomThompson Nick P Department of Gastroenterology, Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE7 7DN, United Kingdom. nick.thompson@nuth.nhs.ukAuthor contributions: All authors contributed to writing this case report and all authors apart from Agrawal N were involved in the care of this patient.\n\nCorrespondence to: Nick P Thompson, MD, Department of Gastroenterology, Newcastle Hospitals NHS Foundation Trust, High Heaton, Newcastle Upon Tyne NE7 7DN, United Kingdom. nick.thompson@nuth.nhs.uk\n\nTelephone: +44-191-2448584 Fax: +44-191-2231249\n\n21 11 2017 21 11 2017 23 43 7807 7812 19 7 2017 28 9 2017 17 10 2017 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.We report a case of ileo-colonic Histoplasmosis without apparent respiratory involvement in a patient who had previously undergone an orthotopic liver transplant (OLT) for primary biliary cholangitis 15 years earlier. The recipient lived in the United Kingdom, a non-endemic region for Histoplasmosis. However, she had previously lived in rural southern Africa prior to her OLT. The patient presented with iron deficiency anaemia, diarrhoea, abdominal pain and progressive weight loss. She reported no previous foreign travel, however, it later became known that following her OLT she had been on holiday to rural southern Africa. On investigation, a mild granulomatous colitis primarily affecting the right colon was identified, that initially improved with mesalazine. Her symptoms worsened after 18 mo with progressive ulceration of her distal small bowel and right colon. Mycobacterial, Yersinia, cytomegalovirus and human immunodeficiency virus infections were excluded and the patient was treated with prednisolone for a working diagnosis of Crohn’s disease. Despite some early symptom improvement following steroids, there was subsequent deterioration with the patient developing gram-negative sepsis and multi-organ failure, leading to her death. Post-mortem examination revealed that her ileo-colonic inflammation was caused by Histoplasmosis.\n\nHistoplasmosisOrthotopic liver transplantPrimary biliary cholangitisPrimary biliary cholangitis\n==== Body\nCore tip: Histoplasmosis is an endemic fungal infection in many parts of the world; the majority of hosts remain asymptomatic. Clinical manifestations are most commonly pulmonary. We present an unusual case of Histoplasmosis occurring in a patient who was living in a non-endemic region, developed the disease after 15 years of immunosuppression following an orthotopic liver transplant, she presented with no pulmonary symptoms but rather luminal GI and systemic symptoms. This highlights the importance of considering Histoplasmosis within the differential of immunosuppressed patients with a past relevant travel history who present with diarrhea, weight loss, abdominal pain and granulomatous colitis.\n\nINTRODUCTION\nGranulomatous inflammation of the terminal ileum and right colon is most commonly caused by Crohn’s disease in the United Kingdom, however chronic infections can cause similar appearances. Infectious causes include Mycobacteria tuberculosis and avium intracellulare complex, Yersinia, cytomegalovirus (CMV) and human immunodeficiency virus (HIV). Histoplasmosis is not endemic in the United Kingdom however this fungus can remain latent for many years following initial asymptomatic exposure and then may become active with a declining host immune response.\n\nCASE REPORT\nA 74-year-old Caucasian woman underwent orthotopic liver transplantation in 1997 for primary biliary cholangitis. She was referred initially to gastroenterology services in 2012 (15 years post-transplant), with new onset iron deficiency anaemia, loose watery stools with urgency occurring up to 3-4 times/wk, cramping lower abdominal pain and weight loss.\n\nIn 2009, she had been investigated for suspected interstitial pneumonitis with a trans-bronchial biopsy. No clear cause was established but she was commenced on steroids with subsequent normal chest imaging. Her other notable past medical history included hypercholesterolaemia, insulin-dependent diabetes mellitus and paroxysmal atrial tachycardia.\n\nHer medications were mycophenolate mofetil (MMF) 1 g twice daily; tacrolimus (Prograf) 1 mg twice daily, prednisolone 5 mg daily, aspirin, diltiazem, irbesartan, perindopril, ursodeoxycholic acid (UDCA), simvastatin, insulin and modafinil. There was no relevant family history. The patient reported no recent foreign travel however she had lived in Africa for almost 20 years during her 2nd-4th decades, spending periods of time in rural housing. Nonetheless, this was many years prior to liver transplantation and she had no known exposure to tuberculosis (TB). Blood results showed: Hb 11.0 gm/dL, MCV 77.2 fL, WCC 8.2 × 109/L, CRP < 5 mg/L, albumin 44 g/L, ferritin 23 μg/L, bilirubin 3 μmol/L, ALP 129 μ/L and ALT 21 μ/L. Coeliac serology was negative.\n\nGastroscopy showed gastritis with scattered antral erosions with a negative Helicobacter urease test. The patient’s gastritis and anaemia were managed with lansoprazole and oral iron replacement, respectively, and aspirin was stopped. Routine repeat gastroscopy 6 wk later showed improvement. A colonoscopy was performed that showed an indistinct mucosal vascular pattern in the ascending colon, with biopsies revealing a moderately active, right-sided, chronic granulomatous colitis. Given the lack of any past history of inflammatory bowel disease (IBD) and the patient’s longstanding immunosuppression, infection was considered. The patient displayed no clinical or laboratory evidence of disseminated infection. She reported no fevers, night sweats, cough or haemoptysis. Inflammatory markers were within normal limits and her chest X-ray (CXR) was normal. Both a Quantiferon gold test and Yersinia serology were negative. A faecal calprotectin was mildly raised at 136 μg/g and small bowel imaging with both magnetic resonance (MR) enterography and a barium follow-through were performed. These showed no significant abnormality, with no evidence of inflammatory bowel disease affecting the small bowel.\n\nAs no infective cause had been found, a presumptive diagnosis of mild Crohn’s colitis was made and the patient was started on a trial of mesalazine in November 2012 with almost complete remission of her symptoms when she was seen in clinic 4 mo later. At that time lansoprazole was replaced with ranitidine in case the proton pump inhibitor had contributed to her symptoms. In June 2013 the patient stopped her mesalazine as she felt so well.\n\nUnfortunately her symptoms recurred in December 2013, and at clinic review in May 2014 she had lost 10 kg of weight, was having loose bowel motions 3-4 times/d with associated urgency, nocturnal symptoms and occasional faecal incontinence. She also complained of indigestion and early satiety although no dysphagia.\n\nGastroscopy in July 2014 showed mild oesophagitis and erythematous gastritis, with biopsy findings of mild focal duodenitis but no granulomatous changes, viral inclusions, parasites, metaplasia or changes suggestive of coeliac disease. Helicobacter urease test was now positive. Repeat colonoscopy showed more significant patchy inflammation and focal ulceration in the right colon. Colonic biopsies showed scattered giant cells and granulomas and terminal ileal biopsies revealed small bowel mucosa distorted with reactive lymphoid tissue and increased eosinophils, lymphocytes and plasma cells in the lamina propria. The pattern was most suggestive of IBD or unusual infections, rather than MMF-related changes, but other drug-related damage could not be excluded. Immunohistochemistry for CMV was negative and acid fast bacilli stain was negative. Mesalazine was restarted, however this time there was no significant symptomatic improvement- prompting a gastroenterology referral.\n\nShe was seen by the gastroenterology service in October 2014 at which time her stool frequency was 20 times/d, with ongoing urgency, incontinence and cramping abdominal pain. There was no evidence of blood in the stool or steatorrhoea. She continued to suffer from early satiety, anorexia and had now lost almost 20 kg in weight in the preceding year. A computed tomography (CT) scan of the chest, abdomen and pelvis showed no malignant lesion to explain her symptoms. However it did confirm the appearance of enterocolitis affecting the distal 15 cm of terminal ileum with associated stricturing, as well as the ascending colon up to the hepatic flexure (Figure 1). No abnormality was seen in the lungs. As atypical infections appeared to have been excluded a presumptive diagnosis of Crohn’s disease was made and her steroid dose was increased from a maintenance dose of prednisolone 5 mg that she had been on since 2010, to 30 mg daily (with a tapering course) which resulted in some improvement of symptoms. Her severe diarrhoea continued and culminated in a hospital admission in November 2014 due to severe dehydration and acute kidney injury. Although this improved with intravenous fluids, a second course of increased steroids was not beneficial. Virology screen confirmed negative HIV status. Bloods tests revealed: Hb 112 g/L, MCV 77.2 fL, WCC 10.8 × 109/L, neutrophils 9.09 × 109/L, CRP 15 mg/L, ESR 9 mm/h, albumin 32 g/L, bilirubin 11 μmol/L, ALP 120 μ/L, ALT 11 μ/L and GGT 107 μ/L. A repeat Quantiferon test was again negative.\n\nFigure 1 Axial image from computed tomography Chest/Abdomen/Pelvis performed with intravenous (IV) and oral contrast showing non-specific colonic wall thickening in the ascending colon (arrowed) and hepatic flexure characterised by discontinuous mucosal hyperenhancement and submucosal oedema reflecting ulceration and inflammation.\n\nGiven a presumptive diagnosis of progressive Crohn’s disease by December 2014, both surgery and infliximab were considered. However, she rapidly deteriorated with evidence of gastrointestinal bleeding. The patient developed Enterococcus septicaemia likely as a secondary complication of her immunosuppressed state and gut inflammation, with subsequent multi-organ failure, and she sadly died in January 2015.\n\nA limited post-mortem examination of the abdomen showed active inflammation and ulceration of the terminal ileum and most of the large intestine. Histological examination revealed abundant intracellular, small oval encapsulated narrow-based budding yeast cells some of which showed a peri-organism halo. The features were those of Histoplasma capsulatum, confirmed with positive Grocott and Giemsa histochemical staining (Figure 2). Her final diagnosis was therefore of gram-negative septicaemia as a complication of gastrointestinal Histoplasmosis, immunosuppression and diabetes. Review of her 2014 ileocolonic biopsies at this time with the addition of Grocott stain highlighted scant forms in keeping with Histoplasmosis.\n\nFigure 2 Extensive infiltration of bowel mucosa by the small histoplasmosis, Grocott stain.\n\nWe discovered on later discussion with her family that although the patient had not lived abroad for any prolonged period following her liver transplant, she had visited Southern Africa during this period and stayed in very basic accommodation. Thus, exposure to Histoplasmosis could have either been at this point, in her already immunosuppressed state, or earlier when she had lived in Africa with a prolonged period of dormancy until transplantation and increasing immunosuppressive treatments.\n\nOn reflection, there were opportunities for considering Histoplasmosis within the differential diagnosis. At the time of the second colonoscopy, the pattern of ulcerating ileo-colitis raised the possibility of an unusual infection especially in a long-term immunosuppressed individual with diabetes as well as Crohn’s disease. Mycobacterial, Yersinia, HIV and CMV infections were excluded, though Histoplasmosis was not considered and as such Grocott stain was not performed at this time.\n\nDISCUSSION\nHistoplasmosis is a fungal infection that is typically acquired by inhalation of microscopic spores of the dimorphic fungus Histoplasma capsulatum, an organism found in parts of central and eastern North America, Central and South America, Africa, Asia and Australia[1-5]. Its spores thrive in and thus are predominantly found in nitrogen or phosphate- enriched soils that are associated with large amounts of bat and bird guano, including in caves colonized by bats[6,7] .\n\nHost exposure occurs after inhalation of airborne microconidia (spores) following disturbance of contaminated material in the soil in daily activities, and is extremely common in endemic areas[7,8]. The inhaled H. capsulatum transforms from a mold to a yeast state in the lungs, and is phagocytosed by alveolar macrophages, in which it can multiply. These macrophages then disseminate the organism throughout the rest of the body via the reticuloandothelial system; generally before a cell mediated immune response can develop[7,9] .\n\nThe majority (> 99%) of people exposed to H. capsulatum will still be asymptomatic or as the lungs are the entry portals for the organism, show only a mild self-limiting respiratory illness[7]. These people have generally undergone haemategenous dissemination of the organism, however the subsequent development of T cell mediated immunity adequately controls and overcomes the primary infection-preventing it progressing or manifesting[7,8,10,11] .\n\nIn the < 1% of patients who do develop clinically appreciable infection, disease severity of Histoplasmosis, is dependent on the number of conidia inhaled and adequacy of the host’s T-cell mediated immune response[7] . As such, the healthy host exposed to a relatively small inoculum of H. capsulatum would remain asymptomatic, while progressive primary disseminated disease would tend to occur in immunosuppressed patients (particularly with cellular immunity compromise), and especially if exposed to large inoculums of the organism.\n\nRisk factors for developing disseminated Histoplasmosis disease at primary infection include: extremes of age, immunosuppressive conditions such as acquired immune deficiency syndrome (AIDS), haematological malignancies, solid organ transplants (SOTs), stem cell transplants and congenital T-cell deficiency syndromes, as well as immunosuppressive agents-particularly tumour necrosis factor antagonists[7,12] .\n\nNonetheless, despite SOT being a risk factor for disseminated histoplasmosis, the absolute incidence of the disease in this patient group still remains low. One prospective surveillance study estimated incidence at 1.6/1000 patients, with the highest incidence being in liver transplant patients, though the most cases overall in kidney transplant recipients, as the latter were so much more common[13]. Subsequent large American studies estimate the overall incidence of Histoplasmosis in patients with SOTs at < 0.5%, despite America having a higher endemic rate of the disease than in Europe[14].\n\nThe highest risk of developing Histoplasmosis in an exposed patient was in the first year post transplant, although the risk persists up to 20 years later[14]. Use of mycophenolate for immunosuppression and presence of fungaemia were the 2 specific risk factors for severe histoplasmosis in SOT patients identified by multivariate risk factor analysis[14]. Graft rejection appeared not to be a risk factor for Histoplasmosis in these patients[15].\n\nMoreover it should be noted that even in healthy hosts, though the cell mediated immune response against H. capsulatum may potentially control the primary infection and prevent symptom manifestation, it does not eradicate the organism. As such H.capsulatum can remain silently viable in scattered foci throughout the body for years following initial infection[7]. Leaving these individuals prone to future reactivation of disease with any subsequent decline in cellular immunity; even if this occurs years after they have left the endemic region where they acquired the primary infection[7].\n\nAlternatively, secondary infection can occur if an individual with past exposure to H.capsulatum returns to an endemic region and is exposed to a second large inoculum in a newly immunosuppressed state[7]. As our patient visited endemic regions for H.capsulatum both before and after her liver transplant, it is impossible to elucidate the mechanism by which she developed infection - new primary infection, secondary infection or reactivation.\n\nIn terms of clinical presentation of Histoplasmosis in the < 1% of patients who develop disease, there is a huge spectrum, with almost all the organ systems having potential for involvement following dissemination of the organism. There is a broad subdivision into either pulmonary Histoplasmosis (for predominantly respiratory disease) or disseminated Histoplasmosis (for clinical, laboratory or imaging evidence of extra pulmonary disease)[7].\n\nThe presentation of pulmonary Histoplasmosis itself is wide-ranging-from rapidly progressive forms which can present like an acute respiratory distress syndrome (ARDS) picture, more chronic cavitatory Histoplasmosis in older patients with underlying past pulmonary disease, and progressive infection of mediastinal lymph nodes causing granulomatous mediastinitis or mediastinal fibrosis[7]. Our patient did present in 2009 with an interstitial fibrosis noted on her CT scans, and was started on steroids for this as no obvious cause was found for it. This seemed to significantly improve both her symptoms and CT scan, her later chest radiology appearances did not suggest any pulmonary disease, so it is presumed this was not a respiratory manifestation of Histoplasmosis.\n\nDisseminated Histoplasmosis manifests even more diversely. It can present with single organ involvement as the sole feature of dissemination, or significant systemic features +/- multi-organ involvement or at the most aggressive end of the spectrum- a systemic inflammatory response syndrome mimicking severe sepsis with complications including hypotension, acute kidney injury and disseminated intravascular coagulation[7].\n\nSystemic symptoms in disseminated histoplasmosis include anorexia, weight loss, fatigue and fevers; examination findings can include lymphadenopathy, hepatosplenomegaly, and in some, mucocutaneous lesions such as ulcerations. Blood tests might reveal raised inflammatory markers including CRP, ESR and ferritin[7].\n\nGastrointestinal histoplasmosis is believed to be a subset of disseminated disease[16,17] and though organisms are often found within the GI tract (one autopsy series identified the organism in 70% cases of disseminated histoplasmosis[18]), significant symptomatic disease affecting this system is strikingly less common with another study reporting the incidence of clinically diagnosed GI disease in only 3%-12% of patients with disseminated histoplasmosis[19]. This discrepancy between autopsy proven presence of the organism and symptomatic disease is present in various other organ systems too, likely because haematagenous dissemination ensures seeding of the organism throughout the body, though organism presence doesn’t necessarily correlate with clinical disease.\n\nObserved specific GI symptoms aside from the systemic ones already mentioned include intermittent abdominal pain and diarrhea (both watery and bloody), which in severe cases led to malabsorption[7]. The most serious complications were bowel perforation and haemorrhage[9]. The most commonly involved sites were the colon, then the small bowel. Radiological findings include bowel wall thickening, mass like lesions and signs of small bowel obstruction[9], while endoscopically mucosal ulcerations were most commonly seen (both unifocal and multiple), as well as polypoid lesions, obstructive masses and strictures[7,20].\n\nIn the case described here, a diagnosis of Histoplamosis was only made at post-mortem examination. However, if the diagnosis had been considered earlier, a urinary Histoplasma antigen test, which is one of the most sensitive diagnostic methods, could have been used[14]. Antigen testing is also suggested as a useful way of monitoring treatment response; antigen concentrations decrease with therapy and increase in disease relapse[8]. Primary detection on ileocolonic biopsy material may also have been possible if a fungal infection had been suspected and Grocott’s methanamine silver stain had been performed at this time.\n\nHistoplasmosis is an eminently treatable disease, with even severe disseminated forms responding well to IV amphotericin B, stepped down to oral azoles for generally at least a 12 mo course[8,14]. If left untreated, this condition often proves fatal.\n\nOverall we have described a case of primarily luminal GI Histoplasmosis, with absent clinical/radiological evidence of pulmonary involvement, occurring 15 years following liver transplantation, in a non-endemic region.\n\nAlthough Histoplasmosis is a relatively rare disease (even in immunosuppressed patients most prone to developing it); it is eminently treatable if appropriately considered and tested for. Severe disseminated Histoplasmosis if left untreated can often prove fatal. For immunosuppressed patients especially, regardless of where they reside, it is important to consider Histoplasmosis within the differential for ileo-colonic inflammation if a thorough travel history reveals stay in an endemic region, with the possibility of exposure to H. capsulatum, even if this was years prior to immunocompromise. The presence of additional pulmonary and/or systemic features may further suggest this disease, although the absence of these features is not enough to disregard the disease.\n\nCOMMENTS\nCase characteristics\nThe patient presented 15 years post liver transplant for primary biliary cholangitis, with an iron deficiency anaemia, diarrhea, abdominal pain and progressive weight loss while living in the United Kingdom. Travel history revealed she had previously lived in rural Africa prior to transplantation and later that she had on holiday there again post transplantation, living in quite basic accommodation.\n\nClinical diagnosis\nThe patient had primarily luminal GI symptoms without any pulmonary symptoms of note since she presented in 2012. She went on to develop multi-organ failure ultimately; the diagnosis of Histoplasmosis was made at post-mortem examination.\n\nDifferential diagnosis\nIncludes Crohn’s disease, as well as other atypical infective causes of colitis including human immunodeficiency virus, Yersinia, Tuberculosis and cytomegalovirus (all of which were excluded). Histoplasmosis could have also been considered within the differential diagnosis at this point, given the deterioration in spite of treatment as probable Crohn’s disease, immunosuppression and the travel history to an endemic region for Histoplasmosis. Her initial travel history was reported as not having been abroad for many years.\n\nLaboratory diagnosis\nAlthough in the case, the diagnosis was only made at post mortem, a urinary Histoplasma antigen test is considered one of the most sensitive diagnostic methods for Histoplasmosis.\n\nImaging diagnosis\nComputed Tomography imaging revealed colonic wall thickening, mucosal hyper-enhancement and submucosal oedema reflecting ulceration and inflammation of the ascending colon and hepatic flexure. Endoscopy revealed ileo-colonic ulceration with granulomatous inflammation.\n\nPathological diagnosis\nGrocott’s methanamine silver staining and Giemsa histochemical staining identifies Histoplasma capsulatum in biopsy material from affected sites (in this case post mortem GI tract).\n\nTreatment\nGenerally should be given to all those presenting with disseminated histoplamosis. Initially treatment consists of intravenous amphotericin B, which can subsequently be stepped down to usually at least a 12-mo treatment course of an oral azole, e.g., itraconazole.\n\nRelated reports\nHistoplasmosis is a usually an asymptomatic fungal infection in > 99% of exposed people, with the small percentage who do manifest symptoms having primarily pulmonary symptoms. It is largely immunosuppressed patients (with AIDS or other immune deficiencies) who develop disseminated Histoplasmosis, with primary GI luminal disease being rarely reported in the literature, especially post liver transplantation.\n\nTerm explanation\nHistoplasmosis is an endemic fungal infection acquired through inhalation of the spores of Histoplasma capsulatum after disruption of soil containing bat and bird guano in endemic regions.\n\nExperiences and lessons\nWe note the importance of considering Histoplasmosis within the differential diagnosis for immunosuppressed patients presenting with a granulomatous entero-colitis even in non-endemic areas. Taking a full and detailed history of travel to an endemic region at any point in the past is especially important.\n\nPeer-review\nThe article of Nikita Agrawal and colaborators shows fatal gastrointestinal histoplasmosis 15 years after orthotopic liver transplantation. This is a good piece of work, data are consistent, paper is well written and conclusions based on presented data.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: United Kingdom\n\nPeer-review report classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): B, B\n\nGrade C (Good): 0\n\nGrade D (Fair): D\n\nGrade E (Poor): 0\n\nInformed consent statement: Consent for publication granted by next of kin.\n\nConflict-of-interest statement: No conflict of interests are declared by any authors.\n\nPeer-review started: July 20, 2017\n\nFirst decision: August 10, 2017\n\nArticle in press: October 17, 2017\n\nP- Reviewer: Lu K, Hilmi I, Paramesh ASS, Zhang JJ S- Editor: Qi Y L- Editor: A E- Editor: Lu YJ\n==== Refs\n1 Manos NE Ferebee SH Kerschbaum WF Geographic variation in the prevalence of histoplasmin sensitivity Dis Chest 1956 29 649 668 13317782 \n2 Colombo AL Tobón A Restrepo A Queiroz-Telles F Nucci M Epidemiology of endemic systemic fungal infections in Latin America Med Mycol 2011 49 785 798 21539506 \n3 Loulergue P Bastides F Baudouin V Chandenier J Mariani-Kurkdjian P Dupont B Viard JP Dromer F Lortholary O Literature review and case histories of Histoplasma capsulatum var. duboisii infections in HIV-infected patients Emerg Infect Dis 2007 13 1647 1652 18217546 \n4 Chakrabarti A Slavin MA Endemic fungal infections in the Asia-Pacific region Med Mycol 2011 49 337 344 21254966 \n5 McLeod DS Mortimer RH Perry-Keene DA Allworth A Woods ML Perry-Keene J McBride WJ Coulter C Robson JM Histoplasmosis in Australia: report of 16 cases and literature review Medicine (Baltimore) 2011 90 61 68 21200187 \n6 Teixeira Mde M Patané JS Taylor ML Gómez BL Theodoro RC de Hoog S Engelthaler DM Zancopé-Oliveira RM Felipe MS Barker BM Worldwide Phylogenetic Distributions and Population Dynamics of the Genus Histoplasma PLoS Negl Trop Dis 2016 10 e0004732 27248851 \n7 Kauffman CA Histoplasmosis: a clinical and laboratory update Clin Microbiol Rev 2007 20 115 132 17223625 \n8 Wheat J Sarosi G McKinsey D Hamill R Bradsher R Johnson P Loyd J Kauffman C Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society of America Clin Infect Dis 2000 30 688 695 10770731 \n9 Psarros G Kauffman CA Colonic histoplasmosis: a difficult diagnostic problem Gastroenterol Hepatol (N Y) 2007 3 461 463 23329906 \n10 Kauffman CA Israel KS Smith JW White AC Schwarz J Brooks GF Histoplasmosis in immunosuppressed patients Am J Med 1978 64 923 932 350045 \n11 Anand A Diagnosis of systemic histoplasmosis in AIDS patients South Med J 1993 86 844 845 \n12 Assi M McKinsey DS Driks MR O’Connor MC Bonacini M Graham B Manian F Gastrointestinal histoplasmosis in the acquired immunodeficiency syndrome: report of 18 cases and literature review Diagn Microbiol Infect Dis 2006 55 195 201 16545932 \n13 Freifeld A Kauffman C Pappas P Endemic fungal infections among solid organ transplant recipients. Presented at Infectious Disease Society of America 43rd Annual Meeting; San Francisco, California; October 6-9, 2005. Abstract 737 \n14 Assi M Martin S Wheat LJ Hage C Freifeld A Avery R Baddley JW Vergidis P Miller R Andes D Histoplasmosis after solid organ transplant Clin Infect Dis 2013 57 1542 1549 24046304 \n15 Kauffman CA Freifeld AG Andes DR Baddley JW Herwaldt L Walker RC Alexander BD Anaissie EJ Benedict K Ito JI Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET) Transpl Infect Dis 2014 16 213 224 24589027 \n16 Kahi CJ Wheat LJ Allen SD Sarosi GA Gastrointestinal histoplasmosis Am J Gastroenterol 2005 100 220 231 15654803 \n17 Cappell MS Mandell W Grimes MM Neu HC Gastrointestinal histoplasmosis Dig Dis Sci 1988 33 353 360 3277825 \n18 Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM Disseminated histoplasmosis: clinical and pathologic correlations Medicine (Baltimore) 1980 59 1 33 7356773 \n19 Wheat LJ Connolly-Stringfield PA Baker RL Curfman MF Eads ME Israel KS Norris SA Webb DH Zeckel ML Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature Medicine (Baltimore) 1990 69 361 374 2233233 \n20 Lamps LW Molina CP West AB Haggitt RC Scott MA The pathologic spectrum of gastrointestinal and hepatic histoplasmosis Am J Clin Pathol 2000 113 64 72 10631859\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "23(43)",
"journal": "World journal of gastroenterology",
"keywords": "Histoplasmosis; Orthotopic liver transplant; Primary biliary cholangitis",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D015746:Abdominal Pain; D000353:Africa, Southern; D000368:Aged; D018798:Anemia, Iron-Deficiency; D015209:Cholangitis, Sclerosing; D003424:Crohn Disease; D003937:Diagnosis, Differential; D003967:Diarrhea; D017809:Fatal Outcome; D005260:Female; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007413:Intestinal Mucosa; D016031:Liver Transplantation; D009102:Multiple Organ Failure; D013997:Time Factors; D000076082:Travel-Related Illness; D015431:Weight Loss",
"nlm_unique_id": "100883448",
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"pages": "7807-7812",
"pmc": null,
"pmid": "29209121",
"pubdate": "2017-11-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2233233;23329906;15654803;16545932;21254966;350045;10631859;13317782;3277825;24046304;27248851;18217546;17223625;10770731;21539506;24589027;8322097;21200187;7356773",
"title": "Fatal gastrointestinal histoplasmosis 15 years after orthotopic liver transplantation.",
"title_normalized": "fatal gastrointestinal histoplasmosis 15 years after orthotopic liver transplantation"
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"abstract": "Compared with other plasmodium species which cause human malaria, Plasmodium malariae is considered to be relatively infrequent and milder, although recent reports indicate that its prevalence and impact have been under-estimated. A 23-month-old boy, born and previously living in a refugee camp in Liberia who presented with P. malariae 6 weeks after arrival in the USA, is reported. Despite ostensibly effective anti-malarial treatment with artemether/lumefantrine and two courses of hydrochloroquine, he experienced recurrent parasitaemia, refractory anaemia and splenomegaly over a 6-month period; the symptoms resolved after he received atovaquone/proguanil. It is hypothesised that the recrudescing clinical malaria in this case was related to the long pre-erythrocytic phase unique to P. malariae, and potentially also to a proportion of the parasites being drug-resistant.",
"affiliations": "a Division of Pediatric Infectious Diseases , University at Buffalo, State University of New York , Buffalo , NY , USA.;b Pediatric Residency Program , University at Buffalo, State University of New York , Buffalo , NY , USA.",
"authors": "Islam|Shamim|S|;Hai|Faizi|F|",
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"country": "England",
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"doi": "10.1080/20469047.2017.1378797",
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"issue": "38(4)",
"journal": "Paediatrics and international child health",
"keywords": "A/L: artemether/lumefantrine; AT-PG: atovaquone-proguanil; G6PD: glucose-6-phosphate dehydrogenase; HCQ: hydrochloroquine; LCM: left costal margin; MCV: mean corpuscular volume; Plasmodium malariae; RT-PCR: reverse transcriptase polymerase chain reaction; anaemia; malaria; refugee and immigrant health; splenomegaly",
"medline_ta": "Paediatr Int Child Health",
"mesh_terms": "D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D053626:Atovaquone; D002738:Chloroquine; D000076263:Communicable Diseases, Imported; D004338:Drug Combinations; D054242:Emigrants and Immigrants; D006801:Humans; D007223:Infant; D007988:Liberia; D008288:Malaria; D008297:Male; D010965:Plasmodium malariae; D002727:Proguanil; D012008:Recurrence; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "101582666",
"other_id": null,
"pages": "290-293",
"pmc": null,
"pmid": "28975859",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recrudescing Plasmodium malariae infection despite appropriate treatment in an immigrant toddler.",
"title_normalized": "recrudescing plasmodium malariae infection despite appropriate treatment in an immigrant toddler"
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"abstract": "Low-molecular-weight heparin is commonly favored over unfractionated heparin because of its predictable pharmacokinetic and pharmacodynamic properties. However, full-dose enoxaparin can cause major soft tissue bleeding that may lead to compartment syndrome and even limb amputation. In patients with spinal cord injury, range of motion exercises should be carefully performed if on full-dose enoxaparin. This vulnerable patient population is particularly susceptible to aggressive stretching, which could lead to bleeding, and compartment syndrome. Providers should also monitor weight fluctuations in patients receiving full-dose enoxaparin. Changes in weight without proper dose adjustment can cause over or under treatment. Attention to both these issues can improve patient care.",
"affiliations": null,
"authors": "Yeung|Vincent|V|;Formal|Christopher|C|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin",
"country": "England",
"delete": false,
"doi": "10.1179/2045772314Y.0000000219",
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"issue": "38(2)",
"journal": "The journal of spinal cord medicine",
"keywords": "Enoxaparin; Hematoma; Spinal cord injury; Tetraplegia",
"medline_ta": "J Spinal Cord Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000925:Anticoagulants; D017984:Enoxaparin; D006470:Hemorrhage; D006801:Humans; D035002:Lower Extremity; D008297:Male; D008875:Middle Aged; D013119:Spinal Cord Injuries",
"nlm_unique_id": "9504452",
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"pages": "236-8",
"pmc": null,
"pmid": "24820930",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19926048;12881837;17321834;6712454;7559695;20170785;21959588",
"title": "Lower extremity hemorrhage in patients with spinal cord injury receiving enoxaparin therapy.",
"title_normalized": "lower extremity hemorrhage in patients with spinal cord injury receiving enoxaparin therapy"
} | [
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"abstract": "BACKGROUND\nLiposomal formulation of anthracyclines provide better systemic and organ-specific tolerance, with potential for less local tissue damage during extravasation. Several small series have reported that most liposomal anthracycline extravasations are consistent with irritant injury without tissue necrosis. There have been no reports published regarding the clinical effects of extravasation of liposomal cytarabine-daunorubicin (CPX-351).\n\n\nMETHODS\nThe patient received CPX-351 for relapsed acute myelogenous leukemia via a left chest wall port-a-catheter. The catheter became dislodged. Once symptoms developed, the infusion was discontinued, with observations demonstrating an 8-cm region of edema, warmth, no erythema, and no drainage. Limited supportive management was performed. Physical examination the following day demonstrated no evidence of necrosis, and erythema resolved completely without additional intervention.\n\n\nCONCLUSIONS\nCPX-351 extravasation behaving as an irritant is consistent with the reports of other liposomal anthracyclines.",
"affiliations": "Division of Hematology Oncology, David Geffen School of Medicine and University of California, Los Angeles, CA, U.S.A.;Division of Hematology Oncology, David Geffen School of Medicine and University of California, Los Angeles, CA, U.S.A.;Division of Hematology Oncology, David Geffen School of Medicine and University of California, Los Angeles, CA, U.S.A. gschiller@mednet.ucla.edu.",
"authors": "Howell|Grant|G|;Oliai|Caspian|C|;Schiller|Gary|G|",
"chemical_list": "D008081:Liposomes; D003561:Cytarabine; D003630:Daunorubicin",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13070",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "38(12)",
"journal": "Anticancer research",
"keywords": "CPX-351; anthracycline extravasation; extravasation; irritant; liposomal daunorubicin; vesicant",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D015505:Chest Tubes; D003561:Cytarabine; D003630:Daunorubicin; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008081:Liposomes; D062666:Vascular Access Devices",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6927-6930",
"pmc": null,
"pmid": "30504411",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Liposomal Cytarabine-Daunorubicin (CPX-351) Extravasation: Case Report and Literature Review.",
"title_normalized": "liposomal cytarabine daunorubicin cpx 351 extravasation case report and literature review"
} | [
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"companynumb": "US-FRESENIUS KABI-FK201813299",
"fulfillexpeditecriteria": "1",
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"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYTARABINE"
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"drugadditional": "1",
... |
{
"abstract": "Background: Saprochaete clavata infection is an emerging issue in immunosuppressed patients, causing fulminant fungaemia. The purpose of this systematic review of cases is to retrieve all cases of S. clavata infection and describe oral lesions as the first manifestation of S. clavata infection. Methods: We report the first case of intraoral S. clavata infection in Acute Myeloid Leukemia (AML) affected subject, presenting as multiple grayish rapidly growing ulcerated swellings, and provide a review of all published cases of infection caused by S. clavata, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, conducted by searching SCOPUS, Medline, and CENTRAL databases. Only articles in English were considered. Individual patient data were analyzed to identify risk factors for S. clavata infection. Results: Seventeen of 68 retrieved articles were included in the review reporting data on 96 patients (mean age 51.8 years, 57 males and 38 females). Most cases were disseminated (86) with a 60.2% mortality rate. Ninety-five were hematological patients, with AML being the most common (57 cases). Conclusions:S. clavata infection in immunosuppressed patients has a poor prognosis: middle-age patients, male gender and Acute Myeloid Leukemia should be considered risk factors. In immunosuppressed patients, the clinical presentation can be particularly unusual, imposing difficult differential diagnosis, as in the reported case.",
"affiliations": "Head and Neck Department, \"Fondazione Policlinico Universitario A. Gemelli-IRCCS\", School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome, Italy.;Head and Neck Department, \"Fondazione Policlinico Universitario A. Gemelli-IRCCS\", School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome, Italy.;Head and Neck Department, \"Fondazione Policlinico Universitario A. Gemelli-IRCCS\", School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome, Italy.;Head and Neck Department, \"Fondazione Policlinico Universitario A. Gemelli-IRCCS\", School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome, Italy.;Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.;Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania Luigi Vanvitelli, Via Luigi de Crecchio, 6, 80138 Naples, Italy.;Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.",
"authors": "Lajolo|Carlo|C|0000-0003-4663-9734;Rupe|Cosimo|C|;Schiavelli|Anna|A|;Gioco|Gioele|G|;Metafuni|Elisabetta|E|;Contaldo|Maria|M|0000-0002-4773-6694;Sica|Simona|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijerph18052385",
"fulltext": "\n==== Front\nInt J Environ Res Public Health\nInt J Environ Res Public Health\nijerph\nInternational Journal of Environmental Research and Public Health\n1661-7827\n1660-4601\nMDPI\n\n10.3390/ijerph18052385\nijerph-18-02385\nReview\nSaprochaete clavata Infection in Immunosuppressed Patients: Systematic Review of Cases and Report of the First Oral Manifestation, Focusing on Differential Diagnosis\nhttps://orcid.org/0000-0003-4663-9734\nLajolo Carlo 1\nRupe Cosimo 1*\nSchiavelli Anna 1\nGioco Gioele 1\nMetafuni Elisabetta 23\nContaldo Maria 4\nSica Simona 23\nTchounwou Paul Academic Editor\nBourgeois Denis Academic Editor\n1 Head and Neck Department, “Fondazione Policlinico Universitario A. Gemelli—IRCCS”, School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome, Italy; carlo.lajolo@policlinicogemelli.it (C.L.); anna.schiavelli@gmail.com (A.S.); gioele.gioco@gmail.com (G.G.)\n2 Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; bettymetafuni@yahoo.it (E.M.); simona.sica@policlinicogemelli.it (S.S.)\n3 Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, 00168 Rome, Italy\n4 Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania Luigi Vanvitelli, Via Luigi de Crecchio, 6, 80138 Naples, Italy; maria.contaldo@unicampania.it\n* Correspondence: cosimo.rupe01@icatt.it\n01 3 2021\n3 2021\n18 5 238513 1 2021\n24 2 2021\n© 2021 by the authors.\n2021\nLicensee 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/).\nBackground: Saprochaete clavata infection is an emerging issue in immunosuppressed patients, causing fulminant fungaemia. The purpose of this systematic review of cases is to retrieve all cases of S. clavata infection and describe oral lesions as the first manifestation of S. clavata infection. Methods: We report the first case of intraoral S. clavata infection in Acute Myeloid Leukemia (AML) affected subject, presenting as multiple grayish rapidly growing ulcerated swellings, and provide a review of all published cases of infection caused by S. clavata, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, conducted by searching SCOPUS, Medline, and CENTRAL databases. Only articles in English were considered. Individual patient data were analyzed to identify risk factors for S. clavata infection. Results: Seventeen of 68 retrieved articles were included in the review reporting data on 96 patients (mean age 51.8 years, 57 males and 38 females). Most cases were disseminated (86) with a 60.2% mortality rate. Ninety-five were hematological patients, with AML being the most common (57 cases). Conclusions: S. clavata infection in immunosuppressed patients has a poor prognosis: middle-age patients, male gender and Acute Myeloid Leukemia should be considered risk factors. In immunosuppressed patients, the clinical presentation can be particularly unusual, imposing difficult differential diagnosis, as in the reported case.\n\nSaprochaete clavata\nGeotrichum clavatum\nrare mycoses\n==== Body\n1. Introduction\n\nOpportunistic fungal infections represent a major cause of morbidity and mortality in patients with malignant hematological diseases [1,2,3]. Aspergillus and Candida species are the most frequent etiological agents, while Geotrichum genus has only recently been detected as an emerging opportunistic pathogen in hematological patients [4,5].\n\nGeotrichum is a ubiquitous, filamentous, yeast-like genus of fungi composed of 18 species, among which Geotrichum clavatum (reclassified as Saprochaete clavata) and Geotrichum capitatum (reclassified as Saprochaete capitata) are the most common pathogens for human infection [6].\n\nThe genus Geotrichum can be found worldwide in soil, water, air, wood, animals, and dairy products. Moreover, it has also been isolated as a commensal fungus in the respiratory secretions and gastrointestinal tract of Mediterranean subjects [7,8]. Orofecal transmission is the most common source of infection [9]; in particular, ingestion of cheese seems to be the most common way, as these fungi are used in cheese maturing.\n\nWhen a S. clavata infection arises in immunosuppressed patients, it may cause fulminant fungaemia with multi-organ involvement and it has a 60% to 80% mortality rate. Disseminated infection initially arises with nonspecific symptoms (i.e., fever, diarrhea, and pulmonary symptoms), and most infections are mainly diagnosed by blood culture [10]. The clinical presentation in immunocompetent patients is less severe and rarely reported [11].\n\nThe most commonly reported risk factors associated with S. clavata infection include hematological malignancy, prolonged neutropenia, high-dose corticosteroid therapy, broad-spectrum antibiotic therapy, previous gastrointestinal colonization, and central venous catheters [4,12,13,14].\n\nThe purpose of this systematic review of cases is to report all cases of S. clavata infection and to describe the first case of oral lesions as the first manifestation of S. clavata infection in an immunosuppressed subject, especially focusing on the differential diagnosis of the oral lesions.\n\n2. Methods\n\nThe present systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive and systematic electronic search in Medline (via PubMed), Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) from database inception to December 2020 was conducted. The date of the last search was 16 December 2020. The database search was conducted by using a combination of the following MeSH terms and free text words: “Saprochaete” OR “Geotrichum” AND “rare mycoses”. A supplementary manual search was conducted for articles published from the journals’ inception dates and December 2020 in the following journals: Oral Oncology; Clinical Oral Investigations; Journal of Oral Pathology and Medicine; Oral Surgery, Oral Medicine, Oral Pathology, and Oral Radiology; Head and Face Medicine; and Oral Diseases. In addition, the bibliographies of all the selected articles were reviewed. Inclusion criteria were: full papers; English literature; observational clinical studies, namely, case reports, perspective and retrospective (cohort and case-control) and randomized clinical trials (RCTs); patients who received an S. clavata infection. All of the articles reporting cases of S. clavata infection were included in this review. No exclusion criteria were applied. Two reviewers (C.R. and C.L.) conducted the screening, independently and in duplicate, by using specially designed data extraction forms. For each included article, the variables collected included the year of publication, country, number of patients, gender and age of patients, underlying disease, clinical manifestation of the infection, and the final outcome of patient. Any disagreements were resolved by a third reviewer (A.S.). All data collected were analyzed using a computer program (SPSS v 21.0, Chicago, IL, USA).\n\n3. Results\n\nThe initial search of the electronic databases yielded 68 articles, and the manual search yielded 2 additional articles. In total, 46 articles were removed on the basis of the review of their titles and abstracts, reporting other fungal infections; thus, 22 full-text articles were selected. Of these studies, 17 were included in the review (Figure 1).\n\nPooled data from the literature review, stratified according to Geographic Distribution, Age, Gender, Anamnesis, and Clinical Features of patients, are shown in Table 1. This systematic review of the literature retrieved 96 cases of S. clavata infection. Most of the cases have been diagnosed in France (46 cases) or Italy (35 cases) and middle age (51.8 years) and male gender (57 males and 38 females) seem to be more frequently affected. Most cases were disseminated (86), leading to death (60.2% of mortality rate). Other sites involved in the infection were gastrointestinal (24 patients had diarrhea) and pulmonary (27). Only one case arose with a single organ involvement (a splenic abscess). Considering the underlying immunodepression cause, 95 were hematological patients (comprising our case report) and only 1 was affected by polycystic kidney disease (PCKD). Among the hematological diseases, Acute Myeloid Leukemia was the most common (57 cases), whereas Lymphomas or Acute Lymphoid Leukemia were diagnosed in 12 and 10 cases, respectively. As concerning infection treatment, data about 48 patients were available; most of the patients (36) were treated by Azoles (30 patients by Voriconazole, 4 by Posaconazole). Other treatments were mainly based on Amphotericin B (27 patients), often in association with Azoles.\n\n4. Case Report\n\nA 56-year-old Caucasian man affected by acute myeloid leukemia (AML) was admitted to the Hematological Department of Policlinico A. Gemelli (Rome, Italy) for febrile neutropenia with multiple oral swellings. The patient’s medical history revealed previous diagnoses of myelodysplastic syndrome (2016), refractory anemia with excess blasts type 1 (RAEB-1), which was treated with ten cycles of decitabine and an allogenic hematopoietic stem cell transplantation. This recurring disease evolved into Acute Myeloid Leukemia (2018). Consequently, re-induction chemotherapy was administered using Chlorambucil and Cytarabine first, followed by a combination of Azacitidine and Venetoclax. In October 2019, the patient was hospitalized for febrile neutropenia with severe thrombocytopenia. At that moment, the patient was receiving antifungal prophylaxis with Posaconazole 300 mg/die. Blood culture was performed and the research for yeasts was negative. The physical examination did not retrieve any skin lesion. The oral examination revealed that three rapidly growing asymptomatic ulcerated swellings, located on both the buccal mucosa and the left mandible, arose 15 days before (Figure 2, Figure 3 and Figure 4).\n\nLesions were light-grayish in color, friable, with a 4 cm diameter, and protruded from the mucosa, interfering with chewing. After a platelet transfusion and local anesthesia (Carbocaine 2% with epinephrine 1:100,000; Dentsply, Verona, Italy), an incisional biopsy was performed together with a microbiological sampling for fungi. The pathology revealed an inflammatory process in association with purulent necrosis and microbial colonies; no granulomas were detected in the specimen. Part of the sample was discharged in liquid Amies medium, then streak-plated on Sabouraud dextrose agar plates supplemented with gentamicin and chloramphenicol (Bio-Rad, Hercules, CA, USA) and BBL CHROMagar Candida plate (BD). We identified species using Bruker Biotyper version MBT 3.1 matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (Bruker) and nucleotide sequence analysis of the internal transcribed spacer (ITS) regions of the rRNA gene. Microbiological sampling was thus positive for S. clavata, thus the final diagnosis indicated an intraoral fungal infection due to S. clavata. The Minimal inhibitory concentrantions (MICs) of antifungal drugs were determined in parallel according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) standardized broth microdilution method [27].\n\nGiven the results of the antifungal susceptibility testing, a therapy based on Voriconazole 200 mg bid was set and resulted in the resolution of the oral lesions and improvement of the overall condition. Two weeks after the beginning of the therapy, the patient was dismissed, continuing the therapy with Voriconazole for two months. Nevertheless, in February 2020, the patient died from a worsening of his general conditions and underlying disease persistence.\n\n5. Discussion\n\nDeep fungal infections represent a major cause of morbidity and mortality in onco-hematological patients undergoing immunosuppressing chemotherapies or those who have undergone bone marrow transplantation. In fact, fungi are responsible for approximately 20% of microbiologically documented intensive care unit (ICU) infections. In the last decade, the incidence of invasive fungal infections has steadily increased as a result of the increasing numbers of both immunocompromised and critically ill patients [1,2,3,4,10,11,28].\n\nIn spite of this, the life expectancy of onco-hematological patients is rising thanks to improved diagnostic and therapeutical techniques; on the other side, the onco-hematological population is increasingly susceptible to rare infections, like S. clavata, which has been recognized as an emerging issue [5]. Three major sources of infection have been recognized: contaminated medical devices or dishes or dairy products have been advocated as major sources of S. clavata [9], but, considering published literature, the source of infection was unclear in the majority of the cases [26,28].\n\nEven if the literature review identified only case reports and case series, probably due to the newly diagnosed entity, the articles included in this systematic review showed some results (Table 2) that should be taken into consideration for clinicians and future studies.\n\nS. clavata infection seems to be more common in males (57 to 38 patients), even if more diagnosed cases are needed to state that male gender is a risk factor for S. clavata infection. The mean age of affected patients was 51.8 years. Middle age should be considered as a risk factor for the development of this infection, even if our results showed how even younger or pediatric patients could be affected. In order to better assess the risk factors linked to this infection, clinical studies providing a higher level of evidence should be performed.\n\nAccording to the available literature, the majority of patients affected by S. clavata had received a diagnosis of Acute Myeloid Leukemia and underwent a therapy based on Cytarabine, an antineoplastic drug that can alter digestive mucosa. It has been hypothesized that the mucosal alteration caused by Cytarabine allows S. clavata translocation from the gastrointestinal tract, thus promoting the diffusion and the infection [9]. Although this hypothesis could explain the pathogenetic mechanism favoring S. clavata infection, it is not clear why mainly hematological patients are affected compared to other immunosuppressed patients (95 to 1 in the reported cases) [29,30].\n\nAlthough S. clavata infection usually arises with nonspecific symptoms, it causes disseminated infection in almost all of the cases (86 out of 96 of the included cases), threatening the survival of infected patients. In this light, it is crucial to reach an early diagnosis in order to start the correct treatment.\n\nConsidering the treatment, three major classes of antifungal agents can be considered: polyenes, azoles, and echinocandins. Polyenes (i.e., amphotericin B, nystatin) bind to ergosterol of fungal membrane, causing its disruption (fungicidal); Azoles (i.e., Voriconazole, Itraconazole) act by inhibiting ergosterol synthesis in the endoplasmic reticulum of the fungal cell (fungistatic) and echinocandins (i.e., Caspofungin, Anidulafungin, Micafungin) and inhibit the synthesis of some components of the fungi cell wall. According to the available literature, S. clavata seems to be intrinsically resistant to echinocandins [31], whereas Voriconazole, Itraconazole, Posaconazole, Amphotericin B, and 5-fluorocytosine showed some efficacy [9,32]; Voriconazole appears to be the most suitable treatment since it has shown effectiveness both in vitro and in vivo [3,9,14,33].\n\nThe results of this systematic review show how Voriconazole and Amphotericin B are the most used treatment: 5 patients were treated by Voriconazole alone, all of them survived. Two patients were treated by Amphotericin B alone, but their outcome was not successful. The association between these two drugs was the treatment of choice for the majority of patients (21): eleven of them survived, while 10 patients died. Although only scattered data could be obtained from our literature review, the hypothesis that Voriconazole is the most effective treatment can be supported, even if further studies are needed to confirm it.\n\nConsidering our experience, even if our patient was already, at the admission, undergoing a prophylactic treatment based on Posaconazole (300 mg die) to prevent opportunistic infections, the susceptibility testing confirmed that both Posaconazole and Voriconazole were effective drugs against S. clavata, but oral lesions healed only after the use of Voriconazole (200 mg bid): this strengthened the hypothesis that Voriconazole is the most effective treatment.\n\nThis case report describes the first case of oral lesions as the first manifestation of S. clavata infection and the literature review did not find any other case with oral involvement, thus differential diagnosis was particularly demanding. The infection manifested as three rapidly growing asymptomatic ulcerated swellings, located on both the buccal mucosa and the left mandible, that arose 15 days before. Lesions were light grayish in color, friable, with a 4 cm diameter, and protruded from the mucosa, interfering with chewing (Figure 1). Since clinical presentation of common and rare diseases can be really unusual in immunosuppressed patients, the diagnosis of these lesions was particularly challenging, but some clinical characteristics drove the differential diagnosis: rapid growth, ulcerating feature, bilateral onset, and absence of any other symptom (i.e., pain, itching, burning sensation). For these reasons, oral or deep fungal infections, other opportunistic infections, relapses, or new onset of hematological diseases and granulomatous diseases have been considered in the differential diagnosis (Table 3).\n\nCandida and Aspergillus are the most common opportunistic fungal infections affecting the oral cavity [5]. In this case, oral candidiasis was excluded because its most common clinical presentations (Pseudomembranous Candidiasis and Acute erythematous candidiasis) do not comprise rapidly growing asymptomatic ulcerated swellings; nevertheless, a microbiological culture was performed to exclude C. albicans and other species infection or its superimposed infection.\n\nAspergillosis is a fungal disease characterized by noninvasive and invasive forms; in immunocompromised hosts, the invasive form can cause disseminated and life-threatening infections. This opportunistic fungal infection is reported as the second most prevalent one worldwide [50]. Aspergillosis spores can colonize the brain, the bones, the lungs, or the endocardium [5,51,52,53,54]. Signs and symptoms that may affect the head and neck district include sinusitis, oropharyngeal colonization, pain, swelling, ulceration, necrosis, and palatal perforation. In addition, the hyphae are able to penetrate the oral mucosa and the arterial wall, which may lead to hematogenous spread, thrombosis, or infarction [55,56]. Considering the clinical presentation of our case, oral Aspergillosis lesions arise generally as swelling with a necrotic ulcerated base, classically located on the palate or posterior tongue [5]. Nevertheless, microbiological culture on the biopsy sample was performed to exclude the diagnosis of oral Aspergillosis.\n\nHistoplasmosis is another clinical entity that can appear as a rapidly growing asymptomatic oral ulceration. Although it is the most common fungal infection in the United States, Histoplasmosis in Europe is rare [57]. Almost 95% of the immunocompetent patients that are exposed to the Histoplasma capsulatum never develop symptoms [58]. Yet, inhaling a large number of spores can cause symptoms even among healthy patients. Histoplasmosis has two manifestations: acute or chronic/disseminated. Only this latter form can affect the oral mucosa, causing painful chronic ulcerations, single or multiple, nonhealing and indurated [59]. The hypothesis of a case of Histoplasmosis was rejected according to the medical history of the patient, thanks to microbiological culture and pathology.\n\nAmong other infections, Syphilis, Tuberculosis, and Actinomycosis must be considered in the differential diagnosis. Treponema Pallidum infection in immunosuppressed individuals can cause diffused ulcerations of the oral cavity, with severe clinical appearance. Nevertheless, in our case, the TPHA (Treponema Pallidum Hemoagglutination Assay) was negative at admission in the hospital [60,61]. Tuberculosis causes ulcerations as well, affecting mainly the tongue and the palate, and usually have an “infiltrating” feature more than exophytic [62]; furthermore, pathology can reveal typical caseous tuberculous granulomas which can drive the diagnosis.\n\nActinomycosis is a chronic bacterial disease that may affect jaws after traumas, surgeries, previous infections, or in patients with other diseases. In the head and neck region, the condition appears as swelling associated with osteomyelitis and often with one or more draining, from the medullary spaces to skin or sinuses [63]. Only a few cases of ulcerations on the tongue associated with A. israelii have been reported in the literature [48]. This diagnosis has been excluded after the microbiological culture on the biopsied specimen.\n\nConsidering other malignancies, lymphomas can appear as rapidly growing asymptomatic ulcerated swellings: Hodgkin’s lymphomas are very rare in the oral cavity but can affect the neck district, whereas, for non-Hodgkin’s lymphomas, the head and neck region represents the second most common extra-nodal site [41,64]. Thus, a relapse of Acute Myeloid Leukemia or a new manifestation of any other hematological malignancy was excluded through pathology, which revealed an inflammatory process in association with purulent necrosis and microbial colonies. Considering other non-hematological malignancies, only verrucous carcinoma could be considered, but the rapid onset and the multifocal nature of these lesions immediately excluded such diagnosis; the following pathology confirmed the exclusion.\n\nFinally, some orofacial granulomatosis should be considered in the differential diagnosis since most of them can present as oral ulcerated swellings. Wegener granulomatosis, Crohn’s disease, sarcoidosis, and Melkersson–Rosenthal Syndrome are the most relevant.\n\nWegener granulomatosis is a rare immune-based inflammatory necrotizing vasculitis of unknown cause, classically characterized by involvement of upper respiratory tract, lungs, and kidneys. The typical oral manifestation is strawberry gingivitis; less frequent findings include oral ulceration, necrosis, and perforation of the nasal septum or palate.\n\nCrohn’s disease may affect the gastrointestinal tract from mouth to anus. A wide range of nonspecific oral lesions has been associated with this condition, including ulcers (aphthous-like, with a granulomatous appearing, or linear aspect), diffuse or nodular swellings, a cobblestone appearance of the mucosa, or macules and plaques involving the gingiva.\n\nSarcoidosis is a multisystem granulomatous disease of unknown cause that can affect any organ but the lungs, the lymph nodes, the skin, the eyes, and the salivary glands are the predominant sites. Oral lesions may occur on any surface, in most cases, as a submucosal mass, ulceration, a nodular swelling, an area of granularity, or an isolated papule. When this condition is characterized by recurring facial paralysis, swelling of the lips and a fissured tongue is called Melkersson–Rosenthal Syndrome.\n\nMelkersson–Rosenthal Syndrome intraoral lesions can include edema, ulcers, papules, swellings, cobblestone mucosal alterations, or focal areas of submucosal enlargement.\n\nFor all these entities, pathology reveals the presence of classic non-caseating granulomas together with some peculiar clinical features (i.e., abdominal pain, diarrhea, rectal blood loss, facial nerve paralysis) [65] or laboratory tests which can help in differentiating each other (i.e., presence of proteinase-3 antineutrophil cytoplasm antibodies—PR3-ANCA, myeloperoxidase antineutrophil cytoplasm antibodies—MPO-ANCA, elevated serum angiotensin-converting enzyme (ACE) levels) [66]. All these diseases were excluded since no granulomas were detected in the oral biopsy.\n\n6. Conclusions\n\nS. clavata infection may cause fulminant fungaemia with multi-organ involvement in immunosuppressed patients with a 60.2% mortality rate: middle-age patients, male gender and Acute Myeloid Leukemia should be considered risk factors. Some reports highlighted that previous therapy with Cytarabine should be considered as a further risk factor. Our case is the first report of intraoral lesions as the first manifestation of S. clavata in an immunodeficient patient. Proliferative oral lesions in the immunosuppressed hematological subject are always challenging for the oral medicine doctor since the immune system response of these patients is abnormal: numerous benign and malignant diseases (i.e., lymphoma, other hematological malignancies, infectious diseases, granulomatous diseases) must be excluded. In this regard, microbiological sampling is fundamental in order to exclude rare mycotic infections.\n\nAuthor Contributions\n\nConceptualization, all authors; methodology, C.L. and C.R.; validation, C.L. and S.S.; formal analysis, C.L. and C.R.; investigation, C.R., A.S., E.M., and G.G.; data curation, C.R. and A.S.; writing—original draft preparation, C.L., C.R., and A.S.; writing—review and editing, C.L. and C.R.; visualization, S.S., E.M., and M.C.; supervision, C.L. and S.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nNot Applicable.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow-chart of the systematic review.\n\nFigure 2 Asymptomatic ulcerated lesion, located on the right buccal mucosa.\n\nFigure 3 Asymptomatic ulcerated lesion, located on the left buccal mucosa.\n\nFigure 4 Asymptomatic ulcerated lesion, located on the left mandible.\n\nijerph-18-02385-t001_Table 1 Table 1 Pooled data from a literature review, stratified according to geographic distribution, age, gender, anamnesis, and clinical features.\n\nStudy\tN. of Cases\tCountry\tGender\tAge\tUnderlying Disease\tClinical Form\tTreatment\tOutcome\t\nLacroix et al., 2007 [15]\t2\tFrance\tM\t14\tAML\tDisseminated\tVCZ, Amph\tSurvived\t\n\t\t\tM\t59\tAML\tDisseminated\tPCZ, Amph, 5-F\tSurvived\t\nPicard et al., 2014 [16]\t3\tFrance\tF\t46\tAML\tDisseminated\tVCZ, Amph\tDied\t\n\t\t\tM\t70\tAML\tDisseminated, Pulmonary\tCaspo\tDied\t\n\t\t\tF\t63\tAML\tDisseminated\tVCZ, Amph\tDied\t\nVaux et al., 2014 [9]\t30\tFrance\tM (15),\nF (15)\t63 (mean)\tAML (21), ALL (6), Other (3)\tDisseminated (26), Pulmonary (12), Diarrhea (18)\tNs\tDied (24), Survived (6)\t\nCamus et al., 2014 [14]\t1\tFrance\tM\t32\tAML\tDisseminated, Peritonitis, Hepatic Lesions\tVCZ\tSurvived\t\nDel Principe et al., 2016 [4]\t3\tItaly\tF\t36\tAML\tPulmonary, Cholecystitis, Hepatosplenic abscesses\tVCZ, Amph\tSurvived\t\n\t\t\tF\t50\tLymphoma\tDisseminated, Pulmonary, Splenic infiltrated\tVCZ, Amph\tDied\t\n\t\t\tM\t21\tAML\tSplenic Abscesses\tVCZ, Amph\tSurvived\t\nFavre et al., 2016 [12]\t1\tFrance\tM\t27\tAA\tDisseminated\tVCZ, Amph\tSurvived\t\nDe Almeida et al., 2016 [17]\t1\tBrazil\tF\t6\tOther\tNs\tVCZ, Amph\tDied\t\n\t18\tItaly\tM (11)\nF (6)\nNs (1)\tNs\tAML (8), Lymphoma (3), AA (2), Other (3), Ns (2)\tDisseminated (18)\t\tNs\t\n\t\t\nEsposto et al., 2018 [18]\tNs\t\n\t\t\n\t\t\nLiu et al., 2018 [19]\t1\tChina\tM\t10\tALL\tDisseminated, Pulmonary\tVCZ, Mica, Amph\tSurvived\t\nSalguero-Fernandez et al., 2018 [20]\t1\tSpain\tM\t47\tLymphoma\tDisseminated, Skin\tAmph, 5-F\tDied\t\nLeoni et al., 2018 [21]\t1\tItaly\tM\t6\tOther\tDisseminated, Pulmonary, Skin, Renal\tVCZ, Amph\tSurvived\t\nBuchta et al., 2019 [22]\t11\tCzechia\tM\t45\tAML\tDisseminated\tVCZ, Amph\tDied\t\n\t\tCzechia\tF\t61\tAML\tDisseminated\tAmph\tDied\t\n\t\tCzechia\tF\t63\tAML\tDisseminated\tVCZ, Amph\tSurvived\t\n\t\tCzechia\tF\t58\tAML\tDisseminated, Pulmonary\tVCZ, Amph\tDied\t\n\t\tCzechia\tF\t50\tAML\tDisseminated, Pulmonary\tAmph\tDied\t\n\t\tCzechia\tF\t66\tLymphoma\tDisseminated\tVCZ, Mica\tDied\t\n\t\tTurkey *\tF\t37\tAML\tDisseminated\tVCZ\tSurvived\t\n\t\tIsrael *\tF\t17\tAML\tDisseminated, Liver, Spleen, CNS\tVCZ, Amph, 5-F\tSurvived\t\n\t\tSpain *\tM\t48\tLymphoma\tDisseminated, CNS, Liver, Pulmonary, Spleen\tVCZ, Amph, 5-F\tDied\t\n\t\tGermany *\tM\t55\tAML\tDisseminated\tVCZ, Amph\tSurvived\t\n\t\tSerbia *\tM\t19\tALL\tDisseminated, Pulmonary\tCaspo\tDied\t\nPavone et al., 2019 [23]\t1\tItaly\tF\t54\tPCKD\tDisseminated, Peritonitis\tVCZ, Amph\tDied\t\nWee et al., 2019 [24]\t1\tSingapore\tM\t13\tALL\tDisseminated, Kidney, Liver, Skin\tVCZ, Amph\tSurvived\t\nStanzani et al., 2019 [10]\t4\tItaly\tM\t66\tLymphoma\tPulmonary\tVCZ\tSurvived\t\n\t\t\tF\t48\tAML\tDisseminated, Pulmonary, Liver, Spleen, Kidney\tVCZ, Amph\tSurvived\t\n\t\t\tM\t34\tLymphoma\tDisseminated\tVCZ\tSurvived\t\n\t\t\tM\t64\tAML\tDisseminated, Pulmonary, Spleen, CNS\tVCZ, Amph\tDied\t\nLo Cascio et al., 2020 [25]\t7\tItaly\tM (6)\nF (1)\t41.1 (mean)\tAML (5), ALL (1), Lymphoma (1)\tDisseminated (7), Diarrhea (3)\tAmph (3), Echi (2), AZ (2)\tDied (3)\nSurvived (4)\t\nMenu et al., 2020 [26]\t9\tFrance\tM (6)\nF (3)\t57.8 (mean)\tAML (4), Lymphoma (2), ALL (1), Other (2)\tDisseminated (8), Pulmonary (3), Diarrhea (3) Digestive Symptoms (2)\tVCZ (4), PCZ (3), Echi (2)\tDied (5)\nSurvived (4)\t\nThis study\t1\tItaly\tM\t56\tAML\tOral Lesions\tVCZ\tSurvived\t\nAML: Acute Myeloid Leukemia; ALL: Acute Lymphoid Leukemia, AA: Aplastic Anemia, PCKD: Polycystic Kidney Disease, CNS: Central Nervous System, Ns: Non-specified, VCZ: Voriconazole, PCZ: Posaconazole, Mica: Micafungin, Caspo: Caspofungin, Amph: Amphotericin B; Echi: Echinocandins; AZ: Azoles; 5-F: 5-fluorocytosine. * Cases retrieved by the international registry FungiScope.\n\nijerph-18-02385-t002_Table 2 Table 2 Main results of the review. * Mortality rate was calculated excluding the articles not reporting the final outcome of patients.\n\nAge\t\t\nYears\t51.8 (mean)\t\nGender\t\t\nMale\t57\t\nFemale\t38\t\nNon-Specified\t1\t\nCountry\tTot 96\t\nFrance\t46\t\nItaly\t35\t\nCzech\t6\t\nOther Countries (Spain, Germany, Brazil, Turkey, Israel, Serbia, China, Singapore)\t9\t\nOutcome\tTotal Number (mortality rate *)\t\nDeath\t47 (60.2%)\t\nSurvival\t31 (38.8%)\t\n\nijerph-18-02385-t003_Table 3 Table 3 Differential diagnosis for oral manifestation of Saprochaete clavata.\n\nClinical Entity\tEtiology and Pathogenesis\tClinical Manifestation\tDiagnosis\tReason for Exclusion during the Diagnostic Flow-Chart\t\nUsual Features\tUnusual Oral Presentation\tSite\t\nOpportunistic Infections\t\t\t\t\t\t\t\nCandidiasis [34]\tC. Albicans and other C. spp.\tPseudomembranous Candidiasis: white, soft plaques, removable, sometimes burning sensation and altered taste.\nAcute erythematous candidiasis: Erythema, usually painful\tRapidly growing exophytic lesions\tBuccal mucosa\nPalate\nDorsal tongue\tMicrobiological culture\tUsually do not comprise rapidly growing asymptomatic ulcerated swellings\t\nAspergillosis\tAspergillus spp.\tOral manifestations do not arise in immunocompetent hosts\tInvasive form: swelling, ulceration, necrosis, usually painful\tParanasal sinuses\nOropharynx\nPalate\nDorsal Tongue\tMicrobiological culture\t(a) Uncommon location of the lesions\n(b) Absence of symptoms\n(c) Microbiological culture\t\nHistoplasmosis\tH. Capsulatum\tHistoplasmosis of the head and neck is rarely seen in immunocompetent patients\tRapidly growing asymptomatic oral ulceration with firm margins, single or multiple, nonhealing.\tTongue,\nPalate,\nBuccal mucosa\tMicrobiological culture and pathology\t(a) Oral Histoplasmosis usually does not appear as a friable swelling\n(b) Medical history: no travels in US\n(c) Microbiological culture and pathology\t\nSyphilis [35,36]\tT. Pallidum\tPrimary syphilis indurated ulcer, asymptomatic.\nSecondary syphilis: red rash characterized by maculopapular areas, oral ulcers covered by membrane, or condyloma lata\tVascular proliferation, multiple ulcerated areas, hemorrhage\tLips, but any other site can be involved\tDirect detection of T. pallidum and serologic testing (treponemal and non-treponemal tests, i.e., TPHA)\t(a) Negative TPHA\n(b) Absence of characteristic systemic symptoms (secondary syphilis)\n(c) Pathology (absence of proliferative endarteritis and infiltration of plasma cells)\t\nTuberculosis [37]\tMycobacterium Tuberculosis\tOral lesions are uncommon and occur due to infected sputum or hematogenous spread\tChronic and indurated ulcer, non-healing extraction sockets, osteomyelitis, and mandibular swellings.\tTongue and palate but any mucosal surface can be involved.\nBone of maxilla or mandible\tMolecular tests (nucleic acid amplification test—Xpert MTB/RIF), Pathology, microbiological tests (mycobacterial growth indicator tube—MGIT)\t(a) Pathology (absence of typical caseous tuberculous granulomas)\n(b) Clinical presentation: Tuberculosis oral lesions usually have an “infiltrating” feature more than exophytic\t\nActinomycosis [38,39]\tActinomyces spp.\tFibrosis, swellings, cutaneous draining sinus tracts\tUlcerations of the tongue and osteomyelitis. One reported case of involvement of floor of the mouth and buccal mucosa\tMandible and surrounding tissues. Salivary glands\tMicrobiological culture and pathology\tMicrobiological culture and pathology (absence of granulomatous inflammatory response)\t\nMalignant Diseases\t\t\t\t\t\t\t\nLymphomas [40,41,42]\tHeterogeneous malignant disease of the lymphatic system\tHodgkin’s lymphomas: very rare in the oral cavity.\nNon-Hodgkin’s lymphomas: rapidly growing asymptomatic ulcerated swellings, bone resorption, or bone loss\tPathologic fracture. Pain, numbness of the lip.\tTonsils,\nSalivary glands,\nmaxilla,\nbase of the tongue,\nSoft palate\tHistopathological examination (presence of Reed-Stemberg cells for Hodgkin’s lymphomas), immunophenotyping, flow cytometry\tPathology and immunohistochemistry according to the lymphoma type\t\nVerrucous Carcinoma [43,44]\tExophytic variant of oral squamous cell carcinoma\n\tPlaque-like or exophytic mass typically white, with a warty, ulcerated, or papillary surface. Slow continuous growth rate. Usually painless\tBone involvement (especially if invasive transformation occurs)\tBuccal mucosa,\nGingiva\tPathology (well-differentiated epithelial cells mass extending into the connective tissue generally with a pushing appearance)\t(a) Pathology\n(b) Rapid onset\n(c) Multiple lesions\t\nOrofacial Granulomatosis\t\t\t\t\t\t\t\nWegener Granulomatosis [45]\tRare immune-based inflammatory necrotizing vasculitis of unknown cause\tStrawberry gingivitis, sinusitis, oral ulceration\tFacial paralysis, Labial mucosal nodules,\nNecrosis and perforation of the nasal septum or palate,\nSwelling and desquamation of the lips,\nSalivary gland enlargement,\nArthralgia of the TMJ\nTongue involvement\tGingiva but any mucosal surface can be involved.\nRarely major salivary glands\tPathology\nClinical diagnostic criteria\nPresence of proteinase-3 antineutrophil cytoplasm antibodies (PR3-ANCA) myeloperoxidase antineutrophil cytoplasm antibodies (MPO-ANCA)\t(a) Pathology (absence of granulomatous lesions, with necrotizing vasculitis)\n(b) Absence of clinical diagnostic criteria (Oral ulcerations or nasal discharge, nodules on chest radiograph, abnormal urinary sediment, granulomatous inflammation upon biopsy)\t\nCrohn’s Disease [46,47]\tChronic inflammatory disease of the gastrointestinal tract\tUlcers, diffuse or nodular swellings, cobblestone appearance of the mucosa, macules and plaques involving the gingiva\tAngular cheilitis\nAlveolar bone loss\tLips\nGingiva\nBuccal mucosa\tEndoscopy\nPathology\t(a) Pathology (absence of classic non-caseating granulomas)\n(b) Absence of peculiar clinical features\t\nSarcoidosis [48]\tMultisystem granulomatous disease of unknown cause that can affect any organ\tOral manifestations are uncommon and associated with salivary gland and lymph node involvement\tSubmucosal mass, ulcerations, nodular swellings, an area of granularity, or an isolated papule. Bone involvement\tSalivary glands\nBuccal mucosa but any mucosal surface can be involved\tSymptoms\nRadiology\nElevated serum angiotensin-converting enzyme (ACE) levelsPathology\t(a) Pathology (absence of classic non-caseating granulomas)\n(b) Absence of peculiar clinical features\t\nMelkersson-Rosenthal Syndrome [49]\tRare disorder of unknown cause\tRecurring facial paralysis, swelling of the lips, and a fissured tongue\tEdema, ulcers, papules, swellings, cobblestone mucosal alterations, or focal areas of submucosal enlargement\tLips\nTongue\tPathology\nClinical diagnostic criteria\t(a) Pathology (absence of classic non-caseating granulomas)\n(b) Absence of clinical diagnostic criteria\n(labial swelling, facial paralysis, and fissured tongue)\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Miceli M.H. Kauffman C.A. 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The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications Blood 2011 117 5019 5032 10.1182/blood-2011-01-293050 21300984\n43. Hosseinpour S. Mashhadiabbas F. Ahsaie M.G. Diagnostic Biomarkers in Oral Verrucous Carcinoma: A Systematic Review Pathol. Oncol. Res. 2017 23 19 32 10.1007/s12253-016-0150-x 27924463\n44. Sonalika W.G. Anand T. Oral verrucous carcinoma: A retrospective analysis for clinicopathologic features J. Cancer Res. Ther. 2016 12 142 145 10.4103/0973-1482.172709 27072227\n45. Almouhawis H.A. Leao J.C. Fedele S. Porter S.R. Wegener’s granulomatosis: A review of clinical features and an update in diagnosis and treatment J. Oral Pathol. Med. 2013 42 507 516 10.1111/jop.12030 23301777\n46. Huang M.L. Wu Y.Q. Ruan W.H. A rare case of pediatric Crohn’s disease and alveolar bone loss: A report and review Transl. Pediatr. 2020 9 720 725 10.21037/tp-20-279 33209737\n47. Laube R. Liu K. Schifter M. Yang J.L. Suen M.K. Leong R.W. Oral and upper gastrointestinal Crohn’s disease J. Gastroenterol. Hepatol. 2018 33 355 364 10.1111/jgh.13866 28708248\n48. Badhey A.K. Kadakia S. Carrau R.L. Iacob C. Khorsandi A. Sarcoidosis of the head and neck Head Neck Pathol. 2015 9 260 268 10.1007/s12105-014-0568-y 25183456\n49. Dhawan S.R. Saini A.G. Singhi P.D. Management Strategies of Melkersson-Rosenthal Syndrome: A Review Int. J. Gen. Med. 2020 13 61 65 10.2147/IJGM.S186315 32161488\n50. Hartwick R. Batsakis J. Sinus aspergillosis and allergic fungal sinusitis Ann. Otol. Rhinol. Laryngol. 1991 100 427 430 10.1177/000348949110000515 2024903\n51. Dreizen S. Keating M. Beran M. Orofacial fungal infections. Nine pathogens that may invade during chemotherapy Postgrad. Med. 1992 91 349 364 10.1080/00325481.1992.11701299 1561171\n52. Benson-Mitchell R. Tolley N. Croft C. Gallimore A. Aspergillosis of the larynx J. Laryngol. Otol. 1994 108 83 85 10.1017/S0022215100128403 7989841\n53. Ibáñez-Martínez E. Ruiz-Gaitán A. Pemán-García J. Update on the diagnosis of invasive fungal infection Rev. Esp. Quimioter. 2017 30 16 21 28882009\n54. Latgé J. Aspergillus fumigatus and aspergillosis Clin. Microbiol. Rev. 1999 12 310 350 10.1128/CMR.12.2.310 10194462\n55. Denning D. Invasive aspergillosis Clin. Infect. Dis. 1998 26 781 803 10.1086/513943 9564455\n56. Dreizen S. Oral complications of cancer therapies. Description and incidence of oral complications NCI Monogr. 1990 9 11 15\n57. Cano M. Hajjeh R. The epidemiology of histoplasmosis: A review Sem. Resp. Inf. 2001 16 109 118 10.1053/srin.2001.24241 11521243\n58. Goldman M. Johnson P. Sarosi G. Fungal pneumonias. The endemic mycoses Clin. Chest Med. 1999 20 507 519 10.1016/S0272-5231(05)70232-X 10516900\n59. Folk G.A. Nelson B.L. Oral Histoplasmosis Head Neck Pathol. 2017 11 513 516 10.1007/s12105-017-0797-y 28220360\n60. Fitzpatrick S. Cohen D. Clark A. Ulcerated Lesions of the Oral Mucosa: Clinical and Histologic Review Head Neck Pathol. 2019 13 91 102 10.1007/s12105-018-0981-8 30701449\n61. Rodríguez-Díaz E. Morán-Estefanía M. López-Avila A. Piris J. Fernández-Blasco G. García J.I. Armijo M. Clinical expression of secondary syphilis in a patient with HIV infection J. Dermatol. 1994 21 111 116 10.1111/j.1346-8138.1994.tb01425.x 8182207\n62. Ahmed S. Ali M. Adegbite N. Vaidhyanath R. Avery C. Actinomycosis of tongue: Rare presentation mimicking malignancy with literature review and imaging features Radiol. Case Rep. 2019 14 190 194 10.1016/j.radcr.2018.10.022 30425772\n63. Valour F. Sénéchal A. Dupieux C. Karsenty J. Lustig S. Breton P. Gleizal A. Boussel L. Laurent F. Braun E. Actinomycosis: Etiology, clinical features, diagnosis, treatment, and management Infect. Drug Resist. 2014 14 183 189\n64. Verma A. Stock W. Lait M. Ferrer K. Quinn J. Platanias L. Actinomycosis presenting as an oral ulcer in a neutropenic patient South Med. J. 2002 95 1105 10.1097/00007611-200209000-00044\n65. Marcoval J. Penín R.M. Histopathological Features of Orofacial Granulomatosis Am. J. Dermatopathol. 2016 38 194 200 10.1097/DAD.0000000000000343 26894770\n66. Dignass A. Van Assche G. Lindsay J.O. Colombel J.F. Danese S. D’Hoore A. Gassull M. Gomollón F. Hommes D.W. Michetti P. The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: Current management J. Crohn’s Colitis 2010 4 28 62 10.1016/j.crohns.2009.12.002 21122489\n\n",
