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"abstract": "There are no effective therapeutic options for locally advanced head and neck squamous cell carcinoma (HNSCC). Additionally, there is no standard therapy for patients subjected to multiple lines of treatment. Angiogenesis plays a key role in tumor growth and metastasis. Therefore, inhibition of tumor angiogenesis is an important strategy for tumor therapy. Apatinib is a novel tyrosine kinase inhibitor that inhibits angiogenesis by targeting vascular endothelial growth factor receptor-2 (VEGFR-2). The effect of apatinib on HNSCC has not been clearly established. In this study, we administered apatinib in combination with anti-epidermal growth factor receptor (EGFR) targeted and systemic chemotherapy for the treatment of oral cancer and to achieve better disease outcomes. To avoid fatal bleeding, after achieving good clinical outcomes, the follow-up treatment plan was adjusted. The efficacy of apatinib combined with anti-EGFR targeted and systemic chemotherapy for the treatment of oral cancer has not been previously reported. Our findings show the therapeutic potential of apatinib for advanced HNSCC patients with multiple lines of chemotherapy, especially for patients with large neck masses.",
"affiliations": "Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230031, People's Republic of China.;Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230031, People's Republic of China.;Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230031, People's Republic of China.;Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230031, People's Republic of China.",
"authors": "He|Jian|J|;Zhang|Yangyang|Y|;Gao|Jin|J|;Qian|Liting|L|",
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"doi": "10.1515/med-2021-0360",
"fulltext": "\n==== Front\nOpen Med (Wars)\nOpen Med (Wars)\nmed\nOpen Medicine\n2391-5463\nDe Gruyter\n\nmed-2021-0360\n10.1515/med-2021-0360\nCase Report\nRapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report\nHe Jian\nZhang Yangyang\nGao Jin 1gaojinUSTC@126.com\n\nQian Liting 1qltUSTC@126.com\n\nDepartment of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230031, People’s Republic of China\nDepartment of Radiation Oncology, Anhui Provincial Cancer Hospital, Hefei, Anhui Province, 230031, People’s Republic of China\n1 There authors contributed equally to this work.\n\ntel:+86-15395005376\ntel: +86-13966716720\n03 11 2021\n2021\n16 1 16681672\n27 4 2021\n11 8 2021\n19 8 2021\n© 2021 Jian He et al., published by De Gruyter\n2021\nJian He et al., published by De Gruyter\nhttps://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License.\n\nAbstract\n\nThere are no effective therapeutic options for locally advanced head and neck squamous cell carcinoma (HNSCC). Additionally, there is no standard therapy for patients subjected to multiple lines of treatment. Angiogenesis plays a key role in tumor growth and metastasis. Therefore, inhibition of tumor angiogenesis is an important strategy for tumor therapy. Apatinib is a novel tyrosine kinase inhibitor that inhibits angiogenesis by targeting vascular endothelial growth factor receptor-2 (VEGFR-2). The effect of apatinib on HNSCC has not been clearly established. In this study, we administered apatinib in combination with anti-epidermal growth factor receptor (EGFR) targeted and systemic chemotherapy for the treatment of oral cancer and to achieve better disease outcomes. To avoid fatal bleeding, after achieving good clinical outcomes, the follow-up treatment plan was adjusted. The efficacy of apatinib combined with anti-EGFR targeted and systemic chemotherapy for the treatment of oral cancer has not been previously reported. Our findings show the therapeutic potential of apatinib for advanced HNSCC patients with multiple lines of chemotherapy, especially for patients with large neck masses.\n\nKeywords\n\napatinib\noral cancer\nhead and neck squamous cell carcinoma\nVEGFR-2\n==== Body\npmc1 Introduction\n\nOral cancer is a malignant tumor that occurs in the oral and maxillofacial regions, and approximately 90% is oral squamous cell carcinoma (SCC). It is the most common SCC of the head and neck. Annually, there are about 350,000 new cases and over 170,000 mortalities associated with oral cancer, globally accounting for 2.0 and 1.9% of new morbidity and mortality cases, respectively [1]. Patients with HNSCC in the early stages are mainly treated with surgery or radiotherapy, while patients with advanced stage HNSCC are treated with surgery, radiotherapy, and chemotherapy as the main therapeutic options. However, the overall efficacy is not good. The 5-year survival rate is only 40–50%, while 40–60% of patients have local recurrence or distant metastasis [2]. Therefore, there is a need to develop new therapeutic options for HNSCC. Apatinib mesylate is a small angiogenesis inhibitor that targets VEGFR-2, which in turn inhibits tumor angiogenesis and tumor growth [3]. Clinically, apatinib, which has a favorable safety profile and efficacy, has been used for the treatment of some advanced cancers. However, the efficacy of apatinib in HNSCC is unknown. In this study, we report the clinical outcomes of a patient with locally advanced HNSCC after apatinib combined with anti-EGFR targeted and chemotherapy. Our findings show that apatinib has a favorable efficacy for the treatment of HNSCC.\n\n2 Case report\n\nA 56-year-old woman presented with a 3-month history of a painful oral ulcer and local mass in the right cheek. The patient denied any history of hypertension, diabetes, coronary heart disease, smoking, drinking, or hereditary disorders. Physical examination revealed a mass of about 8 cm3 × 6 cm3 × 7.5 cm3 on the right neck that invaded adjacent muscles and skin, with an irregular shape, unclear boundaries, and poor movement. There was an ulcer of about 1.5 cm2 × 2 cm2 in the buccal mucosa. Her routine blood and blood biochemical parameters were normal. Her serum SCC antigen level was 2.4 ng/mL (reference range: <1.5 ng/mL), while carcinoembryonic antigen (CEA) level was within normal ranges. The pathological biopsy (right buccal mucosa), which was performed in the dental outpatient clinic, revealed highly differentiated SCC. Immunohistochemistry staining indicated VEGF (+). B-ultrasound revealed a solid cystic mass in the right submandibular with multiple lymphadenopathy. The positron emission tomography computed tomography (PET-CT) scan revealed a deep cystic solid mass in the posterior margin of the right parotid gland with uneven fluorodeoxyglucose uptake. The mass involving surrounding tissues, multiple metastatic cervical lymph nodes, with no clear boundary with the right common carotid artery and no metastasis in other parts. The diagnosis was oral SCC at clinical stage T2N3bM0 (IVB). The patient’s body surface area (BSA) was 1.53 m2. The first-line chemotherapeutic option was intravenous paclitaxel (135 mg/m2) on day 1 and cisplatin (30 mg/m2) on day 1–3. However, there was no decrease in neck mass volume after one cycle. Magnetic resonance imaging (MRI) revealed a soft tissue mass with a volume of about 7.5 cm3 × 5.5 cm3 × 7 cm3 on the right neck that invaded adjacent muscles and skin and multiple enlarged cervical lymph nodes (Figure 1a; Table 1). According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 standard, the tumor was considered as stable disease (SD). Then, the treatment was adjusted to nimotuzumab (200 mg) combined with paclitaxel and cisplatin as second-line chemotherapeutic options, every 3 weeks. After one cycle, the mass became soft and slightly decreased. However, the mass did not continue to shrink after the second cycle of second-line chemotherapy. MRI examination revealed a slight decrease in the volume of the tumor compared to pre-second-line chemotherapy (Figure 1b; Table 1). After consultation with an oncologist and head and neck surgeon, given the large neck mass, insensitive treatment, cost of treatment, and VEGF (+), apatinib was administered (500 mg/day) on 16 December 2019 (Figure 2a). After only 5 days of treatment, the size of the neck mass had significantly reduced and was almost flat (Figure 2b). After apatinib treatment for 10 days, the tumor continuously shrunk. There were no occurrences of hypertension, hand-foot syndrome, proteinuria, oral ulcer, or hematologic toxicities. However, due to rapid tumor shrinkage, a local skin ulceration with exudate was formed (Figure 1c; Table 1). Subsequently, the wound was actively treated with oral cefuroxime sodium, local cleansing, and dressing changes. After a discussion with multiple disciplinary teams, apatinib was withdrawn on 23 January 2020, and the treatment was changed to low-dose maintenance chemotherapy because the patient declined radiotherapy. The specific plan was paclitaxel plus capecitabine every week. Unfortunately, the patient died of a pulmonary infection 3 months later.\n\nFigure 1 Images of neck tumor. (a) Before second-line chemotherapy, MRI revealed a soft tissue mass with a volume of about 7.5 cm3 × 5.5 cm3 × 7 cm3 on the right neck that invaded adjacent muscles and skin, and multiple enlarged cervical lymph nodes. (b) After the second cycle of second-line chemotherapy, MRI examination revealed a slight decrease in the volume of the tumor. (c) After apatinib treatment for 10 days, the computed tomography revealed the neck tumor was markedly reduced.\n\nTable 1 The volumes of the tumor at different time\n\nTime\tBefore second-line chemotherapy\tAfter second-line chemotherapy\tAfter apatinib treatment for 10 days\t\nTumor volume (cm3)\t7.5 × 5.5 × 7.0 (288.75)\t5.3 × 3.4 × 7.0 (126.14)\t1.5 × 1.9 × 2.0 (5.70)\t\n\nFigure 2 Clinical pictures of neck tumor. (a) Before treatment with apatinib on 16 December 2019. (b) After apatinib treatment for 5 days on 21 December 2019.\n\n3 Discussion\n\nDue to the atypical symptoms and signs of oral cancer, more than 60% of patients are diagnosed at stage III or IV. They lose the chance for surgery and can only be comprehensively treated by radiotherapy and chemotherapy [4]. Neoadjuvant chemotherapy can enhance the local control rate of head and neck tumors or the rate of distant metastasis. For patients with unresectable, recurrent, and metastatic head and neck tumors, paclitaxel plus platinum drugs are the recommended chemotherapeutic options [5]. The patient’s tumor was large, and boundaries with internal jugular arteriovenous and peripheral muscles were unclear, implying that the patient could not be operated. Paclitaxel plus cisplatin were administered as first-line chemotherapeutic options. However, after one cycle, there was no obvious decrease in the volume of neck mass. EGFR is closely associated with tumor cell proliferation and metastasis. EGFR is highly expressed in most HNSCC, thereby affecting the prognosis of HNSCC [6]. Anti-EGFR targeted combination therapy can significantly prolong the progression-free survival (PFS) and overall survival (OS) of patients with advanced HNSCC. Moreover, it can significantly improve the patient’s quality of life [7,8]. Clinically applied anti-EGFR monoclonal antibodies include cetuximab and nimotuzumab. However, due to the high cost of anti-EGFR monoclonal antibodies, the patient preferred the combinational therapy of nimotuzumab, paclitaxel, and cisplatin. After two cycles, the mass became soft and slightly decreased.\n\nTumor angiogenesis plays a key role in tumor growth and metastasis. For continuous cell proliferation, tumor tissues rely on oxygen and nutrients provided by neovascularization. The VEGF/VEGFR signaling pathway is considered the most critical step in tumor angiogenesis. VEGFR inhibitors can bind VEGF, which suppresses the binding of VEGF to VEGFR on the surface of vascular endothelial cells, thereby inhibiting biological effects, including tumor micro angiogenesis, invasion, and metastasis [9]. Apatinib was approved by China Food and Drug Administration (CFDA) in 2014 for the treatment of late-stage gastric adenocarcinoma or gastric esophageal junction adenocarcinoma that has progressed or relapsed after treatment with at least two lines of systemic chemotherapy.\n\nApatinib has been clinically used for various late-stage cancers, including hepatocellular carcinoma [10], non-small cell lung cancer [11], osteogenic sarcoma [12], colorectal cancer [13], and cervical cancer [14], with a favorable safety and good efficacy. However, the efficacy of apatinib in HNSCC has seldom been reported, with only individual case reports. Meng et al. [15] reported that the combination of apatinib and S-1 in the treatment of three cases of advanced head and neck tumors achieved partial responses and mild adverse reactions. The efficacy of apatinib combined with anti-EGFR targeted and systemic chemotherapy for the treatment of oral cancer has not been previously reported. In this study, we administered apatinib in combination with nimotuzumab and chemotherapy. The neck tumor was significantly reduced after treatment with apatinib for only 5 days. Since the patient had a large neck mass that was rich in blood vessels, apatinib rapidly exerted antiangiogenic effects. Therefore, the tumor tissue could not be supplied with enough oxygen and nutrients for continuous proliferation, thereby causing tumor necrosis and shrinkage. Zhu et al. [16] reported that apatinib enhances the risk of fatal hemorrhage. This is because during growth, the tumor invades blood vessels, and after apatinib administration, the tumor shrinks, thereby causing bleeding. In addition, drug-induced coagulation dysfunction and reduction of vascular endothelial growth factor synthesis destroy vascular integrity, which may increase the risk of bleeding [17]. To avoid fatal bleeding, we adjusted the follow-up treatment plan in time and achieved good outcomes.\n\nCommon side effects of apatinib, including hypertension, oral ulcer, hand-foot syndrome, proteinuria, and fatigue, are generally manageable and acceptable. The patient did not present these side effects, which were attributed to the short-term application of apatinib. The possible reasons for pulmonary infection in this patient were: i. Poor immunity due to the effects of cancer, making her susceptible to lung infections; ii. Pulmonary metastases, pleural effusions, and other coinfections in the lungs; and iii. Bone marrow suppression and immune deficiency after chemotherapy, which led to pulmonary infections. A direct association between pulmonary infection and apatinib has not been reported. This patient was administered with oral apatinib for one month and did not present any symptoms of pulmonary infection during this period; therefore, it was very unlikely that apatinib caused pulmonary infection. Studies should determine whether apatinib can cause pulmonary infections.\n\nIn this case, apatinib played a rapid and overwhelming role in tumor control. However, for clinical applications of apatinib, various considerations should be paid attention to. First, apatinib is effective for advanced HNSCC patients with multiple lines of chemotherapy treatment, especially in patients with large neck masses. Apatinib can be used in combination with anti-EGFR targeted and systemic chemotherapy, as described in our case. However, the role of apatinib in HNSCC should be confirmed in large-scale prospective clinical trials. Second, there is a need to establish the appropriate cohort of patients to receive apatinib. HNSCC patients with tumor invasions of large blood vessels have a high risk of fatal bleeding; therefore, apatinib should be used with caution. Third, tumor regression and necrosis are closely observed during the treatment of apatinib. Meanwhile, the coagulation function should be regularly monitored, and the treatment plans should be adjusted in time to avoid the risk of fatal bleeding.\n\nIn conclusion, apatinib combined with anti-EGFR targeted therapies and chemotherapy may be effective for advanced HNSCC patients, especially for patients with large neck masses to avoid the occurrence of fatal bleeding. However, the efficacy and safety for apatinib should be confirmed by multicenter large-scale prospective clinical trials, which may provide an effective treatment modality for HNSCC patients.\n\nAbbreviations\n\nHNSCC head and neck squamous cell carcinoma\n\nVEGFR-2 vascular endothelial growth factor receptor-2\n\nEGFR epidermal growth factor receptor\n\nSCC squamous cell carcinoma\n\nCEA carcinoembryonic antigen\n\nPET-CT positron emission tomography computed tomography\n\nBSA body surface area\n\nMRI magnetic resonance imaging\n\nRECIST response evaluation criteria in solid tumors\n\nSD stable disease\n\nPFS progression-free survival\n\nOS overall survival\n\nCFDA China Food and Drug Administration\n\nEthics and consent statements: This study was approved by the ethics committee of Anhui Provincial Cancer Hospital, and written informed consent was obtained from the patient.\n\nFunding information: This research was supported by the Undergraduate Quality Program of University of Science and Technology of China (No. 2021xjyxm126).\n\nAuthor contributions: J.H.: wrote the manuscript. Y.Y.Z.: collected data. J.G. and L.T.Q.: final review of the manuscript. The final version of the manuscript was read and approved by all the authors.\n\nConflict of interest: The authors have no conflicts of interest.\n\nData availability statement: All data in this study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Bray F , Ferlay J , Soerjomataram I , Siegel RL , Torre LA , Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.\nBray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 6 394 424 30207593\n[2] Denaro N , Russi EG , Merlano MC . Pros and cons of the new edition of TNM classification of head and neck squamous cell carcinoma. Oncology. 2018;95(4):202–10.\nDenaro N Russi EG Merlano MC Pros and cons of the new edition of TNM classification of head and neck squamous cell carcinoma Oncology 2018 95 4 202 10 29975952\n[3] Peng QX , Han YW , Zhang YL , Hu J , Fan J , Fu SZ , et al. Apatinib inhibits VEGFR-2 and angiogenesis in an in vivo murine model of nasopharyngeal carcinoma. Oncotarge. 2017;8:52813–22.\nPeng QX Han YW Zhang YL Hu J Fan J Fu SZ Apatinib inhibits VEGFR-2 and angiogenesis in an in vivo murine model of nasopharyngeal carcinoma Oncotarge 2017 8 52813 22.\n[4] Cannon RB , Sowder JC , Buchmann LO , Hunt JP , Hitchcock YJ , Lloyd S , et al. Increasing use of nonsurgical therapy in advanced-stage oral cavity cancer: a population-based study. Head Neck. 2017;39(1):82–91.\nCannon RB Sowder JC Buchmann LO Hunt JP Hitchcock YJ Lloyd S Increasing use of nonsurgical therapy in advanced-stage oral cavity cancer: a population-based study Head Neck 2017 39 1 82 91 27641220\n[5] Mesía R , Vázquez S , Grau JJ , García-Sáenz JA , Lozano A , García C , et al. A phase 2 open label, single‑arm trial to evaluate the combination of cetuximab plus taxotere, cisplatin, and 5‑flurouracil as an induction regimen in patients with unresectable squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2016;94(2):289–96.\nMesía R Vázquez S Grau JJ García-Sáenz JA Lozano A García C A phase 2 open label, single‑arm trial to evaluate the combination of cetuximab plus taxotere, cisplatin, and 5‑flurouracil as an induction regimen in patients with unresectable squamous cell carcinoma of the head and neck Int J Radiat Oncol Biol Phys 2016 94 2 289 96 26675064\n[6] Psyrri A , Seiwert TY , Jimeno A . Molecular pathways in head and neck cancer: EGFR, PI3K, and more. Am Soc Clin Oncol Educ Book. 2013;246–55.\nPsyrri A Seiwert TY Jimeno A Molecular pathways in head and neck cancer: EGFR, PI3K, and more Am Soc Clin Oncol Educ Book 2013 246 55 23714515\n[7] Vermorken JB , Mesia R , Rivera F , Remenar E , Kawecki A , Rottey S , et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27.\nVermorken JB Mesia R Rivera F Remenar E Kawecki A Rottey S Platinum-based chemotherapy plus cetuximab in head and neck cancer N Engl J Med 2008 359 11 1116 27 18784101\n[8] Mesía R . Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2010;21(10):1967–73.\nMesía R Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck Ann Oncol 2010 21 10 1967 73 20335368\n[9] Peng QX , Han YW , Zhang YL , Hu J , Fan J , Fu SZ , et al. Apatinib inhibits VEGFR-2 and angiogenesis in an in vivo murine model of nasopharyngeal carcinoma. Oncotarge. 2017;8:52813–22.\nPeng QX Han YW Zhang YL Hu J Fan J Fu SZ Apatinib inhibits VEGFR-2 and angiogenesis in an in vivo murine model of nasopharyngeal carcinoma Oncotarge 2017 8 52813 22.\n[10] Shen L , Chen S , Qiu Z , Qi H , Yuan H , Cao F , et al. Transarterial chemoembolization combined with apatinib versus transarterial chemoembolization alone for hepatocellular carcinoma with macroscopic vascular invasion: a propensity score matching analysis. J Cancer Res Ther. 2020;16(5):1063–8.\nShen L Chen S Qiu Z Qi H Yuan H Cao F Transarterial chemoembolization combined with apatinib versus transarterial chemoembolization alone for hepatocellular carcinoma with macroscopic vascular invasion: a propensity score matching analysis J Cancer Res Ther 2020 16 5 1063 8 33004748\n[11] Yu Z , Cai X , Xu Z , He Z , Lai J , Wang W , et al. Apatinib plus chemotherapy as a second-line treatment in unresectable non-small cell lung carcinoma: a randomized, controlled, multicenter clinical trial. Oncologist. 2020;25(11):e1640–9.\nYu Z Cai X Xu Z He Z Lai J Wang W Apatinib plus chemotherapy as a second-line treatment in unresectable non-small cell lung carcinoma: a randomized, controlled, multicenter clinical trial Oncologist 2020 25 11 e1640 9 32533785\n[12] Liao Z , Li T , Zhang C , Liu X , Xing R , Teng S , et al. Clinical study of apatinib in the treatment of stage IV osteogenic sarcoma after failure of chemotherapy. Cancer Biol Med. 2020;17(2):501–12.\nLiao Z Li T Zhang C Liu X Xing R Teng S Clinical study of apatinib in the treatment of stage IV osteogenic sarcoma after failure of chemotherapy Cancer Biol Med 2020 17 2 501 12 32587785\n[13] Liang L , Wang L , Zhu P , Xia Y , Qiao Y , Wu J , et al. A pilot study of apatinib as third-line treatment in patients with heavily treated metastatic colorectal cancer. Clin Colorectal Cancer. 2018;17(3):e443–9.\nLiang L Wang L Zhu P Xia Y Qiao Y Wu J A pilot study of apatinib as third-line treatment in patients with heavily treated metastatic colorectal cancer Clin Colorectal Cancer 2018 17 3 e443 9 29576426\n[14] Li N , Wang Z , Yuan G , Sun Y , Zhang R , Li X , et al. An oral small molecule VEGFR2 inhibitor, apatinib, in patients with recurrent or refractory cervical cancer: a real world study. J Oncol. 2020;2020:3852373.\nLi N Wang Z Yuan G Sun Y Zhang R Li X An oral small molecule VEGFR2 inhibitor, apatinib, in patients with recurrent or refractory cervical cancer: a real world study J Oncol 2020 2020 3852373 32655637\n[15] Meng M , Ye X , Yang X , Huang G , Wei Z , Ni Y , et al. Apatinib and S-1 combination therapy for the treatment of advanced head and neck neoplasms: three case reports. J Can Res Ther. 2019;15:442–6.\nMeng M Ye X Yang X Huang G Wei Z Ni Y Apatinib and S-1 combination therapy for the treatment of advanced head and neck neoplasms: three case reports J Can Res Ther 2019 15 442 6\n[16] Zhu X , Liu M , Lv J , Guo L , Li C , Dong L , et al. Good local tumor control but lethal hemorrhage after apatinib treatment for intractable squamous carcinoma of thefloor of the mouth: a case report. Onco Targets Ther. 2018;7(11):8909–13.\nZhu X Liu M Lv J Guo L Li C Dong L Good local tumor control but lethal hemorrhage after apatinib treatment for intractable squamous carcinoma of thefloor of the mouth: a case report Onco Targets Ther 2018 7 11 8909 13\n[17] Wang W , Zhang L , Xie Y , Zhen T , Su G , Zang Q . Fatal hemoptysis in patients with advanced esophageal cancer treated with apatinib. Onco Targets Ther. 2018;11:2565–70.\nWang W Zhang L Xie Y Zhen T Su G Zang Q Fatal hemoptysis in patients with advanced esophageal cancer treated with apatinib Onco Targets Ther 2018 11 2565 70 29765235\n\n",
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"issue": "16(1)",
"journal": "Open medicine (Warsaw, Poland)",
"keywords": "VEGFR-2; apatinib; head and neck squamous cell carcinoma; oral cancer",
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"pages": "1668-1672",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "30964124;32655637;27641220;18784101;26675064;20335368;29576426;29975952;28881773;29765235;32533785;30573977;32587785;33004748;23714515;30207593",
"title": "Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report.",
"title_normalized": "rapid response of locally advanced oral squamous cell carcinoma to apatinib a case report"
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"abstract": "Hypoglycemia presents relatively typical symptoms. However, when it occurs spontaneously - like in insulin autoimmune syndrome - it is difficult to perform scheduled biochemical tests at the laboratory. The study presents the case of a 31-year-old Caucasian female whose recurrent hypoglycemia symptoms were the reason for further diagnostics. The final results revealed a positive test for insulin autoantibody and glutamic acid decarboxylase autoantibody. Therefore, not only the potential causes of hypoglycemia but also an active autoimmune process typical for latent autoimmune diabetes in adults were confirmed. It was concluded that autoimmune hypoglycemia can be a part of the autoimmune process associated with diabetes and pre-diabetes in adults.",
"affiliations": "Medical Division, Department and Division of Medical Rehabilitation, Wroclaw Medical University, Wroclaw, Poland.;Clinical Department of Nephrology and Dialysis Station, Karol Marcinkowski University Hospital, Zielona Gora, Poland.;Medical Division, Wroclaw Medical University, Wroclaw, Poland.",
"authors": "Sutkowska|Edyta|E|0000-0002-1602-8978;Ostrowska|Malgorzata|M|;Sutkowska|Magdalena|M|",
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"fulltext": "\n==== Front\nDiabetes Metab Syndr Obes\nDiabetes Metab Syndr Obes\ndmso\ndmso\nDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy\n1178-7007\nDove\n\n302874\n10.2147/DMSO.S302874\nCase Report\nInsulin Autoimmune Syndrome as Part of Pre-Clinical LADA\nSutkowska et al\nSutkowska et al\nhttp://orcid.org/0000-0002-1602-8978\nSutkowska Edyta 1\nOstrowska Malgorzata 2\nSutkowska Magdalena 3\n1 Medical Division, Department and Division of Medical Rehabilitation, Wroclaw Medical University, Wroclaw, Poland\n2 Clinical Department of Nephrology and Dialysis Station, Karol Marcinkowski University Hospital, Zielona Gora, Poland\n3 Medical Division, Wroclaw Medical University, Wroclaw, Poland\nCorrespondence: Edyta Sutkowska Department and Division of Medical Rehabilitation, Wroclaw Medical University, Borowska 213, Wroclaw, 50-556, PolandTel +48 71 734 32 20 Email edyta.sutkowska@umed.wroc.pl\n09 4 2021\n2021\n14 15571561\n21 1 2021\n04 3 2021\n© 2021 Sutkowska et al.\n2021\nSutkowska et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nHypoglycemia presents relatively typical symptoms. However, when it occurs spontaneously – like in insulin autoimmune syndrome – it is difficult to perform scheduled biochemical tests at the laboratory. The study presents the case of a 31-year-old Caucasian female whose recurrent hypoglycemia symptoms were the reason for further diagnostics. The final results revealed a positive test for insulin autoantibody and glutamic acid decarboxylase autoantibody. Therefore, not only the potential causes of hypoglycemia but also an active autoimmune process typical for latent autoimmune diabetes in adults were confirmed. It was concluded that autoimmune hypoglycemia can be a part of the autoimmune process associated with diabetes and pre-diabetes in adults.\n\nKeywords\n\nautoimmune hypoglycemia\nlatent autoimmune diabetes\ninsulin autoantibodies\npre-clinical diabetes\n==== Body\nIntroduction\n\nThere are many factors causing hypoglycemia that are not related to hypoglycemic treatment. They include: pancreatic islets cell tumors, ectopic insulin secretion, paraneoplastic production of IGF-1 and IGF-2, autoimmunological failure of organs which can release glucose – liver or kidney, sepsis, undernutrition, inadequate secretion of cortisol, growth hormone, glucagon, epinephrine, alcohol overconsumption, or reactive factors, eg, functional hypoglycemia.1 Hypoglycemia is characterised by relatively typical symptoms resulting from the stimulation of the adrenergic system, and also from neuroglycopenia, if it persists for a longer period of time. Nonetheless, in order to confirm that the reported symptoms in fact result from a low glucose level, low concentration of glucose in blood should be confirmed by biochemical test and it should be simultaneously demonstrated that the symptoms subside after consumption of carbohydrates. Those typical symptoms form the criteria of Whipple’s triad.2,3 As most of the hypoglycemia cases other than those resulting from blood-glucose-lowering treatment occur spontaneously, it is difficult to predict situations in which they might occur and, therefore, plan the timely performance of biochemical tests at the laboratory.4 The situation when low glucose levels cannot be confirmed in the laboratory leads to the diagnosis being missed as the causes of hypoglycaemia are investigated only when hypoglycaemia is confirmed. On the other hand, due to the fact that most cases of hypoglycemia in the population of patients not receiving blood-glucose-lowering treatment stem from bad habits (for example, reactive hypoglycemia),2,3 many adult patients experience only mild symptoms which do not concern the patient or the physician in a considerable way.\n\nHyperinsulinemic hypoglycemia, known as Hirata’s disease or IAS (insulin autoimmune syndrome), can be one of the causes of hypoglycemia. It is a rare disease, especially in the Caucasian population.5,6 An interaction of the anti-idiotypic autoantibodies against IAA (insulin autoantibodies) could displace bound insulin from the insulin autoantibodies, resulting in hypoglycemia in patients who have not yet been diagnosed with diabetes and are not treated with insulin. The disease frequently undergoes self-remission, which can also be the reason for underdiagnosis. Meanwhile, it is known that IAA involved in the above-mentioned process play also an important role in the development of T1DM (type 1 diabetes mellitus). Moreover, IAA are present even in patients who have not been diagnosed with diabetes yet but who belong to the diabetes risk group. Being initial autoantibodies, they are encountered more frequently than GADA (Glutamic Acid Decarboxylase Autoantibodies) which usually appear at later stages of the autoaggression process.7 Although the IAA are associated with an early autoimmune process in children, they can also constitute autoantibodies in LADA (Latent Autoimmune Diabetes in Adults).8,9 Even though the autoimmunisation process is sometimes taken into consideration as the reason for hypoglycemia during the diagnostic process thereof, autoimmune hypoglycemia being the first pre-clinical symptom of autoimmune diabetes in the adult population has not been described so far.\n\nCase Presentation\n\nThe patient provided informed oral consent for the publication of her case details through teleconsultations (due to the risk of SARS-CoV-2 pandemic), which was recorded and witnessed. All the obtained data came directly from the patient; they were the patient’s property and were voluntarily provided by the patient to the authors, and thus the institutional approval was not required to publish this case details.\n\nA 31-year-old Caucasian female patient, BMI (body mass index): 26 kg/m2 in 2019 and 24.4 kg/m2 after approximately a year, who had been unsuccessfully trying to get pregnant for 4 years, was hospitalised due to periodically occurring symptoms consistent with hypoglycemia (hunger, trembling hands, excessive sweating, anxiety). The symptoms would occur after excessive physical effort or long breaks (length not specified) between meals, but sometimes also 2–3 hours after a meal, and would disappear after consuming simple carbohydrates. The patient’s family history revealed that her grandmother suffered from T2DM (type 2 diabetes mellitus). The patient did not consume alcohol and smoked approx. 10 cigarettes a day. To her knowledge, she was not suffering from any chronic diseases and she did not use any medications including those that may provoke IAS.5\n\nThe patient’s laboratory basic parameters were within the normal range (glucose, blood cell morphology, transaminases, creatinine, urea, uric acid, ionogram, magnesium, urine test, serum C-reactive protein, lipid profile, TSH – thyroid stimulating hormone), except for slightly elevated concentration of bilirubin, during the first and the second hospitalisation (1.6 and 1.45 mg/dl, respectively). Additional tests and parameters were also normal and included: thyroid ultrasound, abdominal ultrasound, anti- TPO (thyroid peroxidase), anti- TG (thyroglobulin), HbA1c (glycated hemoglobin). Daily in-hospital glycemic profiles measured using a glucometer (both postprandially and randomly) showed glucose levels between 83 and 113 mg/dl (4.62–6.28 mmol/l) but hypoglycemia signs or symptoms never occurred during the hospitalizations. The calculated HOMA IR was 0.87 for the results from the first period, during which metformin was not administered and were calculated from OGTT (0-1-2-3 hours): glucose: 78–178-111-91 mg% (4.3–9.9-6.2–5.1 mmol, respectively); insulin: 4.5–62.1–34.4–15.7 μU/mL. The fasting C-peptide level was 1.08 ng/mL. Based on the clinical picture and the patient’s results, the first diagnosis proposed was “hyperinsulinism without IR (insulin resistance)”, and behavioral treatment as well as metformin were recommended. The diagnosis, however, was changed to “reactive hypoglycemia” as the patient reported worsening of the symptoms between the first and second hospitalisation. Due to her poor tolerance of metformin (recurrent morning diarrhea, recurrent abdominal pain), the patient ceased to take the medicine and reported relief – but not resolution – of hypoglycemia signs and symptoms at the ambulatory follow-up visit. Glycemia measured at home with the use of a glucometer was not lower than 70 mg% (3.89 mmol) after the discontinuation of metformin, however, prior measurements (before the first hospitalisation as well as when patient was taking metformin) were not available. During the ambulatory follow-up visit the results of anti-GAD65kD were available (blood sample for the test was collected during the second hospitalisation), and were confirmed to be positive (anti-GAD = 653.8 IU/mL; N<10 IU/mL; ELISA - enzyme-linked immunosorbent assay method) by the negative results of other tests: ICAs (Islet Cell Cytoplasmic Autoantibodies; N<1:10, IFA-indirect immunofluorescence assay), anti-HBs (ECLIA – Electrochemiluminescence immunoassay method), HCV antibodies (ECLIA), ANA (AntiNuclear Antibodies, ELISA method). Due to the fact that the positive test result indicated an autoimmune process typical of diabetes mellitus, an ambulatory test for IAA and a repeated anti-GAD test were ordered. Results of both tests were positive (IAA = 0.59 U/mL; N<0.4 U/mL and anti-GAD = 526.6 IU/mL; ELISA method in both) and the final diagnosis – pre-clinical LADA – was made. The patient was told to regularly visit a diabetologist, conduct tests typical for DM diagnosis and follow the low glycemic index (GI) diet.\n\nTreatment\n\nAfter the first hospitalisation, which was followed by the proposed diagnosis, the patient was prescribed metformin, in an increasing dose from 500 to 1500mg. Even at the low dose, the prescribed treatment resulted in the occurrence of a much greater number of signs and symptoms of hypoglycemia as well as more side effects than before the beginning of the treatment. Therefore, the medication was withdrawn at an ambulatory visit after the second hospitalisation. Even though metformin can constitute a useful treatment in hyperinsulinism, primarily at the stage of prediabetes preceding T2DM, it can also cause exacerbation of hypoglycemia as it inhibits glucose release from the liver. In our opinion, therefore, there was no indication for metformin whatsoever, despite the previous suggested diagnosis of hyperinsulinism, due to the reported symptoms and signs of hypoglycemia, even if they were not biochemically confirmed.\n\nOutcome and Follow-Up\n\nAfter the discontinuation of metformin, the results of repeated ambulatory OGTT (after approximately 4 weeks) were as follows: 90–86-76 mg% (5.0–4.8-4.2 mmol, respectively) and insulin: 6.1-35-32.3 (uU/mL). The final fasting glucose (one week ago) was 120/6.67 (mg%/mmol). The patient is not undergoing any treatment, except for the implementation of healthy habits.\n\nDiscussion\n\nAccording to the current knowledge,10 the patient presents pre-clinical type of LADA which was confirmed by two positive tests for autoimmune diabetes mellitus. Reported symptoms of hypoglycemia, which were never biochemically confirmed, constituted the starting point for the initiation of the extended diagnostics. It is very unusual to start the diagnostic process without laboratory tests revealing a low level of glucose, and the case should be considered an incidental diagnosis, which is also confirmed by the unusual repeated results of anti-GAD (there is still insufficient information about the role of changes in titers of different autoantibodies), and unjustified use of metformin. However, the result of the final autoimmune test (IAA) can potentially explain hypoglycemia symptoms in the patient, and determine the diagnosis of Hirata’s disease. Although a big disproportion between the concentration of insulin and C-peptide, which is typical for autoimmune insulin syndrome, was not confirmed in the patient, it should be remembered that it depends on the time of the test (during the symptoms and biochemical hypoglycemia, which was the case of our patient), as well as on the laboratory assay used. However, the case fits into the proposed definition of IAS.10 Rare hypoglycemia occurred several months before pre-clinical LADA; it became the reason for the investigation, and finally - the diagnosis, despite the initial misdiagnosis. Although hypoglycemia could be considered as the result of the autoimmune process, it has not been observed to be the first symptom of autoimmune diabetes in the adult population so far. It stems from the fact that the symptoms of diabetes are related to and result from hyperglycemia, not hypoglycemia, and the presence of the detected autoantibodies does not always result in the development of the disease.11 To summarize, after obtaining positive results of the second autoantibody test, it was determined that the patient was at a high risk of typical latent autoimmune diabetes in the future, which is now defined as the first stage of the disease. The patient should control her glycemia on a regular basis and the measurement of C-peptide should be considered. Adequate insulin treatment should be initiated after the patient reaches the level of blood glucose concentration defined for DM. The spontaneous resolution of symptoms of hypoglycemia in IAS as well as gradual decrease in the concentration of endogenous insulin in LADA, which is responsible for lower production of antibodies to insulin, should be associated with gradual disappearance of hypoglycemia symptoms in the patient.\n\nThere is no indication that the patient should require insulin therapy.12 Also, metformin will not reduce the risk as there are no data that the medicine can protect beta cells from the autoimmune process. Due to the fact that the pathogenesis of LADA is known to include both autoimmunity and insulin resistance,13,14 behavioral treatment (diet and physical activity) should also be followed to maintain good insulin sensitivity and to protect patients from cardiovascular complications in the future.\n\nIn cases of recurrent symptoms typical of hypoglycemia, it seems advisable to deepen the diagnosis with atypical causes. In the absence of confirmation of reactive hypoglycemia, monitoring of blood glucose over several days using real-time continuous glucose monitoring – rtCGM, or intermittently scanned continuous glucose monitoring – isCGM, should be considered due to the paroxysmal and unpredictable nature of other types of hypoglycemia. Those methods could be also useful to prevent hypoglycemia episodes after diagnosis. When the autoimmune background of hypoglycemia is suspected, other autoimmune conditions should also be looked at. Behavioral treatment can be helpful in patients prone to low blood glucose levels. Frequent small meals low in carbohydrates during the day and cornstarch, which is slowly absorbed, in the evening to prevent night and/or fasting hypoglycemia should be recommended.15,16 Also, acarbose, which delays carbohydrate absorption, can be a useful option. Some severe cases may also require corticosteroids, rituximab, or even plasmapheresis.5\n\nConclusion\n\nThe symptoms of hypoglycemia led to further diagnostics that revealed not only the potential reasons for those symptoms but also an active autoimmune process typical for LADA.\n\nAlthough the low level of glucose was not detected during the accumulation of symptoms observed at the ambulatory visit, the typical course suggested that hypoglycemia was the reason. At least three diagnoses were proposed during the diagnostic process (hyperinsulinism without insulin resistance; reactive hypoglycemia; pre-clinical LADA) which is quite typical if the results do not clearly identify the disease. The rare Hirata disease was not considered during the diagnostic process, but eventually seemed to be associated with the whole clinical picture.\n\nAcknowledgments\n\nThe authors wish to thank the patient who expressed her consent for describing her case.\n\nFinancial support: Wroclaw Medical University\n\nBullet Points\n\n1. Hypoglycemia can constitute an indicator of pre-clinical LADA.\n\n2. Insulin autoantibodies should be assessed if symptoms of hypoglycemia are present.\n\n3. The autoimmune hypoglycemia can be a part of the autoimmune process associated with diabetes.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n\n1. Zatonska K, Bolanowski M. Hypoglycemia as a diagnostic problem. Adv Clin Exp Med. 2003;12 (3 ):369–373.\n2. Scheen AJ, Lefèbvre PJ. Reactive hypoglycaemia, a mysterious, insidious but non dangerous critical phenomenon. Rev Med Liege. 2004;59 (4 ):237–242.15182036\n3. Brun JF, Fedou C, Mercier J. Postprandial reactive hypoglycemia. Diabetes Metab. 2000;26 (5 ):337–351.11119013\n4. Censi S, Mian C, Betterle C. Insulin autoimmune syndrome: from diagnosis to clinical management. Ann Transl Med. 2018;6 (17 ):335. doi:10.21037/atm.2018.07.32 30306074\n5. Cappellani D, Macchia E, Falorni A, Marchetti P. Insulin autoimmune syndrome (Hirata Disease): a comprehensive review fifty years after its first description. Diabetes Metab Syndr Obes. 2020;13 :963–978. doi:10.2147/DMSO.S219438 32308449\n6. Wong SL, Priestman A, Holmes DT. Recurrent hypoglycemia from insulin autoimmune syndrome. J Gen Intern Med. 2014;29 (1 ):250–254. doi:10.1007/s11606-013-2588-9 23979685\n7. Ilonen J, Hammais A, Laine AP, et al. Patterns of β-cell autoantibody appearance and genetic associations during the first years of life. Diabetes. 2013;62 (10 ):3636–3640. doi:10.2337/db13-0300 23835325\n8. Orban T, Sosenko JM, Cuthbertson D, et al. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care. 2009;32 :2269–2274. doi:10.2337/dc09-0934 19741189\n9. Sosenko JM. Staging the progression to type 1 diabetes with prediagnostic markers. Curr Opin Endocrinol Diabetes Obes. 2016;23 (4 ):297–305. doi:10.1097/MED.0000000000000267 27362539\n10. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015;38 :1964–1974. doi:10.2337/dc15-1419 26404926\n11. Sørgjerd EP, Thorsby PM, Torjesen PA, Skorpen F, Kvaløy K, Grill V. Presence of anti-GAD in a non-diabetic population of adults; time dynamics and clinical influence: results from the HUNT study. BMJ Open Diabetes Res Care. 2015;3 :e000076. doi:10.1136/bmjdrc-2014-000076\n12. Buzzetti R, Tuomi T, Mauricio D, et al. Management of latent autoimmune diabetes in adults: a consensus statement from an international expert panel. Diabetes. 2020;69 (10 ):2037–2047. doi:10.2337/dbi20-0017 32847960\n13. Zhang Z, Li J, Yang L, et al. The cytotoxic role of intermittent high glucose on apoptosis and cell viability in pancreatic beta cells. J Diabetes Res. 2014;2014 :712781. doi:10.1155/2014/712781 24772447\n14. Löfvenborg JE, Ahlqvist E, Alfredsson L, et al. Genotypes of HLA, TCF7L2, and FTO as potential modifiers of the association between sweetened beverage consumption and risk of LADA and type 2 diabetes. European J Nutr. 2020;59 (1 ):127–135. doi:10.1007/s00394-019-01893-x 30656477\n15. Deguchi A, Okauchi Y, Suehara S, et al. Insulin autoimmune syndrome in health supplement user: the effectiveness of cornstarch therapy for treating hypoglycemia. Inter Med. 2013;552 :369–372. doi:10.2169/internalmedicine.52.7844\n16. Lechner K, Auliner B, Brand S, et al. Hydrothermally modified slow release corn starch: a potential new therapeutic option for treating hypoglycemia in autoimmune hypoglycemia (Hirata’s disease). Eur J Clin Nutr. 2015;69 :1369–1370. doi:10.1038/ejcn.2015.151 26373963\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7007",
"issue": "14()",
"journal": "Diabetes, metabolic syndrome and obesity : targets and therapy",
"keywords": "autoimmune hypoglycemia; insulin autoantibodies; latent autoimmune diabetes; pre-clinical diabetes",
"medline_ta": "Diabetes Metab Syndr Obes",
"mesh_terms": null,
"nlm_unique_id": "101515585",
"other_id": null,
"pages": "1557-1561",
"pmc": null,
"pmid": "33859486",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32308449;15182036;23835325;26157582;11119013;30656477;24772447;32847960;23370747;23979685;26404926;30306074;26373963;27362539;19741189",
"title": "Insulin Autoimmune Syndrome as Part of Pre-Clinical LADA.",
"title_normalized": "insulin autoimmune syndrome as part of pre clinical lada"
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"companynumb": "PL-NOVARTISPH-NVSC2021PL283383",
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"abstract": "OBJECTIVE\nTo evaluate the magnetic resonance imaging (MRI) of pediatric patients with infantile spasms (IS) treated with vigabatrin (VGB) in order to investigate whether VGB affects the brain.\n\n\nMETHODS\nOne hundred seven pediatric patients diagnosed with IS and treated with (n = 95) >or=120 mg/kg/day VGB or without (n = 12) VGB were included. MRI and diffusion-weighted imaging (DWI) were retrospectively analyzed.\n\n\nRESULTS\nOf the patients who had MRI scans during, but not before, VGB treatment (n = 81), 25 (30.9%) exhibited abnormal MRI signal intensity and/or restricted DWI in the deep gray nuclei and brainstem. Follow-up scans (performed in 15 of the 25 patients) revealed that these changes were reversible upon withdrawal of the medication. Analysis of patients undergoing scans before, during, and after VGB treatment (n = 14) revealed that four patients had abnormal MRI signal during treatment with VBG, two of whom reversed with cessation of VGB, one reversed without cessation of VGB, and another had persistent abnormal signal while being weaned from the VGB. Patients who had not received VGB treatment (n = 12) displayed normal imaging. Younger infants (<or=12 months) and those with cryptogenic IS were more likely to develop abnormal signal changes on MRI during VGB treatment.\n\n\nCONCLUSIONS\nIn pediatric patients, VGB induces reversible MRI signal changes and reversible diffusion restriction in the globi pallidi, thalami, brainstem, and dentate nuclei. The risk for this phenomenon was greater in younger infants and patients with cryptogenic IS.",
"affiliations": "Department of Ophthalmology & Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada. aphrodite.dracopoulos@gmail.com",
"authors": "Dracopoulos|Aphrodite|A|;Widjaja|Elysa|E|;Raybaud|Charles|C|;Westall|Carol A|CA|;Snead|O Carter|OC|",
"chemical_list": "D020888:Vigabatrin",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1528-1167.2010.02564.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "51(7)",
"journal": "Epilepsia",
"keywords": null,
"medline_ta": "Epilepsia",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D013036:Spasms, Infantile; D020888:Vigabatrin",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1297-304",
"pmc": null,
"pmid": "20384718",
"pubdate": "2010-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Vigabatrin-associated reversible MRI signal changes in patients with infantile spasms.",
"title_normalized": "vigabatrin associated reversible mri signal changes in patients with infantile spasms"
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{
"companynumb": "US-LUNDBECK-DKLU3030955",
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"activesubstancename": "VIGABATRIN"
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"abstract": "OBJECTIVE\nTo assess pregnancy outcomes on women exposed to monotherapy with antiepileptic agents.\n\n\nMETHODS\nQuestionnaires were sent to women with epilepsy in our practice who were pregnant between 2006 and 2011. 62/86 patients (72%) who responded were on monotherapy. 24 fetuses (63%) were exposed to lamotrigine, 11 (28%) to levetiracetam, 2 (5.2%) to topiramate, 1 (2.6%) to gabapentin, 17 (27%) to carbamazepine, 5 to phenytoin and 2 to valproate.\n\n\nRESULTS\nThere were 55 (88%) live births and 7 unsuccessful pregnancies (miscarriages/stillbirths). Unsuccessful pregnancies were reported in 2/24 gestations exposed to lamotrigine, 2/11 to levetiracetam and 3/17 to carbamazepine. Delayed motor development or speech delay requiring therapy and special programming was noted in 2/24 children prenatally exposed to lamotrigine, 3/17 exposed to carbamazepine and 1/2 children exposed to valproate.\n\n\nCONCLUSIONS\nOur pilot study of children exposed to antiepileptic drug monotherapy in-utero demonstrated a favorable trend for successful pregnancy outcomes and developmental trajectory.",
"affiliations": "Minnesota Epilepsy Group, P.A.(®) of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA. Electronic address: arkdimi@hotmail.com.;Minnesota Epilepsy Group, P.A.(®) of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA; Department of Neurology, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, USA.;Minnesota Epilepsy Group, P.A.(®) of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA; Department of Neurology, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, USA.;Minnesota Epilepsy Group, P.A.(®) of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA.;Minnesota Epilepsy Group, P.A.(®) of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA.;Minnesota Epilepsy Group, P.A.(®) of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA.;Minnesota Epilepsy Group, P.A.(®) of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA; Department of Neurology, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, USA.",
"authors": "Arkilo|Dimitrios|D|;Hanna|Julie|J|;Dickens|Deanna|D|;Justesen|Lorna|L|;Brunn|Jenny|J|;Garland|Sarah|S|;Penovich|Patricia|P|",
"chemical_list": "D000927:Anticonvulsants; D014815:Vitamins; D005492:Folic Acid",
"country": "England",
"delete": false,
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"issue": "19(1)",
"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": "Antiepileptic medication; Developmental outcomes; Pregnancy outcomes",
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D000927:Anticonvulsants; D002658:Developmental Disabilities; D005260:Female; D005492:Folic Acid; D006801:Humans; D007805:Language Development Disorders; D009422:Nervous System Diseases; D010865:Pilot Projects; D011247:Pregnancy; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D050497:Stillbirth; D011795:Surveys and Questionnaires; D014815:Vitamins",
"nlm_unique_id": "9715169",
"other_id": null,
"pages": "37-40",
"pmc": null,
"pmid": "25457510",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy and neurodevelopmental outcomes with in-utero antiepileptic agent exposure. A pilot study.",
"title_normalized": "pregnancy and neurodevelopmental outcomes with in utero antiepileptic agent exposure a pilot study"
} | [
{
"companynumb": "US-UCBSA-2014023297",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "FOLIC ACID"
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"... |
{
"abstract": "Aphasic status epilepticus (SE) is a clinical entity of SE, but it has not been well recognized. We report a 43-year-old female with a chronic drug-resistant epilepsy with aphasic SE, treated by resective surgery. The patient showed long-lasting weekly episodes of hypokinesia, slow verbal response, and dysphasia, which were diagnosed as symptoms of aphasic SE. Magnetic resonance imaging showed encephalomalacia in the left frontal lobe with a hemosiderin rim. Intracranial electroencephalography revealed continuous spikes, predominantly on the left superior frontal gyrus with hemosiderin deposit. The aphasic symptoms were seen when ictal discharges gradually spread to the wide area of the left anterior frontal lobe, including the language area. The episodes of recurrent aphasic SE had disappeared by one year after the left anterior frontal resection. We should consider aphasic SE when language impairment is episodic, and consider surgical intervention in cases where it repeatedly occurs despite appropriate medical therapy.",
"affiliations": "Department of Neurological Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.;Department of Neurological Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.;Department of Neurological Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.;Department of Neurological Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.;Department of Neurological Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.;Department of Neurological Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan.",
"authors": "Nakayama|Yukie|Y|;Nishibayashi|Hiroki|H|;Ozaki|Mitsunori|M|;Yamoto|Toshikazu|T|;Nakai|Yasuo|Y|;Nakao|Naoyuki|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ebr.2020.100359",
"fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864 Elsevier \n\nS2589-9864(20)30007-1\n10.1016/j.ebr.2020.100359\n100359\nArticle\nAphasic status epilepticus of frontal origin treated by resective surgery\nNakayama Yukie Nishibayashi Hiroki hirokin@wakayama-med.ac.jp⁎ Ozaki Mitsunori Yamoto Toshikazu Nakai Yasuo Nakao Naoyuki Department of Neurological Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan\n⁎ Corresponding author. hirokin@wakayama-med.ac.jp\n23 3 2020 \n2020 \n23 3 2020 \n14 1003592 10 2019 11 1 2020 12 2 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/).Aphasic status epilepticus (SE) is a clinical entity of SE, but it has not been well recognized. We report a 43-year-old female with a chronic drug-resistant epilepsy with aphasic SE, treated by resective surgery. The patient showed long-lasting weekly episodes of hypokinesia, slow verbal response, and dysphasia, which were diagnosed as symptoms of aphasic SE. Magnetic resonance imaging showed encephalomalacia in the left frontal lobe with a hemosiderin rim. Intracranial electroencephalography revealed continuous spikes, predominantly on the left superior frontal gyrus with hemosiderin deposit. The aphasic symptoms were seen when ictal discharges gradually spread to the wide area of the left anterior frontal lobe, including the language area. The episodes of recurrent aphasic SE had disappeared by one year after the left anterior frontal resection. We should consider aphasic SE when language impairment is episodic, and consider surgical intervention in cases where it repeatedly occurs despite appropriate medical therapy.\n\nHighlights\n• Long-lasting slow verbal response and dysphasia could be manifestations of aphasic status epilepticus of frontal origin\n\n• Epilepsy surgery should be considered for repeat aphasic SE under appropriate medical treatment after definite diagnosis\n\n• Precise time correlations between aphasic symptoms and ictal discharges could be unclear even by intracranial electroencephalography.\n\n\n\nAbbreviations\nSE, status epilepticusEEG, electroencephalogramNCSE, non-convulsive status epilepticusMRI, magnetic resonance imagingKeywords\nAphasic status epilepticusResective surgeryFrontal lobe\n==== Body\n1 Introduction\nA definition had been proposed for non-convulsive status epilepticus (NCSE): a change in behavior and/or mental status associated with 30 min of continuous epileptiform discharges in the electroencephalogram (EEG) [1]. A recent report proposed that emergency treatment should be initiated for focal status epilepticus (SE) with impaired consciousness at 10 min from onset [2]. NCSE is not able to be diagnosed from clinical signs alone. Therefore, emergent EEG is indispensable. Improvement of both clinical and EEG features with the administration of intravenous antiseizure medication may suggest a diagnosis of NCSE [3]. NCSE could be caused by various etiologies, including cerebral stroke [4], infection [5], metabolic disease [6,7], neurological disease [8], or epileptic syndrome as absence epilepsy [9]. It has a higher prevalence in the elderly population and in those with post-stroke epilepsy [4,10]. Aphasia may appear as a focal seizure [11], or as a symptom of SE. Aphasic SE has recently been included in the category of NCSE without coma, and sub-classified in focal SE [2]. Most reported cases with aphasic SE showed de novo onset and improved seizure outcomes with medical therapy [5,7,8,[12], [13], [14], [15], [16], [17], [18]]. However, to the best of our knowledge, no surgical cases via intracranial EEG recording have been reported for repeat aphasic SE. We report the case of a patient with weekly aphasic SE of frontal origin, in which a resective surgery was effective in controlling the aphasic SE.\n\n2 Case presentation\nA 43-year-old right-handed female was admitted to our hospital with a 10-year history of drug-resistant seizures. She showed normal mental and physical development. She reported severe headaches during the postpartum period, seven years previous to the seizure onset; although, no neuroimaging examinations were performed. Her seizures began at the age of 33. Her habitual seizures manifested as the following: a focal aware cognitive seizure (aphasia) with abrupt onset; a focal aware clonic seizure, lasting for over 30 min, on the right-side of her face and arm, followed by post-ictal paralysis; and a long-lasting loss of spontaneous speech and hypokinesia with obscure onset, which occurred intermittently for one to two days. During the long-lasting symptom, she often lay in bed throughout the day without eating. This occurred weekly in the last one year before admission to the hospital, despite polytherapy with carbamazepine, levetiracetam, clobazam and perampanel. Neurological examination revealed no abnormality. The Wechsler Adult Intelligence Scale - Third Edition revealed a low intelligence quotient (IQ) (full IQ: 69, verbal IQ: 69, performance IQ: 74). The Standard Language Test of Aphasia disclosed disturbances in word fluency, semantic comprehension, and calculation (Table 1). Long-term scalp video-EEG showed the patient's indifferent face impression, hypokinesia, decreased spontaneous speech, slow verbal response, and dysphasia with no obvious ictal onset. This occurred approximately when the bilateral frontal dominant continuous slow waves were recorded superimposed by spikes on Fp1, F3, C3 and F7. She could eat and perform activities of daily living during this time, however, this was done slowly. Her EEG findings and her verbal response markedly improved after an intravenous injection of diazepam. As this altered cognitive function continued for over 30 min, we diagnosed this long-lasting symptom as aphasic SE. Magnetic resonance imaging (MRI) showed encephalomalacia with a hemosiderin rim around the left superior frontal sulcus (Fig. 1\nupper right). Interictal [123]-iomazenil single-photon-emission computed tomography showed hypo-accumulation in the left frontal lobe, coincident with the MRI abnormality.Table 1 Preoperative and postoperative results of the Standard Language Test of Aphasia(SLTA).\n\nTable 1SLTA (standard language test of aphasia)\tPre-test\tPost-test\t\nI. Hearing\tAuditory word recognition\t10/10\t10/10\t\nAuditory sentence comprehension\t10/10\t10/10\t\nVerbal sequential commands\t10/10\t6/10\t\nSpeech sound-kana letter choice matching\t10/10\t10/10\t\nII. Speaking\tPicture naming\t18/20\t10/20\t\nWord repetition\t10/10\t10/10\t\nAction naming\t10/10\t5/10\t\nPicture story description\tStage 6\tStage 4\t\nSentence repetition\t5/5\t5/5\t\nAnimal category fluency\t13\t7\t\nOral reading of kanji word\t5/5\t5/5\t\nOral reading of kana letter\t10/10\t10/10\t\nOral reading of kana word\t5/5\t5/5\t\nOral reading of sentence\t5/5\t5/5\t\nIII. Reading\tWritten kanji word-picture choice matching\t10/10\t10/10\t\nWritten kana word-picture choice matching\t10/10\t10/10\t\nWritten sentence-picture choice matching\t9/10\t9/10\t\nWritten sequential commands\t10/10\t8/10\t\nIV. Writing\tWriting kanji names of pictures\t4/5\t1/5\t\nWriting kana names of picture\t5/5\t4/5\t\nWriting picture story\tStage 6\tStage 4\t\nWriting kana letter to dictation\t10/10\t10/10\t\nWriting kanji word to dictation\t4/5\t2/5\t\nWriting kana word to dictation\t5/5\t5/5\t\nWriting dictated sentences\t4/5\t4/5\t\nV. Calculation\t\t13/20\t10/20\t\nFig. 1 Left anterior frontal resection with preserved language related area.\n\nResection line (dotted line) and results of functional mapping.\n\nIII: third finger, V: fifth finger, SF: superior frontal, MF: middle frontal, IF: inferior frontal, OF: orbitofrontal, T: temporal.\n\nPreoperative and postoperative MRI.\n\nFig. 1\n\nConsidering the patient's seizure frequency and drug-resistance, we subsequently pursued epilepsy surgery localized by intracranial EEG monitoring using subdural electrodes. Intracranial EEG showed frequent spikes on the cortex around the cavity, as well as in the middle and inferior frontal gyri, and the orbitofrontal cortex (apparently without symptoms) (Fig. 2A). Subsequently, continuous spikes in these area were seen to coincide with unpleasant moods (Fig. 2B). The discharges then gradually spread to the posterior middle and inferior frontal gyri, at which she showed indifferent face impression, hypokinesia, decreased spontaneous speech, slow verbal response, and dysphasia (Fig. 2C). The clinical symptoms and EEG findings improved by oral administration of diazepam (Fig. 2D). The anterior language area was detected by direct electrical stimulation (rectangular biphasic 50 Hz, 0.2-millisecond pulse width, 1–5-second duration under 7 mA bipolar stimulation) (Fig. 1, left). With consideration of the extent of sustained spikes and the results of functional mapping, we performed the left anterior frontal resection beyond the MRI abnormality (Fig. 1, upper right). Aphasic SE and the other focal seizures have not been seen as of one year after surgery. However, one week after surgery, the Standard Language Test of Aphasia revealed decreased vocabulary, dysphasia and impaired semantic comprehension with dysgraphia, but she retained normal repetition ability (Table 1). Her speech disturbance was assessed as transcortical sensory aphasia, which improved with speech therapy over one month.Fig. 2 Intracranial EEG showed frequent spikes on the cortex around the cavity, also in the middle and inferior frontal gyri, and the orbitofrontal cortex (A), then continuous spikes in these area caused her unpleasant moods (B). The discharges then gradually spread to the posterior middle and inferior frontal gyri (C). An oral administration of diazepam led to improvement of clinical symptoms and EEG findings over time (D).\n\nFig. 2\n\n3 Discussion\nAphasia may be due to a focal seizure or as a symptom of SE. Epileptic aphasia was defined by Rosenbaum et al. with several criteria as follows: speaking during the seizure, aphasic features, alertness, and simultaneous EEG demonstrating seizure activity [19]. Grimes and Guberman reported a case of de novo aphasic SE and proposed a modification of this criteria including that aphasia should be resolved following successful treatment [17]. Recently, aphasic SE was classified in NCSE and sub-classified in NCSE without coma, focal type [2], although the duration of aphasic SE has not been precisely defined. In the present case, we documented the patient's long-lasting slow verbal response and dysphasia during the scalp Video-EEG monitoring. We diagnosed it as aphasic SE because her language fluency and facial impression recovered, corresponding with EEG improvement, due to an intravenous injection of diazepam.\n\nRegarding aphasic SE, various symptoms have been reported as follows: aphemia/stuttering [12], Wernicke type aphasia [13], severe aphasia [14], and global aphasia [20]. NCSE of frontal origin could manifest as affective indifference [21]. The results of intracranial EEG demonstrated her symptoms (e.g., decreased spontaneous speech, slow verbal response, dysphasia with accompanying indifferent facial impression, and hypokinesia), were of frontal origin. Meanwhile, her preserved consciousness could be explained by the thalamus or brainstem being spared from seizure propagation [22]; although, no depth electrodes were implanted in these deeper brain structures.\n\nThe majority of reported cases with aphasic SE showed de novo onset with various etiologies, such as a structural lesion, infection, metabolic disease, neurological disease, or upon antiseizure medication taper [[5], [6], [7], [8],[12], [13], [14],[15], [16], [17], [18],23,24]. Most of these cases had improved seizure outcomes with only medical therapies, if the underlying diseases were well treated. With our patient, however, epilepsy surgery was considered necessary because weekly aphasic SE had occurred over the last one year, despite appropriate use of medications. Recently, a child with drug-resistant epilepsy due to focal cortical dysplasia was successfully treated by complete lesionectomy; this was performed soon after the definite diagnosis of NCSE. Rapid cognitive decline of the patient in the last one year was considered to be related to frequent seizures and NCSE [25]. This clinical entity of aphasic SE is noteworthy; it presents the potential benefit from surgical intervention when disabling recurrent episodes are drug-resistant.\n\nWe performed intracranial EEG recordings as widespread epileptogenicity was suspected, involving language-related areas. It was challenging to decide the precise extent of the resection with the intracranial EEG findings alone during aphasic SE. Continuous spikes were recorded in the wide area of the left anterior frontal lobe, including the language area; although, precise time correlations between the aphasic symptoms and ictal discharges were at times less apparent. According to prior reports, electro-clinical correlation is sometimes unclear in aphasic SE [26], and aphasia may not correspond directly with the epileptiform activity [27]. Deciding on the border of resection considerably depended on the results of the brain anatomy and functional mapping.\n\nRegarding the etiology of encephalomalacia with hemosiderin deposit, a peripartum intracerebral hemorrhagic stroke was suspected at the previous hospital [28]; however, there was no brain computed tomography evidence to provide radiographic support. NCSE occurs more prevalently in the elderly population [4]. It may also develop in middle-aged adults, similar to our patient, due to cerebral stroke as cerebral strokes are the main cause of adult NCSE [4,10].\n\n4 Conclusion\nOur patient presented with unique symptoms due to aphasic SE of frontal origin. This was verified by intracranial EEG. A tailored left anterior frontal resection was effective to control the recurrent episodes of aphasic SE. This case of aphasic SE is remarkable and supports a successful approach from surgical intervention, which may be necessary in cases where aphasic SE is difficult to treat and repetitive resulting in patient disability.\n\nDeclaration of competing interest\nAll the authors have no conflict of interest.\n==== Refs\nReferences\n1 Meierkord H. Holtkamp M. Non-convulsive status epilepticus in adults: clinical forms and treatment Lancet Neurol 6 2007 329 339 17362837 \n2 Trinka E. Cock H. Hesdorffer D. Rossetti A.O. Scheffer I.E. Shinnar S. A definition and classification of status epilepticus –report of the ILAE Task Force on classification of status epilepticus Epilepsia 56 10 2015 1515 1523 26336950 \n3 Beniczky S. Hirsch L.J. Kaplan P.W. Pressler R. Bauer G. Aurlien H. Unified EEG terminology and criteria for nonconvulsive status epilepticus Epilepsia 54 Suppl. 6 2013 28 29 \n4 Knake S. Rosenow F. Vescovi M. Oertel W.H. Mueller H.H. Wirbatz A. Incidence of status epilepticus in adults in Germany: a prospective, population-based study Epilepsia 42 6 2001 714 718 11422324 \n5 Ozkaya G. Kurne A. Unal S. Oguz K.K. Karabudak R. Saygi S. Aphasic status epilepticus with periodic lateralized epileptiform discharges in a bilingual patient as a presenting sign of “AIDS-toxoplasmosis complex” Epilepsy Behav 9 2006 193 196 16697709 \n6 Monti G. Pugnaghi M. Ariatti A. Mirandola L. Giovannini G. Scacchetti S. Non-convulsive status epilepticus of frontal origin as the first manifestation of Hashimoto’s encephalopathy Epileptic Disord 13 3 2011 253 258 21896425 \n7 Kye M.S. Lee J.J. Kim B.K. Kwon O. Park J.M. Kang K. Aphasic status epilepticus associated with uremia J Epilepsy Res 7 2017 115 117 29344470 \n8 Trinka E. Unterberger I. Spiegel M. Niedermuller U. Benke T. Berger T. De novo aphasic status epilepticus as presenting symptom of multiple sclerosis J Neurol 249 2002 782 783 12173579 \n9 Scholtes F.B. Renier W.O. Meinardi H. Non-convulsive status epilepticus: causes, treatment, and outcome in 65 patients J Neurol Neurosurg Psychiatry 61 1996 93 95 8676169 \n10 Power K.N. Gramstad A. Gilhus N.E. Engelsen B.A. Adult nonconvulsive status epilepticus in a clinical setting: semiology, aetiology, treatment and outcome Seizure 24 2015 102 106 25458101 \n11 Fisher R.S. Cross H. D’Souza C. French J.A. Haut S.R. Higurashi N. Instruction manual for the ILAE 2017 operational classification of seizure types Epilepsia 58 4 2017 531 542 28276064 \n12 Kaplan P.W. Stagg R. Frontal lobe nonconvulsive status epilepticus: a case of epileptic stuttering, aphemia, and aphasia- not a sign of psychogenic nonepileptic seizures Epilepsy Behav 21 2011 191 195 21543261 \n13 Patil B. Oware A. De-novo simple partial status epilepticus presenting as Wernicke’s aphasia Seizure 21 2012 219 222 22115817 \n14 Dinner D.S. Luders H.O. Lederman R. Gretter T.E. Aphasic status epilepticus: a case report Neurology 31 1981 888 890 6165933 \n15 Chung P.W. Seo D.W. Kwon J.C. Kim H. Na D.L. Nonconvulsive status epilepticus presenting as a subacute progressive aphasia Seizure 11 2002 449 454 12237073 \n16 Caboclo L.O. De novo aphasic status epilepticus presenting with frontal periodic lateralized epileptiform discharges Clin Neurophysiol 127 2016 973 975 26002614 \n17 Grimes D.A. Guberman A. De novo aphasia status epilepticus Epilepsia 38 8 1997 945 949 9579898 \n18 Hamilton N.G. Matthews T. Aphasia: the sole manifestation of focal status epilepticus Neurology 29 1979 745 748 108612 \n19 Rosenbaum D.H. Siegel M. Barr W.B. Rowan A.J. Epileptic aphasia Neurology 36 1986 822 825 3703288 \n20 Flugel D. Kim O.C.H. Felbecker A. Tettenborn B. De novo status epilepticus with isolated aphasia Epilepsy Behav 49 2015 198 202 26044094 \n21 Thomas P. Zifkin B. Migneco O. Lebrun C. Darcourt J. Andermann F. Nonconvulsive status epilepticus of frontal origin Neurology 52 1999 1174 1183 10214739 \n22 Takaya S. Matsumoto R. Namiki C. Kiyosu H. Isono O. Hashikawa K. Frontal nonconvulsive status epilepticus manifesting somatic hallucinations J Neurol Sci 234 2005 25 29 15939437 \n23 Wells C.R. Labar D.R. Solomon G.E. Aphasia as the sole manifestation of simple partial status epilepticus Epilepsia 33 1 1992 84 87 1370801 \n24 Pasquet E.G. Gaudin E.S. Bianchi A. Mendilaharsu S. Prolonged and monosymptomatic dysphasic status epilepticus Neurology 26 1976 244 247 943053 \n25 Timer E. Charsouei S. Bebek N. Baykan B. Bilgic B. Sabanci P.A. Neurosurgical treatment of nonconvulsive status epilepticus due to focal cortical dysplasia Epilepsy Behav Case Rep 10 2018 4 7 30023174 \n26 Erikson E.J. Gerard E.E. Macken M.P. Schuele S.U. Aphasic status epilepticus: electroclinical correlation Epilepsia 52 8 2011 1452 1458 21627646 \n27 Quintas S. Rodriquez-Carrillo J.C. Toledano R. Toledo M. Barrero F.N. Berbis M.A. When aphasia is due to aphasic status epilepticus: a diagnostic challenge Neurol Sci 39 2018 757 760 29255963 \n28 Ohno Y. Kawai M. Morikawa S. Sakakibara K. Tanaka K. Ishikawa K. Management of eclampsia and stroke during pregnancy Neurol Med Chir (Tokyo) 53 2013 513 519 23979045\n\n",
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"journal": "Epilepsy & behavior reports",
"keywords": "Aphasic status epilepticus; EEG, electroencephalogram; Frontal lobe; MRI, magnetic resonance imaging; NCSE, non-convulsive status epilepticus; Resective surgery; SE, status epilepticus",
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"title": "Aphasic status epilepticus of frontal origin treated by resective surgery.",
"title_normalized": "aphasic status epilepticus of frontal origin treated by resective surgery"
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"abstract": "OBJECTIVE\nWe aim to report our experience managing cases of recurrent focal segmental glomerulosclerosis (FSGS) in a group of pediatric renal transplant recipients.\n\n\nMETHODS\nThis study was a retrospective chart review of pediatric patients who had their first kidney transplant at King Faisal Specialist Hospital & Research Center between 2014 and 2016.\n\n\nRESULTS\nWe reviewed the files of 6 patients, 3 of whom were male. The median age of the children was 2.75 years (range, 2-4 years) at disease onset, with an average time of progression to end-stage renal disease of 19 months (range, 8-30 months). Five of the patients received a living related donor transplant, and 1 received a living nonrelated donor transplant. Patients had FSGS recurrence at varying intervals (1 to 3 days) post transplant. All cases had plasmapheresis prior to receiving abatacept or rituximab. The therapeutic strategy in 4 patients involved switching tacrolimus to cyclosporine. A complete response was observed in 5 of the 6 patients (83.3%), and treatment was well tolerated in 5 patients. Patient 1 had severe oliguria and required intermittent hemodialysis during the first 3 weeks post transplant. He showed minimal response to the therapeutic plasma exchange and rituximab and was subsequently treated with abatacept. However, he died 8 months post transplant of pneumonia and sepsis.\n\n\nCONCLUSIONS\nRituximab and switching tacrolimus to cyclosporine, in conjunction with plasmapheresis, appeared to be effective and safe in children with recurrent FSGS. Conversely, abatacept did not appear to provide clinical benefit.",
"affiliations": "Department of Pediatrics, College of Medicine, King Saud University, King Khalid University Hospital, Riyadh, Saudi Arabia; Organ Transplant Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. Electronic address: kalhasan@ksu.edu.sa.;Department of Pediatrics, College of Medicine, King Saud University, King Khalid University Hospital, Riyadh, Saudi Arabia; Organ Transplant Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatrics, College of Medicine, King Saud University, King Khalid University Hospital, Riyadh, Saudi Arabia.;Pediatric Nephrology Center of Excellence and Department of Pediatrics, King Abdulaziz University, Jeddah, Saudi Arabia.;Organ Transplant Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.",
"authors": "Alhasan|K A|KA|;Alherbish|A|A|;Osman|A|A|;Kari|J A|JA|;Almojalli|H|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab; D000069594:Abatacept; D016572:Cyclosporine; D016559:Tacrolimus",
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"mesh_terms": "D000069594:Abatacept; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D010956:Plasmapheresis; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D000069283:Rituximab; D016559:Tacrolimus; D066027:Transplant Recipients",
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"title": "Successful Treatment of Recurrent Focal Segmental Glomerulosclerosis After Transplantation in Children: A Single-Center Experience.",
"title_normalized": "successful treatment of recurrent focal segmental glomerulosclerosis after transplantation in children a single center experience"
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"abstract": "BACKGROUND\nDiabetes insipidus (DI) is a disease resulting from defects in the arginine vasopressin system responsible for regulating body water homeostasis. It is characterized by polyuria with increased serum osmolality and sodium and can result from congenital or acquired disorders.\n\n\nMETHODS\nA baby was admitted to NICU for extreme prematurity (25 weeks gestation), extreme low birth weight (900 grams) and respiratory distress. He received one dose of Surfactant and was ventilated using high frequency jet ventilation for development of pulmonary interstitial emphysema. After nine days, he still required high settings with development of early chronic lung changes in the form of atelectasis. Therefore, he was started on a course of dexamethasone following the DART study protocol (Dexamethasone: A Randomized Trial). However, after six days (cumulative dose of 0.75 mg/kg/day) he developed polyuria (7.4 ml/kg/h) with increased serum sodium (150 mmol/L) and osmolality (348 mmol/L). He lost 85 grams of his weight in 24 hours, which represented a 9.8 %weight loss. The findings were suggestive of DI and given there were no apparent causes other than dexamethasone, it was discontinued. Over the following 48 hours, polyuria and hypernatremia gradually resolved, reaching 3.5 ml/kg/h, and 140 mmol/L respectively.\n\n\nCONCLUSIONS\nThe use of dexamethasone is not an uncommon practice in tertiary care neonatal units. To our knowledge, our case is the first report of neonatal DI secondary to the use of dexamethasone. We recommend closely monitoring urine output and serum electrolytes in preterm infants receiving dexamethasone.",
"affiliations": "Foothills Medical Centre, University of Calgary and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada.;Peter Lougheed Centre, University of Calgary, Calgary, Canada.;Foothills Medical Centre, University of Calgary and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada.",
"authors": "Eid|Haytham|H|;Al Awad|Essa|E|;Yusuf|Kamran|K|",
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"title": "A case of neonatal diabetes insipidus following dexamethasone for bronchopulmonary dysplasia.",
"title_normalized": "a case of neonatal diabetes insipidus following dexamethasone for bronchopulmonary dysplasia"
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"abstract": "We describe the clinical course of a 64-year-old woman with stage IVa lung adenocarcinoma who presented with over 1 month of fatigue, unintentional weight loss and emesis. She initiated treatment with nivolumab immunotherapy 1 year prior and had been tolerating the treatment well. A comprehensive workup revealed multiple endocrinological abnormalities consistent with hypophysitis leading to hypopituitarism in the form of central adrenal insufficiency and hypogonadism as well as a partially empty sella on imaging. This case demonstrates that while receiving novel forms of treatment such as immunotherapy, patients should be monitored closely for a wide range of adverse effects.",
"affiliations": "Internal Medicine, University of Southern California, Los Angeles, California, USA.;Internal Medicine, University of Southern California, Los Angeles, California, USA.;Internal Medicine, University of Southern California, Los Angeles, California, USA.;Hematology/Oncology, University of Southern California-Norris Comprehensive Cancer Center and Hospital, Los Angeles, California, USA.",
"authors": "Chang|Jeremy|J|;Tran|Jeffrey|J|;Kamel|Dina|D|;Basu|Arnab|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab; D006854:Hydrocortisone",
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"keywords": "lung cancer (oncology); pituitary disorders; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000309:Adrenal Insufficiency; D000893:Anti-Inflammatory Agents; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D004652:Empty Sella Syndrome; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D000072659:Hypophysitis; D007018:Hypopituitarism; D008175:Lung Neoplasms; D008875:Middle Aged; D000077594:Nivolumab; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
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"pmid": "30850565",
"pubdate": "2019-03-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Nivolumab-induced hypophysitis leading to hypopituitarism and secondary empty sella syndrome in a patient with non-small cell lung cancer.",
"title_normalized": "nivolumab induced hypophysitis leading to hypopituitarism and secondary empty sella syndrome in a patient with non small cell lung cancer"
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"abstract": "A 33-year-old man treated with azathioprine for 12 years for Crohn's disease presented with headache, nausea and vomiting accompanied by difficulty in putting words together and slight mental confusion. Prednisolone and antibiotics were without effect. MRI of the brain showed multiple focal lesions with surrounding oedema. There was cerebrospinal fluid pleocytosis, and Epstein-Barr virus (EBV) DNA was detected in the spinal fluid by PCR. A brain biopsy confirmed the suspicion of primary brain lymphoma. EBV-associated primary brain lymphoma is a relevant differential diagnosis in patients with long-standing immune suppression presenting with neurological symptoms. Detection of EBV DNA in the spinal fluid together with characteristic radiological findings may serve as a diagnostic clue for a quick diagnosis.",
"affiliations": "Department of Infectious Disease, Odense University Hospital, Odense, Denmark.;Department of Hematological Disease, Odense University Hospital, Odense, Denmark.;Department of Hematological Disease, Odense University Hospital, Odense, Denmark.;Department of Infectious Disease, Odense University Hospital, Odense, Denmark.",
"authors": "Glesner|Matilde Kanstrup|MK|;Ocias|Lukas Frans|LF|;Larsen|Thomas Stauffer|TS|;Pedersen|Court|C|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D001706:Biopsy; D001921:Brain; D001932:Brain Neoplasms; D003937:Diagnosis, Differential; D006801:Humans; D007166:Immunosuppressive Agents; D008228:Lymphoma, Non-Hodgkin; D008279:Magnetic Resonance Imaging; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25178893",
"pubdate": "2014-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24081592;22764018;14597744;23891975;23094824;18957891;17522336;21830262",
"title": "Primary CNS lymphoma in a patient treated with azathioprine.",
"title_normalized": "primary cns lymphoma in a patient treated with azathioprine"
} | [
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"companynumb": "DK-ROXANE LABORATORIES, INC.-2014-RO-01670RO",
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"abstract": "Treatment of autoimmune haemolytic anaemia is still a challenge to clinicians. Even today it may be lethal. Half of the cases are secondary due to an underlying disease, and the others are primary or idiopathic cases. According to the specificity and type of autoantibodies there are warm and cold type forms of autoimmune haemolytic anaemia. The hallmark of the diagnosis is to detect the presence of haemolysis by clinical and laboratory signs and detect the underlying autoantibodies. Treatment of autoimmune haemolytic anaemia is still a challenge to clinicians. We still loose patients due to excessive haemolysis or severe infections caused by immunosuppression. First line treatment is corticosteroids. Other immunosuppressive agents like: cyclophosphamide, azathioprine, cyclosporine or the off label rituximab can be used in case of corticosteroid refractoriness. Splenectomy is a considerable option in selective cases. The authors discuss treatment options and highlight difficulties by presenting 4 cases.",
"affiliations": "Debreceni Egyetem, Klinikai Központ, Általános Orvostudományi Kar Belgyógyászati Intézet, Hematológiai Tanszék Debrecen Nagyerdei krt. 98. 4032.;Debreceni Egyetem, Klinikai Központ, Általános Orvostudományi Kar Belgyógyászati Intézet, Hematológiai Tanszék Debrecen Nagyerdei krt. 98. 4032.;Debreceni Egyetem, Klinikai Központ, Általános Orvostudományi Kar Belgyógyászati Intézet, Hematológiai Tanszék Debrecen Nagyerdei krt. 98. 4032.;Debreceni Egyetem, Klinikai Központ, Általános Orvostudományi Kar Belgyógyászati Intézet, Hematológiai Tanszék Debrecen Nagyerdei krt. 98. 4032.;Debreceni Egyetem, Klinikai Központ, Általános Orvostudományi Kar Belgyógyászati Intézet, Hematológiai Tanszék Debrecen Nagyerdei krt. 98. 4032.;Debreceni Egyetem, Klinikai Központ, Általános Orvostudományi Kar Belgyógyászati Intézet, Hematológiai Tanszék Debrecen Nagyerdei krt. 98. 4032.;Debreceni Egyetem, Klinikai Központ, Általános Orvostudományi Kar Belgyógyászati Intézet, Hematológiai Tanszék Debrecen Nagyerdei krt. 98. 4032.",
"authors": "Nyilas|Renáta|R|;Székely|Borbála|B|;Váróczy|László|L|;Simon|Zsófia|Z|;Árokszállási|Anita|A|;Illés|Árpád|Á|;Gergely|Lajos|L|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D006454:Hemoglobins; D007166:Immunosuppressive Agents; D000069283:Rituximab; D016572:Cyclosporine; D003520:Cyclophosphamide; D001379:Azathioprine",
"country": "Hungary",
"delete": false,
"doi": "10.1556/OH.2015.30105",
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"issn_linking": "0030-6002",
"issue": "156(11)",
"journal": "Orvosi hetilap",
"keywords": "autoimmun haemolyticus anaemia; autoimmune haemolytic anaemia; bone marrow; csontvelő; infection; infekció; kezelés; lymphoma; rituximab; steroid; szteroid",
"medline_ta": "Orv Hetil",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune; D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D001379:Azathioprine; D003520:Cyclophosphamide; D016572:Cyclosporine; D005260:Female; D006454:Hemoglobins; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D000069283:Rituximab",
"nlm_unique_id": "0376412",
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"pages": "449-56",
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"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Autoimmune haemolytic anaemia: a review and report of four cases.",
"title_normalized": "autoimmune haemolytic anaemia a review and report of four cases"
} | [
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"activesubstancename": "CYCLOPHOSPHAMIDE"
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"abstract": "Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.\n\n\n\nA 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.\n\n\n\nCancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.",
"affiliations": "School of Medicine and Health Sciences, Internal Medicine Program, Fundación Cardioinfantil, Universidad del Rosario, Carrera 24 #63C-69, Bogotá, Colombia. ximena.morales@urosario.edu.co.;Fundación Cardioinfantil, Universidad del Bosque, Bogotá, Colombia.;Division of Cardiology, Fundación Cardioinfantil, Bogotá, Colombia.;Department of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.;School of Medicine and Health Sciences, Public Health Research Group, Universidad del Rosario, Bogotá, Colombia.",
"authors": "Morales|Ximena|X|0000-0002-8945-3625;Garnica|Diego|D|;Isaza|Daniel|D|;Isaza|Nicolas|N|;Durán-Torres|Felipe|F|",
"chemical_list": "D000970:Antineoplastic Agents; D065088:Steroid Synthesis Inhibitors; D000069501:Abiraterone Acetate",
"country": "England",
"delete": false,
"doi": "10.1186/s12872-021-01945-3",
"fulltext": "\n==== Front\nBMC Cardiovasc Disord\nBMC Cardiovasc Disord\nBMC Cardiovascular Disorders\n1471-2261\nBioMed Central London\n\n1945\n10.1186/s12872-021-01945-3\nCase Report\nSyncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation\nhttp://orcid.org/0000-0002-8945-3625\nMorales Ximena ximena.morales@urosario.edu.co\n\n1\nGarnica Diego 2\nIsaza Daniel 3\nIsaza Nicolas 4\nDurán-Torres Felipe 5\n1 grid.412191.e 0000 0001 2205 5940 School of Medicine and Health Sciences, Internal Medicine Program, Fundación Cardioinfantil, Universidad del Rosario, Carrera 24 #63C-69, Bogotá, Colombia\n2 grid.412195.a 0000 0004 1761 4447 Fundación Cardioinfantil, Universidad del Bosque, Bogotá, Colombia\n3 grid.488756.0 Division of Cardiology, Fundación Cardioinfantil, Bogotá, Colombia\n4 grid.239395.7 0000 0000 9011 8547 Department of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA USA\n5 grid.412191.e 0000 0001 2205 5940 School of Medicine and Health Sciences, Public Health Research Group, Universidad del Rosario, Bogotá, Colombia\n12 3 2021\n12 3 2021\n2021\n21 1368 9 2020\n4 3 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nAbiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.\n\nCase presentation\n\nA 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.\n\nConclusions\n\nCancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.\n\nKeywords\n\nProstatic neoplasms\nAbiraterone acetate\nLeuprolide\nAndrogen-deprivation\nVentricular tachycardia\nHypokalemia\nCase presentation\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nThe use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].\n\nAs is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].\n\nWe report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.\n\nCase presentation\n\nA 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.\n\nPhysical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP\n\nFig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)\n\nThe patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery\n\nThe patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).\n\nDiscussion and conclusions\n\nAbiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].\n\nAndrogen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].\n\nDespite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].\n\nMore recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.\n\nIncreased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.\n\nAbbreviations\n\nTdP Torsade de Pointes\n\nECG Electrocardiogram\n\nQTc QT interval corrected for heart rate\n\nFDA Food and Drug Administration\n\nBID bis in die (which means, in Latin, twice a day)\n\nQD quaque die (which means, in Latin, every day/daily\n\nNot applicable.\n\nAuthors' contributions\n\nXM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nData sharing does not apply to this article as no datasets were generated or analyzed during the current study.\n\nDeclarations\n\nCompeting interests\n\nAll authors declare that they have no competing interests.\n\nConsent for publication\n\nThe patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.\n\nEthics approval and consent to participate\n\nNot applicable.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nXimena Morales and Diego Garnica have contributed equally to this work.\n==== Refs\nReferences\n\n1. Cassinello J Arranz JÁ Piulats JM Sánchez A Pérez-Valderrama B Mellado B SEOM clinical guidelines for the treatment of metastatic prostate cancer (2017) Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex 2018 20 1 57 68\n2. Hoy SM Abiraterone acetate: a review of its use in patients with metastatic castration-resistant prostate cancer Drugs 2013 73 18 2077 2091 10.1007/s40265-013-0150-z 24271422\n3. Schrijvers D Abiraterone acetate in the treatment of metastatic castration-resistant prostate cancer: review of clinical data Clin Investig 2012 2 7 707 713 10.4155/cli.12.55\n4. Rehman Y Rehman Y Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer Drug Des Devel Ther. 2012 6 13 8 10.2147/DDDT.S15850\n5. Fizazi K Tran N Fein L Matsubara N Rodriguez-Antolin A Alekseev BY Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer N Engl J Med 2017 377 4 352 360 10.1056/NEJMoa1704174 28578607\n6. Buza V Rajagopalan B Curtis AB Cancer treatment-induced arrhythmias: focus on chemotherapy and targeted therapies Circ Arrhythm Electrophysiol 2017 10.1161/CIRCEP.117.005443 28798022\n7. Porta-Sánchez A Gilbert C Spears D Amir E Chan J Nanthakumar K Incidence, diagnosis, and management of QT prolongation induced by cancer therapies: a systematic review J Am Heart Assoc 2017 10.1161/JAHA.117.007724 29217664\n8. Zhu X Wu S Risk of hypertension in cancer patients treated with abiraterone: a meta-analysis Clin Hypertens 2019 25 1 12 10.1186/s40885-019-0116-x 31168403\n9. Iacovelli R Ciccarese C Bria E Romano M Fantinel E Bimbatti D The cardiovascular toxicity of abiraterone and enzalutamide in prostate cancer Clin Genitourin Cancer 2018 16 3 e645 e653 10.1016/j.clgc.2017.12.007 29339044\n10. Center for Drug Evaluation and Research. October - December 2018 | Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS). FDA [Internet]. 2019 Dec 20 [cited 2020 Jun 13]; Available from: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/october-december-2018-potential-signals-serious-risksnew-safety-information-identified-fda-adverse\n11. Khan A Kneale B Life threatening torsades de pointes due to abiraterone-induced hypokaelemia in a patient with metastatic prostate cancer N Z Med J 2016 129 1445 124 127 27857247\n12. Rodieux F Nieto N Sunthorn H John G Escher M Abiraterone acetate-induced life-threatening Torsade de Pointes Ann Pharmacother 2015 49 1 152 153 10.1177/1060028014555362 25524931\n13. Salem J-E Alexandre J Bachelot A Funck-Brentano C Influence of steroid hormones on ventricular repolarization Pharmacol Ther 2016 167 38 47 10.1016/j.pharmthera.2016.07.005 27452340\n14. Hu J-R Duncan MS Morgans AK Brown JD Meijers WC Freiberg MS Cardiovascular effects of androgen deprivation therapy in prostate cancer: contemporary meta-analyses Arterioscler Thromb Vasc Biol 2020 40 3 e55 64 10.1161/ATVBAHA.119.313046 31969015\n15. Lazzerini PE, Bertolozzi I, Acampa M, Cantara S, Castagna MG, Pieragnoli L, et al. Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes. Front Pharmacol [Internet]. 2020 May 13 [cited 2020 Dec 25];11. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239032/\n16. Salem J-E Waintraub X Courtillot C Shaffer CM Gandjbakhch E Maupain C Hypogonadism as a reversible cause of Torsade de Pointes in men Circulation 2018 138 1 110 113 10.1161/CIRCULATIONAHA.118.034282 29967236\n17. Gagliano-Jucá T Travison TG Kantoff PW Nguyen PL Taplin M-E Kibel AS Androgen deprivation therapy is associated with prolongation of QTc interval in men with prostate cancer J Endocr Soc 2018 2 5 485 496 10.1210/js.2018-00039 29761176\n18. Lu-Yao G Nikita N Keith SW Nightingale G Gandhi K Hegarty SE Mortality and hospitalization risk following oral androgen signaling inhibitors among men with advanced prostate cancer by pre-existing cardiovascular comorbidities Eur Urol 2020 77 2 158 166 10.1016/j.eururo.2019.07.031 31420248\n19. Lazzerini PE, Capecchi PL, El‐Sherif N, Laghi‐Pasini F, Boutjdir M. Emerging Arrhythmic Risk of Autoimmune and Inflammatory Cardiac Channelopathies. J Am Heart Assoc Cardiovasc Cerebrovasc Dis [Internet]. 2018 Nov 13 [cited 2020 Dec 25];7(22). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404431/\n20. Lazzerini PE Laghi-Pasini F Bertolozzi I Morozzi G Lorenzini S Simpatico A Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes Heart 2017 103 22 1821 1829 10.1136/heartjnl-2016-311079 28490617\n21. Tolcher AW Chi KN Shore ND Pili R Molina A Acharya M Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer Cancer Chemother Pharmacol 2012 70 2 305 313 10.1007/s00280-012-1916-9 22752297\n22. Verzoni E Grassi P Ratta R Niger M De Braud F Valdagni R Safety of long-term exposure to abiraterone acetate in patients with castration-resistant prostate cancer and concomitant cardiovascular risk factors Ther Adv Med Oncol 2016 8 5 323 330 10.1177/1758834016656493 27583024\n23. Moreira RB Debiasi M Francini E Nuzzo PV Velasco GD Maluf FC Differential side effects profile in patients with mCRPC treated with abiraterone or enzalutamide: a meta-analysis of randomized controlled trials Oncotarget 2017 8 48 84572 84578 10.18632/oncotarget.20028 29137449\n\n",
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"journal": "BMC cardiovascular disorders",
"keywords": "Abiraterone acetate; Androgen-deprivation; Case presentation; Hypokalemia; Leuprolide; Prostatic neoplasms; Ventricular tachycardia",
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"mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D000970:Antineoplastic Agents; D002304:Cardiac Pacing, Artificial; D005440:Fluid Therapy; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D065088:Steroid Synthesis Inhibitors; D013575:Syncope; D016171:Torsades de Pointes; D016896:Treatment Outcome",
"nlm_unique_id": "100968539",
"other_id": null,
"pages": "136",
"pmc": null,
"pmid": "33711933",
"pubdate": "2021-03-12",
"publication_types": "D002363:Case Reports",
"references": "29217664;29967236;29137449;27452340;31168403;24271422;25524931;22291466;27583024;32477142;31420248;29761176;28798022;31969015;28490617;29134562;28578607;27857247;22752297;29339044",
"title": "Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.",
"title_normalized": "syncope due to non sustained episodes of torsade de pointes associated to androgen deprivation therapy use a case presentation"
} | [
{
"companynumb": "CO-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-312915",
"fulfillexpeditecriteria": "1",
"occurcountry": "CO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL SUCCINATE"
},
... |
{
"abstract": "Right middle lobe (RML) syndrome is defined as recurrent or chronic obstruction or infection of the middle lobe of the right lung. Nonobstructive causes of middle lobe syndrome include inflammatory processes and defects in the bronchial anatomy and collateral ventilation. We report on 2 case patients with RML syndrome, one due to infection with Mycobacterium avium complex followed by M asiaticum infection and the other due to allergic bronchopulmonary aspergillosis. A history of atopy, asthma, or chronic obstructive pulmonary disease has been reported in up to one-half of those with RML. The diagnosis can be made by plain radiography, computed tomography, and bronchoscopy. Medical treatment consists of bronchodilators, mucolytics, and antimicrobials. Patients whose disease is unresponsive to treatment and those with obstructive RML syndrome can be offered surgical treatment.",
"affiliations": "Moffitt Cancer Center, Tampa, FL.;Department of Internal Hospital Medicine, Moffitt Cancer Center and University of South Florida Morsani College of Medicine, Tampa, FL.;Department of Infectious Diseases, Moffitt Cancer Center, Tampa, FL. John.Greene@Moffitt.org.",
"authors": "Rashid|Aatif|A|;Nanjappa|Sowmya|S|;Greene|John N|JN|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001993:Bronchodilator Agents",
"country": "United States",
"delete": false,
"doi": "10.1177/107327481702400110",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1073-2748",
"issue": "24(1)",
"journal": "Cancer control : journal of the Moffitt Cancer Center",
"keywords": null,
"medline_ta": "Cancer Control",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001229:Aspergillosis, Allergic Bronchopulmonary; D001993:Bronchodilator Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D008878:Middle Lobe Syndrome; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D011379:Prognosis",
"nlm_unique_id": "9438457",
"other_id": null,
"pages": "60-65",
"pmc": null,
"pmid": "28178715",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Infectious Causes of Right Middle Lobe Syndrome.",
"title_normalized": "infectious causes of right middle lobe syndrome"
} | [
{
"companynumb": "US-ORION CORPORATION ORION PHARMA-TREX2017-1151",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"druga... |
{
"abstract": "OBJECTIVE\nTo investigate potential drug-drug interactions between topiramate and metformin and pioglitazone at steady state.\n\n\nMETHODS\nTwo open-label studies were performed in healthy adult men and women. In Study 1, eligible participants were given metformin alone for 3 days (500 mg twice daily [BID]) followed by concomitant metformin and topiramate (titrated to 100mg BID) from days 4 to 10. In Study 2, eligible participants were randomly assigned to treatment with pioglitazone 30 mg once daily (QD) alone for 8 days followed by concomitant pioglitazone and topiramate (titrated to 96 mg BID) from days 9 to 22 (Group 1) or to topiramate (titrated to 96 mg BID) alone for 11 days followed by concomitant pioglitazone 30 mg QD and topiramate 96 mg BID from days 12 to 22 (Group 2). An analysis of variance was used to evaluate differences in pharmacokinetics with and without concomitant treatment; 90% confidence intervals (CI) for the ratio of the geometric least squares mean (LSM) estimates for maximum plasma concentration (Cmax), area under concentration-time curve for dosing interval (AUC12 or AUC24), and oral clearance (CL/F) with and without concomitant treatment were used to assess a drug interaction.\n\n\nRESULTS\nA comparison to historical data suggested a modest increase in topiramate oral clearance when given concomitantly with metformin. Coadministration with topiramate reduced metformin oral clearance at steady state, resulting in a modest increase in systemic metformin exposure. Geometric LSM ratios and 90% CI for metformin CL/F and AUC12 were 80% (75%, 85%) and 125% (117%, 134%), respectively. Pioglitazone had no effect on topiramate pharmacokinetics at steady state. Concomitant topiramate resulted in decreased systemic exposure to pioglitazone and its active metabolites, with geometric LSM ratios and 90% CI for AUC24 of 85.0% (75.7%, 95.6%) for pioglitazone, 40.5% (36.8%, 44.6%) for M-III, and 83.8% (76.1%, 91.2%) for M-IV, respectively. This effect appeared more pronounced in women than in men. Coadministration of topiramate with metformin or pioglitazone was generally well tolerated by healthy participants in these studies.\n\n\nCONCLUSIONS\nA modest increase in metformin exposure and decrease in topiramate exposure was observed at steady state following coadministration of metformin 500 mg BID and topiramate 100mg BID. The clinical significance of the observed interaction is unclear but is not likely to require a dose adjustment of either agent. Pioglitazone 30 mg QD did not affect the pharmacokinetics of topiramate at steady state, while coadministration of topiramate 96 mg BID with pioglitazone decreased steady-state systemic exposure to pioglitazone, M-III, and M-IV. While the clinical consequence of this interaction is unknown, careful attention should be given to the routine monitoring for adequate glycemic control of patients receiving this concomitant therapy. Concomitant administration of topiramate with metformin or pioglitazone was generally well tolerated and no new safety concerns were observed.",
"affiliations": "Janssen Research & Development, LLC, Raritan, NJ, USA. Electronic address: PManitpi@its.jnj.com.;Janssen Research & Development, LLC, Raritan, NJ, USA.;Janssen Research & Development, LLC, Raritan, NJ, USA.;Janssen Research & Development, LLC, Raritan, NJ, USA.;Janssen Research & Development, LLC, Raritan, NJ, USA.;Janssen Research & Development, LLC, Raritan, NJ, USA.",
"authors": "Manitpisitkul|Prasarn|P|;Curtin|Christopher R|CR|;Shalayda|Kevin|K|;Wang|Shean-Sheng|SS|;Ford|Lisa|L|;Heald|Donald|D|",
"chemical_list": "D000927:Anticonvulsants; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077236:Topiramate; D005632:Fructose; D008687:Metformin; D000077205:Pioglitazone",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "108(9)",
"journal": "Epilepsy research",
"keywords": "Drug–drug interactions; Metformin; Pharmacokinetics; Pioglitazone; Topiramate",
"medline_ta": "Epilepsy Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000927:Anticonvulsants; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005632:Fructose; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D000077205:Pioglitazone; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones; D013997:Time Factors; D000077236:Topiramate; D055815:Young Adult",
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "1519-32",
"pmc": null,
"pmid": "25219351",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacokinetic interactions between topiramate and pioglitazone and metformin.",
"title_normalized": "pharmacokinetic interactions between topiramate and pioglitazone and metformin"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US02046",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nIn the last 20 years of clinical practice, the senior author has identified these 2 rare cases in which the patients needed extremely high doses of drugs metabolized by CYP3A4 to reach and maintain serum therapeutic concentrations.\n\n\nMETHODS\nThe high metabolic ability of these 2 patients was demonstrated by the low concentration-to-dose ratios (C/D ratios) of several drugs metabolized by CYP3A4.\n\n\nRESULTS\nCase 1 was characterized by a history of high carbamazepine doses (up to 2,000mg/day) and needed 170 mg/day of diazepam in 2 days to cooperate with dental cleaning. The high activity of the CYP3A4 isoenzyme was manifested by fast metabolism for quetiapine and diazepam, which took more than 1 year to normalize after the inducer, phenytoin, was stopped. Case 2 was also very sensitive to CYP3A4 inducers as indicated by very low C/D ratios for carbamazepine, risperidone and paliperidone. The carbamazepine (2,800 mg/day) and risperidone (20 mg/day) dosages for this second patient are the highest doses ever seen for these drugs by the senior author. Risperidone induction appeared to last for many months and metabolism was definitively normal 3 years after stopping carbamazepine. On the other hand, olanzapine C/D ratios were normal for induction.\n\n\nCONCLUSIONS\nThe literature has never described similar cases of very high doses of drugs metabolized by CYP3A4. We speculate that these 2 patients may have unusual genetic profiles at the nuclear receptor levels; these receptors regulate induction of drugs.",
"affiliations": "Addictions Division, Centre for Addiction and Mental Health, Toronto, Canada.;Laboratory of Clinical Psychopharmacology, Beijing Key Lab of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China.;Eastern State Hospital, Lexington, Kentucky, USA.;Apalachee, Inc., Eastside Psychiatric Hospital, Tallahassee, Florida, USA.;Eastern State Hospital, Lexington, Kentucky, USA.;University of Kentucky Mental Health Research Center, Eastern State Hospital, Lexington, Kentucky, USA; Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain; Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Álava, Spain. Electronic address: jdeleon@uky.edu.",
"authors": "Chopra|Nitin|N|;Ruan|Can-Jun|CJ|;McCollum|Betsy|B|;Ognibene|Judy|J|;Shelton|Charles|C|;de Leon|Jose|J|",
"chemical_list": "D014150:Antipsychotic Agents; D065701:Cytochrome P-450 CYP3A Inducers; D002220:Carbamazepine; D010672:Phenytoin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003975:Diazepam",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.rcp.2018.07.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2530-3120",
"issue": "49(2)",
"journal": "Revista Colombiana de psiquiatria (English ed.)",
"keywords": "Carbamazepina; Carbamazepine; Diazepam; Drug interactions; Enzimas; Enzymes; Induction; Interacciones medicamentosas; Quetiapina; Quetiapine; Risperidona; Risperidone; inducción",
"medline_ta": "Rev Colomb Psiquiatr (Engl Ed)",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; D065701:Cytochrome P-450 CYP3A Inducers; D003975:Diazepam; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D010672:Phenytoin; D013997:Time Factors",
"nlm_unique_id": "101778593",
"other_id": null,
"pages": "84-95",
"pmc": null,
"pmid": "32446424",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers.",
"title_normalized": "high doses of drugs extensively metabolized by cyp3a4 were needed to reach therapeutic concentrations in two patients taking inducers"
} | [
{
"companynumb": "CA-BAUSCH-BL-2021-002785",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Modulation of T-cell activity through blockade of coinhibitory molecules has revolutionized the treatment of various malignancies. Several immune checkpoint inhibitors are currently Food and Drug Administration approved which target various coinhibitory pathways including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 receptor (PD-1), and programmed cell death ligand-1. Clinical trials that lead to the Food and Drug Administration approval of these agents often excluded patients with an organ transplant. Excluding these patients was deliberate due to concern that immune checkpoint inhibitor therapy could lead to graft rejection. The PD-1 and CTLA-4 pathways are essential to downregulate our immune system in the setting of T-cell activation to prevent autoimmunity. Furthermore, both pathways are implicated in transplanted organ tolerance and modulation of the pathways may inadvertently lead to peripheral transplant rejection. Currently, there are no guidelines for the treatment of patients with immune checkpoint inhibitors in the setting of a prior organ transplant. Thus far, there are only 10 reported cases of patients in the literature who were treated in this setting. Two additional cases are reported herein, including 1 patient with a prior cardiac transplant receiving nivolumab for non-small cell lung cancer. Of the 12 cases, 4 patients experienced organ rejection. From these observations, the authors hypothesize factors that affect safety and of this treatment modality in this patient population. These factors include the integral role of the PD-1 pathway compared with the CTLA-4 pathway in organ acceptance, sequential implementation of different immune checkpoint inhibitor classes, length of time with a transplant before therapy, strength of immunosuppressive agents to prevent organ transplant rejection, and immunogenicity of the particular organ grafted. Although limited cases have been reported, there are circumstances in which immune checkpoint inhibitors have been used in the setting of organ transplantation without resulting in organ rejection. A thorough discussion with the patient of the potential risks, including graft rejection, and benefits of this therapy is necessary before beginning this treatment. More research is needed to explore the safety and efficacy of immune checkpoint inhibitors in the setting of organ transplantation.",
"affiliations": "Departments of *Hematology and Medical Oncology†Internal Medicine, Oregon Health & Science University, Portland, OR.",
"authors": "Kittai|Adam S|AS|;Oldham|Hayden|H|;Cetnar|Jeremy|J|;Taylor|Matthew|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007166:Immunosuppressive Agents; D061026:Programmed Cell Death 1 Receptor",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000180",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "40(7)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000368:Aged; D000818:Animals; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D056747:Immunomodulation; D007166:Immunosuppressive Agents; D016609:Neoplasms, Second Primary; D016377:Organ Transplantation; D061026:Programmed Cell Death 1 Receptor; D016176:T-Lymphocyte Subsets; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "277-281",
"pmc": null,
"pmid": "28719552",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Immune Checkpoint Inhibitors in Organ Transplant Patients.",
"title_normalized": "immune checkpoint inhibitors in organ transplant patients"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-11877",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"druga... |
{
"abstract": "Breast and cervical cancer are the two most common cancers in female. However, owing to the contrasting risk factors, synchronous breast and cervical cancer has very rarely been reported. However, noncommunicable disease like cardiovascular disease and different infections has tended to make situations complicated because of complex interaction. In recent years, such cases are being seen frequently and their management is challenging. We report such a case of synchronous breast and cervical cancer complicated by HIV infection and myocardial infarction. This highlights the importance of a wide spectrum of clinical knowledge and skill and interdisciplinary coordination.",
"affiliations": "Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Thottian|Antony G|AG|;Mallick|Supriya|S|;Venkatesulu|Bhanuprasad|B|;Kumar|Ranjit|R|;Haresh|Kunhiparambath|K|;Gupta|Subhash|S|;Sharma|Daya Nand|DN|;Julka|Pramod Kumar|PK|;Rath|Goura Kishor|GK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/tbj.12718",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-122X",
"issue": "23(6)",
"journal": "The breast journal",
"keywords": "\nHIV\n; breast; cervix carcinoma; myocardial infraction; synchronous",
"medline_ta": "Breast J",
"mesh_terms": "D001943:Breast Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D015658:HIV Infections; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "9505539",
"other_id": null,
"pages": "731-735",
"pmc": null,
"pmid": "27886418",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Surviving Triple Trouble: Synchronous Breast and Cervical Cancer, HIV Infection and Myocardial Infarction.",
"title_normalized": "surviving triple trouble synchronous breast and cervical cancer hiv infection and myocardial infarction"
} | [
{
"companynumb": "IN-PFIZER INC-2017514150",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Drug reaction with eosinophilia and systemic symptom (DRESS) is a severe adverse drug-induced reaction with a prolonged latency period which is characterized by a variety of clinical manifestations, usually fever, rash, lymphadenopathy, eosinophilia, and a wide range of mild-to-severe systemic presentations. Drugs are an important cause of DRESS in most of the cases. It is challenging to diagnose DRESS because of the diversity of cutaneous eruption and visceral organs involvement. We hereby report a 34-year-old female who developed DRESS syndrome following ingestion of nitrofurantoin for the treatment of urinary tract infection. She was managed conservatively and recovered after few weeks. Our aim of this study is to raise awareness to suspect DRESS syndrome in patients who present with unusual clinical features with skin involvement after initiating any drug.",
"affiliations": "Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Microbiology, Institute of Medical Science, BHU, Varanasi, Uttar Pradesh, India.;Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India.",
"authors": "Singh|Jitendra|J|;Dinkar|Anju|A|;Atam|Virendra|V|;Gupta|Kamlesh K|KK|;Sahani|Krishna Kumar|KK|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/2279-042X.176560",
