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"abstract": "BACKGROUND\nGastric cancer ranks the fifth most common cancer, and the third leading cause of cancer-related deaths worldwide. Gastric cancer with liver metastasis (GCLM) has devastating prognosis, however, optimal treatment of GCLM, especially in elderly patients, has yet to be clarified.\n\n\nMETHODS\nA 75-year-old man was diagnosed with advanced gastric cancer (GC), presenting with acute gastrointestinal bleeding and synchronous metastatic lesion in liver. Based on multidisciplinary team (MDT)'s decision, this patient underwent distal palliative gastrectomy with R1 margin. Histopathological diagnosis was stage IV gastric adenocarcinoma (pT3N2M1), HER2 negative. The patient was treated with chemotherapy and argon-helium cryoablation of liver and lung metastases.HER-2 gene amplification was identified in peripheral blood at later stage of therapy. The patient had been followed-up for 39 months, in sharp contrast to a median survival time of 13.8 months for majority of advanced GC.\n\n\nCONCLUSIONS\nPalliative distal gastrectomy in combination with chemotherapy and cryoablation significantly prolongs overall survival of an elderly patient with GCLM.",
"affiliations": "Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, China.;Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, China.;Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, China.;Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, China.;Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, China.;Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000, China. lzhw0451@163.com.",
"authors": "Li|Qingwei|Q|;Xu|Xuejun|X|;Su|Dan|D|;Zhou|Tianshuo|T|;Wang|Guangyu|G|;Li|Zhiwei|Z|",
"chemical_list": "D000970:Antineoplastic Agents; D000077150:Oxaliplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-019-5683-4",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 568310.1186/s12885-019-5683-4Case ReportLong-term survival of an elderly patient with advanced gastric cancer after combination therapy: a case report and literature review Li Qingwei Xu Xuejun Su Dan Zhou Tianshuo Wang Guangyu Li Zhiwei +86 150 0468 3651lzhw0451@163.com 0000 0004 1808 3502grid.412651.5Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150000 China 16 5 2019 16 5 2019 2019 19 45923 10 2018 8 5 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nGastric cancer ranks the fifth most common cancer, and the third leading cause of cancer-related deaths worldwide. Gastric cancer with liver metastasis (GCLM) has devastating prognosis, however, optimal treatment of GCLM, especially in elderly patients, has yet to be clarified.\n\nCase presentation\nA 75-year-old man was diagnosed with advanced gastric cancer (GC), presenting with acute gastrointestinal bleeding and synchronous metastatic lesion in liver. Based on multidisciplinary team (MDT)‘s decision, this patient underwent distal palliative gastrectomy with R1 margin. Histopathological diagnosis was stage IV gastric adenocarcinoma (pT3N2M1), HER2 negative. The patient was treated with chemotherapy and argon-helium cryoablation of liver and lung metastases.HER-2 gene amplification was identified in peripheral blood at later stage of therapy. The patient had been followed-up for 39 months, in sharp contrast to a median survival time of 13.8 months for majority of advanced GC.\n\nConclusions\nPalliative distal gastrectomy in combination with chemotherapy and cryoablation significantly prolongs overall survival of an elderly patient with GCLM.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12885-019-5683-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nGastric cancerLiver metastasisChemotherapyCombination therapyHAIYAN FOUNDJJLX2016-01Li Zhiwei issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nGastric carcinoma (GC) is the fourth most common malignancies and the third leading cause of cancer-related death worldwide, Surgical resection remains the only curative option [1]. In China, there are estimated 221,478 deaths per year due to GC, accounting for nearly half of the globally total deaths from GC [2]. Most of the patients with GC are diagnosed at advanced stages, frequently presenting invasion or metastasis [3]. Approximately, 25 and 30%, respectively, of Chinese patients have early or late (metastatic) stage GC at diagnosis. While in the United States, 36% of patients have early stage at diagnosis [4].\n\nAt present, an optimal treatment of GCLM (which is classified as M1 clinical stage) remains debated [5, 6]. Hepatic metastases from GC are considered as unresectable since these lesions present as multiple nodules, which are distributed in hepatic lobes, as well as extrahepatic organs [7, 8]. Devastating prognosis is usually expected for unresectable GC. Under this circumstance, palliative chemotherapy will be highly recommended [9]. Among patients treated with chemotherapy alone, their 5-year OS rate was only 1% (with a median survival time of 14 months). Conversion surgery may be attributed to long-term survival in selected patients.\n\nThe role of gastrectomy playing in treating metastatic GC (in the absence of urgent symptoms, such as bleeding or obstruction) is yet to be illustrated. A higher risk from surgery and longer recovery time are expected for elderly patients. Through reducing tumor volume, debulking surgery may prolong survival and/or delay the onset of life-threatening symptoms [10]. Elderly patients with GCLM are under-represented in clinical trials, with few reported studies in this setting.\n\nHere, we have described a specific case of long-term survival after palliative distal gastrectomy combined with chemotherapy and argon-helium cryoablation of liver and lung metastases. The observed improved outcome definitely merits a prospective study to explore potential survival benefits in specifically selected patients, especially for those who urgently require palliation of serious symptoms, such as bleeding or obstruction.\n\nCase presentation\nA 75-year-old man suffered from abdominal pain and melena. Emergency gastroscopy observed large curvature, posterior wall and small curvature of the antrum. Huge flat uplift occupying lesions were identified, with worm-like erosion edges, uneven bottom, visible bleeding from blood vessels and blood clots (Fig. 1 [green frame]; Fig. 2.a.b). An upholstery lesion (in the maximum diameter of 1.5 cm) with white protrusions was observed close to the anterior wall of small curve. Whole body fluorine-18 fluorodeoxyglucose (18F–FDG) positron emission tomography/computed tomography (PET/CT) identified a hypodense mass in segment 6 of liver. Intense 18F–FDG distribution obtained a maximum standardized uptake value (SUV) of 3.5(Fig. 2, c-e). After MDT consultation, R0 resection might be impossible to achieve. Palliative chemotherapy was relatively contraindicated due to a high risk of gastrointestinal bleeding. The patient underwent palliative gastrectomy to prevent from bleeding and perforation. No liver metastatic lesion was resected. On microscopic examination, the primary tumor was identified as a well to mixed differentiated gastric adenocarcinoma (75% papillary adenocarcinoma and 25% moderately differentiated tubular adenocarcinoma), which had invaded subserosa layer. Five of 35 lymph nodes were positive for metastases, without venous or lymphatic vasculature invasion. This GC tumor fulfilled the criteria of stage IVa (pT3N2M1), based on the American Joint Committee on Cancer (AJCC) TNM staging classification for carcinoma of the stomach (7th edition, 2012) [11]. This tumor was negative for HER2 amplification.Fig. 1 Information of this case report has been organized into a timeline\n\nFig. 2 Endoscopy and PET/CT revealed GCLM. a. posterior wall of the antrum: worm-like erosion edges, visible bleeding from blood vessels and blood clots. b. small curvature of the antrum, white protrusions. c The lesion was located in the gastric antrum(SUVmax13.3), indicating GC. d Lymph node metastasis was observed below the gastric antrum (SUVmax3.3). d. Computed Tomography Image revealed a single liver metastasis, located in segments 6. e PET/CT identified localized radionuclide concentration (SUVmax3.5)\n\n\n\nIn the first month post-operation, this patient was transferred to our hospital for comprehensive evaluation. He had received 5 cycles of mFOLFOX6 (5-fluorouracil/folinic acid, oxaliplatin) regimen as the first-line chemotherapy. Liver metastatic lesions were shrunk, so that the efficacy was assessed as partial response (PR) (Fig. 3a). Then the patient received cryoablation with argon and helium on hepatic metastases; subsequently received post-operational chemotherapy (mFOLFOX6 protocol) for 3 cycles. The efficacy was evaluated as stable disease (SD) (Fig. 3b). Chemotherapy was stop ped due to grade3 neutropenia. The patient was regularly followed-up afterwards. Seven months after the cessation of treatment, CT scan identified new lesions in the lungs and liver (Fig. 1 [red frame]; Fig. 4a, b, c). The patient started to receive 3 cycles of Paclitaxel plus S-1 (second-line) chemotherapy since April 2015, however, the short-term effect was assessed as progressive disease (PD)(Fig. 4d, e).Then the patient received mFOLFOX6 chemotherapy for 7 cycles, with the efficacy defined as SD. Afterwards, pulmonary and hepatic metastatic lesions were treated with cryoablation separately (Fig. 5). The patient received another 3 cycles of mFOLFOX6 regimen after cryoablation, undergoing regular observation. Six months later, new metastases were identified and the patient received FOLFIRI regimen chemotherapy for 9 cycles. The efficacy was evaluated as PD. At this point, HER-2 gene amplification was identified using peripheral blood sample (Fig. 6). During the entire treatment period, the patient’s CA19–9 and CEA were basically maintained at normal levels (Additional file 1: Figure S1). On August 30, 2016, the patient was enrolled into a randomized, double-blind, placebo-controlled trial of Anlotinib, which was designed for advanced GC as second-line therapy. After taking 6 cycles of Anlotinib (12/10 mg, d1–14, qd, po, q3w), the efficacy was evaluated as SD (Fig. 7). Treatment-related proteinuria occurred during the second cycle. After the 8th cycle, the efficacy was evaluated as PD. The patient withdrew from the clinical trial on March 17, 2017. On July 24, 2017, the patient died and his overall survival time was 39 months.Fig. 3 Treatment protocol after reduction surgery. a The patient received 5 cycles of mFOLFOX6 regimen chemotherapy. The efficacy was assessed as PR. b The patient received cryoablation of argon and helium with hepatic metastases, and 3 cycles of mFOLFOX6 chemotherapy. The efficacy was evaluated as SD\n\nFig. 4 CT and MRI scans identified new lesions in the lungs and liver espectively seven months after the first-line chemotherapy and cryoablation (April 2015). a. lesion cryoablation was stable, arterial phase. b. new liver lesion. c New metastatic lesions in the lungs. c and d. The efficacy was evaluated as PD after Paclitaxel plus S-1 (second-line) chemotherapy since April 2015\n\nFig. 5 Comparison of tumor status before and after the second cryotherapy\n\nFig. 6 Gene sequencing using peripheral blood sample.Red box highlighted HER2 amplification, which could be treated with pertuzumab (Herceptin)\n\nFig. 7 The patient was enrolled into a randomized, double-blind, placebo-controlled clinical trial of Anlotinib\n\n\n\nDiscussion and conclusions\nGCLM refers to liver lesions originating from primary GC, which remains a major cause of GC-related deaths, with a 5-year survival rate of 0–10% in unselected cases [3]. Surgery with curative attempt is a key component for multidisciplinary approach. Hepatectomy may be performed on a small number of metastatic nodules, and not restricted to a solitary nodule, provided no other non-curable factors. Whether synchronous metastases have better prognosis than metachronous metastases remains controversial. Palliative gastrectomy could be considered for GCLM patients if they fulfill following criteria: (1) Through removing a bulky tumor, potential life-threatening symptoms such as obstruction, perforation, or bleeding maybe eliminated. (2) A decrease in tumor load may render the residual cancer cells more sensitive to adjuvant therapy. (3) Reduction in tumor volume may diminish nutrient burden on the patient exerted by the tumor. (4) As the tumor produce immunosuppressive cytokines, reducing the tumor burden may help activate anti-tumor immunologic machinery [12, 13].In this case, palliative gastrectomy contributes to prolonged survival.\n\nClinical benefit of resecting GCLM remains controversial, especially for elderly patients [14, 15]. Clinical outcome for hepatic resection was disappointing due to high rates of recurrence and death. Occult intrahepatic metastases at the time of surgery may lead to high incidence of intrahepatic recurrence [16]. A second hepatic resection is rarely indicated. Postoperative monitoring of liver and adjuvant chemotherapy may become a feasible strategy for improving survival [17]. In this case, chemotherapy plays a critical role in improving prognosis. Hepatic lesions were used to screen drug sensitivity vs. resistance, and mFOLFOX regimen was indicated to be more effective. Local ablation has emerged as a promising alternative or complement to resection, especially for elderly patients with GCLM. Ablative techniques include radiofrequency thermal ablation (RFA) [18, 19], microwave ablation (MWA) [20, 21], and cryoablation [22]. The average survival time of ablative combined with chemotherapy for liver metastases was 16.1 months [23]. According to the retrospective study, the 5-year survival rate after ablative treatment was not significantly different from that of hepatectomy [24]. This patient underwent 3 times of local cryotherapy. After the first cryotherapy, perioperative chemotherapy was conducted. The patient’s disease-free survival had reached 7 months. This procedure for elderly patients with GCLM is effective and safe (with low mobility), which may be performed repeatedly on an outpatient basis with a good palliative effect.\n\nSupporting evidence from clinical trials is required to guide decision-making when treating elderly patients with GCLM. Age alone is no contraindication for resections of GI. Although no survival benefit for neoadjuvant treatment in patients over 70 years is found [25]. In this case, if the patient was not at risk of bleeding, we may prefer neoadjuvant chemotherapy. Preoperative chemotherapy significantly prolongs the survival of the esophago-gastric adenocarcinomas patient with primary resection [26]. In regards to chemotherapy for advanced/metastatic GC, the experience from general population is unlikely to be directly applicable to elderly patients [27]. It is inappropriate to estimate tolerability of elderly patients to chemotherapy based only on chronological age without considering functions of major organs, comorbidities and medical history. However, an ideal index to comprehensively assess vulnerability of aged individual has yet to be established. Therefore, more comprehensive clinical studies with larger sample sizes on elderly patients with GCLM are guaranteed to validate our findings in the near future.\n\nThis patient participated in a clinical study, which was helpful to extend overall survival. Anlotinib is an oral formulation of a small molecule inhibitor of multiple receptor tyrosine kinases, with abroad spectrum of inhibitory effects on tumor growth and angiogenesis. Anlotinib has been approved in China for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), who have undergone progression or recurrence after ≥2 lines of systemic chemotherapy. The efficacy of Anlotinib in patients with stage 3B/4 NSCLC or metastatic renal cancer (mRCC) has been demonstrated. During 6 cycles of enrollment into this clinical trial, the efficacy was evaluated as SD.\n\nThis patient was HER-2 negative based on postoperative pathological examination. However, in the latter stage of treatment, genetic test using peripheral blood identified amplification in HER-2 gene. On one hand, loss of HER2-positive status occurs after neoadjuvant therapy in patients with primary HER2-positive breast cancer [28]. On the other hand, 3.4% of breast cancer patients with HER2-negative tumors before chemotherapy changed to HER2-positive afterwards [29]. According to this case, we guess that the alteration in HER2 expression may happen in GC, which may be resulted from resistance to chemotherapy as HER2 amplification means poor prognosis.\n\nFor elderly patients with GCLM, combination therapy has efficacy. MDT consultation facilitates the evaluation of clinical stage, feasibility, risk and benefit of individual treatment modality. Palliative gastrectomy for GCLM is reasonable and safe; however, the patients must be strictly selected. Systemic chemotherapy combined with local cryoablation is an important choice for GCLM. To participate inappropriate clinical trials may be indispensable.\n\nAdditional file\n\nAdditional file 1: Figure S1. Levels of change in ca 19–9 and CEA during patient treatment. During the entire treatment period, the patient’s CA19–9 and CEA were basically maintained at normal levels. A.CA19–9; B. CEA. (TIF 27264 kb)\n\n \n\n\nAbbreviations\n18F–FDGfluorine-18 fluorodeoxyglucose\n\nCT scancomputed tomography scan\n\nFOLFIRIfluorouracil, leucovorin, and irinotecan\n\nGCgastric cancer\n\nGCLMgastric cancer with liver metastasis\n\nHER-2Receptor tyrosine-protein kinase erbB-2\n\nMDTmultidisciplinary team\n\nmFOLFOX6Modified Fluorouracil, Leucovorin, and Oxaliplatin\n\nMWAmicrowave ablation\n\nOSoverall survival\n\nPDprogression disease\n\nPET/CTpositron emission tomography/computed tomography\n\nPRpartial remission\n\nRFAradiofrequency thermal ablation\n\nSDstable disease\n\nSUVstandardized uptake value\n\nAcknowledgements\nNot Applicable.\n\nFunding\nThis work was supported by the National Natural Science Foundation of China(Grand No.81773210)and Haiyan Fund of Harbin medical University (Grand No. JJLX2016–01).The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing this manuscript.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding authors upon reasonable request.\n\nAuthors’ contributions\nContributed substantially to study conception and design, data acquisition, data analysis and interpretation: QWL, XJX, DS, TSZ, GYW, ZWL. Involved in drafting the manuscript or revising it critically: QWL, XJX, ZWL. Gave final approval of the version to be published: QWL, XJX, DS, TSZ, GYW, ZWL. Agreed to be held accountable: ZWL. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nAs it is a case report, ethics approval is not applicable. The patient was enrolled in a clinical trial, which is approved by the Ethics Committee of Tumor Hospital of Harbin Medical University (Ethical code:15–12).\n\nConsent for publication\nConsent to publish the case and all details and images described was obtained from the individual in this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests. The patient permitted the publication of the case, the clinical details and images.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Thun MJ DeLancey JO Center MM Jemal A Ward EM The global burden of cancer: priorities for prevention Carcinogenesis 2010 31 1 100 110 10.1093/carcin/bgp263 19934210 \n2. World Health Organization (2014) GLOBOCAN2012: Estimated Cancer Incidence MaPWi.\n3. Liu J Chen L Current status and progress in gastric cancer with liver metastasis Chin Med J 2011 124 3 445 456 21362349 \n4. Strong VE Wu AW Selby LV Gonen M Hsu M Song KY Park CH Coit DG Ji JF Brennan MF Differences in gastric cancer survival between the U.S. and China J Surg Oncol 2015 112 1 31 37 10.1002/jso.23940 26175203 \n5. Vigano L Vellone M Ferrero A Giuliante F Nuzzo G Capussotti L Liver resection for gastric cancer metastases Hepato-gastroenterology 2013 60 123 557 562 23635434 \n6. Hwang SE Yang DH Kim CY Prognostic factors for survival in patients with hepatic recurrence after curative resection of gastric cancer World J Surg 2009 33 7 1468 1472 10.1007/s00268-009-0034-2 19381718 \n7. Sakamoto Y Sano T Shimada K Esaki M Saka M Fukagawa T Katai H Kosuge T Sasako M Favorable indications for hepatectomy in patients with liver metastasis from gastric cancer J Surg Oncol 2007 95 7 534 539 10.1002/jso.20739 17219383 \n8. Takemura N Saiura A Koga R Arita J Yoshioka R Ono Y Hiki N Sano T Yamamoto J Kokudo N Long-term outcomes after surgical resection for gastric cancer liver metastasis: an analysis of 64 macroscopically complete resections Langenbeck's Arch Surg 2012 397 6 951 957 10.1007/s00423-012-0959-z 22615045 \n9. Fukuchi M Ishiguro T Ogata K Suzuki O Kumagai Y Ishibashi K Ishida H Kuwano H Mochiki E Prognostic role of conversion surgery for Unresectable gastric Cancer Ann Surg Oncol 2015 22 11 3618 3624 10.1245/s10434-015-4422-6 25663597 \n10. Fujitani K Yang HK Mizusawa J Kim YW Terashima M Han SU Iwasaki Y Hyung WJ Takagane A Park DJ Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial Lancet Oncol 2016 17 3 309 318 10.1016/S1470-2045(15)00553-7 26822397 \n11. Edge SB Compton CC The American joint committee on Cancer: the 7th edition of the AJCC Cancer staging manual and the future of TNM Ann Surg Oncol 2010 17 6 1471 1474 10.1245/s10434-010-0985-4 20180029 \n12. McCarter MD Fong Y Role for surgical cytoreduction in multimodality treatments for cancer Ann Surg Oncol 2001 8 1 38 43 10.1007/s10434-001-0038-0 11206223 \n13. Saidi RF ReMine SG Dudrick PS Hanna NN Is there a role for palliative gastrectomy in patients with stage IV gastric cancer? World J Surg 2006 30 1 21 27 10.1007/s00268-005-0129-3 16369718 \n14. Cheon S Rha S Jeung H-C Im C-K Kim S Kim H Ahn J Roh J Noh S Chung H Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases Ann Oncol 2008 19 6 1146 1153 10.1093/annonc/mdn026 18304963 \n15. Sakamoto Y Ohyama S Yamamoto J Yamada K Seki M Ohta K-i Kokudo N Yamaguchi T Muto T Makuuchi M Surgical resection of liver metastases of gastric cancer: an analysis of a 17-year experience with 22 patients Surgery 2003 133 5 507 511 10.1067/msy.2003.147 12773978 \n16. Nomura T Kamio Y Takasu N Moriya T Takeshita A Mizutani M Hachiya O Hirai I Kimura W Intrahepatic micrometastases around liver metastases from gastric cancer J Hepato-Biliary-Pancreat Surg 2009 16 4 493 501 10.1007/s00534-009-0081-y \n17. Kakeji Y Morita M Maehara Y Strategies for treating liver metastasis from gastric cancer Surg Today 2010 40 4 287 294 10.1007/s00595-009-4152-0 20339981 \n18. 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Mayo SC Pawlik TM Thermal ablative therapies for secondary hepatic malignancies Cancer J 2010 16 2 111 117 10.1097/PPO.0b013e3181d7ea07 20404607 \n23. Chen J Tang Z Dong X Gao S Fang H Wu D Xiang D Zhang S Radiofrequency ablation for liver metastasis from gastric cancer Eur J Surg Oncol 2013 39 7 701 706 10.1016/j.ejso.2013.03.023 23597495 \n24. Guner A Son T Cho I Kwon IG An JY Kim HI Cheong JH Noh SH Hyung WJ Liver-directed treatments for liver metastasis from gastric adenocarcinoma: comparison between liver resection and radiofrequency ablation Gastric Cancer 2016 19 3 951 960 10.1007/s10120-015-0522-z 26231353 \n25. Nienhueser H Kunzmann R Sisic L Blank S Strowitzk MJ Bruckner T Jager D Weichert W Ulrich A Buchler MW Surgery of gastric cancer and esophageal cancer: does age matter? J Surg Oncol 2015 112 4 387 395 10.1002/jso.24004 26303645 \n26. Schmidt T Alldinger I Blank S Klose J Springfeld C Dreikhausen L Weichert W Grenacher L Bruckner T Lordick F Surgery in oesophago-gastric cancer with metastatic disease: treatment, prognosis and preoperative patient selection Eur J Surg Oncol 2015 41 10 1340 1347 10.1016/j.ejso.2015.05.005 26213358 \n27. Association JGC Japanese gastric cancer treatment guidelines 2014 (ver. 4) Gastric Cancer 2017 20 1 1 19 10.1007/s10120-016-0622-4 \n28. De La Cruz LM Harhay MO Zhang P Ugras S Impact of neoadjuvant chemotherapy on breast Cancer subtype: does subtype change and, if so, how? : IHC profile and neoadjuvant chemotherapy Ann Surg Oncol 2018 25 12 3535 3540 10.1245/s10434-018-6608-1 29981025 \n29. Niikura N Tomotaki A Miyata H Iwamoto T Kawai M Anan K Hayashi N Aogi K Ishida T Masuoka H Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry Ann Oncol 2016 27 3 480 487 10.1093/annonc/mdv611 26704052\n\n",
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"journal": "BMC cancer",
"keywords": "Chemotherapy; Combination therapy; Gastric cancer; Liver metastasis",
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D024221:Antineoplastic Protocols; D003131:Combined Modality Therapy; D003452:Cryosurgery; D005472:Fluorouracil; D005743:Gastrectomy; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D000077150:Oxaliplatin; D013270:Stomach; D013274:Stomach Neoplasms",
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"references": "11206223;12773978;16369718;17219383;18304963;19268571;19360371;19381718;19542847;19934210;20047812;20180029;20210605;20339981;20404607;21362349;22615045;23597495;23635434;25663597;26175203;26213358;26231353;26303645;26704052;26822397;27342689;29981025",
"title": "Long-term survival of an elderly patient with advanced gastric cancer after combination therapy: a case report and literature review.",
"title_normalized": "long term survival of an elderly patient with advanced gastric cancer after combination therapy a case report and literature review"
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"abstract": "We report two end stage renal disease (ESRD) patients, who rapidly developed neurotoxicity after taking baclofen, a centrally acting gamma-aminobutyric acid agonist. They presented to our hospital in a state of confusion. On physical examination, there were no focal neurological deficits and the remainder of the examination was also not diagnostic. Laboratory data were unremarkable. The consciousness improved with supportive treatment and intensive hemodialysis over 3-4 days. In conclusion, physicians should be aware of the possibility of baclofen-induced neurotoxicity in patients with renal disease, especially in ESRD patients and it is necessary to avoid or reduce baclofen dosage in these patients.",
"affiliations": "Department of Nephrology, Faculty of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran.",
"authors": "Mousavi|S S Beladi|SS|;Mousavi|M Beladi|MB|;Motemednia|F|F|",
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"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-22-21010.4103/0971-4065.98762Case ReportBaclofen-induced encephalopathy in patient with end stage renal disease: Two case reports Mousavi S. S. Beladi Mousavi M. Beladi 1Motemednia F. Department of Nephrology, Faculty of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran1 Department of Chemistry, Islamic Azad University, Omidiyeh Branch, Omidiyeh, IranAddress for correspondence: Dr. Seyed Seifollah Beladi Mousavi, Department of Nephrology, Faculty of Medicine, Jundishapur University of Medical Sciences, Ahva, Iran. E-mail: beladimusavi@yahoo.comMay-Jun 2012 22 3 210 212 Copyright: © Indian Journal of Nephrology2012This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We report two end stage renal disease (ESRD) patients, who rapidly developed neurotoxicity after taking baclofen, a centrally acting gamma-aminobutyric acid agonist. They presented to our hospital in a state of confusion. On physical examination, there were no focal neurological deficits and the remainder of the examination was also not diagnostic. Laboratory data were unremarkable. The consciousness improved with supportive treatment and intensive hemodialysis over 3-4 days. In conclusion, physicians should be aware of the possibility of baclofen-induced neurotoxicity in patients with renal disease, especially in ESRD patients and it is necessary to avoid or reduce baclofen dosage in these patients.\n\nBaclofenend stage renal diseaseneurotoxicity\n==== Body\nIntroduction\nBaclofen [4-amino-3-(-4-chlorophenyl)-butanoic acid] is a centrally acting gamma-aminobutyric acid (GABA) agonist. It is currently used for alleviation of signs and symptoms of skeletal muscle spasticity and spasm, particularly in patients with multiple sclerosis or in patients with spinal or cerebral disorders. Although the precise mechanism of action of baclofen is not fully known, it is capable of inhibiting polysynaptic and monosynaptic reflexes at the spinal level by hyperpolarization of afferent terminals.[1–3]\n\nIngested baclofen is rapidly and extensively absorbed; the rate of absorption may be reduced with increasing doses. There is relatively large variation in absorption and/or elimination. In addition, the drug is moderately lipophilic, approximately 30% of baclofen bound to protein and it can cross the blood-brain barrier.[45]\n\nIn a healthy person, most of the ingested baclofen (69–85%) is eliminated by the kidneys without changes in urine and 15% is metabolized by the liver to an inactive form. In the patients with the impaired renal function and especially in the patients with end stage renal disease (ESRD), half-life of the drug is prolonged; it is between 4.5 and 6.8 h in healthy people, but increases in patients with ESRD. Exposure to as little as 5 mg baclofen may cause severe toxicity soon after ingestion.[67]\n\nCase Reports\nTwo ESRD patients, a 48-year-old diabetic man (case 1) and a 79-year-old non diabetic man (case 2) presented with a profound central nervous system depression due to baclofen toxicity. The causes of ESRD were diabetic nephropathy and unknown; also they were on maintenance hemodialysis (4 h, three times a week) for 1 and 2 years. They both had used this drug for their lower back pain.\n\nAfter receiving low dose of baclofen, the patients became disoriented, in a state of confusion and were referred to our hospital for evaluation (cumulative dose of 30 mg in case 1 and 20 mg in case 2). On presentation, they were in a confused state (Glasgow coma scale E4V3M6 in case 1 and E3V3M5 in case 2) and therefore, they were admitted in the intensive care unit (ICU). The vital sign revealed mild hypertension (150/80 and 140/90 mm Hg in case 1, 2 respectively) and their respiratory rate and pulse rate were in the normal range, and they had no fever. In physical exam, there were no focal neurological deficits and the remainder of the examination was also not diagnostic.\n\nLaboratory data including serum sodium, potassium, glucose, calcium, phosphorus, and magnesium, liver transaminases and thyroid function test were unremarkable except for azotemia and mild anemia as would normally be expected (in case 1 hemoglobin 9.8 g/dL, urea 87 mg/dL, creatinine 7.6 mg/dL and in case 2 hemoglobin 10.8 g/dL, urea 76 mg/dL, creatinine 6.8 mg/dL). Computed tomography (CT) of the brain was normal in case 1 and showed cortical atrophy in case 2.\n\nAccording to the differential diagnosis of baclofen-induced encephalopathy and after exclusion of other identifiable causes, baclofen was stopped and they received intensive hemodialysis. With adequate supportive care including mechanical ventilation and intensive hemodialysis, their neurologic symptoms gradually disappeared without any neurologic sequelae over 3 and 4 days respectively.\n\nDiscussion\nAlthough, nervous system side effects including transient drowsiness, sedation, dizziness, weakness, fatigue, coma and respiratory depression are known side effect of baclofen in patients with normal renal function, however, they usually do not occur after use of low dose of the drug, and, in addition, most of the severe nervous system side effects were reported following intrathecal injection. On the other hand, in the patients with the impaired renal function and especially in the patients with ESRD, the half-life of baclofen is significantly increased and the recommended dose or even low doses of baclofen as little as 5 mg daily or a cumulative dose of 15 mg could cause a rapid baclofen accumulation and severe baclofen intoxication. In addition, as we reported in the present case reports profound central nervous system side effects, including coma and respiratory depression could also develop soon after the initiation of therapy.[67]\n\nThere are few report of baclofen intoxication in the patients with chronic kidney disease who also demonstrated the importance of considering level of renal function when prescribing baclofen for each cause. Chu-Lin et al. reported two patients with chronic renal failure not requiring dialysis and baclofen-induced encephalopathy; a 68-year-old male with urea of 45 mg/dL and creatinine of 3.4 mg/dL and a 73-year-old woman with urea of 55 mg/dL and creatinine of 4.8 mg/dL, who were admitted with altered consciousness that rapidly developed after use a low dose of baclofen for intractable hiccups. With supportive treatment, cessation of baclofen and one course HD in second patient, neurologic symptoms recovered completely without any neurologic sequelae.[8]\n\nWu et al.[9] also reported a 70-year-old woman with ESRD who became disoriented and confused after receiving a cumulative dose of oral baclofen 45 mg in 3 days for leg muscle soreness. She received a single 4-h session of emergency HD, and the patient was discharged from the hospital 3 days later with complete recovery of consciousness.\n\nAlthough, mechanism of baclofen elimination during hemodialysis is not well understood up to 79% of the serum baclofen eliminate during one hemodialysis session.[9]\n\nTherefore, although, more data are needed for a routine recommendation, however, according to previous reports and our cases, it seems that HD may be an option for baclofen overdose in the patients with chronic renal failure and especially in the patients with ESRD.\n\nConclusion\nThe half-life of baclofen in patients with CRF and ESRD is significantly increased baclofen could cause rapid and severe intoxication. Therefore, physicians should be aware of this possibility and it is necessary to avoid use or reduce baclofen dosage in patients with the impaired renal function and in finally HD may be an option for baclofen toxicity in these patients and especially in the patients with ESRD.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\n1 Wuis EW Dirks MJ Termond EF Vree TB Van der Kleijn E Plasma and urinary excretion kinetics of oral baclofen in healthy subjects Eur J Clin Pharmacol 1989 37 181 4 2792173 \n2 Dario A Tomei G A benefit-risk assessment of baclofen in severe spinal spasticity Drug Saf 2004 27 799 818 15350152 \n3 Flardh M Jacobson BM Sensitive method for the determination of baclofen in plasma by means of solid-phase extraction and liquid chromatography-tandem mass spectrometry J Chromatogr A 1999 846 169 73 10420608 \n4 Choo YM Kim GB Choi JY Park JH Park JH Yang CW Severe respiratory depression by low-dose baclofen in the treatment of chronic hiccups in a patient undergoing CAPD Nephron 2000 86 546 7 11124626 \n5 Wuis EW Dirks MJ Termond EF Vree TB Van der Kleijn E Plasma and urinary excretion kinetics of oral baclofen in healthy subjects Eur J Clin Pharmacol 1989 37 181 4 2792173 \n6 Bassilios N Launay-Vacher V Mercadal L Deray G Baclofen neurotoxicity [correction of unerotoxicity] in a chronic haemodialysis patient Nephrol Dial Transplant 2000 15 715 6 10809817 \n7 Chen KS Bullard MJ Chien YY Lee SY Baclofen toxicity in patients with severely impaired renal function Ann Pharmacother 1997 31 1315 20 9391686 \n8 Chou CL Chen CA Lin SH Huang HH Baclofen-induced neurotoxicity in chronic renal failure patients with intractable hiccups South Med J 2006 99 1308 9 17195438 \n9 Wu VC Lin SL Lin SM Fang CC Treatment of baclofen overdose by haemodialysis: A pharmacokinetic study Nephrol Dial Transplant 2005 20 441 3 15615812\n\n",
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"abstract": "Eosinophilic gastroenteritis is a rare disease of the gastrointestinal tract characterized by crampy abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, and weight loss associated with peripheral eosinophilia leading to eosinophilic infiltrates in stomach and intestine, usually in a patient with a prior history of atopy. In this article, we describe our encounter with a 59-year-old female presenting with severe abdominal pain, nausea, vomiting, and weight loss with an extensive evaluation including an upper endoscopy with biopsies resulting in a diagnosis of eosinophilic gastroenteritis. The patient was eventually treated with oral prednisone for three weeks with complete resolution of her symptoms.",
"affiliations": "Section on Hospital Medicine, Department of Internal Medicine, Winston Salem, N.C., USA.",
"authors": "Mori|Amit|A|;Enweluzo|Chijioke|C|;Grier|David|D|;Badireddy|Madhu|M|",
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"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000354147crg-0007-0293Published online: July, 2013Eosinophilic Gastroenteritis: Review of a Rare and Treatable Disease of the Gastrointestinal Tract Mori Amit aEnweluzo Chijioke a*Grier David bBadireddy Madhu baSection on Hospital Medicine, Department of Internal Medicine, Winston Salem, N.C., USAbDepartment of Pathology, Wake Forest School of Medicine, Winston Salem, N.C., USA*Chijioke Enweluzo, MD, MPH, Section on Hospital Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, NC 27101 (USA), E-Mail cenweluz@wakehealth.eduMay-Aug 2013 16 7 2013 16 7 2013 7 2 293 298 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Eosinophilic gastroenteritis is a rare disease of the gastrointestinal tract characterized by crampy abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, and weight loss associated with peripheral eosinophilia leading to eosinophilic infiltrates in stomach and intestine, usually in a patient with a prior history of atopy. In this article, we describe our encounter with a 59-year-old female presenting with severe abdominal pain, nausea, vomiting, and weight loss with an extensive evaluation including an upper endoscopy with biopsies resulting in a diagnosis of eosinophilic gastroenteritis. The patient was eventually treated with oral prednisone for three weeks with complete resolution of her symptoms.\n\nKey words\nEosinophilic gastroenteritisDesensitizationSamter's triadInfiltrationErythematousMucosal\n==== Body\nIntroduction\nEosinophilic gastroenteritis (EGE) is a rare gastrointestinal disease characterized by crampy generalized abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding and weight loss or various combinations of the above symptoms. The etiology of the disease remains unknown. It is usually encountered in patients with a history of atopy. The disease may involve any part of the gastrointestinal tract, but the stomach and the small intestine are the most common sites involved. Isolated eosinophilic esophagitis or colitis may occur, but they are not discussed in this article. EGE is associated with peripheral eosinophilia leading to eosinophilic infiltrates in the different layers of the stomach and intestine. Clinical presentation may vary depending on sites and depth of involvement of the gastrointestinal tract. Imaging has very little role in supporting the diagnosis, and therefore a high degree of clinical suspicion is required. The diagnosis is usually confirmed by an upper endoscopy and microscopy that shows more than 20 eosinophils per high-power field in the association with peripheral eosinophilia and the absence of secondary cause of eosinophilia. Although the disease may relapse in some cases after steroid therapy, most patients respond to steroid therapy with full resolution of symptoms. Our experience with this patient demonstrates that early diagnosis will lead to full treatment, thereby preventing unnecessary interventions, and help improve the patient's overall health.\n\nClinical Course\nWe present a 59-year-old Caucasian female with a past medical history of asthma, na-sal polyps, aspirin sensitivity (Samter's triad), sarcoidosis and pancreatitis admitted with 2 weeks of abdominal pain, nausea, and intractable vomiting, diarrhea and weight loss. A few weeks prior to presentation, she underwent aspirin desensitization with about 4 weeks of escalating aspirin dose (81, 162, 325 and 650 mg, escalating weekly). During the fourth week of desensitization, she took aspirin 650 mg twice a day for 1 day and developed severe abdominal pain, nausea, vomiting and inability to tolerate any kind of diet, and was subsequently admitted for further investigation.\n\nShe was managed for presumed acute aspirin-induced pancreatitis with lipase of 353 U/l and mildly dilated biliary tree on abdominal ultrasound. She was noted to have hives and her aspirin was stopped. This was also associated with a mild elevation of her absolute eosinophil count to 3,600 cells/μl even after stopping the offending drug, normocytic mild anemia with Hb of 11.1 g/dl, albumin of 2.3 g/dl, total bilirubin 1.4 and normal AST and ALT (table 1). Gastroenterology was consulted and she underwent abdominal CT, MRCP, upper gastrointestinal series and gastric emptying study, which were all unremarkable except for mild delayed gastric emptying. The patient clinically improved and she was then discharged with plans for outpatient evaluation of her peripheral eosinophilia.\n\nA week later, the patient developed severe abdominal pain, nausea, vomiting and diarrhea again and had to return to the emergency room. She also reported weight loss of about 7 kg in the last 4 weeks. During this admission, her vital signs were: temperature 98.9°F, heart rate 103 beats/min, blood pressure 139/92 mm Hg and oxygen saturation 95% on room air. Her physical exam was only significant for cachexia and epigastric tenderness without rebound or guarding. Pertinent labs on admission showed: white blood cell count 13.8 × 103, hemoglobin 11.6 g/dl, MCV 88.9 fl, absolute eosinophil count of 13,600 cells/μl (72%), albumin 2.0, normal liver function tests and normal lipase level (table 1). Gastroenterology was again consulted. She underwent an EGD that showed mild diffuse gastritis in the entire stomach and moderate to severe duodenitis with erythematous mucosa and edematous villi. Multiple biopsy specimens showed moderate eosinophilic infiltration in the stomach mucosa with similar findings in the duodenal mucosa. Duodenal biopsy showed up to 84 eosinophils per high-power field (normal <10 eosinophils), which was highly indicative of EGE (fig. 1). No invasion to the muscular or subserosal layers was seen. During the work-up for hypereosinophilia she was found to have elevated IgG4 levels, and hematology as well as rheumatology consults were obtained for evaluation of Churg-Strauss vasculitis and hematologic malignancy. She underwent a bone marrow biopsy which showed many atypical eosinophils, most likely driven by a secondary process. However, oncology recommended sending out chromosomal testing to make sure none of the cells showed signs consistent with leukemia, and the work-up for this was subsequently negative including BCR-ABL mutation. Hypereosinophilic syndrome was deemed unlikely because of acute to subacute presentation and older age of the patient. Stool studies for ova and parasites were negative. Serology for Strongyloides was also negative. The diagnosis of hypereosinophilia leading to acute EGE was made.\n\nThe patient was started on prednisone 30 mg daily. After an initial dose of steroids, she clinically improved significantly, her abdominal pain, nausea and vomiting improved, and she tolerated her diet. Her absolute eosinophil count dropped to <1,000 and she was discharged on prednisone 30 mg daily for 2 weeks with subsequent tapering. She was followed up as an outpatient after 3 weeks with complete resolution of her symptoms and weight gain of about 3 kg, normal eosinophil count and albumin of 3.0 g/dl. She thereafter remained symptom-free for 4 months.\n\nDiscussion\nEGE is a rare disease of the gastrointestinal tract that is characterized by crampy abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding and weight loss associated with peripheral eosinophilia leading to eosinophilic infiltrates in the stomach and intestine, usually in a patient with a prior history of atopy [1, 2]. Its incidence is difficult to estimate owing to the rarity of the disease. Since the very first description of this disease by Kaijser in 1937, more than 280 cases have been reported in the medical literature. This disease affects both adults and children. There is a slight male predominance, and it is reported to be more common in Caucasians. In 1970, Klein et al. [3] classified the disease according to the anatomic location of eosinophilic infiltration in different layers of the intestinal wall – the mucosal, muscularis and subserosal layers. They defined three patterns of disease manifestation based on symptoms and location as well as on depth of involvement by eosinophilic infiltration. Presentation may vary depending on location as well as depth and extent of bowel wall involvement and usually runs a chronic relapsing course. It can be classified into mucosal, muscular and serosal types based on the depth of involvement. Any part of the gastrointestinal tract can be involved, however the stomach is the organ most commonly affected, followed by the small intestine and the colon [4, 5]. Isolated pancreatobiliary system involvement has also been reported [6]. The etiology and pathogenesis are not well understood and mostly based on case reports. Many patients have a history of seasonal allergy, atopy, food allergies, asthma and elevated serum IgE levels that may strongly suggest the role of hypersensitivity reactions in the pathogenesis of EGE [7]. Small amount of eosinophils are normally present in the mucosa as a host defense mechanism, but their presence in the deeper layers is almost always abnormal. A review of literature also suggests a role of various cytokines (interleukin 3, interleukin 4, granulocyte macrophage colony-stimulating factor) and eotaxin, which are produced by eosinophils. It is also postulated that food allergens may cross the mucosa and play a role in local recruitment of eosinophils [8, 9].\n\nPatients may have various clinical symptoms based on location and depth of involvement. The mucosal form, which is more common and seen in about 25–100% of cases, usually presents as abdominal pain, nausea, vomiting, dyspepsia, diarrhea, malabsorption, gastrointestinal hemorrhage, protein-losing enteropathy and weight loss. The muscularis form (seen in about 10–60% of cases) usually follows the clinical picture of obstructive symptoms due to pyloric stenosis, gastric outlet obstruction and, rarely, intussusception. The subserosal form, which is less common, usually presents with significant bloating, exudative ascites and a comparably higher number of peripheral eosinophilia than other forms [10, 11, 12].\n\nLaboratory findings that support the diagnosis of EGE include, but are not limited to, peripheral eosinophilia (ranging from 5 to 70%), hypoalbuminemia, abnormal D-xylose test, increased fecal fat, iron deficiency anemia, abnormal liver function tests, prolonged prothrombin time and elevated serum IgE levels. The erythrocyte sedimentation rate is rarely elevated [3, 12]. Barium studies are usually abnormal in the muscularis form and may show luminal narrowing and irregularities in the distal antrum and the proximal small bowel. Diagnosis required high clinical suspicion and upper endoscopies with multiple biopsies from normal- and abnormal-appearing mucosa (in the mucosal form mainly), although laparoscopic full-thickness biopsies may be necessary in the muscularis and subserosal forms of EGE (fig. 1).\n\nThe differential diagnoses, among many other possibilities, include intestinal parasitic infections (can be excluded by stool studies), primary hypereosinophilic syndrome (persistent marked eosinophilia for 6 months or more, rarely involving the gastrointestinal system), malignancies (gastric cancer, lymphoma – excluded by laboratory, immunohistochemistry, biopsy) and the vasculitic phase of Churg-Strauss syndrome [12, 13, 14]. The role of imaging in the diagnosis of EGE is very limited because radiological findings are nonspecific and absent in half of the patients. Endoscopy usually reveals erythematous, friable, sometimes nodular mucosa and rarely ulceration in the stomach. There can also be diffuse enteritis with flattening of the mucosal surface in the proximal small intestine. Rarely, a large ulcerative mass with obstruction can be seen. The most common histologic findings are crypt hyperplasia and eosinophilic infiltration in the lamina propria. Microscopy usually shows an eosinophil count of 20 or more per high-power field (our patient had 78 eosinophils per high-power field) [15].\n\nTreatment is based on the severity of symptoms. Mild symptoms are managed with careful search of inciting food allergens, medication review and avoiding them if found. Most patients present with moderate to severe symptoms. Corticosteroids are the mainstay of therapy in these patients. The usual dose of prednisone is 20–40 mg daily for 2 weeks with tapering thereafter. A vast majority of patients improve with this therapy and do not require further treatment. However, relapse can occur and is treated with long-term, low-dose steroids (prednisone 5–10 mg daily). Among other medications, mast cell stabilizers, antihistamines and selective leukotriene receptor antagonist (montelukast) have shown positive results in some patients [3, 12, 16, 17]. The presentation of our case demonstrates that although EGE is a rare disease, a high level of clinical suspicion, especially in patients with a history of allergy and peripheral eosinophilia, will aid in early diagnosis and prompt treatment. On the other hand, if left untreated or missed altogether, it may lead to further involvement of deep layers of the gastrointestinal system wall, causing further complications that may require invasive measures, thereby affecting quality of life.\n\nDisclosure Statement\nThe authors declare no conflict of interest. There was no grant support.\n\nFig. 1 Duodenal biopsy showed up to 84 eosinophils per high-power field as indicated by arrows, indicative of EGE. Hematoxylin and eosin, ×400.\n\nTable 1 Comparison of laboratory findings during previous hospitalization (1 week prior to admission), at current admission and 3 weeks after prednisone therapy\n\nTest\tReference range\tPrevious hospitalization\tCurrent admission\tAfter prednisone therapy\t\nWhite blood cells, cell/μl\t4.8–10.8×103\t11.5×103\t13.8×103\t8.3×103\t\nHemoglobin, g/dl\t12–16\t11.1\t11.6\t13.4\t\nMCV, fl\t81–99\t86.0\t88.9\t84.0\t\nPlatelets, cells/μl\t160–360×103\t246×103\t371×103\t230×103\t\nAbsolute eosinophils, cells/μl\t0.0–0.5×103\t3,600×103\t13,600×103\t0.1×103\t\nAlbumin, g/dl\t3.2–5\t2.3\t2.0\t3.0\t\nTotal bilirubin, mg/dl\t0.1–1.2\t1.4\t1.1\t1.1\t\nLipase, U/l\t20–50\t353\t33\t27\t\nAST, U/l\t5–50\t65\t39\t34\t\nALT, U/l\t5–50\t59\t36\t29\n==== Refs\nReferences\n1 Kaijser R Zur Kenntnis der allergischen Affektionen des Verdauungskanals vom Standpunkt des Chirurgen aus Arch Klin Chir 1937 188 36 64 \n2 Whitaker I Gulati A McDaid J Bugajska-Carr U Arends M Eosinophilic gastroenteritis presenting as obstructive jaundice Eur J Gastroenterol Hepatol 2004 16 407 409 15028974 \n3 Klein N Hargrove R Sleisenger M Jeffries G Eosinophilic gastroenteritis Medicine (Baltimore) 1970 49 299 319 5426746 \n4 Treiber GG Weidner S Eosinophilic gastroenteritis Clin Gastroenterol Hepatol 2007 5 e16 17428742 \n5 Naylor A Eosinophilic gastroenteritis Scott Med J 1990 35 163 165 2077646 \n6 Jimenez-Saenz M Villar-Rodriguez J Torres Y Carmona I Salas-Herrero E Gonzalez-Vilches J Herrerias-Gutierrez J Biliary tract disease: a rare manifestation of eosinophilic gastroenteritis Dig Dis Sci 2003 48 624 627 12757181 \n7 Oyaizu N Uemura Y Izumi H Morii S Nishi M Hioki K Eosinophilic gastroenteritis. Immunohistochemical evidence for IgE mast-cell mediated allergy Acta Pathol Jpn 1985 35 759 766 3898714 \n8 Desreumaux P Bloget F Seguy D Capron M Cortot A Colombel J Janin A Interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 in eosinophilic gastroenteritis Gastroenterology 1996 110 768 774 8608886 \n9 Mishra A Hogan S Brandt E Rothenberg M An etiological role for aeroallergens and eosinophils in experimental esophagitis J Clin Invest 2001 107 83 90 11134183 \n10 Baig MA Qadir A Rasheed J A review of eosinophilic gastroenteritis J Natl Med Assoc 2006 98 1616 1619 17052051 \n11 Lee CM Changchien CS Chen PC Lin DY Sheen IS Wang CS Tai DI Sheen-Chen SM Chen WJ Wu CS Eosinophilic gastroenteritis: 10 years experience Am J Gastroenterol 1993 88 70 74 8420276 \n12 Cello JP Eosinophilic gastroenteritis – a complex disease entity Am J Med 1979 67 1097 1104 517550 \n13 Roufosse F Cogan E Goldman M Recent advances in pathogenesis and management of hypereosinophilic syndromes Allergy 2004 59 673 689 15180753 \n14 Blackshaw AJ Levison DA Eosinophilic infiltrates of the gastrointestinal tract J Clin Pathol 1986 39 1 7 2869055 \n15 Katz A Goldman H Grand R Gastric mucosal biopsy in eosinophilic (allergic) gastroenteritis Gastroenterology 1977 73 705 709 892374 \n16 Schwartz DA Pardi DS Murray JA Use of montelukast as steroid-sparing agent for recurrent eosinophilic gastroenteritis Dig Dis Sci 2001 46 1787 1790 11508684 \n17 Bolukbas FF Bolukbas C Uzunkoy A Baba F Horoz M Ozturk E A dramatic response to ketotifen in a case of eosinophilic gastroenteritis mimicking abdominal emergency Dig Dis Sci 2004 49 1782 1785 15628703\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "7(2)",
"journal": "Case reports in gastroenterology",
"keywords": "Desensitization; Eosinophilic gastroenteritis; Erythematous; Infiltration; Mucosal; Samter's triad",
"medline_ta": "Case Rep Gastroenterol",
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"nlm_unique_id": "101474819",
"other_id": null,
"pages": "293-8",
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"pmid": "23904840",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports",
"references": "11134183;15028974;5426746;17428742;8420276;17052051;2869055;15180753;517550;2077646;3898714;892374;8608886;15628703;11508684;12757181",
"title": "Eosinophilic gastroenteritis: review of a rare and treatable disease of the gastrointestinal tract.",
"title_normalized": "eosinophilic gastroenteritis review of a rare and treatable disease of the gastrointestinal tract"
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"abstract": "Cystic lung diseases are a group of disorders that appear similar on radiological studies on chest computed tomography. Each disorder is characterized by its own etiology, pathophysiology, course of progression and manifestation. Lymphangioleiomyomatosis (LAM) is one of the cystic lung diseases that can either be hereditary or sporadic. The sporadic form is a rare disease with no accurate prevalence reported but is believed to be less than 10 per million. LAM is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling which regulates cellular growth. The sporadic form is almost confined to premenopausal female population and estrogen is believed to play an important role in the pathogenesis. Pregnancy and use of estrogen based oral contraceptives can aggravate symptoms of already existing LAM. Here we describe a case of LAM that was previously treated as asthma and was diagnosed after exacerbation of respiratory symptoms after pregnancy. We offer a review of the medical literature regarding the etiology, clinical course, diagnosis and treatment of LAM.",
"affiliations": "Rosalind Franklin University of Medicine and Science, USA.;Rosalind Franklin University of Medicine and Science, USA.;Rosalind Franklin University of Medicine and Science, USA.;Centegra Health Care System, USA.;Centegra Health Care System, USA.",
"authors": "Khaddour|Karam|K|;Shayuk|Maryna|M|;Ludhwani|Dipesh|D|;Gowda|Satish|S|;Ward|Wendy L|WL|",
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"doi": "10.1016/j.rmcr.2018.11.010",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30315-010.1016/j.rmcr.2018.11.010Case ReportPregnancy unmasking symptoms of undiagnosed lymphangioleiomyomatosis: Case report and review of literature Khaddour Karam Karam.khaddour@gmail.coma∗Shayuk Maryna aLudhwani Dipesh aGowda Satish bWard Wendy L. ba Rosalind Franklin University of Medicine and Science, USAb Centegra Health Care System, USA∗ Corresponding author. 915 Armistead Lane, McHenry, IL, 60050 USA. Karam.khaddour@gmail.com23 11 2018 2019 23 11 2018 26 63 67 11 10 2018 16 11 2018 17 11 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/).Cystic lung diseases are a group of disorders that appear similar on radiological studies on chest computed tomography. Each disorder is characterized by its own etiology, pathophysiology, course of progression and manifestation. Lymphangioleiomyomatosis (LAM) is one of the cystic lung diseases that can either be hereditary or sporadic. The sporadic form is a rare disease with no accurate prevalence reported but is believed to be less than 10 per million. LAM is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling which regulates cellular growth. The sporadic form is almost confined to premenopausal female population and estrogen is believed to play an important role in the pathogenesis. Pregnancy and use of estrogen based oral contraceptives can aggravate symptoms of already existing LAM. Here we describe a case of LAM that was previously treated as asthma and was diagnosed after exacerbation of respiratory symptoms after pregnancy. We offer a review of the medical literature regarding the etiology, clinical course, diagnosis and treatment of LAM.\n\nKeywords\nLAMLymphangioleiomyomatosissLAMSporadictsLAMTuberous sclerosis\n==== Body\n1 Introduction\nCystic lung diseases are a group of disorders that appear similar on radiological studies on chest computed tomography. Each disorder is characterized by its own etiology, pathophysiology, course of progression and manifestation. Lymphangioleiomyomatosis (LAM) is one of the cystic lung diseases that can either be hereditary or sporadic. The sporadic form is a rare disease with no accurate prevalence reported but is believed to be less than 10 per million. LAM is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling which regulates cellular growth. The sporadic form is almost confined to premenopausal female population and estrogen is believed to play an important role in the pathogenesis. Pregnancy and use of estrogen based oral contraceptives can aggravate symptoms of already existing LAM. Here we describe a case of LAM that was previously treated as asthma and was diagnosed after exacerbation of respiratory symptoms after pregnancy. We offer a review of the medical literature regarding the etiology, clinical course, diagnosis and treatment of LAM.\n\n2 Case\nA 32 year old female G3P2A1 presented with the chief complaint of worsening dyspnea on exertion. Her history was significant for recent delivery three months prior and papillary thyroid carcinoma with partial thyroidectomy and radioactive iodine therapy (RAI). She had symptoms of intermittent dyspnea for one year which was diagnosed as mild intermittent asthma and was treated with bronchodilator inhalers as needed with good control of her dyspnea. However, she noticed worsening of symptoms postpartum after her third delivery without improvement with the use of inhalers, which prompted her to seek medical attention. She was on oral contraceptives (medroxyprogesterone intramuscular injection) after her last pregnancy. The symptoms were aggravated by minimal physical activity such as walking. She was a non-smoker with no prior history of lung disease or allergies other than her asthma. Her family history did not include any genetic or chronic lung diseases. Physical exam was normal except for mild wheezing which was prominent on the lower lung zones bilaterally. Initial chest x-ray was normal (Fig. 1). Pulmonary function tests showed obstructive pattern with FEV/FVC 64%, FEV1 86% of predicted values and DLCO of 42%. Six minute walking test showed requirements of 3 liters per minute of oxygen to maintain saturation above 88% and the patient was started on oxygen treatment. High Resolution Computed Tomography (HRCT) of the chest revealed numerous small cystic spaces bilaterally with diffuse distribution pattern (Fig. 2). There was mild septal thickening between the cyst spaces with no signs of pleural effusion, bronchiectatic or emphysematous changes. Laboratory work up was negative for rheumatoid factor, antinuclear antibody, anti-topoisomerase I, anti-citrulline antibodies. Vascular Endothelial Growth Factors-D was not available at our institution; however, serum levels of VEGF was 48pg/mL (Normal range is less than 96.2 pg/mL).Fig. 1 Chest X-Ray without significant findings. Normal lung architecture.\n\nFig. 1Fig. 2 HCRT of the chest showing bilateral thin-walled numerous cysts (white arrows) which are scattered throughout the lungs with bleb formation (red arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 2\n\nThe patient underwent video assisted thoracoscopic surgery (VATS) with wedge resection for pathological studies. The specimens showed cyclically dilated air spaces with irregular proliferation of smooth muscle cells (Fig. 3). Immunostaining was positive for lesional smooth muscle cells, actin, desmin and focal positive estrogen and progesterone receptors with Ki-67 proliferation index were 5% (Fig. 4).Fig. 3 For H&E. H&E Stain of lung pathology showing plump of spindle-shaped lesional cells from nodules in walls of cystic air spaces. High Magnification of the previous specimen showing spindle-shaped myoid cells in the lung parenchymal wall.\n\nFig. 3Fig. 4 For Immunohistochemical Staining. Lesional cells nuclear stain is focally positive for estrogen receptors. Immunohistochemical stain for smooth muscle myosin is positive in lesional cells. Positive immunohistochemically stain for HMB45.\n\nFig. 4\n\nBased on the radiological and histological findings the diagnosis was lymphangioleiomyomatosis. At that point we were able to order VEGF-D and the serum levels were 1038 pg/mL (Normal < 900 pg/mL). The patient was started on oral Sirolimus 2 mg daily which was titrated to achieve serum levels between 5-15 ng/mL and her Sirolimus trough levels ranged during first year of treatment between 4 and 14 ng/mL. The patient tolerated the medication well and the only adverse events were buccal aphthous and mild headache that resolved spontaneously. She also had pulmonary rehabilitation for three months. She was assured that she could continue her current oral contraceptives. Her repeated pulmonary function testing showed slight decline of DLCO on 6 months follow up that improved and stabilized later with subsequent measurements. Her respiratory symptoms improved although she was still requiring 3 L/m of oxygen during sleep and exertion. Patient received pneumococcal and annual influenza vaccination. She was advised to have annual ultrasounds of her kidneys.\n\n3 Discussion\nCystic lung disease is a group of heterogeneous disease that differs in etiology but have common findings on CT scan.\n\nLAM is a disease of abnormal proliferation, differentiation and migration of smooth muscle-like cells within the lung parenchyma that results in obstruction of small respiratory airway tract which produces a characteristic constellation of clinical, radiological and physiological findings [1]. LAM can be hereditary in which is associated with tuberous sclerosis or can occur sporadically which is the most common form of the disease. The sporadic form is predominantly found in premenopausal female population. The exact prevalence of sporadic Lymphangioleiomyomatosis (sLAM) is unknown but one study estimated the prevalence to range between 3 and 7 per million [2]. The hereditary form was shown to affect 1–3% of patients with tuberous sclerosis from a study that estimated the prevalence between 1939 and 1993 [3]. Another study found that the prevalence was much higher and could reach up to 80% in women with tuberous sclerosis and was higher in older women compared to younger female patients [4]. The hereditary form of LAM which is associated with TS was found to occur in males although females are still predominantly affected [5].\n\nLAM was recently reclassified as a low-grade destructive locally invasive neoplasm after it was reported in multiple cases with a recurrence of the disease following total lung transplantation. The 2015 WHO classification of lung tumors considered LAM to be a mesenchymal tumor [6]. Moreover, the disease was proven to show evidence of clonal origin and potential ability to metastasize although the clinical significance of this remains negligible.\n\nPathophysiology in the hereditary and sporadic forms involve the loss of function of Tuberous Sclerosis Complex 2 (TSC2) gene which plays a role in inhibition of migration of cells and patients with tuberous sclerosis have a loss of the function of TSC2 which can lead to activation of the regulatory kinase mTOR (Mammalian Target of rapamycin) causing an increase in the levels of lymphangiogenic growth factor and a resultant abnormal growth of muscle like cells in the lung parenchyma that can lead to cyst formation and chylous effusions in the alveoli [7]. Kidneys could also be affected in 40–50% of sporadic LAM cases and present as angiomyolipoma which are vascular benign tumors. Another unique manifestation of the abnormal cell growth is perivascular epitheloid cell tumor (PEComa) which is a rare disease that affects the visceral organs. Moreover, estrogen plays a pivotal role of abnormal proliferation in sporadic LAM (sLAM). This is supported by predilection of the disease in premenopausal women, aggravation of symptoms with pregnancy and use of oral estrogen contraceptives. The mechanism is hypothesized to be due to the enhancement of genomic and non-genomic signaling pathways which was proven in vitro studies that showed estradiol to be able to cause enhancement of phosphorylation and activation of Erk1/2 pathway which leads to increased expression of c-myc and resultant expression of proliferative genes [8]. The role of estrogen has also been well established in the activation of mTOR pathway in different cell types like in the case of breast cancer [9].\n\nClinical manifestations are most commonly related to the effect of the disease on pulmonary parenchyma and rarely do patients present with symptoms of extra pulmonary involvement. Respiratory symptoms include dyspnea on exertion which is usually treated initially as asthma or COPD before LAM is diagnosed [10]. Chylous effusions are a common finding and are the result of lymphangiogenesis. Other symptoms that were less frequently reported include spontaneous pneumothorax, cough and fatigue [10,11].\n\nPulmonary function tests (PFTs) show an obstructive pattern and reduced diffusion capacity [12]. Hypoxemia during sleep is a common finding [13]. Chest X-Ray is normal in most patients with LAM unless there is a complication due to pleural effusions or pneumothorax. CT chest shows the hall mark of numerous thin-wall cysts that are diffuse and bilateral with a well-defined boarder [14]. Pulmonary nodules, hilar lymphadenopathy and pneumothorax were reported as well but are less common than cystic findings [15]. Some reports recommend abdominal CT in sporadic LAM to look for angiomyolipoma or lymphangiomyoma in the kidneys [16]. A cyst scoring system has been developed with HRCT that calculates the percentage of cyst volume to the total lung volume and was found to correlate with pulmonary function testing and can assess disease progression and severity [17].\n\nMany reports found a correlation between vascular endothelial growth factor (VEGF-D) concentration in blood and the severity of the disease. VEGF-D is secreted by LAM cells and it acts on the endothelial vascular level causing angiogenesis and lymphangiogenesis [18] and levels of > 800 pg/mL in women with cystic lung disease on HRCT is sufficient for the diagnosis of LAM as they are very specific and can spare patients the need to have a biopsy [19]. One study done by Radzikowska E. et al. suggested that patients with sporadic sLAM and tuberous sclerosis TS/LAM with higher titers of VEGF-D had worse PFTs compared to patients who had low levels of VEGF-D which suggested that the serum levels correlate with disease severity and response to treatment [20]. Recently, CA-125 has been proposed as a marker that correlates with progression of the disease and responsiveness to treatment as high levels of this marker were associated with worsening PFTs [21].\n\nBiopsy remains the gold standard for diagnosis of LAM. The biopsy can be done either through transbronchial or surgical approach. Surgical biopsy has a high yield but is associated with more complications. The American Thoracic Society and the Japanese Respiratory Society recommends transbronchial biopsy of the lung as a diagnostic tool given its good yield and reduced complications compared to surgical resection [22].\n\nHistopathology shows multiple cysts and spindle shaped cells representing vascular smooth muscle cells that can be pleomorphic and has features of perivascular epithelial cells [23,24].\n\nImmunohistochemistry can show co-expression of myogenic and melanocytic markers like HMB-45, HMSA-1 and a-smooth muscle actin which were positive in our patient [25]. Cytology with pleural fluid study can aid in diagnosis when effusion is present but the sensitivity is unknown, but some cases reports were diagnosed through cytology studies of pleural effusions [26].\n\nIn our patient there was no decline in DLCO with the continuous use of progesterone based contraceptives despite positive progesterone receptors seen in the tissue specimen. One retrospective study done by Taveira-DaSilva et al. showed that progesterone use did not alter PFTs in patients with LAM [27]. Although estrogen is more implicated in the pathogenicity and worsening of lymphangioleiomyomatosis, studies have shown that PR receptors are more expressed than ER in patients with LAM [[28], [29], [30]].\tAt diagnosis\t6 months after treatment\t8 months after\t12 months after\t\nFEV1\t86%\t88%\t88%\t90%\t\nDLCO\t42%\t37%\t40%\t44%\t\n\n\nTreatment of LAM is aimed at controlling symptoms and supportive measures with smoking cessation, supplemental oxygen and bronchodilator therapy. The effectiveness of bronchodilator therapy has been debated. One study done by Taveira-DaSilva et al. found no difference in disease duration between patients who responded to bronchodilator therapy and those who did not [31], but in clinical practice bronchodilators are still being used for symptomatic relief.\n\nSirolimus is an mTOR inhibitor of inappropriate activation of mammalian target of rapamycin signaling pathway which is responsible for the proliferation of lymphangioleiomyomatosis cells and is the only FDA approved treatment for LAM. It has shown efficacy in the MILES trial in reducing symptoms, improving quality of life, stabilizing lung functions and decreasing levels of VGEF-D [32]. The MILES trial group recommends Sirolimus blood levels between 5-15 ng/mL for optimal efficacy and good control of LAM which is usually achieved by an oral dose of 2 mg daily. Another observational cohort study done on 15 patients with LAM in Japan assessed the efficacy of lower doses of Sirolimus with lower trough levels and found improvement of pulmonary function tests and resolution of chylous effusions with levels of the drug less than 5 ng/mL [33]. The dose is usually started at 2 mg and then titrated to achieve levels between 5-15 ng/mL. The medication is well tolerated and its adverse event profile is does dependent and less commonly seen with the lower doses that are used for the treatment of LAM. Given the potential of QT prolongation it is recommended to have a baseline ECG before initiating therapy and regularly during therapy. Monitoring also includes checking blood count, hepatic function and serum total cholesterol given that hypercholesterolemia is the most frequently side effect seen with treatment [34]. Also given the potential immunosuppressant effect of Sirolimus it is usually held if severe infection develops and prior to surgeries. No studies have been done to assess the safety of the medication in the long term and usually the strategy of treatment is to continue the medication at the lowest effective dose to achieve control of symptoms and stabilization of pulmonary function tests. Theoretically the concern with the use of Sirolimus is its immunosuppressive effect and the potential to increase the risk of infections and progression of latent malignancies if present and the only study to assess long term safety is an ongoing multicenter international trial (MIDAS Trial) that is expected to have results in 2020. However, one study found an increased risk of respiratory infection in patients with LAM treated with Sirolimus and concluded that there was no increased risk of respiratory infections with the medication and on the contrary that Sirolimus could have a protective effect [35]. In the same manner a new study suggested that mTOR inhibition has the potential to enhance immune function and decrease risk of infections in elderly population [36]. Everolimus is a drug of the same class that is used if there is an allergy to Sirolimus but does not have FDA approval. Pulmonary rehabilitation has shown to be beneficial to improve exercise capacity and quality of life with no effect on the PFTs [37].\n\nEstrogen related therapies have been explored in some studies given the role of estrogen in the pathophysiology of the disease but have been of low yield [38].\n\nLung transplantation is indicated in the severe forms of LAM with severe respiratory functional decline despite medical therapy. There are no absolute contraindications for transplant and indications are yet to be established. It has been shown that lung transplantation improves lung function and quality of life [39]. Some anecdotal cases have been reported of recurrence of LAM after bilateral lung transplant although this recurrence did not seem to affect survival [40].\n\n4 Conclusion\nLAM is a rare cystic lung disease that can present as a part of tuberous sclerosis or sporadically. The sporadic form occurs almost exclusively in premenopausal women. There should be a high threshold of suspicion when premenopausal women present with asthma like symptoms that do not respond well to bronchodilators or when respiratory symptoms are aggravated after pregnancy or use of estrogen based oral contraceptives. Diagnosis is based on radiological findings, serum VGEF-D levels and pathology. Treatment is aimed at controlling and preventing progression of symptoms with Sirolimus. Current evidence together with reports of recurrence of LAM after transplantation suggests that LAM is a low-grade metastatic neoplasm that selectively targets the lungs.\n\nDisclosure\nThe authors have nothing to disclose.\n\nContribution to the manuscript\nDr. Karam Khaddour contributed to production of the case report with the literature review discussion and collection of radiological imaging.\n\nDr. Wendy Ward contributed by providing pathology slides with description.\n\nDr. Maryna Shayuk, Dr. Dipesh Ludhwani, Dr. Sateesh Gowda contributed to review of the written article.\n==== Refs\nReferences\n1 Kalassian K.G. Doyle R. Kao P. Ruoss S. Raffin T.A. Lymphangioleiomyomatosis: new insights Am. J. Respir. Crit. Care Med. 155 1997 1183 1186 9105053 \n2 Harknett E.C. Chang W.Y. Byrnes S. Johnson J. Use of Variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis QJM 104 2011 971 979 21764810 \n3 Hancock E. Osborne J. 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Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors Am. J. Respir. Crit. Care Med. 151 1995 527 533 7842216 \n24 McCormack F.X. Travis W.D. Colby T.V. Henske E.P. Moss J. Lymphangioleiomyomatosis: calling it what it is: a low-grade, destructive, metastasizing neoplasm Am. J. Respir. Crit. Care Med. 186 2012 15 1210 1212 23250499 \n25 Martignoni G. Pea M. Reghellin D. Molecular pathology of lymphangioleiomyomatosis and other perivascular epithelioid cell tumors Arch. Pathol. Lab Med. 134 2010 33 40 20073603 \n26 Rivera G. Gokaslan T. Kurian E.M. Lymphangioleiomyomatosis diagnosed by effusion cytology: a case report J. Cytol. 32 2015 287 289 26811583 \n27 Taveira-DaSilva A.M. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone Chest 126 2004 1867 1874 15596686 \n28 Yano S. Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous oestrogen used for infertility treatment Thorax 57 2002 1085 1086 12454306 \n29 Oberstein E.M. Pulmonary lymphangioleiomyomatosis (LAM): examining oral contraceptive pills and the onset of disease J. Womens Health (Larchmt) 12 2003 81 85 12639372 \n30 Gao L. In pulmonary lymphangioleiomyomatosis expression of progesterone receptor is frequently higher than that of estrogen receptor Virchows Arch. 464 2014 495 503 24570392 \n31 Taveira-DaSilva Angelo M. Reversible airflow obstruction in lymphangioleiomyomatosis Chest 137 2010 744 \n32 McCormack F.X. Inoue Y. Moss J. Efficacy and safety of sirolimus in lymphangioleiomyomatosis N. Engl. J. Med. 28 2011 1595 1606 364 \n33 Ando K. Efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis Respir. Investig. 51 2013 175 183 \n34 Yao J. Taveira-DaSilva A.M. Sustained effects of sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis Am. J. Respir. Crit. Care Med. 190 2014 1 1273 1282 25329516 \n35 Courtwright A.M. Goldberg H.J. Henske E.P. El-Chemaly S. The effect of mTOR inhibitors on respiratory infections in lymphangioleiomyomatosis Eur. Respir. Rev. 2017 17 26 \n36 Mannick Joan B. Morris Melody TORC1 inhibition enhances immune function and reduces infections in the elderly Sci. Transl. Med. 10 449 2018 eaaq1564 \n37 Araujo M.S. Baldi B.G. Freitas C.S. Pulmonary rehabilitation in lymphangioleiomyomatosis: a controlled clinical trial Eur. Respir. J. 47 2016 1452 1460 26917604 \n38 Lu C. Lee H.S. Pappas G.P. A phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis Ann. Am. Thorac. Soc. 14 2017 919 928 28570161 \n39 Maurer J.R. Lung transplantation in the management of patients with lymphangioleiomyomatosis: baseline data from the NHLBI LAM Registry J. Heart Lung Transplant. 26 2007 1293 1299 18096481 \n40 Zaki Khawaja S. Aryan Zahra Mehta Atul C. Akindipe Olufemi Budev Marie Recurrence of lymphangioleiomyomatosis: nine years after a bilateral lung transplantation World J. Transplant. 6 2016 24 249 254 27011924\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "26()",
"journal": "Respiratory medicine case reports",
"keywords": "LAM; Lymphangioleiomyomatosis; Sporadic; Tuberous sclerosis; sLAM; tsLAM",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "63-67",
"pmc": null,
"pmid": "30555778",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10208206;10887241;10934115;11863203;12454306;12639372;12922981;15596686;16210669;16388022;17018601;17034294;18096481;19304711;19447921;20073603;20382711;20560288;21410393;21764810;22217496;23250499;23539171;23978644;24570392;25078640;25329516;25544557;26291008;26386638;26811583;26917604;27011924;28096282;28570161;28576630;29140122;29997249;7842216;9105053",
"title": "Pregnancy unmasking symptoms of undiagnosed lymphangioleiomyomatosis: Case report and review of literature.",
"title_normalized": "pregnancy unmasking symptoms of undiagnosed lymphangioleiomyomatosis case report and review of literature"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0106524",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Tick-borne illnesses are a growing problem in the United States. Human granulocytic anaplasmosis (HGA), carried by the Ixodes scapularis tick, is caused by Anaplasma phagocytophilum. While the clinical manifestations of HGA may be protean, ranging from asymptomatic infection to life-threatening multiorgan failure, renal involvement is uncommon. We report a case of a 64-year-old man presenting with a febrile illness and acute nephritis in the setting of HGA infection. The patient's kidney biopsy was characterized by a membranoproliferative glomerulonephritis pattern and acute interstitial inflammation. After appropriate antibiotic treatment and high-dose steroids, the patient had a marked improvement in kidney function, although a subsequent recrudescence of nephritis required a 6-month course of additional steroids. As the prevalence of tick-borne diseases continues to spread across the United States, raising awareness of the potential for atypical presentations is important, particularly because early diagnosis and treatment can be curative and prevent further complications.",
"affiliations": "Renal Division, Beth Israel Deaconess Medical Center. Electronic address: mzhuo@bidmc.harvard.edu.;Department of Internal Medicine, Beth Israel Deaconess Medical Center.;Department of Internal Medicine, Beth Israel Deaconess Medical Center.;Renal Division, Department of Internal Medicine, Brigham and Women's Hospital.;Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA.;Renal Division, Beth Israel Deaconess Medical Center.",
"authors": "Zhuo|Min|M|;Calev|Hila|H|;Saunders|Staci J|SJ|;Li|Jiahua|J|;Stillman|Isaac E|IE|;Danziger|John|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2019.03.428",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "74(5)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Human granulocytic anaplasmosis (HGA); acute interstitial nephritis (AIN); acute kidney injury (AKI); case report; hematuria; kidney biopsy; membranoproliferative pattern glomerulonephritis; tick-borne illness",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D041081:Anaplasma phagocytophilum; D000712:Anaplasmosis; D000900:Anti-Bacterial Agents; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005938:Glucocorticoids; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "696-699",
"pmc": null,
"pmid": "31200977",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Acute Kidney Injury Associated With Human Granulocytic Anaplasmosis: A Case Report.",
"title_normalized": "acute kidney injury associated with human granulocytic anaplasmosis a case report"
} | [
{
"companynumb": "US-BAYER-2020-022914",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nHIV-infected patients have higher mortality when coinfected with hepatitis B virus (HBV). With potent highly active antiretroviral therapy (HAART) and the use of tenofovir (TDF), outcomes may improve. Our objective was to determine the clinical and virological outcomes of a HIV/HBV-Coinfected cohort at our center since TDF became available.\n\n\nMETHODS\nWe retrospectively studied all HIV/HBV-Coinfected adults followed between 2002 and 2012 for ≥3 months. Outcome measurements included HBV DNA suppression, HBV e-antigen (HBeAg) and HBV surface antigen (HBsAg) clearance, cirrhosis diagnosis, development of liver complications, and overall and liver-related mortality. Predicting factors were assessed with log-rank test and logistic regression.\n\n\nRESULTS\nMedian time to follow-up of the 99 patients included was 5 years. Undetectable HBV DNA and HBsAg loss were achieved by 65% and 18%, respectively. Overall and liver-related mortality rates were 4.58 and 0.91 per 100 person-years, respectively. Most patients died of causes unrelated to the liver. Four patients died from hepatocellular carcinoma (HCC) and one, hepatitis C virus (HCV) coinfected, from liver failure. Higher CD4 counts at last follow-up were associated with HBV suppression (odds ratio [OR] 1.004, 95% confidence interval [CI] 1.001-1.006, P=.007), HBeAg loss (OR 1.003, 95% CI 1-1.005, P=.02), HBsAg loss (CD4 count>700 cells/mm3, OR 3.80, 95% CI 1.06-13.58, P=.04), and survival (OR .994, 95% CI 0.990-0.997, P<.0001). HCV coinfection was associated with higher overall mortality (OR 7.74, 95% CI 1.47-40.81, P=.02).\n\n\nCONCLUSIONS\nMortality was high and most often unrelated to liver disease in this HIV/HBV-Coinfected cohort treated predominantly with TDF-containing HAART. Optimal CD4 counts predicted survival and the achievement of HBV virological end points. Tenofovir prevented liver decompensation but not HCC, which was the predominant cause of liver death.",
"affiliations": "Wake Forest University School of Medicine, Winston-Salem, NC, USA.;Division of Infectious Disease, Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA mnunez@wakehealth.edu.",
"authors": "Huang|Andrew J|AJ|;Núñez|Marina|M|",
"chemical_list": "D019380:Anti-HIV Agents; D004279:DNA, Viral; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine",
"country": "United States",
"delete": false,
"doi": "10.1177/2325957415586258",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-9574",
"issue": "14(4)",
"journal": "Journal of the International Association of Providers of AIDS Care",
"keywords": "HIV infection; chronic hepatitis B; outcomes",
"medline_ta": "J Int Assoc Provid AIDS Care",
"mesh_terms": "D000225:Adenine; D000328:Adult; D019380:Anti-HIV Agents; D060085:Coinfection; D004279:DNA, Viral; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D019694:Hepatitis B, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D012189:Retrospective Studies; D000068698:Tenofovir",
"nlm_unique_id": "101603896",
"other_id": null,
"pages": "360-8",
"pmc": null,
"pmid": "25999329",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcomes in HIV/HBV-Coinfected Patients in the Tenofovir Era Are Greatly Affected by Immune Suppression.",
"title_normalized": "outcomes in hiv hbv coinfected patients in the tenofovir era are greatly affected by immune suppression"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US04347",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EMTRICITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Purpose: To review early withdrawal of immunomodulatory therapy (IMT) for birdshot retinochoroidopathy (BSRC). Design: Retrospective case-series of sixteen patients with Human-leukocyte-antigen-A29-positive BSRC treated with IMT ≥ 1 year and discontinued prior to achieving durable remission, observed ≥ 6 months off IMT. Results: Mean duration on IMT was 42.4 months. At discontinuation, quiescence was achieved in 75.0% of eyes. Subjects off IMT for 6 months, 1 year, and 3 years showed quiescence in 75.0%, 77.8%, and 80.0% of eyes. No significantly decreased vision was found 6 or 12 months after discontinuation. One eye experienced significantly decreased vision following 3 years without IMT. Significantly decreased amplitude on electroretinography and worse deviation parameters in perimetry were found in patients 3 years after withdrawal that experienced early discontinuation when compared with those achieving durable remission on IMT > 2 years (p < 0.05). Conclusion: The possibility of electroretinography and perimetry results worsening after early IMT discontinuation remained if the patients couldn't achieve remission.",
"affiliations": "Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.;Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.;Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.;Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.;Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.;Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.;Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.;Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.;Massachusetts Eye Research and Surgery Institution (MERSI) , Waltham , Massachusetts , USA.",
"authors": "You|Caiyun|C|;Meese|Halea|H|;Stephenson|Andrew|A|;Montieth|Alyssa|A|;Ma|Lina|L|;Hernandez|Mikhail|M|;Kubaisi|Buraa|B|;Syeda|Sarah|S|;Foster|C Stephen|CS|https://orcid.org/0000-0002-6612-5653",
"chemical_list": "D005938:Glucocorticoids; D007155:Immunologic Factors",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2018.1506040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "27(7)",
"journal": "Ocular immunology and inflammation",
"keywords": "birdshot retinochoroidopathy; corticosteroid sparing; immunomodulatory therapy; ocular inflammation; uveitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000328:Adult; D000080365:Birdshot Chorioretinopathy; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D005938:Glucocorticoids; D006801:Humans; D007155:Immunologic Factors; D056747:Immunomodulation; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D000072776:Slit Lamp Microscopy; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1165-1173",
"pmc": null,
"pmid": "30207810",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of \"Early\" Withdrawal of Corticosteroid Sparing Immunomodulatory Therapy for Birdshot Retinochoroidopathy.",
"title_normalized": "outcomes of early withdrawal of corticosteroid sparing immunomodulatory therapy for birdshot retinochoroidopathy"
} | [
{
"companynumb": "US-TEVA-2019-US-1149939",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nUse of endermology (Endermologie®), which consists of a deep mechanical massage, in patients with multiple sclerosis receiving glatiramer acetate suggested improvements in injection-site indurations and panniculitis/lipoatrophy in our previous pilot experience. We aimed to assess the effect of endermology in a larger population of patients with multiple sclerosis receiving glatiramer acetate in clinical practice.\n\n\nMETHODS\nThis was the extension phase of our pilot experience, carried out in patients with relapsing-remitting multiple sclerosis (RRMS) and indurations and/or panniculitis/lipoatrophy associated with long-term glatiramer acetate administration. Patients underwent endermology sessions twice per week, for 6 weeks, according to clinical practice.\n\n\nRESULTS\nSeventy evaluable patients were included (mean age, 42.7±9.3 years; female, 95.7%; mean multiple sclerosis duration, 9.2±8.6 years; mean glatiramer acetate duration, 46.7±29.9 months). Fifty (71.4%) patients showed indurations and 58 (82.9%) panniculitis/lipoatrophy. After 12 endermology sessions, the number of patients with indurations significantly decreased (71.4% vs. 28.6%; p<0.001), as did the number of their indurations (4.2±3.6 vs. 3.7±3.4; p<0.001). Although the number of patients with panniculitis/lipoatrophy did not significantly decrease, there was a significant reduction in the number of areas of panniculitis/lipoatrophy (4.3±2.6 vs. 3.9±2.2; p<0.05). Forty-nine (98.0%) patients with indurations and 57 (98.3%) patients with panniculitis/lipoatrophy felt satisfied/very satisfied with treatment and considered endermology useful/very useful. Endermology was well tolerated, as some pain was reported in eight (11.4%) patients, discomfort in three (4.3%) patients, and local blotch/swelling and transient bruise in one (1.4%) patient each. Endermology enabled glatiramer acetate tolerance to be enhanced in 42 (60.0%) patients.\n\n\nCONCLUSIONS\nThis project represents the largest experience available supporting the benefit of endermology in the reduction/disappearance of indurations and improvement in panniculitis/lipoatrophy in patients with RRMS receiving long-term glatiramer acetate treatment. Moreover, these benefits also contributed to enhancing glatiramer acetate tolerance.",
"affiliations": "Multiple Sclerosis Unit, Hospital Clínico Universitario Virgen de la Arrixaca, Carretera Madrid-Cartagena, S/N, 30120, El Palmar, Spain.",
"authors": "Márquez-Rebollo|Carmen|C|;Vergara-Carrasco|Luisa|L|;Díaz-Navarro|Rosa|R|;Rubio-Fernández|Delia|D|;Francoli-Martínez|Pablo|P|;Sánchez-De la Rosa|Rainel|R|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068717:Glatiramer Acetate",
"country": "United States",
"delete": false,
"doi": "10.1007/s12325-014-0137-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0741-238X",
"issue": "31(8)",
"journal": "Advances in therapy",
"keywords": null,
"medline_ta": "Adv Ther",
"mesh_terms": "D000328:Adult; D005260:Female; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents; D007267:Injections; D008134:Long-Term Care; D008297:Male; D008405:Massage; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D015434:Panniculitis",
"nlm_unique_id": "8611864",
"other_id": null,
"pages": "904-14",
"pmc": null,
"pmid": "25047757",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Benefit of endermology on indurations and panniculitis/lipoatrophy during relapsing-remitting multiple sclerosis long-term treatment with glatiramer acetate.",
"title_normalized": "benefit of endermology on indurations and panniculitis lipoatrophy during relapsing remitting multiple sclerosis long term treatment with glatiramer acetate"
} | [
{
"companynumb": "ES-TEVA-554973ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GLATIRAMER ACETATE"
},
"drugadditional": null,
... |
{
"abstract": "The purpose of this study was to investigate panels of enzyme-linked immunospot assays (ELISpot) to detect drug-specific mediator releasing cells for confirming culprit drugs in severe cutaneous adverse reactions (SCARs).\n\n\nMETHODS\nFrequencies of drug-induced interleukin-22 (IL-22)-, interferon-gamma (IFN-γ)-, and granzyme-B (GrB)-releasing cells were measured by incubating peripheral blood mononuclear cells (PBMCs) from SCAR patients with the culprit drugs. Potential immunoadjuvants were supplemented to enhance drug-induced mediator responses.\n\n\nRESULTS\nTwenty-seven patients, including 9 acute generalized exanthematous pustulosis (AGEP), 10 drug reactions with eosinophilia and systemic symptoms, and 8 Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) were recruited. The average frequencies of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells were 35.5±16.3, 33.0±7.1, and 164.8±43.1 cells/million PBMCs, respectively. The sensitivity of combined IFN-γ/IL-22/GrB ELISpot was higher than that of IFN-γ ELISpot alone for culprit drug detection in all SCAR subjects (77.8% vs 51.9%, P < 0.01). The measurement of drug-induced IL-22- and IFN-γ releasing cells confirmed the culprit drugs in 77.8% of AGEP. The measurement of drug-induced IFN-γ- and GrB-releasing cells confirmed the culprit drugs in 62.5% of SJS/TEN. Alpha-galactosylceramide supplementation significantly increased the frequencies of drug-induced IFN-γ releasing cells.\n\n\nCONCLUSIONS\nThe measurement of drug-induced IFN-γ-releasing cells is the key for identifying culprit drugs. The additional measurement of drug-induced IL-22-releasing cells enhances ELISpot sensitivity to identify drug-induced AGEP, while the measurement of drug-induced GrB-releasing cells could have a role in SJS/TEN. ELISpot sensitivity might be improved by supplementary alpha-galactosylceramide.\n\n\nBACKGROUND\nClinicalTrials.gov Identifier: NCT02574988.",
"affiliations": "Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, The Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand.;Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, The Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand.;Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, The Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand.;King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.;Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Allergy Immunology and Rheumatology Division, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Dermatology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand.;Division of Dermatology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand.;Dermatologic Division, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand.;Division of Dermatology, Department of Medicine, Phramongkutklao Hospital, Phramongkutklao College of Medicine, Bangkok, Thailand.;Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Center for Excellence in Biostatistics, Faculty of Medicine, The Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand.",
"authors": "Klaewsongkram|Jettanong|J|https://orcid.org/0000-0001-6063-2403;Buranapraditkun|Supranee|S|https://orcid.org/0000-0001-9971-4318;Thantiworasit|Pattarawat|P|;Rerknimitr|Pawinee|P|https://orcid.org/0000-0003-2051-5573;Tuchinda|Papapit|P|https://orcid.org/0000-0002-0599-4062;Chularojanamontri|Leena|L|https://orcid.org/0000-0001-6625-6445;Rerkpattanapipat|Ticha|T|https://orcid.org/0000-0002-6630-2795;Chanprapaph|Kumutnart|K|https://orcid.org/0000-0001-7931-3816;Disphanurat|Wareeporn|W|https://orcid.org/0000-0001-7843-4915;Chakkavittumrong|Panlop|P|https://orcid.org/0000-0003-4158-4789;Tovanabutra|Napatra|N|https://orcid.org/0000-0002-9463-5976;Srisuttiyakorn|Chutika|C|https://orcid.org/0000-0002-4335-0583;Srinoulprasert|Yuttana|Y|https://orcid.org/0000-0003-3004-5771;Sukasem|Chonlaphat|C|https://orcid.org/0000-0003-0033-5321;Chongpison|Yuda|Y|https://orcid.org/0000-0001-6690-4123",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4168/aair.2021.13.6.896",