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"journal": "International journal of environmental research and public health",
"keywords": "Geotrichum clavatum; Saprochaete clavata; rare mycoses",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D003937:Diagnosis, Differential; D005260:Female; D016469:Fungemia; D006801:Humans; D016867:Immunocompromised Host; D000072742:Invasive Fungal Infections; D008297:Male; D008875:Middle Aged; D004718:Saccharomycetales",
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"title": "Saprochaete clavata Infection in Immunosuppressed Patients: Systematic Review of Cases and Report of the First Oral Manifestation, Focusing on Differential Diagnosis.",
"title_normalized": "saprochaete clavata infection in immunosuppressed patients systematic review of cases and report of the first oral manifestation focusing on differential diagnosis"
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"abstract": "OBJECTIVE\nAtrial fibrillation is a serious side effect of antipsychotic drugs, it is very rare but can be fatal. In this case report, a subject who developed an atrial fibrillation after receiving clozapine and olanzapine has been presented.\n\n\nMETHODS\nA 49 year-old female patient with a 10-year history of schizophrenia with no additional disease history was admitted to the hospital with the diagnosis of schizophrenia. Clozapine was started to be given as 12,5 mg/day and then it was gradually increased for the patient. After the development of atrial fibrillation when the clozapine dose was at 100 mg/day (25th day of the treatment), the patient was monitored with daily ECG and no medicine was given in this period. Then, after one week, the clozapine was started to be given as 12.5 mg/day and it was increased to a dose of 100 mg per day. Meanwhile, a single dose of 10 mg of olanzapine velotab was given to the patient with no cardiac problems to prevent agitation and atrial fibrillation developed again after that. Holter ECG was within normal limits. Clozapine treatment was discontinued when the treatment dose was 250 mg/day, because atrial fibrillation developed again. After a drug-free one week, atrial fibrillation did not occur during the following haloperidol, risperidone, quetiapine treatments.\n\n\nCONCLUSIONS\nIt is especially very important to monitor the cardiac side-effects in the patients who are using atypical antipsyhotic drugs and ECG monitorization is equally important. More studies are needed to be made towards the research of the antipsychotic arrhythmia relationship.",
"affiliations": null,
"authors": "Çam|Birmay|B|;Gülseren|Leyla|L|;Mete|Levent|L|;Gülseren|Şeref|Ş|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine",
"country": "Turkey",
"delete": false,
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"issue": "26(3)",
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"mesh_terms": "D014150:Antipsychotic Agents; D001281:Atrial Fibrillation; D001569:Benzodiazepines; D003024:Clozapine; D003937:Diagnosis, Differential; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008875:Middle Aged; D000077152:Olanzapine; D012559:Schizophrenia",
"nlm_unique_id": "9425936",
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"pages": "221-6",
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"pmid": "26364178",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Clozapine and Olanzapine Associated Atrial Fibrillation: A Case Report.",
"title_normalized": "clozapine and olanzapine associated atrial fibrillation a case report"
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"abstract": "Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.",
"affiliations": "Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan.;Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan.;Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan.;Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan.;Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan.;Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan.;Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan.;Department of Surgery, Tokyo Women's Medical University, Medical Center East, 2-1-10 Nishiogu, Arakawa, Tokyo 116-8567 Japan.;Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan.",
"authors": "Yokokawa|Hideyuki|H|0000-0002-7827-8147;Kono|Teppei|T|;Shidei|Hiroaki|H|;Oyama|Kunihiro|K|;Ito|Yoshitomo|Y|;Imaizumi|Rie|R|;Miyano|Yutaka|Y|;Shiozawa|Shunichi|S|;Yoshimatsu|Kazuhiko|K|",
"chemical_list": null,
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"doi": "10.1007/s13691-020-00455-x",
"fulltext": "\n==== Front\nInt Cancer Conf J\nInt Cancer Conf J\nInternational Cancer Conference Journal\n2192-3183 Springer Singapore Singapore \n\n455\n10.1007/s13691-020-00455-x\nCase Report\nSuccessful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer\nhttp://orcid.org/0000-0002-7827-8147Yokokawa Hideyuki yokokawa.hideyuki@twmu.ac.jp 12 Kono Teppei 12 Shidei Hiroaki 1 Oyama Kunihiro 1 Ito Yoshitomo 1 Imaizumi Rie 1 Miyano Yutaka 1 Shiozawa Shunichi 2 Yoshimatsu Kazuhiko kyoshsu@twmu.ac.jp 12 1 Department of Surgery, Saitama-ken Saiseikai Kurihashi Hospital, 714-6 Koemon, Kuki, Saitama 349-1105 Japan \n2 grid.410818.40000 0001 0720 6587Department of Surgery, Tokyo Women’s Medical University, Medical Center East, 2-1-10 Nishiogu, Arakawa, Tokyo 116-8567 Japan \n30 10 2020 \n30 10 2020 \n1 2021 \n10 1 87 90\n26 8 2020 12 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/.Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.\n\nKeywords\nInfusion related reactionPanitumumabCetuximabissue-copyright-statement© The Japan Society of Clinical Oncology 2021\n==== Body\nIntroduction\nCetuximab (Cmab) is a chimeric antibody that binds to epidermal growth factor receptor (EGFR) with murine fraction variable regions [1], whereas panitumumab (Pmab) is the first complete human monoclonal antibody similar to Cmab [2]. They both inhibit the proliferation and differentiation of EGFR-expressing normal and neoplastic cells and cause apoptosis. The incidence of documented infusion related reaction (IR) is more common with Cmab (all grades (G) 15—21%, G ¾ 2—5%) than with Pmab (all G 4%, G ¾ 1%) [3–9]. Although anecdotal reports suggest successful rechallenge with Pmab following IR to Cmab [10], there are few known cases that show the opposite pattern [11].\n\nWe herein present a case of locally advanced rectal cancer that was successfully rechallenged with Cmab after IR to Pmab, followed by surgical resection.\n\nCase report\nA 67-year-old female patient was referred to our hospital with tenesmus and frequent bowel movements. Physical and hematochemical examinations revealed loss of body weight, malnutrition and inflammatory changes. Computed tomography (CT) scan revealed a rectal cancer that had developed to the external wall of the rectum and invaded the surrounding tissue (Fig. 1). On admission, induction of chemotherapy was conducted after stoma creation due to the unresectable nature of the tumor. Due to its identification as a wild-type tumor incorporating rat sarcoma viral oncogene homolog (Ras)/v-raf murine sarcoma viral oncogene homolog B (BRAF) genes, a combination of oxaliplatin, 5-fluorouracil and leucovorin (mFOLFOX6) plus Pmab was selected in the hope of causing rapid tumor shrinkage. As pretreatment before initiation of chemotherapy, 1.65 mg of dexamethasone sodium phosphate and 5 mg of chlorpheniramine maleate were injected to prevent adverse events including allergy. Then 260 mg of Pmab was administered intravenously by drip infusion. The patient then complained of dyspnea with shortness of breath and wheezing. Her oxygen saturation decreased to 88%. Chemotherapy was immediately halted and oxygen, plus 250 mg of aminophylline hydrate and 125 mg of methylprednisolone sodium succinate, were given intravenously. As a result of this treatment, her symptoms gradually resolved within a few hours. Due to her successful recovery from IR, mFOLFOX6 without Pmab was administered the following week. No apparent symptoms were observed after this treatment. Diagnosing that the patient had suffered severe IR to Pmab, concomitant use of Cmab was attempted in the next course while monitoring vital signs. Three hundred and twenty mg of Cmab was slowly infused (2.7 mg/minute) after premedication with 1.65 mg of dexamethasone sodium phosphate, 20 mg of famotidine and 50 mg of Restamine calcium. No abnormal vital signs or IR symptoms were detected during administration. Other drugs were also administered without the appearance of any symptoms. Treatment was continued for seven courses due to no toxicities that might suggest the need for dose reduction or postponement, even though the patient experienced toxicities that included G2 dermatitis, G2 peripheral neuropathy, G2 dysgeusia, G2 thrombocytopenia, G1 anemia and G1 neutropenia. Marked tumor shrinkage (Fig. 2) allowed abdomino-perineal resection to be performed. Pathologically, the rectal wall was highly degenerated and showed fibrotic changes. However, live cancer cells remained. Since these were found close to the surgical margin, she was diagnosed with pT4b (pelvic tissue), pN0, pStage II, pRM1, curB.Fig. 1 Abdomino-pelvic CT scan on admission. The tumor originating from the rectum had grown into the extra-rectal wall (white arrow: a) and was suspected of having invaded the gluteus maximus (white arrow: b)\n\nFig. 2 Abdomino-pelvic CT scan after chemotherapy. A marked shrinkage of rectal tumor was demonstrated\n\n\n\nDiscussion\nMonoclonal antibody treatments that act on EGFR, including Cmab and Pmab, are recommended for Ras wild-type-metastatic colorectal cancer as candidates for first-line to third-line therapy [12–14]. Although cutaneous side effects are common, due to inhibition of EGFR expression in normal organs, certain prophylactic measures are commonly used, such as the use of moisturizing ointments or steroids, and oral intake of minocycline hydrochloride [15].\n\nIR is a less common adverse event caused by antibodies to EGFR [2]. The fact that 90% of IRs occur during the first infusion despite antihistamic premedication suggests that these reactions occur without any IgE-mediated reaction [16]. It is possible that IRs to monoclonal antibodies are a reaction to human antichimeric antibodies or anti-human antibodies. In general, IR is more common with Cmab than Pmab. Possible rechallenge with Cmab may be due to differences in the reacting antibodies, even though no correlation between IR and these antibodies has been demonstrated. Another hypothesis for the mechanism that induces IR is that it is associated with the role of complement activation and the release of cytokines [17].\n\nOur study has several limitations. First, mFOLFOX6 alone had a substantial therapeutic effect, and therefore, the benefit of the addition of Cmab were unclear. But previous study showed the superiority in the response rate of advanced colorectal cancer treated with FOLOX plus anti-EGFR antibody compared to FOLFOX [18, 19]. Therefore, in this study, mFOLFOX plus Cmab potentially contributed to shrink tumor. Second, in patients with resectable colorectal liver metastasis, it is currently questionable whether resection of metastatic lesions after shrinking the tumor using Cmab plus mFOLFOX6 [20, 21]. But this is a report about locally advanced rectal cancer without any distant metastases. Resection of the shrinked primary lesion after chemotherapy containing anti-EGFR antibody might have improved her prognosis.\n\nTo our knowledge, this report is the second documentation of a case of successful rechallenge with Cmab after IR to Pmab. Since our case showed tumor shrinkage with concomitant use of Cmab and mFOLFOX6, she was able to undergo radical resection. Although IR is less frequent with Pmab, patients with severe IR to Pmab can be rechallenged with Cmab. However, further studies are needed to elucidate the pathogenesis and mechanisms of antibody-mediated IR and to gauge the safety of re-challenging with the same or different antibodies.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nCompliance With Ethical Standards\nConflict of interest\nThe authors declare that they have no conflicts of interest.\n\nResearch involving human participants and/or animals\nFormal consent is not required for this type of study. This article does not contain any studies with human participants or animals performed by any of the authors.\n\nInformed consent\nInformed consent was obtained from the individual who participated in the study.\n==== Refs\nReferences\n1. Wong SF Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer Clin Ther 2005 27 684 694 10.1016/j.clinthera.2005.06.003 16117976 \n2. Cohenuram M Saif MW Panitumumab the first fully human monoclonal antibody: from the bench to the clinic Anticancer Drugs 2007 18 7 15 10.1097/CAD.0b013e32800feecb 17159497 \n3. Cunningham D Humblet Y Siena S Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer N Engl J Med 2004 351 337 345 10.1056/NEJMoa033025 15269313 \n4. Saltz LB Meropol NJ Loehrer PJ Sr Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor J Clin Oncol 2004 22 1201 1208 10.1200/JCO.2004.10.182 14993230 \n5. Bonner JA Harari PM Giralt J Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck N Engl J Med 2006 354 567 578 10.1056/NEJMoa053422 16467544 \n6. Gibson TB Ranganathan A Grothey A Randomized Phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer Clin Colorectal Cancer 2006 6 29 31 10.3816/CCC.2006.n.01 16796788 \n7. Van Cutsem E Peeters M Siena S Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer J Clin Oncol 2007 25 1658 1664 10.1200/JCO.2006.08.1620 17470858 \n8. Van Cutsem E Siena S Humblet Y An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy Ann Oncol 2008 19 92 98 10.1093/annonc/mdm399 17785764 \n9. Price TJ Peeters M Kim TW Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study Lancet oncol 2014 15 569 579 10.1016/S1470-2045(14)70118-4 24739896 \n10. Saif MW Peccerillo J Potter V Successful rechallenge with panitumumab in patients who developed hypersensitivity reactions to cetuximab: report of three cases and review of literature Cancer Chemother Pharmacol 2008 63 1017 1022 10.1007/s00280-008-0831-6 18781300 \n11. Saif MW Syrigos KI Hotchkiss S Successful desensitization with cetuximab after an infusion reaction to panitumumab in patients with metastatic colorectal cancer Cancer Chemother Pharmacol 2009 65 107 112 10.1007/s00280-009-1009-6 19415280 \n12. Labianca R, Nordlinger B, ESMO Guidelines Working Group, et al. (2020) Primary colon cancer: ESMO Clinical Practice Guidelines for diagnosis, adjuvant treatment and follow-up. Ann Oncol 24 Suppl 6:vi64–72\n13. Benson AB, Venook AP, Al-Hawary MM, et al. (2020) Colon Cancer. Version 2.2020. In: National comprehensive cancer network clinical practice guidelines in oncology (NCCN Guidlines). Available via DIALOG. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed May 2020\n14. Hashiguchi Y Muro K Saito Y Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer Int J Clin Oncol 2020 25 1 42 10.1007/s10147-019-01485-z 31203527 \n15. Kobayashi Y Komatsu Y Yuki S Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study; J-STEPP Future Oncol 2015 11 617 627 10.2217/fon.14.251 25686117 \n16. Kang SP Saif MW Infusion-related and hypersensitivity reactions of monoclonal antibodies used to treat colorectal cancer—identification, prevention, and management J Support Oncol 2007 5 451 457 18019853 \n17. van der Kolk LE Grillo-López AJ Baars JW Complement activation plays a key role in the side-effects of rituximab treatment Br J Haematol 2001 115 807 811 10.1046/j.1365-2141.2001.03166.x 11843813 \n18. Bokemeyer C Bondarenko I Hartmann JT Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study Ann Oncol 2011 22 1535 1546 10.1093/annonc/mdq632 21228335 \n19. Douillard JY Siena S Cassidy L Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer Ann Oncol 2014 25 1346 1355 10.1093/annonc/mdu141 24718886 \n20. Mise Y, Hasegawa K, Oba M, et al. (2019) EXPERT study: Randomized phase III trial of radical surgery and postoperative mFOLFOX6 versus perioperative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable colorectal liver metastases (CLMs). J Clin Oncol 37(4_suppl):652\n21. Bridgewater JA Pugh SA Maishman T Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial Lancet Oncol 2020 21 398 411 10.1016/S1470-2045(19)30798-3 32014119\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2192-3183",
"issue": "10(1)",
"journal": "International cancer conference journal",
"keywords": "Cetuximab; Infusion related reaction; Panitumumab",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "87-90",
"pmc": null,
"pmid": "33489709",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "16796788;19415280;24718886;31203527;11843813;18781300;17159497;24739896;14993230;16117976;17785764;21228335;24078664;25686117;17470858;18019853;15269313;32014119;16467544",
"title": "Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer.",
"title_normalized": "successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2021495148",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CETUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Oncologic therapy is constantly evolving to improve patient outcomes, especially with regard to chemotherapy. The use of combination therapies and development and implementation of molecular targeted therapy lead to iatrogenic conditions that the radiologist must be aware of in interpreting studies of and caring for the oncologic patient. Knowledge of the chemotherapeutic agents and the imaging appearances of associated toxicities can impact patient management and decrease patient morbidity and mortality.",
"affiliations": "Department of Diagnostic Radiology, UT MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1473, Houston, TX 77030, USA. Electronic address: chitra.viswanathan@mdanderson.org.;Department of Diagnostic Radiology, UT MD Anderson Cancer Center, Unit 1478, Houston, TX 77030, USA.;Department of Diagnostic Radiology, UT MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1473, Houston, TX 77030, USA.;Department of Diagnostic Radiology, UT MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1473, Houston, TX 77030, USA.;Department of Diagnostic Radiology, UT MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1473, Houston, TX 77030, USA.",
"authors": "Viswanathan|Chitra|C|;Truong|Mylene|M|;Sagebiel|Tara|T|;Garg|Naveen|N|;Bhosale|Priya|P|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-8389",
"issue": "52(5)",
"journal": "Radiologic clinics of North America",
"keywords": "Abdomen; Complication; Cytotoxic chemotherapy; Pelvis; Targeted therapy; Toxicity",
"medline_ta": "Radiol Clin North Am",
"mesh_terms": "D000970:Antineoplastic Agents; D003952:Diagnostic Imaging; D004066:Digestive System Diseases; D006801:Humans; D007049:Iatrogenic Disease; D014570:Urologic Diseases",
"nlm_unique_id": "0123703",
"other_id": null,
"pages": "1029-40",
"pmc": null,
"pmid": "25173656",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Imaging of chemotherapy-related iatrogenic abdominal and pelvic conditions.",
"title_normalized": "imaging of chemotherapy related iatrogenic abdominal and pelvic conditions"
} | [
{
"companynumb": "PHHY2015US048245",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Graft-versus-host disease (GVHD) is one of the most common and serious complications of hematopoietic stem-cell transplantation that mainly affects the skin, gastrointestinal tract, and liver. Hepatic GVHD is associated with high morbidity and mortality, and its diagnosis can be especially challenging because of nonspecific clinical signs and symptoms. It must be suspected in patients with elevated liver enzymes and cholestasis, especially in those with a history of preceding skin rash and diarrhea. We describe 3 patients with cutaneous and hepatic GVHD that presented with severe hypercholesterolemia and hypertriglyceridemia, and no xanthomatous macular lesions, in which cutaneous biopsies revealed the presence of xanthomatous dermal histiocytes. We propose that the presence of these xanthomatous cells in skin biopsies from patients with cutaneous GVHD could be a dermatopathological clue for the diagnosis of hepatic GVHD.",
"affiliations": "Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain.;Departments of Hematology, and.;Pathology, Hospital Universitario de Salamanca, Salamanca, Spain.;Pathology, Hospital Universitario de Salamanca, Salamanca, Spain.",
"authors": "Gamé|Denise|D|;López|Lucia|L|;Román|Concepción|C|;Santos-Briz|Ángel|Á|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "40(10)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D002648:Child; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006644:Histiocytes; D006801:Humans; D006937:Hypercholesterolemia; D015228:Hypertriglyceridemia; D007150:Immunohistochemistry; D008099:Liver; D008107:Liver Diseases; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012867:Skin; D012871:Skin Diseases; D014973:Xanthomatosis",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "754-757",
"pmc": null,
"pmid": "29570132",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Xanthomatous Cells in Cutaneous Graft-Versus-Host Disease Biopsies: A Clue for the Diagnosis of Hepatic Graft-Versus-Host Disease.",
"title_normalized": "xanthomatous cells in cutaneous graft versus host disease biopsies a clue for the diagnosis of hepatic graft versus host disease"
} | [
{
"companynumb": "ES-MYLANLABS-2019M1119156",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "A 34-year old male was found breathless and panting at home by his girlfriend three hours after a gym workout. Minutes later, he collapsed and died. Autopsy, histological and chemical analyses were conducted. The examination of the heart showed left ventricular hypertrophy, while the right coronary artery showed only a small vascular lumen (3 mm in diameter), due to its anatomical structure. In femoral blood concentrations of approx. 1 μg/L clenbuterol, approx. 56 μg/L stanozolol and approx. 8 μg/L metandienone, with trenbolone (<limit of quantification (LOQ)) were detected. Additionally, there were positive results in urine for boldenone, clomiphene, trenbolone, metandienone, stanozolol, clenbuterol and drostanolone, along with indications of testosterone and/or testosterone prohormones having been taken. In consideration of all aspects of this case, in can be assumed that the long-term consumption of anabolic androgen steroids (AAS) caused apparently pathological changes of the heart. Over and above, the combination of anatomical (small lumed coronary artery, ventricular hypertrophy) and substance-induced risk factors led to the fatal cardiovascular failure.",
"affiliations": "Institute of Legal Medicine, Medical Faculty, University of Cologne, Cologne, Germany.;Institute of Biochemistry, German Sport University Cologne, Cologne, Germany.;Institute of Legal Medicine, Medical Faculty, University of Cologne, Cologne, Germany.;Institute of Biochemistry, German Sport University Cologne, Cologne, Germany.;Institute of Biochemistry, German Sport University Cologne, Cologne, Germany.;Institute of Legal Medicine, Medical Faculty, University of Cologne, Cologne, Germany.;Institute of Legal Medicine, Medical Faculty, University of Cologne, Cologne, Germany.;Institute of Legal Medicine, Medical Faculty, University of Cologne, Cologne, Germany.;Institute of Legal Medicine, Medical Faculty, University of Cologne, Cologne, Germany. Electronic address: martin.juebner@uk-koeln.de.",
"authors": "Lehmann|Sabrina|S|;Thomas|Andreas|A|;Schiwy-Bochat|Karl-Heinz|KH|;Geyer|Hans|H|;Thevis|Mario|M|;Glenewinkel|Frank|F|;Rothschild|Markus Alexander|MA|;Andresen-Streichert|Hilke|H|;Juebner|Martin|M|",
"chemical_list": "D045930:Anabolic Agents; D000732:Androstanols; D002996:Clomiphene; D013739:Testosterone; D013197:Stanozolol; C013915:boldenone; C100263:dromostanolone; D008696:Methandrostenolone; D014204:Trenbolone Acetate; D002976:Clenbuterol",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2019.109925",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "303()",
"journal": "Forensic science international",
"keywords": "Anabolic-androgenic steroids; Bodybuilding; Clenbuterol; Death; Doping agents; Multi-drug abuse",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D045930:Anabolic Agents; D000732:Androstanols; D002976:Clenbuterol; D002996:Clomiphene; D003331:Coronary Vessels; D004300:Doping in Sports; D017809:Fatal Outcome; D006333:Heart Failure; D006801:Humans; D017379:Hypertrophy, Left Ventricular; D008297:Male; D008696:Methandrostenolone; D013197:Stanozolol; D013739:Testosterone; D014204:Trenbolone Acetate",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "109925",
"pmc": null,
"pmid": "31499423",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Death after misuse of anabolic substances (clenbuterol, stanozolol and metandienone).",
"title_normalized": "death after misuse of anabolic substances clenbuterol stanozolol and metandienone"
} | [
{
"companynumb": "DE-PURDUE PHARMA-GBR-2019-0071105",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "STANOZOLOL"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nA case of leukopenia in a patient receiving colchicine for calcium pyrophosphate dihydrate deposition disease, or pseudogout, is reported.\n\n\nCONCLUSIONS\nAn 85-year-old man experienced leukopenia likely due to colchicine. His medical history included chronic lymphocytic leukemia (CLL), pseudogout, osteoarthritis, and hypertension. In February 2011, his white blood cell (WBC) count was 2700 cells/μL, and his absolute neutrophil count (ANC) was 2200 cells/μL. Colchicine 0.6 mg orally daily was initiated in March for the prophylaxis of pseudogout. His WBC count decreased, and his colchicine dosage was reduced to 0.6 mg every other day. Despite this decreased dosage, his WBC count and ANC were 600 and 100 cells/μL, respectively, in September. In October, the patient received chemotherapy for presumed worsening of his CLL. One month later, his WBC count and ANC were 400 and 200 cells/μL, respectively. Subcutaneous filgrastim was administered, and colchicine was discontinued. At the end of November, he received another cycle of chemotherapy followed by pegfilgrastim. On the day of pegfilgrastim administration, the patient's WBC count and ANC were 2000 and 1300 cells/μL, respectively. Two weeks later, his WBC count was 8800 cells/μL, and his ANC was 8300 cells/μL. Daily colchicine was restarted at the end of December. Two months later, his WBC count and ANC were 800 and 500 cells/μL, respectively. Given the symptomatic relief with colchicine, therapy was continued with close monitoring.\n\n\nCONCLUSIONS\nA patient with CLL developed leukopenia in association with colchicine administration for pseudogout.",
"affiliations": "Department ofPharmacy Practice, College of Pharmacy, Belmont University, Nashville, TN 37212, USA. ashton.beggs@belmont.edu",
"authors": "Beggs|Ashton E|AE|;Reeves|David J|DJ|;Noel|Nancy S|NS|",
"chemical_list": "D000970:Antineoplastic Agents; D006074:Gout Suppressants; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim; D003078:Colchicine",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp120330",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "69(24)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002805:Chondrocalcinosis; D003078:Colchicine; D000069585:Filgrastim; D006074:Gout Suppressants; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007970:Leukopenia; D008297:Male; D011994:Recombinant Proteins",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "2147-8",
"pmc": null,
"pmid": "23230037",
"pubdate": "2012-12-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leukopenia associated with long-term colchicine administration.",
"title_normalized": "leukopenia associated with long term colchicine administration"
} | [
{
"companynumb": "US-AMGEN-USASP2020007844",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "Liver transplantation (LT) is a successful treatment for both acute liver failure and end-stage liver disease. The number of women of reproductive age undergoing LT is increasing. Pregnancy outcomes are favorable, but there is still a lack of prognostic markers. We aimed to identify factors predictive of adverse pregnancy outcomes in LT recipients. An analysis of all pregnancies occurring in LT recipients from 1989 to 2016 at King's College Hospital was performed. Clinical data of 162 conceptions in 93 women were reviewed. Descriptive and regression analyses were done to examine associations between laboratory markers and hepatological scores with pregnancy outcomes of live birth and preterm birth. Median age at LT was 23 years (range, 1-41 years), with a median age at conception of 30 years (range, 18-47 years). The live birth rate was 75% (n = 121). Of live births, 35% (n = 39/110 available) were delivered preterm. Preconception creatinine levels were higher in patients who had a preterm birth (85 versus 74 μmol/L; P = 0.008), with a preconception estimated glomerular filtration rate (eGFR) <90 mL/minute significantly associated with preterm delivery (P = 0.04). Progressive decline in eGFR predicted outcome, with gestational length declining with increasing chronic kidney disease (CKD) stage: CKD 0-1 = 39 weeks (median), CKD 2 = 37 weeks, and CKD 3 = 35 weeks. The risk of preterm birth was greatest in women with an eGFR <60 mL/minute (P = 0.004). Moreover, hypertension-related complications during pregnancy, such as gestational hypertension, preeclampsia, or eclampsia, were also associated with prematurity (P = 0.01). Women taking steroid-based immunosuppression had an increased risk of infection during pregnancy or postpartum (15% versus 4%; P = 0.02). In conclusion, although the majority of women have a successful pregnancy outcome after LT, preconception renal function predicts pregnancy outcome and steroids increase risk of infection during pregnancy or postpartum. Liver Transplantation 24 606-615 2018 AASLD.",
"affiliations": "Institute of Liver Studies, King's College Hospital, London, United Kingdom.;Institute of Liver Studies, King's College Hospital, London, United Kingdom.;Institute of Liver Studies, King's College Hospital, London, United Kingdom.;Institute of Liver Studies, King's College Hospital, London, United Kingdom.;Department of Obstetrics, King's College Hospital, London, United Kingdom.;Institute of Liver Studies, King's College Hospital, London, United Kingdom.;Institute of Liver Studies, King's College Hospital, London, United Kingdom.",
"authors": "Lim|Tiong Y|TY|0000-0003-4814-5754;Gonsalkorala|Enoka|E|;Cannon|Mary D|MD|;Gabeta|Stella|S|;Penna|Leonie|L|;Heaton|Nigel D|ND|;Heneghan|Michael A|MA|",
"chemical_list": "D015415:Biomarkers; D007166:Immunosuppressive Agents; D013256:Steroids; D003404:Creatinine",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.25034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "24(5)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D003404:Creatinine; D005260:Female; D005865:Gestational Age; D005919:Glomerular Filtration Rate; D006801:Humans; D046110:Hypertension, Pregnancy-Induced; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D007668:Kidney; D050498:Live Birth; D016031:Liver Transplantation; D016015:Logistic Models; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D047928:Premature Birth; D012189:Retrospective Studies; D012307:Risk Factors; D013256:Steroids; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "606-615",
"pmc": null,
"pmid": "29537127",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful pregnancy outcomes following liver transplantation is predicted by renal function.",
"title_normalized": "successful pregnancy outcomes following liver transplantation is predicted by renal function"
} | [
{
"companynumb": "GB-ACCORD-113426",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "Vancomycin is commonly prescribed to patients undergoing continuous ambulatory peritoneal dialysis (CAPD) for catheter-related infections and acute episodes of peritonitis. Although adverse dermatological reactions have been reported secondary to the rapid intravenous infusion of vancomycin, the intraperitoneal route of administration has been used routinely during CAPD without these effects. This case report describes a CAPD patient with systemic lupus erythematosus who developed erythema multiforme that progressed to exfoliative dermatitis during intermittent intraperitoneal vancomycin therapy for a catheter-related exit-site/tunnel infection.",
"affiliations": "State University of New York, Buffalo.",
"authors": "Gutfeld|M B|MB|;Reddy|P V|PV|;Morse|G D|GD|",
"chemical_list": "D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1177/106002808802201109",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-6578",
"issue": "22(11)",
"journal": "Drug intelligence & clinical pharmacy",
"keywords": null,
"medline_ta": "Drug Intell Clin Pharm",
"mesh_terms": "D000328:Adult; D003873:Dermatitis, Exfoliative; D005260:Female; D006801:Humans; D010531:Peritoneal Dialysis, Continuous Ambulatory; D014640:Vancomycin",
"nlm_unique_id": "0212457",
"other_id": null,
"pages": "881-2",
"pmc": null,
"pmid": "2976665",
"pubdate": "1988-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vancomycin-associated exfoliative dermatitis during continuous ambulatory peritoneal dialysis.",
"title_normalized": "vancomycin associated exfoliative dermatitis during continuous ambulatory peritoneal dialysis"
} | [
{
"companynumb": "US-PFIZER INC-2019367669",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Diffuse large B-cell lymphoma can be classified by gene expression profiling into germinal center and activated B-cell subtypes with different prognoses after rituximab-CHOP. The importance of previously recognized prognostic markers, such as Bcl-2 protein expression and BCL2 gene abnormalities, has been questioned in the new therapeutic era. We analyzed Bcl-2 protein expression, and BCL2 and MYC gene abnormalities by interphase fluorescence in situ hybridization in 327 patients with de novo disease treated with rituximab-CHOP. Isolated BCL2 and MYC rearrangements were not predictive of outcome in our patients as a whole, but only in those with the germinal center subtype of lymphoma. The prognostic relevance of isolated MYC rearrangements was weaker than that of BCL2 isolated translocations, but was probably limited by the rarity of the rearrangements. Seven of eight patients with double hit lymphoma had the germinal center subtype with poor outcome. The germinal center subtype patients with isolated BCL2 translocations had significantly worse outcome than the patients without BCL2 rearrangements (P=0.0002), and their outcome was similar to that of patients with the activated B-cell subtype (P=0.30), but not as bad as the outcome of patients with double hit lymphoma (P<0.0001). Bcl-2 protein overexpression was associated with inferior outcome in patients with germinal center subtype lymphoma, but multivariate analysis showed that this was dependent on BCL2 translocations. The gene expression profiling of patients with BCL2 rearrangements was unique, showing activation of pathways that were silent in the negative counterpart. BCL2 translocated germinal center subtype patients have worse prognosis after rituximab-CHOP, irrespective of MYC status, but the presence of combined gene breaks significantly overcomes the prognostic relevance of isolated lesions.",
"affiliations": "Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Visco|Carlo|C|;Tzankov|Alexander|A|;Xu-Monette|Zijun Y|ZY|;Miranda|Roberto N|RN|;Tai|Yu Chuan|YC|;Li|Yan|Y|;Liu|Wei-min|WM|;d'Amore|Emanuele S G|ES|;Li|Yong|Y|;Montes-Moreno|Santiago|S|;Dybkær|Karen|K|;Chiu|April|A|;Orazi|Attilio|A|;Zu|Youli|Y|;Bhagat|Govind|G|;Wang|Huan-You|HY|;Dunphy|Cherie H|CH|;His|Eric D|ED|;Zhao|X Frank|XF|;Choi|William W L|WW|;Zhao|Xiaoying|X|;van Krieken|J Han|JH|;Huang|Qin|Q|;Ai|Weiyun|W|;O'Neill|Stacey|S|;Ponzoni|Maurilio|M|;Ferreri|Andres J M|AJ|;Kahl|Brad S|BS|;Winter|Jane N|JN|;Go|Ronald S|RS|;Dirnhofer|Stephan|S|;Piris|Miguel A|MA|;Møller|Michael B|MB|;Wu|Lin|L|;Medeiros|L Jeffrey|LJ|;Young|Ken H|KH|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D019253:Proto-Oncogene Proteins c-bcl-2; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2012.066209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "98(2)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
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"title": "Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study.",
"title_normalized": "patients with diffuse large b cell lymphoma of germinal center origin with bcl2 translocations have poor outcome irrespective of myc status a report from an international dlbcl rituximab chop consortium program study"
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"abstract": "Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm. It usually originates from the parietal pleura. SFT originating from the esophagus is exceedingly rare and even more so as a malignancy. We report a 57-year-old patient with a malignant 18 cm SFT of the esophagus that was treated with esophagectomy through a left thoracoabdominal incision. We discuss his surgical and oncologic management.",
"affiliations": "Department of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, FL, USA.;Department of Cardiothoracic Surgery, UT Health San Antonio, San Antonio, TX, USA.;Department of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, FL, USA.;Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA.;Department of General Surgery, Mayo Clinic, Jacksonville, FL, USA.;Department of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, FL, USA.",
"authors": "Jacob|Samuel|S|0000-0001-5656-6474;Carroll|Nels Davis|ND|;El-Sayed Ahmed|Magdy M|MM|;Attia|Steven|S|;Jim Zhai|Qihui|Q|;Bower|Steven P|SP|;Makey|Ian A|IA|",
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"doi": "10.1093/jscr/rjaa152",
"fulltext": "\n==== Front\nJ Surg Case Rep\nJ Surg Case Rep\njscr\nJournal of Surgical Case Reports\n2042-8812 Oxford University Press \n\n10.1093/jscr/rjaa152\nrjaa152\nJscrep/030\nAcademicSubjects/MED00910\nCase Report\nThoracoabdominal resection of giant malignant esophageal solitary fibrous tumor\nhttp://orcid.org/0000-0001-5656-6474Jacob Samuel 1 Carroll Nels Davis 2 El-Sayed Ahmed Magdy M 1 Attia Steven 3 “Jim” Zhai Qihui 4 Bower Steven P 5 Makey Ian A 1 1 \nDepartment of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, FL, USA\n2 \nDepartment of Cardiothoracic Surgery, UT Health San Antonio, San Antonio, TX, USA\n3 \nDivision of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA\n4 \nDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA\n5 \nDepartment of General Surgery, Mayo Clinic, Jacksonville, FL, USA\nCorrespondence address. Department of Cardiothoracic Surgery, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA. Tel: +1-904-956-3212; Fax: +1-904-953-7368; E-mail: Jacob.samuel@mayo.edu\n7 2020 \n14 7 2020 \n14 7 2020 \n2020 7 rjaa15217 4 2020 27 4 2020 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2020.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nSolitary fibrous tumor (SFT) is a rare mesenchymal neoplasm. It usually originates from the parietal pleura. SFT originating from the esophagus is exceedingly rare and even more so as a malignancy. We report a 57-year-old patient with a malignant 18 cm SFT of the esophagus that was treated with esophagectomy through a left thoracoabdominal incision. We discuss his surgical and oncologic management.\n==== Body\nINTRODUCTION\nSolitary fibrous tumor (SFT) typically originates from the parietal pleura. In the past, it was sometimes confused with mesothelioma; hence, the variety of names it has been called [1]. With the advent of immunohistochemical staining (IHC), it is recognized as a separate tumor [2]. SFTs are now known to occur throughout the body [3]. Despite the proximity to the pleura, SFT originating from the esophagus is very uncommon [4, 5]. It is a mesenchymal neoplasm, so in the esophagus, it originates from the submucosa. SFTs are typically benign but they can be malignant, which is defined as greater than four atypical mitoses per 10 high power fields (HPF) [6]. We report a particularly large and aggressive SFT of the esophagus, and performed surgical management and oncologic management once it recurred and spread.\n\nCASE SUMMARY\nA 57-year-old man developed dysphagia and progressive nonexertional chest pain leading to the discovery of a large malignant SFT of the distal esophagus occupying the majority of his left hemithorax. Upon evaluation at another academic center, the tumor was deemed unresectable and he received chemotherapy. He was referred to our center because of our experience with sarcoma and esophageal disease. He underwent five cycles of temozolomide with bevacizumab but had progression of disease. His treatment was switched to pazopanib. Unfortunately, after three cycles of pazopanib progression was again noted. At this point, he was referred to thoracic surgery for evaluation.\n\nImaging revealed tumor dimensions of 15–18 cm in diameter (Fig. 1). Following endoscopic ultrasound and positron emission tomography scan, a multidisciplinary board recommended surgical resection with esophagectomy through a thoracoabdominal incision. He was placed in a semirecumbent position. The costal margin was divided. The diaphragm was divided in a circumferential fashion leaving a rim of diaphragm on the chest wall. Gastric preparation was performed first (Fig. 2). Then, dissection was carried out along the mass into the chest. The mass was adherent to the pericardium and aorta but was encapsulated and not invading those structures. Multiple large aortoesophageal vessels were divided with the Ligasure vessel sealer device (Medtronic MN, etc.). The left lower lobe and inferior pulmonary vein were splayed across the mass. Inadvertent injury of a branch of the inferior pulmonary vein required vascular repair. The mass emanated from the lower one-third of the esophagus (Fig. 3). The esophagus was divided at the level of the left inferior pulmonary vein and the mass removed. Frozen sections of the esophagus, surrounding pleural, pericardium and lung, were performed and were negative. The anastomosis was performed in a typical fashion with a circular end-to-end stapler. The diaphragm was reapproximated, and the extra conduit length was tacked down into the abdomen. The immediate postoperative course was largely uneventful, with negative radiographic leak test performed on postoperative Day 5 and the patient discharged to home on postoperative Day 7.\n\nFigure 1 Axial image from preoperative CT of the chest demonstrating extension from esophagus and relation to the pericardium and thoracic aorta.\n\nFigure 2 Thoracoabdominal exposure of esophageal SFT.\n\nFigure 3 Dissecting the tumor from the chest cavity.\n\nPathologic evaluation demonstrated an 18 cm, 2 kg tumor emanating from the submucosa of the esophagus (Fig. 4). Remarkably, the mucosa remained intact. Periesophageal, gastric, hilar and mediastinal lymph nodes were negative. Margins were confirmed negative. There were 42 mitoses per HPF with 30% necrosis and histologic grade 3. Tumor markers showed positive for CD34, vimentin, BCL-2 and beta-catenin (membranous pattern); weakly positive for caldesmon and negative for CD31, DOG1, CD117, S100, smooth muscle actin, desmin and pancytokeratin. Foundation One testing revealed microsatellite status stable and tumor mutational burden low. Genomic findings revealed STAT6-NAB2-STAT6 fusion and TP53-Y205C (Fig. 5).\n\nFigure 4 Eighteen-centimeter size tumor, 2 kg in weight.\n\nFigure 5 Microscopic pathology of the tumor.\n\nSurveillance scans were negative until 9 months later when multiple bilateral pulmonary nodules were discovered (Fig. 6). Biopsy of one of the nodules revealed recurrent, metastatic disease. He was treated with pembrolizumab for three cycles but had progression. He was then switched to gemcitabine and docetaxel for three cycles but had progression. Most recently, he underwent six cycles of doxorubicin, which showed stable disease.\n\nFigure 6 One-year postoperative CT showing metastases to the lungs.\n\nDISCUSSION\nSFT of the esophagus was first described in 1931 [7]. Most patients with esophageal SFTs present with dysphagia. Leiomyomas and GIST tumors may look similar on barium swallow and endoscopic ultrasound. Biopsy is easily obtained with endoscopy. SFTs histology characteristics are patternless bundles of spindle cells and collagen. IHC markers are CD34 positive and CD 117 negative, which differentiates them from GISTs tumors [8]. Malignancy is reported in only 10–15% of thoracic SFTs and is associated with tumors >7 cm [9]. Surgical resection is the treatment of choice when feasible. We did not give adjuvant radiation therapy given what appeared to be a clean resection with negative margins. We also did not give adjuvant chemotherapy given the paucity of data with this tumor and unclear benefit. Clinicopathologic parameters are currently used in risk prediction models for SFT, but the molecular determinants of malignancy in SFTs remain unknown, Bahrami et al. showed that TERT promoter mutations were strongly associated with high-risk clinicopathologic characteristics and outcome. An adverse event (relapse and death) occurred in 16 of 68 (24%) patients of their targeted study [10]. Like management of other sarcomas, a multidisciplinary approach to malignant SFTs is warranted. With such a large, malignant tumor, such as this, we would probably give adjuvant chemotherapy next time. The thoracoabdominal approach was an excellent choice for this patient as the tumor was difficult to extract even through this large incision. Surgical resection improved his quality of life by giving him back the ability to swallow and undoubtedly improved his survival.\n\nCONFLICT OF INTEREST STATEMENT\nNone.\n\nDISCLOSURES\nThe authors have nothing to disclose.\n==== Refs\nReferences\n1. \nZamora AK , Chopra S , Sahakian A , Kim AW \nNot just your ordinary tumor: a solitary fibrous tumor of the esophagus\n. Semin Thorac Cardiovasc Surg 2020 ;32:1 :176 –178\n.31271852 \n2. \nRobinson DR , Wu YM , Kalyana-Sundaram S , Cao X , Lonigro RJ , Sung YS , et al. \nIdentification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing\n. Nat Genet 2013 ;45 :180 –5\n.23313952 \n3. \nde Perrot M , Fischer S , Bründler MA , Sekine Y , Keshavjee S \nSolitary fibrous tumors of the pleura\n. Ann Thorac Surg 2002 ;74 :285 –93\n.12118790 \n4. \nLi H , Hu B , Li T , Jin M , Hao J \nA rare case of giant solitary fibrous tumor of the esophagus\n. Ann Thorac Surg 2009 ;88 :2019 –21\n.19932285 \n5. \nMakino H , Miyashita M , Nomura T , Katsuta M , Kashiwabara M , Takahashi K , et al. \nSolitary fibrous tumor of the cervical esophagus\n. Dig Dis Sci 2007 ;52 :2195 –200\n.17429725 \n6. \nMubarak MF , Shah JN , Bolton JS , Bansal M , El Chafic AH \nEndoscopic resection of a giant solitary fibrous tumor of the esophagus\n. VideoGIE 2018 ;3 :343 –5\n.30402579 \n7. \nZhu XS , Dai YC , Chen ZX \nGiant solitary fibrous tumor of esophagus resected by endoscopic submucosal dissection\n. Ann Thorac Surg 2015 ;100 :2340 –3\n.26652528 \n8. \nLococo F , Cesario A , Mulè A , Margaritora S \nMalignant solitary fibrous tumor of the esophagus\n. Eur J Cardiothorac Surg 2011 ;39 :595 –7\n.20817543 \n9. \nChick JF , Chauhan NR , Madan R \nSolitary fibrous tumors of the thorax: nomenclature, epidemiology, radiologic and pathologic findings, differential diagnoses, and management\n. AJR Am J Roentgenol 2013 ;200 :W238 .23436868 \n10. \nBahrami A , Lee S , Schaefer IM , Boland JM , Patton KT , Pounds S , et al. \nTERT promoter mutations and prognosis in solitary fibrous tumor\n. Mod Pathol 2016 ;29 :1511 –22\n.27562490\n\n",
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"title": "Thoracoabdominal resection of giant malignant esophageal solitary fibrous tumor.",
"title_normalized": "thoracoabdominal resection of giant malignant esophageal solitary fibrous tumor"
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"abstract": "Possible loss of efficacy and potential interactions between antiepileptic drugs (AEDs) and chemotherapy could complicate the management of patients with brain tumor-related epilepsy (BTRE) that may expose patients to an increased risk of adverse events. Perampanel (PER) is a highly selective, noncompetitive, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptor antagonist. This study evaluates the effectiveness, QoL, cognition, and mood of PER in add-on therapy in BTRE patients.\n\n\n\nObservational pilot study on the effectiveness of PER as add-on therapy in BTRE patients with uncontrolled seizures with a 6-month follow-up.\n\n\n\nWe recruited 26 BTRE patients. During the follow-up, 16 underwent chemotherapy and 11 radiotherapy; 11 had disease progression. Five patients dropped out. Mean daily PER dosage was 6.6 mg in the 21 patients who completed the follow-up and 6.4 mg in the ITT population. The mean number of seizures/month decreased from 10.8 ± 15.03 at baseline to 1.7 ± 4.34 in the 21 patients who reached the final follow-up. Responder rate was 88.4%: Eight patients were seizure-free, 15 had ≥50% seizure reduction, and 3 remained stable. Four patients (15.4%) reported AEs: 2 required PER dose reduction, and 2 dropped out. Neuropsychological, mood, and QoL questionnaires were not statistically different compared to baseline. There were no significant differences in seizure control in patients with/without IDH1 mutation and with/without MGMT methylation.\n\n\n\nPerampanel proved to be effective on seizure control in BRTE patients and to be well tolerated without negative effects on cognition and QoL. Perampanel could be a valid therapeutic option in BTRE.",
"affiliations": "Regina Elena Institute for Hospitalization and Care Scientific, IRCCS - Center for Tumor-Related Epilepsy - UOSD Neuroncology, Rome, Italy.;Regina Elena Institute for Hospitalization and Care Scientific, IRCCS - Center for Tumor-Related Epilepsy - UOSD Neuroncology, Rome, Italy.;Regina Elena Institute for Hospitalization and Care Scientific, IRCCS - Center for Tumor-Related Epilepsy - UOSD Neuroncology, Rome, Italy.;Regina Elena Institute for Hospitalization and Care Scientific, IRCCS - Biostatistic Unit, Rome, Italy.;Regina Elena Institute for Hospitalization and Care Scientific, IRCCS - UOSD Neuroncology, Rome, Italy.;Regina Elena Institute for Hospitalization and Care Scientific, IRCCS - UOSD Neuroncology, Rome, Italy.;Regina Elena Institute for Hospitalization and Care Scientific, IRCCS - UOSD Neuroncology, Rome, Italy.",
"authors": "Maschio|Marta|M|0000-0002-3075-4108;Zarabla|Alessia|A|;Maialetti|Andrea|A|;Giannarelli|Diana|D|;Koudriavtseva|Tatiana|T|;Villani|Veronica|V|;Zannino|Silvana|S|",
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"doi": "10.1002/brb3.1612",
"fulltext": "\n==== Front\nBrain Behav\nBrain Behav\n10.1002/(ISSN)2157-9032\nBRB3\nBrain and Behavior\n2162-3279 John Wiley and Sons Inc. Hoboken \n\n10.1002/brb3.1612\nBRB31612\nOriginal Research\nOriginal Research\nPerampanel in brain tumor‐related epilepsy: Observational pilot study\nMASCHIO et al.Maschio Marta https://orcid.org/0000-0002-3075-4108\n1\nmarta.maschio@ifo.gov.it Zarabla Alessia \n1\n Maialetti Andrea \n1\n Giannarelli Diana \n2\n Koudriavtseva Tatiana \n3\n Villani Veronica \n3\n Zannino Silvana \n3\n \n1 \nRegina Elena Institute for Hospitalization and Care Scientific\nIRCCS ‐ Center for Tumor‐Related Epilepsy ‐ UOSD Neuroncology\nRome\nItaly\n\n\n2 \nRegina Elena Institute for Hospitalization and Care Scientific\nIRCCS ‐ Biostatistic Unit\nRome\nItaly\n\n\n3 \nRegina Elena Institute for Hospitalization and Care Scientific\nIRCCS ‐ UOSD Neuroncology\nRome\nItaly\n\n* Correspondence\n\nMarta Maschio, Regina Elena Institute for Hospitalization and Care Scientific, IRCCS ‐ Center for Tumor‐Related Epilepsy ‐ UOSD Neuroncology, Via Elio Chianesi, 53, 00144 Rome, Italy.\n\nEmail: marta.maschio@ifo.gov.it\n\n14 4 2020 \n6 2020 \n10 6 10.1002/brb3.v10.6e0161214 11 2019 12 2 2020 09 3 2020 © 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nObjective\nPossible loss of efficacy and potential interactions between antiepileptic drugs (AEDs) and chemotherapy could complicate the management of patients with brain tumor‐related epilepsy (BTRE) that may expose patients to an increased risk of adverse events. Perampanel (PER) is a highly selective, noncompetitive, alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA)‐type glutamate receptor antagonist. This study evaluates the effectiveness, QoL, cognition, and mood of PER in add‐on therapy in BTRE patients.\n\nMaterial and Methods\nObservational pilot study on the effectiveness of PER as add‐on therapy in BTRE patients with uncontrolled seizures with a 6‐month follow‐up.\n\nResults\nWe recruited 26 BTRE patients. During the follow‐up, 16 underwent chemotherapy and 11 radiotherapy; 11 had disease progression. Five patients dropped out. Mean daily PER dosage was 6.6 mg in the 21 patients who completed the follow‐up and 6.4 mg in the ITT population. The mean number of seizures/month decreased from 10.8 ± 15.03 at baseline to 1.7 ± 4.34 in the 21 patients who reached the final follow‐up. Responder rate was 88.4%: Eight patients were seizure‐free, 15 had ≥50% seizure reduction, and 3 remained stable. Four patients (15.4%) reported AEs: 2 required PER dose reduction, and 2 dropped out. Neuropsychological, mood, and QoL questionnaires were not statistically different compared to baseline. There were no significant differences in seizure control in patients with/without IDH1 mutation and with/without MGMT methylation.\n\nConclusions\nPerampanel proved to be effective on seizure control in BRTE patients and to be well tolerated without negative effects on cognition and QoL. Perampanel could be a valid therapeutic option in BTRE.\n\nEpilepsy is a very common symptom of brain tumors, and AEDs should be selected especially by tolerability, and drug‐interaction potential. Observational pilot study on 26 brain tumor‐related epilepsy patients treated with PER in add‐on, with 33.3% seizure‐free after 6 months. Perampanel treatment brought a reduction in seizure frequency also in the group of patients with progression disease and seems well tolerated. No influence observed on PER efficacy by factors related to brain tumors, such as systemic therapy, progression, histology, or surgery. We obtained stability on patients' perceived QoL and cognitive domains and a low rate of neuropsychiatric adverse events.\n\nantiepileptic drugsbrain tumorsBTREepilepsymolecular factorsperampanelQoLresponder rate source-schema-version-number2.0cover-dateJune 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:19.06.2020\n\n\nMaschio \nM \n, \nZarabla \nA \n, \nMaialetti \nA \n, et al. Perampanel in brain tumor‐related epilepsy: Observational pilot study\n. Brain Behav . 2020 ;10 :e01612\n10.1002/brb3.1612 \n\n\n\nThe peer review history for this article is available at https://publons.com/publon/10.1002/brb3.1612\n==== Body\n1 INTRODUCTION\nIn patients with brain tumor, epilepsy represents one of the most important symptoms. It has been estimated that seizures occur in rates varying from 20% to 40% of patients with brain tumors; seizures are the onset symptoms in a significant proportion of cases (Maschio et al., 2014; Perucca, 2013; Van Breemen, Wilms, & Vecht, 2007).\n\nApproximately 10% of patients with brain tumor do not have seizures as first symptom, but develop seizures at a later stage (Maschio, 2012).\n\nUp to 90% of patients with glioneuronal tumors, diffuse low‐grade gliomas, grade II astrocytomas, oligodendrogliomas, and meningiomas develop pharmacoresistant epilepsy (Rudà, Bello, Duffau, & Soffietti, 2012). Additionally, brain tumor‐related epilepsy (BTRE) patients may have an increase of adverse event due to a possible interaction with antiepileptic drugs (AEDs) and anticancer therapies (Perucca, 2013).\n\nTherefore, the selection of the appropriate AED therapy in BTRE patients should be driven by multiple factors, which include not only efficacy in the specific type of seizure to be treated, but also tolerability and drug‐interaction potential.\n\nBetween new AEDs, perampanel (PER) is the first‐in‐class, highly selective, noncompetitive, alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA)‐type glutamate receptor antagonist (Rogawski & Hanada, 2013).\n\nPerampanel is approved as add‐on therapy for partial‐onset seizures with or without secondary generalization in adult patients with epilepsy (Raedler, 2016).\n\nPerampanel pharmacokinetic profile is characterized by good bioavailability, rapid absorption, and a long elimination half‐life. Perampanel is metabolized mainly by CYP3A4 and CYP3A5 enzymes. The most common side effects that often disappear with dose reduction are as follows: dizziness, fatigue, psychomotor impairment, somnolence, vertigo, aggressiveness, mood disorders, and cognitive deficits (Meador et al., 2016; Rohracher et al., 2016; Snoeijen‐Schouwenaars, Ool, Tan, Schelhaas, & Majoie, 2017; Steinhoff et al., 2013; Trinka, Steinhoff, & Nikanorova, 2016; van Ool et al., 2016).\n\nThree randomized, double‐blind, placebo‐controlled trials (French et al., 2012, 2013; Krauss et al., 2012) and their extension study (Krauss et al., 2014), proved that, in patients with focal seizures with/without secondary generalization, PER was efficacious and well tolerated, and the proportion of patients that remained on PER treatment was comparable to that of placebo.\n\nFor these reasons, we decided to study PER as add‐on therapy in BTRE patients to evaluate the efficacy on seizure control, as well as tolerability and impact on QoL, cognition and mood for 6 months (European Medicine Agency, 2018).\n\n2 MATERIALS AND METHODS\nObservational pilot cohort study was approved by the Ethical Committee (Prot. n° 0004691.12_04_2017). The study conforms to recognized standards of European Medicines Agency Guidelines for Good Clinical Practices.\n\n2.1 Primary aim\nTo evaluate efficacy of PER as add‐on therapy on seizure control in BTRE patients, after 6 months.\n\n2.2 Secondary aims\n\nTo obtain 50% of patients responders.\n\nTo detect the presence of PER‐related side effect during follow‐up period compared with baseline.\n\nTo monitor PER impact on cognition, mood, and Quality of life after 6 months of therapy, compared with baseline.\n\n\n\n\n2.3 Population\nBTRE patients with uncontrolled seizure activity despite AED therapy with adequate dosages. Perampanel was added as first or second add‐on. Patients were monitored for 6 months and underwent functional and neurological evaluation, count of seizure frequency, monitoring of adverse events, administration of QoL, mood, and cognitive questionnaires. All patients were treated with current standard care for brain tumor, including neuroradiological follow‐up. Any patient that experienced uncontrolled seizures with PER at maximum tolerated doses and needed a new AED was considered treatment failure and analyzed as such (Last Observation Carried Forward “LOCF” will give seizure frequency at AED change).\n\n2.4 Investigational product\nPerampanel as first or second add‐on therapy at dosage ranging from 4 to 12 mg/die was taken as a single oral dose at bedtime. The starting dosage is 2 mg/die with a slow increasing schedule as per label (with a weekly increase of 2 mg/day). Minimal effective dose is 4 mg/day. Depending on seizure control and on occurrence of adverse events, in order to achieve freedom from seizures, PER was titrated up to the maximum approved dosage of 12 mg/day.\n\n2.5 Inclusion criteria\nPatients age ≥ 18 years ≤ 75 (both sexes) with primary (low‐ and high‐grade WHO gliomas) or secondary brain tumor, with biopsy or surgical resection; in a stable phase of disease (evidenced by unchanged neuroradiological examinations), with/without chemotherapy (CT), radiotherapy (RT), and corticosteroids started before PER introduction. Structural epilepsy characterized by focal onset (aware/unaware seizures) (Scheffer et al., 2017); ≥4 seizures in the last month, despite 1–2 AEDs at the maximum tolerated stable dosages. Seizure count in the last month before the enrollment. All persons gave their informed consent prior to their inclusion in the study.\n\n2.6 Exclusion criteria\nAge ≤ 18 years ≥ 75 (both sexes) with primary BT; patients with cerebral lymphoma; patients with secondary BT (brain metastases); Karnofsky Performance Status (Karnofsky et al., 1951) < 60; Mini‐Mental State Examination (Folstein, Folstein, & McHugh, 1975) < 24; patients with other chronic neurological and psychiatric diseases; pregnancy or breastfeeding.\n\n2.7 Study design\nTrial duration for patient: 24 weeks + 1 week for titration of PER up to 4 mg/day.\n\nTotal trial duration including follow‐up: 49 weeks, 24 weeks for recruitment.\n\nWe decided a follow‐up period of 6 months, according to European Medicine Agency‐EMA guidelines (European Medicine Agency, 2018).\n\nThe study schedule is the following:\nVisit 1 (Time 0): Inclusion and exclusion criteria check. Signature of informed consent. Complete neurological evaluation and check out of adverse events by Adverse Event Profile‐AEP (Gilliam et al., 2004) and patients' spontaneous report of adverse events classified according to National Cancer Institute‐Common Terminology Criteria for Adverse Events‐NCI‐CTCAE (Cancer Therapy Evaluation Program, 2003). Seizure count over the last 28 days.\n\n\n\n\nPatients were given a seizure diary to compile in order to register any information about seizure occurrence in the last month. In order to attest seizure occurrence, patients were requested to call the center after each episode and calls were recorded and compared with questionnaire responses. Perampanel initial dosage of 2 mg/day. Patients underwent a neuropsychological battery of tests, including Quality of life and behavioral assessment.\nVisit 2 (1 week): neurological evaluation, check of seizure frequency, adverse event monitoring using both AEP and patients' spontaneous report of adverse events. Perampanel up‐titration of 4 mg/day. Dose adjustment up to a maximum dose of 12 mg/day may be done along all treatment period miming clinical practice.\n\nVisit 3 (3 MONTHS OF TREATMENT PERIOD): neurological examination, check of seizure frequency, adverse event monitoring using both AEP and patients' spontaneous report of adverse events, mood, and quality of life evaluation.\n\nVisit 4 (6 MONTHS ASSESSMENT ‐ LAST STUDY VISIT): neurological examination, adverse event monitoring using both AEP and patients' spontaneous report of adverse events, neurocognitive, mood, and quality of life evaluation.\n\n\n\n\nSeizure diary and Investigational Product check. Patients with improved seizure control continued PER therapy at the appropriate dosage with the marketed drug. If during PER treatment period at maximum tolerated dosage, patients reported seizure activity that requires the introduction of another AED, it would be considered as treatment failure and therefore analyzed as such (seizure frequency would be considered equal to that at study entry).\n\n2.8 Primary efficacy variables\nTo evaluate efficacy of PER, we used the mean seizure frequency in comparison with baseline during the period of 6 months treatment, after having reached minimal effective dose of 4 mg/day and freedom from seizure rate at 6 months of treatment.\n\n2.9 Secondary efficacy variables\nResponders are defined as patients who obtained a ≥50% reduction of seizure frequency in comparison with baseline. Seizure frequency was evaluated as seizure frequency mean through the 6 months of treatment.\n\nPerampanel‐related side effect were detected by mean values of AEP, and with spontaneous reports of adverse event at final follow‐up compared to baseline (visit 3 and 4). Perampanel impact on cognition, mood, and quality of life was assessed by mean values of neuropsychological tests, psychological state, and Quality of life questionnaires at final follow‐up compared to baseline (visit 3 and 4).\n\n2.10 Safety variables\nIncidence of adverse events using PER evaluated by AEP described later.\n\nAn “adverse event” (AE) is whichever unfavorable and unintended sign, symptom, or disease associated temporally with the use of a medical treatment or procedure that might or might not be considered related to the aforementioned treatment or procedure. Disease progression is not considered an AE. Patients who are administered at least one dose of drug will be included in the toxicity analysis. AEs (spontaneously reported or observed) will be recorded in association with details of time of onset and resolution, intensity, need for treatment, and possible connection with the ongoing treatment in the investigator's opinion.\n\n2.11 Specific assessments/tools/scales\n2.11.1 Side effect evaluation\nPresence of side effects was assessed using Adverse Events Profile (Gilliam et al., 2004): a self‐report multi‐item questionnaire specific for the evaluation of AEDs side effects in the last 4 weeks and with patients' spontaneous report of adverse events, classified according to National Cancer Institute‐Common Terminology Criteria for Adverse Events‐NCI‐CTCAE (Cancer Therapy Evaluation Program, 2003) a series of criteria to evaluate side effects in oncology.\n\n2.11.2 Quality of life and psychological state evaluation\nPatients' perceived quality of life was evaluated by Quality of life in Epilepsy Inventory (QOLIE 31P‐v2) (Cramer & Van Hammée, 2003) a 31‐item self‐administered questionnaire for epileptic patients. Psychological state was assessed by Symptom Checklist‐90 (SCL‐90) (Derogatis & Savitz, 2000) a self‐administered 90‐item questionnaire, that assesses the intensity and frequency of psychopathological symptoms in the last week.\n\n2.11.3 Neurocognitive evaluation\nWe administered to patients a battery of standardized neuropsychological tests, which included the following: Mini‐Mental State Examination (MMSE) (Folstein et al., 1975)‐global cognitive status; Raven CPM (Basso, Capitani, & Laiacona, 1987)—nonverbal abstract reasoning; Trail Making Test (TMT) (Giovagnoli et al., 1996) and Visual Search (Spinnler & Tognoni, 1987)‐selective visual attention and oculo‐manual coordination; Rey auditory verbal learning test (RAVLT) (Carlesimo et al., 1996), immediate and delayed recall‐verbal learning; Rey–Osterrieth complex figure (ROCF) (Carlesimo, Buccione, & Fadda, 2002) immediate and delayed recall‐visuo‐spatial learning; and Rey–Osterrieth complex figure (ROCF) (Carlesimo et al., 2002) copy‐visuo‐spatial and visuo‐constructive abilities. Phonemic and semantic fluency (Novelli et al., 1986)—Verbal processing speed; Tower of London (ToL) (Krikorian, Bartok, & Gay, 1994)—executive functions.\n\n2.12 Population size and statistical analysis\nAll enrolled patients will be considered as intention‐to‐treat population (ITT). Safety and efficacy of PER will be evaluated in this patients' population.\n\nThe primary endpoint will be the mean difference in the number of seizure pretreatment and after 6 months. We will use the t test for paired data.\n\nPatients who do not reach 6 months of therapy will be evaluated in the last month of follow‐up available.\n\nBased on an earlier study of a large population of drug‐resistant patients (Kanwaljit et al., 2016), we estimated an average seizure rate of 4 per month before the introduction of Perampanel; assuming that the treatment gives a reduction in the mean seizures number equal to 2 and estimating, from data of the preceding series, that this difference has a standard deviation (SD) of 2.8, 17 patients will be needed to obtain a statistical power of 80% to a level of significance of 5%.\n\n3 RESULTS\nWe recruited 26 BTRE patients with structural epilepsy with focal seizures (16 males, mean age 47.5 years): 8 low‐grade gliomas, 8 high‐grade gliomas, 7 glioblastomas, 2 meningiomas, 1 metastasis. Eleven patients were on AEDs monotherapy (Phenobarbital‐PB: 1 patient; Lamotrigine‐LTG: 1 patient; Oxcarbazepine‐OXC: 1 patient; Zonisamide‐ZNS: 1 patient; Levetiracetam‐LEV: 7 patients) and 15 on polytherapy (see Table 1).\n\nTABLE 1 Patients' clinical and vital data\n\nPat\tAge (years)\tSex\tHistology\tSite of tumor\tIDH1\tMGMT\tSurgery\tCT\tRT\tSeizure type\tNo. of seizures in the month before entering the study\tBaseline AED therapy\tPER dose at final follow‐up (mg/day)\tNo. of seizures/month at final follow‐up\tDrop out: months of follow‐up available and reasons\tSeizure number/last F.U. available\tAdverse events during PER therapy\tDisease progression during PER follow‐up\t\n1\t75\tM\tGBM\tFrontal\tMutated\tNot methylated\tGRT\tOther‡\tNo\tFocal aware seizure\t5\tLCM 300 LEV 3,000\t6\t1\t \t \tNo\tYes\t\n2\t48\tM\tGBM\tFrontal\tNot mutated\tMethylated\tGRT\tBevacizumab‡\tNo\tFocal to bilateral tonic‐clonic\t7\tLCM 400 LEV 3,000\t6\t0\t \t \tNo\tYes\t\n3\t46\tM\tAOA\tMultilobular\tNot mutated\tMethylated\tBiopsy\tTemozolomide‡\tNo\tFocal to bilateral tonic‐clonic\t30\tVPA 1,500 LEV 3,000 LTG 200\t6\t0.5\t \t \tNo\tNo\t\n4\t40\tF\tLGA\tFrontal\tUnknown\tUnknown\tPR\tNo\tNo\tFocal to bilateral tonic‐clonic\t2\tLTG 400\t6\t0.9\t \t \tNo\tNo\t\n5\t60\tM\tLGA\tTemporal\tNot mutated\tNot methylated\tPR\tTemozolomide‡\tNo\tFocal aware seizure\t60\tLCM 400 LEV 3,000\t8\t0\t \t \tNo\tNo\t\n6\t74\tM\tAA\tFrontal\tNot mutated\tMethylated\tPR\tTemozolomide‡\tNo\tFocal aware seizure\t3\tPB 100\t8\t0\t \t \tNo\tNo\t\n7\t42\tM\tLGA\tFrontal\tUnknown\tUnknown\tGRT\tFotemustine†\tNo\tFocal unaware seizure\t2\tOXC 1,800\t12\t0\t \t \tNo\tNo\t\n8\t57\tF\tGBM\tMultilobular\tUnknown\tUnknown\tBiopsy\tFotemustine§\tNo\tFocal aware seizure\t30\tLEV 3,000\t8\t \t2 (Death)\t20\tNo\tYes\t\n9\t69\tF\tLGO\tParietal\tUnknown\tMethylated\tPR\tTemozolomide†\tNo\tFocal aware seizure\t24\tLE 3,000‐LCM 400\t6\t0.8\t \t \tNo\tNo\t\n10\t34\tM\tAA\tFrontal\tMutated\tMethylated\tGRT\tTemozolomide‡\tYes†\tFocal to bilateral tonic‐clonic\t2\tLEV 3,000\t6\t1\t \t \tVertigo (dose reduction)\tYes\t\n11\t36\tM\tLGA\tMultilobular\tMutated\tUnknown\tBiopsy\tTemozolomide\tNo\tFocal unaware seizure\t24\tZNS 300 OXC 1,500\t8\t1.8\t \t \tNo\tYes\t\n12\t37\tM\tAA\tTemporal\tUnknown\tUnknown\tGRT\tTemozolomide†\tNo\tFocal aware seizure\t2\tVPA 1,000 LEV 2,500\t6\t0\t \t \tNo\tNo\t\n13\t52\tM\tLGA\tMultilobular\tUnknown\tUnknown\tGRT\tTemozolomide†\tNo\tFocal unaware seizure\t3\tLEV 3,000\t10\t3\t \t \tNo\tNo\t\n14\t37\tM\tAA\tTemporal\tUnknown\tUnknown\tPR\tFotemustine‡\tYes†\tFocal unaware seizure\t2\tVPA 1,000 LCM 400\t10\t \t4 (Side effects)\t2\tAggressiveness\tNo\t\n15\t32\tM\tAA\tFrontal\tMutated\tMethylated\tPR\tFotemustine§\tYes†\tFocal aware seizure\t30\tLEV 3,000 LCM 400\t6\t20\t \t \tNo\tYes\t\n16\t45\tF\tAA\tMultilobular\tNot mutated\tMethylated\tPR\tNo\tNo\tFocal unaware seizure\t4\tVPA 1,300 LCM 400\t4\t0.33\t \t \tNo\tNo\t\n17\t49\tM\tGBM\tOccipital\tMutated\tUnknown\tGTR\tTemozolomide‡\tYes†\tFocal to bilateral tonic‐clonic\t1\tLEV 3,000\t4\t0\t \t \tNo\tNo\t\n18\t55\tM\tGBM\tParietal\tNot mutated\tUnknown\tGTR\tOther‡\tNo\tFocal aware seizure\t1\tOXC 600 VPA 500 LCM 200 LEV 3,000\t4\t \t2 (Death)\t1\tNo\tYes\t\n19\t56\tF\tGBM\tMultilobular\tNot mutated\tNot methylated\tPR\tTemozolomide‡\tYes‡\tFocal aware seizure\t1\tLEV 3,000\t4\t0\t \t \tVertigo (dose reduction)\tYes\t\n20\t49\tM\tGBM\tMultilobular\tNot mutated\tUnknown\tPR\tTemozolomide‡\tYes†\tFocal aware seizure\t1\tLEV 3,000\t4\t0.3\t \t \tNo\tNo\t\n21\t51\tM\tAA\tFrontal\tNot mutated\tNot methylated\tGTR\tTemozolomide‡\tYes‡\tFocal to bilateral tonic‐clonic\t1\tCBZ 400 LEV 3,000 CNZ 10\t6\t0.5\t \t \tNo\tYes\t\n22\t33\tF\tLGO\tMultilobular\tMutated\tUnknown\tPR\tOther‡\tYes†\tFocal aware seizure\t5\tLEV 1,000\t2\t \t2 (Death)\t0\tNo\tYes\t\n23\t36\tF\tMEN\tParietal\tUnknown\tUnknown\tGTR\tNo\tNo\tFocal aware seizure\t2\tZNS 100\t8\t1\t \t \tNo\tNo\t\n24\t38\tF\tLGO\tParietal\tUnknown\tUnknown\tPR\tTemozolomide‡\tYes†\tFocal aware seizure\t15\tCBZ 800 LCM 100\t8\t1\t \t \tNo\tNo\t\n25\t38\tF\tMET\tParietal\tUnknown\tUnknown\tGTR\tOther‡\tYes†\tFocal unaware seizure\t12\tLEV 2,000 LCM 75 CNZ 10\t4\t \t2 (Side effects)\t1\tVertigo/aggressiveness\tYes\t\n26\t46\tF\tMEN\tParietal\tUnknown\tUnknown\tPR\tNo\tYes†\tFocal to bilateral tonic‐clonic\t8\tLTG 400 VPA 1,000\t8\t5\t \t \tNo\tNo\t\nNote\n‐Histology = MEN: meningioma; LGG: low‐grade glioma; LGO: low‐grade oligodendroglioma; LGA: low‐grade astrocytoma; AA: anaplastic astrocytoma; OAO: oligoastrocytoma; HGG: high‐grade glioma; GBM: glioblastoma; MET: brain metastasis.\n\n‐Surgery = PR: partial resection; GTR: gross total resection.\n\n‐Chemotherapy = † before; ‡ before and during follow‐up; § during follow‐up; TMZ: temozolomide; CCNU: fotemustine; HDU: oncocarbide.\n\n‐Radiotherapy = † before; ‡ before and during follow‐up; § during follow‐up.\n\n‐AEDs (antiepileptic drugs): LEV: levetiracetam; VPA: valproic acid; OXC: oxcarbazepine; LTG: lamotrigine; TPM: topiramate; PB: phenobarbital; LCM: lacosamide; PER: perampanel.\n\nJohn Wiley & Sons, LtdDuring the follow‐up, 16 underwent chemotherapy and 11 radiotherapy; no other therapeutic modifications were made. Eleven had oncological disease progression evidenced using brain magnetic resonance (42.3%).\n\nFive patients dropped out: 3 for disease progression and 2 for side effects: one for aggressiveness and one for vertigo and aggressiveness.\n\nThe mean daily PER dosage was 6.6 mg in the 21 patients who reached the final follow‐up and 6.4 mg in the ITT population.\n\nResults on seizures frequency are reported for the ITT population (including all 26 treated patients) and for the 21 patients who reached 6 months of follow‐up and results are consistent.\n\nThe mean number of seizures/month in the 21 patients who reached the final follow‐up decreased from 10.8 ± 15.03 at baseline to 1.7 ± 4.34 (p = .01).\n\nIn the ITT population (26 patients), the mean number of seizures reduced from 10.6 ± 14.27 at baseline to 2.3 ± 5.3 (p = .004) (last follow‐up available 2.4 months) (see Figure 1). Responder rate at 6 months was 95.2%: seven patients seizure‐free, 13 with a reduction ≥50%, and 1 remained stable (Table 1).\n\nFIGURE 1 Comparison in mean seizure number/month between basal and final follow‐up evaluation in total population (n = 21) and in ITT population (n = 26)\n\nFour patients reported AEs (15.4%): 2 required PER dose reduction for vertigo (grade II of National Cancer Institute‐Common Terminology Criteria for Adverse Events‐NCI‐CTCAE) (Dunn‐Pirio et al., 2018), and 2 dropped out (1 due to aggressiveness/vertigo, and 1 due to vertigo).\n\nThe result at 6 months of neuropsychological, mood, and QoL questionnaires was not statistically different compared to baseline.\n\nAt baseline, quality of life questionnaires were administered in 20 patients because 2 patients had poor compliance and 4 aphasia. At the final follow‐up, 14 out of 20 were administered the quality of life questionnaire because 3 patients had disease progression and 3 dropped out (2 for side effect and 1 for poor compliance).\n\nIn these 14 patients, the comparison between baseline and final follow‐up did not show any statistically significant difference in QOLIE global score (basal: 61.2 ± 18.1; final follow‐up: 64.5 ± 20.7; p = .42), and values remained stable, within normal ranges (Table 2).\n\nTABLE 2 Comparison between quality of life, neuropsychological, psychological tests and AEP profile before and after 6 months of treatment with PER in add‐on therapy\n\n \tBasal\t6‐month follow‐up\t\np\n\t\n(Mean ± SD)\t(Mean ± SD)\t\n\nQuality of life evaluation (n = 14)\n\n\nQOLIE 31‐P\n\n\n\t\nSeizure worry\t45.1 ± 26.0\t50.0 ± 27.5\t.48\t\nQuality of life\t58.3 ± 16.0\t62.6 ± 20.0\t.38\t\nEmotional well‐being\t60.4 ± 16.3\t61.2 ± 23.7\t.86\t\nEnergy/fatigue\t55.4 ± 20.3\t55.7 ± 24.7\t.96\t\nCognitive\t68.0 ± 27.3\t71.8 ± 24.5\t.53\t\nMeds effect\t60.1 ± 28.5\t60.8 ± 29.3\t.93\t\nSocial functioning\t67.2 ± 30.7\t72.7 ± 30.3\t.12\t\nGlobal score\t61.2 ± 18.1\t64.5 ± 20.7\t.42\t\n\nNeurocognitive evaluation (n = 9)\n\n\nNeuropsychological tests\n\n\n\t\nMMSE\t26.9 ± 2.5\t27.0 ± 2.4\t.34\t\nRaven CPM\t28.7 ± 7.1\t30.1 ± 5.6\t.20\t\nVisual Search\t48.4 ± 8.0\t49.5 ± 4.4\t.60\t\nTMT A\t48.4 ± 21.3\t40.8 ± 14.7\t.21\t\nTMT B\t97.8 ± 44.2\t94.3 ± 33.7\t.59\t\nTMT B‐A\t54.7 ± 29.6\t55.6 ± 25.2\t.75\t\nRey Auditory verbal learning test‐immediate recall\t37.7 ± 15.4\t38.7 ± 14.7\t.54\t\nRey Auditory verbal learning test‐delayed recall\t6.3 ± 4.4\t6.6 ± 4.3\t.35\t\nRey–Osterrieth Complex figure‐ copy\t28.7 ± 7.9\t28.2 ± 5.5\t.83\t\nRey–Osterrieth Complex figure‐immediate recall\t17.2 ± 9.5\t17.4 ± 8.8\t.84\t\nRey–Osterrieth Complex figure delayed recall\t16.1 ± 9.0\t16.9 ± 8.9\t.15\t\nTower of London\t30.0 ± 2.5\t31.2 ± 2.9\t.15\t\nPhonemic fluency\t29.3 ± 8.8\t27.8 ± 8.1\t.40\t\nCategorial fluency\t39.2 ± 12.0\t39.3 ± 9.5\t.93\t\n\nPsychological state evaluation (n = 9)\n\n\nSymptom checklist‐90 (SCL‐90)\n\n\n\t\nSCL‐90 somatic\t\n0.70 ± 0.4\n\t\n0.47 ± 0.4\n\t\n.05\n\t\nSCL‐90 obsessive–compulsive\t0.81 ± 0.7\t0.58 ± 0.7\t.26\t\nSCL‐90 interpersonal sensibility\t0.42 ± 0.4\t0.30 ± 0.30\t.42\t\nSCL‐90 depression\t0.72 ± 0.4\t0.72 ± 0.8\t.99\t\nSCL‐90 anxiety\t0.71 ± 0.6\t0.58 ± 0.7\t.35\t\nSCL‐90 Hostility\t0.66 ± 1.0\t0.56 ± 0.8\t.16\t\nSCL‐90 phobia\t0.32 ± 0.4\t0.22 ± 0.2\t.35\t\nSCL‐90 Paranoic\t0.27 ± 0.2\t0.37 ± 0.5\t.49\t\nSCL‐90 psychoticism\t0.41 ± 0.3\t0.38 ± 0.4\t.78\t\nSCL‐90 sleep disturbances\t0.81 ± 1.3\t0.62 ± 0.9\t.33\t\nSCL‐90 global symptoms index\t0.56 ± 0.4\t0.46 ± 0.5\t.44\t\nAEDs' side effect evaluation (n = 9)\t\nAEP‐Adverse Event Profile\t45.0 ± 12.4\t41.7 ± 10.3\t.14\t\nNote\nCoefficients set in bold indicate significant test differences between 6 months and baseline.\n\nAbbreviations: MMSE, Mini‐Mental State Examination; Raven CPM, Raven colored progressive matrices; RAVLT, Rey Auditory Verbal Learning test; ROCF, Rey–Osterrieth complex figure; TMT B‐A, Trail Making Test Part B‐A; TMT A, Trail Making Test Part A; TMT B, Trail Making Test Part B; TOL—Tower of London.