"fulltext": "\n==== Front\nJ Res Pharm PractJ Res Pharm PractJRPPJournal of Research in Pharmacy Practice2319-96442279-042XMedknow Publications & Media Pvt Ltd India JRPP-5-7010.4103/2279-042X.176560Case ReportDrug reaction with eosinophilia and systemic symptoms syndrome associated with Nitrofurantoin Singh Jitendra 1Dinkar Anju 2Atam Virendra 1Gupta Kamlesh K. 1Sahani Krishna Kumar 11 Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India2 Department of Microbiology, Institute of Medical Science, BHU, Varanasi, Uttar Pradesh, IndiaCorresponding author: Dr. Anju Dinkar, E-mail: anjudinkar@gmail.comJan-Mar 2016 5 1 70 73 9 2015 11 2015 Copyright: © Journal of Research in Pharmacy Practice2016This 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.Drug reaction with eosinophilia and systemic symptom (DRESS) is a severe adverse drug-induced reaction with a prolonged latency period which is characterized by a variety of clinical manifestations, usually fever, rash, lymphadenopathy, eosinophilia, and a wide range of mild-to-severe systemic presentations. Drugs are an important cause of DRESS in most of the cases. It is challenging to diagnose DRESS because of the diversity of cutaneous eruption and visceral organs involvement. We hereby report a 34-year-old female who developed DRESS syndrome following ingestion of nitrofurantoin for the treatment of urinary tract infection. She was managed conservatively and recovered after few weeks. Our aim of this study is to raise awareness to suspect DRESS syndrome in patients who present with unusual clinical features with skin involvement after initiating any drug.\n\nDrug reactiondrug reaction with eosinophilia and systemic symptom syndromeeosinophiliaNitrofurantoin\n==== Body\nINTRODUCTION\nNitrofurantoin is an antibacterial drug which was available in the 1950s.[1] It is frequently used in the treatment of urinary tract infections (UTIs). It is generally well-tolerated with common side effects including nausea and headache. The rare side effects are aplastic anemia, peripheral neuropathy, liver toxicity, pulmonary toxicity, and Stevens–Johnson syndrome (SJS).[2] Drug reaction with eosinophilia and systemic symptom (DRESS) due to nitrofurantoin may be life-threatening which is reported very rarely.[23]\n\nCASE REPORT\nA 34-year-old female patient was presented to our medicine emergency with acute skin rashes all over body for 4 days, fever for 3 days, and decreased urine output for 2 days, followed by dizziness. On detailed history, we found that she was on nitrofurantoin 100 mg thrice a day for UTI for 6 days, prescribed by a general physician. Her clinical status was worsening daily even though she continued nitrofurantoin. She was a known case of type II diabetes mellitus, and blood sugar was controlled with drugs. She had no history of asthma and similar episode in the past.\n\nPhysical examination revealed bilateral cheilitis [Figure 1] and pruriginous maculopapular eruptions with desquamation spread all over the body, predominantly over extremities [Figure 2a and b]. Vital signs were as temperature 102°F (febrile), pulse rate 102/min (tachycardia), respiratory rate 20/min (tachypnea), blood pressure 86/64 mmHg (hypotension), and SpO2 87%. The chest auscultation revealed bilateral crepitations. Abdominal palpation did not found organomegaly. Investigations are summarized in Table 1. Arterial blood gas analysis showed metabolic acidosis. Chest X-ray posterior-anterior view showed bilateral infiltrates. Urine analysis was normal. Serology of hepatitis A virus, hepatitis B surface antigen, and hepatitis C antibody were negative. Cultures of urine and blood were sterile. Result for antinuclear antibody was negative.\n\nFigure 1 Cheilitis over both angles of mouth\n\nFigure 2 (a and b) Maculopapular eruptions with desquamation seen on bilateral hands and lower limbs\n\nTable 1 Laboratory parameters of patient\n\nThe aforementioned case was in accordance with a clinical condition as DRESS syndrome associated with nitrofurantoin therapy involving the skin, kidneys, lungs, and hematological abnormalities. Severe skin reaction with systemic symptoms may be challenging to diagnose by clinicians because of clinically close differential diagnosis of toxic epidermal necrolysis and SJS. Dermatology opinion was taken, and the case was managed on the line of DRESS syndrome.\n\nOnce the diagnosis was established with the help of clinical features and investigations, nitrofurantoin was stopped immediately. She was treated with intravenous corticosteroid and antihistamine. Broad-spectrum antibiotics were also administered for a possible sepsis. Blood pressure increased to normal on intravenous fluids. Supportive therapy for the management of the skin and temperature were done during hospitalization. Vitals were monitored closely. Urine production increased on the same day and was in adequate amount the next day. Renal and liver functions and hematological abnormalities normalized subsequently. Skin lesions subsided the following days. She made an uneventful recovery, and no sequelae were found during subsequent follow-up for 2 months.\n\nDISCUSSION\nIn 1950, Chaiken described DRESS syndrome first, and he called it the drug-induced hypersensitivity syndrome. It has an incidence of 1 in 1000–10,000 exposures to drug and death rate of about 10%.[4] In 1996, Bocquet introduced first the acronym “drug rash with eosinophilia and systemic symptoms” to describe patients exhibiting a drug-induced condition characterized by an extensive rash, fever, lymphadenopathy, hematological abnormalities, hepatitis, and involvement of the kidneys, lungs, heart, or pancreas.[5] It may appear in an acute fashion or with a delayed onset (2–6 weeks after drug administration.[2] The cutaneous manifestations in DRESS are urticaria, maculopapular eruption; however, in some instances, vesicles, bullae, pustules, purpura, target lesions, facial edema, cheilitis, and erythroderma may be there.[6] Lesions may later become exfoliated. Desquamation/scaling may occur with healing.[7] While, visceral involvement are as hepatitis, pneumonitis, myocarditis, pericarditis, nephritis, and colitis which remains the major cause of morbidity and mortality in this syndrome. Hematological manifestations may be leukocytosis with eosinophilia (90%) and/or mononucleosis (40%).[6] Literature has showed has that the severity of organ dysfunction does not always correlate with the extent of skin involvement.[7]\n\nAll kinds of drugs can be involved. This syndrome is most frequently seen in association with anticonvulsants and antibiotic agents. A number of drugs including anticonvulsants-carbamazepine (phenytoin, lamotrigine, zonisamide, and phenobarbital), antibiotic agents (sulfonamides, minocycline, and cefadroxil), anti-inflammatory agents (salazosulfapyridine and sulfasalazine), antiretroviral drugs (nevirapine and abacavir), and others–fluoxetine, calcium channel blockers, imatinib, nonsteroidal anti-inflammatory drugs, allopurinol, mexiletine, hydroxychloroquine, esomeprazole, efalizumab, ranitidine, sorbinil, gold salt, zalcitabine, thalidomide, and dapsone.[3]\n\nThe diagnostic criteria are based on clinical and laboratory findings as mentioned [Table 2].[6] DRESS syndrome can be diagnosed if all three of following criteria are present. These are (1) cutaneous eruption; (2) absolute eosinophilia (≥1500/μl) with or without atypical lymphocytes; and (3) systemic involvement (lymphadenopathy ≥2 cm, aspartate aminotransferase ≥2 × upper limit, interstitial nephritis, interstitial pneumonitis, or carditis).[3] The skin biopsy may support diagnosis though nonspecific. The skin biopsy findings may be lymphocytic infiltrate with or without eosinophils in the papillary layer of the dermis.[7]\n\nTable 2 Diagnostic criteria of DRESS syndrome\n\nThe pathogenesis of DRESS syndrome is not well clear and is hypothesized to consist of a complex interaction of the following which includes detoxification defects leading to reactive metabolite formation and subsequent immunological reactions slow acetylation, and reactivation of human herpes including Epstein–Barr virus and human herpesvirus-6 and -7. Other types of viral infection were also reported such as cytomegalovirus reactivation and paramyxovirus infection. It is increasingly apparent that there is a genetic predisposition to adverse drug reactions. It is hoped that further research may define pharmacogenetic disease susceptibility markers to identify people at high risk of developing HSS/DRESS.[5] The DRESS syndrome is treated with corticosteroids in a most of the cases. Corticosteroids inhibit eosinophilic accumulation. It is thought that organ involvement is due to eosinophilic accumulation which acts probably by inhibition of interleukin 5. Unfortunately, use of corticosteroids in the management of DRESS is not well-supported by strong evidence-based data.[8] Our case fulfilled the diagnostic criteria of DRESS syndrome with dermatology opinion. To our best knowledge, there are only few cases of nitrofurantoin-induced DRESS syndrome and no report from India.[23]\n\nMany drugs have been reported causing DRESS syndrome in India; at present, nitrofurantoin has also included in this category. Early diagnosis with appropriate management improves prognosis. Therefore, the patient must be counseled for an adverse reaction before starting any drug.\n\nAUTHORS’ CONTRIBUTION\nThis manuscript is designed, studied, prepared and reviewed by all contributors.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Gupta K Trautner BW Longo DL Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo J Urinary tract infection, pyelonephriti, and prostitis Harrison's Principles of Internal Medicine 2012 18th ed New York McGraw Hill 2387 95 \n2 Leão RN Barreto P Leão RR Ribeiro JV Nitrofurantoin: Cause of DRESS syndrome BMJ Case Rep 2013 2013 pii: Bcr2013008991 \n3 Velema MS Voerman HJ DRESS syndrome caused by nitrofurantoin Neth J Med 2009 67 147 9 19581659 \n4 E L omairi N Abourazzak S Chaouki S Atmani S Hida M Drug reaction with eosinophilia and systemic symptom (DRESS) induced by carbamazepine: A case report and literature review Pan Afr Med J 2014 18 9 25360193 \n5 Bocquet H Bagot M Roujeau JC Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug rash with eosinophilia and systemic symptoms: DRESS) Semin Cutan Med Surg 1996 15 250 7 9069593 \n6 Choudhary S McLeod M Torchia D Romanelli P Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome J Clin Aesthet Dermatol 2013 6 31 7 23882307 \n7 Agu CC Basheer H DRESS syndrome associated with allopurinol Int J Case Rep Images 2014 5 145 9 \n8 Roujeau JC Stern RS Severe adverse cutaneous reactions to drugs N Engl J Med 1994 331 1272 85 7794310\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2279-042X",
"issue": "5(1)",
"journal": "Journal of research in pharmacy practice",
"keywords": "Drug reaction; Nitrofurantoin; drug reaction with eosinophilia and systemic symptom syndrome; eosinophilia",
"medline_ta": "J Res Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "101614023",
"other_id": null,
"pages": "70-3",
"pmc": null,
"pmid": "26985439",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "25360193;23661654;9069593;19581659;7794310;23882307",
"title": "Drug reaction with eosinophilia and systemic symptoms syndrome associated with Nitrofurantoin.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms syndrome associated with nitrofurantoin"
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"abstract": "Fixed and dilated pupils are disturbing when encountered during a physical examination in the pediatric intensive care unit, particularly when sedation or neuromuscular blockade confounds the neurologic examination. Rocuronium, a nondepolarizing neuromuscular drug, does not cross the blood-brain barrier and is not considered a causative agent for fixed mydriasis. We report a case of bilateral fixed and dilated pupils in a 1-week-old low-birth-weight neonate, which we contend was secondary to centrally mediated neuromuscular blockade.",
"affiliations": "From the Division of Pediatric Critical Care Medicine, Weill Cornell Medical College, New York, New York.",
"authors": "Joyce|Christine|C|;Greenwald|Bruce M|BM|;Han|Peggy|P|",
"chemical_list": "D000732:Androstanols; D003473:Neuromuscular Nondepolarizing Agents; D000077123:Rocuronium",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000306",
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"issn_linking": "2325-7237",
"issue": "6(9)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000732:Androstanols; D004385:Duodenostomy; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D015878:Mydriasis; D003473:Neuromuscular Nondepolarizing Agents; D011183:Postoperative Complications; D000077123:Rocuronium",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "286-7",
"pmc": null,
"pmid": "27002754",
"pubdate": "2016-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral Dilated Nonreactive Pupils in a Neonate After Surgery.",
"title_normalized": "bilateral dilated nonreactive pupils in a neonate after surgery"
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"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
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{
"abstract": "OBJECTIVE\nPatients with rheumatoid arthritis (RA) and other systemic rheumatic diseases (SRDs) are at increased risk of developing herpes zoster (HZ). Zoster recombinant adjuvanted (ZRA) is a recombinant vaccine approved by the Food and Drug Administration in 2018. Concern has been raised that the ZRA may trigger disease flares in rheumatology patients who are immunocompromised. We investigated the impact of the ZRA vaccine in patients with RA and SRD and measured the incidence of flares and side effects.\n\n\nMETHODS\nA flare was defined as occurring within 12 weeks of vaccine administration by either 1) documentation of RA flare in office notes, telephone encounter, or patient portal communication or 2) new or increased dose of corticosteroids.\n\n\nRESULTS\nWe identified 403 patients (239 patients with RA and 164 patients with SRD) who received the ZRA vaccine from February 1, 2018, to February 1, 2019. We measured a 6.7% (n = 27) incidence of flare. Side effects occurred in 12.7% (n = 51) of patients. All flares and side effects were regarded as mild. Three cases of HZ were reported as occurring 2, 10, and 11 months after the vaccination.\n\n\nCONCLUSIONS\nIn 403 patients who received the ZRA vaccine, the incidence of disease flares was 7% or less and that of side effects was 13% or less, both of which are less than the incidence rates observed in the pivotal trials.",
"affiliations": "Brigham and Women's Hospital Boston, Massachusetts.;Brigham and Women's Hospital Boston, Massachusetts.;Brigham and Women's Hospital Boston, Massachusetts.;Brigham and Women's Hospital Boston, Massachusetts.;Brigham and Women's Hospital and Massachusetts General Hospital, Boston.;Brigham and Women's Hospital Boston, Massachusetts.",
"authors": "Stevens|Emma|E|https://orcid.org/0000-0002-0338-4439;Weinblatt|Michael E|ME|;Massarotti|Elena|E|;Griffin|Frances|F|;Emani|Srinivas|S|;Desai|Sonali|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/acr2.11150",
"fulltext": "\n==== Front\nACR Open Rheumatol\nACR Open Rheumatol\n10.1002/(ISSN)2578-5745\nACR2\nACR Open Rheumatology\n2578-5745 John Wiley and Sons Inc. Hoboken \n\n10.1002/acr2.11150\nACR211150\nBrief Report\nBrief Report\nSafety of the Zoster Vaccine Recombinant Adjuvanted in Rheumatoid Arthritis and Other Systemic Rheumatic Disease Patients: A Single Center's Experience With 400 Patients\nSafety of Zoster Vaccine Recombinant AdjuvantedSTEVENS ET ALStevens Emma BAhttps://orcid.org/0000-0002-0338-4439\n1\n Weinblatt Michael E. MD\n1\n Massarotti Elena MD\n1\n Griffin Frances RN\n1\n Emani Srinivas PhD\n2\n Desai Sonali MD, MPH\n1\nsdesai5@bwh.harvard.edu \n1 \nBrigham and Women's Hospital Boston\nMassachusetts\n\n\n2 \nBrigham and Women's Hospital and Massachusetts General Hospital\nBoston\n\n* Address correspondence to Sonali Desai, MD, MPH, Brigham & Women's Hospital, Division of Rheumatology, Immunology, and Allergy, Department of Medicine, 60 Fenwood Road, Hale Building, 3rd Floor, Rheumatology Offices, Boston, MA 02215. E‐mail: sdesai5@bwh.harvard.edu.\n15 5 2020 \n6 2020 \n2 6 10.1002/acr2.v2.6357 361\n12 12 2019 14 4 2020 © 2020 The Authors. ACR Open Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Objective\nPatients with rheumatoid arthritis (RA) and other systemic rheumatic diseases (SRDs) are at increased risk of developing herpes zoster (HZ). Zoster recombinant adjuvanted (ZRA) is a recombinant vaccine approved by the Food and Drug Administration in 2018. Concern has been raised that the ZRA may trigger disease flares in rheumatology patients who are immunocompromised. We investigated the impact of the ZRA vaccine in patients with RA and SRD and measured the incidence of flares and side effects.\n\nMethods\nA flare was defined as occurring within 12 weeks of vaccine administration by either 1) documentation of RA flare in office notes, telephone encounter, or patient portal communication or 2) new or increased dose of corticosteroids.\n\nResults\nWe identified 403 patients (239 patients with RA and 164 patients with SRD) who received the ZRA vaccine from February 1, 2018, to February 1, 2019. We measured a 6.7% (n = 27) incidence of flare. Side effects occurred in 12.7% (n = 51) of patients. All flares and side effects were regarded as mild. Three cases of HZ were reported as occurring 2, 10, and 11 months after the vaccination.\n\nConclusion\nIn 403 patients who received the ZRA vaccine, the incidence of disease flares was 7% or less and that of side effects was 13% or less, both of which are less than the incidence rates observed in the pivotal trials.\n\n source-schema-version-number2.0cover-dateJune 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:18.06.2020Dr. Weinblatt's work is supported by research grants from Amgen, Bristol Myers Squibb, Eli Lilly and Company, Crescendo Bioscience, and Sanofi.\n\nEmma Stevens, BA, Michael E. Weinblatt, MD, Elena Massarotti, MD, Frances Griffin, RN, Sonali Desai, MD, MPH: Brigham and Women's Hospital Boston, Massachusetts; 2Srinivas Emani, PhD: Brigham and Women's Hospital and Massachusetts General Hospital, Boston.\n\nDr. Weinblatt owns stock/ownership at Lycera, Vorso, Scipher, Inmedix and Canfite and is a consultant for Abbvie, Amgen, Bristol Myers Squibb, Canfite, Corrona, Crescendo Bioscience, Eli Lilly and Company, Gilead, Glaxo‐Smith Kline, Horizon, Johnson and Johnson, Merck, Novartis, Pfizer, Roche, Samsung Bioepis Co, Ltd, Sanofi, Scipher, and Set Point (more than $10,000 each). Dr. Massarotti is a consultant for Exagen, Sanofi, Bristol Myers Squibb, Union Chimique Belge, and EMD Serono. No other disclosures relevant to this article were reported.\n==== Body\nSignificance & Innovations\n\n\nThis manuscript is the first to report on the experience with the zoster recombinant adjuvanted (ZRA) vaccine in patients with systemic rheumatic diseases, especially rheumatoid arthritis (RA), and examines the rate of disease flares, vaccination reactions, and occurrence of zoster.\n\nPivotal trials of ZRA excluded patients who were known to be immunocompromised; this study supports the use of this vaccine among rheumatology patients exposed to immunosuppressive medications.\n\nOur findings of a disease flare rate of less than 7% and of side effects in less than 13% of immunocompromised rheumatology patients informs clinical decision‐making in the real world; these rates are low, considering a 30% background incidence of RA disease flare observed in our RA registry at Brigham and Women's Hospital over a 6‐month period.\n\n\n\n\n\n\n\nINTRODUCTION\nWith an estimated one‐million new cases of shingles within the United States annually, herpes zoster (HZ) is a prominent public health concern for patients taking immunosuppressive therapies 1, 2. Vaccination preventing HZ is now recommended by the US Center for Disease Control for adults over the age of 50 2.\n\nImmunosuppressant medications used to treat rheumatoid arthritis (RA) and other systemic rheumatic diseases (SRDs) (corticosteroids, methotrexate, biologic disease‐modifying agents, and janus kinase inhibitors) can increase the incidence of HZ 3, 4. The dermatomal rash seen in HZ may be more prolonged and severe in patients with RA or other SRDs 5, 6. The risk of more severe neurologic complications, including myelitis, chronic encephalitis, meningoencephalitis, and cranial palsies, is heightened in this population 7. Furthermore, cutaneous dissemination is seen commonly in patients who are immunosuppressed 8.\n\nA live attenuated vaccine was approved by the Food and Drug Administration (FDA) for HZ prevention in 2006 for adults age 60 or older 2. Although the efficacy of the vaccine differed throughout age groups, the overall efficacy was 51% and could not be given concomitantly in patients taking some background immunosuppressive therapies, such as high dose corticosteroids 9. Approved by the FDA in 2018, the zoster recombinant adjuvanted (ZRA) vaccine is a novel recombinant vaccine that is more effective than the earlier vaccine. In clinical trials in patients older than 60 years of age, the vaccine was more than 90% effective 10. Patients known to be immunosuppressed were excluded in the original trials. Because of the potency of the adjuvant, there has been question as to whether the vaccine could induce a clinical flare of underlying rheumatic disease.\n\nWe evaluated the incidence of disease flares and side effects of the ZRA in patients with RA and other SRDs.\n\nPATIENTS AND METHODS\nSetting\nThis study took place in the rheumatology outpatient center at Brigham and Women's Hospital, a large tertiary‐care academic medical center. ZRA was prescribed to patients with RA and other SRDs.\n\nMethods\nWe performed a retrospective chart review of all patients with RA and SRD who received at least one dose of ZRA from February 1, 2018 to February 1, 2019. ZRA is a two‐dose series, with doses given two to six months apart. All patients were followed after their immunization for a minimum of three months or until a flare occurred. Patients enrolled earlier in the study period were followed through the duration of the study period. Documentation of flares and side effects occurring up to 12 weeks after each dose was abstracted from chart reviews (Figure 1). A flare was defined as occurring within 12 weeks of the ZRA administration by either 1) documentation of an RA or SRD flare in the rheumatologist's office notes, telephone encounter, or patient portal communication, or 2) a new corticosteroid prescription or an increase in the dose of a preexisting corticosteroid prescription. All potential flares were independently reviewed by three rheumatologists (EM, MEW, and SD), and discrepancies were resolved through discussion until consensus was reached.\n\nFigure 1 Depicts the study design timeline. The first dose of vaccine was administered and the second dose of vaccine, if given, was administered two to six months following the first dose. Flares were ascertained in the twelve weeks following the first dose of the vaccine and in the twelve weeks following the second dose of the vaccine.\n\nSide effects were defined as muscle soreness at the injection site, redness, mild swelling, fatigue, fevers, myalgias, headaches, nausea, and abdominal pain. These were abstracted through chart review of the rheumatologist's office notes, telephone encounters, patient portal communications, or phone calls with the rheumatology nurse (FG). Given the lack of experience with ZRA in rheumatology patients, the first 110 rheumatology patients who were administered the vaccine were contacted by the rheumatology nurse (FG) 1 week after vaccination to specifically inquire as to the occurrence of disease flare and side effects.\n\nAn outbreak of HZ was defined as 1) documentation of HZ in the electronic medical record, including visits to the emergency department, office notes, telephone encounters, patient portal communications, or 2) a prescription for antiviral therapy (ie, valacyclovir). All possible HZ outbreaks were identified through chart review and validated by a rheumatologist (SD) to ensure that only true HZ outbreaks were reported.\n\nRESULTS\nA total of 403 patients with RA or another SRD received the new ZRA vaccine between February 1, 2018, and February 1, 2019 (Table 1). The mean age of patients was 67.2 years, 302 (75.0%) patients were women, and 345 (85.6%) patients identified as white. At baseline, 316 (78.4%) patients were treated with immunosuppressive medications: 143 (35.5%) patients were taking methotrexate (median disease duration was 20 mg/week; interquartile range [IQR] 15‐25 mg/wk), 106 (26.3%) patients were taking prednisone (median dose of 5 mg/d; IQR 4‐8 mg/d), 52 (12.9%) patients were taking tofacitinib, 105 (26.1%) patients were taking tumor necrosis factor inhibitors, 49 (12.2%) patients were taking other biologic response modifiers, and 49 (12.2%) patients were taking other immunosuppressants. Some patients (n = 150 [37.2%]) reported taking multiple immunosuppressive medications. Immunosuppressants were not held prior to or after vaccination. More than half of patients (n = 222 [55.1%]) received the second vaccine within the study window. The length of time between doses ranged from 7 to 45 weeks, with an average of 18 weeks. Mean follow‐up with a rheumatologic care provider was 13.2 weeks after vaccination, ranging from 1 to 50 weeks. Additional patient characteristics are shown in Table 1.\n\nTable 1 Baseline characteristics of 403 study subjects at a single center investigation of the safety of the zoster vaccine recombinant\n\nBaseline Patient Characteristics\tResults\t\nAge, mean (SD), y\t67.3 (10.6)\t\nFemales, n (%)\t302 (74.9)\t\nWhite, n (%)\t345 (85.6)\t\nReceived second vaccine, n (%)\t222 (55.1)\t\nTime between first and second vaccine, mean (SD), wk\t18.3 (8.5)\t\nPatients with RA, n (%)\t239 (59.3)\t\nPatients with SRD,a n (%)\t164 (40.7)\t\nMedications\t \t\nOn any immunosuppressant medication, n (%)\t316 (78.4)\t\nMTX, n (%)\t143 (35.5)\t\nMean MTX dose, mg/wk\t17.1\t\nMTX dose, median (IQR), mg/wk\t20 (15‐25)\t\nPrednisone, n (%)\t106 (26.3)\t\nMean prednisone dose, mg/d\t4.7\t\nPrednisone dose, median (IQR), mg/d\t5 (4–8)\t\nTofacitinib, n (%)\t52 (12.9)\t\nTNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), n (%)\t105 (26.1)\t\nOther biologic therapy (abatacept, belimumab, tocilizumab, rituximab, sarilumab), n (%)\t49 (12.2)\t\nOther immunosuppressants (azathioprine, cyclophosphamide, mycophenolic acid, leflunomide), n (%)\t49 (12.2)\t\nAbbreviation: GCA, Giant‐cell arteritis; IQR, interquartile range; MTX, methotrexate; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SRD, systemic rheumatic disease; TNF, tumor necrosis factor.\n\na SRDs include psoriatic arthritis (n = 28), SLE (n = 16), spondylitis (n = 12), Sjogren syndrome (n = 12), GCA (n = 8), and other diseases (n = 88).\n\nJohn Wiley & Sons, LtdFlares were identified in 27 (6.7%) individual patients (an incidence rate of 6.7 cases per 100 patient‐years), with 23 (5.7%) flares occurring after the first dose and 5 (2.3%) flares occurring after the second. One patient experienced a flare following both doses. Nineteen (5.0%) flares were identified in patients with RA, and nine (3.6%) flares were identified in patients with an SRD. The incidence rate of flares in patients with systemic lupus erythematosus was 7.1% versus 8.0% (P < 0.05) in patients with RA. Three (2.7%) flares were identified in the first 110 patients called by the rheumatology nurse, compared with 25 (5.3%) flares found through chart review or prednisone prescription. Flares were commonly treated with a prednisone taper. All flares were mild and self‐limited, responded to treatment with glucocorticoids, and did not warrant a change in immunosuppressive therapy. Additional characteristics of disease flares are shown in Table 2.\n\nTable 2 Flare rate of 403 study subjects at a single‐center investigation of the safety of the zoster vaccine recombinant\n\nPatients Who Experienced Flares\tFlare Rate\t\nAfter first dose, n (%)\t23 (5.7)\t\nAfter second dose, n (%)\t5 (2.3)\t\nAfter both, n (%)\t1 (0.2)\t\nPatients with RA, n (%)\t19 (5.0)\t\nPatients with SRD, n (%)\t9 (3.6)\t\nFirst 110 patients called by nurse, n (%)\t3 (2.7)\t\nAbbreviation: RA, rheumatoid arthritis; SRD, systemic rheumatic disease.\n\nJohn Wiley & Sons, LtdSide effects were noted in 51 (12.7%) patients: 43 (10.7%) patients after the first dose and 12 (5.4%) patients after the second. Four patients experienced side effects following both doses. The most common side effects were soreness at the injection site, rash, fever, stomach ache, nausea, and flu‐like symptoms. All side effects were regarded as mild, reported in previous studies, and not unexpected.\n\nThree cases of HZ were reported. One patient had RA and was taking tofacitinib and methotrexate, a second patient with RA was taking tofacitinib alone, and a third patient with lupus was taking mycophenolate mofetil and belimumab. All cases were self‐limited, occurred in a single dermatome, and were successfully treated with antiviral therapy (Table 3).\n\nTable 3 Description of three herpes zoster cases\n\nPatient\tAge, y\tDx\tMedications Prescribed\tLength of Time Between Vaccine and Herpes Zoster Infection, mo\tDoses Received\t\nA\t42\tSLE\tMycophenolate mofetil and belimumab \t2\t1\t\nB\t79\tRA\tTofacitinib and methotrexate \t11\t2\t\nC\t54\tRA\tTofacitinib \t10\t2\t\nAbbreviation: Dx, diagnosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematous.\n\nJohn Wiley & Sons, LtdDISCUSSION\nIn our experience of 403 rheumatology patients (239 patients with RA and 164 patients with an SRD) who received the ZRA vaccine, the incidence of flares among all patients was less than 7%. The observed flare rate of 5.0% in patients with RA over 12 weeks is lower than the 30% background incidence of RA disease flare observed in our RA registry at Brigham and Women's Hospital over a 6‐month period 11.\n\nThe incidence of side effects was 13% or less, and these were similar to those reported in the nonimmunosuppressed patients studied in the pivotal trials of ZRA 10. In two large randomized double‐blind, placebo‐controlled studies of nonimmunosuppressed patients, the rates of side effects were age dependent. Side effects were reported more frequently among younger patients 9. In the clinical trials of ZRA, the most common side effects included pain, ranging from 68.7% to 79.1%; myalgia, ranging from 31.2% to 46.3%; and fatigue, ranging from 32.9% to 45.9% 10. The lower‐than‐expected incidence of side effects in our population may be related to the effects of the concomitant immunosuppressive therapy 12. Because of the national shortage of ZRA in the United States during the study period, just over half of the patients (222 [55.1%]) received the second vaccine, and not all patients received the vaccine within the recommended 2‐ to 6‐month time frame. A similar study researching ZRA in inflammatory bowel disease found that there was a low (1.5%) flare rate after ZRA administration 15.\n\nIn clinical trials of ZRA, the clinical efficacy was defined as a reduced incidence in the occurrence of zoster in more than 90% of people. The incidence rate of HZ in our population was 0.7%, which is not higher than that observed in the clinical studies 10, 13. Three (0.7%) cases of HZ were reported, and these occurred 2, 10, and 11 months following vaccine administration. One patient was taking mycophenolate mofetil, and two of the patients were taking tofacitinib, which has been associated with an increased risk of zoster (Table 3) 13. Both tofacitinib and tocilizumab have been shown be associated with an increased incidence of HZ 14. In a study comprised of 2500 subjects initiating tofacitinib compared with 67 200 subjects initiating other biologics, the rate of HZ was twice as high in patients taking tofacitinib than in patients taking other biologic medicines 13.\n\nThis study's strengths include the continuity of rheumatology care at a single center and the large number of patients reported. Limitations include the retrospective study design, possible underreporting of flare rate and side effects in the electronic medical record, and lack of a control group. Cases of HZ in patients seen outside of our health care network may not have been fully captured in the retrospective electronic medical record review. We also did not evaluate the immune response to the vaccine following administration. Previous studies report that immunosuppressive therapies commonly used to treat patients with RA and SRD may reduce the vaccine response 12. Further studies are needed to examine the effectiveness and durability of the HZ vaccine in rheumatology patients who are immunocompromised.\n\nIn 403 rheumatology patients who received the new ZRA vaccine, the incidence of disease flares was 7% or less and the incidence of side effects was 13% or less. Both flares and side effects were mild and self‐limited, and did not require a change in disease‐modifying antirheumatic drug therapy. Three cases of HZ were reported. Larger studies of patients vaccinated with ZRA are required to confirm this observation in addition to confirming its efficacy and safety in this population. Based on our results, we encourage the use of the ZRA vaccine in patients with RA and other SRDs treated with immunosuppressive therapies.\n\nAUTHOR CONTRIBUTIONS\nAll authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Ms. Stevens had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nStudy conception and design\nStevens, Weinblatt, Massarotti, Griffin, Emani, Desai.\n\nAcquisition of data\nStevens, Weinblatt, Massarotti, Griffin, Emani, Desai.\n\nAnalysis and interpretation of data\nStevens, Weinblatt, Massarotti, Griffin, Emani, Desai.\n\nACKNOWLEDGMENTS:\nThe authors thank Julie Fiskio for help in identifying patients who received the vaccine.\n==== Refs\nREFERENCES\n1 \n\nWeller \nTH \n. Varicella and herpes zoster: changing concepts of the natural history, control, and importance of a not‐so‐benign virus\n. N Engl J Med \n1983 ;309 :1434 –40\n.6195526 \n2 \n\nDooling \nKL \n, \nGuo \nA \n, \nPatel \nM \n, \nLee \nGM \n, \nMoore \nK \n, \nBelongia \nEA \n, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines\n. MMWR Morb Mortal Wkly Rep \n2018 ;67 :103 –8\n.29370152 \n3 \n\nVeetil \nBM \n, \nMyasoedova \nE \n, \nMatteson \nEL \n, \nGabriel \nSE \n, \nGreen \nAB \n, \nCrowson \nCS \n. Incidence and time trends of herpes zoster in rheumatoid arthritis: a population‐based cohort study\n. Arthritis Care Res (Hoboken) \n2013 ;65 :854 –61\n.23281295 \n4 \n\nWinthrop \nKL \n, \nCurtis \nJR \n, \nLindsey \nS \n, \nTanaka \nY \n, \nYamaoka \nK \n, \nValdez \nH \n, et al. Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant therapy\n. Arthritis Rheumatol \n2017 ;69 :1960 –8\n.28845604 \n5 \n\nTyring \nS \n, \nBelanger \nR \n, \nBezwoda \nW \n, \nLjungman \nP \n, \nBoon \nR \n, \nSaltzman \nRL \n, et al. A randomized, double‐blind trial of famciclovir versus acyclovir for the treatment of localized dermatomal herpes zoster in immunocompromised patients\n. Cancer Invest \n2001 ;19 :13 –22\n.11291551 \n6 \n\nGnann \nJW \n, \nWhitley \nRJ \n. Natural history and treatment of varicella‐zoster in high‐risk populations\n. J Hosp Infect \n1991 ;18 \nSuppl A :317 –29\n.1679798 \n7 \n\nGilden \nDH \n, \nKleinschmidt‐DeMasters \nBK \n, \nLaGuardia \nJJ \n, \nMahalingam \nR \n, \nCohrs \nRJ \n. Neurologic complications of the reactivation of varicella‐zoster virus [published erratum appears in N Engl J Med 2000;342:1063]\n. New Engl J Med \n2000 ;342 :635 –45\n.10699164 \n8 \n\nHarpaz \nR \n, \nOrtega‐Sanchez \nIR \n, \nSeward \nJF \n. Advisory Committee on Immunization Practices Centers for Disease Control and Prevention. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP)\n. MMWR Recomm Rep \n2008 ;57 :1 –30\n.\n9 \n\nTricco \nAC \n, \nZarin \nW \n, \nCardoso \nR \n, \nVeroniki \nAA \n, \nKhan \nPA \n, \nNincic \nV \n, et al. Efficacy, effectiveness, and safety of herpes zoster vaccines in adults aged 50 and older: systematic review and network meta‐analysis\n. BMJ \n2018 ;363 :k4029 .30361202 \n10 \n\nJames \nSF \n, \nChahine \nEB \n, \nSucher \nAJ \n, \nHanna \nC \n. Shingrix: the new adjuvanted recombinant herpes zoster vaccine\n. Ann Pharmacother \n2018 ;52 :673 –80\n.29457489 \n11 \n\nBykerk \nVP \n, \nShadick \nN \n, \nFrits \nM \n, \nBingham \nCO \n, \nJeffery \nI \n, \nIannaccone \nC \n, et al. Flares in rheumatoid arthritis: frequency and management. A report from the BRASS registry\n. J Rheumatol \n2014 ;41 :227 –34\n.24334643 \n12 \n\nWinthrop \nKL \n, \nSilverfield \nJ \n, \nRacewicz \nA \n, \nNeal \nJ \n, \nLee \nEB \n, \nHrycaj \nP \n, et al. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis\n. Ann Rheum Dis \n2016 ;75 :687 –95\n.25795907 \n13 \n\nCurtis \nJR \n, \nXie \nF \n, \nYun \nH \n, \nBernatsky \nS \n, \nWinthrop \nKL \n. Real‐world comparative risks of herpes virus infections in tofacitinib and biologic‐treated patients with rheumatoid arthritis\n. Ann Rheum Dis \n2016 ;75 :1843 –7\n.27113415 \n14 \n\nLiao \nTL \n, \nChen \nYM \n, \nLiu \nHJ \n, \nChen \nDY \n. Risk and severity of herpes zoster in patients with rheumatoid arthritis receiving different immunosuppressive medications: a case‐control study in Asia\n. BMJ Open \n2017 ;7 :e014032.\n15 \n\nSatyam \nVR \n, \nLi \nP \n, \nReich \nJ \n, \nQazi \nT \n, \nNoronha \nA \n, \nWasan \nSK \n, et al. Safety of recombinant zoster vaccine in patients with inflammatory bowel disease\n. Dig Dis Sci \n2020 . E‐pub ahead of print.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2578-5745",
"issue": "2(6)",
"journal": "ACR open rheumatology",
"keywords": null,
"medline_ta": "ACR Open Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101740025",
"other_id": null,
"pages": "357-361",
"pmc": null,
"pmid": "32412669",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": "29370152;10699164;18528318;6195526;25795907;24334643;23281295;30361202;1679798;28057661;27113415;28845604;29457489;11291551",
"title": "Safety of the Zoster Vaccine Recombinant Adjuvanted in Rheumatoid Arthritis and Other Systemic Rheumatic Disease Patients: A Single Center's Experience With 400 Patients.",
"title_normalized": "safety of the zoster vaccine recombinant adjuvanted in rheumatoid arthritis and other systemic rheumatic disease patients a single center s experience with 400 patients"
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"abstract": "Retrospective, observational, single-center, cohort study investigating the safety profile of biological therapy in children with inflammatory bowel disease (IBD).\n\n\n\nRetrospective, observational, cohort study of pediatric patients with IBD, receiving infliximab, adalimumab, vedolizumab, or ustekinumab for at least 2 months. Data related to the immediate and delayed adverse events (AEs) were collected, focusing on the reaction type and severity, the time of onset, the outcome and the temporary or definitive therapy discontinuation secondary to the AE. Number of suspected and confirmed coronavirus disease-209 (COVID-19) cases and their outcomes, as well as flu vaccination coverage were collected.\n\n\n\nOne hundred eighty-five children were included (101 [55%] CD, 82 [44%] UC, and 2 [1%] IBDU): 149 received infliximab (IFX) (81%), 88 (48%) adalimumab (ADA), 18 (21%) vedolizumab, and 4 (2%) ustekinumab. The overall AE rates were 49%, 67% of whom likely medication-related. Eleven (6%) patients experienced more than 1 AE, 18 patients (10%) presented an immediate reaction, and 82 (45%) a delayed AE. Among the 90 patients experiencing at least 1 AE, 97% had mild-to-moderate AEs. Only 4 SAEs were reported (4%). Treatment discontinuation because of AE occurred in 25 patients (14%). Four COVID-19 cases were reported, all with a mild course.\n\n\n\nOur findings confirm a good safety profile of biologics. Infusion reactions to IFX administration remain one of the main issues, significantly linked to its immunogenicity and consequently with an impact on its efficacy and durability.",
"affiliations": "Pediatric Gastroenterology and Liver Unit, Department of Maternal and Child Health, Sapienza University of Rome, Rome, Italy.",
"authors": "D'Arcangelo|Giulia|G|;Distante|Manuela|M|;Raso|Tonia|T|;Rossetti|Danilo|D|;Catassi|Giulia|G|;Aloi|Marina|M|",
"chemical_list": "D000069285:Infliximab; D000068879:Adalimumab",
"country": "United States",
"delete": false,
"doi": "10.1097/MPG.0000000000003044",
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"issue": "72(5)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D000068879:Adalimumab; D001691:Biological Therapy; D000086382:COVID-19; D002648:Child; D015331:Cohort Studies; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "8211545",
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"pages": "736-741",
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"pmid": "33416268",
"pubdate": "2021-05-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Safety of Biological Therapy in Children With Inflammatory Bowel Disease.",
"title_normalized": "safety of biological therapy in children with inflammatory bowel disease"
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"abstract": "Increased risk for the development of therapy-induced myeloid leukemia following the treatment of breast cancer has typically been associated with the use of regimens containing anthracyclines or alkylating agents. We present two cases of estrogen receptor-positive/progesterone receptor-positive/human epidermal growth factor receptor 2-positive (ER+/PR+/HER2+) breast cancer patients, treated with a non-anthracycline, non-alkylating regimen of trastuzumab, carboplatin, docetaxel, and pertuzumab (TCHP), who developed therapy-related acute myeloid leukemia (t-AML) within 30 months of the completion of treatment. Both patients had marked cytogenetic abnormalities, including deletions of chromosomes 5 and 7, and highly aggressive disease that resulted in a poor prognosis. While platinum and taxane-based chemotherapy regimens have been previously linked to the development of t-AML or therapy-related myelodysplastic syndrome (t-MDS) following treatment for ovarian cancer, they have not yet been shown to increase the risk of t-AML/t-MDS after their use for breast cancer therapy. As TCHP is widely used for the treatment of HER2/neu overexpressed breast cancer, these cases highlight the need to further evaluate the link between taxane and platinum-based chemotherapeutics for breast cancer and the development of t-AML/t-MDS.",
"affiliations": "Internal Medicine, Chicago Medical School, Rosalind Franklin University of Medicine, North Chicago, USA.;Internal Medicine, Advocate Lutheran General Hospital, Park Ridge, USA.;Pathology, Advocate Lutheran General Hospital, Park Ridge, USA.;Oncology, Advocate Lutheran General Hospital, Park Ridge, USA.",
"authors": "Gill|Navroop|N|;Chandran|Anjana|A|;Adley|Brian|B|;Bitran|Jacob|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.11957",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.11957\nOncology\nHematology\nTherapy-Related Acute Myeloid Leukemia Following TCHP Chemotherapy in Two HER2+ Breast Cancer Patients\nMuacevic Alexander Adler John R Gill Navroop 1 Chandran Anjana 2 Adley Brian 3 Bitran Jacob 4 \n1 \nInternal Medicine, Chicago Medical School, Rosalind Franklin University of Medicine, North Chicago, USA \n\n2 \nInternal Medicine, Advocate Lutheran General Hospital, Park Ridge, USA \n\n3 \nPathology, Advocate Lutheran General Hospital, Park Ridge, USA \n\n4 \nOncology, Advocate Lutheran General Hospital, Park Ridge, USA \n\nNavroop Gill navroop.gill@my.rfums.org\n7 12 2020 \n12 2020 \n12 12 e119577 12 2020 Copyright © 2020, Gill et al.2020Gill et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/45252-therapy-related-acute-myeloid-leukemia-following-tchp-chemotherapy-in-two-her2-breast-cancer-patientsIncreased risk for the development of therapy-induced myeloid leukemia following the treatment of breast cancer has typically been associated with the use of regimens containing anthracyclines or alkylating agents. We present two cases of estrogen receptor-positive/progesterone receptor-positive/human epidermal growth factor receptor 2-positive (ER+/PR+/HER2+) breast cancer patients, treated with a non-anthracycline, non-alkylating regimen of trastuzumab, carboplatin, docetaxel, and pertuzumab (TCHP), who developed therapy-related acute myeloid leukemia (t-AML) within 30 months of the completion of treatment. Both patients had marked cytogenetic abnormalities, including deletions of chromosomes 5 and 7, and highly aggressive disease that resulted in a poor prognosis. While platinum and taxane-based chemotherapy regimens have been previously linked to the development of t-AML or therapy-related myelodysplastic syndrome (t-MDS) following treatment for ovarian cancer, they have not yet been shown to increase the risk of t-AML/t-MDS after their use for breast cancer therapy. As TCHP is widely used for the treatment of HER2/neu overexpressed breast cancer, these cases highlight the need to further evaluate the link between taxane and platinum-based chemotherapeutics for breast cancer and the development of t-AML/t-MDS.\n\nbreast cancerbreast cancer outcomest-amlt-mdstchpdocetaxelcarboplatinpertuzumabtrastuzumabThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nBreast cancer incidence in the United States has continued to increase with an estimated 12.9% of women being diagnosed with breast cancer during their lifetime. Approximately 66% of newly diagnosed breast cancer patients will be treated with chemotherapy, which has been associated with a 1.5 to 4-fold increased risk of developing therapy-related myelodysplastic syndrome (t-MDS) [1-2]. The risk for the development of treatment-related acute myeloid leukemia (t-AML) is higher than that for t-MDS and higher in those receiving chemotherapy for regional or distant-stage disease as opposed to early-stage disease [2]. Herein, we report two cases of t-AML following docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) therapy for the treatment of human epidermal growth factor receptor 2-positive (HER2+) breast cancer.\n\nCase presentation\nCase 1\n\nIn November 2017, a 58-year-old woman was found to have Stage IIIB, Grade 3 lobular carcinoma that was estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and HER2/neu amplified with right axillary lymph nodes that were positive for breast cancer. She completed six cycles of neoadjuvant TCHP with clinical complete response (CR) and then underwent a modified mastectomy in April 2018. She completed radiation therapy to her right chest wall and axilla in July 2018. After completing her one year of trastuzumab, she started adjuvant endocrine therapy with letrozole. She was followed closely in the clinic. In August 2020, 33 months after the original diagnosis and 30 months after completion of neoadjuvant chemotherapy, she was found to have pancytopenia. A bone marrow biopsy was performed and confirmed AML (Figure 1A) with complex karyotype showing deletion of 5q31, monosomy 7, loss of CEP7, trisomy 8, and deletion of 20q12 (Figure 1B). Shortly after admission, the patient died from invasive fungal pneumonia. \n\nFigure 1 Bone Marrow Biopsy and Karyotype of Case 1\n(a) bone marrow aspirate showing blast cells consistent with acute myeloid leukemia (AML); (b) karyotype of leukemic cells within the bone marrow\n\nCase 2\n\nIn September 2017, a 69-year-old female was diagnosed with Stage IIIA, Grade 2 invasive ductal carcinoma that was ER+, PR+, and HER2/neu amplified. She then underwent bilateral mastectomies with reconstruction. At the time of surgery in November 2017, she was found to have a 1.6 cm focus of invasive carcinoma and five of 23 positive lymph nodes. She then completed six cycles of TCHP. She completed radiation, as well as one year of trastuzumab, and was started on anastrozole in September 2018. She was followed closely, and in January 2020 was found to have pancytopenia 29 months from the original diagnosis and 20 months following the completion of chemotherapy. A bone marrow biopsy revealed AML (20% - 30% blasts) (Figure 2A) with complex cytogenetics most consistent with t-AML which included deletions of 3p, 4q, and 5q, an unbalanced rearrangement involving chromosomes 7 and 22 resulting in the loss of 7p, additional material of unknown origin on 9q, and loss of chromosomes 17 and 22 (Figure 2B). The patient was admitted to the hospital and started on chemotherapy for t-AML with daunorubicin-cytarabine. She failed induction and re-induction. In late March 2020, she was started on salvage decitabine and venetoclax. Her course was complicated by neutropenic fever and hemophagocytic lymphohistiocytosis. Due to the worsening of her overall clinical condition, the patient and her family chose to pursue hospice care and she died in late April 2020.\n\nFigure 2 Bone Marrow Biopsy and Karyotype of Case 2\n(a) bone marrow aspirate showing blast cells consistent with acute myeloid leukemia (AML); (b) karyotype of leukemic cells within the bone marrow \n\nDiscussion\nThe link between t-AML/t-MDS following platinum and taxane-based chemotherapy has been established in patients treated for ovarian cancer [2-4]. To our knowledge, there is only one case report that has reported the causal link of TCHP in a patient with breast cancer who subsequently developed t-AML [5]. In patients treated for ovarian cancer, platinum-containing compounds result in an increased risk of t-MDS/t-AML, with carboplatin specifically, resulting in a latency period of approximately four years and more rare AML subtypes [3-4]. Studies have correlated an increased relative risk of t-MDS/t-AML with increasing doses and cycles of platinum-based therapy. This is consistent with the known leukemogenicity of platinum compounds, which induce DNA interstrand crosslinks [1, 3, 6]. Case reports investigating taxane-related t-AML following gynecological malignancies had a mean onset time of approximately nine months from the beginning of chemotherapy to the diagnosis of leukemia. These case studies specifically included paclitaxel and found no dose-related increase in risk but rather that patients developing t-AML simply had an idiosyncratic response to treatment [4]. Commonly, secondary AML due to paclitaxel-containing chemotherapy results in the M4 subtype with cytogenetic abnormalities and the absence of an antecedent hematologic disorder [4, 7]. \n\nThe link between alkylating and anthracycline agents and t-MDS in breast cancer has been well-established and studied extensively [2, 8-11]. Disease related to alkylating agents typically presents as t-MDS five to seven years following initial treatment. Two-thirds of these patients usually present with bone marrow failure characterized by pancytopenia and typical myelodysplastic marrow changes, including myeloblasts with megaloblastic changes in cell lines [3-4]. Typical cytogenetic changes noted on marrow analysis include the deletion of chromosomes 5 and 7 which confer a poor prognosis and unfavorable response to treatment [4, 6]. t-AML resulting from prior treatment with either topoisomerase II or anthracycline-based chemotherapy regimens typically develops within five years post-chemotherapy, with a mean of two to three years post-treatment. It has no association with t-MDS and is commonly defined by the 11q23 cytogenetic abnormality [10-11]. Studies have suggested that non-anthracycline containing regimens have a decreased incidence of leukemia, as compared to anthracycline-containing regimens when used in the treatment for breast cancer [12]. Additionally, the monoclonal antibody trastuzumab used for the treatment of HER2/neu breast cancer currently has no known association with the development of t-AML or t-MDS [12]. \n\nThe exact pathophysiology underlying the development of t-AML has not yet been identified. It has been proposed that generalized genomic instability induced by chemotherapy may be a critical factor in the origin of genetic alterations that drive the disease. In a case study of t-AML following treatment for breast cancer, several chromosomal abnormalities were noted, including MYC, KMT2A, TP53 which were impacted by rearrangement, deletion, or amplification that were thought to drive disease progression [5]. The MYC amplification and overexpression promoted increased proliferation, instability, and poor outcome. Chromosome 11 contained a 11q23.3 rearrangement affecting KMT2A which has previously been linked to leukemogenesis, and there was a loss of function of TP53 on chromosome 17 that also likely contributed to the development of the t-AML [5]. In studies looking at the development of t-AML after any malignancy and chemotherapy regimen, TP53 was reported to be mutated in 20% - 50% of patients with t-AML, which is significantly higher than patients with de novo AML. Harboring this mutation is linked to intrinsic therapy resistance and worse overall prognosis. Differences in cytogenetics between t-AML in comparison with de novo AML also included a higher incidence of mutations in PTPN11 and a lower incidence of FLT3 and NPM1 [13]. \n\nTypically, the diagnosis of t-MDS/t-AML is made via a combination of blood counts, bone marrow aspirates, flow cell cytometry, and karyotype analysis [3, 5]. The treatment for t-AML is tailored to the patient based upon age, comorbidities, performance status, and cytogenetic features. Patients with t-AML have an unfavorable prognosis with a median survival of eight to 10 months after diagnosis [10-11, 13]. The only curative therapy is allogeneic bone marrow transplantation following induction chemotherapy with daunorubicin-cytarabine (CPX-351) [13].\n\nConclusions\nHerein, we presented the cases of two patients who developed t-AML 20 to 30 months following the completion of primary TCHP chemotherapy for ER+, PR+, HER2+ breast cancer. The use of taxane and platinum-based regimens for the initial treatment of breast cancer has not previously been linked to an increased risk for the development of t-AML. While this link has been established following treatment for ovarian cancer, it warrants further exploration in patients treated for primary breast cancer. Furthermore, the complex cytogenetics of the presented patients are consistent with previous reports of t-AML, conferring an aggressive clinical course and poor overall prognosis. Our case studies add to the limited body of literature linking TCHP chemotherapy for breast cancer to the development of t-AML. Further investigation into this association is warranted, given its widespread use for the treatment of breast cancer.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Cancer Stat Facts: Female Breast Cancer 9 2020 2020 http://seer.cancer.gov/statfacts/html/breast.html \n2 Association of chemotherapy for solid tumors with development of therapy-related myelodysplastic syndrome or acute myeloid leukemia in the modern era JAMA Oncol Morton LM Dores GM Schonfeld SJ 318 325 5 2019 30570657 \n3 Paclitaxel induced MDS and AML: a case report and literature review Case Rep Oncol Med Bhatnagar UB Singh D Glazyrin A Moormeier J 8308179 2016 2016 27057370 \n4 Therapy-related myelodysplasia and acute myeloid leukemia following paclitaxel- and carboplatin-based chemotherapy in an ovarian cancer patient: a case report and literature review Int J Gynecol Cancer Yeasmin S Nakayama K Ishibashi M 1371 1376 18 2008 18217963 \n5 Cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia Cancer Genet Koduru P Chen W Haley B Ho K Oliver D Wilson K 69 75 238 2019 31425928 \n6 Maximizing breast cancer therapy with awareness of potential treatment-related blood disorders Oncologist Kaplan HG Calip GS Malmgren JA 391 397 25 2020 32073195 \n7 Secondary leukemia after treatment with paclitaxel and carboplatin in a patient with recurrent ovarian cancer Int J Gynecol Cancer See HT Thomas DA Bueso-Ramos C Kavanagh J 236 240 16 2006 https://ijgc.bmj.com/content/16/Suppl_1/236.abstract 16515597 \n8 Appearance of acute myelogenous leukemia (AML) in a patient with breast cancer after adjuvant chemotherapy: case report and review of the literature Iran J Cancer Prev Payandeh M Khodarahmi R Sadeghi M Sadeghi E 125 128 8 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411474/ 25960852 \n9 Acute myeloid leukemia and myelodysplastic syndrome after adjuvant chemotherapy: a population-based study among older breast cancer patients Cancer Rosenstock AS Niu J Giordano SH Zhao H Wolff AC Chavez-MacGregor M 899 906 124 2018 29236294 \n10 Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience J Clin Oncol Wolff AC Blackford AL Visvanathan K 340 348 33 2015 25534386 \n11 Acute myeloid leukemia after adjuvant breast cancer therapy in older women: understanding risk J Clin Oncol Patt DA Duan Z Fang S Hortobagyi GN Giordano SH 3871 3876 25 2007 17664457 \n12 Adjuvant trastuzumab in HER2-positive breast cancer N Engl J Med Slamon D Eiermann W Robert N 1273 1283 365 2011 21991949 \n13 Treatment strategies for therapy-related acute myeloid leukemia Clin Lymphoma Myeloma Leuk Dhakal P Pyakuryal B Pudasainee P Rajasurya V Gundabolu K Bhatt VR 147 155 20 2020 31953046\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(12)",
"journal": "Cureus",
"keywords": "breast cancer; breast cancer outcomes; carboplatin; docetaxel; pertuzumab; t-aml; t-mds; tchp; trastuzumab",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e11957",
"pmc": null,
"pmid": "33425535",
"pubdate": "2020-12-07",
"publication_types": "D002363:Case Reports",
"references": "18217963;31425928;17664457;32073195;21991949;16515597;29236294;25534386;25960852;27057370;30570657;31953046",
"title": "Therapy-Related Acute Myeloid Leukemia Following TCHP Chemotherapy in Two HER2+ Breast Cancer Patients.",
"title_normalized": "therapy related acute myeloid leukemia following tchp chemotherapy in two her2 breast cancer patients"
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{
"abstract": "The pneumococcal conjugate vaccines successfully decreased the incidence of invasive pneumococcal diseases and pneumococcal antibiotic resistance. However, they also led to serotype replacements. According to a report by the National Institute of Infectious Diseases (NIID) in 2017, 96% of pneumococcal isolates obtained from children with IPD aged < 5 years were non-PCV13 serotypes. Here, we report the case of a Japanese immunocompetent and vaccinated child who developed refractory meningitis caused by Streptococcus pneumoniae nonvaccine serotype 10A. PCR revealed genotypic penicillin-resistant Streptococcus pneumoniae (gPRSP) with triple mutations (pbp1a + 2b + 2x). Multilocus sequence typing identified the strain as a sequence type (ST) 11189. The ST11189 strain has not been reported in Japan, but it has recently been reported as a cause of invasive infections in Korea. The clinical course was complicated by the development of brain and subdural abscesses that necessitated prolonged antibiotic treatment and multiple burr hole drainages. Unfortunately, the neurological sequelae persisted. Continued molecular surveillance is needed for monitoring emerging virulent clinical strains.",
"affiliations": "Department of General Pediatrics & Interdisciplinary Medicine, National Center for Child Health and Development, Japan.;Office of Infection Control, National Center for Child Health and Development, Japan.;Division of Infectious Diseases, National Center for Child Health and Development, Japan.;Department of Palliative Medicine, National Center for Child Health and Development, Japan.;Division of Hematology, National Center for Child Health and Development, Japan.;Division of Hematology, National Center for Child Health and Development, Japan.;Division of Hematology, National Center for Child Health and Development, Japan.;Department of General Pediatrics & Interdisciplinary Medicine, National Center for Child Health and Development, Japan.;Center for Postgraduate Education and Training, National Center for Child Health and Development, Japan.;Office of Infection Control, National Center for Child Health and Development, Japan.",
"authors": "Minato|Sonoko|S|;Yoshida|Michiko|M|;Shoji|Kensuke|K|;Yotani|Nobuyuki|N|;Takeshita|Kenichi|K|;Takeuchi|Noriko|N|;Ishiwada|Naruhiko|N|;Kubota|Mitsuru|M|;Ishiguro|Akira|A|;Miyairi|Isao|I|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.7883/yoken.JJID.2020.841",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1344-6304",
"issue": "74(5)",
"journal": "Japanese journal of infectious diseases",
"keywords": "Streptococcus pneumoniae; meningitis; multilocus sequence typing; pneumococcal vaccines; serogroup",
"medline_ta": "Jpn J Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "100893704",
"other_id": null,
"pages": "477-480",
"pmc": null,
"pmid": "33518624",
"pubdate": "2021-09-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Case Report of Bacterial Meningitis Caused by an Emerging Strain of Penicillin-Resistant Non-Vaccine Serotype 10A.",
"title_normalized": "a case report of bacterial meningitis caused by an emerging strain of penicillin resistant non vaccine serotype 10a"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2021-21922",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugaddition... |
{
"abstract": "Multiple myeloma (MM) is a monoclonal gammopathy, also known as the malignant proliferation of plasma cells, presenting with typical complications such as hypercalcemia, osteolytic bone lesions, anemia, renal insufficiency, and frequent infections. Central nervous system (CNS) involvement in MM in the form of parenchymal involvement is very uncommon and has been reported only in 1% of patients. CNS involvement as an initial presentation is very rare and has poor prognosis. Also specific treatment guidelines do not exist for the treatment of such patients. We present here a case of a 40-year-old female patient, with complaints of headache and left eye proptosis followed by left-sided hemiparesis, who after complete workup was diagnosed as a de novo case of stage III extramedullary MM with CNS involvement. Patient was treated with whole brain radiation followed by BCD regimen (injection of bortezomib, injection of cyclophosphamide, and tablet dexamethasone). After three cycles of chemotherapy, patient succumbed in view of consolidation and renal failure.",
"affiliations": "Department of Medical Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical Oncology, GCRI, Ahmedabad, Gujarat, India.",
"authors": "Tahiliani|N|N|;Kataria|P|P|;Patel|A|A|;Kendre|P|P|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jpgm.JPGM_623_17",
"fulltext": "\n==== Front\nJ Postgrad MedJ Postgrad MedJPGMJournal of Postgraduate Medicine0022-38590972-2823Medknow Publications & Media Pvt Ltd India 30117481JPGM-64-24310.4103/jpgm.JPGM_623_17Case ReportProptosis and hemiplegia as an initial manifestation of multiple myeloma Tahiliani N Kataria P Patel A Kendre P Department of Medical Oncology, GCRI, Ahmedabad, Gujarat, IndiaAddress for correspondence: Dr. Patel A, E-mail: shrutavpatel@rediffmail.comOct-Dec 2018 64 4 243 246 25 10 2017 24 12 2017 16 2 2018 Copyright: © 2018 Journal of Postgraduate Medicine2018This 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.Multiple myeloma (MM) is a monoclonal gammopathy, also known as the malignant proliferation of plasma cells, presenting with typical complications such as hypercalcemia, osteolytic bone lesions, anemia, renal insufficiency, and frequent infections. Central nervous system (CNS) involvement in MM in the form of parenchymal involvement is very uncommon and has been reported only in 1% of patients. CNS involvement as an initial presentation is very rare and has poor prognosis. Also specific treatment guidelines do not exist for the treatment of such patients. We present here a case of a 40-year-old female patient, with complaints of headache and left eye proptosis followed by left-sided hemiparesis, who after complete workup was diagnosed as a de novo case of stage III extramedullary MM with CNS involvement. Patient was treated with whole brain radiation followed by BCD regimen (injection of bortezomib, injection of cyclophosphamide, and tablet dexamethasone). After three cycles of chemotherapy, patient succumbed in view of consolidation and renal failure.\n\nKEY WORDS:\nBortezomibcentral nervous system involvementextramedullarymultiple myeloma\n==== Body\nIntroduction\nMultiple myeloma (MM) is a monoclonal gammopathy, also known as the malignant proliferation of plasma cells, presenting with typical complications such as hypercalcemia, osteolytic bone lesions, anemia, renal insufficiency, and frequent infections. Central nervous system (CNS) involvement in MM is very uncommon and has been reported only in 1% of patients.[1] Cerebrospinal fluid (CSF) cytology and brain magnetic resonance imaging (MRI) in addition to routine myeloma workup is essential for diagnosis. Different modalities of treatment, including intrathecal chemotherapy, cranial irradiation, and systemic chemotherapy, are used. We present a case of a 40-year-old female patient, with complaints of headache and left eye proptosis, and after complete workup was diagnosed as a de novo case of stage III MM with CNS involvement.\n\nCase Report\nA 40-year-old female patient presented to ophthalmologist with complaints of headache and left eye proptosis of 3 months duration. Proptosis was gradually increasing, painless in nature, and associated with decreased vision, excessive lacrimation, and redness involving the left eye. On ophthalmic examination, left supra and periorbital swelling was appreciable with left eyeball being pushed downwards and inwards with axial proptosis [Figure 1] and restriction of eye movements in all directions. There was increased retrobulbar resistance in left eye. Rest general examination was within normal limit. As patient was being investigated for proptosis by the ophthalmologist, the patient developed left-sided weakness for which consultation was done with neurologist. On neurological examination, left-side power was grade 4/5 in both upper and lower limbs with exaggerated left deep tendon reflexes. Rest cranial nerve examination was within normal limits. Laboratory studies showed following abnormalities: Hemoglobin (6.2 g/dl), serum creatinine (3.5 mg/dl), serum uric acid (8.4 mg/dl), and serum albumin (2.19 g/l). MRI of brain and orbits was done, which showed a 5.2 × 2.9 × 5.6 cm intraaxial mass lesion in right temporo-parieto-occipital region with similar lesion in extraconal compartment of left orbit causing proptosis of left eyeball [Figures 2 and 3]. Along with these findings an unusual finding of multiple varying sized lytic lesions was appreciable involving skull vault, base, and multiple cervical vertebrae. In view of these findings, patient was referred to the oncology department for further workup. As MRI showed presence of multiple lytic areas, skeletal survey was done which confirmed lytic lesion in the MRI mentioned areas, and in addition, few lytic lesions were appreciable within the ribs and pelvic bones. The differential diagnosis of secondaries from an unknown primary, blood cell-related tumor including lymphoma or plasma cell dyscrasias was done. Serum parathyroid and thyroid levels were within normal limits. To look for an unknown primary from the lung, gastrointestinal tract, and breast, endoscopy, colonoscopy, stool examination, and breast examination were done. Computed tomography (CT) (abdomen with pelvis and thorax) did not point to any primary lesion. As a part of the workup for hematological disorder, bone marrow examination was done, which showed presence of 70% plasma cells [Figure 4]. CSF cytology did not show any malignant cells. Serum protein electrophoresis showed presence of monoclonal peak in gamma region. Serum immunofixation study showed the presence of elevated immunoglobulin G [6892 mg/dl (700–1600 mg/dl)] kappa levels. As the patient was not willing for the biopsy from intracranial space occupying lesion, tentative diagnosis of stage III MM with extramedullary involvement (orbital and brain metastasis) was done. As part of the workup, beta-2 microglobulin was done, which was elevated, i.e., 78 ug/ml. Patient received whole brain radiation therapy, i.e., 30Gy/10# for the intracranial lesion. After completion of whole brain radiation therapy, patient was started on chemotherapy consisting of BCD, i.e., injection of bortezomib (1.3 mg/m2, day 0, 7, 14, 28) + injection of cyclophosphamide (300 mg/m2/week) + tab. of dexamethasone 20 mg/week. Post three cycles of chemotherapy, she was admitted to the emergency department with bilateral consolidation. X-ray done was suggestive of bilateral consolidation. Blood investigation showed a nonneutropenic picture; however, the biochemical investigation pointed toward acute kidney injury-like features with electrolyte imbalances. Further, patient was given ventilatory support in view of falling saturation with injectable vancomycin 15 mg/kg twice a day and injectable meropenem 1 g thrice a day. Later on third day, injection of liposomal amphotericin B 3 mg/kg/day was added; however, on day 7 of the admission, patient continuously deteriorated with deranged serum creatinine of 7 mg/dl and succumbed on the day 8 of the ICU admission.\n\nFigure 1 Left eye proptosis - the presenting feature\n\nFigure 2 MRI brain: Soft tissue density lesion (arrow) in extraconal compartment of left orbit causing proptosis of left eyeball\n\nFigure 3 MRI-Brain: 5.2 × 2.9 × 5.6 cm mass (arrow) in right temporo-parieto-occipital region\n\nFigure 4 H and E staining: Large immature plasma cells with basophilic cytoplasm and eccentric nucleus with distinct clear perinuclear region of cytoplasm (arrow)\n\nDiscussion\nMM is a hematological malignancy characterized by a monoclonal proliferation of plasma cells usually presenting with hypercalcemia, osteolytic bone lesions, anemia, renal insufficiency, and frequent infections.\n\nOcular findings in MM may arise from systemic effects of the disease (increased blood viscosity) or infiltration of plasma cells into ocular tissues.[2] These ocular findings may include crystalline corneal deposits, exudative macular detachment, ciliary body cysts, and retinal hemorrhage. Orbital involvement is a rare presentation of the disease.[234] Orbital myeloma most commonly presents as a unilateral solitary soft tissue intraorbital tumor, which is an extension of bony deposit and is associated with bone destruction.[5] The most common clinical sign of orbital involvement in MM is unilateral proptosis, while hyperemia, pain, diplopia, and low vision occur less often.[6]\n\nCNS involvement due to MM can be in the form of central as well as peripheral nervous system involvement. CNS includes either involvement of brain and the meningeal structures or the spinal cord. The various manifestations include either lethargy, nausea, vomiting, headaches, confusion, paresthesia, or seizures, visual, gait, and speech disturbances[7] in case of involvement of brain parenchyma. Those with vertebral collapse or extradural lesions present with spinal cord or root compression.[8] Peripheral nervous system involvement can be an isolated mononeuropathy or polyneuropathy secondary to amyloidosis or as a part of the polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome.[9] Meningeal involvement by a myeloma is an uncommon event, occurring in approximately 1% of cases of MM.[9]\n\nThere are no prescribed guidelines for the management of such cases, however, radiotherapy followed by systemic chemotherapy has been the mainstay of treatment in cases of MM with orbital involvement.[61011]\n\nChemotherapy and intrathecal therapy have been reported as treatments with or without radiotherapy with survivals ranging between 2 and 6 months for CNS-MM. The treatment is based on similar lines as the treatment for leukemias and aggressive lymphomas invading the CNS, and includes intrathecal chemotherapy or combination systemic chemotherapies that cross the blood–brain barrier, with or without cranial irradiation. Systemic chemotherapy agents used with mostly transient responses include a combination of doxorubicin, cyclophosphamide, melphalan, bortezomib, and the immunomodulators thalidomide and lenalidomide.\n\nAlthough most of the chemotherapeutic regimens used to treat CNS myelomatosis, including bortezomib and the immunomodulators thalidomide and lenalidomide, are not known to cross the blood–brain barrier, they have been described to have activity against CNS-MM, which probably could be due to the disruption of the BBB and increased vascular permeability within the tumor.[12] Novel agents such as pomalidomide and marizomib seem to show some promising effects.[1314] Of all the treatment modalities, cranial irradiation has been described as best therapy for this peculiar location of MM since the past. However, with the advent of the immunomodulators, they have been shown to be effective in the treatment of CNS myelomatosis.\n\nMM though usually present as CRAB (alteration in calcium, anemia, renal failure, bone lesions) features, however, proptosis or the brain parenchymal involvement is rare and is being rarely reported. However, in our case, proptosis as well as the parenchymal involvement at presentation was unique feature and to the best of our knowledge this is the first case report of such sort.\n\nConclusion\nProptosis and CNS manifestation such as hemiplegia or cranial nerve involvement can be the initial manifestation of MM and should be considered as the one of the diagnosis especially in patients with appropriate age and other manifestation.\n\nLearning points\n\nCNS presentation or proptosis is a rare presentation of MM.\n\nIt should be considered where circumstances appropriate for the age and symptomatology exists.\n\nNo formal guidelines exist for its management and whatever reports available are just available as documented cases.\n\n\n\n\nDeclaration of patient consent\nThe authors certify that appropriate patient consent was obtained.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Fassas AB Muwalla F Berryman T Benramdane R Joseph L Anaissie E Myeloma of the central nervous system: Association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations Br J Haematol 2002 117 103 8 11918539 \n2 Knapp AJ Gartner S Henkind P Multiple myeloma and its ocular manifestations Surv Ophthalmol 1987 5 343 51 \n3 Rodman HI Font RL Orbital involvement in multiple myeloma. Review of the literature and report of three cases Arch Ophthalmol 1972 87 30 5 4550269 \n4 Sharma S Kaushal M Chaturvedi NK Yadav R Cytodiagnosis of multiple myeloma presenting as orbital involvement: A case report Cyto journal 2006 3 19 16901345 \n5 Ajithkumar TV Sivasankar C Ramachandran K Orbital multiple myeloma: Case report and review of computed tomography features Austr Radiol 2002 46 119 20 \n6 Malik A Narang S Handa U Sood S Multiple myeloma presenting as bilateral orbital proptosis Indian J Ophthalmol 2009 57 3935 \n7 Mendez CE Hwang BJ Destian S Mazumder A Jagannath S Vesole DH Intracranial multifocal dural involvement in multiple myeloma: Case report and review of the literature Clin Lymphoma Myeloma Leuk 2010 10 220 3 20511169 \n8 Somers LJ Shaw B Lyn BE McMillan AM Mahendra P Meningeal myeloma in the absence of systemic disease, and as the initial feature of disease progression Clin Lab Haematol 1998 20 189 90 9681237 \n9 Peest D Multiple myeloma Ther Umsch 1996 53 147 51 8629265 \n10 Wavre A Baur AS Betz M Mühlematter D Jotterand M Zaman K Case study of intracerebral plasmacytoma as an initial presentation of multiple myeloma Neurooncol 2007 9 370 2 \n11 Vatansever M Bozkurt FM Dinç E Yılmaz EB Nayir E Sarı AA Orbital metastasis of multiple myeloma: Case report Turk J Ophthalmol 2016 46 148 50 27800278 \n12 Gozzetti A Cerase A Lotti F Rossi D Palumbo A Petrucci MT GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Myeloma Working Party Extramedullary intracranial localizations of multiple myeloma and treatment with novel agents: A retrospective survey of 50 patients Cancer 2012 118 1574 84 21932386 \n13 Mussetti A Dalto S Montefusco V Effective treatment of pomalidomide in central nervous system myelomatosis Leuk Lymphoma 2013 54 864 6 22880953 \n14 Lawasut P Chauhan D Laubach J Hayes C Fabre C Maglio M New proteasome inhibitors in myeloma Curr Hematol Malig Rep 2012 7 258 66 23065395\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0022-3859",
"issue": "64(4)",
"journal": "Journal of postgraduate medicine",
"keywords": "Bortezomib; central nervous system involvement; extramedullary; multiple myeloma",
"medline_ta": "J Postgrad Med",
"mesh_terms": "D000328:Adult; D016543:Central Nervous System Neoplasms; D005094:Exophthalmos; D017809:Fatal Outcome; D005260:Female; D006429:Hemiplegia; D006801:Humans; D009101:Multiple Myeloma",
"nlm_unique_id": "2985196R",
"other_id": null,
"pages": "243-246",
"pmc": null,
"pmid": "30117481",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19700882;11918539;11966603;23065395;17522337;22880953;8629265;27800278;4550269;16901345;21932386;9681237;20511169;3603371",
"title": "Proptosis and hemiplegia as an initial manifestation of multiple myeloma.",
"title_normalized": "proptosis and hemiplegia as an initial manifestation of multiple myeloma"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-182710",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"d... |
{
"abstract": "Zoledronic acid (ZOL) 5 mg annually was more effective than tenofovir disoproxil fumarate (TDF) switching at increasing bone mineral density (BMD) over 24 months in HIV-infected, osteopenic adults. To determine whether the effects of ZOL would persist without further infusions, we compared changes in left hip and spine BMD over 36 months in participants randomized to ZOL 5 mg at baseline and month 12 (and to continue TDF) or to switch TDF (without receiving ZOL). We also compared changes in the plasma bone turnover markers (BTMs) C-terminal telopeptide of type 1 collagen (CTX; bone resorption), and procollagen type 1 N propeptide (P1NP; bone formation) and determined whether CTX and P1NP changes at month 3 predicted BMD changes at month 36. Changes were compared in the per-protocol populations, which included 32 (74%) of 43 participants randomized to ZOL and 37 (88%) of 42 participants who switched TDF. Despite not receiving ZOL after month 12, mean hip and spine BMD change from baseline were stable and remained greater with ZOL at month 36 than with TDF switching (spine: 7.5% versus 2.7%, mean difference 4.7%, p < 0.001; hip: 5.5% versus 1.5%, mean difference 4.0%, p < 0.001). CTX and P1NP levels declined in both groups but significantly more with ZOL. Only percent changes in P1NP at month 3 correlated inversely with BMD changes at month 36 (spine: rho = -0.442, p < 0.001; hip: rho = -0.373, p = 0.002). Two infusions of ZOL (in the presence of ongoing TDF) yielded sustained BMD increases through month 36 that remained greater than with TDF switching. © 2019 American Society for Bone and Mineral Research.",
"affiliations": "Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia.;Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia.;Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia.;Department of Medicine, Monash University, Melbourne, Australia.;Department of Nuclear Medicine, St Vincent's Hospital, Sydney, Australia.;Infectious Diseases Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.;Infectious Diseases Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.;Department of Medicine, Monash University, Melbourne, Australia.",
"authors": "Carr|Andrew|A|0000-0001-5730-3625;Kerr|Stephen J|SJ|;Richardson|Robyn|R|;Ebeling|Peter|P|0000-0002-2921-3742;Pocock|Nicholas|N|;Rojas|Jhon|J|;Martinez|Esteban|E|;Hoy|Jennifer|J|0000-0002-6948-7086;|||",
"chemical_list": "D015415:Biomarkers; D000077211:Zoledronic Acid; D000068698:Tenofovir",
"country": "United States",
"delete": false,
"doi": "10.1002/jbmr.3834",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-0431",
"issue": "34(12)",
"journal": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research",
"keywords": "BONE MINERAL DENSITY; BONE TURNOVER; HIV; SWITCHING; TENOFOVIR; ZOLEDRONIC ACID",
"medline_ta": "J Bone Miner Res",
"mesh_terms": "D000328:Adult; D015415:Biomarkers; D015519:Bone Density; D016723:Bone Remodeling; D005260:Female; D050723:Fractures, Bone; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D000068698:Tenofovir; D016896:Treatment Outcome; D000077211:Zoledronic Acid",
"nlm_unique_id": "8610640",
"other_id": null,
"pages": "2192-2197",
"pmc": null,
"pmid": "31361922",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prolonged Effect of Zoledronic Acid on Bone Mineral Density and Turnover in HIV-Infected Adults on Tenofovir: A Randomized, Open-Label Study.",
"title_normalized": "prolonged effect of zoledronic acid on bone mineral density and turnover in hiv infected adults on tenofovir a randomized open label study"
} | [
{
"companynumb": "AU-GILEAD-2019-0422262",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nDrug therapy for patients with right ventricular (RV) cardiomyopathy refractory to single-drug therapy and ablation has not been well defined.\n\n\nMETHODS\nWe reviewed our entire RV cardiomyopathy database (31 patients) and found four patients presenting with ventricular arrhythmias of RV origin refractory to single-drug therapy. These patients underwent complete evaluation for arrhythmogenic right ventricular cardiomyopathy (ARVC).\n\n\nRESULTS\nFollowing the revised 2010 task force criteria, of these four patients, three were diagnosed with ARVC, and one with cardiac sarcoidosis. These patients proved to be refractory to drug monotherapy and either failed or deemed to not be candidates for endocardial ablation. Their arrhythmias were ultimately controlled with combinations of sotalol, flecainide, and mexiletine.\n\n\nCONCLUSIONS\nIn our experience, combination drug therapy is an effective treatment strategy for patients with ventricular tachycardia refractory to monotherapy and, in some cases, ablation. In addition, flecainide appears to be safe and effective for those with RV cardiomyopathy without significant left ventricular dysfunction.",
"affiliations": "Cardiovascular Division, Department of Medicine, University of California San Francisco, San Francisco, California.",
"authors": "Ermakov|Simon|S|;Hoffmayer|Kurt S|KS|;Gerstenfeld|Edward P|EP|;Scheinman|Melvin M|MM|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D008801:Mexiletine; D013015:Sotalol; D005424:Flecainide",
"country": "United States",
"delete": false,
"doi": "10.1111/pace.12250",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-8389",
"issue": "37(1)",
"journal": "Pacing and clinical electrophysiology : PACE",
"keywords": "antiarrhythmic medication; arrhythmogenic right ventricular cardiomyopathy; right ventricular cardiomyopathy; ventricular tachycardia",
"medline_ta": "Pacing Clin Electrophysiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents; D019571:Arrhythmogenic Right Ventricular Dysplasia; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D005260:Female; D005424:Flecainide; D006801:Humans; D008297:Male; D008801:Mexiletine; D012189:Retrospective Studies; D013015:Sotalol; D017180:Tachycardia, Ventricular; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "7803944",
"other_id": null,
"pages": "90-4",
"pmc": null,
"pmid": "24102153",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combination drug therapy for patients with intractable ventricular tachycardia associated with right ventricular cardiomyopathy.",
"title_normalized": "combination drug therapy for patients with intractable ventricular tachycardia associated with right ventricular cardiomyopathy"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2017US-132225",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPAFENONE"
},
"dru... |
{
"abstract": "Pure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. Secondary acquired PRCA may be associated with hematologic disorders. A few case reports have described PRCA associated with multiple myeloma (MM). However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide.",
"affiliations": "First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.;First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan.",
"authors": "Ito|Tomoki|T|;Nakaya|Aya|A|;Fujita|Shinya|S|;Satake|Atsushi|A|;Nakanishi|Takahisa|T|;Azuma|Yoshiko|Y|;Tsubokura|Yukie|Y|;Konishi|Akiko|A|;Hotta|Masaaki|M|;Yoshimura|Hideaki|H|;Ishii|Kazuyoshi|K|;Nomura|Shosaku|S|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.lrr.2018.06.005",
"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(17)30060-210.1016/j.lrr.2018.06.005ArticleSecondary pure red cell aplasia in multiple myeloma treated with lenalidomide Ito Tomoki Nakaya Aya nakaya1016@yahoo.co.jp⁎Fujita Shinya Satake Atsushi Nakanishi Takahisa Azuma Yoshiko Tsubokura Yukie Konishi Akiko Hotta Masaaki Yoshimura Hideaki Ishii Kazuyoshi Nomura Shosaku First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010, Japan⁎ Corresponding author. nakaya1016@yahoo.co.jp07 7 2018 2018 07 7 2018 10 4 6 13 11 2017 5 6 2018 29 6 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Pure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. Secondary acquired PRCA may be associated with hematologic disorders. A few case reports have described PRCA associated with multiple myeloma (MM). However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide.\n\nKeywords\nPure red cell aplasiaMultiple myelomaLenalidomide\n==== Body\n1 Introduction\nPure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. This disorder may be congenital or develop as an acute or chronic acquired syndrome. Acquired PRCA may be either a primary disorder or secondary to another disorder or agent. Primary acquired PRCA is an autoimmune disorder that is frequently antibody-mediated. Secondary acquired PRCA may be associated with collagen vascular/autoimmune disorders such as systemic lupus erythematosus; lymphoproliferative disorders such as chronic lymphocytic leukemia or large granular lymphocyte leukemia; infections, particularly B19 parvovirus; thymoma and other solid tumors; or a variety of other disorders, drugs, or toxic agents [1].\n\nAcquired PRCA may present as a primary hematological disorder in the absence of any other disease. A few case reports have described PRCA associated with multiple myeloma (MM) [2], [3], [4], [5]. However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide.\n\n2 Case 1\nA 77-year-old woman was diagnosed with symptomatic MM (IgG λ type), Durie Salmon stage Ⅲ A, ISS Ⅱ. Laboratory examination at the diagnosis showed a white blood cell count of 3.7 × 109/L, hemoglobin of 9.5 g/L, platelet count of 129 × 109/L, lactate dehydrogenase 121 U/L, calcium 8.8 mg/dL, creatine 0.46 mg/dl, estimated glomerular filtration rate 96 mL/min/1.73 m2, and IgG 7229 mg/dL. Bone marrow examination showed a total nucleated cell count of 27,000/µL with plasma cell concentration of 9.4%. She did not have any bone disease on X-ray. She underwent two cycles of an Ld regimen (lenalidomide and dexamethasone). She subsequently developed severe anemia. Laboratory examination showed a white blood cell 2.4 × 109/L, hemoglobin 6.8 g/L, platelet 107 × 109/L, reticulocyte 3.98 × 103/µL, lactate dehydrogenase 1337 U/L, and total bilirubin 1.9 mg/dL. Increase of lactate dehydrogenase and bilirubin were suspected hemolytic anemia, however, coombs test was negative and reticulocyte count was low, which was compatible with ineffective erythropoiesis due to sudden erythroid maturation arrest. Bone marrow examination showed a total nucleated cell count of 14,000/µL with a myeloid cell concentration of 41.2%, erythroid cell concentration of 0.4%, lymphoid cell concentration of 38.4%, monocyte concentration of 12.0%, and plasma cell concentration of 4.2%. The serum vitamin B12 and folic acid concentrations were normal. Expression of CD55 and CD59 on granulocytes was within the reference range. We diagnosed the patient with PRCA and began treatment with cyclosporine at 140 mg/day. Hemoglobin concentration improved from 6.8 g/L to 10.2 g/L within one month. Lenalidomide was suspected to be the cause of the PRCA; therefore, the lenalidomide was stopped and only dexamethasone was given intermittently for treatment of the MM. Although the patient maintained a partial response for 5 years, the MM subsequently relapsed. She began treatment with a VCD regimen (bortezomib, cyclophosphamide, and dexamethasone), which was not sufficiently effective, and was finally switched to pomalidomide. The PRCA did not worsen during treatment with pomalidomide. At the time of this writing, she had stopped all treatment for MM and PRCA because of the development of lung cancer.\n\n3 Case 2\nA 73-year-old man undergoing dialysis for diabetic renal dysfunction was diagnosed with symptomatic MM (IgA λ type), Durie Salmon stage Ⅲ B, ISS Ⅲ. Laboratory examination at the diagnosis showed a white blood cell count of 4.2 × 109/L, hemoglobin of 7.1 g/L, platelet count of 232 × 109/L, lactate dehydrogenase 191 U/L, calcium 9.0 mg/dL, creatine 3.54 mg/dl, estimated glomerular filtration rate 14 mL/min/1.73 m2, and IgA 1821 mg/dL. Bone marrow examination showed a total nucleated cell count of ?/µL with plasma cell concentration of 27.0%. He had old lumbar compression fracture on X-ray. He began treatment with a BD regimen (bortezomib and dexamethasone) as an induction regimen. After nine cycles of the BD regimen, the MM became resistant. The treatment was switched to an Ld regimen (lenalidomide at 5 mg/day and dexamethasone at 20 mg/day). After 11 cycles of Ld, he suddenly developed anemia. Laboratory examination showed a white blood cell count of 12.3 × 109 /L, hemoglobin 7.9 g/L, platelet 153 × 109/L, reticulocyte count 22.5 × 103/µL, lactate dehydrogenase 298 U/L, total bilirubin 0.5 mg/dL. Bone marrow examination showed a total nucleated cell count of 13,200/µL with a myeloid cell concentration of 47.8%, erythroid cell concentration of 3.1%, lymphoid cell concentration of 21.3%, monocyte concentration of 7.1%, and plasma cell concentration of 20.8%. The serum vitamin B12 and folic acid concentrations were normal. Expression of CD55 and CD59 on granulocytes was within the reference range. We diagnosed the patient with PRCA and began treatment with cyclosporine at 200 mg/day. The anemia slowly improved, hemoglobin concentration from 7.9 g/L to 9.9 g/L, and the patient maintained a partial response. Lenalidomide was suspected to be the cause of the PRCA; therefore, the lenalidomide was stopped and the patient was given only dexamethasone for treatment of the MM. However, the MM gradually progressed and the patient died 6 months after the development of PRCA.\n\n4 Discussion\nPRCA is an acquired anemia that may be idiopathic or secondary to a variety of neoplastic, autoimmune, or infectious diseases or to drug exposure. Most cases of PRCA are considered to be autoimmune-mediated. MM is a plasma cell disorder characterized by osteolytic bone lesions, hypercalcemia, renal failure, and anemia. Although anemia is a common end-organ feature of MM, PRCA with erythroid maturation arrest is not a typical finding in patients with MM. Korde et al. recently performed a systematic assessment of monoclonal gammopathy-associated PRCA [6]. They found that among 51 patients with PRCA, 24% had a monoclonal gammopathy disorder. Three patients who were treated with anti-MM drugs exhibited reticulocyte recovery. Therefore, the authors speculated that a functional relationship exists between plasma cell and erythroid precursors in patients with monoclonal gammopathy-associated PRCA. A few case reports have described that patients developed PRCA undergoing treatment with anti-MM drugs [5], [6]. Among them, two patients were using bortezomib. It is difficult to determine whether PRCA is induced by MM itself or induced by drugs. Reports of drug-induced PRCA have mostly involved erythropoietin, phenytoin, isoniazid, azathioprine, and zidovudine [7]. A few reports of lenalidomide-induced PRCA have been described in patients with myelodysplastic syndrome [8], [9], but not in patients with MM. Figs. 1 and 2Fig. 1 Case 1: A 77-year-old woman diagnosed with MM (IgG λ type). She underwent treatment with two cycles of an Ld regimen (lenalidomide and dexamethasone). She subsequently developed severe anemia. Cyclosporine was begun at 140 mg/day, and the anemia improved within 1 month.\n\nFig 1Fig. 2 Case 2: A 73-year-old man diagnosed with MM (IgA λ type). He underwent treatment with a BD regimen (bortezomib and dexamethasone). After nine cycles of the BD regimen, he was switched to the Ld regimen (lenalidomide at 5 mg/day and dexamethasone at 20 mg/day). After 11 cycles of Ld, he suddenly developed anemia. He began treatment with cyclosporine at 200 mg/day. The anemia slowly improved. However, the MM gradually progressed and he died 6 months after the development of PRCA.\n\nFig 2\n\nBoth patients in the present report developed PRCA after treatment with lenalidomide; thus, we considered drug-induced PRCA to be likely, and the lenalidomide was stopped in both patients. However, as Korde et al. described [6], if PRCA is associated with the activity of MM, we should not have stopped the lenalidomide. Although the optimal course of action is very difficult to judge, we suggest that another anti-MM treatment should be continued in patients with poor control of MM.\n\nWe consider that MM itself might be associated with PRCA and that anti-MM treatment agents might trigger the development of PRCA. Further investigation is warranted to elucidate the pathogenetic mechanism between MM and PRCA.\n\nConflict of interest\nThe authors declare no competing financial interest in relation to the work.\n\nAuthors' contributions\n(1) The conception and design of the study, or acquisition of data, or analysis and interpretation of data: A.N., S.F., A.S., T.N., Y.T., Y.A., A.K., M.H., H.Y., K.I., T.I. (2) drafting the article or revising it critically for important intellectual content,: A.N., T.I., S.N. (3) final approval of the version to be submitted.: A.N., T.I.\n\nAppendix Supplementary materials\nImage, application 1 \n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.lrr.2018.06.005.\n==== Refs\nReferences\n1 T. Robert, Jr. Means, Pure red cell aplasia Blood. 2016;128:2504–2509.\n2 Kobayashi T. Hanada T. Sato Y. Shibuya A. Ninomiya H. Nagasawa T,Abe A case of pure red cell aplasia with monoclonal gammopathy: immune-mediated inhibition of erythropoiesis Rinsho Ketsueki 28 11 1987 2029 2033 3128675 \n3 Orchard J1. Myint H. Hamblin T.J. A patient with myeloma who still has pure red cell aplasia despite the most intensive immune modulation Leuk. Res. 21 4 1997 353 354 9150354 \n4 So C.C. Choi W.W. Kwong Y.L. Pure red cell aplasia associated with CD20+ myeloma: complete remission with rituximab Ann. Hematol 92 10 2013 1425 1426 23494205 \n5 Lv Y. Qian W. Treatment of pure red cell aplasia associated with multiple myeloma with biclonal gammopathy using cyclosporine A: a case report Int. J. Clin. Exp. Med. 8 1 2015 15 1498 1500 25785163 \n6 Korde N. Zhang Y. Loeliger K. Poon A. Simakova O. Zingone A. Monoclonal gammopathy-associated pure red cell aplasia Br. J. Haematol. 173 6 2016 876 883 26999424 \n7 Thompson D.F. Gales M.A. Drug-induced pure red cell aplasia Pharmacotherapy 16 6 1996 1002 1008 8947971 \n8 Dolai T.K. Dutta S. Mandal P.K. Saha S. Bhattacharyya M. Lenalidomide-induced pure red cell aplasia Turk. J. Haematol. 31 1 2014 99 100 24764740 \n9 Cerchione C. Catalano L. Cerciello G. Avilia S. Picardi M. Risitano A.M. Pisano I. Alfinito F. Pane F. Role of lenalidomide in the management of myelodysplastic syndromes with del(5q) associated with pure red cell aplasia (PRCA) Ann. Hematol. 94 3 2015 531 534 25135452\n\n",
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"title": "Secondary pure red cell aplasia in multiple myeloma treated with lenalidomide.",
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"abstract": "Midostaurin and gilteritinib are FLT3 inhibitors that have been recently approved for use in FLT3-mutant acute myeloid leukemia (AML). These approved drugs represent a new standard of care for patients with FLT3 mutations in both the first-line and salvage settings. The success of midostaurin used in combination with induction chemotherapy has prompted exploration of newer, more potent and targeted inhibitors (including gilteritinib) in the first-line setting in combination with chemotherapy. At the same time, the success of gilteritinib and other newer FLT3 inhibitors as monotherapy in the salvage setting has been tempered by the development of resistance because of diverse mechanisms. Investigational strategies that incorporate FLT3 inhibitors in combination with hypomethylating agents and as maintenance therapy after allogeneic stem cell transplantation have shown promise. Other novel combination strategies are also undergoing clinical investigation. In this article, we review the current landscape of approved and investigational FLT3 inhibitors in AML, including the current standard of care and investigational strategies.",
"affiliations": "Divsion of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA.",
"authors": "Smith|Catherine C|CC|",
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"mesh_terms": "D064591:Allografts; D000814:Aniline Compounds; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D060046:Maintenance Chemotherapy; D008875:Middle Aged; D011719:Pyrazines; D019311:Staurosporine; D033581:Stem Cell Transplantation; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "100890099",
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"pubdate": "2019-12-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "31088841;31034300;26549589;11535508;14726387;23430109;29227476;27895058;29859851;29187377;28645776;24623852;30651561;23613521;29117486;23969938;23691988;29139135;26789727;27908881;25847190;23377436;25270908;29875101;16150941;27579651;22504184;22368270;23634996;23012328;19654408;20733134;27872058",
"title": "The growing landscape of FLT3 inhibition in AML.",
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"abstract": "BACKGROUND\nRhabdomyolysis is a rare but serious complication of lipid-lowering therapy. Statin and fibrate combination increases the risk of rhabdomyolysis possibly by pharmacodynamic interactions. Advanced age, diabetes, hypothyroidism, polypharmacy, and renal impairment are known to increase the risk of rhabdomyolysis. Management strategies include fluid resuscitation and urine alkalinization. Renal indications such as refractory hyperkalemia, acidosis, fluid overload, or uremic complications mandate renal replacement therapy in rhabdomyolysis.\n\n\nMETHODS\nWe report the case of a 62-year-old Sri Lankan Sinhalese man with dyslipidemia, type 2 diabetes mellitus with renal impairment, and hypothyroidism who was on atorvastatin; he was started on gemfibrozil and developed muscle symptoms. Although gemfibrozil was discontinued soon after, he presented with rhabdomyolysis with acute kidney injury 1 month later. He needed hemodialysis due to refractory hyperkalemia, metabolic acidosis, and fluid overload.\n\n\nCONCLUSIONS\nRhabdomyolysis is a rare but serious complication due to lipid-lowering therapy with statins and fibrates. Treating physicians should be aware and patients should be warned to report about muscle symptoms after starting statins or fibrates. Rhabdomyolysis may occur with mild symptoms and signs and may occur later, even after discontinuation of the drug.",
"affiliations": "Department of Medicine, University of Peradeniya, Peradeniya, Sri Lanka. chamaradalugama@yahoo.com.;Department of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.;Department of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.",
"authors": "Dalugama|Chamara|C|;Pathirage|Manoji|M|;Kularatne|S A M|SAM|",
"chemical_list": "D065687:Cytochrome P-450 CYP2C8 Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069059:Atorvastatin; D003404:Creatinine; D015248:Gemfibrozil",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 168510.1186/s13256-018-1685-0Case ReportDelayed presentation of severe rhabdomyolysis leading to acute kidney injury following atorvastatin-gemfibrozil combination therapy: a case report Dalugama Chamara chamaradalugama@yahoo.com Pathirage Manoji manojipathi@yahoo.com Kularatne S. A. M. samkul@sltnet.lk 0000 0000 9816 8637grid.11139.3bDepartment of Medicine, University of Peradeniya, Peradeniya, Sri Lanka 22 5 2018 22 5 2018 2018 12 14323 11 2017 9 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\nRhabdomyolysis is a rare but serious complication of lipid-lowering therapy. Statin and fibrate combination increases the risk of rhabdomyolysis possibly by pharmacodynamic interactions. Advanced age, diabetes, hypothyroidism, polypharmacy, and renal impairment are known to increase the risk of rhabdomyolysis. Management strategies include fluid resuscitation and urine alkalinization. Renal indications such as refractory hyperkalemia, acidosis, fluid overload, or uremic complications mandate renal replacement therapy in rhabdomyolysis.\n\nCase presentation\nWe report the case of a 62-year-old Sri Lankan Sinhalese man with dyslipidemia, type 2 diabetes mellitus with renal impairment, and hypothyroidism who was on atorvastatin; he was started on gemfibrozil and developed muscle symptoms. Although gemfibrozil was discontinued soon after, he presented with rhabdomyolysis with acute kidney injury 1 month later. He needed hemodialysis due to refractory hyperkalemia, metabolic acidosis, and fluid overload.\n\nConclusions\nRhabdomyolysis is a rare but serious complication due to lipid-lowering therapy with statins and fibrates. Treating physicians should be aware and patients should be warned to report about muscle symptoms after starting statins or fibrates. Rhabdomyolysis may occur with mild symptoms and signs and may occur later, even after discontinuation of the drug.\n\nKeywords\nRhabdomyolysisAcute kidney injuryAtorvastatinGemfibrozilHemodialysisMyoglobinCreatine kinaseissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nDyslipidemia is an important risk factor for cardiovascular (CV) disease [1, 2]. Statins are the mainstay in lipid-lowering therapy. The combination of a statin and a fibrate, particularly in mixed dyslipidemia, offers greater lipid-modifying efficacy. Statins and fibrates are known to cause rhabdomyolysis [3–8]. Combination therapy of a statin and a fibrate increases the risk mainly due to pharmacodynamic interactions [9–12]. Advanced age, diabetes, renal impairment, hypothyroidism, and type and higher doses of statins are recognized as important risk factors of rhabdomyolysis [13–26]. Rhabdomyolysis may present with subtle symptoms and signs and may be delayed at onset even after stopping of the culprit agent. Aggressive fluid resuscitation and urine alkalinization are important management strategies. Myoglobin is not dialyzable owing to its larger size. However, a small subset of patients with rhabdomyolysis might need dialysis for renal indications such as hyperkalemia, acidosis, or fluid overload not responding to medical therapy [27–32]. We report a case of rhabdomyolysis leading to acute kidney injury mandating urgent hemodialysis following treatment with atorvastatin-gemfibrozil combination.\n\nCase presentation\nWe report the case of a 62-year-old Sri Lankan Sinhalese man who presented to our Teaching Hospital, Peradeniya with a history of generalized malaise and anorexia of 1 week’s duration.\n\nHe had had poorly controlled type 2 diabetes for 12 years treated with orally administered hypoglycemic agents, which was complicated by diabetic nephropathy with a baseline serum creatinine of 220 micromol/L which was done 3 months back with urine analysis showing ++ protein. He was on thyroxine 100 mcg for hypothyroidism. He was a hypertensive for 10 years on losartan potassium. He was dyslipidemic and was on orally administered atorvastatin 40 mg daily. Serum lipids done 1 month back revealed high serum cholesterol with elevated triglycerides (TG) of 350 mg/dL. Gemfibrozil 600 mg twice daily was added on top of the statin by his general practitioner. Soon after starting gemfibrozil, our patient developed myalgia and he himself stopped taking gemfibrozil after 5 days. He then noticed gradual resolution of symptoms.\n\nHe developed generalized malaise and anorexia 3 weeks after the initial event. He noticed a reduction in urine output with dark urine for 2 days prior to admission. He noticed a reduction in exercise capacity with shortness of breath at rest.\n\nOn examination his temperature was 36.7 °C (98 °F). He was oriented in time, place, and person. He had mild pallor and bilateral ankle swelling. His pulse rate was 96 beats/minute with a blood pressure of 140/80 mmHg; his precordium examination was normal. He was dyspneic at rest with a respiratory rate of 24 cycles per minute and he had bilateral fine crackles up to mid zone. An abdominal examination was unremarkable. He had mild tenderness of his thigh muscles. He had 4/5 of normal strength against resistance in proximal muscles and his distal muscles had strength close to normal. Deep tendon reflexes were present but diminished.\n\nLaboratory investigations revealed a serum creatinine of 1232 micromol/L with a blood urea of 27.7 mmol/L. His serum potassium was 8 mmol/L with electrocardiographic evidence of hyperkalemia. His serum alanine transaminase (ALT) was 413 U/L and aspartate transaminase (AST) was 229 U/L. Hemoglobin was 9.4 g/dL with a mean corpuscular volume (MCV) of 85 fL. His white cell count was 6.6 × 106/microL and platelet count of 87 × 103/microL. Corrected serum calcium value was 1.63 mmol/L for an albumin value of 31 g/L. His serum phosphate was 4.7 mg/dL (2.5–4.5 mg/dL). His lactate dehydrogenase level was 240 U/L (88–230 U/L) and uric acid was 12.4 mg/dL (2.4–7.4 mg/dL). His C-reactive protein was 68.5 mg/L. Arterial blood gas revealed severe metabolic acidosis with a pH of 7.12: bicarbonate 8.8 mmol/L, partial pressure of carbon dioxide (PCO2) 27 mmHg, and base excess of − 20.5 mmol/L. An ultrasound scan of his kidney-ureter-bladder revealed normal size kidneys with slightly altered corticomedullary demarcation and no obstruction to outflow tract. His creatine kinase (CK) level was 49,146 U/L and urine myoglobin was positive. A diagnosis of rhabdomyolysis leading to acute-onset chronic renal failure was made. His random blood sugar was 145 mg/dL and urine ketone bodies were negative. He was clinically euthyroid while on thyroxine 100 mcg/day and his thyroid-stimulating hormone (TSH) was 6.5 u/L (normal range 0.4–4 u/L). Other causes of rhabdomyolysis, such as hyperthermia, prolonged seizures, trauma, physical muscle damage or stress, dehydration, burns, or alcohol abuse were not evident in our patient. He did not have fever preceding the event. His clinical course and laboratory data suggest that the combination of atorvastatin and gemfibrozil is the most probable cause of rhabdomyolysis.\n\nHe was catheterized. He was given calcium gluconate and insulin dextrose to manage the hyperkalemia. Acidosis was corrected with an 8.4% sodium bicarbonate infusion. He was started on intravenously administered furosemide. Considering his high serum creatinine, severe metabolic acidosis, and hyperkalemia, he was offered urgent hemodialysis via a vascular catheter. His daily renal functions and CK were monitored. He was offered four consecutive hemodialysis sessions every other day. Gradual improvement in his urine output was noted. His CK levels normalized over the days. He was discharged on day 8 of admission with a serum creatinine of 280 micromol/L and normal CK level. On a follow-up visit 1 week later, his serum creatinine was 256 micromol/L with normal CK level.\n\nDiscussion\nCV diseases are a major cause of morbidity and mortality in the world. According to the World Health Organization (WHO), the prevalence of CV diseases will double by 2020 and will rank higher than HIV/AIDS infection [1]. Dyslipidemia is recognized as an important risk factor for CV disease [2]. Statin therapy is recommended as the primary pharmacologic agent to achieve target low-density lipoprotein cholesterol (LDL-C) goals on the basis of morbidity and mortality outcome trials. Fibrates may improve atherosclerotic CV disease (ASCVD) outcomes in primary and secondary prevention when TG concentrations are ≥ 200 mg/dL and high-density lipoprotein cholesterol (HDL-C) concentrations are < 40 mg/dL [33].\n\nRhabdomyolysis is a clinical syndrome in which muscle necrosis leads to release of intramuscular contents into systemic circulation. It has a diverse clinical spectrum ranging from asymptomatic elevation of serum muscle enzymes to life-threatening cases associated with extremely high enzyme levels, electrolyte imbalances, and acute renal failure [3]. Patients may complain of myalgia, muscle weakness, or “tea color” urine. Diagnosis of rhabdomyolysis is often confirmed by elevated serum CK and myoglobinuria [4]. The incidence of rhabdomyolysis from all causes is 1.6 per 100,000 person-years [5].\n\nStatins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Statins are associated with a spectrum of skeletal muscle complaints ranging from asymptomatic elevation of serum CK, myalgia, and muscle cramps and weakness to severe myositis leading to rhabdomyolysis. Persistent myalgia and CK elevations are noted in some patients even after statin withdrawal [6]. The US Food and Drug Administration Adverse Event Reporting System database reports rates of statin-induced rhabdomyolysis of 0.3–13.5 cases per 1,000,000 statin prescriptions [7]. The mechanism of the myotoxic effects of statins is unclear. Statin-induced depletion of isoprenoids and inactivation of small GTPases, especially Rab, are postulated as important mechanisms in statin-induced myotoxicity [8].\n\nThe mechanism of rhabdomyolysis associated with fibrate therapy remains unclear. Although a few cases reported rhabdomyolysis in fibrate monotherapy, most of the cases are associated with statin and fibrate, particularly the gemfibrozil combination. Maiguma et al. described fibrate-medicated activation of the nuclear receptor peroxisome proliferator-activated receptor-A leading to cell-specific injury to human embryonal rhabdomyosarcoma cells in vitro to support a mechanism of fibrate-induced rhabdomyolysis [9]. Gemfibrozil and other fibrates are metabolized by CYP3A4 [10]; however, fibrates do not cause significant inhibition of the enzyme [11]. Pierce et al. reported the plasma levels of active metabolites of lovastatin were not usually elevated in 12 patients with severe myopathy who were receiving combined treatment with gemfibrozil supporting this fact [12]. The interaction between fibrates and statins is thought to be pharmacodynamic rather than pharmacokinetic. Therefore the rhabdomyolysis effect may be increased due to summation and synergism of myotoxicity of both drugs.\n\nMany risk factors have being described in relation to statin-induced rhabdomyolysis. The risk of statin-induced muscle toxicity is more likely with higher doses [13]. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, in which 12,064 patients with a history of myocardial infarction were treated with simvastatin 20 mg or 80 mg daily (mean follow-up 6.7 years), the incidence of myopathy and rhabdomyolysis in patients on 80 mg/day were significantly high [14]. Advanced age and female sex were identified as predisposing factors potentially increasing the risk of statin-induced myopathy [15]. Six statins are currently prescribed: rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, and lovastatin. Cerivastatin was taken off the market by its manufacturer in 2001, as many cases reported cerivastatin-induced rhabdomyolysis [16]. The risk of myopathy does not appear to be significantly different among all the other statins currently available; however, simvastatin at maximal dose of 80 mg was reported to cause more myotoxicity compared to other statins [17]. The risk for serious muscle toxicity appears to be increased in patients with diabetes, particularly in those with background renal impairment [18, 19]. Hypothyroidism increases the risk of statin and/or fibrate-induced rhabdomyolysis [20–22].\n\nDrugs which interfere with statin metabolism or transport leading to increased systemic exposure to the drug increase the risk of myopathy. Nearly 60% of statin-related rhabdomyolysis is related to drug interactions [23]. Many statin–drug interactions involve the CYP3A4/5 (simvastatin, lovastatin, and atorvastatin) or CYP2C8/9 (rosuvastatin) drug metabolizing systems [24]. Some were modulated by the efflux transporter P-glycoprotein [25]. Some drugs interfere with the transporters responsible for hepatic uptake and excretion of statins may also affect the pharmacokinetics of statins and the risk of myopathy [26]. As discussed before, some are pharmacodynamic interactions with summative and synergistic properties of myotoxicity.\n\nFew case reports in the literature describe the occurrence of rhabdomyolysis in patients who were stable with a single lipid-lowering agent, either a statin or a fibrate, and addition of a second agent had initiated myositis and subsequent rhabdomyolysis. Lau et al. described a case of rhabdomyolysis in a patient on long-term fibrate following addition of cerivastatin [27]. Another report by Jozić et al. described rhabdomyolysis in a patient in whom rosuvastatin was replaced with pravastatin and gemfibrozil [28]. Similar to our case, the patient was on long-term high-dose statin and occurrence of rhabdomyolysis followed the addition of a second lipid-lowering agent.\n\nOur patient had many risk factors including advanced age, poorly controlled type 2 diabetes mellitus, background renal impairment, and hypothyroidism. He was on a large dose of statin that was subsequently combined with gemfibrozil resulting in massive rhabdomyolysis. He experienced muscle symptoms soon after adding gemfibrozil and the drug was discontinued. Although his symptoms settled soon after discontinuation, he presented to a health care institution after 4 weeks with uremic symptoms and anuria with a massive elevation of CK. This is the first case reporting rhabdomyolysis with renal impairment presenting 4 weeks after discontinuing fibrate after muscle symptoms. Gemfibrozil is a drug which is extensively metabolized by the liver and excreted mainly by the kidneys with an elimination half-life of 1.5 hours [29]. Underlying chronic renal impairment might have prolonged the elimination half-life. We believe that the summative and synergistic properties of statin and fibrate initiated the muscle damage. Initial myotoxicity would have propagated insidiously over the period of 4 weeks culminating in renal failure with anuria. The damaged muscle would have been more vulnerable to high-dose statin, which our patient continued to take until admission. Gradually worsening renal impairment due to the ongoing rhabdomyolysis could be a vicious cycle leading to more renal damage from the retaining myotoxins. Interestingly, he had minimum muscle symptoms and mild tenderness of thigh muscles despite having a CK of nearly 50,000 U/L.\n\nThe main step in managing rhabdomyolysis-induced acute kidney injury remains the early, aggressive repletion of fluids, but unfortunately it was not an option for our patient who was already in anuric renal failure [30]. Beall et al. proposed administering sodium bicarbonate, which results in an alkaline urine [34]. Alkalinization of urine is known to be advantageous in rhabdomyolysis [31]. First, it is known that precipitation of the Tamm–Horsfall protein–myoglobin complex is increased in acidic urine [32, 33]. Second, alkalinization inhibits reduction–oxidation (redox) cycling of myoglobin and lipid peroxidation in rhabdomyolysis, thus ameliorating tubule injury [35]. Third, it has been shown that metmyoglobin induces vasoconstriction only in an acidic medium in the isolated perfused kidney [36]. Our patient was administered 8.4% sodium bicarbonate to correct severe metabolic acidosis. However, since our patient was anuric, whether the above mentioned mechanisms operated is doubtful.\n\nConventional hemodialysis does not remove myoglobin effectively owing to the size of the protein. When acute kidney injury is severe enough with refractory hyperkalemia, acidosis, or volume overload, renal replacement therapy (RRT) is indicated, principally with intermittent hemodialysis [37]. Therefore the need of RRT should be mandated by renal indications. Our patient had a serum creatinine of more than 1000 micromol/L with severe hyperkalemia and severe metabolic acidosis with features of volume overload and anuria. He needed immediate hemodialysis to correct metabolic derangements. Gradually, he became normouric and the intake was titrated accordingly. Following four cycles of hemodialysis, the urine output of our patient improved, acidosis was corrected, and potassium was normalized. His serum creatinine level declined to 800 mmol/L. Dialysis was withheld and a gradual decline in CK levels and serum creatinine was noticed over the days.\n\nConclusions\nRhabdomyolysis is a rare but serious side effect of statin monotherapy and more common in combination therapy of statin and fibrate. Patients with multiple risk factors such as diabetes, renal impairment, hypothyroidism, and polypharmacy are at increased risk of rhabdomyolysis. Rhabdomyolysis may occur with minimum clinical symptoms and signs, even many weeks after discontinuation of therapy. Treating physicians should be more cautious in prescribing statins or combination therapy of statin and fibrates in those with risk factors and should discuss signs and symptoms of muscle toxicity with patients in order to prevent rhabdomyolysis.\n\nAvailability of data and materials\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nCD, MP, and SAMK examined, assessed, and were involved in the management of the patient. All authors collected data and analyzed. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nEthical approval was not obtained for the publication of this case report as this does not involve sharing of the personal details of the patient.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Doupa D Seck SM Dia CA Dyslipidemia, obesity and other cardiovascular risk factors in the adult population in Senegal Pan Afr Med J 2014 19 article no. 181 10.11604/pamj.2014.19.181.4872 25815102 \n2. Yusuf S Hawken S Ounpuu S Dans T Avezum A Lanas F Effect of potentially modifiable risk factors associated with MI in 52 countries (the INTERHEART study): case-control study Lancet 2004 364 937 952 10.1016/S0140-6736(04)17018-9 15364185 \n3. Line RL Rust GS Acute exertional rhabdomyolysis Am Fam Physician 1995 52 2 502 506 7625324 \n4. Arrington ED Miller MD Skeletal muscle injuries Orthop Clin North Am 1995 26 3 411 412 7609956 \n5. Law M Rudnicka AR Statin safety: a systematic review Am J Cardiol 2006 97 8A 52C 60C 10.1016/j.amjcard.2005.12.010 16581329 \n6. Thompson PD Clarkson P Karas RH Statin-associated myopathy JAMA 2003 289 1681 1690 10.1001/jama.289.13.1681 12672737 \n7. Davidson MH Clark JA Glass LM Statin safety: an appraisal from the adverse event reporting system Am J Cardiol 2006 97 8A 32C 43C 10.1016/j.amjcard.2005.12.008 16581327 \n8. Sakamoto K Kimura J Mechanism of statin-induced rhabdomyolysis J Pharmacol Sci 2013 123 4 289 294 10.1254/jphs.13R06CP 24257439 \n9. Maiguma T Fujisaki K Itoh Y Cell-specific toxicity of fibrates in human embryonal rhabdomyosarcoma cells Naunyn Schmiedeberg’s Arch Pharmacol 2003 367 289 10.1007/s00210-002-0660-9 12644902 \n10. Miller DB Spence JD Clinical pharmacokinetics of fibric acid derivatives (fibrates) Clin Pharmacokinet 1998 34 155 162 10.2165/00003088-199834020-00003 9515185 \n11. Guyton JR Dujovne CA Illingworth DR Dual hepatic metabolism of cerivastatin—clarifications Am J Cardiol 1999 84 497 10.1016/S0002-9149(99)90433-2 10468102 \n12. Pierce LR Wysowski DK Gross TP Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy JAMA 1990 264 71 75 10.1001/jama.1990.03450010075034 2355431 \n13. Armitage J The safety of statins in clinical practice Lancet 2007 370 9601 1781 1790 10.1016/S0140-6736(07)60716-8 17559928 \n14. Armitage J Bowman L Wallendszus K Bulbulia R Rahimi K Haynes R Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial Lancet 2010 376 1658 1669 10.1016/S0140-6736(10)60310-8 21067805 \n15. Joy TR Hegele RA Narrative review: statin-related myopathy Ann Intern Med 2009 150 858 868 10.7326/0003-4819-150-12-200906160-00009 19528564 \n16. Fuhrmans V Bayer discloses higher death toll from Baycol Wall Street J 2002 21 A10 \n17. Backes JM Howard PA Ruisinger JF Moriarty PM Does simvastatin cause more myotoxicity compared with other statins? Ann Pharmacother 2009 43 2012 2020 10.1345/aph.1M410 19920157 \n18. Çetinkaya R Uyanik A Yildirim R Bilen Y Keleş M Fenofibrate monotherapy-induced rhabdomyolysis in a patient with type-2 diabetes Indian J Med Sci 2008 62 11 458 459 10.4103/0019-5359.48458 19265237 \n19. Jacob SS Jacob S Williams C Deeg MA Simvastatin, fenofibrate, and rhabdomyolysis Diabetes Care 2005 28 5 1258 10.2337/diacare.28.5.1258 15855605 \n20. Satarasinghe RL Ramesh R Riyaaz AAA Gunarathne PAKG de Silva AP Hypothyroidism is a predisposing factor for fenofibrate-induced rhabdomyolysis—patient report and literature review Drug Metabol Drug Interact 2007 22 4 279 283 10.1515/DMDI.2007.22.4.279 18447003 \n21. de Sousa AA Kronit HS Neves FAR Amato AA Fenofibrate-induced rhabdomyolysis in a patient with chronic kidney disease: an unusual presenting feature of hypothyroidism Arq Bras Endocrinol Metabol 2009 53 3 383 386 10.1590/S0004-27302009000300015 19578603 \n22. Clouatre Y Leblanc M Ouimet D Pichette V Fenofibrate-induced rhabdomyolysis in two dialysis patients with hypothyroidism Nephrol Dial Transplant 1999 14 4 1047 1048 10.1093/ndt/14.4.1047 10328516 \n23. Chatzizisis YS Koskinas KC Misirli G Vaklavas C Hatzitolios A Giannoglou GD Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment Drug Saf 2010 33 171 187 10.2165/11319380-000000000-00000 20158283 \n24. Frishman WH Horn J Statin–drug interactions: not a class effect Cardiol Rev 2008 16 205 212 10.1097/CRD.0b013e31817532db 18562811 \n25. Holtzman CW Wiggins BS Spinler SA Role of P-glycoprotein in statin drug interactions Pharmacotherapy 2006 26 1601 1607 10.1592/phco.26.11.1601 17064205 \n26. Ieiri I Higuchi S Sugiyama Y Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs Expert Opin Drug Metab Toxicol 2009 5 703 729 10.1517/17425250902976854 19442037 \n27. Lau TK Leachman DR Lufschanowski R Severe Rhabdomyolysis Associated with the Cerivastatin-Gemfibrozil Combination Therapy: Report of a Case Tex Heart Inst J 2001 28 2 142 145 11453128 \n28. Jozić TL Terzić BM Mitrović PM Kostić JD Milanov MZ Stojanović MM Ašanin MR Combined Statin-Fibrate Therapy-Induced Rhabdomyolysis: Case Report Hosp Pharmacol 2014 1 1 22 26 \n29. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Drug Metabolism and Disposition. 2002;30(11):1280-87.\n30. Better OS Stein JH Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis N Engl J Med 1990 322 825 829 10.1056/NEJM199003223221207 2407958 \n31. Ron D Taitelman U Michaelson M Bar-Joseph G Bursztein S Better OS Prevention of acute renal failure in traumatic rhabdomyolysis Arch Intern Med 1984 144 277 280 10.1001/archinte.1984.00350140077012 6696564 \n32. Zager RA Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury Lab Investig 1989 60 619 629 2716281 \n33. Jellinger PS Handelsman Y Rosenblit PD Bloomgarden ZT Fonseca VA Garber AJ Grunberger G Guerin CK Bell DSH Mechanick JI Pessah-Pollack R Wyne K Smith D Brinton EA Fazio S Davidson M American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease Endocr Pract 2017 23 Suppl 2 1 87 10.4158/EP171764.APPGL 28437620 \n34. Beall D, Bywaters EGL, Belsey RHR, Miles JAR. Crush Injury with Renal Failure. BMJ. 1941;1(4185):432–34.\n35. Moore KP Holt SG Patel RP A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure J Biol Chem 1998 273 31731 31737 10.1074/jbc.273.48.31731 9822635 \n36. Heyman SN Greenbaum R Shina A Rosen S Brezis M Myoglobinuric acute renal failure in the rat: a role for acidosis? Exp Nephrol 1997 5 210 216 9208280 \n37. Lameire N Van Biesen W Vanholder R Acute renal failure Lancet 2005 365 417 430 10.1016/S0140-6736(05)70238-5 15680458\n\n",
"fulltext_license": "CC BY",