"fulltext": "\n==== Front\nAllergy Asthma Immunol Res\nAllergy Asthma Immunol Res\nAAIR\nAllergy, Asthma & Immunology Research\n2092-7355\n2092-7363\nThe Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease\n\n34734507\n10.4168/aair.2021.13.6.896\nOriginal Article\nThe Role of In Vitro Detection of Drug-Specific Mediator-Releasing Cells to Diagnose Different Phenotypes of Severe Cutaneous Adverse Reactions\nhttps://orcid.org/0000-0001-6063-2403\nKlaewsongkram Jettanong 12\nhttps://orcid.org/0000-0001-9971-4318\nBuranapraditkun Supranee 12\nThantiworasit Pattarawat 12\nhttps://orcid.org/0000-0003-2051-5573\nRerknimitr Pawinee 23\nhttps://orcid.org/0000-0002-0599-4062\nTuchinda Papapit 4\nhttps://orcid.org/0000-0001-6625-6445\nChularojanamontri Leena 4\nhttps://orcid.org/0000-0002-6630-2795\nRerkpattanapipat Ticha 5\nhttps://orcid.org/0000-0001-7931-3816\nChanprapaph Kumutnart 6\nhttps://orcid.org/0000-0001-7843-4915\nDisphanurat Wareeporn 7\nhttps://orcid.org/0000-0003-4158-4789\nChakkavittumrong Panlop 7\nhttps://orcid.org/0000-0002-9463-5976\nTovanabutra Napatra 8\nhttps://orcid.org/0000-0002-4335-0583\nSrisuttiyakorn Chutika 9\nhttps://orcid.org/0000-0003-3004-5771\nSrinoulprasert Yuttana 10\nhttps://orcid.org/0000-0003-0033-5321\nSukasem Chonlaphat 11\nhttps://orcid.org/0000-0001-6690-4123\nChongpison Yuda 12\n1 Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, The Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand.\n2 King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.\n3 Division of Dermatology, Department of Medicine, Faculty of Medicine, The Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand.\n4 Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.\n5 Allergy Immunology and Rheumatology Division, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.\n6 Division of Dermatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.\n7 Division of Dermatology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand.\n8 Dermatologic Division, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand.\n9 Division of Dermatology, Department of Medicine, Phramongkutklao Hospital, Phramongkutklao College of Medicine, Bangkok, Thailand.\n10 Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.\n11 Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.\n12 Center for Excellence in Biostatistics, Faculty of Medicine, The Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand.\nCorrespondence to Jettanong Klaewsongkram, MD. Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, The Skin and Allergy Research Unit, Chulalongkorn University, 1873 Rama4 Rd, Pathum Wan, Pathum Wan District, Bangkok 10330, Thailand. Tel: +662-2564000 ext. 80601; Fax: +662-2542323; Jettanong.K@chula.ac.th\n11 2021\n15 9 2021\n13 6 896907\n24 1 2021\n28 3 2021\n12 5 2021\nCopyright © 2021 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease\n2021\nThe Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (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.\nPropose\n\nThe purpose of this study was to investigate panels of enzyme-linked immunospot assays (ELISpot) to detect drug-specific mediator releasing cells for confirming culprit drugs in severe cutaneous adverse reactions (SCARs).\n\nMethods\n\nFrequencies of drug-induced interleukin-22 (IL-22)-, interferon-gamma (IFN-γ)-, and granzyme-B (GrB)-releasing cells were measured by incubating peripheral blood mononuclear cells (PBMCs) from SCAR patients with the culprit drugs. Potential immunoadjuvants were supplemented to enhance drug-induced mediator responses.\n\nResults\n\nTwenty-seven patients, including 9 acute generalized exanthematous pustulosis (AGEP), 10 drug reactions with eosinophilia and systemic symptoms, and 8 Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) were recruited. The average frequencies of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells were 35.5±16.3, 33.0±7.1, and 164.8±43.1 cells/million PBMCs, respectively. The sensitivity of combined IFN-γ/IL-22/GrB ELISpot was higher than that of IFN-γ ELISpot alone for culprit drug detection in all SCAR subjects (77.8% vs 51.9%, P < 0.01). The measurement of drug-induced IL-22- and IFN-γ releasing cells confirmed the culprit drugs in 77.8% of AGEP. The measurement of drug-induced IFN-γ- and GrB-releasing cells confirmed the culprit drugs in 62.5% of SJS/TEN. Alpha-galactosylceramide supplementation significantly increased the frequencies of drug-induced IFN-γ releasing cells.\n\nConclusion\n\nThe measurement of drug-induced IFN-γ-releasing cells is the key for identifying culprit drugs. The additional measurement of drug-induced IL-22-releasing cells enhances ELISpot sensitivity to identify drug-induced AGEP, while the measurement of drug-induced GrB-releasing cells could have a role in SJS/TEN. ELISpot sensitivity might be improved by supplementary alpha-galactosylceramide.\n\nTrial Registration\n\nClinicalTrials.gov Identifier: NCT02574988\n\nDrug allergy, diagnosis, in vitro\nT cell\ncytokine\nIFN-γ\n==== Body\npmcINTRODUCTION\n\nThe identification and confirmation of culprit drugs in patients who experience drug-induced severe cutaneous adverse reactions (SCARs) is difficult. Most of the time, the culprit drugs suspected are not re-challenged, so the diagnostic value of the test cannot be validated. The sensitivity of skin tests to identify culprit drugs is limited, and there are risks of exacerbating the allergic reaction.12 In vitro diagnostic tests have been introduced to identify culprit drugs, for example, the lymphocyte transformation test (LTT) and the measurement of drug-specific mediator release using enzyme-linked immunospot assays (ELISpot), which have been reported to be more sensitive than LTT.34 Interferon-gamma (IFN-γ) is the cytokine most often used to study drug-specific T cell responses.56 As several cytokines play roles in the pathogenesis of SCARs, the diagnostic values of IFN-γ ELISpot in different phenotypes of SCAR are still limited.\n\nSeveral factors might affect the results of drug-specific mediator responses in a real-world situation, such as the elapsed time since the last exposure, systemic steroid administration before having blood drawn, and SCAR phenotypes.78 It has been proposed that LTT should be performed during the recovery phase, since the assay may yield false-negative results during the acute drug allergic phase.910 “However, ELISpot data showed that the measurement of drug-specific mediator- releasing cells would be helpful at both acute and recovery phases, although sensitivity would decrease after 2 years since the last reaction”411 Taken together, the exploration of the appropriate panel of drug-specific mediators to yield the maximum sensitivity of the in vitro test is essential.\n\nThe measurement of drug-specific IFN-γ-releasing cells has most commonly been used with the ELISpot technique to identify culprit drugs. However, other mediators also play a role in T-cell-mediated drug reactions.12 There is evidence that cytotoxic signals, such as granulysin, perforin/granzyme B (GrB), and Fas/Fas ligand, are elevated in not only Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), but also in drug reaction with eosinophilia and systemic symptoms (DRESS).1314 Furthermore, the roles of interleukin (IL)-17 family cytokines, such as IL-17 and IL-22, have been demonstrated in inflammatory skin diseases such as pustular psoriasis and acute generalized exanthematous pustulosis (AGEP).151617 The measurement of these mediators released from peripheral blood mononuclear cells (PBMCs) in patients with SCAR would probably be helpful in the identification of culprit drugs.\n\nIn real-world practice, several factors could affect the sensitivity of drug-specific mediator measurements. Many regulatory molecules, particularly immune checkpoint inhibitors, have influences on the magnitude of immune responses. T-cell immunoglobulin and mucin domain 3 (TIM3) is known as a checkpoint receptor and exhaustion marker with both positive and inhibitory functions; reduced expression of TIM3 has been demonstrated in Th1 cells in drug-induced maculopapular exanthema.1819 The administration of immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1), could activate cytotoxic T cell responses in malignancies, but also lead to the development of immune-mediated cutaneous reactions.2021 There is a report that blockade of the PD-1/PD-L1 pathway could induce IFN-γ secretion from drug-specific T- cells.22 Additionally, alpha-galactosylceramide (α-GalCer) has been shown to enhance cellular immune responses, mainly via increasing the functions of natural killer T (NKT) cells.23 It would be interesting to explore whether the manipulation of these molecules could enhance the sensitivity of in vitro testing for drug allergy diagnosis.\n\nThe purpose of this study was to evaluate the diagnostic values of IFN-γ, IL-22, and GrB ELISpot assay as a confirmatory test in patients with a history of drug-induced SCARs and the potential benefit of in vitro adjuvant supplementation.\n\nMATERIALS AND METHODS\n\nTwenty-seven patients with a history of drug-induced SCARs were enrolled in the study. These patients were part of the Thailand Severe Cutaneous Adverse Reactions (ThaiSCARs) cohort. The diagnosis of SCARs was confirmed as probable or definite SJS/TEN, DRESS, or AGEP according to the RegiSCAR diagnostic criteria.242526 The culprit drugs suspected were selected based on those with the highest Naranjo score. 27\n\nCulprit drug preparations\n\nThe tested drugs for ELISpot assay were prepared from the intravenous drugs available in King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand. Ten mg of each culprit drug powder was measured, and dissolved in 1 ml of sterile distilled water, then allowed to settle for 1 hour before adjusting for ELISpot assay concentrations (Supplementary Table S1). The solutions prepared were used immediately after preparation, and the remaining should not be kept for further use. Pure drug substances for which intravenous preparation was not available were purchased from Sigma-Aldrich (St Louis, MO, USA).\n\nELISpot\n\nPBMCs were separated by Ficoll-Hypaque density gradient centrifugation. The frequencies of drug-induced mediator releasing cells were determined using ELISpot assay kits (human IL-22 single-color ELISpot [Mabtech, Stockholm, Sweden] and human IFN-γ/GrB double-color ELISpot [Cellular Technology Limited, Cleveland, OH, USA]). Briefly, 96-well polyvinylidene fluoride membrane plates were coated for 16 hours at 4°C with 5 µg/mL anti-IFN-γ antibody, anti-GrB antibody, and anti-IL-22 antibody provided in the kit and blocked with R10 medium (RPMI1640 supplemented with 100 U/mL penicillin, 100 U/mL streptomycin, and 10% heat-inactivated fetal bovine serum) for 1 hour at room temperature. PBMCs (2.0–2.5 × 105 in 100 µL) were incubated for 48 hours at 37°C in 5% CO2 with the culprit drugs in the presence or absence of α-GalCer (100 ng/mL; Abcam, Cambridge, UK), anti-CTLA4 (10 µg/mL; Merck Millipore, Burlington, MA, USA), anti-TIM-3 (10 µg/mL; Merck Millipore), or anti-PD-1 (5 µg/mL; Biolegend, San Diego, CA, USA). Plates were later washed 6 times with phosphate-buffered saline/Tween 0.05%, and incubated for 2 hours at room temperature with the corresponding biotinylated antibody, and then washed extensively. Spot-forming units (SFU) were developed using streptavidin-alkaline phosphatase, incubated for 1 hour at room temperature, and washed extensively before adding the substrate. The numbers of spots were analyzed using an ImmunoSpot S6 Ultimate Analyzer (Cellular Technology Limited) as shown in Fig. 1. The results were expressed as the highest numbers of SFU/106 PBMCs on stimulation with 2 concentrations of the culprit drugs tested, after subtracting the value obtained from PBMCs cultured without drugs (unstimulated control). The drug concentrations used for the ELISpot assay listed in Supplementary Table S1 were generally in the same range as therapeutic serum concentrations, as mentioned in our previous study.28\n\nFig. 1 Representative figures of drug-induced IL-22, IFN-γ, and GrB releasing cells as demonstrated by ELISpot assay after stimulating PBMCs with the suspected drugs in patients with a history of amoxicillin/clavulanate-induced AGEP (patient No. 4), phenytoin-induced SJS (patient No. 25), and leflunomide-induced DRESS (patient No. 14).\n\nIL, interleukin; AGEP, acute generalized exanthematous pustulosis; IFN-γ, interferon-gamma; SJS, Stevens-Johnson syndrome; GrB, granzyme B; DRESS, drug reaction with eosinophilia and systemic symptoms.\n\nThe frequencies of IL-22-, IFN-γ-, and GrB-releasing cells when incubating PBMCs with the irrelevant non-culprit drugs were also measured in 18 out of the 27 SCAR subjects to evaluate non-specific mediator responses as a control group shown in Fig. 2. The irrelevant non-culprit drugs used in the control group were the culprits suspected in other SCAR subjects, but were not the drugs implicated in the particular SCAR subjects. The ELISpot assay was considered positive if the frequencies of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells in 27 SCAR subjects upon incubating PBMCs with the culprit drugs were higher than the upper limit of the 95% confidence interval (CI) for mean mediator-releasing cells in the non-allergic control group (18.7, 17.2, and 97.7 SFU/106 PBMCs, respectively).\n\nFig. 2 Frequencies of drug-induced mediator releasing cells in different phenotypes of severe cutaneous adverse reactions. The average frequencies of drug-induced IL-22 releasing cells in AGEP subjects were significantly higher than those in non-AGEP SCAR subjects, while those of drug-induced IFN-γ releasing cells were significantly lower.\n\nSFU, spot-forming units; PBMCs, peripheral blood mononuclear cells; IL, interleukin; IFN-γ, interferon-gamma; GrB, granzyme B; AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.\n\n*P values < 0.05.\n\nStatistical analysis\n\nThe average frequencies of drug-induced mediator-releasing cells are expressed as means and 95% CI. Student's t-test was used to compare the frequencies of drug-induced mediator-releasing cells among different phenotypes. McNemar's test was used to comparatively analyze the sensitivity between different types of ELISpot assays. All statistical calculations were analyzed using Prism version 8 software (GraphPad Prism, San Diego, CA, USA). P values < 0.05 were considered statistically significant.\n\nEthics\n\nPBMCs employed in this experiment were cryopreserved specimens from patients enrolled in the ThaiSCAR registry. The registry was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, and the study was conducted in accordance with the Declaration of Helsinki. The informed consent for both study participation and publication of identifying information in an online open-access publication was obtained from all participants. The ThaiSCAR study is registered at ClinicalTrials.gov (NCT02574988).\n\nRESULTS\n\nA total of 27 patients who developed drug-induced SCARs (9 AGEP, 10 DRESS, and 8 SJS/TEN) were included in this study. Seventeen patients (63.0%) were female, with an average age of 54.1 ± 4.8 years. The average ELISpot assay latency (the time from drug reaction onset to PBMC collection for ELISpot assay) was 10.6 ± 2.3 days as shown in Table.\n\nTable Clinical characteristics of 27 patients with severe cutaneous adverse reactions in this study and results of drug-induced mediator-releasing cell measurement by ELISpot (SFU/106 PBMCs)\n\nPatient No.\tSex\tAge (yr)\tPhenotype\tCulprit drugs\tUnderlying diseases\tELISpot assay latency* (days)\tConcurrent steroid\tIL-22\tIFN-γ\tGrB\t\n1\tF\t87\tAGEP\tVancomycin\tDM\t5\tNone\t90\t0\t56\t\n2\tF\t69\tAGEP\tVancomycin\tCellulitis, HT\t6\tNone\t68\t8\t16\t\n3\tF\t65\tAGEP\tMeropenem\tNone\t3\tDexa 20 mg/day for 1 day\t0\t0\t110\t\n4\tF\t50\tAGEP\tAmoxicillin/clavulanate\tPsoriasis\t5\tNone\t297\t4\t249\t\n5\tM\t62\tAGEP\tIRZE\tTuberculosis\t25\tNone\t28\t0\t16\t\n6\tF\t88\tAGEP\tCiprofloxacin\tHT\t4\tNone\t0\t5\t85\t\n7\tF\t82\tAGEP\tPiperacillin/tazobactam\tDM, HT\t2\tPred 60 mg/day for 2 days\t0\t37\t37\t\n8\tM\t88\tAGEP\tCiprofloxacin\tDM, HT\t6\tNone\t340\t20\t30\t\n9\tF\t76\tAGEP\tOmeprazole\tNone\t7\tNone\t0\t40\t90\t\n10\tM\t36\tDRESS\tCo-trimoxazole\tHIV infection\t10\tNone\t20\t5\t545\t\n11\tF\t63\tDRESS\tAllopurinol\tHyperuricemia\t5\tDexa 5 mg/d for 3 days\t15\t20\t980\t\n12\tM\t18\tDRESS\tCo-trimoxazole\tNone\t48\tDexa 10 mg/day for 5 days then Pred 60 mg/day for 1 day\t5\t0\t80\t\n13\tF\t65\tDRESS\tAllopurinol\tHT, gout\t2\tDexa 24 mg/d for 1 day\t0\t75\t50\t\n14\tF\t35\tDRESS\tLeflunomide\tRheumatoid arthritis\t39\tPred 20 mg/d for 90 days†\t0\t80\t300\t\n15\tM\t17\tDRESS\tSulfadiazine\tToxoplasmosis\t14\tNone\t0\t0\t85\t\n16\tF\t15\tDRESS\tCo-trimoxazole\tSystemic vasculitis\t4\tNone\t5\t50\t170\t\n17\tM\t29\tDRESS\tCo-trimoxazole\tHIV infection\t36\tNone\t10\t80\t140\t\n18\tF\t17\tDRESS\tPhenytoin\tRuptured AVM\t5\tPred 60 mg/d for 5 days\t0\t100\t140\t\n19\tM\t19\tDRESS\tPhenytoin\tSeizure\t5\tDexa 15 mg/d for 5 days\t0\t40\t20\t\n20\tF\t65\tSJS\tAllopurinol\tGout\t1\tNone\t0\t8\t0\t\n21\tM\t87\tSJS\tAllopurinol\tGout\t7\tDexa 20mg/d for 1 day\t30\t40\t160\t\n22\tF\t67\tSJS\tAllopurinol\tGout\t5\tNone\t20\t110\t650\t\n23\tM\t74\tTEN\tMeropenem\tBrain abscess\t7\tDexa 5mg/d for 7 days\t0\t10\t210\t\n24\tF\t72\tSJS\tLevofloxacin\tMCTD, lymphoma\t7\tNone\t10\t0\t50\t\n25\tF\t74\tSJS\tPhenytoin\tIntracranial hemorrhage\t2\tDexa 24mg/d for 1 day\t20\t50\t40\t\n26\tM\t36\tSJS\tCo-trimoxazole\tHIV infection, chronic hepatitis C\t16\tPred 40 mg/d for 3 days\t0\t110\t120\t\n27\tF\t51\tSJS\tPhenytoin\tBreast cancer with brain metastasis\t10\tPred 40 mg/d for 14 days then Pred 20 mg/d for 14 days†\t0\t0\t0\t\nBold texts indicate positive ELISpot assays, ELISpot assay latency.\n\nELISpot, enzyme-linked immunospot assays; SFU, spot-forming units; PBMCs, peripheral blood mononuclear cells; IL, interleukin; IFN-γ, interferon-gamma; GrB, granzyme B; AGEP, acute generalized exanthematous pustulosis; DM, diabetes mellitus; HT, hypertension; Dexa, dexamethasone; IRZE, isoniazid/rifampicin/pyrazinamide/ethambutol (anti-tuberculosis agents); DRESS, drug reaction with eosinophilia and systemic symptoms; HIV, human immunodeficiency virus; Pred, prednisolone; AVM, arteriovenous malformation; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; MCTD, mixed connective tissue disease.\n\n*Days: The time from drug reaction onset (the index date) to PBMC collection for ELISpot assay, †Systemic steroid was prescribed for the underlying disease before a drug hypersensitivity reaction developed.\n\nThe average frequencies of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells upon incubating PBMCs with the culprit drugs in all SCAR phenotypes were 35.5 ± 16.3, 33.0 ± 7.1, and 164.8 ± 43.1 SFU/106 cells, respectively. The average frequencies of drug-induced IL-22-releasing cells were significantly higher in AGEP subjects than in non-AGEP SCAR subjects, while those of drug-induced IFN-γ-releasing cells were significantly lower (P = 0.01 and 0.04, respectively) as shown in Fig. 2. A significant difference was demonstrated in the frequencies of drug-induced IFN-γ-releasing cells between AGEP and DRESS (12.7 ± 5.3 SFU/106 cells vs 45.0 ± 11.9 SFU/106 cells, P = 0.03).\n\nUnivariate and multivariate linear regressions were conducted to evaluate whether drug groups (antibiotics vs. non-antibiotics) and SCAR phenotypes (AGEP vs. non-AGEP) could influence cytokine release patterns. The results in Supplementary Fig. S1 demonstrate that the frequencies of drug-induced IL-22-releasing cells were significantly higher in AGEP subjects than in non-AGEP subjects by 83.9 (95% CI, 20.2–147.7) SFU/106 PBMCs. After adjusting for the antibiotic group, the difference in IL-22 levels between patients with AGEP and those with non-AGEP remains statistically significant, with the mean difference of 77.2 (95% CI, 5.4–148.9) SFU/106 PBMCs (P< 0.05).\n\nDiagnostic values of the measurement of drug-specific mediator-releasing cells to identify suspected culprit drugs\n\nAccording to the data in Table, the measurement of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells yielded sensitivities of 33.3%, 51.9%, and 44.4%, respectively, for culprit drug identification in all SCAR subjects if each mediator was separately analyzed. It is worth noting that almost all GrB-positive subjects (except for patients number 3 and 23) could be diagnosed by measuring other mediators as well.\n\nThe results in Fig. 3 indicate that the sensitivity of the 3-mediator combination to confirm the culprit drugs in overall SCAR subjects was significantly higher than that of IFN-γ measurement alone (77.8% vs 51.9%, respectively, P value < 0.01). The culprit drugs in AGEP, DRESS, and SJS/TEN could be identified in 33.3%, 70.0%, and 50.0% of patients, respectively, by using the IFN-γ ELISpot assay, while 88.9%, 80.0%, and 62.5% could be identified using a combination of IL-22, IFN-γ, and GrB ELISpot assays.\n\nFig. 3 The sensitivity of different ELISpot assays to identify the culprit drugs in severe cutaneous adverse reactions (n = 27). The sensitivity of the three-mediator combination to confirm the culprit drugs in overall SCAR subjects was significantly higher than that of IFN-γ measurement alone (77.8% versus 51.9%, respectively).\n\nELISpot, enzyme-linked immunospot assays; SCARs, severe cutaneous adverse reactions; AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; IFN-γ, interferon-gamma; IL, interleukin; GrB, granzyme B.\n\n*P value < 0.01.\n\nThe combined measurement of drug-induced IL-22- and IFN-γ- releasing cells identified the culprit drugs in 77.8%, 80.0%, 50.0%, and 70.4% of AGEP, DRESS, SJS/TEN, and all SCAR patients, respectively. The combined measurement of drug-induced IFN-γ- and GrB-releasing cells identified the culprit drugs in 55.6%, 80.0%, 62.5%, and 66.7% of AGEP, DRESS, SJS/TEN, and all SCAR patients, respectively. The combined measurement of drug-induced IL-22 and GrB identified the culprit drugs in only 48.1% of all SCAR subjects (data not shown).\n\nThe average frequency of drug-induced IL-22-releasing cells upon incubating PBMCs with the culprit drugs was 35.5 ± 16.3 SFU/106 cells, while that upon incubating the culprit drugs with potential adjuvants ranged from to 22.4 ± 8.9 to 36.6 ± 14.1 SFU/106 cells as shown in Fig. 4. The average frequency of drug-induced IFN-γ releasing cells upon incubation with the culprit drugs alone was 33.0 ± 7.1 SFU/106 cells, while supplementation with α-GalCer, anti-TIM-3, and anti-PD-1 increased the frequency to 72.3 ± 18.5*, 63.4 ± 18.5, and 83.9 ± 38.2 SFU/106 cells, respectively (P = 0.02 compared to no adjuvant supplementation). The average frequency of drug-induced GrB-releasing cells upon incubating PBMCs with the culprit drugs was 164.8 ± 43.1 SFU/106 cells, while that upon incubating the culprit drugs with various potential adjuvants ranged from 77.9 ± 16.9 to 153.3 ± 53.1 SFU/106 cells.\n\nFig. 4 The effects of potential immunoadjuvants on the frequencies of drug-induced mediator releasing cells in severe cutaneous adverse reactions (n =27). The average frequencies of drug-induced IFN-γ releasing cells upon incubation with the culprit drugs alone were 33.0 ± 7.1 SFU/106 cells, while supplementation with α-GalCer significantly increased the frequencies to 72.3 ± 18.5 SFU/106 cells.\n\nIL, interleukin; IFN-γ, interferon-gamma; GrB, granzyme B; PD-1, programmed cell death protein 1; TIM3, T-cell immunoglobulin and mucin domain 3; CTLA4, cytotoxic T-lymphocyte-associated protein 4; α-GalCer, alpha-galactosylceramide; SFU, spot-forming units; PBMCs, peripheral blood mononuclear cells.\n\n*P value < 0.05 compared to IFN-γ alone, †P value < 0.05 compared to GrB alone.\n\nDISCUSSION\n\nCulprit drug confirmation is a difficult task, particularly in drug-induced SCARs. Since drug provocation is generally contraindicated in SCARs and the sensitivity of skin tests to identify the culprit drugs is inadequate, the roles of in vitro diagnostic tests are currently being explored. IFN-γ is the cytokine most frequently measured from T-cells in patients with a history of drug allergy. However, the sensitivity of the IFN-γ ELISpot assay is not yet satisfactory. Many obstacles limit the roles of in vitro testing; for example, different SCAR phenotypes have variable mediator expression patterns, and in certain phenotypes, especially DRESS, it is difficult to identify the culprit drugs during the acute allergic phase. Therefore, this study was designed to explore a combination of mediator panels to improve the sensitivity for identifying the culprit drugs in real-world practice in various SCAR phenotypes.\n\nAccording to our study, the measurement of drug-induced IFN-γ-releasing cells is still the key to culprit drug identification in SCARs. The results of this study support the previous literature that the measurement of drug-induced IFN-γ-releasing cells can identify the culprit drugs in at least half of patients with drug-induced SCARs, particularly in those with DRESS or SJS/TEN.429 However, the sensitivity of the test is rather low in those with AGEP.28\n\nOur study demonstrates different patterns of drug-induced mediator-releasing cells in patients with various SCAR phenotypes, and shows that the combination of 3 mediators (IL-22, IFN-γ, and GrB) can enhance the sensitivity of ELISpot to identify the culprit drugs in 77.8% of all SCAR subjects. Interestingly, we found that the measurement of drug-induced IL-22-releasing cells played a predominant role in identifying drug-induced AGEP. In fact, the sensitivity of combined IFN-γ and IL-22 ELISpot for culprit drug identification (70.4%) in SCARs was almost as high as the measurement of 3 mediators (77.8%), but it was slightly lower in SJS/TEN. Our study confirms earlier findings that not only SJS/TEN but also DRESS involve GrB in disease pathogenesis.14 However, drug-induced GrB-releasing cells were often co-expressed with other mediators in this study. As a result, the additional advantage of GrB measurement together with IFN-γ for culprit drug confirmation was only modest, compared to the measurement of drug-specific IFN-γ alone. The IFN-γ/GrB combination might be worth considering if the test was focused on SJS/TEN.\n\nAccording to this study, the supplementation of various potential adjuvants augmented drug-induced IFN-γ release, but had minimal effect on IL-22 and GrB production. Interestingly, we found that the α-GalCer supplement significantly enhanced the frequencies of drug-induced IFN-γ-releasing cells, followed by anti-TIM-3 and anti-PD-1 supplementation, while supplementation with anti-CTLA4 appeared to have little benefit. The fact that the immune checkpoint inhibitors, other than α-GalCer, failed to substantially enhance drug-specific in vitro immune responses probably due to the small number of tested subjects in each phenotype. Besides, further experiments are needed to explore the appropriate incubation time and the concentrations of the adjuvants of interest to achieve optimal responses for each specific cytokine.\n\nIt is well documented that various T cell subsets, such as cytotoxic T-cells, Th1, and Th2 cells, participate in the pathogenesis of SCARs.30 According to our study, several cell types capable of producing IL-22, such as Th17 cells, Th22 cells, γδ T cells, NK cells, NKT cells, and innate lymphoid cells, might play a role in AGEP as well.3132 Nonetheless, the clinical benefit of α-GalCer supplement to increase the sensitivity of IFN-γ ELISpot assay for culprit drug identification needed to be confirmed in further studies. Since α-GalCer can stimulate IFN-γ production from NKT cells,33 the roles of NKT cells in the pathogenesis of SCARs, particularly in DRESS and SJS/TEN, should also be explored.\n\nThere are several limitations to this preliminary study. Further studies with a larger sample size are needed to confirm the results. Additional research should be performed to measure the frequencies of these mediators at various time points after drug reaction onset to find the most appropriate timeline yielding a maximum sensitivity of each cytokine in different SCAR phenotypes. The measurement of other cytokines in the IL-17 family may also be helpful for AGEP diagnosis. Granulysin indeed plays roles in the pathogenesis of SCARs, particularly in SJS/TEN and DRESS.34 However, the incubation time for granulysin expression is too long for a conventional ELISpot assay to detect drug-specific granulysin release.35 High GrB background levels in the control subjects were observed which diminished the sensitivity of the test. The analyses of IFN-γ and GrB ELISpot assays in separated wells may be required to optimize the measurement of drug-induced GrB releasing cells. Whether supplementary adjuvants could increase the sensitivity of the IFN-γ ELISpot assay for culprit drug confirmation without reducing the specificity of the test is yet to be determined.\n\nIn conclusion, our study demonstrated differential mediator expressions among 3 main SCAR phenotypes, and supported the diagnostic value of IFN-γ ELISpot assay as the major tool to identify culprit drugs. While an additional GrB measurement might be helpful in SJS/TEN, the measurement of drug-specific IL-22-releasing cells should be encouraged for culprit drug identification in AGEP. The beneficial effects of in vitro tests for enhancing the detection of drug-induced IFN-γ-releasing cells in SCARs need further verification.\n\nACKNOWLEDGMENTS\n\nThis study has been supported by the Skin and Allergy Research Unit, Chulalongkorn University, and Health Systems Research Institute, Thailand (grant no. 62-043).\n\nSUPPLEMENTARY MATERIALS\n\nSupplementary Table S1\n\nDrug concentrations used for ELISpot in this study\n\nSupplementary Fig. S1\n\nThe impacts of SCAR phenotypes and drug groups on the mean differences of drug-induced mediator releasing cells. The frequencies of drug-induced IL-22 releasing cells in AGEP subjects were significantly higher than those in non-AGEP subjects.\n\nDisclosure: There are no financial or other issues that might lead to conflict of interest.\n==== Refs\n1 Co Minh HB Bousquet PJ Fontaine C Kvedariene V Demoly P Systemic reactions during skin tests with beta-lactams: a risk factor analysis J Allergy Clin Immunol 2006 117 466 468 16461151\n2 Liccardi G D'Amato G Canonica GW Salzillo A Piccolo A Passalacqua G Systemic reactions from skin testing: literature review J Investig Allergol Clin Immunol 2006 16 75 78\n3 Haw WY Polak ME McGuire C Erlewyn-Lajeunesse M Ardern-Jones MR In vitro rapid diagnostic tests for severe drug hypersensitivity reactions in children Ann Allergy Asthma Immunol 2016 117 61 66 27221062\n4 Suthumchai N Srinoulprasert Y Thantiworasit P Rerknimitr P Tuchinda P Chularojanamontri L The measurement of drug-induced interferon γ-releasing cells and lymphocyte proliferation in severe cutaneous adverse reactions J Eur Acad Dermatol Venereol 2018 32 992 998 29478292\n5 Copaescu A Gibson A Li Y Trubiano JA Phillips EJ An updated review of the diagnostic methods in delayed drug hypersensitivity Front Pharmacol 2021 11 573573 33597867\n6 Halevy S Cohen AD Grossman N Clinical implications of in vitro drug-induced interferon gamma release from peripheral blood lymphocytes in cutaneous adverse drug reactions J Am Acad Dermatol 2005 52 254 261 15692470\n7 Kano Y Hirahara K Mitsuyama Y Takahashi R Shiohara T Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption Allergy 2007 62 1439 1444 17983378\n8 Klaewsongkram J Thantiworasit P Suthumchai N Rerknimitr P Sukasem C Tuchinda P In vitro test to confirm diagnosis of allopurinol-induced severe cutaneous adverse reactions Br J Dermatol 2016 175 994 1002 27106261\n9 Polak ME Belgi G McGuire C Pickard C Healy E Friedmann PS In vitro diagnostic assays are effective during the acute phase of delayed-type drug hypersensitivity reactions Br J Dermatol 2013 168 539 549 23106791\n10 Cabañas R Calderón O Ramírez E Fiandor A Caballero T Heredia R Sensitivity and specificity of the lymphocyte transformation test in drug reaction with eosinophilia and systemic symptoms causality assessment Clin Exp Allergy 2018 48 325 333 29265576\n11 Tanvarasethee B Buranapraditkun S Klaewsongkram J The potential of using enzyme-linked immunospot to diagnose cephalosporin-induced maculopapular exanthems Acta Derm Venereol 2013 93 66 69 22722755\n12 Kuechler PC Britschgi M Schmid S Hari Y Grabscheid B Pichler WJ Cytotoxic mechanisms in different forms of T-cell-mediated drug allergies Allergy 2004 59 613 622 15147446\n13 Su SC Chung WH Cytotoxic proteins and therapeutic targets in severe cutaneous adverse reactions Toxins (Basel) 2014 6 194 210 24394640\n14 Yang F Chen SA Wu X Zhu Q Luo X Overexpression of cytotoxic proteins correlates with liver function impairment in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) Eur J Dermatol 2018 28 13 25 29521632\n15 Cavani A Pennino D Eyerich K Th17 and Th22 in skin allergy Chem Immunol Allergy 2012 96 39 44 22433369\n16 Speeckaert R Lambert J Grine L Van Gele M De Schepper S van Geel N The many faces of interleukin-17 in inflammatory skin diseases Br J Dermatol 2016 175 892 901 27117954\n17 Sullivan A Wang E Farrell J Whitaker P Faulkner L Peckham D β-Lactam hypersensitivity involves expansion of circulating and skin-resident TH22 cells J Allergy Clin Immunol 2018 141 235 249.e8 28219704\n18 Banerjee H Kane LP Immune regulation by Tim-3 F1000 Res 2018 7 316\n19 Fernandez-Santamaría R Palomares F Salas M Doña I Bogas G Ariza A Expression of the Tim3-galectin-9 axis is altered in drug-induced maculopapular exanthema Allergy 2019 74 1769 1779 31034608\n20 Plachouri KM Vryzaki E Georgiou S Cutaneous adverse events of immune checkpoint inhibitors: a summarized overview Curr Drug Saf 2019 14 14 20 30058498\n21 Collins LK Chapman MS Carter JB Samie FH Cutaneous adverse effects of the immune checkpoint inhibitors Curr Probl Cancer 2017 41 125 128 28190531\n22 Gibson A Ogese M Sullivan A Wang E Saide K Whitaker P Negative regulation by PD-L1 during drug-specific priming of IL-22-secreting T cells and the influence of PD-1 on effector T cell function J Immunol 2014 192 2611 2621 24510967\n23 Ghinnagow R Cruz LJ Macho-Fernandez E Faveeuw C Trottein F Enhancement of adjuvant functions of natural killer T cells using nanovector delivery systems: application in anticancer immune therapy Front Immunol 2017 8 879 28798749\n24 Sidoroff A Halevy S Bavinck JN Vaillant L Roujeau JC Acute generalized exanthematous pustulosis (AGEP)--a clinical reaction pattern J Cutan Pathol 2001 28 113 119 11168761\n25 Kardaun SH Sidoroff A Valeyrie-Allanore L Halevy S Davidovici BB Mockenhaupt M Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007 156 609 611 17300272\n26 Bastuji-Garin S Rzany B Stern RS Shear NH Naldi L Roujeau JC Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme Arch Dermatol 1993 129 92 96 8420497\n27 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 7249508\n28 Klaewsongkram J Sukasem C Thantiworasit P Suthumchai N Rerknimitr P Tuchinda P Analysis of HLA-B allelic variation and IFN-γ ELISpot responses in patients with severe cutaneous adverse reactions associated with drugs J Allergy Clin Immunol Pract 2019 7 219 227.e4 29800753\n29 Porebski G In vitro assays in severe cutaneous adverse drug reactions: are they still research tools or diagnostic tests already? Int J Mol Sci 2017 18 1737\n30 Bellón T Mechanisms of severe cutaneous adverse reactions: recent advances Drug Saf 2019 42 973 992 31020549\n31 Dudakov JA Hanash AM van den Brink MR Interleukin-22: immunobiology and pathology Annu Rev Immunol 2015 33 747 785 25706098\n32 Colonna M Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity Immunity 2009 31 15 23 19604490\n33 Fujii S Shimizu K Kronenberg M Steinman RM Prolonged IFN-γ-producing NKT response induced with α-galactosylceramide-loaded DCs Nat Immunol 2002 3 867 874 12154358\n34 Chen CB Abe R Pan RY Wang CW Hung SI Tsai YG An updated review of the molecular mechanisms in drug hypersensitivity J Immunol Res 2018 2018 6431694 29651444\n35 Won HK Lee JW Song WJ Klaewsongkram J Kang MG Park HK Lamotrigine-induced toxic epidermal necrolysis confirmed by in vitro granulysin and cytokine assays Asia Pac Allergy 2014 4 253 256 25379485\n\n",
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"issue": "13(6)",
"journal": "Allergy, asthma & immunology research",
"keywords": "Drug allergy, diagnosis, in vitro; IFN-γ; T cell; cytokine",
"medline_ta": "Allergy Asthma Immunol Res",
"mesh_terms": null,
"nlm_unique_id": "101518382",
"other_id": null,
"pages": "896-907",
"pmc": null,
"pmid": "34734507",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": "29560265;7249508;17983378;24510967;25706098;29521632;27106261;12154358;22433369;29265576;29478292;11168761;22722755;27221062;29651444;16461151;28798749;28796198;31020549;28190531;25379485;24394640;15147446;28219704;33597867;27117954;23106791;19604490;30058498;8420497;16689179;15692470;29800753;17300272;31034608",
"title": "The Role of In Vitro Detection of Drug-Specific Mediator-Releasing Cells to Diagnose Different Phenotypes of Severe Cutaneous Adverse Reactions.",
"title_normalized": "the role of in vitro detection of drug specific mediator releasing cells to diagnose different phenotypes of severe cutaneous adverse reactions"
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"abstract": "Immunocompromised patients are predisposed to infections caused by influenza virus. Influenza virus may produce considerable morbidity, including protracted illness and prolonged viral shedding in these patients, thus prompting higher doses and prolonged courses of antiviral therapy. This approach may promote the emergence of resistant strains. Characterization of neuraminidase (NA) inhibitor (NAI)-resistant strains of influenza A virus is essential for documenting causes of resistance. In this study, using quantitative real-time PCR along with conventional Sanger sequencing, we identified an NAI-resistant strain of influenza A (H3N2) virus in an immunocompromised patient. In-depth analysis by deep gene sequencing revealed that various known markers of antiviral resistance, including transient R292K and Q136K substitutions and a sustained E119K (N2 numbering) substitution in the NA protein emerged during prolonged antiviral therapy. In addition, a combination of a 4-amino-acid deletion at residues 245 to 248 (Δ245-248) accompanied by the E119V substitution occurred, causing resistance to or reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir). Resistant variants within a pool of viral quasispecies arose during combined antiviral treatment. More research is needed to understand the interplay of drug resistance mutations, viral fitness, and transmission.",
"affiliations": "Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada.;Division of Infectious Diseases, University Health Network, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada.;Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada.;Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada.;Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada.;University of Toronto, Toronto, Ontario, Canada.;University of Toronto, Toronto, Ontario, Canada.;National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.;National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.;Division of Infectious Diseases, University Health Network, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada.;Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada The Hospital for Sick Children, Toronto, Ontario, Canada jonathan.gubbay@oahpp.ca.",
"authors": "Eshaghi|Alireza|A|;Shalhoub|Sarah|S|;Rosenfeld|Paul|P|;Li|Aimin|A|;Higgins|Rachel R|RR|;Stogios|Peter J|PJ|;Savchenko|Alexei|A|;Bastien|Nathalie|N|;Li|Yan|Y|;Rotstein|Coleman|C|;Gubbay|Jonathan B|JB|",
"chemical_list": "D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D007166:Immunosuppressive Agents; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir; C414210:peramivir",
"country": "United States",
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"doi": "10.1128/AAC.03667-14",
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"issn_linking": "0066-4804",
"issue": "58(12)",
"journal": "Antimicrobial agents and chemotherapy",
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"mesh_terms": "D000146:Acids, Carbocyclic; D000328:Adult; D000998:Antiviral Agents; D003517:Cyclopentanes; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors; D017809:Fatal Outcome; D005260:Female; D006146:Guanidines; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D053122:Influenza A Virus, H3N2 Subtype; D007251:Influenza, Human; D015448:Leukemia, B-Cell; D008958:Models, Molecular; D009154:Mutation; D009439:Neuraminidase; D053139:Oseltamivir; D014184:Transplantation, Homologous; D014764:Viral Proteins; D053243:Zanamivir",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": "7188-97",
"pmc": null,
"pmid": "25246391",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17302366;16169926;23523943;18625765;12103431;24215378;11865415;16208317;11807683;19505943;23061103;16479508;20069535;9780244;19641000;19451168;23965618;23279894;19628174;19917319;20686654;16189083;22966122;21041923;11224828;17109288;12062395;20350163;12606750;23810646;21801626;20836794;10592235;20955912;19046066;20562416;20738864;1438172;23192869;19255111;19216793;21221095;22186145;8387212;15337401;20202427",
"title": "Multiple influenza A (H3N2) mutations conferring resistance to neuraminidase inhibitors in a bone marrow transplant recipient.",
"title_normalized": "multiple influenza a h3n2 mutations conferring resistance to neuraminidase inhibitors in a bone marrow transplant recipient"
} | [
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"abstract": "BACKGROUND\nCANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the β5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib.\n\n\nMETHODS\nWe report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease.\n\n\nCONCLUSIONS\nCANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.",
"affiliations": "Department of Pediatrics, Medical University, Varna, Bulgaria. boyadzhiev.martin@gmail.com.;Department of Pediatrics, Medical University, Varna, Bulgaria.;Department of Pediatrics, Medical University, Varna, Bulgaria.;Department of Pediatrics, Medical University, Varna, Bulgaria.;National Human Genome Research Institute, National Institutes of Health, Washington D.C, USA.;Instituste of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.",
"authors": "Boyadzhiev|M|M|http://orcid.org/0000-0003-3827-4560;Marinov|L|L|;Boyadzhiev|V|V|;Iotova|V|V|;Aksentijevich|I|I|;Hambleton|S|S|",
"chemical_list": "D001384:Azetidines; D000075242:Janus Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D013449:Sulfonamides; D046988:Proteasome Endopeptidase Complex; C000596027:baricitinib",
"country": "England",
"delete": false,
"doi": "10.1186/s12969-019-0322-9",
"fulltext": "\n==== Front\nPediatr Rheumatol Online JPediatr Rheumatol Online JPediatric Rheumatology Online Journal1546-0096BioMed Central London 32210.1186/s12969-019-0322-9Case ReportDisease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome http://orcid.org/0000-0003-3827-4560Boyadzhiev M. boyadzhiev.martin@gmail.com 1Marinov L. marrinovs@abv.bg 1Boyadzhiev V. vessboja@gmail.com 1Iotova V. iotova_v@yahoo.com 1Aksentijevich I. aksentii@arb.niams.nih.gov 2Hambleton S. sophie.hambleton@newcastle.ac.uk 31 0000 0000 8767 9052grid.20501.36Department of Pediatrics, Medical University, Varna, Bulgaria 2 0000 0001 2233 9230grid.280128.1National Human Genome Research Institute, National Institutes of Health, Washington D.C, USA 3 0000 0001 0462 7212grid.1006.7Instituste of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK 2 5 2019 2 5 2019 2019 17 1915 12 2018 12 4 2019 © The Author(s). 2019Open Access This 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\nCANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the β5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib.\n\nCase presentation\nWe report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease.\n\nConclusions\nCANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.\n\nKeywords\nAutoinflammationCANDLE syndromeImmunoproteasomeJAK inhibitorsNephrolithiasisissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nChronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome has been described by Torello et al. in 2010 [1]. CANDLE syndrome patients present in early-infancy, often during the neonatal period, with symptoms of recurrent fevers and a prominent skin rash [1, 2]. The rash tends to be exacerbated during inflammatory episodes. Torello et al. described 4 children between 2 and 14 years of age, presenting with annular purpuric plaques mainly on the body. The authors made a thorough investigation of the skin lesions through repeated skin biopsies [3]. The periorbital swelling also appears during the first months of life. Growth retardation and failure to thrive are some of the most striking features of the syndrome.\n\nThe loss of fat tissue (lipodystrophy) mostly in the upper limbs and face becomes visible later in the disease progress. The lack of fat tissue over the cheeks gives patients a typical “aging” look. The abdominal fat tissue, on the contrary, tends to be increased, which leads to metabolic disturbances [2].\n\nArthralgia and arthritis are almost always present although with variable degrees [4]. Myalgia, myositis and muscle wasting also can lead to reduced patients‘mobility. Other not so common features are clubbed fingers, hepatomegaly and splenomegaly, hypertrichosis, acanthosis, alopecia areata, arterial hypertension, basal ganglia calcification [5]. Roberts et al. reported a South African girl with microdontia and microstomia [6]. The laboratory findings in patients with CANDLE include increased inflammatory markers, CRP, ESR, and marked leukocytosis [7]. Hypertrigliceridemia is a common finding.\n\nThe first disease-causing mutations were identified in the PSMB8 gene and were associated with functional dysregulation of the immunoproteasome complex. Subsequently, mutations in additional genes encoding both immunoproteasome and constitutive proteasome subunits were identified: PSMB4, PSMA3, PSMB9. More recently, heterozygous de novo mutations in the regulatory POMP protein have been reported in patients with autoimmunity, immunodeficiency and autoinflammation resembling CANDLE. Thus the inheritance pattern in CANDLE can be autosomal recessive or in the form of a de novo mutation.\n\nTwo more syndromes with a striking resemblence to the CANDLE syndrome have been reported - Nakajo-Nishimura syndrome (NNS) was first reported in 1939 by Dr. Nakajo [8]. In 1950, Nishimura reported three more cases with similar features. In 2010, Garg et al. [9] reported three adult patients with a disease they named Joint Contractures, Muscle atrophy, microcytic anemia, and Panniculitis-induced lipodystrophy syndrome (JMP). Patients diagnosed with NNS and JMP carry biallelic either homozygous or compound heterozygous mutations in PSMB8. Currently there is no consensus classification of these three syndromes. Some authors use the term PRAAS (proteasome-associated autoinflammatory syndrome), others - ALDD (autoinflammation, lipodystrophy, and dermatitis) [10]. The exact prevalence of CANDLE syndrome is yet unknown.\n\nPRAAS is caused by a dysregulation in the proteasome-immunoproteasome function [11, 12] Immunoproteasomes are found mainly in immune cells. Their structure is very similar to that of the proteasomes [13–15]. Immunoproteasome formation is mainly induced by proinflammatory cytokines such as IFNs and in response to increased demand for protein degradation in cells [16, 17].\n\nThe production of IFNs is increased during viral infections or other types of stress. This leads to increased protein degradation by the immunoproteasomes. When they are not working properly, the pathogen-derived proteins and other damaged proteins accumulate in cells stimulating the production of IFNs. That forms a vicious circle leading to persistent inflammatory state. Since JAK-STAT signalling pathway is activating type 1 and 2 IFNs, it is not surprising that wider and more frequent use of JAK inhibitors in clinical studies leads to remarkable results [18–20]. As mentioned above, in the case of CANDLE syndrome, there is a defect in the immunoproteasome function that leads to activation of the IFNs through the JAK-STAT signaling pathway. The expected efficacy of JAK inhibitors is due to the action they exert on that exact pathway. The long-term prognosis remains unclear because of the recent description and the very limited treatment experience.\n\nCase presentation\nWe present a 6 years old boy, presented soon after birth with erythematous eruption and hemorrhagic blisters (pernio), initially on the palms. Subsequently the rash spread over the entire body, accompanied with solitary subcutaneous nodules and violaceous periorbital swelling. His rash was worse during fever episodes. He was hospitalized multiple times at a tertiary pediatric unit with the clinical picture of severe inflammation. No immunisations were administered after the age of 3 months [21]. Three consecutive skin biopsies were performed from active efflorescences. They showed inflammation with the presence of lymphocytes, neutrophils, macrophages and mastocytes (CD117+). Some parts showed leukocytoclasis. Several autoimmune and autoinflammatory syndromes were considered in the differential diagnosis, including Sweet syndrome, Mevalonate kinase deficiency, CINCA/NOMID and leukocytoclastic vasculitis.\n\nAt the age of 1 year 5 months, he was started on methylprednisolone 1 mg/kg.d-1 with a reasonable effect on the rash and fevers. However, all attempts to taper the dose led to immediate relapse of the symptoms. Succesively, hydroxycloroquine and methotrexate were attempted as GC sparing agents, but they were soon withdrawn due to lack of any clinical effect.\n\nThe boy presented to us at the age of 2 years and 10 months. He was looking pretty unwell, with elevated daily temperatures reaching 39.9 °C, persistent skin eruption with nodules, livid and red papules and macules on the head, body, upper and lower extremities, palms and soles. Purple periorbital swelling was also present (Fig. 1). Hypertrichosis was noted all over the body. Subcutaneous adipose tissue was significant for lipodystrophy. The arms, shoulders and face had well demarcated outline of the muscles, which gave the false impression of increased muscularity. The parents recalled episodes of joint pain and swelling of knees and fingers, but there was no objective evidence of contractures or joint space narrowing. The face was characteristic for atrophic facial musculature and absence of buccal fat pads, thus giving him an appearance of an old-man. He also had hypertelorism and epicanthus. Other symptoms were cough, tachydyspnea and hepatomegaly. The patient appeared very stunted for his age group. Age- and sex-specific growth evaluation showed significant short stature (− 4.1 SDS) and a decreased weight (− 2.3 SDS), www.cdc.gov/growthcharts. His bone age, according to Greulich and Pyle’s atlas, was 1 year 3 months (<− 2.0 SDS). Blood workup showed elevated CRP - 114.09 mg/L (0–5.0), neutrophilia, anemia with serum iron level < 2 mcmol/L (7.2–21.5). Thorough investigation showed no cardiac, pulmonary or neurologic involvment at the time.Fig. 1 The patient: a. When he is 2 years 10 months old; b. When he is 5 years old, just before the start of baricitinib; c. After 7 months of treatment with baricitinib\n\n\n\nCANDLE syndrome was suggested as the most probable diagnosis after discussion and evaluation of the patient’s medical history and current status. Blood samples from the child and both parents were sent to NIH for genetic testing. The patient was found to have compound heterozygous mutations in the PSMB8 gene (p.A92V/p.K105Q). Both parents are carriers of one mutation.\n\nFollow-up\nAfter confirming the diagnosis of CANDLE, we intended to find a way to start therapy with JAK inhibitors. At the age of 3 years 6 months the boy presented with a violent flank pain. Ultrasound examination showed nephrolithiasis, with several small concrements in both kidneys. His mother reported a history of nephrolithiasis. Two months later, an abdominal ultrasound revealed mild hydronephrosis, without any sign of nephrolithiasis. This finding remains until the present time.\n\nOther complications have appeared with time, related to the syndrome and the therapies. At 5 years of age despite the high doses of glucocorticoids, inflammatory flares with fever, and elevated CRP continued to be frequent – at least one episode every month. Failure to thrive was progressing. Arterial hypertension with the blood pressure reaching 160/100 mmHg and frequent headaches necessitated addition of ACE-inhibitor and calcium inhibitor to his therapy. Cholesterol was high for age (5.97 mmol/l).\n\nGastric complaints became frequent with stomach pain and vomiting at least once weekly. While on high doses of methylprednisolone his appetite became voracious. Despite the large food intake his height remained static, while growth velocity was less than 0.5 cm per year (Fig. 1). The patient complained of muscle pain, difficulty walking and easy fatigue.\n\nThe JAK 1/2 inhibitor baricitinib (Olumiant) was started shortly after the patient‘s 5th birthday. The NIH protocol was followed with a starting dose of 6 mg/day for the first 3 days, and after no side effects were observed the dose was increased to 8 mg/day. After 7 months of treatment we witnessed dramatic and objective improvements:No new episodes of systemic inflammation for the past 3 months: no fevers, malaise, and vomiting.\n\nThe first attempt of stopping glucocorticoid treatment completely was undertaken 3 months after the start of baricitinib. The GC dose was quickly tapered down from 1 mg/kg/day to less than 0.1 mg/kg/day during the first month. This led to the new appearance of three violaceous subcutaneous nodules, resembling the typical rash for CANDLE on his foot and fingers), which disappeared in a week. Methylprednisolone treatment was completely stopped at 5th month after the initiation of treatment with baricitinib and without further relapses.\n\nDrastic improvement of the skin rash, and dissapearence of the periorbital swelling (Fig. 1)\n\nNormalisation of the blood pressure, allowing the withdrawal of the calcium inhibitor during the second month of treatment and the ACE-inhibitor after 7 months.\n\nIncreased growth velocity - +8.8 cm/7 months, extrapolated growth velocity of 15 cm/year.\n\nDecreased abdominal circumference by 8 cm - from 65 cm to 57 cm.\n\nImproved mobility with no complaints of fatigue and/or muscle pain. Soon after the start of baricitinib treatment the patient was able to perform longer and more difficult physical activities.\n\nDuring 7 months of treatment the patient needed a 5 day-treatment with an antibiotic due to a common upper airways infection.\n\n\n\nShortly after the start of baricitinib the boy refused to walk, and complained of muscle pain in the thighs. No clinical or laboratory signs of myositis or arthritis were found. Complaints continued for a week, without worsening or further complications.\n\nDuring the patient‘s visit on the seventh month after the start of baricitinib treatment he was feeling much better, with no pain while walking in contrast to his previous visits, with normalized appetite and increased physical endurance. Control blood count showed normal leucocytes and hemoglobin, and normal neutrophil count. Despite the lack of clinical symptoms, elevated CRP values were noted on two occasions, raising the question of the best dose of baricitinib (Table 1). The significant increase in his growth velocity has been documented (Fig. 2). Those findings repeated during the visit at the end of the first year after the start of baricitinib treatment (Fig. 2).Table 1 Inflammation markers during the patient follow up\n\nDate\tAge\tLeucocytes ×109/L\tNeutrophils ×109/L\tCRP mg/L\t\nJune 2015\t2 y 10 mo\t8.27\t7.51\t114.09\t\nApril 2016\t3 y 8 mo\t16.62\t11.01\t23.71\t\nNovember 2016\t4 y 3 mo\t16.12\t12.16\t16.3\t\nJanuary 2017\t4 y 5 mo\t10.81\t9.11\t76.18\t\nMarch 2017\t4 y 7 mo\t10.89\t5.12\t43.04\t\nStart of Baricitinib in August 2017\t\n September 2017\t5 y 0 mo\t16.88\t12.24\t2.8\t\n October 2017\t5 y 2 mo\t8.73\t3.5\t0.13\t\n December 2017\t5 y 4 mo\t7.66\t3.53\t8.78\t\n February 2018\t5 y 5 mo\t7.89\t4.47\t17.13\t\n April 2018\t5 y 7 mo\t6.74\t2.78\t7.48\t\n February 2019\t6 y 5 mo\t7.5\t5.79\t18.63\t\nFig. 2 Growth chart of the patient\n\n\n\nDiscussion\nWe present a young patient with molecularly confirmed CANDLE syndrome. The patient is compound heterozygous: he has two mutations in the PSMB8 gene (p.A92V/p.K105Q). One of the mutations – p.Ala92Val (c.275C > T) is novel and has not been reported, although another mutation affecting the same amino acid residue is reported in patients with CANDLE [22]. The second mutation p.Lys105Gln (c.313A > C; p.K105Q) was recently described in a report from Brehm et al. in 2015 [16].\n\nThe patient was treated with JAK 1/2 inhibitor, baricitinib, for a period of 1 year and 6 months without any side effects and with impressive improvement in all aspects of the disease.\n\nJAK inhibitors are part of a new class of small molecule drugs and they have been used in the treatment of rare oncologic diseases and many autoimmune and autoinflammatory diseases. Janus Kinase inhibition has been used with a different degree of success in myeloproliferative diseases, lupus, psoriatic arthritis, inflammatory bowel diseases [23, 24]. They are especially efficient in the treatment of adult rheumatoid arthritis, showing promising results in comparison with biological agents. JAK inhibitors are also very convenient for the patients because of their oral intake.\n\nTreatment effect of baricitinib described in this article is comparable to the previous published reports in CANDLE patients [18]. The mean dose of baricitinib in this study was 8.5 mg/day. Our patient is on a maintenance dose of 8 mg/day. However, increased values of CRP in our patient were detected during the last couple of visits. No other signs of infections were present. This indicates the presence of persisting subclinical inflammation and raises the question about the best dose of baricitinib.\n\nMontealegre et al. described a decrease in the mean glucocorticoid dose by 73%, and 4 out of 12 patients managed to discontinue glucocorticoids completely. After 5 months of treatment in our patient, the GC treatment was discontinued completely and with no disease relapses.\n\nFive out of six patients with myositis, described by the above referenced study, showed improvement in muscle fatigue and improved physical endurance as it has been the case with our patient [18]. Joint involvement, which is a typical clinical finding for most of the published CANDLE patients, was not a predominating feature in our case.\n\nThe study by Montealegre et al. also described 17 serious adverse events in 4 patients. Most common were those of infectious origin – infections of the upper respiratory tract, one probable Pneumocystis jiroveci pneumonia, Rotavirus and Clostridium difficile infections. One patient has been removed from the study due to a lack of efficacy and development of avascular necrosis. Our patient did not suffer from any serious complications connected to an infectious cause or any other adverse events.\n\nOur patient showed persistently normal hemoglobin levels during the treatment, while two patients reported by Montealegre et al. developed anemia.\n\nThe results from the JAK inhibitor treatment of here described patient with CANDLE syndrome are consistent with the previously published cohort study, with catch-up growth and physical activity improving significantly more in our patient. The short-term effects of JAK 1/2 inhibitor according to our expirience are excellent with no side effects reported, though the long-term effectiveness and possible serious side-effects remain a concern. The increased values of CRP, suggesting persistent subclinical inflammation, raise the question if the best dose of baricitinib is 8 mg/day or higher. Tofacitinib has been used by other authors with beneficial effect [25] but we do not have experience with the drug.\n\nAlthough glucocorticoids control the acute inflammation, the significant side effects make their long term use undesirable. We hope that JAK inhibitors will secure a long-term control of the disease symptoms without severe side-effects and a better quality of life of the children affected by CANDLE syndrome.\n\nConclusion\nThe results from the JAK inhibitor treatment of here described patient with CANDLE syndrome are consistent with the previously published cohort study. Although the short-term effects of JAK 1/2 inhibitor are excellent, the long-term effectiveness and possible serious sideeffects remain a concern.\n\nAbbreviations\nALDDAutoinflammation, lipodystrophy, and dermatitis\n\nANAAntinuclear antibodies\n\nCANDLEChronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature\n\nCINCAChronic infantile neurological cutaneous and articular syndrome\n\nCRPC reactive protein\n\nESRErythrocyte sedimentation rate\n\nGCGlucocorticoids\n\nIFNInterferon\n\nJAKJanus kinase\n\nJMPJoint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome\n\nNIHNational Institute of Health\n\nNNSNakajo-Nishimura syndrome\n\nNOMIDNeonatal onset multisistem inflammatory disease\n\nPRAASProteasome-associated autoinflammatory syndrome\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe authors received no specific funding for this work.\n\nAvailability of data and materials\nPlease contact author for data requests.\n\nAuthors’ contributions\nAll authors have made substantial contributions to the conception of the work. MB, LM, VB and VI are the treating physicians. IA and SH conducted the genetic investigation and provided the treatment reccomendations. All authors were involved in drafting the work or revising it critically for important intellectual content. All authors have read final approval of the version published.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nInformed consent for publication has been obtained from both parents.\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. Torrelo A Patel S Colmenero I Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome J Am Acad Dermatol 2010 62 489 495 10.1016/j.jaad.2009.04.046 20159315 \n2. Torrelo A CANDLE syndrome as a paradigm of proteasome-related autoinflammation Front Immunol 2017 8 927 10.3389/fimmu.2017.00927 28848544 \n3. Torrelo A Colmenero I Requena L Histologic and Immunohistochemical features of the skin lesions in CANDLE syndrome Am J Dermatopathol 2015 37 517 522 10.1097/DAD.0000000000000340 26091509 \n4. Gönül Müzeyyen Cevirgen Cemil Bengu Keseroglu Havva Ozge Kaya Akis Havva New Described Dermatological Disorders BioMed Research International 2014 2014 1 13 10.1155/2014/616973 \n5. Liu Y Ramot Y Torrelo A Mutations in proteasome subunit type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity Arthritis Rheumatism 2012 64 3 895 907 10.1002/art.33368 21953331 \n6. Roberts T Stephen L Scott C CANDLE SYNDROME: Oro-facial manifestations and dental implications Head Face Med 2015 11 38 10.1186/s13005-015-0095-4 26711936 \n7. McDermott A Jacks J Kessler M Proteasome-associated autoinflammatory syndromes: advances in pathogeneses, clinical presentations, diagnosis, and management Int J Dermatol 2015 54 121 129 10.1111/ijd.12695 25521013 \n8. Kanazawa N Nakajo-Nishimura syndrome: an autoinflammatory disorder showing Pernio-like rashes and progressive partial lipodystrophy Allergol Int 2012 61 197 206 10.2332/allergolint.11-RAI-0416 22441638 \n9. Garg A Hernandez M Sousa A An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic Anemia, and panniculitis-associated lipodystrophy J Clin Endocrinol Metab 2010 95 9 E58 E63 10.1210/jc.2010-0488 20534754 \n10. Touitou I Galeotti C Rossi-Semerano L The expanding spectrum of rare monogenic autoinflammatory diseases Orphanet J Rare Dis 2013 8 162 10.1186/1750-1172-8-162 24131530 \n11. Kastner D Aksentijevich I Goldbach-Mansky R Autoinflammatory disease reloaded: a clinical perspective Cell 2010 140 6 784 790 10.1016/j.cell.2010.03.002 20303869 \n12. Ozkurede V Franchi L Immunology in clinic review series; focus on autoinflammatory diseases: role of inflammasomes in autoinflammatory syndromes Clin Exp Immunol 2011 167 382 390 10.1111/j.1365-2249.2011.04535.x \n13. Ferrington D Gregerson D Immunoproteasomes: structure, function, and antigen presentation Prog Mol Biol Transl Sci 2012 109 75 112 10.1016/B978-0-12-397863-9.00003-1 22727420 \n14. Greaney A Leppla S Moayeri M Bacterial exotoxins and the inflammasome Front Immunol 2015 6 570 10.3389/fimmu.2015.00570 26617605 \n15. Kim YK Shin J Nahm M NOD-like receptors in infection, immunity, and diseases Yonsei Med J 2016 57 1 5 14 10.3349/ymj.2016.57.1.5 26632377 \n16. Brehm A Liu Y Sheikh A Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production J Clin Invest 2015 125 11 4196 4211 10.1172/JCI81260 26524591 \n17. Volpi S Picco P Caorsi R Type I interferonopathies in pediatric rheumatology Pediatr Rheumatol 2016 14 35 10.1186/s12969-016-0094-4 \n18. Montealegre G Reinhardt A Brogan P Preliminary response to Janus kinase inhibition with baricitinib in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) Pediatr Rheumatol 2015 13 Suppl 1 O31 10.1186/1546-0096-13-S1-O31 \n19. Di Lernia V Bardazzi F Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis Drug Des Devel Ther 2016 10 533 539 10.2147/DDDT.S82599 26889081 \n20. Gomes Aldrin V. Genetics of Proteasome Diseases Scientifica 2013 2013 1 30 10.1155/2013/637629 \n21. Heijstek M Ott De Bruin L Bijl M EULAR recommendations for vaccination in paediatric patients with rheumatic diseases Ann Rheum Dis 2011 70 1704 1712 10.1136/ard.2011.150193 21813547 \n22. McDermott Amelia Jesus Adriana Almeida Liu Yin Kim Peter Jacks Jennifer Montealegre Sanchez Gina A. Chen Yongqing Kannan Aarthi Schnebelen Alicia Emanuel Peter D. Shalin Sara Hiatt Kim Goldbach-Mansky Raphaela Gao Ling A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations Journal of the American Academy of Dermatology 2013 69 1 e29 e32 10.1016/j.jaad.2013.01.015 23768303 \n23. Furumoto Y Gadina M The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders BioDrugs 2013 27 5 431 438 10.1007/s40259-013-0040-7 23743669 \n24. Kuriya B Cohen M Keystone E Baricitinib in rheumatoid arthritis: evidence-to-date and clinical potential Ther Adv Musculoskelet Dis 2017 9 2 37 44 10.1177/1759720X16687481 28255337 \n25. Kim H Montealegre Sanchez G Goldbach-Mansky R Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus J Mol Med (Berl) 2016 94 10 1111 1127 10.1007/s00109-016-1465-5 27678529\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1546-0096",
"issue": "17(1)",
"journal": "Pediatric rheumatology online journal",
"keywords": "Autoinflammation; CANDLE syndrome; Immunoproteasome; JAK inhibitors; Nephrolithiasis",
"medline_ta": "Pediatr Rheumatol Online J",
"mesh_terms": "D001327:Autoimmune Diseases; D001384:Azetidines; D002648:Child; D002908:Chronic Disease; D003872:Dermatitis; D005334:Fever; D006801:Humans; D000075242:Janus Kinase Inhibitors; D008060:Lipodystrophy; D008297:Male; D009503:Neutropenia; D046988:Proteasome Endopeptidase Complex; D011687:Purines; D011720:Pyrazoles; D013449:Sulfonamides; D013577:Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "101248897",
"other_id": null,
"pages": "19",
"pmc": null,
"pmid": "31046790",
"pubdate": "2019-05-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20159315;20303869;20534754;21813547;21953331;22288581;22441638;22727420;23743669;23768303;24131530;24490108;25243162;25521013;26091509;26524591;26617605;26632377;26711936;26889081;27260006;27678529;28255337;28848544",
"title": "Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome.",
"title_normalized": "disease course and treatment effects of a jak inhibitor in a patient with candle syndrome"
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"abstract": "BACKGROUND\nPost-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis (VL), which may occur after or during treatment. It has been frequently reported from India and the Sudan, but its occurrence in South America has been rarely reported. It may mimic leprosy and its differentiation may be difficult, since both diseases may show hypo-pigmented macular lesions as clinical presentation and neural involvement in histopathological investigations. The co-infection of leprosy and VL has been reported in countries where both diseases are endemic. The authors report a co-infection case of leprosy and VL, which evolved into PKDL and discuss the clinical and the pathological aspects in the patient and review the literature on this disease.\n\n\nMETHODS\nWe report an unusual case of a 53-year-old female patient from Alagoas, Brazil. She presented with leprosy and a necrotizing erythema nodosum, a type II leprosy reaction, about 3 month after finishing the treatment (MDT-MB) for leprosy. She was hospitalized and VL was diagnosed at that time and she was successfully treated with liposomal amphotericin B. After 6 months, she developed a few hypo-pigmented papules on her forehead. A granulomatous inflammatory infiltrate throughout the dermis was observed at histopathological examination of the skin biopsy. It consisted of epithelioid histiocytes, lymphocytes and plasma cells with the presence of amastigotes of Leishmania in macrophages (Leishman's bodies). The diagnosis of post-kala-azar dermal leishmaniasis was established because at this time there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites thus excluding VL. About 2 years after the treatment of PKDL with liposomal amphotericin B the patient is still without PKDL lesions.\n\n\nCONCLUSIONS\nPost-kala-azar dermal leishmaniasis is a rare dermal complication of VL that mimics leprosy and should be considered particularly in countries where both diseases are endemic. A co-infection must be seriously considered, especially in patients who are non-responsive to treatment or develop persistent leprosy reactions as those encountered in the patient reported here.",
"affiliations": "Laboratório de Investigação Médica (LIM-56), Imunodermatologia, Hospital das Clínicas da Universidade de São Paulo, Dr Enéas Carvalho Aguiar 470, 3 andar, prédio 2 Instituto de Medicina Tropical, São Paulo, 05403900, Brazil. angelatrindade@uol.com.br.;Departamento de Dermatologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. lana_luiza@hotmail.com.;Laboratorio de Parasitologia, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil. lmabraz@usp.br.;Departamento de Doenças Infecciosas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. valdiramato@usp.br.;Stichting Global Dermatology, Munnekeburen, The Netherlands. benaafs@dds.nl.;Departamento de Patologia e Dermatologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. mnsotto@usp.br.",
"authors": "Trindade|Maria Angela Bianconcini|MA|;Silva|Lana Luiza da Cruz|LL|;Braz|Lucia Maria Almeida|LM|;Amato|Valdir Sabbaga|VS|;Naafs|Bernard|B|;Sotto|Mirian Nacagami|MN|",
"chemical_list": "D000981:Antiprotozoal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "England",
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"doi": "10.1186/s12879-015-1260-x",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 126010.1186/s12879-015-1260-xCase ReportPost-kala-azar dermal leishmaniasis and leprosy: case report and literature review Trindade Maria Angela Bianconcini angelatrindade@uol.com.br Silva Lana Luiza da Cruz lana_luiza@hotmail.com Braz Lucia Maria Almeida lmabraz@usp.br Amato Valdir Sabbaga valdiramato@usp.br Naafs Bernard benaafs@dds.nl Sotto Mirian Nacagami mnsotto@usp.br Laboratório de Investigação Médica (LIM-56), Imunodermatologia, Hospital das Clínicas da Universidade de São Paulo, Dr Enéas Carvalho Aguiar 470, 3 andar, prédio 2 Instituto de Medicina Tropical, São Paulo, 05403900 Brazil Departamento de Dermatologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil Laboratorio de Parasitologia, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil Departamento de Doenças Infecciosas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil Stichting Global Dermatology, Munnekeburen, The Netherlands Departamento de Patologia e Dermatologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil Rua Cristiano Viana 450, 163, Jardim Paulista, São Paulo, SP CEP: 05411 000 Brazil Posgraduação Instituto de Saúde, Secretaria de Estado da Saúde de São Paulo, São Paulo, Brazil 23 11 2015 23 11 2015 2015 15 54319 4 2015 3 11 2015 © Trindade et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPost-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis (VL), which may occur after or during treatment. It has been frequently reported from India and the Sudan, but its occurrence in South America has been rarely reported. It may mimic leprosy and its differentiation may be difficult, since both diseases may show hypo-pigmented macular lesions as clinical presentation and neural involvement in histopathological investigations. The co-infection of leprosy and VL has been reported in countries where both diseases are endemic. The authors report a co-infection case of leprosy and VL, which evolved into PKDL and discuss the clinical and the pathological aspects in the patient and review the literature on this disease.\n\nCase presentation\nWe report an unusual case of a 53-year-old female patient from Alagoas, Brazil. She presented with leprosy and a necrotizing erythema nodosum, a type II leprosy reaction, about 3 month after finishing the treatment (MDT-MB) for leprosy. She was hospitalized and VL was diagnosed at that time and she was successfully treated with liposomal amphotericin B. After 6 months, she developed a few hypo-pigmented papules on her forehead. A granulomatous inflammatory infiltrate throughout the dermis was observed at histopathological examination of the skin biopsy. It consisted of epithelioid histiocytes, lymphocytes and plasma cells with the presence of amastigotes of Leishmania in macrophages (Leishman’s bodies). The diagnosis of post-kala-azar dermal leishmaniasis was established because at this time there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites thus excluding VL. About 2 years after the treatment of PKDL with liposomal amphotericin B the patient is still without PKDL lesions.\n\nConclusion\nPost-kala-azar dermal leishmaniasis is a rare dermal complication of VL that mimics leprosy and should be considered particularly in countries where both diseases are endemic. A co-infection must be seriously considered, especially in patients who are non-responsive to treatment or develop persistent leprosy reactions as those encountered in the patient reported here.\n\nKeywords\nPost-kala-azar dermal leishmaniasisVisceral leishmaniasisLeprosyLeprosy reactionsissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPost-kala-azar dermal leishmaniasis (PKDL) is a rare skin disease, which may occur after treatment of visceral leishmaniasis (VL) and is encountered mainly in India and in the Sudan, where it was also reported to occur during active VL. It has rarely been reported in the South American literature. It is associated with an inadequate immune response to Leishmania and a possible genetic predisposition. It may mimic leprosy clinically with hypo-pigmented macular lesions usually on the face. Histopathological differentiation may be very difficult because both diseases, particularly in the Sudan, may show neural involvement. Co-infection has been reported in countries where both leprosy and VL are endemic and should be considered when there is a poor response to treatment or when persistent leprosy reactions occur [1].\n\nCase presentation\nThe patient was a 53-year-old woman who had migrated to São Paulo city, Brazil from Arapiraca, Alagoas in the Northeast of Brazil. She visited the dermatology outpatient department of the University of São Paulo Medical School Hospital (HCFMUSP) with complaints of fever and skin lesions that had persisted for over a year and had worsened during the last 3 months. She mentioned that she had been treated for leprosy (MDT-MB) for 14 months, which had ended 3 months earlier. She had used prednisone intermittently for over a year during outbreaks of reactions.\n\nDermatological examination showed a Cushingoid face, widespread erythematous and edematous, some painful plaques and nodules some of which with central necrosis. This led us to establish the diagnosis of sub-polar lepromatous leprosy (LLsp) with a necrotizing erythema nodosum leprosum (ENL) reaction (type-2 leprosy reaction) (Fig. 1).Fig. 1 Erythema nodosum leprosum (ENL). a and b Clinical aspects of ENL episode. c to f Biopsy from skin lesion displaying nodular macrophage infiltrate (c and d), vascular thrombosis (e) and foci of neutrophils exudation (f)\n\n\n\nShe was many times hospitalized during the 3 years after MDT-MB and once in a critical condition with fever, tachycardia and hypotension. Prednisone 40 mg/day and thalidomide 300 mg/day were prescribed at the intensive care unit for treating the reaction. During hospitalization, the patient developed a septic shock. The skin was considered the most likely focus and she was treated with oxacillin.\n\nAfter 6 days, despite general clinical improvement, the skin lesions worsened, but no other focus of infection was found. Histopathological examinations of the skin, one from a biopsy of the right cavum plantaris and one from a biopsy of the left arm were conducted. Both of them showed multi-bacillary leprosy with a regressive response and fragmented acid-fast bacilli (2+/6+).\n\nAfter a few days, the patient had new fever attacks, swelling of the abdomen, generalized edema and worsening of the necrotizing ENL. She had elevated levels of liver enzymes, pancytopenia with progressive hypotension, hepatic and hematologic failure. Empirical antibiotic therapy with vancomycin and imipenem indicated by the infectious disease department was started. Liposomal amphotericin B was also introduced to cover the possibility of fungemia or candidemia (the patient had an esophageal candidiasis diagnosed by endoscopy, supposedly due to the long-term corticosteroid therapy).\n\nThree days later, a new investigation at the emergency department showed hepatosplenomegaly and ascites. VL was diagnosed based on the parasitology of the bone marrow (Fig. 2a), the gold standard for diagnosis of VL and on blood examinations, which showed numerous intracellular and extracellular Leishmania parasites; using rk39 (39 amino acid repeats of a kinesin-like gene found in L. chagasi), a rapid immunochromatographic test specific for the Leishmania donovani complex [2] and by molecular tests (kDNA-PCR = kinetoplast target DNA for PCR and ITS1-DNA-PCR = Internal Transcribed Spacer 1 target DNA for PCR). In addition, after ITS1-RFLP (PCR amplification of the Internal Transcribed Spacer 1 genes (ITS1) and Restriction Fragment Length Polymorphism) (Fig. 2b), fitted-in with the diagnosis of VL, it was demonstrated definitively that L. (L.) infantum chagasi was the etiologic agent, because it presented 184 bp (base pair), 72 and 55 bp fragments [3].Fig. 2 \nLeishmania identification. a Smear from patient myelogram displaying amastigotes of Leishmania within macrophage cytoplasm (arrows). b Identification of L infantum (184, 72 and 55 bp) in clinical material from a patient (sample 31) using ITS1-PCR-RFLP\n\n\n\nLiposomal amphotericin B (4 mg/kg/day for 5 days) was now continued for the treatment of VL (kala-azar). This also led to a significant clinical improvement of her ENL skin lesions. Secondary prophylaxis with amphotericin B (3 mg/kg/day for 21 days each month during 6 months) was introduced by the infectious diseases physicians. During the last dose only the kDNA-PCR with her blood was positive.\n\nAround 6 months after the treatment for VL and free of necrotizing ENL for 1 year and an occasional nodule of ENL, she developed a few hypochromic papules on her forehead (Fig. 3a). Histopathological examination of a biopsy of such a papular lesion showed a granulomatous inflammatory infiltrate throughout the dermis and superficially in the sub-cutis consisting of epithelioid histiocytes, lymphocytes and many plasma cells (Fig. 3b). Leishman bodies were seen within macrophages (Fig. 3c). The presence of Leishmania was further confirmed by immunohistochemistry (Fig. 3d) using a peroxidase-anti-peroxidase technique and a polyclonal antibody to Leishmania produced in rabbits [4]. At this time, there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites. A revision of all previous skin biopsies with immunohistochemistry for Leishmania was performed, but the results were all negative. At that moment, the diagnosis of post-kala-azar dermal leishmaniasis (PKDL) was established and liposomal amphotericin B (3 mg/kg/day for 7 days) was re-introduced resulting in a clinical regression of the skin lesions that was confirmed by histopathological examinations. About 2 years after the treatment of PKDL the patient is still free of PKDL lesions.Fig. 3 Post-kala-azar dermal leishmaniasis. a Hypochromic papule in the forehead. b The skin biopsy showed dermal nodular granulomatous infiltrate. c Few amastigotes of Leishmania were observed within macrophage cytoplasm (arrow) intermingled in the lymph plasmacytic infiltrate. d The parasites were visible better after staining with anti-Leishmania polyclonal antibody\n\n\n\nDiscussion\nPost-kala-azar dermal leishmaniasis is a dermal complication of VL [5], which has been frequently reported from the Indian subcontinent and from the Sudan, where 10–20 % and 50–60 % respectively, of the patients who were treated for VL developed PKDL [6, 7]. In Brazil, only one patient with PKDL was reported and this was associated with AIDS [8].\n\nVisceral leishmaniasis has a worldwide distribution and is considered a public health problem in 88 countries, including Brazil [9]. It is caused by species of the Leishmania donovani complex, transmitted by the bite of a female sand fly (Phlebotomus spp and P. argentipes) [6, 10]. In Latin America, the main causative agent of VL is Leishmania (L) infantum chagasi transmitted by Lutzomiya longipalpis [11, 12]. In Brazil, asymptomatic infections and mild forms (low symptomatic) of the disease are more frequent than the classic VL (Kala-azar) [13]. The asymptomatic forms occur especially in children and may heal spontaneously. The determinant factor in spontaneous healing or evolution to fatal classic disease is malnutrition [14].\n\nThe symptomatology of kala-azar reactivation in immunosuppressed patients is very variable depending on the type and the duration of immunosuppression (transplantation or autoimmune disease), or the time and the duration of immunosuppression by HIV and others diseases [15]. The clinical forms of VL, particularly in these conditions are very variable. In general, the classic symptoms such as bowel and gastric dysfunctions are not highlight to the diagnosis [16, 17].\n\nIn India, the human being is the only known reservoir of VL. This is of epidemiological importance, particularly between epidemic periods of VL. The Leishmania parasites survive and propagate intradermally rendering the exposed skin lesions as an easy access area for the sand fly vector to ingest Leishmania parasites, get infected and develop the promastigotes in their midgut enabling them to transmit the parasite. The presence of only 0.5 % of PKDL patients during a VL epidemic can potentially succeed in making VL endemic [10]. In other areas such as the Sudan, transmission may be anthroponotic and zoonotic, with rodents and canines as candidate reservoirs [18]. In Brazil, VL is zoonotic with canines as the reservoir host [6].\n\nThe causative agent of PKDL in the Sudan and on the Indian subcontinent belongs to the L. donovani sp. Of these species L. (L) infantum chagasi was also found in the skin lesions of Brazilian patients with VL [19]. In Europe and in South America, PKDL may be considered to be a rare clinical entity among Aids patients with L. infantum as the prime causative agent [20]. The same species was also found in the patient reported here.\n\nPost-Kala-azar dermal leishmaniasis may develop during or after treatment of VL [6, 21]. However, some patients have no history of VL and they are easily misdiagnosed as having other skin disorders [18]. In the Sudan, the PKDL cases occur 60 % after VL treatment, 15 % at the same time as VL (called paraKDL), and 10 % even without a history of VL [22]. Indian PKDL appears 6–12 months after the cure of VL [5], whereas in the majority of the Sudanese patients, PKDL occurs within the first 2 months following treatment of VL [23]. It was also reported in HIV/VL co-infected patients receiving HAART [21]. Our patient developed PKDL 6 months after the end of VL treatment, similar to that reported in the Indian patients.\n\nPossible risk factors for developing PKDL include previous VL treatment, its duration and the type of drug used, young age, malnutrition, HIV infection, genetic factors and the parasite strain [24]. Parasite clearance during treatment may have an important influence. Zijlstra et al. [6] reported that patients with a negative tissue aspirate (lymph node or bone marrow) on PCR after VL treatment did not develop PKDL, whereas 36 % of those who were PCR-positive developed PKDL. The patient reported here was PCR-positive in the 4th month of treatment for VL. The presence of a large spleen during VL was also linked to an increased risk of PKDL as were the high serum levels of C-reactive protein as seen in our patient too (data not shown) before treatment for VL, the high level of IL-10 in the peripheral blood and in the normal looking skin during VL [6, 20, 25, 26]. Among all these, incomplete or short treatment of VL seems to be the major risk factor [20]. Our patient had received liposomal amphotericin B (4 mg/kg/day) during 5 days to treat her VL as recommended by the Ministry of Health in Brazil [27] with clinical improvement in few days.\n\nIt was argued that after VL treatment there was a subsequent immune activation that could force the parasites to seek refuge within the dermis making this tissue a reservoir for the parasites [10]. Despite the demonstration of PKDL after inadequate therapy for VL in the Sudan, many authors reported PKDL even after adequate treatment with sodium antimony gluconate (SAG), amphotericin B and miltefosine [28, 29]. Today, PKDL is no longer considered to be a specific drug-dependent manifestation [20].\n\nPost-Kala-azar dermal leishmaniasis is clinically characterized by hypo-pigmented macules, erythematous plaques, papular or nodular lesions with Leishmania parasites [5, 30]. The lesions generally begin on the face and gradually increase in size. They may also spread to the neck, the trunk and the extremities [10]. Papular or nodular lesions are more common in the Sudanese PKDL, whereas a polymorphic presentation with macules, papules and nodules is more common in the Indian patients [6, 31, 32]. Unusual clinical variants such as papillomatous, verrucous, hypertrophic, xanthomatous, annular and lupoid lesions have also been reported [33, 34]. Mucosa involvement in PKDL is very rare [35]. No constitutional symptoms have been reported [36].\n\nAlthough clinical forms may differ in different countries, the hypopigmented macules on the face are generally the first lesions to appear in PKDL. Single lesion occurs in up to 5 % and 10 % respectively, of the PKDL cases in Africa and India [30, 37]. Our patient presented with only a few hypopigmented papules on her forehead as the unique manifestation of the disease.\n\nThe diagnosis is established after assessing the clinical signs and symptoms [38]. History of VL, living in an endemic area and positive antibody tests are helpful in the diagnosis [20, 38]. According to Zijlstra et al. [6], it is important to observe the type of rash as well as its distribution (in the Sudan, the rash generally begins around the mouth, then spreads to the nose and the cheeks and finally to other parts of the face and the body) and the time relation to VL treatment. However, the ideal diagnostic method is to demonstrate the parasite in smears, culture or PCR [18, 20].\n\nIn all clinical types of PKDL, histopathological examination of the skin biopsy shows an epidermis with hyperkeratosis, acanthosis or atrophy and hydropic degeneration of the basal layer. The presence of parasites in biopsies varies with the type of the rash and the duration of the lesions. The biopsy from macular lesions usually consists of sparse inflammatory infiltrate of lymphocytes, histiocytes and a few plasma cells predominantly around the vessels of the superficial vascular plexus. Leishmania amastigotes are usually absent in such lesions, but the presence of plasma cells is an important clue in favor of PKDL. Biopsies from the papules and plaques show a moderate to dense lymphocytic inflammatory infiltrate in the mid-dermis, with histiocytes and plasma cells. In nodular lesions, the histopathological examination of the biopsy shows a diffuse dermal inflammatory infiltrate consisting of histiocytes and plasma cells in large numbers. Compact epithelioid granulomas may also be observed [6].\n\nThe Leishmania amastigotes are intracytoplasmic structures in histiocytes. Amastigotes are observed in 25–50 % of the hematoxylin-eosin-stained biopsies of nodular and plaque lesions of PKDL [39, 40]. In the patient reported here, the papular lesion had Leishmania amastigotes, which was also confirmed by immunohistochemistry with an anti-Leishmania polyclonal antibody.\n\nNeuritis involving small cutaneous nerves similar to that in leprosy was reported in PKDL. However, peripheral large nerves are not involved in PKDL [6, 36].\n\nLeprosy is the main differential diagnosis in PKDL because of the clinical and histopathological similarities [30], but their differentiation may be very difficult [36, 41, 42]. The small hypopigmented lesions seen in PKDL are very similar to those in borderline and lepromatous leprosy [30, 41]. The patients with leprosy and PKDL usually come from the same geographical location where both diseases are endemic [5]. However, leprosy is associated with hypoesthetic lesions [22]. Arora et al. reported that the center-facial involvement and the sparing of ear lobes in PKDL may be distinguishing features from leprosy [5]. Histologically, PKDL displays epithelioid cell granulomas, similar to tuberculoid leprosy. The parasites may be absent in the macular variant of PKDL making it essential to exclude other diseases [30]. Perineural infiltration in PKDL was reported to cause great difficulty in differentiating PKDL from leprosy [30, 35]. However, the main histological difference between these diseases is that in the macular lesions of leprosy, the inflammatory infiltrate is centered in the neurovascular plexus in the lower dermis. Besides this, in the nodular lesions of lepromatous leprosy, the peripheral limits of the infiltrate are infiltrative, whereas those in nodular PKDL have a fairly sharp margin [30].\n\nLeprosy and leishmaniasis are both spectral diseases and co-infections have been reported. Although it is a rare association, it occurs in countries such Ethiopia and India where both diseases are endemic [42]. The case reported here of co-infection with PKDL is the first in Brazil.\n\nLeishmaniasis and leprosy share a lot of similarities. Both diseases are caused by obligate intracellular organisms. The clinical and pathological expressions depend on the host response, probably due to genetic determination and environmental influences [42, 43]. At the hyperergic pole, the patient shows localized lesions with well-formed granulomas with few or absent organisms, whereas at the anergic pole, the lesions are widespread, there is no epithelioid granulomatous reaction and there are numerous parasites [42].\n\nIt was suggested by Bansal et al. that there is a cross-protection between Mycobacterium and Leishmania infection since both diseases increase macrophage activation. However, the immune deficiency in leprosy is apparently specific for M. leprae only and does not dictate the immune response in leishmaniasis. They reported a patient in whom the macular variant of PKDL (‘low-resistance’) coexisted with ‘high-resistance’ borderline tuberculoid leprosy [42]. Our patient presented subpolar lepromatous leprosy with a VL co-infection considered as an anergic pole of both diseases (Th2 response). After developing PKDL, the immunological response changed to the hyperergic pole (Th1 response) of the Leishmania infection, when she showed papules with epithelioid granulomas, but she remained at Th2 pole of leprosy indicating that the immune defect was specific for each microorganism [42, 43].\n\nTo date, there is no consensus and no large studies on the best available treatment for PKDL. Moreover, the evolution of this disease differs in different geographical regions. Fifty per cent of the Sudanese PKDL is self-limiting and heal spontaneously, whereas all Indian PKDL cases required treatment [6, 20, 33]. In cases of severe lesions or lesions persisting for more than 1 year in the Sudan, treatment with sodium stibogluconate (SSG) 20 mg/kg/day for 1–2 months was instituted [6, 10]. Miltefosine administered orally was an effective and safe treatment for Indian visceral leishmaniasis. It may protect against PKDL because it is given for a much longer period. It may be helpful in regions where the parasites are resistant to the current agents [15, 44].\n\nIn cases of SSG-unresponsive treatment, amphotericin B 2 mg/kg/day for 20 days was reported to be effective [6, 10, 20]. Other therapeutic options include miltefosine, ketoconazole and pentamidine [6, 10]. Clinical cure may differ according to the PKDL type. Usually nodules and plaques disappear in 120 days and macular lesions in 200 days [6, 10]. However, parasitological cure may precede the clinical cure, and long treatment regimens need to be carefully monitored [6]. Our patient received liposomal amphotericin B (3 mg/kg/day for 7 days), with clinical healing of the skin PKDL lesions in 3 months.\n\nAt this moment the patient is in good health and without skin lesions indicative of PKDL. She has only regressive macules of leprosy. However, at present she received the 10th dose of a newly started MDT-MB treatment because she had the first symptoms of tibial neuritis about 5 year after leprosy treatment. It is likely that the previous treatment for 14 months may have been inadequate.\n\nConclusions\nPost-kala-azar dermal leishmaniasis is rare and generally occurs after treatment of VL. It shows geographical variation in its clinical presentation and may be multifactorial (genetics of the patient and or parasite, treatment, nutrition and or co-infection). It may mimic leprosy and that must be recognized, especially in countries where these diseases are endemic. Increasing globalization with large number of people travelling should also be seriously considered.\n\nA co-infection may provoke more morbidity and may also lead to more disability. A co-infection should be considered especially in patients not responding to treatment or have a persistent leprosy reaction similar to that described in the patient reported here.\n\nFinally we introduce a serious concern: Visceral leishmaniasis will be able to become an anthropozoonosis in the Americas, like in India (15), because, before and during PKDL, the parasite will be exposed in the skin.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nAbbreviations\nBpBase pair\n\nENLErythema nodosum leprosum\n\nHAARTHighly active antiretroviral therapy\n\nHIVHuman immundeficiency virus\n\nITS1-PCRInternal Transcribed Spacer 1 target DNA for PCR\n\nITS1-RFLPPCR amplification of the Internal Transcribed Spacer 1 genes (ITS1) and Restriction Fragment Length Polymorphism\n\nkDNA-PCRKinetoplast target DNA for PCR\n\nLLspSub-polar lepromatous leprosy\n\nMDT-MBMultidrug therapy multibacillary\n\nPCRPolymerase chain reaction\n\nPKDLPost-kala-azar dermal leishmaniasis\n\nrk3939 amino acid repeats of a kinesin-like gene found in L. chagasi\n\nSAGSodium antimony gluconate\n\nSSGSodium stibogluconate\n\nVLVisceral leishmaniasis\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nMABT conceived of the study, participated in its design, coordinated and drafted the manuscript. LLCS participated in the study design, drafted the manuscript and reviewed it. LMAB worked on laboratorial diagnosis of Leishmania infantum and drafted about the leishmaniasis diagnosis. VSA helped to draft the manuscript and helped to treat the patient. BN helped to draft the manuscript and gave final approval of the version to be published. MNS carried out the histopathological and immunohistochemistry PKDL diagnosis obtained their images and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank Dr. Leandro Utino Taniguchi for the diagnosis of kala-azar at the emergency ward, Dr. Ana Carolina Lessa Moreno for taking care the patient during hospitalization, Natália Souza de Godoy, Regina Maia de Souza e Marcos Andrino for laboratorial assistance in the diagnosis of visceral leishmaniasis Alexandre Vargas for taking clinical images and Bob Tank for correct use of the English language.\n\nFinancial support\nPart of this study (molecular, parasitological and serological tests for Leishmania) was supported by Sao Paulo Research Foundation (FAPESP), grant n° 2010/50304-8 (Lucia Maria Almeida Braz).\n==== Refs\nReferences\n1. Kevric I Cappel MA Keeling JH New world and old world leishmania infections. A practical review Dermatol Clin 2015 33 579 593 10.1016/j.det.2015.03.018 26143433 \n2. 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Saha S Mondal S Ravindran R Bhowmick S Modak D Mallick S IL-10- and TGF-beta-mediated susceptibility in kala-azar and post-kala-azar dermal leishmaniasis: the significance of amphotericin B in the control of Leishmania donovani infection in India J Immunol 2007 179 8 5592 603 10.4049/jimmunol.179.8.5592 17911647 \n29. Das VN Pandey K Verma N Lal CS Bimal S Topno RK Short report: Development of post-kala-azar dermal leishmaniasis (PKDL) in miltefosine-treated visceral leishmaniasis Am J Trop Med Hyg 2009 80 3 336 8 19270277 \n30. Singh A Ramesh V Histopathological features in leprosy, post-kala-azar dermal leishmaniasis, and cutaneous leishmaniasis Indian J Dermatol Venereol Leprol. 2013 79 360 366 10.4103/0378-6323.110795 23619440 \n31. Zijlstra EE El-Hassan AM Leishmaniasis in Sudan. Post kala-azar dermal leishmaniasis Trans R Soc Trop Med Hyg 2001 95 1 S59 76 10.1016/S0035-9203(01)90219-6 11370251 \n32. Ramesh V Post kala azar dermal leishmaniasis Indian J Dermatol Venereol Leprol 1999 65 4 196 20921656 \n33. Sigh S Sharma U Mishra J Post-kala-azar dermal leishmaniasis: recent developments Int J Dermatol. 2011 50 1099 1108 10.1111/j.1365-4632.2011.04925.x 22126871 \n34. Shrivastava SB Haque M Puri P Lupoid plaque- a new variant of post-kala-azar dermal leishmaniasis Int J Dermatol. 2004 43 428 429 10.1111/j.1365-4632.2004.02205.x 15186223 \n35. Salam MA Siddiqui MA Nabi SG Bhaskar KRH Mondal D Post-kala-azar dermal leishmaniasis in with mucosal involvement: an unusual case presentation including successful treatment with miltefosine J Health Popul Nutr 2013 31 2 294 297 10.3329/jhpn.v31i2.16395 23930349 \n36. Elhassan AM Ali MS Zijlstra E Eltoum IA Ghalib HW Ahmed HM Post-kala-azar dermal leishmaniasis in the Sudan: peripheral neural involvement Int J Dermatol 1992 31 6 400 403 10.1111/j.1365-4362.1992.tb02668.x 1512091 \n37. Ramesh V Raman M Singh R Salotra P Hypopigmented post-kala-azar dermal leishmaniasis Int J Dermatol. 2008 47 414 416 10.1111/j.1365-4632.2008.03621.x 18377613 \n38. Adams ER Versteeg I Leeflang MMG Systematic review into diagnostics for post-kala-azar dermal leishmaniasis (PKDL) J Trop Med. 2013 2013 150746 10.1155/2013/150746 23935641 \n39. Rathi SK Pandhi RK Chopra P Khanna N Post-kala-azar dermal leishmaniasis: a histopathological study Indian J Dermatol Venereol Leprol 2005 71 4 250 3 10.4103/0378-6323.16616 16394433 \n40. Beena KR Ramesh V Mukherjee A Identification of parasite antigen, correlation of parasite density and inflammation in skin lesions of post kala-azar dermal leishmaniasis J Cutan Pathol. 2003 30 616 620 10.1034/j.1600-0560.2003.00125.x 14744086 \n41. El Hassan AM Hashim FA Abdullah M Zijlstra EE Ghalib HW Distinguishing post-kala-azar dermal leishmaniasis from leprosy: experience in the Sudan Lepr Rev 1993 64 1 53 9 8464317 \n42. Bansal S Goel A Sardana K Kumar V Khurana N Post-kala-azar dermal leishmaniasis coexisting with borderline tuberculoid leprosy Br J Dermatol. 2007 157 799 846 10.1111/j.1365-2133.2007.08072.x 17635511 \n43. Rijal A Rijal S Bhandari S Leprosy coinfection with kala-azar Int J Dermatol. 2009 48 740 742 10.1111/j.1365-4632.2009.04018.x 19570081 \n44. Mukhopadhyay D Dalton JE Kaye PM Chatterjee M Post kala-azar dermal leishmaniasis: an unresolved mystery Trends Parasitol 2014 30 2 65 74 10.1016/j.pt.2013.12.004 24388776\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "15()",
"journal": "BMC infectious diseases",
"keywords": null,
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000666:Amphotericin B; D000981:Antiprotozoal Agents; D001938:Brazil; D060085:Coinfection; D005260:Female; D006801:Humans; D016773:Leishmaniasis, Cutaneous; D007898:Leishmaniasis, Visceral; D007918:Leprosy; D008264:Macrophages; D008875:Middle Aged; D012867:Skin",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "543",
"pmc": null,
"pmid": "26592919",
"pubdate": "2015-11-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "23533426;23935641;23819611;10708005;23930349;17911647;12625930;24732458;26143433;11370251;24321013;19270277;18377613;20921656;3782864;26090441;14499047;14744086;2063957;8464317;10886148;17627788;8250102;21885919;24213198;9472662;1512091;16778312;24388776;16394433;22126871;19570081;12560194;15186223;8358705;23619440;12967749;23675968;21128917",
"title": "Post-kala-azar dermal leishmaniasis and leprosy: case report and literature review.",
"title_normalized": "post kala azar dermal leishmaniasis and leprosy case report and literature review"
} | [
{
"companynumb": "BR-CELGENE-BRA-2015121932",
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{
"abstract": "Ochronosis is the blue-gray discoloration of collagen-containing tissues due to homogentisic acid (HGA) deposition, secondary to endogenous alkaptonuria or exogenous enzyme inhibition. In renal disease, accumulation of HGA in serum can cause methemoglobinemia. A 60-year-old woman with renal disease and anemia presented with 3 days of weakness and months of gray skin discoloration. Her hemoglobin was 8.1g/dl with 24.5% methemoglobin. Despite treatment with methylene blue, exchange transfusion, and continuous renal replacement therapy, the patient died. Autopsy revealed gray discoloration and ochronotic pigment in the ribs and cartilage. Based on these findings, the patient was diagnosed with ochronosis, suggestive of alkaptonuria, complicated by methemoglobinemia. The differential diagnosis for blue-gray skin discoloration includes argyria, methemoglobinemia, and ochronosis. This patient's clinical and autopsy findings suggested alkaptonuria complicated by methemoglobinemia due to progressive renal dysfunction. Development of methemoglobinemia in the setting of chronic skin discoloration and renal failure should prompt consideration of alkaptonuria.",
"affiliations": "Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.;Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA.;Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA.;Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.",
"authors": "Hugar|Sarah B|SB|;Shulman|Joshua|J|;Yanta|Joseph|J|;Nine|Jeffrey|J|",
"chemical_list": "D006454:Hemoglobins",
"country": "United States",
"delete": false,
"doi": "10.1111/1556-4029.13907",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "64(3)",
"journal": "Journal of forensic sciences",
"keywords": "alkaptonuria; autopsy; forensic science; methemoglobinemia; ochronosis; renal failure; skin discoloration",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000474:Alkaptonuria; D017809:Fatal Outcome; D005260:Female; D006454:Hemoglobins; D006801:Humans; D007676:Kidney Failure, Chronic; D008708:Methemoglobinemia; D008875:Middle Aged; D009794:Ochronosis; D010859:Pigmentation Disorders",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "913-916",
"pmc": null,
"pmid": "30229904",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ochronosis Presenting as Methemoglobinemia.",
"title_normalized": "ochronosis presenting as methemoglobinemia"
} | [
{
"companynumb": "US-ACELLA PHARMACEUTICALS, LLC-2069525",
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"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "DEXBROMPHENIRAMINE MALEATE\\DEXTROMETHORPHAN HYDROBR... |
{
"abstract": "During upward titration of a dose of sodium oxybate therapy for narcolepsy with cataplexy, a 25-year-old woman was observed by her husband to have new onset of knuckle-cracking and moaning behaviors during sleep ≥1 nights each week. The patient did previously occasionally crack her knuckles during the day (but never at night). These behaviors had not been evaluated by polysomnography. After transition of care, polysomnography with video monitoring was ordered and revealed 2 knuckle-cracking episodes that developed out of stage N2 sleep and were likely a non-rapid eye movement sleep parasomnia associated with sodium oxybate treatment.",
"affiliations": "Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida.;Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida.;Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida.;Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida.;Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida.;Pulmonary Division, Department of Pediatrics, University of Florida, Gainesville, Florida.",
"authors": "Carbajal-Mamani|Semiramis|S|;Berry|Richard B|RB|;Al Hourani|Lubna|L|;Khatri|Abhishek|A|;Ryals|Scott|S|;Wagner|Mary H|MH|",
"chemical_list": "D012978:Sodium Oxybate",
"country": "United States",
"delete": false,
"doi": "10.5664/jcsm.9112",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "17(5)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "catathrenia; parasomnia; sodium oxybate",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D000328:Adult; D002385:Cataplexy; D005260:Female; D006801:Humans; D009290:Narcolepsy; D017286:Polysomnography; D012894:Sleep Stages; D012978:Sodium Oxybate",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "1121-1123",
"pmc": null,
"pmid": "33538690",
"pubdate": "2021-05-01",
"publication_types": "D002363:Case Reports",
"references": "25444412;21677903;17682654;28363449;21484510;19968016",
"title": "Knuckle cracking at night associated with sodium oxybate treatment.",
"title_normalized": "knuckle cracking at night associated with sodium oxybate treatment"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-15342",
"fulfillexpeditecriteria": "2",
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"drug": [
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"activesubstancename": "ARMODAFINIL"
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{
"abstract": "Cytomegalovirus (CMV) reactivation is a major cause of morbidity and mortality after organ or hematopoietic stem cell transplantation (HSCT). Letermovir (LTV) is a novel antiviral agent approved for CMV prophylaxis after allogeneic transplantation. In this single-center real-world study, we evidenced the efficacy and safety of LTV for CMV prophylaxis in allogeneic HSCT recipients. A total of 133 consecutive patients who underwent autologous or allogeneic HSCT were included in the study, and a subgroup of 13 allogeneic HSCT recipients received CMV prophylaxis with LTV 240 mg/daily from day +7 to +100 (allo-LTV cohort). All patients in the allo-LTV cohort were at moderate or high risk of reactivation based on donor/recipient serology status, and 62% also received haploidentical HSCT and cyclophosphamide which further increased the CMV reactivation risk. CMV infection rate was also compared to that observed in allogeneic HSCT patients without CMV prophylaxis and autologous recipients who have the lowest reported CMV infection incidence and were used as a control cohort. In our experience, patients receiving LTV showed a significant decline in CMV reactivation incidence to similar rates described in autologous HSCT recipients (7.7% of allogeneic LTV-treated vs 68% of allogeneic recipients without prophylaxis vs 15% of autologous patients; p> 0.0001). The only patient in the allo-LTV cohort with CMV reactivation was a 25-year-old female with a diagnosis of very high-risk acute lymphoblastic leukemia who received a haploidentical HSCT after ex vivo T cell depletion. CMV reactivation occurred beyond LTV course, at +187 days from transplantation. In addition, we confirmed efficacy and safety of valganciclovir 450 mg/daily as pre-emptive therapy or for treatment of CMV disease in allogeneic and autologous HSCT recipients who experienced CMV reactivation even after LTV prophylaxis. However, further clinical trials in larger populations and longer follow-up are required to confirm our preliminary results.",
"affiliations": "Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy; Clinical Pharmacology, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy; Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Baronissi, Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Transfusion Medicine, Molecular Biology Section, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy; Transplant Immunology Laboratory, Molecular Biology Section, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy.;Hematology and Transplant Center, University Hospital \"San Giovanni di Dio e Ruggi d'Aragona\", Salerno, Italy; Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Baronissi, Salerno, Italy.",
"authors": "Serio|Bianca|B|;Giudice|Valentina|V|;Guariglia|Roberto|R|;Fontana|Raffaele|R|;Pezzullo|Luca|L|;Martorelli|Maria Carmen|MC|;Ferrara|Idalucia|I|;Mettivier|Laura|L|;D'Addona|Matteo|M|;Vaccaro|Emilia|E|;Langella|Maddalena|M|;Selleri|Carmine|C|",
"chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C000588473:letermovir",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-9390",
"issue": "29(1)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D000085:Acetates; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D011799:Quinazolines; D066027:Transplant Recipients; D014184:Transplantation, Homologous",
"nlm_unique_id": "9613961",
"other_id": null,
"pages": "102-113",
"pmc": null,
"pmid": "33664179",
"pubdate": "2021-03-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prophylactic letermovir decreases cytomegalovirus reactivation after stem cell transplantation: a single-center real-world evidence study.",
"title_normalized": "prophylactic letermovir decreases cytomegalovirus reactivation after stem cell transplantation a single center real world evidence study"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1087571",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "Hyponatraemia is common in hospital practice, with the syndrome of inappropriate antidiuresis (SIAD) being the most common underlying aetiology. A relatively less frequent but important cause is adrenal insufficiency (AI). We describe the case of a 63-year-old man who presented with symptomatic hyponatraemia and hypoglycaemia associated with abnormal body movements (ballism). The recent commencement of levothyroxine for newly diagnosed hypothyroidism, followed by fluid restriction for presumed SIAD, led to the worsening of a previously undiagnosed AI. His investigations confirmed central AI in association with thyroid and growth hormone deficiencies. The underlying cause of hypopituitarism, in this case, was a traumatic brain injury He responded well to steroid replacement and fluids. This case highlights that SIAD remains a diagnosis of exclusion, and other causes of hyponatraemia, including AI, should always be considered. Second, levothyroxine treatment without steroid replacement can lead to an adrenal crisis in patients with underlying AI.",
"affiliations": "Endocrinology & Diabetes, St Vincent's University Hospital, Dublin, Ireland nusratawan28@gmail.com.;Endocrinology & Diabetes, St Columcille's Hospital, Dublin, Ireland.;Endocrinology & Diabetes, St Vincent's University Hospital, Dublin, Ireland.",
"authors": "Awan|Nusrat Mehmood|NM|;Mat|Arimin|A|http://orcid.org/0000-0001-9066-7957;Canavan|Ronan|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242764",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "adrenal disorders; pituitary disorders; thyroid disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000309:Adrenal Insufficiency; D000070642:Brain Injuries, Traumatic; D006801:Humans; D007010:Hyponatremia; D007018:Hypopituitarism; D007177:Inappropriate ADH Syndrome; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34285022",
"pubdate": "2021-07-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Retracing the tracks for SIAD: hyponatraemia due to post-traumatic brain injury hypopituitarism.",
"title_normalized": "retracing the tracks for siad hyponatraemia due to post traumatic brain injury hypopituitarism"
} | [
{
"companynumb": "IE-TEVA-2021-IE-1966573",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Testicular mixed germ cell tumors (GCTs) represent a spectrum of malignancies that differ in terms of histopathology, clinical complications, and overall outcome. A variety of aggressive combinations containing different histological types have been described among such testicular tumors. However, a histopathology characterized by a combination of teratoma and choriocarcinoma, as seen in this case, in which the teratomatous component shows a secondary transformation to chondrosarcoma, is considered very rare. CASE REPORT The patient presented with progressive hemoptysis and dyspnea secondary to bilateral pulmonary cannon-ball lesions indicative of a metastatic process. His workup was remarkable for primary testicular cancer complicated by liver metastasis and very high levels of B-HCG at more than 175 000 mlU/ml. He deteriorated quickly with no improvement following the first cycle of Etoposide/Cisplatin (EP) chemotherapy regimen and died 15 days after starting cancer treatment. Such non-seminomatous GCTs with extrapulmonary visceral metastasis associated with very high tumor markers are deemed poor risk based on the International Germ Cell Cancer Collaborative Group (IGCCCG) criteria, with a reported 5-year overall survival rate reaching up to 73%. CONCLUSIONS This case is considered unique in terms of rapid clinical deterioration and lack of improvement following the standard EP chemotherapy regimen. This unusual dramatic presentation should draw attention to the possible association between the aggressiveness of the disease and its very rare histopathology.",
"affiliations": "Department of Internal Medicine, King Abdullah Medical City, Makkah, Saudi Arabia.;Department of Internal Medicine, Umm Alqura University, Makkah, Saudi Arabia.",
"authors": "Alrehaili|Mohammad|M|;Tashkandi|Emad|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.922933",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32587232\n10.12659/AJCR.922933\n922933\nArticles\nTesticular Mixed Germ Cell Tumor Combined with Malignant Transformation to Chondrosarcoma: A Very Rare and Aggressive Disease\nAlrehaili Mohammad EF1 Tashkandi Emad EF23 \n1 Department of Internal Medicine, King Abdullah Medical City, Makkah, Saudi Arabia\n\n2 Department of Internal Medicine, Umm Alqura University, Makkah, Saudi Arabia\n\n3 Department of Medical Oncology, King Abdullah Medical City, Makkah, Saudi Arabia\nCorresponding Author: Mohammad Alrehaili, e-mail: dr.rehaili@hotmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n26 6 2020 \n21 e922933-1 e922933-5\n17 1 2020 01 5 2020 20 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 31-year-old\n\nFinal Diagnosis: Testicular mixed germ cell tumor\n\nSymptoms: Hemoptysis • shortness of breath • testicular mass\n\nMedication: —\n\nClinical Procedure: Chemotherapy • CT guided lung biopsy • CT scan • orchiectomy\n\nSpecialty: Oncology\n\nObjective:\nUnusual clinical course\n\nBackground:\nTesticular mixed germ cell tumors (GCTs) represent a spectrum of malignancies that differ in terms of histo-pathology, clinical complications, and overall outcome. A variety of aggressive combinations containing different histological types have been described among such testicular tumors. However, a histopathology characterized by a combination of teratoma and choriocarcinoma, as seen in this case, in which the teratomatous component shows a secondary transformation to chondrosarcoma, is considered very rare.\n\nCase Report:\nThe patient presented with progressive hemoptysis and dyspnea secondary to bilateral pulmonary cannon-ball lesions indicative of a metastatic process. His workup was remarkable for primary testicular cancer complicated by liver metastasis and very high levels of B-HCG at more than 175 000 mlU/ml. He deteriorated quickly with no improvement following the first cycle of Etoposide/Cisplatin (EP) chemotherapy regimen and died 15 days after starting cancer treatment. Such non-seminomatous GCTs with extrapulmonary visceral metastasis associated with very high tumor markers are deemed poor risk based on the International Germ Cell Cancer Collaborative Group (IGCCCG) criteria, with a reported 5-year overall survival rate reaching up to 73%.\n\nConclusions:\nThis case is considered unique in terms of rapid clinical deterioration and lack of improvement following the standard EP chemotherapy regimen. This unusual dramatic presentation should draw attention to the possible association between the aggressiveness of the disease and its very rare histopathology.\n\nMeSH Keywords:\nChondrosarcomaChoriocarcinomaMixed Tumor, MalignantTeratomaTesticular Neoplasms\n==== Body\nBackground\nPrimary testicular malignancies are the most common solid malignant tumor in men 20–35 years of age in the United States. Mixed GCTs of the testis contain 2 or more germ cell components and constitute around 30% of the primary testicular neoplasms [1]. Although they are considered the second most common type after pure seminoma in terms of prevalence among GCTs in adults, there are some histological sub-types which were rarely reported. In this article, we present an extremely aggressive case with very rapid deterioration, which was found to be a mixed GCT consisting of teratoma and choriocarcinoma, in which the teratomatous component showed a secondary transformation to chondrosarcoma. There are a few cases described in the literature with a similar histological combination [2], but the malignant transformation of the teratomatous component into chondrosarcoma was lacking. These unique histopathological findings should be considered as a contributing factor to the severity and aggressiveness of testicular cancer, as seen in this case.\n\nCase Report\nA 31-year-old Saudi man was referred to our medical center for 1-month history of blood-tinged sputum. His chest x-ray revealed bilateral cannon-ball lesions suggestive of metastases (Figure 1). Upon evaluation, the patient reported dyspnea and required 3 liters of oxygen. His performance status, based on Eastern Cooperative Oncology Group (ECOG) scale, was 1. CT chest was performed and showed multiple large pulmonary nodules and masses with central necrosis causing severe compression on the superior vena cava (Figures 2, 3). CT-guided core biopsy of the lung lesion showed changes consistent with a metastatic mixed germ cell tumor. Testicular physical examination was remarkable for a large mass in the right testicle, which was confirmed by a scrotal ultrasound showing a 5.5×4.1 cm lesion of increased irregular vascularity and multiple foci of calcification.\n\nHis B-HCG and LDH levels were elevated at 178 000 mlU/ml and 820 U/L, respectively. His AFP and CEA were normal. A complete blood count showed an elevated white blood cell count of 15×109/L and normocytic normochromic anemia with hemoglobin level at 8–10 g/dL. A tuberculosis workup including acid-fast bacilli (AFB) smear, and TB polymerase chain reaction was negative. Renal function tests were unremarkable. Liver enzymes were normal and total bilirubin was mildly elevated at 2.7 mg/dL, with direct component at 1.7 g/dL. An abdominal CT scan showed a large hypodense hepatic lesion with peripheral enhancement, measuring 3.4×2.3 cm involving segment VII, suggestive of a metastatic deposit (Figure 4).\n\nThe patient subsequently had right-sided orchiectomy, but lymph node dissection was not performed. The tumor was confined to the testis, with a size of 7×6×4 cm. The tunica albuginea and spermatic cord was grossly intact. Histopathology was compatible with the previous biopsy findings from the pulmonary lesion (Figures 5, 6). It confirmed the presence of mixed GCT containing teratoma (80%) with a somatic type malignancy and choriocarcinoma (20%). We found that 99% of the teratomatous component was composed of large lobules of hypercellular chondrocytes that were consistent with grade I chondrosarcoma, and the remaining 1% was characterized by cystic lesions lined by benign epithelial cells with occasional mucinous cells. There was lymphovascular invasion, and multifocal Leydig cell hyperplasia was observed. Immunohistochemistry stains displayed strong positivity for B-HCG, Cytokeratin 19, and placental alkaline phosphatase (PLAB) in the choriocarcinoma component.\n\nDuring the patient’s hospitalization, the hemoptysis was rapidly getting worse and his oxygen requirement had gradually increased. He was started on the standard EP chemotherapy protocol (5-day regimen) consisting of Etoposide and Cisplatin, with no improvement, and radiation therapy was planned. He received only 1 cycle of chemotherapy as his hospital course was complicated by increased oxygen demand requiring intubation with mechanical ventilation and hemodynamic support in the ICU.\n\nA repeat chest x-ray showed no remarkable changes. A septic screen revealed growth of Pseudomonas aeruginosa in both sputum and blood. He was given broad-spectrum antibiotics including Vancomycin and Piperacillin/Tazobactam in addition to Granulocyte-colony stimulating factor (G-CSF), but he showed no signs of positive response, and then died after maximum resuscitative measures were performed.\n\nDiscussion\nMixed GCTs contain 2 or more germ cell elements, and their exact composition varies. Several distinct mixtures of these tumors have been described, but it was shown that certain combinations are more likely to occur, such as those containing teratoma and embryonal carcinoma [3,4]. In a review of 2589 patients with primary testicular tumors, of whom 1765 (68.2%) were diagnosed with mixed GCTs, the commonest histological element in mixed GCTs was embryonal carcinoma (in 84.4% of cases) and then teratoma (in 69.7%) and yolk sac tumor (in 60.1%) [1]. In contrast, the same study showed that the presence of choriocarcinoma with any other histological element was a rare finding, and its frequency was around 17.8% of cases.\n\nSomatic type malignant transformations (SMTs) in mixed GCTs is a well-known phenomenon, but is very rare. It occurs in around 3–6% of these tumors and is believed to develop as a result of malignant transformation of the teratomatous components, although other mechanisms might exist such as abnormal differentiation of primordial germ cells [2,5,6]. Tumors accompanied by malignant transformation are more likely to metastasize at presentation and have further aggressive potential than those without this phenomenon [7]. Among the most frequently delineated histologic transformations are sarcomas, mainly rhabdomyosarcoma, and carcinomas [8]. However, malignant transformation to chondrosarcoma, as seen in this report, is considered unusual and its association with chorio-carcinoma has rarely been reported in the English literature.\n\nTesticular tumor outcome depends largely on clinical stage. According to the International Germ Cell Cancer Collaborative Group (IGCCCG) criteria [9], our patient would be classified to the poor risk group given the presence of non-seminomatous GCT, extrapulmonary visceral metastasis, and B-HCG >50 000. The 5-year overall survival can reach 73% [10] and the presence of pulmonary metastases usually does not imply an unfavorable risk group or staging of the disease. However, since his initial presentation, our patient had had bulky lung metastases in both sides with high tumor burden leading to progressive and rapid deterioration in his respiratory status. He received 1 cycle of EP chemotherapy without any improvement and his oxygen requirement continued to increase followed by intubation. This poor and dramatic outcome was likely related to the histopathology of his testicular disease, as described above.\n\nWe felt that the unusual histological types found in his testicular tumor should be considered as a significant factor that could critically influence the clinical course and contribute to further risk stratification of the disease. Our assumption was based on studies that show a significant association between SMTs to sarcomatous elements and increased disease aggressiveness with shortened survival compared to tumors without malignant transformation [6,11]. Moreover, choriocarcinoma is found to be the most aggressive histological type of all pure GCTs as it is fast-growing and can spread rapidly through the hematogenous route [12].\n\nThe development of SMTs in mixed non-seminomatous GCTs is a challenge in treating such cases. Several studies demonstrated chemoresistance in patients with transformed histology to Cisplatin-based chemotherapy regimens [11,13] that are usually associated with good outcomes in non-transformed malignant germ cell tumors. It was also suggested that chemotherapy should be adapted and targeted against the most aggressive histology for better outcome and disease control [5,13]. However, there is still no consensus regarding the optimal treatment of mixed non-seminomatous GCTs with malignant transformation [14], and further research is needed to establish clear treatment guidelines.\n\nConclusions\nMixed GCT consisting of teratoma with SMT to chondrosarcoma associated with choriocarcinoma is a very rare type of testicular tumor. It seems to have a highly aggressive potential, which can critically influence the clinical course and prognosis. The optimal treatment for such tumors is poorly defined due to insufficient information.\n\nThe article was approved by the Institutional Review Board at King Abdullah Medical City. We would like to thank the Department of Pathology at King Abdullah Medical City, Makkah, Saudi Arabia for their support for this manuscript.\n\nConflict of interest\n\nNone.\n\nFigure 1. Chest x-ray shows bilateral cannon-ball lesions suggestive of metastasis.\n\nFigure 2. CT scan of the chest shows multiple large bilateral lung masses as seen by the white arrows.\n\nFigure 3. Chest CT mediastinal window shows large masses (white arrows) in both lungs and severe compression of the superior vena cava.\n\nFigure 4. Abdominal CT shows a large hypodense hepatic lesion (white arrow) measuring 3.4×2.3 cm involving segment VII suggestive of metastasis.\n\nFigure 5. Teratomatous component of the testicular biopsy showing hypercellular chondrocytes consistent with grade I chondrosarcoma (A). A high-power image of the chondrosarcoma which demonstrates chondrocytes (white arrows) is also seen (B).\n\nFigure 6. Choriocarcinoma component of the mixed germ cell tumor (A) showing admixture of polygonal cells with clear cytoplasm (cytotrophoblast, white arrows) and large multinucleated cells with smudged nuclear chromatin (syncytiotrophoblast, black arrows) on high-power field (B). Immunohistochemistry stains displayed strong positivity with B-HCG (C).\n==== Refs\nReferences:\n1. Mosharafa AA Foster RS Leibovich BC Histology in mixed germ cell tumors. Is there a favorite pairing? J Urol 2004 171 1471 73 15017200 \n2. Aneja A Bhattacharyya S Mydlo J Inniss S Testicular seminomatous mixed germ cell tumor with choriocarcinoma and teratoma with secondary somatic malignancy: A case report J Med Case Rep 2014 8 1 24380446 \n3. Mostofi FK Proceedings: Testicular tumors. Epidemiologic, etiologic and pathologic features Cancer 1973 32 5 1186 201 4148412 \n4. von Hochstetter AR Hedinger CE The differential diagnosis of testicular germ cell tumors in theory and in practice. A critical analysis of two major systems of classification and review of 389 cases Virchows Arch A Pathol Anat Histol 1982 396 3 247 77 6291228 \n5. Shaw A Morrell M Weissferdt A Malignant transformation of testicular teratoma to PNET, adenocarcinoma, and osteosarcoma with complete remission after surgery and combination chemotherapy in a young adult male Case Rep Oncol Med 2018 2018 8460603 30402315 \n6. Stamatiou K Papadopoulos P Perlepes G Mixed germ cell tumor of the testicle with ravdomuosarcomatous component: A case report Cases J 2009 2 1 9299 20062623 \n7. Comiter CV Kibel AS Richie JP Prognostic features of teratomas with malignant transformation: A clinicopathological study of 21 cases J Urol 1998 159 3 859 63 9474169 \n8. Motzer RJ Amsterdam A Prieto V Teratoma with malignant transformation: Diverse malignant histologies arising in men with germ cell tumors J Urol 1998 159 133 38 9400455 \n9. International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group J Clin Oncol 1997 15 2 594 603 9053482 \n10. Adra N Althouse SK Liu H Prognostic factors in patients with poor-risk germ-cell tumors: A retrospective analysis of the Indiana University experience from 1990 to 2014 Ann Oncol 2016 27 5 875 79 26861605 \n11. Malagón HD Valdez AM Moran CA Suster S Germ cell tumors with sarcomatous components: A clinicopathologic and immunohistochemical study of 46 cases Am J Surg Pathol 2007 31 1356 62 17721191 \n12. Go JH Pure choriocarcinoma of testis with tumor-infiltrating lymphocytes and granulomas Yonsei Med J 2006 47 6 887 91 17191322 \n13. El Mesbahi O Terrier-Lacombe M-J Rebischung C Chemotherapy in patients with teratoma with malignant transformation Eur Urol 2007 51 5 1306 12 17081678 \n14. Giannatempo P Pond GR Sonpavde G Treatment and clinical outcomes of patients with teratoma with somatic-type malignant transformation: An International Collaboration J Urol 2016 196 1 95 100 26748165\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D002471:Cell Transformation, Neoplastic; D002813:Chondrosarcoma; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D013736:Testicular Neoplasms",