\n\nJohn Wiley & Sons, LtdAt baseline, neuropsychological questionnaires were administered to 14 out of 26 patients, because 8 patients had poor compliance and 4 aphasia. At the final follow‐up, 9 out of 14 underwent a final evaluation, because 2 patients had disease progression, 2 dropped out for side effects, and 1 had poor compliance. In these 9 patients, the comparison between basaline and final follow‐up did not show any statistically significant difference, indicating performances stably included within normal ranges (Table 2).\n\nAt baseline, mood questionnaire (SCL‐90) and AEP‐adverse event profile were administered to 13 out of 26 patients, because 9 had poor compliance and 4 had aphasia. At the final follow‐up, 9 out of 13 patients underwent final evaluation because 1 had poor compliance, 2 dropped out due to side effects, and 1 had disease progression.\n\nAEP mean scores did not show any statistically significant difference in the comparison between basal and final follow‐up evaluation (AEP basal: 45.0 ± 12.4, final follow‐up 41.7 ± 12.3, p = .14), indicating the presence of moderate AED induced side effects (Table 2).\n\nSCL‐90 tests mean scores showed a statistically significant decrease in psychosomatic symptoms' scale (basal: 0.70 ± 0.4; final: 0.47 ± 0.4, p = .05) and no statistically significant difference in the other questionnaire domains between basaline and final follow‐up evaluation (SCL‐global score basal 0.5 ± 0.4; final follow‐up 0.4 ± 0.5, p = .44), indicating absence of any relevant psychopathological symptoms (Table 2).\n\nIn order to evaluate a potential correlation between seizure frequency during PER therapy and issues related to the oncological disease, we compared the decreasing number of seizures depending on: histology (low/high grade p = .73); surgical procedures (gross total resection/partial resection/biopsy p = .47); presence/absence of chemotherapy (p = .21), radiotherapy (p = .61) and progression disease (p = .65) during PER therapy; IDH1‐mutated/wild type (p = .77) and 06‐methylguanine‐DNA methyltransferase (MGMT) with or without promoter methylation (p = .95).\n\nIn all these, comparisons no significant differences were observed.\n\n4 DISCUSSION\nTo date, there are very limited evidences on the efficacy of AEDs in the treatment of BTRE from randomized controlled trials (Perucca, 2013). Therefore, physicians are often driven for therapeutic choices by data obtained from other epilepsy subpopulations, or from noninterventional studies.\n\nAmong the newest AEDs, the antagonist activity of PER on AMPA glutamate receptor may constitute a basis for the use of this drug in the BTRE treatment.\n\nWe reported the results of an observational pilot study on 26 BTRE patients treated for 6 months with PER as add‐on therapy. We observed a reduction in seizure frequency in the 21 patients who reached the final follow‐up, from 10.8 ± 15.03 to 1.7 ± 4.34 (p = .01), and from 10.6 ± 14.27 to 2.3 ± 5.3 (p = .004) in the ITT population (26 patients) at the recommended dosage of PER treatment.\n\nResponder rate at 6 months (21 patients) was 95.2, with 33.3% of patients who were seizure‐free after 6 months. Seizure frequency remained stable in 1 out of 21 patients, and none had seizures worsening.\n\nLiterature data on BTRE patient populations treated with PER as add‐on are very few; however, they indicated a good seizure response rate; Vecht and colleagues in a prospective study on 12 patients with low‐ and high‐grade gliomas and drug‐resistant epilepsy, assuming PER for 6 months for a median daily dose of 8 mg, reported an high seizure response rate in 9 out of 12 patients (75%), seizure freedom in 6 out of 12 patients (50%), improvement in cognitive functions and acceptable safety profile (Vecht et al., 2017). Izumoto and colleagues evaluated a case series of 12 patients with uncontrollable epilepsy related to both low‐ and high‐grade gliomas treated with PER as add‐on therapy and obtained 10 patients who achieved more than 50% seizure reduction and seizure freedom in 6 patients (60%) (Izumoto et al., 2018). Our results are in line with these evidences, indicating a good seizure response to PER treatment as add‐on in this patient population.\n\nWith reference to adverse events, literature data on non‐oncological epileptic patients and BTRE patients treated with PER report incidence of physical (Dunn‐Pirio et al., 2018; French et al., 2012, 2013; Izumoto et al., 2018; Krauss et al., 2012; Steinhoff et al., 2013) and behavioral disturbances (Coyle, Clough, Cooper, & Mohanraj, 2014; Ettinger et al., 2015; Fycompa, 2016; Rugg‐Gunn, 2014; Vecht et al., 2017). In order to monitor the possible onset of PER‐related side effects, we decided to use three types of measures: patients' subjective reports (classified according to National Cancer Institute‐Common Terminology Criteria for Adverse Events‐NCI‐CTCAE) (Cancer Therapy Evaluation Program, 2003), AEP‐Adverse event profile for physical domains (Gilliam et al., 2004) and SCL‐90 symptoms checklist for psychological state (Derogatis & Savitz, 2000). Regarding patients' subjective reports, 4 out of 26 patients (15.4%) referred presence of side effects. In two patients that reported vertigo (common AEs reported with PER) (Fycompa, 2017), PER was reduced, and in 2 patients that reported aggressiveness, PER was withdrawn. Concerning the evaluation of AEDs related physical side effects (AEP), we observed no statistically significant difference in AEP profile mean scores between basal and final follow‐up which values remain stable indicating the presence of moderate physical side effects (see Table 2). Regarding neuropsychiatric side effects (SCL‐90), we observed a significant decrease in psychosomatic symptoms' scale mean scores and stability in all domains explored by questionnaire, which values remain stable within normal values at basal and at final follow‐up, indicating low incidence of neuropsychiatric disturbances (see Table 2).\n\nStudies on patients with BTRE treated with PER as add‐on indicate the presence of low to moderate side effect evaluated only by patients' subjective reports, which only in few cases required drug's withdrawal. Vecht et al. observed dizziness (33%) and drowsiness (16.6%) and withdrew PER only in 2 cases (16.6%) (Vecht et al., 2017), Izumoto et al. observed 2 patients with dizziness (16.6%) and withdrew PER in only 1 case (8.3%) (Izumoto et al., 2018), Dunn‐Pirio et al. described the appearance of several side effects such as fatigue (63%) and dizziness (25%) during their fast titration period on all 8 patients enrolled but only one patient required PER dose reduction (Dunn‐Pirio et al., 2018). Our results, obtained not only through patients' subjective reports but also through a self‐report multi‐item questionnaire (AEP), are in line with literature evidences indicating low incidence of side effect of PER as add‐on in BTRE patients already in polytherapy with other AEDs.\n\nAs for the possibility that PER efficacy remains stable during oncological disease progression, our results indicate that despite the high number of patients with progression disease during the follow‐up (11 patients, 42.3%), the efficacy of PER on seizure control remains high, also in the group of patients with progression disease (Table 1).\n\nFurthermore, our results did not evidence that the efficacy of PER on seizure control could be influenced by factors related to brain tumors, such as systemic therapy, oncological progression, different histology and malignancy, surgical procedures. This results should be cautiously considered because of low power due to small sample size and short follow‐up (only 6 months).\n\nRegarding the molecular indices analysis, in the different two groups (IDH1‐mutated/wild type, MGMT with or without promoter methylation) we did not observe significative differences. Our results differ from the study results of Dunn‐Pirio et al. (2018) in which they found that, between patients with a decrease in seizure activity, the majority had IDH1‐mutant tumors. This difference could be caused by our low patient number, because for just 15 out of 26 patients we had the analysis for IDH1 and for 11 patients for MGMT.\n\nRegarding QoL evaluation, we did not observe statistically significant differences in QOLIE 31 P mean scores, which values remain within normal ranges at basal and at final follow‐up evaluations (Table 2).\n\nLiterature data on BTRE patients indicate a correlation between good seizure control and improved scores in Quality of life questionnaire (Maschio & Dinapoli, 2012). Probably, in our sample we did not observe significant improvements in questionnaire mean scores because 9 out of 14 patients also performed concomitant oncological treatments (6 out of 14 CT; 2 out of 14 RT) and 2 other patients were in disease progression. However, the good seizure control obtained by patients with PER in add‐on at final follow‐up, contributed to keep QOLIE 31 mean values stable despite the influence of the abovementioned variables, indicating that PER had no impact on perceived quality of life in our patients population.\n\nRegarding cognitive performances, we observed stability in patients' mean scores and at final follow‐up compared to baseline. This result is in line with the only one study in literature which shows a low impact of PER on cognitive functions in glioma patients, tested with a short computerized battery (Vecht et al., 2017).\n\nHowever, our data on tests and questionnaires cannot be generalized due to the small number of patients who repeated control tests at 6 months. With reference to this specific aspect, it could be useful to administer a brief neuropsychological test battery or brief and specific questionnaires in order to avoid the high number of patients with poor compliance, as suggested by literature data (Newton & Maschio, 2015).\n\n5 CONCLUSION\nIn our study, we observed good efficacy on seizure control without negative effects on cognition and on QoL of PER in patients with BTRE.\n\nDespite the limitations due to the small number of patients, PER could be a therapeutic option in BTRE patients due to responders' high rate and number of seizure‐free patients.\n\nThese results need further studies with a longer follow‐up to confirm this high responder rate and the possible correlation with molecular indices, which could be a starting point for truly tailored therapies for patients with BTRE.\n\nCONFLICT OF INTEREST\nDr. Marta Maschio has received support for travel to congresses from EISAI srl; has participated in scientific advisory boards for EISAI; has participated in pharmaceutical industry‐sponsored symposia for UCB Pharma; and has received research grants from UCB Pharma. No conflicts of interest are declared for the other Authors.\n\nAUTHORS' CONTRIBUTIONS\nMM: study design; collection of the cases; writing of the manuscript; editing of the manuscript; AZ: collection of the cases, writing of the manuscript; AM: collection of the cases, writing of the manuscript; DG: study design, statistical analysis; TK: collection of the cases; EG: collection of the cases; VV: collection of the cases; SZ: collection of the cases.\n\nACKNOWLEDGMENTS\nWe thank Dr. Selvaggia Camilla Serini for reviewing this manuscript.\n\nDATA AVAILABILITY STATEMENT\nAt the Biostatistic Unit of Regina Elena National Cancer Institute all dataset analyzed for the current study is available.\n==== Refs\nREFERENCES\n\n\nBasso , A. \n, \nCapitani , E. \n, & \nLaiacona , M. \n (1987 ). Raven's Coloured Progressive Matrices: Normative values on 305 adults normal controls\n. Functional Neurology , 2 , 189 –194\n.3666548 \n\nCancer Therapy Evaluation Program \n(2003 ). 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Long‐term safety of perampanel and seizure outcomes in refractory partial‐onset seizures and secondarily generalized seizures: Results from phase III extension study 307\n. Epilepsia , 55 , 105810 –105868\n.\n\n\nKrauss , G. L. \n, \nSerratosa , J. M. \n, \nVillanueva , V. \n, \nEndziniene , M. \n, \nHong , Z. \n, \nFrench , J. \n, … \nLaurenza , A. \n (2012 ). Randomized phase III study 306: Adjunctive perampanel for refractory partial‐onset seizures\n. Neurology , 78 , 1408 –1415\n.22517103 \n\n\nKrikorian , R. \n, \nBartok , J. \n, & \nGay , N. \n (1994 ). Tower of London Procedure: A standard method and developmental data\n. Journal of Clinical and Experimental Neuropsychology , 16 , 840 –850\n.7890819 \n\n\nMaschio , M. \n (2012 ). Brain tumor‐related epilepsy\n. Current Neuropharmacology , 10 , 124 –133\n.23204982 \n\n\nMaschio , M. \n, & \nDinapoli , L. \n (2012 ). Patients with brain tumor‐related epilepsy\n. 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F. \n (1986 ). Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti normali\n. Archivio di Psicologia, Neurologia e Psichiatria , 47 , 477 –506\n.\n\n\nPerucca , E. \n (2013 ). Optimizing antiepileptic drug treatment in tumoral epilepsy\n. Epilepsia , 54 , 97 –104\n.24328881 \n\n\nRaedler , L. A. \n (2016 ). Fycompa (perampanel hydrate) receives expanded indication for primary generalized tonic‐clonic seizures\n. American Health & Drug Benefits , 9 , 88 .27668051 \n\n\nRogawski , M. A. \n, & \nHanada , T. \n (2013 ). Preclinical pharmacology of perampanel, a selective non‐competitive AMPA receptor antagonist\n. Acta Neurologica Scandinavica. Supplementum , 197 , 19 –24\n.\n\n\nRohracher , A. \n, \nKalss , G. \n, \nLeitinger , M. \n, \nGranbichler , C. \n, \nDeak , I. \n, \nDobesberger , J. \n, … \nTrinka , E. \n (2016 ). Two‐year real‐world experience with perampanel in patients with refractory focal epilepsy: Austrian data\n. Therapeutic Advances in Neurological Disorders , 9 , 445 –453\n.27800020 \n\n\nRudà , R. \n, \nBello , L. \n, \nDuffau , H. \n, & \nSoffietti , R. \n (2012 ). Seizures in low‐grade gliomas: Natural history, pathogenesis, and outcome after treatments\n. Neuro‐Oncology , 14 , 55 –64\n.\n\n\nRugg‐Gunn , F. \n (2014 ). Adverse effects and safety profile of perampanel: A review of pooled data\n. Epilepsia , 55 , 13 –15\n.24400692 \n\n\nScheffer , I. E. \n, \nBerkovic , S. \n, \nCapovilla , G. \n, \nConnolly , M. B. \n, \nFrench , J. \n, \nGuilhoto , L. \n, … \nZuberi , S. M. \n (2017 ). ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology\n. Epilepsia , 58 (4 ), 512 –521\n.28276062 \n\n\nSingh , K. \n, \nShah , Y. D. \n, \nLuciano , D. \n, \nFriedman , D. \n, \nDevinsky , O. \n, & \nKothare , S. V. \n (2016 ). Safety and efficacy of perampanel in children and adults with various epilepsy syndromes: A single‐center postmarketing study\n. Epilepsy & Behavior , 61 , 41 –45\n.27300147 \n\n\nSnoeijen‐Schouwenaars , F. M. \n, \nvan Ool , J. S. \n, \nTan , I. Y. \n, \nSchelhaas , H. J. \n, & \nMajoie , M. H. \n (2017 ). Evaluation of perampanel in patients with intellectual disability and epilepsy\n. Epilepsy & Behavior , 66 , 64 –67\n.28038388 \n\n\nSpinnler , H. \n, & \nTognoni , G. \n (1987 ). Standardizzazione e taratura italiana di test neuropsicologici\n. Italian Journal of Neurological Sciences , S8 (6 ), 44 –46\n.\n\n\nSteinhoff , B. J. \n, \nBen‐Menachem , E. \n, \nRyvlin , P. \n, \nShorvon , S. \n, \nKramer , L. \n, \nSatlin , A. \n, … \nLaurenza , A. \n (2013 ). Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: A pooled analysis of three phase III studies\n. Epilepsia , 54 , 1481 –1489\n.23663001 \n\n\nTrinka , E. \n, \nSteinhoff , B. J. \n, \nNikanorova , M. \n & \nBrodie , M. J. \n (2016 ). Perampanel for focal epilepsy: Insights from early clinical experience\n. Acta Neurologica Scandinavica , 133 , 160 –172\n.26506904 \n\n\nVan Breemen , M. S. \n, \nWilms , E. B. \n, & \nVecht , C. J. \n (2007 ). Epilepsy in patients with brain tumours: Epidemiology, mechanisms, and management\n. The Lancet Neurology , 6 , 421 –430\n.17434097 \n\n\nvan Ool , J. S. \n, \nSnoeijen‐Schouwenaars , F. M. \n, \nSchelhaas , H. J. \n, \nTan , I. Y. \n, \nAldenkamp , A. P. \n, & \nHendriksen , J. G. M. \n (2016 ). A systematic review of neuropsychiatric comorbidities in patients with both epilepsy and intellectual disability\n. Epilepsy & Behavior , 60 , 130 –137\n.27206231 \n\n\nVecht , C. \n, \nDuran‐Peña , A. \n, \nHouillier , C. \n, \nDurand , T. \n, \nCapelle , L. \n, & \nHuberfeld , G. \n (2017 ). Seizure response to perampanel in drug‐resistant epilepsy with gliomas: Early observations\n. Journal of Neuro‐oncology , 133 , 603 –607\n.28492978\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "10(6)",
"journal": "Brain and behavior",
"keywords": "BTRE; QoL; antiepileptic drugs; brain tumors; epilepsy; molecular factors; perampanel; responder rate",
"medline_ta": "Brain Behav",
"mesh_terms": "D000927:Anticonvulsants; D001932:Brain Neoplasms; D004827:Epilepsy; D006801:Humans; D009570:Nitriles; D010865:Pilot Projects; D011728:Pyridones; D011788:Quality of Life; D016896:Treatment Outcome",
"nlm_unique_id": "101570837",
"other_id": null,
"pages": "e01612",
"pmc": null,
"pmid": "32285623",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "14718691;27300147;29970574;27800020;28038388;23480152;26506904;26724782;32285623;3666548;7890819;23204982;24789254;30377587;8915764;1202204;23095831;22843280;27206231;17434097;28492978;24867391;26140524;23663001;22905857;14810268;27668051;28276062;8954307;22528794;24400692;12697135;24328881;25461214;22517103",
"title": "Perampanel in brain tumor-related epilepsy: Observational pilot study.",
"title_normalized": "perampanel in brain tumor related epilepsy observational pilot study"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1063131",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
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{
"abstract": "OBJECTIVE\nTo report a case series of two patients with contralateral anesthesia after retrobulbar block.\n\n\nMETHODS\nRetrospective review of two cases and review of the literature.\n\n\nRESULTS\nTwo patients of one practitioner received contralateral anesthesia after retrobulbar block for posterior segment surgery. Patient 1 suffered from transient contralateral akinesia, whereas Patient 2 experienced transient contralateral amaurosis.\n\n\nCONCLUSIONS\nPosterior spread of anesthetics is a rare but potentially serious complication of retrobulbar anesthesia caused by spread of anesthetics along the optic nerve sheath. Modification of injection technique can decrease the risk of this complication.",
"affiliations": "Vitreous Retina Macula Consultants of New York, New York, New York.;Department of Ophthalmology, Columbia University, New York, New York.;Department of Ophthalmology, Manhattan Eye, Ear and Throat Hospital, New York, New York.;Department of Ophthalmology, Columbia University, New York, New York.",
"authors": "Ghadiali|Quraish|Q|;Ghadiali|Larissa K|LK|;Schiff|William M|WM|;Odel|Jeffrey G|JG|",
"chemical_list": "D000779:Anesthetics, Local",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000455",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "12(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000772:Anesthesia, Local; D000779:Anesthetics, Local; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009407:Nerve Block; D010147:Pain Measurement; D010149:Pain, Postoperative; D012164:Retinal Diseases; D012189:Retrospective Studies; D057586:Vitreoretinal Surgery",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "97-99",
"pmc": null,
"pmid": "27749747",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "CONTRALATERAL ANESTHESIA IN TWO PATIENTS AFTER RETROBULBAR BLOCK.",
"title_normalized": "contralateral anesthesia in two patients after retrobulbar block"
} | [
{
"companynumb": "US-MYLANLABS-2020M1037189",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
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"drugadditional": null,
... |
{
"abstract": "Methotrexate (MTX) is one of the potent drugs for autoimmune diseases (ADs), especially for rheumatoid arthritis. Recent studies suggest that MTX should be immediately withdrawn when patients with AD develop lymphoproliferative disorder (LPD). However, biopsy cannot be performed for diagnosis because LPD regresses quickly after MTX withdrawal, thus making clinical MTX-LPD (c-MTX-LPD) challenging to diagnose. In this study, among the 28 patients with c-MTX-LPD, seven developed a proven LPD (p-LPD) after suspicious LPD (s-LPD) regression, six of which were Hodgkin lymphoma. Four of seven patients with p-LPD + died, whereas all patients with p-LPD- survived. The clinical manifestations indicative of p-LPD include fever, elevated serum C-reactive protein level, and soluble interleukin-2 receptor level. Anti-AD drugs did not appear to affect the pathogenesis of p-LPD development. P-LPD was not observed after 3 years from the time of s-LPD regression.",
"affiliations": "Department of Hematology, Saitama Medical Center, Saitama Medical University , Saitama , Japan.;Department of Medicine, Division of Rheumatology, Keio University School of Medicine , Tokyo , Japan.;Department of Medicine, Division of Rheumatology, Keio University School of Medicine , Tokyo , Japan.;Department of Pathology, Saitama Medical Center, Saitama Medical University , Saitama , Japan.;Department of Pathology, Saitama Medical Center, Saitama Medical University , Saitama , Japan.;Department of Medicine, Division of Hematology, Keio University School of Medicine , Tokyo , Japan.;Department of Medicine, Division of Hematology, Keio University School of Medicine , Tokyo , Japan.;Department of Hematology, Saitama Medical Center, Saitama Medical University , Saitama , Japan.;Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University , Saitama , Japan.;Department of Medicine, Division of Hematology, Keio University School of Medicine , Tokyo , Japan.;Department of Medicine, Division of Rheumatology, Keio University School of Medicine , Tokyo , Japan.;Department of Pathology, Saitama Medical Center, Saitama Medical University , Saitama , Japan.;Department of Hematology, Saitama Medical Center, Saitama Medical University , Saitama , Japan.",
"authors": "Tokuhira|Michihide|M|;Saito|Shuntaro|S|;Suzuki|Katsuya|K|;Higashi|Morihiro|M|;Momose|Shuju|S|;Shimizu|Takayuki|T|;Mori|Takehiko|T|;Kimura|Yuta|Y|;Amano|Koichi|K|;Okamoto|Shinichiro|S|;Takeuchi|Tsutomu|T|;Tamaru|Jun-Ichi|JI|;Kizaki|Masahiro|M|",
"chemical_list": "D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2019.1585841",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "60(10)",
"journal": "Leukemia & lymphoma",
"keywords": "Clinical; lymphoproliferative disorders; methotrexate; proven; rheumatoid arthritis; suspicious",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008232:Lymphoproliferative Disorders; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2508-2515",
"pmc": null,
"pmid": "30947579",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinicopathological features of clinical methotrexate-related lymphoproliferative disorders.",
"title_normalized": "clinicopathological features of clinical methotrexate related lymphoproliferative disorders"
} | [
{
"companynumb": "JP-SILVERGATE PHARMACEUTICALS, INC.-2019SIL00019",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drug... |
{
"abstract": "Osteonecrosis of the jaw (ONJ) following bisphosphonate use is well documented. However, to our knowledge, there are few cases reported on ONJ related to the use of other pharmaceutical agents, such as denosumab--a monoclonal antibody that is prescribed for the treatment of osteoporosis and is used as an anti-cancer agent. Here we present the first case in the UK of a patient who has developed ONJ following treatment with denosumab. The purpose of this report is to highlight the potential effects of this monoclonal antibody on bone turnover and the subsequent results of osteonecrosis of the jaw. It is hoped that this will allow early recognition by medical and dental practitioners, and appropriate referral and treatment. Clinical Relevance: Readers should be aware of other causes of osteonecrosis of the jaw.",
"affiliations": null,
"authors": "Vyas|Sheena|S|;Hameed|Sabina|S|;Murugaraj|Vaidyanathan|V|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D024042:Collagen Type I; D010455:Peptides; D053245:RANK Ligand; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab",
"country": "England",
"delete": false,
"doi": "10.12968/denu.2014.41.5.449",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-5000",
"issue": "41(5)",
"journal": "Dental update",
"keywords": null,
"medline_ta": "Dent Update",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D024042:Collagen Type I; D000069448:Denosumab; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008336:Mandibular Diseases; D010020:Osteonecrosis; D010455:Peptides; D053245:RANK Ligand; D013492:Suppuration; D014081:Tooth Extraction; D020390:Tooth Socket",
"nlm_unique_id": "7805969",
"other_id": null,
"pages": "449-50",
"pmc": null,
"pmid": "25073227",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Denosumab-associated osteonecrosis of the jaw--a case report.",
"title_normalized": "denosumab associated osteonecrosis of the jaw a case report"
} | [
{
"companynumb": "GB-AMGEN-GBRSP2014059987",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstancename": "OMEPRAZOLE"
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... |
{
"abstract": "Smallpox vaccine is contraindicated in immunosuppression due to increased risk for adverse reactions (eg, progressive vaccinia). We describe the first-ever use of tecovirimat as a preemptive vaccinia virus treatment strategy during induction chemotherapy in an active duty service member who presented with acute leukemia and inadvertent autoinoculation after smallpox vaccination.",
"affiliations": "Infectious Disease Service, Joint Base San Antonio-Fort Sam Houston, Texas.;Department of Medicine, San Antonio Military Medical Center, Joint Base San Antonio-Fort Sam Houston, Texas.;Immunization Healthcare Branch, Defense Health Agency, Falls Church, Virginia.;Division of High-Consequence Pathogens and Pathology (Poxvirus and Rabies Branch).;Division of Preparedness and Emerging Infections (Regulatory Affairs), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.;Division of Preparedness and Emerging Infections (Regulatory Affairs), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.;Division of High-Consequence Pathogens and Pathology (Poxvirus and Rabies Branch).;Division of High-Consequence Pathogens and Pathology (Poxvirus and Rabies Branch).;Division of High-Consequence Pathogens and Pathology (Poxvirus and Rabies Branch).;Infectious Disease Service, Joint Base San Antonio-Fort Sam Houston, Texas.",
"authors": "Lindholm|David A|DA|;Fisher|Raymond D|RD|;Montgomery|Jay R|JR|;Davidson|Whitni|W|;Yu|Patricia A|PA|;Yu|Yon C|YC|;Burgado|Jillybeth|J|;Wilkins|Kimberly|K|;Petersen|Brett W|BW|;Okulicz|Jason F|JF|",
"chemical_list": "D000998:Antiviral Agents; D001549:Benzamides; D016756:Immunoglobulins, Intravenous; D054833:Isoindoles; D012900:Smallpox Vaccine; C505045:Tecovirimat",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciz286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "69(12)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "ST-246; leukemia; smallpox vaccine; tecovirimat; vaccinia",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000998:Antiviral Agents; D001549:Benzamides; D006801:Humans; D016756:Immunoglobulins, Intravenous; D054833:Isoindoles; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008889:Military Personnel; D011292:Premedication; D012899:Smallpox; D012900:Smallpox Vaccine; D063189:Symptom Assessment; D016896:Treatment Outcome; D014611:Vaccination; D014616:Vaccinia virus",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "2205-2207",
"pmc": null,
"pmid": "30959520",
"pubdate": "2019-11-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Preemptive Tecovirimat Use in an Active Duty Service Member Who Presented With Acute Myeloid Leukemia After Smallpox Vaccination.",
"title_normalized": "preemptive tecovirimat use in an active duty service member who presented with acute myeloid leukemia after smallpox vaccination"
} | [
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"companynumb": "US-TEVA-2020-US-1171103",
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"actiondrug": "5",
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"activesubstancename": "DAUNORUBICIN"
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... |
{
"abstract": "Historically, safety of intravenous recombinant tissue plasminogen activator (IV rt-PA) for the treatment of acute ischaemic stroke (AIS) is limited to use within 4.5 hours from symptom onset. Recent studies suggest the treatment window may be extended when patients have salvageable brain tissue on advanced neuroimaging. This paper describes a novel use of IV rt-PA for treatment of AIS in a pregnant patient within an extended-time window (>4.5 hours, and <9 hours) based on advanced neuroimaging with a favourable outcome. TWEETABLE ABSTRACT: Novel use of IV rt-PA for treatment of AIS in pregnancy within an extended-time window based on advanced imaging with a favourable outcome.",
"affiliations": "Department of Obstetrics and Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Department of Neurology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.;College of Medicine, The Ohio State University, Columbus, OH, USA.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.",
"authors": "Dinehart|E|E|0000-0001-7570-3227;Leon Guerrero|C|C|0000-0002-5997-5342;Pham|A|A|0000-0003-4672-2159;Chandra|S|S|;Petersen|S M|SM|;Bathgate|S|S|;Ahmadzia|H|H|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": "10.1111/1471-0528.16495",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-0328",
"issue": "128(3)",
"journal": "BJOG : an international journal of obstetrics and gynaecology",
"keywords": "Acute ischaemic stroke; extended window; pregnancy; rt-PA; thrombolysis",
"medline_ta": "BJOG",
"mesh_terms": "D000208:Acute Disease; D061605:Administration, Intravenous; D000328:Adult; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D000083242:Ischemic Stroke; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "100935741",
"other_id": null,
"pages": "516-520",
"pmc": null,
"pmid": "32920999",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Extending the window for thrombolysis for treatment of acute ischaemic stroke during pregnancy: a review.",
"title_normalized": "extending the window for thrombolysis for treatment of acute ischaemic stroke during pregnancy a review"
} | [
{
"companynumb": "US-BOEHRINGERINGELHEIM-2020-BI-049279",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "... |
{
"abstract": "In 2017, local public health authorities in California received reports of 2 elderly patients with suspected botulism who knew each other socially. A multijurisdictional investigation was conducted to determine the source.\nInvestigators reviewed medical records, interviewed family to establish food and drink histories, and inspected a facility that produced liquid herbal tea. Clinical specimens and product were tested for botulinum neurotoxin (BoNT).\nA total of 2 confirmed botulism cases were identified with BoNT type A; both were hospitalized, 1 died. Botulism was not suspected until several days after hospital admission. Case-patients ingested single-serving prepackaged liquid herbal tea. Inspection of the tea production facility identified conditions conducive to product contamination with C botulinum and toxin production. Samples of tea tested negative for botulinum toxin. Local and state public health authorities issued alerts and the facility recalled the liquid herbal tea.\nLiquid herbal tea prepackaged in sealed pouches was the likely source of this type A botulism outbreak because the 2 cases were linked socially and shared no other foods. This type of product has not previously been described in the foodborne botulism literature. In the absence of known risk factors for botulism at the time of presentation, suspicion based on clinically compatible findings is critical so that and treatment with botulinum antitoxin is not delayed. A coordinated response by public health authorities is necessary in identifying a potential food source, inspecting facilities producing the product, alerting medical providers and the public, and preventing further illness.",
"affiliations": "County of Los Angeles, Department of Public Health, California.;Orange County Healthcare Agency, Santa Ana, California.;County of Los Angeles, Department of Public Health, California.;County of Los Angeles, Department of Public Health, California.;County of Los Angeles, Department of Public Health, California.;California Department of Public Health, Sacramento.;California Department of Public Health, Los Angeles.;California Department of Public Health, Los Angeles.;County of Los Angeles, Department of Public Health, California.",
"authors": "Kim|Moon|M|;Zahn|Matt|M|;Reporter|Roshan|R|;Askar|Ziad|Z|;Green|Nicole|N|;Needham|Michael|M|;Rosen|Hilary|H|;Kimura|Akiko|A|;Terashita|Dawn|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofz014",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n30793007\n10.1093/ofid/ofz014\nofz014\nMajor Article\nOutbreak of Foodborne Botulism Associated With Prepackaged Pouches of Liquid Herbal Tea\nKim Moon 1 Zahn Matt 2 Reporter Roshan 1 Askar Ziad 1 Green Nicole 1 Needham Michael 3 Rosen Hilary 4 Kimura Akiko 4 Terashita Dawn 1 1 \nCounty of Los Angeles, Department of Public Health, California\n\n2 \nOrange County Healthcare Agency, Santa Ana, California\n\n3 \nCalifornia Department of Public Health, Sacramento\n\n4 \nCalifornia Department of Public Health, Los Angeles\n\nCorrespondence: Moon Kim, MD, MPH, Medical Epidemiologist, Acute Communicable Disease Control Program, Los Angeles County Department of Public Health, 313 N. Figueroa St., Rm. 222, Los Angeles, CA 90012 (mokim@ph.lacounty.gov).\n2 2019 \n09 2 2019 \n09 2 2019 \n6 2 ofz01412 10 2018 14 1 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nIn 2017, local public health authorities in California received reports of 2 elderly patients with suspected botulism who knew each other socially. A multijurisdictional investigation was conducted to determine the source.\n\nMethods\nInvestigators reviewed medical records, interviewed family to establish food and drink histories, and inspected a facility that produced liquid herbal tea. Clinical specimens and product were tested for botulinum neurotoxin (BoNT).\n\nResults\nA total of 2 confirmed botulism cases were identified with BoNT type A; both were hospitalized, 1 died. Botulism was not suspected until several days after hospital admission. Case-patients ingested single-serving prepackaged liquid herbal tea. Inspection of the tea production facility identified conditions conducive to product contamination with C botulinum and toxin production. Samples of tea tested negative for botulinum toxin. Local and state public health authorities issued alerts and the facility recalled the liquid herbal tea.\n\nConclusions\nLiquid herbal tea prepackaged in sealed pouches was the likely source of this type A botulism outbreak because the 2 cases were linked socially and shared no other foods. This type of product has not previously been described in the foodborne botulism literature. In the absence of known risk factors for botulism at the time of presentation, suspicion based on clinically compatible findings is critical so that and treatment with botulinum antitoxin is not delayed. A coordinated response by public health authorities is necessary in identifying a potential food source, inspecting facilities producing the product, alerting medical providers and the public, and preventing further illness.\n\nbotulismClostridiumfoodborneoutbreaktoxin\n==== Body\nBotulism is a rare but serious and potentially fatal paralytic illness most commonly caused by the neurotoxin produced by the bacterium Clostridium botulinum and is considered a medical emergency. Suspected cases are mandated to be reported immediately to local and state public health authorities. Heptavalent botulinum antitoxin (BAT) is used to treat botulism and can only be released when authorized by local or state public health officials in coordination with the US Centers for Disease Control and Prevention. In Los Angeles County, California, an average of 3 cases of adult botulism were confirmed annually between 2007 and 2017, and cases are primarily wound botulism associated with injection drug use. Foodborne botulism is uncommon; during that same period, only 2 cases of foodborne botulism were reported in Los Angeles County, and none were reported in Orange County. Symptoms of foodborne botulism generally begin 18 to 36 hours after ingesting a contaminated item, but they can begin as soon as 6 hours after exposure or up to 10 days later. Clostridium botulinum spores are found in both soil and water. Under certain conditions, such as low oxygen, low acidity, and unrefrigerated temperatures, C botulinum can proliferate and produce toxin.\n\nIn 2017, 2 elderly residents of California were identified with suspected botulism, presenting at hospitals 22 days apart. The Orange County Healthcare Agency (OCHCA), Los Angeles County Department of Public Health (LACDPH), and California Department of Public Health (CDPH) initiated an investigation to determine the source of illness, describe the clinical course, and prevent further illness.\n\nMETHODS\nEpidemiological Investigation\nA case was defined as an illness in a person clinically compatible with botulism that began between March 1, 2017 and June 1, 2017 and linked to a common ingested product before illness onset, with botulism toxin A detected by mouse bioassay in clinical specimens. Public health investigators conducted home visits to identify high-risk food and drink items and reviewed case-patients’ medical records. Because the case-patients were intubated, family members were interviewed to collect food and drink exposures in the 10 days before illness onset to identify common items. For case-finding, public health also obtained invoice records for other customers who purchased the common product.\n\nEnvironmental Investigation\nLocal and state public health investigators inspected the facility (Company A) where the common product was produced. Investigators reviewed ingredient records and equipment used to produce the product. The owner and workers of Company A were interviewed regarding handling, production, and storage of the liquid herbal tea. Unopened product was obtained for botulinum toxin testing.\n\nLaboratory Testing\nPre-antitoxin stools and serum specimens were tested by the LACDPH Laboratory for Case 1 and CDPH Microbial Diseases Laboratory for Case 2 using the mouse bioassay for C botulinum toxin. Testing of pH levels and presence of C botulinum neurotoxin and neurotoxin producing organisms in the suspected source product was performed by the CDPH Food and Drug Laboratory Branch.\n\nRESULTS\nEpidemiological Investigations\nWe identified 2 patients meeting the case definition. Case-patient 1 was an elderly Asian resident of California who presented to Hospital A in 2017 with slurred speech, bilateral ptosis, and left-sided weakness beginning 3 days before admission. Case-patient 1 required intubation due to respiratory failure later on the same day of admission. Imaging of the brain and cerebrospinal fluid were unremarkable. The disease progressed to complete bilateral paralysis, and on hospital day 13 clinicians consulted with their local public health and CDPH and BAT was released. Investigation conducted by local public health identified no obvious food sources. Case-patient 1 died on hospital day 29. Twenty-two days after Case-patient 1 was admitted, another elderly Asian resident of California was admitted to Hospital B with a 1-day history of vomiting, abdominal pain, diplopia, bilateral symmetric extraocular and facial palsy, dysphagia, and dyspnea. Case-patient 2 required intubation on the day of admission. Exam noted diffuse flaccid paralysis with minimal deep tendon reflexes. Brain imaging was unremarkable; a lumbar puncture was not performed. Clinicians at Hospital B suspected botulism on hospital day 4 and BAT was released by CDPH. No evidence of trauma, wounds, or history of injection drug use were present for either patient. Case-patients did not have any anatomic or functional bowel abnormalities or altered gastrointestinal flora associated with receipt of recent antimicrobials. On hospital day 24, Case-patient 2 was transferred to a long-term care facility for ventilator care and, at 14 months after illness onset, had some improvement in function but was unable to stand or walk.\n\nMembers of Case-patient 2’s family reported to local public health that they knew of Case-patient 1 being ill but denied the 2 sharing meals together. Review of both case-patient’s food histories with family members led to the identification of a single common exposure: both had ingested prepackaged liquid tea pouches containing herbs and deer antlers, which were part of a single purchase from Company A made by a mutual friend. No other shared or common food or drink items were identified. Three additional social contacts also ingested liquid herbal tea pouches from the same purchase. None of these contacts became ill.\n\nEnvironmental Investigation\nThe LACDPH and CDPH conducted a site visit at Company A’s herbal tea production facility. The facility is a 2-story building containing dry herbs stored on shelves in boxes and jars from floor to ceiling. The liquid tea production, filling, and packaging are conducted in a separate room located on the 2nd floor room containing 12 industrial pressure cookers and 2 automated pouch filling and packaging machines. Company A’s customers are mostly from the local area, but their herbal products are also shipped to out-of-state customers. The liquid herbal tea was supplied in sealed pouches and sold in a box of 60 pouches; per Company A, 1 pouch (Figure 1A and B) is usually recommended to be taken twice a day. Instructions to refrigerate the pouches were written on the back of each individual pouch, but the instructions were not written in English. Instructions to refrigerate the pouches were also printed on a label, in English, on the outside of the cardboard box. Both cases reportedly kept the pouches refrigerated before use.\n\nFigure 1. Liquid herbal tea pouch (A) front and (B) back.\n\nCompany A produces pouches of liquid tea containing ingredients as advised by each customer’s herbal medicine practitioner. The liquid herbal tea production steps were described by Company A workers as follows: (1) dry herbs, plant products (eg, onions, dates), roots (eg, ginger), and sometimes sliced deer antlers were placed in a large tea bag (Figure 2A); (2) ingredients and water were boiled for 5 hours in industrial pressure cookers; (3) the liquid tea was either drained into uncovered stainless steel buckets using a flexible hose connected to the pressure cooker spigot or directly drained without hoses into uncovered stainless steel buckets from the spigot (Figure 2B); (4) the contents of the stainless steel bucket were then poured by workers into the reservoir of an automatic pouch filling and packaging machine (Figure 3A and B); (5) the packaging machine aliquoted the liquid tea into individual pouches containing approximately 120 mL liquid tea, which was then heat sealed. Use-by-dates, store identification, or lot numbers were not printed on the pouches. A review of Company A’s invoice records listed the tea ingredients consumed by the case-patients as deer antlers, dates, ginger, and huang qi (a dried root).\n\nFigure 2. Pressure cookers: (A) tea bag inside containing dried herbs; (B) spigot draining into bucket.\n\nFigure 3. (A) Automatic pouch filling machine and spout (white arrow); (B) close up of pouch film and filling spout (white arrow).\n\nDeficiencies noted by public health inspectors included the following: the tea product was exposed to unsterilized pressure cooker drain spigots or hoses that were exposed to the processing room environment and not adequately controlled to prevent contamination; the product was exposed to unsterilized stainless steel buckets that were left uncovered and exposed to the processing room environment, which was not controlled to prevent contamination; the tea product was further exposed to the processing room environment while being carried over to the pouch filling and packaging machine.\n\nInspectors also observed large bags of unpeeled onions stored in the same room as pressure cookers and the pouch filling and packaging machine; the flexible hoses used to drain the liquid tea from the pressure cookers were stored on top of the onion bags. The product was exposed to unsterilized packaging pouch film in the packaging machine that was exposed to the processing room environment. In addition, the facility owner and workers failed to demonstrate knowledge of proper cleaning and sanitizing procedures for the equipment. Inspectors also noted that the gradual, uncontrolled pouch cooling process was inadequate in that the sealed pouches could be exposed to time and temperature ranges favorable to C botulinum spore germination.\n\nDuring the site visit, LACDPH issued directives to Company A to discontinue tea production. The CDPH also directed Company A to cease tea processing immediately because they did not have the required CDPH-issued cannery license to manufacture low-acid canned foods. Review of invoice records showed that the liquid herbal tea pouches were also distributed to customers outside the state of California.\n\nLaboratory Testing\nStool and serum for Case-patients 1 and 2 were positive by mouse bioassay for botulinum neurotoxin, toxin type A. In addition, toxin-producing C botulinum organisms were isolated from the stool of Case-patient 1. Seven unopened liquid tea pouches that remained from the common purchase, including pouches from the 2 case-patients and a friend who ingested the tea but did not become ill, were tested by CDPH and were negative for C botulinum toxin and toxin-producing C botulinum. Seven sealed liquid tea pouches obtained from Company A’s facility were also negative for C botulinum toxin and toxin-producing C botulinum. The pH of the liquid herbal tea obtained from the case-patients’ homes varied and ranged from 5.13 to 7.58.\n\nPublic Health Response\nThe LACDPH issued a press release, including to the local Asian media, warning residents not to consume the liquid herbal tea pouches. That same day, LACDPH distributed an alert to Los Angeles County hospitals providing healthcare providers information on the clinical manifestations of foodborne botulism and immediate reporting of suspected cases to public health authorities. The OCHCA also issued a press release and sent alerts to Orange County hospitals. The CDPH notified public health authorities from the out-of-state jurisdictions listed on customer invoice records and also issued a press release warning consumers regarding herbal tea produced by Company A and the risk of botulism.\n\nIn cooperation with CDPH, Company A issued a voluntarily recall of liquid herbal tea varieties produced between March 1, 2017 and April 30, 2017 due to risk for C botulinum. The recall was posted on the US Food and Drug Administration’s website. No additional botulism cases associated with liquid herbal tea pouches were reported in California or other states.\n\nDISCUSSION\nWe describe an outbreak of botulism associated with the ingestion of liquid herbal tea packaged in sealed pouches [1]. The liquid herbal tea produced at Company A was the most likely source of the illness because the tea was the only common item known to be ingested by both patients; the tea was produced and packaged in air-tight pouches in a facility lacking the required CDPH-issued cannery license, where contamination with C botulinum could have occurred due to improper handling, production, and storage; C botulinum is commonly found in soil, and thus the onions or other root vegetables are inherently contaminated with soil and, as such, may present a more direct risk of food contamination than generic environmental contamination; and the tea was packaged in a low-acid, anaerobic environment, conditions where C botulinum can grow and produce toxin. Case-patients also had no known risk factors for botulism due to adult intestinal colonization and had epidemiologic links to consuming a common food product with high risk for botulism. The detection of neurotoxin-producing C botulinum in the stool of Case-patient 1 at approximately 2 weeks after symptom onset is not atypical. Clostridium botulinum detection in stool culture at 18 days after symptom onset has occurred in a previously reported foodborne botulism outbreak [2].\n\nBotulism can be fatal and clinical recognition is often difficult in elderly patients. The differential diagnosis includes cerebrovascular disease, Guillain-Barre syndrome, and myasthenia gravis. Healthcare providers, most of whom rarely see botulism, might not suspect the diagnosis in patients when a history of injection drug use or ingestion of high-risk home canned or fermented foods is absent. Because laboratory testing for botulism may take days and risk factors might not be apparent at time of presentation, BAT should be given empirically and urgently based on clinical findings to prevent progression of paralysis or respiratory failure [3, 4]. Case 1 did not receive BAT until 2 weeks after hospitalization and later died. A recent review of botulism cases showed that respiratory involvement can occur early, and many patients require intubation on the first or second hospital day as with the 2 confirmed cases in this report [5].\n\nFoods previously associated with botulism have included improperly canned commercial foods, home-canned or fermented fish, herb-infused oils, baked potatoes in aluminum foil, cheese sauce, and bottled garlic [6]. Liquid herbal tea sealed in pouches has not previously been reported in the literature to be associated with foodborne botulism. Low-acid foods have pH values greater than 4.6 and when processed and placed into sealed, air-tight containers such as cans, pouches, or jars, and not stored under temperature control, they can allow the growth of C botulinum and toxin production. Although we were unable to detect botulinum toxin in the liquid herbal tea product samples tested, this may be due to the varying amount of contamination or variations in the pouch environment. Variations in temperature and pH can occur during production and storage and thus not all pouches may have had conditions suitable for C botulinum toxin production.\n\nCONCLUSIONS\nThis outbreak highlights several key points. First, it is important that healthcare providers have a high index of suspicion and immediately report suspected cases of botulism based on clinical findings to local and state public health authorities [4]. Consultation by public health is available around the clock to authorize release of BAT, which can prevent further paralysis or respiratory compromise if administered early in the course of illness, as well as to initiate appropriate diagnostic testing by public health that is not provided by standard commercial laboratories. Second, rapid reporting of suspected botulism by healthcare providers to public health authorities allows for immediate investigation, removal of potentially contaminated sources, and issuing of alerts to prevent further illness. Third, public health investigators should be aware of ingestible sources for botulinum toxin including exposures in drinks as well as foods. Ethnic foods unfamiliar to investigators can be challenging [7]. Prepackaged liquid herbal tea pouches have not, to our knowledge, been previously recognized as a product causing foodborne botulism [6]. However, because the production process is similar to canning, public health investigators should be aware that drink products including those packaged in sealed pouches with low-acid content and low or no oxygen environments can be suitable for C botulinum growth and toxin production if stored or produced improperly. This underscores the importance of governmental regulations and inspection of facilities producing food and drinks. Finally, rapid coordination with local, state, and federal agencies is essential in alerting healthcare providers and the public to a potential foodborne botulism risk.\n\nAcknowledgments\nWe acknowledge June Nakagawa and Lillian Araiza (California Department of Public Health [CDPH] Food and Drug Branch), the CDPH Food and Drug Laboratory Branch, and the CDPH Microbial Diseases Laboratory.\n\n\nPotential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1. California Code of Regulations, Title 17, Section 2500 (a) (14): “Foodborne disease outbreak” means an incident in which 2 or more persons experience a similar illness after ingestion of a common food, and epidemiologic analysis implicates the food as the source of the illness.\n2. \nJuliao PC , Maslanka S , Dykes J , et al \nNational outbreak of type a foodborne botulism associated with a widely distributed commercially canned hot dog chili sauce\n. Clin Infect Dis 2013 ; 56 :376 –82\n.23097586 \n3. \nRao A , Lin N , Jackson K , Mody R \nClinical characteristics of botulism in the United States, 2002–2012\n. Open Forum Infect Dis 2014 ; 1 :S49 –50\n.\n4. \nRao AK , Lin NH , Griese SE , et al \nClinical criteria to trigger suspicion for botulism: an evidence-based tool to facilitate timely recognition of suspected cases during sporadic events and outbreaks\n. Clin Infect Dis 2017 ; 66 :38 –42\n.\n5. \nChatham-Stephens K , Fleck-Derderian S , Johnson SD , et al \nClinical features of foodborne and wound botulism: a systematic review of the literature, 1932–2015\n. Clin Infect Dis 2018 ; 66 :S11 –6\n.\n6. \nFleck-Derderian S , Shankar M , Rao AK , et al \nThe epidemiology of foodborne botulism outbreaks: a systematic review\n. Clin Infect Dis 2017 ; 66 :73 –81\n.\n7. \nHarvey RR , Cooper R , Bennett S , et al \nOutbreak of foodborne botulism in an immigrant community: overcoming delayed disease recognition, ambiguous epidemiologic links, and cultural barriers to identify the cause\n. Clin Infect Dis 2017 ; 66 :82 –4\n.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "6(2)",
"journal": "Open forum infectious diseases",
"keywords": "Clostridium; botulism; foodborne; outbreak; toxin",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofz014",
"pmc": null,
"pmid": "30793007",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "23097586;29293923;29293926;29293929;29293934",
"title": "Outbreak of Foodborne Botulism Associated With Prepackaged Pouches of Liquid Herbal Tea.",
"title_normalized": "outbreak of foodborne botulism associated with prepackaged pouches of liquid herbal tea"
} | [
{
"companynumb": "US-EMERGENT BIOSOLUTIONS CANADA INC.-17BA00027SP",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "EQUINE BOTULINUM NEUROTOXIN A/B/C/D/E/F/G... |
{
"abstract": "Perampanel is one of the latest released antiepileptic drugs (AEDs). Early studies suggest no significant liver enzyme induction from this compound. We report on two patients with medically resistant epilepsy, who had perampanel added to their usual regimen. Both experienced a worsening of their epilepsy and presented in convulsive status epilepticus; concurrent antiepileptic drug levels (phenytoin, phenobarbital, rufinamide) were significantly decreased (<50%) in comparison with levels prior to perampanel introduction. Intravenous load and significant increase of maintenance dosages were needed to restore therapeutic drug levels. In one patient, further increase of perampanel resulted in a new drop of phenytoin level. This suggests that perampanel could, in some subjects, induce liver enzymes and interact with concomitant AEDs; monitoring levels of concomitant compounds could be useful.",
"affiliations": "Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland.",
"authors": "Novy|Jan|J|;Rothuizen|Laura E|LE|;Buclin|Thierry|T|;Rossetti|Andrea O|AO|",
"chemical_list": "D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000362446",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0014-3022",
"issue": "72(3-4)",
"journal": "European neurology",
"keywords": null,
"medline_ta": "Eur Neurol",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D006801:Humans; D008099:Liver; D008297:Male; D009570:Nitriles; D011728:Pyridones; D055815:Young Adult",
"nlm_unique_id": "0150760",
"other_id": null,
"pages": "213-6",
"pmc": null,
"pmid": "25227593",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Perampanel: a significant liver enzyme inducer in some patients?",
"title_normalized": "perampanel a significant liver enzyme inducer in some patients"
} | [
{
"companynumb": "CH-EISAI MEDICAL RESEARCH-E2007-01642-SPO-CH",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PERAMPANEL"
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"drugadditi... |
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"abstract": "Although speech dysfluencies have been hypothesized to be associated with abnormal function of dopaminergic system, the effects of dopaminergic medication on speech fluency in Parkinson's disease (PD) have not been systematically studied. The aim of the present study was, therefore, to investigate the long-term effect of dopaminergic medication on speech fluency in PD. Fourteen de novo PD patients with no history of developmental stuttering and 14 age- and sex-matched healthy controls (HC) were recruited. PD subjects were examined three times; before the initiation of dopaminergic treatment and twice in following 6 years. The percentage of dysfluent words was calculated from reading passage and monolog. The amount of medication was expressed by cumulative doses of L-dopa equivalent. After 3-6 years of dopaminergic therapy, PD patients exhibited significantly more dysfluent events compared to healthy subjects as well as to their own speech performance before the introduction of dopaminergic therapy (p < 0.05). In addition, we found a strong positive correlation between the increased occurrence of dysfluent words and the total cumulative dose of L-dopa equivalent (r = 0.75, p = 0.002). Our findings indicate an adverse effect of prolonged dopaminergic therapy contributing to the development of stuttering-like dysfluencies in PD. These findings may have important implication in clinical practice, where speech fluency should be taken into account to optimize dopaminergic therapy.",
"affiliations": "Department of Circuit Theory, Faculty of Electrical Engineering, Czech Technical University in Prague, Technická 2, 166 27, Prague 6, Czech Republic.",
"authors": "Tykalová|Tereza|T|;Rusz|Jan|J|;Čmejla|Roman|R|;Klempíř|Jiří|J|;Růžičková|Hana|H|;Roth|Jan|J|;Růžička|Evžen|E|",
"chemical_list": "D015259:Dopamine Agents; D007980:Levodopa",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00702-015-1363-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9564",
"issue": "122(8)",
"journal": "Journal of neural transmission (Vienna, Austria : 1996)",
"keywords": null,
"medline_ta": "J Neural Transm (Vienna)",
"mesh_terms": "D000328:Adult; D000368:Aged; D015259:Dopamine Agents; D005260:Female; D006801:Humans; D007980:Levodopa; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D012720:Severity of Illness Index; D013060:Speech; D013061:Speech Acoustics; D013064:Speech Disorders",
"nlm_unique_id": "9702341",
"other_id": null,
"pages": "1135-42",
"pmc": null,
"pmid": "25583417",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "1564476;15212606;12959476;9106763;633872;23872286;20938200;22389682;11215569;1680295;23967947;15159193;17675595;16310964;2746281;2890403;16943402;16075183;17928317;17531310;18475072;22081500;11391759;12706913;21303016;19137234;22920284;10329754;6830460;8956103;18163453",
"title": "Effect of dopaminergic medication on speech dysfluency in Parkinson's disease: a longitudinal study.",
"title_normalized": "effect of dopaminergic medication on speech dysfluency in parkinson s disease a longitudinal study"
} | [
{
"companynumb": "PHHY2015CZ105238",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
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... |
{
"abstract": "Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK)1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited.\n\n\n\nA 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34(+) cells/kg infused were 8.69 × 10(6) kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54.\n\n\n\nAt 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.",
"affiliations": "Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy. shostakowitsch@libero.it.;Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.;Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.;Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.;Department of Oncology, University of Torino, Torino, Italy.;Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.;Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.;Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.;Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.;Department of Pathology, AOU Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.;Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.",
"authors": "Maffini|Enrico|E|0000-0001-7356-2328;Giaccone|Luisa|L|;Festuccia|Moreno|M|;Brunello|Lucia|L|;Buondonno|Ilaria|I|;Ferrero|Dario|D|;Boccadoro|Mario|M|;Dellacasa|Chiara|C|;Busca|Alessandro|A|;Novero|Domenico|D|;Bruno|Benedetto|B|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib",
"country": "England",
"delete": false,
"doi": "10.1186/s13045-016-0298-6",
"fulltext": "\n==== Front\nJ Hematol OncolJ Hematol OncolJournal of Hematology & Oncology1756-8722BioMed Central London 29810.1186/s13045-016-0298-6Case ReportRuxolitinib in steroid refractory graft-vs.-host disease: a case report http://orcid.org/0000-0001-7356-2328Maffini Enrico +39-011-6334354shostakowitsch@libero.it 12Giaccone Luisa 12Festuccia Moreno 12Brunello Lucia 12Buondonno Ilaria 3Ferrero Dario 12Boccadoro Mario 2Dellacasa Chiara 1Busca Alessandro 1Novero Domenico 4Bruno Benedetto 121 Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy 2 Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy 3 Department of Oncology, University of Torino, Torino, Italy 4 Department of Pathology, AOU Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy 8 8 2016 8 8 2016 2016 9 677 6 2016 3 8 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. 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\nAllogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK)1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited.\n\nCase presentation\nA 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34+ cells/kg infused were 8.69 × 106 kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54.\n\nConclusions\nAt 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.\n\nKeywords\nAllogeneic hematopoietic stem cell transplant (HSCT)Steroid-refractory graft-vs.-host disease (SR-GvHD)RuxolitinibRegulatory T cells (Treg)Proinflammatory cytokinesCase reportThis work was supported by Progetti di Ricerca Finalizzata 2008, Progetto di Ricerca Sanitaria Finalizzata 2009, Fondi di Ricerca Locale, Università degli Studi di Torino, Torino, Italy and by Fondazione Neoplasie del sangue (FO.NE.SA.), Torino, Italy.issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nAllogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative for several hematopoietic malignancies. Acute graft-vs.-host disease (aGvHD) remains the major cause of morbidity and mortality. High-dose corticosteroids (methylprednisolone, 1–2 mg/kg per day) are currently considered standard first-line treatment. However, a remarkable number of patients do not respond [1]. Estimated incidence of steroid-refractory aGvHD (SR-GvHD) is some 40 %, and it is associated with poor long-term survival of 5–30 % [2–4]. At present, there are no well-defined treatment approaches although several second-line therapies aimed at inactivating alloreactive donor T cells, pro-inflammatory cytokines or their receptors have been investigated. The weighted average 6-month survival from 25 retrospective studies or phase II trials was 49 % [2]. Among others, agents used included anti-thymocyte globulin, mycophenolate mofetil, anti-CD25 monoclonal antibody (basiliximab), anti-tumor necrosis factor alpha (infliximab and etanercept), anti-interleukin 2 receptor-alpha (inolimomab), anti-CD52 (alemtuzumab), pentostatin, m-Tor inhibitors and extracorporeal photoapheresis [5–13]. Since clinical trials in SR-GvHD are difficult to design given the heterogeneity of treatment policies, direct comparisons of different agents have not been possible.\n\nCase presentation\nA 51-year-old male without significant comorbidities and irrelevant past medical history was diagnosed with refractory anemia with excess blast type-1 (RAEB-1) in 2013 and evolved to RAEB-2 after 24 months. Overall, the patient had a high risk score both by the International (IPSS) and by the WHO prognostic scoring systems (WPSS). Blast count was 15 % on bone marrow biopsy and 11 % on marrow aspirate. Other features included trisomy 8 by cytogenetic analysis and two cytopenias—neutropenia and thrombocytopenia—in the peripheral blood. He never required red blood cell or platelet transfusions. He was initially treated with 2 cycles of induction chemotherapy with fludarabine (30 mg/m2, days 1–5), high-dose cytarabine (2000 mg/m2, days 1–5), and idarubicin (10 mg/m2, days 1–3). Complete remission by histology and by flow cytometry was obtained. However, FISH analysis showed persistent trisomy 8. The patient underwent an allogeneic HSCT with mobilized peripheral blood stem cells from a 9/10 HLA-matched (antigenic mismatch at HLA-A) unrelated donor. Conditioning regimen was busulfan (3.2 mg/kg/day; days −7 to −4) and cyclophosphamide (60 mg/kg/day; days −3 and −2). GvHD prophylaxis consisted of cyclosporine (CsA) (1.5 mg/kg twice daily, from day −1), methotrexate (15 mg/m2, 24 h after transplant, then 10 mg/m2 on days 3, 6, and 11), and thymoglobulin (2.5 mg/kg on days −3 and −2). CD34+ cells/kg infused were 8.69 × 106. Gut decontamination with antibiotics after HSCT was not scheduled. On day 13, the patient stopped oral intake because of grade III mucositis. On day 22, he developed a maculo-papular rash on 50 % of his body surface area (stage 2) and mild (500 ml/24 h) watery diarrhea (stage 1), without fever and/or liver function tests abnormalities suggestive of aGVHD. Stool cultures ruled out gastrointestinal (GI) bacterial, viral or parasitic infections. A chest X-ray ruled out pulmonary infiltrates. Diagnosis of overall grade II aGVHD was made and intravenous (i.v.) corticosteroids at 2 mg/kg/day were promptly started on the same day. However, diarrhea worsened rapidly over the following days to stage 4 GI aGvHD with over 2500 mL/24 h of diarrhea and increasing painful abdominal cramps (Table 1). Clinical conditions did not improve despite the combination of cyclosporine, high-dose steroids and the addition of oral budesonide (3 mg three times per day) on day 28 and i.v. mycophenolate mofetil (MMF) (1 g three times per day) on day 29. An endoscopic evaluation of the upper GI tract with multiple biopsies on day 33 confirmed the diagnosis of aGvHD (Fig. 1a–c). Patient's clinical conditions rapidly deteriorated. Oral Ruxolitinib was started at 5 mg twice per day on day 33. Stools volume progressively and steadily decreased to less than 1000 mL on day 39. MMF was stopped on the same day given its unlikely clinical efficacy and to reduce immunosuppression. Clinical conditions gradually improved. Neutrophil and platelet engraftment (defined as the first of 3 consecutive days of neutrophils ≥500/uL and as the first of 7 consecutive days with platelet counts ≥20,000/uL without transfusion support, respectively) occurred at days 17 and 19. Platelet counts were ≥300.000/uL on day 28 and then dropped below 100,000/uL on day 49 and remained stable around 40,000–50,000/uL until discharge (with concurrent oral Ruxolitinib at 5 mg twice daily). Hemoglobin values peaked at 136 g/L on day 31 and dropped below 100 g/L on day 35. Overall, 4 units of red blood cells were required during hospitalization. Skin lesions disappeared completely by day 50. On day 45, the patient resumed oral food intake without nausea and/or vomiting and by day 61 stools were formed. A second endoscopy with multiple biopsies on day 54 revealed no residual signs of aGvHD in the GI tract (Fig. 1d). Bone marrow biopsy on day 64 showed a hypocellular marrow with normal myeloid maturation without evidence of disease recurrence and full donor engraftment by mixed-chimerism analysis. On day 70, the patient was discharged. Ruxolitinib was initially reduced because of progressive pancytopenia to 5 mg per day on day 100 and to 5 mg every other day on day 107. It was resumed at 5 mg per day on day 113 because of soften stools and abdominal discomfort with prompt improvement of GI symptoms. Platelet counts progressively raised to ≥80,000/uL.Table 1 Patient timeline clinical history\n\nDays from HSCT\tClinical condition/therapeutic intervention\t\n0\tHSCT\t\n17\tNeutrophil recovery\t\n19\tPlatelet recovery\t\n22\taGvHD onset: diarrhea (st.I) and skin (st.II). Started PDN-equivalent 2 mg/kg/iv\t\n28\tDiarrhea exceeded 1500 mL/day (st.III) and started budesonide 3 mg tid po\t\n29\tDiarrhea exceeded 2000 mL/day (st.IV) and started MMF 1 g tid iv\t\n33\tEGDS with biopsies (GvHD confirmation). Started Ruxolitinib 5 mg bid\t\n36\tSteroid taper\t\n39\tDiarrhea below 1000 mL and Ruxolitinib 5 + 10 mg/day. Stop MMF\t\n45\tResumed oral food intake\t\n49\tSwitch to oral CsA\t\n54\tEGDS with biopsies: no signs of GvHD\t\n61\tSwitch PDN po\t\n66\tReduced Ruxolitinib to 5 mg bid\t\n70\tPatient discharged\t\n100\tReduced Ruxolitinib to 5 mg/day\t\n135\tSteroid stopped\t\n156\tRuxolitinib stopped\t\n\nabbreviations: HSCT hematopoietic stem cell transplantation, aGvHD acute graft-vs.-host disease, PDN prednisone, iv intravenously, po orally, MMF mycophenolic acid, EGDS esophagous-gastro-duodenoscopy, CsA cyclosporine A, bid twice daily, tid three times a day, st stage\n\nFig. 1 Histology studies (H&E). a–c Gastrointestinal acute grade I GVHD: focal apoptosis of crypt epithelial cells (white arrows) without abscess or crypt destruction. A clear lymphocytic infiltration of the lamina propria is not present. Moderate mucosal atrophy can be observed. d Duodenum at day +54 post-transplant: complete reconstitution of the mucosa with disappearance of apoptotic crypt cells (courtesy of D. Novero, Pathology, University of Turin)\n\n\n\nCytokine measurement\nSerum levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were measured in serum samples from day +27 (before the start of Ruxolitinib) and day +56 (after 23 days of treatment), by Becton Dickinson Biosciences Human Inflammatory Cytokine kit. Interestingly, we observed a decrease of both these pro-inflammatory markers during Ruxolitinib treatment (Fig. 2). We cannot, however, rule out a potential effect of glucocorticoids and mycophenolic acid [14, 15].Fig. 2 Serum levels of TNF-α and IL-6. TNF-α decreased from 10 pg/mL at day 27 (while on high-dose steroids) to 5 pg/mL at day 54, while IL-6 decreased from 2.3 to 1.5 pg/mL (values are expressed as percentage)\n\n\n\nConclusions\nDonor T cell immune response to recipient antigens represents a key mechanism of GvHD and is combined with a massive production of inflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-2-R. Cytokine-induced activation of the various effector cells—including T cells, dendritic cells, and neutrophils—is mediated by the interplay between cytokine receptors and a number of specialized kinases [16]. Family members of Janus kinases (JAK) are among the most studied. Ruxolitinib is a selective oral JAK1/2 inhibitor approved for the treatment of patients with intermediate-2 or high-risk primary myelofibrosis [17, 18]. Spleen size reduction and improvement of constitutional symptoms are directly correlated with inhibition of JAK-STAT signal transducer hyperactivity and with reduction of both effector cells activity and flogistic cytokine signature [19]. Apart from its ability to depress the pro-inflammatory environment of GvHD, Ruxolitinib shapes T cell mediated immune response toward a FoxP3+ regulatory T cell (Treg) polarization mostly by a sparing mechanism of the JAK3-STAT5 pathway [18]. Tregs improve signs and symptoms of aGvHD and promote immunotolerance [19–23]. These mechanisms have been shown on murine models [14] and also form the rationale for the potential efficacy of Ruxolitinib in the treatment of GvHD in man.\n\nOnly a few clinical experiences have been reported so far. Spoerl et al. [24] explored JAK1/2 inhibition during aGvHD both in a major HLA-mismatched murine model and in a cohort of 6 HSCT recipients who developed SR-aGvHD (GI in 2 and skin in 4). In the murine model, Ruxolitinib was associated with a significantly prolonged survival with reduced weight loss and GvHD severity by histology studies and suppression of the serum inflammatory cytokine profile. Moreover, a reduction of donor alloreactive T cells with a concomitant expansion of CD4+ FoxP3+ Treg in GvHD target organs demonstrated the ability of Ruxolitinib to shift T cell phenotype. In HSCT recipients, response rates were optimal with clinical regression in all and a marked reduction of pro-inflammatory cytokines such as IL-6 and soluble IL-2 receptor. Ruxolitinib was employed at a starting dose of 5 mg twice per day daily with a dose increase to 10 mg twice per day. Neither thrombocytopenia nor anemia were reported. A recent retrospective multi-center survey on 95 HSCT recipients with SR-GVHD—54 acute and 51 chronic GvHD (cGvHD), reported the most significant clinical experience so far completed [25]. Median prior lines of treatment were three (range: 1–7 for aGvHD; 1–10 for cGvHD). Overall response rate was 81.5 % in the aGvHD group (44/54) with 57 % (25/44) complete remissions and of 85.4 % (35/41) in the cGvHD group, respectively. Overall survival was 79 and 97.4 %. Among responders, GvHD flare was 6.8 % for aGvHD and 5.7 % for cGvHD patients. Side effects such as cytopenia (55.6 and 17.1 % in the aGvHD and cGvHD group, respectively) and cytomegalovirus (CMV) reactivation (33.3 and 14.6 %) were comparable to those reported with other agents including steroids, infliximab, alemtuzumab, mycophenolate mofetil, or cyclosporine. Overall, one of the concerns was the loss of a graft-vs.-leukemia effect, given the pharmacological interference with the JAK1/2 signal pathway; however, the reported rate of disease recurrence after Ruxolitinib was of 9.3 and 2.4 % of the patients in the aGVHD and cGVHD groups, respectively. Initial signs of improvement (partial response) of GVHD symptoms were observed 6 days from the start of Ruxolitinib and complete resolution after 3 weeks of treatment. These findings are similar to those reported by Zeiser et al. (median time to response 1.5 weeks, range 1–11). A possible synergistic role with budesonide and MMF cannot be completely ruled out even though these agents were administered only for a very few days. The most effective Ruxolitinib tapering schedule remains to be defined, given the limited clinical experience. Our schedule was purely based on clinical grounds in the light of GvHD signs/symptoms, worsening of cytopenias, or viral reactivation. A steroid-sparing effect in chronic GvHD has also recently been proposed [26] with encouraging results. A similar role in aGvHD has not yet been reported. Ruxolitinib dose-dependent cytopenias are usually expected during treatment [27] even though, in our patient, other factors such as GvHD itself and prolonged immunosuppressive therapy with several agents may have been involved [28]. At 5 months from HSCT, the patient is doing well, with full donor mixed chimerism and in continuous complete remission (confirmed at bone marrow biopsy on day 148) with no signs and/or symptoms of GvHD on CsA taper. Prednisone was stopped on day 135 and Ruxolitinib on day 156. Of note, there was no CMV (though both donor and recipient were CMV seronegative)- nor Epstein Barr Virus-DNAemia breakthrough. Overall, our clinical findings suggest that Ruxolitinib played a fundamental role in the successful GvHD treatment of our patient. SR-GvHD is a challenging complication with no current standard treatment. GI tract involvement is life-threatening also in the light of the long process required for a complete repair of the intestinal mucosa. Therapeutic efficacy of Ruxolitinib is underlined by recent biological insights into the relevant role played by the JAK-STAT signaling pathway in aGvHD. However, treatment duration and possible impacts on graft-vs.-leukemia and immune-responses against infections remain a matter of debate. Thus, larger clinical phase II–III controlled trials and comparisons with best available treatments are warranted. A German multi-center phase II clinical trial on Ruxolitinib in SR-aGvHD is due to start accrual this fall (NCT02396628).\n\nAbbreviations\naGvHD, acute graft-vs.-host disease; cGvHD, chronic GvHD; CMV, cytomegalovirus; GI, gastrointestinal; HSCT, hematopoietic stem cell transplantation; i.v., intravenous; JAK, Janus kinases; MMF, mycophenolate mofetil; RAEB-1, refractory anemia with excess blast type-1; SR-GvHD, steroid-refractory graft-vs.-host disease; Treg, regulatory T cells\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis work was supported by Progetti di Ricerca Finalizzata 2008, Progetto di Ricerca Sanitaria Finalizzata 2009, Fondi di Ricerca Locale, Università degli Studi di Torino, Torino, Italy, and by Fondazione Neoplasie del sangue (FO.NE.SA.), Torino, Italy.\n\nAvailability of data and materials\nThe authors did not use any database, software, or tools for the writing of this manuscript.\n\nAuthors’ contributions\nEM collected the patient’s data and drafted the manuscript along with LG, MF, LB, DF, MB, CD and AB. BB revised the manuscript. DN provided the histological images. IB did the cytokine analysis. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nThe authors obtained informed consent from the patient to publish information on his disease and clinical course.\n\nEthics approval and consent to participate\nEthical approval is not appropriate. The authors obtained patient’s consent to participate.\n==== Refs\nReferences\n1. Deeg J How I, treat refractory acute GVHD Blood 2007 109 10 4119 4126 10.1182/blood-2006-12-041889 17234737 \n2. Martin PJ Rizzo JD Wingard JR Ballen K Curtin PT Cutler C Litzow MR Nieto Y Savani BN Schriber JR Shaughnessy PJ Wall DA Carpenter PA First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation Biol Blood Marrow Transplant 2012 18 8 1150 1163 10.1016/j.bbmt.2012.04.005 22510384 \n3. Xhaard A Rocha V Bueno B Steroid refractory acute GVHD: lack of long-term improved survival using new generation anti cytokine treatment Biol Blood Marrow Transplant 2012 18 3 406 413 10.1016/j.bbmt.2011.06.012 21736868 \n4. Robin M Porcher R de Castro R Initial liver involvement in acute GVHD is predictive for non relapse mortality Transplantation 2009 88 1131 1136 10.1097/TP.0b013e3181bc2583 19898210 \n5. Inagaki J Kodama Y Fukano R Noguchi M Okamura J Mycophenolate mofetil for treatment of steroid-refractory acute graft-versus-host disease after pediatric hematopoietic stem cell transplantation Pediatr Transplant 2015 19 6 652 658 10.1111/petr.12545 26103520 \n6. Nadeau M Perreault S Seropian S Foss F Isufi I Cooper DL The use of basiliximab-infliximab combination for the treatment of severe gastrointestinal acute GvHD Bone Marrow Transplant 2016 51 2 273 276 10.1038/bmt.2015.247 26479982 \n7. Van Groningen LF Liefferink AM de Haan AF Schaap NP Donnelly JP Blijlevens NM van der Velden WJ Combination therapy with inolimomab and etanercept for severe steroid-refractory acute graft-versus-host disease Biol Blood Marrow Transplant 2016 22 1 179 182 10.1016/j.bbmt.2015.08.039 26386320 \n8. Park JH Lee HJ Kim SR Song GW Lee SK Park SY Kim KC Hwang SH Park JS Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation Korean J Intern Med 2014 29 5 630 636 10.3904/kjim.2014.29.5.630 25228839 \n9. Meunier M Bulabois CE Thiebaut-Bertrand A Itzykson R Carre M Carras S Garban F Cahn JY Alemtuzumab for severe steroid-refractory gastrointestinal acute graft-versus-host disease Biol Blood Marrow Transplant 2014 20 9 1451 1454 10.1016/j.bbmt.2014.05.031 24910381 \n10. Abu-Dalle I Reljic T Nishihori T Antar A Bazarbachi A Djulbegovic B Kumar A Kharfan-Dabaja MA Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies Biol Blood Marrow Transplant 2014 20 11 1677 1686 10.1016/j.bbmt.2014.05.017 24867779 \n11. Alam N Atenafu EG Tse G Viswabandya A Gupta V Kim D Lipton JH Messner HA Kuruvilla J Limited benefit of pentostatin salvage therapy for steroid-refractory grade III-IV acute graft-versus host disease Clin Transplant 2013 27 6 930 937 10.1111/ctr.12268 24304375 \n12. Hoda D Pidala J Salgado-Vila N Kim J Perkins J Bookout R Sirolimus for treatment of steroid-refractory acute graft-versus-host disease Bone Marrow Transplant 2010 45 1347 1351 10.1038/bmt.2009.343 19966849 \n13. Ghez D Rubio MT Maillard N Suarez F Chandesris MO Delarue R Rapamycin for refractory acute graft-versus-host disease Transplantation 2009 88 1081 1087 10.1097/TP.0b013e3181ba0a13 19898203 \n14. Brattsand R Linden M Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies Aliment Pharmacol Ther 1996 10 2 81 90 8899106 \n15. Baer PC Wegner B Geiger H Effects of mycophenolic acid on IL-6 expression of human renal proximal and distal tubular cells in vitro Nephro Dyal Transpl 2004 19 47 52 10.1093/ndt/gfg429 \n16. Teshima T Reddy P Zeiser R Acute graft-versus-host disease Biol Blood Marrow Transpl 2016 22 11 16 10.1016/j.bbmt.2015.10.001 \n17. Harrison C Kiladjian JJ Al-Ali HK Gisslinger H Waltzman R Stalbovskaya V McQuitty M Hunter DS Levy R Knoops L Cervantes F Vannucchi AM Barbui T Barosi G JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis N Engl J Med 2012 366 779 787 10.1056/NEJMoa1110556 \n18. Verstovsek S Mesa RA Gotlib J Levy RS Gupta V Di Persio JF Catalano J Deininger M Miller C Silver RT Talpaz M Winton EF Harvey JH Jr Arasoy MO Hexner E Lyons RM Paquette R Raza A Vaddi K Erickson-Vitanen S Koumenis IL Sun W Sandor V Kantarjian HM A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis N Engl J Med 2012 366 9 799 807 10.1056/NEJMoa1110557 22375971 \n19. Hasselbach C Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res 2013 2 214 220 10.1016/j.leukres.2012.10.020 \n20. Teshima T JAK inhibitors: a home run for GVHD patients? Blood 2014 123 24 3691 3693 10.1182/blood-2014-04-570325 24926071 \n21. Zeiser R Negrin RS Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy Cell Cycle 2008 7 4 458 462 10.4161/cc.7.4.5454 18235249 \n22. Koreth J Matsuoka K Kim HT McDonough SM Bindra B Alyea EP 3rd Armand P Cutler C Ho VT Treister NS Bienfang DC Prasad S Tzachanis D Joyce RM Avigan DE Antin JH Ritz J Soiffer RJ Interleukin-2 and regulatory T cells in graft-versus-host disease N Engl J Med 2011 365 22 2055 2066 10.1056/NEJMoa1108188 22129252 \n23. Zeiser R Leveson-Gower DB Zambricki EA Kambham N Beilhack A Loh J Hou JZ Negrin RS Differential impact of mammalian target of rapamycin inhibition on CD4 + CD25 + FoxP3+ regulatory T cells compared with conventional CD4+ T cells Blood 2008 111 1 453 462 10.1182/blood-2007-06-094482 17967941 \n24. Spoerl S Mathew NR Bscheider M Schmitt-Graeff A Chen S Mueller T Verbeek M Fischer J Otten V Schmickl M Maas-Bauer K Finke J Peschel C Duyster J Poeck H Zeiser R von Bubnoff N Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease Blood 2014 123 24 3832 3842 10.1182/blood-2013-12-543736 24711661 \n25. Zeiser R Burchert A Lengerke C Verbeek M Maas-Bauer K Metzelder SK Spoerl S Ditschkowski M Ecsedi M Sockel K Ayuk F Ajib S de Fontbrune FS Na IK Penter L Holtick U Wolf D Schuler E Meyer E Apostolova P Bertz H Marks R Lübbert M Wäsch R Scheid C Stölzel F Ordemann R Bug G Kobbe G Negrin R Brune M Spyridonidis A Schmitt-Gräff A van der Velden W Huls G Mielke S Grigoleit GU Kuball J Flynn R Ihorst G Du J Blazar BR Arnold R Kröger N Passweg J Halter J Socié G Beelen D Peschel C Neubauer A Finke J Duyster J von Bubnoff N Ruxolitinib in corticosteroidrefractory graft-versus-host disease after allogeneic stem cell transplantation: a multi-center survey Leukemia 2015 29 10 2062 2068 26228813 \n26. Khoury HJ, Kota V, Arellano M et al. Ruxolitinib as sparing agent for steroid-dependent chronic graft-versus-host disease (cGVHD). Presented at: 2016 ASH Annual Meeting; December 5–8, 2015. Orlando, Florida; Abstract 1938.\n27. Vertovsek S Gotlib J Gupta V Atallah E Mascarehas J Quintas-Cardama A Sun W Sarlis NJ Sandor V Levy RS Kantarjian HM Mesa RA Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes Onco Targets Ther 2013 7 13 21 10.2147/OTT.S53348 24368888 \n28. Bruno B Gooley T Sullivan KM Davis C Bensinger WI Storb R Nash RA Secondary failure of platelet recovery after hematopoietic stem cell transplantation Biol Blood Marrow Transplant 2001 7 3 154 162 10.1053/bbmt.2001.v7.pm11302549 11302549\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-8722",