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"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "Acute kidney injury; Atorvastatin; Creatine kinase; Gemfibrozil; Hemodialysis; Myoglobin; Rhabdomyolysis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000069059:Atorvastatin; D003404:Creatinine; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D004359:Drug Therapy, Combination; D015248:Gemfibrozil; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D019338:Polypharmacy; D012206:Rhabdomyolysis; D012307:Risk Factors",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "143",
"pmc": null,
"pmid": "29784023",
"pubdate": "2018-05-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9208280;9515185;25815102;6696564;16581327;19265237;19578603;12644902;28437620;20783578;2716281;16581329;15855605;2407958;24257439;17064205;15680458;19920157;18562811;10328516;10468102;15364185;12386136;2355431;17559928;7625324;19528564;18447003;21067805;9822635;12672737;7609956;19442037;20158283;11453128",
"title": "Delayed presentation of severe rhabdomyolysis leading to acute kidney injury following atorvastatin-gemfibrozil combination therapy: a case report.",
"title_normalized": "delayed presentation of severe rhabdomyolysis leading to acute kidney injury following atorvastatin gemfibrozil combination therapy a case report"
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"abstract": "Wilson disease (WD) is a rare genetic condition that results from a build-up of copper in the body. It requires life-long treatment and is mainly characterized by hepatic and neurological features. Copper accumulation has been reported to be related to the occurrence of heart disease, although little is known regarding this association. We have conducted a systematic review of the literature to document the association between WD and cardiac involvement. Thirty-two articles were retained. We also described three cases of sudden death. Cardiac manifestations in WD include cardiomyopathy (mainly left ventricular (LV) remodeling, hypertrophy, and LV diastolic dysfunction, and less frequently LV systolic dysfunction), increased levels of troponin, and/or brain natriuretic peptide, electrocardiogram (ECG) abnormalities, and rhythm or conduction abnormalities, which can be life-threatening. Dysautonomia has also been reported. The mechanism of cardiac damage in WD has not been elucidated. It may be the result of copper accumulation in the heart, and/or it could be due to a toxic effect of copper, resulting in the release of free oxygen radicals. Patients with signs and/or symptoms of cardiac involvement or who have cardiovascular risk factors should be examined by a cardiologist in addition to being assessed by their interdisciplinary treating team. Furthermore, ECG, cardiac biomarkers, echocardiography, and 24-hours or more of Holter monitoring at the diagnosis and/or during the follow-up of patients with WD need to be evaluated. Cardiac magnetic resonance imaging, although not always available, could also be a useful diagnostic tool, allowing assessment of the risk of ventricular arrhythmias and further guidance of the cardiac workup.",
"affiliations": "Department of Neurology, Rothschild Foundation Hospital, Paris, France.;Department of Cardiology, Rothschild Foundation Hospital, Paris, France.;Department of Neurology, Rothschild Foundation Hospital, Paris, France.;Department of Cardiology, Rothschild Foundation Hospital, Paris, France.;Department of Neurology, Rothschild Foundation Hospital, Paris, France.;Department of Cardiology, Rothschild Foundation Hospital, Paris, France.;Department of Neurology, Rothschild Foundation Hospital, Paris, France.",
"authors": "Chevalier|Kevin|K|0000-0001-7823-1827;Benyounes|Nadia|N|;Obadia|Michaël Alexandre|MA|;Van Der Vynckt|Clélie|C|;Morvan|Erwan|E|;Tibi|Thierry|T|;Poujois|Aurélia|A|0000-0002-5640-7534",
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"issue": "44(5)",
"journal": "Journal of inherited metabolic disease",
"keywords": "Wilson disease; arrhythmias; cardiomyopathy; copper; dysautonomia; sudden death",
"medline_ta": "J Inherit Metab Dis",
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"nlm_unique_id": "7910918",
"other_id": null,
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"title": "Cardiac involvement in Wilson disease: Review of the literature and description of three cases of sudden death.",
"title_normalized": "cardiac involvement in wilson disease review of the literature and description of three cases of sudden death"
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"abstract": "OBJECTIVE\nSystemic anticoagulation is the standard treatment for cerebral venous sinus thrombosis (CVST). Several endovascular techniques have been described as salvage therapy for anticoagulation refractory CVST cases. We aim to evaluate the safety and feasibility of endovascular aspiration thrombectomy using the new generation, large bore suction catheters alone or in combination with stentriever devices for the treatment of CVST.\n\n\nMETHODS\nWe collected data on 16 consecutive patients with CVST who received endovascular aspiration thrombectomy at three large academic centers. Second generation reperfusion catheters were used as a large bore suction catheter and advanced to the affected sinus using a coaxial technique. Suction was performed using pump suction. At times, a stentriever was used as an anchor to facilitate advancing the suction catheter and to increase thrombectomy capabilities.\n\n\nRESULTS\nMedian decade of age was the 50s and nine patients were women. Fifty percent of the patients had multiple sinuses involved. All patients received systemic anticoagulation prior to endovascular aspiration thrombectomy. The most common reason to pursue endovascular aspiration thrombectomy in CVST patients was deterioration of initial clinical status (10/16). The mean time from admission to endovascular aspiration thrombectomy was 1.5 days (range 0-6 days). Good recanalization was obtained in all patients. There were no major peri-procedural complications. Most patients were discharged to either home or a rehabilitation facility.\n\n\nCONCLUSIONS\nEndovascular aspiration treatment using large bore suction catheters for CVST is a safe and feasible approach for the treatment of anticoagulation refractory CVST. Heterogeneity of the clinical and radiological presentation requires further investigation to optimize patient selection before evaluating the efficacy of this technique in larger prospective studies.",
"affiliations": "Department of Neurology, University of Iowa Carver College of Medicine, Comprehensive Stroke Center, Iowa City, IA, USA.;Department of Neurology, University of Iowa Carver College of Medicine, Comprehensive Stroke Center, Iowa City, IA, USA.;Division of Interventional Neuroradiology, Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.;Department of Neurology, Southern Illinois University School of Medicine, Comprehensive Stroke Center, Springfield, IL, USA.;Division of Interventional Neuroradiology, Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.;Department of Neurology, Southern Illinois University School of Medicine, Comprehensive Stroke Center, Springfield, IL, USA.;Department of Neurology, University of Iowa Carver College of Medicine, Comprehensive Stroke Center, Iowa City, IA, USA.;Department of Neurology, University of Iowa Carver College of Medicine, Comprehensive Stroke Center, Iowa City, IA, USA.;Department of Neurosurgery, University of Iowa Carver College of Medicine, Comprehensive Stroke Center, Iowa City, IA, USA.;Department of Radiology, University of Iowa Carver College of Medicine, Comprehensive Stroke Center, Iowa City, IA, USA.;Department of Neurology, University of Iowa Carver College of Medicine, Comprehensive Stroke Center, Iowa City, IA, USA.",
"authors": "Dandapat|Sudeepta|S|https://orcid.org/0000-0003-3744-7845;Samaniego|Edgar A|EA|;Szeder|Viktor|V|https://orcid.org/0000-0003-0703-8258;Siddiqui|Fazeel M|FM|;Duckwiler|Gary R|GR|;Kiddy|Ume|U|;Guerrero|Waldo R|WR|;Zheng|Binbin|B|;Hasan|David|D|;Derdeyn|Colin|C|;Ortega-Gutierrez|Santiago|S|",
"chemical_list": "D000925:Anticoagulants",
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"delete": false,
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"issue": "26(1)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Thrombectomy; aspiration; cerebral venous thrombosis; large bore suction catheters; thrombolysis",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D000046:Academic Medical Centers; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D002404:Catheterization; D057785:Catheters; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015424:Reperfusion; D012189:Retrospective Studies; D012851:Sinus Thrombosis, Intracranial; D015607:Stents; D013396:Suction; D017131:Thrombectomy; D016896:Treatment Outcome",
"nlm_unique_id": "9602695",
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"pmc": null,
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"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "21799156;18184347;10066840;19372443;14976332;21990598;16809353;1679154;25899238;8800235;12519565;18340091;21293023;10319961;18635853;22958771",
"title": "Safety and efficacy of the use of large bore intermediate suction catheters alone or in combination for the treatment of acute cerebral venous sinus thrombosis: A multicenter experience.",
"title_normalized": "safety and efficacy of the use of large bore intermediate suction catheters alone or in combination for the treatment of acute cerebral venous sinus thrombosis a multicenter experience"
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"abstract": "Leukemia is observed with increased frequency in patients with severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy. The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period. The patient subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by polymerase chain reaction. This report provides novel insights on leukemia developing in congenital neutropenia.",
"affiliations": "Departments of Pediatrics and Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. sjeha@mdanderson.org",
"authors": "Jeha|S|S|;Chan|K W|KW|;Aprikyan|A G|AG|;Hoots|W K|WK|;Culbert|S|S|;Zietz|H|H|;Dale|D C|DC|;Albitar|M|M|",
"chemical_list": "D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D019272:Leukocyte Elastase",
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"mesh_terms": "D016026:Bone Marrow Transplantation; D002648:Child; D000075202:Contraindications; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D019272:Leukocyte Elastase; D008297:Male; D009154:Mutation; D009503:Neutropenia; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D012075:Remission, Spontaneous; D014184:Transplantation, Homologous",
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"title": "Spontaneous remission of granulocyte colony-stimulating factor-associated leukemia in a child with severe congenital neutropenia.",
"title_normalized": "spontaneous remission of granulocyte colony stimulating factor associated leukemia in a child with severe congenital neutropenia"
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... |
{
"abstract": "There are no prospective studies of aggressive non-Hodgkin lymphoma (NHL) treated with CHOP in sub-Saharan Africa. We enrolled adults with aggressive NHL in Malawi between June 2013 and May 2015. Chemotherapy and supportive care were standardized, and HIV+ patients received antiretroviral therapy (ART). Thirty-seven of 58 patients (64%) were HIV+. Median age was 47 years (IQR 39-56), and 35 (60%) were male. Thirty-five patients (60%) had stage III/IV, 43 (74%) B symptoms, and 28 (48%) performance status ≥ 2. B-cell NHL predominated among HIV+ patients, and all T-cell NHL occurred among HIV- individuals. Thirty-one HIV+ patients (84%) were on ART for a median 9.9 months (IQR 1.1-31.7) before NHL diagnosis, median CD4 was 121 cells/μL (IQR 61-244), and 43% had suppressed HIV RNA. HIV+ patients received a similar number of CHOP cycles compared to HIV- patients, but more frequently developed grade 3/4 neutropenia (84% vs 31%, p = 0.001), resulting in modestly lower cyclophosphamide and doxorubicin doses with longer intervals between cycles. Twelve-month overall survival (OS) was 45% (95% CI 31-57%). T-cell NHL (HR 3.90, p = 0.017), hemoglobin (HR 0.82 per g/dL, p = 0.017), albumin (HR 0.57 per g/dL, p = 0.019), and IPI (HR 2.02 per unit, p<0.001) were associated with mortality. HIV was not associated with mortality, and findings were similar among patients with diffuse large B-cell lymphoma. Twenty-three deaths were from NHL (12 HIV+, 11 HIV-), and 12 from CHOP (9 HIV+, 3 HIV-). CHOP can be safe, effective, and feasible for aggressive NHL in Malawi with and without HIV.",
"affiliations": "UNC Project-Malawi, Lilongwe, Malawi.;Lineberger Comprehensive Cancer Center, Chapel Hill, United States of America.;UNC Project-Malawi, Lilongwe, Malawi.;University of North Carolina Department of Pathology and Laboratory Medicine, Chapel Hill, United States of America.;UNC Project-Malawi, Lilongwe, Malawi.;UNC Project-Malawi, Lilongwe, Malawi.;Kamuzu Central Hospital, Lilongwe, Malawi.;University of Malawi College of Medicine, Blantyre, Malawi.;University of Malawi College of Medicine, Blantyre, Malawi.;UNC Project-Malawi, Lilongwe, Malawi.;UNC Project-Malawi, Lilongwe, Malawi.;UNC Project-Malawi, Lilongwe, Malawi.;University of Malawi College of Medicine, Blantyre, Malawi.;University of Malawi College of Medicine, Blantyre, Malawi.;Kamuzu Central Hospital, Lilongwe, Malawi.;UNC Project-Malawi, Lilongwe, Malawi.;UNC Project-Malawi, Lilongwe, Malawi.;UNC Project-Malawi, Lilongwe, Malawi.;Weill Cornell Medical College, Ithaca, United States of America.;Lineberger Comprehensive Cancer Center, Chapel Hill, United States of America.;UNC Project-Malawi, Lilongwe, Malawi.",
"authors": "Gopal|Satish|S|;Fedoriw|Yuri|Y|;Kaimila|Bongani|B|;Montgomery|Nathan D|ND|;Kasonkanji|Edwards|E|;Moses|Agnes|A|;Nyasosela|Richard|R|;Mzumara|Suzgo|S|;Varela|Carlos|C|;Chikasema|Maria|M|;Makwakwa|Victor|V|;Itimu|Salama|S|;Tomoka|Tamiwe|T|;Kamiza|Steve|S|;Dhungel|Bal M|BM|;Chimzimu|Fred|F|;Kampani|Coxcilly|C|;Krysiak|Robert|R|;Richards|Kristy L|KL|;Shea|Thomas C|TC|;Liomba|N George|NG|",
"chemical_list": "D018501:Antirheumatic Agents; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0150445",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2693405410.1371/journal.pone.0150445PONE-D-15-56410Research ArticleBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesOncologyCancer TreatmentMedicine and Health SciencesOncologyCancers and NeoplasmsHematologic Cancers and Related DisordersLymphomasMedicine and Health SciencesHematologyHematologic Cancers and Related DisordersLymphomasMedicine and Health SciencesPharmaceuticsDrug TherapyCancer TherapyChemotherapyMedicine and Health SciencesOncologyCancer TreatmentChemotherapyMedicine and health sciencesDiagnostic medicineHIV diagnosis and managementPeople and PlacesGeographical LocationsAfricaMalawiBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and health sciencesOncologyCancers and neoplasmsHematologic cancers and related disordersLymphomasNon-Hodgkin lymphomaMedicine and health sciencesHematologyHematologic cancers and related disordersLymphomasNon-Hodgkin lymphomaCHOP Chemotherapy for Aggressive Non-Hodgkin Lymphoma with and without HIV in the Antiretroviral Therapy Era in Malawi CHOP for Aggressive NHL in MalawiGopal Satish 124*Fedoriw Yuri 23Kaimila Bongani 1Montgomery Nathan D. 3Kasonkanji Edwards 1Moses Agnes 14Nyasosela Richard 5Mzumara Suzgo 45Varela Carlos 45Chikasema Maria 1Makwakwa Victor 1Itimu Salama 1Tomoka Tamiwe 4Kamiza Steve 4Dhungel Bal M. 5Chimzimu Fred 1Kampani Coxcilly 1Krysiak Robert 1Richards Kristy L. 6Shea Thomas C. 2Liomba N. George 11 \nUNC Project-Malawi, Lilongwe, Malawi2 \nLineberger Comprehensive Cancer Center, Chapel Hill, United States of America3 \nUniversity of North Carolina Department of Pathology and Laboratory Medicine, Chapel Hill, United States of America4 \nUniversity of Malawi College of Medicine, Blantyre, Malawi5 \nKamuzu Central Hospital, Lilongwe, Malawi6 \nWeill Cornell Medical College, Ithaca, United States of AmericaGalardy Paul J. EditorMayo Clinic, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: SG YF KLR TCS NGL. Performed the experiments: SG YF BK NDM EK AM RN SM CV MC VM SI TT SK BMD FC CK RK KLR TCS NGL. Analyzed the data: SG YF NDM KLR TCS NGL. Contributed reagents/materials/analysis tools: SG YF BK NDM EK AM RN SM CV MC VM SI TT SK BMD FC CK RK KLR TCS NGL. Wrote the paper: SG YF BK NDM EK AM RN SM CV MC VM SI TT SK BMD FC CK RK KLR TCS NGL.\n\n* E-mail: gopal@med.unc.edu2 3 2016 2016 11 3 e015044530 12 2015 15 2 2016 © 2016 Gopal et al2016Gopal et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.There are no prospective studies of aggressive non-Hodgkin lymphoma (NHL) treated with CHOP in sub-Saharan Africa. We enrolled adults with aggressive NHL in Malawi between June 2013 and May 2015. Chemotherapy and supportive care were standardized, and HIV+ patients received antiretroviral therapy (ART). Thirty-seven of 58 patients (64%) were HIV+. Median age was 47 years (IQR 39–56), and 35 (60%) were male. Thirty-five patients (60%) had stage III/IV, 43 (74%) B symptoms, and 28 (48%) performance status ≥2. B-cell NHL predominated among HIV+ patients, and all T-cell NHL occurred among HIV- individuals. Thirty-one HIV+ patients (84%) were on ART for a median 9.9 months (IQR 1.1–31.7) before NHL diagnosis, median CD4 was 121 cells/μL (IQR 61–244), and 43% had suppressed HIV RNA. HIV+ patients received a similar number of CHOP cycles compared to HIV- patients, but more frequently developed grade 3/4 neutropenia (84% vs 31%, p = 0.001), resulting in modestly lower cyclophosphamide and doxorubicin doses with longer intervals between cycles. Twelve-month overall survival (OS) was 45% (95% CI 31–57%). T-cell NHL (HR 3.90, p = 0.017), hemoglobin (HR 0.82 per g/dL, p = 0.017), albumin (HR 0.57 per g/dL, p = 0.019), and IPI (HR 2.02 per unit, p<0.001) were associated with mortality. HIV was not associated with mortality, and findings were similar among patients with diffuse large B-cell lymphoma. Twenty-three deaths were from NHL (12 HIV+, 11 HIV-), and 12 from CHOP (9 HIV+, 3 HIV-). CHOP can be safe, effective, and feasible for aggressive NHL in Malawi with and without HIV.\n\nThis work was supported by grants from the National Institutes of Health (K01TW009488, R21CA180815, and U54CA190152) (S.G.), the Medical Education Partnership Initiative (U2GPS001965) (S.K.), as well as the Lineberger Comprehensive Cancer Center (P30CA016086) and AIDS Malignancy Consortium (U01CA121947). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nNon-Hodgkin lymphoma (NHL) is increasing in sub-Saharan Africa (SSA) [1–3], but clinical features and outcomes are not well described. Reports have typically been retrospective, with many excluded or untreated patients, and high loss to follow-up. Descriptions have also often been before widespread availability of antiretroviral therapy (ART) for HIV.\n\nNHL diagnosis in SSA is frequently based on fine needle aspirates (FNAs) without immunohistochemistry (IHC), flow cytometry, or molecular tools [4–6]. NHL is therefore often treated as a single entity with CHOP being universally applied, given pathology limitations, restricted chemotherapy formularies, and settings where more intense or complex regimens are impractical. Even in resource-rich countries, CHOP remains a standard backbone for many NHL subtypes. The most important advance has been adding rituximab for CD20-positive NHL, which is neither widely available nor well-studied in SSA.\n\nDespite widespread use, there is no prospective description of first-line CHOP for adults with NHL in SSA. In the only clinical trial for this population, CHOP salvage was administered to 11 of 49 HIV-infected NHL patients who failed dose-modified oral chemotherapy in Kenya and Uganda, during 2001–2005 when ART was not widely available [7]. In the modern era, HIV-associated lymphoma patients in resource-rich settings can receive identical treatment with equivalent outcomes to patients without HIV [8–13]. Retrospective descriptions from Uganda and South Africa have also suggested CHOP can be effective, including for HIV-infected individuals receiving ART [14, 15]. Given high infectious burden and limited cancer infrastructure [16], a detailed prospective characterization of CHOP in SSA is important, and was undertaken at a national teaching hospital in Malawi.\n\nMethods\nPatients and procedures\nKamuzu Central Hospital (KCH) is a cancer referral center for eight million people in Malawi, a country which has 10% HIV prevalence, 67% ART coverage, and an annual gross domestic product per capita of 314 US dollars [17, 18]. The KCH Lymphoma Study is an ongoing prospective cohort approved by the University of North Carolina Institutional Review Board and Malawi National Health Sciences Research Committee. Through active case finding across all hospital departments and referring clinics, adults and children with newly diagnosed lymphoma were invited to participate after written informed consent. Informed consent forms and consent procedures were approved by ethics committees in the US and Malawi. All diagnoses were pathologically confirmed using tissue biopsies whenever possible, supported by IHC and weekly telepathology consultation involving 2–4 US and Malawian pathologists [19]. Available IHC stains included CD3, CD20, CD30, CD45, CD138, Ki-67, terminal deoxynucleotidyl transferase (TDT), and latency-associated nuclear antigen (LANA). Other stains included synaptophysin and AE1/AE3 to distinguish lymphomas from neuroendocrine or epithelial tumors when morphology is equivocal. Definitively distinguishing Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and overlapping subtypes was difficult without cytogenetic and molecular tools. These subtypes were therefore grouped as aggressive B-cell NHL and treated with CHOP, since infusional or more intensive regimens for BL or other NHL subtypes were not feasible. All diagnostic specimens were shipped to the US for final classification, although results were not available in time to guide frontline therapy.\n\nPatients underwent comprehensive baseline evaluation including chest x-ray, abdominal ultrasound, and bone marrow examination. Cerebrospinal fluid (CSF) cytology was recommended for patients at high risk for leptomeningeal involvement (>1 extranodal site and elevated lactate dehydrogenase (LDH); involvement of bone marrow, testicular, epidural, ocular, breast, or paranasal sinus sites; or Ki67 >90% suggesting BL or similarly aggressive B-cell NHL). Patients received longitudinal follow-up with active tracing and transportation reimbursement to promote retention. Response was assessed using standardized criteria incorporating physical exam, chest x-ray, and abdominal ultrasound. For this report, we focused on adults >18 years with newly diagnosed aggressive NHL enrolled between June 1, 2013 and May 31, 2015.\n\nThere are no formal cancer treatment guidelines in Malawi. However, efforts to standardize care have been ongoing. CHOP was administered every 21 days with cyclophoshamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1.4 mg/m2 (maximum 2 mg) day 1, and prednisone 60 mg/m2 (maximum 100 mg) days 1–5. Prior to each cycle, an absolute neutrophil count (ANC) of 1.0x103/μL and platelet count of 100x103/μL were recommended. Intrathecal methotrexate 12.5 mg and hydrocortisone 50 mg were recommended for patients at high risk of leptomeningeal involvement as above. There is no radiotherapy in Malawi, and six cycles were administered even for limited-stage disease. Patients who achieved partial response after six cycles, and tolerated treatment without severe adverse events, could receive up to eight cycles.\n\nBlood counts and tests of kidney and liver function were performed on day 1 of each cycle or interim visits as indicated. If blood counts prohibited chemotherapy, they were repeated one week later and treatment proceeded if blood counts allowed. For a first episode of febrile neutropenia or delayed blood count recovery, cyclophosphamide and doxorubicin were reduced by 25%, and for a second episode doses were reduced by 50%, with subsequent dose escalation at the treating physician’s discretion. Hematopoietic growth factors were not available. Patients with age >70 years, performance status >2, and/or baseline cytopenias could receive prephase prednisone and/or ‘mini-CHOP’ with 50% dose reductions of all cytotoxic agents for cycle 1, and subsequent dose escalation at the treating physician’s discretion. Ciprofloxacin prophylaxis was provided during days 8–15 of each cycle for patients with HIV, or patients without HIV >60 years. Cotrimoxazole prophylaxis was continuously provided to all HIV-infected patients. Fluconazole prophylaxis was provided to HIV-infected patients throughout chemotherapy until resolution of neutropenia. Promethazine was provided for antiemesis. Consistent with World Health Organization guidelines and anti-infective prophylaxis provided in US AIDS Malignancy Consortium trials, we continued cotrimoxazole even in patients who developed neutropenia due to demonstrated survival benefits for HIV-infected populations without cancer in SSA through its preventive effects against malaria, bacterial infection, and Pneumocystis.All medicines were freely provided by the Ministry of Health, although drug shortages occurred. External funding enabled a back-up supply to mitigate treatment interruptions. Interval illnesses and complications were recorded prior to each cycle, and patients were encouraged to return promptly for interim concerns. Toxicities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All HIV-infected patients received ART concurrently with chemotherapy, typically with tenofovir-lamivudine-efavirenz. Patients on ART with virologic failure were referred for adherence counseling and consideration of second-line ART. We reduced vincristine by 50% in patients receiving second-line ritonavir-based ART due to cytochrome P450 3A4 interactions.\n\nStatistical analysis\nDifferences between HIV-infected and HIV–uninfected patients were assessed using Fisher’s exact tests, one-way analysis of variance (ANOVA), and Kruskal-Wallis tests. Summative curves for blood counts were derived by plotting median values over time across all patients within each group. Follow-up time was calculated from enrollment or CHOP initiation as specified, until death, loss to follow-up, or administrative censoring on August 31, 2015. Kaplan-Meier curves were used to estimate overall survival (OS), and the log-rank test was used to assess differences in survival between subgroups. Cox proportional hazards were used to estimate unadjusted and adjusted hazard ratios for mortality. All analyses were conducted using Stata version 12.1 (College Station, Texas, USA). A two-sided alpha value of 0.05 was considered statistically significant.\n\nResults\nSixty-two patients ≥18 years with newly diagnosed aggressive NHL presented to KCH between June 1, 2013 and May 31, 2015, and 59 (95%) patients consented to participate. Of those who presented for care, one patient could not give adequate informed consent, one patient elected to receive treatment in Blantyre, and one patient declined study participation. Four additional patients with aggressive NHL were identified through the pathology laboratory, but could not be contacted despite repeated attempts to engage them in care. One additional enrolled patient had follicular lymphoma with DLBCL transformation, leaving 58 enrolled adults with newly diagnosed aggressive NHL without prior indolent lymphoma.\n\nBaseline characteristics are shown in Table 1. Thirty-seven patients (64%) were HIV-infected. Median age was 47 years [interquartile range (IQR) 39–56] and 35 (60%) were male. Thirty-five patients (60%) had stage III/IV disease, B symptoms were present in 43 (74%), and 28 (48%) had performance status ≥2. Aggressive B-cell NHL predominated among HIV-infected patients, and all aggressive T-cell NHL occurred among HIV-negative individuals. There was a tendency for HIV-negative patients to be older with bulkier disease and higher hemoglobin than HIV-positive patients. HIV-negative patients also more frequently reported symptom durations ≥6 months. Thirty-one (84%) HIV-infected patients were on ART at lymphoma diagnosis for a median 9.9 months (IQR 1.1–31.7). Median CD4 at lymphoma diagnosis was 121 cells/μL (IQR 61–244), median HIV RNA was 3.5 log10copies/mL (IQR 1.3–4.8), and 43% had suppressed HIV RNA <400 copies/mL.\n\n10.1371/journal.pone.0150445.t001Table 1 Baseline characteristics for adults with aggressive non-Hodgkin lymphoma in Lilongwe, Malawi, June 2013 to May 2015.\n\tHIV-positive (n = 37)\tHIV-negative (n = 21)\tP\t\nAge, years, median (IQR)\t47.0 (38.1–50.2)\t54.6 (43.9–61.8)\t0.044\t\nMale, n (%)\t22 (59.5%)\t13 (61.9%)\t1.00\t\nBody mass index, kg/m2, median (IQR)\t20.8 (18.9–24.3)\t20.3 (17.7–22.1)\t0.39\t\nHistologic diagnosis, n (%)\t34 (91.9%)\t19 (90.5%)\t1.00\t\nMalawi diagnosisa\t\t\t0.014\t\n Aggressive B-cell lymphoma\t37\t17\t\t\n Aggressive T-cell lymphoma\t―\t4\t\t\nUnited States diagnosisb\t\t\t0.19\t\n Diffuse large B-cell lymphoma\t26\t13\t\t\n Burkitt lymphoma\t2\t1\t\t\n Plasmablastic lymphoma\t2\t1\t\t\n High-grade B-cell lymphoma NOS\t2\t1\t\t\n Extranodal NK/T-cell lymphoma\t―\t3\t\t\n ALK-negative anaplastic large-cell lymphoma\t―\t1\t\t\nSymptom duration ≥6 months, n (%)\t3/36 (8.3%)\t7/20 (35.0%)\t0.025\t\nB symptoms, n (%)\t26 (70.3%)\t17 (81.0%)\t0.54\t\nLargest lymph node mass, cm, median (IQR)\t10 (6–12)\t11 (9–17)\t0.056\t\nPerformance status ≥2, n (%)\t16 (43.2%)\t12 (57.1%)\t0.41\t\nStage III/IV, n (%)\t24 (64.9%)\t11 (52.4%)\t0.41\t\nInternational prognostic index ≥3, n (%)\t12 (32.4%)\t8 (38.1%)\t0.78\t\nWhite blood cells, 103/μL, median (IQR)\t5.7 (4.2–7.6)\t5.6 (4.4–8.9)\t0.59\t\nAbsolute neutrophil count, 103/μL, median (IQR)\t2.6 (1.8–4.1)\t2.9 (2.5–5.7)\t0.14\t\nHemoglobin, g/dL, median (IQR)\t11.0 (9.2–12.4)\t12.4 (11.0–13.3)\t0.038\t\nPlatelets, 103/μL, median (IQR)\t263 (184–402)\t290 (232–425)\t0.40\t\nAlbumin, g/dL, median (IQR)\t3.4 (2.9–4.0)\t3.2 (3.0–3.8)\t0.73\t\nLactate dehydrogenase, IU/L, median (IQR)c\t602 (338–1,294)\t441 (283–571)\t0.11\t\n Abnormal lactate dehydrogenase, n (%)\t33 (89.2%)\t17 (81.0%)\t0.44\t\nBone marrow involvement, n (%)\t5/27 (18.5%)\t0/17 (0.0%)\t0.14\t\n≥2 extranodal sites, n (%)\t6 (16.2%)\t4 (19.0%)\t1.00\t\nHepatitis B surface antigen positive, n (%)\t6/36 (16.7%)\t1/19 (5.3%)\t0.40\t\nART at enrollment, n (%)\t31 (83.8%)\t―\t―\t\n ART duration at enrollment, months, median (IQR)\t9.9 (1.1–31.7)\t\t\t\nCD4 count, cells/μL, median (IQR)\t121 (61–244)\t―\t―\t\nHIV RNA, log10copies/mL, median (IQR)\t3.5 (1.3–4.8)\t―\t―\t\nHIV RNA <400 copies/mL, n (%)\t16 (43.2%)\t―\t―\t\nIQR = interquartile range. NOS = not otherwise specified. ART = antiretroviral therapy.\n\naMalawi diagnoses reflect limited immunohistochemistry staining and weekly consensus telepathology discussion by United States and Malawi pathologists.\n\nbUnited States diagnoses reflect delayed review of 52 cases with additional immunohistochemistry, fluorescence in situ hybridization, and molecular studies in Chapel Hill.\n\ncLaboratory upper limit of normal is 250 IU/L.\n\nFifty patients (86%) initiated cytotoxic treatment, including 31/37 (84%) HIV-positive and 19/21 (90%) HIV-negative individuals. Median time between enrollment and cytotoxic treatment initiation was 7 days (IQR 4–13). All eight patients (6 HIV+, 2 HIV-) not treated with CHOP died before cytotoxic treatment could be initiated. Eleven of 50 patients (22%) treated with CHOP began treatment with either prephase prednisone or dose-reduced mini-CHOP, including 6/31 (19%) HIV-positive and 5/19 (26%) HIV-negative patients. Four (3 HIV+, 1 HIV-) received prephase prednisone followed by dose-reduced cytotoxic treatment with their first cycle, three HIV-positive patients received prephase prednisone followed by full-dose CHOP, and four HIV-negative patients initiated dose-reduced cytotoxic treatment without prephase prednisone. Of eight patients who initiated dose-reduced cytotoxic treatment, four subsequently proceeded to full-dose chemotherapy, with reasons for initial dose reduction being impaired performance status (5), baseline cytopenias (2), and advanced age (1).\n\nAchieved chemotherapy intensity and toxicities are shown in Table 2. HIV-infected patients received a similar number of CHOP cycles compared to HIV-uninfected patients (median 6 vs 5, p = 0.59), but modestly lower cyclophosphamide and doxorubicin doses per cycle, with a longer interval between cycles. Grade 3/4 neutropenia occurred in more HIV-infected than HIV-uninfected patients (84% vs 31%, p = 0.001). Grade 3/4 anemia occurred in 24% of patients overall without significant differences between HIV-positive and HIV-negative individuals, and only one grade 3/4 thrombocytopenia event occurred in the study population. Of 62 grade 3/4 neutropenia events, 54 (87%) were grade 3 and eight (13%) were grade 4 (Fig 1). For both HIV-infected and HIV-uninfected patients, median ANC remained greater than 1x103/μL throughout treatment (Fig 2). Among those with HIV, median CD4 count increased to 146 cells/μL (IQR 98–265) and median HIV RNA decreased to 1.3 log10copies/mL (IQR 1.3–1.6) at six months with 11 of 13 patients (85%) having suppressed HIV RNA <400 copies/mL.\n\n10.1371/journal.pone.0150445.g001Fig 1 Neutropenia during CHOP chemotherapy in Lilongwe, Malawi.\n10.1371/journal.pone.0150445.g002Fig 2 Peripheral blood counts with interquartile ranges during CHOP chemotherapy in Lilongwe, Malawi.\n10.1371/journal.pone.0150445.t002Table 2 Treatment course and toxicities during CHOP chemotherapy in Lilongwe, Malawi.\n\tHIV-positive (n = 31)\tHIV-negative (n = 19)\tP\t\nTotal chemotherapy cycles\t150\t88\t―\t\nCycles per patient, median (IQR)a\t6 (4–6)\t5 (3–6)\t0.59\t\nDays between cycles, median (IQR)\t21 (21–27)\t21 (20–22)\t0.0053\t\n Cycles delayed ≥7 days, n (%)b\t32/119 (26.9%)\t8/69 (11.6%)\t0.016\t\nCyclophosphamide dose per cycle, mg/m2, median (IQR)c\t693.0 (555.6–734.8)\t721.4 (576.9–750.0)\t0.015\t\nDoxorubicin dose per cycle, mg/m2, median (IQR)d\t48.0 (37.6–49.9)\t49.4 (39.3–50.0)\t0.042\t\nReceived <6 cycles, n (%)a\t14/30 (46.7%)\t11/19 (57.9%)\t0.56\t\n Death\t7\t6\t\t\n Progression\t1\t2\t\t\n Toxicity\t5\t1\t\t\n Social\t1\t2\t\t\nGrade 3/4 neutropeniae\t\t\t\t\n Cycles, n (%)\t49/140 (35.0%)\t13/83 (15.7%)\t0.002\t\n Patients, n (%)\t21/25 (84.0%)\t5/16 (31.2%)\t0.001\t\nGrade 3/4 anemiae\t\t\t\t\n Cycles, n (%)\t13/140 (8.9%)\t6/83 (7.2%)\t0.80\t\n Patients, n (%)\t7/25 (28.0%)\t3/16 (18.8%)\t0.71\t\nGrade 3/4 non-hematologic toxicitye\t\t\t\t\n Cycles, n (%)\t6/140 (4.3%)\t12/83 (14.5%)\t0.010\t\n Patients, n (%)\t6/25 (24.0%)\t8/17 (47.1%)\t0.18\t\nIQR = interquartile range.\n\naIncludes 49 patients (30 HIV+, 19 HIV-) who completed first-line CHOP or died as of August 31, 2015.\n\nbExcudes first treatment cycles.\n\ncExcludes 9 missed cyclophosphamide doses due to stock-out (6 HIV-, 3 HIV+).\n\ndExcludes 6 missed doxorubicin doses due to stock-out (4 HIV-, 2 HIV+).\n\neToxicity assessment includes patients and cycles with subsequent follow-up visits making them evaluable for interim toxicity; deaths occurring out of hospital are separately adjudicated (S1 Table) without evaluation for non-fatal interim toxicity.\n\nEighteen grade 3/4 non-hematologic toxicities occurred, including nine grade 3 diarrhea/dehydration, two grade 3 abdominal pain, two grade 3 skin infection, one grade 4 cerebral edema, one grade 4 renal failure, one grade 3 small bowel obstruction, one grade 3 hepatitis, and one grade 3 sepsis without neutropenia. Cerebral edema occurred in a patient with systemic and central nervous system NHL progression. Obstructive renal failure, abdominal pain, and small bowel obstruction occurred in patients with abdominal NHL progressing on CHOP. Both grade 3 skin infections occurred when large masses ulcerated during CHOP and became superinfected. Of 38 CHOP cycles delayed at least seven days (31 HIV+, 7 HIV-), 31 were due to delayed ANC recovery, three for personal or transportation issues, three for clinic scheduling, and one for pharmacy stock-out.\n\nAs of August 31, 2015, vital status was known for all 58 patients with no loss to follow-up after a median 14.9 months among patients still alive (IQR 7.8–24.4). Among 49 patients who initiated first-line CHOP and completed treatment or died before the censoring date, 22 (45%) achieved a complete response (CR) after a median 2 CHOP cycles (IQR 1–3) including 15 of 30 (50%) HIV-infected patients and 7 of 19 (37%) HIV-uninfected patients (p = 0.40). One HIV-infected patient was still receiving first-line CHOP and had achieved CR after four cycles. Kaplan-Meier OS curves are shown in Fig 3, and OS estimates are shown in Table 3 for all enrolled patients and patients who initiated cytotoxic treatment. Kaplan-Meier 12-month OS was 45% [95% confidence interval (CI) 31–57%] for the cohort overall. OS was similar for HIV-infected and HIV-uninfected patients, better for those with international prognostic index (IPI) <3, and better for those with aggressive B-cell NHL than T-cell NHL. Among 50 patients who initiated cytotoxic treatment, estimated 12-month OS was 52% (95% CI 37–65%). For cases confirmed as DLBCL in the US, 12-month OS was 51% (95% CI 34–65%) for all patients (n = 39) and 56% (95% CI 38–71%) for those who initiated cytotoxic treatment (n = 35), with similar survival by HIV status and better survival for those with IPI <3.\n\n10.1371/journal.pone.0150445.g003Fig 3 Overall survival for aggressive non-Hodgkin lymphoma in Lilongwe, Malawi.\n(A) Overall cohort with 95% confidence intervals. (B) Aggressive B-cell non-Hodgkin lymphoma (ABNHL) versus aggressive T-cell non-Hodgkin lymphoma (ATNHL). (C) Stratified by HIV status. (D) Stratified by international prognostic index (IPI). (E) Diffuse large B-cell lymphoma (DLBCL) stratified by HIV status. (F) DBLCL stratified by IPI.\n\n10.1371/journal.pone.0150445.t003Table 3 Overall survival estimates for aggressive non-Hodgkin lymphoma in Lilongwe, Malawi.\n\tN\t12-month OS (%)\t95% CI\t24-month OS (%)\t95% CI\t\nEnrolleda\t\t\t\t\t\t\nAll\t58\t44.7\t31.2–57.3\t34.0\t20.9–47.6\t\n HIV+\t37\t49.7\t32.4–64.9\t37.4\t20.5–54.3\t\n HIV-\t21\t35.6\t15.8–56.1\t28.5\t10.4–49.9\t\n IPI<3\t38\t61.5\t43.6–75.2\t45.1\t26.8–61.9\t\n IPI> = 3\t20\t13.3\t2.6–32.7\t13.3\t2.7–32.7\t\nDLBCL\t39\t50.6\t33.9–65.0\t40.8\t24.8–56.3\t\n HIV+\t26\t52.8\t31.9–69.9\t43.2\t23.2–61.7\t\n HIV-\t13\t46.2\t19.2–69.6\t36.9\t12.5–62.0\t\n IPI<3\t27\t65.8\t44.5–80.6\t51.3\t29.9–69.2\t\n IPI> = 3\t12\t16.7\t2.6–41.3\t16.7\t2.6–41.3\t\nTreatedb\t\t\t\t\t\t\nAll\t50\t51.9\t36.8–65.1\t39.3\t24.1–54.1\t\n HIV+\t31\t59.4\t39.3–74.7\t44.3\t24.2–62.7\t\n HIV-\t19\t39.4\t17.5–60.7\t31.5\t11.4–54.1\t\n IPI<3\t35\t66.8\t47.8–80.1\t48.9\t28.7–66.0\t\n IPI> = 3\t15\t17.8\t3.4–41.4\t17.8\t3.4–41.4\t\nDLBCL\t35\t56.3\t38.2–71.0\t45.2\t27.4–61.4\t\n HIV+\t23\t59.6\t36.5–76.7\t48.2\t25.6–67.6\t\n HIV-\t12\t50.0\t20.8–73.6\t40.0\t13.5–65.7\t\n IPI<3\t24\t74.1\t51.0–87.5\t57.1\t32.9–75.4\t\n IPI> = 3\t11\t18.2\t2.8–44.2\t18.2\t2.8–44.2\t\nOS = overall survival. CI = confidence interval. IPI = International Prognostic Index.\n\naSurvival measured from enrollment.\n\nbSurvival measured from cytotoxic treatment initiation.\n\nRisk factors for mortality are shown in Table 4. In unadjusted analyses, T-cell NHL (HR 3.90, p = 0.017), hemoglobin (HR 0.82 per g/dL increase, p = 0.017), albumin (HR 0.57 per g/dL increase, p = 0.019), and IPI (HR 2.02 per unit increase, p<0.001) were associated with mortality. When individual IPI elements were examined, performance status (HR 1.91 per unit increase, p<0.001), LDH (HR 1.04 per 100 IU/L increase, p = 0.002), number of extranodal sites (HR 1.66 per site, p = 0.006), and stage III/IV (HR 2.33, p = 0.025) were associated with mortality. In adjusted analyses, only IPI was associated with mortality (HR 1.77 per unit increase, p = 0.005). HIV was not associated with mortality, and findings were similar among patients confirmed as DLBCL in the US.\n\n10.1371/journal.pone.0150445.t004Table 4 Risk factors for mortality among aggressive non-Hodgkin lymphoma patients in Lilongwe, Malawi.\n\tUnadjusted hazard ratio\t95% confidence interval\tP\tAdjusted hazard ratioa\t95% confidence interval\tP\t\nAll (n = 58)\t\t\t\t\t\t\t\nHIV infection\t0.82\t0.41–1.61\t0.56\t0.90\t0.39–2.07\t0.81\t\nT-cell non-Hodgkin lymphoma\t3.90\t1.28–11.91\t0.017\t3.06\t0.74–12.72\t0.12\t\nFemale sex\t0.80\t0.40–1.61\t0.53\t0.57\t0.26–1.24\t0.16\t\nHemoglobin, per g/dL\t0.82\t0.70–0.97\t0.017\t0.92\t0.74–1.14\t0.44\t\nAlbumin, per g/dL\t0.57\t0.36–0.91\t0.019\t1.07\t0.53–2.17\t0.85\t\nBody mass index, per kg/m2\t0.95\t0.86–1.05\t0.29\t1.00\t0.90–1.11\t0.98\t\nInternational prognostic index, per unit\t2.02\t1.45–2.82\t<0.001\t1.77\t1.18–2.64\t0.005\t\n Age, per year\t1.00\t0.97–1.02\t0.85\t―\t―\t―\t\n Age >60 years\t0.75\t0.33–1.73\t0.50\t―\t―\t―\t\n Performance status, per unit\t1.91\t1.45–2.52\t<0.001\t―\t―\t―\t\n Performance status ≥2\t4.96\t2.34–10.50\t<0.001\t―\t―\t―\t\n Stage III/IV\t2.32\t1.11–4.85\t0.025\t―\t―\t―\t\n Lactate dehydrogenase, per 100 IU/L\t1.04\t1.01–1.07\t0.002\t―\t―\t―\t\n Abnormal lactate dehydrogenase\t1.81\t0.63–5.16\t0.27\t―\t―\t―\t\n Extranodal sites, per site\t1.66\t1.16–2.38\t0.006\t―\t―\t―\t\n ≥2 extranodal sites\t2.59\t1.13–5.96\t0.025\t―\t―\t―\t\nDLBCL only (n = 39)\t\t\t\t\t\t\t\nHIV infection\t0.86\t0.36–2.05\t0.73\t1.37\t0.50–3.76\t0.54\t\nFemale sex\t1.05\t0.44–2.51\t0.91\t1.99\t0.67–5.91\t0.21\t\nHemoglobin, per g/dL\t0.89\t0.71–1.12\t0.32\t1.07\t0.82–1.41\t0.60\t\nAlbumin, per g/dL\t0.64\t0.33–1.23\t0.18\t0.89\t0.35–2.26\t0.80\t\nBody mass index, per kg/m2\t0.97\t0.87–1.09\t0.65\t1.09\t0.95–1.25\t0.17\t\nInternational prognostic index, per unit\t2.37\t1.49–3.77\t<0.001\t2.94\t1.49–5.83\t0.002\t\n Age, per year\t1.01\t0.98–1.04\t0.62\t―\t―\t―\t\n Age >60 years\t0.79\t0.27–2.33\t0.66\t―\t―\t―\t\n Performance status, per unit\t1.81\t1.27–2.57\t0.001\t―\t―\t―\t\n Performance status ≥2\t6.11\t2.39–15.59\t<0.001\t―\t―\t―\t\n Stage III/IV\t2.54\t0.94–6.91\t0.067\t―\t―\t―\t\n Lactate dehydrogenase, per 100 IU/L\t1.13\t1.06–1.21\t<0.001\t―\t―\t―\t\n Abnormal lactate dehydrogenase\t2.44\t0.57–10.54\t0.23\t―\t―\t―\t\n Extranodal sites, per site\t1.54\t0.99–2.41\t0.057\t―\t―\t―\t\n ≥2 extranodal sites\t3.47\t1.13–10.62\t0.030\t―\t―\t―\t\nDLBCL = diffuse large B-cell lymphoma.\n\naAdjusted for all variables for which hazard ratios are shown.\n\nThere is no national death registration in Malawi. Although patients are encouraged to return promptly for interim illnesses, deaths often occur at home or in facilities with limited diagnostic resources. Central adjudication of 35 deaths was undertaken to attribute cause (S1 Table). Twenty-three were attributed to lymphoma (12 HIV+, 11 HIV-), and 12 to CHOP treatment (9 HIV+, 3 HIV-). As shown, most treatment-related deaths occurred in patients with very adverse NHL characteristics.\n\nDiscussion\nThis is the first prospective description of adults with aggressive NHL receiving frontline CHOP in SSA.\n\nFor HIV-infected NHL patients in Lilongwe, 50% OS at 12 months, and 59% among patients initiating CHOP, are among the best survival estimates reported at this time point from SSA [7, 14, 15]. This is a testament to the Malawi HIV program, which provides ART to 67% of HIV-infected individuals who require treatment [17]. Although 84% of our patients were on ART, median ART duration at lymphoma diagnosis was only 9.9 months with median CD4 count 121 cells/μL, highlighting a need for continued scale-up and earlier ART application. ART coverage, immune status, and HIV control in our cohort are comparable to similar routine-care populations in the US [20]. Although HIV-infected NHL patients with excellent outcomes similar to HIV-negative individuals have been repeatedly described in clinical trials from resource-rich settings (8–13), our prior work in a multicenter routine-care cohort in the US demonstrated a CD4 count of 123 cells/μL and HIV RNA suppression in only 28% at DLBCL diagnosis, among 201 patients with HIV-associated DLBCL receiving care in the ART era between 1996 and 2010, with 56% two-year overall survival (20). These characteristics are fairly similar to our Malawi cohort.\n\nDespite increased treatment-related toxicity and deaths in the Malawi HIV-infected NHL population, our experience attests to the potential safety, effectiveness, and feasibility of CHOP in the current era, when accompanied by standardized monitoring, dose adjustment, supportive care, and ART, as also suggested by other studies [14, 15]. Most deaths among HIV-positive patients were from NHL rather than treatment. Treatment-related mortality occurred primarily in patients with very adverse NHL characteristics, and might be reduced with supportive care refinements. In particular, hematopoietic growth factors, which exist as generic biosimilars although even these are still too expensive for the Malawi public sector, could substantially mitigate toxicity since neutropenia was by far the most frequent adverse event. To our knowledge, the only alternative regimen to CHOP for HIV-associated NHL in SSA with published data is the dose-modified oral chemotherapy regimen (lomustine, etoposide, cyclophosphamide, procarbazine). In 49 patients with HIV-associated NHL in Kenya and Uganda before ART was widely available, this treatment resulted in median survival of 12.3 months and 33% five-year overall survival. Of note, the trial had major exclusions with respect to performance status, anticipated life expectancy, blood counts, and liver/kidney function, resulting in only 33% of screened HIV-associated NHL patients being enrolled, making it difficult to draw direct comparisons with our unselected patient population in Lilongwe.\n\nHIV-negative lymphoma patients in Malawi are very ill with advanced, bulky disease and poor outcomes. More than three-quarters of deaths were attributed to NHL rather than treatment in the HIV-uninfected group. Massive HIV-related investments have occurred in SSA in recent years, which has created a strong network of HIV clinics throughout Malawi. No such primary care network exists for HIV-negative individuals, who consequently suffer from delayed referral and diagnosis. Delays were multifactorial and typically occurred before presentation to our center, as we made concerted efforts to expedite diagnostic work-ups and treatment initiation once patients entered our care. Absent radiotherapy in Malawi also contributes to poor outcomes, particularly for HIV-negative patients, who tend to present with localized, bulky disease, as radiotherapy improves outcomes for bulky NHL compared with chemotherapy alone [21, 22]. Occurrence of particularly aggressive lymphoma subtypes including T-cell NHL among HIV-uninfected patients also resulted in poor survival. Equivalent outcomes for HIV-positive NHL patients in Malawi are consistent with Uganda data suggesting HIV was not associated with worse survival for NHL [23].\n\nStudy strengths include prospective, longitudinal follow-up of NHL cases confirmed using real-time consensus telepathology, supported by IHC and multiple US and Malawi pathologists. This is notable given that diagnostic pathology was unavailable in Lilongwe before July 2011, and only 18% of cases in the Malawi national cancer registry were pathologically confirmed in the most recent report [24]. Subsequent secondary review was also performed by US hematopathologists. Patients underwent detailed and systematic clinical characterization, and those with HIV received concurrent ART in a mature national program. Patients were actively followed, and no enrolled patient has been lost to date with a median follow-up of 14.9 months among patients still alive. Median follow-up in studies from the region ranges from 3.5 to 8.2 months [7, 14, 15], and survival can be significantly overestimated in SSA when patients are lost to follow-up [25, 26]. We also made efforts to standardize chemotherapy, including strategies aimed at frail patients to minimize induction deaths. Our study lacked major exclusions and achieved 95% enrollment among NHL patients presenting for care, of whom 86% initiated cytotoxic therapy. Other NHL studies from SSA have reported 26–67% of patients being excluded or untreated [7, 14, 15].\n\nLimitations include referral bias intrinsic to the Malawi health system, given centralization of cancer services in Lilongwe and Blantyre, the two largest cities. Many NHL patients may die before presenting to a national teaching hospital. Similarly, patients with asymptomatic lymphadenopathy may not travel to central hospitals, leading to underrepresentation of less aggressive disease. Another limitation is absent death certification in Malawi, leading us to attribute causation through centralized review.\n\nOur results suggest a global strategy to improve outcomes for NHL patients is possible. HIV investments should be leveraged for populations with and without HIV. Community and health care worker education can facilitate earlier referral and diagnosis. Supportive care should be standardized and refined, informed by better identification of complications during treatment, with resource-appropriate incorporation of hematopoietic growth factors. Protocol-guided chemotherapy with defined strategies for monitoring and dose adjustment should be adopted. Ensuring continuous chemotherapy supply and incorporating newer agents to provide better first-line and salvage treatment options is also important. We believe a dedicated study of rituximab in SSA is an urgent priority to demonstrate safety and efficacy in severely resource-constrained settings like Malawi. This is important in light of rituximab’s impending patent expiration, successful use of an existing biosimilar, and increasing experience with subcutaneous administration which enhances feasibility for SSA [27, 28]. Non-radiotherapy strategies for localized bulky NHL also deserve investigation given radiotherapy scarcity in SSA [29]. Finally, biologic insights can guide treatment, and we have begun molecular profiling and virologic studies of Malawi NHL specimens to be reported subsequently.\n\nIn conclusion, CHOP can be safe, effective, and feasible for aggressive NHL patients with and without HIV in resource-limited settings in SSA. Among HIV-positive patients, ART use, CD4 count, and HIV RNA at lymphoma diagnosis are comparable to contemporary HIV-associated NHL cohorts in the US, as are outcomes for patients treated with CHOP. Multifaceted approaches are needed to improve survival, and these should target both HIV-infected and HIV-uninfected individuals.\n\nSupporting Information\nS1 Table Central adjudication of deaths among aggressive non-Hodgkin lymphoma patients in Lilongwe, Malawi.\n(DOCX)\n\nClick here for additional data file.\n\n We especially wish to thank patients and their families for participating despite extraordinarily challenging circumstances, which reflects their deep commitment to improving cancer care in Malawi. We also wish to acknowledge Wiza Kumwenda for developing the study database, and Charles Mabedi, Melanie Sion, Jared Gallaher, Carol Shores, and Anthony Charles for assistance obtaining biopsy specimens. We additionally acknowledge leadership of Kamuzu Central Hospital (Jonathan Ngoma), UNC Project-Malawi (Irving Hoffman, Innocent Mofolo, Mina Hosseinipour, Francis Martinson), and Lineberger Comprehensive Cancer Center (Shelley Earp, Ned Sharpless, Lisa Carey, Blossom Damania, Dirk Dittmer) for their support of this study.\n==== Refs\nReferences\n1 Parkin DM , Nambooze S , Wabwire-Mangen F , Wabinga HR . Changing cancer incidence in Kampala, Uganda, 1991–2006 . International journal of cancer Journal international du cancer . 2010 ;126 (5 ):1187 –95 . Epub 2009/08/19. 10.1002/ijc.24838 .19688826 \n2 Chokunonga E , Borok MZ , Chirenje ZM , Nyakabau AM , Parkin DM . Trends in the incidence of cancer in the black population of Harare, Zimbabwe 1991–2010 . International journal of cancer Journal international du cancer . 2013 ;133 (3 ):721 –9 . Epub 2013/02/01. 10.1002/ijc.28063 .23364833 \n3 Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr.\n4 Adesina A , Chumba D , Nelson AM , Orem J , Roberts DJ , Wabinga H , et al\nImprovement of pathology in sub-Saharan Africa . The lancet oncology . 2013 ;14 (4 ):e152 –7 . Epub 2013/04/09. 10.1016/S1470-2045(12)70598-3 .23561746 \n5 Naresh KN , Raphael M , Ayers L , Hurwitz N , Calbi V , Rogena E , et al\nLymphomas in sub-Saharan Africa—what can we learn and how can we help in improving diagnosis, managing patients and fostering translational research? \nBritish journal of haematology . 2011 ;154 (6 ):696 –703 . Epub 2011/06/29. 10.1111/j.1365-2141.2011.08772.x .21707579 \n6 Orem J , Sandin S , Weibull CE , Odida M , Wabinga H , Mbidde E , et al\nAgreement between diagnoses of childhood lymphoma assigned in Uganda and by an international reference laboratory . Clinical epidemiology . 2012 ;4 :339 –47 . Epub 2013/01/02. 10.2147/CLEP.S35671 \n23277743 \n7 Mwanda WO , Orem J , Fu P , Banura C , Kakembo J , Onyango CA , et al\nDose-modified oral chemotherapy in the treatment of AIDS-related non-Hodgkin's lymphoma in East Africa . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2009 ;27 (21 ):3480 –8 . Epub 2009/05/28. 10.1200/JCO.2008.18.7641 \n19470940 \n8 Sparano JA , Lee JY , Kaplan LD , Levine AM , Ramos JC , Ambinder RF , et al\nRituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma . Blood . 2010 ;115 (15 ):3008 –16 . Epub 2009/12/22. 10.1182/blood-2009-08-231613 \n20023215 \n9 Montoto S , Shaw K , Okosun J , Gandhi S , Fields P , Wilson A , et al\nHIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2012 ;30 (33 ):4111 –6 . Epub 2012/10/10. 10.1200/JCO.2011.41.4193 .23045581 \n10 Hentrich M , Berger M , Wyen C , Siehl J , Rockstroh JK , Muller M , et al\nStage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2012 ;30 (33 ):4117 –23 . Epub 2012/10/10. 10.1200/JCO.2012.41.8137 .23045592 \n11 Dunleavy K , Little RF , Pittaluga S , Grant N , Wayne AS , Carrasquillo JA , et al\nThe role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma . Blood . 2010 ;115 (15 ):3017 –24 . Epub 2010/02/05. 10.1182/blood-2009-11-253039 \n20130244 \n12 Dunleavy K , Wilson WH . How I treat HIV-associated lymphoma . Blood . 2012 ;119 (14 ):3245 –55 . Epub 2012/02/18. 10.1182/blood-2011-08-373738 \n22337719 \n13 Dunleavy K , Pittaluga S , Shovlin M , Steinberg SM , Cole D , Grant C , et al\nLow-intensity therapy in adults with Burkitt's lymphoma . The New England journal of medicine . 2013 ;369 (20 ):1915 –25 . 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Malawi Progress Report for 2013. Available: http://www.unaids.org/en/regionscountries/countries/malawi.\n18 United Nations Statistics Division. Malawi country profile. Available: http://data.un.org/CountryProfile.aspx?crName=malawi.\n19 Gopal S , Krysiak R , Liomba NG , Horner MJ , Shores CG , Alide N , et al\nEarly experience after developing a pathology laboratory in Malawi, with emphasis on cancer diagnoses . PloS one . 2013 ;8 (8 ):e70361 Epub 2013/08/21. 10.1371/journal.pone.0070361 \n23950924 \n20 Gopal S , Patel MR , Yanik EL , Cole SR , Achenbach CJ , Napravnik S , et al\nTemporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era . J Natl Cancer Inst . 2013 ;105 (16 ):1221 –9 . 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PloS one . 2010 ;5 (11 ):e14149 Epub 2010/12/15. 10.1371/journal.pone.0014149 \n21152392 \n26 Egger M , Spycher BD , Sidle J , Weigel R , Geng EH , Fox MP , et al\nCorrecting mortality for loss to follow-up: a nomogram applied to antiretroviral treatment programmes in sub-Saharan Africa . PLoS medicine . 2011 ;8 (1 ):e1000390 Epub 2011/01/27. 10.1371/journal.pmed.1000390 \n21267057 \n27 Roy PS , John S , Karankal S , Kannan S , Pawaskar P , Gawande J , et al\nComparison of the efficacy and safety of Rituximab (Mabthera) and its biosimilar (Reditux) in diffuse large B-cell lymphoma patients treated with chemo-immunotherapy: A retrospective analysis . Indian journal of medical and paediatric oncology: official journal of Indian Society of Medical & Paediatric Oncology . 2013 ;34 (4 ):292 –8 . Epub 2014/03/08. 10.4103/0971-5851.125248 \n24604960 \n28 Davies A , Merli F , Mihaljevic B , Siritanaratkul N , Solal-Celigny P , Barrett M , et al\nPharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study . The lancet oncology . 2014 ;15 (3 ):343 –52 . Epub 2014/02/14. 10.1016/S1470-2045(14)70005-1 .24521993 \n29 Abdel-Wahab M , Bourque JM , Pynda Y , Izewska J , Van der Merwe D , Zubizarreta E , et al\nStatus of radiotherapy resources in Africa: an International Atomic Energy Agency analysis . The lancet oncology . 2013 ;14 (4 ):e168 –75 . Epub 2013/04/09. 10.1016/S1470-2045(12)70532-6 .23561748\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(3)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D018501:Antirheumatic Agents; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D015658:HIV Infections; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008295:Malawi; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D016019:Survival Analysis; D014750:Vincristine",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0150445",
"pmc": null,
"pmid": "26934054",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19470940;24604960;21267057;23045592;23797692;23892362;23364833;23950924;20130244;21350364;18413640;20713859;22461494;19688826;21707579;23921614;23561748;23045581;20023215;21152392;24224624;23277743;22424105;22337719;24521993;23561746",
"title": "CHOP Chemotherapy for Aggressive Non-Hodgkin Lymphoma with and without HIV in the Antiretroviral Therapy Era in Malawi.",
"title_normalized": "chop chemotherapy for aggressive non hodgkin lymphoma with and without hiv in the antiretroviral therapy era in malawi"
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"abstract": "When evaluating a Papanicolaou (Pap) smear, the cytology of the squamous epithelial cells is of utmost importance. This is what cytopathologists use to render a diagnosis, ranging from normal to atypical squamous cells of undetermined significance (ASCUS) to high grade squamous intraepithelial lesions, or even squamous cell carcinoma. However, occasionally the pathologist will run into microscopic noncellular material as in our case, such as corpora amylacea on the slides, or even uncommon viral inclusions such as Molluscum contagiosum (MCV). When these less common entities make their way on to a cervical Pap smear, it is important not only to correctly recognize them, but to understand their clinical implications as well. Diagn. Cytopathol. 2017;45:179-181. © 2016 Wiley Periodicals, Inc.",
"affiliations": "Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.;Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio.",
"authors": "Buckley|Kaila|K|;Li|Zaibo|Z|",
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"keywords": "Molluscum contagiosum; Pap smear; cervix; corpora amylacea",
"medline_ta": "Diagn Cytopathol",
"mesh_terms": "D000328:Adult; D000682:Amyloid; D065309:Atypical Squamous Cells of the Cervix; D002582:Cervix Mucus; D005260:Female; D006801:Humans; D008976:Molluscum Contagiosum; D065006:Papanicolaou Test; D014626:Vaginal Smears",
"nlm_unique_id": "8506895",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Corpora amylacea and molluscum contagiosum on a cervical pap smear.",
"title_normalized": "corpora amylacea and molluscum contagiosum on a cervical pap smear"
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"abstract": "Tyrosine kinase inhibitors have revolutionized the chemotherapy arena as targeted therapies for a multitude of malignancies. They are more selective than conventional chemotherapy, and often elicit fewer systemic adverse events, however toxicities still exist. Cutaneous toxicities are common and their management presents a novel challenge to physicians and patients. Ponatinib is a third-generation tyrosine kinase inhibitor increasingly reported to cause cutaneous eruption. A 50-year-old woman with a history of chronic myelogenous leukemia presented with a 4-month history of worsening atrophic and ichthyosiform pink plaques involving the axillae, thighs and abdomen; red patches were also observed on the cheeks and forehead. She was started on the third-generation, ponatinib, 5 months earlier because of disease refractory to previous therapies including interferon, imatinib, dasatinib and bosutinib. A skin biopsy revealed perifollicular fibrosis, alternating orthokeratosis and parakeratosis, and a sparse perivascular lymphocytic infiltrate consistent with a pityriasis rubra pilaris-like reaction. Topical tretinoin 0.025% cream was initiated, resulting in resolution within 3 weeks without discontinuation of ponatinib. A review of previous reports identified significant similarities among the ponatinib-induced drug reactions. Here, we highlight not only that cutaneous eruptions occur on ponatinib therapy, but that the dermatologic manifestations are characteristic and unique, and benefit from retinoid therapy, without requiring interruption of vital chemotherapy.",
"affiliations": "Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, Miami, FL, 33136, USA. a.eber@med.miami.edu.;Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, Miami, FL, 33136, USA.;Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, Miami, FL, 33136, USA.;Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, Miami, FL, 33136, USA.;Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, Miami, FL, 33136, USA.",
"authors": "Eber|Ariel E|AE|;Rosen|Alyx|A|;Oberlin|Kate E|KE|;Giubellino|Alessio|A|;Romanelli|Paolo|P|",
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"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 291389965510.1007/s40800-017-0055-yCase ReportIchthyosiform Pityriasis Rubra Pilaris-Like Eruption Secondary to Ponatinib Therapy: Case Report and Literature Review Eber Ariel E. 305-401-0066305-243-3380a.eber@med.miami.edu Rosen Alyx Oberlin Kate E. Giubellino Alessio Romanelli Paolo 0000 0004 1936 8606grid.26790.3aDepartment of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, Miami, FL 33136 USA 14 11 2017 14 11 2017 12 2017 4 19© The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Tyrosine kinase inhibitors have revolutionized the chemotherapy arena as targeted therapies for a multitude of malignancies. They are more selective than conventional chemotherapy, and often elicit fewer systemic adverse events, however toxicities still exist. Cutaneous toxicities are common and their management presents a novel challenge to physicians and patients. Ponatinib is a third-generation tyrosine kinase inhibitor increasingly reported to cause cutaneous eruption. A 50-year-old woman with a history of chronic myelogenous leukemia presented with a 4-month history of worsening atrophic and ichthyosiform pink plaques involving the axillae, thighs and abdomen; red patches were also observed on the cheeks and forehead. She was started on the third-generation, ponatinib, 5 months earlier because of disease refractory to previous therapies including interferon, imatinib, dasatinib and bosutinib. A skin biopsy revealed perifollicular fibrosis, alternating orthokeratosis and parakeratosis, and a sparse perivascular lymphocytic infiltrate consistent with a pityriasis rubra pilaris-like reaction. Topical tretinoin 0.025% cream was initiated, resulting in resolution within 3 weeks without discontinuation of ponatinib. A review of previous reports identified significant similarities among the ponatinib-induced drug reactions. Here, we highlight not only that cutaneous eruptions occur on ponatinib therapy, but that the dermatologic manifestations are characteristic and unique, and benefit from retinoid therapy, without requiring interruption of vital chemotherapy.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1007/s40800-017-0055-y) contains supplementary material, which is available to authorized users.\n\nissue-copyright-statement© The Author(s) 2017\n==== Body\nKey Points\n\nTyrosine kinase inhibitors are potent anti-cancer therapies, but may result in cutaneous adverse events\t\nPonatinib is a new third-generation tyrosine kinase inhibitor that may induce an ichthyosiform pityriasis rubra pilaris-like eruption\t\nTreatment with topical tretinoin results in resolution of skin disease without requiring termination of chemotherapy\t\n\n\n\nIntroduction\nTyrosine kinase inhibitors (TKIs) have revolutionized the field of chemotherapy as targeted therapies against aberrant cellular pathways. While more selective than conventional chemotherapy, and often with fewer systemic adverse events, toxicities still exist and frequently include cutaneous manifestations. Appropriate management of cutaneous toxicities presents a challenge to physicians and patients. We report a case of an ichthyosiform pityriasis rubra pilaris (PRP)-like eruption resulting after initiation of a third-generation TKI, ponatinib, and demonstrate its effective treatment with topical retinoids.\n\nCase Report\nA 50-year-old woman presented with a 4-month history of a worsening rash on her face, trunk, and extremities. Her main complaint was dryness of the involved areas. She was previously diagnosed with xerosis; however, no improvement was demonstrated with emollients or topical corticosteroids. Past medical history included a 20-year history of chronic myelogenous leukemia. She had been started on the third-generation TKI, ponatinib, 5 months earlier after having a disease refractory to numerous previous therapies including interferon, imatinib, dasatinib, and bosutinib. Our patient was not taking any other medications or modifiers of the cytochrome P450 3A enzyme. After initiation of ponatinib 45 mg once daily, the patient obtained her lowest levels of the associated Bcr-Abl gene as demonstrated by polymerase chain reaction. Physical examination demonstrated xerotic, atrophic, and ichthyosiform pink plaques involving the bilateral axillae, proximal thighs and abdomen; red patches were additionally observed on the malar cheeks and forehead (Fig. 1a–d). Our patient did not demonstrate keratoderma. A skin biopsy of the axilla demonstrated perifollicular fibrosis, alternating orthokeratosis and parakeratosis, and a sparse perivascular lymphocytic infiltrate consistent with a PRP-like reaction (Fig. 2a–d). Specifically, this resembled an eczematous type II PRP-like reaction with the exception of palmoplantar involvement. Treatment with tretinoin 0.025% cream was initiated and significant improvement resulted within 3 weeks of therapy (Fig. 1e–h). Outpatient follow-up confirmed sustained resolution. Written informed consent was obtained from the patient for the publication of this case report and the accompanying images. A copy of the written consent may be requested for review from the corresponding author.Fig. 1 Clinical photographs of the patient before (a–d) and after (e–h) treatment with tretinoin\n\n\nFig. 2 Representative images of histopathologic features. a Low power shows two hair follicles with perifollicular fibrosis and a slightly thickened stratum corneum and a sparse perivascular lymphocytic infiltrate in the upper dermis (magnification 4). b Perifollicular fibrosis is evident around two hair follicles (magnification 10). c Compact orthokeratosis and focal parakeratosis are present (magnification 20). d The perivascular inflammatory infiltrate is composed mainly of lymphocytes (magnification 20)\n\n\n\n\nDiscussion\nSince the advent of TKIs in the late 1980s, and the US Food and Drug Administration approval of imatinib in 2001, a vast array of cutaneous manifestations have been described [1]. The initial clinical trials of the first and second generation Bcr-Abl TKIs (imatinib, dasatinib, and nolitinib) reported high rates of cutaneous adverse events [1–5]; The most common include a keratosis pilaris-like rash, superficial edema, maculopapular rash, dyschromia, lichenoid reaction, psoriasiform eruption, and a hand-foot skin reaction [2, 3]. Recently, a newer broad-spectrum Bcr-Abl TKI has joined the battle against refractory disease.\n\nPonatinib is a third-generation TKI developed for drug-resistant chronic myelogenous leukemia and acute lymphoblastic leukemia. In addition to blocking the constitutively active Bcr-Abl tyrosine kinase implicated in the pathogenesis of chronic myelogenous leukemia, it also inhibits the activity of other kinases including fibroblast growth factor, FMS like tyrosine kinase-3, KIT, platelet-derived growth factor, vascular endothelial growth factor, and the SRC families [6]. This broadened activity, while paramount for treatment-resistant cancers, may contribute to off-target effects in the skin. Dermatologic adverse events in both phase I and II clinical trials were similar in profile to those seen in first- and second- generation TKIs [7, 8]. Since ponatinib became commercially available in 2014, several reports of cutaneous adverse events have been described, all with relevant clinical and histological similarities. Notably, of those reports revealing clinical photos, a follicular rash coalescing into pink-orange plaques demonstrating islands of sparing was almost always seen. Furthermore, several cases described significant xerosis and pruritus. Histologically, the majority of skin biopsies revealed perifollicular fibrosis, hyperkeratosis with varying orthokeratosis and parakeratosis, and scant perivascular lymphocytic infiltrate [9–12].\n\nGiven the similarities in cutaneous eruptions, numerous authors have responded with congruous therapies. Clearance of lesions was achieved without interruption of TKI therapy in ten out of ten cases. Of these, only one patient required a dose reduction [13]. Treatments included topical corticosteroids, keratolytics, retinoids, and antifungals. Systemic corticosteroids (20 mg prednisone, interval not specified) and retinoids (10 mg acitretin, four times daily) were each used in one patient, respectively. Our patient improved significantly on topical retinoids only within 3 weeks of therapy. While the pathogenesis behind retinoids as an effective therapy has not been completely elucidated, a few theories are proposed. First, topical retinoids have been shown to upregulate levels of heparin-binding epidermal growth factor-like growth factor in keratinocytes [14]. Heparin-binding epidermal growth factor-like growth factor is associated with chemotherapeutic resistance [1]. Thus, retinoids may cause local chemotherapeutic resistance in keratinocytes, reducing cutaneous effects. Additionally, all-trans retinoic acid derivatives help terminally differentiate epidermal cells [15]. This may cause diminished uptake of drug therapy within keratinocytes, thereby protecting them from the effects of chemotherapy. Finally, given the similarity to PRP, known treatments such as retinoids, should be effective while continuing critical TKI therapy.\n\nConclusion\nIn summary, TKIs are emerging as novel directed cancer therapies while minimizing adverse effects compared with traditional chemotherapy. However, cutaneous eruptions are common. Our case and literature review reveal that a characteristic rash occurs within the same time frame on similar doses of ponatinib, manifesting as a PRP-like eruption with ichthyosis and xerosis. This observation provides insight into the possibility of a unique pathogenic mechanism. Here, we highlight not only that cutaneous eruptions occur on ponatinib therapy, but that the dermatologic manifestations are characteristic and unique and benefit from retinoid therapy without requiring interruption of life-saving anticancer therapies.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (DOCX 126 kb)\n\n \n\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1007/s40800-017-0055-y) contains supplementary material, which is available to authorized users.\n\nCompliance with Ethical Standards\nAriel Eber, Alyx Rosen, Kate Oberlin, Alessio Giubellino, and Paolo Romanelli have no conflicts of interest directly relevant to the content of this article.\n==== Refs\nReferences\n1. Druker BJ Talpaz M Resta DJ Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med. 2001 344 1031 1037 10.1056/NEJM200104053441401 11287972 \n2. Amitay-Laish I Stemmer SM Lacouture ME Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib Dermatol Ther. 2011 24 386 395 10.1111/j.1529-8019.2011.01431.x 21910796 \n3. Dervis E Ayer M Akin Belli A Barut SG Cutaneous adverse reactions of imatinib therapy in patients with chronic myeloid leukemia: A six-year follow up Eur J Dermatol. 2016 26 133 137 26679005 \n4. Drucker AM Wu S Busam KJ Berman E Amitay-Laish I Lacouture ME Rash with the multitargeted kinase inhibitors nilotinib and dasatinib: meta-analysis and clinical characterization Eur J Haematol. 2013 90 142 150 10.1111/ejh.12052 23240881 \n5. Nicolini FE Turkina A Shen ZX Expanding Nilotinib Access in Clinical Trials (ENACT): an open-label, multicenter study of oral nilotinib in adult patients with imatinib-resistant or imatinib-intolerant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase Cancer. 2012 118 118 126 10.1002/cncr.26249 21732337 \n6. Gozgit JM Wong MJ Wardwell S Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies Mol Cancer Ther. 2011 10 1028 1035 10.1158/1535-7163.MCT-10-1044 21482694 \n7. Cortes JE Kantarjian H Shah NP Ponatinib in refractory Philadelphia chromosome-positive leukemias N Engl J Med 2012 367 2075 2088 10.1056/NEJMoa1205127 23190221 \n8. Cortes JE Kim DW Pinilla-Ibarz J A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias N Engl J Med 2013 369 1783 1796 10.1056/NEJMoa1306494 24180494 \n9. Patel AB Solomon AR Mauro MJ Ehst BD Unique cutaneous reaction to second- and third-generation tyrosine kinase inhibitors for chronic myeloid leukemia Dermatology. 2016 232 122 125 10.1159/000437383 26352467 \n10. Orenay OM Tamer F Sarifakioglu E Yildirim U Lamellar ichthyosis-like eruption associated with ponatinib Acta Dermatovenerol Alp Pannonica Adriat. 2016 25 59 60 27695870 \n11. Alloo A Sheu J Butrynski JE Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities Br J Dermatol. 2015 173 574 577 10.1111/bjd.13692 25736577 \n12. Jack A Mauro MJ Ehst BD Pityriasis rubra pilaris-like eruption associated with the multikinase inhibitor ponatinib J Am Acad Dermatol. 2013 69 e249 e250 10.1016/j.jaad.2013.04.061 24124847 \n13. Renzi D Marchesi F De Angelis G Ponatinib Induces a persistent molecular response and graft-versus-host disease/graft-versus-leukemia effect in a patient with philadelphia-positive acute lymphoblastic leukemia with a T315I mutation following early relapse after allogeneic transplant Chemotherapy. 2017 62 58 61 10.1159/000448750 27618144 \n14. Inokuchi M Ishikawa S Furukawa H Treatment of capecitabine-induced hand-foot syndrome using a topical retinoid: a case report Oncol Lett. 2014 7 444 448 24396465 \n15. Kopan R Traska G Fuchs E Retinoids as important regulators of terminal differentiation: examining keratin expression in individual epidermal cells at various stages of keratinization J Cell Biol. 1987 105 427 440 10.1083/jcb.105.1.427 2440897\n\n",
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"title": "Ichthyosiform Pityriasis Rubra Pilaris-Like Eruption Secondary to Ponatinib Therapy: Case Report and Literature Review.",
"title_normalized": "ichthyosiform pityriasis rubra pilaris like eruption secondary to ponatinib therapy case report and literature review"
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"abstract": "S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive neurometabolic disorder affecting the muscles, liver, and nervous system. The disease occurs by pathogenic variants of AHCY gene encoding S-adenosylhomocysteine hydrolase (AHCY) enzyme. This article reports a patient with presumed AHCY deficiency who was diagnosed by whole exome sequencing due to compound heterozygosity of novel p.T57I (c.170C>T) and p.V217M (c.649G>A) variants of AHCY gene. The patient had diffuse edema, coagulopathy, central nervous system abnormalities, and hypotonia. She died in 3 months due to cardiovascular collapse. Clinical findings of the present case were compatible with previously reported AHCY deficiency patients and the novel variants we found are considered to be the cause of the symptoms. This article also compiles the previous reports and expands clinical spectrum of AHCY deficiency by adding new features.",
"affiliations": "Department of Medical Genetics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.;Department of Medical Genetics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.;Division of Neonatology, Department of Pediatrics, Eskisehir Osmangazi University, Faculty of Medicine, Eskisehir, Turkey.;Department of Radiology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.;Department of Medical Genetics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.;Department of Medical Genetics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.;Department of Medical Genetics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.;Department of Medical Genetics, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.",
"authors": "Bas|Hasan|H|0000-0003-3475-564X;Cilingir|Oguz|O|;Tekin|Neslihan|N|;Saylisoy|Suzan|S|;Durak Aras|Beyhan|B|;Uzay|Elif|E|;Erzurumluoglu Gokalp|Ebru|E|;Artan|Sevilhan|S|",
"chemical_list": "D050938:Glycine N-Methyltransferase; C000627205:AHCY protein, human; D043383:Adenosylhomocysteinase",
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"issue": "182(4)",
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"keywords": "AHCY; S-adenosylhomocysteine hydrolase deficiency; WES; metabolic disorders",
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"title": "A Turkish patient with novel AHCY variants and presumed diagnosis of S-adenosylhomocysteine hydrolase deficiency.",
"title_normalized": "a turkish patient with novel ahcy variants and presumed diagnosis of s adenosylhomocysteine hydrolase deficiency"
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"abstract": "A 4-year-old female child developed cutaneous Langerhans cell histiocytosis 6 months following a diagnosis of T-cell acute lymphoblastic leukemia. Imaging revealed no evidence of systemic disease. Seven months later, the first systemic lesion was discovered on laryngoscopy. Restaging Positron Emission Tomography - Computed Tomography at that time revealed new 18-fluorodeoxyglucose-positive lesions in the left apical pleural margin, right lower peri-esophageal region, left ventricular myocardium, pancreas, upper pole of the left kidney, and inguinal and gluteal regions consistent with progressive systemic disease. Genomic testing revealed a low tumor mutational burden as well as mutations in KRAS G12A, ARID1A Q524, CDKN2A/B loss, and an alteration in NOTCH1.",
"affiliations": "USD Sanford School of Medicine, Sioux Falls, South Dakota.;USD Sanford School of Medicine, Sioux Falls, South Dakota.;Sanford Health, USD Sanford School of Medicine, Sioux Falls, South Dakota.;USD Sanford School of Medicine, Sioux Falls, South Dakota.;USD Sanford School of Medicine, Sioux Falls, South Dakota.;USD Sanford School of Medicine, Sioux Falls, South Dakota.",
"authors": "Jansen|Chandler|C|0000-0002-4576-4157;Dykstra|Jordan|J|;Callaway|Daniel|D|0000-0003-1947-6802;Lynch|Douglas|D|;Cunningham|Arwyn|A|;Frohm|Marcus L|ML|",
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"issue": "67(12)",
"journal": "Pediatric blood & cancer",
"keywords": "Langerhans cell histiocytosis; T-ALL; clonality",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D006646:Histiocytosis, Langerhans-Cell; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma",
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"title": "Aggressive Langerhans cell histiocytosis following T-cell acute lymphoblastic leukemia.",
"title_normalized": "aggressive langerhans cell histiocytosis following t cell acute lymphoblastic leukemia"
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"abstract": "Thiamine deficiency disorders are an under-recognized public health problem in low- and middle-income countries. Infantile beriberi, the most important symptom for children, is suspected to significantly contribute to infant mortality and lifelong neurodevelopmental morbidity. Lack of awareness, varied clinical presentation, and lack of a readily available diagnostic marker lead to frequent misdiagnoses. We report six thriving infants who presented with an acute fulminant illness with varied clinical manifestations mimicking common childhood illnesses like pneumonia and sepsis. Four of them presented with the severe cardiovascular form, called Shoshin beriberi, and severe pulmonary arterial hypertension. Empirical intravenous thiamine administered to four of the six infants resulted in dramatic recovery. Awareness of the clinical definition of infantile beriberi and treatment with empirical thiamine can be lifesaving.",
"affiliations": null,
"authors": "Samprathi|Madhusudan|M|;Mohammad|Faisal|F|;M|Sridhar|S|;Ramachandra|Prakash|P|;Vemgal|Prakash|P|",
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"title": "Case Report: Fulminant Infantile Beriberi: A Report of Six Cases.",
"title_normalized": "case report fulminant infantile beriberi a report of six cases"
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... |
{
"abstract": "Medication-assisted treatment is recommended for individuals with an opioid use disorder, including pregnant women. Medication-assisted treatment during pregnancy provides benefits to the mother and fetus, including better pregnancy outcomes, reduced illicit drug use, and improved prenatal care. An alternative approach, medically supervised withdrawal (detoxification), has, in recent reports, demonstrated a low risk of fetal death and low rates of relapse and neonatal abstinence syndrome. The rates of relapse and neonatal abstinence syndrome are questioned by many who view medically supervised withdrawal as unacceptable based on the concern for the potential adverse consequences of relapse to mother and baby. The impact of opioids on the fetal brain have not been integrated into this debate. Studies in animals and human brain tissues demonstrate opioid receptors in neurons, astroglia, and oligodendrocytes. Age-specific normative data from infants, children, and adults have facilitated investigation of the impact of opioids on the human brain in vivo. Collectively, these studies in animals, human neural tissue, adult brains, and the brains of children and newborns demonstrate that opioids adversely affect the human brain, primarily the developing oligodendrocyte and the processes of myelinization (white matter microstructure), connectivity between parts of the brain, and the size of multiple brain regions, including the basal ganglia, thalamus, and cerebellar white matter. These in vivo studies across the human lifespan suggest vulnerability of specific fronto-temporal-limbic and frontal-subcortical (basal ganglia and cerebellum) pathways that are also likely vulnerable in the human fetal brain. The long-term impact of these reproducible changes in the fetal brain in vivo is unclear, but the possibility of lasting injury has been suggested. In light of the recent data on medically supervised withdrawal and the emerging evidence suggesting adverse effects of opioids on the developing fetal brain, a new paradigm of care is needed that includes the preferred option of medication-assisted treatment but also the option of medically supervised opioid withdrawal for a select group of women. Both these treatment options should offer mental health and social services support throughout pregnancy. More research on both opioid exposure on the developing human brain and the impact of medically supervised withdrawal is required to identify appropriate candidates, optimal dose reduction regimens, and gestational age timing for initiating medically supervised withdrawal.",
"affiliations": "Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA. Electronic address: scaritis@mail.magee.edu.;Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.",
"authors": "Caritis|Steve N|SN|;Panigrahy|Ashok|A|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajog.2019.07.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "221(6)",
"journal": "American journal of obstetrics and gynecology",
"keywords": "MRI; accumbens area; amygdala; astroglia; brainstem; buprenorphine; cerebellum; cerebral cortex; detoxification; fetal neurobiology; magnetic resonance imaging; medically supervised opioid withdrawal; medication-assisted treatment; methadone; neural pathways; oligodendrocytes; opioid dose reduction or elimination; opioids; pallidum; putamen; superior and inferior longitudinal fasciculus and white matter",
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D001921:Brain; D002648:Child; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D007231:Infant, Newborn; D009186:Myelin Sheath; D009357:Neonatal Abstinence Syndrome; D009434:Neural Pathways; D059906:Neuroimaging; D009836:Oligodendroglia; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D012008:Recurrence; D013375:Substance Withdrawal Syndrome; D066127:White Matter",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "602-608",
"pmc": null,
"pmid": "31323217",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": "27679504;1163358;17239623;27808568;18770079;25138998;26996987;26512202;29630016;11520626;4525985;22822467;24945162;29326869;25595574;17513131;23427244;11239921;31151658;22841456;24378955;29112519;20558415;11943501;28742676;19272431;26814280;24474873;18474065;23988427;28187337;20216119;16360292;30231274;30204704;21142534;29614184;25821873;28079573;16194615;27729254;21688258;24717065;21070508;19377504;29443414;20203117;12015209;671413;30511742;22704008;18381654;18701886;30530638;27521465;25735940;9794682;23727040;29075045;28002715;1130446;26233486;19450664",
"title": "Opioids affect the fetal brain: reframing the detoxification debate.",
"title_normalized": "opioids affect the fetal brain reframing the detoxification debate"
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"occurcountry": "US",
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"activesubstancename": "METHADONE HYDROCHLORIDE"
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"abstract": "Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42-59%); 5-year overall survival (OS) was 73% (95% CI 65-80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44-78%) and 5-year OS of 90% (95% CI 72-97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40-75%) and OS of 90% (95% CI 72-97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.",
"affiliations": "Haematology, Erasmus MC Cancer Centre, Rotterdam, Netherlands.;Amsterdam UMC - Locatie VUMC, Amsterdam, Netherlands.;Erasmus MC Cancer Centre, Rotterdam, Netherlands.;Haematology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam and LYMMCARE (lymphoma and myeloma Center), Amsterdam, Netherlands.;Haematology, Haga Teaching Hospital, The Hague, USA.;Haematology, UMC Utrecht Cancer Centre, Utrecht, Netherlands.;UMCN, Nijmegen, Netherlands.;Internal Medicine, Isala Clinic, Zwolle, Netherlands.;Albert Schweitzer Hospital Location Dordwijk, Dordrecht, Netherlands.;Medisch Spectrum Twente, Enschede, Netherlands.;Sint Antonius Hospital, Nieuwegein, Netherlands.;Maastricht University Medical Centre+, Maastricht, Netherlands.;Medical Centre Leeuwarden, Leeuwarden, Netherlands.;Maasstad Ziekenhuis, Rotterdam, Netherlands.;Department of Pathology, Pathology Friesland, Groningen, Netherlands.;Amsterdam UMC - Locatie VUMC, Amsterdam, Netherlands.;Erasmus MC Cancer Center, Rotterdam, Netherlands.;Erasmus MC Cancer Centre, Rotterdam, Netherlands.;Haematology, University Medical Center Groningen, Groningen, Netherlands.",
"authors": "Doorduijn|Jeanette K|JK|0000-0002-1014-0918;Zijlstra|Josee M|JM|;Lugtenburg|Pieternella J|PJ|0000-0002-6735-8651;Kersten|Marie Josee|MJ|;Böhmer|Lara H|LH|;Minnema|Monique C|MC|;MacKenzie|Marius A|MA|;van Marwijk Kooij|Rien|R|;de Jongh|Eva|E|;Snijders|Tjeerd J F|TJF|;de Weerdt|Okke|O|;van Gelder|Michel|M|;Hoogendoorn|Mels|M|;Leys|Rineke B L|RBL|;Kibbelaar|Robby E|RE|;de Jong|Daphne|D|;Chitu|Dana A|DA|;Van't Veer|Mars B|MB|;Kluin-Nelemans|Hanneke C|HC|",
"chemical_list": "D003561:Cytarabine; D000069283:Rituximab; D014750:Vincristine; D000069286:Bortezomib; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D008558:Melphalan; D002330:Carmustine; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.16567",
"fulltext": "\n==== Front\nBr J Haematol\nBr. J. Haematol\n10.1111/(ISSN)1365-2141\nBJH\nBritish Journal of Haematology\n0007-1048 1365-2141 John Wiley and Sons Inc. Hoboken \n\n10.1111/bjh.16567\nBJH16567\nResearch Paper\nHaematological Malignancy ‐ Clinical\nBortezomib maintenance after R‐CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial\nBortezomib Maintenance after ASCT in MCLJ. K. Doorduijn et al.Doorduijn Jeanette K. https://orcid.org/0000-0002-1014-0918\n1\nj.doorduijn@erasmusmc.nl Zijlstra Josee M. \n2\n Lugtenburg Pieternella J. https://orcid.org/0000-0002-6735-8651\n3\n Kersten Marie Josee \n4\n Böhmer Lara H. \n5\n Minnema Monique C. \n6\n MacKenzie Marius A. \n7\n van Marwijk Kooij Rien \n8\n de Jongh Eva \n9\n Snijders Tjeerd J.F. \n10\n de Weerdt Okke \n11\n van Gelder Michel \n12\n Hoogendoorn Mels \n13\n Leys Rineke B.L. \n14\n Kibbelaar Robby E. \n15\n de Jong Daphne \n2\n Chitu Dana A. \n16\n Van’t Veer Mars B. \n3\n Kluin‐Nelemans Hanneke C. \n17\n \n1 \nHaematology\nErasmus MC Cancer Centre\nRotterdam\nNetherlands\n\n\n2 \nAmsterdam UMC – Locatie VUMC\nAmsterdam\nNetherlands\n\n\n3 \nErasmus MC Cancer Centre\nRotterdam\nNetherlands\n\n\n4 \nHaematology\nAmsterdam UMC\nUniversity of Amsterdam\nCancer Center Amsterdam and LYMMCARE (lymphoma and myeloma Center)\nAmsterdam\nNetherlands\n\n\n5 \nHaematology\nHaga Teaching Hospital\nThe Hague\nUSA\n\n\n6 \nHaematology\nUMC Utrecht Cancer Centre\nUtrecht\nNetherlands\n\n\n7 \nUMCN\nNijmegen\nNetherlands\n\n\n8 \nInternal Medicine\nIsala Clinic\nZwolle\nNetherlands\n\n\n9 \nAlbert Schweitzer Hospital Location Dordwijk\nDordrecht\nNetherlands\n\n\n10 \nMedisch Spectrum Twente\nEnschede\nNetherlands\n\n\n11 \nSint Antonius Hospital\nNieuwegein\nNetherlands\n\n\n12 \nMaastricht University Medical Centre+\nMaastricht\nNetherlands\n\n\n13 \nMedical Centre Leeuwarden\nLeeuwarden\nNetherlands\n\n\n14 \nMaasstad Ziekenhuis\nRotterdam\nNetherlands\n\n\n15 \nDepartment of Pathology\nPathology Friesland\nGroningen\nNetherlands\n\n\n16 \nErasmus MC Cancer Center\nRotterdam\nNetherlands\n\n\n17 \nHaematology\nUniversity Medical Center Groningen\nGroningen\nNetherlands\n\n* \nCorrespondence: Jeanette K. Doorduijn, Haematology, Erasmus MC Cancer Centre, Rotterdam, Netherlands.\n\nE‐mail: j.doorduijn@erasmusmc.nl\n\n09 3 2020 \n8 2020 \n190 3 10.1111/bjh.v190.3385 393\n24 11 2019 11 2 2020 15 2 2020 © 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nRituximab‐containing induction followed by autologous stem cell transplantation (ASCT) is the standard first‐line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo‐immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high‐dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m2 intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow‐up of 77·5 months for patients still alive, 5‐year event‐free survival (EFS) was 51% (95% CI 42–59%); 5‐year overall survival (OS) was 73% (95% CI 65–80%). The median follow‐up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5‐year EFS of 63% (95% CI 44–78%) and 5‐year OS of 90% (95% CI 72–97%). The patients randomised to observation had 5‐year PFS of 60% (95% CI, 40–75%) and OS of 90% (95% CI 72–97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.\n\nbortezomibcytarabinemaintenance therapyMantle cell lymphomaphase II trialrandomisedKWF Kankerbestrijding 10.13039/501100004622CKTO 2006‐07Janssen Pharmaceuticals 10.13039/100008897 source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020\n==== Body\nIntroduction\nThe prognosis of mantle cell lymphoma (MCL) has improved considerably with the introduction of rituximab, high‐dose cytarabine and autologous stem cell transplantation (ASCT) in first‐line treatment (Dreyling et al., 2017). The conditioning regimen may consist of BEAM (carmustine, etoposide, cytarabine, melphalan) or total‐body irradiation in combination with chemotherapy (Hoster et al., 2016).\n\nThe Dutch Haematology‐Oncology Cooperative Group (HOVON) has previously investigated the role of three cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) followed in responding patients by one cycle of high‐dose cytarabine (HD‐Ara‐C) and ASCT in MCL (van't Veer et al., 2009). In this phase II study (HOVON 45), the 4‐year progression‐free survival (PFS) was 44%, and the 4‐year overall survival (OS) was 66%. In order to increase the PFS and OS we designed a subsequent study (HOVON 75) in which we changed three aspects: first, HD‐Ara‐C was given to all patients, irrespective of the response to R‐CHOP. Second, we added a second cycle of HD‐Ara‐C to induction therapy based on positive results from studies of the Nordic group (Geisler et al., 2008). Finally, to explore if bortezomib maintenance therapy after ASCT could be of benefit, we randomised transplanted patients to bortezomib maintenance or no further treatment. Bortezomib was chosen for this purpose based on its efficacy in relapsed/refractory MCL. A response rate of about 45% with a median duration of about 12 months was achieved in several clinical studies. Based on these favourable results, bortezomib received approval for the treatment of relapsed/refractory MCL (Fisher et al., 2006; Goy et al., 2009; Kane et al., 2007; Zinzani et al., 2013).\n\nPatients and methods\nEligibility\nPatients 18–65 years with newly‐diagnosed MCL, Ann Arbor stage II to IV, with WHO performance status 0 to 2 and measurable disease were eligible for study participation. Primary diagnosis was made on a representative lymph node or extranodal site biopsy sample and included histological and complete immunohistochemical assessment according to the criteria of the WHO classification (WHO 2008, as valid during inclusion and largely unchanged in the present WHO classification 2016). Confirmation of the diagnosis by central pathology review was part of the quality assessment and performed by two hematopathologists (DDJ, REK) according to routine procedures by the HOVON Pathology Facility (www.hovon.nl). Exclusion criteria were creatinine clearance <50 ml/min, CNS involvement, HIV or hepatitis B or C positivity, peripheral neuropathy >grade 2, other active malignancy and other serious medical conditions that could interfere with study treatment.\n\nPatients who completed BEAM consolidation with ASCT, with recovery of neutrophils to >0·5 × 109/l and platelets to >80 × 109/l, without neuropathy grade 2 or more, were eligible for randomisation between bortezomib maintenance and no further treatment.\n\nStaging procedures and response monitoring\nStaging workup consisted of standard cervical, thoracic and abdominal CT scans. Bone marrow involvement was assessed by cytomorphologic and immunologic examination of bone marrow aspirate and histology of bone marrow trephine. If clinically indicated, endoscopy or other investigations for extranodal localisations were performed. Response was evaluated according to the 1999 Cheson criteria (Cheson et al., 1999). Response evaluation was performed after the 2nd HD‐Ara‐C cycle and after ASCT before randomisation. During the maintenance phase, patients were evaluated with CT‐scan and bone marrow analysis at 3, 6, 12, 18 and 24 months. During further follow‐up, patients were evaluated every 6 months, and at the moment of relapse or progression.\n\nStudy design\nThis investigator‐initiated, multicentre, phase II trial was designed, performed and sponsored by HOVON, and was conducted in 15 centres in the Netherlands. All patients were registered and randomised via the internet through TOP (Trial Online Process; https://www.hdc.hovon.nl/top/logon.asp). No stratification factors according to baseline characteristics were defined.\n\nThe treatment schedule consisted of three cycles of R‐CHOP21 (rituximab 375 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1·4 mg/m2 day 1 (max 2 mg), all intravenous (IV), and prednisone 100 mg day 1–5 orally), followed by two cycles of cytarabine [2 × 2 g/m2 IV day 1–4 (every 12 hours) in a 3‐hours saline infusion] and rituximab (375 mg/m2, IV) on day 11 aiming at in vivo purging of CD20 + mantle cells during mobilisation. One of the cytarabine cycles was used for stem cell mobilisation with G‐CSF to be started at day 8. A minimum of 3 × 106 CD34 + cells/kg was considered sufficient for transplantation. Patients in partial (PR) or complete remission (CR) after the second cycle of HD‐Ara‐C continued with ASCT after BEAM conditioning (carmustine 300 mg/m2 day −7, cytarabine 2 × 100 mg/m2 day −6 to −3, etoposide 2 × 100 mg/m2 day −6 to −3 and melphalan 140 mg/m2 day −2, IV). All other patients went off protocol.\n\nPatients with a PR or CR after ASCT with a neutrophil count >0·5 × 109/l and platelets >80 × 109/l were randomised (1:1) between bortezomib and no further treatment. Bortezomib 1·3 mg/m2 IV (provided by Janssen–Cilag B.V., Beerse, Belgium) was given once every 2 weeks, for 2 years, starting between 6 and 12 weeks after transplantation. If bortezomib was not started within 12 weeks after ASCT, the patient went off protocol. Bortezomib maintenance had to be stopped after progression or relapse and when bortezomib maintenance was interrupted for more than 6 weeks. Before each bortezomib dose, the patient was evaluated for possible toxicities. Bortezomib should be withheld in case of febrile neutropenia until resolution of that condition, grade 4 haematological toxicity until sufficient recovery (haemoglobin >7·0 g/dl, neutrophils >0·5 × 109/l, and platelet count >50 × 109/l) and grade ≥3 non‐hematological toxicity until the toxicity recovered to at least grade 2. After (partial) resolution, the doses had to be adjusted. If the toxicity did not resolve after dosing had been withheld for 2 weeks, the patient discontinued treatment. Neuropathic pain and/or peripheral sensory neuropathy had to be managed following specific guidelines.\n\nAll patients provided written informed consent. The study was approved by the ethical committee of Erasmus MC Rotterdam and the participating sites, and was conducted in accordance with the Declaration of Helsinki. The trial is registered at the Dutch Trial Registry (www.trialregister.nl, no. NTR1772).\n\nStatistical analysis and definition of endpoints\nThis study was explorative as to the effect of bortezomib maintenance. The induction regimen was changed in two ways compared to our previous regimen. To get an indication if, in addition, bortezomib maintenance could be of any benefit, it was decided to have a control arm without maintenance. The aim was to continue to a randomised phase III study if it was feasible and showed an indication of a possible effect, within the limitations of a phase II study. The target number of patients to be randomised was 60, requiring an estimated 90 primary registered patients. However, after registration of 70 patients, only 44% were randomised. Therefore, the target number of patients to be registered was increased to 135 eligible patients.\n\nThe primary endpoint was EFS from randomisation (applied to all eligible randomised patients), defined as the time from randomisation to failure or death from any cause, whichever comes first. OS was defined as the time from registration until death from any cause. Patients still alive at the date of last contact were censored. Failure was defined as either no response on treatment or relapse; PR was not defined as failure.\n\nFor the efficacy of the maintenance treatment, EFS (primary endpoint of this study) and OS were calculated with the method of Kaplan–Meier. The median and probabilities at 2 years were calculated together with 95% confidence intervals. The safety of bortezomib maintenance was evaluated by tabulation of the (serious) adverse events, coded according to the NCI Common Terminology Criteria for Adverse Events, CTCAE version 3.0.\n\nCox regression analysis and the associated likelihood ratio test were used to test for trends with continuous or ordinal variables. P‐values < 0.05 were considered significant.\n\nResults\nPatient characteristics\nBetween October 2007 and March 2012, 140 patients with a median age of 57 (range 34–66) were included. The patient characteristics are presented in Table 1. The majority of the patients were male (78%) and patients presented generally with stage IV disease (86%). Central pathology review was performed in 136/140 registered patients. A diagnosis of CD20 and CyclinD1 positive MCL could be confirmed in 131 cases. In three cases a diagnosis of another B‐cell lymphoma class was made (B‐CLL, NMZL, multiple myeloma), and in two cases material was considered insufficient for a classifying diagnosis. These five patients were considered ineligible in hindsight and excluded from analysis. MIB1 quantification was performed in 87/131 MCL cases confirmed at review with 25/87 (28,7%) with a MIB1 index ≥30%. In 114/131 confirmed MCL, SOX11 was performed, of which four were negative. Of these, however, two cases had either blastoid morphology or P53 protein expression both with high MIB1 indices. A low MIPI score (Hoster et al., 2008) was present in 57% of the patients.\n\nTable 1 Baseline patient and disease characteristics.\n\n \tAll patients n = 135\tRandomised patients after ASCT\t\n \tNo further treatment n = 30\tBortezomib maintenance n = 30\t\nAge (median; range)\t57 (34–66)\t54 (36–65)\t56 (34–66)\t\nMale sex\t78%\t77%\t80%\t\nWHO performance\t\nWHO 0\t105 (78%)\t25 (83%)\t25 (83%)\t\nWHO 1\t60 (19%)\t5 (17%)\t4 (13%)\t\nWHO 2\t5 (4%)\t \t1 (3%)\t\nAnn Arbor stage\t\nII\t11 (8%)\t1 (3%)\t3 (10%)\t\nIII\t8 (6%)\t2 (7%)\t2 (7%)\t\nIV\t116 (86%)\t27 (90%)\t25 (83%)\t\nMIPI score\t\nLow\t77 (57%)\t21 (70%)\t15 (50%)\t\nIntermediate\t43 (32%)\t6 (20%)\t11 (37%)\t\nHigh\t13 (10%)\t3 (10%)\t3 (10%)\t\nUnknown\t2 (1%)\t \t1 (3%)\t\nBone marrow involvement\t112 (83%)\t26 (87%)\t24 (80%)\t\nMIB1\t<30%\t62 (46%)\t11 (37%)\t17 (57%)\t\n≥30%\t25 (18%)\t8 (26%)\t5 (17%)\t\nunknown\t48 (36%)\t11 (37%)\t8 (26%)\t\nP53\t<50%\t68 (50%)\t17 (57%)\t18 (60%)\t\n≥50%\t7 (5%)\t1 (3%)\t0 (0%)\t\nunknown\t60 (45%)\t12 (40%)\t12 (40%)\t\nJohn Wiley & Sons, LtdInduction treatment and ASCT\nThe consort diagram is presented in Fig. 1. Out of 135 eligible patients at registration, 134 received all three R‐CHOP cycles and 127 patients received both HD‐Ara‐C cycles. Response evaluation showed that 79 patients (63%) achieved a CR/CRu and 39 patients (31%) a PR. Three patients had stable disease, two patients had PD and, in four patients, response at this point was unknown. 115 patients proceeded to ASCT (Fig. 1). Reasons for not proceeding to ASCT were insufficient response (n = 6), insufficient stem cell harvest (n = 3) or other reasons (n = 3). The response after BEAM and ASCT improved: 99 patients (86%) achieved a CR/CRu and 15 patients (13%) a PR. One patient was not restaged. A median of three (0–19) platelet transfusions and a median of three (0–16) red blood cell transfusions were given. The median time to white blood cell recovery >0·5 × 109/l was 25 days (16–139); the median recovery time to platelets >50 × 109/l was 27 days (17–632).\n\nFigure 1 Consort diagram of all patients.\n\nMaintenance randomisation after ASCT\nAfter ASCT, 62 of 115 transplanted patients were randomised for bortezomib (n = 31) or no further treatment (n = 31). After randomisation, one patient in each arm was found ineligible, therefore, 30 patients in each study arm were analysed for the maintenance phase. Of 53 patients who were not randomised, the majority were excluded according to protocol (insufficient bone marrow/haematological recovery, especially low platelet count) and refusal (Fig. 1). The characteristics of the randomised patients were well‐balanced between both arms, apart from the MIPI score, with fewer patients with a low MIPI score in the bortezomib arm (50% vs. 70%) (Table 1).\n\nOutcome\nWith a median follow‐up of 77·5 months for all patients alive, the EFS at 5 years was 51%, and the OS 73% (Fig. 2).\n\nFigure 2 Event‐free survival and overall survival of all 135 patients.\n\nThirty‐seven percent of patients (n = 50) died. Causes of death were MCL (n = 26, 52%), treatment‐related (n = 1, 2%), intercurrent disease (n = 5, 10%), secondary malignancy (n = 4, 8%), unknown (n = 4, 8%) and other (n = 10, 20%). Seven of these last 10 patients died of complications from allogeneic stem cell transplantation.\n\nThe median follow‐up of the randomised patients still alive was 71·5 months. The EFS at 2 years was 83% in the bortezomib arm (95% CI 65–93%), and in the patients without maintenance 80% (95% CI 61–90%). The EFS at 5 years was also similar in both arms, with 63% (95% CI 44–78%; P = 0·73) in the patients treated with bortezomib versus 60% (95% CI 40–75%) for the patients without maintenance treatment (Fig. 3). The 5‐year OS was identical with 90% (95% CI 72–97%) in both arms.\n\nFigure 3 Event‐free survival of randomised patients.\n\nToxicity of bortezomib maintenance\nA planned interim analysis was performed in October 2011, based upon data from 2 × 15 randomised patients with a follow‐up of at least 3 months after randomisation. No unexpected toxicity was observed and it was decided to continue enrolment as planned.\n\nThe median duration of maintenance therapy was 21 months. Out of 30 patients randomised to bortezomib maintenance therapy, 15 continued the bortezomib therapy for the planned 24 months, while 15 patients received bortezomib treatment for a median of 14 months (range 0–23). The reasons to stop early were progressive disease (n = 4), excessive toxicity (n = 6), refusal to start (n = 2) or continue after the first dose (n = 1), second malignancy (n = 1) and unknown (n = 1). Neurological adverse events grade 2 were observed in four patients and grade 3 in one patient; no grade 4 neurological adverse events were observed.\n\nSecondary malignancy\nFifteen patients (11%) developed a secondary malignancy; six of these had received bortezomib maintenance. They developed non‐melanoma skin cancer (n = 2), melanoma (n = 1), prostate cancer (n = 1), oropharynx carcinoma (n = 1) and neuro‐endocrine carcinoma (n = 1).\n\nIn the observation arm, nine patients developed a secondary malignancy [non‐melanoma skin cancer (n = 4), adenocarcinoma (n = 3) and lung cancer (n = 2)].\n\nDiscussion\nThis phase II randomised trial (HOVON 75) was designed upon the basis of the earlier HOVON 45 study (van’t Veer et al., 2009). We aimed at improvement in outcome by continuing treatment of all patients after R‐CHOP with high‐dose ARA‐C, irrespective of response, and by giving two cycles of ARA‐C instead of one. Responding patients would continue to ASCT. The outcome of the present study compares favourably to the previous study. Therefore, these interventions seem worthwhile. In the HOVON 45 study, 70% of the patients could be transplanted compared to 85% in the current study. In the previous control study, a 4‐year failure‐free survival of 36% and OS of 66% were achieved; in the current HOVON 75 study, the EFS at 5 years was 51%, and the OS 73%. This suggests an important role of cytarabine in the induction treatment of MCL, as reported in other studies (Geisler et al., 2008;Hermine et al., 2016).\n\nA second aim of our study was to investigate if bortezomib maintenance after ASCT would be feasible and could improve outcome. This approach was new at the time. To this end, we decided to have a parallel control arm without maintenance. Bortezomib maintenance was feasible, although the number of patients that could be randomised was lower than expected due to insufficient recovery of the blood counts after ASCT. Our study did not show any difference in EFS.\n\nThis trial had a few limitations. Compared to the regimen we used before (HOVON 45) we changed the protocol on three points, so it is not clear which of the interventions resulted in the observed better outcome. The study encountered unexpected difficulties in that many patients did not reach the pre‐specified platelet count of >80 × 109/l before week 12 after ASCT, resulting in a lower than expected number of patients to be randomised. The protocol therefore was amended to increase sample size of patients registered in the study. Finally, the small number of patients randomised (phase II design) resulted in a relatively low statistical power and the chance of missing a positive effect. However, the completely overlapping curves suggest that bortezomib monotherapy does not have a benefit in the context of maintenance. Therefore, there is no indication to initiate a phase III study.\n\nBortezomib maintenance in MCL patients has also been studied by the CALGB. In this randomised phase II study (50403), bortezomib maintenance (bortezomib 1·6 mg/m2 weekly 4 of 8 weeks for 18 months), was compared with a consolidation scheme (bortezomib 1·3 mg/m2 days 1, 4, 8 and 11 of a 3 week cycle for four cycles) after ASCT. Both bortezomib arms performed equally at 5 years, showing PFS of 70% vs. 69%, respectively. The authors compared these results with those from their previous study without maintenance or consolidation (59909), which demonstrated a 5‐year PFS of 51%. They suggest a benefit from bortezomib consolidation or maintenance (Kaplan et al., 2015). However, caution should be applied in comparing these studies, as the 50403 study did not have a direct control arm without bortezomib. We conclude, therefore, that there are still no strong data to support the use of bortezomib maintenance after ASCT in MCL.\n\nAt the time our study was designed, there was no scientific evidence to support the added value of maintenance therapy after ASCT. In contrast, rituximab maintenance until progression resulted in an impressive improvement (hazard ratio 0·55) of PFS and even OS in elderly MCL patients after induction therapy with R‐CHOP (Kluin‐Nelemans et al., 2012). Since then, rituximab maintenance is considered standard therapy for elderly patients (Dreyling et al., 2014). Meanwhile, two different approaches were developed for treatment of young MCL patients after ASCT. First, the Nordic group prospectively assessed minimal residual disease (MRD) in patients treated in the MCL2 trial (Andersen et al., 2009). For those patients who developed a molecular relapse after ASCT, pre‐emptive treatment with rituximab was initiated (four weekly administrations of 375 mg/m2). The large majority (92%) converted to molecular remission again, but remission‐free survival curves did not show a plateau, indicating that additional rounds of rituximab or other therapies are needed. The authors stressed that any maintenance therapy should have a duration of more than 2 years, as the mean interval of molecular relapse after transplantation in their study was 18·5 months, with patients relapsing even after 6 years (Andersen et al., 2009). In a long‐term follow‐up it was shown that patients who have a late (>1 year post‐ASCT) molecular relapse did well, whereas patients with short (<1 year from transplant) molecular response duration also had a short clinical response duration (Geisler et al., 2012).\n\nThe second successful approach to improve the remission duration after ASCT was described by the French LyMA group (Le Gouill et al., 2017). In this randomised phase III trial, patients received rituximab every 2 months for 3 years or no further treatment. Rituximab significantly improved both the PFS (83% at 4 years vs. 64%) and the OS (89% vs. 80%). In an ongoing study (MCL0208), the Italian FIL group is investigating the role of maintenance with lenalidomide for the same group of younger post‐ASCT patients.\n\nLenalidomide has been linked with the occurrence of second primary malignancies (Dimopoulos et al., 2012). In our study, in which no lenalidomide was given, we observed 15 cases, of whom six had received bortezomib.\n\nSince the design of our study, other groups have published results of other induction regimens. The European Mantle Cell Lymphoma Network performed a large randomised trial comparing a regimen with high‐dose ARA‐C, that is, alternating R‐CHOP with R‐DHAP with R‐CHOP only (Hermine et al., 2016). The response rate was 94% vs. 90% respectively, and the CR/CRu rate was 55% vs. 39%. The LyMA group used four cycles of R‐DHAP before ASCT, which resulted in a response rate of 94% and 77% CR/CRu. (Le Gouill et al., 2017). Finally, the Nordic MCL2 trial should be mentioned, which used for induction rituximab with augmented CHOP (maxi‐CHOP) followed by ASCT after conditioning with BEAM or BEAC. An updated follow‐up of more than 6·5 years showed a median OS and remission duration of longer than 10 years and a median event‐free survival of 7·4 years (Geisler et al., 2012).\n\nCurrently, a large randomised study of the European Mantle Cell Lymphoma Network is examining the role of ibrutinib in upfront therapy of transplant eligible patients. The basis of induction treatment is the alternating R‐CHOP/R‐DHAP regimen. This is the only induction regimen that has proved to be superior in a randomised study.\n\nIn conclusion, although the outcome of young patients with MCL is still improving, the absence of a plateau in the EFS after induction therapy, including ASCT, demands both improvements in the induction therapy and interventions thereafter. Our study confirmed the important role of ARA‐C in the induction of young MCL patients. There was no indication that bortezomib maintenance after ASCT may improve outcome of MCL patients after ASCT. 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"fulltext_license": "CC BY-NC",
"issn_linking": "0007-1048",
"issue": "190(3)",
"journal": "British journal of haematology",
"keywords": "Mantle cell lymphoma; bortezomib; cytarabine; maintenance therapy; phase II trial; randomised",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D002330:Carmustine; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003561:Cytarabine; D018572:Disease-Free Survival; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009426:Netherlands; D011241:Prednisone; D000077982:Progression-Free Survival; D012074:Remission Induction; D000069283:Rituximab; D014182:Transplantation, Autologous; D017211:Treatment Failure; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "385-393",
"pmc": null,
"pmid": "32150297",
"pubdate": "2020-08",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "25210087;17962512;28953447;19036081;22640180;27313086;23108928;22323483;22873532;10561185;17001068;18625886;26598017;17875757;19074748;19652064;28881919",
"title": "Bortezomib maintenance after R-CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial.",
"title_normalized": "bortezomib maintenance after r chop cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma results of a randomised phase ii hovon trial"
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... |
{
"abstract": "Purpose To evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Patients and Methods After real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2 intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP). Results After a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%). Conclusion Outcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.",
"affiliations": "John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.;John P. Leonard, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA; Kathryn S. Kolibaba and Nicholas J. DiBella, US Oncology Research, The Woodlands; Robert Collins, University of Texas Southwestern Medical Center, Dallas, TX; James A. Reeves, Florida Cancer Specialists, Fort Myers; Julio Hajdenberg, University of Florida Health Cancer Center at Orlando Health, Orlando, FL; Anil Tulpule, Keck Medicine of University of Southern California; Sven de Vos, University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles; Tatjana Kolevska, Kaiser Permanente Medical Center Northern California, Vallejo; Robert Robles, Bay Area Cancer Research Group (Diablo Valley Medical Group), Pleasant Hill; Andrew Horodner, Cancer Care Associates Medical Group, Redondo Beach, CA; Ian W. Flinn, Sarah Cannon Research Institute, Nashville, TN; Christopher R. Flowers, Winship Cancer Institute of Emory University, Atlanta, GA; Nicholas J. DiBella, Rocky Mountain Cancer Centers, Aurora, CO; Steven W. Papish, Summit Medical Group MD Anderson Cancer Center, Camden, NJ; Parameswaran Venugopal, Rush University Medical Center, Chicago, IL; Amir Tabatabai, York Cancer Center/Cancer Care Associates of York, York, PA; and Jaehong Park, Rachel Neuwirth, George Mulligan, Kaveri Suryanarayan, and Dixie-Lee Esseltine, Millennium Pharmaceuticals, Cambridge, MA.",
"authors": "Leonard|John P|JP|;Kolibaba|Kathryn S|KS|;Reeves|James A|JA|;Tulpule|Anil|A|;Flinn|Ian W|IW|;Kolevska|Tatjana|T|;Robles|Robert|R|;Flowers|Christopher R|CR|;Collins|Robert|R|;DiBella|Nicholas J|NJ|;Papish|Steven W|SW|;Venugopal|Parameswaran|P|;Horodner|Andrew|A|;Tabatabai|Amir|A|;Hajdenberg|Julio|J|;Park|Jaehong|J|;Neuwirth|Rachel|R|;Mulligan|George|G|;Suryanarayan|Kaveri|K|;Esseltine|Dixie-Lee|DL|;de Vos|Sven|S|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D000069286:Bortezomib; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2017.73.2784",
"fulltext": null,
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"issn_linking": "0732-183X",
"issue": "35(31)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "3538-3546",
"pmc": null,
"pmid": "28862883",
"pubdate": "2017-11-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Randomized Phase II Study of R-CHOP With or Without Bortezomib in Previously Untreated Patients With Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma.",
"title_normalized": "randomized phase ii study of r chop with or without bortezomib in previously untreated patients with non germinal center b cell like diffuse large b cell lymphoma"
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"abstract": "Epstein-Barr virus (EBV) has been associated with serious or fatal lymphoproliferative disease in immunocompromised patients. EBV nuclear protein 2 and latent membrane protein are characteristically expressed in B lymphocytes proliferating in vitro in response to growth transformation by EBV. These two proteins are thought to be effectors of lymphocyte growth since they increase the expression of B-lymphocyte activation (CD23) and cell-adhesion (LFA 3 and ICAM 1) molecules in vitro. Using monoclonal antibody-immune microscopy, we have demonstrated that these two EBV proteins and their associated B-lymphocyte activation or adhesion molecules are expressed in the infiltrating B lymphocytes in immunocompromised patients with EBV lymphoproliferative disease. These monoclonal antibodies should be useful in the early diagnosis of EBV lymphoproliferative disease and in distinguishing it from other B-lymphocyte cancers associated with EBV, such as Burkitt's lymphoma. The finding of EBV nuclear protein 2 and latent membrane protein and their associated activation or adhesion molecules provides a further pathophysiologic link between EBV and the proliferation of B lymphocytes in immunocompromised patients.",
"affiliations": "Department of Cancer Studies, University of Birmingham, United Kingdom.",
"authors": "Young|L|L|;Alfieri|C|C|;Hennessy|K|K|;Evans|H|H|;O'Hara|C|C|;Anderson|K C|KC|;Ritz|J|J|;Shapiro|R S|RS|;Rickinson|A|A|;Kieff|E|E|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000944:Antigens, Differentiation, B-Lymphocyte; D000956:Antigens, Viral; D015815:Cell Adhesion Molecules; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D011961:Receptors, Fc; D017455:Receptors, IgE; D014763:Viral Matrix Proteins; D014764:Viral Proteins",