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"title": "Testicular Mixed Germ Cell Tumor Combined with Malignant Transformation to Chondrosarcoma: A Very Rare and Aggressive Disease.",
"title_normalized": "testicular mixed germ cell tumor combined with malignant transformation to chondrosarcoma a very rare and aggressive disease"
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"abstract": "Sickle cell disease (SCD) is associated with hematologic complications including delayed hemolytic transfusion reactions (DHTRs) and pregnancy-related morbidity and mortality. Hyperhemolysis syndrome (HS) is the most severe form of DHTR in patients with SCD, in which both transfused and native red blood cells are destroyed. Further transfusions are avoided after a history of HS. Immunosuppressive agents can be used as prophylaxis against life-threatening hemolysis when transfusion is necessary. There is a paucity of evidence for the use of HS prophylaxis before transfusions, the continuation of hydroxyurea (HU) in lieu of chronic transfusion, and the use of erythropoiesis-stimulating agents (ESA) in pregnant SCD patients.\n\n\n\nWe present a case of a pregnant patient with SCD and a previous history of HS. HS prophylaxis was given before transfusion with corticosteroids, intravenous immunoglobulin, and rituximab. In addition, HU was continued during pregnancy to control SCD, along with the use of concomitant ESA to maintain adequate hemoglobin levels and avoid transfusion. We describe a multidisciplinary approach to pregnancy and delivery management including tailored anesthetic and obstetric planning.\n\n\n\nThis is the first published case of HS prophylaxis in a pregnant SCD patient, with good maternal and fetal outcomes after transfusion. HU and ESAs were able to control SCD and mitigate anemia in lieu of prophylactic transfusions during pregnancy. Further prospective studies are necessary to elucidate the ideal management of pregnant SCD patients with a history of HS or other contraindications to chronic transfusion.",
"affiliations": "Department of Medicine, Division of Hematology, Western University, London, Ontario, Canada.;Department of Obstetrics & Gynecology, Western University, London, Ontario, Canada.;Department of Obstetrics & Gynecology, Western University, London, Ontario, Canada.;Department of Anesthesia, Western University, London, Ontario, Canada.;Department of Pediatrics, Division of Clinical Pharmacology, Western University, London, Ontario, Canada.;Department of Obstetrics & Gynecology, Western University, London, Ontario, Canada.;Department of Medicine, Division of Hematology, Western University, London, Ontario, Canada.",
"authors": "Vasanthamohan|Lakshman|L|0000-0002-9774-8597;Choo|Sheryl|S|;Marshall|Tonisha|T|;Symons|Yahui Tammy|YT|;Matsui|Doreen|D|;Eastabrook|Genevieve|G|;Solh|Ziad|Z|0000-0002-1518-1831",
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"issn_linking": "0041-1132",
"issue": "60(10)",
"journal": "Transfusion",
"keywords": "RBC transfusion; transfusion complications- non infectious; transfusion practices (OB GYN)",
"medline_ta": "Transfusion",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000755:Anemia, Sickle Cell; D005260:Female; D006461:Hemolysis; D006801:Humans; D016756:Immunoglobulins, Intravenous; D058725:Peripartum Period; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D000069283:Rituximab; D013577:Syndrome; D065227:Transfusion Reaction",
"nlm_unique_id": "0417360",
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"pages": "2448-2455",
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"pmid": "32851670",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Peripartum hyperhemolysis prophylaxis and management in sickle cell disease: A case report and narrative review.",
"title_normalized": "peripartum hyperhemolysis prophylaxis and management in sickle cell disease a case report and narrative review"
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"abstract": "Drug allergy is a rising problem in the twenty-first century which affects all populations and races, children, and adults, and for which the recognition, diagnosis, management, and treatment is still not well standardized. Classical and new chemotherapy drugs, monoclonal antibodies (MoAbs), and small molecules to treat cancer and chronic inflammatory diseases are aimed at improving quality of life and life expectancy of patients, but an increasing number of reactions including anaphylaxis precludes their use in targeted populations. Women are more affected by drug allergy and up to 27% of women with ovarian and breast cancer develop carboplatin allergy after multiple cycles of treatment. Carriers of BRCA genes develop drug allergy after fewer exposures and can present with severe reactions, including anaphylaxis. Atopic patients are at increased risk for chemotherapy and MoAbs drug allergy and the current patterns of treatment with recurrent and intermittent drug exposures may favor the development of drug allergies. To overcome drug allergy, desensitization has been developed, a novel approach which provides a unique opportunity to protect against anaphylaxis and to improve clinical outcomes. There is evidence that inhibitory mechanisms blocking IgE/antigen mast cell activation are active during desensitization, enhancing safety. Whether desensitization modulates drug allergic and anaphylactic responses facilitating tolerance is currently being investigated. This review provides insight into the current knowledge of drug allergy and anaphylaxis to cancer and chronic inflammatory diseases drugs, the mechanisms of drug desensitization and its applications to personalized medicine.",
"affiliations": "Allergy and Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.",
"authors": "Castells|Mariana|M|",
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"doi": "10.3389/fimmu.2017.01472",
"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2017.01472ImmunologyReviewDrug Hypersensitivity and Anaphylaxis in Cancer and Chronic Inflammatory Diseases: The Role of Desensitizations Castells Mariana 1*1Allergy and Immunology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United StatesEdited by: Vanesa Esteban, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Spain\n\nReviewed by: Michael Breitenbach, University of Salzburg, Austria; Sinisa Savic, University of Leeds, United Kingdom\n\n*Correspondence: Mariana Castells, mcastells@bwh.harvard.eduSpecialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology\n\n08 11 2017 2017 8 147231 5 2017 20 10 2017 Copyright © 2017 Castells.2017CastellsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Drug allergy is a rising problem in the twenty-first century which affects all populations and races, children, and adults, and for which the recognition, diagnosis, management, and treatment is still not well standardized. Classical and new chemotherapy drugs, monoclonal antibodies (MoAbs), and small molecules to treat cancer and chronic inflammatory diseases are aimed at improving quality of life and life expectancy of patients, but an increasing number of reactions including anaphylaxis precludes their use in targeted populations. Women are more affected by drug allergy and up to 27% of women with ovarian and breast cancer develop carboplatin allergy after multiple cycles of treatment. Carriers of BRCA genes develop drug allergy after fewer exposures and can present with severe reactions, including anaphylaxis. Atopic patients are at increased risk for chemotherapy and MoAbs drug allergy and the current patterns of treatment with recurrent and intermittent drug exposures may favor the development of drug allergies. To overcome drug allergy, desensitization has been developed, a novel approach which provides a unique opportunity to protect against anaphylaxis and to improve clinical outcomes. There is evidence that inhibitory mechanisms blocking IgE/antigen mast cell activation are active during desensitization, enhancing safety. Whether desensitization modulates drug allergic and anaphylactic responses facilitating tolerance is currently being investigated. This review provides insight into the current knowledge of drug allergy and anaphylaxis to cancer and chronic inflammatory diseases drugs, the mechanisms of drug desensitization and its applications to personalized medicine.\n\ndesensitizationmonoclonal antibodies in cancerplatinsdrug allergytaxanes\n==== Body\nIntroduction\nWith the unprecedented use of chemotherapies drugs and targeted monoclonal antibodies (MoAbs) and small molecules in the twenty-first century, increased hypersensitivity reactions (HSRs) have emerged worldwide (1, 2). Drug allergic reactions are unexpected, can be severe including anaphylaxis and prevent the use of first-line therapies, with consequent impact in patient’s survival and quality of life (3, 4). These reactions range from mild cutaneous manifestations such as pruritus and hives to life-threatening anaphylaxis with hypotension, oxygen desaturation and cardiovascular collapse, and deaths have been reported after re-exposure to allergic drugs (5, 6). The presentation of symptoms can be atypical such as pain, which has been associated with taxenes reactions, and chills and fever which have been seen with oxaliplatin and MoAbs reactions (7, 8). Delayed reactions occurring more than 24 h after chemotherapy infusions can be due to the prolonged half-life of MoAbs and the presence of premedications, which may mask the acute phase of the reactions (9, 10).\n\nThe traditional classification of drug hypersensitivity and allergy into the classical types I–IV does not encompass the current spectrum of reactions and symptoms occurring in cancer patients and patients with chronic inflammatory diseases (11, 12). Some of the reactions have no known underlying mechanism, others have a known mechanism which is not part of the four described types and some drugs can induce mixed reactions with two or more proposed mechanisms (13, 14). Hypersensitivity to rituximab, a chimeric anti-CD20 MoAb, can induce cytokine-like reactions with chills, fevers, hypotension, and oxygen desaturation, which have been attributed to the release of cytokines such as IL-6, IL-1β, and TNF-α and are named cytokine release syndrome or cytokine storm, which is not contemplated in the Gell and Coombs classification (15). In contrast, some patients have classical IgE-mediated reactions to rituximab and have presented positive skin testing demonstrating that IgE and mast cells are part of the underlying mechanism (16). Some patients reactive to oxaliplatin present mixed reactions with Type I features such as hives and hypotension, along with fever and chills as seen in cytokine storm-like reactions, presenting a complex mixed pattern of reactivity which provides challenges to management and treatment (17). During mixed reactions tryptase, the major mast cell protease, and IL-6 can be elevated in serum indicating mast cell activation and cytokine release from unknown cellular sources. Reactions to taxenes can trigger direct mast cell/basophil activation with elevation of serum tryptase with or without evidence of IgE, indicating that more than one mechanism can explain taxane hypersensitivity. A different receptor than FceRI, such as the recently described MrgprX2 for drugs with THIQ motifs such as quinolones and paralyzing agents such as atracuronium could be activated during non-IgE taxane reactions (13, 18–20).\n\nPatients presenting with delayed cutaneous reactions are at a great concern for Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening conditions which can lead to permanent disability, blindness, and dramatic decrease in the quality of life for survivors (16, 21). The underlying mechanisms of the reactions are poorly understood and up to now no predictive markers have been available. Genetic susceptibility and defined HLA haplotypes are thought to be risk factors for some of the reactions, such as HLA-B 5701 in HIV patients reactive to abacavir. In patients with targeted haplotypes, a new role for viral reactivation of HHV6 and other virus have been demonstrated, and the pathogenic role of the virus is under study (22–24).\n\nTo provide an operational classification which can adapt to the increasing knowledge of the mechanisms of reactions and to the symptoms and clinical presentations, a recent initiative has provided a new terminology, applicable to precision medicine. In the new categorization drug allergy phenotypes are defined by the underlying endotypes and associated biomarkers and can be used in personalized medicine, with each patient being categorized according to her/his symptoms complex presentation. Current phenotypes include acute and delayed reactions with IgE and non-IgE involvement, cytokine storm, and mixed patterns. The endotypes responsible for the expression of symptoms include mast cell and basophil activation through known receptors (FceRI, FcgR, MRGPRX2) and directly through known receptors: complement, kinin and bradykinin activation and COX-1 inhibition. Associated biomarkers include serum tryptase, skin testing, basophil activation test, specific IgE and patch testing among others (13, 25–28).\n\nPatients presenting with reactions compatible with phenotypes consistent with acute and delayed IgE and non-IgE, mast cell/basophil activation, and T cell activation endoptypes may be prevented from the use of first-line therapies for fear of inducing anaphylaxis or more severe delayed reactions upon re-exposure to the allergenic drug. A groundbreaking procedure, desensitization, has emerged in the last 15 years as a proven effective and safe procedure to maintain patients on their first-line medications.\n\nClinical Vignette\nMrs. MFF is a 49-year-old healthy female who was discovered to have ovarian cancer after a routine gynecology ultrasound and was initially treated with surgery and chemotherapy with six courses of carboplatin and paclitaxel and entered remission. Two years later, the CA125 is increased and new masses are found in her abdomen, a diagnosis of recurrent stage 4 ovarian cancer is made and carboplatin and paclitaxel restarted. After the second course of carboplatin, the patient feels her hands itchy but finished the infusion and did not have any further symptoms. On the day of her third infusion, the patient presented flushing, generalized pruritus, shortness of breath, and sudden dizziness. The blood pressure drops below normal range as well as the oxygen saturation and the patient has a syncopal episode and needs to be resuscitated with epinephrine, fluids, anti-histamines, and steroids. She recovers and her diagnosis is of anaphylaxis, a serum tryptase level during the episode is elevated at 52 ng/ml (normal range 11.4 ng/ml). The patient is evaluated for carboplatin allergy and skin testing is positive. Her options are to change to a second-line agent which is likely to reduce her life expectancy or to remain on first-line therapy with carboplatin but because of her anaphylactic reaction this option is not considered safe unless carboplatin can be introduced through desensitization, a powerful and novel intervention which has shown to protect patients against anaphylaxis and permit re-introduction of allergy drugs.\n\nDrug Desensitization\nThe term drug desensitization is currently used to define a process by which a patient’s immune response to a drug is modified to generate temporary tolerance, taking advantage of well characterized inhibitory pathways (6). In the case of IgE-mediated drug allergy, positive skin testing and specific serum IgE can be used as biomarkers along with elevated serum tryptase level during the acute reaction (8, 11, 17). Patients without evidence of IgE mechanism are good candidates for desensitization provided the phenotype of the drug reaction is a type I or a type IV like reaction without features of SJS/TEN (16, 21, 29) (Table 1).\n\nTable 1 Indications, contraindications and risk factors for drug desensitization.\n\nIndications\tHigh-risk patients\tContraindications\t\nReactions type I (mast cells/IgE/basofills) Reaction type IV (except SCARs)\tSevere anaphylaxis (intubation)\tSevere cutaneous adverse reactions (SCARs) (SJS/TEN, DIHS/DRESS, AGEP)\t\nNo alternative drug\tSevere respiratory disease\tImmunocytotoxic reactions (type II reactions)\t\nDrug is more effective and/or associated with less side effects\tSevere cardiac disease\tVasculitis\t\nDrug has a unique mechanism of action\tSevere systemic diseases\tSerum sickness-like (type III reactions)\t\n\tUse of beta-blockers, ACE inhibitors\t\t\nPregnancy\t\nSJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis; DIHS, drug-induced hypersensitivity syndrome; DRESS, drug reaction (rash) with eosinophilia and systemic symptoms; AGEP, acute generalized exanthematous.\n\nThe mechanisms underlying drug desensitization are based on in vitro and in vivo models which have proposed that mast cells and basophils can be induced to predominantly inhibitory pathways by small incremental antigen doses, deactivating signal transduction and mediators release (13) (Figure 1).\n\nFigure 1 In vitro IgE/antigen mouse mast cells activation and desensitization (13). (A) Desensitization of in vitro DNP-IgE sensitized mouse mast cells with DNP inhibits the release of granule mediators such as beta-hexosaminidase. Instead of one single optimal dose, 11 suboptimal sequential doses are given until reaching the optimal dose. (B) Desensitization of in vitro OVA-IgE sensitized mouse mast cells with OVA inhibits the release of granule mediators such as beta-hexosaminidase. Instead of one single optimal dose, 11 suboptimal sequential doses are given until reaching the optimal dose. (C) Desensitization of in vitro DNP-IgE sensitized mouse mast cell mediators with DNP inhibits the de novo generation of cytokines TNF alpha and IL-6 (D). (E) Calcium entry (blue line) occurs after activation of DNP-IgE sensitized mouse mast cells with DNP but not when cells have been desensitized to DNP (red line, * DNP). Desensitization is specific since cells that were DNP desensitized and OVA-IgE sensitized presented calcium entry after OVA activation (red line, * OVA). (F) Membrane events are modified during desensitization with lack of internalization of desensitized antigens: left panels indicate that OVA desensitization does not present internalization of antigen (upper panel) as opposed to activation (lower panel with green labeled OVA internalized) and right panels indicate that after OVA desensitization another non desensitizing antigen such as DNP can be internalized (upper panel) as seen with activation (lower panel).\n\nNegative skin test is seen following desensitization in patients with IgE-mediated reactions, providing evidence of the powerful mechanisms which turn off skin mast cells (30–32). Partitioning of an optimal dose into 11–16 incremental doses starting at 1/1,000 the target dose and delivering them with sufficient time interval to mast cells; inhibits the acute release of beta-hexosaminidase, a mast cell granule mediator, prevents the generation of arachidonic acid and products such as leukotrienes and prostaglandins and the late generation of inflammatory cytokines (Figure 1) (13).\n\nDuring desensitization, calcium influx is abolished and actin polymerization impaired, providing stability to intracellular granules in an antigen-specific fashion (Figure 1) (13). Membrane events that prevent internalization or modify its response to subthreshold doses of antigen occur during desensitization and are associated with incremental unresponsiveness to specific antigen (Figure 2) (13). Association of the FceRI to ITIM containing receptors, capable of dephosphorylating ITAMs receptors has been postulated as one of the mechanisms of desensitization. Mast cells desensitized to one antigen are responsive to a second non desensitizing antigen, providing evidence of compartimentalization and highly specialized and regulated intracellular processes (Figure 1) (13).\n\nFigure 2 Model of in vitro mouse mast cells activation and desensitization. The left side cartoons provide the steps of antigen/IgE/FceRI activation starting from antigen cross-linking, internalization, calcium entry and release of granule mediators, generation of lipd mediators such as prostaglandins and leukotrienes, and production of late phase cytokines. The right sided panel provides the hypothetical membrane capping and rearrangement occurring during the delivery of sequential suboptimal doses of allergen in desensitization preventing internalization of antigen, calcium entry, and mediators release.\n\nThe protocols used for in vitro desensitization have been adapted in vivo and further adaptations have produced safe protocols for human use (Figure 3) with similar dose increments and interval times (25–28). These human protocols have now been used in thousands of cases with remarkable safety since the inhibitory mechanisms of desensitization protect against anaphylaxis (Figure 4) (33, 34).\n\nFigure 3 In vitro and in vivo protocols for induction of IgE/antigen desensitization. In the left panel in black, increasing single doses of antigen induce a dose response release of beta-hexosaminidase in vitro mouse mast cells. In white, the same doses given sequentially induce a profound inhibition of the beta -hexosaminidase release. In the right panel, a model of desensitization protocol used for human desensitization in which 3 bags and 12 steps (4 steps per bag) are used to administer sequential doubling doses every 15 min which provides the target dose of 300 mg after 5.66 h when the last step is completed.\n\nFigure 4 Putative mechanism of protection against anaphylaxis during human desensitizations. By delivering the target dose of the drug by small incremental doubling doses (Figure 3), the threshold for anaphylaxis is re-established at each step and never reaches that of the initial triggering dose.\n\nWhether after multiple desensitizations neutralizing antibodies can be generated which may block allergenic drug epitopes has been hypothesized (6). Maintaining drug desensitization state depends upon continued drug exposure and desensitized drugs require administration at regular intervals to maintain a stable pharmacokinetics state. Desensitization needs to be repeated if several half-lives of the medication have elapsed (6, 33).\n\nProtocols for drug desensitization have been successfully used for antibiotics, chemotherapy drugs, and MoAbs among other drugs in patients with IgE and non-IgE-mediated HSRs (Figure 5) (6, 14, 33, 35). The phenotypes of reactions amendable to desensitization include immediate and delayed reactions. Typical type I reactions usually begin within minutes of initiation of the infusion to few hours after the infusion due to anti-histamine and steroid premedication. The signs and symptoms include puritus, flushing, urticaria, angioedema, throat tightening, wheezing, nausea, diarrhea, hypotension, syncope, seizures, and cardiovascular collapse which can lead to death. Atypical symptoms include back, chest, or abdominal pain (such as seen with taxanes, oxaliplatin, MoAbs such as rituximab) (33, 35).\n\nFigure 5 Symptoms and signs of hypersensitivity reactions amendable to desensitization. Carboplatin and other paltins such as cisplatin and oxaliplatin reactions include classical symptoms of anaphylaxis with cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms. Reactions to taxenes including paclitaxel and docetaxel present with pain as a neuromuscular symptoms in up to 4% of the patients. Doxorubicin/adriamycin and other chemotherapies present with sudden onset hypo or hypertension in up to 60% of patients and rituximab and other monoclonal antibodies present with cutaneous and cardiovascular symptoms in 70% of the patients.\n\nDelayed reactions are attributed to type IV reactions and can occur several days after the infusion and are typically limited to the skin with maculopapular rashes (36). Reactions that involve mucosal membranes and/or are associated with systemic symptoms are not amenable to desensitization due to the risk of inducing a severe systemic reaction with small amounts of drug antigen (16, 21, 29).\n\nDesensitization should be considered in patients with reaction phenotypes consistent with type I and type IV reactions who have no alternative therapy or for whom alternative therapies are of less value or can induce more side effects. The algorithm for the evaluation of these patients is seen in Figure 6 (6, 34, 37). The nature and symptoms of the initial reactions needs to be established and tryptase and skin test provide evidence of IgE and/or mast cell involvement. BAT is a research tool and cannot be applied to current clinical practice.\n\nFigure 6 Algorithm for the evaluation of drug hypersensitivity reactions and the role of desensitization for the re-introduction of the first-line medications, when no alternative is available or the alternative does not provide the same benefits or life expectancy as the first line.\n\nDrug desensitization can be performed in patients of any age and in pregnant women when alternative therapies are not possible or when delaying therapy may incur a shortened life span. Anaphylaxis is the major risk during desensitization since patients are exposed to their allergic drug. Large series have demonstrated that most breakthrough reactions during desensitization are mild and less severe than the patient’s initial HSR and fatalities have not been reported, but all desensitizations can only be performed by an expert allergist familiar with the personalized protocol and potential reactions (Table 1) (17, 33, 35). The safety of desensitizations is paramount and patients with grade 3 severe initial reactions and anaphylaxis can be desensitized with minimal reactions as seen in Table 2.\n\nTable 2 Safety of first desensitization in patients with grades 1, 2, and 3 initial reactions.\n\n\tFirst desensitization reaction grade\t\nInitial hypersensitivity reaction grade\t0\t1\t2\t3\tTotal\t\n1\t76 (61%)\t38 (30%)\t7 (6%)\t4 (3%)\t125\t\n2\t38 (58%)\t22 (34%)\t4 (6%)\t1 (2%)\t65\t\n3\t122 (60%)\t54 (26%)\t10 (5%)\t19 (9%)\t205\t\nTotal\t236\t114\t21\t24\t396\t\nFrom Sloane et al. (33).\n\nDesensitization is not recommended for type II and type III serum sickness-like reactions or in patients with reactions with skin desquamation, EM, Stevens–Johnson syndrome or toxic epidermal necrolysis, because small amounts of drug can induce irreversible and potentially fatal reactions (Table 1) (16, 21, 29).\n\nThe most commonly used intravenous desensitization protocols are standardized 12- to 16-step protocols modeled after in vitro protocols and can be personalized to all drugs with adjustment of the target dose, time intervals between doses and starting dose (Figure 3) (33, 38). Protocols are available for intravenous desensitizations but also for oral, subcutaneous, intraperitoneal, or intravenous routes in the outpatient and inpatient settings (39–41). Desensitization for delayed reactions is also available and may take several days but recent data suggest that some of these reactions may be amenable to shorter time intervals (8, 36, 42). The overall safety of desensitizations is similar for all medications provided the mechanism of the initial reaction is of type I, IgE and non-IgE or type IV. As seen in Figure 7, the overall safety indicates that 93% of patients present with no reaction or grade 1 reactions and all completed the desensitization.\n\nFigure 7 The overall safety of desensitization for common chemotherapy drugs and monoclonal antibodies.\n\nPlatins, taxanes, and MoAbs are the most common chemotherapy currently used in desensitization and are described below.\n\nPlatin Hypersensitivity\nPlatinum compounds are used in ovarian, colorectal, endometrial, glioblastoma, lung, and pancreatic cancer as initial chemotherapy and in second-line or salvage settings. Carboplatin is the most popular since it is less nephrotoxic and neurotoxic than cisplatin. Allergic reactions to platins are IgE-mediated and require sensitization through multiple exposures, with 27% of women becoming allergic after seven life time exposures (12, 43, 44). Allergic symptoms typically start at the second round of treatment, when the cancer recurs and after 1–2 exposures sensitized patients present with flushing and pruritus which can progress to shortness of breath with further exposure and can lead to anaphylaxis, with hypotension and cardiovascular collapse (2, 4, 7, 33, 45). Patients bearing BRCA 1 and 2 gene mutations have an increased risk for carboplatin reactions, which can occur with fewer exposures (46, 47). Most reactions to platins occur during or shortly after the drug infusion and the phenotype is that of type I reaction. In a study of 60 carboplatin sensitized patients, 100% had cutaneous, 60% pulmonary, 40% respiratory, and 42% gastrointestinal symptoms (6).\n\nThe phenotype of reactions to oxaliplatin can be more complex with features including typical IgE-mediated symptoms and atypical symptoms such as back and pelvic pain and cytokine-mediated fever and chills (7, 11, 17, 48, 49). Antibody-mediated thrombocytopenia and immune complex-mediated syndromes with urticaria and proteinuria have also been observed (17, 50).\n\nSkin testing to platins has been safely done (Table 3) and is diagnostic tool to demonstrate an IgE/mast cell mechanism in patients with carboplatin and cisplatin reactions (7, 11, 17). For patients exposed to six or more courses of carboplatin in the last 6 months the positive predictive value is up to 86% (11). Oxaliplatin skin testing is negative in up to 50% of patients presenting type I reactions, indicating other than IgE mechanisms or lack of skin test allergenic determinants (17). Circulating serum specific IgE has been demonstrated and patients reactive to oxaliplatin with detectable serum-specific IgE have also demonstrated IgE to carboplatin and cisplatin without exposure, indicating broad cross-reactivity (51). IgE to platins can be short lived since a study has demonstrated that ST is negative in a high proportion of patients with a remote history of HSR to carboplatin, but re-exposure leads to resensitization and severe reactions (11). When platins are considered as first-line therapy, desensitization is a safe option since increased premedications alone do not prevent anaphylaxis and cross-reactivity may prevent the use of other platins (51). Patients with severe cutanoues reactions, SJS and TEN are currently not candidates since the mechanism of the reactions is unknown and small amounts of medications may induce severe symptoms (1, 16, 21, 29). Desensitization provides a similar life expectancy as non-allergic non desensitized patients (Figure 8) without increased health costs (33).\n\nTable 3 Skin testing for the diagnosis of chemotherapy drug allergy including platins, monoclonal antibodies, and paclitaxel.\n\nMedication\tPrick (mg/ml)\tIntradermal (mg/ml)\t\nCarboplatin\t10\t0.1, 1, 5, and 10\t\nCisplatin\t1\t0.1 and 1\t\nOxaliplatin\t5\t0.5 and 5\t\nRituximab\t10\t0.1, 1, and 10\t\nInfliximab\t10\t0.1, 1, and 10\t\nTocilizumab\t20\t0.2, 2, and 20\t\nCentuximab\t20\t0.2, 2, and 20\t\nTraztuzmab\t21\t0.21, 2.1, and 21\t\nBevacizumab\t25\t0.25, 2.5, and 25\t\nCyclophosphamide\t10\t0.1, 1, and 10\t\nMethotrexate\t25\t0.2, 2.5, and 25\t\nPaclitaxel\t1–6\t0.001 and 0.01\t\nFigure 8 Life expectancy for cancer patients allergic and desensitized to carboplatin and non-allergic to carboplatin [from Sloane et al. (33)]. Allergic and non-allergic ovarian cancer patients treated with carboplatin or carboplatin desensitization presented a similar life expectancy with a non significant advantage for the allergy desensitized patients.\n\nTaxanes\nTaxanes are used in gynecologic, lung, breast, and prostate cancers and reactions to taxenes are among the most frequent chemotherapy reactions and fatalities have been reported (52). Paclitaxel and docetaxel have been the more frequently used and more recently other taxenes such as cabacitaxel and abraxene have become popular (53). Paclitaxel is an insoluble compound originally isolated from the bark of the pacific yew tree, Taxus Baccata tree and solubilized in cremophor and docetaxel is a semi-synthetic molecule derived from a precursor found in European yew tree needles and solubilized in polysorbate 80 (36, 54). The solvents can cause complement activation, generating anaphylotoxins C3a and C5a and leading to mast cell activation (55–57). Taxanes are used with premedications including anti-histamines and steroids due to a high rate of reactions in early clinical studies (54). The rate of reaction has decreased to less than 10% and typically occurs during the first or second lifetime exposure in up to 80% of the patients (54). The phenotype of the reactions include type I symptoms such as throat tightness, flushing, hypotension, and dyspnea but atypical symptoms such as chest, back, or pelvic pain (8, 36, 54).\n\nSkin testing has uncovered IgE-mediated reactions to taxanes and a recent study reported that 103 of 145 taxane reactive patients (71%) had positive results. Negative skin test patients who were challenged were likely to tolerated taxane infusions without desensitization. Atopy was present in over 40% of the patients and because patients react at first or second exposure suggested prior sensitization or cross-reactivity with environmental allergens (8). Risk stratification based on biomarkers such as skin testing can safely guide the management to taxane reactions and allows a significant number of patients to resume regular infusions. For patients with positive skin test and significant initial reaction for whom taxanes are first-line therapy, desensitization should be considered (8).\n\nMonoclonal Antibodies\nThere are over 45 MoAbs currently in use for the treatment of cancer and inflammatory and autoimmune diseases. Reactions to MoAbs depend on their structure and vary from chimeric mouse-human, humanized, to fully human. Some of the most frequently used MoAbs are presented in Table 4, including their targets, incidence of overall injection/infusion site reactions, and HSRs (19, 34, 35).\n\nTable 4 Common monoclonal antibodies in use and rate of overall reactions and hypersensitivity reactions (HSR).\n\nDrug\tTarget\tOverall reactions\tHSR\t\nRituximab (Rituxan®) IV\tCD20\t77% (first infusion) (52)\t5–10% (53)\t\nOfatumumab (Arzerra®) IV\tCD20\t44% (first infusion) (54)\t2% (55)\t\n67% (combination therapy) (55)\t\nObinutuzumab (Gazyva®) IV\tCD20\t66% (56,57)\t(58)*\t\nTrastuzumab (Herceptin®) IV\tHER-2\t40% (mild; first infusion) (59)\t0.6–5% (60)\t\nCetuximab (Erbitux®) IV\tEGFR\t15–21% (61)\t1.1–5% (62–65)\t\n14–27% (Southern USA) (43,66,67)\t\nTocilizumab (Actemra®) IV\tIL-6 receptor\t7–8% (68)\t0.1–0.7% (68)\t\nInfliximab (Remicade®) IV\tTNF-α\t5–18% (69)\t1%* (69)\t\nEtanercent (Enbrel®) SC\tTNF-α\t15–37% (70)\t<2% (70)\t\nAdalimumab (Humira®) SC\tTNF-α\t20% (71)\t1% (71)\t\nGolimumab (Simponi®) SC\tTNF-α\t4–20% (72,73)\tNot reported\t\nCertolizumab (Cimzia®) SC\tTNF-α\t0.8–4.5% (74,75)\tNot reported\t\nBrentuximab (Adcetris®) IV\tCD30\t12% (76)\t(77–79)*\t\nBevacizumab (Avastin®) IV\tVEGF-A\t<3% (80)\tNot reported\t\nOmalizumab(Xolair®) SC\tlgE\t45% (81)\t00.9–0.2% (81,82)\t\n*<p= 0.05\n\nMonoclonal antibodies immunogenicity depends on the human content but fully human MoAbs, such as adalimumab and ofatumumab can induce severe HSRs likely due to the glycosylation patterns in vitro and the generation of neo antigens (58). This is best exemplified in reactions to cituximab which can occur at first exposure in patients sensitized through tick bites to the mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal) (59).\n\nThe phenotypes of MoAbs reactions include limited infusion reactions, IgE-mediated reactions, serum sickness-like reactions, cytokine storm-like reactions, and mixed reactions. Infusion reactions are characterized by nausea, chills, fever, and malaise and for trastuzumab these reactions can occur in up to 40% of patients (34, 35). Like cytokine storm-like reactions, which are more severe, can associate with hypotension, oxygen desaturation, and require treatment with steroids and COX-1 inhibitors, proinflammatory cytokines (such as IL-6 and TNF-α) are thought to be involved (60, 61).\n\nImmediate and delayed HSRs can occur with MoAbs and serum sickness-like reactions, such as seen with infliximab and omalizumab, which can present with rash, myalgia, fever, polyarthralgias, pruritus, edema, and fatigue (35).\n\nMonoclonal antibodies used subcutaneously can elicit injection-site reactions few hours after the injection and persisting for several days. The phenotype of these reactions include local redness, warmth, burning, itching, urticaria, pain, and induration, varying in frequency from 0.8 to 4.5% with certolizumab to up to 45% with omalizumab (39).\n\nReactions to MoAbs can occur during the infusion and should prompt interruption of the treatment and the evaluation of tryptase and inflammatory cytokines to further understand the mechanism of the reactions. Skin testing with the offending agent can be done for type I and mixed reactions 2–4 weeks after the reaction to avoid false negative results, in particular in anaphylactic reactions in which natural desensitization can occur (35). An important consideration is cost of MoAbs; there are no available reagents at the present time for the evaluation of MoAb reactions and using a treatment vial may exceed several thousand dollars, precluding a diagnostic skin test evaluation. The negative predictive value of skin testing is not known and in a study of 23 patients reactive to trastuzumab, infliximab, or rituximab, 13 patients had positive skin test. Positive and negative skin test patient with significant initial reactions are candidates for desensitization and subcutaneous protocols are available. Successful desensitizations to rituximab, ofatumumab, obinutuzumab, trastuzumab, cetuximab, tocilizumab, infliximab, etanercept, adalimumab, golimumab, certolizumab, brentuximab, bevacizumab, and omalizumab have been reported (33–35).\n\nConclusion\nDrug hypersensitivity is an increasing health hazard, which can compromise the quality of life and the life expectancy of cancer patients and patients with chronic inflammatory diseases with reactions to their first-line therapy. Recognition of the mechanisms of the reactions into phenotypes, understanding the underlying endotypes and evaluation of biomarkers is key to personalized medicine and enhanced patient safety allowing for informed decisions regarding drug re-exposure and desensitization. Serum tryptase, skin testing, BAT, and specific IgE are helpful diagnostic tools which will be complemented in the future with genotyping to identify patients at risk before reactions occur. Appropriate treatment of the reactions including epinephrine use and management with personalized desensitization protocols can enhance the quality of life, life expectancy, and safety of an increasing at risk population of patients with cancer and inflammatory diseases allergic to their best medications. Most patients with reactions with phenotypes consistent with type I and type IV reactions are candidates for desensitization, which can provide advancement of personalized treatments. Drug desensitization protects against anaphylaxis and activates inhibitory mechanisms which need further research to uncover cellular and molecular players amendable to pharmacological applications, which can make desensitization safer and more effective.\n\nAuthor Contributions\nAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.\n\nConflict of Interest Statement\nThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1 Kadoyama K Kuwahara A Yamamori M Brown JB Sakaeda T Okuno Y . Hypersensitivity reactions to anticancer agents: data mining of the public version of the FDA adverse event reporting system, AERS . 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J Clin Oncol (1999 ) 17 (4 ):1141 .10.1200/JCO.1999.17.4.1141 10561172 \n45 Polyzos A Tsavaris N Kosmas C Arnaouti T Kalahanis N Tsigris C \nHypersensitivity reactions to carboplatin administration are common but not always severe: a 10-year experience . Oncology (2001 ) 61 (2 ):129 –33 .10.1159/000055363 11528251 \n46 Moon DH Lee JM Noonan AM Annunziata CM Minasian L Houston N \nDeleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions . Br J Cancer (2013 ) 109 (4 ):1072 –8 .10.1038/bjc.2013.389 23867999 \n47 Galvão VR Phillips E Giavina-Bianchi P Castells MC \nCarboplatin-allergic patients undergoing desensitization: prevalence and impact of the BRCA 1/2 mutation . J Allergy Clin Immunol Pract (2017 ) 5 (3 ):816 –8 .10.1016/j.jaip.2016.08.012 27765459 \n48 Thomas RR Quinn MG Schuler B Grem JL . Hypersensitivity and idiosyncratic reactions to oxaliplatin . Cancer (2003 ) 97 (9 ):2301 –7 .10.1002/cncr.11379 12712487 \n49 Maindrault-Goebel F André T Tournigand C Louvet C Perez-Staub N Zeghib N \nAllergic-type reactions to oxaliplatin: retrospective analysis of 42 patients . Eur J Cancer (2005 ) 41 (15 ):2262 –7 .10.1016/j.ejca.2005.06.021 16154353 \n50 Baldo BA . Adverse events to monoclonal antibodies used for cancer therapy: focus on hypersensitivity responses . Oncoimmunology (2013 ) 2 (10 ):e26333 .10.4161/onci.26333 24251081 \n51 Caiado J Venemalm L Pereira-Santos MC Costa L Barbosa MP Castells M . Carboplatin-, oxaliplatin-, and cisplatin-specific IgE: cross-reactivity and value in the diagnosis of carboplatin and oxaliplatin allergy . J Allergy Clin Immunol Pract (2013 ) 1 (5 ):494 –500 .10.1016/j.jaip.2013.06.002 24565621 \n52 Lee C Gianos M Klaustermeyer WB . Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents . Ann Allergy Asthma Immunol (2009 ) 102 (3 ):179 –87; quiz 187–9, 222 .10.1016/S1081-1206(10)60078-6 19354063 \n53 Vasey PA Jayson GC Gordon A Gabra H Coleman R Atkinson R \nPhase III randomized trial of docetaxel–carboplatin versus paclitaxel–carboplatin as first-line chemotherapy for ovarian carcinoma . J Natl Cancer Inst (2004 ) 96 (22 ):1682 –91 .10.1093/jnci/djh323 15547181 \n54 Squibb B-M \nTAXOL® (Paclitaxel) Injection Prescribing Information . FDA , (2012 ).\n55 Qiu S Liu Z Hou L Li Y Wang J Wang H \nComplement activation associated with polysorbate 80 in beagle dogs . Int Immunopharmacol (2013 ) 15 (1 ):144 –9 .10.1016/j.intimp.2012.10.021 23159336 \n56 Weiszhár Z Czúcz J Révész C Rosivall L Szebeni J Rozsnyay Z . Complement activation by polyethoxylated pharmaceutical surfactants: cremophor-EL, tween-80 and tween-20 . Eur J Pharm Sci (2012 ) 45 (4 ):492 –8 .10.1016/j.ejps.2011.09.016 21963457 \n57 Hennenfent KL Govindan R \nNovel formulations of taxanes: a review. Old wine in a new bottle? \nAnn Oncol (2006 ) 17 (5 ):735 –49 .10.1093/annonc/mdj100 16364960 \n58 Sheeley DM Merrill BM Taylor LC . Characterization of monoclonal antibody glycosylation: comparison of expression systems and identification of terminal alpha-linked galactose . Anal Biochem (1997 ) 247 (1 ):102 –10 .10.1006/abio.1997.2036 9126378 \n59 Chung CH Mirakhur B Chan E Le QT Berlin J Morse M \nCetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose . N Engl J Med (2008 ) 358 (11 ):1109 –17 .10.1056/NEJMoa074943 18337601 \n60 Doessegger L Banholzer ML . Clinical development methodology for infusion-related reactions with monoclonal antibodies . Clin Transl Immunology (2015 ) 4 (7 ):e39 .10.1038/cti.2015.14 26246897 \n61 Luheshi GN . Cytokines and fever. Mechanisms and sites of action . Ann N Y Acad Sci (1998 ) 856 :83 –9 .10.1111/j.1749-6632.1998.tb08316.x 9917868\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "8()",
"journal": "Frontiers in immunology",
"keywords": "desensitization; drug allergy; monoclonal antibodies in cancer; platins; taxanes",
"medline_ta": "Front Immunol",
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"title": "Drug Hypersensitivity and Anaphylaxis in Cancer and Chronic Inflammatory Diseases: The Role of Desensitizations.",
"title_normalized": "drug hypersensitivity and anaphylaxis in cancer and chronic inflammatory diseases the role of desensitizations"
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"abstract": "Mucormycosis has multiple clinical phenotypes, which are more common in immunocompromised patients, especially those with diabetes mellitus. Debilitating rhino-orbital-cerebral and pulmonary infections by far represent the most typical clinical phenotypes associated with these fungi. Mucormycosis is an uncommon infection; however, there have been isolated sporadic tiny outbreaks around the world. With the substantial increase in COVID-19 cases in India, there is a parallel increase in the number of cases of Mucormycosis. A few reports raising unusual concomitant mucormycosis in COVID-19 patients have raised a possible association between the two diseases. We report a 59-year-old male with an established history of uncontrolled diabetes mellitus admitted to the hospital with severe COVID-19 pneumonia (severity ascertained according to WHO classification) treated with steroids and discharged home following full recovery. However, one week later, he presented with right eye ophthalmoplegia and complete loss of vision, which was subsequently established as orbital Mucormycosis. This case highlights the need for heightened awareness of this atypical secondary infection (especially systemic mycosis) in patients recovering from COVID-19 infection.",
"affiliations": "Hamad General Hospital, Internal Medicine Department, Doha, Qatar.;Hamad General Hospital, Internal Medicine Department, Doha, Qatar.;Hamad General Hospital, Internal Medicine Department, Doha, Qatar.;Hamad General Hospital, Internal Medicine Department, Doha, Qatar.;Hamad General Hospital, Internal Medicine Department, Doha, Qatar.;Hamad General Hospital, Internal Medicine Department, Doha, Qatar.",
"authors": "Alamin|Mohammed A|MA|;Abdulgayoom|Mohammed|M|;Niraula|Sushil|S|;Abdelmahmuod|Elabbass|E|;Ahmed|Ashraf O|AO|;Danjuma|Mohammed I|MI|",
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"doi": "10.1016/j.idcr.2021.e01293",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00249-3\n10.1016/j.idcr.2021.e01293\ne01293\nCase Report\nRhino-orbital Mucormycosis as a complication of severe COVID-19 pneumonia\nAlamin Mohammed A. Mtbalamin@hotmail.com\n⁎\nAbdulgayoom Mohammed\nNiraula Sushil\nAbdelmahmuod Elabbass\nAhmed Ashraf O.\nDanjuma Mohammed I.\nHamad General Hospital, Internal Medicine Department, Doha, Qatar\n⁎ Correspondence to: Hamad General Hospital, Internal Medicine Department, P.O. Box 3050, Doha, Qatar. Mtbalamin@hotmail.com\n25 9 2021\n2021\n25 9 2021\n26 e012937 8 2021\n18 9 2021\n22 9 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nMucormycosis has multiple clinical phenotypes, which are more common in immunocompromised patients, especially those with diabetes mellitus. Debilitating rhino-orbital-cerebral and pulmonary infections by far represent the most typical clinical phenotypes associated with these fungi. Mucormycosis is an uncommon infection; however, there have been isolated sporadic tiny outbreaks around the world. With the substantial increase in COVID-19 cases in India, there is a parallel increase in the number of cases of Mucormycosis. A few reports raising unusual concomitant mucormycosis in COVID-19 patients have raised a possible association between the two diseases.\n\nWe report a 59-year-old male with an established history of uncontrolled diabetes mellitus admitted to the hospital with severe COVID-19 pneumonia (severity ascertained according to WHO classification) treated with steroids and discharged home following full recovery. However, one week later, he presented with right eye ophthalmoplegia and complete loss of vision, which was subsequently established as orbital Mucormycosis.\n\nThis case highlights the need for heightened awareness of this atypical secondary infection (especially systemic mycosis) in patients recovering from COVID-19 infection.\n\nKeywords\n\nCOVID-19\nMucormycosis\nSARS-CoV2\nRhizopus\nBlack Fungus\n==== Body\npmcIntroduction\n\nMucormycosis or Zygomycosis is a term that represents different syndromes of fungal infection, most commonly manifesting as a severe form of rhino-orbital-cerebral or pulmonary infections [1]. Diabetes Mellitus and immunocompromised patients are most commonly affected [2]. With the emerging COVID-19 pandemic, some cases were reported suggesting a possible association between SARS-Cov2 infection and development of mucormycosis; currently suggested to be possibly due to COVID-19 infection or its treatment (steroids or tocilizumab) [3].\n\nHerein we report a 59 years old male with a known history of diabetes who was treated with steroids and lopinavir/ritonavir for severe covid-19 infection. He presented one week after with right eye ophthalmoplegia and complete loss of vision and was found to have mucormycosis infection due to Rhizopus species. At the time of presentation, the patient was hyperglycemic with no evidence of ketoacidosis.\n\nCase presentation\n\nA 59-Year-old male whose past medical history was significant for type 2 diabetes mellitus (on lifestyle modification) and transsphenoidal surgery in 2019 for symptomatic pituitary adenoma presented with symptomatology consistent with severe covid pneumonia. He was treated with a drug cocktail including dexamethasone and Lopinavir/Ritonavir for five days and subsequently discharged after complete recovery. Prior to this, the patient was not on any long-term medications (notably, he was not on steroids considering his history of transsphenoidal surgery).\n\nOne week after discharge, the patient presented with severe right eye pain, ptosis, and complete loss of vision. On examination, the patient had right-sided total ophthalmoplegia with complete paralysis of extra and intraocular muscles, right eye ptosis (with dilated fixed pupil), and severe pain and tenderness around the periorbital area. On admission, the patient had hyperglycemia (random blood glucose was 20.3 mmol/L) with no evidence of ketoacidosis. C.T. sinuses scan did show partial opacification of the right ethmoid, maxillary, and right frontal sinuses by mucosal thickening and retained secretions (Fig. 1, Fig. 2). Subsequent MRI head and orbit scan showed features suggestive of right orbital pre and post-septal cellulitis (Fig. 3). The patient was commenced on ceftriaxone, vancomycin, and metronidazole, and adjuvant steroids (for possible Tolosa-hunt syndrome). Further into his admission, vancomycin and steroids were discontinued, and anidulafungin was added empirically; however, the patient's symptoms did not improve.Fig. 1 C.T. Head scan with contrast (coronal view) showing partial opacification of the right ethmoid (blue arrow-head) and right maxillary (red arrow-head) sinuses. CT: Computed Tomography.\n\nFig. 1\n\nFig. 2 C.T. Head with contrast showing right maxillary sinus opacification (red \"M\" letter). CT: Computed Tomography.\n\nFig. 2\n\nFig. 3 MRI Head with contrast (T1 weighted coronal view) scan showing enhancement at the right periorbital area (yellow arrow-heads) suggestive of periorbital cellulitis, along with opacification at right ethmoidal (red arrow-head) and right maxillary (blue arrow-head) sinuses. MRI: Magnetic Resonance Imaging. R.T.: Right, L.T.: Left.\n\nFig. 3\n\nFunctional endoscopic sinus surgery was done, which showed polypoidal thickening of the right ethmoid sinuses, no pus or blackish discoloration, with no signs of acute infection. In addition, a tissue culture grew Rhizopus species, and blood cultures grew Microbacterium aurum.\n\nThe patient remained symptomatic and was commenced on hyperbaric oxygen sessions and had his antimicrobial regimen changed to liposomal amphotericin B and later to posaconazole (as the patient developed amphotericin-induced acute kidney injury); no surgical intervention was contemplated. The patient received four sessions of hyperbaric oxygen therapy as an inpatient, with some improvement in his pain. He was subsequently discharged with ophthalmology and ENT outpatient follow-ups and scheduled eye enucleation for total eye blindness.\n\nDiscussion\n\nMucormycosis is emerging as one of the morbidities and mortality-prone complications of covid-19 infection, often in immunocompromised patients and those with type 2 diabetes. This mycosis often presents as debilitating rhino-orbital-cerebral and pulmonary infections [4]. Mucorales organisms are common in nature and can be found on decaying plants and in the soil. Rhizopus, Mucor, and Rhizomucor are the most common species in human infections [5]. Infarction and necrosis of host tissues are hallmarks of mucormycosis, often attributed to hyphae invasion of the vasculature [6]. Rhino-orbital-cerebral mucormycosis is presumed to start with inhalation of spores into the paranasal sinuses of a susceptible host. In contrast, in pulmonary mucormycosis, inhalation of spores into the bronchioles and alveoli is presumed to be the initial trigger [7].\n\nThe exact incidence of mucormycosis is difficult to be estimated as it is an underreported disease, and the risk varies in different populations [8]. A study of 929 instances of mucormycosis recorded between 1940 and 2003 showed that diabetes mellitus was the most prevalent risk factor, accounting for 36% of cases, followed by hematologic malignancies (17%) and solid organ or hematopoietic cell transplantation (12%) [9].\n\nThe mainstay of therapy for mucormycosis is a combination of surgical debridement of affected tissues and antifungal medication; this is besides eliminating its predisposing factors, such as neutropenia, hyperglycemia, and metabolic acidosis. Some individuals with mucormycosis have received hyperbaric oxygen therapy, although the effectiveness of this treatment has yet to be determined [10]. Interestingly, our patient had hyperbaric oxygen therapy with unclear clinical outcomes as his pain and visual loss failed to improve.\n\nMucormycosis is an uncommon infection; however, there have been isolated instances and tiny outbreaks worldwide. Along with the substantial increase in COVID-19 cases in India, mucormycosis cases have also increased. Alongside, with few case reports of mucormycosis infection in COVID-19 patients, this has raised the possible association between the two diseases [11].\n\nSince the initial reports of coronavirus disease 2019 (COVID-19) and the discovery of the new coronavirus that causes it, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infection have grown to encompass more than 150 million confirmed cases globally [12]. Glucocorticoids are affordable and widely available and thus far have been established to be amongst a handful of therapies with proven reduced morbidity and mortality benefit in Hypoxemic patients with COVID-19 clinical syndrome. However, it can increase the risk of secondary infection, hyperglycemia, and DKA, especially in patients with underlying undiagnosed Diabetic Mellitus [13]. Its indiscriminate use in the \"second wave\" of the COVID-19 pandemic, for example, may probably have accounted for the unusually high proportion of case reports of mucormycosis associated with COVID-19 coming from the Indian sub-continent. Suffice it to say that this is still under ongoing epidemiological review. Another drug increasingly used in COVID pneumonia is tocilizumab, which is also linked to an increased risk of secondary infection [14]. Though to our knowledge, no report or study has thus far linked it with mucormycosis.\n\nCOVID 19 infection has also unmasked many underlying undiagnosed immunocompromising conditions like diabetes mellitus and leukemia [15].\n\nAs our knowledge about the biology of COVID-19 and its clinical correlates/therapeutics increase, other explanation for the association between COVID 19 infection and mucormycosis may emerge, but for now, it could be either due to COVID treatment (direct effect or by inducing hyperglycemia and DKA) and/or due to the underline immunocompromising conditions that have been unmasked by the COVID 19. Patients with acute proptosis, an increased intraocular pressure, rapid visual loss, ophthalmoplegia, fixed dilated pupil, or afferent pupillary defect should be suspected of an undiagnosed mucormycosis [16]. Mucormycosis carries a high mortality rate, making early diagnosis and prompt treatment a sine-qua-non to prevent catastrophic outcomes [17].\n\nOur patient appears to have all the risk factors thus far established to predispose to mucormycosis, including COVID 19 pneumonia, uncontrolled diabetes mellitus, receiving steroids for COVID 19, and the history of transnasal transsphenoidal surgery.\n\nConclusion\n\nA wide range of secondary infections and even opportunistic infections can complicate COVID 19 course. Early diagnosis and prompt treatment are essential to improve the outcome in mucormycosis, so high clinical suspicion is required from physicians and ophthalmologists involved in the care of COVID patients (especially those with rhino-orbital-cerebral lesions).\n\nFunding\n\nOpen access funding provided by the Qatar National Library.\n\nEthics approval and consent to participate\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. This case report was approved by Hamad Medical Corporation's Medical Research Center under number MRC-04–21–606.\n\nCRediT authorship contribution statement\n\nMohammed A. Alamin: Writing, Editing, Literature review, Correspondence, Final approval. Mohammed Abdulgayoom: Writing, Editing, Literature review, Final approval. Sushil Niraula: Editing, Final approval. Elabbas Abdelmahmuod: Editing, Final approval. Ashraf O. Ahmed: Imaging interpretation, Reporting, Final approval. Mohammed Danjuma: Editing, Final approval, Supervisor.\n\nAcknowledgments\n\nOpen access funding provided by the Qatar National Library.\n\nDisclosure Statement\n\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Mekonnen Z.K. Ashraf D.C. Jankowski T. Grob S.R. Vagefi M.R. Kersten R.C. Acute invasive Rhino-orbital mucormycosis in a patient with COVID-19-associated acute respiratory distress syndrome Ophthal Plast Reconstr Surg 2 2021 40 42 10.1097/IOP.0000000000001889\n2 Placik D.A. Taylor W.L. Wnuk N.M. Bronchopleural fistula development in the setting of novel therapies for acute respiratory distress syndrome in SARS-CoV-2 pneumonia Radio Case Rep 4 2021 2378 2381 10.1016/j.radcr.2020.09.026\n3 Mehta S. Pandey A. Rhino-orbital mucormycosis associated with COVID-19 Cureus 12 2020 10726\n4 Cornely O.A. Alastruey-Izquierdo A. Arenz D. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium The Lancet Infectious Diseases Vol. 19 2019 Lancet Publishing Group, 405 10.1016/S1473-3099(19)30312-3\n5 WHO Rapid Evidence Appraisal for COVID- Therapies (REACT) Working G. Sterne J. Murthy S. Diaz J.V. Slutsky A.S. Villar J. Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID- 19: a meta-analysis JAMA - J Am Med Assoc 324 2020 1330 1341 10.1001/jama.2020.17023\n6 Koehler P. Bassetti M. Chakrabarti A. Chen S.C.A. Colombo A.L. Hoenigl M. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance The. Lancet Infectious Diseases 21 2021 Lancet Publishing Group, e149 e162 10.1016/S1473-3099(20)30847-1\n7 Pasero D. Sanna S. Liperi C. Piredda D. Branca G.P. Casadio L. A challenging complication following SARS-CoV-2 infection: a case of pulmonary mucormycosis Infection 2020 10.1007/s15010-020-01561-x\n8 Prakash H. Chakrabarti A. Global epidemiology of mucormycosis J Fungi 5 2019 26\n9 Roden MM, Zaoutis TE, Buchanan WL, Knudsen T.A., Sarkisova T.A., Schaufele R.L., Sein M., Sein T., Chiou C.C., Chu J.H., Kontoyiannis D.P., Walsh T.J.: Epidemiology and outcome of Zygomycosis: A review of 929 reported cases. Vol. 41, Clinical Infectious Diseases. Clin Infect Dis. 20052021, 4:634–653. 10.1086/432579.\n10 Butler F.K. Jr. Hagan C. Murphy-Lavoie H. Hyperbaric oxygen therapy and the eye Undersea Hyperb Med 35 2008 333 387 19024664\n11 Apicella M. Campopiano M.C. Mantuano M. Mazoni L. Coppelli A. Del Prato S. COVID-19 in people with diabetes: understanding the reasons for worse outcomes The lancet. Diabetes & endocrinology Vol. 8 2020 Lancet Publishing Group, 782 792 10.1016/S2213-8587(20)30238-2\n12 Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19 Am J Emerg Med 42 42 2021 264 265 10.1016/j.ajem.2020.09.032\n13 Monte Junior E. Santos M. Ribeiro I.B. Luz G.O. Baba E.R. Hirsch B.S. Rare and fatal gastrointestinal mucormycosis (Zygomycosis) in a COVID-19 patient: a case report Clin Endosc 9 2020 746 749 10.5946/ce.2020.180\n14 Garg D. Muthu V. Sehgal I.S. Ramachandran R. Kaur H. Bhalla A. Coronavirus disease (Covid-19) associated mucormycosis (CAM): case report and systematic review of literature Mycopathologia 2 2021 289 298 10.1007/s11046-021-00528-2\n15 Kimmig L.M. Wu D. Gold M. Pettit N.N. Pitrak D. Mueller J. IL-6 inhibition in critically Ill COVID-19 patients is associated with increased secondary infections Front Med 7 2020 583897 10.3389/fmed.2020.583897\n16 Kwon-Chung KJ Taxonomyof fungi causing mucormycosis and entomophthoramycosis (zygomycosis) andnomenclature of the disease: Molecular mycologic perspectives Clin Infect Dis 54 2012 S8 S15 10.1093/cid/cir864 22247451\n17 Kauffman CA Malani AN Zygomycosis: an emerging fungal infection with new options for management Curr Infect Dis Rep 2007 435 440 17999877\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2214-2509",
"issue": "26()",
"journal": "IDCases",
"keywords": "Black Fungus; COVID-19; Mucormycosis; Rhizopus; SARS-CoV2",
"medline_ta": "IDCases",
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"nlm_unique_id": "101634540",
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"title": "Rhino-orbital Mucormycosis as a complication of severe COVID-19 pneumonia.",
"title_normalized": "rhino orbital mucormycosis as a complication of severe covid 19 pneumonia"
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"abstract": "Guidelines state that verapamil is contraindicated in infants. This is based on reports of cardiovascular collapse and even death after rapid intravenous administration of verapamil in infants with supraventricular tachycardia (SVT). We wish to challenge this contraindication for the specific indication of verapamil sensitive ventricular tachycardia (VSVT) in infants.\n\n\n\nRetrospective case series and critical literature review.\n\n\n\nHospitals within New Zealand.\n\n\n\nWe present a series of three infants/young children with VSVT or 'fascicular VT'.\n\n\n\nThree children aged between 8 days and 2 years presented with tachycardia 200-220 beats per minute with right bundle brunch block and superior axis. Adenosine failed to cardiovert and specialist review diagnosed VSVT. There were no features of cardiovascular shock. Verapamil was given as a slow infusion over 10-30 min (rather than as a push) and each successfully cardioverted without incident. Critical review of the literature reveals that cardiovascular collapses were associated with a rapid intravenous push in cardiovascularly compromised infants and/or infants given other long-acting antiarrhythmics prior to verapamil.\n\n\n\nVerapamil is specifically indicated for the treatment of fascicular VT, and for this indication should be used in infancy, as well as in older children, as first-line treatment or after failure of adenosine raises suspicion of the diagnosis. We outline how to distinguish this tachycardia from SVT and propose a strategy for the safe intravenous slow infusion of verapamil in children, noting that extreme caution is necessary with pre-existing ventricular dysfunction.",
"affiliations": "Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand.;Department of Paediatrics, Christchurch Hospital, Christchurch, New Zealand.;Department of Paediatrics, Waikato Hospital, Hamilton, New Zealand.;Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand.;Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand.",
"authors": "Kehr|Jascha|J|;Binfield|Alex|A|;Maxwell|Fraser|F|;Hornung|Tim|T|;Skinner|Jonathan R|JR|0000-0002-3653-0412",
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"doi": "10.1136/archdischild-2018-315617",
"fulltext": "\n==== Front\nArch Dis ChildArch. Dis. ChildarchdischildadcArchives of Disease in Childhood0003-98881468-2044BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 31005896archdischild-2018-31561710.1136/archdischild-2018-315617Original Article1506Fascicular tachycardia in infancy and the use of verapamil: a case series and literature review Kehr Jascha 1Binfield Alex 2Maxwell Fraser 3Hornung Tim 1http://orcid.org/0000-0002-3653-0412Skinner Jonathan R 14\n1 \nGreen Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Auckland, New Zealand\n\n2 \nDepartment of Paediatrics, Christchurch Hospital, Christchurch, New Zealand\n\n3 \nDepartment of Paediatrics, Waikato Hospital, Hamilton, New Zealand\n\n4 \nDepartment of Child Health, University of Auckland, Auckland, New Zealand\nCorrespondence to Dr Jonathan R Skinner, Green Lane Paediatric and Congenital Cardiac Services, Starship Childens Hospital, Auckland 1142, New Zealand; jskinner@adhb.govt.nz8 2019 20 4 2019 104 8 789 792 02 7 2018 26 2 2019 14 3 2019 © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2019This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Objective\nGuidelines state that verapamil is contraindicated in infants. This is based on reports of cardiovascular collapse and even death after rapid intravenous administration of verapamil in infants with supraventricular tachycardia (SVT). We wish to challenge this contraindication for the specific indication of verapamil sensitive ventricular tachycardia (VSVT) in infants.\n\nDesign\nRetrospective case series and critical literature review.\n\nSetting\nHospitals within New Zealand.\n\nPatients\nWe present a series of three infants/young children with VSVT or ‘fascicular VT’.\n\nResults\nThree children aged between 8 days and 2 years presented with tachycardia 200–220 beats per minute with right bundle brunch block and superior axis. Adenosine failed to cardiovert and specialist review diagnosed VSVT. There were no features of cardiovascular shock. Verapamil was given as a slow infusion over 10–30 min (rather than as a push) and each successfully cardioverted without incident. Critical review of the literature reveals that cardiovascular collapses were associated with a rapid intravenous push in cardiovascularly compromised infants and/or infants given other long-acting antiarrhythmics prior to verapamil.\n\nConclusions\nVerapamil is specifically indicated for the treatment of fascicular VT, and for this indication should be used in infancy, as well as in older children, as first-line treatment or after failure of adenosine raises suspicion of the diagnosis. We outline how to distinguish this tachycardia from SVT and propose a strategy for the safe intravenous slow infusion of verapamil in children, noting that extreme caution is necessary with pre-existing ventricular dysfunction.\n\narrhythmiaventricular tachycardiaECGinfantcalcium channel blockersafetycontraindicationspecial-featureunlocked\n==== Body\nWhat is already known on this topic?\nFascicular ventricular tachycardia (VT) is also known as verapamil-sensitive VT because it is uniquely sensitive to verapamil, and will not be cardioverted by other antiarrhythmics.\n\nFeatures of fascicular VT are: right bundle branch block, superior or right axis deviation, ventriculoatrial dissociation (sometimes) with fusion or capture beats.\n\nGuidelines state that intravenous verapamil is contraindicated in infants due to fear of cardiovascular collapse with a rapid intravenous push.\n\nWhat this study adds?\nThis report reminds us that fascicular VT is different from supraventricular tachycardia and requires different management irrespective of age.\n\nVerapamil is effective in terminating fascicular VT and can be used safely in young children, including infants with preserved ventricular function when infused slowly with careful monitoring—this is particularly important if tachycardia has been ongoing for a long time and there is suspicion of depressed myocardial function—we propose infusion of 0.1 mg/kg over at least 10 min.\n\nCalcium should be available at the bedside and concomitant use of atrioventricular blocking agents like beta blockers or digoxin should be avoided.\n\nIntroduction\nIt is generally accepted that intravenous administration of the calcium antagonist verapamil for the treatment of tachyarrhythmias is contraindicated in children under 1 year of age due to a proven risk of haemodynamic collapse and even death in young children. Verapamil is a negative inotrope, and the myocardium of very young children, in particular neonates, may be especially sensitive to changes in intracellular calcium concentrations and the blockade of calcium channels based on knowledge from animal studies.1–3 The first reports of cardiovascular collapse after intravenous administration of verapamil in young infants were published in the mid-1980s. Epstein et al reported three cases of cardiovascular collapse in infants aged 2–6 weeks.4 Based on this case series and a handful of other case reports and small series,5–7 best practice guidelines now state that intravenous verapamil is contraindicated in infants for the treatment of supraventricular tachycardia (SVT) and fascicular ventricular tachycardia (VT).8 With the arrival of adenosine, verapamil disappeared from use in this age group. Nevertheless, calcium channel blockers are uniquely effective as the treatment of fascicular VT, to the point that this arrhythmia is also known as ‘verapamil sensitive ventricular tachycardia’. It typically occurs in children and young adults without structural heart disease.9–14 The underlying mechanism is believed to be a re-entry tachycardia involving the Purkinje fibres of the fascicles—typically the left posterior fascicle of the left bundle branch but also has features of an automatic tachycardia, can be incessant, unresponsive to direct current cardioversion and may lead to cardiomyopathy.\n\nFascicular VT has been classified into three types:Left posterior fascicular VT with right bundle branch block (RBBB) and superior axis deviation.\n\nLeft anterior fascicular VT with RBBB and right axis deviation.\n\nHigh septal VT with normal QRS duration and normal frontal axis plane.\n\n\n\n\nLeft posterior fascicular VT makes up about 90% of cases, followed by left anterior fascicular VT. High septal VT has not been described in young children.\n\nFascicular VT in young children is much less common than SVT but its detection is important because it does not respond to adenosine, nor amiodarone. Intravenous verapamil terminates the tachycardia in 93% of cases in children.15 The reported cases of collapse in infants were associated with a rapid intravenous push of verapamil. Our experience is that a slower infusion is effective and safe in infants for this specific indication, when it is clear there is no circulatory compromise prior and no more than mild left ventricular (LV) dysfunction. We present three illustrative cases, review the literature and suggest a strategy for the safe treatment of such cases.\n\nCase presentation\nResearch Governance Committee approval for this report was obtained from Auckland and Waikato District Health Boards, along with consent from each family.\n\nCase 1\nAn infant presented in the first 3 months of life to the emergency department with 4 days of increased work of breathing, 2 days of cough and on presentation a tachycardia of 220 beats per minute (bpm) with a superior axis and RBBB presumed to be SVT. Ice dunk and four doses of intravenous adenosine to a maximum dose of 500 mcg/kg were unsuccessful. The remote on-call paediatric cardiologist diagnosed verapamil sensitive or fascicular VT from the 12-lead ECG (figure 1A).\n\nFigure 1 (A) ECG of patient 1 on arrival. This shows a tachycardia at about 220 bpm with a superior axis and right bundle branch block. There are no capture beats but ventriculoatrial (VA) dissociation is visible, proving this to be ventricular tachycardia (VT) and not supraventricular tachycardia (SVT) with aberrancy. Superior axis and right bundle branch block (RBBB) make this the most common form of fascicular VT; left posterior fascicular VT. (B) ECG after conversion to sinus rhythm with intravenous verapamil. This shows a normal axis and no fascicular block. This indicates involvement of the posterior fascicle as retrograde limb in the tachycardia circuit.\n\nThe patient remained in the emergency department and verapamil 0.1 mg/kg was infused over 20 min in presence of the neonatal intensive care and emergency department consultants with a resuscitation dose of calcium drawn up at the bedside. After a few minutes the tachycardia reverted to sinus rhythm (figure 1B) and all vital signs including blood pressure (BP) remained stable. After overnight observation in the intensive care unit (ICU), the patient was started on oral verapamil the following day and discharged home. An echocardiogram prior to discharge demonstrated a structurally normal heart with normal systolic function.\n\nCase 2\nAn 8-day-old term baby presented to hospital for a planned review for an antenatally diagnosed muscular ventricular septal defect. The infant was found to be tachycardic (200 bpm) and tachypnoeic at the time of the echocardiogram. The mother reported that tachypnoea began 48 hours prior with increased sweatiness for 24 hours though the baby was still breast feeding satisfactorily. On admission to the neonatal ICU clinical signs and chest X-ray changes were consistent with mild cardiac failure but preserved peripheral perfusion. The echocardiogram showed a small muscular ventricular septal defect and mildly impaired LV systolic function. A dose of furosemide and empiric antibacterial treatment was given. The ECG demonstrated a broad complex tachycardia at a rate of 195 bpm with a superior axis and RBBB. Intravenous adenosine was ineffective four times to a maximum dose of 250 mcg/kg. The on-call paediatric cardiologist reviewed the 12-lead ECG remotely and diagnosed of fascicular VT. A resuscitation dose of calcium gluconate was drawn up and available at the bedside during the verapamil infusions but was not required. A dose of 0.05 mg/kg of intravenous verapamil infused over 30 min did not revert the tachycardia so a second dose of 0.05 mg/kg was given over 30 min and the tachycardia reverted to sinus rhythm 15 min into the infusion. Oral verapamil (1 mg/kg/dose three times a day) was started 4 hours after the end of the infusion. Two further episodes of VT within the next 12 hours reverted with infusions of the same dose of verapamil. The BP remained stable throughout.\n\nCase 3\nA 2-year-old child was referred to a hospital by the general practitioner for a tachycardia and a short history of lethargy, a single vomit and the mother having noticed a fast heartbeat. The heart rate was 199/min on presentation and the respiratory rate was 77/min. The ECG was presumed to show SVT and ice was administered to the patient’s forehead followed by increasing doses of intravenous boluses of adenosine with no effect. The ECGs (figure 2A,B) were reviewed remotely by the on-call paediatric cardiologist and fascicular VT was diagnosed. An echocardiogram demonstrated normal cardiac size and systolic function. An infusion of 0.2 mg/kg of verapamil was started in the resuscitation bay of the emergency department (with calcium available), but was stopped after 0.1 mg/kg after cardioversion to sinus rhythm. BP was stable. A further 0.1 mg/kg of verapamil was infused slowly for a recurrence of the tachycardia 3.5 hours later. The tachycardia reverted within 2 min. For several recurrences of fascicular VT overnight a total of 0.2 mg/kg of verapamil was given as fractionated slow infusions of 1.66 mcg/kg/min (0.1 mg/kg/hour). The oral maintenance dose was increased to 2 mg/kg three times a day and the child was discharged home after a few days of observation without recurrence of tachycardia. Further recurrences of tachycardia at 5 months and 1 year were successfully treated with slow intravenous verapamil infusions followed by an increase of the regular oral dose.\n\nFigure 2 (A) ECG on presentation in the 2-year-old child. It demonstrates tachycardia at 194 bpm with right bundle branch block (RBBB) and superior axis deviation. (B) Three-lead rhythm strip from case 3: this demonstrates ventriculoatrial (VA) dissociation and capture beats proving that this is ventricular tachycardia. Green arrows mark P waves and red arrows mark capture beats.\n\nDiscussion\nThis case series of more than nine intravenous infusions of verapamil in three small children, including two infants, shows that verapamil can be used safely and effectively for the treatment of fascicular VT in haemodynamically stable young children and infants. The cases demonstrate that if intravenous verapamil is given slowly the feared side effect of haemodynamic instability and atrioventricular (AV) block may not occur. Given the fact that other treatments are ineffective for fascicular VT, the opinion that the use of intravenous verapamil is contraindicated in infants needs to be challenged for this type of tachycardia.\n\nThe recommendation to avoid verapamil in young children is based on very limited evidence but is widely accepted. In the current European Heart Rhythm Association/Association for European Paediatric and Congenital Cardiology arrhythmia working group consensus statement on the management of arrhythmias in the paediatric age group8 verapamil is listed as contraindicated in infants under 1 year of age for the treatment of SVT and fascicular VT, citing the article of Porter et al from 198316 in which two cases of junctional ectopic tachycardia treated with intravenous verapamil responded with hypotension requiring resuscitation with calcium. In that original article intravenous verapamil for treatment of SVT was recommended in all age groups nevertheless. In 2013, Lapage et al published a review titled ‘Verapamil in infants: An exaggerated fear?’ in which they evaluate the limited evidence that has led to the acceptance of infancy as a contraindication for intravenous verapamil.17\n\n\nIn most reported cases of cardiovascular collapse after intravenous verapamil additional risk factors for compromise can clearly be identified, typically long duration of tachycardia with signs of poor cardiac output or congestive heart failure, age <6 weeks, concomitant sepsis or myocarditis, pretreatment with AV nodal blocking agents such as digoxin or beta blockers or inadvertent administration of an inappropriately high dose of verapamil. There is only one report of a child older than 6 weeks who had a complication with an adequate dose of verapamil; this infant also had myocarditis.7 Given the availability of adenosine, it is sensible to avoid intravenous verapamil in infants with SVT, especially those with pre-existing haemodynamic compromise or sepsis. However, Roguin et al reported successful verapamil treatment of SVT in two infants aged 20 days and 6 weeks with the administration of calcium gluconate prior to giving intravenous verapamil. They reported haemodynamic stability and no interference with the antiarrhythmic effect of verapamil.18\n\n\nThere are several reports of successful conversion of fascicular VT in young infants with intravenous verapamil.9–12 19 It is interesting to note that in none of these case reports verapamil was used as a first-line agent. All infants were pretreated either with adenosine, a beta blocker, amiodarone, procainamide, lidocaine or a combination of the above and/or overdrive pacing or synchronised cardioversion. No adverse effects of verapamil were reported. A cardioversion rate for intravenous verapamil of 93% was reported in the largest cohort of paediatric patients with fascicular VT to date.15 No adverse events of verapamil were reported though the study focused on success rates of medical and catheter-based treatments and not adverse events. Moran and Colan reported the haemodynamic effects of intravenous verapamil in a prospective study of children under the age of 2 years with hypertrophic cardiomyopathy.20 Verapamil was administered to 22 patients and invasive haemodynamic measurements were obtained in the cardiac catheterisation laboratory. In 21 patients (mean age 5.8 months with a range of 0.3–23 months) they could document a negative inotropic effect with a fall in cardiac index from 4.6±1.2 to 4.1±0.9 L/min/m2 and a fall in BP by 8 points from a mean of 88±16 to 82±14 mm Hg and a reduction in the left ventricular outflow tract gradient. The acute infusion of 0.1 mg/kg followed by 0.007 mg/kg/min was tolerated by all. One patient who was in the ICU for severe congestive heart failure and labile BP experienced increasing hypotension during the initial infusion but a later trial the following day was well tolerated without adverse events. In most reports the usual verapamil dose administered to infants with SVT ranged from 0.1 to 0.2 mg/kg with higher doses of 0.3 mg/kg described in older children. Current recommendations for intravenous verapamil state a dose of 0.1–0.2 mg/kg for children.21 22\n\n\nBased on the available literature, and our own experience, we believe that intravenous verapamil should not be regarded as absolutely contraindicated in infants younger than 1 or 2 years of age in the treatment of fascicular VT. Young infants <6 weeks of age or infants with significant myocardial dysfunction are at increased risk of adverse events during administration of intravenous verapamil and extreme caution is required in this group. We propose that for young infants verapamil should be administered by slow intravenous infusion at a dose of 0.1 mg/kg over at least 10 min, repeated to a total of 0.2 mg/kg, rather than by intravenous bolus, and that calcium be available at the bedside. Close monitoring in an emergency room or intensive care setting is essential. Careful clinical examination of the infant, blood gas analysis and echocardiographic assessment should be employed prior to drug administration, and if abnormal, concurrent inotropic support, and transfer to a tertiary centre with potential extracorporeal membrane oxygenation (ECMO) backup should be considered in these cases.\n\nConclusion\nFascicular VT is rare in infants but needs to be differentiated from SVT because of the treatment implications. If adenosine is not effective in reverting presumed SVT, this diagnosis should be considered.\n\nIdentifying features of fascicular VT are RBBB, superior or right axis deviation, ventriculoatrial dissociation (though not always present) and fusion or capture beats.\n\nIntravenous verapamil can be used safely as first-line treatment for fascicular VT in young children with preserved ventricular function. It should be given as a slow infusion of 0.1 mg/kg/dose over at least 10 min with close monitoring and calcium should be available for resuscitation. If there are features of low cardiac output or ventricular function is more than mildly impaired on echocardiography, transfer to a tertiary care facility is recommended, where circulatory support (including ECMO) should be immediately available.\n\nThe authors gratefully acknowledge Charlene Nell for assistance with manuscript preparation from the Department of Cardiovascular Services, Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand\n\nContributors: JK and JS conceptualised this article and drafted the initial manuscript. AB, FM and TH identified the cases presented, supplied the relevant clinical information and reviewed the article for accuracy. They also revised it critically for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nEthics approval: The Research Governance Committee approval for this report was obtained from Auckland and Waikato District Health Boards.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nPatient consent for publication: Next of kin consent obtained.\n==== Refs\nReferences\n1 \nWetzel GT , Chen F , Klitzner TS \nL- and T-type calcium channels in acutely isolated neonatal and adult cardiac myocytes . Pediatr Res \n1991 ;30 :89 –94 . 10.1203/00006450-199107000-00018 \n1653937 \n2 \nWetzel GT , Klitzner TS \nDevelopmental cardiac electrophysiology recent advances in cellular physiology . Cardiovasc Res \n1996 ;31 (Spec No ):E52 –60 . 10.1016/S0008-6363(95)00158-1 \n8681346 \n3 \nGibson R , Driscoll D , Gillette P , et al \nThe comparative electrophysiologic and hemodynamic effects of verapamil in puppies and adult dogs . Dev Pharmacol Ther \n1981 ;2 :104 –16 . 10.1159/000481036 \n7472105 \n4 \nEpstein ML , Kiel EA , Victorica BE \nCardiac decompensation following verapamil therapy in infants with supraventricular tachycardia . Pediatrics \n1985 ;75 :737 –40 .3982906 \n5 \nRadford D \nSide effects of verapamil in infants . Arch Dis Child \n1983 ;58 :465 –6 . 10.1136/adc.58.6.465 \n6859944 \n6 \nKirk CR , Gibbs JL , Thomas R , et al \nCardiovascular collapse after verapamil in supraventricular tachycardia . Arch Dis Child \n1987 ;62 :1265 –6 . 10.1136/adc.62.12.1265 \n3435161 \n7 \nGarland JS , Berens RJ , Losek JD , et al \nAn infant fatality following verapamil therapy for supraventricular tachycardia: cardiovascular collapse following intravenous verapamil . Pediatr Emerg Care \n1985 ;1 :198 –200 . 10.1097/00006565-198512000-00007 \n3842166 \n8 \nBrugada J , Blom N , Sarquella-Brugada G , et al \nPharmacological and non-pharmacological therapy for arrhythmias in the pediatric population: EHRA and AEPC-Arrhythmia Working Group joint consensus statement . Europace \n2013 ;15 :1337 –82 . 10.1093/europace/eut082 \n23851511 \n9 \nHiremath G , Li W , Foltz R , et al \nVerapamil-sensitive idiopathic left ventricular tachycardia in a 6-month-old: unique considerations in diagnosis and management in an infant . Pediatr Emerg Care \n2015 ;31 :50 –3 . 10.1097/PEC.0000000000000307 \n25526021 \n10 \nSnyder C , Bishara J , Darling R , et al \nVerapamil-sensitive ventricular tachycardia in an infant . Congenit Heart Dis \n2006 ;1 :124 –6 . 10.1111/j.1747-0803.2006.00020.x \n18377557 \n11 \nHuang JH , Saharan S , McCammond A , et al \nBelhassen tachycardia in a 19-month-old child . J Pediatr \n2015 ;166 :200 –200.e1 . 10.1016/j.jpeds.2014.08.038 \n25304921 \n12 \nWang JD , Fu YC , Jan SL , et al \nVerapamil sensitive idiopathic ventricular tachycardia in an infant . Jpn Heart J \n2003 ;44 :667 –71 . 10.1536/jhj.44.667 \n14587648 \n13 \nBelhassen B , Rotmensch HH , Laniado S \nResponse of recurrent sustained ventricular tachycardia to verapamil . Br Heart J \n1981 ;46 :679 –82 . 10.1136/hrt.46.6.679 \n7317238 \n14 \nWard DE , Nathan AW , Camm AJ \nFascicular tachycardia sensitive to calcium antagonists . Eur Heart J \n1984 ;5 :896 –905 . 10.1093/oxfordjournals.eurheartj.a061589 \n6529940 \n15 \nCollins KK , Schaffer MS , Liberman L , et al \nFascicular and nonfascicular left ventricular tachycardias in the young: an international multicenter study . J Cardiovasc Electrophysiol \n2013 ;24 :640 –8 . 10.1111/jce.12105 \n23437865 \n16 \nPorter CJ , Garson A , Gillette PC \nVerapamil: an effective calcium blocking agent for pediatric patients . Pediatrics \n1983 ;71 :748 –55 .6340050 \n17 \nLapage MJ , Bradley DJ , Dick M \nVerapamil in infants: an exaggerated fear? \nPediatr Cardiol \n2013 ;34 :1532 –4 . 10.1007/s00246-013-0739-8 \n23800976 \n18 \nRoguin N , Shapir Y , Blazer S , et al \nThe use of calcium gluconate prior to verapamil in infants with paroxysmal supraventricular tachycardia . Clin Cardiol \n1984 ;7 :613 –6 . 10.1002/clc.4960071112 \n6499292 \n19 \nDhala A , Lewis DA , Garland J , et al \nVerapamil sensitive incessant ventricular tachycardia in the newborn . Pacing Clin Electrophysiol \n1996 ;19 :1652 –4 . 10.1111/j.1540-8159.1996.tb03195.x \n8946465 \n20 \nMoran AM , Colan SD \nVerapamil therapy in infants with hypertrophic cardiomyopathy . Cardiol Young \n1998 ;8 :310 –9 . 10.1017/S1047951100006818 \n9731645 \n21 \nDrugs.com . https://www.drugs.com/dosage/verapamil.html#Usual_Pediatric_Dose_for_Supraventricular_Tachycardia.\n22 \nShann F \nDrug doses . 17 edn \nVictoria, Australia : JR Medical Books , 2017 :128 .\n\n",
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"abstract": "Diabetic ketoacidosis (DKA) is characterized by excessive production of organic acids leading to a low blood pH. Rarely, because of other complicating factors blood pH may be in the alkalemic range and the term diabetic ketoalkalosis has been coined to describe this condition. So far, less than 30 such cases have been reported in the literature. We report a 34-year-old woman who received methylprednisolone pulse therapy for the treatment of pancreas transplant rejection. Thereafter, she developed vomiting and abdominal pain. Her laboratory data showed high blood sugar, hypokalemia, alkalemic pH, elevated plasma anion gap, and significant ketonemia. She responded well to the treatment of DKA. It was concluded that an alkalemic pH does not rule out the presence of ongoing DKA. In suspected cases, changes in plasma anion gap and bicarbonate and the presence of ketonemia should be noted.",
"affiliations": "Department of Internal Medicine, Endocrinology and Metabolism Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran;",
"authors": "Soveid|Mahmood|M|;Ezzatzadegan Jahromi|Shahrokh|S|",
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"title": "Diabetic ketoalkalosis after steroid pulse therapy in a patient with pancreas transplant rejection.",
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"abstract": "Due to the unique side-effect profile of immune checkpoint inhibitors (ICIs), groups of patients deemed to be at high risk of complications were excluded from trials that proved the efficacy and safety of these agents in patients with various malignancies. Among these excluded patients were those with prior solid organ transplantation, chronic viral infections and pre-existing autoimmune diseases including paraneoplastic syndromes. We present follow-up on a patient from a previously published case report with an orthotopic heart transplantation who was treated with both cytotoxic T-lymphocyte antigen 4 and PD-1 inhibition safely, without organ rejection. Additionally, we describe the case of a patient with a cardiac allograft who also did not experience organ rejection after treatment with pembrolizumab. Through smaller trials, retrospective analyses, case series and individual case reports, we are accumulating initial data on how these agents are tolerated by the aforementioned groups. Our survey of the literature has found more evidence of organ transplant rejection in patients treated with PD-1 inhibitors than those treated with inhibitors of cytotoxic T-lymphocyte antigen 4. Patients with chronic viral infections, especially hepatitis C, seem to have little to no risk of treatment-related increase in serum RNA levels. The literature contains few documented cases of devastating exacerbations of pre-existing autoimmune disease during treatment with ICIs, and flares seem to be easily controlled by immunosuppression in the vast majority of cases. Last, several cases allude to a promising role for disease-specific antibodies and other serum biomarkers in identifying patients at high risk of developing certain immune-related adverse events, detecting subclinical immune-related adverse event onset, and monitoring treatment response to immunosuppressive therapy in patients treated with ICIs. Though these excluded populations have not been well studied in randomized placebo-controlled trials, we may be able to learn and derive hypotheses from the existing observational data in the literature.",
"affiliations": "Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.;Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.;Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.",
"authors": "Grant|Michael J|MJ|;DeVito|Nicholas|N|;Salama|April K S|AKS|",
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"doi": "10.2217/mmt-2018-0004",
"fulltext": "\n==== Front\nMelanoma ManagMelanoma ManagMMTMelanoma Management2045-08852045-0893Future Medicine Ltd London, UK 10.2217/mmt-2018-0004ReviewCheckpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high-risk populations Grant, DeVito & SalamaCheckpoint inhibitor use in high-risk populationsGrant Michael J *\n1\nDeVito Nicholas \n2\nSalama April K S \n2\n\n1 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA\n2 Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA*Author for correspondence: Tel.: +1 919 681 9509; Michael.grant@duke.edu12 2018 26 10 2018 5 4 MMT1015 2 2018 03 8 2018 26 10 2018 © 2018 Micheal J Grant2018This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported LicenseDue to the unique side-effect profile of immune checkpoint inhibitors (ICIs), groups of patients deemed to be at high risk of complications were excluded from trials that proved the efficacy and safety of these agents in patients with various malignancies. Among these excluded patients were those with prior solid organ transplantation, chronic viral infections and pre-existing autoimmune diseases including paraneoplastic syndromes. We present follow-up on a patient from a previously published case report with an orthotopic heart transplantation who was treated with both cytotoxic T-lymphocyte antigen 4 and PD-1 inhibition safely, without organ rejection. Additionally, we describe the case of a patient with a cardiac allograft who also did not experience organ rejection after treatment with pembrolizumab. Through smaller trials, retrospective analyses, case series and individual case reports, we are accumulating initial data on how these agents are tolerated by the aforementioned groups. Our survey of the literature has found more evidence of organ transplant rejection in patients treated with PD-1 inhibitors than those treated with inhibitors of cytotoxic T-lymphocyte antigen 4. Patients with chronic viral infections, especially hepatitis C, seem to have little to no risk of treatment-related increase in serum RNA levels. The literature contains few documented cases of devastating exacerbations of pre-existing autoimmune disease during treatment with ICIs, and flares seem to be easily controlled by immunosuppression in the vast majority of cases. Last, several cases allude to a promising role for disease-specific antibodies and other serum biomarkers in identifying patients at high risk of developing certain immune-related adverse events, detecting subclinical immune-related adverse event onset, and monitoring treatment response to immunosuppressive therapy in patients treated with ICIs. Though these excluded populations have not been well studied in randomized placebo-controlled trials, we may be able to learn and derive hypotheses from the existing observational data in the literature.\n\nKeywords: \nautoimmunechallengingcheckpoint inhibitorCTLA-4hepatitis B virushepatitis C virushuman immunodeficiency virusPD-1transplant\n==== Body\nPractice points\nThree groups that were excluded or under-represented in major clinical trials involving immune checkpoint inhibitors were patients with autoimmune disease, solid and hematopoietic stem cell transplants, and chronic viral infections.\n\nRetrospective studies on patients with autoimmune disease treated with immune checkpoint inhibitors show that about 50% of patients will experience either a flare of their pre-existing autoimmune disease or immune-related adverse event that is grade 3 or higher.\n\nMost autoimmune disease flares were well-controlled with corticosteroids and rates of checkpoint inhibitor discontinuation and mortality rates were very low in the studies.\n\nCheckpoint inhibitor therapy seems to be associated with a decrease or at least a stable suppression of viral load/viral antigens in patients with chronic hepatitis B virus and hepatitis C virus infection and this may be related to abrogation of an ‘exhaustive’ T-cell phenotype associated with these infections.\n\nEmerging data on patients with HIV infection and malignancy allude to a promising safety profile in these patients as well as the possible beneficial effect of diminishing HIV reservoirs.\n\nIn the solid organ transplant population, inhibitors of PD-1 and sequential treatment with PD-1 and CTLA-4 inhibitors seem to be more prone to cause rejection.\n\nCase reports support the use of sirolimus for immunosuppression in transplant patients with malignancy (usually in conjunction with low-dose prednisone) and this is further supported by literature on the drug's mechanistic properties.\n\nPatients from all populations discussed in this review should be closely monitored for both disease- and immune checkpoint inhibitor-specific complications that may arise.\n\nIt will be crucial to involve respective specialists in treating these patients including, but not limited to, neurologists, dermatologists, rheumatologists, infectious disease and transplant physicians among many others. A multidisciplinary approach will be invaluable.\n\nPatients should be made aware of possible, even if rare, complications related to therapy and their respective comorbidities. Treatment should only ensue after proper education, and discussions have taken place.\n\nThere is a need for larger retrospective analyses, prospective cohort studies and randomized controlled trials to study the safety and efficacy of immune checkpoint inhibitor use in these populations.\n\nImmune checkpoint inhibitors, including inhibitors of CTLA-4, PD-1 and the ligand to PD-1 (PD-L1) comprise a class of immunotherapeutic agents that have become widely used in the treatment of several common malignancies. These medications work by inhibiting negative regulators (checkpoints) of T-cell function that exist in both immune and tumor cells to enhance antitumor activity of the immune system [1]. Three immune checkpoint inhibitors that are currently US FDA-approved and indicated in the treatment of metastatic melanoma are ipilimumab (anti-CTLA-4), nivolumab and pembrolizumab (anti-PD-1) [85,86,87]. Ipilimumab has been FDA approved for the treatment of metastatic melanoma, and in the adjuvant setting to reduce the risk of recurrence after melanoma resection [85]. In addition to melanoma, nivolumab has been approved for metastatic non-small-cell lung cancer (NSCLC), renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, and microsatellite instability high or mismatch repair deficient metastatic colorectal cancer [86]. Likewise, pembrolizumab is currently also FDA-approved for recurrent or metastatic head and neck cancer and NSCLC as well as unresectable or metastatic, microsatellite instability high or mismatch repair deficient solid tumors [87]. This class of agents has a unique side-effect profile that is directly related to the immune-modulating mechanisms of action. Side effects are often referred to as ‘immune-related adverse events (irAE)’, which result from blocking negative regulators of immunity. This mimics autoreactivity by inciting inflammatory reactions in certain tissues through unchecked immune activation [1]. Several groups have been excluded or under-represented in major clinical trials that demonstrated the efficacy and safety of these agents. This includes patients with autoimmune disease, solid and hematopoietic stem cell transplantation, chronic viral infections (hepatitis C virus [HCV], hepatitis B virus [HBV], HIV), elderly patients, pregnant patients, patients on immune suppression for other reasons, and patients who have developed irAEs with another immune checkpoint inhibitor (ICI). Thus, when clinicians are presented with a patient who has one of these comorbid conditions, only small trials and case reports can assist in directing management. We previously presented a patient with a history of orthotopic heart transplantation who developed metastatic melanoma and was treated with ipilimumab followed by pembrolizumab [4]. In this report, we present follow-up on this case, a new case of a similar patient, and a review of the literature of ICIs in a subset of less well-studied populations: those with previously diagnosed autoimmune disease, chronic viral infections and prior solid organ transplants. Due to the paucity of clinical trial data in patients with cancer and certain immune-related co-morbidities, further study is needed to evaluate the safety of immune checkpoint blockade in these populations.\n\nCase 1: follow-up\nWe previously reported a 62-year-old male patient, who had undergone orthotopic heart transplantation, was maintained on chronic immunosuppression, and subsequently developed BRAF wild-type, NRAS wild-type metastatic melanoma. He was treated with ipilimumab for four cycles with interval increase in size of a fluorodeoxyglucose-avid left subpectoral lymph node as well as two new pulmonary metastases. A repeat PET/CT scan 2 months later showed further increase in size of several subpectoral nodes as well as the pulmonary nodules. At this time, he was initiated on pembrolizumab. After three cycles of pembrolizumab, he had slight enlargement of existing nodes and interval appearance of one subpectoral lymph node. He also had enlargement of previously documented pulmonary nodules. He received an additional four cycles of pembrolizumab, with continued disease progression. During this time, he had no significant adverse events and no signs or symptoms of organ rejection. He then received two cycles of temozolomide; however, scans again showed progressive disease. Because of concern of local symptoms in the axilla, he received a course of radiation therapy to the right axilla, followed by re-initiation of pembrolizumab for four cycles. Scans continued to demonstrate progression, and his overall performance status continued to decline. He ultimately succumbed to metastatic melanoma with pulmonary involvement nearly 2 years after initiation of pembrolizumab. Throughout his melanoma treatment, he was continued on tacrolimus for chronic immunosuppression with no evidence of transplant rejection or impaired cardiac function. An echocardiogram shortly before the patient expired showed only mild left ventricular dysfunction with ejection fraction of 45% with normal right ventricular function consistent with pre-ipilimumab cardiac function. Ultimately, this patient did not have a clinical response to either ipilimumab or pembrolizumab, but demonstrated tolerance to both agents without evidence of significant allograft compromise.\n\nCase 2: new report\nOur second patient is a 67-year-old male who underwent an orthotopic heart transplant in 2008 for ischemic cardiomyopathy who was maintained on tacrolimus and mycophenolate mofetil with a single episode of acute graft rejection in 2011. At this time he was treated with high-dose steroids and antithymocyte globulin with resolution of rejection and preservation of cardiac transplant function. He presented to our institution in 2016 for evaluation of metastatic melanoma.\n\nThe patient was initially diagnosed with melanoma of his right scalp in October 2013 and underwent a wide excision and sentinel lymph node biopsy with 0/7 nodes positive. Three years later, during routine follow-up for his cardiac transplant, he was found to have a new pulmonary nodule on x-ray. He underwent computed tomography (CT) imaging which showed multiple pulmonary nodules and bilateral hilar lymphadenopathy. A lung biopsy was performed in April 2016 and pathology was consistent with metastatic melanoma. PET/CT imaging showed multifocal metastatic disease with both pulmonary and osseous involvement. He presented to the Duke Melanoma Clinic in May 2016 to discuss treatment options. Mutational analysis revealed the presence of an NRASQ61L mutation. Trametinib was initiated, but treatment was complicated by severe rash and the patient was found to have progressive disease on imaging after one cycle. After discussion of the risks and benefits, the patient was initiated on therapy with pembrolizumab. His previous immunosuppression regimen, tacrolimus and mycophenolate mofetil, was maintained throughout the pembrolizumab treatment course. After three cycles, PET/CT showed evidence of progressive disease. Shortly thereafter, the patient's clinical status deteriorated due to disease progression with mediastinal, hilar and pulmonary metastatic disease leading to admission for postobstructive pneumonia. He was ultimately transitioned to comfort care and passed away approximately 5 months after his presentation with metastatic disease. He did not have evidence of cardiac allograft rejection, and echocardiography demonstrated a normal ejection fraction after two cycles of pembrolizumab.\n\nDiscussion\nCheckpoint inhibitor therapy in patients with autoimmune diseases\nSystemic autoimmune disease\nPatients with malignancy and previously diagnosed autoimmune disease were excluded from trials leading to the approval of CTLA-4 and PD-1-inhibiting agents. The case for excluding these patients was based on the theoretical risk of causing an exacerbation of an existing autoimmune disease by blocking innate negative regulators of immunity [1]. Based on the mechanisms of action of these medications, it is not surprising that the clinical presentation of many irAEs mirrors that of common autoimmune syndromes. Polymorphisms of PD-1 and CTLA-4 are associated with various autoimmune conditions [5]. Autoimmune conditions are common in the general population, but also comprise a significant proportion of patients with malignancy. More than a quarter of patients diagnosed with lung and renal cancer were found to have a comorbid autoimmune condition (25 and 30%, respectively) [6]. There is also observational evidence that patients with chronic inflammation from systemic autoimmune conditions are at risk for subsequent development of malignancy [7]. As immune checkpoint inhibitors continue to define cancer treatment algorithms in an increasing number of tumor types, there will undoubtedly be a substantial number of patients with autoimmune disease and malignancy who are considered for immunotherapy.\n\nAt the time of writing this review, there were three larger retrospective analyses and a number of other case reports/case series describing outcomes of patients with known autoimmunity treated with ICIs for metastatic melanoma. Johnson et al. conducted a retrospective analysis of 30 patients with pre-existing autoimmune conditions diagnosed prior to ipilimumab initiation for advanced melanoma [8]. 43% of these patients were being actively treated for their conditions with immunosuppressive therapy at the time of ipilimumab treatment. 27% experienced exacerbations of their autoimmune condition, 33% experienced grades 3–5 irAEs and 40% experienced either outcome (10% experienced both outcomes). The 33% grade ≥3 irAE rate seen in this study is similar to the overall 20–30% incidence of grades 3–5 irAEs quoted in ipilimumab monotherapy trials conducted on the general population [1,9]. However, it is important to note that exacerbations of pre-existing conditions experienced in this patient group were treated successfully with corticosteroids or infliximab [8]. 20% of the patients who received ipilimumab in this study experienced a partial or complete response. With respect to more high-risk autoimmune conditions, six patients in this review had inflammatory bowel disease, two had multiple sclerosis, two had systemic lupus erythematosus and two had sarcoidosis. In another retrospective analysis, 119 patients treated with pembrolizumab or nivolumab for advanced melanoma were reviewed [10]. 52 of these 119 patients had pre-existing autoimmune diseases and 67 had experienced an irAE from previous ipilimumab treatment. Of the 52 patients with autoimmune diseases at baseline, 29% had active symptoms from these conditions and 38% were on immunosuppressive therapy before receiving nivolumab. 38% of patients had symptoms consistent with a flare of their autoimmune condition, which required immunosuppression. Most flares tended to be recurrence/worsening of symptoms they had previously experienced as opposed to new manifestations of an existing condition (i.e., joint manifestations if they had already experienced this rather than new pulmonary disease in a patient with rheumatoid arthritis). The vast majority (85%) of patients who experienced a flare had symptoms consistent with a mild flare (grades 1–2). Only 4% of patients had to discontinue therapy as a direct result of severity of a flare. Of these 52 patients, 29% experienced conventional irAEs, 10% experienced ≥grade 3 toxicities and 8% discontinued treatment due to irAEs (Table 1). Clinical responses of melanoma to nivolumab therapy occurred in 17 of 52 patients (33%). The patients with flares of autoimmune disease (AD) were equally likely to respond to therapy as patients who did not experience a flare of AD. Of note, the majority of patients in this review had clinically inactive autoimmune disease prior to anti-PD-1 therapy. The authors conclude that although these cohorts may have a selection bias toward patients with less severe autoimmune disease, ICIs can be used cautiously in patients with pre-existing autoimmune disease. A third retrospective analysis by Gutzmer et al. looked at 19 patients with pre-existing autoimmune disease treated with PD-1 inhibitor therapy for advanced melanoma [11]. These patients had a wide variety of autoimmune diseases including Churg–Strauss vasculitis, sarcoidosis, ulcerative colitis and Guillain–Barré syndrome and 64% of patients were on baseline hormone supplementation or immunosuppressive therapy for their conditions. 42% of patients suffered from a flare of their disease and 16% of patients experienced an irAE unrelated to their autoimmune disorder. These numbers are comparable to the retrospective analyses discussed above [8,10]. 16% of these flares or new irAEs were grade ≥3 and all of these events were controlled by immunosuppression and symptomatic therapy, and no patients terminated therapy as a result [11]. Use of immunosuppressive medications at baseline, exacerbation of pre-existing AD, and whether or not the patient experienced an irAE all did not correlate with disease response outcomes. This is in contrast to the findings of Menzies et al. [10].\n\nTable 1. \nSummary of key findings from retrospective analyses of patients with pre-existing autoimmune conditions treated with checkpoint inhibitors for advanced melanoma.\n\nStudy\tNumber of patients\tType of checkpoint inhibitor\t% patients experiencing AD flare\t% patients experiencing irAE (grade ≥3)\t% patients with AD flare or grade ≥3 irAE\t% patients with death associated with AD flare or irAE\t% patients with discontinuation of therapy due to flare/irAE\t\nJohnson et al.\t30\tAnti-CTLA-4\t27\t33\t50\t3\tnot reported\t\n\t\nMenzies et al.\t52\tAnti-PD-1\t38\t10\t48\t0\t12\t\n\t\nGutzmer et al.