"issue": "9(1)",
"journal": "Journal of hematology & oncology",
"keywords": "Allogeneic hematopoietic stem cell transplant (HSCT); Case report; Proinflammatory cytokines; Regulatory T cells (Treg); Ruxolitinib; Steroid-refractory graft-vs.-host disease (SR-GvHD)",
"medline_ta": "J Hematol Oncol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000754:Anemia, Refractory, with Excess of Blasts; D004351:Drug Resistance; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D012074:Remission Induction; D016879:Salvage Therapy",
"nlm_unique_id": "101468937",
"other_id": null,
"pages": "67",
"pmc": null,
"pmid": "27502249",
"pubdate": "2016-08-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19898203;24304375;24867779;22375970;22510384;26103520;14671038;26228813;25228839;17967941;21736868;19898210;22129252;26453971;11302549;24368888;23174192;26479982;18235249;22375971;24910381;24711661;8899106;24926071;26386320;17234737;19966849",
"title": "Ruxolitinib in steroid refractory graft-vs.-host disease: a case report.",
"title_normalized": "ruxolitinib in steroid refractory graft vs host disease a case report"
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"abstract": "BACKGROUND\nMarfan syndrome is a rare cause of heart failure due to primary or secondary cardiomyopathy. Recently, sacubitril/valsartan-an angiotensin receptor blocker-neprilysin inhibitor-has been added in clinical practice as a standard therapy for heart failure. To our knowledge, there are no data on sacubitril/valsartan's effects on cardiovascular outcomes in patients with Marfan syndrome.\nA 24-year-old man was admitted to our Internal Medicine Department due to dyspnea, ascites, and leg swelling. Arterial blood gas analysis revealed severe hypoxemia with respiratory and metabolic alkalosis. Hilar congestion was highlighted on chest x-ray.\nRecurrent acute decompensated heart failure with reduced ejection fraction despite optimal medical therapy in Marfan-related cardiomyopathy.\n\n\nRESULTS\nSacubitril/valsartan was added to optimal medical therapy after hemodynamic stabilization allowing progressive clinical, laboratoristic, and echocardiographic improvement. Patient maintained a free survival from heart failure and a good quality of life until 9-month follow-up.\n\n\nCONCLUSIONS\nSacubitril/valsartan should be effective on pathophysiologic mechanisms and cardiovascular outcomes of Marfan syndrome-related cardiovascular complications.",
"affiliations": "Internal Medicine Department, University Campus Bio-Medico of Rome, Rome.;Internal Medicine Department, University G. D'Annunzio, Chieti.;Internal Medicine Department, University Campus Bio-Medico of Rome, Rome.;Internal Medicine Department, University Campus Bio-Medico of Rome, Rome.;Internal Medicine Department, University Campus Bio-Medico of Rome, Rome.;Cardiology Department.;Cardiology Department.;Internal Medicine Department, University Campus Bio-Medico of Rome, Rome.;Unit of Medical Statistic and Molecular Epidemiology.;Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, Rome, Italy.",
"authors": "Spoto|Silvia|S|;Valeriani|Emanuele|E|;Locorriere|Luciana|L|;Anguissola|Giuseppina Beretta|GB|;Pantano|Angelo Lauria|AL|;Terracciani|Francesca|F|;Bono|Maria Caterina|MC|;Costantino|Sebastiano|S|;Ciccozzi|Massimo|M|;Angeletti|Silvia|S|",
"chemical_list": "D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination",
"country": "United States",
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"doi": "10.1097/MD.0000000000017978",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31764806MD-D-19-0386510.1097/MD.0000000000017978179783400Research ArticleClinical Case ReportUse of sacubitril/valsartan in Marfan syndrome–related cardiomyopathy The first case reportSpoto Silvia MDa∗Valeriani Emanuele MDbLocorriere Luciana MDaAnguissola Giuseppina Beretta MDaPantano Angelo Lauria PhDaTerracciani Francesca MDcBono Maria Caterina MDcCostantino Sebastiano MDaCiccozzi Massimo PhDdAngeletti Silvia MDeNA. a Internal Medicine Department, University Campus Bio-Medico of Rome, Romeb Internal Medicine Department, University G. D’Annunzio, Chietic Cardiology Departmentd Unit of Medical Statistic and Molecular Epidemiologye Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, Rome, Italy.∗ Correspondence: Silvia Spoto, Internal Medicine Department, University Campus Bio-Medico of Rome, Italy (e-mail: s.spoto@unicampus.it).11 2019 22 11 2019 98 47 e1797815 5 2019 6 10 2019 17 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nMarfan syndrome is a rare cause of heart failure due to primary or secondary cardiomyopathy. Recently, sacubitril/valsartan—an angiotensin receptor blocker-neprilysin inhibitor—has been added in clinical practice as a standard therapy for heart failure. To our knowledge, there are no data on sacubitril/valsartan's effects on cardiovascular outcomes in patients with Marfan syndrome.\n\nPatient concerns:\nA 24-year-old man was admitted to our Internal Medicine Department due to dyspnea, ascites, and leg swelling. Arterial blood gas analysis revealed severe hypoxemia with respiratory and metabolic alkalosis. Hilar congestion was highlighted on chest x-ray.\n\nDiagnoses:\nRecurrent acute decompensated heart failure with reduced ejection fraction despite optimal medical therapy in Marfan-related cardiomyopathy.\n\nInterventions and outcomes:\nSacubitril/valsartan was added to optimal medical therapy after hemodynamic stabilization allowing progressive clinical, laboratoristic, and echocardiographic improvement. Patient maintained a free survival from heart failure and a good quality of life until 9-month follow-up.\n\nLessons:\nSacubitril/valsartan should be effective on pathophysiologic mechanisms and cardiovascular outcomes of Marfan syndrome–related cardiovascular complications.\n\nKeywords\nheart failureMarfan syndromemidregional-proadrenomedullinN-terminal pro-brain natriuretic peptidesacubitril-valsartanOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nHeart failure (HF) is infrequent in young people showing various etiologies within different world regions. Marfan syndrome (MFS) can be listed as a rare cause of HF.\n\nMFS is a connective-tissue autosomal dominant inherited disorder characterized by 400 individual mutations in the gene of fibrillin-1 with a prevalence of 1.5 to 17.2 per 100,000 person in the general population.[1,2] MFS diagnosis is made by the use of 2010 revised Ghent-2 nosology criteria based on the presence of family history along with other specific diagnostic criteria.[1,3] Single- and multi-organ involvement (ocular, skeletal, and cardiovascular system) and absence of a curative therapy are responsible for the chronic, severe, and life-threatening course of the disease.[1] Nevertheless, amelioration in medical and surgical management produced an increase in life expectancy from 32 to >50 years.[4]\n\nPatients with MFS present primary cardiomyopathy for heart muscle fibrillin-1 deficiency in 3.08% of cases (left ventricular dysfunction due to hypertrophy and dilatation, abnormal chordae tendineae with mitral valve prolapse and regurgitation, and increased prevalence of Wolff-Parkinson-White syndrome) and/or cardiac involvement secondary to ischemic complication of cardiovascular surgery in 8.07% of cases.[4] Furthermore, clinically relevant cardiovascular manifestations consisting in root and descending-aorta dissection and rupture due to progressive aortic dilatation represent the main cause of mortality.[3]\n\nRecently, the angiotensin receptor blocker-neprilysin inhibitor sacubitril/valsartan has been introduced in clinical practice as treatment for HF showing its superiority to ACE inhibition alone in reducing the risks of death and hospitalization.[5–9] Indeed, sacubitril/valsartan influences the 2 HF pathophysiological mechanisms. While valsartan inhibits renin-angiotensin-aldosterone system (RAAS) through angiotensin II type-1 (AT1) receptor blockage, sacubitril inhibits neprilysin and increase natriuretic peptides-atrial natriuretic peptide, brain natriuretic peptide (BNP), C-type natriuretic peptide, bradykinin, and adrenomedullin values.[10]\n\nWe report a case of a III–IV New York Heart Association (NYHA) class, stage C reduced ejection fraction HF in young patient with MFS occurred despite optimal medical therapy and successfully treated with sacubitril/valsartan once reached persistent hemodynamic stabilization.\n\n2 Case presentation\nA 24-year-old man with MFS-related cardiovascular complications was admitted to our Internal Medicine Department because of 3 consecutive episodes of acute decompensated HF with reduced ejection fraction (ADHFrEF) from 2014 through 2017. His remaining medical history includes arterial hypertension, dyslipidemia, hyperthyroidism, anaphylactic shock due to flecainide, and previous tabagic habit.\n\nMFS diagnosis was made in 2010 when ascending aorta and aortic valve substitution with mechanical prosthesis were performed due to type A acute aortic dissection in presence of family history—mother, father, and 3 sons with MFS. During intraoperative period, inferior acute coronary syndrome occurred and was treated with coronary artery bypass graft surgery.\n\nOn May 2014, mechanical descending aorta and aortic arch prosthesis implantation were performed due to chronic dissecting aneurysm. Peri-aortic hematoma and medullary ischemia complicated surgery and caused lower limb paraplegia, dolorific and thermal hypoesthesia, and rectal incontinence. After 2 months, during his first admission for ADHFrEF, laboratory tests were notable for N-terminal pro-BNP (NT-proBNP) of 12,000 pg/mL and transthoracic echocardiogram showed normal prosthesis function, dilatation of all cardiac chambers (mainly the left ones) with moderate mitral and tricuspid insufficiency, left ventricular hypertrophy, inferior wall akinesis, septal dyskinesis, and hypokinesis of the remaining walls with severe left ventricular ejection fraction (LVEF) reduction −20%. He was treated with intravenous diuretics and internal cardiac defibrillator (St. Jude Ellipse DR, DDD mode) without cardiac resynchronization therapy (electrocardiogram criteria not met) and discharged on maximal medical therapy (furosemide, carvedilol, ramipril, spironolactone, digoxin, and amlodipine).\n\nNew episode of ADHFrEF occurred on august 2017. Notable admission laboratoristic values included NT-proBNP of 2719 pg/mL and midregional-proadrenomedullin (MR-proADM) of 1.61 nmol/L, whereas transthoracic and transesophageal echocardiogram showed an LVEF of 35%, normal prosthesis function, severe tricuspid regurgitation, and rupture of the anterior leaflet of the chordae tendineae with severe mitral regurgitation. Patients were treated yet with intravenous diuretics and digoxin and discharged on optimal medical therapy (furosemide, carvedilol, ramipril, spironolactone, digoxin, and amlodipine).\n\nLastly, he was readmitted to our Internal Medicine Department on November 2017 due to third episode of ADHFrEF and infected mediastinal fluid collection secondary to 1 month before severe valvular insufficiency surgical correction with mitral mechanical prosthesis implantation (31-mm ST Jude) and De Vega tricuspid annuloplasty.\n\nPhysical examination was notable for blood pressure 120/80 mm Hg, pulse 82 bpm, respiratory rate 26 apm, O2 saturation 87% on room air with orthopneic obligatory position, and Marfanoid habitus (weight 147 kg, height 2.2 m). Cardiopulmonary evaluation revealed metallic second heart sound, stony dull percussion with reduced tactile vocal fremitus and crackles at the basis of the lungs, widely diminished vesicular breath sounds, presence of abundant ascites, and leg swelling.\n\nNotable laboratoristic values included NT-proBNP of 10,132 pg/mL and MR-proADM of 2.36 nmoL/mL.\n\nArterial blood gas analysis revealed severe hypoxemia with respiratory and metabolic alkalosis (pH 7.56, pO2 46 mm Hg, pCO2 24.8 mm Hg, HCO3− 21.9 mmol/L, alveolar-arterial gradient 31 mm Hg). Although electrocardiogram highlighted atrial fibrillation with ventricular rate of 80 bpm, left ventricular hypertrophy, and inferolateral subepicardial ischemia, transthoracic echocardiogram showed the same features as the previous except for LVEF of 30%, presence of mitral mechanical prosthesis, with paravalvular leak and mean gradient of 9 mm Hg, and mild tricuspid insufficiency (Fig. 1 A and C).\n\nFigure 1 Echocardiographic features before (A, C) and after (B, D) 9 months of sacubitril/valsartan administration. LVEDD = left ventricle end-diastolic diameter, LVESD = left ventricle end-systolic diameter.\n\nHilar congestion with cardiomegaly, right upper lobe pulmonary consolidation, and infected mediastinal fluid collection have been shown on chest x-ray and high-resolution computed tomography, respectively.\n\nPatient was treated with intravenous furosemide 250 mg q.d., canrenone 100 mg q.d., piperacillin/tazobactam 4.5 g q6h, and teicoplanin 12 mg/kg b.i.d., then 12 mg/kg q.d. On day 9, once reaching hemodynamic stabilization, sacubitril/valsartan midrange dose of 49/51 mg b.i.d. has been added to carvedilol 3.125 mg b.i.d., spironolactone 100 mg q.d., furosemide 250 mg q.d., and digoxin 0.25 mg q.d.\n\nOn 1-month follow-up sacubitril/valsartan has been increased to 97/103 mg b.i.d. for patient's good clinical condition, allowing persistent and progressive clinical, laboratory (NT-proBNP reduction and MR-proADM increase), echocardiographic-LVEF increase (42% vs 30%), left ventricle end-systolic diameter, left ventricle end-diastolic diameter, left ventricular mass, and left ventricular mass index reduction, and quality of life improvement without new episodes of ADHFrEF until 9-month follow-up (Fig. 1B and D; Table 1). Because of the lack of a specific dosage regimen for sacubitril/valsartan in MS-related cardiomyopathy, we used the recommended therapeutic scheme.[11]\n\nTable 1 Laboratory variables and echocardiographic features at admission, 3-, 6-, and 9-month follow-up.\n\n3 Discussion\nWe report the successful use of sacubitril/valsartan in a patient with MFS-related cardiomyopathy—NYHA III to IV class; stage C HFrEF with laboratoristic, echocardiographic, and quality of life improvement; and 9-month free survival from acute HF.\n\nBefore adding sacubitril/valsartan, patient presented recurrent ADHFrEF despite optimal medical therapy. To our knowledge, this is the first reported use of sacubitril/valsartan in a patient with HFrEF due to MFS.\n\nAcute HF determines BNP, ADM, bradykinin, and angiotensin II release through natriuretic peptide system and RAAS activation. These peptides are degraded by neprilysin reducing vasoconstriction, sodium retention, and maladaptive remodeling (Fig. 2).[10] Therefore, although BNP and ADM—and its more stable and easily detectable MR-proADM[12]—reflect the effect of sacubitril/valsartan on the heart, NT-proBNP is not a neprilysin substrate and reflects hemodynamic status.\n\nFigure 2 NT-proBNP (A), MR-proADM (B), and LVEF values (C) during the 3 ADHFrEF and 3-, 6-, and 9-month follow-up. ADHFrEF = acute decompensated heart failure with reduced ejection fraction, LVEF = left ventricular ejection fraction, MR-proADM = midregional-proadrenomedullin, NT-proBNP = N-terminal pro-B-type natriuretic peptide.\n\nSacubitril/valsartan effect are confirmed by improvement of echocardiographic features, LVEF increase of 5%, left ventricle end-systolic diameter, left ventricle end-diastolic diameter, left ventricular mass index reduction-free survival from HF (about 1–2 years), and quality of life.[13,14] Furthermore, sacubitril/valsartan showed a higher efficacy, reduced rate of death from cardiovascular complications and hospitalization for HF ,a similar safety profile, and similar rate of adverse event (e.g., worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema) compared with enalapril.[6,9]\n\nIn patients with MFS, FBN1 mutation leads to fibrillin-1 deficiency causing activation of transforming growth factor-β (TGF-β) signaling pathways with improvement of collagen synthesis and elastic fiber disruption in cardiac and vessel wall connective tissue.[15] This remodeling increases aortic stiffness and decreases vasoreactivity resulting in aortic dilatation, impaired diastolic ventricular relaxation, and hypertrophic remodeling.[15]\n\nIndirect inhibition of TGF-β, mediated by sacubitril-related neprilysin inhibition, could be hypothesized knowing that BNP opposes the expression of TGF-β-regulated genes,[16] and that neprilysin inhibition by sacubitril causes an increase in BNP values (Fig. 3).[17]\n\nFigure 3 Acute heart failure determines natriuretic peptide and renin-angiotensin-aldosterone system activation with opposite effects from each other. Although sacubitril blocks neprilysin increasing natriuretic peptide system pathways, NT-proBNP is not a neprilysin substrate, valsartan inhibits angiotensin II type-1 (AT1) receptor reducing renin-angiotensin-aldosterone system effects. Furthermore, sacubitril/valsartan could be effective on MFS-related cardiovascular complications through TGF-β expression and signaling pathways reduction. ADM = adrenomedullin, ANP = atrial natriuretic peptide, AT = angiotensin, BNP = brain natriuretic peptide, CNP = C-type natriuretic peptide, MFS = Marfan syndrome, NT-proBNP = N-terminal pro-B-type natriuretic peptide, TGF-β = transforming growth factor-β.\n\nFurthermore, effectiveness of angiotensin receptor blockers in cardiovascular complication of MFS was previously reported. AT1-receptor blockade showed capacity of reducing TGF-β signaling pathways along with other mechanisms responsible for reduction of cardiovascular disease progression (Fig. 3).[18]\n\nAfter sacubitril/valsartan administration, patient showed persistent and progressive clinical and laboratory data (NT-proBNP reduction and MR-proADM increase), echocardiographic LVEF increase (42% vs 30%), left ventricle end-systolic diameter, left ventricle end-diastolic diameter, left ventricular mass and left ventricular mass index reduction, and quality of life improvement without new episodes of ADHFrEF until 9-month follow-up (Fig. 1B and D; Table 1).\n\nTo our knowledge, this is the first reported case of sacubitril/valsartan administration in patients with MFS-related cardiomyopathy. This case report highlights the beneficial effect of sacubitril/valsartan on pathophysiologic mechanisms of MFS-related cardiovascular complications and its possible administration in III–IV NYHA class, stage C reduced ejection fraction HF, once the hemodynamic stabilization was reached.\n\nAcknowledgments\nAuthors thank Valeriani Stefano for English language revision.\n\nAuthor contributions\nConceptualization: Silvia Spoto, Sebastiano Costantino, Massimo Ciccozzi, Silvia Angeletti.\n\nData curation: Silvia Spoto, Emanuele Valeriani, Luciana Locorriere, Giuseppina Beretta Anguissola, Angelo Lauria Pantano, Maria Caterina Bono, Sebastiano Costantino, Massimo Ciccozzi, Silvia Angeletti.\n\nFormal analysis: Silvia Spoto, Luciana Locorriere, Giuseppina Beretta Anguissola, Angelo Lauria Pantano, Francesca Terracciani, Maria Caterina Bono, Sebastiano Costantino, Silvia Angeletti.\n\nInvestigation: Luciana Locorriere, Giuseppina Beretta Anguissola, Angelo Lauria Pantano, Francesca Terracciani, Sebastiano Costantino.\n\nMethodology: Silvia Spoto, Emanuele Valeriani, Sebastiano Costantino, Silvia Angeletti.\n\nSupervision: Sebastiano Costantino, Silvia Angeletti.\n\nWriting – original draft: Silvia Spoto, Massimo Ciccozzi.\n\nWriting – review and editing: Emanuele Valeriani, Sebastiano Costantino, Massimo Ciccozzi, Silvia Angeletti.\n\nAbbreviations: ADHFrEF = acute decompensated heart failure with reduced ejection fraction, AT1 = angiotensin II type-1, BNP = brain natriuretic peptide, HF = heart failure, LVEF = left ventricular ejection fraction, MFS = Marfan syndrome, MR-proADM = midregional-proadrenomedullin, NT-proBNP = N-terminal pro-brain natriuretic peptide, NYHA = New York Heart Association, RAAS = renin-angiotensin-aldosterone system, TGF-β = transforming growth factor-β.\n\nHow to cite this article: Spoto S, Valeriani E, Locorriere L, Anguissola GB, Pantano AL, Terracciani F, Bono MC, Costantino S, Ciccozzi M, Angeletti S. Use of sacubitril/valsartan in Marfan syndrome–related cardiomyopathy: the first case report. Medicine. 2019;98:47(e17978).\n\nConsent for publication: Written informed consent was obtained from the patient for the publication of this case report.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Von Kodolitsch Y De Backer J Schüler H \nPerspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome . Appl Clin Genet \n2015 ;8 :137 –55 .26124674 \n[2] Seo GH Kim YM Kang E \nThe phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums . Medicine (Baltimore) \n2018 ;97 :e10767 .29768367 \n[3] Loeys BL Dietz HC Braverman AC \nThe revised Ghent nosology for the Marfan syndrome . J Med Genet \n2010 ;47 :476 –85 .20591885 \n[4] Hetzer R Siegel G Delmo Walter EM \nCardiomyopathy in Marfan syndrome . Eur J Cardiothorac Surg \n2016 ;49 :561 –7 . discussion 567-568 .25755184 \n[5] Ponikowski P Voors AA Anker SD \n2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC . Eur Heart J \n2016 ;37 :2129 –200 .27206819 \n[6] McMurray JJ Packer M Desai AS \nAngiotensin-neprilysin inhibition versus enalapril in heart failure . N Engl J Med \n2014 ;371 :993 –1004 .25176015 \n[7] Norberg H Bergdahl E Lindmark K \nEligibility of sacubitril-valsartan in a real-world heart failure population: a community-based single-centre study . ESC Heart Fail \n2018 ;5 :337 –43 .29345425 \n[8] Martens P Beliën H Dupont M \nInsights into implementation of sacubitril/valsartan into clinical practice . ESC Heart Fail \n2018 ;5 :275 –83 .29464879 \n[9] Velazquez EJ Morrow DA DeVore AD \nAngiotensin-neprilysin inhibition in acute decompensated heart failure . N Engl J Med \n2019 ;380 :539 –48 .30415601 \n[10] Solomon SD Rizkala AR Gong J \nAngiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial . JACC Heart Fail \n2017 ;5 :471 –82 .28662936 \n[11] Ponikowski P Voors AA Anker SD \nAuthors/Task Force Members; Document Reviewers . 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC . Eur J Heart Fail \n2016 ;18 :891 –975 .27207191 \n[12] Morgenthaler NG Struck J Alonso C \nMeasurement of midregional proadrenomedullin in plasma with an immunoluminometric assay . Clin Chem \n2005 ;51 :1823 –9 .16099941 \n[13] Almufleh A Marbach J Chih S \nEjection fraction improvement and reverse remodeling achieved with sacubitril/valsartan in heart failure with reduced ejection fraction patients . Am J Cardiovasc Dis \n2017 ;7 :108 –13 .29348971 \n[14] Claggett B Packer M McMurray JJ \nEstimating the long-term treatment benefits of sacubitril-valsartan . N Engl J Med \n2015 ;373 :2289 –90 .26630151 \n[15] Gehle P Robinson PN Heinzel F \nNT-proBNP and diastolic left ventricular function in patients with Marfan syndrome . Int J Cardiol Heart Vasc \n2016 ;12 :15 –20 .28616536 \n[16] Kapoun AM Liang F O’Young G \nB-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation . Circ Res \n2004 ;94 :453 –61 .14726474 \n[17] Packer M McMurray JJ Desai AS \nAngiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure . Circulation \n2015 ;131 :54 –61 .25403646 \n[18] Brooke BS Habashi JP Judge DP \nAngiotensin II blockade and aortic-root dilation in Marfan's syndrome . N Engl J Med \n2008 ;358 :2787 –95 .18579813\n\n",
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"mesh_terms": "D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D006333:Heart Failure; D006801:Humans; D008297:Male; D008382:Marfan Syndrome; D013777:Tetrazoles; D016896:Treatment Outcome; D000068756:Valsartan; D055815:Young Adult",
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"title": "Use of sacubitril/valsartan in Marfan syndrome-related cardiomyopathy: The first case report.",
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"abstract": "Previous studies provided inconclusive evidence for the effectiveness of gonadotropin-releasing hormone analogue on ovarian function protection against chemotherapy-induced genotoxicity in premenopausal patients. This study was designed to examine the efficacy of leuprolide acetate on ovarian function preservation in patients with breast cancer. A total of 220 patients were recruited in this prospective clinical trial and were assigned randomly to receive cyclophosphamide-doxorubicin-based chemotherapy only or chemotherapy plus leuprolide acetate. Resumption of menses or premenopausal levels of both follicle-stimulating hormone (FSH) and estradiol (E2) within 12 months after the end of chemotherapy were considered as effective ovarian preservation. A total of 183 patients were considered evaluable (94 in chemotherapy-only group and 89 in chemotherapy plus leuprolide acetate group). At the end of follow-up, 27 patients in chemotherapy group and 15 in chemotherapy plus leuprolide acetate group resumed menses; seven patients in chemotherapy group and 14 in chemotherapy plus leuprolide acetate group restored premenopausal levels of FSH and E2. The median time to resume menses was 9.2 months for patients in chemotherapy plus leuprolide acetate group and was not reached in chemotherapy-only group. In addition, our results demonstrated that age and chemotherapy doses made no significant difference in the occurrence of premature menopause. The leuprolide acetate treatment simultaneously with cyclophosphamide-doxorubicin-based chemotherapy reduced the risk of developing premature menopause in premenopausal patients with breast cancer.",
"affiliations": "Department of Pharmacy, Jiangyin Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Jiangyin, Jiangsu, China. drsongguiping@gmail.com",
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"title": "Effect of leuprolide acetate on ovarian function after cyclophosphamide-doxorubicin-based chemotherapy in premenopausal patients with breast cancer: results from a phase II randomized trial.",
"title_normalized": "effect of leuprolide acetate on ovarian function after cyclophosphamide doxorubicin based chemotherapy in premenopausal patients with breast cancer results from a phase ii randomized trial"
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"abstract": "Most laboratories routinely determine haemolysis, icterus and lipemia indices to identify lipemic samples and reject potentially affected results. Hypertriglyceridemia is the most common cause of lipemia and severe hypertriglyceridemia (≥ 11.3 mmol/L) is a major risk factor of acute pancreatitis.\nA 56-year-old woman attended the outpatient clinic for a follow-up visit 1 month after a kidney transplantation. Her immunosuppressive therapy consisted of corticosteroids, cyclosporine, and mycophenolic acid. The routine clinical chemistry sample was rejected due to extreme lipemia. The comment \"extreme lipemic sample\" was added on the report, but the requesting physician could not be reached. The Cobas 8000 gave a technical error (absorption > 3.3) for the HIL-indices (L-index: 38.6 mmol/L) which persisted after high-speed centrifugation. The patient was given a new appointment 2 days later. The new sample was also grossly lipemic and gave the same technical error (L-index: 35.9 mmol/L).\nThe second sample was manually diluted 20-fold after centrifugation to obtain a result for triglycerides within the measuring range (0.10-50.0 mmol/L). Triglycerides were 169.1 mmol/L, corresponding to very severe hypertriglyceridemia. This result was communicated to the nephrologist and the patient immediately recalled to the hospital. She received therapeutic plasma exchange the next day and did not develop acute pancreatitis.\nThis case illustrates the delicate balance between avoiding the release of unreliable results due to lipemia and the risk of delayed diagnosis when results are rejected. Providing an estimate of the degree of hypertriglyceridemia might be preferable to rejecting the result.",
"affiliations": "Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.;Clinical department of Nephrology, University Hospitals Leuven, Leuven, Belgium.;Clinical department of Nephrology, University Hospitals Leuven, Leuven, Belgium.;Department of Laboratory Medicine, AZ Sint-Jan Brugge, Belgium.;Clinical department of Nephrology, University Hospitals Leuven, Leuven, Belgium.;Clinical Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium.;Department of Laboratory Medicine, AZ Sint-Jan Brugge, Belgium.;Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.;Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.",
"authors": "Van Elslande|Jan|J|;Hijjit|Samira|S|;De Vusser|Katrien|K|;Langlois|Michel|M|;Meijers|Björn|B|;Mertens|Ann|A|;Van der Schueren|Bart|B|;Frans|Glynis|G|;Vermeersch|Pieter|P|",
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"fulltext": "\n==== Front\nBiochem Med (Zagreb)\nBiochem Med (Zagreb)\nBM\nBiochemia Medica\n1330-0962\n1846-7482\nCroatian Society of Medical Biochemistry and Laboratory Medicine\n\nbm-31-2-021002\n10.11613/BM.2021.021002\nPreanalytical Mysteries\nDelayed diagnosis and treatment of extreme hypertriglyceridemia due to rejection of a lipemic sample\nVan Elslande Jan 1\nHijjit Samira 2\nDe Vusser Katrien 2\nLanglois Michel 3\nMeijers Björn 2\nMertens Ann 4\nVan der Schueren Bart 35\nFrans Glynis 1\nVermeersch Pieter *16\n1 Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium\n2 Clinical department of Nephrology, University Hospitals Leuven, Leuven, Belgium\n3 Department of Laboratory Medicine, AZ Sint-Jan Brugge, Belgium\n4 Clinical Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium\n5 Nutrition & Obesity Unit, Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Aging, KU Leuven, Leuven, Belgium.\n6 Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium\n* Corresponding author: pieter.vermeersch@uzleuven.be\n15 4 2021\n15 6 2021\n31 2 02100211 11 2020\n04 2 2021\nCroatian Society of Medical Biochemistry and Laboratory Medicine.\n2021\nCroatian Society of Medical Biochemistry\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction\n\nMost laboratories routinely determine haemolysis, icterus and lipemia indices to identify lipemic samples and reject potentially affected results. Hypertriglyceridemia is the most common cause of lipemia and severe hypertriglyceridemia (≥ 11.3 mmol/L) is a major risk factor of acute pancreatitis.\n\nLaboratory analysis\n\nA 56-year-old woman attended the outpatient clinic for a follow-up visit 1 month after a kidney transplantation. Her immunosuppressive therapy consisted of corticosteroids, cyclosporine, and mycophenolic acid. The routine clinical chemistry sample was rejected due to extreme lipemia. The comment “extreme lipemic sample” was added on the report, but the requesting physician could not be reached. The Cobas 8000 gave a technical error (absorption > 3.3) for the HIL-indices (L-index: 38.6 mmol/L) which persisted after high-speed centrifugation. The patient was given a new appointment 2 days later. The new sample was also grossly lipemic and gave the same technical error (L-index: 35.9 mmol/L).\n\nWhat happened\n\nThe second sample was manually diluted 20-fold after centrifugation to obtain a result for triglycerides within the measuring range (0.10–50.0 mmol/L). Triglycerides were 169.1 mmol/L, corresponding to very severe hypertriglyceridemia. This result was communicated to the nephrologist and the patient immediately recalled to the hospital. She received therapeutic plasma exchange the next day and did not develop acute pancreatitis.\n\nMain lesson\n\nThis case illustrates the delicate balance between avoiding the release of unreliable results due to lipemia and the risk of delayed diagnosis when results are rejected. Providing an estimate of the degree of hypertriglyceridemia might be preferable to rejecting the result.\n\nKeywords:\n\nextra-analytical phase\nhypertriglyceridemia\ninterferences\nlipemia\nlipoprotein metabolism\n==== Body\nIntroduction\n\nA lipemic blood sample is characterized by increased turbidity, typically caused by hypertriglyceridemia (HTG). The accumulation of the large lipoprotein particles, which are chylomicrons and large very-low density lipoproteins (VLDL), causes absorbance and scattering of light, potentially interfering in spectrophotometric methods and resulting in a “cloudy” sample appearance. Other affected tests include indirect potentiometry (through electrolyte exclusion effect), electrophoresis, and the measurement of hydrophobic analytes such as fat-soluble vitamins and certain drugs (1). The overall frequency of lipemic samples ranges from 0.5-2.5%, with outpatient samples typically showing higher frequencies of lipemic samples than samples from hospitalized patients (2).\n\nHypertriglyceridemia is defined as a fasting triglyceride (TG) concentration of > 1.7 mmol/L, with concentrations of 11.3-22.6 mmol/L and ≥ 22.6 mmol/L classified as severe and very severe HTG, respectively (3). Hypertriglyceridemia is a common finding in Western society, with one quarter to one third of the adult population having serum TG concentrations > 1.7 mmol/L (3). Very severe hypertriglyceridemia, in contrast, is rare with an estimated prevalence of around 0.1% (4). A preanalytical cause of severe and very severe HTG is sampling too soon after the intravenous administration of lipid emulsions (1). Sampling in a non-fasting state can also increase TG concentrations, but this increase is usually not clinically significant (0.3 mmol/L on average) (5). Causes of HTG include diabetes (especially uncontrolled), increased alcohol consumption, metabolic syndrome, certain drugs, nephrotic syndrome, and genetic defects in the triglyceride metabolism (e.g., familial chylomicronemia) (3). Triglycerides concentrations > 11.3 mmol/L pose a risk for hypertriglyceridemia-induced acute pancreatitis. Hypertriglyceridemia is the third most common cause of acute pancreatitis, after alcohol and bile stones. The risk further increases when TG concentrations are higher, and values ≥ 22.6 mmol/L warrant immediate treatment to reduce TG (3). Very severe HTG is usually caused by a combination of pre-existing primary hyperlipidemia and one or more precipitating factors such as alcohol, the administration of certain drugs (e.g., corticosteroids, immunosuppressants, estrogens), or uncontrolled diabetes (6).\n\nMonitoring and management of lipemia in blood samples are handled heterogeneously in laboratories throughout Europe. Most laboratories monitor haemolysis, icterus, and lipemia (HIL) using automated spectrophotometric assays called HIL indices, although visual inspection is also still used (7). While the haemolysis index (H-index) closely correlates with haemoglobin content and can be used to determine cell-free haemoglobin (8), the lipemia index (L-index) is a measure of turbidity and only weakly correlates with TG concentration (9). A recent survey of the European Federation of Laboratory Medicine (EFLM) found that most laboratories reject potentially affected tests when an assay-specific “lipemia-threshold” is exceeded (71.3%), although some laboratories either reject the entire sample (3.8%), release all test results with a specific comment (21.6%) or release all test results without any specific comment (3.3%) (7). Since the decision whether or not to release results potentially affected by HIL interference can have a direct impact on patient care, a pragmatic approach is needed. Laboratory medicine professionals should not only focus on the analytical quality of laboratory test results, but also on the clinical consequences of (not reporting) laboratory results (10). We present a case report where the clinical diagnosis and treatment were delayed by rejecting of results potentially affected by lipemic interference in a patient with extreme HTG.\n\nCase description\n\nA 56-year-old woman with a history of Henoch-Schönlein vasculitis and IgA nephropathy developed kidney failure with positive anti-glomerular basal membrane antibodies (Goodpasture syndrome) 3 years ago. Her renal function deteriorated and she required chronic haemodialysis 2 years later. Her medication consisted of methylprednisolone (8 mg/day), gliquidon, estradiol-dydrogesteron (Femoston), bisoprolol, and several painkillers. After a year of dialysis, she received kidney transplantation, which was accompanied by the administration of a single high dose of corticosteroids (540 mg methylprednisolone). Her daily dose of methylprednisolone was temporarily increased to 16 mg per day and treatment with mycophenolic acid, tacrolimus, and trimethoprim/sulfamethoxazole were started.\n\nThe patient attended the outpatient clinic for a routine follow-up visit one month after transplantation. She reported symptoms of fatigue and diarrhoea. Venous blood was drawn and sent to the laboratory for routine chemistry, haematology, and coagulation testing. The routine chemistry sample was grossly lipemic and generated a technical error for the HIL-indices (Table 1). Since the error persisted after high-speed centrifugation, the whole sample was rejected with a comment “extremely lipemic sample”. TG measurement was initially not requested on the sample. As prescribed by the laboratory protocol, the laboratory technician tried to reach the treating physician by phone, but the attempt was unsuccessful.\n\nTable 1 Selected laboratory results\n\nAnalyte (unit)\tDay 1\n(1st visit)\tDay 3\n(2nd visit)\tDay 3\n(Admission)\tDay 4\tDay 4 (pre-plasma-\npheresis)\tDay 4\n(post-plasma-\npheresis)\tDay 9\n(Discharge)\tReference interval\t\nTriglycerides (mmol/L)\t175.9*\t168.1*\t181.2*\t154.18*\t123.0*\t25.0\t19.5\t< 1.7\t\nLipase (U/L)\t70*\tn.d.\t70*\t87*\tn.d.\t147\t56\t13-60\t\nL-index (mmol/L)\nAfter additional centrifugation\t38.6 (abs)\n33.1 (abs)\t35.9 (abs)\n32.5 (abs)\tClot error\t27.8 (abs)\n28.9 (abs)\t23.1\t4.0\t0.6\t< 0.1\t\nSodium (mmol/L)\t(113.6)†\t(110.5)†\tClot error\t(116.2)†\t(118.9)†\t134.5\tn.d.\t135-145\t\nSodium BGA (mmol/L)\tn.d.\tn.d.\tn.d.\t140\tn.d.\tn.d.\tn.d.\t135-145\t\nCreatinine (µmol/L)\t(134.4)†\t(130.8)†\tClot error\t120.2‡\t108.7‡\t84.0\t92.8\t45.1-84.0\t\nTotal cholesterol (mmol/L)\tn.d.\tn.d.\tn.d.\t38.6\t35.2\tn.d.\tn.d.\t≤ 4.9\t\nDirect LDL cholesterol (mmol/L)\tn.d.\tn.d.\tn.d.\t8.7\t7.4\tn.d.\tn.d.\t≤ 3.0\t\nLipoprotein fractions\t\nAlpha (HDL)\tn.d.\tn.d.\tn.d.\tn.d.\t12.5%\t4.9%\tn.d.\t22-53%\t\nPre-Beta (VLDL)\tn.d.\tn.d.\tn.d.\tn.d.\t56.1%\t73.3%\tn.d.\t4-23%\t\nBeta (LDL)\tn.d.\tn.d.\tn.d.\tn.d.\t8.2%\t6.5%\tn.d.\t38-69%\t\nChylomicrons\tn.d.\tn.d.\tn.d.\tn.d.\t23.2%\t15.3%\tn.d.\t0-2%\t\nAll results were determined using Roche Cobas c702 (Roche Diagnostics, Basel, Switzerland) except sodium BGA which was determined using ABL 90 FLEX blood gas analyser (Radiometer, Copenhagen, Denmark).\n*Value obtained after manual 20-fold dilution using 0.9% saline, †value not reported to clinicians, ‡accompanied by comment of possible interference by lipemia. BGA – blood gas analysis. L-index – lipemia index. abs - Absorbance > 3.3. n.d. – not determined. HDL – high density lipoprotein. LDL – low density lipoprotein. VLDL – very low density lipoprotein.\t\n\nThe patient was given a new appointment 2 days later to perform a second blood draw. The new sample generated the same technical errors, and the clinical pathologist was notified by the laboratory technician. A 1:20 sample dilution using 0.9% saline of the original and the new sample was prepared. TG concentration in both samples was > 150 mmol/L (175.9 mmol/L and 168.1 mmol/L respectively). To rule out a possible life-threatening acute pancreatitis, lipase activity was also determined on the 1:20 dilution. Lipase activity was only slightly elevated in both samples (Table 1). The results for TG and lipase were reported, while the other tests were rejected due to lipemic interference. The clinician was notified and the patient was called immediately to the emergency department.\n\nAt admission, the patient reported frontal headache in addition to previously mentioned symptoms. She did not have any abdominal pain suggestive of acute pancreatitis and no evidence for acute pancreatitis on imaging. Insulin, glucose, and HCO3- infusions were started in the emergency room. Given the extreme HTG, plasmapheresis was performed the next day with therapeutic plasma exchange (albumin 5%) using a Prismaflex system (Baxter, Illinois, USA) with a PF2000N filter. The volume for the exchange was calculated with the Kaplan formula and estimated to be 45 mL/kg (11). The plasmapheresis resulted in a drop of TG concentration by 80% from 123.0 mmol/L to 25.0 mmol/L. The patient did not develop acute pancreatitis, although lipase activity rose to a peak of 147 U/L (reference interval: 13-60 U/L) on the day of the plasmapheresis. Since medication was considered the most likely trigger for the extreme HTG, estradiol-dydrogesteron was stopped, trimethoprim/sulfamethoxazole was changed to dapsone, and fluvastatin was started. The dose of methylprednisolone was reduced from 8 mg to 4 mg per day. The patient was discharged after 6 days of hospitalization without any remaining symptoms.\n\nLaboratory analyses and other diagnostic evaluations\n\nRoutine chemistry parameters were determined with a Cobas 8000 c702 analyser (Roche Diagnostics, Basel, Switzerland), complete blood count with Sysmex XE 5000 (Sysmex, Kobe, Japan), and coagulation tests with ACL-TOP 700 (Werfen, Milan, Italy). Point-of-care testing (POCT) of glucose was performed using Accu-Chek (Roche Diagnostics Basel, Switzerland) and blood gas analysis (BGA) with ABL90 FLEX (Radiometer, Copenhagen, Denmark). HIL indices are determined in all routine biochemistry samples on the Cobas c702, using the standard Serum Index Gen. 2 application (10 minutes). After dilution with 0.9% saline, the absorbances at 660 nm (primary wavelength) and 700 nm (secondary wavelength) are used to provide a semi-quantitative estimate of lipemia/turbidity in the sample.\n\nRoutine biochemistry samples were collected using BD Vacutainer 4mL lithium heparin plasma tubes with gel separator (PSTII), haematology parameters using BD Vacutainer 4mL K2-ethylenediaminetetraacetic acid (EDTA) tubes, and coagulation tests using BD Vacutainer 2.7 mL 0.109 M (3.2%) trisodium citrate tubes (Becton Dickinson, Temse, Belgium). For blood gas collection, electrolyte-balanced heparin (80 IU) coated safePICO aspirators were used (Radiometer, Copenhagen, Denmark). The Roche Cobas 8000 chemistry analyser generated technical error codes Absorbance (abs) > 3.3, Clot, Kin (kinetic), and Proz (prozone) for a majority of requested tests for the first and the second sample for routine biochemistry, including an abs > 3.3 error for the L-index itself. High-speed centrifugation (21,130xg for 10 minutes) was performed, but there was no clear infranatant. The laboratory technician, therefore, rejected all test requests with a comment stating that the sample was “extremely lipemic”. Glucose concentration was 12.5 mmol/L as measured by a POCT device, confirming inadequate glycaemic control. To exclude ionic disturbances, BGA was performed, which showed a slightly elevated potassium concentration (4.6 mmol/L, reference interval 3.5–4.5). Routine haematology showed leukocytosis of 13.6 x109/L (reference interval 4.0-10.0) with neutrophilia, normal platelet count, and increased haemoglobin of 168 g/L (reference interval 120-160 g/L), most likely due to lipemic interference (12). The routine haematology results were reported with the addition of a comment (“Potential interference due to extremely lipemic sample”). A urine sample showed mild proteinuria (18 mg/mmol creatinine, reference ≤ 15 mg/mmol), leukocyturia, and haematuria.\n\nTGs were measured using the Roche Triglyceride assay without glycerol blanking. The normal measuring range of the assay is 0.10–10.0 mmol/L with a built-in decrease run using a 1:5 dilution, which increases the measuring range to 50.0 mmol/L. The product insert states that extremely lipemic samples (TG > 33.9 mmol/L)) can produce falsely decreased results, a finding that has been reported in the literature (13, 14). Lipase activity could be measured in the 1:20 dilution due to the measuring range of this assay (3-300 U/L).\n\nLipoprotein electrophoresis of the blood samples pre-and post-plasmapheresis, as well as the dialysate, was performed by semi-automated agarose gel electrophoresis followed by Sudan Black staining of migrated lipoprotein fractions with the Hydrasys II instrument (Sebia, Vilvoorde, Belgium) using the HYDRAGEL “Lipo + Lp(a)” kit.\n\nConsidered diagnoses and further investigations\n\nFirst, we ruled out a preanalytical cause, although this was considered less likely since the lipemia was present in two samples collected 48 hours apart. The patient did not receive intravenous lipid emulsions and postprandial lipemia was ruled out since this alone could not explain the very severe HTG in this patient (5). The patient reported not to have consumed alcohol.\n\nVery severe HTG is usually caused by a combination of pre-existing primary hyperlipidemia and one or more precipitating factors. Given the patient’s history, uncontrolled diabetes, nephrotic syndrome, and medication were considered as possible precipitating factors. The patient had an elevated blood glucose concentration suggestive of inadequate glycaemic control, but there was no evidence for diabetic keto-acidosis or hyperosmolar hyperglycaemic state. The urine dipstick was negative for ketones and glucose, and BGA (before treatment) revealed a normal pH and bicarbonate. Nephrotic syndrome was excluded since urine total protein was only slightly elevated and plasma albumin concentration was normal. She was taking numerous medications that have been associated with HTG (methylprednisolone, estradiol-dydrogesteron, mycophenolic acid, tacrolimus, trimethoprim/sulfamethoxazole).\n\nA review of the patient’s recent routine laboratory test results revealed she had HTG the day before and the day after her transplantation one month earlier (25.2 mmol/L and 8.8 mmol/L respectively). The patient’s sister was also known with HTG, and her father and two brothers had a history of acute myocardial infarctions between 40 and 50 years of age (with two deaths), suggesting the presence of an underlying genetic predisposition for dyslipidemia. Total and low-density lipoprotein (LDL) cholesterol (measured by a direct LDL assay) were elevated (Table 1) and lipoprotein electrophoresis of the second sample revealed that the predominant lipoprotein particles consisted of a mix of VLDL and chylomicrons, compatible with familial type 5 hyperlipidemia (also called mixed hyperlipidemia). The molar ratio of triglycerides to cholesterol of 3.5:1 on day 4 (pre-plasmapheresis), which is significantly higher than the ratio of 2.2 for TG: VLDL-cholesterol used in the Friedewald formula, also indicates the presence of lipoproteins which are more TG-rich than normal VLDL. Taken together, the acute very severe HTG was most likely caused by a combination of inadequate glycaemic control and drug-induced HTG in a patient with a pre-existing familial hyperlipidemia.\n\nWhat happened?\n\nThe extreme lipemia due to very severe HTG generated technical alarm codes for a majority of the requested biochemical tests including the HIL-indices (abs > 3.3), which persisted after high-speed centrifugation. An abs > 3.3 error indicates that the amount of light passing through the reaction cuvette was too low for a reliable photometric measurement because the increased turbidity blocked (almost all) light transmission. The fact that the predominant lipoprotein particles were mostly VLDL rather than chylomicrons (Table 1) explains why the laboratory technician was unable to completely separate the lipoprotein particles from the aqueous phase by high-speed centrifugation (Figure 1). Since the quality of the results could not be guaranteed, the sample for routine biochemistry was rejected with the comment “extreme lipemic sample” as occasionally happens for patients receiving intravenous lipid emulsions. The requesting physician could not be reached by phone as the outpatient clinic was already closed.\n\nFigure 1 Appearance of blood samples of the patient before plasmapheresis (left) and after plasmapheresis (right). A creamy top layer is visible (arrowhead) in the sample obtained after plasmapheresis.\n\nDespite the comment on the laboratory test report, the clinician was not immediately alarmed the next morning because in renal transplant patients HTG is common and tacrolimus has been described as an etiological factor (15). The patient was given a new appointment for the next day. This led to a delay in treatment of the very severe HTG which could have resulted in acute pancreatitis, a potentially fatal complication. The patient went back home after the second sample was collected and was only recalled and admitted to the emergency department after the clinical pathologist had notified the treating physician about the results of the 1:20 diluted samples for TGs and lipase. In hindsight, the clinician who knew the patient did not receive any intravenous lipid emulsions would most likely have been alerted if he would have had an idea of the magnitude of the HTG. Reporting TG measurements in extremely lipemic samples (TG > 33.9 mmol/L) is, however, not without risk since results can be falsely decreased and grossly underestimated (13, 14).\n\nDiscussion\n\nWe present a case report of a patient with extreme HTG after renal transplantation. Tacrolimus is known to cause HTG, although post-transplant hyperlipidemia is typically more pronounced with cyclosporine and sirolimus (16). Acute pancreatitis is a feared complication of very severe HTG as it is typically associated with more complications than pancreatitis caused by other aetiologies (17). The risk to develop acute pancreatitis rises with increasing TG concentrations, although the severity of pancreatitis does not appear to correlate with TG concentration (18). Despite the extreme HTG, our patient did not develop acute pancreatitis, a finding that has also been demonstrated by other case reports (19, 20). The fast initiation of therapeutic plasma exchange may have contributed to preventing acute pancreatitis since a fast reduction of TG concentration is most effective when initiated shortly after presentation (21). Apheresis has been described to efficiently reduce TG concentrations by an average of 69% after the first session, in line with the 80% reduction we observed (Table 1) (22).\n\nIn our laboratory, 0.22% of routine chemistry samples analysed in the past 2 years (2nd October 2018 to 30th September 2020, N = 767,379) had an L-index of > 1.7 mmol/L as measured by the Roche Cobas c702. Most laboratories monitor HIL in blood samples by applying serum indices on automated routine chemistry analysers. The cut-off above which lipemia significantly affects laboratory results, as well as the direction and magnitude of this interference, depends on the analyte, the method used, and also the manufacturer of a specific method (1). Manufacturers are urged to provide a cut-off but it is not always clear how this cut-off was established (23). Most laboratories rely on the manufacturer method recommendations for acceptable limits and do not verify the manufacturer specified methods (24). It is known that these cut-offs are almost always established by using samples spiked with an emulsion (e.g., Intralipid), but these do not necessarily behave in the same way as native lipemic samples (25). For example, it has been shown that for intralipid spiked samples, high-speed centrifugation is (almost) equivalent to ultracentrifugation in removing lipids from serum samples (26). High-speed centrifugation can separate chylomicrons, however, for patient samples containing mostly VLDL particles, it is not as effective as was illustrated in this case (1). The gold standard to analytically manage lipemic samples would be to perform ultracentrifugation, but this technique cannot realistically be implemented in a routine clinical laboratory offering a 24/7 service. Removal of lipids by polar solvents (e.g., Lipoclear) has also been suggested, although studies have shown this technique produces inaccurate values for several assays (1). Finally, prolonged high-speed centrifugation (e.g., 3 hours at 13,000xg) can also be considered in cases like this one (27).\n\nThere are different post-analytical strategies across laboratories to deal with potentially biased results by HIL interference. This ranges from rejecting the entire sample with a comment, to releasing all results without indicating possible interference because of lipemia (7). We received feedback from the clinicians that a rejected result with a comment stating “extreme lipemia” is not perceived as alarming compared to reporting an estimated value of the actual triglyceridemia. To measure TGs in all severely lipemic samples while avoiding reporting grossly underestimated results, we implemented a new algorithm in our laboratory. If the L-index exceeds 5.1 mmol/L, the sample must be manually diluted 1:20 by the laboratory technician. In the past 2 years, this algorithm would have resulted in the manual dilution of 34 of the 88,976 samples (0.04%) with a request for TGs and an L-index exceeding 5.1 mmol/L (Figure 2). One of these 34 samples, from a patient with very severe HTG, had a grossly underestimated TG result. The Cobas c702 gave a result of 4.6 mmol/L without any technical errors for the TG assay or the HIL-indices despite an L-index of 13.4 mmol/L. A 1:20 manual dilution, however, gave a TG result of 58.3 mmol/L, illustrating that extremely lipemic samples can indeed produce falsely decreased results (13, 14). We now also automatically trigger triglycerides as an add-on test if the L-index exceeds 5.1 mmol/L. This would have resulted in 129 add-on tests of 767,378 samples (0.017%) over the same two-year period. Of note, the European In Vitro Diagnostic (IVD) Regulation 2017/746 will require that modifications to commercial IVD methods should be validated by the laboratory and registered as a lab-developed test (28). It remains unclear whether this will also apply to manual dilution of samples for results above the upper limit of the measuring range (e.g., creatine kinase in rhabdomyolysis, ferritin in hemophagocytic lymphohistiocytosis). This case illustrates the delicate balance between avoiding the release of results biased by HIL interference and the risk that rejecting samples because of HIL interference can delay the diagnosis.\n\nFigure 2 Relationship between L-index and triglyceride concentration (mmol/L) in routine samples in 2018-2020 (N = 88,946). The vertical line corresponds to a L-index of 5.1, while the horizontal line corresponds to the upper limit of the measuring range of the Roche triglyceride assay (50.0 mmol/L) on Cobas c702 analyser (Roche Diagnostics, Basel, Switzerland). Severely haemolytic samples above the Roche-designated threshold for interference were excluded (H-index > 700). The graph includes reported results from Cobas c702 (O), initial results from Cobas c702 (X), later corrected after manual dilution (·). L-index – lipemia index. H-index – haemolysis index.\n\nWhat you can do in your laboratory to prevent such errors\n\nIn case of a technical alarm code due to extreme lipemia, measuring TG concentration after manual dilution is preferable to rejecting the sample with a comment “extreme lipemic sample”\n\nManual dilution of severely lipemic samples (L-index > 5.1 mmol/L)) can help prevent the release of falsely decreased TG results.\n\nPotential conflict of interest\n\nNone declared. PV is a senior clinical investigator of the FWO-Vlaanderen.\n==== Refs\nReferences\n\n1 Nikolac N . Lipemia: Causes, interference mechanisms, detection and management. Biochem Med (Zagreb). 2014;24 :57–67. 10.11613/BM.2014.008 24627715\n2 Simundic AM Nikolac N Vukasovic I Vrkic N . The prevalence of preanalytical errors in a Croatian ISO 15189 accredited laboratory. Clin Chem Lab Med. 2010;48 :1009–14. 10.1515/CCLM.2010.221 20441481\n3 Berglund L Brunzell JD Goldberg AC Goldberg IJ Sacks F Murad MH Evaluation and treatment of hypertriglyceridemia: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012;97 :2969–89. 10.1210/jc.2011-3213 22962670\n4 Esparza MI Li X Adams-Huet B Vasandani C Vora A Das SR Very Severe Hypertriglyceridemia in a Large US County Health Care System: Associated Conditions and Management. J Endocr Soc. 2019;3 :1595–607. 10.1210/js.2019-00129 31384720\n5 Nordestgaard BG Langsted A Mora S Kolovou G Baum H Bruckert E Fasting is not routinely required for determination of a lipid profile: Clinical and laboratory implications including flagging at desirable concentration cut-points - a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J. 2016;37 :1944–58. 10.1093/eurheartj/ehw152 27122601\n6 Inayat F Zafar F Baig AS Chaudhry NA Aslam A Khan ZH Hypertriglyceridemic Pancreatitis Treated with Insulin Therapy: A Comparative Review of 34 Cases. Cureus. 2018;10 :e3501. 10.7759/cureus.3501 30648042\n7 Cadamuro J Cornes M Simundic AM de la Salle B Kristensen GBB Guimaraes JT European survey on preanalytical sample handling – Part 2: Practices of european laboratories on monitoring and processing haemolytic, icteric and lipemic samples. On behalf of the european federation of clinical chemistry and laboratory medicine (EFLM) working group for the preanalytical phase (WG-PRE). Biochem Med (Zagreb). 2019;29 :334–45. 10.11613/BM.2019.020705 31223259\n8 Petrova DT Cocisiu GA Eberle C Rhode KH Brandhorst G Walson PD Can the Roche hemolysis index be used for automated determination of cell-free hemoglobin? A comparison to photometric assays. Clin Biochem. 2013;46 :1298–301. 10.1016/j.clinbiochem.2013.06.018 23830841\n9 Twomey PJ . Unreliability of triglyceride measurement to predict turbidity induced interference. J Clin Pathol. 2003;56 :861–2. 10.1136/jcp.56.11.861 14600133\n10 Cadamuro J Simundic AM Ajzner E Sandberg S . A pragmatic approach to sample acceptance and rejection. Clin Biochem. 2017;50 :579–81. 10.1016/j.clinbiochem.2017.02.001 28163015\n11 Kaplan AA . Therapeutic plasma exchange: A technical and operational review. J Clin Apher. 2013;28 :3–10. 10.1002/jca.21257 23420589\n12 Zeng SG Zeng TT Jiang H Wang LL Tang SQ Sun YM A simple, fast correction method of triglyceride interference in blood hemoglobin automated measurement. J Clin Lab Anal. 2013;27 :341–5. 10.1002/jcla.21568 24038218\n13 Shephard MDS Whiting MJ . Falsely low estimation of triglycerides in lipemic plasma by the enzymatic triglyceride method with modified Trinder’s chromogen. Clin Chem. 1990;36 :325–9. 10.1093/clinchem/36.2.325 2406041\n14 Melnick S Nazir S Gish D Aryal MR . Hypertriglyceridemic pancreatitis associated with confounding laboratory abnormalities. J Community Hosp Intern Med Perspect. 2016;6 :31808. 10.3402/jchimp.v6.31808 27406459\n15 Tory R Sachs-Barrable K Goshko CB Hill JS Wasan KM . Tacrolimus-induced elevation in plasma triglyceride concentrations after administration to renal transplant patients is partially due to a decrease in lipoprotein lipase activity and plasma concentrations. Transplantation. 2009;88 :62–8. 10.1097/TP.0b013e3181aa7d04 19584682\n16 Deleuze S Garrigue V Delmas S Chong G Swarcz I Cristol JP New Onset Dyslipidemia After Renal Transplantation: Is There a Difference Between Tacrolimus and Cyclosporine? Transplant Proc. 2006;38 :2311–3. 10.1016/j.transproceed.2006.06.125 16980075\n17 Nawaz H Koutroumpakis E Easler J Slivka A Whitcomb DC Singh VP Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis. Am J Gastroenterol. 2015;110 :1497–503. 10.1038/ajg.2015.261 26323188\n18 Ewald N Hardt PD Kloer HU . Severe hypertriglyceridemia and pancreatitis: presentation and management. Curr Opin Lipidol. 2009;20 :497–504. 10.1097/MOL.0b013e3283319a1d 19770656\n19 Irie S Anno T Kawasaki F Shigemoto R Nakanishi S Kaku K Severe hypertriglyceridemia in a subject with disturbed life style and poor glycemic control without recurrence of acute pancreatitis: A case report. BMC Endocr Disord. 2019;19 :92. 10.1186/s12902-019-0425-9 31470836\n20 Toor A Toor A Khalighi K Krishnamurthy M . Triglyceride Levels Greater Than 10,000 mg/dL in a 49-Year-Old Female without Evidence of Pancreatitis. Case Rep Endocrinol. 2019;2019 :1–4. 10.1155/2019/6273196 31240137\n21 Ewald N Kloer HU . Treatment options for severe hypertriglyceridemia (SHTG): the role of apheresis. Clin Res Cardiol Suppl. 2012;7 :31–5. 10.1007/s11789-012-0042-x 22528130\n22 Galán Carrillo I Demelo-Rodriguez P Rodríguez Ferrero ML Anaya F . Double filtration plasmapheresis in the treatment of pancreatitis due to severe hypertriglyceridemia. J Clin Lipidol. 2015;9 :698–702. 10.1016/j.jacl.2015.07.004 26350817\n23 Nikolac N Simundic AM Miksa M Lima-Oliveira G Salvagno GL Caruso B Heterogeneity of manufacturers’ declarations for lipemia interference - An urgent call for standardization. Clin Chim Acta. 2013;426 :33–40. 10.1016/j.cca.2013.08.015 23981842\n24 Calmarza P Cordero J . Lipemia interferences in routine clinical biochemical tests. Biochem Med (Zagreb). 2011;21 :160–6. 10.11613/BM.2011.025 22135856\n25 Bornhorst JA Roberts RF Roberts WL . Assay-specific differences in lipemic interference in native and intralipid-supplemented samples. Clin Chem. 2004;50 :2197–201. 10.1373/clinchem.2004.040154 15375017\n26 Dimeski G Jones BW . Lipaemic samples: Effective process for lipid reduction using high speed centrifugation compared with ultracentrifugation. Biochem Med (Zagreb). 2011;21 :86–94. 10.11613/BM.2011.016 22141212\n27 Ting ACC Jones G Segara D Chisholm D . Rapid reversal of the chylomicronaemia syndrome with conservative management. Intern Med J. 2006;36 :682–3. 10.1111/j.1445-5994.2006.01182.x 16958651\n28 Vermeersch P Van Aelst T Dequeker EMC . The new IVD Regulation 2017/746: a case study at a large university hospital laboratory in Belgium demonstrates the need for clarification on the degrees of freedom laboratories have to use lab-developed tests to improve patient care. Clin Chem Lab Med. 2021;59 :101–6. 10.1515/cclm-2020-0804 32692695\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1330-0962",
"issue": "31(2)",
"journal": "Biochemia medica",
"keywords": "extra-analytical phase; hypertriglyceridemia; interferences; lipemia; lipoprotein metabolism",
"medline_ta": "Biochem Med (Zagreb)",
"mesh_terms": "D000208:Acute Disease; D057210:Delayed Diagnosis; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia; D008875:Middle Aged",
"nlm_unique_id": "9610305",
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"pages": "021002",
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"pmid": "33927560",
"pubdate": "2021-06-15",
"publication_types": "D002363:Case Reports",
"references": "22962670;27122601;32692695;30648042;16980075;23420589;22135856;22141212;26323188;31384720;22528130;19770656;15375017;23830841;24627715;31223259;31240137;23981842;14600133;20441481;16958651;31470836;24038218;27406459;26350817;19584682;28163015;2406041",
"title": "Delayed diagnosis and treatment of extreme hypertriglyceridemia due to rejection of a lipemic sample.",
"title_normalized": "delayed diagnosis and treatment of extreme hypertriglyceridemia due to rejection of a lipemic sample"
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"abstract": "BACKGROUND\nExtended follow-up of statin-based low-density lipoprotein cholesterol lowering trials improves the understanding of statin safety and efficacy. Examining cumulative cardiovascular events (total burden of disease) gives a better appreciation of the clinical value of statins. This article evaluates the long-term impact of therapy on mortality and cumulative morbidity in a high-risk cohort of men.\n\n\nRESULTS\nThe West of Scotland Coronary Prevention Study was a primary prevention trial in 45- to 64-year-old men with high low-density lipoprotein cholesterol. A total of 6595 men were randomized to receive pravastatin 40 mg once daily or placebo for an average of 4.9 years. Subsequent linkage to electronic health records permitted analysis of major incident events over 20 years. Post trial statin use was recorded for 5 years after the trial but not for the last 10 years. Men allocated to pravastatin had reduced all-cause mortality (hazard ratio, 0.87; 95% confidence interval, 0.80-0.94; P=0.0007), attributable mainly to a 21% decrease in cardiovascular death (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P=0.0004). There was no difference in noncardiovascular or cancer death rates between groups. Cumulative hospitalization event rates were lower in the statin-treated arm: by 18% for any coronary event (P=0.002), by 24% for myocardial infarction (P=0.01), and by 35% for heart failure (P=0.002). There were no significant differences between groups in hospitalization for noncardiovascular causes.\n\n\nCONCLUSIONS\nStatin treatment for 5 years was associated with a legacy benefit, with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies.",
"affiliations": "From Robertson Centre for Biostatistics (I.F., H.M., C.M.) and College of Medical, Veterinary, and Life Sciences (C.J.P.), University of Glasgow, UK.;From Robertson Centre for Biostatistics (I.F., H.M., C.M.) and College of Medical, Veterinary, and Life Sciences (C.J.P.), University of Glasgow, UK.;From Robertson Centre for Biostatistics (I.F., H.M., C.M.) and College of Medical, Veterinary, and Life Sciences (C.J.P.), University of Glasgow, UK. colin.mccowan@glasgow.ac.uk.;From Robertson Centre for Biostatistics (I.F., H.M., C.M.) and College of Medical, Veterinary, and Life Sciences (C.J.P.), University of Glasgow, UK.",
"authors": "Ford|Ian|I|;Murray|Heather|H|;McCowan|Colin|C|;Packard|Chris J|CJ|",
"chemical_list": "D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin",
"country": "United States",
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"doi": "10.1161/CIRCULATIONAHA.115.019014",
