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"abstract": "Cytomegalovirus can cause severe disease with adverse outcome in immunocompromised patients. Severe cytomegalovirus infection in previously healthy individuals is rare. Here we present an unusual case of cytomegalovirus infection with neurological and pulmonary involvement in a previously healthy young woman with no history of immuno-suppression. Unfortunately, the disease followed a malignant course and despite the efforts of the medical staff the patient died. CMV infection should be considered in the diagnostic work-up of immunocompetent patients with fever and unexplained neurological or pulmonary manifestations. Although uncertainty exists regarding the optimal treatment of CMV in healthy individuals, early recognition and administration of ganciclovir may prevent a fatal outcome.",
"affiliations": "Primary Health Care Centre of Kissamos, Chania, Crete, Greece.;Pulmonary Department, Saint George General Hospital of Chania, Crete, Greece.;Pulmonary Department, Saint George General Hospital of Chania, Crete, Greece.;Intensive Care Unit, Saint George General Hospital of Chania, Crete, Greece.;First Department of Internal Medicine, Saint George General Hospital of Chania, Crete, Greece.",
"authors": "Anyfantakis|Dimitrios|D|;Damianaki|Angeliki|A|;Krietsepi|Vasiliki|V|;Panou|Evdokia|E|;Kastanakis|Serafim|S|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-9390",
"issue": "26(2)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D000328:Adult; D003586:Cytomegalovirus Infections; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007121:Immunocompetence",
"nlm_unique_id": "9613961",
"other_id": null,
"pages": "164-166",
"pmc": null,
"pmid": "29932091",
"pubdate": "2018-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A fatal case of cytomegalovirus disease in an immunocompetent young woman: a case report.",
"title_normalized": "a fatal case of cytomegalovirus disease in an immunocompetent young woman a case report"
} | [
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"companynumb": "GR-FRESENIUS KABI-FK201811443",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "Therapeutic options for thymoma-associated myasthenia gravis (MG) patients complicated with hypertension and/or diabetes post thymectomy are often conventional steroids. As the prevalence of diabetes and hypertension globally increases, other therapeutic options for these patients are of great importance.\n9 patients with thymoma-associated MG complicated with hypertension and/or diabetes after thymectomy were administered 75 mg/m2 of docetaxel and 70 mg/m2 of cisplatin on day 1. The treatment could be repeated at 3-week intervals, ranging from 1 to 4 cycles according to the status of the patients. Therapeutic efficacy and side effects were evaluated.\n2 patients were complicated with type 2 diabetes, 6 with hypertension, and 1 with both diabetes and hypertension. After docetaxel/cisplain therapy, the MG symptoms were markedly improved in all patients (2, complete remission; 3, basic remission; 3, marked improvement; 1, improvement). Acetylcholine receptor (AchR) antibody levels were decreased in 8 patients. Minor adverse effects were observed in 2 patients, 1 with Grade II gastrointestinal reaction, and the other with pulmonary infection.\nDocetaxel plus cisplatin might be an effective therapeutic option for thymoma-associated MG patients complicated with hypertension /diabetes post thymectomy without worsening thymoma and hypertension / diabetes.",
"affiliations": "No. 9 Fangbei Road, Chang'an District, Shijiangzhuang 050011, Hebei Province, China.;Center of Treatment of Myasthenia Gravis Hebei Province, First Hospital of Shijiazhuang, Shijiazhuang050011, China.;Center of Treatment of Myasthenia Gravis Hebei Province, First Hospital of Shijiazhuang, Shijiazhuang050011, China.;Center of Treatment of Myasthenia Gravis Hebei Province, First Hospital of Shijiazhuang, Shijiazhuang050011, China.;Center of Treatment of Myasthenia Gravis Hebei Province, First Hospital of Shijiazhuang, Shijiazhuang050011, China.",
"authors": "Qi|Guoyan|G|;Xue|Yinping|Y|;Li|Yongzhao|Y|;Yang|Hongxia|H|;Zhang|Xiaojing|X|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.1515/med-2017-0058",
"fulltext": "\n==== Front\nOpen Med (Wars)Open Med (Wars)medmedOpen Medicine2391-5463De Gruyter Open med-2017-005810.1515/med-2017-0058Regular ArticlesDocetaxel/cisplatin Therapy in Myasthenia Gravis with Hypertension/diabetes Qi Guoyan *Xue Yinping Li Yongzhao Yang Hongxia Zhang Xiaojing No. 9 Fangbei Road, Chang’an District, Shijiangzhuang 050011, Hebei Province, ChinaCenter of Treatment of Myasthenia Gravis Hebei Province, First Hospital of Shijiazhuang, Shijiazhuang\n050011, China* E-mail: guoyan_qi1976@163.com2 12 2017 2017 12 403 408 30 9 2017 20 10 2017 © 2017 Guoyan Qi et al.2017Guoyan Qi et al.This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.Abstract\nBackground\nTherapeutic options for thymoma-associated myasthenia gravis (MG) patients complicated with hypertension and/or diabetes post thymectomy are often conventional steroids. As the prevalence of diabetes and hypertension globally increases, other therapeutic options for these patients are of great importance.\n\nMaterial/methods\n9 patients with thymoma-associated MG complicated with hypertension and/or diabetes after thymectomy were administered 75 mg/m2 of docetaxel and 70 mg/m2 of cisplatin on day 1. The treatment could be repeated at 3-week intervals, ranging from 1 to 4 cycles according to the status of the patients. Therapeutic efficacy and side effects were evaluated.\n\n Results\n2 patients were complicated with type 2 diabetes, 6 with hypertension, and 1 with both diabetes and hypertension. After docetaxel/cisplain therapy, the MG symptoms were markedly improved in all patients (2, complete remission; 3, basic remission; 3, marked improvement; 1, improvement). Acetylcholine receptor (AchR) antibody levels were decreased in 8 patients. Minor adverse effects were observed in 2 patients, 1 with Grade II gastrointestinal reaction, and the other with pulmonary infection.\n\nConclusion\nDocetaxel plus cisplatin might be an effective therapeutic option for thymoma-associated MG patients complicated with hypertension /diabetes post thymectomy without worsening thymoma and hypertension / diabetes.\n\nKeywords\nMyasthenia gravisTreatmentThymectomyHypertensionDiabetes\n==== Body\n1 Introduction\nMyasthenia gravis is an autoimmune disorder induced by neurotransmission defects at the neuromuscular junction, which is characterized by muscle weakness and fatigue. It has been well-documented that approximately 10-15% of MG patients also suffer from thymoma, and nearly all these patients have detectable AchR antibodies and generalized disease [1]. Approximately 30% of patients with thymoma develop MG, and even more have AchR antibodies without MG [2]. Thymectomy has been recommended for MG patients with thymoma, which could not only reduce the risk of proliferation and invasion, but also improve MG symptoms for most patients [3]. For patients either not responding to thymectomy or suffering from MG recurrence post thymectomy, corticosteroids are the most commonly used and most effective immunosuppressive treatments.\n\nCorticosteroids are the first line treatment of mild to moderate MG, and have been considered to be the standard therapy currently. Though MG patients could do well and have well-controlled disease with corticosteroid, either alone or combined with other immunosuppressive agents [4], most need long-term and even life-long treatment with low-dose steroids treatment. Long-term steroids use will increase the appetite of patients, which increases the risks of central obesity, glucose intolerance and hypertension [1, 3].\n\nAs the prevalence of hypertension and diabetes globally increases [5, 6], the number of thymoma-associated MG patients accompanied by hypertension and/or diabetes is inevitably growing. The presence of hypertension/ diabetes poses an additional burden to a patient with myasthenia gravis. Though hypertension and/or diabetes is not absolute contraindication to steroids, long-term use of steroids would definitely increase the difficulty on the control of blood pressure and/or glucose as hyperglycemia and hypertension are the major side effects of long-term steroids use. This would lead to additional medication in order to control blood pressure/glucose, which increases the treatment cost for patients. Moreover, it also potentially increases the risk of cardiovascular diseases-related death [5], considering that diabetes and hypertension are major predisposing factors. Thus, other therapeutic options for this group of patients are of great clinical importance.\n\nBased on the clinical experiences at our center since 2005, we have observed favorable responses of MG after docetaxel/cisplatin therapy for thymoma-associated MG patients. Even in MG patients with unresectable metastatic thymoma, the MG symptoms could be significantly improved after docetaxel plus cisplatin therapy [7]. In the present study, we report the therapeutic effects and adverse events of docetaxel plus cisplatin therapy in a serial of thymoma-associated MG patients complicated with hypertension and/or diabetes who did not respond to thymectomy or suffered from MG recurrence post thymectomy.\n\n2 Subjects and methods\nDuring the period between January 2014 and June 2015, 9 patients with thymoma-associated MG complicated with hypertension and/or diabetes, either not responding to thymectomy or suffering from MG recurrence, underwent docetaxel plus cisplatin treatment at the Myasthenia Gravis Treatment Center of Hebei Province, First Hospital of Shijiazhuang (Hebei, China). The study was approved by the Ethical Committee of the First Hospital of Shijiazhuang, and informed consent was obtained from all the 9 patients.\n\nThymoma was diagnosed via computed tomography (CT) scan, and histological confirmation was done based on the World Health Organization (WHO) histological classification of thymoma [8]. The clinical and pathologic staging of thymoma was done according to the Masaoka’s staging system [9]. The diagnose of MG was based on the clinical symptoms and other examinations including methyl sulfate neostigmine test, electromyography, and serum antibody tests [10]. The severity and classification of MG were assessed in accordance with modified Osserman scale [11]. Prior to the docetaxel and cisplatin treatment, all patients received surgical resection of thymoma (7 with thoracotomy; 2 with minimally invasive thoracoscopic thymectomy). MG symptoms were not alleviated in 4 patients, and MG recurrence occurred in the other 5 patients. The longest MG course was 96 months, with the median of 18 months. The relative information of medication on blood pressure and/or glucose control in all patients has been provided in Table 1.\n\nTable 1 Characteristics of patients before docetaxel/cisplatin treatment.\n\nPatient #\t#1\t#2\t#3\t#4\t#5\t#6\t#7\t#8\t#9\t\nAge/Sex\t63 F\t57 F\t41 M\t66 M\t52 M\t77 M\t72 F\t59 M\t50 M\t\nDuration of MG (months prior)\t12 mos\t18 mos\t72 mos\t96 mos\t24 mos\t60 mos\t10 mos\t3 mos\t5 mos\t\nMG severity (Before treatment)\tII B\tII B\tII B\tII B\tII B\tII B\tII B\tI\tII B\t\nThymoma\t\t\t\t\t\t\t\t\t\t\nMasaoka stage\tII\tIII\tI\tI\tII\tII\tI\tI\tII\t\nWHO type\tB3\tB2/B3\tB1\tB3\tB3\tB2\tB2\tB2\tB2\t\nThymectomy (months prior)\t18 mos\t1 mo\t50 mos\t1 mo\t7 mos\t55 mos\t4 mos\t1 mo\t1 mo\t\nDiabetes\t\\\t\\\tType 2\t\\\t\\\tType 2\tType 2\t\\\t\\\t\nMedication for DM\t\\\t\\\tinsulin\t\\\t\\\tAcarbose glibenclamide\tinsulin\t\\\t\\\t\nHypertension\tStage 3\tStage 2\t\\\tStage 3\tStage 3\t\\\tStage 3\tStage 3\tStage 2\t\nMedication for Hypertension\tMetoprolol\tKato Pury Nifedipine\t\\\tNifedipine\tIrbesartan Felodipine Metoprolol\t\\\tNifedipine Betaloc\tAdalat Valsartan\tMetoprolol Enalapril Nitrendipines\t\nAdditional features before treatment\t\tChronic hepatitis C; pressure ulcers; right lower limb amputation\t\tParkinson’s disease\t\t\t\tGout\t\t\nAchR antibody before treatment\t7.62\t6.92\t13.99\t8.69\t8.53\t11.19\t13.43\t9.97\t7.38\t\nSeverity of MG is rated according to modified Osserman classification.\n\nMG, myasthenia gravis; WHO: World Health Organization.\n\nAll patients were treated with 75 mg/m2 of docetaxel and 70 mg/m2 of cisplatin on day 1, and the treatment could be repeated at 3-week intervals [7,12,13,14]. The treatment ranged from 1 to 4 cycles, according to the status of the patients. Therapeutic effects of docetaxel/cisplatin on MG symtoms were evaluated based on the clinical relative scoring (CRS) system in China as described previously [15, 16]. Adverse effects during the treatment were evaluated in accordance with the World Health Organization criteria.\n\n3 Results\nAmong the 9 thymoma-associated MG patients, 2 were complicated with type 2 diabetes, 6 with hypertension, and 1 with both diabetes and hypertension. The median age was 59 years, ranging from 41 to 77 years. The characteristics of each patient were shown in Table 1. Previously, all patients underwent surgical resection of thymoma (7 with thoracotomy; 2 with minimally invasive thoracoscopic thymectomy). MG symptoms did not alleviated in 4 patients, and the other 5 suffered from MG recurrence. The median course of MG was 18 months, ranging from 9 to 96 months. Before the docetaxel/cisplatin therapy, 8 patients were stage IIB, and the remaining 1 patient were stage I according to the Osserman classification. The median time from thymectomy to docetaxel/cisplain therapy was 4 months, ranging from one to 55 months.\n\nThe cycle of docetaxel/cisplatin treatment ranged from 1 to 4 (median, 2 cycles), as shown in Table 2. One patient also received radiotherapy (#3), and 1 patient underwent 2 courses of plasmapheresis (#4). After docetaxel/cisplain therapy, the clinical symptoms of MG were significantly improved in all patients, including 2 patients with complete remission (CRS ≥ 95%), 3 with basic remission (80% ≤ CRS < 95%), 3 with marked improvement (50% ≤ CRS < 80%), and 1 with improvement (25% ≤ CRS < 50%). The levels of serum AChR antibodies (AchR-Ab) were reduced in 8 patients; while slight increase was observed in 1 patient (#2) (Table 3). The patients were followed up to 29 months, with a median duration of 18 months. MG recurrence occurred in patient #3 one year after docetaxel/cisplain therapy. No influence of chemotherapy on blood pressure/glucose has been observed, and all patients maintained previous treatment protocols on blood pressure/glucose control. Minor adverse effects were observed in only 2 patients, including 1 patient with Grade II gastrointestinal reaction (#2), and the other with pulmonary infection (#3).\n\nTable 2 Outcome of patients after docetaxel plus cisplatin therapy.\n\nPatient #\t#1\t#2\t#3\t#4\t#5\t#6\t#7\t#8\t#9\t\nDocetaxel/cisplatin (cycle)\t1\t2\t2\t2\t4\t3\t1\t2\t3\t\nOther treatments\t\t\tRT\tPP\t\t\t\t\t\t\nCRS\t\t\t\t\t\t\t\t\t\t\nBefore\t10\t26\t15\t4\t21\t10\t10\t9\t19\t\nAfter\t0\t8\t2\t0\t4\t5\t6\t2\t2\t\nBlood pressure*\t\t\t\t\t\t\t\t\t\t\nBefore\t118/87\t135/75\t139/92\t120/80\t154/97\t130/60\t136/78\t143/88\t132/101\t\nAfter\t\\\t97/62\t134/70\t120/80\t126/83\t130/60\t137/70\t138/90\t127/71\t\nBlood glucose#\t\t\t\t\t\t\t\t\t\t\nBefore\t4.3\t6.4\t18.3\t7.2\t4\t5\t7.8\t5.4\t5.8\t\nAfter\t\\\t6.1\t13.6\t6.2\t4\t7.2\t6.4\t5.4\t3.4\t\nMG response\tCR\tMI\tBR\tCR\tBR\tMI\tIM\tMI\tBR\t\nAdverse effects\t\tGrade II gastrointestinal reaction\tPulmonary infection\t\t\t\t\t\t\t\nFollow up (Months)\t28\t11\t14\t22\t29\t23\t15\t14\t18\t\nRT, radiotherapy; PP, plasmapheresis; CRS, clinical relative score; MG, myasthenia gravis; AchR-Ab, Antiacetylcholine receptor antibodies; CR, Complete remission; BR, basic remission; MI, Marked improvement; IM, improvement.\n\n# Blood glucose in patients with diabetes is detected with relative medication for DM\n\n* Blood pressure in patients with hypertension is detected under daily antihypertensive medication\n\nTable 3 Change in AchR-Ab levels.\n\nPatient #\tPre-docetaxel/cisplatin\tPost docetaxel/cisplatin\t\n#1\t7.62\t0.55\t\n#2\t6.92\t7.66\t\n#3\t13.99\t10.5\t\n#4\t8.69\t4.54\t\n#5\t8.53\t7.28\t\n#6\t11.19\t10.57\t\n#7\t13.43\t2.72\t\n#8\t9.97\t1.8\t\n#9\t7.38\t7.29\t\nAchR-Ab, Antiacetylcholine receptor antibodies.\n\n4 Discussion\nIn the present study, we revealed that 9 thymoma-associated MG patients complicated with hypertension and/or diabetes had favorable responses to docetaxel plus cisplatin therapy. Previously, these patients did not respond to thymectomy or suffered from MG recurrence post thymectomy. The median number of docetaxel/cisplatin treatment cycle was only 2, ranging from 1 to 4. After treatment, 8 out of the 9 (88.9%) patients were achieved at least marked improvement, with 2 patients achieved complete remission. Minor adverse effects were observed in only 2 patients, including 1 patient with Grade II gastrointestinal reaction, and the other with pulmonary infection.\n\nConventional immunosuppressive treatment has been the first-line therapy for adult MG patients, and longterm and even life-long treatment with low-dose steroids is required for most patients. It has been reported that MG patients with corticosteroids treatment had a 1.46-fold increased risk of developing diabetes mellitus as compared with non-MG cohort; while those without corticosteroids had no increase risk of DM [17]. In our study, we found that docetaxel/cisplatin treatment did not influence the medication for hypertension/DM.\n\nSystematic chemotherapy with docetaxel and cisplatin has been used as one of the most common regimens in patients with thymic carcinoma [18]. We have used this regimen in patients with thymic carcinoma back to 2005. Interestingly, we have found that the responses of thymic carcinoma were minor to moderate, but the symptoms of MG were markedly improved by this regimen. Even in MG patients with unresectable metastatic thymoma, the symptom of MG could be markedly improved after docetaxel/cisplatin therapy [7]. Thus far, docetaxel/cisplatin therapy has proved to be generally safe and well tolerated in MG patients with thymoma, based on the observations at our center since 2005. Of the 9 patients treated at our center, almost half of patients (n=4, 44.4%) only received 2 cycles of docetaxel/cisplatin treatment. Over the long run, docetaxel/cisplatin treatment may avoid certain stress in control of bodyweight, blood pressure and blood glucose of long-term treatment with low-dose immunosuppression, with relative short period of treatment. This would especially benefit MG patients complicated with diabetes and/or hypertension.\n\nAll these patients have returned to full active lives without immunosuppressive medications. 88.9% (n=8) patients have achieved at least marked improvement, with 2 patients achieved complete remission. Till now, the longest follow-up so far is 2.4 years, and only 1 patient suffered from MG recurrence. All the 9 patients had antibodies to AChR. The AchR-Ab levels were decreased, but AchR antibody responses still existed in all patients after docetaxel/cisplatin therapy. Our results indicate that docetaxel/cisplatin therapy could produce marked clinical improvement without complete elimination of the AchR-Ab response. Similar observations have been reported by Daniel et al. They reported that clinical improvement was achieved in patients with refractory myasthenia treated with high-dose cyclophosphamide, without complete elimination of AchR antibody response [19, 20].\n\nNevertheless, docetaxel/cisplatin treatment may have certain adverse effects. Though the adverse effects observed varied with studies, myelosuppression and gastrointestinal reaction were considered to be the major toxicity associated with chemotherapy [21, 22,23]. Myelosuppression, nausea, fatigue, and alopecia have been reported to be the most common adverse effects in patients with non-small-cell lung carcinoma treated with cisplatin plus docetaxel [24]. Park et al. reported that grades III/IV neutropenia, grade III leucopenia, diarrhea and nausea were the major side effects in patients with advanced thymic epithelial tumors treated with docetaxel plus cisplatin chemotherapy. Of the 9 patients treated with docetaxel/cisplatin in this report, 1 patient developed Grade II gastrointestinal reaction, and one had pulmonary infection. No obvious side effects were observed in the other 7 patients. Our results infer that docetaxel/cisplatin therapy is generally safe and well tolerated in thymoma-associated MG patients complicated with diabetes and/or hypertension.\n\nTo sum up, in thymoma-associated MG patients complicated with hypertension and/or diabetes, who also either did not respond to thymectomy or suffer from MG recurrence postoperatively, docetaxel/cisplatin therapy may produce impressive and potentially long-term benefits with tolerable side effects. Over the long run, docetaxel/cisplatin treatment may avoid additional stress in the control of bodyweight, blood pressure and blood glucose causing by long-term low-dose immunosuppressive treatment. However, the sample size of this study is relative small, which may affect the generalization of our results. Further additional subjects with longer follow up are needed to test the durability of therapeutic benefits with this regimen.\n\nAcknowledgements\n This work was supported by Shijiazhuang Science and Technology Bureau Foundation (Grant no. 131460613), Science and Technology Agency Foundation of Hebei Province (Grant no. 14277758D), Natural Science Foundation of Hebei Province (Grant no. H2015106020), and Key Project of Hebei Provincial Administration of Traditional Chinese Medicine (Grant no. 2014221).\n\nConflict of interest: The authors declare no conflict of interest.\n==== Refs\nReferences\n[1] Gilhus NE Verschuuren JJ Myasthenia gravis: subgroup classification and therapeutic strategies The Lancet Neurology 2015 14 1023 1036 26376969 \n[2] Marx A Pfister F Schalke B Saruhan-Direskeneli G Melms A Strobel P The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes Autoimmunity reviews 2013 12 875 884 23535159 \n[3] Li Z-Y China guidelines for the diagnosis and treatment of myasthenia gravis Neuroimmunology and Neuroinflammation 2016 3 1 9 \n[4] Palace J Newsom-Davis J Lecky B A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group Neurology 1998 50 1778 1783 9633727 \n[5] Hossain P Kawar B El Nahas M Obesity and diabetes in the developing world--a growing challenge The New England journal of medicine 2007 356 213 215 17229948 \n[6] Gao Y Chen G Tian H Lin L Lu J Weng J Prevalence of hypertension in china: a cross-sectional study PloS one 2013 8 e65938 23776574 \n[7] Qi G Liu P Dong H Gu S Yang H Xue Y Therapeutic Potential of Docetaxel plus Cisplatin Chemotherapy for Myasthenia Gravis Patients with Metastatic Thymoma The Tohoku journal of experimental medicine 2017 241 281 286 28381664 \n[8] Rosai J Sobin L World Health Organization International histological classification of tumors: histological typing of tumors of the thymus 1999 \n[9] Masaoka A Monden Y Nakahara K Tanioka T Follow-up study of thymomas with special reference to their clinical stages Cancer 1981 48 2485 2492 7296496 \n[10] Li Z-Y Bogdos M Giannopoulos S Kosmidou M Mittelbronn M Qi X-K China guidelines for the diagnosis and treatment of myasthenia gravis Neuroimmunol Neuroinfammation 2016 3 1 9 \n[11] Osserman KE Genkins G Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients The Mount Sinai journal of medicine, New York 1971 38 497 \n[12] Ridwelski K Gebauer T Fahlke J Kroning H Kettner E Meyer F Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic gastric cancer Annals of oncology : official journal of the European Society for Medical Oncology 2001 12 47 51 11249048 \n[13] Park S Ahn M-j Ahn JS Sun J-M Shim YM Kim J A prospective phase II trial of induction chemotherapy with docetaxel/cisplatin for Masaoka stage III/IV thymic epithelial tumors J Thorac Oncol 2013 8 959 966 23722169 \n[14] Roka S Kornek G Schüller J Ortmann E Feichtinger J Armbruster C Carcinoma showing thymic-like elements–a rare malignancy of the thyroid gland Br J Surg 2004 91 142 145 14760659 \n[15] Liu G-C Gao B-L Yang H-Q Qi G-Y Liu P The clinical absolute and relative scoring system–A quantitative scale measuring myasthenia gravis severity and outcome used in the traditional Chinese medicine Complement Ther Med 2014 22 877 886 25440379 \n[16] Qi G Liu P Dong H Gu S Yang H Xue Y Metastatic Thymoma-Associated Myasthenia Gravis: Favorable Response to Steroid Pulse Therapy Plus Immunosuppressive Agent Medical science monitor : international medical journal of experimental and clinical research 2017 23 1217 1223 28278141 \n[17] Yeh JH Chen HJ Lin CC Chen YK Chiu HC Kao CH Risk of diabetes mellitus among patients with myasthenia gravis Acta neurologica Scandinavica 2015 132 132 138 25630759 \n[18] Huang J Rizk NP Travis WD Riely GJ Park BJ Bains MS Comparison of patterns of relapse in thymic carcinoma and thymoma J Thorac Cardiovasc Surg 2009 138 26 31 19577051 \n[19] Drachman DB Adams RN Hu R Jones RJ Brodsky RA Rebooting the immune system with high-dose cyclophosphamide for treatment of refractory myasthenia gravis Annals of the New York Academy of Sciences 2008 1132 305 314 18567882 \n[20] Drachman DB Jones RJ Brodsky RA Treatment of refractory myasthenia: “rebooting” with high-dose cyclophosphamide Annals of neurology 2003 53 29 34 12509845 \n[21] Albany C Sonpavde G Docetaxel for the treatment of bladder cancer Expert Opin Investig Drugs 2015 24 1657 1664 \n[22] Betticher DC Schmitz S-FH Tötsch M Hansen E Joss C von Briel C Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non–small-cell lung cancer: A multicenter phase II trial J Clin Oncol 2003 21 1752 1759 12721251 \n[23] Ridwelski K Gebauer T Fahlke J Kröning H Kettner E Meyer F Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic gastric cancer Ann Oncol 2001 12 47 51 11249048 \n[24] Mitsudomi T Morita S Yatabe Y Negoro S Okamoto I Tsurutani J Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial Lancet Oncol 2010 11 121 128 20022809\n\n",
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"issue": "12()",
"journal": "Open medicine (Warsaw, Poland)",
"keywords": "Diabetes; Hypertension; Myasthenia gravis; Thymectomy; Treatment",
"medline_ta": "Open Med (Wars)",
"mesh_terms": null,
"nlm_unique_id": "101672167",
"other_id": null,
"pages": "403-408",
"pmc": null,
"pmid": "29318185",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "23722169;19577051;11249048;4941403;18567882;23776574;12721251;9633727;28278141;25630759;20022809;26535615;7296496;28381664;14760659;23535159;17229948;26376969;12509845;25440379",
"title": "Docetaxel/cisplatin Therapy in Myasthenia Gravis with Hypertension/diabetes.",
"title_normalized": "docetaxel cisplatin therapy in myasthenia gravis with hypertension diabetes"
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"companynumb": "CN-MYLANLABS-2018M1008640",
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"abstract": "BACKGROUND\nIntravenous lipid emulsion (ILE) resuscitation is now frequently being used for severe overdoses due to lipophilic drugs. However, the optimal dose, duration, and safety are still unclear.\n\n\nMETHODS\nA patient with refractory cardiovascular collapse following an amitriptyline overdose was treated with ILE with initial improvement. Instability recurred after ILE discontinuation and lipid therapy was restarted, but high-dose treatment was complicated by severe lipemia. A low-dose infusion was instead used, and the patient did not experience further toxicity despite amitriptyline levels in the toxic range for 21 days. He survived to discharge without long-term sequelae.\n\n\nCONCLUSIONS\nA low-dose infusion of ILE was well tolerated and may have successfully prevented recurrent toxicity in a case of severe tricyclic antidepressant overdose.",
"affiliations": "Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA, ragarwal@wakehealth.edu.",
"authors": "Agarwala|Ravi|R|;Ahmed|Syed Zaki|SZ|;Wiegand|Timothy J|TJ|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D005217:Fat Emulsions, Intravenous; D000639:Amitriptyline",
"country": "United States",
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"doi": "10.1007/s13181-013-0353-4",
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"issue": "10(2)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000328:Adult; D000639:Amitriptyline; D000929:Antidepressive Agents, Tricyclic; D003131:Combined Modality Therapy; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D006949:Hyperlipidemias; D008297:Male; D012008:Recurrence; D012720:Severity of Illness Index; D012769:Shock; D013406:Suicide, Attempted; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "210-4",
"pmc": null,
"pmid": "24173885",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20095812;20923546;18570172;22296992;20605670;15533027;22023355;22627464;21327839;22809934;21989640",
"title": "Prolonged use of intravenous lipid emulsion in a severe tricyclic antidepressant overdose.",
"title_normalized": "prolonged use of intravenous lipid emulsion in a severe tricyclic antidepressant overdose"
} | [
{
"companynumb": "US-MYLANLABS-2014S1016424",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugadditional": null,
... |
{
"abstract": "In an attempt to improve treatment outcome high-dose methylprednisolone (HDMP, 20-30 mg/kg, once a day orally) was used instead of a conventional dose of steroid (2 mg/kg/d, in 3 divided doses) in children with acute lymphoblastic leukemia (ALL) with increased risk factors. HDMP combined with cytotoxic agents (vincristine and L-asparaginase) resulted in an improved complete remission rate (94%) in 48 newly diagnosed children with ALL compared to 81% in 86 historical controls receiving standard dose steroid combined with the same treatment regimen. The bone marrow relapse rate was lower in patients who received HDMP (31%) than in controls (56%). Treatment was discontinued in 56% of 48 patients receiving HDMP and in 35% of 86 controls. The difference was significant (p < 0.05). The 5-yr continuous complete remission rate was significantly greater in patients received HDMP compared with the control patients (60% vs. 43%, p < 0.05). HDMP treatment was well tolerated without significant adverse effects. Moreover, during induction therapy the duration of leukopenia (< 2 x 10(9)/L) was shorter in patients receiving HDMP. We conclude that HDMP combined with other antileukemic agents increased the CR rate and prolonged the duration of remission in children with ALL who had increased risk factors. However, the optimal dosage of HDMP and its role in maintenance therapy should be determined in future, randomized studies.",
"affiliations": "Department of Pediatric Hematology, Ihsan Dogramaci Children's Hospital, Ankara, Turkey.",
"authors": "Hiçsönmez|G|G|;Gümrük|F|F|;Zamani|P V|PV|;Tuncer|M A|MA|;Yetgin|S|S|;Gürgey|A|A|;Atahan|L|L|;Ozsoylu|S|S|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1111/j.1600-0609.1997.tb01406.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "58(1)",
"journal": "European journal of haematology",
"keywords": null,
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008775:Methylprednisolone; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "26-31",
"pmc": null,
"pmid": "9020370",
"pubdate": "1997-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "High-dose methylprednisolone for children with acute lymphoblastic leukemia and unfavorable presenting features.",
"title_normalized": "high dose methylprednisolone for children with acute lymphoblastic leukemia and unfavorable presenting features"
} | [
{
"companynumb": "TR-PFIZER INC-2021028264",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE ACETATE"
},
"drugadditional... |
{
"abstract": "Acute pancreatitis has numerous etiologies, with the most common including gallstones, alcohol abuse, and medications such as angiotensin-converting enzyme (ACE) inhibitors, statins, and diuretics. Mirtazapine has been associated with increased serum cholesterol and serum triglyceride levels. However, few studies have reported dangerously elevated triglyceride levels resulting in acute pancreatitis. This report discusses a case of mirtazapine-induced pancreatitis in a 46-year-old African American female. The patient presented to the emergency department with pancreatitis, presumably alcohol-induced as with a prior admission, but she denied any recent alcohol use. Mirtazapine then became the suspected cause of her hypertriglyceridemia-induced pancreatitis and was discontinued. After discontinuing mirtazapine, and utilizing an insulin infusion, her triglyceride levels normalized and symptoms of pancreatitis resolved. Using the Naranjo Adverse Drug Reaction Probability Scale, a total score of 5 was calculated indicating a probable adverse drug reaction of acute pancreatitis from mirtazapine.",
"affiliations": "Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA.;Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA.;Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA.",
"authors": "Bowers|Riley D|RD|https://orcid.org/0000-0002-6889-0156;Valanejad|Sara M|SM|;Holombo|Ashley A|AA|",
"chemical_list": "D000928:Antidepressive Agents; D000078785:Mirtazapine",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190018760645",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "32(5)",
"journal": "Journal of pharmacy practice",
"keywords": "drug-induced; hypertriglyceridemia; mirtazapine; pancreatitis",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000928:Antidepressive Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D000078785:Mirtazapine; D010195:Pancreatitis",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "586-588",
"pmc": null,
"pmid": "29486665",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mirtazapine-Induced Pancreatitis-A Case Report.",
"title_normalized": "mirtazapine induced pancreatitis a case report"
} | [
{
"companynumb": "US-TEVA-2019-US-1138590",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nLittle is known about the risk of hepatitis B virus (HBV) reactivation in patients receiving interferon (IFN)-free direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV).\n\n\nMETHODS\nPatients who were seropositive for HBV core antibody and who received IFN-free DAAs for HCV were enrolled. Hepatitis B virus reactivation was defined as reappearance of serum HBV deoxyribonucleic acid (DNA) ≥100 IU/mL in patients with baseline undetectable viral load, or ≥2 log10 IU/mL increase of HBV DNA in patients with baseline detectable viral load. Hepatitis B virus-related alanine aminotransferase (ALT) flare was defined as ALT ≥5 times upper limit of normal or ≥2 times of the baseline level. Hepatitis B virus-related hepatic decompensation was defined as presence of jaundice, coagulopathy, hepatic encephalopathy, or ascites.\n\n\nRESULTS\nCompared with no HBV reactivation in 81 HBV surface antigen (HBsAg)-negative patients, 2 of 12 HBsAg-positive patients had HBV reactivation (0% [confidence interval {95% CI}, 0%-4.5%] vs 16.7% [95% CI, 4.7%-44.8%], P = .015). No patients had ALT flare or hepatic decompensation. Baseline HBsAg level at a cutoff value of 500 IU/mL was associated with HBV reactivation in HBsAg-positive patients. There was no HBsAg seroreversion in HBsAg-negative patients.\n\n\nCONCLUSIONS\nHepatitis B virus reactivation is limited to HBsAg-positive patients receiving IFN-free DAAs for HCV. Higher baseline HBsAg levels are associated with HBV reactivation. The risk of ALT flares or hepatic decompensation is low in these patients.",
"affiliations": "Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.;Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.;Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.;Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou.;Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.;Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.;Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.;Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei.",
"authors": "Liu|Chen-Hua|CH|;Liu|Chun-Jen|CJ|;Su|Tung-Hung|TH|;Fang|Yu-Jen|YJ|;Yang|Hung-Chih|HC|;Chen|Pei-Jer|PJ|;Chen|Ding-Shinn|DS|;Kao|Jia-Horng|JH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofx028",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n28480296\n10.1093/ofid/ofx028\nofx028\nMajor Article\nEditor's Choice\nHepatitis B Virus Reactivation in Patients Receiving Interferon-Free Direct-Acting Antiviral Agents for Chronic Hepatitis C Virus Infection\nLiu Chen-Hua 123 Liu Chun-Jen 124 Su Tung-Hung 12 Fang Yu-Jen 3 Yang Hung-Chih 125 Chen Pei-Jer 124 Chen Ding-Shinn 126 Kao Jia-Horng 124 1 \nDepartment of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei\n2 \nHepatitis Research Center, National Taiwan University Hospital, Taipei\n3 \nDepartment of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou\n4 \nGraduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei\n5 \nDepartment of Microbiology, National Taiwan University College of Medicine, Taipei\n6 \nGenomics Research Center, Academia Sinica, Taipei, Taiwan\nCorrespondence: J.-H. Kao, MD, PhD, National Chair Professor, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan (kaojh@ntu.edu.tw).\n\n\nWinter 2017 \n11 2 2017 \n11 2 2017 \n4 1 ofx02809 11 2016 08 2 2017 © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2017This 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\nLittle is known about the risk of hepatitis B virus (HBV) reactivation in patients receiving interferon (IFN)-free direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV).\n\nMethods\nPatients who were seropositive for HBV core antibody and who received IFN-free DAAs for HCV were enrolled. Hepatitis B virus reactivation was defined as reappearance of serum HBV deoxyribonucleic acid (DNA) ≥100 IU/mL in patients with baseline undetectable viral load, or ≥2 log10 IU/mL increase of HBV DNA in patients with baseline detectable viral load. Hepatitis B virus-related alanine aminotransferase (ALT) flare was defined as ALT ≥5 times upper limit of normal or ≥2 times of the baseline level. Hepatitis B virus-related hepatic decompensation was defined as presence of jaundice, coagulopathy, hepatic encephalopathy, or ascites.\n\nResults\nCompared with no HBV reactivation in 81 HBV surface antigen (HBsAg)-negative patients, 2 of 12 HBsAg-positive patients had HBV reactivation (0% [confidence interval {95% CI}, 0%–4.5%] vs 16.7% [95% CI, 4.7%–44.8%], P = .015). No patients had ALT flare or hepatic decompensation. Baseline HBsAg level at a cutoff value of 500 IU/mL was associated with HBV reactivation in HBsAg-positive patients. There was no HBsAg seroreversion in HBsAg-negative patients.\n\nConclusions\nHepatitis B virus reactivation is limited to HBsAg-positive patients receiving IFN-free DAAs for HCV. Higher baseline HBsAg levels are associated with HBV reactivation. The risk of ALT flares or hepatic decompensation is low in these patients.\n\ndirect-acting antiviral agenthepatitis B virushepatitis C virusNational Taiwan University Hospital, Taiwan105-P09\n==== Body\nHepatitis C virus (HCV) infection is the leading cause of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplantation [1–3]. Compared with HCV-infected patients who fail to achieve sustained virologic response (SVR) after antiviral therapies, those who achieve SVR have decreased long-term morbidity and mortality [4, 5]. Treatment of HCV by interferon (IFN)-free direct-acting antiviral agents (DAAs) has shown excellent efficacy and safety. Applying IFN-free DAAs has become the current standard of care for the management of HCV infection.\n\nAlthough treatment with IFN-free DAAs is generally considered to be potent and safe, several case reports have shown that HCV-infected patients who were seropositive for hepatitis B virus (HBV) surface antigen (HBsAg) or isolated HBV core antibody (anti-HBc) developed HBV reactivation after IFN-free DAAs with the presentation of increasing serum HBV viral load, alanine aminotransferase (ALT) elevation, or even hepatic decompensation [6–9]. Based on the case reports, the US Food and Drug Administration and the American Association for the Study of Liver Diseases/Infectious Diseases Society of America posted warning information of potential HBV reactivation for HCV-infected patients receiving IFN-free DAAs [10, 11]. Recently, one study evaluated the risk of HBV reactivation in HCV-infected patients receiving IFN-free DAAs and concluded that HBsAg-positive patients had a higher risk of HBV reactivation than HBsAg-negative patients (30% vs 0%) [12]. However, the incidence and the clinical features of HBV reactivation after IFN-free DAAs for HCV have not been fully addressed by prospective studies. Therefore, we aimed to prospectively evaluate the risk of HBV reactivation in patients receiving IFN-free DAAs for HCV.\n\nMETHODS\nPatients\nBetween April 2015 and September 2016, 134 patients who received IFN-free DAAs for HCV were consecutively enrolled at the National Taiwan University Hospital (NTUH) and NTUH Yun-Lin Branch. All patients were aged ≥20 years and had chronic HCV infection, defined as detectable HCV antibody ([anti-HCV] Abbott HCV EIA 3.0; Abbott Laboratories, Abbott Park, IL) and serum HCV ribonucleic acid (RNA) (Cobas TaqMan HCV Test version 2.0; Roche Diagnostics GmbH, Mannheim, Germany; limit of quantification, 25 IU/mL) for more than 6 months. In addition, all patients received treatment for 12 weeks and off-therapy follow-up for an additional 12 weeks according to label recommendations. The study was approved by the NTUH Institutional Review Board and was conducted in accordance with the principles of Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice. All patients provided written informed consent before participating in the study.\n\nStudy Design\nThis was a prospective cohort study. Baseline demographic data, hemogram, international normalized ratio (INR), serum albumin, serum bilirubin, serum ALT, stage of hepatic fibrosis, anti-HCV, HBsAg (Abbott Architect HBsAg quantification assay; Abbott Laboratories), HBV surface antibody (anti-HBs) (Abbott Architect anti-HBs assay; Abbott Laboratories), anti-HBc (Abbott Architect anti-HBc II assay; Abbott Laboratories), HCV RNA, HCV genotype (Abbott RealTime HCV genotyping II; Abbott Molecular Inc., Chicago, IL), and HBV deoxyribonucleic acid ([DNA] Cobas AmpliPrep/Cobas TaqMan HBV DNA test, version 2.0; limit of detection 12 IU/mL and limit of quantification 20 IU/mL) were assessed before IFN-free DAA treatment [13, 14]. Patients who were seronegative for anti-HBc and who did not complete 12 weeks of IFN-free DAAs were excluded. In addition, Patients were excluded from the study if they received peginterferon or oral nucleos(t)ide analogues that were active against HBV within 24 weeks before the start of IFN-free DAAs.\n\nAfter IFN-free DAAs, all patients received outpatient visits at weeks 1, 2, 4, 6, 8, and then every 4 weeks until the last visit. The hemogram, INR, albumin, bilirubin, ALT, HBsAg, HBV DNA, and HCV RNA were evaluated at each visit. Hepatitis B virus reactivation was defined as reappearance of serum HBV DNA ≥100 IU/mL in patients with baseline undetectable viral load or ≥2 log10 IU/mL increase of HBV DNA in patients with baseline detectable viral load [15, 16]. Furthermore, we evaluated low-level HBV rebound, defined as reappearance of detectable HBV DNA in patients with baseline undetectable viral load or in those with ≥1 log10 IU/mL increase from baseline detectable viral load. Hepatitis B virus-related ALT flare was defined as ALT ≥5 times upper limit of normal or ≥2 times of the baseline level with concomitant HBV DNA reactivation [15]. Hepatitis B virus-related hepatic decompensation was defined as presence of HBV-related ALT flare and presence of jaundice, coagulopathy, hepatic encephalopathy, or ascites. Patients would receive oral entecavir or tenofovir disoproxil fumarate therapy if they developed HBV-related ALT flare and/or hepatic decompensation during the study. Hepatitis B virus surface antigen seroreversion was defined as reappearance of HBsAg after IFN-free DAA treatment in HBsAg-negative patients.\n\nThe risk of HBV reactivation, HBV-related ALT flare, and HBV-related hepatic decompensation were evaluated for all patients who completed 12 weeks of IFN-free DAAs. For patients who had completed off-therapy follow-up for 12 weeks, the risk of off-therapy HBV reactivation and the related clinical events were also evaluated.\n\nStatistical Analyses\nData were analyzed using Statistical Program for Social Sciences (SPSS 17.0; SPSS Inc., Chicago, IL). Patient characteristics were expressed as mean (standard deviation) and percentage when appropriate. The events related to HBV reactivation, ALT flare, hepatic decompensation, and HBsAg seroreversion were shown in numbers and percentages with 95% confidence interval (CI) and were compared by χ2 with Fisher’s exact test when appropriate. All statistical tests were 2-tailed, and the results were statistically significant when a P value was <.05.\n\nRESULTS\nPatient Characteristics\nAmong the 134 enrolled patients, 26 seronegative for anti-HBc were excluded. Of the 108 patients seropositive for anti-HBc, 13 who did not complete 12 weeks of treatment and 2 human immunodeficiency virus (HIV)-infected patients who were seronegative for HBsAg but who receive received nucleos(t)ide reverse-transcriptase inhibitors active against HBV were excluded. Among the 13 patients who did not complete treatment, 1 HBsAg-negative patient developed hepatic decompensation 1 week after paritaprevir/ritonavir, ombitasvir plus dasabuvir (PrOD)-based treatment. The baseline and week-1 HBV DNA levels were undetectable, indicating that this event was not attributed to HBV reactivation. The remaining 12 HBsAg-positive and 81 HBsAg-negative patients were eligible for the study. Furthermore, 86 patients completed off-therapy follow up for 12 weeks (Figure 1). The mean HCV RNA level was 6.2 log10 IU/mL, and 81.7% patients were infected with HCV genotype 1b. With regard to IFN-free DAA regimens, 85.0% of our patients received sofosbuvir (SOF)-based therapies, and the remaining patients received PrOD-based therapies. With regard to HBV serology, 12 (12.9%) patients had HBsAg positivity, 46 (49.5%) had isolated anti-HBc positivity, and 35 (37.6%) had anti-HBs positivity. All HBsAg-negative patients had baseline undetectable serum HBV DNA. For HBsAg-positive patients, 41.7% of them had baseline undetectable serum HBV DNA (Table 1). The baseline HBV viral load ranged from 40 to 282 IU/mL in HBV viremic patients.\n\nFigure 1. Study flow diagram.\n\nTable 1. Baseline Patient Characteristics\n\n\nCharacteristics\n\t\nHBsAg (+), n = 12\n\t\nIsolated Anti-HBc (+), n = 46\n\t\nAnti-HBs (+), n = 35\n\t\nOverall, N = 93\n\t\nAge (year), mean (SD)\t55 (9)\t56 (8)\t 57 (9)\t56 (8)\t\nMale, n (%)\t6 (50.0)\t24 (52.2)\t16 (45.7)\t46 (49.5)\t\nPrior Peg-IFN/RBV failure, n (%)\t6 (50.0)\t25 (54.3)\t17 (48.6)\t48 (51.6)\t\nHCV RNA, log10 IU/mL, mean (SD)\t6.0 (2.3)\t6.4 (2.4)\t6.3 (2.5)\t6.2 (2.2)\t\nHCV Genotype, n (%)\t\n 1a\t0 (0)\t1 (2.2)\t1 (2.9)\t2 (2.2)\t\n 1b\t10 (83.3)\t38 (82.6)\t28 (80.0)\t76 (81.7)\t\n 2\t2 (16.7)\t7 (15.2)\t6 (17.1)\t15 (16.1)\t\nHCV Treatment Regimen, n (%)\t\n LDV/SOF\t5 (50.0)\t23 (50.0)\t18 (51.4)\t46 (49.5)\t\n LDV/SOF + RBV\t2 (20.0)\t9 (19.6)\t7 (20.0)\t18 (19.4)\t\n SOF + RBV\t2 (16.7)\t7 (15.1)\t6 (17.1)\t15 (16.1)\t\n PrOD\t2 (16.7)\t5 (10.9)\t4 (11.4)\t11 (11.8)\t\n PrOD + RBV\t1 (8.3)\t2 (4.3)\t0 (0)\t3 (3.2)\t\nUndetectable HBV DNA, n/n (%)a\t5 (41.7)\t0 (0)\t0 (0)\t5 (5.4)\t\nMETAVIR Fibrosis Stage, n (%)b\t\n F0/F1\t3 (25.0)\t12 (26.1)\t9 (25.7)\t24 (25.8)\t\n F2\t3 (25.0)\t10 (21.7)\t12 (34.3)\t25 (26.9)\t\n F3\t1 (8.3)\t6 (13.0)\t3 (8.6)\t10 (10.8)\t\n F4\t4 (33.3)\t16 (34.8)\t11 (31.4)\t31 (33.3)\t\n Undetermined\t1 (8.3)\t2 (4.3)\t0 (0)\t3 (3.2)\t\nHemoglobin, g/dL, mean (SD)\t14.0 (2.6)\t14.4 (2.4)\t14.2 (2.3)\t14.1 (2.9)\t\nWhite blood cell count, 109/L, mean (SD)\t5320 (2258)\t5532 (2698)\t5038 (2379)\t5226 (2587)\t\nPlatelet count, 109/L, mean (SD)\t168 (54)\t162 (62)\t165 (58)\t166 (58)\t\nINR, mean (SD)\t0.98 (0.08)\t1.03 (0.07)\t1.02 (0.12)\t1.01 (0.10)\t\nAlbumin, g/dL, mean (SD)\t4.4 (1.5)\t4.2 (1.8)\t4.4 (1.7)\t4.3 (1.7)\t\nTotal bilirubin, mg/dL, mean (SD)\t0.8 (0.6)\t2.2 (1.5)\t1.2 (0.7)\t2.5 (2.3)\t\nDirect bilirubin, mg/dL, mean (SD)\t0.3 (0.2)\t1.2 (0.8)\t0.5 (0.3)\t1.1 (1.0)\t\nALT, U/L, mean (SD)\t92 (62)\t84 (72)\t105 (85)\t102 (78)\t\nAbbreviations: ALT, alanine aminotransferase; anti-HBc, hepatitis B virus core antibody; anti-HBs, hepatitis B virus surface antibody; DNA, deoxyribonucleic acid; HBsAg, hepatitis B surface agent; HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized ratio; IQR, interquartile range; LDV, ledipasvir; LOD, limit of detection; Peg-IFN, peginterferon; PrOD, paritaprevir/ritonavir/ombitasvir/dasabuvir; RBV, ribavirin; RNA, ribonucleic acid; SD, standard deviation; SOF, sofosbuvir. \n\n\naDetermined by Cobas AmpliPrep/Cobas TaqMan HBV DNA test, version 2.0 with LOD of 12 IU/mL.\n\n\nbDetermined by transient elastography (Fibroscan; Echosens, Paris, France) according to the cutoff values proposed by Castéra et al [14]. Two HBsAg-negative patients and 1 HBsAg-positive patient had unreliable examination with less than 10 valid measurements, a successful rate of less than 60%, and the IQR more than 30% of the median liver stiffness measurement value.\n\nRisks of Hepatitis B Virus Reactivation After Interferon-Free Direct-Acting Antiviral Agents\n\nTable 2 shows the incidence of HBV reactivation and reactivation-related clinical events in patients completing IFN-free DAAs. None of 81 HBsAg-negative patients and 2 of 12 HBsAg-positive patients developed HBV reactivation (0% [95% CI, 0%–4.5%] vs 16.7% [95% CI, 4.7%–44.8%], P = .015). Neither patients with isolated anti-HBc positivity nor patients with anti-HBs positivity had HBV reactivation (0% [95% CI, 0%–7.7%] and 0% [95% CI, 0%–9.9%], respectively). Neither of the 2 HBsAg-positive patients with HBV reactivation developed ALT flare or hepatic decompensation. No HBsAg-negative and 6 HBsAg-positive patients developed low-level HBV rebound (0% [95% CI, 0%–4.5%] vs 50% [95% CI, 25.4%–74.6%], P < .0001). In addition, there was no HBsAg seroreversion in HBsAg-negative patients. During the off-therapy follow up, there were no additional events in terms of HBV reactivation, ALT flare, or hepatic decompensation.\n\nTable 2. Incidence of HBV Reactivation and Clinical Events in Patients Receiving IFN-Free DAA Therapy\n\n\nIFN-Free DAA Treatment Status\n\t\nHBV Serology\n\t\nHBV Reactivation, n/N (%)\t\nHBV-Related ALT Flare, n/N (%)\t\nHBV-Related Hepatic Decompensation, n/N (%)\t\nHBsAg Seroreversion, n/N (%)\t\n\nHBsAg\n\t\nAnti-HBs\n\t\nAnti-HBc\n\t\nPatients completing 12 weeks of therapy (N = 93)\t+\t−\t+\t2/12 (16.7)\t0/12 (0)\t0/12 (0)\t-\t\n−\t−\t+\t0/46 (0)\t0/46 (0)\t0/46 (0)\t0/46 (0)\t\n−\t+\t+\t0/35 (0)\t0/35 (0)\t0/35 (0)\t0/35 (0)\t\nPatients completing 12 weeks of off-therapy follow-up (N = 86)\t+\t−\t+\t2/12 (16.7)\t0/12 (0)\t0/12 (0)\t-\t\n−\t−\t+\t0/43 (0)\t0/43 (0)\t0/43 (0)\t0/43 (0)\t\n−\t+\t+\t0/31 (0)\t0/31 (0)\t0/31 (0)\t0/31 (0)\t\nAbbreviations: ALT, alanine aminotransferase; anti-HBc, hepatitis B virus core antibody; anti-HBs, hepatitis B virus surface antibody; DAA, direct-acting antiviral agent; HBsAg, hepatitis B surface agent; HBV, hepatitis B virus; IFN, interferon.\n\nHepatitis B Virus Deoxyribonucleic Acid and Hepatitis B Surface Antigen (HBsAg) Dynamics in HBsAg-Positive Patients\n\nTable 3 shows the dynamic changes of serum HBV DNA and HBsAg levels in HBsAg-positive patients receiving IFN-free DAAs. Two patients had on-treatment HBV reactivation. Patient No. 3 was a 66-year-old treatment-naive HCV genotype 1b-infected woman who had stage F2 fibrosis. Her baseline HBV DNA level was undetectable. She had intermittent HBV viremia (peak level: 190 IU/mL at week 4 of treatment) after ledipasvir plus SOF therapy. The baseline ALT level was 179 U/L. The ALT level was 64 U/L after 1 week of treatment and the levels were <30 U/L after 2 weeks of treatment. Patient No. 11 was a 49-year-old HCV genotype 1b-infected man who relapsed from prior peginterferon/ribavirin therapy and who had stage F3 fibrosis. The baseline HBV DNA was 40 IU/mL. The HBV DNA level increased after ledipasvir plus SOF plus therapy, and the viral load peaked at week 4 of treatment (29900 IU/mL). Subsequent HBV DNA levels during off-therapy follow up ranged from 810 to 23200 IU/mL. The baseline ALT level was 58 U/L, and the ALT levels were <30 U/L after 1 week of treatment. Both patients did not receive organ transplantation or immunosuppressive agents or had HIV coinfection.\n\nTable 3. Dynamic Changes of Serum HBV DNA and HBsAg in HBsAg-Positive Patientsa\n\n\nPatient No.\n\t\nHBV Marker\n\t\nBaseline\n\t\nWeek 1\n\t\nWeek 2\n\t\nWeek 4\n\t\nWeek 8\n\t\nWeek 12\n\t\nSVR\n4\n\t\nSVR\n8\n\t\nSVR\n12\n\t\nFirst Time Point of On-Treatment Undetectable HCV RNA\n\t\n1\tHBV DNA\tTND\tTND\tTND\tTND\tTND\tTND\tTND\tTND\tTND\tWeek 4\t\n\tHBsAg\t62.42\t42.81\t33.57\t32.48\t27.55\t24.38\t41.98\t46.52\t48.31\t\t\n2\tHBV DNA\t201\t162\t115\t30\t99\tTND\t30\tTND\t46\tWeek 4\t\n\tHBsAg\t16.22\t5.89\t6.00\t3.89\t3.98\t2.34\t19.51\t21.56\t35.76\t\t\n3\tHBV DNA\tTND\tTND\t31\t190\t73\tTND\tTND\t48\t122\tWeek 2\t\n\tHBsAg\t844.5\t605.32\t398.82\t421.30\t208.58\t201.68\t228.42\t352.37\t445.67\t\t\n4\tHBV DNA\tTND\tTND\tTND\tTND\t29\tTND\tTND\tTND\tTND\tWeek 4\t\n\tHBsAg\t44.36\t32.22\t24.54\t21.93\t29.00\t15.09\t20.93\t18.56\t12.06\t\t\n5\tHBV DNA\tTND\tTND\tTND\tTND\tTND\tTND\tTND\tTND\tTND\tWeek 2\t\n\tHBsAg\t72.56\t56.87\t49.52\t44.43\t40.53\t39.82\t63.68\t70.53\t76.79\t\t\n6\tHBV DNA\t156\t182\t253\t332\t1650\t1128\t829\t1024\t747\tWeek 4\t\n\tHBsAg\t412.35\t398.45\t352.58\t298.54\t284.57\t266.79\t351.56\t376.89\t384.09\t\t\n7\tHBV DNA\t141\t203\t717\t1740\t1900\t1520\t1740\t1900\t1520\tWeek 1\t\n\tHBsAg\t98.82\t87.71\t69.90\t69.26\t37.43\t29.22\t33.23\t49.67\t57.30\t\t\n8\tHBV DNA\tTND\tTND\tTND\t53\t27\tTND\tTND\t28\tTND\tWeek 2\t\n\tHBsAg\t108.73\t97.12\t133.15\t21.93\t72.97\t42.70\t89.83\t109.67\t104.69\t\t\n9\tHBV DNA\t282\t143\t122\t54\t108\t46\t155\t453\t864\tWeek 2\t\n\tHBsAg\t253.42\t211.49\t192.84\t145.32\t132.58\t122.79\t175.62\t189.17\t203.87\t\t\n10\tHBV DNA\t62\t36\tTND\t52\t27\tTND\t181\t84\t74\tWeek 2\t\n\tHBsAg\t185.67\t175.70\t133.68\t118.91\t132.58\t121.53\t151.32\t189.65\t185.62\t\t\n11\tHBV DNA\t40\t146\t818\t29 900\t1220\t351\t810\t5420\t23 200\tWeek 4\t\n\tHBsAg\t585.74\t439.07\t208.62\t246.35\t128.51\t92.76\t229.2\t304.04\t357.98\t\t\n12\tHBV DNA\t177\t155\t241\t264\t651\t303\t519\t486\t529\tWeek 2\t\n\tHBsAg\t11.9\t6.39\t7.69\t6.82\t4.06\t4.17\t20.12\t20.89\t18.75\t\t\nAbbreviations: DNA, deoxyribonucleic acid; HBsAg, hepatitis B surface agent; HBV, hepatitis B virus; HCV, hepatitis C virus; LOD, limit of detection; LOQ, limit of quantification; RNA, ribonucleic acid; SVR, sustained virologic response; TND, target not detected.\n\n\naHBV DNA determined by Cobas AmpliPrep/Cobas TaqMan HBV DNA test, version 2.0 with LOD of 12 IU/mL and LOQ of 20 IU/m, and HBsAg determined by Abbott Architect HBsAg quantification assay (IU/mL), respectively.\n\nWith regard to HBsAg dynamics, the HBsAg levels decreased during DAA therapies and rebounded after stopping treatment in all patients. Furthermore, the changes of HBsAg levels were not correlated to the HBV dynamics. The baseline HBsAg levels of the 2 patients with HBV reactivation were 844.5 and 585.74 IU/mL, respectively. The HBsAg levels were less than 500 IU/mL in the remaining 10 patients without HBV reactivation.\n\nDISCUSSION\nOur study demonstrated the following findings: (1) no HBV reactivation was observed in HBsAg-negative patients receiving IFN-free DAAs for HCV [12, 17]; (2) the HBV reactivation was limited to HBsAg-positive patients, but there were no HBV-related ALT flare and/or hepatic decompensation; (3) there was no additional risk of HBV reactivation after stopping DAA treatment for HCV, which was frequently observed in HBsAg-positive patients receiving immunosuppressive agents [15, 16].\n\nIn recent studies, several case reports indicated that patients who were seropositive for HBsAg or isolated anti-HBc experienced HBV reactivation and its clinical events after IFN-free DAAs for HCV, raising the concerns for HBV monitoring and prophylactic use of oral anti-HBV agents [6–9]. Our study was in line with the Wang et al [12] report that the risk of HBV reactivation was significantly higher in HBsAg-positive patients compared with HBsAg-negative patients. Although the risk of HBV reactivation in HBV-positive patients was comparable between our (16.7% [95% CI, 4.7%–44.8%]) and the Wang et al [12] studies (30.0% [95% CI, 10.8%–60.3%]), we did not observe any HBV-related ALT flare or hepatic decompensation. Furthermore, there was no ALT elevation before or at the peak of HBV DNA levels in HBsAg-positive patients with HBV reactivation, indicating that on-treatment ALT monitoring may not be sensitive enough to detect HBV reactivation.\n\nWith regard to HBsAg-negative patients, our study was also in line with the Wang et al [12] report that none developed HBV reactivation after IFN-fee DAAs for HCV. In addition, none of our HBsAg-negative patients developed HBsAg seroreversion, which was frequently observed in those receiving anti-CD20 or hematopoietic stem cell transplantation [15]. Although 1 case report describing a patient with isolated anti-HBc seropositivity developed HBV reactivation and hepatic decompensation after IFN-free DAAs, the presence of anti-HBc immunoglobulin M and HBsAg may indicate HBV superinfection rather than HBV reactivation [9, 18].\n\nAlthough the HBV DNA dynamics in our HBsAg-positive patients were poorly correlated to the HBsAg dynamics, the HBsAg levels decreased during IFN-free DAAs and rebounded after stopping treatment. The baseline HBsAg levels of 2 patients with HBV reactivation were numerically higher than those of the remaining 10 patients without HBV reactivation. The clinical relevance of HBsAg dynamics to HBV reactivation in HBsAg-positive patients receiving IFN-free DAAs are still unclear. Further studies are needed to explore the potential mechanisms.\n\nOur study had 2 limitations. First, the number for HBsAg-positive patients was small, and more patients should be evaluated to confirm the dynamic changes of serum HBV DNA/HBsAg levels and the clinical events in these patients. Second, our HBsAg-positive patients were all inactive HBV carriers (HBV DNA level <2000 IU/mL). The risk of HBV reactivation and the clinical events in active HBV carriers await more studies.\n\nCONCLUSIONS\nIn conclusion, HBsAg-negative patients receiving IFN-free DAAs for HCV have a low risk of HBV reactivation. In contrast, HBsAg-positive patients receiving IFN-free DAAs for HCV have a significantly higher risk of HBV reactivation, although the risk of HBV-related ALT flare or hepatic decompensation is low. Whether baseline HBsAg levels can predict HBV reactivation after IFN-free DAAs need further confirmation.\n\nAcknowledgments\nWe thank the nurses and the patients involved in the study; Hui-Ju Lin and Po-Chung Liu for clinical data management; the 7th Core Lab of National Taiwan University Hospital; the 1st Common Laboratory of National Taiwan University Hospital; and Yun-Lin Branch for instrumental and technical support.\n\n\nFinancial support. The study was funded by a grant from the National Taiwan University Hospital, Taiwan (Grant 105-P09).\n\n\nPotential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nLauer GM Walker BD \nHepatitis C virus infection\n. N Engl J Med 2001 ; 345 :41 –52\n.11439948 \n2. \nLiu CH Kao JH \nNanomedicines in the treatment of hepatitis C virus infection in Asian patients: optimizing use of peginterferon alfa\n. Int J Nanomedicine 2014 ; 9 :2051 –67\n.24812506 \n3. \nKao JH \nHepatitis C virus infection in Taiwan: past, present, and future\n. J Formos Med Assoc 2016 ; 115 :65 –6\n.26228687 \n4. \nSingal AG Volk ML Jensen D et al. \nA sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus\n. Clin Gastroenterol Hepatol 2010 ; 8 :280 –8\n, 288.e1.19948249 \n5. \nvan der Meer AJ Veldt BJ Feld JJ et al. \nAssociation between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis\n. JAMA 2012 ; 308 :2584 –93\n.23268517 \n6. \nCollins JM Raphael KL Terry C et al. \nHepatitis B virus reactivation during successful treatment of hepatitis C virus with sofosbuvir and simeprevir\n. Clin Infect Dis 2015 ; 61 :1304 –6\n.26082511 \n7. \nTakayama H Sato T Ikeda F Fujiki S \nReactivation of hepatitis B virus during interferon-free therapy with daclatasvir and asunaprevir in patient with hepatitis B virus/hepatitis C virus co-infection\n. Hepatol Res 2016 ; 46 :489 –91\n.26297529 \n8. \nEnde AR Kim NH Yeh MM et al. \nFulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report\n. J Med Case Rep 2015 ; 9 :164 .26215390 \n9. \nDe Monte A Courjon J Anty R et al. \nDirect-acting antiviral treatment in adults infected with hepatitis C virus: reactivation of hepatitis B virus coinfection as a further challenge\n. J Clin Virol 2016 ; 78 :27 –30\n.26967675 \n10. \nU.S. Food and Drug Administration . FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C Available at: http://www.fda.gov/Drugs/DrugSafety/ucm522932.htm Accessed 17 October 2016 .\n11. \nAmerican Association for the Study of Liver Diseases and the Infectious Diseases Society of America . HCV Guidance: recommendations for testing, managing, and treating hepatitis C Available at: http://www.hcvguidelines.org Accessed 17 October 2016 .\n12. \nWang C Ji D Chen J et al. \nHepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents\n. Clin Gastroenterol Hepatol 2017 ; 15 :132 –6\n.27392759 \n13. \nLiu CH Liang CC Liu CJ et al. \nComparison of Abbott realtime HCV genotype II with versant line probe assay 2.0 for hepatitis C virus genotyping\n. J Clin Microbiol 2015 ; 53 :1754 –7\n.25740780 \n14. \nCastéra L Vergniol J Foucher J et al. \nProspective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C\n. Gastroenterology 2005 ; 128 :343 –50\n.15685546 \n15. \nDi Bisceglie AM Lok AS Martin P et al. \nRecent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg?\nHepatology 2015 ; 61 :703 –11\n.25412906 \n16. \nSarin SK Kumar M Lau GK et al. \nAsian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update\n. Hepatol Int 2016 ; 10 :1 –98\n.\n17. \nSulkowski MS Chuang WL Kao JH et al. \nNo evidence of reactivation of hepatitis B virus among patients treated with ledipasvir-sofosbuvir for hepatitis C virus infection\n. Clin Infect Dis 2016 ; 63 :1202 –4\n.27486112 \n18. \nKao JH Chen PJ Lai MY Chen DS \nAcute exacerbations of chronic hepatitis B are rarely associated with superinfection of hepatitis B virus\n. Hepatology 2001 ; 34 (4 Pt 1 ):817 –23\n.11584381\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "4(1)",
"journal": "Open forum infectious diseases",
"keywords": "direct-acting antiviral agent; hepatitis B virus; hepatitis C virus.",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofx028",
"pmc": null,
"pmid": "28480296",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "23268517;26082511;26967675;15685546;26297529;26563120;11439948;26215390;11584381;26228687;27392759;19948249;24812506;27486112;25412906;25740780",
"title": "Hepatitis B Virus Reactivation in Patients Receiving Interferon-Free Direct-Acting Antiviral Agents for Chronic Hepatitis C Virus Infection.",
"title_normalized": "hepatitis b virus reactivation in patients receiving interferon free direct acting antiviral agents for chronic hepatitis c virus infection"
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"abstract": "Mycobacterium haemophilum is a nontuberculous mycobacterium that can infect immunocompromised patients. Because of special conditions required for its culture, this bacterium is rarely reported and there are scarce data for long-term outcomes. We conducted a retrospective study at Siriraj Hospital, Bangkok, Thailand, during January 2012-September 2017. We studied 21 patients for which HIV infection was the most common concurrent condition. The most common organ involvement was skin and soft tissue (60%). Combination therapy with macrolides and fluoroquinolones resulted in a 60% cure rate for cutaneous infection; adding rifampin as a third drug for more severe cases resulted in modest (66%) cure rate. Efficacy of medical therapy in cutaneous, musculoskeletal, and ocular diseases was 80%, 50%, and 50%, respectively. All patients with central nervous system involvement showed treatment failures. Infections with M. haemophilum in HIV-infected patients were more likely to have central nervous system involvement and tended to have disseminated infections and less favorable outcomes.",
"affiliations": null,
"authors": "Nookeu|Pornboonya|P|;Angkasekwinai|Nasikarn|N|;Foongladda|Suporn|S|;Phoompoung|Pakpoom|P|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.3201/eid2509.190430",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n31441427\n19-0430\n10.3201/eid2509.190430\nSynopsis\nSynopsis\nClinical Characteristics and Treatment Outcomes for Patients Infected with Mycobacterium haemophilum\nClinical Characteristics and Treatment Outcomes for Patients Infected with Mycobacterium haemophilum\nPatients Infected with Mycobacterium haemophilum\nNookeu Pornboonya\nAngkasekwinai Nasikarn\nFoongladda Suporn\nPhoompoung Pakpoom\nFaculty of Medicine, Siriraj Hospital, Bangkok, Thailand\nAddress for correspondence: Pakpoom Phoompoung, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wang Lang Rd, Siriraj, Bangkok Noi, Bangkok 10700, Thailand; email: benefat@hotmail.com\n9 2019\n25 9 16481652\nMycobacterium haemophilum is a nontuberculous mycobacterium that can infect immunocompromised patients. Because of special conditions required for its culture, this bacterium is rarely reported and there are scarce data for long-term outcomes. We conducted a retrospective study at Siriraj Hospital, Bangkok, Thailand, during January 2012–September 2017. We studied 21 patients for which HIV infection was the most common concurrent condition. The most common organ involvement was skin and soft tissue (60%). Combination therapy with macrolides and fluoroquinolones resulted in a 60% cure rate for cutaneous infection; adding rifampin as a third drug for more severe cases resulted in modest (66%) cure rate. Efficacy of medical therapy in cutaneous, musculoskeletal, and ocular diseases was 80%, 50%, and 50%, respectively. All patients with central nervous system involvement showed treatment failures. Infections with M. haemophilum in HIV-infected patients were more likely to have central nervous system involvement and tended to have disseminated infections and less favorable outcomes.\n\nKeywords:\n\nMycobacterium haemophilum\nbacteria\ntuberculosis and other mycobacteria\nnontuberculous mycobacteria\nclinical characteristics\ntreatment outcomes\ninfection\nBangkok\nThailand\n==== Body\nMycobacterium haemophilum is a nontuberculous mycobacterium that causes localized and disseminated infections in immunocompromised patients and rarely in immunocompetent patients (1). It is a slow-growing, aerobic, fastidious mycobacterium that requires heme-supplemented culture medium and low temperatures of 30°C–32°C for optimal growth (2). Because of the special conditions required for culture, it is frequently not isolated because of use of inappropriate techniques, and thus is rarely reported in the medical literature.\n\nThe most common clinical manifestation of infection in adult patients is cutaneous disease (3,4), either localized or as part of disseminated disease that occurs mainly in severely immunocompromised patients, such as those infected with HIV, those with autoimmune disease, or those who have undergone solid organ or stem cell transplantation (5–10). Thus, infection with M. haemophilum should be suspected in immunocompromised patients who have unexplained skin lesions and are smear positive for acid-fast bacilli, but show negative results for routine mycobacterial culture.\n\nThere is no current standardized guideline for optimal management of patients infected with M. haemophilum. Furthermore, the long-term outcome of this infection has not been well documented. The purpose of this study was to determine clinical characteristics, treatment, and long-term outcomes for infections with M. haemophilum.\n\nMethods\n\nWe conducted a retrospective cohort study at Siriraj Hospital, the largest academic hospital in Bangkok, Thailand, during January 2012–September 2017. We identified all patients who were given a diagnosis of M. haemophilum infection by culture or molecular methods. Specimens of all types underwent smear microscopic analysis by using auramine–rhodamine staining and mycobacterial culture by using Lowenstein-Jensen solid medium and liquid medium containing mycobacteria growth indicator. All specimens were incubated at 35°C, and those from skin, bone, and joint were also incubated at 30°C. We performed species identification by using the INNO-LiPA Mycobacteria Version 2 Assay (Innogenetics [now Fujiregio], https://www.fujirebio-europe.com). We reviewed baseline demographics, clinical characteristics, microbiological data, antimicrobial and surgical treatment, and clinical outcome. All patients were followed up for >1 year after diagnosis. This study was approved by the institutional review board committee at Siriraj Hospital (Chart of Accounts no. Si 630/2017).\n\nResults\n\nA total of 21 patients were included in this study; 67% were women (median age 53 years, range 25–73 years). All 21 patients were immunocompromised. The most common concurrent condition was HIV infection (8 patients, 38%), followed by systemic lupus erythematosus (5 patients, 23.8%), γ-interferon autoantibody (2 patients, 9.5%), kidney transplantation (2 patients, 9.5%), diabetes mellitus (2 patients, 9.5%), ankylosing spondylitis (1 patient), and nephrotic syndrome (1 patient).\n\nAll HIV-infected patients except 1 had CD4 cell counts <200 cells/mm3. Among non–HIV-infected patients, those with systemic lupus erythematosus, kidney transplantation, and nephrotic syndrome received corticosteroids or other immunosuppressive agents.\n\nThe most common organ involved was skin and soft tissue (13 patients), followed by bone and joint (3 patients), central nervous system (CNS) (3 patients), eye (2 patients), and lymph nodes (1 patient). Two patients (1 with CNS involvement [no. 1] and 1 with bone and joint infection [no. 14]) had concomitant mycobacteremia. The most common cutaneous manifestation was an erythematous nodule that commonly occurred on the extensor surface of elbows, legs, and the auricular area (Figure 1). Of 7 skin biopsy specimens, granulomatous inflammation was the most common pathologic finding. Three patients who had CNS involvement had advanced HIV disease and CD4 cell counts <50 cells/mm3. We obtained computed tomography (CT) and magnetic resonance imaging findings for 3 patients with CNS involvement (Figure 2).\n\nFigure 1 Cutaneous manifestation in non–HIV-infected patients infected with Mycobacterium haemophilum, Bangkok, Thailand. A) Patient 9, B) patient 11, C) patient 12, D) patient 16, E) patient 17, F) patient 21.\n\nFigure 2 Imaging of brain and spine of 3 patients infected with Mycobacterium haemophilum who had involvement of the central nervous system, Bangkok, Thailand. A) Patient 1, axial T1-weighted magnetic resonance imaging scan with gadolinium showing enhanced nodule at left dorsal pons. B) Patient 2, axial contrast-enhanced computed tomography scan showing hypodensity lesions in both thalami and nodular enhancement at the bilateral basal ganglia. C) Patient 3, sagittal T1-weighted magnetic resonance imaging scan with gadolinium showing multiple enhancing nodules at dorsal pons and upper cervical cord.\n\nWe did not perform antimicrobial drug susceptibility testing on any bacterial isolate because of a failure of growth in solid medium. A total of 20/21 patients were treated with a combination of antimycobacterial agents. For 19 patients whose outcomes were available, 11 patients were cured, 1 patient improved with ongoing antimicrobial drug treatment, 3 patients required surgical excision after failure of medical therapy, 3 patients had a relapse of their infection after treatment discontinuation, and 1 patient died from disseminated disease after 1 month of therapy (Table).\n\nTable Clinical characteristics and treatment for 21 patients infected with Mycobacterium haemophilum Bangkok, Thailand*\n\nPatient no.\tAge, y/sex\tDisease or condition, CD4 cell count/mm3\tClinical manifestation\tSite of positive culture\tSurgical treatment\tDrug treatment\tTreatment duration, mo†\tOutcome\t\n1\t25/F\tAIDS, 17\tBrain abscesses, septicemia\tBlood\tNone\tAZM, LVX, EMB\t1\tDied\t\n2\t35/F\tAIDS, 12\tBrain abscesses\tBrain tissue\tNone\tNA\tNA\tLost to follow-up\t\n3\t35F\tAIDS, 40\tMyelitis\tSpinal cord tissue\tNone\tINH, RIF, PZA, EMB, CLR, AMK\t2\tTreatment failure\t\n4\t29/M\tAIDS, 14\tSkin nodule (left popliteal fossa)\tSkin\tNone\tAZM, LVX, RIF\tNA\tLost to follow-up\t\n5\t52/M\tAIDS, 6\tPlague (right hand)\tSkin\tNone\tCLR, CIP, RIF\t6\tCured\t\n6\t46/F\tAIDS, 190\tChronic ulcer (left foot)\tPus\tNone\tMFX\t3\tCured\t\n7\t36/F\tAIDS, 12\tAuricular abscess\tPus\tNone\tAZM, LVX, RIF\t12\tCured\t\n8\t53/F\tHIV+, 657\tPreauricular abscess\tPus\tI and D\tCLR, CIP\t12\tCured\t\n9\t25/F\tSLE\tChronic wound and osteomyelitis (right ankle), olecranon bursitis\tBone\tDebridement\tIMI, AMK; then AZM, CIP, RIF\t6 (1.5/4.5)\tRelapsed\t\n10\t39/F\tSLE\tTenosynovitis (right index finger)\tPus\tDebridement\tAMK; then CLR, LVX\t6 (2/4)\tCured\t\n11\t57/F\tSLE\tSkin nodules (both elbows)\tSkin\tNone\tCLR, CIP, RIF\t6\tCured\t\n12\t47/F\tSLE, dermatomyositis\tSkin nodules (both elbows)\tSkin\tNone\tIMI, AMK; then AZM, CIP, RIF\t6 (0.5/5.5)\tCured\t\n13\t39/F\tSLE, DM\tSkin abscess (right ankle)\tPus\tI and D\tAMK; then CLR, LVX, DCS\t12 (2/10)\tCured\t\n14\t69/M\tIFN-γ autoantibody\tSepticemia, spondylodiscitis\tBlood\tNone\tCLR, LVX, RIF\t24\tRelapsed\t\n15\t73/F\tIFN-γ autoantibody\tLymphadenitis (right cervical node)\tLymph node\tNone\tIMI, CLR; then CLR, CIP, SXT\t12\tCured\t\n16\t60/F\tKidney transplant\tSkin nodules (both arms/legs), septic arthritis (right ankle)\tPus\tDebridement\tAMK, CLR, LVX, LZD; then MFX, AZM, RIF, LZD\t11 (1/10)\tImproved\t\n17\t58/F\tKidney transplant\tPlague (both legs)\tSkin\tNone\tIMI, AMK, CLR; then AZM, LVX, RIF\t12 (1/11)\tRelapsed\t\n18\t65/F\tDM,\nA1C 6.7%\tScleritis and keratitis\tSclera\tEnucleation\tIMI, CLR, LVX, RIF, LZD\t4\tTreatment failure\t\n19\t65/M\tDM,\nA1C 13.3%\tEndophthalmitis\tVitreous fluid\tNone\tIMI, AMK, LVX; then AZM, RIF, DOX\t12 (0.5/11.5)\tCured\t\n20\t53/M\tAnkylosing spondylitis\tSkin nodules (right elbow)\tSkin\tSurgical excision\tCLR, LVX\t6\tTreatment failure\t\n21\t48/M\tNephrotic syndrome\tSkin nodules (right elbow)\tSkin\tNone\tCLR, CIP, RIF\t12\tCured\t\n*AMK, amikacin; AZM, azithromycin; A1C, hemoglobin A1C; CIP, ciprofloxacin; CLR, clarithromycin; DCS, d-cycloserine, DM, diabetes mellitus; DOX, doxycycline; EMB, ethambutol; I and D, incision and drainage; IFN-γ, interferon-γ; IMI, imipenem; INH, isoniazid; LVX, levofloxacin; LZD, linezolid; MFX, moxifloxacin; NA, not available; PZA, pyrazinamide; RIF, rifampin; SLE, systemic lupus erythematosus; SXT, sulfamethoxazole/trimethoprim; +, positive.\n†Values in parentheses are durations for each drug group.\n\nThe success rate of medical therapy for cutaneous infection was 80%. However, this rate was lower (50%) for bone, joint, and ocular infections. All patients with CNS diseases and involvement showed treatment failures.\n\nThe most commonly used regimen included a combination of macrolides and fluoroquinolones (3 patients, 14.3%) or these combined regimens with rifampin (9 patients, 42.9%). Combination therapy with macrolides and fluoroquinolones resulted in a success rate of 60% for treatment of cutaneous infection. Use of rifampin as the third drug for more severe cases also resulted in a modest (66%) success rate. Sulfamethoxazole/trimethoprim, doxycycline, and cycloserine were also replaced with rifampin, which showed clinically successful results. For 11 patients in whom antimicrobial drugs could be discontinued, the median duration of treatment was 12 months (range 3–12 months for skin and soft tissue infections, 6 months for bone and joint infections, and 12 months for lymphadenitis and eye infections).\n\nThe patient who died of disseminated M. haemophilum infection was a 25-year-old man who was given a new diagnosis of infection with HIV and had a CD4 cell count of 17 cells/mm3. He had diplopia for 1 month and a low-grade fever. Physical examination showed multiple left-sided cranial nerve palsies (V [trigeminal], VI [abducens], and VII [facial]) and lower motor neuron lesions. Magnetic resonance imaging of the brain showed multiple, abnormal, high-signal-intensity lesions on T2-weighted imaging with gadolinium, as well as nodular enhancement of the left dorsal pons, right ventral pons, mid pons, left cerebellar peduncle, and medulla (Figure 2, panel A). Examination of cerebrospinal fluid showed standard results; hemoculture grew M. haemophilum. He was given levofloxacin, azithromycin, and ethambutol. However, his clinical condition deteriorated rapidly. Right hemiparesis then developed and he became stuporous. He died from acute respiratory failure secondary to aspiration pneumonia.\n\nWhen we compared HIV-infected and non–HIV-infected patients, HIV-infected patients were younger (median age 36 years vs. 57 years; p = 0.017), more likely to have disseminated infection (37.5% vs. 15.4%; p = 0.325), more likely to have CNS involvement (37.5% vs. 0%; p = 0.042), and more likely to have a less favorable prognosis (50% vs. 77%; p = 0.38).\n\nDiscussion\n\nWe report 21 cases of M. haemophilum infection over a 6-year period at the largest academic hospital in Thailand. M. haemophilum commonly causes infection in immunocompromised persons. Advanced HIV infection remains the most common immunocompromised condition associated with this infection, as reported (1,3). Approximately 60% of patients have skin and soft tissue involvement, and the most commonly involved areas are the extensor surfaces of the extremities and auricular regions, which could be explained by the predilection of the organism for body areas with lower temperatures.\n\nAlthough CNS infection with M. haemophilum is extremely rare and only a few case-patients have been reported (11–13), we identified CNS involvement in 3 of 21 case-patients in our study. All had advanced HIV disease: 2 patients had multiple brain abscesses, which was similar to those previously described, and 1 patient had myelitis. A total of 2 of 3 previous case reports of CNS involvement in patients with M. haemophilum infection were from Thailand and in HIV-infected patients (11,12), whereas the 2 largest case series (23 and 15 cases) reported from the United States found no cases of CNS involvement (3,4). Further study is needed to determine whether genetic or environmental factors will influence clinical manifestations of M. haemophilum infection.\n\nTreatment with a combination of fluoroquinolones, rifampin, and macrolides is suggested for treating M. haemophilum infection (14). However, our study demonstrated that 2 antimycobacterial agents (macrolides and fluoroquinolones) were successfully used for patients with isolated cutaneous diseases. Conversely, surgical resection might be needed for some case-patients, such as those who showed treatment failure or those in which there was CNS involvement. Because of poor penetration of the CNS by these antimicrobial agents, patients who had mycobacterial infections with CNS involvement are often associated with poorer outcomes (15,16). Two previous case reports of persons with CNS disease were successfully treated with surgical excision in combination with antimicrobial drugs, although there were residual neurologic deficits (11,13). Another study reported a case-patient who did not respond to medical therapy alone and subsequently died (12).\n\nTreatment for M. haemophilum infection should last ≈3–12 months and should be tailored on the basis of severity of disease and immunocompromised conditions. Isolated cutaneous disease usually responds well to shorter duration of therapy (3–6 months), and CNS infections, bone and joint infections, and disseminated disease usually require longer therapy (12 months) (1). Relapse cases have been rarely reported (17), and accounted for just 4% in the largest case series (1). However, our study showed a higher relapse rate (14%); therefore, we suggest that careful monitoring after discontinuation of treatment is warranted.\n\nOne limitation of our study was that no antimicrobial susceptibility testing was available because all culture-positive cases were detected in liquid medium. However, no data support the correlation of in vitro susceptibility testing and treatment response for this type of infection.\n\nM. haemophilum infections should be suspected in immunocompromised patients who have unexplained cutaneous lesions, especially at auricular or extensor surfaces of extremities, who are smear positive for acid-fast bacilli, but show negative results for routine mycobacterial culture. Combination antimycobacterial therapy should be given for >3 months and extended to 12 months depending on the site of isolation. CNS involvement might occur more commonly than previously believed and is associated with worse outcome. Relapses are not uncommon; therefore, clinical monitoring after discontinuation of treatment is warranted.\n\nAcknowledgments\n\nWe thank all medical staff and laboratory technicians who were involved in the study and those who cared for the patients.\n\nDr. Nookeu is a physician in the Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. Her primary research interest is nontuberculous mycobacteria.\n\nSuggested citation for this article: Nookeu P, Angkasekwinai N, Foongladda S, Phoompoung P. Clinical characteristics and treatment outcomes for patients infected with Mycobacterium haemophilum. Emerg Infect Dis. 2019 Sep [date cited]. https://doi.org/10.3201/eid2509.190430\n==== Refs\nReferences\n\n1. Lindeboom JA, Bruijnesteijn van Coppenraet LE, van Soolingen D, Prins JM, Kuijper EJ. Clinical manifestations, diagnosis, and treatment of Mycobacterium haemophilum infections. Clin Microbiol Rev. 2011;24 :701–17. 10.1128/CMR.00020-11 21976605\n2. Dawson DJ, Jennis F. Mycobacteria with a growth requirement for ferric ammonium citrate, identified as Mycobacterium haemophilum. J Clin Microbiol. 1980;11 :190–2.7358843\n3. Shah MK, Sebti A, Kiehn TE, Massarella SA, Sepkowitz KA. Mycobacterium haemophilum in immunocompromised patients. Clin Infect Dis. 2001;33 :330–7. 10.1086/321894 11438898\n4. Tyner HL, Wilson JW. Fifteen-year clinical experience with Mycobacterium haemophilum at the Mayo Clinic: a case series. J Clin Tuberc Other Mycobact Dis. 2017;8 :26–32. 10.1016/j.jctube.2017.06.002\n5. Kelley CF, Armstrong WS, Eaton ME. Disseminated Mycobacterium haemophilum infection. Lancet Infect Dis. 2011;11 :571–8. 10.1016/S1473-3099(11)70029-9 21700242\n6. Brix SR, Iking-Konert C, Stahl RA, Wenzel U. Disseminated Mycobacterium haemophilum infection in a renal transplant recipient. BMJ Case Rep. 2016;2016 :bcr2016216042. 10.1136/bcr-2016-216042 27799227\n7. Jacobs SE, Zhong E, Hartono C, Satlin MJ, Magro CM, Jenkins SG, et al. The brief case: disseminated Mycobacterium haemophilum infection in a kidney transplant recipient. J Clin Microbiol. 2017;56 :e00561–17.29279349\n8. Otome O, O’Reilly M, Lim L. Disseminated Mycobacterium haemophilum skeletal disease in a patient with interferon-gamma deficiency. Intern Med J. 2015;45 :1073–6. 10.1111/imj.12875 26429217\n9. Brissot E, Gomez A, Aline-Fardin A, Lalande V, Lapusan S, Isnard F, et al. Report of disseminated Mycobacterium haemophilum infection after double cord blood allo-SCT. Bone Marrow Transplant. 2014;49 :1347–8. 10.1038/bmt.2014.144 25029233\n10. Collins CS, Terrell C, Mueller P. Disseminated Mycobacterium haemophilum infection in a 72-year-old patient with rheumatoid arthritis on infliximab. BMJ Case Rep. 2013;2013 (mar15 1 ):bcr2012008034. 10.1136/bcr-2012-008034 23505273\n11. Phowthongkum P, Puengchitprapai A, Udomsantisook N, Tumwasorn S, Suankratay C. Spindle cell pseudotumor of the brain associated with Mycobacterium haemophilum and Mycobacterium simiae mixed infection in a patient with AIDS: the first case report. Int J Infect Dis. 2008;12 :421–4. 10.1016/j.ijid.2007.11.010 18291698\n12. Buppajarntham A, Apisarnthanarak A, Rutjanawech S, Khawcharoenporn T. Central nervous system infection due to Mycobacterium haemophilum in a patient with acquired immunodeficiency syndrome. Int J STD AIDS. 2015;26 :288–90. 10.1177/0956462414535750 24841195\n13. Barr LK, Sharer LR, Khadka Kunwar E, Kapila R, Zaki SR, Drew CP, et al. Intraventricular granulomatous mass associated with Mycobacterium haemophilum: A rare central nervous system manifestation in a patient with human immunodeficiency virus infection. J Clin Neurosci. 2015;22 :1057–60. 10.1016/j.jocn.2014.11.036 25818941\n14. Medical Section of the American Lung Association. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Am J Respir Crit Care Med. 1997;156 :S1–25.9279284\n15. Jacob CN, Henein SS, Heurich AE, Kamholz S. Nontuberculous mycobacterial infection of the central nervous system in patients with AIDS. South Med J. 1993;86 :638–40. 10.1097/00007611-199306000-00009 8506483\n16. Lee MR, Cheng A, Lee YC, Yang CY, Lai CC, Huang YT, et al. CNS infections caused by Mycobacterium abscessus complex: clinical features and antimicrobial susceptibilities of isolates. J Antimicrob Chemother. 2012;67 :222–5. 10.1093/jac/dkr420 21980068\n17. Ducharlet K, Murphy C, Tan SJ, Dwyer KM, Goodman D, Aboltins C, et al. Recurrent Mycobacterium haemophilum in a renal transplant recipient. Nephrology (Carlton). 2014;19 (Suppl 1 ):14–7. 10.1111/nep.12193 24460607\n\n",
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"keywords": "Bangkok; Mycobacterium haemophilum; Thailand; bacteria; clinical characteristics; infection; nontuberculous mycobacteria; treatment outcomes; tuberculosis and other mycobacteria",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009164:Mycobacterium Infections; D018393:Mycobacterium haemophilum; D012189:Retrospective Studies; D013785:Thailand; D016896:Treatment Outcome",
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"title": "Clinical Characteristics and Treatment Outcomes for Patients Infected with Mycobacterium haemophilum.",
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"abstract": "We report a case of a 16-year-old woman who achieved her third complete remission of acute lymphoblastic leukemia after undergoing allogeneic stem cell transplantation for the second time from an unrelated donor. On post-transplantation day 30, she showed weight gain, hepatomegaly, right hypochondriac pain, and ascites. On day 35, ultrasonography (US) revealed portal vein regurgitation. She was subsequently diagnosed with late-onset sinusoidal obstruction syndrome (SOS) and was transferred to the intensive care unit (ICU) on day 36 for multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation, requiring mechanical ventilation. Her SOS was graded as very severe upon ICU admission. Recombinant human soluble thrombomodulin (380 U/kg/day) and methylprednisolone (2 mg/kg/day) therapies were initiated. Additionally, her intra-abdominal pressure had increased to 19 mmHg, which was thought to be the cause of MODS. Ascites drainage (1,000 ml/day), according to the treatment for abdominal compartment syndrome, improved her SOS and MODS. She was weaned from mechanical ventilation on the 10th day after ICU transfer, and US showed resolution of the portal vein regurgitation. She was transferred to the general ward on the 14th day. She had not experienced disease recurrence at her last visit (527 days after the second transplantation).",
"affiliations": "Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.;Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.;Departments of Anesthesiology and Critical Care Medicine, National Cancer Center Hospital.;Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.;Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.;Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.;Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.;Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.;Department of Pediatric Oncology, National Cancer Center Hospital.;Department of Pediatric Oncology, National Cancer Center Hospital.;Department of Pediatric Oncology, National Cancer Center Hospital.;Department of Pediatric Oncology, National Cancer Center Hospital.;Departments of Anesthesiology and Critical Care Medicine, National Cancer Center Hospital.;Departments of Anesthesiology and Critical Care Medicine, National Cancer Center Hospital.;Departments of Anesthesiology and Critical Care Medicine, National Cancer Center Hospital.;Department of Pediatric Oncology, National Cancer Center Hospital.;Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.",
"authors": "Hirakawa|Tsuneaki|T|;Tanaka|Takashi|T|;Matsumi|Junya|J|;Takeda|Wataru|W|;Kim|Sung-Won|SW|;Inamoto|Yoshihiro|Y|;Ito|Ayumu|A|;Yamaguchi|Kyosuke|K|;Ishimaru|Sae|S|;Kumamoto|Tadashi|T|;Arakawa|Ayumu|A|;Sugiyama|Masanaka|M|;Dan|Liu|L|;Shigematsu|Misako|M|;Sato|Tetsufumi|T|;Ogawa|Chitose|C|;Fukuda|Takahiro|T|",
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"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Abdominal compartment syndrome; Methylprednisolone; Recombinant human soluble thrombomodulin; Sinusoidal obstruction syndrome",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000293:Adolescent; D004211:Disseminated Intravascular Coagulation; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D009102:Multiple Organ Failure; D018180:Thrombomodulin",
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"title": "Successful treatment of very severe late-onset sinusoidal obstruction syndrome with recombinant human soluble thrombomodulin, steroids, and control of intra-abdominal pressure.",
"title_normalized": "successful treatment of very severe late onset sinusoidal obstruction syndrome with recombinant human soluble thrombomodulin steroids and control of intra abdominal pressure"
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"abstract": "Metformin-associated encephalopathy in maintenance hemodialysis is very rare in literature, till now only three to four cases are published. We report a patient on maintenance hemodialysis from standalone unit presented to us with abnormal neurological signs and symptoms. His medication chart included metformin, which he was taking for quite a long time. Computed tomography brain showed hypointensity in bilateral basal ganglia. Magnetic resonance imaging (MRI) brain showed hyperintensity in T2/fluid-attenuated inversion recovery sequences suggestive of Lentiform fork sign. We stopped metformin, and he was continued on regular hemodialysis. He showed dramatic improvement in neurological manifestations. Two months later, we repeated MRI brain, which showed resolution of basal ganglia changes. We should suspect the possibility of this when a diabetic end-stage renal disease presents with unknown etiology of encephalopathy.",
"affiliations": "Department of Nephrology, Rajagiri Hospital, Kochi, Kerala, India.;Department of Nephrology, Rajagiri Hospital, Kochi, Kerala, India.",
"authors": "Simon|S P|SP|;Thomas|J|J|",
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"doi": "10.4103/ijn.IJN_257_17",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Wolters Kluwer - Medknow India IJN-29-19410.4103/ijn.IJN_257_17Case ReportMetformin-associated Encephalopathy in Hemodialysis Simon S. P. Thomas J. Department of Nephrology, Rajagiri Hospital, Kochi, Kerala, IndiaAddress for correspondence: Dr. S. P. Simon, Department of Nephrology, Rajagiri Hospital, Aluva, Kochi, Kerala, India. E-mail: drsnehapsimon@gmail.comMay-Jun 2019 29 3 194 196 Copyright: © 2019 Indian Journal of Nephrology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Metformin-associated encephalopathy in maintenance hemodialysis is very rare in literature, till now only three to four cases are published. We report a patient on maintenance hemodialysis from standalone unit presented to us with abnormal neurological signs and symptoms. His medication chart included metformin, which he was taking for quite a long time. Computed tomography brain showed hypointensity in bilateral basal ganglia. Magnetic resonance imaging (MRI) brain showed hyperintensity in T2/fluid-attenuated inversion recovery sequences suggestive of Lentiform fork sign. We stopped metformin, and he was continued on regular hemodialysis. He showed dramatic improvement in neurological manifestations. Two months later, we repeated MRI brain, which showed resolution of basal ganglia changes. We should suspect the possibility of this when a diabetic end-stage renal disease presents with unknown etiology of encephalopathy.\n\nEncephalopathyend-stage renal diseaseLentiform fork signmetformin\n==== Body\nIntroduction\nGlucose lowering biguanides were discovered in the 1920s. Due to the association of phenformin and buformin with lactic acidosis, they were withdrawn from the market, but metformin was continued to be used, and in fact, it is considered as the first-line drug of choice for type 2 diabetes mellitus (DM) especially in those with normal renal function. It is contraindicated in those with renal failure, liver disease because it increases the risk of lactic acidosis. It can also rarely induce encephalopathy through lactic acidosis, hypoglycemia, renal impairment, and liver failure. There are only few case reports of metformin encephalopathy in end-stage renal disease (ESRD). we report one such case in a patient with end-stage renal failure undergoing maintenance hemodialysis.\n\nCase Report\nOur patient, 63-year-old man a case of type 2 DM, hypertension, old cerebrovascular accident with minimal residual weakness and on maintenance hemodialysis for the past 2 years in outside center. He was on twice-weekly hemodialysis and was compliant. He was admitted to our center with a history of decreased speech output, and difficulty walking for 1 month, with progressive worsening of sensorium, tiredness, drowsiness, and weakness for 2 weeks. No symptomatic improvement noticed after dialysis sessions. No history of fever/headache/focal neurological deficits. Last hemodialysis was done 2 days before admission. On examination, he was drowsy and mute, pulse rate 56/min, blood pressure 180/90 mm of Hg, SpO2 99% on room air, afebrile, and anemic. Neurologic evaluation showed mild weakness of right side limbs with asterexis, rigidity of all limbs and bradykinesia.\n\nBlood investigations revealed blood urea nitrogen 19.63 mmol/L, serum creatinine 609 μmol/L, sodium 138 mmol/L, pottassium 4.8 mmol/L, hemoglobin 104 g/L, total WBC count 4.9, differential count N 57, L 35, M6, E2, platelet count 90,000, serum ammonia 25 umol/L, bilirubin 10.26 μmol/L, serum glutamic pyruvic transaminase 0.47 μkat/L, C-reactive protein 10.48 nmol/L, alkaline phosphatase 4.01 μkat/L, viral markers negative, venous blood gas pH 7.28, HCO3 17.9, PCO2 38, and lactate 7.1.\n\nNoncontrast computed tomography brain [Figure 1] revealed hypodensity in bilateral basal ganglia region. Magnetic resonance imaging (MRI) brain showed hyperintensity in bilateral basal ganglia region (lentiform fork sign) [Figure 2]. Review of his medication chart revealed the long-term use of metformin prescribed by general practisoner at HD unit. We stopped it, and he was continued on regular twice-weekly hemodialysis. After few days, he showed improvement in sensorium. We repeated MRI brain after 2 months, which showed resolution of changes [Figure 3]. Now, he is continuing maintenance hemodialysis.\n\nFigure 1 Noncontrast computed tomography shows hypodensity in bilateral ganglia\n\nFigure 2 Magnetic resonance imaging T2/fluid-attenuated inversion recovery with hyperintense basal ganglia\n\nFigure 3 Magnetic resonance imaging T2/fluid-attenuated inversion recovery with resolution of changes in basal ganglia in repeat imaging 2 months later\n\nDiscussion\nEven though metformin is a first choice anti-diabetic drug, it is contraindicated in patients with renal failure. Rarely, it can unintentially be prescribed to advanced chronic kidney disease (CKD) population. Holstein et al.[1] reported that 19% of all cases of metformin prescription included patients with renal impairment.\n\nAccording to the US Food and Drug Administration, metformin should not be used in men and women with serum creatinine concentration >1.5 and >1.4 mg/dl, respectively. However, according to the American Diabetes Association, metformin seems safe unless estimated glomerular filtration rate (eGFR) falls to <30 ml/min/1.73 m2.[23] According to joint position statements of the American Diabetes Association for the study of diabetes agrees that it is reasonable to use metformin down to a GFR of 30 ml/min/1.73 m2 with dose reduction to eGFR 45 ml/min/1.73 m2.[4] However, even the cutoff of 30 ml/min/1.73 m2 GFR is arbitrary, and Mani has reported its use in >1000 poor patients in India with CKD stages 3 and 4 with no case of lactic acidosis.[5]\n\nExact mechanism of metformin-associated encephalopathy is not clear. It may be caused by overdosage, failure of drug elimination or idiosyncratic susceptibility. Metformin is excreted unchanged in urine, the plasma half-life of metformin may be prolonged, and the drug may easily accumulate in the brain in patients with CKD and ESRD. The progressive neurological manifestations might be explained by cumulative doses resulting from repetitive medications in spite of partial removal by regular dialysis.[6]\n\nThe Lentiform fork sign\nOn T2/fluid-attenuated inversion recovery (FLAIR) sequences, a brightly hyperintense rim delineated the lateral and medial boundaries of both putamina, resembling a fork. The lateral arm of the fork constituted by the edematous external capsule, extended from the anterior end of the putamen at the rostral end of the frontal horn of the lateral ventricle to the stem of the fork, which is formed by the fusion of edematous external and internal capsule at the inferoposterior end of the putamen. The medial arm extended from the stem anteriorly up to one-third of the medial edge where it split into two slightly less T2/FLAIR hyperintense branches engulfing the globus pallidus. These two branches of the medial arm are constituted by the edematous medullary lamina, which divide the lentiform nucleus into three masses (putamen, globus pallidus interna, and externa). Corresponding hypointense changes in T1 sequences [Figure 4].[7]\n\nFigure 4 Lentiform fork sign\n\nLentiform fork sign is nonspecific and nondiagnostic, and it has wide differential diagnosis which includes uremic encephalopathy with metabolic acidosis, owing to deranged neurotransmission and cellular metabolism leading to vasogenic edema.[7] Furthermore, methanol intoxication and ethelene glycol toxicity are also associated with this sign. Diabetic uremic encephalopathy also associated with sign may be by the contribution of DKA. The pathogenic basis of this sign may be attributable to the differences in metabolic vulnerability between neurons and astrocytes. As a final common pathway, through changes in vascular reactivity metabolic acidosis may disrupt blood-brain barrier leading to vasogenic edema and later cytotoxic edema depending on the severity of acidosis and other comorbid metabolic perturbations.[7] The putamens high metabolic demand and its location in the boundary zone of vascular perfusion make it particularly susceptible to vascular damage.\n\nIn ESRD patients, it can be associated with uremic encephalopathy, but in most cases, it is associated with metabolic acidosis. In our case, there was no severe acidosis and the sign resolved with discontinuation of metformin within 2 months. There is no diagnostic criteria for metformin-associated encephalopathy. Serum safety range is not determined, and also serum level does not reflect tissue level. As in literature,[6] diagnosis can be made with reversal of MRI findings on withdrawal of metformin. There are even case reports of metformin encephalopathy without severe metabolic or lactic acidosis.[8]\n\nRathi and Mudrabettu[9] published a case report from India in nondiabetic ESRD patient with severe deranged renal function and metabolic acidosis, whose MRI brain showed Lentiform fork sign, but the patient succumbed. In our knowledge, this is the only case from India in diabetic ESRD on metformin presenting with this sign.\n\nConclusion\nMetformin-associated encephalopathy is a rare cause for encephalopathy. Even though metformin is contraindicated in ESRD, patients are unintentially prescribed and on it. It should be suspected in diabetic ESRD patients, especially if no obvious etiology for encephalopathy is found.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Holstein A Nahrwold D Hinze S Egberts EH Contra-indications to metformin therapy are largely disregarded Diabet Med 1999 16 692 6 10477216 \n2 American Diabetes Association. Standards of medical care in diabetes–2010 Diabetes Care 2010 33 Suppl 1 S11 61 20042772 \n3 Nathan DM Buse JB Davidson MB Ferrannini E Holman RR Sherwin R Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes Diabetes Care 2009 32 193 203 18945920 \n4 Inzucchi SE Bergenstal RM Buse JB Diamant M Ferrannini E Nauck M Management of hyperglycemia in type 2 diabetes: A patient-centered approach: Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care 2012 35 1364 79 22517736 \n5 Mani MK Metformin in renal failure – Weigh the evidence Nephrol Dial Transplant 2009 24 2287 8 19390119 \n6 Kang YJ Bae EJ Seo JW Jeon DH Cho HS Kim HJ Two additional cases of metformin-associated encephalopathy in patients with end-stage renal disease undergoing hemodialysis Hemodial Int 2013 17 111 5 22515914 \n7 Kumar G Goyal MK Lentiform fork sign: A unique MRI picture. Is metabolic acidosis responsible? Clin Neurol Neurosurg 2010 112 805 12 20615611 \n8 Vander T Hallevy H Ifergane G Herishanu YO Metformin-induced encephalopathy without lactic acidosis Diabet Med 2004 21 194 5 \n9 Rathi M Mudrabettu C Lentiform fork sign in a case of end-stage renal disease Kidney Int 2012 82 365 22791329\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "29(3)",
"journal": "Indian journal of nephrology",
"keywords": "Encephalopathy; Lentiform fork sign; end-stage renal disease; metformin",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "194-196",
"pmc": null,
"pmid": "31142967",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10477216;14984458;18945920;19390119;20042772;20615611;22515914;22517736;22791329",
"title": "Metformin-associated Encephalopathy in Hemodialysis.",
"title_normalized": "metformin associated encephalopathy in hemodialysis"
} | [
{
"companynumb": "IN-GLENMARK PHARMACEUTICALS-2019GMK041572",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"... |
{
"abstract": "We report a case of Burkitt's lymphoma, post-transplant lymphoproliferative disorder (BL-PTLD) that was treated with intensive chemotherapy. The patient was a 4-year-old boy who underwent heart transplantation at 7 months of age for refractory heart failure due to dilated cardiomyopathy. He was admitted to our hospital with a chief complaint of abdominal pain associated with an abdominal mass. Computed tomography was notable for a bulky mass arising from the terminal ileum. Fluorodeoxyglucose-positron emission tomography revealed multiple lesions in brain, bone, and lymph nodes. He was diagnosed with BL-PTLD stage III by pathological and clinical scoring. He was Epstein-Barr virus (EBV)-seronegative with a low EBV viral DNA load. No EBV-encoded small RNAs were in his intra-abdominal lymph nodes by in situ hybridization. On cytogenetic examination, the intra-abdominal lymph nodes revealed both a MYC rearrangement and a t(8;14)(q24;32), t(16;19)(q24;q13.1) translocation. Administration of tacrolimus and mycophenolate mofetil was discontinued; immunosuppression was maintained with everolimus. Intensive chemotherapy based on the modified LMB 96 protocol for BL was initiated, resulting in complete remission achieved. During the intensive chemotherapy and immunosuppressive switching period, cardiac dysfunction and allograft rejection had not been shown. The patient has remained well for two years after the treatment with no evidence of relapse. <Learning objective: Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication that can develop after heart transplantation and result in significant morbidity and mortality. In the case presented here, intensive chemotherapy and modified immunosuppressive therapy are among the most effective treatments for PTLD patients with an otherwise poor prognosis. Maintaining a fine balance between management of the PTLD and preventing allograft rejection is critically important.>.",
"affiliations": "Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.;Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.;Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.;Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.;Department of Therapeutic Strategy for Severe Heart Failure, Tokyo Women's Medical University Graduate School of Medical Science, Tokyo, Japan.",
"authors": "Oitani|Yoshiki|Y|;Kato|Fumiyo|F|;Ikeno|Kaoru|K|;Ishido|Mikiko|M|;Nakanishi|Toshio|T|;Sugihara|Shigetaka|S|;Nunoda|Shinichi|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2020.12.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "24(2)",
"journal": "Journal of cardiology cases",
"keywords": "Burkitt's lymphoma; Heart transplantation; Post-transplant lymphoproliferative disorder",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "60-63",
"pmc": null,
"pmid": "34354779",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": "17971586;18267219;16427492;21446044;25552900;26384356;24174972;11889454;20408848;18371107",
"title": "Complete remission from post-heart transplant lymphoproliferative disorder: A case report.",
"title_normalized": "complete remission from post heart transplant lymphoproliferative disorder a case report"
} | [
{
"companynumb": "JP-PBT-000544",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nPreterm neonates are particularly at risk of vitamin D (25-D) deficiency. To prevent rickets and osteopenia in this population, international guidelines vary between 800 and 1000IU per day of vitamin D in Europe and recommend 400IU per day in the USA. Target levels of circulating 25-D are not well identified, with the lower target level 50-75nmol/L and the upper target level probably 120nmol/L.\n\n\nMETHODS\nBetween 2013 and 2015, 16 premature infants (born<35WG) were referred to pediatric nephrology clinics because of symptoms secondary to 25-D overdose during the neonatal period. Clinical and biological data were retrospectively reviewed to better define this population. The results are presented as the median (range).\n\n\nRESULTS\nGestational age was 27 (24-35)WG with a birth weight of 810 (560-2120)g. Nephrocalcinosis was the initial symptom in 37% of cases, hypercalcemia in 44%, and hypercalciuria in 19%. Daily vitamin D doses were 333 (35-676)IU. Age and body weight at initial symptom were 36.6 (27.6-47.6)WG and 2300 (640-3760)g, respectively. The 25-D level at the time of the first dosage was 210 (119-350)nmol/L and the 1-25 vitamin D level was 370 (245-718)pmol/L (local normal values for age<240). During follow-up, 12 patients displayed nephrocalcinosis, ten hypercalciuria, and three hypercalcemia. The 25-D level normalized in ten patients within 10 (3-32)months after vitamin D withdrawal. Nephrocalcinosis improved in ten of 12 patients, within 12 (3-30)months. Vitamin D could be readministered in ten patients. When searched (n=3), no CYP24A1 mutation was identified in two patients, but was identified in the heterozygous state in one.\n\n\nCONCLUSIONS\nA 25-D overdose should be systematically ruled out in the presence of nephrocalcinosis, hypercalcemia, and/or hypercalciuria during infancy in children born preterm. Studies are required to assess the exact frequency of 25-D deficiency and overdose in this population, as well as to evaluate the potential deleterious effects of this imbalance on bone, kidney, and brain development.",
"affiliations": "Centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron, France. Electronic address: melodie.vierge@ap-hm.fr.;Service de néonatologie, hôpital Femme-Mère-Enfant, 69500 Bron, France.;Centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron, France.;Département de biologie, centre hospitalier Lyon-Sud, 69495 Pierre-Bénite, France.;Service de néonatologie, hôpital de la Croix-Rousse, 69004 Lyon, France; Université Claude-Bernard-Lyon 1, 69008 Lyon, France.;Service de néonatologie, hôpital Femme-Mère-Enfant, 69500 Bron, France; Université Claude-Bernard-Lyon 1, 69008 Lyon, France.;Centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron, France; Université Claude-Bernard-Lyon 1, 69008 Lyon, France.",
"authors": "Vierge|M|M|;Laborie|S|S|;Bertholet-Thomas|A|A|;Carlier|M-C|MC|;Picaud|J-C|JC|;Claris|O|O|;Bacchetta|J|J|",
"chemical_list": "D014815:Vitamins; D014807:Vitamin D",
"country": "France",
"delete": false,
"doi": "10.1016/j.arcped.2017.06.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-693X",
"issue": "24(9)",
"journal": "Archives de pediatrie : organe officiel de la Societe francaise de pediatrie",
"keywords": null,
"medline_ta": "Arch Pediatr",
"mesh_terms": "D062787:Drug Overdose; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D053565:Hypercalciuria; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D009397:Nephrocalcinosis; D012189:Retrospective Studies; D014807:Vitamin D; D014815:Vitamins",
"nlm_unique_id": "9421356",
"other_id": null,
"pages": "817-824",
"pmc": null,
"pmid": "28818584",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neonatal intoxication to vitamin D in premature babies: A series of 16 cases.",
"title_normalized": "neonatal intoxication to vitamin d in premature babies a series of 16 cases"
} | [
{
"companynumb": "FR-MYLANLABS-2017M1079362",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Tramadol is a common analgesic, widely prescribed because of its efficiency and safety. We report the case of a 7-year-old child admitted in cardiac intensive care unit for cardiogenic shock due to tramadol intoxication. Without any past history, the child was admitted at emergency room for generalised convulsion, followed by respiratory distress. Cardiogenic shock was suspected after clinical examination and chest X-ray and confirmed by transthoracic echocardiography showing low left ventricular ejection fraction (<30 %) with pulmonary hypertension. No evidence of cardiac infarction or myocarditis was found. Tramadol intoxication was suspected because of empty tramadol tablets found near the child and later confirmed by toxicologic analysis showing high blood concentration of tramadol (>1 mg/L) and O-desmethyltramadol (>1.5 mg/L). Hemodynamic support by inotropic drug infusion and diuretics was necessary. Left ventricular function normalised after 2 days of treatment allowing drug infusion weaning. Cardiac magnetic resonance imaging performed 3 days after admission confirmed normal left ventricular ejection fraction and volumes without evidence of late gadolinium enhancement. Cardiogenic shock due to tramadol intoxication is rare but exists. Negative inotropic effect of high doses of tramadol has been suspected. Quick recovery is possible.",
"affiliations": "Service de Cardiologie Congénitale et Pédiatrique, Hôpital du Haut-Lévêque, CHU Bordeaux, Avenue de Magellan, 33604, Pessac, France, elop85@yahoo.fr.",
"authors": "Perdreau|Elodie|E|;Iriart|Xavier|X|;Mouton|Jean-Baptiste|JB|;Jalal|Zakaria|Z|;Thambo|Jean-Benoît|JB|",
"chemical_list": "D000701:Analgesics, Opioid; D014147:Tramadol",
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-014-9262-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "15(1)",
"journal": "Cardiovascular toxicology",
"keywords": null,
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": "D000701:Analgesics, Opioid; D002648:Child; D062787:Drug Overdose; D004452:Echocardiography; D006801:Humans; D008279:Magnetic Resonance Imaging; D012770:Shock, Cardiogenic; D014147:Tramadol; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "100-3",
"pmc": null,
"pmid": "24811952",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cardiogenic shock due to acute tramadol intoxication.",
"title_normalized": "cardiogenic shock due to acute tramadol intoxication"
} | [
{
"companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2015-01309",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nSmall cell carcinoma of the urinary bladder is a rare and aggressive form of bladder cancer that mainly presents at an advanced stage. As a result of its rarity, it has been described in many case reports and reviews but few retrospective and prospective trials, showing there is no standard therapeutic approach. In the literature the best therapeutic strategy for limited disease is the multimodality treatment and most authors have extrapolated treatment algorithms from the therapy recommendations of small cell lung cancer.\n\n\nMETHODS\nA 71-year-old male patient was referred to our hospital with gross hematuria and dysuria. Imaging and cystoscopy revealed a vegetative lesion of the bladder wall. A transurethral resection of the bladder was performed. Pathological examination revealed a pT2 high-grade urothelial carcinoma with widespread neuroendocrine differentiation. Multimodal treatment with neoadjuvant platinum-based chemotherapy was performed. A CT scan performed after chemotherapy demonstrated a radiological complete response. The patient underwent radical cystectomy and lymphadenectomy. The histopathological finding of bladder and node specimen confirmed a pathological complete response. A post-surgery CT scan showed no evidence of local or systemic disease. Six months after surgery, the patient is still alive and disease-free.\n\n\nCONCLUSIONS\nA standard treatment strategy of small cell cancer of the urinary bladder is not yet well established, but a multimodal treatment of this disease is the best option compared to surgical therapy alone. The authors confirm the use of neoadjuvant chemotherapy in limited disease of small cell carcinoma of the urinary bladder.",
"affiliations": "Department of Medical Oncology Unit A, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.;Department of Medical Oncology, IRCCS San Martino IST, Genoa, Italy.;Department of Gynecology, Obstetrics and Urology, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.;Department of Medical Oncology Unit A, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.;Department of Gynecology, Obstetrics and Urology, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.;Department of Gynecology, Obstetrics and Urology, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.;Department of Gynecology, Obstetrics and Urology, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.;Department of Gynecology, Obstetrics and Urology, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.;Department of Medical Oncology Unit A, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.",
"authors": "Prelaj|Arsela|A|;Rebuzzi|Sara Elena|SE|;Magliocca|Fabio Massimo|FM|;Speranza|Iolanda|I|;Corongiu|Emanuele|E|;Borgoni|Giuseppe|G|;Perugia|Giacomo|G|;Liberti|Marcello|M|;Bianco|Vincenzo|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.896989",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "17()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D018288:Carcinoma, Small Cell; D015653:Cystectomy; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "248-53",
"pmc": null,
"pmid": "27072610",
"pubdate": "2016-04-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9128989;19414678;19457759;19500382;15708041;22078012;18607595;23826453;15947585;21567387;17270661;20664477;26360822;15247709;21555200;15700264;16269089;2549274;22564397;23671508;24024065;6261916;15329903",
"title": "Neoadjuvant Chemotherapy in Neuroendocrine Bladder Cancer: A Case Report.",
"title_normalized": "neoadjuvant chemotherapy in neuroendocrine bladder cancer a case report"
} | [
{
"companynumb": "IT-CORDEN PHARMA LATINA S.P.A.-IT-2016COR000182",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS"
... |
{
"abstract": "Vancomycin is a widely used antibiotic and rarely can cause drug-induced thrombocytopenia. A patient with hospital-acquired meningitis after neurosurgery was treated with systemic and intrathecal vancomycin. On 9th day of antibiotic treatment, the patient's platelets dropped to 0.68×109/L. Multiple platelet transfusions had minimal influence on platelet count. After cessation of vancomycin therapy, platelets returned to normal values without any additional interventions. Diagnosis of vancomycin-induced thrombocytopenia was confirmed by detection of drug-dependent antiplatelet IgG antibodies.",
"affiliations": "Intensive Care, National Medical Research Center for Neurosurgery Named After NN Burdenko, Moscow, Russian Federation yanssavchenko@gmail.com.;Intensive Care, National Medical Research Center for Neurosurgery Named After NN Burdenko, Moscow, Russian Federation.;Neurosurgery, National Medical Research Center for Neurosurgery Named After NN Burdenko, Moscow, Russian Federation.;Laboratory for Immunophenotyping of Blood and Bone Marrow Cells, FSBI National Research Center for Hematology of the Ministry of Health of the Russian Federation, Moscow, Russian Federation.",
"authors": "Savchenko|Ian|I|http://orcid.org/0000-0002-2292-8374;Birg|Tatiana|T|;Sharipov|Oleg|O|;Davydova|Yulia|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-244209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); infection (neurology); infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D006801:Humans; D008581:Meningitis; D010976:Platelet Count; D013921:Thrombocytopenia; D014640:Vancomycin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34389597",
"pubdate": "2021-08-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe vancomycin-induced thrombocytopenia in a patient with meningitis.",
"title_normalized": "severe vancomycin induced thrombocytopenia in a patient with meningitis"
} | [
{