\t19\tAnti-PD-1\t42\t5\t47\t0\t0\t\nAD: Autoimmune disease; CTLA: Cytotoxic T-lymphocyte antigen; irAE: Immune-related adverse event; PD-1: Programmed cell death 1.\n\nThese analyses lacked a significant percentage of patients with autoimmune conditions associated with higher risk for potentially devastating exacerbations. Case reports demonstrate examples of patients with high-risk autoimmune conditions treated with ICI therapy. In contrast, two patients with metastatic melanoma and autoimmune disease, Behcet's disease and ulcerative colitis, treated with ipilimumab and IL-2 experienced an improvement in symptoms related to autoimmune disease [12]. The patient with ulcerative colistis achieved partial remission of metastatic melanoma while the patient with Behcet's disease achieved a complete remission. One patient with Churg–Strauss syndrome with stage 3 involvement (vasculitis) and metastatic melanoma was treated with ipilimumab with progression of disease and development of immunotherapy-induced colitis. Ipilimumab was switched to pembrolizumab and after 16 cycles the patient had sustained partial response with no increase in Churg–Strauss disease activity or colitis [13]. In the literature, there are clear examples of all outcomes, from devastating irAEs to apparent autoimmune disease mitigation and from no treatment response to complete and sustained responses in some patients. Prospective data are needed to confirm that these medications are safe and effective in the autoimmune disease population.\n\nParaneoplastic autoimmune conditions\nCertain malignancies with high rates of paraneoplastic autoimmune complications such as small-cell lung cancer (SCLC) may theoretically see these complications triggered or enhanced by treatment with immunotherapy agents. Recent case reports allude to this phenomenon in patients who experienced treatment-related syndromes suspected to be paraneoplastic in nature. In one case, a patient with squamous NSCLC developed anti-Hu antibody-associated encephalitis when treated with nivolumab [14]. Another patient with melanoma treated with ipilimumab and nivolumab combination therapy developed paraneoplastic acral vascular syndrome [15]. In a preliminary analysis of an ongoing phase II study (NCT01331525) of ipilimumab with carboplatin and etoposide in SCLC, 61% of patients experienced grade 3 or higher adverse effects, 42% of which were deemed possibly ipilimumab related [16]. This is higher than the 31% rate of greater than or equal to grade 3 toxicity determined by a recent meta-analysis of 48 trials [17]. Two patients in the prelim analysis had ipilimumab-related neurological events. One of these was fatal, presenting like an anti-Hu-mediated paraneoplastic syndrome [16]. A phase I/II multicenter, open-label trial, Checkmate-032, demonstrated a durable response in patients with relapsed SCLC treated with nivolumab ± ipilimumab [18]. However, 8% of patients discontinued therapy due to treatment-related adverse events and there were three immune-related deaths in patients who experienced severe pneumonitis, myasthenia gravis and renal failure. Of note, all three deaths were in the combined checkpoint inhibitor arms where patients received combination ipilimumab and nivolumab therapy at variable doses. These findings lend credence to the theoretical concern that life-threatening paraneoplastic syndromes, such as immune-related encephalitis or myasthenia gravis, can be provoked by treatment with checkpoint inhibitors in patients with SCLC. Another phase II trial examined patients with extensive stage SCLC treated with ipilimumab and paclitaxel/carboplatin or paclitaxel/carboplatin alone [19]. Although treatment-related grade 3–4 adverse events were more frequent in the ipilimumab-containing arms than in the control arm, rates of discontinuation due to adverse events were similar across treatment arms. In this trial, patients treated with ipilimumab experienced only mild immune-related adverse events including rash, pruritus and diarrhea. Similarly, the phase Ib KEYNOTE-028 trial, which included 24 patients with PD-L1-expressing SCLC treated with pembrolizumab, showed a safety profile similar to that of other tumor types treated with ICIs [20]. Both the rate and severity of irAEs have implications for treatment tolerance if immunotherapy agents are proven efficacious for SCLC and other malignancies associated with paraneoplastic complications. These trials demonstrate that paraneoplastic complications can be particularly devastating and may be more likely to occur in patients on combination ICI therapy.\n\nPatients with chronic lymphocytic leukemia (CLL) tend to be older and sometimes have comorbid melanoma, renal cell carcinoma, or NSCLC malignancies that may make them candidates for immune checkpoint inhibitors. However, CLL is frequently complicated by secondary autoimmune cytopenias; namely autoimmune hemolytic anemia, immune thrombocytopenia, pure red cell aplasia and autoimmune granulocytopenia. To our knowledge, there are no reports of worsening autoimmune cytopenias in patients with CLL undergoing ICI therapy for a co-existing malignancy. The small and limited trials that have been done on patients treated with checkpoint inhibitors for CLL itself reported no increased rate of irAEs compared with trials in other cancer types [21,22]. The adverse events reported were most commonly immune-related liver enzyme elevation and thyroiditis with no cases of autoimmune cytopenias noted.\n\nCheckpoint inhibitor therapy in patients with chronic viral infections\nPatients with chronic viral infections, namely HCV, HBV and HIV, were another important group excluded from many immune checkpoint inhibitor trials to date. The role of immune checkpoints in patients with chronic viral infections is incompletely understood, and there is concern that checkpoint inhibitors could potentially cause viral reactivation of latent infection or contribute to ongoing hepatitis in these patients. This could be an important consideration in patients with underlying liver disease from chronic hepatitis. Traditional chemotherapy regimens are associated with a significant rate of HCV reactivation. This has an impact on viral-induced end-organ damage, and is associated with chemotherapy regimen modifications or interruptions in therapy, which can negatively affect clinical outcomes [23]. Reactivation has also been reported in patients treated with targeted tyrosine kinase inhibitors such as imatinib [24]. With respect to irAEs, we know that the gastrointestinal system is significantly impacted, with sequelae including diarrhea, colitis or hepatitis [25]. The incidence of immune-related hepatic adverse events with ICI therapy varies, and can be as high as 15–20% with dual ICI treatment. These usually manifest as asymptomatic elevations of aspartate aminotransferase & alanine aminotransferase. Rarely, symptomatic adverse effects related to the liver also arise and these include fulminant hepatitis and death. Many in vitro studies allude to viral manipulation of the CTLA-4 and PD-1 pathways to promote unchecked replication. For instance, chronic hepatitis B and C infections are associated with an ‘exhaustive’ CD8+ T-cell phenotype mediated by upregulation of CTLA-4 and PD-1. Exhausted T-cells exhibit a loss of IL-2 production, reduced proliferative capacity, reduced cytotoxic capacity and impaired production of proinflammatory cytokines [26]. In theory, this effector T-cell exhaustion may be abrogated by immune checkpoint inhibition, and this is supported by ex vivo and in vitro studies [27–33]. Similarly, in addition to CD4+ T-cell depletion in HIV, increased PD-1 expression has been demonstrated on HIV-specific CD8+ T-cells leading to a similar ‘exhaustive’ effect and this correlates with disease progression [34]. There may be a promising role for PD-1 inhibition in restoring normal immune mechanisms in these chronic viral infections; however, additional studies are needed to establish this.\n\nWith these theoretical sequelae in mind, large-scale data in patients with chronic viral infections undergoing ICI therapy are lacking. Patients with HCV and no underlying malignancy who were treated with nivolumab and tremelimumab have exhibited a decrease in viral load (VL) [35,36]. In a phase II, noncontrolled trial of patients with inoperable hepatocellular carcinoma (HCC) and chronic HCV infection, 20 patients were treated with a maximum of four cycles of tremelimumab (a CTLA-4 inhibitor) [37]. At baseline, 43% of these patients had some degree of liver dysfunction. No patients received systemic steroids and there were no treatment-related deaths; however, 45% of patients experienced transient grade 3 or higher transaminitis without associated decline in liver function. Interestingly, treatment with tremelimumab was associated with a significant decrease in average VL and three patients had a complete viral response during follow-up. A recent trial including 32 patients with advanced HCC treated with tremelimumab and radiofrequency ablation or chemoablation demonstrated an approximately 25% partial response rate [38]. Because HCC is often associated with chronic viral infection (namely HBV and HCV), this study can shed some light on the safety of immune checkpoint inhibition in chronically infected individuals. 12 of 14 patients with evaluable HCV VL achieved a VL reduction. The two patients who did not experience a VL reduction derived no antitumor benefit from ICI treatment. Similarly, three of the patients who initially responded had a concurrent reduction in VL until their malignancy progressed, at which point their VL also increased. These elevations clearly coincided with the time of disease progression. In the five patients with HBV infection who were enrolled in this trial, quantitative hepatitis B antigen, a reflection of the number of cells infected, decreased over time in all patients. Overall, this study demonstrated the safety and potential benefit of checkpoint inhibitor treatment in patients with HCC with HBV or HCV infection. Moreover, it alludes to the interesting correlation between HCV VL and HCC disease response. In a case series of nine patients with chronic HBV or HCV and metastatic melanoma (five with HBV, four with HCV) treated with ipilimumab, two out of nine patients experienced elevated transaminase levels during follow-up. The majority of patients had their VLs decrease or remain suppressed throughout the course of therapy although one patient had an increased VL after treatment with IL-2, ipilimumab and temozolomide [39]. Interim analysis from the Phase I/II trial of nivolumab in patients with advanced HCC (CA209-040 trial) showed that monotherapy with nivolumab had a favorable safety profile in patients with HCC compared with patients with other types of cancer [40,41]. Although this is an interim analysis, it alludes to the safety of nivolumab in patients with HBV and HCV infection. One patient with untreated HCV and metastatic merkel cell carcinoma was treated with pembrolizumab and saw a marked tumor response as well as HCV VL reduction [42]. Sharma et al. described a patient with chronic hepatitis B (patient 1) and one with chronic hepatitis C (patient 2) who were treated with ipilimumab for advanced melanoma. Patient 1 was treated with ipilimumab and tenofovir, and achieved reduction in VL to undetectable levels; unfortunately, this patient also had progression of melanoma and expired after receiving only one cycle of ipilimumab. Patient 2 was treated with four cycles of ipilimumab with overall progression of disease and transaminitis, and subsequently had a significant increase in VL months after discontinuing ipilimumab, corresponding with progression of metastatic melanoma. Based on the time course, it was not clear what role ipilimumab played in HCV control or transaminitis, but the elevated transaminase levels were ultimately attributed to an immune-related process [43]. There are currently several ongoing trials and analyses investigating patients with chronic HIV/HCV/HBV infection with and without malignancy being treated with immune checkpoint inhibitors [40]. Davar et al. reported on two patients, one with HCV and one with HIV/HCV coinfection, who were treated with pembrolizumab for metastatic melanoma [44]. The patient with HIV/HCV coinfection progressed after two doses of pembrolizumab but had no increase in HIV or HCV VL, and the patient with HCV infection remained with a stable VL throughout nine cycles of pembrolizumab.\n\nRecently, there has been more literature alluding to the safe treatment of HIV-infected patients. One case report demonstrates a decrease in the HIV reservoir in an HIV-positive patient with NSCLC treated with nivolumab and discusses the mechanisms that may be playing a role [45]. In short, checkpoint inhibitors may transiently reverse the blockade of HIV transcription in memory T-cells serving as reservoirs for chronic infection [46]. Similar to that postulated for chronic infectious hepatitides, checkpoint inhibitors might restore function in ‘exhausted’ HIV-specific T-cells ultimately leading to a ‘drastic and durable diminution of the reservoir’. So far, there are several case reports demonstrating successful viral control and tumor response in HIV-infected patients with malignancies [47–51]. Future considerations should focus on risk of Immune Reconstitution Inflammatory Syndrome in these patients and ICI efficacy in treating malignancy in patients with disease-related defects in T-cell activity. In conclusion, a review of the existing literature of patients treated with HIV, HBV or HCV reveals that there has been no reported direct toxicity from these medications relating to their chronic viral infections.\n\nCheckpoint inhibitor therapy in patients with solid organ transplants\nSkin cancers are the most common malignancies to affect patients who are chronically immunosuppressed in the setting of organ transplantation. There is a 3.6 relative risk for developing melanoma in this population compared with age-matched controls [52]. Similar to some of the other specific populations also discussed, patients with prior solid organ transplantation were excluded from the safety and efficacy trials on immune checkpoint inhibitors. The PD-1/PDL-1 and CTLA-4 pathways are essential for graft acceptance and their blockade results in accelerated organ rejection [53–61]. The mechanisms by which PD-1 blockade leads to graft rejection have been demonstrated in an elegant series of experiments by Thangavelu et al. [61]. Overall, PD-1 was shown to be important for induction and maintenance of tolerance. PD-1 -/- mice had an increase in donor-specific cytotoxic T-cells when compared with wild-type mice after islet cell transplantation. The authors hypothesized that this increase in CD8+ T-cells could be due to reduced PD-1 signals in these cytotoxic T-cells themselves, reduced PD-1 signals in antidonor T-helper cells that lead to expansion of cytotoxic T-cells, or a reduced ability to generate Tregs. Additionally, blocking the PD-1/PD-L1 interaction on the target of rejection, the transplanted organ, may promote anti donor T-cell activity. Both of these mechanisms lead to loss of spontaneous tolerance. Thangavelu et al. did not identify an effect whereby CTLA-4 blockade-mediated rejection but concluded that their studies using CTLA-4 were too limited to completely exclude a role for this pathway in graft acceptance. However, it has been shown that in murine cardiac allografts, CTLA-4 plays a vital role in promoting graft acceptance, peripheral tolerance and intragraft Foxp3+ Tregs [53]. Blazar et al. showed in a murine model that blockade of PD-1 led to severe acute graft-versus-host disease (GvHD) while blockade of CTLA-4 did not. There exists a theory that blockade of PD-1 pathway may lead to increased graft rejection and stronger T-cell alloreactivation than blockade of the CTLA-4 pathway [62]. Though both molecules function as immune checkpoints, their precise mechanisms of action differ and therefore it is entirely plausible that they have differential roles in allograft acceptance and tolerance. With respect to solid organ transplantation, the literature only consists of case reports of patients with a history of renal, hepatic and cardiac transplantation that underwent treatment with ICIs primarily for metastatic melanoma.\n\nCTLA-4 inhibitors in patients with solid organ transplants\nThere have been several case reports of patients treated with ipilimumab that experienced preservation of engrafted organs [63–65] (summarized in Table 2). Lipson described two patients with renal transplants treated with ipilimumab for metastatic melanoma who had partial responses to therapy and no evidence of rejection [66]. We presented a patient with an orthotopic heart transplant who was treated with ipilimumab for metastatic melanoma who also did not have evidence of rejection, although he had no response to therapy [4]. To our knowledge, there is one reported case of acute rejection after treatment with ipilimumab. One patient with a renal allograft for IgA nephropathy developed metastatic choroidal melanoma and was treated with two cycles of ipilimumab before having failure of his graft [67]. Interestingly, a biopsy of the renal transplant showed evidence of T-cell-mediated rejection but also showed evidence of recurrent IgA nephropathy, which the authors speculated may have been a complication of ipilimumab therapy. Therefore, it is unclear what role acute rejection played in graft failure. Case reports comprise the body of evidence for the safety of ipilimumab treatment in patients with organ transplantation and malignancy. Nine such patients have been reported including kidney (n = 6), liver (n = 2) and heart (n = 1) transplant recipients. Eight out of these nine patients demonstrated no rejection during their ipilimumab treatment course and three out of nine had initial response of their respective malignancies, either metastatic melanoma or metastatic cutaneous squamous cell carcinoma. One patient who had an initial response to therapy went on to have progression of disease [66].\n\nTable 2. \nSummary of reported immune checkpoint inhibitors experience in patients with solid organ transplants.\n\nPatient\tStudy\tTransplant\tCancer\tICI agent\tRejection (Y/N)\tImmunosuppression prior to ICI\tImmunosuppression during ICI treatment\tOutcome\t\n1\tLipson et al.\tKidney\tMM\tIpilimumab\tN\tPrednisone/tacrolimus\tPrednisone\tResponse\t\n\t\n2\tLipson et al.\tKidney\tMM\tIpilimumab\tN\tPrednisone/tacrolimus/mycophenolate\tPrednisone\tResponse\t\n\t\n3\tRanganath et al.\tLiver\tMM\tIpilimumab\tN\tTacrolimus\tTacrolimus\tPOD\t\n\t\n4\tMorales et al.\tLiver\tMM\tIpilimumab\tN\tRapamycin/mycophenolate\tRapamycin\tResponse\t\n\t\n5\tJose et al.\tKidney\tMetastatic Choroidal Melanoma\tIpilimumab\tY\tTacrolimus\tPrednisolone\tNot Reported\t\n\t\n6\tHerz et al.\tKidney\tMM\tIpilimumab\tN\tPrednisone/tacrolimus\tPrednisone/tacrolimus\tPOD\t\n\t\nNivolumab (after ipilimumab)\t \t \t \t \t \t \t \t \t\n\t\n7\tSpain et al.\tKidney\tMM\tIpilimumab\tN\tPrednisone/tacrolimus\tPrednisone\tPOD\t\n\t\nNivolumab (after ipilimumab)\tY\tPrednisone\tResponse\t \t \t \t \t \t\n\t\n8\tAlhamad et al.\tKidney\tMetastatic SCC of skin\tIpilimumab\tN\tCyclosporine/prednisone\tPrednisone\tPOD\t\n\t\nNivolumab (after ipilimumab)\tY\tPrednisone\tNot reported\t \t \t \t \t \t\n\t\n9\tQin et al.\tHeart\tMM\tIpilimumab\tN\tTacrolimus\tTacrolimus\tPOD\t\n\t\nPembrolizumab (after ipilimumab)\t \t \t \t \t \t \t \t \t\n\t\n10\tGrant et al.\tHeart\tMM\tPembrolizumab\tN\tTacrolimus/mycophenolate\tTacrolimus/mycophenolate\tPOD\t\n\t\n11\tOng et al.\tKidney\tMM\tNivolumab\tY\tPrednisone/tacrolimus/mycophenolate\tPrednisone\tResponse\t\n\t\n12\tLipson et al.\tKidney\tMetastatic SCC of skin\tPembrolizumab\tY\tCyclosporine/prednisone\tPrednisone\tResponse\t\n\t\n13\tOwonikoko et al.\tHeart\tMetastatic SCC of skin\tNivolumab\tY\tTacrolimus/sirolimus\tPrednisone/tacrolimus\tNot reported\t\n\t\n14\tBarnett et al.\tKidney\tMetastatic Adenocarcinoma of the Duodenum\tNivolumab\tN\tPrednisone/tacrolimus/mycophenolate\tPrednsione/sirolimus\tResponse\t\n\t\n15\tBoils et al.\tKidney\tStage IV NSCLC\tNivolumab\tY\tCyclosporine/prednisone\tReduced dose cyclosporine/prednisone\tNot reported\t\n\t\n16\tKittai et al. [68]\tKidney\tMetastatic SCC of skin\tNivolumab\tN\tPrednisone/tacrolimus/mycophenolate\tPrednisone/sirolimus\tResponse\t\n\t\n17\tKittai et al.\tOrthotopic Heart Transplant\tStage IV NSCLC\tNivolumab\tN\tPrednisone/cyclosporine/mycophenolate\tReduced dose cyclosporine/reduced dose mycophenolate\tResponse\t\nICI: Immune checkpoint inhibitor; MM: Metastatic melanoma; N: No; NSCLC: Non-small-cell lung cancer; POD: Progression of disease; SCC: Squamous cell carcinoma; Y: Yes.\n\nPD-1 inhibitors in patients with solid organ transplants\nThe body of existing case reports suggests a less promising safety profile for anti-PD-1 antibody therapy (Table 2), though our patients received anti-PD-1 therapy without evidence of rejection. Our review of the literature revealed 13 solid organ transplant patients treated with PD-1 inhibitors, 4 of whom had already been treated and experienced progression of disease with ipilimumab [4,63,69,70]. Pembrolizumab was used in three cases while nivolumab was used in ten patients. Transplanted organs included kidney (n = 9) and heart (n = 4). Malignancies for which PD-1 inhibitor treatment was used included stage IV NSCLC, metastatic melanoma, squamous cell carcinoma of the skin and metastatic adenocarcinoma of the duodenum. Seven out of 13 patients experienced organ rejection and six out of 13 patients had disease response to PD-1 inhibitor therapy. Two patients with renal transplantation underwent treatment with nivolumab for metastatic squamous cell carcinoma and shortly thereafter developed acute rejection and graft failure [71,72]. One of these patients had their graft explanted and was maintained on hemodialysis with continued nivolumab treatment after experiencing a marked response to therapy. This patient had a substantial improvement in performance status and quality of life [71]. A patient with cardiac allograft for familial dilated cardiomyopathy, who suffered from chronic cardiac allograft vasculopathy, was diagnosed with metastatic cutaneous squamous cell carcinoma 16 years post-transplant. The patient was treated with nivolumab after failure of frontline cytotoxic chemotherapy and developed acute rejection precipitating cardiogenic shock. This improved with high doses of immunosuppression. He was ultimately not retreated with nivolumab and passed away 8 months later [73]. Another patient with a renal allograft was treated with nivolumab for metastatic melanoma [74]. She had graft failure and had to be transitioned to hemodialysis, but, due to the response of her disease to nivolumab, treatment was reinitiated. At the time of publication she maintained a response 8 months after restarting nivolumab [74]. There are two examples of patients with solid organ transplants and malignancy who progressed but did not experience rejection on ipilimumab, and were subsequently treated with anti-PD-1 antibodies, and experienced graft failure shortly after [69,70]. However, our patient is an example of one who did not experience rejection with PD-1 inhibition. Last, one patient with a renal allograft who was treated with ipilimumab then nivolumab for metastatic melanoma showed no evidence of rejection or graft failure but ultimately did not respond to either form of immunotherapy [63]. It is difficult to draw conclusions with the limited number of organ transplant patients treated with ICI therapy; however, there have been more reported cases of organ rejection with PD-1 inhibitors than with CTLA-4 inhibitors. As more patients are treated with these agents, different classes of ICIs may demonstrate a better safety profile in patients with transplanted organs and this may have implications for first-line management. Although they admit their analyses are limited, one particular study alludes to a more profound role of PD-1 blockade than CTLA-4 blockade in transplant rejection [61]. Our review of the existing case report literature agrees with this and may suggest a more important role of the PD-1 pathway in allograft tolerance. This will need to be explored in a more controlled setting.\n\nOther considerations\nThere have been several patients reported with prior kidney transplants that have had rejection and were transitioned to hemodialysis, but have had long-term survival attributed to ICI therapy [71,74]. Considering that metastatic melanoma is a life-limiting condition, the possible survival benefit associated with ICI treatment may be worth the risk of graft rejection in certain patients. Of course, this will depend on the organ transplanted. For instance, considering transplant rejection in the face of impending malignancy-related mortality, renal transplant patients may choose to be treated with ICIs and accept the risk of organ failure and transition to dialysis [75]. Unfortunately, liver transplant patients do not have an analogous option for emergent replacement of organ function. These scenarios will undoubtedly require expert communication between the patient, oncologist and multidisciplinary transplant team. Last, as more physicians consider using these agents in transplant patients with malignancy, they will be faced with decisions regarding the handling of immunosuppression for transplant tolerance.\n\nThere is a large difference between the immunosuppression used in patients with active autoimmune disease and that used in patients with organ transplants. In a systematic review of all reported cases of immune checkpoint inhibitor use in patients with cancer and pre-existing autoimmune disease, it was found that 27% (27/107) of patients with autoimmune disease were on immunosuppressive medications for their condition prior to initiation of a checkpoint inhibitor [76]. 21% of these patients were on corticosteroids and 14% were on disease-modifying antirheumatic drugs including methotrexate, hydroxychloroquine, sulfasalazine, azathioprine, leflunomide and mycophenolate mofetil. A report on whether or not patients responded to immunotherapy is lacking in this study, but a smaller percentage of patients on immunosuppressive therapy suffered exacerbations of existing autoimmune disease or de novo irAEs than patients with autoimmune disease not on immunosuppressive therapy. In terms of whether concomitant systemic corticosteroids attenuate the anticancer response of immune checkpoint inhibitors, the verdict is still out but there is little evidence to suggest this. Several studies conclude that corticosteroid use, when the indication is treatment of irAEs, has no effect on overall survival or time to treatment failure [77–79].\n\nUnlike in patients being treated for autoimmune disease, calcineurin inhibitor therapy is a mainstay of maintainance immunosuppression regimens for transplant patients. Calcineurin inhibitors (CNIs) prevent synthesis of IL-2 and other cytokines that would otherwise be produced by T-cells activated by allografts [80]. Just as there is a theoretical concern for attenuation of anticancer response to checkpoint inhibition with concomitant corticosteroid use, this concern is even greater for T-cell-specific immunosuppression such as calcineurin inhibitors. Unfortunately, what we know about patients being treated simultaneously with ICIs and CNIs is solely from isolated case reports. In these reports, treatment with ICI in the setting of immunosuppression with a calcineurin inhibitor was only associated with malignancy response in one out of nine cases. This includes both of our cases, patients who were left on a calcineurin inhibitor and neither had rejection nor tumor response when treated with an ICI. In the one responder, reduced dose cyclosporine (compared with pre-ICI treatment immunosuppression regimen) was used in addition to reduced-dose mycophenolate mofetil [68]. Two patients who remained on CNI therapy still had the undesired outcome of allograft rejection. They received a PD-1 inhibitor, nivolumab, and malignancy response was either not seen or not reported [72,73]. It is possible that treatment with checkpoint inhibitors cannot overcome the potent suppression of T-cell cytokine production resulting from calcineurin inhibition. PD-1 and CTLA-4 inhibitors in essence ‘remove the brakes’ on the adaptive immune system, but T-cell function is still required for these drugs to work. These complex interactions need to be further investigated in the lab and in a larger cohort before firm conclusions are drawn.\n\nInterestingly, several transplant patients have had tumor response without rejection when their immunosuppressive regimen contains sirolimus [65,68,81]. Sirolimus, an mTOR inhibitor, exerts its immunosuppressive effects by blocking signal transduction from many cell surface cytokine receptors including IL-2 [80]. Moreover, the antitumor activity of sirolimus is well described [82]. This agent has also been shown to selectively preserve the development of Tregs, which are important for graft tolerance [83]. This is particularly relevant in the setting of PD-1 pathway inhibitor use as blockade of the PD-1/PD-L1 interaction has been shown to impair Treg cells in the renal allograft [84]. An ideal immunosuppression regimen in the transplant patient with malignancy has two main features: it preserves graft tolerance in the transplant patient while allowing the immune antitumor effects promoted by checkpoint inhibitors. With case reports alluding to success in this arena, sirolimus may be an agent uniquely poised to mediate the battle between immune suppression and activation [65,68,81].\n\nConclusion\nThis review touches on only a subset of the challenging, poorly studied populations treated with immunotherapy agents. Other populations that need to be better studied in the context of ICIs before subjected to widespread use are elderly patients, pregnant patients, patients on immune suppression for other reasons than those mentioned, and patients who have developed serious irAEs with other class of immunotherapy agents. The use of these medications in certain patient populations raises concerns based on immunological mechanisms related to immune checkpoint inhibition and limited clinical trial experience. However, with the successful treatment of many patients with otherwise terminal disease, these medications need to be explored clinically in challenging patients as well before excluding them based on theoretical mechanisms. So far, based on limited clinical evidence, it seems that cautious use in patients with certain autoimmune diseases can be considered, while acknowledging that there is a risk of disease exacerbation. Overall, the risk of severe or treatment-refractory exacerbations appears to be low, but further study is needed. It will be important to weigh the risks and benefits of treatment with immune checkpoint inhibitors in these patients and involve patients in decision making. When considering the care of these patients, it will be essential to involve consultants from rheumatology, endocrinology, neurology, and all other possible intersecting subspecialties for extended risk/benefit discussions. We will need to study differential responses and side-effect profiles with different classes (PD-1 vs PD-L1 vs CTLA-4) of checkpoint inhibitors in each of the high-risk groups that were excluded from the initial clinical trials. In patients with chronic hepatitis, ICIs have been well tolerated with very few accounts of increased viral activity, fulminant hepatitis or death. While patients with HCV seem to be more susceptible to immune-related elevations in transaminases than the general population, these generally are self limited, asymptomatic and unrelated to viral activity [37]. There is also mounting clinical evidence that ICI treatment causes VL suppression in HCV and that response of malignancy to ICI therapy corresponds with HCV VL reduction [35,37,38]. These are very promising findings which need further investigation. The transplant community represents arguably the most complex group of patients to be considered for use of immunotherapy agents. From the data collected to date, it seems that CTLA-4 inhibitors have been better tolerated in transplant patients treated with ICIs, demonstrating less risk of rejection than PD-1/PD-L1 inhibitors. Our review of the existing case report literature agrees with this and may suggest a more important role of the PD-1 pathway in allograft tolerance. There is a need for larger retrospective analyses, prospective cohort studies, as well as RCTs to study the safety and efficacy of ICI use in patients with autoimmune disease, chronic viral infections and solid organ transplants. Until then, we must extract what we can from anecdotal evidence, knowing the limitations of utilizing this information to draw conclusions and direct management.\n\nFuture perspective\nImmunotherapy, especially checkpoint inhibitor therapy, is a subset of cancer treatment that is advancing on a daily basis making it difficult to foresee changes in standard practice. Although excluded from most of the clinical trials demonstrating the efficacy of ICIs in certain malignancies, patients with chronic viral infections including HIV, HCV and HBV will benefit from inclusion in upcoming trials. Similarly, although at risk for flares or significant irAEs, most patients with autoimmune disease with sensitive malignancies can be safely treated with ICIs and may also be included in future clinical trials. On the other hand, the intricate immune interactions involving checkpoint inhibitors and patients with transplanted organs will need to be further studied before physicians are comfortable treating them on a larger scale. Until then, it will be interesting to see if sirolimus and low-dose prednisone for immunosuppression in transplant patients are used effectively as immunosuppression to prevent rejection but permit antitumor activity of ICIs. In the future, prospective and retrospective trials will both be useful to identify risk factors and other patient characteristics that will predict low adverse event profiles (such as irAEs, autoimmune flares, other irAEs) in patients treated with ICIs. Moreover, isolated cases suggest a promising role for disease-specific antibodies and other serum biomarkers for this purpose. Last, we will hopefully identify other interventions that can augment antitumor effects of ICIs while preventing the adverse effects. Some ideas on the horizon to boost the cancer-specific T-cell repertoire are the clinical use of tumor infiltrating lymphocytes, vaccines, adoptive T-cells, and adjunctive radiation, cytotoxic chemotherapy, or targeted therapy.\n\n\nFinancial & competing interests disclosure\n\n\nAKS Salama has the following conflicts of interest to disclose: Research Funding (paid to institution): Bristol-Myers Squibb, Celldex, Dynavax, Genentech, Immunocore, Merck, Reata. Consultant for the following: Array, Merck. Speaker for the following: Bristol-Meyers Squibb. Other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\n\nInformed Consent Disclosure\n\n\nThe authors affirm that they are in compliance with institutional standards regarding informed consent.\n\n\nOpen access\n\n\nThis work is licensed under theAttribution-NonCommercial-NoDerivatives 4.0 Unported License. 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Exp. Med. 188 1 199 204 1998 9653096 \n60 Li W Zheng XX Kuhr CS Perkins JD CTLA4 engagement is required for induction of murine liver transplant spontaneous tolerance Am. J. Transplant. 5 5 978 986 2005 15816877 \n61 Thangavelu G Murphy KM Yagita H Boon L Anderson CC The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants Immunobiology 216 8 918 924 2011 21281982 \n62 Blazar BR Carreno BM Panoskaltsis-Mortari A Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism J. Immunol. 171 3 1272 1277 2003 12874215 \n63 Herz S Hofer T Papapanagiotou M Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient Eur. J. Cancer 67 66 72 2016 27614165 \n64 Ranganath HA Panella TJ Administration of ipilimumab to a liver transplant recipient with unresectable metastatic melanoma J. Immunother. 38 5 211 2015 25962109 \n65 Morales RE Shoushtari AN Walsh MM Grewal P Lipson EJ Carvajal RD Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation J. Immunother. Cancer 3 22 2015 26082835 \n66 Lipson EJ Bodell MA Kraus ES Sharfman WH Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma J. Clin. Oncol. 32 19 e69 e71 2014 24493726 \n67 Jose A Yiannoullou P Bhutani S Renal allograft failure after ipilimumab therapy for metastatic melanoma: a case report and review of the literature Transplant. Proc. 48 9 3137 3141 2016 27932166 \n68 Kittai AS Oldham H Cetnar J Taylor M Immune checkpoint inhibitors in organ transplant patients J. Immunother. 40 7 277 281 2017 28719552 •• Highlights the key concepts in treating transplant patients with malignancy with immune checkpoint inhibitors.\n\n\n69 Spain L Higgins R Gopalakrishnan K Turajlic S Gore M Larkin J Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma Ann. Oncol. 27 6 1135 1137 2016 26951628 • Highlights the key concepts in treating transplant patients with malignancy with immune checkpoint inhibitors.\n\n\n70 Alhamad T Venkatachalam K Linette GP Brennan DC Checkpoint inhibitors in kidney transplant recipients and the potential risk of rejection Am. J. Transplant. 16 4 1332 1333 2016 26752406 \n71 Lipson EJ Bagnasco SM Moore J Jr Tumor regression and allograft rejection after administration of anti-PD-1 N. Engl. J. Med. 374 9 896 898 2016 \n72 Boils CL Aljadir DN Cantafio AW Use of the PD-1 pathway inhibitor nivolumab in a renal transplant patient with malignancy Am. J. Transplant. 16 8 2496 2497 2016 26988410 \n73 Owonikoko TK Kumar M Yang S Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report Cancer Immunol. Immunother. 66 1 45 50 2017 27771741 \n74 Ong M Ibrahim AM Bourassa-Blanchette S Canil C Fairhead T Knoll G Antitumor activity of nivolumab on hemodialysis after renal allograft rejection J. Immunother. Cancer 4 64 2016 27777773 \n75 Pham PT Everly M Faravardeh A Pham PC Management of patients with a failed kidney transplant: dialysis reinitiation, immunosuppression weaning, and transplantectomy World J. Nephrol. 4 2 148 159 2015 25949929 \n76 Abdel-Wahab N Shah M Lopez-Olivo MA Suarez-Almazor ME Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: a systematic review Ann. Intern. Med. 168 2 121 130 2018 29297009 \n77 Horvat TZ Adel NG Dang TO Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center J. Clin. Oncol. 33 28 3193 3198 2015 26282644 \n78 Yang JC Hughes M Kammula U Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis J. Immunother. 30 8 825 830 2007 18049334 \n79 Downey SG Klapper JA Smith FO Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade Clin. Cancer Res. 13 22 Pt 1 6681 6688 2007 17982122 \n80 Chinen J Buckley RH Transplantation immunology: solid organ and bone marrow J. Allergy Clin. Immunol. 125 2 Suppl. 2 S324 S335 2010 20176267 \n81 Barnett R Barta VS Jhaveri KD Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab N. Engl. J. Med. 376 2 191 192 2017 28076715 • Highlights the key concepts in treating transplant patients with malignancy with immune checkpoint inhibitors.\n\n\n82 Law BK Rapamycin: an anti-cancer immunosuppressant? Crit. Rev. Oncol. Hematol. 56 1 47 60 2005 16039868 \n83 Coenen JJ Koenen HJ Van Rijssen E Hilbrands LB Joosten I Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+ CD25+ regulatory T cells Blood 107 3 1018 1023 2006 16210336 \n84 Riella LV Paterson AM Sharpe AH Chandraker A Role of the PD-1 pathway in the immune response Am. J. Transplant. 12 10 2575 2587 2012 22900886 \n85 YERVOY (ipilimumab) [package insert] Bristol-Meyers Squibb Company Princeton, NJ 2015 Accessed January 20, 2018 \n86 OPDIVO (nivolumab) [package insert] Bristol-Meyers Squibb Company Princeton, NJ 2017 Accessed: January 20, 2018 \n87 KEYTRUDA (pembrolizumab) [package insert] Merck Sharpe & Dohme Corp. Whitehouse Station, NJ 2016 Accessed: January 20, 2018\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2045-0885",
"issue": "5(4)",
"journal": "Melanoma management",
"keywords": "CTLA-4; PD-1; autoimmune; challenging; checkpoint inhibitor; hepatitis B virus; hepatitis C virus; human immunodeficiency virus; transplant",
"medline_ta": "Melanoma Manag",
"mesh_terms": null,
"nlm_unique_id": "101649842",
"other_id": null,
"pages": "MMT10",
"pmc": null,
"pmid": "30459942",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "28393361;12874215;26633184;17982122;28950303;27932166;20353465;20176267;26448890;23390376;22900715;27730287;27605882;28945858;25131771;22858559;27803003;21739672;27269741;18049334;17911605;16210336;26282644;19889124;27023060;25962109;28719552;9653096;19800335;26962927;21281982;28734759;27148254;26765102;27777773;29297009;28499411;11994415;27771741;26951628;23717490;26988410;28147363;27400264;15905503;23466307;28124291;28076715;26540029;28615920;28350581;28424162;28334399;22271089;24493726;16921384;16039868;30190859;28577954;28223062;25317333;22900886;28214654;27816492;27614165;28228726;15816877;28562196;28813164;25227926;26082835;27687304;25628259;25949929;26752406;23775956;27367787;22493341;21749640;29206889;19247441",
"title": "Checkpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high-risk populations.",
"title_normalized": "checkpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high risk populations"
} | [
{
"companynumb": "US-ASTELLAS-2018US051441",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo document reversible cognitive deterioration associated to high doses of zonisamide, using the Reliable Change Index to control practice effects derived from repetitive neuropsychological assessments.\n\n\nMETHODS\nA 11 year-old boy with tuberous sclerosis complex and left frontal refractory epilepsy, evaluated within a paediatric epilepsy surgery program. The epileptogenic zone was found to be related with a tuber situated on the left inferior frontal gyrus. The effects of high doses of zonisamide simulate a disturbance of eloquent cortex within the epileptogenic zone and the impact of uncontrolled seizures on cognitive functioning over the language-dominant hemisphere. Drug withdrawal significantly improved total intelligence index, verbal comprehension intellectual index and specific language-sustained cognitive abilities, beyond practice effects.\n\n\nCONCLUSIONS\nThe differentiation between cognitive effects of drugs and functional deficits resulting from eloquent cortex involvement within the epileptogenic zone can be of crucial importance in the decision-making process for epilepsy surgery.",
"affiliations": "Hospital Infantil Universitario Nino Jesus, 28009 Madrid, Espana.",
"authors": "Fournier-Del Castillo|M Concepción|MC|;Melero-Llorente|Javier|J|;Blanco-Beregana|Miriam|M|;Robles-Bermejo|Fernando|F|;Budke|Marcelo|M|;Garcia-Fernandez|Marta|M|;Garcia-Penas|Juan José|JJ|;Perez-Jimenez|M Ángeles|MÁ|",
"chemical_list": "D000081:Acetamides; D000927:Anticonvulsants; D003984:Dibenzazepines; D007555:Isoxazoles; D009570:Nitriles; D011728:Pyridones; D001569:Benzodiazepines; D000078306:Clobazam; D000078305:Zonisamide; D000078334:Lacosamide; C551441:perampanel; C571001:eslicarbazepine",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0210-0010",
"issue": "60(2)",
"journal": "Revista de neurologia",
"keywords": null,
"medline_ta": "Rev Neurol",
"mesh_terms": "D000081:Acetamides; D000927:Anticonvulsants; D001569:Benzodiazepines; D002648:Child; D000078306:Clobazam; D003072:Cognition Disorders; D003984:Dibenzazepines; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial; D005625:Frontal Lobe; D006801:Humans; D007555:Isoxazoles; D000078334:Lacosamide; D007806:Language Disorders; D007859:Learning Disabilities; D008297:Male; D008569:Memory Disorders; D059906:Neuroimaging; D009570:Nitriles; D011728:Pyridones; D014402:Tuberous Sclerosis; D000078305:Zonisamide",
"nlm_unique_id": "7706841",
"other_id": null,
"pages": "75-80",
"pmc": null,
"pmid": "25583590",
"pubdate": "2015-01-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible neuropsychological deterioration associated to zonisamide in a paediatric patient with tuberous sclerosis.",
"title_normalized": "reversible neuropsychological deterioration associated to zonisamide in a paediatric patient with tuberous sclerosis"
} | [
{
"companynumb": "ES-MYLANLABS-2021M1059747",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZONISAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "A pregnant woman at 25weeks of gestation was diagnosed with laryngeal tuberculosis following a failed intubation for upper gastrointestinal endoscopy. Laryngeal tuberculosis represents approximately 1% of all cases of tuberculosis in the United States and presents a unique diagnostic challenge, because accompanying laryngeal changes are both varied and nonspecific. This report highlights both the challenges of the pregnant airway and the diagnosis and treatment of laryngeal tuberculosis.",
"affiliations": "Mount-Sinai West Hospital, 1000 10th Avenue NY, NY 10019, United States.;Mount-Sinai West Hospital, 1000 10th Avenue NY, NY 10019, United States. Electronic address: borlando@chpnet.org.",
"authors": "Geier|J|J|;Orlando|B|B|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijoa.2017.08.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-289X",
"issue": "33()",
"journal": "International journal of obstetric anesthesia",
"keywords": "Airway, difficult; Tuberculosis, laryngeal",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D000769:Anesthesia, Inhalation; D000773:Anesthesia, Obstetrical; D002585:Cesarean Section; D016099:Endoscopy, Gastrointestinal; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007442:Intubation, Intratracheal; D011247:Pregnancy; D013902:Radiography, Thoracic; D014387:Tuberculosis, Laryngeal; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "75-77",
"pmc": null,
"pmid": "29017739",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary and laryngeal tuberculosis in a 25-weeks' gestation parturient, diagnosed after failed tracheal intubation.",
"title_normalized": "pulmonary and laryngeal tuberculosis in a 25 weeks gestation parturient diagnosed after failed tracheal intubation"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2018GMK032785",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional... |
{
"abstract": "Acquired epidermodysplasia verruciformis (AEV) describes epidermodysplasia verruciformis developing in an immunocompromised host. There is limited information in the literature regarding AEV in the pediatric population; of the patients reported, most patients described had HIV, with only two reported cases of children who developed AEV post-transplantation. This case series describes three pediatric patients who developed AEV on immunosuppressant therapy following cardiac transplantation. We review risk factors, treatment options, and prognosis of AEV in the pediatric population.",
"affiliations": "Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.;Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.;Department of Dermatology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.;Department of Dermatology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.;Department of Pathology, Weill Cornell Medical College, New York, NY, USA.;Department of Dermatology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.",
"authors": "Kinariwalla|Neha|N|https://orcid.org/0000-0002-3700-0528;Coromilas|Alexandra J|AJ|;Garzon|Maria C|MC|;Levin|Laura E|LE|https://orcid.org/0000-0001-9393-6585;Magro|Cynthia|C|;Lauren|Christine T|CT|https://orcid.org/0000-0002-7278-4831",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14701",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": null,
"journal": "Pediatric dermatology",
"keywords": "childhood EV; immunocompromised; post-transplant AEV",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8406799",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34669978",
"pubdate": "2021-10-20",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acquired epidermodysplasia verruciformis (AEV) in three children after cardiac transplantation: A case series and review of the literature.",
"title_normalized": "acquired epidermodysplasia verruciformis aev in three children after cardiac transplantation a case series and review of the literature"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-323395",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Belly dancer syndrome, also called belly dance syndrome or belly dancer dyskinesia, is a kind of abdominal dyskinesia with painful sensation. Its etiology is still unclear and there are few studies reporting its association with antipsychotics. Quetiapine is an atypical antipsychotic that causes lower risk of extrapyramidal symptoms than typical antipsychotics. Here, we presented the first case of belly dancer syndrome in a 71-year-old woman with major depressive disorder after short-term use of quetiapine.",
"affiliations": null,
"authors": "Yeh|Jia-Yin|JY|;Tu|Kun-Yu|KY|;Tseng|Ping-Tao|PT|;Lee|Yu|Y|;Lin|Pao-Yen|PY|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "41(2)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000009:Abdominal Muscles; D000368:Aged; D014150:Antipsychotic Agents; D003865:Depressive Disorder, Major; D004409:Dyskinesia, Drug-Induced; D005260:Female; D006801:Humans; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "73-74",
"pmc": null,
"pmid": "29474193",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Onset of Abdominal Muscle Dyskinesia ('Belly Dancer Syndrome') From Quetiapine Exposure: A Case Report.",
"title_normalized": "acute onset of abdominal muscle dyskinesia belly dancer syndrome from quetiapine exposure a case report"
} | [
{
"companynumb": "GR-ALKEM LABORATORIES LIMITED-GR-ALKEM-2018-02610",
"fulfillexpeditecriteria": "2",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "The performance of regional blockade on a patient with a preexisting neurologic condition or a history of neurologic complications after regional anesthesia is controversial. We present a case of recurring brachial plexus neuropathy in a diabetic patient after two shoulder procedures performed 4 mo apart. In both cases, the patient underwent intensive physical therapy with continuous postoperative interscalene analgesia.",
"affiliations": "Departments of Anesthesiology, Orthopedic Surgery, and Neurology, Mayo Clinic, Rochester, MN 55905, USA. horlocker.terese@mayo.edu",
"authors": "Horlocker|T T|TT|;O'Driscoll|S W|SW|;Dinapoli|R P|RP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/00000539-200009000-00035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "91(3)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000328:Adult; D020516:Brachial Plexus Neuropathies; D003922:Diabetes Mellitus, Type 1; D004576:Electromyography; D005260:Female; D006801:Humans; D009407:Nerve Block; D011183:Postoperative Complications; D012008:Recurrence; D012782:Shoulder",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "688-90",
"pmc": null,
"pmid": "10960400",
"pubdate": "2000-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurring brachial plexus neuropathy in a diabetic patient after shoulder surgery and continuous interscalene block.",
"title_normalized": "recurring brachial plexus neuropathy in a diabetic patient after shoulder surgery and continuous interscalene block"
} | [
{
"companynumb": "US-PFIZER INC-2021257601",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPIVACAINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Steroids are commonly used for fatigue relief in terminally ill cancer patients. However, steroid-induced adverse effects including depression, myopathy, and hyperglycemia may contribute to fatigue. We report our experiences with aggravation of fatigue with steroid use in three cases. Case 1 was a 65-year-old man with advanced gastric cancer. He was started on betamethasone (2 mg/d) for fatigue, but the fatigue worsened due to steroid-induced depression. Discontinuation of steroids and initiation of an antidepressant ameliorated the fatigue. Case 2 was a 68-year-old man with advanced lung cancer. He complained of fatigue. Betamethasone (1 mg/d) was started and alleviated the fatigue. However, when the betamethasone dose was increased to 2 mg/d, the fatigue, with muscle weakness and myalgia, worsened due to steroid-induced myopathy. We therefore switched from betamethasone (2 mg/d) to prednisolone (10 mg /d). The fatigue resolved and the patient returned to his previous condition. Case 3 was a 73-year-old man with recurrent bile duct cancer. He also had diabetes mellitus. He developed fatigue, anorexia and fever. We started betamethasone (1.5 mg/d) for these symptoms, but the fatigue and anorexia worsened due to steroid-induced hyperglycemia. Blood glucose rose to 532 mg/dL. Therefore, insulin therapy was started, and the dose of betamethasone was reduced to 0.5 mg/d. His glucose level decreased to less than 320 mg/dL and he recovered from the fatigue while achieving moderate oral intake. In conclusion, the possibility of steroid-induced secondary fatigue in terminally ill cancer patients should be taken into consideration.",
"affiliations": "1Hospice, Medical corporation Junkei-kai Sotoasahikawa Hospital, Akita, Japan.",
"authors": "Matsuo|Naoki|N|;Yomiya|Kinomi|K|",
"chemical_list": "D001623:Betamethasone",
"country": "United States",
"delete": false,
"doi": "10.1177/1049909113485280",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1049-9091",
"issue": "31(3)",
"journal": "The American journal of hospice & palliative care",
"keywords": "adverse effect; depression; fatigue; hyperglycemia; myopathy; steroid",
"medline_ta": "Am J Hosp Palliat Care",
"mesh_terms": "D000368:Aged; D001623:Betamethasone; D001650:Bile Duct Neoplasms; D003863:Depression; D005221:Fatigue; D006801:Humans; D006943:Hyperglycemia; D008175:Lung Neoplasms; D008297:Male; D009135:Muscular Diseases; D009369:Neoplasms; D013274:Stomach Neoplasms",
"nlm_unique_id": "9008229",
"other_id": null,
"pages": "341-4",
"pmc": null,
"pmid": "23588576",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aggravation of fatigue by steroid therapy in terminally ill patients with cancer.",
"title_normalized": "aggravation of fatigue by steroid therapy in terminally ill patients with cancer"
} | [
{
"companynumb": "PHHY2015JP101457",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nClostridium difficile infection (CDI) is the most frequent cause of nosocomial diarrhoea in adults. Cancer patients, in particular, are at a higher risk for CDI. Limited clinical data exist regarding the use of tigecycline for the treatment of CDI, especially in patients with oncologic and haematologic malignancies.\n\n\nOBJECTIVE\nTo characterize the use of tigecycline for treatment of CDI in oncology patients at an academic cancer centre.\n\n\nMETHODS\nThis was a retrospective, single-centre, single-arm, chart review evaluating the use of tigecycline for the management of CDI in oncology patients at an academic cancer centre.\n\n\nRESULTS\nThe median age of CDI diagnosis in this patient group (N=66) was 65 years (range: 16-84) and the majority of patients had solid tumour malignancies. Fifty-six percent of patients had severe CDI, 70.3% of which were classified as having severe complicated disease. The median time to initiation of tigecycline therapy was 2 days (mean: 3.83) and the median number of tigecycline doses was 13 (range: 1-50). Twelve non-CDI breakthrough infections were observed, and four patients developed CDI while receiving tigecycline for non-CDI indications. The rate of death was 18% and the recurrence rate was 15.2%.\n\n\nCONCLUSIONS\nTigecycline did not lead to overt benefits in outcomes of oncology patients with CDI when compared to historical data. In addition, several breakthrough CDIs were observed in patients who received the drug for a non-CDI indication. Further prospective research is needed to validate the use of tigecycline for management of CDI.",
"affiliations": "Indiana University Simon Cancer Center - Indiana University Health, Indianapolis, IN, USA. Electronic address: bbrinda@iuhealth.org.;Department of Pharmacy, Moffitt Cancer Center, Tampa, FL, USA.;Department of Pharmacy, Moffitt Cancer Center, Tampa, FL, USA.;Department of Pharmacy, Moffitt Cancer Center, Tampa, FL, USA.;Department of Infectious Diseases, Moffitt Cancer Center, Tampa, FL, USA.",
"authors": "Brinda|B J|BJ|;Pasikhova|Y|Y|;Quilitz|R E|RE|;Thai|C M|CM|;Greene|J N|JN|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline",
"country": "England",
"delete": false,
"doi": "10.1016/j.jhin.2016.12.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-6701",
"issue": "95(4)",
"journal": "The Journal of hospital infection",
"keywords": "Clostridium difficile colitis; Haematology; Oncology; Severe Clostridium difficile colitis; Severe complicated Clostridium difficile colitis; Tigecycline",
"medline_ta": "J Hosp Infect",
"mesh_terms": "D000046:Academic Medical Centers; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016360:Clostridioides difficile; D003015:Clostridium Infections; D003092:Colitis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline; D009369:Neoplasms; D012189:Retrospective Studies; D000078304:Tigecycline; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8007166",
"other_id": null,
"pages": "426-432",
"pmc": null,
"pmid": "28153556",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of tigecycline for the management of Clostridium difficile colitis in oncology patients and case series of breakthrough infections.",
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"abstract": "A 37-year-old man with AIDS presented with altered mental status four weeks after stopping his medications for Mycobacterium avium-intracellulare (MAI). He had low CD4 cell count and severe hypercalcemia. Bone marrow biopsy revealed bone marrow infiltration by granulomas positive for acid-fast bacilli and cultures grew MAI. His hypercalcemia continued to worsen with the initiation of MAI therapy but we were able to treat it successfully with pamidronate and calcitonin.",
"affiliations": "University of New Mexico Health Sciences Centre, Albuquerque, NM, USA. Electronic address: hayoubieh@salud.unm.edu.;University of New Mexico Health Sciences Centre, Albuquerque, NM, USA.",
"authors": "Ayoubieh|Houriya|H|;Alkhalili|Eyas|E|",
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"doi": "10.1016/j.bjid.2016.08.002",
"fulltext": "\n==== Front\nBraz J Infect Dis\nBraz J Infect Dis\nThe Brazilian Journal of Infectious Diseases\n1413-8670\n1678-4391\nElsevier\n\nS1413-8670(16)30167-2\n10.1016/j.bjid.2016.08.002\nCase Report\nMycobacterium avium-intracellulare and the unpredictable course of hypercalcemia in an AIDS patient\nAyoubieh Houriya hayoubieh@salud.unm.edu\nh.ayoubieh@gmail.com\n⁎\nAlkhalili Eyas\nUniversity of New Mexico Health Sciences Centre, Albuquerque, NM, USA\n⁎ Corresponding author. hayoubieh@salud.unm.eduh.ayoubieh@gmail.com\n15 9 2016\nJan-Feb 2017\n15 9 2016\n21 1 116118\n31 5 2016\n1 8 2016\n© 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda.\n2016\nSociedade Brasileira de Infectologia\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 37-year-old man with AIDS presented with altered mental status four weeks after stopping his medications for Mycobacterium avium-intracellulare (MAI). He had low CD4 cell count and severe hypercalcemia. Bone marrow biopsy revealed bone marrow infiltration by granulomas positive for acid-fast bacilli and cultures grew MAI. His hypercalcemia continued to worsen with the initiation of MAI therapy but we were able to treat it successfully with pamidronate and calcitonin.\n\nKeywords\n\nHypercalcemia\nAIDS\nMycobacterium infection\n==== Body\npmcIntroduction\n\nHypercalcemia above 14 mg/dL is often attributed to malignancy, but patients with HIV warrant further investigation into opportunistic infections such as Mycobacterium avium-intracellulare (MAI). Although previous reports discussed the association between MAI and hypercalcemia, the onset and clinical course of hypercalcemia is not known. We present a case of hypercalcemia with MAI that worsened with the initiation of anti-mycobacterial therapy and a review of the literature of the onset of hypercalcemia in relation with MAI diagnosis and explore potential triggers.\n\nCase presentation\n\nA 37-year-old man with AIDS on highly active antiretroviral therapy (HAART) and chronic therapy for Mycobacterium avium-intracellulare (MAI) presented with altered mental status four weeks after stopping his medications. His family reported progressive confusion and weight loss. He did not have any recent history of sick contacts, travel, animal exposure, nor illicit drug use. On physical examination, his temperature was 38.1 °C, blood pressure 130/50, heart rate 118, respiratory rate 16 with O2 saturation 95% on room temperature. He was somnolent and cachectic.\n\nLaboratory work-up showed normocytic anemia with a hemoglobin of 8 g/dL, leukopenia 0.9/μL thrombocytopenia 60/μL, CD4 count 7/mm3, creatinine 1.4 mg/dL, corrected calcium 12 mg/dL (ref 8.4–10.4 mg/dL), ionized calcium 1.6 mmol/L (ref 1.15–1.27 mmol/L), phosphorus 2 mg/dL (ref 2.3–5.6), and albumin 1.8 g/dL (ref 3.5–5 d/dL). His 25-hydroxycalciferol level was low 9 ng/ml (ref 30–100), PTH was suppressed 6 pg/mL (ref 11–80 pg/mL) and PTH-related peptide was undetectable.\n\nMagnetic resonance imaging (MRI) of the brain showed scattered areas of abnormal parenchymal signal intensity likely from tuberculous meningoencephalitis (Fig. 1). Computed tomography (CT) of the chest, abdomen and pelvis revealed necrotic mesenteric lymph nodes and splenomegaly.Fig. 1 Magnetic resonance imaging of the brain showing areas of abnormal parenchymal signal intensity (arrows) involving cortex and subcortical white matter within the frontal lobes, right temporal lobe, and left insula.\n\nSerum protein electrophoresis and skeletal survey were negative. Bone marrow biopsy revealed bone marrow infiltration by granulomas positive for acid-fast bacilli and cultures grew MAI. His hypercalcemia was treated with intravenous fluids and he was started on clarithromycin, rifampin and ethambutol for MAI. His serum calcium trended up from 12 mg/dL on admission to 14 mg/dL by hospital day six so he was started on calcitonin and pamidronate with normalization of serum calcium and improvement in the patient's mental status within 24 h.\n\nThe patient's calcium levels remained within normal range but his clinical condition deteriorated as he developed severe sepsis, disseminated intravascular coagulation (DIC), and respiratory failure requiring endotracheal intubation and mechanical ventilation secondary to hospital-acquired pneumonia. A follow-up brain CT showed worsening in the size of the lesions secondary to hemorrhage in the setting of DIC. After extubation, he was found to have major cognitive deficits with being oriented only to self. At the time of discharge, his hypercalcemia, sepsis, and DIC have all resolved, however, his cognitive impairment persisted.\n\nDiscussion\n\nBetween 1981 and 1987, 5.5% of AIDS cases reported to the Centers for Disease Control (CDC) had non-tuberculous mycobacterial infection, with MAI being the culprit in 96% of cases.1 The incidence of opportunistic infections decreased with the advent of HAART and a more recent study from 1994 to 2007 suggested that the rate of Mycobacterium avium complex infection is 2.5 per 1000 person-years in individuals with AIDS.2 The mechanism of hypercalcemia in granulomatous disease is thought to be related to vitamin D dysregulation but this does not always correlate with vitamin D metabolite levels.3\n\nA review of the literature yielded only eight cases of MAI-associated hypercalcemia (Table 1). Three of these cases presented with hypercalcemia at the time of diagnosis of MAI3, 4, 5; Tsao et al. described hypercalcemia presenting as part of the spectrum of immune reconstitution inflammatory syndrome (IRIS) against MAI.6 Four reports described hypercalcemia in patients who were undergoing treatment for MAI, soon after starting or changing antimicrobial therapy.7, 8 One patient was diagnosed three weeks after initiating treatment for vitamin D deficiency.3 Our patient presented with hypercalcemia at the time of diagnosis, which worsened within days of restarting MAI therapy. In all these cases, no association between the development of hypercalcemia and organ involvement or choice of anti-MAI therapy was observed.Table 1 Previous reports of MAI-associated hypercalcemia.\n\nTable 1Study\tTimeframe of MAI diagnosis in relation to hypercalcemia\tPotential hypercalcemia trigger\tHypercalcemia treatment\t\nTsao et al.6\tAt presentation\tStarting HAART with subsequent development of IRIS\tSteroids\t\nShrayyef et al.3\tAt presentation\tInitiation of vitamin D and calcium supplementation three weeks prior\tUnknown\t\nChoudhary et al.7\tSix months prior\tChanges in MAI therapy\tSteroids\t\n\n\n\t\nPlayford et al.8\t\n Case 1\tFour months prior\tChanges in MAI therapy\tBisphosphonate\t\n Case 2\tFour weeks prior\tInitiating MAI therapy\tBisphosphonate\t\n\n\n\t\nAly et al.4\tAt presentation\tSix months after starting HAART\tBisphosphonate\t\nNewell et al.12\tSix months prior\tUnknown\tBisphosphonate\t\nDelahunt et al.5\tAt presentation\tUnknown\tBisphosphonate and steroids\t\n\nThe suggested treatment of hypercalcemia in granulomatous disease is steroids which are thought to downregulate calcitriol synthesis by macrophages.9 Given our concern for lymphoma as part of our differential diagnosis, we elected not to use steroids as they cause histopathological alterations on biopsy and delay in making the diagnosis.10 Our patient was treated with calcitonin and pamidronate. Bisphosphonates can be safely used for the treatment of osteoporosis in HIV patients,11 and Shrayef et al. previously used pamidronate successfully for the treatment of hypercalcemia with MAI.3\n\nIt is unknown if there is a genetic predisposition for some individuals with AIDS who are infected with MAI to develop hypercalcemia. Our review of the literature suggests that certain triggers may be implicated such as immune reconstitution after starting HAART, improved host defence mechanism after initiating or incurring change in anti-MAI therapy or dysregulated response to vitamin D treatment.\n\nConclusions\n\nWhile hypercalcemia is a known complication of granulomatous disease, clinicians should be aware of the variability in presentation of hypercalcemia with MAI, whether as the first manifestation or a late presenter in the disease course. As we showed in this case, hypercalcemia may worsen within days of initiating anti-mycobacterial therapy. We suggest careful monitoring of serum calcium levels upon diagnosis of MAI infection and after initiation of mycobacterial therapy or vitamin D supplementation. Pamidronate and calcitonin are acceptable treatment alternatives to steroids for hypercalemia treatment.\n\nConflicts of interest\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n\n1 Horsburgh C.R. Jr. Selik R.M. The epidemiology of disseminated nontuberculous mycobacterial infection in the acquired immunodeficiency syndrome (AIDS) Am Rev Respir Dis 139 1989 4 7 2912355\n2 Buchacz K. Baker R.K. Palella F.J. Jr. AIDS-defining opportunistic illnesses in US patients, 1994–2007: a cohort study AIDS 24 2010 1549 1559 20502317\n3 Shrayyef M.Z. DePapp Z. Cave W.T. Wittlin S.D. Hypercalcemia in two patients with sarcoidosis and Mycobacterium avium intracellulare not mediated by elevated vitamin D metabolites Am J Med Sci 342 2011 336 340 21760475\n4 Aly E.S. Baig M. Khanna D. Baumann M.A. Hypercalcaemia: a clue to Mycobacterium avium intracellulare infection in a patient with AIDS Int J Clin Pract 53 1999 227 228 10665139\n5 Delahunt J.W. Romeril K.E. Hypercalcemia in a patient with the acquired immunodeficiency syndrome and Mycobacterium avium intracellulare infection J Acquir Immune Defic Syndr 7 1994 871 872 8021822\n6 Tsao Y.T. Lee S.W. Hsu J.C. Ho F.M. Wang W.J. Surviving a crisis of HIV-associated immune reconstitution syndrome Am J Emerg Med 30 2012 1661 e5-1661.e7\n7 Choudhary M. Rose F. Posterior reversible encephalopathic syndrome due to severe hypercalcemia in AIDS Scand J Infect Dis 37 6–7 2005 524 526 16012020\n8 Playford E.G. Bansal A.S. Looke D.F. Whitby M. Hogan P.G. Hypercalcaemia and elevated 1,25(OH)(2)D(3) levels associated with disseminated Mycobacterium avium infection in AIDS J Infect 42 2001 157 158 11531324\n9 Sandler L.M. Winearls C.G. Fraher L.J. Clemens T.L. Smith R. O’Riordan J.L. Studies of the hypercalcaemia of sarcoidosis: effect of steroids and exogenous vitamin D3 on the circulating concentrations of 1,25-dihydroxy vitamin D3 Q J Med 53 Spring 1984 165 180 6087399\n10 Kan E. Levi I. Benharroch D. Alterations in the primary diagnosis of lymphomas pretreated with corticosteroid agents Leuk Lymphoma 52 2011 425 428 21323522\n11 Vescini F. Grimaldi F. Bisphosphonates in the treatment of HIV-related osteoporosis Endocrine 48 2015 358 359 25424437\n12 Newell A. Nelson M.R. Hypercalcaemia in a patient with AIDS and Mycobacterium avium intracellulare infection Int J STD AIDS 8 1997 405 9179654\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1413-8670",
"issue": "21(1)",
"journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases",
"keywords": "AIDS; Hypercalcemia; Mycobacterium infection",
"medline_ta": "Braz J Infect Dis",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D001853:Bone Marrow; D018791:CD4 Lymphocyte Count; D006801:Humans; D006934:Hypercalcemia; D008279:Magnetic Resonance Imaging; D008297:Male; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection",
"nlm_unique_id": "9812937",
"other_id": null,
"pages": "116-118",
"pmc": null,
"pmid": "27620657",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mycobacterium avium-intracellulare and the unpredictable course of hypercalcemia in an AIDS patient.",
"title_normalized": "mycobacterium avium intracellulare and the unpredictable course of hypercalcemia in an aids patient"
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"abstract": "Drug-induced neurotoxicity is a rare adverse reaction associated with ertapenem. Encephalopathy is a type of neurotoxicity that is defined as a diffuse disease of the brain that alters brain function or structure. We report a patient with normal renal function who developed ertapenem-induced encephalopathy manifesting as altered mental status, hallucinations, and dystonic symptoms. The patient's symptoms improved dramatically following ertapenem discontinuation, consistent with case reports describing ertapenem neurotoxicity in renal dysfunction. Since clinical evidence strongly suggested ertapenem causality, we utilized the Naranjo Scale to estimate the probability of an adverse drug reaction to ertapenem. Our patient received a Naranjo Scale score of 7, suggesting a probable adverse drug reaction, with a reasonable temporal sequence to support our conclusion.",
"affiliations": "University of South Carolina, Columbia, SC, USA.;University of South Carolina, Columbia, SC, USA.;Dorn Veterans Affairs Medical Center, Columbia, SC, USA.;Dorn Veterans Affairs Medical Center, Columbia, SC, USA.;University of South Carolina, Columbia, SC, USA.",
"authors": "Sutton|S Scott|SS|;Jumper|Mark|M|;Cook|Sean|S|;Edun|Babatunde|B|;Wyatt|Michael D|MD|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961668937610.1177_2324709616689376Case ReportErtapenem-Induced Encephalopathy in a Patient With Normal Renal Function Sutton S. Scott PharmD1Jumper Mark PharmD1Cook Sean DO2Edun Babatunde MD2Wyatt Michael D. PhD11 University of South Carolina, Columbia, SC, USA2 Dorn Veterans Affairs Medical Center, Columbia, SC, USAS. Scott Sutton, PharmD, University of South Carolina, 715 Sumter Street, Columbia, SC 29201, USA. Email: sutton@sccp.sc.edu01 1 2017 Jan-Mar 2017 5 1 232470961668937626 10 2016 17 11 2016 20 12 2016 © 2017 American Federation for Medical Research2017American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Drug-induced neurotoxicity is a rare adverse reaction associated with ertapenem. Encephalopathy is a type of neurotoxicity that is defined as a diffuse disease of the brain that alters brain function or structure. We report a patient with normal renal function who developed ertapenem-induced encephalopathy manifesting as altered mental status, hallucinations, and dystonic symptoms. The patient’s symptoms improved dramatically following ertapenem discontinuation, consistent with case reports describing ertapenem neurotoxicity in renal dysfunction. Since clinical evidence strongly suggested ertapenem causality, we utilized the Naranjo Scale to estimate the probability of an adverse drug reaction to ertapenem. Our patient received a Naranjo Scale score of 7, suggesting a probable adverse drug reaction, with a reasonable temporal sequence to support our conclusion.\n\ndrug-induced encephalopathyertapenemdrug-induced neurotoxicitycover-dateJanuary-March 2017\n==== Body\nIntroduction\nDrug-induced neurotoxicity is a rare adverse reaction associated with carbapenem antibiotics.1-3 The data demonstrating a neurotoxic association for carbapenems stems from animal models, observational analyses, randomized controlled trials, meta-analysis, and case reports.1-3,7-14 Imipenem is considered to have the highest incidence of neurotoxicity among carbapenems, although there are published literature that refute this consensus.3,7,15-19 Encephalopathy is a type of neurotoxicity that is defined as a diffuse disease of the brain that alters brain function or structure. Encephalopathy is characterized by an altered mental state with additional symptoms including progressive loss of memory and cognitive ability, personality changes, myoclonus, nystagmus, tremor, and seizures. Carbapenem neurotoxicity is often evaluated and reported in terms of seizures, and data on encephalopathy are limited. There are case reports of ertapenem neurotoxic effects consisting of encephalopathy in patients with end-stage renal disease or mild renal dysfunction. We report a patient with normal renal function who developed ertapenem-induced encephalopathy manifesting as altered mental status, hallucinations, and dystonic symptoms.\n\nCase Description\nA 67-year-old male with a history of normal cognitive function was admitted with complaints of hallucinating for approximately 1 week. Past medical history was significant for chronic lumbar spine methicillin-sensitive Staphylococcus aureus osteomyelitis maintained on life-long cephalexin suppression (discontinued 2 weeks before presentation), non-Hodgkin’s lymphoma in remission for 20 years, hypertension, atrial fibrillation, type 2 diabetes for 13 years (current HgA1C 8.2), ankylosing spondylitis, and esophagitis. Table 1 lists the medication history at hospital admission. The patient’s chronic lumbar spine osteomyelitis led to numerous surgical manipulations of the spinal region, the last of which was in 2012. The spine site became reinfected in 2015 requiring hardware removal and multiple surgical debridements. The spinal abscess wound cultures were positive for Enterobacter sp, Lactobacillus sp, and Candida glabrata. Treatment was initiated with oral fluconazole 600 mg daily, piperacillin/tazobactam 4.5 g every 6 hours (changed to ertapenem 1 g daily), and a wound vacuum-assisted closure dressing placed over the surgical site. Encephalopathic symptoms including hallucinations began 5 days after ertapenem was started. Clinical examination at the bedside revealed the patient to be responsive and alert but clearly lethargic with clouded sensorium, lip smacking, mild asterixis and tremor, and incoherent speech. Through the entire hospitalization the patient remained afebrile with normal vital signs. Leukocyte count remained normal at an average of 5.5 × 109/L (6 readings). His renal function remained stable and electrolytes were normal, as were random glucose checks, thyroid function test, and ammonia level (Table 2). Calculated creatinine clearance by the Cockcroft-Gault equation was 66 mL/min on admission (Table 2). Urine and repeated blood culture sets were negative. Urinalysis was unremarkable. Arterial blood gas was noncontributory. Chest radiograph revealed a left upper lobe pulmonary nodule but subsequent thoracic computed tomography scan with contrast showed no contributing pathology and was stable. Computed tomography of the head revealed no acute intracranial pathology. Electroencephalogram was also normal. An extensive literature review of ertapenem, neurotoxicity, and encephalopathy yielded case reports of ertapenem-induced central nervous system (CNS) events. Ertapenem was stopped and ceftazidime 2 g every 8 hours was started. His hallucinations and related neurological symptoms began to improve and the patient recovered to his baseline mental status within 2 days.\n\nTable 1. Medication History at Time of Admission.\n\nAtorvastatin 80 mg daily\t\nCephalexin 500 mg every 12 hoursa\t\nDiltiazem 120 mg daily\t\nErtapenem 1 g dailyb\t\nFluconazole 600 mg daily\t\nGabapentin 300 mg 3 times per day as needed\t\nGlipizide 10 mg twice daily\t\nMetformin 500 mg twice daily\t\nMetoprolol tartrate 25 mg twice daily\t\nRivaroxaban 20 mg daily\t\na Cephalexin was discontinued 2 weeks priors to presentation for altered mental status.\n\nb Ertapenem was administered intravenously; all other medications were orally administered.\n\nTable 2. Summary of the Blood Test Results of Our Patient on Admission.\n\nParameters\tReadings\tNormal Ranges\t\nWhite cell count\t6.8\t3.6-11.1 K/mm3\t\nHemoglobin\t10.5\t12.9-16.1 g/dL\t\nPlatelet\t476\t165-353 K/mm3\t\nSodium\t136\t135-145 mmol/L\t\nPotassium\t4.3\t3.5-5.1 mmol/L\t\nBlood urea nitrogen\t16\t7-26 mg/dL\t\nCreatinine\t1.2a\t0.5-1.3 mg/dL\t\nCalcium\t9\t8.4-10.2 mg/dL\t\nAlbumin\t2.2\t3.5-5.0 g/dL\t\nTotal bilirubin\t0.3\t0.2-1.2 mg/dL\t\nAlkaline phosphatase\t107\t40-150 U/L\t\nAlanine aminotransferase\t102\t0-55 U/L\t\nAspartate aminotransferase\t76\t5-34 U/L\t\nAmmonia\t29\t18-72 Umol/L\t\nThyroid-stimulating hormone\t5.93\t0.35-4.94 µIU/mL\t\nFree T4\t0.95\t0.70-1.48 ng/dL\t\na The serum creatinine ranged from 1.1 to 1.2 mg/dL over 2 years prior to admission. The creatinine clearance calculation by the Cockcroft-Gault method was 66 mL/min using adjusted body weight (actual body weight 92 kg; adjusted body weight 78 kg; ideal body weight 68 kg). Regardless of the weight utilized (ideal, actual, or adjusted), the patients ertapenem dose of 1 g daily is correct based off creatinine clearance dosing recommendations.19\n\nDiscussion\nOur report demonstrates a case of ertapenem-induced encephalopathy manifesting as hallucinations and altered mental status. The patient’s symptoms improved dramatically following ertapenem discontinuation, consistent with case reports describing ertapenem neurotoxicity in renal dysfunction. No other medication regimen changes were done during the hospitalization, and no medical history was identified as a cause of the encephalopathy. Since clinical evidence strongly suggested ertapenem causality, we utilized the Naranjo Scale to estimate the probability of an adverse drug reaction to ertapenem.20 Our patient received a Naranjo Scale score of 7, suggesting a probable adverse drug reaction, with a reasonable temporal sequence to support our conclusion (Table 3).\n\nTable 3. Naranjo Adverse Reaction Probability Scale.\n\nQuestion\tYes\tNo\tDo Not Know\tCase Report Score\t\nAre there previous conclusive reports about the reaction\t+1\t0\t0\t+1\t\nDid the adverse event appear after the suspected drug was administered?\t+2\t−1\t0\t+2\t\nDid the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?\t+1\t0\t0\t+1\t\nDid the adverse event reappear when the drug was re-administered?\t+2\t−1\t0\t0\t\nAre there alternative causes (other than the drug) that could on their own have caused the reaction?\t−1\t+2\t0\t+2\t\nDid the reaction reappear when a placebo was given?\t−1\t+1\t0\t0\t\nWas the drug detected in blood (or other fluids) in concentrations known to be toxic?\t+1\t0\t0\t0\t\nWas the reaction more severe when the dose was increased or less severe when the dose was decreased?\t+1\t0\t0\t0\t\nDid the patient have a similar reaction to the same or similar drugs in any previous exposure?\t+1\t0\t0\t0\t\nWas the adverse event confirmed by any objective evidence?\t+1\t0\t0\t+1\t\nTotal score = 7a\t\na Total score 5 to 8 = probable adverse drug reaction, with a reasonable temporal sequence to support the reaction.\n\nImipenem has demonstrated the highest neurotoxic adverse reaction rates among the carbapenems, while drug-induced encephalopathy is rare with ertapenem and other carbapenems. Imipenem neurotoxicity rates in adults range from 0.4% to 10%, compared to less than 1% for meropenem, doripenem, and ertapenem.3 Specifically for ertapenem, postmarketing literature documenting ertapenem neurotoxicity is scarce and limited to case reports with patient-related factors (eg, renal dysfunction, history of central nervous system disorders).10,11,21-25 Published case reports include the following:\n\nDuquaine et al reported 2 patients who developed unusual mental status changes while receiving ertapenem 1 g daily.21 One patient had acute renal dysfunction prior to starting therapy. Symptoms resolved on drug discontinuation for both patients.\n\nWen et al reported 2 patients with advanced renal failure who received ertapenem at 500 mg daily and subsequently developed acute prolonged neurotoxicity.22 Baseline mental function returned 2 weeks after discontinuation of therapy for both patients.\n\nLee et al reported 4 patients on hemodialysis that developed unexplained central nervous system toxicity and hallucinations after receiving 500 mg.23 Discontinuing the drug led to symptom resolution in all 4 patients.\n\nShea et al reported a patient with moderate renal impairment who developed encephalopathy with delayed recovery of 2 weeks. The patient exhibited a full recovery after cessation of ertapenem.24\n\nOo et al reported 2 cases of ertapenem neurotoxicity, including psychosis and encephalopathy.10 Symptoms resolved within 3 and 10 days of discontinuing ertapenem.\n\nKong et al reported a case of ertapenem-induced visual hallucinations.11 Subsequent re-introduction of ertapenem resulted in almost identical symptoms. Complete resolution of symptoms occurred after discontinuation of ertapenem, as observed in our case study.\n\nRisk factors for carbapenem neurotoxic adverse reactions include the following: (1) basicity strength of the C-2 amino group for carbapenems; (2) accumulation in the CNS, specifically in cases of excessive dosage or impaired renal clearance; (3) patients with CNS disorders (eg, past medical history of seizure disorder).5,25-27 Among these risk factors, molecular structure is the most important compound-related factor and renal insufficiency is the most important patient-related factor predisposing to carbapenem neurotoxicity. Pharmacokinetic-related factors may also influence the neurotoxic reactions related to ertapenem. Neurotoxicity risk factors include the following:\n\nCompound related: Carbapenems have discordant rates of neurotoxic adverse reactions potentially because of structural differences within side chains.1-3,6-9 Available data demonstrate the probable neurotoxic mechanism is via interactions with the γ-amino butyric acid receptor A (GABAA).8,9 This interaction is through the side chain on the second carbon atom (C-2) in the carbapenem nucleus. A carbapenem with a basic C-2 side chain increases the binding to GABAA resulting in higher neurotoxic activity in animal models. Because of a basic C-2 side chain, imipenem has a higher tendency to produce neurotoxic adverse reactions compared to meropenem because of the less basic side C-2 side chain of meropenem.1-3,6-9 Conversely, ertapenem has an acidic carboxyl group at the C-2 position, is expected to have the lowest binding to GABAA, and subsequently is thought to have the lowest potential for neurotoxic activity.\n\nPatient related: Patient-related risk factors for carbapenem neurotoxicity include advanced age, history of CNS disease, renal insufficiency, low body weight, and concurrent use of drugs that are nephrotoxic or that may lower the seizure threshold.4,5 Published literature demonstrates that renal dysfunction (end-stage renal disease or mild renal dysfunction) is the primary patient-related factor.\n\nPharmacokinetic related: There are pharmacokinetic parameters of ertapenem that also could contribute to the drug’s ability to affect the CNS. These factors include a high volume of distribution, high lipophilicity, high protein binding, strong CNS penetration, and metabolites that can also inhibit GABA receptors.8,9\n\nOur patient is unique because he had no baseline cerebrovascular disease or history of renal dysfunction. Characteristics of our patient that may have contributed include his age (67), low albumin levels, potential overestimation of his renal function, and prior cephalexin suppression. Ertapenem is highly protein bound—up to 95% bound to albumin; thus, our patient may have been exposed to excessive free drug as his albumin was low. In addition, ertapenem is renally excreted, up to 80%, requiring dosage adjustments for creatinine clearance of less than 30 mL/min. Our patient’s creatinine clearance could have been overestimated as serum creatinine measurements are not as accurate in the elderly.28 The creatinine clearance calculation of 66 mL/min utilized the adjusted body weight of the patient. Regardless of the weight utilized (ideal, actual, or adjusted), the patients ertapenem dose of 1 g daily is correct based off creatinine clearance dosing recommendations (Table 2). Furthermore, while there is no known interaction between cephalexin and ertapenem, it is possible that cephalexin suppression could have had an impact on this case. However, the patient tolerated the cephalexin while receiving and tolerated ceftazidime after developing the CNS symptoms. Furthermore, cephalexin was discontinued 2 weeks prior to presentation; therefore, it is unlikely that cephalexin has a role in the symptoms.\n\nPrevious studies and reviews on carbapenem antibiotics indicated that the high degree of neurotoxicity is not a class phenomenon for carbapenems, and that there are carbapenems that have a lower degree of neurotoxicity. Therefore, non-imipenem carbapenems are thought to be safely administered at high doses and are useful in the treatment of CNS infections. While this may be true, non-imipenem carbapenems have demonstrated a neurotoxic potential, and our case report demonstrates a carbapenem with an acidic carboxyl group administered to a patient with no neurotoxic risk factors can still develop encephalopathy. Our case report aims to add to the growing body of literature of ertapenem-induced neurotoxicity with the goal of increasing education regarding the potential for these neurotoxic effects.\n\nConclusion\nWe are sharing our experience of a patient with normal renal function who developed neurotoxicity following standard dosing of ertapenem. The goal of this case report is to draw attention to the neurologic and encephalopathic potential of ertapenem. Identifying ertapenem as a potential causative agent of these conditions can spare unnecessary investigations and health care expenditures. In our patient, supportive care following discontinuation of ertapenem resulted in complete resolution of his hallucinations and altered mental status.\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==== Refs\nReferences\n1 \nNorby SR \nNeurotoxicity of carbapenem antibiotics: consequences for their use in bacterial meningitis . J Antimicrob Chemother . 2000 ;45 :5 -7 .10629006 \n2 \nChow KM Hui AC Szeto CC \nNeurotoxicity induced by beta-lactam antibiotics: from bench to bedside . Eur J Clin Microbiol Infect Dis . 2005 ;24 :649 -653 .16261307 \n3 \nMiller AD Ball AM Bookstaver PB Dornblaser EK Bennett CL \nEpileptogenic potential of carbapenem agents: mechanism of action, seizure rates, and clinical considerations . Pharmacotherapy . 2011 ;31 :408 -423 .21449629 \n4 \nGrill MF Maganti RK \nNeurotoxic effects associated with antibiotic use: management considerations . Br J Clin Pharmacol . 2011 ;72 :381 -393 .21501212 \n5 \nSchliamser SE Cars O Norrby SR \nNeurotoxicity of β-lactam antibiotics: predisposing factors and pathogenesis . J Antimicrob Chemother . 1991 ;27 :405 -425 .1856121 \n6 \nHoriuchi M Kimura M Tokumura M Hasebe N Arai T Abe K \nAbsence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics . Toxicology . 2006 ;222 :114 -124 .16549226 \n7 \nCannon JP Lee TA Clark NM Setlak P Grim SA \nThe risk of seizures among the carbapenems: a meta-analysis . J Antimicrob Chemother . 2014 ;69 :2043 -2055 .24744302 \n8 \nHikida M Masukawa Y Nishiki K Inomata N \nLow neurotoxicity of LJC 10,627, a novel 1-beta-methyl carbapenem antibiotic inhibition of gamma-aminobutyric acid A, benzodiazepine, and glycine receptor binding in relation to lack of central nervous system toxicity in rats . Antimicrob Agents Chemother . 1993 ;37 :199 -202 .8383938 \n9 \nSunagawa M Matsumura H Sumita Y Nouda H \nStructural features resulting in convulsive activity of carbapenem compounds: effect of C-2 side chain . J Antibiot (Tokyo) . 1995 ;48 :408 -416 .7797443 \n10 \nOo Y Packham D Tau W Munckhof WJ \nEtrapenem-associated psychosis and encephalopathy . Intern Med J . 2014 ;44 :817 -819 .25081048 \n11 \nKong V Beckert L Awunor-Renner C \nA case of beta lactam-induced visual hallucinations . N Z Med J . 2009 ;122 :76 -77 .\n12 \nKuchinskas S Reger C \nTactile hallucinations as a side effect of ertapenem on an acute rehabilitation floor . Am J Phys Med Rehabil . 2006 ;85 (3 ):267 .\n13 \nCalandra GB Brown KR Grad LC Ahonkhai VI Wang C Aziz MA \nReview of adverse experiences and tolerability in the first 2,516 patients treated with imipenem/cilastatin . Am J Med . 1985 ;78 :73 -78 .3859218 \n14 \nWong VK Wright HT JrRoss LA Mason WH Inderlied CB Kim KS \nImipenem/cilastatin treatment of bacterial meningitis in children . Pediatr Infect Dis J . 1991 ;10 :122 -125 .2062603 \n15 \nNorrby SR \nCarbapenems in serious infections: a risk-benefit assessment . Drug Saf . 2000 ;22 :191 -194 .10738843 \n16 \nNorrby SR \nNeurotoxicity of carbapenem antibacterials . Drug Saf . 1996 ;15 :87 -90 .8884160 \n17 \nPrimaxin [Package insert] . Whitehouse Station, NJ : Merck & Co, Inc ; 2012 .\n18 \nMerrem [Package insert] . Wilmington, DE : Astra Zeneca ; 2010 .\n19 \nInvanz [Package insert] . Whitehouse Station, NJ : Merck & Co, Inc ; 2012 .\n20 \nNaranjo CA Busto U Sellers EM \nA method for estimating the probability of adverse drug reaction . Clin Pharmacol Ther . 1981 ;30 :239 -245 .7249508 \n21 \nDuquaine S Kitchell E Tate T Tannen RC Wickremasinghe IM \nCentral nervous system toxicity associated with ertapenem use . Ann Pharmacother . 2011 ;45 :e6 .21177419 \n22 \nWen MJ Sung CC Chau T Lin SH \nAcute prolonged neurotoxicity associated with recommended doses of ertapenem in 2 patients with advanced renal failure . Clin Nephrol . 2013 ;80 :474 -478 .22579271 \n23 \nLee KH Ueng YF Wu CW Chou YC Ng YY Yang WC \nThe recommended dose of ertapenem poses a potential risk for central nervous system toxicity in haemodialysis patients—case reports and literature reviews . J Clin Pharm Ther . 2015 ;40 :240 -244 .25487647 \n24 \nShea Y Mok M Cheng K Hon FK Chu LW \nDelayed recovery from ertapenem induced encephalopathy: case-report and a possible mechanism . Int J Clin Pharm . 2013 ;35 :535 -537 .23801127 \n25 \nCalandra G Lydick E Carrigan J Weiss L Guess H \nFactors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin . Am J Med . 1988 ;84 :911 -918 .3284342 \n26 \nWallace KL \nAntibiotic-induced convulsions . Crit Care Clin . 1997 ;13 :741 -762 .9330839 \n27 \nChow KM Szeto CC Hui AC Li PK \nMechanisms of antibiotic neurotoxicity in renal failure . Int J Antimicrob Agents . 2004 ;23 :213 -217 .15164960 \n28 \nGoldberg TH Finkelstein MS \nDifficulties in estimating glomerular filtration rate in the elderly . Arch Intern Med . 1987 ;147 :1430 -1433 .3453695\n\n",
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"abstract": "A 79-year-old female was diagnosed with epilepsy because she experienced loss of consciousness twice in January and February and then had a seizure in June 2016. She was treated with 800 mg sodium valproate (sustained release). After 3 days, she experienced loss of appetite, and more than 3 days later, disturbance of consciousness. Serum valproic acid (VPA) concentration was 128.3 μg/ml and serum ammonia was 404 μmol/l. Cerebral edema and status epilepticus occurred. Severe neurological dysfunction remained, even after treatment with continuous hemodiafiltration and levocarnitine. VPA is widely used for the treatment of generalized epilepsy. VPA-induced hyperammonemic encephalopathy is a rare but serious adverse event of VPA. Thus, we must pay attention to serum ammonia levels when using VPA, even VPA monotherapy.",
"affiliations": "Department of Neurology, Hiroshima Prefectural Hospital.;Department of Neurology, Hiroshima University Hospital.;Department of Neurology, Hiroshima Prefectural Hospital.;Department of Neurology, Hiroshima Prefectural Hospital.;Department of Neurology, Hiroshima Prefectural Hospital.;Department of Neurology, Hiroshima Prefectural Hospital.",
"authors": "Yamada|Hidetada|H|;Shishido|Takeo|T|;Mukai|Tomoya|T|;Araki|Mutsuko|M|;Naka|Hiromitsu|H|;Tokinobu|Hiroshi|H|",
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"title": "Valproic acid-induced hyperammonemic encephalopathy in a patient receiving valproic acid monotherapy.",
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"abstract": "Cardiac arrest occurred in an 85-year-old female administered osimertinib for advanced lung cancer expressing epidermal growth factor receptor (EGFR) mutations. Electrocardiogram (ECG) recorded at recurrence of spontaneous circulation showed sinus rhythm associated with mild QT prolongation (QTc = 455 ms) to which silent myocardial ischemia and coadministration of itraconazole and herbal drug causing hypokalemia (2.1 mEq/L) may have contributed. Discontinuation of osimertinib, itraconazole and herbal drug, potassium supplementation and percutaneous coronary intervention alleviated QT prolongation (QTc = 432 ms). Osimertinib is the third-generation tyrosine kinase inhibitor lengthening QT interval, and careful monitoring of ECG, serum potassium and drugs coadministered during chemotherapy including osimertinib are highly required.",
"affiliations": "Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan.;Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan.;Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan.;Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan.;Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan.;Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan.;Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan.;Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan.;Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan.",
"authors": "Kondo|Moë|M|;Kisanuki|Megumi|M|;Kokawa|Yosuke|Y|;Gohara|Seiichiro|S|;Kawano|Osamu|O|;Kagiyama|Shuntaro|S|;Maruyama|Toru|T|;Odashiro|Keita|K|;Maehara|Yoshihiko|Y|",
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"doi": "10.3389/fcvm.2021.655808",
"fulltext": "\n==== Front\nFront Cardiovasc Med\nFront Cardiovasc Med\nFront. Cardiovasc. Med.\nFrontiers in Cardiovascular Medicine\n2297-055X\nFrontiers Media S.A.\n\n10.3389/fcvm.2021.655808\nCardiovascular Medicine\nCase Report\nCase Report: QT Prolongation and Abortive Sudden Death Observed in an 85-Year-Old Female Patient With Advanced Lung Cancer Treated With Tyrosine Kinase Inhibitor Osimertinib\nKondo Moë 1\nKisanuki Megumi 1\nKokawa Yosuke 1\nGohara Seiichiro 1\nKawano Osamu 1\nKagiyama Shuntaro 1\nMaruyama Toru 2*\n\nOdashiro Keita 1\nMaehara Yoshihiko 1\n1Division of Cardiology, Department of Internal Medicine, Kyushu Central Hospital, Fukuoka, Japan\n2Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan\nEdited by: Margaret Rose Cunningham, University of Strathclyde, United Kingdom\n\nReviewed by: Gavin Oudit, University of Alberta, Canada; Martino Deidda, University of Cagliari, Italy\n\n*Correspondence: Toru Maruyama maruyama@artsci.kyushu-u.ac.jp\nThis article was submitted to Cardio-Oncology, a section of the journal Frontiers in Cardiovascular Medicine\n\n19 3 2021\n2021\n8 65580819 1 2021\n22 2 2021\nCopyright © 2021 Kondo, Kisanuki, Kokawa, Gohara, Kawano, Kagiyama, Maruyama, Odashiro and Maehara.\n2021\nKondo, Kisanuki, Kokawa, Gohara, Kawano, Kagiyama, Maruyama, Odashiro and Maehara\nThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nCardiac arrest occurred in an 85-year-old female administered osimertinib for advanced lung cancer expressing epidermal growth factor receptor (EGFR) mutations. Electrocardiogram (ECG) recorded at recurrence of spontaneous circulation showed sinus rhythm associated with mild QT prolongation (QTc = 455 ms) to which silent myocardial ischemia and coadministration of itraconazole and herbal drug causing hypokalemia (2.1 mEq/L) may have contributed. Discontinuation of osimertinib, itraconazole and herbal drug, potassium supplementation and percutaneous coronary intervention alleviated QT prolongation (QTc = 432 ms). Osimertinib is the third-generation tyrosine kinase inhibitor lengthening QT interval, and careful monitoring of ECG, serum potassium and drugs coadministered during chemotherapy including osimertinib are highly required.\n\ncancer\nherbal drug\nosimertinib\nQT prolongation\ncardiooncology\n==== Body\nIntroduction\n\nCardiovascular complications of anticancer drugs are the main interest within the field of cardiooncology (1). Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is a first-line therapy for patients with cancer expressing epidermal growth factor receptor (EGFR) mutations. This anticancer drug has adverse effects including cardiotoxicity such as coronary tonus elevation and QT prolongation in electrocardiogram (ECG), because vascular and cardiac potassium channels are regulated largely by EGFR tyrosine kinase (2). However, osimertinib-induced QT prolongation leading to the possible development of Torsades de Pointes (TdP) has received less attention (3). We herein describe a case of 85-year-old female patient with EGFR driver mutant lung cancer treated with osimertinib, which lengthened QT interval causing abortive sudden cardiac death (SCD).\n\nCase Description\n\nAn 85-year-old female was conveyed by ambulance to the emergency room of our hospital due to cardiac arrest. She had lost her consciousness at 15:15 after she visited the outpatient clinic of another hospital for the treatment with advanced lung cancer (adenocarcinoma: cT2aN1M1b, Stage IVB). Bystander resuscitation was started immediately after the cardiac arrest, and emergency call was requested at 15:18. Ambulance crews confirmed cardiac arrest at 15:28, and she restored spontaneous circulation at 15:34 after the first discharge of public automated external defibrillator (AED). When she admitted to our hospital by ambulance at 15:40, her body temperature was 36.2°C, consciousness level in Glasgow Coma Scale was E1V1M1, and reflex to light was prompt. Blood pressure was 154–103 mmHg, pulse was regular, and its rate was 81 bpm. No abnormal physical findings were found. She had been started administration of oral osimertinib (40 mg once daily) as a first-line therapy of lung cancer after confirming EGFR mutation (T790M), oral itraconazole (200 mg once daily) for prevention of opportunistic fungal infection and crude herbal anticancer drug used in Chinese traditional medicine (TJ-48). She had no complaint of chest oppression or syncope nor family history of unexpected or abortive SCD in her relatives.\n\nLaboratory examination on admission included serum chemistry showing total protein 5.8 g/dL, albumin 3.2 g/dL, CK 215 IU/L (CK-MB 19 IU/L), CRP 0.3 mg/dL, BNP 348.5 pg/mL, troponin T (TnT) 0.01 ng/mL, Na 139 mEq/L, Ca 9.2 mEq/L, and K 2.1 mEq/L. Hematology indicated mild anemia (hemoglobin of 10.3 g/dl) associated with white blood cell and platelet counts of 8,500/μL and 25.1 × 104/μL, respectively. ECG showed sinus rhythm, left axis deviation, flat or inverted T waves observed in II, III, aVF, V5−6, and QT prolongation (grade I), i.e., QT interval corrected by heart rate (QTc = QT/RR0.5) was 455 ms (Figure 1A). Chest X-ray showed cardiomegaly and chest computed tomography demonstrated bilateral pleural effusion (Figures 2A,B). Ejection fraction was 64% on echocardiogram. Chemotherapeutic regimen including osimertinib, oral itraconazole and herbal medicine (TJ-48) were discontinued, and supplementation of potassium was started. Considering possible ischemic T wave changes (Figure 1A), coronary angiogram was performed. Stenotic lesion (99%) was found in the right coronary artery (segment 1) and collateral circulation supplied from left anterior descending artery was observed (Figures 3A,B). Percutaneous coronary intervention (PCI) was completed successfully by stent implantation at the culprit lesion (Figures 3C,D). QTc interval after the successful PCI and restoration of hypokalemia (K of 4.0 mEq/L) was 432 ms (Figure 1B), and she discharged on foot 33 days after admission without any neurological sequelae of cardiac arrest. Administration of osimertinib (40 mg once daily) was resumed in the hospital where she had been started chemotherapy under the monitoring of ECG and serum potassium concentration while coadministration of itraconazole and herbal drug was interrupted.\n\nFigure 1 Twelve-lead electrocardiogram (ECG) on admission (A) and before discharge (B). QTc interval was 455 ms (A) and 432 ms (B), respectively. Herat rate correction of QT interval was performed by Bazett's formula.\n\nFigure 2 Chest X-ray on admission (A) and chest computed tomography during hospitalization (B).\n\nFigure 3 Right coronary angiogram showed severe (99%) stenotic lesion in segment 1 (A). Collateral circulation from left anterior descending artery was visualized (B). Stent implantation was performed (C) and right coronary angioplasty was completed (D).\n\nDiscussion\n\nOsimertinib is an oral, third-generation TKI as an emerging therapeutic modality in various cancers with EGFR T790M mutation (2). One of the obstacles for wide use of this promising anticancer agent is QT prolongation. QT interval is lengthened as a result of ventricular potassium current reduction and late sodium current augmentation (4). Bian et al. (5) reported a first case of 85-year-old male patient with advanced non-small cell lung cancer associated with TdP induced by oral osimertinib (80 mg once daily) and concomitant intravenous moxifloxacin, a broad-spectrum fluoroquinolone antibiotics known to lengthen the QT interval (QTc of 484 ms). Hypokalemia (2.94 mEq/L), impaired left ventricular ejection fraction (41%) and coadministration of moxifloxacin were concluded to underlie the development of TdP. They lost this case and hence cautioned cardio-oncologists to identify cancer patients at high risk of QT prolongation leading to the development of TdP (5). Cancer development and apoptosis is governed by driver mutation of signal transduction process mediated by several growth factor receptor including EGFR which is linked to many potassium channels, i.e., Kv1.3 (6), Kv10.1 (7), Kv4.3 (8), and Kir2.3 (9) are modulated by EGFR kinase via phosphorylation of tyrosine in their specific residues. These potassium channels regulate vascular tonus and QT interval in ECG. Therefore, EGFR-TKI shows variable cardiotoxicity including vascular constriction and QT prolongation. Although the serum concentration of osimertinib was not monitored, and genetic testing of hereditary long QT syndrome was not performed in this case, careful ECG monitoring is essential for cancer patients under the chemotherapy including osimertinib (10).\n\nQT interval is regulated strictly by many factors including basic heart rate, electrolytes, body temperature, sex hormones, and so on. Therefore, key factor of QT prolongation in this case is not determined easily. This case is an 85-year-old female patient, and old woman per se is a risk factor of QT prolongation (1). Oral itraconazole, a representative antifungal agent, is known to elevate the serum concentration of osimertinib due to competitive metabolism mediated by cytochrome P450 3A4 (CYP3A4). Chronic myocardial ischemia requiring PCI and hypokalemia (2.1 mEq/L) caused partly by Chinese herbal drug may have also contributed to the QT prolongation. Osimertinib causes coronary tonus elevation induced by vascular constriction mediated by inhibition of vascular EGFR (10), which may have aggravated silent myocardial ischemia in this case. Chinese traditional medicine of TJ-48 is used widely in Japan under the adjuvant anticancer therapeutic strategy as in this case. This herbal medicine is reported to enhance the efficacy of chemotherapy and to attenuate the adverse effects and complications of anticancer treatment (11). However, long-term use of Chinese herbal medicines is sometimes associated with hypokalemia caused by pseudoaldosteronism that is evoked by licorice contained in many herbal medicines. Although the incidence of hypokalemia induced by the administration of TJ-48 is not reported, such incidence by other Chinese medicine ranges from 6.6% (TJ-54) to 33% (TJ-9 and TJ-68) according to the Japanese Adverse Drug Report Database (12).\n\nConsidering the serum chemistry (normal CK-MB isozyme and negative TnT test) and echocardiographic left ventricular wall motion, cardiac arrest caused by acute coronary syndrome was unlikely. Silent myocardial ischemia is associated with QT prolongation caused by electrical instability and sympathovagal imbalance (13), and QT prolongation per se is responsible for SCD whatever the causes to prolong QT intervals are (14). Well-developed collateral circulation may have made coronary artery disease silent in this case (Figures 3A,B). This case description includes limitations, i.e., ECG was not retrieved from AED, serum TnT was assayed only once, and serum concentration of osimertinib was not assayed. In spite of these limitations, cardiac arrest in this case was supposed to be due to possible development of TdP based on several predisposing factors lengthening QT interval. Because defibrillation by means of public AED restored her spontaneous circulation, and recurrence of cardiac arrest was prevented after normalization of QT interval by elective PCI, discontinuation of causative drugs and potassium supplementation. Although QT prolongation in this case was grade I, this interval was measured at rest and supine position. QT interval dynamicity is accentuated by daily physical activity (15), and the relation between sudden increase in QT interval and the development of TdP is open to debate. This case taught us the necessity of collaboration between oncologists and cardiologists in the earlier clinical course of cancer patients.\n\nConclusions\n\nWe have described an 85-year-old female patient with EGFR-mutant advanced lung cancer treated with standard regimen of osimertinib, which underlay in part grade I QT prolongation causing abortive SCD. Reversible factors promoting QT prolongation were removed after admission and this patient was discharged safely. Although osimertinib-induced QT prolongation is mild to moderate (grade I or II) and not frequent (3–10%) in AURA study and FLAURA trial to verify the safety and efficacy of osimertinib (16, 17), TdP may be induced by standard dose of osimertinib, when multiple risk factors to lengthen QT interval are incidentally overlapped. Careful ECG monitoring and appropriate management of risk factors lengthening QT interval such as interacting drugs, electrolyte imbalance and cardiac ischemia during chemotherapy including osimertinib are highly required.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nThis case report article was carried out in collaboration between all coauthors. MKo was taking main care of this case. MKi had an equal contribution to this case report. YK was supervising MKo and MKi. SG was performing PCI in this case. OK was investigating the novelty and the rarity of this case. SK was exploring the literature relating to this case. TM performed writing of the main part of this manuscript. KO had the initial concept of this manuscript preparation and provided this manuscript with deep insight. YM supervised collaboration of the cardiology team. All authors read and approved the final manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe thank ward staffs of Kyushu Central Hospital for clinical assistance.\n==== Refs\nReferences\n\n1. Sadasivan C Zhabyeyev P Labib D White JA Paterson DI Oudit GY . Cardiovascular toxicity of PI3Kα inhibitors. Clin Sci. (2020) 134 :2595–622. 10.1042/CS20200302\n2. Schiefer M Hendriks LEL Dinh T Lalji U Dingemans AC . Current perspective: osimertinib-induced QT prolongation: new drugs with new side-effects need careful patient monitoring. Eur J Cancer. (2018) 91 :92–8. 10.1016/j.ejca.2017.12.011 29413968\n3. 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) 6 :e007724. 10.1161/JAHA.117.007724 29217664\n4. Zhabyeyev P McLean B Chen X Vanhaesebroeck B Oudit GY . Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na+ current, contractility, and Ca2+ release in murine hearts. J Mol Cell Cardiol. (2019) 132 :98–109. 10.1016/j.yjmcc.2019.05.008 31095940\n5. Bian S Tang X Lei W . A case of torsades de pointes induced by the third- generation EGRF-TKI, osimertinib combined with moxifloxacin. BMC Pulm Med. (2020) 20 :181. 10.1186/s12890-020-01217-4 32580784\n6. Teisseyre A Palko-Labuz A Sroda-Pomianek K Michalak K . Voltage-gated potassium channel Kv1.3 as a target in therapy of cancer. Front Oncol. (2019) 9 :933. 10.3389/fonc.2019.00933 31612103\n7. Wu W Dong MQ Wu XG Sun HY Tse HF Lau CP . Human ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase. Biochim Biophys Acta. (2012) 1823 :282–9. 10.1016/j.bbamcr.2011.10.010 22061963\n8. Zhang YH Wu W Sun HY Deng XL Cheng LC Li X . Modulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases. Cardiovasc Res. (2012) 93 :424–33. 10.1093/cvr/cvr347 22198508\n9. Zhang DY Zhang YH Sun HY Lau CP Li GR . Epidermal growth factor receptor tyrosine kinase regulates the human inward rectifier potassium K(IR)2.3 channel, stably expressed in HEK 293 cells. Br J Pharmacol. (2011) 164 :1469–78. 10.1111/j.1476-5381.2011.01424.x 21486282\n10. Chaar M Kamta J Ait-Oudhia S . Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities. Onco Targets Ther. (2018) 11 :6227–37. 10.2147/OTT.S170138 30288058\n11. Wang Z Qi F Cui Y Zhao L Sun X Tang W . An update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics. Biosci Trends. (2018) 12 :220–39. 10.5582/bst.2018.01144 30012913\n12. Ishida T Kawada K Morisawa S Jobu K Morita Y Miyamura M . Risk factors for pseudoaldosteronism with Yokusankan use: analysis using the Japanese Adverse Drug Report (JADER) database. Biol Pharm Bull. (2020) 43 :1570–6. 10.1248/bpb.b20-00424 32999167\n13. Tomassoni G Pisanó E Gardner L Krucoff MW Natale A . QT prolongation and dispersion in myocardial ischemia and infarction. J Electrocardiol. (1998) 30 (Suppl. ):187–90. 10.1016/s0022-0736(98)80073-3 9535498\n14. O'Neal WT Singleton MJ Roberts JD Tereshchenko LG Sotoodehnia N Chen LY . Association between QT interval components and sudden cardiac death: the ARIC study. Circ Arrhythm Electrophysiol. (2017) 10 :e005485. 10.1161/CIRCEP.117.005485 29030380\n15. Nakaji G Fujihara M Fukata M Yasuda S Odashiro K Maruyama T . Open-loop, clockwise QT-RR hysteresis immediately before the onset of torsades de pointes in type 2 long QT syndrome. J Electrocardiol. (2010) 43 :261–3. 10.1016/j.jelectrocard.2009.12.005 20079908\n16. Yang JCH Ahn MJ Kim DW Ramalingam SS Sequist LV Su WC . Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. (2017) 35 :1288–96. 10.1200/JCO.2016.70.3223 28221867\n17. Soria JC Ohe Y Vansteenkiste J Reungwetwattana T Chewaskulyong B Lee KH . Osimertinib in untreated EGFR mutated advanced non-small-cell lung cancer. N Engl J Med. (2018) 378 :113–25. 10.1056/NEJMoa1713137 29151359\n\n",
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"issue": "8()",
"journal": "Frontiers in cardiovascular medicine",
"keywords": "QT prolongation; cancer; cardiooncology; herbal drug; osimertinib",
"medline_ta": "Front Cardiovasc Med",
"mesh_terms": null,
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"title": "Case Report: QT Prolongation and Abortive Sudden Death Observed in an 85-Year-Old Female Patient With Advanced Lung Cancer Treated With Tyrosine Kinase Inhibitor Osimertinib.",