"fulltext": "\n==== Front\nCirculationCirculationCIRCirculation0009-73221524-4539Lippincott Williams & Wilkins 0000610.1161/CIRCULATIONAHA.115.019014100621003410069Original ArticlesEpidemiology and PreventionLong-Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy 20-Year Follow-Up of West of Scotland Coronary Prevention StudyFord Ian PhDMurray Heather MScMcCowan Colin PhDPackard Chris J. DScFrom Robertson Centre for Biostatistics (I.F., H.M., C.M.) and College of Medical, Veterinary, and Life Sciences (C.J.P.), University of Glasgow, UK.Correspondence to Colin McCowan, PhD, Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK, G12 8QQ. E-mail colin.mccowan@glasgow.ac.uk15 3 2016 14 3 2016 133 11 1073 1080 © 2016 The Authors.2016Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.Supplemental Digital Content is available in the text.\n\nBackground—\nExtended follow-up of statin-based low-density lipoprotein cholesterol lowering trials improves the understanding of statin safety and efficacy. Examining cumulative cardiovascular events (total burden of disease) gives a better appreciation of the clinical value of statins. This article evaluates the long-term impact of therapy on mortality and cumulative morbidity in a high-risk cohort of men.\n\nMethods and Results—\nThe West of Scotland Coronary Prevention Study was a primary prevention trial in 45- to 64-year-old men with high low-density lipoprotein cholesterol. A total of 6595 men were randomized to receive pravastatin 40 mg once daily or placebo for an average of 4.9 years. Subsequent linkage to electronic health records permitted analysis of major incident events over 20 years. Post trial statin use was recorded for 5 years after the trial but not for the last 10 years. Men allocated to pravastatin had reduced all-cause mortality (hazard ratio, 0.87; 95% confidence interval, 0.80–0.94; P=0.0007), attributable mainly to a 21% decrease in cardiovascular death (hazard ratio, 0.79; 95% confidence interval, 0.69–0.90; P=0.0004). There was no difference in noncardiovascular or cancer death rates between groups. Cumulative hospitalization event rates were lower in the statin-treated arm: by 18% for any coronary event (P=0.002), by 24% for myocardial infarction (P=0.01), and by 35% for heart failure (P=0.002). There were no significant differences between groups in hospitalization for noncardiovascular causes.\n\nConclusion—\nStatin treatment for 5 years was associated with a legacy benefit, with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies.\n\nclinical trial [publication type]coronary diseaseheart failureprimary preventionsafetyCMECMEOPEN-ACCESSTRUE\n==== Body\nLowering of low-density lipoprotein (LDL) cholesterol is accepted as a key objective in the prevention of cardiovascular disease.1,2 Controversies remain, however, as to which kind of subjects to treat, the use of goals, the magnitude of the benefit, and potential harms, especially in the context of primary prevention.3–6 Examination of the long-term (lifetime) consequences of lowering LDL cholesterol can assist greatly in understanding more fully the efficacy and safety of this intervention, and a number of studies have reported extended observations beyond the end of the formal trial.7–11 In the West of Scotland Coronary Prevention Study (WOSCOPS), in which follow-up was first examined ≈10 years after the end of the 5-year trial,7 there was evidence of further reduction in coronary events over the 15-year period and, as indicated by the available data, no emergent safety issues. Overall, there was a reduction in all-cause mortality (hazard ratio [HR]=0.88; 95% confidence interval [CI], 0.79–0.99; P=0.03) and in the outcome of death or hospitalization for coronary heart disease (HR=0.75; 95% CI, 0.68–0.83; P<0.001). Furthermore, over the 15-year period, treatment with pravastatin for 5 years was shown to be cost-saving in terms of overall health service costs,12 adding an important economic dimension to the clinical outcome analysis. Previous work had shown that there was a relatively low uptake of statin treatment in the first 5 years of extended follow-up after the trial, which means that WOSCOPS is uniquely placed to investigate the legacy effects of 5 years of statin treatment in terms of ongoing benefit and potential safety issues later in life.\n\nClinical Perspective on p 1080\n\nWe have now increased the period of follow-up to 20 years to examine a range of mortality and morbidity outcomes as a first event and as a total burden of disease in the form of cumulative hospital admissions. More detailed interrogation of hospitalization rates has allowed a fuller picture of benefits and risks to emerge. Given a mean age at randomization of 55 years, the extended observation period to a mean of 75 years (range, 65–84 years) gives an approximation of the lifetime benefit of this pharmacological intervention.\n\nMethods\nThe design of WOSCOPS and its long-term follow-up have been described elsewhere.13–15 It was a randomized trial of pravastatin (40 mg once daily) versus placebo in men 45 to 64 years of age (mean age, 55 years) with raised cholesterol who had no evidence of previous myocardial infarction (based on medical history and a baseline, centrally read ECG). Participants had a mean±SD plasma cholesterol level of 272±23 mg/dL (7.0±0.6 mmol/L) and a mean±SD LDL cholesterol level of 192±17 mg/dL (5.0±0.44 mmol/L); 44% were current smokers; 16% had a history of hypertension; and 1% had a history of diabetes mellitus. Between 1989 and 1991, 6595 men gave written informed consent and were enrolled in the trial. The average follow-up was 4.9 years (range, 3.5–6.1 years), with final study visits in May 1995.\n\nAfter the end of the trial, use of lipid-lowering therapy during the first 5 years of extended follow-up was monitored by review of case records. In the original pravastatin and placebo groups, 28.6% and 24.3% at 1 year after the trial, 33.6% and 29.4% at 3 years, and 38.7% and 35.2% at 5 years, respectively, were found to be on statins.7 No further data on statin treatment were available after this point. Extended follow-up for clinical events was based entirely on linkage to national electronic hospital discharge records held by the Information Services Division in Edinburgh, the Scottish Cancer Registry, and the Scottish General Register Office death records by means of established methods.16,17 Data were extracted from the beginning of the trial to October 2011 and classified with International Classification of Diseases codes and Office of Population, Censuses and Surveys Classification of Surgical Operations and Procedures codes. Cancer Registry Data were available only until November 2010.\n\nThe original trial was approved by the ethics committees of the University of Glasgow and participating health boards in Scotland, and the long-term follow-up and associated record linkage were approved by the ethics committee of the Glasgow Royal Infirmary and the Privacy Advisory Committee of the National Health Service for Scotland. All participants gave informed consent to take part in the trial and for the examination of their medical records.\n\nPrevious analyses focused on time to first event for deaths, incident cancers, and composite cardiovascular outcomes7,14 and health economics evaluation.12 In the present report, we assessed the impact on mortality, incident cancers, and cumulative number of hospital admissions over 20 years or until death. We report hospital admissions for noncardiovascular causes, cardiovascular causes, coronary heart disease, myocardial infarction, heart failure, and stroke, and we describe the cumulative number of coronary revascularizations (coronary artery bypass graft, percutaneous coronary intervention, or angioplasty).\n\nStatistical Methods\nCumulative incidence functions, accounting for the competing risk of death from other causes, were used to describe the incidence of cause-specific deaths or time to first incident cancer. To estimate treatment effects for cause-specific mortality and incident cancers, Cox proportional hazards models were fitted, including the treatment group and baseline risk factors of age, body mass index, systolic and diastolic blood pressures, high-density lipoprotein and LDL cholesterol levels, log-transformed triglyceride level, nitrate use, history of angina, history of diabetes mellitus, history of hypertension (all yes or no), smoking status (current, former, never), and a 7-category social deprivation score.18 Treatment effects (pravastatin versus placebo) were expressed as HRs with 95% CIs and corresponding P values.\n\nThe cumulative numbers of hospital admissions of each type were presented without adjustment for the competing risk of death to represent the true difference in healthcare resource use over 20 years (all participants had a potential follow-up of a minimum of 20 years). We also calculated the crude rates of hospital admission of each type, correcting for the different total periods of follow-up in each randomized group resulting from the increased survival and consequent greater exposure to risk in the statin-treated group. These statistics were compared with the use of rerandomization tests (based on 10 000 rerandomizations).\n\nBecause of the interest in the long-term impact of statin treatment on diabetes mellitus and its complications, we identified all noncardiovascular hospital admissions that were associated with diabetes mellitus or its complications either as a reason for admission or as a factor complicating the admission. Cardiovascular admissions were omitted from this analysis because of the potential bias associated with the overall reduction in cardiovascular admissions resulting from statin treatment. Similarly, we reported other noncardiovascular hospital admissions grouped by International Classification of Diseases, 10th Revision codes to examine the long-term safety of statin use. These analyses were further subdivided into day cases and non–day cases.\n\nThe data analysis was generated with SAS software, version 9.3 of the SAS System for Windows (Cary, NC).\n\nResults\nThe mean follow-up until censoring date or death in the pravastatin-treated group was 18.6 compared with 18.3 years for the placebo group. Baseline characteristics of the 2 randomized groups have been reported previously.15 There were no differences in characteristics at baseline between the 2 groups, including age, body mass index, blood pressure, cholesterol, alcohol use, smoking, employment, and medical history.\n\nMortality\nIn the total follow-up period, 1253 (38%) of those originally randomized to placebo died compared with 1145 (34.7%) in the pravastatin group (HR=0.87; 95% CI, 0.80–0.94; P=0.0007). There were also reductions in cardiovascular mortality (HR=0.79; 95% CI, 0.69–0.90; P=0.0004) and coronary mortality (HR=0.73; 95% CI, 0.62–0.86; P=0.0002) but not stroke. There was no evidence of an increased risk of noncardiovascular or cancer mortality in the pravastatin group (Table 1, Figure 1A–1D, and Figure Ia in the online-only Data Supplement).\n\nTable 1. Number of Events and HRs for Pravastatin Treatment Effect for Mortality Outcomes\n\nFigure 1. Cumulative events over the 20-year follow-up period. Cumulative incidence functions are provided for the outcomes of death resulting from (A) all causes, (B) cardiovascular disease, (C) coronary heart disease, and (D) noncardiovascular disease. P values were determined by Cox proportional hazards model.\n\nIncident Cancers\nThere was no evidence of an increased risk of overall incident cancer (809 [24.6%] participants had events in the placebo-treated group compared with 802 [24.3%] on pravastatin; P=0.24) or of cause-specific cancers (Table I and Figure Ib in the online-only Data Supplement).\n\nCumulative Hospital Admissions\nIn the group of 3293 participants originally randomized to placebo, 1546 experienced a total of 4102 cardiovascular admissions compared with 1398 participants (of 3302) in the pravastatin group who had 3436 admissions (P<0.0001; Table 2 and Figure 2A). Similarly, there were significant reductions in recurrent coronary (P=0.0006), myocardial infarction (P=0.0002), and heart failure (P=0.01) admissions (Figure IIa in the online-only Data Supplement and Figure 2B–2C) but not stroke admissions (Figure IIb in the online-only Data Supplement). There was a significant reduction in hospital admissions involving coronary revascularization (percutaneous coronary intervention, coronary artery bypass surgery or angioplasty), with 1210 events in the placebo group and 1029 in the pravastatin group (P=0.0078; Figure 2D).\n\nTable 2. Subjects With Events, Cumulative Recurrent Events, and Event Rates per 10 Years of Follow-Up Between Randomized Groups\n\nFigure 2. Cumulative numbers of hospital admissions for the outcomes of (A) cardiovascular disease, (B) myocardial infarction, (C) heart failure, and (D) coronary revascularization. P values were computed by rerandomization tests.\n\nThere were numerically more noncardiovascular admissions in the pravastatin group, but after adjustment for duration of follow-up, the rates were similar (2.97 events in 10 years for placebo compared with 3.03 events in 10 years for pravastatin). Neither comparison achieved statistical significance (Table 2 and Figure IIc in the online-only Data Supplement).\n\nIn a further exploration, hospitalizations were divided into day cases and non–day cases (ie, events involving an overnight stay). Subjects in the pravastatin group had fewer hospitalizations for cardiovascular reasons in both categories (Table 3). Tables II and III in the online-only Data Supplement give the frequency of noncardiovascular admissions by International Classification of Diseases body system classification for day cases and non–day cases. Overall, the numbers of subjects and cumulative events were balanced between the 2 groups for non–day cases. For day cases, it was noted that the pravastatin group had an apparent increased risk of events associated with diseases of the eye and adnexa (P=0.03 uncorrected for multiple comparisons), which was attributable for the most part to an excess of admissions for cataract surgery (not individually statistically significant). There were numerically more day-case events but not subjects with events associated with neoplasms and diseases of the digestive system.\n\nTable 3. Subjects With Events, Cumulative Recurrent Events, and Event Rates per 10 Years of Follow-Up Between Randomized Groups, Subdivided by Day Case/Non–Day Case\n\nHospital Admissions Associated With Complications of Diabetes Mellitus\nIn the placebo group, a total of 221 participants experienced 911 noncardiovascular hospital admissions that contained a diabetes-related International Classification of Diseases code compared with 201 participants (770 admissions) in the pravastatin-treated group (HR=0.81; 95% CI, 0.67–0.98; P=0.030). For hospital admissions involving complications of diabetes mellitus, 29 participants in the placebo group experienced 80 admissions compared with 12 participants (44 admissions) in the pravastatin-treated group (HR=0.33; 95% CI, 0.16–0.66; P=0.0016). There were 23 deaths for which diabetes mellitus was given as the cause (15 patients on placebo and 8 patients on pravastatin).\n\nDiscussion\nThis 20-year follow-up of the WOSCOPS identified a continued legacy benefit from 5 years of LDL cholesterol lowering with a statin through improved survival resulting from decreased mortality from cardiovascular causes and an ongoing reduction in cardiovascular hospital admissions. Cumulative event rates are presented for both treatment arms to assess the impact of therapy on the total burden of disease. We observed a substantial and significant benefit: Cumulative event rates were 18% lower for cardiovascular disease and 24% lower for myocardial infarction in the pravastatin group. Our focus on recurrent events reflects current interest in the impact of interventions on the total burden of disease. We also observed continuing divergence of the cumulative event curves for heart failure hospitalization over 20 years, with a 35% lower rate in the pravastatin arm.\n\nMore than 2 decades since the publication of the first successful primary prevention trial of a statin,15 with subsequent studies19,20 and meta-analyses5,21,22 also confirming the benefits of LDL cholesterol reduction, there are still concerns about side effects of treatment, long-term safety, impact on all-cause mortality, and cost-effectiveness3–6,23,24 that lead a number of commentators to continue to express caution when wider use of statins in primary prevention strategies is promoted.25,26 The present study found no increased incidence of cancer overall, and enhanced site-specific data show no imbalance between the 2 groups (Note the balanced rates for prostate cancer compared with the previous report).7 Examination of noncardiovascular hospital admissions also showed no differences, with the exception of a possible increased risk of day-case hospital admissions associated with diseases of the eye for patients using pravastatin. The significance of this latter finding, which should be treated cautiously because of the borderline significance and the multiple adverse effects investigated, lies in its link to historical concern that inhibition of cholesterol synthesis would lead to risk of corneal opacity.27,28 Epidemiological studies have suggested both increased and decreased risk of cataracts linked to statin use.29–31 However, these studies will not have the length of follow-up available in WOSCOPS or the benefits of randomization in minimizing confounding factors. It should be noted that any treatment that improves cardiovascular survival will inevitably result in an increase in hospital admissions for noncardiovascular causes. We saw no evidence of this for non–day-case admissions. However, the trend toward increased day-case admissions, including treatment for cancer but not number of participants with cancer, particularly for events associated with advancing age, in the later years of follow-up could be early evidence of this survival bias effect.\n\nReduction in heart failure as an outcome has been reported recently in a meta-analysis of 14 trials of statin-based LDL lowering with a risk reduction of 10%.32 The mean duration of observation in these studies was 4.3 years. Data presented here suggest that this additional clinical benefit may be underestimated in short-term studies, particularly in primary prevention. As Preiss et al32 noted, we found that the number of heart failure admissions was reduced in subjects who had and in those who did not have an antecedent myocardial infarction (data not shown). The overall mechanism by which LDL lowering leads to a reduced incidence of heart failure is not fully clear. However, we note that much of the WOSCOPS follow-up was before the use of troponin assays and certainly before newer high-sensitivity assays. Hence, many of the events classified as other coronary hospitalizations would today be classified as myocardial infarction. Likewise, the reduced need for revascularization in statin-treated participants indicates lower levels of ischemia, the repeated occurrence of which could be a mechanism for the development of heart failure.\n\nWe did not demonstrate a reduction in stroke at 20 years. There was no effect in the original trial,15 although we saw evidence of stroke reduction in the 15-year follow-up.7 However, WOSCOPS was a primary prevention trial in relatively young subjects compared with the majority of trials in the Cholesterol Treatment Trialists Collaborators (CTTC) analysis, which were secondary prevention studies in participants ≈10 years older at randomization and had shorter periods of follow-up.22 It is therefore difficult to compare directly the findings in CTTC with extended observations made when the original treatment arms are predicted to be receiving statin therapy at the same level after the trial.\n\nIn the assessment of the long-term impact of interventions in primary prevention, it is essential that there is a balanced evaluation of the benefits resulting from reduction in cardiovascular events and the potential for adverse clinical outcomes. Muscle-related side effects of statins have been studied in detail.33 They can lead to intolerance to the medication and, in rare instances, rhabdomyolysis.1,2 Statin therapy has also been shown in a number of studies to increase the propensity to develop type 2 diabetes mellitus,34,35 with an HR of ≈1.09 compared with placebo; a similar increase in diabetes risk is associated with the use of high- versus low-dose statin therapy.35 This is one of the issues raised by those concerned about the more widespread use of statins in the prevention of disease in lower-risk subjects.3–6 Diabetes mellitus is defined on the basis of blood glucose levels and is a disorder associated with macrovascular but also microvascular/noncardiovascular complications. Statins reduce cardiovascular disease, and it has been estimated that their use will prevent 5 incidences of myocardial infarction for every new case of diabetes mellitus.36 In this study, we were able to report that statin treatment was also associated over a 20-year follow-up with significantly fewer hospital admissions associated with noncardiovascular complications of diabetes mellitus. This raises the possibility that although statin use may affect blood glucose levels, this does not necessarily translate into deleterious noncardiovascular pathologies. It should be noted, however, that WOSCOPS was unusual in that the incidence of type 2 diabetes mellitus was lower in the actively treated arm during the original trial.37\n\nThere are limitations to this form of long-term follow-up based on electronic health records as noted previously.7,16 Critically, we do not know what lipid-regulating therapy was being used by the participants for the last 10 years of the study, and this limits the interpretation of data with regard to the magnitude of the 20-year benefit. If in the second half of the extended follow-up more subjects originally assigned to the placebo arm compared with the pravastatin arm were placed on a statin (as a result of having a coronary event or as a primary prevention measure by the general practitioner), then the difference in event rates between the 2 groups would be diminished, and the observed HR would be an underestimate of the long-term risk reduction attributable to statin therapy. In addition, we are dependent on the stability of the population to allow comprehensive capture of hospitalizations within the healthcare information systems. However, Scotland is an area of relatively low social mobility after people reach middle age, which allowed us to achieve 100% follow-up at the end of the study. We also flagged all of our participants with the death registry in England and Wales and identified only 15 deaths (0.6%) there from a total of 2398 deaths. We have no current method for identifying hospital admissions outside Scotland but do not feel this would have altered our findings. Finally, as a substantial number of participants die, analyses are complicated by competing risks.\n\nConclusions\nIn this primary prevention trial in high-risk men with elevated LDL cholesterol but without a history of myocardial infarction, we observed a long-term legacy benefit of LDL lowering by statin therapy. Because over the 20 years the cohort aged from an average of 55 to 75 years, the cumulative event rate is an estimate of the total burden of disease (more specifically of premature morbidity and mortality; male life expectancy in Scotland is 76.8 years), and the reduction in cardiovascular events is a measure of the lifetime benefit of the intervention. The reduction in cumulative cardiovascular events is substantial both numerically (with attendant economic savings) and in terms of relative risk (especially for heart failure). The observation that 5 years of statin therapy led to a prolonged risk reduction raises the issue that treatment might not need to be lifelong. That is, the legacy risk reduction after a 5- to 10-year treatment period may be sufficient to produce a clinically meaningful benefit while limiting lifetime exposure to the drug. We cannot address this question fully using the information in the present study, although it is clear that therapy would have to be maintained for subjects to experience maximum risk reduction because we saw a diminution in the treatment effect in the posttrial compared with the in-trial phases. The data on diabetes-associated noncardiovascular events indicate that further work is required to understand the clinical consequences of the statin-induced increase in the incidence of this disorder. These long-term efficacy findings, particularly on all-cause mortality, and detailed safety data should allay concerns over strategies to promote the more widespread use of statins in the population.\n\nAcknowledgments\nDr Ford and H. Murray had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.\n\nSources of Funding\nThe study was supported by a grant from Merck, Sharp & Dohme, Kenilworth, NJ, as part of an Investigator Initiated Program. The funder had no role in the design or conduct of the study or in the analysis of the data and preparation of the manuscript. The funder was provided with a draft for comment and made nonbinding suggestions.\n\nDisclosures\nDr Packard reports research grants from Roche and honoraria from Merck, Sharpe & Dohme, and Sanofi. The other authors report no conflicts.\n\nSupplementary Material\nThe online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.019014/-/DC1.\n\nCLINICAL PERSPECTIVE\nAdoption of statin therapy for the primary prevention of cardiovascular disease is an area of controversy in clinical practice. There is perceived uncertainty about long-term efficacy with respect to vascular and all-cause mortality and the long-term safety of treatment. The findings of the present study should help alleviate at least some of these concerns. Extended follow-up of this primary prevention trial in high-risk men with raised low-density lipoprotein cholesterol but without a history of myocardial infarction demonstrated a long-term legacy benefit of low-density lipoprotein lowering by statin therapy with a significant reduction in cardiovascular mortality and improved survival when viewed over the entire 20 years of follow-up. Furthermore, the reduction in cumulative cardiovascular events, representing the total burden of disease, was substantial both numerically (with attendant economic savings) and clinically in terms of relative risk across a range of cardiovascular outcomes. The finding of a late posttrial benefit of a reduced risk of heart failure gives further impetus to the need to start treatment early. These long-term efficacy findings, particularly for all-cause mortality, and detailed safety data should allay concerns over strategies to promote the more widespread use of statins in the population.\n==== Refs\nReferences\n1. 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Lancet 2010 375 735 742 doi: 10.1016/S0140-6736(09)61965-6 20167359 \n35. Preiss D Seshasai SR Welsh P Murphy SA Ho JE Waters DD DeMicco DA Barter P Cannon CP Sabatine MS Braunwald E Kastelein JJ de Lemos JA Blazing MA Pedersen TR Tikkanen MJ Sattar N Ray KK Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011 305 2556 2564 doi: 10.1001/jama.2011.860 21693744 \n36. Preiss D Sattar N Statins and the risk of new-onset diabetes: a review of recent evidence. Curr Opin Lipidol 2011 22 460 466 21897230 \n37. Freeman DJ Norrie J Sattar N Neely RD Cobbe SM Ford I Isles C Lorimer AR Macfarlane PW McKillop JH Packard CJ Shepherd J Gaw A Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001 103 357 362 11157685\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0009-7322",
"issue": "133(11)",
"journal": "Circulation",
"keywords": "clinical trial [publication type]; coronary disease; heart failure; primary prevention; safety",
"medline_ta": "Circulation",
"mesh_terms": "D002318:Cardiovascular Diseases; D002423:Cause of Death; D008078:Cholesterol, LDL; D048909:Diabetes Complications; D003920:Diabetes Mellitus; D005500:Follow-Up Studies; D006760:Hospitalization; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009369:Neoplasms; D017035:Pravastatin; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012606:Scotland; D016019:Survival Analysis",
"nlm_unique_id": "0147763",
"other_id": null,
"pages": "1073-80",
"pmc": null,
"pmid": "26864092",
"pubdate": "2016-03-15",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10922429;11157685;11978335;1624967;17928595;18701534;18997196;20167359;20488911;20585067;21693744;21709063;21873710;21897230;22115874;22496261;22555213;22607822;2307197;23440795;23839541;24149819;24222016;24276813;24311734;24758622;25475465;25694464;25728729;25802390;7566020;7653449;7804046;8514493;8534671;8543958;9613910",
"title": "Long-Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy: 20-Year Follow-Up of West of Scotland Coronary Prevention Study.",
"title_normalized": "long term safety and efficacy of lowering low density lipoprotein cholesterol with statin therapy 20 year follow up of west of scotland coronary prevention study"
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"companynumb": "GB-CIPLA LTD.-2016US02918",
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"abstract": "There are few data on the real-world experience of FDA-approved oral hepatitis C virus (HCV) direct-acting antiviral (DAA) drug combinations in HIV/HCV-coinfected patients. We evaluated the safety and efficacy of DAA therapies in a cohort of HIV/HCV patients in a large urban clinic in Chicago.\n\n\n\nHIV/HCV-coinfected adults (≥18 years) enrolled in the Northwestern University Viral Hepatitis Registry between January 2013 and June 2015 were analysed. Treated patients received one of the following DAA combinations: sofosbuvir/ledipasvir, sofosbuvir/ribavirin, sofosbuvir/simeprevir or paritaprevir/ritonavir/ombitasvir/dasabuvir ± ribavirin. The primary outcome was sustained virological response at 12 weeks after DAA completion (SVR12).\n\n\n\nSeventy-seven HIV/HCV patients were evaluated for DAA therapy. Most patients were male (62/77, 81%) and infected with HCV genotype 1 (67/77, 87%). Some 32/77 (42%) were cirrhotic and 29/77 (38%) had received prior treatment with an IFN-containing regimen. DAA therapy was more likely to be started in Caucasians than persons of other ethnicities (P = 0.01). The overall SVR12 rate was 92% in 52 patients who completed therapy and had follow-up by the end of the study: sofosbuvir/simeprevir, 32/33 (97%); sofosbuvir/ribavirin, 4/7 (57%); sofosbuvir/ledipasvir, 11/11 (100%); and paritaprevir/ritonavir/ombitasvir/dasabuvir, 1/1 (100%). Four patients relapsed after therapy with sofosbuvir/simeprevir (n = 1) or sofosbuvir/ribavirin (n = 3). Adverse events were uncommon and did not result in DAA treatment interruption or discontinuation.\n\n\n\nThe HCV DAA combinations of sofosbuvir/ledipasvir and sofosbuvir/simeprevir were highly effective and well tolerated in this diverse population of HIV/HCV-coinfected patients, many of whom had advanced liver disease. HIV coinfection should not be considered a barrier to successful HCV treatment with DAAs.",
"affiliations": "Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA c-hawkins@md.northwestern.edu.;Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Feinberg School of Medicine, Chicago, IL, USA.;Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA.;Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.;Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.",
"authors": "Hawkins|Claudia|C|;Grant|Jennifer|J|;Ammerman|Lauren Rose|LR|;Palella|Frank|F|;Mclaughlin|Milena|M|;Green|Richard|R|;Mcgregor|Donna|D|;Stosor|Valentina|V|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkw203",
"fulltext": null,
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"issn_linking": "0305-7453",
"issue": "71(9)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D002641:Chicago; D015331:Cohort Studies; D060085:Coinfection; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "2642-5",
"pmc": null,
"pmid": "27330060",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "12883497;16729309;17005764;23281974;23607593;24725237;24725239;25706092;25706232;26066094;26196502;26196665",
"title": "High rates of hepatitis C virus (HCV) cure using direct-acting antivirals in HIV/HCV-coinfected patients: a real-world perspective.",
"title_normalized": "high rates of hepatitis c virus hcv cure using direct acting antivirals in hiv hcv coinfected patients a real world perspective"
} | [
{
"companynumb": "US-JNJFOC-20160827043",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
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... |
{
"abstract": "For percutaneous minimally-invasive local ablation therapies of malignant lesions within the liver computed tomography (CT) fluoroscopy or ultrasound (US) can be applied for the positioning of ablation probes. However, lesions in liver segment I and in the upper part of liver segment VIII are difficult to reach with CT fluoroscopy and US guidance even for experienced interventionalists as steep and transcostal access paths may be needed. In addition, there is always the risk to lacerate crucial vessels near the liver hilus. We report on the use of a CT-based stereotactic navigation system (CAS-One, CAScination AG, Bern, Switzerland) for the precise positioning of the ablation probe to perform a percutaneous stereotactic image-guided microwave ablation of a breast cancer liver metastasis in liver segment I that was unreachable with conventional CT or US guidance. Based on the initial planning scan and image-to-patient registration a precise positioning of the probe was possible sparing vital structures like the directly adjacent vulnerable vessels. The ablation was performed without complications fully covering the metastatic lesion with the ablation zone. To this day, there was no recurring tumor 18 months after the intervention.",
"affiliations": "Department of Diagnostic, Interventional and Paediatric Radiology, Bern University Hospital, Inselspital, University of Bern, Freiburgstr. 10, 3010 Bern, Switzerland.;Department of Surgery, Bern University Hospital, Inselspital, University of Bern, Freiburgstr. 10, 3010 Bern, Switzerland.;Department of Diagnostic, Interventional and Paediatric Radiology, Bern University Hospital, Inselspital, University of Bern, Freiburgstr. 10, 3010 Bern, Switzerland.",
"authors": "Fischer|Tim|T|;Lachenmayer|Anja|A|;Maurer|Martin Helmut|MH|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2018.10.010",
"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(18)30110-910.1016/j.radcr.2018.10.010Interventional RadiologyCT-guided navigated microwave ablation (MWA) of an unfavorable located breast cancer metastasis in liver segment I Fischer Tim MD, Dr. med.tim.fischer@insel.chaLachenmayer Anja MD, Priv.-Doz. Dr. med.anja.lachenmayer@insel.chbMaurer Martin Helmut MD, MBA, Priv.-Doz. Dr. med. Dr. rer. medicmartin.maurer@insel.chc⁎a Department of Diagnostic, Interventional and Paediatric Radiology, Bern University Hospital, Inselspital, University of Bern, Freiburgstr. 10, 3010 Bern, Switzerlandb Department of Surgery, Bern University Hospital, Inselspital, University of Bern, Freiburgstr. 10, 3010 Bern, Switzerlandc Department of Diagnostic, Interventional and Paediatric Radiology, Bern University Hospital, Inselspital, University of Bern, Freiburgstr. 10, 3010 Bern, Switzerland⁎ Corresponding author. martin.maurer@insel.ch30 10 2018 2 2019 30 10 2018 14 2 146 150 27 9 2018 8 10 2018 13 10 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/).For percutaneous minimally-invasive local ablation therapies of malignant lesions within the liver computed tomography (CT) fluoroscopy or ultrasound (US) can be applied for the positioning of ablation probes. However, lesions in liver segment I and in the upper part of liver segment VIII are difficult to reach with CT fluoroscopy and US guidance even for experienced interventionalists as steep and transcostal access paths may be needed. In addition, there is always the risk to lacerate crucial vessels near the liver hilus. We report on the use of a CT-based stereotactic navigation system (CAS-One, CAScination AG, Bern, Switzerland) for the precise positioning of the ablation probe to perform a percutaneous stereotactic image-guided microwave ablation of a breast cancer liver metastasis in liver segment I that was unreachable with conventional CT or US guidance. Based on the initial planning scan and image-to-patient registration a precise positioning of the probe was possible sparing vital structures like the directly adjacent vulnerable vessels. The ablation was performed without complications fully covering the metastatic lesion with the ablation zone. To this day, there was no recurring tumor 18 months after the intervention.\n\nKeywords\nMicrowave ablationComputed tomography based navigationLiverMinimally-invasive treatment\n==== Body\nIntroduction\nThe liver is a common site for metastatic disease, especially from colorectal cancer [1]. Today surgical approaches, eg, resection or liver transplantation are pursued, however, only a minority fits the necessary requirements [2]. To overcome this, various interventional treatment options have become available. For local thermal ablation, radiofrequency ablation (RFA) and more recently microwave ablation (MWA) have been developed. Other methods for a local therapy are laser-induced interstitial thermotherapy, cryotherapy, computed tomography guided interstitial high-dose rate brachytherapy, or irreversible electroporation [3]. In our institution MWA is the most commonly used procedure and we report the successful treatment of a breast carcinoma liver metastasis in a very unfavorable location in liver segment I using CT-based stereotactic image-guided microwave ablation (SIMWA).Fig. 1 FDG PET-CT (A, arrow), MRI in hepatobilliary phase (using Gadoxetate (Primovist); B, dotted circle) and contrast enhanced CT in venous phase (C, dotted circle) show the metastasis in the caudate lobe, directly adjunct to the left portal vein and the inferior vena cava.\n\nFig. 1.\n\nCase report\nThe patient presented in this report was part of a prospective clinical study with the aim to evaluate short-term clinical outcome of patients undergoing percutaneous SIMWA for liver metastases (excluding colorectal metastases). The study was approved by the local ethical committee. In May 2016 a 52-year-old female patient with an abnormal finding in her right breast on the screening mammogram presented at our institution. Biopsy revealed an invasive ductal carcinoma (estrogen receptor 60%, progesterone receptor 5%-20%, Ki67 25%, HER positive). The subsequent FDG PET-CT showed an active lesion in the caudate lobe of the liver. The final tumor stage was T2, N0, M1. Chemotherapy with Trastuzumab (Herceptin), Pertuzumab (Perjeta), and Docetaxel (Taxotere) with a total of 5 cycles (dose reduction of Docetaxel due to major side effects), followed by systemic therapy with Trastuzumab and Pertuzumab was admitted. The FDG PET-CT, 4 months after starting the chemotherapy showed decreased activity of the liver metastases (Fig. 1A). Surgery of the right breast (segmental resection, negative tumor margins) was followed by adjuvant high dose brachytherapy (cumulative dose 32 Gray (Gy)) 1 month later.\n\nDue to the unfavorable location in the caudate lobe (Fig. 1) with a distance of only 4 mm to the inferior cava vein and a distance of 3 mm to the left portal vein surgery would be invasive and extensive. The interdisciplinary tumor board therefore recommended a CT-based SIMWA for therapy considering the oncological circumstances of the patient.\n\nAs the lesion was located just between the left portal vein and the inferior vena cava, it would have been very difficult even for an experienced interventionalist to position the ablation probe precisely within the lesion while not risking to injure the vessels and otherwise to ensure a full therapeutic coverage of the lesion. Therefore, a navigation system (CAS-One, CAScination AG, Bern, Switzerland) was used to perform the procedure. This system allows to import the imaging data of an initial contrast enhanced CT planning scan acquired while the patient is under general anesthesia using jet ventilation [4]. Six markers are attached to the skin of the patient before the planning scan that allow a real-time image-to-patient registration. A 3D planning of the precise probe access path is based on the CT data. Real-time tracking of both the patient position and of the aiming enables the interventionalist to insert die ablation probe in just the right angle and the exact planned depth to reach the center of the planned ablation zone.\n\nThe initial contrast enhanced CT planning scan showed the known metastasis with a diameter of 8 mm in liver segment I (Fig. 2A). The ablation probe (Accu2ioTMA, Angiodynamics, NY) was introduced via a transcostal approach, penetrating a distance of 11 cm through the liver parenchyma. A reformatted, preinterventional control scan showed the precise probe position in the middle of the lesion. The planning algorithm within the navigation device was used to define the expected ablation area with a sufficient safety margin while sparing sensible vessel structures (Fig. 2A). Intensity and duration of required energy were calculated and microwave ablation was applied as planned with a power of 100W for 2 minutes. Immediate postinterventional contrast enhanced control scan (Fig. 2B) revealed an ablation area of 30 × 16 mm, exactly as planned and fully covering the initial lesion also providing an adequate safety margin. The inferior vena cava and the left portal vein were not affected.Fig. 2 Prior MWA 3D planning of the ablation area (A) allows the precise definition of a safety margin while sparing sensible vessel structures. Post interventional control (B) shows near perfect match between planned and treated tissue.\n\nFig. 2.\n\nThe 3- and 6-month follow-up Gadoxetate enhanced MRI showed expected postinterventional change with diminished intracellular uptake of the contrast agent (Fig. 3B) without any trace of residual tumor also considering MR sequences of contrast dynamic and diffusion-weighted imaging.Fig. 3 In the CT control scan after the ablation the lesion is fully covered leaving the adjacent left portal vein branch and a major liver vein unimpaired (A, asterisks). The access route via liver parenchyma is routinely treated with small energies during needle retraction to prevent spreading tumor cells. The coagulated access route is nicely seen in the control scan after the ablation (A, dotted arrows). Six-month follow-up MRA in hepatobiliary phase using Gadoxetate shows a slightly retracted scar in the caudate lobe.\n\nFig. 3.\n\nSystemic chemotherapy with Trastuzumab and Pertuzumab ended in April 2017 the patient is under single therapy with Trastuzumab until today.\n\nDiscussion\nEffectiveness of local ablation procedures depends on physical properties of the applied technique and on precise positioning of the probe within the lesion. Temperature of the target tissue is critical, which is influenced by tissue density, thermal conductivity, and loss of temperature due to tissue perfusion (so called heat-sink-effect). Heat is transmitted via a probe which can be placed percutanously or laparoscopically. For successful ablation the temperature should be homogenously raised to 50°C-60°C [5]. In RFA heat is generated by alternating current in the RF range of 200 Mhz-3 Ghz. Only few millimeters of tissue surrounding the tumor undergo active heating, most of the tissue is heated by conduction [6].\n\nIn our case, MWA is favorable because of the superior physical properties. MWA generates radiation between 900 Mhz and 2,4 Ghz [7] and in comparison to RFA, it is not susceptible to increasing impedance from ablated tissue and is not completely dependent on hydrated tissue [6]. In MWA more direct energy deposition is possible resulting in more uniform heating [8]. Furthermore, due to the close proximity to the vessels (portal vein and hepatic vein) a significant heat-sink effect was to expect. In MWA this effect is less evident and the proximity to large vessels is a contraindication for RFA [9]. MWA also seems to be more effective in preventing long term progression and local recurrences [10].\n\nThe use of the navigation system allowed to define a safe access route and a precise positioning of the tip of the probe as well as a predefinition of the expected areal of ablation depending on the applied energy and duration of ablation time. A contrast-enhanced control scan after the ablation procedure can be fused with the preinterventional imaging allowing a precise control of the ablation margins. Extensive surgery could be avoided, post-treatment complication rates are expected to be low [11].\n\nPercutaneous ablation techniques are a major advance in the treatment of liver tumors and can represent an excellent alternative treatment strategy in patients that are poor surgical candidates because of comorbidity or the underlying liver disease. Using a CT-based stereotactic navigation system seems technically feasible and safe and might offer minimal-invasive treatment options for conventionally unreachable tumor locations adjacent to sensible intra- and extrahepatic structures.\n\nStatements\nAll authors declare that they have no conflicts of interest.\n\nAppendix Supplementary materials\nImage, application 1 \n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.radcr.2018.10.010.\n==== Refs\nReferences\n1 Poston GJ Tait D O'Connell S Bennett A Berendse S Diagnosis and management of colorectal cancer: summary of NICE guidance BMJ 343 2011 d6751 22074710 \n2 Van Cutsem E Cervantes A Adam R Sobrero A Van Krieken JH Aderka D ESMO consensus guidelines for the management of patients with metastatic colorectal cancer Ann Oncol 27 8 2016 1386 1422 27380959 \n3 Schnapauff D Denecke T Grieser C Collettini F Seehofer D Sinn M Computed tomography-guided interstitial HDR brachytherapy (CT-HDRBT) of the liver in patients withirresectable intrahepatic cholangiocarcinoma Cardiovasc Intervent Radiol 35 3 2012 581 587 21833806 \n4 Engstrand J Toporek G Harbut P Jonas E Nilsson H Freedman J Stereotactic CT-guided percutaneous microwave ablation of liver tumors with the use of high-frequency jet ventilation: an accuracy and procedural safety study AJR Am J Roentgenol 208 2017 193 200 27762601 \n5 Vogl TJ Nour-Eldin NA Hammerstingl RM Panahi B Naguib NNN Microwave ablation (MWA): basics, technique and results in primary and metastatic liver neoplasms—review article RoFo 189 2017 1055 1066 28834968 \n6 Salati U Barry A Chou FY Ma R Liu DM State of the ablation nation: a review of ablative therapies for cure in the treatment of hepatocellular carcinoma Future Oncol 13 2017 1437 1448 28685607 \n7 Hoffmann R Rempp H Clasen S Microwave tumor ablation. New devices, new applications? Der Radiologe 52 2012 22 28 22249698 \n8 Yang D Converse MC Mahvi DM Webster JG Measurement and analysis of tissue temperature during microwave liver ablation IEEE Trans Bio-Med Eng 54 2007 150 155 \n9 Liang P Wang Y Yu X Dong B Malignant liver tumors: treatment with percutaneous microwave ablation–complications among cohort of 1136 patients Radiology 251 2009 933 940 19304921 \n10 Correa-Gallego C Fong Y Gonen M D’Angelica MI Allen PJ DeMatteo RP A retrospective comparison of microwave ablation vs. radiofrequency ablation for colorectal cancer hepatic metastases Ann Surg Oncol 21 13 2014 4278 4283 24889486 \n11 Song P Sheng L Sun Y An Y Guo Y Zhang Y The clinical utility and outcomes of microwave ablation for colorectal cancer liver metastases Oncotarget 8 2017 51792 51799 28881688\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "14(2)",
"journal": "Radiology case reports",
"keywords": "Computed tomography based navigation; Liver; Microwave ablation; Minimally-invasive treatment",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101467888",
"other_id": null,
"pages": "146-150",
"pmc": null,
"pmid": "30405865",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": "28881688;28834968;27762601;22249698;21833806;22074710;28685607;27380959;24889486;17260866;19304921",
"title": "CT-guided navigated microwave ablation (MWA) of an unfavorable located breast cancer metastasis in liver segment I.",
"title_normalized": "ct guided navigated microwave ablation mwa of an unfavorable located breast cancer metastasis in liver segment i"
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"companynumb": "CH-SA-2018SA318360",
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"patient": {
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"activesubstancename": "TRASTUZUMAB"
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"abstract": "Multiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut-off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1-15) and 14% of patients had received ≥10 prior lines of therapy. Fifty-three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9-10.3) months and median OS was 28.4 (95% CI 14.6-not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily-treated patients with relapsed/refractory MM, particularly the t(11;14) patient-population.",
"affiliations": "Haematology Department, Fiona Stanley Hospital, Perth, Western Australia, Australia.;College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematopathology, Mayo Clinic Rochester, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Sidiqi|M Hasib|MH|0000-0003-1089-3853;Al Saleh|Abdullah S|AS|0000-0003-1111-556X;Kumar|Shaji K|SK|0000-0001-5392-9284;Leung|Nelson|N|0000-0002-5651-1411;Jevremovic|Dragan|D|;Muchtar|Eli|E|0000-0003-2210-2174;Gonsalves|Wilson I|WI|0000-0001-6890-969X;Kourelis|Taxiarchis V|TV|0000-0001-8573-9434;Warsame|Rahma|R|0000-0003-0240-0326;Buadi|Francis K|FK|;Lacy|Martha Q|MQ|;Kyle|Robert A|RA|;Go|Ronald|R|;Hobbs|Miriam|M|;Dispenzieri|Angela|A|0000-0001-8780-9512;Dingli|David|D|;Hayman|Suzanne R|SR|;Gertz|Morie A|MA|0000-0002-3853-5196;Rajkumar|S Vincent|SV|0000-0002-5862-1833;Kapoor|Prashant|P|",
"chemical_list": "D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; D003907:Dexamethasone; C579720:venetoclax",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.26269",
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"issn_linking": "0361-8609",
"issue": "96(9)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003907:Dexamethasone; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D013449:Sulfonamides; D016896:Treatment Outcome",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "1131-1136",
"pmc": null,
"pmid": "34115387",
"pubdate": "2021-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Venetoclax for the treatment of multiple myeloma: Outcomes outside of clinical trials.",
"title_normalized": "venetoclax for the treatment of multiple myeloma outcomes outside of clinical trials"
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"companynumb": "US-AMGEN-USASP2021130592",
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"abstract": "Methadone is a synthetic μ-opioid receptor agonist that is used in the management of pain, neonatal abstinence withdrawal syndrome, and opioid dependence. Overdose can cause miosis, respiratory depression, and central nervous system depression. Rarely, hypoglycemia has been reported. We present the case of an 11-month-old male who developed hypoketotic, hyperinsulinemic, hypoglycemia after an acute, unintentional methadone exposure.\n\n\n\nThe patient was a previously healthy 11-month-old male who presented in respiratory failure. He was intubated and transferred to a large tertiary care center where his physical exam was notable for miosis. His labs were notable for a blood glucose of 17 mg/dL, an elevated insulin level, and suppressed serum beta-hydroxybutyrate. The patient was given a dextrose bolus with improvement in blood glucose. Administration of IV naloxone improved his miosis and mental status. A quantitative methadone level was sent upon arrival and was 123 ng/mL. Testing for ethanol, salicylates, sulfonylureas, and metabolic causes of hypoglycemia was negative. A fasting study showed euglycemia with suppression of insulin and appropriate ketosis. Case discussion: We present the case of an 11-month-old male who developed hypoketotic, hyperinsulinemic, hypoglycemia after an acute, unintentional methadone exposure. Alternative explanations for hypoketotic hypoglycemia were rule out. Methadone-induced hypoglycemia has been reported in cancer patients receiving methadone for pain, but a mechanism has not been identified. Based on this case, we believe that the patient's hypoglycemia was the result of methadone-induced insulin secretion.\n\n\n\nThis case proposes that hyperinsulinism is the mechanism responsible for methadone-associated hypoglycemia. Methadone exposure should be included in the differential diagnosis of new onset hypoglycemia.",
"affiliations": "a Harvard Medical Toxicology Program , Boston Children's Hospital , Boston , MA , USA.;b Division of Endocrinology, Department of Medicine , Boston Children's Hospital , Boston , MA , USA.;b Division of Endocrinology, Department of Medicine , Boston Children's Hospital , Boston , MA , USA.;a Harvard Medical Toxicology Program , Boston Children's Hospital , Boston , MA , USA.",
"authors": "Toce|Michael S|MS|0000-0002-7013-5432;Stefater|Margaret A|MA|;Breault|David T|DT|;Burns|Michele M|MM|",
"chemical_list": "D009270:Naloxone; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1338347",
"fulltext": null,
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"issn_linking": "1556-3650",
"issue": "56(1)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Pediatric; hyperinsulinism; opioid; overdose",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D006801:Humans; D007003:Hypoglycemia; D007223:Infant; D008297:Male; D008691:Methadone; D009270:Naloxone",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "74-76",
"pmc": null,
"pmid": "28650702",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "18671992;16175061;28114820;26087717;21436765;18331375;23669129;23467779;23709301;20132125;6991319;26342726",
"title": "A case report of methadone-associated hypoglycemia in an 11-month-old male.",
"title_normalized": "a case report of methadone associated hypoglycemia in an 11 month old male"
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-00291",
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"abstract": "We herein present the case of a 27-year-old woman with clinical and biochemical features of virilism. Imaging studies revealed the presence of a bilateral adrenal tumor. Although the secretion of androgens was remarkable, the autonomous production of cortisol was also evident because of a loss of circadian rhythm and the absence of cortisol suppression by dexamethasone. The surgical excision of both adrenal tumors was performed, and the histological examination showed no malignancy. We also report the successful pregnancy and delivery of the patient who showed evolving adrenocortical insufficiency along with virilization and Cushing's syndrome and who continued to receive glucocorticoid replacement therapy during pregnancy.",
"affiliations": "Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.;Departments of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Japan.;Departments of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Japan.;Departments of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Japan.;Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan.",
"authors": "Kobayashi|Toshihiro|T|;Imachi|Hitomi|H|;Sato|Seisuke|S|;Ibata|Tomohiro|T|;Fukunaga|Kensaku|K|;Yoshimoto|Takuo|T|;Kikuchi|Fumi|F|;Yonezaki|Kazuko|K|;Yamaji|Nao|N|;Lyu|Jingya|J|;Dong|Tao|T|;Nagata|Hiromi|H|;Kadota|Kyuichi|K|;Kushida|Yoshio|Y|;Haba|Reiji|R|;Murao|Koji|K|",
"chemical_list": "D006854:Hydrocortisone",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.0790-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3021010510.2169/internalmedicine.0790-18Case ReportBilateral Adrenocortical Adenomas along with Virilization and Cushing's Syndrome Kobayashi Toshihiro 1Imachi Hitomi 1Sato Seisuke 1Ibata Tomohiro 1Fukunaga Kensaku 1Yoshimoto Takuo 1Kikuchi Fumi 1Yonezaki Kazuko 1Yamaji Nao 1Lyu Jingya 1Dong Tao 1Nagata Hiromi 1Kadota Kyuichi 2Kushida Yoshio 2Haba Reiji 2Murao Koji 1\n1 Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Japan\n2 Departments of Diagnostic Pathology, Faculty of Medicine, Kagawa University, JapanCorrespondence to Dr. Toshihiro Kobayashi, koba1987@med.kagawa-u.ac.jp\n\n12 9 2018 1 2 2019 58 3 405 409 8 1 2018 8 7 2018 Copyright © 2019 by The Japanese Society of Internal Medicine2019The 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/).We herein present the case of a 27-year-old woman with clinical and biochemical features of virilism. Imaging studies revealed the presence of a bilateral adrenal tumor. Although the secretion of androgens was remarkable, the autonomous production of cortisol was also evident because of a loss of circadian rhythm and the absence of cortisol suppression by dexamethasone. The surgical excision of both adrenal tumors was performed, and the histological examination showed no malignancy. We also report the successful pregnancy and delivery of the patient who showed evolving adrenocortical insufficiency along with virilization and Cushing’s syndrome and who continued to receive glucocorticoid replacement therapy during pregnancy.\n\nadrenocortical adenomabilateralCushing's syndrome\n==== Body\nIntroduction\nCases of bilateral adrenal tumor along with virilism are extremely rare and can have several clinical manifestations (1). Adrenal virilism is a syndrome in which the excessive production of adrenal androgens causes virilization. A clinical diagnosis is confirmed based on elevated androgen levels. The symptoms include excess facial and body hair, deepening of the voice, baldness, acne, and increased muscularity and sex drive (2). To the best of our knowledge, there have only been two reported cases of bilateral adrenal tumors along with virilization (3,4). We herein report a case of bilateral virilizing tumors along with Cushing’s syndrome, and describe the successful pregnancy and delivery of the patient who showed evolving adrenocortical insufficiency due to bilateral adrenalectomy.\n\nCase Report\nA 27-year-old woman was admitted to our hospital due to progressive hirsutism and amenorrhea. Menarche occurred at 13 years of age. Her menstrual cycle had been regular until 22 years of age. She had visited a gynecologist at 25 years of age due to amenorrhea. At the time, hormone therapy was administered with estradiol and progesterone to treat the symptoms of amenorrhea. However, these symptoms did not improve. Upon admission to our hospital, a physical examination revealed a masculine appearance along with hirsutism and systemic pigmentation. She also had several clinical sings of Cushing’s syndrome, including moon face, buffalo hump and skin striae.\n\nHer laboratory data are shown in Table. The results of routine laboratory evaluations were normal. Her thyroid function and the levels of other pituitary hormones were normal. Her serum aldosterone and plasma renin activity were within the normal ranges. Her serum levels of testosterone, free testosterone, dehydroepiandrosterone sulfate, estrogen and 17-ketosteroid were markedly increased (Table). Her cortisol level was elevated (23.5 μg/dL), and her corticotrophin concentration was lower than detectable levels. The daily secretion pattern of cortisol did not exhibit a normal circadian rhythm. Both low-dose (1 mg) and high-dose (8 mg) dexamethasone overnight suppression tests revealed non-suppressed serum cortisol levels. The clinical diagnosis was Cushing’s syndrome with virilism.\n\nTable. The Summary of Laboratory Data.\n\nEndocrine\t\t\t\tReference\t\t\t\tCatecholamine (Plasma)\t\t\t\tReference\t\nCortisol(µg/dL)\t\t23.5\t\t4.5-21.1\t\t\t\tAdrenaline(pg/mL)\t\t5.0\t\t≤100\t\nU-17-OHCS(mg/day)\t\t7.9\t\t2.2-7.3\t\t\t\tDopamine(pg/mL)\t\t5.0\t\t≤30\t\nU-17-KS(mg/day)\t\t491.8\t\t2.4-11.0\t\t\t\t\t\t\t\t\t\nTestosterone(ng/mL)\t\t5.3\t\t0.06-0.80\t\t\t\tCatecholamine (Urine)\t\t\t\t\t\nFree testosterone(pg/mL)\t\t40.7\t\t0.4-2.3\t\t\t\tNoradrenaline(µg/day)\t\t37.0\t\t31.0-160.0\t\nDHEA-S(ng/mL)\t\t33,500\t\t180-3,910\t\t\t\tDopamine(µg/day)\t\t464.1\t\t280.0-1,100.0\t\n17α-OHP(ng/mL)\t\t6.2\t\t0.2-4.5\t\t\t\tVMA(mg/day)\t\t3.10\t\t1.50-4.90\t\nU-estrogen(mg/day)\t\t226\t\t0.005-0.02\t\t\t\t\t\t\t\t\t\nPregnanediol(mg/day)\t\t9.70\t\t0.28-6.83\t\t\t\tDEX 1mg suppression test\t\t\t\t\t\nPregnanetriol(mg/day)\t\t7.79\t\t0.13-1.90\t\t\t\tCortisol(µg/dL)\t\t21.9\t\t\t\nAldosterone(pg/mL)\t\t316.0\t\t29.9-158.8\t\t\t\tTestosterone(ng/mL)\t\t4.6\t\t\t\nPlasma renin activity(ng/mL/h)\t\t2.0\t\t0.2-2.3\t\t\t\tU-17-KS(mg/day)\t\t60.4\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\tDEX 8mg suppression test\t\t\t\t\t\n\t\t\t\t\t\t\t\tCortisol(µg/dL)\t\t20.9\t\t\t\n\t\t\t\t\t\t\t\tTestosterone(ng/mL)\t\t3.6\t\t\t\n\t\t\t\t\t\t\t\tU-17-KS(mg/day)\t\t472.0\t\t\t\n\t\t\t\t\t\t\t\tU-17-OHCS(mg/day)\t\t14.9\t\t\t\nAbdominal computed tomography (CT) showed bilateral homogeneous adrenal masses of 7 cm in diameter on the right side and 5 cm in diameter on the left side without calcification (Fig. 1a). These masses were homogeneously enhanced on contrast CT. The characteristics of the adrenal glands on CT was not consistent with autonomous, macronodular adrenal hyperplasia. This result was confirmed via magnetic resonance imaging (MRI) (Fig. 1b). MRI showed bilateral adrenal masses with low signal intensity on the T1-weighted imaging and high signal intensity on T2-weighted imaging. Moreover, out-of-phase MRI scan showed the homogeneous suppression of the fat-containing area of the tumor. No evidence of locoregional invasion or metastasis was observed. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) and 131I-iodocholesterol scintigraphy, but not iodinated metaiodobenzylguanidine (131I-MIBG), revealed a significant uptake of radiotracer in the bilateral adrenal tumors (Fig. 1c, d). Thus, a clinical diagnosis of bilateral adrenocortical tumor was made, and malignancy was also suspected.\n\nFigure 1. Abdominal CT (a) and MRI (b) showing bilateral adrenal tumors, 131I-iodocholesterol scintigraphy (c) and FDG-PET (d) revealing bilateral abdominal accumulation. (e) The right adrenal tumor: The tumor was a well-circumscribed mass, and showed alveolar nests and trabecular architecture. (f) The right adrenal tumor: Tumor cells had an eosinophilic and partially clear cytoplasm; some of them showed nuclear atypia.\n\nThe patient underwent bilateral adrenalectomy. The right and left adrenal tumors were 7 cm and 5 cm in diameter, respectively. Both tumors were well circumscribed and soft with a brown cut surface, and were sharply demarcated from the normal gland (Fig. 2). A gross examination revealed that the right adrenal tumor was 7.0 cm in diameter, which was considered to be the largest tumor measurement; the left tumor was 4.7 cm in diameter. Upon serial sectioning, both tumors were well circumscribed. Microscopically, the tumor cells of both tumors showed alveolar nest and trabecular architecture with eosinophilic and partially clear cytoplasm. Some of the tumor cells had nuclear atypia. However, we did not identify high mitotic activity, atypical mitotic figures, tumor necrosis, venous invasion, sinusoid invasion, or capsular invasion. An atrophic adrenal cortex was observed at the periphery of the tumors. Based on the Weiss criteria, these tumors were considered to represent adrenal cortical adenoma (Fig. 1e, f).\n\nFigure 2. The macroscopic appearance of the left adrenal tumor (a) (b) and the right adrenal tumor (c) (d).\n\nThe clinical data showed the over-secretion of cortisol and adrenal androgens from the tumors. Since 17α-hydroxylase (P450c17) is reported to be only be present in zona fasciculate and reticularis, leading to the production of cortisol and adrenal androgens, respectively (5), P450c17 was immunohistochemically analyzed. The tumors were mainly composed of compact cells with a pronounced P450c17 immunoreactivity, indicating the ability to synthesize glucocorticoids and androgens (Fig. 3).\n\nFigure 3. The expression of P450c17 in the left adrenal tumor tissue (a) and right adrenal tumor tissue (b).\n\nAfter the operation, the patient's serum ACTH (12 pg/mL), cortisol (20.9 μg/dL) and DHEA-S (135 ng/mL) levels (during glucocorticoid replacement therapy) were within normal ranges. The post-operative course of the patient was unremarkable, since she was on daily hormone replacement therapy (20 mg of hydrocortisone). The clinical signs of virilism progressively decreased. She subsequently achieved pregnancy at 33 years of age. Hydrocortisone replacement was continued during the pre-gestational period after increasing the dose by 1.5 times. She remained normotensive, and neither proteinuria nor glycosuria was observed during her pregnancy. At 38 weeks of gestation, she was given a stress dose of intravenous hydrocortisone (100 mg) before caesarean section, and hydrocortisone weaning was scheduled for infant delivery. No fetal or maternal complications were observed. The latest follow-up examination showed that the patient and her 6-year-old child were both mentally and physically healthy.\n\nDiscussion\nAdrenal virilism is the development or premature development of male secondary sexual characteristics caused by the excessive production of androgens by the adrenal gland. In children and infants, adrenal virilism is usually the result of adrenal gland enlargement at birth (referred to as congenital adrenal hyperplasia), which is associated with a disease-causing gene that promotes severe enzyme deficiency. In rare cases, adrenal virilism is caused by an adrenal gland tumor. The tumor can be benign (adrenal adenoma) or malignant (adrenal carcinoma) (6).\n\nAdrenal tumors are very common, accounting for 3-10% of the human population; most tumors are small benign nonfunctional adrenocortical adenoma (ACA). Adrenocortical cancer (ACC) is an extremely rare disease (1). In our case, CT of the abdomen revealed bilateral homogenous adrenal masses with of 7 cm and 5 cm in diameter on the right and left sides, respectively. Upon clinical presentation, ACC tumors are typically large, often measuring >6 cm in diameter (7). Moreover, the tumors in ACC tend to vary in appearance with frequent heterogeneous enhancement (e.g., internal hemorrhage, calcification, and necrosis. In our case and common ACC, CT and MRI showed the homogenous appearance of the tumors with/without enhancement. Based on PET imaging, ACC patients typically present with a large mass with an intense FDG uptake that is greater than the liver background. Groussin et al. reported that 18F-FDG-PET showed 100% sensitivity and 88% specificity in distinguishing benign lesions from malignant lesions in a study of 77 patients with a clinically proven diagnosis of ACA or ACC (8). In our case, the significant accumulation of [18F] FDG-PET was observed. Arlt et al. pointed out significant differences in the steroid hormone precursor and metabolite profiles of the urine of ACC patients in comparison to patients with benign adrenal tumors (9). However most of these metabolites are not routinely measured. In our case, the patient exhibited large bilateral adrenal tumors along with virilism and Cushing’s syndrome, and malignancy of the adrenal tumor was also suspected. However, the results of the pathological examination revealed adrenocortical adenoma, not carcinoma. To the best of our knowledge, there are only two other reported cases of bilateral ACC.\n\nAdrenal adenomas generally only secrete glucocorticoids. In contrast, androgen excess usually occurs in women with adrenal cancer or ACTH-stimulated hyperandrogenism (10). In our patient, however, the serum DHEAS levels (33500 ng/mL) were very high before surgery and below the normal range (135 ng/mL) after adrenalectomy. Adrenal cancer was ruled out using the Weiss score. An immunohistochemical analysis of the resected adrenal adenomas revealed the pronounced expression of P450c17. These enzymes are implicated in glucocorticoid and androgen production in the normal zona fasciculate and reticularis, suggesting the overproduction of glucocorticoids and androgens in bilateral adenomas. a finding consistent with the clinical endocrine data. As for ruling out ACTH-independent macronodular adrenocortical hyperplasia, the cut surface of the adenomas appeared reddish brown in color without multiple yellowish nodules; thus, the findings may not be compatible with a diagnosis of AIMAH.\n\nThe hypothalamic-pituitary-adrenal axis, which controls fertility, arterial blood pressure, hydroelectrolyte balance, and delivery, plays an important role during pregnancy. Untreated adrenocortical hypofunction increases maternal and fetal morbidity and mortality (11). In our case, the patient was normotensive and did not develop electrolyte imbalance at any stage in her pregnancy while under glucocorticoid therapy without mineralocorticoid therapy. Despite the absence of lethargy in our case, the hydrocortisone dose was increased by 1.5 times in the third trimester to catch up with the normally increasing serum cortisol levels as pregnancy progressed. We reported that pregnancy and delivery were successful in a patient with evolving adrenocortical insufficiency due to the treatment of bilateral adrenocortical adenomas along with virilization and Cushing’s syndrome, who continued glucocorticoid replacement therapy during pregnancy. This study may be helpful for patients with adrenal insufficiency who wish to have a successful pregnancy and delivery-although the optimal management of adrenal insufficiency during pregnancy and delivery has not been determined.\n\nIn conclusion, we herein described a unique case of bilateral adrenal adenomas along with virilization and Cushing’s syndrome.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Else T , Kim AC , Sabolch A , et al \nAdrenocortical carcinoma . Endocr Rev \n35 : 282 -326 , 2014 .24423978 \n2. Fassnacht M , Libé R , Kroiss M , Allolio B \nAdrenocortical carcinoma: a clinician's update . Nat Rev Endocrinol \n7 : 323 -335 , 2011 .21386792 \n3. Hintze G , Kobberling J , Becker HD , Helmchen U , Hoffmann W \nBilateral virilizing adrenal tumor in a 17-year-old woman . J Endocrinol Invest \n8 : 465 , 1985 .2934465 \n4. Delgrange E , Goethals P , Laka A , Maiter D , Lambert M \nAn unusual case of bilateral virilizing adrenal adenoma co-secreting androgens and cortisol . J Endocrinol Invest \n19 : 377 -381 , 1996 .8844458 \n5. Sasano H , Mason JI , Sasano N \nImmunohistochemical study of cytochrome P-45017 alpha in human adrenocortical disorders . Hum Pathol \n20 : 113 -117 , 1989 .2914700 \n6. Gabrilove JL , Seman AT , Sabet R , Mitty HA , Nicolis GL \nVirilizing adrenal adenoma with studies on the steroid content of the adrenal venous effluent and a review of the literature . Endocr Rev \n2 : 462 -470 , 1981 .6796401 \n7. Johnson PT , Horton KM , Fishman EK \nAdrenal mass imaging with multidetector CT: pathologic conditions, pearls, and pitfalls . Radiographics \n29 : 1333 -1351 , 2009 .19755599 \n8. Groussin L , Bonardel G , Silvéra S , et al \n18F-Fluorodeoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients . J Clin Endocrinol Metab \n94 : 1713 -1722 , 2009 .19190108 \n9. Arlt W , Biehl M , Taylor AE , et al \nUrine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors . J Clin Endocrinol Metab \n96 : 3775 -3784 , 2011 .21917861 \n10. Nieman L \nPitfalls in the diagnosis and differential diagnosis of Cushing's syndrome . Clin Endocrinol (Oxf) \n80 : 333 -334 , 2014 .24303816 \n11. de Corbière P , Ritzel K , Cazabat L , et al \nPregnancy in women previously treated for an adrenocortical carcinoma . J Clin Endocrinol Metab \n100 : 4604 -4611 , 2015 .26461265\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(3)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Cushing's syndrome; adrenocortical adenoma; bilateral",
"medline_ta": "Intern Med",
"mesh_terms": "D000306:Adrenal Cortex Neoplasms; D018246:Adrenocortical Adenoma; D000328:Adult; D002940:Circadian Rhythm; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D011247:Pregnancy; D014770:Virilism",
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"title": "Bilateral Adrenocortical Adenomas along with Virilization and Cushing's Syndrome.",
"title_normalized": "bilateral adrenocortical adenomas along with virilization and cushing s syndrome"
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"abstract": "Imatinib mesylate has dramatically improved the outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph* ALL) and is now included as first-line therapy. Uncommon adverse effects of this drug for pediatric use, however, are largely unknown. We report the first case of a 9-year-old child who developed severe acute hepatitis with grade 4 transaminases and bilirubin elevation during imatinib treatment for Ph* ALL. Liver biopsy showed extensive lobular and pericentral necrosis of hepatocytes. Liver function recovered after discontinuing imatinib with a 4-week prednisolone. Extensive hepatic necrosis should be considered not only in adults but also in children under imatinib administration.",
"affiliations": "*Department of Child Health, Graduate School of Comprehensive Human Sciences, University of Tsukuba Departments of †Child Health ‡Pathology, Faculty of Medicine §Clinical Laboratory, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.",
"authors": "Suzuki|Ryoko|R|;Kobayashi|Chie|C|;Sakai|Aiko|A|;Fukushima|Hiroko|H|;Tagawa|Manabu|M|;Satomi|Kaishi|K|;Nanmoku|Toru|T|;Sumazaki|Ryo|R|;Fukushima|Takashi|T|",
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"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001549:Benzamides; D002648:Child; D005260:Female; D006505:Hepatitis; D006801:Humans; D000068877:Imatinib Mesylate; D010677:Philadelphia Chromosome; D010879:Piperazines; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011239:Prednisolone; D011379:Prognosis; D011743:Pyrimidines",
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"title": "Imatinib-induced Severe Hepatitis in a 9-Year-old Girl With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.",
"title_normalized": "imatinib induced severe hepatitis in a 9 year old girl with philadelphia chromosome positive acute lymphoblastic leukemia"
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{
"abstract": "5-Aminosalicylic acid (5-ASA) nephrotoxicity is a rare and idiosyncratic condition in patients with inflammatory bowel disease (IBD), which may lead to end-stage kidney failure. Kidney function monitoring is recommended in clinical practice to prevent this complication. However, no data is available regarding the knowledge and adherence of patients with IBD to this monitoring.\n\n\n\nAs a part of routine practice, patients with IBD under treatment or previously treated with 5-ASA were systematically interviewed about knowledge of 5-ASA nephrotoxicity and adherence to kidney function monitoring. We reported here the experience among the first 103 consecutive patients seen in a French referral center.\n\n\n\nA total of 103 patients (93.2% ulcerative colitis, 5.8% Crohn's disease, and 1% unclassified colitis) were analyzed. Among them, 70% were informed about the need for kidney function monitoring, and in most cases, information was provided by their gastroenterologist (94.4%). The adherence rate to monitoring was very high (84.7%). Monitoring consisted of serum creatinine and estimated glomerular filtration rate in most cases (97.2%), while 24-h proteinuria was less frequently used (69.4%). These tests were performed twice or ≥3 times per year by 44.4 and 41.7% of patients, respectively. One case of isolated elevation of proteinuria related to 5-ASA treatment was observed.\n\n\n\nWe reported for the first time that patients with IBD are well informed and adherent to kidney function monitoring of treatment with 5-ASA. The monitoring performed by their treating physician was generally in accordance with current recommendations.",
"affiliations": "Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy.;Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy.;Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy.;Department of Biomedical Sciences, Humanitas University, Pieve Emanuele.;Inserm, CIC-1433 Clinical Epidemiology, University Hospital of Nancy, Université de Lorraine.;Inserm, CIC-1433 Clinical Epidemiology, University Hospital of Nancy, Université de Lorraine.;Inserm, CIC-1433 Clinical Epidemiology, University Hospital of Nancy, Université de Lorraine.;Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy.;Department of Nephrology and Inserm CIC-EC CIE6, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France.",
"authors": "Weislinger|Lucie|L|;Guillo|Lucas|L|;D'Amico|Ferdinando|F|;Danese|Silvio|S|;Achit|Hamza|H|;Ayav|Carole|C|;Guillemin|Francis|F|;Peyrin-Biroulet|Laurent|L|;Frimat|Luc|L|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000002008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "33(9)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D006801:Humans; D015212:Inflammatory Bowel Diseases; D007668:Kidney; D019804:Mesalamine; D051437:Renal Insufficiency",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "1148-1152",
"pmc": null,
"pmid": "33252416",
"pubdate": "2021-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Knowledge of 5-aminosalicylic acid nephrotoxicity and adherence to kidney function monitoring of patients with inflammatory bowel disease.",
"title_normalized": "knowledge of 5 aminosalicylic acid nephrotoxicity and adherence to kidney function monitoring of patients with inflammatory bowel disease"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-328672",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drug... |
{
"abstract": "A 71-year-old woman was operated on for undifferentiated lung adenocarcinoma. Four months after surgery, she developed bone and adrenal metastases. She underwent palliative radiation therapy of left scapula and right iliac bone. Thereafter, she started immune checkpoint inhibitor (ICI) therapy with anti-PD-1 antibodies achieving complete tumor response. Twenty months later, a follow-up 18F-FDG PET/CT confirmed tumor response and revealed high radiotracer accumulation in correspondence of retroperitoneal and subcutaneous fat opacities. The contiguous fasciae were mildly thickened. The temporal relation with ICI therapy together with tumor response and corticosteroids therapy effectiveness led to conclude for ICI-related adverse events.",
"affiliations": "From the Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, Messina, Italy.",
"authors": "Minutoli|Fabio|F|;Parisi|Silvana|S|;Laudicella|Riccardo|R|;Pergolizzi|Stefano|S|;Baldari|Sergio|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/RLU.0000000000003806",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-9762",
"issue": "47(1)",
"journal": "Clinical nuclear medicine",
"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": null,
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "e39-e40",
"pmc": null,
"pmid": "34269732",
"pubdate": "2022-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "18F-FDG PET/CT Imaging of Immune Checkpoint Inhibitor-Related \"Retroperitoneal Panniculitis\".",
"title_normalized": "18f fdg pet ct imaging of immune checkpoint inhibitor related retroperitoneal panniculitis"
} | [
{
"companynumb": "IT-009507513-2201ITA004012",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nIn patients with multiple myeloma, bendamustine monotherapy is effective as 1st and 2nd line therapy. However, data for patients with advanced multiple myeloma is rare.\n\n\nMETHODS\nIn this retrospective analysis we have identified 39 patients with relapsed or refractory multiple myeloma by means of case research, who have been treated at our institution with bendamustine as salvage therapy. After in median 2 lines of prior therapy (range: 1-5) patients received in median 3 (range: 1-10) cycles of bendamustine. Bendamustine dosage was 80-150 mg on day 1+2 of a monthly cycle. Bendamustine was administered as monotherapy in 39% of patients, whereas 61% received concomitant steroids.\n\n\nRESULTS\nToxicity was mild to moderate. Response rates were as follows: 3% vgPR, 33% PR, 18% MR, 26% SD and 20% PD. The median event-free and overall survival were 7 and 17 months, respectively.\n\n\nCONCLUSIONS\nIn conclusion, in patients with advanced multiple myeloma bendamustine is effective and associated with mild toxicity. Therefore, the role of bendamustine in patients with multiple myeloma should be investigated in further clinical trials.",
"affiliations": "Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Duesseldorf, Germany.",
"authors": "Michael|M|M|;Bruns|I|I|;Bölke|E|E|;Zohren|F|F|;Czibere|A|A|;Safaian|N N|NN|;Neumann|F|F|;Haas|R|R|;Kobbe|G|G|;Fenk|Roland|R|",
"chemical_list": "D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D000069461:Bendamustine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1186/2047-783x-15-1-13",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0949-2321",
"issue": "15(1)",
"journal": "European journal of medical research",
"keywords": null,
"medline_ta": "Eur J Med Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000069461:Bendamustine Hydrochloride; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009588:Nitrogen Mustard Compounds; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "9517857",
"other_id": null,
"pages": "13-9",
"pmc": null,
"pmid": "20159666",
"pubdate": "2010-01-29",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12170425;9753033;18032762;18182663;19541580;9081208;12170429;18673366;18783399;16835968;19001321;19258212;18282361;19224851;15958804;12170428;16154860;14695409;16402269;12170427;8826610;18282362;17653574;16098074;16445831;11368287;19380290;18752593;18067009;12736280",
"title": "Bendamustine in patients with relapsed or refractory multiple myeloma.",
"title_normalized": "bendamustine in patients with relapsed or refractory multiple myeloma"
} | [
{
"companynumb": "DE-TEVA-2020-DE-1832900",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Background: There is scanty guidance in the literature on the management of patients with glutamic acid decarboxylase (GAD65) antibody associated autoimmune epilepsy (GAD-epilepsy). GAD-epilepsy is a rare distinct neurological syndrome with a wide clinical spectrum. We describe six GAD-epilepsy patients with special emphasis on the treatment timing and the relationship between immunologic and anti-epileptic therapy. Methods: Six patients diagnosed with GAD-epilepsy in Tampere University Hospital who had received immunotherapy from 2013 to 2017 were retrospectively analyzed from patient records. Data about symptom onset, including antibody levels, magnetic resonance imaging (MRI), electroencephalograms, immunotherapy and anti-epileptic treatment timing and treatment responses were collected and analyzed. Kruskall-Wallis test was used in the statistical evaluation. Results: All patients were female aged 9-54 at symptom onset. Three had hypothyroidism, none had diabetes, two had migraine. Five patients had very high (>2,000 IU/ml) and one had high (52-251 IU/ml) GAD65 antibody titers. All patients presented with seizure disorders. Patients who received early initiation of immunotherapy (3-10 months) responded well to treatment; patients in whom the immunotherapy was started later (15-87 months) did not respond (p = 0.0495). The first patient was seizure-free after 1 year of regular intravenous immunoglobulin and one antiepileptic drug (AED). The second patient developed unilateral temporal lobe T2 signal changes in MRI; she responded well to immunotherapy, experiencing a significant reduction in seizure frequency and resolution of MRI abnormalities. However, seizures continued despite trials with several AEDs. The third patient responded well to immunoadsorption and rituximab with one AED, with lowering of GAD65 titers (from >2,000 to 300). There was a long delay in the diagnosis of GAD-epilepsy in the three patients who had developed refractory epilepsy, one with hippocampal sclerosis. They all received immunotherapy but none responded. However, AED modification or vagus nerve stimulation reduced the seizure frequency in two patients. Epilepsy surgery was ineffective. Conclusions: These results highlight the importance of early detection of GAD65 antibodies in refractory epilepsy as immunotherapy can be effective if administered in the early stages of the disease when it can prevent permanent brain tissue damage.",
"affiliations": "Department of Neurology, University of Tampere, Tampere University Hospital Tampere, Finland.;Department of Neurology, University of Tampere, Tampere University Hospital Tampere, Finland.;Department of Radiology, Medical Imaging Centre, Tampere University Hospital Tampere, Finland.;Department of Neurology, University of Tampere, Tampere University Hospital Tampere, Finland.",