"companynumb": "RU-AXELLIA-003869",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "1",
"drug... |
{
"abstract": "BACKGROUND\nHypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) can affect children, with the mechanism proposed being inhibition of the cyclooxygenase enzyme-1 (COX-1). In these patients nonchemically related NSAIDs, including COX-2 inhibitors, can induce the reaction, hampering treatment of fever and inflammatory processes.\n\n\nOBJECTIVE\nTo analyse retrospectively tolerance to etoricoxib, a selective COX-2 inhibitor, and to meloxicam, a preferential COX-2 inhibitor, in children with hypersensitivity to NSAIDs.\n\n\nMETHODS\nClinical records of children (aged 1-14 years) diagnosed with hypersensitivity reactions to NSAIDs from January 2006 to January 2013 were included. The diagnosis was confirmed by oral drug provocation test (DPT) with the culprit NSAIDs and acetylsalicylic acid (ASA). Tolerance to paracetamol, etoricoxib and meloxicam was also evaluated.\n\n\nRESULTS\nThe study included 41 children with a positive DPT with ASA and the culprit NSAID. DPT with paracetamol and etoricoxib was negative in all children, although two (4.9%) children developed a reaction after the administration of meloxicam.\n\n\nCONCLUSIONS\nThese data indicate that both etoricoxib and meloxicam are good alternatives for treatment in older children with hypersensitivity to NSAIDs.",
"affiliations": "Pediatric Service, Carlos Haya Hospital/IBIMA, Plaza del Hospital Civil s/n, pabellón 5, sótano, 29009, Malaga, Spain.",
"authors": "Corzo|J L|JL|;Zambonino|M A|MA|;Muñoz|C|C|;Mayorga|C|C|;Requena|G|G|;Urda|A|A|;Gallego|C|C|;Blanca|M|M|;Torres|M J|MJ|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011725:Pyridines; D013450:Sulfones; D013843:Thiazines; D013844:Thiazoles; D000077239:Meloxicam; D000077613:Etoricoxib",
"country": "England",
"delete": false,
"doi": "10.1111/bjd.12674",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "170(3)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
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"title": "Tolerance to COX-2 inhibitors in children with hypersensitivity to nonsteroidal anti-inflammatory drugs.",
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"abstract": "BACKGROUND\nRelapsed or refractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, showing survival rates of less than a year even with the use of novel therapies. In this report, we describe the safe and effective use of trametinib combined with dasatinib in a patient with acute lymphoblastic leukemia (ALL). To the best of our knowledge, this is the first report on the successful use of 2 targeted drugs such as trametinib and dasatinib in a pediatric patient with Ph+ ALL and recurrent pancreatitis.\nA 6-year-old boy with ALL and Philadelphia chromosome (Ph+) who had recurrent asparaginase-associated pancreatitis.\n\n\nMETHODS\nThe patient was diagnosed with ALL, based on clinical features, laboratory analyses, bone marrow aspiration evaluation in morphology, immunology, cytogenetics, and molecular.\n\n\nMETHODS\nThe patient was treated with dasatinib combined with an intermediate risk-oriented chemotherapy. However, owing to recurrent asparaginase-associated pancreatitis, the patient has to abandon asparaginase in consolidation. Considering the high risk of relapse, we used trametinib and dasatinib combined with chemotherapy as maintenance chemotherapy.\n\n\nRESULTS\nAfter 6 months, there were no obvious side effects or residual disease.\n\n\nCONCLUSIONS\nWe suggest that the combination of trametinib and dasatinib may represent a viable option to treat patients with potential relapsed/refractory Ph+ ALL.",
"affiliations": "Ningbo Women and Children's Hospital, Ningbo.;Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China.;Ningbo Women and Children's Hospital, Ningbo.;Ningbo Women and Children's Hospital, Ningbo.",
"authors": "Wang|Jing|J|0000-0003-3951-4749;Shen|Shu-Hong|SH|;Hu|Bin-Fei|BF|;Wang|Guan-Ling|GL|",
"chemical_list": "D011728:Pyridones; D011744:Pyrimidinones; D003561:Cytarabine; C560077:trametinib; D003520:Cyclophosphamide; D001215:Asparaginase; D001379:Azathioprine; D000069439:Dasatinib",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n34160436\nMD-D-21-02423\n10.1097/MD.0000000000026440\n26440\n4800\nResearch Article\nClinical Case Report\nSuccessful use of trametinib and dasatinib combined with chemotherapy in the treatment of Ph-positive B-cell acute lymphoblastic leukemia\nA case report\nhttp://orcid.org/0000-0003-3951-4749\nWang Jing MS a∗\nShen Shu-Hong MD, PhD b\nHu Bin-Fei MS a\nWang Guan-Ling MS a\nSaranathan. Maya\na Ningbo Women and Children's Hospital, Ningbo\nb Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China.\n∗ Correspondence: Jing Wang, Ningbo Women and Children's Hospital, 339 Liuting Street, Haishu District, Ningbo City 315000, Zhejiang Province, China (e-mail: 564357094@qq.com).\n25 6 2021\n25 6 2021\n100 25 e264403 4 2021\n19 5 2021\n7 6 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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/4.0\n\nAbstract\n\nRationale:\n\nRelapsed or refractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, showing survival rates of less than a year even with the use of novel therapies. In this report, we describe the safe and effective use of trametinib combined with dasatinib in a patient with acute lymphoblastic leukemia (ALL). To the best of our knowledge, this is the first report on the successful use of 2 targeted drugs such as trametinib and dasatinib in a pediatric patient with Ph+ ALL and recurrent pancreatitis.\n\nPatient concerns:\n\nA 6-year-old boy with ALL and Philadelphia chromosome (Ph+) who had recurrent asparaginase-associated pancreatitis.\n\nDiagnosis:\n\nThe patient was diagnosed with ALL, based on clinical features, laboratory analyses, bone marrow aspiration evaluation in morphology, immunology, cytogenetics, and molecular.\n\nInterventions:\n\nThe patient was treated with dasatinib combined with an intermediate risk-oriented chemotherapy. However, owing to recurrent asparaginase-associated pancreatitis, the patient has to abandon asparaginase in consolidation. Considering the high risk of relapse, we used trametinib and dasatinib combined with chemotherapy as maintenance chemotherapy.\n\nOutcomes:\n\nAfter 6 months, there were no obvious side effects or residual disease.\n\nLessons:\n\nWe suggest that the combination of trametinib and dasatinib may represent a viable option to treat patients with potential relapsed/refractory Ph+ ALL.\n\nKeywords\n\nacute lymphoblastic leukemia\ncase report\nchemotherapy\ntargeted drug\ntrametinib\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nIntroduction of tyrosine kinase inhibitors (TKIs) has significantly improved the management and prognosis of patients with the Philadelphia chromosome (Ph+) and acute lymphoblastic leukemia (ALL). Complete response rates range between 91% and 98%, with an unprecedented 4-year overall survival rate of up to 71%.[1] The relapse rate of pediatric patients with Ph+ ALL is high when they receive an inadequate course of the planned asparaginase therapy. The outcomes of these patients are inferior compared with those of patients that receive adequate doses of the planned therapy.[2]\n\nSome data indicate that inhibition of the mitogen-activated protein kinase pathway increases chemosensitivity to glucocorticoids and possibly to other agents, making it an attractive target for the prevention and/or treatment of relapsed disease.[3] Here, we report a very rare case of Ph+ ALL and recurrent pancreatitis treated with trametinib combined with dasatinib. Furthermore, we demonstrate the safe and effective use of these targeted drugs in a pediatric patient.\n\n2 Case report\n\nA 6-year-old boy was admitted to our hospital with fever and shoulder pain in September 2018. Physical examination revealed splenomegaly. Laboratory analyses showed the following results: hemoglobin 157 g/L, platelet count 132 × 109/L, white blood cell count (WBC) 75.8 × 109/L. A peripheral blood smear evaluation revealed a large number of immature cells. Bone marrow aspiration evaluation demonstrated an immature B-cell immunophenotype in 92% of the lymphoblasts. Cytogenetic studies revealed the following karyotype: 45XY,-3,-7,der (9) add(9)(p24)t(9;22)(q34;q11.2), der(22)t(9;22),+mar (8)/46, XY(12). Reverse transcription polymerase chain reaction analysis showed a positive result for the BCR-ABL P190 mutation.\n\nThe patient was treated according to the protocol of the Chinese Children's Cancer Group study ALL-2015 with the following drugs as induction therapy: vincristine, 2.4 mg iv on days 1, 8, 15, and 21; idarubicin, 6.4 mg ivgtt on days 5 and 12; prednisone, 35 mg orally daily; and perasparaginase 1600 IU im on days 12 and 26. In addition, TKI dasatinib 65 mg was administered orally daily from the time we were informed that the Philadelphia chromosome was positive.\n\nPost-induction bone marrow aspiration evaluation demonstrated complete remission when assessing minimal residual disease (MRD) on days 19 and 46. Subsequently, the patient received a CAT (cyclophosphamide, cytarabine, and azathioprine) regimen consisting of cyclophosphamide, 0.8 g on day 1; cytarabine 80 mg on days 1 to 7; and azathiopurine, 40 mg on days 1 to 7, as first consolidation treatment. Unexpectedly, the patient developed severe pancreatitis after chemotherapy. Therefore, we switched to asparaginase Erwinia at a dose of 10,000 IU/m2 twice weekly after the pancreatitis was under control. During the third asparaginase Erwinia dose, a mild pancreatitis recurred. To avoid a third pancreatitis episode, both perasparaginase and asparaginase Erwinia were excluded from the protocol.\n\nOn April 2020, MRD assessment showed 0.01% positive cells. The patient's parents refused bone marrow transplantation because the transplant risk was relatively high. To prevent a relapse, we obtained informed consent from the patient's parents to add trametinib to the maintenance chemotherapy regimen. Details were as follows: trametinib, 0.025 mg/kg on days 1 to 14 every 4 weeks for 18 cycles orally; maintenance therapy: dexamethasone 6 mg/m2 on days 1 to 7 every 8 weeks; cyclophosphamidum, 300 mg/m2 on day 1; cytarabine, 300 mg/m2 on day 1; and amethopterin, 25 mg/m2 weekly. During this period, echocardiographic examination was performed every 3 months. Routine and biochemical blood tests were performed regularly every 1 to 3 weeks.\n\nSurprisingly, there was no significant hematologic toxicity after 12 months of treatment. The MRD has always been negative. He has been going to school and lived a normal life. During this time, there were only 2 mild infective fever episodes. Now, let me report his laboratory examinations. In peripheral blood, hemoglobin was above 100 g/L and platelet count was higher than 100 × 109/L when measured at all timepoints (Fig. 1). After using trametinib, the WBC fluctuated between 2.4 and 7.14 × 109/L. Moreover, WBC remained above 3 × 109/L more frequently after using trametinib than before introducing the drug (83%=20/24 vs 77% = 14/18). The absolute neutrophil count (ANC) fluctuated between 0 and 4.42 × 109/L, only falling below 0.5 × 109/L in 4 instances. Moreover, ANC remained above 0.5 × 109/L more frequently after using trametinib than before introducing the drug (83% = 20/24 vs 72% = 13/18) (Fig. 2). Glutamic amino transferase and aspartic amino transferase serum values were 15.25 and 27.714 U/L before using trametinib, and 31.625 and 27 U/L after using trametinib, respectively. Creatinine and urea concentrations were 37.87 vs 42 μmol/L and 4.125 vs 3.9 mmol/L before and after using trametinib, respectively (Fig. 3). During the trametinib regime, 2 echocardiographic evaluations were performed. Cardiac ejection fraction was 60% and 66%. MRD assessment was performed every 3 months, showing negative results (Fig. 4).\n\nFigure 1 Changes in hemoglobin (HB) level and platelet (PLT) count before and after the introduction of trametinib. Blue curve: changes in HB levels. Orange curve: changes in PLT count. The black vertical line separates the period before and after trametinib introduction.\n\nFigure 2 Changes in white blood cell (WBC) count and absolute neutrophil count (ANC) before and after the introduction of trametinib. Blue curve: changes in WBC count. Orange curve: changes in ANC. The black vertical line separates the period before and after trametinib introduction.\n\nFigure 3 Changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), and urea levels before and after the introduction of trametinib. Blue curve: changes in ALT levels. Orange curve: changes in AST levels. Purple curve: changes in CREA levels. Yellow curve: changes in urea levels. The black vertical line separates the period before and after trametinib introduction.\n\nFigure 4 Changes in minimal residual disease (MRD) levels from the first to the most recent morphological complete remission. The black vertical line marks the date trametinib was introduced.\n\n3 Discussion\n\nAccording to the extent of asparaginase exposure, previous studies reported that asparaginase-associated pancreatitis (AAP) may occur in 11% of pediatric patients with ALL.[4–7] Although premature asparaginase discontinuation may decrease cure rates,[7,8] AAP represents one of the most common reasons for asparaginase withdrawal in children. Moreover, many pediatric patients experience AAP recurrence after asparaginase reintroduction.[4,7,9] Herein, we described a case of Ph+ ALL in which the patients developed AAP twice. The patient was treated with dasatinib combined with an intermediate risk-oriented induction therapy, achieving a molecular complete remission on day 19. The patient received 2 doses of perasparaginase and 3 doses of asparaginase Erwinia. Using this approach, MRD assessment always resulted negative. Fifteen months later, the MRD assessment result was 0.01%. Considering that the patient was Ph+ and refused bone marrow transplantation, increasing his risk of relapse, we decided to add trametinib to the protocol.\n\nAlthough the introduction of TKIs has revolutionized the outcomes of Ph+ ALL patients, a proportion of these patients are still unable to achieve a long-term cure because of drug resistance, even when performing hematologic stem cell transplantation. However, with the advent of other novel agents, we are entering an era where we hope to reduce the reliance on transplantation in this disease.[10]\n\nIn the present case report, we demonstrated that the mitogen-activated protein kinase (MEK) inhibitor trametinib combined with dasatinib display a safe and effective treatment profile in patients with Ph+ ALL. First, MEK inhibition may overcome TKI resistance. The substitution of threonine for isoleucine at residue 315 in Abl (BCR-ABLT315I) forms a protein that is tolerant to almost all TKIs because Bcr-Abl inhibitors do not stimulate the BCR-ABLT315I pathway, whereas TKIs and MEK inhibitors act synergistically to inhibit the growth of BCR-ABLT315I Ba/F3 cells. This induces a synthetic lethality in drug-resistant chronic myeloid leukemia in mice[11] and represents a beneficial therapeutic strategy in patients with AML.[12] Trametinib in combination with TKIs may prevent the development of drug resistance through its regulatory molecule MEK. As suggested in other studies,[13,14] the addition of submaximal concentrations of a MEK inhibitor halts ERK reactivation and sensitizes cells to TKI treatment, resulting in a synergistic combination.[13]\n\nALL patients with poor prognosis, such as infant ALL and Ph+ ALL, tend to have poor clinical response to glucocorticoid agonists.[15,16] Recently, some studies found that trametinib displayed powerful anti-leukemic effects against ALL cells with RAS mutation and MLL rearrangement, as MEK inhibition enhances prednisolone sensitivity.[17] In addition, Jones et al[3] supported the use of trametinib as a potential treatment for relapsed ALL. They suggested that the inhibition of the MEK1/2 pathway combined with chemotherapy not only enhances cell death in relapsed ALL but also overcomes human bone marrow stromal cell protection, which is imperative for therapeutic success in vivo. Moreover, the combination of MEK1/2 inhibitors with traditional cytotoxic chemotherapy may counteract resistance to chemotherapy in relapsed ALL, as MEK2 knockdown or inhibition increases sensitivity to chemotherapy in a p53-dependent manner.[3] Although these experiments were performed in vitro, ex vivo, and in vivo in mice, pediatric clinical trials are underway and could expedite the clinical application of these MEK inhibitors in Ph+ ALL.\n\nIn our case, we demonstrated that the drug combination did not display any significant enhancement of cytotoxic activity compared with dasatinib alone.[18] After including trametinib in the treatment regimen, WBC and ANC remained above 3 × 109/L and 0.5 × 109/L, respectively, more frequently than before introducing the drug (77% vs 83% and 72% vs 83%, respectively); this may be related to an infection fever just before trametinib treatment. The mean values of glutamic amino transferase, aspartic amino transferase, and creatinine were slightly higher after the combined treatment with trametinib, while those of urea were similar. Thus, the combination therapy had an increased toxic effect on hepatic and renal function. However, the clinical significance of these differences remains uncertain, requiring studies with a long-term follow-up.\n\nIn conclusion, our findings support the use of trametinib as a potential treatment for relapsed ALL. Other studies, such as large sample multicenter studies, are needed to further elucidate the effectiveness and safety of this treatment regimen.\n\nAcknowledgments\n\nWe would like to express our gratitude to Professor Shu-hong Shen of Shanghai Children's Medical Center, for his valuable advice.\n\nAuthor contributions\n\nGLW analyzed and interpreted the patient data regarding the hematological disease. JW performed data collection, and was a major contributor in writing the manuscript. BFH and SHS confirm the authenticity of all raw data. All authors read and approved the final manuscript.\n\nData curation: Bin-Fei Hu.\n\nInvestigation: Shu-Hong Shen, Guan-Ling Wang.\n\nResources: jing wang, Bin-Fei Hu, Guan-Ling Wang.\n\nSupervision: Shu-Hong Shen, Bin-Fei Hu.\n\nWriting – original draft: jing wang.\n\nWriting – review & editing: Shu-Hong Shen, Bin-Fei Hu.\n\nAbbreviations: AAP = Asparaginase-associated pancreatitis, ALL = Acute lymphoblastic leukemia, ANC = Absolute neutrophil count, MEK = mitogen-activated protein kinase, MRD = minimal residual disease, TKIs = tyrosine kinase inhibitors, WBC = white blood cell count.\n\nHow to cite this article: Wang J, Shen SH, Hu BF, Wang GL. Successful use of trametinib and dasatinib combined with chemotherapy in the treatment of Ph-positive B-cell acute lymphoblastic leukemia: A case report. Medicine. 2021;100:25(e26440).\n\nNo funding was received.\n\nThe datasets generated and/or analyzed during the current study are not publicly available due to privacy concerns but are available from the corresponding author on reasonable request.\n\nInformed consent for participation in the study or use of their tissue was obtained from the participant and his parents.\n\nInformed consent for publication was obtained from the participant's parents.\n\nThe authors declare that they have no competing interests.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n\n[1] Shen S Chen X Cai J . Effect of dasatinib vs imatinib in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: a randomized clinical trial. JAMA Oncol 2020;6 :358–66.31944221\n[2] Rank CU Wolthers BO Grell K . Asparaginase-associated pancreatitis in acute lymphoblastic leukemia: results from the NOPHO ALL2008 treatment of patients 1-45 years of age. J Clin Oncol 2020;38 :145–54.31770057\n[3] Jones CL Gearheart CM Fosmire S . MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. Blood 2015;126 :2202–12.26324703\n[4] Wolthers BO Frandsen TL Abrahamsson J . Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. Leukemia 2017;31 :325–32.27451978\n[5] Liu C Yang W Devidas M . Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia. J Clin Oncol 2016;34 :2133–40.27114598\n[6] Place AE Stevenson KE Vrooman LM . Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia (DFCI 05-001): a randomized, open-label phase 3 trial. Lancet Oncol 2015;16 :1677–2169.26549586\n[7] Kearney SL Dahlberg SE Levy DE . Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis. Pediatr Blood Cancer 2009;53 :162–7.19405141\n[8] Aldoss I Pullarkat V Martinez D . The number of PEG-asparaginase doses administered is a determinant of relapse risk in adult ALL treated with a pediatric-like regimen. Blood 2013;122 :3915.\n[9] Wolthers BO Frandsen TL Baruchel A . Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study. Lancet Oncol 2017;18 :1238–48.28736188\n[10] Ravandi F . How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2019;133 :130–6.30442680\n[11] Packer LM Rana S Hayward R . Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell 2011;20 :715–27.22169110\n[12] Kerstjens M Pinhancos SS Castro PG . Trametinib inhibits RAS-mutant MLL-rearranged acute lymphoblastic leukemia at specific niche sites and reduces ERK phosphorylation in vivo. Haematologica 2018;103 :e147–50.29419436\n[13] Nishioka C Ikezoe T Yang J . Blockade of MEK/ERK signaling enhances sunitinib-induced growth inhibition and apoptosis of leukemia cells possessing activating mutations of the FLT3 gene. Leuk Res 2008;32 :865–72.17983653\n[14] Bruner JK Ma HS Li L . Adaptation to TKI treatment reactivates ERK signaling in tyrosine kinase-driven leukemias and other malignancies. Cancer Res 2017;77 :5554–63.28923853\n[15] Dördelmann M Reiter A Borkhardt A . Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 1999;94 :1209–17.10438708\n[16] Schrappe M Aricò M Harbott J . Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 1998;92 :2730–41.9763557\n[17] Zhang W Borthakur G Gao C . The dual MEK/FLT3 inhibitor E6201 exerts cytotoxic activity against acute myeloid leukemia cells harboring resistance-conferring FLT3 mutations. Cancer Res 2016;76 :1528–37.26822154\n[18] Ahmad S He Q Williams KP . Identification of a triple drug combination that is synergistically cytotoxic for triple-negative breast cancer cells using a novel combination discovery approach. SLAS Discov 2020;25 :923–38.32441190\n\n",
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"title": "Successful use of trametinib and dasatinib combined with chemotherapy in the treatment of Ph-positive B-cell acute lymphoblastic leukemia: A case report.",
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"affiliations": "Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan. iida@med.nagoya-cu.ac.jp.;Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Bristol-Myers Squibb K.K., Tokyo, Japan.;Bristol-Myers Squibb K.K., Tokyo, Japan.;Bristol-Myers Squibb, Princeton, NJ, USA.;Bristol-Myers Squibb, Princeton, NJ, USA.;Bristol-Myers Squibb, Princeton, NJ, USA.;Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.",
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"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D003907:Dexamethasone; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D007970:Leukopenia; D008231:Lymphopenia; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D012008:Recurrence; D016879:Salvage Therapy; D000071176:Signaling Lymphocytic Activation Molecule Family; D013792:Thalidomide; D016896:Treatment Outcome",
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"title": "Elotuzumab with lenalidomide and dexamethasone for Japanese patients with relapsed/refractory multiple myeloma: phase 1 study.",
"title_normalized": "elotuzumab with lenalidomide and dexamethasone for japanese patients with relapsed refractory multiple myeloma phase 1 study"
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"abstract": "An 81-year-old lady was admitted to our hospital with a 3-year history of noninfective diarrhoea and recurrent syncopal events over the last 3 months. Her initial electrocardiogram (ECG) revealed trigeminy and prolonged QTc interval. She had a structurally normal heart with no coronary artery disease. Investigations revealed low potassium at 3.0 mmol/L. Sigmoidoscopy and colonoscopy suggested a possible diagnosis of diverticulitis. Soon after admission she had an unresponsive episode with spontaneous recovery. Telemetry and Holter analysis confirmed multiple episodes of polymorphic ventricular tachycardia (Torsade de Pointes). Following electrolyte supplementation the episodes of polymorphic VT improved. Due to the protracted nature of the diarrhoea, the recurrent syncopal events, and recurrent hypokalaemia documented over recent years, an Implantable Cardioverter Defibrillator (ICD) was sanctioned by the multidisciplinary team (MDT). In summary, chronic diarrhoea may result in life threatening polymorphic VT due to hypokalaemia and QTc prolongation. In these patients an ICD may be considered.",
"affiliations": "Frimley Health NHS Foundation Trust, Wexham Park Hospital, Cardiology Department, Slough SL2 4HL, UK.;King's College London BHF Centre, King's College Hospital, London SE1 7EH, UK.;Frimley Health NHS Foundation Trust, Wexham Park Hospital, Cardiology Department, Slough SL2 4HL, UK.",
"authors": "Mouyis|Kyriacos|K|;Okonko|Darlington|D|;Missouris|Constantinos G|CG|",
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"country": "United States",
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"doi": "10.1155/2016/3845108",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2016/3845108Case ReportIdiopathic Intractable Diarrhoea Leading to Torsade de Pointes Mouyis Kyriacos \n1\nOkonko Darlington \n2\nMissouris Constantinos G. \n1\n\n*\n1Frimley Health NHS Foundation Trust, Wexham Park Hospital, Cardiology Department, Slough SL2 4HL, UK2King's College London BHF Centre, King's College Hospital, London SE1 7EH, UK*Constantinos G. Missouris: dinos.missouris@fhft.nhs.ukAcademic Editor: Kjell Nikus\n\n2016 23 5 2016 2016 384510823 2 2016 24 4 2016 26 4 2016 Copyright © 2016 Kyriacos Mouyis et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.An 81-year-old lady was admitted to our hospital with a 3-year history of noninfective diarrhoea and recurrent syncopal events over the last 3 months. Her initial electrocardiogram (ECG) revealed trigeminy and prolonged QTc interval. She had a structurally normal heart with no coronary artery disease. Investigations revealed low potassium at 3.0 mmol/L. Sigmoidoscopy and colonoscopy suggested a possible diagnosis of diverticulitis. Soon after admission she had an unresponsive episode with spontaneous recovery. Telemetry and Holter analysis confirmed multiple episodes of polymorphic ventricular tachycardia (Torsade de Pointes). Following electrolyte supplementation the episodes of polymorphic VT improved. Due to the protracted nature of the diarrhoea, the recurrent syncopal events, and recurrent hypokalaemia documented over recent years, an Implantable Cardioverter Defibrillator (ICD) was sanctioned by the multidisciplinary team (MDT). In summary, chronic diarrhoea may result in life threatening polymorphic VT due to hypokalaemia and QTc prolongation. In these patients an ICD may be considered.\n==== Body\n1. Introduction\nElectrolyte abnormalities are common in patients with prolonged diarrhoea. We report the case of a lady, the first we are aware of, who suffered from hypokalaemia and a history of recurrent syncopal events related to Torsades de Pointes as a result of persistent and intractable diarrhoea.\n\n2. Case Presentation\nAn 81-year-old lady was admitted to our hospital with recurrent falls associated with brief loss of consciousness. She denied any other cardiac symptoms. Her past medical history included an embolic cerebrovascular event a year earlier with no residual focal neurology, hypertension, treated hypothyroidism, diverticulosis, anaemia of chronic disease, and chronic noninfective diarrhoea of 3 years' duration. This had been extensively investigated by several gastroenterologists and colorectal surgeons.\n\nOn admission she was passing 8–10 loose motions a day. She was on treatment with levothyroxine 125 micrograms OD, clopidogrel 75 mg OD, aspirin 75 mg OD, atorvastatin 40 mg OD, ranitidine 150 mg BD, zopiclone 7.5 mg OD, citalopram 10 mg OD, folic acid 5 mg OD, loperamide 2 mg TDS, co-codamol 8/500 2 tablets QDS, and desloratadine 5 mg OD.\n\nOn examination she was apyrexial, the pulse was 60 beats per minute and regular, and the supine blood pressure was 157/55 mmHg. Saturation on air was 95%. The rest of the cardiovascular, respiratory, and abdominal examination was within normal limits. There were no history of liquorice use, no clinical evidence of somatic neuropathy, and no evidence of adrenal adenomas on abdominal CT examination done prior to admission.\n\nThe investigations were as follows: haemoglobin 12.7 g/L, sodium 143 mmol/L, potassium 3.0 mmol/L, chloride 101 mmol/L, bicarbonate 27.6 mmol/L, pH 7.46, magnesium 0.72 mmol/L, adjusted calcium 2.21 mmol/L, phosphate 1.08 mmol/L, TSH 0.22 μ/mL, free T4 25 pmol/L, and C Reactive Protein (CRP) 89 mg/L. The admission resting ECG revealed ventricular bigeminy and prolongation of the QTc at 519 msec (normal for females < 470 msec), measured using Bazett's formula as heart rate was less than 65 bpm. Telemetry and Holter analysis confirmed the presence of multiple episodes of polymorphic VT (Torsades de Pointes) (Figure 1). An echocardiogram confirmed a structurally normal heart with a normal ejection fraction of greater than 55%. Coronary angiography confirmed normal appearances with no evidence of overt coronary artery disease.\n\nThe patient's episodes of polymorphic VT stopped following administration of intravenous and oral potassium as well as magnesium supplementation (Figure 2) and the discontinuation of citalopram, which has been associated with development of long QT syndrome and Torsade de Pointes as an adverse drug reaction [1]. The QTc normalised within 48 hours following this. The patient was treated with loperamide 4 mg prn and amiloride 5 mg daily to correct the hypokalaemia. Following these interventions potassium levels remained above 4.0 mmol/L. Despite the administration of amiloride and normalisation of the potassium the patient was still experiencing ongoing diarrhoea. Additionally there were past blood tests (ordered by the patient's GP) documenting low potassium levels in the preceding 2 years. With that in mind the cardiology MDT felt that the precipitating cause of the Torsades de Pointes was not fully addressed and thus an ICD would offer the best change of preventing an arrhythmic death. An ICD (dual chamber, Medtronic Evera) was thus prophylactically implanted. Due to the patient's age and in the absence of any previous or family history of syncope and ventricular arrhythmias no genetic tests were performed.\n\nOn follow-up after six months, she remained asymptomatic with no further syncopal events or symptoms of light headedness, blurred vision, or feeling faint. Repeat blood tests by her GP at 3 and 6 months showed potassium of 4.1 and 4.2 mmol/L, respectively, and she was continuing to take amiloride. No arrhythmias were detected on interrogation of the ICD at the follow-up.\n\n3. Discussion\nPolymorphic VT (Torsade de Pointes) is a distinctive form of ventricular tachycardia characterised by oscillation of the QRS complex around the isoelectric axis and it predisposes to sudden cardiac death. QT interval prolongation is a prerequisite for this arrhythmia. Prolonged repolarisation is mediated via several subtypes of sodium and potassium channels in cardiac myocytes, mainly by inhibiting the rapid component of the delayed rectifier potassium current (I\nKr) [2].\n\nConditions that cause a prolonged QT interval such as congenital syndromes (e.g., Jervell and Lange Nielsen, Romano Ward) predispose to polymorphic VT. Women also have an inherently longer QT interval due to intrinsic sex differences in the cardiac conductive tissue and so are more at risk. Furthermore, electrolyte abnormalities, and in particular hypokalaemia (but also hypomagnesemia and hypocalcaemia), predispose to the above arrhythmia by increasing the length of delayed repolarisation and consequently the QT interval [2]. Possible precipitants for hypokalaemia include drugs (e.g., diuretics such as indapamide, amphotericin B, aminoglycosides, and psychotropic medications), excessive GI tract losses (e.g., diarrhoea, vomiting), or renal losses (e.g., renal artery stenosis, primary hyperaldosteronism) [2].\n\nA small number of case reports have been published establishing an association between diarrhoea-induced hypokalaemia and polymorphic VT. In one report hypokalaemia was precipitated by the use of the antipsychotic drug thioridazine and in another by the use of laxatives [3, 4]. In both cases the polymorphic VT was terminated following the withdrawal of the implicating drug. In another study Kusano et al. reported nonsustained VT with normal QTc interval in the context of hypokalaemia and diarrhoea [5]. Krahn et al. reported a patient with hypokalaemia secondary to inadvertent laxative abuse who required cardioversion for Torsades de Pointes [4].\n\nIn our case the patient had more than one reason for prolonged QT and subsequent Torsades de Pointes. We believe that the temporal relationship of events offers some support to our assertion of hypokalaemia being the driver of the arrhythmia rather than citalopram use. Citalopram has a half-life of approximately 35 hours and is often prolonged in the elderly. The patient's arrhythmic episodes resolved after less than 48 hours following correction and maintenance of potassium levels at more than 4.0 mmol/L. Additionally there is evidence for a dose related relationship between citalopram and QTc prolongation. This lady was on 10 mg which is a low dose regime; thus, it is less likely that this would have caused a significant QTc prolongation.\n\nOur case report demonstrates that long standing diarrhoea is an important and reversible cause of hypokalaemia and QTc prolongation that can result in life threatening polymorphic VT. In addition, it demonstrates that due to the protracted nature of the diarrhoea and the recurrent syncopal events an Implantable Cardioverter Defibrillator (ICD) was deemed to be of potential benefit. This was because no definitive treatment was found for her diarrhoea which likely precipitated her hypokalaemia and the subsequent ventricular arrhythmia. One could argue that the initiation of amiloride and the discontinuation of citalopram were sufficient to terminate the arrhythmic episodes without the need for an ICD implantation. Nonetheless, the Torsade de Pointes load and the ongoing diarrhoeal episodes were such that the unanimous decision of the cardiology MDT was in favour of implanting an ICD as some of the above life threatening events may occur long after the implantation of the device.\n\nAll patients, therefore, presenting with syncope (or symptoms of light headedness, blurred vision, or feeling faint) and long term diarrhoea, should be assessed for hypokalaemia and electrolyte disturbances that may predispose to polymorphic VT. In these patients correction of the above electrolyte abnormalities, with or without ICD implantation, is likely to improve cardiovascular prognosis and outcome.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nFigure 1 Rhythm strip recorded during the episodes of syncope showing polymorphic VT, preceded by sinus rhythm with atrial ectopic beats.\n\nFigure 2 12-lead ECG recorded after termination of episodes of TdP, showing prolongation of the QTc interval.\n==== Refs\n1 Hasnain M. Vieweg W. V. R. QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review CNS Drugs 2014 28 10 887 920 10.1007/s40263-014-0196-9 2-s2.0-84910110656 25168784 \n2 Trinkley K. E. Page R. P. Lien H. Polymorphic ventricular tachycardia of torsades de pointes type in a patient with schizophrenia treated with thioridazine Current Medical Research and Opinion 2013 29 12 1919 1926 \n3 Sinkiewicz W. Balak W. Fares I. Karasek D. Małyszka P. Papke M. Polymorphic ventricular tachycardia of torsade de pointes type in patient with schizophrenia treated with thioridazine Polskie Archiwum Medycyny Wewntrznej 2006 116 6 1188 1191 2-s2.0-50449088735 \n4 Krahn L. E. Lee J. Richardson J. W. Martin M. J. O'Connor M. K. Hypokalemia leading to torsades de pointes. Munchausen's disorder or bulimia nervosa? General Hospital Psychiatry 1997 19 5 370 377 10.1016/s0163-8343(97)00057-1 2-s2.0-0030804596 9328782 \n5 Kusano K. F. Hata Y. Yumoto A. Emori T. Sato T. Ohe T. Torsade de pointes with a normal QT interval associated with hypokalemia: a case report Japanese Circulation Journal 2001 65 8 757 760 10.1253/jcj.65.757 2-s2.0-0034879430 11502056\n\n",
"fulltext_license": "CC BY",
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"title": "Idiopathic Intractable Diarrhoea Leading to Torsade de Pointes.",
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"abstract": "We report the case of a 2-year-old girl with end-stage renal disease managed by peritoneal dialysis (PD) who developed methicillin-resistant staphylococcal osteomyelitis of the left shoulder and was successfully treated with intraperitoneal (IP) administration of vancomycin for 2 weeks followed by oral clindamycin therapy.\n\n\n\nThe patient was hospitalized with tactile fever and a 3-day history of worsening fussiness. Radiography of the left shoulder showed findings indicative of osteomyelitis. Vancomycin was administered via central venous line for 3 days, during which time the patient underwent PD 24 hours a day. After magnetic resonance imaging revealed proximal humeral osteomyelitis, septic arthritis of the shoulder joint, and osteomyelitis of the scapula, the patient underwent incision and drainage of the left shoulder joint. Both blood and joint drainage cultures grew methicillin-resistant Staphylococcus aureus that was sensitive to vancomycin. The patient's central venous catheter was removed on hospital day 4; due to difficulties with peripheral i.v. access and a desire to avoid placing a peripherally inserted central venous catheter, vancomycin administration was changed to the IP route, with vancomycin added to the PD fluid. During IP treatment, serum vancomycin levels were maintained at 13.5 to 18.5 mg/L, and the calculated ratio of vancomycin area under the curve to minimum inhibitory concentration was maintained above 400. After completing a 14-day course of IP vancomycin therapy, the patient was switched to oral clindamycin, with subsequent complete resolution of osteomyelitis.\n\n\n\nIP vancomycin was effective for treatment of invasive S. aureus infection in this case. This approach should be considered in patients undergoing PD for whom peripheral i.v. access options are limited and/or not preferred.",
"affiliations": "Department of Pediatrics, Wayne State University, Detroit, MI.;Department of Pediatrics, Wayne State University, Detroit, MI.;Department of Pediatrics, Wayne State University, Detroit, MI.;Department of Pharmacy, Children's Hospital of Michigan, Detroit, MI.;Department of Pediatrics, Wayne State University, Detroit, MI.;Department of Pediatrics, Wayne State University, Detroit, MI.",
"authors": "Abid|Qassim|Q|;Asmar|Basim|B|;Kim|Edward|E|;Molloy|Leah|L|;Gregory|Melissa|M|;Valentini|Rudolph P|RP|",
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"mesh_terms": "D000900:Anti-Bacterial Agents; D002675:Child, Preschool; D005260:Female; D015312:Hemodialysis Solutions; D006801:Humans; D007676:Kidney Failure, Chronic; D008279:Magnetic Resonance Imaging; D055624:Methicillin-Resistant Staphylococcus aureus; D010019:Osteomyelitis; D010530:Peritoneal Dialysis; D013203:Staphylococcal Infections; D016896:Treatment Outcome; D014640:Vancomycin",
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"title": "Intraperitoneal vancomycin treatment of multifocal methicillin-resistant Staphylococcus aureus osteomyelitis in a patient on peritoneal dialysis.",
"title_normalized": "intraperitoneal vancomycin treatment of multifocal methicillin resistant staphylococcus aureus osteomyelitis in a patient on peritoneal dialysis"
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"abstract": "Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is very limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have an HLA-matched donor identified by the time of two induction failures. We used clofarabine cytoreduction immediately followed by fludarabine (Flu) and busulfan (Bu) × 3 with total-body irradiation (TBI) conditioning (Flu/Bu3/TBI) for haploidentical peripheral blood stem cell transplant with post-transplant cyclophosphamide for two cases of refractory AML with a very high tumor burden at transplant and achieved complete remission by day + 30 in both cases.",
"affiliations": "Department of Medicine, Division of Hematology/Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA. krakszawski@pennstatehealth.psu.edu.;School of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Medicine, Division of Hematology/Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Radiation Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of Pathology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of Medicine, Division of Hematology/Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Department of Medicine, Division of Hematology/Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.",
"authors": "Rakszawski|Kevin|K|http://orcid.org/0000-0001-7441-9531;Miki|Kosuke|K|;Claxton|David|D|;Wagner|Henry|H|;Shike|Hiroko|H|;Mineishi|Shin|S|;Naik|Seema|S|",
"chemical_list": "D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D007166:Immunosuppressive Agents; D000077866:Clofarabine; D003520:Cyclophosphamide; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine",
"country": "Japan",
"delete": false,
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"issue": "108(3)",
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"keywords": "AML; Induction failure; Transplantation",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000227:Adenine Nucleotides; D000328:Adult; D001087:Arabinonucleosides; D002066:Busulfan; D000077866:Clofarabine; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D015470:Leukemia, Myeloid, Acute; D008297:Male; D012074:Remission Induction; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical; D016896:Treatment Outcome; D047368:Tumor Burden; D014740:Vidarabine",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Clofarabine followed by haploidentical stem cell transplant using fludarabine, busulfan, and total-body irradiation with post-transplant cyclophosphamide in non-remission AML.",
"title_normalized": "clofarabine followed by haploidentical stem cell transplant using fludarabine busulfan and total body irradiation with post transplant cyclophosphamide in non remission aml"
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"abstract": "To describe an unusual immune-related adverse event (irAE), acquired generalized lipodystrophy (AGL), from checkpoint inhibitor therapy in a patient treated with pembrolizumab.\nThis is a case report of a 67-year-old male with metastatic melanoma who was treated with pembrolizumab. Prior to pembrolizumab, the patient was treated with another immune-checkpoint inhibitor and developed autoimmune hemolytic anemia. After starting pembrolizumab, he developed a scrotal mass consistent with panniculitis and after several subsequent cycles, he developed AGL.\nLoss of subcutaneous fat, unexplained weight loss in combination with worsening insulin resistance and worsening hypertriglyceridemia after initiation of pembrolizumab were consistent with AGL. Autoimmune disorders and other etiologies were ruled out. Despite this irAE, the patient continued to receive pembrolizumab given stabilization of melanoma with treatment.\nWe report the second case of a patient who developed AGL secondary to pembrolizumab, and the fourth case to report such complication secondary to antiprogrammed cell death receptor-1 inhibitors. As use of checkpoint inhibitors becomes more common to treat several types of cancer, it is vital for clinicians to recognize these rare irreversible complications that are not frequently reported in clinical trials.",
"affiliations": null,
"authors": "Bedrose|Sara|S|;Turin|Christie G|CG|;Lavis|Victor R|VR|;Kim|Sang T|ST|;Thosani|Sonali N|SN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/ACCR-2019-0234",
"fulltext": null,
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"issn_linking": "2376-0605",
"issue": "6(1)",
"journal": "AACE clinical case reports",
"keywords": null,
"medline_ta": "AACE Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101670593",
"other_id": null,
"pages": "e40-e45",
"pmc": null,
"pmid": "32524008",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "15028826;30814440;30283460;28689073;27761609;29704234;29644599;31077337;30649742;3688906;30788189;9724849;27710244;30779841;16502214;19096512;22068254;31434650",
"title": "A CASE OF ACQUIRED GENERALIZED LIPODYSTROPHY ASSOCIATED WITH PEMBROLIZUMAB IN A PATIENT WITH METASTATIC MALIGNANT MELANOMA.",
"title_normalized": "a case of acquired generalized lipodystrophy associated with pembrolizumab in a patient with metastatic malignant melanoma"
} | [
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"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-2022-026948",
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"activesubstancename": "NIVOLUMAB"
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"abstract": "OBJECTIVE\nPrevious studies have shown that docetaxel and cisplatin, as single agents, are effective and relatively well tolerated in patients with advanced gastric cancer. The aim of this study was to assess efficacy and toxicity of a biweekly regimen of docetaxel plus cisplatin in patients with advanced gastric cancer.\n\n\nMETHODS\nFifty-five patients with histologically proven advanced gastric cancer with at least 1 measurable lesion and ECOG PS ≤ 2 were enrolled. Patients received docetaxel 50 mg/m(2) and cisplatin 50 mg/m(2) every 2 weeks until progression disease, unbearable toxicity or a maximum of 12 cycles.\n\n\nRESULTS\nIn total, 426 cycles were administered (median 8.5 cycles) to 52 evaluable patients. One patient (1.9 %) showed a complete response, while 21 (40.4 %) had partial responses. The objective response rate was 42.3 % (95 % CI 28.9-55.7), the median time to progression was 5.5 months (95 % CI 4.0-7.0), and the median overall survival was 8.9 months (95 % CI 6.0-11.9). The most common grade 3-4 toxicities per cycle were haematological [neutropenia (5.9 %)].\n\n\nCONCLUSIONS\nBiweekly administration of docetaxel and cisplatin in advanced gastric cancer has a manageable toxicity profile and shows a promising antitumour activity as a first-line therapy.",
"affiliations": "Hospital Universitario Lucus, Augusti, Lugo, Spain.;Complejo Hospitalario Universitario de Vigo, CHUVI, Vigo, Spain.;Complejo Hospitalario Universitario de Vigo, CHUVI, Vigo, Spain.;Complejo Hospitalario de Ourense, CHOU, Ourense, Spain.;Complejo Hospitalario Universitario de Santiago, CHUS, Santiago de Compostela, Spain.;Hospital Universitario Lucus, Augusti, Lugo, Spain.;Complejo Hospitalario Universitario de Vigo, CHUVI, Vigo, Spain.;Complejo Hospitalario Universitario de Vigo, CHUVI, Vigo, Spain.;Complejo Hospitalario de Ourense, CHOU, Ourense, Spain. afm1003@hotmail.com.;Hospital Universitario Lucus, Augusti, Lugo, Spain.;Complejo Hospitalario Universitario de Vigo, CHUVI, Vigo, Spain.;Complejo Hospitalario Universitario de Vigo, CHUVI, Vigo, Spain.;Complejo Hospitalario Universitario de Vigo, CHUVI, Vigo, Spain.;Complejo Hospitalario Universitario de Santiago, CHUS, Santiago de Compostela, Spain.;Hospital Universitario Lucus, Augusti, Lugo, Spain.",
"authors": "Quintero-Aldana|G|G|;Jorge|M|M|;Grande|C|C|;Salgado|M|M|;Gallardo|E|E|;Varela|S|S|;López|C|C|;Villanueva|M J|MJ|;Fernández|A|A|;Alvarez|E|E|;González|P|P|;Castellanos|J|J|;Casal|J|J|;López|R|R|;Campos Balea|B|B|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-015-2839-z",
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"issue": "76(4)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Advanced gastric cancer; Cisplatin; Combination chemotherapy; Docetaxel",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma; D002945:Cisplatin; D000077143:Docetaxel; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia; D010166:Palliative Care; D013030:Spain; D013274:Stomach Neoplasms; D016019:Survival Analysis; D043823:Taxoids",
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"other_id": null,
"pages": "731-7",
"pmc": null,
"pmid": "26242221",
"pubdate": "2015-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase II study of first-line biweekly docetaxel and cisplatin combination chemotherapy in advanced gastric cancer.",
"title_normalized": "phase ii study of first line biweekly docetaxel and cisplatin combination chemotherapy in advanced gastric cancer"
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"companynumb": "ES-SA-2015SA126283",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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"abstract": "OBJECTIVE\nTo investigate the types, frequency and clinical profiles of uveitic glaucoma seen at a tertiary care center and also to have an idea about the distribution of uveitic glaucoma types in Turkish population.\n\n\nMETHODS\nConsecutive case notes of all patients attending a specialized uveitis clinic over a 3-month period were reviewed retrospectively.\n\n\nRESULTS\nOne hundred and seven eyes of 96 patients were included. Sixty-five of the eyes had anterior, one intermediate, nine posterior uveitis while 32 of them had panuveitis. Twenty-three eyes had acute, 52 chronic and 32 recurrent uveitis. Herpes virus associated iridocyclitis was the leading cause of anterior uveitis-associated uveitic glaucoma followed by cytomegalovirus (CMV) associated anterior uveitis; while steroid-induced glaucoma accounted for the majority of chronic uveitis with glaucoma followed by Fuchs' uveitis syndrome (FUS). The most common causes of glaucoma among the cases were steroid-induced in 30 eyes (28%), Herpes virus anterior uveitis in 24 eyes (22%), CMV anterior uveitis in 20 eyes (18%), FUS in 15 eyes (14%), ocular toxoplasmosis in 5 eyes (4%). Behçet's uveitis was the most common (n = 11, 36%) cause of steroid-induced glaucoma. The need for surgical intervention was 23.32% (n = 25; 12 of them were FUS, 8 steroid-dependent, 1 HSV and 3 CMV anterior uveitis and 1 angle closure glaucoma with idiopathic uveitis) in our cases.\n\n\nCONCLUSIONS\nUveitic glaucoma is a common complication in a tertiary clinic. The most common causes are steroid-induced, FUS, viral anterior uveitis. The most common disease causing steroid induced glaucoma was Behçet's disease. Glaucoma surgery is required in a significant number of cases.",
"affiliations": "University of Health Sciences Turkey, Beyoglu Eye Training and Research Hospital, Bereketzade Street Number: 2, Beyoglu, Istanbul, Turkey. cigdem_altan@yahoo.com.;University of Health Sciences Turkey, Beyoglu Eye Training and Research Hospital, Bereketzade Street Number: 2, Beyoglu, Istanbul, Turkey.",
"authors": "Altan|Cigdem|C|http://orcid.org/0000-0002-0908-6619;Basarir|Berna|B|http://orcid.org/0000-0002-4948-948X",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-021-01783-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "41(6)",
"journal": "International ophthalmology",
"keywords": "Aetiology of uveitic glaucoma; Glaucoma; Uveitic glaucoma; Uveitis",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D005901:Glaucoma; D006801:Humans; D015863:Iridocyclitis; D012189:Retrospective Studies; D014605:Uveitis; D014606:Uveitis, Anterior",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "2225-2234",
"pmc": null,
"pmid": "33730317",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "24682184;31354205;32799547;28087345;19477709;20857175;26558280",
"title": "Aetiology and clinical characteristics of uveitic glaucoma in Turkish patients.",
"title_normalized": "aetiology and clinical characteristics of uveitic glaucoma in turkish patients"
} | [
{
"companynumb": "TR-LUPIN PHARMACEUTICALS INC.-2021-13308",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
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"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of androgens to estrogens in peripheral tissues. It is used as adjuvant therapy for early-stage hormone-sensitive breast cancer in postmenopausal women. Significant side effects of anastrozole include osteoporosis and increased levels of cholesterol. To date, seven case reports on anastrozole hepatotoxicity have been published. We report the case of an 81-year-old woman with a history of breast cancer, arterial hypertension, type 2 diabetes mellitus, hyperlipidemia, and chronic renal insufficiency. Four days after switching hormone therapy from tamoxifen to anastrozole, icterus developed along with a significant increase in liver enzymes (measured in the blood). The patient was admitted to hospital, where a differential diagnosis of jaundice was made and anastrozole was withdrawn. Subsequently, hepatic functions quickly normalized. The observed liver injury was attributed to anastrozole since other possible causes of jaundice were excluded. However, concomitant pharmacotherapy could have contributed to the development of jaundice and hepatotoxicity, after switching from tamoxifen to anastrozole since several the patient's medications were capable of inhibiting hepatobiliary transport of bilirubin, bile acids, and metabolized drugs through inhibition of ATP-binding cassette proteins. Telmisartan, tamoxifen, and metformin all block bile salt efflux pumps. The efflux function of multidrug resistance protein 2 is known to be reduced by telmisartan and tamoxifen and breast cancer resistance protein is known to be inhibited by telmisartan and amlodipine. Moreover, the activity of P-glycoprotein transporters are known to be decreased by telmisartan, amlodipine, gliquidone, as well as the previously administered tamoxifen. Finally, the role of genetic polymorphisms of cytochrome P450 enzymes and/or drug transporters cannot be ruled out since the patient was not tested for polymorphisms.",
"affiliations": "Third Faculty of Medicine, Department of Pharmacology, Charles University, Prague, Czech Republic and Faculty of Medicine, Department of Pharmacology and Toxicology, Charles University, Pilsen, Czech Republic.;2nd Department of Internal Medicine, University Hospital Královské Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.",
"authors": "Potmešil|Petr|P|https://orcid.org/0000-0003-2855-848X;Szotkowská|Radka|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2040622320964152",
"fulltext": "\n==== Front\nTher Adv Chronic Dis\nTher Adv Chronic Dis\nTAJ\nsptaj\nTherapeutic Advances in Chronic Disease\n2040-6223\n2040-6231\nSAGE Publications Sage UK: London, England\n\n10.1177/2040622320964152\n10.1177_2040622320964152\nCase Report\nDrug-induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes\nhttps://orcid.org/0000-0003-2855-848X\nPotmešil Petr Third Faculty of Medicine, Department of Pharmacology, Charles University, Prague, Czech Republic and Faculty of Medicine, Department of Pharmacology and Toxicology, Charles University, Pilsen, Czech Republic\n\nSzotkowská Radka 2nd Department of Internal Medicine, University Hospital Královské Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic\n\npetr.potmesil@lf3.cuni.cz\n16 11 2020\n2020\n11 20406223209641529 6 2020\n15 9 2020\n© The Author(s), 2020\n2020\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nAnastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of androgens to estrogens in peripheral tissues. It is used as adjuvant therapy for early-stage hormone-sensitive breast cancer in postmenopausal women. Significant side effects of anastrozole include osteoporosis and increased levels of cholesterol. To date, seven case reports on anastrozole hepatotoxicity have been published. We report the case of an 81-year-old woman with a history of breast cancer, arterial hypertension, type 2 diabetes mellitus, hyperlipidemia, and chronic renal insufficiency. Four days after switching hormone therapy from tamoxifen to anastrozole, icterus developed along with a significant increase in liver enzymes (measured in the blood). The patient was admitted to hospital, where a differential diagnosis of jaundice was made and anastrozole was withdrawn. Subsequently, hepatic functions quickly normalized. The observed liver injury was attributed to anastrozole since other possible causes of jaundice were excluded. However, concomitant pharmacotherapy could have contributed to the development of jaundice and hepatotoxicity, after switching from tamoxifen to anastrozole since several the patient’s medications were capable of inhibiting hepatobiliary transport of bilirubin, bile acids, and metabolized drugs through inhibition of ATP-binding cassette proteins. Telmisartan, tamoxifen, and metformin all block bile salt efflux pumps. The efflux function of multidrug resistance protein 2 is known to be reduced by telmisartan and tamoxifen and breast cancer resistance protein is known to be inhibited by telmisartan and amlodipine. Moreover, the activity of P-glycoprotein transporters are known to be decreased by telmisartan, amlodipine, gliquidone, as well as the previously administered tamoxifen. Finally, the role of genetic polymorphisms of cytochrome P450 enzymes and/or drug transporters cannot be ruled out since the patient was not tested for polymorphisms.\n\nanastrozole\nbreast carcinoma\ncholestasis\ndrug–drug interactions\ndrug-induced liver injury\ncover-dateJanuary-December 2020\ntypesetterts1\n==== Body\nIntroduction\n\nTamoxifen is a mixed estrogenic antagonist/partial agonist that is used in breast cancer to block the estrogenic stimulation of tumor cell growth.1 Anastrozole is a selective third-generation aromatase inhibitor.2,3 Anastrozole competitively inhibits the enzyme cytochrome P450 (CYP) 19A1, which converts androgens, produced in the adrenal glands, to estrogens.4 Therefore, aromatase inhibition leads to a decrease in the concentration of estrogens in serum and breast cancer tissue, which slows tumor growth. Anastrozole is indicated for adjuvant treatment of advanced breast cancer, in postmenopausal women, following tamoxifen therapy.4,5 Unlike tamoxifen, aromatase inhibitors do not increase the risk of thromboembolic complications.2,5 Both tamoxifen and anastrozole are extensively metabolized by several CYP enzymes.6 After enterohepatic circulation, metabolites of tamoxifen appear in the stool. The major excretory pathway for anastrozole is the liver and biliary tract.3,6 Drug-induced liver injury (DILI) is a serious medical condition that can be induced by various medicinal products. It can be caused by anti-infective drugs such as amoxicillin/clavulanate, isoniazid, and certain macrolide antibiotics. It is also caused by anti-seizure drugs (carbamazepine, valproate), immune modulators (interferon-alpha, methotrexate), non-steroidal anti-inflammatory drugs (diclofenac and nimesulide), antidepressants (agomelatine), and certain tyrosine-kinase inhibitors.7–11 Three major types of DILI have been described: hepatocellular, cholestatic, and mixed liver injury due to a major underlying mechanism.12,13 The fourth type of hepatotoxicity, that is, indirect liver injury, is not a completely accepted category of DILI.14 In the United States, pharmaceuticals were linked to about 20% of the jaundice cases seen in the elderly in the year 2000.15,16\n\nCase report\n\nWe report the case of an 81-year-old woman who presented with a history of breast carcinoma pT1a pN0 M0, G1, ER 100%, PR 80%, HER2 negative, KI-67 10–15%. In November 2015, she underwent breast resection followed by radiotherapy and was treated with tamoxifen thereafter. The patient had regular follow-ups without signs of disease reoccurrence. In addition, she was treated for arterial hypertension, type 2 diabetes mellitus, chronic renal insufficiency, hyperlipidemia, and non-alcoholic fatty liver disease. The patient was admitted to the hospital in September 2016 for painless icterus that had started 2 days prior. She was afebrile, weak, tired, and dehydrated at the time of admission. She described nausea and abdominal discomfort in the epigastrium; palpation found no pain or tenderness. Serum analysis found hyperbilirubinemia and elevated levels of ALT, AST, ALP, and GGT (Table 1). C-reactive protein was mildly elevated but, without leukocytosis, there was a progression of her chronic renal insufficiency as well as asymptomatic bacteriuria.\n\nTable 1. The patient’s laboratory results (2016).\n\nParameter\tUnits\tReference interval\t14 April\t8 September\t9 September\t10 September\t12 September\t18 October\t\nBilirubin\tμmol/L\t<21\t11.9\t132.8\t106.1\t85.8\t68.7\t17.8\t\nALT\tµkat/L\t<0.73\t0.54\t2.14\t1.77\t1.68\t1.42\t0.4\t\nAST\tµkat/L\t<0.67\t0.92\t3.13\t2.48\t2.38\t1.84\t0.89\t\nALP\tµkat/L\t0.66–2.20\t1.16\t2.56\t2.28\t2.31\t2.19\t1.47\t\nGGT\tµkat/L\t<1.10\t3.22\t7.35\t6.56\t6.98\t7.16\t4.1\t\nCreatinine\tμmol/L\t46–90\t162\t200\t197\t207\t135\t157\t\nALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase.\n\nAbnormal values are shown in bold.\n\nThe patient’s medical history showed that the patient’s oncologist had changed her hormone therapy 4 days prior to symptom onset. The oncologist switched tamoxifen, which the patient had taken for more than 1 year, to anastrozole. Other medications, which the patient had been taking for several years, remained unchanged. At the time of her visit to her oncologist, the patient was symptom-free, had no reported problems, and none of the examinations, including a computer tomography scan, indicated a relapse of her oncologic disease. During hospitalization, a differential diagnosis of the icterus was made, mainly because elevated conjugated bilirubin; the blood count was normal (without atypical blood cells or blast cells), a diagnosis of hemolytic anemia was excluded. Due to the rapid onset of the disease and well-documented normal liver function only a few weeks before neither autoimmune hepatitis nor primary biliary sclerosis were considered as possible underlying causes of her jaundice. An abdominal ultrasound was performed to exclude a bile duct obstruction and liver metastases; the examination found liver steatosis and minor cholecystolithiasis [without dilatation of the common bile duct (ductus hepatocholedochus) or the bile ducts]. Both disorders had been described in the past. In addition, neither the inferior vena cava nor the hepatic veins were dilated, and there were no signs of blood congestion found in the venous system of the liver. Coagulation parameters were also completely normal; the patient had not traveled outside the Czech Republic during the previous 5 years, there was no history of risky contacts, and no fever or abdominal pain before admission to the hospital. Infectious hepatitis A, B, and C were excluded serologically. For the previously mentioned reasons, DILI was considered as a primary possible cause of her icterus and abnormal liver function tests. During hospitalization, the patient received intravenous hydration and was put on bed rest. After consulting her oncologist, anastrozole therapy was withdrawn and her statin and metformin medications were temporarily suspended. After 5 days, there was a significant decrease in her bilirubin and liver enzyme levels and the patient was discharged home. At the 1 month post-discharge outpatient follow up, hepatic parameters had already returned to her normal long-term baseline. The time course of the patient’s bilirubin concentrations and levels of liver transaminases, alkaline phosphatase, and gamma glutamyl transferase are shown in Figure 1. The time course of the patient’s creatinine and urea concentrations are shown in Figure 2.\n\nFigure 1. Axis Y: concentrations of bilirubin and enzymes ALT, AST, ALP, and GGT are plotted in multiples of the upper limits of the normal values. Axis X: time – dates of measurement in 2015 and 2016. Medicinal product Anaprex® containing anastrozole was started on 5 September 2016 and withdrawn on 8 September 2016.\n\nFigure 2. Axis Y: concentrations of creatinine and urea in serum are plotted in multiples of the upper limits of the normal values. Axis X: time – dates of measurement of creatinine and urea concentrations in 2015 and 2016. Medicinal product Anaprex® containing anastrozole was started on 5 September 2016 and withdrawn on 8 September 2016.\n\nDiscussion\n\nClinical point of view\n\nDILI\n\nIt can be difficult to accurately identify the drug causing a serious adverse drug reaction when the patient is taking multiple medications. Proving that an episode of liver injury is caused by a specific drug can be challenging because other diseases of the liver and biliary system can produce a similar clinical picture. Thus differential diagnosis of DILI requires several separate supportive assessment variables that collectively lead to a high level of certainty, including a temporal association with the time of onset, time to resolution, biochemical findings, phenotype of the hepatic injury and extrahepatic features, and the likelihood that the suspect agent is to blame based on its drug safety record.17 The first case of anastrozole-induced hepatitis was reported in 2006.18 To date, six more case reports have entered the literature, bringing the total number of case reports describing anastrozole hepatotoxicity to seven.19–24 If we consider how many women use anastrozole around the world, this complication is very rare. That said, anastrozole is known to be associated with the development of fatty liver disease.25 A Chinese randomized study by Lin et al. showed that anastrozole-induced fatty liver disease occurs less often than with tamoxifen (cumulative incidence of 9.6% versus 32.6% after 3 years of treatment, respectively) and that both of these drugs could similarly affect liver function.25 In most cases, there was only a slight elevation of liver enzymes (classified as grade 1 or 2 according to NCI Common Terminology Criteria for Adverse Events); however, testing for HBV infection was not done and a history of diabetes and/or hyperlipoproteinemia, as risk factors for liver steatosis, were not taken into account. An Italian tamoxifen chemoprevention trial showed that in women taking a placebo the incidence of abnormal ALT was low, while in tamoxifen-treated women ALT was elevated, and levels ⩾ 1.5 times the normal upper limit were associated with steatohepatitis.26\n\nIn 2014 Chalasani et al. and in 2019 the European Association for the Study of the Liver published clinical practice guidelines for diagnosis and management of DILI.9,13 According to the recommendations in these guidelines we calculated an ALT/ALP ratio (R), value of R for our patient was 2.5; R = (patient’s ALT/upper limit of normal of ALT) divided by (patient’s ALP/upper limit of normal of ALP). R-values > 5 indicate a hepatocellular injury, 2–5 indicate a mixed injury, and <2 indicate a cholestatic injury.9,13 Thus, the liver injury in our patient was classified as mixed. When the Roussel Uclaf Causality Assessment Method was used to assess the causality of our patient’s DILI, the final score was 6 points; therefore, her DILI was probably due to the anastrozole therapy.27 When we used the Naranjo Algorithm Assessment to estimate the probability of an adverse drug reaction to anastrozole, the final Naranjo score was 5, indicating that an adverse drug reaction to anastrozole was probable.28 The rapid onset of DILI after switching from tamoxifen to anastrozole (over several days) might provide a clue that anastrozole caused the DILI mainly through hypersensitivity that is, the immune-allergic mechanism.29\n\nHost risk factors\n\nOlder age is also a risk factor for DILI since aging decreases cytochrome mediated hepatic metabolism and older patients more often present with a cholestatic pattern of liver injury compared with younger individuals.12,13,30 Patient gender may also influence the risk of DILI; for example, the immune-mediated model of DILI found more severe hepatitis in females.12,29,30 Our patient was an 81-year-old woman with advanced chronic kidney disease (CKD G4), which could have contributed to the hepatotoxic side effects by reducing renal clearance of the various medication she was taking, resulting in higher plasma levels. As such, our patient had several risk factors that enhanced susceptibility to DILI before taking her first dose of anastrozole. In our case, a liver biopsy was not performed because of the quick resolution of jaundice and the rapid improvement in her liver function tests after anastrozole was withdrawn.\n\nPharmacological point of view\n\nAccording to the Arimidex® summary of product characteristics, changes in liver function tests with or without jaundice occurs in less than 1 in 10,000 patients. Renal elimination is not a significant route of elimination for anastrozole; thus, anastrozole clearance remains unchanged even with renal impairment. The pharmacokinetic parameters of anastrozole can be affected by drug interactions via the CYP system but the parameters are not known to be altered by co-administration of tamoxifen.6 However, we found results from older literature showing that concomitant application of tamoxifen and anastrozole can lower the concentration of anastrozole.22 Be that as it may, no new safety concerns were reported after completion of the large ATAC trial in 2010 that compared the efficacy and safety of anastrozole (1 mg daily) taken together with tamoxifen (20 mg daily), both given orally every day for 5 years with a median follow-up of 120 months.31 Our patient took anastrozole for only 4 days, therefore, it was unlikely that a drug taken concomitantly with anastrozole could significantly increase anastrozole concentrations above therapeutic concentrations, especially since a steady state of anastrozole requires 7 days of repeated dosing. To verify that there were no clinically significant drug–drug interactions occurring, we first checked potential drug–drug interactions using two drug-interactions checkers on a web page maintained for health care professionals, those being UpToDate and Dynamed, (see www.uptodate.com/drug-interactions and www.dynamed.com/drug-interactions; accessed 18 March 2020). Then we made a list of all the drugs being taken by the patient and we reviewed their metabolism using summaries of product characteristics or other reliable information sources, for example, the thirteenth edition of Goodman and Gilman’s The Pharmacological Basis of Therapeutics or the Canadian web-based drug database DrugBank4 (Table 2). We also studied selected systematic reviews and guidelines describing types of DILI13,14,32 as well as articles explaining potential drug–drug interactions associated with membrane transporters.15,16,33–37 Anastrozole is a substrate for the CYP3A4 enzyme, but it is not a substrate for the P-glycoprotein. Amlodipine and gliquidone were identified as inhibitors of both the CYP3A4 enzyme and P-glycoprotein, which could result in an increase in systemic exposure to drugs that are substrates for CYP3A4 and P-glycoprotein. The patient took both of these drugs daily (i.e. 5 mg of amlodipine daily for high blood pressure (maximal recommended dose of amlodipine is 10 mg daily) and 60 mg of gliquidone daily for type II diabetes (maximal recommended dose of gliquidone is 180 mg daily). Neither amlodipine nor gliquidone have been reported to be strong inhibitors of the CYP superfamily of biotransformation enzymes in the medical literature.38\n\nTable 2. Selected biotransformation data for drugs taken by the patient.\n\nDrug name\tMetabolism\tSubstrate of CYP enzymes\tInhibitor of CYP enzymes?\tInductor of CYP enzymes?\tHepatic side effects of the drug written in SPC?\tEffect of renal insufficiency on pharmacokinetics?\tReference SPC, date of SPC revision\tOther references\t\nAmlodipine 5 mg daily\tCYP enzymes\t3A4\tYes: 1A2, 2C9/19, 3A4\tNo\tVery rare\tNo\tAgen® 2016\tWishart et al.4\t\nAnastrozole 1 mg daily\tCYP enzymes, UGT\t3A4/5/7 2C8, 2D6, 2B6\tYes: 1A2, 2C9, 3A4\tNo\tVery rare\tNo\tArimidex®\tHertz et al.,3 Wishart et al.,4 Isaacs et al.39\t\nBetaxolol 20 mg daily\tCYP enzymes\t1A2, 2D6\tYes: 2D6\tNo\tNo\tYes, the dosage should be reduced if creatinine clearance <20 ml/min.\tBetamed® 2013\tWishart et al.4\t\nHydrochlorothiazide 12.5 mg daily\tNot metabolized in the liver\tN/A\tN/A\tN/A\tYes, rare\tYes, hydrochlorothiazide is contraindicated if creatinine clearance <30 ml/min.\tMicardis Plus® Hydrochloro-thiazide Léčiva®\t\t\nGliquidone 60 mg daily\tCYP enzymes\t3A4, 2C9\t3A4\tNo\tNo\tNo\tGlurenorm® 2016\t\t\nMetformin\tNo metabolism, renal route of elimination\tNo\tNo\tNo\tVery rare\tYes\tMetformin Zentiva ® 2017\t\t\nRilmenidine 2 mg daily\tVery modest biotransformation\tYes\tNo\tNo\tno\tNo; if creatinine clearance >15 ml/min.\tTenaxum® 2017\t\t\nRosuvastatin\tCYP enzymes\tMainly 2C9; 2C19, 3A4, 2D6\tNo\tNo\tPossible AST, ALT increase\tNo\tCrestor® 2017\t\t\nPrevious tamoxifen\tCYP enzymes\tMainly 3A4/5,2D6 Then 2B6, 2C9/19\tYes:1A2, 2D6\tNo\tVery rare\tNo\tTamoxifen Ebewe® 2016\tWishart et al.,4 Isaacs et al.39\t\nTelmisartan 80 mg daily\tBy conjugation to acylglucuronide\tNo\tYes: 2C19\tNo\tRare, in Japanese\tNo\tMicardis® 2016\tWishart et al.,4 Weiss et al.36\t\nCYP enzymes, biotransformation enzymes belonging to the cytochrome P450 family; N/A, not applicable; SPC, summary of product characteristics; UGT, uridine diphosphate glucuronosyltransferase. Drugs highlighted in bold were not prescribed during hospitalization.\n\nMechanisms of drug-induced cholestasis\n\nA variety of medications can influence the function of transport proteins in hepatocytes, which can lead to drug-induced cholestasis. Evidence supports the hypothesis that drug-induced functional disorders in hepatic bile acid transporters can lead to intracellular accumulation of bile acids, resulting in cholestatic hepatocyte damage. Bile acids are mainly taken up by the sodium taurocholate co-transporting polypeptide transporter and excreted into the bile by the canalicular efflux transporter bile salt export pump (BSEP). Bilirubin is taken up by 1B1, an organic anion transporter. After bilirubin conjugation, bilirubin glucuronide is excreted into the bile by multidrug resistance protein 2 (MRP2) and transported into the blood by MRP3. Cholestasis or hyperbilirubinemia can be caused by the inhibition of these transporters by certain drugs.40 However, not all drugs that inhibit BSEP cause cholestasis. This might be due to compensatory mechanisms of bile acid transport by the basolateral efflux transporters MRP3 and MRP4, which, under normal conditions, play a minor role, but can be up-regulated during cholestasis. Thus the impaired function of these transporters, by drugs or genetic predisposition, may result in cholestasis when there is also BSEP inhibition.16 In addition, although BSEP is not directly involved in drug metabolism, its inhibition can lead to the development of harmful side effects.40 The oncologic patient in our case report was taking several drugs that had the potential to affect the function of membrane transporters significantly involved with drug pharmacokinetics or involved in the metabolism of bilirubin or bile salts. Telmisartan, which the patient was taking for hypertension, differs from other angiotensin receptor blockers in that it has a strong potential to inhibit several ABC-transporters that are important in the pharmacokinetics: MDR1, (that is P-glycoprotein), MRP2, and BCRP.36 MRP2 is responsible for the active transport of conjugated bilirubin into the bile and is also considered to be the primary transporter that effluxes many drug conjugates across the canalicular membrane of hepatocytes. The MRP2 export pump is also important in excreting drug metabolites and endogenous compounds, such as bilirubin, into the urine.33 Thus inhibition of MRP2 by telmisartan could contribute to the elevation of bilirubin. In addition, telmisartan has also been identified as a BSEP inhibitor.34 By blocking BSEP function, telmisartan could contribute to the accumulation of toxic bile acids inside hepatocytes. In one clinical study, telmisartan, by inhibiting rosuvastatin efflux and mediated by ATP binding cassette transporter G2, was shown to significantly increase systemic exposure to rosuvastatin after single and multiple doses.41 Concomitant use of telmisartan (40 mg daily) and rosuvastatin (10 mg daily) increased the maximum plasma concentration of rosuvastatin by 76% in healthy Chinese volunteers.41 At the time of hospital admission, the patient was taking 80 mg of telmisartan daily and 20 mg of rosuvastatin daily; rosuvastatin was suspended immediately and the dose of telmisartan was reduced to 40 mg daily on the following day. Therefore, telmisartan could have increased systemic exposure to rosuvastatin in our patient before hospital admission; however, our patient was white [ native Czech ] and the study documenting an interaction between telmisartan and rosuvastatin was conducted in Chinese volunteers. In general, statins can increase the risk of hepatic dysfunction including mild elevations of aminotransferases during therapy.42,43 Acute DILI related to rosuvastatin monotherapy is rare.43,44 In our patient, re-introduction of rosuvastatin after resolution of the DILI did not result in an increase in aminotransferases or bilirubin, thus an interaction between telmisartan and rosuvastatin was probably not associated with the hepatotoxicity and cholestasis seen after starting anastrozole. Newer angiotensin II receptor blockers such as olmesartan, telmisartan, and eprosartan have not been linked to cases of hepatotoxicity.45 Even so, there was one interesting case in 2014 that reported a drug–drug interaction between telmisartan and fluvastatin. The patient had a single nucleotide polymorphism that resulted in the decreased function of the MRP2 biliary transporter. Consequently, creatine kinase levels were elevated after combination therapy with telmisartan and fluvastatin. Elevation of transaminase enzymes or bilirubin was not present.46 Like rosuvastatin, tamoxifen is also a BSEP substrate. Tamoxifen inhibits both BSEP and MRP2 – two efflux transporters that move bile into the bile ducts. In addition, tamoxifen also inhibits MRP3 and MRP4, which are basolateral bile acid transporters, the inhibition of which is a known risk factor for the development of cholestasis.16,35,47 Tamoxifen has a very long half-life (4–11 days) and a significantly longer terminal t1/2s for tamoxifen have been observed.39 This means that even after switching from tamoxifen to anastrozole, a significant amount of tamoxifen was still present in our patient and was able to interact with enzymes or drug transporters (i.e. BSEP and MRP2, MRP3, and MRP4). Because the inhibitory potency of BSEP alone is usually not sufficient to determine DILI risk during pharmacotherapy,30 we made a table of known drug and drug metabolite effects on membrane transporters, particularly as they related to hepatobiliary or renal activity (Table 3).48–54\n\nTable 3. Effect of drugs on the transporters involved in pharmacokinetic processes or the handling of bilirubin and bile salts.\n\nTransporter\tBSEP\tBCRP\tMDR1 (P-gp)\tMRP2\tMRP3\tMRP4\tNTCP\tOATP1B1\tOCT1\tDeferm et al.,37 Giacomini and Sugiyama,40 Jansen54\t\nOther name\tABC B11\tABC G2\tABC B1\tABC C2\tABC C3\tABC C4\tSLC10 A1\tSLCO1B1\tSLC22A1\tWishart et al.,4 Konig et al.,33 Deferm et al.,37 Jansen,54 Fernández-Murga et al.55\t\nHepatocyte membrane\tCanalicular apical\tCanalicular apical\tCanalicular apical\tCanalicular apical\tSinusoidal basolateral\tSinusoidal basolateral\tSinusoidal basolateral\tSinusoidal basolateral\tSinusoidal basolateral\tDeferm et al.,37 Jansen,54 Fernández-Murga et al.55\t\nFunction\tEfflux\tEfflux\tEfflux\tEfflux\tEfflux\tEfflux\tUptake\tUptake\tUptake\tDeferm et al.,37 Fernández-Murga et al.55\t\nAmlodipine\t?\tInhibitor\tSubstrate, inhibitor\t?\t?\t?\t?\t?\t?\tWishart et al.,4 Yang et al.,16 Giacomini and Sugiyama,40 Ivanyuk et al.53\t\nAnastrozole\t?\t?\tNon-substrate non-inhibitor\t?\t?\t?\t?\t?\t?\tWishart et al.,4 Yang et al.,16 Giacomini and Sugiyama 40\t\nBetaxolol\t?\t?\tSubstrate non-inhibitor\t?\t?\t?\t?\t?\t?\tWishart et al.,4 Yang et al.16\t\nHydro- chlorothiazide\t?\t?\t?\t?\t?\tRenal MRP4 substrate, inhibitor\t?\t?\t?\tWishart et al.,4 Yang et al.,16 Ivanyuk et al.53\t\nGliquidone\t?\t?\tSubstrate, inhibitor\t?\t?\t?\t?\t?\t?\tWishart et al.,4 Yang et al.16\t\nMetformin\tinhibitor\t?\tNon-substrate, non-inhibitor\t?\t?\t?\t?\t?\tSubstrate, inhibitor\tDeferm et al.,37 Morris and Morse,51 Ivanyuk et al.53\t\nRilmenidine\t?\t?\t?\t?\t?\t?\t?\t?\t?\tWishart et al.,4 Yang et al.16\t\nRosuvastatin\tSubstrate\tSubstrate\tNon-substrate, non-inhibitor\tSubstrate\t?\tSubstrate\tSubstrate\tSubstrate inhibitor\t?\tWishart et al.,4 Giacomini and Sugiyama,40 Hu et al.,41 Corsini and Bortolini,49 Morris and Morse51\t\nprevious tamoxifen\tSubstrate, inhibitor\tSubstrate\tSubstrate: induces MDR1 expression inhibits its action.\tInhibitor\tInhibitor\tInhibitor\t?\t?\tOCTN2, inhibitor\tWishart et al.,4 Keppler,35 Deferm et al.,37 Kock et al.,47 Ivanyuk et al.53\t\nTelmisartan\tInhibitor\tInhibitor\tInhibitor\tInhibitor, substrate\t?\t?\t?\t?\tInhibitor\tWishart et al.,4 Weiss et al.,36 Hu et al.,41 Ivanyuk et al.53\t\nThe other drugs were taken before admission to the hospital and also in the hospital.\n\nBCRP/ABCG2, breast cancer resistant protein/ATP-binding cassette subfamily G2; BSEP/ABCB-11, bile salt export pump/ATP-binding cassette protein subfamily B-11; MDR-1, multidrug resistance protein-1 or P-glycoprotein is an expression for ABCB1; MRP-2/ABCC2, multidrug resistance-associated protein-2/ATP-binding cassette protein subfamily C 2; MRP-3/ABCC3, multidrug resistance-associated protein-3/ATP-binding cassette protein subfamily C-3; MRP-4/ABCC4, multidrug resistance-associated protein-4/ATP-binding cassette protein subfamily C-4; NTCP, sodium taurocholate co-transporter polypeptide that is, solute carrier family 10 transporter A1; OATP1B1, organic anion transport protein 1B1 that is, SLCO 1B1, solute carrier organic anion transporter family member 1B1; OCT1, organic cation transporter, that is, SLC22A1, solute carrier family 22 transporter A1; OCTN2, organic cation/carnitine transporter.\n\n“?” means that information regarding the effect of the drug on the transporter was not found in Drugbank database or in other literature sources specified in the right-hand column of Table 3.\n\nNote: Drugs highlighted in bold (anastrozol, metformin, rosuvastatin and previous tamoxifen) were not prescribed in the hospital.\n\nBesides the potential contribution of impaired bile acid homeostasis, mechanisms such as the immune-mediated hypersensitivity reaction, dose, and lipophilicity of the drug itself, as well as combinations of these factors together with individual risk factors, seem to be important in the onset of acute DILI.56 In addition, drug–drug interactions can alter a drug’s toxicity profile, which could potentially lead to hepatotoxicity. However, causality assessment in DILI cases can be challenging and the “last prescribed drug” cannot be assumed to be the only responsible agent.49 Potential DDIs are especially important in the treatment of older patients who usually have multiple chronic conditions requiring concomitant therapies.56 Physicians should consider the need for inter-professional co-working that would include consultancy with a clinical pharmacologist or pharmacist when investigating potential drug–drug interactions at the level of membrane drug transporters. Computer programs used to analyze drug safety may not be completely up-to-date and often not precise enough to give meaningful information on the impact of inhibitory potencies in the interactive interplay between cytochrome P450 enzymes and transporters.\n\nConclusion\n\nDILI in our patient was most probably an idiosyncratic response to anastrozole since all other common causes of jaundice were excluded. This opinion is substantiated by the rapid improvement of clinical and biochemical findings after ceasing anastrozole therapy. The interplay between the patient’s individual risk factors and the properties of the drugs she had been prescribed prior to anastrozole was potentially an indirect cause of DILI. The combination of her prescribed treatments, as well as the residual tamoxifen in her system, could have contributed to the rapid development of jaundice and hepatotoxicity after being switched to anastrozole. Our research showed that several of the drugs she was taking were able to inhibit the hepatobiliary transport of drugs and drug metabolites as well as affect bilirubin homeostasis. Telmisartan and tamoxifen both block bile salt efflux pumps and MRP2 efflux transporters, which are significantly involved in the transport of bile acids and bilirubin, respectively, from hepatocytes into bile canaliculi. Breast cancer resistance protein is also inhibited by telmisartan and amlodipine. Anastrozole is a substrate for P-glycoprotein and as such, the efflux function of this transporter can be decreased by telmisartan, amlodipine, gliquidone or the previously prescribed tamoxifen. Finally, the role of genetic polymorphisms of the CYP enzymes, which determine the level of drug biotransformations, or the presence of gene polymorphisms that decrease the activity of membrane drug transporters cannot be ruled out since these genetic polymorphisms were not tested for in our patient.\n\nConflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthics approval statement: Ethics committee approval is not required for case reports that do not constitute research at University Hospital of the 3rd Medical Faculty, Charles University. Upon admission to hospital, the patient signed an informed consent for care at the university hospital, which includes consent to anonymous publishing of non-personal data. The anonymity of the patient was completely preserved.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the research project Progress Q35 and Progress Q28 of the Charles University, Prague.\n\nInformed consent: Written informed consent for patient information to be published was provided by the patient.\n\nORCID iD: Petr Potmešil https://orcid.org/0000-0003-2855-848X\n==== Refs\nReferences\n\n1. Luellmann H Mohr K Hein L. (eds). Antiestrogen and antiprogestin active principles. In: Color atlas of pharmacology. 5th ed. Stuttgart, Germany: Thieme, 2018, pp.252–253.\n2. Luellmann H Mohr K Hein L. (eds). Aromatase inhibitors. In: Color atlas of pharmacology. 5th ed. Stuttgart, Germany: Thieme, 2018, pp.254–255.\n3. Hertz DL Henry NL Rae JM. Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients. Pharmacogenomics 2017; 18 : 481–499.28346074\n4. Wishart DS Feunang YD Guo AC , et al DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res 2018; 46 : D1074-D1082.29126136\n5. Anastrozole. In: Brayfield A (ed.) Martindale: the complete drug reference. 39th ed. Pharmaceutical Press, 2017, pp.752–753.\n6. Hilal-Dandan R Brunton LL. (ed.). Natural products in cancer chemotherapy: hormones and related agents. In: Goodman and Gilman’s manual of pharmacology and therapeutics. 2nd ed. New York, NY: McGraw Hill Medical, 2014, pp.1080–1089.\n7. Freiesleben SD Furczyk K. A systematic review of agomelatine-induced liver injury. J Mol Psychiatry 2015; 3 : 4.25932327\n8. Shetty A Cho W Alazawi W , et al Methotrexate hepatotoxicity and the impact of nonalcoholic fatty liver disease. Am J Med Sci 2017; 354 : 172–181.28864376\n9. Chalasani NP Hayashi PH Bonkovsky HL , et al ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014; 109 : 950–966; quiz 67.\n10. Bunchorntavakul C Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis 2017; 21 : 115–134.27842767\n11. Alexander G. Chapter 34 - Liver and biliary tract. In: Bennett PN Brown MJ Sharma P (eds) Clinical pharmacology. 11th ed. Oxford: Churchill Livingstone, 2012, pp.546–556.\n12. DiPaola FW Fontana RJ. Drug-induced liver injury. In: Dooley JS Lok ASF Garcia-Tsao G , et al (eds) Sherlock’s diseases of the liver and biliary system. Hoboken, NJ: John Wiley and Sons Ltd, 2018, pp.468–486.\n13. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol 2019; 70 : 1222–1261.30926241\n14. Hoofnagle JH Bjornsson ES. Drug-induced liver injury - types and phenotypes. N Engl J Med 2019; 381 : 264–273.31314970\n15. Rodrigues AD Lai Y Cvijic ME , et al Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity: mechanistic considerations beyond the direct inhibition of the bile salt export pump. Drug Metab Dispos 2014; 42 : 566–574.24115749\n16. Yang K Kock K Sedykh A , et al An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters. J Pharm Sci 2013; 102 : 3037–3057.23653385\n17. Lee WM Dienstag JL. Toxic and drug-induced Hepatitis. In: Jameson JL Fauci AS Kasper DL , et al (eds) Harrison’s principles of internal medicine. 20th ed. New York, NY: McGraw-Hill Education, 2018.\n18. Zapata E Zubiaurre L Bujanda L , et al Anastrozole-induced hepatotoxicity. Eur J Gastroenterol Hepatol 2006; 18 : 1233–1234.17033446\n19. Lacey R Evans A. An unusual cause of jaundice in a patient with breast cancer. BMJ Case Rep 2014; 2014 : bcr2014205764.\n20. Islam MS Wright G Tanner P , et al A case of anastrazole-related drug-induced autoimmune hepatitis. Clin J Gastroenterol 2014; 7 : 414–417.26184021\n21. Inno A Basso M Vecchio FM , et al Anastrozole-related acute hepatitis with autoimmune features: a case report. BMC Gastroenterol 2011; 11 : 32.21453541\n22. de la Cruz L Romero-Vazquez J Jimenez-Saenz M , et al Severe acute hepatitis in a patient treated with anastrozole. Lancet 2007; 369 : 23–24.17208628\n23. Klapko O Ghoulam E Jakate S , et al Anastrozole-induced autoimmune hepatitis: a rare complication of breast cancer therapy. Anticancer Res 2017; 37 : 4173–4176.28739702\n24. Xie C Abdullah HMA Abdallah M , et al Anastrozole-induced liver injury after a prolonged latency: a very rare complication of a commonly prescribed medication. BMJ Case Rep 2019; 12 : e231741.\n25. Lin Y Liu J Zhang X , et al A prospective, randomized study on hepatotoxicity of anastrozole compared with tamoxifen in women with breast cancer. Cancer Sci 2014; 105 : 1182–1188.24975596\n26. Bruno S Maisonneuve P Castellana P , et al Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. BMJ 2005; 330 : 932.15746106\n27. Danan G Teschke R. Drug-induced liver injury: why is the Roussel Uclaf Causality Assessment Method (RUCAM) still used 25 years after its launch? Drug Saf 2018; 41 : 735–743.29502198\n28. Naranjo CA Busto U Sellers EM , et al A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30 : 239–245.7249508\n29. Lewis JH. Chapter 10 - Drug-induced and toxic liver disease. In: Friedman LS Martin P (eds) Handbook of liver disease. 4th ed. Philadelphia: Elsevier, 2018, pp.130–157.\n30. Chen M Suzuki A Borlak J , et al Drug-induced liver injury: interactions between drug properties and host factors. J Hepatol 2015; 63 : 503–514.25912521\n31. Cuzick J Sestak I Baum M , et al Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010; 11 : 1135–1141.21087898\n32. Watkins PB. Idiosyncratic drug-induced liver injury in patients: detection, severity assessment, and regulatory implications. Adv Pharmacol 2019; 85 : 165–193.31307586\n33. Konig J Muller F Fromm MF. Transporters and drug–drug interactions: important determinants of drug disposition and effects. Pharmacol Rev 2013; 65 : 944–966.23686349\n34. Pedersen JM Matsson P Bergstrom CA , et al Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci 2013; 136 : 328–343.24014644\n35. Keppler D. The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos 2014; 42 : 561–565.24459177\n36. Weiss J Sauer A Divac N , et al Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters. Biopharm Drug Dispos 2010; 31 : 150–161.20222053\n37. Deferm N De Vocht T Qi B , et al Current insights in the complexities underlying drug-induced cholestasis. Crit Rev Toxicol 2019; 49 : 520–548.31589080\n38. Correia MA. Drug biotransformation. In: Katzung BG (ed.) Basic and clinical pharmacology. 13th ed. New York, NY: McGraw-Hill Education, 2015, pp.56–73.\n39. Isaacs C Wellstein A Riedel AT. Hormones and related agents in the therapy of cancer. In: Brunton LL Hilal-Dandan R Knollmann BC (eds) Goodman and Gilman’s: the pharmacological basis of therapeutics. 13th ed. New York, NY: Mc-Graw Hill Education, 2018, pp.1237–1247.\n40. Giacomini KM Sugiyama Y. Membrane transporters and drug response. In: Brunton LL Hilal-Dandan R Knollmann BC (eds) Goodman and Gilman’s: the pharmacological basis of therapeutics. 13th ed. New York, NY: McGraw Hill Medical, 2018, pp.65–83.\n41. Hu M Lee HK To KK , et al Telmisartan increases systemic exposure to rosuvastatin after single and multiple doses, and in vitro studies show telmisartan inhibits ABCG2-mediated transport of rosuvastatin. Eur J Clin Pharmacol 2016; 72 : 1471–1478.27651239\n42. Yebyo HG Aschmann HE Kaufmann M , et al Comparative effectiveness and safety of statins as a class and of specific statins for primary prevention of cardiovascular disease: a systematic review, meta-analysis, and network meta-analysis of randomized trials with 94,283 participants. Am Heart J 2019; 210 : 18–28.30716508\n43. Rosuvastatin. LiverTox: clinical and research information on drug-induced liver injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, 2012.\n44. Shah J Lingiah V Pyrsopoulos N , et al Acute liver injury in a patient treated with Rosuvastatin: a rare adverse effect. Gastroenterology Res 2019; 12 : 263–266.31636777\n45. Devarbhavi H Bonkovsky HL Russo M , et al 56 - Drug-induced liver injury. In: Sanyal AJ Boyer TD Lindor KD , et al (eds) Zakim and Boyer’s hepatology. 7th ed. Philadelphia: Content Repository Only, 2018, pp.844–890.e17.\n46. Meyer zu Schwabedissen HE Siegmund W Kroemer HK , et al Creatine kinase elevation caused by a combination of fluvastatin and telmisartan in a patient heterozygous for the CYP2C9*3 and ABCC2 -24C > T variants: a case report. BMC Res Notes 2014; 7 : 688.25280537\n47. Kock K Ferslew BC Netterberg I , et al Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4. Drug Metab Dispos 2014; 42 : 665–674.24154606\n48. Patel M Taskar KS Zamek-Gliszczynski MJ. Importance of hepatic transporters in clinical disposition of drugs and their metabolites. J Clin Pharmacol 2016; 56 (Suppl. 7 ): S23–S39.27385177\n49. Corsini A Bortolini M. Drug-induced liver injury: the role of drug metabolism and transport. J Clin Pharmacol 2013; 53 : 463–474.23436293\n50. Garzel B Zhang L Huang SM , et al A change in bile flow: looking beyond transporter inhibition in the development of drug-induced cholestasis. Curr Drug Metab 2019; 20 : 621–632.31288715\n51. Morris ME Morse BL. Membrane and drug transporters. In: Roche VF Zito SW Lemke T , et al (eds) Foye’s principles of medicinal chemistry. 8th ed. Wolters Kluwer, 2020, pp.131–154.\n52. Gessner A Konig J Fromm MF. Clinical aspects of transporter-mediated drug–drug interactions. Clin Pharmacol Ther 2019; 105 : 1386–1394.30648735\n53. Ivanyuk A Livio F Biollaz J , et al Renal drug transporters and drug interactions. Clin Pharmacokinet 2017; 56 : 825–892.28210973\n54. Jansen PLM Jaundice and cholestasis. In: Dooley JS Lok ASF Garcia-Tsao G , et al (eds) Sherlock’s diseases of the liver and biliary system. 13th ed. Hoboken, NJ: John Wiley and Sons Ltd, 2018, pp.231–251.\n55. Fernández-Murga ML Petrov PD Conde I , et al Advances in drug-induced cholestasis: clinical perspectives, potential mechanisms and in vitro systems. Food Chem Toxicol 2018; 120 : 196–212.29990576\n56. Schadt HS Wolf A Pognan F , et al Bile acids in drug induced liver injury: key players and surrogate markers. Clin Res Hepatol Gastroenterol 2016; 40 : 257–266.26874804\n\n",
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"journal": "Therapeutic advances in chronic disease",
"keywords": "anastrozole; breast carcinoma; cholestasis; drug-induced liver injury; drug–drug interactions",
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"title": "Drug-induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes.",
"title_normalized": "drug induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes"
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"abstract": "A 54-year-old female living in Europe presented with gait ataxia, dizziness, and bilateral hearing loss. Magnetic resonance imaging (MRI) revealed non-specific white matter changes. The patient's condition gradually deteriorated over two years without diagnosis. The patient continued to decline cognitively and neurologically with worsening ataxia and upper motor neuron signs. Repeat MRI showed worsening white matter changes. Lumbar puncture, not previously done, showed positive Lyme testing. Treatment with intravenous ceftriaxone resulted in marked neurological improvement. Four years after symptom, the patient has short-term memory deficits and chronic fatigue, but is otherwise neurologically, cognitively, and functionally intact. Follow up MRI findings remain largely unchanged. Because cases of intraparenchymal or encephalopathic neuroborreliosis in America are lacking, so are treatment options. We present a rare case and discuss our experience with antibiotic treatment. This case lends evidence to define optimal treatment of this disease, imperative for hastening neurological recovery.",
"affiliations": "Department of Medicine, University of Pittsburgh Medical Center , PA, USA.;Department of Medicine, University of Pittsburgh Medical Center , PA, USA.;Division of Neurology, University of Pittsburgh Medical Center , PA, USA.;Division of Neurology, University of Pittsburgh Medical Center , PA, USA.;Department of Medicine, University of Pittsburgh Medical Center , PA, USA ; Division of Infectious Diseases, University of Pittsburgh Medical Center , PA, USA.",
"authors": "Verma|Vivek|V|;Roman|Matthew|M|;Shah|Disha|D|;Zaretskaya|Marina|M|;Yassin|Mohamed H|MH|",
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"doi": "10.4081/idr.2014.5496",
"fulltext": "\n==== Front\nInfect Dis RepInfect Dis RepIDRInfectious Disease Reports2036-74302036-7449PAGEPress Publications, Pavia, Italy 10.4081/idr.2014.5496Case ReportA Case of Chronic Progressive Lyme Encephalitis as a Manifestation of Late Lyme Neuroborreliosis Verma Vivek 1Roman Matthew 1Shah Disha 2Zaretskaya Marina 2Yassin Mohamed H. 131 Department of Medicine, University of Pittsburgh Medical Center, PA, USA2 Division of Neurology, University of Pittsburgh Medical Center, PA, USA3 Division of Infectious Diseases, University of Pittsburgh Medical Center, PA, USAUniversity of Pittsburgh Medical Center, Mercy Hospital, 10550 Ermire Building, 1400 Locust Street, Pittsburgh, PA 15219, USA. +1.412.232.7798 - +1.412.232.3292. yassinm@upmc.eduContributions: VV and MR analyzed data and patient records, obtained references, prepared figures and table, and overall wrote the manuscript; MZ and MHY supervised the aforementioned and took care of the patient in this case report in an inpatient and outpatient setting.\n\nConflict of interests: the authors declare no potential conflict of interest.\n\n11 12 2014 19 11 2014 6 4 549621 7 2014 30 9 2014 30 9 2014 ©Copyright V. Verma et al.2014Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.A 54-year-old female living in Europe presented with gait ataxia, dizziness, and bilateral hearing loss. Magnetic resonance imaging (MRI) revealed non-specific white matter changes. The patient’s condition gradually deteriorated over two years without diagnosis. The patient continued to decline cognitively and neurologically with worsening ataxia and upper motor neuron signs. Repeat MRI showed worsening white matter changes. Lumbar puncture, not previously done, showed positive Lyme testing. Treatment with intravenous ceftriaxone resulted in marked neurological improvement. Four years after symptom, the patient has short-term memory deficits and chronic fatigue, but is otherwise neurologically, cognitively, and functionally intact. Follow up MRI findings remain largely unchanged. Because cases of intraparenchymal or encephalopathic neuroborreliosis in America are lacking, so are treatment options. We present a rare case and discuss our experience with antibiotic treatment. This case lends evidence to define optimal treatment of this disease, imperative for hastening neurological recovery.\n\nKey words\nLyme neuroborreliosisBorrelia burgdorferiencephalopathy\n==== Body\nIntroduction\nLyme neuroborreliosis (LNB) is an infectious disorder of the nervous system caused by tick-borne spirochetes of the Borrelia burgdorferi sensu lato complex. It can commonly start with a bull’s eye rash (erythema migrans) and can systemically spread, causing arthritis, heart block, and effects in both the central and peripheral nervous systems.1 In Europe, LNB is most often caused by B. garinii, less frequently by B. afzelii, and rarely by B. burgdorferi sensu stricto (which is predominantly in North America).2\nBorrelia subspecies are thus responsible for significant differences in the clinical presentations of LNB observed in North America and Europe. Early LNB can cause lymphocytic meningitis; involvement of cranial and peripheral nerves is reported to occur in 5-15% of untreated patients.2 Late LNB, which is considerably rarer, can involve brain/spinal cord parenchymal inflammation.2,3\n\nThere are important clinical consequences of these different species and their geographic distributions, possibly as a result of differential species pathogenicity, as illustrated in one study.4 Neuroborreliosis is the most common disseminated infection of Lyme disease in Europe, but is infrequently reported in the United States. Furthermore, even though all three aforementioned subspecies exist in Europe, the same study notes that the North American-predominant subspecies (B. burgdorferi sensu stricto) is responsible for only 8-11% of neuroborreliosis cases in Europe.4 Thus, this could explain the fact that reports of neuroborreliosis reported in the US (particularly with encephalopathy, for instance) are rare, especially in the adult population. As a result, optimal treatment regimens of central nervous system (CNS) parenchymal neuroborreliosis are incomplete, according to the American Academy of Neurology (AAN).3 The present case describes a patient with chronic Lyme neuroborreliosis; potentially adding much-needed evidence on effective management of this rare but serious disease.\n\nCase Report\nA 54-year-old Caucasian female with past medical history of uncomplicated migraines first noticed dizziness and ataxic gait in April 2009. The woman, American by nationality, was living with her husband in the Netherlands at the time. Shortly thereafter, she developed bilateral hearing loss and noticed a 20-pound unintentional weight loss over the previous couple months. She was admitted to a hospital in the Netherlands, where reportedly blood work, electroencephalography (EEG), and echocardiogram were normal. Magnetic resonance imaging (MRI) at the time apparently showed nonspecific white matter changes present over both cerebral hemispheres. The patient remained relatively stable until her next episode that occurred in April 2011. A new, sudden-onset gait imbalance triggered further workup. Though magnetic resonance angiography (MRA) was normal, MRI was initially read as being suspicious of an apparent small, acute non-hemorrhagic stroke in the left cerebellar peduncle as well as progressive white matter changes (on a reviewed re-read, it was not read as a stroke). EEG showed sharp waves over the left temporal lobe but no foci of epileptiform activity. Her workup was otherwise unrevealing; it included complete blood count, basic metabolic panel, creatine phosphokinase, lactate, echocardiogram with bubble study, chest radiograph, vasculitis and hypercoagulable profiles. At that time, she was started on aspirin 81 mg daily as well as levetiracetam 250 mg twice daily.\n\nThe patient was then referred to our facility for neurological evaluation. The patient reported subjective generalized weakness/fatigue, but denied any fevers, rash, joint pains, swallowing difficulty, or visual problems. She had no family history of any neurological disorders. Her examination revealed slowed speech, bilateral decrease in hearing, and bilateral non-sustained nystagmus on horizontal gaze. She was alert and oriented times three, but had poor cognition and insight into her disease history. Bilateral dysmetria, ataxic gait, hyperreflexia with nonsustained clonus and bilateral Babinski reflexes were also found on exam. Repeat brain MRI at our facility (Figure 1) showed relatively unchanged scattered round-oval hyperintensities in the subcortical and periventricular white matter, as well as cerebellum and pons. Spinal MRI did not show any lesions. B12 level was low-normal at 242 pg/mL (normal range 200-900), for which she was empirically started on weekly subcutaneous B12 injections (1000 mcg) to make sure B12 levels did not drop and potentially compound symptoms. Lumbar puncture (LP) done at that time revealed normal opening pressure with 200 white blood cells (65% monocytes, 35% neutrophils), zero red blood cells, low glucose level of 11 (serum level 107), and elevated protein 324 mg/dl (normal range 15-45).\n\nThe patient was admitted to the hospital and the infectious diseases service was consulted. Repeat LP two days post-admission showed similar results (yellow-colored fluid, 229 white blood cells (55% monocytes, 45% neutrophils), 12 red blood cells, glucose 14, protein 290). Autoimmune workup was negative for antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor; angiotensin-converting enzyme, aldolase, erythrocyte sedimentation rate, and C-reactive protein levels were normal. Antibodies to cardiolipin, myeloperoxidase-3, proteinase-3, Sjogren-A/B, and paraneoplastic antibodies against neuronal nuclei and Purkinje cells anti-neuronal nuclear antibody (ANNA), and Purkinje cell cytoplasmic antibody (PCCA) were negative. Infectious diseases workup that was negative is listed in Table 1. Screening cerebrospinal fluid (CSF) enzyme-linked immunosorbent assay (ELISA) for Lyme disease was positive at 4.42 (reference range <1.1). A confirmatory Western blot subsequently revealed positive bands at 18, 23, 41, and 58 kDa. Though antibodies were detected in the CSF, polymerase chain reaction (PCR) for Lyme DNA in CSF was negative times two. The overall CSF immunoglobulin (IgG) level was elevated to 65.6 (reference range 0.8 to 7.7), as was the IgG index (0.89, normal <0.6) with oligoclonal bands. CSF myelin basic protein was normal, however. All CSF cultures for bacteria (including mycobacteria) and fungi remained negative.\n\nOn review of these results, the patient was diagnosed with LNB. IV ceftriaxone 2 g daily was administered via a peripherally inserted intravenous catheter (PICC) for 28 days. The patient finished her course of ceftriaxone and followed up as outpatient with both Neurology and Infectious Diseases. After her antibiotic course, the patient noted complete resolution of her ataxia, dizziness, hearing loss, and improvement of weakness/fatigue. Levetiracetam was stopped in March 2012. At the time of last follow-up (March 2013), almost four years after initial symptoms, the patient’s only reported symptoms were chronic fatigue (much improved relative to before antibiotics started), and some impairment in formation of short-term memories. On exam, she does display 0/3 word recall at five minutes, slightly decreased fine motor coordination, and is slightly hyperreflexic (albeit markedly less so compared to initial exam). Otherwise she remains neurologically, cognitively, and functionally intact. Follow up brain MRI showed slight decrease in size of the pontine and cerebellar peduncular lesions, but otherwise no changes (Figure 2).\n\nDiscussion\nThe present patient was probably infected with a European-specific species of Borrelia (B. garinii or B. afzelii); although European in origin, this case adds data to the overall data that is reported in the United States. Though the causative agent was not specifically genotyped, it would not have changed clinical management diagnostically nor therapeutically.\n\nOn radiological review, the main item on the differential diagnosis of the patient’s MRI lesions, and certainly more common in North America, included demyelinating conditions. Hence, multiple sclerosis (MS) should be at the forefront of a differential diagnosis of similar brain lesions, as should other infectious causes (e.g., syphilis and other infectious causes in Table 1). Vitamin B12 deficiency and autoimmune conditions such as systemic lupus erythematosus are important to consider, as well as the rare but frequently missed acute disseminated encephalomyelitis.5\n\nIn this patient, the main distinction that needed to be made was LNB versus MS. Though oligoclonal bands were present on CSF analysis as well, it has been well established that this is an expected finding in LNB.6 The patient had a negative CSF myelin basic protein level, which is a relatively specific marker for MS.7 Additionally, the CSF measles/mumps antibody titer was not elevated, which is a reliable indicator of differentiating LNB from MS.8,9 In our case CSF Lyme DNA PCR was negative, which is a common finding in chronic neuroborreliosis; detection by PCR or CSF culture occurs in only 10-30% of patients.2,10 Furthermore, radiologic findings in this patient are not typical of MS lesions.11 The vast majority of MS cases have at least one ovoid/round and well-demarcated lesion, and periventricular lesions are often perpendicular to the ventricles (Dawson’s fingers); this patient’s lesions were radiologically irregular with ragged borders and ill-defined margins. Moreover, two prominent lesions in this patient (in the cerebellar peduncle and pons) differ from MS lesions that are largely around CSF/ventricular flow. Most importantly, the patient’s clinical status vastly and rapidly improved within weeks of IV antibiotic therapy without any relapse or new symptoms at two year follow up.9 Chronically progressing neurological symptoms that disappeared without exacerbation after antibiotic use (no corticosteroids or newer anti-inflammatory MS agents were used) further points to LNB over MS. Overall, a salient point to glean from this clinical diagnostic process is that often in clinical medicine, some items on the differential diagnosis can never be fully excluded (e.g. recurrent or multiphasic disseminated encephalomyelitis), but based on a constellation of many diverse supporting factors (in this patient, multiple laboratory tests, clinical picture, radiology, and treatment course), a principal diagnosis can indeed be reached.\n\nDiagnosis in this patient was highly suspected based the presence of intrathecal anti-Borrelia antibodies. In accordance with both the European Federation of Neurological Societies and the AAN, the gold standard of LNB diagnosis involves intrathecal anti-Borrelia antibodies together with the clinical patient picture.9,12 Though serum Lyme serology was not checked due to initial suspicion for MS, both aforementioned guidelines endorse that clinically diagnosing LNB is essential. The patient’s rapid and relapse-free improvement for two years after IV ceftriaxone further supports the diagnosis. Additionally, it was uncertain why hypoglycorrhachia was present, which is atypical of LNB, but it could possibly be related to the relatively long duration of the illness in this patient before the diagnosis was made.\n\nAt the time of follow-up, neither Lyme serology nor repeat lumbar puncture for monitoring intrathecal antibodies was done. These have been shown to be of relatively lower yield as follow-up measures because they can be persistently elevated for years after treatment, irrespective of symptomatic remission.13,14 Recent research, however, has helped to identify biomarkers such as CXCL13 with high sensitivity and specificity to identify acute LNB as well as monitor during follow-up.15 This is especially important in rare cases without intrathecal antibody production to cement a diagnosis without perpetuating neurological symptoms. Though further work will need to be done, novel biomarkers remain intriguing options as diagnostic aids for this disease.\n\nIt is also noteworthy that at most recent (2 year) follow-up, the patient’s MRI signals have not changed for the most part (only the signal abnormalities in the pons and cerebellar peduncle improved). More importantly, as long as the patient’s clinical status is (and remains) improved and nearly intact, this is in our opinion of little consequence. It could be possible that because this patient had chronic disease, and/or the nature of the infection, the lesions may never change despite the patient being clinically normal. Indeed, there are radiology reports that support this notion, including one with a five-year follow-up.16\n\nThis case supports the use of parenteral antibiotics to treat this patient, since the patient had an excellent clinical response with 2 g IV ceftriaxone. In terms of antibiotic therapy, our treatment is consistent with recommendations from the Infectious Diseases Society of America and the AAN, though the latter report mentions that there is a dearth of supportive data for cases involving the CNS parenchyma.3,17 Though we continued Levetiracetam for seizure prophylaxis in this patient, we did not use corticosteroids; it is apparent that more research needs to be done on this issue, although the AAN hints that there may be no major impact of using corticosteroids.3 To prevent future cases of delayed diagnosis while the patient has continuing neurological symptoms, it is important for clinicians to keep Lyme disease on the differential diagnosis of any lingering neurological symptoms. This pathogen, possibly depending on the strain, can be very difficult to clear by the immune system. Indeed, animal studies have showed that if Borrelia can survive the initial innate immune response, there are very few barriers to developing long-term infection within distant tissues such as the brain.18 Clinically, this means Lyme disease should be high on a lingering neurological disease differential diagnosis.\n\nLastly, in patients with documented history of LNB, there are salient complications for clinicians to regularly monitor, which this patient displayed as well. As many as 15% of patients can experience chronic symptoms (such as fatigue, depression, memory or concentration defects, and musculoskeletal pain) which can occur years after completion of therapy, despite positive clinical response to initial antibiotic therapy.10,19 Unfortunately, these symptoms do not respond to additional antibiotics, so their administration is largely not warranted; management is best done symptomatically and with gentle reassurance/counseling.10 It is also important for physicians to not completely ignore recurrence of Lyme-specific symptoms (such as erythema migrans), because a small proportion of patients develop recurrent Lyme disease, which is thought to be due to reinfection with a different strain rather than relapse from the previous strain.20 These cases would be managed with repeat antibiotics; management would be as if the patient were Lyme-naïve.\n\nConclusions\nThe present case serves to show that a patient presenting with many neurological deficits not localized to one area must be investigated thoroughly to rule out rare diseases such as LNB. In suspected cases, though data is greatly lacking in the USA, doing a prompt and deep investigation (also ruling out other causes on the differential diagnosis such as multiple sclerosis) is important to provide early treatment for the patient instead of causing lingering and possibly additive neurological deficits. Once diagnosed, however, our experience shows that parenteral antibiotic treatment works quite effectively for near-complete resolution of clinical symptoms, regardless of the predictable persistence of radiologic findings.\n\nFigure 1. Fluid-attenuated inversion recovery - fast spin echo sequence images of the patient’s brain on initial presentation to our hospital. Lesions are present in the periventricular areas (A), white matter (A,B), pons (C, arrow), and middle cerebellar peduncle (left>right, D).\n\nFigure 2. Fluid-attenuated inversion recovery - conventional spin echo sequence images of the patient’s brain at two-year follow-up. Lesions persist in the periventricular areas and white matter (A,B), but show decreased signal in the pons (C) and middle cerebellar peduncle (D) relative to corresponding images in Figure 1.\n\nTable 1. Negative infectious disease workup in this patient.\n\n1\tHerpes simplex virus-1 and -2 PCR, CSF\t\n2\tEpstein-Barr virus PCR, CSF\t\n3\tCytomegalovirus PCR, CSF\t\n4\tMycobacterial stain and culture, CSF\t\n5\tSyphilis, CSF\t\n6\tCryptococcus antigen, CSF\t\n7\tHistoplasma antigen, urine\t\n8\tHIV ELISA, serum\t\n9\tWest Nile virus serology, CSF\t\n10\tLymphocytic choriomeningitis virus serology, CSF\t\n11\tCoxsackievirus serology panel, CSF\t\n12\tMeasles serology, CSF\t\n13\tMumps serology, CSF\t\n14\tSt. Louis encephalitis serology, CSF\t\n15\tEastern/Western equine encephalitis serology, CSF\t\n16\tCalifornia encephalitis serology, CSF\t\n17\tEchovirus serology, CSF\t\n18\tAdenovirus serology, CSF\t\n19\tInfluenza A/B antibody testing, nasopharyngeal swab\t\nPCR, polymerase chain reaction; CSF, cerebrospinal fluid.\n==== Refs\nReferences\n1. Stanek G Wormser GP Gray J Strle F \nLyme borreliosis . Lancet 2012 ;379 :461 -73 .21903253 \n2. Strle F Stanek G \nClinical manifestations and diagnosis of Lyme borreliosis . Curr Probl Dermatol 2009 ;37 :51 -110 .19367097 \n3. Halperin JJ Shapiro ED Logigian E \nPractice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology . Neurology 2007 ;69 :91 -102 .17522387 \n4. Wang G van Dam AP Schwartz I Dankert J \nMolecular typing of Borrelia burgdorferi sensu lato: taxonomic, epidemiological, and clinical implications . Clin Microbiol Rev 1999 ;12 :633 -53 .10515907 \n5. Rocha R Lisboa L Neves J \nNeuroborreliosis presenting as acute disseminated encephalomyelitis . Pediatr Emer Care 2012 ;28 :1374 -6 .\n6. Hansen K Cruz M Link H \nOligoclonal Borrelia burgdorferi-specific IgG antibodies in cerebrospinal fluid in Lyme neuroborreliosis . J Infect Dis 1990 ;161 :1194 -202 .2345300 \n7. Schmutzhard E \nMultiple sclerosis and Lyme borreliosis . Wien Klin Wochenschr 2002 ;114 :539 -43 .12422598 \n8. Heller J Holzer G Schimrigk K \nImmunological differentiation between neuroborreliosis and multiple sclerosis . J Neurol 1990 ;237 :465 -70 .2074447 \n9. Mygland Å Ljøstad U Fingerle V \nEFNS guidelines on the diagnosis and management of European Lyme neuroborreliosis . Eur J Neurol 2010 ;17 :8 -16 .19930447 \n10. Feder HM JrJohnson BJB O’Connell S \nA critical appraisal of chronic Lyme disease . N Engl J Med 2007 ;357 :1422 -30 .17914043 \n11. Miller DH Kesselring J McDonald I \nMagnetic resonance in multiple sclerosis . 1st ed. Cambridge, UK : Cambridge University Press ; 1997 .\n12. Halperin JJ Logigian EL Finkel MF Pearl RA \nPractice parameters for the diagnosis of patients with nervous system Lyme borreliosis (Lyme disease) . Neurology 1996 ;46 :619 -27 .\n13. Hammers-Berggren S Hansen K Lebech AM Karlsson M \nBorrelia burgdorferi-specific intrathecal antibody production in neuroborreliosis . Neurology 1993 ;43 :169 -75 .8423881 \n14. Hammers-Berggren S Lebech AM Karlsson M \nSerological follow-up after treatment of patients with erythema migrans and neuroborreliosis . J Clin Microbiol 1994 ;32 :1519 -25 .8077398 \n15. Borde JP Meier S Fingerle V \nCXCL13 may improve diagnosis in early neuroborreliosis with atypical laboratory findings . BMC Infect Dis 2012 ;12 :344 .23228054 \n16. Hildenbrand P Craven DE Jones R Nemeskal P \nLyme neuroborreliosis: manifestations of a rapidly emerging zoonosis . Am J Neuroradiol 2009 ;30 :1079 -87 .19346313 \n17. Wormser GP Dattwyler RJ Shapiro ED \nThe clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America . Clin Infect Dis 2006 ;43 :1089 -134 .17029130 \n18. Troy EB Lin T Gao L \nUnderstanding barriers to Borrelia burgdorferi dissemination during infection using massively parallel sequencing . Infect Immun 2013 ;81 :2347 -57 .23608706 \n19. Eikeland R Mygland Å Herlofson K Ljøstad U \nEuropean neuroborreliosis: quality of life 30 months after treatment . Acta Neurol Scand 2011 ;124 :349 -54 .21303350 \n20. Nadelman RB Hanincova K Mukherjee P \nDifferentiation of reinfection from relapse in recurrent Lyme disease . N Engl J Med 2012 ;367 :1883 -90 .23150958\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2036-7430",