"country": "United States",
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"doi": "10.1056/NEJM198910193211604",
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"issue": "321(16)",
"journal": "The New England journal of medicine",
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"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000944:Antigens, Differentiation, B-Lymphocyte; D000956:Antigens, Viral; D001402:B-Lymphocytes; D015815:Cell Adhesion Molecules; D003937:Diagnosis, Differential; D019309:Epstein-Barr Virus Nuclear Antigens; D005260:Female; D006566:Herpesviridae Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D007108:Immune Tolerance; D007150:Immunohistochemistry; D008198:Lymph Nodes; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders; D008297:Male; D011961:Receptors, Fc; D017455:Receptors, IgE; D014763:Viral Matrix Proteins; D014764:Viral Proteins",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease.",
"title_normalized": "expression of epstein barr virus transformation associated genes in tissues of patients with ebv lymphoproliferative disease"
} | [
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"abstract": "Parathyroid carcinoma is a rare cause of hyperparathyroidism and leads to severe hypercalcemia. The etiology is not fully known. Parathyroid cancer should be considered in the differential diagnosis, if serum calcium and parathyroid hormone levels increase, and parathyroid gland is palpable. Severe hypercalcemia is the most common cause of death in patients diagnosed with parathyroid carcinoma. Fluid replacement, diuretic therapy, bisphosphonates, and calcimimetic agents are the main treatment steps in the control of life-threatening hypercalcemia. Surgery is the primary treatment option, while denosumab is a treatment option for refractory hypercalcemia caused by parathyroid carcinoma, or for patients who are not eligible for surgery. There are few case reports in literature about denosumab treatment for parathyroid carcinoma. Herein, we report a case of a patient who presented with the complaint of leg pain and was diagnosed with parathyroid carcinoma. The elevated calcium level of the patient was controlled with denosumab. Key Words: Parathyroid carcinoma, Denosumab, Hypercalcemia, Hyperparathyroidism.",
"affiliations": "Department of Endocrinology and Metabolism, University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey.;Department of Endocrinology and Metabolism, Uludag University Medical School, Turkey.;Department of Endocrinology and Metabolism, Uludag University Medical School, Turkey.;Department of Endocrinology and Metabolism, Uludag University Medical School, Turkey.;Department of Endocrinology and Metabolism, Uludag University Medical School, Turkey.;Department of Internal Medicine, Uludag University Medical School, Turkey.",
"authors": "Çalapkulu|Murat|M|;Gul|Ozen Oz|OO|;Cander|Soner|S|;Ersoy|Canan|C|;Erturk|Erdinc|E|;Sagiroglu|Muhammed Fatih|MF|;Saraydaroglu|Ozlem|O|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D010281:Parathyroid Hormone; D000069448:Denosumab",
"country": "Pakistan",
"delete": false,
"doi": "10.29271/jcpsp.2020.07.757",
"fulltext": null,
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"issn_linking": "1022-386X",
"issue": "30(7)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D050071:Bone Density Conservation Agents; D000069448:Denosumab; D004164:Diphosphonates; D006801:Humans; D006934:Hypercalcemia; D010281:Parathyroid Hormone; D010282:Parathyroid Neoplasms",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "757-759",
"pmc": null,
"pmid": "32811610",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Control of Refractory Hypercalcemia with Denosumab in a Case of Metastatic Parathyroid Carcinoma.",
"title_normalized": "control of refractory hypercalcemia with denosumab in a case of metastatic parathyroid carcinoma"
} | [
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"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-268128",
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"actiondrug": "5",
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"activesubstancename": "ZOLEDRONIC ACID"
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... |
{
"abstract": "Calciphylaxis is a rare life-threatening condition, with calcification of small and medium-sized vessels leading to skin necrosis. It has a high morbidity and mortality, and most of the patients die from wound superinfection and sepsis. A 48-year-old man with a history of end-stage renal disease on haemodialysis and Coumadin therapy for venous thromboembolism presented with pulmonary oedema after missing two haemodialysis treatment. At examination, he had bilateral lower extremity dark brown, possibly necrotic, painful ulcers. He was diagnosed with calciphylaxis and treated with sevelamer hydrochloride, low calcium dialysate and sodium thiosulfate with haemodialysis. He received daily wound care with topical collagenase. After daily wound care treatment for 4 months, the patient's ulcers completely healed. The patient had been followed for 8 months, which included 29 additional readmissions, 3 admissions related to bacteraemia and 26 admissions with the diagnosis of pulmonary oedema and hyperkalaemia requiring haemodialysis.",
"affiliations": "Internal Medicine, Jackson Memorial Hospital, Miami, Florida, USA.;Internal Medicine, Jackson Memorial Hospital, Miami, Florida, USA.;Internal Medicine, Jackson Memorial Hospital, Miami, Florida, USA.;Internal Medicine, Jackson Memorial Hospital, Miami, Florida, USA dcasadesus@hotmail.com.",
"authors": "Schnur|Jack|J|;Sinawe|Hadeer|H|;Yoham|Athina Lidia|AL|;Casadesus|Damian|D|",
"chemical_list": "D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240310",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "dialysis; medical management; renal system; skin",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002115:Calciphylaxis; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D061205:Vascular Calcification; D014859:Warfarin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33762282",
"pubdate": "2021-03-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vascular calcifications and calciphylaxis in a patient on concurrent haemodialysis and Coumadin therapy.",
"title_normalized": "vascular calcifications and calciphylaxis in a patient on concurrent haemodialysis and coumadin therapy"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-035591",
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"activesubstancename": "WARFARIN SODIUM"
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{
"abstract": "Cladophialophora bantiana is a neurotropic dematiaceous fungus which rarely causes disseminated disease. We report a case of proven C. bantiana osteomyelitis in a renal transplant recipient, complicated with probable cerebral disease. Stable disease was reached after combined antifungal therapies, immune enhancement and amputation of the infected lower limb.",
"affiliations": "Department of Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven - University of Leuven, Belgium; Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.;Department of Microbiology and Immunology, Laboratory of Nephrology, KU Leuven - University of Leuven, Belgium; Department of Nephrology, Dialysis and Renal Transplantation, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.;Department of Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven - University of Leuven, Belgium; Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.;Department of General Internal Medicine, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.;Department of Orthopedic Surgery, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.;Department of Haematology, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.;Department of Pathology, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.;Department of Radiology, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.;Department of Microbiology and Immunology, Laboratory of Nephrology, KU Leuven - University of Leuven, Belgium; Department of Nephrology, Dialysis and Renal Transplantation, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium.",
"authors": "Desmet|Stefanie|S|;Smets|Liesbeth|L|;Lagrou|Katrien|K|;Derdelinckx|Inge|I|;Neyt|Jeroen|J|;Maertens|Johan|J|;Sciot|Raf|R|;Demaerel|Philip|P|;Bammens|Bert|B|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2016.07.002",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(16)30039-210.1016/j.mmcr.2016.07.002Case ReportCladophialophora bantiana osteomyelitis in a renal transplant patient Desmet Stefanie ab1Smets Liesbeth cd1Lagrou Katrien abDerdelinckx Inge eNeyt Jeroen fMaertens Johan gSciot Raf hDemaerel Philip iBammens Bert bert.bammens@uzleuven.becd⁎a Department of Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven – University of Leuven, Belgiumb Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgiumc Department of Microbiology and Immunology, Laboratory of Nephrology, KU Leuven – University of Leuven, Belgiumd Department of Nephrology, Dialysis and Renal Transplantation, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgiume Department of General Internal Medicine, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgiumf Department of Orthopedic Surgery, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgiumg Department of Haematology, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgiumh Department of Pathology, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgiumi Department of Radiology, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium⁎ Corresponding author at: Department of Microbiology and Immunology, Laboratory of Nephrology, KU Leuven – University of Leuven, Belgium.Department of Microbiology and Immunology, Laboratory of Nephrology, KU Leuven – University of LeuvenBelgium bert.bammens@uzleuven.be1 Stefanie Desmet and Liesbeth Smets contributed equally to this manuscript.\n\n09 7 2016 6 2016 09 7 2016 12 17 20 14 6 2016 23 6 2016 8 7 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cladophialophora bantiana is a neurotropic dematiaceous fungus which rarely causes disseminated disease. We report a case of proven C. bantiana osteomyelitis in a renal transplant recipient, complicated with probable cerebral disease. Stable disease was reached after combined antifungal therapies, immune enhancement and amputation of the infected lower limb.\n\nKeywords\nCladophialophora bantianaOsteomyelitisPhaeohyphomycosisImmunocompromisedTransplantation\n==== Body\n1 Introduction\nCladophialophora bantiana is a black fungus with worldwide distribution, but a general preference for warm climates with high humidity [1]. It is a strongly neurotropic fungus which mostly causes life-threatening cerebral phaeohyphomycosis [1]. A recent review of 124 C. bantiana brain abscess cases showed an equal distribution in immunocompetent and immunocompromised hosts with a significantly higher mortality in the latter group [2]. Complete excision of the brain lesions in immunocompetent hosts led to significant better survival. Non-cerebral C. bantiana infections are extremely uncommon and include mainly cutaneous and pulmonary manifestations [1]. In this case report, we describe a C. bantiana osteomyelitis in a renal transplant patient. C. bantiana, as well as other dematiaceous fungi, only rarely cause osteomyelitis or arthritis [3]. One recent case of a young immunocompetent man with disseminated C. bantiana infection reported biopsy proven vertebral osteomyelitis [4]. Another fatal case of C. bantiana septic arthritis of the knee was described by Lim et al. [5]. C. bantiana bone or joint infection with concomitant cerebral infection is a life-threatening disease. In contrast to the two previous reported cases, stable disease was reached after combined antifungal therapies, immune enhancement and amputation of the infected lower limb.\n\n2 Case\nA 34-year-old woman of North African origin, who had undergone kidney transplantation 17 months before, presented at day 0 with progressive pain in the left lower leg since 3 weeks. One year before, in her homeland, she had suffered a traumatic wound of the same leg, which had resolved spontaneously and without sequelae.\n\nUpon presentation, immunosuppressive treatment consisted of tacrolimus, mycophenolate mofetil (MMF) and low dose methylprednisolone. She had been treated with a course of high dose steroids for biopsy-proven allograft rejection 5 months earlier. Other relevant medical history included new-onset diabetes after transplantation and splenectomy following thrombosis of the vena lienalis.\n\nShe presented with a C-reactive protein (CRP) of 61.4 mg/L (reference <5 mg/L) and a normal neutrophil count. Graft function was stable with a serum creatinine level of 1.49 mg/dL (reference 0.51–0.95 mg/dL). Magnetic Resonance Imaging (MRI) of the left lower limb showed subacute osteomyelitis of the left proximal tibia with bifocal Brodie abscesses in the proximal diaphysis.\n\nSurgical debridement was performed at day +6 with sampling for bacterial, fungal and mycobacterial culture and panbacterial and panfungal PCR (UMD-Universal, Molzym, Germany). Initial bacterial culture results revealed growth of three organisms (Staphylococcus capitis, Corynebacterium amycolatum and Staphylococcus epidermidis) and anatomopathologically no inflammation was found. Intravenous amoxicillin-clavulanic acid (2 g BID) was started with careful follow-up. At day +9, panfungal PCR on the perioperative sample tested positive. Additional deeper bone biopsy sections showed a chronic osteomyelitis with presence of hyphae. Fungal cultures showed a black fungus, which was identified by internal transcribed spacer (ITS) sequencing and morphological characteristics as C. bantiana on day +29. ITS sequencing was performed in both sequencing directions with primer pairs ITS1/ITS4 and ITS86/ITS4. The aligned sequence had closest hit in GenBank with C. bantiana (accession number KP131826.1) indicating 98% sequence identity for ITS1 and ITS2 region and showed 100% sequence identity with the ITS2 C. bantiana barcode identifier (accession number EU103989) described by Heinrichs et al. [6]. In the meantime, the patient had developed neurological symptoms, with progressive right-sided weakness and loss of sensibility. Cerebrospinal fluid (CSF) analysis showed normal white blood cell count (2.4/µL), normal protein and glucose level. Bacterial and fungal cultures and molecular diagnostics for viruses on CSF were negative. Brain MRI revealed acute diffuse encephalomyelitis with bilateral thalamic involvement, compatible with cerebral infection (Fig. 1).\n\nGiven the location of the lesions, neurosurgical intervention was considered hazardous and no tissue biopsy was performed to confirm the diagnosis of cerebral phaeohyphomycosis. Antifungal treatment with oral voriconazole was started on day +30 and amoxicillin-clavulanic acid was stopped. In addition, MMF was stopped and lower tacrolimus trough levels were targeted (6 µg/L). Despite improvement of inflammatory parameters and having adequate voriconazole trough levels of 3.2–6.8 mg/L, new neurological symptoms of left-sided paresthesia and stiffness developed. Follow-up brain MRI showed progressive disease. Liposomal amphotericin B (3 mg/kg QD) was added to voriconazole on day +59.\n\nWorsening of the osteomyelitis urged for a second surgical debridement on day +71. All perioperative samples again showed the abundant presence of C. bantiana (Fig. 2), triggering a complete withdrawal of all immunosuppressive drugs and transplantectomy. Hemodialysis was started on day +92. Unfortunately, clinical assessment and novel imaging showed further disease progression in bone and brain.\n\nSusceptibility testing of the isolate was performed by both Clinical and Laboratory Standards institute (CLSI) and European Committee on Antimicrobial Susceptibility testing (EUCAST) broth dilution method for voriconazole (minimal inhibitory concentration (MIC) 0.5 mg/L), amphotericin B (MIC <0.5 mg/L), isavuconazole (MIC 0.25 mg/L (CLSI), 4 mg/L (EUCAST)), posaconazole (MIC 0.016 mg/L (CLSI), 0.5 mg/L (EUCAST)) and anidulafungin (MIC 0.031 mg/L). Given the unfavorable evolution, liposomal amphotericin B - voriconazole therapy was switched to liposomal amphotericin B - isavuconazole (200 mg TID on first and second day, then 200 mg QD) combination therapy, reaching therapeutic serum isavuconazole through levels (range: 1.6–2.3 mg/mL).\n\nUnfortunately, the disease progressed despite adaptation of the antifungal regimen. Local progression in the bone, with incipient involvement of the knee joint, urged for above-the-knee amputation of the left leg on day +129. Hereafter, isavuconazole was stopped. Oral delayed-release tablets of posaconazole (loading dose of 300 mg BID on first day; then 300 mg QD) and intravenous flucytosine (25 mg/kg QD) were added to the liposomal amphotericin B therapy, now at a higher dose of 10 mg/kg QD.\n\nFollowing surgery there was no recurrence of osteomyelitis, but cerebral lesions further progressed. The first serum through level of posaconazole was 1.0 mg/L. The dose of posaconazole was doubled (300 mg BID) on day +156, which resulted in posaconazole trough levels ranging from 1.7 to 4.1 mg/L. Because of increased intracranial pressure, methylprednisolone (40 mg TID, intravenously) was associated on day +172. Following tapering and stopping steroids on day +224, intracranial overpressure relapsed and steroids were restarted.\n\nCombination antifungal therapy with posaconazole, flucytosine, and liposomal amphotericin B and low dose steroids has finally resulted in clinical and radiological stabilization of the cerebral disease, without recurrence of osteomyelitis. Anti-fungal treatment was eventually downgraded to monotherapy with oral posaconazole and the patient started an intensive rehabilitation program while obviously continuing thrice weekly hemodialysis. At present (day +539), the patient has regained her ability to walk using a leg prosthesis.\n\n3 Discussion\nWe report a case of C. bantiana osteomyelitis in a transplant recipient, with probable cerebral involvement. Trauma is the main cause of the rarely described cases of osteomyelitis with melanized fungi [1]. Our patient suffered a minor trauma 1 year before presentation. The often indolent characteristics of fungal osteomyelitis can explain the absence of symptoms until 3 weeks before hospitalization. In cerebral phaeohyphomycosis, C. bantiana is assumed to primarily colonize the lung, followed by hematogenous spread to the central nervous system (CNS) [7]. The surgical debridement may have theoretically induced hematogenous spread from bone to brain. However, since initially no brain imaging was performed and given the indolent nature of these infections, cerebral involvement may have already been present on day 0. Therefore, in non-cerebral C. bantiana infections, cerebral imaging at presentation should be considered.\n\nC. bantiana infection is difficult to treat with a high mortality rate of approximately 70% [8]. Timely diagnosis of the fungal infection is important, but the challenging identification of C. bantiana may delay start of treatment. Complete surgical excision, combined antifungal therapy and immune enhancement seem to be the best treatment option for cerebral phaeohyphomycosis and fungal osteomyelitis [3], [7], [8].\n\nIn our patient, surgical bone debridement and finally amputation of the leg resulted in resolution of the osteomyelitis. In contrast, treatment of the cerebral lesions relied solely on antifungals since neurosurgical resection could not be performed due to the high risk of collateral neurological damage.\n\nExperience with antifungal treatment is limited to isolated cases or small series, which mostly involved amphotericin B, a triazole (itraconazole, voriconazole or posaconazole) and/or flucytosine [3], [7], [8], [9].\n\nData concerning in vitro susceptibility of C. bantiana isolates and animal studies are sparse, but our in vitro susceptibility results of C. bantiana are in accordance with previously reported MICs [9]. Posaconazole, isavuconazole and amphotericin B showed the highest in vitro activity, with slightly higher MICs for voriconazole. However, voriconazole penetrates good in brain tissue and abscess material [10]. In cerebral C. bantiana infections, both successes and clinical failures have been reported with voriconazole [1].\n\nAmphotericin B in mono- or combination therapy showed mixed results [8]. Furthermore, animal models showed less activity of amphotericin B compared to itraconazole and posaconazole [11]. In our case, association of liposomal amphotericin B could not stop progression.\n\nPosaconazole has good in vitro susceptibility concerning C. bantiana, but the in vivo activity in CNS infections is not well documented. Only a limited number of clinical cases are available [10]. In murine models, brain tissue concentrations of posaconazole were 50–80% of those in serum [12], [13]. Moreover, animal studies reported better survival outcomes and better reduction of the brains fungal burden with posaconazole compared to itraconazole and amphotericin B [11].\n\nIsavuconazole has low MICs for C. bantiana\n[9]. Furthermore, isavuconazole penetrates in the CNS of animal models with invasive candidiasis and few cases of successful treatment of cerebral mucormycosis are described [14], [15]. More animal and clinical data are needed to investigate the role of isavuconazole in treating C. bantiana infections.\n\nFinally flucytosine, also with an excellent CNS penetration, was added to the therapy with posaconazole and liposomal amphotericin B [10]. In murine models with disseminated C. bantiana infections synergism and prolonged survival were seen when combining posaconazole, flucytosine and micafungin [16]. Furthermore, case series of C. bantiana infection reported a better survival with the combination of amphotericin B, flucytosine and an azole [7], [8].\n\nIn our patient, steroids had an important role in controlling cerebral edema. It remains unclear whether this edema was mainly caused by disease progression or by CNS-immune reconstitution syndrome (IRIS) after immune enhancement. IRIS, as seen in human immunodeficiency virus (HIV)-infected patients, has also been observed in solid organ transplant (SOT) patients with fungal (mainly Cryptococcosis) infections. SOT recipients developed IRIS typically 4–6 weeks (but until up to 9 months) after initiating antifungal therapy and IRIS preferentially manifested in the CNS. No cases of C. bantiana infection related IRIS were described. The optimal management of IRIS in SOT recipients remains unknown, but based on case reports and series corticosteroids have been suggested [17].\n\nStabilization of the cerebral infection was finally achieved with a combined use of liposomal amphotericin B, posaconazole and flucytosine as well as low dose methylprednisolone.\n\nConflict of interest\nKatrien Lagrou has received research grants, travel support and lecture honoraria from Gilead, MSD and Pfizer. Inge Derdelinckx received travel support van Gilead sciences, MSD, ViiV, Boehringer-Ingelheim, Janssen-Cilag. Johan Maertens has served as consultant to Schering-Plough, Gilead Sciences, Merck, Sharp & Dohme, Pfizer Inc., Bio-Rad, Fujisawa healthcare Inc., Astellas, Nextar, Zeneus (Cephalon), Viropharma, and Boehringer-Ingelheim; has received research funding from Bio-Rad, Merck, Sharp & Dohme, and Pfizer Inc., and is on the speaker's bureau for Schering-Plough, Gilead Sciences, Merck, Sharp & Dohme, Pfizer Inc., Bio-Rad, Fujisawa healthcare, Inc, Astellas and Zeneus (Cephalon).\n\nAcknowledgments\nWe thank Walsh Thomas J. (Infectious Diseases Section, National Cancer Institute, Bethesda, Maryland, USA), Revankar Sanjay G. (Division of Infectious Diseases, Wayne State University, Detroit, Michigan, USA), Marr Kieren A. (Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, USA), Avery Robin (Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, USA), Kontoyiannis Dimitrios (Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, USA) and Temesgen Zelalem (Division of Clinical Microbiology, Mayo Clinic and Foundation, Rochester, Minnesota, USA) for their availability to remotely discuss the case and the treatment steps on multiple occasions. We thank Meis Jacques (Canisius-Wilhelmina Ziekenhuis, Department of Medical Microbiology and Infectious Diseases, Nijmegen, Netherlands) for performing the susceptibility testing.\n\nBasilea Pharmaceutica International Ltd and Astellas Pharma Inc. are acknowledged for providing isavuconazole through their compassionate use program.\n\nFig. 1 T2 weighted brain magnetic resonance imaging shows bilateral diffuse thalamic abnormalities with edema in the internal capsules (a). Multiple confluent micronodules with small cystic components are seen on a gadolinium enhanced T1 weighted image (b). An area of diffusion restriction, indicated by arrows, is noted in the right thalamus on diffusion weighted imaging, reflecting the presence of pus (c,d).\n\nFig. 1Fig. 2 Hematoxylin-eosin stain of tibia bone biopsy (day +71). Granuloma with central hyphae and giant cells, surrounded by mononuclear inflammatory cells. Hyphae (blue arrows) are mainly present in the cytoplasm of the multinucleated giant cells (red arrows). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).\n\nFig. 2\n==== Refs\nReferences\n1 Revankar S.G. Sutton D.A. Melanized fungi in human disease Clin. Micro. Rev. 23 2010 884 928 20930077 \n2 Chakrabarti A. Kaur H. Rudramurthy S.M. Appannanavar S.B. Patel A. Mukherjee K.K. Brain abscess due to Cladophialophora bantiana: a review of 124 cases Med. Mycol. 54 2016 111 119 26483430 \n3 Chowdhary A. Meis J.F. Guarro J. de Hoog G.S. Kathuria S. Arendrup M.C. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi Clin. Microbiol. Infect. 20 2014 47 75 24483780 \n4 Mansour A. Jordan K. Disseminated Cladophialophora bantiana disease in a patient with prediabetes BMJ Case Rep. 2014 \n5 Lim A. Speers D. Inderjeet C. Cladophialophora (Xylohypha) bantiana – an unusual cause of septic arthritis Rheumatology 52 2013 958 959 23196194 \n6 Heinrichs G. de Hoog G.S. Haase G. Barcode identifiers as a practical tool for reliable species assignment of medically important black yeast species J. Clin. Microbiol. 50 2012 3023 3030 22785187 \n7 Li D.M. de Hoog G.S. Cerebral phaeohyphomycosis – a cure at what lengths? Lancet Infect. Dis. 9 2009 376 383 19467477 \n8 Revankar S.G. Sutton D.A. Rinaldi M.G. Primary central nervous system phaeohyphomycosis: a review of 101 cases Clin. Infect. Dis. 38 2004 206 216 14699452 \n9 Badali H. de Hoog G.S. Curfs-Breuker I. Klaassen C.H. Meis J.F. Use of amplified fragment length polymorphism to identify 42 Cladophialophora strains related to cerebral phaeohyphomycosis with in vitro antifungal susceptibility J. Clin. Microbiol. 48 2010 2350 2356 20421439 \n10 Felton T. Troke P.F. Hope W.W. Tissue penetration of antifungal agents Clin. Micro. Rev. 27 2014 68 88 24396137 \n11 Al-Abdely H.M. Najvar L.K. Bocanegra R. Graybill J.R. Antifungal therapy of experimental cerebral phaeohyphomycosis due to Cladophialophora bantiana Antimicrob. Agents Chemother. 49 2005 1701 1707 15855484 \n12 Calvo E. Pastor F.J. Rodriguez M.M. Pujol I. Guarro J. Antifungal therapy in a murine model of disseminated infection by Cryptococcus gattii Antimicrob. Agents Chemother. 54 2010 4074 4077 20625150 \n13 Calvo E. Pastor F.J. Rodriguez M.M. Mayayo E. Salas V. Guarro J. Murine model of a disseminated infection by the novel fungus Fonsecaea monophora and successful treatment with posaconazole Antimicrob. Agents Chemother. 54 2010 919 923 20008773 \n14 Majithiya J. Sharp A. Parmar A. Denning D.W. Warn P.A. Efficacy of isavuconazole, voriconazole and fluconazole in temporarily neutropenic murine models of disseminated Candida tropicalis and Candida krusei J. Antimicrob. Chemother. 63 2009 161 166 19008255 \n15 Ervens J. Ghannoum M. Graf B. Schwartz S. Successful isavuconazole salvage therapy in a patient with invasive mucormycosis Infection 42 2014 429 432 24217961 \n16 Marine M. Pastor F.J. Guarro J. Combined antifungal therapy in a murine model of disseminated infection by Cladophialophora bantiana Med. Mycol. 47 2009 45 49 19085457 \n17 Sun H.Y. Singh N. Opportunistic infection-associated immune reconstitution syndrome in transplant recipients Clin. Infect. Dis. 53 2011 168 176 21690625\n\n",
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"keywords": "Cladophialophora bantiana; Immunocompromised; Osteomyelitis; Phaeohyphomycosis; Transplantation",
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"title": "Cladophialophora bantiana osteomyelitis in a renal transplant patient.",
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"abstract": "In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother's second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.\nCH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.",
"affiliations": "Leicester Clinical Genetics, Women's and Children's Services, Leicester Royal Infirmary, LeicesterUK.;Leicester Clinical Genetics, Women's and Children's Services, Leicester Royal Infirmary, LeicesterUK.;University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, CambridgeUK.;Department of Obstetrics and Gynaecology, Women's and Prenatal Services, Leicester General Hospital, LeicesterUK.;Department of Paediatric Endocrinology, Leicester Royal Infirmary, LeicesterUK.;Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, CambridgeUK.;University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, CambridgeUK.",
"authors": "Vasudevan|Pradeep|P|;Powell|Corrina|C|;Nicholas|Adeline K|AK|;Scudamore|Ian|I|;Greening|James|J|;Park|Soo-Mi|SM|;Schoenmakers|Nadia|N|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-17-0040EDM170040Unique/Unexpected Symptoms or Presentations of a DiseaseIntrauterine death following intraamniotic triiodothyronine and thyroxine therapy for fetal goitrous hypothyroidism associated with polyhydramnios and caused by a thyroglobulin mutation P Vasudevan and othersFetal goitre and TG mutationsVasudevan Pradeep 1Powell Corrina 1Nicholas Adeline K 2Scudamore Ian 3Greening James 4Park Soo-Mi 5Schoenmakers Nadia 21 Leicester Clinical Genetics, Women’s and Children’s Services, Leicester Royal Infirmary, LeicesterUK2 University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, CambridgeUK3 Department of Obstetrics and Gynaecology, Women’s and Prenatal Services, Leicester General Hospital, LeicesterUK4 Department of Paediatric Endocrinology, Leicester Royal Infirmary, LeicesterUK5 Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, CambridgeUKCorrespondence should be addressed to N Schoenmakers; Email: naaa2@cam.ac.uk07 6 2017 2017 2017 17-004026 4 2017 10 5 2017 © 2017 The authors2017The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother’s second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.\n\nLearning points:\nCH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.\n\nCH due to TG mutations may manifest with variable phenotypes, even within the same kindred.\n\nTreatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.\n\nGenetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.\n==== Body\nBackground\nCongenital hypothyroidism (CH) is the commonest neonatal endocrine disorder, (incidence 1:1500 in Europe) and a national UK screening programme enables prompt diagnosis and initiation of levothyroxine treatment (1). Dyshormonogenesis, in which there is inadequate thyroid hormone biosynthesis due to a specific defect in one of the protein components of the thyroid hormone biosynthetic machinery, usually arises due to mutations in the following genes: TG, TPO, DUOX2, DUOXA2, IYD, SLC26A4 and SLC5A5. European Society for Paediatric Endocrinology (ESPE) guidelines recommend genetic counselling in such cases, although we have observed interregional variability in the proportion of cases undergoing molecular genetic ascertainment in the UK (2).\n\nSignificant fetal hypothyroid goitre is a rare consequence of fetal dyshormonogenesis, and complications include polyhydramnios due to oesophageal compression and malpresentation due to neck hyperextension at delivery; additionally, neonatal tracheal compression may cause fatal respiratory compromise (3, 4). The infrequent occurrence of non-autoimmune fetal hypothyroid goitre and the risks associated with intrauterine diagnosis and therapy have precluded large-scale studies of optimal treatment. Intraamniotic T4 may be beneficial in reducing goitre size however in the UK, parenteral T4 is not readily available, and there is one reported UK case in which intraamniotic T3 administered prior to T4 initiation achieved a successful outcome. The optimal dosing regimen for either drug remains to be ascertained (2, 4, 5).\n\nWe describe the second case of hypothyroid fetal goitre to be treated with intraamniotic T3 injection whilst T4 was being sourced, and the resulting intrauterine death which highlights the fetal compromise which may occur in this context. Genetic ascertainment in the surviving sibling with dyshormonogenic CH showed that compound heterozygous TG mutations were the likely aetiology for the fetal presentation, enabling appropriate genetic counselling to be initiated.\n\nCase presentation\nA male infant (Fig. 1: P1) weighing 3.58 kg was born at term to non-consanguineous, euthyroid Indian parents after an uncomplicated pregnancy. Following an instrumental delivery, he required resuscitation (Apgar scores were 5 (1 min) and 7 (5 min)) and sustained a depressed frontal bone and left sided facial nerve palsy due to birth trauma, which were conservatively managed. Neonatal screening revealed CH (fT4: 7 pmol/L normal range (NR): 9.0–25.0), Thyroid-stimulating hormone (TSH) >100 mU/L (NR: 0.3–5.0)), and a subsequent isotope scan demonstrated appropriate uptake in a normally-sited thyroid gland (Fig. 2). He had prolonged jaundice but was otherwise healthy and prompt initiation of levothyroxine treatment has enabled normal growth and development.\nFigure 1 Pedigree diagram for the affected family. Black bars denote those individuals who have been genotyped; black and grey shading denotes confirmed (P1) and presumed (P2) compound heterozygous genoypes, heterozygotes for one of the two mutations are denoted by a central black dot.\n\n\nFigure 2 Technetium-99m pertechnetate thyroid scintigraphy performed in P1 aged 29 days, demonstrating appropriate radionuclide uptake in a normally-sited thyroid gland, consistent with dyshormonogenesis. (A) Anterior and (B) lateral images.\n\n\n\n\nThere was no family history of thyroid disease however his mother exhibited congenital shortened right limbs; his father was well and had fathered 4 healthy children in a previous relationship (Fig. 1). They went on to have a second pregnancy complicated by a fetal goitre detected on routine ultrasound (Fig. 3).\nFigure 3 Sequential fetal ultrasound images with gestational age annotated demonstrating progressive fetal goitre (white arrow). A coronal view at 23 + 3 weeks gestation demonstrates a goitre measuring 42.8 mm × 26.6 mm which persists aged 24 + 4 weeks (sagittal view) and has enlarged to 54 mm × 36 mm × 52 mm aged 29 + 2 weeks gestation (sagittal view), 48 h prior to intrauterine liothyronine therapy.\n\n\n\n\nInvestigation\nDuring the second pregnancy, a 20-week obstetric scan revealed a fetal thyroid goitre which continued to enlarge between 23 + 3 and 29 + 2 weeks, with associated polyhydramnios (Fig. 3). Maternal biochemistry confirmed euthyroidism (TSH: 3.2 mIU/L; NR: 0.3–5.0) with absent autoantibodies (TPO <20 IU/mL; NR: 0–60), and amniotic fluid TSH measurements at 29 + 4 weeks were consistent with fetal hypothyroidism: TSH: 1.5 mIU/L (NR <0.51).\n\nTreatment\nThe large hypothyroid fetal goitre and polyhydramnios supported a diagnosis of fetal dyshormonogenesis with obstructive dysphagia, due to local oesophageal compression. A decision was made to commence intraamniotic thyroid hormone replacement, initially by injection of 120 µg T3 at 29 + 4 weeks with concomitant amniocentesis (260 mL). T3 was selected in the first instance due to the fact that we encountered difficulties sourcing parenteral T4 in the UK and the requirement for local approval to be granted prior to its administration would have resulted in significant treatment delay had we opted for first-line T4 therapy. At 31 weeks gestation, considerable polyhydramnios and fetal hypothyroidism persisted (amniotic TSH: 5.3 mIU/L (NR <0.51), compared with TSH 1.5 mIU/L at 29 + 4 weeks) therefore 150 µg intraamniotic T4 was administered following further amniocentesis having been sourced and locally approved in the interim.\n\nOutcome and follow-up\nAt 31 + 3 weeks gestation, an obstetric scan was performed for reduced fetal movements, which revealed an intrauterine death in association with significant polyhydramnios including accumulation of amniotic fluid in the extraamniotic/subchorionic space. The stillborn infant (P2) was male, weighing 1.62 kg, with a normal male karyotype on amniotic fluid analysis. There was no evidence of intrauterine infection and postmortem was declined.\n\nAlthough DNA was not extracted from the fetus, the history of CH in the elder sibling prompted genetic screening of TPO (thyroid peroxidase) and TG (thyroglobulin). Compound heterozygous TG mutations were identified, comprising a novel, paternally-inherited single nucleotide deletion (c.5178delT, p.A1727Hfs*26), and a maternally-inherited missense mutation (c.7123G > A, p.G2375R), which has been previously reported in association with CH without fetal goitre (6) Fig. 4).\nFigure 4 Sequencing electropherograms from the proband (P1), mother and father, illustrating compound heterozygous TG mutations, comprising a novel, paternally-inherited single nucleotide deletion (c.5178delT, p.A1727Hfs*26), and a maternally-inherited missense mutation (c.7123G > A, p.G2375R).\n\n\n\n\nDiscussion\nAlthough biallelic TG mutations commonly underlie CH due to dyshormonogenesis, their absolute frequency is low, and fetal goitre is a rare complication which may be associated with significant morbidity (3, 7, 8). The proband in this family harboured compound heteroygous TG mutations, and although the stillborn fetus was not genotyped, his goitrous hypothyroidism in utero supports an identical genetic diagnosis. Although the proband did not have goitre, he exhibited biochemically moderate-severe CH at diagnosis, and such phenotype variability occurs in other kindreds harbouring TG mutations. The phenotypic modulators remain uncharacterized although dietary iodine intake, (not quantified here), may be implicated (9).\n\nESPE guidelines recommend genetic counselling in patients with dyshormonogenetic CH, since most patients have an underlying genetic basis. Fetal goitre has been reported in association with TG and TPO mutations however both discordance and recurrence in successive pregnancies has been documented (2, 3, 10). A genetic diagnosis in the kindred enabled us to counsel the parents that future offspring had a 25% probability of inheriting biallelic mutations and developing CH with a consequent risk of fetal goitre. In subsequent pregnancies, prenatal genetic diagnosis could facilitate management by mandating stringent surveillance for fetal goitre, and optimization of maternal iodine status. Additionally, given the practical difficulties in obtaining parenteral T4 in the UK, this could be pre-emptively acquired in the event of a positive genetic diagnosis in the fetus, in case intraamniotic T4 therapy became necessary.\n\nManagement of hypothyroid fetal goitre remains controversial, as there are significant risks associated with both diagnostic amniocentesis/cordocentesis and intraamniotic thyroid hormone therapy including miscarriage. Although cordocentesis is the gold standard for assessment of fetal thyroid status, we felt the clinical likelihood of fetal hypothyroidism was high (euthyroid mother, negative autoantibodies and brother with CH), and therefore measured amniotic fluid thyroid hormone levels since this could be achieved simultaneously with therapeutic amniocentesis and intraamniotic injection (2, 7).\n\nTreatment of fetal hypothyroid goitre requires optimization of maternal thyroid status including minimizing doses of antithyroid drugs, followed by either conservative management with neonatal levothyroxine administration, or direct fetal treatment in utero with thyroid hormone, since the placenta is not readily permeable to maternally-administered thyroxine or liothyronine (8, 11). Fetal hypothyroid dyshormonogenic goitre in the context of maternal euthyroidism has been managed successfully with radiological surveillance, followed by elective delivery and neonatal levothyroxine treatment, especially in cases presenting at late gestational ages. However intubation and ventilation may be required to support neonatal respiratory compromise at birth, and concerns regarding dystocia may necessitate Caesarean section. MRI may be more effective than ultrasound in assessing the degree of tracheal compression (8, 12, 13).\n\nCases treated in utero have usually been given intraamniotic levothyroxine, for which one retrospective cohort study supports a beneficial effect in reducing goitre size. Intraamniotic T3 (three injections of 60, 60 and 120 µg at 30 + 5–32 + 3 weeks) prior to T4 initiation has also been used successfully in another UK case. Treatment response is assessed by monitoring goitre size and resolution of polyhydramnios, sometimes in addition to sequential fetal thyroid hormone measurements. 3D ultrasonography may prove a superior tool to standard techniques in monitoring fetal goitre size in the future (3, 2, 4, 14). The optimal dosing regimen for intraamniotic therapy and effect on neonatal thyroid hormone status remains undefined, and associated complications include premature delivery, intrauterine infection and death. Published records describe preterm labour and chorioamnionitis following intraamniotic T4, and a case of fetal death is alluded to in one report (8, summarized in (15)). In view of these caveats, intraamniotic therapy is generally considered only when there is progressive hydramnios or likely tracheal occlusion, although conservative management in this context may also be associated with preterm delivery and neonatal death (3, 7, 13, 15).\n\nIn our patient, logistical barriers (sourcing parenteral T4 in the UK, obtaining local approval for therapy) initially precluded the use of intraamniotic T4. However worsening polyhydramnios compelled us to administer an intraamniotic injection of the active thyroid hormone T3 (which has a shorter half-life and greater potency than T4) until parenteral T4 became available. Treatment with intraamniotic T4 would have been preferable to T3, which will cause more precipitous fluctuations in hormone levels and has only one case report to support its use. The precise cause for the intrauterine death in our case was undertermined, although significant polyhydramnios with extension into the extraamniotic/subchorionic space was observed and is likely to have played a major role. Additionally, although there was no evidence of intrauterine infection, the treatment itself may have contributed to fetal demise, given the known risk of fetal loss associated with amniocentesis and the short time interval between intraamniotic injection and intrauterine death. At 31 weeks gestation, we selected a dose of intraamniotic T4 similar to that used in the previous intraamniotic T3/T4 combination therapy report (150 µg) however others have reported successful outcomes with higher doses of T4 alone (200–400 µg at similar gestational age), raising the possibility this dose was insufficient (4, 5). Dysphagia due to tracheo-oesophageal compression may also have impaired the ability of the fetus to ingest intraamniotic medication such that that earlier initiation of thyroid hormone therapy may have been more effective (5).\n\nDifficulties in obtaining parenteral T4 in the UK compound management of fetal goitrous hypothyroidism and our case emphasizes the requirement for further studies before T3 is considered a suitable therapeutic alternative. Additionally, our report highlights the morbidity and mortality associated with hypothyroid fetal goitre and its intrauterine treatment, which may be obscured in the literature due to a tendency for under-reporting adverse outcomes in similar complex cases (8). Although not universally undertaken, genetic ascertainment in such families may help predict risk of recurrence in future pregnancies and guide antenatal management.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis work was supported by funding from the Wellcome Trust (grant number 100585/Z/12/Z to N S) and the National Institute for Health Research Biomedical Research Centre Cambridge (N S). The Genomics/Transcriptomics Core Facility is supported by the UK Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/5) and a Wellcome Trust Strategic Award (100574/Z/12/Z).\n\nPatient consent\nWe confirm that written informed consent has been obtained from the patients’ mother for publication of the submitted article and accompanying images.\n\nAuthor contribution statement\nN S initiated genetic studies in the patient and wrote the manuscript, A K N performed the genetic studies, I S oversaw obstetric management, J G oversaw endocrine management and C P, P V and S-M P oversaw clinical genetic management of the patients. The authors acknowledge the Genomics and Transcriptomics Core Facility at the Wellcome Trust-MRC Institute of Metabolic Science for assistance with Sanger sequencing.\n==== Refs\nReferences\n1 Persani L \n2012 \nCongenital hypothyroidism with gland in situ is more frequent than previously thought . Frontiers in Endocrinology \n3 Article 18. (10.3389/fendo.2012.00018 )\n2 Leger J Olivieri A Donaldson M Torresani T Kriude H van Vliet G Polak M Butler G on behalf of ESPE-PES-SLEP-JSPE-APEG-APPES-ISPAE & The Congenital Hypothyroidism Consensus Conference Group \n2014 \nEuropean Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis and management of congenital hypothyroidism. \nJournal of Clinical Endocrinology and Metabolism \n99 \n363 –384 . (10.1210/jc.2013-1891 )24446653 \n3 Ghazi A-A M Ordookhani A Pourafkari M Fallahian M Bahar A Hedayati M Hafizi A Azizi F \n2005 \nIntrauterine diagnosis and management of fetal goitrous hypothyroidism: a report of an Iranian family with three consecutive pregnancies complicated by fetal goiter\nThyroid \n15 \n1341 –1347 . (10.1089/thy.2005.15.1341 )16405406 \n4 Ribault V Castanet M Bertrand A-M Guibourdenche J Vuillard E Luton D Polak M The French Fetal Goiter Study Group \n2009 \nExperience with intraamniotic thyroxine treatment in nonimmune fetal goitrous hypothyroidism in 12 cases . Journal of Clinical Endocrinology and Metabolism \n94 \n3731 –3739 . (10.1210/jc.2008-2681 )19737924 \n5 Agrawal P Ogilvy-Stuart A Lees C \n2002 \nIntrauterine diagnosis and management of congenital goitrous hypothyroidism . Ultrasound in Obstetrics and Gynecology \n19 \n501 –505 . (10.1046/j.1469-0705.2002.00717.x )11982986 \n6 Hishinuma A Fukata S Nishiyama S Nishi Y Oh-Ishi M Murata Y Ohyama Y Matsuura N Kasai K Harada S \n2006 \nHaplotype analysis reveals founder effects of thyroglobulin gene mutations C1058R and C1977S in Japan . Journal of Clinical Endocrinology and Metabolism \n91 \n3100 –3104 . (10.1210/jc.2005-2702 )16720658 \n7 Polak M Luton D \n2014 \nFetal thyroidology . Best Practice and Research Clinical Endocrinology and Metabolism \n28 \n161 –173 . (10.1016/j.beem.2013.04.013 )24629859 \n8 Reynolds BC Simpson JH Macara L Watt AJB Kubba H Donaldson MDC Pohlenz J \n2006 \nGoitrous congenital hypothyroidism in a twin pregnancy causing respiratory obstruction at birth: implications for management . Acta Pediatrica \n95 \n1345 –1348 . (10.1080/08035250600711074 )\n9 Pardo V Rubio IGS Knobel M Aguiar-Oliveira MH Santos MM Gomes SA Oliveira CRP Targovnik HM Medeiros-Neto G \n2008 \nPhenotypic variation among four family members with congenital hypothyroidism caused by two distinct thyroglobulin gene mutations . Thyroid \n18 \n783 –787 . (10.1089/thy.2007.0321 )18631008 \n10 Borgel K Pohlenz J Holzgreve W Bramswig JH \n2005 \nIntrauterine therapy of goitrous hypothyroidism in a boy with new compound heterozygous mutation (Y453D ad C800R) in the thyroid peroxidase gene. A long-term follow-up . American Journal of Obstetrics and Gynecology \n193 \n857 –858 . (10.1016/j.ajog.2005.01.060 )16150286 \n11 Davidson KM Richards DS Schatz DA Fisher DA \n1991 \nSuccessful in utero treatment of fetal goiter and hypothyroidism . New England Journal of Medicine \n324 \n543 –546 . (10.1056/NEJM199102213240807 )1992308 \n12 Bae JY Joo LH Jung JE Hong SY \n2015 \nPrenatal diagnosis of fetal goiter in a euthyroid mother . Korean Journal of Perinatology \n26 \n365 –368 . (10.14734/kjp.2015.26.4.365 )\n13 Gungoren A Dolapcioglu K Hakverdi AU Balci A Guzelmansur I \n2010 \nFetal goiter in the absence of maternal thyroid disease: a case report . Perinatal Journal \n18 \n101 –104 .\n14 Kim MJ Chae Y-H Park SY Kim MY \n2016 \nIntra-amniotic thyroxine to treat fetal goiter . Obstetrics and Gynecology Science \n59 \n66 –70 . (10.5468/ogs.2016.59.1.66 )26866040 \n15 Stoppa-Vaucher S Francoeur D Grignon A Alos N Pohlenz J Hermanns P Van Vliet G Deladoëy J \n2010 \nNon-immune goiter and hypothyroidism in a 19-week old fetus: a plea for conservative treatment . Journal of Pediatrics \n156 \n1026 –1029 . (10.1016/j.jpeds.2010.01.018 )20304420\n\n",
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"title": "Intrauterine death following intraamniotic triiodothyronine and thyroxine therapy for fetal goitrous hypothyroidism associated with polyhydramnios and caused by a thyroglobulin mutation.",
"title_normalized": "intrauterine death following intraamniotic triiodothyronine and thyroxine therapy for fetal goitrous hypothyroidism associated with polyhydramnios and caused by a thyroglobulin mutation"
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"abstract": "Optimization of the salvage regimen is required to improve prognosis in primary refractory or relapsed acute myeloid leukemia (AML). In fit patients, a bridge to allogeneic transplant is the primary purpose of salvage. We tested the combination of fractionated gemtuzumab ozogamicin with cytarabine and mitoxantrone (MYLODAM schema) with primary endpoint of efficacy and safety. We also attempted to define predictive factors for survival and response after salvage. We included 58 patients with a median age at salvage of 56 years. The overall response rate was 67%. Leukemia-free survival (LFS) and overall survival (OS) at 2 years was 36% (95% CI: 23-49) and 54% (95% CI: 39-68), respectively. Treatment-related mortality was 7%. Three veno-occlusive diseases (SOS/VOD) occurred during salvage. In the allogeneic group of 28 patients (48%), LFS and OS at 2 years was 57 % (95% CI: 36.3-77.5) and 69 % (95% CI: 49.3-88.7), respectively. Incidences of nonrelapse mortality, grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD were 16%, 40%, and 45%, respectively. A GO-based intensive regimen is a viable option for salvage therapy and a feasible schedule as a bridge to allogeneic transplant.",
"affiliations": "Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France. pierre-edouard.debureaux@aphp.fr.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Sorbonne Université, Paris, France.;Sorbonne Université, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.;Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France.",
"authors": "Debureaux|Pierre-Edouard|PE|http://orcid.org/0000-0002-2358-4278;Labopin|Myriam|M|;Mamez|Anne-Claire|AC|;Lapusan|Simona|S|;Isnard|Francoise|F|;Adaeva|Rosa|R|;Bonnin|Agnès|A|;Hirsch|Pierre|P|;Delhommeau|Francois|F|;Battipaglia|Giorgia|G|;Duléry|Remy|R|;Malard|Florent|F|http://orcid.org/0000-0002-3474-0002;Vekhoff|Anne|A|;Mohty|Mohamad|M|;Legrand|Ollivier|O|;Brissot|Eolia|E|",
"chemical_list": "D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D003561:Cytarabine; D000079982:Gemtuzumab",
"country": "England",
"delete": false,
"doi": "10.1038/s41409-019-0690-2",
"fulltext": null,
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"issn_linking": "0268-3369",
"issue": "55(2)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D000079982:Gemtuzumab; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D016879:Salvage Therapy",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "452-460",
"pmc": null,
"pmid": "31554931",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fractionated gemtuzumab ozogamicin in association with high dose chemotherapy: a bridge to allogeneic stem cell transplantation in refractory and relapsed acute myeloid leukemia.",
"title_normalized": "fractionated gemtuzumab ozogamicin in association with high dose chemotherapy a bridge to allogeneic stem cell transplantation in refractory and relapsed acute myeloid leukemia"
} | [
{
"companynumb": "FR-PFIZER INC-2019428530",
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"actiondrug": "5",
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"activesubstancename": "GEMTUZUMAB OZOGAMICIN"
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"abstract": "OBJECTIVE\nAxitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study.\n\n\nMETHODS\nPatients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m(2) once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival.\n\n\nRESULTS\nAmong Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months-not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4-10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525-2.274]). Median survival follow-up (range) was 5.1 months (0.02-12.3) with axitinib/gemcitabine vs. 5.4 months (1.8-10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival.\n\n\nCONCLUSIONS\nAxitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.",
"affiliations": "Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka ioka-ta@mc.pref.osaka.jp.;Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo.;Department of Gastroenterology, Kanagawa Cancer Center, Kanagawa.;Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka.;Department of Clinical Oncology, Kawasaki Medical School, Okayama.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Oncology, San Diego, CA, USA.;Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan.",
"authors": "Ioka|Tatsuya|T|;Okusaka|Takuji|T|;Ohkawa|Shinichi|S|;Boku|Narikazu|N|;Sawaki|Akira|A|;Fujii|Yosuke|Y|;Kamei|Yoichi|Y|;Takahashi|Satori|S|;Namazu|Katsushi|K|;Umeyama|Yoshiko|Y|;Bycott|Paul|P|;Furuse|Junji|J|",
"chemical_list": "D007093:Imidazoles; D007191:Indazoles; D003841:Deoxycytidine; C056507:gemcitabine; D000077784:Axitinib",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyv011",
"fulltext": "\n==== Front\nJpn J Clin OncolJpn. J. Clin. OncoljjcojjcoJapanese Journal of Clinical Oncology0368-28111465-3621Oxford University Press 10.1093/jjco/hyv011hyv011Original ArticlesHepato-biliary and Pancreatic MedicineEfficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial Ioka Tatsuya 1*Okusaka Takuji 2Ohkawa Shinichi 3Boku Narikazu 4Sawaki Akira 5Fujii Yosuke 6Kamei Yoichi 6Takahashi Satori 6Namazu Katsushi 6Umeyama Yoshiko 6Bycott Paul 7Furuse Junji 81 Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka2 Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo3 Department of Gastroenterology, Kanagawa Cancer Center, Kanagawa4 Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka5 Department of Clinical Oncology, Kawasaki Medical School, Okayama6 Pfizer Japan Inc., Tokyo, Japan7 Pfizer Oncology, San Diego, CA, USA8 Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan* For reprints and all correspondence: Tatsuya Ioka, Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3, Nakamichi, Higashinari-ku, Osaka 537-8511, Japan. E-mail: ioka-ta@mc.pref.osaka.jp5 2015 03 2 2015 03 2 2015 45 5 439 448 5 12 2014 12 1 2015 © The Author 2015. Published by Oxford University Press.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comObjective\nAxitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1–3. This analysis compared efficacy and safety of axitinib plus gemcitabine in patients with advanced pancreatic cancer from Japan, North America and the European Union, enrolled in a randomized Phase III study.\n\nMethods\nPatients (n = 632), stratified by disease extent, were randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. Axitinib was administered at a starting dose of 5 mg orally twice daily and gemcitabine at 1000 mg/m2 once weekly for 3 weeks in 4 week cycles. Primary endpoint was overall survival.\n\nResults\nAmong Japanese patients, median overall survival was not estimable (95% confidence interval, 7.4 months—not estimable) with axitinib/gemcitabine (n = 58) and 9.9 months (95% confidence interval, 7.4–10.5) with placebo/gemcitabine (n = 56) (hazard ratio 1.093 [95% confidence interval, 0.525–2.274]). Median survival follow-up (range) was 5.1 months (0.02–12.3) with axitinib/gemcitabine vs. 5.4 months (1.8–10.5) with placebo/gemcitabine. Similarly, no difference was detected in overall survival between axitinib/gemcitabine and placebo/gemcitabine in patients from North America or the European Union. Common adverse events with axitinib/gemcitabine in Japanese patients were fatigue, anorexia, dysphonia, nausea and decreased platelet count. Axitinib safety profile was generally similar in patients from the three regions, although there were differences in incidence of some adverse events. An exploratory analysis did not show any correlation between axitinib/gemcitabine-related hypertension and overall survival.\n\nConclusions\nAxitinib/gemcitabine, while tolerated, did not provide survival benefit over gemcitabine alone in patients with advanced pancreatic cancer from Japan or other regions.\n\naxitinibgemcitabineJapanesepancreatic cancer\n==== Body\nIntroduction\nPancreatic cancer was diagnosed in an estimated 337 872 patients and claimed ∼330 372 deaths worldwide in 2012 (1). The estimated incidences and deaths, respectively, were 42 885 and 41 509 in the USA, 79 331 and 78 651 in the European Union and 32 899 and 31 046 in Japan (1). Currently, surgical resection is the only potentially curative treatment of pancreatic cancer, but patients are often diagnosed with advanced unresectable disease (2). For advanced pancreatic cancer, combination chemotherapy with FOLFIRINOX (5-fluorouracil/leucovorin, oxaliplatin and irinotecan) or gemcitabine with nab-paclitaxel or erlotinib (an inhibitor of epidermal growth factor receptor), as well as gemcitabine monotherapy, are recommended by the National Comprehensive Cancer Network (2). Pancreatic cancer is associated with the poorest 5-year survival rate (6%) of any cancer in the USA (3). Therefore, new treatment options are urgently needed to improve survival of patients with advanced pancreatic cancer.\n\nVascular endothelial growth factor (VEGF) is highly expressed in pancreatic cancer, with the level of expression correlated with microvascular density (4–6) and possibly with poor prognosis (5,6). Axitinib is a potent and selective inhibitor of VEGF receptors 1, 2 and 3 (7), approved for second-line treatment of advanced renal cell carcinoma. Based on promising activity against advanced pancreatic cancer reported in an open-label randomized Phase II study (8), a randomized Phase III study was conducted globally to evaluate the efficacy and safety of axitinib in combination with gemcitabine (9). At the pre-planned interim analysis, median overall survival (OS), the primary endpoint of the study, was 8.5 months in the axitinib/gemcitabine arm (n = 314) compared with 8.3 months in the placebo/gemcitabine arm (n = 316) (hazard ratio [HR] 1.014; 95% confidence interval [CI], 0.786–1.309; P = 0.5436, stratified one-sided log-rank test), and the independent Data Monitoring Committee (DMC) concluded that the futility boundary had been crossed (9). Thus, the study failed to demonstrate survival benefit of adding axitinib to gemcitabine in the treatment of advanced pancreatic cancer in the overall population.\n\nTo the best of our knowledge, there has been no report describing potential geographic differences in efficacy and safety outcomes in patients with advanced pancreatic cancer treated with anticancer drugs, including antiangiogenic agents. Therefore, we have undertaken in-depth analyses of the data from this Phase III study to evaluate the efficacy and safety of axitinib/gemcitabine in Japanese patients and compare the results with those from North America and the European Union in order to assess potential geographic differences in patient outcomes. In addition, based on a post hoc exploratory analysis of data from the Phase II study of axitinib/gemcitabine in advanced pancreatic cancer, which indicated a longer median OS in patients who experienced diastolic blood pressure (BP) ≥90 mm Hg during treatment compared with those who did not (8), the exploratory analysis was expanded using the data from this Phase III study to further assess potential correlations between the axitinib efficacy outcome and hypertension in these patients.\n\nMethods\nStudy design\nThis was a randomized, double-blind Phase III study conducted in 24 countries, including Japan. The details of the study design and treatment have been published previously (9). In brief, eligible patients were stratified by extent of the disease (metastatic vs. locally advanced pancreatic cancer), and randomly assigned (1:1) to receive axitinib/gemcitabine or placebo/gemcitabine. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. For Japanese patients enrolled in the study, an additional review of the first 16 patients was conducted by the DMC to evaluate the safety of axitinib/gemcitabine, and subsequent enrollment and initiation of treatment was based on the feedback from the DMC.\n\nThe study protocol, amendments and informed consent documentation were reviewed and approved by the institutional review boards and independent ethics committees at each center. The study was conducted in accordance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines as well as applicable local regulatory requirements. All patients provided written informed consent prior to study entry. This study is registered with ClinicalTrials.gov (identifier NCT00471146).\n\nPatients\nAs previously described in detail (9), eligible patients were aged 18 years or older (≥20 years old in Japan) with histologically or cytologically confirmed metastatic or locally advanced unresectable pancreatic adenocarcinoma; Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1; adequate bone marrow, hepatic, renal and coagulation function; and without uncontrolled hypertension, i.e. baseline BP readings must be ≤140/90 mm Hg. Use of antihypertensive medications was permitted. Exclusion criteria included prior systemic chemotherapy; prior therapy with gemcitabine, axitinib or VEGF inhibitors; or active seizure or brain metastasis.\n\nStudy treatment\nPatients received gemcitabine (1000 mg/m2) as a 30 min intravenous infusion once weekly for 3 weeks followed by 1 week off. Gemcitabine dose could be reduced to 750, 550 or 425 mg/m2 to manage toxicities. Axitinib or placebo was administered at a starting dose of 5 mg twice daily (BID) orally with food. Axitinib or placebo dose could be increased stepwise to 7 mg BID, and then to the maximum 10 mg BID, in patients who had no drug-related, Grade ≥3 adverse event (AE) per Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 for consecutive 2-week periods, and had BP ≤150/90 mm Hg without any antihypertensive medication. Axitinib or placebo dose could be reduced to 3 mg BID, and then to 2 mg BID, if necessary, to manage treatment-related toxicity. Patients were treated in 4-week cycles until disease progression, unmanageable AEs or withdrawal of consent.\n\nAssessments\nAs reported previously (9), tumor assessments were conducted at screening and repeated every 8 weeks until 28 days after the last dose and whenever disease progression was suspected. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Safety was monitored throughout the study and AEs were graded per CTCAE version 3.0. BP was measured in-clinic at screening and once every week. In addition, all patients were provided with a BP-monitoring device and instructed to measure BP twice daily at home and to contact their physician if BP was >150/100 mm Hg or symptoms related to elevated BP developed. Plasma level of thyroid-stimulating hormone and free thyroxine was monitored during treatment period, and hypothyroidism was treated with standard medication. Urinalysis was performed at screening and once every cycle.\n\nStatistical analyses\nStatistical analyses were previously described in detail (9). For time-to-event endpoints (OS, PFS), median and two-sided 95% CIs were estimated using the Kaplan–Meier method in the two treatment arms in each region (Japan, North America and the European Union). The OS and PFS between the two treatment arms within each region were compared using a log-rank test (one-sided), stratified by extent of the disease. The ORR and corresponding exact two-sided 95% CI were summarized in the two treatment arms in each region, and Cochran–Mantel–Haenszel test (two-sided), stratified by the stratification factor, was used for comparison between the two treatment arms. To explore potential correlation between OS and hypertension, univariate Cox proportional regression was performed using maximum diastolic BP during Cycle 1 as a categorical variable. Patients were divided into two groups; one group with patients who experienced maximum diastolic BP ≥90 mm Hg during Cycle 1 and the other group with patients who did not.\n\nResults\nPatient baseline characteristics\nOf 632 randomized patients with advanced pancreatic cancer (n = 316 in each arm), two patients in the axitinib/gemcitabine arm did not have randomization information in the clinical database at the time of the analysis, and were excluded from the analyses. Randomized patients were from Japan (n = 114), North America (n = 158), the European Union (n = 264), Asia other than Japan (n = 55) and other countries/regions (Argentina, Australia and South Africa; n = 39). By country, Japan had the second highest number of patients closely following the USA (n = 119). Due to small number of patients, Asia other than Japan, Argentina, Australia and South Africa were not included in the current analysis.\n\nMedian age and the proportion of male and female patients were comparable among Japanese, North American and European Union patients (Table 1). However, a higher percentage of Japanese patients had ECOG PS 0 and locally advanced disease compared with those in the other two regions.\nTable 1. Patient demographics and baseline characteristics\n\n\tOverall study population\tJapan\tNorth America\tEuropean Union\t\nAxitinib/Gem (n = 314)\tPlacebo/Gem (n = 316)\tAxitinib/Gem (n = 58)\tPlacebo/Gem (n = 56)\tAxitinib/Gem (n = 77)\tPlacebo/Gem (n = 81)\tAxitinib/Gem (n = 132)\tPlacebo/Gem (n = 132)\t\nAge, years\t\n Median\t61\t62\t60\t61\t62\t65\t60\t62\t\n Range\t34–84\t35–89\t43–77\t39–77\t39–84\t37–89\t34–82\t35–81\t\nSex, %\t\n Male\t60.8\t59.5\t69.0\t62.5\t54.5\t60.5\t55.3\t56.1\t\n Female\t39.2\t40.5\t31.0\t37.5\t45.5\t39.5\t44.7\t43.9\t\nRace, %\t\n White\t67.2\t69.6\t0\t0\t85.7\t91.4\t97.7\t97.0\t\n Black\t2.5\t2.2\t0\t0\t9.1\t6.2\t0\t0.8\t\n Asian\t28.3\t26.6\t100\t100\t2.6\t0\t0.8\t0\t\n Other\t1.9\t1.6\t0\t0\t2.6\t2.5\t1.5\t2.3\t\nECOG PSa, %\t\n 0\t46.8\t50.0\t77.6\t76.8\t37.7\t38.3\t44.7\t50.8\t\n 1\t51.6\t48.7\t22.4\t23.2\t62.3\t61.7\t51.5\t47.7\t\nDisease stageb, %\t\n Locally advanced\t24.2\t23.7\t31.0\t33.9\t19.5\t19.8\t25.0\t25.0\t\n Metastatic\t75.8\t76.3\t69.0\t66.1\t80.5\t80.2\t75.0\t75.0\t\nPrior surgerya,c, %\t\n Yes\t11.8\t10.8\t3.4\t10.7\t5.2\t6.2\t17.4\t14.4\t\n No\t86.3\t86.4\t93.1\t76.8\t93.5\t93.8\t80.3\t84.8\t\nPrior adjuvant therapy, %\t\n Yes\t3.8\t3.5\t1.7\t5.4\t0\t2.5\t5.3\t3.8\t\n No\t96.2\t96.5\t98.3\t94.6\t100\t97.5\t94.7\t96.2\t\nPrior radiotherapya, %\t\n Yes\t3.2\t4.1\t0\t0\t1.3\t7.4\t3.0\t5.3\t\n No\t95.5\t94.3\t98.3\t98.2\t97.4\t92.6\t95.5\t91.7\t\nGem, gemcitabine; ECOG PS, Eastern Cooperative Oncology Group performance status.\n\naThe remaining percent due to missing and/or unknown.\n\nbAt randomization.\n\ncResected or partially resected.\n\n\n\nTreatments and patient disposition\nThe exposure to study drugs in each region as well as in the overall population is summarized in Table 2. Median treatment duration for gemcitabine in the axitinib/gemcitabine- and placebo/gemcitabine-treated patients was generally similar between Japan and the European Union. In North America, however, patients in the axitinib/gemcitabine arm received fewer days of gemcitabine treatment compared with those in the placebo/gemcitabine arm (43 vs. 71 days, respectively), and had more gemcitabine dose interruptions (72.0 vs. 54.3%, respectively). For axitinib treatment, median duration was longest for patients in Japan, followed by those in the European Union and then North America (95 vs. 84 vs. 63 days, respectively). However, axitinib dose interruptions and dose reductions, respectively, were more frequent among Japanese patients (87.7 and 31.6%) compared with those in North America (78.7 and 16.0%) or the European Union (64.6 and 26.0%).\nTable 2. Exposure to study drugsa\n\n\tOverall study population\tJapan\tNorth America\tEuropean Union\t\nAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\t\nGemcitabine\tn = 305\tn = 308\tn = 57\tn = 56\tn = 75\tn = 81\tn = 127\tn = 126\t\n No. cycles startedb,c\t\n Median\t3\t3\t5\t4\t2\t3\t3\t4\t\n Range\t1–13\t1–12\t1–10\t1–10\t1–9\t1–12\t1–13\t1–10\t\n Days on treatmentc,d\t\n Median\t71\t73\t119\t99\t43\t71\t71\t85\t\n Range\t1–336\t1–358\t1–267\t1–267\t1–232\t1–334\t1–336\t1–358\t\n Dose interruption, n (%)\t194 (63.6)\t165 (53.6)\t33 (57.9)\t29 (51.8)\t54 (72.0)\t44 (54.3)\t73 (57.5)\t62 (49.2)\t\n Dose reduction, n (%)\t125 (41.0)\t100 (32.5)\t37 (64.9)\t27 (48.2)\t23 (30.7)\t26 (32.1)\t42 (33.1)\t34 (27.0)\t\n Relative dose intensityc,e, %\t\n Median\t77.4\t79.4\t70.1\t72.8\t70.8\t78.8\t81.7\t83.0\t\n Range\t27.7–106.4\t19.6–106.3\t32.1–104.5\t33.3–101.3\t27.7–101.4\t19.6–104.5\t32.5–106.4\t32.7–106.3\t\nAxitinib or placebo\tn = 298\tn = 301\tn = 57\tn = 56\tn = 75\tn = 81\tn = 127\tn = 126\t\n Days on treatmentd,f\t\n Median\t84\t85\t95\t88\t63\t84\t84\t111\t\n Range\t1–335\t2–361\t24–280\t5–280\t2–251\t2–361\t1–335\t4–281\t\n Days on drugf,g\t\n Median\t84\t84\t91\t88\t59.5\t84\t84\t91\t\n Range\t1–336\t2–334\t24–280\t5–280\t2–251\t2–334\t1–336\t4–288\t\n Dose interruption, n (%)\t223 (74.8)\t183 (60.8)\t50 (87.7)\t36 (64.3)\t59 (78.7)\t60 (74.1)\t82 (64.6)\t61 (48.4)\t\n Dose reduction, n (%)\t74 (24.8)\t30 (10.0)\t18 (31.6)\t4 (7.1)\t12 (16.0)\t8 (9.9)\t33 (26.0)\t12 (9.5)\t\n Dose increase, n (%)\t95 (31.9)\t131 (43.5)\t7 (12.3)\t32 (57.1)\t16 (21.3)\t29 (35.8)\t51 (40.2)\t57 (45.2)\t\n Relative dose intensitye,f, %\t\n Median\t100.0\t100.0\t100.0\t117.1\t100.0\t100.0\t100.0\t100.0\t\n Range\t36.3–186.7\t50.0–190.2\t40.0–184.4\t55.6–190.2\t48.2–179.6\t54.4–168.0\t38.4–186.7\t62.6–188.1\t\nGem, gemcitabine\n\naBased on patients who received study treatment.\n\nbIf patients took at least some gemcitabine, they were considered to have started a cycle.\n\ncn = 304 and 302 for Axitinib/Gem and Placebo/Gem, respectively, in the overall study population; n = 74 and 79 for Axitinib/Gem and Placebo/Gem, respectively, in North America; and n = 123 for Placebo/Gem in the European Union.\n\ndTime period starting from date of the first dose to date of the last dose or data cutoff.\n\ne(Actual total dose/intended total dose) × 100.\n\nfn = 55 and 53 for Axitinib/Gem and Placebo/Gem, respectively, in Japan; n = 72 and 79 for Axitinib/Gem and Placebo/Gem, respectively, in North America; and n = 125 and 124 for Axitinib/Gem and Placebo/Gem, respectively, in the European Union.\n\ngTotal number of days on which axitinib or placebo was actually administered.\n\n\n\nAt the time of final analysis (data cutoff date: 23 January 2009), 24 and 27% of Japanese patients in the axitinib/gemcitabine and placebo/gemcitabine arms, respectively, discontinued study treatment, whereas a higher percentage of patients in North America (74 and 67%) and in the European Union (50 and 56%) discontinued treatment. The main reason for discontinuation in each arm was disease progression.\n\nThe most common systemic treatment administered to Japanese patients following the study treatment was S-1, whereas gemcitabine, 5-FU and oxaliplatin were the common follow-up treatments received by patients in North America and the European Union (Supplementary Material 1).\n\nEfficacy\nThe OS in the overall study population and individual region by study treatment arm is presented in Table 3. In the overall study population, there was no statistically significant difference in OS between the axitinib/gemcitabine and placebo/gemcitabine arms (HR 1.014; P = 0.5436; Fig. 1A), as previously reported (9).\nTable 3. Summary of overall survival in the overall study population and by disease extent and region\n\n\tOverall study population\tJapan\tNorth America\tEuropean Union\t\nAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\t\nOverall\t\n No. of patients\t314\t316\t58\t56\t77\t81\t132\t132\t\n No. of events (%)\t118 (37.6)\t120 (38.0)\t15 (25.9)\t15 (26.8)\t45 (58.4)\t44 (54.3)\t41 (31.1)\t41 (31.1)\t\n Follow-up period\t\n Median, months\t4.4\t4.8\t5.1\t5.4\t4.3\t5.1\t4.1\t4.7\t\n (range)\t(0.02–12.8)\t(0.02–11.9)\t(0.02–12.3)\t(1.8–10.5)\t(0.2–12.1)\t(0.4–11.9)\t(0.02–12.8)\t(0.02–10.6)\t\n Median OS, months\t8.5\t8.3\tNE\t9.9\t5.6\t6.6\t10.1\t8.7\t\n (95% CI)\t(6.9–9.5)\t(6.9–10.3)\t(7.4–NE)\t(7.4–10.5)\t(4.6–8.5)\t(5.3–10.3)\t(6.9–NE)\t(7.1–NE)\t\n Hazard ratioa,b (95% CI)\t1.014 (0.786–1.309)\t1.093 (0.525–2.274)\t1.288 (0.849–1.954)\t1.018 (0.659–1.571)\t\n P valuec\t0.5436\t0.5937\t0.8845\t0.5309\t\nLocally advanced disease\t\n No. of patients\t76\t75\t18\t19\t15\t16\t33\t33\t\n No. of events (%)\t21 (27.6)\t13 (17.3)\t3 (16.7)\t3 (15.8)\t8 (53.3)\t5 (31.3)\t7 (21.2)\t4 (12.1)\t\n Follow-up period\t\n Median, months\t5.1\t6.0\t6.0\t6.8\t3.0\t5.5\t4.2\t6.0\t\n (range)\t(0.02–10.6)\t(0.4–11.9)\t(0.02–10.3)\t(2.9–10.5)\t(1.3–10.0)\t(1.4–11.9)\t(0.02–10.6)\t(0.4–10.6)\t\n Median OS, months\t9.5\t10.6\tNE\t9.9\t6.3\tNE\t10.1\t10.4\t\n (95% CI)\t(7.4–NE)\t(9.9–NE)\t(8.0–NE)\t(9.9–10.5)\t(3.0–9.5)\t(5.0–NE)\t(7.3–NE)\t(10.4–NE)\t\n Hazard ratioa (95% CI)\t2.079 (1.031–4.189)\t1.939 (0.319–11.787)\t2.273 (0.741–6.974)\t2.351 (0.684–8.086)\t\n P valued\t0.9818\t0.7678\t0.9330\t0.9187\t\nMetastatic disease\t\n No. of patients\t238\t241\t40\t37\t62\t65\t99\t99\t\n No. of events (%)\t97 (40.8)\t107 (44.4)\t12 (30.0)\t12 (32.4)\t37 (59.7)\t39 (60.0)\t34 (34.3)\t37 (37.4)\t\n Follow-up period\t\n Median, months\t4.3\t4.4\t4.9\t4.8\t4.4\t5.1\t4.0\t4.3\t\n (range)\t(0.2–12.8)\t(0.02–11.7)\t(1.1–12.3)\t(1.8–10.4)\t(0.2–12.1)\t(0.4–11.7)\t(0.5–12.8)\t(0.02–9.8)\t\n Median OS, months\t7.0\t6.9\tNE\tNE\t5.5\t6.2\t7.5\t8.2\t\n (95% CI)\t(5.8–9.3)\t(6.2–8.0)\t(6.9–NE)\t(6.4–NE)\t(4.3–8.5)\t(5.2–8.0)\t(6.1–NE)\t(6.4–NE)\t\n Hazard ratioa (95% CI)\t0.904 (0.686–1.190)\t0.972 (0.435–2.170)\t1.170 (0.746–1.837)\t0.897 (0.563–1.430)\t\n P valued\t0.2345\t0.4721\t0.2456\t0.3230\t\nGem, gemcitabine; OS, overall survival; CI, confidence interval; NE, not estimable.\n\naAxitinib/gemcitabine vs. placebo/gemcitabine; assuming proportional hazards model, a hazard ratio <1 indicates a reduction in hazard rate in favor of axitinib/gemcitabine and a hazard ratio >1 indicates a reduction in favor of placebo/gemcitabine.\n\nbHazard ratio stratified by extent of the disease (locally advanced vs. metastatic pancreatic cancer).\n\ncFrom a one-sided log-rank test of treatment stratified by extent of the disease (locally advanced vs. metastatic pancreatic cancer).\n\ndFrom a one-sided, unstratified log-rank test.\n\n\nFigure 1. Kaplan–Meier estimates for overall survival for axitinib/gemcitabine vs. placebo/gemcitabine in the overall study population (A), and in patients in Japan (B), North America (C) and the European Union (D). Panel A reprinted from The Lancet Oncology, 12 (3), Kindler HL, et al. (9). Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised Phase 3 study, 256–62, Copyright 2011, with permission from Elsevier.\n\n\n\nSince the study was terminated, which was recommended by the independent DMC due to the futility at the interim analysis, median survival follow-up period among all Japanese patients was short as well as those in other regions. The HR for OS between the axitinib/gemcitabine vs. placebo/gemcitabine arms in all Japanese patients was 1.093 (95% CI, 0.525–2.274; P = 0.5937; Fig. 1B). In Japanese patients with locally advanced disease, HR for OS was 1.939 (95% CI, 0.319–11.787; P = 0.7678), whereas in those with metastatic disease, it was 0.972 (95% CI, 0.435–2.170; P = 0.4721) (Table 3). Similarly, median OS did not differ between the two treatment arms in patients from North America or the European Union (Fig. 1C and D).\n\nThe PFS in each treatment arm is summarized in Table 4. In the overall study population, PFS was also similar between the axitinib/gemcitabine and placebo/gemcitabine arms (HR 1.006; 95% CI, 0.779–1.298; P = 0.5203; Supplementary Material 2A) (9). Among all Japanese patients, there was no difference in median PFS between the two treatment arms (HR 0.905; 95% CI, 0.416–1.968; P = 0.5995; Supplementary Material 2B). There was no difference in PFS between the two treatment arms in patients from North America or the European Union as well (Supplementary Material 2C and D).\nTable 4. Summary of progression-free survival in the overall study population and by disease extent and region\n\n\tOverall study population\tJapan\tNorth America\tEuropean Union\t\nAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\tAxitinib/Gem\tPlacebo/Gem\t\nOverall\t\n No. of patients\t314\t316\t58\t56\t77\t81\t132\t132\t\n No. of events (%)\t116 (36.9)\t125 (39.6)\t12 (20.7)\t16 (28.6)\t39 (50.6)\t38 (46.9)\t44 (33.3)\t47 (35.6)\t\n Median, months\t4.4\t4.4\t5.8\t5.8\t4.1\t3.7\t5.7\t4.9\t\n (95% CI)\t(4.0–5.6)\t(3.7–5.2)\t(4.8–7.2)\t(4.0–10.5)\t(2.9–5.3)\t(3.4–5.7)\t(3.7–7.5)\t(3.8–7.0)\t\n Hazard ratioa,b (95% CI)\t1.006 (0.779–1.298)\t0.905 (0.416–1.968)\t1.290 (0.814–2.045)\t0.908 (0.594–1.390)\t\n P valuec\t0.5203\t0.5995\t0.8635\t0.6707\t\nLocally advanced disease\t\n No. of patients\t76\t75\t18\t19\t15\t16\t33\t33\t\n No. of events (%)\t22 (28.9)\t17 (22.7)\t4 (22.2)\t2 (10.5)\t7 (46.7)\t4 (25.0)\t7 (21.2)\t9 (27.3)\t\n Median, months\t5.9\t9.1\t5.8\t10.5\t7.2\t9.0\t7.3\t10.4\t\n (95% CI)\t(4.2–7.3)\t(5.8–10.6)\t(5.6–NE)\t(5.8–10.5)\t(1.7–9.5)\t(2.0–9.0)\t(4.2–9.5)\t(4.1–10.4)\t\n Hazard ratioa (95% CI)\t1.888 (0.978–3.645)\t4.775 (0.531–42.915)\t1.477 (0.413–5.287)\t1.384 (0.500–3.832)\t\n P valued\t0.9732\t0.9382\t0.7273\t0.7379\t\nMetastatic disease\t\n No. of patients\t238\t241\t40\t37\t62\t65\t99\t99\t\n No. of events (%)\t94 (39.5)\t108 (44.8)\t8 (20.0)\t14 (37.8)\t32 (51.6)\t34 (52.3)\t37 (37.4)\t38 (38.4)\t\n Median, months\t4.2\t3.8\t7.2\t4.1\t4.1\t3.7\t3.9\t4.1\t\n (95% CI)\t(3.7–5.4)\t(3.6–4.5)\t(4.8–7.2)\t(3.5–7.4)\t(2.4–5.3)\t(3.2–5.4)\t(3.5–7.5)\t(3.5–5.9)\t\n Hazard ratioa (95% CI)\t0.897 (0.679–1.184)\t0.629 (0.259–1.527)\t1.264 (0.770–2.073)\t0.834 (0.523–1.329)\t\n P valued\t0.2214\t0.1506\t0.1718\t0.2206\t\nGem, gemcitabine; CI, confidence interval; NE, not estimable\n\naAxitinib/gemcitabine vs. placebo/gemcitabine; assuming proportional hazards model, a hazard ratio <1 indicates a reduction in hazard rate in favor of axitinib/gemcitabine and a hazard ratio >1 indicates a reduction in favor of placebo/gemcitabine.\n\nbHazard ratio stratified by extent of the disease (locally advanced vs. metastatic pancreatic cancer).\n\ncFrom a one-sided log-rank test of treatment stratified by extent of the disease (locally advanced vs. metastatic pancreatic cancer).\n\ndFrom a one-sided, unstratified log-rank test.\n\n\n\nThe ORR in the overall population was numerically higher with axitinib/gemcitabine than placebo/gemcitabine (4.9 vs. 1.6%, respectively; P = 0.038). The ORR for the axitinib/gemcitabine and placebo/gemcitabine arms, respectively, was 6.7% (95% CI, 0.8–22.1) and 0% (95% CI, 0–9.7) (P = 0.145) in Japanese patients, 3.1% (95% CI, 0.4–10.8) and 2.6% (95% CI, 0.3–9.2) (P = 0.885) in patients in North America, and 4.6% (95% CI, 1.5–10.5) and 1.0% (95% CI, 0–5.3) (P = 0.117) in patients in the European Union.\n\nSafety\nAll-causality AEs reported by >20% of patients in each arm in the overall study population and in individual regions are summarized in Table 5. Among Japanese patients, fatigue, anorexia, dysphonia, nausea and decreased platelet count were common AEs in patients treated with axitinib/gemcitabine, whereas anorexia and decreased neutrophil count were common with placebo/gemcitabine treatment. Grade ≥3 AEs reported by ≥10% of Japanese patients included decreased neutrophil count, anorexia, decreased platelet count and hypertension with axitinib/gemcitabine, decreased neutrophil count and decreased platelet count with placebo/gemcitabine. The profile of common AEs was generally similar between Japanese patients and the overall study population, North American or the European Union patients, although there were some differences in incidence rates for some AEs.\nTable 5. Treatment-emergent, all-causality adverse events reported by >20% of patients in any arm in any region\n\nAll grades/≥3 Grade, %\tOverall study population\tJapan\tNorth America\tEuropean Union\t\nAxitinib/\nGem (n = 305)\tPlacebo/\nGem (n = 308)\tAxitinib/\nGem (n = 57)\tPlacebo/\nGem (n = 56)\tAxitinib/\nGem (n = 75)\tPlacebo/\nGem (n = 81)\tAxitinib/\nGem (n = 127)\tPlacebo/\nGem (n = 126)\t\nNon-hematologic adverse events\t\n Nausea\t47/4\t37/3\t58/2\t46/5\t45/8\t36/2\t41/4\t37/1\t\n Fatigue\t42/9\t37/7\t70/9\t46/9\t49/13\t53/11\t26/6\t25/5\t\n Anorexia\t37/6\t27/4\t68/16\t52/4\t33/5\t21/5\t24/4\t22/3\t\n Diarrhea\t33/1\t22/2\t39/2\t16/0\t27/1\t26/1\t29/0\t25/2\t\n Vomiting\t32/4\t33/3\t39/0\t34/0\t28/5\t40/4\t33/6\t32/4\t\n Constipation\t29/1\t31/2\t49/0\t41/4\t24/3\t38/4\t21/0\t22/1\t\n Hypertension\t28/7\t9/2\t44/12\t4/2\t31/7\t14/5\t23/5\t10/0\t\n Dysphonia\t22/<1\t4/0\t60/2\t18/0\t17/0\t2/0\t10/0\t0\t\n Abdominal pain\t21/7\t19/6\t7/2\t4/0\t24/9\t25/10\t24/8\t22/5\t\n Stomatitis\t17/0\t4/<1\t46/0\t2/0\t12/0\t2/1\t8/0\t6/0\t\n Pyrexia\t16/1\t16/<1\t23/0\t20/0\t12/1\t23/0\t18/2\t11/1\t\n Rash\t14/1\t14/1\t21/0\t32/2\t8/1\t16/1\t13/1\t7/1\t\n Asthenia\t14/5\t13/2\t0\t0\t12/11\t12/2\t23/6\t21/3\t\n Weight decreased\t14/<1\t10/<1\t21/0\t11/2\t9/0\t16/0\t14/1\t10/0\t\n Alopecia\t10/0\t6/0\t25/0\t11/0\t1/0\t5/0\t7/0\t6/0\t\n Dyspnea\t9/2\t8/3\t0\t7/2\t20/7\t12/5\t8/0\t8/3\t\n Edema peripheral\t8/0\t16/1\t2/0\t11/2\t13/0\t33/0\t6/0\t9/0\t\n Hand–foot syndrome\t6/<1\t1/0\t25/2\t2/0\t0\t0\t2/0\t1/0\t\nHematologic abnormalities\t\n Neutropeniaa\t24 /17\t18/11\t9/7\t7/5\t21/15\t20/12\t25/17\t17/11\t\n Thrombocytopeniab\t16/5\t12/3\t0\t0\t27/9\t21/7\t11/2\t13/2\t\n Platelet count decreasedb\t14/4\t13/4\t51/14\t38/13\t11/4\t14/4\t2/0\t4/0\t\n Neutrophil count decreaseda\t10/7\t13/9\t42/32\t50/39\t8/3\t7/5\t1/1\t4/2\t\n Anemiac\t9/1\t18/3\t0\t0\t12/3\t27/5\t10/0\t23/2\t\n White blood cell count decreased\t7/1\t5/1\t30/4\t21/7\t1/1\t1/0\t1/1\t0\t\n Hemoglobin decreasedc\t6/1\t9/2\t21/2\t23/2\t7/3\t11/2\t0\t4/1\t\nGem, gemcitabine\n\naUsing terminology of neutropenia or neutrophil count decreased was based on physician's discretion.\n\nbUsing terminology of thrombocytopenia or platelet count decreased was based on physician's discretion.\n\ncUsing terminology of anemia or hemoglobin decreased was based on physician's discretion.\n\n\n\nIn Japanese patients, axitinib/gemcitabine treatment was associated with higher (>20%) incidence of all-causality fatigue, diarrhea, hypertension, dysphonia, stomatitis and hand–foot syndrome than with placebo/gemcitabine treatment. In addition, hypothyroidism and proteinuria were more common in Japanese patients treated with axitinib/gemcitabine compared with placebo/gemcitabine (hypothyroidism: 8.8 vs. 1.8%; proteinuria: 15.8 vs. 5.4%), but the majority were Grades 1–2.\n\nAEs that led to discontinuation of axitinib treatment in Japanese patients were fatigue, general physical health deterioration, pneumonia, anorexia, neoplasm progression, gastrointestinal perforation and intestinal fistula (one patient [1.8%] each). General disorders (8.0%), including asthenia (4.0%), gastrointestinal disorders (4.0%) and psychiatric disorders (2.7%), were the reasons for axitinib treatment discontinuation in patients in North America, and general disorders (3.9%), including disease progression (2.4%), and hepatobiliary disorders (2.4%), among patients in the European Union.\n\nExploratory analysis for relationship between OS and hypertension\nThe results indicated that there were no notable differences in OS between axitinib/gemcitabine-treated patients who experienced hypertension (maximum diastolic BP ≥90 mm Hg) during Cycle 1 compared with those who did not develop hypertension in the overall study population, in North America or the European Union (Fig. 2A, C and D). Among Japanese patients treated with axitinib/gemcitabine, OS seemed to be slightly longer in those who experienced hypertension than those who did not (Fig. 2B). However, it is unlikely of clinical significance since it was similar to that in placebo/gemcitabine-treated Japanese patients who did not experience hypertension.\nFigure 2. Kaplan–Meier estimates for overall survival by maximum diastolic blood pressure during Cycle 1 for axitinib/gemcitabine vs. placebo/gemcitabine in the overall study population (A), and in patients in Japan (B), North America (C) and the European Union (D).\n\n\n\nDiscussion\nThe current analysis by region (Japan, North America and the European Union) of the Phase III trial of axitinib in combination with gemcitabine in patients with advanced pancreatic cancer revealed several findings. First, a combination treatment of axitinib and gemcitabine did not improve OS over gemcitabine alone in Japanese patients with advanced pancreatic cancer, which is consistent with results reported in the overall study population (9). Similarly, no survival benefit of adding axitinib to gemcitabine was observed in patients in North America or in the European Union. Second, although the previous Phase II open-label randomized study suggested greater survival benefit of axitinib/gemcitabine in patients with locally advanced than metastatic pancreatic cancer (8), this Phase III study failed to confirm better survival in patients with locally advanced disease in any of the three regions. Third, no difference was found for PFS between the two treatment arms in each region. Although the use of follow-up systemic treatment ranged between 9.1% and 22.2% in the three regions, interpretation of such data to determine their impact on OS would be complicated, given that many of the patients were still on study treatment at the time of the final analysis. It is noteworthy that HR for OS was close to 2 for locally advanced disease and ∼1 for metastatic disease in each region. These results suggested that patients with locally advanced and those with metastatic disease might not respond to study treatment in the same way and thus should be evaluated separately in a clinical study, as has been done in some other Phase III studies (10,11).\n\nAlthough the lack of efficacy with the combination therapy was consistent across the three regions evaluated, we observed some geographic differences in clinical practice as well as baseline characteristics of patients enrolled in the study. Patients in Japan received gemcitabine treatment for the longest duration (5 and 4 cycles started and 119 and 99 days on gemcitabine treatment in the axitinib/gemcitabine and placebo/gemcitabine arms, respectively) and those in North America were the shortest (2 and 3 cycles started and 43 and 71 days, respectively). Generally, longer treatment duration as observed with gemcitabine in Japanese patients in this study may contribute to the better efficacy. The majority of patients in Japan (78 and 77% in the axitinib/gemcitabine vs. placebo/gemcitabine arm, respectively) had ECOG PS 0, in contrast to 38% of patients in either arm in North America. The percentage of patients who had locally advanced rather than metastatic disease was highest in Japan (31 and 34% in the axitinib/gemcitabine vs. placebo/gemcitabine arm, respectively) and lowest in North America (20% in either arm), which might have impacted treatment duration. During treatment, the percentage of Japanese patients with axitinib dose reduction or dose interruption was higher than that in the other two regions, and conversely, a lower percentage of Japanese patients had axitinib dose increase. It is noteworthy that axitinib plasma exposures were similar between Japanese and Caucasian subjects (12,13). Thus, axitinib pharmacokinetics does not seem to account for the higher rate of axitinib dose decrease or the lower rate of axitinib dose increase in Japanese patients. The higher percentage of patients with dose reduction for gemcitabine or axitinib in Japan than in the other two regions could be partly explained by the fact that Japanese patients were on treatment longer, and thus, had more opportunities for dose reduction.\n\nCommon AEs experienced by Japanese patients treated with placebo/gemcitabine in this study included anorexia, fatigue and gastrointestinal and hematologic toxicities, which were similar to those reported previously in Japanese patients with advanced pancreatic cancer treated with gemcitabine (14–16). Addition of axitinib to gemcitabine was associated with ≥20% increase in the incidence of dysphonia, stomatitis, hypertension, fatigue, diarrhea and hand–foot syndrome in Japanese patients, but not among patients in North America or the European Union. Decreased platelet counts, neutrophil counts, white blood cell counts and hemoglobin levels were more frequently reported by Japanese patients treated with either axitinib/gemcitabine or placebo/gemcitabine compared with patients in North America or the European Union. On the other hand, neutropenia, thrombocytopenia and anemia were more common in patients in North America and the European Union. In light of the fact that axitinib plasma exposures were similar between Japanese and Caucasian (12,13), it is unclear whether differences in some AEs between Japanese patients and patients from the other two regions indicate pharmacogenomic differences. Additionally, the use of different terminologies (e.g. ‘neutropenia’ vs. ‘decreased neutrophil count’) by the investigators in different regions might have led to some extent to the different incidence rates of hematologic toxicities. Although there were some notable differences in the incidence of some AEs, the current analysis showed that the safety profile of axitinib in Japanese patients was generally comparable to that observed in patients in North America or the European Union.\n\nHypertension is a known AE associated with axitinib treatment, and a correlation between BP and efficacy outcome has been shown in axitinib-treated patients with advanced renal cell carcinoma (13,17). An exploratory analysis of data from the Phase II study of axitinib/gemcitabine suggested a possible association between hypertension and OS in advanced pancreatic cancer (8). However, the current analysis did not reveal any significant relationship.\n\nThe limitation of the current analyses is that follow-up period in this Phase III study was short, and consequently, there were few events that had occurred before the study was terminated. Hence, OS did not mature at the time of the interim analysis. The lack of efficacy for the combination therapy seen here, however, is in line with disappointing results reported in other randomized Phase III studies of gemcitabine in combination with two other antiangiogenic agents, bevacizumab or sorafenib (18–20). These results suggest antiangiogenic agents, including axitinib, do not appear to enhance the survival of patients with advanced pancreatic cancer when combined with gemcitabine. Hence, novel agents with different mode of action and/or new approaches are needed to improve survival in these patients.\n\nIn conclusion, the addition of axitinib to gemcitabine did not improve OS in patients with advanced pancreatic cancer in Japan, North America or the European Union. Although incidence rates for some AEs differed between patients in Japan and those in the other regions, the nature of common AEs and overall safety profile were generally similar.\n\nSupplementary data\nSupplementary data are available at http://www.jjco.oxfordjournals.org\n\nFunding\nThis work was funded by Pfizer Inc. Funding to pay the Open Access publication charges for this article was provided by Pfizer Japan Inc.\n\nConflict of interest statement\nTatsuya Ioka has management/advisory affiliation with Chugai Pharmaceutical. Takuji Okusaka received speaker honoraria and research funding from Pfizer. Shinichi Ohkawa, Narikazu Boku and Akira Sawaki have no conflict of interest to disclose. Yosuke Fujii, Yoichi Kamei, and Satori Takahashi are employed by Pfizer Japan. Katsushi Namazu and Yoshiko Umeyama are employed by Pfizer Japan and own stock in Pfizer. Paul Bycott is employed by and owns stock in Pfizer. Junji Furuse received consulting fees from Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly Japan, Pfizer, Bayer Pharmaceutical, and Zeria Pharmaceutical.\n\nSupplementary Material\nSupplementary Data\n Acknowledgements\nWe thank Hiroko Godai of Pfizer Japan Inc. for data analysis. Medical writing support was provided by Mariko Nagashima, PhD, of Engage Scientific Solutions (Southport, CT) and was funded by Pfizer Inc.\n==== Refs\nReferences\n1 Ferlay J Soerjomataram I Ervik M \n[Internet]. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. 2013 [cited 2014 January 31] \nLyon, France : International Agency for Research on Cancer (EUCAN) \nAvailable from : http://globocan.iarc.fr .\n2 National Comprehensive Cancer Network (NCCN) . [Internet]. NCCN Clinical Practice Guidelines in Oncology. Pancreatic Adenocarcinoma, V.I.2014 [cited 2014 January 14] \nFort Washington, PA : NCCN \nAvailable from : http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf .\n3 Siegel R Ma J Zou Z Jemal A \nCancer statistics, 2014 . CA Cancer J Clin \n2014 ;64 :9 –29 .24399786 \n4 Itakura J Ishiwata T Friess H \nEnhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression . Clin Cancer Res \n1997 ;3 :1309 –16 .9815813 \n5 Seo Y Baba H Fukuda T Takashima M Sugimachi K \nHigh expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma . Cancer \n2000 ;88 :2239 –45 .10820344 \n6 Kuwahara K Sasaki T Kuwada Y Murakami M Yamasaki S Chayama K \nExpressions of angiogenic factors in pancreatic ductal carcinoma: a correlative study with clinicopathologic parameters and patient survival . Pancreas \n2003 ;26 :344 –9 .12717266 \n7 Hu-Lowe DD Zou HY Grazzini ML \nNonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3 . Clin Cancer Res \n2008 ;14 :7272 –83 .19010843 \n8 Spano JP Chodkiewicz C Maurel J \nEfficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study . Lancet \n2008 ;371 :2101 –8 .18514303 \n9 Kindler HL Ioka T Richel DJ \nAxitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study . Lancet Oncol \n2011 ;12 :256 –62 .21306953 \n10 Conroy T Desseigne F Ychou M \nFOLFIRINOX versus gemcitabine for metastatic pancreatic cancer . N Engl J Med \n2011 ;364 :1817 –25 .21561347 \n11 Von Hoff DD Ervin T Arena FP \nIncreased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine . N Engl J Med \n2013 ;369 :1691 –703 .24131140 \n12 Pithavala YK Tortorici M Toh M \nEffect of rifampin on the pharmacokinetics of Axitinib (AG-013736) in Japanese and Caucasian healthy volunteers . Cancer Chemother Pharmacol \n2010 ;65 :563 –70 .19603168 \n13 Rini BI Garrett M Poland B \nAxitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis . J Clin Pharmacol \n2013 ;53 :491 –504 .23553560 \n14 Nakai Y Isayama H Sasaki T \nA multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study . Br J Cancer \n2012 ;106 :1934 –9 .22555398 \n15 Ozaka M Matsumura Y Ishii H \nRandomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study) . Cancer Chemother Pharmacol \n2012 ;69 :1197 –204 .22249272 \n16 Ueno H Ioka T Ikeda M \nRandomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study . J Clin Oncol \n2013 ;31 :1640 –8 .23547081 \n17 Motzer RJ Escudier B Tomczak P \nAxitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial . Lancet Oncol \n2013 ;14 :552 –62 .23598172 \n18 Kindler HL Niedzwiecki D Hollis D \nGemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303) . J Clin Oncol \n2010 ;28 :3617 –22 .20606091 \n19 Goncalves A Gilabert M Francois E \nBAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer . Ann Oncol \n2012 ;23 :2799 –805 .22771827 \n20 Van Cutsem E Vervenne WL Bennouna J \nPhase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer . J Clin Oncol \n2009 ;27 :2231 –7 .19307500\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0368-2811",
"issue": "45(5)",
"journal": "Japanese journal of clinical oncology",
"keywords": "Japanese; axitinib; gemcitabine; pancreatic cancer",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077784:Axitinib; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005062:European Union; D005260:Female; D006801:Humans; D007093:Imidazoles; D007191:Indazoles; D007564:Japan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009656:North America; D016017:Odds Ratio; D010190:Pancreatic Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "439-48",
"pmc": null,
"pmid": "25647781",
"pubdate": "2015-05",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "10820344;24399786;9815813;18514303;19010843;19307500;19603168;20606091;21306953;21561347;22249272;22555398;22771827;23553560;23547081;23598172;24131140;12717266",
"title": "Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial.",
"title_normalized": "efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer subgroup analyses by region including japan from the global randomized phase iii trial"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP01227",
"fulfillexpeditecriteria": "1",
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{
"abstract": "BACKGROUND\nOral corticosteroids remain the mainstay of treatment for moderately active ulcerative colitis (UC). In patients who fail to respond to oral corticosteroids, attempting the intravenous route before starting rescue therapies is an alternative, although no evidence supports this strategy.\n\n\nOBJECTIVE\nTo evaluate clinical outcomes after a course of intravenous corticosteroids for moderate attacks of UC according to the failed oral corticosteroids or not.\n\n\nMETHODS\nAll episodes of active UC admitted to three university hospitals between January 2005 and December 2011 were identified and retrospectively reviewed. Only moderately active episodes treated with intravenous corticosteroids were included. Treatment outcome was compared between episodes which failed to outpatient oral corticosteroids for the index flare and those directly treated by intravenous corticosteroids.\n\n\nRESULTS\n110 episodes were included, 45% of which failed to outpatient oral corticosteroids (median dose 60mg/day [IQR 50-60], median length of course 10days [IQR 7-17]). Initial response (defined as mild severity or inactive disease at day 7 after starting intravenous corticosteroids, without rescue therapy) was achieved in 75%, with no between-group differences (78% vs. 75%). After a median follow-up of 12months (IQR 4-24), 35% of the initial responders developed steroid-dependency and up to 13% required colectomy. Unsuccessful response to oral corticosteroids was the only factor associated with steroid-dependency in the long term (P=0.001).\n\n\nCONCLUSIONS\nIntravenous corticosteroids are efficient for inducing remission in moderately active UC unresponsive to oral corticosteroids, but almost half of these patients develop early steroid-dependency. Alternative therapeutic strategies should be assessed in this clinical setting.",
"affiliations": "Hospital de la Santa Creu i Sant Pau (Barcelona), Universitat Autònoma de Barcelona, Catalonia, Spain.;Hospital Universitari Germans Trias i Pujol (Badalona), CiberEHD, Catalonia, Spain.;Hospital Universitari de Bellvitge, IDIBELL (L'Hospitalet de Llobregat), Catalonia, Spain.;Hospital de la Santa Creu i Sant Pau (Barcelona), Universitat Autònoma de Barcelona, Catalonia, Spain; Hospital Universitari Germans Trias i Pujol (Badalona), CiberEHD, Catalonia, Spain.;Hospital Universitari Germans Trias i Pujol (Badalona), CiberEHD, Catalonia, Spain.;Hospital Universitari de Bellvitge, IDIBELL (L'Hospitalet de Llobregat), Catalonia, Spain.;Hospital Universitari Germans Trias i Pujol (Badalona), CiberEHD, Catalonia, Spain.;Hospital de la Santa Creu i Sant Pau (Barcelona), Universitat Autònoma de Barcelona, Catalonia, Spain.;Hospital Universitari de Bellvitge, IDIBELL (L'Hospitalet de Llobregat), Catalonia, Spain.;Hospital Universitari Germans Trias i Pujol (Badalona), CiberEHD, Catalonia, Spain. Electronic address: eugenidomenech@gmail.com.",
"authors": "Llaó|Jordina|J|;Naves|Juan E|JE|;Ruiz-Cerulla|Alexandra|A|;Marín|Laura|L|;Mañosa|Míriam|M|;Rodríguez-Alonso|Lorena|L|;Cabré|Eduard|E|;Garcia-Planella|Esther|E|;Guardiola|Jordi|J|;Domènech|Eugeni|E|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000069285:Infliximab; D011241:Prednisone; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "8(11)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Corticosteroids; Intravenous; Oral; Refractory; Ulcerative colitis",
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D003082:Colectomy; D003093:Colitis, Ulcerative; D016572:Cyclosporine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D011241:Prednisone; D019233:Retreatment; D012189:Retrospective Studies; D012720:Severity of Illness Index; D017211:Treatment Failure",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "1523-8",
"pmc": null,
"pmid": "25066954",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intravenous corticosteroids in moderately active ulcerative colitis refractory to oral corticosteroids.",
"title_normalized": "intravenous corticosteroids in moderately active ulcerative colitis refractory to oral corticosteroids"
} | [
{
"companynumb": "ES-FRESENIUS KABI-FK201504694",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional":... |
{
"abstract": "We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43-0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36-0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25-0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478.",
"affiliations": "Medical University of Vienna, Dept. of Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center, Vienna, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria ulrich.jaeger@meduniwien.ac.at.;Institute of Hematology and Blood Transfusion, 1st Dept. of Medicine, 1st Faculty of Medicine, Charles University, General Hospital, Czech Lymphoma Study Group, Praha, Czech Republic.;Medical University of Vienna, Dept. of Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center, Vienna, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;Assign Data Management and Biostatistics GmbH Assign Group, Innsbruck, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;Dept. of Internal Medicine, Faculty of Medicine, Chiang Mai University, Thailand.;Dept. of Hematology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Australasian Leukaemia & Lymphoma Group, East Melbourne, Australia.;Clinic for Hematology, Clinical Center Serbia, Belgrade, Serbia.;Ankara University School of Medicine, Dept. of Hematology, Ankara, Turkey.;NOU, Klenova Bratislava, Slovakia.;Dept. of Internal Medicine, Sundsvall Hospital, Sweden.;Division of Hematology and Oncology, Dept. of Medicine, Taipei Veterans General Hospital, and National Yang-Ming University, Taipei, Taiwan.;University Medical Unit, Queen Mary Hospital, Hong Kong, China.;Dept. of Internal Medicine IV, Wels-Grieskirchen Hospital, Wels, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;1st Medical Dept., Landesklinikum Wiener Neustadt, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;3rd Medical Dept., Hanusch Hospital, Vienna, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;LBI-ACR & ACR-ITR Vienna, Kaiser Franz Josef-Spital, Vienna, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;Medical University of Vienna, Dept. of Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center, Vienna, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;Assign Data Management and Biostatistics GmbH Assign Group, Innsbruck, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;Institute of Pathology and Microbiology, Wilhelminenspital, Vienna, Austria.;3rd Dept. of Medicine, AKH-Linz, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.;Dept. of Internal Medicine III, Private Medical University of Salzburg, Austria Arbeitsgemeinschaft Medikamentöse Tumortherapie, AGMT, Salzburg, Austria.",
"authors": "Jaeger|Ulrich|U|;Trneny|Marek|M|;Melzer|Helen|H|;Praxmarer|Michael|M|;Nawarawong|Weerasak|W|;Ben Yehuda|Dina|D|;Goldstein|David|D|;Mihaljevic|Bilijana|B|;Ilhan|Osman|O|;Ballova|Veronika|V|;Hedenus|Michael|M|;Hsiao|Liang-Tsai|LT|;Au|Wing-Yan|WY|;Burgstaller|Sonja|S|;Weidinger|Gerhard|G|;Keil|Felix|F|;Dittrich|Christian|C|;Skrabs|Cathrin|C|;Klingler|Anton|A|;Chott|Andreas|A|;Fridrik|Michael A|MA|;Greil|Richard|R|;|||",
"chemical_list": "D000069283:Rituximab",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2015.125344",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "100(7)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D057194:Intention to Treat Analysis; D008224:Lymphoma, Follicular; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D000069283:Rituximab; D012737:Sex Factors; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "955-63",
"pmc": null,
"pmid": "25911553",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "16754935;16524969;18400558;19211444;19567453;20713859;21176949;21062969;21300984;21940214;22057732;22305028;22337718;22252721;22511498;22649138;23091101;23175624;24297867;24550425;24493716;24928834;25113753;25403207;18226581;16648042;10561185;11807147;8141877;7477169;9704731;15955905",
"title": "Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial.",
"title_normalized": "rituximab maintenance for patients with aggressive b cell lymphoma in first remission results of the randomized nhl13 trial"
} | [
{
"companynumb": "AT-JNJFOC-20160602179",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Pregnancy results in many physiologic changes that can alter the pharmacokinetic profiles of medications used during pregnancy. One of the primary factors leading to these pharmacokinetic changes is altered activity of drug-metabolizing enzymes. Ondansetron is a substrate of cytochrome P450 (CYP) 3A4 (primary metabolic pathway), 2D6, and 1A2, all of which are altered during pregnancy. We evaluated the pharmacokinetics of ondansetron at three different gestational time points in a 26-year-old, pregnant, Caucasian woman with normal liver and kidney function, who was maintained on ondansetron 8 mg administered orally 3 times/day throughout her pregnancy. Serial plasma samples were collected from the subject over one 8-hour dosing interval at 14, 24, and 35 weeks' gestation (representing early-, mid-, and late-pregnancy time points, respectively). Ondansetron plasma concentrations were determined using liquid chromatography-tandem mass spectrometry. Ondansetron area under the plasma concentration-time curve decreased progressively across gestation (634 ng hr/ml in early pregnancy, 553 ng hr/ml in mid-pregnancy, and 387 ng hr/ml in late pregnancy), with a corresponding increase in apparent oral clearance (12.6 L/hr in early-pregnancy, 14.5 L/hr in mid-pregnancy, and 20.7 L/hr in late-pregnancy). The decreased area under the plasma concentration-time curve and exposure to ondansetron across gestation is likely due to increased activity of CYP3A4 and CYP2D6 during pregnancy. We were not able to study this patient during the postpartum period; however, as with other CYP3A4 and CYP2D6 substrates, the apparent activities of these isoenzymes are likely return to baseline. To our knowledge, this is the first report to describe ondansetron pharmacokinetics across gestation. Additional pharmacokinetic and pharmacodynamic data are needed to confirm our results and to evaluate clinical impact; however, in the meantime, clinicians should be aware of these pharmacokinetic changes in ondansetron exposure during pregnancy.",
"affiliations": "Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Pharmaceutical Science, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.;Departments of Pharmacy and Obstetrics, and Gynecology, University of Washington, Seattle, Washington.;Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas.;Department of Obstetrics and Gynecology Medicine, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Pharmaceutical Science, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania. rv@pitt.edu.",
"authors": "Lemon|Lara S|LS|;Zhang|Hongfei|H|;Hebert|Mary F|MF|;Hankins|Gary D|GD|;Haas|David M|DM|;Caritis|Steve N|SN|;Venkataramanan|Raman|R|",
"chemical_list": "D017294:Ondansetron; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1796",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "36(9)",
"journal": "Pharmacotherapy",
"keywords": "ondansetron; pharmacokinetics; pregnancy",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000328:Adult; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D005260:Female; D006801:Humans; D017294:Ondansetron; D011247:Pregnancy",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e139-41",
"pmc": null,
"pmid": "27374186",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports",
"references": "7586904;25281357;26452316;26053159;15696014",
"title": "Ondansetron Exposure Changes in a Pregnant Woman.",
"title_normalized": "ondansetron exposure changes in a pregnant woman"
} | [
{
"companynumb": "US-APOTEX-2017AP017121",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ONDANSETRON HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "As no standard chemotherapy exists for pancreatoblastoma (PB), surgical resection is the most effective way of achieving complete remission.\n\n\n\nA 3-year-old girl with PB causing portal vein obstruction was referred to our hospital. Because of the portal vein involvement, she initially received 5 cycles of preoperative chemotherapy after biopsy, consisting of cyclophosphamide, vincristine, pirarubicin, and cisplatin. After chemotherapy, she underwent distal pancreatectomy, and the tumor was resected completely. She has been disease free for 4 years since the operation.\n\n\n\nEven in cases of advanced PB, complete surgical resection with appropriate chemotherapy can lead to complete remission.",
"affiliations": "*Departments of Pediatric Surgery †Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.",
"authors": "Ibuka|Souji|S|;Uehara|Shuichiro|S|;Ueno|Takehisa|T|;Oue|Takaharu|T|;Miyamura|Takako|T|;Hashii|Yoshiko|Y|;Okuyama|Hiroomi|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000842",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "39(5)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D011169:Portal Vein; D012074:Remission Induction; D014689:Venous Insufficiency",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e275-e278",
"pmc": null,
"pmid": "28538503",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complete Resection of Pancreatoblastoma With Portal Vein Obstruction After High-dose Chemotherapy: A Case Report.",
"title_normalized": "complete resection of pancreatoblastoma with portal vein obstruction after high dose chemotherapy a case report"
} | [
{
"companynumb": "JP-TEVA-824838ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Although novel agents have changed the treatment landscape of multiple myeloma (MM), cytotoxic chemotherapy regimens continue to have a role in aggressive or rapidly progressive disease. In such cases, our institution has utilized a hyperfractionated cyclophosphamide regimen (termed mCAD), similar to hyper-CVAD, in which vincristine is omitted or replaced with a proteasome inhibitor (PI), either bortezomib or carfilzomib. On occasion, doxorubicin is also omitted because of patient history and provider preference.\n\n\n\nWe retrospectively reviewed the charts of adult patients with MM receiving mCAD regimens at our institution between 2012 and 2016 and analyzed utilization patterns, toxicity profiles, and clinical outcomes.\n\n\n\nA total of 131 patients received mCAD, including 9% for newly diagnosed MM (NDMM), 18% attempting to optimize response to frontline therapy (OPT-MM), and 73% for treatment of relapsed/refractory MM (RRMM). Renal dysfunction was common; 31% had estimated glomerular filtration rate < 50 mL/min and 14% were dialysis dependent. The overall response rate was 83%, 63%, and 67% with a median progression-free survival of 17.4, 23.7, and 4.2 months, respectively, for NDMM, OPT-MM, and RRMM. Median overall survival was not reached for NDMM or OPT-MM, and was 15.2 months for RRMM. Most patients (90%) bridged to subsequent therapy, including 32% who proceeded to autologous transplantation. Hematologic, infectious, and cardiac toxicities were common and were similar to those expected for cytotoxic chemotherapy.\n\n\n\nmCAD regimens were safe and active across patient groups, including patients with renal dysfunction. Most patients were able to bridge to subsequent therapy.",
"affiliations": "Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.;Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.;Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.;School of Pharmacy, University of California, San Francisco, San Francisco, CA.;School of Pharmacy, University of California, San Francisco, San Francisco, CA.;School of Pharmacy, University of California, San Francisco, San Francisco, CA.;School of Pharmacy, University of California, San Francisco, San Francisco, CA.;Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.;Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.;Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.;Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.;Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA. Electronic address: Jeffrey.Wolf@ucsf.edu.",
"authors": "Narayan|Rupa|R|;Galligan|Derek|D|;Lazar|Ann A|AA|;Kim|Sarah|S|;Fong|Richard|R|;Tan|Marisela|M|;Lo|Mimi|M|;Arora|Shagun|S|;Shah|Nina|N|;Wong|Sandy W|SW|;Martin|Thomas|T|;Wolf|Jeffrey|J|",
"chemical_list": "D061988:Proteasome Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2020.07.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "20(12)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Bortezomib; Carfilzomib; Chemotherapy; Renal failure; Renal insufficiency",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D061988:Proteasome Inhibitors; D012189:Retrospective Studies",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e961-e985",
"pmc": null,
"pmid": "32839138",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Modified Hyper-CVAD With Proteasome Inhibition for Multiple Myeloma: A Single-Center Retrospective Analysis.",
"title_normalized": "modified hyper cvad with proteasome inhibition for multiple myeloma a single center retrospective analysis"
} | [
{
"companynumb": "US-AMGEN-USASP2020142401",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IXAZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTuberculosis (TB) is associated with high morbidity and mortality in solid organ transplant (SOT) recipients. Also, SOT patients have a 20- to 74-fold increase in the chance of developing TB compared to the general population. Here we evaluated the incidence of hepatotoxicity in SOT recipients on treatment for TB and determined risk factors for liver toxicity in these patients.\n\n\nMETHODS\nRetrospective cohort conducted in a reference hospital for SOT in Southern Brazil. All SOT recipients who underwent TB treatment during the years 2000-2012 were considered for the study.\n\n\nRESULTS\nA total of 69 patients were included in the study and 23 had liver toxicity (incidence 33.3%). Independent risk factors for hepatotoxicity were rifampin use at doses of ≥600 mg daily (P = .016; OR 2.47; 95% CI, 1.18-5.15) and lung transplantation (P = .017; OR 2.05; 95% CI, 1.14-3.70). Kidney transplantation appeared as a protective factor (P = .036; OR 0.50; 95% CI, 0.26-0.96). Mortality was higher in the patients who had hepatotoxicity (43.5%), compared with those who did not (19.6%).\n\n\nCONCLUSIONS\nIn this study, the use of rifampin at doses of 600 mg daily or higher was found to be an independent risk factor for liver toxicity in SOT recipients. The importance of additional risk factors for hepatotoxicity, such as lung transplantation as well as the protective role of kidney transplantation, should be better investigated in SOT recipients being treated for TB.",
"affiliations": "Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil.;Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil; Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil.;Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil.;Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil.;Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil; Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil. Electronic address: pasqualotto@santacasa.tche.br.",
"authors": "Schultz|V|V|;Marroni|C A|CA|;Amorim|C S|CS|;Baethgen|L F|LF|;Pasqualotto|A C|AC|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000995:Antitubercular Agents; D001938:Brazil; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D014376:Tuberculosis",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3606-10",
"pmc": null,
"pmid": "25498098",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk factors for hepatotoxicity in solid organ transplants recipients being treated for tuberculosis.",
"title_normalized": "risk factors for hepatotoxicity in solid organ transplants recipients being treated for tuberculosis"
} | [
{
"companynumb": "BR-JNJFOC-20150417544",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "A 27-year-old man treated with quetiapine for anxiety disorder developed hypertriglyceridaemia-induced acute pancreatitis and diabetic ketoacidosis. He was otherwise physically healthy with no family history of hyperlipidaemia. Despite aggressive intensive therapy he died of multiorgan failure within 36 h from initial presentation. While second-generation antipsychotics are well known to be causally linked to diabetes and hyperlipidaemia, this is to my knowledge the first-described case of a fatal triad of extreme hypertriglyceridaemia, acute pancreatitis and diabetic ketoacidosis possibly induced by quetiapine. Clinicians should be aware of this rare clinical presentation since rapid progression to multiorgan failure can occur. Early supportive therapy should be initiated. Lactescent serum and ketoacidosis in severe acute pancreatitis should not be overlooked-initiate insulin therapy and possibly plasmapheresis in case of extreme hypertriglyceridaemia.",
"affiliations": "Multidisciplinary Intensive Care, Odense University Hospital, Odense, Denmark.",
"authors": "Madsen|Kristian Roerbaek|KR|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001008:Anxiety Disorders; D057210:Delayed Diagnosis; D016883:Diabetic Ketoacidosis; D003937:Diagnosis, Differential; D003987:Dibenzothiazepines; D004305:Dose-Response Relationship, Drug; D017809:Fatal Outcome; D006801:Humans; D015228:Hypertriglyceridemia; D008297:Male; D010179:Pancreas; D019283:Pancreatitis, Acute Necrotizing; D010698:Phobic Disorders; D011618:Psychotic Disorders; D000069348:Quetiapine Fumarate; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24403385",