"authors": "Mäkelä|Kari-Matti|KM|;Hietaharju|Aki|A|;Brander|Antti|A|;Peltola|Jukka|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2018.00579",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2018.00579NeurologyCase ReportClinical Management of Epilepsy With Glutamic Acid Decarboxylase Antibody Positivity: The Interplay Between Immunotherapy and Anti-epileptic Drugs Mäkelä Kari-Matti 1*Hietaharju Aki 1Brander Antti 2Peltola Jukka 11Department of Neurology, University of Tampere, Tampere University Hospital\nTampere, Finland2Department of Radiology, Medical Imaging Centre, Tampere University Hospital\nTampere, FinlandEdited by: Thomas Seifert-Held, Graz University Hospital, Austria\n\nReviewed by: Anna Fogdell-Hahn, Karolinska Institutet (KI), Sweden; Nico Melzer, Universität Münster, Germany\n\n*Correspondence: Kari-Matti Mäkelä karimatti.makela@gmail.comThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n13 7 2018 2018 9 57903 5 2018 26 6 2018 Copyright © 2018 Mäkelä, Hietaharju, Brander and Peltola.2018Mäkelä, Hietaharju, Brander and PeltolaThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: There is scanty guidance in the literature on the management of patients with glutamic acid decarboxylase (GAD65) antibody associated autoimmune epilepsy (GAD-epilepsy). GAD-epilepsy is a rare distinct neurological syndrome with a wide clinical spectrum. We describe six GAD-epilepsy patients with special emphasis on the treatment timing and the relationship between immunologic and anti-epileptic therapy.\n\nMethods: Six patients diagnosed with GAD-epilepsy in Tampere University Hospital who had received immunotherapy from 2013 to 2017 were retrospectively analyzed from patient records. Data about symptom onset, including antibody levels, magnetic resonance imaging (MRI), electroencephalograms, immunotherapy and anti-epileptic treatment timing and treatment responses were collected and analyzed. Kruskall-Wallis test was used in the statistical evaluation.\n\nResults: All patients were female aged 9–54 at symptom onset. Three had hypothyroidism, none had diabetes, two had migraine. Five patients had very high (>2,000 IU/ml) and one had high (52–251 IU/ml) GAD65 antibody titers. All patients presented with seizure disorders. Patients who received early initiation of immunotherapy (3–10 months) responded well to treatment; patients in whom the immunotherapy was started later (15–87 months) did not respond (p = 0.0495). The first patient was seizure-free after 1 year of regular intravenous immunoglobulin and one antiepileptic drug (AED). The second patient developed unilateral temporal lobe T2 signal changes in MRI; she responded well to immunotherapy, experiencing a significant reduction in seizure frequency and resolution of MRI abnormalities. However, seizures continued despite trials with several AEDs. The third patient responded well to immunoadsorption and rituximab with one AED, with lowering of GAD65 titers (from >2,000 to 300). There was a long delay in the diagnosis of GAD-epilepsy in the three patients who had developed refractory epilepsy, one with hippocampal sclerosis. They all received immunotherapy but none responded. However, AED modification or vagus nerve stimulation reduced the seizure frequency in two patients. Epilepsy surgery was ineffective.\n\nConclusions: These results highlight the importance of early detection of GAD65 antibodies in refractory epilepsy as immunotherapy can be effective if administered in the early stages of the disease when it can prevent permanent brain tissue damage.\n\nclinical managementglutamic acid decarboxylase antibodylimbic encephalitisautoimmune epilepsycase series\n==== Body\nIntroduction\nAutoimmunity is increasingly being recognized as a cause of epilepsy (1). Glutamic acid decarboxylase 65-kilodalton isoform (GAD65) antibodies have been associated with multiple non-neurological and neurological syndromes including autoimmune epilepsy (2).\n\nGAD65 is an intracellular antigen, highly expressed in the presynaptic terminals of inhibitory neurons in the central nervous system (CNS) and in pancreatic β-cells (3). GAD65 antibodies possibly serve as a surrogate marker for organ specific autoimmune disorders mediated by cytotoxic T cells (4). However, there might also be some currently unknown pathogenic surface-antigens targeted against hippocampi co-existing with the GAD65 antibody and contributing to temporal-lobe epilepsy (TLE) (5). Furthermore, the related pathological processes can lead to hippocampal sclerosis and refractory epilepsy (6). Moreover, widespread white matter changes have been observed in GAD65 antibody related limbic encephalitis (LE) (7).\n\nRecently, anti-neuronal antibodies were detected in 20.5% of epilepsies of unknown etiology and of these, 64% were high titer GAD65 antibodies (8). Previously, it has been estimated that between 1.7% (9) and 8.7% (10) of epilepsy patients are harboring GAD65 antibodies.\n\nGAD65 antibody associated autoimmune epilepsy (GAD-epilepsy) is a rare but distinct neurological syndrome with a wide clinical spectrum ranging from mild non-pharmacoresistant epilepsy (10) to refractory TLE (11), LE (12), and also extra-limbic encephalitis (ELE) (13). It seems that indolent GAD65 autoimmunity can develop into more severe forms over time (14).\n\nThe literature contains only a few case reports dealing with the management of refractory GAD-epilepsy (15). In addition to anti-epileptic drugs (AEDs), a plethora of immunotherapies has been tried with variable or unsatisfactory results (11, 15, 16). Overall, the response to immunotherapy is poor and only a few patients achieve seizure-freedom (17).\n\nSince there is no clear guidance in the literature with respect to the timing or on the combination of immunotherapy with AEDs in the management of GAD-epilepsy, here we describe six GAD-epilepsy cases treated with immunotherapy during different disease stages and compare the results of immunotherapy with those achieved by AEDs.\n\nMaterials and methods\nStudy cohort\nPatients treated in Tampere University Hospital Department of Neurology for GAD-epilepsy between the years 2012 and 2017 were studied. The clinical data was analyzed retrospectively from patient records. The initial diagnosis was suspected due to the clinical symptoms and then supported by highly elevated titers of serum GAD65 antibodies. Written informed consent was obtained from the participants for the publication of this case series.\n\nStatistics\nAll statistical calculations were done in R version 3.4.3 (www.r-project.org). Kruskall-Wallis test was used to compare treatment results in immunotherapy responders vs. non-responders.\n\nLaboratory and imaging studies\nGAD65 antibody levels were analyzed in Fimlab laboratories (Tampere, Finland) with standard clinical methods. In most patients, Euroimmun (Luebeck, Germany) anti-GAD ELISA (IgG) was used according to the manufacturer's protocol. Prior to 2014, the Medizym (Berlin, Germany) anti-GAD ELISA (IgG) was used according to the manufacturer's protocol. Most serum and cerebrospinal fluid (CSF) neuronal autoantibody panels were determined in Wieslab (Malmö, Sweden) with standard methods. In patient 1, CSF neuronal antibodies were analyzed in the Institut D'Investigacions Biomédiques August Pi I Sunyer, (Hospital Clinic, University of Barcelona, Spain). Other laboratory studies were undertaken with standard laboratory methods at Fimlab laboratories. Brain magnetic resonance images (MRI) were obtained according to a dedicated epilepsy protocol on a 3 Tesla scanner. Electroencephalograms (EEG) were obtained with standard protocols.\n\nTherapeutic interventions\nImmunotherapy, including immunoadsorption, was administered in all patients by following generally accepted clinical principles. Accordingly, AED treatment was provided to all patients in order to achieve maximum seizure control and tolerability. Selective amygdalo-hippocampectomy (SAH) and vagus nerve stimulator (VNS) were offered to some drug-resistant patients after they had undergone comprehensive pre-surgical diagnostics according to the current standards.\n\nTreatment outcomes\nOutcome variables were the seizure or other main symptom frequencies estimated from patient records such that an over 50% symptom reduction was considered as a good treatment response; changes in the GAD65 antibody titer levels were also determined.\n\nResults\nAll six patients were female aged 9–54 at symptom onset (Table 1) and presented with seizure disorders (Table 2). Patients 1–3 displayed a positive response whereas patients 4–6 exhibited a negative response to immunotherapy; in the former group, the mean delay from symptom onset to immunotherapy initiation was only 5.7 months (range = 3–10 months) whereas in the latter group, it was significantly longer, 66 months (range = 15–87 months) p = 0.0495.\n\nTable 1 Individual patient characteristics, serological and cerebrospinal fluid studies.\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\t\nAge at onset, years\t54\t19\t20\t9\t14\t16\t\nSex\tFemale\tFemale\tFemale\tFemale\tFemale\tFemale\t\nSymptom onset\t2014/2\t2012/7\t2014/6\t2007/12\t2011/3\t2014/1\t\nImmunotherapy initiated\t2014/5\t2013/5\t2014/10\t2015/3\t2012/6\t2016/3\t\nComorbidities\tHypothyroidism\tMigraine\tHypothyroidism, migraine\tHypothyroidism\t-\t-\t\nGAD65 ab, serum, IU/ml\t52–251\tover 2,000\tover 2,000\tover 2,000\tover 2,000\tover 2,000\t\nGAD65 ab, CSF\tNegative\tPositive\tNegative\tNegative\tPositive\tNot done\t\nSerum studies, positive\tTPO, VGKC (low), B2GP (low)*#£$%″\tAll negative¤$#+x\tAll negativeμ#−x&z\tICA (5120 IU/ml)*£#∧i\tANA*#£∧x&\tANA*#″c\t\nCSF studies, positive\tVGKC (low)*\tAll negative¤!\tAll negativeμ\tAll negative*\tAll negative*\tAll negative*\t\nCSF (WBC, protein, IgG-index, oligoclonal bands)\t1, 1443-923, elevated, no\t11-3, normal, elevated, yes\tAll normal\tNormal, normal, normal, yes\tNormal, elevated, elevated, yes\t6, normal, normal, yes\t\nThe individual laboratory studies are indicated with superscripts; only positive results are shown.\n\nab, antibody; aCL, anticardiolipin ab; ANA, anti-nuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; B2GP, Beta-2 Glycoprotein 1 Antibodies; caspr2, contactin-associated protein-like 2; CCP, cyclic citrullinated peptide ab; CSF, cerebrospinal fluid; C, complement; DNA, Deoxyribonucleic acid; ENA, Extractable nuclear antigen; GABA, gamma-aminobutyric acid; GAD65, Glutamic acid decarboxylase 65-kilodalton isoform; HbA1c, Hemoglobin A1c; HHV, Human herpesvirus; HIV, Human immunodeficiency virus; HSV-PCR, herpes simplex virus polymerase chain reaction; ICA, islet cell antibodies; LGI1, leucine-rich glioma inactivated 1; mGluR, metabotropic glutamate receptor; NMDA, N-Methyl-D-aspartate receptor; MPO, myeloperoxidase ab; PR3, anti-proteinase 3; RF, rheumatoid factor; RNP, ribonucleoprotein; SSA, anti-Sjögren's-syndrome-related antigen A; SSB, anti-Sjögren's-syndrome-related antigen B; TPO, thyroid peroxidase; TSH, thyreotropin; TTGA, Tissue transglutaminase ab; VGKC, voltage gated potassium channel; WBC, white blood cells;\n\n* AMPA-1, caspr2, GABA-B, LGI1, mGluR1, mGluR5, NMDA;\n\n# ampiphysin, ANA, ANCA, DNA, ENA\n\n$ borrelia, aCL, B2GP;\n\n£ CV2, Hu, Ma1, Ma2, Ri, Sox1, Yo;\n\n¤ NMDA,VGKC, AMPA-1, GABA-B, HHV-6;\n\nμ NMDA, VGCK;\n\n% HIV, 14-3-3;\n\n+ TTGA;\n\n− MPO;\n\n″ TPO;\n\n∧ RNP, SSA, SSB;\n\ni ICA\n\n! HSV-PCR;\n\nx C3, C4;\n\n& RF;\n\nz CCP, HbA1c, TSH, thyroxine;\n\nc cryoglobulin.\n\nTable 2 Seizure types, imaging studies, treatments, and treatment responses.\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\t\nSeizure types (18)\tNCSE\tFIAS\tFBTCS, FIAS, FAS\tFIAS\tFIAS\tFBTCS, FAS\t\nOther symptoms\tFast cognitive decline, vertigo, tremor, dystonia, aphasia, hallucinations.\tMemory defect, depression, vertigo.\tHeadache, cognitive impairment, tremor, anxiety, left sided weakness.\tCognitive slowing, nausea, depression.\tMemory problems, compulsive thoughts, fear, anxiety.\tEczema, joint symptoms.\t\nEpilepsy type\tFocal (onset unknown)\tFocal (bitemporal)\tFocal (temporal)\tFocal (bitemporal)\tFocal (bitemporal)\tFocal (multifocal)\t\nEEG\tDuring the SE episode slow wave discharges bilaterally with frontal maximum.\tIctally left or right temporal lobe discharges.\tInterictal normal, no ictal recordings.\tIctally left or right temporal lobe discharges.\tIctally left or right temporal lobe discharges.\tIctally left or right widespread discharges without definitive localizing features.\t\nMRI\tNormal\tLeft temporomesial T2 signal change which resolved after treatment.\tNormal\tNormal\tLeft hippocampal sclerosis.\tMarginal right hippocampal atrophy.\t\nImmunotherapies\tIVIg, MP, PR, RTX, MMF\tIVIg, MP, PR, MMF, RTX, IA\tIVIg, MP, IA, RTX\tIVIg, MP, IA, RTX\tIVIg, AZP, IA, RTX\tIVIg, HCQ\t\nCurrent AEDs\tLCM\tCBZ, LCM, LEV, ZNS\tTPM\tOCZ, ZNS\tAZM, LCM, ZNS\tECZ, LEV, OCZ\t\nPrior AEDs\tCBZ, LEV, LZP, PEH, TPM, VLP, CLB\tOCZ\t–\tLEV\tCBZ\tCBZ, CLB, LEV, OCZ, PRG, VLP\t\nEpilepsy surgery\tNo\tNo\tNo\tYes, left temporal lobe, no HS. VNS.\tYes, left temporal lobe, HS.\tNo\t\nTreatment response\tSymptom-free after 1 year with regular IVIG.\tGood response to IA, nevertheless refractory epilepsy.\tGood response to IA and RTX, however multiple relapses.\tNo response to late immunotherapy, response to VNS.\tNo response to late immunotherapy, surgery or AED.\tNo response to late immunotherapy, response to AED.\t\nAED, anti-epileptic drug; AZM, acetazolamide; AZP, azathioprine; CBZ, carbamazepine; CLB, clobazam; CP, Cyclophosphamide; ECZ, eslicarbazepine; EEG, Electroencephalography; FAS, Focal aware seizure; FBTCS, Focal to bilateral tonic–clonic seizure; FIAS, Focal impaired awareness seizure; HS, hippocampal sclerosis; HCQ, hydroxychloroquine; IA, immunoadsorption; IVIg, intravenous immunoglobulin; LCM, lacosamide; LEV, levetiracetam; LZP; lorazepam; MMF, mycophenolate mofetil; MP, methylprednisolone; MRI, Magnetic resonance imaging; NCSE, non-convulsive status epilepticus; OCZ, oxcarbazepine; PEH, phenytoin; PR, prednisolone; PRG, pregabalin; RTX, rituximab; TPM, topiramate; VNS, vagus nerve stimulation; VLP, sodium valproate; ZNS, zonisamide.\n\nA 54-year-old woman (patient 1; Figure 1A) presented in the emergency department with a few weeks' history of cognitive decline and fluctuating vertigo, aphasia and tremor. The neurological examination detected a fine tremor in all limbs and total aphasia. The EEG revealed non-convulsive status epilepticus (NCSE) without definitive lateralizing or localizing features and this was treated with intravenous immunoglobulin (IVIg) and IV AEDs. The NCSE resolved within 24 h. However, she experienced several relapses which mostly started with speech difficulties leading to total aphasia, confusion, anxiety, mild gait abnormality and tremor. NCSE relapsed three times and of these two were treated successfully with IVIg. One NCSE was successfully treated with propofol. Ultimately, the patient was suffering only a mild speech impairment and gait disturbance at the end of her immunotherapy cycle. Because of no relapses for 3 years with IVIg, the gradual reduction of dosage and increase of treatment interval is ongoing. The patient is still on AED monotherapy.\n\nFigure 1 Individual characteristics of treatment responses and therapies provided in the studied GAD-epilepsy patients are shown. X-axis shows the time-points in months starting from symptom onset. The blue line displays seizures / no seizures. Dotted lines refer to the interventions. Orange dots are GAD65 antibody levels. Discontinuation of therapies is shown in parenthesis. 4 wk means 4-week intervals. Patient 1 (A) responded well to early initiation of immunotherapy. With patient 2 (B), there was longer delay before immunotherapy and she continued to experience seizures even after several AED and immunotherapy trials. However, her MRI pathology resolved. Patient 3 (C) responded well to immunoadsorption with decreasing of GAD65 antibody levels after every trial. Patients 4–6 (D–F) did not respond to late immunotherapy. In patient 4, a vagus nerve stimulator ultimately reduced seizure levels. In patient 6, AED modification reduced her seizure levels. AED, antiepileptic drugs; AZM, acetazolamide; AZP, azathioprine; CBZ, carbamazepine; CLB, clobazam; CP, Cyclophosphamide; ECZ, eslicarbazepine; GAD65, Glutamic acid decarboxylase 65-kilodalton isoform; HCQ, hydroxychloroquine; IA, immunoadsorption; IVIG, intravenous immunoglobulin; LCM, lacosamide; LEV, levetiracetam; LZP; lorazepam; MMF, mycophenolate mofetil; MP, methylprednisolone; OCZ, oxcarbazepine; PEH, phenytoin; PR, prednisolone; RTX, rituximab; SAH, selective amygdalohippocampectomy; TPM, topiramate; VNS, vagus nerve stimulation: wk, week; VLP, sodium valproate; ZNS, zonisamide;.\n\nA 19-year-old woman (patient 2; Figure 1B) was brought to the emergency department with daily focal impaired awareness seizures (FIAS) (18, 19) and complaints of memory impairment. TLE was diagnosed and the patient was almost symptom-free for 6 months with one AED, experiencing only mild aura symptoms once a month. Her seizure frequency increased and a second AED was initiated but with no clear response. GAD-epilepsy was diagnosed during further examinations and her response to immunotherapy was dramatic, resulting in almost complete resolution of seizures. A follow-up MRI revealed a novel left temporomesial signal change and edema correlating with the EEG findings (Figure 2). In later follow-up MRIs after repeated immunotherapy, the signal changes had started to resolve and in due course, disappeared completely. A mild memory impairment was confirmed in the neuropsychological examination; this did not respond to immunotherapy. The patient continued to have only a few FIAS daily. Immunotherapy was eventually terminated since it did not provide any further reduction in her seizure activity and the MRI abnormalities had resolved. This caused neither increase in seizure frequency nor worsening of her condition. She is still experiencing regular FIAS and is being treated with four AEDs.\n\nFigure 2 (A) The coronal fluid attenuation inversion recovery (FLAIR) magnetic resonance (MRI) -image taken during the acute stage of the illness shows an abnormally hyperintense and swollen head of the left hippocampus (arrow). (B) Five months later, the finding has mostly resolved, although slight hyperintensity of the left hippocampal head can still be seen (arrow). (C) In a control image, 3 years and 8 months after the acute stage, the abnormal finding has totally resolved (arrow). There are no signs of atrophy in the primarily affected area.\n\nA 20-year-old woman (patient 3; Figure 1C) presented in the emergency department after focal to bilateral tonic-clonic seizures (FBTCS). On arrival, she had mild left sided weakness and aphasia which soon resolved and she was discharged. For a few weeks before the seizure, she had experienced mild cognitive symptoms, mainly confusion. Headache, left-sided weakness and the feelings of confusion relapsed without there being any seizures. GAD-epilepsy was diagnosed early and immunotherapy initiated to prevent worsening of the symptoms. AED was provided mainly for migraine prevention. There was no clear response to the initial immunotherapies and they had to be stopped due to adverse effects. The patient started to suffer anxiety and fear-like emotions after a second FBTCS. She was provided with secondary immunotherapy with immunoadsorption (IA) and there was clear resolution of symptoms and also a lowering of GAD65 antibody levels. However, she continued to experience focal unaware seizures (FAS) with mild right sided arm twitching and there was a return of the high GAD65 antibody titer levels; therefore, IA was repeated with a good response.\n\nA 9-year-old girl (patient 4; Figure 1D) presented with nausea, abdominal pain and excessive swallowing and TLE was diagnosed. She was symptom-free with one AED for 1 year until she started to have 40 FIAS on a monthly basis. Multiple AEDs and epilepsy surgery did not reduce her seizure frequency. High GAD65 antibody levels were detected when performing an extensive serology panel before VNS implantation 7 years after symptom onset. Since primary immunotherapy achieved no effects, secondary immunotherapy with IA and rituximab was tried but with no symptom relief and no effect on GAD65 antibody levels. Immunotherapy was discontinued and a VNS implanted, which when combined with two AEDs, achieved an initial response, i.e., the patient became seizure-free.\n\nA 14-year-old girl (patient 5; Figure 1E) presented with FIAS and TLE was diagnosed. Brain MRI revealed left hippocampal sclerosis. Multiple AEDs and epilepsy surgery did not reduce her seizure frequencies. GAD-epilepsy was diagnosed 15 months after symptom onset. She received primary immunotherapy but it offered no benefits. Some years later, IA and rituximab were tried but these neither eased her symptoms nor reduced her antibody levels. She is still experiencing regular FIAS despite therapy with three AEDs.\n\nA 16-year-old girl (patient 6; Figure 1F) presented with FBTCS, eczema and joint pain. Despite treatment with two AEDs, she continued to experience FIAS and high serum GAD65 antibody levels were detected 26 months after symptom onset. Primary immunotherapy had no effect on seizures and it was discontinued due to adverse effects. Hydroxychloroquine eased her joint symptoms and this therapy was continued but she still experienced FIAS. With AED modification, her seizure levels declined and thus secondary immunotherapy was not tried.\n\nDiscussion\nWe have described the clinical management of six patients with GAD-epilepsy. Three patients responded well to early immunotherapy initiated within 10 months after symptom onset and one patient's brain MRI abnormalities resolved after regular immunotherapy. Immunotherapy achieved no objective benefit in three patients who already had developed refractory epilepsy. Instead, AED modification or VNS implantation achieved better clinical results than immunotherapy in patients in whom the diagnosis of GAD-epilepsy had been delayed. Epilepsy surgery was ineffective in these patients.\n\nEven though the biological process is most likely a continuum, our results suggest that the clinical course of GAD-epilepsy forms three major stages. In the first stage, reversible acute immunoactivation causes the first seizure (20). In this stage, the main focus of management should be placed on immunotherapy since this can prevent permanent brain tissue damage and stop the epilepsy from becoming refractory, as was seen with patients 1 and 3. In the second stage of GAD-epilepsy, there is already subtle irreversible brain tissue damage (4), which causes refractory epilepsy (Patient 2). During the second stage, immunotherapy can still be highly effective as was seen with the resolution of brain MRI abnormalities in patient 2. However, it seems that after the resolution of the immunoactivation, the focus in management should shift to managing the refractory epilepsy. In the third stage, there has been progressive damage leading to hippocampal sclerosis and to a more diffuse brain damage and cognitive symptoms (7). In this stage, immunotherapy seems to be ineffective and the emphasis should be on the management of the refractory epilepsy.\n\nAll of the evidence surrounding the management of GAD-epilepsy has been based on small case reports and the treatment results have been variable (15). The patients in our study largely resemble previous study populations with a female sex predominance and young age. In patients with diabetes, GAD65 antibody titer levels of over 200 IU/ml are considered high (21). In GAD-epilepsy, both high and very high (over 1,000 IU/ml) GAD65 antibody titer levels have been detected (2) which is in accordance with the findings in our patients. CSF was abnormal in all but one of our patients. Especially patients 2 and 5 showed significant immunoactivation in the CSF. Malignancy is rarely associated with GAD-epilepsy (15) as was also shown in our data. Many GAD65 antibody positive patients harbor other autoantibodies indicative of polyautoimmunity (22). Accordingly, two of our patients had ANA and one harbored TPO-antibodies. GAD-epilepsy patients can also develop diabetes or other neurological GAD65 antibody associated syndromes (3) although this was not observed in our patients. Even in non-diabetic patients, the GAD65 antibody positivity is strongly associated with thyroid disease (23) which was also present in 50% of our patients. Patient 1 had low titer antibodies against the VGKC complex but tested negative for Caspr2 and LGI1. This finding is of uncertain clinical value (24). In our previous study, we did not detect the presence of VGKC antibodies in GAD-epilepsy patients (25).\n\nIn most case reports, IVIg and MP are the standard first line immunotherapies administered (11, 15, 26) in GAD-epilepsy as was the case with our patients. Some patients have benefited also from plasma exchange (PLEX) (26, 27). The effects of IVIg and immunoadsorption have been usually unsatisfactory. However, in many of these studies, there has been a long delay from symptom onset to treatment (11, 26). We used immunoadsorption successfully in patient 3. CSF-filtration has also been tried, however with a long delay from symptom onset (11). Second line therapy usually includes cyclophosphamide and rituximab (11, 26). We administered rituximab as second line therapy but not cyclophosphamide in view of its adverse effects in young female patients. Other immunosuppressive agents such as azathioprine and mycophenolate mofetil (MMF) have often been tried (11) with varying results, as also in our patients. Moreover, natalizumab has been tried to block T-cell entry into the CNS (11). In one case report, GAD-epilepsy was successfully managed with basiliximab (28); this was attributed to a reduction in the numbers of activated T-cells via interleukin-2 receptor blockade. Rituximab has an indirect inhibiting effect on pathogenic T-cells (29) which could in part explain its effect as the pathology of GAD-epilepsy seems to be mediated by cytotoxic T cells (4).\n\nIt is generally accepted that immunotherapy in GAD-epilepsy should be initiated as soon as possible (15), however there is no clear evidence defining when immunotherapy will no longer be effective. In many previous studies, there has been a long delay to diagnosis and immunotherapy initiation. For example, when there was a 4.5 (±0.4) year delay in immunotherapy, only every fifth patient showed any improvement (26). Furthermore, when the median disease duration was 18 months, it was reported that treatment results were poor (11).\n\nOur results suggest that one obtains optimal results when immunotherapy is initiated during the early stages of acute immunoactivation when no brain MRI changes are yet visible as was seen with patients 1 and 3. In some case reports it has been shown similarly that early initiation of immunotherapy provides complete seizure freedom (30). Thus, there is convincing evidence that early immunotherapy can be effective in the first stage of GAD-epilepsy.\n\nIn the second stage of GAD-epilepsy, there is already irreversible brain tissue damage causing refractory epilepsy as was observed in patient 2 and in many previous case series which have demonstrated a poor treatment response to immunotherapy (11). However, we could show that the already developed brain MRI abnormalities could be resolved after regular immunotherapy. In some case reports, immunotherapy has also achieved a similar resolution of the MRI abnormalities (16, 31). There is one case report describing the empirical initiation of MP, IVIg, plasmapheresis, rituximab and cyclophosphamide in refractory status epilepticus which later proved to be GAD-epilepsy (16). After 1 month, that patient was almost symptom-free with only occasional breakthrough seizures with regular rituximab infusions and 5 AEDs with resolution of the MRI abnormalities (16). This evidence is suggesting that even during the second stage of GAD-epilepsy, immunotherapy can reverse brain tissue damage and possibly prevent a more severe clinical course of GAD-epilepsy. However, in this stage, the management of GAD-epilepsy shifts from immunotherapy to managing the refractory epilepsy.\n\nIn third stage of GAD-epilepsy, there already has occurred permanent progressive damage, possibly hippocampal sclerosis and permanent cognitive symptoms. One of our patients with late GAD-epilepsy diagnosis had developed hippocampal sclerosis, as has often been shown before (6) as the cytotoxic process seems to initially involve limbic areas (4). Moreover, widespread white matter changes have been detected in GAD-LE (7) suggesting that there is also a more widespread pathology. Late immunotherapy in refractory GAD-epilepsy had little effect, which is in line with previous evidence (26). However, there is one case report which claimed that PLEX exerted a clear effect 7 years after symptom onset even though MP and IVIg had no effect (27) and in one study, basiliximab showed temporal resolution of seizures also 7 years after diagnosis (28). For these reasons, immunotherapy should be tried at least shortly, even in late GAD-epilepsy diagnosis.\n\nAED selection in GAD-epilepsy is undertaken according to the normal clinically accepted principles in attempts to achieve maximum seizure control and tolerability (15). Only a few GAD-epilepsy patients become seizure-free exclusively with AEDs (32). AEDs also have immunomodulatory effects which could in part explain their effect on the autoimmune epilepsies (32). All but one of our patients required multiple AEDs. However, after the symptoms were controlled with immunotherapy, some AEDs could be discontinued. Moreover, we recommend that when immunotherapy is no longer effective, it is advisable to concentrate on the management of epilepsy. One of our patients responded well to VNS which has not been shown previously in GAD-epilepsy patients. Epilepsy surgery was performed on two of our patients but it exerted no clear effect on seizure levels and this resembles the situation in other GAD-epilepsy patients (6). The better response to VNS than to epilepsy surgery might be because of the diffuse pathology in GAD-epilepsy (7). In all three of our refractory patients, however, the epileptic focus was eventually bilateral, pointing to an insidious continuing cytotoxic process. It seems that early immunotherapy can halt the destructive process and epilepsy surgery could be avoided.\n\nA clear limitation of our study is the low number of patients and the retrospective nature of the study design. However, GAD-epilepsy is a rare entity and large patient materials are difficult to obtain. Moreover, our patients showed varying symptoms. Previously only GAD-TLE or GAD-LE patients have been studied. In this study, we combined GAD-epilepsy patients with different presentations and also the diagnoses had been made with varying delays. However, this also shows that GAD-epilepsy should be suspected in many different clinical scenarios and we have provided new evidence on the timing of the treatments.\n\nIn conclusion, these results highlight the importance of early detection of GAD65 antibodies in refractory epilepsy as immunotherapy can be effective during the early stages of the disease and it can possibly prevent the development of permanent brain tissue damage.\n\nEthics statement\nA case report is a medical/educational activity that does not meet the DHHS definition of research, which is: a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Therefore, the activity does not have to be reviewed by a IRB.\n\nAuthor contributions\nK-MM, AH, AB, JP conceived and designed the study. K-MM, AH, AB, JP analyzed the data. AB analyzed MRI images. K-MM, AH, AB, JP wrote the paper.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Bauer J Becker AJ Elyaman W Peltola J Ruegg S Titulaer MJ . Innate and adaptive immunity in human epilepsies . Epilepsia (2017 ) 58 (Suppl. 3 ):57 –68 . 10.1111/epi.13784 28675562 \n2. Peltola J Kulmala P Isojarvi J Saiz A Latvala K Palmio J . Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy . Neurology (2000 ) 55 :46 –50 . 10.1212/WNL.55.1.46 10891904 \n3. McKeon A Tracy JA . GAD65 neurological autoimmunity . Muscle Nerve (2017 ) 56 :15 –27 . 10.1002/mus.25565 28063151 \n4. Bien CG Vincent A Barnett MH Becker AJ Blumcke I Graus F . Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis . Brain (2012 ) 135 :1622 –38 . 10.1093/brain/aws082 22539258 \n5. 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(2014 ) 108 :592 –6 . 10.1016/j.eplepsyres.2013.12.015 24447612 \n26. Hansen N Widman G Witt JA Wagner J Becker AJ Elger CE . Seizure control and cognitive improvement via immunotherapy in late onset epilepsy patients with paraneoplastic versus GAD65 autoantibody-associated limbic encephalitis . Epilepsy Behav (2016 ) 65 :18 –24 . 10.1016/j.yebeh.2016.10.016 27855355 \n27. Mazzi G Roia DD Cruciatti B Mata S Catapano R . Plasma exchange for anti GAD associated non paraneoplastic limbic encephalitis . Transfus Apher Sci. (2008 ) 39 :229 –33 . 10.1016/j.transci.2008.09.005 18955013 \n28. Widman G Golombeck K Hautzel H Gross CC Quesada CM Witt JA . Treating a GAD65 antibody-associated limbic encephalitis with basiliximab: a case study . Front Neurol. (2015 ) 6 :167 . 10.3389/fneur.2015.00167 26284025 \n29. Dalakas MC . B cells as therapeutic targets in autoimmune neurological disorders . Nat Clin Pract Neurol. (2008 ) 4 :557 –67 . 10.1038/ncpneuro0901 18813230 \n30. Incecik F Herguner OM Besen S Yilmaz M . Autoimmune encephalitis associated with glutamic acid decarboxylase antibodies: a case series . Acta Neurol Belg. (2018 ). 10.1007/s13760-018-0880-5 . [Epub ahead of print].\n31. Kobayakawa Y Tateishi T Kawamura N Doi H Ohyagi Y Kira J . A case of immune-mediated encephalopathy showing refractory epilepsy and extensive brain MRI lesions associated with anti-glutamic acid decarboxylase antibody . Rinsho Shinkeigaku (2010 ) 50 :92 –7 . 10.5692/clinicalneurol.50.92 20196490 \n32. Feyissa AM Lopez Chiriboga AS Britton JW . Antiepileptic drug therapy in patients with autoimmune epilepsy . Neurol Neuroimmunol Neuroinflamm. (2017 ) 4 :e353 . 10.1212/NXI.0000000000000353 28680914\n\n",
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"issue": "9()",
"journal": "Frontiers in neurology",
"keywords": "autoimmune epilepsy; case series; clinical management; glutamic acid decarboxylase antibody; limbic encephalitis",
"medline_ta": "Front Neurol",
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"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19817821;26749370;18813230;20437582;23464826;23998423;28234800;21620774;26161431;29433947;28276064;24447612;26216686;28166327;18955013;26878120;26157582;27855355;10891904;29349679;28063151;25867471;22353320;28276060;20196490;28680914;27573939;26420440;26284025;26906964;28675562;22539258",
"title": "Clinical Management of Epilepsy With Glutamic Acid Decarboxylase Antibody Positivity: The Interplay Between Immunotherapy and Anti-epileptic Drugs.",
"title_normalized": "clinical management of epilepsy with glutamic acid decarboxylase antibody positivity the interplay between immunotherapy and anti epileptic drugs"
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"abstract": "Voriconazole is the standard treatment for invasive aspergillosis but requires therapeutic drug monitoring to optimize therapy. We report two cases of central nervous system aspergillosis treated with voriconazole. Because of low trough plasma concentrations, we identified gain-of-function mutations in CYP2C19 that were partially responsible for the therapeutic failure of voriconazole. We suggest that systematic voriconazole pharmacogenomic investigation of cerebral aspergillosis be performed to avoid effective therapy delay in this life-threatening disease.",
"affiliations": "Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France.;Paris Descartes University, Hôpital Européen Georges Pompidou, Department of Pharmacology, AP-HP, Paris, France.;Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France.;Centre Hospitalier Universitaire de Nancy, Department of Infectious Diseases and Tropical Medicine, Nancy, France.;Hôpital Saint-Antoine, Department of Hematology and Cellular Therapy, AP-HP, Paris, France.;Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Intensive Care Unit, Paris, France.;Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France.;Paris Descartes University, Hôpital Européen Georges Pompidou, Department of Clinical Chemistry, AP-HP, Paris, France.;Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France.;Paris Descartes University, Necker-Enfants Malades University Hospital, Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, AP-HP, Paris, France olivier.lortholary@aphp.fr.",
"authors": "Danion|François|F|0000-0003-3907-0658;Jullien|Vincent|V|;Rouzaud|Claire|C|;Abdel Fattah|Manal|M|;Lapusan|Simona|S|;Guéry|Romain|R|;Bigé|Naïke|N|;Morgand|Marjolaine|M|;Pallet|Nicolas|N|;Lanternier|Fanny|F|;Lortholary|Olivier|O|",
"chemical_list": "D000935:Antifungal Agents; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole",
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"pmc": null,
"pmid": "29967027",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22890768;29544767;26775563;24379304;27981572;12167683;21131690;27165788;26684607;27365388",
"title": "Is It Time for Systematic Voriconazole Pharmacogenomic Investigation for Central Nervous System Aspergillosis?",
"title_normalized": "is it time for systematic voriconazole pharmacogenomic investigation for central nervous system aspergillosis"
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"companynumb": "FR-ACCORD-157511",
"fulfillexpeditecriteria": "1",
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"abstract": "Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC.\n\n\n\nPatients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles).\n\n\n\nA total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively.\n\n\n\nRadium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC.\n\n\n\nClinicalTrials.govNCT02023697.",
"affiliations": "Englander Institute for Precision Medicine, Weill Cornell Medical Center, New York, USA. Electronic address: cns9006@med.cornell.edu.;Montreal Cancer Institute, Montreal University Hospital Center (CHUM), Montreal, QC, Canada.;Knight Cancer Institute, Oregon Health and Science University and VA Portland Health Care System, Portland, USA.;Department of Oncology, Rambam Health Care Center, Haifa, Israel.;Department of Oncology, Wayne State University/Karmanos Cancer Institute, Detroit, USA.;Division of Nuclear Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.;Institute of Oncology, Rabin Medical Center-Davidoff Cancer Center, Petah Tikva, Israel.;Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia.;Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital, Sydney, Australia.;Department of Medicine, Monash University, Melbourne, Australia; Eastern Health, Melbourne, Australia.;Clinical Statistics Oncology, Bayer HealthCare Pharmaceutical Inc, Whippany, USA.;Global Clinical Development, Bayer Consumer Care AG, Basel, Switzerland.;Global Clinical Development, Bayer Consumer Care AG, Basel, Switzerland.;Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, USA.",
"authors": "Sternberg|C N|CN|;Saad|F|F|;Graff|J N|JN|;Peer|A|A|;Vaishampayan|U N|UN|;Leung|E|E|;Rosenbaum|E|E|;Gurney|H|H|;Epstein|R J|RJ|;Davis|I D|ID|;Wu|B|B|;Trandafir|L|L|;Wagner|V J|VJ|;Hussain|M|M|",
"chemical_list": "D011868:Radioisotopes; C000615150:Radium-223; D011883:Radium",
"country": "England",
"delete": false,
"doi": "10.1016/j.annonc.2019.10.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "31(2)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "bone metastases; mCRPC; radium-223 dose; safety; symptomatic skeletal events",
"medline_ta": "Ann Oncol",
"mesh_terms": "D001859:Bone Neoplasms; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D011868:Radioisotopes; D011883:Radium",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "257-265",
"pmc": null,
"pmid": "31959342",
"pubdate": "2020-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer.",
"title_normalized": "a randomised phase ii trial of three dosing regimens of radium 223 in patients with bone metastatic castration resistant prostate cancer"
} | [
{
"companynumb": "US-AMGEN-USASP2020021926",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
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"drugadditional": nul... |
{
"abstract": "Introduction: Palmoplantar pustular psoriasis (PPPP) is a debilitating inflammatory skin disorder of the palms and soles that poses a high burden on affected patients. Satisfactory treatment response is rarely achieved using current treatment options, little is known about the potential benefit of the PDE4 inhibitor apremilast in the treatment of refractory PPPP patients. We aimed to evaluate the use of apremilast in PPPP patients. Patients and Methods: Six patients, four with severe physician global assessment (PGA) = 3 on a scale of 0-4 and two with very severe (PGA = 4) treatment-refractory PPPP [mean age (years ± SD): 56.2 ± 15.6], were included in this study. Five patients had concomitant psoriatic arthritis (PsA). Prior to apremilast administration, topical corticosteroids, psoralen-UVA and multiple systemic oral and biologic anti-inflammatory treatments were insufficient to improve their skin condition or had to be discontinued due to adverse events. Apremilast (titrated to a maintenance dose of 30 mg 2x/d) was commenced in all patients with clinical follow-up over 18 months. Results: Within the first 4 weeks of treatment, each patient's symptoms improved as assessed by PGA score. At 3 months, four patients had a mild PGA score and two were cleared from PPPP. After 18 months of follow-up, three patients improved from PGA = 3 to PGA = 1 and one patient from PGA = 4 to PGA = 1. Two patients discontinued treatment, one due to a lack of efficacy against PsA and the other to a desire to have a child. However, both patients recorded improvements before discontinuing treatment. Conclusion: Apremilast may be a promising treatment option for refractory and severely affected PPPP patients. Our observation, however, requires further validation.",
"affiliations": "Department of Dermatology, University of Lübeck, Lübeck, Germany.;Department of Dermatology, University of Lübeck, Lübeck, Germany.;Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.;Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany.",
"authors": "Ständer|Sascha|S|;Syring|Felicia|F|;Ludwig|Ralf J|RJ|;Thaçi|Diamant|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2020.543944",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X Frontiers Media S.A. \n\n10.3389/fmed.2020.543944\nMedicine\nOriginal Research\nSuccessful Treatment of Refractory Palmoplantar Pustular Psoriasis With Apremilast: A Case Series\nStänder Sascha 1† Syring Felicia 1† Ludwig Ralf J. 2 Thaçi Diamant 3* 1Department of Dermatology, University of Lübeck, Lübeck, Germany\n2Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany\n3Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany\nEdited by: Peter Wolf, Medical University of Graz, Austria\n\nReviewed by: Igor Vujic, Wiener Krankenanstaltenverbund, Austria; Cristina Albanesi, Institute of Dermatology Immaculate (IRCCS), Italy\n\n*Correspondence: Diamant Thaçi diamant.thaci@uksh.deThis article was submitted to Dermatology, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work\n\n\n15 10 2020 \n2020 \n7 54394408 5 2020 03 9 2020 Copyright © 2020 Ständer, Syring, Ludwig and Thaçi.2020Ständer, Syring, Ludwig and ThaçiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction: Palmoplantar pustular psoriasis (PPPP) is a debilitating inflammatory skin disorder of the palms and soles that poses a high burden on affected patients. Satisfactory treatment response is rarely achieved using current treatment options, little is known about the potential benefit of the PDE4 inhibitor apremilast in the treatment of refractory PPPP patients. We aimed to evaluate the use of apremilast in PPPP patients.\n\nPatients and Methods: Six patients, four with severe physician global assessment (PGA) = 3 on a scale of 0–4 and two with very severe (PGA = 4) treatment-refractory PPPP [mean age (years ± SD): 56.2 ± 15.6], were included in this study. Five patients had concomitant psoriatic arthritis (PsA). Prior to apremilast administration, topical corticosteroids, psoralen-UVA and multiple systemic oral and biologic anti-inflammatory treatments were insufficient to improve their skin condition or had to be discontinued due to adverse events. Apremilast (titrated to a maintenance dose of 30 mg 2x/d) was commenced in all patients with clinical follow-up over 18 months.\n\nResults: Within the first 4 weeks of treatment, each patient's symptoms improved as assessed by PGA score. At 3 months, four patients had a mild PGA score and two were cleared from PPPP. After 18 months of follow-up, three patients improved from PGA = 3 to PGA = 1 and one patient from PGA = 4 to PGA = 1. Two patients discontinued treatment, one due to a lack of efficacy against PsA and the other to a desire to have a child. However, both patients recorded improvements before discontinuing treatment.\n\nConclusion: Apremilast may be a promising treatment option for refractory and severely affected PPPP patients. Our observation, however, requires further validation.\n\npsoriasisapremilastpustular palmoplantar psoriasistreatmentcase series\n==== Body\nIntroduction\nPalmoplantar pustular psoriasis (PPPP) is a chronic inflammatory IL-17/23-pathway- driven skin condition characterized by the development of sterile pustules on the palms and soles (1). The prevalence ranges from 0.01 to 0.05% in Western Europe and North America with slightly higher rates of ~0.12% in Japan. PPPP predominantly affects females who smoke and is associated with a relatively high rate of concomitant arthritis (2, 3). PPPP leads to debilitating skin conditions and significantly impaired quality of life. Additionally, PPPP patients report higher usage of potent topical anti-inflammatory treatment compared with patients with moderate-to-severe plaque-type psoriasis (4).\n\nDespite the debilitation effects of this disease, insights into the pathogenesis of PPPP are scant. Several studies indicate a dominant role of IL-17 and IL-22 in palmoplantar pustulosis (5, 6). Pathogenetic hallmarks of PPPP include increased cutaneous expression of IL-17A and, in contrast to psoriasis, lower IL-23 expression (7). Since the driving pathologic mechanisms of the disease are not well illuminated, treatment of PPPP is often challenging. Although medications used for the management of psoriasis vulgaris generally do not have regulatory approval for PPPP, they are often used in these patients due to limited treatment options. Current treatments for PPPP, based on low evidence levels and expert opinions, [e.g., phototherapy, cyclosporine A (CsA) and topical corticosteroids], result in remission in some patients (8). However, prolonged immunosuppression is required to maintain remission and relapses occur frequently. Additionally, treatment-related adverse events and morbidity further add to the patients' burden and to a reduced quality of life. Hence, investigation of novel effective and safe treatment options is highly warranted.\n\nApremilast is a small molecule oral phosphodiesterase (PDE) 4 inhibitor that has been approved for moderate-to-severe plaque psoriasis and psoriatic arthritis (9). On a molecular level, apremilast prevents cAMP hydrolysis which leads to increased intracellular cAMP levels and down-stream signaling with subsequent reduction of NF-kappa-B-dependent anti-inflammatory signaling (e.g., protein kinase A mediated release of IL-10) (10, 11). Randomized trials and real-world studies have recently documented the efficacy and safety of apremilast in psoriasis patients (12–15). While safety has been proven in numerous patients, the efficacy of apremilast in PPPP has not been well-studied and data on the use of apremilast in both treatment-refractory and treatment-naïve PPPP patients are scarce. Hence, to add further insight into the use of apremilast in PPPP patients, we retrospectively analyzed the effectiveness of apremilast administration in severe to very severe PPPP patients refractory to multiple prior topical and systemic treatments.\n\nPatients and Methods\nSix patients [mean age (years ± SD): 56.2 ± 15.6, four female, two male] with refractory PPPP [mean disease duration (years ± SD): 13.7 ± 10.6] were included. Four patients were observed for 18 months and two for 6 months. Data were analyzed retrospectively. Five patients had concurrent psoriatic arthritis (PsA). Diagnosis of PsA was based on the fulfillment of the CASPAR classification criteria and confirmed by our in-house rheumatologists. The patients' characteristics are summarized in Table 1. All six patients had been previously treated with locally applied highly potent glucocorticosteroids (GCs), partially under occlusion, psoralen-ultraviolet A (UVA), methotrexate (MTX) and at least four different systemic anti-inflammatory drugs prior to initiation of apremilast treatment. Most of the patients were treated with oral retinoids [acitretin (5/6) or alitretinoin (2/6)] (Table 2). Four patients received CsA and three were treated with biologics. In all individuals, the prior treatment had failed or was discontinued due to adverse effects. Apremilast treatment was commenced with an initially low and subsequently increasing dose until the maintenance dose of 30 mg 2x/d was reached. Clinical condition was scored by physician global assessment (PGA) as PGA = 0 [cleared (0 pustules)], PGA = 1 [mild (1–3 pustules)], PGA = 2 [moderate (3–10 pustules)], PGA = 3 [severe (10–20 pustules)], PGA = 4 [very severe (>20 pustules)] within a region effected by pustules e.g., palms or/and soles. Ethical approval was not required f or the retrospective analysis of these.\n\nTable 1 Characteristics of six treatment refractory PPPP patients treated with apremilast.\n\nCase\tAge (years)\tSex\tPGA at baseline\tPGA at follow-up endpoint\tFollow-up (months)\tDisease duration (years)\tSmoking history\tConcomitant disease\t\n1\t76\tFemale\t3\t1\t18\t33\tpositive\tPsA, fibromyalgia\t\n2\t56\tFemale\t4\t1\t18\t7\tnegative\tPsA, arterial hypertension, type II diabetes, depression, obesity\t\n3\t48\tMale\t3\t1\t18\t6\tpositive\tDepression, arterial hypertension\t\n4\t36\tFemale\t3\t0\t6\t12\tpositive\tPsA\t\n5\t73\tFemale\t3\t1\t18\t18\tpositive\tPsA, arterial hypertension, Hypothyreosis, Asthma\t\n6\t48\tMale\t4\t0 (soles) \n 1 (palms)\t6\t6\tpositive\tPsA, depression\t\nTable 2 Prior treatment before the treatment with apremilast.\n\nCase\tAcit\tAlit\tPUVA\tMTX\tCsA\tGCS\tAZA\tETN\tUST\tADA\tSEC\t\n1\tx\t\tx\tx\tx\t\t\t\t\t\t\t\n2\tx\t\tx\tx\tx\tx\t\tx\tx\tx\t\t\n3\tx\tx\tx\tx\t\t\t\t\t\t\t\t\n4\t\t\tx\tx\tx\tx\tx\t\t\t\tx\t\n5\tx\tx\tx\tx\t\tx\t\t\t\t\t\t\n6\tx\t\tx\tx\tx\tx\t\t\t\t\tx\t\nAcit, acitretin; Alit, alitretinoin; PUVA, psoralen-UVA; MTX, methotrexate; CsA, cyclosporine A; GCs, glucocorticosteroids; AZA, azathioprin UST, ustekinumab; ADA, adalimumab; SEC, secukinumab.\n\nResults\nAfter treatment initiation, the patients' skin condition improved within the first 4 weeks of treatment, from PGA = 4 in two cases and PGA = 3 in four cases to PGA = 1 in five cases and PGA = 2 in one case. After the 12-week follow- up visit, four patients had a PGA = 1 score and two had a PGA = 0 score. Four patients had a PGA = 1 score after 18 months, whereas two patients discontinued the drug after 6 months, one due to a lack of effect on joint involvement and the other due to the desire for children (Figure 1). In all six patients, adverse effects were mild and included tolerable gastrointestinal side effects (e.g., nausea, diarrhea) after the first oral apremilast doses. No severe adverse events under apremilast were observed.\n\nFigure 1 Improvement of pustular PGA at the end of observation time. Paired t-test p < 0.001.\n\nIn more detail, Patient 1 (75-year-old female) was diagnosed PPPP 33 years earlier. Concomitant diseases were PsA and fibromyalgia. Previous treatment of PPPP included systemic acitretin (20 mg/day) in combination with psoralen-UVA, MTX (15 mg/week s.c.), and CsA (3 mg/kg/bw). These treatments were not tolerated and were therefore discontinued. Five weeks after apremilast initiation, the patient's PsA improved substantially and her PPPP was scored as PGA = 1 after an initial PGA = 3 (Figure 2). At the follow-up visit after 5 months, the patient presented with a relapse of PPPP following discontinuation of apremilast 3 weeks before the visit (relapse experienced 2 weeks after discontinuation and 1 week before the visit). Several days after apremilast was re-administered, she achieved a score of PGA = 1 that remained stable at subsequent visits.\n\nFigure 2 Palms and soles of patient 1 with numerous pustules on scaled red skin at baseline (A–C) and after 5 weeks of apremilast treatment (D–F) with partial remission and reduced inflammation.\n\nPatient 2 (55-year-old female) was diagnosed with PPPP 7 years before presentation. Concomitantly, she suffered from PsA, arterial hypertension, depression, obesity and type II diabetes. Previous treatment with acitretin (30 mg/d), psoralen-UVA, CsA (300 mg/day), adalimumab, ustekinumab, and secukinumab did not improve the skin lesions. Due to adverse effects (e.g., infections), biologic treatments were discontinued. After apremilast initiation, the patient reported rapid subjective relieve of symptoms within several days. After 4 weeks, pustules decreased in number and size and disease activity improved from a PGA = 4 to a PGA = 2. After 3 months of treatment with apremilast and at all subsequent follow-up visits, the patient recorded a PGA = 1 (Figure 3).\n\nFigure 3 Left sole of patient 2 with numerous conflating pustules on inflamed skin at baseline (a) and after 12 weeks of apremilast treatment (b) with substantial decrease of inflammation and pustules.\n\nPatient 3 (54-year-old male) was diagnosed with PPPP 6 years earlier. Previous treatment included alitretinoin (30 mg/d), acitretin (50 mg/d), MTX (20 mg/week), and psoralen-UVA. None of these therapies was effective in inducing remission. The patient presented clinically with severe PPPP (PGA = 3). After apremilast initiation, the patient reported a significant subjective improvement of the skin within 10 days. However, the drug was discontinued due to a depressive episode after 4 months (no suicidal ideation) with a subsequent new onset of pustules within 2 days. After interdisciplinary psychiatric consultation, therapy with apremilast was reintroduced leading to major improvement of skin lesions within 1 week. The patient maintained a PGA = 1 at all following visits.\n\nPatient 4 (35-year-old female) was diagnosed with PPPP 12 years previously and had concomitant PsA. Previous treatments included oral GCs, psoralen-UVA, secukinumab, CsA (250 mg/d), azathioprine (dose not recalled), and MTX (20 mg/week s.c.). The patient suffered from severe skin involvement PGA = 3. Skin lesions improved within 2 weeks after apremilast initiation to PGA = 1. At the week 12 follow-up visit pustules on the palms and soles were observed to resolve completely (PGA = 0). However, apremilast was subsequently discontinued due to the patient's desire to have a child.\n\nPatient 5 (72-year-old female) was diagnosed with PPPP 18 years previously; she also had concomitant PsA. Previous therapies included oral GCs, MTX (25 mg/week), psoralen-UVA, alitretinoin (30 mg/d) and acitretin (25 mg/d). After initial paradoxical worsening of severe palmoplantar skin lesions to PGA = 3, improvement to PGA = 2 was observed after 4 weeks. At the next visit the patient recorded a PGA = 1 for the palms and PGA = 1–2 for the soles. The patient's skin condition remained stable at PGA = 1 for 18 months during ongoing apremilast treatment.\n\nPatient 6 (47-year-old male) was diagnosed with PPPP 6 years earlier and had concomitant PsA and depression. Previous treatment with acitretin (40 mg/d), psoralen-UVA, MTX (20 mg/week), CsA (up to 400 mg/d), oral corticosteroids GCs (up to 10 mg/d), and secukinumab (300 mg/month) were discontinued due to lack of efficacy and/or adverse effects. Due to highly painful joint involvement under the current therapy regimen, including combined secukinumab and CsA, the patient received prednisolone (10 mg/d) several weeks both before and initially during the first days of apremilast treatment. Four weeks after apremilast initiation, the patient reported clinical improvements to a PGA = 1. At the week 12 follow-up, disease activity decreased to PGA = 2 with five pustules on the palms. The soles displayed no pustules but slight desquamation on erythematous skin (PGA = 0). However, due to an exacerbation of PsA, apremilast was discontinued after 6 months in order to initiate TNF-alpha inhibitor treatment. At the time of apremilast discontinuation, the patient had cleared soles and a PGA = 1 of the palms. In all six patients, adverse effects were mild and included tolerable gastrointestinal side effects (e.g., nausea, diarrhea) after the first oral apremilast administrations. No severe adverse events under apremilast were observed.\n\nDiscussion\nTherapeutic approaches for PPPP have limited effectiveness and many patients remain refractory to all available agents; novel treatment options for this condition are greatly needed. Apremilast, a small-molecule PDE4-inhibitor, is a novel anti-inflammatory drug that has proven its efficacy in plaque type psoriasis and PsA over the past years, but has not been well-studied refractory PPPP. However, case reports have highlighted apremilast as an alternative in refractory and severe PPP patients. Controlled observations concerning the use of apremilast in PPPP, however, remain scant.\n\nBy inhibition of PDE4, apremilast increases intracellular cyclic AMP, which is an important second messenger in immune cells influencing inflammatory cascade (16). In PPPP, T-cells produce numerous cytokines, including TNF-a, IL-17, and IL-22, which stimulate keratinocytes to proliferate (17). Inhibition of proinflammatory cytokines such as IL-23 by apremilast decreases recruitment of Th1 and Th17 to the skin. In patients with moderate-to-severe psoriasis, treatment with apremilast was associated with significant reductions in plasma levels of interleukin (IL)-17F, IL-17A, IL-22, and TNF-α. Furthermore, PDE4 blockade inhibits neutrophil chemotaxis through decreased production of leukotriene B4 and IL-8 and prevents the migration of neutrophils to the epidermis (16). IL-36RN (receptor antagonist) gene mutation might play an important role in pustular forms of psoriasis like GPP (generalized pustular psoriasis) and acrodermatitis continua of Hallopeau. In contrast PPP seems not to be related to IL36 RN mutation and have a different pathogenesis from GPP (18). Since apremilast modulates both pro- and anti-inflammatory mediators it could explain in a part clinical efficacy in PPPP.\n\nOur case series adds to the body of evidence on the use of apremilast in PPPP. To our knowledge, this is the first cases series to describe the successful use of apremilast in six severe, treatment-refractory PPPP patients, five of whom had concomitant PsA, over a period of 18 months. All the patients improved during apremilast treatment and there were no reports of severe adverse events under treatment.\n\nThese observations seem to be a first promising hint toward the use of apremilast in severe and refractory PPPP. Our data support the initiation of larger, randomized, controlled studies of apremilast in both treatment-naïve and treatment-refractory PPPP patients.\n\nData Availability Statement\nAll datasets generated for this study are included in the article/supplementary material.\n\nEthics Statement\nEthical approval for this study was not required in accordance with local legislation and national guidelines, as the study describes routine care which does not require ethical approval. Written informed consent was obtained from all participants for the publication of any identifiable images or data in the article.\n\nAuthor Contributions\nDT designed the study. DT and FS treated and documented the patients. SS extracted all data from the electronic documentation. SS, FS, RL, and DT wrote the manuscript and contributed to the revision, read and approved the submitted version. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nRL has received honoraria and/or research grants from the following companies: Admirx, Almirall, Amryth, ArgenX, Biotest, Biogen, Euroimmun, Incyte, Immungenetics, Lilly, Novartis, UCB Pharma, Topadur, True North Therapeutics, and Tx Cell. DT has received honoraria or fees for serving on advisory boards, acting as a speaker, or as a consultant, from AbbVie, Amgen, Almirall, Beiersdorf, Bioskin, Biogen, Boehringer Ingelheim, Celgene, Galapagos, GlaxoSmithKline, Dignity-Science, Leo Pharma, Medac, Merck Sharp & Dohme, Morphosys, Lilly, Novartis, Janssen, Pfizer, Regeneron, Sanofi, Samsung, Sandoz, Hexal, Sun Pharmaceuticals, UCB; and has received grants from Celgene and Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. This research was supported by the German Research Foundation (DFG) under Germanys Excellence Strategy-EXC 2167-390884018 Precision Medicine in Chronic Inflammation to DT and RL.\n==== Refs\nReferences\n1. Bissonnette R Fuentes-Duculan J Mashiko S Li X Bonifacio KM Cueto I . Palmoplantar pustular psoriasis (PPPP) is characterized by activation of the IL-17A pathway\n. J Dermatol Sci. (2017 ) 85 :20 –6\n. 10.1016/j.jdermsci.2016.09.019 27743912 \n2. Brunasso AM Puntoni M Aberer W Delfino C Fancelli L Massone C . Clinical and epidemiological comparison of patients affected by palmoplantar plaque psoriasis and palmoplantar pustulosis: a case series study\n. Br J Dermatol. (2013 ) 168 :1243 –51\n. 10.1111/bjd.12223 23301847 \n3. Kubota K Kamijima Y Sato T Ooba N Koide D Iizuka H . Epidemiology of psoriasis and palmoplantar pustulosis: a nationwide study using the Japanese national claims database\n. BMJ Open. (2015 ) 5 :e006450 . 10.1136/bmjopen-2014-006450 25588781 \n4. Chung J Duffin KC Takeshita J Shin DB Krueger GG Robertson AD . Palmoplantar psoriasis is associated with greater impairment of health-related quality of life compared with moderate to severe plaque psoriasis\n. J Am Acad Dermatol. (2014 ) 71 :623 –32\n. 10.1016/j.jaad.2014.04.063 24894455 \n5. Murakami M Hagforsen E Morhenn V Ishida-Yamamoto A Iizuka H . Patients with palmoplantar pustulosis have increased IL-17 and IL-22 levels both in the lesion and serum\n. Exp Dermatol. (2011 ) 20 :845 –7\n. 10.1111/j.1600-0625.2011.01325.x 21732985 \n6. Hagforsen E Hedstrand H Nyberg F Michaëlsson G . Novel findings of Langerhans cells and interleukin-17 expression in relation to the acrosyringium and pustule in palmoplantar pustulosis\n. Br J Dermatol. (2010 ) 163 :572 –9\n. 10.1111/j.1365-2133.2010.09819.x 20426778 \n7. Bissonnette R Nigen S Langley RG Lynde CW Tan J Fuentes-Duculan J \nIncreased expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled trial\n. J Eur Acad Dermatol Venereol. (2014 ) 28 :1298 –305\n. 10.1111/jdv.12272 24112799 \n8. Sevrain M Richard MA Barnetche T Rouzaud M Villani AP Paul C \nTreatment for palmoplantar pustular psoriasis: systematic literature review, evidence-based recommendations and expert opinion\n. J Eur Acad Dermatol Venereol JEADV 28 Suppl. (2014 ) 5 :13 –6\n. 10.1111/jdv.12561 \n9. Keating GM . Apremilast: a review in psoriasis and psoriatic arthritis\n. Drugs. (2017 ) 77 :459 –72\n. 10.1007/s40265-017-0709-1 28213862 \n10. Schafer PH Parton A Capone L Cedzik D Brady H Evans JF . Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity\n. Cell Signal. (2014 ) 26 :2016 –29\n. 10.1016/j.cellsig.2014.05.014 24882690 \n11. Schafer P . Apremilast mechanism of action and application to psoriasis and psoriatic arthritis\n. Biochem Pharmacol. (2012 ) 83 :1583 –90\n. 10.1016/j.bcp.2012.01.001 22257911 \n12. Vujic I Herman R Sanlorenzo M Posch C Monshi B Rappersberger K . Apremilast in psoriasis - a prospective real-world study\n. J Eur Acad Dermatol Venereol. (2018 ) 32 :254 –9\n. 10.1111/jdv.14598 28925560 \n13. Reich K Gooderham M Bewley A Green L Soung J Petric R \nSafety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment: findings from the LIBERATE study\n. J Eur Acad Dermatol Venereol. (2018 ) 32 :397 –402\n. 10.1111/jdv.14738 29220542 \n14. Crowley J Thaçi D Joly P Peris K Papp KA Goncalves J . Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2)\n. J Am Acad Dermatol. (2017 ) 77 :310 –7\n.e1. 10.1016/j.jaad.2017.01.052 28416342 \n15. Papadavid E Rompoti N Theodoropoulos K Kokkalis G Rigopoulos D . Real-world data on the efficacy and safety of apremilast in patients with moderate-to-severe plaque psoriasis\n. J Eur Acad Dermatol Venereol. (2018 ) 32 :1173 –9\n. 10.1111/jdv.14832 29388335 \n16. Schafer PH Parton A Gandhi AK Capone L Adams M Wu L . Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis\n. Br J Pharmacol. (2010 ) 159 :842 –55\n. 10.1111/j.1476-5381.2009.00559.x 20050849 \n17. Murakami M Terui T . Palmoplantar pustulosis: current understanding of disease definition and pathomechanism\n. J Dermatol Sci. (2020 ) 98 :13 –9\n. 10.1016/j.jdermsci.2020.03.003 32201085 \n18. Mössner R Frambach Y Wilsmann-Theis D Löhr S Jacobi A Weyergraf A . Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-of-function mutations in IL36RN in European patients\n. J Invest Dermatol. (2015 ) 135 :2538 –41\n. 10.1038/jid.2015.186 \n25989471\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "7()",
"journal": "Frontiers in medicine",
"keywords": "apremilast; case series; psoriasis; pustular palmoplantar psoriasis; treatment",
"medline_ta": "Front Med (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101648047",
"other_id": null,
"pages": "543944",
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"pmid": "33178709",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
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"title": "Successful Treatment of Refractory Palmoplantar Pustular Psoriasis With Apremilast: A Case Series.",
"title_normalized": "successful treatment of refractory palmoplantar pustular psoriasis with apremilast a case series"
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"abstract": "BACKGROUND\nIntrauterine fetal demise due to fetal vascular malperfusion in mid-gestation is a rare occurrence. Abnormally long and hypercoiled umbilical cords are associated with an increased risk of umbilical cord blood flow restriction, which in turn can result in adverse perinatal and maternal outcomes. The factors that regulate umbilical cord development, specifically umbilical cord length and coiling, are poorly understood.\n\n\nMETHODS\nMaternal history, along with fetal and placental findings (post-mortem, pathological, and molecular), were reviewed for a series of 3 consecutive pregnancies that ended in second trimester intrauterine fetal demise.\n\n\nRESULTS\nAll 3 umbilical cords were exceptionally long and hypercoiled, and all placentas showed evidence of high-grade fetal vascular malperfusion. At fetopsy, all 3 fetuses were developmentally normal for gestational age and lacked congenital anomalies. Maternal medical history and antenatal testing (including an extensive work-up for maternal hypercoagulability syndromes) were normal and/or noncontributory.\n\n\nCONCLUSIONS\nAlthough excessively long and hypercoiled cords are generally thought of as sporadic, nongenetic events, rare examples of recurrent intrauterine fetal demise secondary to such exist have been reported. This intrafamilial clustering of a rare event is suggestive that at least a subset of hypercoiled, long umbilical cords may have an underlying genetic etiology.",
"affiliations": "Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada.;Department of Pathology, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.",
"authors": "Slack|Jonathan C|JC|;Boyd|Theonia K|TK|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1177/1093526620962061",
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"issue": "24(1)",
"journal": "Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society",
"keywords": "avascular villi; fetal vascular malperfusion; hypercoiled umbilical cord; long umbilical cord; placenta; stem vessel obliteration; villous-stromal karyorrhexis",
"medline_ta": "Pediatr Dev Pathol",
"mesh_terms": "D000328:Adult; D005260:Female; D005313:Fetal Death; D005333:Fetus; D005865:Gestational Age; D006801:Humans; D010920:Placenta; D021041:Placental Circulation; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D012008:Recurrence; D012039:Regional Blood Flow; D014470:Umbilical Cord",
"nlm_unique_id": "9809673",
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"pages": "12-18",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Fetal Vascular Malperfusion Due To Long and Hypercoiled Umbilical Cords Resulting in Recurrent Second Trimester Pregnancy Loss: A Case Series and Literature Review.",
"title_normalized": "fetal vascular malperfusion due to long and hypercoiled umbilical cords resulting in recurrent second trimester pregnancy loss a case series and literature review"
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"abstract": "OBJECTIVE\nDespite the known significant drug-drug interaction between isavuconazole and tacrolimus, there are no recommendations on dose adjustment when these drugs are given concomitantly. We report on a patient with a mediastinal Aspergillus fumigatus infection resistant to posaconazole and describe how she was successfully managed with tacrolimus therapeutic drug-level monitoring.\n\n\nMETHODS\nOur patient presented with a mediastial Aspergillus fumigatus infection, 2 years after lung transplantation. A. fumigatus was resistant to posaconazole, and the patient had intolerance to voriconazole shown by elevated transaminases. The patient was given isavuconazole with drug-level monitoring. She was managed successfully with no adverse events. Tacrolimus concentration continued to increase after more than 2 weeks of therapy and required a further reduction to 72% of the usual dose to maintain the target concentrations over a 8-week period.\n\n\nCONCLUSIONS\nWhen isavuconazole is given to patients on tacrolimus, the dose of the latter will need considerable reduction. We would suggest an initial 50% reduction and recommend close weekly monitoring of tacrolimus concentration. Further dose decreases of 25-50% may be required.",
"affiliations": "Pharmacy Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.;Office of Safety and Epidemiology, US Food and Drug Administration, Silver Spring, MD, USA.;Pharmacy Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.;Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.",
"authors": "Kim|T|T|;Jancel|T|T|;Kumar|P|P|;Freeman|A F|AF|",
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"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12308",
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"issue": "40(5)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "drug-drug interaction; new antifungal agent; therapeutic drug monitoring",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "609-611",
"pmc": null,
"pmid": "26248976",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports",
"references": "20653361;19190525",
"title": "Drug-drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring.",
"title_normalized": "drug drug interaction between isavuconazole and tacrolimus a case report indicating the need for tacrolimus drug level monitoring"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2015SP001128",
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"abstract": "BACKGROUND\nChronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of a derivative chromosome 22 [der(22)] commonly called Philadelphia chromosome (Ph). The Ph chromosome is a product of the reciprocal translocation t(9;22)(q34.1;q11.2). Additional genetic changes occur in less than 10 % of CML cases at the time of diagnosis and other genetic changes are seen in 60-80 % of the cases in advanced disease. Even though deletions in chromosome 9 are not rare findings in advanced phase-CML, del(9)(p23p11.1) as sole additional abnormality detected by fluorescence in situ hybridization (FISH) technique, to our knowledge has not been described in the literature.\n\n\nRESULTS\nA complete cytogenetic and molecular cytogenetic analysis, molecular biology method (reverse transcription polymerase chain reaction (RT-PCR)), and immunophenotype confirmed to be a CML case in blast crisis (BC). It revealed del(9)(p23p11.1) as sole abnormality detected by FISH technique besides Ph chromosome, which leads to monoallely of tumor suppressor gene CDKN2A (cyclin-dependent kinase inhibitor 2A) before Imatinib mesylate (IM) treatment.\n\n\nCONCLUSIONS\nThe patient did not demonstrate a good response to IM treatment. The underlying mechanisms and prognostic implications of these cytogenetic abnormalities are discussed.",
"affiliations": "Department of Molecular Biology and Biotechnology, Human Genetics Division, Atomic Energy Commission, P.O. Box 6091, Damascus, Syria.;Department of Molecular Biology and Biotechnology, Human Genetics Division, Atomic Energy Commission, P.O. Box 6091, Damascus, Syria.;Department of Molecular Biology and Biotechnology, Mammalians Biology Division, Atomic Energy Commission, Damascus, Syria.;Institute of Human Genetics, Jena University Hospital, Jena, Germany.;Department of Molecular Biology and Biotechnology, Human Genetics Division, Atomic Energy Commission, P.O. Box 6091, Damascus, Syria.",
"authors": "Wafa|Abdulsamad|A|;Asa'ad|Manar|M|;Ikhtiar|Adnan|A|;Liehr|Thomas|T|;Al-Achkar|Walid|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13039-015-0165-0",