"title_normalized": "case report qt prolongation and abortive sudden death observed in an 85 year old female patient with advanced lung cancer treated with tyrosine kinase inhibitor osimertinib"
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"companynumb": "JP-JUBILANT CADISTA PHARMACEUTICALS-2021JUB00213",
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"abstract": "Most epidemiological studies indicate that incidence of cancer in multiple sclerosis patients is lower than general population. However these studies were performed prior to the emergence of disease-modifying therapies (DMTs). The incidence of cancer may be influenced by newer generation DMTs which are immunomodulatory or immunosuppressant. We describe an atypical case of intracerebral plasmacytic lymphoproliferative disorder in a 47 years old patient on fingolimod. As worldwide usage of oral and infusion DMTs increases, heightened clinical suspicion and early recognition of these serious adverse events remain crucial.",
"affiliations": "Partners MS Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Departments of Neurology and.;Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.;Partners MS Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.",
"authors": "Baharnoori|Moogeh|M|;Mahajan|Rahul|R|;Solomon|Issac H|IH|;Pinkus|Geraldine|G|;Houtchens|Maria|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "United States",
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"issue": "26(4)",
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"mesh_terms": "D001706:Biopsy; D001921:Brain; D001932:Brain Neoplasms; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D007952:Leukemia, Plasma Cell; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009103:Multiple Sclerosis",
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"references": null,
"title": "Fingolimod-Associated Intracerebral Lymphoproliferative Disorder.",
"title_normalized": "fingolimod associated intracerebral lymphoproliferative disorder"
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"abstract": "The prevalence of medical conditions representing a risk for thromboembolic complications and requiring antithrombotic therapy increases gradually with age. Two cases of fatal noncritical organ bleeding complication that occurred during the conversion period from initial fondaparinux to vitamin K antagonist are presented. An 81-year-old obese female patient (body mass index 43 kg/m(2)) with previous postoperative thrombosis underwent uneventful total knee replacement under spinal anesthesia. She presented with popliteal hematoma during conversion to oral anticoagulant. A 92-year-old female patient (body mass index 33 kg/m(2)) with left lower limb thrombosis was referred to our orthopedics department from her senior citizens' home for right lower limb hematoma and ischemia that occurred during conversion to oral anticoagulant. Thromboembolic and bleeding events in the elderly are real public health problems. Specific guidelines dedicated to this particular population are needed, which will improve the management of anticoagulation and decrease risk of complications.",
"affiliations": "Clinique du Parc Saint Lazare, 1 et 3 Avenue Jean Rostand, 60000 Beauvais, France. Electronic address: balnasser@orange.fr.",
"authors": "Al-Nasser|Bassam|B|",
"chemical_list": "D000925:Anticoagulants; D011134:Polysaccharides; D014812:Vitamin K; D000077425:Fondaparinux",
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"keywords": "Anesthesia; Bleeding; Elderly; Fondaparinux; Venous thromboembolism; Vitamin K antagonist",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000367:Age Factors; D000369:Aged, 80 and over; D000925:Anticoagulants; D017809:Fatal Outcome; D005260:Female; D000077425:Fondaparinux; D006470:Hemorrhage; D006801:Humans; D009765:Obesity; D011134:Polysaccharides; D012307:Risk Factors; D013923:Thromboembolism; D013927:Thrombosis; D014812:Vitamin K",
"nlm_unique_id": "8812166",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anticoagulant conversion in the elderly: pitfalls.",
"title_normalized": "anticoagulant conversion in the elderly pitfalls"
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"companynumb": "FR-MYLANLABS-2017M1002567",
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"abstract": "A 17-year old boy with hypertrophic obstructive cardiomyopathy (HOCM) developed repeated short runs of self terminating ventricular tachycardia 12 hours after starting oral verapamil, which was substituted for propranolol therapy. It is suggested that alterations in sympathetic tone induced by changing from a beta-blocker to a calcium antagonist might have increased myocardial irritability thus favouring genesis of severe ventricular arrhythmias. Verapamil is often considered to be more effective than propranolol in the treatment of HOCM. However, if propranolol is replaced by verapamil one has to take account of the possibility of serious arrhythmias as demonstrated by our case.",
"affiliations": null,
"authors": "Wessel|A|A|;Seiffert|P|P|;Dettmann|R|R|;Heintzen|P H|PH|",
"chemical_list": "D014700:Verapamil",
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"mesh_terms": "D000293:Adolescent; D002312:Cardiomyopathy, Hypertrophic; D006801:Humans; D008297:Male; D013610:Tachycardia; D014700:Verapamil",
"nlm_unique_id": "8006263",
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"references": null,
"title": "Verapamil-induced ventricular tachycardia in hypertrophic cardiomyopathy.",
"title_normalized": "verapamil induced ventricular tachycardia in hypertrophic cardiomyopathy"
} | [
{
"companynumb": "DE-RECRO GAINESVILLE LLC-REPH-2019-000093",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
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... |
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"abstract": "EGFR and BRAF V600E mutations are both early driven and usually mutually exclusive. We report the case of a 59-year-old woman diagnosed with advanced lung adenocarcinoma harboring coexisting EGFR exon 18 G719A and BRAF V600E mutations. She experienced a long-term response to oral afatinib, with a progression-free survival rate of 33 months and an overall survival rate of 11 years. Lung adenocarcinoma with synchronous EGFR G719A and BRAF V600E mutations is rare and has not been previously reported. This case highlights the importance of an adequate response to afatinib and provides an optimal therapeutic option for such patients.",
"affiliations": "Department of Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"authors": "Huang|Qing|Q|;Chen|Changchun|C|;Hu|Sheng|S|;Wu|Huijing|H|;Yu|Ding|D|;Zhu|Xianmin|X|;Xue|Chang|C|;Wu|Yuebing|Y|;Tang|Jing|J|;Xie|Rong|R|;Ran|Fengming|F|",
"chemical_list": null,
"country": "England",
"delete": false,
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"issue": null,
"journal": "Anti-cancer drugs",
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"medline_ta": "Anticancer Drugs",
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"nlm_unique_id": "9100823",
"other_id": null,
"pages": null,
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"pmid": "34387589",
"pubdate": "2021-08-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term survival in a patient with advanced lung adenocarcinoma harboring synchronous EGFR exon 18 G719A and BRAF V600E mutations and treated with afatinib: a case report.",
"title_normalized": "long term survival in a patient with advanced lung adenocarcinoma harboring synchronous egfr exon 18 g719a and braf v600e mutations and treated with afatinib a case report"
} | [
{
"companynumb": "CN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2021-BI-122329",
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"patient": {
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"activesubstancename": "AFATINIB"
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"abstract": "Treatment with programmed cell death 1 inhibitors is associated with a wide range of cutaneous immune-related adverse events, with lichenoid eruptions representing one of the major cutaneous toxicities. We describe the case of an 81-year-old man with metastatic melanoma treated with pembrolizumab who subsequently developed a delayed-onset generalized lichenoid dermatitis. After failing multiple lines of systemic immunosuppression, narrowband ultraviolet B (NBUVB) phototherapy three times per week for 17 sessions resulted in a significant clinical response in his cutaneous eruption and was well tolerated. NBUVB is a safe, lower-cost modality that induces local, skin-specific immunosuppression without the toxicities of traditional systemic immunosuppressive agents. To date, this is the first report of use of NBUVB in immune-related lichenoid dermatitis resistant to multiple standard therapies.",
"affiliations": "Division of Oncology, Department of Medicine, McGill University, Montreal, Quebec, Canada khashayar.esfahani@mcgill.ca.;Division of Dermatology, Department of Medicine, McGill University, Montreal, Quebec, Canada.;Division of Dermatology, Department of Medicine, McGill University, Montreal, Quebec, Canada.;Division of Dermatology, Department of Medicine, McGill University, Montreal, Quebec, Canada.;Division of Dermatology, Department of Medicine, McGill University, Montreal, Quebec, Canada.;Department of Pathology, McGill University, Montreal, Quebec, Canada.;Division of Dermatology, Department of Medicine, McGill University, Montreal, Quebec, Canada.;Division of Oncology, Department of Medicine, McGill University, Montreal, Quebec, Canada.",
"authors": "Esfahani|Khashayar|K|;Henderson Berg|Meagan-Helen|MH|0000-0002-4622-2931;Zargham|Hanieh|H|;Billick|Robin|R|;Pehr|Kevin|K|;Redpath|Margaret|M|;Roshdy|Osama|O|;Miller|Wilson H|WH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2020-001831",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\njitc-2020-001831\n10.1136/jitc-2020-001831\nCase Report\n1506\n2518 1619\nNarrowband ultraviolet B therapy for refractory immune-related lichenoid dermatitis on PD-1 therapy: a case report\nEsfahani Khashayar 1\nhttp://orcid.org/0000-0002-4622-2931\nHenderson Berg Meagan-Helen 2\nZargham Hanieh 2\nBillick Robin 2\nPehr Kevin 2\nRedpath Margaret 3\nRoshdy Osama 2\nMiller Wilson H 1\n1 Division of Oncology, Department of Medicine, McGill University, Montreal, Quebec, Canada\n2 Division of Dermatology, Department of Medicine, McGill University, Montreal, Quebec, Canada\n3 Department of Pathology, McGill University, Montreal, Quebec, Canada\nCorrespondence to Dr Khashayar Esfahani, Department of Medicine, Division of Oncology, Jewish General Hospital, Montreal, Canada; khashayar.esfahani@mcgill.ca\nKE and M-HHB are joint first authors.\n\n2021\n25 3 2021\n9 3 e00183110 2 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttp://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.\n\nTreatment with programmed cell death 1 inhibitors is associated with a wide range of cutaneous immune-related adverse events, with lichenoid eruptions representing one of the major cutaneous toxicities. We describe the case of an 81-year-old man with metastatic melanoma treated with pembrolizumab who subsequently developed a delayed-onset generalized lichenoid dermatitis. After failing multiple lines of systemic immunosuppression, narrowband ultraviolet B (NBUVB) phototherapy three times per week for 17 sessions resulted in a significant clinical response in his cutaneous eruption and was well tolerated. NBUVB is a safe, lower-cost modality that induces local, skin-specific immunosuppression without the toxicities of traditional systemic immunosuppressive agents. To date, this is the first report of use of NBUVB in immune-related lichenoid dermatitis resistant to multiple standard therapies.\n\nimmunotherapy\nmelanoma\ninflammation\ncase reports\nautoimmunity\nspecial-featureunlocked\n==== Body\nIntroduction\n\nImmune checkpoint inhibitors (ICIs) directed against T-lymphocyte-associated antigen 4, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have transformed long-term outcomes in advanced melanoma. Their use can come at the expense of a wide range of immune-related adverse events, of which cutaneous manifestations can account for up to 30% of the reported toxicities.1 A variety of reactions have been described, including morbilliform, lichenoid, eczematous, immune-bullous, psoriasiform eruptions, and vitiligo-like depigmentation.2 Although most cases are managed with topical corticosteroids and/or oral corticosteroids, a subset of patients will be refractory to this first line of therapy and require systemic immunosuppression with other agents. In those cases, no clear standard of care exists, and treatments are often tailored to the clinical phenotype of the adverse reaction, to the findings on histopathology, or to similar treatments used in the primary forms of the same autoimmune skin reactions. Finding the right therapy can be challenging, as the benefits of systemic immunosuppression must be weighed against the risks of opportunistic infections or the potential blunting of cancer immune surveillance.3\n\nNarrowband ultraviolet B (NBUVB) phototherapy is an established, lower cost, and often preferred treatment option for many common skin conditions, both benign and malignant, and carries a relatively benign side-effect profile. NBUVB can induce T-cell anergy and reduce the local production of inflammatory cytokines with minimal systemic toxicity.4 Interestingly, although its use has been reported previously, treatment with NBUVB has not yet been described in cutaneous immune-related toxicities that are refractory to multiple standard therapies, where the avoidance of systemic immunosuppression is particularly appealing. Herein, we report a case of a patient on pembrolizumab who developed generalized lichenoid dermatitis refractory to steroids and three lines of systemic immunosuppressive agents (mycophenolate mofetil, methotrexate, and cyclosporine) and who achieved excellent control of his dermatological toxicity with NBUVB phototherapy.\n\nCase presentation\n\nThe patient is an 81-year-old man with metastatic BRAF V600R mutated melanoma. He is known for a remote history of mantle cell lymphoma for which he is in remission post-stem cell transplantation, mild oral lichen planus, for which he had never required treatment, gout, gastroesophageal reflux disease, chronic bronchitis, benign prostatic hyperplasia, and depression. There is no history of hepatitis C infection, renal disease, or diabetes mellitus. After failing a first-line course of BRAF-targeted therapy with dabrafenib and trametinib, he started with second-line pembrolizumab in November of 2018. In May of 2019, pembrolizumab was discontinued due to the serial progression of disease on imaging. Within 6 weeks of discontinuation of therapy, the patient presented with a generalized skin eruption, composed of multiple scaly erythematous papules and plaques, some with central hyperkeratotic crust, in a symmetric distribution on the arms, chest, back, abdomen, and upper legs. No other medications were introduced prior to development of the cutaneous eruption (figure 1). A skin biopsy was performed on his right arm to evaluate the lesions. Histopathology revealed a lichenoid interface dermatitis with typical histological features of a lichenoid drug reaction, such as eosinophils and the presence of dyskeratotic cells (colloid bodies) above the basal layer of the epidermis (figure 2). Immunohistochemical staining revealed high expression of CD3, CD4>CD8, and CD163 in the infiltrate. Associated PD-L1 expression, as well as scarce Foxp3+ cells, was observed.\n\nFigure 1 (A) Onset of immune-related lichenoid reaction on programmed cell death 1 therapy. The patient had multiple erythematous papules and plaques with central hyperkeratosis on the arms, trunk and upper legs, associated with significant discomfort and pruritus. (B) Magnified view of the lesions. (C) Minimal response after multiple lines of immunosuppression, including high-potency topical and oral corticosteroids, mycophenolate mofetil, methotrexate and cyclosporine. (D) Significant clinical response after 17 sessions of narrowband ultraviolet B therapy, resulting in healing of the patient’s lesions and resolution of associated clinical symptoms.\n\nFigure 2 H&E-stained section of the right arm lesion showed a lichenoid interface dermatitis. On higher power, exocytosis of lymphocytes and eosinophils can be seen. There are clusters of dyskeratotic cells (colloid bodies) along the basal layer and single dyskeratotic keratinocytes higher up in the epidermis. Immunohistochemical examination revealed that the lichenoid infiltrate was composed mainly of T cells, with a predominance of CD4+ cells; CD8+ T cells were less abundant. CD163+ histiocytes and scarce Foxp3+ regulatory T cells were also seen in the infiltrate. Staining for CD20 was negative. PD-L1 was expressed by the infiltrate. PD-L1, programmed cell death ligand 1.\n\nThe patient was initially treated with high-dose potency topical steroids and rapidly moved to prednisone 1 mg/kg when he did not have an adequate response. He had a mild initial good response, but the lesions flared on the taper of steroids at the same time as a grade 2 immune-related colitis. On increase of corticosteroids, the patient had a resolution of his colitis and stability of his lesions; prednisone was tapered for a total of 2 months of treatment. He was subsequently serially treated with methotrexate for 4 weeks, followed by mycophenolate mofetil for 4 weeks, and then cyclosporine for 4 weeks, with a mild response to therapy at best. His lesions remained symptomatic, with significant discomfort and pruritus (figure 1).\n\nAfter consultation in a multidisciplinary immune-toxicity team, it was decided that NBUVB phototherapy could be considered. Of interest, our patient also experienced immune-related uveitis before the start of phototherapy, which was treated with corticosteroid eye drops. The patient received 17 total sessions, which induced a significant healing of his lesions and the resolution of the pruritus and skin discomfort. Subsequent to his immune-toxicities, a significant systemic antitumor response was noted on his staging scans, which are currently ongoing over 12 months after cessation of PD-1 therapy.\n\nDiscussion\n\nImmune-related lichenoid eruptions constitute up to 25% of the cutaneous adverse events on ICIs.5 These have similar features to lichen planus and may present with flat-topped erythematous-to-violaceous scaly papules, oral or genital ulcers, leukoplakia, hypertrophic plaques, and nail dystrophy. These reactions may present with a delayed onset and even after discontinuation of ICIs,6 as was the case with our patient. An exacerbation of pre-existing mucocutaneous disease may also be observed, such as our patient’s known lichen planus (oral). The predominant histological feature is lichenoid interface changes, with a CD3-positive infiltrate with a high CD4:CD8 ratio.2 6 Our immunohistochemical analyses support that lichenoid eruptions associated with PD-1 inhibitors are largely driven by T cells with macrophage participation. Furthermore, ICIs can shift antigen-induced reactivity towards an inflammatory Th1/Th17 response, the same response which has also been observed with lichen planus.7 Therapeutic NBUVB suppresses many cell-mediated immune responses and induces a shift from a Th1/Th17 to a Th2 milieu in both preclinical and clinical models of inflammatory skin diseases.8\n\nNBUVB phototherapy for immune-related lichenoid dermatitis has been reported as a first-line therapy in four patients,2 6 as well as in one patient who failed a steroid taper,9 but not for refractory cases. Our case also differs in that our patient responded to NBUVB as monotherapy, whereas the previously described patient concomitantly received systemic steroids.9 Our report therefore strengthens the evidence for effectiveness of NBUVB in this setting. In addition, our case is of interest, given a good response to this therapy after failure of multiple systemic lines of immunosuppression, including corticosteroids, methotrexate, mycophenolate mofetil, and cyclosporine. Due to patient preference, NBUVB was not trialed sooner, which could have spared him exposure to the other immunosuppressants. Also, although use of topical calcineurin inhibitors has been previously reported, they have not been showed to be superior to high-potency topical corticosteroids.10\n\nFor lichen planus, an average of 18–23 sessions of NBUVB, fractionated over three times per week, is necessary to induce an objective response. As with our case, we would therefore recommend a trial of at least 17 sessions of NBUVB three times weekly (6 weeks) before assessing treatment efficacy. Short-term side effects may include erythema, xerosis associated with pruritus, and occasional blistering. To date, no study has found a significant association between NBUVB therapy and a heightened risk of developing cutaneous squamous cell carcinoma, basal cell carcinoma, or melanoma.\n\nImmune-related skin reactions are often associated with several favorable outcomes, including overall response rate, progression-free survival, and overall survival. This was the case with our patient, who achieved a near complete remission of his metastatic melanoma 12 months after pembrolizumab was discontinued.\n\nConclusion\n\nWith the increasing use of ICIs in clinical practice, a significant rise in immune-related cutaneous adverse events has emerged. Although most cases can be successfully managed with topical high-potency or oral corticosteroids, the refractory cases pose a clinical challenge. Our case supports further exploration of NBUVB phototherapy in this setting, given the relative long track record of safety and efficacy of this approach for primary models of inflammatory skin diseases.\n\nKE and M-HHB contributed equally.\n\nOR and WHM contributed equally.\n\nContributors: KE and M-HHB contributed equally to this work and are cofirst authors. KE, M-HHB, and HZ analyzed and interpreted the patient case, and wrote and edited the manuscript. KE and RB were the main treating physicians. KP reviewed the manuscript. MR performed the pathological interpretation and provided the histopathology figure. WHM and OR supervised this case report and reviewed the manuscript. All authors have read and approved the final manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Not required.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Hodi FS, Chiarion-Sileni V, Gonzalez R, et al . Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018;19 :1480–92. 10.1016/S1470-2045(18)30700-9 30361170\n2 Coleman E, Ko C, Dai F, et al . Inflammatory eruptions associated with immune checkpoint inhibitor therapy: a single-institution retrospective analysis with stratification of reactions by toxicity and implications for management. J Am Acad Dermatol 2019;80 :990–7. 10.1016/j.jaad.2018.10.062 30399387\n3 Esfahani K, Elkrief A, Calabrese C, et al . Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol 2020;17 :504–15. 10.1038/s41571-020-0352-8 32246128\n4 Sigmundsdottir H, Johnston A, Gudjonsson JE, et al . Narrowband-UVB irradiation decreases the production of pro-inflammatory cytokines by stimulated T cells. Arch Dermatol Res 2005;297 :39–42. 10.1007/s00403-005-0565-9 15889264\n5 Hwang SJE, Carlos G, Wakade D, et al . Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort. J Am Acad Dermatol 2016;74 :455–61. 10.1016/j.jaad.2015.10.029 26793994\n6 Shi VJ, Rodic N, Gettinger S, et al . Clinical and histologic features of lichenoid mucocutaneous eruptions due to Anti-Programmed cell death 1 and Anti-Programmed cell death ligand 1 immunotherapy. JAMA Dermatol 2016;152 :1128–36. 10.1001/jamadermatol.2016.2226 27411054\n7 Solimani F, Pollmann R, Schmidt T, et al . Therapeutic targeting of Th17/Tc17 cells leads to clinical improvement of lichen planus. Front Immunol 2019;10 :10. 10.3389/fimmu.2019.01808 30723470\n8 Weichenthal M, Schwarz T. Phototherapy: how does UV work? Photodermatol Photoimmunol Photomed 2005;21 :260–6. 10.1111/j.1600-0781.2005.00173.x 16149939\n9 Donaldson M, Owen JL, Chae YK, et al . Management of persistent pruritus and lichenoid reaction secondary to nivolumab with Narrowband ultraviolet B phototherapy. Front Oncol 2018;8 :405. 10.3389/fonc.2018.00405 30319970\n10 El-Batawy MMY, Bosseila MA-W, Mashaly HM, et al . Topical calcineurin inhibitors in atopic dermatitis: a systematic review and meta-analysis. J Dermatol Sci 2009;54 :76–87. 10.1016/j.jdermsci.2009.02.002 19303745\n\n",
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"abstract": "Atherosclerotic renal arterial disease (ARAD) is becoming a more important cause of end-stage renal failure. Diagnosis is more easily achieved because of greater clinical suspicion and more refined screening tools. However, the medical and interventional management of patients with ARAD is not well defined in the literature because there have been few randomized trials. Because the use of angiotensin-converting enzymes (ACE) inhibitors, and more recently angiotensin-antagonists, has become much more widespread, it is inevitable that we should, knowingly or not, give these drugs to patients with ARAD. We describe 2 case studies in which the angiotensin-antagonist irbesartan was given to 2 patients with effectively single-functional kidneys after successful renal arterial radiologic intervention. The rationale for the use of irbesartan was to control BP, which had not responded to the initial arterial intervention, and took place in patients both refractory to, and intolerant of, many other anti-hypertensive drugs. Irbesartan successfully and safely reduced systemic BP, measured by use of ambulatory BP, without prejudicing renal function (measured by use of individual kidney function GFR).",
"affiliations": "Departments of Renal Medicine and Radiology, Guy's Hospital, London, United Kingdom. David. goldsmith@gstt. sthames.nhs.uk",
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"abstract": "We present a patient with peritoneal carcinosarcoma who was treated with the alkylating agent ifosfamide and experienced a rapid decline in mental status. Electroencephalogram (EEG) displayed generalized periodic epileptiform discharges, which raised suspicion for nonconvulsive status epilepticus (NCSE). Following administration of midazolam, the patient's clinical condition and EEG improved. We review the 8 documented cases of ifosfamide-induced NCSE, and demonstrate the similarity in clinical features when compared with ifosfamide neurotoxicity that is not classified as NCSE. EEG findings suggesting an ictal pattern are subtle and heterogeneous, but they are essential for a diagnosis. Since it is unlikely that EEGs are uniformly obtained in instances of ifosfamide neurotoxicity, many cases of NCSE may go unrecognized.",
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"abstract": "A significant proportion of patients with lymphoid malignancies are hard-to-mobilize with a combination of chemotherapy plus granulocyte colony-stimulating factor (G-CSF) (chemomobilization). Plerixafor is a novel drug used to improve mobilization of blood stem cells. However, it has been studied mainly in association with G-CSF mobilization. We evaluated the efficacy of 'pre-emptive' use of plerixafor after chemomobilization in patients who seem to mobilize poorly. During a 15 month period, altogether 63 patients with lymphoid malignancies were admitted to our department for blood stem cell collection. Sixteen patients (25%) received plerixafor after the first mobilization due to the low blood (B) CD34(+) cell counts (n = 12) or poor yield of the first collection (n = 4). The median number of plerixafor injections was 1 (1-3). The median B-CD34(+) count after the first plerixafor dose was 39 × 10(6) /L (<1-81) with the median increase of fivefold. Stem cell aphaereses were performed in 14/16 patients (88%) receiving plerixafor and a median of 2.9 × 10(6) /kg (1.6-6.1) CD34(+) cells were collected with a median of one aphaeresis (1-3). Altogether 13/16 patients mobilized with a combination of chemomobilization and plerixafor received high-dose therapy with stem cell support and all engrafted. Pre-emptive use of plerixafor after chemomobilization is efficient and safe and should be considered in poor mobilizers to avoid collection failure. In patients with low but rising B-CD34(+) counts, the use of plerixafor might be delayed as late mobilization may occur. Further studies are needed to optimize patient selection and timing of plerixafor.",
"affiliations": "Department of Medicine, Kuopio University Hospital, Kuopio, Finland University of Eastern Finland/Institute of Clinical Medicine, Kuopio, Finland. esa.jantunen@kuh.fi",
"authors": "Jantunen|Esa|E|;Kuittinen|Taru|T|;Mahlamäki|Eija|E|;Pyörälä|Marja|M|;Mäntymaa|Pentti|P|;Nousiainen|Tapio|T|",
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"title": "Efficacy of pre-emptively used plerixafor in patients mobilizing poorly after chemomobilization: a single centre experience.",
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"abstract": "The initiation of continuous renal replacement therapy (CRRT) in acute kidney injury (AKI) with severe hypernatremia is challenging since sodium concentrations in commercial replacement fluid (RF) and dialysate solutions are usually fixed at 140 mEq/L. We present a case of AKI with severe hypernatremia successfully treated with CRRT using commercial RF solutions customized to prevent rapid correction of hypernatremia. None of the few case reports published on hypernatremia and AKI requiring CRRT have included formulas to help modulate the sodium content in the solutions. We present an equation to facilitate adjustment of the sodium concentration in this setting.",
"affiliations": "Department of Medicine, Division of Nephrology , Sacre-Coeur Hospital of Montreal , Montreal, Quebec , Canada.;Department of Medicine, Division of Nephrology , Sacre-Coeur Hospital of Montreal , Montreal, Quebec , Canada.;Department of Medicine, Division of Nephrology , Sacre-Coeur Hospital of Montreal , Montreal, Quebec , Canada.;Department of Medicine, Division of Nephrology , Sacre-Coeur Hospital of Montreal , Montreal, Quebec , Canada.;Department of Medicine, Division of Nephrology , Sacre-Coeur Hospital of Montreal , Montreal, Quebec , Canada.",
"authors": "Paquette|François|F|;Goupil|Rémi|R|;Madore|François|F|;Troyanov|Stéphan|S|;Bouchard|Josée|J|",
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"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfw036sfw036ElectrolytesContinuous venovenous hemofiltration using customized replacement fluid for acute kidney injury with severe hypernatremia Paquette François Goupil Rémi Madore François Troyanov Stéphan Bouchard Josée Department of Medicine, Division of Nephrology, Sacre-Coeur Hospital of Montreal, Montreal, Quebec, CanadaCorrespondence and offprint requests to: Josée Bouchard; E-mail: josee.bouchard.1@umontreal.ca8 2016 26 5 2016 26 5 2016 9 4 540 542 11 1 2016 11 4 2016 © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.2016This 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.comThe initiation of continuous renal replacement therapy (CRRT) in acute kidney injury (AKI) with severe hypernatremia is challenging since sodium concentrations in commercial replacement fluid (RF) and dialysate solutions are usually fixed at 140 mEq/L. We present a case of AKI with severe hypernatremia successfully treated with CRRT using commercial RF solutions customized to prevent rapid correction of hypernatremia. None of the few case reports published on hypernatremia and AKI requiring CRRT have included formulas to help modulate the sodium content in the solutions. We present an equation to facilitate adjustment of the sodium concentration in this setting.\n\nacute kidney injuryacute renal failurecontinuous renal replacement therapydialysishypernatremia\n==== Body\nBackground\nHypernatremia is common in critically ill patients, with a prevalence as high as 26% [1]. Whether hypernatremia represents a marker of disease severity or an independent prognostic factor remains a subject of controversy [2]. Patients with hypernatremia have a higher risk of mortality and longer lengths of stay compared with critically ill patients with normal sodium concentrations [1, 2]. When treating a patient with severe hypernatremia and acute kidney injury (AKI) requiring dialysis, clinicians face a therapeutic challenge, as the sodium content in replacement fluid (RF) and/or dialysate solutions is not easily adjustable. Therefore, they must be aware of the potential risk for a rapid decline in serum sodium concentrations if no modifications are made to these solutions. We present a case of severe hypernatremia and AKI successfully treated with continuous venovenous hemofiltration (CVVH), along with an equation to help calculate the required adjustments in sodium concentrations in the RF and/or dialysate.\n\nCase report\nA 53-year-old 56-kg man was brought to our emergency department for a decreased level of consciousness for 3 days. His past medical history was relevant for hypertension and bipolar disorder. His medications included hydrochlorothiazide 25 mg daily, triamterene 50 mg daily and lithium 300 mg thrice daily.\n\nOn arrival, he had decreased responsiveness and his Glasgow coma scale (GCS) was 9. His blood pressure was 121/95 mmHg, heart rate was 124 beats/min, respiration rate was 30 breaths/min, pulse oximetry was 98% on room air and temperature was 36.4°C. He presented signs of profound dehydration. The rest of the physical exam was unremarkable. Initial laboratory findings showed the following: serum sodium concentration, 184 mEq/L; serum creatinine level, 755 µmol/L (8.5 mg/dL) with a baseline level of 107 µmol/L (1.2 mg/dL) 3 months before; and blood urea nitrogen (BUN) level, 57.1 mmol/L (160 mg/dL). Other laboratory results were as follows: chloride, 133 mEq/L; potassium, 4.0 mEq/L; bicarbonate, 14.1 mEq/L; lactate level, 5.5 mmol/L (0.6 mg/dL); and creatine kinase level, 1500 U/L. Other relevant findings included a negative toxic screen, normal osmolal gap and glucose levels and undetectable alcohol, aspirin, methanol, ethylene glycol and lithium concentrations. Arterial blood gas showed a pH of 7.26, partial pressure of CO2 30 mmHg and HCO3– 13 mmol/L. Complete blood count showed increased white blood cells (32.8 × 109) and hemoglobin level [225 g/L (22.5 g/dL)]. The patient was nonoliguric (urine output 1.1 L/day) and his urinalysis was normal. His urine osmolality was 394 mOsm/L and urine sodium concentration was 38 mmol/L. Additional investigations included normal head computed tomography, abdominal ultrasound and chest X-ray. The AKI diagnosis was attributed to an acute tubular necrosis (ATN) caused by severe dehydration and sepsis. A partial nephrogenic diabetes insipidus caused by chronic lithium administration was also suspected. The patient was brought to the ICU, where he received intravenous antibiotics for a suspected gastrointestinal source.\n\nThe patient initially received 2 L of 0.9% NaCl followed by an infusion at 150 mL/h to correct hypovolemia. We then estimated the total body water deficit at 10.5 L and subsequently modified the fluid composition for a 5% dextrose water at 80 mL/h, aiming to decrease the sodium concentration level to a maximum rate of 10 mEq/L in 24 h. Given the small improvement in creatinine [719 µmol/L (8.1 mg/dL)], BUN [60.8 mmol/L (170 mg/dL)] and sodium concentration (177 mEq/L) after 24 h, and in the absence of improvement in the patient clinical status, we initiated CVVH (Aquarius, Baxter, Mississauga, ON, Canada) to treat severe AKI with suspected uremic encephalopathy and to lower sodium safely. At our institution, commercially available RF solutions are used and custom-made RF solutions are not routinely available. The dialysis prescription was as follows: hemofilter Aquamax HF19 (Baxter), with a blood flow rate of 250 mL/min, and an initial RF rate of 20 mL/kg/h with a modified hypertonic RF solution, adding 23% NaCl to Prismasol 4 mEq/L solution (Baxter) (Table 1). The initial corrections in serum sodium levels were too conservative, so we modified sodium levels in the RF. We also increased the RF flow rate to 25 mL/kg/h on Day 3. The patient received CVVH for 72 h without ultrafiltration. His sodium levels decreased as expected (Figure 1), with gradual improvement in his level of consciousness. The patient was discharged from hospital 2 weeks later with a creatinine of 134 mmol/L (1.5 mg/dL).\nTable 1. Target sodium concentrations in RF solution with required volume of 23% NaCl and 3% NaCl to add to the RF solution\n\nTarget final sodium concentration in RF\t170 mEq/L\t165 mEq/L\t160 mEq/L\t155 mEq/L\t150 mEq/L\t145 mEq/L\t\nVolume of 23.4% NaCl to add in a 5-L bag of RFa\t38 mL (150 mEq)\t31 mL (125 mEq)\t25 mL (100 mEq)\t19 mL (75 mEq)\t13 mL (50 mEq)\t6 mL (25 mEq)\t\nVolume of 3% NaCl to add in a 5-L bag of RFb\t294 mL (150 mEq)\t245 mL (125 mEq)\t196 mL (100 mEq)\t147 mL (75 mEq)\t98 mL (50 mEq)\t49 mL (25 mEq)\t\na1 mL 23.4% NaCl = 234 mg/mL × 17 mEq/g = 3.98 mEq NaCl/mL.\n\nb1 mL 3% NaCl = 50 mg/mL × 17 mEq/g = 0.51 mEq NaCl/mL.\n\n\nFig. 1. Serum sodium concentrations before and during CVVH with customized RF solutions. The expected decline in serum sodium concentrations was calculated with the equation provided in the text.\n\n\n\nDiscussion\nChronic hypernatremia is associated with an accumulation of organic osmolytes in brain cells, which constitutes a cerebral adaptation to this hypertonic environment. Therefore, when treating chronic hypernatremia, a rapid correction of the total body water deficit can lead to cerebral edema. Current recommendations suggest a maximal decrease in sodium concentration of 0.5 mEq/L/h mainly based on results from pediatric patients [3].\n\nManagement of severe hypernatremia and AKI requiring dialysis represents a therapeutic challenge. One must choose the composition of the RF for the renal replacement therapy wisely to prevent a rapid decrease in serum sodium concentrations. Expected serum sodium changes during conventional intermittent hemodialysis (IHD), sustained efficiency dialysis (SLED) and CVVH are usually higher than the suggested decrease of 0.5 mEq/L/h [4]. In CVVH, the rate of electrolyte equilibration with the concentration in the RF is influenced by the initial difference between the serum and RF sodium concentration and the CVVH prescription itself [5]. A more rapid decrease in sodium levels is seen with higher RF rates and higher blood flow rates. Some kinetic models can help predict serum sodium changes during treatment [4]. Therefore, CVVH with customized RF solution can safely lower serum sodium concentration in a stepwise manner. There are only limited cases reported in the literature, and none of them have included equations to help adjust the sodium content in the RF and/or dialysate [6–8].\n\nIn our case, the customized RF solution was prepared by adding 23% NaCl to the initial RF solution (Na 140 mEq/L) following the data presented in Table 1. The addition of 3% NaCl instead of 23% NaCl would require larger volumes to be added in the RF solution, which would have affected the concentration of other electrolytes. We estimated the RF sodium concentration using the following kinetic equation [4]: Replacement fluid[Na+]=desired serum Δ[Na+](1−e(−Cl×24h)/V)+initial serum[Na+] \nwhere Cl is the Na+ filter clearance, V is the total body water volume and desired serum Δ[Na+] represents a negative value when treating hypernatremia and a positive value when treating hyponatremia.\n\nThe clearance depends on the predilution or postdilution mode: Clpredilution=QbQb+Qrf×SCNa+×(Qrf+Quf) \n Clpostdilution=SCNa+×(Qrf+Quf) \nwhere Qb is the blood flow rate (L/h), Qrf is the RF flow rate (L/h), Quf is the ultrafiltration rate (L/h) and SCNa is the Na+ sieving coefficient (∼1).\n\nFor example, if the initial blood sodium concentration is 177 mEq/L and the target blood sodium concentration is 170 mEq/L, the desired correction rate would be −7 mEq/L in 24 h. V is the total body water volume, which equals 0.5 × estimated dry weight for females and 0.6 × estimated dry weight for males; V was estimated as 33.5 L in this case, Qb was 250 mL/min (15 L/h), Qrf was 17 mL/min (1 L/h), Quf was 0 L/h, e was 2.72 (constant) and Cl was 0.94, as calculated with previous values. Therefore, the customized sodium concentration in the RF should be 163 mEq/L.\n\nIn conclusion, the treatment of AKI and severe hypernatremia using CVVH is facilitated by the use of customized commercially available RF solutions. The solutions should be prepared cautiously to prevent any sterility breach, and sodium levels can easily be estimated based on the sodium kinetic model presented in this report.\n\nConflict of interest statement\nNone declared. The results presented in this paper have not been published previously in whole or part, except in abstract format.\n\nAcknowledgements\nJ.B. and S.T.'s research efforts are supported by the Fonds de la Recherche du Québec-Santé.\n==== Refs\nReferences\n1 Pokaharel M , Block CA \nDysnatremia in the ICU . Curr Opin Crit Care \n2011 ; 17 : 581 –593 22027406 \n2 Lindner G , Funk GC , Schwarz C et al \nHypernatremia in the critically ill is an independent risk factor for mortality . Am J Kidney Dis \n2007 ; 50 : 952 –957 18037096 \n3 Sterns RH \nDisorders of plasma sodium—causes, consequences, and correction . N Engl J Med \n2015 ; 372 : 55 –65 25551526 \n4 Yessayan L , Yee J , Frinak S et al \nTreatment of severe hyponatremia in patients with kidney failure: role of continuous venovenous hemofiltration with low-sodium replacement fluid . Am J Kidney Dis \n2014 ; 64 : 305 –310 24792353 \n5 Ostermann M , Dickie H , Tovey L et al \nManagement of sodium disorders during continuous haemofiltration . Crit Care \n2010 ; 14 : 418 20519032 \n6 Park HS , Hong YA , Kim HG et al \nUsefulness of continuous renal replacement therapy for correcting hypernatremia in a patient with severe congestive heart failure . Hemodial Int \n2012 ; 16 : 559 –563 22515501 \n7 Yang YF , Wu VC , Huang CC \nSuccessful management of extreme hypernatraemia by haemofiltration in a patient with severe metabolic acidosis and renal failure . Nephrol Dial Transplant \n2005 ; 20 : 2013 –2014 15985507 \n8 Huang C , Zhang P , Du R et al \nTreatment of acute hypernatremia in severely burned patients using continuous veno-venous hemofiltration with gradient sodium replacement fluid: a report of nine cases . Intensive Care Med \n2013 ; 39 : 1495 –1496 23653182\n\n",
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"issue": "9(4)",
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"keywords": "acute kidney injury; acute renal failure; continuous renal replacement therapy; dialysis; hypernatremia",
"medline_ta": "Clin Kidney J",
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"pages": "540-2",
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"title": "Continuous venovenous hemofiltration using customized replacement fluid for acute kidney injury with severe hypernatremia.",
"title_normalized": "continuous venovenous hemofiltration using customized replacement fluid for acute kidney injury with severe hypernatremia"
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"abstract": "BACKGROUND\nOpioid-based postsurgical analgesia exposes patients undergoing laparoscopic colectomy to elevated risk for gastrointestinal motility problems and other opioid-related adverse events (ORAEs). The purpose of our research was to investigate postsurgical outcomes, including opioid consumption, hospital length of stay, and ORAE risk associated with a multimodal analgesia regimen, employing a single administration of liposome bupivacaine as well as other analgesics that act by different mechanisms.\n\n\nMETHODS\nWe analyzed combined results from 6 Phase IV, prospective, single-center studies in which patients undergoing laparoscopic colectomy received opioid-based intravenous patient-controlled analgesia (PCA) or multimodal analgesia incorporating intraoperative administration of liposome bupivacaine. As-needed rescue therapy was available to all patients. Primary outcome measures were postsurgical opioid consumption, hospital length of stay, and hospitalization costs. Secondary measures included time to first rescue opioid use, patient satisfaction with analgesia (assessed using a 5-point Likert scale), and ORAEs.\n\n\nRESULTS\nEighty-two patients underwent laparoscopic colectomy and did not meet intraoperative exclusion criteria (PCA n = 56; multimodal analgesia n = 26). Compared with the PCA group, the multimodal analgesia group had significantly lower mean total postsurgical opioid consumption (96 vs 32 mg, respectively; P < 0.0001) and shorter median postsurgical hospital length of stay (3.0 vs 4.0 days; P = 0.0019). Geometric mean costs were $11,234 and $13,018 in the multimodal analgesia and PCA groups, respectively (P = 0.2612). Median time to first rescue opioid use was longer in the multimodal analgesia group versus PCA group (1.1 hours vs 0.6 hours, respectively; P=0.0003). ORAEs were experienced by 41% of patients receiving intravenous opioid PCA and 8% of patients receiving multimodal analgesia (P = 0.0019). Study limitations included use of an open-label, nonrandomized design; small population size; and the inability to isolate treatment-related effects specifically attributable to liposome bupivacaine.\n\n\nCONCLUSIONS\nCompared with intravenous opioid PCA, a liposome bupivacaine-based multimodal analgesia regimen reduced postsurgical opioid use, hospital length of stay, and ORAEs, and may lead to improved postsurgical outcomes following laparoscopic colectomy.",
"affiliations": "Department of Anesthesiology, University of Miami Leonard Miller School of Medicine, Miami, Florida.;Department of Surgery, University of Miami School of Medicine, Miami, Florida.;Department of Surgery, Albany Medical College, Albany, New York.;Department of Anesthesiology and Neurological Surgery, Wexner Medical Center, The Ohio State University, Columbus, Ohio.;Department of Surgery, Division of Colon and Rectal Surgery, Wexner Medical Center, The Ohio State University, Columbus, Ohio.;Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida.;Department of Surgery, Section of Colon and Rectal Surgery, MedStar Washington Hospital Center, Washington, DC.;Colorectal Surgical Associates, Ltd, LLP, Houston, Texas.",
"authors": "Candiotti|Keith A|KA|;Sands|Laurence R|LR|;Lee|Edward|E|;Bergese|Sergio D|SD|;Harzman|Alan E|AE|;Marcet|Jorge|J|;Kumar|Anjali S|AS|;Haas|Eric|E|",
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"doi": "10.1016/j.curtheres.2013.12.001",
"fulltext": "\n==== Front\nCurr Ther Res Clin ExpCurr Ther Res Clin ExpCurrent Therapeutic Research, Clinical and Experimental0011-393X1879-0313Elsevier S0011-393X(13)00036-210.1016/j.curtheres.2013.12.001ArticleLiposome Bupivacaine for Postsurgical Analgesia in Adult Patients Undergoing Laparoscopic Colectomy: Results from Prospective Phase IV Sequential Cohort Studies Assessing Health Economic Outcomes☆ Candiotti Keith A. MDKCandiot@med.miami.edu1⁎Sands Laurence R. MD2Lee Edward MD3Bergese Sergio D. MD4Harzman Alan E. MD5Marcet Jorge MD6Kumar Anjali S. MD7Haas Eric MD81 Department of Anesthesiology, University of Miami Leonard Miller School of Medicine, Miami, Florida2 Department of Surgery, University of Miami School of Medicine, Miami, Florida3 Department of Surgery, Albany Medical College, Albany, New York4 Department of Anesthesiology and Neurological Surgery, Wexner Medical Center, The Ohio State University, Columbus, Ohio5 Department of Surgery, Division of Colon and Rectal Surgery, Wexner Medical Center, The Ohio State University, Columbus, Ohio6 Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida7 Department of Surgery, Section of Colon and Rectal Surgery, MedStar Washington Hospital Center, Washington, DC8 Colorectal Surgical Associates, Ltd, LLP, Houston, Texas⁎ Address correspondence to: Keith A. Candiotti, MD, Department of Anesthesiology, University of Miami Leonard M. Miller School of Medicine, 1611 NW 12th Ave, Central 300, Miami Beach, FL 33136. KCandiot@med.miami.edu27 12 2013 27 12 2013 12 2014 76 1 6 2 12 2013 © 2013 The Authors2013This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Background\nOpioid-based postsurgical analgesia exposes patients undergoing laparoscopic colectomy to elevated risk for gastrointestinal motility problems and other opioid-related adverse events (ORAEs). The purpose of our research was to investigate postsurgical outcomes, including opioid consumption, hospital length of stay, and ORAE risk associated with a multimodal analgesia regimen, employing a single administration of liposome bupivacaine as well as other analgesics that act by different mechanisms.\n\nMethods\nWe analyzed combined results from 6 Phase IV, prospective, single-center studies in which patients undergoing laparoscopic colectomy received opioid-based intravenous patient-controlled analgesia (PCA) or multimodal analgesia incorporating intraoperative administration of liposome bupivacaine. As-needed rescue therapy was available to all patients. Primary outcome measures were postsurgical opioid consumption, hospital length of stay, and hospitalization costs. Secondary measures included time to first rescue opioid use, patient satisfaction with analgesia (assessed using a 5-point Likert scale), and ORAEs.\n\nResults\nEighty-two patients underwent laparoscopic colectomy and did not meet intraoperative exclusion criteria (PCA n = 56; multimodal analgesia n = 26). Compared with the PCA group, the multimodal analgesia group had significantly lower mean total postsurgical opioid consumption (96 vs 32 mg, respectively; P < 0.0001) and shorter median postsurgical hospital length of stay (3.0 vs 4.0 days; P = 0.0019). Geometric mean costs were $11,234 and $13,018 in the multimodal analgesia and PCA groups, respectively (P = 0.2612). Median time to first rescue opioid use was longer in the multimodal analgesia group versus PCA group (1.1 hours vs 0.6 hours, respectively; P=0.0003). ORAEs were experienced by 41% of patients receiving intravenous opioid PCA and 8% of patients receiving multimodal analgesia (P = 0.0019). Study limitations included use of an open-label, nonrandomized design; small population size; and the inability to isolate treatment-related effects specifically attributable to liposome bupivacaine.\n\nConclusions\nCompared with intravenous opioid PCA, a liposome bupivacaine-based multimodal analgesia regimen reduced postsurgical opioid use, hospital length of stay, and ORAEs, and may lead to improved postsurgical outcomes following laparoscopic colectomy.\n\nKey Words\nhospitalization costlaparoscopic colectomylength of staymultimodal analgesiaopioid-related adverse eventssurgery\n==== Body\nIntroduction\nAs a result of their demonstrated efficacy, opioid analgesics continue to be the foundation for most postsurgical pain management regimens; however, opioid-related adverse events (ORAEs) exact a high toll in morbidity, hospital length of stay (LOS), and hospitalization costs.1 Patients undergoing gastrointestinal (GI) surgery appear to be especially vulnerable to exacerbation of GI motility problems (postoperative ileus and small bowel obstruction).2,3\n\nThe management of postsurgical pain has been the focus of increasing attention during the past 3 decades; consensus recommendations for more effective postsurgical analgesia have been developed and published by government, regulatory, and medical organizations.4–7 Despite these efforts, improvement in reducing the incidence and severity of postsurgical pain has been slow. Patient surveys conducted during the past 2 decades have failed to demonstrate improvement over time, consistently reporting high incidences of postoperative pain (>75% of surgical patients), with most affected patients describing their pain as moderate, severe, or extreme.8–10\n\nThe application of laparoscopic techniques in colectomy procedures has helped reduce postsurgical morbidity, pain severity, and LOS, although postsurgical pain remains a significant driver of prolonged recovery time.11 In the context of laparoscopic colectomy, multimodal analgesia has been shown to reduce postsurgical opioid use, pain, time to resumption of a normal diet, and LOS, in comparison with conventional intravenous (IV) opioid-based patient-controlled analgesia (PCA).12–14 Moreover, guidelines issued by the American Society of Anesthesiologists strongly endorse the use of multimodal analgesia in the perioperative setting whenever possible.4 Multimodal analgesic techniques involve the use of 2 or more analgesic drugs that act by different mechanisms delivered by the same or different routes of administration to improve pain control and minimize ORAEs.4,15\n\nLiposome bupivacaine is a long-acting liposomal formulation of bupivacaine indicated for injection into the surgical site to produce postsurgical analgesia. In clinical studies involving a range of different surgical settings, liposome bupivacaine has been well tolerated and shown to provide postsurgical analgesia for up to 72 hours, extend the time to first opioid use, and reduce postsurgical opioid consumption and incidence of ORAEs when administered as a key component of multimodal analgesic regimens.16–19\n\nThere are no previous reports from studies of liposome bupivacaine in patients undergoing minimally invasive GI surgery. This article reports combined results from studies of liposome bupivacaine (collectively known as Extended PaIn Relief Trial Utilizing the Infiltration of a Long-Acting Multivesicular LiPosome FoRmulation Of BupiVacaine, Exparel [IMPROVE]) in adults undergoing laparoscopic colectomy under general anesthesia. The objective of our analysis was to compare total opioid burden and health economic outcomes for patients who received liposome bupivacaine-based multimodal analgesia versus those who received a conventional IV opioid PCA regimen for postsurgical pain following laparoscopic colectomy.\n\nPatients and Methods\nResults from 6 single-center studies, later amended to 2 multicenter studies, were combined and analyzed. Combined analysis of data from the individual studies was prespecified in study protocols, and was performed to improve statistical power to detect differences in outcomes between the treatment groups. These were Phase IV, prospective, multicenter, open-label, sequential-cohort studies designed to evaluate opioid burden and health economic outcomes associated with a multimodal analgesia regimen incorporating intraoperatively administered liposome bupivacaine 266 mg compared with standard of care (postsurgical PCA) using IV morphine or hydromorphone (IV opioid PCA).\n\nAll study protocols were approved by the institutional review boards of the participating institutions and the studies were conducted in accordance with International Conference on Harmonisation Guideline for Good Clinical Practice and/or US Food and Drug Administration Title 21 Code of Federal Regulations Part 56. All patients provided written informed consent before participation.\n\nPatients were eligible for study inclusion if they were aged 18 years or older and were scheduled to undergo laparoscopic segmental colectomy with a primary anastomosis. Key exclusion criteria included pregnancy or unwillingness to use acceptable birth control; a history of drug or alcohol abuse; severe hepatic impairment; any concomitant condition that, in the opinion of the investigator, could preclude study participation; any concomitant surgical procedure(s) or unplanned changes in surgery (eg, multiple segmental resections, conversion from laparoscopic to open colectomy); or treatment with intraoperative opioids (other than fentanyl), nonsteroidal anti-inflammatory drugs, local anesthetics (other than liposome bupivacaine), or alvimopan.\n\nApart from the difference in surgical model and the multicenter nature of these studies, the study protocols were similar to that employed by Cohen20 in a single-center study of patients undergoing open colectomy. Sequential cohorts (IV opioid PCA cohort followed by liposome bupivacaine-based multimodal analgesia cohort) of eligible patients were enrolled and underwent screening procedures within 2 weeks of the planned surgery.\n\nStudy treatment of patients in the IV opioid PCA cohort was initiated as soon as possible after surgery on Study Day 1 (ie, day of surgery). Patients in the liposome bupivacaine-based multimodal analgesia cohort received a single dose of liposome bupivacaine (266 mg in 40 mL 0.9% normal saline) administered using a moving-needle technique before wound closure. A 30-mL aliquot of liposome bupivacaine was divided into 2 15-mL aliquots for equal administration into the left and right sides of the surgical site; from these aliquots, approximately 25% was infused into the junction between the subcutaneous and dermal regions (Figure 1)21 and 75% was infused into the perifascial region (Figure 2).21 The remaining 10 mL was divided across the trocar sites, using a 75%/25% split for the perifascial region and the subcutaneous-dermal junction region, respectively (Figure 3).21 Patients in the liposome bupivacaine-based multimodal analgesia group also received IV ketorolac 30 mg (or nonsteroidal anti-inflammatory drug equivalent) at the end of surgery, followed by IV or oral acetaminophen 1000 mg given every 6 hours and oral ibuprofen 600 mg every 6 hours (starting when oral therapy was first tolerated), for 72 hours after surgery or until hospital discharge, whichever came first. All patients in both treatment arms were offered rescue therapy with IV opioid and/or oral opioid/acetaminophen combination on an as-needed basis (acetaminophen use was limited to 4000 mg/d). Other facets of perioperative management were carried out according to the standard of care at each individual study site.\n\nPostsurgically, IV opioid PCA was continued in the IV opioid PCA group and as-needed rescue analgesics were continued in both treatment groups until hospital discharge, with cumulative opioid use and adverse events (AEs) recorded through the earlier of Day 30 or discharge. AEs were assessed through Study Day 30, and patient questionnaires were administered on Day 30 to assess postsurgical complications and overall satisfaction with postsurgical analgesia.\n\nThe primary efficacy outcome measures included total amount of opioids consumed after surgery, total hospitalization cost, and postsurgical LOS (time between wound closure and discharge or Day 30, whichever came first). Secondary outcome measures included postsurgical incidence of ORAEs (eg, somnolence, respiratory depression, hypoventilation, hypoxia, dry mouth, nausea, vomiting, constipation, sedation, confusion, pruritus, urinary retention, or postoperative ileus) and AEs through Day 30; patient overall satisfaction with postsurgical analgesia assessed on Day 30 using a 5-point Likert scale (patient response options included “extremely satisfied,” “satisfied,” “neither satisfied nor dissatisfied,” “dissatisfied,” and “extremely dissatisfied”); and patient responses to a follow-up survey on Day 30 regarding hospital readmission, unplanned medical visits, health-related problems, and contact with health care providers.\n\nThe safety population included all patients who underwent the planned surgery. The efficacy population included all patients who underwent laparoscopic colectomy as planned and who did not meet any of the intraoperative exclusion criteria. A 1-way ANOVA model after a natural logarithm transformation was used for between-group comparisons of continuous efficacy measures (eg, amount of opioids consumed and total hospitalization costs); all opioid consumption amounts were converted to morphine equivalents to facilitate comparisons. Geometric mean values for total hospitalization costs, a common metric for reporting cost data,22,23 were calculated by taking the nth root of the product of total hospitalization costs for the patients in each treatment group, where n = the number of patients in the treatment group. For categorical measures, between-group comparisons were conducted using Fisher’s exact test. Kaplan-Meier analysis with a log-rank test was used for comparison of LOS and time to first postsurgical opioid use. Significance tests were 2-sided and based on a significance level of 0.05; no adjustments were made for multiple tests.\n\nResults\nA total of 105 patients underwent the planned laparoscopic colectomy; 82 received study treatment as prescribed in the study protocols (56 in the IV opioid PCA group and 26 in the liposome bupivacaine-based multimodal analgesia group). Patient demographics and baseline characteristics are summarized in Table I. The IV opioid PCA group was, on average, slightly older, had a higher proportion of black patients, a lower proportion of white patients, and had more patients with comorbidities (based on American Society of Anesthesiologists classification) than the multimodal analgesia group.\n\nThe mean (SD) total amount of postsurgical opioid consumption was 32 (53) mg in the liposome bupivacaine-based multimodal analgesia group, compared with 96 (78) mg in the IV opioid PCA group (P < 0.0001). The median (range) postsurgical LOS was 3.0 (1.9–10.7) days in the multimodal analgesia group compared with 4.0 (0–30.0) days in the IV opioid PCA group (P = 0.0019). The geometric mean total hospitalization cost was $11,234 in the multimodal analgesia group compared with $13,018 in the IV opioid PCA group (P = 0.2612).\n\nResults for the secondary efficacy measures are summarized in Table II. The time to first opioid use was significantly longer in the liposome bupivacaine-based multimodal analgesia group than in the IV opioid PCA group (median = 1.1 vs 0.6 hours, respectively; P = 0.0003). Although results for the remaining outcomes favored the multimodal analgesia group (higher proportion of patients extremely satisfied with analgesia, lower proportion of patients who reported unplanned visits to or contact with health care providers), between-group differences for these measures did not reach statistical significance.\n\nAdverse events are summarized in Table III. Overall, the most frequently reported AEs were nausea (25%), abdominal pain (7%), headache (7%), and anemia (6%). In the IV opioid PCA group, 17 patients (25%) experienced AEs that were considered by the investigator to be related to the study drug; there were no reports of AEs related to the study drug in the liposome bupivacaine-based multimodal analgesia group. In the IV opioid PCA group, 9 patients (13%) experienced a total of 14 serious AEs; in the multimodal analgesia group, 5 patients (13%) experienced 15 serious AEs.\n\nORAEs, summarized based on the efficacy population, are shown in Table IV. One or more ORAEs were experienced by 23 patients (41%) in the IV opioid PCA group compared with 2 patients (8%) in the liposome bupivacaine-based multimodal analgesia group (P = 0.0019). Fewer patients in the multimodal analgesia group experienced ORAEs of nausea than in the IV opioid PCA group (8% vs 30%, respectively; P = 0.0261); there were no other ORAEs reported in the multimodal analgesia group. The mean (SD) number of ORAEs reported per patient was 0.6 (0.8) in the IV opioid PCA group and 0.1 (0.3) in the multimodal analgesia group (P = 0.0020).\n\nDiscussion\nThe IMPROVE series of studies has evaluated the influence of an opioid-sparing liposome bupivacaine-based multimodal analgesic regimen compared with IV opioid-based PCA on clinical and health economic outcomes in patients undergoing GI surgery. The IMPROVE studies have addressed 3 GI surgery models (ie, open colectomy, laparoscopic colectomy, and ileostomy reversal) in both single- and multi-institutional settings. In a previously published IMPROVE study report,20 patients undergoing open colectomy treated with a liposome bupivacaine-based multimodal regimen were shown to have significantly reduced postsurgical opioid consumption, cost of hospitalization, and hospital LOS compared with patients assigned to opioid-based IV PCA.\n\nIn our combined analysis of 6 IMPROVE studies of patients undergoing laparoscopic colectomy, the use of liposome bupivacaine-based multimodal analgesia for the management of postsurgical pain was associated with a statistically significant improvement compared with IV opioid-based PCA in 2 of 3 coprimary outcome measures. The multimodal analgesia regimen reduced mean postsurgical opioid consumption by 67% and reduced median LOS by 1 day compared with a standard IV opioid-based PCA analgesia regimen. Multimodal analgesia was also associated with a nonstatistically significant 14% reduction in mean total hospitalization cost ($1784) compared with an IV opioid PCA regimen. Although the observed reduction in hospital costs was not statistically significant, it was clinically meaningful and suggests that improvements in the other 2 measures may have mitigated the product cost of liposome bupivacaine. This is an encouraging observation given the increased focus on evidence-based medicine and comparative effectiveness research that takes into account both patient outcomes and the treatment costs associated with novel medical interventions.\n\nEncouraging results were also observed with respect to secondary outcome measures. Compared with IV opioid PCA, liposome bupivacaine-based multimodal analgesia significantly extended the time to first postsurgical opioid use, which is consistent with the reduction in opioid consumption observed on the primary outcome measure for the multimodal group and also significantly reduced the incidence of ORAEs overall (as well as nausea, specifically). Although between-group differences in other secondary measures did not reach statistical significance, 65% of patients in the multimodal analgesia group reported being “extremely satisfied” with their postsurgical analgesia regimen, which suggests this regimen was well accepted by most patients in this treatment group.\n\nOur results mirror those observed by Cohen20 in a similarly designed single-center study of patients undergoing open colectomy. In that study, a liposome bupivacaine-based multimodal analgesia regimen was associated with significant reductions in opioid consumption, LOS, and hospitalization costs compared with an IV opioid PCA regimen.20\n\nWe conducted these studies against a backdrop of an increasing trend toward the use of accelerated or enhanced recovery pathways for patients undergoing colorectal surgical procedures.24–27 The reductions in opioid consumption and LOS observed in these studies are encouraging in light of this trend, and suggest that liposome bupivacaine-based multimodal analgesic regimens may play a role in supporting continued efforts to improve and shorten the recovery experience for patients undergoing colorectal surgery.\n\nImportant limitations of this analysis include the open-label design, small study populations, and the use of sequential cohorts instead of randomization; it is possible that the latter may have introduced some level of unanticipated variability in patient populations that were enrolled. Also, the treatment effects that can be specifically attributed to liposome bupivacaine in this study are difficult to quantify, because the multimodal analgesic regimen was composed of several analgesic medications (ie, ketorolac, acetaminophen, ibuprofen, and liposome bupivacaine), and these were not evaluated separately.\n\nConclusions\nOur analysis showed that liposome bupivacaine-based multimodal analgesia significantly reduced postsurgical opioid consumption and hospital LOS, as well as the incidence of ORAEs, when compared with conventional opioid-based IV PCA in patients undergoing laparoscopic colectomy. Liposome bupivacaine-based multimodal analgesia may be an important tool in improving postsurgical outcomes associated with this procedure.\n\nConflicts of Interest\nKC: Received research funding from Pacira Pharmaceuticals, Inc. LS: Received honorarium as a consultant from Pacira Pharmaceuticals, Inc. EL: Received a research grant from Pacira Pharmaceuticals, Inc. SB: No conflict of interest to disclose. AH: No conflict of interest to disclose. JM: Has no personal financial relationship to disclose; however, his employer, the University of South Florida, received a research grant for the Division of Sponsored Research from Pacira Pharmaceuticals, Inc. AK: No conflict of interest to disclose. EH: Served as a consultant for and received educational grants from Pacira Pharmaceuticals, Inc. This analysis was funded by Pacira Pharmaceuticals, Inc., which contributed to the study design, statistical analysis, manuscript preparation, and patient recruitment costs for the studies included in the analysis.\n\nAcknowledgments\nThis study is connected with US National Institutes of Health clinical trial identifiers NCT01460485, NCT01534988, NCT01509820, NCT01461122, NCT01461135, and NCT01963975. This analysis was funded by Pacira Pharmaceuticals, Inc. Editorial assistance was provided by Michael Morren, RPh, MBA, of Peloton Advantage, LLC, and was supported by Pacira Pharmaceuticals, Inc. The authors were fully responsible for the content, editorial decisions, and opinions expressed in the current article. All authors contributed equally. The authors did not receive an honorarium related to the development of this manuscript.\n\n☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nFig. 1 (A) Front view of infiltration path for administration of liposome bupivacaine into subcutaneous and dermal regions. About 4 mL study drug solution was administered on each side of the surgical site following the paths shown. (B) Axial view of infiltration depth into subcutaneous and dermal regions. The dotted line shows depth of liposome bupivacaine administration. Reprinted with permission from Best Infiltration Practices: Local Analgesic Infiltration Techniques for Abdominal Surgery PocketGuide. Copyright © 2012 International Guidelines Center. www.GuidelineCentral.com. All rights reserved.21\n\nFig. 2 (A) Front view of infiltration path for administration of liposome bupivacaine into perifascial regions. About 1 mL study drug solution was administered to deep tissue on each side of the surgical site following the paths shown. (B) Axial view of infiltration depth into perifascial (deep tissue) regions. The dotted line shows depth of liposome bupivacaine administration. Reprinted with permission from Best Infiltration Practices: Local Analgesic Infiltration Techniques for Abdominal Surgery PocketGuide. Copyright © 2012 International Guidelines Center. www.GuidelineCentral.com. All rights reserved.21\n\nFig. 3 (A) Front view of anticipated trocar sites. About 10 mL study drug solution was divided and administered across trocar sites. The dotted arrows show locations for trocar placement. (B) Axial view of liposome bupivacaine infiltration into the trocar tract. Reprinted with permission from Best Infiltration Practices: Local Analgesic Infiltration Techniques for Abdominal Surgery PocketGuide. Copyright © 2012 International Guidelines Center. www.GuidelineCentral.com. All rights reserved.21\n\nTable I Patient demographics and selected baseline characteristics.*\n\nCharacteristic\tIV opioid PCA regimen (n = 56)\tLiposome bupivacaine-based multimodal regimen (n = 26)\t\nAge, y\t59 (15)\t55 (10)\t\nSex\t\t\t\n Male\t28 (50)\t12 (46)\t\n Female\t28 (50)\t14 (54)\t\nRace\t\t\t\n White\t45 (80)\t23 (89)\t\n Black\t7 (13)\t2 (8)\t\n Asian\t1 (2)\t1 (4)\t\n Other\t3 (5)\t0\t\nBody mass index\t28.9 (7.0)\t26.6 (5.4)\t\nASA physical status classification\t\t\t\n 1\t1 (2)\t0\t\n 2\t27 (48)\t19 (73)\t\n 3\t26 (46)\t7 (27)\t\n 4\t2 (4)\t0\t\nASA = American Society of Anesthesiologists; IV = intravenous; PCA = patient-controlled analgesia.\n\n⁎ Values for age and body mass index are given as mean (SD). Values for sex, race, and ASA physical status classification are given as n (%).\n\nTable II Summary of results for secondary outcome measures.*\n\nResult\tIV opioid PCA regimen (n = 56)\tLiposome bupivacaine-based multimodal regimen (n = 26)\tP\t\nTime to first opioid use, h\t0.6 (0, 21)\t1.1 (0.2, 119)\t0.0003\t\nProportion of patients who reported being extremely satisfied with their postsurgical pain treatment\t54\t65\t0.278\t\nProportion of patients who made unplanned visits with a health care provider after surgery\t16\t4\t0.156\t\nProportion of patients who made contact with a health care provider to discuss recovery after surgery\t13\t8\t0.711\t\nIV = intravenous; PCA = patient-controlled analgesia.\n\n⁎ Values for time to first opiod use given as median (range). Other values are given as %.\n\nTable III Summary of adverse events occurring in ≥5% of patients in any treatment group (safety population).*\n\nAdverse event\tIV opioid PCA regimen (n = 67)\tLiposome bupivacaine-based multimodal regimen (n = 38)\t\nPatients with any adverse event\t53 (79)\t15 (40)\t\nNausea\t23 (34)\t3 (8)\t\nAbdominal pain\t5 (8)\t2 (5)\t\nHeadache\t7 (10)\t0\t\nAnemia\t4 (6)\t2 (5)\t\nAbdominal distension\t5 (8)\t0\t\nPruritus\t5 (8)\t0\t\nUrinary retention\t5 (8)\t0\t\nVomiting\t5 (8)\t0\t\nLeukocytosis\t4 (6)\t0\t\nTachycardia\t2 (3)\t2 (5)\t\nUrinary tract infection\t4 (6)\t0\t\nHypokalemia\t1 (2)\t2 (5)\t\nCellulitis\t0\t2 (5)\t\nIV = intravenous; PCA = patient-controlled analgesia.\n\n⁎ Values are given as n (%).\n\nTable IV Summary of opioid-related adverse events (efficacy population).*\n\nAdverse event\tIV opioid PCA regimen (n = 56)\tLiposome bupivacaine-based multimodal regimen (n = 26)\t\nPatients with any opioid-related adverse event\t23 (41)\t2 (8)†\t\nNausea\t17 (30)\t2 (8)‡\t\nPruritus\t5 (9)\t0\t\nUrinary retention\t4 (7)\t0\t\nVomiting\t4 (7)\t0\t\nPostoperative ileus\t2 (4)\t0\t\nSomnolence\t1 (2)\t0\t\nIV = intravenous; PCA = patient-controlled analgesia.\n\n⁎ Values are given as n (%).\n\n† P = 0.0019 for between-group comparison.\n\n‡ P = 0.0261 for between-group comparison.\n==== Refs\nReferences\n1 Oderda G.M. Said Q. Evans R.S. Opioid-related adverse drug events in surgical hospitalizations: impact on costs and length of stay Ann Pharmacother 41 2007 400 407 17341537 \n2 Senagore A.J. Pathogenesis and clinical and economic consequences of postoperative ileus Am J Health Syst Pharm 64 20 Suppl 13 2007 S3 S7 17909274 \n3 Oderda GM, Robinson SB, Gan TJ, et al. Impact of postsurgical opioid use and ileus on economic outcomes in gastrointestinal surgeries. Abstract presented at: Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research; June 2–6, 2012; Washington, DC.\n4 Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management Anesthesiology 116 2012 248 273 22227789 \n5 The Management of Postoperative Pain Working Group. VHA/DoD clinical practice guideline for the management of postoperative pain, 2002. http://www.healthquality.va.gov/pop/pop_fulltext.pdf. Accessed August 22, 2012.\n6 Pain Management Guideline Panel Clinicians’ quick reference guide to postoperative pain management in adults. Agency for Health Care Policy and Research, US Department of Health and Human Services J Pain Symptom Manage 7 1992 214 228 1517644 \n7 The Joint Commission. Facts about pain management, 2012. http://www.jointcommission.org/pain_management/. Accessed August 21, 2012.\n8 Warfield C.A. Kahn C.H. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults Anesthesiology 83 1995 1090 1094 7486160 \n9 Apfelbaum J.L. Chen C. Mehta S.S. Gan T.J. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged Anesth Analg 97 2003 534 540 12873949 \n10 Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged. Abstract presented at: Annual Fall Pain Meeting and Workshops of the American Society of Regional Anesthesia and Pain Medicine; November 15–18, 2012; Miami Beach, Fla.\n11 Schwenk W. Haase O. Neudecker J. Muller J.M. Short term benefits for laparoscopic colorectal resection. Cochrane Database Syst Rev 2005 CD003145 \n12 Wongyingsinn M. Baldini G. Stein B. Spinal analgesia for laparoscopic colonic resection using an enhanced recovery after surgery programme: better analgesia, but no benefits on postoperative recovery: a randomized controlled trial Br J Anaesth 108 2012 850 856 22408272 \n13 Zafar N. Davies R. Greenslade G.L. Dixon A.R. The evolution of analgesia in an ‘accelerated’ recovery programme for resectional laparoscopic colorectal surgery with anastomosis Colorectal Dis 12 2010 119 124 19207712 \n14 Kaba A. Laurent S.R. Detroz B.J. Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy Anesthesiology 106 2007 11 18 17197840 \n15 Elvir-Lazo O.L. White P.F. The role of multimodal analgesia in pain management after ambulatory surgery Curr Opin Anaesthesiol 23 2010 697 703 20847690 \n16 Bergese S.D. Ramamoorthy S. Patou G. Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia J Pain Res 5 2012 107 116 22570563 \n17 Dasta J. Ramamoorthy S. Patou G. Sinatra R. Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting Curr Med Res Opin 28 2012 1609 1615 22900785 \n18 Viscusi E.R. Sinatra R. Onel E. Ramamoorthy S.L. The safety of liposome bupivacaine, a novel local analgesic formulation Clin J Pain 2013 Feb 26 [Epub ahead of print] \n19 Haas E. Onel E. Miller H. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation Am Surg 78 2012 574 581 22546131 \n20 Cohen S.M. Extended pain relief trial utilizing infiltration of Exparel®, a long-acting multivesicular liposome formulation of bupivacaine: a Phase IV health economic trial in adult patients undergoing open colectomy J Pain Res 5 2012 567 572 23204866 \n21 Best Infiltration Practices: Local Analgesic Infiltration Techniques for Abdominal Surgery. Lake Mary, Fla: International Guidelines Center; 2012.\n22 Marcet J.E. Nfonsam V.N. Larach S. An extended paIn relief trial utilizing the infiltration of a long-acting Multivesicular liPosome foRmulation Of bupiVacaine, EXPAREL (IMPROVE): a Phase IV health economic trial in adult patients undergoing ileostomy reversal J Pain Res 6 2013 549 555 23901290 \n23 Vogel J.D. Liposome bupivacaine (EXPAREL®) for extended pain relief in patients undergoing ileostomy reversal at a single institution with a fast-track discharge protocol: an IMPROVE Phase IV health economics trial J Pain Res 6 2013 605 610 23935387 \n24 Patel G.N. Rammos C.K. Patel J.V. Estes N.C. Further reduction of hospital stay for laparoscopic colon resection by modifications of the fast-track care plan Am J Surg 199 2010 391 394 20226917 \n25 Raue W. Haase O. Junghans T. ‘Fast-track’ multimodal rehabilitation program improves outcome after laparoscopic sigmoidectomy: a controlled prospective evaluation Surg Endosc 18 2004 1463 1468 15791370 \n26 Bardram L. Funch-Jensen P. Kehlet H. Rapid rehabilitation in elderly patients after laparoscopic colonic resection Br J Surg 87 2000 1540 1545 11091243 \n27 Basse L. Hjort J.D. Billesbolle P. A clinical pathway to accelerate recovery after colonic resection Ann Surg 232 2000 51 57 10862195\n\n",
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"abstract": "While immunotherapy with nivolumab is promising for patients with renal cell carcinoma (RCC), overactivation of the immune system can lead to serious side effects. Immune-related meningoencephalitis without a viral or microbial etiology is a rare complication that may occur in patients treated with checkpoint inhibitors (CPI). Herein, we report a 66-year-old man who underwent a partial nephrectomy which revealed a papillary RCC with clear cell component. Three years later, an abdomen and pelvic CT revealed metastatic lesions in the left psoas muscle and in the left 12th rib. The patient was treated with pazopanib which was discontinued after 2 weeks due to significant hepatic and renal toxicity. He subsequently started sunitinib. Two months later, a chest, abdomen, and pelvic CT demonstrated progressive metastatic RCC in the retroperitoneal mass of the left psoas muscle and paraspinal musculature as well as a left renal mass. The patient was treated with 7 cycles of the CPI nivolumab. He was subsequently hospitalized for 3 weeks after experiencing bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. A CSF analysis demonstrated a lymphocyte pleocytosis with elevated protein and no bacterial or viral growth. The patient was treated with high-dose steroids after which his symptoms resolved. Chest, abdomen, and pelvic CT scans over the next 3 years revealed no evidence of metastatic disease, reflecting a progression-free survival of 40 months. We highlight the unique case of a patient with metastatic RCC who experienced immune-related meningoencephalitis following immunotherapy with nivolumab. Medical oncologists should be alert to the potential development of immune-related encephalitis in patients treated with nivolumab and should promptly diagnose and treat this concerning condition. The excellent oncologic outcome of this case emphasizes the need for continued aggressive measures for management of CNS toxicity resulting from CPI therapy.",
"affiliations": "Norton Neuroscience Institute, Norton Healthcare, Louisville, Kentucky, USA.;Norton Neuroscience Institute, Norton Healthcare, Louisville, Kentucky, USA.;Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, California, USA.;Norton Cancer Institute, Norton Healthcare, Louisville, Kentucky, USA.",
"authors": "Shields|Lisa B E|LBE|;Alsorogi|Mohammad S|MS|;Mar|Nataliya|N|;Rezazadeh Kalebasty|Arash|A|",
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"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000513001\ncro-0014-1051\nCase Report\nImmune-Related Meningoencephalitis following Nivolumab in Metastatic Renal Cell Carcinoma\nShields Lisa B.E. a\nAlsorogi Mohammad S. a\nMar Nataliya b\nRezazadeh Kalebasty Arash c*\naNorton Neuroscience Institute, Norton Healthcare, Louisville, Kentucky, USA\nbChao Family Comprehensive Cancer Center, University of California Irvine, Orange, California, USA\ncNorton Cancer Institute, Norton Healthcare, Louisville, Kentucky, USA\n*Arash Rezazadeh Kalebasty, arez@uci.edu\nMay-Aug 2021\n1 7 2021\n1 7 2021\n14 2 10511058\n29 10 2020\n5 11 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.\nWhile immunotherapy with nivolumab is promising for patients with renal cell carcinoma (RCC), overactivation of the immune system can lead to serious side effects. Immune-related meningoencephalitis without a viral or microbial etiology is a rare complication that may occur in patients treated with checkpoint inhibitors (CPI). Herein, we report a 66-year-old man who underwent a partial nephrectomy which revealed a papillary RCC with clear cell component. Three years later, an abdomen and pelvic CT revealed metastatic lesions in the left psoas muscle and in the left 12th rib. The patient was treated with pazopanib which was discontinued after 2 weeks due to significant hepatic and renal toxicity. He subsequently started sunitinib. Two months later, a chest, abdomen, and pelvic CT demonstrated progressive metastatic RCC in the retroperitoneal mass of the left psoas muscle and paraspinal musculature as well as a left renal mass. The patient was treated with 7 cycles of the CPI nivolumab. He was subsequently hospitalized for 3 weeks after experiencing bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. A CSF analysis demonstrated a lymphocyte pleocytosis with elevated protein and no bacterial or viral growth. The patient was treated with high-dose steroids after which his symptoms resolved. Chest, abdomen, and pelvic CT scans over the next 3 years revealed no evidence of metastatic disease, reflecting a progression-free survival of 40 months. We highlight the unique case of a patient with metastatic RCC who experienced immune-related meningoencephalitis following immunotherapy with nivolumab. Medical oncologists should be alert to the potential development of immune-related encephalitis in patients treated with nivolumab and should promptly diagnose and treat this concerning condition. The excellent oncologic outcome of this case emphasizes the need for continued aggressive measures for management of CNS toxicity resulting from CPI therapy.\n\nKeywords\n\nOncology\nRenal cell carcinoma\nImmunotherapy\nMeningoencephalitis\nMeningitis\nNivolumab\nCheckpoint inhibitor\n==== Body\nIntroduction\n\nIn 2020, the American Cancer Society projects that 73,750 new cases of renal cell cancer (RCC) will be diagnosed and that 14,830 people will die from this disease [1]. The lifetime risk for developing RCC is 2% for men and 1% for women. Approximately 25–30% of patients present with metastatic RCC at the time of diagnosis which is associated with a high mortality [2]. Nivolumab is a fully human immunoglobulin programmed death 1 (PD-1) immune checkpoint inhibitor (CPI) antibody that selectively blocks the interaction between PD-1 expressed on activated T cells with its ligands PD-L1 and PD-L2 expressed on antigen-presenting cells and cancer cells that result in significant enhancement of T-cell function [2, 3, 4, 5]. Nivolumab has been approved by the US Food and Drug Administration for non-small cell lung cancer, RCC, melanoma, hepatocellular carcinoma, and recurrent or metastatic head and neck cancer [5, 6]. It has demonstrated antitumor activity with improved overall survival and a manageable safety profile for metastatic RCC [5, 7, 8].\n\nThe heightened immune response due to nivolumab use may trigger a myriad of immune-related adverse events such as hepatitis, colitis, diabetes mellitus, pericarditis, pneumonitis, arthritis, acute interstitial nephritis, aplastic anemia, and uveitis [3, 9]. Immune-related neurotoxicity affects approximately 1% of patients treated with nivolumab and includes peripheral neuropathy, aseptic meningitis, encephalitis, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathy, Guillain-Barré syndrome, and multifocal central nervous system demyelination [3, 8, 9, 10, 11]. Immune-related adverse events are due to the inhibition of immune checkpoints that spur local and systemic autoimmune responses and most likely involve neuronal damage by T-cells, autoantibodies, and cytokine-mediated inflammation [4, 12].\n\nWe report the exceedingly rare case of a patient with metastatic clear cell RCC (CCRCC) who experienced immune-related meningoencephalitis following treatment with nivolumab. The distinctive characteristics, differential diagnosis, management, and prognosis of immune-related encephalitis are discussed.\n\nCase Description\n\nA 66-year-old African-American man (height: 6' 6” (1.981 m); weight: 258 lbs (117.028 kg); body mass index: 29.82 kg/m2) reported that a mass of the upper pole of the left kidney was incidentally discovered 4 years earlier while undergoing a lumbar MRI. He underwent a retroperitoneal partial nephrectomy which revealed a papillary renal cell carcinoma (RCC) with a clear cell component measuring 6.6 × 5.2 × 3.8 cm. There were no sarcomatoid features, and the histologic grade was Fuhrman nuclear grade 3/4. The tumor was limited to the kidney without vascular invasion. The tumor stage was pT1aNX. The patient underwent surveillance of his RCC with repeat chest, abdomen, and pelvic CT scans. Past medical history was significant for aortic aneurysm, diabetes mellitus, hypercholesterolemia, proteinuria, hypertension, kidney stones, cerebrovascular accident, atrial flutter with a history of ablation, warfarin use, renal failure, and neuropathy. The patient's mother was diagnosed with tuberculosis (TB).\n\nThree years after the partial nephrectomy, an abdomen and pelvic CT revealed evidence of 2 metastatic lesions, with one measuring 4.0 cm in diameter involving the left psoas muscle in the posterior paraspinal musculature and retroperitoneal fat. The 2nd mass measuring 2.3 cm was located along the lateral aspect of the left 12th rib. The patient underwent a left retroperitoneal exploration and excisional biopsy. The pathology confirmed benign fibroadipose tissue with fat necrosis associated with dystrophic calcification of the retroperitoneal mass. The 12th rib mass showed a focus of metastatic clear cell carcinoma involving a 2.5-mm fibrous scar (2.5 mm). Immunostains supported metastatic CCRCC. The patient underwent close surveillance with chest, abdomen, and pelvic CT scans for the next year, all of which demonstrated no metastatic disease.\n\nA PET scan 1 year following the excisional biopsy demonstrated activity at the 11–12 intercostal space, left psoas muscle, and quadratus lumberum below the lower pole of the left kidney. A biopsy of the mass confirmed recurrent RCC. The patient initiated the tyrosine kinase inhibitor pazopanib 800 mg which was discontinued after 2 weeks due to gout and elevated levels of bilirubin and creatinine. An abdominal MRI showed metastatic disease involving the left psoas muscle which extended out of the prior left lateral abdominal wall surgical tract. The patient subsequently started the tyrosine kinase inhibitor sunitinib 50 mg. Two months later a chest, abdomen, and pelvic CT revealed a retroperitoneal mass of the left psoas and paraspinal musculature and a left renal mass measuring 2.7 cm in diameter. A left radical nephrectomy and periaortic lymphadenectomy was performed which revealed a recurrent CCRCC measuring 8.0 × 3.0 × 2.6 cm with a Fuhrman grade 2. An abdominal MRI with and without gadolinium contrast demonstrated 3 separate areas of enhancing tissue in the left abdomen: left psoas muscle, left posterior lateral abdominal wall musculature, and subcutaneous tissues in the left posterior lateral flank (Fig. 1A, B).\n\nA QuantiFERON TB Gold test was positive, indicating the likelihood of Mycobacterium tuberculosis (MTB) infection due to the patient's exposure to TB 30 years earlier. Therefore, he was unable to participate in an immunotherapy trial. The patient tolerated 7 cycles of nivolumab 240 mg without any complaints. He was subsequently hospitalized for 3 weeks after experiencing bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. Upon admission, he developed hypothermia and was admitted to the intensive care unit (ICU) and was intubated. A CSF analysis demonstrated a lymphocyte pleocytosis (white blood cell count 27, protein 70, lymphs 78%). A CSF virus culture and gram stain demonstrated no growth, the CSF pathogen panel was negative, and the cryptococcal antigen was negative. The blood culture demonstrated no growth, and there was no acid-fast bacilli by fluorochrome. A brain MRI revealed evidence of diffuse leptomeningeal enhancement as well as a 1.7 × 1.0 × 1.0 cm area of focal decreased T1 signal intensity involving the junction between the midbrain and pons on the left posteriorly, although the latter finding had been present for 4 years without any alterations (Fig. 2A–C). The MTB polymerase chain reaction (PCR) test was negative. The patient was treated with prednisone 90 mg for 6 days followed by a tapering dose. He also received isoniazide 300 mg and pyridoxine 50 mg for a latent TB infection as well as levetiracetam, since it was thought that his hyperthermia may have been due to a diencephalic seizure.\n\nThe patient's symptoms of immune-related meningoencephalitis resolved within 2 weeks of his hospitalization. He was successfully extubated after 14 days on a ventilator. He recovered fully after a short course of acute rehab admission. He did not receive any additional treatment with nivolumab or any other agent for his metastatic CCRCC. Chest, abdomen, and pelvic CT scans over the next 3 years revealed no evidence of metastatic disease, indicating a progression-free survival of 40 months (Fig. 3A, B).\n\nDiscussion\n\nA thorough investigation is warranted in a patient who is treated with nivolumab and develops neurological adverse effects. Patients who present with confusion or delirium, headaches, altered behavior, short-term memory loss, speech abnormalities, fatigue, focal weakness, decreased level of consciousness, hallucinations, aspastic tremors, fever, or vomiting may have evidence of meningoencephalitis associated with nivolumab [3, 9, 10]. The diagnostic evaluation and treatment of immune-related meningoencephalitis is presented in Table 1. Special attention should rule out other conditions that may cause neurological impairment such as disease progression, seizure activity, infection (in particular herpes simplex virus), and metabolic alterations [3, 9]. In most cases, the immunotherapy must be permanently discontinued. Treatment for immune-related meningoencephalitis involves hospitalization with high-dose corticosteroids as well as intravenous immunoglobulins and plasmapheresis in severe cases [9, 12, 13]. Immune CPI neurotoxicity generally occurs within the first 6 weeks of treatment [6, 13] but theoretically can happen at any point during the treatment.\n\nDifferentiating between aseptic meningitis and immune-related encephalitis or meningoencephalitis following nivolumab necessitates close scrutiny. These conditions often reveal a lymphocyte pleocytosis, elevated protein, and negative bacterial and viral infection by CSF analysis, abnormal leptomeningeal enhancement on brain MRI, and improvement with high-dose corticosteroids [9]. Patients with these conditions may present with headaches, vomiting, and fever; however, patients with aseptic meningitis often have a normal mental status unlike immune-related encephalitis. Drug-induced meningitis should also be considered in the differential diagnosis, as is reported with certain antibiotics, IVIG, refocoxib, and infliximab. Considering that our patient was not on any of these drugs, this diagnosis may be ruled out.\n\nThe patient in the present case had metastatic CCRCC and had been treated with nivolumab for 7 cycles prior to the onset of bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. Due to the patient's positive QuantiFERON TB Gold test, there was consideration that the patient had a suspected latent TB infection.\n\nA total of 1.5 million people died from TB in 2018, and multidrug-resistant TB is a significant issue worldwide [14]. Patients with a positive QuantiFERON TB Gold test are generally excluded from enrollment in clinical trials involving treatment with CPI. This is largely due to the potential risk of TB reactivation. Moreover, in case of immune-related side effects and need for high-dose steroids, there is a concern for reactivation of TB. Additionally, metastatic kidney cancer has a poor prognosis especially after treatment failure with tyrosine kinase inhibitors. In the current case, treatment with nivolumab led to an excellent outcome with durable complete response. Ongoing trials are evaluating the efficacy and safety of nivolumab in patients with metastatic cancer and significant autoimmune diseases. This patient population was excluded from the initial trial with CPIs. Similar trials in patients with positive QuantiFERON TB Gold test may be helpful in assessing the safety and efficacy of CPIs and providing guidance in using antitubercular agents in this setting.\n\nIn our case, the CSF culture and the MTB PCR test were negative, and there were no findings consistent with TB on chest X-ray. Additionally, the left midbrain/pons lesion was unlikely to be a tuberculoma as the mass had been present for 4 years without changes and remained unchanged for the next several years after receiving treatment for latent TB. He received isoniazide and pyridoxine for the suspected latent TB infection as he was at risk for TB reactivation on a high-dose steroid. He started levetiracetam, as the patient's hyperthermia may have been due to a diencephalic seizure.\n\nWhile aseptic meningitis and tuberculous meningitis were in the differential diagnosis, the patient's presenting symptoms including an altered mental status, the CSF findings of a lymphocyte pleocytosis, elevated protein, and negative bacterial and viral infection, his 3-week hospital stay including his need for ICU admission and ventilator use, as well as leptomeningeal enhancement on brain MRI strongly supported the diagnosis of immune-related meningoencephalitis. This diagnosis was further substantiated by clinical improvement with immunosuppression and lack of empiric antibiotic therapy for meningoencephalitis. He attained complete resolution of his immune-related encephalitis within 2 weeks following discontinuation of nivolimab and a course of high-dose corticosteroids. Furthermore, he did not have any evidence of disease progression for the subsequent 40 months with respect to his metastatic CCRCC. Ruling out the other possibilities in the differential diagnosis, the most probable diagnosis of the present case is drug-induced autoimmune meningoencephalitis caused by nivolumab.\n\nConclusion\n\nImmune-related meningoencephalitis is a rare phenomenon following treatment with nivolumab for metastatic RCC. The American Society of Clinical Oncology strongly recommends that patients are educated about the adverse effects that may arise with immunotherapy [9]. Due to the morbidity and potential mortality that may be associated with nivolumab, a high index of suspicion is warranted for immune-related neurotoxicities. Early diagnosis and prompt treatment are necessary to curtail the devastating sequelae that may ensue. Communication between different medical specialties including medical oncologists, neurologists, infectious disease specialists, and primary care physicians is of utmost importance in minimizing the risk of immune-related meningoencephalitis.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. The University of Louisville Institutional Review Board has determined that our project does not meet the “Common Rule” definition of human subjects' research and does not require IRB review. The Institutional Review Board number is 20.0710.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nNone.\n\nAuthor Contributions\n\nLisa B.E. Shields: Data conception, design, acquisition, analysis, and interpretation; drafted the manuscript; critically revised the manuscript and gave final approval. Mohammad S. Alsorogi: Data conception, design, acquisition, analysis, and interpretation; critically revised the manuscript and gave final approval. Nataliya Mar: Data conception, design, acquisition, analysis, and interpretation; critically revised the manuscript and gave final approval. Arash Rezazadeh Kalebasty: Data conception, design, acquisition, analysis, and interpretation; critically revised the manuscript and gave final approval.\n\nAcknowledgment\n\nWe acknowledge Norton Healthcare for their continued support.\n\nFig. 1 A, B An abdominal MRI with and without gadolinium contrast demonstrated 3 separate areas of enhancing tissue in the left abdomen: left psoas muscle, left posterior lateral abdominal wall musculature, and subcutaneous tissues in the left posterior lateral flank (arrows).\n\nFig. 2 Brain MRI revealed a mass in the left midbrain/pons (A; arrow) and leptomeningeal enhancement (B, C; arrows).\n\nFig. 3 A, B Abdominal CT scan performed 1 month following the conclusion of nivolumab, demonstrating the resection bed without evidence of metastatic disease (arrows).\n\nTable 1 Diagnostic evaluation for immune-related meningoencephalitis associated with nivolumab\n\nSymptoms\n − Confusion or delirium, headaches, altered behavior, short-term memory loss, speech abnormalities, fatigue, focal weakness, seizures, decreased level of consciousness, hallucinations, aspastic tremors, fever, or vomiting\t\nBrain MRI with and without gadolinium contrast\n − Diffuse dural enhancement without parenchymal abnormalities\n − Abnormal leptomeningeal enhancement\n − Rule out stroke/ischemia and brain metastasis\t\nCSF analysis\n − Lymphocytic pleocytosis, normal glucose, increased protein level\t\nEEG\n − Diffuse non-specific slowing\n − Rule out seizure activity\t\nNerve conduction studies/electromyography\n − Confirms sensory or weakness symptoms\t\nToxicity screen\t\nBlood and CSF paraneoplastic panel (anti-N-methyl-d-aspartate receptor and anti-Ma2 antibodies)\t\nThyroid panel\t\nComplete blood chemistry with differential panel\t\nNeurology consult Treatment\n − Empirical broad-spectrum antibiotics and antiviral therapy until microbiological findings confirmed\n − High-dose corticosteroids (methylprednisolone, prednisone, dexamethasone)\n − Intravenous immunoglobulins and plasmapheresis in severe cases\n==== Refs\nReferences\n\n1 American Cancer Society Key statistics for lung cancer Accessed October 29, 2020. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html\n2 Hammers HJ Plimack ER Infante JR Rini BI McDermott DF Lewis LD Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study J Clin Oncol 2017 35 JCO2016721985 8\n3 Baraibar I Melero I Ponz-Sarvise M Castanon E Safety and tolerability of immune checkpoint inhibitors (PD-1 and PD-L1) in cancer Drug Saf 2019 42 (2) 281 94 30649742\n4 Darvin P Toor SM Sasidharan Nair V Elkord E Immune checkpoint inhibitors: recent progress and potential biomarkers Exp Mol Med 2018 50 (12) 1 11\n5 De Giorgi U Cartenì G Giannarelli D Basso U Galli L Cortesi E Safety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access programme BJU Int 2019 123 (1) 98 105 29956884\n6 Weber JS Postow M Lao CD Schadendorf D Management of adverse events following treatment with anti-programmed death-1 agents Oncologist 2016 21 (10) 1230 40 27401894\n7 Motzer RJ Rini BI McDermott DF Redman BG Kuzel TM Harrison MR Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial J Clin Oncol 2015 33 (13) 1430 7 25452452\n8 Shah S Dunn-Pirio A Luedke M Morgenlander J Skeen M Eckstein C Nivolumab-induced autoimmune encephalitis in two patients with lung adenocarcinoma Case Rep Neurol Med 2018 2018 2548528 30073101\n9 Brahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline J Clin Oncol 2018 36 (17) 1714 68 29442540\n10 Larkin J Chmielowski B Lao CD Hodi FS Sharfman W Weber J Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis Oncologist 2017 22 (6) 709 18 28495807\n11 Williams TJ Benavides DR Patrice KA Dalmau JO de Ávila AL Le DT Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer JAMA Neurol 2016 73 (8) 928 33 27271951\n12 Kopecky J Kubecek O Geryk T Slovackova B Hoffmann P Ziaran M et al Nivolumab induced encephalopathy in a man with metastatic renal cell cancer: a case report J Med Case Rep 2018 12 262 30217214\n13 Burke M Hardesty M Downs W A case of severe encephalitis while on PD-1 immunotherapy for recurrent clear cell ovarian cancer Gynecol Oncol Rep 2018 24 51 3 29915799\n14 World Health Organization. Tuberculosis https://www.who.int/news-room/fact-sheets/detail/tuberculosis. Accessed October 29, 2020\n\n",
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"keywords": "Checkpoint inhibitor; Immunotherapy; Meningitis; Meningoencephalitis; Nivolumab; Oncology; Renal cell carcinoma",
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"abstract": "Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.\nWe report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.\nManagement of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.\nICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.",
"affiliations": "Department of Endocrinology, UZ Brussel, Laarbeeklaan, Brussels, Belgium.;Department of Endocrinology, UZ Brussel, Laarbeeklaan, Brussels, Belgium.;Department of Medical Oncology, UZ Brussel, Laarbeeklaan, Brussels, Belgium.;Department of Radiology, UZ Brussel, Laarbeeklaan, Brussels, Belgium.;Department of Medical Oncology, UZ Brussel, Laarbeeklaan, Brussels, Belgium.;Department of Endocrinology, UZ Brussel, Laarbeeklaan, Brussels, Belgium.;Department of Medical Oncology, UZ Brussel, Laarbeeklaan, Brussels, Belgium.;Department of Endocrinology, UZ Brussel, Laarbeeklaan, Brussels, Belgium.",
"authors": "Sol|Bastiaan|B|;de Filette|Jeroen M K|JMK|;Awada|Gil|G|;Raeymaeckers|Steven|S|0000-0003-0822-1919;Aspeslagh|Sandrine|S|;Andreescu|C E|CE|;Neyns|Bart|B|;Velkeniers|Brigitte|B|0000-0001-8577-9698",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab; D000077594:Nivolumab",
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"fulltext": "\n==== Front\nEur J Endocrinol\nEur J Endocrinol\nEJE\nEuropean Journal of Endocrinology\n0804-4643 1479-683X Bioscientifica Ltd Bristol \n\n33112279\n10.1530/EJE-20-0151\nEJE-20-0151\nBrief Report\nImmune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?\nB Sol, J M K de Filette and othersICI therapy for pituitary carcinomaSol Bastiaan 1* de Filette Jeroen M K 1* Awada Gil 2 http://orcid.org/0000-0003-0822-1919Raeymaeckers Steven 3 Aspeslagh Sandrine 2 Andreescu C E 1 Neyns Bart 2 http://orcid.org/0000-0001-8577-9698Velkeniers Brigitte 1 1 Department of Endocrinology, UZ Brussel, Laarbeeklaan, Brussels, Belgium\n2 Department of Medical Oncology, UZ Brussel, Laarbeeklaan, Brussels, Belgium\n3 Department of Radiology, UZ Brussel, Laarbeeklaan, Brussels, Belgium\nCorrespondence should be addressed to B Sol; Email: bastiaan.sol@uzbrussel.be*(B Sol and J M K de Filette contributed equally to this work)\n\n\n1 2021 \n05 10 2020 \n184 1 K1 K5\n02 3 2020 05 10 2020 © 2021 The authors2021The authors This work is licensed under a Creative Commons Attribution 4.0 International License.Background\nPituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.\n\nCase\nWe report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.\n\nDiscussion\nManagement of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.\n\nConclusion\nICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.\n==== Body\nBackground\nPituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.\n\nCase\nA 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.\n\nIn 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.\nFigure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.\n\n\nFigure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.\n\n\nTable 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.\n\nDate\t08:00 h Cortisol1 (µg/L)\t08:00 h ACTH2 (ng/L)\tUFC3 (µg/L)\tTreatment\t\nJun/17\t378.5\t225\t606.2\tKetoconazole 1000 mg + Pasireotide 0.6 mg twice daily started\t\nSep/17\t151.6\t231\t47.8\tBilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started\t\nMay/18\t132\t357.3\t177\tHydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted\t\nAug/18\t145\t418\t243.8\tTemozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg\t\nApr/19\t208\t419.9\t284.7\tIpilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg\t\nAug/19\t199\t338.9\t140.7\tNivolumab 240 mg every 2 weeks + ketoconazole 800 mg\t\nNov/19\t196\t346.9\t136.6\tNivolumab 240 mg every 2 weeks + ketoconazole 800 mg\t\nFeb/20\t74\t293.7\t74.1\tNivolumab 240 mg every 2 weeks + ketoconazole 800 mg\t\n\n1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.\n\n\n\nDiscussion\nPituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).\n\nThe pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).\n\nConsidering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.\n\nPituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.\n\nConclusion\nTreatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nInformed consent has been obtained from the patient for publication of the case report and accompanying images.\n==== Refs\nReferences\n1 Pichard C Gerber S Laloi M Kujas M Clemenceau S Ponvert D Bruckert E Turpin G Pituitary carcinoma: report of an exceptional case and review of the literature\n. Journal of Endocrinological Investigation \n2002 \n25 \n65 –72\n. (10.1007/BF03343963 )11883868 \n2 Mete O Lopes MB Overview of the 2017 WHO classification of pituitary tumors\n. Endocrine Pathology \n2017 \n28 \n228 –2\n43\n. (10.1007/s12022-017-9498-z )28766057 \n3 Raverot G Burman P McCormack A Heaney A Petersenn S Popovic V Trouillas J Dekkers OM European Society of Endocrinology. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas\n. European Journal of Endocrinology \n2018 \n178 \nG1 –G24\n. (10.1530/EJE-17-0796 )29046323 \n4 Yoo F Kuan EC Heaney AP Bergsneider M Wang MB Corticotrophic pituitary carcinoma with cervical metastases: case series and literature review\n. Pituitary \n2018 \n21 \n290 –301\n. (10.1007/s11102-018-0872-8 )29404894 \n5 Lin AL Jonsson P Tabar V Yang TJ Cuaron J Beal K Cohen M Postow M Rosenblum M Shia J et al\nMarked response of a hypermutated ACTH-secreting pituitary carcinoma to ipilimumab and nivolumab\n. Journal of Clinical Endocrinology and Metabolism \n2018 \n103 \n3925 –3\n93\n0\n. (10.1210/jc.2018-01347 )30085142 \n6 Barber TM Adams E Ansorge O Byrne JV Karavitaki N Wass JAH Nelson’s syndrome\n. European Journal of Endocrinology \n2010 \n163 \n495 –507\n. (10.1530/EJE-10-0466 )20668020 \n7 Ilie MD Vasiljevic A Raverot G Bertolino P The microenvironment of pituitary tumors-biological and therapeutic implications\n. Cancers \n2019 \n11 1605. (10.3390/cancers11101605 )\n8 Caturegli P Di Dalmazi G Lombardi M Grosso F Larman HB Larman T Taverna G Cosottni M Lupi I Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series\n. American Journal of Pathology \n2016 \n186 \n3225 –3\n23\n5\n. (10.1016/j.ajpath.2016.08.020 )27750046 \n9 Barroso-Sousa R Barry WT Garrido-Castro AC Hodi FS Min L Krop IE Tolaney SM Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis\n. JAMA Oncology \n2018 \n4 \n173 –1\n82\n. (10.1001/jamaoncol.2017.3064 )28973656 \n10 de Filette J Andreescu CE Cools F Bravenboer B Velkeniers B A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors\n. Hormone and Metabolic Research \n2019 \n51 \n145 –1\n56\n. (10.1055/a-0843-3366 )30861560 \n11 Mei Y Bi WL Greenwald NF Du Z Agar NY Kaiser UB Woodmansee WW Reardon DA Freeman GJ Fecci PE et al\nIncreased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors\n. Oncotarget \n2016 \n7 \n76565 –76\n576\n. (10.18632/oncotarget.12088 )27655724 \n12 Wang PF Wang TJ Yang YK Yao K Li Z Li YM Yan CX The expression profile of PD-L1 and CD8+ lymphocyte in pituitary adenomas indicating for immunotherapy\n. Journal of Neuro-Oncology \n2018 \n139 \n89 –95\n. (10.1007/s11060-018-2844-2 )29680903\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0804-4643",
"issue": "184(1)",
"journal": "European journal of endocrinology",
"keywords": null,
"medline_ta": "Eur J Endocrinol",
"mesh_terms": "D049913:ACTH-Secreting Pituitary Adenoma; D000236:Adenoma; D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma; D059447:Cell Cycle Checkpoints; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D000077594:Nivolumab",
"nlm_unique_id": "9423848",
"other_id": null,
"pages": "K1-K5",
"pmc": null,
"pmid": "33112279",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30085142;28973656;27750046;27655724;28766057;29404894;11883868;20668020;30861560;31640258;29046323;29680903",
"title": "Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?",
"title_normalized": "immune checkpoint inhibitor therapy for acth secreting pituitary carcinoma a new emerging treatment"
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"abstract": "Few published reports highlight intravenous tissue plasminogen activator use during the first trimester of pregnancy and provide outcomes for mother and fetus. Little guidance is available regarding body weight dosing of intravenous tissue plasminogen activator during pregnancy.\nHere, we present a patient who received intravenous tissue plasminogen activator in the emergency department during her first trimester of pregnancy for the treatment of an acute ischemic stroke. Outcomes are presented for mother and fetus, as well as discussion about the dosing weight utilized for the intravenous tissue plasminogen activator dose calculation.\nA 35-year-old, Gravida 7 Para 6, presented to the emergency department at 9 weeks gestation with acute stroke symptoms. Her initial National Institutes of Health Stroke Scale was 7. Imaging revealed a hyperdense right middle cerebral artery sign. Intravenous tissue plasminogen activator was administered 57 min after her arrival and based on her actual body weight during pregnancy. Post tissue plasminogen activator imaging revealed recanalization of the vessel and the patient's National Institutes of Health Stroke Scale was 0. The patient progressed to delivery of a healthy female infant. The patient did not experience any bleeding complications throughout pregnancy.\nWe present positive outcomes of a mother and fetus after receipt of intravenous tissue plasminogen activator using actual body weight during the first trimester of pregnancy for an acute ischemic stroke. Additional information is necessary to provide recommendations for the application to future patients in early pregnancy.",
"affiliations": "Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA.;Department of Pharmacy, Emory University Hospital, Atlanta, GA, USA.;Department of Emergency Medicine, Rush University Medical Center, Chicago, IL, USA.",
"authors": "Peksa|Gary D|GD|https://orcid.org/0000-0003-3625-8137;Ostrem|Jamie|J|;Davis|Teresa|T|",