"pubdate": "2014-01-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15118491;16940728;19724733;23278567",
"title": "Fatal hypertriglyceridaemia, acute pancreatitis and diabetic ketoacidosis possibly induced by quetiapine.",
"title_normalized": "fatal hypertriglyceridaemia acute pancreatitis and diabetic ketoacidosis possibly induced by quetiapine"
} | [
{
"companynumb": "DK-ROXANE LABORATORIES, INC.-2014-RO-01659RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
"... |
{
"abstract": "Clear cell carcinoma (CCC) of the uterus is a rare but aggressive histology for which the role of adjuvant therapy for stage I-II disease is unclear. Our study investigated outcomes and patterns of failure in these patients.\n\n\n\nWe found 64 cases of CCC, including 26 of pure CCC, 22 mixed with endometrioid adenocarcinoma, and 16 mixed with uterine papillary serous carcinoma. Adjuvant treatment was given to 55%.\n\n\n\nMedian follow-up was 51.9 months. By Kaplan-Meier estimate, 5-year vaginal recurrence-free survival (RFS) was 91.3%, pelvic RFS was 92.6%, distant metastasis RFS was 81.6%, disease-free survival was 79.6%, and overall survival was 79.7%. Median time to recurrence was 20.7 months (range, 2 to 40.5 mo). Patients treated adjuvantly had higher proportion of stage II disease (40% vs. 6.9% observed, P=0.0031) and 20% (7/35) recurred. There were no significant differences in outcomes by histologic subtypes but numerically more recurrences with uterine papillary serous involvement. By univariate analysis, higher stage, presence of lymphovascular invasion, and lack of lymph node dissection were predictive of worse overall survival. Age 65 years and above was predictive of worse cancer-specific survival. Of 12 who progressed, only 1 was salvaged and 11 died of disease. Of progressors, 10 had documented distant metastasis. Median time from recurrence to death was 4.5 months (range, 0.2 to 21.2 mo).\n\n\n\nGiven aggressive and often unsalvageable nature of recurrence, consideration of adjuvant treatment (including chemotherapy and radiation) is warranted for early-stage CCC, particularly for stage II or those with poor prognostic factors.",
"affiliations": "Departments of Radiation Oncology.;Pathology, Kaiser Permanente Southern California, Los Angeles, CA.;Departments of Radiation Oncology.",
"authors": "Chang-Halpenny|Christine N|CN|;Natarajan|Sathima|S|;Hwang-Graziano|Julie M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0000000000000277",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "41(4)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D018262:Adenocarcinoma, Clear Cell; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059186:Chemoradiotherapy, Adjuvant; D018284:Cystadenocarcinoma, Serous; D016889:Endometrial Neoplasms; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D015996:Survival Rate; D014594:Uterine Neoplasms",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "371-378",
"pmc": null,
"pmid": "26950465",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Early-stage Uterine Pure and Mixed Clear Cell Carcinoma: Outcomes and Recurrence With and Without Adjuvant Therapy.",
"title_normalized": "early stage uterine pure and mixed clear cell carcinoma outcomes and recurrence with and without adjuvant therapy"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US16640",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Sphenoid sinus metastasis from hepatocellular carcinoma (HCC) has been reported only rarely. We present a case of solitary sphenoid sinus metastasis of a 2.7 × 2.3 cm single HCC lesion. (Hepatology 2016;63:2050-2053).",
"affiliations": "Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH.;Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH.;Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH.",
"authors": "Lee|Tae Hoon|TH|;Rangan|Vikram|V|;Khallafi|Hicham|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/hep.28516",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "63(6)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D006528:Carcinoma, Hepatocellular; D006801:Humans; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010255:Paranasal Sinus Neoplasms; D013101:Sphenoid Sinus",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "2050-3",
"pmc": null,
"pmid": "26928869",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Sphenoid Sinus Metastasis in Hepatocellular Carcinoma.",
"title_normalized": "a case of sphenoid sinus metastasis in hepatocellular carcinoma"
} | [
{
"companynumb": "US-BAYER-2016-159522",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"... |
{
"abstract": "Four patients refractory to doxorubicin (DX) and 9 patients refractory to 4'epidoxorubicin (4'EpiDX) were treated with verapamil (VRP) (120 mg every 6 h for 3 days) plus 4'EpiDX (80 mg/m2 i.v. bolus, together with the 6th VRP administration). Three patients had partial remissions lasting 3, 3.5 and 7 months, respectively. Toxicity grading did not exceed usual levels. The study demonstrates that VRP, when added at conventional doses to 4'EpiDX, can induce objective responses in some patients refractory to anthracyclines.",
"affiliations": "Divisione di Radioterapia e Oncologia, U.S.S.L. 28, Legnago, Italy.",
"authors": "Demicheli|R|R|;Jirillo|A|A|;Bonciarelli|G|G|;Lonardi|F|F|;Balli|M|M|;Bandello|A|A|",
"chemical_list": "D015251:Epirubicin; D014700:Verapamil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "75(3)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D004351:Drug Resistance; D015251:Epirubicin; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D013964:Thyroid Neoplasms; D014700:Verapamil",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "245-7",
"pmc": null,
"pmid": "2773076",
"pubdate": "1989-06-30",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "4'epidoxorubicin plus verapamil in anthracycline--refractory cancer patients.",
"title_normalized": "4 epidoxorubicin plus verapamil in anthracycline refractory cancer patients"
} | [
{
"companynumb": "IT-PFIZER INC-2020246052",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EPIRUBICIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "The authors report a case of a 15-year-old girl with hypopituitarism due to pituitary stalk interruption syndrome diagnosed in the neonatal period. The patient was admitted to the emergency room with impaired consciousness and hypoglycaemia. The day before, she increased her water intake to about 1.5 L to perform a pelvic ultrasound. In the following hours, she developed vomiting and food refusal. Blood analysis revealed hypoglycaemia, hyponatraemia, decreased serum osmolality and normal urinary density. Hyponatraemia and adrenal crisis were managed with a gradual but slow resolution of consciousness and electrolytic balance. This case describes an episode of iatrogenic water intoxication in a patient under desmopressin treatment. Although uncommon, dilutional hyponatraemia is the main complication of desmopressin treatment. We reinforce the importance of patients and caregivers' long-life education for the potential complications of an increase in fluid intake in patients treated with desmopressin.",
"affiliations": "Department of Endocrinology, Hospital de Braga, Braga, Portugal.;Department of Endocrinology, Hospital de Braga, Braga, Portugal.;Pediatric Endocrinology Unit, Hospital de Braga, Braga, Portugal.;Pediatric Endocrinology Unit, Hospital de Braga, Braga, Portugal.",
"authors": "Monteiro|Ana Margarida|AM|http://orcid.org/0000-0001-9820-1940;Marques|Olinda|O|;Martins|Sofia|S|;Antunes|Ana|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "endocrine system; pituitary disorders; radiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000359:Aftercare; D000893:Anti-Inflammatory Agents; D004326:Drinking; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007003:Hypoglycemia; D007010:Hyponatremia; D007018:Hypopituitarism; D007049:Iatrogenic Disease; D009994:Osmolar Concentration; D016896:Treatment Outcome; D014474:Unconsciousness; D014869:Water Intoxication",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29523609",
"pubdate": "2018-03-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20622630;23843580;27044859;24854529;26051300;27156759;20223403;22734682;23884783;23692728",
"title": "Iatrogenic water intoxication in a female adolescent with hypopituitarism.",
"title_normalized": "iatrogenic water intoxication in a female adolescent with hypopituitarism"
} | [
{
"companynumb": "PT-MYLANLABS-2018M1023544",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DESMOPRESSIN"
},
"drugadditional": "3",
... |
{
"abstract": "Anxiety disorders (ADs) are commonly associated with high-functioning Autism Spectrum Disorder (HF-ASD) and often worsen with age. Buspirone is a commonly prescribed anxiolytic drug with a favorable tolerability profile that may offer potential benefits in anxiety management for patients with HF-ASD. This study examines inadequately explored tolerability and effectiveness of buspirone in treating ADs comorbid with high-functioning ASD.\n\n\n\nA retrospective chart review of a 1-year period was conducted in psychiatrically referred population of HF-ASD youth with AD (age 8-17 years) who were treated with buspirone (N = 31). Information on the demographics and treatment history was recorded. Effectiveness was assessed through the Clinical Global Impressions Scale (CGI) severity (CGI-S) and improvement (CGI-I) scores noted by the treating clinician.\n\n\n\nA total of 31 patients were prescribed buspirone during the determined period, at a mean dose of 41.61 ± 24.10 mg for an average duration of 272 ± 125 days. Change in the CGI-S mean scores with treatment suggests an overall improvement in the severity of anxiety symptoms (MT1 = 4.9 ± 0.7; MT2 = 2.8 ± 0.87; p < 0.001). Significant improvement in anxiety symptoms (CGI-I ≤ 2) was observed in 58% and mild improvement (CGI-I = 3) in 29% of the HF-ASD patients who received buspirone treatment. Buspirone was well tolerated with no adverse events reported by the majority of participants, with the exception of two subjects who developed treatment emergent adverse events (activation and mood lability).\n\n\n\nFindings from this retrospective chart review suggest a promising role of buspirone in managing anxiety among youth with HF-ASD. Further research with prospective and randomized-controlled trials is necessary.",
"affiliations": "1 Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital , Boston, Massachusetts.;1 Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital , Boston, Massachusetts.;1 Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital , Boston, Massachusetts.;1 Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital , Boston, Massachusetts.;1 Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital , Boston, Massachusetts.;1 Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital , Boston, Massachusetts.;1 Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital , Boston, Massachusetts.;1 Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, Massachusetts General Hospital , Boston, Massachusetts.",
"authors": "Ceranoglu|Tolga Atilla|TA|;Wozniak|Janet|J|;Fried|Ronna|R|;Galdo|Maribel|M|;Hoskova|Barbora|B|;DeLeon Fong|Melissa|M|;Biederman|Joseph|J|;Joshi|Gagan|G|",
"chemical_list": "D002065:Buspirone",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2018.0021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "29(1)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": "anxiety; autism spectrum disorder; buspirone; child and adolescent; clinical trial; psychopharmacology",
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D001007:Anxiety; D000067877:Autism Spectrum Disorder; D010054:Brief Psychiatric Rating Scale; D002065:Buspirone; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D011600:Psychopharmacology; D012189:Retrospective Studies",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "28-33",
"pmc": null,
"pmid": "30452283",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24988818;2870640;2723129;9699121;15939837;20309621;17674186;7621695;29076153;26746121;15985922;11098879;17031447;6130069;6130066;16157377;21735077;25451017;16845581;29188907;9394940;9501886;9466232;6130078;19223098",
"title": "A Retrospective Chart Review of Buspirone for the Treatment of Anxiety in Psychiatrically Referred Youth with High-Functioning Autism Spectrum Disorder.",
"title_normalized": "a retrospective chart review of buspirone for the treatment of anxiety in psychiatrically referred youth with high functioning autism spectrum disorder"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP002313",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSPIRONE HYDROCHLORIDE"
},
"dr... |
{
"abstract": "This report describes a case of kaposiform hemangioendothelioma arising in an adult man during the course of rheumatoid arthritis treated with steroids and methotrexate. The vascular proliferation began in the terminal phase of the disease, which culminated in acute renal failure and death. We discuss the possible relationship between rheumatoid arthritis, its treatment, and the onset of vascular proliferation, as well as the role of kaposiform hemangioendothelioma in aggravating the autoimmune disease and leading to its fatal outcome.",
"affiliations": "Department of Anatomic Pathology, Ospedale Fond. Card. Panico, Tricase (LE), Italy.;Dermatology Unit, Ospedale \"Perrino\", Brindisi, Italy.",
"authors": "Filotico|M|M|;Filotico|R|R|",
"chemical_list": "D018501:Antirheumatic Agents; D013256:Steroids; D008727:Methotrexate",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-2983",
"issue": "109(3)",
"journal": "Pathologica",
"keywords": "Kaposiform hemangioendothelioms; Vascular tumors",
"medline_ta": "Pathologica",
"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D006390:Hemangioendothelioma; D006801:Humans; D059885:Kasabach-Merritt Syndrome; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012514:Sarcoma, Kaposi; D013256:Steroids",
"nlm_unique_id": "0401123",
"other_id": null,
"pages": "143-147",
"pmc": null,
"pmid": "29154372",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Kaposiform hemangioendothelioma in an adult with rheumatoid arthritis.",
"title_normalized": "kaposiform hemangioendothelioma in an adult with rheumatoid arthritis"
} | [
{
"companynumb": "IT-PFIZER INC-2017505471",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nRapid drug desensitization is known to be a good strategy in patients with drug hypersensitivity to chemotherapy. However, changes in maximal drug concentration and exposure time in blood through desensitization may alter other adverse reactions and efficacy of the drug. We investigated rapid desensitization for carboplatin in terms of severe adverse drug reactions (ADRs) and efficacy compared with the standard infusion.\n\n\nMETHODS\nA retrospective cohort study was conducted on patients with recurrent ovarian cancer who received carboplatin chemotherapy from 2017 to 2019. We compared serious adverse events (SAEs), ADRs according to organ classes, time to progression (TTP), and overall survival (OS).\n\n\nRESULTS\nOf 108 desensitization procedures performed in 21 patients, 104 were successfully accomplished (96.3%). There were compared with 271 procedures in 41 patients who received the standard infusion method. There were 8 (7.7%) SAEs in the rapid desensitization group and 34 (12.5%) in the control group. One drug-related death occurred in the rapid desensitization group. In the rapid desensitized group, except for neutropenia, there was no statistically significant increase in SAEs and over grade 3 of ADRs according to organ classes compared with the control group. In the efficacy analysis, TTP and OS were similar in the 2 groups.\n\n\nCONCLUSIONS\nRapid desensitization of carboplatin can lower the risk of immediate hypersensitivity reactions without changing the inherent effect and severe ADRs.",
"affiliations": "Department of Allergy and Clinical Immunology, School of Medicine, Kyungpook National University, Daegu, Korea. haan33@gmail.com.;Department of Oncology, School of Medicine, Kyungpook National University, Daegu, Korea. sj.lee@knu.ac.kr.;Department of Allergy and Clinical Immunology, School of Medicine, Kyungpook National University, Daegu, Korea.;Department of Allergy and Clinical Immunology, School of Medicine, Kyungpook National University, Daegu, Korea.;Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Daegu, Korea.",
"authors": "Park|Han Ki|HK|https://orcid.org/0000-0002-5460-9917;Lee|Soo Jung|SJ|https://orcid.org/0000-0003-0066-4109;Kim|Sujeong|S|https://orcid.org/0000-0002-2494-9216;Lee|Jong Myung|JM|https://orcid.org/0000-0001-7019-6051;Hong|Dae Gy|DG|https://orcid.org/0000-0003-4646-9317",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4168/aair.2020.12.6.1046",
"fulltext": "\n==== Front\nAllergy Asthma Immunol Res\nAllergy Asthma Immunol Res\nAAIR\nAllergy, Asthma & Immunology Research\n2092-7355 2092-7363 The Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease \n\n10.4168/aair.2020.12.6.1046\nOriginal Article\nDoes Carboplatin Rapid Desensitization Change Its Adverse Drug Reactions Other than Hypersensitivity and Efficacy in Patients With Ovarian Cancer?\nhttps://orcid.org/0000-0002-5460-9917Park Han-Ki 1 https://orcid.org/0000-0003-0066-4109Lee Soo Jung 2 https://orcid.org/0000-0002-2494-9216Kim Sujeong 1 https://orcid.org/0000-0001-7019-6051Lee Jong-Myung 1 https://orcid.org/0000-0003-4646-9317Hong Dae Gy 3 1 Department of Allergy and Clinical Immunology, School of Medicine, Kyungpook National University, Daegu, Korea.\n2 Department of Oncology, School of Medicine, Kyungpook National University, Daegu, Korea.\n3 Department of Obstetrics and Gynecology, School of Medicine, Kyungpook National University, Daegu, Korea.\nCorrespondence to Han-Ki Park, MD. Department of Allergy and Clinical Immunology, School of Medicine, Kyungpook National University Chilgok Hospital, Hoguk-ro, Buk-gu, Daegu 41404, Korea. Tel: +82-53-200-2617; Fax: +82-53-200-2029; haan33@gmail.comCorrespondence to Soo Jung Lee, MD, PhD. Department of Oncology, School of Medicine, Kyungpook National University Chilgok Hospital, Hoguk-ro, Buk-gu, Daegu 41404, Korea. Tel: +82-53-200-2625; Fax: +82-53-200-2029; sj.lee@knu.ac.kr\n11 2020 \n13 7 2020 \n12 6 1046 1059\n21 4 2020 21 5 2020 26 5 2020 Copyright © 2020 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease2020The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory DiseaseThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nRapid drug desensitization is known to be a good strategy in patients with drug hypersensitivity to chemotherapy. However, changes in maximal drug concentration and exposure time in blood through desensitization may alter other adverse reactions and efficacy of the drug. We investigated rapid desensitization for carboplatin in terms of severe adverse drug reactions (ADRs) and efficacy compared with the standard infusion.\n\nMethods\nA retrospective cohort study was conducted on patients with recurrent ovarian cancer who received carboplatin chemotherapy from 2017 to 2019. We compared serious adverse events (SAEs), ADRs according to organ classes, time to progression (TTP), and overall survival (OS).\n\nResults\nOf 108 desensitization procedures performed in 21 patients, 104 were successfully accomplished (96.3%). There were compared with 271 procedures in 41 patients who received the standard infusion method. There were 8 (7.7%) SAEs in the rapid desensitization group and 34 (12.5%) in the control group. One drug-related death occurred in the rapid desensitization group. In the rapid desensitized group, except for neutropenia, there was no statistically significant increase in SAEs and over grade 3 of ADRs according to organ classes compared with the control group. In the efficacy analysis, TTP and OS were similar in the 2 groups.\n\nConclusions\nRapid desensitization of carboplatin can lower the risk of immediate hypersensitivity reactions without changing the inherent effect and severe ADRs.\n\nDesensitizationhypersensitivityantineoplastic agentscarboplatindrug-related side effects and adverse reactionsdrug effectssurvivalovarian neoplasmKyungpook National University Hospitalhttps://doi.org/10.13039/501100004600\n==== Body\nINTRODUCTION\nImmediate drug hypersensitivity reactions (HSRs), which are manifested as hives, angioedema, rhinitis, bronchospasm, and anaphylactic shock, can occur within 1-6 hours after taking a causative drug.12 These reactions are difficult to predict, progress rapidly, and can lead to life-threatening reactions like anaphylaxis.3 Avoidance is the best way to prevent HSR. Despite, in some cases, knowing that a chemotherapeutic agent may cause immediate drug HSR, re-administration may be considered due to the significant benefit of the drug.\n\nRapid drug desensitization (RDD) is a safe approach to prevent HSRs to chemotherapeutic agents.4 The concept of RDD is to induce temporary non-reactivity by administering the causative drug at a concentration of 1/100 to 1/10,000 of the normal dose depending on the degree of risk, and gradually increasing the infusion rate every 15 to 20 minutes until the target dose is achieved.567 After introduction of RDD, 90% or more patients experienced no breakthrough reaction (BTR) or only mild BTR. Overall health costs between an RDD group and a standard infusion group were not different.89 So, RDD is a safe and efficient method in patients who have experienced immediate HSR to chemotherapeutic agents.\n\nHowever, when the drug is administered by RDD, the administration rate and duration of exposure is changed. Carboplatin is recommended to be administered for 30 minutes to 1 hour, but by RDD, carboplatin will be administered for more than 4 hours, and the final rate will also be different from the standard method.101112 Adjusting the rate of drug administration changes the blood concentration and exposure time of the drug, so it can change adverse drug reactions (ADRs) and efficacy. Twenty-four-hour continuous infusion of amphotericin B reduces renal toxicity and infusion reaction without increasing mortality compared with a 4-hour infusion.13 Doxorubicin administered as a 48-hour or 96-hour continuous intravenous infusion reduced cardiac toxicity.14 Thus, continuous infusion is known as a method of lowering some toxicity by reducing the peak blood drug concentration. However, the ADRs of other chemotherapeutic drugs have been reported to increase due to continuous administration. There has been a meta-analysis of paclitaxel 3-hour and 24-hour infusions. In the 24-hour infusion group, there were more frequent side effects and severe toxicity, especially febrile neutropenia, diarrhea, and sore mouth. In contrast, 24-hour infusions caused less nerve toxicity.1516 Mucositis and stomatitis when treated with 5-fluorouracil are also known as ADRs that require more attention in continuous infusion.17 RDD is a drug administration method that changes the infusion rate of a drug and involves a change in the blood drug concentration. Therefore, it is necessary to accumulate knowledge about the effects of these methods of administration on ADRs and efficacy of drugs. But, studies of ADRs and efficacy of RDD for chemotherapeutic agents are scarce.\n\nIn this study, we compared severe ADRs and efficacy between RDD and standard administration in patients with relapsed ovarian cancer who received carboplatin as a palliative chemotherapy.\n\nMATERIALS AND METHODS\nInformed consent statement\nThis study was approved by the Institutional Review Board (IRB) of Kyungpook National University Chilgok Hospital (IRB number: 2020-02-013).\n\nStudy protocol and study population\nA retrospective cohort study was performed on patients with the following inclusion criteria: 1) carboplatin based chemotherapy from 2017 to 2019 at Kyungpook National University Chilgok Hospital; 2) age ≥ 20 years; 3) tubo-ovarian cancer or primary peritoneal carcinomatosis; 4) platinum sensitive relapsed cancer; and 5) chemotherapy regimen: carboplatin + gemcitabine or carboplatin + paclitaxel (± bevacizumab). Patients who did not the complete chemotherapy schedule of the cycle for any reason were excluded.\n\nEach patient received a standard 6 to 9 cycles of carboplatin area under the curve 6 and paclitaxel 175 mg/m2 every 3 weeks as a frontline chemotherapy previously. All the patients underwent radical debulking tumor surgery. Subsequently, a second-line or later-line chemotherapy regimen was administered due to recurring ovarian cancer between 2017 and 2019. The group to which carboplatin was administered through RDD was labelled as the RDD group, and the group to which carboplatin was administered as a 1-hour infusion, which is a standard method, was labelled as the control group. We retrospectively reviewed the patients' electronic medical records and obtained the patients' baseline characteristics (such as age, sex and underling diseases), previous chemotherapy history, chemotherapy regimen, chemotherapy cycle number, carboplatin dose, whether desensitization performed, and desensitization result. The severity of the initial HSR and BTR was scored according to Brown's anaphylaxis classification as in previous studies.818 A grade 1 reaction (mild) was defined as involving only skin and subcutaneous tissue. Systemic involvement of respiratory, cardiovascular and gastrointestinal (GI) organs was regarded as a grade 2 reaction (moderate). Concurrent systemic organ involvement and vital sign changes (such as hypoxia, hypotension, and neurological changes) were classified as a grade 3 reaction (severe).\n\nRapid desensitization protocol\nThe 1-bag, 12-step desensitization protocol was previously reported by Lee et al.10 and Chung et al.\n19 and we performed desensitization with a modified protocol (Fig. 1). The 1-bag protocol started at 1/1,500 of the final infusion rate without dilution. Each step, except the last one, consuming 15 minutes, and the dose at each step was increased to 1.6 to 2.1 times the previous step until reaching a rate of 300 mL/hr as the final step. Since the 1-bag protocol use an undiluted drug, only a very small amount of the drug enters the initial step, and 5% dextrose water was administered as a side stream at a rate of 40 mL/hr throughout the entire desensitization process. H1 blockers (fexofenadine 180 mg and chlorpheniramine 4 mg) and montelukast (10 mg) were given 1 hour before chemotherapy as premedication. Systemic steroid (dexamethasone 5 mg) was administered as an antiemetic, regardless of the RDD.\n\nFig. 1 The 1-bag 12-step carboplatin desensitization protocol. For example: 400 mg carboplatin, mixed with 500 mL of 5% dextrose, and 0.741 mg/mL of carboplatin is administered. Start at 1/1,500 final speed, increase speed at 15-minute intervals. The 5% dextrose water was administered as a side stream at a rate of 40 mL/hr.\nNA, not available.\n\nOutcome measures\nADRs\nThe primary outcome was the incidence of serious adverse events (SAEs) as compared with the RDD group and the control group. SAEs were defined as follows: 1) death; 2) life-threatening; 3) admission to hospital, prolongation of hospitalization or emergency room visit; 4) disability or permanent damage; and 5) congenital anomaly/birth defect. The secondary outcome was the incidence of over grade 3 of ADRs according to organ classes. Organ classes were classified based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (NCI CTCAE v5.0). The grades are classified according to the following symptoms and signs: grade 1 reactions where the patient has mild symptoms and additional interventions are not required; grade 2 reactions where the patient has moderate symptoms and requires oral medication; grade 3 reactions where the patient shows severe symptoms and requires hospitalization or intravenous medication; grade 4 reactions where the patient exhibits life-threatening; grade 5 reactions where a drug reaction was related to patient death. Laboratory tests were performed on days 8 and 22 after carboplatin administration, and the ADR grade was according to CTCAE 5.0.value.\n\nEfficacy\nThe primary outcome was time to progression (TTP) as compared with the RDD group and the control group. TTP was defined as the period from the start of the chemotherapy regimen to the determination of cancer progression. The secondary outcome was 12-month survival, 24-month survival and overall survival (OS). OS was defined as the time of death for any reason from the onset of the second-line chemotherapy due to cancer recurrences.\n\nStatistical analysis\nWhen we performed univariate analysis of ADRs, we analyzed the same chemotherapy cycles separately. Categorical variables are presented as number and percentages, and they were analyzed using Pearson's χ2 test and Fisher's exact test. Continuous variables are presented as mean ± standard deviation ranges and were analyzed using Student's t test or the Mann-Whitney U test with a 95% confidence interval. A multivariable logistic regression test for ADRs was performed between the RDD group and the control group. Age, carboplatin dose, chemotherapy regimen, and previous chemotherapy history were corrected by logistic regression. TTP and survival analysis were compared between groups using Kaplan-Meier survival curves and a log-rank test. We assessed the multivariate effects of covariates with Cox regression analysis to estimate the efficacy adjusted by the following variables: age; time to relapse; previous chemotherapy history; Eastern Cooperative Oncology Group (ECOG) performance status (PS), concurrent chemotherapeutic drug. All results with a P value of < 0.05 were considered statistically significant. Statistical analyzes were performed with IBM SPSS Statistics (version 24.0; SPSS Inc., Chicago, IL, USA).\n\nRESULTS\nPatient selection flow and baseline characteristics\nFrom 2017 to 2019, 21 patients received a total of 108 desensitization procedures. Four procedures were excluded from the ADR analysis because the administration of carboplatin was not completed due to BTR symptoms. One patient was excluded from the analysis because excluded RDD procedure was the only carboplatin containing chemotherapy (Supplementary Fig. S1). Accordingly, there were 104 cycles in 20 patients included in the ADR analysis as the RDD group. The control group comprised 271 cycles in a total of 41 patients (Table 1). The mean ages of patients in the RDD group and the control group were 61.10 ± 9.79 years and 62.51 ± 9.95 years, respectively. There were no significant differences between clinical and demographic characteristics of the RDD and the control groups. All patients were diagnosed as female relapsed ovarian cancer who received palliative chemotherapy, including carboplatin. The RDD group had the mean cycle of 7.20 ± 5.54 in the same-line chemotherapy regimen, of which 5.35 ± 4.64 were administered through RDD. The control group had the mean cycle of 6.29 ± 3.79 in the same-line chemotherapy regimen. The time to the first relapse, number of previous total chemotherapy cycles and number of total carboplatin cycles tended to be higher in the RDD group, but this was statistically insignificant. ECOG PS 2, hypertension, diabetes, and cardiovascular disease were more prevalent in the control group, but there was no significant difference between the 2 groups. In the efficacy analysis, 4 patients in the RDD group who had to change regimen due to BTR were excluded and 17 RDD and 41 control patients were analyzed (Supplementary Fig. S1).\n\nTable 1 Clinical characteristics of the study subjects\nCharacteristics\tRDD group (n = 20)\tControl group (n = 41)\tP value\t\nAge (yr)\t61.10 ± 9.79\t62.51 ± 9.95\t0.603\t\nSex:female\t20 (100)\t41 (100)\t1.000\t\nTotal cycle\t104\t271\t\t\nAverage cycle per patient\t\t\t\t\n\tCycle in the same-line chemotherapy regimen\t7.20 ± 5.54\t6.29 ± 3.79\t0.456\t\n\tRapid desensitization\t5.35 ± 4.64\t-\t\t\nTime to first relapse after initial diagnosis (mon)\t30.35 ± 17.75\t24.46 ± 15.46\t0.189\t\nTreatment course before current chemotherapy regimen\t\t\t\t\n\tPrevious total chemotherapy cycle\t15.40 ± 9.09\t13.54 ± 7.77\t0.437\t\n\tPrevious total carboplatin cycle\t12.15 ± 6.11\t9.34 ± 5.18\t0.066\t\nInitial ECOG PS (0/1/2)\t1/17/2\t3/31/7\t0.699\t\nUnderlying disease\t\t\t\t\n\tDiabetes\t3 (15.0)\t9 (22.0)\t0.521\t\n\tHypertension\t3 (15.0)\t15 (36.6)\t0.083\t\n\tDyslipidemia\t3 (15.0)\t5 (12.2)\t0.761\t\n\tCardiovascular disease\t0 (0)\t3 (7.3)\t0.215\t\n\tChronic liver disease\t0 (0)\t1 (2.4)\t0.481\t\n\tRespiratory disease\t0 (0)\t1 (2.4)\t0.481\t\n\tOther cancer\t2 (10.0)\t4 (9.8)\t0.976\t\nValues are presented as mean ± standard deviation or number (%).\n\nRDD, rapid drug desensitization; ECOG PS, Eastern Cooperative Oncology Group performance status.\n\nOutcomes of RDD\nThe results of 108 desensitization cycles among 21 patients were analyzed. In the initial HSR evaluation, 9 (42.9%) patients of grade 1, 9 (42.9%) patients of grade 2 and 3 (14.3%) patients of grade 3 were observed. Out of 108 RDDs, 104 cycles were completed with a success rate of 96.3% (Supplementary Table S1). Among 108 RDDs cycles, no BTRs occurred in 74 cycles (68.5%) while grade 1 BTRs occurred in 26 cycles (24.1%). Six patients suffered from moderate to severe BTRs out of 8 RDDs, 1 of which was a severe reaction (Fig. 2A). Four patients had to change chemotherapy regimen to one that did not contain carboplatin due to BTR. In grade 2 or grade 3 BTRs, 6/8 were first or second cycles of RDD (Fig. 2B).\n\nFig. 2 Number and severity of BTRs during RDD. (A) Total RDD. (B) According to cycles of RDD.\nBTR, breakthrough reaction; RDD, rapid drug desensitization.\n\nADRs\nPrimary outcome\nThere were 8 SAEs (7.7%) in 104 RDD procedures and 34 SAEs (12.5%) in 272 standard procedures. The most frequent SAE was infection or infestations that were observed in 6 (5.8%) in the RDD group and 11 (4.1%) in the control group. Nausea and nutritional disorder were the second most common SAE, with 2 (1.9%) in the RDD group and 8 (3.0%) in the control group. Other kinds of SAE, such as GI and general disorders, occurred only in the control group. One drug-related death (pneumonia with neutropenic fever) was observed in the RDD group (Table 2). The SAEs were analyzed comparing the same chemotherapy cycle of the 2 groups. There was no significant increase in SAEs in the RDD group from the first to the ninth chemotherapy cycles (Fig. 3A and Supplementary Table S2). No significant increase in SAEs in the RDD group was observed even after correction for age, carboplatin dose, comorbid chemotherapy, and previous total chemotherapy cycle number by logistic regression analysis (Table 3).\n\nTable 2 Severe adverse events according to rapid drug desensitization\nSevere adverse events\tRDD group (n = 104)\tControl group (n = 271)\t\nDeath\t1 (1.0)\t0 (0.0)\t\nCardiac disorders\t0 (0.0)\t1 (0.4)\t\nGastrointestinal disorders (except nausea)\t0 (0.0)\t8 (3.0)\t\nInfection and infestations\t6 (5.8)\t11 (4.1)\t\nInjury, poisoning and procedural complications\t0 (0.0)\t1 (0.4)\t\nNausea and nutrition disorders\t2 (1.9)\t8 (3.0)\t\nGeneral disorders\t0 (0.0)\t3 (1.1)\t\nRespiratory, thoracic and mediastinal disorders\t0 (0.0)\t1 (0.4)\t\nSkin and subcutaneous tissue disorders\t0 (0.0)\t1 (0.4)\t\nTotal\t8 (7.7)\t34 (12.5)\t\nRDD, rapid drug desensitization.\n\nFig. 3 Severe adverse drug reactions according to the cycle of palliative chemotherapy containing carboplatin. (A) Severe adverse events. (B) Over grade 3 of any adverse drug reactions.\nRDD, rapid drug desensitization.\n\nTable 3 Risk assessment of comparison of severe adverse events in the RDD group by multivariate analysis\nChemotherapy cycles\tSevere adverse events\t\nOdds ratio\t95% CI\tP value\t\n1st\t0.714\t0.062–8.218\t0.787\t\n2nd\t0.632\t0.030–13.278\t0.768\t\n3rd\t0.507\t0.032–8.124\t0.507\t\n4th\t0.587\t0.027–12.691\t0.734\t\n5th\t1.573\t0.070–35.485\t0.776\t\n6th\t1.777\t0.097–32.589\t0.699\t\nRDD, rapid drug desensitization; CI, confidence interval.\n\nSecondary outcome\nOver grade 3 of any ADRs were observed in 70 (67.3%) of the RDD group and in 160 (59.0%) of the control group. Over grade 3 of any ADRs were analyzed comparing the same chemotherapy cycle of the 2 groups. There was no statistically significant difference between the 2 groups from the first cycle to the ninth cycle (Fig 3B and Supplementary Table S2). When analyzed through multiple logistic regression analysis, the risk of over grade 3 of ADRs was significantly lower in RDD group in the 3rd cycle, and there was no statistical difference in the other cycles (Supplementary Table S3). Over grade 3 of neutropenia was significantly higher in the RDD group on the 6th cycle (84.6% vs. 30.8%, P = 0.002) (Supplementary Fig. S2D and Supplementary Table S2). This continued even after adjustment by logistic regression (odds ratio, 10.249; 95% confidence interval [CI], 1.669–62.922; P = 0.012; Supplementary Table S3). Other cytopenia indicators (like anemia and thrombocytopenia) did not show a statistically significant difference in the RDD group. Over grade 3 of the ADRs by other organ system were not increased by the RDD group (Table 4 and Supplementary Fig. S2).\n\nTable 4 Adverse drug reactions according to organ class\nCharacteristics\tRDD group (n = 104)\tControl group (n = 271)\t\nAny ≥ Grade 3\t70 (67.3)\t160 (59.0)\t\nGastrointestinal disorder (except nausea)\t\t\t\n\t≥ Grade 2\t61 (58.7)\t160 (59.0)\t\n\t≥ Grade 3\t0 (0.0)\t8 (3.0)\t\nInfection and infestation\t\t\t\n\t≥ Grade 2\t15 (13.9)\t26 (9.6)\t\n\t≥ Grade 3\t6 (5.6)\t11 (4.1)\t\nNausea and nutrition disorders\t\t\t\n\t≥ Grade 2\t46 (44.2)\t136 (50.2)\t\n\t≥ Grade 3\t2 (1.9)\t8 (3.0)\t\nNervous system disorder\t\t\t\n\t≥ Grade 2\t33 (30.6)\t98 (36.2)\t\n\t≥ Grade 3\t0 (0.0)\t0 (0.0)\t\nHepatotoxicity\t\t\t\n\t≥ Grade 2\t5 (4.6)\t8 (3.0)\t\n\t≥ Grade 3\t1 (1.0)\t2 (0.7)\t\nNephrotoxicity\t\t\t\n\t≥ Grade 2\t1 (1.0)\t5 (1.8)\t\n\t≥ Grade 3\t1 (1.0)\t0 (0.0)\t\nNeutropenia\t\t\t\n\t≥ Grade 2\t84 (77.8)\t184 (67.9)\t\n\t≥ Grade 3\t62 (57.4)\t107 (39.5)\t\nAnemia\t\t\t\n\t≥ Grade 2\t82 (75.9)\t202 (74.5)\t\n\t≥ Grade 3\t25 (23.1)\t73 (26.9)\t\nThrombocytopenia\t\t\t\n\t≥ Grade 2\t45 (41.7)\t89 (32.8)\t\n\t≥ Grade 3\t22 (20.4)\t66 (24.4)\t\nRDD, rapid drug desensitization.\n\nEfficacy\nPrimary outcome\nWe compared the efficacy of 17 carboplatin-desensitized patients and 41 control patients. The median TTP for the total regimen was 17.14 months (95% CI, 12.28–22.00) in the RDD group and 14.27 months (95% CI, 10.95–17.59) in the control group. When limited to the 2nd line regimen, the median TTP was 19.94 months in the RDD group, and 17.23 months in the control group. There was no significant difference in TTP between the 2 groups (Fig. 4). TTP for total regimen after correction for age, time to relapse, previous chemotherapy history and ECOG PS, hazard ratio of desensitization was 0.733 (95% CI, 0.320–1.680; P = 0.463). When comparing only 2nd line regimen, hazard ratio of desensitization was 1.945 (95% CI, 0.476–7.951; P = 0.355) (Table 5).\n\nFig. 4 Curves for time to progression of the RDD group and the control group, defined as the time from 1st cycle of regimen to cancer progression. (A) Total regimen. (B) Second line regimen.\nRDD, rapid drug desensitization.\n\nTable 5 Multivariate cox regression analysis of TTP and OS\nCharacteristics\tTTP\tOS\t\nTotal\t2nd line regimen\t\nHR (95% CI)\tP value\tHR (95% CI)\tP value\tHR (95% CI)\tP value\t\nRapid desensitization of carboplatin\t0.733 (0.320–1.680)\t0.463\t1.945 (0.476–7.951)\t0.355\t1.310 (0.432–3.974)\t0.634\t\nAge (yr)\t1.010 (0.960–1.063)\t0.700\t1.042 (0.970–1.121)\t0.262\t0.942 (0.871–1.019)\t0.138\t\nTime to relapse (mon)\t0.970 (0.943–0.999)\t0.042\t0.885 (0.809–0.967)\t0.007\t0.952 (0.909–0.998)\t0.040\t\nPrevious chemotherapy cycle (number)\t1.086 (1.024–1.151)\t0.006\t0.983 (0.882–1.096)\t0.759\t0.988 (0.913–1.069)\t0.767\t\nECOG PS\t\t\t\t\t\t\t\n\t1\t1.302 (0.399–4.250)\t0.661\t2.832 (0.385–20.841)\t0.669\t1.776 (0.208–15.163)\t0.600\t\n\t2\t1.840 (0.437–7.744)\t0.405\t8.674 (0.843–89.314)\t0.101\t3.734 (0.307–45.415)\t0.301\t\nConcurrent chemotherapeutic drug (gemcitabine)\t2.018 (0.696–5.849)\t0.196\t3.356 (0.783–14.391)\t0.103\t0.652 (0.194–2.191)\t0.489\t\nTTP, time to progression; OS, overall survival; HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status.\n\nSecondary outcome\nThe 12-month survival rate was not significantly different between the RDD and control groups (14/15, 93.3% vs. 27/31, 87.1%). The 24-month survival rate was also 66.7% (8/12) for RDD group and 68.2% (15/22) for the control group, there was no significant difference between the 2 groups. The estimated median survival time was 47.84 months (95% CI, 33.23–63.45) for the RDD group and 41.22 months (95% CI, 33.86–48.59) for the control group. There was no significant difference in OS between the 2 groups (Log-rank P = 0.944) (Fig. 5). OS after correction for age, time to relapse, previous chemotherapy history and ECOG PS, hazard ratio of desensitization was 1.310 (95% CI, 0.432–3.974; P = 0.634) (Table 5).\n\nFig. 5 Curves for overall survival of the RDD group and the control group, defined as the time from cancer recurrence to death.\nRDD, rapid drug desensitization.\n\nDISCUSSION\nOur study demonstrated that RDD does not increase the frequency of severe ADRs compared with the standard administration method and has similar efficacy. Our study is meaningful in that it compared a relatively similar group of patients for the first time. Based on our findings, we suggest that RDD is not only an effective way to reduce the risk of HSRs, but also a way to administer drugs without affecting efficacy and other severe ADRs.\n\nCommon SAEs of chemotherapy include infection, cytopenia, nausea, GI motility symptoms, malnutrition and constitutional/dehydration symptoms.20 Platinum compounds are also known to have neurotoxicity, nephrotoxicity, and ototoxicity, but carboplatin is rarer than cisplatin.212223 In our study, infection or infestations was the most common SAE. Malnutrition by nausea and anorexia, and GI symptoms including diarrhea and abdominal distension were also observed in some patients. As for neurotoxicity, more than 30% procedures were associated with neurotoxicity below grade 2 and grade 3 neurotoxicity was not observed. Only 6 procedures were accompanied by an increase in creatinine above grade 2, and there was no increase above grade 3 except in the fatal cases who progress multi-organ failure due to infection, so nephrotoxicity was tolerable.\n\nGI disorder, nausea, anorexia, malnutrition and general disorder tended to be lower in the RDD group, especially as regards grade 3 reactions requiring hospitalization or emergency room visits. ADRs particularly common in platinum compounds, such as neurotoxicity and nephrotoxicity, also tended to be lower. However, the infection and infestations tended to be higher in the RDD group. Among all patients, there was one death related to ADR of chemotherapy, and this was the death caused by infection with neutropenia in the RDD group. In addition, neutropenia above grade 3 tended to increase in the RDD group as the order of chemotherapy cycle increased, especially after the sixth cycle, showing statistically significant differences. Cochrane review for paclitaxel presents the lower prevalence of neutropenia in short duration infusions than long duration infusions of paclitaxel.15 Our study showed similar results to the above study that the incidence of neutropenia was higher in the desensitized group, which required more than 4 hours of administration time than the control group that received carboplatin for 1 hour, which is the conventional administration time. Since, in our study, the number of patients with anemia and thrombocytopenia did not significantly change, further research is required to determine whether RDD causes bone marrow suppression but more careful observation of bone marrow suppression may be required in rapid desensitization.\n\nPrevious studies showed the relationship between RDD and OS. In relapsed ovarian cancer, there was no difference in OS between patients with RDD and the control patients.8 In a recent study, oxaliplatin administration in colon cancer showed that there was no difference in OS between RDD and control groups.24 Another study showed that patients who were desensitized to carboplatin hypersensitivity had longer OS than patients without hypersensitivity to carboplatin not undergoing desensitization.25 TTP was analyzed for the first time in this study. Although there was no statistical difference, the RDD group showed a longer TTP, despite the time to relapse and the number of previous chemotherapy cycles being higher. Through this, administration of carboplatin through RDD is not expected to decrease efficacy, and it is thought that it can be applied to other chemotherapeutic agents. In addition, 12-month survival, 24-month survival and OS were not statistically different, so it can be confirmed again that RDD does not affect OS.\n\nCarboplatin is one of the most important chemotherapeutic agents in ovarian cancer, and is mostly used as 1st line chemotherapy.26 Despite progress in the first-line treatment of ovarian cancer, the majority of patients relapse, so it is important to re-administer carboplatin for carboplatin sensitive ovarian cancers.2728 However, one of the major problems with re-administration of carboplatin is the frequent occurrence of immediate HSR. Carboplatin immediate HSRs are known to increase as the cycle is repeated (6.5% for 6 cycles and 27% for 7 cycles, and 44% for 3rd line re-administration).293031 When a carboplatin immediate HSR occurs in patients with carboplatin sensitive ovarian cancer, it has been well known from previous studies that administration of drugs through RDD significantly benefits OS compared with avoiding carboplatin. Therefore, a safe method for administering carboplatin was needed in these patients, and successful administration through RDD was reported.832 In our study, RDD had to be performed for a known HSR in approximately 1/3 of patients who used carboplatin for recurrent ovarian cancer patients who used carboplatin as the 1st line.\n\nThe success rate and number of BTR in the RDD group were similar to those results in previous carboplatin desensitization studies. Platinum compounds, such as carboplatin, were reported to have a higher BTR incidence than those of paclitaxel or monoclonal antibodies.83334 Carboplatin infusion through RDD was reported to cause grade 2 or higher BTR in 5% to 10%.7353637 According to Sloane et al.,8 the BTR results of 1,069 desensitization therapies of carboplatin showed a similar rate to the BTR results of our study. It was also demonstrated in this study that the risk of BTR decreases as the number of desensitization therapies is repeated.1038\n\nIn this study, we adopted a 1-bag desensitization protocol. RDD using 1-bag protocol has proven to be good in previous studies. In a previous study, 1-bag 12-step chemotherapy was successfully performed with platinum compounds,19 In another retrospective cohort study, success rate and BTR frequency were not statistically different between 3-bag system and 1-bag system for paclitaxel administration.10 In addition, when using the 1-bag system, it was possible to reduce the infusion time compared with the multi-bag protocol, thereby reducing the effort of medical staff.10 In this study, carboplatin 400 mg was administered for 254 minutes, showing a similar infusion time to previous 1-bag studies.\n\nThere are some limitations to this study. First, our study was conducted retrospectively in a single hospital with a resultant small sample size and reduced statistical power. ADRs may be sensitive to the patient's underlying condition. Prospective double-blind randomized trials would be ideal for ADR evaluation. Despite these limitations, however, our research was conducted consistently, so the desensitization protocol, treatment to ADRs, and cancer treatment protocol were able to follow up the patient under the most unified conditions, allowing a valid comparison between the 2 groups. In addition, due to the nature of RDD, it is not possible to conduct a randomized clinical trial. In order to further generalize as a conclusion of our research, there should be larger multicenter research in the future. Secondly, in our study, in patients with carboplatin immediate HSR, there was no comparison between the group that gave up carboplatin and the carboplatin RDD group. We attempted to re-administer all patients who developed carboplatin hypersensitivity during the study period, and only patients with moderate or higher BTR despite RDD tried other treatments than carboplatin. There were 4 patients who changed carboplatin, and the number of patients was too small to analyze separately. Thirdly, this study did not evaluate the mechanism of carboplatin hypersensitivity prior to desensitization. However, this study was aimed at analyzing the drug efficacy and toxicity according to infusion methods, so drug hypersensitivity mechanisms would not have had a significant influence. In addition, carboplatin is generally known to induce immunoglobulin E-mediated hypersensitivity as the carboplatin cycle repeats. The RDD group in our study showed almost one-third of patients who used carboplatin for recurrent ovarian cancer and had administered more than 10 times before RDD. This is reasonable considering the previous evidence of carboplatin hypersensitivity in more than 25% of patients after 6 cycles.39\n\nIn conclusion, RDD did not increase severe ADRs compared to the standard drug administration method, and it was confirmed that there was no difference in efficacy of drug. Based on the results of this study, it is suggested that rapid desensitization of carboplatin is similar to the standard infusion method in terms of efficacy and severe ADRs.\n\nACKNOWLEDGMENTS\nThis work was supported by Biomedical Research Institute grant, Kyungpook National University Hospital (2018).\n\nDisclosure: There are no financial or other issues that might lead to conflict of interest.\n\nSUPPLEMENTARY MATERIALS\nSupplementary Table S1\nClinical characteristic of initial HSR and BTR\n\n Supplementary Table S2\nAnalysis of univariate for each cycle for severe ADRs according to RDD\n\n Supplementary Table S3\nRisk assessment of comparison of ADRs over grade 3 and neutropenia over grade 3 in the RDD group by multivariate analysis\n\n Supplementary Fig. S1\nFlow chart of study patient selection.\n\n Supplementary Fig. S2\nAdverse drug reactions according to the cycle of palliative chemotherapy containing carboplatin.\n==== Refs\n1 Romano A Torres MJ Castells M Sanz ML Blanca M Diagnosis and management of drug hypersensitivity reactions J Allergy Clin Immunol 2011 127 S67 73 21354502 \n2 Lee Y Chang HY Kim SH Yang MS Koh YI Kang HR A prospective observation of psychological distress in patients with anaphylaxis Allergy Asthma Immunol Res 2020 12 496 506 32141262 \n3 Montañez MI Mayorga C Bogas G Barrionuevo E Fernandez-Santamaria R Martin-Serrano A Epidemiology, mechanisms, and diagnosis of drug-induced anaphylaxis Front Immunol 2017 8 614 28611774 \n4 Castells M Sancho-Serra MC Simarro M Hypersensitivity to antineoplastic agents: mechanisms and treatment with rapid desensitization Cancer Immunol Immunother 2012 61 1575 1584 22576054 \n5 Cernadas JR Brockow K Romano A Aberer W Torres MJ Bircher A General considerations on rapid desensitization for drug hypersensitivity - a consensus statement Allergy 2010 65 1357 1366 20716314 \n6 Madrigal-Burgaleta R Berges-Gimeno MP Angel-Pereira D Ferreiro-Monteagudo R Guillen-Ponce C Pueyo C Hypersensitivity and desensitization to antineoplastic agents: outcomes of 189 procedures with a new short protocol and novel diagnostic tools assessment Allergy 2013 68 853 861 23647576 \n7 Castells MC Tennant NM Sloane DE Hsu FI Barrett NA Hong DI Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases J Allergy Clin Immunol 2008 122 574 580 18502492 \n8 Sloane D Govindarajulu U Harrow-Mortelliti J Barry W Hsu FI Hong D Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies J Allergy Clin Immunol Pract 2016 4 497 504 26895621 \n9 Madrigal-Burgaleta R Bernal-Rubio L Berges-Gimeno MP Carpio-Escalona LV Gehlhaar P Alvarez-Cuesta E A large single-hospital experience using drug provocation testing and rapid drug desensitization in hypersensitivity to antineoplastic and biological agents J Allergy Clin Immunol Pract 2019 7 618 632 30098410 \n10 Lee JH Moon M Kim YC Chung SJ Oh J Kang DY a one-bag rapid desensitization protocol for paclitaxel hypersensitivity: a noninferior alternative to a multi-bag rapid desensitization protocol J Allergy Clin Immunol Pract 2020 8 696 703 31678295 \n11 O'Cearbhaill R Zhou Q Iasonos A Hensley ML Tew WP Aghajanian C The prophylactic conversion to an extended infusion schedule and use of premedication to prevent hypersensitivity reactions in ovarian cancer patients during carboplatin retreatment Gynecol Oncol 2010 116 326 331 19944454 \n12 Pornwattanakrilert W Suprasert P Comparison of hypersensitivity reactions to carboplatin retreatment in gynecologic cancer patients between one and two hour infusions: a randomized trial study Asian Pac J Cancer Prev 2017 18 425 430 28345825 \n13 Eriksson U Seifert B Schaffner A Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial BMJ 2001 322 579 582 11238151 \n14 Hortobagyi GN Frye D Buzdar AU Ewer MS Fraschini G Hug V Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma Cancer 1989 63 37 45 2910423 \n15 Williams C Bryant A Short versus long duration infusions of paclitaxel for any advanced adenocarcinoma Cochrane Database Syst Rev 2011 CD003911 21563139 \n16 Williams C Collingwood M Simera I Grafton C Short versus long duration infusions of paclitaxel for any adenocarcinoma Cochrane Database Syst Rev 2002 CD003911 12519619 \n17 Macdonald JS Toxicity of 5-fluorouracil Oncology (Williston Park) 1999 13 33 34 10442356 \n18 Brown SG Clinical features and severity grading of anaphylaxis J Allergy Clin Immunol 2004 114 371 376 15316518 \n19 Chung SJ Kang SY Kang RY Kim YC Lee KH Kim TY A new non-dilution rapid desensitization protocol successfully applied to all-grade platinum hypersensitivity Cancer Chemother Pharmacol 2018 82 777 785 30105458 \n20 Hassett MJ O'Malley AJ Pakes JR Newhouse JP Earle CC Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer J Natl Cancer Inst 2006 98 1108 1117 16912263 \n21 Rajeswaran A Trojan A Burnand B Giannelli M Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials Lung Cancer 2008 59 1 11 17720276 \n22 Neijt JP Engelholm SA Tuxen MK Sørensen PG Hansen M Sessa C Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer J Clin Oncol 2000 18 3084 3092 10963636 \n23 Steiner H Höltl L Wirtenberger W Berger AP Bartsch G Hobisch A Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study Urology 2002 60 324 328 12137835 \n24 Madrigal-Burgaleta R Does rapid drug desensitization to chemotherapy affect survival outcomes? J Investig Allergol Clin Immunol 2019 \n25 Altwerger G Florsheim EB Menderes G Black J Schwab C Gressel GM Impact of carboplatin hypersensitivity and desensitization on patients with recurrent ovarian cancer J Cancer Res Clin Oncol 2018 144 2449 2456 30255380 \n26 Vergote I Scambia G O'Malley DM Van Calster B Park SY Del Campo JM Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial Lancet Oncol 2019 20 862 876 31076365 \n27 Pfisterer J Plante M Vergote I du Bois A Hirte H Lacave AJ Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG J Clin Oncol 2006 24 4699 4707 16966687 \n28 Pfisterer J Vergote I Du Bois A Eisenhauer E AGO-OVAR NCIC CTG Combination therapy with gemcitabine and carboplatin in recurrent ovarian cancer Int J Gynecol Cancer 2005 15 Suppl 1 36 41 15839957 \n29 Makrilia N Syrigou E Kaklamanos I Manolopoulos L Saif MW Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review Met Based Drugs 2010 2010 207084 20886011 \n30 Markman M Kennedy A Webster K Elson P Peterson G Kulp B Clinical features of hypersensitivity reactions to carboplatin J Clin Oncol 1999 17 1141 10561172 \n31 Hoekstra AV Hurteau JA Kirschner CV Rodriguez GC The combination of monthly carboplatin and weekly paclitaxel is highly active for the treatment of recurrent ovarian cancer Gynecol Oncol 2009 115 377 381 19800107 \n32 Hesterberg PE Banerji A Oren E Penson RT Krasner CN Seiden MV Risk stratification for desensitization of patients with carboplatin hypersensitivity: clinical presentation and management J Allergy Clin Immunol 2009 123 1262 1267.e1 19501233 \n33 Picard M Pur L Caiado J Giavina-Bianchi P Galvão VR Berlin ST Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions J Allergy Clin Immunol 2016 137 1154 1164.e12 26725998 \n34 Kendirlinan R Gümüşburun R Çerçi P Özbek E Altıner S Çelebi Sözener Z Rapid drug desensitization with chemotherapeutics (platins, taxanes, and others): a single-center retrospective study Int Arch Allergy Immunol 2019 179 114 122 30893688 \n35 Castells Guitart MC Rapid drug desensitization for hypersensitivity reactions to chemotherapy and monoclonal antibodies in the 21st century J Investig Allergol Clin Immunol 2014 24 72 79 \n36 Kang Y Kwon OY Jung H Kang M An J Lee JH Breakthrough reactions during rapid drug desensitization: clinical outcome and risk factors Ann Allergy Asthma Immunol 2019 123 48 56.e1 31108181 \n37 Castells M Drug hypersensitivity and anaphylaxis in cancer and chronic inflammatory diseases: the role of desensitizations Front Immunol 2017 8 1472 29163536 \n38 O'Malley DM Vetter MH Cohn DE Khan A Hays JL Outpatient desensitization in selected patients with platinum hypersensitivity reactions Gynecol Oncol 2017 145 603 610 28410757 \n39 Zanotti KM Rybicki LA Kennedy AW Belinson JL Webster KD Kulp B Carboplatin skin testing: a skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy J Clin Oncol 2001 19 3126 3129 11408510\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2092-7355",
"issue": "12(6)",
"journal": "Allergy, asthma & immunology research",
"keywords": "Desensitization; antineoplastic agents; carboplatin; drug effects; drug-related side effects and adverse reactions; hypersensitivity; ovarian neoplasm; survival",
"medline_ta": "Allergy Asthma Immunol Res",
"mesh_terms": null,
"nlm_unique_id": "101518382",
"other_id": null,
"pages": "1046-1059",
"pmc": null,
"pmid": "32935494",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": "12519619;28345825;28410757;28611774;19800107;30893688;31678295;10963636;16912263;26895621;30255380;12137835;29163536;18502492;11238151;23647576;26725998;21354502;17720276;15839957;31188129;20716314;22576054;19501233;21563139;20886011;2910423;30105458;15316518;31108181;10442356;24834769;31076365;30098410;32141262;11408510;19944454;16966687;10561172",
"title": "Does Carboplatin Rapid Desensitization Change Its Adverse Drug Reactions Other than Hypersensitivity and Efficacy in Patients With Ovarian Cancer?",
"title_normalized": "does carboplatin rapid desensitization change its adverse drug reactions other than hypersensitivity and efficacy in patients with ovarian cancer"
} | [
{
"companynumb": "KR-MYLANLABS-2021M1035082",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Excess dosing of anticoagulant agents has been linked to increased risk of bleeding after percutaneous coronary intervention (PCI) for women compared with men, but these studies have largely included older patients. We sought to determine the prevalence and gender-based differences of excess dosing of anticoagulants including glycoprotein IIb/IIIa inhibitors, bivalirudin, and unfractionated heparin in young patients with acute myocardial infarction who underwent PCI and to examine its association with bleeding. Of 2,076 patients enrolled in the Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients study who underwent PCI, we abstracted doses of unfractionated heparin, bivalirudin, and glycoprotein IIb/IIIa inhibitors administered during PCI from the medical records. At least 47.2% received at least 1 excess dose of an anticoagulant, which did not differ by gender. We used logistic regression to determine the predictors of excess dosing and the association of excess dosing with bleeding. In multivariable analysis, only lower body weight and younger age were significant predictors of excess dosing. Bleeding was higher in young women who received excess dosing versus those who did not (9.3% vs 6.0%, p = 0.03) but was comparable among men (5.2% vs 5.9%, p = 0.69) in univariate analysis. In multivariable analysis, there was a trend to an association between excess dosing and bleeding (odds ratio 1.33, 95% confidence interval 0.92 to 1.91) although not statistically significant. In conclusion, approximately half of the patients received excess dosing of anticoagulant drugs during PCI, which did not vary based on gender. There was a trend toward an association between excess dosing and increased bleeding, although not statistically significant.",
"affiliations": "Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.;Department of Internal Medicine, University of California, Irvine, California.;Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.;Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City, Kansas City, Missouri.;Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut.;Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut.;Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut.;Department of Emergency Medicine, Yale University School of Medicine, New Haven, Connecticut.;Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.;Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina.;Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Robert Wood Johnson Clinical Scholars Program, Yale University School of Medicine, New Haven, Connecticut; Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut.;Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut. Electronic address: jeptha.curtis@yale.edu.",
"authors": "Gupta|Aakriti|A|;Chui|Philip|P|;Zhou|Shengfan|S|;Spertus|John A|JA|;Geda|Mary|M|;Lorenze|Nancy|N|;Lee|Ike|I|;D' Onofrio|Gail|G|;Lichtman|Judith H|JH|;Alexander|Karen P|KP|;Krumholz|Harlan M|HM|;Curtis|Jeptha P|JP|",
"chemical_list": "D000925:Anticoagulants; D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; D006493:Heparin; C074619:bivalirudin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9149",
"issue": "116(1)",
"journal": "The American journal of cardiology",
"keywords": null,
"medline_ta": "Am J Cardiol",
"mesh_terms": "D000328:Adult; D017677:Age Distribution; D015906:Angioplasty, Balloon, Coronary; D000925:Anticoagulants; D000991:Antithrombins; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D006470:Hemorrhage; D006493:Heparin; D006629:Hirudins; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010446:Peptide Fragments; D062645:Percutaneous Coronary Intervention; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D015995:Prevalence; D011994:Recombinant Proteins; D018570:Risk Assessment; D012307:Risk Factors; D017678:Sex Distribution; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "0207277",
"other_id": null,
"pages": "1-7",
"pmc": null,
"pmid": "25937348",
"pubdate": "2015-07-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "19942100;19710484;20299365;21081748;14503111;12686338;22111719;16380591;16784919;16982940;16803468;17541128;17933995;18724971;20031719",
"title": "Frequency and Effects of Excess Dosing of Anticoagulants in Patients ≤55 Years With Acute Myocardial Infarction Who Underwent Percutaneous Coronary Intervention (from the VIRGO Study).",
"title_normalized": "frequency and effects of excess dosing of anticoagulants in patients 55 years with acute myocardial infarction who underwent percutaneous coronary intervention from the virgo study"
} | [
{
"companynumb": "US-JNJFOC-20150700390",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BIVALIRUDIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Recognition and appropriate management of right ventricular (RV) infarction is essential, as RV injury increases mortality and substantially alters management during acute coronary syndrome. We report a case of RV infarction presenting with new right bundle branch block (RBBB), and therapeutic use of inhaled epoprostenol to reduce RV afterload and augment cardiac output during refractory cardiogenic shock. CASE REPORT A 53-year-old male presented to our institution in ventricular fibrillation with subsequent development of RBBB in the setting of proximal right coronary artery occlusion. Following percutaneous coronary intervention, the patient developed severe RV dysfunction with refractory cardiogenic shock. This was successfully managed with inhaled epoprostenol with normalization of right ventricular systolic function. CONCLUSIONS Although typically associated with anterior myocardial infarction, new RBBB should be recognized as a potential presenting sign of acute RV infarction. The use of inhaled epoprostenol in the setting of RV infarction has not been previously described, but it may augment right ventricular cardiac output via pulmonary vasodilatation.",
"affiliations": "School of Medicine, University of Colorado, Aurora, CO, USA.;School of Medicine, University of Colorado, Aurora, CO, USA.;School of Medicine, University of Colorado, Aurora, CO, USA.;School of Medicine, University of Colorado, Aurora, CO, USA.",
"authors": "Held|Natalie|N|;Little|Nathaniel|N|;Krantz|Mori J|MJ|;Stauffer|Brian L|BL|",
"chemical_list": "D000959:Antihypertensive Agents; D011464:Epoprostenol",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.901975",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "18()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000280:Administration, Inhalation; D000959:Antihypertensive Agents; D002037:Bundle-Branch Block; D054059:Coronary Occlusion; D011464:Epoprostenol; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D012770:Shock, Cardiogenic; D018497:Ventricular Dysfunction, Right",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "271-275",
"pmc": null,
"pmid": "28298620",
"pubdate": "2017-03-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16815572;27017617;15052203;9286941;24828526;26438636;20227777;26070575;12225706;24222834;12819949",
"title": "Refractory Cardiogenic Shock from Right Ventricular Infarction Successfully Managed with Inhaled Epoprostenol.",
"title_normalized": "refractory cardiogenic shock from right ventricular infarction successfully managed with inhaled epoprostenol"
} | [
{
"companynumb": "US-BAUSCH-BL-2017-012711",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PHENYLEPHRINE\\PHENYLEPHRINE HYDROCHLORIDE"
},
... |
{
"abstract": "A 66-year-old male diagnosed with transverse colon cancer was admitted to our hospital. Computed tomography, colonoscopy, and esophagogastroduodenoscopy revealed locally advanced cancer with invasion of the gastric antrum. We staged the disease as cT4a, cN2, cM0, Stage ⅢB, with wild-type RAS expression. We performed an ileostomy prior to administering chemotherapy. The patient received 4 courses of modified FOLFOXIRI plus bevacizumab and 2 courses of FOLFIRI. The size of the tumor noticeably decreased after chemotherapy. The patient experienced grade 3 neutropenia, anorexia, and oral mucositis during chemotherapy. We performed a right hemicolectomy(D3), partial gastrectomy and ileum resection after administering neoadjuvant chemotherapy. The pathological stage of the disease was ypT2, ypN0, ypM0, ypStageⅠ, and the effect of the chemotherapy was Grade 1b. After the resection, he received mFOLFOX6 and CapeOX for 3 months as adjuvant chemotherapy. He remained cancer-free for 1 year and 3 months after the surgery. This result suggests that preoperative modified FOLFOXIRI plus bevacizumab chemotherapy is a useful regimen for the treatment of locally advanced colon cancer.",
"affiliations": "Dept. of Gastrointestinal Surgery, Hikone Municipal Hospital.",
"authors": "Kanto|Satoshi|S|;Takeji|Satoru|S|;Okamura|Miru|M|;Sakikubo|Morito|M|;Tatsumi|Kentarou|K|;Yasuda|Seiichi|S|;Kawabe|Atsushi|A|",
"chemical_list": "D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D044684:Colon, Transverse; D003110:Colonic Neoplasms; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds; D011706:Pyloric Antrum",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1517-1520",
"pmc": null,
"pmid": "33130754",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Neoadjuvant Chemotherapy with Modified FOLFOXIRI plus Bevacizumab for Transverse Colon Cancer with Invasion of the Gastric Antrum.",
"title_normalized": "a case of neoadjuvant chemotherapy with modified folfoxiri plus bevacizumab for transverse colon cancer with invasion of the gastric antrum"
} | [
{
"companynumb": "JP-ACCORD-216624",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "1",
"druga... |
{
"abstract": "ABSTRACT Objective: To evaluate the efficacy and safety of enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) in docetaxel-naive and docetaxel-pretreated patients.\n\n\nMETHODS\nObservational study.\n\n\nMETHODS\nHSU Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Department of Medical Oncology, Ankara, Turkey, from March 2017 to July 2019.\n\n\nMETHODS\nA total of 67 patients with mCRPC were retrospectively evaluated. Castration-naive patients and non-metastatic patients were excluded from the study. Comorbid diseases, ECOG performance status, PSA response, and the radiological response of the patients were recorded. Kaplan-Meier method was used for survival analysis, and a Cox regression model was formed.\n\n\nRESULTS\nThe overall survival (OS) was significantly longer in patients with eastern cooperative oncology group performance status (ECOG PS) 0 (26.0 vs. 14.0 months, p=0.031), PSA response (26.0 vs. 7.0 months, p=0.002), radiological response (26.0 vs. 10.0 months, p=0.006) and duration of enzalutamide ≥9 months (26.0 vs. 7.0 months, p<0.001) compared to ECOG PS 1. According to Cox regression analysis, patients with PSA response had 0.35 fold (CI.95% 0.13-0.94) reduced the risk of death and 0.36-fold (CI.95%0.16-0.85) reduced the risk of progression compared to those without PSA response. Moreover, longer enzalutamide treatment (≥9 months) was noted to decrease the risk of death.\n\n\nCONCLUSIONS\nPSA response, radiological response and duration of enzalutamide treatment may predict the improvement of survival in patients with mCRPC treated with enzalutamide. Key Words: Enzalutamide, Docetaxel, Castration-resistant prostate cancer, Overall survival, Progression-free survival.",
"affiliations": "Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Gaziantep University Medical Faculty Hospital, Gaziantep, Turkey.;Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey.;Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey.",
"authors": "Bilgetekin|Irem|I|;Basal|Fatma Bugdayci|FB|;Cinkir|Havva Yesil|HY|;Esin|Ece|E|;Oksuzoglu|Berna|B|;Demirci|Umut|U|",
"chemical_list": "D001549:Benzamides; D009570:Nitriles; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C540278:enzalutamide; D017430:Prostate-Specific Antigen",
"country": "Pakistan",
"delete": false,
"doi": "10.29271/jcpsp.2020.08.815",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "30(8)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D001549:Benzamides; D000077143:Docetaxel; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D016896:Treatment Outcome; D014421:Turkey",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "815-821",
"pmc": null,
"pmid": "32893792",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Enzalutamide Treatment in Metastatic Castration-resistant Prostate Cancer: Before and after Docetaxel.",
"title_normalized": "enzalutamide treatment in metastatic castration resistant prostate cancer before and after docetaxel"
} | [
{
"companynumb": "TR-ASTELLAS-2019US049132",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENZALUTAMIDE"
},
"drugadditional": "2",
... |
{
"abstract": "BACKGROUND\nRecurrent infection with the hepatitis C virus (HCV) after liver transplantation (LT) is associated with decreased graft and patient survival. Direct-acting antiviral (DAA) therapies have changed the landscape of HCV due to their excellent safety profile and cure rates. Our aim was to evaluate the efficacy and tolerability of antiviral therapy in recurrent HCV after LT with DAA therapy.\n\n\nMETHODS\nOur retrospective analysis included 46 LT recipients with HCV recurrence. Patients received therapy with DAA therapy between November 2014 and May 2016. Stage of fibrosis was documented by transient elastography (FibroScan).\n\n\nRESULTS\nThirty-three of the patients were men (71.7%), with a mean age of 59.6 years. Most patients were infected with HCV genotype 1 (71.7%) (1a = 7, 1b = 26) or genotype 3 (19.6%). Cirrhosis was present in 10 (21.7%). The most frequent immunosuppression regimen was tacrolimus + mycophenolate mofetil (MMF) (41.3%). Most patients received sofosbuvir + simeprevir (SOF+SMV) (n = 13, 28.3%) and sofosbuvir + daclatasvir (SOF+DCV) (n = 15, 32.6%). A virologic response at posttreatment week 12 was detected in 93.8% of the patients. Two patients failed treatment (1 had resistance-associated variants [RAVs] Y93H in NS5A). Three patients died due to chronic rejection, acute arterial thrombosis, and spontaneous bacterial peritonitis. Adverse events were observed in 23 patients (50%). The most common events were asthenia in 17 (37%) and headache in 6 (13%) patients. One patient discontinued treatment due to serious adverse events attributable to the drug's interaction with tacrolimus.\n\n\nCONCLUSIONS\nDAAs are safe and effective for use in treating HCV recurrence after LT, with results similar to those seen in the general population, including patients with cirrhosis.",
"affiliations": "Department of Hepatology, \"Virgen de las Nieves\" University Hospital, Granada, Spain. Electronic address: flornogueras@gmail.com.;Department of Hepatology, \"Virgen de las Nieves\" University Hospital, Granada, Spain.;Department of Hepatology, \"Virgen de las Nieves\" University Hospital, Granada, Spain.;Department of Hepatology, \"Virgen de las Nieves\" University Hospital, Granada, Spain.;Department of Hepatology, \"Virgen de las Nieves\" University Hospital, Granada, Spain.;Department of Hepatology, \"Virgen de las Nieves\" University Hospital, Granada, Spain.",
"authors": "Nogueras López|F|F|;López Garrido|A|A|;Ortega Suazo|E J|EJ|;Vadillo Calles|F|F|;Valverde López|F|F|;Espinosa Aguilar|M D|MD|",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.09.057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(2)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D016867:Immunocompromised Host; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D014775:Virus Activation",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "631-633",
"pmc": null,
"pmid": "29579872",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Therapy With Direct-Acting Antiviral Agents for Hepatitis C in Liver Transplant Recipients.",
"title_normalized": "therapy with direct acting antiviral agents for hepatitis c in liver transplant recipients"
} | [
{
"companynumb": "ES-ACCORD-108498",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "A 26-year-old patient with a history of chemotherapy for acute lymphoblastic leukemia presented with secondary amenorrhea and cyclic abdominal pain, and she was found to have vaginal stenosis due to adhesion of vaginal wall. The cause of the adhesion was considered to be vaginal inflammation induced by anticancer agents themselves. It was also considered that poor estrogenization of vaginal mucosa as a result of gonadotropin-releasing hormone agonist therapy, conducted for ovarian protection during chemotherapy, might have exacerbated it. Because it is more likely than ever for us to encounter patients who will undertake or had undertaken chemotherapy with gonadotropin-releasing hormone agonist therapy, keen observation and proper intervention would be important.",
"affiliations": "Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.",
"authors": "Sato|Masakazu|M|;Harada|Miyuki|M|;Oishi|Hajime|H|;Wada-Hiraike|Osamu|O|;Hirata|Tetsuya|T|;Nagasaka|Kazunori|K|;Koga|Kaori|K|;Fujii|Tomoyuki|T|;Osuga|Yutaka|Y|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal",
"country": "United States",
"delete": false,
"doi": "10.1097/LGT.0000000000000175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1089-2591",
"issue": "20(2)",
"journal": "Journal of lower genital tract disease",
"keywords": null,
"medline_ta": "J Low Genit Tract Dis",
"mesh_terms": "D000328:Adult; D018931:Antineoplastic Agents, Hormonal; D003251:Constriction, Pathologic; D005260:Female; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014623:Vaginal Diseases",
"nlm_unique_id": "9704963",
"other_id": null,
"pages": "e11-3",
"pmc": null,
"pmid": "26735150",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vaginal Stenosis After Gonadotropin-Releasing Hormone Agonist Therapy During Treatment for Acute Lymphoblastic Leukemia.",
"title_normalized": "vaginal stenosis after gonadotropin releasing hormone agonist therapy during treatment for acute lymphoblastic leukemia"
} | [
{
"companynumb": "JP-TEVA-664261ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
},
"drugadditional": null,
"... |
{
"abstract": "Filamentary keratitis is frequently a recurrent corneal condition characterized by the presence of filaments attached to the cornea. This condition can be challenging to manage because the clinician must treat the underlying cause and filament formation. N-acetylcysteine, a mucolytic agent, should be considered as adjunctive therapy to manage refractory cases.\n\n\n\nThis case demonstrates the utility of a mucolytic agent, N-acetylcysteine, to treat and manage filamentary keratitis when conventional therapies failed to provide long-term symptomatic relief and reduction of further filament formation.\n\n\n\nA 70-year-old man with recurrent filamentary keratitis (first occurrence 8 years prior) presented to the clinic with worsening red and painful eyes for 2 days. Prior treatment and management included artificial tears and ointments, punctal plugs, topical corticosteroids, contact lenses, and eyelid hygiene. Slit-lamp examination revealed multiple corneal filaments that were removed with forceps. He was diagnosed with recurrent filamentary keratitis secondary to dry eye disease and treated with preservative-free ophthalmic ointment, oral doxycycline, and 10% N-acetylcysteine ophthalmic solution. The patient had complete resolution of corneal filaments with significant relief of symptoms at 3-week, 5-month, and 10-month follow-up examinations.\n\n\n\nN-acetylcysteine is not commercially available in an ophthalmic solution and must be compounded by a local pharmacist for patient use. Because filamentary keratitis can be challenging to manage because of frequent recurrences, addition of N-acetylcysteine to the treatment regimen should be considered a viable option in refractory cases when other therapies have failed to provide sustained symptomatic relief and resolution of filaments.",
"affiliations": null,
"authors": "Crist|Andrew J|AJ|",
"chemical_list": "D000111:Acetylcysteine",
"country": "United States",
"delete": false,
"doi": "10.1097/OPX.0000000000001701",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-5488",
"issue": "98(6)",
"journal": "Optometry and vision science : official publication of the American Academy of Optometry",
"keywords": null,
"medline_ta": "Optom Vis Sci",
"mesh_terms": "D000111:Acetylcysteine; D000368:Aged; D003315:Cornea; D015352:Dry Eye Syndromes; D006801:Humans; D007634:Keratitis; D008297:Male; D013666:Tears",
"nlm_unique_id": "8904931",
"other_id": null,
"pages": "547-551",
"pmc": null,
"pmid": "34039909",
"pubdate": "2021-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case Report: Management of Refractory Filamentary Keratitis with N-acetylcysteine.",
"title_normalized": "case report management of refractory filamentary keratitis with n acetylcysteine"
} | [
{
"companynumb": "US-MLMSERVICE-20220304-3415226-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditiona... |
{
"abstract": "Varicella zoster virus (VZV) infection sometimes result in visceral disseminated VZV infection (VD-VZV), which is a fulminant disease featured by abdominal pain and the absence of skin lesions, particularly occurs in the immunosuppressive patients. Brachial plexus neuritis (BPN) is another rare type of VZV infection usually appears without blisters. Few diagnostic images of both VD-VZV and BPN-VZV have been reported. A 25-year-old woman receiving allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia. Unexplained severe pain in the left upper extremity followed by severe stomachache, liver dysfunction and unconsciousness appeared on day 344 post-HSCT. Computed tomography (CT) showed left brachial plexus hypertrophy and edematous changes to the hepatoduodenal ligament, fluorodeoxyglucose positron emission tomography (FDG-PET) showed increased uptake in both lesions. Intravenous acyclovir therapy was started and successfully resolved all symptoms. Several days later, blisters appeared all over the body and positive VZV DNA from blood using polymerase chain reaction test was obtained. FDG-PET and CT may offer supportive findings for detecting or diagnosing blister-less VZV infectious diseases.",
"affiliations": "Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Hematology, Fukui Red Cross Hospital, 2-4-1 Tsukimi, Fukui City, Fukui, 918-8501, Japan. Electronic address: leesin.581020@gmail.com.;Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Hematology, Fukui Red Cross Hospital, 2-4-1 Tsukimi, Fukui City, Fukui, 918-8501, Japan.;Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan.",
"authors": "Lee|Shin|S|;Tsukasaki|Hikaru|H|;Yamauchi|Takahiro|T|",
"chemical_list": "D000998:Antiviral Agents; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000212:Acyclovir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2019.02.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "25(7)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Brachial plexus neuritis; CT; FDG-PET; Visceral disseminated VZV",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000212:Acyclovir; D061605:Administration, Intravenous; D000328:Adult; D000998:Antiviral Agents; D001917:Brachial Plexus; D020968:Brachial Plexus Neuritis; D005260:Female; D019788:Fluorodeoxyglucose F18; D018380:Hematopoietic Stem Cell Transplantation; D014645:Herpesvirus 3, Human; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D014057:Tomography, X-Ray Computed; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D000073618:Varicella Zoster Virus Infection",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "556-558",
"pmc": null,
"pmid": "30879980",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Visceral disseminated varicella zoster virus infection with brachial plexus neuritis detected by fluorodeoxyglucose positron emission tomography and computed tomography.",
"title_normalized": "visceral disseminated varicella zoster virus infection with brachial plexus neuritis detected by fluorodeoxyglucose positron emission tomography and computed tomography"
} | [
{
"companynumb": "NVSJ2019JP000946",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nTo report a case of retinal and vitreous hemorrhage after intravitreal injection of dexamethasone implant (0.7 mg Ozurdex) and its management.\n\n\nMETHODS\nA 49-year-old man treated for diabetic macular edema developed vitreous and retinal hemorrhage after intravitreal injection of dexamethasone implant caused by a retinal impact during the injection procedure.\n\n\nRESULTS\nRetinal and vitreous hemorrhage absorbed spontaneously after 3 months. No retinal damage was detected. Intraocular pressure increased to 38 mm Hg after the injection and was well-controlled by medical therapy (dorzolamide hydrochloride-timolol maleate ophthalmic solution administered BID and oral acetazolamide 250 mg once a day). Since the surgeon performed the injection carefully without exerting any pressure on the eye, a device malfunction likely caused the implant to be injected too powerfully.\n\n\nCONCLUSIONS\nVitreous and retinal hemorrhage can occur after direct impact of an Ozurdex implant against the retina during the injection. So far this has never been described in the literature. Intraocular pressure elevation can worsen due to trabecular blockage by red blood cells. Spontaneous resolution can occur but vitrectomy is a therapeutic option if the hemorrhage persists.",
"affiliations": "Eye Clinic, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona - Italy.;Eye Clinic, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona - Italy.;Eye Clinic, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona - Italy.",
"authors": "Casati|Stefano|S|;Bruni|Enrico|E|;Marchini|Giorgio|G|",
"chemical_list": "D004343:Drug Implants; D005938:Glucocorticoids; D003907:Dexamethasone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "26(3)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D003907:Dexamethasone; D004343:Drug Implants; D005131:Eye Injuries; D005938:Glucocorticoids; D006801:Humans; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D012160:Retina; D012166:Retinal Hemorrhage; D014792:Visual Acuity; D014821:Vitrectomy; D014823:Vitreous Hemorrhage",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "e55-7",
"pmc": null,
"pmid": "26692056",
"pubdate": "2016-04-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Retinal and vitreous hemorrhage after traumatic impact of dexamethasone implant in a vitrectomized eye.",
"title_normalized": "retinal and vitreous hemorrhage after traumatic impact of dexamethasone implant in a vitrectomized eye"
} | [
{
"companynumb": "IT-ALLERGAN-1600275US",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Aspergillus endocarditis (AE) is a life-threatening condition with mortality rates approximating 80%. Herein, we describe the case of a 19-year-old patient with congenitally corrected transposition of great arteries, ventricular septal defect, and pulmonary atresia, who underwent seven cardiac surgical procedures in the past. The patient was operated for AE of a previously implanted pulmonary valve homograft associated with septic pulmonary embolism and right heart failure but succumbed to multi-organ failure three months later. To our knowledge, this is one of two reported cases of Aspergillus infection of a pulmonary homograft, indicating the rarity of the disease.",
"affiliations": "Department of Cardiac Surgery, Mitera Hospital, Athens, Greece.;Department of Congenital Cardiology, Mitera Hospital, Marousi, Athens, Greece.;Department of Cardiac Surgery, Mitera Hospital, Athens, Greece.;Adult and Congenital Heart Disease, Royal Brompton, Syndney Street, London, United Kingdom.;Department of Congenital Cardiology, Mitera Hospital, Marousi, Athens, Greece.;Department of Cardiac Surgery, Mitera Hospital, Athens, Greece.",
"authors": "Karangelis|Dimos|D|;Tzifa|Aphrodite|A|;Mylonas|Konstantinos S|KS|https://orcid.org/0000-0002-2356-6694;Gatzoulis|Michael A|MA|;Kavvouras|Charalampos|C|;Mitropoulos|Fotis|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2150135120988640",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2150-1351",
"issue": null,
"journal": "World journal for pediatric & congenital heart surgery",
"keywords": null,
"medline_ta": "World J Pediatr Congenit Heart Surg",
"mesh_terms": null,
"nlm_unique_id": "101518415",
"other_id": null,
"pages": "2150135120988640",
"pmc": null,
"pmid": "33956543",
"pubdate": "2021-05-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Aspergillus Endocarditis of Pulmonary Homograft in a Congenital Heart Disease Patient.",
"title_normalized": "aspergillus endocarditis of pulmonary homograft in a congenital heart disease patient"
} | [
{
"companynumb": "GR-GILEAD-2022-0571730",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3",
... |
{
"abstract": "An 18-year-old man with a history of right ventricle to pulmonary artery conduit implantation for repair of congenital heart disease and vasculitis requiring chronic immunosuppression with azathioprine presented to the University of Ottawa with bacteremia. A transthoracic echocardiogram revealed no abnormalities at the site of the conduit. A fludeoxyglucose positron emission tomography scan was subsequently obtained that demonstrated an infected right ventricle to pulmonary artery conduit. It is important to remember that, as is true for classic valve endocarditis, an unremarkable transthoracic echocardiogram does not rule out an infected conduit in this population, and nuclear imaging may have important diagnostic utility.",
"affiliations": "Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.;Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.;Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.;Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.;Division of Pediatric Cardiac Surgery, Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada.;Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.",
"authors": "Parlow|Simon|S|;Beamish|Paul|P|;Desjardins|Isabelle|I|;Fulop|John|J|;Maharajh|Gyaandeo|G|;Castellucci|Lana|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.cjco.2019.08.001",
"fulltext": "\n==== Front\nCJC Open\nCJC Open\nCJC Open\n2589-790X Elsevier \n\nS2589-790X(19)30051-4\n10.1016/j.cjco.2019.08.001\nCase Report\nInfected Rastelli Conduit in an Immunocompromised Patient That Was Not Visible on Transthoracic Echocardiogram\nParlow Simon MDsparlow@toh.caa∗ Beamish Paul MDa Desjardins Isabelle MDa Fulop John MDb Maharajh Gyaandeo MDc Castellucci Lana MD, MScdef a Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada\nb Division of Cardiology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada\nc Division of Pediatric Cardiac Surgery, Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada\nd Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada\ne School of Epidemiology and Public Health, University of Ottawa, Ontario, Canada\nf Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada\n∗ Corresponding author: Dr Simon Parlow, Department of Medicine, University of Ottawa, 737 Parkdale Ave, Ottawa, Ontario K1Y 4E9, Canada. sparlow@toh.ca\n07 10 2019 \n11 2019 \n07 10 2019 \n1 6 324 326\n10 7 2019 12 8 2019 © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc.2019Canadian Cardiovascular SocietyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).An 18-year-old man with a history of right ventricle to pulmonary artery conduit implantation for repair of congenital heart disease and vasculitis requiring chronic immunosuppression with azathioprine presented to the University of Ottawa with bacteremia. A transthoracic echocardiogram revealed no abnormalities at the site of the conduit. A fludeoxyglucose positron emission tomography scan was subsequently obtained that demonstrated an infected right ventricle to pulmonary artery conduit. It is important to remember that, as is true for classic valve endocarditis, an unremarkable transthoracic echocardiogram does not rule out an infected conduit in this population, and nuclear imaging may have important diagnostic utility.\n\nRésumé\nUn homme de 18 ans, chez qui on avait implanté un conduit ventricule droit-artère pulmonaire (VD-AP) pour réparer une cardiopathie congénitale et qui avait des antécédents de vascularite nécessitant une immunosuppression continue par l’azathioprine, s’est présenté à l’hôpital affilié à l'Université d'Ottawa pour une bactériémie. Une échocardiographie transthoracique n’a révélé aucune anomalie au site du conduit. Elle a été suivie d’un examen de tomographie par émission de positrons (TEP) au fludésoxyglucose, qui a mis en évidence une infection du conduit VD-AP. Il est important de retenir que, comme dans le cas d’une endocardite valvulaire classique, un échocardiogramme transthoracique sans particularité ne permet pas d’exclure une infection de conduit dans cette population, et que l’imagerie nucléaire peut être d’une grande utilité diagnostique.\n==== Body\nNovel Teaching Point\n• In patients with suspected IE of a surgical prosthesis implanted for repair of congenital heart disease, nuclear imaging may play an important role in the diagnosis by improving sensitivity of echocardiography alone.\n\n\n\n\n\nCase Description\nAn 18-year-old man presented to the University of Ottawa’s emergency department with a 4-day history of fevers, chills, and rigors. He had a history of congenital heart disease and was born with d-transposition of the great vessels (d-TGA), ventricular septal defect (VSD), and right ventricular outflow tract (RVOT) obstruction. On his first day of life, he underwent the Rastelli procedure, involving implantation of a right ventricular to pulmonary artery (RV-PA) conduit to bypass the RVOT obstruction. In 2008, he was diagnosed with antineutrophil cytoplasmic antibody–associated systemic vasculitis with rapidly progressive glomerulonephritis resulting in stage III chronic kidney disease. His vasculitis has since remained quiescent with chronic azathioprine therapy for immunosuppression. He had no history of intravenous drug use or other high-risk behaviours.\n\nOn presentation, the patient was hypotensive, tachycardic, and febrile. He had normal neurological examination results. His precordial examination revealed a loud S2 and a III/VI crescendo-decrescendo systolic murmur heard loudest at his left upper sternal border with no radiation. He had normal dentition. In the emergency department, he underwent chest radiography and urine microscopy testing. The results were normal, and the patient was empirically administered vancomycin and piperacillin-tazobactam. On the first day of admission, his blood cultures returned positive for methicillin-sensitive Staphylococcus aureus, and his antibiotic choice was narrowed to intravenous cloxacillin. He then underwent transthoracic echocardiography (TTE) to assess for infective endocarditis (IE) as a source for his bacteremia, and no vegetations were seen on his native valves or his RV-PA conduit in long-axis view (Fig. 1). On day 5 of admission, computed tomography scans of his head, abdomen, and pelvis were obtained and did not reveal any source of infection. Repeat blood cultures were persistently positive, and because suspicion for endocarditis remained high, he was referred for a fludeoxyglucose positron emission tomography (FDG-PET) scan. This test was chosen instead of transesophageal echocardiography (TEE) because the team believed it would be of higher diagnostic yield given his complex cardiac anatomy. The FDG-PET scan showed significant radiotracer uptake at the site of the RV-PA conduit, consistent with active conduit infection (Fig. 2).Figure 1 Transthoracic echocardiogram showing the right ventricular to pulmonary artery (RV-PA) conduit without (L) and with (R) colour Doppler flow displaying no identifiable vegetation.\n\nFigure 2 Significant radiotracer uptake at the site of the RV-PA conduit seen on positron emission tomography (PET) scan in coronal (L), sagittal (C), and transverse (R) views.\n\n\n\nAfter 9 weeks of intravenous antibiotics, most of which were given in the inpatient setting, he was taken electively to the operating room for replacement of his RV-PA conduit. He was discharged to his home in stable condition after a brief admission to the cardiac surgery intensive care unit.\n\nDiscussion\nThe Rastelli procedure was initially described by Rastelli and colleagues1 in 1969 and remains the procedure of choice for surgical repair of d-TGA associated with VSD and RVOT obstruction. It involves baffling of the VSD to the aorta and bypass of the RVOT using an extracardiac conduit. IE after a Rastelli operation is rare. Morris et al.2 followed a population-based registry of all patients in the state of Oregon who had congenital heart disease that was surgically repaired from 1958 to 1998, and cumulative incidence of IE at 20 years after surgery in all patients with surgically repaired d-TGA was 4%.\n\nAlthough TEE plays an important role in the diagnosis of IE and is recommended by the American Heart Association and American College of Cardiology in patients who have persistently positive blood cultures despite negative TTE results,3 nuclear medicine technology (NMT) remains an important alternative diagnostic tool for clinicians to consider in this case. NMT can aid in the diagnosis of IE when echocardiography is inconclusive and has been shown to have high sensitivity for detecting IE in the setting of congenital heart disease.4 In a recent meta-analysis, FDG-PET improved the diagnostic sensitivity of prosthetic valve IE to greater than 80% when used as an adjunct to echocardiography,5 and in a cohort of 39 patients with suspected infected cardiac prosthesis despite an inconclusive TEE, FDG-PET definitively diagnosed 14 patients.6 In addition, recent data have led the European Society of Cardiology to recommend the use of PET imaging in the diagnosis of prosthetic valve endocarditis.7 However, it should be noted that the diagnostic sensitivity of NMT can be affected by the adequate preparation of the patient before the image is acquired and the methodology used for image interpretation,8 and currently no guidelines exist outlining criteria for either of these 2 factors.\n\nConclusion\nTo our knowledge, we present the first case report of a patient with previous RV-PA conduit placement who was immunosuppressed and subsequently developed IE. His diagnosis was eventually confirmed using NMT. As is true for valvular endocarditis, a negative TTE should never be used to definitively rule out infection of an implanted conduit, and further diagnostic modalities such as TEE may be necessary to confirm the diagnosis. NMT also should be considered as a method of improving diagnostic sensitivity in this population by improving sensitivity of echocardiography alone.\n\nAcknowledgements\nThe authors thank the University of Ottawa’s Department of Medicine for its support in the preparation of this case report.\n\nDisclosures\nThe authors have no disclosures to declare.\n\nEthics Statement: The research reported in this article has adhered to all relevant ethical guidelines.\n\nSee page 325 for disclosure information.\n==== Refs\nReferences\n1 Rastelli G.C. Wallace R.B. Ongley P.A. Complete repair of transposition of the great arteries with pulmonary stenosis. A review and report of a case corrected by using a new surgical technique Circulation 39 1969 83 95 5782810 \n2 Morris C.D. Reller M.D. Menashe V.D. Thirty-year incidence of infective endocarditis after surgery for congenital heart defect JAMA 279 1998 599 603 9486754 \n3 Nishimura R.A. Otto C.M. Bonow R.O. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 63 2014 e57 e185 24603191 \n4 Meyer Z. Fischer M. Koerfer J. The role of FDG-PET-CT in pediatric cardiac patients and patients with congenital heart defects Int J Cardiol 220 2016 656 660 27393845 \n5 Mahmood M. Kendi A.T. Ajmal S. Meta-analysis of 18F-FDG PET/CT in the diagnosis of infective endocarditis J Nucl Cardiol 26 2019 922 935 29086386 \n6 Rouzet F. Chequer R. Benali K. Respective performance of 18F-FDG PET and radiolabeled leukocyte scintigraphy for the diagnosis of prosthetic valve endocarditis J Nucl Med 55 2014 1980 1985 25453046 \n7 Jiménez-Ballvé A. Pérez-Castejón M.J. Delgado-Bolton R.C. Assessment of the diagnostic accuracy of 18F-FDG PET/CT in prosthetic infective endocarditis and cardiac implantable electronic device infection: comparison of different interpretation criteria Eur J Nucl Med Mol Imaging 43 2016 2401 2412 27596984 \n8 Habib G. Lancellotti P. Antunes M.J. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM) Eur Heart J 36 2015 3075 3128 26320109\n\n",
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"title": "Infected Rastelli Conduit in an Immunocompromised Patient That Was Not Visible on Transthoracic Echocardiogram.",
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"abstract": "Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a critical strategy to overcome the COVID-19 pandemic. Multiple SARS-CoV-2 vaccines have been developed in a rapid timeframe to combat the pandemic. While generally safe and effective, rare cases of venous thromboembolism (VTE) have been reported after two adenovirus-based vaccines, the AstraZeneca ChAdOx1 nCoV-19 vaccine and the Janssen Ad.26.COV2.S vaccine, as well as after the Pfizer-BioNTech BNT162b2 mRNA vaccine. Here, we present the case of a patient who developed acute pulmonary emboli (PE) shortly after his second dose of the Moderna mRNA-1273 SARS-CoV-2 vaccine. We report the results of an extensive thrombophilia workup that was normal except for the identification of positive lupus anticoagulant (LA) signals. It is our goal to contribute to the body of knowledge regarding SARS-CoV-2 vaccines and encourage vaccine adverse event reporting so that clinicians can have a full appreciation and awareness of the possible adverse events related to these critical vaccines.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.;Division of Laboratory Medicine and Pathology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.;Department of Hospital Internal Medicine, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.",
"authors": "Wiest|Nathaniel E|NE|0000-0002-6211-2716;Johns|Gretchen S|GS|;Edwards|Eric|E|",
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"fulltext": "\n==== Front\nVaccines (Basel)\nVaccines (Basel)\nvaccines\nVaccines\n2076-393X\nMDPI\n\n10.3390/vaccines9080903\nvaccines-09-00903\nCase Report\nA Case of Acute Pulmonary Embolus after mRNA SARS-CoV-2 Immunization\nhttps://orcid.org/0000-0002-6211-2716\nWiest Nathaniel E. 1\nJohns Gretchen S. 2\nEdwards Eric 3*\nTripp Ralph A. Academic Editor\n1 Department of Internal Medicine, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA; wiest.nathaniel@mayo.edu\n2 Division of Laboratory Medicine and Pathology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA; johns.gretchen@mayo.edu\n3 Department of Hospital Internal Medicine, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA\n* Correspondence: edwards.eric@mayo.edu; Tel.: +1-904-953-2000\n14 8 2021\n8 2021\n9 8 90325 5 2021\n06 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nVaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a critical strategy to overcome the COVID-19 pandemic. Multiple SARS-CoV-2 vaccines have been developed in a rapid timeframe to combat the pandemic. While generally safe and effective, rare cases of venous thromboembolism (VTE) have been reported after two adenovirus-based vaccines, the AstraZeneca ChAdOx1 nCoV-19 vaccine and the Janssen Ad.26.COV2.S vaccine, as well as after the Pfizer-BioNTech BNT162b2 mRNA vaccine. Here, we present the case of a patient who developed acute pulmonary emboli (PE) shortly after his second dose of the Moderna mRNA-1273 SARS-CoV-2 vaccine. We report the results of an extensive thrombophilia workup that was normal except for the identification of positive lupus anticoagulant (LA) signals. It is our goal to contribute to the body of knowledge regarding SARS-CoV-2 vaccines and encourage vaccine adverse event reporting so that clinicians can have a full appreciation and awareness of the possible adverse events related to these critical vaccines.\n\nCOVID-19\nSARS-CoV-2\nvaccination\npulmonary embolus\nadverse event\n==== Body\n1. Introduction\n\nThe COVID-19 pandemic has claimed nearly four million lives and disrupted societies and economies globally [1]. Vaccines against SARS-CoV-2 were developed in record time and across a variety of vaccine platforms, including adenovirus vectors, protein subunit, and newer mRNA-based platforms [2]. Recently, reports of rare venous thromboembolism (VTE) and thrombocytopenia events were described for two adenovirus-based vaccines, the AstraZeneca ChAdOx1 nCoV-19 vaccine and the Janssen Ad.26.COV2.S vaccine, leading to further regulatory and safety review [3,4,5]. Furthermore, two cases of VTE were recently described shortly after patients received the Pfizer-BioNTech BNT162b2 mRNA vaccine [6,7]. While these events are fortunately rare, VTE is a potentially life-threatening adverse event whose prompt recognition is critical. Here, we describe a case of acute PE that occurred shortly after the second dose of the Moderna mRNA-1273 SARS-CoV-2 vaccine.\n\n2. Case Report\n\nA 66-year-old male with past medical history of hypertension, hyperlipidemia, and surgically resected renal cell carcinoma (RCC) presented to the emergency department with a chief complaint of right flank pain and right pleuritic chest pain. He was in his usual state of health until he received his second dose of the Moderna SARS-CoV-2 vaccine dose 10 days prior. 24 h after the immunization he experienced fevers, chills, and arthralgias that transitioned to progressive right-sided flank pain and pleuritic chest pain. There was no history of recent immobility or surgery, and he was exercising daily before presenting. He denied any personal or family history of VTE, PE, or known hypercoagulable state. His oncologic history was notable for clinical stage II, pathologic stage T1aNXM0 RCC status-post left partial nephrectomy two years prior with clear surgical margins and no evidence of recurrence on surveillance imaging. His age-appropriate cancer screening was up to date. A full review of systems was positive only for fatigue, pleuritic chest pain, and flank pain and was otherwise negative.\n\nIn the emergency department, the patient’s vital signs were normal with a temperature of 36.8 degrees Celsius, pulse rate of 65, blood pressure of 138/84 mmHg, respiratory rate of 17, and oxygen saturation of 97% on room air. Inspiratory crackles were heard at the right lung base; physical examination was otherwise unremarkable including no jugular venous distension and no extremity edema. Laboratory analysis is described in Table 1. Briefly, the patient had a normal chemistry panel and a normal complete blood count. However, he had elevated C-reactive protein and D-dimer levels. CT scan of the abdomen and pelvis without contrast demonstrated no acute intraabdominal process, including no evidence of recurrent RCC. However, PE-protocol CT angiogram of the chest demonstrated extensive multifocal pulmonary emboli involving both right and left lower lobe pulmonary arteries with evidence of right ventricular strain (Figure 1).\n\nFollowing the diagnosis of PE, a 1 mg/kg subcutaneous injection of enoxaparin was immediately administered by the emergency department and labs were drawn approximately three hours later by the admitting team. A coagulation evaluation and thrombophilia workup were initiated (Table 1). The patient’s prothrombin time (PT) and international normalized ratio (INR) were mildly prolonged and corrected when mixed 50:50 with normal pooled plasma, consistent with a possible factor deficiency. However, measured factor levels were within normal limits. The patient’s prothrombin G20210A and factor V Leiden R506Q mutation tests were negative, and he demonstrated normal protein C activity, free protein S antigen, protein S activity, and antithrombin activity. A dilute PT assay was positive, and the StaClot LA assay was borderline positive, suggesting the possible presence of LA. Beta-2 glycoprotein 1 antibodies and antiphospholipid IgG antibodies were undetected; however, antiphospholipid IgM antibodies were weakly positive. SARS-CoV-2 nucleocapsid antibodies were undetected while SARS-CoV-2 spike antibodies were strongly positive, consistent with robust vaccine-induced immunity but no history of COVID-19. Antinuclear antibodies were negative and serum homocysteine levels were normal. The patient was transitioned to apixaban for anticoagulation and discharged in stable condition with hematology follow up.\n\n3. Discussion\n\nIn this report, we describe the case of a 66-year-old male with no prior thromboembolic or hypercoagulable history who developed acute, bilateral pulmonary emboli promptly following his second Moderna SARS-CoV-2 immunization. One possibility is that these two events are coincidental, as there is a known 1.3–1.8 per thousand baseline annual incidence of VTE in patients age 65–69 [8]. However, the striking overlap of systemic symptoms from the mRNA immunization and the flank and pleuritic chest pain attributed to the PE are suggestive of a possible association.\n\nThere is significant interest in the topic of VTE after COVID-19 immunization based on reports of a rare syndrome of VTE and thrombocytopenia in patients who received the adenovirus-platform AstraZeneca ChAdOx1 and Janssen Ad.26.COV2.S vaccines [3,4]. Scully et al. described 23 patients who received the AstraZeneca ChAdOx1 nCoV-19 vaccine in the United Kingdom and developed thrombosis and thrombocytopenia. Furthermore, 22 of 23 patients with this syndrome, which the authors entitled vaccine-induced immune thrombocytopenia (VITT), were found to have circulating platelet factor 4 (PF4) antibodies [4]. Greinacher et al. described 11 patients in Germany and Austria who developed VITT after the AstraZeneca ChAdOx1 nCoV-19 vaccine, and Schultz et al., described five patients in Norway who developed VITT after the AstraZeneca ChAdOx1 nCoV-19 vaccine [9,10]. All of the patients in these two reports who were tested for PF4 antibodies had positive ELISA results. Similarly, a cohort of patients who developed VTE after the Janssen Ad.26.COV2.S vaccine in the United States had a syndrome of cerebral venous thrombosis (CVT) and thrombocytopenia in 12/15 cases, though PF4 antibody levels were not reported [3]. Those authors described the syndrome as thrombosis with thrombocytopenia syndrome (TTS). PF4 antibodies are usually found in heparin-induced thrombocytopenia (HIT), a dangerous thrombotic condition that typically occurs after heparin exposure and is mediated partly by PF4 immune complexes that activate platelets and promote thrombin generation [11,12]. Thrombophilia, antinuclear antibody, and antiphospholipid antibodies were negative in the UK VITT patients, though 5/10 patients tested for LA had a positive result that was considered potentially unreliable [4]. Amongst the case series of the VITT/TTS patients, notable similarities include that most of the patients were young (<50 years old), female (61–100%), and many developed either disseminated intravascular coagulation or multiple sites of thrombosis including portal vein and CVT leading to serious illness with mortality in 20–60% of cases [3,4,9,10].\n\nIn contrast, there have been comparatively few published reports of VTE after mRNA SARS-CoV-2 immunizations. Carli et al. described a case of a 66-year-old woman who developed a right calf DVT two days after the second dose of the Pfizer-BioNTech BNT162b2 vaccine [6]. Al-Maqbali et al. described the case of a 59-year-old woman who developed DVT and PE seven days following the first dose of the Pfizer-BioNTech BNT162b2 vaccine [7]. That patient’s laboratory testing was notable for normal platelets (182 × 109/L) but a positive HIT ELISA test with an optical density assay of 0.617 (normal <0.4). HIT functional confirmatory assays were not available in that report, and previous platelet levels were not reported to allow an assessment for possible decline in platelet count after immunization. Notably, that patient was hospitalized for COVID-19 pneumonia seven months prior to the immunization, and it is unclear if she had exposure to heparin products. Nonetheless, the findings of the patient described by Al-Maqbali et al. contrast with the VITT/TTS patients who experienced both severe thrombocytopenia and positive HIT ELISAs. Neither of these case reports described thrombophilia test results and both patients were treated successfully with oral anticoagulants.\n\nWe did not test for PF4 antibodies in our patient as we had no clinical suspicion for HIT and VITT/TTS after COVID-19 immunization was not yet described. Unfortunately, no stored serum remained from our patient’s hospital encounter for us to send for PF4 antibody testing after VITT/TTS was described. Our patient’s D-dimer level was 3840 ng/mL fibrinogen equivalent units (FEU), whereas the median D-dimer level in the VITT patients was 31,301 FEU, or approximately ten times that of our patient [4,13]. This, combined with the fact that our patient had a normal platelet count, significantly reduces the likelihood that VITT/TTS was the mechanism of thrombosis in our patient, though we cannot rule out a mechanism similar to that of the Al-Maqbali et al. report with normal platelets and a positive HIT ELISA [7]. We look forward to the publication of more reports of VTE after SARS-CoV-2 immunizations so that a better assessment of potential mechanisms and comparison of patient characteristics and laboratory data can be performed.\n\nWe note that the only positive signals from the thrombophilia workup in our patient were found in the LA workup and included a positive dilute PT study, a borderline positive StaClot LA assay, and a weakly positive antiphospholipid IgM level. In the dilute PT test, patient plasma is added to two different dilutions of thromboplastin. This decreases the amount of phospholipid and enhances sensitivity to the presence of a lupus anticoagulant, which if present will prolong the patient’s PT compared to a corresponding pooled normal plasma PT [14]. Our patient had a strong positive result for the dilute PT study. In the StaClot LA test, patient plasma and normal plasma are mixed 1:1 and the aPTT is assessed both in the presence and absence of hexagonal phase phospholipid (HEX) that neutralizes LA antibodies. A positive StaClot test signifies that the HEX reagent was able to decrease the rate of clot formation for the aPTT, implying the presence of LA [15]. Our patient had a borderline positive StaClot result.\n\nAntiphospholipid antibodies are autoantibodies that target proteins binding to phospholipids such as the cellular lipid bilayer [16]. A pathologic quantity of antiphospholipid antibodies is usually defined as >40 mean phospholipid units (MPU), whereas our patient had a weakly positive result of 27.1 MPU of antiphospholipid IgM [17]. Taken together, these studies imply the presence of LA but do not yet meet the diagnostic threshold for antiphospholipid syndrome (APS), which requires positive LA testing on two or more occasions at least 12 weeks apart [17]. Possible explanations for our patient’s LA signals include an early APS, the transient presence of a LA, or potentially false positives either due to nonspecific cross reactivity by other antibodies in the patient’s plasma or interference from the injection of enoxaparin that was given before the labs were drawn. Of note, therapeutic dose enoxaparin is not expected to affect either the dilute PT test, StaClot assay, or antiphospholipid antibody levels [18]. Repeat testing, including for PF4 antibodies, will be performed six months after PE diagnosis after the patient is off anticoagulation for two weeks to eliminate the possible interference from anticoagulants.\n\nInterestingly, antiphospholipid antibodies have been correlated to VTE in patients with COVID-19 [19,20]. If a relationship between VTE and positive LA tests after mRNA SARS-CoV-2 immunization is reported in other patients, then this may suggest at least one similarity in mechanism of VTE between COVID-19 infection and mRNA immunization. Another possibility is that some patients with an underlying autoimmune predisposition may have flare ups after mRNA immunization, as suggested by reports of flares in conditions including familial thrombocytopenia [21], though data assessing the relationship between mRNA SARS-CoV-2 immunization and autoimmune conditions is currently lacking.\n\nIt is very important to emphasize here that the risk of VTE after SARS-CoV-2 immunization is significantly lower than the risk of VTE during COVID-19 infection, which is approximately 21% per infection in a recent meta-analysis [22]. In fact, VTE was not reported as an adverse event during Phase III studies of the Pfizer-BioNTech and Moderna SARS-CoV-2 mRNA vaccines, illustrating the rarity of these events [23,24]. While large scale epidemiologic data comparing the risk of VTE after COVID-19 infection versus mRNA immunization is not widely available yet, one pre-publication retrospective cohort study in the United Kingdom reports that the incidence of CVT was 39.0 per million people over a 2-week period after COVID-19 diagnosis versus 4.1 per million people over a 2-week period after receiving either the Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273 vaccines [25]. Given that the background risk of CVT was 0.41 per million per 2-week period in this study, these data potentially support the hypothesis that there may be an increased risk of VTE after COVID-19 mRNA immunization that is significantly less than the risk incurred by natural COVID-19 infection. Additionally, data from the WHO VigiBase database indicate a rate of 0.21 cases of thrombotic events per 1 million person vaccinated-days in patients who received either the Pfizer, Moderna, or AstraZeneca vaccines [26]. Interestingly, the proportion of arterial thrombotic events was higher in the Pfizer and Moderna (mRNA) vaccine groups than the AstraZeneca (adenovirus) group, supporting the hypothesis that the mechanism of vaccine induced thrombosis is likely different between adenovirus and mRNA platform vaccines. Of note, these data were not compared to matched unvaccinated controls and as such cannot be used to compare to a background rate of venous and arterial thrombosis [26]. We eagerly await the final published version of the UK report as well as the publication of epidemiologic data from other countries including the United States. As more clinicians report adverse events and laboratory data from VTE events after COVID immunization, a better understanding of the magnitude and possible mechanisms of these adverse events will be obtained.\n\n4. Conclusions\n\nIn summary, we encourage clinicians to remain vigilant for adverse events after SARS-CoV-2 immunization and to report these events to the Vaccine Adverse Event Reporting System (VAERS) in the United States or the equivalent system in other countries [27]. Given the rarity of VTE after SARS-CoV-2 mRNA immunization, we wholeheartedly endorse continued immunization in line with national and international guidelines as well as full reporting of possible vaccine related adverse events to build a better understanding of the adverse effect profiles of these critically important vaccines.\n\nAcknowledgments\n\nWe gratefully acknowledge the assistance of Candido Rivera (Mayo Clinic hematology) in the review of this manuscript.\n\nAuthor Contributions\n\nN.E.W. and E.E. wrote the manuscript; G.S.J. provided hematopathology results interpretation and numerous significant intellectual contributions to the content of this manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding. Departmental funds (E.E.) were used to support publication of this report.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nWritten informed consent was obtained from the patient for his anonymous information to be published in this report.\n\nConflicts of Interest\n\nThe authors declare no potential conflict of interest.\n\nFigure 1 Acute pulmonary emboli after SARS-CoV-2 mRNA vaccination. CT PE protocol axial images demonstrate bilateral segmental and subsegmental pulmonary emboli. Arrows indicate contrast filling defects at locations of pulmonary emboli. RLL = right lower lobe. LLL = left lower lobe.\n\nvaccines-09-00903-t001_Table 1 Table 1 Laboratory studies. Indicated tests with patient’s laboratory values, reference ranges, and units are provided. Abnormal values highlighted in orange. WBC = white blood cell. BUN = blood urea nitrogen. GFR = glomerular filtration rate. BSA = body surface area. ESR = eosinophil sedimentation rate. PT = prothrombin time. INR = international normalize ratio. APTT = activated partial thromboplastin time. DRVVT = dilute Russell viper venom time. MPL = IgM phospholipid units. GPL = IgG phospholipid units. Ab = antibody.\n\nLaboratory Studies\tCoagulation Studies\tThrombophilia Studies\t\nTest\tValue\tReference\tTest\tValue\tReference\tTest\tValue\tReference\t\nHemoglobin\t13.8 g/dL\t13.2–16.6 g/dL\tPT\t14.0 s\t9.4–12.5 s\tProthrombin G20210A mutation\tNegative\tNegative\t\nPlatelet Count\t176 × 109/L\t135–317 × 109/L\tINR\t1.2\t0.9–1.1\tFactor V leiden (R506Q) mutation\tNegative\tNegative\t\nWBC count\t9.2 × 109/L\t3.4–9.6 × 109/L\tAPTT\t35 s\t25–37 s\tAntithrombin activity\t81%\t80–130%\t\nSodium\t141 mmol/L\t135–145 mmol/L\tFactor II Assay\t120%\t75–145%\tProtein C activity\t102%\t70–150%\t\nPotassium\t4.2mmol/L\t3.6–5.2 mmol/L\tFactor V Assay\t119%\t70–165%\tProtein S antigen, Free\t105%\t65–160%\t\nChloride\t104 mmol/L\t98–107 mmol/L\tFactor VII Assay\t76%\t65–180%\tProtein S activity\t137%\t65–160%\t\nBUN\t17 mg/dL\t8–24 mg/dL\tFactor X Assay\t105%\t70–150%\tPT dilution 1:2\t12.4s\t9.4–12.5 s\t\nCreatinine\t1.14 mg/dL\t0.74–1.35 mg/dL\tThrombin Time\t20.9s\t15.8–24.9 s\tDilute PT 1:50 ratio\t1.7\t<1.1\t\nGlucose\t104 mg/dL\t70–140 mg/dL\t\t\t\tDilute PT 1:500 ratio\t1.7\t<1.1\t\nEstimated GFR.\t77 mL/min/BSA\t>60 mL/min/BSA\t\t\t\tDRVVT ratio\t1.1\t0–1.1\t\nC-reactive protein\t38.2 mg/L\t<8.0 mg/L\t\t\t\tStaClot LA\t10.7 s\t<8 s\t\nESR\t14 mm/1 h\t0–22 mm/1 h\t\t\t\tHomocysteine\t14.4 nmol/L\t7.1–16.3 nmol/L\t\nD-dimer\t3840 ng/mL FEU\t<500 ng/mL FEU\t\t\t\tAntinuclear Ab\t0.1 U\t<1.0 U\t\nSARS-CoV-2 RNA, Nasal Swab\tNegative\tNegative\t\t\t\tBeta 2 Glycoprotein 1 Ab IgM\t<9.4 U/mL\t<15.0 U/mL\t\nSARS-CoV-2 Nucleocapsid Total Ab\tNegative\tNegative\t\t\t\tBeta 2 Glycoprotein 1 Ab IgG\t<9.4 U/mL\t<15.0 U/mL\t\nSARS-CoV-2 Spike Ab\t>2500 U/mL\t<0.8 U/mL\t\t\t\tPhospholipid Ab IgM\t27.1 MPL\t<15.0 MPL\t\n\t\t\t\t\t\tPhospholipid Ab IgG\t<9.4 GPL\t<15.0 GPL\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University Available online: https://coronavirus.jhu.edu/map.html (accessed on 24 June 2021)\n2. Li Y.D. Chi W.Y. Su J.H. Ferrall L. Hung C.F. Wu T.C. Coronavirus vaccine development: From SARS and MERS to COVID-19 J. Biomed. Sci. 2020 27 104 10.1186/s12929-020-00695-2 33341119\n3. MacNeil J.R. Su J.R. Broder K.R. Guh A.Y. Gargano J.W. Wallace M. Hadler S.C. Scobie H.M. Blain A.E. Moulia D. Updated Recommendations from the Advisory Committee on Immunization Practices for Use of the Janssen (Johnson & Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients—United States, April 2021 MMWR Morb. Mortal Wkly. Rep. 2021 70 651 656 10.15585/mmwr.mm7017e4 33914723\n4. Scully M. Singh D. Lown R. Poles A. Solomon T. Levi M. Goldblatt D. Kotoucek P. Thomas W. Lester W. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination N. Engl. J. Med. 2021 384 2202 2211 10.1056/NEJMoa2105385 33861525\n5. Mahase E. Covid-19: Unusual blood clots are “very rare side effect” of Janssen vaccine, says EMA BMJ 2021 373 n1046 10.1136/bmj.n1046 33883164\n6. Carli G. Nichele I. Ruggeri M. Barra S. Tosetto A. Deep vein thrombosis (DVT) occurring shortly after the second dose of mRNA SARS-CoV-2 vaccine Intern. Emerg. Med. 2021 16 803 804 10.1007/s11739-021-02685-0 33687691\n7. Al-Maqbali J.S. Al Rasbi S. Kashoub M.S. Al Hinaai A.M. Farhan H. Al Rawahi B. Al Alawi A.M. A 59-Year-Old Woman with Extensive Deep Vein Thrombosis and Pulmonary Thromboembolism 7 Days Following a First Dose of the Pfizer-BioNTech BNT162b2 mRNA COVID-19 Vaccine Am. J. Case Rep. 2021 22 e932946 10.12659/AJCR.932946 34117206\n8. Kniffin W.D. Jr. Baron J.A. Barrett J. Birkmeyer J.D. Anderson F.A. Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly Arch. Intern. Med. 1994 154 861 866 10.1001/archinte.1994.00420080053005 8154949\n9. Greinacher A. Thiele T. Warkentin T.E. Weisser K. Kyrle P.A. Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination N. Engl. J. Med. 2021 384 2092 2101 10.1056/NEJMoa2104840 33835769\n10. Schultz N.H. Sorvoll I.H. Michelsen A.E. Munthe L.A. Lund-Johansen F. Ahlen M.T. Wiedmann M. Aamodt A.H. Skattor T.H. Tjonnfjord G.E. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination N. Engl. J. Med. 2021 384 2124 2130 10.1056/NEJMoa2104882 33835768\n11. Lee G.M. Arepally G.M. Heparin-induced thrombocytopenia Hematol. Am. Soc. Hematol. Educ. Program 2013 2013 668 674 10.1182/asheducation-2013.1.668 24319250\n12. Nevzorova T.A. Mordakhanova E.R. Daminova A.G. Ponomareva A.A. Andrianova I.A. Le Minh G. Rauova L. Litvinov R.I. Weisel J.W. Platelet factor 4-containing immune complexes induce platelet activation followed by calpain-dependent platelet death Cell Death Discov. 2019 5 106 10.1038/s41420-019-0188-0 31263574\n13. Thachil J. Longstaff C. Favaloro E.J. Lippi G. Urano T. Kim P.Y. SSC Subcommittee on Fibrinolysis of the International Society on Thrombosis and Haemostasis The need for accurate D-dimer reporting in COVID-19: Communication from the ISTH SSC on fibrinolysis J. Thromb. Haemost. 2020 18 2408 2411 10.1111/jth.14956 32881272\n14. Arnout J. Vanrusselt M. Huybrechts E. Vermylen J. Optimization of the dilute prothrombin time for the detection of the lupus anticoagulant by use of a recombinant tissue thromboplastin Br. J. Haematol. 1994 87 94 99 10.1111/j.1365-2141.1994.tb04876.x 7947261\n15. Schjetlein R. Wisloff F. An evaluation of two commercial test procedures for the detection of lupus anticoagulant Am. J. Clin. Pathol. 1995 103 108 111 10.1093/ajcp/103.1.108 7817935\n16. Radic M. Pattanaik D. Cellular and Molecular Mechanisms of Anti-Phospholipid Syndrome Front. Immunol. 2018 9 969 10.3389/fimmu.2018.00969 29867951\n17. Miyakis S. Lockshin M.D. Atsumi T. Branch D.W. Brey R.L. Cervera R. Derksen R.H. De Groot P.G. Koike T. Meroni P.L. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) J. Thromb. Haemost. 2006 4 295 306 10.1111/j.1538-7836.2006.01753.x 16420554\n18. De Kesel P.M.M. Devreese K.M.J. The effect of unfractionated heparin, enoxaparin, and danaparoid on lupus anticoagulant testing: Can activated carbon eliminate false-positive results? Res. Pract. Thromb. Haemost. 2020 4 161 168 10.1002/rth2.12264 31989098\n19. Tung M.L. Tan B. Cherian R. Chandra B. Anti-phospholipid syndrome and COVID-19 thrombosis: Connecting the dots Rheumatol. Adv. Pract. 2021 5 rkaa081 10.1093/rap/rkaa081 33615129\n20. Bowles L. Platton S. Yartey N. Dave M. Lee K. Hart D.P. MacDonald V. Green L. Sivapalaratnam S. Pasi K.J. Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19 N. Engl. J. Med. 2020 383 288 290 10.1056/NEJMc2013656 32369280\n21. Toom S. Wolf B. Avula A. Peeke S. Becker K. Familial thrombocytopenia flare-up following the first dose of mRNA-1273 Covid-19 vaccine Am. J. Hematol. 2021 96 E134 E135 10.1002/ajh.26128 33580970\n22. Malas M.B. Naazie I.N. Elsayed N. Mathlouthi A. Marmor R. Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis EClinicalMedicine 2020 29 100639 10.1016/j.eclinm.2020.100639 33251499\n23. Baden L.R. El Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. Diemert D. Spector S.A. Rouphael N. Creech C.B. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine N. Engl. J. Med. 2021 384 403 416 10.1056/NEJMoa2035389 33378609\n24. Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. Perez J.L. Perez Marc G. Moreira E.D. Zerbini C. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine N. Engl. J. Med. 2020 383 2603 2615 10.1056/NEJMoa2034577 33301246\n25. Taquet M. Husain M. Geddes J. Luciano S. Harrison P.J. Cerebral Venous Thrombosis: A Retrospective Cohort Study of 513,284 Confirmed COVID-19 Cases and a Comparison with 489,871 People Receiving a COVID-19 mRNA Vaccine medRxiv 2021 Available online: https://www.medrxiv.org/content/10.1101/2021.04.27.21256153v1 (accessed on 25 May 2021)\n26. Smadja D.M. Yue Q.Y. Chocron R. Sanchez O. Lillo-Le Louet A. Vaccination against COVID-19: Insight from arterial and venous thrombosis occurrence using data from VigiBase Eur. Respir. J. 2021 10.1183/13993003.00956-2021 33863748\n27. (HHS) USDoHaHS Vaccine Adverse Event Reporting System (VAERS) Available online: https://vaers.hhs.gov/ (accessed on 25 May 2021)\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-393X",