"issue": "6(4)",
"journal": "Infectious disease reports",
"keywords": "Borrelia burgdorferi; Lyme neuroborreliosis; encephalopathy",
"medline_ta": "Infect Dis Rep",
"mesh_terms": null,
"nlm_unique_id": "101537203",
"other_id": null,
"pages": "5496",
"pmc": null,
"pmid": "25568755",
"pubdate": "2014-11-19",
"publication_types": "D002363:Case Reports",
"references": "10515907;12422598;17029130;17522387;17914043;19346313;19367097;19930447;2074447;21303350;21903253;23150958;23222106;23228054;2345300;23608706;8077398;8423881;8618716",
"title": "A case of chronic progressive lyme encephalitis as a manifestation of late lyme neuroborreliosis.",
"title_normalized": "a case of chronic progressive lyme encephalitis as a manifestation of late lyme neuroborreliosis"
} | [
{
"companynumb": "US-UCBSA-2016040785",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report a case of globe rupture in a patient with post-laser in situ keratomileusis (LASIK) ectasia after blunt trauma.\n\n\nMETHODS\nObservational case report.\n\n\nRESULTS\nA 42-year-old man with a history of post-LASIK ectasia sustained paracentral corneal rupture secondary to blunt trauma from a fist to his left eye (OS). Slit-lamp examination revealed rupture in the posterior stroma (inferior paracentral) of the OS with an overlying intact LASIK flap; however, the inferior edges of the LASIK flap were Seidel positive. The anterior chamber was flat. Although he was initially managed with cyanoacrylate glue and a bandage contact lens, the patient eventually required tectonic penetrating keratoplasty. The postoperative course was unremarkable, and over 1 year later, the visual acuity OS was 20/25 with -7.50 + 2.00 × 0.50.\n\n\nCONCLUSIONS\nGlobe rupture from blunt trauma has not been shown to be more common in patients with a history of LASIK. Although blunt trauma to the post-LASIK globe would generally incur a similar risk of rupture to that of the normal eye, keratectasia after LASIK may predispose the globe to rupture.",
"affiliations": "*Department of Ophthalmology, Beaumont Health System, Oakland University William Beaumont School of Medicine, Royal Oak, MI; and†Michigan Cornea Consultants, Southfield, MI.",
"authors": "Cheung|Albert Y|AY|;Heidemann|David G|DG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000000973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "35(12)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000328:Adult; D065306:Corneal Injuries; D004108:Dilatation, Pathologic; D006801:Humans; D007640:Keratoconus; D020731:Keratomileusis, Laser In Situ; D015948:Keratoplasty, Penetrating; D008297:Male; D009216:Myopia; D011183:Postoperative Complications; D012421:Rupture; D014792:Visual Acuity; D014949:Wounds, Nonpenetrating",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1662-1664",
"pmc": null,
"pmid": "27467046",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Globe Rupture of a Post-LASIK Keratectasia Eye From Blunt Trauma.",
"title_normalized": "globe rupture of a post lasik keratectasia eye from blunt trauma"
} | [
{
"companynumb": "US-BAYER-2017-018924",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
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"activesubstancename": "MOXIFLOXACIN"
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... |
{
"abstract": "OBJECTIVE\nThe aim of this paper is to report the first case of drug-induced eosinophilic myocarditis (EM) in a patient with hereditary periodic fever syndrome (PFS).\n\n\nMETHODS\nA 28-year-old man with hyper-IgD syndrome, one of the PFS, developed a sulfasalazine-induced systemic hypersensitivity reaction complicated by EM. Thirteen days after sulfasalazine introduction, which had been given for arthritis, the patient developed fever, facial/neck edema, rash and cardiogenic shock, and died within 8 h. The autopsy revealed hemophagocytosis, while acute heart failure caused by necrotizing EM was established as the cause of death.\n\n\nCONCLUSIONS\nThis was a case of drug-induced EM in a patient with PFS that had an atypical presentation, rapid evolution and poor outcome.",
"affiliations": "Institute of Rheumatology, University of Belgrade, Belgrade, Serbia.",
"authors": "Jeremic|Ivica|I|;Vujasinovic-Stupar|Nada|N|;Terzic|Tatjana|T|;Damjanov|Nemanja|N|;Nikolic|Milos|M|;Bonaci-Nikolic|Branka|B|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D012460:Sulfasalazine",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000369584",
"fulltext": "\n==== Front\nMed Princ PractMed Princ PractMPPMedical Principles and Practice1011-75711423-0151S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 2553120410.1159/000369584mpp-0024-0195Case ReportFatal Sulfasalazine-Induced Eosinophilic Myocarditis in a Patient with Periodic Fever Syndrome Jeremic Ivica ac*Vujasinovic-Stupar Nada acTerzic Tatjana bcDamjanov Nemanja acNikolic Milos cdBonaci-Nikolic Branka ceaInstitute of Rheumatology, University of Belgrade, Belgrade, SerbiabInstitute of Pathology, University of Belgrade, Belgrade, SerbiacFaculty of Medicine, University of Belgrade, Belgrade, SerbiadClinics of Dermatovenereology, Clinical Center of Serbia, Belgrade, SerbiaeClinics of Allergy and Clinical Immunology, Clinical Center of Serbia, Belgrade, Serbia* Ivica Jeremic, MD, PhD, Institute of Rheumatology, Resavska 69, RS-11000 Belgrade (Serbia), E-Mail ivicaje@yahoo.com2 2015 16 12 2014 16 12 2014 24 2 195 197 10 12 2013 5 11 2014 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.Objective\nThe aim of this paper is to report the first case of drug-induced eosinophilic myocarditis (EM) in a patient with hereditary periodic fever syndrome (PFS).\n\nCase\nA 28-year-old man with hyper-IgD syndrome, one of the PFS, developed a sulfasalazine-induced systemic hypersensitivity reaction complicated by EM. Thirteen days after sulfasalazine introduction, which had been given for arthritis, the patient developed fever, facial/neck edema, rash and cardiogenic shock, and died within 8 h. The autopsy revealed hemophagocytosis, while acute heart failure caused by necrotizing EM was established as the cause of death.\n\nConclusion\nThis was a case of drug-induced EM in a patient with PFS that had an atypical presentation, rapid evolution and poor outcome.\n\nKey Words\nEosinophilic myocarditisDrug-induced hypersensitivity syndromeSulfasalazineHyper-IgD syndromePeriodic fever syndrome\n==== Body\nIntroduction\nDrug-induced hypersensitivity syndrome (DIHS), also known as drug rash with eosinophilia and systemic symptoms – DRESS – syndrome, is a rare (1/1,000–10,000 exposures) but potentially fatal (10s%) systemic reaction, which occurs 1–8 weeks after exposure to anticonvulsants, sulfasalazine, allopurinol or antiretrovirals, etc. [1]. DIHS typically manifests with a rash and hepatic dysfunction, but may include nephritis, pneumonitis and rarely hemophagocytosis and eosinophilic myocarditis (EM) [1]. Hyper-IgD syndrome, one of the genetically defined periodic fever syndromes (PFS), also known as autoinflammatory syndromes, is characterized by reduced activity of mevalonate kinase and lifelong recurrent febrile attacks of a noninfectious origin [2]. It is not known how exactly a reduced activity of mevalonate kinase leads to PFS, but it has been reported that proinflammatory cytokine production in patients with hyper-IgD syndrome is strongly enhanced [3]. We hereby report a case of DIHS in a patient with PFS.\n\nCase Report\nA 28-year-old man presented to the Emergency Department of the Clinical Center of Serbia, Belgrade, with fever of 39.9°C, facial/neck edema, erythematous rash, cervical lymphadenopathy, malaise and shortness of breath that had commenced 24 h previously. He was tachycardic with a gallop rhythm, had dull heart sounds, and was tachypneic (20/min) and hypotensive (60/10 mm Hg). No murmurs or rubs were present. An electrocardiogram showed sinus tachycardia (150/min) with occasional premature ventricular extrasystoles. The patients' personal history revealed PFS present since childhood. He had had febrile attacks once a month, accompanied with cervical lymphadenopathy, abdominal cramps and arthritis. His febrile attacks had been treated with nonsteroid anti-inflammatory drugs and short prednisone courses. Previous attacks had been associated with high inflammatory markers, anemia and mild hepatosplenomegaly. His heart function had always been normal. He had been treated with sulfasalazine (500 mg t.i.d.) for ankle joint arthritis 2 weeks before this latest admission.\n\nOn admission, blood tests revealed leukocytosis 18.4 × 109 (78s% neutrophils without eosinophilia and atypical lymphocytes) and the following elevated inflammatory markers: C-reactive protein (151 mg/l), ferritin (19,455 μg/l), creatine kinase (313 U/l), MB (muscle brain) creatine kinase isoenzyme (81 U/l), troponin T (1.6 μg/l), aspartate aminotransferase (287 U/l) and alanine aminotransferase (238 U/l). Metabolic acidosis (HCO3 4.6 mmol/l, pH 7.16, pCO2 1.7 kPa) was present. Chest X-rays showed cardiac enlargement. Plasma N-terminal pro-B-type natriuretic peptide was also elevated at 215 ng/l (normal is <100 ng/l).\n\nA diagnosis of cardiogenic shock was made and therapy with oxygen, fluids, inotropic agents, methylprednisolone (120 mg i.v.) and antibiotics was initiated. Despite this treatment, the patient died 8 h after admission.\n\nThe autopsy revealed EM with prominent interstitial edema and inflammatory infiltrate composed of eosinophils and mononuclear cells (fig. 1a, b). Vascular congestion of alveolar wall capillaries and alveolar damage were present (fig. 1c). Eosinophilic infiltrates were found in the stomach and skeletal muscles, while massive hemophagocytosis was observed in bone marrow and lymph nodes (fig. 1d). Acute heart failure caused by EM followed by pulmonary edema was established as the cause of death. The diagnosis of DIHS was confirmed by the first 5 of the following 6 diagnostic criteria: (i) a maculopapular rash developing 2–6 weeks after starting new therapy, (ii) lymphadenopathy, (iii) fever (>38°C), (iv) leukocytosis >10 × 109/l (without atypical lymphocytes and eosinophilia but with prominent tissue eosinophilia), (v) hepatitis (alanine aminotransferase, ALT >100 U/ml) and (vi) human herpes virus 6 reactivation (not tested) [1]. Genetic testing results, which were received postmortem, showed two heterozygous mutations in the gene for mevalonate kinase in exone 11 (C.1129G>A leading to P.V377I) and exone 6 (C.564.G>A leading to P.W188X) localized on 12q24.11, thus confirming hyper-IgD syndrome as one of the genetically defined hereditary periodic fever syndromes.\n\nDiscussion\nOur patient with PFS had a fulminant presentation of EM, with the first symptoms occurring 13 days after the drug introduction, with cardiogenic shock and fatal outcome in the next 24 h. EM is an under-recognized manifestation of DIHS that may occur in an acute form or can lead to progressive heart failure [4,5]. Ampicillin, aromatic anticonvulsants and allopurinol are most frequently responsible for cardiac involvement in DIHS [5]. Myocarditis associated with DIHS often occurs one to several months later and even after the offending drug has been discontinued [5]. Myocardial injury is mediated by toxic cationic proteins, oxygen metabolites and lipid mediators produced by eosinophils [5].\n\nAcute necrotizing EM is a rare and severe complication of DIHS that usually presents with acute chest pain, ST-segment elevation and an increase in cardiac enzymes, frequently with rapid deterioration of systolic function and a mortality rate above 50s% [4]. Pericarditis and cardiac arrhythmias are also possible presentations [5]. In most cases the diagnosis is established on autopsy.\n\nNecrotizing EM, presenting as acute myocardial infarction, has been described in a patient with ankylosing spondylitis 6 weeks after starting sulfasalazine therapy [6]. Due to the increase of IL-1 family cytokines in hyper-IgD syndrome [3], our patient had the hyperacute course of DIHS.\n\nThe relationship between toxic, viral and immune mechanisms in DIHS remains unresolved. A role of viral reactivation (especially of human herpes virus 6 and cytomegalovirus) is well known [1]. In our patient, contribution of viral reactivation could not be excluded, considering the presence of mixed cellular heart infiltrate and hemophagocytosis. The reactivation of Epstein-Barr virus and hemophagocytosis associated with sulfasalazine treatment have both been described [7].\n\nVariability in clinical and laboratory presentation and concomitant use of anti-inflammatory drugs may delay the diagnosis of DIHS in patients with PFS. No blood eosinophilia together with tissue eosinophilia, as found in our patient, has been previously described [4]. Therefore, the absence of blood eosinophilia does not rule out the diagnosis of drug-induced EM. A positive in vitro lymphocyte transformation test, which was not performed in our patient, may be helpful in the diagnosis of sulfasalazine-induced DIHS. After 6 days of culture, the lymphocyte transformation test measures drug-specific proliferation (3H-thymidine incorporation) in comparison with negative and positive controls [8].\n\nThe diagnosis of EM is based on clinical criteria including electrocardiography, echocardiography and cardiac enzymes. The diagnosis is confirmed by endomyocardial biopsy [5]. In subacute and chronic EM, intracardiac thrombi, endomyocardial fibrosis and restrictive cardiomyopathy can be found.\n\nA prompt diagnosis, immediate withdrawal of the offending drug and immunosuppressant therapy may decrease mortality in drug-induced acute EM [1]. High-dose systemic corticosteroids (1 g/day for 3 days with slow tapering), intravenous Ig therapy (1 g/kg), mycophenolate mofetil (1.5 g b.i.d.), azathioprine, rituximab and cyclosporine are possible treatment modalities [5].\n\nIn conclusion, this was a case of drug-induced EM in a patient with PFS that had atypical presentation, rapid evolution and a poor outcome.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nAcknowledgements\nWe would like to thank Marco Gattorno, Isabella Ceccherini and Gordana Susic for genetic testing. This work was supported, in part, by the Ministry of Education and Science of the Republic of Serbia, Grant No. 175065.\n\nFig. 1 a Heart histopathology:interstitial inflammation, focal necrosis (arrow) and disarray of myocardial cells. Hematoxylin and eosin stain. ×100. b Heart histopathology:perivascular infiltrates of eosinophils and mononuclear cells (arrow), and some myocardial cells in disarray, undergoing necrosis. Hematoxylin and eosin stain. ×400. c Lung histopathology: vascular congestion of alveolar wall capillaries (arrow) and alveolar damage. d Bone marrow: prominent active hemophagocytic CD68-positive macrophages. CD68 immunoperoxidase staining. ×1,000.\n==== Refs\nReferences\n1 Ushigome Y Kano Y Ishida T Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution J Am Acad Dermatol 2013 68 721 728 23182063 \n2 Haas D Hoffmann GF Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome Orphanet J Rare Dis 2006 26 1 13 \n3 Galeotti C Meinzer U Quartier P Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency Rheumatology (Oxford) 2012 51 1855 1859 22740624 \n4 Al Ali AM Straatman LP Allard MF Eosinophilic myocarditis: case series and review of literature Can J Cardiol 2006 22 1233 1237 17151774 \n5 Bourgeois GP Cafardi JA Groysman V A review of DRESS-associated myocarditis J Am Acad Dermatol 2012 66 e229 e236 21658796 \n6 Daoulah A Alqahtani AA Ocheltree SR Acute myocardial infarction in a 56-year-old female patient treated with sulfasalazine Am J Emerg Med 2012 30 638 e1-e3. \n7 Komatsuda A Okamoto Y Hatakeyama T Sulfasalazine-induced hypersensitivity syndrome and hemophagocytic syndrome associated with reactivation of Epstein-Barr virus Clin Rheumatol 2008 27 395 397 17952482 \n8 Zawodniak A Lochmatter P Beeler A Cross-reactivity in drug hypersensitivity reactions to sulfasalazine and sulfamethoxazole Int Arch Allergy Immunol 2010 153 152 156 20413982\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "24(2)",
"journal": "Medical principles and practice : international journal of the Kuwait University, Health Science Centre",
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"medline_ta": "Med Princ Pract",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001168:Arthritis; D001344:Autopsy; D004802:Eosinophilia; D017809:Fatal Outcome; D005334:Fever; D006801:Humans; D008297:Male; D009205:Myocarditis; D012770:Shock, Cardiogenic; D012460:Sulfasalazine",
"nlm_unique_id": "8901334",
"other_id": null,
"pages": "195-7",
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"pubdate": "2015",
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"references": "21658796;17151774;22740624;20413982;17952482;21514761;16722536;23182063",
"title": "Fatal sulfasalazine-induced eosinophilic myocarditis in a patient with periodic fever syndrome.",
"title_normalized": "fatal sulfasalazine induced eosinophilic myocarditis in a patient with periodic fever syndrome"
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"abstract": "A 50-year-old man with lung adenocarcinoma (c-T1aN2M1b) experienced reddish purpura mainly on the lower legs after receiving 12 cycles of second-line chemotherapy with docetaxel. There was tumor enlargement on computed tomography performed to assess the therapeutic response, so paraneoplastic IgA vasculitis was considered. IgA vasculitis was diagnosed based on a biopsy of the skin lesion and histology of an upper gastrointestinal hemorrhagic mucosal erosion. As IgA vasculitis can lead to serious gastrointestinal or systemic complications, IgA vasculitis should be considered as a differential diagnosis for rashes in patients with malignancy.",
"affiliations": "Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.;Division of Pathology, Teikyo University School of Medicine, Japan.;Division of Medical Oncology, Teikyo University School of Medicine, Japan.",
"authors": "Ota|Shuji|S|;Haruyama|Terunobu|T|;Ishihara|Masashi|M|;Natsume|Maika|M|;Fukasawa|Yoko|Y|;Sakamoto|Takahiko|T|;Tanzawa|Shigeru|S|;Usui|Ryo|R|;Honda|Takeshi|T|;Ichikawa|Yasuko|Y|;Watanabe|Kiyotaka|K|;Sasajima|Yuko|Y|;Seki|Nobuhiko|N|",
"chemical_list": "D007070:Immunoglobulin A; D043823:Taxoids; D000077143:Docetaxel",
"country": "Japan",
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"doi": "10.2169/internalmedicine.9651-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2927949610.2169/internalmedicine.9651-17Case ReportParaneoplastic IgA Vasculitis in an Adult with Lung Adenocarcinoma Ota Shuji 1Haruyama Terunobu 1Ishihara Masashi 1Natsume Maika 1Fukasawa Yoko 1Sakamoto Takahiko 1Tanzawa Shigeru 1Usui Ryo 1Honda Takeshi 1Ichikawa Yasuko 1Watanabe Kiyotaka 1Sasajima Yuko 2Seki Nobuhiko 1\n1 Division of Medical Oncology, Teikyo University School of Medicine, Japan\n2 Division of Pathology, Teikyo University School of Medicine, JapanCorrespondence to Dr. Nobuhiko Seki, nseki@med.teikyo-u.ac.jp\n\n27 12 2017 1 5 2018 57 9 1273 1276 13 6 2017 31 8 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 50-year-old man with lung adenocarcinoma (c-T1aN2M1b) experienced reddish purpura mainly on the lower legs after receiving 12 cycles of second-line chemotherapy with docetaxel. There was tumor enlargement on computed tomography performed to assess the therapeutic response, so paraneoplastic IgA vasculitis was considered. IgA vasculitis was diagnosed based on a biopsy of the skin lesion and histology of an upper gastrointestinal hemorrhagic mucosal erosion. As IgA vasculitis can lead to serious gastrointestinal or systemic complications, IgA vasculitis should be considered as a differential diagnosis for rashes in patients with malignancy. \n\nIgA vasculitislung cancerparaneoplastic vasculitisdrug eruption\n==== Body\nIntroduction\nIgA vasculitis is a form of vasculitis that affects the small blood vessels of the entire body, with manifestation of purpura on the upper and lower limbs, abdominal symptoms, arthropathy, and renal disorder. The disease typically affects children, with adult onset accounting for only 5% of all cases (1). We encountered a case of IgA vasculitis that occurred in association with tumor progression during chemotherapy for lung adenocarcinoma. IgA vasculitis as a paraneoplastic syndrome is rare. IgA vasculitis should therefore be considered in the differential diagnosis when encountering patients experiencing rash during chemotherapy.\n\nCase Report\nThe patient was a 50-year-old man who had been diagnosed with stage IV primary lung adenocarcinoma (c-T1aN2M1b stage IVA; eighth edition of the tumor-node-metastasis (TNM) classification) 1 year earlier. The adenocarcinoma was poorly differentiated, and thyroid transcription factor (TTF)-1 was negative in immunohistochemistry. No epidermal growth factor receptor (EGFR) gene mutation or anaplastic lymphoma kinase (ALK) rearrangement was detected. First-line combination chemotherapy consisting of cisplatin and pemetrexed was performed for four cycles, with the best response assessed as ‘stable disease'. Second-line chemotherapy with docetaxel was then started. While the best response was stable disease and the therapy was ongoing on an outpatient basis, on day 8 of cycle 12, the patient made an emergency visit with chief complaints of upper abdominal pain and petechiae on both lower legs (Fig. 1). This was initially considered to be drug eruption due to docetaxel, and the case was managed via outpatient observation for four days, but the petechiae worsened, and the patient was admitted for a detailed examination.\n\nFigure 1. Photograph showing purpura on the lower leg at the time of admission.\n\nUpon admission, the patient's performance status score was 1. He was not taking any medication, and he was a never smoker. A physical examination revealed upper abdominal tenderness and palpable papular petechiae on both lower legs. Laboratory tests upon admission showed no particular abnormalities in the complete blood count, biochemistry, or coagulation parameters, and immunoglobulin quantification showed a normal IgA level of 236 mg/dL. Urinalysis showed no abnormalities, such as hematuria or proteinuria, while fecal occult blood testing was positive. Computed tomography (CT) performed upon admission revealed the primary lesion in the upper left lung lobe along with swollen mediastinal lymph nodes, showing a 30% enlargement compared with CT obtained 1 month earlier. Thus, the tumor response to docetaxel was assessed as ‘progressive disease'. Duodenal and upper jejunal wall thickening was also observed (Fig. 2).\n\nA skin biopsy of the petechial rash was performed after admission. Histology from the skin specimens showed no changes in the epidermis but did reveal perivascular infiltration of neutrophils and lymphocytes in the superficial dermis (Fig. 3A). The perivascular areas also contained fragmented nuclei, extravasation of red blood cells, and hemosiderin deposition; these findings were consistent with leukocytoclastic vasculitis (Fig. 3B). Although IgA staining using the direct fluorescent antibody technique was negative, the histological findings were compatible with IgA vasculitis. Upper gastrointestinal endoscopy revealed easily hemorrhagic mucosal erosion in the duodenum to the upper jejunum. Histology from this erosion showed perivascular infiltration of neutrophils and lymphocytes consistent with leukocytoclastic vasculitis, similar to the skin biopsy. Based on these findings, IgA vasculitis was diagnosed.\n\nFigure 2. Contrast-enhanced computed tomography of the abdomen upon admission showed wall thickening of the duodenum to the upper jejunum.\n\nFigure 3. A histopathological examination of skin biopsy specimens from the lower leg. A: The superficial dermis had perivascular infiltration of neutrophils (thin arrows) and lymphocytes (thick arrows). Original magnification ×100. B: The superficial dermis contained perivascular fragmented nuclei (thin arrow), extravasation of red blood cells (arrowhead), and hemosiderin deposition (thick arrow). Original magnification ×150.\n\nThe initial treatment was watchful waiting, which led to worsening of the skin symptoms and no improvement in the abdominal symptoms. Thus, on hospital day 13, systemic corticosteroid therapy was started (20 mg oral prednisolone once daily), and the skin and abdominal symptoms promptly resolved. However, there was marked enlargement of the primary lung tumor with the onset of brain metastasis accompanied by brain edema, for which the prednisolone was subsequently continued. No relapse of IgA vasculitis occurred after the initiation of prednisolone administration.\n\nDiscussion\nIgA vasculitis, formerly known as Henoch-Schönlein purpura, is an idiopathic form of vasculitis that affects the small blood vessels of the entire body and manifests with systemic symptoms mainly involving the skin, gastrointestinal tract, kidneys, and joints (1). According to the American College of Rheumatology diagnostic criteria for Henoch-Schönlein purpura, 1) clinically palpable purpura is a characteristic finding, and other criteria include 2) age ≤20 years at the disease onset, 3) the presence of gastrointestinal symptoms resulting from vasculitis, and 4) histopathological evidence of inflammation, mainly of small blood vessels in the affected areas of the skin, kidney, gastrointestinal tract, or other organs, along with histopathological findings of leukocytoclastic vasculitis on Hematoxylin and Eosin staining and deposits of IgA immune complexes on immunohistochemical staining. IgA vasculitis is diagnosed when at least two of these four criteria are met (2). Our patient met three of these criteria, although he was older than 20 years of age. Immunostaining of skin biopsy specimens from our patient showed no IgA deposits in the walls of the blood vessels. However, cutaneous IgA deposition is reportedly detected only in approximately 70% of all cases, as opposed to renal IgA deposition, which is detected in nearly 100% of all cases; hence. Therefore, the absence of cutaneous IgA deposits does not necessarily rule out a diagnosis of IgA vasculitis (3).\n\nParaneoplastic vasculitis is rare and accounts for approximately 2.5-5% of all cases of adult vasculitis (4), of which IgA vasculitis accounts for approximately 5% (5). However, the prevalence of malignancy among patients with adult-onset IgA vasculitis is as high as 29-43% (4). Malignancy in patients with IgA vasculitis is typically in the form of solid tumors, such as lung cancer (6, 7). There have been several reports of IgA vasculitis associated with pulmonary adenocarcinoma (8-10). However, this case is the first report of IgA vasculitis occurring during chemotherapy.\n\nOne suggested etiology of IgA vasculitis as a paraneoplastic syndrome is decreased clearance and overproduction of immune complexes (including IgA antibodies and tumor antigens) due to the presence of malignancy, leading to the deposition of the immune complexes in the vascular walls and mesangial areas, thereby causing inflammation (11). Another theory is that tumor cells react with antigens on the vascular endothelial cells and induce damage to the vascular walls (11). It has also been suggested that increased blood viscosity due to malignancy may play a role in the onset of the disease by promoting the deposition of immune complexes in the vascular walls (12).\n\nRegarding the cause of IgA vasculitis in the present case, the patient had had no preceding common cold symptoms or signs of infection. Other vasculitis markers showed negative results for streptolysin O, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibody, cryoglobulin, and rapid plasma reagin. There had been no initiation of any new medications. Thus, the onset of IgA vasculitis due to cancer progression was considered likely. IgA vasculitis did not recur in the present case despite further subsequent cancer progression, presumably due to the continued corticosteroid administration for the brain edema. IgA vasculitis reportedly responds well to corticosteroid therapy (8).\n\nIn patients with rash occurring during or after medication administration, drug eruption is considered the most likely differential diagnosis. For this reason, drug eruption due to docetaxel was initially considered in the present case. IgA vasculitis generally has a good prognosis. However, the appropriate diagnosis is necessary, as approximately 30% of patients with adult-onset IgA vasculitis have gastrointestinal symptoms and are at risk for major complications, such as intestinal perforation, necrotizing enterocolitis, and gastrointestinal hemorrhaging, which can lead to a serious outcome (13, 14). For this reason, when patients with malignancy present with a rash, clinicians should consider IgA vasculitis as a differential diagnosis and perform detailed assessments, rather than simply making a diagnosis of drug eruption based merely on the history.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nJennette JC , Falk RJ \nThe pathology of vasculitis involving the kidney . Am J Kidney Dis \n24 : 130 -141 , 1994 .8023818 \n2. \nMills JA , Michel BA , Bloch DA , et al \nThe American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura . Arthritis Rheum \n33 : 1114 -1121 , 1990 .2202310 \n3. \nPertuiset E , Lioté F , Launay-Russ E , Kemiche F , Cerf-Payrastre I , Chesneau AM \nAdult Henoch-Schönlein purpura associated with malignancy . Semin Arthritis Rheum \n29 : 360 -367 , 2000 .10924021 \n4. \nMitsui H , Shibagaki N , Kawamura T , Matsue H , Shimada S \nA clinical study of Henoch-Schönlein purpura associated with malignancy . J Eur Acad Dermatol Venereol \n23 : 394 -401 , 2009 .19207675 \n5. \nFain O , Hamidou M , Cacoub P , et al \nVasculitides associated with malignancies: analysis of sixty patients . Arthritis Rheum \n57 : 1473 -1480 , 2007 .18050165 \n6. \nCairns SA , Mallick NP , Lawler W , et al \nSquamous cell carcinoma of bronchus presenting with Henoch-Schönlein purpura . Br Med J \n2 : 474 , 1978 .\n7. \nMaurice TR \nCarcinoma of bronchus presenting with Henoch-Schönlein purpura . Br Med J \n2 : 831 , 1978 .\n8. \nMifune D , Watanabe S , Kondo R , et al \nHenoch Schönlein purpura associated with pulmonary adenocarcinoma . J Med Case Rep \n5 : 226 , 2011 .21696580 \n9. \nWeiler-Bisig D , Ettlin G , Brink T , et al \nHenoch Schönlein purpura associated with esophagus carcinoma and adenocarcinoma of the lung . Clin Nephrol \n63 : 302 , 2005 .15847258 \n10. \nSolans-Laqué R , Bosch-Gil JA , Pérez-Bocanegra C , et al \nParaneoplastic vasculitis in patients with solid tumors: report of 15 cases . J Rheumatol \n35 : 294 , 2008 .18085729 \n11. \nFortin PR \nVasculitides associated with malignancy . Curr Opin Rheumatol \n8 : 30 -33 , 1996 .8867536 \n12. \nMagro CM , Crowson AN \nA clinical and histologic study of 37 cases of immunoglobulin A-associated vasculitis . Am J Dermatopathol \n21 : 234 -240 , 1999 .10380044 \n13. \nChan JC , Li PK , Lai FM , Lai KN \nFatal adult Henoch-Schönlein purpura due to small intestinal infarction . J Intern Med \n232 : 181 -184 , 1992 .1506816 \n14. \nBissonnette R , Dansereau A , D'Amico P , Pateneaude JV , Paradis J \nPerforation of large and small bowel in Henoch-Schönlein purpura . Int J Dermatol \n36 : 361 -363 , 1997 .9199985\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "57(9)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "IgA vasculitis; drug eruption; lung cancer; paraneoplastic vasculitis",
"medline_ta": "Intern Med",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D003937:Diagnosis, Differential; D000077143:Docetaxel; D005076:Exanthema; D006801:Humans; D007070:Immunoglobulin A; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010257:Paraneoplastic Syndromes; D011693:Purpura; D043823:Taxoids; D016896:Treatment Outcome; D014657:Vasculitis",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1273-1276",
"pmc": null,
"pmid": "29279496",
"pubdate": "2018-05-01",
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"references": "9199985;1506816;19207675;21696580;10924021;698755;15847258;8867536;10380044;18085729;678928;2202310;8023818;18050165",
"title": "Paraneoplastic IgA Vasculitis in an Adult with Lung Adenocarcinoma.",
"title_normalized": "paraneoplastic iga vasculitis in an adult with lung adenocarcinoma"
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"abstract": "OBJECTIVE\nTo assess the efficacy of a combination therapy of intravitreal ranibizumab together with a dexamethasone implant in comparison with ranibizumab monotherapy in neovascular age-related macular degeneration.\n\n\nMETHODS\nForty eyes of recurrent or persistent neovascular age-related macular degeneration were included in this prospective study. Patients were randomly assigned to two groups. Based on a pro re nata treatment regimen, the first group received intravitreal ranibizumab monotherapy (IVM). The second group received a combination of intravitreal dexamethasone implant and ranibizumab (intravitreal combination [IVC]) at baseline and was retreated with ranibizumab as needed. A second dexamethasone implant was allowed for retreatment after at least 6 months. Retreatment criteria included evidence of subretinal fluid, cystoid macular edema or new hemorrhage, and/or a visual acuity decrease of 5 Early Treatment Diabetic Retinopathy Study letters.\n\n\nRESULTS\nDuring 12 months, a mean of 7.95/5.5 (IVM/IVC; P = 0.042) retreatments were given. The median time until first retreatment differed significantly between the groups (P = 0.004). Functional variables could be maintained in both groups with no differences between them. Visual acuity changed from 62 letters at baseline to 67 at Month 12 in the IVM and remained stable at 68 letters in the IVC group (P = 0.68); macular sensitivity changed from 6.95 dB to 7.01 dB in IVM and from 7.24 dB to 7.12 dB in IVC (P = 0.4). Central retinal thickness decreased, however, with no difference between the groups (P = 0.38). In the IVM/IVC group, 11/12 (55/60%) patients were phakic at the time of study entry. One (9%) patient from the IVM and 4 (33%) from the IVC group were referred to cataract surgery after study completion (P = 0.4).\n\n\nCONCLUSIONS\nThis pilot study indicates combined therapy to delay retreatment in patients with persistent/recurrent neovascular age-related macular degeneration and an overall reduction in required ranibizumab retreatments compared with ranibizumab monotherapy with consistent functional outcomes.",
"affiliations": "*Department of Ophthalmology, Medical University of Vienna, Vienna, Austria; and †Department of Medical Statistics, Medical University of Vienna, Vienna, Austria.",
"authors": "Rezar-Dreindl|Sandra|S|;Eibenberger|Katharina|K|;Buehl|Wolf|W|;Georgopoulos|Michael|M|;Weigert|Guenther|G|;Krall|Christoph|C|;Dunavoelgyi|Roman|R|;Schmidt-Erfurth|Ursula|U|;Sacu|Stefan|S|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D003692:Delayed-Action Preparations; D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000001264",
"fulltext": null,
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"issn_linking": "0275-004X",
"issue": "37(5)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D020256:Choroidal Neovascularization; D003692:Delayed-Action Preparations; D003907:Dexamethasone; D004343:Drug Implants; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D000069579:Ranibizumab; D019233:Retreatment; D014792:Visual Acuity; D057135:Wet Macular Degeneration",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "962-970",
"pmc": null,
"pmid": "27575409",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "ROLE OF ADDITIONAL DEXAMETHASONE FOR THE MANAGEMENT OF PERSISTENT OR RECURRENT NEOVASCULAR AGE-RELATED MACULAR DEGENERATION UNDER RANIBIZUMAB TREATMENT.",
"title_normalized": "role of additional dexamethasone for the management of persistent or recurrent neovascular age related macular degeneration under ranibizumab treatment"
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"companynumb": "AT-ROCHE-2197876",
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"abstract": "Acute myeloid leukemia (AML) with fetal liver tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is associated with poor prognosis, and allogeneic stem cell transplantation (Allo-SCT) seems to be the preferred therapeutic approach. However, the predictors of post-transplant outcomes were not well-defined. The aim of the study was to evaluate the significance of FLT3/ITD mutation by polymerase chain reaction as minimal residual disease (MRD) marker of outcomes after transplantation. We identified 43 patients (28 females and 15 males) with FLT3-mutated AML at the median age of 45 years who were allografted between 2009 and 2019. Hematological status at transplant was as follows: the first complete remission (CR1) in 29 patients, CR2 in 5, and 9 patients were transplanted in marrow aplasia (MA). Twenty-seven patients were FLT3 MRD negative at transplant. Median time from diagnosis to transplant was 16.7 months. Post-allograft CR rate was 88%. The relapse incidence (RI) was lower for patients who were FLT3 MRD negative at transplant when compared with those with FLT3 MRD positivity (41% vs 59%; p = 0.01). The patients who eradicated FLT3/ITD at day + 30 after transplant had lower RI than those with detectable FLT3/ITD (23% vs 76%; p = <0.001). The 2-year LFS and OS were 53% and 54%, with the median OS and LFS of 28 months and 27 months, respectively. Patients with CR1/2 and FLT3 MRD(-) had a 2-year OS of 80%. The FLT3 MRD negativity at transplant prolonged LFS in multivariate analysis (HR 5.3 95%CI 1.97-14.2); p < 0.001), whereas FLT3 MRD negativity and unrelated donor predicted favorable OS.",
"affiliations": "Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland. ghelbig@o2.pl.;Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.",
"authors": "Helbig|Grzegorz|G|https://orcid.org/0000-0003-3703-1268;Koclęga|Anna|A|;Wieczorkiewicz-Kabut|Agata|A|;Woźniczka|Krzysztof|K|;Kopińska|Anna|A|;Boral|Kinga|K|;Grygoruk-Wiśniowska|Iwona|I|;Stachowicz|Małgorzata|M|;Karolczyk|Agnieszka|A|",
"chemical_list": "C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-04026-1",
"fulltext": "\n==== Front\nAnn Hematol\nAnn. Hematol\nAnnals of Hematology\n0939-5555 1432-0584 Springer Berlin Heidelberg Berlin/Heidelberg \n\n4026\n10.1007/s00277-020-04026-1\nOriginal Article\nPre-transplant FLT3/ITD status predicts outcome in FLT3-mutated acute myeloid leukemia following allogeneic stem cell transplantation\nhttps://orcid.org/0000-0003-3703-1268Helbig Grzegorz ghelbig@o2.pl Koclęga Anna Wieczorkiewicz-Kabut Agata Woźniczka Krzysztof Kopińska Anna Boral Kinga Grygoruk-Wiśniowska Iwona Stachowicz Małgorzata Karolczyk Agnieszka grid.411728.90000 0001 2198 0923Department of Hematology and Bone Marrow Transplantation, School of Medicine in Katowice, Medical University of Silesia, Dąbrowski street 25, 40-032 Katowice, Poland \n24 4 2020 \n24 4 2020 \n2020 \n99 8 1845 1853\n17 1 2020 6 4 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons 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/.Acute myeloid leukemia (AML) with fetal liver tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is associated with poor prognosis, and allogeneic stem cell transplantation (Allo-SCT) seems to be the preferred therapeutic approach. However, the predictors of post-transplant outcomes were not well-defined. The aim of the study was to evaluate the significance of FLT3/ITD mutation by polymerase chain reaction as minimal residual disease (MRD) marker of outcomes after transplantation. We identified 43 patients (28 females and 15 males) with FLT3-mutated AML at the median age of 45 years who were allografted between 2009 and 2019. Hematological status at transplant was as follows: the first complete remission (CR1) in 29 patients, CR2 in 5, and 9 patients were transplanted in marrow aplasia (MA). Twenty-seven patients were FLT3 MRD negative at transplant. Median time from diagnosis to transplant was 16.7 months. Post-allograft CR rate was 88%. The relapse incidence (RI) was lower for patients who were FLT3 MRD negative at transplant when compared with those with FLT3 MRD positivity (41% vs 59%; p = 0.01). The patients who eradicated FLT3/ITD at day + 30 after transplant had lower RI than those with detectable FLT3/ITD (23% vs 76%; p = <0.001). The 2-year LFS and OS were 53% and 54%, with the median OS and LFS of 28 months and 27 months, respectively. Patients with CR1/2 and FLT3 MRD(−) had a 2-year OS of 80%. The FLT3 MRD negativity at transplant prolonged LFS in multivariate analysis (HR 5.3 95%CI 1.97–14.2); p < 0.001), whereas FLT3 MRD negativity and unrelated donor predicted favorable OS.\n\nKeywords\nAcute myeloid leukemiaFLT3/ITD mutationAllogeneic stem cell transplantationOverall survivalLeukemia-free survivalMinimal residual diseaseMedical University of Silesiaissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nThe FMS-like tyrosine kinase-3 (FLT3) is expressed by myeloid and lymphoid progenitors, and it is responsible for differentiation, proliferation, and apoptosis of the cells. Internal tandem duplication in the juxtamembrane domain of FLT3 (FLT3/ITD) is frequent molecular aberration which is detected in approximately 30% of the patients with acute myeloid leukemia and normal diploid karyotype (AML-CN). This mutation leads to ligand-independent activation of the receptor and its signaling pathways [1]. Many studies have demonstrated that the occurrence of FLT3/ITD mutation in AML remains a poor prognostic factor owing for high relapse rate and shortened survival [2, 3]. However, it was recently shown that this aberration produces a negative effect only if the ratio of mutated to normal alleles is > 0.5 [4].\n\nThe role of allogeneic stem cell transplantation (Allo-SCT) in FLT3-mutated patients in the first complete remission (CR1) seems to be controversial, especially in the view of the newest findings in the molecular signature of AML. The assessment of FLT3/ITD allelic ratio and co-occurrence of NPM1 mutation have a confirmed impact on risk stratification and therapeutic approaches [4–6]. The results from the donor versus no donor study of adult patients with FLT3/ITD mutation treated according to the United Kingdom Medical Research Council (UK MRC) AML protocol have demonstrated lower relapse rate for patients with donor, but no difference in overall survivals (OS) between compared groups [7]. It was also found that FLT3-mutated patients when compared with FLT3-unmutated had higher relapse incidence (RI) and lower leukemia-free survival (LFS) even after Allo-SCT. Nevertheless, more than 50% of the transplanted patients carrying this mutation were leukemia free at 2 years. Of note is that other predictors than FLT3/ITD mutation may play a role in leukemia relapse after transplantation [8]. The FLT3/ITD mutation may serve as a marker of minimal residual disease (MRD), and its utility has been evaluated in a single study so far [9].\n\nThe aim of the study was to evaluate the potential factors which may have an impact on a post-transplant outcome in FLT3-mutated patients with AML following Allo-SCT.\n\nMaterial and methods\nThe study patients were retrospectively identified through the use of our institutional database of medical records. The diagnosis of AML and response criteria to therapy were based on European Leukemia Net Recommendations [4]. Marrow aplasia (MA) was defined as pancytopenia with bone marrow aplasia after salvage chemotherapy. Patients were treated according to Polish Adult Leukemia Group (PALG) protocol [www.palg.witaj.pl] and induction chemotherapy included DA+/− C regimen (daunorubicin, cytarabine, cladribine). For those who achieved complete remission, 2 cycles of consolidative chemotherapy consisting of mitoxantrone with cytarabine (HAM) or cytarabine alone (ARA-C) were administered. For patients with resistant disease (RD) after 2 inductions, 3 different salvage regimens were given according to the treating physician: CLAM (cladribine, cytarabine, mitoxantrone), MEC (mitoxantrone, etoposide, cytarabine), and FLAG-IDA (fludarabine, cytarabine, idarubicin, G-CSF). All patients who were FLT3-mutated at diagnosis were proceeded to Allo-SCT according to the center policy.\n\nThe FLT3/ITD and nucleophosmin (NPM1) mutation analysis were performed at diagnosis, and FLT3/ITD was then performed before conditioning commencement and at day + 30 after procedure. Multiplex fluorescence-based PCR method was performed on DNA isolated from bone marrow aspirate sample as described elsewhere. The sensitivity of this assay is approximately 5% [10]. All patients were grouped according to the molecular and cytogenetic genetic stratification of the European Leukemia Net (ELN) 2010 [11] as most AML patients (38/43) were diagnosed < 2017. Data on FLT3/ITD allelic ratio was available only for 4 patients, and therefore this parameter was not analyzed. Chimerism of unseparated blood leukocytes was assessed by a short tandem repeat polymerase chain reaction.\n\nStatistics\nTime to event was assessed from the day of transplantation. Nonparametric comparisons of group means were performed by using the Mann-Whitney U test. Proportions were compared by Fisher exact test. The Kruskal-Wallis test was used to compare more than two independent groups of variables. Non-relapse mortality (NRM) was defined as all deaths before disease recurrence. The distribution for overall survival (OS) and leukemia-free survival (LFS) was estimated using the method of Kaplan and Meier and compared using the log-rank test. A p value less than 0.05 was considered significant. Proportional hazards models (Cox regression) were fitted to investigate effects of prognostic factors for OS.A Spearman’s rank test was used to assess the correlation between variables. All computations were performed with StatSoft Poland analysis software (version 10.0).\n\nResults\nPatient characteristics\nForty-three patients (28 females and 15 males) with AML at median age of 45 years (range 19–67) underwent Allo-SCT between 2009 and 2019. Four patients were ≥ 60 years at transplant and 3 had prior myelodysplastic syndrome. All patients demonstrated detectable FLT3/ITD mutation by polymerase chain reaction (PCR). Sixty percent of the subjects had normal diploid karyotype, and trisomy 8 was the most common cytogenetic abnormality (n = 4). Study patients were stratified into the following risk groups: 2 patients were categorized to adverse risk group as they had monosomies of chromosomes 5 and 7; 4 patients were in intermediate-2 group as they had cytogenetic abnormalities not classified as favorable or adverse; and 30 patients were in intermediate-1 group, and in 7 patients, no metaphases were obtained (they were stratified to intermediate-1 category based on molecular status only).\n\nInduction regimen consisted of DAC (n = 30) or DA (n = 13). No induction death was observed. Thirty patients (70%) achieved the first complete remission (CR1), and CR2 was demonstrated in 4 after re-induction. Nine subjects developed irreversible marrow aplasia after chemotherapy.\n\nHematological status at transplant was as follows: CR1 in 29 patients, CR2 in 5, and 9 patients were transplanted in MA. Twenty-seven patients had FLT3 MRD negativity before procedure. Median time from diagnosis to transplant was 16.7 months (range 5.1–76). Patients’ characteristics are shown in Table 1.Table 1 Patients characteristics\n\nVariable\tn = 43\t\n Gender (female/male)\t28/15\t\n Age, years; median, range\t45 (19–67)\t\n Hemoglobin level (g/dl); median, range\t8.8 (5.7–13.0)\t\n Leukocyte count (× 109/l); median, range\t47.5 (1.7–197.0)\t\n Platelet count (× 109/l); median, range\t66 (5–148)\t\n Blasts in blood (%); median, range\t79 (11–100)\t\n Blasts in bone marrow (%); median, range\t87 (24–100)\t\n Splenomegaly, n; %\t12 (28)\t\n Hepatomegaly, n; %\t7 (16)\t\n Lymphadenopathy, n; %\t11 (25)\t\nFAB subtype\n\n M1\n\n M2\n\n M4\n\n M5\n\n\t7\n\n15\n\n18\n\n3\n\n\t\nKaryotype, n; %\n\n diploid\n\n + 8\n\n − 5q\n\n + 11\n\n inv9\n\n − 7q\n\n t(1;7)\n\n + 3,+ 13\n\n no metaphases\n\n\t26 (60)\n\n4 (9)\n\n1 (2)\n\n1 (2)\n\n1 (2)\n\n1 (2)\n\n1 (2)\n\n1 (2)\n\n7 (19)\n\n\t\nPrior MDS, n; %\t3 (7)\t\nHematologic response at transplant, n; %\n\n First or second complete remission\n\n Marrow aplasia\n\n\t34 (79)\n\n9 (21)\n\n\t\nFLT3/ITD mutation at transplant, n; %\n\n Negative\n\n Positive\n\n\t27 (63)\n\n16 (27)\n\n\t\nTime from diagnosis to transplant in months; median, range\t16.7 (5.1–76.0)\t\n\n\nTransplant data\nBaseline characteristics of the transplanted patients\nTwelve patients were transplanted from HLA-matched sibling, and 30 patients received either 10/10 HLA-matched unrelated donor (n = 22) or 9/10 HLA-mismatched grafts (n = 8). One patient underwent haploidentical transplantation from sister. Peripheral blood was a source of stem cells for all transplanted patients. In total, 26 patients received myeloablative conditioning (MAC), whereas reduced-intensity conditioning (RIC) was provided for 17 subjects. MAC consisted of busulfan and cyclophosphamide (BuCy), and fludarabine-based regimens were given as RIC. Anti-thymocyte globulin (ATG) was administered for all patients who had received a graft from the unrelated donors. Graft versus host disease (GHVD) prophylaxis included cyclosporine and methotrexate in all but one patient with haploidentical transplantation who received cyclosporine with mycophenolate mofetil and post-transplant cyclophosphamide.\n\nOutcome of the transplanted patients\nThere were no primary graft failures (PGF). Median time from transplantation to acute graft versus host disease (GVHD) was 17 days (range 7–106). Acute and chronic GVHD developed in 58% and 14% of patients, respectively. Acute GVHD grade III/IV was present in 6 patients. Two patients had limited and 4 extensive chronic GVHD.\n\nTwelve patients demonstrated mucositis grade 3 or 4 after transplantation. No other severe infectious complications were demonstrated. Two subjects developed post-cyclophosphamide hemorrhagic cystitis, one patient had veno-occlusive disease and one had acute renal failure. Six patients had CMV reactivation prior to day + 30. No patients died within the first 30 days, whereas 6 patients expired prior to day + 100 after transplantation: 3 due to early leukemia progression and subsequent chemo-resistance, 2 as a consequence of steroid-resistant acute GVHD, and 1 patient for aspergillosis.\n\nPost-allograft CR rate amounted to 88% including 4 patients who were transplanted in MA and converted to CR. Five patients who were transplanted in MA had leukemia progression. In total, among 9 patients transplanted in MA, 4 patients were alive at last contact. Twenty-eight (65%) patients achieved FLT3/ITD negativity at day + 30 after Allo-SCT, and 21 of them are still alive. In contrast, only 1 patient is alive among those who were FLT3-mutated at day + 30. Non-relapse mortality (NRM) at 2 years was 7%.\n\nIn total, 17 patients relapsed after median of 4.8 months (range 0.9–27.4) following transplantation. We look at different variables which may have an impact on the incidence of relapse. The following factors were analyzed: hematological status at transplant, donor source, type of conditioning, the occurrence of acute GVHD, and the presence of FLT3/ITD mutation at transplantation and at day + 30 after procedure. The relapse incidence (RI) was lower for patients who were FLT3 MRD negative at transplant when compared with those who remained FLT3 MRD positive (41% vs 59%; r = 0.36; p = 0.01). The patients who eradicated FLT3/ITD mutation at day + 30 post-transplantation had significantly lower RI than those who had detectable FLT3/ITD (23% vs 76%; r = 0.7; p < 0.001). No other correlations were found. Five patients who were FLT3-mutated at transplant eradicated this mutation after allografting. Four patients are alive and remain in CR, and one patient died due to severe GVHD with subsequent infectious complications. Of note is that the latter one had no features of leukemia relapse. Moreover, a strong positive correlation between the post-transplant FLT3/ITD status and survival was demonstrated (r = 0.65; p < 0.001).\n\nNPM1 mutation at diagnosis was tested in 22 AML patients and was detectable in 10 (45%). There were 7 post-transplant relapses in FLT3 MRD(+)/NPM(+) group, and 2 subjects had leukemia recurrence in FLT3 MRD(+)/NPM(−) group (p = 0.62). There was one leukemia recurrence in FLT3 MRD(−)/NPM(−) group.\n\nData on MRD measured by flow cytometry (MRD-FC) at transplant were available in 28 patients, and positive results were demonstrated in 21. There was a strong positive correlation between FLT3 MRD(+) and MRD-FC(+) (r = 0.53; p = 0.03).\n\nThere were 8/13 (62%) post-transplant leukemia relapses in patients who were FLT3 MRD(+)/MRD-FC(+), 2/8 (25%) relapses in FLT3 MRD(−)/MRD-FC (+,) group and 1/7 (14%) disease recurrence in those who had FLT3 MRD(+)/MRD-FC(−).\n\nAt the last follow-up, 21 (49%) patients died. The main causes of death included disease progression (n = 15), infectious complications (n = 2), and steroid-resistant GVHD (n = 2). In 2 cases, the cause of death remained unknown. In total, there were 18 (86%) deaths within the first 2 years after transplant.\n\nTwenty-wo patients (51%) are alive at the last contact, and 21 remain in hematological and molecular CR. All those patients had full donor chimerism. One patient had leukemia relapse and received salvage chemotherapy. Median follow-up from diagnosis and from transplantation was 2.1 years (range 0.6–10.9) and 15 months (range 1–119), respectively. Median follow-up for those who are alive after procedure is 34.1 month (range 1.0–119.6). Transplant data are summarized in Table 2.Table 2 Transplant data\n\nVariable\tn = 43\t\nType of donor, n;%\n\n Related\n\n 10/10-HLA matched unrelated\n\n 9/10-HLA-matched unrelated\n\n haploidentical\n\n\t12 (28)\n\n22 (51)\n\n8 (19)\n\n1 (2)\n\n\t\nMyeloablative conditioning, n; %\t26 (60)\t\nConditioning regimen, n; %\n\n Busulfan/cyclophosphamide\n\n Treosulfan/fludarabine\n\n Busulfan/fludarabine\n\n Fludarabine/TBI\n\n\t26 (60)\n\n10 (23)\n\n3 (7)\n\n4 (10)\n\n\t\nNumber of transplanted CD34-positive cells (× 106/kg); median, range\t5.4 (3.1–20.4)\t\nANC > 0.5 (× 109/L); median, range\t16 (11–29)\t\nPLT > 20 (× 109/L); median, range\t15 (10–32)\t\nAcute GVHD, n; %\t12 (58)\t\nAcute GVHD III/IV, n; %\t6 (14)\t\nChronic GVHD, n; %\t6 (14)\t\nHematologic relapse, n; %\t17 (39)\t\nAlive at last contact, n; %\t22 (51)\t\nFLT3/ITD mutation at day + 30, n; %\n\n Negative\n\n Positive\n\n\t28 (65)\n\n15 (35)\n\n\t\nMedian follow-up from transplantation, months; median, range\t15 (1–119)\t\nANC absolute neutrophil count; GVHD graft versus host disease; PLT platelet count; TBI total body irradiation\n\n\n\nPatients who relapsed after transplantation received a variety of salvage treatments depending on whether they were fit or frail. In total, 11 patients were eligible for intensive chemotherapy and they received CLAM (n = 4), COAP (cyclophosphamide, vincristine, cytarabine, prednisone; n = 3), high-dose cytarabine (n = 2), DAC (n = 1), and multi-kinase inhibitor—lestaurtinib (n = 1). Two patients underwent second allogeneic transplantation following intensive chemotherapy. Six patients received palliative treatments which are the following: hydroxyurea (n = 3) and low-doses cytarabine (n = 3). None of the patients received midostaurin and any other FLT3-inhibitor as maintenance.\n\nThe 2-year LFS and OS were 53% and 54%, respectively. Figures 1 and 2.Median OS from diagnosis and from Allo-SCT were 3.2 years and 28 months. Median LFS after Allo-SCT was 27 months. There was no statistical difference in OS between patients transplanted in CR1/2 and MA. Estimated OS at 2 years were 59% and 33%; (p = 0.17), respectively. In univariate analysis, unrelated donor, undetectable FLT3/ITD mutation, and normal liver size before transplant were found to influence LFS; however, only FLT3 status remained significance in multivariate analysis (HR 5.3 95%CI 1.97–14.2); p < 0.001). The following factors influenced the OS in multivariate analysis: type of donor and mutational status. Details are presented in Tables 3 and 4.Fig. 1 Overall survival for FLT3-mutated AML patients\n\nFig. 2 Leukemia-free survival for FLT3-mutated AML patients\n\nTable 3 Univariate and multivariate analysis of risk factors for overall survival\n\nUnivariate analysis (log rank)\tMultivariate analysis (Cox regression)\t\nRisk factor\tOS at 2 years\tP value\tHR (95% CI)\tP value\t\nType of donor\t\n Related n=12\t19%\t0.01\t0.35 (0.12-1.0)\t0.05\t\n Unrelated n=31\t68%\t\nFLT3/ITD status at transplant\t\n Negative n=27\t74%\t0.001\t2.67 (0.94-7.56)\t0.06\t\n Positive n=16\t21%\t\nTable 4 Univariate and multivariate analysis of risk factors for leukemia-free survival\n\nUnivariate analysis (log rank)\tMultivariate analysis (Cox regression)\t\nRisk factor\tLFS at 2 years\tP value\tHR (95%CI)\tP value\t\nFLT3/ITD status at transplant\t\n Negative n=27\t74%\t0.001\t5.3 (1.97-14.2)\t< 0.001\t\n Positive n=16\t25%\t\nType of donor\t\n Unrelated n=31\t67%\t0.02\t-\t\t\n Related n=12\t28%\t\nHepatomegaly at diagnosis\t\n No n=36\t61%\t0.09\t-\t\t\n Yes n=7\t38%\t\n\n\nDiscussion\nBeneficial role of Allo-SCT in FLT3-mutated AML patients in CR1 remains unclear as these patients had poor prognosis even after procedure. Of note is that the presented data are limited by selection bias and the small number of included patients [7, 8]. To light up this controversy, a systemic review of 9 studies with 772 FLT3-mutated AML patients has been performed. This meta-analysis has demonstrated that SCT (autologous and allogeneic were lumped together) when compared with chemotherapy alone reduced the relapse rate and prolonged OS and LFS. Unexpectedly, there was no advantage of Allo-SCT over Auto-SCT in terms of OS and LFS, and this probably resulted from the higher transplant-related mortality and lower relapse rate (RR) for patients who received allograft. Higher RR for auto-transplanted patients should be explained by no “graft versus leukemia” effect. An interesting observation is that some FLT3-mutated AML patients with no suitable donor may benefit from the Auto-SCT. Of note is that these conclusions were based on 3 studies only, and the results were limited by selection bias, the number of included patients, and inclusion of retrospective and non-randomized studies [12] (Figs. 3 and 4).Fig. 3 Overall survival depending on FLT3 MRD status at transplant\n\nFig. 4 Overall survival depending on donor source\n\n\n\nIn contrast, there are several studies showing that Allo-SCT improves outcome in FLT3-mutated AML when performed in CR1. The median LFS in FLT3/ITD-transplanted AML population was 54.1 month when compared with 8.6 months for FLT3/ITD-non-transplanted group (p = 0.03) [13]. The comparable parameters for our cohort were 27 and 3 months, respectively [data not published].The FLT3-mutated patients who received Allo-SCT as consolidation at CR1 had longer OS and relapse-free survival (RFS) than patients left on chemotherapy alone. OS at 3 year were 54% and 24%, respectively. Multivariate analysis showed the advantage of Allo-SCT over chemotherapy irrespective of FLT3/ITD allelic ratio [14]. The results of transplantation for FLT3-mutated AML beyond CR1 are less encouraging. The post-transplant outcome of 200 FLT3-mutated AML patients was presented by MD Anderson Group. The patients were transplanted both in CR1 and beyond, including those with active disease. Median follow-up was 27 months, and OS and LFS for the entire study cohort at 2 years were 43% and 41%, respectively. RR was the lowest for those who were transplanted in CR1/CR2 and with FLT3 MRD negativity. The worst outcome was demonstrated for patients transplanted in active disease; 85% of them had relapse. In multivariate analysis, hematological/morphological remission and undetectable FLT3 MRD at transplant were found to improve outcome [9].\n\nMedian follow-up for our cohort was 15 months, and OS and LFS at 2 years were found to be slightly better than those reported in Gaballa study [9]—54% and 53%, respectively. Of note is that disease status had no impact on the post-transplant outcome. OS at 2 years did not differ between patients transplanted in CR1/2 or MA: 59% and 33%, respectively. Patients who had pre-transplant CR1/2 and FLT3 MRD negativity had the excellent 2-year OS (80%). We have also demonstrated that FLT3 MRD negativity is a strong predictor of OS and LFS in multivariate analysis. The 2-year OS for FLT3 MRD negative and FLT3 MRD positive groups at transplant was 74% and 21%, respectively. Our results strongly suggest that pre-transplant detection of FLT3/ITD mutation by PCR may serve as a reliable MRD marker which predicts post-transplant outcome better than the hematological disease status. Data on the influence of pre-transplant FLT3/ITD status on outcome after allogeneic transplantation are scarce and actually limited to Gaballa study [9]. Our results are in line with this report, despite lower number of recruited patients. Nevertheless, further studies with larger number of patients are needed to draw final conclusions.\n\nIn contrary to previously mentioned report [9], it was demonstrated that FLT3/ITD mutation may occur at any time during leukemia course, and this mutation should not be used as MRD marker in AML [15]. The introduction of more advanced PCR techniques may increase the sensitivity of PCR method and therefore early therapeutic intervention [16]. Moreover, it would be valuable to correlate different MRD methods which are the following: PCR assay for FLT3/ITD and multi-parameter flow cytometry (FC).The results of MRD by flow cytometry (MRD-FC) at transplant were available in 28 patients from our cohort, and MRD-FC was positive in 21. There was a strong positive correlation between pre-transplant FLT3 MRD(+) and MRD-FC(+). Data on the role of pre-transplant MRD measured by FC in FLT3-mutated patients have been published recently. Only MRD-FC-positive patients transplanted from HLA-matched sibling donor were found to have poor outcome when compared with MRD-FC-negative transplants from both sibling and haploidentical donors. Interestingly, the outcome of haplo-SCT for MRD-FC-positive patients was comparable with that demonstrated for subjects with pre-transplant MRD-FC-negativity [17]. In the light of the recent findings and when confirmed in prospective studies, it seems reasonable to consider FLT3 inhibitor as a part of induction therapy and post-transplant maintenance [18, 19]. A double-blind randomized study showed that the addition of midostaurin to standard chemotherapy significantly improved overall and event-free survival in FLT3-positive AML patients; however, midostaurin was not beneficial as maintenance treatment after transplantation [18]. In the phase II RADIUS study, FLT3-positive AML patients who underwent Allo-SCT in CR1 were randomized to receive standard of care (SOC) with or without midostaurin. No differences in relapse-free survivals (RFS) between arms at 18 months and 24 months post-transplantation were demonstrated [20]. In contrast, post-transplant sorafenib improved RFS and OS when compared with placebo in the SORMAIN trial [21].\n\nReturning to our cohort, patients who received a graft from unrelated donor fared much better than those transplanted from sibling. The latter stands in contrast with Gaballa study [9], in which unrelated donor was a predictor of worse outcome (LFS/NRM). Our findings are difficult to explain, especially in the context of recent studies which showed the comparable results of Allo-SCT irrespective of donor source [22]. There was no impact of pre-transplant conditioning on the results of transplantation for FLT3-mutated AML, both in MD Anderson [9] and in our study; however, other groups found MAC to be more effective than RIC in terms of LFS [23]. It was also demonstrated that older age (> 60 years) was not associated with the worse outcome in FLT3-mutated AML patients undergoing Allo-SCT. This procedure was found to be feasible with RIC, and CR1 at transplant was a predictor of favorable outcome [24]. There were only 4 elderly patients in our cohort and 3 of them are alive; however, the follow-up is relatively short (11 months).\n\nIn conclusion, patients with FLT3-mutated AML should proceed to allogeneic stem cell transplantation as soon as possible in the disease course. Most promising results are associated with the FLT3 MRD eradication before transplantation. Post-transplant maintenance with FLT3 inhibitors may increase survival.\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\nGH has received a speaker honorarium from Novartis. All other authors declare no conflict of interest.\n\nEthical approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any animal studies performed by any of the authors.\n\nInformed consent\nInformed consent was obtained from all individual participants included in the study.\n==== Refs\nReferences\n1. Stirewalt DL Radich JP The role of FLT3 in hematopoietic malignancies Nat Rev Cancer 2003 3 650 665 10.1038/nrc1169 12951584 \n2. Frӧhling S Schlenk RF Breitruck J Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML study group Ulm Blood. 2002 100 4372 4380 10.1182/blood-2002-05-1440 12393388 \n3. Rombouts WJ Blokland I Lowenberg B Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene Leukemia. 2000 14 675 683 10.1038/sj.leu.2401731 10764154 \n4. Dӧhner H Estey E Grimwade D Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel Blood. 2017 129 424 447 10.1182/blood-2016-08-733196 27895058 \n5. Bornhauser M Illmer T Schaich M Improved outcome after stem-cell transplantation in FLT3-ITD positive AML Blood. 2007 109 2264 2265 10.1182/blood-2006-09-047225 17312001 \n6. Lin PH Lin CC Yang HI Li LY Bai LY Chiu CF Liao YM Lin CY Hsieh CY Lin CY Ho CM Yang SF Peng CT Tsai FJ Yeh SP Prognostic impact of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia patients with internal tandem duplication of FLT3 Leuk Res 2013 37 287 292 10.1016/j.leukres.2012.10.005 23276395 \n7. Gale RE Hills R Kottaridis PD No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials Blood. 2005 106 5658 5665 \n8. Brunet S Labopin M Esteve J Cornelissen J Socié G Iori AP Verdonck LF Volin L Gratwohl A Sierra J Mohty M Rocha V Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis J Clin Oncol 2012 30 735 741 10.1200/JCO.2011.36.9868 22291086 \n9. Gaballa S Saliba R Oran B Brammer JE Chen J Rondon G Alousi AM Kebriaei P Marin D Popat UR Andersson BS Shpall EJ Jabbour E Daver N Andreeff M Ravandi F Cortes J Patel K Champlin RE Ciurea SO Relapse risk and survival in patients with FLT3 mutated acute myeloid leukemia undergoing stem cell transplantation Am J Hematol 2017 92 331 337 10.1002/ajh.24632 28052408 \n10. Huang Q, Chen W, Gaal KK et al A rapid, one step assay for simultaneous detection of FLT3/ITD and NPM1 mutations in AML with normal cytogenetics. Br J Haematol 142:489–492\n11. Dohner H Estey EH Amadori S Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet Blood. 2010 115 453 474 10.1182/blood-2009-07-235358 19880497 \n12. Ma Y Wu Y Shen Z Is allogeneic transplantation really the best treatment for FLT3/ITD-positive acute myeloid leukemia? A systemic review Clin Transpl 2015 29 149 160 10.1111/ctr.12495 \n13. DeZern AE Sung A Kim S Smith BD Karp JE Gore SD Jones RJ Fuchs E Luznik L McDevitt M Levis M Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly-diagnosed patients from a single institution Biol Blood Marrow Transplant 2011 17 1404 1409 10.1016/j.bbmt.2011.02.003 21324374 \n14. Oran B Cortes J Beitinjaneh A Chen HC de Lima M Patel K Ravandi F Wang X Brandt M Andersson BS Ciurea S Santos FP de Padua Silva L Shpall EJ Champlin RE Kantarjian H Borthakur G Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD-positive acute myelogenous leukemia Biol Blood Marrow Transplant 2016 22 1218 1226 10.1016/j.bbmt.2016.03.027 27058617 \n15. Nazha A Cortes J Faderl S Pierce S Daver N Kadia T Borthakur G Luthra R Kantarjian H Ravandi F Activating internal tandem duplication mutations of the fms-like tyrosine kinase-3 (FLT3-ITD) at complete remission and relapse in patients with acute myeloid leukemia Haematologica. 2012 97 1242 1245 10.3324/haematol.2012.062638 22532519 \n16. Grunwald MR Tseng LH Lin MT Improved FLT3/ITD PCR assay predicts outcome following allogenic transplant for AML Biol Blood Marrow Transplant 2004 20 1989 1995 10.1016/j.bbmt.2014.08.015 \n17. Zhao X Wang Z Ruan G Liu Y Wang Y Zhang X Xu L Huang X Chang Y Impact of pre-transplantation minimal residual disease determined by multiparameter flow cytometry on the outcome of AML patients with FLT3-ITD after allogeneic stem cell transplantation Ann Hematol 2018 97 967 975 10.1007/s00277-018-3265-1 29423758 \n18. Stone RM Mandrekar SJ Sanford BL Laumann K Geyer S Bloomfield CD Thiede C Prior TW Döhner K Marcucci G Lo-Coco F Klisovic RB Wei A Sierra J Sanz MA Brandwein JM de Witte T Niederwieser D Appelbaum FR Medeiros BC Tallman MS Krauter J Schlenk RF Ganser A Serve H Ehninger G Amadori S Larson RA Döhner H Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation N Engl J Med 2017 377 454 464 10.1056/NEJMoa1614359 28644114 \n19. Bazarbachi A Labopin M Battipaglia G Allogeneic stem cell transplantation for FLT3-mutated acute myeloid leukemia: in vivo T-cell depletion and posttransplant sorafenib maintenance improve survival. A retrospective acute leukemia working party- European Society for Blood and Marrow Transplant Study Clin Hematol Int 2019 1 58 74 10.2991/chi.d.190310.001 \n20. Maziarz RT, Patnaik MM, Scott BL, et al. (2018) Radius: a phase 2 randomized trial investigating standard of care +/− midostaurin after allogeneic stem cell transplantation in FLT3/ITD-mutated AML. 60th ASH Annual Meeting and Exposition, San Diego, CA. Abstract 633\n21. Burchert A, Bug G, Finke J, et al. (2018) Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: results from the randomized, double-blind, placebo-controlled multicenter Sormain Trial. . 60th ASH Annual Meeting and Exposition, San Diego, CA. Abstract 661\n22. Di Stasi A Milton DR Poon LM Similar transplantation outcome for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors Biol Blood Marrow Transplant 2014 20 1975 1981 10.1016/j.bbmt.2014.08.013 25263628 \n23. Fleischmann M Schnetzke U Schrenk KG Schmidt V Sayer HG Hilgendorf I Hochhaus A Scholl S Outcome of FLT3-ITD-positive acute myeloid leukemia: impact of allogeneic stem cell transplantation and tyrosine kinase inhibitor treatment J Cancer Res Clin Oncol 2017 143 337 345 10.1007/s00432-016-2290-5 27778197 \n24. Poire X Labopin M Polge E Allogeneic stem cell transplantation benefits for patients ≥60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the acute leukemia working Party of the European Society for blood and marrow transplantation Haematologica. 2018 103 256 265 10.3324/haematol.2017.178251 29242299\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0939-5555",
"issue": "99(8)",
"journal": "Annals of hematology",
"keywords": "Acute myeloid leukemia; Allogeneic stem cell transplantation; FLT3/ITD mutation; Leukemia-free survival; Minimal residual disease; Overall survival",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D064591:Allografts; D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D033581:Stem Cell Transplantation; D015996:Survival Rate; D061349:Unrelated Donors; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1845-1853",
"pmc": null,
"pmid": "32333156",
"pubdate": "2020-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "29423758;25263628;19880497;22532519;17312001;29242299;10764154;12393388;27895058;25240816;16076872;27778197;12951584;23276395;22291086;27058617;18477048;21324374;25430616;28644114;28052408",
"title": "Pre-transplant FLT3/ITD status predicts outcome in FLT3-mutated acute myeloid leukemia following allogeneic stem cell transplantation.",
"title_normalized": "pre transplant flt3 itd status predicts outcome in flt3 mutated acute myeloid leukemia following allogeneic stem cell transplantation"
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"abstract": "Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.",
"affiliations": "Rheumatology, Tallaght University Hospital, Dublin, Ireland colmkirby11@gmail.com.;Radiology, Beaumont Hospital, Dublin, Ireland.;Pathology, Tallaght University Hospital, Dublin, Ireland.;Rheumatology, Tallaght University Hospital, Dublin, Ireland.",
"authors": "Kirby|Colm|C|http://orcid.org/0000-0001-7131-6721;Herlihy|Darragh|D|;Clarke|Lindsey|L|;Mullan|Ronan|R|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C555450:secukinumab",
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"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n33619146\nbcr-2020-240615\n10.1136/bcr-2020-240615\nCase Report\n1506\n539\n532\n536\nSarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis\nhttp://orcid.org/0000-0001-7131-6721Kirby Colm 1 Herlihy Darragh 2 Clarke Lindsey 3 Mullan Ronan 1 1 Rheumatology, Tallaght University Hospital, Dublin, Ireland\n2 Radiology, Beaumont Hospital, Dublin, Ireland\n3 Pathology, Tallaght University Hospital, Dublin, Ireland\nCorrespondence to Dr Colm Kirby; colmkirby11@gmail.com\n2021 \n22 2 2021 \n22 2 2021 \n14 2 e24061508 2 2021 © BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2021http://creativecommons.org/licenses/by-nc/4.0/This is an open access article 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. See: http://creativecommons.org/licenses/by-nc/4.0/.Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.\n\ndrugs: musculoskeletal and joint diseasesbiological agentsspecial-featureunlocked\n==== Body\nBackground\nSarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.\n\nCase presentation\nA 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.\n\nMedical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.\n\nClinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.\n\nInvestigations\nLaboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.\n\nDifferential diagnosis\nOur patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.\n\nTreatment\nAfter failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.\n\nOutcome and follow-up\nSix months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.\n\nFigure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.\n\nLaboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).\n\nFigure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.\n\nFigure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.\n\nFigure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).\n\nA diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.\n\nDiscussion\nIn recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15\n\nSecukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24\n\nThe apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.\n\nPatient’s perspective\nSince this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.\n\nI developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.\n\nAll of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.\n\nAfter my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.\n\nOf course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.\n\nMy rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.\n\nThis has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.\n\nLearning points\nThis is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).\n\nIL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.\n\nThe paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.\n\nOur case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.\n\nTwitter: @ckirb19\n\nContributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Durcan \nR , Heffron \nC , Sweeney \nB \nNatalizumab induced cutaneous sarcoidosis-like reaction\n. J Neuroimmunol \n2019 ;333 :476955. 10.1016/j.jneuroim.2019.04.015 31108403 \n2 Fukuchi \nK , Hikawa \nM , Sano \nY , et al \nSarcoid-like reaction and vitiligo occurring after nivolumab therapy in a patient with metastatic melanoma\n. J Dermatol \n2019 ;46 :e359 –60\n. 10.1111/1346-8138.14887 30985014 \n3 Lu \nY \nFdg PET/CT course of Pembrolizumab-Associated multiorgan sarcoidosis\n. Clin Nucl Med \n2019 ;44 :167 –8\n. 10.1097/RLU.0000000000002408 30516667 \n4 Faviez \nG , Bousquet \nE , Rabeau \nA , et al \n[Sarcoid-like granulomatosis in cancer patients treated with immune checkpoints inhibitors]\n. Rev Mal Respir \n2018 ;35 :963 –7\n. 10.1016/j.rmr.2018.08.003 30220489 \n5 Heppt \nM , Niesert \nAC , Flaig \nM , et al \nSarcoidosis triggered by immune checkpoint blockade]\n. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete \n2018 ;69 :11 –13\n.\n6 Shono \nY , Kamata \nM , Takeoka \nS , et al \nCutaneous sarcoidosis in a patient with rheumatoid arthritis receiving tocilizumab\n. J Dermatol \n2018 ;45 :e217 –8\n. 10.1111/1346-8138.14268 29500868 \n7 Pescitelli \nL , Emmi \nG , Tripo \nL , et al \nCutaneous sarcoidosis during rituximab treatment for microscopic polyangiitis: an uncommon adverse effect?\n\nEuropean Journal of Dermatology \n2017 ;27 :667 –8\n. 10.1684/ejd.2017.3143 29165307 \n8 Powell \nJB , Matthews \nP , Rattehalli \nR , et al \nAcute systemic sarcoidosis complicating ustekinumab therapy for chronic plaque psoriasis\n. British Journal of Dermatology \n2015 ;172 :834 –6\n. 10.1111/bjd.13365 \n9 Yung \nS , Han \nD , Lee \nJK \nCutaneous sarcoidosis in a patient with severe asthma treated with omalizumab\n. Canadian Respiratory Journal \n2015 ;22 :315 –6\n. 10.1155/2015/265734 26401982 \n10 Judson \nMA , Elicker \nBM , Colby \nTV , et al \nThe development of sarcoidosis in patients receiving daclizumab: a case series from multiple clinical trials\n. Respir Med \n2019 ;149 :23 –7\n. 10.1016/j.rmed.2019.01.015 30885425 \n11 Willis \nMD , Hope-Gill \nB , Flood-Page \nP , et al \nSarcoidosis following alemtuzumab treatment for multiple sclerosis\n. Multiple Sclerosis Journal \n2018 ;24 :1779 –82\n. 10.1177/1352458518790391 30307364 \n12 Antoniu \nSA \nTargeting the TNF-α pathway in sarcoidosis\n. Expert Opin Ther Targets \n2010 ;14 :21 –9\n. 10.1517/14728220903449244 20001207 \n13 Harper \nLJ , McCarthy \nM , Ribeiro Neto \nML , et al \nInfliximab for refractory cardiac sarcoidosis\n. Am J Cardiol \n2019 ;124 :1630 –5\n. 10.1016/j.amjcard.2019.07.067 31500815 \n14 Santos \nE , Shaunak \nS , Renowden \nS , et al \nTreatment of refractory neurosarcoidosis with infliximab\n. Journal of Neurology, Neurosurgery & Psychiatry \n2010 ;81 :241 –6\n. 10.1136/jnnp.2008.149989 \n15 Sebode \nM , Weidemann \nS , Wehmeyer \nM , et al \nAnti-TNF-α for necrotizing sarcoid granulomatosis of the liver\n. Hepatology \n2017 ;65 :1410 –2\n. 10.1002/hep.28966 27981598 \n16 Hohenberger \nM , Cardwell \nLA , Oussedik \nE , et al \nInterleukin-17 inhibition: role in psoriasis and inflammatory bowel disease\n. Journal of Dermatological Treatment \n2018 ;29 :13 –18\n. 10.1080/09546634.2017.1329511 \n17 Agostini \nC , Adami \nF , Semenzato \nG \nNew pathogenetic insights into the sarcoid granuloma\n. Curr Opin Rheumatol \n2000 ;12 :71 –6\n. 10.1097/00002281-200001000-00012 10647958 \n18 Agostini \nC , Trentin \nL , Facco \nM , et al \nRole of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis\n. Journal of immunology \n1996 ;157 :910 –8\n.\n19 Girgis \nRE , Basha \nMA , Maliarik \nM , et al \nCytokines in the bronchoalveolar lavage fluid of patients with active pulmonary sarcoidosis\n. Am J Respir Crit Care Med \n1995 ;152 :71 –5\n. 10.1164/ajrccm.152.1.7599865 7599865 \n20 Larousserie \nF , Pflanz \nS , Coulomb-L'Herminé \nA , et al \nExpression of IL-27 in human Th1-associated granulomatous diseases\n. J Pathol \n2004 ;202 :164 –71\n. 10.1002/path.1508 14743498 \n21 Sakthivel \nP , Bruder \nD \nMechanism of granuloma formation in sarcoidosis\n. Curr Opin Hematol \n2017 ;24 :59 –65\n. 10.1097/MOH.0000000000000301 27755127 \n22 Shigehara \nK , Shijubo \nN , Ohmichi \nM , et al \nIl-12 and IL-18 are increased and stimulate IFN-γ production in sarcoid lungs\n. The Journal of Immunology \n2001 ;166 :642 –9\n. 10.4049/jimmunol.166.1.642 11123348 \n23 ten Berge \nB , Paats \nMS , Bergen \nIM , et al \nIncreased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis\n. Rheumatology \n2012 ;51 :37 –46\n. 10.1093/rheumatology/ker316 22075064 \n24 Eichhoff \nG \nManagement with secukinumab of tumour necrosis factor inhibitor‐induced pulmonary sarcoidosis‐like reaction in a patient with psoriasis\n. Clin Exp Dermatol \n2020 ;45 :455 –6\n. 10.1111/ced.14101 31541476\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "biological agents; drugs: musculoskeletal and joint diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015535:Arthritis, Psoriatic; D005260:Female; D006801:Humans; D008875:Middle Aged; D012507:Sarcoidosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33619146",
"pubdate": "2021-02-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30220489;10647958;31541476;11123348;14743498;28521565;30307364;30985014;30516667;30885425;31500815;29165307;31108403;22075064;26401982;7599865;18977810;8752945;27755127;27981598;20001207;29500868;30264301;25141774",
"title": "Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.",
"title_normalized": "sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis"
} | [
{
"companynumb": "NVSC2021IE056091",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SECUKINUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "A woman developed a prolonged QT interval and torsade de pointes while on methadone treatment for heroin addiction. We think methadone, or its impaired metabolism, was the major cause for her prolonged QT interval and progression to torsade. However, torsade is often multifactorial, as was likely so in this case. We advise physicians treating patients taking methadone to obtain careful medication and drug-use histories, screen for risk factors associated with long QT syndrome, counsel patients about potential drug interactions, and measure the QT interval before and during methadone treatment in high-risk patients.",
"affiliations": "Division of General Internal Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. kropfp@upmc.edu",
"authors": "Lamont|Patricia|P|;Hunt|Susan C|SC|",
"chemical_list": "D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1525-1497.2006.00588.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-8734",
"issue": "21(11)",
"journal": "Journal of general internal medicine",
"keywords": null,
"medline_ta": "J Gen Intern Med",
"mesh_terms": "D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008691:Methadone; D008875:Middle Aged; D016171:Torsades de Pointes",
"nlm_unique_id": "8605834",
"other_id": null,
"pages": "C9-C12",
"pmc": null,
"pmid": "17026725",
"pubdate": "2006-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10560690;15774410;12230351;12230382;12388652;15781034;15963159;12496496;12586234;12704598;12791438;12861106;14556883;14999113;2876691;7736582;9604234;15721475;11286435",
"title": "A twist on torsade: a prolonged QT interval on methadone.",
"title_normalized": "a twist on torsade a prolonged qt interval on methadone"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-06638",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nEosinophilic otitis media (EOM) is a rare middle ear disease that may closely resemble therapy-resistant otitis media with effusion (OME). The diagnosis is made if eosinophil-rich fluid is present with two or more of the following minor criteria: (a) history of nasal polyps or, (b) bronchial asthma, with (c) viscous fluid in the middle-ear, or (d) conventional otitis media treatment has no effect.\n\n\nMETHODS\nA 70-year-old male with a history of the ASA triad (bronchial asthma, nasal/ethmoidal polyposis and aspirin intolerance) presented with progressive mixed hearing loss. Otoscopy showed bilateral otitis media with effusion (OME). Conventional treatment of this had no effect. Myringotomy resulted in the evacuation of highly viscous middle-ear effusion containing abundant eosinophils. After treatment with oral corticosteroids his symptoms improved considerably. Following later optimisation of his asthma treatment, corticosteroid treatment was stopped and his hearing remained stable.\n\n\nCONCLUSIONS\nThe adequate recognition and treatment of EOM will result in the prevention of permanent hearing loss.",
"affiliations": "Maastricht Universitair Medisch Centrum, afd. Keel-, Neus- en Oorheelkunde, Maastricht.",
"authors": "de Jong|Monique A M|MA|;Smithuis|L O M J Otto|LO|;Stokroos|Robert J|RJ|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "158()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D001249:Asthma; D004804:Eosinophils; D034381:Hearing Loss; D006801:Humans; D008297:Male; D010034:Otitis Media with Effusion",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "A8044",
"pmc": null,
"pmid": "25387983",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Eosinophilic otitis media.",
"title_normalized": "eosinophilic otitis media"
} | [
{
"companynumb": "NL-BAYER-2014-173879",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Drug interactions are a common cause of morbidity and mortality and may require prompt discontinuation of therapeutic regimens due to harmful side effects. Patients with acute coronary syndromes are likely to be prescribed multiple medications that are metabolized through the cytochrome P450 system, increasing the probability for drug interaction. Atorvastatin and simvastatin are both well known to interact with the oral P2Y12 agent ticagrelor. The purpose of this paper is to describe the interaction of ticagrelor with rosuvastatin leading to rhabdomyolysis, which is less clearly defined in the literature.\nWe report a case of a 74-year-old male who presented with bilateral lower extremity weakness and difficulty ambulating for one month after being prescribed ticagrelor for a drug eluting stent, in the setting of already being on rosuvastatin. His clinical picture and laboratory findings were consistent with a diagnosis of rhabdomyolysis. His medications were adjusted to a regimen of clopidogrel and alirocumab. One month later, he returned to his baseline status.\nThe mechanism of interaction between rosuvastatin and ticagrelor appears to be multifactorial. It may be caused by CYP450-mediated metabolism from a small amount of crossover between isoenzymes. Ticagrelor may also cause acute kidney injury, increasing the concentration of rosuvastatin. Other mechanisms of interaction include genetic differences in the organic anion transporter polypeptides and transportation through p-glycoprotein.\nFuture pharmacokinetic studies are warranted to better understand the interaction.",
"affiliations": "New York University School of Medicine, New York City, USA.;New York University School of Medicine, New York City, USA.;New York University School of Medicine, New York City, USA.",
"authors": "Sibley|Rachel A|RA|https://orcid.org/0000-0002-5761-0681;Katz|Alyson|A|;Papadopoulos|John|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0018578720928262",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "56(5)",
"journal": "Hospital pharmacy",
"keywords": "adverse drug reactions; anticoagulants; cardiac agents; cardiovascular; drug interactions",
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "537-542",
"pmc": null,
"pmid": "34720158",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": "12860216;21177984;29734517;17984166;23137503;29521318;18612079;9741509;18408300;26003161;7566020;28223230;15030249;28630772;29167415;22922682;19717846;23380426;19694740;11277825;27754879;5677720;25935875;19149497;29104841;25852115;17389673;24602118;23469685;31745500;15531279;30003466;23407140",
"title": "The Interaction Between Rosuvastatin and Ticagrelor Leading to Rhabdomyolysis: A Case Report and Narrative Review.",
"title_normalized": "the interaction between rosuvastatin and ticagrelor leading to rhabdomyolysis a case report and narrative review"
} | [
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-053907",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TICAGRELOR"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nMore than 100 drugs have been registered as inducing subacute cutaneous lupus erythematosus (SCLE). Recently, some types of chemotherapy have also been incriminated. If SCLE develops in a setting of neoplasia, two possibilities should be considered: it is either a paraneoplastic syndrome or it is caused by the chemotherapy, thus calling for important decisions on the benefit/risk of stopping potentially effective medication. We report a case of SCLE induced by Xeloda (capecitabine).\n\n\nMETHODS\nA 50-year-old female patient consulted with an annular erythematosquamous and pruriginous eruption, predominantly on areas of the body exposed to sunlight, occurring 4 months after the initiation of capecitabine for advanced colon cancer. She had presented systemic lupus erythematosus (SLE) for many years, which was not treated, was not progressive and had no cutaneous manifestations. The appearance of the cutaneous lesions, positivity for anti-SSA antibodies and the histological aspect led to diagnosis of SCLE. The lesions were resistant to treatment with hydroxychloroquine and systemic corticosteroids, but disappeared after discontinuation of capecitabine, suggesting chemotherapy-induced SCLE.\n\n\nCONCLUSIONS\nSome types of chemotherapy such as capecitabine may reveal or induce SCLE lesions, whether or not there is a previous history of SLE. Cases of chemotherapy-induced cutaneous lupus reported to the French pharmacovigilance agency are rare, but this side effect must be recognised due to the constantly rising use of this type of anticancer agent.",
"affiliations": "Service de dermatologie, CHU La Timone, 13005 Marseille, France; Service de médecine interne, centre de compétence PACA Ouest pour la prise en charge des pathologies auto-immunes systémiques, CHU de la Conception, 147, boulevard Baille, 13005 Marseille, France.;Service de médecine interne, centre de compétence PACA Ouest pour la prise en charge des pathologies auto-immunes systémiques, CHU de la Conception, 147, boulevard Baille, 13005 Marseille, France.;Cabinet de dermatologie, 47B, avenue Maréchal-Foch, 83390 Cuers, France.;Service de médecine interne, centre de compétence PACA Ouest pour la prise en charge des pathologies auto-immunes systémiques, CHU de la Conception, 147, boulevard Baille, 13005 Marseille, France.;Pharmacovigilance, hôpital Salvator, 13009 Marseille, France.;Laboratoire d'anatomopathologie, 219, rue Revel, 83000 Toulon, France.;Service de médecine interne, centre de compétence PACA Ouest pour la prise en charge des pathologies auto-immunes systémiques, CHU de la Conception, 147, boulevard Baille, 13005 Marseille, France.;Service de dermatologie, CHU La Timone, 13005 Marseille, France.;Service de médecine interne, centre de compétence PACA Ouest pour la prise en charge des pathologies auto-immunes systémiques, CHU de la Conception, 147, boulevard Baille, 13005 Marseille, France. Electronic address: laurent.chiche@ap-hm.fr.",
"authors": "Fongue|J|J|;Meunier|B|B|;Lardet|D|D|;Dicostanzo|M-P|MP|;Rouby|F|F|;Terrier|J-P|JP|;Harlé|J-R|JR|;Richard|M-A|MA|;Chiche|L|L|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "141(10)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": "Capecitabine; Capécitabine; Chemotherapy; Chimiothérapie; Induced cutaneous lupus erythematosus; Lupus cutané induit; Lupus érythémateux subaigu; Subacute cutaneous lupus erythematosus",
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D003110:Colonic Neoplasms; D003841:Deoxycytidine; D003937:Diagnosis, Differential; D005260:Female; D005472:Fluorouracil; D005602:France; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous; D008875:Middle Aged",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "593-7",
"pmc": null,
"pmid": "25288062",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Capecitabine-induced subacute cutaneous lupus: a case report.",
"title_normalized": "capecitabine induced subacute cutaneous lupus a case report"
} | [
{
"companynumb": "FR-ROCHE-1282437",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nCombined treatment with a selective serotonin reuptake inhibitor (SSRI) plus mirtazapine has shown superior efficacy in some studies of depression, but has not been studied in posttraumatic stress disorder (PTSD). This study aimed to assess acceptability of combined sertraline plus mirtazapine treatment for PTSD and to estimate its effect size relative to sertraline plus placebo.\n\n\nMETHODS\nThirty-six adults with PTSD were randomized to 24 weeks of double-blind treatment with sertraline plus mirtazapine or sertraline plus placebo. Outcomes were analyzed with mixed effects models.\n\n\nRESULTS\nThe combined treatment group showed a significantly greater remission rate (P = .042) and improvement in depressive symptoms (P = .023) than the sertraline plus placebo group. There were no significant group differences in the two primary outcomes of treatment retention and PTSD severity, or in other secondary outcomes (sleep impairment, sexual functioning, quality of life, and physical and mental functioning), but the combined treatment group showed numerical advantages on all of these outcomes, and effect sizes relative to sertraline plus placebo ranged from small to moderate (d = .26-.63). Both treatments were well-tolerated, with significantly increased appetite but not weight gain in the combined treatment group.\n\n\nCONCLUSIONS\nFindings suggest that combined treatment of PTSD with sertraline plus mirtazapine may have clinically meaningful advantages in symptomatic improvement, relative to SSRI treatment alone, and acceptable tolerability. Combined treatment with an SSRI plus mirtazapine in PTSD deserves additional study as initial treatment or as an augmentation strategy for nonresponders to an SSRI.",
"affiliations": "New York State Psychiatric Institute, New York, New York.;New York State Psychiatric Institute, New York, New York.;Hispanic Family Mental Health Center, Woodside, New York.;Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.;New York State Psychiatric Institute, New York, New York.;New York State Psychiatric Institute, New York, New York.;New York State Psychiatric Institute, New York, New York.;New York State Psychiatric Institute, New York, New York.;New York State Psychiatric Institute, New York, New York.",
"authors": "Schneier|Franklin R|FR|;Campeas|Raphael|R|;Carcamo|Jaime|J|;Glass|Andrew|A|;Lewis-Fernandez|Roberto|R|;Neria|Yuval|Y|;Sanchez-Lacay|Arturo|A|;Vermes|Donna|D|;Wall|Melanie M|MM|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D010919:Placebos; D017367:Serotonin Uptake Inhibitors; D008803:Mianserin; D000078785:Mirtazapine; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1002/da.22384",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1091-4269",
"issue": "32(8)",
"journal": "Depression and anxiety",
"keywords": "antidepressants; anxiety; combined treatment; norepinephrine; posttraumatic stress disorder; psychopharmacology; randomized clinical trial; serotonin",
"medline_ta": "Depress Anxiety",
"mesh_terms": "D000328:Adult; D000929:Antidepressive Agents, Tricyclic; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008803:Mianserin; D008875:Middle Aged; D000078785:Mirtazapine; D017063:Outcome Assessment, Health Care; D010919:Placebos; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D013313:Stress Disorders, Post-Traumatic; D055815:Young Adult",
"nlm_unique_id": "9708816",
"other_id": null,
"pages": "570-9",
"pmc": null,
"pmid": "26115513",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15491244;12880643;12637842;8290681;11729012;10631623;15533706;15487537;11495091;14608246;20008946;24486520;16892419;8636062;3335835;25213835;10693114;20346193;12411239;20160171;16437445;10793320;15076016;10761674;11411812;10954063;19345072;2748771;10770145;7492257;21536692;14399272;11822997;14558871;17803838;11387733;20717484",
"title": "COMBINED MIRTAZAPINE AND SSRI TREATMENT OF PTSD: A PLACEBO-CONTROLLED TRIAL.",
"title_normalized": "combined mirtazapine and ssri treatment of ptsd a placebo controlled trial"
} | [
{
"companynumb": "US-CIPLA (EU) LIMITED-2018US18323",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "Polonium-210 ((210)Po) gained widespread notoriety after the poisoning and subsequent death of Mr Alexander Litvinenko in London, UK, in 2006. Exposure to (210)Po resulted initially in a clinical course that was indistinguishable from infection or exposure to chemical toxins, such as thallium.\n\n\n\nA 43-year-old man presented to his local hospital with acute abdominal pain, diarrhoea, and vomiting, and was admitted to the hospital because of dehydration and persistent gastrointestinal symptoms. He was initially diagnosed with gastroenteritis and treated with antibiotics. Clostridium difficile toxin was subsequently detected in his stools, which is when he first raised the possibility of being poisoned and revealed his background and former identity, having been admitted under a new identity with which he had been provided on being granted asylum in the UK. Within 6 days, the patient had developed thrombocytopenia and neutropenia, which was initially thought to be drug induced. By 2 weeks, in addition to bone marrow failure, he had evidence of alopecia and mucositis. Thallium poisoning was suspected and investigated but ultimately dismissed because blood levels of thallium, although raised, were lower than toxic concentrations. The patient continued to deteriorate and within 3 weeks had developed multiple organ failure requiring ventilation, haemofiltration, and cardiac support, associated with a drop in consciousness. On the 23rd day after he first became ill, he suffered a pulseless electrical activity cardiorespiratory arrest from which he could not be resuscitated and was pronounced dead.\n\n\n\nUrine analysis using gamma-ray spectroscopy on day 22 showed a characteristic 803 keV photon emission, raising the possibility of (210)Po poisoning. Results of confirmatory analysis that became available after the patient's death established the presence of (210)Po at concentrations about 10(9)-times higher than normal background levels. Post-mortem tissue analyses showed autolysis and retention of (210)Po at lethal doses in several organs. On the basis of the measured amounts and tissue distribution of (210)Po, it was estimated that the patient had ingested several 1000 million becquerels (a few GBq), probably as a soluble salt (eg, chloride), which delivered very high and fatal radiation doses over a period of a few days.\n\n\n\nEarly symptoms of (210)Po poisoning are indistinguishable from those of a wide range of chemical toxins. Hence, the diagnosis can be delayed and even missed without a high degree of suspicion. Although body surface scanning with a standard Geiger counter was unable to detect the radiation emitted by (210)Po, an atypical clinical course prompted active consideration of poisoning with radioactive material, with the diagnosis ultimately being made with gamma-ray spectroscopy of a urine sample.\n\n\n\nUK NHS, Public Health England, and the UK Department of Health.",
"affiliations": "Department of Haematology, UCL Cancer Institute, London, UK; Department of Haematology, Royal Free London NHS Foundation Trust Hospital, London, UK; Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust Hospital, London, UK; National Health Services Blood and Transplant, Watford, UK. Electronic address: amit.nathwani@ucl.ac.uk.;Intensive Care Unit, University College London Hospitals NHS Foundation Trust, London, UK.;Intensive Care Unit, University College London Hospitals NHS Foundation Trust, London, UK.;Intensive Care Unit, University College London Hospitals NHS Foundation Trust, London, UK.;Clinical Toxicology, Guy's & St Thomas' NHS Foundation Trust, London, UK; Faculty of Life Sciences and Medicine, King's College London, London, UK.;Department of Haematology, Royal Free London NHS Foundation Trust Hospital, London, UK.;Public Health England, London, UK.;Public Health England, London, UK.;Public Health England, London, UK.",
"authors": "Nathwani|Amit C|AC|;Down|James F|JF|;Goldstone|John|J|;Yassin|James|J|;Dargan|Paul I|PI|;Virchis|Andres|A|;Gent|Nick|N|;Lloyd|David|D|;Harrison|John D|JD|",
"chemical_list": "D011059:Polonium",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(16)00144-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "388(10049)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D000505:Alopecia; D003244:Consciousness Disorders; D057210:Delayed Diagnosis; D003937:Diagnosis, Differential; D004739:England; D017809:Fatal Outcome; D005759:Gastroenteritis; D006323:Heart Arrest; D006801:Humans; D008297:Male; D052016:Mucositis; D009102:Multiple Organ Failure; D009503:Neutropenia; D011041:Poisoning; D011059:Polonium; D012131:Respiratory Insufficiency; D013921:Thrombocytopenia",
"nlm_unique_id": "2985213R",
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"references": null,
"title": "Polonium-210 poisoning: a first-hand account.",
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"abstract": "BACKGROUND\nIn the treatment of secondary hyperparathyroidism of chronic kidney disease, calcimimetics - allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia and significantly reduce circulating parathyroid hormone levels. They have a major impact on the management of secondary hyperparathyroidism.\n\n\nMETHODS\nWe present the clinical case of a 41-year-old Caucasian man undergoing chronic hemodialysis, who had a parathyroidectomy to treat severe secondary hyperparathyroidism resistant to cinacalcet treatment. Preoperatively, 24 months after high-dose cinacalcet hydrochloride, we observed a persistently elevated intact parathyroid hormone serum level, and detected clear parathyroid gland hyperplasia regression on ultrasound. We performed a three-gland parathyroidectomy, which was assumed to be total, associated with a hemithyroidectomy. Our patient then entered a hypoparathyroid state. A histopathological examination showed that the removed parathyroid glands were of small size, with a total weight of 1g, associated with a multifocal small papillary thyroid cancer.\n\n\nCONCLUSIONS\nIn the management of secondary hyperparathyroidism, cinacalcet hydrochloride effectively reduces total parathyroid gland hyperplasia. However, a persisting elevated intact parathyroid hormone serum level may be observed, demonstrating that reduced parathyroid hyperplastic tissue may still be associated with severe secondary hyperparathyroidism. Even if calcimimetics are very effective in secondary hyperparathyroidism treatment, further studies are necessary for a better understanding of their actions.",
"affiliations": "Department of Anesthesiology, Surgical and Emergency Science, VII Division of General and Endocrine Surgery, Second University of Naples, Via Gen, G, Orsini 42, Napoli, 80132, Italy. giovanni.conzo@unina2.it.",
"authors": "Conzo|Giovanni|G|;Perna|Alessandra F|AF|;Napolitano|Salvatore|S|;Mauriello|Claudio|C|;Gambardella|Claudio|C|;Satta|Ersilia|E|;Ciancia|Giuseppe|G|;Capasso|Giovanbattista|G|;Santini|Luigi|L|",
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"country": "England",
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"doi": "10.1186/1752-1947-6-417",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-6-4172323202710.1186/1752-1947-6-417Case ReportPartial response to cinacalcet treatment in a patient with secondary hyperparathyroidism undergoing hemodialysis: a case report Conzo Giovanni 1giovanni.conzo@unina2.itPerna Alessandra F 2alessandra.perna@unina2.itNapolitano Salvatore 1dottornapolitano@gmail.comMauriello Claudio 1claudio.mauriello@live.itGambardella Claudio 1claudiog86@hotmail.itSatta Ersilia 2ersilia.satta@unina2.itCiancia Giuseppe 3giuseppe.ciancia@unina.itCapasso Giovanbattista 2giovanni.capasso@unina2.itSantini Luigi 1luigi.santini@unina2.it1 Department of Anesthesiology, Surgical and Emergency Science, VII Division of General and Endocrine Surgery, Second University of Naples, Via Gen. G. Orsini 42, Napoli, 80132, Italy2 Department of Cardio-thoracic and Respiratory Sciences, First Division of Nephrology, Second University of Naples, Naples, Italy3 Department of Biomorphology and Functional Sciences, “Federico II” University of Naples, Naples, Italy2012 11 12 2012 6 417 417 27 8 2012 6 11 2012 Copyright ©2012 Conzo et al.; licensee BioMed Central Ltd.2012Conzo et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nIn the treatment of secondary hyperparathyroidism of chronic kidney disease, calcimimetics - allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia and significantly reduce circulating parathyroid hormone levels. They have a major impact on the management of secondary hyperparathyroidism.\n\nCase presentation\nWe present the clinical case of a 41-year-old Caucasian man undergoing chronic hemodialysis, who had a parathyroidectomy to treat severe secondary hyperparathyroidism resistant to cinacalcet treatment. Preoperatively, 24 months after high-dose cinacalcet hydrochloride, we observed a persistently elevated intact parathyroid hormone serum level, and detected clear parathyroid gland hyperplasia regression on ultrasound. We performed a three-gland parathyroidectomy, which was assumed to be total, associated with a hemithyroidectomy. Our patient then entered a hypoparathyroid state. A histopathological examination showed that the removed parathyroid glands were of small size, with a total weight of 1g, associated with a multifocal small papillary thyroid cancer.\n\nConclusion\nIn the management of secondary hyperparathyroidism, cinacalcet hydrochloride effectively reduces total parathyroid gland hyperplasia. However, a persisting elevated intact parathyroid hormone serum level may be observed, demonstrating that reduced parathyroid hyperplastic tissue may still be associated with severe secondary hyperparathyroidism. Even if calcimimetics are very effective in secondary hyperparathyroidism treatment, further studies are necessary for a better understanding of their actions.\n==== Body\nIntroduction\nSecondary hyperparathyroidism (2HPT) of chronic kidney disease has a negative effect on patient morbidity, inducing a higher mortality rate, particularly due to cardiovascular complications. In patients undergoing hemodialysis (HD), the incidence of 2HPT increases with dialysis ‘vintage’. Prior to the calcimimetic era, a parathyroidectomy (PTx) was necessary in 15% of cases after 10 years, rising to 38% after 20 years [1]. First marketed in 2004, calcimimetics - allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia and significantly reduce circulating parathyroid hormone (PTH) levels [2]. Before their introduction, standard medical treatment, consisting of phosphate chelators (calcium carbonate, sevelamer, lanthanum carbonate), dialysis baths with various calcium concentrations, and vitamin D and its analogues, was ineffective in many patients. Calcimimetics have demonstrated a major impact on 2HPT management. Nevertheless, nodular hyperplasia, typically associated with more advanced 2HPT, is less responsive to conservative treatment, presumably because of the reduced expression of calcium-sensing receptors (CaSR) and vitamin D receptors (VDR). Although cinacalcet hydrochloride effectively reduces intact parathyroid hormone (iPTH) levels, and is also effective in patients refractory to vitamin D therapy, the effect of cinacalcet hydrochloride in marked glandular hyperplasia is still the subject of active research [3]. We report the case of a patient with 2HPT, documenting that cinacalcet hydrochloride is able to reduce gland size, but is not able in all cases to reduce PTH secretion.\n\nCase presentation\nWe observed a 41-year-old Caucasian male patient who underwent, at the age of 10 years, resection of epileptogenic tubers for tuberous sclerosis. He was also treated with anticonvulsants for postoperative secondary refractory epilepsy (last therapy: phenobarbital 200mg per day; levetiracetam 1000mg per day; lamotrigine 150mg per day; vigabatrin 1500mg per day). He had giant kidney angiomyolipomas and polycystic kidney disease. At 35 years old, he was started on standard three-weekly HD treatment required for end-stage renal disease. A bilateral nephrectomy was then performed.\n\nOur patient developed severe 2HPT, and was managed by paricalcitol (Zemplar®, 5μg three times a week) and sevelamer (Renvela®, 7.2g per day). Subsequently, he developed acute alcoholic pancreatitis, and during this period his compliance to therapy was insufficient. In addition, he was ineligible for transplantation because of his severe comorbidities. His 2HPT became resistant to medical treatment and was associated with an iPTH serum level of 1123pg/mL (normal range 4.6 to 58.1pg/mL), serum calcium of 7.3mg/dL (normal range 8.9 to 10.3mg/dL, value corrected with serum albumin), serum phosphate (P) of 4.7mg/dL (normal range 2.4 to 4.1mg/dL) and 25-hydroxy vitamin D of 15ng/mL (normal range 30 to 74ng/mL) (Table 1). Cinacalcet hydrochloride (30mg per day) was administered from January 2010, and the dose was titrated upwards in the following period. In March 2011, his iPTH level was 1367pg/mL, and a cinacalcet hydrochloride dosage of 180mg per day was required. Our patient was referred to surgery for 2HPT resistant to medical treatment, associated with persistently elevated serum iPTH levels and clinical symptoms - anemia resistant to erythropoiesis-stimulating agent therapy, arthromyalgias, osteopenia and mood alterations. However, due to several intervening complications (arteriovenous fistula closure, catheter infection), surgery was postponed and performed in February 2012.\n\nTable 1 Mean monthly measurements performed during the year\n\n \t2010\t2011\t2012\t\nParathyroid hormone (pg/mL)\t1123\t1367\t848\t\nCalcium (mg/dL)\t7.3\t7.9\t7.5\t\nPhosphate (mg/dL)\t4.7\t5.4\t5.5\t\nAlkaline phosphatase (U/L)\t770\t678\t700\t\nHemoglobin (g/dL)\t10.0\t9.2\t9.0\t\nCinacalcet dose (mg/day)\t30\t90 to 180\t180\t\nParicalcitol (mg/week)\t15\t15\t15\t\nSevelamer (mg/day)\t4.8\t7.2\t7.2\t\nErythropoietin beta (UI)\t3000×3\t6000×2\t6000×3\t\nOf note, asymptomatic hypocalcaemia is present as well as anemia resistant to erythropoietin administration, requiring the increase of the erythropoietin dose (the patient was iron replete).\n\nPreoperative instrumental work-up had consisted of measurements of his iPTH, calcium, phosphate, alkaline phosphatase, free tri-iodothyronine, free thyroxine, thyroid-stimulating hormone and thyroglobulin serum levels; high resolution neck ultrasound (US); ear, nose and throat examination; and technetium-99m sestamibi scintigraphy. The LIAISON® intact PTH Assay (DiaSorin Inc., Stillwater, MN, USA), based on a chemiluminescence immunoassay, was used for the quantitative determination of iPTH. A cardiac evaluation included a 12-lead echocardiogram and epiaortic two-dimensional and color Doppler transthoracic echocardiogram. US examination showed two bilateral hypoechoic hyperplastic parathyroid glands, of 2.8×1.5×1.5cm (right gland) and 2.3×1.3×1.4cm (left gland). A technetium-99 sestamibi scintigraphy revealed hyperactive uptake activity in the same areas. Twelve months after initiating cinacalcet hydrochloride therapy, a regression of the parathyroid gland hyperplasia was detected by US (right gland: 2.2×1.0×0.9cm; left gland: 1.9×1.0×0.7cm).\n\nAfter an extensive neck exploration, including comprehensive exploration of the thyrothymic ligament, bilateral thymic tongues and the jugular-carotid axis to rule out the presence of ectopic and supernumerary glands, only three glands were removed. Extemporary histological examination confirmed the nature of these removed glands. We performed a, presumed total, PTx, not associated with autoimplantation. We also carried out a right loboisthmusectomy associated with thyrothymic ligament resection to look for an intrathyroidal parathyroid gland. Parathyroid tissue was not cryopreserved for re-transplant.\n\nOur patient’s iPTH serum level was 629pg/mL before anesthesia induction, 45pg/mL 20 minutes after surgery, and 4pg/mL 24 hours after surgery. Severe hypocalcemia was observed postoperatively, which was, however, never associated with hypocalcemic seizures. A pathological examination showed three hyperplastic nodular parathyroid glands and a multifocal small papillary thyroid carcinoma. The macroscopic parathyroid gland features are reported in Figure 1. Parathyroid tissue showed diffuse hyperplasia of chief cells with minimal fat. A focally nodular pattern was observed, while infarction, and fibrous or cystic degeneration were not observed. In order to assess the degree of apoptosis in the examined parathyroid tissue, an immunohistochemical study with the B-cell lymphoma-2 protein was performed, with adequate controls, using a monoclonal antibody, clone 124-Ventana® (Ventana Medical Systems, Inc., Tucson, AZ, USA). No B-cell lymphoma-2 positive-staining cells were detected in any of the examined glands.\n\nFigure 1 Removed parathyroid glands. Left lower parathyroid gland: 1.2×0.8×0.3cm, weight 0.5g; left upper parathyroid gland: 1.7×0.5×0.2cm, weight 0.3g; right upper parathyroid gland: 0.7×0.6×0.3cm, weight 0.2g.\n\nOur patient’s postoperative course was uneventful and he was discharged on day 4. Hypoparathyroidism (iPTH <4pg/mL) associated with persisting severe hypocalcemia was recorded two weeks and one month after surgery. Two months postoperatively, our patient had a subarachnoid hemorrhage and was moved to our intensive unit care in a comatose status. Fourteen days later, after recovery to generally acceptable clinical conditions, our patient was discharged.\n\nDiscussion\nIn 2HPT of chronic kidney disease, parathyroid gland hyperplasia, especially in its nodular form, is associated with reduced expression of CaSR and VDR, determining medical therapy resistance. Before cinacalcet hydrochloride was introduced, calcitriol and other vitamin D analogues, which also enhance calcium and phosphate serum levels, were considered the cornerstone of medical therapy. A glandular volume greater than 500mm3 and nodular hyperplasia, often observed in patients refractory to vitamin D treatment, are still considered the main medical treatment resistance factors. Subsequently, it has been shown that cinacalcet hydrochloride effectively reduces iPTH levels while maintaining calcium and phosphate levels within the normal range [3]. Komaba [4] reported calcium treatment efficacy, confirming a rapid decline in serum PTH levels, by 50%, in patients affected by severe 2HPT associated with suspected nodular hyperplasia and reduced expression of CaSR and VDR. Cinacalcet hydrochloride therapy has been shown to upregulate VDR and CaSR expression, facilitating medical therapy outcomes. Experiments carried out in animal models demonstrated reduced vascular and extraosseous calcifications.\n\nCinacalcet hydrochloride effects on the parathyroid gland may also result in cell hypertrophy reduction and increased apoptosis, determining the decrease in iPTH serum levels. Its use may also increase oxyphil to chief cell ratios and cystic degeneration. According to literature data [4-6], a decrease in PTH serum level is considered the main effect of cinacalcet hydrochloride therapy, whereas parathyroid gland hypertrophy reduction is not reported in all patients. On the contrary, in the reported case, despite high-dose cinacalcet hydrochloride therapy (180mg/day), carried out for a significant amount of time (over six months), a significant reduction in glandular volume, associated with persisting high iPTH serum level, was observed on US. Only after PTx did a hypoparathyroid state with severe hypocalcemia follow. However, we have to consider that prolonged therapy with anticonvulsants may cause vitamin D deficiency and hypocalcaemia [7].\n\nWe can consider several reasons for the low calcium levels observed in the face of high iPTH: a small amount of VDR expression in the cells; low compliance to oral calcium therapy; and drug interaction by anticonvulsants. In addition, other factors besides CaSR and VDR activity influence PTH release and synthesis. In particular, the latter is regulated by PTH and CaSR gene transcription, and variations in the amounts of messenger ribonucleic acid (mRNA)-encoding PTH-binding proteins, which are important for mRNA stability, can occur. RNA-binding proteins interact with sequence-specific elements, adenine- and uridine-rich elements, regulating the rate at which mRNAs are translated or degraded [8]. In addition, fibroblast growth factor 23 (FGF-23), usually much increased in patients on HD, has direct actions on the parathyroid gland, where it suppresses PTH secretion [9]. A markedly decreased expression of FGF receptor 1 and Klotho protein (a transmembrane protein required for FGF-23 receptor activation) in a hyperplastic parathyroid gland is present in patients on HD [10]. It is possible to hypothesize that variations of one of these factors are at play in explaining the reason that high PTH levels were present in our patient in association with a reduction in gland size.\n\nConclusions\nOur data suggest that further studies are necessary for a better understanding of the actions of cinacalcet hydrochloride that cause its pharmacological effects. In particular, after cinacalcet therapy, we observed an unusual small gland volume compared with other reported cases of 2HPT, while iPTH levels remained elevated. A few considerations can be made: first, in patients with 2HPT and persistently elevated iPTH serum levels after six months of high-dosage cinacalcet hydrochloride, medical resistance is present and surgical intervention should be recommended, especially in young patients. Second, regarding surgical treatment, a <10% intraoperative decrease of iPTH with respect to the baseline value, 20 minutes after PTx, may be considered predictive of total PTx [1]. Therefore, we suggest that autoimplantation is a better choice in patients on a waiting list for renal transplantation, especially when only three parathyroid glands are intraoperatively identified and removed [11]. In fact, it is well recognized that in only about 3% of patients with 2HPT on HD will three glands be present [1]. The third consideration is that, in cases of unresponsiveness to medical treatment for 2HPT, especially in young patients on HD, a multidisciplinary, early, aggressive treatment (early surgery or high-dose calcimimetics therapy) must be recommended to avoid severe cardiovascular events and other complications related to chronic kidney disease, and to ameliorate quality of life.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nGC and AFP analyzed and interpreted the patient’s data and were major contributors in writing the manuscript. GC undertook pathological evaluation of the parathyroid glands. All authors read and approved the final manuscript.\n==== Refs\nConzo G Perna A Avenia N de Santo RM Della pietra C Palazzo A Sinisi AA Stanzione F Santini L Evaluation of ‘putative’ role of intraoperative intact parathyroid hormone assay during parathyroidectomy for secondary hyperparathyroidism. a retrospective study on 35 consecutive patients Endocrine 2012 Epub ahead of print \nCunningham J Danese M Olson K Klassen P Chertow GM Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism Kidney Int 2005 68 1793 1800 10.1111/j.1523-1755.2005.00596.x 16164656 \nBlock GA Zeig S Sugihara J Chertow GM Chi EM Turner SA Bushinsky DA Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism Nephrol Dial Transplant 2008 23 2311 2318 10.1093/ndt/gfn026 18310602 \nKomaba H Nakanishi S Fujimori A Tanaka M Shin J Shibuya K Nishioka M Hasegawa H Kurosawa T Fukagawa M Cinacalcet effectively reduces parathyroid hormone secretion and gland volume regardless of pretreatment gland size in patients with secondary hyperparathyroidism Clin J Am Soc Nephrol 2010 5 12 2305 2314 10.2215/CJN.02110310 20798251 \nYano S Brown EM Takase H Wada A Suzuki K Kobayashi A Sugimoto T Calcium-corrected intact PTH: a clinically useful parameter for quantifying parathyroid function in patients undergoing hemodialysis Nephron Clin Pract 2010 115 1 c51 c58 10.1159/000286350 20173350 \nEriguchi R Umakoshi J Tominaga Y Sato Y Successful treatment of inoperable recurrent secondary hyperparathyroidism with cinacalcet HCl NDT Plus 2008 1 4 218 220 10.1093/ndtplus/sfn058 19461861 \nAli FE Al-Bustan MA Al-Busairi WA Al-Mulla FA Loss of seizure control due to anticonvulsant-induced hypocalcemia Ann Pharmacother 2004 38 6 1002 1005 10.1345/aph.1D467 15084684 \nKumar R Thompson JR The regulation of parathyroid hormone secretion and synthesis J Am Soc Nephrol 2011 22 216 224 10.1681/ASN.2010020186 21164021 \nBen-Dov IZ Galitzer H Lavi-Moshayoff V The parathyroid is a target organ for FGF23 in rats J Clin Invest 2007 117 4003 17992255 \nKomaba H Goto S Fujii H Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients Kidney Int 2010 77 232 10.1038/ki.2009.414 19890272 \nConzo G Perna AF Sinisi AA Palazzo A Stanzione F Della Pietra C Livrea A Total parathyroidectomy without autotransplantation in the surgical treatment of chronic kidney disease J Endocrinol Invest 2012 1 8 13 21427530\n\n",