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"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1982824710.1177_2050313X19828247Case ReportIntravenous tissue plasminogen activator for ischemic stroke in early pregnancy dosed by actual body weight https://orcid.org/0000-0003-3625-8137Peksa Gary D 12Ostrem Jamie 3Davis Teresa 21 Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA2 Department of Emergency Medicine, Rush University Medical Center, Chicago, IL, USA3 Department of Pharmacy, Emory University Hospital, Atlanta, GA, USAGary D Peksa, Department of Pharmacy, Rush University Medical Center, 1653 W Congress Parkway, Atrium 0036, Chicago, IL 60612, USA. Email: gary_d_peksa@rush.edu08 2 2019 2019 7 2050313X1982824731 10 2017 10 1 2019 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Introduction:\nFew published reports highlight intravenous tissue plasminogen activator use during the first trimester of pregnancy and provide outcomes for mother and fetus. Little guidance is available regarding body weight dosing of intravenous tissue plasminogen activator during pregnancy.\n\nMethods:\nHere, we present a patient who received intravenous tissue plasminogen activator in the emergency department during her first trimester of pregnancy for the treatment of an acute ischemic stroke. Outcomes are presented for mother and fetus, as well as discussion about the dosing weight utilized for the intravenous tissue plasminogen activator dose calculation.\n\nResults:\nA 35-year-old, Gravida 7 Para 6, presented to the emergency department at 9 weeks gestation with acute stroke symptoms. Her initial National Institutes of Health Stroke Scale was 7. Imaging revealed a hyperdense right middle cerebral artery sign. Intravenous tissue plasminogen activator was administered 57 min after her arrival and based on her actual body weight during pregnancy. Post tissue plasminogen activator imaging revealed recanalization of the vessel and the patient’s National Institutes of Health Stroke Scale was 0. The patient progressed to delivery of a healthy female infant. The patient did not experience any bleeding complications throughout pregnancy.\n\nConclusion:\nWe present positive outcomes of a mother and fetus after receipt of intravenous tissue plasminogen activator using actual body weight during the first trimester of pregnancy for an acute ischemic stroke. Additional information is necessary to provide recommendations for the application to future patients in early pregnancy.\n\nIschemicpregnancystroketissue plasminogen activatorcover-dateJanuary-December 2019\n==== Body\nIntroduction\nPregnant patients were excluded from large clinical trials examining the use of intravenous (IV) tissue plasminogen activator (tPA) for acute ischemic stroke.1 Up to 58% of pregnant or postpartum patients with acute ischemic stroke do not receive IV tPA due to pregnancy itself as a reported exclusion.2 Few published reports highlight IV tPA use in early pregnancy and provide outcomes for mother and fetus. Furthermore, little guidance is available regarding body weight dosing of IV tPA during pregnancy. Here, we present a patient who received IV tPA in the emergency department (ED) during her first trimester of pregnancy for the treatment of an acute ischemic stroke. Outcomes are presented for mother and fetus, as well as discussion about the dosing weight utilized for the IV tPA dose calculation.\n\nCase report\nA 35-year-old, Gravida 7 Para 6, presented to the ED at 9 weeks gestation after losing balance and being unable to move the left side of her body. Past medical history included pre-eclampsia, gestational diabetes, depression, and history of postpartum hemorrhage requiring blood transfusion. Her medications included prenatal vitamins and acetaminophen, and she denied using any tobacco products. On presentation, blood pressure was 133/83 mmHg and labs and other vital signs were within normal limits. Immediate computed tomography (CT) imaging revealed a hyperdense right middle cerebral artery (MCA) sign ischemic infarct (Figure 1). Per family and patient, left upper and lower extremity weakness improved upon presentation to the ED, and left facial droop and left visual field deficits persisted. The neurology consultant did not appreciate limb weakness or ataxia. Her National Institutes of Health Stroke Scale (NIHSS) was 7 and Glasgow Coma Scale (GCS) was 15. Scoring for NIHSS included complete hemianopia (2 points), partial facial paralysis (2 points), mild-to-moderate dysarthria (1 point), and profound hemi-inattention or extinction to more than one modality and does not recognize own hand or orients to one side of space (2 points). Prior to symptoms, her Modified Rankin Scale (mRS) was 0.\n\nFigure 1. CT without contrast of the brain completed upon presentation to the emergency department. Hyperdense right middle cerebral artery sign consistent with a right middle cerebral artery ischemic infarct.\n\nIV tPA 0.9 mg/kg was administered based on her actual body weight (63.6 kg) as 10% bolus and 90% by infusion over 60 min, initiated 87 min after her last known normal and 57 min after her arrival to the ED. Head CT angiography identified a filling defect in the right MCA M1 segment (Figure 2). On admission, further magnetic resonance imaging (MRI) without contrast approximately 5 h post-tPA showed interval recanalization of the right MCA M1 segment and no acute hemorrhage (Figure 3). Diffusion weighted imaging (DWI) MRI showed only faint hyperintense DWI signal involving the right insula (Figure 4). Hypercoagulable workup returned unremarkable, including homocysteine, antiphospholipid antibodies, prothrombin 20210, factor V Leiden, methylene tetrahydrofolate reductase, antithrombin III, protein C, and protein S. A laboratory D-dimer was elevated at 39.43 mg/L, and subsequent lower extremity ultrasound showed no significant findings. A transthoracic echocardiogram with bubble study showed a right to left shunt. Ultimately, the etiology of her stroke was unclear and classified as cryptogenic. The patient was discharged on post-stroke day 3 with an NIHSS of 0 and mRS of 1. She was prescribed aspirin 325 mg daily and enoxaparin 1 mg/kg subcutaneous every 12 h for the duration of her pregnancy.\n\nFigure 2. CT angiography of the brain completed during the administration of intravenous tissue plasminogen activator. Filling defect in the right distal middle cerebral artery (MCA) M1 segment. The superior division of the right MCA is not seen.\n\nFigure 3. MRI without contrast of the brain completed approximately 5 h after the administration of intravenous tissue plasminogen activator. There is interval recanalization of the right distal most middle cerebral artery (MCA) M1 segment and of the superior division of the right MCA.\n\nFigure 4. MRI including diffusion weighted imaging (DWI) of the brain completed approximately 5 h after the administration of intravenous tissue plasminogen activator. Only faint hyperintense DWI signal involving the right insula. No large territorial infarct.\n\nResidual stroke symptoms persisted during pregnancy, including weakness of the left arm and increased salivation and drooling, but NIHSS and mRS remained 0 and 1, respectively. The patient required iron therapy for anemia and routine studies revealed gestational thrombocytopenia with nadir of 79 K/µL platelets. Anemia and thrombocytopenia were thought to be unrelated to receipt of IV tPA. The hematologist consultant recommended stopping aspirin and changing enoxaparin to heparin 2 weeks prior to scheduled induction of labor. The pregnancy was otherwise uncomplicated.\n\nThe patient presented at 39 weeks and 3 days for induction of labor with a Bishop score of 4. On ultrasound, fetus was found to be in transverse position, and external cephalic version was attempted and successful. Induction with misoprostol 1000 mcg per rectum was started, and she progressed to vaginal delivery of a live female infant with a weight of 3600 g and Apgar score of 9 at 1 and 5 min after birth. Baby required phototherapy for hyperbilirubinemia, but otherwise, baby and patient recovered well. The patient was discharged on prophylactic enoxaparin and aspirin for 6 weeks with hematology follow-up. On discharge, NIHSS and mRS remained 0 and 1, respectively. At 4 months post-partum, the patient reported no new complications and baby was doing well.\n\nDiscussion\nTo our knowledge, this is the first case report describing tPA and the body weight used for dosing during pregnancy and adds to the limited literature reporting outcomes for both mother and fetus when IV tPA is administered during the first trimester for acute ischemic stroke. In a previous case report, a patient at gestational week 12 had good outcomes along with good fetal outcomes, but experienced a hemorrhagic infarction post IV tPA.3 In addition, Murugappan et al.4 published a case series with three patients who received IV tPA and were in their first trimester of pregnancy. The first patient had a minor complication (intrauterine hematoma), the second patient had no complications, and the third patient died from dissection during angioplasty. In the first two cases, pregnancies were medically terminated, and the latter resulted in fetal death. Hirano5 completed a review and reported five additional patients with good outcomes for mother and fetus; however, all patients were past their first trimester of pregnancy. More recently, a large study analyzed the outcomes of thrombolytic therapy from the “Get with the Guidelines-Stroke” registry from 2008 to 2013.2 Of the 338 pregnant or postpartum patients with ischemic stroke, 7 patients received tPA monotherapy during pregnancy. Details regarding pregnancy term and fetal outcomes were not provided. In contrast to previous literature, our case resulted in successful outcomes for mother and fetus after receiving IV tPA during the first trimester of pregnancy without bleeding complications.\n\nThe use of pre-pregnancy versus actual body weight presented a challenge when calculating IV tPA for our patient. Previously published literature acknowledges IV tPA dosed as 0.9 mg/kg in pregnancy; however, previous literature is silent on the body weight used (e.g. pre-pregnancy versus pregnancy) for IV tPA dosing despite significant weight changes throughout pregnancy.2–5 Women are expected to gain 5–18 kg of body weight throughout pregnancy.6 This leads to uncertainty regarding the correct weight to use for dosing calculations. Furthermore, plasma volume increases by 42% during pregnancy and increases the volume of distribution of drugs.7 The volume of distribution of tPA is similar to that of plasma.8 Therefore, theoretically the volume of distribution of tPA will also increase during pregnancy.\n\nIn the patient presented, the body weight was 6.9 kg higher at the time of event than the last documented pre-pregnancy weight. The actual body weight was utilized for dosing calculations which equated to a 6.2% increase in dose compared to the pre-pregnancy weight. Actual body weight was utilized in this case to reflect the increase in plasma volume. In patients with more drastic weight differences during pregnancy, it is unknown if actual, adjusted, or pre-pregnancy body weight should be utilized for dosing calculations of IV tPA. The theoretical risk of bleeding with higher doses should be taken into consideration.\n\nConclusion\nWithout randomized controlled trials regarding the use of IV tPA for the treatment of ischemic stroke during pregnancy, the acute management must be individualized. The benefits and risks should be carefully discussed with all parties on the medical team as well as the patient and caregivers. We present positive outcomes of a mother and fetus after receipt of IV tPA using actual body weight during the first trimester of pregnancy for an acute ischemic stroke. Additional information is necessary to provide recommendations for the application to future patients in early pregnancy.\n\nWe would like to acknowledge Benjamin Bienia and Victor D. Nguyen for assistance with radiological imaging selection.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: Gary D Peksa \nhttps://orcid.org/0000-0003-3625-8137\n==== Refs\nReferences\n1 \nNational Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group . Tissue plasminogen activator for acute ischemic stroke . N Engl J Med \n1995 ; 333 : 1581 –1587 .7477192 \n2 \nLeffert LR Clancy CR Bateman BT et al \nTreatment patterns and short-term outcomes in ischemic stroke in pregnancy or postpartum period . Am J Obstet Gynecol \n2016 ; 214 : 723.e1 –723.e11 .26709084 \n3 \nDapprich M Boessenecker W. \nFibrinolysis with alteplase in a pregnant woman with stroke . Cerebrovasc Dis \n2002 ; 13 (4 ): 290 .12011557 \n4 \nMurugappan A Coplin WM Al-Sadat AN et al \nThrombolytic therapy of acute ischemic stroke during pregnancy . Neurology \n2006 ; 66 (5 ): 768 –770 .16534124 \n5 \nHirano T. \nAcute revascularization therapy in pregnant patients . Neurol Med Chir \n2013 ; 53 (8 ): 531 –536 .\n6 \nIOM (Institute of Medicine) and NRC (National Research Council) . 2009 \nWeight Gain During Pregnancy: Reexamining the Guidelines . Washington, DC : The National Academies Press .\n7 \nFeghali M Venkataramanan R Caritis S. \nPharmacokinetics of drugs in pregnancy . Semin Perinatol \n2015 ; 39 (7 ): 512 –519 .26452316 \n8 \nAlteplase (package insert). San Francisco, CA : Genentech , 1987 .\n\n",
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"abstract": "Pyoderma gangrenosum (PG) is a rare inflammatory dermatosis that is most often associated with inflammatory bowel disease, but which can occur as a pathergic reaction around surgical incisions. The authors report the case of a patient who developed postoperative PG over the course of several months after undergoing extensive spinal instrumentation between the T4 and iliac levels. This is only the second such case occurring after spine surgery to be reported. The authors additionally review the literature to characterize treatment approaches and outcomes for this condition. The case highlights a potentially severe adverse effect of surgery that can be difficult to recognize and causes delays in effective treatment. It also demonstrates the importance of multidisciplinary collaboration in the effective care of patients.",
"affiliations": "Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;2Dermatology, University of Virginia Health System, Charlottesville, Virginia; and.;Departments of1Neurological Surgery and.;Departments of1Neurological Surgery and.;3Department of Neurosurgery, Duke Health, Durham, North Carolina.;Departments of1Neurological Surgery and.",
"authors": "Snyder|M Harrison|MH|;Ampie|Leonel|L|;Forrester|Vernon J|VJ|;Wilson|JoAnne C|JC|;Nguyen|James H|JH|;Shaffrey|Christopher I|CI|;Buchholz|Avery L|AL|",
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"keywords": "IBD = inflammatory bowel disease; PG = pyoderma gangrenosum; PPG = postoperative PG; RA = rheumatoid arthritis; RCT = randomized controlled trial; SSI = surgical site infection; WBC = white blood cell; dermatology; infection; postoperative complications; pyoderma gangrenosum; spinal instrumentation; spine surgery; vac = vacuum-assisted closure",
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"title": "Postoperative pyoderma gangrenosum after spinal fusion with instrumentation: case report.",
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"abstract": "This study presents a case of severe water intoxication in a female patient with delusional infestation. Self-induced excessive water ingestion is a rare medical condition, which has not been reported in patients with delusional infestation yet. The patient in this case study was a 60-year-old Chinese woman, who was admitted to our hospital because of a feeling of skin infestation. She suffered from loss of consciousness and generalized tonic-clonic seizure after drinking 12 L of water during bowel cleansing before colonoscopy. Sufficient laboratory and imaging examinations were performed to exclude other possible causes of severe hyponatremia, such as hypothyroidism, diabetes insipidus, and syndrome of inappropriate antidiuretic hormone. Besides, the cystic lesion in the posterior pituitary revealed by cranial magnetic resonance imaging was not accountable for her delusional symptoms as well as excessive drinking behavior. Her delusional symptoms were in complete remission with a combination of risperidone and aripiprazole. However, nearly 3 months after discharge, this patient suffered from depressed mood and was diagnosed with depressive syndrome, and even attempted suicide. This case highlights the possibility of self-induced water intoxication in patients with delusional infestation, inevitably adding to the complexity of the disease, and indicates the necessity of precautions for secondary psychotic or mood problems after symptomatological remission.",
"affiliations": "Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.;Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.;Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China; The Key Laboratory of Mental Disorder's Management in Zhejiang Province, Hangzhou, People's Republic of China.;Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China; The Key Laboratory of Mental Disorder's Management in Zhejiang Province, Hangzhou, People's Republic of China.",
"authors": "Lai|Jianbo|J|;Lu|Qiaoqiao|Q|;Xu|Yi|Y|;Hu|Shaohua|S|",
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"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S102993ndt-12-517Case ReportSevere water intoxication and secondary depressive syndrome in relation to delusional infestation Lai Jianbo 1Lu Qiaoqiao 1Xu Yi 12Hu Shaohua 121 Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China2 The Key Laboratory of Mental Disorder’s Management in Zhejiang Province, Hangzhou, People’s Republic of ChinaCorrespondence: Shaohua Hu, Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, No 79, Qingchun Road, Hangzhou 310003, People’s Republic of China, Tel +86 571 5672 3002, Fax +86 571 5672 3001, Email dorhushaohua@zju.edu.cn2016 29 2 2016 12 517 521 © 2016 Lai et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.This study presents a case of severe water intoxication in a female patient with delusional infestation. Self-induced excessive water ingestion is a rare medical condition, which has not been reported in patients with delusional infestation yet. The patient in this case study was a 60-year-old Chinese woman, who was admitted to our hospital because of a feeling of skin infestation. She suffered from loss of consciousness and generalized tonic–clonic seizure after drinking 12 L of water during bowel cleansing before colonoscopy. Sufficient laboratory and imaging examinations were performed to exclude other possible causes of severe hyponatremia, such as hypothyroidism, diabetes insipidus, and syndrome of inappropriate antidiuretic hormone. Besides, the cystic lesion in the posterior pituitary revealed by cranial magnetic resonance imaging was not accountable for her delusional symptoms as well as excessive drinking behavior. Her delusional symptoms were in complete remission with a combination of risperidone and aripiprazole. However, nearly 3 months after discharge, this patient suffered from depressed mood and was diagnosed with depressive syndrome, and even attempted suicide. This case highlights the possibility of self-induced water intoxication in patients with delusional infestation, inevitably adding to the complexity of the disease, and indicates the necessity of precautions for secondary psychotic or mood problems after symptomatological remission.\n\nKeywords\ndelusional infestationdepressive syndromesuicidewater intoxication\n==== Body\nIntroduction\nDelusional infestation (DI) is a rare psychocutaneous condition complicated by various causes and comorbidities. In contrast to the primary form of DI, which is independent from underlying diseases, the secondary form of DI presents as a concomitant phenomenon in other dominant conditions.1 As was documented in literature, neuropsychiatric diseases, psychotropic drugs, nutrient deficiency, infections, and even homeostatic imbalance all possibly facilitate the onset and development of secondary DI.2 Self-induced water intoxication is another uncommon emergency condition that needs prompt management. However, it has been reported that exaggerated water intake may occur in almost any psychiatric disorder, especially those with psychotic traits.3 Self-induced water intoxication in patients with DI has never been previously documented.\n\nIn affected patients, DI significantly weakens psychosocial functioning and impairs the quality of life. Owing to the lack of insight on disease nature, patients with DI are always reluctant to visit a psychiatrist and have a poor compliance, which further worsens their condition. These patients easily feel anxious, and as a result, establishing a therapeutic rapport with them requires great effort. Managing primary diseases is the immediate task, and antipsychotics can be used to eliminate psychotic symptoms related to DI.2,4 However, long-term follow-ups were not found to be of great importance in previous studies after a full remission from DI.\n\nThis study reports an impressive case of a female patient with DI who developed generalized tonic–clonic seizure after drinking 12 L of water during bowel cleansing before colonoscopy. After recovering from acute water intoxication, her delusional symptoms were well alleviated by a combination of risperidone and aripiprazole. However, nearly 3 months after discharge, this patient suffered from depressed mood and was diagnosed with depressive syndrome. Her mood problem did not respond well to the antidepressant therapy, and she even made a suicide attempt. This single case highlighted that patients with DI may also have a risk of self-induced excessive water intake, which inevitably adds to the complexity of the disease and warranted the importance of continuous health monitoring for possible psychotic or mood disorders during follow-ups. This work was approved by the First Affiliated Hospital of Zhejiang University School of Medicine Ethics Committee. Written informed consent was given by the patient after her recovery from water intoxication.\n\nCase presentation\nMrs X, a 60-year-old Chinese woman, was admitted to the Department of Infectious Diseases, First Affiliated Hospital of Zhejiang University School of Medicine, because of the feeling of skin infestation. Since her travel to a rural area 4 months ago, she had been persistently feeling insects crawling and breeding under her skin. She complained that these insects bit her skin, causing intolerable pain and itch. She insisted that her living room was full of insects of different sizes, and numerous insect eggs could have washed off when washing her hair. Before admission, she was diagnosed with “pediculosis, allergic dermatitis”, and prescribed desloratadine and metronidazole by a dermatologist. Not surprisingly, these agents did not help relieve her sufferings. Since the onset of the aforementioned symptoms, her body weight consequently went down by 8 kg.\n\nIn her past medical history, she suffered from hypertension for 9 years, which is well controlled by amlodipine 5 mg daily. She denied any personal history of other physical or mental illnesses, illicit drug abuse, or intoxication, as well as a family history of psychiatric conditions. No irritant or traumatic events happened before her current presentation. Besides, she was allergic to sulfonamides and levofloxacin. She had an open appendectomy 40 years before admission and gave birth to her son by cesarean delivery 30 years before admission.\n\nA full-body skin examination revealed scattered excoriations with pigmentation caused by self-inflicted scratching. Further laboratory screenings, including profiles of routine blood, urine, stool tests, serum biochemistry, coagulation function, thyroid function, myocardial enzymes, troponin-I, C-reactive protein, rheumatoid factor, erythrocyte sedimentation rate, serum tumor markers, antinuclear antibodies, prolactin, serum VitB12, folate level, hepatitis B and C, human immunodeficiency virus, syphilis, cytomegalovirus, and Epstein–Barr virus, were all within normal limits except that fecal occult blood test was positive. Besides, electrocardiogram and chest computed tomography (CT) were normal. Color Doppler ultrasonography detected a diffusely enlarged thyroid with multiple nodules, and a small hepatic cyst. Cranial magnetic resonance imaging (MRI) (3.0 T) indicated a cystic lesion in the posterior pituitary (Figure 1A). Meanwhile, the patient complained about archorrhagia and insect eggs washing off when cleaning her anus. Therefore, an anorectal consultation was immediately requested. Digital rectal examination was negative, and colonoscopy was suggested. Unexpectedly, when preparing for a bowel cleansing before colonoscopy, this patient ingested five thermos jugs of water (appropriately 12 L) in a few hours. Consequently, she began to feel short of breath, although bedside heart and lung auscultation was normal. Blood pressure was 143/76 mmHg. About 20 minutes later, she became irritated and could not stop scratching her face and head. Rapid blood glucose was 7.7 mmol/L. After another half an hour, in a sitting position, the patient vomited appropriately 50 mL of water, with eyes tightly closed and hands involuntarily trembling. Direct and consensual reactions on both pupils were sensitive. Her neck was soft, but bilateral Babinski’s sign became positive. Another 15 minutes later, the patient experienced a seizure, characterized by loss of consciousness, turning up of the eyes, biting of the tongue, clenching of the teeth, frothing of the mouth, and urinary incontinence. After about 5 minutes, seizure gradually alleviated, but the patient remained irritated and her hands repetitively grasped in an involuntary pattern. Immediately, 10 mg of diazepam was intramuscularly injected. A neurological consult considered the aforementioned symptoms to be an epileptic attack and suggested the use of sodium valproate. A quick check on serum electrolytes indicated hyponatremia (120 mmol/L, reference interval: 136–145 mmol/L), hypochloremia (82 mmol/L, reference interval: 96–108 mmol/L), and hypokalemia (3.27 mmol/L, reference interval: 3.50–5.20 mmol/L), which possibly linked to the overintake of water and accounted for the epilepticus insultus. Cranial CT acquisitions were generally normal, although data were not that clear because of noncooperation of the patient. The results of lumbar puncture excluded intracranial infections and revealed a low level of cerebrospinal fluid chlorine. The arterial blood gas analysis indicated uncompensated alkalosis (pH value 7.52, reference interval: 7.35–7.45). As the situation was urgent, the patient was transferred to the Department of Intensive Care Unit (ICU) for further examinations and treatments. In the ICU, vital signs and urine volume of this patient were closely monitored. She was treated with meticulous supportive and nursing care (eg, oxygen uptake, catheter care, and perineal cleaning), intravenous sodium valproate pumping, nasal levetiracetam feeding, and intravenous potassium and sodium supplement at a well-controlled speed. The patient has experienced fever when she was in a mild coma about 1 day after the epileptic attack, and her body temperature increased to a maximum of 39°C. The auscultation of lungs revealed bilateral crackles, and the routine blood test revealed increased count of white blood cells and neutrophils over normal limits. Lung infection was therefore indicated, and antibiotics were prescribed. Meanwhile, hematological tests documented elevated hepatic enzymes and cardiac enzymes. In addition, urine sodium and osmolality, and serum adrenocorticotropic hormone and cortisol levels were screened to exclude diabetes insipidus and syndrome of inappropriate antidiuretic hormone (SIADH). About 45 hours after the epileptic attack, her deteriorated consciousness completely cleared, whereas her cutaneous concerns remained the same as before. After 4 days in the ICU, laboratory examinations basically returned to normal, and the patient was transferred back to the Department of Infectious Diseases. Psychiatric consulting was asked to deal with her persistent psychotic symptoms. Because the patient had abnormal skin sensations without any trace of infection, confirmedly convincing herself of being infected with insects, she met the criteria proposed in 20092 and was thereof diagnosed with DI. Accordingly, she was administered risperidone, titrated to 4 mg/day (1.5 mg at noon and 2.5 mg at night). However, laboratory monitoring revealed an elevated serum level of prolactin (highest at 189.6 ng/mL, reference interval: 2.8–29.2 mmol/L). Furthermore, 3.0 T MRI scanning of the pituitary reported a similar result as earlier (Figure 1B and C). Considering risperidone to be the culprit for prolactin disturbance, its dose was gradually decreased to 2.5 mg/d (night only), and 5 mg aripiprazole (night only) was added together with bromocriptine. Consequently, serum prolactin gradually declined to the normal level. After a 2-month inpatient treatment with atypical antipsychotics, her tactile hallucinations and somatic delusions significantly improved, and continuous medication was suggested after discharge.\n\nDuring outpatient follow-ups, symptomatological remission of DI was maintained. However, the patient developed symptoms of depressed mood and loss of appetite and interest nearly 3 months after hospital discharge. In a psychiatric visit, her Hamilton Depression Rating Scale (17 items) reached a score of 27. She was diagnosed with depressive syndrome after comprehensive psychiatric assessments. Accordingly, citalopram was prescribed and gradually titrated to 40 mg/day. Meanwhile, she was advised to continue her antipsychotics for DI. However, her depressed mood did not significantly improve after a 2-week treatment with citalopram. Nearly 1 month after citalopram was initiated, this woman was reported to have attempted suicide in her own house. She was found trying to jump from the balcony and was stopped after much persuasion. She was then inevitably lost to follow-up, although repeated phone calls were made.\n\nDiscussion\nSevere water intoxication elicited by drinking excessive water is a rare emergency condition. The overintake of water causes a rapid decline in serum electrolyte concentration and encephaledema, which further disrupts neuron membrane stability and even progresses to seizure in some susceptible individuals.5 In this case with DI, the patient unexpectedly ingested a large amount of water during bowel cleansing before colonoscopy. The overconsumption of approximately 12 L of water in a few hours was indeed a terrifying thing, which ultimately caused a grand mal seizure in this patient. Sufficient laboratory and imaging examinations were performed to exclude other possible causes of severe hyponatremia, such as hypothyroidism, diabetes insipidus, and SIADH. Besides, the cystic lesion in the posterior pituitary revealed by cranial MRI was not accountable for her delusional symptoms as well as excessive drinking behavior. Before hospitalization, medications for “pediculosis” were of poor efficacy. However, a combination of risperidone and aripiprazole helped to dispel her cutaneous concerns. A final diagnosis of DI was further confirmed.\n\nStill, this incident that happened in a hospital complicated the course of disease and was worth reflecting on. Whether this patient had a chronic overintake of water before admission was unknown; however, bowel cleansing before colonoscopy indeed became a prerequisite for her dangerous excessive water ingestion. Considering patients with DI always being in a state of anxiety and lacking insights into disease nature, clinicians are responsible to make patients and their caregivers understand every detail of any examination. Besides, previous studies have reported that patients with psychiatric disorders had an increased risk for self-induced water intoxication,3 which was known as psychogenic polydipsia.6 It is estimated that psychogenic polydipsia has an incidence of approximately 6%–20% in psychiatric patients.7 Chronic schizophrenics, chronic alcoholics, and middle-aged women with anxiety disorders constitute the main part of this population.3,8,9 For example, one case report documented a schizophrenic patient who drank a large quantity of water to flush away imaginary parasites from his body and consequently suffered a similar course of acute water intoxication as observed in the present study.10 Therefore, it is reasonable to speculate that the patient in the present case drank excessive water possibly for the same reason. Such drinking behavior, together with self-inflicted skin scratches, reflected a lack of insight into the disease nature in these patients, which may also be used to assess the severity of symptoms. In addition, psychotic and anxious traits in patients with DI may also contribute to their compulsive water drinking.\n\nIn outpatient follow-ups, considering that medication adjustment to monotherapy might weaken her compliance, this patient was advised to continue her antipsychotics. She was still taking risperidone and aripiprazole when citalopram was added for depression treatment. It has already been reported that severe secondary depression occurred in more than half of DI patients, and suicide ideations or attempts were not uncommon,11 which was further confirmed in the present case. In a recent structural neuroimaging study, alterations in prefrontal and temporal areas were indicated in patients with DI,12 which were consistent with the findings in patients with major depressive disorder.13 Therefore, DI and depression may not be two isolated psychiatric conditions. They seem to present as different manifestations or stages of a disease spectrum, which means these two conditions possibly share intimate neural correlates.\n\nTo conclude, although underlying neural pathophysiology of DI remains largely unknown, the clinical picture of the patient in this case highlights that patients with DI may have a potential risk for self-induced water intoxication, which deserves more attention in clinical practice. Moreover, this case emphasizes that long-term follow-ups are necessary even after symptom remission to monitor the possible onset of other psychotic or mood disorders in later life.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Data from cranial 3.0 T MRI scanning.\n\nNotes: (A) A cystic lesion (orange arrow) in the posterior pituitary with high signal intensity on T2 weight sequence (data collected before water intoxication); (B) low signal intensity of the cystic lesion on T1 weight sequence (data collected after prolactin elevation); (C) following the injection of contrast, signal intensity in the cystic lesion was not obviously enhanced on T1 weight sequence (data collected after prolactin elevation).\n\nAbbreviation: MRI, magnetic resonance imaging.\n==== Refs\nReferences\n1 Ganner H Lorenzi E Delusions of skin infestations Psychiatr Clin (Basel) 1975 8 1–2 31 44 1082604 \n2 Freudenmann RW Lepping P Delusional infestation Clin Microbiol Rev 2009 22 4 690 732 19822895 \n3 Ferrier IN Water intoxication in patients with psychiatric illness Br Med J 1985 291 6509 1594 1596 3935199 \n4 Heller MM Wong JW Lee ES Delusional infestations: clinical presentation, diagnosis and treatment Int J Dermatol 2013 52 7 775 783 23789596 \n5 Fraser CL Arieff AI Epidemiology, pathophysiology, and management of hyponatremic encephalopathy Am J Med 1997 102 1 67 77 9209203 \n6 Illowsky BP Kirch DG Polydipsia and hyponatremia in psychiatric patients Am J Psychiatry 1988 145 6 675 683 3285701 \n7 Verghese C de Leon J Josiassen RC Problems and progress in the diagnosis and treatment of polydipsia and hyponatremia Schizophr Bull 1996 22 3 455 464 8873296 \n8 Dundas B Harris M Narasimhan M Psychogenic polydipsia review: etiology, differential, and treatment Curr Psychiatry Rep 2007 9 3 236 241 17521521 \n9 Cronin RE Psychogenic polydipsia with hyponatremia: report of eleven cases Am J Kidney Dis 1987 9 5 410 416 3107377 \n10 Alexander ER Crow TJ Hamilton SM Water intoxication in relation to acute psychotic disorder Br Med J 1973 1 5845 89 20791879 \n11 Munro A Monosymptomatic hypochondriacal psychosis Br J Psychiatry Suppl 1988 2 37 40 3072051 \n12 Wolf RC Huber M Depping MS Abnormal gray and white matter volume in delusional infestation Prog Neuropsychopharmacol Biol Psychiatry 2013 46 19 24 23791615 \n13 Fung G Deng Y Zhao Q Distinguishing bipolar and major depressive disorders by brain structural morphometry: a pilot study BMC Psychiatry 2015 15 1 298 26590556\n\n",
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"abstract": "After maternal exposure to mycophenolate in pregnancy a high number of fetal losses and a specific pattern of birth defects consisting of microtia, cleft lip, and other anomalies have been reported. However, so far, prospective data on pregnancy outcome allowing quantitative risk assessment are missing. We report on 57 prospectively ascertained pregnancies after maternal therapy with mycophenolate (mycophenolate mofetil or mycophenolate sodium) identified by European Teratology Information Services (ETIS) through their risk consultation process. The outcome of these prospective pregnancies was as follows: 16 spontaneous abortions, 12 elective terminations of pregnancy (ETOP) (including two late terminations for multiple malformations consistent with mycophenolate embryopathy), and 29 liveborn infants. The probability of spontaneous abortion was about 45% (95% CI 29 to 66%) estimated using survival analysis technique. Six out of 29 live born infants had major congenital defects: Two with external auditory canal atresia (EACA) (with and without microtia), one with tracheo-esophageal atresia, one with severe hydronephrosis, one with an atrial septal defect (ASD) and one with a myelomeningocele. Thus, at least four fetuses/infants of our prospective case series had a clinical phenotype consistent with mycophenolate embryopathy. Our results confirm a high incidence of major malformations (26%) after first trimester exposure to mycophenolate. Apart from exposure to mycophenololate, the underlying maternal disease and concomitant medication may also have contributed to the other poor pregnancy outcomes such as a high rate of spontaneous abortions, prematurity (62%), and low birth weight (31%).",
"affiliations": "Pharmakovigilanzzentrum Embryonaltoxikologie, Charité Universitätsmedizin Berlin, Germany. Hoeltzenbein@embryotox.de",
"authors": "Hoeltzenbein|Maria|M|;Elefant|Elisabeth|E|;Vial|Thierry|T|;Finkel-Pekarsky|Victoriya|V|;Stephens|Sally|S|;Clementi|Maurizio|M|;Allignol|Arthur|A|;Weber-Schoendorfer|Corinna|C|;Schaefer|Christof|C|",
"chemical_list": "D013723:Teratogens; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.35223",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "158A(3)",
"journal": "American journal of medical genetics. Part A",
"keywords": null,
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000022:Abortion, Spontaneous; D000013:Congenital Abnormalities; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007231:Infant, Newborn; D009173:Mycophenolic Acid; D011247:Pregnancy; D011256:Pregnancy Outcome; D011446:Prospective Studies; D013723:Teratogens",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "588-96",
"pmc": null,
"pmid": "22319001",
"pubdate": "2012-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services.",
"title_normalized": "teratogenicity of mycophenolate confirmed in a prospective study of the european network of teratology information services"
} | [
{
"companynumb": "DE-STRIDES ARCOLAB LIMITED-2016SP019065",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"dru... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy of flecainide and digoxin combination in foetal supraventricular tachycardia.\n\n\nMETHODS\nThis study was carried out in a tertiary referral centre.\n\n\nMETHODS\nWe conducted a retrospective review of 29 patients diagnosed with supraventricular foetal tachycardia between 2001 and 2009. Mode of presentation, foetal cardiac function, maternal anti-arrhythmic serum levels, drug tolerance, and maternal electrocardiogram recordings were assessed. The postnatal outcome of each infant was also evaluated for tachycardia recurrence.\n\n\nRESULTS\nIn all, 27 foetuses were treated with digoxin and flecainide combination, and two foetuses were delivered without any treatment. Of the 27 foetuses treated, six [corrected] had atrial flutter and the remaining 21 [corrected] had atrioventricular re-entry tachycardia. There were eight foetuses with hydrops (27%), of whom three had atrial flutter and five had atrioventricular re-entry tachycardia; 26 foetuses (96%) responded to flecainide and digoxin combination, with restoration of sinus rhythm in 22 (81.4%) and rate control in the other four. In one severely hydropic foetus, there was no response to treatment. In all, 26 treated infants were delivered alive, but one pregnancy was terminated for non-cardiac causes when the foetus was in sinus rhythm. There was no intrauterine death due to tachycardia. Although there were minor side effects to anti-arrhythmic medications, none of the pregnant women developed proarrhythmia.\n\n\nCONCLUSIONS\nFlecainide and digoxin combination treatment offers a safe and effective treatment for foetal supraventricular tachycardia with fast restoration of sinus rhythm.",
"affiliations": "Department of Paediatric Cardiology, University Hospital of Wales, Cardiff, Wales, United Kingdom. orhan.uzun@wales.nhs.uk",
"authors": "Uzun|Orhan|O|;Babaoglu|Kadir|K|;Sinha|Anju|A|;Massias|Spyridon|S|;Beattie|Bryan|B|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D004077:Digoxin; D005424:Flecainide",
"country": "England",
"delete": false,
"doi": "10.1017/S1047951111001272",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "22(4)",
"journal": "Cardiology in the young",
"keywords": null,
"medline_ta": "Cardiol Young",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents; D001282:Atrial Flutter; D004077:Digoxin; D004359:Drug Therapy, Combination; D004452:Echocardiography; D005260:Female; D005315:Fetal Diseases; D005424:Flecainide; D005865:Gestational Age; D006801:Humans; D015160:Hydrops Fetalis; D007231:Infant, Newborn; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D013611:Tachycardia, Atrioventricular Nodal Reentry; D013617:Tachycardia, Supraventricular; D016896:Treatment Outcome; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "372-80",
"pmc": null,
"pmid": "22008551",
"pubdate": "2012-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rapid control of foetal supraventricular tachycardia with digoxin and flecainide combination treatment.",
"title_normalized": "rapid control of foetal supraventricular tachycardia with digoxin and flecainide combination treatment"
} | [
{
"companynumb": "PHHY2019GB190112",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Recently, the benefit of adding daratumumab to the proteasome inhibitor-based, 3-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hemopoietic cell transplant was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor-based, 3-drug combination of carfilzomib, lenalidomide, and dexamethasone.\nTo assess the safety and effectiveness of carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy for patients with newly diagnosed multiple myeloma, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant.\nClinical and correlative pilot study at the Memorial Sloan Kettering Cancer Center in New York, New York. Patients with newly diagnosed multiple myeloma were enrolled between October 1, 2018, and November 15, 2019. The median follow-up from start of treatment was 20.3 months (95% CI, 19.2-21.9 months).\nEight 28-day cycles with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); oral lenalidomide, 25 mg, (days 1-21); dexamethasone, 40 mg weekly, orally or intravenously (cycles 1-4), and 20 mg after cycle 4; and intravenous daratumumab, 16 mg/kg (days 1, 8, 15, and 22 [cycles 1-2]; days 1 and 15 [cycles 3-6]; and day 1 [cycles 7 and 8]).\nThe primary end point was the minimal residual disease (MRD) rate, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Secondary end points included determining safety and tolerability, evaluating rates of clinical response per the International Myeloma Working Group, and estimating progression-free survival (PFS) and overall survival (OS) rates.\nForty-one evaluable patients were enrolled (median age, 59 years; range, 30-70 years); 25 (61%) were female, and 20 (49%) had high-risk multiple myeloma. The primary end point (MRD negativity in the bone marrow; 10-5 sensitivity) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), and therefore the trial was deemed successful. Median time to MRD negativity was 6 cycles (range, 1-8 cycles). Secondary end points of the overall response rate and the very good partial response or complete response rate were 100% (41 of 41 patients) and 95% (39 of 41 patients), respectively. At 11 months of the median follow-up, the 1-year PFS rate and the OS rate were 98% (95% CI, 93%-100%) and 100%, respectively. Most common (≥2 patients) grade 3 or 4 adverse events were neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]). There were no deaths.\nIn this nonrandomized clinical trial, carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy was associated with high rates of MRD negativity in patients with newly diagnosed multiple myeloma and high rates of PFS.",
"affiliations": "Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.;Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Landgren|Ola|O|;Hultcrantz|Malin|M|;Diamond|Benjamin|B|;Lesokhin|Alexander M|AM|;Mailankody|Sham|S|;Hassoun|Hani|H|;Tan|Carlyn|C|;Shah|Urvi A|UA|;Lu|Sydney X|SX|;Salcedo|Meghan|M|;Werner|Kelly|K|;Rispoli|Jenna|J|;Caple|Julia|J|;Sams|Allison|A|;Verducci|Dennis|D|;Jones|Katie|K|;Concepcion|Isabel|I|;Ciardello|Amanda|A|;Chansakul|Aisara|A|;Schlossman|Julia|J|;Tavitian|Elizabet|E|;Shekarkhand|Tala|T|;Harrison|Angela|A|;Piacentini|Casey|C|;Rustad|Even H|EH|;Yellapantula|Venkata|V|;Maclaughlan|Kylee|K|;Maura|Francesco|F|;Landau|Heather J|HJ|;Scordo|Michael|M|;Chung|David J|DJ|;Shah|Gunjan|G|;Lahoud|Oscar B|OB|;Thoren|Katie|K|;Murata|Kazunori|K|;Ramanathan|Lakshmi|L|;Arcila|Maria E|ME|;Ho|Caleb|C|;Roshal|Mikhail|M|;Dogan|Ahmet|A|;Derkach|Andriy|A|;Giralt|Sergio A|SA|;Korde|Neha|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2021.0611",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-2437",
"issue": "7(6)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": null,
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "862-868",
"pmc": null,
"pmid": "33856405",
"pubdate": "2021-06-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial.",
"title_normalized": "safety and effectiveness of weekly carfilzomib lenalidomide dexamethasone and daratumumab combination therapy for patients with newly diagnosed multiple myeloma the manhattan nonrandomized clinical trial"
} | [
{
"companynumb": "US-JNJFOC-20210449903",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DARATUMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Elderly treated with dual antiplatelet therapy after percutaneous coronary intervention (PCI) represent a challenging population because of increased risk of both ischemic and bleeding events. We aimed to investigate the association between high on-treatment platelet reactivity (HPR) and long-term outcome in elderly with non-ST-elevated acute coronary syndromes (NSTE-ACS) undergoing PCI.\n\n\n\nPlatelet reactivity was measured by vasodilator-stimulated phosphoprotein (VASP) assay at three time-points (baseline, discharge, 1 month after PCI) in 1053 NSTE-ACS patients (311 elderly) treated with clopidogrel. Major adverse cardiac events (MACE) were assessed up to 1 year-follow-up.\n\n\n\nElderly with HPR at discharge showed a significantly higher incidence of overall MACE (13 vs 4%, p = .006), cardiac death (6 vs 0.7%, p = .020), myocardial infarction (MI, 12 vs 4%, p = .031) and a trend for higher stent-thrombosis (5 vs 0.7%, p = .068). Similarly, elderly with 1-month-HPR showed between 1 month and 1 year significantly higher incidence of MACE (10 vs 4%, p = .012), cardiac death (6 vs 0.7%, p = .019) and composite cardiac death/MI (11 vs 4%, p = .014). Up to 1 year, elderly with HPR showed a 4-fold increased risk of MACE compared to both elderly without HPR (for discharge-HPR: p = .005; for 1-month-HPR: p = .01) and non-elderly with HPR (for discharge-HPR: p < .001; for 1-month-HPR: p < .0001). At multivariable analysis, HPR could independently predict 1-year-MACE in elderly (for discharge-HPR: HR = 3.191, CI: 1.373-7.417, p = .007; for 1-month-HPR: HR = 3.542, CI: 1.373-9.137, p = .009).\n\n\n\nIn elderly with NSTE-ACS undergoing PCI and treated with clopidogrel, HPR was independently associated with an increased risk of MACE up to 1 year.",
"affiliations": "Department of Cardiology, San Giovanni di Dio e Ruggi d'Aragona University Hospital, Salerno, Italy.;Cardiovascular Department, Policlinico S. Orsola, Bologna, Italy.;Cardiology and Coronary Care Unit, Policlinico S. Matteo, Pavia, Italy.;Department of Cardiology, San Giovanni di Dio e Ruggi d'Aragona University Hospital, Salerno, Italy.;Cardiology and Coronary Care Unit, Policlinico S. Matteo, Pavia, Italy.;Cardiology and Coronary Care Unit, Policlinico S. Matteo, Pavia, Italy.;Department of Cardiovascular Science, Second University of Naples, AO dei Colli, Monaldi, Napoli, Italy.;Department of Health Science, University of Milan, Milano, Italy.;Cardiothoracic Department, Spedali Civili di Brescia, Brescia, Italy.;Division of Cardiology, Prato Hospital, Prato, Italy.;Monzino Heart Center, Milano, Italy.;Monzino Heart Center, Milano, Italy.;Catheterization Laboratory, Cardiothoracic and Vascular Department, University of Pisa, Pisa, Italy.;Cardio-Thoracic-Vascular Department, Ferrarotto Hospital, University of Catania, Catania, Italy.;Columbia University Medical Center and the Cardiovascular Research Foundation, New York, United States.;Division of Cardiology, Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, United States.;Department of Cardiology, San Giovanni di Dio e Ruggi d'Aragona University Hospital, Salerno, Italy. Electronic address: fpiscione@unisa.it.;Department of Cardiology, San Giovanni di Dio e Ruggi d'Aragona University Hospital, Salerno, Italy.",
"authors": "De Rosa|Roberta|R|;Palmerini|Tullio|T|;De Servi|Stefano|S|;Belmonte|Marta|M|;Crimi|Gabriele|G|;Cornara|Stefano|S|;Calabrò|Paolo|P|;Cattaneo|Marco|M|;Maffeo|Diego|D|;Toso|Anna|A|;Bartorelli|Antonio|A|;Palmieri|Cataldo|C|;De Carlo|Marco|M|;Capodanno|Davide|D|;Genereux|Philippe|P|;Angiolillo|Dominick|D|;Piscione|Federico|F|;Galasso|Gennaro|G|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijcard.2018.01.057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-5273",
"issue": "259()",
"journal": "International journal of cardiology",
"keywords": "Clopidogrel; Elderly; Non-ST-elevated acute coronary syndromes; Platelet reactivity",
"medline_ta": "Int J Cardiol",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072658:Non-ST Elevated Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "20-25",
"pmc": null,
"pmid": "29579602",
"pubdate": "2018-05-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "High on-treatment platelet reactivity and outcome in elderly with non ST-segment elevation acute coronary syndrome - Insight from the GEPRESS study.",
"title_normalized": "high on treatment platelet reactivity and outcome in elderly with non st segment elevation acute coronary syndrome insight from the gepress study"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1077455",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
... |
{
"abstract": "\"Head Start\" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma.\n\n\n\nFollowing surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction.\n\n\n\nBetween 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. Five-year event-free survival (EFS) and overall survival (OS) rates (±SE) were 46 ± 5% and 62 ± 5% for all patients, 61 ± 8% and 77 ± 7% for localized medulloblastoma, and 35 ± 7% and 52 ± 7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ± 6% and 89 ± 6% compared with 26 ± 6% and 53 ± 7% for classic and 38 ± 13% and 46 ± 14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age, and sex (P <0.0001). Five-year irradiation-free EFS was 78 ± 8% for ND and 21 ± 5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity, with 2 toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis. IQ and memory scores were within average range overall, whereas processing speed and adaptive functioning were low-average.\n\n\n\nWe report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.",
"affiliations": "Division of Pediatric Hematology-Oncology, University of Alabama Birmingham, Birmingham, Alabama, USA.;Division of Neurology and The Saban Research Institute, Children's Hospital Los Angeles (CHLA), Los Angeles, California, USA.;Department of Preventive Medicine, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA.;Division of Hematology-Oncology CHLA, Los Angeles, California, USA.;Division of Hematology-Oncology CHLA, Los Angeles, California, USA.;Department of Radiology CHLA, Los Angeles, California, USA.;Department of Pathology CHLA, Los Angeles, California, USA.;Division of Pediatric Hematology-Oncology, NYU Medical Center, New York, New York, USA.;Division of Pediatric Hematology-Oncology, NYU Medical Center, New York, New York, USA.;Division of Pediatric Hematology-Oncology, Helen DeVos Children's Hospital, Grand Rapids, Michigan, USA.;Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indianapolis, Indiana, USA.;Division of Pediatric Hematology-Oncology, New York Presbyterian Hospital, New York, New York, USA.;Division of Pediatric Hematology-Oncology, Nationwide Children's Hospital, Columbus, Ohio, USA.;Division of Pediatric Hematology-Oncology, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.;Division of Pediatric Hematology-Oncology, Penn State Hershey Children's Hospital, Hershey, Pennsylvania, USA.;Division of Pediatric Hematology-Oncology, Lurie Children's Hospital, Chicago, Illinois, USA.;Division of Pediatric Hematology-Oncology, Children's Medical Center of New York, New York, New York, USA.;Division of Pediatric Hematology-Oncology, Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.;Departments of Psychiatry and Behavioral Sciences and Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Division of Hematology-Oncology CHLA, Los Angeles, California, USA.;Division of Pediatric Hematology-Oncology, Nationwide Children's Hospital, Columbus, Ohio, USA.",
"authors": "Dhall|Girish|G|;O'Neil|Sharon H|SH|;Ji|Lingyun|L|;Haley|Kelley|K|;Whitaker|Ashley M|AM|;Nelson|Marvin D|MD|;Gilles|Floyd|F|;Gardner|Sharon L|SL|;Allen|Jeffrey C|JC|;Cornelius|Albert S|AS|;Pradhan|Kamnesh|K|;Garvin|James H|JH|;Olshefski|Randal S|RS|;Hukin|Juliette|J|;Comito|Melanie|M|;Goldman|Stewart|S|;Atlas|Mark P|MP|;Walter|Andrew W|AW|;Sands|Stephen|S|;Sposto|Richard|R|;Finlay|Jonathan L|JL|",
"chemical_list": "D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1093/neuonc/noaa102",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-8517",
"issue": "22(12)",
"journal": "Neuro-oncology",
"keywords": "desmoplastic; infants; medulloblastoma; myeloablative chemotherapy",
"medline_ta": "Neuro Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002528:Cerebellar Neoplasms; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018479:Early Intervention, Educational; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma; D011446:Prospective Studies; D015996:Survival Rate",
"nlm_unique_id": "100887420",
"other_id": null,
"pages": "1862-1872",
"pmc": null,
"pmid": "32304218",
"pubdate": "2020-12-18",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
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"title": "Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on \"Head Start\" III: a multi-institutional, prospective clinical trial.",
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"abstract": "Pregnant women affected by Alport syndrome often struggle with worsening of renal function during pregnancy. We focused the attention on the optimal management of the kidney disease in these women in order to avoid maternal-fetal complications.",
"affiliations": "Department of Obstetric and Gynecology San Marco Hospital Catania Italy.;Department of Medical Surgical Specialties University of Catania Catania Italy.;Department of Medical Surgical Specialties University of Catania Catania Italy.;Department of Medical Surgical Specialties University of Catania Catania Italy.;Department of Medical Surgical Specialties University of Catania Catania Italy.;Department of Medical Surgical Specialties University of Catania Catania Italy.;Department of Anesthesia and Intensive Care AOU Policlinico Vittorio Emanuele Catania Italy.;Department of Urology Cannizzaro Hospital Catania Italy.",
"authors": "Pepe|Franco|F|;Di Guardo|Federica|F|https://orcid.org/0000-0002-2562-7323;Zambrotta|Elisa|E|;Di Gregorio|Luisa Maria|LM|;Insalaco|Giulio|G|;Cutello|Silvia|S|;La Rosa|Valeria|V|;Pepe|Pietro|P|",
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"doi": "10.1002/ccr3.3328",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3328\nCCR33328\nCase Report\nCase Reports\nRenal impairment in Alport syndrome pregnant woman: Case report and review of the literature\nPEPE et al.Pepe Franco \n1\n Di Guardo Federica https://orcid.org/0000-0002-2562-7323\n2\nfediguardo@gmail.com Zambrotta Elisa \n2\n Di Gregorio Luisa Maria \n2\n Insalaco Giulio \n2\n Cutello Silvia \n2\n La Rosa Valeria \n3\n Pepe Pietro \n4\n \n1 \nDepartment of Obstetric and Gynecology\nSan Marco Hospital\nCatania\nItaly\n\n\n2 \nDepartment of Medical Surgical Specialties\nUniversity of Catania\nCatania\nItaly\n\n\n3 \nDepartment of Anesthesia and Intensive Care\nAOU Policlinico Vittorio Emanuele\nCatania\nItaly\n\n\n4 \nDepartment of Urology\nCannizzaro Hospital\nCatania\nItaly\n\n* Correspondence\n\nFederica Di Guardo, Department of Medical Surgical Specialties,Gynecology and Obstetrics Section,University of Catania, Via Santa Sofia 78, 95123 Catania, Italy.\n\nEmail: fediguardo@gmail.com\n\n15 9 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.123003 3007\n23 4 2020 05 8 2020 16 8 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nPregnant women affected by Alport syndrome often struggle with worsening of renal function during pregnancy. We focused the attention on the optimal management of the kidney disease in these women in order to avoid maternal‐fetal complications.\n\nPregnant women affected by Alport syndrome often struggle with worsening of renal function during pregnancy. We focused the attention on the optimal management of the kidney disease in these women in order to avoid maternal‐fetal complications.\n\n\nAlport syndromekidney diseasepreeclampsiapregnancy source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nPepe \nF \n, \nDi Guardo \nF \n, \nZambrotta \nE \n, et al. Renal impairment in Alport syndrome pregnant woman: Case report and review of the literature\n. Clin Case Rep . 2020 ;8 :3003 –3007\n. 10.1002/ccr3.3328\n==== Body\n1 INTRODUCTION\nAlport Syndrome (AS) is a heterogeneous genetic disease caused by defects in type IV collagen, a major component of glomerular basement membrane (GBM), causing progressive renal damage, ocular impairment, and hearing defects. AS prevalence is reported to be 1:50 000 live births\n1\n; moreover, it seems to affect 2% of pediatric patients on dialysis or requiring kidney transplant\n2\n and 5% of all patients receiving renal replacement therapy.\n3\n\n\n\nIn 65% of cases, AS is an X‐linked disease arising from mutations in the COL4A5 gene on the X‐chromosome (encoding the alpha 5 chains of type IV collagen), while the possibility of an autosomal recessive or autosomal dominant inheritance has been reported in 15% of cases.\n4\n Moreover, some cases of digenic inheritance in autosomal AS have been recently described in literature.\n5\n\n\n\nClinical aspects of the disease have been widely investigated in both sexes during the last 10 years.\n6\n, \n7\n, \n8\n, \n9\n In general, female patients affected by AS report low grade of renal impairment which may rapidly vary leading to a wide spectrum of renal outcomes.\n7\n However, the end‐stage renal disease (ESRD) is diagnosed in 12% of women under 40 years and in 30% of female patients aged 60.\n10\n On the other hand, about 50% of males with X‐linked AS needs dialysis or renal transplantation by age of 25 years and almost 90% develops ESRD at age <40 years. In this context, although it is possible that the inactivation of chromosome X may play a role in the disease severity for heterozygous female with AS, Yamamura et al (2017)\n11\n did not report any specific genotype‐phenotype correlation in female X‐linked AS.\n\nWith regard to kidney impairment, it may manifest with hematuria that is developed by 95% of patients and is accompanied by proteinuria in 75% of women. Proteinuria increases the risk of ESRD; moreover, extra kidney pathology is associated with early renal failure.\n12\n The diagnosis of AS relies on clinical diagnostic criteria (hematuria, hearing defects, and ocular anomalies), genetic/pedigree study, and renal or skin biopsy.\n13\n, \n14\n Although the performance of kidney/skin biopsy may be challenging, genetic testing can today provide a definitive diagnosis in the majority of cases.\n8\n Moreover, genetic study represents the best solution to distinguish females who are carriers of X‐linked AS from those with heterozygous COL4A3 or COL4A4 mutations. This distinction may be especially relevant in women planning a pregnancy, since in the former situation male offspring have a significant risk of ESRD during childhood and prenatal diagnosis should be suggested.\n14\n\n\n\nPregnancy in AS women may be risky, accelerating the progression of kidney impairment with hematuria, proteinuria, until hypertension and development of preeclampsia.\n\nIn this context, a strong consensus about the management of AS pregnant patients has not yet been established. The aim of the presented study is to report a case of successful pregnancy in a woman affected by AS and to review the recent literature about this topic.\n\n2 CASE REPORT\nA 21‐year‐old woman affected by AS accessed our obstetrical first aid department at the 31st week of an unplanned pregnancy for hypertension. Patient's obstetrical history reported two previous voluntary interruption of pregnancy (VIP).\n\nAccording to the patient's anamnesis, the first episode of microhematuria occurred when she was 6 years old and after puberty she developed hypoacusia. AS was previously diagnosed due to a kidney biopsy demonstrating kidney AS ultrastructural findings such as glomeruli with thickening and thinning of the basement membrane. Immunofluorescence features showed segmental/mosaic staining of the GBM and Bowman's capsule with the alpha 3 and alpha 5 chains of type IV collagen. Moreover, the complete absence of these collagen chains in the GBM as well as in the distal tubular basement membrane (dTBM) was detected by the use of immunohistochemistry.\n\nFamily history did not report any episode of proteinuria or renal failure neither AS was diagnosed in her relatives; however, her mother and grandmother experienced microhematuria and parents were consanguineous.\n\nThe patient was in therapy with angiotensin‐converting enzyme (ACE) inhibitors (Enapren 2.5 mg), before the pregnancy was detected, and then, ACE inhibitor was stopped and replaced by alfa‐metil‐dopa 250 mg three times per die. The pregnancy had been uncomplicated until the 30th week (50th percentile fetal growth—normal umbilical and cerebral artery blood flow). Uterine arteries Doppler was reported to be normal at the 26th week of pregnancy.\n\nWhen the woman accessed our department, she had high blood pressure (145/90 mm Hg) and diffuse legs edema. Routine analyses were conducted including urine test that showed proteinuria >300 mg/dL on dipstick, and 3.07g/24‐hour. Laboratory workup revealed low total serum protein (4.5 gr/dL), a significant reduction in serum albumin (1.6 mg/dL), and an increase in uric acid (6.1 mg/dL). Serum creatinine (0.7 mg/dL), creatinine clearance (101 mL/min), complete blood count, and coagulation were normal. Daily administration of low‐molecular‐weight heparin (LMWH) was started at the dosage of 4000 IU as thrombosis prophylaxis; moreover, spironolactone 50 mg/day was administered in order to reduce the edema. Fetal cardiotocographic test did not reveal any alteration.\n\nFinally, fetal lung maturity was induced with betamethasone 12 mg intramuscular/daily for 2 days.\n\nAlthough the therapy administration, patient's parameters rapidly worsened in the subsequent 4 days: edema and blood pressure increased (170/95 mm/Hg) and proteinuria reached nephrotic range (10.42 g/24 hour). Moreover, a decrease in hemoglobin (8.8 g/dL) and red blood cell concentration (2 860 000 mm3) was also registered. Treatment with furosemide 20 mg intravenous twice a day was then started but did not reveal any benefit. Continuous monitoring of cardiotocography, fetal growth, umbilical and cerebral fetal Doppler were effectuated twice a day and were normal.\n\nDue to the critical maternal condition and unfavorable obstetric conditions (0 Bishop score), the decision to perform cesarean section was taken. The newborn showed an appropriate weight for gestational age (1975 g), and the Apgar score was 9 at 1st minute and 10 at 5 minutes. The anatomo‐pathological examination of placenta was normal. After delivery, maternal blood pressure and renal function recovered to normal and 24‐hour proteinuria reached progressively prepregnancy levels. The patient was discharged after 6 days in good conditions.\n\nFollow‐up after 5 months showed no worsening of the renal function with proteinuria at pregnancy level and some erythrocytes in urine. The neonate was healthy.\n\nGenetic study (Medical Genetics, University of Siena, Siena, Italy) in the pregnant woman showed a mutation associated with autosomal AS in exon 25 on COLA43 gene (mutation c.1616delGp.Glu539Lysfs*567) in 100% of analyzed molecules (next‐generation sequencing on 454 Junior Roche Platform). However, the exclusion of other undetected mutations is not possible.\n\nNo genetic study has been performed on the neonate or other family's members.\n\n3 DISCUSSION\nWe report the case of a young pregnant women at 31st week affected by autosomal AS presenting with hypertension. Family history was negative for extra‐renal manifestations of AS. However, her mother and grandmother experienced microhematuria in their life. The patient developed nephrotic range proteinuria and signs of progressive renal impairment (Table 1). Due to our pharmacological and interventional approach, she delivered a healthy baby; furthermore, maternal blood pressure and renal function recovered to normal during the puerperium.\n\nTABLE 1 Patient baseline characteristics at the access to the first aid department\n\nPatient baseline characteristics\t\nAge\t21 y old\t\nPregnancy weeks\t31 wk\t\nFamily history\tMicrohematuria (mother and grandmother)\t\nTherapy during pregnancy\tAlfa‐metil‐dopa 250 mg three times per die\t\nAccess symptoms\tHypertension and legs edema\t\nFirst analysis alterations\t\nProteinuria >300 mg/dL on dipstick and 3.07 g/24‐h\n\n\nTotal serum protein: 4.5 gr/dL\n\n\nSerum albumin: 1.6 mg/dL\n\n\nUric acid: 6.1 mg/dL\n\n\nSerum creatinine: 0.7 mg/dL\n\n\nCreatinine clearance: 101 mL/min\n\n\n\t\nJohn Wiley & Sons, LtdAlport's syndrome is a genetic hereditary disease involving mature basement membranes of kidney, eyes and ears due to the altered production, deposition and/or function in alpha chains of type IV collagen. Few cases of pregnancy in AS patients have been described in literature so far, making difficult to manage AS pregnant women, which, in the majority of cases, show renal disease at different stages of kidney failure.\n15\n However, the severity of the renal impairment in AS pregnant patients seems to result from a wide complex interaction of genetic, hormonal and environmental factors.\n16\n In this scenario, the pregnancy impact on AS patients’ renal outcomes needs to be further investigated.\n\nAlthough pregnancy in AS women seems to accelerate the progression of the kidney impairment, recent evidence acquired on chronic kidney failure (CKF) underlines that pregnancy contributes to the worsening of CKF in those women who already showed advanced grade of renal disease at the initiation of the pregnancy.\n17\n In contrast with this last evidence, data presented in literature described also the rapid declining of the renal function even in those women with normal kidney function or low grade of renal impairment before pregnancy (Table 2).\n\nTABLE 2 Literature studies evidencing renal impairment in AS pregnant women\n\nStudy\tRF before pregnancy\tRF during pregnancy\t\nOmori H. et al 2004\n18\n\n\tNormal\tProteinuria, reduced creatinine clearance and hypertension (third trimester)\t\nMatsuo K. et al 2007\n21\n\n\tNormal renal function with 1‐2 g/24 h proteinuria\tIncreased creatinine, preeclampsia and acute renal failure\t\nZhang H. et al 2007\n19\n\n\tNormal\tRenal function deterioration and IUGR\t\nCrovetto F. et al 2013\n31\n\n\tNormal renal function, normal blood pressure and proteinuria <2 g/24 h\tIncreased proteinuria\t\nMetha S. et al 2013\n32\n\n\tNormal\tSevere hypertension with 15 g/24 h proteinuria and acute kidney damage (29th week of pregnancy)\t\nNishizawa Y. et al 2016\n22\n\n\tNormal renal function, normal blood pressure and proteinuria < 2 g/24 h\tNephrotic range proteinuria (third trimester)\t\nAbbreviation: RF: renal function.\n\nJohn Wiley & Sons, LtdSigns of renal failure in pregnant AS patients seem to occur during the 29‐32 weeks, with reduced creatinine clearance, elevated creatinine, massive proteinuria, edema and hypertension until nephrotic syndrome, preeclampsia and/or eclampsia.\n18\n Moreover, AS patients showing signs of renal function deterioration are more likely to develop fetal complications such as preterm delivery\n18\n and/or intrauterine gestational restriction (IUGR).\n19\n However, the entity of proteinuria, in women with preeclampsia, is not always able to predict maternal or fetal outcomes\n20\n; indeed, cases of successful pregnancy with delivery of a healthy baby are also described in literature.\n21\n, \n22\n, \n23\n, \n24\n, \n25\n\n\n\nWith regard to the pharmacological management, the use of ACE inhibitors until conception may be considered acceptable in patients with proteinuria in order to reduce the kidney damage.\n26\n Once a pregnancy occurs, alfa‐metil‐dopa may be administered as an established therapy for arterial hypertension in pregnancy without any adverse effects on utero‐placental flow or fetal well‐being.\n27\n Moreover, low dose of acetylsalicylate (75 mg/day) may be administered to prevent preeclampsia.\n28\n, \n29\n When proteinuria is in the nephrotic range (3 and 3.5 g/24 h/1.73 m2), the administration of LMWH may be indicated for thromboembolism prevention and edema may be treated with diuretics, accompanied by an accurate monitoring for oligo‐hydramnios. However, evidence about the treatment of heavy edema is still insufficient to use albumin infusion, that is reported to could paradoxically increase the proteinuria.\n26\n According to the data reported in literature, maternal and fetal outcomes seem to be reassuring if pregnancy kidney function is maintained under control with parameters near to normal renal function, trying to avoid the development of preeclampsia and severe proteinuria. However, the presence of these symptoms in AS patients during pregnancy seems to not imply a permanent kidney damage with reversibility of the renal damage after delivery or during the puerperium months.\n30\n\n\n\n4 CONCLUSIONS\nThe management of AS during pregnancy may be challenging, and gynecologist may support AS women during their entire life.\n7\n, \n8\n, \n16\n However, gynecologist‐obstetricians should encourage AS patients to get pregnant only after an accurate counseling about their risks. Patients counseling should include information about the possibility of developing the syndrome in the offspring and prenatal diagnosis may represent a considerable option. Pregnancy should be avoided if a significant kidney damage is already present and planned when the administration of teratogenic drugs, such as ACE inhibitors, has been stopped. To the best of our knowledge, a strict monitoring, including the study of the renal function, is advisable, especially during pregnancy, with high alert for possible maternal‐fetal complications. Finally, admission to the hospital should be indicated in case of worsening of patients’ conditions; similarly, delivery timing should consider maternal‐fetal risk eventually linked also to prematurity.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nFP: was responsible for patient management and wrote the case presentation. FDG: prepared the manuscript, is responsible for tables design and English review. EL: contributed to the manuscript review. LMDG, GI, and SC: contributed to the research of studies suitable for the review. VLR and PP were responsible for the follow‐up of the patient. All authors discussed the results and approved the final manuscript.\n\nETHICAL APPROVAL\nThe nature of the study (case report) did not require Ethics Committee approval.\n\nACKNOWLEDGMENTS\nWe thank Medical Genetics, University of Siena for the detailed information on the case. Published with written consent of the patient.\n==== Refs\nREFERENCES\n1 \n\nLevy \nM \n, \nFeingold \nJ \n. Estimating prevalence in single‐gene kidney diseases progressing to renal failure\n. Kidney Int . 2000 ;58 (3 ):925 ‐943\n.10972657 \n2 \n\nBertram \nJF \n, \nGoldstein \nSL \n, \nPape \nL \n, \nSchaefer \nF \n, \nShroff \nRC \n, \nWarady \nBA \n. Kidney disease in children: latest advances and remaining challenges\n. 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Kidney Int Rep . 2017 ;2 (5 ):850 ‐855\n.29270492 \n12 \n\nJais \nJP \n, \nKnebelmann \nB \n, \nGiatras \nI \n, et al. X‐linked Alport syndrome: natural history and genotype‐phenotype correlations in girls and women belonging to 195 families: a “European community Alport syndrome concerted action” study\n. J Am Soc Nephrol . 2003 ;14 (10 ):2603 ‐2610\n.14514738 \n13 \n\nHaas \nM \n. Alport syndrome and thin glomerular basement membrane nephropathy: a practical approach to diagnosis\n. Arch Pathol Lab Med . 2009 ;133 (2 ):224 ‐232\n.19195966 \n14 \n\nZhang \nH \n, \nDing \nJ \n, \nWang \nF \n, \nYang \nH \n. Prenatal diagnosis and genetic counseling of a Chinese Alport syndrome kindred\n. Genetic testing . 2008 ;12 (1 ):1 ‐7\n.18373399 \n15 \n\nKashtan \nC \n. Alport syndrome: facts and opinions\n. F1000Res . 2017 ;6 :50 .28163907 \n16 \n\nPiccoli \nGB \n, \nAlrukhaimi \nM \n, \nLiu \nZH \n, \nZakharova \nE \n, \nLevin \nA \n, World Kidney Day Steering Committee \n. What we do and do not know about women and kidney diseases; questions unanswered and answers unquestioned: reflection on World Kidney Day and International Woman’s Day\n. Blood Purif . 2018 ;45 (4 ):364 ‐375\n.29478067 \n17 \n\nFitzpatrick \nA \n, \nMohammadi \nF \n, \nJesudason \nS \n. Managing pregnancy in chronic kidney disease: improving outcomes for mother and baby\n. Int J of Women's Health . 2016 ;8 :273 .27471410 \n18 \n\nOmori \nH \n. A case of Alport syndrome with deteriorating nephrosis during pregnancy\n. Nihon Jinzou Gakkaishi . 2004 ;46 :532 .\n19 \n\nZhang \nHW \n, \nDing \nJ \n, \nWang \nF \n, \nYang \nHX \n. Follow‐up study on the pregnancy of an X‐linked dominant Alport syndrome female\n. Beijing Da Xue Xue Bao Yi Xue Ban . 2007 ;39 (4 ):351 ‐354\n.17657257 \n20 \n\nThangaratinam \nS \n, \nCoomarasamy \nA \n, \nO'Mahony \nF \n, et al. Estimation of proteinuria as a predictor of complications of pre‐eclampsia: a systematic review\n. 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Pregnancy in Alport syndrome: a report of two differently‐evolving cases\n. J Obstet Gynaecol . 2014 ;34 (1 ):98 ‐100\n.24359068 \n26 \n\nPiccoli \nGB \n, \nCabiddu \nG \n, \nAttini \nR \n, et al. Pregnancy in chronic kidney disease: questions and answers in a changing panorama\n. Best Pract Res Clin Obstet Gynaecol . 2015 ;29 (5 ):625 ‐642\n.25825329 \n27 \n\nMontan \nS \n, \nAnandakumar \nC \n, \nArulkumaran \nS \n, \nIngemarsson \nI \n, \nRatnam \nSS \n. Effects of methyldopa on uteroplacental and fetal hemodynamics in pregnancy‐induced hypertension\n. Am J Obstet Gynecol . 1993 ;168 (1 ):152 ‐156\n.8420318 \n28 \n\nDuley \nL \n, \nMeher \nS \n, \nHunter \nKE \n, \nSeidler \nAL \n, \nAskie \nLM \n. Antiplatelet agents for preventing pre‐eclampsia and its complications\n. Cochrane Database Syst Rev . 2019 10 \n\n29 \n\nCabiddu \nG \n, \nCastellino \nS \n, \nGernone \nG \n, et al. A best practice position statement on pregnancy in chronic kidney disease: the Italian study group on kidney and pregnancy\n. J Nephrol . 2016 ;29 (3 ):277 ‐303\n.26988973 \n30 \n\nBrunini \nF \n, \nZaina \nB \n, \nGianfreda \nD \n, et al. Alport syndrome and pregnancy: a case series and literature review\n. Arch Gynecol Obstet . 2018 ;297 (6 ):1421 ‐1431\n.29492669 \n31 \n\nCrovetto \nF \n, \nMoroni \nG \n, \nZaina \nB \n, \nAcaia \nB \n, \nOssola \nMW \n, \nFedele \nL \n. Pregnancy in women with Alport syndrome\n. Int Urol Nephrol . 2013 ;45 (4 ):1223 ‐1227\n.22418765 \n32 \n\nMehta \nS \n, \nSaifan \nC \n, \nAbdellah \nM \n, \nChoueiry \nR \n, \nNasr \nR \n, \nEl‐Sayegh \nS \n. Alport's syndrome in pregnancy\n. Case Rep Med . 2013 ;2013 : 10.1155/2013/374020\n\n",
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"issn_linking": "2050-0904",
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"journal": "Clinical case reports",
"keywords": "Alport syndrome; kidney disease; preeclampsia; pregnancy",
"medline_ta": "Clin Case Rep",
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"pubdate": "2020-12",
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"title": "Renal impairment in Alport syndrome pregnant woman: Case report and review of the literature.",
"title_normalized": "renal impairment in alport syndrome pregnant woman case report and review of the literature"
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"abstract": "We report an unusual case of drug-associated granulomatous CD30+ T-cell pseudolymphoma secondary to amlodipine. A 55-year-old Chinese man presented with a 6-month eruption of disseminated erythematous dermal papulonodules and annular infiltrated plaques over his neck and limbs symmetrically. Histopathology revealed a perivascular and interstitial infiltrate of histiocytes, eosinophils and morphologically normal lymphocytes associated with CD30 expression. The eruption improved rapidly after discontinuation of amlodipine and did not recur.",
"affiliations": "Tan Tock Seng Hospital, Singapore, Singapore.;Tan Tock Seng Hospital, Singapore, Singapore.;Department of Pathology, National University Health System and National University of Singapore, Singapore, Singapore.;National Skin Centre, Singapore, Singapore.",
"authors": "Cheong|Kah Wai|KW|https://orcid.org/0000-0003-1093-6606;Lim|Gareth Zigui|GZ|https://orcid.org/0000-0003-3589-7105;Tan|Kong Bing|KB|;Lim|Joel Hua-Liang|JH|",
"chemical_list": "D000959:Antihypertensive Agents; D017730:Ki-1 Antigen; D017311:Amlodipine",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.13240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "61(3)",
"journal": "The Australasian journal of dermatology",
"keywords": "CD30+ lymphoproliferative disorder; amlodipine; cutaneous T cell lymphoma; drug-associated reversible granulomatous T-cell dyscrasia; drug-induced pseudolymphoma; eosinophilia; interstitial granulomatous drug reaction; mycosis fungoides",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D017311:Amlodipine; D000959:Antihypertensive Agents; D003875:Drug Eruptions; D006099:Granuloma; D006801:Humans; D017730:Ki-1 Antigen; D008297:Male; D008875:Middle Aged; D019310:Pseudolymphoma; D013601:T-Lymphocytes",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "e346-e350",
"pmc": null,
"pmid": "31965571",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An instructive case of amlodipine-induced reversible granulomatous CD30+ T-cell pseudolymphoma.",
"title_normalized": "an instructive case of amlodipine induced reversible granulomatous cd30 t cell pseudolymphoma"
} | [
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"companynumb": "JP-STRIDES ARCOLAB LIMITED-2020SP011434",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"druga... |
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"abstract": "To describe a clinical case of indapamide induced bilateral angle narrowing and acute myopia.\nClinical case report.\nA 37-year-old Caucasian emmetropic man presented to the Emergency Department with complaints of acute-onset bilateral blurry vision, nine days after starting treatment for arterial hypertension with a combination of indapamide and amlodipine. Clinical examination revealed the presence of myopia and appositional closure of the anterior chamber angle. Ultrasound biomicroscopy and mode B ultrasonography disclosed bilateral ciliochoroidal effusion with anterior rotation of the ciliary body and iridocorneal angle narrowing. After intraocular pressure control with brimonidine and timolol, and replacement of indapamide/amlodipine by amlodipine only, the patient was discharged. Complete resolution of the clinical manifestations was observed after three weeks, with no sequelae.\nIndapamide may cause acute myopia and angle closure secondary to ciliochoroidal effusion that are fully reversible after drug withdrawal, as long as timely diagnosis is established. Therefore, indapamide, as well as other sulfonamide-derived drugs, must always be considered in the differential diagnosis of acute myopia and angle closure.",
"affiliations": "Department of Ophthalmology, Centro Hospitalar São João, Porto, Portugal.;Department of Ophthalmology, Centro Hospitalar São João, Porto, Portugal.;Department of Ophthalmology, Centro Hospitalar São João, Porto, Portugal.;Department of Ophthalmology, Centro Hospitalar São João, Porto, Portugal.;Department of Ophthalmology, Centro Hospitalar São João, Porto, Portugal.;Department of Ophthalmology, Centro Hospitalar São João, Porto, Portugal.",
"authors": "Pedrosa|Ana Catarina|AC|0000-0001-6831-5488;Araújo|Joana Rodrigues|JR|;Macedo|João Paulo|JP|;Silva|Sérgio Estrela|SE|;Melo|António|A|;Falcão-Reis|Fernando|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/1486128",
"fulltext": "\n==== Front\nCase Rep Ophthalmol MedCase Rep Ophthalmol MedCRIOPMCase Reports in Ophthalmological Medicine2090-67222090-6730Hindawi 10.1155/2018/1486128Case ReportBilateral Angle Narrowing and Acute Myopia Induced by Indapamide: A Case Report http://orcid.org/0000-0001-6831-5488Pedrosa Ana Catarina catarina.c.pedrosa@gmail.com\n1\nAraújo Joana Rodrigues \n1\nMacedo João Paulo \n1\nSilva Sérgio Estrela \n1\nMelo António \n1\nFalcão-Reis Fernando \n1\n\n2\n\n1Department of Ophthalmology, Centro Hospitalar São João, Porto, Portugal\n2Department of Sense Organs, Faculty of Medicine of the University of Porto, Porto, PortugalAcademic Editor: Claudio Campa\n\n2018 2 12 2018 2018 148612828 7 2018 10 10 2018 Copyright © 2018 Ana Catarina Pedrosa et al.2018This 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.Purpose\n To describe a clinical case of indapamide induced bilateral angle narrowing and acute myopia.\n\n Materials and Methods\n Clinical case report.\n\n Results\n A 37-year-old Caucasian emmetropic man presented to the Emergency Department with complaints of acute-onset bilateral blurry vision, nine days after starting treatment for arterial hypertension with a combination of indapamide and amlodipine. Clinical examination revealed the presence of myopia and appositional closure of the anterior chamber angle. Ultrasound biomicroscopy and mode B ultrasonography disclosed bilateral ciliochoroidal effusion with anterior rotation of the ciliary body and iridocorneal angle narrowing. After intraocular pressure control with brimonidine and timolol, and replacement of indapamide/amlodipine by amlodipine only, the patient was discharged. Complete resolution of the clinical manifestations was observed after three weeks, with no sequelae.\n\n Conclusions\n Indapamide may cause acute myopia and angle closure secondary to ciliochoroidal effusion that are fully reversible after drug withdrawal, as long as timely diagnosis is established. Therefore, indapamide, as well as other sulfonamide-derived drugs, must always be considered in the differential diagnosis of acute myopia and angle closure.\n==== Body\n1. Introduction\nAcute myopia and secondary angle closure are potential adverse effects of sulfa-containing medications [1–3]. Topiramate is the most frequently reported but numerous other drugs may be involved [1]. Although these adverse effects are described as rare [4], the causative drugs are commonly prescribed, and thus this entity may be more frequently encountered in clinical practice than one could expect. In this paper, we describe a case of acute myopia and secondary angle narrowing induced by indapamide, a sulfonamide-derived drug.\n\n2. Materials and Methods\nThis is a clinical case report.\n\n3. Results\nA 37-year-old Caucasian man presented to the Emergency Department with complaints of acute-onset bilateral blurry vision. The symptoms had started two days before, and though distance vision was severely affected, near vision was preserved. The patient had never worn glasses or contact lenses and reported excellent previous uncorrected visual acuity in both eyes. He was overweight and had been recently diagnosed with arterial hypertension. Nine days before, he had started treatment with a combination of indapamide (1.5 mg) and amlodipine (5 mg). The medical history was otherwise unremarkable, regarding general and ocular health.\n\nDistance visual acuity was 20/100 unaided in both the right eye (OD) and left eye (OS). However, it increased bilaterally to 20/20 with correction of -2.75 -1.25x100 in OD and of -3.50 -0.75x80 in OS. Uncorrected near visual acuity was preserved, as the patient was able to read J1 when holding the Jaeger Eye Chart at a distance of 35 cm. Pupillary reflexes were normal. On slit-lamp examination, both eyes presented shallow anterior chambers, centrally and peripherally (grade 2, according to the Van Herick classification system). Intraocular pressure measured by Goldmann applanation tonometry was 36 mmHg in OD and 34 mmHg in OS. Gonioscopy revealed appositional closure of the anterior chamber angle (grade 2, according to the Shaffer classification system, and (A)B20b2+, according to the Spaeth classification system). Undilated fundus examination was unremarkable, with normal optic discs. Ultrasound biomicroscopy and mode B ultrasonography were performed. They disclosed bilateral ciliochoroidal effusion with anterior rotation of the ciliary body and iridocorneal angle narrowing (Figures 1–3).\n\nAfter topical treatment with brimonidine, 2 mg/mL, and timolol, 5mg/mL, the intraocular pressure decreased to 24 mmHg in both eyes. Thus, the patient was discharged under treatment with those drugs, and indapamide/amlodipine (1.5 mg/ 5 mg) was replaced by amlodipine (10 mg) only.\n\nThe patient was then regularly monitored, and complete resolution of the symptoms was seen after three weeks. By then, distance visual acuity was 20/20 unaided in both eyes, and intraocular pressure was 16 mmHg in OD and 14 mmHg in OS without treatment. Ultrasound biomicroscopy confirmed resolution of the supraciliary effusion, with deepening of the anterior chamber and widening of the iridocorneal angle (Figures 1 and 2), and Humphrey automated perimetry showed no defects.\n\n4. Conclusions\nTo date, there are four published cases of indapamide-induced acute myopia [3, 5–7], and only one of acute angle closure [6]. Our patient's complaints were mainly attributable to the myopic shift but objective examination showed that he also had moderate ocular hypertension secondary to appositional angle closure. The temporal relationship between the beginning of treatment with indapamide and the onset of symptoms, as well as the prompt resolution of all clinical findings after indapamide withdrawal, clearly indicates that indapamide was the causative agent.\n\nIn all cases reported to date, including ours, acute myopia and angle closure caused by indapamide were associated with ciliochoroidal effusion [3, 5, 6]. Although this is not definitively established, it is believed that ciliochoroidal effusion caused by indapamide and other sulfonamides represents an idiosyncratic reaction [1, 4]. Thus, it develops in rare susceptible patients, probably mediated by an abnormally increased synthesis of prostaglandins [2]. In fact, it has been shown that indapamide stimulates the synthesis of prostaglandin E2; in susceptible individuals, the presence of other contributing factors, such as an inborn error in eicosanoid metabolism or a clinical or subclinical infection, might lead to the local accumulation of prostaglandins during treatment with indapamide, causing vasodilation, increased vascular permeability, and ultimately ciliochoroidal effusion [2]. With ciliochoroidal effusion and anterior rotation of the ciliary body, the iris-lens diaphragm moves forward, the zonules relax, and the lens thickens, which results in myopic shift and narrowing or closure of the anterior chamber angle [1, 4].\n\nAccording to the available evidence, indapamide-induced acute myopia and angle closure appear to have an excellent prognosis, as long as timely diagnosis is established [3–6]. However, failure to identify indapamide as the etiological factor might prevent adequate treatment and lead to irreversible optic nerve damage in cases of angle closure. Iridotomy is not effective as the pathogenic mechanism is not pupillary block [3, 5]. Therefore, sulfonamide-derived drugs such as indapamide must always be considered in the differential diagnosis of acute myopia and angle closure.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nFigure 1 Ultrasound biomicroscopy showing, at diagnosis, supraciliary effusion, anterior rotation of the ciliary body and iridocorneal angle narrowing ((a) right eye; (b) left eye) and, three months later, resolution of the effusion and widening of the iridocorneal angle ((c) right eye; (d) left eye).\n\nFigure 2 Ultrasound biomicroscopy showing shallow anterior chamber at diagnosis ((a) right eye, with anterior chamber depth of 2.22 mm; (b) left eye, with anterior chamber depth of 2.07 mm), and deepening of the anterior chamber three months later ((c) right eye, with anterior chamber depth of 2.92 mm; (d) left eye, with anterior chamber depth of 2.94 mm).\n\nFigure 3 Mode B ultrasonography showing choroidal effusion at diagnosis ((a) right eye; (b) left eye).\n==== Refs\n1 Murphy R. M. Bakir B. O’Brien C. Wiggs J. L. Pasquale L. R. Drug-induced bilateral secondary angle-closure glaucoma Journal of Glaucoma 2016 25 2 e99 e105 10.1097/IJG.0000000000000270 25943730 \n2 Krieg P. H. Schipper I. Drug-induced ciliary body oedema: A new theory Eye 1996 10 1 121 126 2-s2.0-0029867205 10.1038/eye.1996.21 8763317 \n3 Végh M. Hári-Kovács A. Réz K. Tapasztó B. Szabó Á. Facskó A. Indapamide-induced transient myopia with supraciliary effusion: case report BMC Ophthalmology 2013 13 1 10.1186/1471-2415-13-58 \n4 Araújo J. R. Silva S. E. Cruz F. Falcão-Reis F. Acute transient myopia with shallowing of the anterior chamber induced by sulfamethoxazole in a patient with pseudoxanthoma elasticum Journal of Glaucoma 2014 23 6 415 417 2-s2.0-84905437534 10.1097/IJG.0000000000000074 25075463 \n5 Blain P. Paques M. Massin P. Erginay A. Santiago P.-Y. Gaudric A. Acute transient myopia induced by indapamide American Journal of Ophthalmology 2000 129 4 538 540 2-s2.0-0034070243 10.1016/S0002-9394(99)00402-X 10764870 \n6 Senthil S. Garudadri C. Rao H. B. L. Maheshwari R. Bilateral simultaneous acute angle closure caused by sulphonamide derivatives: a case series Indian Journal of Ophthalmology 2010 58 3 248 252 10.4103/0301-4738.62657 2-s2.0-77954697923 20413935 \n7 Boissonnot L. Boissonnot M. Charles-Gervais C. Breux J. P. Acute myopia caused by indapamide Presse Medicale 1986 15 17 802 803 2-s2.0-0023057365\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2018()",
"journal": "Case reports in ophthalmological medicine",
"keywords": null,
"medline_ta": "Case Rep Ophthalmol Med",
"mesh_terms": null,
"nlm_unique_id": "101581018",
"other_id": null,
"pages": "1486128",
"pmc": null,
"pmid": "30627467",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "10764870;20413935;24138779;25075463;25943730;2940532;8763317",
"title": "Bilateral Angle Narrowing and Acute Myopia Induced by Indapamide: A Case Report.",
"title_normalized": "bilateral angle narrowing and acute myopia induced by indapamide a case report"
} | [
{
"companynumb": "PT-MYLANLABS-2019M1062032",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INDAPAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Delusional infestation (DI), a form of psychosis, has rarely been reported in patients with Parkinson disease (PD). The clinical presentation and successful treatment of DI is illustrated through 5 cases. Each patient developed DI during treatment for moderate to advanced Parkinson's disease, and only 2 had cognitive impairment. Two patients were on monotherapy: 1 on a dopamine agonist and the other on trihexyphenidyl. Three patients were receiving complex combination therapy with 2 to 5 different anti-Parkinsonian medications at the onset of their delusion. Selective discontinuation or reduction of these medications was key to the resolution of DI in each patient. Although the medication adjustments differed, the changes resulted in the reduction of anticholinergic effects or extracellular striatal dopamine levels. This series emphasizes the clinical features and management strategies for this disruptive form of psychosis in patients with PD.",
"affiliations": "Movement Disorders Program Department of Neurology Medical College of Georgia Augusta Georgia USA.;Movement Disorders Program Department of Neurology Medical College of Georgia Augusta Georgia USA.;Movement Disorders Program Department of Neurology Medical College of Georgia Augusta Georgia USA.;Movement Disorders Program Department of Neurology Medical College of Georgia Augusta Georgia USA.",
"authors": "Davis|Jennie L|JL|;Kurek|Julie A|JA|;Sethi|Kapil D|KD|;Morgan|John C|JC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/mdc3.12352",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2330-1619",
"issue": "4(1)",
"journal": "Movement disorders clinical practice",
"keywords": "Parkinson's disease; delusional infestation; delusional parasitosis",
"medline_ta": "Mov Disord Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101630279",
"other_id": null,
"pages": "111-115",
"pmc": null,
"pmid": "30713955",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "11697685;17134847;18665659;19822895;20345988;20614418;23680417;23899625;9874482",
"title": "Delusional Infestation in Parkinson's Disease.",
"title_normalized": "delusional infestation in parkinson s disease"
} | [
{
"companynumb": "US-MYLANLABS-2019M1063693",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMANTADINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND Mycophenolic acid is an immunosuppressive drug commonly used in solid organ transplantation to prevent acute and chronic allograft rejection. There are 2 common preparations of mycophenolic acid including mycophenolate mofetil (Cellcept), and enteric-coated mycophenolate sodium (Myfortic) which was developed to reduce the high rate of gastrointestinal side effects seen with Cellcept. Cases of mycophenolate mofetil induced colitis have been described in solid organ transplant patients and rarely in heart transplant patients, but enteric-coated mycophenolate sodium induced colitis is very rare and has not been reported in heart transplant patients. CASE REPORT A 66-year old male with an orthotopic heart transplant was admitted with diarrhea. The patient was on an immunosuppression regimen including mycophenolate mofetil for 10 weeks post-transplantation until complaining of soft stools and bloating. At this time, he was switched to enteric-coated mycophenolate sodium. At week 11 post-transplantation, the patient was admitted to the hospital with worsening diarrhea. Extensive workup was unrevealing. Colonoscopy with biopsy showed features of mycophenolic acid induced colitis. Enteric coated mycophenolate sodium was discontinued, and the patient's diarrhea markedly improved over the next 48 hours. The patient had no signs of colitis or solid organ rejection at 7-month follow up appointment. CONCLUSIONS Although a diagnosis of exclusion, enteric-coated mycophenolate sodium induced colitis should be considered in the differential of an orthotopic heart transplant patient with diarrhea as discontinuing the medication can improve symptoms and avoid costly workups, however, patients should be monitored closely for signs of rebound rejection.",
"affiliations": "Sarver Heart Center, University of Arizona College of Medicine, Tucson, AZ, USA.;Sarver Heart Center, University of Arizona College of Medicine, Tucson, AZ, USA.;Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.;Sarver Heart Center, University of Arizona College of Medicine, Tucson, AZ, USA.;Sarver Heart Center, University of Arizona College of Medicine, Tucson, AZ, USA.",
"authors": "Morris|Craig C|CC|;Stroud|Steven C|SC|;Golconda|Umamaheshwari|U|;Gregoire|Sharon A|SA|;Juneman|Elizabeth B|EB|",
"chemical_list": "D007166:Immunosuppressive Agents; D013608:Tablets, Enteric-Coated; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.920235",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32404861\n10.12659/AJCR.920235\n920235\nArticles\nOrthotopic Heart Transplant Recipient with Enteric-coated Mycophenolate Sodium (Myfortic) Induced Colitis\nMorris Craig C. ABCDEFG1 Stroud Steven C. ABCDEF1 Golconda Umamaheshwari BDE2 Gregoire Sharon A. ABCDEFG1 Juneman Elizabeth B. ABCDEFG1 \n1 Sarver Heart Center, University of Arizona College of Medicine, Tucson, AZ, U.S.A.\n\n2 Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, U.S.A.\nCorresponding Author: Craig C. Morris, e-mail: craigmorris@email.arizona.edu, craigm18@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n14 5 2020 \n21 e920235-1 e920235-4\n22 9 2019 17 2 2020 09 4 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 66-year-old\n\nFinal Diagnosis: Drug-induced colitis\n\nSymptoms: Abdominal discomfort • anorexia • diarrhea • weight loss\n\nMedication: Enteric-coated mycophenolate sodium (Myfortic)\n\nClinical Procedure: Colonoscopy • colon biopsy\n\nSpecialty: Cardiology • Infectious Disease\n\nObjective:\nRare disease\n\nBackground:\nMycophenolic acid is an immunosuppressive drug commonly used in solid organ transplantation to prevent acute and chronic allograft rejection. There are 2 common preparations of mycophenolic acid including mycophenolate mofetil (Cellcept), and enteric-coated mycophenolate sodium (Myfortic) which was developed to reduce the high rate of gastrointestinal side effects seen with Cellcept. Cases of mycophenolate mofetil induced colitis have been described in solid organ transplant patients and rarely in heart transplant patients, but enteric-coated mycophenolate sodium induced colitis is very rare and has not been reported in heart transplant patients.\n\nCase Report:\nA 66-year old male with an orthotopic heart transplant was admitted with diarrhea. The patient was on an immunosuppression regimen including mycophenolate mofetil for 10 weeks post-transplantation until complaining of soft stools and bloating. At this time, he was switched to enteric-coated mycophenolate sodium. At week 11 post-transplantation, the patient was admitted to the hospital with worsening diarrhea. Extensive workup was unrevealing. Colonoscopy with biopsy showed features of mycophenolic acid induced colitis. Enteric coated mycophenolate sodium was discontinued, and the patient’s diarrhea markedly improved over the next 48 hours. The patient had no signs of colitis or solid organ rejection at 7-month follow up appointment.\n\nConclusions:\nAlthough a diagnosis of exclusion, enteric-coated mycophenolate sodium induced colitis should be considered in the differential of an orthotopic heart transplant patient with diarrhea as discontinuing the medication can improve symptoms and avoid costly workups, however, patients should be monitored closely for signs of rebound rejection.\n\nMeSH Keywords:\nColitisHeart TransplantationMycophenolic Acid\n==== Body\nBackground\nMycophenolic acid is an immunosuppressive drug commonly used in solid organ transplantations to prevent acute and chronic allograft rejection. It inhibits inosine monophosphate dehydrogenase, a key enzyme in the de novo purine biosynthesis pathway, thus inhibiting DNA synthesis and cell division [1]. There are 2 common preparations of mycophenolic acid including mycophenolate mofetil (Cellcept), which is directly absorbed in the stomach with a high bioavailability, and mycophenolate sodium (Myfortic), an enteric coated formulation absorbed in the intestine which was developed to reduce the high rate of gastrointestinal side effects seen with Cellcept [2]. The efficacy of preventing rejection has been shown to be similar between the 2 formulations in kidney and liver transplant patients [3–5]. Cases of mycophenolate mofetil induced colitis have been described in solid organ transplant patients, and rarely in heart transplant patients [6–7]. However, to the authors knowledge after a review of English literature, there has not been a case reported of enteric-coated mycophenolate sodium induced colitis in an orthotopic heart transplant patient.\n\nCase Report\nA 66-year-old male with a history of ischemic heart disease refractory to intervention and reduced ejection fraction underwent an orthotopic heart transplantation with immuno-suppression induction including pre-operative tacrolimus and mycophenolate mofetil, intra-operative basiliximab and methylprednisolone, and post-operative basiliximab and methylprednisolone with an oral prednisone taper.\n\nImmunosuppression was maintained with a regimen including mycophenolate mofetil 1500 mg 2 times daily, tacrolimus 0.5 mg 2 times daily with dose adjusted for target serum level of 10–15 ng/mL, and prednisone 10 mg every morning and 5 mg every night. Additionally, the patient was on an antimicrobial prophylaxis regimen including fluconazole, valganciclovir, and sulfamethoxazole-trimethoprim.\n\nThe patient did well until post-transplantation week 10 when he was seen in clinic with 5.3 kg weight loss (8% body mass) over the preceding month accompanied by bloating, anorexia, and 3 loose non-bloody bowel movements per day. At this time, he was taking magnesium oxide, senna glycoside (Senokot), mycophenolate mofetil, and pantoprazole, which can all cause diarrhea. Physical examination was non-contributory with soft, non-tender, nondistended abdomen. With mycophenolate mofetil as a potential cause of diarrhea the patient was switched to enteric-coated mycophenolate sodium 1080 mg 2 times daily. Additionally, senna glycoside was discontinued, and magnesium oxide was switched to magnesium chloride.\n\nThe patient continued to have watery diarrhea, weight loss, and dehydration requiring hospital admission on post-transplantation week 11. At this time, the differential included infectious colitis (e.g., cytomegalovirus, bacterial pathogens, and adenovirus), medication induced colitis (e.g., mycophenolic acid, proton pump inhibitors), and less likely, ischemic colitis. In the hospital, extensive infectious disease workup was positive only for parainfluenza virus from nasopharyngeal swab and negative for all else including blood culture, blood serology, Helicobacter Pylori antigen, gastrointestinal polymerase chain reaction (PCR) panel, stool culture, viral PCR, toxoplasma IgG antibody, Clostridium difficile antigen/toxin, and cytomegalovirus PCR. The patient had an endomyocardial biopsy on post-transplantation week 11 which was negative for acute cellular rejection (ISHLT 2004 grade 0) and negative for pathologic and chronic antibody-mediated rejection (ISHLT 2013 grade pAMR0). His serum trough mycophenolic acid level was 2.4 mcg/mL. A computed tomography (CT) scan of the abdomen and pelvis was unrevealing.\n\nThe patient was sent for colonoscopy which showed mildly congested mucosa through the entire colon in a patchy distribution predominantly at the colonic folds (Figure 1) and an area of significantly congested mucosa at the appendiceal orifice and cecum (Figure 2). Colonic biopsies revealed features (Figure 3) that have been associated with mycophenolate mofetil related colitis, including crypt abscess formation involving dilated crypts with flattened and attenuated epithelium and apoptotic bodies [6,8,9]. Additionally, PCR for cytomegalovirus in the colon biopsy was negative.\n\nEnteric-coated mycophenolate sodium was discontinued, and the patient’s gastrointestinal symptoms resolved over the next 48 hours. His immunosuppressant regimen after the colitis episode included tacrolimus 0.5 mg 2 times daily with dose adjusted for target serum level of 10–15 ng/mL, and prednisone 10 mg every morning and 5 mg every night. With endomyocardial biopsies showing no signs of rejection, the patient was tapered off prednisone and placed on a calcineurin-inhibitor sparing regimen of tacrolimus plus sirolimus, both at 0.5 mg twice daily. Up to post-transplantation week 40, the patient had no further symptoms of colitis and no signs of rejection based on endomyocardial biopsy despite the modified immuno-suppression regimen. Because the lack of colitis symptoms he did not undergo an additional colonoscopy.\n\nDiscussion\nLymphocytes rely almost exclusively on de novo synthesis of purine and therefore mycophenolic acid adequately suppresses T and B lymphocytes responsible for cytotoxic and antibody mediated graft rejection [10]. Notably, enterocytes are only approximately 50% dependent on the de novo pathway and can utilize the purine salvage pathway as well [11]. However, under certain conditions, such as anorexia where dietary intake of purines is reduced, enterocytes become more reliant on the de novo synthesis pathway and the presence of mycophenolic acid can halt cell divisions of enterocytes resulting in epithelial injury and gastrointestinal symptoms including diarrhea [12].\n\nColitis induced by mycophenolate mofetil and enteric-coated mycophenolate sodium are very rare and remain a diagnosis of exclusion [1,3,10]. Two case reports of mycophenolate mofetil induced colitis after heart transplantation have been reported in the English literature. One report discusses a case arising 13 years after the initiation of mycophenolate mofetil therapy suggesting that the diagnosis should be considered in the evaluation of late onset post-transplantation diarrhea [7]. Another case discusses the importance of considering mycophenolate mofetil induced colitis in heart transplant patients and the difficulty of the diagnosis given that the disease can mimic other more common causes of the symptoms such as infectious colitis, irritable bowel disease (IBD), ischemic colitis and rarely graft versus host disease (GVHD) [13].\n\nCases of rebound rejection after discontinuation of mycophenolic mofetil have been reported [10] and thus for mild and moderate cases of diarrhea, continuation of mycophenolic mofetil with a dose reduction or switching to enteric-coated mycophenolate sodium can be considered. At onset of gastrointestinal symptoms, our patient was switched from mycophenolate mofetil to enteric-coated mycophenolate sodium with hope of symptom resolution, however, his diarrhea persisted for 18 more days. The colonic biopsy showed features typical of mycophenolate induced colitis including cryptitis, crypt abscess formation involving dilated crypts with flattened and attenuated epithelium, and apoptotic bodies [3,8,10]. With the infectious workup negative and no signs of ischemic colitis, the most likely diagnosis was drug induced colitis.\n\nEnteric-coated mycophenolate sodium was discontinued, and the diarrhea symptoms resolved over the next few days. At 40 weeks post-transplantation, our patient has not had another episode of colitis and has showed no signs of rejection on follow-up endomyocardial biopsies.\n\nConclusions\nThough a diagnosis of exclusion, enteric-coated mycophenolate sodium induced colitis should be considered in the differential of an orthotopic heart transplant patient with diarrhea as discontinuing the medication can improve symptoms and avoid costly workups, however, patients should be monitored closely for signs of rebound rejection.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Colonoscopy showing ascending colon, transverse colon, and descending colon (from left to right) with mildly congested mucosa through the entire colon in a patchy distribution predominantly at the colonic folds.\n\nFigure 2. Colonoscopy showing appendiceal orifice with significantly congested mucosa (left) and cecum with edematous mucosa (right).\n\nFigure 3. Colonic biopsies with cryptitis and crypt abscess formation B) involving dilated crypts with flattened and attenuated epithelium A) and apoptotic bodies C).\n==== Refs\nReferences:\n1. Allison AC Eugui EM Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection Transplantation 2005 80 S181 90 16251851 \n2. Bjarnason I Enteric coating of mycophenolate sodium: a rational approach to limit topical gastrointestinal lesions and extend the therapeutic index of mycophenolate Transplant Proc 2001 33 3238 40 11750388 \n3. Zolezzi M Mycophenolate sodium versus mycophenolate mofetil: A review of their comparative features Saudi J Kidney Dis Transpl 2005 16 140 45 18202489 \n4. Lopez-Solis R1 DeVera M Steel J Gastrointestinal side effects in liver transplant recipients taking enteric-coated mycophenolate sodium vs . mycophenolate mofetil Clin Transplant 2014 28 783 88 24754682 \n5. Sollinger HW Sundberg AK Leverson G Mycophenolate mofetil versus enteric-coated mycophenolate sodium: A large, single-center comparison of dose adjustments and outcomes in kidney transplant recipients Transplantation 2010 89 4 446 51 20177347 \n6. Nguyen T Park JY Scudiere JR Mycophenolic acid (Cellcept and Myofortic) induced injury of the upper GI tract AM J Surg Pathol 2009 33 1355 63 19542873 \n7. Curtin BF Rachakonda VP Von Rosenvinge EC Unusually late-onset mycophenolate mofetil-related colitis Am J Health Syst Pharm 2014 71 1858 61 25320135 \n8. Papadimitriou JC Cangro CB Lustberg A Histologic features of mycophenolate mofetil-related colitis: A graft-versus-host disease like pattern Int J Surg Pathol 2003 11 295 302 14615824 \n9. Calmet FH Yarur AJ Pukazhendhi G Endoscopic and histological features of mycophenolate mofetil colitis in patients after solid organ transplantation Ann Gastroenterol 2015 28 366 73 26126799 \n10. Behrend M Adverse gastrointestinal effects of mycophenolate mofetil: Aetiology, incidence and management Drug Saf 2001 24 645 63 11522119 \n11. Behrend M Braun F Enteric-coated mycophenolate sodium: Tolerability profile compared with mycophenolate mofetil Drugs 2005 65 1037 50 15907141 \n12. McCauley R Kong Se Hall J Glutamine and nucleotide metabolism within enterocytes J Parenter Enteral Nutr 1998 22 2 105 11 \n13. Tayyem O Saraireh H Hanayneh MA Heart transplant recipient with mycophenolate mofetil-induced colitis: The great imitator BMJ Case Rep, BMJ Case Rep 2018 2018 pii: bcr-2017-224035\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D003092:Colitis; D003113:Colonoscopy; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009173:Mycophenolic Acid; D013608:Tablets, Enteric-Coated; D066027:Transplant Recipients",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e920235",
"pmc": null,
"pmid": "32404861",
"pubdate": "2020-05-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18202489;24754682;11750388;14615824;16251851;15907141;20177347;26126799;29930181;11522119;9527969;25320135;19542873",
"title": "Orthotopic Heart Transplant Recipient with Enteric-coated Mycophenolate Sodium (Myfortic) Induced Colitis.",