"issue": "9(8)",
"journal": "Vaccines",
"keywords": "COVID-19; SARS-CoV-2; adverse event; pulmonary embolus; vaccination",
"medline_ta": "Vaccines (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101629355",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34452028",
"pubdate": "2021-08-14",
"publication_types": "D002363:Case Reports",
"references": "33883164;16420554;32881272;33615129;34117206;33687691;33863748;33378609;33580970;7817935;33835768;31263574;32369280;33341119;7947261;33861525;29867951;33251499;33914723;33835769;24319250;31989098;33301246;8154949",
"title": "A Case of Acute Pulmonary Embolus after mRNA SARS-CoV-2 Immunization.",
"title_normalized": "a case of acute pulmonary embolus after mrna sars cov 2 immunization"
} | [
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-071554",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
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{
"abstract": "BACKGROUND\nData on the clinical course of primary sclerosing cholangitis (PSC) during pregnancy remain scarce. Herein, we assessed the maternal and fetal outcomes of pregnancy in this condition.\n\n\nMETHODS\nWe reviewed 104 consecutive female outpatients with PSC using a structured questionnaire. The outcomes were assessed both before and after the diagnosis of PSC.\n\n\nRESULTS\nIn total, 62 patients (60%) reported 126 pregnancies. Of these, 25 patients reported 44 pregnancies occurring after the diagnosis of PSC. There were two (5%) pregnancies in progress, and among the completed pregnancies there were 34 (80%) live births, six (14%) miscarriages, one (2%) stillbirth, and one (2%) termination. The median neonatal APGAR score was 10, the median body weight was 3375 g and the median body length was 55 cm. In three pregnancies, there was a flare-up of inflammatory bowel disease. In 45 patients, 82 pregnancies occurred before PSC was diagnosed with comparable maternal and fetal outcomes. Out of 42 pregnancies following PSC diagnosis, in 29 UDCA was continued. There was no difference in the fetal outcomes between the UDCA and non-UDCA groups.\n\n\nCONCLUSIONS\nPregnancy in patients with PSC seems to be well tolerated, but should be closely monitored by an obstetrician and an experienced hepatologist.",
"affiliations": "Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland.;Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland.;Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland; Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland. Electronic address: p.milkiewicz@wp.pl.",
"authors": "Wronka|Karolina M|KM|;Bik|Emil|E|;Milkiewicz|Piotr|P|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2021.08.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": null,
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Liver disease; Pregnancy; Primary sclerosing cholangitis; Ursodeoxycholic acid",
"medline_ta": "Dig Liver Dis",
"mesh_terms": null,
"nlm_unique_id": "100958385",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34518127",
"pubdate": "2021-09-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcome of pregnancy in patients with primary sclerosing cholangitis.",
"title_normalized": "outcome of pregnancy in patients with primary sclerosing cholangitis"
} | [
{
"companynumb": "PL-ALLERGAN-2132954US",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "URSODIOL"
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"dr... |
{
"abstract": "BACKGROUND\nKounis syndrome (KS) is defined as the occurrence of acute coronary syndrome (ACS) associated with an anaphylactic reaction, and there have only been a few reports of its occurrence under general anesthesia.\n\n\nMETHODS\nA 69-year-old woman underwent transurethral resection of a bladder tumor under general anesthesia. Cefazolin was administered intravenously after induction of general anesthesia. During the operation, we suspected ACS from sudden ST segment depression on electrocardiogram. The delayed onset of an erythematous rash reminded us of the anaphylactic reaction of KS. Coronary artery spasm of type 1 KS was diagnosed based upon the findings of coronary computerized tomography. Eleven days after the first surgery, the patient underwent nephroureterectomy uneventfully by a change in antibiotics. Finally, cefazolin proved to be the trigger drug by the intradermal test.\n\n\nCONCLUSIONS\nWhen electrocardiogram changes suggesting ACS occur during general anesthesia, it is necessary to take KS into consideration as a differential diagnosis.",
"affiliations": "Department of Anesthesia, Kyoto City Hospital, 1-2 Mibuhigashitakada-cho, Nakagyo-ku, Kyoto, 604-8845, Japan. masami@kb3.so-net.ne.jp.;Department of Anesthesia, Kyoto City Hospital, 1-2 Mibuhigashitakada-cho, Nakagyo-ku, Kyoto, 604-8845, Japan.",
"authors": "Sato|Masami|M|;Arai|Toshiyuki|T|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s40981-019-0269-3",
"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJA Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 26910.1186/s40981-019-0269-3Case ReportA case of Kounis syndrome presenting as coronary artery spasm associated with cefazolin-induced anaphylaxis during general anesthesia Sato Masami +81-75-311-5311masami@kb3.so-net.ne.jp Arai Toshiyuki arai@kuhp.kyoto-u.ac.jp 0000 0004 0377 2487grid.415597.bDepartment of Anesthesia, Kyoto City Hospital, 1-2 Mibuhigashitakada-cho, Nakagyo-ku, Kyoto, 604-8845 Japan 31 7 2019 31 7 2019 12 2019 5 499 6 2019 23 7 2019 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nKounis syndrome (KS) is defined as the occurrence of acute coronary syndrome (ACS) associated with an anaphylactic reaction, and there have only been a few reports of its occurrence under general anesthesia.\n\nCase presentation\nA 69-year-old woman underwent transurethral resection of a bladder tumor under general anesthesia. Cefazolin was administered intravenously after induction of general anesthesia. During the operation, we suspected ACS from sudden ST segment depression on electrocardiogram. The delayed onset of an erythematous rash reminded us of the anaphylactic reaction of KS. Coronary artery spasm of type 1 KS was diagnosed based upon the findings of coronary computerized tomography. Eleven days after the first surgery, the patient underwent nephroureterectomy uneventfully by a change in antibiotics. Finally, cefazolin proved to be the trigger drug by the intradermal test.\n\nConclusion\nWhen electrocardiogram changes suggesting ACS occur during general anesthesia, it is necessary to take KS into consideration as a differential diagnosis.\n\nKeywords\nKounis syndromeCoronary artery spasmAnaphylaxisGeneral anesthesiaCefazolinissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nKounis syndrome (KS), also known as allergic angina, has been described as an acute coronary syndrome (ACS) associated with an anaphylactic reaction. In KS, a spastic contraction of coronary smooth muscle cells that could progress to acute myocardial damage or immediate coronary thrombosis is caused by the release of inflammatory mediators from mast cells during the allergic activation process [1]. After the first detailed report of the allergic angina syndrome as KS in 1991 [2], recognition of KS has increased recently in emergency and cardiovascular medicine [3, 4]. On the other hand, in the field of anesthesia, this syndrome is considered to be underdiagnosed, and to date, there have only been a few reports describing its occurrence and management during general anesthesia (GA).\n\nHerein, we describe a patient who showed ST segment depression on electrocardiogram (ECG) and hypotension that suggested ACS and was subsequently diagnosed as KS after the appearance of a cefazolin-induced anaphylactic erythematous rash under GA.\n\nCase presentation\nA 69-year-old woman (141 cm, 45 kg) was scheduled to undergo transurethral resection of bladder tumor (TUR-BT) and laparoscopic left nephroureterectomy under the diagnosis of bladder cancer and ureteral cancer. She was treated with trichlormethiazide for hypertension and did not have any history of allergy or ACS. Preoperative ECG showed a flat ST segment. Routine laboratory investigations were normal. Within the past year, the patient had undergone TUR-BT twice under spinal anesthesia and once under GA using propofol, desflurane, fentanyl, remifentanil, and rocuronium. Cefazolin was administered intravenously during every surgery.\n\nAfter placement of a thoracic epidural catheter, GA was induced with propofol, rocuronium, and fentanyl, and it was maintained with desflurane, remifentanil, and rocuronium. After the trachea was intubated, cefazolin was administered intravenously and TUR-BT started. Forty-five minutes after induction of GA, the resistance of the respiratory tract increased gradually under sufficient effect of rocuronium without any mechanical respiratory problem. Tidal volume in the mechanical ventilator decreased approximately from 350 to 250 ml under pressure-controlled ventilation. Percutaneous oxygen saturation (SpO2) decreased from 100 to 94% with a fraction of inspired oxygen of 40% without wheeze. Sixty minutes after induction of GA, the ST segment in lead II of the ECG decreased to − 1.0 mV and isosorbide dinitrate was administered intermittently under the suspicion of ACS. Because of further progression of ST segment depression, we initiated continuous intravenous infusion of nitroglycerin and nicorandil. As the systolic blood pressure (SBP) dropped to 70 mmHg, continuous phenylephrine and intermittent ephedrine were administered to maintain SBP at 80 mmHg. Seventy-three minutes after induction of GA, TUR-BT was finished and the ST segment decreased to − 3.4 mV maximally. When the surgical drape was removed, an anaphylactic erythematous rash was observed on the abdomen, chest, arms, and legs. Then, we suspected anaphylactic reaction to an unknown agent of KS. Corticosteroid and chlorpheniramine were administered immediately.\n\nTransthoracic echocardiography findings were within normal limits. The 12-lead ECG revealed ST depression in I, II, aVF, and V3–6. The laboratory findings for troponin and CK-MB were normal. As the patient responded well to the treatment for anaphylaxis, we were able to stop continuous phenylephrine administration 101 min after induction of GA and the ST depression began to return gradually. Subsequent left nephroureterectomy was postponed and ureteral stent insertion was carried out. When the ureteral stent insertion ended 166 min after induction of GA, blood pressure and the ST depression returned to almost normal with nitroglycerin and nicorandil support. The cutaneous symptoms diminished and SpO2 returned to 100% under the same oxygen concentration. Rocuronium was reversed by sugamadex and the trachea was extubated. The vital signs were stable and the patient was free of chest pain and respiratory discomfort. She was transferred to the ICU in order to observe any recurrence of anaphylactic reaction and stayed overnight uneventfully. Based upon the findings of normal coronary vasculature in coronary computerized tomography (CT) 4 days after TUR-BT, the cardiologist diagnosed the case as type 1 variant KS. Five days after TUR-BT, intradermal tests with all of the drugs used during GA were negative.\n\nEleven days after TUR-BT, laparoscopic left nephroureterectomy was performed under GA and epidural anesthesia. Since cefazolin was one of suspected causes of KS at that time, ciprofloxacin was administered in the ward before surgery and no reaction was observed. Preventative intravenous corticosteroid and chlorpheniramine were administered before GA, and continuous intravenous nicorandil was administered during surgery. GA was induced by thiamylal and suxamethonium and maintained with desflurane, fentanyl, and remifentanil. The minimum dose of rocuronium was administered intermittently to keep T1 of train-of-four under neuromuscular monitoring throughout the surgery. The surgery was completed uneventfully. The patient was discharged on the 18th day after the first operation. The intradermal test performed 8 months later proved that cefazolin was a trigger drug.\n\nDiscussion\nKS has three variants [1, 5]; type 1 includes patients with normal coronary arteries in whom coronary artery spasm occurs as a result of the release of inflammatory mediators during an acute anaphylactic reaction. Patients with preexisting atheromatous disease in whom an anaphylactic reaction induces plaque erosion or rupture leading to ACS comprise the type 2 variant. Type 3 KS involves patients with coronary artery stent thrombosis. Since the present case exhibited an episode of ST depression on ECG that was diagnosed as coronary vasospasm based upon coronary CT, cardiac echography, and laboratory investigation, she proved to be the type 1 variant KS.\n\nKS might result in severe conditions, including death, usually as a consequence of myocardial infarction [4, 6]. Therapeutic management of KS needs to treat both cardiac and anaphylactic symptoms simultaneously [3, 7]. However, the drugs to treat KS should be chosen carefully. The use of morphine, which is administered in ACS, can be detrimental due to its histamine-releasing property in KS. The administration of epinephrine to treat anaphylactic reaction can be hazardous due to its alpha-receptor-mediated coronary vasoconstriction, so it should be reserved only for severe cases [7]. With respect to type 1 KS, which is the most common type of KS, vasospasm can be reversed easily by coronary vasodilators, steroids, and anti-histamine drugs, and a good prognosis is expected with appropriate treatment [4]. The present case of type 1 KS also recovered smoothly in response to treatment, and epinephrine was not administered due to the concern of aggravation of coronary artery spasm and stability of the vital signs.\n\nSeveral causes have been reported to induce KS, including drugs, food, environmental exposures, and drug-eluting stents. The case reports of KS under GA have described rocuronium [8], cisatracurium [9], protamine [10], and diclofenac [11] as suspected triggers. A skin test to determine the trigger drug of anaphylaxis should be performed 4–6 weeks after the anaphylactic reaction, in order to allow recovery of allergic mediators from mast cells and basophils [12]. In our case, the first skin test was performed 5 days after TUR-BT in order to allow early operation to remove ureteral cancer. The reason why the responsible allergen was not identified was the suppression of the immune response, judging from the fact that the skin test response to histamine was also negative.\n\nIt has been reported that antibiotics are the most frequently involved drugs in KS and that rocuronium is associated with a high incidence of anaphylaxis [6, 13]. Thus, we estimated that cefazolin or rocuronium were more likely to be the possible anaphylaxis-inducing drugs before the second surgery. In the second surgery, a different antibiotic from cefazolin was administered preoperatively to the monitored awake patient. As 40% of patients diagnosed with rocuronium anaphylaxis have been reported to exhibit cross-reactivity to vecuronium, another available non-depolarizing neuromuscular agent in Japan [13], we chose to use rocuronium carefully again. After all, cefazolin proved to be the trigger of KS. Given that the patient had been exposed to cefazolin three times prior to the initial surgery, cefazolin would have sensitized the patient.\n\nThe time from exposure to trigger to the onset of KS has been reported to be within 1 h in 80% of KS patients [4]. As many drugs, including anesthetics, neuromuscular blocking drugs, and antibiotics, are administered during GA, identification of the anaphylaxis-inducing trigger drug is difficult in rapid succession, especially during induction of GA. The clinical manifestations of KS in anesthetized patients who do not exhibit subjective symptoms often differ from those who are awake. Among clinical signs of anaphylaxis, respiratory manifestations are less common during GA. Moreover, cutaneous symptoms are not always manifested and can be difficult to detect because of surgical drapes. Initial symptoms of KS under GA have been reported to be ECG changes or hypotension in 3 of 4 previous reports [8, 10, 11], and respiratory symptoms were only reported in one of these reports [9]. In our case, the decreased SpO2 without any special causes 45 min after induction of GA, which might have been initial symptom of KS, did not immediately remind us of anaphylaxis.\n\nWhen ECG changes suggestive of ACS occur during GA, it is important to monitor the respiratory and cutaneous symptoms carefully, in consideration of anaphylactic manifestation of KS as a differential diagnosis.\n\nAbbreviations\nACSAcute coronary syndrome\n\nCTComputerized tomography\n\nECGElectrocardiogram\n\nGAGeneral anesthesia\n\nKSKounis syndrome\n\nSBPSystolic blood pressure\n\nSpO2Percutaneous oxygen saturation\n\nTUR-BTTransurethral resection of bladder tumor\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank PALABRA for the English language editing.\n\nAuthors’ contributions\nMS conducted the anesthetic management and wrote the draft of the manuscript. TA reviewed the manuscript. The final version of the manuscript was approved by all authors.\n\nFunding\nThe authors declare that they have no funding.\n\nAvailability of data and materials\nThe data are not available for public access because of patient privacy concerns, but are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Kounis NG Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management Clin Chem Lab Med 2016 54 1545 1559 10.1515/cclm-2016-0010 26966931 \n2. Kounis NG Zavras GM Histamine-induced coronary artery spasm: the concept of allergic angina Br J Clin Pract 1991 45 121 128 1793697 \n3. Renda F Landoni G Trotta F Piras D Finco G Felicetti P Pimpinella G Pani L Kounis syndrome: an analysis of spontaneous reports from international pharmacovigilance database Int J Cardiol 2016 203 217 220 10.1016/j.ijcard.2015.10.003 26512841 \n4. Abdelghany M Subedi R Shah S Kozman H Kounis syndrome: a review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome Int J Cardiol 2017 232 1 4 10.1016/j.ijcard.2017.01.124 28153536 \n5. Tsigkas G Chouchoulis K Theodoropoulos K Kounis NG Alexopoulos D Allergic reaction reveals a non-lethal late stent thrombosis. A new subtype of Kounis syndrome? Int J Cardiol 2011 149 281 282 10.1016/j.ijcard.2011.02.060 21429602 \n6. Renda F Marotta E Landoni G Belletti A Cuconato V Pani L Kounis syndrome due to antibiotics: a global overview from pharmacovigilance databases Int J Cardiol 2016 224 406 411 10.1016/j.ijcard.2016.09.066 27684599 \n7. Fassio F Losappio L Antolin-Amerigo D Peveri S Pala G Preziosi D Massaro I Giuliani G Gasperini C Caminati M Heffler E Kounis syndrome: a concise review with focus on management Eur J Intern Med 2016 30 7 10 10.1016/j.ejim.2015.12.004 26795552 \n8. Fagley RE Woodbury A Visuara A Wall M Rocuronium-induced coronary vasospasm-“Kounis syndrome” Int J Cardiol 2009 137 e29 e32 10.1016/j.ijcard.2008.05.052 18804883 \n9. Yang YL Huang HW Yip HK Jawan B Tseng CC Lu HF Acute coronary syndrome in cisatracurium-induced anaphylactic shock: Kounis syndrome Acta Anaesthesiol Taiwanica 2008 46 184 186 10.1016/S1875-4597(09)60007-2 \n10. Lee S Nikai T Kanata K Koshizaki M Nomura T Saito Y A case of severe coronary artery spasm associated with anaphylactic reaction caused by protamine administration. (in Japanese with English abstract) Masui (Jpn Anesthesiol) 2005 54 1043 1046 \n11. Kerai S Sehrawat L Saxena KN Taneja B Occurrence of Kounis syndrome under anesthesia J Anaesthesiol Clin Pharmacol 2017 33 276 277 28781470 \n12. Mertes PM Malinovsky JM Jouffroy L Working Group of the SFAR and SFA Aberer W Terreehorst I Brockow K Demoly P ENDA, EAACI Interest Group on Drug Allergy Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice J Investig Allergol Clin Immunol 2011 21 442 453 21995177 \n13. Sadleir PHM Clarke RC Bunning DL Platt PR Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011 Br J Anaesth 2013 110 981 987 10.1093/bja/aes506 23335568\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2363-9024",
"issue": "5(1)",
"journal": "JA clinical reports",
"keywords": "Anaphylaxis; Cefazolin; Coronary artery spasm; General anesthesia; Kounis syndrome",
"medline_ta": "JA Clin Rep",
"mesh_terms": null,
"nlm_unique_id": "101682121",
"other_id": null,
"pages": "49",
"pmc": null,
"pmid": "32026020",
"pubdate": "2019-07-31",
"publication_types": "D016428:Journal Article",
"references": "28153536;28781470;26795552;21995177;21429602;16167803;23335568;26966931;19097966;18804883;27684599;26512841;1793697",
"title": "A case of Kounis syndrome presenting as coronary artery spasm associated with cefazolin-induced anaphylaxis during general anesthesia.",
"title_normalized": "a case of kounis syndrome presenting as coronary artery spasm associated with cefazolin induced anaphylaxis during general anesthesia"
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},
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... |
{
"abstract": "Aripiprazole is an atypical antipsychotic agent commonly used in the management of schizophrenia. Aripiprazole has not been reported to have an association with interstitial lung disease. We describe a case of a 36-year-old woman who began to experience respiratory issues shortly after starting aripiprazole and presented to us 4 years later with progressive exertional shortness of breath. High-resolution CT of the chest showed a bilateral ground glass pattern. Video-assisted thoracoscopy with biopsy revealed alveolar septal thickening and an inflammatory infiltrate composed mainly of lymphocytes, suggestive of chronic hypersensitivity pneumonitis. After discontinuing aripiprazole and initiating prednisolone therapy, the patient's pulmonary symptoms improved. This case highlights that aripiprazole can cause hypersensitivity pneumonitis in susceptible individuals.",
"affiliations": "Henry Ford Health System, Detroit, USA.;Internal Medicine, Sinai Grace Hospital, Detroit, USA.;Division of Pulmonary and Critical Care, Henry Ford Health System, Detroit, USA.;Internal Medicine, Pulmonary and Critical Care, Bassett Healthcare, Cooperstown, USA.",
"authors": "Gunasekaran|Kulothungan|K|;Murthi|Swetha|S|;Jennings|Jeffrey|J|;Lone|Nazir|N|",
"chemical_list": "D014150:Antipsychotic Agents; D000068180:Aripiprazole",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219929",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "exposures; interstitial lung disease; psychiatry (drugs and medicines); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000542:Alveolitis, Extrinsic Allergic; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D012559:Schizophrenia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28487307",
"pubdate": "2017-05-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18843175;19555801;19648533;20062766;22296317;22896776;23374544;24245774;25237379;25487626;26176964;26479131;6606534",
"title": "Aripiprazole-induced hypersensitivity pneumonitis.",
"title_normalized": "aripiprazole induced hypersensitivity pneumonitis"
} | [
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"companynumb": "US-HETERO CORPORATE-2017HINLIT0477",
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"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
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{
"abstract": "OBJECTIVE\nRecent limited epidemiologic and case reports suggest that gabapentin is being misused, especially among prescription opioid misusers. However, no apparent studies have reported data from law enforcement on the diversion and misuse of gabapentin.\n\n\nMETHODS\nCase report data are drawn from a quarterly survey of prescription drug diversion completed by a national sample of law enforcement and regulatory agencies who engage in drug diversion investigations. Rates of gabapentin diversion per 100 000 population were calculated for each quarter from 2002 through 2015. Qualitative data are drawn from a brief questionnaire completed by a subsample of survey respondents and were organized and presented by theme.\n\n\nRESULTS\nIn total, 407 new cases of diverted gabapentin were reported during the time period, with diversion rates steadily increasing from zero cases in the first 2 quarters of 2002 to a high of 0.027 cases per 100 000 population in the fourth quarter of 2015. Qualitative data suggest that gabapentin is being misused in conjunction with prescription opioids and that gabapentin and heroin are being combined and consumed together. Law enforcement reporters found these drug use trends to be contributing to gabapentin diversion.\n\n\nCONCLUSIONS\nThe recent increase in gabapentin diversion appears to be related to the opioid epidemic, based on law enforcement descriptions of gabapentin being misused in combination with opioids. Yet epidemiological data related to this finding is limited and research conducted among gabapentin misusers is needed to understand this problem in more depth. Greater monitoring of gabapentin abuse and diversion appear warranted.",
"affiliations": "Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, Miami, FL, USA.;Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, Miami, FL, USA.;Rocky Mountain Poison & Drug Center, Denver, CO, USA.;Rocky Mountain Poison & Drug Center, Denver, CO, USA.",
"authors": "Buttram|Mance E|ME|http://orcid.org/0000-0002-5001-7391;Kurtz|Steven P|SP|;Dart|Richard C|RC|;Margolin|Zachary R|ZR|",
"chemical_list": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "England",
"delete": false,
"doi": "10.1002/pds.4230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "26(9)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "diversion; gabapentin; heroin; prescription opioids",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D003625:Data Collection; D005260:Female; D000077206:Gabapentin; D006801:Humans; D035846:Law Enforcement; D008297:Male; D064226:Prescription Drug Diversion; D036301:Qualitative Research; D019966:Substance-Related Disorders; D011795:Surveys and Questionnaires; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "1083-1086",
"pmc": null,
"pmid": "28493425",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Law enforcement-derived data on gabapentin diversion and misuse, 2002-2015: diversion rates and qualitative research findings.",
"title_normalized": "law enforcement derived data on gabapentin diversion and misuse 2002 2015 diversion rates and qualitative research findings"
} | [
{
"companynumb": "US-DEPOMED, INC.-US-2018DEP001296",
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"activesubstance": {
"activesubstancename": "GABAPENTIN"
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{
"abstract": "Idiopathic hypereosinophilic syndrome (IHES) is characterized by blood hypereosinophilia with no underlying cause and eosinophilia-associated organ dysfunction. Thirty-three patients, 20 female (61%) and 13 male (29%), with a median age of 56 years at diagnosis (range 16-77 years) were included in the study. The median blood eosinophilia at diagnosis was 7.6 × 10(9)/L and the median percentage of eosinophils in the bone marrow was 39.5%. The most common clinical manifestations were splenomegaly and cardiac involvement. Corticosteroids (CS) as monotherapy were initiated in all study patients. The median starting dose of prednisone was 30 mg daily (range 5-85 mg), and the maintenance dose varied from 5 mg twice weekly to 60 mg daily. Overall, 21 patients (64%) responded to CS within a week. Seven patients (21%) were resistant or intolerant to CS. Five patients (15%) achieved a 50% reduction of blood eosinophilia. In conclusion, CS were found to be highly effective in IHES with manageable side effects.",
"affiliations": "Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland. ghelbig@o2.pl",
"authors": "Helbig|Grzegorz|G|;Wiśniewska-Piąty|Katarzyna|K|;Francuz|Tomasz|T|;Dziaczkowska-Suszek|Joanna|J|;Kyrcz-Krzemień|Sławomira|S|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2012.731602",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "54(4)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D004804:Eosinophils; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "807-11",
"pmc": null,
"pmid": "22988896",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Diversity of clinical manifestations and response to corticosteroids for idiopathic hypereosinophilic syndrome: retrospective study in 33 patients.",
"title_normalized": "diversity of clinical manifestations and response to corticosteroids for idiopathic hypereosinophilic syndrome retrospective study in 33 patients"
} | [
{
"companynumb": "PL-ROXANE LABORATORIES, INC.-2014-BI-32202GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditi... |
{
"abstract": "This case demonstrates the therapeutic challenges encountered when managing an acute pulmonary embolism in a cancer patient with thrombocytopenia. A 64-year-old man with a history of lung cancer receiving chemotherapy was admitted to Walsall Manor Hospital with haemodynamic instability consistent with a pulmonary embolism, proven on computed tomographic pulmonary angiogram. His platelet count was noted to be 35×109/l (chemotherapy-induced thrombocytopenia). After discussions, he was deemed not suitable for thrombolysis based on risk versus benefits. The patient was initially transfused one adult dose of platelets and treated with half the therapeutic dose of low molecular weight heparin (LMWH). The same management plan was followed until the platelet count exceeded 50×109/l, after which the patient was established on the full therapeutic dose of LMWH. Clinically, the patient improved and was discharged. Three months after discharge, follow-up revealed sustained clinical improvement while the patient continued to be on the full therapeutic dose of LMWH with a stable platelet count.\nCancer patients have a three-fold higher risk of venous thromboembolism compared with non-cancer patients, but also a higher risk of bleeding, hence neoplasm is considered an absolute contraindication to thrombolysis by the European Society of Cardiologists.The management of an acute pulmonary embolism in cancer patients with thrombocytopenia is still debated. However, a few recognised medical societies and expert opinions have established recommendations on this specific area, such as the British Committee for Standards in Haematology, the American Society of Clinical Oncology and the International Society of Thrombosis and Haemostasis.Expert opinion agrees on: giving the full therapeutic dose of low molecular weight heparin (LMWH) if the platelet count is above 50×109/l; if it drops below 50×109/l, halving the dose of LMWH with or without platelet transfusion until the platelet count improves above 50×109/l; and when the platelet count is below 20-30×109/l, withholding anticoagulation and considering the insertion of an inferior vena cava filter.",
"affiliations": "General Internal Medicine, Walsall Manor Hospital, United Kingdom.;Geriatrics and General Internal Medicine, Walsall Manor Hospital, United Kingdom.;Consultant in Diabetes and General Internal Medicine, Walsall Manor Hospital, United Kingdom.;Consultant in Haematology and General Internal Medicine, AlKhums General Hospital, Libya.",
"authors": "Sreh|Abuajela|A|;Nakeshree|Shailesh|S|;Krishnasamy|Senthil-Kumar|SK|;Alfasi|Nuri|N|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2017_000713",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2017_000713713-1-4252-1-10-20171114ArticlesTherapeutic Challenges in the Management of Acute Pulmonary Embolism in a Cancer Patient with Chemotherapy-induced Thrombocytopenia Sreh Abuajela 1Nakeshree Shailesh 2Krishnasamy Senthil-Kumar 3Alfasi Nuri 4\n1 General Internal Medicine, Walsall Manor Hospital, United Kingdom\n2 Geriatrics and General Internal Medicine, Walsall Manor Hospital, United Kingdom\n3 Consultant in Diabetes and General Internal Medicine, Walsall Manor Hospital, United Kingdom\n4 Consultant in Haematology and General Internal Medicine, AlKhums General Hospital, Libya2018 31 1 2018 5 1 00071326 7 2017 07 10 2017 © EFIM 20172017This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseThis case demonstrates the therapeutic challenges encountered when managing an acute pulmonary embolism in a cancer patient with thrombocytopenia. A 64-year-old man with a history of lung cancer receiving chemotherapy was admitted to Walsall Manor Hospital with haemodynamic instability consistent with a pulmonary embolism, proven on computed tomographic pulmonary angiogram. His platelet count was noted to be 35×109/l (chemotherapy-induced thrombocytopenia). After discussions, he was deemed not suitable for thrombolysis based on risk versus benefits. The patient was initially transfused one adult dose of platelets and treated with half the therapeutic dose of low molecular weight heparin (LMWH). The same management plan was followed until the platelet count exceeded 50×109/l, after which the patient was established on the full therapeutic dose of LMWH. Clinically, the patient improved and was discharged. Three months after discharge, follow-up revealed sustained clinical improvement while the patient continued to be on the full therapeutic dose of LMWH with a stable platelet count.\n\nLEARNING POINTS\nCancer patients have a three-fold higher risk of venous thromboembolism compared with non-cancer patients, but also a higher risk of bleeding, hence neoplasm is considered an absolute contraindication to thrombolysis by the European Society of Cardiologists.\n\nThe management of an acute pulmonary embolism in cancer patients with thrombocytopenia is still debated. However, a few recognised medical societies and expert opinions have established recommendations on this specific area, such as the British Committee for Standards in Haematology, the American Society of Clinical Oncology and the International Society of Thrombosis and Haemostasis.\n\nExpert opinion agrees on: giving the full therapeutic dose of low molecular weight heparin (LMWH) if the platelet count is above 50×109/l; if it drops below 50×109/l, halving the dose of LMWH with or without platelet transfusion until the platelet count improves above 50×109/l; and when the platelet count is below 20–30×109/l, withholding anticoagulation and considering the insertion of an inferior vena cava filter.\n\nPulmonary embolismPEvenous thromboembolismVTEcancerthrombocytopenia\n==== Body\nCASE DESCRIPTION\nA 64-year-old man presented with acute-onset shortness of breath worsening dramatically over 24 hours in the absence of cough, chest pain or haemoptysis.\n\nThe patient had a background history of hypertension, osteoarthritis and lung cancer (squamous cell carcinoma stage T4N2M1a) for which he had been treated with chemotherapy (gemcitabine and cisplatin). He was known to subsequently have chemotherapy-induced thrombocytopenia. His performance status was zero.\n\nHe had previously had a pulmonary embolism (PE) 2 months before this current admission where he had received the full therapeutic dose of low molecular weight heparin (LMWH) for only 14 days after which it was stopped due to severe thrombocytopenia. Repeat computed tomographic pulmonary angiogram (CTPA) at this time had demonstrated a normal pulmonary angiographic scan. There was no family history of malignancies, haematological disorders or venous thromboembolism (VTE).\n\nOn examination, the patient was alert and well orientated but not able to complete one full sentence with a respiratory rate of 28 breaths per minute. His oxygen saturation level was 91% on room air, and his temperature was 36.5°C. Chest examination revealed a central trachea with reduced air entry over the right lower hemi-thorax which was dull to percussion. Cardiovascular examinations revealed tachycardia with a heart rate of 114 beats per minute which was regular in nature, and blood pressure of 103/70 (the last blood pressure recorded in the outpatient department was 130/78). Abdominal examinations were not significant. Both calves were of equal size, soft and non-tender.\n\nMETHODS AND PROCEDURES\nInitial investigations on admission included: arterial blood gas which demonstrated type 1 respiratory failure (PaO2 6.7 kPa) with normal pH, PaCO2, electrolytes and lactate. An electrocardiogram showed sinus tachycardia at 114 beats per minute with an S1Q3T3 pattern. Chest x-ray showed right middle and lower zone patchy changes, with no new changes compared to previous x-rays (right-sided lung cancer). Venous bloods showed thrombocytopenia (platelet count of 35×109/l, that had been fluctuating as per chemotherapy cycles), normal haemoglobin and white cell count, and mildly raised C-reactive protein. Otherwise the clotting profile was normal with normal kidney and liver functions.\n\nThree hours into the patient’s admission, he required more oxygen (8 l/min) and his blood pressure dropped to 93/55 from 103/70 mmHg. He had an urgent CTPA, which confirmed multiple PEs in the left pulmonary artery and its branches with the tumour occluding the right pulmonary artery (Fig. 1). Ultrasound Doppler was performed and confirmed deep vein thrombosis (DVT) in both the right and left popliteal veins.\n\nOnce the diagnosis of PE was confirmed on the CTPA, the patient was discussed with the out-of-hours medical consultant who advised discussing the thrombolysis option with the patient. The Intensive Care Unit team were involved, at which point the patient’s blood pressure improved, therefore removing the indication for thrombolysis due to the greater chance of bleeding than of benefit.\n\nThe patient was observed closely until seen by the on-call consultant on the morning ward-round, who reinforced the difficulties of treating acute PE in thrombocytopenia. The patient agreed to have half the dose of LMWH. The case was discussed with the on-call haematologist and oncologist regarding further management and anticoagulation.\n\nThe repeated platelet count dropped to 26×109/l and the oncology team on-call reviewed the patient and suggested not giving LMWH at this stage until the platelet count improved.\n\nHowever, the patient continued to improve clinically without any anticoagulation treatment (36 hours into his admission) and remained haemodynamically stable requiring no oxygen therapy.\n\nOn day two of admission, the platelet count dropped to 25×109/l. The patient was discussed with the haematologist on-call who suggested giving one adult dose of platelets with half the therapeutic dose of LMWH, and advised the platelet count should be monitored every 12 hours and the case be re-discussed with the haematologist for further advice.\n\nOn day three, the repeated platelet count improved to 40×109/l. Further Haematology input suggested another adult dose of platelets with half the therapeutic dose of LMWH as before. The patient was reviewed by the oncologist again who agreed to continue with half the therapeutic dose of LMWH until the platelet count improved to more than 50×109/l.\n\nOn day four, the platelet count was noted to be 64×109/l. The haematologist advised commencing a full therapeutic dose of LMWH with regular monitoring of factor Xa levels to ensure that the patient was over-coagulated.\n\nOn day five, the patient had clinically and biochemically improved with the platelet count noted to be 80×109/l. The patient was discharged home on a full therapeutic dose of LMWH with a plan to repeat his platelet count in the community in 1 week’s time and to be reviewed in the oncology outpatient clinic in 2 weeks following discharge.\n\nOUTCOME AND FOLLOW UP PLAN\nThe patient was reviewed by the oncologist in the outpatient clinic 2 weeks after his discharge, and continued to improve. Overall, the patient had completed two and a half cycles of gemcitabine and cisplatin instead of the initially proposed four-cycle course. The oncology team decided that the patient should not receive any more chemotherapy at this stage due to the radiological improvement in cancer size as well as his increased risk of both thrombocytopenia and recurrent VTEs if chemotherapy were continued.\n\nThe patient then was followed up 3 months after discharge. He continued to improve while on the full therapeutic dose of LMWH. He exhibited no symptoms or signs suggestive of a recurrent VTE and had been showing a consistently stable platelet count since his discharge. The plan is to continue with the full therapeutic dose of LMWH until he is reviewed in the oncology outpatient clinic in 6 months’ time.\n\nDISCUSSION\nCancer patients have a higher risk of developing VTEs as well as thrombocytopenia than non-cancer patients[1,2]. According to the European Society of Medical Oncology, cancer patients have a three-fold higher risk of PE compared with non-cancer patients. Also, cancer patients receiving chemotherapy have a seven-fold higher risk of PE compared with non-cancer patients [2].\n\nThrombocytopenia is defined as a platelet count of less than 100×109/l and in cancer patients is usually attributed to bone marrow suppression. The incidence rate of thrombocytopenia in cancer patients varies according to different factors including type of cancer (solid organ or blood cancer), use of chemotherapeutic agents or drugs with a known risk of thrombocytopenia (such as heparin), and co-existing haematological disorders or other co-morbidities such as sepsis, etc. [1,3]. Based on these factors, the estimated rate of thrombocytopenia in cancer patients can vary between 21% and 70% [4].\n\nIn cancer patients with a low bleeding risk, different international organisations (the American Society of Clinical Oncology (ASCO), International Society of Thrombosis and Haemostasis (ISTH) and British Committee for Standards in Haematology (BCSH)) have established recommendations on the management of VTE and its secondary prevention[5,6]. Strong evidence has been found to support the use of extended anticoagulation therapy if the bleeding risk is not high[1,5,6]. LMWH is recommended as a drug of choice when treating an acute VTE episode in cancer patients [1, 5–8]. The lack of randomised controlled trials means the use of the novel oral anticoagulants (NOACs) for either the prevention or the treatment of VTE in patients with cancer is not recommended until more data become available [5].\n\nOn the other hand, it is still not clear how VTE should be managed in cancer patients with a high bleeding risk (e.g. concomitant thrombocytopenia). A literature review was carried out using MEDLINE, EMBASE, CINAHL, NICE Evidence, The Cochrane Library and a general web search. Some recommendations have been established based on expert opinion among the panel members of well-recognised medical societies as summarised below.\n\nISTH guidance was established to help clinicians managing challenging cases of cancer-associated VTE (including proximal DVTs and segmental or more proximal artery PEs) in those with concomitant thrombocytopenia. The ISTH guidance emphasised the importance of dealing with such patients on an individual basis, accounting for variable factors including the possible aetiology of the thrombocytopenia, its severity and expected duration, risk factors for bleeding as well as patient preference[9]. The ISTH consensus guidance agreed on a platelet count of 50×109/l as the empirical cut-off for platelet transfusion when managing patients with cancer-associated VTE and thrombocytopenia. They strongly recommended the use of full therapeutic doses of anticoagulation without platelet transfusion in patients with cancer-associated VTE and a platelet count of more than 50×109/l. When the platelet count drops below 50×109/l, full therapeutic doses of anticoagulation with platelet transfusion is recommended until the platelet count reaches the empirical cut-off (i.e. 50×109/l)[9]. If platelet transfusion is contraindicated, the ISTH suggests (with weak evidence) the insertion of a retrievable inferior vena cava filter and its removal when the platelet count recovers after which anticoagulation is to be resumed[7,9].\n\nThe BCSH recommends the use of a full therapeutic dose of LMWH to treat established VTE in cancer patients with a platelet count above 50×109/l, while half the dose of LMWH is recommended when the platelet count is between 25×109/l and 50×109/l. It is recommended that anticoagulation therapy be withheld when the platelet count is below 25×109/l[6].\n\nASCO has identified a platelet count cut-off when withholding therapeutic anticoagulation in cancer patients with VTE should be considered. ASCO recommends that severe thrombocytopenia (platelet count below 20×109/l) is an absolute contraindication to therapeutic anticoagulation, while a platelet count of less than 50×109/l is considered a relative contraindication[5]. Unfortunately, no further details are provided regarding the alternative therapeutic options for these patients.\n\nThe literature review revealed one retrospective study by Kopolovic et al. that estimated the risk of a haemorrhagic event versus VTE recurrence after treating acute VTE in 74 cancer patients with associated thrombocytopenia[1]. VTE episodes included PEs, DVTs or thromboses in other venous systems. Based on the severity of the thrombocytopenia, three main approaches were followed: no anticoagulation therapy, partial treatment with LMWH (using a prophylactic dose, a 50–75% therapeutic dose or a shorter therapeutic duration), or full-dose anticoagulation with or without platelet transfusions. Their results are summarised in Table 1.\n\nAcknowledgements\nThe authors would like to thank Liz Askew, evidence-based information specialist librarian, Walsall Manor Hospital, Walsall, United Kingdom.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Computed tomographic pulmonary angiogram. (R) refers to the right pulmonary artery which is occluded by a tumour. (L) refers to multiple pulmonary emboli in the left pulmonary artery branches\n\nTable 1 Risk of a haemorrhagic event or venous thromboembolism (VTE) recurrence in 74 patients\n\nNo anticoagulation\tPartial anticoagulation\tFull anticoagulation\t\t\nPlatelet count (average)\t21×109/l\t45×109/l\t63×109/l\t\nRecurrent VTE <3 months\t47%\t44%\t10%\t\nHaemorrhagic event <3 months\t12%\t33%\t7%\n==== Refs\nREFERENCES\n1 Kopolovic I Lee A Wu C Management and outcomes of cancer-associated venous thromboembolism in patients with concomitant thrombocytopenia: a retrospective cohort study Ann Hematol 2015 94 329 336 25190031 \n2 Mandalà M Falanga A Roilaet F on behalf of the ESMO Guidelines Working Group Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines Ann Oncol 2011 22 Suppl 6 vi85 vi92 Available from: https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdr392 21908511 \n3 Valent J Schiffer CA Thrombocytopenia and platelet transfusions in patients with cancer Cancer Treat Res 2011 157 251 265 21052961 \n4 Curtis BR Drug-induced immune thrombocytopenia: incidence, clinical features, laboratory testing, and pathogenic mechanisms Immunohematology 2014 30 55 65 25247620 \n5 Lyman G Khorana A Kuderer N Lee A Arcelus J Balaban E Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update J Clin Oncol 2013 31 2189 2204 23669224 \n6 Watson H Keeling D Laffan M Laffan M Tait R Makris M Guideline on aspects of cancer-related venous thrombosis Br J Haematol 2015 170 640 648 26114207 \n7 Noble S Shelley M Coles B Williams S Wilcock A Johnson M Management of venous thromboembolism in patients with advanced cancer: a systematic review and meta-analysis Lancet Oncol 2008 9 577 584 18510989 \n8 Jaff M McMurtry M Archer S Cushman M Goldenberg N Goldhaber SZ Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association Circulation 2011 123 1788 1830 Available from: http://circ.ahajournals.org/content/123/16/1788.long 21422387 \n9 Carrier M Khorana A Zwicker JI Noble S Lee A Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH J Thromb Haemost 2013 11 1760 1765 23809334\n\n",
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"journal": "European journal of case reports in internal medicine",
"keywords": "PE; Pulmonary embolism; VTE; cancer; thrombocytopenia; venous thromboembolism",
"medline_ta": "Eur J Case Rep Intern Med",
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"pubdate": "2018",
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"title": "Therapeutic Challenges in the Management of Acute Pulmonary Embolism in a Cancer Patient with Chemotherapy-induced Thrombocytopenia.",
"title_normalized": "therapeutic challenges in the management of acute pulmonary embolism in a cancer patient with chemotherapy induced thrombocytopenia"
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"abstract": "Patients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments.\n\n\n\nTo develop and externally validate a prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies.\n\n\n\nThe risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C-statistic, the calibration slope and the calibration in the large.\n\n\n\nOverall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism-corrected C-statistic of 0·64 [95% confidence interval (CI) 0·60-0·69], calibration in the large of 0·02 (95% CI -0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70-1·07), while external validation performance was poor, with C-statistic 0·52 (95% CI 0·42-0·62), calibration in the large 0·06 (95% CI -0·25 to 0·37) and calibration slope 0·36 (95% CI -0·24 to 0·97).\n\n\n\nWe present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision-making process.",
"affiliations": "Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Manchester, M13 9PT, U.K.;IVDP - Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Arthritis Research U.K. Epidemiology Unit, The University of Manchester, Manchester, M13 9PT, U.K.;IVDP - Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;IVDP - Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;IVDP - Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Manchester, M13 9PT, U.K.;Centre for Pharmacoepidemiology and Drug Safety, School of Health Sciences, The University of Manchester, Manchester, M13 9PT, U.K.;Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Manchester, M13 9PT, U.K.;Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Manchester, M13 9PT, U.K.",
"authors": "Yiu|Z Z N|ZZN|0000-0002-1831-074X;Sorbe|C|C|;Lunt|M|M|;Rustenbach|S J|SJ|;Kühl|L|L|;Augustin|M|M|0000-0002-4026-8728;Mason|K J|KJ|0000-0002-5419-0669;Ashcroft|D M|DM|;Griffiths|C E M|CEM|0000-0001-5371-4427;Warren|R B|RB|;|||",
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"fulltext": "\n==== Front\nBr J DermatolBr. J. Dermatol10.1111/(ISSN)1365-2133BJDThe British Journal of Dermatology0007-09631365-2133John Wiley and Sons Inc. Hoboken 10.1111/bjd.17421BJD17421Medical DermatologyOriginal ArticlesMedical DermatologyDevelopment and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy Z.Z.N. Yiu et al.Yiu Z.Z.N. https://orcid.org/0000-0002-1831-074X\n1\n\n2\nzenas.yiu@manchester.ac.uk Sorbe C. \n3\nLunt M. \n4\nRustenbach S.J. \n3\nKühl L. \n3\nAugustin M. https://orcid.org/0000-0002-4026-8728\n3\nMason K.J. https://orcid.org/0000-0002-5419-0669\n1\nAshcroft D.M. \n2\nGriffiths C.E.M. https://orcid.org/0000-0001-5371-4427\n1\nWarren R.B. \n1\nthe BADBIR Study GroupOrmerod Anthony D. Barker Jonathan N.W.N. Evans Ian McElhone Kathleen Smith Catherine H. Reynolds Nick J. Murphy Ruth Benham Marilyn David Burden A. Hussain Sagair Kirby Brian Lawson Linda Owen Caroline M. \n1 \nDermatology Centre\nSalford Royal NHS Foundation Trust\nThe University of Manchester\nManchester Academic Health Science Centre\nNIHR Manchester Biomedical Research Centre\nManchester\nM13 9PT\nU.K\n\n2 \nCentre for Pharmacoepidemiology and Drug Safety\nSchool of Health Sciences\nThe University of Manchester\nManchester\nM13 9PT\nU.K\n\n3 \nIVDP – Institute for Health Services Research in Dermatology and Nursing\nUniversity Medical Center Hamburg‐Eppendorf\nHamburg\nGermany\n\n4 \nArthritis Research U.K. Epidemiology Unit\nThe University of Manchester\nManchester\nM13 9PT\nU.K\n* \nCorrespondence\n\nZenas Yiu.\n\nE‐mail: zenas.yiu@manchester.ac.uk\n15 1 2019 4 2019 180 4 10.1111/bjd.2019.180.issue-4894 901 05 11 2018 © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of DermatologistsThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Summary\nBackground\nPatients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments.\n\nObjectives\nTo develop and externally validate a prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies.\n\nMethods\nThe risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C‐statistic, the calibration slope and the calibration in the large.\n\nResults\nOverall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism‐corrected C‐statistic of 0·64 [95% confidence interval (CI) 0·60–0·69], calibration in the large of 0·02 (95% CI −0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70–1·07), while external validation performance was poor, with C‐statistic 0·52 (95% CI 0·42–0·62), calibration in the large 0·06 (95% CI −0·25 to 0·37) and calibration slope 0·36 (95% CI −0·24 to 0·97).\n\nConclusions\nWe present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision‐making process.\n\n\nWhat's already known about this topic?\n\n\n\nPatients and their clinicians are often concerned about the risk of serious infection associated with biological therapies for the treatment of psoriasis.\n\nHowever, there are no current tools available to estimate an individual's risk of serious infection when starting a systemic therapy.\n\n\n\n\n\nWhat does this study add?\n\n\n\nThis study found that the serious infection risk prediction model had good calibration and moderate discrimination\n\nThe model included chronic obstructive pulmonary disease, alcohol intake, number of comorbidities and employment status, in addition to age, sex, Psoriasis Area and Severity Index, choice of starting therapy and body mass index.\n\nThese are the first results of the multivariable prediction model, which may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision‐making process.\n\n\n\n\n\nhttps://www.bjdonline.com/article/Development-and-validation-of-a-multivariable-risk-prediction-model-for-serious-infection-in-patients-with-psoriasis-receiving-systemic-therapy/\n\n\n\nhttps://doi.org/10.1111/bjd.17664 available online\n\n source-schema-version-number2.0cover-dateApril 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:12.11.2019\nThe funding sources and conflicts of interest statements can be found in Appendix \n1\n.\n\n\nThe BADBIR study group includes Anthony D. Ormerod, Jonathan N.W.N. Barker, Ian Evans, Kathleen McElhone, Catherine H. Smith, Nick J. Reynolds, Ruth Murphy, Marilyn Benham, A. David Burden, Sagair Hussain, Brian Kirby, Linda Lawson and Caroline M. Owen.\n\n\nhttps://doi.org/10.1111/bjd.17664 available online\n==== Body\nGiven that the majority of systemic therapies for psoriasis suppress the immune system, patients and their clinicians are often concerned about an associated risk of serious infection. Patients with psoriasis often experience comorbidity and have lifestyle factors that themselves may be associated with a higher risk of serious infection than in the general population.1\n\n\nA recent study found that in patients who do receive systemic therapies, 12% of patients practise intentional nonadherence, where patients decide not to follow the prescribed medication regimen.2 This may stem from concerns about potential negative effects of treatment such as the associated risk of infection or other serious adverse events. It could lead to a missed opportunity of achieving a good clinical outcome, in turn impacting on the achievable quality of life for the patient. Addressing patient concerns about the risk of serious infection associated with systemic therapies is, therefore, a vital aspect of any consultation prior to initiating such therapies. To our knowledge, there are no tools available to help patients with psoriasis or their clinicians to estimate the risk of serious infection when starting a systemic therapy.\n\nOur objective was to develop a multivariable prediction model for serious infection within 1 year of systemic therapy initiation in patients with psoriasis. Within the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance network of psoriasis registries (http://www.psonet.eu), we used a national, prospective psoriasis registry to develop and test the internal validity of the model [the British Association of Dermatologists Biologic Interventions Register (BADBIR)]. We then applied the model to a second national, prospective psoriasis registry (PsoBest, Germany) to test the external validity. Such a model would enable the dermatologist and patient to determine a personalized risk of first serious infection within 1 year of systemic therapy initiation.\n\nPatients and methods\nData sources and study population\nData from BADBIR3 were used to develop the serious infection risk prediction model. To test whether this risk prediction model was generalizable to other populations, external validation using a cohort from the German Psoriasis Registry PsoBest4 was performed. The structures of these two registries are very similar.\n\nDevelopment cohort (U.K. and Republic of Ireland)\nBADBIR is a large, ongoing, prospective pharmacovigilance registry of patients with psoriasis. It was established in 2007 in the U.K. and Ireland to compare the safety of biological therapies against nonbiological systemic therapies. In total 153 secondary‐care dermatology centres in the U.K. and Ireland have contributed to the registry in this data snapshot. Patients with a Psoriasis Area and Severity Index (PASI) ≥ 10 and Dermatology Life Quality Index (DLQI) > 10 initiating a systemic biological or nonbiological medication are eligible for inclusion in the register. In England, the National Institute for Health and Care Excellence (NICE) recommends that all patients with psoriasis on biological therapies should be registered on BADBIR. Data are collected 6 monthly for the first 3 years, then annually thereafter. Detailed assessments at baseline and follow‐up have been performed. A data snapshot from February 2017 was used in the development dataset.\n\nValidation cohort (Germany)\nThe German Psoriasis Registry PsoBest is a national prospective patient registry established in 2008. In total 865 dermatology practices (n = 797) and clinics (n = 68) are registered in PsoBest from across Germany.4 Detailed assessments at baseline and follow‐up are also performed, similarly to those with BADBIR.5 A data snapshot from June 2017 was used as the validation dataset.\n\nData analysis\nEligible criteria from both BADBIR and PsoBest include patients with chronic plaque psoriasis starting either a licensed biological therapy for psoriasis – for example etanercept (Enbrel), adalimumab (Humira), ustekinumab (Stelara) and infliximab (Remicade) – and patients starting acitretin, psoralen–ultraviolet A, ciclosporin, fumaric acid esters, methotrexate and hydroxycarbamide.\n\nPatients in both cohorts contributed to the study if they had a follow‐up period of 1 year or more, or had < 1 year of follow‐up but developed one or more serious infections within the follow‐up period. Follow‐up was measured from the first prescribed dose of the first therapy while registered in either cohort.\n\nIn BADBIR we defined serious infection as any infection that was associated with or prolonged hospitalization, required intravenous antimicrobial therapy or led to death.6 A similar definition was used for serious infections in the PsoBest registry, but it was not possible to include the use of intravenous antimicrobial therapy in the definition. Four additional cases were included from BADBIR based only on the use of intravenous antimicrobial therapy. We limited the outcome to having had one or more serious infections within the first year. Prior to model development, we performed descriptive analysis of the baseline covariates in both cohorts.\n\nModel development\nBaseline predictor covariates were identified a priori from consensus in the BADBIR research analysis group and a literature review.7 A two‐tier predictor selection process was performed. The first tier identified covariates that were highly likely important factors for the development of serious infections. These covariates were age, sex, PASI, choice of starting therapy and body mass index (BMI) at baseline. The nearest PASI score within 6 months of the date of therapy initiation was eligible for inclusion.\n\nRegardless of the bivariate analysis results, these covariates were included in the final multiple logistic regression model. The second tier identified covariates that were probable important factors for the development of serious infections. These covariates were alcohol intake per week, cigarettes smoked per day, chronic obstructive pulmonary disease (COPD), asthma, depression, diabetes, hypertension, employment status, number of comorbidities, presence of psoriatic arthritis, total number of previous biological therapies, and total number of previous nonbiological systemic treatments. The number of comorbidities denoted the patient's self‐identified list of comorbidities. Employment status was divided into three categories as previously defined:8 (i) those working full time, part time or full time in the home, or who were students; (ii) those who were unemployed but seeking work or not working due to disability or ill health; and (iii) those who were retired.\n\nThe information for the predictors was captured from patient‐reported baseline questionnaires and clinician‐completed questionnaires. As we included only variables available to the clinicians at baseline prior to initiation of therapy, we did not include time‐varying factors such as switching of therapy or use of concomitant or combination systemic therapies. For this list of predictors a ratio of 10 events per predictor variable was achieved.\n\nThe outcome of serious infection within 1 year of treatment initiation was treated as a binary outcome, with values of 0 for no infection and 1 for at least one infection within 1 year. Bivariate logistic regression models were performed to obtain unadjusted odds ratios. The second‐tier potential predictors were assessed for inclusion using backward elimination in a logistic regression model, with a P‐value of 0·1 as the cut‐off. The equation for the prediction of serious infection was produced from the resulting multiple logistic regression model.\n\nInternal validation\nThe model's discriminative performance was assessed by the concordance statistic (C‐statistic, equivalent to the area under the receiver operating characteristic curve), representing the probability that the model would identify patients having had a serious infection in the 1 year as having a higher predicted risk than patients without such an event. The model calibration was assessed using the calibration slope and the calibration in the large (CITL). CITL measures whether the predicted prevalence was less than (CITL < 0) or greater than the observed prevalence (CITL > 0). The calibration slope primarily detects whether the model is overfitted (slope < 1).9 Internal validation was performed on the prediction model; the statistical details are presented in Appendix S1 (see Supporting Information).\n\nExternal validation\nThe final risk prediction model, after adjustment for overfitting, was applied to each participant in the external validation cohort. The performance of the model was similarly assessed by the C‐statistic (discrimination), the calibration slope and the CITL (calibration).\n\nAll analyses were performed using Stata version 15·1 (StataCorp, College Station, TX, U.S.A.). The study was conducted and reported according to the Transparent Reporting of a multivariate prediction model for Individual Prediction Or Diagnosis (TRIPOD) guidelines.10\n\n\nEthical approval\nBADBIR was approved in March 2007 by the National Health Service Research Ethics Committee North West England, reference 07/MRE08/9. All patients gave written informed consent for their participation in the registry. Approval for PsoBest was obtained in July 2007 from the ethics commission of the State Medical Association Hamburg (no. 2805).\n\nResults\nIn the development cohort from BADBIR, 10 033 patients were eligible for inclusion. In the validation cohort from PsoBest, 2423 patients were eligible for inclusion (Fig. 1). Table S1(see Supporting Information) summarizes the background characteristics of the two registry populations. Broadly, patients from PsoBest were older and more likely to be current smokers, drink more alcohol, be currently working and have less comorbidity, but were less likely to have a BMI > 30 kg m−2 or depression. Regarding treatment, patients from PsoBest were more likely to receive nonbiological options and less likely to receive biological options.\n\nFigure 1 Flow diagram depicting the participant selection numbers of the development dataset (British Association of Dermatologists Biologic Interventions Register, BADBIR) and the validation dataset (PsoBest).\n\nModel development, performance and validation\nFrom BADBIR, 175 patients (1·7%) developed a serious infection within 1 year of starting systemic therapy. The location types of serious infections in both cohorts as coded by the High‐Level Term in the Medical Dictionary for Regulatory Activities are presented in Table 1, and the associations between the baseline covariates and serious infection in bivariate models are presented in Table S2 (see Supporting Information). In the multiple logistic regression backward selection model, the variables of COPD, alcohol intake, number of comorbidities and employment status were selected in addition to age, sex, PASI, choice of starting therapy and BMI (Table 2). The apparent and internal validation performance statistics of the final multivariable model are presented in Table 3.\n\nTable 1 Location types of serious infections as coded by the MedDRA High‐Level Terms in BADBIR and the equivalent numbers in PsoBest\n\n\tBADBIR\tPsoBest\t\nLower respiratory tract and lung infections\t73 (0·7)\t5 (0·2)\t\nUrinary tract infections\t32 (0·3)\t< 5\t\nAbdominal and gastrointestinal infections\t15 (0·1)\t9 (0·4)\t\nSkin structures and soft‐tissue infections\t12 (0·1)\t< 5\t\nSepsis, bacteraemia, viraemia and fungaemia\t11 (0·1)\t< 5\t\nUpper respiratory tract infections\t11 (0·1)\t5 (0·2)\t\nEar infections\t8 (0·1)\t< 5\t\nCardiac infections\t6 (0·1)\t0\t\nBone and joint infections\t5 (0)\t0\t\nFemale reproductive tract infections\t< 5\t< 5\t\nMale reproductive tract infections\t0\t< 5\t\nHepatobiliary and spleen infections\t< 5\t< 5\t\nDental and oral soft‐tissue infections\t0\t< 5\t\nMuscle and soft‐tissue infections\t0\t< 5\t\nEye and eyelid infections\t0\t< 5\t\nVascular infections\t0\t< 5\t\nThe data are the number (percentage proportion) of each type of serious infection out of all participants; n‐values < 5 are censored due to patient confidentiality. MedDRA, Medical Dictionary for Regulatory Activities; BADBIR, British Association of Dermatologists Biologic Interventions Register.\n\nJohn Wiley & Sons, LtdTable 2 Final multivariable prediction model for risk of serious infection 1 year after initiation of therapy in the development cohort (British Association of Dermatologists Biologic Interventions Register)\n\nVariable\tOR (95% CI)\t\nAge\t1·00 (0·98–1·01)\t\nFemale sex\t1·35 (1·13–1·95)\t\nStarting drug\t\nNonbiological systemics\tReference\t\nEtanercept\t0·87 (0·54–1·40)\t\nInfliximab\t3·55 (2·03–6·21)\t\nAdalimumab\t1·10 (0·77–1·54)\t\nUstekinumab\t1·30 (0·87–1·93)\t\nPASI\t1·01 (0·99–1·02)\t\nAlcohol (units per week)\t1·01 (1·00–1·02)\t\nNumber of comorbidities\t1·08 (1·04–1·13)\t\nCOPD\t1·78 (1·01–3·11)\t\nBody mass index\t1·01 (0·99–1·03)\t\nWorking status\t\nWorking\tReference\t\nUnemployed\t1·42 (0·99–2·04)\t\nRetired\t2·05 (1·28–3·31)\t\nPASI, Psoriasis Area and Severity Index; COPD, chronic obstructive pulmonary disease; OR, odds ratio; CI, confidence interval.\n\nJohn Wiley & Sons, LtdTable 3 Internal and external validation model diagnostics (95% confidence intervals)\n\n\t\nC‐statistic\tCalibration in the large\tCalibration slope\t\nApparent performance\t0·68 (0·63–0·72)\t0·006 (−0·15–0·16)\t1·02 (0·84–1·20)\t\nInternal validation test performance\t0·66 (0·61–0·70)\t0·009 (−0·14–0·16)\t0·87 (0·69–1·04)\t\nAverage optimism\t0·033\t−0·009\t0·13\t\nOptimism‐corrected performance\t0·64 (0·60–0·69)\t0·015 (−0·14–0·17)\t0·88 (0·70–1·07)\t\nExternal validation performance\t0·52 (0·42–0·62)\t0·057 (−0·25–0·37)\t0·36 (−0·24–0·97)\t\nJohn Wiley & Sons, LtdThe optimism‐adjusted model discrimination gave a C‐statistic of 0·64 [95% confidence interval (CI) 0·60–0·69], and the optimism‐adjusted model calibration gave a CITL of 0·015 (95% CI −0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70–1·07). A uniform shrinkage factor of 0·87 (the calibration slope of the test performance, Table 3) was applied to the beta‐coefficients of the multivariable model. The mean predicted probability of serious infection within 1 year of initiating therapy after adjustment for overfitting was 0·017 (SD 0·014, range 0·006–0·35).\n\nAs examples using the shrinked coefficients, if a 1% risk cut‐off was applied to identify serious infection, the sensitivity of the test would be 90·3% and the specificity 16·9%. If a 2% risk cut‐off was applied to identify serious infection, the sensitivity of the test would be 46·3% and the specificity would be 78·3%. The risk prediction equation for the log odds of the 1‐year serious infection risk is given in Appendix 2.\n\nExternal validation\nFrom PsoBest, 41 patients (1·7%) developed a serious infection within 1 year of starting systemic therapy. The performance of the final risk prediction model in the PsoBest dataset gave a C‐statistic of 0·52 (95% CI 0·42–0·62), a CITL of 0·06 (95% CI −0·25 to 0·37) and a calibration slope of 0·36 (95% CI −0·24 to 0·96). The mean predicted risk of serious infection within 1 year after systemic therapy initiation was 0·016 (SD 0·011, range 0·006–0·18). Table S3 (see Supporting Information) shows low relatedness between the BADBIR and the PsoBest datasets. In an additional exploratory analysis, hypertension was selected in addition to the other covariates of the BADBIR prediction model as a strong predictor of 1‐year serious infection in the PsoBest cohort (Table S4; see Supporting Information). The C‐statistic of this exploratory model was 0·67 (95% CI 0·59–0·75).\n\nDiscussion\nWe developed a multivariable model to predict the risk of serious infection within 1 year of starting a systemic therapy in patients with moderate‐to‐severe psoriasis. To our knowledge, this is the first study to use two large psoriasis treatment registries to develop and validate externally for serious infection after starting systemic therapy for psoriasis. However, the discriminative activity of the model after internal validation and adjustment for optimism was not perfect, with a C‐statistic of 0·64. At this stage, we feel that this is the first in several systematic steps in working towards a clinically applicable model for predicting serious infection in patients with psoriasis.\n\nThe strengths of this study are (i) the use of a large, national, prospective registry representative of patients with moderate‐to‐severe psoriasis in the real world to develop the algorithm and (ii) detailed data capture allowing inclusion of covariates that are clinically most relevant to the risk of infection for consideration in the model. The covariates included are readily available in a clinical setting, and the risk prediction score can be easily applied in the clinic.\n\nThe main limitation of the model was a C‐statistic below 0·70. Thus, it is likely that factors or interactions between variables that might be predictive of serious infection were not included. For example, previous history of a serious infection was not captured consistently, we do not measure adherence to medication, and geographical location may be influential in the risk of serious infection. Due to the high proportion of missing data, DLQI11 could not be included as a covariate. There may be residual confounding from covariates that were not known to be associated with the risk of serious infection, for example from nonmedical domains such as demographical factors, personal hygiene practices, predisposing work conditions and other lifestyle factors, and were therefore not included.\n\nAnother limitation is the low number of outcome events. As sample size in prediction models is dictated by the number of events per variable, the number of serious infection events (175) restricted the number of covariates that could be included in the model. This limits our ability to include other variables that could potentially improve the discrimination of the model.\n\nWe found statistically significant clinical covariates that were predictors for serious infection in patients receiving systemic therapies for psoriasis. Female patients had 35% higher odds of developing a serious infection than male patients. This result was unsurprising, given that we had previously reported that female participants in the BADBIR cohort had a 79% higher risk of discontinuing biological therapies due to an adverse event.12\n\n\nThe total number of comorbidities, a proxy for patient frailty, was also a significant predictor, and each additional comorbidity was associated with an 8% higher odds of serious infection. COPD was selected in the model as an important comorbidity, associated with an odds ratio of 1·78 of serious infection. This is because many patients are hospitalized for treatment of infective exacerbations of COPD. Alcohol intake was associated with a small but significant increase in the odds of serious infection, with each unit per week associated with an odds ratio of 1·01.\n\nAlthough age was a covariate forced into the model, surprisingly this was not a statistically significant predictor of infection. This is likely due to the fact that working status, which is a proxy of functional status and overall health, was also included and adjusted for in the model, with retired participants associated with twice the odds of serious infection than participants who were working. The predictor with the highest strength of association with serious infection was treatment with infliximab. In separate time‐to‐event analyses, participants on infliximab in BADBIR13 and the Psoriasis Longitudinal Assessment and Registry, a large U.S.A.‐based psoriasis registry,14 also found that infliximab was associated with a higher risk of serious infection.\n\nThe BADBIR and PsoBest registry cohorts are substantially different from each other (Table S4; see Supporting Information). This difference is exemplified by the results of an additional exploratory analysis. We found that hypertension, which was not significant in the BADBIR cohort, was strongly predictive for serious infection in the PsoBest cohort. In addition, the odds ratios of working status, female sex, individual treatments and the number of comorbidities were also very different between the two models (Table S4).\n\nThere are several notable differences between the two registries. Firstly, there are differences in the proportions of patients on nonbiological systemic therapies and biological therapies (Table S1 ; see Supporting Information). Secondly, patients in BADBIR on nonbiologics are predominantly using methotrexate,15 while patients in PsoBest on nonbiologics are predominantly using fumaric acid esters.16 In addition, infliximab is only recommended to be used in the U.K. for patients with very severe psoriasis (PASI ≥ 20, DLQI > 18). This introduces confounding by indication that is not present in the PsoBest population.\n\nBoth the heterogeneity of outcome frequency and poor model transportability between the two different psoriasis registries are not surprising. A study by Psonet, a European collaboration of psoriasis registries, investigated the risk of serious infection in patients receiving tumour necrosis factor inhibitors with data from Italian (Psocare) and Spanish (BIOBADADERM) psoriasis registries and a healthcare database in Israel (Clalit Health Service database).17 That study showed marked heterogeneity in the infection rates between the individual countries (I\n2 > 90%). The authors attributed this to variation in the definition of what constituted a ‘serious’ infection, which is also likely to have contributed to differences between BADBIR and PsoBest.\n\nThe propensity to admit a patient into the hospital, a key determinant of whether an infection is classed as ‘serious’, varies between countries, and it is notable that all of the BADBIR centres were from hospital clinics in secondary care, in contrast to the participation of predominately individual dermatology clinics and practices of primary care in PsoBest. This difference in healthcare systems may also introduce confounding by indication. For example, individual practices in primary care in Germany may be more reluctant to prescribe infliximab given that it needs to be administered in a hospital setting. It is possible that patients attending hospital clinics may be more likely to be admitted directly into the hospital if a serious infection was suspected compared with primary‐care clinics.\n\nThe risk prediction model would facilitate discussions between the clinician and the patient regarding risk factors for serious infection. As the interpretation of the risk of serious infection and decision regarding treatment choice may reflect the personal values of the patient, such a model could facilitate the shared decision‐making process. However, it is not possible to quantify the risk of serious infection precisely at the present stage of model development.\n\nIn conclusion, we have developed a preliminary prediction model for the risk of developing a serious infection within 1 year of initiation of systemic therapy in patients with psoriasis. We envisage that such an algorithm could help clinicians and the patient to choose the right starting therapy, discuss lifestyle choices and identify risk‐minimizing modifiable behaviours in shared decision making with their patients. Further development of the model, for example the inclusion of other predictors, and temporal validation using the U.K. and Ireland population of patients in BADBIR, is warranted after further data accrual.\n\nSupporting information\n\nAppendix S1 Supplementary methods.\n\nClick here for additional data file.\n\n \nTable S1 Background characteristics of the development cohort (British Association of Dermatologists Biologic Interventions Register) and validation cohort (PsoBest).\n\nClick here for additional data file.\n\n \nTable S2 Crude odds ratios from bivariate logistic regression models.\n\nClick here for additional data file.\n\n \nTable S3 Assessment and measures of relatedness between the development and validation datasets.\n\nClick here for additional data file.\n\n \nTable S4 Comparison of the final multivariable prediction model for risk of serious infection 1 year after initiation of therapy in the British Association of Dermatologists Biologic Interventions Register and an exploratory multiple logistic regression model with additionally selected covariates in PsoBest. \n\nClick here for additional data file.\n\n \nVideo S1 Author video.\n\nClick here for additional data file.\n\n Acknowledgments\nWe thank all of the patient participants in BADBIR, without whom we would not be able to carry out the project. The substantial contribution of the BADBIR team to the administration of the project has been vital, and we especially acknowledge the pharmacovigilance team – Kathleen McElhone, Shamila Irshad, Victoria Wilde and Saliha Tahir – for their tireless work, Hassan Ali from the BADBIR team for his advice and support, and Sagair Hussain for his support as the clinical project manager of BADBIR. We thank Joie Ensor, Lecturer in Biostatistics at Keele University, for helping with the Stata code for bootstrap validation including multiple imputation. We are grateful to the members of the Data Monitoring Committee (DMC) – Robert Chalmers, Carsten Flohr (Chair), David Prieto‐Merino, Richard Weller – and the BADBIR Steering Committee (in alphabetical order) – Jonathan Barker, Marilyn Benham (CEO of BAD), David Burden (Chair), Christopher Griffiths (Chief Investigator), Ian Evans, Sagair Hussain, Brian Kirby, Linda Lawson, Kathleen McElhone, Tess Macpherson, Kayleigh Mason, Ruth Murphy, Anthony Ormerod, Caroline Owen, Nick Reynolds (Chair, Research Committee), Catherine Smith and Richard Warren. Finally, we acknowledge the enthusiastic collaboration of all of the dermatologists and specialist nurses in the U.K. and the Republic of Ireland who provided the data. The principal investigators at the participating sites at the time of data cut‐off are listed at http://www.badbir.org. PsoBest thanks all the patients contributing to the registry, without whom this research would not be possible. We especially acknowledge the substantial contribution of the PsoBest team – Zinaida Foos, Kristina Haack, Saskia Knopf, Marita Mahling, Marc Radtke and Kathrin Wetzel. We are grateful to the members of the PsoBest Advisory Board (in alphabetical order) – Wolf‐Henning Boehncke, Alexander Enk, Ulrich Mrowietz, Kristian Reich (Chair), Klaus Strömer, Diamant Thaci, Ralph von Kiedrowski and Petra Staubach‐Renz. Finally, we acknowledge the enthusiastic collaboration of all of the dermatologists and specialist nurses in Germany who provided the data. BADBIR and PsoBest are grateful to the European network of psoriasis registries (Psonet) and all researchers collaborating in this network.\n\nAppendix 1 Conflicts of interest and funding sources\nFunding sources: BADBIR is coordinated by the University of Manchester and funded by the British Association of Dermatologists (BAD). The BAD receives income from Celgene, Hexal AG, Almirall, Pfizer, Janssen‐Cilag, AbbVie, Novartis, Samsung Bioepis and Eli Lilly for providing pharmacovigilance services. This income finances a separate contract between the BAD and the University of Manchester, who coordinate BADBIR. All decisions concerning analysis, interpretation and publication are made independently of any industry contribution. All relevant information regarding serious adverse events mentioned in this publication has been reported to the appropriate company as per the contractual agreements and standard operating procedures. PsoBest is coordinated by CVderm (the German Center for Health Services Research in Dermatology) of the Institute for Health Services Research in Dermatology and Nursing at the University Medical Center Hamburg‐Eppendorf. PsoBest is supported by AbbVie Deutschland GmbH, Almirall Hermal GmbH, Biogen GmbH, Celgene GmbH, Hexal AG, Janssen‐Cilag GmbH, LEO Pharma GmbH, Lilly Deutschland GmbH & Co. KG and Pfizer Deutschland GmbH. All decisions concerning analysis, interpretation and publication are made independently of any industry contribution. Z.Z.N.Y. is funded by a National Institute for Health Research (NIHR) Doctoral Research Fellowship (no. DRF‐2015‐08‐089). BADBIR acknowledges the support of the NIHR through the clinical research networks and the contribution made by clinical research associates who continue to facilitate recruitment into the registry. The research was supported by the NIHR Manchester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. C.E.M.G. is an NIHR Senior Investigator. C.E.M.G., D.M.A. and R.B.W. are funded in part by the Medical Research Council (MR/L011808/1).\n\nConflicts of interest: C.E.M.G. is an NIHR Senior Investigator and reports grants from the NIHR, during the conduct of the study; grants and personal fees from GSK, AbbVie, Lilly, Novartis, Pfizer, Janssen, LEO and Celgene; grants from Sandoz; personal fees from Sun Pharmaceuticals, UCB Pharma and Almirall; and grants and personal fees from outside the submitted work. D.M.A. has received research grants from AbbVie and LEO Foundation. K.J.M. has received honoraria from Janssen‐Cilag and Eli Lilly. R.B.W. has received research grants from AbbVie, Pfizer, Novartis and LEO; and reports personal fees from AbbVie, Amgen, Boehringer Ingelheim Pharma, Celgene, Janssen‐Cilag, LEO, Lilly, Novartis, Pfizer and Xenoport outside the submitted work. Z.Z.N.Y. has received nonfinancial support from Novartis outside the submitted work. M.A. has served as a consultant and/or paid speaker for, and/or has received research grants and/or honoraria for consulting and/or scientific lectures for, and/or has received travel expenses reimbursed by, and/or has participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis including AbbVie, Almirall, Amgen, Biogen (Biogen Idec), Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, Galderma, Janssen‐Cilag, LEO, Medac, MSD, Mundipharma, Novartis, Pfizer, Sandoz and Xenoport. C.S., L.K. and S.J.R. are employees of University Medical Center Hamburg‐Eppendorf. M.L. has no conflicts of interests to disclose.\n\nAppendix 2 Risk prediction model\nThe risk score from a logistic regression model to predict serious infection within 1 year of initiation of systemic therapy for psoriasis:\n\nLog odds of serious infection within 1 year =−4·985364 − (0·0042559 × age) + (0·3036825 × female sex) + (0·0062117 × PASI) + (0·0084999 × units of alcohol per week) + (0·0809034 × number of comorbidities)+ (0·5743102 × COPD) + (0·0098085 × BMI) + (0·354117 × unemployed or not currently working)+ (0·7202485 × retired) − (0·140139 × etanercept) + (1·267439 × infliximab) + (0·0975531 × adalimumab) + (0·2599529 × ustekinumab).\n==== Refs\nReferences\n1 \n\nWakkee \nM \n, \nde Vries \nE \n, \nvan den Haak \nP \n\net al\nIncreased risk of infectious disease requiring hospitalization among patients with psoriasis: a population‐based cohort . J Am Acad Dermatol \n2011 ; 65 :1135 –44 .21664719 \n2 \n\nThorneloe \nRJ \n, \nGriffiths \nCEM \n, \nEmsley \nR \n\net al\nIntentional and unintentional medication non‐adherence in psoriasis: the role of patients’ medication beliefs and habit strength . J Invest Dermatol \n2018 ; 138 :785 –94 .29183731 \n3 \n\nBurden \nAD \n, \nWarren \nRB \n, \nKleyn \nCE \n\net al\nThe British Association of Dermatologists’ Biologic Interventions Register (BADBIR): design, methodology and objectives . Br J Dermatol \n2012 ; 166 :545 –54 .22356636 \n4 \n\nAugustin \nM \n, \nSpehr \nC \n, \nRadtke \nMA \n\net al\nGerman psoriasis registry PsoBest: objectives, methodology and baseline data . J Dtsch Dermatol Ges \n2014 ; 12 :48 –57 .24393314 \n5 \n\nOrmerod \nAD \n, \nAugustin \nM \n, \nBaker \nC \n\net al\nChallenges for synthesising data in a network of registries for systemic psoriasis therapies . Dermatology \n2012 ; 224 :236 –43 .22678413 \n6 \n\nYiu \nZZN \n, \nSmith \nCH \n, \nAshcroft \nDM \n\net al\nRisk of serious infection in patients with psoriasis receiving biologic therapies: a prospective cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR) . J Invest Dermatol \n2018 ; 138 :534 –41 .29054603 \n7 \n\nYiu \nZZ \n, \nExton \nLS \n, \nJabbar‐Lopez \nZ \n\net al\nRisk of serious infections in patients with psoriasis on biologic therapies: a systematic review and meta‐analysis . J Invest Dermatol \n2016 ; 136 :1584 –91 .27085754 \n8 \n\nDavison \nNJ \n, \nWarren \nRB \n, \nMason \nKJ \n\net al\nIdentification of factors that may influence the selection of first‐line biological therapy for people with psoriasis: a prospective, multicentre cohort study . Br J Dermatol \n2017 ; 177 :828 –36 .28386916 \n9 \n\nSteyerberg \nEW \n, \nVickers \nAJ \n, \nCook \nNR \n\net al\nAssessing the performance of prediction models: a framework for traditional and novel measures . Epidemiology \n2010 ; 21 :128 –38 .20010215 \n10 \n\nCollins \nGS \n, \nReitsma \nJB \n, \nAltman \nDG \n\net al\nTransparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement . BMJ \n2015 ; 350 :g7594 .25569120 \n11 \n\nFinlay \nAY \n, \nKhan \nGK \n. Dermatology Life Quality Index (DLQI) – a simple practical measure for routine clinical use . Clin Exp Dermatol \n1994 ; 19 :210 –16 .8033378 \n12 \n\nWarren \nRB \n, \nSmith \nCH \n, \nYiu \nZZ \n\net al\nDifferential drug survival of biologic therapies for the treatment of psoriasis: a prospective observational cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR) . J Invest Dermatol \n2015 ; 135 :2632 –40 .26053050 \n13 \n\nYiu \nZZN \n, \nAshcroft \nDM \n, \nEvans \nI \n\net al\nInfliximab is associated with an increased risk of serious infection in patients with psoriasis in the United Kingdom and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR) . Br J Dermatol \n2018 \n10.1111/bjd.17036 \n\n14 \n\nKalb \nRE \n, \nFiorentino \nDF \n, \nLebwohl \nMG \n\net al\nRisk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) . JAMA Dermatol \n2015 ; 151 :961 –9 .25970800 \n15 \n\nIskandar \nIY \n, \nAshcroft \nDM \n, \nWarren \nRB \n\net al\nDemographics and disease characteristics of patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register . Br J Dermatol \n2015 ; 173 :510 –18 .25989336 \n16 \n\nReich \nK \n, \nMrowietz \nU \n, \nRadtke \nMA \n\net al\nDrug safety of systemic treatments for psoriasis: results from The German Psoriasis Registry PsoBest . Arch Dermatol Res \n2015 ; 307 :875 –83 .26358263 \n17 \n\nGarcia‐Doval \nI \n, \nCohen \nAD \n, \nCazzaniga \nS \n\net al\nRisk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti‐tumor necrosis factor agents versus classic therapies: prospective meta‐analysis of Psonet registries . J Am Acad Dermatol \n2017 ; 76 :299 –308 .27693008\n\n",
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"title": "Development and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy.",
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"abstract": "Preclinical activity of irinotecan has been seen in glioma models, but only modest efficacy has been noted in clinical studies, perhaps related to drug distribution and/or pharmacokinetic limitations. In preclinical testing, irinotecan liposome injection (nal-IRI) results in prolongation of drug exposure and higher tissue levels of drug due to slower metabolism and the effect of enhanced permeability and retention. The objective of the current study was to assess the safety and pharmacokinetics (PK) of nal-IRI and to determine the maximum tolerated dose (MTD) in patients with recurrent high-grade glioma stratified based on UGT1A1 genotyping.\n\n\n\nThis phase I study stratified patients with recurrent high-grade glioma into 2 groups by UGT1A1 status: homozygous WT (\"WT\") vs heterozygous WT/*28 (\"HT\"). Patients who were homozygous *28 were ineligible. The design was a standard 3 + 3 phase I design. WT patients were started at 120 mg/m2 intravenously every 3 weeks with dose increases in 60 mg/m2 increments. HT patients were started at 60 mg/m2, with dose increases in 30 mg/m2 increments. The assessment period for dose-limiting toxicity was 1 cycle (21 days).\n\n\n\nIn the WT cohort (n = 16), the MTD was 120 mg/m2. In the HT cohort (n = 18), the MTD was 150 mg/m2. Dose-limiting toxicity in both cohorts included diarrhea, some with associated dehydration and/or fatigue. PK results were comparable to those seen in other PK studies of nal-IRI; UGT1A1*28 genotype (WT vs. HT) did not affect PK parameters.\n\n\n\nNal-IRI had no unexpected toxicities when given intravenously. Of note, UGT1A1 genotype did not correlate with toxicity or affect PK profile.",
"affiliations": "Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA. clarkej@neurosurg.ucsf.edu.;Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.;Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.;Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.;Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.;Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.;Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA.;Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA.;Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA.;Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA.;Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.;Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.;Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.;Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St., San Francisco, CA, 94115, USA.;Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA.",
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"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Chemotherapy; Glioblastoma; High-grade glioma; Irinotecan; Liposomes",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D001932:Brain Neoplasms; D002166:Camptothecin; D015331:Cohort Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D005910:Glioma; D014453:Glucuronosyltransferase; D006801:Humans; D007275:Injections, Intravenous; D000077146:Irinotecan; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "603-610",
"pmc": null,
"pmid": "28233053",
"pubdate": "2017-03",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma.",
"title_normalized": "a phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high grade glioma"
} | [
{
"companynumb": "US-CIPLA (EU) LIMITED-2018US17837",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null... |
{
"abstract": "We describe the case of a 76-year-old man who presented with bilateral lower limb weakness associated with decreased urine output. His initial blood results showed acute kidney injury (AKI) stage 3 with substantially raised serum creatine kinase concentration of 37 950 IU/L (normal range <171 U/L). He had been on high-dose rosuvastatin for 4 years with a recent brand change occurring 1 week prior to onset of symptoms. There was no history of pre-existing neuromuscular disease. Statin-related rhabdomyolysis was suspected and rosuvastatin was withheld. His muscle strength gradually improved. He required haemodialysis for 10 weeks. He was discharged home after a complicated course of hospitalisation. His renal function improved and he became dialysis-independent; however, he was left with residual chronic kidney disease.",
"affiliations": "General Medicine, Goulburn Valley Health, Shepparton, Victoria, Australia dockohu@gmail.com.;Nephrology and General Medicine, Goulburn Valley Health, Shepparton, Victoria, Australia.",
"authors": "Hussain|Kosar|K|http://orcid.org/0000-0002-0437-5788;Xavier|Anil|A|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000068718:Rosuvastatin Calcium",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229244",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "Acute renal failure; Muscle disease; Unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D020335:Paraparesis; D006435:Renal Dialysis; D012206:Rhabdomyolysis; D000068718:Rosuvastatin Calcium; D028761:Withholding Treatment",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31601550",
"pubdate": "2019-10-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26090508;11898964;21249398;29878063;26515829;23327834;15572716;24799748;24793443;26886523;23511950;28778365;18997196;23441644;16344427;24952854;25043142;19571284;11573861;29942498",
"title": "Rosuvastatin-related rhabdomyolysis causing severe proximal paraparesis and acute kidney injury.",
"title_normalized": "rosuvastatin related rhabdomyolysis causing severe proximal paraparesis and acute kidney injury"
} | [
{
"companynumb": "AU-TEVA-2019-AU-1135126",
"fulfillexpeditecriteria": "1",
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"patient": {
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"activesubstance": {
"activesubstancename": "BISOPROLOL"
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... |
{
"abstract": "Osteonecrosis is a disease with diverse pathophysiology, clinical presentation, and management. It may be associated with some medications used to treat systemic issues with bone metabolism. A few cases of jaw bone osteonecrosis have been associated with raloxifene. In this paper, the authors present a clinical report of a 64-year-old woman who presented with a necrosis foci in the right alveolar ridge of the mandible, associated with continued raloxifene use.",
"affiliations": "João de Barros Barreto University Hospital, Federal University of Pará, Pará, Brazil.",
"authors": "Pontes|Hélder Antônio Rebelo|HAR|;Souza|Lucas Lacerda de|LL|;Uchôa|Daniel Cavalléro Colares|DCC|;Cerqueira|João Mateus Mendes|JMM|",
"chemical_list": "D050071:Bone Density Conservation Agents; D020849:Raloxifene Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1097/SCS.0000000000004278",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1049-2275",
"issue": "29(3)",
"journal": "The Journal of craniofacial surgery",
"keywords": null,
"medline_ta": "J Craniofac Surg",
"mesh_terms": "D050071:Bone Density Conservation Agents; D005260:Female; D006801:Humans; D008336:Mandibular Diseases; D008875:Middle Aged; D010020:Osteonecrosis; D010024:Osteoporosis; D020849:Raloxifene Hydrochloride",
"nlm_unique_id": "9010410",
"other_id": null,
"pages": "e257-e259",
"pmc": null,
"pmid": "29303860",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mandibular Osteonecrosis Associated With Raloxifene.",
"title_normalized": "mandibular osteonecrosis associated with raloxifene"
} | [
{
"companynumb": "BR-AMNEAL PHARMACEUTICALS-2018AMN00644",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RALOXIFENE HYDROCHLORIDE"
},
"dr... |
{
"abstract": "A 36-year-old man with a history of Graves' disease was admitted complaining of dyspnea. He was diagnosed with acute heart failure and severe liver dysfunction accompanied by thyroid storm. Left ventricular ejection fraction was 19%, and liver enzyme levels were markedly elevated followed with coagulation disorders. In addition to the conventional therapy, we performed plasma exchange emergently. Thyroid hormone levels promptly normalized, then his clinical condition improved. Finally, his cardiac and liver function almost normalized from a fatal condition without serious complications. Hyperthyroidism can cause myocardial and liver injury, hence thyroid hormone removal in acute phase is important. Prompt plasma exchange is effective in the acute phase for heart and liver failure accompanied by thyroid storm. <Learning objective: Thyroid storm is a life-threatening condition. Prompt reduction of serum free thyroid hormone is important in fatal conditions. Because plasma exchange (PE) can decrease serum thyroid hormone and improve critical condition, PE should be conducted emergently. In the present case, we promptly performed PE for the patient with potentially fatal heart and liver failure. We could treat him without any complication. We wish to emphasize the importance of prompt PE in acute phase of thyroid storm.>.",
"affiliations": "Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Yodogawa Christian Hospital, Osaka, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Zeng|Feibi|F|;Takaya|Tomofumi|T|;Yoshida|Naofumi|N|;Ito|Tatsuro|T|;Suto|Makiko|M|;Hatani|Yu|Y|;Sano|Hiroyuki|H|;Ito|Jun|J|;Fukuoka|Hidenori|H|;Yamashita|Tomoya|T|;Hirata|Ken-Ichi|KI|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2016.11.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "15(3)",
"journal": "Journal of cardiology cases",
"keywords": "Acute heart failure; Acute liver failure; Plasma exchange; Thyroid storm",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "100-103",
"pmc": null,
"pmid": "30279751",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports",
"references": "11445692;5536311;2228998;12205333;25547548;22107688;15978201;1292653;22082892",
"title": "A case of fatal heart and liver failure accompanied by thyroid storm treated with prompt plasma exchange.",
"title_normalized": "a case of fatal heart and liver failure accompanied by thyroid storm treated with prompt plasma exchange"
} | [
{
"companynumb": "JP-BAUSCH-BL-2017-010067",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Radiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.",
"affiliations": "Heart and Vascular Institute, Carle Foundation Hospital, USA.;Heart and Vascular Institute, Carle Foundation Hospital, USA.;Heart and Vascular Institute, Carle Foundation Hospital, USA.;Heart and Vascular Institute, Carle Foundation Hospital, USA.",
"authors": "Okuya|Yoshiyuki|Y|;Park|Jae Yoon|JY|;Garg|Anuj|A|;Moussa|Issam|I|",
"chemical_list": "D007545:Isoproterenol",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.6130-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33162486\n10.2169/internalmedicine.6130-20\nCase Report\nCoronary Artery Spasm During Catheter Ablation Caused by the Intravenous Infusion of Isoproterenol\nOkuya Yoshiyuki 1\nPark Jae Yoon 12\nGarg Anuj 12\nMoussa Issam 12\n1 Heart and Vascular Institute, Carle Foundation Hospital, USA\n2 Carle Illinois College of Medicine, University of Illinois - Urbana Champaign, USA\nCorrespondence to Dr. Yoshiyuki Okuya, Yoshiyuki.Okuya@carle.com\n\n9 11 2020\n15 4 2021\n60 8 12211224\n17 8 2020\n23 9 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nRadiofrequency ablation is an established treatment for atrial fibrillation (AF). However, coronary artery spasm (CAS) is a rare but a potentially lethal complication associated with this procedure. A 54-year-old man with paroxysmal AF underwent pulmonary vein isolation. The procedure was completed and AF could not be induced after burst pacing and the administration of isoproterenol. Suddenly, ST-segment elevation developed in the anterior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation. The diagnosis of CAS was made by urgent coronary angiography. We identified isoproterenol as a potential cause of CAS. Physicians should be aware of this potentially lethal side effect.\n\ncoronary artery spasm\nisoproterenol\ncatheter ablation\natrial fibrillation\n==== Body\nIntroduction\n\nRadiofrequency (RF) ablation has become a standard treatment modality for atrial fibrillation (AF), and it is generally considered to be a safe procedure. However, serious complications can occur. Case reports demonstrating coronary artery spasm (CAS) as a potential lethal complication of catheter ablation for AF have been published (1, 2). The occurrence of CAS during RF ablation is probably multifactorial, and its underlying mechanisms have not yet been fully determined. We herein report a patient who experienced severe CAS during RF ablation for AF due to the intravenous infusion of isoproterenol.\n\nCase Report\n\nA 54-year-old Caucasian man with history of hypertension, atrial flutter, nicotine dependence, and alcohol abuse was referred to our institution for RF ablation of paroxysmal AF. He previously underwent cavo-tricuspid isthmus ablation of atrial flutter and had isoproterenol infusion post ablation without any complications. The patient had been implanted with a loop recorder eighteen months prior to this presentation. His height was 180 cm and body weight was 90.4 kg. He had no known allergies or family history of sudden death or cardiac disease. He had no prior resting or exercising angina, and a pharmacologic nuclear stress test demonstrated normal myocardial perfusion with normal wall motion prior to the procedure.\n\nThe ablation strategy employed pulmonary vein isolation under general anesthesia. There was no hemodynamic instability nor hypoxemia during the procedure. The sheath was removed from left atrium. AF could not be induced after burst pacing and the administration of isoproterenol at 5 μg/min. Therefore, the procedure was concluded.\n\nSix minutes after stopping isoproterenol, the 12 lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (Fig. 1A). Urgent coronary angiography was performed which showed an occluded mid-left anterior descending artery and moderate-severe narrowing of left circumflex artery and right coronary artery (Fig. 1B). After the intracoronary administration of 200 μg nitroglycerin, the coronary narrowing and ST-segment elevation resolved (Fig. 2A, B). Diltiazem was added to the patient's medical regimen and he was discharged the following day without any complications. Smoking and alcohol intake were strictly prohibited.\n\nFigure 1. The 12-lead surface electrocardiogram showed ST-segment elevation in the anterior and inferior leads and frequent premature ventricular contractions followed by non-sustained ventricular fibrillation (A). Coronary angiography showed an occluded mid-left anterior descending artery (arrow) and moderate-severe narrowing of left circumflex artery and right coronary artery (B).\n\nFigure 2. After the intracoronary administration of nitroglycerin, the 12-lead surface electrocardiogram showed an improvement of ST-segment elevation (A), and angiographic stenosis (B).\n\nDiscussion\n\nRF ablation is an established treatment for AF in terms of efficacy and safety. However, coronary artery related complications have been reported after RF ablation; these include direct thermal injury by RF energy (3), embolus (4) and CAS (1, 2, 5). To the best of our knowledge, this is the first case which showed severe CAS on angiography caused by isoproterenol during catheter ablation.\n\nPatients with paroxysmal AF have high positive rates of drug-provoked CAS (6). Although the underlying mechanism responsible for CAS remains unclear, CAS during and after catheter ablation has been attributed to several different mechanisms such as direct thermal damage from RF energy to coronary artery (7), indirect effects via cryoenergy-induced blood cooling (8), an imbalance in the autonomic nervous system activity caused by the affected ganglionated plexus through a thermal or cooling injury (1), and an imbalance in the autonomic discharge, such as stimulation of α-2 adrenergic receptors induced by dexmedetomidine (9). The CAS in the present case occurred after the ablation procedure. Moreover, neither cryoballoon nor dexmedetomidine was used. The present case was a rare case which showed CAS caused by isoproterenol infusion. The use of isoproterenol in the electrophysiology lab to study triggers of AF is well established (10). The mechanisms which isoproterenol induces AF may include an increase in intracellular calcium that facilitates abnormal automaticity or early after depolarizations and triggered activity. Accentuated antagonism leading to enhanced parasympathetic tone also may play a role in the inducibility of AF by isoproterenol (11). The relationship between the autonomic nervous system and CAS is complex. Although the parasympathetic activity is well known to be a trigger of CAS, sympathetic stimuli may also play a role. CAS has been shown to occur more frequently during the rapid eye movement phase of sleep at night when there is a reduction in vagal activity and an increase in adrenergic activity (12), suggesting that CAS is not necessarily induced by parasympathetic activity. Moreover, several case reports have suggested that CAS can be induced by various sympathetic related stimuli (13, 14). Hung et al. showed that a head-up tilt test with isoproterenol can provoke CAS, which suggests that the induction of CAS is associated with a rapid elevation of sympathetic activity during augmented parasympathetic activity (15). The present case report describes the intravenous administration of isoproterenol, a non-selective β adrenoreceptor agonist, as a potential cause of CAS during catheter ablation for AF. Physicians should be aware of this potentially lethal side effect. A through a preoperative history should be taken to determine whether a patient has a risk of CAS. The main risk factors for CAS are age, a smoking history, Japanese ethnicity, hypertension, and diabetes mellitus, and it can be precipitated by various factors such as mental exercise, cold exposure, hyperventilation, or alcohol consumption (16). Although this patient was Caucasian and did not have alcohol flushing syndrome, the present case had history of nicotine dependence and alcohol abuse. Mizuno et al. reported that East Asian variants of the aldehyde dehydrogenase 2 genotype was associated with CAS in Japanese (17). The administration of a calcium channel blocker and smoking cessation before RF ablation may avoid CAS during these procedures. The 12-lead electrocardiogram should be continuously monitored throughout the procedure with special attention to ischemic changes. Moreover, coronary angiography and the administration of coronary vasodilator should be performed when ST changes are observed.\n\nConclusions\n\nIsoproterenol administration during AF ablation may provoke severe CAS, possibly due to an autonomic nervous system imbalance. This is a rare complication of AF ablation and it should be considered when performing these procedures.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Hishikari K , Kuwahara T , Takahashi A , Isobe M . Severe coronary artery spasm during radiofrequency ablation for atrial fibrillation. Int J Cardiol 172 : e513-e515, 2014.24508111\n2. Yajima K , Yamase Y , Oishi H , Ikehara N , Asai Y . Coronary artery spasm during cryoballoon ablation in a patient with atrial fibrillation. Intern Med 57 : 819-822, 2018.29093410\n3. Wong KC , Lim C , Sadarmin PP , et al . High incidence of acute sub-clinical circumflex artery 'injury' following mitral isthmus ablation. Eur Heart J 32 : 1881-1890, 2011.21531742\n4. Kuwahara T , Takahashi A , Takahashi Y , et al . Clinical characteristics of massive air embolism complicating left atrial ablation of atrial fibrillation: lessons from five cases. Europace 14 : 204-208, 2012.21937478\n5. Tada H , Naito S , Oshima S , Taniguchi K . Vasospastic angina shortly after left atrial catheter ablation for atrial fibrillation. Heart Rhythm 2 : 867-870, 2005.16051126\n6. Kawakami T , Ohno H , Tanaka N , Ishihara H , Kobayakawa H , Sakurai T . The relationship between paroxysmal atrial fibrillation and coronary artery spasm. Pacing Clin Electrophysiol 37 : 591-596, 2014.24215419\n7. Takahashi Y , Jaïs P , Hocini M , et al . Acute occlusion of the left circumflex coronary artery during mitral isthmus linear ablation. J Cardiovasc Electrophysiol 16 : 1104-1107, 2005.16191121\n8. Lehrmann H , Potocnik C , Comberg T , et al . Near-fatal coronary artery spasm during cryoballoon pulmonary vein isolation: an unreported complication. Circ Arrhythm Electrophysiol 7 : 1273-1274, 2014.25516586\n9. Furui K , Morishima I , Kanzaki Y , Tsuboi H . Coronary vasospasm caused by intravenous infusion of dexmedetomidine: unrecognized pitfall of catheter ablation procedures of atrial fibrillation. J Cardiol Cases 20 : 221-224, 2019.31762838\n10. Oral H , Crawford T , Frederick M , et al . Inducibility of paroxysmal atrial fibrillation by isoproterenol and its relation to the mode of onset of atrial fibrillation. J Cardiovasc Electrophysiol 19 : 466-470, 2008.18266669\n11. Oral H , Ozaydin M , Tada H , et al . Mechanistic significance of intermittent pulmonary vein tachycardia in patients with atrial fibrillation. J Cardiovasc Electrophysiol 13 : 645-650, 2002.12139285\n12. Otsuka K , Yanaga T , Watanabe H . Variant angina and REM sleep. Am Heart J 115 : 1343-1346, 1988.3376864\n13. Lindsay PJ , Frank RC , Bittner EA , Berg S , Chang MG . ST elevations and ventricular tachycardia secondary to coronary vasospasm upon extubation. Case Rep Anesthesiol 2020 : 1527345, 2020.32099682\n14. Sogut O , Kaya H , Gokdemir MT , Sezen Y . Acute myocardial infarction and coronary vasospasm associated with the ingestion of cayenne pepper pills in a 25-year-old male. Int J Emerg Med 5 : 5, 2012.22264348\n15. Hung MJ , Wang CH , Cherng WJ . Provocation of coronary vasospastic angina using an isoproterenol head-up tilt test. Angiology 55 : 271-280, 2004.15156260\n16. Matta A , Bouisset F , Lhermusier T , et al . Coronary artery spasm: new insights. J Interv Cardiol 2020 : 5894586, 2020.32508542\n17. Mizuno Y , Harada E , Morita S , et al . East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome. Circulation 131 : 1665-1673, 2015.25759460\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(8)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "atrial fibrillation; catheter ablation; coronary artery spasm; isoproterenol",