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"title": "Partial response to cinacalcet treatment in a patient with secondary hyperparathyroidism undergoing hemodialysis: a case report.",
"title_normalized": "partial response to cinacalcet treatment in a patient with secondary hyperparathyroidism undergoing hemodialysis a case report"
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"abstract": "A 79-year-old Japanese man with polymyalgia rheumatica was admitted to hospital with coronavirus disease (COVID-19). On admission, he was treated with ciclesonide inhalation, ivermectin, and meropenem. He was intubated 6 days after admission, and methylprednisolone therapy was initiated (1000 mg/day). Hypoxemia and chest radiographic findings temporarily improved. However, chest computed tomography showed bilateral ground-glass attenuations, multiple nodules, and consolidation. Aspergillus fumigatus was cultured from the tracheal aspirate and he was diagnosed with COVID-19-associated invasive pulmonary aspergillosis (CAPA) and treated with liposomal amphotericin B. However, he died 28 days after admission.",
"affiliations": "Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan. Electronic address: yamasaki@med.uoeh-u.ac.jp.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.;Department of Respiratory Medicine, University Graduate School of Biomedical Sciences, Nagasaki City, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.",
"authors": "Iwanaga|Yuto|Y|;Kawanami|Toshinori|T|;Yamasaki|Kei|K|;Sakakibara|Hideki|H|;Ikushima|Issei|I|;Ikegami|Hiroaki|H|;Tahara|Masahiro|M|;Akata|Kentaro|K|;Mukae|Hiroshi|H|;Yatera|Kazuhiro|K|",
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"keywords": "Acute respiratory distress syndrome; COVID-19; COVID-19 associated invasive pulmonary aspergillosis",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D001232:Aspergillus fumigatus; D000086382:COVID-19; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D008297:Male; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed",
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"title": "A fatal case of COVID-19-associated invasive pulmonary aspergillosis.",
"title_normalized": "a fatal case of covid 19 associated invasive pulmonary aspergillosis"
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"abstract": "BACKGROUND\nIn a study of the oral administration of a single dose of metformin to healthy participants, the estimated half-life (t½ ) for the elimination of the drug from erythrocytes was found to be 23.4 h (compared with 2.7 h for metformin in plasma). However, these pharmacokinetic indices have not been well defined in metformin accumulation.\n\n\nMETHODS\nWe systematically reviewed all the data on plasma and erythrocyte metformin assays available in our centre. We then selected patients with a plasma metformin concentration ≥ 5 mg/l and in whom the metformin concentration had been remeasured once or more at least 5 days after admission.\n\n\nRESULTS\nTwelve patients met the aforementioned criteria. All but one of these patients displayed generally severe lactic acidosis on admission (mean ± sd pH and lactate: 6.88 ± 0.35 and 14.8 ± 6.56 mmol/l, respectively) and 11 were treated with dialysis. The mean ± sd time interval between the first and last blood sample collections for metformin measurement was 8.3 ± 3.2 days (range 5-14 days). Five days after the first sample had been collected, metformin was still detectable in plasma and in erythrocytes in all patients. Metformin remained detectable for up to 13 days (both in plasma and in erythrocytes). The estimated mean terminal t½ for metformin in plasma and erythrocytes was 51.9 and 43.4 h, respectively.\n\n\nCONCLUSIONS\nThe prolonged elimination of accumulated metformin (even after dialysis therapy) challenges the traditional view that the drug clears rapidly because of a short half-life in plasma.",
"affiliations": "Service d'Endocrinologie-Nutrition, Hôpital Sud, Amiens, France.;Laboratoire de Pharmacologie clinique, Hôpital Sud, Amiens, France.;Laboratoire de Pharmacologie clinique, Hôpital Sud, Amiens, France.;Laboratoire de Pharmacologie clinique, Hôpital Sud, Amiens, France.;Service d'Endocrinologie-Nutrition, Hôpital Sud, Amiens, France.",
"authors": "Kajbaf|F|F|;Bennis|Y|Y|;Hurtel-Lemaire|A-S|AS|;Andréjak|M|M|;Lalau|J-D|JD|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
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"issue": "33(1)",
"journal": "Diabetic medicine : a journal of the British Diabetic Association",
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"mesh_terms": "D000140:Acidosis, Lactic; D058186:Acute Kidney Injury; D000368:Aged; D000465:Algorithms; D001769:Blood; D003924:Diabetes Mellitus, Type 2; D003928:Diabetic Nephropathies; D004912:Erythrocytes; D005260:Female; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008499:Medical Records; D008687:Metformin; D008875:Middle Aged; D006435:Renal Dialysis; D065667:Renal Elimination; D012720:Severity of Illness Index; D014018:Tissue Distribution",
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"title": "Unexpectedly long half-life of metformin elimination in cases of metformin accumulation.",
"title_normalized": "unexpectedly long half life of metformin elimination in cases of metformin accumulation"
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
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"abstract": "A 43-year-old woman, diagnosed with ulcerative colitis (UC) at age of 30, received outpatient treatment with corticosteroids. However, flare-up occurred, and adalimumab (ADA) treatment commenced in July 2009. A complete remission with mucosal healing was achieved by 32 weeks after initiation of ADA therapy. Because of progressive skin eruptions, ADA maintenance was discontinued at 124 weeks. Regardless, complete remission with mucosal healing was maintained until 176 weeks. We concluded that ADA is an effective therapy to achieve a complete remission in a patient with steroid-refractory UC, and that long-term complete remission may be an important indication to discontinue biological therapy.",
"affiliations": "Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.",
"authors": "Tanida|Satoshi|S|;Mizoshita|Tsutomu|T|;Ozeki|Keiji|K|;Tsukamoto|Hironobu|H|;Mori|Yoshinori|Y|;Kubota|Eiji|E|;Kataoka|Hiromi|H|;Kamiya|Takeshi|T|;Joh|Takashi|T|",
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"fulltext": "\n==== Front\nJ Clin Med ResJ Clin Med ResElmer PressJournal of Clinical Medicine Research1918-30031918-3011Elmer Press 10.14740/jocmr1991wCase ReportThe First Case of Biological Therapy Discontinuation After a Complete Remission Induced by Maintenance Therapy With Adalimumab for Refractory Ulcerative Colitis Adalimumab Discontinuation in UCTanida Satoshi abMizoshita Tsutomu aOzeki Keiji aTsukamoto Hironobu aMori Yoshinori aKubota Eiji aKataoka Hiromi aKamiya Takeshi aJoh Takashi aa Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japanb Corresponding Author: Satoshi Tanida, Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan. Email: stanida@med.nagoya-cu.ac.jp2 2015 19 11 2014 7 2 118 121 24 9 2014 Copyright 2015, Tanida et al.2015This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 43-year-old woman, diagnosed with ulcerative colitis (UC) at age of 30, received outpatient treatment with corticosteroids. However, flare-up occurred, and adalimumab (ADA) treatment commenced in July 2009. A complete remission with mucosal healing was achieved by 32 weeks after initiation of ADA therapy. Because of progressive skin eruptions, ADA maintenance was discontinued at 124 weeks. Regardless, complete remission with mucosal healing was maintained until 176 weeks. We concluded that ADA is an effective therapy to achieve a complete remission in a patient with steroid-refractory UC, and that long-term complete remission may be an important indication to discontinue biological therapy.\n\nRefractory ulcerative colitisAdalimumabBiologic discontinuationComplete remission\n==== Body\nIntroduction\nUlcerative colitis (UC) is characterized by mucosal ulceration, rectal bleeding, diarrhea, and abdominal pain. Studies have described the efficacy and safety of adalimumab (ADA) and infliximab (IFX) for treatment of patients with moderate-to-severe UC who failed to achieve clinical remission or to respond to conventional therapy consisting of corticosteroids, azathioprine, and/or aminosalicylic acid (5-ASA) [1-3]. A statement from the World Congress of Gastroenterology suggests that biologics therapy can be withdrawn in cases of complete mucosal healing in patients with Crohn’s disease (CD) [4]. However, there is currently a lack of evidence supporting the discontinuation of anti-tumor necrosis factor (TNF)-α antibodies for UC patients in complete remission. To our best knowledge, there is also no case report of discontinuation of ADA after institution of scheduled maintenance. This report describes the first case of a patient with refractory UC in which biologic therapy was terminated after achieving complete remission in response to scheduled maintenance therapy with ADA.\n\nCase Report\nA 43-year-old woman, diagnosed with total UC at age 30, received outpatient treatment with corticosteroids. In April 2009, she experienced a flare-up of colitis and required daily oral sulfasalazine (4,500 mg/day) and 10 mg of prednisolone. However, these drugs could not induce clinical remission. The Mayo score, measured after 2 weeks to evaluate disease severity was 9 points (stool frequency, 3 points; rectal bleeding, 1 point; physician’s global assessment, 2 points; endoscopy subscore, 3 points (Fig. 1A)), indicating moderately active UC. Laboratory investigations revealed a white blood cell (WBC) count of 7,240 μ/L, a red blood cell (RBC) count of 379 × 104/μL, a hemoglobin (Hb) of 13.1 g/dL, a total protein (TP) of 6.9 g/dL, and a C-reactive protein (CRP) of 0.11 mg/dL. ADA induction therapy (160/80 mg) was initiated in July 2009 (at 0 week), followed by 40 mg at 4 weeks and every other week thereafter. At 32 weeks, complete remission with mucosal healing was achieved (Mayo score, 1 point; endoscopy subscore, 0 (Fig. 1B)). Corticosteroids were tapered off by 20 weeks on the basis of a good response to ADA treatment.\n\nFigure 1 Colonoscopy before (at 0 week) and at 32 weeks after induction and maintenance therapy with ADA (160/80/40 mg every other week). (A) The first colonoscopy reveals some ulcers with erythematous and edematous changes within the mucosa of the sigmoid and rectum. Mayo endoscopy subscore, 3 points. (B) Colonoscopy reveals mucosal healing with scars within the mucosa of the sigmoid colon following 32 weeks of treatment. \n\nAt 52 weeks, the patient developed skin eruptions at the injection site that progressed to involve her arm and neck. Skin eruptions receded soon after administration of anti-allergic agents. However, skin eruptions persisted at the injection site in her arm. Subsequently, skin eruptions again progressed to extend from her arm to her eyelids, and erythematous changes were finally seen in her conjunctiva at 124 weeks, so ADA was immediately discontinued. Skin eruptions gradually disappeared in a couple of weeks. She has not experienced allergic skin eruptions since a definite diagnosis of UC was made, and skin eruptions were improved soon after ADA was discontinued. This clinical course suggested that she was considered to be allergic for ADA, but not to have a complication of UC. Complete remission with mucosal healing (endoscopy subscore, 0) was noted at that time and was sustained beyond 176 weeks without additional therapeutic agents for UC treatment (Table 1).\n\nTable 1 The Clinical Course of Mayo Scores and Eruption Severity With Concomitant Drugs’ Doses Including SASP, Prednisolone, and ADA\nTimes from ADA start (weeks)\t-2\t0\t2\t4\t8\t32\t52\t78\t104\t124\t130\t176\t\nSASP (mg)\t4,500\t4,500\t4,500\t4,500\t4,500\t4,500\t4,500\t4,500\t4,500\t4,500\t4,500\t4,500\t\nCorticoteroids (mg)\t10\t10\t10\t10\t10\t0\t0\t0\t0\t0\t0\t0\t\nADA injections (mg)\t-\t160\t80\t40\t40\t40\t40\t40\t40\tDiscontinued\t-\t-\t\nMayo scores\t9\t6#\t\t\t6\t1\t1\t1\t1\t1#\t1\t1\t\nBowel movements (points)\t3\t3\t\t\t3\t1\t1\t1\t1\t1\t1\t1\t\nAnal bleeding (points)\t1\t1\t\t\t1\t0\t0\t0\t0\t0\t0\t0\t\nEndoscopic score (points)\t3\t\t\t\t1\t0\t0\t0\t0\t\t0\t0\t\nAdverse events\t\t\t\t\t\t\t\t\t\t\t\t\t\nSkin eruptions\t-\t-\t\t\t-\t-\t+\t++\t+\t+++\t-\t-\t\n#Partial Mayo scores without endoscopy subscore. -: none; +: mild; ++: moderate; +++: severe.\n\nDiscussion\nIn the clinical setting, there are little data to guide optimal discontinuation of ADA after institution of scheduled maintenance. The present report described the first case of a patient who achieved biologic discontinuation after a complete remission induced by induction/maintenance therapy with ADA for the treatment of refractory UC.\n\nAnti-TNF-α antibodies, such as IFX and ADA, are effective therapies that can lead to sustained clinical remission in patients with moderate-to-severe active UC [1, 2]. Treatment with anti-TNF-α antibodies has revolutionized the treatment of refractory UC. Clinical remission or mucosal healing is currently a realistic goal for most patients. Many studies have assessed strategies for discontinuation of biologic therapy in patients with CD and rheumatoid arthritis.\n\nOne prospective cohort study involved 115 patients with CD who were treated for at least 1 year with scheduled IFX and an antimetabolite and had been in corticosteroid-free remission for at least 6 months, and who subsequently received IFX discontinuation during a study of IFX discontinuation in CD patients in stable remission on combined therapy with immunosuppressors (STORI) trial. The study showed that risk factors for relapse involved the absence of surgical resection, male sex, leukocyte counts > 6.0 × 109/L, levels of Hb ≤ 145 g/L, and CRP ≥ 5.0 mg/L, and fecal calprotectin ≥ 300 μg/g, and that patients with no more than two of these risk factors had a remarkably low risk of relapse [5].\n\nAn open-label pilot study of the feasibility of discontinuation of ADA in rheumatoid arthritis patients in stable clinical remission demonstrated that 20% of patients receiving ADA treatment achieved biologic discontinuation for the first 28 weeks and that failure of sustained low disease activity index (DAS28) of rheumatoid arthritis failed to discontinue biologics [6]. On the other hand, a systematic review evaluating biologic discontinuation in patients with rheumatoid arthritis could not show any significant factors relevant to biologic discontinuation or failure of biologic discontinuation, as collective studies reviewed were relatively small [7]. Thus, although the feasibility factors of biologic discontinuation remain to be defined, long-standing clinical remission or remarkably low disease activity may be an important indication for biologic discontinuation.\n\nLogistic regression analysis in a prospective observational study evaluating predictors of relapse in patients with UC in remission after 1 year of IFX treatment showed that only previous biological therapy (repeated treatment with IFX) was associated with the necessity of restarting IFX therapy and that none of the analyzed demographic and clinical parameters (including sex, smoking, steroid/thiopurine therapy, history of colon surgery, appendectomy, dose intensification, and CRP level) was associated with the necessity of restarting IFX therapy. In addition, restart of IFX therapy seems to be more common in patients without mucosal healing at the time of IFX discontinuation, although there was no significant correlation between mucosal healing and the frequency of, nor time to, clinical relapse [8].\n\nTwo-year complete remission with mucosal healing (Mayo endoscopy subscore, 0) was maintained in patients with UC who were treated for about 2.5 years with scheduled ADA and also in the present case where the patient had been in corticosteroid-free remission for 2 years. Therefore, mucosal healing was considered to be an indication for successful biologic discontinuation. Because of adverse events, ADA was discontinued in the present case.\n\nOn the other hand, a recent retrospective observational study assessing prognostic role of mucosal healing in 22 Hungarian patients with UC after 1 year of biological therapy concluded that mucosal healing did not predict sustained clinical remission in patients in whom the biological therapy had been stopped based on the result that all of five UC patients achieving both mucosal healing and clinical remission received retreatment of biological therapy within 1 year [9]. Further prospective study is needed to determine whether long-term complete remission with mucosal healing enables UC patients to discontinue biologics.\n\nIn conclusion, ADA is an effective therapy to achieve a complete remission in patients with refractory UC and long-term complete remission may be an important indication of discontinuing biological therapy.\n\nCompeting Interest\nAuthors declare that no financial or other conflict of interest exists in relation to the content of the article.\n\nAbbreviations\nUCulcerative colitis\n\nCDCrohn’s disease\n\nCRPC-reactive protein\n\nADAadalimumab\n\nIFXinfliximab\n\nSASPsulfasalazine\n\n5-ASA5-aminosalicylic acid\n\nDASdisease activity score\n==== Refs\nReferences\n1 Reinisch W Sandborn WJ Hommes DW D'Haens G Hanauer S Schreiber S Panaccione R et al Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial Gut 2011 60 6 780 787 10.1136/gut.2010.221127 21209123 \n2 Sandborn WJ van Assche G Reinisch W Colombel JF D'Haens G Wolf DC Kron M et al Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2012 142 2 257 265 e251-253 22062358 \n3 Rutgeerts P Sandborn WJ Feagan BG Reinisch W Olson A Johanns J Travers S et al Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 2005 353 23 2462 2476 10.1056/NEJMoa050516 16339095 \n4 D'Haens GR Panaccione R Higgins PD Vermeire S Gassull M Chowers Y Hanauer SB et al The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011 106 2 199 212 quiz 213 10.1038/ajg.2010.392 21045814 \n5 Louis E Mary JY Vernier-Massouille G Grimaud JC Bouhnik Y Laharie D Dupas JL et al Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped Gastroenterology 2012 142 1 63 70 e65; quiz e31 21945953 \n6 Chatzidionysiou K Turesson C Teleman A Knight A Lindqvist E Larsson P Coester L et al A multicenter, randomized, controlled, open-label pilot study of the feasibility of discontinuation of adalimumab in rheumatoid arthritis patients in stable clinical remission Arthritis Rheuma 2012 64 suppl 10 S336 \n7 Yoshida K Sung YK Kavanaugh A Bae SC Weinblatt ME Kishimoto M Matsui K et al Biologic discontinuation studies: a systematic review of methods Annals of the rheumatic diseases 2014 73 1 595 599 23723316 \n8 Farkas K Lakatos PL Nagy F Szepes Z Miheller P Papp M Palatka K et al Predictors of relapse in patients with ulcerative colitis in remission after one-year of infliximab therapy Scand J Gastroenterol 2013 48 12 1394 1398 10.3109/00365521.2013.845906 24131338 \n9 Farkas K Lakatos PL Szucs M Pallagi-Kunstar E Balint A Nagy F Szepes Z et al Frequency and prognostic role of mucosal healing in patients with Crohn's disease and ulcerative colitis after one-year of biological therapy World J Gastroenterol 2014 20 11 2995 3001 10.3748/wjg.v20.i11.2995 24659890\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1918-3003",
"issue": "7(2)",
"journal": "Journal of clinical medicine research",
"keywords": "Adalimumab; Biologic discontinuation; Complete remission; Refractory ulcerative colitis",
"medline_ta": "J Clin Med Res",
"mesh_terms": null,
"nlm_unique_id": "101538301",
"other_id": null,
"pages": "118-21",
"pmc": null,
"pmid": "25436030",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports",
"references": "21209123;23723316;16339095;21945953;21045814;24131338;24659890;22062358",
"title": "The first case of biological therapy discontinuation after a complete remission induced by maintenance therapy with adalimumab for refractory ulcerative colitis.",
"title_normalized": "the first case of biological therapy discontinuation after a complete remission induced by maintenance therapy with adalimumab for refractory ulcerative colitis"
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"abstract": "Adenosine is an effective agent for termination of most re-entrant supraventricular arrhythmias involving the atrioventricular node and often also used as a diagnostic agent for wide QRS tachycardias. Adenosine terminates 90-99% of re-entrant supraventricular tachycardias but it may rarely accelerate tachycardias. Adenosine-induced tachycardia acceleration is a rare phenomenon, as only a handful of cases have been described in the literature. We present a case of a 36-year-old man with a narrow complex, short RP tachycardia at a rate of 165 bpm and an initial blood pressure of 110/78 mm Hg. A bolus of 12 mg of adenosine resulted in slowing of the tachycardia to 150 bpm for 2-3 s, followed by acceleration of the tachycardia to 185 bpm that lasted for approximately 20 s and returned to baseline at 165 bpm. The main mechanism of adenosine-induced acceleration may be the secondary sympathetic stimulation, which may be preceded by transient bradycardia and/or hypotension.",
"affiliations": "Michigan State University, Lansing, Michigan, USA.;Department of Cardiology, Michigan State University, Lansing, Michigan, USA.;Department of Cardiology, Sparrow Thoracic and Cardiovascular Institute, Lansing, Michigan, USA.",
"authors": "Singh|Vini|V|;Salehi|Negar|N|;Thakur|Ranjan Kumar|RK|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000241:Adenosine",
"country": "England",
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"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000241:Adenosine; D000328:Adult; D000889:Anti-Arrhythmia Agents; D004562:Electrocardiography; D006339:Heart Rate; D006801:Humans; D008297:Male; D013611:Tachycardia, Atrioventricular Nodal Reentry; D013617:Tachycardia, Supraventricular",
"nlm_unique_id": "101526291",
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"pmid": "25628324",
"pubdate": "2015-01-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1605147;9312997;9809901;11428480;2193560;2789911;2022024;2022011;10051297;6640877",
"title": "Adenosine-induced tachycardia acceleration: an unusual proarrhythmia.",
"title_normalized": "adenosine induced tachycardia acceleration an unusual proarrhythmia"
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"companynumb": "US-MYLANLABS-2015M1006245",
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"abstract": "OBJECTIVE\nComparison of effectiveness and safety of solifenacin and mirabegron, as well as their combination, for managing heavy symptoms of overactive bladder.\n\n\nMETHODS\nAll patients who participated in the examination (average age: 71.2) were split into 4 groups. Patients included in Group А (n=63) were treated with mirabegron 50mg/day/6 weeks, in Group B (n=52)-with solifenacin 10mg/day/6 weeks, in Group С (n=65)-with the same doses of both drugs simultaneously/6 weeks, and in Group D (n=59)-with placebo. Monitoring was carried out using OAB-questionnaires, bladder diaries and urodynamic examination.\n\n\nRESULTS\nIn elderly patients with initial frequency of episodes of incontinence (EI)≥3/day standard doses of mirabegron (50mg/day) and solifenacin 10mg/day administered during 6 weeks result with the decrease in frequency of EI with high correlation (r=0,74, p≤0.05); final results in both groups are significantly different from initial value of p≤0.05. In the group, where patients were taking both drugs simultaneously, final results significantly differ from both initial values of the parameters in these groups (EI: 5.1→1.6 per day, p≤0.01; urination: 9.1→5.3 per day, p≤0.01; post-void residual 19.4→29.9, p≤0.01) and final values in Groups A and B (p≤0.05). The percentage of side effects in this group does not significantly differ from that in the groups, where patients were receiving monotherapy.\n\n\nCONCLUSIONS\nCombined treatment for severe symptoms of OAB in elderly men and women with standard doses of solifenacin and mirabegron provides satisfactory therapeutic effect within short period of time without increasing the risk of side effects, which undoubtedly improves quality of life and self-esteem of patients. At the same time, taking any of these drugs separately for the treatment of severe malfunction of lover urinary tracts in elderly people may turn out to be insufficient for effective symptom management.",
"affiliations": "School of Humanities, Far Eastern Federal University, Primorsky Region, Ayax 10, F733 Vladivostok, Russian Federation. Electronic address: oton2000@mail.ru.;Department of Urology, City polyclinic No. 3, St. Lugovaya 55, Vladivostok, Russian Federation. Electronic address: Lurd1973@mail.ru.;Far Eastern Fisheries University, St. Lugovaya 52a, Vladivostok, Russian Federation. Electronic address: marina.iwanowsckaya@yandex.ru.;Department of the Functional Methods of Examination, Med. Association No. 2 of Vladivostok-sity, St. Prihodko 4a,Vladivostok, Russian Federation. Electronic address: Lileka2@yandex.ru.",
"authors": "Kosilov|Kirill|K|;Loparev|Sergay|S|;Ivanovskaya|Marina|M|;Kosilova|Liliya|L|",
"chemical_list": "D000083:Acetanilides; D013844:Thiazoles; D064804:Urological Agents; D000069464:Solifenacin Succinate; C520025:mirabegron",
"country": "Netherlands",
"delete": false,
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"issue": "61(2)",
"journal": "Archives of gerontology and geriatrics",
"keywords": "Elderly; Mirabegron; Overactive bladder; Solifenacin",
"medline_ta": "Arch Gerontol Geriatr",
"mesh_terms": "D000083:Acetanilides; D000368:Aged; D000369:Aged, 80 and over; D019468:Disease Management; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D000069464:Solifenacin Succinate; D011795:Surveys and Questionnaires; D013844:Thiazoles; D016896:Treatment Outcome; D001743:Urinary Bladder; D053201:Urinary Bladder, Overactive; D014549:Urinary Incontinence; D014554:Urination; D014563:Urodynamics; D064804:Urological Agents",
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"pmid": "26169181",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "A randomized, controlled trial of effectiveness and safety of management of OAB symptoms in elderly men and women with standard-dosed combination of solifenacin and mirabegron.",
"title_normalized": "a randomized controlled trial of effectiveness and safety of management of oab symptoms in elderly men and women with standard dosed combination of solifenacin and mirabegron"
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"activesubstancename": "SOLIFENACIN SUCCINATE"
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"abstract": "BACKGROUND\nComplications exclusive of new neurological deficits/injuries that follow extreme lateral interbody fusion (XLIF) and related lateral lumbar interbody techniques should be better recognized to determine the safety of these procedures. Unfortunately, a review of the XLIF literature did not accurately reflect the frequency of these \"other complications\" as few US surgeons publish such adverse events that may lead to medicolegal suits.\n\n\nMETHODS\nMajor complications occurring with XLIF included sympathectomy, major vascular injuries, bowel perforations, sterile seromas, and instrumentation failures.\n\n\nRESULTS\nThe frequency of sympathectomy was 4% for XLIF vs. 15% for anterior lumbar interbody fusion (ALIF). There were three major vascular injuries for XLIF; one fatal intraoperative event, one life-threatening retroperitoneal hematoma, and one iatrogenic lumbar artery pseudoaneurysm that was successfully embolized. Two bowel perforations were reported, whereas a third was a \"direct communication.\" One patient developed a sterile recurrent seroma due to vancomycin powder utilized for an XLIF. One study cited malpositioning of an XLIF cage resulting in a lateral L3-L4 extrusion, whereas the second series looked at the 45% risk of cage-overhang when XLIF devices were placed in the anterior one-third of the vertebral body.\n\n\nCONCLUSIONS\nExcluding new neurological deficits, XLIF techniques resulted in multiple other major complications. However, these small numbers likely reflect just the tip of the iceberg (e.g., 10%) and the remaining 90% may never be known as many US-based spine surgeons fail to publish such adverse events as they are discoverable in a court of law and may lead to medicolegal suits.",
"affiliations": "Department of Neuroscience, Winthrop Neuroscience, Winthrop University Hospital, Mineola, New York, USA.",
"authors": "Epstein|Nancy E|NE|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/2152-7806.191071",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-7-65610.4103/2152-7806.191071Surgical Neurology International: SpineNon-neurological major complications of extreme lateral and related lumbar interbody fusion techniques Epstein Nancy E. nancy.epsteinmd@gmail.com*Department of Neuroscience, Winthrop Neuroscience, Winthrop University Hospital, Mineola, New York, USA* Corresponding author\n2016 22 9 2016 7 Suppl 25 SNI: Spine, a supplement to Surgical Neurology InternationalS656 S659 12 6 2016 14 6 2016 Copyright: © 2016 Surgical Neurology International2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nComplications exclusive of new neurological deficits/injuries that follow extreme lateral interbody fusion (XLIF) and related lateral lumbar interbody techniques should be better recognized to determine the safety of these procedures. Unfortunately, a review of the XLIF literature did not accurately reflect the frequency of these “other complications” as few US surgeons publish such adverse events that may lead to medicolegal suits.\n\nMethods:\nMajor complications occurring with XLIF included sympathectomy, major vascular injuries, bowel perforations, sterile seromas, and instrumentation failures.\n\nResults:\nThe frequency of sympathectomy was 4% for XLIF vs. 15% for anterior lumbar interbody fusion (ALIF). There were three major vascular injuries for XLIF; one fatal intraoperative event, one life-threatening retroperitoneal hematoma, and one iatrogenic lumbar artery pseudoaneurysm that was successfully embolized. Two bowel perforations were reported, whereas a third was a “direct communication.” One patient developed a sterile recurrent seroma due to vancomycin powder utilized for an XLIF. One study cited malpositioning of an XLIF cage resulting in a lateral L3–L4 extrusion, whereas the second series looked at the 45% risk of cage-overhang when XLIF devices were placed in the anterior one-third of the vertebral body.\n\nConclusion:\nExcluding new neurological deficits, XLIF techniques resulted in multiple other major complications. However, these small numbers likely reflect just the tip of the iceberg (e.g., 10%) and the remaining 90% may never be known as many US-based spine surgeons fail to publish such adverse events as they are discoverable in a court of law and may lead to medicolegal suits.\n\nBowel perforationextreme lateral interbody fusionlateral cage extrusionmajor vessel injurynon-neurological complicationspersistent seromaretroperitoneal hematomasympathectomy\n==== Body\nINTRODUCTION\nExcluding new neurological deficits, other major complications following extreme lateral interbody fusions (XLIF) and related lateral lumbar interbody techniques should be better recognized to determine the safety of these procedures. The initial list of complications included sympathectomy, major vascular injuries, bowel perforations, seromas, and instrumentation failures. Unfortunately, this list does not likely accurately reflect the real frequency of these “other complications” as few US-based surgeons publish their personal/series-based adverse events due to medicolegal exposure (e.g., “discoverable” in a court of law and potentially leading to a suit). Therefore, the list of major XLIF complications likely constitutes just the tip of the iceberg (e.g., 10%), while the remaining 90% is yet to be published, leaving us wonder just how “safe” XLIF are.\n\nEXCLUDING NEW NEUROLOGICAL DEFICITS, COMPLICATIONS OF MINIMALLY INVASIVE EXTREME LATERAL INTERBODY FUSION AND RELATED TECHNIQUES\nRisk of sympathectomy with anterior lumbar interbody fusion vs. extreme lateral interbody fusion\nHrabalek et al. in 2015 retrospectively analyzed the risk of sympathectomy (utilizing thermography) performing anterior lumbar interbody fusion (ALIF) vs. XLIF procedures between the T12–L5 levels [Table 1].[4] They found that ALIF correlated with a 15% rate of sympathectomy versus the 4% encountered with XLIF.\n\nTable 1 Non-neurological complications (COMP.) following minimally invasive surgery (MIS) extremelateral lumbar interbody fusion (XLIF)\n\nThree major vascular injuries attributed to extreme lateral interbody fusion\nThree authors cited major vascular injuries attributed to XLIF. Santillan et al. in 2010 observed an iatrogenic lumbar artery pseudoaneurysm that followed a L4–L5 XLIF; it was successfully endovascularly embolized.[8] In 2014, Assina et al. noted the advantages of minimally invasive surgery (MIS) XLIF that included “wide access to the lumbar disc space” without using a separate access surgeon, and mininal tissue disruption [Table 1].[1] However, they reported a 50-year-old female who underwent an L4–L5 XLIF and sustained a fatal major intraoperative vascular injury. Subsequently, Peiro-Garcia et al. in 2015 cited the potential pros of a stand-alone XLIF approach to the lumbar spine (e.g., reduced intraoperative/postoperative bleeding/less tissue injury) along with its potential cons (e.g., trauma to segmental arteries and great vessels leading to retroperitoneal haematomas).[5] Their patient developed hemorrhagic shock (e.g., tachycardia, hypotension, and anemia) due to a retroperitoneal hematoma directly resulting from a major vessel injury occurring during an XLIF.\n\nRare bowel perforations attributed to extreme lateral interbody fusion\nTwo studies documented bowel perforations resulting from XLIF procedures, whereas a third case was a personal communication to the author.[29] Tormenti et al., in 2010, examined the complications of 8 XLIF/pedicles screw fusions utilized to treat adult scoliosis, and contrasted these results with 4 other patients undergoing posterior-only procedures/fusions.[9] Complications exclusive of new neurological deficits for the 8 patients included one bowel perforation requiring laparotomy/colon resection (later followed by a posterior procedure only), whereas 1 of the 4 patients undergoing posterior surgery required revision of instrumentation. In 2015, Balsano et al. wrote that XLIF procedures were developed to avoid/limit the morbidity of ALIF (e.g. especially major vessel/visceral injuries) [Table 1].[2] However, they presented a 70-year-old male who, following an L3–L4 and L4–L5 transpsoas XLIF fusion, sustained a bowel injury.\n\nThrough a personal communication, the author was also told of a patient who within 12 hours of XLIF surgery was draining feces.\n\nCase of sterile seroma after multilevel extreme lateral interbody fusion due to vancomycin powder\nYoussef et al. in 2014 cited a 59-year-old female who developed a recurrent sterile postoperative seroma following the application of 2 g of vancomycin powder to the XLIF wound; 1 g/bone graft/fusion and 1 g placed in the soft tissues [Table 1].[10] Six weeks later, due to a fall, the patient had a magnetic resonance (MRI) study that showed a surgical sacral fracture and a large epidural L3–L5 fluid collection; the fracture had to be repaired, and the seroma drained. Nevertheless, the fluid collection later required multiple additional aspirations. Notably, there was no clear explanation as to the etiology of this untoward event although one major differential diagnosis was an allergic response to the vancomycin.\n\nMalpositioning of extreme lateral interbody fusion cages: Migration and overhang\nMalpositioning and overhang are two technical surgical complications that must be considered when performing XLIF interbody cage procedures.[36] Daffner and Wang in 2010 presented a 49-year-old female who underwent a L3–L4 XLIF cage placement to address a pseudarthrosis resulting from a fusion attempted caudad to an old scoliosis arthrodesis.[3] When the cage extruded laterally 1 month postoperatively, it was removed/replaced though a mini-open lateral approach and supplemented with a lateral plate (e.g., to additionally address the “significant coronal deformity/lateral listhesis” due to the scoliosis). Furthermore, in 2010, Regev et al. noted that MIS XLIF or MIS direct lateral interbody fusion (DLIF) cage overhang (beyond the disc space) could occur if the cage length was solely estimated/based on anteroposterior fluoroscopy.[6] Using both MR and CT studies, they determined that 45% of cages were placed centrally (vertebral width was widest at 50 ± 4 mm), 34% were placed in the anterior one-third of the disc (vertebral body width was narrowest 41.7 ± 6 mm), whereas 7% were placed in the posterior one-third of the disc space (width 49 ± 1 mm). For those placed in the anterior one-third of the disc space, 45% demonstrated overhang that could potentially compromise the contralateral neural foramen in addition to other structures. They, therefore, recommended that surgeons consider shortening cages by 15% if they plan anterior placement.\n\nMedical vs. surgical complications of extreme lateral interbody fusion\nRodgers et al. in 2011 evaluated intraoperative/postoperative complications of 600 predominantly 1–2 level MIS XLIF (741 levels) that included a 99.2% instrumentation rate (83.2% pedicle screws).[7] Perioperative complications (up to 6 postoperative weeks) occurred in 6.2% of patients; in the hospital, these included 9 (1.5%) surgical and 17 (2.8%) medical events; out of the hospital 6 (1.0%) were surgery-related, whereas 5 (0.8%) consisted of medical events. They reported no wound infections, vascular injuries, or intraoperative visceral injuries, but 11 (1.8%) patients required additional surgery. Notably, this study demonstrated that MIS XLIF are not without their medical risks as 3.6% of patients had significant medical complications within 6 postoperative weeks. Furthermore, the surgical reported risks of just 2.3% within this short 6-week postoperative interval probability missed some of the 6-week postoperative complications (note: the series involved 600 cases and data analysis may not always be performed by experts), along with the even more critical 3, 6, and 12-month postoperative adverse events.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nhttp://surgicalneurologyint.com/Non-neurological-major-complications-of-extreme-lateral-and-related-lumbar-interbody-fusion-techniques/\n==== Refs\nREFERENCES\n1 Assina R Majmundar NJ Herschman Y Heary RF First report of major vascular injury due to lateral transpsoas approach leading to fatality J Neurosurg Spine 2014 21 794 8 25192374 \n2 Balsano M Carlucci S Ose M Boriani L A case report of a rare complication of bowel perforation in extreme lateral interbody fusion Eur Spine J 2015 24 Suppl 3 S405 8 \n3 Daffner SD Wang JC Migrated XLIF cage: Case report and discussion of surgical technique Orthopedics 2010 33 518 20608623 \n4 Hrabalek L Sternbersky J Adamus M Risk of sympathectomy after anterior and lateral lumbar interbody fusion procedures Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2015 159 318 26 24263213 \n5 Peiró-García A Domínguez-Esteban I Alía-Benítez J Retroperitoneal hematoma after using the extreme lateral interbody fusion (XLIF) approach: Presentation of a case and a review of the literature Rev Esp Cir Ortop Traumatol 2015 pii: S1888-4415(15)00019-3 \n6 Regev GJ Haloman S Chen L Dhawan M Lee YP Garfin SR Incidence and prevention of intervertebral cage overhang with minimally invasive lateral approach fusions Spine 2010 35 1406 11 20505573 \n7 Rodgers WB Gerber EJ Patterson J Intraoperative and early postoperative complications in extreme lateral interbody fusion: An analysis of 600 cases Spine 2011 36 26 32 21192221 \n8 Santillan A Patsalides A Gobin YP Endovascular embolization of iatrogenic lumbar artery pseudoaneurysm following extreme lateral interbody fusion (XLIF) Vasc Endovascular Surg 2010 44 601 3 20675335 \n9 Tormenti MJ Maserati MB Bonfield CM Okonkwo DO Kanter AS Complications and radiographic correction in adult scoliosis following combined transpsoas extreme lateral interbody fusion and posterior pedicle screw instrumentation Neurosurg Focus 2010 28 E7 \n10 Youssef JA Orndorff DG Scott MA Ebner RE Knewitz AP Sterile Seroma Resulting from Multilevel XLIF Procedure as Possible Adverse Effect of Prophylactic Vancomycin Powder: A Case Report Evid Based Spine Care J 2014 5 127 33 25364326\n\n",
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"issue": "7(Suppl 25)",
"journal": "Surgical neurology international",
"keywords": "Bowel perforation; extreme lateral interbody fusion; lateral cage extrusion; major vessel injury; non-neurological complications; persistent seroma; retroperitoneal hematoma; sympathectomy",
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"title": "Non-neurological major complications of extreme lateral and related lumbar interbody fusion techniques.",
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"abstract": "BACKGROUND\nAromatase inhibitors (AIs) are a class of drugs widely used in the treatment of estrogen sensitive breast and ovarian cancer which convert testosterone to estradiol and androstenedione to estrogen. The AIs of third generation, including anastrazole, letrozole and exemestane, have actually become the standard of care of estrogen-receptor-positive breast cancer in menopausal women and are recommended as adjuvant treatment after surgery in place of/or following tamoxifen. Their main side-effects include reduction in bone mineral density, occurrence of menopausal manifestations and development of musculoskeletal symptoms which are, usually, transient, but sometimes evolve into a typical form of arthritis, such as rheumatoid arthritis (RA). Recently, a pathogenic linkage with other autoimmunity diseases, such as Sjogren syndrome (SjS), anti-synthetase antibody syndrome (ASAS), systemic sclerosis (SS) and subacute cutaneous lupus erythematosus (SCLE), was also described.\nHere, we report the first case of a patient with primary antiphospholipid syndrome (APS) developed during treatment with anastrazole.\n\n\nMETHODS\nThe patient developed a sudden onset of speech disturbance and disorientation, due to ischemic lesions, after 6 months of AIs therapy and the laboratory examination showed the positivity of anti-Cardiolipin antibodies, anti-β2 Glycoprotein 1 antibodies and Lupus Anticoagulant, so a certain diagnosis of APS was achieved.\n\n\nMETHODS\nThe patient was treated with warfarin associated to hydroxychloroquine and monthly cycles of low doses intravenous immunoglobulins.\n\n\nRESULTS\nA good control of the disease was obtained despite the continuation of anastrazole; the patient's clinical and laboratory situation remained not modified after AIs withdrawal.\n\n\nCONCLUSIONS\nWe discussed the possible role of anastrazole treatment in inducing APS in our patient, reporting the available literature data about the association between AIs treatment and autoimmune diseases. Furthermore, we analyzed the mechanism of action of estrogens in the pathophysiology of autoimmune rheumatic disorders.",
"affiliations": "Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, Azienda Ospedaliera Universitaria Senese.;Scleroderma Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Viale Bracci 1.;Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS Polyclinic San Martino Hospital, Genoa.;Neurology and Neurophysiology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Viale Bracci 1, Siena, Italy.;Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, Azienda Ospedaliera Universitaria Senese.",
"authors": "Tenti|Sara|S|;Giordano|Nicola|N|;Cutolo|Maurizio|M|;Giannini|Fabio|F|;Fioravanti|Antonella|A|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30921233MD-D-18-0829110.1097/MD.0000000000015052150525750Research ArticleClinical Case ReportPrimary antiphospholipid syndrome during aromatase inhibitors therapy A case report and review of the literatureTenti Sara MDaGiordano Nicola MD, PhDbCutolo Maurizio MD, PhDcGiannini Fabio MD, PhDdFioravanti Antonella MD, PhDa∗NA. a Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, Azienda Ospedaliera Universitaria Seneseb Scleroderma Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Viale Bracci 1c Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, IRCCS Polyclinic San Martino Hospital, Genoad Neurology and Neurophysiology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Viale Bracci 1, Siena, Italy.∗ Correspondence: Antonella Fioravanti, Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Bracci 1, 53100 Siena, Italy (e-mail: fioravanti7@virgilio.it).3 2019 15 3 2019 98 13 e1505213 11 2018 11 2 2019 5 3 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nAromatase inhibitors (AIs) are a class of drugs widely used in the treatment of estrogen sensitive breast and ovarian cancer which convert testosterone to estradiol and androstenedione to estrogen. The AIs of third generation, including anastrazole, letrozole and exemestane, have actually become the standard of care of estrogen-receptor-positive breast cancer in menopausal women and are recommended as adjuvant treatment after surgery in place of/or following tamoxifen. Their main side-effects include reduction in bone mineral density, occurrence of menopausal manifestations and development of musculoskeletal symptoms which are, usually, transient, but sometimes evolve into a typical form of arthritis, such as rheumatoid arthritis (RA). Recently, a pathogenic linkage with other autoimmunity diseases, such as Sjogren syndrome (SjS), anti-synthetase antibody syndrome (ASAS), systemic sclerosis (SS) and subacute cutaneous lupus erythematosus (SCLE), was also described.\n\nPatient concerns:\nHere, we report the first case of a patient with primary antiphospholipid syndrome (APS) developed during treatment with anastrazole.\n\nDiagnosis:\nThe patient developed a sudden onset of speech disturbance and disorientation, due to ischemic lesions, after 6 months of AIs therapy and the laboratory examination showed the positivity of anti-Cardiolipin antibodies, anti-β2 Glycoprotein 1 antibodies and Lupus Anticoagulant, so a certain diagnosis of APS was achieved.\n\nInterventions:\nThe patient was treated with warfarin associated to hydroxychloroquine and monthly cycles of low doses intravenous immunoglobulins.\n\nOutcomes:\nA good control of the disease was obtained despite the continuation of anastrazole; the patient's clinical and laboratory situation remained not modified after AIs withdrawal.\n\nLessons:\nWe discussed the possible role of anastrazole treatment in inducing APS in our patient, reporting the available literature data about the association between AIs treatment and autoimmune diseases. Furthermore, we analyzed the mechanism of action of estrogens in the pathophysiology of autoimmune rheumatic disorders.\n\nKeywords\nanastrazoleantiphospholipid syndromearomatase inhibitorsautoimmune diseasesautoimmunitycase reportestrogensOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAromatase inhibitors (AIs) are a class of drugs widely used in the treatment of estrogen sensitive breast and ovarian cancer. Their mechanism of action consists in inhibiting the aromatase enzyme which is responsible for the conversion of testosterone to estradiol and androstenedione to estrogen.[1] The AIs of third generation, including anastrazole, letrozole and exemestane, have actually become the standard of care of estrogen-receptor-positive breast cancer in menopausal women and are recommended as adjuvant treatment after surgery in place of/or following tamoxifen, considered for decades the cornerstone of endocrine therapy in this field.[2] AIs insure more efficacy and induce less life-threatening adverse events than tamoxifen.[3] The main side-effects of AIs therapy include reduction in bone mineral density (BMD), occurrence of menopausal manifestations and development of musculoskeletal symptoms, such as arthralgia, morning stiffness, tenosynovitis, trigger finger, and carpal tunnel syndrome.[4,5] Joint pain is usually transient and tends to disappear after therapy discontinuation, but growing evidence has demonstrated that AIs can sometimes induce or exacerbate a typical arthritis, as rheumatoid arthritis (RA)[6–10] or some subsets of spondyloarthropaty (SpA).[11] A pathogenic linkage between treatment with AIs and other autoimmunity diseases, such as Sjogren syndrome (SjS), anti-synthetase antibody syndrome (ASAS), systemic sclerosis (SS) and subacute cutaneous lupus erythematosus (SCLE), was also reported.[12–19] AIs reduce the synthesis of estrogens, which are known to affect the immune response, exerting opposite immunostimolant or immunodepressive effects, according to the dose and the duration of exposure.[20–23] Furthermore, the increase of aromatase activity in normal tissue occurs during aging and is responsible for the production of the main amount of peripheral estrogens which modulate the immune reactivity and cell proliferation.[22]\n\nHere, we describe the first case of antiphospholipid syndrome (APS), a systemic autoimmune disease defined by the occurrence of venous and arterial thromboses and recurrent fetal losses, in the presence of antiphospholipid antibodies (aPL), which developed during treatment with anastrazole.[24]\n\n2 Case presentation\nIn October 2012, a 56 years old female patient was admitted to the Neurology Unit for sudden onset of speech disturbance and disorientation. She had a history of right breast cancer (ductal carcinoma estrogen-receptor positive; T1N0M0) diagnosed in March 2010 and treated with upper-outer quadrantectomy and adjuvant radiotherapy in the months of August and September 2010. At the end of the radiotherapy cycle, she received treatment with tamoxifen (20 mg/day). In February 2012, she experienced a superficial venous thrombophlebitis of the left femoral vein; at this time, the patient was not taking any pharmacological therapy, including glucocorticoids, except for tamoxifen. Laboratory analysis showed an increase of D-dimer (1.2 ng/ml, range <500 ng/ml), fibrinogen (590 mg/dl, range 200–400) and C reactive protein (CRP) (1.2 mg/dl, vn <0.5 mg/dl), while the thrombophilia tests, including protein C, protein S, antithrombin III, homocysteine resulted within normal limits. Furthermore, the aPL, anti-Cardiolipin antibodies (aCL), anti-β2 Glycoprotein 1 antibodies (aGP1), Lupus Anticoagulant (LAC) and anti-nuclear antibodies (ANA), were negative. The thrombophlebitis was managed with low molecular weight heparin (LMWH) (fondaparinux 7,5 mg/day tapered to 2,5 mg/day in June 2012), switched to ticlopidine 500 mg/day a month later. The occurrence of thrombophlebitis was supposed to be due to tamoxifen, considering the known risk of this drug of inducing thrombotic events;[25,26] so, tamoxifen was switched to anastrazole (1 mg/day). In August 2012, after 6 months of anastrazole therapy, despite the ticlopidine treatment, she developed a transient motor aphasia and she was admitted to Stroke Unit. Brain magnetic resonance imaging (MRI) showed multiple lacunar infarcts. Unfortunately, no evaluation for autoimmunity or thrombophilia markers was performed. Anticoagulant therapy with warfarin was introduced during the hospitalization. In September 2012, she went to the emergency department complaining of a band-like abdominal pain; a computed tomoghraphy (CT) scan of the abdomen showed the enlargement of left adrenal gland with evidence of recent haemorrage. Warfarin was stopped and LMWH treatment (enoxaparin 6000 UI/day) was started.\n\nIn October 2012, she was first time referred to the Neurology Unit. At the admission, she was not oriented to person, place, and time and she spoke hesitantly and non-fluently (motor aphasia). Neurological examination also showed moderate right facial and limb hemi-paresis and no sensory deficit. The blood pressure was severely reduced (max value 55 mmHg) while cardiac examination was normal. The neck and skin examinations were normal, showing no lymphadenopathy, malar rash, acrocyanosis, or livedo reticularis. No significant abnormalities were found during lung auscultation; the abdomen was soft, not-tender, and not-distended with no hepatosplenomegaly. No signs of edema or thrombosis were pointed out.\n\nLaboratory examinations revealed mild thrombocytopenia (120,000/mmc, range 150,000–400,000), mild erythrocyte sedimentation rate (ESR) increase (47 mm/h, range 0–35 mm/h), D-dimer and fibrinogen elevation, prolonged activated partial thromboplastin time (APTT) and normal prothrombin time (PT), International normalized ratio (INR), CRP, thrombophilia screening, kidney and liver function, hemoglobin, electrolytes, glycemia, immunoglobulins, C3, C4 complement factors and urinalysis (Table 1). Consistently with a sub-acute adrenal insufficiency, basal serum concentrations of cortisol were reduced and adrenocorticotropic hormone (ACTH) increased. The serum levels of dehydroepiandrosterone sulfate (DHEAS), testosterone and androstenedione resulted extremely low, while the concentrations of estradiol (E2), progesterone and 17-OH progesterone were within normal range according to the age of the patient (Table 1). Immunological tests showed positive ANA, (1:640, homogeneous pattern), high titer of aCL antibodies IgG and IgM (94.3 GPLU/ml, range <10; 16.4 MPLU/ml, range <7, respectively), aGP1 antibodies IgG, IgM and IgA (81.3 U/ml, range <5; 18.1 U/ml, range <5; 28.2 U/ml, range <5, respectively). The test for the detection of LAC was positive, as well as antiphosphatydilserine antibodies IgG and IgM (106 GPLU/ml, range <10; 18 MPLU/ml, range <10). Anti-dsDNA, extractable nuclear antigens (ENA), anti-cyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor (RF) were negative.\n\nTable 1 Coagulation tests and endocrine screening results in the patient described in the text at the time of admission at Neurology Unit.\n\nThe brain Diffusion-Weighted MRI revealed lesions with restricted diffusion in the left occipital and temporo-parietal lobe, and in the left insular cortex not detectable in the previous examination and consistent with subacute ischemia. The brain CT- angiography showed occlusion of the first tract of left-sided middle cerebral artery (MCA1). The other performed instrumental examinations (chest radiography, abdomen ultrasonography, electrocardiogram, echocardiogram, arterial and venous lower limb Doppler ultrasonography) did not show anything significant except for a mild-moderate mitral insufficiency.\n\nConsidering the multiple episodes of cerebral ischemia and the high titer positivity of all aPL subtypes, a diagnosis of primary APS, according to the 2006 updated criteria,[24] was made.\n\nThe patient was treated with enoxaparin 6000 UI for 2 times a day and then a bridging therapy with warfarin was introduced until the achievement of an optimal INR value (3–4). Furthermore, she started a replacement treatment for adrenal insufficiency with hydrocortone acetate (intravenous flebocortid at the dosage of 50 mg every 6 hours for 48 hours), followed by oral cortone acetate at the dosage of 25 mg at 8 hours and of 6.5 mg at 13 hours and at 18 hours. Before the discharge, a cycle of intravenous human immunoglobulins (Flebogamma) at a dosage of 400 mg/kg/day for 5 consecutive days was administered and hydroxychloroquine (400 mg/day) was added.\n\nConsidering the high risk of cancer recurrence when AIs therapy lasts less than 5 years, the patient continued anastrazole therapy.[27] As the time of writing, the patient is still on therapy with warfarin, hydroxychloroquine (400 mg/day) and monthly cycles of low-dose intravenous immunoglobulins (400 mg/kg/day in a single monthly infusion), according to the dose protocol previously experienced in systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE) and primary and secondary APS.[28–30] Her clinical conditions appeared stable over time and no more ischemic or thrombotic events occurred. The patient discontinued anastrazole after the recommended 5 years without any changes in her clinical history.\n\nInformed consent was obtained from the patient for publication of this case report.\n\n3 Discussion and review of the literature\nWe presented the case of a patient with primary APS occurred after 6 months of anastrazole treatment. The diagnosis was made after recurrent episodes of cerebral ischemia and the detection of a triple positivity for aPL (LAC+ aCL antibodies+ aGP1 antibodies). We think that the APS occurred and has been caused by 6 months of anastrazole treatment. Conversely, one could argue that the onset of APS following AIs therapy is just coincidence rather than a causal relationship.\n\nIt is actually known that one of the major side effects associated to AIs therapy is represented by arthralgias.[31–33] Although being usually mild or moderate, these musculoskeletal symptoms may cause an important impact on quality of life and significantly reduce the compliance to the AIs therapy.[34] The first description of the frequent occurrence of arthralgia during AIs therapy came back to 2001, when Donnellan et al[35] reported that the 16% of 77 patients treated with AIs for breast cancer developed joint pain. Subsequently, more studies explored the frequency of musculoskeletal complaints during AIs therapy, observing a much higher prevalence (about 40%).[36,37] Furthermore, the term AIs-induced musculoskeletal symptoms (AIMSS) has been introduced to indicate the association of arthralgia, symmetric morning stiffness which improves with activity, a feeling of abrupt aging and soft tissue thickening.[31,32] The incidence of AIMSS in woman treated with AIs widely varies from 5% to 47%, due to the lacking of formal diagnostic criteria for this syndrome.[37] The exact mechanism responsible for AIMSS is not fully understood, but a major role is played by estrogens deprivation.[38] Indeed, it was demonstrated that estrogens have anti-nociceptive and pain modulating properties.[39]\n\nMore recently, a pathogenic linkage between AIs therapy and well established autoimmune diseases has been hypothesized.\n\nWe conducted a search of the literature concerning clinical reports on the development of autoimmune diseases during AIs therapy in September 2018 (the period examined was September 2007–August 2018). The strategy to select the literature data consisted in a detailed search in scientific databases PubMed, Scopus, Cochrane Library and EMBASE. A MEDLINE search was conducted using the MeSH terms “aromatase inhibitors”, “anastrazole”, “letrozole”, “exemestane” in combination with “autoimmune diseases\" \"autoimmunity\" and “rheumatological disorders”. Studies were considered eligible if they met the following criteria:\n\n1. patients with a diagnosis of autoimmune and rheumatic diseases,\n\n2. therapy with anastrazole, letrozole or exemestane,\n\n3. studies published from 2007 to the present, totally written in English language.\n\nThe studies which were excluded from the review were the following:\n\n1. those analyzing the effects of AIs therapy on the development of musculoskeletal symptoms, as arthralgia, not conclusive for the diagnosis of autoimmune rheumatic diseases,\n\n2. review articles,\n\n3. anti-estrogen drugs other than AIs.\n\nIn total, 46 potential studies were found; no additional papers were found by hand searching of references. Of these, 2 were excluded because they were written in a language other than English. Based on the title and the abstract content, 21 of these articles were not included in our review. The full texts of the remaining 23 studies were read, and a further 7 studies were excluded, because the patients analyzed were not diagnosed with autoimmune rheumatic diseases. Finally, we identified 16 assessable articles reporting the development of rheumatic diseases during AIs therapy (Table 2).\n\nTable 2 Summary of literature data about rheumatic diseases associated to AIs therapy for breast cancer in post-menopausal women.\n\nFour reports showed a potential association between AIs and RA (Table 2).[6–9] The first paper was published in 2007 and described the case of a woman with a history of advanced right breast cancer treated with exemestane who developed, after few days from the beginning of the therapy, joint pain of her hips, shoulders, knees, wrists and hands associated to prolonged morning stiffness. After 4 weeks, she presented a symmetric and active arthritis with wrists, metacarpophalangeal (MCF) and proximal interphalangeal (PIP) swellings which did not improve after exemestane discontinuation. ESR and CRP resulted increased and hands radiographs and MRI showed typical erosions, so the diagnosis of RA was made.[6] Another similar report was described by Bruzzese et al.[7] Also in this case, after 1 year from the starting of anastrazole, the patient firstly experienced widespread arthralgias evolving 3 years later in high activity RA with positivity of RF and anti-CCP. In the same year, Bertolini et al[8] presented 3 cases of RA occurred after AIs therapy (anastrazole in 1 patient and letrozole followed by exemestane in the other 2 patients). The symptoms characterized mainly by hands arthralgias developed after few weeks from the AIs initiation, while the diagnosis of RA was obtained after a mean period of 33 months. A correlation between AIs therapy and cutaneous nodulosis, a particular RA manifestation, was also reported. Indeed, a woman with a pre-existent long-standing RA, who took letrozole for breast cancer, developed, after 16 months, multiple small subcutaneous nodules on the fingers of both hands diagnosed as \"accelerated cutaneous nodulosis\". After the drug discontinuation, a slow decrease in size and tenderness of the nodules was observed.[9]\n\nNot only RA, but also other definite types of arthritis in the field of SpA, were found to be associated to AIs treatment (Table 2). Indeed, Scarpa et al[11] carefully evaluated 18 post-menopausal women in treatment with AIs for breast cancer and, according to the European Spondyloarhropathy Study Group,[40] diagnosed 10 subjects with undifferentiated spondyloarhropathy, 2 with oligoarthritis and simple arthralgia the other 6 patients.\n\nInterestingly, Laroche et al[12] referred 24 women treated with AIs and experiencing pain greater than 5/10 on a visual analog scale, to rheumatologic consultation to find out if any established condition could cause these complaints (Table 2). Apart from 5 patients with osteoarthritis, shoulder tendinitis or paraneoplastic aponeurositis, Authors classified 10 patients as having sicca syndrome of the eyes and mouth, of whom 7 with probable SjS and 1 definite SjS, according to San Diego criteria.[41] Furthermore, the number of patients with autoantibodies resulted higher than they expected. A relationship between AIs and SjS was suggested also in a more recent case-series study which describes the development of primary SjS, according to the 2002 European criteria,[42] in 3 women during the first year of adjuvant therapy (anastrazole in 2 patients and letrozole in 1 patient) for breast cancer (Table 2).[13] These findings confirm the protective role of estrogens against apoptosis of the exocrine secretory glands, previously suggested.[43] Others presented the case of a patient who developed SjS with neuropathy of both legs, after anastrazole therapy for breast cancer (Table 2). The Authors, after excluding other possible causes of neuropathy, such as chemotherapy side effects, paraneoplastic manifestation or cryoglobulinemia-related vasculitis, concluded that there was a causal relationship between AIs and SjS.[14]\n\nAlso a case of ASAS, after treatment with AIs, in a patient with a previous diagnosis of RA was described (Table 2).[15] The woman developed dyspnea related to a severe bilateral interstitial lung disease and necrotizing myopathy associated to a creatine kinase (CK) increase and positivity of anti-Jo1 and antiRo52 antibodies, after 3 months of therapy with letrozole. After the drug withdrawal and the establishment of immunosuppressive treatment, the myositis and the interstitial disease significantly improved, but a re-exacerbation was reported, after the introduction of a second AIs agent (anastrazole). The temporal correlation between AIs administration and the onset of the clinical manifestations and the rapid recurrence induced by the resume of the therapy, strongly supported an etiological association between these drugs and ASAS.\n\nAmong the wide range of connective tissue disorders, also SS, in a very early phase, has been described as associated to AIs therapy (Table 2). However, in this case the patient started to present hand joint pain and stiffness after two years of letrozole therapy and 2 years later was diagnosed as having early SS; letrozole was switched to exemestane and an improvement of the articular pain was noted.[16]\n\nParticularly interesting are the reports of SCLE induced by AIs, because the role of estrogens in lupus disease activity have been the subject of debate for many years (Table 2).[17–19] Indeed, opposite to what observed during AIs treatment, reports in women with lupus showed an increase of disease flares due to estrogen-containing hormone replacement therapy and animal model studies demonstrated a significant clinical improvement of SLE, after anti-estrogen therapy.[44,45]\n\nFinally, there are some reports supporting the hypothesis of a role of AIs in triggering also autoimmune hepatitis (AIH), probably affecting immune regulation.[46–48]\n\nIn the current case, it seems that the APS is not occurred by chance, since the AIs therapy have induced some pathogenetic changes of the immune system which persisted over time, also after anastrazole discontinuation. There are several factors known to trigger the development of thrombosis in APS including infection, malignancies, trauma, surgery, withdrawal of oral anticoagulation and drugs.[49,50] At this regard, several pharmacological agents, including anti-epileptic, anti-hypertensive, anti-arrhythmic drugs and antibiotics, have been linked to the occurrence of aPL antibodies, especially LA and rarely to the development of clinical manifestations of APS.[51] More recently, the detection of aPL antibodies was demonstrated also to be associated to immunotherapy (interferon-α and Interleukin-2) and tumor necrosis factor inhibitors.[52] It was hypothesized that drugs could insult cell membranes leading to the formation of neo-antigens or increasing the density of antigens bound to the cell surface; alternately, they could induce the production of circulating antibodies.[52] Although such evidence, there are no previous published data about estrogens antagonists and APS. It was actually demonstrated that estrogens play a pivotal role in the pathophysiology of autoimmune rheumatic diseases, considering for instance the prevalence of such disorders in female gender or their ability to influence the diseases flares.[22] However, various in vitro and in vivo studies showed that the estrogens may exert opposite functions on immune system, as inhibiting T cell autoimmunity and stimulating antibodies production from B cells. These multifaced effects of estrogens on autoimmunity could depend on their different concentrations, on the phase of the disease in which they act and on ability to generate various types of metabolites which are effectively active hormones.[53,54] The blockade of aromatase, the key enzyme for the conversion of androgens to estrogens, has been associated to the development of a wide range of autoimmune diseases, as described above. It has been suggested that estrogens may play an anti-inflammatory, protective role before the autoimmunity occurrence, while AIs, reducing the estrogens levels, could acts as triggering factors.[54] At this regard, some Authors investigated the involvement of aromatase blockade in the development of SjS. They used female aromatase gene knockout (ArK0) mice as a model of estrogen deficiency, observing that ArK0 mice presented SjS-like autoimmune lesions in lacrimal and salivary glands, due to B-cell proliferation and production of autoantibodies. Furthermore, they reported a significant amount of adiposity of the ArK0 mice salivary glands with an increased number of macrophages and consequent cytokines production, compared to wild type mice. Finally, the autoimmune lesions were exacerbated by administration of an AI, hypothesizing a key role of estrogens deficiency in the pathogenesis of autoimmunity.[55]\n\nActually, the role of AIs in APS remains totally unexplored, despite a correlation between the estradiol serum levels with aCL antibodies and ischemic attacks was previously reported.[56]\n\nOur case report and review of the literature highlight that AIs therapy for breast cancer can trigger the onset of autoimmune changes resulting in various rheumatic diseases, which persisted over time, such as APS. These considerations may be useful in the clinical practice, because we think it should be very important to screen the patients starting AIs therapy for rheumatological remarks. However, the pathogenetic mechanism behind the development of APS, after AIs treatment, still remains unexplored. So preclinical studies are needed to investigate the pathophysiology of APS induced by this class of drugs and large clinical studies are mandatory to confirm our experience.\n\nAuthor contributions\nAuthor Resources: Fabio Giannini, Antonella Fioravanti.\n\nConceptualization: Fabio Giannini, Antonella Fioravanti.\n\nFormal analysis: Sara Tenti.\n\nResources: Fabio Giannini, Antonella Fioravanti.\n\nValidation: Nicola Giordano.\n\nWriting – Original Draft: Sara Tenti, Fabio Giannini, Antonella Fioravanti.\n\nWriting – Review & Editing: Nicola Giordano, Maurizio Cutolo.\n\nAbbreviations: aCL = anti-cardiolipin antibodies, ACTH = adrenocorticotropic hormone, aGP1 = anti-β2 Glycoprotein 1 antibodies, AIH = autoimmune hepatitis, AIMSS = aromatase inhibitors-induced musculoskeletal symptoms, AIs = aromatase inhibitors, ANA = anti-nuclear antibodies, anti-CCP = anti-cyclic citrullinated peptide antibodies, aPL = antiphospholipid antibodies, APS = antiphospholipid syndrome, APTT = prolonged activated partial thromboplastin time, ASAS = anti-synthetase antibody syndrome, BMD = bone mineral density, CK = creatine kinase, CRP = C reactive protein, CT = computed tomoghraphy, DHEAS = dehydroepiandrosterone sulfate, DLE = discoid lupus erythematosus, E2 = estradiol, ENA = extractable nuclear antigens, ESR = erythrocyte sedimentation rate, INR = International normalized ratio, LAC = lupus anticoagulant, LMWH = low molecular weight heparin, MCA = middle cerebral artery, MCF = metacarpophalangeal, MRI = magnetic resonance imaging, PIP = proximal interphalangeal, PT = prothrombin time, RA = rheumatoid arthritis, RF = rheumatoid factor, SCLE = subacute cutaneous lupus erythematosus, SjS = Sjogren syndrome, SLE = systemic lupus erythematosus, SpA = spondyloarthropaty, SS = systemic sclerosis.\n\nFG and AF contributed equally to this work.\n\nInformed written consent was obtained from the patient for publication of this case report and accompanying images.\n\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n==== Refs\nReferences\n[1] Winer EP Hudis C Burstein HJ \nAmerican Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004 . J Clin Oncol \n2005 ;23 :619–29 .15545664 \n[2] Burstein HJ Prestrud AA Seidenfeld J \nAmerican Society of Clinical Oncology clinical practice practice guideline: Update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer . J Clin Oncol \n2010 ;28 :3784–96 .20625130 \n[3] Buzdar A Howell A Cuzick J \nComprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial . Lancet Oncol \n2006 ;7 :633–43 .16887480 \n[4] Henry NL Giles JT Stearns V \nAromatase inhibitor-associated musculoskeletal symptoms: etiology and strategies for management . Oncology (Williston Park) \n2008 ;22 :1401–8 .19086600 \n[5] Amir E Seruga B Niraula S \nToxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis . J Natl Cancer Inst \n2011 ;103 :1299–309 .21743022 \n[6] Morel B Marotte H Miossec P \nWill steroidal aromatase inhibitors induce rheumatoid arthritis? \nAnn Rheum Dis \n2007 ;66 :557–8 .17360783 \n[7] Bruzzese V Hassan C Zullo A \nRheumatoid arthritis: a complication of aromatase inhibitor therapy? \nInt J Immunopathol Pharmacol \n2011 ;24 :1099–101 .22230418 \n[8] Bertolini E Letho-Gyselinck H Prati C \nRheumathoid arthritis and aromatase inhibitors . Joint Bone Spine \n2011 ;78 :62–4 .20621535 \n[9] Chao J Parker BA Zvaifler NJ \nAccelerated cutaneous nodulosis associated with aromatase inhibitor therapy in a patient with rheumatoid arthritis . J Rheumatol \n2009 ;36 :1087–8 .19435976 \n[10] Chen JY Ballou SP \nThe effect of antiestrogen agents on risk of autoimmune disorders in patients with breast cancer . J Rheumatol \n2015 ;42 :55–9 .25274893 \n[11] Scarpa R Atteno M Peluso R \nRheumatic complaints in women taking aromatase inhibitors for treatment of hormone-dependent breast cancer . J Clin Rheumatol \n2011 ;17 :169–72 .21617557 \n[12] Laroche M Borg S Lassoued S \nJoint pain with aromatase inhibitors: abnormal frequency of Sjögren's syndrome . J Rheumatol \n2007 ;34 :2259–563 .17937464 \n[13] Guidelli GM Martellucci I Galeazzi M \nSjögren's syndrome and aromatase inhibitors treatment: is there a link? \nClin Exp Rheumatol \n2013 ;31 :653–4 .23558055 \n[14] Yasar Bilge NS Korkmaz C \nDoes Aromatase Inhibitors Cause Sjogren's Syndrome and Polyneuropathy? \nWorld J Oncol \n2014 ;5 :181–2 .29147400 \n[15] Mascella F Gianni L Affatato A \nAromatase inhibitors and anti-synthetase syndrome . Int J Immunopathol Pharmacol \n2016 ;29 :494–7 .27225465 \n[16] Pokhai G Buzzola R Abrudescu A \nLetrozole-induced very early systemic sclerosis in a patient with breast cancer: a case report . Arch Rheumatol \n2014 ;29 :126–9 .\n[17] Trancart M Cavailhes A Balme B \nAnastrozole-induced subacute cutaneous lupus erythematosus . Br J Dermatol \n2008 ;158 :628–9 .18070201 \n[18] Fisher J Patel M Miller M \nAnastrozole-induced subacute cutaneous lupus erythematosus . Cutis \n2016 ;98 :E22–26 .\n[19] Zarkavelis G Kollas A Kampletsas E \nAromatase inhibitors induced autoimmune disorders in patients with breast cancer: a review . J Adv Res \n2016 ;7 :719–26 .28275510 \n[20] Castagnetta L Granata OM Traina A \nA role for sex steroids in autoimmune diseases: a working hypothesis and supporting data . Ann N Y Acad Sci \n2002 ;966 :193–203 .12114272 \n[21] Cutolo M Capellino S Montagna P \nNew roles for estrogens in rheumatoid arthritis . Clin Exp Rheumatol \n2003 ;21 :687–90 .14740444 \n[22] Cutolo M Sulli A Straub RH \nEstrogen metabolism and autoimmunity . Autoimmun Rev \n2012 ;11 :A460–464 .22155198 \n[23] Chighizola C Meroni PL \nThe role of environmental estrogens and autoimmunity . Autoimmun Rev \n2012 ;11 :A493–501 .22172713 \n[24] Miyakis S Lockshin MD Atsumi T \nInternational consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) . J Thromb Haemost \n2006 ;4 :295–306 .16420554 \n[25] Cosman F Baz-Hecht M Cushman M \nShort-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature . Thromb Res \n2005 ;116 :1–3 .15850603 \n[26] Takayanagi H Hayami R Tsuneizumi M \nThrombophlebitis in an Elderly Japanese Woman treated with tamoxifen for breast cancer . Gan To Kagaku Ryoho \n2015 ;42 :1203–5 .26489549 \n[27] Forbes JF Cuzick J Buzdar A \nArimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group . Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial . Lancet Oncol \n2008 ;9 :45–53 .18083636 \n[28] Sherer Y Kuechler S Jose Scali J \nLow dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases . Isr Med Assoc J \n2008 ;10 :55–7 .18300575 \n[29] Tenti S Fabbroni M Mancini V \nIntravenous Immunoglobulins as a new opportunity to treat discoid lupus erythematosus: a case report and review of the literature . Autoimmun Rev \n2018 ;17 :791–5 .29885539 \n[30] Tenti S Guidelli GM Bellisai F \nLong-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy . Clin Exp Rheumatol \n2013 ;31 :877–82 .23985161 \n[31] Burstein HJ \nAromatase inhibitor-associated arthralgia syndrome . Breast \n2007 ;16 :223–34 .17368903 \n[32] Burstein HJ Winer EP \nAromatase inhibitors and arthralgias: a new frontier in symptom management for breast cancer survivors . J Clin Oncol \n2007 ;25 :3797–9 .17761968 \n[33] Coleman RE Bolten WW Lansdown M \nAromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations . Cancer Treat Rev \n2008 ;34 :275–82 .18082328 \n[34] Garreau JR Delamelena T Walts D \nSide effects of aromatase inhibitors versus tamoxifen: the patients’ perspective . Am J Surg \n2006 ;192 :496–8 .16978958 \n[35] Donnellan PP Douglas SL Cameron DA \nAromatase inhibitors and arthralgia . J Clin Oncol \n2001 ;19 :2767.\n[36] Moxley G \nRheumatic disorders and functional disability with aromatase inhibitor therapy . Clin Breast Cancer \n2010 ;10 :144–7 .20299320 \n[37] Shanmugam VK McCloskey J Elston B \nThe CIRAS study: a case control study to define the clinical, immunologic, and radiographic features of aromatase inhibitor-induced musculoskeletal symptoms . Breast Cancer Res Treat \n2012 ;131 :699–708 .22076476 \n[38] Din OS Dodwell D Wakefield RJ \nAromatase inhibitor-induced arthralgia in early breast cancer: what do we know and how can we find out more? \nBreast Cancer Res Treat \n2010 ;120 :525–38 .20157776 \n[39] Dawson-Basoa M Gintzler AR \nInvolvement of spinal cord delta opiate receptors in the antinociception of gestation and its hormonal simulation . Brain Res \n1997 ;757 :37–42 .9200497 \n[40] Dougados M van der Linden S Juhlin R \nThe European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy . Arthritis Rheum \n1991 ;34 :1218–27 .1930310 \n[41] Fox RI Howell FV Bone RC \nPrimary Sjogren syndrome: clinical and immunopathologic features . Semin Arthritis Rheum \n1984 ;14 :77–105 .6399627 \n[42] Vitali C Bombardieri S Jonsson R \nEuropean Study Group on Classification Criteria for Sjögren's Syndrome . Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group . Ann Rheum Dis \n2002 ;61 :554–8 .12006334 \n[43] Konttinen YT Fuellen G Bing Y \nSex steroids in Sjögren's syndrome . J Autoimmun \n2012 ;39 :49–56 .22300712 \n[44] Lateef A Petri M \nHormone replacement and contraceptive therapy in autoimmune diseases . J Autoimmun \n2012 ;38 :J170–176 .22261500 \n[45] Sthoeger ZM Zinger H Mozes E \nBeneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZBxNZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies . Ann Rheum Dis \n2003 ;62 :341–6 .12634234 \n[46] Inno A Basso M Vecchio FM \nAnastrozole-related acute hepatitis with autoimmune features: a case report . BMC Gastroenterol \n2011 ;11 :32.21453541 \n[47] Islam MS Wright G Tanner P \nA case of anastrazole-related drug-induced autoimmune hepatitis . Clin J Gastroenterol \n2014 ;7 :414–7 .26184021 \n[48] Klapko O Ghoulam E Jakate S \nAnastrozole-induced autoimmune hepatitis: a rare complication of breast cancer therapy . Anticancer Res \n2017 ;37 :4173–6 .28739702 \n[49] Schreiber K Sciascia S de Groot PG \nAntiphospholipid syndrome . Nat Rev Dis Primers \n2018 ;4 :18005.29368699 \n[50] Gómez-Puerta JA Cervera R Espinosa G \nAntiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients . Semin Arthritis Rheum \n2006 ;35 :322–32 .16616155 \n[51] Sherer Y Blank M Shoenfeld Y \nAntiphospholipid syndrome (APS): where does it come from? \nBest Pract Res Clin Rheumatol \n2007 ;21 :1071–8 .18068862 \n[52] Dlott JS Roubey RA \nDrug-induced lupus anticoagulants and antiphospholipid antibodies . Curr Rheumatol Rep \n2012 ;14 :71–8 .22160568 \n[53] Zandman-Goddard G Peeva E Shoenfeld Y \nGender and autoimmunity . Autoimmun Rev \n2007 ;6 :366–72 .17537382 \n[54] Capellino S Straub RH Cutolo M \nAromatase and regulation of the estrogen-to-androgen ratio in synovial tissue inflammation: common pathway in both sexes . Ann N Y Acad Sci \n2014 ;1317 :24–31 .24684533 \n[55] Iwasa A Arakaki R Honma N \nAromatase controls Sjögren syndrome-like lesions through monocyte chemotactic protein-1 in target organ and adipose tissue-associated macrophages . Am J Pathol \n2015 ;185 :151–61 .25447050 \n[56] Kaliterna DM Radić M Ljutić D \nDoes estrogen stimulate the pathogenic sort of anticardiolipin antibodies? \nIsr Med Assoc J \n2014 ;16 :197–8 .\n\n",
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"issue": "98(13)",
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"mesh_terms": "D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal; D016736:Antiphospholipid Syndrome; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "2985248R",
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"pmid": "30921233",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Primary antiphospholipid syndrome during aromatase inhibitors therapy: A case report and review of the literature.",
"title_normalized": "primary antiphospholipid syndrome during aromatase inhibitors therapy a case report and review of the literature"
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"abstract": "We report here a case of clinically significant liver toxicity after a brief course of rosuvastatin, which is the first statin approved by the regulatory authorities since the withdrawal of cerivastatin. Whether rosuvastatin has a greater potential compared with other statins to damage the liver is unclear and the involved mechanisms are also unknown. However, rosuvastatin is taken up by hepatocytes more selectively and more efficiently than other statins, and this may reasonably represent an important variable to explain the hepatotoxic potential of rosuvastatin. Our report supports the view that a clinically significant risk of liver toxicity should be considered even when rosuvastatin is given at the range of doses used in common clinical practice.",
"affiliations": "Department of Internal Medicine, San Camillo Hospital, Circonvallazione Gianicolense, Rome 00152, Italy. gfamular@scamilloforlanini.rm.it",
"authors": "Famularo|Giuseppe|G|;Miele|Luca|L|;Minisola|Giovanni|G|;Grieco|Antonio|A|",
"chemical_list": "D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium",
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"issue": "13(8)",
"journal": "World journal of gastroenterology",
"keywords": null,
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"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D003324:Coronary Artery Disease; D005464:Fluorobenzenes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides",
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"pages": "1286-8",
"pmc": null,
"pmid": "17451217",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11317178;12062007;12211221;12386119;12605844;15998357;15030249;15162892;7249508;8749903;15911706;14567716",
"title": "Liver toxicity of rosuvastatin therapy.",
"title_normalized": "liver toxicity of rosuvastatin therapy"
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"abstract": "Idiopathic Idiopathic membranous nephropathy (iMN) is an immune-complex mediated renal disease which is usually associated with the nephrotic syndrome (NS). The course of the disease is variable. Some patients maintain normal kidney function with or without a spontaneous remission of proteinuria, while others progress to end-stage renal failure or die from complications related to the nephrotic syndrome. Whether or not to treat a patient with idiopathic membranous nephropathy is still controversial. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients.\nThe aim of this study was to describe our experience of treatment of an idiopathic membranous nephropathy (iMN), efficacy and complications rate.\nOur patient was older, mail gender, in high-risk group with persistent proteinuria 10,68 g/day and stable renal function. We have taken these factors into consideration, along with age and other comorbidities, that may significantly elevate the risk of treatment. We chose to start with early treatment, following the Ponticelli's group protocol based on high dose corticosteroids (odd months) alternating with clorambucil (even months) for six months. This treatment was accompanied by the steroid side effects, including hyperglycaemia dependance on insulin therapy and pulmonary thromboembolism despite administered prophylactically low molecular weight heparin. The six-month treatment was successfully completed with the reduction of proteinuria to nephritic values 2,86 g/day, despite many complications. Complete remission of the disease with non-significant proteinuria and with stable renal function was achieved in 14 months which has been maintained for 2 years.\nWe suggest that decisions on the timing of start of therapy, whom to treat, best sequence of the use of the various immunosuppressive drugs must be based on an individualized assessment of risks and benefits.",
"affiliations": "Urology Clinic, University Clinical Center of Sarajevo, Sarajevo, Bosnia and Herzegovina and Clinic of Nephrology, Clinics Center, Sarajevo, Bosnia and Herzegovina.;Urology Clinic, University Clinical Center of Sarajevo, Sarajevo, Bosnia and Herzegovina and Clinic of Nephrology, Clinics Center, Sarajevo, Bosnia and Herzegovina.;Faculty of Health Studies, University of Sarajevo, Bosnia and Herzegovina.;Urology Clinic, University Clinical Center of Sarajevo, Sarajevo, Bosnia and Herzegovina and Clinic of Nephrology, Clinics Center, Sarajevo, Bosnia and Herzegovina.;Institute for Clinical Biochemistry and Immunology University of Sarajevo, Clinics Center, Sarajevo, Bosnia and Herzegovina.",
"authors": "Uncanin|Snezana|S|;Dzemidzic|Jasminka|J|;Serdarevic|Nafija|N|;Muslimovic|Alma|A|;Haskovic|Denis|D|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D018906:Antineoplastic Agents, Alkylating; D002699:Chlorambucil; D011241:Prednisone; D008775:Methylprednisolone",
"country": "Bosnia and Herzegovina",
"delete": false,
"doi": "10.5455/medarh.2020.74.228-232",
"fulltext": "\n==== Front\nMed Arch\nMed Arch\nMedical Archives\nMedical Archives\n0350-199X 1986-5961 Academy of Medical Sciences of Bosnia and Herzegovina \n\n10.5455/medarh.2020.74.228-232\nCase Report\nIdiopathic Membranous Nephropathy and Treatment Related Complications\nUncanin Snezana 12 Dzemidzic Jasminka 1 Serdarevic Nafija 23 Muslimovic Alma 1 Haskovic Denis 3 1 Urology Clinic, University Clinical Center of Sarajevo, Sarajevo, Bosnia and Herzegovina and Clinic of Nephrology, Clinics Center, Sarajevo, Bosnia and Herzegovina\n2 Faculty of Health Studies, University of Sarajevo, Bosnia and Herzegovina\n3 Institute for Clinical Biochemistry and Immunology University of Sarajevo, Clinics Center, Sarajevo, Bosnia and Herzegovina\nCorresponding author:Assistant professor Snezana Uncanin, MD, PhD. Clinic of Nephrology. Clinical Center of Sarajevo University. Faculty of Health Studies, SarajevoBosnia and HerzegovinaBolnicka 25 71000 Sarajevo+38761245604snedrag3@gmail.com\nORCID ID: http//www.orcid.org/0000-0001-9387-5081\n6 2020 \n74 3 228 232\n12 4 2020 10 6 2020 © 2020 Snezana Uncanin, Jasminka Dzemidzic, Nafija Serdarevic, Alma Muslimovic, Denis Haskovic2020This 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.Introduction:\nIdiopathic Idiopathic membranous nephropathy (iMN) is an immune-complex mediated renal disease which is usually associated with the nephrotic syndrome (NS). The course of the disease is variable. Some patients maintain normal kidney function with or without a spontaneous remission of proteinuria, while others progress to end-stage renal failure or die from complications related to the nephrotic syndrome. Whether or not to treat a patient with idiopathic membranous nephropathy is still controversial. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40–50% of patients.\n\nAim:\nThe aim of this study was to describe our experience of treatment of an idiopathic membranous nephropathy (iMN), efficacy and complications rate.\n\nCase report:\nOur patient was older, mail gender, in high-risk group with persistent proteinuria 10,68 g/day and stable renal function. We have taken these factors into consideration, along with age and other comorbidities, that may significantly elevate the risk of treatment. We chose to start with early treatment, following the Ponticelli’s group protocol based on high dose corticosteroids (odd months) alternating with clorambucil (even months) for six months. This treatment was accompanied by the steroid side effects, including hyperglycaemia dependance on insulin therapy and pulmonary thromboembolism despite administered prophylactically low molecular weight heparin. The six-month treatment was successfully completed with the reduction of proteinuria to nephritic values 2,86 g/day, despite many complications. Complete remission of the disease with non-significant proteinuria and with stable renal function was achieved in 14 months which has been maintained for 2 years.\n\nConclusion:\nWe suggest that decisions on the timing of start of therapy, whom to treat, best sequence of the use of the various immunosuppressive drugs must be based on an individualized assessment of risks and benefits.\n\nMembranous nephropathyPonticelli’s protocolpulmonary thromboembolism\n==== Body\n1. INTRODUCTION\nMembraneous nephropathy (MN) is the most common cause of the nephrotic syndrome in adults in Europe countries (1). Although MN can occur secundary to infections, systemic diseases, use of drugs, or malignancies. Awareness of malignacy is particularly important in the elderly. The prevalence of malignancy was 4,1 % in patients < 60 years, and 19,4% in patients > 60 years of age (2). In most patients no underlying cause is identified idiopathic membranous nephropathy (iMN). The clinical course of patients with iMN and nephrotic proteinuria is quite variable. One-third exibit spontaneous remission of disease, usually in the first 2 years after diagnosis, although remission can occur at any time. One-third exibit chronic persistent proteinuria with preservation of renal function, and one-third progress slowly to end stage renal disease (ESRD). Untreated 40-50% of patients with iMN and nephrotic proteinuria will develop end stage renal disease (3, 4). The treatment of iMN is heavily debated (5-7). Although several studies have claimed success of immunosuppressive therapy (8-12). A meta analysis and Cochrane review concluded that there is insufficient evidence of the efficacy of immunosuppressive therapy (13), and many studies have reported a relatively good outcome in untreated patients (14, 15). The perception that immunosuppressive is of limited benefits may lead to therapeutic nihilism. Guidelines for all common histologic variants of iMN have recently been published under the auspices of the KDIGO (Kidney Disease: Improving Global Outcomes) initiative (16). These guidelines, graded by the quality of evidence, were established to help the clinician’s, but not to replace physician. Cyclophosphamide is preferred over chlorambucil (13, 14). The optimal duration of therapy is debated. The use of alkylating agents is complicated by serious side effects, like as infertility and risk of late malignancies.\n\nAdditionally, the risk of complications from cyclophosphamide may be higher in older individuals and/or in those with a reduced glomerular filtrate rate (GFR). On the other hand, cyclosporine is often difficult to manage and not as well tolerated in patients with reduced GFR and/or in those with severe underlying vascular damage on kidney biopsy, which tends to accentuate the calcineurin inhibitor (CNI) nephrotoxicity (17, 18). Recently, there has been evidence suggesting that treatment with rituximab (19-21) and synthetic adrenocorticotropic hormone (ACTH) can be an effective alternative to these agents (22, 23). One of the first immunosuppressive regimens proven to be effective against iMN was the combination of chlorambucil and prednisone (8). Ponticelli et al. (8) showed a significant increase in complete and partial remissions compared to symptomatic management. In our clinic, we usually prescribe these regimens with some modification.\n\n2. CASE REPORT\nA 60 years old man with a history of newly diagnosed proteinuria was admitted to our hospital with a two months history of fatigue, with trace lower extremity edema. The patient had arthralgias of both knees and hands that had not changed in intensity. There was no hystory of rash, cough, sinus symptoms, chest pain or gastrointestinal complaints. He had long standing nocturia, and increased urinary frequency, but no dysuria. He had undergone routine cholecystectomy 4 months prior to current presentation. On admission, physical exam revealed man in good condition, with trace lower extremity edema, and normal cardiac, pulmonary and abdominal exam, no ascites or hepatosplenomegaly was detected. There was no rash, livedo reticularis, joint effusions or synovitis. He was afebrile, with blood pressure of 110/60 mmHg, heart rate 80 beat /min. Laboratory exam revealed a white blood count (WBC) of 6,15 x109/L (4-109/L), red blood count (RBC ) was 5,32 1012/L (4,30-5,70 x 10 12/L), normal hemoglobin 170 g/L (135-175 g/L), platelet count 254 x109/L (150-400 x 109/L, APTT 32,5 sec (27,4-37,7 sec), and INR 0,85 (0,80-1,20). Erytrocyte sedimentation rate was mild elevated 48 mm/hr, as was the value of iron 37,2 μmol/L (9-31,3 μmol/L). Urinalysis revealed 3+ proteine, no nitrites or glucose. Evaluation of urine sediment revealed several granulated casts, with 20-25/μl RBC, 8-10 /μl WBC. Renal function was normal with serum creatinine 86 μmol/L (63 -109 μmol/L). Urine protein was quantified at 10,68 gr/24h (<150 mg/24 hours), Bence-Jones proteins were not detected in urine specimen. Serum total protein and albumin were respectively of 46,0 g/L (62,0-82,0 g/L) and 17,0 g/L (35,0-50,0 g/L). The total cholesterol was 7,6 mmol/L (<5,3 mmol/L), and triglyceride of 1,82 mmol/L (0,4-0,9 mmol/L). A diagnosis of nephrotic syndrome was confirmed. Our patient received no drugs; no features of acute or chronic infections were found. The investigating for secundary causes of this membranous glomerulonephritis included: anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies and antinuclear antibodies (ANA), titers for antineutrophil cytoplasmic antibodies (ANCA), complement levels and tests for cryoglobulins and rheumatoid factor, thyroid hormone, were negative or normal. Serologies for hepatitis A, B, C and HIV, were nonreactive. Measurement of tumor markers Ca -125 showed mild elevated 37,7 U/ml (0-35 U/ml). Thoracoabdominal tomography, stool for fecal occult blood, prostate – specific tumor markers (PSA) were normal or negative. Chest x ray showed no evidence of infiltrate, vascular congestion or cardiac enlargment (the chest radiography was normal). By ultrasound the right kidney’s longitudinal diameter was 13,8 cm and left kidney 14,2 cm, with no pelviectasis, but mild increases parenhimal echogenicity. No renal venous thrombosis was faund on the Doppler sonography. Renal biopsy showed that this was caused by membranous nephropathy. It showed glomeruli with thickening of the capillary walls and capillary loops. There was no mesangial hypercellularity and 40% of interstitium was fibrous. Imunofluorescence showed strong granular IgG along the capillary wall. No IgA deposition and complement were seen.\n\n3. CLINICAL FOLLOW UP\nTreatment was based on the alternating pulse of methylprednisolone, oral corticosteroid and chlorambucil. Treatment consisted of 1 g intravenous methylprednisolone given every 24 hours for three consecutive days, followed by oral prednisone at a dose of 0,5 mg/kg/day in a single morning administration for 27 days. After the first month prednisone was stopped and the patient was given chlorambucil, 0,2 mg/kg/day for one month. The whole treatment lasted six months, three with corticosteroids and three with chlorambucil. Before start treatment with high dose prednisone, which might predispose to thrombosis, and low serum albumin which was <20 g/L, the patient was initially treated with prophylactic anticoagulation (low molecular weight heparin), angiotenzin converting enzyme inhibitors (ACEi), statins and dietary sodium restrictio. After the first month of treatment, the proteinuria decresed at 6,97 g/24h, the patient felt well, had no difficulty. At the end of the second month, after cycle with chlorambucil, proteinuria was in a slight decline 6,21 g/24h, and the patient was admitted to the hospital, where he continued terapy with methylprednisolone 1,0 g intravenous for 3 days. On the third day, a few hours after methilprednisolone bolus, he presented with chest pain, cough, and dyspnoea. He had smoked 40 cigarettes every day for years. On physical examination, his body temperature was 37,5 degrees Celsius, with a respiratory rate of 30 breaths per minute, a heart rate of 120 beats per minute, and arterial pressure of 100/80 mmHg. The heart sounds were regular, with no added murmurs. His breathing sounds were reduced bilaterally at the lower lung fields with a few crackeles. The electrocardiogram showed sinus tachycardia and no other abnormalities. The arterial blood gases were normal, with a pH of 7,446 (7,35-7,45), partial pressure of oxygen (PaO2) 8,58 (11.1-14.4 kPa), partial pressure of carbon dioxide (PaCO2) 5,14 (4,7-6,4 kPa), and bicarbonate of 26,1 (22-26 mmol/L). D -Dimers were high 1314 (0-0,55 mg/L FEU). A spiral CT angiogram was then performed, which showed a large thrombus in the right pulmonary artery and an infarct of the lower lobe. Acute pulmonary embolism was diagnosed and the dose of anticoagulant therapy was increased to heparin in bolus 80 IU/kg TT + continue infusion at 18 IU/kg TT for 24h after very careful evaluation and monitoring the risk of bleeding. On the fifth day of terapy, oral anticoagulant (acenocoumarol) was included in addition to heparin, and heparin was discontinued after seven days. Oral prednisone was continued in the divided daily dose in two separate dose twice daily.\n\nAt the end of the cycle with prednisone and at beginning of the fourth month of tretament there was no swelling in his legs. The proteinuria decresed at 4,08 g/24h, but lipids increased as did glycemia. Glucose rate was elevated at 15,9 mmol/l, total cholesterol 13,5 mmol/L and triglyceride of 2,79 mmol/L. There was no significant variaton in other laboratory findings. Insulin therapy was also initiated at the time of diagnosis of diabetes mellitus iatrogenes. The next dose of chlorambucil, the forth month of treatment, was reduced to 0,15 mg/kg day, because the average protein excretion in urine was slightly descreased in the months of chlorambucil, while in the months of prednisolone, it decreased significantly. On the fifth month of tretament, in the third cycle of methilprednisolone, we reduced the pulse dose to 500mg/day for 3 days, followed by oral prednisolone divided daily dose in two separate dose twice daily. At the end of the sixth month of tretament, proteinuria decresed at 2,86 g/24h. In continuation of treatment, steroid therapy and cyclophosphamide were exluded. In therapy, the patient continues to use angiotenzin converting enzyme inhibitors (ACEi), statins and prophylactic oral anticoagulation for the next six months, dietary sodium restriction with monthly monitoring of proteinuria and renal function and waiting for a reasonable period of time (about 8 months) to see whether or not spontaneous remission (complete or partial) occurs. Each month proteinuria gradually declined and renal function remained maintained. After fourteen months of follow-up, complete remission of the disease with non-significant proteinuria was achieved. The patient did not have a recurrence of the disease within two years after the end of treatment.\n\n4. DISCUSSION\nOptimum treatment of idiopathic membranous nephropaty is controversial and challenging because there are very few randomized trials in patients with iMN, the natural hystory of iMN is quite variable, and many studies have reported a relatively good outcome in untreated patients (13-15). Without immunosuppresive therapy, >50% of patients would have developed a spontaneous remission. Moreover, 38% of patients needed a second course of therapy because of initial treatment failure or relapse. The immunosuppressive agents have serious side effects, and it is quite difficult to balance the risk and benefits (13, 14). The most extensively studied and frequently used immunosuppressive regimens for this disease comprise alkylating agents plus corticosteroids or cyclosporin. All of these treatment options have inherent problems. The optimal timing of start of therapy is uncetain. In the study of Hofstra JM et all., early treatment resulted in a more rapid onset of remission and there fore shortened the duration of the nephrotic phase, it did not result in a better presevation of renal function at the end of follow-up (7). It therefore seems that treatment can safely be postponed until renal function deteriorates. Hower, when postponing treatment, there might be a larger risk of both nephrotic syndrome - related and treatment-related side effects. Finally, elderly patients are more prone to develop treatment-related comlications. Membranous nephropathy is the most cause of nephrotic syndrome in patients over age of 60 years (24, 25). This age group accounts for 23% of patients diagnosed with iMN (25). Older patients will require attention given their lower reserve of kidney function at baseline, but age alone should not preclude therapy. Several works, especially those from Cattran’s group, have shown that male gender, age older than 50 years, and the presence of sustained proteinuria >8 g/day for longer than 6 months are criteria for a poor prognosis, and thus lower possibility of spontaneous remission (26). When risk asessment leads to the decision not to start treatment in an individual patient, re-evaluation should take place after 6 months or earlier if the clinical condition of the patients changes. Treatment with alkylating agents is usually combined with high dose steroid treatment. The dose and duration of steroid tretamnet varies and clinical trials are lacking. The most popular immunosuppressive regimen for MGN is from Ponticelli’s group, based on high dose steroids alternating with chlorambucil (8). Our patient was older, mail gender, in high-risk group with persistent proteinuria 10,68 g/day and stable renal function. We have taken these factors into consideration, along with age and other comorbidities, that may significantly elevate the risk of treatment, we chose to start therapy earlier than the 6 months of observation. He received supportive therapy and six month therapy with methylprednisolone and chlorambucil alternated every other month. After three months of treatment, due to complications (pulmonary thromboembolism and iatrogenic diabetes), we had to reduce the doses of the medication chlorambucil and the pulse dose methylprednisolone, oral prednisolone divided daily dose in two separate dose twice daily. He was initially treated with prophylactic anticoagulation, but when a large thrombus in the right pulmonary artery and an infarct of the lower lobe were diagnosed, prophylactic low molecular weight heparin was changed to high dose heparin in bolus end continued infusion for 24h after very careful evaluation and monitoring the risk of bleeding. Nephrotic syndrome is also associated with increased arterial as well as venous thromboembolism (27, 28). The majority of thromboembolic events occur within 6 months of the diagnosis of nephrotic syndrome (28, 29). Patients with nephrotic syndrome demonstrate urinary loss of anticoagulants (antithrombin III) with increased liver procoagulant synthesis (fibrinogen, factor V, factor VIII), increased platelet activation and aggregability, decreased fibrinolytic activity and localized clotting activation in the kidney (27). Despite the urinary loss of hemostatic proteins levels, some proteins, including fibrinogen, are increased and correlate with the hypoalbuminemia (30). It is believed that hypoalbuminemia stimulates the hepatic synthesis of hemostatic proteins to make up for the urinary loss (31). Hypoalbuminemia increased risk of venous thromboembolic events when serum albumin was below 25g/L (32). In some studies, massive proteinuria has been found to be a more significant predictor of venous thromboembolic events than serum albumin (33). Dehydration, diuretic use, trauma, steroid use as well as immobility (28, 29) are other frequently quoted, non hematologic reasons for thrombotic tendecies in this population of patients. Established risk factors for arterial TE in NS include age, sex, hypertension, smoking, diabetes and low estimated glomerular filtration rate (eGFR) (32). Alkylating agents in combination with steroids are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data are limited (17, 18). Relapses of the nephrotic syndrome after cessation of treatment are a common problem in iMN. Experience with the use of rituximab in iMN is growing, but this drug is still considered an experimental therapy (19-21). Adrenocorticotropic hormones and mycophenolate mofetil may play a role in iMN, but research is still too limited to make formal recommendations regarding the routine use of these treatments.\n\n5. CONCLUSION\nWe believe that a general conservative therapy for nephrotic syndrome should be prescribed in every patient with iMGN, including ACEIs or ARA and statins, and wait for a reasonable time period to see whether or not spontaneous remission (complete or partial) occurs. In those cases with massive proteinuria not showing a decreasing trend, and especially in male patients aged > 50 years, it is reasonable to shorten the observation period. We prefer to start with early treatmen, with steroids plus an alkylating agents, as this may allow a good chance of remission and may protect renal function in the long-term, with relatively few side-effects. We suggest that decisions on the timing of start of therapy, whom to treat, best sequence of the use of the various immunosuppressive drugs must be based on an individualized assessment of risks and benefits. Treatment should be restricted to high-risk patients who can be identified by the level and /or the composition of urinary proteins.\n\nAuthors contribution:\nAll authors were included in all steps of preparation zhis article. Final proof reading was made by the first author.\n\nConflict of interest:\nNone declared.\n\nFinancial support and sponsorship:\nNil.\n==== Refs\nREFERENCES\n1. McQuarrie EP Mackinnon B Stewart GA Geddes CC Membranous nephropathy remains the commonest primary cause of nephrotic syndrome in a northern European Caucasian population Nephrol Dial Transplant 2010 25 1009 1010 20037184 \n2. Lefaucheur C Stengel B Nochy D Martel P Hill GS Jacquot C Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk cancer association Kidney Int 2006 70 1510 1517 16941021 \n3. Mazuecos AM Praga M Araque A Hernandez E Sanchez R Andres A Evolucion a largo plazo de las glomerulonefritis membranosas idiopaticas no tratadas Nefrologia 1993 13 299 305 \n4. Fulladosa X Praga M Segarra A Martinez Ara J Glomerulonefritis membranosa Nefrologia 2007 27 Supl. 2 70 86 \n5. du Buf-Vereijken PW Feith GW Hollander D Gerlag PGG Wirtz JJJM Noordzij TC Restrictive use of immunosuppressive treatment in patients with idiopathic membranous nephropathy: high renal survival in a large patient cohort QJM 2004 97 353 360 15152109 \n6. du Buf-Vereijken PW Branten AJ Wetzels JF Cytotoxic therapy for membranous nephropathy and renal insufficiency: improved renal survival but high relapse rate Nephrol Dial Transplant 2004 19 1142 1148 14993502 \n7. Hofstra JM Wetzels JF Alkylating agents in membranous nephropathy: efficacy proven beyond doubt Nephrol Dial Transplant 2010 25 1760 1766 20133280 \n8. Ponticelli C Zucchelli P Passerini P Cesana B Locatelli F Pasquali S A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy Kidney Int 1995 45 1600 1604 \n9. Jha V Ganguli A Saha TK Kohli HS Sud K Gupta KL A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy J Am Soc Nephrol 2007 18 1899 1904 17494881 \n10. Aaltonen S Honkanen E Outcome of idiopathic membranous nephropathy using targeted stepwise immunosuppressive treatment strategy Nephrol Dial Transplant 2011 26 9 2871 7 21427071 \n11. Kalliakmani P Koutroulia E Sotsiou F Vlachojannis JG Goumenos DS Benefit and cost from the long-term use of cyclosporine-A in idiopathic membranous nephropathy Nephrology (Carlton) 2010 15 762 767 21175962 \n12. Branten AJW du Buf-Vereijken PWG Vervloet M Wetzels JF Mycophenolate mofetil in idiopathic membranous nephropathy: a clinical trial with comparison to a historic control group treated with cyclophosphamide Am J Kidney Dis 2007 50 248 256 17660026 \n13. Chen Y Schieppati A Cai G Chen X Zamora J Giuliano GA Immunosuppression for Membranous Nephropathy: A Systematic Review and Meta-Analysis of 36 Clinical Trials Clin J Am Soc Nephrol 2013 8 787 796 23449768 \n14. Howman A Chapman TL Langdon MM Ferguson C Adu D Feehally J Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial Lancet 2013 381 9868 744 51 23312808 \n15. Polanco N Gutierrez E Covarsi A Ariza F Carreno A Vigil A Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy J Am Soc Nephrol 2010 21 697 704 20110379 \n16. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group KDIGO clinical practice guideline for glomerulonephritis Kidney Int 2012 Suppl. 2 186 197 \n17. Alexopoulos E Papagianni A Tsamelashvili M Leontsini M Memmos D Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome Nephrol Dial Transplant 2006 21 3127 3132 16968719 \n18. Cattran DC Appel GB Hebert LA Hunsicker LG Pohl MA Hoy WE Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial Kidney Int 2001 59 1484 1490 11260412 \n19. Fervenza FC Abraham RS Erickson SB Irazabal MV Eirin A Specks U Rituximab therapy in idiopathic membranous nephropathy: a 2-year study Clin J Am Soc Nephrol 2010 5 2188 2198 20705965 \n20. Bomback AS Derebail VK Mc Gregor JG Kshirsagar AV Falk RJ Nachman PH Rituximab therapy for membranous nephropathy: a systematic review Clin J Am Soc Nephrol 2009 4 734 744 19279120 \n21. Ruggenenti P Cravedi P Chianca A Perna A Ruggiero B Gaspari F Rituximab in idiopathic membranous nephropathy J Am Soc Nephrol 2012 23 1416 1425 22822077 \n22. Ponticelli C Passerini P Salvadori M Manno C Viola BF Pasquali S A randomized pilot trial comparing methylprednisolone plus a cytotoxic agent versus synthetic adrenocorticotropic hormone in idiopathic membranous nephropathy Am J Kidney Dis 2006 47 233 240 16431252 \n23. Hladunewich MA Cattran D Beck LH Odutayo A Sethi S Ayalon R A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar RGel) in nephrotic syndrome due to idiopathic membranous nephropathy Nephrol Dial Transplant 2014 29 1570 1577 24714414 \n24. Cameron JS Nephrotic syndrome in the elderly Semin Nephrol 1996 16 319 329 8829270 \n25. Zent R Nagai R Cattran DC Idiopathic membranous nephropathy in the elderly: a comparative study Am J Kidney Dis 1997 29 200 206 9016890 \n26. Cattran D Pei Y Greenwood C Ponticelli C Passerini P Honkanen E Validation of a predictive model of idiopathic membranous nephropathy: its clinical and researh implications Kidney Int 1997 51 901 907 9067928 \n27. Christiansen CF Schmidt M Lamberg AL Horvath-Puho E Baron JA Jespersen B Kidney disease and risk of venous thromboembolism: a nation wide population-based case-control study J Thromb Haemost 2014 12 1449 54 25040558 \n28. Kerlin BA Ayoob R Smoyer WE Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease Clin J Am Soc Nephrol 2012 7 513 20 22344511 \n29. Pincus KJ Hynicka LM Prophylaxis of thromboembolic events in patients with nephrotic syndrome Ann Pharmacother 2013 47 725 34 23613095 \n30. Lee T Biddle AK Lionaki S Derebail VK Barbour SJ Tannous S Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy Kidney Int 2014 85 1412 1420 24336031 \n31. Hofstra JM Wetzels JFM Should aspirin be used for primary prevention of thrombotic events in patients with membranous nephropathy? Kidney Int 2016 89 981 983 27083274 \n32. Lee T Derebail VK Kshirsagar AV Chung Y Fine JP Mahoney S Patients with primary membranous nephropathy are at high risk of cardiovascular events Kidney Int 2016 89 1111 1118 26924046 \n33. Mahmoodi BK ten Kate MK Waanders F Veeger NJ Brouwer JL Vogt L High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: Results from a large retrospective cohort study Circulation 2008 15 2 224 230\n\n",
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"title": "Idiopathic Membranous Nephropathy and Treatment Related Complications.",
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"abstract": "Dronedarone is a relatively new antiarrhythmic drug approved for paroxysmal or persistent atrial fibrillation. Dronedarone can inhibit P-glycoprotein-mediated digoxin clearance and increase steady-state digoxin level 2.5 times. It is important to closely monitor plasma digoxin levels or administer a lower loading dose of digoxin in patients taking dronedarone concomitantly. We report a case of digoxin toxicity in a patient taking concomitant dronedarone as a result of interaction between digoxin and dronedarone.",
"affiliations": "Department of Medicine, Maimonides Medical Center, Brooklyn, NY.",
"authors": "Vallakati|Ajay|A|;Chandra|Preeti A|PA|;Pednekar|Manali|M|;Frankel|Robert|R|;Shani|Jacob|J|",
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"title": "Dronedarone-induced digoxin toxicity: new drug, new interactions.",