"title_normalized": "orthotopic heart transplant recipient with enteric coated mycophenolate sodium myfortic induced colitis"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP007678",
"fulfillexpeditecriteria": "2",
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"abstract": "To assess the incremental long-term prognostic value of vasodilator stress perfusion cardiovascular magnetic resonance (CMR) in patients without known coronary artery disease (CAD).\n\n\n\nBetween 2010 and 2011, consecutive patients with cardiovascular risk factors without known CAD referred for stress CMR were followed for the occurrence of major adverse cardiac events (MACE), defined by cardiovascular mortality or recurrent non-fatal myocardial infarction (MI). Uni- and multivariable Cox regressions were performed to determine the prognostic value of ischemia and unrecognized MI defined by sub-endocardial or transmural late gadolinium enhancement (LGE).\n\n\n\nAmong 2,295 patients without known CAD, 2058 (89.7%) (71.2 ± 12.5 years; 37.5% males) completed the follow-up (median [IQR]: 8.3 [7.3-8.7] years), and 203 had MACE (9.9%). Using Kaplan-Meier analysis, ischemia and unrecognized MI were associated with MACE (hazard ratio, HR: 4.64 95% CI: 3.69-6.17 and HR: 2.88; 95% CI: 2.08-3.99, respectively; both p < 0.001). In multivariable stepwise Cox regression, ischemia and unrecognized MI were independent predictors of MACE (HR = 3.71; 95% CI 2.73-5.05, p < 0.001 and HR = 1.73; 95% CI 1.22-2.45, p = 0.002; respectively) and cardiovascular mortality (HR: 3.13; 95% CI: 2.17-4.51, p < 0.001 and HR = 1.73; 95% CI 1.15-2.62, p = 0.009; respectively). The addition of ischemia and unrecognized MI led to an improved model discrimination for MACE (change in C statistic from 0.61 to 0.72; NRI = 0.431; IDI = 0.053).\n\n\n\nInducible ischemia and unrecognized MI identified by stress CMR have incremental long term prognostic value for the incidence of MACE in patients without known CAD over traditional risk factors and left ventricular ejection fraction.",
"affiliations": "CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300, Massy, France.;CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300, Massy, France.;CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300, Massy, France.;CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300, Massy, France.;CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300, Massy, France.;Siemens Healthcare France, 93200, Saint-Denis, France.;CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300, Massy, France.;CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300, Massy, France.;CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300, Massy, France. jgarot@angio-icps.com.",
"authors": "Pezel|Théo|T|;Unterseeh|Thierry|T|;Kinnel|Marine|M|;Hovasse|Thomas|T|;Sanguineti|Francesca|F|;Toupin|Solenn|S|;Champagne|Stéphane|S|;Garot|Philippe|P|;Garot|Jérôme|J|0000-0003-3714-1256",
"chemical_list": "D014665:Vasodilator Agents; D004176:Dipyridamole",
"country": "England",
"delete": false,
"doi": "10.1186/s12968-021-00737-0",
"fulltext": "\n==== Front\nJ Cardiovasc Magn Reson\nJ Cardiovasc Magn Reson\nJournal of Cardiovascular Magnetic Resonance\n1097-6647\n1532-429X\nBioMed Central London\n\n737\n10.1186/s12968-021-00737-0\nResearch\nLong-term prognostic value of stress perfusion cardiovascular magnetic resonance in patients without known coronary artery disease\nPezel Théo 12\nUnterseeh Thierry 1\nKinnel Marine 1\nHovasse Thomas 1\nSanguineti Francesca 1\nToupin Solenn 3\nChampagne Stéphane 1\nGarot Philippe 1\nhttp://orcid.org/0000-0003-3714-1256\nGarot Jérôme jgarot@angio-icps.com\n\n1\n1 grid.477415.4 CMR Department, Institut Cardiovasculaire Paris Sud, Cardiovascular Magnetic Resonance Laboratory, Hôpital Privé Jacques CARTIER, Ramsay Santé, 6 Avenue du Noyer Lambert, 91300 Massy, France\n2 grid.21107.35 0000 0001 2171 9311 Division of Cardiology, Johns Hopkins University, Baltimore, MD 21287-0409 USA\n3 Siemens Healthcare France, 93200 Saint-Denis, France\n8 4 2021\n8 4 2021\n2021\n23 4323 9 2020\n21 2 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\nTo assess the incremental long-term prognostic value of vasodilator stress perfusion cardiovascular magnetic resonance (CMR) in patients without known coronary artery disease (CAD).\n\nMethods\n\nBetween 2010 and 2011, consecutive patients with cardiovascular risk factors without known CAD referred for stress CMR were followed for the occurrence of major adverse cardiac events (MACE), defined by cardiovascular mortality or recurrent non-fatal myocardial infarction (MI). Uni- and multivariable Cox regressions were performed to determine the prognostic value of ischemia and unrecognized MI defined by sub-endocardial or transmural late gadolinium enhancement (LGE).\n\nResults\n\nAmong 2,295 patients without known CAD, 2058 (89.7%) (71.2 ± 12.5 years; 37.5% males) completed the follow-up (median [IQR]: 8.3 [7.3–8.7] years), and 203 had MACE (9.9%). Using Kaplan–Meier analysis, ischemia and unrecognized MI were associated with MACE (hazard ratio, HR: 4.64 95% CI: 3.69–6.17 and HR: 2.88; 95% CI: 2.08–3.99, respectively; both p < 0.001). In multivariable stepwise Cox regression, ischemia and unrecognized MI were independent predictors of MACE (HR = 3.71; 95% CI 2.73–5.05, p < 0.001 and HR = 1.73; 95% CI 1.22–2.45, p = 0.002; respectively) and cardiovascular mortality (HR: 3.13; 95% CI: 2.17–4.51, p < 0.001 and HR = 1.73; 95% CI 1.15–2.62, p = 0.009; respectively). The addition of ischemia and unrecognized MI led to an improved model discrimination for MACE (change in C statistic from 0.61 to 0.72; NRI = 0.431; IDI = 0.053).\n\nConclusions\n\nInducible ischemia and unrecognized MI identified by stress CMR have incremental long term prognostic value for the incidence of MACE in patients without known CAD over traditional risk factors and left ventricular ejection fraction.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12968-021-00737-0.\n\nKeywords\n\nCardiovascular magnetic resonance\nStress testing\nIschemia\nUnrecognized myocardial infarction\nPerfusion\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nThe primary prevention to stratify cardiovascular risk of subjects without known cardiovascular disease (CAD) is crucial for public health and health care costs [1]. To date, decisions regarding the management of these individuals have relied mostly on the assessment of traditional risk factors. However, noninvasive cardiac stress testing may also play an important role for risk stratification, and therefore constitutes a cornerstone of the management of these subjects in the European and American guidelines [2, 3].\n\nStress cardiovascular magnetic resonance (CMR) imaging has emerged as a cost-effective modality for the diagnosis of CAD, and for risk stratification of cardiovascular events through the detection of both inducible myocardial ischemia and myocardial scar [4–7]. Prior studies have shown that beyond the major prognostic role of inducible ischemia, the depiction of an unrecognized myocardial infarction (MI) in individuals without known CAD is a strong predictor of cardiovascular events in the general population [8–11]. Recently, Nagel et al. demonstrated that a noninvasive diagnostic strategy based on stress CMR was noninferior to fractional flow reserve (FFR), in terms of outcomes in patients with suspected CAD [12].\n\nSeveral large stress CMR prognostic studies have included subjects without known CAD [4, 6, 7, 11, 13, 14]. In addition, targeted prognostic data in those patients without known CAD were described in specific subpopulations such as asymptomatic, elderly or obese patients [5, 15–17]. However, the incremental prognostic value of the presence of inducible myocardial ischemia and unrecognized MI vs. traditional risk factors has not been evaluated.\n\nWe hypothesized that inducible myocardial ischemia and unrecognized MI assessed by stress CMR could identify patients at higher risk for cardiovascular event in primary prevention. This study aimed to assess the long-term prognostic value of vasodilator stress perfusion CMR in subjects without known CAD and to evaluate the incremental risk stratification of stress CMR over traditional risk factors and left ventricular ejection fraction (LVEF).\n\nMethods\n\nStudy population\n\nBetween December 2010 and December 2011, we conducted a single-centre longitudinal study with retrospective enrollment of consecutive patients without known CAD, referred for vasodilator stress perfusion CMR. Exclusion criteria were: (i) history of CAD [percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) or MI, defined by a history of MI on the medical records or presence of significant Q wave on 12-lead electrocardiogram (ECG) in a coronary territory]; (ii) contraindication to CMR (cerebral clips, metallic eye implant); (iii) contraindication to dipyridamole; (iv) known cardiomyopathy (e.g. hypertrophic, dilated, or infiltrative) and acute or chronic myocarditis; (v) known allergy to gadolinium-based contrast medium; and (vi) estimated glomerular filtration rate < 30 mL/min/1.73 m2. Clinical data were collected according to medical history and clinical examination on the day of stress CMR. All patients provided informed written consent. The study was approved by the local ethic committee of our institutions and conducted in accordance with the 1964 Declaration of Helsinki. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.\n\nPatients follow-up and clinical outcome\n\nThe follow-up consisted of a clinical visit as part of usual care (63%) or by direct contact with the subject or the referring cardiologist (37%). A clinical questionnaire with a detailed description of clinical study outcomes was filled out by three senior cardiologists. Data collection was ended on January 2020. The primary outcome was the occurrence of at least one of the combined major adverse cardiac events (MACE) defined as cardiovascular mortality or non-fatal MI. The secondary outcome was cardiovascular mortality. Clinical event adjudication was based on the follow-up clinical visit or contact, with a consensus reached by two senior cardiologists. Non-fatal MI was defined by typical angina of ≥ 20 min duration, ECG changes, and a rise in troponin or creatine kinase level above the 99 percentile of the upper reference limit [18]. Cardiovascular mortality was defined as sudden cardiac death with documented fatal arrhythmias or any death immediately preceded by acute MI, acute or exacerbation of heart failure, or stroke. All clinical events were defined according to the published standardized definitions [19]. In patients with multiple events, only the first event was considered for event-free survival analysis. According to guidelines, an hospitalization for heart failure was defined by symptoms and/or signs of heart failure with evidence of diastolic or systolic dysfunction by echocardiography and elevated levels of brain natriuretic peptide ((BNP) > 35 pg/ml and/or NT-proBNP > 125 pg/ml)) [20]. Ventricular tachycardia was defined as documented sustained ventricular tachycardia on 12-leads ECG. Elective late coronary revascularization was defined by a revascularization occurring > 90 days after CMR. For patients who underwent PCI < 90 days after the index examination, peri-procedural events (MI or cardiovascular mortality) [21] were not included in the analysis.\n\nCMR protocol\n\nThe detailed CMR protocol has already been published in our previous studies [15, 16]. CMR was performed on a 1.5 T CMR scanner (MAGNETOM Espree, Siemens Healthineers, Erlangen, Germany) with an 18-channel anterior body coil. Long-axis (2-, 3-, and 4-chamber) and short-axis cine images encompassing the left ventricle (LV) from base to apex were obtained with a segmented retrospectively gated balanced steady state free precession (bSSFP) sequence. Vasodilatation was induced with dipyridamole injected at 0.84 mg/kg over 3 min for all patients. At the end of dipyridamole infusion, a bolus of gadolinium-based contrast agent (0.1 mmol/kg, Dotarem®, Guerbet, France) was injected at a rate of 5.0 ml/s with an injector (Optistar® Elite, Mallinckrodt). Stress perfusion imaging was performed using an ECG-triggered saturation-prepared bSSFP sequence with the following typical parameters: repetition time/echo time (TR/TE) = 287/1.2 ms, acceleration factor = 2, field of view = 370 × 314 mm, matrix = 224 × 180, reconstructed pixel size = 1.7 × 1.7 × 8 mm. A series of six slices (four short-axis views: a 2-chamber and a 4-chamber view) were acquired every other heartbeat. Then, theophylline was injected intravenously (250 mg over 5 min) to null the effect of dipyridamole. Ten minutes after contrast injection, breath-hold contrast-enhanced 3D T1-weighted inversion-recovery gradient-echo sequence was acquired with the same prescriptions to detect late gadolinium enhancement (LGE). The inversion time was individually adjusted to null normal myocardium. In case of artifacts on LGE, additional 2D single-shot bSSFP images with phase sensitive inversion recovery reconstruction were acquired. Patients were asked to refrain from caffeine at least 12 h before CMR. Safety was studied with clinical monitoring 1 h after CMR to assess major adverse events. A 12-lead ECG was performed both before and after CMR examination.\n\nCMR image analysis\n\nThe syngo.via software (Siemens Healthineers) was used for image display and processing, and Hemolia (Clinigrid Inc., Paris, France) was used for reporting. LV volumes and function were quantified on the short-axis cine stack. Stress perfusion and LGE images were evaluated according to the 17-segment model of the American Heart Association [22]. The analysis of perfusion images was done visually by two experienced cardiologists (JG and FS) blinded to clinical and follow-up data. Inducible ischemia was defined as a subendocardial perfusion defect that (1) occurred in at least one myocardial segment, (2) persisted for at least three phases beyond peak contrast enhancement, (3) followed a coronary distribution, and (4) occurred in the absence of LGE in the same segment [13, 23–25]. An unrecognized MI was defined by LGE with ischemic patterns defined by subendocardial or transmural LGE [26]. The total number of ischemic segments was calculated for each patient. LGE was semi-quantitatively assessed using the number of LGE segments. Mild, moderate, and severe ischemia were defined as the involvement of 1–2, 3–5, and ≥ 6 myocardial segments, respectively.\n\nStatistical analysis\n\nContinuous variables were expressed as mean ± standard deviation (SD) and categorical variables as frequency with percentage. Follow-up was presented as median and interquartile range (IQR). Differences between patients with and without inducible ischemia in terms of baseline clinical and CMR characteristics were compared using the Student’s t-test or the Wilcoxon rank-sum test for continuous variables and the chi-square or Fisher’s exact test for categorical variables, as appropriate. Normal distribution was assessed using the Shapiro–Wilk test. Cumulative incidence rates of individual and composite outcomes were estimated using the Kaplan–Meier method and compared with the log-rank test. The proportional hazard assumption was visually assessed using Schoenfeld residuals (Additional file 1: Figure S1). Data on patients who were lost to follow-up were censored at the time of the last contact. Cox proportional hazards methods were used to identify the predictors of MACE among patients with and without ischemia. The assumption of proportional hazards ratio (HR) was verified.\n\nThe different multivariable models used for adjustment were as follows:\n\nModel 1: used a stepwise forward Cox regression strategy to select the strongest parsimonious set of clinical covariates for MACE and cardiovascular mortality, considering all clinical covariates with a p-value ≤ 0.2 on univariable screening (without the presence of ischemia and unrecognized MI).\n\nModel 2: model 1 + presence of unrecognized MI.\n\nModel 3: model 1 + presence of unrecognized MI and presence of ischemia.\n\nThe discriminative capacity of each model for predicting MACE was determined according to the Harrell’s C-statistic at baseline and after addition of CMR-assessed ischemia and MI. The additional predictive value of the presence of ischemia and MI was calculated by the Harrell’s C-statistic increment, the categorical net reclassification improvement (NRI), and the integrative discrimination index (IDI) [27]. NRI and IDI were computed at the end of follow-up using the R package “survIDINRI” [28].\n\nIn addition, the prognostic value of stress CMR in different subsamples of clinical interest was investigated by a Forest Plot. A two-tailed p-value < 0.05 was considered statistically significant. Statistical analysis was performed using R software, version 3.3.1 (R Project for Statistical Computing).\n\nResults\n\nPatients characteristics\n\nDuring the inclusion period, 2295 patients without known CAD were referred for dipyridamole stress CMR (Fig. 1). Amongst them, 2,058 patients completed the clinical follow-up and constituted our study cohort. Baseline subject characteristics and baseline CMR data are shown in Table 1. Among those 2,058 subjects (71.2 ± 12.5 years; 37.5% males), 66.0% had hypertension, 48.9% dyslipidemia, 35.3% obesity, 34.1% diabetes mellitus, 24.9% family history of CAD, and 21.2% were smokers. Most subjects were in sinus rhythm (99.6%). The overall study cohort had an LVEF of 52.6 ± 12.7%. An unrecognized MI was diagnosed by LGE with an ischemic pattern in 210 (10.2%) patients, and inducible ischemia was detected in 267 (13.0%) patients (Fig. 2).Fig. 1 Flowchart. Flowchart of study patients\n\nFig. 2 Examples of inducible ischemia on stress CMR in patients without prior CAD. a fifty-three-year-old female without prior CAD but with diabetes, dyslipidemia and hypertension. Stress CMR revealed no perfusion defect and no LGE, excluding the diagnosis of CAD. b Fifty-eight-year-old female without prior CAD but with diabetes and obesity referred for atypical chest pain. Stress CMR showed a subendocardial perfusion defect on the anteroseptal wall on first-pass perfusion images (white arrows) without myocardial scar on LGE, indicative of myocardial ischemia. Coronary angiography revealed a high-grade stenosis of the LAD. c Seventy-one-year-old male without prior CAD but with diabetes, hypertension and heredity referred for atypical chest pain. Stress CMR showed a transmural anteroseptal MI on LGE (orange arrows) without perfusion defect, therefore no ischemia. Coronary angiography confirmed the chronic occlusion of the LAD and the absence of other significant stenosis. CAD coronary artery disease, LAD left anterior descending, LGE late gadolinium enhancement, RCA right coronary artery\n\nPatients with ischemia were older (74.7 ± 11.4 vs. 70.8 ± 12.6 years, p < 0.001) and more commonly male (59.6% vs. 34.2%, p < 0.001). Patients with ischemia presented a higher cardiovascular risk using the ten-year risk for fatal CAD score [29] (3.4 [1.7–6.4]% vs. 2.4 [0.9–5.4]%, p < 0.001) and the Framingham Risk Score > 20% risk of CAD at 10 years [30] (56.9% vs. 31.9%, p < 0.001).\n\nOf the 267 patients with ischemia, 196 (73.4%) underwent coronary angiography with early revascularization < 90 days after CMR. Among those, 9 patients were censored due to the recurrence of MI or cardiovascular mortality within 90 days after CMR.\n\nCMR study\n\nOf 2295 patients without known CAD, 2247 (97.9%) completed the stress CMR protocol. Reasons for failure to complete CMR are presented in Fig. 1. No patient died during or shortly after CMR. There was one case of unstable angina and one patient with persistent atrial fibrillation, but no cases of transient ischemic attack, disabling stroke, ST elevation MI or sustained ventricular tachycardia after stress CMR. The main adverse events during or immediately after stress CMR were: headaches (N = 276, 12.3%), chest discomfort (N = 198, 8.8%), nausea or vomiting (N = 195, 8.7%), dizziness (N = 54, 2.4%) and angina with ECG evidence of ischemia (N = 42, 1.9%). For all patients, symptoms resolved quickly after an intravenous injection of theophylline and with additional sublingual nitrates and/or intravenous beta blockers in 29 patients (1.3%).\n\nPrognostic value\n\nAmong 2247 patients who underwent the stress CMR protocol, 2058 (91.6%) completed the follow-up with a median (IQR) follow-up of 8.3 (7.3–8.7) years. There were 203 MACE (9.9%), including 150 cardiovascular mortality (7.3%) and 53 non-fatal MI (2.6%). Furthermore, 296 all-cause mortality (14.4%), 116 hospitalizations for heart failure (5.6%), 105 elective late coronary revascularizations (5.1%) (5 CABG), and 41 sustained documented ventricular tachycardia (2.0%) were recorded. The annualized event rates for MACE and cardiovascular mortality, depending on the presence and severity of ischemia, are shown in Additional file 1: Figure S2.\n\nThe univariable analysis of baseline patients and CMR characteristics for the prediction of MACE and cardiovascular mortality is shown in Table 2. Age, male gender, the presence of ischemia, the number of ischemic segments, the presence of unrecognized MI, LVEF and both LV end-diastolic and end-systolic volumes indexed were all significantly associated with MACE. Using Kaplan–Meier analysis, ischemia and unrecognized MI were associated with the occurrence of MACE (HR: 4.64 95% CI: 3.69–6.17 and HR: 2.88; 95% CI: 2.08–3.99, respectively; both p < 0.001) (Fig. 3). In addition, ischemia was associated with cardiovascular mortality (HR: 4.00; 95% CI: 2.85–5.61), non-fatal MI (HR: 6.20; 95% CI: 3.61–10.70) and all-cause mortality (HR: 2.74; 95% CI: 2.11–3.55, all p < 0.001; Additional file 1: Table S1). The presence of ischemia was significantly associated with MACE in men (HR: 5.29; 95% CI: 3.57–7.84) and in women (HR: 3.33; 95% CI: 2.08–5.34, both p < 0.001). The prognostic value of the presence of ischemia to predict MACE was significant in both asymptomatic and symptomatic patients (HR: 3.84; 95% CI: 2.53–5.82 and HR: 5.55; 95% CI: 3.74–8.24, respectively, both p < 0.001).Table 1 Baseline and CMR characteristics of patients with and without inducible ischemia (N = 2058)\n\n\tAll patients\n(N=2058)\tNo ischemia\n(N=1791)\tPositive ischemia\n(N=267)\tp value\t\nAge, years\t71.2 ± 12.5\t70.8 ± 12.6\t74.7 ± 11.4\t<0.001\t\nMales, n (%)\t772 (37.5)\t613 (34.2)\t159 (59.6)\t<0.001\t\nBody mass index, kg/m²\t29.4 ± 6.6\t29.6 ± 6.7\t28.3 ± 5.7\t<0.001\t\nCoronary artery disease risk factors, n (%)\t\t\t\n Diabetes mellitus\t702 (34.1)\t618 (34.5)\t84 (31.5)\t0.363\t\n Hypertension\t1358 (66.0)\t1193 (66.6)\t165 (61.8)\t0.139\t\n Dyslipidemia\t1007 (48.9)\t875 (48.9)\t132 (49.4)\t0.911\t\n Current or previous smoking\t436 (21.2)\t378 (21.1)\t58 (21.7)\t0.881\t\n Family history of coronary disease\t512 (24.9)\t450 (25.1)\t62 (23.2)\t0.551\t\n Obesitya\t726 (35.3)\t644 (36.0)\t82 (30.7)\t0.109\t\nMedical history of cardiovascular disease, n (%)\t\t\t\n Peripheral atheroma\t52 (2.5)\t45 (2.5)\t7 (2.6)\t0.662\t\n Ischemic stroke\t90 (4.4)\t78 (4.4)\t12 (4.5)\t0.877\t\n Pacemaker\t10 (0.5)\t9 (0.5)\t1 (0.4)\t1.000\t\n Renal failureb\t23 (1.1)\t21 (1.2)\t2 (0.7)\t0.759\t\n Prior hospitalization for heart failure\t49 (2.4)\t43 (2.4)\t6 (2.3)\t1.000\t\nIndications to stress CMR (multiple possible), n (%)\t\t\t\n High cardiovascular disease riskc\t724 (35.2)\t572 (31.9)\t152 (56.9)\t<0.001\t\n Symptomatic angina\t530 (25.8)\t447 (25.0)\t83 (31.1)\t0.039\t\n Dyspnea\t547 (26.6)\t490 (27.4)\t57 (21.3)\t0.046\t\n Inconclusive stress test\t410 (19.9)\t360 (20.1)\t50 (18.7)\t0.658\t\n Inconclusive coronary CT angiogramd\t26 (1.3)\t24 (1.3)\t2 (0.7)\t0.566\t\nTen-year risk for fatal CAD (%)e\t2.6 (1.1–5.6)\t2.4 (0.9–5.4)\t3.4 (1.7–6.4)\t<0.001\t\nCardiac rhythm, n (%)\t\t\t\t\t\n Sinus rhythm\t1507 (73.2)\t1288 (71.9)\t219 (82.0)\t<0.001\t\n Sinus rhythm with extrasystoles\t542 (26.3)\t495 (27.6)\t47 (17.6)\t\t\n Atrial fibrillation/supraventricular arrhythmias\t9 (0.4)\t8 (0.4)\t1 (0.4)\t\t\nLV ejection fraction, %\t52.6 ± 12.7\t52.9 ± 12.7\t50.6 ± 12.7\t0.007\t\nLV end-diastolic volume index, ml/m2\t81.1 ± 27.5\t81.1 ± 27.3\t81.5 ± 29.5\t0.844\t\nLV end-systolic volume index, ml/m2\t40.6 ± 23.4\t40.3 ± 23.3\t42.3 ± 24.4\t0.208\t\nLV mass, g/m2\t75.5 ± 7.7\t72.9 ± 7.7\t77.9 ± 7.8\t<0.001\t\nRV ejection fraction, %\t65.9 ± 12.3\t65.9 ± 12.3\t65.8 ± 12.5\t0.831\t\nPresence of unrecognized MI, n (%)\t210 (10.2)\t135 (7.5)\t75 (28.1)\t<0.001\t\nNumber of segments of LGE\t0.3 ± 1.0\t0.2 ± 0.9\t0.8 ± 1.6\t<0.001\t\nNumber of segments of ischemia\t0.3 ± 1.1\t0.0 ± 0.0\t2.6 ± 1.7\t<0.001\t\nHeart rate at baseline, beats/min\t80 ± 13\t80 ± 13\t81 ± 15\t0.688\t\nHeart rate at stress, beats/min\t92 ± 12\t92 ± 11\t94 ± 13\t0.569\t\nRPP at baseline, mmHg/beats/min\t9.1 (7.6–10.8)\t9.1 (7.6–10.7)\t9.2 (7.6–10.9)\t0.733\t\nRPP at stress, mmHg/beats/min\t10.4 (8.8–12.6)\t10.4 (8.8–12.2)\t11.2 (9.8–13.3)\t0.363\t\nValues are n (%), mean ± SD, or median (interquartile range)\n\nBMI body mass index, CAD coronary artery disease, CTA computed tomography, CMR cardiovascular magnetic resonance, LGE late gadolinium enhancement, LV left ventricle, MI myocardial infarction, RPP rate-pressure product (pressure mmHg x Heart rate bpm)/1000, RV right ventricle, SD standard deviation\n\naDefined by body mass index ≥ 30 kg/m2\n\nbDefined by estimated glomerular filtration rate < 60 ml/min/1.73 m2\n\ncDefined by Framingham Risk Score > 20% of risk of CAD at 10 years\n\ndDefined by coronary stenosis of unknown significance on coronary CT angiography\n\nFig. 3 Kaplan–Meier curves for MACE (a) and cardiovascular mortality (b) stratified by the presence of ischemia. Kaplan Meier curves of MACE (cardiovascular mortality or non-fatal MI) as a function of length of follow-up for those with and without myocardial ischemia. Test comparing the two groups was based on the log-rank test\n\nThe prognostic value of ischemia remained consistent in all other subsamples of clinical interest such as diabetics and non-diabetics, and regardless of LVEF (Fig. 4). In addition, the presence of ischemia had a similar prognostic value regardless of the age (Additional file 1: Figure S3).Fig. 4 Subgroup analysis. Forest-plot of incidence of MACE based on the presence of ischemia in prespecified subgroups. *N events/N subgroup: number of patients who had a major adverse clinical event (MACE) / number of patients in the subgroup\n\nIn multivariable stepwise Cox regression (model 2), the presence of ischemia and unrecognized MI were independent predictors of MACE (HR = 3.71; 95% CI 2.73–5.05, p < 0.001 and HR = 1.73; 95% CI 1.22–2.45, p = 0.002; respectively) and cardiovascular mortality (HR: 3.13; 95% CI: 2.17–4.51, p < 0.001 and HR = 1.73; 95% CI 1.15–2.62, p = 0.009; respectively) (Table 3).Table 2 Univariable analysis of clinical and CMR characteristics for prediction of adverse events\n\n\tMACE\tCardiovascular mortality\t\n\tHazard ratio (95% CI)\tp value\tHazard ratio (95% CI)\tp value\t\nAge\t1.02 (1.01–1.03)\t0.002\t1.03 (1.02–1.05)\t< 0.001\t\nMale\t1.68 (1.27–2.21)\t < 0.001\t1.60 (1.16–2.20)\t0.004\t\nBody mass index\t0.98 (0.95–1.02)\t0.311\t1.01 (0.95–1.03)\t0.485\t\nHypertension\t0.83 (0.62–1.10)\t0.190\t0.88 (0.63–1.22)\t0.431\t\nDiabetes mellitus\t0.86 (0.64–1.15)\t0.307\t0.87 (0.62–1.23)\t0.429\t\nDyslipidemia\t1.00 (0.76–1.32)\t0.978\t1.00 (0.73–1.38)\t0.978\t\nCurrent or previous smoking\t0.96 (0.68–1.35)\t0.811\t0.81 (0.53–1.22)\t0.309\t\nFamily history of coronary artery disease\t0.72 (0.51–1.02)\t0.064\t0.61 (0.40–0.94)\t0.023\t\nStroke\t0.77 (0.37–1.83)\t0.371\t0.74 (0.30–1.19)\t0.466\t\nRenal failure\t1.36 (0.44–4.26)\t0.595\t1.27 (0.31–5.12)\t0.738\t\nPeripheral atheroma\t1.12 (0.29–3.37)\t0.566\t1.54 (0.34–4.45)\t0.319\t\nPrior hospitalization for heart failure\t1.57 (0.74–3.34)\t0.240\t1.87 (0.83–4.24)\t0.133\t\nPresence of ischemia\t4.64 (3.49–6.17)\t < 0.001\t4.00 (2.85–5.61)\t< 0.001\t\nNumber of segments of ischemia\t1.60 (1.51–1.70)\t < 0.001\t1.51 (1.40–1.62)\t< 0.001\t\nPresence of unrecognized MI\t2.88 (2.08–3.99)\t < 0.001\t2.77 (1.89–4.06)\t< 0.001\t\nNumber of segments of LGE\t1.52 (1.41–1.63)\t < 0.001\t1.49 (1.37–1.62)\t< 0.001\t\nLV ejection fraction, per 10%\t0.88 (0.79–0.97)\t0.014\t0.93 (0.82–1.05)\t0.245\t\nLV end-diastolic volume index, per 10 ml/m2\t1.06 (1.01–1.11)\t0.025\t1.03 (0.97–1.09)\t0.348\t\nLV end-systolic volume index, per 10 ml/m2\t1.06 (1.02–1.13)\t0.009\t1.04 (0.97–1.11)\t0.252\t\nRV ejection fraction, %\t0.96 (0.79–1.19)\t0.411\t1.06 (0.78–1.53)\t0.681\t\nCI confidence interval, CMR cardiovascular magnetic resonance, LGE late gadolinium enhancement, LV left ventricle, MACE major adverse cardiac events, MI myocardial infarction, RV right ventricle\n\nIncremental prognostic value of stress CMR\n\nFor the prediction of MACE, we observed baseline C statistic values of 0.61 (95% CI, 0.56–0.65) for model 1 with stepwise variable selection. The addition of unrecognized MI significantly improved the C statistic to 0.66 (95% CI, 0.60–0.71; C statistic improvement for model 1: 0.05; NRI = 0. 252; IDI = 0.037). Furthermore, the addition of unrecognized MI and ischemia significantly improved the C statistic to 0.72 (95% CI, 0.69–0.76; C statistic improvement for model 1: 0.11; NRI = 0.431; IDI = 0.053) (Table 4).Table 3 Multivariable cox regression analysis for the prediction of adverse events\n\n\tMACE\tCardiovascular mortality\t\n\tHazard ratio\n(95% CI)\tp value\tHazard ratio\n(95% CI)\tp value\t\nModel 1a\t\t\t\t\t\nAge\t1.03 (1.01–1.05)\t0.002\t1.04 (1.02–1.07)\t < 0.001\t\nMale\t1.91 (1.32–2.76)\t < 0.001\t1.85 (1.22–2.82)\t0.004\t\nFamily history of coronary artery disease\t0.74 (0.49–1.10)\t0.131\t0.66 (0.41–1.05)\t0.076\t\nLV end-systolic volume index, per 10 ml/m2\t2.70 (0.99–7.37)\t0.053\t3.81 (1.38–10.5)\t0.010\t\nModel 2b\t\t\t\t\t\nPresence of unrecognized MI\t1.82 (1.28–2.49)\t < 0.001\t1.76 (1.18–2.66)\t0.007\t\nModel 3c\t\t\t\t\t\nPresence of unrecognized MI\t1.73 (1.22–2.45)\t0.002\t1.73 (1.15–2.62)\t0.009\t\nPresence of ischemia\t3.71 (2.73–5.05)\t < 0.001\t3.13 (2.17–4.51)\t < 0.001\t\nCI confidence interval, MACE major adverse cardiac events, LV left ventricle, MI myocardial infarction\n\naCovariates in the model 1 by stepwise variable selection with entry and exit criteria set at the p ≤ 0.2 level: for MACE: age, male, hypertension, family history of CAD, LVEF per 10%, LV end-systolic volume index, per 10 ml/m2. for CV mortality: age, male, family history of CAD, family history of CAD\n\nbCovariates in the model 2: model 1 with unrecognized MI\n\ncCovariates in the model 3: model 1 with unrecognized MI and ischemia\n\nTable 4 Discrimination and reclassification associated with ischemia and LGE for prediction of MACE\n\n\tMACE\t\nC-index (95%CI)\tNRI (95%CI)\tIDI (95%CI)\t\nModel 1 (stepwise selection)a\t0.61 (0.56–0.65)\tReference\tReference\t\nModel 2 (model 1 + unrecognized MI)b\t0.66 (0.60–0.71)\t0.252 (0.065–0.439)\t0.037 (0.016–0.058)\t\nModel 3 (model 1 + unrecognized MI and ischemia)c\t0.72 (0.69–0.76)\t0.431 (0.212–0.650)\t0.053 (0.030–0.076)\t\nCI confidence interval, IDI integrative discrimination index, MACE major adverse cardiac events, MI myocardial infarction, NRI net reclassification improvement\n\naCovariates in the model 1 by stepwise variable selection with entry and exit criteria set at the p ≤ 0.2 level: age, male, hypertension, family history of coronary artery disease, LVEF per 10%, LV end-systolic volume index, per 10 ml/m2\n\nbCovariates in the model 2: model 1 with unrecognized MI\n\ncCovariates in the model 3: model 1 with unrecognized MI and ischemia\n\nDiscussion\n\nIn this large single center study of patients without known CAD referred for stress CMR, our main findings demonstrate that: (1) inducible ischemia and unrecognized MI were independent long-term predictors of MACE and cardiovascular mortality; (2) the presence of inducible ischemia and unrecognized MI improved model discrimination for the prediction of MACE, after adjusting for covariates; (3) 13.0% of patients had inducible ischemia and 10.2% had unrecognized MI.\n\nPrevious studies in patients with suspected or known CAD reported that the prevalence of CMR-inducible ischemia ranged between 7 and 26% [4, 6, 15–17]. In the current study including low-risk patients without known CAD, the prevalence of inducible ischemia was 13.0%. The prevalence of unrecognized MI detected by CMR has been shown to range between 0.2 and 30% in the general population [9, 31, 32], about 15% in symptomatic patients [11], and less than 6% in asymptomatic patients with suspected CAD [17]. In the present study, the prevalence of unrecognized MI was 10.2%. Consistently with prior cohorts of patients without known CAD [4, 13, 15–17], the rate of MACE was 9.9% over a median follow-up of 8.3 years.\n\nStress-CMR inducible ischemia and unrecognized MI were independently associated with MACE in the sole subset of patients without known CAD. Such findings extend the aggregate data on the prognostic value of stress CMR [4, 6, 11, 15, 16, 33, 34]. Consistently, the extent of ischemia was a strong prognosticator of MACE and cardiovascular mortality, as already described in patients with known or suspected CAD [13]. Several studies have shown similar accuracy to diagnose CAD and predict cardiovascular events in men and women [35, 36]. In line with these data, the current study suggests a similar prognostic value of stress CMR in women and men.\n\nAlthough some studies have suggested the prognostic value of stress CMR in patients without known CAD [5, 15–17], they have not evaluated the incremental prognostic value of stress CMR to predict cardiovascular events over traditional risk factors in this population. The current study demonstrates an incremental prognostic value of unrecognized MI to predict MACE above traditional cardiovascular risk factors and LVEF. This finding is in line with the recent SPINS registry of the Society for Cardiovascular Magnetic Resonance showing that presence of unrecognized MI portended a significant risk for cardiovascular events, independently of the presence of ischemia [11]. In the current, the addition of inducible ischemia to the model containing traditional risk factors and unrecognized MI, further improved the prognostic value for predicting MACE. These data highlight the importance of integrating both inducible ischemia and unrecognized MI in risk stratification models.\n\nThis addition of unrecognized MI and ischemia by stress CMR in risk stratification models led to an incremental prognostic value, as illustrated by a rise in the C-index from 0.61 to 0.66 and 0.72, respectively. Whereas this prognostic incremental value of stress CMR could be cost-effective remains to be evaluated. The SPINS registry [4] demonstrated that the average cost of ischemic testing was lower for stress CMR than other stress testing [37]. If cost-effective, the current data support the use of stress CMR to identify high-risk patients who could benefit from improved clinical and therapeutic management [38, 39].\n\nStudy limitations\n\nOur study has several limitations. First, the study was retrospective, with a risk of referral bias. Overall, 189 (8.4%) patients were lost to follow-up, which can be explained by a relatively long follow-up and the design of the study. However, the French National Registry of Death was carefully reviewed, which strengthens the data on mortality. Despite the good prognostic value of stress CMR in AF patients [40], the low proportion of AF patients referred for stress CMR is likely due to the reluctance of referring cardiologists. This study was not designed to compare the prognostic value in women and men. The analysis of CMR stress perfusion images was visual, which represents the most widely accepted clinical method with optimal diagnostic accuracy. Stress perfusion CMR protocol included six slices (4 short-axis views, and long-axis views) acquired every other heartbeat to optimize anatomical coverage of the LV, at the cost of a slight decrease in temporal resolution. This retrospective study could not capture all of the confounding factors regarding the association between management decisions after the stress CMR exam and patient risk. Finally, the extent of myocardial scar was assessed semi-quantitatively by the number of infarcted segments and not quantitatively by semi-automated methods.\n\nConclusions\n\nStress perfusion CMR has a good discriminative long-term prognostic value in patients without known CAD. Stress-CMR inducible ischemia and unrecognized MI are independently associated with non-fatal MI and cardiovascular mortality over a long-term follow-up and offer incremental prognostic value over traditional risk factors.\n\nSupplementary Information\n\nAdditional file 1: Figure S1. The assessment of the proportional hazard assumption. Figure S2. Annualized event rates of MACE (A) and cardiovascular mortality (B) stratified by the extent of ischemia (N = 2058). Table S1. Univariable analysis of inducible myocardial ischemia for prediction of adverse events (N = 2058). Figure S3. Annualized event rates of MACE stratified by age and presence/absence of ischemia.\n\nAbbreviations\n\nBMI Body mass index\n\nBNP Brain natriuretic peptide\n\nbSSFP Balanced steady state free precession\n\nCABG Coronary artery bypass graft\n\nCAD Coronary artery disease\n\nCI Confidence interval\n\nCMR Cardiovascular magnetic resonance\n\nECG Electrocardiogram\n\nFFR Fractional flow reserve\n\nHR Hazard ratio\n\nIDI Integrative discrimination index\n\nLGE Late gadolinium enhancement\n\nLV Left ventricle/left ventricular\n\nLVEF Left ventricular ejection fraction\n\nMACE Major adverse cardiac event\n\nMI Myocardial infarction\n\nNRI Net reclassification improvement\n\nPCI Percutaneous coronary intervention\n\nSD Standard deviation\n\nIQR Interquartile range\n\nAcknowledgements\n\nWe thank the medical, paramedical and research staff of Hôpital Privé J. CARTIER.\n\nAuthors' contributions\n\nAll authors participated in the discussion of the concept of the study. TP and JG conceived the study design. TP, FS, MK, TH, SC, TU, PG and JG, obtained CMR images and analyzed CMR scans. TP and JG analyzed data and drafted the manuscript with critical revision. JG and ST have technically defined the CMR protocol. As authors, we attest to each of our substantial contributions to the manuscript and revision. All authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nAll data generated or analysed during this study are included in this published article [and its Additional information files].\n\nEthics approval and consent to participate\n\nThe study was evaluated and approved by the local ethic committee of our institutions and conducted in accordance with the 1964 Declaration of Helsinki. All patients enrolled in this study were required to understand and give their consent for participation.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nSolenn Toupin is an employee of Siemens Healthcare. Other authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Benjamin EJ Muntner P Alonso A Bittencourt MS Callaway CW Carson AP Heart disease and stroke statistics—2019 update: a report from the American Heart Association Circulation 2019 139 10 e56 528 10.1161/CIR.0000000000000659 30700139\n2. Knuuti J Wijns W Saraste A Capodanno D Barbato E Funck-Brentano C 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes Eur Heart J. 2020 41 3 407 477 10.1093/eurheartj/ehz425 31504439\n3. 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Stone GW Ben-Yehuda O Sabik JF Kappetein AP Serruys PW Considerations for an optimal definition of procedural myocardial infarction Eur Heart J 2020 41 17 1704 1705 10.1093/eurheartj/ehaa185 32227168\n22. Cerqueira MD Weissman NJ Dilsizian V Jacobs AK Kaul S Laskey WK Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association Circulation 2002 105 4 539 542 10.1161/hc0402.102975 11815441\n23. Schwitter J Wacker CM van Rossum AC Lombardi M Al-Saadi N Ahlstrom H MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial Eur Heart J 2008 29 4 480 489 10.1093/eurheartj/ehm617 18208849\n24. Schwitter J Wacker CM Wilke N Al-Saadi N Sauer E Huettle K MR-IMPACT II: Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary artery disease Trial: perfusion-cardiac magnetic resonance vs. single-photon emission computed tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial Eur Heart J. 2013 34 10 775 781 10.1093/eurheartj/ehs022 22390914\n25. Plein S Kozerke S Suerder D Luescher TF Greenwood JP Boesiger P High spatial resolution myocardial perfusion cardiac magnetic resonance for the detection of coronary artery disease Eur Heart J 2008 29 17 2148 2155 10.1093/eurheartj/ehn297 18641047\n26. Mahrholdt H Wagner A Judd RM Sechtem U Kim RJ Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies Eur Heart J 2005 26 15 1461 1474 10.1093/eurheartj/ehi258 15831557\n27. Pencina MJ D’Agostino RB D’Agostino RB Vasan RS Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond Stat Med. 2008 27 2 157 172 10.1002/sim.2929 17569110\n28. Uno H Tian L Cai T Kohane IS Wei LJ A unified inference procedure for a class of measures to assess improvement in risk prediction systems with survival data Stat Med 2013 32 14 2430 2442 10.1002/sim.5647 23037800\n29. Conroy RM Pyörälä K Fitzgerald AP Sans S Menotti A De Backer G Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project Eur Heart J 2003 24 11 987 1003 10.1016/S0195-668X(03)00114-3 12788299\n30. Wilson PW D’Agostino RB Levy D Belanger AM Silbershatz H Kannel WB Prediction of coronary heart disease using risk factor categories Circulation 1998 97 18 1837 1847 10.1161/01.CIR.97.18.1837 9603539\n31. Barbier CE Nylander R Themudo R Ahlström H Lind L Larsson E-M Prevalence of unrecognized myocardial infarction detected with magnetic resonance imaging and its relationship to cerebral ischemic lesions in both sexes J Am Coll Cardiol 2011 58 13 1372 1377 10.1016/j.jacc.2011.06.028 21920267\n32. Kwong RY Chan AK Brown KA Chan CW Reynolds HG Tsang S Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease Circulation 2006 113 23 2733 2743 10.1161/CIRCULATIONAHA.105.570648 16754804\n33. Lipinski MJ McVey CM Berger JS Kramer CM Salerno M Prognostic value of stress cardiac magnetic resonance imaging in patients with known or suspected coronary artery disease: a systematic review and meta-analysis J Am Coll Cardiol 2013 62 9 826 838 10.1016/j.jacc.2013.03.080 23727209\n34. Kelle S Chiribiri A Vierecke J Egnell C Hamdan A Jahnke C Long-term prognostic value of dobutamine stress CMR JACC Cardiovasc Imaging 2011 4 2 161 172 10.1016/j.jcmg.2010.11.012 21329901\n35. Greenwood JP Motwani M Maredia N Brown JM Everett CC Nixon J Comparison of cardiovascular magnetic resonance and single-photon emission computed tomography in women with suspected coronary artery disease from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) Trial Circulation 2014 129 10 1129 1138 10.1161/CIRCULATIONAHA.112.000071 24357404\n36. Coelho-Filho OR Seabra LF Mongeon F-P Abdullah SM Francis SA Blankstein R Stress myocardial perfusion imaging by CMR provides strong prognostic value to cardiac events regardless of patient’s sex JACC Cardiovasc Imaging 2011 4 8 850 861 10.1016/j.jcmg.2011.04.015 21835377\n37. Ge Y Pandya A Steel K Bingham S Jerosch-Herold M Chen Y-Y Cost-effectiveness analysis of stress cardiovascular magnetic resonance imaging for stable chest pain syndromes JACC Cardiovasc Imaging 2020 13 7 1505 1517 10.1016/j.jcmg.2020.02.029 32417337\n38. Ridker PM Everett BM Thuren T MacFadyen JG Chang WH Ballantyne C Antiinflammatory therapy with canakinumab for atherosclerotic disease N Engl J Med. 2017 377 12 1119 1131 10.1056/NEJMoa1707914 28845751\n39. Eikelboom JW Connolly SJ Bosch J Dagenais GR Hart RG Shestakovska O Rivaroxaban with or without aspirin in stable cardiovascular disease N Engl J Med. 2017 377 14 1319 1330 10.1056/NEJMoa1709118 28844192\n40. Pezel T Sanguineti F Kinnel M Landon V Toupin S Unterseeh T Feasibility and prognostic value of vasodilator stress perfusion CMR in patients with atrial fibrillation JACC Cardiovasc Imaging. 2021 14 2 379 389 10.1016/j.jcmg.2020.07.041 33129729\n\n",
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"journal": "Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance",
"keywords": "Cardiovascular magnetic resonance; Ischemia; Perfusion; Stress testing; Unrecognized myocardial infarction",
"medline_ta": "J Cardiovasc Magn Reson",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003326:Coronary Circulation; D004176:Dipyridamole; D005260:Female; D006439:Hemodynamics; D006801:Humans; D015994:Incidence; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia; D055414:Myocardial Perfusion Imaging; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014665:Vasodilator Agents",
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"title": "Long-term prognostic value of stress perfusion cardiovascular magnetic resonance in patients without known coronary artery disease.",
"title_normalized": "long term prognostic value of stress perfusion cardiovascular magnetic resonance in patients without known coronary artery disease"
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"abstract": "Candida auris is a fungal pathogen that was first identified in 2009. Since its definition, it has spread globally and has caused life-threatening nosocomial infections. Increases in the number of immunocompromised individuals, empirical use of broad-spectrum antimicrobials and widespread use of catheterizations are the predisposing factors in the development of infection. There are problems for the identification of C.auris with the routine methods. In this case report, infections with C.auris, isolated for the first time from three patients in our hospital's intensive care units (ICU) between November 2020-January 2021, were presented. The first case was a 46-year-old male patient with laryngeal carcinoma who developed cardiopulmonary arrest during anesthesia induction in the tumor operation, and was followed up in the ICU. C.auris growth was detected in the blood and intravenous (IV) catheter tip cultures on the 66th day of admittance. Cure achieved on the 24th day under caspofungin treatment as no growth was determined. Second case was a 71-year-old female patient admitted to the emergency department with shortness of breath and general condition disorder that developed after COVID-19 infection and hospitalized in ICU with the diagnosis of pneumonia and acute renal failure. In the 16th day of admittance C.auris growth was detected in blood and from catheter tip cultures and the patient died in the 18th day. The third case was a 49-year-old male patient, followed up in ICU with the diagnosis of subarachnoid hemorrhage after he admitted to the emergency department with confusion. In the 35th day of admittance, 100000 CFU/ mL C auris growth was detected in urine culture. The patient was accepted as asymptomatic fungiuria and followed up in the ICU. It was determined that the three patients were intubated, had urinary and femoral venous catheters and were being followed under wide spectrum antibiotherapy when the growth of C.auris was detected. Isolates identified as C.auris by MALDI-TOF Microflex LT/SH Smart MS in the Medical Microbiology Laboratory were then confirmed by conventional methods and DNA sequencing in the National Mycology Reference Laboratory. Antifungal susceptibility tests were performed by broth microdilution method. Fluconazole MIC values were >256 mg/ml for all cases. Long-term survival in hospital environments, colonization on skin, resistance to disinfectants of C.auris, facilitate the spread of the fungi and resistance to antifungals lead to treatment failures. In this case report, it was aimed to draw attention to the infections with C.auris, its diagnosis and risk factors.",
"affiliations": "Basaksehir Cam and Sakura City Hospital, Laboratory of Medical Microbiology, Istanbul, Turkey.;General Directorate of Public Health, National Mycology Reference Laboratory, Ankara, Turkey.;Basaksehir Cam and Sakura City Hospital, Laboratory of Medical Microbiology, Istanbul, Turkey.;Basaksehir Cam and Sakura City Hospital, Laboratory of Medical Microbiology, Istanbul, Turkey.;Basaksehir Cam and Sakura City Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Istanbul, Turkey.",
"authors": "Kömeç|Selda|S|;Karabıçak|Nilgün|N|;Ceylan|Ayşe Nur|AN|;Gülmez|Abdurrahman|A|;Özalp|Onur|O|",
"chemical_list": "D000935:Antifungal Agents",
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"issue": "55(3)",
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"medline_ta": "Mikrobiyol Bul",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D000086382:COVID-19; D002175:Candida; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000086402:SARS-CoV-2; D014421:Turkey",
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"pages": "452-460",
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"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three Candida auris Case Reports from Istanbul, Turkey.",
"title_normalized": "three candida auris case reports from istanbul turkey"
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"abstract": "Severe hepatotoxicity from combination chemotherapy with cisplatin and 5-fluorouracil is a rare adverse effect. In this case report, we present a case with severe hepatotoxicity immediately following chemotherapy with cisplatin and 5-fluorouracil. This female patient had previously been treated with this combination with no hepatotoxicity. The elevated liver enzymes quickly normalized after chemotherapy was stopped. There were no specific changes in liver imaging. As hepatotoxicity occurred after repeated administration of cisplatin, we suggest that this hepatotoxicity might represent a case of allergic hepatitis caused by cisplatin. Severe hepatotoxicity should be watched for with repeated administration of cisplatin.",
"affiliations": "1Department of Pharmacy, Niigata University Medical and Dental Hospital, 754-banchi, Asahimati-dori 1-bancho, Chuo-ku, Niigata, 951-8520 Japan.;1Department of Pharmacy, Niigata University Medical and Dental Hospital, 754-banchi, Asahimati-dori 1-bancho, Chuo-ku, Niigata, 951-8520 Japan.;1Department of Pharmacy, Niigata University Medical and Dental Hospital, 754-banchi, Asahimati-dori 1-bancho, Chuo-ku, Niigata, 951-8520 Japan.;1Department of Pharmacy, Niigata University Medical and Dental Hospital, 754-banchi, Asahimati-dori 1-bancho, Chuo-ku, Niigata, 951-8520 Japan.;2Department of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.;3Department of Medical Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.;1Department of Pharmacy, Niigata University Medical and Dental Hospital, 754-banchi, Asahimati-dori 1-bancho, Chuo-ku, Niigata, 951-8520 Japan.",
"authors": "Yaegashi|Ayaka|A|;Yoshida|Kensuke|K|;Suzuki|Naoto|N|;Shimada|Izumi|I|;Tani|Yusuke|Y|;Saijo|Yasuo|Y|;Toyama|Akira|A|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-019-00394-2",
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"issn_linking": "2192-3183",
"issue": "9(1)",
"journal": "International cancer conference journal",
"keywords": "5-Fluorouracil; Cisplatin; Hepatotoxicity",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "24-27",
"pmc": null,
"pmid": "31950013",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports",
"references": "20886011;29767581;3017230;28562536;28334858;18271750;3898450;12783586;12852346;21879261;23568356;1584260;7828281;10673530;23970648;5074970;28420850",
"title": "A case of severe hepatotoxicity induced by cisplatin and 5-fluorouracil.",
"title_normalized": "a case of severe hepatotoxicity induced by cisplatin and 5 fluorouracil"
} | [
{
"companynumb": "JP-ACCORD-170555",
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{
"abstract": "Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon, life-threatening drug reaction. The basic findings are skin rash, multiorgan involvement, and eosinophilia. Most of the aromatic anticonvulsants, such as phenytoin, phenobarbital and carbamazepine can induce DRESS. Herein we report a 14-year-old patient with DRESS syndrome related to carbamazepine use. The patient presented with signs of involvement of the skin, lungs, liver, and microscopic hematuria. Carbamazepine treatment was discontinued; antihistamines and steroids were started. Hyperglycemia, commencing on the first dose of the steroid given, persisted even after the discontinuation of steroids and improvement of other signs. There were no signs of pancreatitis or type 1 diabetes clinically in laboratory tests. Her blood glucose levels were regulated at first with insulin and later with metformin. Within 1 year of follow-up, still regulated with oral antidiabetics, she has been diagnosed with type 2 diabetes. Formerly, long-term sequelae related to \"drug rash with eosinophilia and systemic symptoms syndrome\" such as hepatic and renal failure, type 1 diabetes mellitus, Grave's disease, autoimmune hemolytic anemia, and lupus have also been reported. However, up to date, no cases with type 2 diabetes have been reported as long-term sequelae. To our knowledge, this is the first case in the literature presenting with type 2 diabetes as long-term sequelae.",
"affiliations": "Department of Pediatric Allergy, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, Turkey.;Department of Pediatric Allergy, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, Turkey.;Department of Pediatric Allergy, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, Turkey.;Department of Pediatric Allergy, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, Turkey.;Department of Pediatric Endocrinology, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, Turkey.;Department of Pediatric Allergy, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, Turkey.",
"authors": "Erdem|Semiha Bahceci|SB|;Nacaroglu|Hikmet Tekin|HT|;Bag|Ozlem|O|;Karkiner|Canan Sule Unsal|CS|;Korkmaz|Huseyin Anil|HA|;Can|Demet|D|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/ceji.2015.54606",
"fulltext": "\n==== Front\nCent Eur J ImmunolCent Eur J ImmunolCEJICentral-European Journal of Immunology1426-39121644-4124Polish Society of Experimental and Clinical Immunology 268623172588710.5114/ceji.2015.54606Case ReportDRESS syndrome associated with type 2 diabetes in a child Erdem Semiha Bahceci 1Nacaroglu Hikmet Tekin 1Bag Ozlem 1Karkiner Canan Sule Unsal 1Korkmaz Huseyin Anil 2Can Demet 11 Department of Pediatric Allergy, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, Turkey2 Department of Pediatric Endocrinology, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, TurkeyCorrespondence: Hikmet Tekin Nacaroglu, MD, Department of Pediatric Allergy, Dr. Behcet Uz Children Disease and Surgery Training and Research Hospital, Izmir, Turkey. e-mail: tekin212@gmail.com. tel.: 90 232 441 56 56, fax: 90 232 489 23 1515 1 2016 2015 40 4 493 496 04 3 2015 12 8 2015 Copyright © Central European Journal of Immunology 20162016This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon, life-threatening drug reaction. The basic findings are skin rash, multiorgan involvement, and eosinophilia. Most of the aromatic anticonvulsants, such as phenytoin, phenobarbital and carbamazepine can induce DRESS. Herein we report a 14-year-old patient with DRESS syndrome related to carbamazepine use. The patient presented with signs of involvement of the skin, lungs, liver, and microscopic hematuria. Carbamazepine treatment was discontinued; antihistamines and steroids were started. Hyperglycemia, commencing on the first dose of the steroid given, persisted even after the discontinuation of steroids and improvement of other signs. There were no signs of pancreatitis or type 1 diabetes clinically in laboratory tests. Her blood glucose levels were regulated at first with insulin and later with metformin. Within 1 year of follow-up, still regulated with oral antidiabetics, she has been diagnosed with type 2 diabetes. Formerly, long-term sequelae related to “drug rash with eosinophilia and systemic symptoms syndrome” such as hepatic and renal failure, type 1 diabetes mellitus, Grave's disease, autoimmune hemolytic anemia, and lupus have also been reported. However, up to date, no cases with type 2 diabetes have been reported as long-term sequelae. To our knowledge, this is the first case in the literature presenting with type 2 diabetes as long-term sequelae.\n\nDRESS syndromecarbamazepinepneumoniatype 2 diabetes\n==== Body\nIntroduction\nDrug rash with eosinophilia and systemic symptoms (DRESS) syndrome was first described by Bocquet et al. in 1996. DRESS is a life-threatening and seldom-seen drug reaction. The incidence has reported as ranging from 1/1000 to 1/10 000 [1]. Reactions to numerous drugs leading to DRESS syndrome have been observed. However, the most frequent causes are anticonvulsants, sulfonamides, dapsone, allopurinol, minocycline, and gold salts [1–3]. In addition to hematologic, hepatic, cardiac, neurological, gastrointestinal, and endocrine abnormalities, pulmonary involvement is observed rarely [1]. In this study, DRESS syndrome was presented with multiorgan involvement based on carbamazepine use in a 14-year-old female patient. Pulmonary involvement presented in the form of pleurisy and atelectasis, different from the literature, and as a long-term sequela, type 2 diabetes was observed in our case.\n\nCase report\nA 14-year-old female patient presented at our clinic due to skin rash and fever lasting for 1 week. It was found in her history that carbamazepine treatment had been initiated owing to epilepsy 15 days before her symptoms began. There had been no transmitted chronic disease history such as viral, bacterial, or parasitic infection before the patient's reaction in question. On the physical examination, she had 38.5°C core temperature, and there was a bilateral crepitant rale condition determined by listening on her respiratory system examination. No lymphadenopathy was determined at the organomegaly and pathologic level. In the dermatological examination, there were maculopapular rashes in the process of healing with desquamation that involved > 50% of the body (Fig. 1A). Her WBC was 24 000/mm3 (eosinophil 23%), ALT was 91 IU/L, and GGT was 123 IU/L. There was microscopic hematuria in her total urinalysis. In the viral serological evaluation of the case, Ebstein-Barr virus (EBV), herpes virus type 1-2, hepatitis A-B-C virus, HIV, and toxoplasma were established as negative. Anti-nuclear antibodies (ANA) and Anti ds-DNA were negative. Immunoglobulins, C3 and C4 levels, urinalysis were normal. In the punch biopsy obtained from the skin lesions, lymphocyte infiltration was identified in the papillary dermis (Fig. 1B). Due to the drug intake history and the clinical, laboratory, and histopathological findings, carbamazepine treatment was discontinued in our patient. Desloratadine antihistaminic 5 mg/day treatment and systemic steroid 1 mg/kg/day (40 mg/day) were added to the therapy. Owing to the chest pain and the reduction in lung sounds in basals and since the sinuses were monitored as closed in the chest radiography, thorax ultrasonography was carried out, and bilateral pleural effusion 6 mm thick was determined. In the thorax CT performed on the patient, a local consolidated area in the middle lobe segment of the right lung, atelectatic changes in the lower lobes of both lungs, and thickness in the left fissure were seen. Since there was symptomatic hyperglycemia on the second day of steroid treatment, the steroid was discontinued. The patient was found hyperglycemic (fasting blood glucose: 120-180 mg/dl, postprandial blood glucose:160-250 mg/dl). The 33-year-old mother was diagnosed with type 2 diabetes at the age of 26 years. Physical examination revealed a weight of 52.8 kg (64th percentile, 0.38 SDS), a height of 151 cm (8 percentile, –1.38 SDS), body mass index of 23.56 (1.52 SDS) and normal vital signs. Islet cells cytoplasmic autoantibodies (ICA) were negative as tested by indirect immunofluorescence and her glutamic acid decarboxylase autoantibodies (GADA), which was measured by radioimmunoassay, were also negative and fasting levels of C-peptide and insulin (Electrochemiluminescent immunoassay; Roche Diagnostics, Penzberg, Germany) remained detectable throughout the observation period (C-peptide 2.1-6.23 ng/ml). With an HbA1c value of 8.6%, she was diagnosed with diabetes mellitus. The combination of long-standing non-ketotic hyperglycemia, glycosuria, at a relatively high fasting and postprandial blood glucose, and negative pancreatic auto-antibodies in a child with a diabetic mother raised the possibility of MODY. Direct DNA sequencing of all exons and intron-exon bounders of the MODY genes revealed no mutation in our patient. Insulin treatment was carried out due to persisting hyperglycemia. Insulin treatment was discontinued as the hyperglycemia disappeared, and metformin treatment was initiated with the type 2 diabetes diagnosis. The patient was discharged from the hospital after the lung, skin, liver, and renal findings regressed. A patch test was performed with carbamazepine 10% concentration 6 weeks later. As a result of the evaluation carried out 48, 72, and 96 h later, +1 sensitivity was determined (Fig. 2). Although the skin, liver, renal and lung findings resolved during the 1-year follow-up period, regulation of type 2 diabetes with an oral antidiabetic continued.\n\nFig. 1 A) Maculopapular lesion in the recovery process with desquamation on the erythematous base. B) Skin biopsy determined by lymphocytic infiltration in the papillary dermis\n\nFig. 2 Epicutaneous patch test with carbamazepine\n\nDiscussion\nDRESS syndrome, known as drug hypersensitivity syndrome, is a quite rare acute, idiosyncratic, and life-threatening drug reaction characterized by fever, skin rash, and single or multiple internal organ involvement [3, 4]. There is an average 3- to 9-week latent period (0.5-16 weeks) between drug use and the emergence of symptoms [5]. These findings can persist or exacerbate although the responsible drug is discontinued [1, 3, 5]. Fever, skin rash, liver involvement, hypereosinophilia, and lymphadenopathy can be seen in almost all patients. Symptoms had appeared 2 weeks after carbamazepine treatment was initiated in our patient. There was pulmonary involvement presented by pulmonary atelectasia and pleurisy as well as maculopapular rash, fever, and hypereosinophilia, liver involvement manifested with transaminase elevation, and renal involvement was characterized by microscopic hematuria in the case.\n\nThe pathophysiology of DRESS syndrome has not been entirely clarified yet. It has been suggested that there is a delayed hypersensitivity reaction related to T lymphocytes against toxic metabolites of drugs, and viral infections (EBV, human herpes virus, types 6 and 7) can also play a role in the etiology. It has been reported in the literature that there can be a genetic predisposition, and families of patients diagnosed with DRESS syndrome are also at risk in terms of this syndrome. It has been maintained in recent years that human herpes virus type 6 reactivation can also be used as a diagnostic marker [1, 3, 6, 7]. The viral serological study carried out in our patient was identified as negative. No similar history was established in her family. The positive result on the patch test with carbamazepine conducted 6 weeks later supports that there was a delayed hypersensitivity reaction.\n\nThe main principle in the treatment of DRESS syndrome is to discontinue the drug or drugs thought to be suspicious immediately and provide supportive care. Steroid and IVIG can be utilized in the treatment. Systemic steroid is particularly recommended in internal organ involvement [2, 3, 7]. It has also been stated in cases that parenteral pulse steroid treatment is beneficial [8]. Systemic steroid and antihistamine treatment were applied to our patient. Hyperglycemia thought to be dependent on steroid treatment in the first place preceded although steroid treatment was discontinued and insulin treatment had to be commenced. Type 1 diabetes and pancreatitis have been reported in patients with DRESS syndrome in the literature [6, 9]. However, our patient's lipase level was normal, and no laboratory finding supporting type 1 diabetes was diagnosed in our patient. Although the hyperglycemia finding in the patient was not linked to DRESS syndrome in the first place, it was evaluated as DRESS syndrome related to type 2 diabetes by the endocrine department since it had a clinical table regulated by oral antibiotic in 1-year follow-up period.\n\nIn the literature, various long-term sequelae concerning DRESS syndrome have been observed. In a study by Chen et al. [9], a long-term sequelae rate was reported as 11.5% in analyses of 52 patients of whom 9 were lost and 43 recovered. The researchers reported that a total of 4 patients had autoimmunity disease, including 2 with Grave's disease, 1 with type 1 diabetes, and 1 with autoimmune hemolytic anemia. They also observed that lifetime hemodialysis was necessary due to renal failure in 2 patients with organ involvement. In a study in which 34 patients were evaluated, however, the researchers reported that autoimmune disease developed in 2 patients, including 1 with lupus erythematosus and 1 with autoimmune thyroiditis [10]. Duboıs-Laforgue et al. [11] reported 11 patients with type 1 diabetes related to DRESS syndrome and observed that half of the patients developed non-autoimmune fulminant type 1 diabetes. However, no case of type 2 diabetes associated with DRESS syndrome has been reported thus far. To the best of our knowledge, this case is the first in whom DRESS syndrome initially developed followed by type 2 diabetes.\n\nDRESS syndrome is an acute, life-threatening, and rarely seen drug reaction. It should be considered a definitive diagnosis in patients with fever, diffuse skin rash, and internal organ involvement. The drugs used by patients should be questioned. It should be kept in mind that a variety of organ involvement as well as long-term sequelae can also be seen in patients with DRESS syndrome. Our case showed that one of these sequelae could be type 2 diabetes.\n\n\nAuthors declare no conflict of interest.\n==== Refs\nReferences\n1 Cacoub P Musette P Descamps The DRESS Syndrome: A Literatüre Review Am J Med 2011 124 588 597 21592453 \n2 Lee JH Park HK Heo J Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Syndrome Induced by Celecoxib and Anti-tuberculosis Drugs J Korean Med Sci 2008 23 521 525 18583892 \n3 Giri PP Roy S Bhattyacharya S DRESS Syndrome With Sepsıs, Acute Respıratory Dıstress Syndrome And Pneumomedıastınum Indian J Dermatol 2011 56 763 765 22345792 \n4 Bourgeois GP Cafardi JA Groysman V Hugey LC A review of DRESS-associated myocarditis J Am Acad Dermatol 2012 66 229 236 21596455 \n5 Alkhateeb H Said S Cooper CJ DRESS syndrome following ciprofloxacin exposure: An unusual association Am J Case Rep 2013 14 526 528 24340128 \n6 Zou CC Liang L Fu JF Type 1 diabetes mellitus in a child with phenobarbital hypersensitivity syndrome J Endocrinol Invest 2008 31 360 363 18475056 \n7 Omairi NE Abourazzak S Chaouki S Drug reaction with eosinophilia and systemic symptoms (DRESS) induced by carbamazepine: a case report and literature review Pan African Medical Journal 2014 18 9 \n8 Natkunarajah J Goolamali S Craythorne E Ten cases of drug reaction with eosinophilia and systemic symptoms (DRESS) treated with pulsed intravenous methylprednisolone Eur J Dermatol 2011 21 385 391 21527371 \n9 Chen YC Chang CY Cho YT Long-term sequelae of drug reaction with eosinophilia and systemis symptoms: a retrospective cohort study from Taiwan J Am Acad Dermatol 2013 68 459 465 22959230 \n10 Ushigome Y Kano Y Ishida T Short and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution J Am Acad Dermatol 2013 68 721 728 23182063 \n11 Dubois-Laforgue D Moachon L Laude H Timsit J Fulminant type 1 diabetes in the course of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome Diabetes Care 2013 36 68\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1426-3912",
"issue": "40(4)",
"journal": "Central-European journal of immunology",
"keywords": "DRESS syndrome; carbamazepine; pneumonia; type 2 diabetes",
"medline_ta": "Cent Eur J Immunol",
"mesh_terms": null,
"nlm_unique_id": "9702239",
"other_id": null,
"pages": "493-6",
"pmc": null,
"pmid": "26862317",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "21658796;25360193;21527371;23613608;22959230;18583892;24340128;18475056;21592453;22345792;23182063",
"title": "DRESS syndrome associated with type 2 diabetes in a child.",
"title_normalized": "dress syndrome associated with type 2 diabetes in a child"
} | [
{
"companynumb": "TR-ACTAVIS-2016-02535",
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"abstract": "The 7.5% icodextrin solution is widely used for long-dwell in peritoneal dialysis (PD) regimens as an alternative osmotic agent to glucose. It has been defined as a biocompatible agent because of its iso-osmolarity and is generally safe and well tolerated. Icodextrin and its hydrolyzed metabolites are found in systemic circulation. In serum, icodextrin interferes with amylase determination causing a significantly decreased plasma amylase level making it unreliable for the diagnosis of acute pancreatitis. Lipase measurement provides an alternative and accurate method for diagnosing acute pancreatitis (AP) in patients using icodextrin. Icodextrin-induced acute pancreatitis is not well described. The literature appears limited to two case reports. We describe a case of a man with end-stage renal disease (ESRD) on PD who developed acute pancreatitis following icodextrin use. We also provide a novel possible mechanism for understanding how icodextrin causes AP.
.",
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"mesh_terms": "D015314:Dialysis Solutions; D005936:Glucans; D005947:Glucose; D006801:Humans; D000077607:Icodextrin; D007676:Kidney Failure, Chronic; D008297:Male; D010195:Pancreatitis; D010530:Peritoneal Dialysis",
"nlm_unique_id": "0364441",
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"title": "Icodextrin-induced acute pancreatitis in a peritoneal dialysis patient: a case report and literature review
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"title_normalized": "icodextrin induced acute pancreatitis in a peritoneal dialysis patient a case report and literature review"
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"abstract": "Hepatitis B virus (HBV) reactivation in chronic hepatitis C (CHC) patients treated with direct-acting antivirals (DAAs) became an issue. However, its frequency has been poorly estimated, because of the varying definitions used and evaluation of heterogeneous study populations, including those concurrently treated for HBV.\n\n\n\nWe prospectively followed HBV surface antigen (HBsAg)-positive Egyptians undergoing interferon-free DAAs, to estimate the risk of HBV reactivation and HBV-related hepatitis. We also conducted a meta-analysis to estimate the reactivation risk using published data obtained from a systematic review of PubMed/Embase, in addition to our Egyptian data. We applied a standard definition of HBV reactivation proposed by the international liver associations (APASL and AASLD).\n\n\n\nOf 4471 CHC patients, 35 HBsAg-positive patients started interferon-free DAAs without HBV nucleos(t)ide analogues in our Egyptian cohort. Ten experienced HBV reactivation (28.6%), of whom 1 developed hepatitis (10.0%). Our systematic review identified 18 papers. The pooled reactivation risk in HBsAg-positive patients was 18.2% (95% CI: 7.9%-30.7%) without HBV therapy and 0.0% (95% CI: 0.0%-0.0%) with HBV nucleos(t)ide analogue. The pooled risk of hepatitis in those with HBV reactivation was 12.6% (95% CI: 0.0%-34.7%). The pooled reactivation risk in HBsAg-negative, antibody to HBV core antigen-positive (anti-HBc-positive) patients was negligible (0.1%, 95% CI: 0.0%-0.3%), irrespective of the presence of antibody to HBsAg (anti-HBs).\n\n\n\nWe confirmed high HBV reactivation risk in HBsAg-positive patients undergoing DAAs, with only a minority developing clinically important hepatitis. The risk is negligible for HBsAg-negative anti-HBc-positive patients.",
"affiliations": "Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt.;Unité d'Epidémiolotie des Maladies Emergentes, Institut Pasteur, Paris, France.;Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.;Unité d'Epidémiolotie des Maladies Emergentes, Institut Pasteur, Paris, France.;Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt.;Department of Tropical Medicine, Faculty of Medicine, Al-Azhar University, Damietta, Egypt.;Department of Tropical Medicine, Faculty of Medicine, Al-Azhar University, Damietta, Egypt.;Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.;Unité d'Epidémiolotie des Maladies Emergentes, Institut Pasteur, Paris, France.",
"authors": "El Kassas|Mohamed|M|0000-0002-3396-6894;Shimakawa|Yusuke|Y|0000-0002-4198-4785;Ali-Eldin|Zainab|Z|;Funk|Anna-Louise|AL|0000-0003-2440-7553;Wifi|Mohamed Naguib|MN|;Zaky|Samy|S|;El-Raey|Fathiya|F|;Esmat|Gamal|G|;Fontanet|Arnaud|A|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D007372:Interferons",
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"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "direct-acting antivirals; hepatitis B; hepatitis C; reactivation",
"medline_ta": "Liver Int",
"mesh_terms": "D000998:Antiviral Agents; D060085:Coinfection; D004279:DNA, Viral; D004534:Egypt; D005260:Female; D016174:Hepacivirus; D006509:Hepatitis B; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D019698:Hepatitis C, Chronic; D006801:Humans; D007372:Interferons; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011446:Prospective Studies; D014775:Virus Activation",
"nlm_unique_id": "101160857",
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"references": null,
"title": "Risk of hepatitis B virus reactivation with direct-acting antivirals against hepatitis C virus: A cohort study from Egypt and meta-analysis of published data.",
"title_normalized": "risk of hepatitis b virus reactivation with direct acting antivirals against hepatitis c virus a cohort study from egypt and meta analysis of published data"
} | [
{
"companynumb": "EG-GILEAD-2019-0384407",
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"activesubstancename": "SOFOSBUVIR"
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... |
{
"abstract": "Insomnia and parasomnias are common patient complaints during hospital stay. New environment, the severity of underlying disease, level of care, medications, and infections are all known factors that contribute toward insomnia. Zolpidem is a common sleep aid used for this purpose. We report a case of Zolpidem-induced visual hallucination in a septuagenarian in the inpatient setting.",
"affiliations": "Internal Medicine, University of California San Francisco, Fresno, USA.",
"authors": "Mian|Raza|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.3848",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3848Family/General PracticeInternal MedicineNeurologyVisual Hallucinations from Zolpidem Use for the Treatment of Hospital Insomnia in a Septuagenarian Muacevic Alexander Adler John R Mian Raza 1\n1 \nInternal Medicine, University of California San Francisco, Fresno, USA \nRaza Mian raza.mian@outlook.com8 1 2019 1 2019 11 1 e384818 12 2018 4 1 2019 Copyright © 2019, Mian et al.2019Mian 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/16858-visual-hallucinations-from-zolpidem-use-for-the-treatment-of-hospital-insomnia-in-a-septuagenarianInsomnia and parasomnias are common patient complaints during hospital stay. New environment, the severity of underlying disease, level of care, medications, and infections are all known factors that contribute toward insomnia. Zolpidem is a common sleep aid used for this purpose. We report a case of Zolpidem-induced visual hallucination in a septuagenarian in the inpatient setting.\n\nzolpidemambienhallucinationinsomniaThe 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\nInsomnia is a common complaint in the inpatient setting. Increasing age, disease severity, underlying psychiatric condition, pain, location, and medications contribute to insomnia. Therapies include non-pharmacological and pharmacological interventions. Sleep aids make the cornerstone of pharmacological interventions. The use of sleep aids in the inpatient setting is also common. These include sedating antihistamines, melatonin, antidepressants, and antipsychotics. Zolpidem is a commonly used sleep aid. We report a case of Zolpidem-induced visual hallucination in a patient in his seventies.\n\nCase presentation\nA septuagenarian patient presented to the hospital with a complaint of worsening back pain. He had a pertinent previous medical history of recently diagnosed multiple myeloma. He reported sudden-onset, non-traumatic, spontaneous, mid-to-low, non-radiating, midline back pain that started two weeks ago. He denied association with bladder or bowel dysfunction, lower-extremity weakness, or paresthesia. His primary care provider had prescribed him non-steroidal anti-inflammatory agents without significant improvement. On presentation, he remained afebrile with normal vital signs. He had no saddle analgesia and a normal rectal tone. Post-void urinary bladder ultrasound revealed an empty bladder. He had a normal and symmetric sensation to light touch, vibration, and temperature. Patellar reflexes were normal and he had a normal Babinski's test. Hematological lab tests revealed microcytic anemia. Imaging studies revealed a compression fracture of the ninth and tenth thoracic vertebrae. Neurosurgery evaluated the patient recommending against surgical fixation. A spinal brace was provided to assist with comfort. Radiation oncology evaluated the patient and a decision was made to pursue radiation therapy.\n\nThe patient complained of insomnia during the hospital stay and was prescribed Zolpidem of 5 mg. At six o'clock, the next morning, the patient was noticed by nursing staff to be delirious reporting seeing graphic looking cats on the wall. Conservative measures and reorientation led to the subsequent resolution of the symptoms over a period of 10 minutes. The patient had complete recollection of the event. During the subsequent hospital stay, no further doses of Zolpidem were administered. No further episodes of visual hallucination occurred. \n\nDiscussion\nInsomnia is a common patient complaint in the inpatient setting [1]. Various risk factors are known in this setting, which can contribute to insomnia, including disease severity, poor quality or amount of sleep, new environment, and disturbed wake-sleep cycle, lack of exercise, medications, and infections [2]. Hospital-acquired delirium shares some of the same risk factors [3]. Treatment is sought by employing non-pharmacological and pharmacological tools. These include improved daytime lighting including sunlight exposure, ambulation, reduced nighttime disturbance, and continued treatment of the underlying disease process [4]. However, many times, non-pharmacological aids are supplemented by pharmacological agents. Commonly employed agents include melatonin, sedative-hypnotics, antidepressants, and antipsychotic agents [5]. Zolpidem is a commonly used sedative-hypnotic.\n\nThe common side effects of Zolpidem include a headache, drowsiness, dizziness, lethargy, depression, and constipation. Severe side effects of Zolpidem include suicidal ideation, aggressive behavior, impaired mental alertness the following day, hallucinations, amnesia, anaphylaxis, angioedema, and withdrawal [6-9].\n\nThis case report discussed visual hallucination in a patient with risk factors associated with disturbed inpatient sleep and hospital delirium. Zolpidem was used as a sleep aid. Subsequently, hallucinations and delirium were noticed. Brodeur et al. reported a case of an octagenarian patient with a similar hallucination side effect; however, the symptoms lasted longer [10]. The impact on patient health during these episodes can be varied. There have been reports of somnambulism as well as homicide [11]. Advanced, female gender, concomitant use of selective serotonin reuptake inhibitors (SSRI), and Zolpidem dosage >10 mg have been reported to be associated with hallucinogenic side effects of Zolpidem; however, it can be seen in the younger population as well [10-13].\n\nAlthough relatively safe, it is important to identify and recognize the potential side effects of this drug. Caution is advised in the at-risk population.\n\nConclusions\nInsomnia is a common inpatient complaint. Symptomatic management with the use of sleep aids is common, and Zolpidem is a commonly used agent. Visual hallucinations can occur after Zolpidem administration. At-risk patients should avoid Zolpidem as a sleep agent.\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 Pharmacists interventions to reduce sedative/hypnotic use for insomnia in hospitalized patients Saudi Pharm J Badr AF Kurdi S Alshehri S McManus C Lee J 1204 1207 26 2018 30510473 \n2 Delirium: is sleep important? Best Pract Res Clin Anaesthesiol Watson PL Ceriana P Fanfulla F 355 366 26 2012 23040286 \n3 Delirium in older persons: evaluation and management Am Fam Physician Virginia BK Joseph EG Brian KU 150 158 90 2014 https://www.aafp.org/afp/2014/0801/p150.html 25077720 \n4 Nonpharmacological treatments of insomnia for long-term painful conditions: a systematic review and meta-analysis of patient-reported outcomes in randomized controlled trials Sleep Tang NK Lereya ST Boulton H Miller MA Wolke D Cappuccio FP 1751 1764 38 2015 25902806 \n5 Guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline J Clin Sleep Med Sateia MJ Buysse DJ Krystal AD Neubauer DN Heald JL 307 349 13 2017 27998379 \n6 Spontaneous adverse event reports associated with zolpidem in the United States 2003-2012 J Clin Sleep Med Wong CK Marshall NS Grunstein RR 223 234 13 2017 http://dx.doi.org/10.5664/jcsm.6452 27784418 \n7 Zolpidem-induced hallucinations: a brief case report from the Indian subcontinent Indian J Psychol Singh G Loona N 212 213 35 213 http://www.ijpm.info/article.asp?issn=0253-7176;year=2013;volume=35;issue=2;spage=212;epage=213;aulast=Singh \n8 A novel clinical pattern of visual hallucination after zolpidem use J Toxicol Clin Toxicol Tsai MJ Huang YB Wu PC 869 872 41 2003 https://www.ncbi.nlm.nih.gov/pubmed/14677799 14677799 \n9 Zolpidem in insomnia: a 3-year post-marketing surveillance study in Switzerland J Int Med Res Ganzoni E Santoni J Chevillard V Sébille M Mathy B 61 73 23 1995 https://journals.sagepub.com/doi/10.1177/030006059502300108 7774760 \n10 Delirium associated with zolpidem Ann Pharmacother Brodeur MR Stirling AL 1562 1564 35(12 35 2001 11793620 \n11 Two cases of zolpidem-associated homicide Prim Care Companion CNS Disord Paradis CM Siegel LA Kleinman SB 14 2012 \n12 Adverse reactions to zolpidem: case reports and a review of the literature Prim Care Companion J Clin Psychiatry Inagaki T Miyaoka T Tsuji S Inami Y Nishida A Horiguchi J 0 12 2010 \n13 Multimodal hallucination (audio-visual, kinaesthetic and scenic) associated with the use of zolpidem Clin Psychopharmacol Neurosci Ram D Eiman N Gowdappa B 215 217 13 2015 26243852\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(1)",
"journal": "Cureus",
"keywords": "ambien; hallucination; insomnia; zolpidem",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e3848",
"pmc": null,
"pmid": "30891388",
"pubdate": "2019-01-08",
"publication_types": "D002363:Case Reports",
"references": "11793620;14677799;21494350;23040286;23251862;24049236;25077720;25902806;26243852;27784418;27998379;30510473;7774760",
"title": "Visual Hallucinations from Zolpidem Use for the Treatment of Hospital Insomnia in a Septuagenarian.",
"title_normalized": "visual hallucinations from zolpidem use for the treatment of hospital insomnia in a septuagenarian"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP007338",
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZOLPIDEM TARTRATE"
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{
"abstract": "OBJECTIVE\nTo determine the survival of infants and young children with non-metastatic medulloblastoma using intensive myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR).\n\n\nMETHODS\nTwenty-one children less than 3 years old at diagnosis with non-metastatic medulloblastoma were enrolled on two identical serial studies, \"Head Start\" I and \"Head Start\" II. After surgery, patients received five cycles of induction chemotherapy consisting of vincristine, cisplatin, cyclophosphamide and etoposide. Following induction, all patients underwent myeloablative chemotherapy using carboplatin, thiotepa and etoposide with AuHCR. Irradiation was used only at relapse.\n\n\nRESULTS\nThe 5-year event-free (EFS) and overall survival (OS) rates (+/-SE) for all patients, patients with gross total resection, and patients with residual tumor were 52 +/- 11% and 70 +/- 10%, 64 +/- 13% and 79 +/- 11%, and 29 +/- 17% and 57 +/- 19%, respectively. The 5-year EFS and OS ( +/- SE) for patients with desmoplastic and classical medulloblastoma were 67 +/- 16% and 78 +/- 14%, and 42 +/- 14 and 67 +/- 14%, respectively. There were four treatment related deaths. The majority of survivors (71%) avoided irradiation completely. Mean intellectual functioning and quality of life (QoL) for children surviving without irradiation was within average range for a majority of survivors tested.\n\n\nCONCLUSIONS\nThis strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning. The excellent survival rates are somewhat dampened by high toxic mortality.",
"affiliations": "Childrens Hospital Los Angeles, Los Angeles, California, USA. gdhall@chla.usc.edu",
"authors": "Dhall|Girish|G|;Grodman|Howard|H|;Ji|Lingyun|L|;Sands|Stephen|S|;Gardner|Sharon|S|;Dunkel|Ira J|IJ|;McCowage|Geoffrey B|GB|;Diez|Blanca|B|;Allen|Jeffrey C|JC|;Gopalan|Anjali|A|;Cornelius|Albert S|AS|;Termuhlen|Amanda|A|;Abromowitch|Minnie|M|;Sposto|Richard|R|;Finlay|Jonathan L|JL|",
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"issn_linking": "1545-5009",
"issue": "50(6)",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002528:Cerebellar Neoplasms; D002652:Child Behavior; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D007361:Intelligence Tests; D008297:Male; D008527:Medulloblastoma; D009483:Neuropsychological Tests; D011788:Quality of Life; D015996:Survival Rate",
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"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the \"Head Start\" I and II protocols.",
"title_normalized": "outcome of children less than three years old at diagnosis with non metastatic medulloblastoma treated with chemotherapy on the head start i and ii protocols"
} | [
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"abstract": "Postural orthostatic tachycardia syndrome (POTS) is a debilitating disease that predominantly affects young women. It is a multifactorial disorder that is characterized by severe tachycardia and orthostatic intolerance. Patients with POTS experience a variety of cardiac, neurological, and immunological symptoms that significantly reduce quality of life. In this review, a comprehensive framework is provided to aid in helping identify and treat patients with POTS. Given its heterogenous nature, it is crucial to understand each component of POTS in relation to one another instead of distinct parts. The framework highlights the overlap among the five main subtypes of POTS based on its pathophysiology (neuropathic, hypovolemic, primary hyperadrenergic, joint-hypermobility-related, and immune-related). Emphasis is placed on incorporating a multidisciplinary approach when treating patients with POTS, especially with a new focus towards immunotherapy. Although research has advanced our knowledge of POTS, there is still a critically unmet need to further our understanding and provide patients with the relief they need.",
"affiliations": "Division of Cardiovascular Medicine, University of California San Diego, 9300 Campus Point Drive MC 7411, La Jolla, CA, 92037, USA.;Division of Rheumatology, Allergy, and Immunology, University of California San Diego, La Jolla, CA, USA.;Division of Cardiovascular Medicine, University of California San Diego, 9300 Campus Point Drive MC 7411, La Jolla, CA, 92037, USA.;Division of Cardiovascular Medicine, University of California San Diego, 9300 Campus Point Drive MC 7411, La Jolla, CA, 92037, USA. ptaub@ucsd.edu.",
"authors": "Zadourian|Adena|A|;Doherty|Taylor A|TA|;Swiatkiewicz|Iwona|I|;Taub|Pam R|PR|http://orcid.org/0000-0002-0684-0655",
"chemical_list": null,
"country": "New Zealand",
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"issue": "78(10)",
"journal": "Drugs",
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"medline_ta": "Drugs",
"mesh_terms": "D015673:Fatigue Syndrome, Chronic; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D054971:Orthostatic Intolerance; D054972:Postural Orthostatic Tachycardia Syndrome; D011788:Quality of Life",
"nlm_unique_id": "7600076",
"other_id": null,
"pages": "983-994",
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"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "14981179;16301478;12010910;24721800;26198889;19207771;17709712;2160509;21690484;17303993;22041891;18805903;19808400;20460983;10037112;27729043;22795533;27702852;25980576;24685354;10750641;21509337;21906029;26245264;22143364;16221781;23720636;10684912;23753844;10995864;23562385;21431947;29343965;26690066;20579544;27563801;15710782;18506020;19687359;10518084;23472781;28780942;25156902;23002038;22331415;7884158;23358630;23538032;27617091;25001527;11018167;20376184;19506222;7081280;9244228;26092297;15911704;20035362;28160388;17110507;8423877;16943900;21062792;26979650;21410722;29357955;18704621;12133874;15781744;24572257;10037110;28161150;26399744;1387890;6295714;9815870;770030;17036177;3511818;28352654;26846691;29618472;12867232;26132314;29403541;10373232;28738696;11150109;18977825;17352367",
"title": "Postural Orthostatic Tachycardia Syndrome: Prevalence, Pathophysiology, and Management.",
"title_normalized": "postural orthostatic tachycardia syndrome prevalence pathophysiology and management"
} | [
{
"companynumb": "US-TEVA-2018-US-938925",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDROCORTISONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAplasia cutis congenita is a disorder where e newborn child is missing skin from certain areas. It is a rare condition with no particular race or sex more at risk. May occur by itself or be associated with other physical syndromes or disorders. A classification system exists for aplasia cutis congenital consisting of 9 groups, based on the number and location of the skin defects and the presence or absence of other malformations. Causes of aplasia congenital could be heredity, teratogenic substances, placental infarcts, intrauterine infections, ectodermal dysplasias etc. Diagnosis is made based on the clinical findings. Prognosis depends of the other organs malfunction level and lesions size.\n\n\nMETHODS\nOur case was an 22 months old Albanian girl, who was recommended to dermatology for a consultation by a pediatric surgeon because of the changes she had on her parietal part of the scalp with missing hair areas. The child has stenosis congenita ani and to her was installed stoma. In order to investigate other accompanied anomalies of the disease, there are made specific consults by neurologist, orthopedist, cardiologist, nephrologists and citogenetics.\n\n\nCONCLUSIONS\nIt was found out a minor visual discoordination, Sy Floppy, Digiti V superductus pedis bill. Laxitas articularum generalisata. It was a great challenge for us to find out that during the first trimester of the pregnancy (unplanned pregnancy), her mother used Diclofenac. Since there is limited information regarding to teratogenic effects of diclofenac, we considered it interesting to present this case.",
"affiliations": "Department of Dermatology, University Clinical Centre of Kosovo, Prishtina, Republic of Kosovo. laurapajaziti@yahoo.com",
"authors": "Pajaziti|Laura|L|;Rexhepi|Syzana|S|;Shatri-Muça|Ylfete|Y|;Ferizi|Mybera|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1757-1626-2-150",
"fulltext": "\n==== Front\nCases JCases Journal1757-1626BioMed Central 1757-1626-2-1501994652110.1186/1757-1626-2-150Case ReportThe role of diclofenack on inducing of aplasia cutis congenita: a case report Pajaziti Laura 1laurapajaziti@yahoo.comRexhepi Syzana 1syzanarexhepi@hotmail.comShatri-Muça Ylfete 1grelorgen@yahoo.comFerizi Mybera 1myberaf@hotmail.com1 Department of Dermatology, University Clinical Centre of Kosovo, Prishtina, Republic of Kosovo2009 12 10 2009 2 150 150 16 9 2009 12 10 2009 Copyright ©2009 Pajaziti et al; licensee BioMed Central Ltd.2009Pajaziti et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nAplasia cutis congenita is a disorder where e newborn child is missing skin from certain areas. It is a rare condition with no particular race or sex more at risk. May occur by itself or be associated with other physical syndromes or disorders. A classification system exists for aplasia cutis congenital consisting of 9 groups, based on the number and location of the skin defects and the presence or absence of other malformations. Causes of aplasia congenital could be heredity, teratogenic substances, placental infarcts, intrauterine infections, ectodermal dysplasias etc. Diagnosis is made based on the clinical findings. Prognosis depends of the other organs malfunction level and lesions size.\n\nCase report\nOur case was an 22 months old Albanian girl, who was recommended to dermatology for a consultation by a pediatric surgeon because of the changes she had on her parietal part of the scalp with missing hair areas. The child has stenosis congenita ani and to her was installed stoma. In order to investigate other accompanied anomalies of the disease, there are made specific consults by neurologist, orthopedist, cardiologist, nephrologists and citogenetics.\n\nConclusion\nIt was found out a minor visual discoordination, Sy Floppy, Digiti V superductus pedis bill. Laxitas articularum generalisata.\n\nIt was a great challenge for us to find out that during the first trimester of the pregnancy (unplanned pregnancy), her mother used Diclofenac.\n\nSince there is limited information regarding to teratogenic effects of diclofenac, we considered it interesting to present this case.\n==== Body\nIntroduction\nAplasia cutis congenita is one of the disorders of the skin embrional development. It is characterized by a limited defect of the skin where the skin layers and its adnexes are not created. This feature is rare, about 1 in 3000 alive born children [1-3].\n\nExcept sporadic cases, there are familiar cases, which are explained by autosomal -dominant heredity [4]. Causes of aplasia could be teratogenic substances, placental infarcts, intrauterine infections, ectodermal displasias etc [5,6].\n\nThe disorders during the skin development can include one or all skin layers. Sometimes the other deep structures like fascia, ossa and dura are missing (which can be followed by different cosmetic defects of the skin until the deformities incompatible with life). Aplasia cutis congenita is manifested by the defects of the skin mostly oval, 1-3 cm in diameter, with localization on the parietal part of scalp (60%) and rarely on the face and extremities. It belongs to the group of congenital cicatricial alopecia. Aplasia cutis congenita can be associated by a lot of anomalies as: labium leporinum, polycystic kidneys, psychomotor retardation, developing disorders of the eyes, spinal cord, ears, chromosomal aberationes, cutis marmorata, congenital organoid nevus on the scalp and face, anomalies on extremities, intestines and genital organs. Based on the presence of these anomalies and their association with the other diseases as bullous epidermolysis, growth and development stagnation, etc, congenital aplasias of the skin are classified in 9 groups.\n\nDiagnosis is made based on the clinical findings, and the histopathology is not necessary.\n\nPrognosis depends of the other organs malfunction level and lesions size.\n\nThe lesions can resolve spontaneously, but sometimes is needed surgery operation (punch-graft-transplant).\n\nCase presentation\nPatient aged 22 months, Albanian female, hospitalized in Clinic, by pediatric surgeon recommendation, because of the changes on the scalp with missing hair areas. This alteration persists from the birth without tendency for shape changing.\n\nOn the parietal part of the scalp appear two oval shaped areas without hair, confluated, with light depth and shinny bases (Figure 1).\n\nFigure 1 The parietal part of the scalp appear two oval shaped areas without hair, confluated, with light depth and shinny bases.\n\nHer mother mentioned that during the first trimester of the pregnancy (she did not know that she was pregnant) has taken Diclofenac amp. (five days) because she had abdominal pains. During pregnancy she did not have any infectious disease. Family history is negative.\n\nIn the surgery clinic the child was operated and treated under the diagnoses: Stenosis congenita ani and was installed stoma (Figure. 2). For associated defects in other organs, there are made specific consults.\n\nFigure 2 Installed stoma (anus praeternaturalis).\n\nConsultant orthopedist concluded the digiti V superductus pedis bilateralis, laxitas articularum generalisata and Sy Floppy (Figure 3a and Figure 3b).Consultant neurologist indicated minor visualmotor discoordination. Cardiologists and nephrolog consulting resulted on the common stage. Citogenetic report has shown Cariotype 46, XX with no changes on the chromosome number and structure.\n\nFigure 3 a and b: Digiti V superductus pedis bill. Laxitas articularum generalisata Sy Floppy.\n\nThe routine laboratory examinations resulted with common values except the blood SE rate, which was increased (60/1 h). After the antibiotic ordination (Cephalexin sir. A 125 mg), the same fall down to 15/1 h. The patient was discharged home with recommendation to follow up the pediatric surgeon visits.\n\nConclusion\nAplasia cutis congenita is very rare anomaly (1:3000). Causes of congenital aplasia could be teratogenic substances [7]. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), commonly used by reproductive age women for the treatment of variety of conditions. NSAID inhibit the biosynthesis of prostanoids. Women may incidentally become pregnant while receiving NSAID therapy (unplanned pregnancy) [8]. The diclofenac crosses the placenta readily in the first trimester of human pregnancy resulting in a fetal diclofenac concentration. which is the same as the maternal serum concentration [9]. The drug may also accumulate in fetal tissue with time [9]. Usually diclofenac is given in multiple doses, so the possibility to reach teratogenic levels of fetal tissue concentrations is real in patients who are taking diclofenac. In our case the pregnant women received diclofenac 75 mg per day, five days. Diclofenac has also been shown to inhibit implantation and embryogenic development in rats when given on gestation day 5 [10]. A positive association between use of NSAID during pregnancy and miscarriages was reported by a study [11]. However, information regarding teratogenecity of NSAID during the critical period of organogenesis is lacking. Because aspirin and other NSAID share a similar mechanism of action (inhibition of prostaglandin synthesis) it was postulated that NSAID might induce congenital abnormalities when given during the critical period of organogenesis [12].\n\nWe present patient with aplasia cutis congenita accompanied by stenosis congenita ani, digiti V superductus pedis bill., laxitas articularum generalisata-sy Floppy and minor visualmotor discoordination. Based on mentioned studies and real clinical situation we concluded that Diclofenac used in early trimester of pregnancy might induce those abnormalities and considered reasonable to present this case.\n\nAbbreviations\nNSAID: non-steroidal anti-inflammatory drug; Sy: Syndrome.\n\nConsent\nWritten informed consent was obtained from the patient's mother for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nLP, SR, YSHM and MF analyzed and interpreted the patients' data. LP was a major contributor in writing the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to acknowledge Consultant Orthopedist, Cardiologists and Nephrology consulting, Neurologist, and Cytogenetist who contributed on provided information about the patient.\n==== Refs\nBraun-Falco O Plewig G Wolf HH Dermatology 1999 2 Springer \nKaradagliæ D Dermatologija Beograd 2000 \nMark A Crowe MD Aplasia cutis congenita 2006 \nChitnis MR Carachi R Galea P Familial aplasia cutis congenita Eur J Pediatr Sturg 1996 6 100 1 10.1055/s-2008-1066481 \nWhite G Levene's color atlas of Dermatology 1997 2 Mosby-Wolfe \nLipozencic J Dermatovenerologija Medicinska naklada Zagreb 1999 \nDobriæ I Dermatovenerologija Zagreb 2005 \nChan LY Chiu PY Siu SSN Lau TK A study of diclofenac - induced teratogenicity during organogenesis sing a whole rat embryo culture model Human Reproduction 2001 16 11 2390 2393 11679526 \nSiu SSN Yeung JHK Lau TK A study on placental transfer of diclofenac in first trimester of human pregnancy Human Reproduction 2000 15 11 2423 2425 10.1093/humrep/15.11.2423 11056146 \nCarp HJA Fein A Nebel L Effect of diclofenac on implantation and embryonic development in the rat Eur J Obstet Gynecol Reprod Biol 1988 28 273 277 10.1016/0028-2243(88)90038-X 3208969 \nNielsen GL Sorensen HT Larsen H Risk of adevrse birth outcome and miscarriage in pregnant users of non-steroidal anti inflammatory drugs: population based observational study and case control study Br Med J 2001 322 266 270 10.1136/bmj.322.7281.266 \nKlein KL Scott WJ Clark KE A possible mechanism of aspirin teratogenesis Teratology 1980 21 50 10.1002/tera.1420210211\n\n",
"fulltext_license": "CC BY",
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"issue": "2()",
"journal": "Cases journal",
"keywords": null,
"medline_ta": "Cases J",
"mesh_terms": null,
"nlm_unique_id": "101474272",
"other_id": null,
"pages": "150",
"pmc": null,
"pmid": "19946521",
"pubdate": "2009-10-12",
"publication_types": "D016428:Journal Article",
"references": "11056146;8740132;11679526;3208969;11157526",
"title": "The role of diclofenack on inducing of aplasia cutis congenita: a case report.",
"title_normalized": "the role of diclofenack on inducing of aplasia cutis congenita a case report"
} | [
{
"companynumb": "RS-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-114893",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drug... |
{
"abstract": "Pyoderma gangrenosum is a neutrophilic dermatosis clinically characterised by the presence of painful skin ulcerations with erythematous and undetermined borders and histologically by the presence of neutrophilic infiltrates in the dermis. Granulocyte and monocyte adsorption apheresis, also called granulocytapheresis, is a therapeutic strategy for extracorporeal immunomodulation that selectively removes activated granulocytes and monocytes/macrophages from the peripheral blood. Here, we report a case of a 73-year-old patient affected by a severe form of pyoderma gangrenosum presenting with multiple painful ulcers and pustules on his trunk and extremities. The disease was resistant to high doses of methylprednisolone and methotrexate and successfully treated by granulocyte and monocyte adsorption apheresis. To the best of our knowledge, this is the first report on the efficacy of granulocyte and monocyte adsorption apheresis in pyoderma gangrenosum in Europe.",
"affiliations": "Unit of Dermatology, University of Padua, Padua, Italy.;Unit of Dermatology, University of Padua, Padua, Italy.;Apheresis Unit, University of Padua, Padua, Italy.;Apheresis Unit, University of Padua, Padua, Italy.;Apheresis Unit, University of Padua, Padua, Italy.;Unit of Dermatology, University of Padua, Padua, Italy.;Unit of Dermatology, University of Padua, Padua, Italy.",
"authors": "Russo|Irene|I|;Miotto|Serena|S|;Colpo|Anna|A|;Marson|Piero|P|;Tison|Tiziana|T|;Ferrazzi|Anna|A|;Alaibac|Mauro|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/iwj.12684",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-4801",
"issue": "14(1)",
"journal": "International wound journal",
"keywords": "Granulocyte and monocyte adsorption apheresis; Neutrophilic dermatosis; Pyoderma gangrenosum",
"medline_ta": "Int Wound J",
"mesh_terms": "D000327:Adsorption; D000368:Aged; D001781:Blood Component Removal; D005060:Europe; D006098:Granulocytes; D006801:Humans; D008297:Male; D009000:Monocytes; D017511:Pyoderma Gangrenosum; D016896:Treatment Outcome",
"nlm_unique_id": "101230907",
"other_id": null,
"pages": "282-284",
"pmc": null,
"pmid": "27790848",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports",
"references": "17497998;21078086;22356259;26726081;17845399;12921115;15017514;19727102;8563873;16076369;16817789;14730244;18804557;23007291;25213386;21752760;25848350;24303809;12140486;24527305;26386221;11309823",
"title": "Successful treatment of pyoderma gangrenosum with granulocyte and monocyte adsorption apheresis.",
"title_normalized": "successful treatment of pyoderma gangrenosum with granulocyte and monocyte adsorption apheresis"
} | [
{
"companynumb": "IT-BAUSCH-BL-2017-001648",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "A patient with invasive mucormycosis whose disease progresses despite optimal treatment including surgical debridement, intravenous (IV) amphotericin B, and control of the predisposing factors can be clinically challenging. We report a case of a 67-year-old Caucasian man with invasive mucormycosis that did not respond to first-line treatment. He was subsequently started on isavuconazole in addition to amphotericin B. The patient's disease progression stopped; he then received IV amphotericin B for 50 days and isavuconazole for four months. Repeated magnetic resonance imaging (MRI) of the orbit and face nine months later, while off the antifungal medications, showed stable disease. This outcome is promising for patients with invasive mucormycosis who are either intolerant to amphotericin B or do not respond favorably to it.",
"affiliations": "Department of Internal Medicine, University of Missouri Kansas City (UMKC).;Department of Internal Medicine, University of Missouri Kansas City (UMKC).;Department of Internal Medicine, University of Missouri Kansas City (UMKC).;Department Chair - Infectious Disease, Saint Luke's hospital , Plaza , Kansas City , Missouri.",