"medline_ta": "Intern Med",
"mesh_terms": "D001281:Atrial Fibrillation; D017115:Catheter Ablation; D003331:Coronary Vessels; D006801:Humans; D007262:Infusions, Intravenous; D007545:Isoproterenol; D008297:Male; D008875:Middle Aged; D011667:Pulmonary Veins; D013035:Spasm; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1221-1224",
"pmc": null,
"pmid": "33162486",
"pubdate": "2021-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16051126;32508542;32099682;21937478;31762838;22264348;18266669;15156260;29093410;25516586;25759460;3376864;12139285;24215419;16191121;21531742;24508111",
"title": "Coronary Artery Spasm During Catheter Ablation Caused by the Intravenous Infusion of Isoproterenol.",
"title_normalized": "coronary artery spasm during catheter ablation caused by the intravenous infusion of isoproterenol"
} | [
{
"companynumb": "US-CIPLA LTD.-2020US08938",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISOPROTERENOL"
},
"drugadditional": "1",
... |
{
"abstract": "Granulibacter bethesdensis is a pathogen reported to cause recurrent lymphadenitis exclusively in persons with chronic granulomatous disease. We report a case of fatal meningitis caused by a highly virulent G. bethesdensis strain in an adolescent in Europe who had chronic granulomatous disease.",
"affiliations": null,
"authors": "Rebelo|Mafalda|M|;Ding|Li|L|;Cordeiro|Ana Isabel|AI|;Neves|Conceição|C|;Simões|Maria João|MJ|;Zelazny|Adrian M|AM|;Holland|Steven M|SM|;Neves|João Farela|JF|",
"chemical_list": "D012336:RNA, Ribosomal, 16S",
"country": "United States",
"delete": false,
"doi": "10.3201/eid2505.181505",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n31002074\n18-1505\n10.3201/eid2505.181505\nDispatch\nDispatch\nFatal Meningitis in Patient with X-Linked Chronic Granulomatous Disease Caused by Virulent Granulibacter bethesdensis\nFatal Meningitis in Patient with X-Linked Chronic Granulomatous Disease Caused by Virulent Granulibacter bethesdensis\nFatal Meningitis Caused by G. bethesdensis\nRebelo Mafalda 1\nDing Li 1\nCordeiro Ana Isabel\nNeves Conceição\nSimões Maria João\nZelazny Adrian M.\nHolland Steven M. 2\nNeves João Farela 2\nHospital Dona Estefânia—Centro Hospitalar de Lisboa Central, Entidade Publica Empresarial, Lisbon, Portugal (M. Rebelo, A.I. Cordeiro, C. Neves, J.F. Neves);\nNational Institute of Allergy and Infectious Diseases of the National Institutes of Health, Bethesda, Maryland, USA (L. Ding, A.M. Zelazny, S.M. Holland);\nNational Institute of Health Dr. Ricardo Jorge, Lisbon (M.J. Simões);\nChronic Diseases Research Center, NOVA Medical School, Lisbon (J.F. Neves)\nAddress for correspondence: João Farela Neves, Primary Immunodeficiencies Unit, Hospital Dona Estefânia, Rua Jacinta Marto, 1145, Lisbon, Portugal; email: joao.farelaneves@chlc.min-saude.pt\n5 2019\n25 5 976979\nGranulibacter bethesdensis is a pathogen reported to cause recurrent lymphadenitis exclusively in persons with chronic granulomatous disease. We report a case of fatal meningitis caused by a highly virulent G. bethesdensis strain in an adolescent in Europe who had chronic granulomatous disease.\n\nKeywords:\n\nChronic granulomatous disease\nGranulibacter bethesdensis\nmeningitis/encephalitis\nvirulent strain\nX-linked defect\nbacteria\nimmunodeficiency\n==== Body\nChronic granulomatous disease (CGD) is a primary immunodeficiency characterized by a deficient nicotinamide adenine dinucleotide phosphate oxidative burst that impairs phagocyte superoxide formation and killing of certain pathogens. Mutations can occur in any of the 5 subunits of nicotinamide adenine dinucleotide phosphate oxidase. Most cases are inherited as X-linked defects (gp91phox), but they also can occur in an autosomal recessive manner (1). Increased susceptibility develops to recurrent infections of the skin, lymph nodes, lungs, and other organs (2), mostly caused by bacteria and fungi, including Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Salmonella spp., Nocardia spp., and Aspergillus spp. (2). Emerging organisms, such as Granulibacter bethesdensis and other methylotrophs, occur almost exclusively in CGD patients (3,4).\n\nG. bethesdensis was first described in 2006, when it was isolated in a CGD patient with lymphadenitis (4). It is a gram-negative, aerobic, oxidase-negative, catalase-positive, nonmotile coccobacillus to rod-shaped bacterium belonging to the Acetobacteraceae family (5,6). G. bethesdensis was the first of these Acetobacteraceae family bacteria with proven pathogenicity in humans, causing invasive disease in CGD patients and mice (4). It has been mostly linked to indolent nonfatal lymphadenitis and deep neck infections in patients in North America. The infection can recur over several years by reactivation of the same strain or reinfection with different strains (3,7–9). The first fatal infection was reported in a 10-year-old boy from Spain, who died of fulminant sepsis (10). In vitro, G. bethesdensis shows extensive resistance to various antimicrobial drugs, although its slow growth makes susceptibility testing difficult. Ceftriaxone, aminoglycosides, doxycycline, and trimethoprim/sulfamethoxazole showed activity in vitro (7).\n\nWe report a case of G. bethesdensis meningitis in a patient with X-linked CGD. We also report animal data comparing this G. bethesdensis strain with the strain recovered from recurrent lymphadenitis in a US CGD patient.\n\nThe Study\n\nThe patient was a 16-year-old boy whose X-linked CGD (CYBB exon 13 deletion) was diagnosed when he was 2 years old. His disease had been well-controlled with cotrimoxazole, itraconazole, and interferon-γ. In September 2014, he was hospitalized with a deep cervical abscess (Figure 1, panel A) and received a 5-week course of intravenous ciprofloxacin, doxycycline, and ceftriaxone that resulted in complete clinical and radiologic resolution, followed by 6 weeks of oral amoxicillin/clavulanic acid, doxycycline, and ciprofloxacin along with his usual prophylaxis. No pathogen was identified despite blood cultures, bronchoalveolar lavage, and lymph node biopsy cultures and broad-range bacterial PCR.\n\nFigure 1 Most relevant imaging results from a 16-year-old boy with X-linked chronic granulomatous disease who died of meningitis caused by a virulent Granulibacter bethesdensis strain. A) Computed tomography image showing deep cervical abscess (arrow), July 2012. B) Radiograph showing pneumonia with pleural effusion, October 2012. C) Cranial magnetic resonance image showing multiple intraparenchymal brain abscesses (arrows), December 2012. D) The patient died of obstructive hydrocephalus (shown) and multiorgan failure, April 2013.\n\nAfter this regimen was completed, the boy was readmitted for 8 weeks with pneumonia with pleural effusion (Figure 1, panel B). Full 16S rRNA gene sequencing (≈1,500 bp) identified Cupriavidus spp. in pleural fluid. He received meropenem, amikacin, ciprofloxacin, teicoplanin, doxycycline, and voriconazole, and his condition improved. However, 2 weeks later, fever returned, along with splenomegaly, hemodynamic instability, pancytopenia, hypofibrinogenemia, hyperferritinemia, and elevated soluble CD25. He received intravenous immunoglobulin and dexamethasone for this inflammatory condition and fully recovered. Neck and lung computed tomography images and positron emission tomography performed 1 month later showed no signs of active infection.\n\nNevertheless, a few days later, the patient sought care for altered mental status, hallucinations, aggressiveness, and respiratory instability requiring admission to the pediatric intensive care unit. He had extensive bilateral pneumonia and multiple intraparenchymal brain abscesses (Figure 1, panel C). Meropenem, ciprofloxacin, amikacin, doxycycline, teicoplanin, and voriconazole were started; results of cerebrospinal fluid (CSF) and lung biopsy samples were unremarkable. Teicoplanin was switched to linezolid and voriconazole to caspofungin and liposomal amphotericin B because of toxicity concerns. Four weeks later, he was discharged from the intensive care unit. One month later, fever, vomiting, and focal neurologic deficits developed. CSF showed pleocytosis and hypoglycorrhachia with elevated protein levels. Cerebral imaging confirmed leptomeningitis. Isoniazid, clarithromycin, and rifampin were added to his treatment regimen, but his neurologic status continued to deteriorate. Obstructive hydrocephalus (Figure 1, panel D) and multiorgan failure developed, and he died 3 months later.\n\nCSF cultures yielded yellow-brown, shiny, small colonies (2–4 mm) on chocolate agar after 4 day’s incubation. (Figure 2, panels A, B). Full 16S RNA sequencing (≈1,500 bp) showed 99.7% match to the type strain of G. bethesdensis CGDNIH1T (ATCC BAA-1260T, DSM 17861T) from North America and 100% match to a previously reported G. bethesdensis strain from Spain. Nonstandardized susceptibility test using Etest, performed in Mueller Hinton agar supplemented with 5% sheep blood agar with an overnight air incubation at 37°C, showed resistance to doxycycline (MIC 24 mg/L) and ceftriaxone (MIC >32 mg/L).\n\nFigure 2 Granulibacter bethesdensis colonies and pathology results after inoculation on mouse models. A, B) CSF on chocolate agar for 4 days showed slowly growing brown-yellow, shiny colonies 2–4 mm in diameter. Full 16S RNA sequencing (≈1,500 bp) led to identification of G. bethesdensis (with 99.7% match). C) Survival of gp91/p47 KO mice after inoculation of different G. bethesdensis strains. D) Pathology images of gp91 KO mouse lung after CSF strain infection. E) Pathology images of gp91 KO mouse lungs after type strain infection. F) Quantification of G. bethesdensis strains in spleens of gp91/p47 KO mice after inoculation. CSF, cerebrospinal fluid; type, National Institutes of Health type strain; WT, wild type.\n\nWe used mouse models of CGD to determine whether differences existed in immune response, pathogenicity, or severity of disease between the European (CSF strain) and the US (type strain) strains. We intraperitoneally infected gp91phox−/− mice with 107 CFU of G. bethesdensis type strain and p47phox−/− mice intraperitoneally with 107 CFU of CSF strain and monitored moribundity during infection. We euthanized gp91phox−/− mice 4 weeks and p47phox−/− mice 8 weeks after infection and collected brain, spleen, lung, lymph nodes, and blood for culture, bacterial enumeration, and histopathologic examination. Plasma cytokines were assayed.\n\nAlthough we observed differences between gp91phox−/− and p47phox−/− mice, both CGD mice models showed high rates of death when infected with CSF strain. No deaths occurred in mice infected with type strain, nor did CSF strain cause disease in wild-type mice (Figure 2, panel C). CSF strain–infected mice showed more severe pathologic organ changes than did type strain–infected mice (Figure 2, panels D, E; Appendix Figure 1). We performed quantitative cultures to assess bacterial load in the spleens of inoculated mice. CSF strain CFUs were 100–1,000 times higher than those of type strain 4 and 8 weeks after infection (Table; Figure 2, panel F). In addition, infection with CSF strain yielded 100–1,000 times higher CFUs in spleens of CGD mice than in wild-type mice 4 and 8 weeks after infection. (Appendix Figure 2). CSF strain showed faster growth on solid and in liquid media and a higher optimal growth temperature (37°C) than previously described North America lymph node isolates (Appendix Figure 3). CGD mice infected with CSF strain showed higher plasma interleukin-1β, tumor necrosis factor–α, and interleukin-6 than those infected with type strain 4 and 8 weeks after infection, which correlated with differences in tissue bacterial load. Cytokine levels did not increase in wild-type mice infected with CSF strain (Appendix Figure 4).\n\nTable Bacterial culture from blood and brain samples of GP91 KO mouse infected with Granulibacter bethesdensis after 4 weeks*\n\nMouse\tStrain\tSample\t\nBlood\tBrain\t\ngp91−/−, n = 10\tType, USA\t0\t0\t\ngp91−/−, n = 10\tCSF, Portugal\t5\t2\t\np47−/−, n = 5\tType\t0\t0\t\np47−/−, n = 5\tCSF\t0\t0\t\nWT, n = 9\tCSF, Portugal\t0\tND\t\n*Bold indicates the results of the inoculation of CSF strain in the gp91 KO mouse. CSF, cerebrospinal fluid; ND, not done; WT, wild type.\n\nConclusions\n\nG. bethesdensis is an emerging pathogen shown to cause infection exclusively in CGD patients and has a spectrum of disease severity ranging from chronic and recurrent infections to fulminant sepsis, central nervous system infection, and death (3,7,10). Until recently, all reported North America cases were nonfatal chronic infections; 1 case from Europe (Spain) was fatal. Recently, Mayer et al. reported a X-linked CGD patient in the United States who died of fulminant infection with an organism with 100% identity to 500 bp of G. bethesdensis 16S (11). Unfortunately, that G. bethesdensis isolate was not available for analysis and comparison with other G. bethesdensis strains. The previous strain from Europe was highly resistant to antimicrobial agents, including colistin, most β-lactams, and quinolones (10).\n\nWe found that a CSF G. bethesdensis strain, showing an identical 16S sequence to a previously described fulminant strain from Europe, was more virulent and lethal in a mouse model than the G. bethesdensis US type strain and more virulent in gp91phox−/− than in p47 phox−/− mice. A fatal case of G. bethesdensis infection in the United States suggests that heterogeneity might exist among North America G. bethesdensis strains. Bacterial genome sequencing may identify discrete virulence factors. G. bethesdensis must be included as a cause of fatal disseminated infection in CGD.\n\nAppendix\n\nAdditional images of mice experimentally infected with virulent Granulibacter bethesdensis strain.\n\nThis work was supported through the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.\n\nDr. Rebelo is a pediatrics resident in Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central. Her primary research interests are clinical immunology, primary immunodeficiencies, and infectious diseases\n\nSuggested citation for this article: Rebelo M, Ding L, Cordeiro AI, Neves C, Simões MJ, Zelazny AM, et al. Fatal meningitis in patient with X-linked chronic granulomatous disease caused by virulent Granulibacter bethesdensis. Emerg Infect Dis. 2019 May [date cited]. https://doi.org/10.3201/eid2505.181505\n\n1 These authors contributed equally to this article.\n\n2 These authors contributed equally to this article.\n==== Refs\nReferences\n\n1. Holland SM. Chronic granulomatous disease. [viii.]. Hematol Oncol Clin North Am. 2013;27 :89–99, viii. 10.1016/j.hoc.2012.11.002 23351990\n2. Gennery A. Recent advances in understanding and treating chronic granulomatous disease. F1000 Res. 2017;6 :1427. 10.12688/f1000research.11789.1 28868142\n3. Falcone EL, Petts JR, Fasano MB, Ford B, Nauseef WM, Neves JF, et al. Methylotroph infections and chronic granulomatous disease. Emerg Infect Dis. 2016;22 :404–9. 10.3201/eid2203.151265 26886412\n4. Greenberg DE, Ding L, Zelazny AM, Stock F, Wong A, Anderson VL, et al. A novel bacterium associated with lymphadenitis in a patient with chronic granulomatous disease. PLoS Pathog. 2006;2 :e28. 10.1371/journal.ppat.0020028 16617373\n5. Greenberg DE, Porcella SF, Stock F, Wong A, Conville PS, Murray PR, et al. Granulibacter bethesdensis gen. nov., sp. nov., a distinctive pathogenic acetic acid bacterium in the family Acetobacteraceae. Int J Syst Evol Microbiol. 2006;56 :2609–16. 10.1099/ijs.0.64412-0 17082400\n6. Greenberg DE, Porcella SF, Zelazny AM, Virtaneva K, Sturdevant DE, Kupko JJ III, et al. Genome sequence analysis of the emerging human pathogenic acetic acid bacterium Granulibacter bethesdensis. J Bacteriol. 2007;189 :8727–36. 10.1128/JB.00793-07 17827295\n7. Greenberg DE, Shoffner AR, Zelazny AM, Fenster ME, Zarember KA, Stock F, et al. Recurrent Granulibacter bethesdensis infections and chronic granulomatous disease. Emerg Infect Dis. 2010;16 :1341–8. 10.3201/eid1609.091800 20735916\n8. Zarember KA, Marshall-Batty KR, Cruz AR, Chu J, Fenster ME, Shoffner AR, et al. Innate immunity against Granulibacter bethesdensis, an emerging gram-negative bacterial pathogen. Infect Immun. 2012;80 :975–81. 10.1128/IAI.05557-11 22184421\n9. Chu J, Song HH, Zarember KA, Mills TA, Gallin JI. Persistence of the bacterial pathogen Granulibacter bethesdensis in chronic granulomatous disease monocytes and macrophages lacking a functional NADPH oxidase. J Immunol. 2013;191 :3297–307. 10.4049/jimmunol.1300200 23956436\n10. López FC, de Luna FF, Delgado MC, de la Rosa II, Valdezate S, Nieto JA, et al. Granulibacter bethesdensis isolated in a child patient with chronic granulomatous disease. J Infect. 2008;57 :275–7. 10.1016/j.jinf.2008.04.011 18558432\n11. Mayer EFF, Gialanella P, Munjal I, Cunningham-Rundles C, Dara J. Fulminant sepsis due to Granulibacter bethesdensis in a 4-year-old boy with X-linked chronic granulomatous disease. Pediatr Infect Dis J. 2017;36 :1165–6. 10.1097/INF.0000000000001659 28650935\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1080-6040",
"issue": "25(5)",
"journal": "Emerging infectious diseases",
"keywords": "Chronic granulomatous disease; Granulibacter bethesdensis; X-linked defect; bacteria; immunodeficiency; meningitis/encephalitis; virulent strain",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D016947:Acetobacteraceae; D000293:Adolescent; D000818:Animals; D004195:Disease Models, Animal; D017809:Fatal Outcome; D016905:Gram-Negative Bacterial Infections; D006105:Granulomatous Disease, Chronic; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D016920:Meningitis, Bacterial; D051379:Mice; D018345:Mice, Knockout; D012336:RNA, Ribosomal, 16S; D013902:Radiography, Thoracic; D014774:Virulence",
"nlm_unique_id": "9508155",
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"pages": "976-979",
"pmc": null,
"pmid": "31002074",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": "18558432;17082400;23956436;23351990;22184421;17827295;28868142;26886412;28650935;20735916;16617373",
"title": "Fatal Meningitis in Patient with X-Linked Chronic Granulomatous Disease Caused by Virulent Granulibacter bethesdensis.",
"title_normalized": "fatal meningitis in patient with x linked chronic granulomatous disease caused by virulent granulibacter bethesdensis"
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"abstract": "Kawasaki disease (KD) is the leading cause of acquired cardiac disease in children, in developed countries.\n\n\n\nTo identify predictive factors for resistance to intravenous immunoglobulin (IVIG), calculate the effectiveness of Japanese predictive models and characterize cardiac complications.\n\n\n\nRetrospective analysis of KD cases admitted in a Portuguese paediatric hospital between january 2006 and july 2018. ROC curves were used to determine predictive factors for resistance and the multivariate logistic regression analysis was used to develop the predictive model. A significance level of 5% was used.\n\n\n\n48 patients with a median age of 36 months were included. The IVIG resistance was 21%. Echocardiographic anomalies were noted in 46%, with coronary involvement in 25% of the sample population. As predictive variable of resistance, the C-reactive protein (CRP) presented an AUC ROC = 0.789, optimal cut-off value 15.1 mg/dL, sensitivity (Sn) 77.8% and specificity (Sp) 78.9%. The erythrocyte sedimentation rate (ESR) presented an AUC ROC = 0.781, optimal cut-off value 90.5 mm/h, Sn 66.7% and Sp 85.7%. The model with the two variables showed p = 0.042 and AUC ROC = 0.790. Predictive strength of Japanese models were: Kobayashi (Sn 63.6%, Sp 77.3%), Egami (Sn 66.7%, Sp 73.1%), Sano (Sn 28.6%, Sp 94.1%).\n\n\n\nCRP and ESR are independent variables that were related to IVIG resistance, with optimal cut-off points of 15.1 mg/dL and 90.5 mm/h, respectively. About half of the patients had some form of cardiac involvement. The Japanese models appeared to be inadequate in our population. (Arq Bras Cardiol. 2021; 116(3):485-491).",
"affiliations": "Centro Hospitalar e Universitário de Coimbra EPE - Cardiologia Pediátrica, Coimbra - Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Cardiologia Pediátrica, Coimbra - Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Urgência e Unidade de Infeciologia, Coimbra - Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Cardiologia Pediátrica, Coimbra - Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Urgência e Unidade de Infeciologia, Coimbra - Portugal.;Centro Hospitalar e Universitário de Coimbra EPE - Cardiologia Pediátrica, Coimbra - Portugal.",
"authors": "Faim|Diogo|D|0000-0001-7047-4170;Henriques|Cláudio|C|0000-0001-7506-0647;Brett|Ana|A|;Francisco|Andreia|A|;Rodrigues|Fernanda|F|;Pires|António|A|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "Brazil",
"delete": false,
"doi": "10.36660/abc.20190758",
"fulltext": "\n==== Front\nArq Bras Cardiol\nArq Bras Cardiol\nabc\nArquivos Brasileiros de Cardiologia\n0066-782X\n1678-4170\nSociedade Brasileira de Cardiologia - SBC\n\n33470332\nabc.20190758\n10.36660/abc.20190758\nArtigo Original\nDoença de Kawasaki: Preditores de Resistência à Imunoglobulina Intravenosa e Complicações Cardíacas\nhttps://orcid.org/0000-0001-7047-4170\nFaim Diogo 1\nhttps://orcid.org/0000-0001-7506-0647\nHenriques Cláudio 1\nBrett Ana 2\nFrancisco Andreia 1\nRodrigues Fernanda 2\nPires António 1\n1 Centro Hospitalar e Universitário de Coimbra EPE Coimbra Portugal Centro Hospitalar e Universitário de Coimbra EPE - Cardiologia Pediátrica, Coimbra - Portugal\n2 Centro Hospitalar e Universitário de Coimbra EPE Coimbra Portugal Centro Hospitalar e Universitário de Coimbra EPE - Urgência e Unidade de Infeciologia, Coimbra - Portugal\nCorrespondência: Diogo Faim • Centro Hospitalar e Universitário de Coimbra EPE - Praceta, R. Prof. Mota Pinto, 3075 Coimbra 3000-075 – Portugal. E-mail: diogofaim92@gmail.com\nContribuição dos Autores\n\nConcepção e desenho da pesquisa: Faim D, Henriques C, Brett A, Francisco A, Rodrigues F, Pires A; Obtenção de dados: Faim D, Henriques C; Análise e interpretação dos dados: Faim D, Brett A, Francisco A; Análise estatística e Redação do manuscrito: Faim D; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Faim D, Brett A, Francisco A, Rodrigues F, Pires A.\n\nPotencial Conflito de Interesses\n\nOs autores declaram não haver conflito de interesses pertinentes.\n\n03 3 2021\n3 2021\n116 3 485491\n30 10 2019\n04 3 2020\n04 3 2020\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License\nResumo\n\nFundamento:\n\nA doença de Kawasaki (DK) é a principal causa de cardiopatia adquirida em idade pediátrica nos países desenvolvidos.\n\nObjetivos:\n\nIdentificar fatores preditores de resistência à imunoglobulina intravenosa (IGIV), calcular a eficácia dos modelos preditores japoneses e caracterizar as complicações cardíacas.\n\nMétodos:\n\nAnálise retrospectiva dos casos de DK entre janeiro de 2006 e julho de 2018 em um hospital pediátrico português. Foram construídas curvas ROC para encontrar fatores preditores de resistência e utilizada regressão logística multivariada para elaborar o modelo preditor. O nível de significância utilizado foi de 5%.\n\nResultados:\n\nForam incluídos 48 pacientes com mediana de idade de 36 meses. Verificou-se resistência à IGIV em 21%. Ocorreram alterações ecocardiográficas em 46%, com envolvimento coronário em 25%. Como variáveis preditoras de resistência, a proteína C-reativa (PC-R) apresentou uma AUC ROC = 0,789, ponto de corte = 15,1 mg/dL, sensibilidade (S) = 77,8% e especificidade (E) = 78,9%. A velocidade de sedimentação (VS) apresentou uma AUC ROC = 0,781, ponto de corte = 90,5 mm/h, S = 66,7% e E = 85,7%. O modelo com as duas variáveis apresentou valor p = 0,042 e AUC ROC = 0,790. O modelo Kobayashi apresentou S = 63,6% e E = 77,3%; Egami, S = 66,7% e E = 73,1%; e Sano, S = 28,6% e E = 94,1%.\n\nConclusão:\n\nA PC-R e a VS são variáveis independentes que mostraram tendência preditora de resistência à IGIV com pontos de corte ótimos de 15,1 mg/dL e 90,5 mm/h, respectivamente. Cerca de metade dos pacientes teve algum tipo de envolvimento cardíaco. Os modelos japoneses não têm utilidade nessa população. (Arq Bras Cardiol. 2021; 116(3):485-491)\n\nPalavras-chave:\n\nDoença de Kawasaki/complicações\nSíndrome de Linfonodos Mucocutâneos/complicações\nResistência à Medicamentos\nDoenças da Artéria Coronariana\nImunoglobulina\nCriança\n==== Body\nIntrodução\n\nA doença de Kawasaki (DK) é uma vasculite aguda e autolimitada que afeta os vasos de média dimensão, sendo a principal causa de cardiopatia adquirida em idade pediátrica.1\n\nA sua etiologia continua incerta, mas vários fatores têm sido associados à doença, nomeadamente genéticos, ambientais e inflamatórios.2 Embora com distribuição mundial, a sua maior prevalência é no Japão, com incidência crescente.3 Em Portugal, um estudo epidemiológico realizado em 2017 descreveu uma incidência anual média de 6,5 por 100.000 crianças com menos de 5 anos de idade.4\n\nCom base nos critérios da American Pediatric Academy de 2004,5 considera-se DK clássica se febre ≥ 5 dias e presença de pelo menos 4 de 5 critérios clínicos adicionais: conjuntivite bilateral não exsudativa, alterações dos lábios e da mucosa oral, exantema polimorfo, alterações das extremidades e linfadenopatia cervical não supurativa. Se febre ≥ 5 dias e apenas 2 ou 3 critérios adicionais, considera-se DK atípica e é necessário recorrer a dados laboratoriais e ecográficos para melhor sustentar o diagnóstico.2\n\nSe não tratada atempadamente, a DK pode complicar-se com aneurismas das artérias coronárias (AAC) em até 25% dos casos.2 Apesar de o envolvimento coronário ser a consequência mais temida da doença, são possíveis outras complicações cardíacas.2,6–8 O tratamento com imunoglobulina intravenosa (IGIV) na fase aguda continua a ser a principal terapêutica e, se administrada nos primeiros 10 dias de doença, diminui a incidência de AAC para 4%.2 A resistência à IGIV ocorre em 10% a 20% dos casos, aumentado a probabilidade de envolvimento coronário.2 Há diferentes abordagens possíveis quando há resistência, nomeadamente uma segunda dose de IGIV, corticosteroides e/ou anticorpos monoclonais.9 Não há descrição de benefício na administração inicial de corticosteroide juntamente com a IGIV a todos os pacientes, sendo atualmente tal terapêutica reservada para os casos refratários.10 Com o objetivo de identificar os casos que potencialmente poderiam ser resistentes ao tratamento com IGIV, e como tal beneficiar de outras terapêuticas na fase inicial, foram desenvolvidos modelos com base em um sistema de escores, nomeadamente os de Kobayashi,11 Egami12 e Sano,13 que foram validados para a população japonesa. No entanto, diversos estudos mostraram que esses modelos são fracos preditores em diversas populações ocidentais.10,14,15\n\nO objetivo desse estudo foi identificar fatores preditores clínicos e analíticos de resistência à IGIV e de envolvimento coronário e construir um modelo preditor de resistência mais adequado para essa população. Como objetivos adicionais, pretendeu-se caracterizar os casos de DK em um hospital pediátrico de nível III nos últimos anos, calcular a eficácia dos escores japoneses nessa amostra e analisar as complicações cardíacas não coronárias da DK.\n\nMétodos\n\nAmostra\n\nEstudo retrospectivo dos casos diagnosticados com DK desde 1º de janeiro de 2006 a 30 de junho de 2018 no Hospital Pediátrico – Centro Hospitalar e Universitário de Coimbra (HP-CHUC). Foram incluídas todas as crianças e adolescentes com idades entre 30 dias e < 18 anos, com diagnóstico e terapêutica de fase aguda realizados no HP-CHUC. Foram excluídos todos os pacientes transferidos para o HP-CHUC já com diagnóstico e/ou terapêutica realizados em outro hospital.\n\nForam utilizados os critérios da American Academy of Pediatrics para diagnóstico de DK clássica e de DK atípica. Considerou-se D1 de febre o dia inaugural de febre, definida como temperatura axilar ≥ 38°C. Considerou-se resistência à IGIV se a febre persistiu 36 horas após a sua administração, tendo sido excluídos todos os casos em que foi administrado corticosteroide concomitantemente com a primeira dose de IGIV.\n\nPara classificar o envolvimento coronário, foram usados os escores z (desvios padrões) de Dallaire, definindo-se dilatação se escore z entre 2 e 2,4, aneurisma pequeno se escore z entre 2,5 e 4,9, aneurisma médio se entre 5 e 9,9 e dimensão absoluta inferior a 8 mm, aneurisma gigante se escore z ≥ 10 ou dimensão absoluta ≥ 8 mm. Nos casos em que a informação foi insuficiente para se calcular o escore z, utilizaram-se os valores absolutos, sendo aneurisma pequeno se ≥ 2,5mm e < 4mm, médio se ≥ 4mm e < 8mm e gigante se ≥ 8 mm.\n\nNas complicações cardíacas, os achados ecocardiográficos de hiperecogenicidade e afunilamento das artérias coronárias não foram considerados.\n\nPara calcular a eficácia dos modelos, foram excluídos todos os pacientes que não apresentavam os dados necessários para serem considerados como alto ou baixo risco de resistência para determinado modelo. A pontuação e a categorização em pacientes de alto ou baixo risco foram realizadas conforme evidenciado na Tabela 1.\n\nTabela 1 Sistema de pontuação dos modelos avaliados\n\nEscore\tPontos\tAlto risco\t\nKobayashi\t\t≥ 4 pontos\t\nAST > 100 U/L\t2\t\nNa ≤ 133 mmol/L\t2\t\nIGIV com febre ≤ D4\t2\t\nNeutrófilos/Leucócitos ≥ 80%\t2\t\nPC-R ≥ 10 mg/dL\t1\t\nIdade ≤ 1 ano\t1\t\nPlaquetas ≤ 300.000/uL\t1\t\nEgami\t\t≥ 3 pontos\t\nALT ≥ 80 U/L\t2\t\nIGIV com febre ≤ D4\t1\t\nPC-R ≥ 8 mg/dL\t1\t\nIdade ≤ 6 meses\t1\t\nPlaquetas ≤ 300.000/uL\t1\t\nSano\t\t≥ 2 pontos\t\nAST > 200 U/L\t1\t\nBilirrubina total ≥ 0,9 mg/dL\t1\t\nPC-R ≥ 7 mg/dL\t1\t\nALT: alanina aminotransferase; AST: aspartato aminotransferase; dL: decilitro; L: litro; mg: miligrama; IGIV: imunoglobulina intravenosa; mmol: milimole; Na: sódio plasmático; PC-R: proteína C-reativa; U: unidade internacional; uL: microlitro.\n\nAnálise Estatística\n\nAnálise estatística efetuada com recurso ao programa SPSS® (IBM®, SPSS® Statistics Inc., Chicago), versão 25.0. Para testar a normalidade da amostra, foi utilizado o teste de Shapiro-Wilk. As variáveis contínuas com distribuição normal foram descritas por meio de média e desvio padrão, as variáveis contínuas sem distribuição normal foram descritas através de mediana e amplitude interquartil (AIQ). Para comparação de variáveis categóricas, foi utilizado o teste exato de Fisher; das variáveis numéricas paramétricas, o teste de t-student não pareado; e das variáveis numéricas não paramétricas, o teste de Mann-Whitney. Foram construídas curvas receiver operating characteristic (ROC) para avaliar a capacidade discriminativa individual de cada variável e identificar pontos de corte para a predição de resistência à IGIV. As variáveis foram consideradas preditoras se com uma area under the curve (AUC) superior a 0,75. Para a elaboração de um modelo preditor de resistência, foi utilizada a regressão logística multivariada. O nível de significância utilizado nesse estudo foi de 5%.\n\nResultados\n\nCumpriram critérios de DK 48 pacientes, sendo 32 (66,7%) do sexo masculino. A mediana de idades foi de 36 meses (AIQ 16,75-89,25), com 62,5% abaixo dos 5 anos de idade e 10,4% acima dos 9 anos. No dia de admissão, a totalidade dos pacientes apresentava-se com febre, com uma mediana de 5 dias de febre (AIQ 4-8), mínimo de 1 e máximo de 14 dias. Dos cinco critérios clínicos principais, observou-se conjuntivite não purulenta em 94%, alterações orais em 90%, exantema em 84%, alterações das extremidades em 75% e linfadenopatia cervical em 69%. Dentre as alterações orais, as mais prevalentes foram a queilite (67%) e o eritema labial (67%), seguidos de eritema da orofaringe (50%) e língua em framboesa (48%). Entre as alterações das extremidades, a mais prevalente foi eritema (52%), seguido de edema duro (31%) e descamação (25%). Os sinais inflamatórios no local de inoculação da vacina Bacillus Calmette-Guérin (BCG) foram descritos em 23%. Foi diagnosticada DK atípica em 17% dos casos. A mediana de dias de internamento foi de 2 dias (AIQ 1-6,75).\n\nA totalidade dos pacientes foi medicada em fase aguda com IGIV 2 g/kg com mediana do dia de administração de 6,5 dias (AIQ 5-8). Foram medicados em fase aguda 47 pacientes com ácido acetilsalicílico (AAS) em doses entre 45 a 100mg/kg/dia. Cinco pacientes foram ainda medicados com corticosteroide juntamente com a primeira dose de IGIV. Após a fase aguda, todos os pacientes foram medicados com AAS em dose de 3 a 5 mg/kg/dia, três pacientes com clopidogrel e um com enoxaparina. Verificou-se resistência à IGIV em nove casos (21%), dos quais havia um caso de DK atípica (p = 0,543). Dos nove pacientes resistentes à terapêutica, foi administrada uma segunda dose de IGIV 2 g/kg e a cinco destes, metilprednisolona na dose de 30 mg/kg/dia.\n\nEntre as diferentes variáveis avaliadas como preditoras de resistência (Tabela 2), a proteína C-reativa (PC-R) apresentou uma AUC ROC de 0,78 (IC95%: 0,632-0,947) e a velocidade de sedimentação (VS) uma AUC ROC de 0,781 (IC95%: 0,585-0,977). O ponto de corte para a PC-R foi de 15,1 mg/dL com uma sensibilidade (S) de 0,778 e especificidade (E) de 0,789 [Odds ratio (OR) = 13,125 IC95%: 2,271-75,858]. O ponto de corte para a VS foi de 90,5 mm/h, verificando-se uma sensibilidade de 0,667 e especificidade de 0,857 (OR = 12,000 IC95%: 1,718-83,803). Foi ajustado um modelo logístico com as duas variáveis PC-R e VS, modelo este que apresentou um valor p de 0,042 e AUC ROC de 0,790 (IC95%: 0,589-0,992). No ponto de corte ótimo, a sensibilidade foi de 0,833 e a especificidade foi de 0,771. Apresentou ainda uma variância de 25% (Nagelkerke R2 = 0,254).\n\nTabela 2 Análise ROC de diversas variáveis para predizer resistência à IGIV\n\nVariável\tAUC [IC 95%]\t\nIdade\t0,542 [0,377; 0,708]\t\nDia de administração IGIV\t0,595 [0,403; 0,787]\t\nHemoglobina\t0,611 [0,416; 0,806]\t\nLeucócitos\t0,525 [0,331; 0,719]\t\nNeutrófilos\t0,637 [0,447; 0,828]\t\nPlaquetas\t0,513 [0,295; 0,732]\t\nVS\t0,781 [0.585; 0,977]\t\nPC-R\t0,789 [0,632; 0,947]\t\nNa\t0,715 [0,475; 0,955]\t\nAST\t0,648 [0,434; 0,862]\t\nALT\t0,693 [0,486; 0,901]\t\nBilirrubina total\t0,500 [0,139; 0,861]\t\nAlbumina\t0,693 [0,459; 0,928]\t\nALT: alanina aminotransferase; AST: aspartato aminotransferase; AUC: área abaixo da curva; IC: intervalo de confiança; IGIV: imunoglobulina intravenosa; Na: sódio plasmático; PC-R: proteína C-reativa; ROC: receiver operating curve; VS: velocidade de sedimentação.\n\nOcorreu envolvimento coronário em 12 casos (25%). Sete pacientes desenvolveram dilatação das artérias coronárias e cinco, AAC. Na Tabela 3, comparam-se os grupos sem e com envolvimento coronário. Observaram-se diferenças apenas na duração da febre e na utilização de corticosteroides. O tempo total de febre foi mais elevado no grupo com envolvimento coronário (p = 0,038). Esse grupo recebeu mais vezes corticosteroide (p = 0,009). Quatro desses pacientes já tinham diagnóstico de envolvimento coronário prévio à administração desse fármaco. Dos pacientes com AAC, três cumpriram critérios para aneurismas pequenos, um para aneurismas médios e um para aneurismas gigantes. Esses pacientes estão caracterizados na Tabela 4.\n\nTabela 3 Características dos grupos com e sem envolvimento coronário\n\nVariáveis\tSem envolvimento coronário (n =36)\tEnvolvimento coronário (n = 12)\tp\t\nCorticosteroide (n = 10) N\t4\t6\t0,009\t\nResistência à IGIV (n = 9) N\t5\t4\t0,173\t\nIdade (meses) Média ± DP\t59,7 ± 57\t47,5 ± 30,1\t0,35\t\nDia de resolução da febre Média ± DP\t7,4 ± 2,8\t9,4 ± 3\t0,038\t\nDia de administração de IGIV Média ± DP\t6,5 ± 2,9\t7,6 ± 3,5\t0,283\t\nDK atípica n\t6\t2\t0,686\t\nHemoglobina (g/dL) Média ± DP\t11,5 ± 1,3\t11,2 ± 1,3\t0,359\t\nLeucócitos (/uL) Média ± DP\t14.174 ± 6.010\t15.216 ± 6.918\t0,619\t\nNeutrófilos (/uL) Média ± DP\t9.515 ± 4.770\t10.994 ± 5.629\t0,378\t\nPlaquetas (/uL) Média ± DP\t32.8389 ± 12.7125\t36.2667 ± 28.2652\t0,691\t\nPC-R (mg/dL) Média ± DP\t10,4 ± 8,8\t19,6 ±25\t0,243\t\nVS (mm/h) Média ± DP\t71,6 ± 19\t76,7 ± 33,4\t0,672\t\nNa (mmol/L) Média ± DP\t137 ± 4\t137 ± 5\t0,869\t\nAST (U/L) Média ± DP\t64 ± 53\t101 ± 91\t0,222\t\nALT (U/L) Média ± DP\t99 ± 116\t113 ± 86\t0,712\t\nBilirrubina total (mg/dL) Média ± DP\t1,9 ± 2\t2,8 ± 3\t0,538\t\nAlbumina (g/L) Média ± DP\t35,6 ± 4,3\t34,9 ± 7,2\t0,77\t\nAIQ: amplitude interquartil; ALT: alanina aminotransferase; AST: aspartato aminotransferase; dL: decilitro; DK: doença de Kawasaki; DP: desvio padrão; g: grama; h: hora; IGIV: imunoglobulina intravenosa; L: litro; mg: miligrama; mmol: milimole; n: número absoluto; Na: sódio plasmático; p: valor p; PC-R: proteína C-reativa; U: unidade internacional; uL: microlitro; VS: velocidade de sedimentação.\n\nTabela 4 Características dos pacientes com aneurismas das artérias coronárias\n\nVariáveis\tPaciente 1\tPaciente 2\tPaciente 3\tPaciente 4\tPaciente 5\t\nIdade de diagnóstico (meses)\t12\t60\t108\t63\t4\t\nSexo masculino\tSim\tSim\tSim\tSim\tSim\t\nDias de febre\t7\t6\t8\t9\t14\t\nDK clássico\tSim\tSim\tSim\tSim\tNão\t\nDia de febre na 1ᵃ dose IGIV\t7\t6\t4\t6\t14\t\nResistência ao tratamento IGIV\tNão\tNão\tSim\tSim\tNA\t\nDia de febre na 2ᵃ dose IGIV\tNA\tNA\t6\t8\tNA\t\nMPDN (30mg/kg/dia)\nCom 1ᵃ dose IGIV\nCom 2ᵃ dose IGIV\tNão\nNA\nNA\tNão\nNA\nNA\tNão\nNão\nSim\tSim\nNão\nSim\tSim\nSim\nNão\t\nClassificação AAC\tPequenos\tPequenos\tPequenos\tMédios\tGigantes\t\nZ escore máximo\tNA\t4,46\t3,56\t6,94\t13,81\t\nArtérias atingidas\tACD; TC\tACD; ACE\tACE\tACE; ACD\tACD; CIR; DAE\t\nAAC: aneurismas das artérias coronárias; ACD: artéria coronária direita; ACE: artéria coronária esquerda; CIR: artéria circunflexa; DAE: descendente anterior esquerda; DK: doença de Kawasaki; IGIV: imunoglobulina intravenosa; MPDN: metilprednisolona; NA: não aplicável; TC: tronco comum.\n\nNa fase aguda, para além do envolvimento coronário, observou-se derrame pericárdico em 10 casos, insuficiência valvular mitral ligeira em três e disfunção ventricular em três, um dos quais com choque cardiogênico. Um apresentou bloqueio atrioventricular (BAV) de 1ºgrau variável. Após a fase aguda, um paciente manteve envolvimento do sistema de condução e dilatação do ventrículo esquerdo (VE) e um ficou com hipertrofia do VE.\n\nOs valores de S, E, valor preditivo positivo (VPP) e valor preditivo negativo (VPN) para os diferentes modelos estão apresentados na tabela 5, sendo apenas incluídos os pacientes a quem foi possível categorizar com alto ou baixo risco.\n\nTabela 5 Sensibilidade, especificidade, valores preditivos positivos e negativos dos diferentes modelos\n\nModelo\tn\tS\tE\tVPP\tVPN\t\nKobayasahi\t34\t63,6%\t77,3%\t53,8%\t81%\t\nEgami\t39\t66,7%\t73,1%\t50%\t82,6%\t\nSano\t25\t28,6%\t94,1%\t66,7%\t77,3%\t\nE: especificidade; n: número de casos incluídos; S: sensibilidade; VPN: valor preditivo negativo; VPP: valor preditivo positivo.\n\nDiscussão\n\nA DK é uma vasculite que, embora não tendo uma incidência tão elevada como no Japão, é, ainda assim uma causa importante de doença em idade pediátrica na nossa população. Um diagnóstico e introdução de terapêutica precoces constituem dois fatores muito importantes para reduzir o risco de envolvimento cardíaco.\n\nO presente estudo revelou uma percentagem de casos resistentes à IGIV coincidentes com os 10 a 20% descritos na literatura.2 Ao longo dos anos têm sido desenvolvidos esforços no sentido de encontrar fatores clínicos e laboratoriais que possam prever esta resistência de modo a introduzir mais precocemente terapêuticas coadjuvantes. Existem diversos parâmetros descritos na literatura tais como idade, albumina, transaminases, bilirrubina total, neutrófilos, plaquetas, PC-R, VS, entre outros.14,16–20 Neste estudo observou-se que a PC-R e a VS apresentaram capacidade preditora estatisticamente significativa de resistência à IGIV. No caso da PC-R, o ponto de corte ótimo foi de 15,1 mg/dL, com uma sensibilidade de 0,778, especificidade de 0,789 e um OR de 13,125. Pacientes com PC-R superior a 15,1mg/dL apresentam uma probabilidade de resistência à IGIV cerca de 13 vezes superior aos que têm valores inferiores. Relativamente à VS, o ponto de corte ótimo foi de 90,5 mm/h, com uma sensibilidade de 0,667, especificidade 0,857 e OR 12,000. Pacientes com VS superior a 90,5 mm/h apresentam uma probabilidade de resistência à IGIV cerca de 12 vezes superior aos que têm valores inferiores. Combinando estas duas variáveis independentes obteve-se um modelo estatisticamente significativo (p = 0,042), cujo ponto de corte apresenta uma sensibilidade de 0,833 e especificidade de 0,771. No entanto, a variância explicada pelo modelo é apenas de 25% (Nagelkerke R2 = 0,254), pelo que, embora seja estatisticamente significativo, não pode ser validado, o que se deve em grande parte ao tamanho reduzido da amostra. Todavia, é importante realçar esta tendência no sentido de que as duas variáveis poderão ser importantes para prever a resistência à IGIV, antes da sua infusão. O fato destas variáveis terem sido preditoras de resistência, realça o papel da inflamação exuberante nesta doença, etiologia que é defendida como possível precipitante da resposta imunológica que culmina numa vasculite.21\n\nA etiologia da DK continua incerta, no entanto vários fatores são apontados como predisponentes. Um deles é a imaturidade do sistema imunitário, condição que é apoiada pelo fato de afetar predominantemente crianças com idade inferior a cinco anos. Neste estudo 62,5% dos pacientes pertenciam a esta faixa etária, o que, embora corresponda à maioria da amostra, fica aquém dos 80% descritos na literatura.1 Uma possível explicação para estes resultados é a contribuição genética, sendo as percentagens reportadas baseadas em estudos com variedade étnica alargada, incluindo asiáticos.\n\nVerificou-se envolvimento coronário em 25% dos casos, com sete a cumprir critérios de dilatação e cinco de aneurismas das artérias coronárias. Os 10% de incidência de AAC, foram superiores aos 4% reportados para os casos devidamente tratados. Comparando os grupos com e sem envolvimento coronário, verificou-se diferença estatisticamente significativa relativamente ao tempo total de febre (p = 0,038). Este resultado corrobora a ideia da persistência da febre ser deletéria e a necessidade da administração de IGIV preferencialmente até ao 10º dia para evitar sequelas cardíacas.9 O uso de corticosteróide na DK continua a ser tema de debate e controvérsia. O mais consensual é usar metilprednisolona por via intravenosa (MPDN iv) na dose de 15 a 30mg/kg/dia durante três dias.9 A MPDN iv, nos pacientes com DK refratária à IGIV, suprime os níveis de citocinas inflamatórias mais rapidamente que uma 2ᵃ dose de IGIV,9 no entanto não está recomendada como primeira linha. Sleeper et al.10 avaliaram o uso de corticosteróide em diferentes momentos, observando-se diferença estatisticamente significativa no aparecimento de AAC apenas nos pacientes refratários à IGIV e que levaram a administração de segunda dose.\n\nNeste estudo também se avaliaram complicações cardíacas e achados ecográficos que não o envolvimento coronário. Das complicações cardíacas em fase aguda mais graves destacaram-se três casos de disfunção ventricular esquerda, um com choque cardiogénico e um BAV de 1º grau, complicações essas também descritas na literatura.2,7 Na fase aguda, foi ainda possível observar 10 pacientes com derrame pericárdico sem compromisso hemodinâmico e três com insuficiência valvular mitral ligeira. Em Paris, Chbeir et al.22 obtiveram relação estatisticamente significativa entre resistência à IGIV, AAC e achados na ecografia cardíaca inicial, tais como derrame pericárdico, hiperecogenicidade das coronárias e dilatação coronária. Os autores desse estudo não consideraram a hiperecogenicidade e o afunilamento das coronárias como fatores relevantes, visto que são achados subjetivos, pouco reprodutíveis e podem ser encontrados tanto em doenças febris como em crianças saudáveis.23 Na fase crônica, um paciente manteve envolvimento do sistema de condução e dilatação do VE e outro ficou com hipertrofia do VE. As repercussões cardíacas a longo prazo na DK estão ainda pouco esclarecidas. Friedman et al.6 mostraram maior ocorrência de efeitos adversos cardíacos a longo prazo, tais como morte, transplante cardíaco, cirurgias de bypass coronário e angioplastia primária em pacientes com DK que desenvolveram AAC com escores z superiores e que foram resistentes à IGIV. Um estudo realizado por Holve et al.8 revelou baixa incidência de efeitos adversos cardíacos até os 21 anos de idade, mas uma maior probabilidade de desenvolver hipertensão arterial após os 15 anos de idade.\n\nOs modelos validados no Japão apresentaram fraca utilidade clínica no presente estudo (Tabela 4). O modelo com maior especificidade foi o de Sano, embora com sensibilidade muito baixa e apenas com um pequeno número de casos incluído. O modelo de Egami foi o mais sensível para esta amostra, mas, ainda assim, insuficiente para ser validado. Na base dessa diferença de resultados, pode estar o componente genético. Aliás esses resultados vão ao encontro de outros trabalhos realizados fora do Japão, em que nenhum deles conseguiu validar os modelos nas suas amostras.10,14–17,20 É necessário levar em consideração ainda que existiram algumas diferenças no desenho do estudo relativamente aos modelos japoneses, nomeadamente aplicados apenas a pacientes com DK clássica. Um estudo japonês falhou em validar os modelos em uma amostra de pacientes apenas com DK atípica.24 O modelo de Kobayashi foi validado na população japonesa com uma sensibilidade de 0,86 e especificidade de 0,67.11 Ao contrário do presente estudo, a IGIV foi administrada na dose de 1 g/kg em dois dias consecutivos e foi considerada resistência se febre persistente após 24 horas de início de terapêutica, ou se recrudescência com sintomas após período apirético. O modelo de Egami foi validado com uma sensibilidade de 0,78 e especificidade de 0,76; no entanto, foi definida resistência se ausência de diminuição do valor de PC-R em mais de 50% e persistência da febre 48 horas após administração de IGIV.12 Loomba et al.25 não conseguiram validar o modelo de Egami, mesmo aplicando-o separadamente à DK clássica, atípica e por etnias. O modelo de Sano, validado com uma sensibilidade de 0,77 e especificidade de 0,86, foi o único dos três a ajustar o tamanho dos AAC à superfície corporal.13 No entanto, também usou administração de IGIV na dose de 1 g/kg em 2 dias consecutivos e definiu resistência se persistência de febre após 24 horas do término da terapêutica.\n\nEste trabalho apresenta as limitações inerentes ao fato de ser um estudo retrospectivo e com uma amostra de tamanho reduzido.\n\nConclusão\n\nA PC-R e a VS são variáveis independentes que mostraram tendência preditora de resistência à IGIV com pontos de corte ótimos de 15,1 mg/dL e 90,5 mm/h, respectivamente. Existe, no entanto, necessidade de um estudo com uma amostra de dimensões adequadas para validar um modelo baseado nesses dois dados analíticos. As complicações cardíacas não se resumem às artérias coronárias, devendo ser mais abrangentes o estudo e o seguimento desses pacientes. Os modelos validados para a população japonesa apresentam utilidade muito limitada na amostra deste estudo, reforçando ainda mais a necessidade e a importância de novas abordagens.\n\nOriginal Article\nKawasaki Disease: Predictors of Resistance to Intravenous Immunoglobulin and Cardiac Complications\nhttps://orcid.org/0000-0001-7047-4170\nFaim Diogo 1\nhttps://orcid.org/0000-0001-7506-0647\nHenriques Cláudio 1\nBrett Ana 2\nFrancisco Andreia 1\nRodrigues Fernanda 2\nPires António 1\n1 Coimbra Portugal Centro Hospitalar e Universitário de Coimbra EPE - Cardiologia Pediátrica Coimbra - Portugal\n2 Coimbra Portugal Centro Hospitalar e Universitário de Coimbra EPE - Urgência e Unidade de Infeciologia, Coimbra - Portugal\nMailing Address: Diogo Faim • Centro Hospitalar e Universitário de Coimbra EPE - Praceta, R. Prof. Mota Pinto, 3075 Coimbra 3000-075 – Portugal. E-mail: diogofaim92@gmail.com\nAbstract\n\nBackground:\n\nKawasaki disease (KD) is the leading cause of acquired cardiac disease in children, in developed countries.\n\nObjectives:\n\nTo identify predictive factors for resistance to intravenous immunoglobulin (IVIG), calculate the effectiveness of Japanese predictive models and characterize cardiac complications.\n\nMethods:\n\nRetrospective analysis of KD cases admitted in a Portuguese paediatric hospital between january 2006 and july 2018. ROC curves were used to determine predictive factors for resistance and the multivariate logistic regression analysis was used to develop the predictive model. A significance level of 5% was used.\n\nResults:\n\n48 patients with a median age of 36 months were included. The IVIG resistance was 21%. Echocardiographic anomalies were noted in 46%, with coronary involvement in 25% of the sample population. As predictive variable of resistance, the C-reactive protein (CRP) presented an AUC ROC = 0.789, optimal cut-off value 15.1 mg/dL, sensitivity (Sn) 77.8% and specificity (Sp) 78.9%. The erythrocyte sedimentation rate (ESR) presented an AUC ROC = 0.781, optimal cut-off value 90.5 mm/h, Sn 66.7% and Sp 85.7%. The model with the two variables showed p = 0.042 and AUC ROC = 0.790. Predictive strength of Japanese models were: Kobayashi (Sn 63.6%, Sp 77.3%), Egami (Sn 66.7%, Sp 73.1%), Sano (Sn 28.6%, Sp 94.1%).\n\nConclusion:\n\nCRP and ESR are independent variables that were related to IVIG resistance, with optimal cut-off points of 15.1 mg/dL and 90.5 mm/h, respectively. About half of the patients had some form of cardiac involvement. The Japanese models appeared to be inadequate in our population. (Arq Bras Cardiol. 2021; 116(3):485-491)\n\nKeywords:\n\nKawasaki Disease/complications\nMucocutaneous Lymph Node Syndrome/complications\nDrug Resistance\nCoronary Artery Disease\nImmunoglobulin\nChild\nIntroduction\n\nKawasaki disease (KD) is an acute self-limiting vasculitis, which affects medium-sized vessels and is the leading cause of acquired cardiac disease in pediatric age groups.1\n\nIts etiology remains uncertain, but several factors have been associated to it, namely genetic, environmental, and inflammatory ones.2 Although with a worldwide distribution, its highest prevalence is in Japan, where the incidence is on the rise.3 In Portugal, an epidemiological study carried out in 2017 showed an mean annual incidence of 6.5 per 100,000 children under 5 years of age.4\n\nBased on the 2004 American Pediatric Academy criteria,5 classic KD is considered if fever persists for five days or more and if at least four of five additional clinical criteria are observed: nonexudative bilateral conjunctivitis, alterations of the lips and oral cavity, erythematous rash, changes in the extremities, and cervical lymphadenopathy. If fever lasts for five or more days and only two or three additional criteria are present, it is considered atypical KD, if supported by laboratory and echocardiographic data.2\n\nIf not treated within an established period, KD can be complicated by coronary artery aneurysms (CAA) in up to 25% of cases.2 Although coronary artery involvement is the most feared consequence of the disease, other cardiac complications are possible.2,6–8 Treatment with intravenous immunoglobulin (IVIG) in the acute phase administered in the first 10 days of illness reduces the incidence of CAA to 4%.2 IVIG resistance occurs in 10-20% of cases, increasing the likelihood of coronary involvement.2 There are different possible approaches in case of IVIG resistance, such as a second dose of IVIG, corticosteroids and/or monoclonal antibodies.9 No benefit has been described when corticosteroids are used in addition to IVIG in the first instance and this therapeutics is currently reserved for refractory cases.10 In order to identify the cases that could potentially be resistant to treatment with IVIG, and benefit from adjuvant therapies in the initial phase, models based on a scoring system have been developed. Three have been validated in the Japanese population, namely the Kobayashi,11 Egami,12 and Sano scoring systems.13 However, several studies have shown that these models are poor predictors in many western populations.10,14,15\n\nThe aim of this study was to identify clinical and laboratory predictive factors regarding resistance to IVIG and coronary artery involvement, and to develop a more suitable predictor model of resistance in this population. Secondary objectives regard characterizing the KD cases admitted to a central pediatric hospital over a period of 13 years, to verify the effectiveness of the Japanese scoring systems in our population sample and to analyze the non-coronary cardiac complications of KD.\n\nMethods\n\nSample\n\nRetrospective analysis of KD cases admitted to the Hospital Pediátrico – Centro Hospitalar e Universitário de Coimbra (HP-CHUC) diagnosed from 01/01/2006 to 06/30/2018. All patients between 30 days and <18 years with KD and treated with IVIG at diagnosis at HP-CHUC were included in the study. All the patients transferred from outlying centers with a diagnosis of KD and managed at these institutions were excluded.\n\nThe diagnosis of typical and atypical KD was based on the American Academy of Pediatrics criteria. We considered day one of fever on the day the fever started, defined as axillar temperature ≥ 38ºC.\n\nResistance to IVIG was considered if the fever persisted 36 hours after its administration. All patients who received corticosteroids simultaneously with the first dose of IVIG were excluded from the resistance quantification.\n\nDallaire z scores were used to classify the coronary artery morphology defining: coronary artery ectasia if z score between 2 and 2.4, small aneurysm if z score between 2.5 and 4.9, medium aneurysm if z score between 5 and 9.9 and absolute dimension < 8 mm, and giant aneurysm if z score ≥ 10 or absolute dimension ≥ 8 mm. If unable to calculate the z score, the absolute dimensions were used, being small aneurysm if ≥ 2.5 mm and < 4mm, medium aneurysm if ≥ 4 mm and < 8 mm and giant aneurysm if ≥ 8 mm.\n\nRegarding other cardiac complications, the coronary artery hyperechogenicity and lack of tapering on echocardiography were not considered as echocardiographic diagnostic criteria.\n\nTo calculate the effectiveness of the Japanese models, all patients who did not have the necessary data to be considered as high or low risk of IVIG resistance were excluded. Scoring and categorization in high or low risk patients were performed as shown in Table 1.\n\nTable 1 Scoring system of the Japanese modelss\n\nModel\tScore\tHigh risk\t\nKobayashi\t\t≥ 4 points\t\nAST > 100 U/L\t2\t\nNa ≤ 133 mmol/L\t2\t\nIVIG with fever ≤ 4 days\t2\t\nNeutrophils/Leucocytes ≥ 80%\t2\t\nCRP ≥ 10 mg/dL\t1\t\nAge ≤ 1 year old\t1\t\nPlatelets ≤ 300,000/µL\t1\t\nEgami\t\t≥ 3 points\t\nALT ≥ 80 U/L\t2\t\nIVIG with fever ≤ 4 days\t1\t\nCRP ≥ 8 mg/dL\t1\t\nAge ≤ 6 months\t1\t\nPlatelets ≤ 300,000/µL\t1\t\nSano\t\t≥ 2 points\t\nAST > 200 U/L\t1\t\nTotal bilirubin ≥ 0.9 mg/dL\t1\t\nCRP ≥ 7 mg/dL\t1\t\nAST: aspartate transaminase; U: international unity; L: liter; Na: serum sodium; mmol: millimole; IVIG: intravenous immunoglobulin; CRP: C-reactive protein; mg: milligram; dL: deciliter; µL: microliter; ALT: alanine transaminase.\n\nStatistical Analysis\n\nThe SPSS® (IBM®, SPSS® Statistics Inc., Chicago) program version 25.0 was used the performed the statistical analysis. The Shapiro-Wilk test was used to test the normality of the variables. The continuous variables with normal distribution were described using mean and standard deviation (SD) and continuous variables without normal distribution were described using median and interquartile range (IQR). We used the Fisher’s exact test to compare categorical variables, the Student’s t-test to compare parametric variables and the Mann-Whitney test to compare the non-parametric ones. The Receiver Operating Characteristic (ROC) curves were used to evaluate the individual discriminative capacity of each variable and to identify the optimal cutoff points to predict resistance to IVIG. The variables were considered as good predictors if the area under the curve (AUC) > 0.75. Multivariate logistic regression analysis was used to develop the predictive resistance model. A significance level of 5% was used.\n\nResults\n\nForty-eight patients met the KD criteria, of whom 32 (66.7%) were male. The median age was 36 months (IQR 16.75-89.25), 62.5% of patients were less than five years old and 10.4% over nine years old. On the day of admission, all the patients presented with fever, with a median duration of five days (IQR 4-8), minimum of one day and maximum of 14 days. Among the five main clinical criteria, nonexudative bilateral conjunctivitis was observed in 94% of cases, alterations of the lips and oral cavity in 90%, erythematous rash in 84%, changes in extremities in 75%, and cervical lymphadenopathy in 69%. The most common findings among oral alterations were cheilitis (67%) and lip erythema (67%), followed by erythema of the oropharynx (50%) and the strawberry tongue (48%). The most prevalent changes in the extremities were erythema (52%), followed by swelling (31%) and peeling (25%). Inflammatory signs at the Bacillus Calmette-Guérin (BCG) vaccination site were observed in 23% of patients. Atypical KD was diagnosed in 17% of the cases. The median duration of hospital stay was two days (IQR 1-6.75).\n\nDuring the acute phase, IVIG 2g/kg was administered to all patients. The median day of illness of the administration was 6.5 (IQR 5-8). Simultaneously, 45-100mg/kg of acetylsalicylic acid (ASA) were administered to 47 patients in the acute phase. Five children received corticosteroids together with the first dose of IVIG. After the acute phase, all patients were medicated with ASA 3-5 mg/kg/day, three patients with clopidogrel and one with enoxaparin. Nine patients were resistant to the IVIG (21%), of which one had atypical KD (p = 0.543). All nine repeated IVIG administration, five of which with methylprednisolone 30 mg/kg/day.\n\nAmong the variables evaluated as predictors of IVIG resistance (Table 2), C-reactive protein (CRP) presented an AUC ROC of 0.78 (95% confidence interval (CI): 0.632 – 0.947), and the erythrocyte sedimentation rate (ESR), an AUC ROC of 0.781 (95%CI: 0.585 – 0.977). The optimal cut-off value for CRP was 15.1 mg/dL with sensitivity (Sn) of 77.8% and specificity (Sp) of 78.9% (Odds ratio (OR) = 13.125 95%CI: 2.271 – 75.858). The optimal cut-off value for ESR was 90.5 mm/h, with Sn of 66.7% and Sp of 85.7% (OR = 12.000 95%CI: 1.718 – 83.803). A logistic model was developed with these two variables, with a p-value of 0.042, AUC ROC of 0.79 (95%CI: 0.589 – 0.992), with Sn of 83.3% and Sp of 77.1%, but with a 25% variance (Nagelkerke R2 = 0.254).\n\nTable 2 Receiver operating characteristic analysis of several variables to predict resistance to intravenous hemoglobulin\n\nCharacteristic\tAUC [95%CI]\t\nAge\t0.542 [0.377; 0.708]\t\nIVIG administration day\t0.595 [0.403; 0.787]\t\nHemoglobin\t0.611 [0.416; 0.806]\t\nLeucocytes\t0.525 [0.331; 0.719]\t\nNeutrophils\t0.637 [0.447; 0.828]\t\nPlatelets\t0.513 [0.295; 0.732]\t\nESR\t0.781 [0.585; 0.977]\t\nCRP\t0.789 [0.632; 0.947]\t\nNa\t0.715 [0.475; 0.955]\t\nAST\t0.648 [0.434; 0.862]\t\nALT\t0.693 [0.486; 0.901]\t\nTotal bilirubin\t0.500 [0,139; 0.861]\t\nAlbumin\t0.693 [0.459; 0.928]\t\nAUC: area under the curve; CI: confidence interval; IVIG: intravenous immunoglobulin; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; Na: serum sodium; AST: aspartate transaminase; ALT: alanine transaminase.\n\nCoronary artery changes were found in 12 children (25%), seven with ectasia and five with CAA. The comparison between groups with and without coronary artery involvement is shown in Table 3. The duration of fever and the use of corticosteroids were the only significant differences between these two groups. Patients with coronary artery involvement had longer duration of fever (p = 0.038) and greater need for corticotherapy (p = 0.009). Four patients had CAA when methylprednisolone was started. Among the five patients with CAA, three met the criteria for small aneurysms, one for medium aneurysms and one for giant ones. These patients are summarized in Table 4.\n\nTable 3 Characteristics of groups with and without coronary artery involvement\n\nCharacteristics\tWithout coronary involvement (n =36)\tCoronary involvement (n= 12)\tp - value\t\nCorticoid (n=10) n\t4\t6\t0.009\t\nResistance to IVIG (n=9) n\t5\t4\t0.173\t\nAge (months) Mean ± sd\t59.7 ± 57\t47.5 ± 30.1\t0.35\t\nFever duration (days) Mean ± sd\t7.4 ± 2.8\t9.4 ± 3\t0.038\t\nIVIG administration day Mean ± sd\t6.5 ± 2.9\t7.6 ± 3.5\t0.283\t\nAtypical KD n\t6\t2\t0.686\t\nHaemoglobin (g/dL) Mean ± sd\t11.5 ± 1.3\t11.2 ± 1.3\t0.359\t\nLeucocytes (/µL) Mean ± sd\t14,174 ± 6,010\t15,216 ± 6,918\t0.619\t\nNeutrophils (/µL) Mean ± sd\t9,515 ± 4,770\t10,994 ± 5,629\t0.378\t\nPlatelets (/µL) Mean ± sd\t328,389 ± 127,125\t362,667 ± 282,652\t0.691\t\nCRP (mg/dL) Mean ± sd\t10.4 ± 8.8\t19.6 ±25\t0.243\t\nESR (mm/h) Mean ± sd\t71.6 ± 19\t76.7 ± 33.4\t0.672\t\nNa (mmol/L) Mean ± sd\t137 ± 4\t137 ± 5\t0.869\t\nAST (U/L) Mean ± sd\t64 ± 53\t101 ± 91\t0.222\t\nALT (U/L) Mean ± sd\t99 ± 116\t113 ± 86\t0.712\t\nTotal bilirubin (mg/dL) Mean ± sd\t1.9 ± 2\t2.8 ± 3\t0.538\t\nAlbumin (g/L) Mean ± sd\t35.6 ± 4.3\t34.9 ± 7.2\t0.77\t\nn: absolute value; IVIG: intravenous immunoglobulin; sd: standard deviation; KD: Kawasaki disease; g: gram; dL: deciliter; µL: microliter; CRP: C-reactive protein; mg: milligram; ESR: erythrocyte sedimentation rate; h: hour; Na: serum sodium; mmol: millimole; L: litre; AST: aspartate transaminase; U: international unity; ALT: alanine transaminase.\n\nTable 4 Characteristics of patients with coronary artery aneurysms\n\nCharacteristics\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\t\nAge (months)\t12\t60\t108\t63\t4\t\nMale\tYes\tYes\tYes\tYes\tYes\t\nFever duration (days)\t7\t6\t8\t9\t14\t\nClassic KD\tYes\tYes\tYes\tYes\tNo\t\nDay of fever in IVIG 1st dose\t7\t6\t4\t6\t14\t\nResistance to IVIG\tNo\tNo\tYes\tYes\tNA\t\nDay of fever in IVIG 2nd dose\tNA\tNA\t6\t8\tNA\t\nMPDN (30mg/Kg/day)\nWith IVIG 1st dose\nWith IVIG 2nd dose\tNo\nNA\nNA\tNo\nNA\nNA\tYes\nNo\nYes\tYes\nNo\nYes\tYes\nYes\nNo\t\nCAA classification\tSmall\tSmall\tSmall\tMedium\tGiant\t\nMaximum z score\tNA\t4.46\t3.56\t6.94\t13.81\t\nArteries involved\tRCA; CT\tRCA; LCA\tLCA\tRCA; LCA\tRCA; LAD; LCX\t\nKD: Kawasaki disease; IVIG: intravenous immunoglobulin; MPDN: methylprednisolone; mg: milligram; Kg: kilogram; CAA: coronary artery aneurysms; RCA: right coronary artery, CT: common trunk; LCA: left coronary artery; LAD: left anterior descending artery; NA: not applicable; LCX: left circumflex artery.\n\nIn the acute phase, in addition to coronary involvement, 10 patients presented with pericardial effusion, three with mild mitral valve regurgitation, two with left ventricular systolic dysfunction, one with cardiogenic shock and one with variable first degree atrioventricular (AV) block. After the acute phase, the patient with the AV block developed left ventricle (LV) dilation and another patient developed LV hypertrophy.\n\nTable 5 summarizes Sn, Sp,and the positive (PPV) and negative predictive values (NPV) for the Japanese models in our sample.\n\nTable 5 Statistical values of the Japanese models in our study\n\nModel\tn\tSn (%)\tSp (%)\tPPV (%)\tNPV (%)\t\nKobayasahi\t34\t63.6\t77.3\t53.8\t81\t\nEgami\t39\t66.7\t73.1\t50\t82.6\t\nSano\t25\t28.6\t94.1\t66.7\t77.3\t\nn: absolute value; Sn: sensitivity; Sp: Specificity; PPV: positive predictive value; NPV: negative predictive value.\n\nDiscussion\n\nDespite the lower incidence compared to Japan, KD is a vasculitis that is still an important cause of pediatric disease in our population. Early diagnosis and management are two important factors that appear to reduce cardiac involvement.\n\nOur study revealed an incidence of IVIG resistance similar to the 10 to 20% described in the literature.2 Over the years, efforts have been made to find clinical and laboratory factors that can predict this resistance in order to introduce adjuvant therapies at an early stage of the disease. There are several parameters in the literature that have been studied for this purpose, such as age, serum albumin, transaminases, total bilirubin, neutrophils count, platelet count, CRP, ESR, among others.14,16–20 In our study, CRP and ESR presented a statically significant predictive capacity in relation to IVIG resistance. For CRP, the optimal cut-off point was 15.1 mg/dL (Sn 77.8%, Sp 78.9%, OR 13.125). Patients with CRP values above 15.1 mg/dL are about 13 times more likely to be resistant to IVIG than those with lower values. Concerning ESR, the optimal cut-off point was 90.5 mm/h (Sn 66.7%, Sp 85.7%, OR 12.000). Patients with ESR greater than 90.5 mm/h have a probability of resistance to IVIG approximately 12 times higher than those with lower values. Combining these two independent variables, a statistically significant model was obtained (p = 0.042), whose cut-off point has Sn of 83.3% and Sp of 77.1%. Despite these encouraging results, the variance explained by the model is only 25% (Nagelkerke R2 = 0.254). Thus, although statistically significant, it cannot be validated, which is largely due to the small sample size. Nevertheless, based on these trends, the base-line values for CRP and ESR should be known prior to IVIG administration. The resistance predictor capacity highlights the role of inflammation in this disease, a possible underlying trigger in KD vasculitis.21\n\nThe etiology of KD remains uncertain, however, predisposing factors have been put forward. One, is the immaturity of the immune system, a theory that is supported by the fact that KD predominantly affects children under the age of five. In our study, 62.5% of the patients belonged to this age group, which, although corresponding to the majority of the sample, is below the 80% described in the literature.1 A possible explanation for this result is genetic contribution, since the incidences described in the literature are from studies with a wide range of ethnicities, including Asian children.\n\nCoronary artery involvement occurred in 12 (25%) children, seven with ectasia and five with CAA. Therefore, the incidence of CAA was 10%, which is higher than the 4% reported in the literature. Comparing the groups with and without coronary artery involvement, a statistically significant difference was found regarding the duration of fever (p = 0.038). This result highlights the deleterious effects of persistent fever and the need for IVIG administration, preferably up to the tenth day of the disease, in order to avoid cardiac sequelae.9 The use of corticosteroids in KD is still a topic of debate and controversy. The most consensual is the use intravenous methylprednisolone (MPDN) at a dose of 15 to 30 mg/kg/day, for three days.9 In patients with refractory KD, MPDN supresses the inflammatory cytokine levels more quickly than a second dose of IVIG,9 although it is not recommended as a first-line treatment. Sleeper et al.10 evaluated the impact of corticosteroids at different times of the disease and showed that, with regards to the development of CAA, the only statistically significant difference was in those refractory to the first dose of IVIG which combined corticosteroids with the second dose of IVIG.\n\nThe cardiac complications and echocardiographic findings, others than coronary artery involvement were also evaluated. Three cases of left ventricular systolic dysfunction were identified, one of which with cardiogenic shock, a complication also described in the literature.2,7 In the acute phase, ten patients presented with pericardial effusion without hemodynamic compromise, three patients with mild mitral valve regurgitation and one with first degree AV block. Chbeir et al.22 found a relation between resistance to IVIG, CAA, and initial cardiac echocardiographic findings such as pericardial effusion, coronary hyperechogenicity, and coronary ectasia. The coronary hyperechogenicity and the lack of tapering on echocardiography were not considered as relevant factors, since they are subjective findings, poorly reproducible and can be found both in febrile illnesses and in healthy children.23 During the chronic phase, one patient remained with conduction system impairment and developed LV dilation, and another patient developed LV hypertrophy. The long-term cardiac repercussions in KD remain unclear. Friedman et al.6 reported an increase in the occurrence of long-term adverse cardiac effects, leading to primary angioplasty, coronary bypass surgery, heart transplantation, and death, in patients who developed CAA with higher z scores and who were initially resistant to IVIG. A study by Holve et al.8 revealed a low incidence of adverse cardiac effects in subjects up to 21 years of age, but a greater likelihood of developing high blood pressure from the age of 15.\n\nJapanese predictive models presented poor clinical utility in this study (Table 4). The model with the highest specificity was Sano’s, although with very low sensitivity and with only a small number of cases included. Egami’s model was the most sensitive, however, not powerful enough to be validated. The genetic component may be the explanation for these differences. In fact, the results presented here are similar to those of other studies carried out outside Japan, in which none were able to validate the models in their samples.10,14–17,20 It is still important to note the differences in the study design in relation to the Japanese models, namely that they were applied only to patients with classical KD. Another Japanese study failed to validate the models in a sample exclusively composed of atypical KD cases.24 The Kobayashi model was validated for the Japanese population with Sn of 86% and Sp of 67%.11 Contrary to the present study, IVIG was administered at a dose of 1 g/kg on two consecutive days and resistance was considered if fever persisted 24 hours after the beginning of the treatment, or in case of recurrence after a period without fever. The Egami model was validated with Sn of 78% and Sp of 76%, however, resistance was considered if the CRP value did not decrease by more than 50% and fever persisted for longer than 48 hours after IVIG administration.12 Loomba et al.25 were not able to validate the Egami model even when applying it separately to classical and atypical KD, and by ethnicity. The Sano model, validated with Sn of 77% and Sp of 86%, was the only one of the three to adjust the size of the CAA to the body surface.13 However, it also used IVIG at a dose of 1 g/kg on two consecutive days and defined resistance if fever persisted 24 hours after the end of therapy.\n\nThe main limitations of this analysis are related to its retrospective methodology and sample size.\n\nConclusions\n\nCRP and ESR are independent variables that showed a predictive trend regarding resistance to IVIG, with optimal cut-off values of 15.1 mg/dL and 90.5 mm/h, respectively. However, there is a need for a multicenter study with a sample of adequate dimensions to validate a model based on these two analytical parameters. Cardiac complications are not limited to coronary arteries, and the study and follow-up of these patients should be more widespread. The validated models for the Japanese population have very limited utility in our population, further reinforcing the need and importance of new approaches.\n\nFontes de Financiamento\n\nO presente estudo não contou com fontes de financiamento externas.\n\nVinculação Acadêmica\n\nNão há vinculação deste estudo a programas de pós-graduação.\n\nAprovação Ética e Consentimento Informado\n\nEste artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.\n\nAuthor Contributions\n\nConception and design of the research: Faim D, Henriques C, Brett A, Francisco A, Rodrigues F, Pires A; Data acquisition: Faim D, Henriques C; Analysis and interpretation of the data: Faim D, Brett A, Francisco A; Statistical analysis and Writing of the manuscript: Faim D; Critical revision of the manuscript for intellectual content: Faim D, Brett A, Francisco A, Rodrigues F, Pires A.\n\nPotential Conflict of Interest\n\nThe authors report no conflict of interest concerning the materials and methods used in this study or the findings specified in this paper.\n\nSources of Funding\n\nThere was no external funding source for this study.\n\nStudy Association\n\nThis study is not associated with any thesis or dissertation.\n\nEthics Approval and Consent to Participate\n\nThis article does not contain any studies with human participants or animals performed by any of the authors.\n==== Refs\nReferências\n\n1 Newburger JW Takahashi M Burns JC Kawasaki disease J Am Coll Cardiol 2016 67 14 1738 1749 27056781\n1. 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J Pediatr Pharmacol Ther. 2015;20(3):163-77.\n10 Sleeper LA Minich LL Mccrindle BM Li JS Mason W Colan SD Evaluation of Kawasaki disease risk scoring systems for intravenous immunoglobulin resistance J Pediatr 2011 158 5 831 835 21168857\n10. Sleeper LA, Minich LL, Mccrindle BM, Li JS, Mason W, Colan SD, et al. Evaluation of Kawasaki disease risk scoring systems for intravenous immunoglobulin resistance. J Pediatr. 2011;158(5):831-5.\n11 Kobayashi T Inoue Y Takeuchi K Okada Y Tamura K Tomomasa T Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease Circulation 2006 113 22 2606 2612 16735679\n11. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113(22):2606-12.\n12 Egami K Muta H Ishii M Suda K Sugahara Y Iemura M Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease J Pediatr 2006 149 2 237 240 16887442\n12. Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. 2006;149(2):237-40.\n13 Sano T Kurotobi S Matsuzaki K Yamamoto T Maki I Miki K Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment Eur J Pediatr 2007 166 2 131 137 16896641\n13. Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, et al. Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. Eur J Pediatr. 2007;166(2):131-7.\n14 Davies S Sutton N Blackstock S Gormley S Hoggart CJ Levin M Predicting IVIG resistance in UK Kawasaki disease Arch Dis Child 2015 100 4 366 368 25670405\n14. Davies S, Sutton N, Blackstock S, Gormley S, Hoggart CJ, Levin M, et al. Predicting IVIG resistance in UK Kawasaki disease. Arch Dis Child. 2015;100(4):366-8.\n15 Jakob A von Kries R Horstmann J Hufnagel M Stiller B Berner R Failure to predict high-risk Kawasaki disease patients in a population-based study cohort in Germany Pediatr Infect Dis J 2018 37 9 850 855 29406464\n15. Jakob A, von Kries R, Horstmann J, Hufnagel M, Stiller B, Berner R, et al. Failure to predict high-risk Kawasaki disease patients in a population-based study cohort in Germany. Pediatr Infect Dis J. 2018;37(9):850-5.\n16 Arane K Mendelsohn K Mimouni M Mimouni F Koren Y Simon DB Japanese scoring systems to predict resistance to intravenous immunoglobulin in Kawasaki disease were unreliable for Caucasian Israeli children Acta Paediatr 2018 107 12 2179 2184 29797463\n16. Arane K, Mendelsohn K, Mimouni M, Mimouni F, Koren Y, Simon DB, et al. Japanese scoring systems to predict resistance to intravenous immunoglobulin in Kawasaki disease were unreliable for Caucasian Israeli children. Acta Paediatr. 2018;107(12): 2179-84.\n17 Chantasiriwan N Silvilairat S Makonkawkeyoon K Pongprot Y Sittiwangkul R Predictors of intravenous immunoglobulin resistance and coronary artery aneurysm in patients with Kawasaki disease Paediatr Int Child Health 2018 38 3 209 212 29768976\n17. Chantasiriwan N, Silvilairat S, Makonkawkeyoon K, Pongprot Y, Sittiwangkul R. Predictors of intravenous immunoglobulin resistance and coronary artery aneurysm in patients with Kawasaki disease. Paediatr Int Child Health. 2018;38(3):209-12.\n18 Kim BY Kim D Kim YH Ryoo E Sun YH Jeon IS Non-responders to intravenous immunoglobulin and coronary artery dilatation in Kawasaki disease: predictive parameters in Korean children Korean Circ J 2016 46 4 542 549 27482264\n18. Kim BY, Kim D, Kim YH, Ryoo E, Sun YH, Jeon IS, et al. Non-responders to intravenous immunoglobulin and coronary artery dilatation in Kawasaki disease: predictive parameters in Korean children. Korean Circ J. 2016;46(4):542-9.\n19 Shin J Lee H Eun L Verification of current risk scores for Kawasaki disease in Korean children J Korean Med Sci 2017 32 12 1991 1996 29115081\n19. Shin J, Lee H, Eun L. Verification of current risk scores for Kawasaki disease in Korean children. J Korean Med Sci. 2017;32(12)1991-6.\n20 Rangel MA Soares D Santos H Rodrigues L Carriço A Moreira D Preditores clínico-analíticos da doença de Kawasaki refratária à Imunoglobulina endovenosa Acta Pediátrica Port 2018 49 2 152 160\n20. Rangel MA, Soares D, Santos H, Rodrigues L, Carriço A, Moreira D. Preditores clínico-analíticos da doença de Kawasaki refratária à Imunoglobulina endovenosa. Acta Pediátrica Port. 2018;49(2):152-60.\n21 Galeotti C Kaveri SV Cimaz R Koné-Paut I Bayry J Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease Drug Discov Today 2016 21 11 1850 1857 27506874\n21. Galeotti C, Kaveri SV, Cimaz R, Koné-Paut I, Bayry J. Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease. Drug Discov Today. 2016;21(11):1850-7.\n22 Chbeir D Gaschignard J Bonnefoy R Beyler C Melki I Faye A Kawasaki disease: abnormal initial echocardiogram is associated with resistance to IV Ig and development of coronary artery lesions Pediatr Rheumatol Online J. Pediatric Rheumatol 2018 16 1 48 48\n22. Chbeir D, Gaschignard J, Bonnefoy R, Beyler C, Melki I, Faye A, et al. Kawasaki disease: abnormal initial echocardiogram is associated with resistance to IV Ig and development of coronary artery lesions. Pediatr Rheumatol Online J. Pediatric Rheumatol. 2018;16(1):48.\n23 Rabinowitz EJ Rubin LG Desai K Hayes DA Tugertimur A Know E Examining the utility of coronary artery lack of tapering and perivascular brightness in incomplete Kawasaki disease Pediatr Cardiol 2019 40 1 147 153 30196380\n23. Rabinowitz EJ, Rubin LG, Desai K, Hayes DA, Tugertimur A, Know E, et al. Examining the utility of coronary artery lack of tapering and perivascular brightness in incomplete Kawasaki disease. Pediatr Cardiol.2019;40(1):147-53.\n24 Kanamitsu K Kakimoto H Shimada A Nakata Y Ochi H Watanabe H Verification of risk scores to predict i.v. immunoglobulin resistance in incomplete Kawasaki disease Pediatr Int 2016 58 2 146 151 26190225\n24. Kanamitsu K, Kakimoto H, Shimada A, Nakata Y, Ochi H, Watanabe H, et al. Verification of risk scores to predict i.v. immunoglobulin resistance in incomplete Kawasaki disease. Pediatr Int. 2016;58(2):146-51.\n25 Loomba RS Raskin A Gudausky TM Kirkpatrick E Role of the egami score in predicting intravenous immunoglobulin resistance in Kawasaki disease among different ethnicities Am J Ther 2016 23 6 e1293 e1299 25611359\n25. Loomba RS, Raskin A, Gudausky TM, Kirkpatrick E. Role of the egami score in predicting intravenous immunoglobulin resistance in Kawasaki disease among different ethnicities. Am J Ther. 2016;23(6):e1293-9.\n\n",
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"abstract": "We report two serious and unusual complications of benzodiazepine withdrawal in a single patient: takotsubo cardiomyopathy and catatonia. This 61-year-old female patient was brought to the emergency department with lethargy and within hours had declined into a state of catatonia. Although there was never a complaint of chest pain, ECG showed deep anterior T-wave inversions and cardiac enzymes were elevated. An echocardiogram was consistent with takotsubo cardiomyopathy. She later received 1 mg of midazolam and within minutes had resolution of catatonic symptoms. Careful history revealed that she had omitted her daily dose of lorazepam for 3 days prior to admission. To our knowledge, the case presented herein is the first report of simultaneous catatonia and takotsubo cardiomyopathy in the setting of benzodiazepine withdrawal. The pathogenesis of both conditions is poorly understood but may be indirectly related to the sudden decrease in γ-aminobutyric acid (GABA) signaling during benzodiazepine withdrawal.",
"affiliations": "Boston University School of Medicine, Boston, MA 02118, USA.;Department of Internal Medicine, Boston Medical Center, Boston, MA 02118, USA.;Department of Internal Medicine, Boston Medical Center, Boston, MA 02118, USA.",
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"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2016/8153487Case ReportTakotsubo Cardiomyopathy and Catatonia in the Setting of Benzodiazepine Withdrawal Peng Teng J. \n1\nhttp://orcid.org/0000-0003-2251-4910Patchett Nicholas D. \n2\nhttp://orcid.org/0000-0001-9394-1448Bernard Sheilah A. \n2\n\n*\n1Boston University School of Medicine, Boston, MA 02118, USA2Department of Internal Medicine, Boston Medical Center, Boston, MA 02118, USA*Sheilah A. Bernard: sheilah.bernard@bmc.orgAcademic Editor: Filippo M. Sarullo\n\n2016 28 7 2016 2016 815348726 4 2016 17 7 2016 Copyright © 2016 Teng J. Peng 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.We report two serious and unusual complications of benzodiazepine withdrawal in a single patient: takotsubo cardiomyopathy and catatonia. This 61-year-old female patient was brought to the emergency department with lethargy and within hours had declined into a state of catatonia. Although there was never a complaint of chest pain, ECG showed deep anterior T-wave inversions and cardiac enzymes were elevated. An echocardiogram was consistent with takotsubo cardiomyopathy. She later received 1 mg of midazolam and within minutes had resolution of catatonic symptoms. Careful history revealed that she had omitted her daily dose of lorazepam for 3 days prior to admission. To our knowledge, the case presented herein is the first report of simultaneous catatonia and takotsubo cardiomyopathy in the setting of benzodiazepine withdrawal. The pathogenesis of both conditions is poorly understood but may be indirectly related to the sudden decrease in γ-aminobutyric acid (GABA) signaling during benzodiazepine withdrawal.\n==== Body\n1. Introduction\nWe report here a patient presenting with two rare diagnoses: benzodiazepine withdrawal catatonia and takotsubo cardiomyopathy. Catatonia is a behavioral syndrome of immobility, rigidity, and mutism and at times restlessness and dysautonomia [1]. Takotsubo cardiomyopathy is a transient left ventricular systolic dysfunction after psychological or physical stress; the condition typically mimics myocardial infarction with apical akinesis, modest elevation in cardiac enzymes, and evolutionary EKG changes (ST elevation or depression or T-wave inversions) [2].\n\n2. Case Presentation\nA 61-year-old white female was brought to our hospital by family for 8 hours of lethargy and confusion. Medical history was significant for COPD on home oxygen, stage 1A adenocarcinoma of the lung (status post-RLL lobectomy), prior opiate abuse (in stable remission on oral buprenorphine-naloxone), prior alcohol abuse (in stable remission per family), and anxiety treated with lorazepam (2 mg daily). One week prior to presentation, she developed increased dyspnea, cough, subjective fevers, and fatigue. The patient's family administered her usual medications during her acute illness but had omitted her lorazepam for the past 3 days. She became increasingly somnolent and was found on the morning of presentation with a “blank stare” and slurred speech.\n\nOn arrival at the hospital, vitals were as follows: temperature 36.8°C, HR 104 beats/min, BP 177/110 mmHg, RR 16, and SpO2 96% on 2 L nasal cannula oxygen. She was moderately somnolent but interacted normally and was oriented to person, place, and time. Within hours, she became persistently disoriented with impaired short-term memory and difficulty following commands. All psychoactive medications were held. After 12 hours, symptoms had progressed to near-complete unresponsiveness, immobility, and periodic agitation. Extensive workup showed no abnormalities to explain symptoms. Blood counts, chemistries, liver enzymes, arterial blood gas, TSH, B12, chest X-ray, and brain MRI were unremarkable. Blood cultures, urine cultures, sputum cultures, and Lyme serology were negative. Urine toxic screen was negative for drugs of abuse, including benzodiazepines. Neurology examined the patient and found no focal neurologic deficits. Based on their exam, they also endorsed low clinical suspicion for nonconvulsive status epilepticus.\n\nDespite absence of chest pain or acute coronary syndrome (ACS) equivalents, admission ECG showed deep anterior T-wave inversions. Troponin I was 0.16 ng/L (normal < 0.013) and rose to 1.37 ng/L over 18 hours. However, ACS treatment was not pursued as the patient was known to have a coronary calcium score of zero and her exercise ECG stress test ten months priorly had shown no inducible ischemia. Urgent TTE was obtained, which revealed hypokinesis and dilation of the left ventricle consistent with takotsubo cardiomyopathy. Left ventricular ejection fraction (LVEF) was 35%, down from 60% ten months priorly.\n\nTwenty-four hours after initial presentation, the patient became too restless to allow completion of a routine ECG, so 1 mg of midazolam was given. Within minutes of receiving this medication, she began to talk again and became aware of her surroundings. She was able to recognize her daughter, follow commands, and walk. Scheduled lorazepam was initiated. Within 48 hours, the patient was back to her baseline mental status except for feeling fatigued. She denied chest pain and had no symptoms of congestive heart failure. The patient was discharged on hospital day 3 with a lorazepam taper and metoprolol succinate; TTE 10 weeks later showed reversal of apical remodeling and improvement in LVEF back to 60% (Figure 1).\n\n3. Discussion\nCatatonia and takotsubo cardiomyopathy are distinct disorders with mechanisms that are not well understood. They have rarely been reported to occur simultaneously [3], and both syndromes have been separately reported in the setting of benzodiazepine withdrawal [4–10]; however, we are not aware of any prior reports of benzodiazepine withdrawal possibly triggering both simultaneously.\n\nBenzodiazepine withdrawal-induced takotsubo has been described twice in published case reports. One [4] described a 49-year-old woman who had her home lorazepam dose (2 mg daily) temporarily withdrawn during a hospital admission. After 28 hours, she began to have symptoms of benzodiazepine withdrawal along with ST-segment elevations on EKG, with a TTE showing apical akinesis and LVEF of 45%. The second [5] described a 65-year-old woman who self-discontinued several long-term psychiatric medications, including a benzodiazepine, and then presented with syncope and a TTE suggestive of takotsubo cardiomyopathy.\n\nBenzodiazepine withdrawal-induced catatonia has been reported several times [6–10]. In these reports, each patient stopped long-standing benzodiazepine therapy, then subsequently became confused and mute with symptoms including muscle rigidity or psychomotor agitation, and then experienced rapid reversal of symptoms after resuming benzodiazepines. None of these reports describe concurrent cardiomyopathy, but several predate the first description of takotsubo cardiomyopathy. Benzodiazepine withdrawal occasionally also precipitates absence status epilepticus, a prolonged seizure that appears similar to catatonia, with symptoms of confusion, disorientation, and a trance-like state [11]. Our patient's symptoms resolved before an EEG could be obtained, so it remains unproven whether her event was ictal or neuropsychiatric in etiology, although our consulting neurologist favored the latter.\n\nWhile the pathogeneses of catatonia and takotsubo cardiomyopathy are not well understood, their neurohormonal milieu shares common features with benzodiazepine withdrawal. Benzodiazepines potentiate γ-aminobutyric acid (GABA) receptor, and thus their withdrawal suddenly decreases the basal inhibitory tone of GABA signaling. Catatonic patients are known to exhibit decreased cortical GABA signaling [12], although this is just one of several postulated mechanisms for catatonia [1]. Takotsubo cardiomyopathy has been reported during withdrawal from multiple other GABA agonists including alcohol [13] and baclofen [14]; therefore, takotsubo may relate at least indirectly to decreased GABA signaling. The direct cause of takotsubo cardiomyopathy is thought to be increased catecholamine release from sympathetic nerves, which induces neurogenic myocardial stunning [15]. In animal models, benzodiazepine withdrawal has been shown to increase catecholamine release in the brain and increases symptoms typical of peripheral sympathetic activity [16].\n\nThe case presented herein is the first documented report of simultaneous catatonia and takotsubo cardiomyopathy in the setting of benzodiazepine withdrawal. We propose that the pathophysiology of both conditions may be at least indirectly related to the sudden decrease in central GABAergic tone seen in the setting of benzodiazepine withdrawal, underscoring the “brain-heart” connection in the field of neurocardiology.\n\nCompeting Interests\nThe authors declare that there are no competing interests regarding the publication of this paper.\n\nFigure 1 Echocardiogram images obtained during the hospitalization (a) and ten weeks later (b). An apical four-chamber view is shown at end diastole (left) and at end systole (right).\n==== Refs\n1 Dhossche D. M. Stoppelbein L. Rout U. K. Etiopathogenesis of catatonia: generalizations and working hypotheses Journal of ECT 2010 26 4 253 258 10.1097/yct.0b013e3181fbf96d 2-s2.0-78650485010 21076339 \n2 Pavin D. Le Breton H. Daubert C. Human stress cardiomyopathy mimicking acute myocardial syndrome Heart 1997 78 5 509 511 10.1136/hrt.78.5.509 2-s2.0-0030732719 9415014 \n3 Singh D. Williams O. Catatonia, major depression and Takotsubo cardiomyopathy in an elderly patient Australasian Psychiatry 2013 21 2 181 182 10.1177/1039856212469848 2-s2.0-84879208627 23568868 \n4 Chan C. M. J. Wong S. M. R. Chang Y. K. T. Takotsubo cardiomyopathy associated with sudden benzodiazepine withdrawal Clinical Toxicology 50, article 23 Abstracts of XXXII International Congress of Poison Centres and Clinical Toxicologists, 2012 \n5 Marabotti C. Venturini E. Marabotti A. Pingitore A. Delayed multifocal recurrent stress-induced cardiomyopathy after antidepressants withdrawal Heart & Lung 2014 43 3 225 230 10.1016/j.hrtlng.2014.03.003 2-s2.0-84899685950 24794783 \n6 Rosebush P. I. Mazurek M. F. Catatonia after benzodiazepine withdrawal Journal of Clinical Psychopharmacology 1996 16 4 315 319 10.1097/00004714-199608000-00007 2-s2.0-0030037836 8835707 \n7 Sivakumar T. Yadav A. Sood M. Khandelwal S. K. Lorazepam withdrawal catatonia: a case report Asian Journal of Psychiatry 2013 6 6 620 621 10.1016/j.ajp.2013.05.008 2-s2.0-84888878508 24309887 \n8 Glover S. G. Escalona R. Bishop J. Saldivia A. Catatonia associated with lorazepam withdrawal Psychosomatics 1997 38 2 148 150 10.1016/S0033-3182(97)71484-1 2-s2.0-0031027811 9063046 \n9 Deuschle M. Lederbogen F. Benzodiazepine withdrawal—induced catatonia Pharmacopsychiatry 2001 34 1 41 42 10.1055/s-2001-15188 2-s2.0-0035142918 11229621 \n10 Brown M. Freeman S. Clonazepam withdrawal-induced catatonia Psychosomatics 2009 50 3 289 292 10.1176/appi.psy.50.3.289 2-s2.0-67650927316 19567771 \n11 Thomas P. Beaumanoir A. Genton P. Dolisi C. Chatel M. ‘De novo’ absence status of late onset: report of 11 cases Neurology 1992 42 1 104 110 10.1212/wnl.42.1.104 2-s2.0-0026569313 1734289 \n12 Northoff G. Steinke R. Czcervenka C. Decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia: investigation of in vivo benzodiazepine receptor binding Journal of Neurology, Neurosurgery & Psychiatry 1999 67 4 445 450 10.1136/jnnp.67.4.445 2-s2.0-0032837458 \n13 Suzuki K. Osada N. Akasi Y. J. An atypical case of ‘Takotsubo cardiomyopathy’ during alcohol withdrawal: abnormality in the transient left ventricular wall motion and a remarkable elevation in the ST segment Internal Medicine 2004 43 4 300 305 10.2169/internalmedicine.43.300 2-s2.0-2542464164 15168772 \n14 Pizon A. F. Lovecchio F. Reversible cardiomyopathy complicating intrathecal baclofen withdrawal: a case report Journal of Medical Toxicology 2007 3 4 187 189 10.1007/bf03160938 2-s2.0-38749094509 18072175 \n15 Wittstein I. S. Thiemann D. R. Lima J. A. C. Neurohumoral features of myocardial stunning due to sudden emotional stress The New England Journal of Medicine 2005 352 6 539 548 10.1056/nejmoa043046 2-s2.0-13444293219 15703419 \n16 Grant S. J. Galloway M. P. Mayor R. Precipitated diazepam withdrawal elevates noradrenergic metabolism in primate brain European Journal of Pharmacology 1985 107 2 127 132 10.1016/0014-2999(85)90050-0 2-s2.0-0021917869 3920054\n\n",
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"title": "Takotsubo Cardiomyopathy and Catatonia in the Setting of Benzodiazepine Withdrawal.",
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"abstract": "BACKGROUND\nToxic effects of hydroxychloroquine, like chloroquine, include membrane stabilization and hypokalemia, which is correlated with the severity of the overdose. Correction of hypokalemia can expose patients to the risk of ventricular arrhythmia.\n\n\nMETHODS\nA 19-year-old woman who had ingested 6 grams of hydroxychloroquine was admitted to intensive care with severe hypokalemia (1.5 mmol/L on admission). Thirty-six hours after correction of the hypokalemia, circulatory arrest followed ventricular fibrillation. Her potassium level at that time was 5.8 mmol/L. Outcome was favorable after it returned to normal.\n\n\nCONCLUSIONS\nBecause its pathogenesis remains debatable, the hypokalemia following hydroxychloroquine poisoning must be corrected with care, even when severe. This correction is difficult, and extracellular transfer of the excess potassium after elimination of the toxin exposes the patient to the risk of ventricular arrhythmia.",
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"abstract": "A 35-year-old male presented to our university hospital with night sweats, fevers, ulcerated skin lesions to the lower mouth and posterior neck, shortness of breath, and an enlarging cervical lymph node. The patient was evaluated 2 months prior for respiratory symptoms, cervical lymphadenopathy, and skin lesions resulting in a diagnosis of primary pulmonary coccidioidomycosis and was treated with a 4-week course of fluconazole. On presentation to our hospital, initial laboratory test results revealed leukocytosis, increased liver enzymes, elevated inflammatory markers, and hypercalcemia. Computed tomography scan of the chest revealed lung nodules in a miliary pattern and prominent mediastinal lymphadenopathy. Magnetic resonance imaging revealed multiple vertebral and iliac bone lesions, as well as bilateral psoas muscle lesions. Serum ELISA (enzyme linked immunosorbent assay) detected elevated serological markers against coccidioides, and sputum culture revealed coccidioides arthroconidia, confirming the presence of an acute coccidioides infection. Biopsy of the right iliac crest and cervical lymph node revealed spherules resembling coccidioides, escalating the diagnosis to disseminated coccidioidomycosis. The patient's hospital course was complicated by septic shock, acute respiratory distress syndrome requiring several days of mechanical ventilation, and acute kidney injury. He was ultimately treated with several weeks of voriconazole and liposomal amphotericin-B. He made a full recovery and was discharged on an extended course of oral voriconazole. Our case highlights the importance of recognition and appropriate treatment duration of disseminated coccidioidomycosis at initial presentation. Failure to do so may lead to increased morbidity and mortality.",
"affiliations": "University of Texas Health Sciences Center, San Antonio, TX, USA.;University of Texas Health Sciences Center, San Antonio, TX, USA.;University of Texas Health Sciences Center, San Antonio, TX, USA.;University of Texas Health Sciences Center, San Antonio, TX, USA.",
"authors": "Dev|Ameesh|A|0000-0003-4441-6705;Janysek|Dawn|D|;Gnecco|James|J|0000-0001-5054-0492;Haghayeghi|Kamyar|K|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620949315\n10.1177_2324709620949315\nCase Report\nDisseminated Coccidioidomycosis Following Insufficient Treatment at Initial Presentation: Case Report\nhttps://orcid.org/0000-0003-4441-6705Dev Ameesh BS1* Janysek Dawn BS1* https://orcid.org/0000-0001-5054-0492Gnecco James IVDO1 Haghayeghi Kamyar DO1 1 University of Texas Health Sciences Center, San Antonio, TX, USA\nKamyar Haghayeghi, DO, Department of Internal Medicine, UT Health San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA. Email: haghayeghi@uthscsa.edu* Authors contributed equally.\n\n\n18 8 2020 \nJan-Dec 2020 \n8 232470962094931512 5 2020 19 7 2020 20 7 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis 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 page (https://us.sagepub.com/en-us/nam/open-access-at-sage).A 35-year-old male presented to our university hospital with night sweats, fevers, ulcerated skin lesions to the lower mouth and posterior neck, shortness of breath, and an enlarging cervical lymph node. The patient was evaluated 2 months prior for respiratory symptoms, cervical lymphadenopathy, and skin lesions resulting in a diagnosis of primary pulmonary coccidioidomycosis and was treated with a 4-week course of fluconazole. On presentation to our hospital, initial laboratory test results revealed leukocytosis, increased liver enzymes, elevated inflammatory markers, and hypercalcemia. Computed tomography scan of the chest revealed lung nodules in a miliary pattern and prominent mediastinal lymphadenopathy. Magnetic resonance imaging revealed multiple vertebral and iliac bone lesions, as well as bilateral psoas muscle lesions. Serum ELISA (enzyme linked immunosorbent assay) detected elevated serological markers against coccidioides, and sputum culture revealed coccidioides arthroconidia, confirming the presence of an acute coccidioides infection. Biopsy of the right iliac crest and cervical lymph node revealed spherules resembling coccidioides, escalating the diagnosis to disseminated coccidioidomycosis. The patient’s hospital course was complicated by septic shock, acute respiratory distress syndrome requiring several days of mechanical ventilation, and acute kidney injury. He was ultimately treated with several weeks of voriconazole and liposomal amphotericin-B. He made a full recovery and was discharged on an extended course of oral voriconazole. Our case highlights the importance of recognition and appropriate treatment duration of disseminated coccidioidomycosis at initial presentation. Failure to do so may lead to increased morbidity and mortality.\n\ndisseminated coccidioidomycosisvalley feverinsufficient treatmentpulmonary coccidioidomycosiscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nCoccidioides immitis is a soil-dwelling, dimorphic fungus endemic to the southwest region of the United States.1 It is usually inhaled into lungs as small barrel-shaped structures called arthroconidia. These arthroconidia develop into spherules in the lungs and are ingested by macrophages. Many cases only involve the lungs and are known as primary pulmonary coccidioidomycosis, or “Valley Fever,” due to the pathogen’s original discovery in the San Joaquin Valley in California.2 However, in some cases, macrophages that ingest the arthroconidia enter the lymphatic system and lead to disseminated disease.3 The severity of disease can vary from mild to life-threatening disease.4 The organs involved in disseminated disease include the skin, bones, joints, and central nervous system.5 Risk factors for the development of disseminated coccidioides (DC) include HIV/AIDS, immunosuppressive medication, race/ethnicity, old age, diabetes, and late-stage pregnancy.5-8\n\nWe are reporting a rare case of DC in a young, relatively healthy individual with no major risk factors for dissemination of disease. This patient was diagnosed with coccidioides 2 months prior to presentation to our hospital. However, his disease was only treated as a primary pulmonary infection, despite having features of disseminated disease (skin lesions, lymphadenopathy). Our case report highlights the unusual presentation of DC in a healthy young male. It also highlights the importance of recognizing and treating DC appropriately to prevent life-threatening progression of the disease.\n\nCase Presentation\nA 35-year-old Samoan American male from California with congenital deafness, hypertension, and asthma presented to a university hospital in San Antonio, Texas, with worsening night sweats, rash, productive cough, shortness of breath, fevers, intermittent back pain, and enlarging neck nodule. The patient had been diagnosed with Valley Fever 2 months prior while living in California. His initial symptoms included night sweats, facial rash, fever, worsening hearing loss, cough, skin lesions, cervical lymphadenopathy, and shortness of breath. At that time, he was given a 1-month course of fluconazole 400 mg orally daily, and no further treatment was recommended. While on fluconazole, he had noted some improvement in his symptoms. Physical examination at the time of hospital admission revealed scaling plaques to the right forehead, small ulcerated lesions to the right lower mouth and posterior neck, coarse breath sounds in the left upper lung fields, and a 3.5 cm × 3.5 cm nontender lymph node to the left anterior neck. He had no neurological deficits on examination. He was afebrile and tachycardic (120 bpm) with SpO2 of 91% on room air.\n\nInitial laboratory results were significant for leukocytosis with predominant neutrophilia, elevated erythrocyte sedimentation rate and C-reactive protein, elevated liver enzymes, total protein of 10.0 g/dL, albumin of 1.7 g/dL, corrected calcium of 11.0 mg/dL, elevated alkaline phosphatase of 167 U/L, elevated lactic acid of 2.7 mmol/L, elevated lactate dehydrogenase of 341 U/L, and ferritin of 3366 ng/mL. The patient also had anemia of chronic disease. A respiratory viral panel was positive for respiratory syncytial virus.\n\nOur differential diagnosis included disseminated fungal diseases such as coccidioidomycosis, histoplasmosis, or blastomycosis, as well as tuberculosis, secondary hemophagocytic lymphohistiocytosis, HIV, and malignancy. Infectious Diseases was consulted given high likelihood of disseminated coccidioidomycosis.\n\nSerum coccidioides IgG ELISA (enzyme linked immunosorbent assay) was 8.3 IV (reference range ≤0.9 IV) and IgM ELISA was 3.0 IV (reference range ≤0.9 IV). Direct microscopy of the sputum revealed spherules resembling coccidioides. Magnetic resonance imaging (MRI) was obtained to further workup the elevated alkaline phosphatase and hypercalcemia. MRI of the spine (Figures 1-3) revealed a diffusely abnormal signaling with numerous discrete variable sized hyperintense lesions throughout the spine, sacrum, and iliac bones. Indeterminate hyperintense lesions in the bilateral psoas muscles were also present. To confirm that these lesions represented infection and not a potential malignancy, a computed tomography–guided biopsy was performed of the right iliac crest and cervical lymph node. Both biopsies revealed spherules and cultures grew coccidioidomycosis, confirming the presence of a disseminated infection. Lumbar puncture revealed no evidence of cerebrospinal fluid involvement. Laboratory testing for blastomycosis, histoplasmosis, Epstein-Barr virus, cytomegalovirus, HIV, syphilis, tuberculosis, hemophagocytic lymphohistiocytosis, multiple myeloma, and other malignancies were all negative.\n\nFigure 1. Magnetic resonance imaging of the spine, sagittal view (without contrast): numerous discrete, variable-sized lesions throughout the spine, most notably seen in T12, L1, and L3-L5 vertebrae.\n\nFigure 2. Magnetic resonance imaging of the spine, coronal view (without contrast): lesions in the sacrum.\n\nFigure 3. Magnetic resonance imaging of pelvis, axial view (without contrast): variable-sized lesions in bilateral iliac crests.\n\nInitially, the patient was admitted to the general medicine floor. He required high-flow nasal cannula and multiple boluses of intravenous fluids to maintain mean arterial pressure of 65 mm Hg. Despite treatment with itraconazole, liposomal amphotericin B, and supplemental oxygen, his respiratory rate continued to increase, and he developed worsening hypoxemia. He was transferred to the intensive care unit, intubated, and given vasopressors. A chest X-ray at that time demonstrated diffuse bilateral reticulonodular opacities consistent with acute respiratory distress syndrome (Figure 4).\n\nFigure 4. Chest X-ray: Diffuse bilateral fine nodular reticular pattern of interstitial prominence with some fullness to the mediastinum and hila concerning for adenopathy.\n\nThe patient required increased FiO2 and PEEP (positive end-expiratory pressure) while intubated; therefore, a computed tomography scan of the chest was done. The imaging found a miliary pattern of pulmonary nodules with focal consolidations posteriorly, along with prominent and confluent superior mediastinal lymphadenopathy obliterating the left upper bronchus resulting in postobstructive consolidation of the left upper lobe. In addition to antifungals, ceftriaxone and azithromycin were started for possible concomitant community-acquired pneumonia. Despite broad spectrum antifungals and antibiotics, his respiratory status continued to worsen. Liposomal amphotericin B treatment resulted in acute kidney injury with creatinine peaking at 4.2 mg/dL (patient’s baseline 0.7 mg/dL). His course was further complicated by paralytic ileus, right internal jugular deep vein thrombosis, and a gluteal hematoma. After weeks of treatment with liposomal amphotericin B, voriconazole, and mechanical ventilation, the patient made a full pulmonary and renal recovery. On the day of discharge, his creatinine was within normal limits, and he did not need supplemental oxygen. He was discharged on an extended course of oral voriconazole with plans to reevaluate treatment after outpatient infectious disease specialist follow-up. He was discharged to an intensive inpatient rehabilitation program for severe physical deconditioning after a prolonged hospitalization.\n\nDiscussion\nThe patient described in this report resided in an area endemic to coccidioidomycosis; however, he possessed no major risk factors for dissemination of this disease. Our workup for HIV/AIDS and other immunocompromising processes was negative, and he denied the use of outpatient immunosuppressant medications. There have been previously documented cases of low-risk individuals developing DC.3,9 Many cases reported that the progression of disease in these individuals was due to a delay in diagnosis at initial presentation.9 Although our patient’s treatment was not delayed, the duration of his treatment was inappropriate. His initial presentation indicated the presence of extrapulmonary disease, evidenced by the presence of ulcerating skin lesions and cervical lymphadenopathy. Therefore, his diagnosis 2 months prior to presenting to our hospital should have been disseminated coccidioidomycosis rather than primary pulmonary coccidioidomycosis, and the duration of treatment should have been much longer than 4 weeks.\n\nThe guidelines for the treatment of coccidioidomycosis vary depending on the extent of disease.10 For uncomplicated coccidioidal pneumonia with mild or nondebilitating symptoms, patients may be treated with education, close observation, and supportive care. For those with uncomplicated disease but significant debility or comorbidities, a 3- to 6-month course of an oral azole (such as fluconazole) is recommended. For patients with evidence of soft tissue coccidioidomycosis, such as skin lesions and subcutaneous abscesses, at least 6 to 12 months of oral azole therapy is recommended. For patients with evidence of bone or joint involvement, treatment with an oral azole (itraconazole or fluconazole) is given for a period of 3 years or up to a lifetime. Amphotericin B may also be used in severe bone involvement, especially when there is concern for cord compression with vertebral lesions.2\n\nThe appropriate treatment regimen for this patient would have been a minimum of 6 to 12 months of an oral azole, given the presence of extrapulmonary soft tissue infection at initial presentation.2 However, our patient was treated with fluconazole 400 mg daily for 1 month. We believe that this inadequate treatment led to further progression of his respiratory disease and the development of additional extrapulmonary manifestations. The progression of his infection resulted in a complicated and life-threatening disease course. The patient spent 6 weeks in the hospital, developed septic shock, acute respiratory distress syndrome, and significant physical deconditioning requiring an additional 2 weeks of inpatient physical rehabilitation.\n\nThe likely culprit behind this patient’s complicated infection was inadequate duration of treatment, but other factors may have contributed to his prolonged disease course. Inpatient evaluation for an immunodeficiency included HIV testing and measurement of T-lymphocytes. Although the patient had a normal CD4 count, it was on the lower side of normal (462 cells/mcL). It is possible the patient has an unknown form of immunodeficiency that may be evaluated in the future by immunogenetics. On admission, the patient also had respiratory syncytial virus and quickly developed hypoxic respiratory failure. The compounded effect of a viral and fungal pneumonia is unknown, but may have contributed to the patient’s rapid decline. Even though the role of dual antifungal therapy in coccidioidomycosis is unknown (unless the patient has additional dissemination to central nervous system), we added itraconazole and later switched it to voriconazole in addition to liposomal amphotericin B before clinical improvement was seen. The minimum inhibitory concentration for his Coccidioides immitis was 8 µg/mL for fluconazole and 0.25 µg/mL for voriconazole. No minimum inhibitory concentration was measured for itraconazole by our hospital’s microbiology laboratory.\n\nOur report presents a rare case of disseminated coccidioidomycosis in a young, relatively healthy male. This case highlights the importance of adjusting treatment regimens based on the symptoms and physical examination findings identified at initial presentation in order to prevent further dissemination of the disease and reduce the risk of morbidity and mortality.\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\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iDs: Ameesh Dev \nhttps://orcid.org/0000-0003-4441-6705\n\nJames Gnecco IV \nhttps://orcid.org/0000-0001-5054-0492\n==== Refs\nReferences\n1 \nAkram SM Koirala J. \nCoccidioidomycosis . StatPearls ; 2020 \nAccessed May 10, 2009 \nhttps://www.ncbi.nlm.nih.gov/books/NBK448161/\n2 \nGalgiani JN Ampel NM Blair JE , et al\n2016 Infectious Diseases Society of America (IDSA) clinical practice guideline for the treatment of coccidioidomycosis\n. Clin Infect Dis . 2016 ;63 :e112 -e146\n.27470238 \n3 \nMalik U Cheema H Kandikatla R , et al\nDisseminated coccidioidomycosis presenting as carcinomatosis peritonei and intestinal coccidioidomycosis in a patient with HIV\n. Case Rep Gastroenterol . 2017 ;11 :114 -119\n.28611563 \n4 \nBrown J Benedict K Park BJ Thompson GR 3rd \nCoccidioidomycosis: epidemiology\n. Clin Epidemiol . 2013 ;5 :185 -197\n.23843703 \n5 \nGarcia SCG Alanis JCS Flores MG Gonzalez SEG Cabrera LV Candiani JO \nCoccidioidomycosis and the skin: a comprehensive review\n. An Bras Dermatol . 2015 ;90 :610 -619\n.26560205 \n6 \nOdio CD Marciano BE Galgiani JN Holland SM. \nRisk factors for disseminated coccidioidomycosis, United States\n. Emerg Infect Dis . 2017 ;23 :308 -311\n.\n7 \nSantelli AC Blair JE Roust LR. \nCoccidioidomycosis in patients with diabetes mellitus\n. Am J Med . 2006 ;119 :964 -969\n.17071165 \n8 \nBercovitch RS Catanzaro A Schwartz BS Pappagianis D Watts DH Ampel NM. \nCoccidioidomycosis during pregnancy: a review and recommendations for management\n. Clin Infect Dis . 2011 ;53 :363 -368\n.21810749 \n9 \nCrum NF Lederman ER Hale BR Lim ML Wallace MR. \nA cluster of disseminated coccidioidomycosis cases at a US military hospital\n. Mil Med . 2003 ;168 :460 -464\n.12834136 \n10 \nAmpel NM. \nThe treatment of coccidioidomycosis\n. Rev Inst Med Trop Sao Paulo . 2015 ;57 (suppl 19 ):51 -56\n.26465370\n\n",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "disseminated coccidioidomycosis; insufficient treatment; pulmonary coccidioidomycosis; valley fever",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D003045:Coccidioides; D003047:Coccidioidomycosis; D003937:Diagnosis, Differential; D005334:Fever; D006801:Humans; D008172:Lung Diseases, Fungal; D008279:Magnetic Resonance Imaging; D008297:Male; D012871:Skin Diseases; D065819:Voriconazole",
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"title": "Disseminated Coccidioidomycosis Following Insufficient Treatment at Initial Presentation: Case Report.",
"title_normalized": "disseminated coccidioidomycosis following insufficient treatment at initial presentation case report"
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"abstract": "Invasive aspergillosis (IA) is increasingly diagnosed in high-risk patients. The lesions are usually located in the lungs and/or sinuses, and the fungus may spread haematogenously to different organs; however, involvement of the heart during IA is very rare. We describe a unique case of invasive aspergillosis of the heart septum and the lungs in the allogeneic haematopoietic stem cell transplant recipient.",
"affiliations": "Department of Microbiology, Public Central Teaching Hospital in Warsaw, Warsaw, Poland.;Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.;Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.;Department of Pathomorphology, Medical University of Warsaw, Warsaw, Poland.;Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.;Department of Microbiology, Public Central Teaching Hospital in Warsaw, Warsaw, Poland. zms1@wum.edu.pl.",
"authors": "Sulik-Tyszka|Beata|B|;Kacprzyk|Piotr|P|;Mądry|Krzysztof|K|;Ziarkiewicz-Wróblewska|Bogna|B|;Jędrzejczak|Wiesław|W|;Wróblewska|Marta|M|",