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"abstract": "BACKGROUND\nPerioperative use of cefazolin has been associated with severe allergic reactions, and patients are usually labelled as allergic to penicillin afterwards. The aim of our study was to describe a group of patients with immediate reactions to cefazolin, with proven selective hypersensitivity reactions.\n\n\nMETHODS\nSystematic review of all patients followed at our drug centre with cefazolin-related reactions, between January 2012 and December 2016. All patients were investigated according to the European Network for Drug Allergy (ENDA) recommendations through skin testing (major and minor penicillin determinants, penicillin, amoxicillin, cefazolin, cefuroxime and ceftriaxone) and oral challenges tests.\n\n\nRESULTS\nWe included 7 patients (median age 40 years) with perioperative anaphylactic reactions immediately after cefazolin injection, 4 with hypotension and 1 with Kounis syndrome (KS) type I. The presence of a selective IgE-mediated hypersensitivity through positive skin tests to cefazoline has been proven in all patients. Two patients experienced systemic reactions during skin testing. All patients were successfully challenged with amoxicillin, and they tolerated cefuroxime.\n\n\nCONCLUSIONS\nCefazolin can be responsible for immediate severe allergic reactions in perioperative setting, including KS. Allergological workup is essential for an accurate diagnosis and to explore cross-reactivity between cefazolin and other beta-lactams. Our experience confirmed that patients with IgE-mediated hypersensitivity reactions to cefazolin can tolerate other beta-lactams. This selective pattern of clinical reactivity may be explained by its particular chemical structure, whose R1 side-chain is different from other beta-lactams.",
"affiliations": null,
"authors": "Mota|Inês|I|;Gaspar|Ângela|Â|;Morais-Almeida|Mário|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002437:Cefazolin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000490182",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-2438",
"issue": "177(3)",
"journal": "International archives of allergy and immunology",
"keywords": "Anaphylaxis; Cefazolin; Diagnostic workup; Drug Allergy; Drug provocation tests; Drug-induced anaphylaxis; Kounis syndrome; Skin tests",
"medline_ta": "Int Arch Allergy Immunol",
"mesh_terms": "D000328:Adult; D000707:Anaphylaxis; D000900:Anti-Bacterial Agents; D002437:Cefazolin; D003429:Cross Reactions; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D000074962:Kounis Syndrome; D008297:Male; D008875:Middle Aged; D059035:Perioperative Period; D012882:Skin Tests",
"nlm_unique_id": "9211652",
"other_id": null,
"pages": "269-273",
"pmc": null,
"pmid": "29913447",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Perioperative Anaphylaxis Including Kounis Syndrome due to Selective Cefazolin Allergy.",
"title_normalized": "perioperative anaphylaxis including kounis syndrome due to selective cefazolin allergy"
} | [
{
"companynumb": "PHHY2018PT148412",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFAZOLIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "To report the efficacy and safety of interferon alpha 2b in the treatment of pseudophakic cystoid macular edema resistant to conventional therapy.\nA 64-year-old patient presented with pseudophakic cystoid macular edema in her left eye, which developed two months after an uncomplicated cataract surgery and was resistant to multiple topical NSAIDs and multiple intravitreal bevacizumab injections over the course of nine months. She also developed side effects to oral acetazolamide and intravitreal triamcinolone injection; a skin rash and a rise in intraocular pressure (34 mmHg), respectively. She was subsequently started on topical interferon alpha 2b (1 MIU/ml) four times a day nine months after developing pseudophakic cystoid macular edema. Cystoid macular edema improved significantly in four weeks and completely resolved after twelve weeks. Her vision improved from 20/100 before starting treatment to 20/25 twelve weeks after starting treatment. Macular structure and visual acuity were stable throughout a thirty-six weeks follow-up period.\nand Importance: This case report displays the potential efficacy and safety of interferon alpha 2b in the treatment of refractory cystoid macular edema after cataract surgery. Ocular surface irritation was the only reported adverse effect of the treatment in our patient, this responded to lubricants.",
"affiliations": "Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran.;Eye Research Center, Rasool Akram Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran.;University of Central Florida College of Medicine, Orlando, FL, USA.",
"authors": "Maleki|Arash|A|;Aghaei|Hossein|H|;Lee|Stacey|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2018.03.005",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(17)30332-810.1016/j.ajoc.2018.03.005Case reportTopical interferon alpha 2b in the treatment of refractory pseudophakic cystoid macular edema Maleki Arash arash.maleki01@gmail.comabc∗Aghaei Hossein bLee Stacey da Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iranb Eye Research Center, Rasool Akram Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iranc Byers Eye Institute, Stanford University, Palo Alto, CA, USAd University of Central Florida College of Medicine, Orlando, FL, USA∗ Corresponding author. Noor Ophthalmology Research Center, Noor Eye Hospital, 96 Esfandiar St., 7th Floor, Valiasr St., Tehran, 19686-53111, Iran. arash.maleki01@gmail.com07 3 2018 6 2018 07 3 2018 10 203 205 30 10 2017 26 2 2018 5 3 2018 © 2018 The Authors. Published by Elsevier Inc.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report the efficacy and safety of interferon alpha 2b in the treatment of pseudophakic cystoid macular edema resistant to conventional therapy.\n\nObservations\nA 64-year-old patient presented with pseudophakic cystoid macular edema in her left eye, which developed two months after an uncomplicated cataract surgery and was resistant to multiple topical NSAIDs and multiple intravitreal bevacizumab injections over the course of nine months. She also developed side effects to oral acetazolamide and intravitreal triamcinolone injection; a skin rash and a rise in intraocular pressure (34 mmHg), respectively. She was subsequently started on topical interferon alpha 2b (1 MIU/ml) four times a day nine months after developing pseudophakic cystoid macular edema. Cystoid macular edema improved significantly in four weeks and completely resolved after twelve weeks. Her vision improved from 20/100 before starting treatment to 20/25 twelve weeks after starting treatment. Macular structure and visual acuity were stable throughout a thirty-six weeks follow-up period.\n\nConclusions\nand Importance: This case report displays the potential efficacy and safety of interferon alpha 2b in the treatment of refractory cystoid macular edema after cataract surgery. Ocular surface irritation was the only reported adverse effect of the treatment in our patient, this responded to lubricants.\n\nKeywords\nCystoid macular edemaInterferon α2bPseudophakia\n==== Body\nList of abbreviations\nNSAIDsnonsteroidal anti-inflammatory drugs\n\nanti-VEGFanti-vascular endothelial growth factor\n\nα2balpha 2b\n\nILinterleukin\n\nmlmilliliter\n\nMIUmillion international unit\n\n1 Introduction\nDespite the observed decrease in the incidence of complications after cataract surgery due to advanced surgical techniques, postoperative cystoid macular edema remains a substantial cause of decreased visual acuity following cataract surgery.\n\nBased on most research studies, prostaglandins play the most important role in the pathogenesis of cystoid macular edema after cataract surgery.1 However, lately, the importance of other inflammatory mediators such as vascular endothelial growth factor and other cytokines have been considered.1\n\nTopical and oral nonsteroidal anti-inflammatory drugs (NSAIDs),2 intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections,3 steroids,4 and oral acetazolamide5 have all been used in the treatment of pseudophakic cystoid macular edema with varying results. Subcutaneous interferon alpha has also been used effectively in the treatment of pseudophakic cystoid macular edema.6\n\nThe safety and efficacy of topical interferon α2b has been demonstrated in the treatment of ocular surface tumors.7 However, it has not been employed in the treatment of pseudophakic cystoid macular edema.\n\nIn this case report, we employed topical interferon α2b in the treatment of refractory pseudophakic cystoid macular edema.\n\n2 Case report\nA 64-year-old female had undergone an uncomplicated cataract surgery in her left eye eleven months before presenting to our center. Based on previous reports, she had developed cystoid macular edema 2 months after surgery, and her vision had decreased from 20/25 to 20/100. Topical NSAIDs therapies (ketorolac, diclofenac) and multiple intravitreal bevacizumab injections had proved unsuccessful for nine months. Cystoid macular edema was responsive to intravitreal bevacizumab injections; however, it recurred a few weeks after each injection. She had developed side effects to oral acetazolamide (a skin rash) and intravitreal triamcinolone injection (a rise in intraocular pressure to 34 mmHg was observed one month after injection).\n\nUpon initial presentation to our center, nine months after developing cystoid macular edema, her vision was 20/100 in the left eye. The anterior and posterior segment exams were completely normal. Intraocular pressure was within the normal range. Optical coherence tomography (retinal thickening and cystic hyporeflective areas) and fluorescein angiography (perifoveal leakage and optic disc staining) both confirmed cystoid macular edema. Fluorescein angiography did not appreciate disc leakage, large vessels leakage, or staining. Ultrasound biomicroscopy was obtained to locate the lens haptics position. The results revealed lens in capsular bag and no contact between the lens haptics and the iris (Fig. 1). Various laboratory tests associated with infectious and non-infectious uveitis were performed and all results were within the normal limit, negative, or nonreactive. The patient was reluctant to continue intravitreal anti-VEGF therapy and was seeking another method of treatment. After a discussion regarding the treatment options, the patient agreed to initiate experimental topical interferon α2b therapy four times a day (1 MIU/ml). Topical drops were prepared by our compounding pharmacy by adding two milliliters of distilled water to one milliliter of interferon α2b three MIU (3 MIU/ml vial). Four weeks after initiating treatment, optical coherence tomography showed significant decrease in foveal thickness and cystic spaces. Treatment was continued for twelve weeks using the same protocol, after which we confirmed the stability of the macular structure and began tapering the treatment dose every eight weeks by one drop. At her last visit, she was using one drop a day. The only reported side effect was ocular surface irritation, which improved with the use of lubricants (artificial tears).Fig. 1 Ultrasound biomicroscopy of the study eye, which shows intracapsular intraocular lens implantation with good centration and no contact between the intraocular lens haptics and iris.\n\nFig. 1\n\nWe have planned to continue one drop a day for eight weeks and then one drop every other day for another eight weeks before ceasing treatment (Table 1). The optical coherence tomography obtained at her last visit did not demonstrate any cystoid macular edema, and vision in the left eye was 20/25. Fig. 2 demonstrates the changes in central macular optical coherence tomography from the first visit (before starting treatment) to the last visit (thirty-six months after starting treatment).Fig. 2 Changes in central macular optical coherence tomography (A) before starting treatment, (B) four weeks after starting treatment, (C) twelve weeks after starting treatment, (D) twenty-four weeks after starting treatment, and (F) thirty-six weeks after starting treatment.\n\nFig. 2Table 1 Treatment schedule.\n\nTable 1Treatment Schedule\tDuration of Treatment\t\nFour times a day\tTwelve weeks as there was an improvement after one month of experimental treatment\t\nThree times a day\tEight weeks\t\nTwo times a day\tEight weeks\t\nOne time a day\tEight weeks\t\nOne time every other day\tEight weeks\t\n\n\n3 Discussion\nTo our best knowledge, this is the first case report in which topical interferon α2b was employed in the treatment of refractory cystoid macular edema after cataract surgery. Interferon α2b acts against various biologic targets such as VEGF, interleukin-8 (IL-8), IL-10, TGF-β, and TNF-α.8 It has been shown that interferon alpha improves the barrier effect of retinal vessel endothelial cells in the retina,9 and can also penetrate the sclera despite having a large molecular structure.10 Systemic adverse effects such as flu-like symptoms (90%), leukopenia (30%), alopecia (10%), depression (8%), gastrointestinal disturbances (>1%), and increased liver enzymes (<1%) have been previously reported with systemic interferon alpha employment.[11], [12], [13], [14]\n\nBased on its anti-inflammatory, anti-proliferative, and anti-angiogenic effects, systemic and subtenon interferon alpha has been employed in the treatment of a wide range of posterior segment problems with an inflammatory component such as: diabetic macular edema, age related macular degeneration, posterior uveitis, uveitic cystoid macular edema, and Irvine-Gass syndrome.6,9,[15], [16], [17] The fact that a good response is observed in inactive uveitis with cystoid macular edema and pseudophakic cystoid macular edema supports the mechanism of stabilization of the blood-retina barrier by interferon alpha.6,9\n\nTopical interferon α2b has been employed in the treatment of different types of ocular surface tumors, and its safety and efficacy have been shown in multiple studies.7,[18], [19], [20] The major side effects reported are irritant conjunctivitis and keratitis which are treated with lubricants without treatment discontinuation.7,[18], [19], [20] None of the adverse effects of systemic administration of interferon alpha has been reported with topical treatment.7,[18], [19], [20]\n\nIn our patient, standard treatment modalities failed. We started our patient on topical interferon α2b based on the efficacy and safety profiles of this treatment in ocular surface tumors. The only concern was that of adequate penetration to the posterior vitreous and retina via topical administration. Lincoff et al. demonstrated high concentration of interferon alpha in the choroid after retrobulbar injection.10 Moreover, the efficacy of interferon α2b via subtenon administration has been demonstrated in the treatment of diabetic macular edema15 which may also indicate good penetration of the sclera despite its high molecular weight. However, animal studies are needed to investigate the pharmacokinetic and pharmacodynamic properties of topical interferon α2b. Our patient responded to the proposed experimental treatment after 4 weeks which may indicate reasonable penetration to the posterior vitreous and retina. The temporal relationship between the use of topical interferon α2b and the resolution of chronic cystoid macular edema (unresponsive cystoid macular edema for nine months) points to the efficacy of this treatment and not spontaneous resolution. As efficacy was shown in the initial trial period, we continued the treatment, tapering the treatment dose every eight weeks by one drop. Surface irritation was the only reported side effect in our patient; it was treated successfully with lubricants.\n\n4 Conclusions\nThis case report points to the potential efficacy and safety of topical interferon α2b in the treatment of refractory pseudophakic cystoid macular edema. Further potent and randomized control studies are required to prove our findings.\n\nPatient consent\nThe written informed consent was given by the patient for publishing the data and left eye images.\n\nAcknowledgements and disclosures\nFunding: No funding or grant support.\n\nConflicts of interest: The following authors have no financial disclosures: (AM, HA, SL).\n\nAuthorship: All authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements: The authors thank Andrew Phillips Stephenson for his help with revising the manuscript.\n==== Refs\nReferences\n1 Wielders L.H. Schouten J.S. Aberle M.R. Treatment of cystoid macular edema after cataract surgery J Cataract Refract Surg 43 2 2017 276 284 28366377 \n2 Shelsta H.N. Jampol L.M. Pharmacologic therapy of pseudophakic cystoid macular edema; 2010 update Retina 31 1 2011 4 12 21187730 \n3 Falavarjani K.G. Parvaresh M.-M. Modarres M. Intravitreal bevacizumab for pseudophakic cystoid macular edema; a systematic review J Ophthalmic Vis Res 7 3 2012 235 239 23264866 \n4 Heier J.S. Topping T.M. Baumann W. Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema Ophthalmology 107 11 2000 2034 2038 11054327 \n5 Curkovi c T. Vukojevi c N. Bu can K. Treatment of pseudophakic cystoid macular oedema Coll Antropol 29 suppl 1 2005 103 105 16193688 \n6 Deuter C.M. Gelisken F. Stübiger N. Successful treatment of chronic pseudophakic macular edema (Irvine-Gass syndrome) with interferon alpha: a report of three cases Ocul Immunol Inflamm 19 3 2011 216 218 21595541 \n7 Kusumesh R. Ambastha A. Sinha B. Kumar R. Topical interferon α-2b as a single therapy for primary ocular surface squamous neoplasia Asia Pac J Ophthalmol (Phila) 4 5 2015 279 282 26176194 \n8 George P.M. Badiger R. Alazawi W. Pharmacology and therapeutic potential of interferons Pharmacol Ther 135 1 2012 44 53 22484806 \n9 Gillies M.C. Su T. Interferon-alpha 2b enhances barrier function of bovine retinal microvascular endothelium in vitro Microvasc Res 49 3 1995 277 288 7643749 \n10 Lincoff H. Stango P. Movshovich A. Choroidal concentration of interferon after retrobulbar injection Invest Ophthalmol Vis Sci 37 13 1996 2768 2771 8977493 \n11 Plskova J. Greiner K. Forrester J.V. Interferon- α as an effective treatment for noninfectious posterior uveitis and panuveitis Am J Ophthalmol 144 1 2007 55 61 17601428 \n12 Kötter I. Günaydin I. Zierhut M. Stübiger N. The use of interferon α in Behçet disease: review of the literature Semin Arthritis Rheum 33 5 2004 320 355 15079763 \n13 Tugal- Tutkun I. Onal S. Altan- Yaycioglu R. Kir N. Urgancioglu M. Neovascularization of the optic disc in Behçet's disease Jpn J Ophthalmol 50 3 2006 256 265 16767382 \n14 Bodaghi B. Gendron G. Wechsler B. Efficacy of interferon alpha in the treatment of refractory and sight threatening uveitis: a retrospective monocentric study of 45 patients Br J Ophthalmol 91 3 2007 335 339 17050581 \n15 Cellini M. Balducci N. Strobbe E. Campos E.C. Subtenon injection of natural leukocyte interferon α-2a in diabetic macular edema: a case report BMC Ophthalmol 13 2013 63 \n16 Paire V. Lebreton O. Weber M. Effectiveness of interferon alpha in the treatment of uveitis macular edema refractory to corticosteroid and/or immunosuppressive treatment J Fr Ophthalmol 33 3 2010 152 162 \n17 Butler N.J. Suhler E.B. Rosenbaum J.T. Interferon alpha 2b in the treatment of uveitic cystoid macular edema Ocul Immunol Inflamm 20 2 2012 86 90 22409560 \n18 Pagán Carrasco S. Arranz Maestro D. Topical interferon alpha-2B topic as the first therapeutic option in a clinical case of conjunctival intraepithelial neoplasia Arch Soc Esp Oftalmol 92 9 2017 442 446 28292536 \n19 Kikuchi I. Kase S. Ishijima K. Ishida S. Long-term follow-up of conjunctival melanoma treated with topical interferon alpha-2b eye drops as adjunctive therapy following surgical resection Graefes Arch Clin Exp Ophthalmol 255 11 2017 2271 2276 28752368 \n20 Singh M. Gautam N. Gupta A. Kaur M. Interferon alfa-2b in the management of recurrent conjunctival papillomatosis Indian J Ophthalmol 64 10 2016 778 780 27905345\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "10()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Cystoid macular edema; Interferon α2b; Pseudophakia",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "203-205",
"pmc": null,
"pmid": "29560479",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": "22484806;15079763;7643749;16193688;21595541;20181409;28292536;27905345;8977493;26176194;24165224;16767382;28366377;17601428;17050581;21187730;23264866;28752368;11054327;22409560",
"title": "Topical interferon alpha 2b in the treatment of refractory pseudophakic cystoid macular edema.",
"title_normalized": "topical interferon alpha 2b in the treatment of refractory pseudophakic cystoid macular edema"
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"abstract": "We report a case of a 48-year-old female patient with newly diagnosed multiple myeloma. She developed recurrent torsade de pointes and required cardiopulmonary resuscitation and defibrillation. Atrial arrhythmias in patients with multiple myeloma and hypercalcaemia have been described, but, to the best of our knowledge, this is the first report of torsade de pointes in this setting.",
"affiliations": "Department of Internal Medicine 3 - Haematology and Oncology, Kepler University Hospital, Linz, Austria.",
"authors": "Fuchs|D|D|;Voskova|D|D|;Krenosz|K J|KJ|;Lambert|T|T|;Fridrik|M A|MA|",
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"journal": "The Netherlands journal of medicine",
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"mesh_terms": "D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D008875:Middle Aged; D009101:Multiple Myeloma; D016171:Torsades de Pointes",
"nlm_unique_id": "0356133",
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"pages": "208-210",
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"pmid": "28653942",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Torsade de pointes in a patient with severe hypercalcaemia and multiple myeloma.",
"title_normalized": "torsade de pointes in a patient with severe hypercalcaemia and multiple myeloma"
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"abstract": "Methadone overdoses are increasing in parallel with the increased frequency of opiate substitution therapy in adults. Although unintentional methadone intoxication in children is rare, it is becoming more frequently recognized. We report 3 cases of unintentional methadone overdose in toddlers who initially displayed central nervous system depression associated with severe nonketotic hyperglycemia and discuss the possible pathophysiologic mechanisms of an underrecognized symptom of opiate intoxication in young children.",
"affiliations": "Intensive Care Unit, Department of Pediatrics, Bicetre Hospital, Le Kremlin-Bicêtre, France.",
"authors": "Tiras|Sinan|S|;Haas|Vincent|V|;Chevret|Laurent|L|;Decobert|Marion|M|;Buisine|Anne|A|;Devictor|Denis|D|;Durand|Philippe|P|;Tissières|Pierre|P|",
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"mesh_terms": "D000061:Accidents, Home; D000818:Animals; D001925:Brain Damage, Chronic; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1; D003951:Diagnostic Errors; D004280:Dobutamine; D004349:Drug Packaging; D004837:Epinephrine; D005260:Female; D005602:France; D006801:Humans; D006944:Hyperglycemic Hyperosmolar Nonketotic Coma; D007223:Infant; D007328:Insulin; D007515:Islets of Langerhans; D008297:Male; D008691:Methadone; D051379:Mice; D009102:Multiple Organ Failure; D009203:Myocardial Infarction; D009270:Naloxone; D011972:Receptor, Insulin; D017450:Receptors, Opioid, mu; D012770:Shock, Cardiogenic; D013549:Sweetening Agents; D013997:Time Factors",
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"title": "Nonketotic hyperglycemic coma in toddlers after unintentional methadone ingestion.",
"title_normalized": "nonketotic hyperglycemic coma in toddlers after unintentional methadone ingestion"
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"abstract": "Although heatstroke commonly occurs in summer, herein, we present a case of heatstroke that occurred in March. The patient has been schizophrenic for over 20 years and has been receiving long-term medications, such as lithium carbonate, clozapine, and lorazepam. We analyzed the evolution of her cerebellar magnetic resonance imaging characteristics to determine the association of heatstroke in schizophrenia. Patients with schizophrenia are at high risk for developing heatstroke, possibly due to the use of antipsychotic drugs.",
"affiliations": "School of Nursing, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China.;School of Nursing, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China. z.xyd@163.com.",
"authors": "Liu|Kuikui|K|;Zhang|Xueyan|X|http://orcid.org/0000-0003-4439-2707",
"chemical_list": "D014150:Antipsychotic Agents",
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"issue": "120(2)",
"journal": "Acta neurologica Belgica",
"keywords": "Drugs; Heat stroke; Magnetic resonance imaging; Shizophrenia",
"medline_ta": "Acta Neurol Belg",
"mesh_terms": "D014150:Antipsychotic Agents; D002531:Cerebellum; D005260:Female; D018883:Heat Stroke; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D012559:Schizophrenia",
"nlm_unique_id": "0247035",
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"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Evolution of MRI characteristics of heatstroke in a patient with schizophrenia maintained with antipsychotic drugs.",
"title_normalized": "evolution of mri characteristics of heatstroke in a patient with schizophrenia maintained with antipsychotic drugs"
} | [
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"companynumb": "CN-ACCORD-070269",
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"actiondrug": "5",
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"activesubstancename": "CLOZAPINE"
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"abstract": "BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.",
"affiliations": "City Of Hope National Medical Center, Duarte, CA, USA.;Knight Cancer Institute at Oregon Health & Science University, Portland, OR, USA.;City Of Hope National Medical Center, Duarte, CA, USA.;Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.;Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.;Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA.;Dana-Farber Cancer Institute, Boston, MA, USA. Jennifer_Brown@dfci.harvard.edu.",
"authors": "Danilov|Alexey V|AV|;Spurgeon|Stephen E|SE|;Siddiqi|Tanya|T|;Quinson|Anne-Marie|AM|;Maier|Daniela|D|;Smith|Dionne|D|;Brown|Jennifer R|JR|0000-0003-2040-4961",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-020-01056-4",
"fulltext": "\n==== Front\nInvest New Drugs\nInvest New Drugs\nInvestigational New Drugs\n0167-6997\n1573-0646\nSpringer US New York\n\n33683501\n1056\n10.1007/s10637-020-01056-4\nPhase I Studies\nA phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia\nDanilov Alexey V. 1\nSpurgeon Stephen E. 2\nSiddiqi Tanya 1\nQuinson Anne-Marie 3\nMaier Daniela 3\nSmith Dionne 4\nhttp://orcid.org/0000-0003-2040-4961\nBrown Jennifer R. Jennifer_Brown@dfci.harvard.edu\n\n5\n1 grid.410425.6 0000 0004 0421 8357 City Of Hope National Medical Center, Duarte, CA USA\n2 grid.5288.7 0000 0000 9758 5690 Knight Cancer Institute at Oregon Health & Science University, Portland, OR USA\n3 grid.420061.1 0000 0001 2171 7500 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany\n4 grid.418412.a 0000 0001 1312 9717 Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT USA\n5 grid.65499.37 0000 0001 2106 9910 Dana-Farber Cancer Institute, Boston, MA USA\n8 3 2021\n8 3 2021\n2021\n39 4 10991105\n26 10 2020\n16 12 2020\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons 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/.\nSummary\n\nBI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.\n\nKeywords\n\nBI 836826\nCD37\nChronic lymphocytic leukemia\nPhase Ib\nRelapsed\nhttp://dx.doi.org/10.13039/100008349 Boehringer Ingelheim N/A issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2021\n==== Body\nIntroduction\n\nThe Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, is well established in the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL) [1–3]. While ibrutinib monotherapy is associated with impressive response rates in CLL patients, including those with del(17p) [1, 4], deep responses are rare, thus necessitating continuous use. This can result in cumulative toxicities, leading to treatment discontinuation [5]. Furthermore, patients often become resistant to long-term treatment, potentially leading to disease progression or transformation [6]. Therefore, there is clinical rationale for combining ibrutinib with other agents that could increase depth of response and delay development of resistance.\n\nPreclinical and clinical studies have demonstrated that CD37, a tetraspanin B cell surface molecule, is a potential drug target in patients with CLL [7–10].\n\nBI 836826 is a chimeric mouse–human anti-CD37 monoclonal antibody engineered to enhance binding and effector function that mediates direct antibody-dependent cell-mediated cytotoxicity (ADCC) against CLL cells [11]. A phase I, dose escalation study of BI 836826 in patients with relapsed/refractory CLL demonstrated acceptable tolerability and notable efficacy, particularly in patients with poor-risk features such as del(17p) and TP53 mutations [12]. In this phase Ib, dose-escalation study, we investigated the combination of ibrutinib and BI 836826 in patients with relapsed/refractory CLL.\n\nPatients and methods\n\nPatients\n\nEligible patients were ≤ 18 years old with relapsed/refractory CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria [13]. All patients had received at least one prior line of systemic treatment. Prior BTK inhibitors were not allowed. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2; clinically quantifiable disease burden (absolute lymphocyte count > 10,000/µL, measurable lymphadenopathy, or quantifiable bone marrow infiltration); adequate organ function; and residual non-hematological toxicity from prior treatment of grade ≤ 1.\n\nKey exclusion criteria were: any CD37-targeting antibody or CD37 antibody-drug conjugate; allogeneic stem cell transplant within 1 year or active graft-versus-host disease; known transformation of CLL to an aggressive B-cell malignancy at the time of screening; history of non-CLL malignancy except for adequately treated in-situ, stage I or II carcinoma in complete response (CR) or any other cancer that had been in CR for ≥ 2 years after the end of cancer treatment; and active uncontrolled autoimmune cytopenia.\n\nThe trial was carried out in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, applicable regulatory requirements and Boehringer Ingelheim standard operating procedures. The study protocol was approved by the Institutional Review Boards of all participating institutions. Written informed consent was obtained from all patients.\n\nStudy design and treatment\n\nThe primary objectives of this single arm, open-label, dose escalation phase Ib study were to determine the recommended phase II dose (RP2D) of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, and the number of patients with dose-limiting toxicities (DLTs) during the maximum tolerated dose (MTD) evaluation period (Cycle 1). Other objectives were the determination of the MTD, safety and efficacy of the combination.\n\nEligible patients underwent a two-week run-in phase with ibrutinib and remained on ibrutinib throughout the trial at a constant dose of 420 mg daily. BI 836826 was planned at dose levels of 100, 200, 400, 600, 800 and 1400 mg. Mandatory pre-medication (antihistamine, analgesic and glucocorticoid) to mitigate the risk of infusion-related reactions (IRRs) was given 30–120 min prior to BI 836826 administration. BI 836826 was then administered via rate-controlled intravenous infusion in Cycle 1 as a 10 mg dose on Day 1, on Days 2 and 8 at 50% of the assigned dose on each day, and on Day 15 at 100% of the assigned dose. In Cycles 2–4, BI 836826 was administered at the assigned dose on Days 1 and 15 of each cycle. In Cycles 5–12, BI 836826 was administered at the assigned dose on Day 1 only. BI 836826 was administered in 4-week cycles. At the end of Cycle 12, bone marrow biopsies were performed to evaluate response. Patients with a CR, CR with incomplete marrow recovery (CRi), or minimal residual disease (MRD)-negative partial response (PR) could choose to receive 12 additional treatment cycles of the combination. Following completion of 12 or 24 cycles, or discontinuation due to disease progression, unacceptable toxicity, or withdrawal of consent, patients could continue to receive ibrutinib outside of the study at the discretion of the treating investigator.\n\nStudy assessments\n\nSafety was assessed by determining the incidence and severity of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Assessment of laboratory parameters, vital signs, physical examination and ECG was also undertaken. DLTs were defined as: any non-hematologic adverse event of grade ≥ 3 related to BI 836826 or ibrutinib, except IRRs and grade 3 alanine aminotransferase and/or aspartate aminotransferase elevation without concomitant bilirubin elevation or any other asymptomatic grade 3 laboratory abnormality with spontaneous recovery within 1 week; hematologic adverse events related to BI 836826 or ibrutinib including grade 4 neutropenia with concomitant infection; grade 4 febrile neutropenia, and grade 3 febrile neutropenia not resolving within 72 hours; grade 4 thrombocytopenia with clinically significant bleeding; grade 4 anemia; any grade 5 hematologic adverse event. Adverse events of special interest (AESIs) included DLTs, infusion-related reactions of grade ≥ 3, late-onset infections, events indicative of drug-induced liver injury, and tumor lysis syndrome. Adverse events consistent with the definition of a DLT but occurring after the MTD evaluation period were also considered AESIs.\n\nOverall response, duration of response, MRD and reduction in size of tumor lymph nodes were exploratory endpoints. Overall response was defined as patients who achieved CR, CRi, PR or PR with lymphocytosis (PR-L) according to modified IWCLL guidelines [13]. MRD was evaluated in both blood and bone marrow samples and was defined as < 1 leukemic cell per 10,000 leukocytes detected by multi-parameter flow cytometry.\n\nStatistical methods\n\nAll analyses were descriptive and exploratory. No formal statistical analysis was conducted. Dose escalation was guided by a Bayesian 5-parameter logistic regression model (BLRM) with overdose control [14, 15] that was fitted to binary toxicity outcomes.\n\nResults\n\nPatients and treatment exposure\n\nBetween July 7, 2016 and July 9, 2019, 10 patients were screened, of whom 7 entered the run-in period with ibrutinib. Six patients were treated with BI 836826 plus ibrutinib across three sites in the United States (100 mg BI 836826: n = 3; 200 mg BI 836826: n = 3). The median age among treated patients was 71.0 years (range 57–76 years); all patients were Caucasian (Table 1).\n\nTable 1 Patient demographics\n\n\tBI 836826 dosea\t\n\t100 mg\n(n = 3)\t200 mg\n(n = 3)\tTotal\n(N = 6)\t\nMale, n (%)\t1 (33)\t2 (67)\t3 (50)\t\nRace, n (%)\t\t\t\t\n White\t3 (100)\t3 (100)\t6 (100)\t\nEthnicity, n (%)\t\t\t\t\n Not Hispanic/Latino\t2 (67)\t3 (100)\t5 (83)\t\n Hispanic/Latino\t1 (33)\t0\t1 (17)\t\n Median age, years (range)\t75.0 (68–76)\t67.0 (57–74)\t71.0 (57–76)\t\nECOG PS at baseline, n (%)\t\t\t\t\n 0\t1 (33)\t1 (33)\t2 (33)\t\n 1\t2 (67)\t2 (67)\t4 (67)\t\nRAI stage at diagnosis, n (%)\t\t\t\t\n 0\n\n I\n\n II\n\n III\n\n IV\n\n\t1 (33)\n\n0\n\n1 (33)\n\n0\n\n1 (33)\n\n\t1 (33)\n\n1 (33)\n\n0\n\n1 (33)\n\n0\n\n\t2 (33)\n\n1 (17)\n\n1 (17)\n\n1 (17)\n\n1 (17)\n\n\t\nMean time from first diagnosis, years (SD)\t10.4 (4.9)\t11.1 (5.1)\t10.7 (4.5)\t\nMedian number of previous CLL therapies (range)\t1 (1–1)\t4 (1–5)\t1 (1–5)\t\nStatus after prior treatment\t\t\t\t\nRelapsed\n\nRefractory\n\n\t2 (67)\n\n1 (33)\n\n\t2 (67)\n\n1 (33)\n\n\t4 (67)\n\n2 (33)\n\n\t\naGiven in combination with ibrutinib 420 mg/day\n\nCLL chronic lymphocytic leukemia, ECOG PS Eastern Cooperative Oncology Group Performance Status, RAI staging system for CLL [16], SD standard deviation\n\nIn the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. The patients in the 200 mg cohort received 12, 16 and 20 cycles of BI 836826, respectively. All six patients discontinued treatment with BI 836826 (disease progression, n = 1; investigator discretion, n = 3; lack of response by cycle 12, n = 2). Mean duration of BI 836826 exposure was 440.2 days. There were no dose reductions. Two patients in the 100 mg BI 836826 cohort had at least one important protocol deviation. Both patients continued treatment with BI 836826 beyond cycle 12 without having a CR, CRi, or MRD-negative PR. One of these patients did not receive pre-medication with glucocorticoid in Cycle 3, as required per protocol.\n\nDLTs during the MTD evaluation period, MTD and RP2D\n\nNo DLTs were reported during the MTD evaluation period with 100 or 200 mg BI 836826. However, the trial was discontinued before patients were treated with 400 mg BI 836826, and the MTD and RP2D were therefore not determined.\n\nSafety\n\nAll six patients had at least one adverse event that was considered by the investigator to be related to BI 836826. The most common BI 836826-related adverse events (any grade/grade ≥ 33) were IRR (67%/17%), neutropenia (50%/33%), anemia (33%/33%), lymphopenia (33%/33%) and fatigue (33%/0%; Table 2). All IRRs (ten in four patients) were grade ≤ 2 except for one grade 3 IRR. The majority of IRRs occurred within the first two cycles and were resolved within a day.\n\nTable 2 Adverse events considered related to BI 836826 occurring in > 2 patients\n\n\tAny-grade\nn (%)\tGrade 3/4\nn (%)\t\nInfusion-related reactions\t4 (67)\t1 (17)\t\nNeutropenia\t3 (50)\t2 (33)\t\nAnemia\t2 (33)\t2 (33)\t\nLymphopenia\t2 (33)\t2 (33)\t\nFatigue\t2 (33)\t0\t\n\nFive patients had serious adverse events (considered related to study drug in 4 patients), including neutropenia, acute coronary syndrome, cellulitis, pseudomonal bacteremia and Bowen’s disease. No serious adverse event was experienced by more than one patient. There were no fatal adverse events, and no dose reductions or permanent discontinuations of BI 836826 due to adverse events. One patient had an ibrutinib dose reduction due to grade 2 neutropenia. After the MTD evaluation period, two patients in the 200 mg cohort reported grade 3 DLTs: a duodenal ulcer occurring on Day 325 and pseudomonal bacteremia (considered as related to study drug) on Day 280.\n\nThree AESIs were recorded: the two DLTs reported after the MTD evaluation period and grade 2 basal cell carcinoma (Day 622).\n\nBased on laboratory data, grade 4 neutropenia was reported for two patients (one patient in each dose cohort). Neither episode was associated with a concomitant infection. One patient in the 100 mg dose cohort had an episode of grade 4 thrombocytopenia, which was not associated with concomitant bleeding. Two patients (one in each dose cohort) had an episode of grade ≥ 3 decreased CD4 + T-cell count but there were no concomitant CD4+-related specific infections.\n\nEfficacy\n\nOverall response rate was 83% among the 6 evaluable patients (one CR and four PRs; Table 3) The ORR in the 200 mg cohort was 100% (one CR, two PR). Of five patients who underwent peripheral blood-based MRD analysis, two were MRD-negative, one in each cohort including the patient who achieved CR. Three patients had bone marrow aspirate samples analyzed for MRD. None were MRD-negative but one patient developed MRD-negative CR a month after study completion.\n\nTable 3 Best overall response in patients receiving BI 836826 plus ibrutinib\n\n\tBI 836826 dose\t\t\t\nPatients with response, n (%)\t100 mg\nn = 3\t200 mg\nn = 3\tTotal\nN = 6\t\nOverall response\t2 (67)\t3 (100)\t5 (83)\t\nCR\t0\t1 (33)\t1 (17)\t\nCRi\t0\t0\t0\t\nPR\t2 (67)\t2 (67)\t4 (67)\t\nPR-L\t0\t0\t0\t\nStable disease\t\t\t\t\nProgressive disease\t1 (33)\t0\t1 (17)\t\nCR complete response, CRi complete response with incomplete marrow recovery, OR overall response (CR + CRi + PR + PR-L), PR partial response; PR-L partial response with lymphocytosis\n\nAll five patients were censored for the analysis of duration of overall response since they had discontinued before progression or death was observed. Mean (standard deviation [SD]) duration of response was 538.0 (31.1) days and 312.0 (143.96) days in the 100 mg and 200 mg BI 836826 cohorts, respectively. The median best percentage change from baseline in the SPD of lymph nodes was -81.2% (range -84% to -51%) in the 100 mg dose group and -79.2% (range -92% to -59%) in the 200 mg dose group (Fig. 1). Tumor size was reduced in all six patients.Fig. 1 Maximum change in SPD of lymph node lesions at best response\n\nDiscussion\n\nIn this phase Ib, dose-escalation study of BI 836826 plus ibrutinib in patients with relapsed/refractory CLL, no DLTs were observed during the MTD evaluation period in either the 100 mg or 200 mg BI 836320 cohorts. Despite these promising findings, the sponsor took the strategic decision to discontinue the clinical development of BI 836826, due to the rapidly evolving CLL treatment landscape. Accordingly, the MTD was not reached and the RP2D was not determined. There were no safety reasons to terminate the program. Nevertheless, the results from this study suggest that BI 836826 can be safely combined with ibrutinib, with no apparent additive toxicity. Adverse events associated with the combination were consistent with previous clinical experience with BI 836826 [12] or ibrutinib monotherapy [4].\n\nThe efficacy of ibrutinib in relapsed/refractory CLL is well established [4, 17, 18], with an objective response rate of 63% observed in the phase III study, RESONATE [4]. Of note, overall response rate to ibrutinib generally deepens over time [17, 19], and had increased to 91% by the final analysis of RESONATE [2, 20]. Our preliminary findings (83% overall response rate) suggest that the addition of anti-CD37 agents to ibrutinib could potentially improve efficacy. While the sample size is limited, the promising efficacy of this combination especially at the 200 mg dose (100%), supports ongoing exploration of agents, including those that target CD37, for fixed-duration therapy in CLL.\n\nA number of CD37-based therapeutics are currently undergoing investigation in CLL, including otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein [8]. Notably, in phase II studies, the addition of otlertuzumab to bendamustine greatly enhanced response compared with bendamustine alone in relapsed CLL patients [21]. Additionally, 212Pb-NNV003, a CD37-targeted radioimmunotherapy, has demonstrated notable anti-tumor effects in an animal model of CLL [22].\n\nIn conclusion, BI 836826 plus ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL, and no DLTs were reported in the MTD evaluation period. While the RPTD and MTD were not formally established, our findings suggest that an anti-CD37 antibody may be combined with ibrutinib, or potentially other BTK inhibitors, for the treatment of relapsed/refractory CLL. Since continuous therapy with BTK inhibitors leads to toxicities, therapeutic resistance and is associated with high costs, exploration of novel combinations involving active agents with different therapeutic targets remains an unmet medical need.\n\nAcknowledgements\n\nWe thank the patients, their families, and all the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.\n\nFunding\n\nThe conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.\n\nData availability\n\nThe clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.\n\nCompliance with ethical standards\n\nConflict of interest\n\nAVD has received consulting fees from AstraZeneca, Abbvie, BeiGene, Genentech, TG Therapeutics, Janssen, Rigel Pharmaceutical, Nurix, Bayer Oncology, Karyopharm and Pharmacyclics and has ongoing research funding from AstraZeneca, Takeda Oncology, Gilead Sciences, Bayer Oncology, Genentech, Verastem Oncology, MEI and Bristol Myers Squibb. \n\nSES reports grants from Boehringer Ingelheim during the conduct of the study and personal fees from Pharmacyclics outside the submitted work. \n\nTS reports institutional funds fees from Boehringer Ingelheim during the conduct of the study; personal fees from AstraZeneca, PCYC, Janssen, Juno, Celgene, BeiGene and Kite Pharma outside the submitted work. \n\nAMQ, DM and DS are employees of Boehringer Ingelheim. \n\nJRB reports personal fees from Abbvie, Acerta/AstraZeneca, Astellas, BeiGene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Janssen, Juno/Celgene, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Redx, Rigel, Sun, Sunesis, Teva, and TG Therapeutics; grants and personal fees from Gilead, Loxo/Lilly and Verastem outside the submitted work. She has sat on Data Safety Monitoring Boards for Invectys and Morphosys. \n\nEthical approval\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. \n\nInformed consent\n\nInformed consent was obtained from all individual participants included in the study.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Burger JA Barr PM Robak T Owen C Ghia P Tedeschi A Bairey O Hillmen P Coutre SE Devereux S Grosicki S McCarthy H Simpson D Offner F Moreno C Dai S Lal I Dean JP Kipps TJ Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study Leukemia 2019 34 3 787 798 10.1038/s41375-019-0602-x 31628428\n2. Byrd JC Hillmen P O’Brien S Barrientos JC Reddy NM Coutre S Tam CS Mulligan SP Jaeger U Barr PM Furman RR Kipps TJ Thornton P Moreno C Montillo M Pagel JM Burger JA Woyach JA Dai S Vezan R James DF Brown JR Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab Blood 2019 133 19 2031 2042 10.1182/blood-2018-08-870238 30842083\n3. Hallek M Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment Am J Hematol 2019 94 11 1266 1287 10.1002/ajh.25595 31364186\n4. Byrd JC Brown JR O’Brien S Barrientos JC Kay NE Reddy NM Coutre S Tam CS Mulligan SP Jaeger U Devereux S Barr PM Furman RR Kipps TJ Cymbalista F Pocock C Thornton P Caligaris-Cappio F Robak T Delgado J Schuster SJ Montillo M Schuh A de Vos S Gill D Bloor A Dearden C Moreno C Jones JJ Chu AD Fardis M McGreivy J Clow F James DF Hillmen P Investigators R Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia N Engl J Med 2014 371 3 213 223 10.1056/NEJMoa1400376 24881631\n5. Gordon MJ Churnetski M Alqahtani H Rivera X Kittai A Amrock SM James S Hoff S Manda S Spurgeon SE Choi M Cohen JB Persky D Danilov AV Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib Cancer 2018 124 15 3192 3200 10.1002/cncr.31554 29797667\n6. Pula B, Golos A, Gorniak P, Jamroziak K (2019) Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia. Cancers (Basel) 11(12). 10.3390/cancers11121834\n7. Beckwith KA Frissora FW Stefanovski MR Towns WH Cheney C Mo X Deckert J Croce CM Flynn JM Andritsos LA Jones JA Maddocks KJ Lozanski G Byrd JC Muthusamy N The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model Leukemia 2014 28 7 1501 1510 10.1038/leu.2014.32 24445867\n8. Byrd JC Pagel JM Awan FT Forero A Flinn IW Deauna-Limayo DP Spurgeon SE Andritsos LA Gopal AK Leonard JP Eisenfeld AJ Bannink JE Stromatt SC Furman RR A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia Blood 2014 123 9 1302 1308 10.1182/blood-2013-07-512137 24381226\n9. Maaland AF Heyerdahl H O’Shea A Eiriksdottir B Pascal V Andersen JT Kolstad A Dahle J Targeting B-cell malignancies with the beta-emitting anti-CD37 radioimmunoconjugate (177)Lu-NNV003 Eur J Nucl Med Mol Imaging 2019 46 11 2311 2321 10.1007/s00259-019-04417-1 31309259\n10. Sawas A, Savage KJ, Perez RP, Advani RH, Zaine JM, Lackey JM Trave F, Anand B, Chu R, Reyno LM, O'Connor OA (2017) A phase 1 study of the anti-CD37 antibody-drug conjugate AGS67E in advanced lymphoid malignancies. Interim results. Presented at the 14th International Conference on Malignant Lymphoma, Lugano, Switzerland, 14–17 June, 2017. Hematol Oncol 35(S2)\n11. Heider KH Kiefer K Zenz T Volden M Stilgenbauer S Ostermann E Baum A Lamche H Kupcu Z Jacobi A Muller S Hirt U Adolf GR Borges E A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC and high proapoptotic activity for treatment of B-cell malignancies Blood 2011 118 15 4159 4168 10.1182/blood-2011-04-351932 21795744\n12. Stilgenbauer S Aurran Schleinitz T Eichhorst B Lang F Offner F Rossi JF Schroyens W Van Den Neste E Ysebaert L von Wangenheim U Ursula Kress U Blum P Zenz T Phase 1 first-in-human trial of the anti-CD37 antibody BI 836826 in relapsed/refractory chronic lymphocytic leukemia Leukemia 2019 33 10 2531 2535 10.1038/s41375-019-0475-z 31089249\n13. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ, International Workshop on Chronic Lymphocytic L (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111 (12):5446–5456. 10.1182/blood-2007-06-093906\n14. Babb J Rogatko A Zacks S Cancer phase I clinical trials: efficient dose escalation with overdose control Stat Med 1998 17 10 1103 1120 10.1002/(sici)1097-0258(19980530)17:10<1103::aid-sim793>3.0.co;2-9 9618772\n15. Neuenschwander B Branson M Gsponer T Critical aspects of the Bayesian approach to phase I cancer trials Stat Med 2008 27 13 2420 2439 10.1002/sim.3230 18344187\n16. Rai KR Sawitsky A Cronkite EP Chanana AD Levy RN Pasternack BS Clinical staging of chronic lymphocytic leukemia Blood 1975 46 2 219 234 10.1182/blood.V46.2.219.219 1139039\n17. O’Brien S Furman RR Coutre S Flinn IW Burger JA Blum K Sharman J Wierda W Jones J Zhao W Heerema NA Johnson AJ Luan Y James DF Chu AD Byrd JC Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience Blood 2018 131 17 1910 1919 10.1182/blood-2017-10-810044 29437592\n18. Huang X Qiu L Jin J Zhou D Chen X Hou M Hu J Hu Y Ke X Li J Liang Y Liu T Lv Y Ren H Sun A Wang J Zhao C Salman M Sun S Howes A Wang J Wu P Li J Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study Cancer Med 2018 7 4 1043 1055 10.1002/cam4.1337 29533000\n19. Byrd JC Furman RR Coutre SE Burger JA Blum KA Coleman M Wierda WG Jones JA Zhao W Heerema NA Johnson AJ Shaw Y Bilotti E Zhou C James DF O’Brien S Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib Blood 2015 125 16 2497 2506 10.1182/blood-2014-10-606038 25700432\n20. Munir T Brown JR O’Brien S Barrientos JC Barr PM Reddy NM Coutre S Tam CS Mulligan SP Jaeger U Kipps TJ Moreno C Montillo M Burger JA Byrd JC Hillmen P Dai S Szoke A Dean JP Woyach JA Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma Am J Hematol 2019 94 12 1353 1363 10.1002/ajh.25638 31512258\n21. Robak T Hellmann A Kloczko J Loscertales J Lech-Maranda E Pagel JM Mato A Byrd JC Awan FT Hebart H Garcia-Marco JA Hill BT Hallek M Eisenfeld AJ Stromatt SC Jaeger U Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia Br J Haematol 2017 176 4 618 628 10.1111/bjh.14464 27977057\n22. Saidi A Maaland A Torgue J Heyerdah H Dahle J 212Pb-NNV003 as a novel targeted alpha therapy for CD37 positive B-cell chronic lymphocytic leukemia (CLL) and non-hodgkin lymphoma (NHL) J Med Imaging Radiat Sci 2019 50 1 S8 10.1016/j.jmir.2019.03.025 31791914\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0167-6997",
"issue": "39(4)",
"journal": "Investigational new drugs",
"keywords": "BI 836826; CD37; Chronic lymphocytic leukemia; Phase Ib; Relapsed",
"medline_ta": "Invest New Drugs",
"mesh_terms": null,
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "1099-1105",
"pmc": null,
"pmid": "33683501",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "29437592;30842083;9618772;21795744;31766355;25700432;27977057;29797667;31628428;1139039;18216293;24881631;24381226;31089249;24445867;29533000;31364186;31512258;31309259;18344187",
"title": "A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.",
"title_normalized": "a phase ib open label dose escalation trial of the anti cd37 monoclonal antibody bi 836826 in combination with ibrutinib in patients with relapsed refractory chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-ABBVIE-21K-163-3834874-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": "3",
... |
{
"abstract": "Aminocaproic acid is frequently used in patients with hematologic malignancy that present with thrombocytopenia with or without hemorrhage. We conducted a retrospective study to evaluate the safety of aminocaproic acid in 109 patients with hematologic malignancies. Patients were included if aminocaproic acid had been administered for at least 24 hours for the prevention or treatment of thrombocytopenic hemorrhage. Our primary outcome was thromboembolic complications defined as arterial or venous thrombotic events objectively confirmed by imaging studies. Thromboembolic complications occurred in five patients (4.6%) and all were venous thromboses. Other than the underlying malignancy, these patients also had many concurrent risk factors including indwelling central venous catheters, which could have contributed to thromboses. In conclusion, in our population of patients with a variety of hematological malignancies, aminocaproic acid does not appear to be associated with a high incidence of thromboembolic complications.",
"affiliations": "a Department of Pharmacy , The Ohio State University Wexner Medical Center and Arthur G. James Cancer Hospital and Richard J Solove Research Institute , Columbus , OH , USA.;a Department of Pharmacy , The Ohio State University Wexner Medical Center and Arthur G. James Cancer Hospital and Richard J Solove Research Institute , Columbus , OH , USA.;b Division of Hematology, Department of Internal Medicine , The Ohio State University Wexner Medical Center and Arthur G. James Cancer Hospital and Richard J Solove Research Institute , Columbus , OH , USA.;c College of Pharmacy , The Ohio State University , Columbus , OH , USA.;a Department of Pharmacy , The Ohio State University Wexner Medical Center and Arthur G. James Cancer Hospital and Richard J Solove Research Institute , Columbus , OH , USA.",
"authors": "Juhl|Rebecca C|RC|;Roddy|Julianna V F|JVF|;Wang|Tzu-Fei|TF|;Li|Junan|J|;Elefritz|Jessica L|JL|",
"chemical_list": "D000933:Antifibrinolytic Agents; D015119:Aminocaproic Acid",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2018.1434882",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "59(10)",
"journal": "Leukemia & lymphoma",
"keywords": "Aminocaproic acid; hematologic; malignancy; safety; thrombosis",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D015119:Aminocaproic Acid; D000933:Antifibrinolytic Agents; D002405:Catheterization, Central Venous; D002408:Catheters, Indwelling; D005260:Female; D019337:Hematologic Neoplasms; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D013921:Thrombocytopenia; D013923:Thromboembolism; D016896:Treatment Outcome",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2377-2382",
"pmc": null,
"pmid": "29424601",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thromboembolic complications following aminocaproic acid use in patients with hematologic malignancies.",
"title_normalized": "thromboembolic complications following aminocaproic acid use in patients with hematologic malignancies"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0111394",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMINOCAPROIC ACID"
},
"drugadditional": ... |
{
"abstract": "Inflammatory bowel disease (IBD) is rare in sub-Saharan Africa. Five cases in Nigerian children are presented to highlight the occurrence, pattern of clinical presentation and management challenges. The patients were identified following a retrospective review of all diagnosed cases of IBD between 1 January 2011 and 31 December 2018 seen at the Paediatric Gastroenterology, Hepatology and Nutrition Unit of Lagos State University Teaching Hospital. The median age (range) was 9 (7-13) years. Three cases were diagnosed because bloody diarrhoea persisted despite treatment at various health facilities for its common causes in the tropics and sub-tropics. The other two cases were confirmed after surgical intervention undertaken for symptoms of acute abdomen owing to appendicitis and intestinal obstruction. IBD should be considered in the differential diagnosis of children with chronic symptoms of bloody diarrhoea, weight loss, abdominal pain or abdominal masses.",
"affiliations": "Department of Paediatrics and Child Health, Lagos State University College of Medicine , Ikeja, Lagos, Nigeria.;Department of Paediatrics and Child Health, Lagos State University Teaching Hospital , Ikeja, Lagos State, Nigeria.;Department of Paediatrics and Child Health, Lagos State University Teaching Hospital , Ikeja, Lagos State, Nigeria.;Department of Paediatrics and Child Health, Lagos State University Teaching Hospital , Ikeja, Lagos State, Nigeria.;Department of Pharmacology and Therapeutics, Lagos State University College of Medicine , Ikeja, Lagos, Nigeria.",
"authors": "Senbanjo|Idowu|I|;Akinola|Ayodeji|A|;Kumolu-Johnson|Tolulope|T|;Igbekoyi|Olayinka|O|;Oshikoya|Kazeem|K|",
"chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1080/20469047.2019.1662658",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2046-9047",
"issue": "40(3)",
"journal": "Paediatrics and international child health",
"keywords": "Inflammatory bowel disease; Nigeria",
"medline_ta": "Paediatr Int Child Health",
"mesh_terms": "D000293:Adolescent; D002648:Child; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D008297:Male; D009549:Nigeria; D012189:Retrospective Studies",
"nlm_unique_id": "101582666",
"other_id": null,
"pages": "143-147",
"pmc": null,
"pmid": "31495301",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Inflammatory bowel disease in Nigerian children: case series and management challenges.",
"title_normalized": "inflammatory bowel disease in nigerian children case series and management challenges"
} | [
{
"companynumb": "NG-ACCORD-204190",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Diffuse alveolar hemorrhage is an uncommon and often fatal condition in children that is characterized by distinct histopathological etiologies. Herein, we discuss the case of an 11-year-old girl who presented with acute worsening of hypoxia and left-sided chest pain. The patient had lung biopsy-proven idiopathic pulmonary capillaritis and was being treated with prednisolone every alternate day, azathioprine, and hydroxychloroquine. A contrast-computed tomography (CT) scan of the chest showed an acute left lower-lobe pulmonary embolism. Negative results were obtained on a test for thrombophilia. In children, pulmonary embolism with anti-neutrophil cytoplasmic antibody-negative idiopathic pulmonary capillaritis is a rare clinical condition. The exact cause of thrombus formation in this case is unknown; however, obesity, immobility, and chronic systemic corticosteroid therapy probably played a role.",
"affiliations": "Department of Pediatrics, College of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia. E-mail. alsoheel11@gmail.com.",
"authors": "Asseri|Ali A|AA|;Zeng|Yi|Y|;Daines|Cori L|CL|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D006495:Heparin, Low-Molecular-Weight; C488629:azathiopurine; D006886:Hydroxychloroquine; D011239:Prednisolone; D015122:Mercaptopurine",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.15537/smj.2019.6.24210",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-5284",
"issue": "40(6)",
"journal": "Saudi medical journal",
"keywords": null,
"medline_ta": "Saudi Med J",
"mesh_terms": "D000208:Acute Disease; D019268:Antibodies, Antineutrophil Cytoplasmic; D002196:Capillaries; D002637:Chest Pain; D002648:Child; D005260:Female; D006470:Hemorrhage; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D006886:Hydroxychloroquine; D000860:Hypoxia; D008168:Lung; D008171:Lung Diseases; D015122:Mercaptopurine; D011239:Prednisolone; D011650:Pulmonary Alveoli; D011655:Pulmonary Embolism; D016896:Treatment Outcome; D014657:Vasculitis",
"nlm_unique_id": "7909441",
"other_id": null,
"pages": "610-613",
"pmc": null,
"pmid": "31219497",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25018131;17505192;24907055;15756223;28248576;25883536",
"title": "Acute pulmonary embolism in a child with ANCA-negative Idiopathic Pulmonary Capillaritis.",
"title_normalized": "acute pulmonary embolism in a child with anca negative idiopathic pulmonary capillaritis"
} | [
{
"companynumb": "PHHY2019SA169749",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "This report describes 2 patients whose septic arthritis of the temporomandibular joint (SATMJ) presented atypically, resulting in treatment delay and complications. A 49-year-old man developed left-side facial allodynia, which was first treated unsuccessfully as trigeminal neuralgia. On day 21, the patient sustained facial trauma from a fall and presented to the emergency department (ED). Maxillofacial contrast-enhanced computed tomographic (CT) scan was suggestive of parotiditis, SATMJ, or hemarthrosis. His condition did not improve with empiric antibiotic treatment. On day 30, contrast-enhanced magnetic resonance imaging (MRI) confirmed SATMJ. Incision and drainage yielded 6 mL of pus and produced clinical improvement. Cultures grew methicillin-resistant Staphylococcus aureus, which was treated with amoxicillin plus clavulanate and sulfamethoxazole plus trimethoprim for 30 days. On day 59, the patient still had slight preauricular pain and CT-proved TMJ osteoarthritic changes. A 56-year-old woman developed right-side facial pain after a crown procedure on her right mandibular second molar. Oral prednisone (and clindamycin) produced partial relief. Her primary physician suspected temporal arteritis, but its biopsy result on day 11 was normal. Gradually, the patient developed trismus and malocclusion refractory to various medicines. On day 49, she presented to the ED. A contrast-enhanced maxillofacial CT scan suggested SATMJ. Incision and drainage yielded 30 mL of pus and produced clinical improvement. During days 50 to 57, the patient received intravenous ampicillin plus sulbactam and metronidazole. However, preauricular tenderness and drainage from the surgical incision persisted. On day 55, CT scan showed a residual abscess. Secondary debridement yielded 5 mL of pus. Culture grew coagulase-negative S aureus. On day 141, the patient still had slight preauricular pain and TMJ osteoarthritic changes on MRI. In these cases, the SATMJ diagnosis was delayed owing to the mildness of local and systemic manifestations, the possibility of confounding conditions, and the rarity of SATMJ. Contrast-enhanced CT and MRI facilitated the diagnosis. Abscess drainage alleviated the symptoms. Postinfectious osteoarthritis developed possibly from treatment delay. SATMJ should be considered in all patients with enigmatic preauricular pain, trismus, or malocclusion.",
"affiliations": "Resident, Department of Oral and Maxillofacial Surgery, University of Washington, Seattle, WA.;Clinical Associate Professor and Program Director, Department of Oral and Maxillofacial Surgery, University of Washington, Seattle, WA. Electronic address: dillonj5@uw.edu.",
"authors": "Lohiya|Sapna|S|;Dillon|Jasjit|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D003287:Contrast Media",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "74(1)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D000038:Abscess; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D003287:Contrast Media; D057210:Delayed Diagnosis; D003937:Diagnosis, Differential; D005157:Facial Pain; D005260:Female; D013700:Giant Cell Arteritis; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D010003:Osteoarthritis; D010309:Parotitis; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D013705:Temporomandibular Joint Disorders; D014057:Tomography, X-Ray Computed; D014277:Trigeminal Neuralgia",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "87-94",
"pmc": null,
"pmid": "26183013",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Septic Arthritis of the Temporomandibular Joint--Unusual Presentations.",
"title_normalized": "septic arthritis of the temporomandibular joint unusual presentations"
} | [
{
"companynumb": "US-TEVA-629568USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "According to the Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus in Japan, the standard treatment of esophageal cancer with cStage II / III is preoperative chemotherapy and radical resection. But when the tumor has deep ulcer, the perforation of it is sometimes occurred due of the anti-tumor effect and we are forced to change the standard treatment. In this time, we report a case of emergency resection of esophageal cancer which is on the brink of perforation after neoadjuvant chemotherapy. A 62-year-old woman had locally advanced esophageal cancer(cT4N2M0)and performed neoadjuvant chemotherapy(NAC). After 2 courses of NAC, the patient got into critical condition that the esophageal cancer was on the brink of perforation, thus we immediately performed emergency resection of the tumor. Unfortunately, the tumor was not completely resected because of invasion to the Botallo ligament, but we were able to avoid a critical state such as mediastinitis or penetration to the aorta. In multimodality therapy for locally advanced tumor, immediate response to oncologic emergency is significantly required, impacting on the prognosis and quality of life.",
"affiliations": "Dept. of Surgery, Kindai University Faculty of Medicine.",
"authors": "Yasuda|Atsushi|A|;Yasuda|Takushi|T|;Kimura|Yutaka|Y|;Kato|Hiroaki|H|;Hiraki|Yoko|Y|;Iwama|Mitsuru|M|;Shiraishi|Osamu|O|;Shinkai|Masayuki|M|;Imano|Motohiro|M|;Imamoto|Haruhiko|H|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D000077143:Docetaxel; D004632:Emergency Medical Services; D004938:Esophageal Neoplasms; D004939:Esophageal Perforation; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D043823:Taxoids",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1943-1945",
"pmc": null,
"pmid": "29394828",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Emergency Resection of Esophageal Cancer Which is on the Brink of Perforation after Neoadjuvant Chemotherapy.",
"title_normalized": "a case of emergency resection of esophageal cancer which is on the brink of perforation after neoadjuvant chemotherapy"
} | [
{
"companynumb": "JP-SA-2018SA142354",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nOsteogenesis imperfecta (OI) is a rare condition with limited data on fetal and maternal impact for almost all subtypes. OI type V is a very rare, autosomal dominant, inherited subtype of OI. The care of pregnant women with OI is managed by an interdisciplinary team, and fetal diagnosis is possible through amniocentesis, which may assist in delivery planning.\n\n\nMETHODS\nThis report is the first to describe a case of maternal and fetal OI type V. We detail maternal and fetal management during pregnancy and delivery planning. While no major complications occurred during pregnancy or delivery, the neonate developed multiple fractures in the first few months of life.\n\n\nCONCLUSIONS\nOur case shows favourable maternal and pregnancy outcomes with OI type V and emphasizes the importance of fetal diagnosis.",
"affiliations": "Department of Obstetrics and Gynaecology, Division of Maternal-Fetal Medicine, Sunnybrook Health Sciences Centre, Toronto, ON; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON.;Department of Obstetrics and Gynaecology, Division of Maternal-Fetal Medicine, Sunnybrook Health Sciences Centre, Toronto, ON; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON. Electronic address: anne.berndl@sunnybrook.ca.",
"authors": "Anabusi|Saja|S|;Berndl|Anne|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jogc.2020.08.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1701-2163",
"issue": null,
"journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC",
"keywords": "osteogenesis imperfecta; pregnancy; prenatal care",
"medline_ta": "J Obstet Gynaecol Can",
"mesh_terms": null,
"nlm_unique_id": "101126664",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34756406",
"pubdate": "2020-09-16",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Osteogenesis Imperfecta Type V in a Mother and Baby Pair: First Case Report of Pregnancy and Delivery.",
"title_normalized": "osteogenesis imperfecta type v in a mother and baby pair first case report of pregnancy and delivery"
} | [
{
"companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2021-21628",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditio... |
{
"abstract": "Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.\n\n\n\nThe purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib.\n\n\n\nThis study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC025 (lower end of the IC 95% credibility interval) >0 is significant.\n\n\n\nThis study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC025: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC025: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC025: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC025: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC025: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC025: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC025: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases).\n\n\n\nSevere and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215).",
"affiliations": "Sorbonne Université, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Center, Pitié-Salpêtrière Hospital, UNICO-GRECO.6 Cardio-Oncology Program, Department of Pharmacology, Paris, France; Departments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: joe-elie.salem@aphp.fr.;Departments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt University Medical Center, Nashville, Tennessee.;Sorbonne Université, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Center, Pitié-Salpêtrière Hospital, UNICO-GRECO.6 Cardio-Oncology Program, Department of Pharmacology, Paris, France.;Sorbonne Université, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Center, Pitié-Salpêtrière Hospital, UNICO-GRECO.6 Cardio-Oncology Program, Department of Pharmacology, Paris, France.;Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts.;Departments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt University Medical Center, Nashville, Tennessee.;Departments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt University Medical Center, Nashville, Tennessee.;Departments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt University Medical Center, Nashville, Tennessee.;Sorbonne Université, INSERM CIC-1421, AP-HP, Regional Pharmacovigilance Center, Pitié-Salpêtrière Hospital, UNICO-GRECO.6 Cardio-Oncology Program, Department of Pharmacology, Paris, France.;CLL Center, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School, Boston, Massachusetts.;Departments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.;Departments of Medicine and Pharmacology, Cardio-Oncology program, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: javid.moslehi@vumc.org.",
"authors": "Salem|Joe-Elie|JE|;Manouchehri|Ali|A|;Bretagne|Marie|M|;Lebrun-Vignes|Bénédicte|B|;Groarke|John D|JD|;Johnson|Douglas B|DB|;Yang|Tao|T|;Reddy|Nishitha M|NM|;Funck-Brentano|Christian|C|;Brown|Jennifer R|JR|;Roden|Dan M|DM|;Moslehi|Javid J|JJ|",
"chemical_list": "D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacc.2019.07.056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1097",
"issue": "74(13)",
"journal": "Journal of the American College of Cardiology",
"keywords": "atrial fibrillation; cardiac failure; cardio-oncology; cardiology; ibrutinib; oncology; ventricular tachycardia",
"medline_ta": "J Am Coll Cardiol",
"mesh_terms": "D000225:Adenine; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D009026:Mortality; D060735:Pharmacovigilance; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D012189:Retrospective Studies",
"nlm_unique_id": "8301365",
"other_id": null,
"pages": "1667-1678",
"pmc": null,
"pmid": "31558250",
"pubdate": "2019-10-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cardiovascular Toxicities Associated With Ibrutinib.",
"title_normalized": "cardiovascular toxicities associated with ibrutinib"
} | [
{
"companynumb": "FR-JNJFOC-20191011061",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nThe optimal sequencing of the multiple active agents now available for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Prior reports have suggested diminished responses to sequential lines of androgen receptor (AR)-targeted therapies, but it is unknown whether subsequent taxane-based chemotherapy may be more effective than sequential AR-targeting treatment. We sought to evaluate the clinical activity of enzalutamide versus docetaxel in men with mCRPC who progressed on abiraterone.\n\n\nMETHODS\nWe performed a single-institution retrospective analysis of consecutive mCRPC patients who had progressed on abiraterone therapy and subsequently received either enzalutamide (n=30) or docetaxel (n=31). We evaluated clinical outcomes including prostate-specific antigen decline of >30% (PSA30) or >50% (PSA50), PSA-progression-free survival (PSA-PFS), and clinical/radiographic PFS. We performed multivariable modeling to control for baseline and on-treatment differences between groups.\n\n\nRESULTS\nCompared to subjects who received enzalutamide post-abiraterone, subjects who received docetaxel post-abiraterone had more bone metastases, more visceral metastases, higher baseline PSA, and had more frequent PSA tests while on-treatment. There were no significant differences in PSA30 (41% for enzalutamide vs. 53% for docetaxel) or PSA50 (34% vs. 40%) response rates between the two groups; there remained no difference after stratifying by presence/absence of prior response to abiraterone. Median PSA-PFS was 4.1 versus 4.1 months for the enzalutamide and docetaxel cohorts, respectively (HR 1.35, 95% CI, 0.53-3.66, P=0.502). Median PFS was 4.7 versus 4.4 months, respectively (HR 1.44, 95% CI, 0.77-2.71, P=0.257). PSA-PFS and PFS did not differ after stratifying by prior response to abiraterone. In multivariable analyses, there were no significant differences in PSA-PFS or PFS between the two groups.\n\n\nCONCLUSIONS\nTreatment with either enzalutamide or docetaxel produced modest PSA responses and PFS intervals in this abiraterone-pretreated mCRPC population. In this retrospective study with small sample size, no significant differences in outcomes were observed between groups. Therefore, either enzalutamide or docetaxel may be a reasonable option in men who have progressed on abiraterone.",
"affiliations": "The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.",
"authors": "Suzman|Daniel L|DL|;Luber|Brandon|B|;Schweizer|Michael T|MT|;Nadal|Rosa|R|;Antonarakis|Emmanuel S|ES|",
"chemical_list": "D000736:Androstenes; D000737:Androstenols; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone",
"country": "United States",
"delete": false,
"doi": "10.1002/pros.22844",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-4137",
"issue": "74(13)",
"journal": "The Prostate",
"keywords": "abiraterone; docetaxel; enzalutamide; prostate cancer; sequencing",
"medline_ta": "Prostate",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000736:Androstenes; D000737:Androstenols; D000970:Antineoplastic Agents; D001549:Benzamides; D001859:Bone Neoplasms; D018450:Disease Progression; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010669:Phenylthiohydantoin; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "8101368",
"other_id": null,
"pages": "1278-85",
"pmc": null,
"pmid": "25053178",
"pubdate": "2014-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "21807635;24200698;21799031;15470213;18309951;22995653;11900250;22771826;23585511;24491307;24647231;23576708;24556717;24382803;23849416;22894553",
"title": "Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone.",
"title_normalized": "clinical activity of enzalutamide versus docetaxel in men with castration resistant prostate cancer progressing after abiraterone"
} | [
{
"companynumb": "US-JNJFOC-20141014557",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
},
"drugadditional": null,
... |
{
"abstract": "We encountered three cases of retroperitoneal hematoma caused by spontaneous lumbar artery rupture, a rare vascular complication. At the time of retroperitoneal hematoma, two patients were on anticoagulant/antiplatelet therapy. One patient was not taking any anticoagulant/antiplatelet agents but was receiving hemodialysis treatment with heparin. Lumbar artery rupture was successfully controlled by transcatheter arterial embolization in all patients, but one patient developed multiple organ failure and died. We suggest that spontaneous lumbar artery rupture may occur in patients being treated with maintenance hemodialysis or anticoagulant/antiplatelet therapy. Therefore, clinicians should suspect lumbar artery rupture in patients with unstable vital signs and rapid onset of anemia because early diagnosis and appropriate intervention are necessary to decrease the risks of morbidity and mortality.",
"affiliations": "Department of Internal Medicine & Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.;Department of Internal Medicine & Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.;Department of Internal Medicine & Research Institute for Convergence of Biomedical Science and Technology, Yangsan Pusan National University Hospital, Yangsan, Korea.;Department of Internal Medicine & Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.;Department of Internal Medicine & Research Institute for Convergence of Biomedical Science and Technology, Yangsan Pusan National University Hospital, Yangsan, Korea.;Department of Internal Medicine & Research Institute for Convergence of Biomedical Science and Technology, Yangsan Pusan National University Hospital, Yangsan, Korea.;Department of Internal Medicine & Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.;Department of Radiology & Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.;Department of Internal Medicine & Biomedical Research Institute, Pusan National University Hospital, Busan, Korea.",
"authors": "Hwang|Na Kyoung|NK|;Rhee|Harin|H|;Kim|Il Young|IY|;Seong|Eun Young|EY|;Lee|Dong Won|DW|;Lee|Soo Bong|SB|;Kwak|Ihm Soo|IS|;Kim|Chang Won|CW|;Song|Sang Heon|SH|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12491",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "21(1)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Anticoagulant; hemodialysis; lumbar artery; spontaneous retroperitoneal hematoma",
"medline_ta": "Hemodial Int",
"mesh_terms": "D000328:Adult; D006470:Hemorrhage; D006801:Humans; D008161:Lumbosacral Region; D008297:Male; D006435:Renal Dialysis; D012422:Rupture, Spontaneous",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "E18-E21",
"pmc": null,
"pmid": "27670146",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Three cases of spontaneous lumbar artery rupture in hemodialysis patients.",
"title_normalized": "three cases of spontaneous lumbar artery rupture in hemodialysis patients"
} | [
{
"companynumb": "KR-INGENUS PHARMACEUTICALS NJ, LLC-ING201705-000265",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
... |
{
"abstract": "Herpes zoster, commonly called shingles, is a disease that results from the reactivation of varicella zoster virus. Local trauma has been reported as a precipitant for reactivation, but this condition is rarely seen localized to a fresh surgical incision. We present the case of a patient who developed shingles overlying the incision site of a recently buried central venous access port, illustrating the need to consider this diagnosis as a unique imposter of localized infection or reaction at sites of recent procedural trauma.",
"affiliations": "*University of Michigan Department of Emergency Medicine,Ann Arbor,MI.;*University of Michigan Department of Emergency Medicine,Ann Arbor,MI.;*University of Michigan Department of Emergency Medicine,Ann Arbor,MI.",
"authors": "Hess|Rebecca A|RA|;Gunnerson|Kyle|K|;Kahler|John|J|",
"chemical_list": "D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1017/cem.2016.340",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1481-8035",
"issue": "19(1)",
"journal": "CJEM",
"keywords": "Bard PowerPort; Herpes zoster; Shingles; wound healing",
"medline_ta": "CJEM",
"mesh_terms": "D000212:Acyclovir; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D055499:Catheter-Related Infections; D062905:Central Venous Catheters; D005260:Female; D005500:Follow-Up Studies; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D016896:Treatment Outcome; D000077483:Valacyclovir; D014633:Valine",
"nlm_unique_id": "100893237",
"other_id": null,
"pages": "75-78",
"pmc": null,
"pmid": "27461420",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Herpes Zoster Overlying Recently Placed Central Venous Access Site: A Case Report.",
"title_normalized": "herpes zoster overlying recently placed central venous access site a case report"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201710105",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nHypersensitivity reactions to platinum-based chemotherapies are well documented and are often a limiting factor in treating a variety of cancers. Allergy skin testing has been used to determine if repeat exposure is safe. We report a case of a false negative skin allergy test in an atypical presentation of cisplatin hypersensitivity reaction.\n\n\nMETHODS\nA 64-year-old male diagnosed with stage IVa squamous cell carcinoma of the hypopharynx who developed a delayed reaction of face swelling and dysphagia following exposure to a single dose of cisplatin. Skin allergy testing performed and was negative. On second dosing of cisplatin, the patient developed an immediate hypersensitivity reaction. Cisplatin was discontinued, and the patient was transitioned to cetuximab. The rest of chemoradiation therapy was completed without further incident.\n\n\nCONCLUSIONS\nThis case demonstrates the limited efficacy of skin allergy testing for cisplatin. Furthermore, it is an atypical presentation of cisplatin-related hypersensitivity as it occurred following the patient's first dose despite no prior exposure to platinum-based chemotherapy.\n\n\nCONCLUSIONS\nSkin allergy testing has limited sensitivity for platinum-based chemotherapy and caution should be exercised in weighing risk and benefits of re-exposure. Although rare, cisplatin hypersensitivity can present after first exposure.",
"affiliations": "Department of Hematology and Oncology, Huntsman Cancer Institute at The University of Utah, Salt Lake City, UT, USA.;Department of Hematology and Oncology, Huntsman Cancer Institute at The University of Utah, Salt Lake City, UT, USA.",
"authors": "Solomon|Benjamin|B|;Colonna|Sarah|S|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1177/1078155217735154",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(2)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Cisplatin; head and neck cancer; hypersensitivity; platinum chemotherapy; skin allergy testing",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D004342:Drug Hypersensitivity; D005188:False Negative Reactions; D006801:Humans; D007012:Hypopharyngeal Neoplasms; D008297:Male; D008875:Middle Aged; D012882:Skin Tests",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "481-483",
"pmc": null,
"pmid": "29022851",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent cisplatin hypersensitivity reaction after first exposure: A case report.",
"title_normalized": "recurrent cisplatin hypersensitivity reaction after first exposure a case report"
} | [
{
"companynumb": "US-ACCORD-060264",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"... |
{
"abstract": "Sorafenib is a multikinase inhibitor increasingly used for the treatment of several solid tumors. Different types of keratotic lesions, such as squamous cell carcinoma, actinic keratosis, or infundibular cyst, have been reported in association with this therapy. We present a 15-year-old male diagnosed with desmoid fibromatosis who developed multiple penile and scrotal infundibular cysts while receiving treatment with sorafenib.",
"affiliations": "Department of Dermatology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Department of Pathology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Department of Dermatology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.",
"authors": "Mateos-Mayo|Ana|A|https://orcid.org/0000-0001-9507-005X;Colmenero|Isabel|I|https://orcid.org/0000-0001-6859-187X;Ramírez-Lluch|Mar|M|https://orcid.org/0000-0003-0267-5901;Martos-Cabrera|Luisa|L|https://orcid.org/0000-0002-0072-6157;Hernández-Martín|Ángela|Á|https://orcid.org/0000-0001-7260-8718;Torrelo|Antonio|A|https://orcid.org/0000-0002-5940-6916",
"chemical_list": "D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14521",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "38(2)",
"journal": "Pediatric dermatology",
"keywords": "hyperkeratosis; infundibular cysts; kinase inhibitor; sorafenib",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000293:Adolescent; D002294:Carcinoma, Squamous Cell; D006801:Humans; D008297:Male; D009536:Niacinamide; D010671:Phenylurea Compounds; D012878:Skin Neoplasms; D000077157:Sorafenib",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "518-519",
"pmc": null,
"pmid": "33481286",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Penile and scrotal infundibular cysts in an adolescent treated with sorafenib.",
"title_normalized": "penile and scrotal infundibular cysts in an adolescent treated with sorafenib"
} | [
{
"companynumb": "ES-BAYER-2021-062167",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nThe objective of this analysis was to determine the factors associated with early onset treatment-related toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care.\n\n\nMETHODS\nA total of 1463 patients previously included in a prospective cohort study and treated with standard-of-care capecitabine-based anticancer regimens (monotherapy or combined with other chemotherapy or radiotherapy) were analysed. Logistic regression models were developed to investigate associations between patient- and treatment-related factors and occurrence of early--i.e. cycle one or two--severe (grade ≥ 3) treatment-related toxicity, toxicity-related hospitalisation, and toxicity-related treatment discontinuation. Performance of models was evaluated using receiver-operating characteristic (ROC) curves and internal validity was explored using bootstrap analysis.\n\n\nRESULTS\nAmong 1463 patients included, 231 patients (16%) experienced early severe toxicity, 132 patients (9%) were hospitalised for toxicity, and 146 patients (10%) discontinued treatment for toxicity; in total, 321 patients (22%) experienced any early toxicity-related adverse outcome. Predictors of early grade ≥ 3 toxicity, after adjustment for treatment regimen, were renal function (odds ratio [OR] 0.85 per 10 ml/min/1.73 m(2), p = 0.0007), body surface area (BSA) (OR 0.33 per m(2), p = 0.0053), age (OR 1.14 per decade, p = 0.0891), and elevated pre-treatment uracil concentrations (OR 2.41 per 10 ng/ml, p = 0.0046). Age was significantly associated with fatal treatment-related toxicity (OR 5.75, p = 0.0008). Area under the ROC curve (AUC) of a model to predict early grade ≥ 3 toxicity was 0.704 (95% confidence interval 0.666-0.743, optimism-corrected AUC 0.690).\n\n\nCONCLUSIONS\nRenal function, BSA, and age, in addition to pre-treatment uracil, are associated with clinically relevant differences in risk of early severe toxicity in patients treated with capecitabine in routine clinical care.",
"affiliations": "Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.;Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.;Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.;Division of Gastroenterology and Hepatology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.;Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands. Electronic address: j.schellens@nki.nl.",
"authors": "Meulendijks|Didier|D|;van Hasselt|J G Coen|JGC|;Huitema|Alwin D R|ADR|;van Tinteren|Harm|H|;Deenen|Maarten J|MJ|;Beijnen|Jos H|JH|;Cats|Annemieke|A|;Schellens|Jan H M|JHM|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2015.10.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "54()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Capecitabine; Fluoropyrimidine-associated toxicity; Safety; Toxicity; adverse events",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D001830:Body Surface Area; D000069287:Capecitabine; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006760:Hospitalization; D006801:Humans; D007668:Kidney; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012372:ROC Curve; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9005373",
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"title": "Renal function, body surface area, and age are associated with risk of early-onset fluoropyrimidine-associated toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care.",
"title_normalized": "renal function body surface area and age are associated with risk of early onset fluoropyrimidine associated toxicity in patients treated with capecitabine based anticancer regimens in daily clinical care"
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"abstract": "We present a case of an accidental fatal fentanyl overdose caused by increased uptake of the drug from a transdermal patch while experiencing the heat of a sauna.The transdermal patch administers fentanyl at a relatively constant rate through the skin. However, in the subcutaneous tissue, blood circulation greatly influences the rate of this drug's systemic intake. In the present case, an elderly woman with multiple health conditions was prescribed fentanyl patches but was unaware of the risks associated with external heat sources when one wears the patch. She was found dead in the sauna with a postmortem femoral blood concentration of fentanyl that was elevated (15 μg/L). The cause of death was determined to be fatal poisoning by fentanyl with the contributing factor of external heat from the sauna.Risks associated with transdermal administration of a potent opioid-like fentanyl are widely described in the scientific literature and described in the manufacturer's summary of product characteristics. Physicians and pharmacists should take particular care to ensure that patients understand these risks.",
"affiliations": null,
"authors": "Kriikku|Pirkko|P|;Ojanperä|Ilkka|I|;Lunetta|Philippe|P|",
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"mesh_terms": "D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D005260:Female; D005283:Fentanyl; D006801:Humans; D029002:Steam Bath; D057968:Transdermal Patch",
"nlm_unique_id": "8108948",
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"pages": "313-314",
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"title": "Death in Sauna Associated With a Transdermal Fentanyl Patch.",
"title_normalized": "death in sauna associated with a transdermal fentanyl patch"
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"abstract": "A case of primary oral mucosal diffuse large B-cell lymphoma(DLBCL)due to long-term use of methotrexate(MTX)for the treatment of rheumatoid arthritis(RA)was admitted to the Department of Hematology,Fujian Medical University Union Hospital.We analyzed and discussed the clinical features,diagnosis and treatment,and prognosis of specific malignant lymphoma induced by MTX in this RA patient.Our purpose is to improve the awareness and knowledge of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of clinicians and pathologists.This study provides a new reference for the clinical diagnosis and treatment of MTX-associated DLBCL.",
"affiliations": "First Clinical Medical College,First Affiliated Hospital of Gannan Medical University,Ganzhou,Jiangxi 341000,China.;Department of Pathology, Fujian Medical University Union Hospital,Fuzhou 350001,China.;Department of Cell Morphology, Fujian Medical University Union Hospital,Fuzhou 350001,China.;Department of Hematology, Fujian Medical University Union Hospital,Fuzhou 350001,China.;Department of Hematology, Fujian Medical University Union Hospital,Fuzhou 350001,China.;Department of Hematology, Fujian Medical University Union Hospital,Fuzhou 350001,China.;Department of Hematology, Fujian Medical University Union Hospital,Fuzhou 350001,China.",
"authors": "Liu|Yan-Quan|YQ|;Hu|Xiao-Mei|XM|;Yin|Yue|Y|;Zhang|Lang-Hui|LH|;Fu|Hai-Ying|HY|;Liu|Ting-Bo|TB|;Shen|Jian-Zhen|JZ|",
"chemical_list": "D008727:Methotrexate",
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"issue": "43(3)",
"journal": "Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae",
"keywords": "extranodal lymphoma; immunosuppressive agents; lymphoma; methotrexate; methotrexate-associated lymphoproliferative disorders; other iatrogenic immunodeficiency-associated lymphoproliferative disorders",
"medline_ta": "Zhongguo Yi Xue Ke Xue Yuan Xue Bao",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008232:Lymphoproliferative Disorders; D008727:Methotrexate",
"nlm_unique_id": "8006230",
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"pages": "488-493",
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"pmid": "34238428",
"pubdate": "2021-06-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oral Mucosal Diffuse Large B-cell Lymphoma Caused by Long-term Oral Methotrexate:Report of One Case.",
"title_normalized": "oral mucosal diffuse large b cell lymphoma caused by long term oral methotrexate report of one case"
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"companynumb": "CN-ACCORD-232683",
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"abstract": "BACKGROUND\nIn vitro fertilization is becoming more and more popular lately, as such light is to be shed on any possible related complication. One of these complications is the possible hormonal effect on the lipid profile of the patients.\n\n\nMETHODS\nWe present a case of a 39-year-old woman with no prior or family history of dyslipidemia, who presented with post in vitro fertilization severe hypertriglyceridemia and secondary acute pancreatitis and diabetic ketoacidosis. Discussion of the case is followed by a brief review of the literature related to in vitro fertilization-induced hypertriglyceridemia.\n\n\nCONCLUSIONS\nThis is, up to our knowledge, the sixth reported case of in vitro fertilization-induced hypertriglyceridemia with secondary acute pancreatitis. This is a serious and life-threatening complication. As such, it might be wise at least in high-risk patients (such as patients with diabetes mellitus, polycystic ovaries syndrome, obesity, and family and personal history of dyslipidemia) to screen for lipid abnormalities before initiating in vitro fertilization and monitor these levels afterward.",
"affiliations": "Department of Internal Medicine, Ain Wazein Hospital, El Chouf, Lebanon.;Department of Internal Medicine, Ain Wazein Hospital, El Chouf, Lebanon.",
"authors": "Issa|Claire Michael|CM|;Abu Khuzam|Rani Hazar|RH|",
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"doi": "10.1177/2050313X16689209",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1668920910.1177_2050313X16689209Case ReportIn vitro fertilization–induced hypertriglyceridemia with secondary acute pancreatitis and diabetic ketoacidosis Issa Claire Michael Abu Khuzam Rani Hazar Department of Internal Medicine, Ain Wazein Hospital, El Chouf, LebanonClaire Michael Issa, Department of Internal Medicine, Ain Wazein Hospital, Mount Lebanon, El Chouf, Lebanon. Email: claireissa_md@yahoo.com18 1 2017 2017 5 2050313X166892099 9 2016 20 12 2016 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page(https://us.sagepub.com/en-us/nam/open-access-at-sage).Introduction:\nIn vitro fertilization is becoming more and more popular lately, as such light is to be shed on any possible related complication. One of these complications is the possible hormonal effect on the lipid profile of the patients.\n\nCase presentation:\nWe present a case of a 39-year-old woman with no prior or family history of dyslipidemia, who presented with post in vitro fertilization severe hypertriglyceridemia and secondary acute pancreatitis and diabetic ketoacidosis. Discussion of the case is followed by a brief review of the literature related to in vitro fertilization–induced hypertriglyceridemia.\n\nConclusion:\nThis is, up to our knowledge, the sixth reported case of in vitro fertilization–induced hypertriglyceridemia with secondary acute pancreatitis. This is a serious and life-threatening complication. As such, it might be wise at least in high-risk patients (such as patients with diabetes mellitus, polycystic ovaries syndrome, obesity, and family and personal history of dyslipidemia) to screen for lipid abnormalities before initiating in vitro fertilization and monitor these levels afterward.\n\nIn vitro fertilizationhypertriglyceridemiamixed dyslipidemiaacute pancreatitisdiabetic ketoacidosiscover-dateJanuary-December 2017\n==== Body\nIntroduction\nWith in vitro fertilization (IVF) becoming more and more popular, an increased level of awareness as to the possible associated complications becomes necessary. One of these complications, which can be life threatening, is the hormonal effects on the lipid profile of the patient. We hereby present a case of IVF-induced severe hypertriglyceridemia with secondary severe hemorrhagic acute pancreatitis.\n\nCase presentation\nWe present a case of a 39-year-old woman with a history significant for infertility, a type II diabetes mellitus, and a body mass index (BMI) of 27.5, who presented to our emergency department (ED) 10 days after an IVF procedure with severe epigastric pain and several episodes of nausea and vomiting that started one day prior to presentation. On initial evaluation in the ED, she was afebrile and hemodynamically stable. Her physical examination was significant only for epigastric and left upper quadrant pain. Her BMI was 27.5. Initial laboratory work-up could not be accurately interpreted due to severe lipemia (Figure 1); however, it revealed a serum level of lipase of 2470 U/L, amylase of 1000 U/L, blood glucose of 301 mg/dL, sodium of 117 meq/L, chloride of 92 meq/L, bicarbonate of 12 meq/L, aspartate transaminase of 60 U/L, alanine transaminase of 24 U/L, gamma-glutamyl transferase of 14 U/L, and alkaline phosphatase of 66 U/L. Arterial serum lactate was 0.78 meq/L, and urine ketone levels was valued as 4+ on urine dipstick. An ultrasound of the abdomen was performed and revealed fatty liver infiltration. A computed tomography scan of the abdomen and pelvis, done 48 h later, revealed acute hemorrhagic pancreatitis with peri-pancreatic fluid. The patient was admitted with a diagnosis of severe hypertriglyceridemia-induced acute pancreatitis, hypertriglyceridemia associated pseudo-hyponatremia, and possible diabetic ketoacidosis. The patient was admitted to the intensive care unit and started on aggressive intravenous (IV) hydration and intravenous insulin. The second day, her triglycerides dropped to 9234 mg/dL, her low-density lipoprotein (LDL) was 366 mg/dL, and her high-density lipoprotein (HDL) was 40 mg/dL. Her symptoms improved progressively every day and her pain became better. The third day, triglycerides dropped to 1455 mg/dL, and after confirmation of absence of pregnancy, she was started on fibrates and statins on day 3 of admission, after which her triglyceride level continued to drop (Table 1).\n\nFigure 1. Patient’s lipemic blood on presentation.\n\nTable 1. Triglyceride levels during hospital stay.\n\n\tDay 1\tDay 2\tDay 3\tDay 4\tDay 5\tDay 8\tDay 10\t\nTriglyceride (mg/dL)\t15,050\t9234\t3930\t1455\t887\t252\t325\t\nThe patient had a negative family history for dyslipidemia. No previous history of acute pancreatitis. She was maintained at home on oral metformin 850 mg daily for mild type II diabetes mellitus, estradiol 2 mg daily, progesterone 200 mg twice daily, aspirin 100 mg daily, and subcutaneous hydroxyprogesterone 500 mg daily and enoxaparin 40 mg daily as part of a regimen for IVF.\n\nDiscussion\nThis is a case of IVF-induced severe hypertriglyceridemia and mixed dyslipidemia complicated by acute pancreatitis and diabetic ketoacidosis.\n\nA thorough review of the literature revealed several reported cases of pregnancy-associated hyperlipidemia-induced acute pancreatitis. However, to our knowledge, this is the sixth reported case of IVF-induced hypertriglyceridemia with secondary acute pancreatitis. The pathophysiology of IVF-induced hypertriglyceridemia has not yet been clearly delineated but is most likely related to estrogen therapy. Estrogens are known to increase triglycerides level by several mechanisms. Such mechanisms include an increase in the synthesis of triglycerides in the liver followed by its secretion into the circulation as very-low-density lipoprotein (VLDL),1 an increase in newly synthesized triglycerides in the liver, and the hypersecretion of triglycerides and apoprotein B.2,3 Another, still controversial, mechanism of IVF-induced hypertriglyceridemia is through estrogens’ effect on lipid metabolism, particularly through its inhibitory effect on lipoprotein lipase (LpL) promoter activity, resulting in LpL deficiency,4 an effect that was not found in another study.5 This effect on triglyceride levels seems to be more encountered in oral rather than transdermal estrogen forms.6\n\nThis case is interesting because it witnessed a paradoxical increase in the level of LDL, thus defying the effect of estrogen. Usually estrogen decreases LDL levels through both receptor-dependent and receptor-independent effects on the LDL receptors. Estrogen increases the expression of the LDL receptors and decreases the production of LDL.7 Estrogen also increases hepatic production of HDL and prolongs the half-life of circulating HDL by decreasing its clearance.7 In the study by Hammadeh et al.,8 a similar effect was achieved by demonstrating a decrease in LDL, an increase in HDL, and interestingly an increase in ketones. What complicates the interpretation of the increased levels of LDL in our patient is the fact that there were no previous records of her LDL level before the IVF. She might have had chronically high level of LDL, and thus there is no baseline level to compare to.\n\nFurthermore, all the changes mentioned earlier rarely lead to the very high levels of triglycerides found in our patient. An exception to this rational is the presence of an underlying genetic familial disease, a remote possibility in our patient’s case particularly in the absence of a personal and family history of dyslipidemia.\n\nDespite the fact that the lack of previous records of lipid levels makes it hard for a cause–effect relationship to be firmly concluded, it is highly unlikely for other etiologies to cause such high levels of triglycerides reaching 15,000 as in our patient. Uncontrolled diabetes as well as diabetic ketoacidosis can lead to hypertriglyceridemia but unlikely to such high levels.\n\nThe management of hypertriglyceridemia-induced pancreatitis in the acute phase is similar to other causes of acute pancreatitis with the addition of various other modalities that target specifically hypertriglyceridemia such as insulin, heparin, fibric acid derivatives, and in extreme cases plasmapheresis.9 The patient presented above responded to aggressive IV hydration in addition to fibrates and IV insulin that was helpful also in controlling her ketoacidosis.\n\nIn conclusion, our patient is one of the rare cases of reported IVF-induced severe hypertriglyceridemia with secondary acute pancreatitis. The occurrence of hypertriglyceridemia is a serious complication of IVF, particularly during pregnancy, which might lead to further increase in triglyceride level, and consequently an increased risk on both the mother and the fetus. As such, with the increasing popularity of IVF, and aiming at the prevention of such life-threatening complications, prescreening of patients with lipid levels before IVF should be highly considered, especially in those who might be at a higher risk (such as patients with diabetes mellitus, polycystic ovaries syndrome, obesity, and family and personal history of dyslipidemia).\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient for their anonymized information to be published in this article.\n==== Refs\nReferences\n1 \nMelmed S Polonsky KS Larsen PR \nWilliams textbook of endocrinology . 13th ed. \nToronto, ON, Canada : Elsevier .\n2 \nDashti N Kelley JL Thayer RH \nConcurrent inductions of avian hepatic lipogenesis, plasma lipids, and plasma apolipoprotein B by estrogen . J Lipid Res \n1983 ; 24 : 368 –380 .6854148 \n3 \nWalsh BW Schiff I Rosner B \nEffects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins . N Engl J Med \n1991 ; 325 : 1196 –1204 .1922206 \n4 \nHomma H Kurachi H Nishio Y \nEstrogen suppresses transcription of lipoprotein lipase gene. Existence of a unique estrogen response element on the lipoprotein lipase promoter . J Biol Chem \n2000 ; 275 : 11404 –11411 .10753956 \n5 \nApplebaum DM Goldberg AP Pykalisto OJ \nEffect of estrogen on post-heparin lipolytic activity. Selective decline in hepatic triglyceride lipase . J Clin Invest \n1977 ; 59 : 601 –608 .845252 \n6 \nVrablika M Fait T Kovar J \nOral but not transdermal estrogen replacement therapy changes the composition of plasma lipoproteins . Metabolism \n2008 ; 57 (8 ): 1088 –1092 .18640386 \n7 \nBarton M \nCholesterol and atherosclerosis: modulation by oestrogen . Curr Opin Lipidol \n2013 ; 24 : 214 –220 .23594711 \n8 \nHammadeh ME Munz W Meisinger M \nEffects of ovarian stimulation on serum concentrations of lipids and ketone bodies in patients undergoing IVF/ICSI treatment . Zentralbl Gynakol \n2004 ; 126 (2 ): 67 –72 (in German).15112131 \n9 \nCoskun A Erkan N Yakan S \nTreatment of hypertriglyceridemia-induced acute pancreatitis with insulin . Prz Gastroenterol \n2015 ; 10 (1 ): 18 –22 .25960810\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "5()",
"journal": "SAGE open medical case reports",
"keywords": "In vitro fertilization; acute pancreatitis; diabetic ketoacidosis; hypertriglyceridemia; mixed dyslipidemia",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X16689209",
"pmc": null,
"pmid": "28228964",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
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"title": "In vitro fertilization-induced hypertriglyceridemia with secondary acute pancreatitis and diabetic ketoacidosis.",
"title_normalized": "in vitro fertilization induced hypertriglyceridemia with secondary acute pancreatitis and diabetic ketoacidosis"
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"abstract": "OBJECTIVE\nTo investigate the outcome of intravitreal ranibizumab and/or dexamethasone implant treatment for treatment of macular edema (ME) secondary to central or branch retinal vein occlusion (CRVO or BRVO) in a clinical setting.\n\n\nMETHODS\nRetrospective analysis of consecutive patients followed for at least 6 months. Data recorded included the type of occlusion, initial and final visual acuity, and number of injections.\n\n\nRESULTS\nSixty-five patients were included, 26 had CRVO and 39 BRVO. Mean (± SD) follow-up duration was 16 (± 7.7) months. Twenty-four (36.9%) patients received ranibizumab in monotherapy, 19 patients (29.3%) dexamethasone in monotherapy, and 22 patients (33.8%) received successively both treatments. In dexamethasone-treated patients, mean (± SD) visual acuity gain was 5.8 ± 10.7 letters for BRVO and 16.8 ± 15.6 letters for CRVO. In ranibizumab-treated patients, mean (± SD) visual acuity gain was 9.2 ± 10 letters for BRVO and 18.2 ± 20.5 letters for CRVO.\n\n\nCONCLUSIONS\nBoth intravitreal ranibizumab and dexamethasone intravitreal implant could be used as first-line therapy for patients with ME secondary to retinal vein occlusion.",
"affiliations": "Centre Ophtalmologique d'Imagerie et de Laser, Paris, France.",
"authors": "Nghiem-Buffet|Sylvia|S|;Fajnkuchen|Franck|F|;Buffet|Marc|M|;Ayrault|Sandrine|S|;Le Gloahec-Lorcy|Anna|A|;Grenet|Typhaine|T|;Delahaye-Mazza|Corinne|C|;Quentel|Gabriel|G|;Cohen|Salomon Y|SY|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone; D000069579:Ranibizumab",
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"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003907:Dexamethasone; D004343:Drug Implants; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema; D008297:Male; D000069579:Ranibizumab; D012170:Retinal Vein Occlusion; D012189:Retrospective Studies; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity; D014822:Vitreous Body",
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"title": "Intravitreal ranibizumab and/or dexamethasone implant for macular edema secondary to retinal vein occlusion.",
"title_normalized": "intravitreal ranibizumab and or dexamethasone implant for macular edema secondary to retinal vein occlusion"
} | [
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"abstract": "This case report concerns a 63-year-old man affected by metastatic undifferentiated liposarcoma. After receiving pembrolizumab as a second-line treatment in a clinical trial, the patient experienced an immune-mediated myocarditis, myositis and myasteniform syndrome. The last two adverse events showed significant clinical relevance in terms of severity, duration and the required specific treatment.Initial treatment approach consisted in pulses of 1 g of methylprednisolone, followed by 2 mg/kg/day, with clinical improvement. After 12 days, the immune-mediated myasteniform syndrome worsened, with dysphagia, dysphonia, bilateral palpebral ptosis and respiratory difficulty. Due to the refractoriness to glucocorticoid treatment, it was decided to initiate intravenous immunoglobulin at 2 g/kg, followed by 2 mg/kg every 4 weeks once discharged and mycophenolate 500 mg/12 hours, in order to reduce the dose of glucocorticoids.After 2 months, the patient presented an optimal clinical evolution, without muscular weakness and referred to an improvement in dysphagia and speech.",
"affiliations": "Pharmacy Department, Hospital Vall d'Hebron, Barcelona, Spain pablo.sanchez.vhebron@gmail.com.;Systemic Autoimmune Diseases Unit, Hospital Vall d'Hebron, Barcelona, Spain.;Rheumatology Unit, Hospital Vall d'Hebron, Barcelona, Spain.;Medical Oncology, Hospital Vall d'Hebron, Barcelona, Spain.;Pharmacy Department, Hospital Vall d'Hebron, Barcelona, Spain.",
"authors": "Sanchez-Sancho|Pablo|P|http://orcid.org/0000-0001-8861-4768;Selva-O'Callaghan|Albert|A|;Trallero-Araguás|Ernesto|E|;Ros|Javier|J|;Montoro|Bruno|B|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; C582435:pembrolizumab; D008775:Methylprednisolone",
"country": "England",
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"doi": "10.1136/bcr-2021-241766",
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"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "neurology; oncology; unwanted effects / adverse reactions",
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"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009220:Myositis",
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"title": "Myositis and myasteniform syndrome related to pembrolizumab.",
"title_normalized": "myositis and myasteniform syndrome related to pembrolizumab"
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"abstract": "We report a case of recurrent small cell carcinoma of the uterine cervix that showed a complete response to paclitaxel, carboplatin, and bevacizumab (TC + Bev) combination therapy. Small cell carcinoma of the uterine cervix is extremely rare, with an incidence of only 1.3% in Japan, and a poor outcome. The patient was a 62-year-old woman with a chief complaint of irregular vaginal bleeding. Magnetic resonance imaging showed a 10-cm irregular mass from the uterine corpus's posterior wall to the cervix. Abdominal total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node sampling were performed for suspected uterine sarcoma. Histopathological findings revealed small cell carcinoma with lymph node metastasis. Although 6 cycles of etoposide + cisplatin were performed, para-aortic lymph node recurrence was found 3 months after chemotherapy. Subsequently, the patient received 8 cycles of TC + Bev, which eliminated the metastases. The patient is currently alive at 24 months.",
"affiliations": "Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Nakao|Yuri|Y|;Tamauchi|Satoshi|S|;Yoshikawa|Nobuhisa|N|;Suzuki|Shiro|S|;Kajiyama|Hiroaki|H|;Kikkawa|Fumitaka|F|",