"fulltext": "\n==== Front\nMol CytogenetMol CytogenetMolecular Cytogenetics1755-8166BioMed Central London 16510.1186/s13039-015-0165-0Case ReportDeletion 9p23 to 9p11.1 as sole additional abnormality in a Philadelphia positive chronic myeloid leukemia in blast crisis: a rare event Wafa Abdulsamad Asa’ad Manar Ikhtiar Adnan Liehr Thomas Al-Achkar Walid 00963-11-2132580ascientific@aec.org.sy Department of Molecular Biology and Biotechnology, Human Genetics Division, Atomic Energy Commission, P.O. Box 6091, Damascus, Syria Department of Molecular Biology and Biotechnology, Mammalians Biology Division, Atomic Energy Commission, Damascus, Syria Institute of Human Genetics, Jena University Hospital, Jena, Germany 4 8 2015 4 8 2015 2015 8 5915 4 2015 18 7 2015 © Wafa et al. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nChronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of a derivative chromosome 22 [der(22)] commonly called Philadelphia chromosome (Ph). The Ph chromosome is a product of the reciprocal translocation t(9;22)(q34.1;q11.2). Additional genetic changes occur in less than 10 % of CML cases at the time of diagnosis and other genetic changes are seen in 60–80 % of the cases in advanced disease. Even though deletions in chromosome 9 are not rare findings in advanced phase-CML, del(9)(p23p11.1) as sole additional abnormality detected by fluorescence in situ hybridization (FISH) technique, to our knowledge has not been described in the literature.\n\nResults\nA complete cytogenetic and molecular cytogenetic analysis, molecular biology method (reverse transcription polymerase chain reaction (RT-PCR)), and immunophenotype confirmed to be a CML case in blast crisis (BC). It revealed del(9)(p23p11.1) as sole abnormality detected by FISH technique besides Ph chromosome, which leads to monoallely of tumor suppressor gene CDKN2A (cyclin-dependent kinase inhibitor 2A) before Imatinib mesylate (IM) treatment.\n\nConclusions\nThe patient did not demonstrate a good response to IM treatment. The underlying mechanisms and prognostic implications of these cytogenetic abnormalities are discussed.\n\nKeywords\nChronic myeloid leukemiaPhiladelphia chromosomedel(9)(p24p12)CDKN2A genePrognostic factorsissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nChronic myeloid leukemia (CML) is a myeloproliferative disorder. It is mainly characterized by the presence of a derivative chromosome 22 [der(22)], the so-called Philadelphia chromosome (Ph), which is due to a reciprocal translocation t(9;22)(q34.1;q11.2). This rearrangement involves the breakpoint cluster region (BCR) gene 22q11.2 and the c-Abelson (ABL1) gene 9q34, resulting in the BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase protein [1].\n\nThe Ph chromosome can be observed as a sole chromosomal anomaly during the early chronic phase (CP) of CML (in more than 90 % of the CML cases), additional genetic changes occur in less than 10 % of cases at the time of diagnosis and other genetic changes are seen in 60–80 % of the cases in advanced disease [1]. The identification of this abnormality is important for the diagnosis of the disease determined by the WHO Tumor Classification [2] and for treatment purposes. The first therapeutic choice, tyrosine kinas inhibitors, has shown great therapeutic efficacy [3]. Imatinib mesylate (IM = Glivec, formerly STI571) is a chemically designed drug able to block BCR/ABL1 tyrosine kinase activity and is successfully used in CML patients [4].\n\nHere we presented a de novo untreated Ph-positive CML case in BC phase with del(9)(p23p11.1) as sole additional abnormality detected by FISH technique, which leads to monoallely of tumor suppressor gene CDKN2A (cyclin-dependent kinase inhibitor 2A). This patient did not demonstrate a good response to IM treatment.\n\nCase presentation\nIn October 2013 a 40-year-old male was diagnosed as suffering from CML. Physical examination revealed the indicative symptoms as hepatosplenomegaly, loss of weight, fever, anemia, and thrombocytopenia. Routine peripheral blood test showed elevated white blood cells (WBC) of 243.1 × 109/l (41 % of cells were blasts), red blood cell (RBC) count was 3.62 × 106/mm3, hemoglobin level was 6.8 g/dl and the platelet count 26 × 109/l. Serum lactate dehydrogenase value (LDH) was 1,543 U/l (normal level <460 U/l). The patient was diagnosed as CML-BC according to WHO recommendations, in a high Sokal risk of 29.7 (0.8–1.2), high Hasford (Euro) risk of 2,856 (>1,480), low Eutos risk of 40 (<87) and Etous probability of no complete cytogenetic response (CCgR) at 18 months was 15 %. In fact, the patient started on IM treatment (400 mg/day) for overall 1 month; then he increased IM daily dose to 800 mg for 1 month but the treatment was not successful and the patient had a toothache, anemia, and thrombocytopenia. Later he was given IM 400 mg daily dose for 2 months. Under the latter therapy the previous reported relevant symptoms disappeared. Unfortunately the patient died 7 months after diagnosis from the disease under the treatment for unknown reason.\n\nResults\nPrior to the IM-treatment GTG-banding revealed a karyotype of 46,XY,t(9;22)[11]/ 46,XY,t(9;22),del(9)(p?)[9] (Fig. 1). Further molecular cytogenetics studies were performed (Fig. 2). Dual-color-fluorescence in situ hybridization (FISH) prior to IM-treatment using a specific probe for BCR and ABL1 revealed two fusion signals, on the der(9) and der(22), respectively (Fig. 2a). A probe-set specific for subtelomeric (ST) regions in 9p and 9q revealed one green and one red signal on der(9), and one green, and one red signal on the der(9) and der(22), respectively (Fig. 2b). Chromosome 9 was studied with whole chromosome painting (WCP) probe and did not provide any hint on cryptic translocations (data not shown). A probe specific for CDKN2A confirmed that the deletion visible in the short arm encompassed subband 9p21 (Fig. 2c). Multicolor banding (MCB) using a specific probe for chromosome 9 confirmed a terminal deletion of 9p23 to 9p11.1 (Fig. 2d). RT-PCR pre IM treatment confirmed the presence of the BCR-ABL1 fusion (b2a2 transcript) revealing a major M-BCR transcript, most often identified in CML (data not shown). Thus, the following final karyotype prior IM-treatment was determined:Fig. 1 GTG-banding revealed a deletion of the short arm of a derivative chromosome 9 del(9)(p?). A derivative chromosome is marker by arrowhead\n\nFig. 2 Karyotype and chromosomal aberrations were confirmed using molecular cytogenetic approaches. a FISH using probes for BCR (green) and ABL (red) showed 2 copies of BCR/ABL on Ph chromosome and on der(9), respectively. b FISH using probes for ST 9p (green) and ST 9q (red) showed; 1 green and 1 red signal on der(9); and 1 red signal on Ph chromosome and 1 green signal on der(9). c The deletion of CDKN2A was identified on the der(9). d The application of MCB 9 characterized the del(9)(p24p12) comprehensively. Abbreviations: # = chromosome; der = derivative chromosome\n\n\n\n46,XY,t(9;22)(q34;q11.2)[11]/46,XY,der(9)(9pter- > 9p23::9p11.1- > 9q34::22q11.2- > 22qter),der(22)t(9;22)(q34;q11.2)[9].\n\nThe abnormal cell population (~42-45 % blasts in peripheral blood specimen) showed the following immunophenotype, which was consistent with CML-BC (WHO recommendations): CD45+dim, CD13+, CD33+, CD32+ ,CD22+, CD10+, CD41a+, CD34−, HLADr−, CD5−, CD7-, CD2−, CD209−, CD11c−, CD79b−, sIgM−, sIgD−, CD103−, CD138−, CD56−, CD57− and expressed CD64, CD38, and CD4 heterogeneously.\n\nConclusions\nWe described a de novo untreated CML case in BC with del(9)(p23p11.1) as sole additional acquired abnormality, which leads to monoallely of tumor suppressor gene CDKN2A as located at 9p21. Up to date, there are 7 CML cases listed in Mitelman Database showed the involvement of the short arm of chromosome 9, two of them revealed involvement of 9p21 [5]. Also, loss of a part of the short arm of chromosome 9 (p12 and/or p21) in CML-BC are reviewed in two previous studies [5, 6]. To the best of our knowledge, this chromosomal abnormality del(9)(p23p11.1) has not been previously observed in CML [7].\n\nAccording to the literature, approximately 10 % of CML patients present in advanced phases called accelerated phase (CML-AP) or CML-BC, without a clinically evident CP [8]. Even with the advent of tyrosine kinase inhibitor (TKI) therapy, the phase of disease remains an important prognostic factor in CML [9, 10].\n\nThe progression to advanced phases of disease is caused by the development of genetic lesions in addition to BCR-ABL1 translocation; secondary cytogenetic changes are identified in more than 80 % of patients by the time of progression to CML-BC [11]. Even in the absence of other features of CML-AP or CML-BC, the acquisition of new cytogenetic abnormalities in patients treated with IM is associated with loss of response and poor prognosis [12, 13].\n\nThe t(9;22) or a variant Ph are frequently the sole chromosomal anomaly during the CP [1]. The most common secondary chromosomal aberrations in advanced phase CML are +8, +Ph, i(17q), +19, −Y, +21, +17, −7, and −17 [1].\n\nThe median time to progression from CML-CP to CML-BC is 3–5 years in untreated patients or in patients treated with hydroxyurea [14]. However, BC is typically preceded by an intermediate AP of disease by a period of 4–6 months [15], but up to 25 % of CML-BC cases develop without any clinically evident preceding AP [16].\n\nThe molecular events associated with CML progression are complex and are likely related to genetic instability and impaired DNA repair mechanisms that are consequences of BCR-ABL1 activity [17–19]. In addition to cytogenetic aberrations, BCR-ABL1 amplification, gene mutations, and epigenetic changes such as gene methylation also appear to play a role in disease progression [20]. Interestingly, different BC phenotypes have been associated with unique patterns of molecular evolution: ABL kinase domain mutations that confer resistance to TKIs occur frequently in lymphoid BC, while myeloid BC is more commonly associated with cytogenetic evolution. BCR-ABL1 amplification is seen in about 31 % of both myeloid and lymphoid BC cases [21].\n\nCDKN2A and CDKN2B are tumor suppressor genes located in 9p21. They belong to the family of inhibitors of cyclin-dependent kinases. The CDKN2A gene encodes two proteins, p14ARF and p16INK4a, and the CDKN2B gene p15 INK4b protein, which as key regulators of G1 phase cell-cycle arrest and senescence [22]. These genes product is inactivated in a wide range of human cancers through epigenetic mechanisms [22, 23],\n\nDeletion at 9p21 is especially frequent in acute lymphocytic leukemia (ALL), occurring at more than of 20 % in B-cell precursor ALL and approximately 50 % T-ALL patients [24]. The 9p21 deletions have been suggested to be associated with unfavorable outcome in both adult ALL and pediatric ALL, although the prognostic impact of CDKN2A deletions in pediatric ALL appears controversial [24–27].\n\nRecently, FOXA1 is a key transcription (TF) factor for CDKN2A expression [23, 28]. FOXA1 is a member of forkhead family TFs with remarkable pioneering activity to open closed chromatin for its subsequent cooperation with other master TF in embryogenesis and organ development [29, 30].\n\nIn conclusion, we described de novo untreated CML case in BC with del(9)(p23p11.1) as sole additional acquired abnormality detected by FISH technique, which leads to monoallely of tumor suppressor gene CDKN2A as located at 9p21. The patient did not demonstrate a good response to Imatinib treatment.\n\nMaterials and Methods\nChromosome analysis\nChromosome analysis applying GTG-banding according to standard procedures [31] was performed prior IM treatment. 20 metaphase cells derived from unstimulated bone marrow culture were analyzed. Karyotypes were described according to the International System for Human Cytogenetic Nomenclature (ISCN 2009).\n\nMolecular cytogenetics\nFluorescence in situ hybridization (FISH) using the LSI BCR/ABL dual color dual fusion translocation probe (Abbott Molecular/Vysis, Des Plaines, IL, USA), a locus specific probe for CDKN2A gene (LSI p16 in 9p21) with a probe for centromere nine, and a subtelomeric probe for 9p and 9q (Abbott Molecular/Vysis, Abbott Park, IL, USA) were applied together with whole chromosome painting (WCP) probe for chromosome 9 (MetaSystems, Altlussheim, Germany) according to manufacturer’s instructions [31]. Also a multicolor banding probe (MCB) sets based on microdissection derived region-specific libraries for chromosome 9 was applied as previously described [32]. A minimum of ten metaphase spreads was analyzed, using a fluorescence microscope (AxioImager.Z1 mot, Carl Zeiss Ltd., Hertfordshir, UK) equipped with appropriate filter sets to discriminate between a maximum of five fluorochromes plus the counterstain DAPI (4',6- diamino-2-phenylindole). Image capture and processing were performed using an ISIS imaging system (MetaSystems, Altlussheim, Germany).\n\nReverse transcriptase-polymerase chain reaction (RT-PCR) and for BCR/ABL1 fusion transcripts\nTotal RNA extracted from peripheral blood sample using the InviTrap RNA kit (Invitek, Berlin, Germany) according to the manufacturer’s recommendations. cDNA was prepared from 5 μg of total RNA with the Genequality BCR-ABL1 kit (AB Analitica, Padova, Italy) and BCR-ABL1 fusion transcript was performed according to the manufacturer’s instructions (AB Analitica, Padova, Italy).\n\nFlow cytometric immunophenotype\nFlow cytometry of leukemic blasts was performed using a general panel of fluorescent antibodies against the following antigens typical for different cell lineages and cell types: CD1a, CD2, CD3, CD4, CD5, CD8, CD10, CD11b, CD11c, CD13, CD14, CD15, CD16, CD19, CD20, CD22, CD23, CD32, CD33, CD34, CD38, CD41a, CD45, CD56, CD57, CD64, CD103, CD117, CD123, CD209, CD235a and CD243; in addition antibodies against Kappa and Lambda light Chains, sIgD, sIgM, and HLADr were applied (BD Biosciences). Four-color immunophenotyping on peripheral blood specimen was performed. Samples were stained and analyzed on a BD FACSCalibur™ flow cytometer according to BD Biosciences manuals and products insert sheets. Autofluorescence, viability, and isotype controls were included. Flow cytometric data acquisition and analysis were conducted by BD Cellquest™ Pro software.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case Report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe author(s) declare that they have no competing interests.\n\nAuthors’ contributions\n\nAW, MA and FM provided the case and/or did primary cytogenetic and main part of the FISH-tests; AA did the flow cytometry analysis; TL did detailed FISH studies. WA supervised the cytogenetic analysis as Head of HGD. AW and TL drafted the paper and all authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank Prof. I. Othman, the Director General of Atomic Energy Commission of SYRIA (AECS) and Dr. N. Mirali, Head of Molecular Biology and Biotechnology Department for their support. This work was supported by the AECS, in parts by the DAAD.\n==== Refs\nReferences\n1. Johansson B Fioretos T Mitelman F Cytogenetic and molecular genetic evolution of chronic myeloid leukemia Acta Haematol 2002 107 76 94 10.1159/000046636 11919388 \n2. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. WHO Classification of tumors of haematopoietic andlymphoid tissues. 4th ed. WHO press: IARC; 2008. p. 439.\n3. Baccarani M Deininger MW Rosti G Hochhaus A Soverini S Apperley JF Cervantes F Clark RE Cortes JE Guilhot F Hjorth-Hansen H Hughes TP Kantarjian HM Kim DW Larson RA Lipton JH Mahon FX Martinelli G Mayer J Müller MC Niederwieser D Pane F Radich JP Rousselot P Saglio G Saußele S Schiffer C Silver R Simonsson B Steegmann JL Goldman JM Hehlmann R European LeukemiaNet recommendationsfor the management of chronic myeloid leukemia: 2013 Blood 2013 122 871 884 10.1182/blood-2013-05-501569 \n4. Druker BJ Guilhot F O’Brien SG Gathmann I Kantarjian H Gattermann N Deininger MW Silver RT Goldman JM Stone RM Cervantes F Hochhaus A Powell BL Gabrilove JL Rousselot P Reiffers J Cornelissen JJ Hughes T Agis H Fischer T Verhoef G Shepherd J Saglio G Gratwohl A Nielsen JL Radich JP Simonsson B Taylor K Baccarani M So C Letvak L Larson RA Investigators IRIS Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia N Engl J Med 2006 355 2408 2417 10.1056/NEJMoa062867 17151364 \n5. Mitelman Database of Chromosome Aberrations in Cancer (2015). Mitelman F, Johansson B and Mertens F (Eds.), http://cgap.nci.nih.gov/Chromosomes/Mitelman\" [last accessed 04.02.2015].\n6. Pollak C Hagemeijer A Abnormalities of the short arm of chromosome 9 with partial loss of material in hematological disorders Leukemia 1987 1 541 548 3312844 \n7. Van PN Xinh PT Kano Y Tokunaga K Sato Y Establishment and characterization of A novel Philadelphia-chromosome positive chronic myeloid leukemia cell line, TCC-S, expressing P210 and P190 BCR/ABL transcripts but missing normal ABL gene Hum Cell 2005 18 25 33 10.1111/j.1749-0774.2005.tb00054.x 16130897 \n8. Jabbour E Kantarjian H Jones D Talpaz M Bekele N O’Brien S Zhou X Luthra R Garcia-Manero G Giles F Rios MB Verstovsek S Cortes J Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate Leukemia 2006 20 1767 1773 10.1038/sj.leu.2404318 16855631 \n9. Mitchell B Deininger M Techniques for risk stratification of newly diagnosed patients with chronic myeloid leukemia Leuk Lymphoma 2011 52 4 11 10.3109/10428194.2010.546916 21299455 \n10. IRIS Investigators O’Brien SG Guilhot F Larson RA Gathmann I Baccarani M Cervantes F Cornelissen JJ Fischer T Hochhaus A Hughes T Lechner K Nielsen JL Rousselot P Reiffers J Saglio G Shepherd J Simonsson B Gratwohl A Goldman JM Kantarjian H Taylor K Verhoef G Bolton AE Capdeville R Druker BJ Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia N Engl J Med 2003 348 994 1004 10.1056/NEJMoa022457 12637609 \n11. Gribble SM Sinclair PB Grace C Green AR Nacheva EP Comparative analysis of G-banding, chromosome painting, locusspecific fluorescence in situ hybridization, and comparative genomic hybridization in chronic myeloid leukemia blast crisis Cancer Genet Cytogenet 1999 111 7 17 10.1016/S0165-4608(98)00213-1 10326584 \n12. Cortes JE Talpaz M Giles F O’Brien S Rios MB Shan J Garcia-Manero G Faderl S Thomas DA Wierda W Ferrajoli A Jeha S Kantarjian HM Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy Blood 2003 101 3794 3800 10.1182/blood-2002-09-2790 12560227 \n13. O’Dwyer ME Mauro MJ Blasdel C Farnsworth M Kurilik G Hsieh YC Mori M Druker BJ Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate Blood 2004 103 451 455 10.1182/blood-2003-02-0371 14512312 \n14. Sokal JE Baccarani M Russo D Tura S Staging and prognosis in chronic myelogenous leukemia Semin Hematol 1988 25 49 61 3279515 \n15. Griesshammer M Heinze B Hellmann A Popp C Anger B Heil G Bangerter M Heimpel H Chronic myelogenous leukemia in blast crisis: retrospective analysis of prognostic factors in 90 patients Ann Hematol 1996 73 225 230 10.1007/s002770050233 8959940 \n16. Kantarjian HM Deisseroth A Kurzrock R Estrov Z Talpaz M Chronic myelogenous leukemia: a concise update Blood 1993 82 691 703 8338938 \n17. Melo JV Barnes DJ Chronic myeloid leukaemia as a model of disease evolution in human cancer Nat Rev Cancer 2007 7 441 453 10.1038/nrc2147 17522713 \n18. Salloukh HF Laneuville P Increase in mutant frequencies in mice expressing the BCR-ABL activated tyrosine kinase Leukemia 2000 14 1401 1404 10.1038/sj.leu.2401855 10942235 \n19. Calabretta B Perrotti D The biology of CML blast crisis Blood 2004 103 4010 4022 10.1182/blood-2003-12-4111 14982876 \n20. Asimakopoulos FA Shteper PJ Krichevsky S Fibach E Polliack A Rachmilewitz E Ben-Neriah Y Ben-Yehuda D ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia Blood 1999 94 2452 2460 10498618 \n21. Jones D Luthra R Cortes J Thomas D O’Brien S Bueso-Ramos C Hai S Ravandi F de Lima M Kantarjian H Jorgensen JL BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome-positive leukemias Blood 2008 112 5190 5192 10.1182/blood-2008-04-148791 18809762 \n22. Collado M Blasco MA Serrano M Cellular senescence in cancer and aging Cell 2007 130 223 233 10.1016/j.cell.2007.07.003 17662938 \n23. Zhang Y Tong T FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis Biochem Biophys Res Commun 2014 453 172 178 10.1016/j.bbrc.2014.09.092 25264199 \n24. Sulong S Moorman AV Irving JA Strefford JC Konn ZJ Case MC Minto L Barber KE Parker H Wright SL Stewart AR Bailey S Bown NP Hall AG Harrison CJ A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups Blood 2009 113 100 107 10.1182/blood-2008-07-166801 18838613 \n25. Heyman M Rasool O Borgonovo Brandter L Liu Y Grandér D Söderhäll S Gustavsson G Einhorn S Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia J Clin Oncol 1996 14 1512 1520 8622065 \n26. Kees UR Burton PR Lu C Baker DL Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome Blood 1997 89 4161 4166 9166859 \n27. Heerema NA Sather HN Sensel MG Liu-Mares W Lange BJ Bostrom BC Nachman JB Steinherz PG Hutchinson R Gaynon PS Arthur DC Uckun FM Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: a report from the Children’s Cancer Group Blood 1999 94 1537 1544 10477677 \n28. Li Q Zhang Y Fu J Han L Xue L Lv C Wang P Li G Tong T FOXA1 mediates p16(INK4a) activation during cellular senescence EMBO J 2013 32 858 873 10.1038/emboj.2013.35 23443045 \n29. Jozwik KM Carroll JS Pioneer factors in hormone-dependent cancers Nat Rev Cancer 2012 12 381 385 10.1038/nrc3263 22555282 \n30. Katoh M Igarashi M Fukuda H Nakagama H Katoh M Cancer genetics andgenomics of human FOX family genes Cancer Lett 2013 328 198 206 10.1016/j.canlet.2012.09.017 23022474 \n31. AL-achkar W Nweder MS WA A complex translocation t(5;9;22) in Philadelphia cells involving the short arm of chromosome 5 in a case of chronic myelogenous leukemia J Exp Clin Cancer Res 2007 26 411 415 17987804 \n32. Liehr T Heller A Starke H Rubtsov N Trifonov V Mrasek K Weise A Kuechler A Claussen U Microdissection based high resolution multicolor banding for all 24 human chromosomes Int J Mol Med 2002 9 335 339 11891523\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1755-8166",
"issue": "8()",
"journal": "Molecular cytogenetics",
"keywords": "CDKN2A gene; Chronic myeloid leukemia; Philadelphia chromosome; Prognostic factors; del(9)(p24p12)",
"medline_ta": "Mol Cytogenet",
"mesh_terms": null,
"nlm_unique_id": "101317942",
"other_id": null,
"pages": "59",
"pmc": null,
"pmid": "26244056",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "16130897;8959940;21299455;8622065;10942235;23022474;18838613;3279515;18809762;9166859;25264199;12560227;17987804;17662938;22555282;17522713;14982876;11891523;10498618;23803709;10477677;14512312;8338938;23443045;10326584;17151364;3312844;12637609;11919388;16855631",
"title": "Deletion 9p23 to 9p11.1 as sole additional abnormality in a Philadelphia positive chronic myeloid leukemia in blast crisis: a rare event.",
"title_normalized": "deletion 9p23 to 9p11 1 as sole additional abnormality in a philadelphia positive chronic myeloid leukemia in blast crisis a rare event"
} | [
{
"companynumb": "PHHY2015SY099607",
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"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
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... |
{
"abstract": "Despite precise definitions and exclusions for 19 syndromes of neuropsychiatric systemic lupus erythematosus (NPSLE), under some circumstances it appears to be difficult to differentiate whether neuropsychiatric symptoms are caused by SLE or by other reasons such as primary mental disorders or substance-induced mood disorders, especially induced by glucocorticoids or antimalarials. We report the case of a male patient with SLE who presented with an exacerbation of bipolar disorder triggered by chloroquine. Firstly, when the patient was diagnosed with SLE, he underwent six months of therapy with chloroquine without any psychiatric symptoms. Later, the SLE returned and the patient was prescribed chloroquine again, without any mental illness. When the third exacerbation of SLE occurred, it coincided with a severe depressive episode with psychotic features that became aggravated for the first time after the administration of chloroquine. The chloroquine was subsequently replaced with hydroxychloroquine for the next six months without any behavioral problems, following which, the SLE and mood disorder were in remission. Later, a bipolar disorder relapse occurred, manifested by a manic episode, and in the following three months, despite psychiatric treatment, a manic episode with psychotic features developed four days after chloroquine was prescribed for arthritis. It was the second time that the mood disorder was exacerbated by chloroquine. Since that time, chloroquine has been withdrawn. Currently the patient is undergoing treatment with hydroxychloroquine and psychiatric drugs with good response. Our case points out that although chloroquine-induced psychosis is rare, patients presenting with behavioral changes need physicians' attention in order to diagnose early and efficiently treat encountered mood disorders.",
"affiliations": "1Department of Dermatology and Venereology, Medical University of Lodz, Poland.",
"authors": "Bogaczewicz|J|J|;Sobów|T|T|;Bogaczewicz|A|A|;Robak|E|E|;Bienkowski|P|P|;Sysa-Jedrzejowska|A|A|;Wozniacka|A|A|",
"chemical_list": "D000962:Antimalarials; D006886:Hydroxychloroquine; D002738:Chloroquine",
"country": "England",
"delete": false,
"doi": "10.1177/0961203313513818",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "23(2)",
"journal": "Lupus",
"keywords": "Systemic lupus erythematosus; chloroquine; neuropsychiatric lupus",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D000962:Antimalarials; D001714:Bipolar Disorder; D002738:Chloroquine; D006801:Humans; D006886:Hydroxychloroquine; D008180:Lupus Erythematosus, Systemic; D020945:Lupus Vasculitis, Central Nervous System; D008297:Male",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "188-93",
"pmc": null,
"pmid": "24297641",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Exacerbations of bipolar disorder triggered by chloroquine in systemic lupus erythematosus--a case report.",
"title_normalized": "exacerbations of bipolar disorder triggered by chloroquine in systemic lupus erythematosus a case report"
} | [
{
"companynumb": "PL-WATSON-2014-23745",
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"activesubstance": {
"activesubstancename": "CHLOROQUINE\\CHLOROQUINE PHOSPHATE"
},
"drugadditi... |
{
"abstract": "Mycobacterium bovis Bacillus Calmette-Guérin (BCG) instillations are used in bladder cancer treatment. Adverse effects can occur. Osteoarticular complications are mainly reactive arthritis, but true infections have been described, such as vertebral osteomyelitis. We made a review of M. bovis BCG vertebral osteomyelitis after instillations for bladder cancer using PubMed search. We added three new French cases. Twenty-seven cases of BCG vertebral osteomyelitis had been reported on PubMed. Of the 30 cases, all were male, averaging 73.4 ± 8.7 years old. Median time between diagnosis and first and last instillation was 22.5 and 14 months respectively. Half of vertebral osteomyelitis was thoracic and lumbar in the other half. Sensitivo-motor deficit was present at diagnosis in 42% of cases. Other infectious locations were common, mainly infectious abdominal aortic aneurysms (20%). Rifampicin, ethambutol and isoniazid were the usual therapy. Poor outcomes were reported with 50% of one or more spine surgery. M. bovis BCG vertebral osteomyelitis following bladder instillation for bladder cancer is a rare complication. However, the late onset of back pain after instillations differentiates them from reactive arthritis. Concomitant septic location such as infectious abdominal aortic aneurysms must be known.",
"affiliations": "Department of Rheumatology, Centre Hospitalier Universitaire de Rennes, 16 Boulevard de Bulgarie, 35200, Rennes, France. simon.cadiou@chu-rennes.fr.;Department of Rheumatology, Centre Hospitalier René Dubos, 95301, Pontoise, France.;Department of Rheumatology, Hôpital St Philibert GHICL, 249 Rue du grand but, 59462, Lomme, France.;Department of Rheumatology, Centre Hospitalier Universitaire de Rennes, 35000, Rennes, France.;Department of Medical Imaging, Centre Hospitalier Universitaire de Rennes, 35000, Rennes, France.;Infectious Diseases and Intensive Care Unit, CHU Univ Rennes, Inserm U 1230, F-35000, Rennes, France.;Department of Rheumatology, Centre Hospitalier Universitaire de Rennes, 35000, Rennes, France.;Department of Rheumatology, Hôpital St Philibert GHICL, 249 Rue du grand but, 59462, Lomme, France.;Department of Rheumatology, Centre Hospitalier René Dubos, 95301, Pontoise, France.;Department of Rheumatology, Centre Hospitalier Universitaire de Rennes, 35000, Rennes, France.",
"authors": "Cadiou|Simon|S|http://orcid.org/0000-0002-4846-6956;Al Tabaa|Omar|O|;Nguyen|Chi-Duc|CD|;Faccin|Marine|M|;Guillin|Raphaël|R|;Revest|Matthieu|M|;Guggenbuhl|Pascal|P|;Houvenagel|Eric|E|;Pertuiset|Edouard|E|;Coiffier|Guillaume|G|",
"chemical_list": "D001500:BCG Vaccine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-019-04500-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "38(6)",
"journal": "Clinical rheumatology",
"keywords": "BCG instillation; Bladder cancer; Interferon-γ release assay; Mycobacterium bovis; Vertebral osteomyelitis",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000283:Administration, Intravesical; D000368:Aged; D001500:BCG Vaccine; D001416:Back Pain; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009163:Mycobacterium bovis; D010019:Osteomyelitis; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "1773-1783",
"pmc": null,
"pmid": "30868320",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10189456;10325395;11010830;11936937;11964626;15877007;1621315;17959764;19303342;19501456;19808254;20130477;20876624;21358881;21941579;22140647;22960467;23151379;23355584;23816569;23832635;2585658;26110060;26229122;26232534;26652884;26788410;26839794;26928510;26969570;27158574;27313927;27534910;28478023;28902383;29034173;29093394;29189087;29740727;29954321;30065051;30286596;7474640;8086533;820877;8329515;8437271;8629686;8751686;8968889",
"title": "Back pain following instillations of BCG for superficial bladder cancer is not a reactive complication: review of 30 Mycobacterium bovis BCG vertebral osteomyelitis cases.",
"title_normalized": "back pain following instillations of bcg for superficial bladder cancer is not a reactive complication review of 30 mycobacterium bovis bcg vertebral osteomyelitis cases"
} | [
{
"companynumb": "FR-009507513-1903FRA012412",
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"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN"
... |
{
"abstract": "Giant cell arteritis is a granulomatous immune-mediated vasculitis of medium and large vessels. It most commonly affects white females over the age of 50 and is the most common primary vasculitis in the United States. Treatment of this disease has classically been with high-dose corticosteroids, but this therapy has been associated with severe morbidity and mortality. Tocilizumab, a humanized monoclonal antibody targeting the interleukin-6 receptor, has been used with great efficacy and safety in rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis. As interleukin-6 has been shown to be a key cytokine in giant cell arteritis, the use of an inhibiting agent has been explored. In the 15 case reports/series that were reviewed, most patients were given tocilizumab due to refractory giant cell arteritis and/or intolerance to glucocorticoid therapy, and most experienced remission of symptoms. At this time, there are only 2 randomized control trials to evaluate the efficacy and safety of tocilizumab use in giant cell arteritis. The phase II trial by Villiger et al and the GiACTA trial both showed that tocilizumab greatly increased the rate of sustained remission in giant cell arteritis over the course of 1 year. The most common adverse events were similar to those seen with use in rheumatoid arthritis: infections, neutropenia, and increases in lipids and liver function test enzymes. Based on the results of numerous case studies and the 2 randomized control trials, tocilizumab is the first agent to be approved by the Food and Drug Administration for treatment of giant cell arteritis.",
"affiliations": "From the Department of Medicine, Brown University/Rhode Island Hospital, Providence, RI.;Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, NY.",
"authors": "Mariano|Vincent J|VJ|;Frishman|William H|WH|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/CRD.0000000000000204",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1061-5377",
"issue": "26(6)",
"journal": "Cardiology in review",
"keywords": null,
"medline_ta": "Cardiol Rev",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D013700:Giant Cell Arteritis; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome",
"nlm_unique_id": "9304686",
"other_id": null,
"pages": "321-330",
"pmc": null,
"pmid": "29570475",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Tocilizumab in Giant Cell Arteritis.",
"title_normalized": "tocilizumab in giant cell arteritis"
} | [
{
"companynumb": "ES-MYLANLABS-2019M1063248",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Clonidine is a central alpha(2)-agonist antihypertensive used widely for opioid/alcohol withdrawal, attention deficit hyperactivity disorder and chronic pain management. We describe a case of clonidine withdrawal causing life-threatening hypertensive crisis and stress-induced cardiomyopathy. A 47-year-old man with chronic back pain, treated with clonidine for many years via intrathecal pump (550 mcg/24 h), presented following a collapse and complaining of sudden worsening of back pain, severe headache, diaphoresis, nausea and vomiting. A few hours prior to presentation, his subcutaneous pump malfunctioned. On presentation, vital signs included pulse 100 bpm, BP 176/103 mmHg, temperature 37.8 °C and O2 saturation 100 % (room air). Acute clonidine withdrawal with hypertensive crisis was suspected. Intravenous clonidine loading dose and a 50 mcg/h infusion were commenced. Five hours later, severe chest pain, dyspnoea, tachycardia, hypoxia, with BP 180/120 mmHg and pulmonary edema ensued. ECG showed sinus tachycardia with no ST elevation. Repeated intravenous clonidine doses were given (25 mcg every 5-10 min), with ongoing clonidine infusion to control blood pressure. Glyceryl trinitrate infusion, positive pressure ventilation and intravenous benzodiazepines were added. Bedside echocardiogram showed stress-induced cardiomyopathy pattern. Serum troponin-I was markedly elevated. His coronary angiography showed minor irregularities in the major vessels. Over the next 3 days in the ICU, drug infusions were weaned. Discharge was 12 days later on oral clonidine, metoprolol, perindopril, aspirin and oxycodone-SR. Two months later, his echocardiogram was normal. The intrathecal pump was removed. We report a case of stress-induced cardiomyopathy resulting from the sudden cessation of long-term intrathecal clonidine. This was managed by re-institution of clonidine and targeted organ-specific therapies.",
"affiliations": "Monash Health Clinical Toxicology and Addiction Medicine Service, Monash, Health, Dandenong Hospital, David Street, Dandenong, VIC, 3175, Australia. hweeminlee@gmail.com.;Monash Health Clinical Toxicology and Addiction Medicine Service, Monash, Health, Dandenong Hospital, David Street, Dandenong, VIC, 3175, Australia.;Monash Health Clinical Toxicology and Addiction Medicine Service, Monash, Health, Dandenong Hospital, David Street, Dandenong, VIC, 3175, Australia.",
"authors": "Lee|Hwee Min D|HM|;Ruggoo|Varuna|V|;Graudins|Andis|A|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D003000:Clonidine",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-015-0505-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "12(1)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Cardiomyopathy; Clonidine; Intrathecal; Sympathomimetic; Withdrawal",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D058647:Adrenergic alpha-2 Receptor Agonists; D001416:Back Pain; D059350:Chronic Pain; D003000:Clonidine; D004562:Electrocardiography; D004868:Equipment Failure; D006801:Humans; D015918:Infusion Pumps, Implantable; D060186:Infusions, Spinal; D008297:Male; D008875:Middle Aged; D013375:Substance Withdrawal Syndrome; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "134-8",
"pmc": null,
"pmid": "26370679",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18182964;1985511;1173448;14654180;3813760;15495025;8659804;3015176;7011348;25068020;16398849;2068045;24020058;8853097;22297544;24665248;25298075;15985928;22773717;23510078",
"title": "Intrathecal Clonidine Pump Failure Causing Acute Withdrawal Syndrome With 'Stress-Induced' Cardiomyopathy.",
"title_normalized": "intrathecal clonidine pump failure causing acute withdrawal syndrome with stress induced cardiomyopathy"
} | [
{
"companynumb": "AU-UNICHEM LABORATORIES LIMITED-UCM201506-000415",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CLONIDINE HYDROCHLORIDE"
},
... |
{
"abstract": "Although it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.\n\n\n\nWe present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.\n\n\n\nIn patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.",
"affiliations": "MD, PhD. Neurologist and Assistant Professor, Department of Neurology, University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey.",
"authors": "Gunduz|Zahide Betül|ZB|0000-0002-6421-1857",
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"doi": "10.1590/1516-3180.2020.0659.R1.08122020",
"fulltext": "\n==== Front\nSao Paulo Med J\nSao Paulo Med J\nSao Paulo Med J\nSão Paulo Medical Journal\n1516-3180\n1806-9460\nAssociação Paulista de Medicina - APM\n\n33605306\n10.1590/1516-3180.2020.0659.R1.08122020\nCase Report\nVenous sinus thrombosis during COVID-19 infection in pregnancy: a case report\nGunduz Zahide Betül I Study design, data collection, data analysis and writing of the paper\nI MD, PhD. Neurologist and Assistant Professor, Department of Neurology, University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey.\nAddress for correspondence: Zahide Betül Gunduz. Department of Neurology, University of Health Sciences, Konya Education and Research Hospital. Ayanbey Mah. Yeni Meram Cad. No: 97, Meram - Konya, Turkey. Tel. (+90) 532620-8182. E-mail: drzahidebetul@yahoo.com\nConflicts of interest: None\n\n15 2 2021\n2021\n139 2 190195\n07 11 2020\n21 11 2020\n08 12 2020\n© 2022 by Associação Paulista de Medicina\n2022\nAssociação Paulista de Medicina\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons license.\nABSTRACT\n\nBACKGROUND:\n\nAlthough it is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract, cases of this disease with a wide clinical spectrum are emerging as information is shared.\n\nCASE REPORT:\n\nWe present the case of a pregnant woman who was diagnosed with venous sinus thrombosis after she developed headache and hemiparesis. Polymerase chain reaction (PCR) positivity lasted for two weeks after COVID-19 had been diagnosed.\n\nCONCLUSIONS:\n\nIn patients with suspected COVID-19, especially in the presence of causes of hypercoagu- lability and presence of atypical features, venous sinus thrombosis needs to be kept in mind in making the differential diagnosis.\n\nKEY WORDS (MeSH terms):\n\nCOVID-19 [supplementary concept]\nPregnancy\nHeadache\nFemale\nAUTHORS’ KEY WORDS:\n\nVenous sinus thrombosis\nHypercoagulability\nInfectious disease\n==== Body\npmcINTRODUCTION\n\nThe effects of COVID-19 are not limited to the lungs alone. After the virus enters the body, it causes various symptoms through viremia.1 COVID-19 has been implicated in occurrences of cardiovascular and thromboembolic complications due to systemic inflammation and coagulopathy, in the light of the increasing amount of data that has become available over time.2,3,4,5,6,7,8 On the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 It has been suggested that COVID-19 predisposes patients to thrombotic pathological conditions in both the venous and the arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 Nevertheless, cases of neurological and cardiac involvement in COVID-positive patients with TMA have also been reported.9\n\nWhile the mechanism for the susceptibility to thrombosis that has been seen among COVID-19 patients continues to be debated, we wanted through this report to share information regarding the common venous thrombus of the central nervous system that emerged during the subclinical course of COVID-19 in a pregnant patient, which caused rapid parenchymal infarction.\n\nCASE REPORT\n\nA 22-year-old patient who was 35 weeks pregnant was evaluated in the emergency department with a complaint of right-sided weakness. The COVID-19 polymerase chain reaction test was performed and was found to be positive. However, she did not have fever or respiratory distress and then was followed up at home without medication.\n\nThe patient started to have throbbing headaches that did not respond to analgesic treatment (paracetamol 1000 mg/day) for four days. The intensity of her headaches gradually increased, such that she was being awakened from sleep, and this condition was accompanied by nausea and vomiting.\n\nAfter this four-day period, she again felt weakness on her right side when she woke up in the morning. Twelve hours later, she went back to the emergency department because her weakness was increasing. At the emergency department, the patient was found to be normotensive, conscious, cooperative and oriented in a neurological examination. No fundus examination was performed, given that she was COVID-positive. Examinations on the patient’s visual field and vision showed normal results. Other cranial nerve examinations were normal. Her muscle strength ratio was 3/5 in the upper right extremity, 2/5 in the lower right extremity and 5/5 in the upper and lower left extremities. The foot sole skin reflex of the right lower extremity consisted of an extensor response. She presented decreased speech fluency and had difficulty in word finding, which were diagnosed as mild motor aphasia. Laboratory tests revealed high levels of fibrinogen (899 g/l; normal is 180-400) and D-dimer (6.38 mg/l; normal is 0-2). It was noted that the patient had also had high levels of fibrinogen (665 g/l) and D-dimer (2.2 mg/l) in examinations performed 10 days previously.\n\nDiffusion magnetic resonance imaging (MRI) showed cortical diffusion restriction in the left parietal region (Figure 1a) and a hypointense response in the apparent diffusion coefficient (ADC) (Figure 1b). The result from the diffusion MRI was suggestive of venous sinus thrombosis. Widespread loss of flow in the superior sagittal sinus and right transverse sinus, suggesting partial venous thrombosis in the left transverse sinus, was observed in brain magnetic resonance imaging (Figure 2a) and magnetic resonance venous angiography (Figure 2b). The brain MRI and magnetic resonance venography confirmed the diagnosis of venous sinus thrombosis. Thrombosis was not investigated in other parts of the body.\n\nFigure 1. a) Diffusion magnetic resonance imaging; b) Apparent diffusion coefficient.\n\nFigure 2. a) Cranial magnetic resonance imaging; b) Magnetic resonance imaging venography.\n\nThe polymerase chain reaction was repeated and the result was again positive. The patient was then hospitalized with the diagnoses of COVID-19 infection and venous sinus thrombosis. Other genetic, hematological and rheumatological examinations were planned, in order to investigate the etiology of her condition. Anticoagulant treatment (low molecular weight heparin) was started after the patient had been found to present a low platelet count (107,000/mm3), through evaluation of a peripheral blood smear.\n\nDiffuse contractions were observed in a non-stress test (NST), and tocolysis was started, consisting of nifedipine and betamethasone treatment. However, the patient’s labor could not be stopped after 18 hours of hospitalization. She was then admitted for an emergency cesarean section because the intracranial pressure was increasing. A healthy baby was delivered.\n\nSubsequently, the patient’s postpartum headache complaints decreased and her speech became fluent without any change in muscle strength deficit. Her thrombocyte counts decreased to 67,000/mm3. Anticoagulant therapy was continued, with peripheral smear follow-ups. Thoracic computed tomography was performed on the patient, who did not present respiratory distress, and the findings were compatible with COVID-19 pneumonia after birth (Figure 3). There was an increase in infection parameters, and the patient was started on hydroxychloroquine and ceftriaxone treatment.\n\nFigure 3. Thoracic computed tomography.\n\nIn the examinations performed to ascertain risk factors, the patient was found to be positive for antinuclear antibodies (ANA) and showed prothrombin heterozygous mutation. The patient was negative for anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA), and tests on lupus anticoagulant, homocysteine, protein C, protein S and antithrombin 3 showed results within normal limits.\n\nOn the third day following the birth, the patient’s headache complaint became completely resolved, her thrombocyte counts stopped decreasing and her thrombocytopenia improved over the subsequent days. The infection parameters regressed. Partial regression of the lesions was observed on control thoracic computed tomography. The patient’s general condition stabilized and she was discharged on the 10th day of hospitalization, with muscle strength 4-5/5 on the right side, which was mobilized without support. Continuation of low molecular weight heparin (LMWH) treatment was planned, along with neurological and hematological control tests at a polyclinic.\n\nDISCUSSION\n\nIt is known that the new coronavirus disease (COVID-19), which was first seen in Wuhan, China, in December 2019 and has affected the whole world, mainly targets the respiratory tract. Cases of this disease with a wide clinical spectrum are emerging as information is shared.\n\nAlthough the mechanism for thrombotic events in the course of COVID-19 remains unclear, it is known that there is a tendency for such events to occur within the course of this disease. Pulmonary embolism was shown to be the cause of death in an autopsy series.6 The etiology of embolic events is generally multifactorial: it is accepted that these events are triggered by environmental factors on the basis of genetic predisposition. Nonetheless, no reports on underlying genetic or other acquired causes in cases of COVID-19-positive pulmonary embolism have yet been published in the literature.\n\nAn increasing number of case reports and series on COVID-19-positive patients are describing a wide variety of neurological symptoms. Encephalopathy has been reported in a total of 93 patients, including 16 (7%) out of 214 hospitalized patients with COVID-19 in Wuhan, China, and 40 (69%) out of 58 patients in intensive care with COVID-19 in France. To date, encephalitis has been described in eight patients and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) of some patients. Anosmia and agnosia are common and may occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease has also emerged as an important complication: stroke was reported in 2-6% of patients hospitalized with COVID-19 in a cohort study.10\n\nLi et al. stated that in a retrospective study in which 219 COVID-19 positive patients were screened, 10 of these patients (4.6%) were ischemic and one of them presented hemorrhagic cerebrovascular disease (0.5%), after an average of 10 days after the onset of COVID-19. They pointed out that the mean age of these patients was greater and their cardiovascular and cerebrovascular risk factors were more severe.11\n\nCOVID-19 is thought to predispose patients to thrombotic pathological conditions in both venous and arterial circulation due to inflammation, platelet activation, endothelial dysfunction and stasis.4 The initial signs of coagulopathy due to COVID-19 have been found to be marked increases in fibrin/fibrinogen-degradation products and D-dimer levels. It was observed that our patient had high levels of fibrinogen and D-dimer from the time when she was diagnosed with COVID-19 to the time when she was diagnosed with venous sinus thrombosis.\n\nIn the early stages of the disease, abnormalities in prothrombin time, partial thromboplastin time and platelet count are uncommon.5 Detection of deep vein thrombosis (58%) as the autopsy finding among more than half of the 12 patients who died of COVID-19, and pulmonary embolism as the cause of death among one third of the patients, has emphasized the importance of not ignoring the tendency towards occurrences of thrombosis in the course of this disease. Hence, anticoagulants should be included during treatment planning.6 Analysis on the data on 184 patients with COVID-19 infection who were monitored in an intensive care unit showed that 31% of them had thrombotic complications. Thus, prophylaxis for thrombosis was strongly recommended for patients hospitalized with this diagnosis.7\n\nOn the other hand, some published papers have argued that the signs and symptoms of severe COVID-19 infection are more similar to the pathophysiology and phenotype of complement-mediated thrombotic microangiopathy (TMA), rather than to sepsis-induced coagulopathy or diffuse intravascular coagulation (DIC).8 Thrombotic microangiopathy is characterized by organ damage such as microangiopathic hemolytic anemia, thrombocytopenia, and neurological, renal and cardiac dysfunction. Thrombocytopenia and neurological deficits were also observed in our patient. In another study, anemia, increased lactate dehydrogenase (LDH), thrombocytopenia and organ damage (neurological in all patients and cardiac in one) were explained by thrombotic microangiopathy in three patients with a diagnosis of COVID-19.9\n\nCerebral venous thrombus differs significantly from arterial infarctions in terms of risk factors. Hypercoagulability is an important risk factor and an important cause of stroke in young people. Women are affected three times more often than men. The most common symptoms are headache, seizures and focal neurological deficits. The diagnosis can be confirmed by magnetic resonance imaging, computed tomography-venography or catheter angiography.\n\nThe primary treatment for venous sinus thrombosis is anticoagulation, based on the limited evidence from randomized trials. Although a small series of cases has indicated that endovascular therapy may be promising, these data require confirmation through a randomized trial. Decompressive surgery can be lifesaving for patients at risk of herniation. The prognosis is generally better than that for arterial stroke.12 Although venous sinus thrombosis was previously considered to be a life-threatening condition, it is known that the mortality rate in these cases declines over time. Moreover, increased clinical awareness, development of neuroimaging techniques and improvement in therapeutic management have provided better prognoses through enabling earlier diagnosis and identification of less severe cases.13\n\nPregnancy and the puerperium are common causes of transient prothrombotic conditions. About 2% of pregnancy-related strokes can be attributed to venous sinus thrombosis. In the puerperium, the rate of venous sinus thrombosis is 12 cases per 100,000 births. This venous rate in the puerperal period is only slightly lower than that of arterial stroke. Women are at risk of venous thromboembolic events during pregnancy and for up to six to eight weeks after delivery. Most cases of pregnancy-related venous sinus thrombosis are seen in the third trimester or, more often, in the puerperium, when the body prepares for delivery through hypercoagulation. In a paper published in Canada, it was reported that frequency of venous sinus thrombosis in the postpartum period is much higher than during pregnancy. In the puerperium period, the presence of infection and use of instrumental delivery or cesarean section increase the risk of venous sinus thrombosis. During pregnancy, it is known that the risk of venous sinus thrombosis increases in the presence of hypertension, infections and excessive vomiting, and as the maternal age increases.14 The European Academy of Neurology has recommended that treatment for acute venous sinus thrombosis should start with oral anticoagulant therapy (vitamin K antagonists) for 3-12 months, according to risk factors.15\n\nAnother risk factor with a relationship to venous sinus thrombosis that is clearly known is inflammation. Venous sinus thrombosis is associated with systemic inflammatory conditions such as Behçet’s disease and inflammatory bowel disease, in addition to infections such as otitis, mastoiditis, sinusitis, dental infections and skin abscesses in neighboring tissues and meningitis.13 In the anamnesis and examination of our patient, no finding suggesting adjacent tissue infection or Behçet’s or inflammatory bowel disease was found.\n\nAntinuclear antibody positivity can be seen in autoimmune diseases, especially systemic lupus erythematosus, but it is not a laboratory test specific to autoimmune diseases. Since antinuclear antibody positivity can be observed in acute or chronic infectious processes,16 it was planned that our patient would undergo this examination after discharge. The anamnesis of our patient was negative for rheumatological diseases.\n\nThe etiology of venous sinus thrombosis can be explained in terms of the classical Virchow triad, i.e. blood flow stasis, vessel wall changes and changes in blood content. We believe that the combination of pregnancy and systemic inflammation due to COVID-19 caused thrombosis in our patient, on the basis of genetic prothrombin heterozygous mutation.\n\nOne of the clinical manifestations of COVID-19 is nonspecific headache, as is also frequently observed during other viral infections. However, this symptom can often be mild enough to lag behind other clinical findings. If there is no visual impairment, focal neurological deficit or seizure, venous sinus thrombosis can be neglected in the differential diagnosis. Our patient was diagnosed not after occurrences of headache and nausea-vomiting, but after admission to the hospital because of the accompanying symptoms of right hemiparesis. In our case, like what has been described in the literature,11 the central nervous system event started on the ninth day after COVID-19 infection began, and a stroke occurred on the 13th day. Thus, within four days, the rapid clinical progression resulted in parenchymal ischemia. The neurological clinical findings rapidly improved in parallel with the end of pregnancy, start of administration of low molecular weight heparin and decrease in infection parameters.\n\nReports correlating COVID-19, headache and pregnancy are very rare (Table 1).\n\nTable 1. Search of the literature in medical databases for case reports on COVID-19, pregnancy and headache on November 6, 2020\n\nDatabase\tSearch strategies\tPapers found\tPapers related (to pregnancy, headache and COVID-19)\tEtiology\tMain neurological symptom\t\nMEDLINE\n\n(via PubMed)\n\n\tCOVID-19 [MESH]\n\nPregnancy [MESH]\n\nHeadache [MESH]\n\nCase Report [ptyp]\n\n\t2\t2\tSpinal anesthesia 1\n\nPituitary apoplexy 1\n\n\tHeadache\t\nCochrane\tCOVID-19 [MESH]\n\nPregnancy [MESH]\n\nHeadache [MESH]\n\nCase Report [ptyp]\n\n\t0\t0\t0\t0\t\nEmbase\tCOVID-19 [MESH]\n\nPregnancy [MESH]\n\nHeadache [MESH]\n\nCase Report [ptyp]\n\n\t0\t0\t0\t0\t\n\nCONCLUSION\n\nHeadache is one of the common symptoms of COVID-19. In the presence of other risk factors accompanying COVID-19, the risk of thromboembolic events increases significantly. Among patients with suspected COVID-19, considering venous sinus thrombosis in the differential diagnosis may be life-saving, through enabling early diagnosis and treatment. This is especially so in the presence of causes of hypercoagulability such as pregnancy, malignancy and presence of atypical features like analgesic unresponsiveness, awakening from sleep, visual impairment, neurological deficits or seizures.\n\n1 University of Health Sciences, Konya Education and Research Hospital, Konya, Turkey\n\nSources of funding: None\n==== Refs\nREFERENCES\n\n1 Li T Lu H Zhang W Clinical observation and management of COVID-19 patients Emerg Microbes Infect 2020 9 1 687 690 10.1080/22221751.2020.1741327 32208840\n2 Long B Brady WJ Koyfman A Gottlieb M Cardiovascular complications in COVID-19 Am J Emerg Med 2020 38 7 1504 1507 10.1016/j.ajem.2020.04.048 32317203\n3 Akhmerov A Marbán E COVID-19 and the Heart Circ Res 2020 126 10 1443 1455 10.1161/CIRCRESAHA.120.317055 32252591\n4 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 2973 10.1016/j.jacc.2020.04.031 32311448\n5 Connors JM Levy JH COVID-19 and its implications for thrombosis and anticoagulation Blood 2020 135 23 2033 2040 10.1182/blood.2020006000 32339221\n6 Wichmann D Sperhake JP Lütgehetmann M Autopsy Findings and Venous Thromboembolism in Patients With COVID-19 Ann Intern Med 2020 173 4 268 277 10.7326/M20-2003 32374815\n7 Klok FA Kruip MJHA van der Meer NJM Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Thromb Res 2020 191 145 147 10.1016/j.thromres.2020.04.013 32291094\n8 Gavriilaki E Brodsky RA Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily Br J Haematol 2020 189 6 e227 e230 10.1111/bjh.16783 32369610\n9 Zhang Y Xiao M Zhang S Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19 N Engl J Med 2020 382 17 e38 10.1056/NEJMc2007575 32268022\n10 Ellul MA Benjamin L Singh B Neurological associations of COVID-19 Lancet Neurol 2020 19 9 767 783 10.1016/S1474-4422(20)30221-0 32622375\n11 Li Y Li M Wang M Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study Stroke Vasc Neurol 2020 5 3 279 284 10.1136/svn-2020-000431 32616524\n12 Zuurbier SM Coutinho JM Cerebral Venous Thrombosis Adv Exp Med Biol 2017 906 183 193 10.1007/5584_2016_115 27628005\n13 Coutinho JM Zuurbier SM Stam J Declining mortality in cerebral venous thrombosis: a systematic review Stroke 2014 45 5 1338 1341 10.1161/STROKEAHA.113.004666 24699058\n14 Saposnik G Barinagarrementeria F Brown RD Jr Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke 2011 42 4 1158 1192 10.1161/STR.0b013e31820a8364 21293023\n15 Ferro JM Bousser MG Canhão P European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis - endorsed by the European Academy of Neurology Eur J Neurol 2017 24 10 1203 1213 10.1111/ene.13381 28833980\n16 Litwin CM Binder SR ANA testing in the presence of acute and chronic infections J Immunoassay Immunochem 2016 37 5 439 452 10.1080/15321819.2016.1174136 27050929\n\n",
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"issue": "139(2)",
"journal": "Sao Paulo medical journal = Revista paulista de medicina",
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"mesh_terms": "D000086382:COVID-19; D000086742:COVID-19 Testing; D002681:China; D005260:Female; D006261:Headache; D006801:Humans; D010291:Paresis; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D000086402:SARS-CoV-2; D012851:Sinus Thrombosis, Intracranial; D019851:Thrombophilia; D020246:Venous Thrombosis",
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"title": "Venous sinus thrombosis during COVID-19 infection in pregnancy: a case report.",
"title_normalized": "venous sinus thrombosis during covid 19 infection in pregnancy a case report"
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"abstract": "We report a young patient with a variant of juvenile idiopathic arthritis, who, after 4 years of infliximab treatment, developed miliary tuberculosis (TB) with central nervous system involvement (meningitis and multiple tuberculomas). After anti-TB treatment, clinical and radiologic responses were observed, but severe cerebrospinal fluid and brain inflammatory reaction, nonresponsive to corticosteroids, persisted. It was considered a life-threatening paradoxical reaction based on initial cerebrospinal fluid isolation of Mycobacterium tuberculosis fully sensitive to primary anti-TB drugs. After 4 months in the hospital, infliximab was administered considering that infliximab is a potent tumor necrosis factor α inhibiting agent that participates in the formation and preservation of granulomas and may help to modulate the exaggerated cell-mediated immune response against mycobacterial antigens. Clinical complications associated to brain inflammation resolved, and after 3 years of follow-up, the patient remains self-sufficient without neurologic sequels.",
"affiliations": "Rheumatology Department, Centro Médico ISSEMYM, Toluca, México. jorjaimes@yahoo.com",
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"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000995:Antitubercular Agents; D001171:Arthritis, Juvenile; D005938:Glucocorticoids; D006801:Humans; D000069285:Infliximab; D008279:Magnetic Resonance Imaging; D008297:Male; D009169:Mycobacterium tuberculosis; D014057:Tomography, X-Ray Computed; D014390:Tuberculosis, Meningeal; D014391:Tuberculosis, Miliary; D055815:Young Adult",
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"title": "A life-threatening central nervous system-tuberculosis inflammatory reaction nonresponsive to corticosteroids and successfully controlled by infliximab in a young patient with a variant of juvenile idiopathic arthritis.",
"title_normalized": "a life threatening central nervous system tuberculosis inflammatory reaction nonresponsive to corticosteroids and successfully controlled by infliximab in a young patient with a variant of juvenile idiopathic arthritis"
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"abstract": "Background Pazopanib is approved for metastatic renal cell carcinoma (RCC). We assessed the safety and efficacy of pazopanib with a low fat meal (LFM): <400 cal and < 20% fat or 10 g per meal. Methods A single arm study of pazopanib with a LFM in 16 adult patients with metastatic RCC with a clear cell component, RECIST 1.1 measurable disease, ECOG PS ≤ 2, and ≤ 3 prior therapies. Pazopanib at 400 mg daily given with LFM for 12 weeks. Incremental dose increases up to 800 mg, or irreversible decreases to 200 mg, allowed every 2 weeks. Primary study endpoint was safety; adverse events (AE) measured per CTCAE version 4.0. Secondary endpoints of RECIST 1.1 response with assessment as 12 weeks; pharmacokinetic (PK) analysis at nine time points, and CYP3A4 polymorphism evaluation. Results Pazopanib with a LFM was well tolerated; 13 of 16 subjects completed all 12 weeks. Three patients withdrew due to adverse events (AEs), with five occurrences of grade 3 AEs. Conclusions Pazopanib with a LFM has acceptable safety and comparable efficacy to fasting administration. Total median pazopanib dose per subject for the study duration was 63.5% of maximum possible conventional dose. A larger study is warranted. Clinical Trial Registration Number: NCT02729194.",
"affiliations": "Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA. mreimers@med.umich.edu.;Swedish Medical Center, Swedish Cancer Institute, Seattle, WA, USA.;Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.;College of Literature, Arts and Sciences, University of Michigan, Ann Arbor, MI, USA.;Rogel Cancer Center, University of Michigan Health System, Ann Arbor, MI, USA.;College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.;University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA.;College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.;College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA.;Department of Internal Medicine, Division of Hematology/Oncology, Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.;Department of Internal Medicine, Division of Hematology/Oncology, Ann Arbor, MI, USA.;Department of Internal Medicine, Division of Hematology/Oncology, Ann Arbor, MI, USA.",
"authors": "Reimers|Melissa A|MA|0000-0002-5167-3630;Shango|Maryann M|MM|;Daignault-Newton|Stephanie|S|;Dedinsky|Rachel|R|;Karsies|Danielle|D|;Kraft|Shawna|S|;Riddle|Liam|L|;Felton|Jeremy A|JA|;Wen|Bo|B|;Gersch|Christina|C|;Rae|James M|JM|;Redman|Bruce G|BG|;Alva|Ajjai S|AS|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib",
"country": "United States",
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"journal": "Investigational new drugs",
"keywords": "Advanced disease; Fat meal; Pazopanib; Renal cell carcinoma; Tyrosine kinase inhibitor therapy",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D002292:Carcinoma, Renal Cell; D003131:Combined Modality Therapy; D018752:Diet, Fat-Restricted; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011743:Pyrimidines; D013449:Sulfonamides",
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"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "20980999;25777155;28678138;17620431;19509175;22918879;23964934;27470967;22917595;20100962;28500677;29590007",
"title": "Pazopanib with low fat meal (PALM) in advanced renal cell carcinoma.",
"title_normalized": "pazopanib with low fat meal palm in advanced renal cell carcinoma"
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"companynumb": "PHHY2018US162459",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nNevirapine 400 mg extended release tablets (nevirapine-XR) are a once-daily alternative to nevirapine 200 mg immediate release tablets (nevirapine-IR). Study objectives were to describe the effectiveness and tolerability of nevirapine-XR in clinical practice and, for patients who switched from once daily 2×200 mg nevirapine-IR to nevirapine-XR, compare virological suppression and plasma nevirapine concentrations during each treatment period.\n\n\nMETHODS\nHIV-1-infected adults entered the study cohort if they initiated nevirapine-XR in British Columbia (BC) Canada between 1 April 2012 and 30 September 2012 and were followed until 30 September 2013. Demographic and clinical variables were abstracted from the BC Centre for Excellence in HIV/AIDS databases. Patients who switched from once daily nevirapine-IR to nevirapine-XR were monitored for 6 months pre- and post-switch with comparison of virological suppression (McNeamer's test) and median random plasma nevirapine concentrations (Wilcoxon-Mann-Whitney test) in each period.\n\n\nRESULTS\nThe 536 nevirapine-XR-treated patients were 96% male, median (IQR) age 49.9 (44.0-56.9) years. Median follow-up was 15.6 (14.7-16.5) months, with 474/536 (88%) maintaining virological suppression. Emergent drug resistance developed in 5/536 (1%), adverse drug reactions in 17/536 (3%) and, although 31/536 (6%) reported 'whole' tablets in their stools, this was not associated with adverse outcomes. Among the 305 patients who switched from nevirapine-IR to nevirapine-XR, median (IQR) random plasma nevirapine concentration was higher during nevirapine-IR 5,000 (3,690-6,090) ng/ml than nevirapine-XR 3,930 (3,050-5,150) ng/ml (P<0.001), but there was no difference in virological suppression, 89% and 87% respectively (P=0.414).\n\n\nCONCLUSIONS\nThis post-marketing study affirms the effectiveness and tolerability of nevirapine-XR as an alternative to nevirapine-IR in adults.",
"affiliations": "BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.",
"authors": "Lepik|Katherine J|KJ|;Yip|Benita|B|;McGovern|Rachel A|RA|;Ding|Erin|E|;Nohpal|Adriana|A|;Watson|Birgit E|BE|;Toy|Junine|J|;Akagi|Linda|L|;Harrigan|P Richard|PR|;Moore|David M|DM|;Hogg|Robert S|RS|;Montaner|Julio S G|JS|;Barrios|Rolando|R|",
"chemical_list": "D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D013607:Tablets; D019829:Nevirapine",
"country": "England",
"delete": false,
"doi": "10.3851/IMP2908",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "20(7)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D001955:British Columbia; D015331:Cohort Studies; D003692:Delayed-Action Preparations; D016903:Drug Monitoring; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D019829:Nevirapine; D011159:Population Surveillance; D011358:Product Surveillance, Postmarketing; D019233:Retreatment; D013607:Tablets; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "721-30",
"pmc": null,
"pmid": "25960569",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Post-marketing experience with nevirapine extended release (XR) tablets: effectiveness and tolerability in a population-based cohort in British Columbia, Canada.",
"title_normalized": "post marketing experience with nevirapine extended release xr tablets effectiveness and tolerability in a population based cohort in british columbia canada"
} | [
{
"companynumb": "CA-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-17357BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
... |
{
"abstract": "BACKGROUND\nCrimean-Congo Hemorrhagic fever (CCHF) is endemic in certain areas of Pakistan with 14 outbreaks in addition to many sporadic cases so far. It is highly fatal zoonotic disease caused by bite of infected tick. The objective of our study is to describe clinical features, treatment and outcome of CCHF positive cases during its outbreak in Hazara division, with the intention to bring focus to this fatal emerging disease.\n\n\nMETHODS\nThis study was conducted in Medical A Unit of Ayub Teaching Hospital, Abbottabad for a period of three months. All patients presenting with fever and platelet count less than 50,000/mm3 were included in the study. Apart from baseline investigations their blood samples were sent for the detection of CCHF virus. All patients were given supportive treatment including fresh frozen plasma and were started on oral Ribavirin. All patients were isolated and barrier personal precautions were observed by health care givers.\n\n\nRESULTS\nEighty-eight patients with fever and thrombocytopenia were included. Among these, 8 were found to be positive for CCHF. Supportive treatment with oral Ribavirin was given to all patients. One patient with CCHF died. One left against advice and six patients recovered completely.\n\n\nCONCLUSIONS\nAll patients presenting with acute fever and thrombocytopenia should be suspected and evaluated for CCHF. Oral Ribavirin is safe and effective in the treatment of CCHF.",
"affiliations": null,
"authors": "Malik|Saqib|S|;Diju|Inayat Ullah|IU|;Naz|Farhat|F|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin",
"country": "Pakistan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1025-9589",
"issue": "23(2)",
"journal": "Journal of Ayub Medical College, Abbottabad : JAMC",
"keywords": null,
"medline_ta": "J Ayub Med Coll Abbottabad",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D004196:Disease Outbreaks; D005260:Female; D006479:Hemorrhagic Fever, Crimean; D006801:Humans; D008297:Male; D008875:Middle Aged; D010154:Pakistan; D010976:Platelet Count; D012254:Ribavirin; D016896:Treatment Outcome",
"nlm_unique_id": "8910750",
"other_id": null,
"pages": "90-2",
"pmc": null,
"pmid": "24800352",
"pubdate": "2011",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Crimean Congo hemorrhagic fever in Hazara division.",
"title_normalized": "crimean congo hemorrhagic fever in hazara division"
} | [
{
"companynumb": "PK-KADMON PHARMACEUTICALS, LLC-KAD201407-000740",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadd... |
{
"abstract": "BACKGROUND\nPemphigus vulgaris patients with exclusive oral involvement (OPV) treated with conventional immunosuppressive therapy may be non-responders or experience severe side effects and/or relapses. In such cases, rituximab could be used as an adjuvant in recalcitrant OPV patients.\n\n\nMETHODS\nA retrospective single-center study on patients with oral pemphigus vulgaris treated with RTX at a dose of 375 mg/m2 was performed, evaluating the complete clinical and immunological remission, side effects of RTX, and possible correlation between anti-desmoglein (Dsg) 3 antibodies and clinical remission.\n\n\nRESULTS\nWe treated 10 OPV patients, of which 60% had a moderate and 40% mild disease severity before therapy with RTX. Complete clinical remission (CCR) was achieved in 100% of OPV patients, of which 20% developed side effects and 20% experienced a relapse in a mean time of 15.2 ± 10.2 weeks. The mean time for CCR was achieved in 19.8 ± 10.3 weeks, whereas the duration of the CCR consisted in 37.4 ± 33.5 weeks. OPV patients underwent a mean follow-up of 57.2 ± 37.7 weeks. In all patients, the mean of pemphigus disease area index (PDAI) decreased from 20.3 ± 14.1 to 0.4 ± 0.0, whereas the mean Dsg3 value dropped from 157.1 ± 40.6 to 67.0 ± 26.6 after therapy with RTX. However, no correlation was found between PDAI and anti-Dsg3 antibodies before and after therapy with RTX (P > .05).\n\n\nCONCLUSIONS\nRTX represents a valid and safe alternative as an adjuvant in OPV patients with low rate of relapses and side effects.",
"affiliations": "Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy.;Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy.;Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy.;Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy.;Department of Economics and Statistics, Federico II University of Naples, Naples, Italy.;Department of Medicine, Surgery and Dentistry, University of Salerno, Fisciano, Italy.;Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University of Naples, Naples, Italy.",
"authors": "Fortuna|Giulio|G|https://orcid.org/0000-0001-7655-3523;Calabria|Elena|E|;Ruoppo|Elvira|E|;Adamo|Daniela|D|https://orcid.org/0000-0002-3784-4229;Aria|Massimo|M|;Amato|Massimo|M|;Mignogna|Michele D|MD|",
"chemical_list": "D051184:Desmoglein 3; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "Denmark",
"delete": false,
"doi": "10.1111/jop.12951",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0904-2512",
"issue": "49(1)",
"journal": "Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology",
"keywords": "OPV; desmoglein; disease severity; oral pemphigus vulgaris; remission; rituximab",
"medline_ta": "J Oral Pathol Med",
"mesh_terms": "D051184:Desmoglein 3; D006801:Humans; D007166:Immunosuppressive Agents; D010392:Pemphigus; D012189:Retrospective Studies; D000069283:Rituximab",
"nlm_unique_id": "8911934",
"other_id": null,
"pages": "91-95",
"pmc": null,
"pmid": "31420993",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The use of rituximab as an adjuvant in the treatment of oral pemphigus vulgaris.",
"title_normalized": "the use of rituximab as an adjuvant in the treatment of oral pemphigus vulgaris"
} | [
{
"companynumb": "IT-CELLTRION INC.-2019IT025136",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nWe conducted a randomized, multicenter, phase III trial to compare S-1 plus docetaxel (DS) with S-1 plus cisplatin (SP) as adjuvant chemotherapy for stage III gastric cancer patients.\nStage III gastric cancer patients who had received curative gastrectomy with D2 lymphadenectomy were randomized into equal groups to receive adjuvant chemotherapy of eight cycles of DS (S-1 70 mg/m2 /day on days 1-14 plus docetaxel 35 mg/m2 on days 1 and 8) every 3 weeks or SP (S-1 70 mg/m2 /day on days 1-14 plus cisplatin 60 mg/m2 on day 1) every 3 weeks. The primary endpoint was 3-year disease-free survival (DFS) rate.\n\n\nRESULTS\nBetween November 2010 and July 2013, 153 patients (75 patients to DS and 78 patients to SP) were enrolled from 8 institutions in Korea. After the capecitabine plus oxaliplatin was approved based on the CLASSIC study, itwas decided to close the study early. With a median follow-up duration of 56.9 months, the 3-year DFS rate between two groups was not significantly different (49.14% in DS group vs. 52.5% in SP group). The most common grade 3-4 adverse event was neutropenia (42.7% in DS and 38.5% in SP, p=0.351). SP group had more grade 3-4 anemia (1.3% vs. 11.5%, p=0.037), whereas grade 3-4 hand-foot syndrome (4.1% vs. 0%, p=0.025) and mucositis (10.7% vs. 2.6%, p=0.001) were more common in DS group. Fifty-one patients (68%) in DS group and 52 (66.7%) in SP group finished planned treatment.\n\n\nCONCLUSIONS\nOur findings suggest that SP or DS is an effective and tolerable option for patients with curatively resected stage III gastric cancer.",
"affiliations": "Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.;Department of Biostatistics, Yonsei University College of Medicine, Seoul, Korea.;Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea.;Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea.;Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang, Korea.;Division of HematologyOncology, Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.;Division of HematoOncology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.;Department of Surgery, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.;Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.",
"authors": "Lee|Choong-Kun|CK|;Jung|Minkyu|M|;Kim|Hyo Song|HS|;Jung|Inkyung|I|;Shin|Dong Bok|DB|;Kang|Seok Yun|SY|;Zang|Dae Young|DY|;Kim|Ki Hyang|KH|;Lee|Moon Hee|MH|;Kim|Bong-Seog|BS|;Lee|Kyung Hee|KH|;Cheong|Jae-Ho|JH|;Hyung|Woo Jin|WJ|;Noh|Sung Hoon|SH|;Chung|Hyun Cheol|HC|;Rha|Sun Young|SY|",
"chemical_list": "D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D000077143:Docetaxel; D010094:Oxonic Acid; D002945:Cisplatin",
"country": "Korea (South)",
"delete": false,