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"fulltext": "\n==== Front\nMycopathologiaMycopathologiaMycopathologia0301-486X1573-0832Springer Netherlands Dordrecht 1210.1007/s11046-016-0012-9ArticleAspergillosis of the Heart and Lung and Review of Published Reports on Fungal Endocarditis Sulik-Tyszka Beata Kacprzyk Piotr Mądry Krzysztof Ziarkiewicz-Wróblewska Bogna Jędrzejczak Wiesław Wróblewska Marta +48 22 5191776zms1@wum.edu.pl Department of Microbiology, Public Central Teaching Hospital in Warsaw, Warsaw, Poland Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland Department of Pathomorphology, Medical University of Warsaw, Warsaw, Poland Department of Dental Microbiology, Medical University of Warsaw, 1a Banacha Street, 02-097 Warsaw, Poland 31 5 2016 31 5 2016 2016 181 583 588 23 9 2015 25 4 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Invasive aspergillosis (IA) is increasingly diagnosed in high-risk patients. The lesions are usually located in the lungs and/or sinuses, and the fungus may spread haematogenously to different organs; however, involvement of the heart during IA is very rare. We describe a unique case of invasive aspergillosis of the heart septum and the lungs in the allogeneic haematopoietic stem cell transplant recipient.\n\nKeywords\nInvasive aspergillosisHeartLungStem cell transplantationAmphotericin Bissue-copyright-statement© Springer Science+Business Media Dordrecht 2016\n==== Body\nIntroduction\nPatients receiving chemo- and/or radiotherapy treated with glucocorticosteroids and immunosuppressive agents are at high risk of systemic fungal infection [1, 2]. Another high-risk group constitutes patients with acquired immune deficiency syndrome (AIDS), solid organ transplant (SOT) recipients and with congenital immune deficiencies [1]. At particularly high risk of systemic fungal infections, compared to other groups of patients, are patients hospitalised in haematological wards [3]. Risk factors for these infections are neutropaenia, particularly deep (<500 neutrophils/mm3) and long lasting (>7 days), and lymphopaenia, pertaining especially to CD4+ cells.\n\nHowever, the highest risk of systemic fungal infections is reported in the recipients of allogeneic haematopoietic stem cell transplants [2]. Furthermore, graft-versus-host disease (GVHD) and its treatment with corticosteroids make these patients susceptible to fungal infections caused by moulds classified in the genus Aspergillus or yeast-like fungi of Candida spp. [4]. Moreover, in the aspect of defective immune response, the chronic form of GVHD causes functional asplenia in these patients.\n\nThe most common aetiological factors of invasive fungal infection (IFI) remain Candidaalbicans and Aspergillus fumigatus [3]. The broad use of fluconazole in prophylaxis of these infections caused an increase in isolation rates of Candida non-albicans strains as well as a further increase in frequency of Aspergillus spp. infections. Among patients with invasive aspergillosis with pneumonia and sinusitis, with subsequent haematogenous spread to other organs, mortality may reach 80–90 % [5–10].\n\nCase Report\nA 45-year-old man was admitted as an emergency to the haematology ward because of fever, nausea, vomiting, diarrhoea and severe prostration, which have been lasting for several days. The patient suffered from a mantle cell lymphoma and was in the 45th day after allogeneic transplantation of haematopoietic stem cells (alloHSCT) from a related donor, after myeloablative conditioning. On physical examination tachycardia, hypotension, high levels of inflammatory markers and marked dehydration were detected. Laboratory tests showed acute renal insufficiency of complex aetiology: prerenal (due to dehydration) and intrinsic—with the symptoms of thrombotic thrombocytopenic purpura (TTP) and kidney damage, which resulted from cyclosporine nephrotoxicity. In histopathological examination of biopsy specimens obtained during sigmoidoscopy, acute graft-versus-host disease (aGVHD) had been diagnosed. During high-resolution computed tomography (HR-CT) scan of the chest, a typical radiological picture of pulmonary mycosis was detected. Galactomannan (GM) has been detected in the patient’s serum, while the test for the presence of GM in the bronchoalveolar lavage (BAL) fluid was not done. Therapy with lipid complex amphotericin B was administered (5 mg/kg/day), and control examinations showed a slow regression of inflammatory lesions in the lungs. Due to a marked fur on oral mucous membranes, several mycological cultures were done, which yielded the growth of Pichia kluyveri and Candida albicans. Mycological cultures of BAL and sputum were negative. Treatment with lipid complex amphotericin B was continued.\n\nDuring subsequent weeks of hospitalisation, the patient was treated for hypogammaglobulinaemia, reactivation of cytomegalovirus (CMV), Epstein–Barr virus (EBV) and adenovirus in peripheral blood, as well as for Giardia lamblia infection of the gastrointestinal tract. He was also diagnosed with papillary carcinoma of the thyroid gland, for which strumectomy was performed. Two episodes of ileus were recorded during hospital stay.\n\nDuring the patient’s hospitalisation, several evaluations of post-transplant chimerism were done. Results of all tests (done on peripheral blood and on bone marrow samples taken >100 days after alloPBSCT) were normal. Myelogram of the trepanobiopsy specimen revealed dysmegakaryopoiesis; however, phenotyping of the bone marrow cells did not show lymphoma relapse. Cytogenetic tests also did not show aberrations. HR-CT scans of the chest, abdominal cavity and neck were performed in search for possible relapse of the basic disease. A single enlarged (dimension of 19 mm), probably reactive, lymph node was detected in the abdominal cavity.\n\nDue to episodes of septic shock, the patient was treated with antibiotics (imipenem, colistin, linezolid, tigecycline), an antiviral agent (acyclovir) and a lipid complex of amphotericin B, as well as a granulocyte colony stimulating factor (G-CSF). At that stage, laboratory tests showed increasing levels of inflammatory markers as well as increasing lactic acidosis and its respiratory compensation. The patient required oxygen therapy.\n\nPulmonary embolism was excluded during bedside echocardiography examination. The lipid complex of amphotericin B was temporarily discontinued (after 93 days of therapy) in fear for development of acidosis as an unwanted effect of this antifungal agent (renal canalicular and tubular acidosis). Furthermore, clinical symptoms of acute pancreatitis and a sudden increase in pancreatic enzyme levels had been recorded. During subsequent days, the patient suffered from increasing shortness of breath; however, in a chest X-ray examination neither obvious parenchymal lung lesions nor haemostasis in the pulmonary circulation had been detected. After nephrological consultation of the patient, a dialysis catheter had been inserted into the femoral vein, and therefore, amphotericin B therapy was not continued. Due to an increasing metabolic acidosis (pH 7.3) and lactate levels, symptoms of acute pancreatitis and persistent paralytic ileus, a CT scan of the abdominal cavity was performed to exclude mesenteric artery thrombosis and intestinal ischaemia as a possible cause of these abnormalities. However, no mesenteric embolism or clear signs of acute pancreatitis were detected. There were also no indications for surgical intervention. The patient’s condition continued to deteriorate, and he was transferred to the intensive care unit (ICU). On admission to the ICU, his condition was severe, with borderline respiratory function. His status of consciousness was assessed as score 14 of the Glasgow Coma Scale (GCS). Haemodialysis was performed; however, despite intensive therapy, hypoglycaemia and acidosis were deepening and the patient died.\n\nBlood culture of a sample obtained just before his death had shown the presence of non-fermenting Gram-negative rod Brevundimonas nasdae. No fungi were cultured. An autopsy examination revealed marked hyperaemia and tissue oedema in both lungs, as well as irregular regions of increased consistency, particularly in the lower lobes of both lungs. Microscopically, the lesions had been described as organising abscesses with necrosis in the central zone and the presence of hyphae typical for Aspergillus spp. (Fig. 1). In the interventricular septum of the heart, hypertrophy of single cardiomyocytes had been noted, as well as an abscess with Aspergillus spp. hyphae present within the central necrosis zone (Figs. 2, 3, 4).Fig. 1 Lung: necrosis within the Aspergillus spp. mycelium. Haematoxylin and eosin staining. Magnification ×40\n\nFig. 2 Heart: spherical mycelium of Aspergillus spp. with cardiomyocytes visible around it. Haematoxylin and eosin staining. Magnification ×40\n\nFig. 3 Heart: Aspergillus spp. mycelium with branching hyphae. Small mixed inflammatory infiltrations seen around it. Haematoxylin and eosin staining. Magnification ×100\n\nFig. 4 Heart: radial arrangement of Aspergillus spp. hyphae. Grocott’s methenamine silver staining. Magnification ×100\n\n\n\nDiscussion\nIn the described case, allogeneic transplantation of peripheral blood haematopoietic stem cells (alloPBHSCT) constituted a major risk factor for IFI caused by moulds classified in the genus Aspergillus. Fungal lesions with hyphae characteristic for Aspergillus spp. had been detected in anatomopathological investigations both in the heart and in the lungs, despite treatment of the patient with amphotericin B, according to the Infectious Diseases Society of America (IDSA) guidelines. Furthermore, after transplantation the patient suffered from GVHD. This complication develops in 60–80 % of alloHSCT recipients. It results from a reaction of allogeneic T lymphocytes, derived from the transplanted cells and directed against the recipient’s antigens.\n\nA disease developing within 100 days after transplantation is called an acute GVHD. In the case of alloHSCT, recipients remain in deep immunosuppression, which makes them prone to IFIs, caused by yeast-like fungi of the genus Candida, as well as by moulds Aspergillus spp. [4]. The most common is invasive aspergillosis (3–14 %). The fungal spores of Aspergillus are inhaled; therefore, the most common clinical forms are infections of the respiratory tract and systemic infections, involving all types of organs, including the heart, although this location is very rare [11–14].\n\nInvasive aspergillosis often begins with invasion of the blood vessels; their obstruction caused by thrombus with mycelium, as well as with haemorrhagic infarctions, which are very characteristic for this type of infections [15]. The infarction zone comprises ischaemic necrosis caused by blood vessel blockage. Hyphae of the mould are seen within the necrotic tissues. Haematogenous spread may involve the brain, heart, kidneys and gastrointestinal tract mucous membranes. The presence of Aspergillus hyphae in the tissue justifies the diagnosis of invasive aspergillosis; however, it is recommended to send such material also for mycological culture for species identification.\n\nBapat and Young [16] reported a case of fungal endocarditis in a 73-year-old man, in whom this complication followed surgical replacement of the aortic valve and coronary artery bypass surgery (Table 1). A diagnosis of fungal endocarditis on clinical grounds alone is very difficult because of non-specific symptoms, such as fever (72 %), embolic episodes (69 %), new or changing heart murmurs (41 %) or sudden visual loss (13 %) [17]. Diagnosis is further complicated by the fact that blood cultures are usually negative [2, 3]. Unfortunately, very often a diagnosis is made at post-mortem examination. In the described case, a laboratory diagnosis was made on the basis of histopathological tests of the thrombus removed during embolectomy, as endocarditis may rarely cause emboli in the peripheral blood vessels. To avoid a relapse of the fungal infection, it is recommended to perform surgery and administer long-term antifungal therapy with amphotericin B [16].Table 1 Published reports on fungal endocarditis\n\nPublication [ref. no.]\tClinical presentation\tLaboratory diagnosis\t\nBapat and Young [16]\tFungal endocarditis in a 73-year-old man, after surgical replacement of the aortic valve and coronary artery bypass surgery\tHistopathological examination of the thrombus removed during embolectomy\t\nAlvarez et al. [18]\tFungal endocarditis in a 12-year-old girl with acute lymphoblastic leukaemia at haematological remission\tVegetations detected in echocardiography; culture of the vegetation removed during surgery (growth of A. terreus)\t\nAbuzaid et al. [19]\tFungal endocarditis in a 64-year-old woman who 1 month earlier underwent mitral valve repair surgery\tSevere mitral regurgitation observed in echocardiography; isolation of a strain of A. fumigatus from the heart valve removed during surgery\t\nSatish et al. [20]\tExtensive cardiothoracic aspergillosis in a 47-year-old man no risk factors for immunosuppression\tEchocardiography, magnetic resonance imaging and computed tomography: extensive infiltration of the atria and ventricles by the mediastinal lesion; histopathological examination of the subcutaneous nodule on the chest revealed Aspergillus granuloma (growth of A. fumigatus in culture); fine-needle aspiration cytology from the mediastinum revealed Aspergillus granuloma; no fungal mycelium was detected in the endomyocardial biopsy from the right atrial side of the atrial septum\t\n\n\nAlvarez et al. [18] described a case of a 12-year-old girl with acute lymphoblastic leukaemia at haematological remission, hospitalised due to fever, nausea, vomiting, abdominal pains and pancytopaenia. Upon admission, a combined antimicrobial therapy with vancomycin, gentamycin and amphotericin B was started. During echocardiography, masses had been noticed in the apex of the left ventricle of the heart. She underwent surgery, and culture of clinical specimens revealed the growth of Aspergillus terreus. Embolic infarctions of the spleen, liver and the kidneys were detected in CT. There were no symptoms or signs of relapse of endocarditis caused by Aspergillus spp.; however, 28 days after surgery she suffered from severe headaches and dizziness. CT scan showed cerebral haemorrhage, which comprised the right temporal lobe of the brain. The patient died the following day. Due to an increasing number of patients treated with immunosuppressive agents, as well as an increase in frequency of fungal infections caused by Aspergillus strains, early diagnosis and proper antifungal therapy increase the chance for patients’ survival. However, in the described case the patient died despite rapid surgical intervention. It is therefore important to stress that fungal endocarditis in patients with acute leukaemia may compromise their prognosis and decrease the rate of survival [18].\n\nAbuzaid et al. [19] published a case of a 64-year-old woman admitted to an emergency ward due to acute respiratory failure, with several underlying diseases: diabetes, arterial hypertension and hypercholesterolaemia. Severe mitral regurgitation was observed in echocardiography, and the patient was qualified for surgical valve replacement. Vancomycin and gentamycin were administered as empiric therapy. Several days later, aspergillosis of the heart was confirmed by the isolation of a strain of A. fumigatus from her heart valve removed during surgery and treatment was changed to intravenous voriconazole. Both rapid surgical intervention and proper antifungal therapy improve prognosis of patients with infective endocarditis caused by Aspergillus spp. Similarly, early administration of proper antifungal therapy and fast surgical intervention also improve the chance for survival of patients with invasive aspergillosis of the heart. However, due to non-specific clinical symptoms (fever, episodes of thrombosis, heart murmurs) additional tests—such as histopathology, echocardiography, mycological cultures and serological assays—are useful [2].\n\nSatish et al. [20] described a case of cardiothoracic aspergillosis, although no fungal mycelium was detected in the heart. We report a case of invasive aspergillosis located in the interventricular septum of the heart and in both lungs of an immunocompromised patient. On histopathological examination, hyphae typical for Aspergillus spp. were observed. The patient died despite therapy with amphotericin B, according to the IDSA guidelines. Recently it has been suggested that combination therapy with voriconazole and anidulafungin may improve the outcome of IA [21]. It is known that strains of Aspergillus spp. may form a biofilm, which might be disrupted by echinocandins, while azoles do not penetrate it.\n\nDue to an increasing number of patients on immunosuppressive therapy and an increase in frequency of cases of invasive aspergillosis, in each case of probable infection of this aetiology, other tests (such as histopathology, imaging, non-culture diagnostic assays)—apart from clinical signs and symptoms—are recommended, as they may help with earlier diagnosis and improved survival of these patients [3, 19, 22].\n==== Refs\nReferences\n1. Baddley JW Clinical risk factors for invasive aspergillosis Med Mycol 2011 49 Suppl. 1 S7 S12 10.3109/13693786.2010.505204 20718606 \n2. Marr KA Carter RA Boeckh M Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors Blood 2002 100 13 4358 4366 10.1182/blood-2002-05-1496 12393425 \n3. Barton RC Laboratory diagnosis of invasive aspergillosis: from diagnosis to prediction of outcome Scientifica 2013 24278780 \n4. Labbe AC Su SH Laverdiere M Pepin J Patino C Cohen S Kiss T Lachance S Sauvageau G Busque L Roy DC Roy J High incidence of invasive aspergillosis associated with intestinal graft-versus-host disease following nonmyeloablative transplantation Biol Blood Marrow Transplant 2007 13 10 1192 1200 10.1016/j.bbmt.2007.06.013 17889356 \n5. Norkin M, Wingard JR. Invasive fungal infections in patients with acute leukemia and hematopoietic stem cell transplant recipients. In: Gholamrezanezhad A, editor. Stem cells in clinic and research. InTech. 2011. doi:10.5772/22537.\n6. Rovira M, Mensa J, Carreras E. Infections after HSCT. In: Apperley J, Carreras E, Gluckman E, Masszi T, editors. The ESH-EBMT handbook on haematopoietic stem cell transplantation. 6th ed., chap 12. ESH (European School of Haematology); EBMT (European Society for Blood and Marrow Transplantation); 2012. p. 196–215. https://ebmtonline.forumservice.net/media/12/tex/content_alt/EBMT_Handbook2012_CHAP12.pdf.\n7. Garcia-Vidal C Upton A Kirby KA Marr KA Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation Clin Infect Dis 2008 47 1041 1050 10.1086/591969 18781877 \n8. Neofytos D Horn D Anaissie E Steinbach W Olyaei A Fishman J Pfaller M Chang C Webster K Marr K Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) alliance registry Clin Infect Dis 2009 48 3 265 273 10.1086/595846 19115967 \n9. Seferyńska I Pałynyczko G Warzocha K Invasive fungal infections: etiology, diagnosis and new therapeutic options Acta Haematol Pol 2005 36 1 45 54 \n10. Tomblyn M Chiller T Einsele H Gress R Sepkowitz K Storek J Wingard JR Young JA Boeckh MJ Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective Biol Blood Marrow Transplant 2009 15 10 1143 1238 10.1016/j.bbmt.2009.06.019 19747629 \n11. Pappas PG Kauffman A Andes D Benjamin DK Jr Calandra TF Edwards JE Jr Filler SG Fisher JF Kullberg BJ Ostrosky-Zeichner L Reboli AC Rex JH Walsh TJ Sobel JD Infectious Diseases Society of America Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America Clin Infect Dis 2009 48 5 503 535 10.1086/596757 19191635 \n12. Dykiewicz CA Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients Clin Infect Dis 2001 33 139 144 10.1086/321805 11418871 \n13. Bow EJ Invasive fungal infection in haematopoietic stem cell transplant recipients: epidemiology from the transplant physician’s viewpoint Mycopathologia 2009 168 6 283 297 10.1007/s11046-009-9196-6 19343534 \n14. Marks DI Pagliuca A Kibbler CC Glasmacher A Heussel CP Kantecki M Miller PJ Ribaud P Schlamm HT Solano C Cook G IMPROVIT Study Group Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem–cell transplantation Br J Haematol 2011 155 3 318 327 10.1111/j.1365-2141.2011.08838.x 21880032 \n15. Guarner J Brandt ME Histopathologic diagnosis of fungal infections in the 21st century Clin Microbiol Rev 2011 24 2 247 280 10.1128/CMR.00053-10 21482725 \n16. Bapat V Young C Aspergillus endocarditis presenting as massive peripheral embolism following open heart surgery EJVES Extra 2005 10 1 27 29 10.1016/j.ejvsextra.2005.04.014 \n17. Sorrell VL Koutlas TC Ohl C Fungal endocarditis at the aortotomy site after aortic valve replacement Clin Cardiol 2000 23 387 389 10.1002/clc.4960230518 10803451 \n18. Alvarez JR Quiroga JS Taboada CR Gonzalez AF Torres FM Garcia-Bengochea J Cardiac aspergillosis with pedunculated mass in the left ventricle Tex Heart Inst J 2004 31 4 439 441 15745301 \n19. Abuzaid AA Zaki M Tarif H Atypical early Aspergillus endocarditis post prosthetic mitral valve repair: a case report Heart Views 2015 16 1 30 33 10.4103/1995-705X.152999 25838877 \n20. Satish OS Alfred JM Sundaram C Rao DS Extensive invasive cardiothoracic aspergillosis Circulation 2006 114 e562 e563 10.1161/CIRCULATIONAHA.106.632554 17075019 \n21. Marr KA Schlamm HT Herbrecht R Rottinghaus ST Bow EJ Cornely OA Heinz WJ Jagannatha S Koh LP Kontoyiannis DP Lee DG Nucci M Pappas PG Slavin MA Queiroz-Telles F Selleslag D Walsh TJ Wingard JR Maertens JA Combination antifungal therapy for invasive aspergillosis: a randomized trial Ann Intern Med 2015 162 2 81 89 10.7326/M13-2508 25599346 \n22. Arvanitis M Mylonakis E Diagnosis of invasive aspergillosis: recent developments and ongoing challenges Eur J Clin Invest 2015 45 6 646 652 10.1111/eci.12448 25851301\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0301-486X",
"issue": "181(7-8)",
"journal": "Mycopathologia",
"keywords": "Amphotericin B; Heart; Invasive aspergillosis; Lung; Stem cell transplantation",
"medline_ta": "Mycopathologia",
"mesh_terms": "D001230:Aspergillus; D004696:Endocarditis; D018380:Hematopoietic Stem Cell Transplantation; D006651:Histocytochemistry; D006801:Humans; D016867:Immunocompromised Host; D055744:Invasive Pulmonary Aspergillosis; D008168:Lung; D008297:Male; D008853:Microscopy; D008875:Middle Aged; D009206:Myocardium; D014184:Transplantation, Homologous",
"nlm_unique_id": "7505689",
"other_id": null,
"pages": "583-8",
"pmc": null,
"pmid": "27245170",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15745301;19115967;20718606;25851301;21482725;10803451;24278780;11418871;25838877;12393425;19343534;19747629;18781877;17075019;17889356;25599346;21880032;19191635",
"title": "Aspergillosis of the Heart and Lung and Review of Published Reports on Fungal Endocarditis.",
"title_normalized": "aspergillosis of the heart and lung and review of published reports on fungal endocarditis"
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"abstract": "Acute retinal necrosis (ARN) is a rapidly progressive and severe retinitis resulting in a poor visual outcome. Infections caused by herpes viruses such as herpes simplex virus (HSV) types 1 and 2 or the varicella zoster virus (VZV) are known to be implicated in the development of ARN. In the present study, an 80-year-old female with ARN was examined. She had been affected with rheumatoid arthritis and had taken methotrexate for over 10 years. Her right eye showed clinical features of ARN, and her left eye showed mild retinitis. The genomic DNA in the aqueous humor and vitreous fluid from her right eye were analyzed by a comprehensive polymerase chain reaction (PCR) assay to screen infectious pathogens including viruses. The Epstein-Barr virus (EBV) was detected from both specimens, but neither HSV or VZV nor cytomegalovirus was detected. She underwent intraocular surgery following systemic corticosteroid and acyclovir applications. However, although the retinitis of her right eye was extinguished, the final visual outcome was blindness due to optic nerve atrophy. There are few reports indicating that EBV is associated with ARN development. The present findings suggest that EBV alone can be the causative agent of ARN.",
"affiliations": "Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.;Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.;Department of Ophthalmology, JR Sapporo Hospital, Sapporo, Hokkaido, Japan.;Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan.",
"authors": "Oe|Chiaki|C|;Hiraoka|Miki|M|;Tanaka|Sachie|S|;Ohguro|Hiroshi|H|",
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"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000445372cop-0007-0195Published online: April, 2016Acute Retinal Necrosis Associated with Epstein-Barr Virus in a Patient Undergoing Immunosuppressive Therapy Oe Chiaki aHiraoka Miki a*Tanaka Sachie bOhguro Hiroshi aaDepartment of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, JapanbDepartment of Ophthalmology, JR Sapporo Hospital, Sapporo, Hokkaido, Japan*Miki Hiraoka, MD, PhD, Department of Ophthalmology, School of Medicine, Sapporo Medical University, S1 W16 Chuo-ku, Sapporo, Hokkaido 060-8543 (Japan), E-Mail mikihira@sapmed.ac.jpJan-Apr 2016 12 4 2016 12 4 2016 7 1 195 201 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Acute retinal necrosis (ARN) is a rapidly progressive and severe retinitis resulting in a poor visual outcome. Infections caused by herpes viruses such as herpes simplex virus (HSV) types 1 and 2 or the varicella zoster virus (VZV) are known to be implicated in the development of ARN. In the present study, an 80-year-old female with ARN was examined. She had been affected with rheumatoid arthritis and had taken methotrexate for over 10 years. Her right eye showed clinical features of ARN, and her left eye showed mild retinitis. The genomic DNA in the aqueous humor and vitreous fluid from her right eye were analyzed by a comprehensive polymerase chain reaction (PCR) assay to screen infectious pathogens including viruses. The Epstein-Barr virus (EBV) was detected from both specimens, but neither HSV or VZV nor cytomegalovirus was detected. She underwent intraocular surgery following systemic corticosteroid and acyclovir applications. However, although the retinitis of her right eye was extinguished, the final visual outcome was blindness due to optic nerve atrophy. There are few reports indicating that EBV is associated with ARN development. The present findings suggest that EBV alone can be the causative agent of ARN.\n\nKey Words\nAcute retinal necrosisEpstein-Barr virusMethotrexatePolymerase chain reaction\n==== Body\nIntroduction\nAcute retinal necrosis (ARN) was first described in 1971 [1]. The typical clinical features of ARN include anterior uveitis and various retinal changes such as multifocal exudation, occlusive vasculopathy, retinal edema, retinal necrosis starting from the peripheral retina and extending to its posterior area, dense vitreous clouding and optic neuropathy. It can be unilateral or bilateral. The etiology of ARN is thought to be related to the retinal viral reactivation. The most common cause is the Herpesviridae family, particularly the varicella zoster virus (VZV) and herpes simplex virus (HSV) types 1 and 2 [2, 3].\n\nThe Epstein-Barr virus (EBV) is a DNA virus of the Herpesviridae family. It is believed that more than 90% of the subjects infected with EBV transmit it orally or through blood. EBV is known to cause mononucleosis syndrome and is also associated with Burkitt lymphoma and nasopharyngeal carcinoma. The virus exhibits affinity to B lymphocytes and nasopharyngeal epithelial cells [4]. However, primary infection with EBV in childhood is commonly subclinical, and in most cases, EBV-infected B lymphocytes are latent. The clinical symptoms in adulthood are magnified when the EBV in infected B cells is reactivated. The viral reactivation is often observed in an immunosuppressive state. The clinical feature of ocular disease by EBV infection is not clear.\n\nAlthough the diagnosis of ARN is made by its typical ocular features, the examination of pathogens, especially herpes viruses, is important. For the last decade, the advances made in molecular analytical techniques, including genomic screening of multiple pathogens, were remarkable. It is now more preferable to test focal samples rather than conducting a serum antibody titer for viruses. The multiplex polymerase chain reaction (PCR) system has made it possible to detect multiple pathogens from small volume samples such as those in the aqueous humor and vitreous fluid [5]. The ample evidence of herpes virus existing in ocular fluid or ocular tissues can lead to a greater understanding of the etiology of ARN [6].\n\nIn this report, we describe a case of ARN in which EBV was detected in intraocular fluid. These findings suggest that EBV is implicated as a cause of ARN.\n\nCase Presentation\nThe medical records of our patient with ARN were retrospectively reviewed. An 80-year-old woman developed blurred vision in both eyes 1 month before presenting to JR Sapporo Hospital. Upon entering, an examination found evidence of iritis, vitreous opacity, a mild vitreous hemorrhage and extensive multifocal exudation around the optic disc in her right eye (fig. 1a), as well as mild vitreous opacity, an optic disc hemorrhage and peripheral white granulomatous exudation in her left eye (fig. 1b). A fluorescein fundus angiography demonstrated hyperfluorescence of the optic disc and a wide range of occlusive vasculitis in her right eye (fig. 1c), and retinal vasculitis in the nasal area in her left eye (fig. 1d). The aqueous humor of the right eye was subsequently collected for pathogen analysis by the PCR system. Since the serological analysis was positive for cytomegalovirus (CMV) IgG, she was presumed to have CMV retinitis. She received ganciclovir (75 mg/day) orally, but this triggered no effective response. The uveoretinitis in her right eye deteriorated, and after 1 week, she was transferred to our hospital. Upon admittance, she disclosed that she had been taking oral methotrexate for over 10 years for rheumatoid arthritis.\n\nThe initial ophthalmic examination showed a best-corrected visual acuity of light perception in the right eye and 20/25 in the left eye. The intraocular pressure was 13 mm Hg in the right eye and 10 mm Hg in the left eye. A slit-lamp examination demonstrated moderate cell infiltration in the anterior chamber, severe vitreous infiltration, an inferior vitreous hemorrhage and massive exudation in the posterior pole in her right eye. There was no sign of apparent progression in her left eye (fig. 1f). Both eyes showed substantial anterior chamber depth without goniosynechia, and mild senile cataracts.\n\nResults of the laboratory investigations of serum including antinuclear antibodies, anti-double stranded DNA antibodies, an adult T-cell leukemia antigen and antineutrophil cytoplasmic antibodies were unremarkable except for a high rheumatoid factor value. Serological analyses indicated that there was no active infection of syphilis, tuberculosis, human T-cell lymphoma virus 1 or toxoplasma gondii. The virus antibody titer screen was negative for IgM and positive for IgG for HSV, VZV, and CMV. The EBV antibody test showed negative for either IgG against an early antigen or IgM against a viral capsid antigen and positive for both IgG against a viral capsid antigen and IgG against a nuclear antigen.\n\nThe patient received continuous administration of topical betamethasone and intravenous aciclovir (700 mg/day) upon admission. Due to the progressive symptoms in her right eye, vitrectomy, retinal photocoagulation and silicone oil tamponade were applied, and phacoemulsification surgery was conducted 5 days after admission. The fundus findings during surgery showed the occlusive vasculopathy of the entire retina, retinal fibrosis and retinal detachment with retinal breaks and vitreous traction (fig. 1e). The vitreous fluid was collected for cytology and pathogen screening. The cytological examination of infiltrated cells in vitreous fluid showed lymphocytes and a few neutrophils but no atypical cells. The culture examination using vitreous fluid was negative for bacteria or fungus. The genomic DNA in vitreous fluid was analyzed by comprehensive PCR to screen infectious pathogens including bacteria, parasites and viruses. The PCR analysis was performed in the laboratory for retinal regeneration at Riken's Center for Developmental Biology (Kobe, Japan), as previously described [5].\n\nBoth the aqueous humor that was collected at the former hospital and vitreous fluid that was collected during surgery showed high copies of EBV but were negative to HSV, VZV, CMV and other pathogens (table 1). Two days after surgery, the patient received oral valaciclovir (1,500 mg/day) and predonisolone (30 mg/day). The dosage of valaciclovir and predonisolone administration was reduced gradually without recurrence of retinitis or development of side effects. Retinal atrophy occurred in her right eye in the necrosis area, and optic nerve atrophy also developed. This resulted in a loss of light perception in the eye. The lesion in her left eye was diminished by the drug treatment. No relapse was observed in 1 year.\n\nDiscussion\nIn this report, we described a case of ARN. The genomic DNA analysis for virus testing of intraocular fluids showed a high copy number of EBV but was negative for HSV and VZV.\n\nThe clinical diagnosis of ARN is based on its characteristic ocular outcome. In addition, the high frequency in detecting VZV and HSV in intraocular fluid or tissues leads to the belief that the causative pathogens of ARN are VZV and HSV [2, 3, 7]. Since the predilection age of ARN is during adulthood, it is thought that the development of ARN is introduced by reactivation of latent viruses such as VZV and HSV. Due to advances in genomic DNA analysis, it is possible to screen pathogens using small sizes of local specimens. These results help elucidate the etiology of many diseases. In intraocular inflammation, the pathogen screening of the aqueous humor and vitreous fluid is not only harmless but also informative in the diagnosis and determination of the treatment. Recently, Sugita et al. [5] developed a two-step PCR protocol to examine multiple pathogens from small-volume ocular fluids. The first step is to screen the genomic DNA of several pathogens by multiplex PCR. Every positive pathogen detected by multiplex PCR is then examined by real-time PCR for quantification of the pathogen load. In ARN, high copy numbers of HSV and VZV can be detected through this method [6]. This emphasizes that the reactivation of HSV or VZV in the eye is responsible for the development of ARN. In our case, several pathogens in ocular fluid were examined using this two-step PCR.\n\nThe initial infection of EBV is thought to occur in young children without any symptoms or with acute inflammatory diseases that are not recognized as being due to EBV. The major host cells of EBV are B lymphocytes, and infected B cells are persistent throughout life. However, EBV in infected B cells is mostly latent. Although the trigger has yet to be clarified, latent infected B cells can be stimulated to reactivate EBV, which results in the production of a large number of viruses [4]. The EBV reactivation is often observed in individuals undergoing immunosuppression. It is speculated that immunosuppression, either by medication or illness, makes the immune system lose control of EBV replication.\n\nEBV DNA was detected even in ocular tissues from healthy donors by PCR [8]. This suggests that the large amount of EBV production by reactivation in the eye can lead to the development of intraocular diseases such as uveitis [9]. Previously, some uveitis cases were reported to be associated with EBV from the profile of EBV antibody titers in serum and the aqueous humor [10, 11]. In a recent report, patients receiving long-term systemic corticosteroids showed a high copy number of EBV DNA with severe intraocular inflammation [9].\n\nThere have been recent reports on the involvement of EBV in ARN. Several studies showed that EBV DNA was found in the ocular fluid of ARN patients who were also positive to VZV DNA [2, 3, 6, 9]. Those patients in whom both VZV and EBV were detected developed more severe symptoms than those with VZV alone [6].\n\nHowever, there are also reports stating that only EBV is associated with ARN development. In these reports, EBV DNA was detected from ocular fluid and retinal tissues that were absent from HSV, VZV or CMV [12, 13, 14]. Among these cases, 1 patient was affected with a lymphoproliferative disorder, and another patient was receiving systemic methylprednisolone and infliximab. It is likely that the long-term application of methotrexate induced a reactivation of EBV in the eyes of our case. The virus load of the aqueous humor and vitreous fluid showed a high copy number of EBV (2.07 × 105 [5] and 5 × 106 copies/ml, respectively), with a lack of other pathogens. These results indicate that EBV alone is associated with the development of ARN in our case. The ophthalmic outcome of the right eye in our case was typical of ARN, other than the retinal necrosis lesions being severe in the peripapillary rather than peripheral area. Usui and Sakai [10] reported that the vasculitis is prominent in the peripapillary area in EBV-associated uveitis. It is possible that pathological change is dominant in the peripapillary area in EBV associated with ARN. The causative pathogens of ARN are known as VZV and HSV. Although to date there have been few cases of EBV-associated ARN, even with the addition of our present study, our results are informative in that they show that EBV activation in ocular tissue can lead to the development of ARN. Reviewing the characteristic traits among those EBV-associated ARN cases should help lead to a greater understanding of the pathology of ARN.\n\nThe present findings suggest EBV alone can cause ARN, especially in individuals undergoing immunosuppression. Because EBV exists in unaffected tissues, it is important to determine the pathogenic value of the virus load from local samples. Further investigation with increased numbers of case studies and statistical analysis may lead to the establishment of reliable criteria for EBV-associated ARN.\n\nStatement of Ethics\nThe present study protocol was approved by the Ethics Committee of the Sapporo Medical University School of Medicine.\n\nDisclosure Statement\nThe authors declare that they have no conflicts of interest.\n\nAcknowledgement\nWe would like to thank Dr. Sunao Sugita from the Laboratory for Retinal Regeneration at the Riken Center for Developmental Biology for his pathogen analysis by PCR.\n\nTable 1 Results of pathogen analysis by multiplex PCR in ocular fluids of the patient\n\nPathogen\tAqueous humor\tVitreous fluid\t\nHSV type 1\tN.D.\tN.D.\t\nHSV type 2\tN.D.\tN.D.\t\nVZV\tN.D.\tN.D.\t\nCMV\tN.D.\tN.D.\t\nEBV\t2.07 × 105 copies/ml\t5.0 × 106 copies/ml\t\nToxoplasma gondii\tN.D.\tN.D.\t\nTuberculosis\tN.P.\tN.D.\t\nCandida\tN.P.\tN.D.\t\nN.D. = Not detected; N.P. = not performed.\n\nFig. 1 Fundus photographs and fluorescein fundus angiography. a Fundus photographs of the right eye with vitreous opacity, a mild vitreous hemorrhage and extensive multifocal exudation around the optic disc. b Fundus photographs of the left eye with mild vitreous opacity, an optic disc hemorrhage and peripheral white granulomatous exudation. c Fluorescein fundus angiography of the right eye with hyperfluorescence of the optic disc and a wide range of occlusive vasculitis. d Fluorescein fundus angiography of the left eye with retinal vasculitis in the nasal area. e Fundus photographs of the right eye, showing the occlusive vasculopathy with multiple hemorrhages and exudation of the entire retina and retinal fibrosis. f Fundus photographs of the right eye without any sign of apparent progression.\n==== Refs\nReferences\n1 Urayama A Yamada N Sasaki T Nishiyama Y Watanabe H Wakusawa S Unilateral acute uveitis with retinal periarteritis and detachment. Rinsho Ganka 1971 25 607 619 \n2 Lau CH Missotten T Salzmann J Lightman SL Acute retinal necrosis features, management, and outcomes. Ophthalmology 2007 114 756 762 17184841 \n3 Hillenkamp J Nolle B Bruns C Rautenberg P Fickenscher H Roider J Acute retinal necrosis: clinical features, early vitrectomy, and outcomes. Ophthalmology 2009 116 1971 1975e2 19592111 \n4 Odumade OA Hogquist KA Balfour HH Jr Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev 2011 24 193 209 21233512 \n5 Sugita S Shimizu N Watanabe K Use of multiplex PCR and real-time PCR to detect human herpes virus genome in ocular fluids of patients with uveitis. Br J Ophthalmol 2008 92 928 932 18408082 \n6 Sugita S Iwanaga Y Kawaguchi T Detection of herpesvirus genome by multiplex polymerase chain reaction (PCR) and real-time PCR in ocular fluids of patients with acute retinal necrosis. Nippon Ganka Gakkai Zasshi 2008 112 30 38 18240601 \n7 Takase H Okada AA Goto H Development and validation of new diagnostic criteria for acute retinal necrosis. Jpn J Ophthalmol 2015 59 14 20 25492579 \n8 Chodosh J Gan YJ Sixbey JW Detection of Epstein-Barr virus genome in ocular tissues. Ophthalmology 1996 103 687 690 8618773 \n9 Yamamoto S Sugita S Sugamoto Y Shimizu N Morio T Mochizuki M Quantitative PCR for the detection of genomic DNA of Epstein-Barr virus in ocular fluids of patients with uveitis. Jpn J Ophthalmol 2008 52 463 467 19089567 \n10 Usui M Sakai J Three cases of EB virus-associated uveitis. Int Ophthalmol 1990 14 371 376 2174420 \n11 Wong KW D'Amico DJ Hedges TR III Soong HK Schooley RT Kenyon KR Ocular involvement associated with chronic Epstein-Barr virus disease. Arch Ophthalmol 1987 105 788 792 3034222 \n12 Hamam RN Mansour A El Mollayess G Positive Epstein-Barr virus polymerase chain reaction in a case of acute retinal necrosis. Can J Ophthalmol 2012 47 e61 e62 23217525 \n13 Schaal S Kagan A Wang Y Chan CC Kaplan HJ Acute retinal necrosis associated with Epstein-Barr virus: immunohistopathologic confirmation. JAMA Ophthalmol 2014 132 881 882 24743882 \n14 Hershberger VS Hutchins RK Witte DP Schneider S Harris RE McGonegle SJ Epstein-Barr virus-related bilateral acute retinal necrosis in a patient with X-linked lymphoproliferative disorder. Arch Ophthalmol 2003 121 1047 1049 12860814\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "7(1)",
"journal": "Case reports in ophthalmology",
"keywords": "Acute retinal necrosis; Epstein-Barr virus; Methotrexate; Polymerase chain reaction",
"medline_ta": "Case Rep Ophthalmol",
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"pages": "195-201",
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"title": "Acute Retinal Necrosis Associated with Epstein-Barr Virus in a Patient Undergoing Immunosuppressive Therapy.",
"title_normalized": "acute retinal necrosis associated with epstein barr virus in a patient undergoing immunosuppressive therapy"
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"abstract": "Glioblastoma is the most common and malignant primary brain tumour in adults. Maximum feasible surgical resection, radiotherapy and temozolomide chemotherapy at initial diagnosis have improved prognosis but rapid recurrence is typical and survival remains brief. There is an urgent need for effective new treatments and approval of the antiangiogenic agent bevacizumab for recurrent glioblastoma by Health Canada in 2009 has been the most notable recent therapeutic advance for this disease. This review with illustrative case studies highlights how bevacizumab has been incorporated into the treatment of glioblastoma in Canada and describes the ongoing controversies surrounding its clinical application.",
"affiliations": "Department of Medicine,Princess Margaret Cancer Centre and University of Toronto,Toronto,Ontario,Canada.",
"authors": "Mason|Warren P|WP|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab",
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"issue": "42(3)",
"journal": "The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques",
"keywords": "vascular endothelial growth factor",
"medline_ta": "Can J Neurol Sci",
"mesh_terms": "D000328:Adult; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D001932:Brain Neoplasms; D018450:Disease Progression; D004830:Epilepsy, Tonic-Clonic; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012640:Seizures; D016896:Treatment Outcome",
"nlm_unique_id": "0415227",
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"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bevacizumab in recurrent glioblastoma: five informative patient scenarios.",
"title_normalized": "bevacizumab in recurrent glioblastoma five informative patient scenarios"
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"abstract": "The purpose of this study was to evaluate the outcome after Radium-223-dichloride ((223)RaCl₂) treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body (18)F-Fluoride PET/CT. Sodium (18)F-fluoride [(18)F]-NaF PET/CT was performed prior the treatment of (223)RaCl₂, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [(18)F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [(18)F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during (223)RaCl₂. Our results (although preliminary) suggest that (18)F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases.",
"affiliations": "Departments of Molecular Radiotherapy & Nuclear Medicine, Docrates Cancer Center, Saukonpaadenranta 2, Helsinki FI-00180, Finland. kalevi.kairemo@docrates.com.;Departments of Radiotherapy and Medical Oncology, Docrates Cancer Center, Saukonpaadenranta 2, Helsinki FI-00180, Finland. timo.joensuu@docrates.com.",
"authors": "Kairemo|Kalevi|K|;Joensuu|Timo|T|",
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"doi": "10.3390/diagnostics5040413",
"fulltext": "\n==== Front\nDiagnostics (Basel)Diagnostics (Basel)diagnosticsDiagnostics2075-4418MDPI 10.3390/diagnostics5040413diagnostics-05-00413ArticleRadium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT Kairemo Kalevi 1†*Joensuu Timo 2Assinder Stephen Academic Editor1 Departments of Molecular Radiotherapy & Nuclear Medicine, Docrates Cancer Center, Saukonpaadenranta 2, Helsinki FI-00180, Finland2 Departments of Radiotherapy and Medical Oncology, Docrates Cancer Center, Saukonpaadenranta 2, Helsinki FI-00180, Finland; E-Mail: timo.joensuu@docrates.com† Present Address: Department of Nuclear Medicine, University of Texas MD Anderson Cancer Center, 1400 Pressler, Houston, TX 77030, USA.\n\n* Author to whom correspondence should be addressed; E-Mail: kalevi.kairemo@docrates.com; Tel.: +358-10-773-2000; Fax: +358-10-773-2099.13 10 2015 12 2015 5 4 413 427 21 8 2015 29 9 2015 © 2015 by the authors; licensee MDPI, Basel, Switzerland.2015This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).The purpose of this study was to evaluate the outcome after Radium-223-dichloride (223RaCl2) treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body 18F-Fluoride PET/CT. Sodium 18F-fluoride [18F]-NaF PET/CT was performed prior the treatment of 223RaCl2, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [18F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [18F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during 223RaCl2. Our results (although preliminary) suggest that 18F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases.\n\nprostate cancersodium fluorideskeletal metastasesradium-223-dichloride\n==== Body\n1. Introduction\nProstate cancer is the most common cancer in Europe and 10%–20% of patients present with advanced or metastatic disease with associated symptomatic bone metastases [1]. Bone is the most frequent metastatic site in prostate cancer, with approximately 90% of patients with metastatic castration resistant prostate cancer (mCRPC) having radiological evidence of bone metastases [2]. Bone metastases profoundly affect an individual’s quality of life, increase the risk of bone marrow failure [3] and skeletal-related events (SREs) such as pathological fractures and spinal cord compression [4], and significantly reduce life expectancy [5,6]. The main cause of disability and death among those with mCRPC is bone metastases.\n\nAccording to EANM guidelines, patients considered for therapy with beta-emitting radiopharmaceuticals such as 89Sr-Cl, 153Sm-EDTMP or 186Re-HEDP therapy had to fail in conventional analgesics and anti-tumor therapy, chemotherapy or hormone therapy. Pain had to be severe enough to limit normal activities and/or require regular analgesics, and patients had to undergo recent (within 8 weeks or less) bone scintigraphy documenting increased osteoblastic activity at painful sites. These radionuclide treatments are palliative, where 60%–80% of patients benefit from the treatment and they do not cure metastatic cancer [7,8]. All of these agents have demonstrated improved overall survival in retrospective controlled studies [9,10,11], but there are not yet randomized controlled studies which support these findings, only studies which do not improve survival [12]. In 2010’s, the bone-seeking radiopharmaceutical, radium-223 dichloride (223RaCl2), was introduced into clinical practice. 223RaCl2 is indicated for the treatment of patients with mCRPC and symptomatic bone metastases, offering overall survival benefits comparable to the other new treatment options available [13,14,15]. The availability of 223RaCl2 has generated considerable interest amongst the nuclear medicine community, and in many centers around the world nuclear medicine physicians have joined the multidisciplinary treatment team involved in the management of patients with mCRPC.\n\nThis 223RaCl2 is an alpha-emitting bone targeting agent, which has favorable pharmacokinetic and pharmacodynamic characteristics: at 10 min 12%, at 1 h 6% and at 24 h <1% of the injected activity is in the blood and the skeletal uptake is 44%–77% at 4 h. Fecal excretion is the major elimination route, but additionally 5% is excreted in the urinary tract [15,16]. In regards to diagnostic imaging of these patients, the Society for Nuclear Medicine published guidelines for [18F]-NaF PET/CT bone scans [17]. Bone uptake of 18F-NaF reflects bone remodeling, and it is part of the mineralization of bone matrix. [18F−] ion is exchanged for [OH−] so that hydroxy apatite bone matrix is transformed into fluoro apatite, indicating that high uptake of [18F]-NaF reflects bone reactions to bone injury, not to prostate cancer. Positive findings with [18F]-NaF PET/CT are due to both benign and malignant bone disorders. In the literature, ten articles described the use of [18F]-NaF PET/CT scans in the diagnosis of metastatic prostate cancer [18,19,20,21,22,23,24,25,26,27]. In our own meta-analysis about [18F]-NaF PET/CT in 3918 patients [28], 1289 (33%) had positive scans. Use of [18F]-NaF and 18F-Choline PET/CT had similar diagnostic accuracy at staging for patients with prostate cancer but 18F-Choline has higher specificity at restaging for recurrence [28].\n\nIn this article, the outcome of 223RaCl2 treatment was analyzed using [18F]-NaF-PET.\n\n2. Methods and Patients\nPatients: Prostate cancers were diagnosed between 2001 and 2013. In this retrospective one institute analysis we included all those patients who had received at least 6 cycles of 223RaCl2 therapy. Men’s ages ranged from 49 to 83 years; Gleason scores were 6–10; initial PSA values varied from 5.5 to 15,500 μg/L, and all patients had T3-T4 disease. All the patients had skeletal metastases, and two of them additionally had visceral metastases. The radiological TNM staging before 223RaCl2 was performed using [18F]-NaF-PET and [18F]-fluorocholine-PET in all patients, most (9 out of 10) of the patients had also pelvic MRI and diagnostic whole body CT. The 223RaCl2 injections were given every 4 weeks and follow up studies were done with [18F]-NaF. Two of them had previous surgery, 8 had previous radiotherapy, all 10 had androgen deprivation therapy (ADT) as well having received chemotherapy, 2 had received Sm-153-EDTMP therapy, and 9 additionally received denosumab prior 223RaCl2. The patient characteristics are summarized in Table 1.\n\nThis work is a retrospective treatment analysis of our ten first Ra-223 patients followed with [18F]-NaF PET/CT imagings. This retrospective analysis was performed, according to the principles of the Declaration of Helsinki and our patient database was approved by the Finnish authority for the protection of privacy and personal data. All patients gave a written informed consent for the use their data.\n\nImaging PET/CT protocol: Imaging was done on Siemens Biograph PET Scanner, combined with low-dose CT. The injected activity dose of [18F]-NaF ranged 212–290 MBq. Whole body imaging was performed by starting at 60 ± 3.0 min (range 58–76 min) from the calvarium to the tips of the toes using 2.5 min per bed position. All analyzed patients were treated with 6 cycles of radium-223-dichloride (223RaCl2) and [18F]-NaF PET/CT imaging was applied before Ra-223 therapy in all patients, in 6 patients after the 1st cycle and in all patients after the last 6th cycle (Table 2). In one patient (no. 6) there was a production failure of 223RaCl2 and the interval between the 1st and 2nd cycle was 10 weeks instead of normal 4 weeks. He was imaged after the 2nd cycle, and received a total of 7 cycles. The [18F]-NaF after the first (second) cycle was performed 3 weeks after 223RaCl2 infusion. The last control was performed within 4 weeks after the last 6th (7th) cycle in all patients. The tracer [18F]-NaF was provided from MAP Medical Technologies Oy (Helsinki, Finland).\n\nAlpha-therapy:\n223RaCl2 (Xofigo®) was acquired from Bayer Healthcare AG (Berlin, Germany), each single-use vial contained 6 mL of solution at a concentration of 1000 kBq/mL (27 μCi/mL) and a total radioactivity of 6 MBq/vial (162 μCi/vial) at the reference date [29]. The used activity dose of 223RaCl2 is 50 kBq/kg body weight (1.35 μCi/kg) given at 4-weekly intervals for six cycles, the cumulative activities are listed in Table 2. The volume administered was calculated using the patient’s body weight (kg), the dosage level (50 kBq/kg body weight), the radioactivity concentration of the product at the reference date, and the decay correction factor provided with each vial.\n\nPrior to the first dose, patients were analyzed for a full blood count (FBC) to assess bone marrow function. Treatment was given if: haemoglobin level >10 g/dL, absolute neutrophil count (ANC) ≥1.5 × 109/L, and platelet count ≥100 × 109/L. Due to the potential myelotoxic effects of treatment, a FBC was undertaken prior to all subsequent treatment cycles. The decision to administer the next cycle depended on recovery of the ANC and platelet counts to levels of ≥1.5 × 109/L and ≥100 × 109/L, respectively. The cumulative doses in 6 cycles varied from 16.45 to 31.57 MBq.\n\ndiagnostics-05-00413-t001_Table 1Table 1 The patient characteristics.\n\nPatient Age\tDiagnosis Gleason Score, TNM (Year)\tDistribution (before Ra-223)\tDx/modality *\tCycles * Cumulative Activity\tInitial S-PSA\tOther Treatments before Xofigo\t\n1\nm/63\tGS 9, T4N1M1 (-13)\tProstate Bone lnn\tNaF, FCH, MRI, CT\t6\n30.86 MBq\t410\tDegarelix, Bicalutamide, Docetaxel, Abiraterone, Enzalutamide, Denosumab\t\n2\nm/77\tGS 7, pT3N0M0 (-01)\tBone\tNaF, FCH, FACBC, MRI, CT\t6\n24.80 MBq\t5.5\tRRP, EBRT (PO), Bicalutamide, Docetaxel, Abiraterone, Enzalutamide, Denosumab, Goserelin\t\n3\nm/68\tGS 8, T4N1M1 (-13)\tBone\tNaF, FCH, MRI, CT\t6\n27.08 MBq\t15,500\tDegarelix,Bicalutamide, Denosumab, EBRT (B), Docetaxel, Abiraterone, EBRT (P), Enzalutamide, Denosumab, Goserelin\t\n4\nm/49\tGS 9, T4N1M1 (-13)\tBone\tNaF, FCH, MRI, CT\t6\n31.57 MBq\t700\tCyproterone, Degarelix, Bicalutamide, Zoledronate, Docetaxel, Sm-153-EDTMP, Mitoxantrone, EBRT (P), Docetaxel, Abiraterone\t\n5\nm/67\tGS 9, T3N1M1 (-13)\tBone\tNaF, FCH, MRI, CT\t6\n25.87 MBq\t430\tDegarelix, Bicalutamide, Denosumab, Docetaxel, Goserelin, Enzalutamide\t\n6\nm/69\tGS 8, T4N1M1 (-11)\tBone\tNaF, FCH, MRI, CT\t7\n24.13 MBq\t16.2\tBicalutamide, Goserelin, EBRT (P), Abiraterone, Denosumab, Docetaxel, Enzalutamide\t\n7\nm/56\tGS 10, T4NxM1 (-13)\tBone\tNaF, FCH, MRI, CT\t6\n22.78 MBq\t790\tBicalutamide, Lupron, Denosumab, EBRT (P), Sm-153-EDTMP, Mitoxantrone, Docetaxel, Abiraterone\t\n8\nm/58\tGS 9, T3N0M1 (-12)\tBone\tNaF, FCH, MRI, CT\t6\n23.71MBq\t6.5\tDenosumab, Degarelix, Bicalutamide, EBRT (P), Goserelin, Docetaxel\t\n9\nm/60\tGS 9, T4M1N1 (-12)\tBone\tBS, NaF, FCH, MRI, CT\t6\n16.45 MBq\t18\tBicalutamide, Buserelin, TURP, Docetaxel, EBRT (B), Abiraterone, Denosumab, Cabazitaxel, Enzalutamide\t\n10\nm/83\tGS 6, T3NxM0 (-01)\tBone Liver lnn\tNaF, FCH\t6\n24.06 MBq\t18\tLeuprolin, EBRT (P), Docetaxel, Abiraterone, Mitoxantrone, Zoledronate, Denosumab\t\n* BS = bone scintigraphy, CT = computer tomography, FACBC = F-18-ACBC PET/CT, FCH = F-18-choline PET/CT, MRI = magnetic resonance imaging, NaF = F-18-fluoride PET/CT; Abbreviations: P = radical radiotherapy of prostate, B = radiotherapy of bone metastases, PO = postoperative radiotherapy, lnn = lymph nodes, GS = Gleason score.\n\nImage analysis: Lesions were considered abnormal when focal tracer accumulation was greater than background activity, usually if the SUV values were higher than 10.\n\nInterpretation of bone lesions (benign or malignant) depended on anatomical localization; and the five regions: skull, vertebral column, thoracic girdle, pelvic girdle and extremities were estimated quantitatively using modified PERCIST criteria for NaF. In the classic PERCIST analysis, the skeleton is considered as organ, and a maximum of two lesions per organ are taken into account out of the total sum of five lesions. Therefore, here two highest SUVmax values of skeletal uptakes from two regions were summed. The results were compared with those of base line, the change of 6% were considered significant as in conventional PERCIST consisting of 5 lesions, where 15% change is considered significant which is analogous to PERCIST criteria for early response [30].\n\ndiagnostics-05-00413-t002_Table 2Table 2 The summary of the NaF imaging results.\n\nPatient Age\tBone Distribution # (before Ra-223) \tNaF-% Change after 1st/ 6th Cycle (2nd/7th)\tNumber of Cycles Cumulative Activity\tS-PSA Response\tTreatments during Xofigo\t\n1\nm/63\tBone 3/3\t+0.8/−13.8\t6\n30.86 MBq\tPD\tDegarelix, Enzalutamide, Denosumab\t\n2\nm/77\tBone 2/3\t+6.2/−6.9\t6\n24.80 MBq\tPR\tEnzalutamide, Denosumab, Goserelin\t\n3\nm/68\tBone 3/3\t−10.8/−9.2\t6\n27.08 MBq\tCR\tEnzalutamide, Denosumab, Goserelin\t\n4\nm/49\tBone 3/3\tnd/−13.0\t6\n31.57 MBq\tPD/SD\tLupron,Denosumab, Abiraterone\t\n5\nm/67\tBone 1/3\t−6.5/−7.8\t6\n25.87 MBq\tPR\tDenosumab, Goserelin, Enzalutamide\t\n6\nm/69\tBone 3/3\t−10.4/−11.7\t7\n24.13 MBq\tPR\tGoserelin, Denosumab, Enzalutamide\t\n7\nm/56\tBone 3/3\tnd/−11.4\t6\n22.78 MBq\tPR\tLupron, Denosumab, Abiraterone\t\n8\nm/58\tBone 3/3\tnd/−43.0\t6\n23.71MBq\tSD/PD\tDenosumab, Degarelix, Abiraterone\t\n9\nm/60\tBone 2/3\tnd/−68.4\t6\n16.45 MBq\tSD\tBuserelin, Denosumab, Enzalutamide\t\n10\nm/83\tBone 1/3\t+6.3/−63.5\t6\n24.06 MBq\tPR\tDenosumab, Degarelix, Enzalutamide\t\n# 1/3 10%–25% of the skeleton affected; 2/3 25%–50% of the skeleton affected; 3/3 >50% of the skeleton affected. Abbreviations: CR =complete response, PD = progressive diseased, PR = partial response, SD = stable disease; nd = not done.\n\nStatistical analysis: The acquired results were expressed as the mean ± SEM for each index. Comparison of data among various groups was performed with Student’s unpaired t-test. A p < 0.05 was considered statistically significant. Correlation between groups was calculated using linear regression analysis.\n\n3. Results\nThe summary of imaging results is presented in Table 2. All patients responded to their treatment according to the [18F]-NaF imaging data. Their PSA-curves are shown in Figure 1. Partial response, i.e., 25%–75% decrease in S-PSA values was seen 5 patients. One patient demonstrated complete response, i.e., S-PSA values were = 0.0 or decreased >75%. Stable disease <25% decrease or increase was seen in 3 patients and 1 patient had progressive disease.\n\nFigure 1 PSA-curves before, during 6 cycles, and 1 month after Ra-223 treatments in all patients; response, if >25% decrease in S-PSA values. SD = stable disease, PR = partial response (>25% decrease), CR = complete response (>75% decrease), PD = progressive disease (>25% increase). The number refers to patient number (Table 1 and Table 2), y-axis S-PSA concentration in μg/L, x-axis time in days, starting from the day of 1st Ra-223 treatment. Numbers 1–10 refer to patient number in Table 1, Table 2 .\n\nA few patient examples with imaging data are shown. Figure 2 demonstrates the [18F]-NaF imagings before, one interim analysis (after two cycles) and one evaluation after the 6 six cycles in a 69-year old male (patient no. 6). His Gleason score was 8 (diagnosed in 2012), treated earlier with Casodex, Zoladex, PSA 671 μg/L at initial visit (in VII/14), and he was treated with 6 cycles of 223RaCl2. Three evaluations are shown: A [18F]-NaF-PET-CT before, one interim (after two cycles) and one after the 6 six cycles of Ra-223. There were quantitative changes (−10.4% and −11.7%) in both the interim and post therapy NaF-PET. The PSA-curve demonstrated partial response (6, Figure 1), but the ALP curve clearly demonstrated the delay in response due to 223RaCl2 production failure (interval between 1. and 2. cycle was 10 weeks).\n\nFigure 2 69-year old male, Gleason score 8 (diagnosed in 2012), treated earlier with Casodex, Zoladex, S-PSA 671 ng/mL at initial visit in (VII/14), was treated with 6 cycles of 223RaCl2. A NaF-PET-CT study before (IX-14), one interim study (after two cycles, II-15) and one study (IV-15) after the 6 six cycles are shown. There is a quantitative response (−10.4% and −11.7%) in both the interim and post therapy NaF-PET-maximum intensity projection images.\n\nFigure 3 demonstrates another patient (no. 2) with Gleason score 7 treated with radical prostatectomy, (diagnosed in 2001), and with postoperative external beam radiation therapy, then with bicalutamide, docetaxel, abiraterone, enzalutamide, denosumab and goserelin. He demonstrated a biochemical relapse with a few findings on [18F]-FACBC-PET-CT [31], but with more findings on [18F]-FCH-PET-CT 3 months later. The response to the treatment was seen on [18F]-FCH-PET in 8 months, where the changes in the bone marrow had dramatically disappeared. However, [18F]-NaF-PET on the following day demonstrated a widespread active cortical bone disease. This did not respond to the treatment after 1st cycle (+6.2% change), but after 6 cycles a minor response was seen (−6.2% change).\n\nFigure 4 demonstrates a young patient (49 years, patient no. 4) with Gleason score 9, treated earlier with cyproterone, degarelix, bicalutamide, zoledronate, docetaxel, Sm-153-EDTMP, mitoxantrone, EBRT (P), docetaxel, abiraterone.\n\nA response to the treatments is seen on [18F]-FCH–PET in 10 months, especially in the bone marrow disease.\n\n[18F]-NaF-PET 6 weeks later demonstrated a widespread active cortical bone disease. This responded to the Ra-223 treatment, because after 6 cycles a response was seen (−13.0% change).\n\nFigure 5 demonstrates an old patient (83 years) with Gleason score 6 (patient no. 10). The [18F]-NaF-PET before the Ra-223 treatment is shown, but no essential change in the total [18F]-NaF-PET activity due to the Ra-223 treatment was seen after 1st cycle (+6.3% change), whereas after 6 cycles a dramatic response was seen (−63.5% change).\n\nFigure 3 Demonstrates a patient with Gleason score 7 treated originally with radical prostatectomy in 2001, treated subsequently with external beam radiation therapy, then with bicalutamide, docetaxel, abiraterone, enzalutamide, denosumab, doserelin. He demonstrated a biochemical relapse with a few findings on FACBC-PET (V-13), but with more findings on FCH-PET 3 months later (VIII-13). The response to the treatment was seen on FCH –PET in 8 months (IV-14), where the changes in the bone marrow had dramatically disappeared. However, NaF-PET on the following day (IV-14) demonstrated a widespread active cortical bone disease. This did not respond to the treatment after 1st cycle (+6.2% change, V-14), but after 6 cycles a response was seen (−6.2% change, IX-14).\n\nFigure 4 Demonstrates a young patient (49 years) with Gleason score 9, treated earlier with cyproterone, Degarelix, bicalutamide, zoledronate, docetaxel, Sm-153-EDTMP, mitoxantrone, EBRT (P), docetaxel, abiraterone. A response to the treatments is seen on FCH-PET in 10 months, especially in the bone marrow disease, MIP-image, sagittal fusion FCH-PET on CT and sagittal FCH-PET figures are shown in July 2013 (VII-13) and corresponding data in May 2014 (V-14). NaF-PET 6 weeks (VII-14) later in July 2014 demonstrated a widespread active cortical bone disease. This responded to the Ra-223 treatment, because after 6 cycles a response was seen in January 2015 (−13.0% change, I-15).\n\nFigure 5 Demonstrates an old patient (83 years) with Gleason score 6. The NaF-PET before the Ra-223 treatment 6 cycles is shown (II-15), but no essential response to the treatment after 1st cycle (+6.3% change, III-15) was seen, whereas after 6 cycles a dramatic response was seen (−63.5% change, VIII-15). Many of the lesions have disappeared, especially in the thoracic girdle.\n\n4. Discussion\nOur patients with active mCRPC all responded to their treatments, because quantitatively there was a significant decrease in [18F]-NaF-PET findings after 6 cycles of 223RaCl2 as compared to the baseline measurements. The quantitative decrement varied from −6.9% to −68.4%. The change can be visually seen in Figure 5 (quantitatively −63.5%), but no so easily in Figure 2, Figure 3 and Figure 4 (quantitatively −6.9% to 13.0%). Therefore, quantification is important in widespread, i.e. more than 10% of skeleton, metastatic bone disease. According to the S-PSA measurements all patients except one (patient no. 1) showed some response in an active aggressive (T3-T4) widespread skeletal disease.\n\nThere are now multiple new therapies providing options for the treatment of patients having metastatic castration-resistant prostate cancer (mCRPC). For these patients, therapies were just very recently exceptionally ineffective and extremely limited to the use of docetaxel. These new therapies include androgen synthesis inhibitor (abiraterone) [32], androgen receptor signaling inhibitor (enzalutamide) [33], radionuclide therapy (radium-223) [34,35,36,37] and cabazitaxel chemotherapy [38].\n\nRadium-223 was the first bone-seeking radionuclide that is reported to increase overall survival, and quality of life by providing pain relief in their late stage disease from symptomatic skeletal events (SSEs) such as bone pain, pathological fractures, or spinal cord compression seen in up to 90% of mCRPC patients. This new drug, radium-223-dichloride (223RaCl2) is a new bone-seeking calcium analogue alpha-emitter, first of its kind in clinical use (Marketing authorization EU/1/13/873/001). It targets increased bone turnover developed by metastatic bone disease. In its double-blinded randomized registration trial, the 223RaCl2 receiving patients demonstrated median overall survival of 14 months, vs. 11.2 months for those on placebo [34,35].\n\nOur patients with active mCRPC all responded to the given therapies. The common denominator was that they all received multimodality treatments with response. All of them received radium-223-dichloride (223RaCl2) plus denosumab, but otherwise this group of 10 patients was very heterogeneous. This is usually the case in retrospective analysis describing the clinical practice, when it comes to their demographics and previous and concomitant therapies (Table 1 and Table 2).\n\nIn addition to the overall survival and QOL benefits, all the secondary endpoints were also met in the Phase 3 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) registration trial [30,31,32,33], which included the delay in time to first skeletal-related events: first events occurred in 13.6 months in the 223RaCl2 group as compared to 8.4 months in the placebo group—an improvement of 64%. 33% of 223RaCl2 patients had total alkaline phosphatase normalization as compared to just 1% in the placebo group. Additionally, the 223RaCl2 patients had an improvement of 49% in time to PSA progression.\n\nVery little, however, is known about the response evaluation of Ra-223 treatment. Although it has been shown that 223RaCl2 is a bone targeting treatment, its response using bone targeting imaging has not yet been assessed in the literature. There is evidence that NaF-PET can be used as a prognostic factor of the outcome of Ra-223 treatment [39]. They demonstrated that skeletal metastatic burden on baseline will reflect on the outcome of 223RaCl2 treatment and appearance of skeletal related events. In the PERCIST criteria [30] early minor response is recorded, if there is a 15% decrease in a total sum of 5 lesions; however, a maximum of two lesions can be taken from the same organ. In our modified criteria we therefore selected just the two lesions to represent the whole skeleton. If we use the 30% criteria for partial response as in PERCIST [30], the limit would be 12%, meaning that only 5 of our 10 patients demonstrated response. In the MD Anderson Cancer Center study [40], also the total skeletal volume was analyzed based on SUV-threshold of 10. However, this cannot be applied in the clinical routine, and it does not exclude heterogeneity in the metastatic distribution. It is a challenge to identify the best possible way of interpreting total malignant activity in the skeleton. In this work we wanted to present a simple method for routinely analyzing the overall skeletal situation, and it seems, at least preliminarily, that we have been successful. The threshold has to be settled in a larger patient population.\n\nAll our patients were diagnosed with multiple PET tracers which all can be used for assessment of skeletal metastatic distribution. It is obvious, e.g., patient no. 2 who was scanned with [18F]-fluorocholine (FCH), [18F]-fluciclovine (FACBC) and [18F]-NaF, that all these tracers give different information about the in vivo biochemistry in prostate cancer. [18F]-FCH is an indicator for lipid metabolism and cell membrane synthesis in prostate cancer, [18F]-FACBC as an amino acid analog for protein synthesis and [18F]-NaF marker for an increased phosphate turnover in reactive osteoblastic cells. In our patients, bone marrow uptake is typical to [18F]-FCH, cortical bone uptake for NaF. The distribution for FCH and NaF can be totally different, as shown in Figure 3 on studies on consecutive days.\n\nFlare phenomenon might have been seen in 3 out of 6 patients (Figure 3 and Figure 5), which may indicate that the treatment response analysis after 1st cycle is not useful. The interim [18F]-NaF uptake may also be due to disease progression, but the S-PSA values do not support this finding. At least, in this limited material there was no trend in the interim [18F]-NaF values after first or second cycle. The [18F]-NaF uptake after 6 cycles, however, was significantly lower in all 10 patients as compared to the baseline.\n\nTherefore, we postulate that skeletal response to therapies can be assessed with [18F]-NaF. There was also a change in PSA (Figure 1). Response to the therapies can be due to combined effect of abiraterone, enzalutamide or denosumab and Ra-223 alone. Ra-223 and denosumab were the only common regimens in all these therapies. On the other hand Ra-223 can be combined with other therapies with success even though the mechanisms and combinations have to be studied carefully in order to understand the causality.\n\n5. Conclusion\nOur results suggest that 18F-Fluoride PET/CT is the most useful PET method in the follow-up of castration resistant prostate cancer with skeletal metastases. The presented quantification technique suits for response evaluation of 223RaCl2 in clinical routine.\n\nAuthor Contributions\nBoth authors participated in all elements of the study (design, data collection, clinical evaluation etc.). Kalevi Kairemo was mainly responsible for imaging evaluations and quantification method development, whereas Timo Joensuu was mainly responsible for patient selection for Ra-223 and oncologic treatments. Both authors participated in manuscript writing.\n\nConflicts of Interest\nKalevi Kairemo has received consultancy fees from Bayer Healthcare AG (Wuppertal, Germany). Timo Joensuu is a shareholder of Docrates Cancer Center (Helsingfors, Finland).\n==== Refs\nReferences\n1. Wirth M. Horninger W. How I treat metastatic prostate cancer J. OncoPathol. 2014 2 13 26 10.13032/tjop.2052-5931.100102 \n2. Petrylak D.P. Tangen C.M. Hussain M.H. Lara P.N. Jr. Jones J.A. Taplin M.E. Burch P.A. Berry D. Moinpour C. Kohli M. 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Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline J. Clin. Oncol. 2014 32 3436 3448 10.1200/JCO.2013.54.8404 25199761 \n40. Etchebehere E.C. Araujo J.C. Fox P.S. Swanston N.M. Macapinlac H.A. Rohren E.M. Prognostic factors in patients treated with Ra-223: The role of skeletal tumor burden on baseline 18 F-fluoride-PET/CT in predicting overall survival J. Nucl. Med. 2015 56 1177 1184 10.2967/jnumed.115.158626 26069307\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "5(4)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "prostate cancer; radium-223-dichloride; skeletal metastases; sodium fluoride",
"medline_ta": "Diagnostics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101658402",
"other_id": null,
"pages": "413-27",
"pmc": null,
"pmid": "26854163",
"pubdate": "2015-10-13",
"publication_types": "D016428:Journal Article",
"references": "18465129;24578240;25199761;22894553;23021204;18467311;15958630;21738117;23326203;22341993;24343987;15470214;19403881;12359855;24991547;25832684;25155428;21976530;22502982;16455635;24836273;18649080;10520701;23142059;12571218;21051652;24127064;23096187;10453276;25808958;22691503;23377765;23863050;21403668;21076343;26069307;21191494",
"title": "Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer-Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT.",
"title_normalized": "radium 223 dichloride in castration resistant metastatic prostate cancer preliminary results of the response evaluation using f 18 fluoride pet ct"
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"abstract": "To describe the human temporal bone pathology in two patients who incurred furosemide induced ototoxicity.\n\n\n\n1) A 46-year-old woman in acute liver and renal failure treated with high doses of furosemide for anasarca who developed a rapidly progressive severe-to-profound asymmetric sensorineural hearing loss. 2) A 65-year-old woman with undifferentiated small cell carcinoma of the lung who received intravenous furosemide 1 day prior to death for pulmonary edema.\n\n\n\nRemoval of temporal bones, histologic processing, and light microscopy of temporal bones.\n\n\n\nTemporal bone histopathology and correlation with clinical and audiometric data.\n\n\n\nAll three temporal bones demonstrated edema and cystic changes in the stria vascularis. In the first case the furosemide exposure was associated with hearing loss and the pathological changes were more extensive including cystic changes in the Hensen's cells, collapse of Reissner's membrane and the tectorial membrane and diffuse loss of inner and outer hair cells with only modest reduction in the spiral ganglion cell population. In the second case, without attributable hearing loss, there was only modest reduction in hair cell and spiral ganglion cell counts. Pathological changes were not observed in the ampullae of the semicircular canals or epithelium of the saccular or utricular maculae in either case.\n\n\n\nThe temporal bone pathologic correlate for furosemide-induced ototoxicity is edema and cystic degeneration of the stria vascularis. The degree of degenerative change appears dose-dependent. We infer that pathological changes may occur in the absence of a measurable immediate clinical effect.\n\n\n\nNA.",
"affiliations": "Department of Otolaryngology, Massachusetts Eye and Ear Infirmary Boston Massachusetts U.S.A.;Department of Otolaryngology, Massachusetts Eye and Ear Infirmary Boston Massachusetts U.S.A.",
"authors": "Santos|Felipe|F|0000-0002-3523-665X;Nadol|Joseph B|JB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/lio2.108",
"fulltext": "\n==== Front\nLaryngoscope Investig OtolaryngolLaryngoscope Investig Otolaryngol10.1002/(ISSN)2378-8038LIO2Laryngoscope Investigative Otolaryngology0023-852X2378-8038John Wiley and Sons Inc. Hoboken 10.1002/lio2.108LIO2108Otology, Neurotology, and NeuroscienceOtology, Neurotology, and NeuroscienceOtopathology ReportTemporal bone histopathology of furosemide ototoxicity Santos and NadolHistopathology of Furosemide OtotoxicitySantos Felipe MDhttp://orcid.org/0000-0002-3523-665Xfelipe_santos@meei.harvard.edu \n1\n\n2\nNadol Joseph B. MD\n1\n\n2\n\n1 \nDepartment of Otolaryngology, Massachusetts Eye and Ear Infirmary\nBoston\nMassachusetts\nU.S.A.\n\n2 \nDepartment of Otolaryngology\nHarvard Medical School\nBoston\nMassachusetts\nU.S.A.\n* Send correspondence to Felipe Santos, MD, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114. E‐mail: felipe_santos@meei.harvard.edu25 9 2017 10 2017 2 5 10.1002/lio2.v2.5204 207 15 6 2017 03 8 2017 © 2017 The Authors Laryngoscope Investigative Otolaryngology published by Wiley Periodicals, Inc. on behalf of The Triological SocietyThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Objectives\nTo describe the human temporal bone pathology in two patients who incurred furosemide induced ototoxicity.\n\nPatients\n1) A 46‐year‐old woman in acute liver and renal failure treated with high doses of furosemide for anasarca who developed a rapidly progressive severe‐to‐profound asymmetric sensorineural hearing loss. 2) A 65‐year‐old woman with undifferentiated small cell carcinoma of the lung who received intravenous furosemide 1 day prior to death for pulmonary edema.\n\nInterventions\nRemoval of temporal bones, histologic processing, and light microscopy of temporal bones.\n\nMain Outcome Measures\nTemporal bone histopathology and correlation with clinical and audiometric data.\n\nResults\nAll three temporal bones demonstrated edema and cystic changes in the stria vascularis. In the first case the furosemide exposure was associated with hearing loss and the pathological changes were more extensive including cystic changes in the Hensen's cells, collapse of Reissner's membrane and the tectorial membrane and diffuse loss of inner and outer hair cells with only modest reduction in the spiral ganglion cell population. In the second case, without attributable hearing loss, there was only modest reduction in hair cell and spiral ganglion cell counts. Pathological changes were not observed in the ampullae of the semicircular canals or epithelium of the saccular or utricular maculae in either case.\n\nConclusions\nThe temporal bone pathologic correlate for furosemide‐induced ototoxicity is edema and cystic degeneration of the stria vascularis. The degree of degenerative change appears dose‐dependent. We infer that pathological changes may occur in the absence of a measurable immediate clinical effect.\n\nLevel of Evidence\nNA.\n\nOtotoxicityfurosemidesensorineural hearing lossstria vascularisNIDCD\nU24DC013983‐01\n source-schema-version-number2.0component-idlio2108cover-dateOctober 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:25.10.2017Funding: NIDCD U24DC013983‐01. There are no conflicts of interest.\n\nWe are grateful to Garyfallia Pagonis, Meng Yu Zhu, Barbara Burgess, Diane Jones and Jennifer T. O'Malley for technical assistance.\n==== Body\nINTRODUCTION\nOtotoxicity refers to drug induced changes that affect hearing and/or balance. The loop diuretics are known to have the potential to induce hearing loss. These drugs are commonly used for the treatment of hypertension and edema. They act on the ascending loop of Henle to inhibit the resorption of sodium, chloride, and potassium. Furosemide, ethacrynic acid, and bumetanide are the most commonly prescribed loop diuretics. Sudden, progressive, reversible, and profound hearing loss have been ascribed to loop diuretics, including furosemide.1\n\n\nIn human temporal bone studies, cystic changes in the stria vascularis and dark cells of the vestibular organs, and loss of inner and outer hair cells have been observed in cases of ethacrynic acid and ethacrynic acid with concurrent furosemide exposure.2, 3, 4 Animal studies of furosemide otoxicity have also demonstrated pathological change in the stria vascularis.5, 6\n\n\nWe describe here the temporal bone histopathology, clinical course, and audiometry of two patients with and without sensorineural hearing loss after administration of furosemide. To our knowledge, this is the first otopathology report of isolated furosemide ototoxicity.\n\nMETHODS\nClinical history and audiologic evaluations were collected during life through enrollment in the National Institute on Deafness and Other Communication Disorders (NIDCD) National Temporal Bone, Hearing, and Balance Pathology Resource Registry.\n\nAfter death, the temporal bones were fixed in formalin. The temporal bones then underwent standard processing for histologic examination, including decalcification with ethylenediamine tetra‐acetic acid (EDTA) and celloidin embedding. The specimens were sectioned serially in the horizontal plane at a section thickness of 20 um. Every 10th section was stained with hematoxylin and eosin and mounted on a glass slide. The slides were examined by light microscopy. Graphic reconstruction of the cochlea was performed to quantify hair cells, pathologic changes to the stria vascularis, and loss of cochlear neuronal cells.\n\nRESULTS\nCase 1\nThe patient had a history of rheumatoid arthritis. At the age of 45 she developed new onset idiopathic anasarca, myopathy, and weight loss. She was treated with increasing doses of furosemide (up to 600 mg daily) over 9 months and began to note hearing loss in both ears. Her hearing loss progressed for 5 months during which time she was diagnosed with panniculitis. She was treated with prednisone and mepron (for Pneumocystis jirovecii prophylaxis) for the panniculitis. Seven weeks later she was terminally admitted in acute liver and renal failure. An audiogram showed a profound loss in the left ear and a severe flat loss in the right ear with a speech discrimination score of 40%. An MRI of the brain and internal auditory canals at the time showed no evidence of retrocochlear pathology. An autopsy revealed acute liver and renal failure with evidence of Clostridium perfringes bacteremia.\n\nThe histopathological findings were similar in both ears. There was severe loss of inner and all three rows of outer hair cells from the base to the apex of the cochlea as graphically represented in the cytocochleogram (Figs. 1 and 2).\n\nFigure 1 Audiocytocochleogram for Case 1 Right Ear. There is a severe sensorineural hearing loss in the right ear. Speech discrimination in the right ear was 40%. In the cytocochleogram black bars indicate loss and for the stria vacularis percentage of cystic change. There was severe loss of inner and outer hair cells. The stria vascularis showed cystic changes primarily in the apex. There was a 32.2% loss of spiral ganglion cells compared to aged matched controls.\n\nFigure 2 Audiocytocochleogram for Case 1 Left Ear. There is a profound loss on the left prior to death. No responses were elicited from the left ear during audiometric testing. In the cytocochleogram black bars indicate loss and for the stria vacularis percentage of cystic change. There was severe loss of inner and outer hair cells. The stria vascularis showed cystic changes primarily in the apex. There was a 24% loss of spiral ganglion cells compared to aged matched controls.\n\nThere was a cystic separation of the basal cells of the stria vascularis from the spiral ligament. This was associated with a partial collapse of Reissner's membrane in both cochleae, most severe at the apex. The Hensen's cells exhibited a cystic dilation from the basilar membrane. These findings were evident in the right (Fig. 3) and left ear (Fig. 4). There was collapse of the tectorial membrane throughout the organ of Corti. There were no pathological changes in the dark cells or hair cells of the vestibular organs.\n\nFigure 3 Case 1. Right ear. Apical section of the organ of Corti. There is cystic separation of the stria vascularis from the spiral ligament (arrow head). Reissner's membrane and the tectorial membrane are collapsed. Hensen's cells are flattened and elevated from the basilar membrane by a cyst (asterix).\n\nFigure 4 Case 1. Left ear. Basal section of the left organ of Corti. There is a cystic separation of the stria vascularis from the spiral ligament (arrow head). The tectorial membrane is collapsed. Hensen's cells are flattened and elevated from the basilar membrane by a cyst (asterix).\n\nCompared to age matched controls there was 24% loss of spiral ganglion cells in the left ear and 32.2% on the right.\n\nCase 2\nThis previously healthy woman presented at the age of 65 with pneumonia and a right hilar mass that on biopsy revealed small cell undifferentiated carcinoma. During the ensuing 3 months she received antibiotics, diuretics, chemotherapy (Adriamycin, Cytoxan and VP‐16), and radiation. A baseline audiogram showed symmetric thresholds of 15 dB to 2000 Hz with a descending pattern in the high frequencies. She tolerated her treatment until she developed acute onset fatigue, fever, chills, and nausea and died several days later. In addition to the carcinoma of the lung, autopsy revealed pulmonary edema, a pleural effusion, and chronic pancreatitis. One day prior to death and 9 days following the audiogram she received 2,040 mg of furosemide.\n\nOnly the left temporal bone was available for study. The predominant feature of the ear was edema of the intermediate layer of the stria vascularis. There was cystic degeneration along the margin of the stria vascularis adjacent to the spiral prominence (Fig. 5). All three layers appeared affected. In the remainder of the stria vascularis the marginal and basal cell layers were intact. There was only modest reduction of inner and outer hair cells and spiral ganglion neurons as graphically represented in the cytocochleogram (Fig. 6). There were no pathological changes in the dark cells or hair cells of the vestibular organs. Compared to age matched controls there was 27% loss of spiral ganglion cells in the left ear.\n\nFigure 5 Case 2. Left Ear. Upper basal turn of the cochlea. There is a cystic dilation of the stria vascularis (arrow head) above the spiral prominence. The cytoarchitecture of the organ of Corti is well preserved.\n\nFigure 6 Audiocytocochleogram for Case 2 left ear. There is a moderately severe to severe high frequency sensorineural above 4 Hz. Speech discrimination was normal. In the cytocochleogram black bars indicate loss and for the stria vacularis percentage of cystic change. There was minimal loss of inner and outer hair cells. The stria vascularis showed patchy cystic changes throughout the cochlea. There was a 27% loss of spiral ganglion cells compared to aged matched controls.\n\nDISCUSSION\nThe primary pathologic change in both cases was edema with cystic dilations in the stria vascularis. This is consistent with previous reports of human pathological changes in loop diuretic ototoxicity. Human temporal bone studies of ethacrynic acid ototoxicity have demonstrated edema in the stria vascularis, loss of outer hair cells and cystic changes in the ampullae of the posterior canal and saccule.2 Arnold et al. observed cystic dilations in the stria vascularis and dark cells of the vestibular system in patients with sudden hearing loss and ataxia after furosemide and ethacrynic acid administration.4 While Hensen's cell cysts as observed in case 1 have been reported in human specimens before,7 they have not been described in association with ototoxicity. The significance of this finding is unknown.\n\nEdema of the stria vascularis has also been observed in animal models of furosemide ototoxicity. The primary finding of electron microscopy studies of guinea pigs following intraperitoneal injections of furosemide was enlargement of the extracellular spaces from the marginal cell tight junctions to the basal cell layer with widening of the stria vascularis.5 Outer hair cell damage was observed in specimens that exhibited a greater degree of stria vascularis damage. This latter finding was interpreted as being a secondary effect resulting from changes in the stria vascularis.\n\nThe clinical manifestation of loop diuretic ototoxicity is sensorineural hearing loss. The hearing loss can be reversible or maybe permanent and is often dose–dependent.1 There was a longer exposure to furosemide in case 1 and accordingly a greater degree of injury to the stria vascularis and hair cell loss and degree of hearing loss. This patient also had renal and hepatic insufficiencies that are known to potentiate ototoxic effects.\n\nThe pharmacokinetics of loop diuretics and who is affected by ototoxicity are governed by many physiologic parameters. These drugs are highly bound to plasma protein and subject to hepatic and renal metabolism and excretion. It follows that a patient in hepatic and renal failure would be susceptible to higher concentrations of drug and therefore an increased risk of ototoxicity. Specifically, Rybak et al. have shown an increased reduction in the endocochlear potential in a low serum albumin mouse model of furosemide ototoxicity.8 Prior to death the albumin level in case 1 was abnormally low and liver function tests abnormally high consistent with hepatic failure.\n\nIn case 2, where only a single dose of furosemide was administered close to death, the extent of pathology of the stria vascularis was less severe and accordingly there was minimal hair cell loss. The patient died 24 hours following this administration and there was no documentation of additional hearing loss or tinnitus in the available clinical records.\n\nThe described histopathological findings supported by animal studies provide a mechanistic explanation for changes in hearing with furosemide; increasing doses of loop diuretics have an effect on the stria vascularis and could thereby reduce the endocochlear potential.9 The stria vascularis is known to play a role in potassium recycling for maintenance of the endolymphatic potential.10 Animal studies have also shown loop diuretics to reduce the cochlear microphonic potential11 and the eighth nerve action potential.12 Loop diuretic induced reduction in these physiologic parameters has not yet been measured in humans.\n\nWhile the systemic administration of the drug in case 1 would predict a more symmetric pattern to the hearing loss, the measured asymmetry in hearing serves as an important reminder to the clinician of the variable patterns of presentation of ototoxicity given the number of potential physiologically dependent variables. The number of observed surviving spiral ganglion cell counts has been positively correlated to word recognition scores in patients with a cochlear implant during life.13 In case 1 the number of surviving spiral ganglion cell counts measures favorably to documented cases of patients with a cochlear implant in life who were good to excellent performers with fewer surviving spiral ganglion cells 14 therefore predicting a favorable outcome for cochlear implant candidates following loop diuretic ototoxicity.\n\nCONCLUSION\n\nThe primary otopathological correlate of furosemide ototoxicity is edema and cystic dilation of the stria vascularis\n\nThe hearing loss of loop diuretic ototoxicity may be asymmetric.\n\nRenal and liver failure may increase susceptibility to loop diuretic ototoxicity.\n\nPatients with severe to profound hearing loss from loop diuretic therapy may benefit from cochlear implantation.\n\n\n\n\nACKNOWLEDGMENTS\nThe authors wish to thank Diane Jones, Jennifer O'Malley, Barbara Burgess, and Mengyu Zhu for preparation of the temporal bone specimen, and Garyfallia Pagonis for assistance with preparation of the figures and photomicrographs.\n==== Refs\nBIBLIOGRAPHY\n1 \n\nRybak \nLP. \n\nOtotoxicity of loop diuretics . Otolaryngol Clin North Am \n1993 ;26 :829 –844 .\n8233492 \n2 \n\nMatz \nGJ \n, \n\nBeal \nDD \n, \n\nKrames \nL. \n\nOtotoxicity of ethacrynic acid. Demonstrated in a human temporal bone . Arch Otolaryngol \n1969 ;90 :152 –155 .\n5794874 \n3 \n\nMatz \nGJ. \n\nThe ototoxic effects of ethacrynic acid in man and animals . Laryngoscope \n1976 ;86 :1065 –1086 .\n1084946 \n4 \n\nArnold \nW \n, \n\nNadol \nJB \nJr\n, \n\nWeidauer \nH. \n\nUltrastructural histopathology in a case of human ototoxicity due to loop diuretics . Acta Otolaryngol \n1981 ;91 :399 –414 .\n6973908 \n5 \n\nForge \nA \n, \n\nBrown \nAM. \n\nUltrastructural and electrophysiological studies of acute ototoxic effects of furosemide . Br J Audiol \n1982 ;16 :109 –116 .\n7093562 \n6 \n\nHirose \nK \n, \n\nLi \nSZ \n, \n\nOhlemiller \nKK \n, \n\nRansohoff \nRM. \n\nSystemic lipopolysaccharide induces cochlear inflammation and exacerbates the synergistic ototoxicity of kanamycin and furosemide . J Assoc Res Otolaryngol \n2014 ;15 :555 –570 .\n24845404 \n7 \n\nDjeric \nD \n, \n\nSchuknecht \nHF. \n\nHensen's cell cyst of the organ of Corti . Acta Otolaryngol \n1989 ; 108 :55 –61 .\n2763836 \n8 \n\nRybak \nLP \n, \n\nWhitworth \nC \n, \n\nScott \nV. \n\nFurosemide ototoxicity is enhanced in analbuminemic rats . Arch Otolaryngol Head Neck Surg \n1993 ;119 :758 –761 .\n8318205 \n9 \n\nWhitworth \nC \n, \n\nMorris \nC \n, \n\nScott \nV \n, \n\nRybak \nLP. \n\nDose‐response relationships for furosemide ototoxicity in rat . Hear Res \n1993 ;71 :202 –207 .\n8113137 \n10 \n\nKikuchi \nT \n, \n\nKimura \nRS \n, \n\nPaul \nDL \n, \n\nAdams \nJC. \n\nGap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis . Anat Embryol (Berl) \n1995 ;191 :101 –118 .\n7726389 \n11 \n\nGoldman \nWJ \n, \n\nBielinski \nTC \n, \n\nMattis \nPA. \n\nCochlear microphonic potential response of the dog to diuretic compounds . Toxicol Appl Pharmacol \n1973 ;25 :259 –266 .\n4715488 \n12 \n\nBrown \nRD. \n\nComparative acute cochlear toxicity of intravenous bumetanide and furosemide in the purebred beagle . J Clin Pharmacol \n1981 ;21 :620 –627 .\n7338573 \n13 \n\nSeyyedi \nM \n, \n\nViana \nLM \n, \n\nNadol \nJB \nJr.\n\nWithin‐subject comparison of word recognition and spiral ganglion cell count in bilateral cochlear implant recipients . Otol Neurotol \n2014 ;35 :1446 –1450 .\n25120196 \n14 \n\nFayad \nJN \n, \n\nLinthicum \nFH \nJr.\n\nMultichannel cochlear implants: relation of histopathology to performance . Laryngoscope \n2006 ;116 :1310 –1320 .\n16885730\n\n",
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"issue": "2(5)",
"journal": "Laryngoscope investigative otolaryngology",
"keywords": "Ototoxicity; furosemide; sensorineural hearing loss; stria vascularis",
"medline_ta": "Laryngoscope Investig Otolaryngol",
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"pages": "204-207",
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"title": "Temporal bone histopathology of furosemide ototoxicity.",
"title_normalized": "temporal bone histopathology of furosemide ototoxicity"
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"abstract": "Bacillus clausii is a gram-positive rod used as a probiotic to treat diarrhea and the side effects of antibiotics such as pseudomembranous colitis. We report a case of B. clausii bacteremia in a non-immunocompromised patient with active peptic ulcer disease and acute diarrhea. The probiotic was administered during the patient´s hospitalization due to diarrhea of infectious origin. B. clausii was identified in the bloodstream of the patient through Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) days after her discharge. Given the wide use of probiotics, we alert clinicians to consider this microorganism as a causative agent when signs of systemic infection, metabolic compromise, and hemodynamic instability establish after its administration and no pathogens have been identified that could explain the clinical course.",
"affiliations": "Semillero de Investigación de Medicina Interna, Universidad Tecnológica de Pereira, Pereira, Colombia. juan.garcia@utp.edu.co.;Departamento de Medicina Interna, Universidad Tecnológica de Pereira, Pereira, Colombia. juanhope9@hotmail.com.;Departamento de Medicina Interna, Universidad Tecnológica de Pereira, Pereira, Colombia. alexalzatej@gmail.com.;Laboratorio de Microbiología, Hospital Universitario San Jorge, Pereira, Colombia. edil2690@hotmail.com.",
"authors": "García|Juan Pablo|JP|;Hoyos|Julián Andrés|JA|;Alzate|John Alexander|JA|;Cristancho|Edilberto|E|",
"chemical_list": null,
"country": "Colombia",
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"doi": "10.7705/biomedica.5662",
"fulltext": "\n==== Front\nBiomedica\nBiomedica\nbio\nBiomédica\n0120-4157\n2590-7379\nInstituto Nacional de Salud\n\n34669274\n10.7705/biomedica.5662\nCase Report\nBacteremia after Bacillus clausii administration for the treatment of acute diarrhea: A case report\nBacteriemia tras la administración de Bacillus clausii para el tratamiento de la diarrea aguda: reporte de un casoGarcía Juan Pablo 1 *\nAlzate John Alexander 2\nHoyos Julián Andrés 2\nCristancho Edilberto 3\n1 Semillero de Investigación de Medicina Interna, Universidad Tecnológica de Pereira, Pereira, Colombia Universidad Tecnológica de Pereira Universidad Tecnológica de Pereira Pereira Colombia\n2 Departamento de Medicina Interna, Universidad Tecnológica de Pereira, Pereira, Colombia Universidad Tecnológica de Pereira Universidad Tecnológica de Pereira Pereira Colombia\n3 Laboratorio de Microbiología, Hospital Universitario San Jorge, Pereira, Colombia Hospital Universitario San Jorge Pereira Colombia\n* Corresponding author: Juan Pablo García, Carrera 23 No 13-12, Camino de Álamos, Pereira, Colombia Teléfono: (321) 741 1310 juan.garcia@utp.edu.co\nConflicts of interest: Authors declared not having any conflicts of interest\n\n15 10 2021\n10 2021\n41 Suppl 2 1320\n02 7 2020\n04 3 2021\n04 3 2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License\nAbstract\n\nBacillus clausii is a gram-positive rod used as a probiotic to treat diarrhea and the side effects of antibiotics such as pseudomembranous colitis. We report a case of B. clausii bacteremia in a non-immunocompromised patient with active peptic ulcer disease and acute diarrhea. The probiotic was administered during the patient's hospitalization due to diarrhea of infectious origin. B. clausii was identified in the bloodstream of the patient through Matrix- Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) days after her discharge. Given the wide use of probiotics, we alert clinicians to consider this microorganism as a causative agent when signs of systemic infection, metabolic compromise, and hemodynamic instability establish after its administration and no pathogens have been identified that could explain the clinical course.\n\nResumen\n\nBacillus clausii es un bacilo Gram positivo usado como probiótico para tratar la diarrea y efectos adversos de los antibióticos, como la colitis pseudomembranosa. Se reporta un caso de bacteriemia por B. clausii en una paciente inmunocompetente con enfermedad ulcerosa péptica activa y diarrea aguda. El probiótico le fue administrado durante la hospitalización debido al origen infeccioso de la diarrea. B. clausii se identificó en el torrente sanguíneo de la paciente, utilizando espectrometría de desorción/ionización mediante láser asistido por matriz (Matrix-Assisted Laser Desorption/Ionization, MALDI), acoplada a un detector de iones (Time of Flight, TOF) (MALDI-TOF), días después de haber sido dada de alta.\n\nDado el amplio uso de los probióticos, alertamos a los clínicos para que consideren este microorganismo como agente causal cuando se detecten signos de infección sistémica, compromiso metabólico, e inestabilidad hemodinámica tras su administración, y no se haya identificado ningún patógeno que pueda explicar el cuadro clínico.\n\nKeywords:\n\nBacillus clausii\nbacteremia\ndiarrhea\nprobiotics\ngram-positive bacteria\nPalabras clave:\n\nBacillus clausii\nbacteriemia\ndiarrea\nprobióticos, bacterias Gram positivas\n==== Body\npmcBacillus clausii is a gram-positive, spore-forming rod, widely used as a probiotic (1). Probiotics have been used for hundreds of years to treat different diseases. Since the 1960s they have been used to treat viral diarrhea in children and the side effects of antibiotic administration (2). Antibiotic-associated side effects and Clostridioides difficile diarrhea are well-known scenarios where probiotics are proven to be efficient (3). Recent studies on the safety of B. clausii administration have concluded that it has intrinsic resistance mechanisms to some antibiotics (e.g. macrolides), but no toxin-producing genes or transferrable antimicrobial resistance, which makes it very safe (4,5). However, other studies have shown no related side effects linked to its use (6-8), and, on the other hand, side effects have been inconsistently reported and not adequately assessed. Anyway the World Health Organization has acknowledged probiotics might be responsible for systemic infections and deleterious metabolic activity (9).\n\nEthical considerations\n\nThe patient gave her informed consent to access and submit her clinical data as a case report for scientific purposes. We submitted the manuscript and the informed consent to the ethics committee at Universidad Tecnológica de Pereira and obtained its endorsement to publish the case.\n\nTable 1 Blood analysis, renal function, electrolyte control, and hemostatic parameters\n\n\tPrevious to admission\tAdmission day\tReference values\t\nWhite blood cells (cell/ml)\t10,510\t8,080\t4,500\t-10,000\t\nNeutrophils (cell/μΙ)\t8,600\t6,230\t2,200\t- 6,500\t\nHemoglobin (g/dl)\t13.5\t14.3\t13.5\t- 17.5\t\nPlatelets (cell/μΙ)\t198,000\t240,000\t150,000-\t350,000\t\nChloride (mmol/L)\t79\t76\t98\t- 107\t\nPotassium (mmol/L)\t2.2\t2\t3.6\t- 5\t\nSodium (mmol/L)\t122\t122\t137\t- 145\t\nGlucose (mg/dl)\t98\t105\t60\t- 110\t\nCreatinine (mg/dl)\t\t0.3\t0.66\t- 1.25\t\nBlood urea nitrogen (mg/dl)\t\t9\t9\t- 21\t\nThromboplastin partial time (s)\t\t30.1\t23.6\t- 34.8\t\nProthrombin time (s)\t\t15.3\t11\t- 15\t\n\nCase report\n\nAn 87-year-old woman arrived at the emergency room of a third-level hospital in Colombia reporting 12 days of watery, abundant, fetid diarrhea accompanied by brown-colored vomit and melena. She was referred from a first-level hospital with several laboratory tests completed. After admission, critical care clinicians evaluated the patient and admitted her to the intermediate care unit. Her medical history included arterial hypertension, chronic obstructive lung disease (COPD), and a cholecystectomy.\n\nThe patient appeared somnolent throughout the initial physical evaluation. She also had elevated systolic blood pressure (150/80 mm Hg) and tachypnea (22 breaths per minute), she had no fever (36,1°C), her pulse was 80 beats per minute, her oxygen saturation 97%, the Glasgow Coma Scale score was 13/15, she had dried oral mucosa and rales in both of her pulmonary fields. The examination was otherwise normal.\n\nThe previous laboratory findings and those during the patient's admission are summarized in table 1. We initially administered ampicillin/sulbactam (1.5 grams every six hours) as Klebsiella pneumoniae was documented in a urine culture brought by the patient (taken five days before admission) and bacterial diarrhea was suspected. There was no previous or recent documentation of any urinary symptoms and, therefore, asymptomatic bacteriuria was suspected.\n\nTwo days later, an upper gastrointestinal endoscopy was done. It showed three Forrest Class III gastric ulcers for which proton pump inhibitors were administered. Sodium, potassium, and water deficits were in constant reposition. The patient did not present new episodes of melena or vomit, only occasional diarrheic depositions during her stay at the intermediate care unit.\n\nBased on her clinical evolution, the patient was then transferred to the internal medicine unit ten days after admission. She appeared disorientated, but no additional signs or symptoms were present, aside from diarrheic depositions. An astringent diet was started but abdominal pain and diarrhea persisted. The internal medicine physician decided to prescribe an Enterogermina™ probiotic (2 billion/5 ml B. clausii spore suspension, strains: SIN, O/C, T, and N/R) every six hours as of the 16th day of her hospital stance.\n\nOn day 19, we interviewed the patient again in search of urinary symptoms and she reported having dysuria and abdominal pain, which she associated with a previous bladder catheterization. At this point, urine analysis, Gram stain, culture, and antimicrobial susceptibility testing were done. The urine analysis revealed positive leukocyte esterase, pyuria, and bacteriuria. The Gram stain identified a Gram-negative rod characterized three days later in the urine culture as Escherichia coli with an inhibitor-resistance TEM (IRT) pattern as shown by evidence of resistance to ampicillin (MIC ≥32 μg/ ml), ampicillin/sulbactam (MIC ≥32 μg/ml), and preserved sensibility to all cephalosporins. We established a diagnosis of probable urinary tract infection (UTI) and, given that the antimicrobial susceptibility testing results were only available 3 days later, we started the empirical administration of cephalothin (1 g/6 h) pending results.\n\nOn the 20th day of the hospital stay, the patient began shivering, sweating, and did not appear well. Her heart rate was 137 beats per minute, her respiratory rate was 30 breaths per minute, her temperature was 38.7 °C, her blood pressure was 89/48 mm Hg, and her oxygen saturation was 88% without oxygen support. There were signs of phlebitis on the right upper limb where the peripheral catheter was placed. The blood analysis showed a white blood cell count of 9,020/mm3 [4,500-10,000], neutrophilia of 89%, hemoglobin of 9.8 g/dl [12-15.5], and C-reactive protein of 6.3 mg/dl [0-5] (table 2). A pair of anaerobic and aerobic blood cultures were drawn from peripheral intravenous access. Cephalothin was suspended and intravenous vancomycin (1 g/12 h) and cefepime (1 g/12 h) were started to target microorganisms responsible for sepsis in the context of a Gram-negative rod UTI and Gram-positive cocci phlebitis. Supplementary oxygen was administered by nasal cannula due to low oxygen arterial pressure. Figure 1 summarizes the clinical course after the administration of Enterogermina™.\n\nTable 2 Laboratory and microbiology test results on the 20th day of hospital stance\n\n\t20 th day of hospital stance\t26th day of hospital stance\tReference values\t\nWhite blood cells (cell/ml)\t9,020\t4,960\t4,500 - 10,000\t\nNeutrophils (cell/μl)\t7,810\t2,460\t2,200 - 6,500\t\nHemoglobin (g/dl)\t9.8\t10.9\t13.5 - 17.5\t\nMean corpuscular volume (fl)\t85.5\t83.4\t82 - 96\t\nRed cell distribution width (%)\t14.4\t14.5\t11 - 15.5\t\nPlatelets (cell/pl)\t257,000\t246,000\t150,000 - 350,000\t\nC-reactive protein (mg/dl)\t6.3\t-\t0 - 5\t\nSerum creatinine (mg/dl)\t0.5\t-\t0.52 - 1.04\t\nBlood urea nitrogen (mg/dl)\t8\t-\t7 - 18\t\nArterial blood gases (20th day)\t\npH\t7.48\t\t\t\npCO2 (mm Hg)\t24\t\t35 - 45\t\npO2 (mm Hg)\t66\t\t80 - 110\t\nHCO3 std (mmol/L)\t21.1\t\t-\t\nA-aD3O2\t26\t\t-\t\nPotassium (mmol/L)\t3\t\t3,6 - 5\t\nSodium (mmol/L)\t130\t\t137 - 145\t\nGlucose (mg/dl)\t122\t\t60 - 110\t\nBlood cultures (20th day)\t\nAerobic\tGram-positive rods\t\tNone\t\nAnaerobic\tGram-positive rods\t\tNone\t\nGastrointestinal Film Array Panel™ (22nd day)\t\nEnteroaggregative and Enteropathogenic E. coli\t\n\nFigure 1 Summary of bacteremia course\n\nOne day later, the patient's vital signs were back to normal. She tolerated oral intake, but still had diarrhea. Periodically, we assessed the renal function in creatinine and blood urea nitrogen (BUN) samples, which were never out of range. However, abdominal pain and diarrhea persisted. On day 22, we did coprology, stool culture, gastrointestinal FilmArray™, colonoscopy, and abdominal ultrasonography in search of the infectious source of diarrhea. Four days later, the FilmArray™ was positive for enteroaggregative and enteropathogenic E. coli (Protocol: Stool FA v2.3, Pouch: GI Panel v2.1). The other microbiological tests and diagnostic images were normal. By the 26th day, a new complete blood cell count was within normal range, except for the persistence of mild anemia.\n\nThe results from the blood culture Gram stain were available on day 22 (figure 2), upon which we added intravenous ampicillin (2 g/4 h) to the previous antimicrobial therapy to target the Gram-positive rods identified. An infectious disease specialist assessed the therapy and decided to start intravenous gentamicin (5 m/kg in two doses per day for 7 days), continue the recently added ampicillin, and suspend the empiric therapy with vancomycin and cefepime. The patient's clinical course improved and her vital signs were within normal range. The last episode of diarrhea was on the 27th day. The 7-day antimicrobial treatment was completed and supplementary oxygen was gradually removed. The patient was discharged on the 33rd day with complete clinical recovery.\n\nFigure 2 Gram stain, blood culture, and MALDI-TOF results. Left: Blood culture, Gram stain, 100X. Right: Gram-positive rod colonies that grew on blood culture in solid medium, Agar Columbia (BioMérieux brand). MALDITOF result: Type of sample: blood culture. Identified microorganism: Bacillus clausii. This is a sensitive and high-precision technique for the identification of microorganisms through mass spectrometry analysis. Methods sequencing the 16s subunit have a 98% concordance for microorganism identification (Score: 2.4, highly reliable identification at genera and species levels)\n\nAs the typification of the Gram-positive rod identified in the blood culture Gram stain was not possible, we resorted to MALDI-TOF spectrometry whose results were available 2 days after the patient was discharged reporting the presence of B. clausii (figure 2).\n\nDiscussion\n\nWe reported the case of an 87-year-old female patient with upper gastrointestinal bleeding, diarrhea of infectious origin, and recent use of proton pump inhibitors in whom probiotics containing B. clausii were administered and later identified as the cause of bacteremia and hemodynamic instability. We discuss here previously published case reports of bacteremia due to B. clausii administration, recommended scenarios to administer probiotics, and the potential risk factors/clinical profiles that could make a patient susceptible to bacteremia caused by probiotics containing Bacillus spp.\n\nThe systemic infections, especially Bacillus spp. bacteremia, are rare conditions and, frequently, they are considered contaminant bacteria in blood cultures. The most common agent of Bacillus spp. bacteremia is Bacillus cereus but there are reports of bacteremia by probiotics containing Bacillus subtilis and B. clausii like the case we are now reporting (10,11).\n\nRecently, three cases of immunocompromised patients who developed clinically significant bloodstream infections by B. clausii were reported (12). Two patients had stage IV lung cancer and the third one presented with septic shock due to ischemic colitis. As in these cases, our patient also had a fever and an increased count of white blood cells. While these patients died from other causes not related to B. clausii bacteremia, our patient survived throughout the hospital stance after adequate treatment of upper gastrointestinal bleeding and timely antimicrobial therapy. A limitation in our case report is the absence of antimicrobial susceptibility testing on B. clausii.\n\nConversely, the isolate from one of the reported patients was penicillin-, clindamycin-, and tetracycline-resistant.\n\nPrincess, et al. published a case report of bacteremia in an immunocompetent adult with acute diarrhea under broad-spectrum antibiotics prescribed to treat K. pneumoniae respiratory and surgical wound infection in a patient that had evacuating craniectomy after cerebral vein thrombosis and intraparenchymal bleeding (13). The patient also had a fever after probiotic administration. B. claussi was initially isolated in blood cultures as a Grampositive rod and identified through a MALDI-TOF assay, as was our case. We treated our patient with ampicillin plus gentamicin while Princess, et al. prescribed teicoplanin; our patient's isolate was penicillin-resistant only (MIC: 32 μg/ml) but, besides vancomycin and ciprofloxacin, no other antibiotics were tested given there were no interpretative guidelines. Another limitation of our study was that no control blood culture was done to assess the microbiological response to treatment.\n\nJoshi, et al. reported the case of a pediatric patient with congenital heart disease and recurrent lower respiratory tract infections that received B. clausii probiotic to treat acute diarrhea (14) and was treated with IV vancomycin. The isolate from three blood culture samples was identified through MALDI-TOF. The strain was not associated with penicillin resistance but it is noteworthy that B. clausii bacteremia recurred although there was no repeated probiotic dose and the agent persisted in the blood culture despite appropriate vancomycin IV therapy.\n\nThe main conclusion from this case series is the importance of being cautious when using probiotics, especially if there is a risk of a fatal outcome. Our case report adds to a previous one of B. clausii bacteremia with no underlying immunocompromising conditions such as active cancer or severe malnourishment. Even though there is no formal description of risk factors to develop infections by this probiotic, we can conclude that they may occur irrespective of the patient's immune status. In table 3 we summarize the profile of the patients reported highlighting those characteristics that may behave as risk factors and encouraging awareness among attending physicians. It has yet to be determined if bacteremia by B. clausii could be related to worse outcomes as there are now two out of six patients who succumbed to conditions apparently not related to probiotic administration. The conditions related to an increased risk of bacteremia due to other types of probiotics (e.g., Lactobacillus) are older age, congenital immune deficiencies, treatment with antitumoral chemotherapy or ionizing radiation, extensive gastrointestinal ulcers, treatments with broad-spectrum antibiotics, and diabetes (15).\n\nTable 3 Profile of patients documented with bacteremia due to Bacillus clausii administration\n\nAuthors\tYear of publication\tAge\tPatients' profile\tTreatment\tAntimicrobial susceptibility\t\nGargar JD, et al.\t2019\tND\tStage IV lung cancer and pneumonia\tND\tOne case reported resistance to clindamycin, penicillin, and tetracycline.\t\nGargar JD, et al.\t2019\tND\tStage IV lung cancer and pneumonia\tND\t\nGargar JD, et al.\t2019\tND\tSeptic shock from ischemic colitis\tND\t\t\nHubiche T, et al.\t2019\t5 months\tCongenital heart disease, malnourishment, recurrent respiratory tract infections, repeated hospital/ICU admissions, and broad-spectrum antibiotics\tVancomycin\tSusceptibility to vancomycin and penicillin (E-test)\t\nPrincess, et al.\t2020\tMiddle aged\tType 2 diabetes, decompressive craniotomy, and broad-spectrum antibiotics\tTeicoplanin\tSusceptibility to ciprofloxacin and vancomycin. Resistance to penicillin (E-test)\t\n\nBacillus clausii safety profile has been confirmed in randomized control trials for efficient treatment of acute diarrhea related to viral infection, Clostridioides difficile infection, and antibiotic-associated diarrhea (16). Notwithstanding the published recommendations, the risks of Bacillus probiotics include the production of enteric toxins and toxicity for normal cells (17). Physicians are more aware of probiotics' benefits than of their risks, and, therefore, further research and case reporting are necessary to identify their potential harm in certain clinical contexts. We observed that Enterogermina™ was not efficient to treat our patient's diarrhea by enteropathogenic and enteroaggregative E. coli as diarrhea persisted for 11 days after its administration. Enterogermina™ (Bacillus clausii) administration in patients with recent upper gastrointestinal bleeding, acute diarrhea, and the use of proton pump inhibitors, which can diminish stomach pH and favor bacterial colonization, may lead to bacteremia through direct invasion or gut translocation. Therefore, B. claussi should be considered as a possible agent in the presence of systemic signs of infection, metabolic compromise, and hemodynamic instability when no other pathogens are identified to explain the clinical course. In such cases, the treatment should be aimed at fighting this Gram-positive rod with antibiotics other than clindamycin, erythromycin, and chloramphenicol, as B. clausii has intrinsic resistance against them (4).\n\nAuthor contributions:\n\nFunding:\n\nCitation: García JP, Hoyos JA, Alzate JA, Cristancho E. Bacteremia after Bacillus clausii administration for the treatment of acute diarrhea: a case report. Biomédica. 2021;41(Supl.2):13-20. https://doi.org/10.7705/biomedica.5662\n\nJohn Alexander Alzate: attending physician and idea of presenting the case report\n\nJuan Pablo García: reviewed the patient's record to build up the case report and was directly involved with the patient's in-hospital attention.\n\nJulián Andrés Hoyos: reviewed the patient's record to build up the case report, validated the laboratory results according to the patient's clinical course, and assessed the antimicrobial therapy administered to the patient\n\nEdilberto Cristancho: re-certified the laboratory results and the microbiology samples and cultures All authors read, edited, wrote, and approved the final manuscript.\n\nNone.\n==== Refs\nReferences\n\n1 Duc LH Hong HA Barbosa TM Henriques AO Cutting SM Characterization of Bacillus probiotics available for human use Appl Environ Microbiol 2004 70 2161 2171 https://doi.Org/10.1128/AEM.70.4.2161 15066809\n2 Jayanthi N Ratna MS Bacillus clausii - The probiotic of choice in the treatment of diarrhoea J Yoga Phys Ther 2015 5\n3 Guarino A Guandalini S Lo Vecchio A Probiotics for prevention and treatment of diarrhea J Clin Gastroenterol 2015 49 Suppl.1 37 45 10.1097/MCG.0000000000000349\n4 Lakshmi SG Jayanthi N Saravanan M Ratna MS Safety assesment of Bacillus clausii UBBC07, a spore forming probiotic Toxicol Rep 2017 4 62 71 10.1016/j.toxrep.2016.12.004 28959626\n5 Upadrasta A Pitta S Madempudi RS Draft genome sequence of Bacillus clausii UBBC07, a spore-forming probiotic strain Genome Announc 2016 4 10.1128/genomeA.00235-16\n6 Sudha MR Bhonagiri S Kumar MA Efficacy of Bacillus clausii strain UBBC-07 in the treatment of patients suffering from acute diarrhoea Benef Microbes 2013 4 211 216 10.3920/BM2012.0034 23443952\n7 Ianiro G Rizzatti G Plomer M Lopetuso L Scaldaferri F Franceschi F Bacillus clausii for the treatment of acute diarrhea in children: A systematic review and meta-analysis of randomized controlled trials Nutrients 2018 10 1074 10.3390/nu10081074\n8 Drugs.com Bacillus clausii. Wolters Kluwer Health 2018 https://www.drugs.com/npp/bacillus-clausii.html\n9 Doron S Snydman DR Risk and safety of probiotics Clin Infect Dis 2015 60 Suppl. 2 S129 S134 10.1093/cid/civ085 25922398\n10 Bennet J Dolin R Blaser M Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases 9th edition Philadelphia Elsevier 2020 2571 2573\n11 Oggioni M Pozzi G Valensin P Galieni P Bigazzi C Recurrent septicemia in an immunocompromised patient due to probiotic strains of Bacillus subtilis J Clin Microbiol 1998 36 325 326 10.1128/JCM.36.1325-326.1998 9431982\n12 Gargar JD Divinagracia RM When good things go bad: A case series of bacteremia from probiotics Chest 2019 155:92A 155:92A 10.1016/j.chest.2019.02.091 30296418\n13 Princess I Natarajan T Ghosh S When good bacteria behave badly: A case report of Bacillus clausii sepsis in an immunocompetent adult Access Microbiol 2020 2 1 3 10.1099/acmi.0O00097\n14 Sangeeta J Soonu U Supratim S Suverna K Anjali S Bacillus clausii septicemia in a pediatric patient after treatment with probiotics Pediatr Infect Dis J 2019 38 228 230 10.1097/INFO000000000002350\n15 Brunser O Inocuidad, prevención y riesgos de los probióticos Rev Chil Pediatr 2017 88 534 540 10.4067/S0370-41062017000400015 28898324\n16 Castro J de Kesavelu D Lahiri KR Chaijitraruch N Chongsrisawat V Jog PP Recommendations for the adjuvant use of the poly-antibiotic - resistant probiotic Bacillus clausii (O/C, SIN, N/R, T) in acute, chronic, and antibiotic-associated diarrhea in children: Consensus from Asian experts Trop Dis Travel Med Vaccines 2020 4 1 15 10.1186/s40794-020-00120-4\n17 Paik NLWKH Bacillus strains as human probiotics: Characterization, safety, microbiome, and probiotic carrier Food Sci Biotechnol 2019 28 1297 1305 10.1007/s10068-019-00691-9 31695928\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0120-4157",
"issue": "41(Sp. 2)",
"journal": "Biomedica : revista del Instituto Nacional de Salud",
"keywords": "Bacillus clausii; bacteremia; diarrhea; probiotics; gram-positive bacteria",
"medline_ta": "Biomedica",
"mesh_terms": null,
"nlm_unique_id": "8205605",
"other_id": null,
"pages": "13-20",
"pmc": null,
"pmid": "34669274",
"pubdate": "2021-10-15",
"publication_types": "D016428:Journal Article",
"references": "30103531;25922398;33110611;28898324;23443952;33005864;28959626;31033906;9431982;26447963;27103711;31695928;15066809",
"title": "Bacteremia after Bacillus clausii administration for the treatment of acute diarrhea: A case report.",
"title_normalized": "bacteremia after bacillus clausii administration for the treatment of acute diarrhea a case report"
} | [
{
"companynumb": "CO-AUROBINDO-AUR-APL-2022-004440",
"fulfillexpeditecriteria": "1",
"occurcountry": "CO",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPICILLIN SODIUM\\SULBACTAM SODIUM"
},
... |
{
"abstract": "BACKGROUND\nLong-term survivors of cystic fibrosis (CF) have a dramatic increase in the risk of osteoporosis and incident fracture. The objective of this work is to characterize a CF related bone disease in a Portuguese cohort of CF patients.\n\n\nMETHODS\nWe performed a cross-sectional, observational study on a cohort of CF adult patients. Clinical status, laboratory parametres, nutrition, lung function tests, genetics and bone mineral density (BMD) data were collected from a CF reference centre.\n\n\nRESULTS\nOf 30 patients, 53.3% were males (n=16). Median age was 32.5 (27.0; 32,5) and median body mass index (BMI) was 22,04 (19,85; 24,55), with 4 patients (13.3%) being underweight (BMI<18.5 kg/m²). Four patients (13.3 %) were diagnosed with osteoporosis and 15 patients (50%) has low BMD. Among them, 2 (6.7%) had fragility fractures. A moderate correlation was found between the lumbar spine (LS) BMD and BMI and, as expected, femural neck BMD and LS BMD has moderate to strong correlations with BMD Z scores.\n\n\nCONCLUSIONS\nDespite the young middle age we found a high prevalence of low BMD and osteoporosis in patients with CF. Early recognition and treatment are the most effective strategies for reducing the morbidity due to osteoporosis in these patients.",
"affiliations": "Rheumatology, Centro Hospitalar Universitário São João.;Rheumatology, Centro Hospitalar Universitário São João.;Pneumology, Centro Hospitalar Universitário São João.;Pneumology, Centro Hospitalar Universitário São João.;Rheumatology, Centro Hospitalar Universitário São João.",
"authors": "Garcia|Salomé|S|;Terroso|Georgina|G|;Amorim|Adelina|A|;Redondo|Margarida|M|;Costa|Lúcia|L|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-464X",
"issue": "46(3)",
"journal": "Acta reumatologica portuguesa",
"keywords": null,
"medline_ta": "Acta Reumatol Port",
"mesh_terms": "D000328:Adult; D015519:Bone Density; D003430:Cross-Sectional Studies; D003550:Cystic Fibrosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis; D011174:Portugal; D055815:Young Adult",
"nlm_unique_id": "0431702",
"other_id": null,
"pages": "283-285",
"pmc": null,
"pmid": "34667140",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Bone involvement in young adults with cystic fibrosis - a Portuguese cohort.",
"title_normalized": "bone involvement in young adults with cystic fibrosis a portuguese cohort"
} | [
{
"companynumb": "PT-AMGEN-PRTSP2021157603",
"fulfillexpeditecriteria": "2",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
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