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"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000506446\ncro-0013-0373\nCase Report\nComplete Response of Recurrent Small Cell Carcinoma of the Uterine Cervix to Paclitaxel, Carboplatin, and Bevacizumab Combination Therapy\nNakao Yuri Tamauchi Satoshi * Yoshikawa Nobuhisa Suzuki Shiro Kajiyama Hiroaki Kikkawa Fumitaka Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan\n*Satoshi Tamauchi, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsurumai-cho 65, Showa-ku, Nagoya 466-8550 (Japan), tama-sato@med.nagoya-u.ac.jp\nJan-Apr 2020 \n9 4 2020 \n9 4 2020 \n13 1 373 378\n7 2 2020 10 2 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.We report a case of recurrent small cell carcinoma of the uterine cervix that showed a complete response to paclitaxel, carboplatin, and bevacizumab (TC + Bev) combination therapy. Small cell carcinoma of the uterine cervix is extremely rare, with an incidence of only 1.3% in Japan, and a poor outcome. The patient was a 62-year-old woman with a chief complaint of irregular vaginal bleeding. Magnetic resonance imaging showed a 10-cm irregular mass from the uterine corpus's posterior wall to the cervix. Abdominal total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node sampling were performed for suspected uterine sarcoma. Histopathological findings revealed small cell carcinoma with lymph node metastasis. Although 6 cycles of etoposide + cisplatin were performed, para-aortic lymph node recurrence was found 3 months after chemotherapy. Subsequently, the patient received 8 cycles of TC + Bev, which eliminated the metastases. The patient is currently alive at 24 months.\n\nKeywords\nSmall cell carcinomaCervical cancerBevacizumab\n==== Body\nIntroduction\nSmall cell carcinoma of the uterine cervix is a very aggressive neuroendocrine tumor that accounts for only 1.3% of cervical cancers [1]. Lymph node metastasis and distant metastasis can occur at an early stage with poor outcomes [2, 3]. The 4-year overall survival (OS) was reported as follows: FIGO stage IB1, 63%; stage IB2, 67%; stage IIB, 30%; stage IIIB, 29%; and stage IVB, 25% [4]. The optimal initial therapeutic approach has not been identified; therefore, we often follow the treatment regimens for small cell lung cancer, such as cisplatin and etoposide [5, 6]. However, it is a bigger challenge to treat recurrent small cell carcinoma, and no treatment consensus has been reached to date.\n\nBevacizumab is a humanized monoclonal antibody that targets the vascular endothelial growth factor, which promotes angiogenesis [7, 8]. In Japan, the National Health Insurance program has suggested the treatment of advanced recurrent uterine cervical carcinoma with a combination of bevacizumab and paclitaxel since 2016, which was based on the GOG 240 study [9]. In that study, the addition of bevacizumab to combination chemotherapy for patients with recurrent metastatic cervical cancer was associated with an improved median OS. Bevacizumab is known to be efficient for patients with recurrent cervical cancer [9, 10]. Combination therapy with bevacizumab could also be adapted for the treatment of small cell carcinoma, but the number of small cell carcinoma cases is insufficient to establish an effective treatment.\n\nHere, we present a case of small cell carcinoma of the uterine cervix in a 62-year-old female in which para-aortic lymph node recurrence was completely eliminated by paclitaxel, carboplatin, and bevacizumab (TC + Bev) combination therapy.\n\nCase Report\nThe patient was a 62-year-old woman with a history of five pregnancies and four childbirths. She first noted irregular vaginal bleeding, which persisted for 3 months. Magnetic resonance imaging showed a 10 × 9 × 8 cm, irregular, poorly defined mass growing from the posterior wall of the uterine corpus to the cervix and high intensity on T2-weighted images, which suggested uterine sarcoma. When the patient was first seen at our department, an enlarged left supraclavicular lymph node was recognized. Laboratory tests showed that her white blood cell count was 9,000/μL, hemoglobin was 11.2 g/dL, the platelet count was 549 × 103/μL, and lactate dehydrogenase was 723 IU/L. Regarding tumor markers, squamous cell carcinoma antigen was 0.7 ng/mL, carbohydrate antigen 19-9 was 7 U/mL, and carbohydrate antigen 125 was 54.9 U/mL. Cervical and endometrial smears were performed, which revealed no malignancy. Computed tomography (CT) scans showed an enlarged uterus and enlarged lymph nodes, including the para-aortic lymph nodes (Fig. 1). Uterine sarcoma was primarily suspected, and the patient underwent abdominal total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node sampling.\n\nMacroscopic examination of a surgical specimen revealed a bulky tumor from the uterine cervix to part of the corpus. Microscopic examination (Fig. 2a, b) revealed a prevalent solid pattern composed of small cells with hyperchromatic nuclei. On immunohistochemical analysis, CD56 (Fig. 2c) and chromogranin A (Fig. 2d), which are specific to neuroendocrine tumors, were positive. However, mesenchymal markers such as desmin, α-SMA, or vimentin were not positive. Thus, the pathological diagnosis was FIGO stage IVB small cell carcinoma of the uterine cervix (pT2bN1M1). Distant metastasis was assessed to the left supraclavicular lymph node. The level of neuron-specific enolase (NSE) was determined using serum on the day of surgery, and it was found to be 58.6 ng/mL. Because the lesions remained in the para-aortic lymph nodes, she was started on 6 cycles of etoposide + cisplatin (EP) therapy (E: 100 mg/m2, days 1–3; P: 80 mg/m2, day 1), based on the treatment for small cell lung cancer, which she tolerated well. After 6 cycles of EP, CT scans revealed that the para-aortic lymph node lesions were decreasing in size, which we assessed as a partial response to the treatment and then followed up at stated intervals. At 3 months after chemotherapy, her NSE level had increased, and CT scans showed an increase in the size of the para-aortic lymph node lesions (Fig. 3a), for which recurrence was diagnosed.\n\nTC + Bev was administered (T: 180 mg/m2; C: AUC = 6; Bev: 15 mg/kg). She showed some adverse chemotherapy effects, including pancytopenia, hypertension, and urine protein. After 6 cycles of chemotherapy, the lesions had partially responded to the treatment, and after 2 more cycles, they had completely responded. In total, 8 cycles of chemotherapy were administered. CT scans revealed that the para-aortic lymph node lesions had diminished (Fig. 3b) and the patient's NSE level had normalized. The patient is currently alive at 24 months after the TC + Bev therapy was completed, and no sign of recurrence has been observed.\n\nDiscussion\nSmall cell carcinoma is a fast-growing tumor with neuroendocrine differentiation that usually occurs in the lungs. In Japan, small cell carcinoma of the uterine cervix is very rare, accounting for only 1.3% of uterine cervical carcinomas [1]; therefore, it is difficult to conduct a prospective study. The poor prognosis is because of early lymph node development, distant organ metastases, and vascular invasion, which are risk factors for recurrence [2, 3]. The first symptom is usually postmenopausal bleeding. Radical hysterectomy with adjuvant chemotherapy or chemoradiation has improved survival [2, 11]. However, because no effective therapy has been established, we often follow the treatment regimens for small cell lung cancer or squamous cell carcinoma of the uterine cervix, which include cisplatin and etoposide [5, 6]. It is more difficult to treat recurrent small cell carcinoma, and no consensus has been reached.\n\nThe GOG 240 study revealed that bevacizumab along with chemotherapy (paclitaxel + cisplatin [TP] or paclitaxel + topotecan) prolonged OS with recurrent/persistent or advanced cervical cancer. The researchers randomly assigned 452 patients to chemotherapy with or without bevacizumab. Chemotherapy with bevacizumab was associated with increased OS and increased progression-free survival. The response rate was markedly higher among those patients who received bevacizumab than among those who did not (relative probability of a response, 1.35; 95% CI, 1.08–1.68; p = 0.008) [9]. On the basis of that study, Godoy-Ortiz et al. [10] compared the efficacy and safety of chemotherapy with bevacizumab with their clinical patients and demonstrated the efficacy of bevacizumab as part of first-line treatment for advanced cervical cancer.\n\nFrumovitz et al. [12] retrospectively analyzed 34 women with recurrent small cell carcinoma of the uterine cervix who received chemotherapy as the primary therapy; 13 received topotecan, paclitaxel, and bevacizumab for recurrence, and 21 received another chemotherapy that was primarily platinum with or without a taxane. The median progression-free survival was 7.8 months for treatment with topotecan, paclitaxel, and bevacizumab and 4.0 months for the other group (HR, 0.21; 95% CI, 0.09–0.54; p = 0.001). The median OS was 9.7 months for treatment with topotecan, paclitaxel, and bevacizumab and 9.4 months for the other group (HR, 0.53; 95% CI, 0.23–1.22, p = 0.13). In the topotecan, paclitaxel, and bevacizumab group, 3 patients (23%) showed a complete response. To our knowledge, no studies except those described have focused on the effectiveness of combined chemotherapy with bevacizumab for recurrent small cell carcinoma [11].\n\nIn Japan, combined chemotherapy with topotecan is not widely used, and TC or TP is more common for gynecological cancers. Hirasawa et al. [13] reported on a patient with recurrent refractory small cell carcinoma of the uterine cervix for whom combined therapy with TP + Bev was effective. After postoperative adjuvant chemotherapy with EP and radiation therapy, multiple liver metastases were detected, which indicated refractory disease. That patient received TP + Bev, and is currently alive at 16 months after recurrence was detected.\n\nIn our case, we administered TC + Bev to treat recurrent small cell carcinoma of the uterine cervix. TC is a relevant regimen, and we are accustomed to TC use in terms of adverse effects or management. The JCOG0505 trial showed that TC was not inferior to TP in metastatic or recurrent cervical cancer [14]. After 6 cycles of this combined therapy, the size of the para-aortic lymph nodes was partially reduced, and 2 more cycles achieved a complete response. At present, the para-aortic lesions are no longer detectable.\n\nA limited number of case reports have suggested the effectiveness of bevacizumab, but no studies have reported that bevacizumab + TC or TP prolonged the prognosis of small cell carcinoma of the uterine cervix. Bevacizumab therapy should be considered as a potentially beneficial therapy for recurrent small cell carcinoma of the uterine cervix.\n\nStatement of Ethics\nTo report this case, we obtained written consent from the patient.\n\nDisclosure Statement\nThe authors declare that they have no conflicts of interest.\n\nFunding Sources\nWe did not receive any funding for this report.\n\nAuthor Contributions\nY.N. wrote this manuscript; S.T. and N.Y. revised the manuscript; S.S. is the attending doctor of this patient; S.S., H.K., and F.K. supervised this article.\n\nAcknowledgements\nWe sincerely thank all the members of the Department of Obstetrics and Gynecology, Nagoya University Hospital.\n\nFig. 1 Computed tomography findings at the first diagnosis. Para-aortic lymph nodes were enlarged (arrows). a Sagittal plane. b Coronal plane.\n\nFig. 2 Histological findings in the uterine cervix. a, b A prevalent solid pattern composed of small cells with hyperchromatic nuclei may be seen. HE. a ×100. b ×400. Scale bars, 100 μm. c Immunohistochemical staining for CD56. ×400. Scale bar, 100 μm. d Immunohistochemical staining for chromogranin A. ×400. Scale bar, 100 μm.\n\nFig. 3 Computed tomography (CT) findings. a The size of the para-aortic lymph nodes was increased (arrow) at 3 months after etoposide + cisplatin therapy. Because of the lowering of renal function, only plain CT was successful. b The para-aortic lymph nodes have diminished (arrow) at 18 months after paclitaxel, carboplatin, and bevacizumab combination therapy.\n==== Refs\nReferences\n1 Nagase S Ohta T Takahashi F Enomoto T 2017 Committee on Gynecologic Oncology of the Japan Society of Obstetrics and Gynecology Annual report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology: annual patients report for 2015 and annual treatment report for 2010 J Obstet Gynaecol Res 2019 45 (2) 289 98 30426591 \n2 Cohen JG Kapp DS Shin JY Urban R Sherman AE Chen LM Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients Am J Obstet Gynecol 2010 203 (4) 347.e1 6 20579961 \n3 Viswanathan AN Deavers MT Jhingran A Ramirez PT Levenback C Eifel PJ Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence Gynecol Oncol 2004 93 (1) 27 33 15047210 \n4 Kuji S Hirashima Y Nakayama H Nishio S Otsuki T Nagamitsu Y Diagnosis, clinicopathologic features, treatment, and prognosis of small cell carcinoma of the uterine cervix; Kansai Clinical Oncology Group/Intergroup study in Japan Gynecol Oncol 2013 129 (3) 522 7 23480872 \n5 Gardner GJ Reidy-Lagunes D Gehrig PA Neuroendocrine tumors of the gynecologic tract: a Society of Gynecologic Oncology (SGO) clinical document Gynecol Oncol 2011 122 (1) 190 8 21621706 \n6 Satoh T Takei Y Treilleux I Devouassoux-Shisheboran M Ledermann J Viswanathan AN Gynecologic Cancer InterGroup (GCIG) consensus review for small cell carcinoma of the cervix Int J Gynecol Cancer 2014 24 (9 Suppl 3) S102 8 25341572 \n7 Leung DW Cachianes G Kuang WJ Goeddel DV Ferrara N Vascular endothelial growth factor is a secreted angiogenic mitogen Science 1989 246 (4935) 1306 9 2479986 \n8 Ferrara N Hillan KJ Gerber HP Novotny W Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer Nat Rev Drug Discov 2004 3 (5) 391 400 15136787 \n9 Tewari KS Sill MW Long HJ 3rd Penson RT Huang H Ramondetta LM Improved survival with bevacizumab in advanced cervical cancer N Engl J Med 2014 370 (8) 734 43 24552320 \n10 Godoy-Ortiz A Plata Y Alcaide J Galeote A Pajares B Saez E Bevacizumab for recurrent, persistent or advanced cervical cancer: reproducibility of GOG 240 study results in “real world” patients Clin Transl Oncol 2018 20 (7) 922 7 29222647 \n11 Monk BJ Tewari KS Koh WJ Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions J Clin Oncol 2007 25 (20) 2952 65 17617527 \n12 Frumovitz M Munsell MF Burzawa JK Byers LA Ramalingam P Brown J Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix Gynecol Oncol 2017 144 (1) 46 50 27823771 \n13 Hirasawa T Kajiwara H Machida H Iida T Ikeda M Shida M Recurrent small cell carcinoma of the uterine cervix responding to combined therapy with paclitaxel, cisplatin, and bevacizumab: a case report Tokai J Exp Clin Med 2018 43 (3) 81 4 30191540 \n14 Nishio S Kitagawa R Shibata T Yoshikawa H Konishi I Prognostic factors from a randomized phase III trial of paclitaxel and carboplatin versus paclitaxel and cisplatin in metastatic or recurrent cervical cancer: Japan Clinical Oncology Group (JCOG) trial: JCOG0505-S1 Cancer Chemother Pharmacol 2016 78 (4) 785 90 27553435\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Bevacizumab; Cervical cancer; Small cell carcinoma",
"medline_ta": "Case Rep Oncol",
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"title": "Complete Response of Recurrent Small Cell Carcinoma of the Uterine Cervix to Paclitaxel, Carboplatin, and Bevacizumab Combination Therapy.",
"title_normalized": "complete response of recurrent small cell carcinoma of the uterine cervix to paclitaxel carboplatin and bevacizumab combination therapy"
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"abstract": "OBJECTIVE\nEosinophilic pneumonia (EP) is an important subset of patients who present with pulmonary infiltrates and eosinophilia (PIE). EP is classified by chronicity and etiology and drug-induced EP is the main cause of secondary EP. The primary goal of this review was to examine all the case reports published since the syndrome was defined in 1990. It remains unclear whether acute or chronic EP (AEP or CEP) represent different diseases, and the secondary goal of this review is to determine if there are factors that may help distinguish these 2 entities.\n\n\nMETHODS\nPubMed (MEDLINE and Medical Subject Headings) was searched for case reports of drug-induced EP or PIE syndrome published between 1990 and 2017. Case reports were only included if the diagnostic criteria for AEP or CEP were fulfilled. For each case, data were extracted pertaining to age, sex, type of medication associated with the disease, time from the onset of symptoms to diagnosis, eosinophil counts in the blood, eosinophil fractions in bronchoalveolar lavage (BAL) fluid, initial chest radiograph and computed tomography results, use of mechanical ventilation, and use of steroid treatment and recurrence.\n\n\nRESULTS\nWe found 196 case reports describing drug-induced EP. The leading cause was daptomycin. From our review, we found that AEP is more common in younger patients with no gender preference. Eosinophilia in the blood at the time of diagnosis characterized only the CEP patients (80% in CEP vs. 20% in AEP). Abnormal findings on radiographic imagine was similar in both syndromes. A significant portion of AEP patients (20%) presented with acute respiratory failure requiring mechanical ventilation. Most patients with EP were treated with steroids with a higher rate of relapse observed in patients with CEP.\n\n\nCONCLUSIONS\nAEP is a much more fulminant and severe disease than the gradual onset and slowly progressive nature of CEP. The pathogenesis of AEP and CEP remains unclear. However, there is significant clinical overlap among AEP and CEP that are associated with drug toxicity, suggesting the possibility that AEP and CEP are distinct clinical presentations that share a common pathogenic pathway.",
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"authors": "Bartal|Carmi|C|;Sagy|Iftach|I|;Barski|Leonid|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D012460:Sulfasalazine; D019804:Mesalamine; D008911:Minocycline; D017576:Daptomycin",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29369189MD-D-17-0489010.1097/MD.0000000000009688096886700Research ArticleSystematic Review and Meta-AnalysisDrug-induced eosinophilic pneumonia A review of 196 case reportsBartal Carmi MD, MHA∗Sagy Iftach MDBarski Leonid MDDalar. Levent Internal Medicine Division, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.∗ Correspondence: Carmi Bartal, Internal Medicine Division, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel (e-mail: carmibtl@gmail.com).1 2018 26 1 2018 97 4 e96888 8 2017 30 12 2017 2 1 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This 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\nBackground and objective:\nEosinophilic pneumonia (EP) is an important subset of patients who present with pulmonary infiltrates and eosinophilia (PIE). EP is classified by chronicity and etiology and drug-induced EP is the main cause of secondary EP. The primary goal of this review was to examine all the case reports published since the syndrome was defined in 1990. It remains unclear whether acute or chronic EP (AEP or CEP) represent different diseases, and the secondary goal of this review is to determine if there are factors that may help distinguish these 2 entities.\n\nMethods:\nPubMed (MEDLINE and Medical Subject Headings) was searched for case reports of drug-induced EP or PIE syndrome published between 1990 and 2017. Case reports were only included if the diagnostic criteria for AEP or CEP were fulfilled. For each case, data were extracted pertaining to age, sex, type of medication associated with the disease, time from the onset of symptoms to diagnosis, eosinophil counts in the blood, eosinophil fractions in bronchoalveolar lavage (BAL) fluid, initial chest radiograph and computed tomography results, use of mechanical ventilation, and use of steroid treatment and recurrence.\n\nResults:\nWe found 196 case reports describing drug-induced EP. The leading cause was daptomycin. From our review, we found that AEP is more common in younger patients with no gender preference. Eosinophilia in the blood at the time of diagnosis characterized only the CEP patients (80% in CEP vs. 20% in AEP). Abnormal findings on radiographic imagine was similar in both syndromes. A significant portion of AEP patients (20%) presented with acute respiratory failure requiring mechanical ventilation. Most patients with EP were treated with steroids with a higher rate of relapse observed in patients with CEP.\n\nConclusion:\nAEP is a much more fulminant and severe disease than the gradual onset and slowly progressive nature of CEP. The pathogenesis of AEP and CEP remains unclear. However, there is significant clinical overlap among AEP and CEP that are associated with drug toxicity, suggesting the possibility that AEP and CEP are distinct clinical presentations that share a common pathogenic pathway.\n\nKeywords\nblood eosinophiliadrug inducedeosinophilic pneumoniaseverityOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nEosinophilic pneumonia (EP), also known as pulmonary infiltrates with eosinophilia (PIE syndrome), is a rare and heterogeneous syndrome that is classified according to chronicity and etiology. This syndrome, which was first described in 1989, may be classified as acute EP (AEP) or chronic EP (CEP) and may be due to primary (idiopathic) or secondary causes.[1] The currently used classification system of EP was described by Allen and Davis in 1994.[2] There is some overlap in the characteristics of these 2 syndromes, including eosinophilic infiltration of the pulmonary parenchyma and clinical symptoms such as dry cough, dyspnea, chest pain, and fever. AEP is characterized by symptoms lasting less than 1 month and usually less than 1 week.[3] Imaging findings typically include bilateral reticular ground-glass opacities that expand as the disease progresses. Patients with AEP generally present with neutrophilic leukocytosis without an elevated eosinophilic fraction. Differential cell counts of bronchoalveolar lavage (BAL) fluid shows >25% of all white blood cells in BAL fluid are eosinophils in both syndromes. Lung biopsy is rarely necessary to make the diagnosis of EP. In contrast to AEP, CEP has a gradual onset and the average time from onset to diagnosis is 5 months. The clinical features of CEP include cough (42%), which is usually productive, fever (67%), and dyspnea (80%) as well as B symptoms such as weight loss (60%) and night sweats (47%). Peripheral blood eosinophilia is commonly present and the absolute eosinophil count is usually greater than 1000 cells/μL. Additionally, total immunoglobulin E (IgE) levels are increased in 50% of the patients.[4] Laboratory results commonly indicate a chronic inflammatory process with thrombocytosis and an elevated C-reactive protein level or sedimentation rate. Although there is some overlap, the imaging presentation of AEP is somewhat different and includes bilateral peripheral or pleural-based nonsegmental consolidative opacities and with less prevalence, ground glass opacities. These opacities are located in the upper lung zones in 50% of patients and are migratory in 25% of patients. Reticulation and nodules are not typical in cases of AEP, and the BAL fluid eosinophil fraction is almost always >25% and is >40% in 80% of cases.[5]\n\nThe main difference between AEP and CEP is that AEP usually has a fulminant presentation with severe hypoxemia. In some studies, more than 50% of patients with AEP required mechanical ventilation.[4]\n\nThe main causes of secondary EP include drugs and toxins. Less common causes include parasitic or fungal infection, transpulmonary passage of helminths (usually Ascaris species) and Loeffler syndrome. In this review, we analyze case reports of drug-induced EP published since 1990 to examine the hypothesis that AEP and CEP are different clinical entities.\n\n2 Material and methods\nEthics approval was not sought for this retrospective review of previously published case reports.\n\nPubMed (MEDLINE and Medical Subject Headings) was searched for all case reports describing drug-induced EP or drug-induced PIE syndrome published between 1990 and 2017. We excluded cases of toxin-induced EP, case reports for which the full text could not be acquired and duplicate cases. For each case, we collected data regarding age, sex, type of medication associated with the disease, time from onset of symptoms to diagnosis, eosinophil counts in the blood, eosinophil fraction in BAL fluid, initial chest radiograph and computed tomography results, use of mechanical ventilation, and use of steroid treatment and recurrence. Case reports were only included if the diagnostic criteria for AEP or CEP were fulfilled.\n\nThe diagnostic criteria for EP include respiratory complaints (dyspnea/cough/hypoxemia), pulmonary parenchymal infiltrates, peripheral blood eosinophilia, a BAL fluid eosinophil fraction >25% or histopathological results from a transbronchial biopsy and a negative work-up for other causes of peripheral blood eosinophilia.\n\nAEP was defined by the presence of symptoms for <1 month at the time of diagnosis. If the symptoms began > 1 month before the time of diagnosis, we defined the syndrome as CEP. EP cases were defined as severe if patients had an oxygen saturation (SpO2) < 88% on room air and a respiratory rate >30 breaths/min, were admitted to the intensive care unit and required invasive or noninvasive mechanical ventilation. Moderate cases of EP were defined by dyspnea, SpO2 between 88% and 92% on room air and a respiratory rate between 20 and 30 breaths/min. Mild cases of EP were defined by dyspnea, SpO2 >92% on room air and a respiratory rate <20 breaths/min. For statistical comparisons, we divided all of the case reports into 2 groups (AEP and CEP).\n\n2.1 Statistical analysis\nStatistical analysis was conducted using SPSS version 23.0 (IBM Corporation, Armonk, NY). We investigated demographic, clinical, imaging, and therapeutic differences between cases of AEP and CEP. Descriptive statistics (frequencies, means, and standard deviations) were used to characterize the study sample. The χ2 statistics and independent samples t test were used to compare categorical and continuous variables between patients with AEP and CEP. Statistical significance was set at P values < .05.\n\n3 Results\nDrug-induced EP is a rare condition. In total, we found only 228 cases reported between 1990 and March of 2017. Ultimately, 196 full-text case reports met the criteria to be included in our analysis.\n\n3.1 Associated drugs\nMany medications were implicated in drug-induced EP (Table 1) and the most commonly cited drugs were daptomycin, mesalamine, sulfasalazine, and minocycline.\n\nTable 1 Drugs associated with eosinophilic pneumonia.\n\n3.2 Clinical and laboratory findings\nTable 2 shows a comparison of clinical and laboratory findings between the 2 groups. AEP was more commonly reported in the medical literature than CEP. The prevalence of syndromes was not significantly different between the sexes. The mean and median ages were significantly lower in the AEP group compared with the CEP group (48 and 38 years for the AEP group versus 56 and 44 years for the CEP group). The average time from the onset of symptoms to diagnosis was 9.8 days for the AEP group and 4.14 months for the CEP group. Peripheral blood eosinophilia was common in both types of EP (69% of cases with AEP and 77.6% of cases with CEP). There was no significant difference in the peripheral blood eosinophil count between the AEP and CEP groups (1232 cells/μL in the AEP group and 1490 cells/μL in the CEP group).\n\nTable 2 Demographic, clinical, and laboratory results of the acute eosinophilic pneumonia and chronic eosinophilic pneumonia groups.\n\nBAL was performed in only 70% of the cases in this study. Significantly more patients with CEP who underwent BAL had an eosinophil fraction >25% in the BAL fluid compared with the AEP group (95% vs 80%; P = .02).\n\n3.3 Imaging\nTable 3 compares the imaging findings between the AEP and CEP groups. The 2 groups shared some imaging features in common. In the AEP group, 30% of cases had bilateral peripheral infiltrates with segmental consolidation. The second most common imaging finding in the AEP group was diffuse reticular or interstitial findings (26.7%), which were detected in only 14.7% of patients with CEP. Diffuse ground-glass infiltrates were detected in 11% of patients with AEP but in none of the patients with CEP. In CEP, the main imaging finding was bilateral peripheral segmental infiltrates, observed in 49% of patients. Wandering peripheral consolidations were seen in 10% of patients with CEP but in none of the patients with AEP. A few patients in each group presented with pleural effusion in addition to parenchymal findings (2 cases of AEP and 3 cases of CEP).\n\nTable 3 Comparison of imaging findings between patients with acute and chronic eosinophilic pneumonia.\n\n3.4 Severity of the clinical presentation\nA comparison of the severity of the clinical presentation between the 2 groups is summarized in Table 4. Among the patients with CEP, 96.7% presented with mild severity and mild respiratory distress. Conversely, 20.8% of AEP patients presented with severe respiratory distress and 19.2% required mechanical ventilation. Six patients with AEP who required mechanical ventilation presented with acute respiratory distress syndrome (ARDS), which was diagnosed radiographically. From 1994 to 2012, the diagnosis of ARDS was based on the American–European Consensus Conference criteria[6] and the Berlin definition of ARDS has been used since 2012.[7]\n\nTable 4 Comparison of severity, use of steroid treatment, and recurrence.\n\nAs expected, significantly more patients were treated with steroids in the AEP group compared with the CEP group (82.2% vs 65.5%; P = .015). In the 34.5% of CEP patients who were not treated with steroids, treatment consisted of cessation of the implicated medication. Furthermore, the recurrence rate was significantly higher in patients who were treated with steroids than in those not treated with steroids (6.5% vs 3.7%; P = .027). Recurrence has been defined by the authors as recurrent symptoms and the need for re-treatment at any time after stopping initial treatment.\n\n4 Discussion\nAlthough EP is a rare disease, we found that almost every family of medication was implicated. Moreover, we found a higher prevalence among a few pharmacological families such as antibiotics,[8,9] nonsteroidal anti-inflammatory drugs[10,11] and antiepileptic drugs,[12] which suggests the possibility that there is a connection between the pathogenesis of EP and the mechanism of action of those commonly used medications.[10,13]\n\n4.1 Pathogenesis\nThe cause of AEP and CEP remains unknown. It is also unclear whether these 2 entities share common pathophysiological mechanisms. One theory suggests that AEP is a hypersensitivity reaction to an unidentified inhaled antigen.[14] This theory has been strengthened by several reports regarding inhaled cigarette smoke,[15] airborne sand in military personnel deployed in Iraq[16] and other environmental factors.\n\nWhile the triggering factor of AEP is unknown, this syndrome is currently believed to be the result of eosinophilic-specific chemoattractants, including eotaxin, T-cell-expressed chemokines, and interleukin-5 released from T2 lymphocytes. The role of serotonin in the pathophysiology of asthma is well established, as 5-HT2A stimulates different signaling pathways and regulates cytokine release in airway epithelial cells.[17] 5-HT2A has also been reported to play a role as a mediator of inflammation in the immune response outside the central nervous system.[18] Both serotonin and eotaxin have been recently described as having an eosinophil chemoattractant profile, which may explain the connection between the pathogenesis of AEP and CEP and antipsychotic and antiepileptic drugs.[12]\n\nOther mechanisms have also been suggested for drug-induced EP. Certain drugs, especially nitrofurantoin[19] and daptomycin,[11] have been reported to cause oxidant injury. Direct cytotoxic effects on alveolar capillary endothelial cells, injury mediated by deposition of phospholipids within the cell and immune-mediated injury causing symptoms of systemic lupus erythematosus have also been reported.[20] Mesalamine, one of the leading causes of drug-induced EP, is believed to cause damage through immune-mediated alveolitis, as evidenced by lymphocytic infiltration.[21]\n\nMoreover, amiodarone toxicity of the lung has been extensively investigated. Amiodarone toxicity may present as CEP, and some of the mechanisms of injury could explain how other drugs induce EP. Amiodarone toxicity is suggested to result from a combination of different mechanisms, such as (i) a “cytotoxic” effect to type-II pneumocytes as well as other cells of the lung parenchyma, such as inflammatory cells, endothelial cells, and fibroblasts; (ii) an “immune”-mediated mechanism in genetically predisposed patients and (iii) activation of the angiotensin enzyme system.[22,23]\n\nThese toxic mechanisms lead to a disruption of the lysosomal membranes by amiodarone molecules through protein C activation and the subsequent release of toxic oxygen radicals; oxygen radicals may induce activation of the caspase pathways and lead to apoptosis of lung epithelial cells. Furthermore, over the past decade, in vitro studies in both primary cultures of rat type-II pneumocytes and the human A549 alveolar epithelial cell line have shown that amiodarone induces alveolar epithelial cell apoptosis that is abrogated by antagonists of angiotensin II.[24–27]\n\nBoth the “cytotoxic” and the “immune” pathophysiological mechanisms could either independently or in combination lead to different forms of lung injury. In this review, we were unable to elucidate the main pathophysiological mechanism of EP syndromes; however, the evidence supports a multifactorial etiology.\n\n4.2 Demographic features\nA few intriguing clinical and laboratory results were observed in our investigation.\n\nAEP has been reported to occur twice as often in men than in women[28,29] and in CEP the ratio between men and women is reported to be equal.[30] However, we did not observe these trends in our review. On the contrary, there was a trend toward male predominance among the patients with CEP and cases of AEP were equally distributed between men and women. As previously reported, AEP patients tend to be younger (20–40 years old),[28,29] which is consistent with our findings.\n\n4.3 Clinical features\nAEP is a severe and dramatic syndrome. This explains the early detection (average of 9.8 days after the onset of symptoms). In comparison, the mean time to diagnosis of CEP is 4.14 months. It has been reported that most patients with AEP are diagnosed within the first week, but the longer time to diagnosis of CEP emphasizes the difficulty in diagnosing this syndrome in an outpatient setting. The severity of AEP is evidenced by the fact that 21% of patients had acute hypoxemic respiratory failure and 19.8% required mechanical ventilation. None of the patients with CEP had respiratory failure and 97% had only mild respiratory symptoms. Our results are consistent with those of Philit et al,[31] who reported that 63% of patients had respiratory failure.\n\n4.4 Imaging findings\nAfter analyzing the radiographic findings, there was some degree of overlap between the 2 syndromes; however, we were unable to find a common pattern. Peripheral segmental/patchy bilateral infiltrates were more commonly seen in patients with CEP than in those with AEP (49% vs 30.4%), and this result was close to statistical significance (P = .06). These infiltrates have been previously described as being prototypical of CEP.[32] In addition to peripheral segmental/patchy bilateral infiltrates, reticular/interstitial findings have been described significantly more often in cases of AEP than in cases of CEP (26.7% vs 14.7%; P <.025). Pleural effusion with parenchymal lesions was rarely found in either group (2.2% of AEP cases and 3.3% of CEP cases). Diffuse ground-glass opacities and an ARDS presentation were exclusively found in the AEP group (11% and 4.4%, respectively). Wandering infiltrates in both lungs is a unique finding of EP and was present in similar rates in both groups.\n\n4.5 Eosinophil counts\nOur data showed that peripheral blood eosinophilia was common in the initial presentation of CEP (77% of patients) with an average absolute eosinophil count of 1490/μL. In contrast, patients with AEP generally presented with an initial neutrophilic leukocytosis with no elevated fraction of eosinophils. As the disease progresses, the eosinophil count increases.[3,33] In this study, only 20.7% of patients with AEP had eosinophil counts >500 cells/μL and the average among those with initial peripheral blood eosinophilia was 1390 cells/μL.\n\nThe diagnostic criterion of an eosinophil fraction >25% in the BAL fluid was observed in both syndromes, but significantly more in AEP group (95.6% of cases in the AEP group and 80% of cases in the CEP group). No case report could define EP without the presence of either peripheral blood eosinophilia or an elevated eosinophil fraction in the BAL fluid.\n\n4.6 Treatment and recurrence\nThere are no guidelines for treating these EP syndromes with steroids. The cure rate for both AEP and CEP was very high: 96.6% in the AEP group and 90.1% in the CEP group. In this study, the recurrence rate was significantly higher in the CEP group, which is similar to what has been previously described.[34,35] In the AEP group, recurrence was rare and the rate was lower than that anticipated based on previous descriptions of a small series of cases.[36] Upon analyzing the use of steroid treatment, we found that 35% of CEP patients were treated only with cessation of the instigating drug, and the associated recurrence rate was only 3.3%. The patients with CEP who were treated with steroids (65%) had a higher recurrence rate (6.5%) and this difference was statistically significant. In the AEP group, the recurrence rate was much lower (3.7%) and most of the patients were treated with steroids (82%). There was no recurrence among AEP patients who were not treated with steroids. One possible explanation for this finding is that the patients with AEP who were not treated with steroids had a milder disease course.\n\nUpon comparing patients treated with steroids in both groups, there was a significantly higher recurrence rate in the CEP group. It is logical to assume that the severity of the initial clinical presentation led to earlier steroid treatment, but the higher recurrence rate among patients with CEP treated with steroids may be due to premature discontinuation of steroid treatment. The optimal duration of steroid treatment for EP is unknown, but the more common approach is to slowly taper steroids over 2 to 3 months.[33,34] Although steroid treatment resulted in a very high cure rate and a low recurrence rate in CEP cases, our data analysis revealed that cessation of the implicated drug resulted in no further need for steroid treatment. Steroid-sparing treatment with omalizumab may also be used in patients with recurrent disease if IgE levels are elevated; omalizumab has been recommended as a second-line treatment in patients with recurrence who did not improve with steroid treatment.[37] Because most case reports did not report data regarding IgE levels and because the correlation between IgE levels and eosinophil counts has not been examined in a large series, we cannot currently support the use of treatments based on IgE levels.\n\n4.7 Limitations\nDue to the rarity of this syndrome, very few cases reports have been published during the past few decades, thus restricting the statistical power of this analysis. In addition, the heterogeneity of the published case reports decreases the quality of this data analysis.\n\n5 Conclusions\nIn conclusion, there are more commonalities than differences between AEP and CEP. There is no doubt that AEP is a much more severe disease than CEP. Nevertheless, similarities in the blood eosinophil counts and the eosinophil fractions in BAL fluid, radiographic manifestations, and response rates to steroid treatment raises the possibility that both syndromes are on the same clinical spectrum. It is quite possible that, although they are generated by different drugs, both AEP and CEP share a common pathogenic pathway. Therefore, defining EP as AEP or CEP may have no practical use and only the severity of the EP presentation would determine the treatment. Most patients with a severe presentation of EP required mechanical ventilation, therefore, patients who are suspected of having severe EP should be monitored in an intensive care unit. On the basis of our findings, we recommend using a course of steroids with slow tapering over 2 to 3 months for all patients with EP and steroid treatment for 9 to 12 months for recurrent cases.\n\nRegardless of age or sex, drug-induced EP should be suspected in any patient who has recently started taking a new medication and presents with new-onset dyspnea, bilateral infiltrates on chest radiograph, and peripheral blood eosinophilia with a negative eosinophilia work-up.\n\nAcknowledgments\nThe authors have no sources of funding to declare. We would like to thank Editage (www.editage.com) for English language editing.\n\nAbbreviations: AEP = acute eosinophilic pneumonia, ARDS = acute respiratory distress syndrome, BAL = bronchoalveolar lavage, CEP = chronic eosinophilic pneumonia, EP = eosinophilic pneumonia, PIE = pulmonary infiltrates with eosinophilia, SpO2 = oxygen saturation.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Allen JN Pacht ER Gadek JE \nAcute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure . N Engl J Med \n1989 ;321 :569 –74 .2761601 \n[2] Allen JN Davis WB \nEosinophilic lung disease . Am J Respir Crit Care Med \n1994 ;150 :1423 –38 .7952571 \n[3] Katz U Shoenfeld Y \nPulmonary eosinophilia . Clin Rev Allergy Immunol \n2008 ;34 :367 –71 .18197481 \n[4] Jhun BW Kim SJ Kim K \nOutcomes of rapid corticosteroid tapering in acute eosinophilic pneumonia patients with initial eosinophilia . Respirology \n2015 ;20 :1241 –7 .26333129 \n[5] Rossi SE Erasmus JJ McAdams HP \nPulmonary drug toxicity: radiologic and pathologic manifestations . Radiographics \n2000 ;20 :1245 –59 .10992015 \n[6] Bernard GR Artigas KL Carlet J \nReport of the American–European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee . J Crit Care \n1994 ;9 :72 –81 .8199655 \n[7] Definition Task Force ARDS Ranieri VM Rubenfeld GD \nAcute respiratory distress syndrome: the Berlin Definition . JAMA \n2012 ;307 :2526 –33 .22797452 \n[8] Klerkx S Pat K Wuyts W \nMinocycline induced eosinophilic pneumonia: case report and review of the literature . Acta Clin Belg \n2009 ;64 :349 –54 .19810425 \n[9] Hirai J Hagahara M Haranaga S \nEosinophilic pneumonia caused by daptomyc: six cases from two institutions and a review of the literature . J Infect Chemother \n2017 ;23 :245 –9 .28003110 \n[10] Anan E Shirai R Kai N \nAcute eosinophilic pneumonia caused by several drugs including ibuprofen [in Japanese] . Nihon Kokyuki Gakkai Zasshi \n2009 ;47 :443 –7 .19514510 \n[11] Kim HK Lee JH Koh ES \nAcute eosinophilic pneumonia related to a mesalazine suppository . Asia Pac Allergy \n2013 ;3 :136 –9 .23667838 \n[12] Rizos E Tsigkaropoulou E Lambrou P \nRisperidone-induced acute eosinophilic pneumonia . In Vivo \n2013 ;27 :651 –4 .23988901 \n[13] Solomon J Schwarz M \nDrug-, toxin-, and radiation therapy-induced eosinophilic pneumonia . Semin Respir Crit Care Med \n2006 ;27 :192 –7 .16612770 \n[14] Badesch DB King TE JrSchwarz MI \nAcute eosinophilic pneumonia: a hypersensitivity phenomenon? \nAm Rev Respir Dis \n1989 ;139 :249 –52 .2912347 \n[15] Uchiyana H Suda T Nakamura Y \nAlterations in smoking habits are associated with acute eosinophilic pneumonia . Chest \n2008 ;133 :1174 –80 .18263675 \n[16] Shorr AF Scoville SL Cersovsky SB \nAcute eosinophilic pneumonia among US Military personnel deployed in or near Iraq . JAMA \n2004 ;292 :2997 –3005 .15613668 \n[17] Bayer H Müller T Myrtek D \nSerotoninergic receptors on human airway epithelial cells . Am J Respir Cell Mol Biol \n2007 ;36 :85 –93 .16873768 \n[18] Boehme SA Lio FM Sikora L \nCutting edge: serotonin is a chemotactic factor for eosinophils and functions additively with eotaxin . J Immunol \n2004 ;173 :3599 –603 .15356103 \n[19] Kabbara WK Kordahi MC \nNitrofurantoin-induced pulmonary toxicity: a case report and review of the literature . J Infec Public Health \n2015 ;8 :309 –13 .25747822 \n[20] Tanigawa K Sugiyama K Matsuyama H \nMesalazine-induced eosinophilic pneumonia . Respiration \n1999 ;66 :69 –72 .9973695 \n[21] Sviri S Gafanovich I Kramer MR \nMesalamine induced hypersensitivity pneumonitis: a case report and review of the literature . J Clin Gastroenterol \n1997 ;24 :34 –6 .9013348 \n[22] Papiris SA Triantafillidou C Kolilekas L \nAmiodarone: review of pulmonary effects and toxicity . Drug Saf \n2010 ;33 :540 –58 .\n[23] Kosseifi SG Halawa A Bailey B \nReduction of amiodarone pulmonary toxicity in patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers . Ther Adv Respir Dis \n2009 ;3 :289 –94 .19850648 \n[24] Bargout R Jankov A Dincer E \nAmiodarone induces apoptosis of human and rat alveolar epithelial cells in vitro . Am J Physiol Lung Cell Mol Physiol \n2000 ;278 :L1039 –44 .10781436 \n[25] Uhal BD Wang R Laukka J \nInhibition of amiodarone-induced lung fibrosis but not alveolitis by angiotensin system antagonists . Pharmacol Toxicol \n2003 ;92 :81 –7 .12747577 \n[26] Uhal BD Zhang H Abdul-Hafez A \nAmiodarone induces angiotensinogen gene expression in lung alveolar epithelial cells through activation protein-1 . Basic Clin Pharmacol Toxicol \n2007 ;100 :59 –66 .17214612 \n[27] Nikaido A Tada T Nakamura K \nClinical features of the effects of angiotensin system antagonists on amiodarone-induced pulmonary toxicity . Int J Cardiol \n2010 ;140 :328 –35 .19106010 \n[28] Rhee CK Min KH Yim NY \nClinical characteristics and corticosteroid treatment of acute eosinophilic pneumonia . Eur Respir J \n2013 ;41 :402 –9 .22599359 \n[29] Pop-Harman AL Davis WB Allen ED \nAcute eosinophilic pneumomia. A summary of 15 cases and review of the literature . Medicine (Baltimore) \n1996 ;75 :334 –42 .8982150 \n[30] Mochimaru H Kawamoto M Fukuda Y \nClinicopathological differences between acute and chronic eosinophilic pneumonia . Respirology \n2005 ;10 :76 –85 .15691242 \n[31] Philit F Etienne-Mastroïanni B Parrot A \nIdiopathic acute eosinophilic pneumonia: a study of 22 patients . Am J Respir Crit Care Med \n2002 ;166 :1235 –9 .12403693 \n[32] Souza CA Müller NL Johkoh T \nDrug-induced eosinophilic pneumonia: high-resolution CT findings in 14 patients . Am J Radiol \n2006 ;186 :368 –73 .\n[33] Giovannini-Chami L Blanc S Hadchouel A \nEosinophilic pneumonias in children: a review of the epidemiology, diagnosis, and treatment . Pediatr Pulmonol \n2016 ;51 :203 –16 .26716396 \n[34] Naughton M Fahy J FitzGerald MX \nChronic eosinophilic pneumonia. A long-term follow-up of 12 patients . Chest \n1993 ;103 :162 –5 .8031327 \n[35] Kaya H Gümüş S Uçar E \nOmalizumab as a steroid-sparing agent in chronic eosinophilic pneumonia . Chest \n2012 ;142 :513 –6 .22871762 \n[36] Janz DR O’Neal HR JrEly EW \nAcute eosinophilic pneumonia: a case report and review of the literature . Crit Care Med \n2009 ;37 :1470 –4 .19242348 \n[37] Domingo C Pomares X \nCan omalizumab be effective in chronic eosinophilic pneumonia? \nChest \n2013 ;143 :274 .\n\n",
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"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002908:Chronic Disease; D017576:Daptomycin; D004804:Eosinophils; D005260:Female; D006801:Humans; D008297:Male; D019804:Mesalamine; D008875:Middle Aged; D008911:Minocycline; D011657:Pulmonary Eosinophilia; D012460:Sulfasalazine",
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"pubdate": "2018-01",
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"title": "Drug-induced eosinophilic pneumonia: A review of 196 case reports.",
"title_normalized": "drug induced eosinophilic pneumonia a review of 196 case reports"
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"abstract": "To evaluate the uptake of perinatal HIV preventive interventions by the risk of perinatal HIV transmission in mother-infant pairs in a high-HIV prevalence area in the US.\n\n\n\nThis was a retrospective cohort study of mother-infant pairs with perinatal HIV exposure during 2013-2017 managed at a subspecialty pediatric HIV program in Washington, DC. We collected demographic data, maternal HIV history, delivery mode, maternal and infant antiretroviral drug (ARV) use, and infant HIV test results. We compared the uptake of recommended preventive interventions in low-risk (ie, mothers on antiretroviral therapy [ART] with viral suppression) and high-risk (mothers without ART or viral suppression) mother-infant pairs using the Pearson chi-square, Fisher exact, and Wilcoxon rank-sum tests and logistic regression.\n\n\n\nWe analyzed 551 HIV-exposed infants (HEIs) and 542 mothers living with HIV. The majority of mothers received ARVs (95.5%), had HIV RNA ≤1000 copies/mL before delivery (81.9%), and received intrapartum zidovudine (ZDV; 65.5%). The majority of all HEIs were low risk (82.6%) and received postpartum ARVs (98.9%). Among the low-risk infants, 53.2% were delivered via cesarean delivery (CD), and 62.9% and 96.5% were administered intrapartum and postpartum ZDV, respectively. Among high-risk infants, 84.4% were delivered via CD, 78.1% received intrapartum ZDV, and 62.5% received combination ART. Nine high-risk infants acquired HIV perinatally.\n\n\n\nIn an area of high HIV prevalence in the US, a large proportion of low-risk HEIs received intrapartum ZDV and were delivered via CD. We also observed missed opportunities for the prevention of perinatal HIV transmission.",
"affiliations": "Division of Infectious Diseases, Children's National Hospital, Washington, DC; Department of Pediatrics, School of Medicine and Health Sciences, The George Washington University, Washington, DC. Electronic address: wkoay@childrensnational.org.;Columbian College of Arts and Sciences, The George Washington University, Washington, DC; R&D Biostatistics, Abbott US, Abbott Park, IL.;Division of Infectious Diseases, Children's National Hospital, Washington, DC.;Division of Infectious Diseases, Children's National Hospital, Washington, DC.;Department of Pediatrics, School of Medicine and Health Sciences, The George Washington University, Washington, DC; Department of Epidemiology, Milken Institute School of Public Health, The George Washington University, Washington, DC.;MedStar Health Research Institute & Washington Hospital Center, Washington, DC; School of Medicine, Georgetown University, Washington, DC.;Division of Infectious Diseases, Children's National Hospital, Washington, DC; Department of Pediatrics, School of Medicine and Health Sciences, The George Washington University, Washington, DC.;Division of Infectious Diseases, Children's National Hospital, Washington, DC; Department of Pediatrics, School of Medicine and Health Sciences, The George Washington University, Washington, DC; Elizabeth Glaser Pediatrics AIDS Foundation, Washington, DC.",
"authors": "Koay|Wei Li A|WLA|;Zhang|Jiaqi|J|;Manepalli|Krishna V|KV|;Griffith|Caleb J|CJ|;Castel|Amanda D|AD|;Scott|Rachel K|RK|;Ferrer|Kathleen T|KT|;Rakhmanina|Natella Y|NY|",
"chemical_list": "D004279:DNA, Viral",
"country": "United States",
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"doi": "10.1016/j.jpeds.2020.09.041",
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"issn_linking": "0022-3476",
"issue": "228()",
"journal": "The Journal of pediatrics",
"keywords": "antiretroviral treatment; cesarean delivery; infants; mothers; pregnancy",
"medline_ta": "J Pediatr",
"mesh_terms": "D000328:Adult; D004279:DNA, Viral; D005260:Female; D006678:HIV; D015658:HIV Infections; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D015995:Prevalence; D011379:Prognosis; D012189:Retrospective Studies; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "0375410",
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"pages": "101-109",
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"pmid": "32971142",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Prevention of Perinatal HIV Transmission in an Area of High HIV Prevalence in the United States.",
"title_normalized": "prevention of perinatal hiv transmission in an area of high hiv prevalence in the united states"
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"companynumb": "US-VIIV HEALTHCARE LIMITED-US2020GSK261195",
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"abstract": "To investigate efficacy and safety of a single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infected adults.\n\n\n\nPhase-3, randomized, active-controlled, double-blind, international, multicenter, noninferiority study (NCT02431247).\n\n\n\nSeven hundred and twenty-five participants were randomized (1 : 1) to D/C/F/TAF (362) or control (363). The primary objective was to demonstrate noninferiority of D/C/F/TAF vs. control for percentage viral load less than 50 copies/ml (FDA-snapshot analysis) at 48 weeks (10% margin).\n\n\n\nAt week 48, D/C/F/TAF was noninferior to control (91.4 vs. 88.4% achieved viral load <50 copies/ml, respectively; difference 2.7%; 95% CI -1.6 to 7.1; P < 0.0001), with 4.4 vs. 3.3% of patients, respectively, having viral load greater or equal to 50 copies/ml. No treatment-emergent mutations associated with darunavir or TAF/TDF resistance were observed in either group. One patient (D/C/F/TAF) was identified with M184I/V conferring resistance to emtricitabine. Incidences of grades 3 and 4 adverse events (5 vs. 6%), serious adverse events (5 vs. 6%) and adverse event-related discontinuations (2 vs. 4%) were low and similar between groups. Mean decrease in urine protein/creatinine ratio was greater with D/C/F/TAF than control (-22.42 vs. -10.34 mg/g, P = 0.033). Mean percentage change in bone mineral density with D/C/F/TAF vs. control was 0.21 vs. -2.73%, P < 0.0001 (hip), -0.68 vs. -2.38%, P = 0.004 (lumbar spine), and -0.26 vs. -2.97%, P < 0.0001 (femoral neck). Median change from baseline in total cholesterol/HDL-cholesterol ratio was 0.20 vs. 0.08, P = 0.036.\n\n\n\nD/C/F/TAF achieved a high virologic suppression rate (91.4%) and was noninferior to darunavir/cobicistat with F/TDF. D/C/F/TAF also demonstrated the bone and renal safety advantages of TAF in combination with darunavir/cobicistat.",
"affiliations": "The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.;Department of Infection and Immunity, Royal London Hospital and Queen Mary University, Barts Health NHS Trust, London, UK.;Southwest CARE Center, Santa Fe, New Mexico, USA.;Department of Infectious Diseases, St-Louis Hospital APHP, University of Paris Diderot, Paris, France.;Lluita contra la Sida Foundation, Germans Trias i Pujol University Hospital, Barcelona, Spain.;National Institute for Infectious Diseases, L. Spallanzani IRCCS, Rome, Italy.;Southern California Men's Medical Group, Los Angeles, California, USA.;Montpellier University Hospital, Montpellier, France.;Janssen Pharmaceutica NV, Beerse, Belgium.;Janssen Pharmaceutica NV, Beerse, Belgium.;Janssen Pharmaceutica NV, Beerse, Belgium.;Janssen Pharmaceutica NV, Beerse, Belgium.;Janssen Pharmaceutica NV, Beerse, Belgium.;Janssen Pharmaceutica NV, Beerse, Belgium.",
"authors": "Eron|Joseph J|JJ|;Orkin|Chloe|C|;Gallant|Joel|J|;Molina|Jean-Michel|JM|;Negredo|Eugenia|E|;Antinori|Andrea|A|;Mills|Anthony|A|;Reynes|Jacques|J|;Van Landuyt|Erika|E|;Lathouwers|Erkki|E|;Hufkens|Veerle|V|;Jezorwski|John|J|;Vanveggel|Simon|S|;Opsomer|Magda|M|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D004338:Drug Combinations",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000001817",
"fulltext": "\n==== Front\nAIDSAIDSAIDSAIDS (London, England)0269-93701473-5571Lippincott Williams & Wilkins AIDS-D-18-0015010.1097/QAD.000000000000181700006Clinical ScienceA week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients Eron Joseph J. aOrkin Chloe bGallant Joel cMolina Jean-Michel dNegredo Eugenia eAntinori Andrea fMills Anthony gReynes Jacques hVan Landuyt Erika iLathouwers Erkki iHufkens Veerle iJezorwski John iVanveggel Simon iOpsomer Magda ion behalf of the AMBER study group a The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USAb Department of Infection and Immunity, Royal London Hospital and Queen Mary University, Barts Health NHS Trust, London, UKc Southwest CARE Center, Santa Fe, New Mexico, USAd Department of Infectious Diseases, St-Louis Hospital APHP, University of Paris Diderot, Paris, Francee Lluita contra la Sida Foundation, Germans Trias i Pujol University Hospital, Barcelona, Spainf National Institute for Infectious Diseases, L. Spallanzani IRCCS, Rome, Italyg Southern California Men's Medical Group, Los Angeles, California, USAh Montpellier University Hospital, Montpellier, Francei Janssen Pharmaceutica NV, Beerse, Belgium.Correspondence to Professor Chloe Orkin, Department of Infection and Immunity, Royal London Hospital and Queen Mary University, Barts Health NHS Trust, London E1 1BB, UK. E-mail: Chloe.Orkin@bartshealth.nhs.uk17 7 2018 02 7 2018 32 11 1431 1442 6 2 2018 8 3 2018 Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Objectives:\nTo investigate efficacy and safety of a single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infected adults.\n\nDesign:\nPhase-3, randomized, active-controlled, double-blind, international, multicenter, noninferiority study (NCT02431247).\n\nMethods:\nSeven hundred and twenty-five participants were randomized (1 : 1) to D/C/F/TAF (362) or control (363). The primary objective was to demonstrate noninferiority of D/C/F/TAF vs. control for percentage viral load less than 50 copies/ml (FDA-snapshot analysis) at 48 weeks (10% margin).\n\nResults:\nAt week 48, D/C/F/TAF was noninferior to control (91.4 vs. 88.4% achieved viral load <50 copies/ml, respectively; difference 2.7%; 95% CI −1.6 to 7.1; P < 0.0001), with 4.4 vs. 3.3% of patients, respectively, having viral load greater or equal to 50 copies/ml. No treatment-emergent mutations associated with darunavir or TAF/TDF resistance were observed in either group. One patient (D/C/F/TAF) was identified with M184I/V conferring resistance to emtricitabine. Incidences of grades 3 and 4 adverse events (5 vs. 6%), serious adverse events (5 vs. 6%) and adverse event-related discontinuations (2 vs. 4%) were low and similar between groups. Mean decrease in urine protein/creatinine ratio was greater with D/C/F/TAF than control (−22.42 vs. −10.34 mg/g, P = 0.033). Mean percentage change in bone mineral density with D/C/F/TAF vs. control was 0.21 vs. −2.73%, P < 0.0001 (hip), −0.68 vs. −2.38%, P = 0.004 (lumbar spine), and −0.26 vs. −2.97%, P < 0.0001 (femoral neck). Median change from baseline in total cholesterol/HDL-cholesterol ratio was 0.20 vs. 0.08, P = 0.036.\n\nConclusion:\nD/C/F/TAF achieved a high virologic suppression rate (91.4%) and was noninferior to darunavir/cobicistat with F/TDF. D/C/F/TAF also demonstrated the bone and renal safety advantages of TAF in combination with darunavir/cobicistat.\n\nKeywords\ndarunavir/cobicistat/emtricitabine/tenofovir alafenamideefficacyonce dailysafetysingle-tablet HIV-1 regimenOPEN-ACCESSTRUE\n==== Body\nIntroduction\nCombination antiretroviral therapy (ART) regimens for HIV-1-infected patients are now more effective, safe and convenient. However, treatment adherence, emergence of resistant virus with virologic failure, and tolerability remain important challenges [1]. Convenient once-daily, single-tablet regimens (STR) can facilitate treatment adherence and improve treatment effectiveness [2,3].\n\nSince its initial approval in 2006, substantial clinical trial data and clinical experience with darunavir have accumulated, demonstrating the potent and durable virologic response, high genetic barrier to resistance, and favorable safety profile in ART-naive, HIV-1-infected patients [4,5]. A substantial proportion of newly diagnosed patients in the United States and Europe are treated with a boosted protease inhibitor [6,7], and darunavir is the recommended protease inhibitor in treatment guidelines [8–10]. United States guidelines recommend two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NRTIs) combined with an integrase strand transfer inhibitor (INSTI), or in certain clinical situations boosted darunavir 800 mg once daily or a nonnucleoside reverse transcriptase inhibitor (NNRTI) [8,9]. Boosted darunavir is recommended for patients with uncertain adherence, those who require a regimen with a high-resistance barrier, or those patients without available resistance results [8]. European guidelines recommend two NRTIs combined with either an INSTI, boosted darunavir or an NNRTI for all ART-naive patients [10], with both darunavir and atazanavir as recommended protease inhibitors in the BHIVA guidelines [11].\n\nPhase-3 studies have established the noninferior antiviral efficacy and improved renal and bone safety of ART regimens containing tenofovir alafenamide (TAF), a newer tenofovir prodrug, vs. tenofovir disoproxil fumarate (TDF), combined with different third agents [12,13], making TAF an optimal backbone component.\n\nDarunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is the first and only once-daily protease inhibitor-containing STR in development, combining the antiviral efficacy, and resistance barrier of darunavir with the safety of TAF. D/C/F/TAF was approved for use in Europe in September 2017, and is investigational and currently undergoing regulatory review in the United States. D/C/F/TAF is being evaluated in two international, randomized, phase-3 studies: AMBER (NCT02431247) in ART-naive, HIV-1-infected adults, and EMERALD (NCT02269917) in treatment-experienced adults with virologically suppressed HIV infection [14]. We present the 48-week primary analysis of AMBER, which evaluated D/C/F/TAF vs. darunavir/cobicistat in combination with emtricitabine/TDF (F/TDF).\n\nMethods\nStudy design\nAMBER (TMC114FD2HTX3001; ClinicalTrials.gov NCT02431247; EudraCT 2015–000754–38) is a phase-3, randomized, active-controlled, double-blind, noninferiority study being conducted at 121 sites across 10 countries in North America (USA, Canada) and Europe (Belgium, France, Germany, Italy, Poland, Russia, Spain, UK). The trial included a ∼30-day screening period (up to ≤6 weeks) and a 48-week treatment period. In addition, all patients continue to receive D/C/F/TAF in an open-label, single-arm treatment phase up to week 96, and then in a roll-over extension phase.\n\nParticipants were randomized (1 : 1) using a computer-generated interactive web-response system to receive D/C/F/TAF 800/150/200/10 mg (q.d.) daily or darunavir/cobicistat 800/150 mg fixed-dose combination (FDC) co-administered with F/TDF 200/300 mg FDC daily (control). Participants received placebo tablets matching the alternative treatment – three tablets in total – and were instructed to take all study drugs and matching placebo tablets with food at approximately the same time each morning. Randomization was stratified by screening viral load (≤ or >100 000 copies/ml) and CD4+ cell count (< or ≥200 cells/μl).\n\nThe trial was conducted in accordance with the principles of Good Clinical Practice and Declaration of Helsinki. The protocol and amendments were reviewed and approved by an institutional review board or independent ethics committee. All study participants provided written informed consent.\n\nStudy population\nEligible patients were treatment-naive, HIV-1-infected adults (≥18 years) with a screening plasma viral load at least 1000 copies/ml, CD4+ cell count greater than 50 cells/μl, genotypic sensitivity to darunavir, emtricitabine, and tenofovir (GenoSure MG HIV-1 protease/reverse transcriptase genotype assay; Monogram Biosciences, South San Francisco, California, USA), and an estimated glomerular filtration rate based on serum creatinine (eGFRcr) at least 70 ml/min (Cockcroft–Gault formula) [15]. Main exclusion criteria included diagnosis of a new AIDS-defining condition within 30 days prior to screening, hepatitis B or C coinfection, clinically significant disease (e.g. malignancy, severe infections), and pregnancy or breastfeeding in women. Medications or herbal supplements known or suspected to have drug interactions with the investigational medications were disallowed.\n\nMain study assessments and outcomes\nStudy visits were at baseline, weeks 2, 4, 8, and 12, and then every 12 weeks until week 96. Adverse events were graded according to the Division of AIDS grading table [16] and coded using the Medical Dictionary for Regulatory Activities (version 19.1). At each visit, urine and blood samples were collected for plasma viral load (COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, V2.0; Roche Diagnostics, Basel, Switzerland) and CD4+ cell count determinations, biochemistry, hematology, urinalysis and urine chemistry, serum cystatin C for calculating eGFRcyst [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula] [17], and serum creatinine for calculating eGFRcr (Cockcroft–Gault formula and CKD-EPI formula) [15,17]. Treatment adherence was monitored at each visit (except week 2) by drug accountability (pill count and patient log booklet). The renal proteinuria biomarkers, urinary retinol-binding protein (RBP), and beta-2-microglobulin were measured at baseline, weeks 2, 4, 12, 24, and 48 in the fasted state. Fasted metabolic profile assessments (total, high-density lipoprotein [HDL]-cholesterol and low-density lipoprotein [LDL]-cholesterol, triglycerides) were performed at baseline, weeks 24 and 48. Pharmacokinetic sampling was performed at weeks 2, 4, 8, 12, 24, 36, 48, and study endpoint.\n\nProtocol-defined virologic failure (PDVF) was defined as virologic nonresponse (viral load <1 log10 reduction from baseline and ≥50 copies/ml at week 8, confirmed at next visit) or virologic rebound (confirmed viral load ≥50 copies/ml after confirmed, consecutive viral load <50 copies/ml or confirmed viral load >1 log10 increase from the nadir) and/or viremia at the final time point (viral load ≥400 copies/ml at study endpoint or study discontinuation after week 8). Post screening resistance testing (PhenoSense GT) was performed on samples from patients with PDVF and viral load greater or equal to 400 copies/ml at time of failure (preferably confirmed, or otherwise unconfirmed) or at later time points.\n\nThe primary objective was the noninferiority evaluation of D/C/F/TAF vs. darunavir/cobicistat co-administered with F/TDF in the proportion of patients with viral load less than 50 copies/ml (response rate) by the Food and Drug Administration (FDA)-snapshot analysis at week 48.\n\nSecondary outcomes included proportion of patients with viral load <20 and <200 copies/ml (FDA-snapshot analysis) and viral load<50 copies/ml (time-to-loss-of-virologic-response algorithm) at week 48; changes from baseline in log10 viral load and CD4+ cell count; antiretroviral resistance development in PDVFs; safety and tolerability through 48 weeks; changes from baseline at week 48 in serum creatinine, eGFRcr, eGFRcyst, and ratios of total urine protein, urine albumin, urine RBP, and beta-2-microglobulin to creatinine (UPCR, UACR, RPB:Cr, and B2M:Cr, respectively).\n\nBone investigation substudy\nThe bone investigation substudy was performed at selected study sites in consenting participants from both randomization groups. Endpoints at weeks 24 and 48 were percentage changes from baseline in spine, hip, and femoral neck bone mineral density (BMD; measured by dual-energy X-ray absorptiometry scans); changes in associated T score (normal BMD defined as a T score ≥−1; osteopenia as a T score from ≥−2.5 to <−1; and osteoporosis as a T score <−2.5); and changes in bone biomarkers, alkaline phosphatase (ALP), procollagen type N-terminal propeptide (P1NP), C-type collagen sequence (CTX), parathyroid hormone (PTH), and 25-hydroxy vitamin (25[OH]D), measured in the fasted state.\n\nStatistical analysis\nThe week-48 primary analysis was performed on the intent-to-treat population (constituting all patients who were randomized and received at least one dose of study drug). A per-protocol analysis was also performed, excluding patients with major protocol violations or other predefined criteria that potentially affected efficacy. Data analysis was performed using SAS software (SAS Institute, Inc, Cary, North Carolina, USA) version 9.2.\n\nAssuming a response rate of 80% at week 48 (FDA-snapshot analysis) for both treatment groups, 335 patients needed to be enrolled in each group to establish noninferiority of D/C/F/TAF to control, with a noninferiority margin of 10% at 90% power and a one-sided significance level of 2.5%. For the bone investigation substudy, at least 85 patients per treatment group were required to detect an absolute difference between groups in BMD of at least 2% with 90% power, assuming a 4% inter-subject variability and a one-sided significance level of 2.5%.\n\nNoninferiority of D/C/F/TAF to control would be demonstrated if the lower limit of the two-sided 95% confidence interval (CI) of the stratum-adjusted (viral load ≤100 000 or >100 000 copies/ml and CD4+ cell count <200 or ≥200 cells/μl) Mantel–Haenszel difference between treatment groups (D/C/F/TAF minus control) in the week-48 response rate was greater than −10%. Superiority would be established if the lower limit of the 95% CI was greater than 0.\n\nThe difference between groups in least square mean (LSM) change from baseline at week 48 in CD4+ cell count and associated 95% CIs were constructed using analysis of covariance (ANCOVA), including CD4+ cell count at baseline as a continuous covariate. In patients who discontinued, CD4+ cell count values after discontinuation were imputed with the baseline value (noncompleter = failure). For other missing values, the last observation was carried forward.\n\nBaseline and postbaseline HIV-1 genotypes were analyzed for protease resistance-associated mutations (RAMs) [including International Antiviral Society (IAS)–USA primary PI RAMs] and reverse transcriptase RAMs (including IAS-USA NRTI RAMs and IAS–USA NNRTI RAMs), as well as specific RAMs to the study drugs [18]. Antiretroviral sensitivity, based on the genotype/phenotype report, was also assessed.\n\nWithin-treatment comparisons of mean changes from baseline in renal and bone biomarkers, and fasting lipids were performed using the Wilcoxon signed-rank test. Between-treatment comparisons were assessed using the Wilcoxon rank-sum test. Between-treatment differences in change from baseline in serum creatinine, eGFR, and BMD were tested using ANCOVA, including treatment as a factor and corresponding baseline values as covariates.\n\nResults\nPatient disposition and baseline characteristics\nThe study began on 6 July 2015, and the cut-off date for the week-48 primary analysis was 13 March 2017. Of 866 screened patients, 725 were randomized and included in the intent-to-treat population (Fig. 1); 362 received D/C/F/TAF and 363 received darunavir/cobicistat with F/TDF.\n\nFig. 1 Patient disposition through 48 weeks.\n\nAE, adverse event; Control regimen, darunavir/cobicistat with emtricitabine/tenofovir disoproxil fumarate once daily; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily. aReceived at least one dose of study medication. bBased upon the ‘Trial Termination’ electronic case report form page as reported by the investigators. Reasons for discontinuation may not match those reported in Supplementary Table 1, because patients may have viral load data within the week-48 window, which was used to determine the FDA-snapshot category. cOccurred in the follow-up phase (11 days after last study drug intake). FDA, Food and Drug Administration.\n\nThrough 48 weeks, 93.6% (339/362) of patients in the D/C/F/TAF group and 92.3% (335/363) in the control group completed therapy (Fig. 1). The most common reasons for discontinuing the study, as reported by the investigators, were adverse events, withdrawn consent, and loss to follow-up.\n\nBaseline characteristics were balanced between the two groups (Table 1). Median age was 34 years, 88% were men, 83% were white, and 18% had viral load at least 100 000 copies/ml. Median baseline CD4+ cell count was 453 cells/μl.\n\nAs depicted by the protocol, at screening, all enrolled participants demonstrated genotypic sensitivity to darunavir, emtricitabine, and tenofovir based on the genotype report. Few had viruses with at least one darunavir RAMs (1%) or primary PI RAMs (2%) (Table 1). No RAMs related to emtricitabine or TDF/TAF were detected. NNRTI and NRTI RAMs were detected in 16 and 5% of patients, respectively (Table 1).\n\nEfficacy\nIn the primary analysis of virologic response at week 48 (FDA-snapshot analysis), noninferiority of D/C/F/TAF [91.4% (331/362)] vs. control [88.4% (321/363)] was demonstrated (difference 2.7%; 95% CI −1.6 to 7.1; P < 0.0001; Fig. 2a and Supplemental Table S1). A low proportion of participants in the D/C/F/TAF group [4.4% (16/362)] and control group [3.3% (12/363)] had a viral load greater or equal to 50 copies/ml at week 48 (FDA-snapshot analysis).\n\nFig. 2 Week-48 Food and Drug Administration-snapshot analysis (<50 copies/ml).\n\n(a) Virologic outcomes overall and (b) subgroup analyses of week-48 response rates. CI, confidence interval; control regimen, darunavir/cobicistat with emtricitabine/tenofovir disoproxil fumarate once daily; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily; VL, viral load. aLast viral load in the week-48 window at least 50 copies/ml, or discontinuations for efficacy reasons, or premature discontinuations not because of efficacy, adverse events or death with a last viral load at least 50 copies/ml. bCalculated with Mantel–Haenszel test adjusting for screening viral load (≤ or >100 000 copies/ml) and CD4+ cell count (< or ≥200 cells/μl). cP value for noninferiority at 10% margin.\n\nResults from the per-protocol analysis confirmed noninferiority of D/C/F/TAF [94% (327/348)] to control [92.2% (317/344)] (difference 1.5%; 95% CI −2.3 to 5.2; P < 0.0001), as did other sensitivity analyses (Supplementary Table 2). Week-48 response rates (FDA-snapshot analysis) were consistent across a range of patient subgroups (Fig. 2b).\n\nA similar proportion of patients in each group also achieved a viral load <200 or <20 copies/ml (FDA-snapshot analysis) at week 48 (Supplementary Table 2). LSM increases (P < 0.0001) from baseline in CD4+ cell count (noncompleter = failure) at week 48 were 190.5 cells/μl for D/C/F/TAF vs. 172.0 cells/μl for control (P = 0.213 between groups; Supplementary Table 2).\n\nVirology\nThrough week 48, eight (D/C/F/TAF) and six (control) participants had PDVF, with paired screening and postbaseline on-treatment genotypes available for seven vs. two patients, respectively. No darunavir, primary protease inhibitor, or TDF/TAF RAMs emerged in any patient. An M184V/I mutation associated with phenotypic resistance to emtricitabine and lamivudine was identified in one patient receiving D/C/F/TAF. This patient harbored a K103N mutation at screening, indicating transmitted NNRTI (efavirenz and nevirapine) resistance. Although the patient appeared to have good adherence (≥95% based on pill count), darunavir plasma concentrations were low [32–192 ng/ml, except at week 4 (1440 ng/ml)], indicating nonadherence that resulted in the patient being discontinued from the study after week 48. All other participants had virus that remained susceptible to all drugs in the treatment regimens.\n\nAdherence\nThrough week 48, 88.3% (264/299) vs. 88.3% (271/307) of patients in the D/C/F/TAF and control groups, respectively, were at least 95% adherent as measured by pill count (all patients took three tablets daily based on the study design).\n\nSafety\nSafety profiles were similar between groups (Table 2). Most adverse events regardless of causality were grade 1 or 2. The most common (≥5% in either group) study drug-related adverse events through week 48 were diarrhea, rash, and nausea (Table 2). All episodes of study drug-related diarrhea were mild or moderate (grade 1 or 2) and mostly transient in duration. Only one patient in each group (0.3%) discontinued the study because of diarrhea. There were no nervous system study drug-related adverse events greater than 5% nor discontinuations in either group.\n\nRenal adverse events regardless of causality occurred in 2% (7/362) of D/C/F/TAF vs. 6% (21/363) of control patients. No renal adverse events were suggestive of treatment-emergent proximal renal tubulopathy and no renal adverse events led to discontinuation.\n\nGrades 3 and 4 adverse events regardless of causality, serious adverse events, and adverse event-related discontinuations were rare (Table 2). The only grade 4 adverse event reported for at least two patients was suicide attempt, reported in two (0.6%) patients in the control group. There were no deaths during the treatment phase in either group (Table 2). However, one patient in the control group died following grade 4 sepsis in the follow-up phase (11 days after last study drug intake), which was not considered related to study drug (Fig. 1). Incidences and types of laboratory abnormalities were similar in both treatment groups, being mostly grade 1 or 2.\n\nMedian changes from baseline at week 48 for fasting lipid parameters were higher for D/C/F/TAF than control (Table 2 and Supplementary Figure 1). Changes in HDL-cholesterol favored D/C/F/TAF and remaining lipid increases favored control, with a small, statistically significant difference in the change from baseline in total cholesterol/HDL-cholesterol ratio between groups. Six (1.7%) vs. two (0.6%) patients, respectively, initiated a lipid-lowering drug during the treatment period (P = 0.1770 between groups).\n\nSerum creatinine increased from baseline to week 48 in the D/C/F/TAF group (4.8 μmol/l), consistent with cobicistat inhibition of creatinine tubular secretion [19], but less so than in the control group (8.2 μmol/l; P < 0.0001, ANCOVA D/C/F/TAF vs. control). Consequently, the mean decrease in eGFRcr (CKD-EPI formula) at week 48 was less for D/C/F/TAF than control (−5.9 vs. −9.3 ml/min per 1.73 m2, respectively; P < 0.0001, ANCOVA; Fig. 3a), although mean eGFRcr was within normal limits. However, mean eGFRcyst (CKD-EPI formula) actually increased at week 48, and the increase was greater for D/C/F/TAF than control (5.3 vs. 2.9 ml/min per 1.73 m2, respectively; P = 0.001, ANCOVA) (Fig. 3b).\n\nFig. 3 Mean change from baseline to week 48 in kidney and bone parameters.\n\nMean change in (a) eGFRcr and (b) eGFRcyst was based on serum concentrations and the Kidney Disease Epidemiology Collaboration formula. BMD of the (c) hip, (d) lumbar spine, and (e) femoral neck was analyzed with dual energy X-ray absorptiometry. Bars show SE. ANCOVA, analysis of covariance; BMD, bone mineral density; Control regimen, darunavir/cobicistat with emtricitabine/tenofovir disoproxil fumarate once daily; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily; eGFRcr, estimated glomerular filtration rate based on serum creatinine; eGFRcyst, estimated glomerular filtration rate based on serum cystatin C; SE, standard error. aP-value for between-treatment comparison estimated using ANCOVA, including treatment as a factor and corresponding baseline eGFR as a covariate; within-group changes from baseline at week 48, P < 0.0001 (both groups for eGFRcr and eGFRcyst). bP value for between-treatment comparison estimated using ANCOVA, including treatment as a factor and baseline BMD as a covariate; Within-group changes from baseline at week 48 at each site, P < 0.0001 (D/C/F/TAF); P = nonsignificant (control).\n\nAt week 48, all quantitative measures demonstrated less proteinuria for D/C/F/TAF vs. control, as determined by mean changes from baseline in UPCR [−22.42 mg/g (SD 71.98) vs. −10.34 mg/g (118.18), respectively; P = 0.033], UACR [−2.45 mg/g (23.81) vs. −0.58 mg/g (68.93); P = 0.003], RBP:Cr [16.84 μg/g (317.31) vs. 401.12 μg/g (2688.91); P < 0.0001], and B2M:Cr [−100.58 μg/g (788.60) vs. 837.63 μg/g (6122.87); P < 0.0001].\n\nBaseline characteristics in the bone investigation substudy were well balanced between the D/C/F/TAF (N = 113) and control (N = 99) groups (Supplementary Table 3). Hip, lumbar spine, and femoral neck BMD from baseline to week 48 were stable with D/C/F/TAF (mean percentage change 0.21, −0.68, and −0.26% at each site, respectively; Fig. 3), whereas they decreased significantly at week 48 in the control group [−2.73, −2.38, and −2.97%, respectively; P < 0.0001 (hip and femoral neck) and P = 0.004 (spine) for between-treatment comparisons]. Fewer patients receiving D/C/F/TAF had at least 3% decreases from baseline in BMD at each site than in the control group. More patients had at least 3% increases in the D/C/F/TAF group (Supplementary Table 4). A similar trend was seen for at least 5 and at least 7% increases or decreases in BMD (Supplementary Table 4). At week 48, a greater proportion of participants receiving D/C/F/TAF had improvements in T score at each site than in the control group, and a smaller proportion of participants receiving D/C/F/TAF had worsening BMD status (Supplementary Table 4). Fractures occurred infrequently and were not different between groups [1.1% (4/362) D/C/F/TAF vs. 0.6% (2/363) control; P = 0.451]; all were traumatic and none were suspected to be osteoporotic. New antiosteoporotic treatment was started by 9/362 (2.5%) vs. 16/363 (4.4%) patients, respectively, during the treatment phase. Changes from baseline in bone biomarker levels (ALP, P1NP, CTX, and PTH) suggested less bone turnover for D/C/F/TAF than control (Supplementary Figure 2). 25[OH]D levels increased from baseline in both groups.\n\nDiscussion\nIn this investigational phase-3, double-blinded, randomized, controlled trial, the D/C/F/TAF once-daily STR was virologically noninferior to darunavir/cobicistat co-administered with F/TDF in ART-naive patients. Response rates were similar across age, sex, race, and baseline HIV characteristics including CD4+ cell count less than 200 cells/μl and viral load greater than 100 000 copies/ml. Although INSTI-based regimens have rapidly moved up in global treatment guidelines [8–10], there are still many patients who might benefit from the established characteristics of the protease inhibitor darunavir, such as high genetic barrier to resistance, efficacy in the face of resistance and uncertain adherence, provider comfort, and experience. Well powered, phase-3, double-blinded, randomized studies provide the most rigorous evidence to drive treatment guidelines. The week-48 virologic response rate (FDA-snapshot analysis) of 91.4% for D/C/F/TAF was among the highest achieved by a STR in phase-3 trials (range 80–93%) of ART-naive patients [12,20–26], and higher than in prior phase-3 trials with darunavir [4,23,27,28].\n\nNo treatment-emergent mutations associated with darunavir or tenofovir resistance were observed. Only one patient (D/C/F/TAF) was found to have M184I/V, conferring resistance to emtricitabine; this patient also had a transmitted K103N mutation at screening. M184V was detected pretreatment by deep sequencing (Illumina MiSeq) as a minority variant (9.4%). In addition, for this patient, darunavir plasma concentrations were low and much lower than the steady-state predose concentration (∼692 ng/ml), indicating potential nonadherence, which in fact resulted in discontinuation from the study. The observation of no darunavir phenotypic resistance and the genotypic results are consistent with previous darunavir studies [4,5,27,29], confirming the high resistance barrier of darunavir-based initial ART with no emergence of DRV resistance. D/C/F/TAF is the only STR in development that combines the high barrier to resistance of darunavir with the F/TAF backbone. In this context, D/C/F/TAF may have an important role for treating patients with uncertain adherence or who plan to start treatment prior to the availability of resistance-testing results [8]. Patients with transmitted NNRTI and NRTI resistance were included in the study. As D/C/F/TAF does not require HLA B∗5701 screening or hepatitis or resistance testing before treatment initiation, it is currently being evaluated in a rapid initiation protocol (NCT03227861). These characteristics suggest D/C/F/TAF is a highly feasible option in a test and treat setting or for very early treatment-naive patients where rapid combination ART initiation could be warranted.\n\nSafety profiles were similar between the two treatment groups. However, adverse event-related discontinuations were lower for D/C/F/TAF (2%) than control (4%), and similar to those reported in phase-3 studies of other recently approved STRs [12,20–26]. The low incidences and similar types of adverse events, grade 3 or 4 adverse events, and serious adverse events between groups reflects the well characterized safety profiles for darunavir and cobicistat reported previously [4,27,29]. Given the low incidence of nervous system adverse events, D/C/F/TAF may be an important treatment option for ART-naive patients at risk of nervous system adverse events, such as insomnia and depression.\n\nLess renal tubular proteinuria, and more favorable hip and spine BMD for D/C/F/TAF compared with control are consistent with TAF vs. TDF effects [12,13,29–31]. The improvement in eGFRcyst could reflect ART-related improvement in HIV-associated renal impairment, as was seen in the START study [32]. The favorable renal tubular and BMD outcomes at the 48-week time point are reassuring, given the fact that the cumulative adverse effects of TDF on renal and bone outcomes have been greater whenever TDF was combined with boosted protease inhibitors [33]. Median increases from baseline in fasting lipids were higher for D/C/F/TAF vs. control, with the increase in HDL-cholesterol favoring D/C/F/TAF and remaining lipid increases favoring control. There was a small, statistically significant difference in the total cholesterol/HDL-cholesterol ratio between groups. Differences in lipid profiles were likely because of the loss of the lipid-lowering effect of TDF rather than an adverse effect of TAF or any other of the components on lipids [12,13].\n\nAs in other recent phase-3 trials in ART-naive patients [20–26], study limitations were inclusion of more than 80% white patients and a comparatively small proportion of female or older (>50 years) participants or who had high viral loads. The latter most likely reflects earlier initiation of ART based on current guideline recommendations [8–11]. Phase-3 studies often lack power to detect rare clinical safety events; however, the large clinical safety database for darunavir and substantial clinical experience counterbalance this limitation. Renal and bone safety were assessed using surrogate markers rather than clinical events, and bone safety was assessed in a smaller number of patients.\n\nIn conclusion, D/C/F/TAF was noninferior to a regimen of darunavir/cobicistat co-administered with F/TDF at week 48, with a high virologic response (91.4%) in ART-naive, HIV-1-infected adults. D/C/F/TAF was associated with a better bone and renal safety profile than control, with few moderate, severe, or serious adverse events. Changes in HDL-cholesterol favored D/C/F/TAF and remaining lipid increases favored control. D/C/F/TAF is a novel STR that combines the known efficacy and high-genetic barrier to resistance of darunavir with the safety advantages of TAF to provide a new option for the treatment of ART-naive, HIV-1-infected patients.\n\nAcknowledgements\nThis study was sponsored by Janssen.\n\nWe thank the patients and their families for their participation and support during the study, the central and local Janssen AMBER study teams, study center staff, and the principal investigators:\n\nBelgium: S. De Wit, E. Florence, L. Vandekerckhove, B. Vandercam; Canada: J. Brunetta, M. Klein, D. Murphy, A. Rachlis, S. Walmsley; France: F. Ajana, L. Cotte, P.-M. Girard, C. Katlama, J.-M. Molina, I. Poizot-Martin, F. Raffi, D. Rey, J. Reynes, E. Teicher, Y. Yazdanpanah; Germany: K. Arastéh, M. Bickel, J. Bogner, S. Esser, G. Faetkenheuer, H. Jessen, W. Kern, J. Rockstroh, C. Spinner, H.-J. Stellbrink, A. Stoehr; Italy: A. Antinori, F. Castelli, A. Chirianni, A. De Luca, A. Di Biagio, M. Galli, A. Lazzarin, F. Maggiolo, R. Maserati, C. Mussini; Poland: A. Garlicki, J. Gasiorowski, W. Halota, A. Horban, M. Parczewski, A. Piekarska; Russia: E. Belonosova, O. Chernova, N. Dushkina, V. Kulagin, E. Ryamova, A. Shuldyakov, N. Sizova, O. Tsybakova, E. Voronin, A. Yakovlev; Spain: A. Antela, J.R. Arribas, J. Berenguer, J. Casado, V. Estrada, M.J. Galindo, M. Garcia Del Toro, J.M. Gatell, M. Gorgolas, F. Gutierrez, M.D.M. Gutierrez, E. Negredo, J.A. Pineda, D. Podzamczer, J. Portilla Sogorb, A. Rivero, R. Rubio, P. Viciana, I. De Los Santos; UK: A. Clarke, B.G. Gazzard, M.A. Johnson, C. Orkin, I. Reeves, L. Waters; United States: P. Benson, L. Bhatti, F. Bredeek, G. Crofoot, D. Cunningham, E. DeJesus, J. Eron, F. Felizarta, R. Franco, J. Gallant, D. Hagins, K. Henry, D. Jayaweera, C. Lucasti, C. Martorell, C. McDonald, J. McGowan, A. Mills, J. Morales-Ramirez, D. Prelutsky, M. Ramgopal, B. Rashbaum, P. Ruane, J. Slim, A. Wilkin, J. deVente.\n\nWe also thank other Janssen staff members for their input into this manuscript. We acknowledge Ian Woolveridge of Zoetic Science, an Ashfield company, Macclesfield, UK, for assistance in drafting the manuscript and coordinating and collating author contributions, which was funded by Janssen. Week-48 data were presented in part at the 16th European AIDS Conference, 25–27 October 2017, Milan, Italy.\n\nContributors: J.G., C.O., J.-M.M., E.N., A.A., A.M., J.E., and J.R. were investigators in the study and reported data for the patients. E.V.L., E.L., V.H., J.J., S.V., and M.O. were involved in the data analyses. All authors had full access to the data, were involved in the development of the primary manuscript and interpretation of data, have read and approved the final version, and have met the criteria for authorship as established by the ICMJE. The corresponding author had final responsibility to submit the manuscript for publication.\n\nConflicts of interest\nSource of funding: This study was sponsored by Janssen. The funder was involved in the study design, study conduct, data collection, and data analysis.\n\nJ.E. has received research grants from Janssen, Gilead Sciences, and ViiV Healthcare, and has served as a consultant to Bristol Myers Squibb (BMS), Merck, Janssen, Gilead Sciences, and ViiV Healthcare. C.O. has received speaker honoraria or consulting fees for attending speakers’ bureaus or advisory boards and research grants from Janssen, Merck, ViiV Healthcare, and Gilead Sciences. J.G. has received consulting fees or advisory board honoraria from BMS, Gilead Sciences, Merck, ViiV Healthcare, and Theratechnolgies, and research grants from AbbVie, BMS, Gilead Sciences, Janssen Therapeutics, Merck, Sangamo Biosciences, and ViiV Healthcare/GlaxoSmithKline. He has since become a full-time employee of Gilead Sciences. J.-M.M. has participated in advisory boards for Merck, Gilead Sciences, Janssen, ViiV Healthcare, BMS, and Teva, and a speakers’ bureau for Gilead. He has received research grants from Merck and Gilead Sciences. E.N. has received speaker honoraria or consulting fees from ViiV Healthcare, Merck, Janssen Cilag, BMS, Gilead Sciences, and AbbVie. A.A. has served as a consultant to BMS, Gilead Sciences, Janssen Cilag, Merck, ViiV Healthcare, and AbbVie. He has received institutional research grants from BMS, Gilead Sciences, Janssen Cilag, and ViiV Healthcare. A.M. has received grants and personal fees from Gilead Sciences, ViiV Healthcare, Janssen and Merck, and grants from BMS and Sangamo. J.R. has received grants and personal fees from Janssen, Gilead Sciences, Merck, and ViiV Healthcare. E.V.L., E.L., V.H., J.J., S.V., and M.O. are all full-time employees of Janssen and potential stockholders of Johnson and Johnson.\n\nSupplementary Material\nSupplemental Digital Content\n Table 1 Patient baseline demographics and disease characteristics.\n\nDemographics, n (%), unless stated\tD/C/F/TAF 800/150/200/10 mg once daily, N = 362\tControl regimen, N = 363\tTotal, N = 725\t\nMedian age (IQR), years\t34 (27–42)\t34 (27–42)\t34 (27–42)\t\n More than 50\t36 (10)\t32 (9)\t68 (9)\t\nGender\t\n Female\t44 (12)\t41 (11)\t85 (12)\t\n Male\t318 (88)\t322 (89)\t640 (88)\t\nRace\t\n White\t300 (83)\t300 (83)\t600 (83)\t\n Black/African-American\t40 (11)\t40 (11)\t80 (11)\t\n Other\t22 (6)\t23 (6)\t45 (6)\t\nEthnicity\t\n Hispanic or Latino\t50 (14)\t45 (12)\t95 (13)\t\nBaseline disease characteristics\t\nMedian (IQR) time since diagnosis, months\t5.73 (2.53–25.59)\t4.30 (2.07–17.74)\t4.83 (2.33–21.62)\t\nMedian (IQR) log10 viral load, copies/ml\t4.44 (4.03–4.82)\t4.57 (4.15–4.88)\t4.52 (4.10–4.87)\t\nViral load at least 100 000 copies/ml, n (%)\t60 (17)\t70 (19)\t130 (18)\t\nMedian (IQR) CD4+ cell count, cells/μl\t461.5 (342–617)\t440.0 (325–594)\t453.0 (333–601)\t\nCD4+ cell count less than 200 cells/μl, n (%)\t22 (6)\t29 (8)\t51 (7)\t\nMedian (IQR) eGFRcr, ml/min (Cockcroft–Gault)\t119.3 (104.8–135.2)\t118.4 (103.2–138.4)\t119.1 (104.4–136.5)\t\nGenotypea at screening, n (%) [18]\tN = 361b\tN = 362b\tN = 723\t\n At least one darunavir resistance-associated mutation\t3 (1)\t4 (1)\t7 (1)c\t\n At least one primary protease inhibitor resistance-associated mutation\t7 (2)\t8 (2)\t15 (2)\t\n At least one NRTI resistance-associated mutation\t18 (5)\t16 (4)\t34 (5)d\t\n At least one NNRTI resistance-associated mutation\t55 (15)\t63 (17)\t118 (16)e\t\nControl regimen, darunavir/cobicistat plus emtricitabine/tenofovir disoproxil fumarate once daily; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily; eGFRcr, estimated glomerular rate based on serum creatinine; IQR, interquartile range; NNRTI, nonnucleoside analogue reverse transcriptase inhibitor; NRTI, nucleoside or nucleotide analogue reverse transcriptase inhibitor.\n\naGenoSureMG.\n\nbOne patient in each group had failed screening genotypes and were enrolled based on local genotypes.\n\ncSix V11I, one L33F.\n\ndThe most prevalent NRTI mutation: A62V: 21/725 (2.9%).\n\neThe most prevalent NNRTI mutation: K103N 26/725 (3.6%).\n\nTable 2 Treatment-emergent adverse events and laboratory abnormalities through 48 weeks.\n\n\tD/C/F/TAF 800/150/200/10 mg once daily, N = 362\tControl regimen, N = 363\t\nAny adverse event regardless of causality\t312 (86)\t307 (85)\t\nAny study drug-related adverse event\t126 (35)\t151 (42)\t\nAny grade 3 or 4 adverse event regardless of causality\t19 (5)\t22 (6)\t\nAny serious adverse event regardless of causalitya\t17 (5)\t21 (6)\t\nAdverse events leading to permanent discontinuationb\t7c (2)\t16 (4)\t\nDeathd\t0\t0\t\nMost common adverse events regardless of causality (≥5% of patients in either group)\t\n Diarrheae\t71 (20)\t66 (18)\t\n Headache\t47 (13)\t32 (9)\t\n Nasopharyngitis\t40 (11)\t31 (9)\t\n Rash\t32 (9)\t25 (7)\t\n Nausea\t28 (8)\t45 (12)\t\n Upper respiratory tract infection\t20 (6)\t21 (6)\t\n Fatigue\t19 (5)\t18 (5)\t\n Syphilis\t17 (5)\t19 (5)\t\n Osteopenia\t17 (5)\t27 (7)\t\n Bronchitis\t14 (4)\t19 (5)\t\nAdverse events at least possibly related to study drug (≥5% of patients in either group)\t\n Diarrheae\t31 (9)\t40 (11)\t\n Rash\t22 (6)\t14 (4)\t\n Nausea\t20 (6)\t36 (10)\t\nMedian (IQR) change from baseline in fasting lipids at week 48\t\n Total cholesterol (mg/dl)\t28.6 (12.8 to 47.2)f\t10.4 (−8.0 to 29.8)\t\n HDL-cholesterol (mg/dl)\t4.3 (−1.2 to 12.0)f\t1.5 (−3.9 to 8.1)\t\n LDL-cholesterol (mg/dl)\t17.4 (2.9 to 32.9)f\t5.0 (−10.8 to 19.0)\t\n Triglycerides (mg/dl)\t23.9 (−3.0 to 58.5)g\t14.2 (−12.0 to 40.7)\t\n Total cholesterol/HDL-cholesterol ratio\t0.20 (−0.28 to 0.67)h\t0.08 (−0.41 to 0.53)\t\nData are n (%) unless otherwise stated.\n\nControl regimen, darunavir/cobicistat plus emtricitabine/tenofovir disoproxil fumarate once daily; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide once daily; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein.\n\naConsidered study drug-related in zero (D/C/F/TAF group) vs. six patients (1.7% control; rash and toxic skin eruption in two patients each, and bone marrow edema and Stevens–Johnson syndrome in one patient each).\n\nbD/C/F/TAF (n = 7): rash (n = 4), generalized rash, maculopapular rash, diarrhea (n = 1 each); control (n = 16): rash/erythema (n = 7), toxic skin eruption (n = 2), neoplasms (n = 2), Stevens–Johnson syndrome, diarrhea, bone marrow edema, increased beta-2-microglobulin, and arthralgia (n = 1 each).\n\ncOne fewer patient in the D/C/F/TAF group (compared with Fig. 1) had an adverse event assessed as leading to discontinuation as data are taken from the adverse event electronic case report form (whether or not the drug was withdrawn), and the patient had interrupted treatment.\n\ndOne death occurred in the control arm, but in follow-up (not considered related to study drug).\n\neThe majority of episodes of diarrhea were mild: grade 1: 16 vs. 13% (related: 7 vs. 9%) and grade 2: 4 vs. 5% (related: 2 vs. 2%).\n\nfP < 0.0001 (total cholesterol, HDL-cholesterol, LDL-cholesterol).\n\ngP = 0.001 (triglycerides).\n\nhP = 0.036 (total cholesterol/HDL-cholesterol ratio) for D/C/F/TAF group vs. control group.\n==== Refs\nReferences\n1. Nachega JB Marconi VC van Zyl GU Gardner EM Preiser W Hong SY \nHIV treatment adherence, drug resistance, virologic failure: evolving concepts . Infect Disord Drug Targets \n2011 ; 11 :167 –174 .21406048 \n2. Clay PG Nag S Graham CM Narayanan S \nMeta-analysis of studies comparing single and multitablet fixed dose combination HIV treatment regimens . Medicine (Baltimore) \n2015 ; 94 :e1677 .26496277 \n3. Cotte L Ferry T Pugliese P Valantin MA Allavena C Cabié A \nDat’AIDS Study Group Effectiveness and tolerance of single tablet versus once daily multiple tablet regimens as first-line antiretroviral therapy - results from a large french multicenter cohort study . PLoS One \n2017 ; 12 :e0170661 .28152047 \n4. Orkin C DeJesus E Khanlou H Stoehr A Supparatpinyo K Lathouwers E \nFinal 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial . HIV Med \n2013 ; 14 :49 –59 .\n5. Lathouwers E Wong EY Luo D Seyedkazemi S De Meyer S Brown K \nHIV-1 resistance rarely observed in patients using darunavir once-daily regimens across clinical studies . HIV Clin Trials \n2017 ; 18 :196 –204 .29143565 \n6. Borges ÁH Lundh A Tendal B Bartlett JA Clumeck N Costagliola D \nNonnucleoside reverse-transcriptase inhibitor- vs ritonavir-boosted protease inhibitor-based regimens for initial treatment of HIV infection: a systematic review and metaanalysis of randomized trials . Clin Infect Dis \n2016 ; 63 :268 –280 .27090986 \n7. Mahlich J Groß M Kuhlmann A Bogner J Heiken H Stoll M \nThe choice between a ritonavir-boosted protease inhibitor- and a nonnucleoside reverse transcriptase inhibitor-based regimen for initiation of antiretroviral treatment - results from an observational study in Germany . J Pharm Policy Pract \n2016 ; 9 :39 .28050254 \n8. DHHS guidelines . Panel on Antiretroviral Guidelines for Adults and Adolescents . Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents . Department of Health and Human Services. 1–239 (updated May 30, 2018). Available at: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf \n[Accessed 6 June 2018]\n9. Günthard HF Saag MS Benson CA del Rio C Eron JJ Gallant JE \nAntiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA Panel . JAMA \n2016 ; 316 :191 –210 .27404187 \n10. EACS . European AIDS Clinical Society Guidelines. Version 9.0. October 2017 . Available at: http://www.eacsociety.org/files/guidelines_9.0-english.pdf \n[Accessed 15 January 2018]\n11. BHIVA guidelines for the treatment of HIV-1-positive adults with ART 2015 (2016 interim update) . Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2016/treatment-guidelines-2016-interim-update.pdf \n[Accessed 15 January 2018]\n12. Sax PE Wohl D Yin MT Post F DeJesus E Saag M \nGS-US-292-0104/0111 Study Team Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, noninferiority trials . Lancet \n2015 ; 385 :2606 –2615 .25890673 \n13. Gallant JE Daar ES Raffi F Brinson C Ruane P DeJesus E \nEfficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial . Lancet HIV \n2016 ; 3 :e158 –e165 .27036991 \n14. Orkin C Molina J-M Negredo E Arribas JR Gathe J Eron JJ \nEfficacy and safety of switching from boosted protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once-daily complete HIV-1 regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in virologically suppressed, HIV-1-infected adults through 48 weeks (EMERALD): a phase 3, randomized, noninferiority trial . Lancet HIV \n2018 ; 5 :e23 –e34 .28993180 \n15. Cockcroft DW Gault MH \nPrediction of creatinine clearance from serum creatinine . Nephron \n1976 ; 16 :31 –41 .1244564 \n16. NIAID . Division of AIDS table for grading the severity of adult and pediatric adverse events – version 2 . November 2014 \nAvailable at: http://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf \n[Accessed 15 January 2018]\n17. Levey AS Stevens LA Schmid CH Zhang YL Castro AF 3rd \nCKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) A new equation to estimate glomerular filtration rate . Ann Intern Med \n2009 ; 150 :604 –612 .19414839 \n18. Wensing AM Calvez V Gunthard HF Johnson VA Paredes R Pillay D \n2014 update of the drug resistance mutations in HIV-1 . Top Antivir Med \n2014 ; 22 :642 –650 .25101529 \n19. German P Liu HC Szwarcberg J Hepner M Andrews J Kearney BP \nEffect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function . J Acquir Immune Defic Syndr \n2012 ; 61 :32 –40 .22732469 \n20. Cohen C Wohl D Arribas JR Henry K Van Lunzen J Bloch M \nWeek 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults . AIDS \n2014 ; 28 :989 –997 .24508782 \n21. Sax PE DeJesus E Mills A Zolopa A Cohen C Wohl D \nGS-US-236-0102 study team Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks . Lancet \n2012 ; 379 :2439 –2448 .22748591 \n22. Walmsley SL Antela A Clumeck N Duiculescu D Eberhard A Gutiérrez F \nSINGLE Investigators Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection . N Engl J Med \n2013 ; 369 :1807 –1818 .24195548 \n23. Clotet B Feinberg J van Lunzen J Khuong-Josses MA Antinori A Dumitru I \nING114915 study team Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study . Lancet \n2014 ; 383 :2222 –2231 .24698485 \n24. Sax PE Pozniak A Montes ML Koenig E DeJesus E Stellbrink HJ \nCoformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, noninferiority trial . Lancet \n2017 ; 390 :2073 –2082 .28867499 \n25. Gallant J Lazzarin A Mills A Orkin C Podzamczer D Tebas P \nBictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled noninferiority trial . Lancet \n2017 ; 390 :2063 –2072 .28867497 \n26. Squires KE Molina J-M Sax PE Wong WW Orkin C Sussmann O \nFixed dose combination of doravirine/lamivudine/TDF is noninferior to efavirenz/emtricitabine/TDF in treatment-naïve adults with HIV-1 infection: week 48 results of the Phase 3 DRIVE-AHEAD study [abstract TUAB0104LB] . 9th IAS Conference on HIV Science , 23–26 July 2017 .\n27. Tashima K Crofoot G Tomaka FL Kakuda TN Brochot A Van de Casteele T \nCobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a Phase IIIb, open-label single-arm trial . AIDS Res Ther \n2014 ; 11 :39 .25926858 \n28. Lennox JL Landovitz RJ Ribaudo HJ Ofotokun I Na LH Godfrey C \nACTG A5257 Team Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial . Ann Intern Med \n2014 ; 161 :461 –471 .25285539 \n29. Mills A Crofoot G JrMcDonald C Shalit P Flamm JA Gathe J Jr \nTenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized Phase 2 study . J Acquir Immune Defic Syndr \n2015 ; 69 :439 –445 .25867913 \n30. Orkin C DeJesus E Ramgopal M Crofoot G Ruane P LaMarca A \nSwitching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, noninferiority study . Lancet HIV \n2017 ; 4 :e195 –e204 .28259777 \n31. DeJesus E Ramgopal M Crofoot G Ruane P LaMarca A Mills A \nSwitching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, noninferiority study . Lancet HIV \n2017 ; 4 :e205 –e213 .28259776 \n32. Mocroft A Achra AC Ross M Ryom L Avihingsanon A Bakowska E \nDeferred antiretroviral therapy is associated with lower estimated glomerular filtration rate in HIV-positive individuals with high CD4 counts [abstract WEPDB0101] . 21st International AIDS Conference , 18–22 July 2016 .\n33. Morlat P Vivot A Vandenhende M-A Dauchy FA Asselineau J Déti E \nthe Groupe D’epidémiologie Clinique du Sida en Aquitaine (Gecsa) Role of traditional risk factors and antiretroviral drugs in the incidence of chronic kidney disease, ANRS CO3 Aquitaine Cohort, France, 2004–2012 . PLoS One \n2013 ; 8 :e66223 .23776637\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0269-9370",
"issue": "32(11)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents; D004311:Double-Blind Method; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "8710219",
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"pages": "1431-1442",
"pmc": null,
"pmid": "29683855",
"pubdate": "2018-07-17",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "28259777;25285539;28050254;26496277;22748591;25101529;29143565;28993180;19414839;25867913;27036991;27090986;25890673;23088336;28259776;1244564;24508782;21406048;24698485;23776637;28867499;27404187;28867497;22732469;28152047;25926858;24195548",
"title": "A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.",
"title_normalized": "a week 48 randomized phase 3 trial of darunavir cobicistat emtricitabine tenofovir alafenamide in treatment naive hiv 1 patients"
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"abstract": "BACKGROUND\nNon-small-cell lung cancers with MET amplification may respond to c-MET inhibitors.\n\n\nMETHODS\nWe examined lung adenocarcinoma patients for mutations and amplification status of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS, MET. The clinical characteristics of patients with MET amplification and their responses to MET inhibitor therapy were studied.\n\n\nRESULTS\nOf the 76 patients analyzed, 5 were positive for c-MET gene amplification and 4 cases showed an intermediate result. For 12 patients who were EGFR positive, a c-MET analysis on secondary biopsy tissue was performed following disease progression. All 5 c-MET-positive patients were men. The age range in the study was 34-83 years. 4 of the 5 patients were started on crizotinib. 2 of these cases were positive following tyrosine kinase inhibitor therapy. 3 patients showed a response. 1 patient showed no response and was later found to have a concurrent T790M mutation.\n\n\nCONCLUSIONS\nThere are 2 categories of MET gene amplification in lung cancer patients, de novo and that secondary to TKI therapy. These patients can benefit from MET inhibitor therapy. Dual mechanisms of resistance, EGFR T790M mutation and c-MET amplification after TKI therapy, may suggest a poor prognosis.",
"affiliations": null,
"authors": "Suryavanshi|Moushumi|M|;Shah|Aekta|A|;Kumar|Dushyant|D|;Panigrahi|Manoj K|MK|;Metha|Anurag|A|;Batra|Ullas|U|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met",
"country": "Netherlands",
"delete": false,
"doi": "10.1159/000457801",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-5270",
"issue": "40(4)",
"journal": "Oncology research and treatment",
"keywords": null,
"medline_ta": "Oncol Res Treat",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D016896:Treatment Outcome",
"nlm_unique_id": "101627692",
"other_id": null,
"pages": "198-202",
"pmc": null,
"pmid": "28324883",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "MET Amplification and Response to MET Inhibitors in Stage IV Lung Adenocarcinoma.",
"title_normalized": "met amplification and response to met inhibitors in stage iv lung adenocarcinoma"
} | [
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"companynumb": "IN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-026793",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
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"activesubstancename": "GEFITINIB"
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"abstract": "To evaluate the safety and efficacy of percutaneous microwave ablation (MWA) combined with simultaneous transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) or extrahepatic metastases (EHM).\nBetween August 2012 and April 2017, 101 patients with MVI/EHM of HCC underwent percutaneous MWA combined with simultaneous TACE at our center. The clinical data were collected and analyzed for survival and prognostic factors.\nThe mean follow-up time was 23.6 ± 14.7 months. One patient had grade 3 complications, and the median overall survival was 12.0 months (95% confidence interval 9.7-14.3). Multivariate analysis showed that Child-Pugh class, serum alpha-fetoprotein level, and Eastern Cooperative Oncology Group performance status were independent factors of survival.\nOur results suggest that percutaneous MWA combined with simultaneous TACE is a safe and effective treatment for HCC with MVI/EHM.",
"affiliations": "Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.;Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.;Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.;Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.;Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.;Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.;Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.;Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.;Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.",
"authors": "Wu|Mengfei|M|;Gao|Shanshan|S|;Song|Huadan|H|;Zhang|Zihan|Z|;Zheng|Zhiyuan|Z|;Yan|Zhiping|Z|;Wang|Xiaolin|X|;Wang|Jianhua|J|;Liu|Lingxiao|L|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.1016/j.jimed.2019.07.003",
"fulltext": "\n==== Front\nJ Interv Med\nJ Interv Med\nJournal of Interventional Medicine\n2096-3602\n2590-0293\nKeAi Publishing\n\nS2096-3602(19)30085-7\n10.1016/j.jimed.2019.07.003\nArticle\nPercutaneous microwave ablation combined with simultaneous transarterial chemoembolization for hepatocellular carcinoma with macrovascular invasion or extrahepatic metastases\nWu Mengfei a\nGao Shanshan ab\nSong Huadan a\nZhang Zihan a\nZheng Zhiyuan ab\nYan Zhiping ab\nWang Xiaolin ab\nWang Jianhua ab\nLiu Lingxiao liu.lingxiao@zs-hospital.sh.cn\nab∗\na Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China\nb Shanghai Institute of Medical Imaging, Shanghai, 200032, China\n∗ Corresponding author. Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. liu.lingxiao@zs-hospital.sh.cn\n30 7 2019\n5 2019\n30 7 2019\n2 2 5559\n© 2019 Shanghai Journal of Interventional Medicine Press. Production and hosting by Elsevier B.V. on behalf of KeAi.\n2019\nShanghai Journal of Interventional Medicine Press\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nTo evaluate the safety and efficacy of percutaneous microwave ablation (MWA) combined with simultaneous transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) or extrahepatic metastases (EHM).\n\nMethods\n\nBetween August 2012 and April 2017, 101 patients with MVI/EHM of HCC underwent percutaneous MWA combined with simultaneous TACE at our center. The clinical data were collected and analyzed for survival and prognostic factors.\n\nResults\n\nThe mean follow-up time was 23.6 ± 14.7 months. One patient had grade 3 complications, and the median overall survival was 12.0 months (95% confidence interval 9.7–14.3). Multivariate analysis showed that Child-Pugh class, serum alpha-fetoprotein level, and Eastern Cooperative Oncology Group performance status were independent factors of survival.\n\nConclusion\n\nOur results suggest that percutaneous MWA combined with simultaneous TACE is a safe and effective treatment for HCC with MVI/EHM.\n\nKeywords\n\nHepatocellular carcinoma\nCombination therapy\nMicrowave ablation\nSurvival\n==== Body\npmcIntroduction\n\nHepatocellular carcinoma (HCC) has a high incidence worldwide.1 Although hepatology and oncology societies recommend regular monitoring of high-risk populations2, most of the developing countries does not have a well-established HCC surveillance system. In that condition, 30–35% of patients are diagnosed at stage C HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging system(3), which means the patients have macrovascular invasion (MVI), extrahepatic metastases (EHM), or poor performance status (PS).4 Currently, the BCLC system is widely used in most clinical treatment decisions. Targeted drugs represented by sorafenib are recommended treatment for patients with stage C HCC. Although the use of sorafenib has been shown to prolonged the median overall survival (OS) of patients with stage C HCC, the high cost of this drug5 has hindered the full implementation of the BCLC recommendation. Moreover, this recommendation does not adequately take into account the heterogeneity of patients with stage C HCC.3 Researchers are making unceasing efforts to improve the treatment of patients with stage C HCC.6,7 This study aimed to retrospectively analyzed the survival of HCC patients with MVI and/or EHM treated by percutaneous microwave ablation (MWA) combined with simultaneous transarterial chemoembolization (TACE) treatment at our center.\n\nMaterials and methods\n\nPatients\n\nA total of 101 HCC patients with description above between August 2011 and April 2017 were included in this retrospective study. All patients signed and consented their conditions to be used as analytical data.\n\nThe inclusion criteria were: (i) HCC diagnosed on the basis of pathologic evaluation or the diagnostic criteria of American Association for the Study of Liver Diseases(8), (ii) MVI (incomplete portal occlusion or presence of portal vein collateral circulation) or EHM on radiology, (iii) Child-Pugh class A/B, and (iv) Eastern Cooperative Oncology Group (ECOG) PS 0–2 score. The exclusion criteria were (i) uncorrectable coagulation abnormalities, (ii) hepatic encephalopathy, massive ascites, or other serious complications, and (iii) other malignant tumors.\n\nPreoperative examination\n\nAbdominal enhanced computed tomography (CT)/magnetic resonance imaging (MRI) examination was performed within 2 weeks before treatment. Moreover, routine blood parameters, liver and kidney function, electrolytes, coagulation function, and levels of serum alpha-fetoprotein (AFP), carbohydrate antigen 199 (CA199), and carcinoembryonic antigen (CEA) were regularly measured. Patients with treatment contraindications were excluded to avoid fatal intraoperative or postoperative complications. All patients were deprived of fluid for at least 4 h before treatment.\n\nTreatment procedure\n\nAll treatments were done in a single phase, under sedation or local anesthesia. The patients were placed supine on a digital subtraction angiography (DSA) bed.\n\nTumor confirmation\n\nThe right femoral artery was punctured by following the modified Seldinger method. Hepatic artery and superior mesenteric artery angiography was performed to observe the location, size, number, and staining of the tumors. The location, boundary, and visibility of the tumors were observed using ultrasound.\n\nUltrasound-guided percutaneous MWA\n\nTaking into account the findings of preoperative abdominal enhanced CT/MRI, combined with intraoperative DSA, the ultrasound examination was performed to determine the ablation of the tumors and to establish a suitable puncture path (through 1 cm liver parenchyma and the shortest path avoiding large blood vessels, gallbladder, bile duct, and intestine). Under ultrasound guidance, the tumor was directly punctured with a 14G microwave antenna. To cover the target tumor with the ablation range and reach 0.5–1 cm beyond the tumor boundary, multipoint ablation was adopted. After the end of the ablation procedure, the needle was withdrawn while applying 50W to ablate the needle track.\n\nTACE treatment\n\nAfter the MWA procedure, hepatic angiography was performed again to observe the effect of ablation. Moreover, the blood supply and staining of residual lesions were also observed. At the same time, the presence of bleeding and signs of an arteriovenous fistula were checked. A microcatheter was superselected to the target artery, and a suspension oxaliplatin (50–150 mg) + epirubicin (20–50 mg) + ultra -liquefied Lipiodol (5–20 ml)+ contrast agent was injected. When blood flow was observed to be stagnant, the injection would be stopped. Angiography of the infraorbital artery or left gastric artery and embolization were performed if necessary.\n\nPostoperative treatment\n\nAfter the removal of the catheter and vascular sheath, a pressure bandage was applied to the puncture site. The patient was asked to keep the right lower limb straight and immobilized for 6 h. After 24 h, the pressure bandage was removed. Vital signs were monitored 24 h after treatment, and the patients were provided with liver protection, hydration, antiemetics, urine alkalization agents, and nutritional support treatments.\n\nPostoperative follow-ups and evaluation\n\nAbdominal enhanced CT/MRI was performed at 1, 3, 6, 9, and 12 months after treatment. Moreover, routine blood parameters, liver and kidney function, electrolytes, and levels of serum AFP, CA199, and CEA were also measured. According to the modified Response Evaluation Criteria in Solid Tumors (m-RECIST) standard9, the therapeutic response of target tumors was divided into complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). If residual tumors, recurrences, or metastases were found during follow-up visits, the treatment was rescheduled based on the patient's condition. When there was no enhanced lesion on abdominal enhanced CT/MRI within 1 year, further follow-up imaging would be scheduled every 6 months. Complications were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.\n\nData and statistical analysis\n\nAll data were obtained from electronic medical records or via telephone follow-up. Data analysis was performed using SPSS24 (Chicago, IL, USA). Measurement data were expressed as mean ± standard deviation and analyzed using an independent sample t-test. Count data were expressed as percentages and analyzed using the chi-square test. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test and Cox proportional hazards model were used to analyze risk factors that may affect survival. Values of p < 0.05 were considered statistically significant.\n\nResults\n\nBasic clinical characteristics of the patients\n\nA total of 101 patients with HCC with MVI or/and EHM were included in this study. HCC was diagnosed pathologically in 27 patients and according to the diagnostic criteria of American Association for the Study of Liver Diseases8 in the remaining patients. A total of 140 percutaneous MWA combined with simultaneous TACE treatments were performed, which meant an average of 1.4 times per patient. The cohort comprised 93 men and 8 women, with an average age of 54.2 ± 12.1 years (range, 22–81 years). Among the patients with MVI, 7 had portal vein invasion or tumor thrombosis, 38 had portal vein branch invasion, and 38 had both portal vein invasion and branch invasion or tumor thrombosis. There were also 21 patients with vena cava invasion or tumor thrombosis. There were 16 patients with EHM, including 1 patient with multiple organ metastases. The clinical characteristics of the patients are shown in Table 1.Table 1 Basic clinical and tumor characteristics of patients.\n\nTable 1Characteristics\tMVI (n = 85, 84.2%)\tEHM (n = 12, 11.9%)\tMVI + EHM (n = 4, 3.9%)\tp-Value\t\nAge (years)\t\t\t\t0.301\t\n <65\t69\t9\t2\t\t\n ≥65\t16\t3\t2\t\t\nSex\t\t\t\t0.188\t\n Male\t80\t10\t3\t\t\n Female\t5\t2\t1\t\t\nPre-session serum AFP (ng/mL)\t\t\t\t0.501\t\n <400\t45\t7\t1\t\t\n ≥400\t40\t5\t3\t\t\nECOG-PS\t\t\t\t0.265\t\n 0–1\t70\t10\t2\t\t\n 2\t15\t2\t2\t\t\nChild-Pugh class\t\t\t\t0.288\t\n A\t72\t12\t3\t\t\n B\t13\t0\t1\t\t\nRecurrence after surgical resection\t\t\t\t0.088\t\n Yes\t6\t3\t1\t\t\n No\t79\t9\t3\t\t\nNo. of tumors\t\t\t\t0.547\t\n <3\t45\t6\t1\t\t\n ≥3\t40\t6\t3\t\t\nTumor size (cm)\t\t\t\t0.109\t\n <5\t16\t5\t0\t\t\n ≥5\t69\t7\t4\t\t\nMVI: Microvascular Invasion; EHM: Extrahepatic Metastases; AFP: Alpha Fetoprotein; ECOG-PS: Eastern Cooperative Oncology Group Performance Status.\n\nComplications\n\nThe commonly observed complications were post-embolic syndrome, including fever, abdominal pain, nausea, and vomiting. These symptoms were usually were resolved 3–10 days after symptomatic treatment. Biloma (CTCAE grade 3) was detected on 1 patient at 11 month after treatment, which was CTCAE grade 3. There were no complications such as bleeding, adjacent organ damage, and other grade 3 complications that prolonged the hospital stays or caused disability or death.\n\nLocal efficacy evaluation\n\nTwo radiologists with >10 years of experience in abdominal diagnosis evaluated the efficacy of the treatment of target tumors according to the m-RECIST criteria. There were 13 patients with CR, 59 patients with PR, 25 patients with SD, and 4 patients with PD based on abdominal enhanced CT/MRI scans 1 month after treatment. 3 months after treatment, there were 13 patients with CR, 60 patients with PR, 14 patients with SD, and 14 patients with PD.\n\nSurvival\n\nThe mean follow-up time was 23.6 ± 14.7 months. The OS rates at 0.5, 1, 1.5, 2, and 3 years were 81.2%, 50%, 28.1%, 18.6%, and 12.4%, respectively. The median OS was 12.0 months (95% confidence interval [CI] 9.7–14.3). The median OS of MVI, EHM, and MVI + EHM was 11.7 months (95% CI 8.55–14.9), 14.8 months (95% CI 11.2–18.5), and 4.8 months (95% CI 2.4–7.3), respectively. EHM had a longer median OS than MVI (p = 0.375) and MVI had a longer median OS than MVI + EHM, with no statistical difference (p = 0.087). The median OS of EHM was longer than that of MVI + EHM, and the difference was statistically significant (p = 0.042) (Fig. 1) (see Fig. 2).Fig. 1 A: Survival curve for the entire cohort. B: Survival curves for MVI, EHM, and MVI + EHM. MVI, microvascular invasion; EHM, extrahepatic metastases.\n\nFig. 1\n\nFig. 2 Hepatocellular carcinoma in the left hepatic lobe with thoracic spine metastasis in a 28-year-old man. A and B: Preoperative enhanced magnetic resonance images showing large left-lobe lesions. C and D: Enhanced magnetic resonance images showing tumor necrosis at 1 month after surgery.\n\nFig. 2\n\nPrognostic factors\n\nWe analyzed the prognostic factors (sex, age, recurrence, number of tumors, tumor size, Child-Pugh class, and AFP level) that may affect the survival of patients with HCC with MVI or/and EHM treated with MWA combined with simultaneous TACE. Univariate analysis revealed that tumor size, Child-Pugh class, serum AFP, and ECOG-PS were associated with survival. Furthermore, multivariate analysis showed that Child-Pugh class, serum AFP level, and ECOG-PS were independent factors affecting the survival of patients (Table 2). Patients with Child-Pugh B, serum AFP ≥400 ng/ml, and ECOG-PS = 2 had shorter survival period.Table 2 Results of univariate and multivariate analyses.\n\nTable 2Clinical characteristics\tUnivariate analysis\tMultivariate analysis\t\nHR (95% CI)\tp-Value\tHR (95% CI)\tp-Value\t\nSex\t\n Male\t0.975\t0.961\tNA\tNA\t\n Female\t0.351–2.709\t\nAge (years)\t\n <65\t1.155\t0.614\tNA\tNA\t\n ≥65\t0.659–2.023\t\nChild-Pugh classification\t\n A\t5.196\t<0.001\t4.656\t<0.001\t\n B\t2.724–9.911\t2.333–9.291\t\nSerum AFP (ng/mL)\t\n <400\t1.886\t0.010\t2.173\t0.002\t\n ≥400\t1.167–3.048\t1.326–3.560\t\nECOG-PS\t\n 0–1\t4.384\t<0.001\t3.719\t<0.001\t\n 2\t2.523–7.616\t2.086–6.628\t\nRecurrence after surgical resection\t\n No\t1.304\t0.459\tNA\tNA\t\n Yes\t0.646–2.630\t\t\t\t\nTumor size (cm)\t\n <5.0\t2.055\t0.023\t1.408\t0.294\t\n ≥5\t1.106–3.819\t0.743–2.669\t\nNo. of tumors\t\n <3\t1.193\t0.465\tNA\tNA\t\n ≥3\t0.743–1.915\t\nHR: hazard ratio; CI: confidence interval; MVI: microvascular invasion; EHM: extrahepatic metastases; AFP: alpha fetoprotein; ECOG-PS: Eastern Cooperative Oncology Group performance status; NA: not applicable.\n\nBold indicates that the data is statistically significant.\n\nDiscussion\n\nTill now, there have been many attempts to find therapy strategies for HCC with stage C, include sorafenib, TACE, TACE combined with sorafenib, portal vein stent placement plus 125I seed strand combined with TACE, and radioembolization.5, 6, 7,10 Currently, targeted drugs represented by sorafenib are BCLC-recommended method for treating patients with BCLC stage C HCC.4 The SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol)11,9 and Asia Pacific trials12 have also confirmed that sorafenib confers a longer survival time than does placebo, thus support the recommendation for BCLC stage C patients to use sorafenib. However, in most of the developing countries, sorafenib is not universally applicable because of its expenses. Besides, some patients have concerns about the adverse effects of sorafenib and the impact on the quality of life. Considering the high incidence and the late diagnosis of HCC in China13, the Chinese guideline recommends that patients with BCLC stage C HCC to choose TACE (in the absence of TACE contraindications) and/or receive sorafenib. The effect of thermal ablation in the treatment of HCC is counted into the consideration. MWA is being increasingly applied owing to its fast heating and large ablation range. At our center, we perform percutaneous MWA combined with simultaneous TACE on patients with BCLC stage C HCC who were unwilling to take sorafenib.\n\nIn our study, HCC patients with EHM had longer median OS than those with MVI or MVI + EHM, and patients with MVI had longer median OS than those with MVI + EHM, which is consistent with the trends reported in another study.3 However, there was a difference in the existence of a statistical significance, which may be related to the proportionality of the cases. The proportion of HCC with MVI cases in our study (84.2%) was much higher than that of the other cases, whereas the proportion of MVI + EHM cases was only 3.9% (n = 4).\n\nOur study concluded that the median OS of percutaneous MWA combined with simultaneous TACE for HCC with MVI and EHM reached 11.7 and 14.8 months, respectively. According to the results of existing studies, the median OS of sorafenib and TACE in the treatment of HCC with MVI was 3.0 and 4.1 months5, respectively. The median OS of HCC with EHM was 7 and 8 months, respectively.14 Percutaneous MWA, a localized radical treatment, combined with TACE can result in larger necrosis areas in tumors. Most patients with stage C HCC have large tumors and a large tumor burden. In our study, patients with tumors >5 cm in size accounted for 79.2%.Because of the complicated blood supply of large tumors, the effect of TACE alone is poor and the tumor necrosis rate is also low.15 In simultaneous therapy, MWA first inactivates most tumors, which reduces the tumor burden, then TACE embolizes residual tumors and injects chemotherapy drugs. This method not only greatly reduces the amount of Lipiodol and chemotherapeutic drugs16, but also allows observations of the ablation effect of MWA through DSA during TACE. At the same time, bleeding and arteriovenous fistula can be detected and treated in timely with TACE.17\n\nOur study found that Child-Pugh class, serum AFP level, and ECOG-PS were independent prognostic factors of survival in patients with MVI or EHM HCC. This is consistent with previous studies.18 The role of serum AFP levels in the prognosis of patients with HCC is well known. Patients with Child-Pugh class A had a longer survival than those with Child-Pugh class B, which has been confirmed in many studies, meaning that good liver function status is beneficial to the prognosis.19 The prognostic role of ECOG-PS is also evident. Patients with PS 1–2 HCC are classified into BCLC stage C even if there is no MVI or EHM.\n\nLimitations\n\nThis is a retrospective study with limitations such as selection bias, recall bias, and limited data. Prospective clinical trials are needed to further investigate the benefits of concurrent therapy for patients with BCLC stage C HCC. Randomized controlled trials are needed to compare the efficacy of concurrent therapy with combination therapy and other replacement therapy therapies to sorafenib.\n\nConclusion\n\nOur data suggests that percutaneous MWA combined with simultaneous TACE is a safe and effective treatment for patients with MVI or EHM HCC. However, prospective clinical studies are still needed to validate our recommendations.\n\nConflict of interest\n\nNo conflict of interest to declare.\n\nFunding\n\nNone.\n==== Refs\nReferences\n\n1 Chiang C.L. Chan M.K.H. Yeung C.S.Y. Combined stereotactic body radiotherapy and trans-arterial chemoembolization as initial treatment in BCLC stage B-C hepatocellular carcinoma Strahlenther Onkol 195 2019 254 264 30413833\n2 European Association For The Study Of The Liver European Organisation For Research And Treatment Of Cancer EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma J Hepatol 56 2012 908 943 22424438\n3 Giannini E.G. Bucci L. Garuti F. Patients with advanced hepatocellular carcinoma need a personalized management: a lesson from clinical practice Hepatology 67 2018 1784 1796 29159910\n4 Forner A. Reig M.E. de Lope C.R. Current strategy for staging and treatment: the BCLC update and future prospects Semin Liver Dis 30 2010 61 74 20175034\n5 Luo J.J. Zhang Z.H. Liu Q.X. Endovascular brachytherapy combined with stent placement and TACE for treatment of HCC with main portal vein tumor thrombus Hepatol Int 10 2016 185 195 26341514\n6 Huang M. Lin Q. Wang H. Survival benefit of chemoembolization plus Iodine125 seed implantation in unresectable hepatitis B-related hepatocellular carcinoma with PVTT: a retrospective matched cohort study Eur Radiol 26 2016 3428 3436 26792430\n7 Ali R. Gabr A. Abouchaleh N. Survival analysis of advanced HCC treated with radioembolization: comparing impact of clinical performance status versus vascular invasion/metastases Cardiovasc Interv Radiol 41 2018 260 269\n8 Bruix J. Sherman M. American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update Hepatology 53 2011 1020 1022 21374666\n9 Eisenhauer E.A. Therasse P. Bogaerts J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 45 2009 228 247 19097774\n10 Bruix J. Cheng A.L. Meinhardt G. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies J Hepatol 67 2017 999 1008 28687477\n11 Llovet J.M. Ricci S. Mazzaferro V. Sorafenib in advanced hepatocellular carcinoma N Engl J Med 359 2008 378 390 18650514\n12 Cheng A.L. Kang Y.K. Chen Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial Lancet Oncol 10 2009 25 34 19095497\n13 Chen W. Zheng R. Baade P.D. Cancer statistics in China, 2015 CA Cancer J Clin 66 2016 115 132 26808342\n14 Kirstein M.M. Voigtlander T. Schweitzer N. Transarterial chemoembolization versus sorafenib in patients with hepatocellular carcinoma and extrahepatic disease United Eur Gastroenterol J 6 2018 238 246\n15 Ni J.Y. Sun H.L. Chen Y.T. Prognostic factors for survival after transarterial chemoembolization combined with microwave ablation for hepatocellular carcinoma World J Gastroenterol 20 2014 17483 17490 25516662\n16 Yang G.W. Zhao Q. Qian S. Percutaneous microwave ablation combined with simultaneous transarterial chemoembolization for the treatment of advanced intrahepatic cholangiocarcinoma OncoTargets Ther 8 2015 1245 1250\n17 Si Z.M. Wang G.Z. Qian S. Combination therapies in the management of large (>/= 5 cm) hepatocellular carcinoma: microwave ablation immediately followed by transarterial chemoembolization J Vasc Interv Radiol 27 2016 1577 1583 27103146\n18 Adhoute X. Penaranda G. Raoul J.L. Prognosis of advanced hepatocellular carcinoma: a new stratification of Barcelona Clinic Liver Cancer stage C: results from a French multicenter study Eur J Gastroenterol Hepatol 28 2016 433 440 26695429\n19 Lee S. Kim B.K. Kim S.U. Clinical outcomes and prognostic factors of patients with advanced hepatocellular carcinoma treated with sorafenib as first-line therapy: a Korean multicenter study J Gastroenterol Hepatol 29 2014 1463 1469 25273508\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2590-0293",