"doi": "10.4143/crt.2018.028",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 2939765910.4143/crt.2018.028crt-2018-028Original ArticleS-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial Lee Choong-kun 1Jung Minkyu 1Kim Hyo Song 1Jung Inkyung 2Shin Dong Bok 3Kang Seok Yun 4Zang Dae Young 5Kim Ki Hyang 6Lee Moon Hee 7Kim Bong-Seog 8Lee Kyung Hee 9Cheong Jae-Ho 10Hyung Woo Jin 10Noh Sung Hoon 10Chung Hyun Cheol 11112Rha Sun Young 11112\n1 Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea\n2 Department of Biostatistics, Yonsei University College of Medicine, Seoul, Korea\n3 Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea\n4 Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea\n5 Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang, Korea\n6 Division of HematologyOncology, Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea\n7 Division of Hematology-Oncology, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea\n8 Division of HematoOncology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Korea\n9 Division of Hematology-Oncology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea\n10 Department of Surgery, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea\n11 Song-Dang Institutefor Cancer Research, Yonsei University College of Medicine, Seoul, Korea\n12 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Sun Young Rha, MD, PhD Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: 82-2-2228-8050 Fax: 82-2-362-5592 E-mail: rha7655@yuhs.ac* Choong-kun Lee and Minkyu Jung contributed equally to this work.\n\n1 2019 5 2 2018 51 1 1 11 9 1 2018 30 1 2018 Copyright © 2019 by the Korean Cancer Association2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nWe conducted a randomized, multicenter, phase III trial to compare S-1 plus docetaxel (DS) with S-1 plus cisplatin (SP) as adjuvant chemotherapy for stage III gastric cancer patients.\n\nMaterials and Methods\nStage III gastric cancer patients who had received curative gastrectomy with D2 lymphadenectomy were randomized into equal groups to receive adjuvant chemotherapy of eight cycles of DS (S-1 70 mg/m2/day on days 1-14 plus docetaxel 35 mg/m2on days 1 and 8) every 3 weeks or SP (S-1 70 mg/m2/day on days 1-14 plus cisplatin 60 mg/m2on day 1) every 3 weeks. The primary endpoint was 3-year disease-free survival (DFS) rate.\n\nResults\nBetween November 2010 and July 2013, 153 patients (75 patients to DS and 78 patients to SP) were enrolled from 8 institutions in Korea. After the capecitabine plus oxaliplatin was approved based on the CLASSIC study, itwas decided to close the study early. With a median follow-up duration of 56.9 months, the 3-year DFS rate between two groups was not significantly different (49.14% in DS group vs. 52.5% in SP group). The most common grade 3-4 adverse event was neutropenia (42.7% in DS and 38.5% in SP, p=0.351). SP group had more grade 3-4 anemia (1.3% vs. 11.5%, p=0.037), whereas grade 3-4 hand-foot syndrome (4.1% vs. 0%, p=0.025) and mucositis (10.7% vs. 2.6%, p=0.001) were more common in DS group. Fifty-one patients (68%) in DS group and 52 (66.7%) in SP group finished planned treatment.\n\nConclusion\nOur findings suggest that SP or DS is an effective and tolerable option for patients with curatively resected stage III gastric cancer.\n\nStomach neoplasmsStage IIIS-1 based doubletDocetaxelCisplatinAdjuvant chemotherapy\n==== Body\nIntroduction\nGastric cancer is the second leading cause of the cancer death worldwide, and is particularly prevalent in Eastern Asia, Eastern Europe, and South America [1]. The overall 5-year relative survival rate was 37.8% in the Surveillance, Epidemiology, and End Results data [2], and 55.7% in the Korea National Cancer Incidence Database [3] for locally advanced gastric cancer. Complete surgical resection remains the only chance of a cure in gastric cancer patients, and gastrectomy with D2 lymphadenectomy is a standard surgical treatment for locally advanced gastric cancer. Since approximately 40% to 80% of gastric cancer patients still suffer recurrence and ultimately die from the disease [4], there has always been an urgent need for effective adjuvant chemotherapy or radiotherapy. The recent adjuvant trials in gastric cancer have shown improved survival in patients treated with adjuvant chemotherapy compared to those who underwent surgery alone [5,6] especially in Asia. Based on individual patient data from 17 randomized clinical trials, metaanalysis from the GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) group showed that postoperative adjuvant chemotherapy based on a fluorouracil regimen was associated with longer survival in gastric cancer compared with surgery alone [7]. In 2007, a large-scale study by the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) group reported the first positive phase III result addressing superiority of adjuvant chemotherapy with an oral fluoropyrimidine, S-1 monotherapy versus surgery [5]. However, subgroup analysis revealed that S-1 only provided a survival benefit among patients with an early disease stage (II or IIIA) who had undergone D2 gastrectomy [8]. Therefore, a more efficient chemotherapy regimen, for example one based on a drug doublet, is needed to improve the outcome of patients with locally advanced—especially stage III—gastric cancer after curative resection. With only limited adjuvant S-1 monotherapy benefit in stage III gastric cancer patients even after 5-year follow up period of the ACTS-GC trial [8], and no general consensus about the best adjuvant treatment option, we designed a phase III trial to establish the effectiveness of an S-1 containing doublet regimen for advanced American Joint Committee on Cancer (AJCC) seventh stage III patients after curative gastrectomy. Capecitabine plus oxaliplatin seems to be effective for advanced stage II and III gastric cancer patients, but the high incidence of hand-foot syndrome and peripheral neuropathy are toxic for many patients [6]. And the CLASSIC trial result was not available when we planned this phase III trial. Because S-1 is tolerable and widely accepted as an effective therapeutic agent for resected gastric cancer in an adjuvant setting, adding other cytotoxic agent seemed reasonable.\n\nIn order to identify an efficient doublet antineoplastic regimen that could improve treatment outcome, among late stage advanced gastric cancer patients after D2 gastrectomy, the Post Operation chemotherapy with S-1 and Taxotere in curatively resected gastric cancer of stage III (POST) study was designed. This study compared the effect of two adjuvant S-1 based doublet regimens, S-1 plus docetaxel (DS) with S-1 plus cisplatin (SP), on the disease-free survival (DFS) of D2 resected stage III gastric cancer patients. There have been several previous randomized control trials of DS or SP as palliative treatments in metastatic gastric cancer [9-11], but there has been no phase III study to directly compare these two doublet regimens, or to assess their use in adjuvant therapy for D2 resected stage III advanced gastric cancer.\n\nMaterials and Methods\n1. Study design and treatment\nThe POST trial was an open-label, phase III, randomized controlled study, performed in eight centers in South Korea. The primary aim of the study was to compare the DFS following S-1 doublets between DS and SP. Gastrectomy with D2 lymphadenectomy has been performed as a standard procedure by all of the surgeons who participated in this trial and the pathology reports were standardized based on D2 dissection in each institute. The patients were randomly assigned to 6 months of treatment with eight cycles of either DS (intravenous docetaxel [35 mg/m2 on days 1 and 8 of each cycle] plus oral S-1 [35 mg/m2 twice daily on days 1 to 14 of each cycle]) every 3 weeks, or SP (intravenous cisplatin [60 mg/m2 on day 1] plus S-1 [same dosage utilized in DS]) every 3 weeks. Oral S-1 was ministered after meal within one hour. Pre-hydration before intravenous cisplatin following the institutional protocol was mandatory to prevent nephrotoxicity. The randomization was stratified by institution and disease stage (IIIA vs. IIIB vs. IIIC). Each stratum was randomized using the randomly permuted block method.\n\n2. Patients\nInclusion criteria for patients were that they should have histopathologically confirmed AJCC seventh stage III gastric adenocarcinoma; undergone R0 resection (with no residual microscopic tumor cells including margin) with D2 lymph node dissection; age of 20 years or older; adequate renal function (creatinine clearance > 50 mL/min), hepatic function (total bilirubin ≤ 1.5 times the upper limit of normal [ULN], aspartate or alanine aminotransferase ≤ 2.5 times the ULN, alkaline phosphatase ≤ 2.5 times the ULN), and hematological function (absolute neutrophil count ≥ 1.5×109/L or platelet count ≥ 100×109/L); and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion criteria were as follows: a tumor other than adenocarcinoma; pregnancy or breast feeding; evidence of metastasis including peritoneal or distant metastasis; any previous treatment of cytotoxic chemotherapy, radiotherapy, or immunotherapy for gastric cancer; previous major surgery within 4 weeks before the start of the trial, or a failure to recover from the surgery; previous history of other malignancies within 5 years except for cured skin basal cell carcinoma or cured in situ cervix cancer; gastrointestinal obstruction or malabsorption syndrome that can negatively affect S-1 absorptions; R1 or R2 resection; other severe medical conditions; known dihydropyrimidine dehydrogenase deficiency; sensitivity to platinum agents or docetaxel; and inadequate organ function. All the patients had been randomized into either treatment group within 8 weeks after surgery.\n\n3. Study end points and assessments\nThree-year DFS rate was chosen as the primary endpoint because a recent meta-analysis showed that DFS is an acceptable surrogate end point for overall survival (OS) in trials of cytotoxic agents for gastric cancer in the adjuvant setting [12]. DFS was defined as the time from randomization to the time of recurrence of gastric cancer or death from any cause, and was to be analyzed by intent-to-treat. Secondary end points included OS, defined as the time from randomization to the time of death from any cause, and safety profiles (adverse events). Tumors were assessed radiographically using computed tomography at screening (baseline), every 3 months after randomization during years 1 and 2, every 6 months during year 3, and then yearly.\n\nToxicity was closely monitored during each treatment cycle, and adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events ver. 4.0. The dose of each chemotherapeutic agent could be reduced if any of the following toxicities occurred in the preceding cycle: grade 4 leukopenia, neutropenia or thrombocytopenia, febrile neutropenia grade 3 or higher, non-hematologic toxicity grade 3 or higher except for hand foot syndrome, cardiac toxicity, and elevated bilirubin of grade 2 or higher. The study drugs were discontinued if recovery did not occur within 3 weeks from the planned day 1.\n\n4. Statistical methods\nThe intent-to-treat (ITT) patient population, the population for all primary analyses, included all randomly assigned patients who had received at least one cycle of their allocated treatment. Three-year DFS rate, the primary end point, was predicted to be 40.0% and 55.0% in SP group and DS group, respectively (hazard ratio [HR], 0.65), based on two docetaxel and cisplatin combined studies [9,13]. Kaplan-Meier estimates and Cox regression analyses of DFS and OS were calculated. The two groups were compared using the stratified log-rank test. With a predicted median follow-up duration of 3 years, 173 events were necessary to ensure 80% power for a twosided test at a significance level of 0.05. A sample size of 145 patients in each group was planned, allowing for a 10% dropout rate. The safety analysis included all the ITT patients. SPSS ver. 20 (IBM Corp., Armonk, NY) and the statistical software package R ver. 13.0 were used for statistical analyses. A p-value of less than 0.05 was considered statistically significant.\n\n5. Accrual and time of analysis\nIn January 2012, the phase III capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study showed a survival benefit of adjuvant capecitabine and oxaliplatin chemotherapy compared to surgery alone, among stage II-III gastric cancer patients who had undergone curative D2 gastrectomy [6]. Based on this trial, in March 2013, the Korean Food and Drug Administration approved the use of capecitabine and oxaliplatin for adjuvant chemotherapy after curative gastrectomy. Since patients could be reimbursed by National Insurance of Korea for the use of capecitabine and oxaliplatin as an adjuvant therapy, the accrual rate of the POST trial was reduced. The trial committee decided to close the study early with the last patient enrolled in July 2013, and the data cut-off date was April 30, 2017.\n\n6. Ethical statement\nThe protocol was approved by the institutional review and ethics board of each participating center. The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines defined by the International Conference on Harmonization. All patients provided written, informed consent before enrollment. The trial is registered at ClinicalTrials.gov (NCT01283217).\n\nResults\n1. Patient characteristics\nBetween November 2010 and July 2013, a total of 153 patients from eight centers in South Korea were randomly assigned to DS (n=75) or SP (n=78) treatment groups (S1 Fig.). Patient demographics and baseline disease characteristics were well balanced between the two groups. Poorly differentiated and diffuse types of adenocarcinoma were the most common histological type. Most of the patients had AJCC seventh edition stage IIIB (n=69, 45.1%) or stage IIIC disease (n=65, 42.5%) (Table 1).\n\n2. Treatment compliance and toxicity\nThe median number of treatment cycles in each group was 8 (range, 1 to 8 cycles). The median relative dose intensity (RDI) was 0.86 for both docetaxel and S-1 in DS group and 0.83 for cisplatin and 0.86 for S-1 in SP group. The RDI of S-1 in both groups was reduced from the second cycle, and the RDI of docetaxel in DS group and cisplatin in SP group was reduced from the third cycle (Fig. 1). The number of the patients who could not complete the full eight cycles of chemotherapy was 24 (32.0%) in DS group and 26 (33.3%) in SP group (p=0.683).\n\nMost patients (98.7%) reported at least one adverse event. The total incidence of grade 3 or 4 adverse events was 46 (61.3%) in DS group and 44 (56.4%) in SP group (p=0.536). The most common grade 3 or 4 adverse event was neutropenia (42.7% in DS group and 38.5% in SP group, p=0.351) (Table 2). SP treatment was associated with more frequent hematologic adverse events such as grade 3 or 4 anemia (1.3% vs.11.5%, p=0.037) or any grade of thrombocytopenia (2.6% vs. 24.3%, p < 0.001). However, grade 3 or 4 non-hematologic adverse events including hand-foot syndrome (4.1% vs. 0%, p=0.025) and mucositis (10.7% vs. 2.6%, p=0.001) were more commonly observed in DS group. Grade 1 or 2 paronychia (10.7% vs. 0%, p=0.003) and alopecia (45.3% vs. 5.1%, p < 0.001) were also more common in DS group. There was one treatment-related death in DS group, from a thromboembolic event. The day after starting the seventh cycle of DS treatment, this 67-year-old female patient’s dyspnea on exertion worsened, and the patient died due to left pulmonary artery thromboembolism. The patient did not have any other pre-disposing factor for pulmonary thromboembolism.\n\nAmong total 495 treatment cycles for DS group and 512 cycles for SP group, 130 cycles (26.3%) in DS group and 172 cycles (33.6%) in SP group (p=0.011) were delayed. The chemotherapy dose was reduced in 71 cycles (14.3%) in DS group and 56 cycles (10.9%) in SP group (p=0.104). Overall, the most common reason for delay in the initiation of treatment in each cycle and for the dose reduction was neutropenia (76.8% for of delayed cycles and 52.0% of dose reduced cycles) (Table 3). With respect to adverse events (Table 2), treatment delays were more common in SP group which was associated with more frequent hematologic toxicities, whether dose reductions were more common in DS group which experienced more non-hematologic toxicities.\n\nThe treatment discontinuations were permanently developed from 24 patients in DS group and from 26 patients in SP groups. The main reason for discontinued treatment was toxicity (12 [50.0%] in DS group and 13 [50.0%] in SP group) (S1 Fig.). The reasons for discontinuation due to toxicity in DS group were allergic reaction (n=3), neutropenia, afferent loop syndrome, skin rash, thromboembolic event, ileus, hand-foot syndrome, general weakness, dyspnea, and nausea/vomiting (n=1 for each). In SP group, toxicities that resulted in treatment discontinuation were neutropenia (n=3), general weakness (n=2), thrombocytopenia, myocardiac infarction, neuropathy, skin rash, anorexia, acute cerebral infarction and pneumonitis (n=1 for each). Three patients in DS group and four patients in SP group were off the study because of gastric cancer recurrence during the course of the trial treatment.\n\n3. Survival analysis\nThe median duration of follow-up was 53.6 months (range, 1.1 to 74.0 months) for DS group and 57.3 months (range, 1.7 to 73.1 months) for SP group. At the cut-off date for data collection on April 30, 2017, 43 patients (57.3%) in DS group and 40 patients (53.3%) in SP group developed DFS events. The most common site of recurrence was the peritoneum (20 and 11 cases in DS and SP groups, respectively) (Table comparing pattern of recurrences in S2 Table). Primary endpoint, the 3-year DFS rate, was 49.1% in DS group (median DFS, 35.5 months) and 52.5% in SP group (median DFS, 39.3 months). The 3-year survival rate was 60.7% among DS group and 66.4% among SP group, with 31 (41.3%) and 32 (41.0%) deaths in DS group (median OS, not reached) and SP group (median OS, 64.4 months), during the follow-up period. Every death was cancer-related. There was no statistically significant difference in DFS (HR, 1.201; 95% confidence interval [CI], 0.781 to 1.848; p=0.404) or OS (HR, 1.081; 95% CI, 0.659 to 1.772; p=0.757) between DS and SP groups (Fig. 2). The DFS and OS of eligible patients were also analyzed according to sex, age, ECOG performance status, cancer stage based on AJCC seventh, tumor stage, and nodal stage. Stage IIIC subgroup among SP group showed significant benefit of DFS (HR, 2.018; 95% CI, 1.108 to 3.675; p=0.022), and OS (HR, 2.149; 95% CI, 1.018 to 4.533; p=0.048), but there was no significant interaction between the treatment group and any other subgroups in terms of survival (Forest plots in S3 Fig.).\n\nDiscussion\nThis POST trial is the first randomized phase III trial comparing efficacy and tolerability of two S-1 based doublet regimens, DS and SP, in curatively resected stage III gastric cancer patients based on the AJCC seventh edition. Unfortunately, because of the early termination, we could not show any statistically significant advantage in terms of OS or DFS for either regimen. However, both treatments seem to be an effective and tolerable option for these patients.\n\nS-1 was regarded to have advantages over capecitabine among Asians in terms of reducing incidence of toxicities such as stomatitis and hand-foot syndrome [15]. Several chemotherapeutic regimens combining S-1 with other anticancer agents have been shown to improve the response rate or median survival time in gastric cancer, mostly in phase II studies [16-20]. From among many possible combinations of anti-cancer drugs, we compared S-1 plus taxane (DS) with S-1 plus platinum (SP) in this phase III study. Taxanes like docetaxel has been shown to prolong survival when used as a palliative treatment for advanced gastric cancer [21]. The phase III START trial showed that the combination of S-1 and docetaxel is more effective than S-1 monotherapy for metastatic gastric cancer patients, with longer survival (12.5 months vs. 10.8 months, p=0.032) and a significant (16%) reduction in the risk of death [22]. In addition, a phase II study comparing docetaxel plus S-1 to docetaxel plus cisplatin suggested that DS was more effective (OS, 16 vs. 8.3 months) among chemotherapy naïve stage IV advanced gastric cancer patients [9]. Recently, another large phase III adjuvant trial (SAMIT) result was published [14]. The study tried to assess the superiority of adding paclitaxel to oral fluoropyrimidines as sequential treatment to locally advanced gastric cancer patients after D2 dissection, but the trial failed to show survival improvement. Cisplatin is generally accepted as a benchmark treatment when combined with 5-fluorouracil for advanced gastric cancer, although it has several drawbacks, including high incidences of nausea, vomiting [23] and renal toxicity [24]. Cisplatin has also been shown to have an additive effect when combined with S-1 in advanced gastric cancer. In the phase III SPIRIT trial, SP resulted in significantly longer survival compared to S-1 alone (OS, 13 months vs. 11 months; p=0.04) and a better response rate (54% vs. 31%) [25]. Based on these previous studies, the aim of this study was compare two S-1 based doublets to determine whether there was a significant increase in the 3-year DFS rate when DS or SP were used to treat patients with stage III gastric cancer.\n\nThe addition of docetaxel or cisplatin to S-1 was well-tolerated. We compared compliances and toxicities of our study (POST) with three published phase III studies of adjuvant chemotherapy for gastric cancer; ACTS-GC, CLASSIC, and SAMIT (Table 4) [5,6,14]. Sixty-eight percent of patients in DS group and 66.7% of patients in SP group completed 8 cycles as planned, which was comparable to that achieved in the ACTS-GC (65.8% for S-1 monotherapy), SAMIT (61.5% for S-1 monotherapy or 70.4% for paclitaxel then S-1 sequential therapy), and CLASSIC (67% for capecitabine plus oxaliplatin) trials. The median RDI was 86% for S-1 in both groups, 86% for docetaxel in DS group, and 83% for cisplatin in SP group. These findings were also comparable to those of CLASSIC trial (capecitabine 85% and oxaliplatin 98%). Comparing toxicities among patients treated using DS or SP with those who were administered S-1 monotherapy (ACTSGC and SAMIT) revealed that adding docetaxel or cisplatin increased hematologic toxicity (neutropenia and anemia) but did not increased non-hematologic toxicities. In the capecitabine plus oxaliplatin group of the CLASSIC trial, 56% of patients experienced grade 3 or 4 adverse events, while in our study 61.3% and 56.4% of patients in DS and SP groups, respectively. A comparison of the treatment groups in this study revealed that patients treated with DS more frequently had non-hematologic toxicities, while those treated with SP more frequently suffered from hematologic toxicities (Table 2). These higher incidences of non-hematologic adverse events in DS group was related to more frequent dose reduction, and higher incidences of hematologic adverse events observed in SP group was related to more frequent treatment cycle delays (Table 3). S4 Table shows a comparison of compliancy rates and toxicities in previously reported adjuvant DS or SP chemotherapy trials, excluding those in which S-1 was given as a monotherapy during the first cycle [26-30].\n\nThe relative small number of accrued patients reduced the statistical power of our study. It is hard to compare survival outcomes of our study to that of previous studies, because this study only included stage III gastric cancer patients diagnosed on the basis of the AJCC seventh edition, and the previous adjuvant phase III studies included patients with stage II or III gastric cancer based on the AJCC sixth edition [6,8]. The more recent staging system classifies more than 15 positive nodes (N3b) as stage IIB or III, whereas it would have been classified as stage IV by the AJCC sixth edition staging system. Furthermore, invasion of the adjacent structure (T4b in the AJCC seventh edition and T4 in the AJCC sixth edition) with any positive node was classed as stage IV disease in the AJCC sixth edition but stage IIIB or IIIC disease in the AJCC seventh edition (S5 Fig.). Comparing the distribution of disease stages according to the AJCC seventh and sixth editions showed that 45 patients (3 patients with stage IIIA, 15 patients with stage IIIB, and 27 patients with stage IIIC; 29.4% in total) in this study would have been stage IV according to the AJCC sixth edition, and would thus not be eligible for the previous ACTS-GC or CLASSIC trials (S6 Fig.). So it is difficult to compare precisely, but our study has enrolled higher stage patients, and survival is similar when compared to Stage IIIB patients of CLASSIC or ACTS-GC trials.\n\nIn conclusion, postoperative DS and SP regimens were well tolerated, and the safety data presented here are comparable with that of previous studies. Since the trial was closed early, it didn’t have sufficient statistical power to show a survival advantage for either regimen. We believe that our preliminary findings warrant further clinical investigation.\n\nThe drugs were supplied by Sanofi-Aventis Korea and Jeil Pharmaceutical.\n\nWe thank the patients, their families, all the investigators, subinvestigators, nurses and study teams. This research was supported by the Public Welfare & Safety Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (2010-0020841).\n\nElectronic Supplementary Material\nSupplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).\n\n Fig. 1. Median relative dose intensities per regimen and cycle. Median relative dose intensities (RDIs) of S-1 in both groups (A) and RDIs of docetaxel in docetaxel plus S-1 (DS) group or cisplatin in S-1 plus cisplatin (SP) group (B).\n\nFig. 2. Kaplan-Meier curves of disease-free survival (A) and overall survival (B) in the intention-to-treat population.\n\nTable 1. Baseline patients’ characteristics\n\nCharacteristic\tDS (n=75)\tSP (n=78)\t\nSex\t\t\t\n Male\t46 (61.3)\t56 (71.8)\t\n Female\t29 (38.7)\t22 (28.2)\t\nAge, median (range, yr)\t54 (33-74)\t58 (25-72)\t\nECOG performance\t\t\t\n 0\t45 (60.0)\t53 (67.9)\t\n 1\t30 (40.0)\t25 (32.1)\t\nCell type (WHO classification)\t\t\t\n Tubular adenocarcinoma well differentiated\t0\t2 (0.3)\t\n Tubular adenocarcinoma moderately differentiated\t20 (26.7)\t26 (33.3)\t\n Tubular adenocarcinoma poorly differentiated\t34 (45.2)\t35 (44.9)\t\n Signet ring cell\t17 (22.7)\t13 (16.7)\t\n Hepatoid adenocarcinoma\t1 (2.4)\t0\t\n Mucinous adenocarcinoma\t2 (2.7)\t1 (2.4)\t\n Undifferentiated adenocarcinoma\t1 (2.4)\t1 (2.4)\t\nLauren classification\t\t\t\n Intestinal type\t11 (14.7)\t16 (20.5)\t\n Diffuse type\t29 (38.7)\t18 (23.1)\t\n Mixed\t2 (2.7)\t8 (10.3)\t\n Unknown\t33 (44.0)\t36 (45.2)\t\nNo. of retrieved lymph nodes, median (interquartile range)\t43 (34-55)\t40 (29-53)\t\nTumor stage\t\t\t\n T2\t2 (2.7)\t3 (3.8)\t\n T3\t15 (20.0)\t24 (30.8)\t\n T4\t58 (77.3)\t51 (65.4)\t\nNodal stage\t\t\t\n 0\t1 (1.3)\t0\t\n 1\t5 (6.7)\t1 (1.3)\t\n 2\t23 (30.7)\t24 (30.8)\t\n 3\t46 (61.3)\t53 (56.7)\t\nAJCC 7th stage\t9 (12.0)\t10 (12.8)\t\n IIIA\t\t\t\n IIIB\t33 (44.0)\t36 (46.2)\t\n IIIC\t33 (44.0)\t32 (41.0)\t\nAJCC 6th stage\t4 (5.3)\t6 (7.7)\t\n II\t\t\t\n IIIA\t26 (34.7)\t31 (39.7)\t\n IIIB\t18 (24.0)\t20 (25.6)\t\n IV\t25 (33.3)\t20 (25.6)\t\nDuration from surgery to initiate chemotherapy, median (range, wk)\t6.13 (2.7-8.7)\t5.66 (2.5-7.8)\t\nValues are presented as number (%) unless otherwise indicated. DS, docetaxel plus S-1; SP, S-1 plus cisplatin; ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization; AJCC, American Joint Committee on Cancer.\n\nTable 2. Adverse events (n=153)\n\nTreatment-related adverse event\tDS (n=75)\tSP (n=78)\tp-value\t\nAll\tG3/4\tAll\tG3/4\t\nAny\t74 (98.7)\t46 (61.3)\t77 (98.7)\t44 (56.4)\t0.536\t\nHematologic toxicity\t\t\t\t\t\t\n Febrile neutropenia\t3 (4.0)\t2 (2.7)\t3 (3.8)\t3 (3.8)\t0.548\t\n Neutropenia\t51 (68.0)\t32 (42.7)\t28 (35.9)\t30 (38.5)\t0.351\t\n Anemia\t41 (54.0)\t1 (1.3)\t45 (57.6)\t9 (11.5)\t0.037\t\n Thrombocytopenia\t2 (2.6)\t1 (1.3)\t19 (24.3)\t1 (1.3)\t< 0.001\t\nNon-hematologic toxicity\t\t\t\t\t\t\n Abdominal pain\t24 (32.0)\t3 (4.1)\t15 (19.2)\t2 (2.6)\t0.193\t\n Anorexia\t48 (64.0)\t5 (6.7)\t47 (60.2)\t5 (6.4)\t0.892\t\n Nausea\t49 (65.3)\t2 (2.7)\t51 (65.4)\t2 (2.6)\t0.999\t\n Vomiting\t16 (21.3)\t1 (1.3)\t17 (21.8)\t1 (1.3)\t0.997\t\n Hand foot syndrome\t18 (24.0)\t3 (4.1)\t7 (9.0)\t0\t0.025\t\n Mucositis\t39 (52.0)\t8 (10.7)\t18 (23.1)\t2 (2.6)\t0.001\t\n Diarrhea\t40 (53.3)\t2 (2.7)\t35 (44.9)\t3 (3.8)\t0.478\t\n Paronychia\t8 (10.7)\t0\t0\t0\t0.003\t\n Alopecia\t34 (45.3)\t0\t4 (5.1)\t0\t< 0.001\t\n Fatigue\t12 (16.0)\t1 (1.3)\t14 (18.0)\t1 (1.3)\t0.944\t\n General weakness\t16 (21.3)\t1 (1.3)\t23 (29.5)\t2 (2.6)\t0.493\t\n Neuropathy\t17 (22.7)\t0\t15 (19.2)\t1 (1.3)\t0.487\t\nValues are presented as number (%). One treatment related death in DS group: thromboembolism event. DS, docetaxel plus S-1; SP, S-1 plus cisplatin.\n\nTable 3. The reasons for chemotherapy cycle delays and reductions\n\n\tDelayed cycles\tDose reduced cycles\t\nDS (n=495)\tSP (n=512)\tDS (n=495)\tSP (n=512)\t\nHematologic\t84\t152\t35\t33\t\n Neutropenia\t83\t149\t35\t31\t\n Febrile neutropenia\t1\t1\t0\t1\t\n Anemia\t0\t1\t0\t0\t\n Thrombocytopenia\t0\t1\t0\t1\t\nNon-hematologic\t46\t20\t36\t23\t\n General weakness\t8\t2\t4\t4\t\n Nausea/Vomiting\t5\t1\t5\t4\t\n Patients' refusal\t4\t6\t2\t0\t\n Mucositis\t4\t2\t9\t2\t\n Urticaria/Skin rash\t4\t0\t1\t0\t\n Anorexia\t3\t4\t3\t3\t\n Hand-foot syndrome\t3\t0\t4\t0\t\n Weight loss\t3\t0\t1\t3\t\n Fatigue\t0\t3\t3\t1\t\n Diarrhea\t0\t2\t1\t3\t\n Hemorrhoid\t2\t0\t0\t0\t\n Nail Infection\t2\t0\t1\t0\t\n Abdominal pain\t1\t0\t0\t2\t\n Generalized edema\t2\t0\t0\t0\t\n Common cold\t2\t0\t0\t0\t\n Herpes zoster\t1\t0\t1\t0\t\n Intestinal obstruction\t1\t0\t0\t0\t\n Bilirubin elevation\t1\t0\t1\t0\t\n Dizziness\t0\t0\t0\t1\t\nTotal, n (%)\t130 (26.3)\t172 (33.6)\t71 (14.3)\t56 (10.9)\t\nDS, docetaxel plus S-1; SP, S-1 plus cisplatin.\n\nTable 4. Comparison of phase III gastric cancer adjuvant chemotherapy studies\n\nReference\tStudy design\tNo.\tStage\tRegimen\tCompletion of total cycles (%)\tRDI\tMedian follow up duration (mo)\t3-Year DFS rate (%)\tG3/4 hematologic toxicity, n (%)\tG3/4 nonhematologic toxicities, n (%)\t\nACTS-GC [5]\tS-1 vs. observation\t529\tAJCC 6th II-IIIB\tS-1 80 mg/m2/D D1-28, q6wks, for 1 yr\t65.8\tN/A\t34.8\t72.2\tLeukopenia 6 (1.2), anemia 6 (1.2)\tAnorexia 31 (6.0), nausea 19 (3.7), deiarrhea 16 (3.1)\t\nCLASSIC [6]\tXELOX vs. observation\t520\tAJCC 6th II-IIIB\tCapecitabine 1,000 mg/m2 BID D1-14, oxaliplatin 130 mg/m2 D1, q3wks, 8 cycles\t67.0\t85% (capecitabine)\t34.2\t74\tNeutropenia 107 (22), thrombocytopenia 40 (8)\tNausea 39 (8.0), vomiting 37 (7.0), decreased appetite, fatigue 23 (5.0)\t\n98% (oxaliplatin)\t\nSAMIT (S-1 only) [14]\tUFT±paclitaxel vs. S-1±paclitaxel\t364\tAJCC 6th I-IV (M0)\tS-1 80 mg/m2 BID D1-14, q3wks, 16 cycles\t61.5\tN/A\t62.8\tN/A (54.0 for monotherapy group)\tNeutropenia 48 (13), anemia 11 (3)\tAnorexia 24 (7), fatigue 12 (3), abnormal total bilirubin 10 (3)\t\nSAMIT (paclitaxel then S-1) [14]\tUFT±paclitaxel vs. S-1±paclitaxel\t355\tAJCC 6th I-IV (M0)\tPalitaxel 80 mg/m2 D1, 8, 1 wk rest then D1, 15 q4wks, 2 cycles (total 3 cycles) → S-1 80 mg/m2 BID D1-14, q3wks, 12 cycles\t70.4\tN/A\t61.3\tN/A (57.2 for sequential group)\tNeutropenia 83 (23), leukopenia 16 (4)\tAnorexia 18 (5), fatigue 16 (4), diarrhea 11 (3)\t\nCurrent study (DS)\tDS vs. SP\t75\tAJCC 6th IIIB-IV (AJCC 7th III)\tS-1 70 mg/m2/D D1-14, docetaxel 35 mg/m2, D1, 8, q3wks, 8 cycles\t68.0\t86% (S-1 and docetaxel)\t53.6\t49.1\tNeutropenia 32 (42.7)\tMucositis 8 (10.8), anorexia 5 (6.8), abd pain 3 (4.1), HFS 3 (4.1)\t\nCurrent study (SP)\tDS vs. SP\t78\tAJCC 6th IIIB-IV (AJCC 7th III)\tS-1 70 mg/m2/D D1-14, docetaxel 60 mg/m2, D1, 8, q3wks, 8 cycles\t66.7\t86% (S-1)\t57.3\t52.5\tNeutropenia 30 (38.5), anemia 9 (11.7)\tAnorexia 5 (6.5), nausea 3 (3.9)\t\n83% (cisplatin)\t\nRDI, relative dose intensity; DFS, disease-free survival; ACTS-GC, Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer; AJCC, American Joint Committee on Cancer; q6wks, ever 6 weeks; N/A, not available; XELOX, Xeloda (capecitabine) plus oxaliplatin; BID, twice a day; q3wks, ever 3 weeks; UFT, uracil-tegafur; q4wks, every 4 weeks; DS, docetaxel plus S-1; SP, S-1 plus cisplatin; HFS, hand-foot syndrome.\n==== Refs\nReferences\n1 Jemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics CA Cancer J Clin 2011 61 69 90 21296855 \n2 Seyedin S Wang PC Zhang Q Lee P Benefit of adjuvant chemoradiotherapy for gastric adenocarcinoma: a SEER population analysis Gastrointest Cancer Res 2014 7 82 90 25276261 \n3 Jung KW Won YJ Kong HJ Oh CM Shin A Lee JS Survival of korean adult cancer patients by stage at diagnosis, 2006-2010: national cancer registry study Cancer Res Treat 2013 45 162 71 24155674 \n4 Gallo A Cha C Updates on esophageal and gastric cancers World J 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2013 105 1600 7 24108812 \n13 Ajani JA Moiseyenko VM Tjulandin S Majlis A Constenla M Boni C Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group J Clin Oncol 2007 25 3205 9 17664467 \n14 Tsuburaya A Yoshida K Kobayashi M Yoshino S Takahashi M Takiguchi N Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial Lancet Oncol 2014 15 886 93 24954805 \n15 Lee JL Kang YK Kang HJ Lee KH Zang DY Ryoo BY A randomised multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer Br J Cancer 2008 99 584 90 18665164 \n16 Koizumi W Tanabe S Saigenji K Ohtsu A Boku N Nagashima F Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer Br J Cancer 2003 89 2207 12 14676796 \n17 Yoshida K Ninomiya M Takakura N Hirabayashi N Takiyama W Sato Y Phase II study of docetaxel and S-1 combination therapy for advanced or recurrent gastric cancer Clin Cancer Res 2006 12 11 Pt 1 3402 7 16740764 \n18 Kakeji Y Oki E Egashira A Sadanaga N Takahashi I Morita M Phase II study of biweekly docetaxel and S-1 combination therapy for advanced or recurrent gastric cancer Oncology 2009 77 49 52 19556809 \n19 Mochiki E Ohno T Kamiyama Y Aihara R Haga N Ojima H Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer Br J Cancer 2006 95 1642 7 17133268 \n20 Inokuchi M Yamashita T Yamada H Kojima K Ichikawa W Nihei Z Phase I/II study of S-1 combined with irinotecan for metastatic advanced gastric cancer Br J Cancer 2006 94 1130 5 16570038 \n21 Van Cutsem E Moiseyenko VM Tjulandin S Majlis A Constenla M Boni C Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group J Clin Oncol 2006 24 4991 7 17075117 \n22 Koizumi W Kim YH Fujii M Kim HK Imamura H Lee KH Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START) J Cancer Res Clin Oncol 2014 140 319 28 24366758 \n23 American Society of Clinical Oncology Kris MG Hesketh PJ Somerfield MR Feyer P Clark-Snow R American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006 J Clin Oncol 2006 24 2932 47 16717289 \n24 Arany I Safirstein RL Cisplatin nephrotoxicity Semin Nephrol 2003 23 460 4 13680535 \n25 Koizumi W Narahara H Hara T Takagane A Akiya T Takagi M S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial Lancet Oncol 2008 9 215 21 18282805 \n26 Tamura S Fujitani K Kimura Y Tsuji T Matsuyama J Iijima S Phase II feasibility study of adjuvant S-1 plus docetaxel for stage III gastric cancer patients after curative D2 gastrectomy Oncology 2011 80 296 300 21778769 \n27 Fujitani K Tamura S Kimura Y Tsuji T Matsuyama J Iijima S Three-year outcomes of a phase II study of adjuvant chemotherapy with S-1 plus docetaxel for stage III gastric cancer after curative D2 gastrectomy Gastric Cancer 2014 17 348 53 23736741 \n28 Lee SS Jeung HC Chung HC Noh SH Hyung WJ Ahn JY A pilot study of S-1 plus cisplatin versus 5-fluorouracil plus cisplatin for postoperative chemotherapy in histological stage IIIB-IV (M0) gastric cancer Invest New Drugs 2012 30 357 63 20734110 \n29 Kang BW Kim JG Chae YS Lee YJ Lee SJ Moon JH Pilot study of adjuvant chemotherapy with 3-week combination of S-1 and cisplatin for patients with stage II-IV (M0) gastric cancer Invest New Drugs 2012 30 1671 5 21845514 \n30 Fujii M Chemotherapy for advanced gastric cancer: ongoing phase III study of S-1 alone versus S-1 and docetaxel combination (JACCRO GC03 study) Int J Clin Oncol 2008 13 201 5 18553228\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-2998",
"issue": "51(1)",
"journal": "Cancer research and treatment",
"keywords": "Adjuvant chemotherapy; Cisplatin; Docetaxel; S-1 based doublet; Stage III; Stomach neoplasms",
"medline_ta": "Cancer Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D005743:Gastrectomy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid; D056910:Republic of Korea; D013274:Stomach Neoplasms; D016019:Survival Analysis; D005641:Tegafur; D016896:Treatment Outcome",
"nlm_unique_id": "101155137",
"other_id": null,
"pages": "1-11",
"pmc": null,
"pmid": "29397659",
"pubdate": "2019-01",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "13680535;14676796;16570038;16717289;16718845;16740764;17075117;17133268;17664467;17978289;18282805;18553228;18665164;19556809;20442389;20734110;21296855;21523716;21778769;21845514;22010012;22226517;22617130;22824079;23736741;24108812;24155674;24366758;24954805;25276261",
"title": "S-1 Based Doublet as an Adjuvant Chemotherapy for Curatively Resected Stage III Gastric Cancer: Results from the Randomized Phase III POST Trial.",
"title_normalized": "s 1 based doublet as an adjuvant chemotherapy for curatively resected stage iii gastric cancer results from the randomized phase iii post trial"
} | [
{
"companynumb": "KR-HQ SPECIALTY-KR-2019INT000150",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis study assessed the impact of the strain-guided therapeutic approach on cancer therapy-related cardiac dysfunction (CTRCD) and rate of cancer therapy (CT) interruption in breast cancer.\n\n\nRESULTS\nWe enrolled 116 consecutive female patients with HER2-positive breast cancer undergoing a standard protocol by EC (epirubicine + cyclophosphamide) followed by paclitaxel + trastuzumab (TRZ). Coronary artery, valvular and congenital heart disease, heart failure, primary cardiomyopathies, permanent or persistent atrial fibrillation, and inadequate echo-imaging were exclusion criteria. Patients underwent an echo-Doppler exam with determination of ejection fraction (EF) and global longitudinal strain (GLS) at baseline and every 3 months during CT. All patients developing subclinical (GLS drop >15%) or overt CTRCD (EF reduction <50%) initiated cardiac treatment (ramipril+ carvedilol). In the 99.1% (115/116) of patients successfully completing CT, GLS and EF were significantly reduced and E/e' ratio increased at therapy completion. Combined subclinical and overt CTRCD was diagnosed in 27 patients (23.3%), 8 at the end of EC and 19 during TRZ courses. Of these, 4 (3.4%) developed subsequent overt CTRCD and interrupted CT. By cardiac treatment, complete EF recovery was observed in two of these patients and partial recovery in one. These patients with EF recovery re-started and successfully completed CT. The remaining patient, not showing EF increase, permanently stopped CT. The other 23 patients with subclinical CTRCD continued and completed CT.\n\n\nCONCLUSIONS\nThese findings highlight the usefulness of 'strain oriented' approach in reducing the rate of overt CTRCD and CT interruption by a timely cardioprotective treatment initiation.",
"affiliations": "Department of Advanced Biomedical Science, Federico II University Hospital Naples, Via Pansini 5, 80131Naples, Italy.;Department of Advanced Biomedical Science, Federico II University Hospital Naples, Via Pansini 5, 80131Naples, Italy.;Department of Advanced Biomedical Science, Federico II University Hospital Naples, Via Pansini 5, 80131Naples, Italy.;Department of Advanced Biomedical Science, Federico II University Hospital Naples, Via Pansini 5, 80131Naples, Italy.;Department of Clinical Medicine, Federico II University Hospital Naples, Naples, Italy.;Department of Advanced Biomedical Science, Federico II University Hospital Naples, Via Pansini 5, 80131Naples, Italy.;Department of Advanced Biomedical Science, Federico II University Hospital Naples, Via Pansini 5, 80131Naples, Italy.;Department of Clinical Medicine, Federico II University Hospital Naples, Naples, Italy.;Department of Clinical Medicine, Federico II University Hospital Naples, Naples, Italy.;Department of Advanced Biomedical Science, Federico II University Hospital Naples, Via Pansini 5, 80131Naples, Italy.;University of Liège Hospital, GIGA Cardiovascular Sciences, Liège, Belgium.;Department of Clinical Medicine, Federico II University Hospital Naples, Naples, Italy.;Department of Advanced Biomedical Science, Federico II University Hospital Naples, Via Pansini 5, 80131Naples, Italy.",
"authors": "Santoro|Ciro|C|;Esposito|Roberta|R|;Lembo|Maria|M|;Sorrentino|Regina|R|;De Santo|Irene|I|;Luciano|Federica|F|;Casciano|Ofelia|O|;Giuliano|Mario|M|;De Placido|Sabino|S|;Trimarco|Bruno|B|;Lancellotti|Patrizio|P|;Arpino|Grazia|G|;Galderisi|Maurizio|M|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": "10.1093/ehjci/jez194",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2047-2404",
"issue": "20(12)",
"journal": "European heart journal. Cardiovascular Imaging",
"keywords": "breast cancer; cancer therapeutics related cardiac dysfunction; ejection fraction; global longitudinal strain; heart failure",
"medline_ta": "Eur Heart J Cardiovasc Imaging",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D004452:Echocardiography; D005260:Female; D006331:Heart Diseases; D006801:Humans; D013318:Stroke Volume; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "101573788",
"other_id": null,
"pages": "1345-1352",
"pmc": null,
"pmid": "31326981",
"pubdate": "2019-12-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Strain-oriented strategy for guiding cardioprotection initiation of breast cancer patients experiencing cardiac dysfunction.",
"title_normalized": "strain oriented strategy for guiding cardioprotection initiation of breast cancer patients experiencing cardiac dysfunction"
} | [
{
"companynumb": "IT-TEVA-2020-IT-1203685",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "The aim of this pilot study is to confirm the safety and efficacy of neoadjuvant therapy and also treatment duration efficacy using modified FOLFIRINOX for patients with borderline resectable pancreatic cancer (BRPC).\n\n\n\nThe study is a prospective multicenter pilot trial conducted on patients with BRPC. Intervention for clinical trials: Modified FOLFIRINOX (without bolus 5-FU and LV, also decreased the dose of irinotecan; FIRINOX) was given to the first five patients in the 4-cycle group of the regimen and next five patients in the 8-cycle group. The primary end point was the toxicity of the therapy and one of the secondary end points were the optimal duration.\n\n\n\nThe overall rate of grade 3 and 4 events was 80 %: 3 patients (60 %) in the four-cycle group and five patients (100 %) in the eight-cycle group had grade 3 or 4 adverse events. There was no incidence of serious adverse effect such as febrile neutropenia, sepsis, liver abscess or uncontrollable diarrhea. There was no clinically relevant morbidity presented in patients who underwent surgery. R0 rates by intention to treat were 60.0 % in the four-cycle group and 40 % in the eight-cycle group (P = 0.999). The histopathologic treatment effect based on the Evans grade revealed grade I (n = 1), IIa (n = 3) in the four-cycle group and grade I (n = 2), IIa (n = 1) in the eight-cycle group.\n\n\n\nFIRINOX therapy was feasible and safe for strictly selected patients with BRPC. Four cycles of FIRINOX would be sufficient for patients with BRPC as neoadjuvant therapy.",
"affiliations": "Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.;Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.;Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.;Department of Surgery, Kansai Medical University, Hirakata, Japan.;Department of Surgery, Kansai Medical University, Hirakata, Japan.;Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.;Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.;Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.;Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan.;Second Department of Surgery, Wakayama Medical University, Wakayama, 641-8510, Japan. yamaue-h@wakayama-med.ac.jp.",
"authors": "Okada|Ken-Ichi|K|;Kawai|Manabu|M|;Hirono|Seiko|S|;Satoi|Sohei|S|;Yanagimoto|Hiroaki|H|;Ioka|Tatsuya|T|;Miyazawa|Motoki|M|;Shimizu|Atsushi|A|;Kitahata|Yuji|Y|;Yamaue|Hiroki|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D005472:Fluorouracil",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-016-3121-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "78(4)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Borderline resectable; Neoadjuvant chemotherapy; Pancreatic carcinoma; Treatment duration",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D023381:Endpoint Determination; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010190:Pancreatic Neoplasms; D010865:Pilot Projects; D011183:Postoperative Complications; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "719-26",
"pmc": null,
"pmid": "27501851",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of treatment duration of neoadjuvant FIRINOX in patients with borderline resectable pancreatic cancer: a pilot trial.",
"title_normalized": "impact of treatment duration of neoadjuvant firinox in patients with borderline resectable pancreatic cancer a pilot trial"
} | [
{
"companynumb": "JP-CIPLA LTD.-2016JP20573",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs).\n\n\n\nWe established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs.\n\n\n\nIn addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors.\n\n\n\nWe found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.",
"affiliations": "Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.;Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain.;Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra and Navarra Health Research Institute (IDISNA), Pamplona, Spain.;Molecular Genetics Unit, Rare Diseases Institute of Research (IIER), Health Institute Carlos III, Majadahonda, Madrid, Spain.;Molecular Genetics Unit, Rare Diseases Institute of Research (IIER), Health Institute Carlos III, Majadahonda, Madrid, Spain.;Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.;Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain.;CNAG-CRG, Centre for Genomic Regulation (CRG), Institute of Science and Technology (BIST) and University Pompeu Fabra (UPF), Barcelona, Spain.;CNAG-CRG, Centre for Genomic Regulation (CRG), Institute of Science and Technology (BIST) and University Pompeu Fabra (UPF), Barcelona, Spain.;Pathology Department, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.;Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain.;Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain.;Hereditary Cancer Program, Catalan Institute of Oncology, ICO-Oncobell-IDIBELL, Madrid, Spain; CIBERONC, Health Institute Carlos III, Madrid, Spain.;Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra and Navarra Health Research Institute (IDISNA), Pamplona, Spain.;Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra and Navarra Health Research Institute (IDISNA), Pamplona, Spain; CIBERONC, Health Institute Carlos III, Madrid, Spain.;Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.;Hereditary Cancer Program, Catalan Institute of Oncology, ICO-Oncobell-IDIBELL, Madrid, Spain; CIBERONC, Health Institute Carlos III, Madrid, Spain.;Thoracic Surgery Department, Hospital Universitario Virgen de la Arrixaca, El Palmar-Murcia, Spain.;Department of Otolaryngology and Head and Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, Maryland.;Oncology Department, Thoracic Tumors Unit, Clinic Hospital, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.;Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra and Navarra Health Research Institute (IDISNA), Pamplona, Spain; CIBERONC, Health Institute Carlos III, Madrid, Spain.;Biomarkers and Precision Medicine Unit, Research Institute La Fe and Department of Medical Oncology, La Fe University Hospital, Valencia, Spain.;Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain; Clinical Research in Solid Tumors Group (CReST), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain.;Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.;Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra and Navarra Health Research Institute (IDISNA), Pamplona, Spain; CIBERONC, Health Institute Carlos III, Madrid, Spain; Department of Pathology, Anatomy and Physiology, Schools of Medicine and Sciences, University of Navarra, Pamplona, Spain.;Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain. Electronic address: mscespedes@carrerasresearch.org.",
"authors": "Pros|E|E|;Saigi|M|M|;Alameda|D|D|;Gomez-Mariano|G|G|;Martinez-Delgado|B|B|;Alburquerque-Bejar|J J|JJ|;Carretero|J|J|;Tonda|R|R|;Esteve-Codina|A|A|;Catala|I|I|;Palmero|R|R|;Jove|M|M|;Lazaro|C|C|;Patiño-Garcia|A|A|;Gil-Bazo|I|I|;Verdura|S|S|;Teulé|A|A|;Torres-Lanzas|J|J|;Sidransky|D|D|;Reguart|N|N|;Pio|R|R|;Juan-Vidal|O|O|;Nadal|E|E|;Felip|E|E|;Montuenga|L M|LM|;Sanchez-Cespedes|M|M|",
"chemical_list": "D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; C120551:TACC3 protein, human; D044767:Ubiquitin-Protein Ligases; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "England",
"delete": false,
"doi": "10.1016/j.annonc.2019.09.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "31(2)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "EGFR; RB1; lung adenocarcinoma; nonsmokers; tyrosine kinase inhibitors; whole-exome sequencing",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D006801:Humans; D008175:Lung Neoplasms; D008869:Microtubule-Associated Proteins; D009154:Mutation; D047428:Protein Kinase Inhibitors; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "274-282",
"pmc": null,
"pmid": "31959344",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.",
"title_normalized": "genome wide profiling of non smoking related lung cancer cells reveals common rb1 rearrangements associated with histopathologic transformation in egfr mutant tumors"
} | [
{
"companynumb": "ES-MYLANLABS-2020M1020809",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEFITINIB"
},
"drugadditional": "4",
... |
{
"abstract": "The incidence of visceral leishmaniasis (VL) after solid organ transplantation (SOT) is increasing. The optimal therapy for post-transplant VL remains unclear, as relapses after liposomal amphotericin B (L-AmB) are common. Miltefosine has been shown to be effective for treating VL in immunocompetent patients, although data in the specific population of SOT recipients are lacking. In the setting of an outbreak of leishmaniasis occurring in Southwest Madrid, we reviewed our experience in 6 SOT recipients with persistent or relapsing VL who received a 28-day course of miltefosine (2.5 mg/kg/day) as salvage therapy. All patients had been treated previously with L-AmB as first-line therapy. The incident episode of VL occurred at a median of 14 months after transplantation. Two patients experienced persistent infection and the remaining 4 had a relapse after a median interval of 168 days since the completion of the course of L-AmB. All the patients had an apparent initial clinical improvement with miltefosine. However, VL relapsed in 3 of them (after a median interval of 46 days), which required retreatment with L-AmB-based regimens. Miltefosine therapy was followed by a prolonged secondary prophylaxis with L-AmB in the only 2 cases with sustained clinical response and ongoing immunosuppression. No adverse effects associated with miltefosine were observed. Albeit limited, our experience suggests that miltefosine monotherapy likely has a limited utility to obtain a long-lasting clinical response in complicated (persistent or relapsing) forms of post-transplant VL, although its role in association with L-AmB-based secondary prophylaxis may merit further investigation.",
"affiliations": "Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.;Department of Respiratory Medicine, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.;Department of Nephrology, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.;Department of Nephrology, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario \"12 de Octubre\", Instituto de Investigación Hospital \"12 de Octubre\" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.",
"authors": "Pérez-Jacoiste Asín|Maria A|MA|;Carrasco-Antón|Nerea|N|;Fernández-Ruiz|Mario|M|;San Juan|Rafael|R|;Alonso-Moralejo|Rodrigo|R|;González|Esther|E|;Andrés|Amado|A|;López-Medrano|Francisco|F|;Aguado|Jose M|JM|",
"chemical_list": "D000981:Antiprotozoal Agents; C068538:liposomal amphotericin B; D010767:Phosphorylcholine; C039128:miltefosine; D000666:Amphotericin B",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "19(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "miltefosine; salvage therapy; solid organ transplantation; visceral leishmaniasis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000666:Amphotericin B; D000981:Antiprotozoal Agents; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D016030:Kidney Transplantation; D018314:Leishmania infantum; D007898:Leishmaniasis, Visceral; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D010767:Phosphorylcholine; D012189:Retrospective Studies; D016879:Salvage Therapy; D055502:Secondary Prevention; D013030:Spain; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27768239",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Experience with miltefosine for persistent or relapsing visceral leishmaniasis in solid organ transplant recipients: A case series from Spain.",
"title_normalized": "experience with miltefosine for persistent or relapsing visceral leishmaniasis in solid organ transplant recipients a case series from spain"
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"abstract": "In 2003, our institution adopted triweekly carboplatin (tCb) area under the curve (AUC) 5 as an alternative to high-dose cisplatin (100 mg/m) for select patients receiving definitive concurrent chemoradiation for locally advanced laryngeal carcinoma (LALC). Here, we present our experience and outcomes with this definitive concurrent chemoradiation regimen.\n\n\n\nFrom January 2003 through December 2013, 53 patients with stage III (60%) or IVA (40%) LALC were treated with tCb AUC 5 and concurrent radiotherapy to 70 Gy without neoadjuvant chemotherapy. Reasons for using carboplatin instead of cisplatin in these patients were: age 70 and older (21%), poor renal function (6%), presence of 1 or more major comorbid condition(s) (36%), and per discretion of the treating medical oncologist (38%). Primary disease site was glottis in 22 (42%) patients and supraglottis in 31 (58%) patients.\n\n\n\nMedian follow-up time was 63 months for surviving patients. Out of the 53 patients, 43 (81%) received all 3 cycles of carboplatin and all patients received their intended dose of radiotherapy. Although 17 (32%) patients required a feeding tube during treatment, only 2 (4%) required it long term. There were no acute treatment-related grade 4 or 5 hematologic toxicities. On last follow-up, 14 (26%) patients had died of intercurrent disease. For the subgroup of \"RTOG 9111 eligible\" patients in our cohort (n=46), 5-year estimates of overall survival, disease-free survival, laryngectomy-free survival, larynx preservation, and locoregional control were: 49%, 42%, 39%, 80%, and 63%, respectively.\n\n\n\nIn patients with LALC who are suboptimal candidates for high-dose cisplatin, our experience suggests that tCb AUC 5 with concurrent radiotherapy provides acceptable outcomes with tolerable toxicity.",
"affiliations": "Departments of Radiation Oncology.;Departments of Radiation Oncology.;Medical Oncology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA.;Medical Oncology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA.",
"authors": "Lu|Sharon M|SM|;Iganej|Shawn|S|;Abdalla|Iman A|IA|;Buchschacher|Gary L|GL|",
"chemical_list": "D016190:Carboplatin; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0000000000000330",
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"issn_linking": "0277-3732",
"issue": "41(6)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007822:Laryngeal Neoplasms; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "595-600",
"pmc": null,
"pmid": "27635621",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Concurrent Radiotherapy and Triweekly Carboplatin for the Definitive Treatment of Locally Advanced Laryngeal Carcinoma.",
"title_normalized": "concurrent radiotherapy and triweekly carboplatin for the definitive treatment of locally advanced laryngeal carcinoma"
} | [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
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"abstract": "Lactic acidosis occurs when lactate production exceeds its metabolism. There are many possible causes of lactic acidosis, and in any given patient, several causes may coexist. This Attending Rounds presents a case in point. Metformin's role in the pathogenesis of lactic acidosis in patients with diabetes mellitus is complex, as the present case illustrates. The treatment of lactic acidosis is controversial, except for the imperative to remedy its underlying cause. The use of sodium bicarbonate to treat the often alarming metabolic derangements may be quite efficacious in that regard but is of questionable benefit to patients. Renal replacement therapies (RRTs) have particular appeal in this setting for a variety of reasons, but their effect on clinical outcomes is untested.",
"affiliations": "Division of Nephrology, Cooper Medical School of Rowan University, Cooper University Health Care, Camden, New Jersey Weisberg-Lawrence@CooperHealth.edu.",
"authors": "Weisberg|Lawrence S|LS|",
"chemical_list": "D015415:Biomarkers; D007004:Hypoglycemic Agents; D017693:Sodium Bicarbonate; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.10871014",
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"issn_linking": "1555-9041",
"issue": "10(8)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": "acidosis; congestive heart failure; diabetes mellitus; dialysis; intoxication",
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D000136:Acid-Base Equilibrium; D000140:Acidosis, Lactic; D015415:Biomarkers; D003924:Diabetes Mellitus, Type 2; D017809:Fatal Outcome; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D006435:Renal Dialysis; D017693:Sodium Bicarbonate; D016896:Treatment Outcome",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "1476-83",
"pmc": null,
"pmid": "25762524",
"pubdate": "2015-08-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21545617;16129872;2827525;16356239;17699401;18158437;18045860;18176310;10923730;11412284;11576874;12093242;14687589;5018151;3248127;2500402;2693799;2156475;2331007;2193525;1311664;1590462;10148241;7623903;8569826;9142581;9441244;9666950;18782901;19487945;20393934;20394011;20701406;21039727;21171991;21517988;21977945;22945490;23481366;23508758;23953803;24079682;23960029;24235282;24283301;24636927;24363178;24847880;24929216;24909998;25079826;24599253;34793;6774247;6283899;10230584",
"title": "Lactic Acidosis in a Patient with Type 2 Diabetes Mellitus.",
"title_normalized": "lactic acidosis in a patient with type 2 diabetes mellitus"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-118686",
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
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"abstract": "BACKGROUND\nVarious antiepileptic drugs can potentially cause psychiatric side effects in patients with epilepsy, but the precise mechanism of these actions remains unknown. In recent years, the common polymorphism C677T in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has attracted attention for its role in the onset of psychiatric diseases. MTHFR and several vitamins (as cofactors) are crucial for remethylation of homocysteine via folate and homocysteine metabolism. We report a case of a Japanese patient who presented with reversible schizophrenia-like symptoms during antiepileptic drug therapy.\n\n\nMETHODS\nOur patient had frontal lobe epilepsy and had been treated with several antiepileptic drugs since the age of 13 years. He developed auditory hallucinations and multiple personalities at 17 years of age, several months after the initiation of phenytoin and phenobarbital, despite these antiepileptic drugs being used within the therapeutic ranges. Genetic analysis revealed that he was homozygous for the C677T polymorphism of MTHFR. Hyperhomocysteinemia, hypomethionemia, and multiple vitamin deficiencies, including folate, riboflavin, and pyridoxal, were identified at the age of 23 years. Vitamin supplementation and alteration of the antiepileptic drugs improved his psychotic symptoms. Multiple vitamin deficiencies with homozygous MTHFR C677T should be considered in patients presenting with schizophrenia-like symptoms during antiepileptic drug therapy.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first report of antiepileptic drug-induced psychosis associated with homozygous C677T and multiple vitamin deficiencies. Our findings will contribute to the elucidation of the pathogenesis of the psychiatric side effects of antiepileptic drugs and lead to improved medical management for patients with epilepsy.",
"affiliations": "Department of Pediatrics, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan. m-sim@tokyo-med.ac.jp.;Department of Pediatrics, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.;Department of Pediatrics, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.;Department of Pediatrics, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.;Department of Pediatrics, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.;Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.;Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.",
"authors": "Shimura|Masaru|M|http://orcid.org/0000-0002-1998-7349;Yamada|Hikari|H|;Takahashi|Hidekuni|H|;Yamada|Naoto|N|;Go|Soken|S|;Yamanaka|Gaku|G|;Kawashima|Hisashi|H|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D010634:Phenobarbital",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2188-3",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 218810.1186/s13256-019-2188-3Case ReportAntiepileptic drug-induced psychosis associated with MTHFR C677T: a case report http://orcid.org/0000-0002-1998-7349Shimura Masaru +81-29-887-1161m-sim@tokyo-med.ac.jp 12Yamada Hikari 1Takahashi Hidekuni 1Yamada Naoto 1Go Soken 1Yamanaka Gaku 2Kawashima Hisashi 21 0000 0004 0386 8171grid.412784.cDepartment of Pediatrics, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395 Japan 2 0000 0001 0663 3325grid.410793.8Department of Pediatrics and Adolescent Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023 Japan 12 8 2019 12 8 2019 2019 13 25021 6 2019 4 7 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nVarious antiepileptic drugs can potentially cause psychiatric side effects in patients with epilepsy, but the precise mechanism of these actions remains unknown. In recent years, the common polymorphism C677T in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has attracted attention for its role in the onset of psychiatric diseases. MTHFR and several vitamins (as cofactors) are crucial for remethylation of homocysteine via folate and homocysteine metabolism. We report a case of a Japanese patient who presented with reversible schizophrenia-like symptoms during antiepileptic drug therapy.\n\nCase presentation\nOur patient had frontal lobe epilepsy and had been treated with several antiepileptic drugs since the age of 13 years. He developed auditory hallucinations and multiple personalities at 17 years of age, several months after the initiation of phenytoin and phenobarbital, despite these antiepileptic drugs being used within the therapeutic ranges. Genetic analysis revealed that he was homozygous for the C677T polymorphism of MTHFR. Hyperhomocysteinemia, hypomethionemia, and multiple vitamin deficiencies, including folate, riboflavin, and pyridoxal, were identified at the age of 23 years. Vitamin supplementation and alteration of the antiepileptic drugs improved his psychotic symptoms. Multiple vitamin deficiencies with homozygous MTHFR C677T should be considered in patients presenting with schizophrenia-like symptoms during antiepileptic drug therapy.\n\nConclusions\nTo the best of our knowledge, this is the first report of antiepileptic drug-induced psychosis associated with homozygous C677T and multiple vitamin deficiencies. Our findings will contribute to the elucidation of the pathogenesis of the psychiatric side effects of antiepileptic drugs and lead to improved medical management for patients with epilepsy.\n\nKeywords\n5,10-Methylenetetrahydrofolate reductaseMTHFRC677TSchizophreniaPsychosisAntiepileptic drugsHyperhomocysteinemiaVitamin deficiencyFolateissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nThe riboflavin-dependent enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR; MIM 607093; EC 1.5.1.20) converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate during folate and homocysteine metabolism (Fig. 1) [1, 2]. Several vitamins, such as riboflavin (vitamin B2), pyridoxal (vitamin B6), and cobalamin (vitamin B12), play important roles as cofactors in the metabolism of homocysteine. The remethylation of homocysteine is a pivotal reaction, because adequate concentrations of methionine are required for S-adenosylmethionine (SAM) to act as a methyl donor for the methylation of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and other small molecules [3, 4].Fig. 1 Folate pathway and homocysteine metabolism. CBS Cystathionine β-synthetase, SAH S-adenosylhomocysteine, THF Tetrahydrofolate\n\n\n\nSevere MTHFR deficiency, a rare autosomal recessive disorder, results in defects in the remethylation of homocysteine. Early-onset MTHFR deficiency manifests as feeding difficulties, hydrocephalus, and apnea during infancy, whereas adult-onset MTHFR deficiency manifests as seizures, cognitive impairment, and behavior or psychiatric disorders [2]. MTHFR C677T polymorphism (rs1801133) causes thermolability leading to a mild reduction in enzyme activity. Although this polymorphism is not associated with severe MTHFR deficiency, it is related to various vascular and neuropsychiatric diseases [2, 5, 6].\n\nVarious antiepileptic drugs (AEDs) can cause psychiatric side effects, but the pathogenesis of these effects has not been fully elucidated [7]. We describe a patient with homozygous MTHFR C677T who presented with reversible psychosis during AED therapy. To the best of our knowledge, this is the first report of AED-induced psychosis associated with MTHFR C677T and multiple vitamin deficiencies.\n\nCase presentation\nThe patient was a Japanese male who was born at 38 weeks of gestation as the first child to nonconsanguineous parents. His newborn screening tests had yielded normal findings. His development and growth were uneventful, and his diet was balanced. He had no family history of coronary artery disease, stroke, or neuropsychiatric diseases. He presented with abnormal behavior such as running into the street, sudden sleep attacks, and personality changes from the age of 10. His first tonic seizure occurred at the age of 13. Electroencephalogram (EEG) findings revealed sharp wave runs in the frontal region, and he was diagnosed with frontal lobe epilepsy. His clinical course is depicted in Fig. 2. Although treatment with zonisamide, carbamazepine, and gabapentin was initiated, his seizures were not controlled. Treatment with phenytoin and phenobarbital was initiated at the age of 17. Subsequently, regular follow-up blood tests revealed that his mean corpuscular volume (MCV) was elevated to > 100 fl without a decline in hemoglobin levels. Six months after the introduction of treatment with phenytoin and phenobarbital, the patient reported auditory hallucinations, and multiple personalities appeared. Although he was treated with phenytoin, phenobarbital, and levetiracetam within the relevant therapeutic ranges for 6 years, epileptic seizures occurred repetitively with EEG abnormalities, and his schizophrenia-like symptoms gradually progressed. He and his parents were referred to a psychiatrist, but the patient refused treatment. He went on to study at a university without experiencing any problems; however, he abruptly left the university during his fourth year. He subsequently exhibited slow movement, intention tremor, impairment of short-term memory, and dysgraphia. He remained at home without a job after graduating from the university.Fig. 2 Clinical course of the patient. The changes in the mean corpuscular volume, serum homocysteine levels, plasma methionine levels, and venous partial pressure of carbon dioxide levels with neuropsychiatric symptoms and treatments are indicated\n\n\n\nUpon admission to our hospital due to a tonic seizure at the age of 23, the patient underwent a detailed examination. He had no gingival overgrowth but did have macrocytosis without anemia (hemoglobin, 16.8 g/dl; MCV, 102.8 fl). We observed mild elevation of the partial pressure of carbon dioxide (PCO2) and bicarbonate without acidemia in the venous blood, suggesting chronic CO2 retention (pH, 7.386; PCO2, 50.9 mmHg; bicarbonate, 29.2 mmol/L). The blood concentrations of all AEDs were within the relevant therapeutic ranges (phenytoin, 13.35 μg/ml [therapeutic range, 10–20 μg/ml]; phenobarbital, 20.81 μg/ml [10–35 μg/ml]; levetiracetam, 15.8 μg/ml [12–46 μg/ml]). The patient’s serum levels of folate, riboflavin, and pyridoxal decreased to below-normal ranges, and his cobalamin level decreased to the lower limit of the normal range (folate, 1.6 ng/ml [normal range, 3.6–12.9 ng/ml]; riboflavin, 3.6 μg/dl [12.8–27.6 μg/dl]; pyridoxal, 3.9 ng/ml [6.0–40.0 ng/ml]; cobalamin, 275 pg/ml [233–914 pg/ml]). Plasma amino acid analysis revealed a decrease in the methionine level and a marked elevation in the plasma homocysteine level, whereas other essential amino acids were within normal ranges (methionine, 15.2 μmol/L [18.9–40.5 μmol/L]; homocysteine, 202 μmol/L [5.0–15.0 μmol/L]). Urine organic acid analysis revealed no abnormal findings, including methylmalonic acid. A chest x-ray demonstrated a slight elevation of the right diaphragm relative to the findings of a previous x-ray (Fig. 3a, b). Brain magnetic resonance imaging revealed no abnormalities. Genetic analysis identified three homozygous polymorphisms in the MTHFR gene (NM_005957.4): c.665C>T (p.Ala222Val; also known as C677T), c.1166 + 31C>T, and c.1305C>T (p.Phe435=). Supplementation with folic acid (15 mg/day), pyridoxal phosphate (30 mg/day), and methylcobalamin (1.5 mg/day) was started, and phenytoin and phenobarbital were switched to lamotrigine. Thereafter, the patient’s MCV decreased to < 100 fl, and his methionine level was normalized to the vitamin levels. PCO2 and bicarbonate levels in the venous blood continued to decrease, which was accompanied by a normalization of the diaphragm position (Figs. 2 and 3c). The patient’s auditory hallucinations, multiple personalities, lethargy, and other neuropsychological symptoms improved as serum homocysteine levels were reduced to within normal ranges with supplementation. However, his seizure attacks still occurred once per month.Fig. 3 Changes in the diaphragm position on chest x-rays. The horizontal dotted line indicates the left diaphragm position. b A slight elevation of the right diaphragm can be observed relative to its position in (a). c Chest x-ray obtained after normalization of the serum homocysteine level illustrating the right diaphragm in a lower position than in (b)\n\n\n\nDiscussion and conclusions\nThe presented case highlighted two important issues: (1) Long-term administration of AEDs to patients with homozygous MTHFR C677T can cause hyperhomocysteinemia and schizophrenia-like psychosis, similar to that which is observed in adult-onset MTHFR deficiency; and (2) AED-induced psychosis is associated with homozygous C677T and multiple vitamin deficiencies.\n\nOur patient had three homozygous polymorphisms in MTHFR. The allele frequencies of c.665C>T (also known as C677T), c.1166 + 31C>T, and c.1305C>T in East Asian populations are reported to be 0.2903, 0.7592, and 0.9991, respectively, according to the Genome Aggregation Database. The associations of MTHFR C677T with various diseases have been well documented. In particular, the correlation between this polymorphism and the risk of coronary artery disease, stroke, and neuropsychiatric diseases has received considerable attention in recent years [6, 8]. Polymorphism of this gene is also a risk factor for folate deficiency, which results in neural tube defects [1]. The C677T allele frequency differs greatly among ethnic groups, with a T allele frequency ranging from 1% in African Americans to 30% in Japanese and Europeans [9, 10]. In a Japanese population, the C677T allele frequency was very high, and the frequency of homozygous genotypes was 11% [11]. The residual enzyme activity from cultured fibroblasts of patients with severe MTHFR deficiency was < 20%, and the age of onset and severity of the disease correlated with the enzyme activity [12, 13]. MTHFR C677T also reduced the enzyme activity, resulting in a 30% decrease in heterozygotes and a 65% decrease in homozygotes [14]. In this context, the common polymorphism C677T has not been considered as a cause of severe MTHFR deficiency [2, 15].\n\nFolate, riboflavin, pyridoxine, and cobalamin deficiencies, as observed in our patient, can cause hyperhomocysteinemia because these vitamins are involved in folate and homocysteine metabolism [16]. Elevation of MCV was observed soon after the initiation of phenytoin and phenobarbital supplementation, suggesting a folate or cobalamin deficiency. Folate deficiency has been reported to contribute to the onset of psychiatric diseases such as schizophrenia and bipolar disorder [8]. Furthermore, a causal relationship between homocysteine levels affected by C677T and schizophrenia was revealed in a meta-analysis [17]. Both folate deficiency and MTHFR C677T contribute to impaired remethylation of homocysteine to methionine, resulting in a decrease in SAM. It is plausible that SAM deficiency causes abnormal methylation of DNA, proteins, and neurotransmitter and DNA strand breaks, leading to psychiatric diseases [18]. Homocysteine-reducing strategies using folic acid, pyridoxine, and vitamin B12 have been demonstrated to improve clinical symptoms in schizophrenia [19].\n\nThe psychiatric side effects of various AEDs have been described in many studies over several decades [7]. Although the forced normalization of EEG is associated with AED-induced psychosis, our patient did not exhibit EEG normalization during his clinical course. Phenytoin-induced schizophrenia-like psychoses, the mechanism of which remains poorly understood, may be dose-dependent, but serum levels in our patient were maintained within the therapeutic ranges [20]. However, a decrease in MTHFR activity by phenytoin treatment at therapeutic plasma levels was observed in mice [21]. Enzyme-promoting AEDs such as phenytoin and phenobarbital are known to cause riboflavin and folate deficiencies via induction of cytochrome P450 [16, 22]. It has been reported that phenytoin decreases serum pyridoxal levels, leading to hyperhomocysteinemia [23]. Furthermore, phenytoin administration in patients with epilepsy who have the MTHFR TT genotype markedly increased plasma homocysteine levels compared with levels induced by administration of other AEDs [24]. Thus, the marked elevation of plasma homocysteine in our patient may have been caused by multiple factors, namely the common homozygous C677T; the folate, riboflavin, and pyridoxal deficiencies; and the enzyme-promoting AED.\n\nThe patient had mildly increased CO2 levels and slight elevation of the right diaphragm, which improved with normalization of serum homocysteine levels. Neonates and young infants with severe MTHFR deficiency often present with respiratory complications such as apnea and phrenic nerve palsy [2, 25]. Although the precise mechanism of these respiratory complications remains poorly understood, it has been presumed to result from central and peripheral neurological impairment; this can be attributed to SAM deficiency, which is involved in dysmyelination [4, 26]. To our knowledge, no clinical studies have documented MTHFR C677T-related respiratory symptoms. C677T-associated hyperhomocysteinemia should be considered as a differential diagnosis in patients presenting with respiratory symptoms during AED therapy.\n\nTo the best of our knowledge, this is the first report of AED-induced psychosis associated with homozygous C677T and multiple vitamin deficiencies, which was similar to that observed in adult-onset MTHFR deficiency. The long-term administration of AEDs in patients with the homozygous MTHFR c.677C>T genotype can cause folate, riboflavin, pyridoxal, and cobalamin deficiencies, leading to hypomethionemia and hyperhomocysteinemia, even when the administered AEDs are within the therapeutic ranges. In cases of schizophrenia-like symptoms during AED therapy, vitamin deficiencies should be suspected, which can be treated with vitamin supplementation and different AEDs. Further reports are needed to confirm these findings and elucidate the pathogenesis of AED-induced psychosis.\n\nAbbreviations\nAEDAntiepileptic drug\n\nEEGElectroencephalogram\n\nMCVMean corpuscular volume\n\nMTHFR5,10-Methylenetetrahydrofolate reductase\n\nPCO2Partial pressure of carbon dioxide\n\nSAMS-adenosylmethionine\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe gratefully thank Dr. Osamu Sakamoto and Dr. Yoichi Wada of the Department of Pediatrics at Tohoku University School of Medicine for the genetic analysis. We also thank Dr. Shinji Suzuki and Dr. Yasuyuki Morishima for their support and advice. We thank the Genome Aggregation Database and the groups that provided exome and genome variant data to this resource. A full list of these contributing groups can be found at https://gnomad.broadinstitute.org/about. We thank Editage (www.editage.jp) for English-language editing.\n\nAuthors’ contributions\nMS conceptualized this report and drafted the initial manuscript. HY, HT, and SG participated in patient follow-up and data interpretation and reviewed and revised the manuscript. NY was involved in patient follow-up and reviewed the manuscript. GY and HK assessed the clinical data and critically reviewed and revised the manuscript. All authors read and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nFunding\nNo funding was secured for this study.\n\nAvailability of data and materials\nThe datasets supporting the conclusions of this article are included within the article.\n\nEthics approval and consent to participate\nThis case report was written in accordance with the Helsinki declaration of 1975, as revised in 2000.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s parent for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Hiraoka M Kagawa Y Genetic polymorphisms and folate status Congenit Anom (Kyoto) 2017 57 142 149 10.1111/cga.12232 28598562 \n2. Huemer M Diodato D Schwahn B Schiff M Bandeira A Benoist JF Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency J Inherit Metab Dis 2017 40 21 48 10.1007/s10545-016-9991-4 27905001 \n3. Crider KS Yang TP Berry RJ Bailey LB Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role Adv Nutr 2012 3 21 38 10.3945/an.111.000992 22332098 \n4. Broomfield A Abulhoul L Pitt W Jameson E Cleary M Reversal of respiratory failure in both neonatal and late onset isolated remethylation disorders JIMD Rep 2014 16 51 56 24997712 \n5. Yamada K Chen Z Rozen R Matthews RG Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase Proc Natl Acad Sci U S A 2001 98 14853 14858 10.1073/pnas.261469998 11742092 \n6. Liew SC Gupta ED Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases Eur J Med Genet 2015 58 1 10 10.1016/j.ejmg.2014.10.004 25449138 \n7. Schmitz B Effects of antiepileptic drugs on mood and behavior Epilepsia. 2006 47 Suppl 2 28 33 10.1111/j.1528-1167.2006.00684.x 17105456 \n8. Wan L Li Y Zhang Z Sun Z He Y Li R Methylenetetrahydrofolate reductase and psychiatric diseases Transl Psychiatry 2018 8 242 10.1038/s41398-018-0276-6 30397195 \n9. Herrmann W Herrmann M Obeid R Hyperhomocysteinaemia: a critical review of old and new aspects Curr Drug Metab 2007 8 17 31 10.2174/138920007779315008 17266521 \n10. Munisamy M Al-Gahtany M Tripathi M Subbiah V Impact of MTHFR (C677T) gene polymorphism on antiepileptic drug monotherapy in North Indian epileptic population Ann Saudi Med 2015 35 51 57 10.5144/0256-4947.2015.51 26142939 \n11. Nishio H Lee MJ Fujii M Kario K Kayaba K Shimada K A common mutation in methylenetetrahydrofolate reductase gene among the Japanese population Jpn J Hum Genet 1996 41 247 251 10.1007/BF01875985 8771990 \n12. Goyette P Frosst P Rosenblatt DS Rozen R Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency Am J Hum Genet 1995 56 1052 1059 7726158 \n13. Froese DS Huemer M Suormala T Burda P Coelho D Guéant JL Mutation update and review of severe methylenetetrahydrofolate reductase deficiency Hum Mutat 2016 37 427 438 10.1002/humu.22970 26872964 \n14. Frosst P Blom HJ Milos R Goyette P Sheppard CA Matthews RG A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase Nat Genet 1995 10 111 113 10.1038/ng0595-111 7647779 \n15. Tsang BL Devine OJ Cordero AM Marchetta CM Mulinare J Mersereau P Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies Am J Clin Nutr 2015 101 1286 1294 10.3945/ajcn.114.099994 25788000 \n16. Apeland T Mansoor MA Pentieva K McNulty H Strandjord RE Fasting and post-methionine loading concentrations of homocysteine, vitamin B2 , and vitamin B6 in patients on antiepileptic drugs Clin Chem 2003 49 6 1005 1008 10.1373/49.6.1005 12766014 \n17. Nishi A Numata S Tajima A Kinoshita M Kikuchi K Shimodera S Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia Schizophr Bull 2014 40 1154 1163 10.1093/schbul/sbt154 24535549 \n18. Rai V Yadav U Kumar P Yadav SK Gupta S Methylenetetrahydrofolate reductase A1298C genetic variant and risk of schizophrenia: a meta-analysis Indian J Med Res 2017 145 437 447 28862175 \n19. Levine J Stahl Z Sela BA Ruderman V Shumaico O Babushkin I Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia Biol Psychiatry 2006 60 265 269 10.1016/j.biopsych.2005.10.009 16412989 \n20. Kanemoto K Tsuji T Kawasaki J Reexamination of interictal psychoses based on DSM IV psychosis classification and international epilepsy classification Epilepsia. 2001 42 98 103 10.1046/j.1528-1157.2001.09000.x 11207792 \n21. Billings RE Decreased hepatic 5,10-methylenetetrahydrofolate reductase activity in mice after chronic phenytoin treatment Mol Pharmacol 1984 25 459 466 6374425 \n22. Chandrasekaran S Patil S Suthar R Attri SV Sahu JK Sankhyan N Hyperhomocysteinaemia in children receiving phenytoin and carbamazepine monotherapy: a cross-sectional observational study Arch Dis Child 2017 102 346 351 10.1136/archdischild-2016-311436 27821519 \n23. Tamura T Aiso K Johnston KE Black L Faught E Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy Epilepsy Res 2000 40 7 15 10.1016/S0920-1211(00)00101-7 10771253 \n24. Yoo JH Hong SB A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants Metabolism. 1999 48 1047 1051 10.1016/S0026-0495(99)90204-4 10459572 \n25. Tsuji M Takagi A Sameshima K Iai M Yamashita S Shinbo H 5,10-Methylenetetrahydrofolate reductase deficiency with progressive polyneuropathy in an infant Brain and Development 2011 33 521 524 10.1016/j.braindev.2010.08.013 20850942 \n26. Surtees R Leonard J Austin S Association of demyelination with deficiency of cerebrospinal-fluid S -adenosylmethionine in inborn errors of methyl-transfer pathway Lancet. 1991 338 8782–8783 1550 1554 10.1016/0140-6736(91)92373-A 1683972\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "5,10-Methylenetetrahydrofolate reductase; Antiepileptic drugs; C677T; Folate; Hyperhomocysteinemia; MTHFR; Psychosis; Schizophrenia; Vitamin deficiency",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D001361:Avitaminosis; D004827:Epilepsy; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D010634:Phenobarbital; D010672:Phenytoin; D011110:Polymorphism, Genetic; D011605:Psychoses, Substance-Induced; D055815:Young Adult",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "250",
"pmc": null,
"pmid": "31401974",
"pubdate": "2019-08-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10459572;10771253;11207792;11742092;12766014;16412989;1683972;17105456;17266521;20850942;22332098;24535549;24997712;25449138;25788000;26142939;26872964;27821519;27905001;28598562;28862175;30397195;6374425;7647779;7726158;8771990",
"title": "Antiepileptic drug-induced psychosis associated with MTHFR C677T: a case report.",
"title_normalized": "antiepileptic drug induced psychosis associated with mthfr c677t a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-220253",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"druga... |
{
"abstract": "Adolescent and young adult (AYA) patients with very high risk sarcomas have poor outcomes and are in need of novel therapies.\n\n\n\nFrom January 2005 to February 2016, we retrospectively identified all AYA patients with relapsed or metastatic high-grade sarcomas, who were treated with at least one cycle of docetaxel (T), bevacizumab (A), and gemcitabine (G) (TAG ; T = 100 mg/m2 Day 8, A = 15 mg/kg Day 1, G = 1,000 mg/m2 Days 1 and 8).\n\n\n\nFourteen patients, median age of 20 (15-30), received a total of 80 cycles of TAG, and were followed for a median of 83 months. Diagnosis included osteosarcoma (OST; 8), Ewing sarcoma (3), and soft tissue sarcoma (3). Five of 14 patients achieved clinical remission (CR), 3 had partial responses (PR), 3 had stable disease (SD), and 3 had progressive disease (PD). The median progression-free survival and overall survival were 7 and 19 months, respectively. The objective response rate (CR + PR) and tumor control rate (CR + PR + SD) were 57% and 79%, respectively, with two patients alive after 5 years; toxicities included thrombocytopenia, neutropenia, and capillary leak syndrome.\n\n\n\nOur study builds on previous studies utilizing TAG in adult leiomyosarcoma (LMS) by focusing on AYA, non-LMS sarcomas, especially OST. Our experience suggests that TAG is well tolerated and has activity in very high risk sarcomas in AYA.",
"affiliations": "Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois.;Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Division of Medical Oncology, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.;Division of Hematology/Oncology, Department of Pediatrics, University of Illinois College of Medicine, Peoria, Illinois.;Division of Hematology/Oncology, Department of Pediatrics, Advocate Christ Medical Center, Oak Lawn, Illinois.",
"authors": "Kuo|Christopher|C|;Kent|Paul M|PM|;Logan|Antonio D|AD|;Tamulonis|Karen B|KB|;Dalton|Kristen L|KL|;Batus|Marta|M|;Fernandez|Karen|K|;Mcfall|Rebecca E|RE|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D000068258:Bevacizumab; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(4)",
"journal": "Pediatric blood & cancer",
"keywords": "Ewing sarcoma; bevacizumab; docetaxel; gemcitabine; osteosarcoma; soft tissue sarcomas",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D003841:Deoxycytidine; D000077143:Docetaxel; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D012509:Sarcoma; D015996:Survival Rate; D043823:Taxoids; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28221727",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Docetaxel, bevacizumab, and gemcitabine for very high risk sarcomas in adolescents and young adults: A single-center experience.",
"title_normalized": "docetaxel bevacizumab and gemcitabine for very high risk sarcomas in adolescents and young adults a single center experience"
} | [
{
"companynumb": "US-TEVA-762046USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dr... |
{
"abstract": "The occurrence of metabolic acidosis with increased anion gap in the context of chronic paracetamol intoxication is an easily treatable clinical situation. Its rapid recognition is essential given its complete reversibility in the event of adequate management by eviction of the toxic agent, in this case paracetamol. It has an unknown cause and therefore potentially under-diagnosed, to be considered in the same way as the other more frequent etiologies. Because of this lack of knowledge, its frequency is probably underestimated considering the widespread consumption of paracetamol in the population.",
"affiliations": "Service des Urgences, CHU Liège, Belgique.;Service des Soins intensifs, CHU Liège, Belgique.;Faculté de Médecine, ULiège; Service de Toxicologie clinique, médicolégale, de l'Environnement et en Entreprise, CHU Liège, Belgique.;Service des Soins intensifs, CHU Liège, Belgique.",
"authors": "Morreale|A|A|;Canivet|J L|JL|;Charlier|C|C|;Misset|B|B|",
"chemical_list": "D000082:Acetaminophen; D011761:Pyrrolidonecarboxylic Acid",
"country": "Belgium",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0370-629X",
"issue": "76(7-8)",
"journal": "Revue medicale de Liege",
"keywords": " 5; Acetaminophen; Pyroglutamic acidemia ; Elevated anion gap metabolic acidosis ; oxoprolinemia ",
"medline_ta": "Rev Med Liege",
"mesh_terms": "D000082:Acetaminophen; D000136:Acid-Base Equilibrium; D000138:Acidosis; D006801:Humans; D007049:Iatrogenic Disease; D011761:Pyrrolidonecarboxylic Acid",
"nlm_unique_id": "0404317",
"other_id": null,
"pages": "620-624",
"pmc": null,
"pmid": "34357715",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Chronic paracetamol intoxication : under-diagnosed iatrogenic cause of metabolic acidosis with increased anion gap.",
"title_normalized": "chronic paracetamol intoxication under diagnosed iatrogenic cause of metabolic acidosis with increased anion gap"
} | [
{
"companynumb": "BE-MLMSERVICE-20210929-3095449-2",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "1... |
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