"issue": "2(2)",
"journal": "Journal of interventional medicine",
"keywords": "Combination therapy; Hepatocellular carcinoma; Microwave ablation; Survival",
"medline_ta": "J Interv Med",
"mesh_terms": null,
"nlm_unique_id": "9918265602006676",
"other_id": null,
"pages": "55-59",
"pmc": null,
"pmid": "34805873",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": "18650514;19095497;29511553;28687477;28879621;22424438;27103146;26808342;25273508;26695429;26792430;21374666;25516662;30413833;19097774;20175034;26060410;29159910;26341514",
"title": "Percutaneous microwave ablation combined with simultaneous transarterial chemoembolization for hepatocellular carcinoma with macrovascular invasion or extrahepatic metastases.",
"title_normalized": "percutaneous microwave ablation combined with simultaneous transarterial chemoembolization for hepatocellular carcinoma with macrovascular invasion or extrahepatic metastases"
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"abstract": "The molecular effects of etoposide in haemopoietic cells suggest that mixed lineage leukaemia (MLL) abnormalities can be biomarkers of patient susceptibility to the genotoxic effects of topoisomerase 2 (topo 2) inhibitors. We have prospectively studied treatment-related MLL cleavage and rearrangement in serial samples from 71 children receiving chemotherapy, using Southern blot analysis and panhandle PCR. The results were related to patient demographics, treatment details and outcome. MLL cleavage was identified in six bone marrow samples from five patients 2-10 months after the start of therapy. There was no obvious relationship between the degree of MLL cleavage and cumulative dose or schedule of topo 2 inhibitors. Three children with low percentage (23-30%) cleavage remained well and two were still receiving treatment at study completion. One child with two consecutively positive samples and higher level of MLL cleavage (45-48%) died from treatment-related toxicities and relapsed leukaemia. A patient with haemophagocytic lymphohistiocytosis developed the highest level of MLL cleavage (50%) at 3 months and a treatment-related leukaemia with MLL rearrangement 6 months after the start of treatment. It would appear that some patients are inherently more susceptible to the genotoxic effect of topo 2 inhibitors. The degree and persistence of MLL cleavage may identify patients at risk.",
"affiliations": "Immunogenetics Laboratory, University of Manchester and Central Manchester and Manchester Children's University Hospital Trust, Manchester, UK.",
"authors": "Ng|A|A|;Taylor|G M|GM|;Wynn|R F|RF|;Eden|O B|OB|",
"chemical_list": "D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2403599",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "19(2)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007938:Leukemia; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes; D044469:Racial Groups; D014157:Transcription Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "253-9",
"pmc": null,
"pmid": "15592432",
"pubdate": "2005-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effects of topoisomerase 2 inhibitors on the MLL gene in children receiving chemotherapy: a prospective study.",
"title_normalized": "effects of topoisomerase 2 inhibitors on the mll gene in children receiving chemotherapy a prospective study"
} | [
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"companynumb": "GB-MYLANLABS-2018M1052677",
"fulfillexpeditecriteria": "1",
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{
"abstract": "A 2-year-old boy presented with a large cystic and solid chest mass arising from the lung, radiographically consistent with pleuropulmonary blastoma (PPB). He underwent right lower lobectomy with resection of a well-circumscribed, mixed solid and cystic mass. The solid areas were composed of cords and nests of tumor cells in the myxoid stroma and retiform foci whose pathologic and immunophenotypic findings were consistent with a sex cord-stromal tumor with features of a Sertoli-Leydig cell tumor. Tumor testing showed a pathogenic variant in the DICER1 RNase IIIb hotspot domain. Family history was suggestive of DICER1 germline pathogenic DICER1 variation in absence of a detectable germline variant. He received 12 cycles of chemotherapy with ifosfamide, vincristine, dactinomycin and doxorubicin (IVADo) and surgery with complete response. One year after completion of chemotherapy, imaging studies showed concern for recurrence confirmed by thorascopic biopsy of a pleural-based mass. He is currently receiving cisplatin-based chemotherapy with reduction in tumor size. Review of the literature showed no similar cases; however, review of our pathology files revealed a single similar case of anterior mediastinal Sertoli cell tumor in a 3-year-old girl.",
"affiliations": "Division of Pediatric Hematology/Oncology, Stead Family Children's Hospital, Iowa City, Iowa, USA.;Division of Pediatric Surgery, Stead Family Children's Hospital, Iowa City, Iowa, USA.;International PPB/DICER1 Registry, Children's Minnesota, Minneapolis, Minnesota, USA.;International PPB/DICER1 Registry, Children's Minnesota, Minneapolis, Minnesota, USA.;Division of Pediatric Hematology/Oncology, Stead Family Children's Hospital, Iowa City, Iowa, USA.;International PPB/DICER1 Registry, Children's Minnesota, Minneapolis, Minnesota, USA.;ResourcePath, Arlington, Virginia, USA.;Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology and Immunology, Washington University Medical Center, St. Louis, Missouri, USA.;Department of Pathology and Laboratory Medicine, Children's National Medical Center, Washington, District of Columbia, USA.;International PPB/DICER1 Registry, Children's Minnesota, Minneapolis, Minnesota, USA.",
"authors": "Terry|William|W|;Carlisle|Erica M|EM|;Mallinger|Paige|P|;Nelson|Alexander T|AT|https://orcid.org/0000-0002-1611-4577;Gordon|David|D|;Messinger|Yoav H|YH|https://orcid.org/0000-0001-7990-1802;Field|Amanda|A|;Dehner|Louis P|LP|;Hill|D Ashley|DA|;Schultz|Kris Ann P|KAP|https://orcid.org/0000-0002-1788-5832",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.29284",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "68(11)",
"journal": "Pediatric blood & cancer",
"keywords": "DICER1; Sertoli-Leydig cell tumor; pleuropulmonary blastoma; thoracic tumor",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": null,
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e29284",
"pmc": null,
"pmid": "34398502",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "19266086;26925222;19556464;33782093;21501861;3911780;26428316;26206391;31527943;29037807;15502809;28445692;29343557;30935425;22187960;7020914;24481001;33760357;27036314",
"title": "Thoracic Sertoli-Leydig cell tumor: An alternative type of pleuropulmonary blastoma associated with DICER1 variation.",
"title_normalized": "thoracic sertoli leydig cell tumor an alternative type of pleuropulmonary blastoma associated with dicer1 variation"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-55412",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "6",
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"abstract": "BACKGROUND Chronic intake of high-dose corticosteroids is associated with multiple adverse clinical effects, including hypertension, insulin resistance, impaired wound healing, immunosuppression, myopathy, and osteoporosis. In cases of autoimmune disease, use of steroid-sparing treatment modalities is preferred over chronic steroid therapy to limit these side effects. Glucocorticoid-induced myopathy is a less common side effect of chronic steroid use in patients treated with <10 mg/day of prednisone. However, doses exceeding 40-60 mg/day can induce clinically significant myopathy and weakness. CASE REPORT A 35-year-old woman with a past medical history of hypothyroidism, systemic lupus erythematosus (SLE), and end-stage renal disease secondary to lupus nephritis, on hemodialysis, presented to the local emergency department with progressive bilateral proximal lower extremity weakness. Three months before admission, when her insurance company prematurely discontinued her monthly cyclophosphamide injections, at which time, she was treated with prednisone 60 mg daily. Two months before hospital admission, she reported increasing fatigue, weight gain, difficulty in standing from a seated position and climbing stairs. CONCLUSIONS Elucidating the etiology of progressive neuromotor deficit in immunosuppressed patients can be difficult. The management of SLE and other autoimmune diseases with chronic high-dose steroids is associated with recognized side effects. Differentiating natural disease progression from iatrogenic etiologies is important in this subset of patients, particularly to reduce prolonged clinical management and hospital admissions.",
"affiliations": "School of Medicine, University of California Riverside, Riverside, CA, USA.;Department of Internal Medicine, Riverside University Health System, Moreno Valley, CA, USA.",
"authors": "Silver|Elliot M|EM|;Ochoa|William|W|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.906377",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2952581010.12659/AJCR.906377906377ArticlesGlucocorticoid-Induced Myopathy in a Patient with Systemic Lupus Erythematosus (SLE): A Case Report and Review of the Literature Silver Elliot M. ABCDEF1Ochoa William EG2\n1 School of Medicine, University of California Riverside, Riverside, CA, U.S.A.\n2 Department of Internal Medicine, Riverside University Health System, Moreno Valley, CA, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Elliot M. Silver, e-mail: Elliot.M.Silver@gmail.com2018 11 3 2018 19 277 283 25 7 2017 14 12 2017 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 35\n\nFinal Diagnosis: Glucocorticoid-induced myopathy\n\nSymptoms: Generalized weakness\n\nMedication: Prednisone\n\nClinical Procedure: —\n\nSpecialty: General and Internal Medicine\n\nObjective:\nUnusual clinical course\n\nBackground:\nChronic intake of high-dose corticosteroids is associated with multiple adverse clinical effects, including hypertension, insulin resistance, impaired wound healing, immunosuppression, myopathy, and osteoporosis. In cases of autoimmune disease, use of steroid-sparing treatment modalities is preferred over chronic steroid therapy to limit these side effects. Glucocorticoid-induced myopathy is a less common side effect of chronic steroid use in patients treated with <10 mg/day of prednisone. However, doses exceeding 40–60 mg/day can induce clinically significant myopathy and weakness.\n\nCase Report:\nA 35-year-old woman with a past medical history of hypothyroidism, systemic lupus erythematosus (SLE), and end-stage renal disease secondary to lupus nephritis, on hemodialysis, presented to the local emergency department with progressive bilateral proximal lower extremity weakness. Three months before admission, when her insurance company prematurely discontinued her monthly cyclophosphamide injections, at which time, she was treated with prednisone 60 mg daily. Two months before hospital admission, she reported increasing fatigue, weight gain, difficulty in standing from a seated position and climbing stairs.\n\nConclusions:\nElucidating the etiology of progressive neuromotor deficit in immunosuppressed patients can be difficult. The management of SLE and other autoimmune diseases with chronic high-dose steroids is associated with recognized side effects. Differentiating natural disease progression from iatrogenic etiologies is important in this subset of patients, particularly to reduce prolonged clinical management and hospital admissions.\n\nMeSH Keywords:\nGlucocorticoidsLupus Erythematosus, SystemicMuscular Diseases\n==== Body\nBackground\nThe term, myopathy, refers to the loss of contractile function of muscle that results in weakness. Myopathies are distinct from neuromuscular junction disease and neuropathic causes of weakness, in that the primary defect is within the muscle tissue. The etiology of myopathy varies widely and includes endocrine disorders, nutritional deficiency, metabolic disease, drug-induced or toxic causes, congenital disease, inflammatory, and infectious processes.\n\nEndocrine disorders of the thyroid, parathyroid, adrenal, and pituitary glands can produce hormonally-mediated alterations in metabolism that can disrupt myocyte function, leading to weakness. Electrolyte and vitamin abnormalities including hypokalemia (serum potassium <2.5 mEq/l), hypercalcemia (serum calcium >14 mg/dl), and vitamin D deficiency (25(OH) D3) (<10 ng/ml) may also lead to symptomatic weakness [1]. Metabolic myopathies include disorders of carbohydrate, purine, and lipid metabolism [1]. The presentation of metabolic myopathies can vary, and affected individuals may present with dynamic symptoms, such as exercise intolerance, acutely reversible weakness, and myoglobinuria, or may present with static symptoms, including fixed weakness, cardiomyopathy, and neuropathy.\n\nIatrogenic causes of myopathy include the chronic use of corticosteroids, colchicine, antimalarials, and statins, and are often reversible with cessation of use of the drug. Illicit drug use and alcohol abuse have recognized associations with myopathy. Specifically, cocaine is proposed to induce muscle injury through increased sympathomimetic activity and arterial vasoconstriction [2]. Alcohol and its metabolites can disrupt intracellular metabolism and cellular membrane structures, and there are reported cases of both acute and chronic myopathy following ‘binge’ drinking and chronic consumption, respectively [3].\n\nCongenital myopathies include central-core disease, nema-line and myotubular myopathies, which are usually present at birth or infancy. Affected individuals can present with variable degrees of non-progressive or slowly progressive generalized weakness, hypotonia and, in severe cases, may present as a ‘floppy infant.’ The diagnosis of congenital myopathies requires histological examination to identify pathological features of type-1 muscle fibers that are unique to these diseases. Conversely, inflammatory myopathies more commonly present in adulthood and fall into three distinct categories: infectious, noninfectious inflammatory, and systemic inflammatory disease. Infection-related myopathies are often viral in origin, and are due to influenza, parainfluenza, human immune deficiency virus (HIV), Epstein Barr virus (EBV), and Echovirus, but may also be due to bacterial myositis (Lyme disease) and parasitic (toxoplasmosis) etiologies. Noninfectious inflammatory myopathies include dermatomyositis, polymyositis, and inclusion body myositis (hereditary inflammatory myopathy). Systemic inflammatory myopathies are often associated with autoimmune diseases and include systemic lupus erythematosus (SLE), Sjögren’s syndrome, rheumatoid arthritis, and scleroderma.\n\nSLE is a prototypic multisystem disease of autoimmune origin and is characterized by a fundamental failure of mechanisms that maintain self-tolerance. Autoimmune injury leads to tissue damage and apoptosis, together with an inadequate clearance of nuclear material, that may result in the exposure of a large burden of nuclear antigens to the immune system. Underlying abnormalities in B-lymphocytes and T-lymphocytes allow for the survival of self-reactive lymphocytes, which are then stimulated by ‘self’ nuclear antigens, allowing antibody production against these antigens. The net result is a cycle of antigen release and immune cell activation resulting in the production of high-affinity autoantibodies [4]. As a result, virtually any organ in the body may be affected in SLE, including skeletal muscle.\n\nThe mainstay of treatment of inflammatory myopathies is immune suppression, including the use of corticosteroids. However, the prolonged use of corticosteroids is associated with multiple adverse effects, including hypertension, insulin resistance, poor wound healing, immunosuppression, myopathy, and osteoporosis. Glucocorticoids have been shown to induce myopathy by their direct catabolic effect on skeletal muscle, leading to increased levels of amino acids that can be utilized by the liver for gluconeogenesis. Also, glucocorticoid-induced suppression of the serine/threonine-protein kinase, AKT1, has been shown to increase ubiquitin-ligase atrogin-1 (MAFbx) that targets skeletal muscle proteins for degradation [5]. In cases of autoimmune disease, use of steroid-sparing treatment modalities is preferred over chronic steroid therapy, to limit the side effects.\n\nGlucocorticoid-induced myopathy is a less frequent effect of chronic steroid use in patients treated with <10 mg/day of prednisone. However, doses exceeding 40–60 mg/day can induce clinically significant weakness in less than two weeks [6]. The likelihood of developing glucocorticoid-induced myopathy increases with duration of use. However, the overall frequency of this adverse effect is not well defined.\n\nThis case report describes a 35-year-old woman who presented with progressive bilateral lower extremity weakness in the setting of hypothyroidism, nephritis due to SLE, and chronic steroid use.\n\nCase Report\nA 35-year-old woman with a past medical history of hypothyroidism, systemic lupus erythematosus (SLE), and end-stage renal disease secondary to lupus nephritis was treated with hemodialysis on alternate days, three days a week. She presented to the emergency department of her local hospital with progressive bilateral proximal lower extremity weakness.\n\nThe patient had been in her usual state of health until approximately three months before admission when her insurance company prematurely discontinued her monthly cyclophosphamide injections for treatment of lupus nephritis. She was then started on prednisone 60 mg daily. Two months before admission, she reported increasing fatigue, weight gain and muscle weakness with increasing difficulty standing from a seated position and difficulty climbing stairs. At this time, she also reported increasing numbness and tingling in her distal lower extremities. One month before admission her weakness progressed, and she was no longer able to ambulate independently. Her symptoms were reportedly constant, without aggravating or alleviating factors. On admission, she denied any previous episodes of weakness, pain, urinary or fecal incontinence, recent illness, fever, chills, nausea, vomiting, or diaphoresis.\n\nOn examination, the patient appeared well with a Cushingoid habitus. Her blood pressure was 127/59 mmHg, pulse rate 110 beats per minute, temperature 37.1°C, respiratory rate 18 breaths per minute, oxygen saturation 98% while on room air, and she rated her level of pain as 0 out of 10. Cardiac and respiratory examination findings were normal. Examination of the abdomen showed central obesity with multiple linear striae along the bilateral flanks but was otherwise normal. Inspection of her lower limbs showed symmetrical muscle tone without atrophy. Her skin was intact without erythema, ecchymoses, or signs of skin thinning. Palpation of the lower limbs showed no tenderness or myalgia. There was decreased sensation to light touch in the L4/L5 dermatomes. Motor function in all four extremities was grossly intact, but on strength testing, findings included, bilateral dorsiflexion +5, plantarflexion +5, and hip flexion +1. Biceps, triceps, patellar, and Achilles reflexes were 2+ and normal.\n\nLaboratory test results showed hematocrit (35%), hemoglobin (9.4 g/dl), mean corpuscular volume (MCV) 95 μm3, white blood cell count (WBC) 6.5 per mm3, platelets 73,000 per mm3, urea nitrogen 44 mg/dl, and creatinine 6.23 mg/dl. Blood levels of electrolytes, glucose, total protein, total bilirubin, alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were normal. An electrocardiogram (ECG) showed sinus tachycardia.\n\nMagnetic resonance imaging (MRI) of her lumbar spine was obtained and showed a compression deformity of the superior endplate of L1, with approximately 40% height loss and 1mm fragment retropulsion without evidence of significant stenosis of the central spinal canal or neural foraminal stenosis. MRI T2-weighted imaging showed increased signal intensity in the disc space and adjacent endplates above L1, which were findings that were supportive for spondylodiscitis (discitis). Neurosurgery consultation resulted in the decision to treat the L1 fracture conservatively with a thoracolumbosacral orthosis (TLSO) brace. Following this hospital admission, the patient resumed her previous medications that included hydroxychloroquine, nifedipine, levothyroxine, and prednisone, and she resumed her regular hemodialysis schedule. Cyclophosphamide treatment was reinitiated for management of lupus nephropathy.\n\nOn the third hospital day, a nuclear medicine three-phase bone scan was performed to further evaluate discitis as a cause of her persistent weakness. The bone scan showed a mild increase in uptake at the L1 vertebral body, but overall findings were nonspecific. In the absence of fever, leukocytosis, or back pain in the area of the compromised vertebrae, her radiculopathy symptoms were considered to be unlikely for underlying discitis or epidural abscess.\n\nWith low clinical suspicion for spinal cord compression, the diagnostic workup proceeded to evaluate a myopathic etiology for the symptoms of weakness in this patient. On the fourth hospital day, chemistry, urinalysis, and serologic tests for infectious, inflammatory, and endocrine myopathies were obtained. Serum creatine kinase (CK), lactate dehydrogenase (LDH), and aldolase were normal, as shown in Table 1. Urine myoglobin was not detected. Serological studies for antibodies to for influenza, parainfluenza, adenovirus, Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human immune deficiency virus (HIV) were negative, and the rapid plasma reagin (RPR) test for syphilis was non-reactive. The patient’s history of hypothyroidism raised the possibility of hypothyroid myopathy. However, the patient reported no other symptoms of hypothyroidism, and serum thyroid-stimulating hormone (TSH) was found to be within normal limits. Anti-Jo-1 and anti-Mi2 serologies were obtained to evaluate for inflammatory myositis (dermatomyositis, polymyositis) and were non-reactive. Autoimmune serology included measurement of anti-Ro (Sjögren’s), anti-La (Sjögren’s), anti-cyclic citrullinated peptide (CCP) (rheumatoid arthritis), anti-centromere (scleroderma), and anti-Scl-70 (scleroderma) were negative, and are listed in Table 2.\n\nOn the tenth hospital day, electromyography (EMG) was performed and showed low-amplitude motor unit potentials, consistent with a myopathic process. On the eleventh hospital day the patient was scheduled for a biopsy of her proximal thigh muscle; however, a left anterior tibialis biopsy was performed instead, and a proximal muscle biopsy was not obtained. Histological examination showed no necrosis or inflammatory infiltrates to suggest myositis. In the absence of serological or pathological evidence of myopathy, the patient was continued on high doses of steroids due to concerns for an atypical SLE myelopathy (transverse myelitis). Treatment with intravenous immunoglobulins (IVIG) was initiated for possible idiopathic immune-mediated neuromuscular disease but without clinical improvement.\n\nOn the eighteenth hospital day, the patient was transferred to the intensive care unit (ICU) with acute encephalopathy and hypotension. Computed tomography (CT) and MRI of the brain were negative for acute intracranial abnormalities. Anti-ribosomal P protein serology was negative, which excluded neuropsychiatric manifestations of SLE. Cerebrospinal fluid (CSF) and blood cultures were obtained and found to be positive for Group B Streptococcus (GBS), Streptococcus agalactiae. The patient received appropriate antibiotic treatment, and all subsequent blood cultures were negative for GBS. In the following weeks, the patient’s hospital course was complicated by extended ICU care, cytomegalovirus (CMV) gastritis, and colitis. Her clinical complications while in hospital are listed in Table 3.\n\nAfter two months in the hospital, the patient was severely debilitated, and on examination, her lower extremity weakness remained unchanged. Although physical therapy had been attempted, this had been limited due to previous spinal surgery. A repeat MRI of her lumbar spine showed a stable compression deformity of the L1 vertebrae without evidence of osteomyelitis or discitis. In the absence of conclusive evidence of spinal cord compression, neuropathic, or myopathic disease, the patient was titrated off of her steroid regimen in an attempt to exclude glucocorticoid-induced myopathy. Intensive twice-daily physical therapy was initiated in the following weeks. The patient progressed from sitting at the edge of the bed to brief periods of standing with assistance. The correlation between the improvement in her symptoms and tapering of steroids supported a diagnosis of glucocorticoid-induced myopathy; however, repeat EMG was not performed.\n\nFollowing a complicated three-month hospitalization, the patient was discharged to a subacute level of care for continued intensive physical rehabilitation. She was discharged in a stable condition with persistent paresthesiae, but with improved bilateral lower extremity motor strength.\n\nDiscussion\nUnderstanding the pathophysiology of glucocorticoid-induced myopathy is essential for distinguishing organic versus iatrogenic etiologies of new-onset muscle weakness. Physical examination, measurement of serum creatine kinase (CK) or aldolase, electrophysiologic studies, and muscle biopsy findings can provide important information regarding the etiology of patients presenting with these symptoms. In patients with systemic lupus erythematosus (SLE), it is important to exclude reversible causes, including glucocorticoid-induced muscle weakness [7,8]. The differential diagnosis of progressive bilateral lower extremity may vary widely in patients with autoimmune disease. In this case, in the absence of apparent spinal cord compression, the differential diagnosis of myopathy included drug-induced myopathy, SLE neuropathy, SLE myopathy, SLE myelopathy, uremic polyneuropathy, and vitamin D deficiency.\n\nThe clinical manifestations of glucocorticoid-induced myopathy include proximal muscle weakness and atrophy of proximal muscle groups without myalgia or muscle tenderness. Weakness most commonly appears in the lower extremities prior to affecting the upper extremities. The onset of weakness may be dose-dependent and duration-dependent, and studies have shown that doses of 40–60 mg/day can induce weakness within two weeks [6]. Muscle atrophy may be exacerbated by inactivity, which sensitizes skeletal muscle to the catabolic effects of steroids. Serum CK or aldolase levels are typically within normal limits and are rarely elevated [6,9]. However, serum lactate dehydrogenase (LDH) levels may be elevated. Electromyography studies often show no abnormalities in conduction rates. Muscle biopsy of the affected muscle groups may show increased numbers of sarcolemmal nuclei, loss of fiber cross-striations of type IIb fibers, without necrosis or inflammation [6,9,10]. The diagnosis of glucocorticoid-induced myopathy is most often based on history and physical examination, as there is no definitive test for this condition. Symptoms of weakness commonly show improvement after three to four weeks following discontinuation of steroid therapy.\n\nChloroquine and hydroxychloroquine are commonly prescribed for the treatment of SLE. These medications impair complement-dependent antigen-antibody reactions and provide a useful tool in the management of severe or refractory SLE. However, chronic use of chloroquine and hydroxychloroquine can lead to proximal muscle myopathies, with associated weakness and atrophy. Muscle enzyme levels, particularly CK levels, are usually normal. The gold standard method for the diagnosis of drug-induced myopathy is muscle biopsy. Microscopic findings include presence of autophagic membrane-bound vacuoles containing membranous debris within myocytes. There are characteristic curvilinear bodies with short curved membranous structures with alternating light and dark zones most commonly seen in type 1 fibers [4]. Treatment includes cessation of the causative drug.\n\nIn between 10–15% of patients with SLE, peripheral neuropathy secondary to vasculopathies of small arteries supplying the affected nerves can be a complication [11]. Clinically, patients often present with asymmetric paresthesiae and numbness of the digits that is worse at night [12]. Acute forms of peripheral neuropathy can present with ascending areflexic motor weakness without sensory loss. The diagnosis of peripheral neuropathy is made with electromyography and nerve conduction studies, which show polyphasic conduction velocities of long duration and high amplitude, consistent with generalized sensorimotor peripheral neuropathy. This type of neuropathy responds well to glucocorticoid treatment, usually within three weeks. A rare form of SLE neuropathy is chronic inflammatory demyelinating polyradiculoneuropathy (CIPD) that presents with recurrent episodes of Guillain-Barré syndrome-like symptoms, mononeuritis multiplex, or symmetric polyradiculopathy, over a period of weeks to months [13,14]. Treatment may involve glucocorticoids and intravenous immunoglobulins (IVIG) or plasmapheresis.\n\nUp to 70% of patients with SLE may present with myalgia, muscle tenderness, or weakness [15,16]. However, severe muscle weakness, atrophy, or myositis are uncommon, occurring in between 7–15% of patients [15,16]. Typically, diagnosis is made with muscle biopsy which shows perivascular and perifascicular mononuclear cell infiltrates in 25% of patients, or other inflammatory cell infiltration characteristic of SLE [17]. The diagnosis is supported by elevations in serum CK and aldolase. Conversely, antimalarial and glucocorticoid-induced myopathies show no inflammation, and serum CK and aldolase are usually normal. Treatment may involve glucocorticoids, with symptomatic improvement seen within two to three weeks.\n\nSLE myelopathy involving the central nervous system (CNS) rarely occurs in SLE, affecting between 1–2% of patients [18]. Symptoms include the acute or subacute development of neurological signs and symptoms consistent with motor, sensory and/or autonomic dysfunction. Sudden onset of lower extremity weakness or sensory loss are common reasons for patients to seek medical evaluation, and fecal and urinary incontinence is usually present. The pathogenesis is thought to be secondary to arteritis, resulting in ischemic necrosis of the spinal cord. MRI, with and without gadolinium, should be used to exclude other causes of spinal cord compression. On T2-weighted MRI, hyperintense foci and localized edema around the spinal cord is a characteristic diagnostic feature. Analysis of cerebrospinal fluid (CSF) should be performed to rule out infection. However, CSF findings are abnormal in only half of all patients diagnosed with transverse myelitis [19]. Findings may include moderate lymphocytosis (typically <100/mm3) and elevated protein (100–120 mg/dl) with normal glucose levels. Treatment may include the combination of prednisone, plasmapheresis, and cyclophosphamide [19].\n\nThe prevalence of uremic polyneuropathy increases linearly with increasing serum creatinine [16]. Initial sensory symptoms include paresthesiae involving the distal lower extremities that ascend with disease progression. In more advanced stages, patients may experience motor symptoms, including distal weakness, myoclonus, and potential paralysis [19]. Physical examination in early disease shows loss of position sense and vibration sense with decreased deep tendon reflexes. Late findings may include muscle atrophy and motor symptoms. The diagnosis of uremic polyneuropathy usually requires electrophysiologic studies to measure motor conduction velocity of the peroneal nerve and sensory conduction velocity of the sural nerve [20]. Treatment may range from medical management, dialysis, or renal transplantation.\n\nHypovitaminosis D is prevalent in more than half of patients with SLE, leading to loss of trabecular bone density [21,22]. In the setting of osteomalacia, vitamin D deficiency-induced myopathy is associated with proximal muscle weakness, hypotonia, and muscle wasting [23]. In patients with end-stage renal disease, serum levels of 25-hydroxyvitamin D, or 25(OH)D, below 50 nmol/l has been correlated with decreased quadriceps strength [24]. Vitamin D sufficiency can be assessed by measuring serum levels of 25(OH)D or calcidiol, and can be supplemented orally. In this case, measurement of vitamin D levels would have been useful in helping determine whether vitamin D insufficiency was a contributing factor to this patient’s condition, but the findings may not have changed patient management.\n\nConclusions\nThis report is of a case of a patient who was first diagnosed with an incidental L1 compression fracture that prompted hospital admission and evaluation for discitis as a cause of bilateral lower extremity weakness. This case has been presented to raise the clinical suspicion for glucocorticoid-induced myopathy in patients presenting with muscle weakness in the context of chronic high-dose steroid use. Also, this case highlights the use of steroid-sparing modalities when appropriate, and recognizes the need for a multidisciplinary approach to the evaluation and treatment of patients with complex, multisystem autoimmune diseases, such as SLE.\n\nThe authors would like to thank Dr. David Lo of the University of California Riverside School of Medicine, and Riverside University Health System.\n\nConflict of interest\n\nNone.\n\nTable 1. Laboratory data (with reference ranges) on the day of admission.\n\nVariable\tReference range (adults)\tOn admission\t\nWBC count (per mm3)\t4,500–11,000\t6,700\t\nDifferential count\t\t\t\n Neutrophils (%)\t54–62\t64\t\n Lymphocytes (%)\t25–33\t26.8\t\n Monocytes (%)\t3–7\t7.6\t\n Eosinophils (%)\t1–3\t1.2\t\n Basophils (%)\t0–0.75\t0.4\t\nHemoglobin (g/dL)\t12.0–16.0\t9.4\t\nHematocrit (%)\t36–46\t35\t\nRBC (1012/L)\t3.94–5.66\t4.22\t\nMCV (fL)\t80–96\t97.7\t\nPlatelets (mm3)\t150,000–400,000\t73,000\t\nSodium (mmol)\t136–145\t147\t\nPotassium (mmol)\t3.6–5\t4.5\t\nCalcium (mg/dL)\t8.5–10.1\t9.0\t\nMagnesium (mg/dL)\t1.8–2.4\t2.0\t\nPhosphorous (mg/dL)\t2.5–4.9\t2.4\t\nUrea nitrogen (mg/dL)\t7–18\t44\t\nCreatinine (mg/dL)\t0.6–1.2\t6.23\t\nHemoglobin A1c (%)\t≤6\t5.6\t\nB12 (pg/mL)\t>250\t523\t\nVitamin D\tN/A\tN/A\t\nFolate (ng/dL)\t3.1–17.5\t12\t\nTSH (μU/mL)\t0.5–5.0\t3.4\t\nSerum creatine kinase (CK) U/L\t10–70\t62\t\nLactate dehydrogenase (LDH) (U/L)\t45–90\t59\t\nAldolase (U/L)\t<7.5\t4.1\t\nCopper (μg/dL)\t63–140\t82\t\nFe (μg/dL)\t40–155\t92\t\nTIBC (μg/dL)\t250–450\t127\t\nFerritin (μg/L)\t15–150\t682\t\nC-reactive protein (CRP) (mg/L)\t0–10\t1.45\t\nErythrocyte sedimentation rate (mm/hr)\t<30\t36\t\nWBC – white blood cells; RBC – red blood cells; MCV – mean cell volume; TSH – thyroid stimulating hormone; Fe – iron; TIBC – total iron-binding capacity.\n\nTable 2. Serology data during admission.\n\nAntigen\tResult\t\nAnti-Sm\t1.1 Positive\t\nAnti-Sm RNP\t>8 Positive\t\nAnti-DS DNA\t9 Positive\t\nANA\t1: 320\t\nRPR\tNon-reactive\t\nHIV\tNon-reactive\t\nInfluenza\tNon-reactive\t\nParainfluenza\tNon-reactive\t\nAdenovirus\tNon-reactive\t\nEpstein-Barr virus\tNon-reactive\t\nHepatitis B virus\tNon-reactive\t\nHepatitis C virus\tNon-reactive\t\nAnti-Jo-1\tNon-reactive\t\nAnti-Mi2\tNon-reactive\t\nAnti-Ro\tNon-reactive\t\nAnti-La\tNon-reactive\t\nAnti-CCP\tNon-reactive\t\nAnti-centromere\tNon-reactive\t\nAnti-Scl-70\tNon-reactive\t\nSm – smooth muscle; RNP – ribonucleoprotein; ANA – anti-nuclear antibody; RPR – rapid plasma reagin; HIV – human immune deficiency virus; CCP – cyclic citrullinated peptide.\n\nTable 3. Medical problems prior to hospital admission.\n\nMedical condition\tComplications\t\n\nLupus nephritis with ESRD\n\nL1compression fracture\n\nCMV colitis and gastritis\n\nHypertension\n\nThrombocytopenia\n\nNormocyticanemia\n\nDiscoid lupus under right breast\n\nOral herpes simplex virus\n\nHypothyroidism\n\n\t\nSeizure-like activity during hemodialysis\n\nGBS meningitis and bacteremia; Resolved\n\nLower GI bleeding\n\nRepeatedtransient hypoglycemia\n\nVRE UTI\n\nKlebsiella UTI\n\nHospital-acquiredpneumonia\n\nSteroid-inducedmyopathy\n\n\t\nUTI – urinary tract infection; ESRD – end-stage renal disease; CMV – cytomegalovirus; VRE – vancomycin-resistant E. coli; GI – gastrointestiunal; GBS – Group B Streptococcus.\n==== Refs\nReferences:\n1. Inzucchi SE Understanding hypercalcemia. Its metabolic basis, signs, and symptoms Postgrad Med 2004 115 4 69 70 73 76 15095538 \n2. Zamora-Quezada JC Dinerman H Stadecker MJ Kelly JJ Muscle and skin infarction after free-basing cocaine (crack) Ann Intern Med 1988 108 4 564 66 3348564 \n3. Haller RG Knochel JP Skeletal muscle disease in alcoholism Med Clin North Am 1984 68 1 91 103 6361420 \n4. Vinay K Abbas AK Fausto N Robbins and cotran pathologic basis of disease 8th ed. Philadelphia Elsevier Saunders 2010 219 21 \n5. Stitt TN Drujan D Clarke BA The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors Mol Cell 2004 14 3 395 403 15125842 \n6. Bowyer SL Lamothe MP Hollister JR Steroid myopathy: Incidence and detection in a population with asthma J Allergy Clin Immunol 1985 76 2 Pt 1 234 42 4019954 \n7. Isenber DA Snaith ML Muscle disease in systemic lupus erythematosus: A study of its nature, frequency and cause J Rheumatol 1981 8 6 917 24 7328567 \n8. Stevens MB Musculoskeletal manifestations. The clinical management of systemic lupus erythematosus Schur PH Grune and Stratton New York 1983 \n9. Khaleeli AA Edwards RH Gohil K Corticosteroid myopathy: A clinical and pathological study Clin Endocrinol (Oxf) 1983 18 2 155 66 6851197 \n10. Afifi AK Bergman RA Harvey JC Steroid myopathy. Clinical, histologic and cytologic observations Johns Hopkins Med J 1968 123 4 158 73 5681186 \n11. Florica B Aghdassi E Su J Peripheral neuropathy in patients with systemic lupus erythematosus Semin Arthritis Rheum 2011 41 2 203 11 21641018 \n12. Omdal R Henriksen OA Mellgren SI Husby G Peripheral neuropathy in systemic lupus erythematosus Neurology 1991 41 6 808 11 1646422 \n13. Lewis M Gibson T Systemic lupus erythematous with recurrent Guillain-Barré-like syndrome treated with intravenous immunoglobulins Lupus 2003 12 11 857 59 14667104 \n14. Vina ER Fang AJ Wallace DJ Weisman MH Chronic inflammatory demyelinating polyneuropathy in patients with systemic lupus erythematosus: Prognosis and outcome Semin Arthritis Rheum 2005 35 3 175 84 16325658 \n15. Dubois EL Wallace DJ Clinical and laboratory manifestations of SLE. Dubois LE Wallace DJ Dubois EL Lea and Febiger Philadelphia 1987 317 \n16. Ropes MW Systemic lupus erythematosus Harvard University Press Cambridge 1976 \n17. Rothfield N Clinical features of systemic lupus erythematosus. Textbook of rheumatology. Kelley WN Harris ED Ruddy S Sledge CB WB Saunders Philadelphia 1981 \n18. Beatriz Lavras C Ferreira DM Lavras Costallat LT Appenzeller S Myelopathy in systemic lupus erythematosus: Clinical, laboratory, radiological and progression findings in a cohort of 1,193 patients Rev Bras Reumatol Engl Ed 2016 56 3 240 51 27267643 \n19. Bertsias GK Ioannidis JP Aringer M EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: Report of a task force of the EULAR standing committee for clinical affairs Ann Rheum Dis 2010 69 12 2074 82 20724309 \n20. Aggarwal HK Sood S Jain D Evaluation of spectrum of peripheral neuropathy in predialysis patients with chronic kidney disease Ren Fail 2013 35 10 1323 29 23964701 \n21. Ruiz-Irastorza G Egurbide MV Olivares N Vitamin D deficiency in systemic lupus erythematosus: Prevalence, predictors and clinical consequences Rheumatology (Oxford) 2008 47 6 920 23 18411213 \n22. Bhattoa HP Kiss E Bettembuk P Balogh A Bone mineral density, biochemical markers of bone turnover, and hormonal status in men with systemic lupus erythematosus Rheumatol Int 2001 21 3 97 102 11765229 \n23. Lips P van Schoor NM Bravenboer N Vitamin D-related disorders. Primer on the metabolic bone diseases and disorders of mineral metabolism 8th ed Rosen CJ John Wiley & Sons, Inc Ames 2013 \n24. Boudville N Inderjeeth C Elder GJ Glendenning P Association between 25-hydroxyvitamin D, somatic muscle weakness and falls risk in end-stage renal failure Clin Endocrinol (Oxf) 2010 73 3 299 304 20507339\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D003520:Cyclophosphamide; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D007273:Injections, Intramuscular; D008180:Lupus Erythematosus, Systemic; D009135:Muscular Diseases; D011241:Prednisone",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "277-283",
"pmc": null,
"pmid": "29525810",
"pubdate": "2018-03-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "5681186;20507339;11765229;21641018;7328567;16325658;14667104;15095538;3348564;15125842;18411213;1646422;4019954;27267643;6361420;6851197;20724309;23964701",
"title": "Glucocorticoid-Induced Myopathy in a Patient with Systemic Lupus Erythematosus (SLE): A Case Report and Review of the Literature.",
"title_normalized": "glucocorticoid induced myopathy in a patient with systemic lupus erythematosus sle a case report and review of the literature"
} | [
{
"companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201805-001455",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "BACKGROUND\nCanagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM).\n\n\nOBJECTIVE\nOur objective is to describe the effects of canagliflozin on bone mineral density (BMD) and bone biomarkers in patients with T2DM.\n\n\nMETHODS\nThis was a randomized study, consisting of a 26-week, double-blind, placebo-controlled period and a 78-week, double-blind, placebo-controlled extension.\n\n\nMETHODS\nThis study was undertaken in 90 centers in 17 countries.\n\n\nMETHODS\nPatients were aged 55-80 years (N = 716) and whose T2DM was inadequately controlled on a stable antihyperglycemic regimen.\n\n\nMETHODS\nCanagliflozin 100 or 300 mg or placebo were administered once daily.\nBMD was assessed using dual-energy x-ray absorptiometry at weeks 26, 52, and 104. Bone strength was assessed using quantitative computed tomography and finite element analysis at week 52. Serum collagen type 1 β-carboxy-telopeptide, osteocalcin, and estradiol were assessed at weeks 26 and 52.\n\n\nRESULTS\nCanagliflozin doses of 100 and 300 mg were associated with a decrease in total hip BMD over 104 weeks, (placebo-subtracted changes: -0.9% and -1.2%, respectively), but not at other sites measured (femoral neck, lumbar spine, or distal forearm). No meaningful changes in bone strength were observed. At week 52, canagliflozin was associated with an increase in collagen type 1 β-carboxy-telopeptide that was significantly correlated with a reduction in body weight, an increase in osteocalcin, and, in women, a decrease in estradiol.\n\n\nCONCLUSIONS\nIn older patients with T2DM, canagliflozin showed small but significant reductions in total hip BMD and increases in bone formation and resorption biomarkers, due at least in part to weight loss.",
"affiliations": "Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Mercy Health Osteoporosis and Bone Health Services (N.B.W.), Cincinnati, Ohio 45236; Janssen Research & Development, LLC (K.U., A.F., D.S., N.R.), Raritan, New Jersey 08869; and Janssen Research & Development, LLC (D.P.), San Diego, California 92121.;Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Mercy Health Osteoporosis and Bone Health Services (N.B.W.), Cincinnati, Ohio 45236; Janssen Research & Development, LLC (K.U., A.F., D.S., N.R.), Raritan, New Jersey 08869; and Janssen Research & Development, LLC (D.P.), San Diego, California 92121.;Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Mercy Health Osteoporosis and Bone Health Services (N.B.W.), Cincinnati, Ohio 45236; Janssen Research & Development, LLC (K.U., A.F., D.S., N.R.), Raritan, New Jersey 08869; and Janssen Research & Development, LLC (D.P.), San Diego, California 92121.;Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Mercy Health Osteoporosis and Bone Health Services (N.B.W.), Cincinnati, Ohio 45236; Janssen Research & Development, LLC (K.U., A.F., D.S., N.R.), Raritan, New Jersey 08869; and Janssen Research & Development, LLC (D.P.), San Diego, California 92121.;Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Mercy Health Osteoporosis and Bone Health Services (N.B.W.), Cincinnati, Ohio 45236; Janssen Research & Development, LLC (K.U., A.F., D.S., N.R.), Raritan, New Jersey 08869; and Janssen Research & Development, LLC (D.P.), San Diego, California 92121.;Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Mercy Health Osteoporosis and Bone Health Services (N.B.W.), Cincinnati, Ohio 45236; Janssen Research & Development, LLC (K.U., A.F., D.S., N.R.), Raritan, New Jersey 08869; and Janssen Research & Development, LLC (D.P.), San Diego, California 92121.;Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Mercy Health Osteoporosis and Bone Health Services (N.B.W.), Cincinnati, Ohio 45236; Janssen Research & Development, LLC (K.U., A.F., D.S., N.R.), Raritan, New Jersey 08869; and Janssen Research & Development, LLC (D.P.), San Diego, California 92121.",
"authors": "Bilezikian|John P|JP|;Watts|Nelson B|NB|;Usiskin|Keith|K|;Polidori|David|D|;Fung|Albert|A|;Sullivan|Daniel|D|;Rosenthal|Norm|N|",
"chemical_list": "D015415:Biomarkers; D024042:Collagen Type I; D007004:Hypoglycemic Agents; D000068896:Canagliflozin",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2015-1860",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "101(1)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D015502:Absorptiometry, Photon; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001835:Body Weight; D015519:Bone Density; D000068896:Canagliflozin; D024042:Collagen Type I; D003924:Diabetes Mellitus, Type 2; D004311:Double-Blind Method; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "44-51",
"pmc": null,
"pmid": "26580234",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "21457428;14555280;24026211;17555504;23680739;24227660;25398756;24528605;22124465;23464594;16636211;25825948;21611972;23279307;24843589;17396005;18716852;23850055;23564919;22354851;23585665;25421015;22190134;25130857;22492586;26580237;24118688;23412078;15197544;21925297;16415531;22745857;19049327;8279220;25289773;22355316;25523498;21986718;25495720",
"title": "Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin.",
"title_normalized": "evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin"
} | [
{
"companynumb": "US-JNJFOC-20151206243",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nA four-drug cytochrome P450 (CYP) phenotyping cocktail was developed to rapidly and safely determine CYP2D6, CYP2C19, CYP2C9 and CYP1A2 enzyme activity and phenotype.\n\n\nMETHODS\nThe cocktail consisted of the single CYP phenotyping probes of 50 mg tramadol (CYP2D6), 20 mg omeprazole (CYP2C19), 25 mg losartan (CYP2C9) and 200 mg caffeine (CYP1A2) and was administered as a single oral dose. For enzyme activity measurements, urine was collected as 8 h post-administration and blood was sampled at 4 h. The enzyme activity was determined by metabolic ratios of molar concentrations of the drugs and their enzyme catalyzed metabolites and was correlated to the relevant genotypes.\n\n\nRESULTS\nIn a pilot study in 12 healthy male volunteers the CYP genotype-phenotype correlation and robustness of the cocktail was successfully determined without detection of any adverse drug reactions. In the subsequent population study, four female volunteers experienced unexpected and unacceptable moderate and severe adverse reactions (ARs) of headache, dizziness, nausea, vomiting, blue fingers, nails and lips and difficulties in urinating, which led to the study being prematurely terminated after inclusion of only 22 subjects (15 males, 7 females) [corrected].\n\n\nCONCLUSIONS\nAttention must be paid to adverse reactions when designing new combinations of phenotype cocktails regardless of the doses and drugs involved. We specifically warn against the combination of tramadol, omeprazole, losartan and caffeine.",
"affiliations": "Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, J.B. Winslowsvej 19, 5000, Odense, Denmark, rpedersen@health.sdu.dk.",
"authors": "Pedersen|Rasmus Steen|RS|;Damkier|Per|P|;Christensen|Mette Marie Hougaard|MM|;Brosen|Kim|K|",
"chemical_list": "D004338:Drug Combinations; D014147:Tramadol; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D019808:Losartan; D009853:Omeprazole",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-013-1561-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "69(12)",
"journal": "European journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D002110:Caffeine; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System; D004338:Drug Combinations; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D019808:Losartan; D008297:Male; D008875:Middle Aged; D009853:Omeprazole; D010641:Phenotype; D014147:Tramadol; D055815:Young Adult",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "1997-9",
"pmc": null,
"pmid": "23917460",
"pubdate": "2013-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15197523;19404631;12172216;8747407;12811361;8738764;15961977;12065063;9088579;9156694;17259951;10976551;17392720;19281600;22623016;1309873;15509185;22698264",
"title": "A cytochrome P450 phenotyping cocktail causing unexpected adverse reactions in female volunteers.",
"title_normalized": "a cytochrome p450 phenotyping cocktail causing unexpected adverse reactions in female volunteers"
} | [
{
"companynumb": "DK-LUPIN PHARMACEUTICALS INC.-2014-01591",
"fulfillexpeditecriteria": "2",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAFFEINE"
},
"drugadditional"... |
{
"abstract": "Cutaneous lesions in the presence of fever in patients undergoing immunosuppressive therapy are a diagnostic challenge and may represent manifestations of multiple diseases, such as fungal infections, nocardiosis, lymphoproliferative diseases, zoonosis, and tuberculosis. The authors report a case of a 66-year-old white man with chronic kidney disease since 2014 (chronic pyelonephritis) who had a renal transplant in the previous 6 months. Induction therapy was performed with thymoglobulin, and his current immunosuppression scheme included tacrolimus, mycophenolate mofetil, and prednisolone. The patient had no history of pulmonary tuberculosis. The patient presented with 2 cutaneous lesions, localized on the back and abdomen, that appeared to be firm, painful, subcutaneous, erythematous nodules with an approximately 5 cm diameter overlying an infected focus and purulent material inside. The patient also had a fever and fatigue. Blood analysis showed pancytopenia with an elevation of inflammatory markers and graft dysfunction. Tissue cultures and skin biopsy with histological analysis were performed. Histopathology of the lesion showed a nonspecific inflammatory infiltrate without granulomas, and acid-fast bacillus staining was negative. Nevertheless, serum QuantiFERON testing was positive. But polymerase chain reaction finally confirmed the presence of Mycobacterium tuberculosis, which confirmed the diagnosis of cutaneous tuberculosis. A chest computed tomography scan showed a lung pattern of miliary tuberculosis. The patient was treated with multidrug tuberculosis therapy, resulting in lesion clearance after 3 weeks. Tuberculosis is a serious infection, especially in high-risk patients, such as those in an immunocompromised state. The incidence of cutaneous tuberculosis is rare, but it should be considered in patients presenting with atypical skin lesions suggestive of an underlying infectious etiology.",
"affiliations": "Nephrology Department, Amato Lusitano Hospital, Castelo Branco, Portugal. Electronic address: dcoelho.ines@gmail.com.;Nephrology Department, Coimbra University Hospital Center, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.;Nephrology Department, Coimbra University Hospital Center, Coimbra, Portugal.;Nephrology Department, Coimbra University Hospital Center, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.;Nephrology Department, Coimbra University Hospital Center, Coimbra, Portugal.;Nephrology Department, Coimbra University Hospital Center, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.;Nephrology Department, Coimbra University Hospital Center, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.;Nephrology Department, Coimbra University Hospital Center, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.;Urology and Kidney Transplantation Department, Coimbra University Hospital Center, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal.",
"authors": "Coelho|I D|ID|;Romãozinho|C|C|;Teixeira|A C|AC|;Rodrigues|L|L|;Ferreira|E|E|;Santos|L|L|;Macário|F|F|;Alves|R|R|;Figueiredo|A|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.02.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D014382:Tuberculosis, Cutaneous; D014391:Tuberculosis, Miliary",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1618-1620",
"pmc": null,
"pmid": "31155204",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Rare Manifestation of Tuberculosis in a Renal Transplant Patient: A Case Report.",
"title_normalized": "a rare manifestation of tuberculosis in a renal transplant patient a case report"
} | [
{
"companynumb": "PT-MYLANLABS-2019M1070107",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nClozapine, an antipsychotic medication, can ordinarily cause gastrointestinal hypomotility, but clozapine-related Ogilvie Syndrome (colonic pseudo-obstruction) has been reported rarely.\n\n\nMETHODS\nA 29-year-old male was admitted to the emergency department (ED) with complaints of vomiting, abdominal pain, and distension lasting for a day. He was on clozapine therapy due to schizophrenia. An abdominal-CT scan revealed dilation from the cecum to the ileum and he was diagnosed with Ogilvie syndrome. During the observation period in the ED, respiratory distress, hypotension, and alteration in consciousness were observed, and the patient was intubated electively. Arterial blood gas showed primary metabolic acidosis, with a normal anion gap with full respiratory compensation. In the control CT scan there was no visible perforation but distension persisted; the cecum diameter was 93 mm and the colonic wall was thickened. After the CT scan, the patient went into cardiac arrest and died 13 hours after his admission. In this case, excessive colonic dilatation, high WBC, and lactate levels and increased thickness of the colon wall suggest sepsis due to intestinal ischemia.\n\n\nCONCLUSIONS\nClozapine-related gastrointestinal hypomotility (CRGH) is not a trivial symptom. It can cause Ogilvie syndrome, which can be fatal due to complications. In the current clozapine prescription content, information on CRGH is insufficient. Higher levels of suspicion, lower diagnostic thresholds in the case of mental and psychiatric patients may prevent delays in diagnosis and treatment and result in lower mortality.",
"affiliations": "Department of Emergency Medicine, School of Medicine, Hacettepe University, Ankara, Turkey.;Department of Emergency Medicine, School of Medicine, Du¨zce University, Turkey.",
"authors": "Akkaş|Meltem|M|;Demir|Mehmet Cihat|MC|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "Italy",
"delete": false,
"doi": "10.1708/3301.32720",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-6484",
"issue": "55(1)",
"journal": "Rivista di psichiatria",
"keywords": null,
"medline_ta": "Riv Psichiatr",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D003112:Colonic Pseudo-Obstruction; D017809:Fatal Outcome; D005769:Gastrointestinal Motility; D006801:Humans; D008297:Male; D012559:Schizophrenia; D014057:Tomography, X-Ray Computed",
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"title": "Clozapine related Ogilvie syndrome with fatal outcome.",
"title_normalized": "clozapine related ogilvie syndrome with fatal outcome"
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"abstract": "We report the case of a patient with B-cell prolymphocytic leukemia who was successfully treated with the novel humanized monoclonal antibody obinutuzumab. This patient was previously treated with the combination of rituximab and bendamustine and had recurrent infusion reactions. Her treatment with rituximab and bendamustine was discontinued when she developed disease progression after 3 cycles of therapy. She was then treated with obinutuzumab 1000 mg on day 1 of every cycle and chlorambucil 0.5 mg/kg on days 1 and 15 every 28 days to which she had greater tolerability. After 4 cycles of treatment, she had resolution of her clinical symptoms, massive splenomegaly, and normalization of her white blood cell count.",
"affiliations": "University of Florida, Jacksonville, FL, USA.;University of Florida, Jacksonville, FL, USA.;University of Florida, Jacksonville, FL, USA.;University of Florida, Jacksonville, FL, USA.",
"authors": "Hew|Jason|J|;Pham|Dat|D|;Matthews Hew|Trevanne|T|;Minocha|Vinay|V|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961878867410.1177_2324709618788674Case ReportA Novel Treatment With Obinutuzumab-Chlorambucil in a Patient With\nB-Cell Prolymphocytic Leukemia: A Case Report and Review of the\nLiterature Hew Jason MD1Pham Dat MD1Matthews Hew Trevanne MD1Minocha Vinay MD11 University of Florida, Jacksonville, FL,\nUSAJason Hew, Department of Internal Medicine,\nDivision of Medical Oncology, University of Florida College of Medicine, 655\nWest 8th St, Pavilion 4N, Jacksonville, FL 32209, USA. Email:\nJason.Hew@jax.ufl.edu17 7 2018 Jan-Dec 2018 6 232470961878867417 1 2018 20 6 2018 23 6 2018 © 2018 American Federation for Medical\nResearch2018American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which\npermits any use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).We report the case of a patient with B-cell prolymphocytic leukemia who was\nsuccessfully treated with the novel humanized monoclonal antibody obinutuzumab.\nThis patient was previously treated with the combination of rituximab and\nbendamustine and had recurrent infusion reactions. Her treatment with rituximab\nand bendamustine was discontinued when she developed disease progression after 3\ncycles of therapy. She was then treated with obinutuzumab 1000 mg on day 1 of\nevery cycle and chlorambucil 0.5 mg/kg on days 1 and 15 every 28 days to which\nshe had greater tolerability. After 4 cycles of treatment, she had resolution of\nher clinical symptoms, massive splenomegaly, and normalization of her white\nblood cell count.\n\nB-cell prolymphocytic leukemiaobinutuzumabelderly patient with leukemiaanti-CD20 monoclonal antibodycover-dateJanuary-December 2018\n==== Body\nBackground\nB-cell prolymphocytic leukemia (B-PLL) is a rare mature B-cell neoplasm that\ntypically occurs in the elderly population. This disease is clinically characterized\nby a rapidly rising lymphocyte count, splenomegaly, fever, night sweats, and weight\nloss. Lymphadenopathy is not generally a prominent feature of this malignancy. The\ndiagnosis of B-PLL is made on a combination of immunophenotypic and genetic findings\nin the peripheral blood and bone marrow. By definition the diagnosis requires that\nthe prolymphocytes exceed 55% of all lymphoid cells in the peripheral blood.1 Flow cytometry is used to distinguish B-PLL from similar neoplasms and\nusually demonstrates light chain restriction, bright surface immunoglobulin, and the\nexpression of B-cell antigens including CD20, CD22, FMC7, and CD79a. CD5 and CD23\nexpression is often weak or absent. CD11c, CD103, CD10, and CD25 are not expressed.1 Tumors demonstrating t(11;14)(q13;q32) must be tested by either conventional\ncytogenetics, fluorescence in situ hybridization, or by immunohistochemical stains\nfor cyclin D1 to exclude the diagnosis of mantle cell lymphoma.\n\nB-PLL frequently follows an aggressive clinical course and has historically been\nassociated with a poor prognosis with an estimated median overall survival of 3 years.2 Despite advances in the understanding of tumor biology, optimal treatment\noptions have not yet been identified and there are no randomized studies available\nfor clinical reference. Treatment strategies have therefore been fashioned from that\nof similar but more common neoplasms including chronic lymphocytic leukemia (CLL)\nand mantle cell lymphoma. Conventional chemotherapy has been used in the past\nincluding combination regimens such as cyclophosphamide, doxorubicin, Oncovin, and\nprednisolone (CHOP), which has yielded only partial responses. In addition, these\nresponses are not durable with relapses usually occurring within 12 months. Another\noption for selected patients is allogeneic stem cell transplant. This offers\ncurative potential and there are reports of long-term remissions exceeding 5 years.\nAllogeneic stem cell transplant, however, is best reserved for the few, younger and\nfit patients with this disease. It is associated with a high risk of morbidity and\nmortality. More recently, there have been case reports of treatments with the\ncombination of the anti-CD20 monoclonal antibody, rituximab, and chemotherapy, which\nhave produced excellent responses.2 There are, however, no known reports of the more novel humanized type II\nanti-CD20 monoclonal antibody obinutuzumab in the treatment of B-PLL. Obinutuzumab\nhas been compared head to head with rituximab and has yielded superior results in\nthe management of CLL in a pivotal phase III trial.3 This drug is approved by the Food Drug Administration (FDA) for first-line\nuse in CLL and is a preferred regimen in the elderly.\n\nCase Report\nA 78-year-old female was referred to our clinic for evaluation of anemia and\nthrombocytopenia. She complained of fatigue, early satiety, and had an unintentional\nweight loss of 80 pounds over the past 2 years. She denied fevers, night sweats,\nnausea, vomiting, or abdominal pain. Physical examination revealed massive\nsplenomegaly, but no hepatomegaly or lymphadenopathy. A complete metabolic profile\nand lactate dehydrogenase were normal. Her hemoglobin and platelet counts were 10.0\ng/dL and 91 × 109/L, respectively. Her white blood cell count was 8.7 ×\n109/L with 67% lymphocytes and 5% atypical lymphocytes. The\nperipheral smear showed abundant prolymphocytes (Figure 1). A bone marrow aspirate and biopsy\nrevealed a marrow that was diffusely infiltrated by atypical, homogenous lymphocytes\nwith medium to large size moderately condensed chromatin and prominent nucleoli.\nThese lymphocytes accounted for about 50% of marrow cellularity, with B- and\nT-lymphocyte ratio estimated to be 2:1 (Figure 2). Flow cytometric analysis of the\nbone marrow aspirate with additional markers revealed that B cells were positive for\nCD20 and FMC7 (relatively dim and variable) and negative for CD23 and surface\nimmunoglobulin M and immunoglobulin D. The bone marrow pathology and immunophenotype\nwas consistent with a diagnosis of B-PLL. Cytogenetic analysis of the bone marrow\naspirate revealed no chromosomal abnormalities. A positron emission tomography (PET)\nscan revealed the spleen to be massively enlarged measuring 29 × 12 × 8 cm with\nsignificant mass effect on the intra-abdominal contents, with displacement of the\nleft kidney to the midline and compression of the colonic splenic flexure (Figure 3). There were also a\nfew scattered mildly hypermetabolic lymph nodes throughout the body. Her initial\nECOG (Eastern Cooperative Oncology Group) performance status was 1.\n\nFigure 1. Peripheral blood smear showing 3 medium to large prolymphocytes with moderate\nbasophilic cytoplasm, indented nuclei, and prominent vesicular nucleoli.\nThese prolymphocytes account for >55% of the circulating cells.\n\nFigure 2. Bone marrow biopsy shows a marrow diffusely infiltrated by predominantly\nCD20-positive B-lymphocytes accounting for about 50% of marrow cellularity.\nB- and T-lymphocyte ratio is estimated to be 2:1. The infiltration is\ninterstitial and with focal micronodularity.\n\nFigure 3. Positron emission tomography/computed tomography at the time of diagnosis and\nprior to the initiation of treatment. The spleen is massively enlarged,\nmeasuring 29.2 × 11.4 × 11.7 cm. There is homogeneous density and\nhomogeneous FDG activity similar to the liver with a maximum SUV of 2.6.\n\nThe patient was started on treatment with rituximab and bendamustine; however, she\nexperienced recurrent infusion reactions with rituximab, which worsened with every\ntreatment. Rituximab was stopped after the third cycle. After receiving 3 cycles of\ntreatment, a repeat PET scan showed interval development of bilateral cervical\nhypermetabolic lymphadenopathy, persistent mediastinal, periportal hypermetabolic\nlymph nodes, and persistent splenic enlargement. She also developed bilateral\npleural effusions (Figure\n4). Her posttreatment hemoglobin and platelet counts were 10.0 g/dL and 50 ×\n109/L, respectively. Her white blood cell count decreased to 5.3 ×\n109/L but consisted predominantly of lymphocytes and prolymphocytes.\nShe was therefore considered to have disease progression because of her persistent\ncytopenias, the progressive worsening of her lymphadenopathy and splenomegaly, and\noverall decline in her performance status to an ECOG of 2. She expressed a desire to\ncontinue treatment for her B-PLL, so it was decided to change therapy to a\ncombination of obinutuzumab and chlorambucil. This regimen entailed the\nadministration of obinutuzumab 1000 mg on day 1 of every cycle and chlorambucil 0.5\nmg/kg on days 1 and 15 every 28 days. She demonstrated greater tolerability to this\nregimen and did not experience any infusion reactions. After 4 cycles of\nobinutuzumab-chlorambucil, she had gained weight with improved appetite and energy\nlevel. On physical examination, her spleen was no longer palpable. A repeat\nposttreatment PET scan showed a decreased spleen size, which measured approximately\n18.5 × 10.0 × 7.3 cm, and her lymphadenopathy and pleural effusions had resolved\n(Figure 5). She also had\nan improvement in her anemia and thrombocytopenia posttreatment with normalization\nof the lymphocyte count. Prolymphocytes were no longer noted on the peripheral\nsmear. She achieved a clinical partial remission and was then placed on maintenance\nobinutuzumab 1000 mg monotherapy every 2 months. In total she completed 8 cycles of\ntreatment with obinutuzumab. Therapy was held thereafter as she had no evidence of\nactive disease and she was switched to surveillance. No major adverse events\noccurred during her treatment with obinutuzumab and chlorambucil or while on\nmonotherapy with obinutuzumab. At the time of this report, she was still alive at 81\nyears old with no evidence of disease progression and has been off treatment for\ngreater than a year.\n\nFigure 4. Positron emission tomography/computed tomography showing disease progression\nafter treatment with rituximab and bendamustine. The study was done prior to\nher initial treatment with obinutuzumab and chlorambucil. There is interval\ndevelopment of bilateral cervical, mediastinal, and periportal adenopathy.\nThe spleen is massively enlarged measuring 29 × 12 × 8 cm. There is diffuse\nincreased uptake within the spleen with maximum SUV being 3.2.\n\nFigure 5. Positron emission tomography/computed tomography after 4 cycles of treatment\nwith obinutuzumab and chlorambucil. The spleen is decreased in size compared\nwith prior study, now measuring approximately 18.5 × 10.0 × 7.3 cm and\ndecreased in uptake with maximum SUV now measuring 1.9, which is slightly\nabove blood pool and less than liver uptake.\n\nDiscussion\nIn this study, we report the case of an elderly female with a diagnosis of B-PLL who\ndisplayed an excellent clinical response to chemo-immunotherapy with a combination\nof obinutuzumab and chlorambucil after failing initial treatment with bendamustine\nand rituximab. Cases of B-PLL are extremely rare, accounting for 1% of lymphocytic leukemias,1 and consequently, there are very little published data regarding optimal\ntreatment for this disease. There is a considerable overlap in the clinicopathologic\npresentation of this disorder and other mature B-cell leukemias/lymphomas, such as\nCLL, hairy cell leukemia variant, and splenic marginal zone lymphoma. Most treatment\ndata have been derived from case reports or small series and have been extrapolated\nto include regimens that have been used in the more common B-cell\ndisorders.2,4\nAlthough previous cases have described good outcomes with a conventional\nchemo-immunotherapy approach using rituximab, we describe the first case of a\npatient with B-PLL who had a successful outcome using a combination of obinutuzumab\nand chlorambucil.\n\nThe development of monoclonal antibodies have had a major impact in altering the\nnatural history of both malignant and benign immune-mediated diseases. Rituximab is\nthe first FDA licensed and still the most commonly used anti-CD20 monoclonal\nantibody in B-cell malignancies.5 Since its approval for relapsed/refractory non-Hodgkin’s lymphoma in 1997,\nrituximab has been endorsed for use in the treatment of numerous other B-cell malignancies.6 This achievement ignited the era of direct monoclonal antibody therapy. The\nsuccess and failure of rituximab have also improved the understanding of how\nmonoclonal antibodies work. It has also paved the way for the development of more\nnovel drugs that have improved efficacy. In a literature search, only a few case\nreports were found describing the successful treatment of B-PLL. Rituximab\nmonotherapy and combinations of rituximab with fludarabine or bendamustine together\nwith an anthracycline such as mitoxantrone or epirubicin (FMR, FER, and BMR) have\nbeen reported to have activity in B-PLL.7-10\n\nFunctionally anti-CD20 monoclonal antibodies may be classified as either type I or\ntype II. The type I anti-CD20 monoclonal antibodies, rituximab and ofatumumab, lead\nto complement-dependent cytotoxicity, stimulation of signaling leading to apoptosis,\nand antibody-dependent cell-mediated cytotoxicity through the recruitment of immune\nmediator cells.11 Obinutuzumab is a type II anti-CD20 monoclonal antibody that recognizes the\nsame CD20 epitope as rituximab but binds to it in a different orientation and over a\nlarger surface area, allowing a superior induction of direct cell death, enhanced\nnatural killer cell activation, and antibody-dependent cell cytotoxicity. It is,\nhowever, less potent in inducing complement-dependent cytotoxicity.3 The mechanism of action of obinutuzumab, in contrast to that of rituximab and\nofatumumab, may provide greater efficacy.11 For this reason, obinutuzumab-based treatment may display a superior response\nin patients with B-PLL as was evidenced in our case.\n\nThe FDA authorized the use of obinutuzumab in combination with chlorambucil in 2013\nfor the elderly and frail patient with treatment-naïve CLL. Approval was granted\nbased on the results of the phase III CLL-11 study. This 3-arm study compared the\ncombination of obinutuzumab and chlorambucil versus rituximab and chlorambucil\nversus chlorambucil alone. The results of this study showed marked superiority of\nthe obinutuzumab combination in response rates and survival compared with the\nrituximab-based regimen and chlorambucil alone. The median progression-free survival\nwas 26.7 months with obinutuzumab-chlorambucil versus 16.3 months with\nrituximab-chlorambucil versus 11.1 months with chlorambucil alone. Safety and\ntolerance to treatment was another key measure shown in this study. Less patients\ndied from an adverse event with obinutuzumab-chlorambucil (4%) than in the\nrituximab-chlorambucil and chlorambucil-alone groups (6% and 9%, respectively).12 The efficacy and safety data from this study served as the catalyst for using\nthis regimen in this case.\n\nThe authors of this report also acknowledge that chlorambucil has proven efficacy in\nthe treatment of CLL and other lymphoproliferative disorders. It may have therefore\ncontributed significantly to the disease response observed in this case. In a\nsystematic review by Lepretre et al, response rates of 31% to 72% were reported with\nchlorambucil monotherapy in the treatment of CLL; however, complete responses were\nas low as 0% to 10%.13 This oral alkylating agent was first approved for use in 1957 for the\ntreatment of CLL. The use of chlorambucil has since largely fallen out of favor in\npreference to more novel agents, which have improved response rates. It is still\nindicated for use in the elderly and frail patient due to its safety and tolerance.\nImproved complete response rates and progression-free survival are seen when\nchlorambucil is combined with an anti-CD20 monoclonal antibody.\n\nIn conclusion, the combination of obinutuzumab and chlorambucil may have a promising\nrole in the treatment of patients with B-PLL and deserves consideration either in\nthe frontline setting or in the subset of patients who progress on rituximab-based\nregimens. More studies are needed to investigate the efficacy of this regimen in\npatients with B-PLL and the optimal length of therapy.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized\ninformation to be published in this article.\n==== Refs\nReferences\n1 \nDungarwalla M Matutes E Dearden CE. \nProlymphocytic leukaemia of B- and T-cell subtype: a\nstate-of-the-art paper . Eur J Haematol .\n2008 ;80 :469 -476 .18331594 \n2 \nDearden CE. \nHow I treat prolymphocytic leukemia .\nBlood .\n2012 ;120 :538 -551 .22649104 \n3 \nShah A. \nObinutuzumab: a novel anti-CD20 monoclonal antibody for\npreviously untreated chronic lymphocytic leukemia .\nAnn Pharmacother .\n2014 ;48 :1356 -1361 .25037849 \n4 \nDearden CE. \nManagement of prolymphocytic leukemia .\nHematology Am Soc Hematol Educ Program .\n2015 ;2015 :361 -367 .26637744 \n5 \nJain N O’Brien S. \nTargeted therapies for CLL: practical issues with the changing\ntreatment paradigm . Blood Rev .\n2016 ;30 :233 -244 .26776345 \n6 \nMarshall MJE Stopforth RJ Cragg MS \nTherapeutic antibodies: what have we learnt from\ntargeting CD20 and where are we going? \nFront Immunol .\n2017 ;8 :1245 . doi:10.3389/fimmu.2017.01245 .29046676 \n7 \nDearden CE. \nB- and T-cell prolymphocytic leukemia: antibody\napproaches . Hematology Am Soc Hematol Educ\nProgram .\n2012 ;2012 :645 -651 .23233647 \n8 \nTempescul A Feuerbach J Ianotto JC et al \nA combination therapy with fludarabine,\nmitoxantrone and rituximab induces complete immunophenotypical remission in\nB-cell prolymphocytic leukaemia . Ann\nHematol .\n2009 ;88 :85 -88 .18654781 \n9 \nChow KU Kim SZ von Neuhoff N et al \nClinical efficacy of immunochemotherapy with\nfludarabine, epirubicin and rituximab in the treatment for chronic\nlymphocytic leukaemia and prolymphocytic leukaemia .\nEur J Haematol .\n2011 ;87 :426 -433 .21749447 \n10 \nWeide R Pandorf A Heymanns J Koppler H. \nBendamustine/mitoxantrone/rituximab (BMR): a very effective, well\ntolerated outpatient chemoimmunotherapy for relapsed and refractory\nCD20-positive indolent malignancies. Final results of a pilot\nstudy . Leuk Lymphoma .\n2004 ;45 :2445 -2449 .15621757 \n11 \nEvans SS Clemmons AB. \nObinutuzumab: a novel anti-CD20 monoclonal antibody for chronic\nlymphocytic leukemia . J Adv Pract Oncol .\n2015 ;6 :370 -374 .26705497 \n12 \nGoede V Fischer K Busch R et al \nObinutuzumab plus chlorambucil in patients with\nCLL and coexisting conditions . N Engl J\nMed .\n2014 ;370 :1101 -1110 .\ndoi:10.1056/nejmoa1313984. 24401022 \n13 \nLepretre S Dartigeas C Feugier P Marty M Salles G. \nSystematic review of the recent evidence for the efficacy and\nsafety of chlorambucil in the treatment of B-cell\nmalignancies . Leuk Lymphoma .\n2016 ;57 :852 -865 .\ndoi:10.3109/10428194.2015.108552. 26308278\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "6()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "B-cell prolymphocytic leukemia; anti-CD20 monoclonal antibody; elderly patient with leukemia; obinutuzumab",
"medline_ta": "J Investig Med High Impact Case Rep",
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"pages": "2324709618788674",
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"pmid": "30038912",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "21749447;26308278;25037849;22649104;29046676;18331594;23233647;26637744;24401022;18654781;26776345;15621757;26705497",
"title": "A Novel Treatment With Obinutuzumab-Chlorambucil in a Patient With B-Cell Prolymphocytic Leukemia: A Case Report and Review of the Literature.",
"title_normalized": "a novel treatment with obinutuzumab chlorambucil in a patient with b cell prolymphocytic leukemia a case report and review of the literature"
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"abstract": "5-Fluorouracil (5FU), Folinic acid (FA), and Oxaliplatin (FOLFOX) or 5FU, FA, and Irinotecan (FOLFIRI) are standard regimens for palliative chemotherapy of metastatic colon cancer. Since data showing the influence of dose reduction in palliative treatment are rare, the objective of this single center, retrospective study was to further characterize the influence of dose reduction on efficacy of these therapeutic regimens.\n\n\n\nOne hundred nine patients, diagnosed with stage IV colon cancer between 2004 and 2012 and receiving palliative first-line chemotherapy with either FOLFOX or FOLFIRI regimens in our outpatient clinic were analyzed for treatment efficacy. Patients who received dose reductions due to side effects usually received doses of 80% or lower of per protocol dose. Survival data were obtained from the Regensburg Tumor Registry. Survival analysis was performed using Kaplan-Meier statistical analysis and multivariable analysis.\n\n\n\nA dose reduction due to side effects was necessary in 46 (42%) patients. Dose reduction was independent of age. Major reasons for dose reduction were neutropenia (30%) followed by polyneuropathy (16%) and diarrhea (14%). Dosage was more often reduced in patients receiving FOLFOX based therapy. Comparison of patients with dose reduction versus patients with full dosage showed no significant difference on overall survival (p = 0.430). Subgroup analysis revealed dose reduction in patients with N2 stage disease was associated with improved survival. Patients who underwent dose reduction received more cycles of chemotherapy (13.7 vs. 10.8 cycles) and cumulative dosage was similar in both groups.\n\n\n\nContrary to our expectations, the need to reduce chemotherapy dosage due to side effects does not indicate a worse prognosis in our retrospective analysis. We believe this can in part be explained by better adaption to interindividual pharmacokinetics and longer time of treatment.",
"affiliations": "Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 95053, Regensburg, Germany. stefan.munker@klinik.uni-regensburg.de.;Cancer Center, Institute for quality assurance and health services research, University of Regensburg, Regensburg, Germany.;Medical Informatics Unit, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 95053, Regensburg, Germany.;Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 95053, Regensburg, Germany.;Department of Surgery, University Hospital Regensburg, Regensburg, Germany.;Department of Radiology, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.;Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.;Department of Radiology, University Hospital Regensburg, Regensburg, Germany.;Department of Surgery, University Hospital Regensburg, Regensburg, Germany.;Department of Pathology, University Hospital Regensburg, Regensburg, Germany.;MedicDAT GmbH, Regensburg, Germany.;Cancer Center, Institute for quality assurance and health services research, University of Regensburg, Regensburg, Germany.;Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 95053, Regensburg, Germany. andreas.teufel@klinik.uni-regensburg.de.",
"authors": "Munker|Stefan|S|;Gerken|Michael|M|;Fest|Petra|P|;Ott|Claudia|C|;Schnoy|Elisabeth|E|;Fichtner-Feigl|Stefan|S|;Wiggermann|Philipp|P|;Vogelhuber|Martin|M|;Herr|Wolfgang|W|;Stroszczynski|Christian|C|;Schlitt|Hans Jürgen|HJ|;Evert|Matthias|M|;Reng|Michael|M|;Klinkhammer-Schalke|Monika|M|;Teufel|Andreas|A|",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 438010.1186/s12885-018-4380-zResearch ArticleChemotherapy for metastatic colon cancer: No effect on survival when the dose is reduced due to side effects Munker Stefan stefan.munker@klinik.uni-regensburg.de 1Gerken Michael Michael.Gerken@klinik.uni-regensburg.de 2Fest Petra Petra.Fest@rz.uni-regensburg.de 3Ott Claudia claudiaott4@t-online.de 1Schnoy Elisabeth elisabeth.schnoy@klinikum-augsburg.de 1Fichtner-Feigl Stefan stefan.fichtner@uniklinik-freiburg.de 4Wiggermann Philipp philipp.wiggermann@klinik.uni-regensburg.de 5Vogelhuber Martin martin.vogelhuber@klinik.uni-regensburg.de 6Herr Wolfgang wolfgang.herr@klinik.uni-regensburg.de 6Stroszczynski Christian christian.Stroszczynski@klinik.uni-regensburg.de 5Schlitt Hans Jürgen Hans.Schlitt@klinik.uni-regensburg.de 4Evert Matthias Matthias.Evert@klinik.uni-regensburg.de 7Reng Michael michael.reng@medicdat.de 8Klinkhammer-Schalke Monika Monika.Klinkhammer-Schalke@klinik.uni-regensburg.de 2Teufel Andreas +49-941-944-7003andreas.teufel@klinik.uni-regensburg.de 11 0000 0000 9194 7179grid.411941.8Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 95053 Regensburg, Germany 2 0000 0001 2190 5763grid.7727.5Cancer Center, Institute for quality assurance and health services research, University of Regensburg, Regensburg, Germany 3 0000 0000 9194 7179grid.411941.8Medical Informatics Unit, University Hospital Regensburg, Regensburg, Germany 4 0000 0000 9194 7179grid.411941.8Department of Surgery, University Hospital Regensburg, Regensburg, Germany 5 0000 0000 9194 7179grid.411941.8Department of Radiology, University Hospital Regensburg, Regensburg, Germany 6 0000 0000 9194 7179grid.411941.8Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany 7 0000 0000 9194 7179grid.411941.8Department of Pathology, University Hospital Regensburg, Regensburg, Germany 8 MedicDAT GmbH, Regensburg, Germany 23 4 2018 23 4 2018 2018 18 45523 5 2016 16 4 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\n5-Fluorouracil (5FU), Folinic acid (FA), and Oxaliplatin (FOLFOX) or 5FU, FA, and Irinotecan (FOLFIRI) are standard regimens for palliative chemotherapy of metastatic colon cancer. Since data showing the influence of dose reduction in palliative treatment are rare, the objective of this single center, retrospective study was to further characterize the influence of dose reduction on efficacy of these therapeutic regimens.\n\nMethods\nOne hundred nine patients, diagnosed with stage IV colon cancer between 2004 and 2012 and receiving palliative first-line chemotherapy with either FOLFOX or FOLFIRI regimens in our outpatient clinic were analyzed for treatment efficacy. Patients who received dose reductions due to side effects usually received doses of 80% or lower of per protocol dose. Survival data were obtained from the Regensburg Tumor Registry. Survival analysis was performed using Kaplan-Meier statistical analysis and multivariable analysis.\n\nResults\nA dose reduction due to side effects was necessary in 46 (42%) patients. Dose reduction was independent of age. Major reasons for dose reduction were neutropenia (30%) followed by polyneuropathy (16%) and diarrhea (14%). Dosage was more often reduced in patients receiving FOLFOX based therapy. Comparison of patients with dose reduction versus patients with full dosage showed no significant difference on overall survival (p = 0.430). Subgroup analysis revealed dose reduction in patients with N2 stage disease was associated with improved survival. Patients who underwent dose reduction received more cycles of chemotherapy (13.7 vs. 10.8 cycles) and cumulative dosage was similar in both groups.\n\nConclusion\nContrary to our expectations, the need to reduce chemotherapy dosage due to side effects does not indicate a worse prognosis in our retrospective analysis. We believe this can in part be explained by better adaption to interindividual pharmacokinetics and longer time of treatment.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12885-018-4380-z) contains supplementary material, which is available to authorized users.\n\nKeywords\nDose reductionCancerColorectal cancerChemotherapyissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nColon cancer is the third most common cancer and a major cause of morbidity and mortality worldwide [1]. During the last few decades, improvement in therapeutic regimens for advanced colorectal cancer led to a dramatic increase in efficacy, reduction of mortality rates, and improved survival. Upon diagnosis, 20% of newly diagnosed colorectal cancer patients present with metastatic disease with no curative treatment options currently available. Among the chemotherapy regimens considered effective in palliative treatment, Irinotecan or Oxaliplatin in combination with 5-Fluorouracil regimens are standard back bones of current systemic treatment [2, 3].\n\nThese chemotherapy regimens were initially tested for efficacy in well-defined study populations not necessarily reflecting average (multimorbid older) patients in real life settings [4, 5]. Clinicians increasingly realize the shortcoming of the initial studies [6] since these mostly included younger patients better able to cope with adverse side effects or toxicities [7]. But especially in elderly and comorbid patients, side effects, organ toxicities and therefore potentially limited survival need to be considered [8]. In clinical practice, these effects are prevented or mitigated by a dose reduction of chemotherapy with the suspected consequence of worse tumor related survival [9]. We therefore believe that there is a need to further investigate the impact of dose reduction of the currently used therapeutic “standard” regimens on survival and side effects in different subgroups. Hence, we performed a retrospective analysis of our patient cohort with advanced stage colorectal cancer patients to assess outcome of reduced chemotherapy dosage.\n\nMethods\nStudy design\nA retrospective analysis was performed based on clinical data obtained from the population-based clinical cancer registry at the Regensburg Tumor Center in Eastern Bavaria, Germany. Epidemiological data and survival were investigated in a cohort of colon cancer diagnosed between 2004 and 2012 receiving chemotherapy in the outpatient clinic of the University Medical Center Regensburg. Patients with stage IV colorectal cancer undergoing palliative combination chemotherapy were divided into dose reduction (≤ 80%) and full dosage (100%) groups. We intend to analyze survival time by Kaplan Meier method and to estimate 2- and 3-year survival rates and mean and median survival time. Data collection and retrospective analysis of patient information were anonymized in accordance with the Declaration of Helsinki, and in line with the Bavarian Law of Cancer Registration.\n\nBackground and data collection\nThe baseline cohort of the present study consisted of patients with the ICD-10-GM (http://www.dimdi.de/static/de/klassi/icd-10-gm/index.htm) diagnosis C18, i.e. a malignant neoplasm of colon. 109 patients with advanced stage colon carcinoma (UICC Stage IV) with histologically confirmed adenocarcinoma of the colon between 2002 and 2012 receiving palliative chemotherapy in our University Medical Center were included in the study. Neuroendocrine tumors were excluded. 3 Patients receiving only 5FU based chemotherapy regimens without Irinotecan or Oxaliplatin were excluded. Prior to palliative chemotherapy, 72 patients received palliative or oncological tumor resection. In this subgroup, the diagnosis of metastasized colon cancer was made during surgery or in follow up examinations. Patients were routinely assessed prior to chemotherapy by a physician trained in oncology. Efficacy evaluation was performed by CT scans in 3-month intervals. Patients who died of cancer unrelated causes and patients with death within one month after start of palliative chemotherapy were censored.\n\nBaseline characteristics are shown in Table 1. For assessing comorbidities a scoring according to the Charlson Score comorbidities index [10] was performed Additional file 1: Table S1. Patients receiving either FOLFOX, FOLFIRI or sequentially both chemotherapy regimens were included in this study. Mode of administration was exclusively i.v.. Chemotherapy dosing values were calculated and registered with a chemotherapy planning software (OnkoDAT®) [11]. A patient was considered receiving reduced dosage of chemotherapy if he received ≥3 cycles of less than 80% of 5FU, Oxaliplatin, or Irinotecan. Survival information were obtained from the Regensburg Tumor Center founded in 1991. The Cancer registry includes epidemiological and clinical data from all consenting patients with malignancies diagnosed and treated in Eastern Bavaria (2.1 million population). All data were extracted, recorded, and fed into a central database by trained personnel. The patients’ life status and disease recurrence were ascertained from clinical reports, death certificates issued by the local public health departments, and the registration offices of the respective residential districts. Data were processed and secured according to the Bavarian Law of Cancer Registration.\n\nStatistical analysis\nContinuous data were described as means, median, minimum, maximum values and standard deviation, and categorical data were expressed as absolute frequencies and relative percentages. Patient characteristics were compared with t-tests for normally distributed continuous data, otherwise by means of non-parametric Mann-Whitney-U- and Chi-square tests for categorical variables. Tumor-specific survival rates (OS) were analyzed from the start of palliative chemotherapy until the event of death or last patient contact. Survival rates of patients with and without dose reduction were described by Kaplan-Meier analysis. Survival differences were tested for statistical significance by the two-sided Log Rank in Kaplan-Meier analyses; the level of significance was set to 0.05. The follow-up period and survival times were right censored using December 31, 2012 as cut-off date. To determine the influence of further co-variables on overall survival, we performed univariable and multivariable regression analysis using Cox proportional hazard models. In multivariable analysis, the hazard ratio (HR) was adjusted for the co-variables age, sex, TNM status, grading, lymph vessel invasion, vein invasion, Charlson score for comorbidities, surgery and further chemotherapy, i.e. number of lines and regimens. Again, a two-sided p-value of 0.05 was considered to indicate statistical significance. Hazard ratios and corresponding 95% confidence intervals (CI) were calculated and considered statistically significant when the CI excluded 1.0. All analyses were performed using IBM SPSS Statistics, version 23.0.\n\nResults\nReduction of chemotherapy dosage\nAmong 109 patients 67% (73/109) of the patients received both (FOLFOX and FOLFIRI) regimens sequentially. The majority 78% (57/73) began with FOLFOX and changed during the course of disease to FOLFIRI, 21% (23/109) of the patients received exclusively FOLFOX, whereas FOLFIRI chemotherapy regimens were used exclusively in 12% (13/109) of patients. 43% (47/109) received additional treatment with a biological agent.\n\nUpon discretion of the treating physician, in most cases dosage was reduced to 80% of the protocol dosage. We therefore used reduction to 80% of protocol dosage as a cut off to investigate the clinical effectiveness of standard chemotherapy in patients receiving reduced dosage.\n\nIn 42% (46/110) of our patients a dose reduction to 80% or less was performed during the course of chemotherapy. Those 46 patients who received a dose reduction, received in average 14 chemotherapy cycles in our clinic (Mean: 13.7 cycles; + − 12.3 cycles). Patients continuing on protocol chemotherapy doses, received 10.5 cycles (stdv 10.8, p = 0.149). In more detail, the majority of chemo cycles (72%, median: 81%; stdv: 27%) in these patients were applied with reduced dosage. Average cumulative dosage and dose intensities for 5-Flourouracil, Irinotecan and Oxaliplatin were calculated for full dosage and dose reduction subgroups (Table 2). As expected, relative dose intensities were significantly different. Even though a trend to a higher cumulative dosage can be observed, t-test revealed no significant differences for cumulative dosages.\n\nDose reduction in subgroups – analysis of distribution\nIn preparation to compare survival rates, we compared the distribution of the co-variables age, sex, TNM status, grading, lymph vessel invasion, vein invasion, Charlson score for comorbidities, surgery and further chemotherapy, i.e. number of lines and regimens in the dose reduction and full dosage group.\n\nNo significant difference was seen except for lymph vessel and vein invasion, CTX regimen and adverse side effects, when Chi-square test for independence was performed. As expected, subgroups of patients suffering from severe symptoms/side effects related to chemotherapy such as diarrhea (p < 0.001), PNP (p < 0.001), or neutropenia (p = 0.02) received dose reduction almost exclusively. Detailed summary of the distribution of dose reductions in different subgroups is given in Table 1.Table 1 Patient characteristics according to dosage reduction and in total\n\n\tDosage reduction\t\t\nYes (<=80% dosage)\tNo (=100% dosage)\tTotal\tT-test Chi2\t\n\nN\n\t(%)\t\nN\n\t(%)\t\nN\n\t(%)\tp value\t\nAge\tMean/Median\t56.5\t59.0\t58.4\t58.0\t57.6\t59.0\t.440\t\n\t< 65\t32\t69.6%\t42\t66.7%\t74\t67.9%\t.749\t\n> = 65\t14\t30.4%\t21\t33.3%\t35\t32.1%\t\t\nSex\tMale\t29\t63.0%\t46\t73.0%\t75\t68.8%\t.267\t\nFemale\t17\t37.0%\t17\t27.0%\t34\t31.2%\t\t\nT stage\tT3\t17\t37.0%\t23\t36.5%\t40\t36.7%\t\t\nT4\t22\t47.8%\t22\t34.9%\t44\t40.4%\t.205\t\nTx\t7\t15.2%\t18\t28.6%\t25\t22.9%\t\t\nN stage\tN0\t4\t8.7%\t5\t7.9%\t9\t8.3%\t\t\nN1\t14\t30.4%\t16\t25.4%\t30\t27.5%\t.796\t\nN2\t18\t39.1%\t23\t36.5%\t41\t37.6%\t\t\nNx\t10\t21.7%\t19\t30.2%\t29\t26.6%\t\t\nGrading\tG2\t27\t58.7%\t40\t63.5%\t67\t61.5%\t\t\nG3\t18\t39.1%\t19\t30.2%\t37\t33.9%\t.419\t\nGx\t1\t2.2%\t4\t6.3%\t5\t4.6%\t\t\nL stage\tL0\t6\t13.0%\t7\t11.1%\t13\t11.9%\t\t\nL1\t23\t50.0%\t15\t23.8%\t38\t34.9%\t.010\t\nLx\t17\t37.0%\t41\t65.1%\t58\t53.2%\t\t\nV stage\tV0\t13\t28.3%\t11\t17.5%\t24\t22.0%\t\t\nV1\t14\t30.4%\t10\t15.9%\t24\t22.0%\t.030\t\nVx\t19\t41.3%\t42\t66.7%\t61\t56.0%\t\t\nCharlson Comorbidity Score\t6\t32\t69.6%\t44\t69.8%\t76\t69.7%\t\t\n7\t7\t15.2%\t13\t20.6%\t20\t18.3%\t\t\n8\t6\t13.0%\t4\t6.3%\t10\t9.2%\t.336\t\n9\t0\t0.0%\t2\t3.2%\t2\t1.8%\t\t\n10\t1\t2.2%\t0\t0.0%\t1\t0.9%\t\t\nOncological resection/Surgery\tYes\t35\t76.1%\t37\t58.7%\t72\t66.1%\t.059\t\nNo\t11\t23.9%\t26\t41.3%\t37\t33.9%\t\t\nNo. of CTX lines\t1\t11\t23.9%\t17\t27.0%\t28\t25.7%\t\t\n2\t23\t50.0%\t34\t54.0%\t57\t52.3%\t\t\n3\t11\t23.9%\t11\t17.5%\t22\t20.2%\t.587\t\n4\t0\t0.0%\t1\t1.6%\t1\t0.9%\t\t\n5\t1\t2.2%\t0\t0.0%\t1\t0.9%\t\t\nBiological\tYes\t21\t45.7%\t26\t41.3%\t47\t43.1%\t.648\t\nNo\t25\t54.3%\t37\t58.7%\t62\t56.9%\t\t\nCTX regimen sequence\tFOLFOX- > FOLFIRI\t30\t65.2%\t27\t42.9%\t57\t52.3%\t\t\nFOLFIRI- > FOLFOX\t3\t6.5%\t13\t20.6%\t16\t14.7%\t.044\t\nFOLFOX\t10\t21.7%\t13\t20.6%\t23\t21.1%\t\t\nFOLFIRI\t3\t6.5%\t10\t15.9%\t13\t11.9%\t\t\nTotal\t46\t100.0%\t63\t100.0%\t109\t100.0%\t\t\nTable 2 Dose intensity and cumulative dosage for the dose-reduction and full dosage subgroups\n\n\tSubstance\tDose group\tMean in mg\tstandard deviation\tp-value\t\nCumulative Dosage\t5-Fluorouracil\t100%\t54,934\t55,617\t0.42\t\n< 80%\t64,321\t61,824\t\nOxaliplatin\t100%\t1046\t852\t0.34\t\n< 80%\t1245\t976\t\nIrinotecan\t100%\t2861\t3295\t0.77\t\n< 80%\t3099\t3296\t\nDose intensity\t5-Fluorouracil\t100%\t5383\t1450\t0.002\t\n< 80%\t4547\t1178\t\nOxaliplatin\t100%\t173\t31\t0.03\t\n< 80%\t156\t35\t\nIrinotecan\t100%\t311\t74\t0.04\t\n< 80%\t274\t65\t\nP-values were calculated with t-test\n\nTable 3 Reasons for dose reduction\n\nDistribution of adverse effects\t\nN\n\t%\t\nLeukopenia\t20\t30%\t\nPolyneuropathy\t11\t16%\t\nDiarrhea\t10\t14%\t\nWorsening of general condition\t6\t9%\t\nHand-foot-syndrome\t5\t7%\t\nThrombocytopenia\t5\t7%\t\nHyperemesis\t3\t4%\t\nElevated bilirubin\t2\t3%\t\nDeterioration of kidney function\t1\t1%\t\nMucositis\t1\t1%\t\nNot specified\t5\t7%\t\nTable 4 Results of univariable and multivariable Cox-regression for survival according to dosage reduction\n\n\t\t\t95% CI for HR\t\np value\tHazard ratio\tLower\tUpper\t\nUnivariable Cox-regression\t\nDosage reduction\tNo\t\t1.000\t\t\t\nYes\t.431\t.841\t.547\t1.294\t\nMultivariable Cox-regression\t\n Dosage reduction\tNo\t\t1.000\t\t\t\nYes\t.600\t.861\t.492\t1.506\t\n Age\tcontinuous\t.118\t.981\t.958\t1.005\t\n Sex\tMale\t\t1.000\t\t\t\nFemale\t.446\t1.264\t.692\t2.310\t\n T stage\tT3\t\t1.000\t\t\t\nT4\t.229\t1.541\t.761\t3.117\t\nTX\t.890\t.916\t.265\t3.170\t\n N stage\tN0\t\t1.000\t\t\t\nN1\t.981\t.988\t.345\t2.824\t\nN2\t.713\t1.225\t.415\t3.615\t\nNX\t.927\t.922\t.161\t5.266\t\n Grading\tG2\t\t1.000\t\t\t\nG3\t.302\t1.354\t.761\t2.407\t\nGX\t.458\t.576\t.134\t2.474\t\n L stage\tL0\t\t1.000\t\t\t\nL1\t.726\t1.215\t.408\t3.620\t\nLX\t.289\t.469\t.116\t1.901\t\n V stage\tV0\t\t1.000\t\t\t\nV1\t.872\t.920\t.334\t2.531\t\nVX\t.164\t2.620\t.675\t10.165\t\n Charlson Score\t6\t\t1.000\t\t\t\n7\t.750\t.892\t.443\t1.797\t\n8\t.909\t.954\t.426\t2.138\t\n9\t.609\t1.605\t.262\t9.822\t\n Oncological resection/Surgery\tNo\t\t1.000\t\t\t\nYes\t.227\t.483\t.149\t1.570\t\n No of CTX lines\tcontinuous\t.797\t1.053\t.712\t1.556\t\n Biological CTX\tNo\t\t1.000\t\t\t\nYes\t.178\t.663\t.364\t1.207\t\n CTX regimen\tFOLFOX- > FOLFIRI\t\t1.000\t\t\t\nFOLFIRI- > FOLFOX\t.691\t1.177\t.527\t2.627\t\nFOLFOX\t.001\t3.601\t1.656\t7.827\t\nFOLFIRI\t.921\t.945\t.309\t2.892\t\nTable 5 Subgroup analysis. Comparison of the survival after dose reduction versus full dosage in different subgroups analyzed by Kaplan-Meier procedure and Log-Rank test (Chemotherapy (CTX))\n\n\tDosage reduction\tLog-rank\t\nYes (≤ 80%)\tNo (100%)\t\t\nMean (Median) survival in months\tp-value\t\nAge\t< 65\t22.0 (14.6)\t17.1 (12.0)\t.170\t\n≥65\t18.8 (14.9)\t21.2 (15.8)\t.764\t\nSex\tMale\t23.5 (16.0)\t18.6 (14.9)\t.339\t\nFemale\t17.2 (13.1)\t17.4 (12.7)\t.170\t\nT stage\tT3\t27.8 (26.4)\t25.8 (14.9)\t.525\t\nT4\t15.6 (13.8)\t14.1 (12.7)\t.960\t\nTx\t24.3 (10.4)\t14.1 (7.7)\t.273\t\nN stage\tN0\t25.9 (23.6)\t30.5 (14.9)\t.851\t\nN1\t20.7 (13.9)\t24.1 (12.3)\t.669\t\nN2\t21.3 (26.4)\t13.3 (16.7)\t.024\t\nNx\t20.4 (16.0)\t13.2 (7.7)\t.294\t\nGrading\tG2\t24.1 (17.8)\t22.0 (16.1)\t.570\t\nG3\t17.5 (14.5)\t10.6 (10.4)\t.062\t\nGx\t26.8 (26.8)\t25.5 (3.0)\t.808\t\nL stage\tL0\t19.7 (17.8)\t30.7 (21.0)\t.541\t\nL1\t23.3 (13.9)\t16.9 (17.5)\t.485\t\nLx\t18.1 (14.8)\t16.3 (12.0)\t.561\t\nV stage\tV0\t28.8 (23.6)\t26.9 (21.0)\t.828\t\nV1\t20.3 (13.9)\t15.7 (16.7)\t.311\t\nVx\t16.9 (14.5)\t15.9 (11.8)\t.671\t\nCharlson Score for Comorbidities\t6\t20.6 (14.8)\t19.6 (12.0)\t.424\t\n7–10\t23.3 (15.0)\t19.6 (16.1)\t.632\t\nOncological resection/Surgery\tYes\t22.1 (14.9)\t23.8 (17.5)\t.997\t\nNo\t19.6 (12.9)\t12.9 (7.6)\t.301\t\nNo. of CTX lines\t1\t10.1 (10.4)\t8.4 (3.0)\t.565\t\n2\t23.1 (17.9)\t23.5 (15.8)\t.896\t\n3\t24.7 (23.6)\t16.6 (12.3)\t.238\t\nBiological CTX\tYes\t29.4 (26.8)\t23.5 (11.8)\t.371\t\nNo\t13.2 (13.1)\t14.6 (14.9)\t.823\t\nCTX regimen sequence\tFOLFOX- > FOLFIRI\t22.0 (20.2)\t26.5 (17.5)\t.425\t\nFOLFIRI- > FOLFOX\t12.3 (12.3)\t16.4 (14.9)\t.631\t\nFOLFOX\t9.7 (12.9)\t7.7 (3.6)\t.829\t\nFOLFIRI\t62.3 (90.7)\t13.0 (3.9)\t.300\t\n\n\nReasons for dose reduction\nThe most common reason for dose reduction of chemotherapy was neutropenia (30%). Other common side effects leading to dose reduction were polyneuropathy (16%) and diarrhea (14%). Polyneuropathy was generally due to treatment with Oxaliplatin (10 patients, 14%). Diarrhea was observed at similar rates in both Oxaliplatin (6/48 patients, 13%) and Irinotecan treated patients (4/30 patients, 13%). Less common reasons for dose reduction included mostly symptom-related causes, hyperemesis, worsening of general condition, hand foot syndrome and mucositis. A complete overview of the reasons for dose reduction of chemotherapy is shown in Table 3.\n\nSurvival in dose reduced versus full dose 5-FU based regimens\nIn terms of tumor-specific survival, we did not observe any differences between patients receiving full dose and reduced dose chemotherapy (Log Rank, p = 0.430) (Fig. 1). Median survival for patients receiving full dosage was 13.0 months (Mean 19.1), for patients with dosage reduction 14.9 months (Mean 21.2). Two-year survival was 19.5% (full dosage) vs 35.8% (reduced dosage). Three-year survival rate of patients with full dose and reduced dose chemotherapeutic treatment was 19.5% and 9.1%. A univariable Cox regression rendered a hazard ratio of 0.841 (95% CI 0.547–1.294; p = 0.431) for the dose reduction group versus full reduction. After adjustment for age, sex, TNM status, grading, lymph vessel invasion, vein invasion, Charlson score for comorbidities, surgery and further chemotherapy, i.e. number of lines and regimens in a multivariable Cox regression analysis the hazard ratio for patients with dose reduction was 0.861 (95% CI 0.492–1.506; p = 0.600) Table 4.Fig. 1 Kaplan Meier analysis of survival in patients with reduced and full dosage of standard chemotherapy back bone (FOLFIRI, FOLFOX). Survival analysis showed no difference in survival (p = 0.430, Log Rank)\n\n\n\nEfficacy – subgroup analysis\nWe performed a subgroup analysis to identify potential subgroups in which reduction of chemotherapy might be beneficial or harmful. Table 5 summarizes survival in several subgroups with respect to dose reduction. In most subgroups, no significant differences in survival were observed. Unexpectedly, in the stage N2 lymph node subgroup with 41 patients dose reduction was associated with improved survival (Log Rank p = 0.024).\n\nDiscussion\nOver the past decades a considerable progress has been made in the management of colorectal cancer by medical oncologists. The studies leading to these advances were predominantly performed on young and healthy populations; hence the common practice of dose reduction in elderly or frail patients was not a primary issue. Thus, these studies were mainly performed on a subgroup not suffering from relevant co-morbidities and being in good performance status.\n\nIn recent years, the need to investigate real life populations and the common practice of dose reduction has been recognized by the scientific community. However, (retrospective) studies investigating the effects of dose reduction in a palliative setting have been published but are still sparse. In 2001, a retrospective analysis of patients with Stage II-III colon cancer demonstrated that in an adjuvant setting 5-FU based chemotherapy may be safely administered in the elderly, but this study did not elaborate the dose reduction needed [12]. In 2011 Langley et al. published the Focus II study, a first randomized controlled trial including only the frail and old patients with colorectal cancer. This study incorporated primary dose reduction as the standard treatment for all treatment arms. However, it was not designed to investigate whether dose reduction itself could be performed if required without affecting PFS or OS [13].\n\nIn order to evaluate whether dose reduction has an effect on survival in patients with advanced colorectal cancer and suffering from side effects under standard treatment dose, we performed this retrospective analysis of such patients in our outpatient clinic. In our current study, we chose a cutoff for dose reduction of 80% since in our experience a dose reduction to 80% is a commonly performed reduction in case of adverse reactions. Since only very few patients received further dose reduction (n = 4), we chose not to include these patients as a separate group with dose reduction of ≤50% but rather included these patients in the group of patients with reduction of chemotherapy dosage. Thus, the overall average dose reduction in this patient group was even more than 20%. In these patients, a dose reduction was applied to the majority of cycles (72%), emphasizing that this group predominantly received a reduced chemotherapy dosage throughout the course of therapy.\n\nIn daily clinical routine, clinicians are more likely to reduce the dose of elderly patients. Therefore, one might assume that in the elderly (> 65 years) in our collective dose reduction would be more common. However, dose reduction was evenly distributed among younger and elderly patients and thus independent of age. Also, additional subgroup analysis (T-stage, N-stage, M-stage, gender, and chemotherapy regimen) showed an even distribution of dose reduction.\n\nSince clinical trials showed the effectiveness of per protocol chemotherapy, in theory a reduced dosage of chemotherapy would be expected to affect survival, which has also been confirmed by several publications for other entities [9]. It is therefore common belief, that dose reduction should be avoided. Additionally, clinicians choose a dose reduction often due to symptom-related causes or deterioration of laboratory findings. Many of these reasons (recurring neutropenia, deterioration of general condition) are associated with a poor clinical outcome. Therefore, one might assume, that dose reduction is more common in patients with clinical features suggesting a poor prognosis. Interestingly, statistical analysis of our data showed that a moderate dose reduction does not affect survival significantly.\n\nIn a recently published manuscript, the influence of the relative dose intensity (RDI, of adjuvant 5FU and Oxaliplatin combination treatment in veterans with Stage III colon cancer had been further investigated. Aspinalli et al. showed that a major reduction of RDI (< 70%) to be associated with worse overall survival in this patient group [14]. In addition to the bias of the patient group which consisted mainly of male veterans, there was a bias towards dose reduction in the frail and elderly. In comparison with our study also the magnitude of dose reduction was more pronounced.\n\nWhen Oxaliplatin was introduced to the treatment of CRC, a retrospective analysis of three phase II studies of pretreated colorectal cancer showed that higher dose intensity leads to improved survival [15]. In contrast to our study, these study populations had been pretreated and in two out of the three studies patients’ inclusion age was limited to younger patients. In another more recent study, Nakayama et al. showed that a dose reduction in metastasized CRC led to poorer survival of the respective (Irinotecan) patient group. A comparison with our study population is difficult, since per protocol Irinotecan dosage in Japan is already 12% lower than in the western countries and further dose reduction adds up to even more pronounced dose reductions. For the patient group receiving Oxaliplatin only PFS was significantly associated to RDI [16].\n\nNevertheless, in clinical practice, patients often experience side effects and need dose reduction. For these patients, our data in treatment-naive patients suffering from stage IV colorectal cancer, suggest that a moderate dose reduction does not necessarily result in less efficacy. Until now, only limited data were reported on this issue, which we believe to be of high clinical relevance. Thus, we suggest further randomized studies potentially leading to more personalized treatment strategies depending on tolerance of treatment and co-morbidities and a more side effect oriented approach on chemotherapy dosing.\n\nConclusion\nIn our group of patients with colorectal cancer treated in a palliative setting, the need for a moderate reduction of chemotherapy due to side effects has no measurable effect on survival. This may be in part due to better adaption to interindividual pharmacokinetics and to a longer treatment of patients with reduced chemotherapy dosage if side effects cause dose reduction.\n\nAdditional file\n\nAdditional file 1: Table S1. Summary of comorbidities. (DOCX 13 kb)\n\n \n\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12885-018-4380-z) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nWe greatly appreciate all the authors for their endeavor.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nComment\nPart of this study was presented at the ASCO GI Meeting 2017 San Francisco. Permission was obtained for final publication [17].\n\nAuthors’ contributions\nSM, MG, AT carried out the primary data analysis. SM, AT, SFF, CS, HJS, CO, ES, PW, MV, WH, ME, MR, PF, MKS were responsible for the treatment of patients with CRC at the Regensburg University Medical Center. SM, AT, MG, PW and HJS helped to draft the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nDue to the analysis of data from a clinical cancer registry, no ethics approval was necessary. This was confirmed by the Ethics Committee at the Regensburg University, Regensburg, Germany.\n\nCompeting interests\nThe authors declare that they have no competing interest.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Siegel R Desantis C Jemal A Colorectal cancer statistics, 2014 CA Cancer J Clin 2014 64 104 117 10.3322/caac.21220 24639052 \n2. Kelly H Goldberg RM Systemic therapy for metastatic colorectal cancer: current options, current evidence J Clin Oncol 2005 23 4553 4560 10.1200/JCO.2005.17.749 16002847 \n3. Braun MS Seymour MT Balancing the efficacy and toxicity of chemotherapy in colorectal cancer Ther Adv Med Oncol 2011 3 43 52 10.1177/1758834010388342 21789155 \n4. Hutchins LF Unger JM Crowley JJ Underrepresentation of patients 65 years of age or older in cancer-treatment trials N Engl J Med 1999 341 2061 2067 10.1056/NEJM199912303412706 10615079 \n5. Kordatou Z Kountourakis P Papamichael D Treatment of older patients with colorectal cancer: a perspective review Ther Adv Med Oncol 2014 6 128 140 10.1177/1758834014523328 24790652 \n6. Hurria A Dale W Mooney M Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations J Clin Oncol 2014 32 2587 2594 10.1200/JCO.2013.55.0418 25071116 \n7. Leo S Accettura C Gnoni A Systemic treatment of gastrointestinal cancer in elderly patients J Gastrointest Cancer 2013 44 22 32 10.1007/s12029-012-9447-5 23150086 \n8. Bluhm M, Connell CM, Janz N, et al. Oncologists' End of Life Treatment Decisions: How Much Does Patient Age Matter? J Appl Gerontol. 2015;36(4):416–40.\n9. Havrilesky LJ Reiner M Morrow PK A review of relative dose intensity and survival in patients with metastatic solid tumors Crit Rev Oncol Hematol 2015 93 203 210 10.1016/j.critrevonc.2014.10.006 25459671 \n10. Charlson ME Pompei P Ales KL A new method of classifying prognostic comorbidity in longitudinal studies: development and validation J Chronic Dis 1987 40 373 383 10.1016/0021-9681(87)90171-8 3558716 \n11. Reng C Fest P Mackensen A OnkoDAT – Unterstützung der Chemotherapieplanung PraxisComputer 2002 18 10 12 \n12. Fata F Mirza A Craig G Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colon carcinoma: a 10-year experience of the Geisinger Medical Center Cancer 2002 94 1931 1938 10.1002/cncr.10430 11932894 \n13. Seymour MT Thompson LC Wasan HS Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial Lancet 2011 377 1749 1759 10.1016/S0140-6736(11)60399-1 21570111 \n14. Aspinall SL Good CB Zhao X Adjuvant chemotherapy for stage III colon cancer: relative dose intensity and survival among veterans BMC Cancer 2015 15 62 10.1186/s12885-015-1038-y 25884851 \n15. Maindrault-Goebel F de Gramont A Louvet C Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR) Ann Oncol 2000 11 1477 1483 10.1023/A:1026520812351 11142489 \n16. Nakayama G Tanaka C Uehara K The impact of dose/time modification in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer Cancer Chemother Pharmacol 2014 73 847 855 10.1007/s00280-014-2416-x 24577566 \n17. Munker S. Chemotherapy for metastatic colon cancer: Effect on survival when the dose is reduced due to side effects. J Clin Oncol. 2017;35\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Cancer; Chemotherapy; Colorectal cancer; Dose reduction",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D010166:Palliative Care; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
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"pages": "455",
"pmc": null,
"pmid": "29685155",
"pubdate": "2018-04-23",
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"references": "21570111;21789155;25884851;24639052;11932894;16002847;3558716;10615079;24790652;11142489;25071116;24577566;25459671;23150086",
"title": "Chemotherapy for metastatic colon cancer: No effect on survival when the dose is reduced due to side effects.",
"title_normalized": "chemotherapy for metastatic colon cancer no effect on survival when the dose is reduced due to side effects"
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"abstract": "Treatment of cesarean scar pregnancy is based on clinical context. This report describes two rare complications of conservative management: non-steroidal anti-inflammatory drug-induced methotrexate myelosuppression and myometrial pseudoaneurysm.\n\n\n\nA 34-year-old woman was treated conservatively for a cesarean scar pregnancy with systemic methotrexate and intragestational potassium chloride, resulting in pancytopenia secondary to concurrent non-steroidal anti-inflammatory drug use. She presented again with a myometrial pseudoaneurysm, which was treated with bilateral uterine artery embolization and, ultimately, hysterectomy. The final pathology report confirmed a pseudoaneurysm, retained villi within the myometrium, and acute endometritis and myometritis.\n\n\n\nMyelosuppression resulting from use of non-steroidal anti-inflammatory drugs affecting renal excretion of methotrexate can occur at low dosages. Additionally, there is a risk of pseudoaneurysms with vascular damage and trophoblastic tissue. Drug interactions and procedure-related risks must be considered when managing cesarean scar pregnancy conservatively.",
"affiliations": "Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB.;Department of Oncology, Faculty of Medicine, University of Calgary, Calgary, AB. Electronic address: preuss@ualberta.ca.;Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry University of Alberta, Edmonton, AB.;Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry University of Alberta, Edmonton, AB.",
"authors": "Omand|Alexandra|A|;Aubrey|Christa|C|;Mills|Ginevra|G|;Tankel|Jonathan|J|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D008727:Methotrexate",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jogc.2019.08.023",
"fulltext": null,
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"issn_linking": "1701-2163",
"issue": "42(6)",
"journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC",
"keywords": "aneurysm, false; cesarean section; ectopic pregnancy; methotrexate; pancytopenia",
"medline_ta": "J Obstet Gynaecol Can",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D017541:Aneurysm, False; D002585:Cesarean Section; D002921:Cicatrix; D000072700:Conservative Treatment; D005260:Female; D006801:Humans; D008727:Methotrexate; D009215:Myometrium; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D016896:Treatment Outcome",
"nlm_unique_id": "101126664",
"other_id": null,
"pages": "798-801",
"pmc": null,
"pmid": "31864915",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Myometrial Pseudoaneurysm and Myelosuppression Following Conservative Management of Cesarean Scar Ectopic Pregnancy.",
"title_normalized": "myometrial pseudoaneurysm and myelosuppression following conservative management of cesarean scar ectopic pregnancy"
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"abstract": "BACKGROUND\nMyasthenia gravis (MG) crisis has no specific reported correlation with atrial fibrillation (AF). We present a series of patients observed from a single general neurologist's outpatient and inpatient practice over a 9-year period who experienced the combination of MG crisis and AF.\n\n\nMETHODS\nRetrospective chart review of patients within 1 neurologist's inpatient and outpatient practice was done. Charts were selected based on the occurrence of newly diagnosed AF during MG crisis over a 9-year period. Most patients were diagnosed in the hospital and then followed as outpatients. Charts were reviewed to determine factors that may have played a role in the co-occurrence of these 2 conditions. Eight patients were identified that had co-occurring MG crisis and AF. All patients had very active MG, and were in or had recently been in MG crisis at the time their AF was discovered. Patients tended to have late-onset MG to be male, to be acetylcholinesterase receptor antibody positive, and to have improvement or remission of their AF once the MG achieved better clinical control.\n\n\nCONCLUSIONS\nNew-onset AF can occur during MG crisis. The cardiac outcome improves with treatment of the underlying disease, after initial cardiac stabilization.",
"affiliations": "Department of Neurology, University of Central Florida College of Medicine, Orlando, FL.",
"authors": "Jacobs|Daniel H|DH|",
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"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000246",
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"issn_linking": "1074-7931",
"issue": "25(1)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D012189:Retrospective Studies",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "1-3",
"pmc": null,
"pmid": "31876650",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Myasthenia Gravis Crisis and Atrial Fibrillation.",
"title_normalized": "myasthenia gravis crisis and atrial fibrillation"
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-00961",
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"abstract": "Pneumonitis due to primary toxoplasmosis in an immunocompetent subject is rare. Here, the mononucleosis-like syndrome, associated with serological evidence of https://bit.ly/3qHE2U7.",
"affiliations": "Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.;Comissão de Controle de Infecções Hospitalares, Hospital Unimed Rio, Rio de Janeiro, Brazil.;Hospital Universitário Pedro Ernesto, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil.",
"authors": "Steinhauser Motta|João Pedro|JP|;Barbosa Cleinman|Isabella|I|;Palermo Bruno|Leonardo|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1183/20734735.0165-2020",
"fulltext": "\n==== Front\nBreathe (Sheff)\nBreathe (Sheff)\nBREATHE\nbreathe\nBreathe\n1810-6838\n2073-4735\nEuropean Respiratory Society\n\n33664833\n10.1183/20734735.0165-2020\nEDU-0165-2020\nVersion of Record\nExpert Opinion\nCase Report\nAn immunocompetent young man with diffuse pulmonary infiltrates\nAn immunocompetent young man with diffuse pulmonary infiltrates\nSteinhauser Motta João Pedro 1\nBarbosa Cleinman Isabella 2\nPalermo Bruno Leonardo 3\n1 Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil\n2 Comissão de Controle de Infecções Hospitalares, Hospital Unimed Rio, Rio de Janeiro, Brazil\n3 Hospital Universitário Pedro Ernesto, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil\nE-mail: joaosteinhauser@gmail.com\n12 2020\n16 4 2001656 7 2020\n6 12 2020\nCopyright ©ERS 2021\n2021\nhttp://creativecommons.org/licenses/by-nc/4.0/ Breathe articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.\nA 30-year-old doctor, without comorbidities, presented to the emergency department of our hospital in Rio de Janeiro with a 2-week history of intermittent high fever (reaching 39°C), headache and abdominal pain. A week later the patient developed a dry cough, dyspnoea, and cervical lymphadenopathy. As relevant epidemiological data, the patient had travelled to Canada 15 days before the start of these manifestations. He denied contact with sick people, visits to caves or rural areas, and eating of raw food. Treatment for community-acquired pneumonia with levofloxacin was started. As there was no clinical improvement, he was admitted to the intensive care unit (ICU) of our hospital for investigation and treatment.\n\nPneumonitis due to primary toxoplasmosis in an immunocompetent subject is rare. Here, the mononucleosis-like syndrome, associated with serological evidence of T. gondii infection and positive PCR for T. gondii in BAL, allowed us to establish the diagnosis. https://bit.ly/3qHE2U7\n==== Body\nA 30-year-old doctor, without comorbidities, presented to the emergency department of our hospital in Rio de Janeiro with a 2-week history of intermittent high fever (reaching 39°C), headache and abdominal pain. A week later the patient developed a dry cough, dyspnoea, and cervical lymphadenopathy. As relevant epidemiological data, the patient had travelled to Canada 15 days before the start of these manifestations. He denied contact with sick people, visits to caves or rural areas, and eating of raw food. Treatment for community-acquired pneumonia with levofloxacin was started. As there was no clinical improvement, he was admitted to the intensive care unit (ICU) of our hospital for investigation and treatment.\n\nOn admission in the ICU, the patient was dyspnoeic and hypoxaemic, depending on high-flow oxygen support and intermittent noninvasive mechanical ventilation. Physical examination revealed cervical bilateral lymphadenopathy, pulmonary auscultation with discrete bilateral pulmonary rales, and abdominal palpation with hepatosplenomegaly. Initial laboratory findings demonstrated mild liver injury and elevated C-reactive protein. Serological panel showed both reactive anti-Toxoplasma gondii IgM and IgG and IgG avidity was low. HIV serology was negative. Chest computed tomography (CT) showed bilateral ground-glass opacities, mediastinal lymphadenopathy, and slight pleural effusion (figures 1 and 2). Abdominal CT revealed hepatosplenomegaly.\n\nFigure 1 Chest CT showing bilateral ground-glass opacities associated with peripheral septal thickening.\n\nFigure 2 Chest CT showing bilateral ground-glass opacities associated with slight pleural effusion.\n\nTask 1\n\nWhich of the following is the main diagnostic hypothesis? a) Disseminated tuberculosis\n\nb) Lymphoma\n\nc) Mononucleosis-like syndrome\n\nd) Hantavirosis\n\ne) Disseminated histoplasmosis\n\nAnswer 1\n\nAll of the diagnostic hypotheses listed may present with a clinical picture of fever, lymphadenopathy and hepatosplenomegaly. Among such hypotheses, mononucleosis-like syndrome would be the most common in a young patient without comorbidities. Lymphoma would be a plausible possibility for the case and cannot be ruled out at this time. However, the rapid clinical evolution seems more acute than expected for cases of lymphoproliferative disease, and the B-symptoms of lymphoma are characterised by lower fever than that presented by the patient and by night sweats, which does not appear in the clinical history. For a severe condition of lymphoma already evolving with respiratory failure, changes in the patient's blood count would be expected, which is not demonstrated in the clinical case. Disseminated tuberculosis would be more commonly associated with immunosuppression and is also generally characterised by a fever that is less high than the fever of the patient in question, in addition to being more common in the evening and associated with night sweats. In the same way as lymphoma, tuberculosis usually has a more insidious evolution. The CT changes evidenced with ground-glass opacities are not typical of disseminated tuberculosis, which is characterised by diffuse micronodular infiltrates, randomly distributed, whose small nodules measure between 2 and 3 mm in diameter with a predominance in the upper lobes. Disseminated histoplasmosis is generally associated with environmental exposure to bat faeces. Hantavirus is related to exposure to urine, faeces, or rodent saliva (not described in the case) and is not usually related to hepatosplenomegaly.\n\nTask 2\n\nWhat would be the next step? a) Surgical lung biopsy\n\nb) Sulfadiazine with pyrimethamine\n\nc) Bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial ultrasound\n\nd) Amphotericin B\n\nAnswer 2\n\nThe serological panel with positive IgM and IgG results for T. gondii and low IgG avidity test indicate the diagnosis of acute toxoplasmosis, an aetiology compatible with the mononucleosis-like syndrome presented by the patient. The recommended treatment for severe cases of disseminated toxoplasmosis is sulfadiazine with pyrimethamine. The use of trimethoprim-sulfamethoxazole is a therapeutic alternative if sulfadiazine with pyrimethamine is not available or if it is not possible to take medication through the digestive tract.\n\nBecause of suspected toxoplasmosis and due to the case severity and respiratory impairment we chose to start treatment with intravenous medication (trimethoprim-sulfamethoxazole, 10–50 mg·kg−1·day−1). Despite treatment, he developed respiratory worsening in the next 24 h and it was decided to carry out an open lung biopsy and bronchoscopy. A histopathological study from the lung biopsy demonstrated diffuse alveolar damage. Gram, Ziehl Nielsen and Fontana-Masson stains did not demonstrate specific pathogens. BAL T. gondii PCR was positive.\n\nTask 3\n\nWhat is the best therapeutic choice? a) High-dose corticosteroid therapy\n\nb) Empiric therapy with amphotericin B, piperacillin-tazobactam, azithromycin and corticosteroid\n\nc) Keep the treatment for toxoplasmosis\n\nd) Start ganciclovir\n\ne) None of the above\n\nAnswer 3\n\nThe finding of diffuse alveolar damage on lung biopsy is not specific to a particular disease and can be the result of different inflammatory and/or infectious processes. Diffuse alveolar damage is the histopathological finding found in acute respiratory distress syndrome (ARDS). The absence of common pathogens in the histopathology of lung tissue, associated with positive T. gondii PCR obtained from BAL, led us to establish that the toxoplasmosis was responsible for the pneumonitis aetiology, so the treatment with trimethoprim-sulfamethoxazole should be continued.\n\nIt was decided to keep the treatment for toxoplasmosis and add low-dose corticosteroids as part of the treatment of ARDS. After 3 days, it was possible to wean from mechanical ventilation and switch to oral medication (sulfadiazine 6 g·day−1 and pyrimethamine 75 mg loading dose, followed by 25 mg·day−1). After 10 days of hospitalisation, the patient was discharged with significant clinical and laboratory improvement, and recommendation to complete a 4-week course of anti-Toxoplasma treatment. The control CT performed before hospital discharge showed a slight residual pneumothorax after removal of the chest drain and an important evolutionary improvement of the bilateral pulmonary infiltrate in ground glass (figure 3).\n\nFigure 3 Chest CT before hospital discharge showing improvement in ground-glass opacities and small residual pneumothorax and pneumomediastinum after surgical biopsy.\n\nTask 4\n\nWhich of the following is not correct about the diagnosis of toxoplasmosis? a) Raw food intake is often related to illness\n\nb) Fever, lymphadenopathy and hepatosplenomegaly are usually present in cases with clinical manifestations\n\nc) The disease is usually symptomatic in immunocompetent patients\n\nd) Infections due to cytomegalovirus (CMV) and Epstein–Barr virus (EBV) viruses can manifest similar symptoms\n\ne) None of the above\n\nAnswer 4\n\nToxoplasmosis is a zoonosis caused by the parasite T. gondii. Felids are infected as definite hosts, and humans as intermediate hosts. T. gondii infection in humans most often occurs through the ingestion of uncooked meat contaminated by cysts, ingestion of food or water contaminated by oocysts, or by mother–child transmission during pregnancy [1]. Toxoplasmosis is an endemic disease in developing countries [2–4]. Usually, toxoplasmosis presents as an asymptomatic disease or a nonspecific infectious syndrome, the most common manifestations are fatigue, fever, headache, lymphadenopathy, and hepatosplenomegaly [2, 3]. Young adults are the most often affected, predominantly men [2, 3]. The disease can be life-threatening in immunocompromised individuals, such as HIV carriers, patients who have undergone haematopoietic stem cell transplant and solid organ transplant recipients [5–7]. In rare situations, the primary infection can manifest as a severe infirmity in otherwise healthy people [8–10]. Infections with the EBV and CMV viruses can manifest as a mononucleosis-like syndrome (fever, lymphadenopathy and hepatosplenomegaly) and, therefore, are part of the differential diagnoses for the case presented.\n\nDiscussion\n\nHere, we report a case of acute toxoplasmosis infection with pneumonitis in an immunocompetent patient. The primary infection is supported by documented seroconversion of IgM and IgG antibodies and low IgG avidity test. There are few reports of lung involvement associated with T. gondii infection in immunocompetent patients [8–12]. The absence of common pathogens in the histopathology study of lung tissue, associated with positive T. gondii PCR obtained from BAL, led us to establish the pneumonitis aetiology. Other studies had demonstrated that PCR is an important tool in acute toxoplasmosis diagnosis, and can be detected from different clinical samples, such as BAL, blood, amniotic fluid and cerebrospinal fluid [9, 10, 13, 14].\n\nAlthough standard toxoplasmosis treatment is sulfadiazine and pyrimethamine, trimethoprim-sulfamethoxazole is supported as an option in the treatment of disseminated infection in immunocompetent people [15–17]. Our initial choice for treatment with trimethoprim-sulfamethoxazole was due to patient respiratory impairment and the difficulty of swallowing pills.\n\nConclusion\n\nThe diagnostic of pneumonitis due to primary toxoplasmosis in an immunocompetent subject is very rare. The severity of the clinical case presented by the patient required rapid and accurate diagnostic and therapeutic approaches. The clinical presentation of mononucleosis-like syndrome, associated with serological evidence of recent T. gondii infection and the finding of positive PCR for T. gondii in BAL allowed us to define the diagnosis. The rapid clinical recovery of the patient after beginning adequate therapy, with hospital discharge after only 10 days, confirms the correct therapeutic decision.\n\nConflict of interest: J.P. Steinhauser Motta has nothing to disclose.\n\nConflict of interest: I. Barbosa Cleinmann has nothing to disclose.\n\nConflict of interest: L.P. Palermo Bruno has nothing to disclose.\n==== Refs\nReferences\n\n1 Cuomo G, D'Abrosca V, Rizzo V, et al. Severe polymyositis due to Toxoplasma Gondii in an adult immunocompetent patient: a case report and review. Infection 2013; 41 : 859–862. doi:10.1007/s15010-013-0427-x 23543435\n2 Carme B, Bissuel F, Ajzenberg D, et al. Severe acquired toxoplasmosis in immunocompetent adult patients in French Guiana. J Clin Microbiol 2002; 40 : 4037–4044. doi:10.1128/JCM.40.11.4037-4044.2002 12409371\n3 Anand R, Jones CW, Ricks JH, et al. Acute primary toxoplasmosis in travelers returning from endemic countries. J Travel Med 2012; 19 : 57–60. doi:10.1111/j.1708-8305.2011.00564.x 22221813\n4 Sun X, Lu H, Jia B, et al. A comparative study of Toxoplasma Gondii seroprevalence in three healthy Chinese populations detected using native and recombinant antigens. Parasit Vectors 2013; 6 : 241. doi:10.1186/1756-3305-6-241 23958280\n5 Schmidt M, Sonneville R, Schnell D, et al. Clinical features and outcomes in patients with disseminated toxoplasmosis admitted to intensive care: a multicenter study. Clin Infect Dis 2013; 57 : 1535–1541. doi:10.1093/cid/cit557 23994819\n6 Fernandez-Sabé N, Cervera C, Fariñas MC, et al. Risk factors, clinical features, and outcomes of toxoplasmosis in solid-organ transplant recipients: a matched case-control study. Clin Infect Dis 2012; 54 : 355–361. doi:10.1093/cid/cir806 22075795\n7 Balkhair AA, Al Murharrmii ZK, Ganguly S, et al. Spectrum of AIDS-defining opportunistic infections in a series of 77 hospitalized HIV-infected Omani patients. Clin Basic Res 2012; 12 : 442–448.\n8 Rodrigues Cal RG, Rodrigues Marra A, Salomão Levy D. Toxoplasmose pulmonar – ocorrência em adulto imunocompetente [Pulmonary toxoplasmosis: occurrence in an immunocompetent adult]. Rev Ass Med Bras 2003; 49 : 133–134. doi:10.1590/S0104-42302003000200027 12886386\n9 De Salvador-Guillouet F, Ajzenberg D, Chaillou-Opitz S, et al. Severe pneumonia during primary infection with an atypical strain of Toxoplasma gondii in an immunocompetent man. J Infect 2006; 53 : 47–50. doi:10.1016/j.jinf.2005.10.026\n10 Leal FE, Cavazzana CL, Franco de Andrade H, et al. Toxoplasma gondii pneumonia in immunocompetent subjects: case report and review. Clin Infect Dis 2007; 44 : e62–e66. doi:10.1086/511871 17304443\n11 Souza Neves E, Kropf A, Fernandes Bueno W, et al. Disseminated toxoplasmosis: an atypical presentation in an immunocompetent patient. Trop Doct 2011; 41 : 59–60. doi:10.1258/td.2010.100228 21062937\n12 Simanaityte D, Le Gouellec N, Ajana F, et al. Primary pulmonary toxoplasmosis in an immunocompetent patient. Med Mal Infect 2010; 40 : 713–715. doi:10.1016/j.medmal.2010.03.013 20413237\n13 Smati M, Taillé C, Menotti J, et al. Contribution of Toxoplasma-gondii specific PCR for the diagnosis of disseminated toxoplasmosis in a non-HIV and non-grafted adult patient. Med Mal Infect 2010; 40 : 596–599. doi:10.1016/j.medmal.2010.01.004 20172671\n14 Ferreira IMR, Vidal JE, Brandão de Mattos C, et al. Toxoplasma gondii isolates: Multilocus RFLP-PCR genotyping from human patients in São Paulo state, Brazil identified distinct fenotypes. Exp Parasitol 2011; 129 : 190–195. doi:10.1016/j.exppara.2011.06.002 21741380\n15 Yan J, Huang B, Liu G, et al. Meta-analysis of prevention and treatment of toxoplasmic encephalitis in HIV-infected patients. Acta Trop 2013; 127 : 236–244. doi:10.1016/j.actatropica.2013.05.006 23707647\n16 Béraud G, Pierre-François S, Foltzer A, et al. Cotrimoxazole for treatment of cerebral toxoplasmosis: an observational cohort study during 1994–2006. Am J Trop Med Hyg 2009; 80 : 583–587. doi:10.4269/ajtmh.2009.80.583 19346380\n17 Torre D, Casari S, Speranza F, et al. Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS. Antimicrob Agents Chemother 1998; 42 : 1346–1349. doi:10.1128/AAC.42.6.1346 9624473\n\n",
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"title": "An immunocompetent young man with diffuse pulmonary infiltrates.",
"title_normalized": "an immunocompetent young man with diffuse pulmonary infiltrates"
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"abstract": "A 77-year-old woman was referred to our hospital because of blood in feces and anal pain. Colonoscopy revealed a villous semicircular tumor in the rectum. A biopsy showed well-differentiated adenocarcinoma. Miles' operation was performed because of the persistence of anal pain and blood in feces. Histological and immunohistochemical analysis showed coexistent tubulovillous adenoma, tubulovillous adenocarcinoma, and large cell neuroendocrine carcinoma (LCNEC), which was positive for CD56, chromogranin A, and synaptophysin. Pathological examination revealed that most of the lesion was occupied by the LCNEC. The tumor was therefore diagnosed as LCNEC of the rectum. The patient underwent adjuvant chemotherapy with cisplatin (CDDP), irinotecan (CPT-11), and mFOLFOX6, but died because of LCNEC progression 10 months after the operation. LCNEC rarely occurs in the gastrointestinal tract; here we report a case of rectal LCNEC.",
"affiliations": "Department of Internal Medicine, Engaru Kosei General Hospital.",
"authors": "Muto|Mizue|M|;Ichiki|Kazuhiko|K|;Muto|Momotaro|M|;Ishikawa|Chisato|C|;Inoue|Mitsutaka|M|;Aoki|Takanori|T|;Hashimoto|Michinori|M|;Inaba|Satoshi|S|;Yamamoto|Masahiro|M|",
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"doi": "10.11405/nisshoshi.112.683",
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"issue": "112(4)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D018278:Carcinoma, Neuroendocrine; D005260:Female; D006801:Humans; D012004:Rectal Neoplasms",
"nlm_unique_id": "2984683R",
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"pages": "683-9",
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"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A case of large cell neuroendocrine carcinoma of the rectum.",
"title_normalized": "a case of large cell neuroendocrine carcinoma of the rectum"
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"companynumb": "JP-BAUSCH-BL-2016-019098",
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"abstract": "OBJECTIVE\nThe study investigated whether renal complications affected the efficacy and safety of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase.\n\n\nMETHODS\nFifty-seven patients with SLE (A: 30 cases with renal complication, B: 27 cases without renal complications) were included. The presence of renal complications was defined as proteinuria ≥0.5 g/day and lupus nephritis on renal biopsy. Major outcome measures included SLE disease activity index (SLEDAI), steroid dose, serum anti-dsDNA Ab, C3 and creatinine (Cr) levels and estimated glomerular filtration rate (eGFR). The patient's background factors included age, gender, disease duration and ACE-I/angiotensin II receptor blocker and statin therapies. We compared these outcome measures pre treatment and after 1 year of treatment.\n\n\nRESULTS\nThe SLEDAI and serum C3 levels improved in both groups from pretreatment period to post-treatment period: from 7.2±5.0 to 2.8±2.3 in A and 6.4±3.8 to 2.4±2.2 in B, p<0.001, and from 65.9±24.6 to 77.7±18.2 mg/dL in A and 81.8±23.0 to 90.6±19.4 mg/dL in B, p=0.002, respectively. The anti-dsDNA antibody level was reduced, and the serum Cr and eGFR levels were slightly elevated. No patients developed end-stage renal failure that required artificial dialysis.\n\n\nCONCLUSIONS\nTacrolimus combination therapy had additive beneficial effects on reduced proteinuria and increased serum C3 levels in patients with SLE with renal complications during a maintenance phase.",
"affiliations": "Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.;Division of Rheumatology, Department of Medicine , Showa University School of Medicine , Tokyo , Japan.",
"authors": "Ishii|Sho|S|;Miwa|Yusuke|Y|;Otsuka|Kumiko|K|;Nishimi|Shinichiro|S|;Nishimi|Airi|A|;Saito|Mayu|M|;Miura|Yoko|Y|;Oguro|Nao|N|;Tokunaga|Takahiro|T|;Takahashi|Ryo|R|;Kasama|Tsuyoshi|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/lupus-2015-000091",
"fulltext": "\n==== Front\nLupus Sci MedLupus Sci MedlupusscimedlupusLupus Science & Medicine2053-8790BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR lupus-2015-00009110.1136/lupus-2015-000091Lupus Nephritis15062255Influence of renal complications on the efficacy and adverse events of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase: a single-centre, prospective study Ishii Sho Miwa Yusuke Otsuka Kumiko Nishimi Shinichiro Nishimi Airi Saito Mayu Miura Yoko Oguro Nao Tokunaga Takahiro Takahashi Ryo Kasama Tsuyoshi Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, JapanCorrespondence to Dr Yusuke Miwa; y.miwa@mbf.ocn.ne.jp2015 29 5 2015 2 1 e0000913 3 2015 5 5 2015 10 5 2015 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2015This is an Open Access article 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. See: http://creativecommons.org/licenses/by-nc/4.0/Objectives\nThe study investigated whether renal complications affected the efficacy and safety of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase.\n\nMethods\nFifty-seven patients with SLE (A: 30 cases with renal complication, B: 27 cases without renal complications) were included. The presence of renal complications was defined as proteinuria ≥0.5 g/day and lupus nephritis on renal biopsy. Major outcome measures included SLE disease activity index (SLEDAI), steroid dose, serum anti-dsDNA Ab, C3 and creatinine (Cr) levels and estimated glomerular filtration rate (eGFR). The patient's background factors included age, gender, disease duration and ACE-I/angiotensin II receptor blocker and statin therapies. We compared these outcome measures pre treatment and after 1 year of treatment.\n\nResults\nThe SLEDAI and serum C3 levels improved in both groups from pretreatment period to post-treatment period: from 7.2±5.0 to 2.8±2.3 in A and 6.4±3.8 to 2.4±2.2 in B, p<0.001, and from 65.9±24.6 to 77.7±18.2 mg/dL in A and 81.8±23.0 to 90.6±19.4 mg/dL in B, p=0.002, respectively. The anti-dsDNA antibody level was reduced, and the serum Cr and eGFR levels were slightly elevated. No patients developed end-stage renal failure that required artificial dialysis.\n\nConclusions\nTacrolimus combination therapy had additive beneficial effects on reduced proteinuria and increased serum C3 levels in patients with SLE with renal complications during a maintenance phase.\n\nSystemic Lupus ErythematosusLupus NephritisDisease ActivityOutcomes research\n==== Body\nKey messages\nTacrolimus combination therapy had additive beneficial effects and increased serum C3 levels in SLE patients with or without renal complications during a maintenance phase.\n\nTacrolimus reduced the steroid dosage, improved the SLEDAI and reduced anti-dsDNA antibody levels in patients with or without renal complications.\n\nNotably, serum Cr and eGFR levels were mildly elevated.\n\nBackground\nSystemic lupus erythematosus (SLE) is an autoimmune disease that results in the production of several autoantibodies.1\n2 SLE treatment largely consists of remission induction therapy and maintenance therapy. Immunosuppressive drugs and high-dose steroid therapy are generally used for remission induction therapy, although the therapy regimen depends on the type of renal lesions. Standard therapies include the immunosuppressive drugs intravenous cyclophosphamide (IVCY)3 and mycophenolate mofetil (MMF).4 One recent study reported the use of tacrolimus (TAC) for multitarget therapy,5 while azathioprine (AZA), MMF and rituximab (RTX) are often used for maintenance therapy.6 However, the primary disease sometimes relapses even with the use of AZA or MMF. Additionally, side effects such as bone marrow suppression and infectious diseases can occur. Moreover, in some cases steroid use must be discontinued or reduced due to conditions such as a slight fever, rash, a feeling of malaise and abnormal test values.\n\nTAC is widely used as an immunosuppressive drug after organ transplantation, including kidney7 and liver.8 TAC is also attracting attention due to its immunosuppressive effect, and therefore is used for the treatment of various autoimmune diseases, such as rheumatoid arthritis,9 polymyositis10 and myasthenia gravis.11 Moreover, TAC is used in Japan for the treatment of lupus nephritis12 and SLE without renal lesions.13 The efficacy of TAC against lupus nephritis has been reported in a number of articles to date. However, only a few reports have investigated cases of non-lupus nephritis. The efficacy of TAC has been validated in both diseases, but differences in efficacy and safety due to the presence or absence of renal lesions have not been reported. Some studies have reported the use of TAC during the maintenance therapy period. For example, one small-scale study reported an approximately 6-month observation period,14 and a clinical practice report of 38 cases used TAC for 1 year.15 However, there have not been reports of a large-scale clinical practice study, such as the inclusion of more than 50 cases followed up for 1 year. However, one report suggested that the long-term use of TAC caused renal dysfunction.16 Therefore, this study examined whether TAC combination therapy affected efficacy and safety due to the presence or absence of renal lesions during maintenance therapy in patients with SLE.\n\nMethods\nPatients with SLE in maintenance therapy undergoing outpatient treatment were enrolled at the Division of Rheumatology, Department of Medicine, Showa University School of Medicine. The study was conducted from 1 January 2009 to 30 April 2013 with a 52-week observation period. A single centre prospective study was used as the study design. Patients with SLE diagnosed according to the 1997 revised criteria for the classification of SLE from the American College of Rheumatology were eligible for enrolment.17 The criterion used to enrol patients was daily steroid consumption below the limit of ≤20 mg/day of prednisolone. The initial dose of TAC was defined as 1–2 mg/day; this amount was adjusted to achieve blood trough levels of 5–10 ng/mL at 12 h after medication, with a maximum dose of 4 mg/day.6 The dose of steroid prescribed during the observation period was not changed, but it could be tapered or discontinued based on the attending doctor's judgement. When adverse effects appeared (ie, eruption, cytopenia or liver damage), the patient was switched from the previous immunosuppressive drug to TAC. Moreover, we added TAC to the regimens of patients who had used a current immunosuppressive drug for more than 6 months but showed evidence of the lack of the drug's effectiveness because TAC would not reduce the steroid's efficacy or induce adverse effects in combination with the immunosuppressive drug. The SLE disease activity index (SLEDAI) was used to assess disease activity. A case was defined as possessing renal lesions when the urine protein levels were ≥0.5 g/day and lupus nephritis was observed by renal biopsy.13 All other cases were defined as non-renal lesions.\n\nThe following background factors were examined: age, sex, height, weight, SLE disease duration, the dose of steroids prescribed at the beginning of TAC combination therapy, the presence or absence of angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin II receptor blocker (ARB), the presence or absence of statin use, the presence or absence of steroid-pulse therapy during the remission induction period, prednisolone dosage prior to TAC treatment (1 year, 6 months, 3 months or 1 month) and the types of immunosuppressive drugs used previously. The body mass index (BMI) was calculated based on height and weight. The following measurements were examined: serum C3 levels before and 52 weeks after TAC treatment (normal range: 86–160 mg/dL), anti-ds DNA antibody titres (measured by radioimmunoassay, normal range: <12 IU/mL), serum creatinine levels and the estimated glomerular filtration rate (eGFR). Additionally, we also investigated the presence or absence of SLE relapse during the observation period (ie, whether the patient developed end-stage renal disease (ESRD) or was treated with artificial dialysis) and TAC side effects.\n\nPatients with renal lesions were defined as group A, while patients without renal lesion were defined as group B. The following discontinuation criteria were defined: the presence of TAC side effects, a patient proceeding to ESRD, a patient starting artificial dialysis, an increase in the amount of steroids due to primary disease relapse, an increase or initiation of an immunosuppressive drug regimen, patient relocation resulting in the inability to visit the hospital or the submission of a proposal of discontinuation by the patient.\n\nThe analysis was performed via comparisons between the group of survivors and the group of non-survivors. Statistical tests included Fisher’s exact probability test, Welch’s t test and χ2 for independence tests, as well as repeated measures analysis of covariance. The significance level was set to 5%. The statistical analysis was performed with the JMP10 software (2012 SAS Institute, Japan, Tokyo, Japan). This study was conducted with the approval of the Bio-Ethical Committee of Showa University School of Medicine (No. 1195). We acquired written informed consent from all patients enrolled in the study.\n\nResults\nThe basic patient population included 30 patients and 27 patients who were classified into groups A and group B, respectively (table 1). The histological types of renal lesions in group A included eight patients with Type II, one patient with Type II+V, three patients with Type III, two patients with Type III+V, five patients with Type IV, four patients with Type IV+V and seven patients with Type V (table 2). The immunosuppressive drugs IVCY, ciclosporin A, AZA, mizoribine (MZR), methotrexate, RTX and MMF were used prior to the initiation of TAC treatment. There were no significant differences in the presence or absence of renal lesions (p=0.305) (table 3). MZR and AZA were concomitantly used as immunosuppressive drugs after the initiation of TAC treatment, but there were no significant differences in the presence or absence of renal lesions (p=0.429) (table 4).\n\nTable 1 Patient characteristics before treatment\n\n\tRenal (+)\tRenal (–)\tp Value\t\nN\t30\t27\t\t\nAge (years, mean±SD)\t42.2±15.7\t37.7±13.2\t0.23*\t\nSex (male/female)\t8/22\t3/24\t0.29†\t\nDisease duration (years, mean±SD)\t8.6±6.0\t7.1±8.7\t0.45*\t\nBMI (mean±SD)\t20.2±3.8\t20.9±3.1\t0.49*\t\nDose of TAC at start (mg/day, mean±SD)\t1.6±0.9\t1.7±0.7\t>0.05*\t\nDosage of PSL at start (mg/day, mean±SD)\t13.2±9.2\t12.6±7.8\t>0.05*\t\nRate of ACE/ARB use\t15/30 (50.0%)\t6/27 (22.2%)\t0.028†\t\nRate of statin use\t11/30 (36.7%)\t6/27 (22.2%)\t0.184†\t\n*Analysis by Welch’s t test.†Analysis by Fisher's exact probability test.\n\nARB, angiotensin II receptor blocker; BMI, body mass index; PSL, prednisolone; TAC, tacrolimus.\n\nTable 2 Histological type of kidney lesions in Group A\n\nType\tn\t\nI\t8\t\nII+V\t1\t\nIII\t3\t\nIII+V\t2\t\nIV\t5\t\nIV+V\t4\t\nV\t7\t\nTable 3 Breakdown of combination treatment with immunosuppressive agents prior to tacrolimus treatment\n\n\tRenal (+)\tRenal (−)\t\nIVCY\t10\t5\t\nCyA\t10\t10\t\nAZA\t5\t10\t\nMZR\t8\t6\t\nMTX\t1\t5\t\nRTX\t0\t1\t\nMMF\t2\t2\t\np=0.305.χ2 for independent test.\n\nAZA, azathioprine; CyA, ciclosporin A; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; MTX, methotrexate; MZR, mizoribine; RTX, rituximab.\n\nTable 4 Breakdown of combination treatment with immunosuppressive agents after tacrolimus treatment\n\n\tRenal (+)\tRenal (−)\t\nMZR\t8\t5\t\nAZA\t0\t1\t\np=0.429.\n\nFisher’s exact probability test.\n\nAZA, azathioprine; MZR, mizoribine.\n\nSignificant improvements in the SLEDAI were observed in each group before and after treatment: from 7.2±5.0 (mean±SD) to 2.8±2.3 in group A (p=0.000) and from 6.4±3.8 to 2.4±2.2 in group B (p=0.000) (table 5). A repeated measures analysis of variance (ANOVA) revealed no interaction, but a significant difference before and after treatment was confirmed (p=0.000) regardless of the presence of renal lesions (p=0.367). Serum C3 levels improved from 65.9±24.6 mg/dL to 77.7±18.2 mg/dL before and after treatment in group A (p=0.002), but showed only a slight improvement in group B (from 81.8±23.0 mg/dL to 90.6±19.4 mg/dL), with no significant difference found before and after treatment (p=0.065). A repeated measures ANOVA revealed no interaction, but a significant difference was confirmed before and after treatment (p=0.002) regardless of the presence of renal lesions (p=0.006). The dose of prednisolone decreased from 13.2±9.2 mg/day to 7.4±4.0 mg/day (p=0.0004) in the A group and from 12.6±7.8 mg/day to 7.4±4.0 mg/day in the B group (p=0.003), thereby demonstrating a significant difference before and after treatment (p=0.000). However, there were no significant differences based on the presence or absence of renal lesions (p=0.836). The anti-ds DNA antibody titre in the A group decreased from 56.7±99.0 IU/mL to 33.3±56.8 IU/mL, which was not significant but represented a downward trend (p=0.057). The anti-ds DNA antibody DNA titre decreased significantly in the B group from 30.9±33.2 IU/mL to 18.4±18.6 IU/mL (p=0.007). A repeated measures ANOVA revealed no interaction, but a significant difference before and after the treatment was confirmed (p=0.027). However, there was no significant difference based on the presence or absence of renal lesions (p=0.186). Serum Cr levels were slightly elevated, with a significant increase from 0.76±0.31 mg/dL to 0.82±0.42 mg/dL (p=0.029) in the A group and from 0.65±0.21 mg/dL to 0.68±0.23 mg/dL (p=0.040) in the B group regardless of the presence of renal lesions (p=0.011). The eGFR level decreased slightly from 57.9±9.68 mL/min/1.73 m2 to 57.0±9.79 mL/min/1.73 m2 (p=0.0029) in the A group and from 59.4±9.27 mL/min/1.73 m2 to 58.4±9.26 mL/min/1.73 m2 in the B group regardless of the presence of renal lesions (p=0.001). No significant differences were observed between the two groups in the following background factors: age, sex, disease duration, BMI, the dose of TAC and steroids at the beginning of TAC treatment and the presence or absence of combinational statin use. However, a significant difference was observed in the combinational use of ACE and ARB (p=0.028), which was prescribed more often in the A group (table 5).\n\nTable 5 Clinical feature and laboratory data before and after tacrolimus treatment\n\n\tRenal (+)\t\tRenal (−)\t\tInteraction\tVariation between individuals\tIntraindividual variability\t\n\tPre\tPost\tp Value\tPre\tPost\tp Value\tp Value\tp Value\tp Value\t\nDisease activity index (SLEDAI) at start (mean±SD, range)\t7.2±5.0\t2.8±2.3\t0.000\t6.4±3.8\t2.4±2.2\t0.000\t0.793\t0.367\t0.000\t\nPrednisolone dosage (mean±SD, mg/day)\t13.2±9.2\t7.4±4.0\t0.0004\t12.6±7.8\t7.4±4.0\t0.0025\t0.776\t0.836\t0.000\t\nAnti-ds-DNA antibody titre (mean±SD, IU/mL)\t56.7±99.0\t33.3±56.8\t0.057\t30.9±33.1\t18.4±18.6\t0.0065\t0.506\t0.186\t0.027\t\nSerum C3 concentration (mean±SD, mg/dL)\t65.9±24.6\t77.7±18.3\t0.0022\t81.8±23.6\t90.6±19.4\t0.065\t0.647\t0.006\t0.002\t\nSerum creatinine level (mg/dL)\t0.76±0.31\t0.82±0.42\t0.029\t0.65±0.21\t0.68±0.23\t0.040\t0.591\t0.147\t0.011\t\neGFR (mL/min/1.73 m2\t57.9±9.7\t57.0±9.8\t0.0029\t59.7±9.3\t58.4±9.3\t0.0013\t0.772\t0.571\t0.000\t\nDosage of TAC (mg/day)\t1.6±0.9\t3.0±0.7\t0.000\t1.7±0.7\t2.8.±0.6\t0.000\t0.350\t0.805\t0.000\t\nProtein urea (g.gCr)\t1.9±5.6\t0.78±1.3\t0.14\t0.07±0.21\t0.0±0.0\t0.05\t0.352\t0.25\t0.026\t\neGFR, estimated glomerular filtration rate; SLEDAI, systemic lupus erythematosus disease activity index; TAC, tacrolimus.\n\nAlthough the patients were prescribed a relatively high dose of glucocorticoid at the initiation of TAC treatment, they were not in the midst of tapering glucocorticoid after the induction of remission (table 6).\n\nTable 6 Prednisolone dosage before treatment with tacrolimus\n\n\tRenal (+)\tRenal (−)\t\nBefore 1 year\t12.5±9.9\t9.6±8.5\t\nBefore 6 months\t15.7±12.4\t8.8±5.0\t\nBefore 3 months\t12.8±7.5\t9.8±6.2\t\nBefore 1 month\t11.7±6.6\t11.2±6.8\t\nAt start\t13.2±9.2\t12.6±7.8\t\n\tp Value\t\t\nInteraction\t0.052\t\t\nVariation between individuals\t0.089\t\t\nIntraindividual variability\t0.42\t\t\nThe patients had remarkable improvement of symptoms including headache, arthritis, rash, alopecia, mucosal ulcer and fever among the components of SLEDAI. Moreover, the examination found improvement of haematuria, pyuria, hypocomplementaemia and anti-DNA antibody among close to half of the patients. On the other hand, thrombocytopenia was not improved although leucopenia was improved (table 7).\n\nTable 7 Components of SLEDAI before and after treatment of tacrolimus\n\n\tPre\tPost\t\nHeadache\t7\t1\t\nArthritis\t3\t0\t\nRash\t6\t0\t\nAlopecia\t5\t0\t\nMucosal ulcer\t2\t0\t\nFever\t5\t1\t\nHaematuria\t7\t3\t\nPyuria\t14\t7\t\nLow complement\t22\t13\t\nAnti-DNA antibody\t23\t11\t\nLeucopenia\t4\t0\t\nThrombocytopenia\t1\t1\t\nSLEDAI, systemic lupus erythematosus disease activity index.\n\nSide effects were observed in one patient in the A group (pruritus) and four patients in the B group (rhabdomyolysis, muscle cramp, alopecia and diarrhoea observed in all patients), all of which improved following treatment discontinuation. The patient who developed rhabdomyolysis in the B group used statin concomitantly, which increased the likelihood that this side effect was caused by statin monotherapy or the concomitant use of statin and TAC. No patients developed ESRD or required artificial dialysis. Moreover, none of the patients experienced a relapse of the primary disease, required an increase in the dosage of steroids or required an increase or new initiation of the immunosuppressive drugs that were used concomitantly.\n\nDiscussion\nThis study demonstrated that TAC combination therapy had additional beneficial effects on increased serum C3 levels in patients with SLE with or without renal complications during a maintenance phase in a clinical setting. TAC effectively decreased disease activity during the maintenance phase of SLE during our 52-week observation period without requiring an increase in the corticosteroid and/or immunosuppressants dose in our study. Moreover, non-severe side effects were observed in only five patients (5.3%) during the 52-week period. The results of our prospective study indicated that TAC is an effective agent for the treatment of SLE. Duddrige and Powell administered TAC to three patients with SLE and found that cutaneous vasculitis, leucopenia, arthritis and hypocomplementaemia improved in two patients.2 Maruoka et al18 reported that TAC effectively treated a patient with lupus cystitis. Subsequently, several reports noted the efficacy of TAC for nephritis.19–21 Maintenance therapy of SLE was previously reported only in studies of patients with or without lupus nephritis,12\n13\n22 including one small group study and one short-duration study.14\n15 No previous assessments of long-term TAC therapy were reported in a larger group of patients with SLE with and without renal complications, as performed in this study. We investigated whether renal complication affected the efficacy and safety of TAC combination therapy in patients with SLE during a maintenance phase.\n\nOur study had several limitations. Our study enrolled consecutive patients during specific periods to avoid selection bias, which differed from many of the aforementioned case series. A significant difference was observed in the combinational use of ACE-I and ARB. The patients were assigned to groups according to the decisions of the involved physicians, and not by randomisation. Our survey focused on real-world scenarios and the ordinary practice of TAC treatment for SLE. Therefore, a fully randomised study would not have suited our purposes, and it would not have been suitable for our investigation into the dose optimisation of TAC to ensure its efficacy and safety for all patients with and without renal complications. The number of cases of patients for whom SLE activity could not be controlled through the use of a middle dose of steroids and/or an immunosuppressive drug has decreased. SLE is a heterogeneous disease, and this characteristic is a limitation of this study. Each physician carefully ascertained the dose of TAC after considering multiple factors for each patient, including disease activity, complications such as hypertension, diabetes mellitus and hyperlipidaemia age, renal function, serum concentrations of TAC and complications due to other collagen diseases.\n\nClinical trials that included patients with rheumatoid arthritis demonstrated that the main adverse reactions caused by TAC were renal impairment, hypertension, glucose intolerance and gastrointestinal symptoms.23 Adverse events were observed in three patients in our study, and renal function was mildly elevated.24 However, these symptoms were reversible and improved after the discontinuation of TAC. The reason for this difference between patients with SLE and rheumatoid arthritis is not known, but the different pathologies underlying the diseases, patient ages and concurrent treatments (eg, non-steroidal anti-inflammatory drugs) might have played a role.\n\nConclusion\nTAC combination therapy had additive beneficial effects and increased serum C3 levels in patients with SLE with or without renal complications during a maintenance phase. TAC reduced the steroid dosage, improved the SLEDAI and reduced anti-dsDNA antibody levels in patients with or without renal complications. Notably, serum creatinine and eGFR levels were mildly elevated.\n\nContributors: Conception and design: SI, YM and KO. Analysis of the data: YM and KO. Critical revision of the article for important intellectual content: SI and YM. Final approval of the article: all authors. Provision of study materials or patients: SI, YM and KO. Administrative, technical or logistic support: TK. Collection and assembly of data: SI, AN, MS, SN, YM, NO, TT and RT.\n\nCompeting interests: YM received research grants from Astellas Pharm, Mitsubishi Tanabe Pharma Corporation, AbbVie CK, Pfizer Japan, Chugai Pharmaceutical Co., and Eizai Co. TK received research grants from Mitsubishi Tanabe Pharma Corporation and AbbVie CK.\n\nPatient consent: Obtained.\n\nEthics approval: This study was conducted with the approval of the Bio-Ethical Committee of Showa University School of Medicine (No. 1195). We acquired written informed consent from all patients enrolled in the study.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: No additional data are available.\n==== Refs\nReferences\n1 Takeuchi T , Tsuzaka K , Abe T \nT cell abnormalities in systemic lupus erythematosus . Autoimmunity \n2005 ;38 :339 –46 . doi:10.1080/0891693050012398316227148 \n2 Duddridge M , Powell RJ \nTreatment of severe and difficult cases of systemic lupus erythematosus with tacrolimus. A report of three cases . Ann Rheum Dis \n1997 ;56 :690 –2 . doi:10.1136/ard.56.11.6909462174 \n3 Arends S , Berden JH , Grootscholten C \nInduction therapy with short-term high-dose intravenous cyclophosphamide followed by mycophenolate mofetil in proliferative lupus nephritis . Neth J Med \n2014 ;72 :481 –90 .25431394 \n4 Moroni G , Raffiotta F , Trezzi B \nRituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study . Rheumatology (Oxford) \n2014 ;53 :1570 –7 . doi:10.1093/rheumatology/ket46224505125 \n5 Liu Z , Zhang H , Liu Z \nMultitarget therapy for induction treatment of lupus nephritis: a randomized trial . Ann Intern Med \n2015 ;162 :18 –26 . doi:10.7326/M14-103025383558 \n6 Kizawa T , Nozawa T , Kikuchi M \nMycophenolate mofetil as maintenance therapy for childhood-onset systemic lupus erythematosus patients with severe lupus nephritis . Mod Rheumatol \n2014 ;27 :1 –5 .\n7 McCormack PL \nExtended-release tacrolimus: a review of its use in de novo kidney transplantation . Drugs \n2014 ;74 :2053 –64 . doi:10.1007/s40265-014-0316-325352392 \n8 Gu J , Wu X , Lu L \nRole of steroid minimization in the tacrolimus-based immunosuppressive regimen for liver transplant recipients: a systematic review and meta-analysis of prospective randomized controlled trials . Hepatology international \n2014 ;8 :198 –215 . doi:10.1007/s12072-014-9523-y24765218 \n9 Kawai S , Hashimoto H , Kondo H \nComparison of tacrolimus and mizoribine in a randomized, double-blind controlled study in patients with rheumatoid arthritis . J Rheumatol \n2006 ;33 :2153 –61 .16960930 \n10 Kurita T , Yasuda S , Oba K \nThe efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis . Rheumatology (Oxford) \n2015 ;54 :39 –44 . doi:10.1093/rheumatology/keu16624764266 \n11 Yagi Y , Sanjo N , Yokota T \nTacrolimus monotherapy: a promising option for ocular myasthenia gravis . Eur Neurol \n2013 ;69 :344 –5 . doi:10.1159/00034706823549260 \n12 Miyasaka N , Kawai S , Hashimoto H \nEfficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study . Mod Rheumatol \n2009 ;19 :606 –15 . doi:10.3109/s10165-009-0218-519688181 \n13 Kusunoki Y , Tanaka N , Kaneko K \nTacrolimus therapy for systemic lupus erythematosus without renal involvement: a preliminary retrospective study . Mod Rheumatol \n2009 ;19 :616 –21 . doi:10.3109/s10165-009-0220-y19711149 \n14 Suzuki K , Kameda H , Amano K \nSingle center prospective study of tacrolimus efficacy and safety in the treatment of various manifestations in systemic lupus erythematosus . Rheumatol Int \n2011 ;31 :757 –63 . doi:10.1007/s00296-010-1366-920169348 \n15 Otsuka K , Miwa Y , Ishii S \nSteroid-Sparing Effect of Tacrolimus in the Maintenance Phase of Systemic Lupus Erythematosus: A Single-Center, Prospective Study \n2014 .\n16 Fernandes MB , Caldas HC , Toloni LD \nSupplementation with omega-3 polyunsaturated fatty acids and experimental tacrolimus-induced nephrotoxicity . Exp Clin Transplant \n2014 ;12 :522 –7 .25489802 \n17 Hochberg MC \nUpdating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum \n1997 ;40 :1725 \ndoi:10.1002/art.17804009289324032 \n18 Maruoka H , Honda S , Takeo M \nTacrolimus treatment for refractory lupus cystitis . Mod Rheumatol \n2006 ;16 :264 –6 . doi:10.3109/s10165-006-0494-216906381 \n19 Politt D , Heintz B , Floege J \nTacrolimus- (FK 506) based immunosuppression in severe systemic lupus erythematosus . Clin Nephrol \n2004 ;62 :49 –53 . doi:10.5414/CNP6204915267013 \n20 Mok CC , Tong KH , To CH \nTacrolimus for induction therapy of diffuse proliferative lupus nephritis: an open-labeled pilot study . Kidney Int \n2005 ;68 :813 –7 . doi:10.1111/j.1523-1755.2005.00461.x16014060 \n21 Mok CC \nTherapeutic options for resistant lupus nephritis . Semin Arthritis Rheum \n2006 ;36 :71 –81 . doi:10.1016/j.semarthrit.2006.04.00816884971 \n22 Chen W , Liu Q , Tang X \nOutcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial . Lupus \n2012 ;21 :944 –52 . doi:10.1177/096120331244225922438027 \n23 Kitahara K , Kawai S \nCyclosporine and tacrolimus for the treatment of rheumatoid arthritis . Curr Opin Rheumatol \n2007 ;19 :238 –45 . doi:10.1097/BOR.0b013e328099af8017414949 \n24 Hosonuma R , Fujiwara S , Sasazaki M \nUsefulness of a slow-release tacrolimus for a patient with tacrolimus-induced renal injury after hemopoietic stem cell transplantation . [Rinsho ketsueki] \n2012 ;53 :469 –71 .\n\n",
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"journal": "Lupus science & medicine",
"keywords": "Disease Activity; Lupus Nephritis; Outcomes research; Systemic Lupus Erythematosus",
"medline_ta": "Lupus Sci Med",
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"pubdate": "2015",
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"references": "9324032;15267013;19711149;20169348;9462174;22687983;16884971;25383558;16960930;22438027;16906381;25352392;25489802;19688181;25431394;24505125;17414949;23549260;24764266;24765218;25159157;16227148;16014060",
"title": "Influence of renal complications on the efficacy and adverse events of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase: a single-centre, prospective study.",
"title_normalized": "influence of renal complications on the efficacy and adverse events of tacrolimus combination therapy in patients with systemic lupus erythematosus sle during a maintenance phase a single centre prospective study"
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"abstract": "Brain hemorrhages are rare complications of acute methanol poisoning. There is a debate on association of brain hemorrhage in methanol toxicity and application of systemic anticoagulation during hemodialysis (HD). A 70-year-old male presented to us with severe metabolic acidosis and a methanol level of 7.6 mg/dL. Ethanol and folinic acid were administered, and HD was performed. Brain computed tomography (CT) scan which was normal on presentation showed extensive bilateral subcortical supratentorial hypodensities on the 3rd day after commencing the treatment. However, the next CT scan performed 2 weeks later revealed expanding hemorrhagic transformation in previous hypodensities. Hemorrhagic changes could not be explained by patient's coagulation profile on the 3rd day. Anticoagulation agents such as heparin are used routinely during a dialysis session to prevent clot formation in dialysis circuits. This case is possibly questioning the role of heparin in hemorrhagic brain lesions of methanol intoxication.",
"affiliations": "Toxicological Research Center, Department of Clinical Toxicology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Radiology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Toxicological Research Center, Department of Clinical Toxicology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Internal Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.;Brain Mapping Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Hassanian-Moghaddam|Hossein|H|;Bahrami-Motlagh|Hooman|H|;Zamani|Nasim|N|;Fazeli|Seyed Amirhossein|SA|;Behnam|Behdad|B|",
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"doi": "10.4103/jrpp.JRPP_17_39",
"fulltext": "\n==== Front\nJ Res Pharm PractJ Res Pharm PractJRPPJournal of Research in Pharmacy Practice2319-96442279-042XMedknow Publications & Media Pvt Ltd India JRPP-6-18610.4103/jrpp.JRPP_17_39Case ReportIntracranial Hemorrhage in Methanol Toxicity: Challenging the Probable Heparin Effect during Hemodialysis Hassanian-Moghaddam Hossein 1Bahrami-Motlagh Hooman 2Zamani Nasim 1Fazeli Seyed Amirhossein 3Behnam Behdad 41 Toxicological Research Center, Department of Clinical Toxicology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran2 Department of Radiology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran3 Department of Internal Medicine, Zahedan University of Medical Sciences, Zahedan, Iran4 Brain Mapping Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IranAddress for correspondence: Dr. Hossein Hassanian-Moghaddam, E-mail: hassanian@sbmu.ac.irJul-Sep 2017 6 3 186 189 4 2017 7 2017 Copyright: © 2017 Journal of Research in Pharmacy Practice2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Brain hemorrhages are rare complications of acute methanol poisoning. There is a debate on association of brain hemorrhage in methanol toxicity and application of systemic anticoagulation during hemodialysis (HD). A 70-year-old male presented to us with severe metabolic acidosis and a methanol level of 7.6 mg/dL. Ethanol and folinic acid were administered, and HD was performed. Brain computed tomography (CT) scan which was normal on presentation showed extensive bilateral subcortical supratentorial hypodensities on the 3rd day after commencing the treatment. However, the next CT scan performed 2 weeks later revealed expanding hemorrhagic transformation in previous hypodensities. Hemorrhagic changes could not be explained by patient's coagulation profile on the 3rd day. Anticoagulation agents such as heparin are used routinely during a dialysis session to prevent clot formation in dialysis circuits. This case is possibly questioning the role of heparin in hemorrhagic brain lesions of methanol intoxication.\n\nKEYWORDS\nHemodialysisheparin-induced thrombocytopeniaintracranial hemorrhageMethanoltoxicity\n==== Body\nINTRODUCTION\nMethanol, a flammable colorless liquid, is commonly used in industry and household solvents while it can also be present in liquors manufactured illicitly. Formate is the key metabolite responsible for metabolic acidosis and symptoms related to methanol poisoning.[1] Methanol toxicity can lead to death if it is not diagnosed and treated early. Patients usually manifest with nausea, vomiting, blurred vision, seizure, and even coma within 72 h after methanol consumption.[2] On both computed tomography (CT) scan and magnetic resonance imaging, methanol toxicity is commonly characterized by putamen and white matter necrosis.[34]\n\nBrain hemorrhages are considered as rare complications of acute methanol poisoning.[56] There is a debate on the association of brain hemorrhage in methanol toxicity and application of systemic anticoagulation during hemodialysis (HD).[56] Previous studies report a brain hemorrhage rate of 13.5%–16.4% in methanol-poisoned patients on presentation, but there are limited studies on patients who developed hemorrhages after presentation with on-arrival normal imaging studies.[7] We present an interesting case to review brain CT scanning of a methanol-intoxicated patient in different time intervals before and after conventional HD.\n\nCASE REPORT\nA 70-year-old man was referred to our toxicology department due to suspected methanol toxicity. In the local hospital, he had presented with drowsiness. His family had claimed that he had drunk alcohol about 7 h before presentation. His past medical history was positive for hypertension (HTN), dyslipidemia, and Alzheimer's disease, and his medication history included hydrochlorothiazide 25 mg twice daily, metoprolol 25 mg twice daily, atorvastatin 80 mg daily, lorazepam 2 mg daily, and citalopram 10 mg daily. There was no history of trauma or recent infectious disease. He was a chronic alcohol abuser and cigarette smoker (30 packs/year).\n\nOn physical examination, he was in afebrile comatose state with poorly controlled blood pressure of 140/80 mmHg, pulse rate of 85/min, and O2 saturation of 95%. His pupils were midsize and reactive to light bilaterally without any nystagmus. Deep tendon reflexes were absent, and plantar reflexes were extensor. Other examinations were normal, and laboratory tests were not significant except for hyperglycemia and metabolic acidosis.\n\nOn arrival, the patient underwent orotracheal intubation due to his low level of consciousness and metabolic acidosis. Table 1 summarizes important laboratory findings simultaneous with imaging. Initial brain CT scan on presentation was normal. However, the next CT on the 3rd day depicted extensive bilateral subcortical hypodensities in the supratentorial area. Subsequent CT scan on day 14 revealed hemorrhagic changes in previous hypodensities which showed marked deterioration after another week [Figure 1].\n\nTable 1 Serial venous blood gas, electrolytes, and coagulation profile\n\nFigure 1 Brain computed tomography scanning of the methanol-poisoned patients in different intervals. First day computed tomography scan (a) is unremarkable. In day 3, (b) there is extensive symmetric hypodensity involving periventricular white matters. Further hemorrhagic transformation present in left occipital lobe in computed tomography scan done in day 14 (c) which has progressed to involve frontal and parietal lobes depicted in computed tomography scan done 21 days after admission (d)\n\nBased on methanol level (7.6 mg/dl, normal: 0.2–3 mg/dl), history, and clinical manifestations, the diagnosis of methanol toxicity was confirmed. Therefore, ethanol 20% gavage (800 mg/kg bolus dose followed by 130 mg/kg/h via nasogastric tube), folinic acid (50 mg intravenous [IV] every 6 h), and NaHCO3 infusion (2 meq/kg IV followed by 25 meq/h IV infusion) were initiated. Almost 2 h postarrival in our referral center, HD through jugular catheter was applied in 2 consecutive days for 4 h (JMS dialyzer machine, anticoagulant: heparin, buffer: bicarbonate, filter: high flux). The patient received his medications to control HTN during hospitalization, and his blood pressure was within normal range.\n\nDespite appropriate treatment and supportive care, the patient did not show any improvement in his level of consciousness. He was admitted and stayed in intensive care unit for about 3 months until he died. No autopsy was performed. Written informed consent was taken from the patient's next of kin for case report.\n\nDISCUSSION\nHerein, we report a case of late intracranial hemorrhage after methanol toxicity to discuss probable mechanism of hemorrhage in this poisoning.\n\nAs reported by Sanei Taheri et al.[8] and Vyas et al.,[4] intracranial hemorrhages including putaminal hemorrhage and subcortical necrosis are of the complications that occur rarely with unknown mechanism and have been associated with high mortality rates. Phang et al.[9] reported 6 of 21 patients and Giudicissi et al.[5] reported one case with brain hemorrhagic necrosis after HD, suggesting a deleterious role of systemic anticoagulation during HD.\n\nHeparin is the most common anticoagulation agent used for dialysis. Although it may increase the risk of the central nervous system (CNS) bleeding, its short half-life and available antidote (protamine sulfate) which rapidly restores normal coagulation profile promote large use of heparin as a safe anticoagulation agent for the dialysis even in high-risk conditions such as methanol poisoning.\n\nCerebral hemorrhage related to methanol poisoning is usually bilateral and not expansive.[7] Our patient had a high blood sugar, severe metabolic acidosis, and mild thrombocytopenia with normal coagulation time before HD, and HD was performed with systemic heparinization in the dialysis circuit.\n\nBleeding is one of the most common side effects of any anticoagulant. The preexisting necrosis in the brain, heparin, and chronic uncontrolled HTN could increase the risk of bleeding and promote the hemorrhagic transformation. Whether such hemorrhagic event was a bleeding diathesis directly due to anticoagulation by heparin or a pure hemorrhagic transformation following acute alcohol ingestion is the main question. A prolonged activated partial thromboplastin time (aPTT) and peripheral ecchymosis can be in favor of heparin role. However, aPTT is not a sensitive and reliable predictor for bleeding.[10]\n\nIn the current case, the 14-day interval between HD sessions and the onset of the first episode of the intracranial hemorrhage, the normal coagulation profile, and the lack of other symptoms significant for heparin-mediated bleeding in skin and other organs may rule out the role of heparin as the initial trigger for bleeding. However, a contributing role can be considered for heparin as well as chronic uncontrolled HTN.\n\nThe patient's mild thrombocytopenia might be caused by alcohol intoxication or as a sequel of underlying alcoholic chronic liver disease.[11] No evidence of thrombocytopenia such as skin petechial rashes or wet purpura of buccal mucosa was found. Furthermore, the platelet counts in our case were not severely low (below 5000–10000) predisposing to life-threatening bleeding such as intracranial hemorrhage. Given these findings, thrombocytopenia could not be the main culprit initiating the hemorrhagic process in the preexisting necrotic areas. However, in the context of prior CNS lesions, thrombocytopenia can contribute to CNS bleeding diathesis.\n\nIn a recent study by Zakharov et al., no association was found between brain hemorrhage and systemic anticoagulation during dialysis. However, bleeding complications occurred in 27% of their patients during treatment. They suggested that high doses of heparin or low molecular weight heparin could apparently facilitate bleeding in necrotic areas of brain.[12] Aisa and Ballut did not show any relation between methanol-associated CNS hemorrhage and heparin used in HD, either.[13] In agreement with their study, this case is questioning the role of heparin in hemorrhagic brain lesions of methanol intoxication.\n\nEarly CNS bleeding following a dialysis session may be attributed to anticoagulation methods used in the dialysis. However, given the short half-life of heparin, delayed intracranial hemorrhage, as seen in our patient, can be induced by methanol toxicity itself. It seems that alternate anticoagulation strategies cannot reduce the risk of bleeding.\n\nAUTHORS' CONTRIBUTION\nHossein Hassanian-Moghaddam contributed in the concept and design of the study. Hooman Bahrami-Motlagh revised intellectual contents. Behdad Behnam and Seyed Amirhossein Fazeli acquired data and review the literature and contributed in manuscript preparation. Nasim Zamani, Hossein Hassanian-Moghaddam and Hooman Bahrami-Motlagh edited the manuscript. All authors had substantial role in manuscript review.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Barceloux DG Bond GR Krenzelok EP Cooper H Vale JA American Academy of Clinical Toxicology Ad Hoc Committee on the Treatment Guidelines for Methanol Poisoning, et al . American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning J Toxicol Clin Toxicol 2002 40 415 46 12216995 \n2 Hassanian-Moghaddam H Pajoumand A Dadgar SM Shadnia Sh Prognostic factors in methanol poisoning Hum Exp Toxicol 2007 26 583 6 17884962 \n3 Sefidbakht S Rasekhi AR Kamali K Borhani Haghighi A Salooti A Meshksar A Methanol poisoning: Acute MR and CT findings in nine patients Neuroradiology 2007 49 427 35 17294234 \n4 Vyas S Kaur N Sharma N Singh P Khandelwal N Methanol poisoning Neurol India 2009 57 835 6 20139536 \n5 Giudicissi Filho M Holanda CV Nader NA Gomes SR Bertolucci PH Bilateral putaminal hemorrhage related to methanol poisoning: A complication of hemodialysis? Case report Arq Neuropsiquiatr 1995 53 485 7 8540827 \n6 Hernández MA Holanda MS Tejerina EE González C López M Hernández JL Methanol poisoning and heparin: A dangerous couple? Am J Emerg Med 2004 22 620 1 15666275 \n7 Taheri MS Moghaddam HH Moharamzad Y Dadgari S Nahvi V The value of brain CT findings in acute methanol toxicity Eur J Radiol 2010 73 211 4 19101105 \n8 Taheri MS Noori M Shakiba M Jalali AH Brain CT-scan findings in unconscious patients after poisoning Int J Biomed Sci 2011 7 1 5 23675213 \n9 Phang PT Passerini L Mielke B Berendt R King EG Brain hemorrhage associated with methanol poisoning Crit Care Med 1988 16 137 40 3342624 \n10 Ronco C Ricci Z De Backer D Kellum JA Taccone FS Joannidis M Renal replacement therapy in acute kidney injury: Controversy and consensus Crit Care 2015 19 146 25887923 \n11 Murali AR Attar BM Katz A Kotwal V Clarke PM Utility of platelet count for predicting cirrhosis in alcoholic liver disease: Model for identifying cirrhosis in a US population J Gen Intern Med 2015 30 1112 7 25701049 \n12 Zakharov S Kotikova K Vaneckova M Seidl Z Nurieva O Navratil T Acute methanol poisoning: Prevalence and predisposing factors of haemorrhagic and non-haemorrhagic brain lesions Basic Clin Pharmacol Toxicol 2016 119 228 38 26806851 \n13 Aisa TM Ballut OM Methanol intoxication with cerebral hemorrhage Neurosciences (Riyadh) 2016 21 275 7 27356664\n\n",
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"keywords": "Hemodialysis; Methanol; heparin-induced thrombocytopenia; intracranial hemorrhage; toxicity",
"medline_ta": "J Res Pharm Pract",
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"title": "Intracranial Hemorrhage in Methanol Toxicity: Challenging the Probable Heparin Effect during Hemodialysis.",
"title_normalized": "intracranial hemorrhage in methanol toxicity challenging the probable heparin effect during hemodialysis"
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"abstract": "To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with progressive rheumatoid arthritis-related interstitial lung disease (RA-ILD) in whom more conventional therapy has failed.\n\n\n\nLongitudinal retrospective observational study of a cohort of patients with RA-ILD that started treatment with RTX due to ongoing progressive ILD despite treatment with glucocorticoids and csDMARDs or immunosuppressants (IS). All patients were treated with two or more cycles of RTX and evaluated for at least 12 months. Ongoing therapy with csDMARDs or IS remained unchanged.\n\n\n\nThirty-one patients were analyzed. Before initiation of RTX the mean decline (delta) in %pFVC and %pDLCO from the ILD diagnosis (median 21 months) was -16.5% and -19.7%, respectively. After 1 year of treatment, RTX was able to reverse the decline of pulmonary function test (PFTs) parameters: ∆%pFVC +8.06% compared to baseline (95% CI: -10.9 to -5.2; p<0.001) and ∆%pDLCO +12.7% (95% CI: -16.3 to -9.1; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 26% of cases. Dividing the population into UIP and non-UIP patterns, we observed a significant increase in PFTs parameters in both groups. In the 25 patients (80.6%) that completed 2 years of treatment, the statistically significant amelioration in PFTs parameters observed at one year was maintained: ∆%pFVC +11.2% (95% CI: -15.6 to -6.8; p<0.001) and ∆%pDLCO +14.8% (95% CI: -19.3 to -10.3; p<0.001). At the end of the follow-up period (median 32 months; IQR 25th-75th 26-64), only 23 of the 31 patients (74.2%) were still undergoing treatment with RTX: in 3 cases (10%) it was stopped due to adverse events, in another 3 (10%) treatment failed ultimately requiring a lung transplant, and 2 patients (6%) died due to progression of the ILD and infectious complications. The frequency of adverse events reached 32% of cases.\n\n\n\nBased on our results, RTX appears to be effective as rescue therapy in a considerable proportion of patients with progressive RA-ILD unresponsive to conventional treatment.",
"affiliations": "Departments of Rheumatology, Hospital Universitario de Bellvitge, Barcelona, Spain. Electronic address: fjnarvaez@bellvitgehospital.cat.;Pneumology (Unit of Interstitial Lung Diseases), Hospital Universitario de Bellvitge, Barcelona, Spain.;Pneumology (Unit of Interstitial Lung Diseases), Hospital Universitario de Bellvitge, Barcelona, Spain.;Pneumology (Unit of Interstitial Lung Diseases), Hospital Universitario de Bellvitge, Barcelona, Spain.;Radiology, Hospital Universitario de Bellvitge, Barcelona, Spain.;Departments of Rheumatology, Hospital Universitario de Bellvitge, Barcelona, Spain; Department of Radiology, Hospital Altos de Salta, Salta, Argentina.;Department of Rheumatology, Hospital Universitario Dr Peset, Valencia, Spain.;Departments of Rheumatology, Hospital Universitario de Bellvitge, Barcelona, Spain.",
"authors": "Narváez|Javier|J|;Robles-Pérez|Alejandro|A|;Molina-Molina|Maria|M|;Vicens-Zygmunt|Vanesa|V|;Luburich|Patricio|P|;Yañez|Marcos Anibal|MA|;Alegre|Juan José|JJ|;Nolla|Joan M|JM|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab",
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"doi": "10.1016/j.semarthrit.2020.08.008",
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"issue": "50(5)",
"journal": "Seminars in arthritis and rheumatism",
"keywords": "Interstial lung disease; Rheumatoid arthritis; Rituximab; Treatment",
"medline_ta": "Semin Arthritis Rheum",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D006801:Humans; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D000069283:Rituximab; D016896:Treatment Outcome",
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"references": null,
"title": "Real-world clinical effectiveness of rituximab rescue therapy in patients with progressive rheumatoid arthritis-related interstitial lung disease.",
"title_normalized": "real world clinical effectiveness of rituximab rescue therapy in patients with progressive rheumatoid arthritis related interstitial lung disease"
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"abstract": "We report a case with extramedullary tumors affecting the supraclavicular region that presented as a relapse of acute myeloid leukemia (AML) with FLT3-ITD mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Treatment with gilteritinib resulted in remarkable response with disappearance of both the medullary and extramedullary tumors. Subsequently, a 2nd allo-HSCT was performed in an attempt to cure his AML and complete molecular response has been sustained with gilteritinib resumption without worsening GVHD. Targeted therapy with gilteritinib for medullary and extramedullary relapse of FLT3-ITD AML could be effective and suitable as a bridging therapy for allo-HSCT.",
"affiliations": "Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.;Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan.",
"authors": "Kumode|Takahiro|T|;Rai|Shinya|S|;Tanaka|Hirokazu|H|;Espinoza|J Luis|JL|;Kakutani|Hiroaki|H|;Watatani|Yosaku|Y|;Minamoto|Shuji|S|;Taniguchi|Yasuhiro|Y|;Nakayama|Shoko|S|;Morita|Yasuyoshi|Y|;Ashida|Takashi|T|;Matsumura|Itaru|I|",
"chemical_list": null,
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"doi": "10.1016/j.lrr.2020.100219",
"fulltext": "\n==== Front\nLeuk Res Rep\nLeuk Res Rep\nLeukemia Research Reports\n2213-0489 Elsevier \n\nS2213-0489(20)30025-X\n10.1016/j.lrr.2020.100219\n100219\nArticle\nTargeted therapy for medullary and extramedullary relapse of FLT3-ITD acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation\nKumode Takahiro Rai Shinya rai@med.kindai.ac.jp⁎ Tanaka Hirokazu Espinoza J. Luis Kakutani Hiroaki Watatani Yosaku Minamoto Shuji Taniguchi Yasuhiro Nakayama Shoko Morita Yasuyoshi Ashida Takashi Matsumura Itaru Department of Hematology and Rheumatology, Kindai University Hospital, Faculty of Medicine, Osakasayama, Japan\n⁎ Corresponding author. rai@med.kindai.ac.jp\n07 8 2020 \n2020 \n07 8 2020 \n14 10021923 5 2020 3 8 2020 5 8 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case with extramedullary tumors affecting the supraclavicular region that presented as a relapse of acute myeloid leukemia (AML) with FLT3-ITD mutation after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Treatment with gilteritinib resulted in remarkable response with disappearance of both the medullary and extramedullary tumors. Subsequently, a 2nd allo-HSCT was performed in an attempt to cure his AML and complete molecular response has been sustained with gilteritinib resumption without worsening GVHD. Targeted therapy with gilteritinib for medullary and extramedullary relapse of FLT3-ITD AML could be effective and suitable as a bridging therapy for allo-HSCT.\n\nKeywords\nMyeloid sarcomaAcute myeloid leukemiaFLT3-ITDGilteritinib\n==== Body\n1 Introduction\nMutations of fms-like tyrosine kinase 3 (FLT3) gene are frequently detectable in acute myeloid leukemia (AML) patients and the most common form of the mutations is an internal tandem duplication (ITD) mutation, being a poor prognostic factor for AML [1]. Currently, several FLT3 inhibitors have been developed in order to improve the dismal prognosis of AML patients harboring FLT3 mutations [2], and gilteritinib, 2nd generation selective FLT3 inhibitor, was recently approved for relapsed/refractory adult AML patients with FLT3 mutations in Japan [3].\n\nMyeloid sarcoma (MS) is a solid collection of leukemic cells occurring at extramedullary sites other than the bone marrow (BM) [4], with the skin and the gums being the most frequently involved areas. MS may occur de novo, may precede or coincide with myeloid neoplasms such as AML, myeloproliferative neoplasm, and myelodysplastic syndromes [5]. MS can be the initial manifestation of AML relapse after allogenic stem cell transplantation (allo-HSCT) [6]. Extramedullary relapse occurs in 5–12% of patients who have undergone allo-HSCT for AML [7,8], however, the efficacy of FLT3 inhibitors for extramedullary tumors bearing FLT3-ITD remains to be determined. Here, we report a case of FLT3-ITD mutated AML with both medullary and extramedullary relapse following allo-HSCT, and gilteritinib showed remarkable clinical and molecular response.\n\n2 Case presentation\nA previously healthy 38-year-old male was initially diagnosed as having AML with myelodysplasia-related changes with FLT3-ITD. Induction therapy with idarubicin and cytarabine was immediately started, however, hematological complete remission was not achieved. Because severe pancytopenia persisted, we directly performed allogenic bone marrow transplantation (allo-BMT) from an HLA-DR.. one locus mismatched unrelated donor using a myeloablative conditioning regimen consisting of busulfan and cyclophosphamide three months after the initial diagnosis. A minimal residual disease monitoring was performed using Wilms tumor gene-1 (WT-1) expression in the peripheral blood. WT-1 was negative on day 26 after allo-BMT, however, it increased to 102 copies/μgRNA on day 53, suggesting imminent hematological relapse of AML. Immunosuppressants were stopped and then two courses of DLI were administrated on day 119 and 155. WT-1 became negative on day 173, however, idiopathic pneumonia syndrome, dry eye, and dry mouth caused by chronic GVHD were observed, for which he was initially treated with prednisolone (1 mg/kg/day) and cyclosporine in an attempt to control the GVHD. Within 4 weeks, an improvement in the clinical manifestations was observed, and the immunosuppressants could be tapered to the level of prednisolone (5 mg/day), cyclosporine (off) without worsening the GVHD.\n\nApproximately 400 days later, a right supraclavicular mass was observed, and computed tomography (CT) scan showed the presence of a right supraclavicular tumor and subcutaneous mass on the right chest. A biopsy of the supraclavicular tumor suggested a hematolymphoid neoplasm with a large number of cells having atypical nuclei and scant cytoplasm, which were positive for CD68, myeloperoxidase, lysozyme, CD99, slightly positive for CD117, and negative for CD34, and terminal deoxynucleotidyl transferase (Fig. 1). BM examination revealed increased AML blasts (6.9%), and these cells both in the extramedullary and medullary harbored FLT3-ITD mutation. He was administered gilteritinib at 120 mg/day from day 446, and a remarkable tumor regression on CT scan was observed 20 days after gilteritinib administration (on day 466) (Fig. 2). Furthermore, both complete molecular response in BM and disappearance of tumors on CT scan were confirmed 126 days after the commencement of gilteritinib (on day 572) (Fig. 2). However, grade 4 adverse events (AEs) with severe neutropenia and thrombocytopenia induced by gilteritinib occurred, requiring several rounds of platelet transfusions. These AEs were attenuated after reducing the dosage or temporally interrupting gilteritinib, and eventually the dose of gilteritinib was fixed on 80 mg/day (Fig. 2).Fig. 1 Histological examination of myeloid sarcoma. Hematoxylin-eosin (H-E) and immunostaining, objective magnification, × 40.\n\nFig 1Fig. 2 Clinical course after the administration of gilteritinib. Computed tomography (CT) scan showed the presence of a right supraclavicular tumor (101 mm × 55 mm in size) which involved the right internal jugular vein (in red circle). CT scan also showed the findings after the administration of gilteritinib.\n\nAbbreviation: BM, bone marrow; MS, myeloid sarcoma; G3, grade3; G4, grade4; FLU, fludarabine; BU, busulfan; HSCT, hematopoietic stem cell transplantation; TAC, Tacrolimus; FRCZ, fluconazole.\n\nFig 2\n\nConsequently, he underwent 2nd allo-BMT from an HLA-DR.. one locus mismatched unrelated donor using a myeloablative conditioning regimen consisting of busulfan and fludarabine in the state of complete molecular remission 149 days after the gilteritinib administration (on day 595). Gilteritinib (80 mg/day) was resumed 48 days after 2nd allo-BMT (on day 643). A complete molecular response (CMR) has been maintained for 150 after 2nd allo-BMT without AEs or worsening of GVHD.\n\n3 Discussion\nWe presented here a case of medullary and extramedullary relapse of FLT3-ITD AML following allo-BMT. Although DLI induced transient remission for molecular relapse of AML, the leukemic blasts perhaps escaped from the graft versus leukemia (GVL) effect mediated by DLI and manifested as a relapse with extramedullary involvement. The diagnosis was based on a biopsy of the right supraclavicular tumor, and the leukemic blasts both in the extramedullary and medullary sites harbored FLT3-ITD mutation. Eventually, gilteritinib showed a remarkable response, and complete molecular response has been sustained with gilteritinib resumption without worsening of GVHD.\n\nIn general, the immune response to AML mediated by the GVL effect after allo-HSCT preferentially maintains BM remission, which is a major mechanism for the curative effect of allo-HSCT. However, it has been reported that extramedullary relapse of AML in the form of MS occurs in 5–12% of patients who have undergone allo-HSCT for AML, and the incidence of relapse after DLI or a 2nd allo-HSCT is even higher [8]. Furthermore, in comparison with patients with BM relapse, those with extramedullary relapse are more likely to have had preceding GVHD [8].\n\nIn the present case, the GVL effect for molecular BM relapse and chronic GVHD co-occurred after the DLI, and immunosuppression required to treat the GVHD until when the extramedullary tumors eventually relapsed. Collectively, these observations suggest that the GVL effect associated with an occurrence of GVHD is less effective in preventing the relapse of the extramedullary tumors, however, the precise mechanism remains to be clarified.\n\nTreatment guidelines for MS have not been established because of the rarity of the disease, especially in the relapse setting after allo-HSCT. Although systemic chemotherapy or a 2nd allo-HSCT should be considered, the prognosis with these treatment strategies remains extremely poor [8]. In recent years, the efficacy of targeted therapies for MS, such as a humanized anti-CD33 monoclonal antibody, tyrosine kinase inhibitors (for FIP1L1-PDGFR, and FLT3-ITD), and DNA methyltransferase inhibitors, have been reported and these agents may change the disease outcome [5,[9], [10], [11]].\n\nAlthough the molecular abnormalities in MS have not been well investigated, there have been several reports analyzing gene mutations, which have shown the frequent occurrence of FLT3 mutations in MS [7]. Interestingly, a discordance of FLT3-ITD mutational status in leukemic blasts between medullary and extramedullary sites has been demonstrated in some cases. In our case, however, we confirmed FLT3-ITD mutation in the leukemic blasts at both medullary and extramedullary sites.\n\nAs for FLT3 inhibitors, 1st generation multikinase inhibitors, such as lestaurtinib, sorafenib, and midostaurin, have been investigated, however, clinical efficacies for AML with FLT3 mutations are still limited, and may contribute to adverse effects due to the inhibition of multiple other kinases [2]. Therefore, next-generation FLT3 inhibitors have been developed to overcome these hurdles. Gilteritinib, which is a 2nd generation selective FLT3 inhibitor, was shown to improve the overall survival for relapsed or refractory AML with FLT3 mutations compared to conventional chemotherapy [3], however, the efficacy for relapsed MS after allo-HSCT was not mentioned in the trial. In our patient, a remarkable response for the extramedullary tumors and a complete molecular response in BM were seen. Although grade 4 hematological AEs were observed, these AEs were manageable and gilteritinib could be administered in the outpatient setting. Because our patient was young with good performance status and his AML relapse co-occurred not only at extramedullary but also at medullary sites, we performed 2nd allo-BMT in an attempt to cure his AML. Furthermore, gilteritinib could be resumed after 2nd allo-BMT without AEs nor worsening of GVHD. Because the efficacy of gilteritinib as maintenance therapy after allo-HSCT remains unknown and the impact on GVHD of FLT3 inhibitors is controversial, future studies are necessary to address these issues.\n\nTo our knowledge, this is the first report of medullary and extramedullary relapse of FLT3-ITD AML after allo-BMT successfully treated with gilteritinib followed by 2nd allo-BMT. In the future, large prospective studies for MS are needed to establish the best strategy for using targeted therapies.\n\nDeclaration of Competing Interests\nItaru Matsumura\n\nHonoraria: Astellas, Otsuka Pharmaceuticals, Novartis, Sanofi, Shionogi Pharmaceuticals,\n\nNo other potential conflicts of interest were reported.\n==== Refs\nReferences\n1 Stirewalt D.L. Radich J.P. The role of FLT3 in haematopoietic malignancies Nat. Rev. Cancer 3 9 2003 650 665 12951584 \n2 Daver N. Schlenk R.F. Russell N.H. Levis M.J Targeting FLT3 mutations in AML: review of current knowledge and evidence Leukemia 33 2 2019 299 312 30651634 \n3 Perl A.E. Martinelli G. Cortes J.E. Gilteritinib or chemotherapy for relapsed or refractory N. Engl. J. Med. 381 18 2019 1728 1740 31665578 \n4 Swerdlow S.H. Campo E. Pileri S.A. The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 127 20 2016 2375 2390 26980727 \n5 Magdy M. Abdel Karim N. Eldessouki I. Gaber O. Rahouma M. Ghareeb M Myeloid Sarcoma Oncol. Res. Treat. 42 4 2019 224 229 30840960 \n6 Pileri S.A. Ascani S. Cox M.C. Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients Leukemia 21 2 2007 340 350 17170724 \n7 Ansari-Lari M.A. Yang C.F. Tinawi-Aljundi R. FLT3 mutations in myeloid sarcoma Br. J. Haematol. 126 6 2004 785 791 15352981 \n8 Yoshihara S. Ando T. Ogawa H Extramedullary relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: an easily overlooked but significant pattern of relapse Biol. Blood Marrow Transplant 18 12 2012 1800 1807 22634018 \n9 Védy D. Muehlematter D. Rausch T. Stalder M. Jotterand M. Spertini O Acute myeloid leukemia with myeloid sarcoma and eosinophilia: prolonged remission and molecular response to imatinib J. Clin. Oncol. 28 3 2010 e33 e35 19901109 \n10 Minoia C. de Fazio V. Scognamillo G. Long-Lasting remission in De Novo Breast myeloid sarcoma treated with decitabine and radiotherapy Diagnostics (Basel) 9 3 2019 \n11 Kida M. Kuroda Y. Kido M. Chishaki R. Kuraoka K. Ito T Successful treatment with gilteritinib for isolated extramedullary relapse of acute myeloid leukemia with FLT3-ITD mutation after allogeneic stem cell transplantation Int. J. Hematol. 2020\n\n",
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"issue": "14()",
"journal": "Leukemia research reports",
"keywords": "Acute myeloid leukemia; FLT3-ITD; Gilteritinib; Myeloid sarcoma",
"medline_ta": "Leuk Res Rep",
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"nlm_unique_id": "101608906",
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"pages": "100219",
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"title": "Targeted therapy for medullary and extramedullary relapse of FLT3-ITD acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "targeted therapy for medullary and extramedullary relapse of flt3 itd acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation"
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"abstract": "Our aim was to evaluate the temporal changes in left ventricular (LV) diastolic filling in relation to other LV parameters using cardiac MRI (CMR) in patients with HER2 positive breast cancer receiving trastuzumab therapy. Fourty-one women with early stage HER2+ breast cancer underwent serial CMR (baseline, 6, 12, and 18 months) after initiation of trastuzumab therapy. A single, blinded observer measured LV parameters on de-identified CMRs in random order. Linear mixed models were used to investigate temporal changes. Compared to baseline, there were significant decreases in systolic function as measured by both left ventricular ejection fraction (LVEF) (p <0.001 at 6 and 12 months) and peak ejection rate corrected for end-diastolic volume (PER/LVEDV) (p = 0.008 at 6 months, p = 0.01 at 12 months). However, these differences were no longer significant at 18 months. In contrast, significant reductions in diastolic function as measured by LV peak filling rate corrected for end-diastolic volume (PFR/LVEDV) were observed at 6 months (p = 0.012), 12 months (p = 0.031), and up to 18 months (p = 0.034). There were no significant temporal changes in the time to peak filling rate corrected for cardiac cycle (TPF/RR). The reduction in PFR/LVEDV at 18 months was no longer significant when corrected for heart rate. In conclusion, there were significant subclinical deleterious effects on both LV systolic and diastolic function among patients receiving trastuzumab. While there was recovery in LV systolic function after therapy cessation at 18 months, reduction in PFR/LVEDV appeared to persist. Thus, diastolic dysfunction may serve as a marker of trastuzumab-induced cardiotoxicity that needs to be confirmed in a larger study.",
"affiliations": "Terrence Donnelly Heart Centre, St Michael's Hospital, Toronto, Canada; University of Toronto, Toronto, Canada.;University of Toronto, Toronto, Canada; Division of Hematology/Oncology, St Michael's Hospital, Toronto, Canada.;Schulich Heart Research Program, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, Canada.;Schulich Heart Research Program, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, Canada.;University of Toronto, Toronto, Canada; Department of Medical Imaging, St Michael's Hospital, Toronto, Canada.;University of Toronto, Toronto, Canada; Sunnybrook Odette Cancer Centre, Canadian Centre for Applied Research in Cancer Control, Toronto, Canada.;University of Toronto, Toronto, Canada; Division of Hematology/Oncology, St Michael's Hospital, Toronto, Canada.;University of Toronto, Toronto, Canada; Sunnybrook Odette Cancer Centre, Toronto, Canada.;Schulich Heart Research Program, Sunnybrook Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, Canada.;University of Toronto, Toronto, Canada; Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Canada.;Department of Radiology, Christian Medical College, Vellore, India.;Department of Radiology, University of Calgary, Calgary, Canada.;Terrence Donnelly Heart Centre, St Michael's Hospital, Toronto, Canada; University of Toronto, Toronto, Canada.;Terrence Donnelly Heart Centre, St Michael's Hospital, Toronto, Canada; University of Toronto, Toronto, Canada. Electronic address: yana@smh.ca.",
"authors": "Song|Lan|L|;Brezden-Masley|Christine|C|;Ramanan|Venkat|V|;Ghugre|Nilesh|N|;Barfett|Joseph J|JJ|;Chan|Kelvin K W|KKW|;Haq|Rashida|R|;Petrella|Teresa|T|;Dhir|Vinita|V|;Jimenez-Juan|Laura|L|;Chacko|Binita Riya|BR|;Kotha|Vamshi|V|;Connelly|Kim A|KA|;Yan|Andrew T|AT|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjcard.2018.12.046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9149",
"issue": "123(7)",
"journal": "The American journal of cardiology",
"keywords": null,
"medline_ta": "Am J Cardiol",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D001943:Breast Neoplasms; D003971:Diastole; D005260:Female; D005500:Follow-Up Studies; D006352:Heart Ventricles; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D013318:Stroke Volume; D013599:Systole; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left; D016277:Ventricular Function, Left; D017725:Ventricular Pressure",
"nlm_unique_id": "0207277",
"other_id": null,
"pages": "1173-1179",
"pmc": null,
"pmid": "30683420",
"pubdate": "2019-04-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Serial Measurements of Left Ventricular Systolic and Diastolic Function by Cardiac Magnetic Resonance Imaging in Patients with Early Stage Breast Cancer on Trastuzumab.",
"title_normalized": "serial measurements of left ventricular systolic and diastolic function by cardiac magnetic resonance imaging in patients with early stage breast cancer on trastuzumab"
} | [
{
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{
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{
"abstract": "Ibogaine is a psychotropic indole alkaloid extracted from the roots of the Tabernanthe iboga shrub from the Apocynaceae family. Depending on the taken dose, it can lead to stimulant effects, euphoria, visual and auditory hallucinations, along with auditory, olfactory, and gustatory synesthesia. In addition to its historical usage in spiritual rituals of African tribes, these days iboga extract presents a prohibited, alternative drug widely used as a part of addiction treatment. Ibogaine used in opioid withdrawal is associated with serious side effects and sudden deaths. Besides its main use as an anti-addiction medication in alternative medicine, in moderate doses (from 100mg to 1g) ibogaine most commonly causes a \"trance-like state\".In this paper, we report the case of a heroin addict who died suddenly 5-12 hours after oral ingestion of powder labeled Tabernanthe iboga which had been bought online and used in the process of detoxification during an addiction treatment. The man was found dead in a rented apartment, where he was undergoing the addiction treatment.External examination revealed no lesions other than nonspecific injuries on the legs. The autopsy showed congestion of internal organs and pulmonary edema. Histopathological analysis of the heart showed neither macroscopic nor microscopic abnormalities. The concentration of ibogaine was 3.26mg/L. Moreover, systematic toxicological analyses of biological samples showed the presence of morphine and codeine. These data suggest that death, which occurred unnaturally after initiation of the \"treatment\", was probably the result of the cardiovascular effects caused by the ibogaine powder.The presented case highlights the worldwide problem of various products being widely available over the internet and the danger associated with consumption thereof.",
"affiliations": "Institute of Forensic Medicine \"Milovan Milovanović\", School of Medicine, University of Belgrade, Deligradska 31a, Belgrade, Serbia. tijana.durmic@med.bg.ac.rs.;Institute of Forensic Medicine \"Milovan Milovanović\", School of Medicine, University of Belgrade, Deligradska 31a, Belgrade, Serbia.;Institute of Forensic Medicine \"Milovan Milovanović\", School of Medicine, University of Belgrade, Deligradska 31a, Belgrade, Serbia.;Institute of Forensic Medicine \"Milovan Milovanović\", School of Medicine, University of Belgrade, Deligradska 31a, Belgrade, Serbia.;Institute of Forensic Medicine \"Milovan Milovanović\", School of Medicine, University of Belgrade, Deligradska 31a, Belgrade, Serbia.;Institute of Forensic Medicine \"Milovan Milovanović\", School of Medicine, University of Belgrade, Deligradska 31a, Belgrade, Serbia.",
"authors": "Aćimović|Tijana|T|;Atanasijević|Tatjana|T|;Denić|Kristina|K|;Lukić|Vera|V|;Popović|Vesna|V|;Bogdanović|Milenko|M|",
"chemical_list": "D001952:Bridged-Ring Compounds; D006213:Hallucinogens; D026121:Indole Alkaloids; C413805:ibogamine; D007050:Ibogaine; C008100:ibogaline; C094385:noribogaine",
"country": "United States",
"delete": false,
"doi": "10.1007/s12024-020-00342-0",
"fulltext": null,
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"issn_linking": "1547-769X",
"issue": "17(1)",
"journal": "Forensic science, medicine, and pathology",
"keywords": "Forensic science; Ibogaine; Opioid detoxification; Substance abuse; Toxicology",
"medline_ta": "Forensic Sci Med Pathol",
"mesh_terms": "D000328:Adult; D001952:Bridged-Ring Compounds; D017809:Fatal Outcome; D006213:Hallucinogens; D006556:Heroin Dependence; D006801:Humans; D007050:Ibogaine; D026121:Indole Alkaloids; D008297:Male",
"nlm_unique_id": "101236111",
"other_id": null,
"pages": "126-129",
"pmc": null,
"pmid": "33433774",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Death due to consumption of ibogaine: case report.",
"title_normalized": "death due to consumption of ibogaine case report"
} | [
{
"companynumb": "RS-ALKEM LABORATORIES LIMITED-RS-ALKEM-2021-00478",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
... |
{
"abstract": "Forced normalization is a clinical entity defined by the appearance of psychiatric disturbance following control of epileptic seizures that were previously uncontrolled. It was first described by Landolt in 1953. The first cases described were mostly psychosis, however, subsequent work suggested that any behavioural disturbance of acute/or subacute onset concomitant with seizure control could be considered as forced normalization. We report the case of a 65-year-old, right-handed Caucasian patient who was followed in the Epilepsy Centre of Marseille, for left temporal drug-resistant epilepsy. The frequency of seizures was one seizure per month at the time before surgery. Left anterior temporal lobectomy was proposed based on presurgical evaluation. The patient remained seizure-free after surgery, but he presented with an episode of acute psychosis three months after. At this point, EEG was performed, showing rare left temporal epileptiform activity mainly provoked by hyperventilation, with breach rhythm over the left temporal surgical. The appearance of acute psychosis after cessation of epileptic seizures and reduced epileptiform activity on the EEG led us to question the forced normalization process in this case. Another hypothesis would be the effect of surgery itself, since there is an increased risk of any psychiatric disturbance unrelated to seizure cessation during the postoperative period. In conclusion, psychosis in this case could have resulted from the combination of several factors, including the effect of surgery itself and seizure cessation. This case illustrates the need for specific psychiatric care in the perioperative period in patients with epilepsy.",
"affiliations": "APHM, Timone Hospital, Epileptology Department, Marseille, France.;APHM, Timone Hospital, Epileptology Department, Marseille, France, Aix Marseille University, APHM, INSERM, INS, Inst Neurosci Syst, Timone Hospital, Epileptology Department, Marseille, France.;APHM, Timone Hospital, Epileptology Department, Marseille, France, Aix Marseille University, APHM, INSERM, INS, Inst Neurosci Syst, Timone Hospital, Epileptology Department, Marseille, France.;APHM, Timone Hospital, Epileptology Department, Marseille, France, Aix Marseille University, APHM, INSERM, INS, Inst Neurosci Syst, Timone Hospital, Epileptology Department, Marseille, France.",
"authors": "Arthuis|Marie|M|;Lagarde|Stanislas|S|;Mcgonigal|Aileen|A|;Bartolomei|Fabrice|F|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1684/epd.2021.1380",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": null,
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "drug-resistant epilepsy; epilepsy surgery; forced normalization; partial epilepsy; psychosis; temporal lobe seizure",
"medline_ta": "Epileptic Disord",
"mesh_terms": null,
"nlm_unique_id": "100891853",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34796883",
"pubdate": "2021-11-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "De novo psychosis after left temporal lobectomy: a case of forced normalization?",
"title_normalized": "de novo psychosis after left temporal lobectomy a case of forced normalization"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-332377",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"dru... |
{
"abstract": "This case report describes a 10-year-old female patient who underwent ketamine sedation for fracture reduction and experienced asymptomatic ventricular tachycardia after the sedation. She had no history of syncope, chest pain, palpations, or light-headedness and had a normal physical examination. This is the first reported case of a patient experiencing ventricular tachycardia after ketamine use for sedation. This case demonstrates a serious and potentially harmful possible adverse effect of ketamine administration.",
"affiliations": "From the *Division of Emergency Medicine, Nationwide Children's Hospital; †Ohio State University College of Medicine; and ‡Division of Cardiology, Division of Neonatology, Nationwide Children's Hospital, Columbus, OH.",
"authors": "Stukus|Kristin S|KS|;Przybylowicz|Ryle W|RW|;Backes|Carl H|CH|;Cohen|Daniel M|DM|",
"chemical_list": "D000778:Anesthetics, Dissociative; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000237",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "30(10)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000778:Anesthetics, Dissociative; D002648:Child; D016292:Conscious Sedation; D005260:Female; D006801:Humans; D007649:Ketamine; D011885:Radius Fractures; D017180:Tachycardia, Ventricular; D014458:Ulna Fractures",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "730-2",
"pmc": null,
"pmid": "25275353",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ventricular tachycardia after ketamine sedation for fracture reduction.",
"title_normalized": "ventricular tachycardia after ketamine sedation for fracture reduction"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2015GSK119580",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": null... |
{
"abstract": "Discovered in swine manure relatively recently, Robsinoniella peoriensis is a gram-positive anaerobic bacilli that has been reported to cause human infections. Its antimicrobial susceptibility, epidemiology and overall pathogenicity are still not fully understood. We report a case of a hardware related soft tissue infection in the right femur caused by Robinsoneilla peoriensis following an open reduction internal fixation in a 67 year old immunocompetent woman. The patient was successfully treated with six weeks of ertapenem.",
"affiliations": "Presbyterian Healthcare Services, Albuquerque, NM, United States.;Infectious Disease and Internal Medicine Associates P.C., Albuquerque, NM, United States.;Tricore Reference Laboratories, Albuquerque, NM, United States.",
"authors": "Schmetterer|Justin|J|;Gorvetzian|Joseph|J|;Yang|Shaun|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2017.10.003",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(17)30180-410.1016/j.idcr.2017.10.003ArticleRobinsoniella peoriensis infection related to right femoral hardware Schmetterer Justin Jschmette2@phs.orga⁎Gorvetzian Joseph bYang Shaun ca Presbyterian Healthcare Services, Albuquerque, NM, United Statesb Infectious Disease and Internal Medicine Associates P.C., Albuquerque, NM, United Statesc Tricore Reference Laboratories, Albuquerque, NM, United States⁎ Corresponding author. Present/permanent address: 1100 Central SE, Albuquerque, NM 87106, United States. Jschmette2@phs.org13 10 2017 2017 13 10 2017 10 115 116 22 9 2017 11 10 2017 11 10 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Discovered in swine manure relatively recently, Robsinoniella peoriensis is a gram-positive anaerobic bacilli that has been reported to cause human infections. Its antimicrobial susceptibility, epidemiology and overall pathogenicity are still not fully understood. We report a case of a hardware related soft tissue infection in the right femur caused by Robinsoneilla peoriensis following an open reduction internal fixation in a 67 year old immunocompetent woman. The patient was successfully treated with six weeks of ertapenem.\n\nKeywords\nRobinsoniella peoriensisRobinsoniellaR. peoriensisAbscessHardware\n==== Body\nIntroduction\nRobinsoniella peoriensis is a gram-positive, anaerobic, spore-forming bacilli that has been isolated in the feces of swine, turtles and more recently, in the human gut of healthy premature neonates [1]. The bacterium belongs to phylum Firmicutes within the family Lachnospiraceae. In recent years, R. peoriensis has been increasingly isolated from human infections including intra-abdominal, bloodstream, soft tissue and prosthetic joint/hardware infections. The patient outcomes in these studies varied significantly depending on the site of the infection [1], [2], [3], [4], [5], [6]. We describe a patient with a subperiosteal abscess of the right femur that developed subsequent to a right femur open reduction internal fixation (ORIF).\n\nCase report\nA 67-year old woman with a past medical history significant for chronic kidney disease and hypertension, sustained a fracture of her right femur in December 2015 requiring a distal femur ORIF. Approximately one month later, the patient was seen for signs of hardware failure and a small superficial abscess at the distal end of her incision. She underwent revision of the ORIF on 20 January 2016. Repeat X-rays demonstrated healing of the fracture. The patient was non-weight bearing and primarily used a wheelchair thereafter.\n\nOn 13 May 2016, approximately six months from initial hardware placement, the patient reported to an urgent care clinic with three days of flu-like symptoms associated with aches and chills. She developed swelling in her right leg tracking from her thigh to her knee. She was discharged on oral clindamycin. Over the next several days the lateral lower thigh became swollen and fluctuant. The patient presented to her orthopedic surgeon and underwent an incision and drainage (I&D) of the developing distal femur abscess. Copious amounts of purulent fluid was noted deep in the wound concerning for an infection of her implants. Gram stain yielded gram-positive cocci however cultures remained negative, potentially due to oral antimicrobial exposure prior to sampling. The patient completed a six-week course of intravenous daptomycin dosed at 6 mg/kg every 24 h on 22 June 2016. She received three months of oral doxycycline 100 mg twice daily thereafter.\n\nRadiographic studies revealed signs of a nonunion of the femur, and a fractured rod was noted in July 2016. Antimicrobials were held for two weeks and she was admitted to our hospital on 17 August 2016. The patient was taken back to the operating room for right femur deep hardware removal and debridement of deep tissue and bone. Seven cultures were obtained at multiple sites along the femur bone, hardware plate and tissues surrounding the hardware. On admission, the patient was afebrile and demonstrated a white blood cell count of 11,300 cells/mm3. C-reactive protein was 7.3 mg/L, and the erythrocyte sedimentation rate was 61 millimeters per hour (mm/h).\n\nVancomycin was initiated on day one of admission and adjusted by serum trough levels accordingly. On day five of hospitalization ampicillin/sulbactam 3 g IV every 6 h was initiated. Six out of the seven cultures obtained from the surgical procedure were all positive for R. peoriensis identified by the 16S ribosomal RNA sequencing. The organism was initially reported by the clinical microbiology lab as an anaerobic gram-positive bacilli. The lab routinely uses MALDI-TOF (matrix assisted laser desorption ionization-time of flight), a mass spectrometry based technology for bacterial species identification. However, it couldn’t provide the further result on the isolate most likely due to the limitation of the mass spectrometry database. On day seven the patient had several febrile episodes with a maximum temperature of 101.1 °F. The patient’s antimicrobials were converted to ertapenem 1 g IV daily and she was discharged on day eight after the fevers resolved. The patient was maintained on a non-weight bearing status. A peripherally inserted central catheter was placed and the patient was then followed by Infectious Disease in an outpatient setting.\n\nThe isolate was sent to ARUP laboratories to establish minimum inhibitory concentrations. There are no currently established susceptibility breakpoints specifically for Robinsoniella spp. Antimicrobial susceptibility was tested via a custom panel broth microdilution panel and evaluated using the Clinical and Laboratory Standards Institute (CLSI) breakpoints for gram-positive anaerobes. The strain revealed elevated minimal inhibitory concentrations (MIC) against penicillin (8.0 mcg/mL), and clindamycin (4 mcg/mL) after 48 h of anaerobic incubation using both the Etest and ATB ANA strip. Low MIC's were found for ampicillin/sulbactam (1/0.5 mcg/ml), piperacillin-tazobactam (8/4 mcg/mL), meropenem (0.5 mcg/mL), and metronidazole (0.5 mcg/mL) (Table 1). The patient responded well and completed a six-week course of Ertapenem on 5 October 2016. Laboratory values obtained 14 November 2016 were improved with an ESR of 43 mm/h and C-reactive protein of 0.3 mg/L. On 7 December 2016 the patient underwent a right intramedullary rodding that was uneventful.Table 1 Robinsoniella spp. susceptibly panel.\n\nTable 1Antimicrobial\tMIC (mcg/ml)\t\nAmpicillin/Sulbactam\t1/0.5\t\nClindamycin\t4\t\nMeropenem\t0.5\t\nMetronidazole\t0.5\t\nPenicillin\t8\t\nPiperacillin/tazobactam\t8/4\t\n\n\nDiscussion\nRobinsoniella peoriensis was first isolated in 2003 from a swine-manure storage pit [7]. Strains of this species have been identified from the gastrointestinal (GI) tracts of a variety mammals, suggesting it may be a member of the commensal microflora of these animals [3]. However, it is unclear if this organism is also part of the human GI tract commensal microflora or could transiently colonize the human GI tract. Phylogenetic analysis showed that this organism fits into the clostridial rRNA cluster XIVa subgroup, with the closest related genus being Ruminococcus [8]. The organism was named R. peoriensis after an American scientist working in livestock related microbiology [1]. Cotta et al. described R. peoriensis as an oval-to-rod shaped bacterium with subterminal spores that grows in 5% CO2 or under anaerobic conditions at 37 °C. It produces small, nonhemolytic colonies (0.5–1.5 mm) and ferments glucose, lactose, and maltose. It does not reduce nitrate or produce indole [7].\n\nThis organism may be problematic to identify and differentiate from other anaerobic bacterial species of similar morphologies without more advanced technologies. Whitehead et al. describes the use of specific PCR primers to the 16S rDNA gene of R. peoriensis to rapidly and accurately identify the strain when recovered from human infections as well as other ecological sources. In our case, the clinical microbiology laboratory identified the organism by using the 16S ribosomal RNA sequencing, which is the only reliable method for its identification.\n\nThis organism appears to have variable susceptibility patterns. Some cases reported low MICs to ampicillin, piperacillin/tazobactam, ertapenem, metronidazole and vancomycin [2], [8]. Other studies have reported elevated MICs to penicillin, clindamycin, and moxifloxacin [1], [2], [8]. Overall, piperacillin/tazobactam, ertapenem, and metronidazole seemed to be effective for treatment based on a limited number of case reports and our own experience.\n\nIt is difficult to discern how the patient acquired the organism. She did not report any unusual animal or food exposure, nor had the patient had any recent travel. She was not on immunosuppressive agents and had no significant past medical history. The patient spiked multiple fevers after one week of ampicillin/sulbactam and vancomycin. It is unclear if this was due to treatment failure or drug induced fever. Drug fever seemed conceivable due to a lack of leukocytosis although the patient did become tachycardic during the febrile episode. It is quite clear though, that the first course of antimicrobials of daptomycin and doxycycline were not the right regimen to treat this organism and thus did not clear the infection.\n\nConclusion\nRobinsoniella peoriensis is an emerging human pathogen diagnosed more frequently in recent years primarily due to the utilization of molecular sequencing in clinical microbiology laboratories. This organism may have been under recognized as a human pathogen because traditionally most laboratories would only report it as gram-positive, spore-forming, anaerobic rod without further workup. This organism has been reported to cause serious infections including bacteremia, soft tissue infections, prosthetic joint infections, and in our case, subperiosteal abscess related to hardware implantation in the femur. In most cases, there was no clear epidemiological link to explain where patients acquired this organism, which is typically found in swine manure. However, a recent study reported the isolation of R. peoriensis in the stool of healthy premature neonates suggesting humans may be colonized at an early age [9]. The prevalence of colonization remains under further investigation. In most cases, R. peoriensis was reported to be susceptible to piperacillin-tazobactam, ertapenem and metronidazole, but resistant to penicillin and clindamycin. In our case, the patient responded well to six weeks of intravenous ertapenem. More studies are necessary to establish a better understanding of this organism’s virulence, transmission, and antimicrobial susceptibility patterns.\n\nConflicts of interest\nNone of the above authors have competing interests to declare.\n\nFunding\nThere was no financial support for the conduct of the research or preparation of the article.\n==== Refs\nReferences\n1 Rieber H. Frontzek A. Bell A. Frommelt L. Robinsoniella peoriensis, originally isolated from swine manure, and early periprosthetic hip infection: case report and review of the literature Anaerobe 42 December 2016 33 36 27481335 \n2 Gomez E. Gustafson D. Colgrove R. Isolation of Robinsoniella peoriensis from four human specimens J Clin Microbiol January 2011 458 460 21048018 \n3 Whitehead T. Anoma C. McLaughlin R. Rapid identification of Robinsoniella peoriensis using specific 16S rRNA gene PCR primers Anaerobe 43 February 2017 39 42 Epub 2016 Nov 247 27890692 \n4 Illiaquer M. Corvic S. Anaerobes isolated from bone and joint infections and their susceptibility to antibiotics J Infect 65 2012 473e475 22960134 \n5 Jeon Y. Kim T.S. Kim H.B. Park K.U. Song J. Kim E.C. First Korean case of Robinsoniella peoriensis bacteremia in a patient with aspiration pneumonia Ann Lab Med 32 2012 370e374 22950075 \n6 Lopez P. Belda S. Garcia M. Royo G. Infection of a spontaneous muscular hematoma due to Robinsoniella peoriensis, in a patient with alcoholic liver cirrhosis Enferm Infecc Microbiol Clin 28 2010 565e567 20627461 \n7 Cotta M.A. Whitehead T.R. Zeltwanger R. Isolation, characterization and comparison of bacteria from swine faeces and manure storage pits Environ Microbiol 5 2003 737e745 12919409 \n8 Cassir N. Laget L. Renvoise A. Robinsoniella perotiensis infection following surgery for scoliosis: a case report J Med Case Rep 6 2012 174 22742769 \n9 Ferraris L.1 Aires J. Butel M.J. Isolation of Robinsoniella peoriensis from the feces of premature neonates Anaerobe 18 February (1) 2012 172 173 Epub 2011 Dec 3 22155447\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "10()",
"journal": "IDCases",
"keywords": "Abscess; Hardware; R. peoriensis; Robinsoniella; Robinsoniella peoriensis",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "115-116",
"pmc": null,
"pmid": "29147640",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "22960134;22742769;27481335;22950075;22155447;12919409;21048018;27890692;20627461",
"title": "Robinsoniella peoriensis infection related to right femoral hardware.",
"title_normalized": "robinsoniella peoriensis infection related to right femoral hardware"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP014386",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
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