"authors": "Shafiq|Muhammad|M|;Ali|Zafar|Z|;Ukani|Rehman|R|;Brewer|Joseph|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.2547",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.2547Internal MedicineInfectious DiseaseIsavuconazole: A Promising Salvage Therapy for Invasive Mucormycosis Muacevic Alexander Adler John R Shafiq Muhammad 1Ali Zafar 1Ukani Rehman 1Brewer Joseph 2\n1 \nDepartment of Internal Medicine, University of Missouri Kansas City (UMKC) \n2 \nDepartment Chair - Infectious Disease, Saint Luke's hospital , Plaza , Kansas City , Missouri. \nMuhammad Shafiq shafiqmu@umkc.edu29 4 2018 4 2018 10 4 e254727 3 2018 24 4 2018 Copyright © 2018, Shafiq et al.2018Shafiq 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/11532-isavuconazole-a-promising-salvage-therapy-for-invasive-mucormycosisA patient with invasive mucormycosis whose disease progresses despite optimal treatment including surgical debridement, intravenous (IV) amphotericin B, and control of the predisposing factors can be clinically challenging. We report a case of a 67-year-old Caucasian man with invasive mucormycosis that did not respond to first-line treatment. He was subsequently started on isavuconazole in addition to amphotericin B. The patient’s disease progression stopped; he then received IV amphotericin B for 50 days and isavuconazole for four months. Repeated magnetic resonance imaging (MRI) of the orbit and face nine months later, while off the antifungal medications, showed stable disease. This outcome is promising for patients with invasive mucormycosis who are either intolerant to amphotericin B or do not respond favorably to it.\n\ninvasive mucormycosisisavuconazolesalvage therapyamphotericin bThe 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\nMucormycosis predominantly affects patients with underlying comorbidities such as immunosuppression or diabetes mellitus. Early recognition and timely management are the keys to successful treatment. Amphotericin B and its lipid formulations are considered first-line antifungal agents in the treatment of mucormycosis [1-2]. However, when the patient’s invasive disease progresses despite optimal treatment with surgical debridement, intravenous (IV) amphotericin B, and control of the predisposing factors, this presents a clinical challenge as there are no good data available yet to suggest the next step.\n\nCase presentation\nA 67-year-old Caucasian man with a significant history of recently diagnosed type 2 diabetes mellitus (T2DM) and essential hypertension presented to the hospital with chief concerns of diplopia with an extreme gaze, right eye pain, and sinus congestion for about two weeks.\n\nAt the time of admission, the patient was afebrile, had a blood pressure of 160/67 mmHg and pulse of 64/minute but had a white blood cell count of 14,540/µL. The patient’s blood glucose was 469 mg/dL, anion gap levels were within reference range, and his glycosylated hemoglobin (HbA1c) was 12.4%. Computed tomography (CT) and magnetic resonance imaging (MRI) of the orbit and face revealed severe sinusitis with possible orbital cellulitis and optic nerve compression (Figure 1).\n\nFigure 1 Magnetic resonance image of the axial section of the orbits and face\nRight eye proptosis, right-sided sinuses involvement, and compression of the right optic nerve (red arrow) can be seen.\n\nOn the day of admission, the patient was started on an IV ampicillin and sulbactam combination (3000 mg/mL every six hours) and IV vancomycin (1500 mg/mL loading dose; 1250 mg/mL every 12 hours maintenance dose; target vancomycin trough of 10 to 20 mg/mL due to the severity of the infection). The patient was seen by the infectious disease (ID) team on day two of admission. The ID team recommended continuing vancomycin, switched the ampicillin/sulbactam combination medication to piperacillin/tazobactam (3375 mg/mL every six hours) and started the patient on empiric IV liposomal amphotericin B (400 mg/mL daily) given the concerns for invasive fungal infection. The patient was seen by ophthalmology team, and they recommended no acute surgical intervention. However, the otorhinolaryngology (ENT) team performed an endoscopy of the nasal sinuses on the second hospital day, and the patient required extensive debridement of the necrotic tissue of the right sinuses.\n\nBiopsy results from the nasal sinuses showed broad hyphae with infrequent septations, haphazard branching, and numerous bizarre forms. These morphologic features were consistent with mucormycosis. Given this finding, the patient was continued on IV liposomal amphotericin B.\n\nA second MRI of the orbit and face was repeated on the fourth hospital day and showed the progression of the disease including involvement of right retrobulbar fat and right optic nerve, persistent non-enhancing, and likely necrotic tissue extending from the right pterygopalatine fossa into the right masticator space (Figure 2). Suspected osteomyelitis was noted at the base of the skull, and we noted asymmetric right frontotemporal pachymeningeal enhancement with wispy leptomeningeal enhancement along the middle cranial fossa, which was suggestive of meningitis.\n\nFigure 2 Magnetic resonance image of the axial section of the orbits and face\nDestruction of the right-side maxillary sinus can be seen (red arrow).\n\nThe neurosurgery team was consulted as the patient had meningeal spread as well. The neurosurgery team deemed the patient inoperable.\n\nGiven the progression of the disease despite the standard-of-care treatment (i.e., surgical debridement, IV amphotericin B, and control of blood glucose), a literature search was done to find the next best step. Isavuconazole has been used, according to a few case reports [3-5], as salvage treatment in patients whose condition either failed the IV amphotericin B or were intolerant to it. Therefore, our patient was started on IV isavuconazole (372 mg/mL every eight hours) on the fifth hospital day, and IV amphotericin B (400 mg/mL daily) was continued. Since patient tissue aerobic and anaerobic cultures as well as blood cultures remained negative, piperacillin/tazobactam and vancomycin were discontinued on the fifth hospital day.\n\nAn MRI of the orbit and face was repeated 48 hours after the patient was started on isavuconazole and revealed a stable disease. The patient’s IV isavuconazole dose was reduced to 372 mg/mL daily (after receiving IV isavuconazole every eight hours for 48 hours). An MRI was obtained one week later, and it also showed stable disease with no further progression. The patient was switched to oral isavuconazole (372 mg daily), and IV amphotericin B (400 mg/mL daily) was continued. As the patient continued to improve, he was ultimately discharged after 19 hospital days on this regimen with a plan for outpatient follow-up evaluations with the ID, ENT, and ophthalmology teams. The patient was blind in his right eye with cranial nerves III, IV and VI palsies at the time of discharge. However, his left eye was completely intact with normal vision and movement.\n\nDuring outpatient care, he continued to receive IV amphotericin B (400 mg/mL daily) and oral isavuconazole (372 mg daily). An MRI of the orbit and face after five weeks of this therapy showed some interval improvement of the infectious process (Figure 3). After receiving IV amphotericin B (400 mg/mL daily) for 50 days, the medication was stopped, and the patient was continued on oral isavuconazole (372 mg daily). The patient's renal function was checked weekly as the patient was on IV amphotericin B. The patient had baseline creatinine of 1.0 mg/dL, it peaked at 1.8 mg/dL and returned to 1.4 mg/dL once the IV amphotericin B was stopped. Fungal cultures and blood samples were monitored for six weeks, and they remained negative.\n\nFigure 3 Magnetic resonance image of the axial section of the orbits and face\nRight eye proptosis has improved and right-sided sinuses involvement remains stable.\n\nAn MRI of the orbit and face was obtained two months later while the patient was treated with oral isavuconazole (372 mg daily), and the imaging continued to show stable disease. Therefore, oral isavuconazole was stopped. By this time, the patient had isavuconazole for a total of four months (both via IV and oral doses). Besides headaches, the patient tolerated the isavuconazole well without any other significant side effects.\n\nAn MRI of the orbit and face was obtained again nine months after stopping oral isavuconazole, and his disease process has remained stable. Imaging at this time showed some improvement in the condition. The ID team stated the patient was cured. The ENT team still monitors the patient periodically, and, as of this writing, the patient has been over one year off of antifungal medications.\n\nRegarding the patient’s diagnosis of uncontrolled T2DM, the patient was initially started on basal insulin while as an inpatient, but he was discharged on oral antihyperglycemic agents (metformin, 500 mg twice daily with meals and sitagliptin, 100 mg daily) given better control with oral agents at the time of discharge. His HbA1c improved to 5.0% from 12.4% in three months. The patient’s metformin has been stopped, and his sitagliptin dose has been reduced to 50 mg daily and is the only diabetic medication for the patient as of this writing.\n\nDiscussion\nNo good data exists yet for the appropriate next steps in treating invasive or disseminated mucormycosis that has continued to progress despite surgical debridement, IV amphotericin B, and control of predisposing factors. Our case report represents a life-threatening invasive rhinocerebral mucormycosis that failed the conventional first-line treatment. However, when isavuconazole was used as salvage therapy, our patient’s disease did not progress further. Rather, radiography images suggest the condition has improved. This is a promising outcome for patients with invasive or disseminated mucormycosis who are intolerant to amphotericin B or their condition does not respond to it. A few other case reports have supported this as well [3-5].\n\nIsavuconazole is a new triazole that was recently compared with amphotericin B in a single arm, open-label trial that found similar efficacy if isavuconazole is used as the first-line agent [6]. However, no randomized trials are yet available to suggest the superiority of one anti-fungal agent over another. The common side effects related to isavuconazole are nausea, vomiting, diarrhea, headaches, fatigue, insomnia, peripheral edema, hypokalemia, and occasionally dyspnea. Besides a headache, our patient didn’t experience any other side effects.\n\nDelaying the anti-fungal therapy by more than six days can double the mortality associated with mucormycosis by the end of 12 weeks [2]. Therefore, early initiation of anti-fungal drugs, surgical debridement of the necrotic tissue as soon as the diagnosis is confirmed, and reversal of the predisposing factors are the key elements in overall management.\n\nMucormycosis predominantly affects patients who are immunocompromised or have diabetes [7]. Clinical presentation depends largely on the site of involvement. Rhinocerebral mucormycosis is the most common form of this infection which is thought to occur after inhalation of spores into the paranasal sinuses. It mainly affects patients with diabetes, and one study reported 70% of patients with rhino-cerebral mucormycosis had diabetes and many had ketoacidosis at the time of presentation [8]. Other sites that can be involved include lungs, skin, gastrointestinal tract, or it can present as a disseminated infection [9-10].\n\nConclusions\nIf a patient fails to respond to standard first-line management for invasive mucormycosis which includes early initiation of IV amphotericin B, surgical debridement of the necrotic tissue as soon as the diagnosis is confirmed, and reversal of the predisposing factors, isavuconazole is a very reasonable option as salvage therapy in such scenarios.\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 Mold infections of the central nervous system New Eng J Med McCarthy M Rosengart A Schuetz AN Kontoyiannis DP Walsh TJ 150 160 371 2014 25006721 \n2 Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis Clin Infect Dis Chamilos G Lewis RE Kontoyiannis DP 503 509 47 2008 18611163 \n3 Successful isavuconazole salvage therapy in a patient with invasive mucormycosis Infection Ervens J Ghannoum M Graf B Schwartz S 429 432 42 2014 24217961 \n4 Isavuconazole treatment of a patient with disseminated mucormycosis J Clin Microbiol Peixoto D Gagne LS Hammond SP 1016 1019 52 2014 24403304 \n5 Isavuconazole as salvage therapy for mucormycosis Med Mycol Case Rep Graves B Morrissey CO Wei A 36 39 11 2016 27158585 \n6 Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis Lancet Infect Dis Marty FM Ostrosky-Zeichner L Cornely OA 828 837 16 2016 26969258 \n7 Mucormycoses Infect Dis Clin North Am Farmakiotis D Kontoyiannis DP 143 163 30 2016 26897065 \n8 Rhinocerebral mucormycosis: predisposing factors Laryngoscope McNulty JS 1140 1143 92 1982 7132514 \n9 Epidemiology and outcome of zygomycosis: a review of 929 reported cases Clin Infect Dis Roden MM Zaoutis TE Buchanan WL 634 653 41 2005 16080086 \n10 Epidemiology and clinical manifestations of mucormycosis Clin Infect Dis Petrikkos G Skiada A Lortholary O Roilides E Walsh TJ Kontoyiannis DP 23 34 54 2012\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "10(4)",
"journal": "Cureus",
"keywords": "amphotericin b; invasive mucormycosis; isavuconazole; salvage therapy",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e2547",
"pmc": null,
"pmid": "29963341",
"pubdate": "2018-04-29",
"publication_types": "D002363:Case Reports",
"references": "24403304;26897065;27158585;7132514;25006721;26969258;18611163;22247442;16080086;24217961",
"title": "Isavuconazole: A Promising Salvage Therapy for Invasive Mucormycosis.",
"title_normalized": "isavuconazole a promising salvage therapy for invasive mucormycosis"
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{
"companynumb": "US-ASTELLAS-2018US031802",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": ... |
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"abstract": "Opioid analgesics have greatly contributed to the advancement of pain management. However, although opioids have been appropriately used in Japan, they rarely induce serious adverse events, such as respiratory depression. The present study aimed to investigate the temporal changes in the occurrence of opioid-related adverse events and deaths between 2004 and 2017 in Japan using the Japanese Adverse Drug Event Report (JADER) database. We analyzed the following points using data extracted from JADER website: 1) temporal changes in the number and proportion of opioid-related adverse event reports; 2) temporal changes in the number of morphine-, oxycodone-, and fentanyl-related adverse event reports per annual consumption; and 3) cases in which the reported outcome following opioid-related adverse events was death. Our results showed no dramatic changes in the overall incidence of opioid-related adverse events, despite the temporal changes in the annual consumption and shared component of each opioid during the survey period. However, the number and rate of fentanyl-related adverse events and their outcome \"death\" increased since 2010, being the highest among all adverse event including those related to morphine and oxycodone. Outcome \"death\" by fentanyl-related adverse events was caused mainly due to respiratory depression. These findings suggest that, although opioid-related adverse events can be controlled through proper monitoring and management by medical personnel in Japan, extra caution should be continuously paid for the rare but serious fentanyl-induced adverse events.",
"affiliations": "Department of Clinical Drug Informatics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical & Health Science, Kanazawa University.;Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.;Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.;Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.;Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.;Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.;Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.;Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.;Research Promotion Committee, Japanese Society for Pharmaceutical Palliative Care and Sciences.",
"authors": "Suga|Yukio|Y|;Uchida|Mayako|M|;Suzuki|Shinya|S|;Sugawara|Hideki|H|;Torigoe|Kazuhiro|K|;Futamura|Akihiko|A|;Uesawa|Yoshihiro|Y|;Nakagawa|Takayuki|T|;Takase|Hisamitsu|H|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine; D010098:Oxycodone; D000077432:Tapentadol; D008691:Methadone; D005283:Fentanyl",
"country": "Japan",
"delete": false,
"doi": "10.1248/bpb.b18-00997",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-6158",
"issue": "42(5)",
"journal": "Biological & pharmaceutical bulletin",
"keywords": "Japanese Adverse Drug Event Report; adverse event; opioid analgesic; opioid-related death; proper use",
"medline_ta": "Biol Pharm Bull",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000701:Analgesics, Opioid; D016208:Databases, Factual; D005283:Fentanyl; D006801:Humans; D007564:Japan; D008691:Methadone; D009020:Morphine; D010098:Oxycodone; D000077432:Tapentadol",
"nlm_unique_id": "9311984",
"other_id": null,
"pages": "801-806",
"pmc": null,
"pmid": "31061323",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Current Status of Adverse Events Related with Opioid Analgesics in Japan: Assessment Based on Japanese Adverse Drug Event Report Database.",
"title_normalized": "current status of adverse events related with opioid analgesics in japan assessment based on japanese adverse drug event report database"
} | [
{
"companynumb": "JP-COLLEGIUM PHARMACEUTICAL, INC.-JP-2019COL000700",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"actiondrug": "6",
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"activesubstancename": "OXYCODONE"
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{
"abstract": "BACKGROUND\nInduction immunosuppression is a mainstay of rejection prevention after transplantation. Studies have suggested a connection between antibody induction agents and cancer development, potentially limiting important immunosuppression protocols.\n\n\nMETHODS\nWe used a linkage of U.S. transplantation data and cancer registries to explore the relationship between induction and cancer after transplantation. A total of 111,857 kidney recipients (1987-2009) in the Transplant Cancer Match Study, which links the Scientific Registry for Transplant Recipients and U.S. Cancer Registries, were included. Poisson regression models were used to estimate adjusted incidence rate ratios (aIRR) of non-Hodgkin lymphoma (NHL) and other cancers with increased incidence after transplantation (lung, colorectal, kidney, and thyroid cancers, plus melanoma).\n\n\nRESULTS\nTwo thousand seven hundred sixty-three cancers of interest were identified. Muromonab-CD3 was associated with increased NHL (aIRR, 1.37; 95% CI, 1.06-1.76). Alemtuzumab was associated with increased NHL (aIRR, 1.79; 95% CI, 1.02-3.14), colorectal cancer (aIRR, 2.46; 95% CI, 1.03-5.91), and thyroid cancer (aIRR, 3.37; 95% CI, 1.55-7.33). Polyclonal induction was associated with increased melanoma (aIRR, 1.50; 95% CI, 1.06-2.14).\n\n\nCONCLUSIONS\nOur findings highlight the relative safety with regard to cancer risk of the most common induction therapies, the need for surveillance of patients treated with alemtuzumab, and the possible role for increased melanoma screening for those patients treated with polyclonal anti-T-cell induction.",
"affiliations": "1 Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD. 2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD. 3 Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, MD.",
"authors": "Hall|Erin C|EC|;Engels|Eric A|EA|;Pfeiffer|Ruth M|RM|;Segev|Dorry L|DL|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D016853:Muromonab-CD3; D015375:Receptors, Interleukin-2; D000074323:Alemtuzumab",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000000449",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "99(5)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016853:Muromonab-CD3; D009369:Neoplasms; D015375:Receptors, Interleukin-2; D013601:T-Lymphocytes",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "1051-7",
"pmc": null,
"pmid": "25340595",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17617273;19855238;16611348;9044505;19563337;21264909;10083567;16314791;14974943;14678038;17093248;22009989;16684987;14627905;15147424;22226225;21930332;14657684;17868060;21693205;19443660;16176420;20164816;22009990;22045767;19114864;21591943",
"title": "Association of antibody induction immunosuppression with cancer after kidney transplantation.",
"title_normalized": "association of antibody induction immunosuppression with cancer after kidney transplantation"
} | [
{
"companynumb": "US-JNJFOC-20150509932",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
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"activesubstancename": "MUROMONAB-CD3"
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... |
{
"abstract": "Serial analysis of circulating tumor cells (CTCs) such as androgen receptor splice variant 7 is useful in selecting treatments for castration-resistant prostate cancer (CRPC). We report a case who had been positive for androgen receptor splice variant 7 in CTCs before docetaxel, and was subsequently treated with abiraterone rechallenge because of the negative conversion of androgen receptor splice variant 7 following docetaxel. Although, the rechallenge of anti-androgen agent based on CTCs analysis is expected to be an effective approach, it is yet to be reported. Thus, we chose the candidate for abiraterone rechallenge based on serial CTCs analyses by the AdnaTest. As a result, the patient responded to abiraterone that he once had developed resistance to. Our findings reinforce the utility of AR-V7 as a biomarker in the setting of post-chemo androgen-targeted-therapy rechallenge.",
"affiliations": "Department of Urology, Juntendo University Graduate School of Medicine, Bunkyo, Japan.;Department of Urology, Juntendo University Graduate School of Medicine, Bunkyo, Japan.;Department of Urology, Juntendo University Graduate School of Medicine, Bunkyo, Japan.;Department of Urology, Juntendo University Graduate School of Medicine, Bunkyo, Japan.",
"authors": "Nagaya|Naoya|N|;Kanayama|Mayuko|M|;Nagata|Masayoshi|M|;Horie|Shigeo|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.00495",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00495\nOncology\nCase Report\nAbiraterone Rechallenge Based on Sequential Testing of Androgen Receptor Splice Variant 7 Expression in Circulating Tumor Cells: A Case Report\nNagaya Naoya Kanayama Mayuko Nagata Masayoshi Horie Shigeo * Department of Urology, Juntendo University Graduate School of Medicine, Bunkyo, Japan\nEdited by: Marzia Del Re, University of Pisa, Italy\n\nReviewed by: Ugo De Giorgi, Romagnolo Scientific Institute for the Study and Treatment of Tumors (IRCCS), Italy; Antonello Veccia, Ospedale Santa Chiara, Italy; Chengfei Liu, UC Davis Medical Center, United States\n\n*Correspondence: Shigeo Horie shorie@juntendo.ac.jpThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology\n\n\n08 4 2020 \n2020 \n10 49513 1 2020 19 3 2020 Copyright © 2020 Nagaya, Kanayama, Nagata and Horie.2020Nagaya, Kanayama, Nagata and HorieThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Serial analysis of circulating tumor cells (CTCs) such as androgen receptor splice variant 7 is useful in selecting treatments for castration-resistant prostate cancer (CRPC). We report a case who had been positive for androgen receptor splice variant 7 in CTCs before docetaxel, and was subsequently treated with abiraterone rechallenge because of the negative conversion of androgen receptor splice variant 7 following docetaxel. Although, the rechallenge of anti-androgen agent based on CTCs analysis is expected to be an effective approach, it is yet to be reported. Thus, we chose the candidate for abiraterone rechallenge based on serial CTCs analyses by the AdnaTest. As a result, the patient responded to abiraterone that he once had developed resistance to. Our findings reinforce the utility of AR-V7 as a biomarker in the setting of post-chemo androgen-targeted-therapy rechallenge.\n\nabitateroneandrogen receptor splice variant 7castration-resistant prostate cancercirculating tumor cellsrechallengeAstellas Pharma10.13039/501100004948\n==== Body\nBackground\nMost metastatic prostate cancers are treated with androgen deprivation therapy (ADT) at the outset. Nevertheless, most of them progress to acquire resistance to the primary ADT, which is a state called castration-resistant prostate cancer (CRPC). Novel anti-androgen agents (enzalutamide, apalutamide, and darolutamide), CYP17A1 inhibitor that inhibit the production of testosterone (abiraterone), two taxane-based chemotherapies (docetaxel and cabazitaxel) and radium-223 have been approved by the US Food and Drug Administration for CRPC treatments (1–3).\n\nDespite a variety of treatment options available for CRPC, there is no predictive biomarker used for treatment selection. Instead, clinicians decide on a course of treatment based on the several prospective randomized controlled phase 3 trials. For instance, most prostate cancer experts have consensus that asymptomatic men with metastatic CRPC should receive abiraterone or enzalutamide as the first-line treatment (4).\n\nHowever, from the perspective of personalized medicine, we should choose treatments based on the genomic profiles of CRPC. Since genomic analysis of biopsy samples from metastatic lesions is not practical, liquid biopsy such as circulating tumor cells (CTCs) and circulating tumor DNA are drawing attention in recent years. In terms of CTCs, Antonarakis's study propounded testing androgen receptor splice variant 7 (AR-V7) expression in CTCs (5, 6). In their study, AR-V7-negative cohort showed a better prostate-specific antigen (PSA) response to novel anti-androgen agents than AR-V7-positive cohort. Furthermore, serial testing of AR-V7 in CTCs can be useful in selecting treatments for CRPC. However, this CTC analysis is yet to be acknowledged as the standard companion diagnosis. To further verify the utility of CTC analysis, prospective studies are currently underway (6).\n\nTo this end, we performed a feasible bedside CTC testing for CRPC patients. Herein, we report a case of a CRPC patient who was successfully treated based on sequential CTC analysis (Figure 1).\n\nFigure 1 Changes of the serum PSA, treatment course, metastasis lesion, and the status of CTCs. The upper graph shows the changes of serum PSA and CTC status including AR-V7 expression. The treatment course is showed in the middle and the status of metastasis lesion is shown in the bottom. During the first-round abiraterone administration, when the serum PSA level rose twice, we analyzed AR-V7 expression in CTCs. Due to positive AR-V7 expression, we chose docetaxel as the second-line CRPC treatment. Because of rising PSA level during a drug holiday after docetaxel, we rechallenged abiraterone based on the negative conversion of AR-V7 expression, which resulted in PSA decline. When PSA rose to 4.00 ng/dl 10 months after abiraterone rechallenge, the expression of AR-V7 was converted to positive. Subsequently, cabazitaxel was started.\n\nThis study was approved by the institutional review board of Juntendo hospital (admission number: 14-052), and all experiments were carried out in accordance with approved guidelines. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\n\nCase presentation\nIn November 2007, a 62-year-old man was diagnosed as localized prostate cancer with no metastasis (cT3bN0M0, Gleason score 4 + 4, initial PSA 46.3 ng/dl) and underwent radical prostatectomy. In April 2008, he had a PSA recurrence (2.4 ng/dl) and the combination androgen blockade therapy (LH-RH agonist + bicalutamide 80 mg/day) was initiated. In March 2015, he presented a local recurrence, and the treatment was switched to abiraterone (1,000 mg/day) combined with LH-RH antagonist and prednisolone. In addition, radiation therapy (60 Gy/30 fr) was done against the local recurrence, which resulted in marked tumor disappearance. His disease was well-managed with abiraterone for 13 months. In June 2016, he showed PSA progression and a liver metastasis occurred. At this point, AR-V7 was positive by the AdnaTest (QIAGEN, Germany). Therefore, we selected docetaxel of every 4 week (70 mg/m2) and a total of six cycles was given. Radiofrequency ablation (RFA) was performed for a liver metastasis since it was a singular and small lesion (<30 mm), which is the indication for RFA. After the administration of docetaxel, PSA declined to 0.166 ng/dl. Furthermore, CTC analysis confirmed the negative conversion of AR-V7 in CTCs. Due to the favorable response to docetaxel, docetaxel treatment was suspended and only LH-RH antagonist was continued for the following 5 months as a drug holiday. Subsequently, when PSA rose to the pre-docetaxel level (2.29 ng/dl), we tested AR-V7 expression again. Resultantly, because AR-V7 still remained negative, we opted for abiraterone rechallenge based on the following discussion with patient. The attending physician explained to the patient that enzalutamide may cause adverse events, such as fatigue and anorexia. Because the patient had no adverse events during the administration of abiraterone, he wanted to resume abiraterone. Also, because he had experienced symptoms of alopecia and numbness that adversely affected his job at the time of docetaxel administration, he did not want to be treated with chemotherapy while at work.\n\nAs a result, 6 months after the abiraterone rechallenge, PSA value became lower (1.08 ng/dl) than the level before abiraterone rechallenge. In line with this, no other metastases were found. PSA elevation was not observed for 8 months. Afterward, when PSA rose to 4.00 ng/dl 10 months after abiraterone rechallenge, we analyzed AR-V7 expression in CTC again. CTC analysis showed that the expression of AR-V7 was converted to positive. Based on the CTC analysis, subsequent cabazitaxel was started. Although, PSA was well-controlled for 9 months after cabazitaxel administration, PSA rose continually after 10 cycles of cabazitaxel, and computed tomography image showed the emerge of the bladder invasion.\n\nDiscussion and Conclusions\nHere, we reported the case of a CRPC patient with liver metastases, who was treated with abiraterone rechallenge based on AR-V7 status in CTCs.\n\nNakazawa et al. (7) reported the dynamic transition of AR-V7 status in CTCs and its utility for treatment selections. Their study showed the results of detailed CTC profiles and treatment courses in 14 patients. In this study, there was one patient showing continuous AR-V7 positivity, who was treated with androgen-targeted therapy rechallenge after docetaxel. However, he did not benefit from this rechallenge. Also, there was another patient who benefited from the first time abiraterone after docetaxel, when CTCs' AR-V7 status changed from positive to negative following docetaxel. However, unlike our case, there was no patient who benefited from the androgen-targeted-therapy rechallenge following chemotherapies in Nakazawa's study.\n\nThe clinical outcome of treatment with abiraterone or enzalutamide for patients who progressed on abiraterone has been shown in COU-AA-302 trial. Most of these patients received chemotherapy before subsequent abiraterone or enzalutamide. PSA response (defined as a PSA reduction of at least 50% from baseline) was observed in 24 of 55 patients who received subsequent abiraterone and in 22 of 33 patients who received subsequent enzalutamide (8). Besides, the results of phase III clinical trial, CARD trial, showed that cabazitaxel significantly improved clinical outcomes compared with androgen-targeted therapy (abiraterone or enzalutamide) in patients with metastatic CRPC previously treated with docetaxel (9). Although, the benefit of post-chemotherapy abiraterone or enzalutamide rechallenge was limited to some patient, these results still suggested that some cancer regained abiraterone or enzalutamide sensitivity after chemotherapy. However, we need to accurately identify the candidate patient who potentially benefit from androgen-targeted-therapy rechallenge. Therefore, our case provides clinical and biological rationale for AR-V7-based patients selection for the androgen-targeted-therapy rechallenge following chemotherapies.\n\nIn our report, changes in AR-V7 expression appeared to be reflective of the treatment effect. For example, the negative conversion of AR-V7 occurred after docetaxel and RFA for liver metastasis, both of which could have eliminated AR-V7-positive CTCs. Then, the withdrawal of docetaxel possibly stimulated the expansion of AR-V7-negative cells expressing full-length AR, which might have resulted in regained susceptibility to abiraterone rechallenge. Although, PSA elevation was observed after the abiraterone rechallenge, this treatment was able to suppress the increase in PSA for the following 8 months and delay the initiation of subsequent cabazitaxel treatment. Furthermore, abiraterone was effective only when AR-V7 was negative. These findings reinforce the utility of AR-V7 as a biomarker in the setting of post-chemo androgen-targeted-therapy rechallenge.\n\nOn the other hand, we have a variety of issues we need to address in CTC research. Firstly, whether CTCs represent the entire tumor characteristics is questionable. Secondly, AR-V7 is not the only mechanism driving CRPC progression. The states of other mechanisms responsible for treatment resistance in CRPC such as dysregulated PI3K–AKT signaling, WNT signaling pathway and DNA repair defects need to be elucidated (10). Thirdly, not only the wild-type full-length AR and AR splice variants mediate AR-signaling in CRPC, but also gene amplification and gain-of-function mutations are reportedly implicated in the sustained AR signaling in CRPC (11). Further investigations and technical developments are required to clarify the underlying heterogeneity of CTCs and CRPC biology in CTCs.\n\nTo the best of our knowledge, this is the first reported case of regaining susceptibility to the post-chemo anti-androgen agent with the concurrent negative conversion of AR-V7. Our result suggests that the rechallenge of post-chemo AR-targeted therapy based on AR-V7 testing can be a good strategy in treating CRPC.\n\nEthics Statement\nWritten informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAll authors have significantly contributed to the study and are in agreement with the content of the manuscript. Each author's contribution is as follows: NN and MK performed the experiments. NN, MK, MN, and SH designed the study. NN and MK wrote the manuscript, and MN and SH revised it.\n\nConflict of Interest\nSH has research grants from Astellas and Sanofi Aventis, honorarium from Astellas, Takeda, Astrazeneca and Sanofi Aventis and Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe would like to thank Dr. Yuji Tanaka (RIKEN) and the staff at Kyodo-ken for technical assistance.\n==== Refs\nReferences\n1. Smith MR Saad F Chowdhury S Oudard S Hadaschik BA Graff JN . Apalutamide treatment and metastasis-free survival in prostate cancer\n. N Engl J Med. (2018 ) 378 :1408 –18\n. 10.1056/NEJMoa1715546 29420164 \n2. Fizazi K Shore N Tammela TL Ulys A Vjaters E Polyakov S . Darolutamide in nonmetastatic, castration-resistant prostate cancer\n. N Engl J Med . (2019 ) 380 :1235 –46\n. 10.1056/NEJMoa1815671 30763142 \n3. Parker C Gillessen S Heidenreich A Horwich A . Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up\n. Ann Oncol . (2015 ) 26 (Suppl 5 ):v69 –77\n. 10.1093/annonc/mdv222 26205393 \n4. Gillessen S Attard G Beer TM Beltran H Bossi A Bristow R \nManagement of patients with advanced prostate cancer: the report of the advanced prostate cancer consensus conference APCCC 2017\n. Eur. Urol . (2018 ) 73 :178 –211\n. 10.1016/j.eururo.2017.08.010 28655541 \n5. Antonarakis ES Lu C Wang H Luber B Nakazawa M Roeser JC . AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer\n. N Engl J Med . (2014 ) 371 :1028 –38\n. 10.1056/NEJMoa1315815 25184630 \n6. Antonarakis ES Lu C Luber B Wang H Chen Y Zhu Y . Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide\n. J Clin Oncol. (2017 ) 35 :2149 –56\n. 10.1200/JCO.2016.70.1961 28384066 \n7. Nakazawa M Lu C Chen Y Paller CJ Carducci MA Eisenberger MA . Serial blood-based analysis of AR-V7 in men with advanced prostate cancer\n. Ann Oncol . (2015 ) 26 :1859 –65\n. 10.1093/annonc/mdv282 26117829 \n8. Smith MR Saad F Rathkopf DE P.Mulders FA de Bono JS Small EJ . Clinical outcomes from androgen signaling-directed therapy after treatment with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-302\n. Eur Urol . (2017 ) 72 :10 –3\n. 10.1016/j.eururo.2017.03.007 28314611 \n9. de Wit R de Bono J Sternberg CN Fizazi K Tombal B Wulfing C \nCabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer\n. N Engl J Med . (2019 ) 381 :2506 –18\n. 10.1056/NEJMoa1911206 31566937 \n10. Yap TA Smith AD Ferraldeschi R Al-Lazikani B Workman P de Bono JS \nDrug discovery in advanced prostate cancer: translating biology into therapy\n. Nat Rev Drug Discov . (2016 ) 15 :699 –718\n. 10.1038/nrd.2016.120 27444228 \n11. Mateo J Sharp A de Bono JS \nInvestigating genomic aberrations of the androgen receptor: moving closer to more precise prostate cancer care?\n\nEur Urol . (2017 ) 72 :201 –4\n. 10.1016/j.eururo.2017.02.005 28233594\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "abitaterone; androgen receptor splice variant 7; castration-resistant prostate cancer; circulating tumor cells; rechallenge",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "495",
"pmc": null,
"pmid": "32373521",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26117829;28655541;31566937;28233594;25184630;30763142;28384066;27444228;29420164;26205393;28314611",
"title": "Abiraterone Rechallenge Based on Sequential Testing of Androgen Receptor Splice Variant 7 Expression in Circulating Tumor Cells: A Case Report.",
"title_normalized": "abiraterone rechallenge based on sequential testing of androgen receptor splice variant 7 expression in circulating tumor cells a case report"
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"abstract": "Idiopathic granulomatous mastitis (IGM) is a disfiguring inflammatory breast disease without effective treatment. We report the largest IGM cohort treated with methotrexate (MTX) monotherapy.\n\n\n\nChart review was performed on patients evaluated by the Stanford Immunology and Rheumatology Clinic, with histopathologically established IGM treated with MTX, and at least 1 followup appointment.\n\n\n\nNineteen female patients with a mean age of 33.5 years were identified. Most failed treatment with antibiotics, prednisone, and surgical intervention. By 15 months of treatment with MTX, 94% had disease improvement and 75% achieved disease remission.\n\n\n\nMTX monotherapy is an effective treatment for IGM.",
"affiliations": "From the Division of Immunology and Rheumatology, Department of Pathology, Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA. postolov@stanford.edu.;From the Division of Immunology and Rheumatology, Department of Pathology, Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA.;From the Division of Immunology and Rheumatology, Department of Pathology, Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA.;From the Division of Immunology and Rheumatology, Department of Pathology, Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA.",
"authors": "Postolova|Anna|A|;Troxell|Megan L|ML|;Wapnir|Irene L|IL|;Genovese|Mark C|MC|0000-0001-5294-4503",
"chemical_list": "D011241:Prednisone; D008727:Methotrexate",
"country": "Canada",
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"doi": "10.3899/jrheum.181205",
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"issue": "47(6)",
"journal": "The Journal of rheumatology",
"keywords": "AUTOIMMINE DISEASE; GRANULOMATOUS MASTITIS; METHOTREXATE",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D005260:Female; D058890:Granulomatous Mastitis; D006801:Humans; D008727:Methotrexate; D011241:Prednisone; D016896:Treatment Outcome",
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"title": "Methotrexate in the Treatment of Idiopathic Granulomatous Mastitis.",
"title_normalized": "methotrexate in the treatment of idiopathic granulomatous mastitis"
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"abstract": "Venlafaxine is a serotonergic and noradrenergic reuptake inhibitor which is used for the treatment of depression. We report a case of galactorrhea in a patient with major depressive disorder after starting treatment with venlafaxine. In particular, we discuss the course of hyper and normoprolactinemic galactorrhea. We managed this side effect initially by dose reduction and further by switching to essitalopram. Physicians should be aware of endocrinologic side effects such as galactorrhea during the serotonin and noradrenaline reuptake inhibitor treatment.",
"affiliations": "Department of Psychiatry, Afşin State Hospital, Afşin, Turkey.;Department of Psychiatry, Selçuk University School of Medicine, Selçuk, Turkey.;Department of Psychiatry, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey.;Department of Internal Medicine, Afşin State Hospital, Afşin, Turkey.",
"authors": "Camkurt|Mehmet Akif|MA|;Gülpamuk|Gizem|G|;Fındiklı|Ebru|E|;Elve|Rengin|R|",
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"country": "Korea (South)",
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"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2844956710.9758/cpn.2017.15.2.181cpn-15-181Case ReportDose Dependent Course of Hyperprolactinemic and Normoprolactinemic Galactorrhea Induced by Venlafaxine Camkurt Mehmet Akif 1Gülpamuk Gizem 2Fındiklı Ebru 3Elve Rengin 41 Department of Psychiatry, Afşin State Hospital, Afşin, \nTurkey4 Department of Internal Medicine, Afşin State Hospital, Afşin, \nTurkey2 Department of Psychiatry, Selçuk University School of Medicine, Selçuk, \nTurkey3 Department of Psychiatry, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, \nTurkeyAddress for correspondence: Mehmet Akif Camkurt, MD, Department of Psychiatry, Afşin State Hospital, Yeşilyurt Mah., Kemal Ertekin Cad., Afşin 46500, Turkey, Tel: +90-506-4404400, Fax: +90-344-5112966, E-mail: dr.akif@gmail.com5 2017 31 5 2017 15 2 181 183 22 2 2016 19 3 2016 03 4 2016 Copyright © 2017, Korean College of Neuropsychopharmacology2017This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Venlafaxine is a serotonergic and noradrenergic reuptake inhibitor which is used for the treatment of depression. We report a case of galactorrhea in a patient with major depressive disorder after starting treatment with venlafaxine. In particular, we discuss the course of hyper and normoprolactinemic galactorrhea. We managed this side effect initially by dose reduction and further by switching to essitalopram. Physicians should be aware of endocrinologic side effects such as galactorrhea during the serotonin and noradrenaline reuptake inhibitor treatment.\n\nVenlafaxine hydrochlorideGalactorrheaProlactinDepressionTherapeuticsManagement\n==== Body\nINTRODUCTION\nVenlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI), is a major drug for the treatment of major depressive disorder. However, it often causes gastrointestinal side effects such as nausea, vomiting and diarrhea. Less frequently, venlafaxine is responsible for adverse sexual side effects as well.1,2)\n\nAlthough galactorrhea is frequently reported with antipsychotic drugs—which block the dopaminergic receptors and accompany elevated prolactin levels—there are several reports of galactorrhea with different classes of antidepressants.3) The first report of galactorrhea was with clomipramine. Afterwards, there have been reports of galactorrhea with mostly serotonergic antidepressants, but rarely with SNRIs.4–7) Another interesting feature of galactorrhea as a side effect of antidepressants is normoprolactinemic galactorrhea. Furthermore, galactorrhea may be dose-dependent in some cases.8) In this case, we report a dose-dependent galactorrhea case involving both increased and normal prolactin levels, and the management of this condition in a depressed patient who used venlafaxine in a dose range of 225 to 75 mg/day.\n\nCASE\nA 34-year-old female patient was admitted to our clinic with complaints of anhedonia, decreased appetite, loss of sexual desire, irritability and passive suicidal thoughts. These complaints had lasted about two months. The patient was considered to have major depressive disorder, so we initiated venlafaxine, 75 mg/day. Six months after this initiation, we increased the dose of venlafaxine to 150 mg, because the patient was not admitted to the clinic regularly.\n\nThree months later (the ninth month of treatment), we increased the venlafaxine dose to 225 mg/day. The patient started to experience galactorrhea while she was taking 150 mg/day, but she did not inform us about this side effect during our examination, so we increased the dose of venlafaxine. Ten days after taking venlafaxine at a dose of 225 mg/day, the patient was admitted to our clinic again for galactorrhea that was so severe she could not endure it anymore. Brain magnetic resonance imaging was performed for her pituitary tumor, but the result was normal. We checked her hormone levels: FSH, LH, T3, T4 and TSH were within the normal range; however, her prolactin level was 156 ng/ml. We considered the galactorrhea and the increased prolactin levels were a result of venlafaxine the patient had been taking. Consequently, we decreased the venlafaxine dose to 150 mg/day.\n\nOne month later, although her prolactin level had decreased to 9 ng/ml, the galactorrhea persisted. So we decreased the venlafaxine dose to 75 mg/day. At the patient’s next visit, she stated that while she was taking 75 mg/day, the galactorrhea symptoms had been significantly relieved, but she felt worse, so she started to take 150 mg/day again, which once more caused a severe case of galactorrhea. We decreased the dose of venlafaxine to 75 mg/day; afterwards, we switched the patient to escitalopram 10 mg/day, and lorazepam 2 mg/day. One month later, we increased the escitalopram dose to 20 mg/day, and over the course of the following four weeks, we tapered the lorazepam dose. With a treatment of escitalopram 20 mg/day, the patient has reported that she is feeling very well; she was experiencing only minimal galactorrhea, but she chose to continue with escitalopram.\n\nDISCUSSION\nAs far as we know, there is a limited number of case reports in literature involving galactorrhea with a measurement of increased prolactin levels developed under venlafaxine treatment.\n\nVenlafaxine-induced galactorrhea, as seen in our case, was defined by Sternbach8) in 2003. He presented a 38 year-old-woman treated for depression and a binge eating disorder with a dosage of venlafaxine, 225 mg/day. Six weeks after initiation of the treatment with venlafaxine (225 mg/day), buspirone 45 mg was added to the treatment. While she was on this treatment for one week, she began to experience galactorrhea; her prolactin level was 32 μg/L (expected to be lower than 18 μg/L). Despite a withdrawal of buspirone, her galactorrhea persisted at first, then stopped after the venlafaxine was withdrawn as well. Although venlafaxine 75 mg/day was reapplied, the galactorrhea recurred. Meanwhile her prolactin level was 10 μg/L.\n\nMoreover, some of the clinicians managed hyperprolactinemia symptoms by reducing the dose of venlafaxine or stopping it.8–11) When we decreased the dose of venlafaxine from 225 to 150 mg/day, her prolactin level decreased from 156 to 9 ng/ml, and interestingly enough, her galactorrhea continued, as in the cases of Sternbach,8) Ashton and Longdon.10)\n\nThe interesting points of our case are the facts that galactorrhea was both hyperprolactinemic and normoprolactinemic, and that the severity of the galactorrhea was clearly dose-related. At the beginning, we preferred to decrease the dose of venlafaxine in order to manage this side effect. Although the galactorrhea symptoms improved significantly after reducing the dose of venlafaxine to 75 mg/day, the patient’s depressive symptoms occurred again, so we planned to switch to escitalopram. During the escitalopram treatment, she was still experiencing galactorrhea, but it was at a more tolerable level than during the venlafaxine treatment.\n\nThe most important observations of our report are as following; in our case, that venlafaxine was the only medication related to galactorrhea, because when the patient began taking a dosage of 150 mg/day again, there were clear signs of an association existing between galactorrhea and venlafaxine. As stated previously, the more the venlafaxine dose is increased, the more the serotonergic transmission grows stronger. Also, the noradrenergic effects of venlafaxine start with doses of 225 mg/day. Probable mechanisms related to both normoprolactinemic and hyperprolactinemic galactorrhea are serotonergic and noradrenergic pathways.6)\n\nVenlafaxine and its active metabolite (O-desmethylvenlafaxine) are SNRIs that weakly inhibit dopamine reuptake in high doses.6) It is not clear by which mechanism serotonergic agents increase prolactin levels or cause galactorrhea, but there are two pathways suggested to be related to these side effects.12) Primarily, serotonin can directly stimulate 5-hydroxytryptamine (5-HT) receptors in the paraventricular nucleus of the hypothalamus, and this stimulation induces the release of vasoactive intestinal peptide (VIP) and oxytocin (OT). Both VIP and OT are known as prolactin-releasing factors. Another mechanism of serotonin-induced prolactin release is the indirect inhibition of dopaminergic neurons of the tuberoinfundibular pathway through 5-HT. Eventually, both mechanisms explain serotonin’s potential effects on the neuroendocrine system.13)\n\nIn light of the observations from this case, we propose that venlafaxine is associated with both hyperprolactinemic and normoprolactinemic galactorrhea. Moreover, this report can help medical professionals to more effectively identify the association between venlafaxine and galactorrhea. Possible options for management of galactorrhea include dose reduction or switching to another antidepressant. Clinicians should be aware of that serotonergic or noradrenergic drugs may be associated with endocrinological side effects, especially galactorrhea.\n==== Refs\nREFERENCES\n1 Camkurt MA Spontaneous ejaculation; caused by venlafaxine, reverted by mirtazapine Eur Res J 2015 1 157 159 10.18621/eurj.2015.1.3.157 \n2 Tang M Osser DN The psychopharmacology algorithm project at the harvard south shore program: 2012 update on psychotic depression J Mood Disord 2012 2 168 179 10.5455/jmood.20121222120547 \n3 Albayrak Y Ünsal C Beyazyüz M Kuloğlu M Comparison of short term effects of risperidone and paliperidone on serum prolactin levels in female patients J Mood Disord 2014 4 7 13 10.5455/jmood.20130926044115 \n4 Anand VS Clomipramine-induced galactorrhoea and amenorrhoea Br J Psychiatry 1985 147 87 88 10.1192/bjp.147.1.87 4063616 \n5 Camkurt MA Şimşek N Sertralin induced normoprolactinemic galactorrhea J Neurobehav Sci 2015 2 34 35 \n6 Tesia SS Tesia P Gowda MR Preeti S Escitalopram induced euprolactinemic galactorrhoea J Mood Disord 2012 2 15 16 \n7 Chatterjee SS Mitra S Mallik N Emerging hyperprolactinemic galactorrhea in obsessive compulsive disorder with a stable dose of fluoxetine Clin Psychopharmacol Neurosci 2015 13 316 318 10.9758/cpn.2015.13.3.316 26598592 \n8 Sternbach H Venlafaxine-induced galactorrhea J Clin Psychopharmacol 2003 23 109 110 10.1097/00004714-200302000-00023 12544389 \n9 Yang MS Cheng WJ Huang MC Dose-related hyperprolactinemia induced by venlafaxine Prog Neuropsychopharmacol Biol Psychiatry 2009 33 733 734 10.1016/j.pnpbp.2009.03.010 19303910 \n10 Ashton AK Longdon MC Hyperprolactinemia and galactorrhea induced by serotonin and norepinephrine reuptake inhibiting antidepressants Am J Psychiatry 2007 164 1121 1122 10.1176/ajp.2007.164.7.1121a 17606668 \n11 Wichman CL Cunningham JL A case of venlafaxine-induced galactorrhea? J Clin Psychopharmacol 2008 28 580 581 10.1097/JCP.0b013e318185a719 18794664 \n12 Muth EA Haskins JT Moyer JA Husbands GE Nielsen ST Sigg EB Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative Biochem Pharmacol 1986 35 4493 4497 10.1016/0006-2952(86)90769-0 3790168 \n13 Emiliano AB Fudge JL From galactorrhea to osteopenia: rethinking serotonin-prolactin interactions Neuropsychopharmacology 2004 29 833 846 10.1038/sj.npp.1300412 14997175\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "15(2)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Depression; Galactorrhea; Management; Prolactin; Therapeutics; Venlafaxine hydrochloride",
"medline_ta": "Clin Psychopharmacol Neurosci",
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"nlm_unique_id": "101207332",
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"pages": "181-183",
"pmc": null,
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"references": "19303910;3790168;14997175;26598592;17606668;12544389;4063616;18794664",
"title": "Dose Dependent Course of Hyperprolactinemic and Normoprolactinemic Galactorrhea Induced by Venlafaxine.",
"title_normalized": "dose dependent course of hyperprolactinemic and normoprolactinemic galactorrhea induced by venlafaxine"
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"abstract": "A 79-year-old man developed bilateral intermittent claudication. Peritoneal dialysis had been initiated at 55 years of age to manage chronic renal failure. In addition, he underwent kidney transplantation at 61 years of age. His Ankle-Brachial Index (ABI) was 0.82 and 0.71 for the right leg and left leg, respectively. Furthermore, his serum creatinine level had increased from 0.98 mg/dL to 2.38 mg/dL over the past 2 years. CT angiography revealed focal calcified stenosis in the terminal abdominal aorta. However, ultrasound revealed no significant stenotic lesion in the supplied artery bound to the transplanted kidney from the right external iliac artery. We performed endovascular therapy for abdominal aortic stenosis using the pressure gradient. Following the procedure, the patient's symptoms disappeared and the ABI increased to 1.25 and 1.14 in the right leg and left leg, respectively. Furthermore, the serum creatinine level improved to 0.96 mg/dL.",
"affiliations": "Cardiology, Kitaharima Medical Center, Ono, Japan shigeyasutsuda@yahoo.co.jp.",
"authors": "Tsuda|Shigeyasu|S|",
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"issue": "14(5)",
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"mesh_terms": "D000368:Aged; D001012:Aorta, Abdominal; D001024:Aortic Valve Stenosis; D003251:Constriction, Pathologic; D006801:Humans; D007083:Iliac Artery; D016030:Kidney Transplantation; D008297:Male",
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"references": null,
"title": "Endovascular abdominal aortic stenosis treatment alleviates renal failure after kidney transplantation.",
"title_normalized": "endovascular abdominal aortic stenosis treatment alleviates renal failure after kidney transplantation"
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{
"abstract": "Chemotherapy induced thrombopenia (CIT) is difficult to treat, as previous treatment options, including recombinant human thrombopoietin proved to be of limited efficacy. Here we report a case of a mantle cell lymphoma patient treated with intensive chemotherapy, who belongs to Yehova's witnesses and therefore did not accept platelet transfusions. At the time of severe thrombocytopenia (zero thrombocytes/ per mikroliter) and gastrointestinal bleeding, on day 13 following the start of hyperCVAD B chemotherapy, romiplostim treatment was given resulting in quick normalisation of the platelet count followed by thrombocytosis. Based on our observation in further studies modification of the dose and timing of romiplostim injection in CIT should be considered.",
"affiliations": "First Department of Medicine, Faculty of Medicine, Semmelweis University, Korányi Sándor utca 2/A, Budapest 1083, Hungary. demjud@bel1.sote.hu",
"authors": "Demeter|Judit|J|;Istenes|Ildiko|I|;Fodor|Anikó|A|;Paksi|Melinda|M|;Dombi|Peter|P|;Valasinyószki|Erika|E|;Csomor|Judit|J|;Matolcsy|András|A|;Nagy|Zsolt G|ZG|",
"chemical_list": "D000970:Antineoplastic Agents; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim",
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"issue": "17(1)",
"journal": "Pathology oncology research : POR",
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"medline_ta": "Pathol Oncol Res",
"mesh_terms": "D000970:Antineoplastic Agents; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013921:Thrombocytopenia; D013926:Thrombopoietin",
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"references": "15183904;16518601;18841052",
"title": "Efficacy of romiplostim in the treatment of chemotherapy induced thrombocytopenia (CIT) in a patient with mantle cell lymphoma.",
"title_normalized": "efficacy of romiplostim in the treatment of chemotherapy induced thrombocytopenia cit in a patient with mantle cell lymphoma"
} | [
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... |
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"abstract": "A 65-year-old man visited us with a painful penis after receiving an injection of hyaluronic acid into the penis for male genital augmentation. On admission, physical examination revealed black necrotic lesions and ulcerations on his glans penis. We performed partial penectomy to remove the necrotic tissues. Histopathological examination showed necrosis with severe inflammatory infiltration in the dermis and subcutis. Glans penile necrosis due to hyaluronic acid injected into the glans penis for male genital augmentation is exceedingly rare. This case is reported herein along with a review of the Japanese literature.",
"affiliations": "The Department of Urology, Japanese Red Cross Nagasaki Genbaku Hospital; The Department of Urology, Kouseikai Hospital.;The Department of Urology, Japanese Red Cross Nagasaki Genbaku Hospital.;The Department of Urology, Japanese Red Cross Nagasaki Genbaku Hospital.;Sakaguchi Urological Clinic.;The Department of Urology, Japanese Red Cross Nagasaki Genbaku Hospital.",
"authors": "Yamasaki|Yasuto|Y|;Asai|Akihiro|A|;Maruta|Sugure|S|;Sakaguchi|Miki|M|;Tsurusaki|Toshifumi|T|",
"chemical_list": "D006820:Hyaluronic Acid",
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"delete": false,
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"issue": "67(8)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
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"mesh_terms": "D000368:Aged; D006801:Humans; D006820:Hyaluronic Acid; D007267:Injections; D008297:Male; D009336:Necrosis; D010409:Penile Diseases; D010413:Penis",
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"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of Glans Penile Necrosis Due to Hyaluronic Acid into the Penis for Male Genital Augmentation.",
"title_normalized": "a case of glans penile necrosis due to hyaluronic acid into the penis for male genital augmentation"
} | [
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{
"abstract": "Infection with the emerging pathogen Clostridioides (Clostridium) difficile might lead to colonization of the gastrointestinal tract of humans and mammals eventually resulting in antibiotic-associated diarrhea, which can be mild to possibly life-threatening. Recurrences after antibiotic treatment have been described in 15-30% of the cases and are either caused by the original (relapse) or by new strains (reinfection). In this study, we describe a patient with ongoing recurrent C. difficile infections over 13 months. During this time, ten C. difficile strains of six different ribotypes could be isolated that were further characterized by phenotypic and genomic analyses including motility and sporulation assays, growth fitness and antibiotic susceptibility as well as whole-genome sequencing. PCR ribotyping of the isolates confirmed that the recurrences were a mixture of relapses and reinfections. One recurrence was due to a mixed infection with three different strains of two different ribotypes. Furthermore, genomes were sequenced and multi-locus sequence typing (MLST) was carried out, which identified the strains as members of sequence types (STs) 10, 11, 14 and 76. Comparison of the genomes of isolates of the same ST originating from recurrent CDI (relapses) indicated little within-patient microevolution and some concurrent within-patient diversity of closely related strains. Isolates of ribotype 126 that are binary toxin positive differed from other ribotypes in various phenotypic aspects including motility, sporulation behavior and cell morphology. Ribotype 126 is genetically related to ribotype 078 that has been associated with increased virulence. Isolates of the ribotype 126 exhibited elongated cells and a chaining phenotype, which was confirmed by membrane staining and scanning electron microscopy. Furthermore, this strain exhibits a sinking behavior in liquid medium in stationary growth phase. Taken together, our observation has proven multiple CDI recurrences that were based on a mixture of relapses and reinfections.",
"affiliations": "Institute of Medical Microbiology, University Medical Center Göttingen, Kreuzbergring 57, Göttingen, Germany. Electronic address: ugross@gwdg.de.;Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, Germany; Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, Department of Prosthetic Dentistry and Biomedical Materials Science, Hannover Medical School, Stadtfelddamm 34, Hannover, Germany.;Institute of Medical Microbiology, University Medical Center Göttingen, Kreuzbergring 57, Göttingen, Germany.;Institute of Functional and Applied Anatomy, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, Germany.;National Consulting Laboratory for Clostridium difficile, Germany.;Institute of Medical Microbiology, University Medical Center Göttingen, Kreuzbergring 57, Göttingen, Germany.;Institute of Medical Microbiology, University Medical Center Göttingen, Kreuzbergring 57, Göttingen, Germany.;Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, Germany; Max von Pettenkofer Institute, Ludwig-Maximilians-Universität München, Pettenkoferstr. 9a, 80336 Munich, Germany; DZIF German Center for Infection Research, Hannover-Braunschweig and Munich Partner Sites, Germany.",
"authors": "Sachsenheimer|F E|FE|;Yang|I|I|;Zimmermann|O|O|;Wrede|C|C|;Müller|L V|LV|;Gunka|K|K|;Groß|U|U|;Suerbaum|S|S|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Germany",
"delete": false,
"doi": "10.1016/j.ijmm.2018.02.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1438-4221",
"issue": "308(3)",
"journal": "International journal of medical microbiology : IJMM",
"keywords": "Clostridium difficile; Diversity; Genome; Recurrence; Reinfection; Relapse",
"medline_ta": "Int J Med Microbiol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D016360:Clostridioides difficile; D003015:Clostridium Infections; D005243:Feces; D014644:Genetic Variation; D016680:Genome, Bacterial; D005838:Genotype; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D058885:Multilocus Sequence Typing; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012008:Recurrence; D021521:Ribotyping; D000073336:Whole Genome Sequencing",
"nlm_unique_id": "100898849",
"other_id": null,
"pages": "364-377",
"pmc": null,
"pmid": "29490877",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Genomic and phenotypic diversity of Clostridium difficile during long-term sequential recurrences of infection.",
"title_normalized": "genomic and phenotypic diversity of clostridium difficile during long term sequential recurrences of infection"
} | [
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"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2018-03313",
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"abstract": "We report a case of acute middle cerebral territory ischemic infarction caused by left ventricular thrombus (LVT) in a doxorubicin cardiomyopathy patient. A major adverse effect of doxorubicin is cardiotoxicity. In doxorubicin cardiomyopathy, as the ventricular contractility decreases, LVT can occur and lead to systemic embolic events such as stroke.",
"affiliations": "Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea.",
"authors": "Lee|Eung-Joon|EJ|;Yoon|Byung-Woo|BW|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000502414",
"fulltext": null,
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"issn_linking": "1662-680X",
"issue": "12(Suppl 1)",
"journal": "Case reports in neurology",
"keywords": "Brain infarction; Cardiomyopathy; Doxorubicin; Stroke; Young adults",
"medline_ta": "Case Rep Neurol",
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"nlm_unique_id": "101517693",
"other_id": null,
"pages": "178-182",
"pmc": null,
"pmid": "33505292",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "19031015;4353012;26089924;6347112;20016174;22729833;18660728;22465037;7606656;25672172",
"title": "Acute Ischemic Stroke in a Young Patient with Left Ventricular Thrombus Attributed to Doxorubicin Cardiomyopathy.",
"title_normalized": "acute ischemic stroke in a young patient with left ventricular thrombus attributed to doxorubicin cardiomyopathy"
} | [
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"companynumb": "KR-BAXTER-2021BAX000880",
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"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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{
"abstract": "Chronic back pain is a multifactorial disease that occurs particularly in adults and has many negative effects on the quality of daily life. Therapeutic strategies are often multimodal and designed for a long-term therapy period. In some cases, one option is joint infiltration or intrathecal injection with local anaesthetics. An adverse effect of this intervention may be necrotic fasciitis, a disease with high mortality and few therapeutic options.\n\n\n\nThis case shows a 53-year-old female patient who developed necrotic fasciitis after infiltrations of the sacroiliac joint and after epidural-sacral and intrathecal injections.\n\n\n\nThanks to early and aggressive surgical intervention, antibiotic treatment and hyperbaric oxygenation, she survived this serious complication and was able to return to life.",
"affiliations": "Department of Anesthesiology and Surgical Intensive Care, University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany. lilit.floether@uk-halle.de.;Department of Anesthesiology and Surgical Intensive Care, University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany.;Department of Clinical Pharmacy and Pharmacotherapy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.;Department of Anesthesiology and Surgical Intensive Care, University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany.",
"authors": "Floether|Lilit|L|0000-0003-4825-327X;Bucher|Michael|M|;Benndorf|Ralf|R|;Burgdorff|Anna-Maria|AM|",
"chemical_list": "D000779:Anesthetics, Local; D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12871-020-01161-0",
"fulltext": "\n==== Front\nBMC Anesthesiol\nBMC Anesthesiol\nBMC Anesthesiology\n1471-2253 BioMed Central London \n\n1161\n10.1186/s12871-020-01161-0\nCase Report\nNecrotizing fasciitis caused by the treatment of chronic non-specific back pain\nhttp://orcid.org/0000-0003-4825-327XFloether Lilit lilit.floether@uk-halle.de 1 Bucher Michael 1 Benndorf Ralf 2 Burgdorff Anna-Maria 1 1 grid.461820.90000 0004 0390 1701Department of Anesthesiology and Surgical Intensive Care, University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany \n2 grid.9018.00000 0001 0679 2801Department of Clinical Pharmacy and Pharmacotherapy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany \n26 9 2020 \n26 9 2020 \n2020 \n20 2453 6 2020 15 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nChronic back pain is a multifactorial disease that occurs particularly in adults and has many negative effects on the quality of daily life. Therapeutic strategies are often multimodal and designed for a long-term therapy period. In some cases, one option is joint infiltration or intrathecal injection with local anaesthetics. An adverse effect of this intervention may be necrotic fasciitis, a disease with high mortality and few therapeutic options.\n\nCase presentation\nThis case shows a 53-year-old female patient who developed necrotic fasciitis after infiltrations of the sacroiliac joint and after epidural-sacral and intrathecal injections.\n\nConclusion\nThanks to early and aggressive surgical intervention, antibiotic treatment and hyperbaric oxygenation, she survived this serious complication and was able to return to life.\n\nKeywords\nChronic back painNecrotizing fasciitisHyperbaric oxygenationInfiltrationissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nChronic back pain is a worldwide disease that affects 70–80% of all adults during their life. Due to the duration and persistence of pain, it is associated with a significant disability in everyday life as well as a high psychosocial burden. This leads to high health care costs, absenteeism and economic burden [1, 2].\n\nDue to the complexity of chronic non-specific back pain, curative therapy usually consists of a multimodal concept. In the national German guidelines for the treatment of non-specific back pain, various non-drug measures (exercise therapy, acupuncture, psychological care) and drug measures (non-opioid analgesics, opioids) are recommended, whereby no recommendation could be given for invasive or intramuscular (subcutaneous) application [3]. Similarly, the European Guidelines for management of chronic nonspecific low back pain do not recommend epidural corticosteroids, intra-articular (facet) steroid injections and some other invasive treatments [4]. A necrotizing fasciitis may be a possible, albeit very rare, complication of such an invasive procedure. Causes of necrotizing fasciitis are usually bacterial infections (often beta-hemolytic Group A Streptococci or mixed infections) through injuries to the skin, e.g. punctures or perforations. Risk factors are diseases that often lead to microtrauma of the skin or wound infections, such as peripheral arterial disease, diabetes mellitus or obesity. Its course is characterized by a rapid progression and a high mortality rate of about 20% [5]. The therapeutic strategies of necrotizing fasciitis include early surgical intervention, antibiotic therapy and adjuvant measures such as hyperbaric oxygenation [6]. In this context, HBO, as part of a multimodal strategy consisting of surgery, antibiotics and intensive care, may reduce mortality from 34 to 11.9% compared to standard care [7].\n\nThe following casuistry describes a 53-year-old female patient who developed a fulminant necrotizing fasciitis after infiltration therapy for chronic non-specific back pain.\n\nCase presentation\nThe 53-year-old patient came to our department as an acute transfer via our central emergency room and presented with clinical symptoms of necrotizing fasciitis.\n\nFor more than 6 years, the patient has been complaining of recurrent pain in the lumbar spine with radiation into the right lower leg but without a sensorimotor deficit. In the past years she has presented several times as an outpatient and inpatient for pain therapy, where she received facet joint infiltrations and epidural-sacral injections, which provided her with short-term pain relief. Before her transfer to our clinic, the patient had received infiltrations of the sacroiliac joint (ISG) on January 14 and 18 with bupivacaine 0.5% and dexmethasone 4 mg, epidural-sacral on January 15 and 17 with prilocaine 1%, bupivacaine 0.5% and triamcinolone 40 mg and intrathecal injections on January 21 with bupivacaine 0.5% and triamcinolone 40 mg as a part of another inpatient multimodal therapy. Previously known from a computer tomography as reason for the pain episode were intervertebral disc protrusion L2-S1 with spondylarthrosis and facet joint arthrosis as well as irritation of the nerve from L5. The maximum score according Numeric Rating Scale (NRS) was given as 8–10 (previous year NRS 7–8), the walking distance was the same at 400-500 m, and there were still no sensorimotor deficits. The patient’s home pain medication included celecoxib 2x100mg p.o. In addition, oxycodone/naloxone 2x20mg p.o. and metamizole 4x1g intravenously were administered in the hospital. Additional known comorbidities were disc protrusions L3-S1 on the left, accompanied by spondyloarthritis of the lumbar spine, arterial hypertension, epilepsy, hypothyroidism and moderate depressive episodes. Therefore, the patient was also treated with torasemide 1x5mg, bisoprolol 1x5mg, levothyroxine 1 × 125 μg, candesartan 1x16mg, amlodipine 1x5mg and valproate 2x300mg.\n\nShortly thereafter, the patient showed signs of septic shock which began on January 23 with hypotension and increasing infection parameters (interleukin 6: 2610 pg/ml, CRP 358 mg/l, PCT 1,79 μg/l). This was interpreted to be associated with the abovementioned injection therapy. The patient had to be transferred to the intensive care unit. There she received a catecholamine therapy (norepinephrine perfusion with up to 0.2 μg/kg/min) and calculated antibiosis with meropenem (3 × 2 g) and clindamycin (3 × 600 mg). Since the patient had progressive pain in the back, right flank and right thigh, a computer tomography examination was performed to find the cause. This examination revealed a necrotizing fasciitis - suspicious finding consisting of subcutaneous fluid and air extending from the right thigh to the right knee. The patient presented clinically in a reduced general and obese nutritional state (BMI 31) and exhibited a mild circulatory depression. She suffered from massive pain in the entire right leg and back with accompanying redness of the area descending from the back over the right hip to the right knee. Furthermore, edematous soft tissue tension was palpable ranging from the right ankle to the right shoulder.\n\nDue to the rapidly progressing findings and the prevailing circulatory conditions, the immediate emergency surgical indication for an aggressive debridement of the necrotic tissue was made. The patient received an oral explanation and was intubated and ventilated in the operating room. The clinical findings were examined under anaesthesia, followed by wound debridement and vacuum-assisted-closure therapy (VAC). The patient had to remain intubated and ventilated on the intensive care unit of our hospital. An interdisciplinary discussion of the medical staff made the indication for an adjunctive therapy with HBO. She received a paracentesis and we started immediately with HBO. HBO was carried out according to Boerema TS 300–90 (one fraction) and Marx TS 240–90 (23 fractions). We continued antibiotic therapy extended by ciprofloxacin (3x400mg), after microbiological detection of Escherichia coli. In the following weeks, further wound revisions and HBO therapy sessions were carried out. To complement the pain therapy, the patient received a hydromorphone PCIA with 0.5 mg boli to cope pain peaks as well as metamizole 1 g every 6 h (Patient controlled intravenous analgesia) and was supported by the pain service unit. Five weeks after admission, the patient underwent plastic surgery with a rotating plastic flap on the right lower leg to the right patella and negative microbiological swab smears (Fig. 1). The further course of the patient was without complications.\nFig. 1 Results after multiple wound revisions and secondary wound closure\n\n\n\nDiscussion and conclusion\nThere are few conservative therapy methods with a significantly positive long-term effect for the treatment of chronic non-specific back pain. For therapy-refractory patients, as described in the present case, a multimodal therapy concept is always required. Injection therapy can be used after individual consideration, but has no evidence-based proven long-term effect [8]. Based on two meta-analyses [9, 10], the use of intrathecal and lumbosacral intra-articular injections can be proposed for the treatment of chronic spinal pain and chronic low back pain. However, there are only a few studies that have systematically investigated these procedures, which, moreover, must be regarded as studies of rather limited scientific conclusiveness. In these studies, no hazardous complications such as infections were reported. For instance, Kanai et al. (2017) described the therapy of chronic lower back pain using intrathecal bupivacaine injection as safe and effective [9].\n\nThe development of necrotizing fasciitis through injection therapy is nevertheless possible and is accompanied with an extremely complicated course with high lethality [5, 10]. In addition to the injection, the patient showed other risk factors including arterial hypertension and obesity, as mentioned previously,to develop complications such as necrotizing fasciitis [5, 10, 11]. This emphasizes the importance of the individual risk-benefit assessment that must be carried out before such invasive procedures are used. Nevertheless, the timely diagnosis of necrotizing fasciitis and the transfer to a center with HBO possibility, as presented in our case, led to a cure of this potential lethal disorder.\n\nThe treatment of necrotizing fasciitis consists primarily of early and aggressive surgical treatment as well as accompanying antibiotic therapy and supportive care. It was reported that a treatment delay (mortality from intervention within 24 h 6%, between 24 and 48 h 24%), of the operative care as well as an insufficient surgical debridement contribute to an increase in the mortality rate [6]. There are only few reported experimental data for HBO therapy in necrotizing fasciitis, although clostridial gangrene is considered well studied with this therapy. Nonetheless, a reduction in mortality and morbidity for necrotizing fasciitis with HBO is suggested based upon results from smaller studies [6, 11].\n\nIn conclusion the therapy of chronic non-specific back pain continues to be a challenge for doctors and patients. As part of the multimodal pain concept, invasive therapy measures should be discussed and implemented individually. When using injection therapies, these must be carried out strictly aseptically. The development of pain after injections should be accompanied by an immediate consultation with the attending physician in order to be able to identify and treat serious life-threatening, such as necrotizing fasciitis.\n\nThe mainstays of therapy of a necrotizing fasciitis include early and aggressive surgical debridement, antibiotics and supportive care. Adjuvant methods such as protein synthesis inhibitors, hyperbaric oxygen and intravenous immunoglobulin may play a role in the treatment, but further proof of efficacy is necessary to allow for an evidence-based recommendation.\n\nAbbreviations\nBMIBody-Mass-Index\n\nHBOHyperbaric oxygenation\n\nNRSNumeric Rating Scale\n\nISGSacroiliac joint\n\nVACVacuum-assisted-closure therapy\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nLF manage the patient and write the manuscript. MB and RB helped write the manuscript. AMB conduct the background research and helped write the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe University and State Library of the Martin-Luther-University Halle-Wittenberg supports open access publications with a publication fund to finance the publication fees. The donors had no interest or influence to any parts of this manuscript. They have no knowledge about the content. Open Access funding enabled and organized by Projekt DEAL.\n\nAvailability of data and materials\nThe datasets generated and analysed for the case report are not publicly available due to protect participant confidentiality. They 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 to publish the case was obtained from the patient. Institutional consent is available.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Mathieson S Kasch R Maher CG Pinto RZ McLachlan AJ Koes BW Combination drug therapy for the Management of low Back Pain and Sciatica: systematic review and meta-analysis J Pain 2019 20 1 15 10.1016/j.jpain.2018.06.005 30585164 \n2. Paolucci T Attanasi C Cecchini W Marazzi A Capobianco SV Santilli V Chronic low back pain and postural rehabilitation exercise: a literature review J Pain Res 2019 12 95 107 10.2147/JPR.S171729 30588084 \n3. Bundesärztekammer, Kassenärztliche Bundesvereinigung, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften: Nationale VersorgungsLeitlinie Nicht-spezifischer Kreuzschmerz – Langfassung. 2. Auflage. Version 1. Belin; 2017.\n4. Airaksinen O Brox JI Cedraschi C Hildebrandt J Klaber-Moffett J Kovacs F Chapter 4. European guidelines for the management of chronic nonspecific low back pain Eur Spine J 2006 15 Suppl 2 S192 S300 10.1007/s00586-006-1072-1 16550448 \n5. Friederichs J Torka S Militz M Bühren V Hungerer S Necrotizing soft tissue infections after injection therapy: higher mortality and worse outcome compared to other entry mechanisms J Inf Secur 2015 71 312 316 \n6. Young MH Engleberg NC Mulla ZD Aronoff DM Therapies for necrotising fasciitis Expert Opin Biol Ther 2006 6 155 165 10.1517/14712598.6.2.155 16436041 \n7. Escobar SJ Slade JB Jr Hunt TK Cianci P Adjuvant hyperbaric oxygen therapy (HBO2) for treatment of necrotizing fasciitis reduces mortality and amputation rate Undersea Hyperb Med 2005 32 437 443 16509286 \n8. Bredow J Bloess K Oppermann J Boese CK Löhrer L Eysel P Konservative Therapie beim unspezifischen, chronischen Kreuzschmerz: Evidenz der Wirksamkeit - eine systematische Literaturanalyse Orthopade 2016 45 573 578 10.1007/s00132-016-3248-7 27075679 \n9. Kanai A Okamoto T Hayashi N Shimao J Nagahara Y Fujii K Short-term results of intrathecal injection of low-dose bupivacaine in outpatients with chronic low back and lower extremity pain Eur Spine J 2019 28 250 258 10.1007/s00586-018-5801-z 30367241 \n10. Young MH Aronoff DM Engleberg NC Necrotizing fasciitis: pathogenesis and treatment Expert Rev Anti-Infect Ther 2005 3 279 294 10.1586/14787210.3.2.279 15918785 \n11. Leiblein M Marzi I Sander AL Barker JH Ebert F Frank J Necrotizing fasciitis: treatment concepts and clinical results Eur J Trauma Emerg Surg 2018 44 279 290 10.1007/s00068-017-0792-8 28484782\n\n",
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"journal": "BMC anesthesiology",
"keywords": "Chronic back pain; Hyperbaric oxygenation; Infiltration; Necrotizing fasciitis",
"medline_ta": "BMC Anesthesiol",
"mesh_terms": "D000779:Anesthetics, Local; D000900:Anti-Bacterial Agents; D001416:Back Pain; D059350:Chronic Pain; D019115:Fasciitis, Necrotizing; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D007278:Injections, Spinal; D008875:Middle Aged",
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"pubdate": "2020-09-26",
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"title": "Necrotizing fasciitis caused by the treatment of chronic non-specific back pain.",
"title_normalized": "necrotizing fasciitis caused by the treatment of chronic non specific back pain"
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"abstract": "A case of acute generalized exanthematous pustulosis (AGEP) is presented. The case is notable for the recurrent episodes of AGEP, caused by three beta-lactam antibiotics (piperacillin, ceftazidime, and meropenem) in septicemic patient. The case represents the first report of the reaction developing in response to these three antibiotics. The report is also notable for the spontaneous resolution of the rash in all the three episodes.",
"affiliations": "Salmaniya Hospital, PB 12, Manama, Bahrain. venkatm@batelco.com.bh",
"authors": "Mysore|V|V|;Ghuloom|A|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D013845:Thienamycins; D002442:Ceftazidime; D000077731:Meropenem; D010878:Piperacillin",
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"title": "A case of recurrent acute generalized exanthematous pustulosis due to beta-lactam antibiotics: a case report.",
"title_normalized": "a case of recurrent acute generalized exanthematous pustulosis due to beta lactam antibiotics a case report"
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{
"abstract": "OBJECTIVE\nProspective data on the safety of endovascular thrombectomy in acute stroke patients on non-vitamin K antagonist oral anticoagulants are lacking.\n\n\nMETHODS\nProspective multicenter observational study. Patients with ischemic stroke undergoing thrombectomy with or without preceding thrombolysis were enrolled into the Registry of Acute Ischemic Stroke Under New Oral Anticoagulants. Baseline characteristics and functional outcome at 3 months were assessed. Hemorrhagic transformation and symptomatic intracranial hemorrhage were analyzed. Reperfusion was graded using the modified Thrombolysis in Cerebral Infarction score.\n\n\nRESULTS\nOf 28 patients treated with thrombectomy, 5 had received also systemic thrombolysis (18%). Intracranial hemorrhage was observed in 46%, but symptomatic intracranial hemorrhage occurred only in 1 patient. Successful reperfusion (Thrombolysis in Cerebral Infarction score, 2b-3) was achieved in 59%. At 3 months, 19% had a modified Rankin Scale score of 0 to 2, and mortality was 26%.\n\n\nCONCLUSIONS\nThrombectomy in non-vitamin K antagonist oral anticoagulant patients seems safe although a comparatively high rate of asymptomatic hemorrhagic transformation was noted. Confirmation in larger prospective controlled cohorts is necessary.\n\n\nBACKGROUND\nURL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797.",
"affiliations": "From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.).;From the Departments of Neurology (J.C.P., T.R., S.K., P.A.R., R.V.) and Neuroradiology (M.W.), University Hospital Heidelberg, Heidelberg, Germany; Institute of Clinical Epidemiology and Biometry (K.H., P.U.H.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Münster, Münster, Germany (R.D.); Department of Neurology (C.K.), and Comprehensive Heart Failure Center and Clinical Trial Center (P.U.H.), University Hospital Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Kiel, Kiel, Germany (A.B.); Department of Neurology, University Hospital Mainz, Mainz, Germany (K.G.); Department of Neurology, University Hospital Mannheim, Mannheim, Germany (M.G.H.); Departments of Neuroradiology (K.L.) and Stroke Medicine (R.V.), Imperial College London, London, United Kingdom; Department of Neurology, University Hospital Tübingen, Tübingen, Germany (S.P.); Department of Neurology, Asklepios Klinik Nord, Hamburg, Germany (G.S.); and Department of Neurology, Klinikum Fulda, Fulda, Germany (T.N.-H.). r.veltkamp@imperial.ac.uk.",
"authors": "Purrucker|Jan C|JC|;Wolf|Marcel|M|;Haas|Kirsten|K|;Rizos|Timolaos|T|;Khan|Shujah|S|;Dziewas|Rainer|R|;Kleinschnitz|Christoph|C|;Binder|Andreas|A|;Gröschel|Klaus|K|;Hennerici|Michael G|MG|;Lobotesis|Kyriakos|K|;Poli|Sven|S|;Seidel|Günter|G|;Neumann-Haefelin|Tobias|T|;Ringleb|Peter A|PA|;Heuschmann|Peter U|PU|;Veltkamp|Roland|R|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1161/STROKEAHA.116.012684",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0039-2499",
"issue": "47(4)",
"journal": "Stroke",
"keywords": "anticoagulants; intracranial hemorrhage; stroke; thrombectomy",
"medline_ta": "Stroke",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D002545:Brain Ischemia; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D011446:Prospective Studies; D020521:Stroke; D017131:Thrombectomy; D015912:Thrombolytic Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "0235266",
"other_id": null,
"pages": "1127-30",
"pmc": null,
"pmid": "26931156",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety of Endovascular Thrombectomy in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulants.",
"title_normalized": "safety of endovascular thrombectomy in patients receiving non vitamin k antagonist oral anticoagulants"
} | [
{
"companynumb": "GB-ROCHE-1750626",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nTo describe the outcome of using diode laser transscleral cyclophotocoagulation (cyclodiode laser) as a safe technique in managing acute angle closure refractory to conventional treatment.\n\n\nMETHODS\nThis is a retrospective case series from two ophthalmic units in the United Kingdom. Five patients with acute angle closure refractory to medical and laser treatment underwent cyclodiode laser treatment. Demographic information, symptoms, medical and surgical treatment, visual outcomes, and intraocular pressure (IOP) control were recorded.\n\n\nMETHODS\nAll five patients had symptomatic acute angle closure. Conventional management, including topical and systemic medical treatment, laser iridotomy and laser iridoplasty, did not achieve adequate IOP control or relieve symptoms. Emergency cyclodiode laser treatment was performed within 2-23 days of presentation. All patients subsequently required lensectomy at a later date. At final follow-up (6-14 months), all patients had visual acuity of 6/12 or better with well-controlled IOPs (≤ 17 mm Hg). Only one patient was on topical treatment. One patient developed a persistent low-grade anterior uveitis.\n\n\nCONCLUSIONS\nCyclodiode laser is a safe alternative to emergency lensectomy or trabeculectomy in cases of acute angle closure, which do not respond to treatment.",
"affiliations": "Birmingham Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK. a.manna@nhs.net",
"authors": "Manna|A|A|;Foster|P|P|;Papadopoulos|M|M|;Nolan|W|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/eye.2011.361",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0950-222X",
"issue": "26(5)",
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D002924:Ciliary Body; D005260:Female; D015812:Glaucoma, Angle-Closure; D006801:Humans; D007429:Intraocular Pressure; D032801:Iridectomy; D017075:Laser Coagulation; D054023:Lasers, Semiconductor; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014065:Tonometry, Ocular; D016896:Treatment Outcome; D014792:Visual Acuity",
"nlm_unique_id": "8703986",
"other_id": null,
"pages": "742-5",
"pmc": null,
"pmid": "22302062",
"pubdate": "2012-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21127509;12897582;18164064;10889101;11713091;12483091;15741811;11162972;11772581;8640440;10201585",
"title": "Cyclodiode laser in the treatment of acute angle closure.",
"title_normalized": "cyclodiode laser in the treatment of acute angle closure"
} | [
{
"companynumb": "ALCN2012GB005096",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE SODIUM PHOSPHATE"
},
"drugadditional": "... |
{
"abstract": "Mucositis is a common side effect due to chemo and/radiation therapy. Caphosol has been a proven preventive strategy against mucositis in randomized clinical trials. However, its efficacy to treat active mucositis in patients treated for solid tumors with chemotherapy is unknown. The objective was to evaluate the efficacy of Caphosol to treat mucositis by comparing the grade of mucositis before and after treatment and documenting the duration of treatment.\nA retrospective review was conducted on consecutive adult patients at London Regional Cancer Program (LRCP) who developed chemotherapy-induced oral mucositis and were then treated with Caphosol. This study was approved by ethics committee at University of Western Ontario.\nA total of 21 patients, two males (one with cancer esophagus and another with lung cancer) and 19 females (all with breast cancer), with a median age of 59 years were evaluated. Grade 3 mucositis was present in 4 patients who completely resolved with Caphosol in an average of 4 days of treatment, without needing any hospitalization. Fifteen patients with grade 2 mucositis reverted back to grade 0 by using Caphosol for an average of 3.5 days. One patient with no effect had grade 1 mucositis dating prior to treatment with chemotherapy and remained as such. Another patient with no initial improvement had oral candidiasis and once treated with Fluconozole and Caphosol had a complete resolution. No obvious side effects were reported by patients related to the use of Caphosol.\nOur case series, for the first time, shows that Caphosol may be used as a potentially effective treatment in patients with solid tumor, who develop chemotherapy-induced mucositis.",
"affiliations": "Department of Medical Oncology, London Regional Cancer Program, London, ON N6A 4L6, Canada.;Department of Nursing, London Regional Cancer Program, Canada.;Department of Social Sciences, University of Western Ontario, Canada.;Department of Pharmacy, London Regional Cancer Program, London, ON N6A 4L6, Canada.",
"authors": "Younus|Jawaid|J|;Kligman|Lynda|L|;Jawaid|M A|MA|;Dhalla|Ally|A|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.4021/wjon683e",
"fulltext": "\n==== Front\nWorld J OncolWorld J OncolElmer PressWorld Journal of Oncology1920-45311920-454XElmer Press 10.4021/wjon683eOriginal ArticleTreatment of Active Mucositis With Caphosol (Calcium Phosphate): A Retrospective Case-Series Treatment of Active Mucositis With CaphosolYounus Jawaid aKligman Lynda bJawaid M. A. cDhalla Ally da Department of Medical Oncology, London Regional Cancer Program, London, ON N6A 4L6, Canadab Department of Nursing, London Regional Cancer Program, Canadac Department of Social Sciences, University of Western Ontario, Canadad Department of Pharmacy, London Regional Cancer Program, London, ON N6A 4L6, Canadae Corresponding author: Jawaid Younus, Department of Medical Oncology, London Regional Cancer Program, London, ON N6A 4L6, Canada. Email: jawaid.younus@lhsc.on.ca6 2013 15 7 2013 4 3 147 150 11 6 2013 Copyright 2013, Younus et al.2013This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nMucositis is a common side effect due to chemo and/radiation therapy. Caphosol has been a proven preventive strategy against mucositis in randomized clinical trials. However, its efficacy to treat active mucositis in patients treated for solid tumors with chemotherapy is unknown. The objective was to evaluate the efficacy of Caphosol to treat mucositis by comparing the grade of mucositis before and after treatment and documenting the duration of treatment.\n\nMethods\nA retrospective review was conducted on consecutive adult patients at London Regional Cancer Program (LRCP) who developed chemotherapy-induced oral mucositis and were then treated with Caphosol. This study was approved by ethics committee at University of Western Ontario.\n\nResults\nA total of 21 patients, two males (one with cancer esophagus and another with lung cancer) and 19 females (all with breast cancer), with a median age of 59 years were evaluated. Grade 3 mucositis was present in 4 patients who completely resolved with Caphosol in an average of 4 days of treatment, without needing any hospitalization. Fifteen patients with grade 2 mucositis reverted back to grade 0 by using Caphosol for an average of 3.5 days. One patient with no effect had grade 1 mucositis dating prior to treatment with chemotherapy and remained as such. Another patient with no initial improvement had oral candidiasis and once treated with Fluconozole and Caphosol had a complete resolution. No obvious side effects were reported by patients related to the use of Caphosol.\n\nConclusion\nOur case series, for the first time, shows that Caphosol may be used as a potentially effective treatment in patients with solid tumor, who develop chemotherapy-induced mucositis.\n\nMucositisChemotherapyCaphosolCalcium phosphate\n==== Body\nIntroduction\nOral mucositis is a common side effect induced by chemotherapy and or radiation therapy [1, 2]. Although the incidence varies with the chemotherapy agents and the use of overlapping radiation therapy, it is estimated that oral mucositis may be present in about 35% of such patients [1, 2]. The incidence is likely higher [3] with targeted therapies against epidermal growth factor receptor (like Gefitinib and Erlotinib) and with mTOR inhibitors (for example: Everolimus). The mucosal injury process may require several steps but results in mild to moderate discomfort in the mouth with erythema and/ulceration (grade 1 and 2 respectively). The progression causes inability to eat and may require intra-venous fluid/enteral support usually in the hospital setting (grade 3 and 4 severity respectively).\n\nThe treatment of mucositis has been largely symptomatic with the use of routine oral care, the use of soft toothbrush, soft and less irritating foods and analgesia. The present literature [4] has no support for the use of benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and “magic mouthwash” (lidocaine solution, diphenhydramine hydrochloride and aluminum hydroxide suspension).\n\nNeutral supersaturated calcium phosphate rinse (Caphosol) has been found to be an effective preventive strategy against mucositis [5, 6]. Caphosol reduced the duration of days with mucositis as well as the pain severity along with the reduction in the use of narcotic analgesics among the treated patients. Although the exact mechanism is unknown, Caphosol may help mucositis by altering oral pH and providing calcium and phosphate ions to the local tissues for faster wound healing [5]. There is presently no data regarding the use or efficacy of Caphosol against the developed mucositis inpatients with solid tumors. Here we present a case series of 21 consecutive patients with chemotherapy-induced mucositis treated with Caphosol.\n\nStudy Design/Method\nWe conducted a retrospective chart review on adult oncology patients, treated at London Regional Cancer Program, London, ON, who developed chemotherapy-induced mucositis and were treated with Caphosol. These patients were not treated with radiation therapy either prior to concomitant with chemotherapy. No other mouth rinse or mouth wash was used in the study patients. This study was approved by ethics committee at University of Western Ontario. Caphosol was provided as a compassionate supply by Suparna Pharma, Canada. These patients who were prescribed and provided with Caphosol from this compassionate supply program between June and November of 2012 were tracked through the LRCP pharmacy. Their age, diagnosis, chemotherapy regimen, grade of mucositis before and after the use of Caphosol, side effects with the use of Caphosol, frequency of Caphosol use per day and total number of days taken to achieve the best response were recorded from their electronic and paper charts. These patients were instructed to combine the two ampoules (calcium and phosphate) and use it as swish and spit in two quick sessions for each dose, four times daily till resolution of symptoms. This was a pilot observational study and therefore no statistical computations were considered for the design or results.\n\nResults\nA total of 21 patients were evaluated. The median age was 59 years. Majority (19) of patients had the diagnosis of breast cancer, while one patient had cancer of esophagus and another patient had non-small cell lung cancer. Both of these patients were males. The chemotherapy regimens for these patients as well as other parameters are listed in Table 1. The most severe grade of mucositis prior to Caphosol treatment was 3, present in 4 patients. All four patients experienced complete resolution of mucositis after treatment with Caphosol. Among these four patients, the duration of Caphosol treatment was three days for two patients and 5 days for other two patients, with average of 4 days. Two patients used it four times daily while the other two used it twice or three times. These patients were able to avoid hospitalization. Grade 2 mucositis was present in 15 patients prior to the treatment. This was reverted back to grade 0 by using Caphosol for an average of 3.5 days (range: 2 - 7 days). One patient who had grade 1 mucositis had no improvement with Caphosol therapy. It was later confirmed that this patient had her symptoms dating back to several months prior to starting chemotherapy. Another patient who presented with grade 2 mucositis experienced no initial improvement with Caphosol. On a subsequent visit she was found to have oral candidiasis. Fluconozole was added to the Caphosol therapy and the patient had a complete resolution within 5 days. The most common frequency of Caphosol use was recorded as 4 times per day (range: 2 - 4). No obvious side effects were reported by patients with the use of Caphosol.\n\nTable 1 The Chemotherapy Regimens and Other Parameters\nAge (Yrs)\tDiagnosis\tChemotherapy\tWorst Grade Initial\tGrade - Post Treatment\tDuration of Treatment (Days)\tFrequency X/Day\t\n1. 72\tNon-Small Cell Lung Ca\tCarboplatin + Vinblastine\t2\t0\t1\t4\t\n2. 54\tBreast Ca\tTC\t3\t0\t5\t4\t\n3. 50\tBreast Ca\tAC x 4\nDoc x 4 Herceptin\t2\t0\t2\t4\t\n4. 57\tBreast Ca\tFEC-D\t2\t0\t2\t2\t\n5. 68\tBreast Ca\tAC/T Dose dense\t2\t0\t5\t4\t\n6. 76\tBreast Ca\tFEC-D\t3\t0\t3\t2\t\n7. 47\tBreast Ca\tTC\t2\t0\t2\t4\t\n8. 67\tBreast Ca\tCMF\t1\t1\t5\t4\t\n9. 51\tBreast Ca\tAC/T Dose dense Herceptin\t2\t2\t7\t4\t\n10. 50\tBreast Ca\tAC/T Dose dense\t2\t0\t2\t2\t\n11. 67\tEsophageal Ca\tECF\t3\t0\t5\t4\t\n12. 59\tBreast Ca\tWeekly Doc\t2\t0\t3\t3\t\n13. 45\tBreast Ca\tCapecitibine\t3\t0\t7\t4\t\n14. 70\tBreast Ca\tFEC-D\t2\t1\t3\t2\t\n15. 53\tBreast Ca\tFEC-D\t2\t0\t6\t3\t\n16. 64\tBreast Ca\tFEC-D\t2\t0\t7\t4\t\n17. 60\tBreast Ca\tCis + Gem\t2\t0\t5\t4\t\n18. 40\tBreast Ca\tFEC-D\t2\t0\t3\t4\t\n19. 59\tBreast Ca\tFEC-D\t2\t0\t5\t4\t\n20. 63\tBreast Ca\tTC\t2\t0\t3\t4\t\n21. 57\tBreast Ca\tFEC-D\t2\t0\t4\t4\t\nTC: Taxotere and Cyclophosphamide, AC: Adriamycin and Cyclophosphamide, Doc: Docetaxel (Taxotere), FEC-D: 5 Flourouracil, Epirubicin and Cyclophosphamide-Taxotere, AC/T: Adriamycin, Cyclophosphamide and Paclitaxel, CMF: Cyclophosphamide, Methotrexate and 5 Flourouracil, ECF: Epirubicin, Cisplatin and 5 Flourouracil, Cis + Gem: Cisplatin and Gemcitibine.\n\nDiscussion\nOral mucositis continues to be a challenging symptom to the treating physicians as very few therapeutic options are currently available. The most recent update by the mucositis study group from multi-national association of supportive care in cancer (MASCC) does not list any active treatment in patients who have developed chemotherapy-induced mucositis [7]. We treated 21 patients with Caphosol, who presented with variable grades of mucositis induced by chemotherapy. Almost all patients in our case series experienced complete resolution of their symptoms with oral mucositis. The duration of Caphosol therapy was only 4 - 5 days with no reported side effects.\n\nThe efficacy of Caphosol (calcium-phosphate solution) as a preventive strategy against mucositis is well established through prospective clinical trials [5, 6]. As a preventive strategy, Caphosol treatment duration of few weeks may be well justified with the high proportion of patients developing significant mucositis, particularly among patients with head and neck cancer or in patients undergoing high dose chemo-radiation therapy for bone marrow transplant. The efficacy of Caphosol is not known as an active treatment for patients with solid tumors suffering from mucositis induced by chemotherapy. Certainly, the incidence of oral mucositis is comparatively lower in patients with solid tumors treated with chemotherapy. However, mucositis will be seen more frequently in oncology patients with solid tumors as we will be increasingly using targeted therapies. In these patients, instead of a preventive treatment, amelioration of mucositis symptoms through an active therapy appears more reasonable.\n\nOur case series has a number of limitations. In addition to being a retrospective analysis, we only followed 21 patients and these were selected on the basis of being treated with Caphosol, through a compassionate supply from the Canadian distributor. The severity, duration and recovery of neutropenia that could have potentially affected the improvement in mucositis were not recorded. The grade of mucositis were recorded by the physicians using the same scale, however, individual variation is possible. There were no side effects recorded with the use of Caphosol but this information is self-reported and subject to the recall bias.\n\nAs we have observed in our case series, Caphosol may be a potentially effective therapy in patients with solid tumors suffering from chemotherapy-induced mucositis. Despite the limitations listed for our case-series, we are encouraged by majority of patients responding so well to Caphosol. Since there has been no published trial or case-series evaluating the role of Caphosol as an active treatment for mucositis, this case series may be considered to provide some basis to conduct a larger randomized study in future.\n==== Refs\nReferences\n1 Sonis ST Elting LS Keefe D Peterson DE Schubert M Hauer-Jensen M Bekele BN et al Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients Cancer 2004 100 9 Suppl 1995 2025 10.1002/cncr.20162 15108222 \n2 Keefe DM Schubert MM Elting LS Sonis ST Epstein JB Raber-Durlacher JE Migliorati CA et al Updated clinical practice guidelines for the prevention and treatment of mucositis Cancer 2007 109 5 820 831 10.1002/cncr.22484 17236223 \n3 Boers-Doets CB Epstein JB Raber-Durlacher JE Ouwerkerk J Logan RM Brakenhoff JA Lacouture ME et al Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review Oncologist 2012 17 1 135 144 10.1634/theoncologist.2011-0111 22207567 \n4 Worthington HV Clarkson JE Eden OB Interventions for treating oral mucositis for patients with cancer receiving treatment Cochrane Database Syst Rev 2002 1 CD001973 11869616 \n5 Papas AS Clark RE Martuscelli G O'Loughlin KT Johansen E Miller KB A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation Bone Marrow Transplant 2003 31 8 705 712 10.1038/sj.bmt.1703870 12692611 \n6 Wasko-Grabowska A Rzepecki P Oborska S Barzal J Mlot B Gawronski K Wasko M et al A supersaturated calcium phosphate solution seems to effectively prevent and treat oral mucositis in haematopoietic stem cell transplanted cancer patients - single centre experience J BUON 2012 17 2 363 368 22740219 \n7 Keefe DM Schubert MM Elting LS Sonis ST Epstein JB Raber-Durlacher JE Migliorati CA McGuire DB Hutchins RD Peterson DE Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology Cancer 2007 3 1 109 5 820 831 10.1002/cncr.22484 17236223\n\n",
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"abstract": "The incidence of breast cancer in female-to-male (FTM) transsexuals who received mastectomy and sex reassignment surgery is very rare. In fact, there is only one previous medical report of such a case. We experienced a case of an FTM transsexual who developed breast cancer 12 years after mastectomy and hysterectomy with bilateral salpingo-oophorectomy. Because he had been continuously receiving testosterone during the last 15 years and because histopathological examination revealed positive estrogen receptor and androgen receptor expression, we suggest that exogenous testosterone may have initiated the development of breast cancer via two distinct pathways. We describe the clinical course and condition of the patient and recommend that medical personnel consider the possibility of hormone-related cancer in FTM transsexuals receiving cross-sex hormones.",
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"title": "A very rare case of breast cancer in a female-to-male transsexual.",
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"abstract": "The novel coronavirus (Covid-19) continues to wreck havoc across China, European countries, USA and now seems to gain a strong foothold in India. The aim of this report is to describe the clinical profiles of these Covid-19 infected patients admitted in Sawai Mansingh Hospital(S.M.S), Jaipur ranging from their age, sex, travel history, clinical symptoms, laboratory evaluation, radiological characteristics, treatment provided along with common side effects and the final outcome. The described cases are one of the earliest cases of Covid-19 in the Indian subcontinent.\nEpidemiological, clinical, laboratory, and radiological characteristics and treatment and outcomes data were obtained with data collection forms from electronic medical records and history given by 21 Covid-19 infected patients admitted in S.M.S., Jaipur. Patients were tested for Covid-19 by real-time reverse transcription polymerase chain reaction (RT-PCR) assay of 2019-nCoVRNA.\nDuring the course of this study 21 Covid-19 positive patients were admitted in S.M.S Hospital, Jaipur. Male patients constituted 66.66% of total patients and majority of the patients (80.90%) were below 60 years of age. Most of the patients (71.40%) were either foreigners or had a history of foreign travel suggesting that these cases were not community acquired except for 4 cases from textile producing district Bhilwara (known as Manchester of India), an epicenter of North India. Approximately 33.33% patients were completely asymptomatic and of those who were symptomatic cough was the most common symptom (85.71%) followed by fever (78.57%), myalgia (64.28%), headache (28.57%) and dyspnea (28.57%). Three patients (14.28 %) had underlying co morbidity in the form of hypertension, diabetes mellitus, hypothyroidism, chronic kidney disease or coronary artery disease. 11 patients (52.38%) had lymphopenia in their hemogram during the course of admission. 3 patients (14.28%) had leucocytosis and 4 patients (19.04%) presented with thrombocytopenia. All 4 patients in the severe category had raised FDP, D-Dimer levels and they needed oxygen support. These patients had deranged liver functions and had elevated pro-calcitonin levels, serum ferritin levels and LDH levels. 1 out of the these 4 cases went into ARDS during the course of treatment. 10 patients yielded negative results for Covid-19. The mean duration from admission to getting 1st Covid-19 sample negative was 8.3 days. 18 patients (85.71%) are still under treatment.\nClinical investigations in initial Covid-19 patients in the Indian subcontinent reveal lymphopenia as predominant finding in hemogram. Patients with older age and associated comorbid conditions (COPD and diabetes) seem to have greater risk for lung injury thereby requiring oxygen support during the course of disease and these patients also had greater derangement in their biochemical profile.",
"affiliations": "SMS Medical College and Attached Group of Hospital, Jaipur, Rajasthan.;SMS Medical College and Attached Group of Hospital, Jaipur, Rajasthan.;Associate Professor, Department of Medicine, SMS Medical College, Jaipur, Rajasthan.;SMS Medical College and Attached Group of Hospital, Jaipur, Rajasthan.;SMS Medical College and Attached Group of Hospital, Jaipur, Rajasthan.;SMS Medical College and Attached Group of Hospital, Jaipur, Rajasthan.",
"authors": "Bhandari|Sudhir|S|;Bhargava|Abhishek|A|;Sharma|Shrikant|S|;Keshwani|Prakash|P|;Sharma|Raman|R|;Banerjee|Subrata|S|",
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"title": "Clinical Profile of Covid-19 Infected Patients Admitted in a Tertiary Care Hospital in North India.",
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"abstract": "Atraumatic splenic rupture (ASR) is a rare complication of acute pancreatitis with high mortality and morbidity rates. We present a case of a 63-year-old woman with a history of hypertension, presenting with acute pancreatitis who subsequently developed a splenic rupture requiring a laparotomy and splenectomy. ASR is a rare but life-threatening complication requiring prompt recognition and management and should be considered in patient with pancreatitis who develops sudden haemodynamic compromise and worsening anaemia.",
"affiliations": "Surgery, Austin Health, Heidelberg, Victoria, Australia roshini.nadaraja@gmail.com.;Surgery, Austin Health, Heidelberg, Victoria, Australia.;Surgery, Austin Health, Heidelberg, Victoria, Australia.;Surgery, Austin Health, Heidelberg, Victoria, Australia.",
"authors": "Nadaraja|Roshini|R|;Yahya|Zarif|Z|;Mori|Krinal|K|;Aly|Ahmad|A|",
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"title": "Atraumatic splenic rupture in patient with acute pancreatitis.",
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"abstract": "Hepatosplenic T cell lymphoma (HSTCL) is a type of hematologic neoplasia with a poor prognosis and a high frequency of refractoriness to conventional chemotherapy. The results obtained by high dose chemotherapy followed by autologous stem cells transplantation seem to be a more effective option but still unsatisfactory. Also the role of allogeneic stem cell transplantation is still unclear, although the few cases reported on the literature would seem to show good results in overall survival rates. In this paper, we reported the patient׳s medical history affected by a αβ variant of hepatosplenic T cell successfully rescued with a haploidentical transplant.",
"affiliations": "Hematology and Marrow Transplant, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Hematology and Marrow Transplant, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Hematology and Marrow Transplant, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Hematology and Marrow Transplant, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Division of Anatomic-Pathology, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Department of Pathology, Center for Experimental Research and Medical Studies, University of Torino, Turin, Italy.;Divison of Transfusion Medicine, A.O. SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Divison of Transfusion Medicine, A.O. SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Hematology and Marrow Transplant, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Hematology and Marrow Transplant, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.",
"authors": "Catania|Gioacchino|G|;Zallio|Francesco|F|;Monaco|Federico|F|;Corsetti|Maria Teresa|MT|;Trincheri|Nicol|N|;Bonello|Lisa|L|;Mele|Lia|L|;Dallavalle|Franco|F|;Salvi|Flavia|F|;Pini|Massimo|M|",
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"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(14)00019-310.1016/j.lrr.2014.09.001Case ReportSuccessful HLA haploidentical myeloablative stem cell transplantation for aggressive hepatosplenic alpha/beta (αβ) T-cell lymphoma Catania Gioacchino danycatania2@hotmail.ita⁎Zallio Francesco aMonaco Federico aCorsetti Maria Teresa aTrincheri Nicol bBonello Lisa cMele Lia dDallavalle Franco dSalvi Flavia aPini Massimo aa Hematology and Marrow Transplant, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italyb Division of Anatomic-Pathology, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italyc Department of Pathology, Center for Experimental Research and Medical Studies, University of Torino, Turin, Italyd Divison of Transfusion Medicine, A.O. SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy⁎ Corresponding author. danycatania2@hotmail.it28 10 2014 28 10 2014 2014 3 2 90 93 27 5 2014 2 9 2014 15 9 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Hepatosplenic T cell lymphoma (HSTCL) is a type of hematologic neoplasia with a poor prognosis and a high frequency of refractoriness to conventional chemotherapy. The results obtained by high dose chemotherapy followed by autologous stem cells transplantation seem to be a more effective option but still unsatisfactory. Also the role of allogeneic stem cell transplantation is still unclear, although the few cases reported on the literature would seem to show good results in overall survival rates.\n\nIn this paper, we reported the patient׳s medical history affected by a αβ variant of hepatosplenic T cell successfully rescued with a haploidentical transplant.\n\nHighlights\n• Hepatosplenic T-cell lymphoma is associated with a poor prognosis.\n\n• Allogeneic stem cell transplantation has a role in treatment of refractory lymphoma.\n\n• The haploidentical SCT may offer a strategy in patients without a matched donor.\n\n\n\nKeywords\nHepatosplenic T-cell lymphomaαβ T-lymphocytesTCR rearrangementHaploidentical-SCT\n==== Body\n1 Introduction\nHepatosplenic T cell lymphoma (HSTCL) is a very rare type of hematologic malignancy, making up about 5% of peripheral T-cell lymphomas. It predominantly affects young male adults, with a higher incidence in patients submitted to immunosuppressive treatment for chronic inflammatory bowel disease. This unfrequent lymphoma is characterized by extranodal infiltration of mature malignant post-thymic T-lymphocytes into sinusoids of the liver and spleen, so it usually presents with hepatosplenomegaly (without lymphadenopathy) and the presence of peripheral blood cytopenia, which reflects a high incidence of bone marrow infiltration [1].\n\nTwo subtypes of HSTCL are described in the last World Health Organization (WHO) classification: a more common form expressing γδ T-cell receptor (TCR) chain and a rarer second one expressing αβ TCR chain. Both present similar onset and clinical course and the αβ subtype of HSTCL is considered an immunophenotypic variant.\n\nHSTCL is a highly aggressive malignancy associated with a poor prognosis, because the results obtained by conventional chemotherapy usually are disappointing, with a median overall survival barely exceeding 1 year [2]. Given the rarity and the aggressiveness of the disease, several investigators have explored the use of high dose chemotherapy supported by autologous stem cell transplantation (SCT), without drawing any definite conclusions [3,4].\n\nAllogeneic SCT (BMT) has a well established role in the treatment of otherwise incurable malignancies; in relapsed or refractory peripheral T-cell lymphoma, alloSCT enables to achieve a long-term remission in nearly 40% of the patients [5].\n\nIn patients affected by HSTCL there are anedoctal reports and small case series reporting beneficial effect of the allografting procedure, using HLA identical sibling or matched unrelated donors (MUD) [6–8].\n\nIn this report we describe, probably, the first case of refractory HSTCL to a previous autologous SCT and successfully rescued by a haploidentical allogeneic stem cell transplant (Haploidentical-SCT).\n\n2 Case report\nA 48-year-old man, without any relevant past medical problems and no social/physiological abnormalities, was referred to our service in May 2012 with fever, fatigue, weight loss, sweating and abdominal pain. He showed a considerable hepatomegaly (extending for 8 cm below the right costal margin) and splenomegaly (extending for 14 cm below the left costal margin). Laboratory data showed: haemoglobin level 11 g/dL, platelet count 72×109/L, white blood cell count 3.5×109/L with neutropenia (0.96×109/L) without morphological abnormalities; AST 184 IU/L and ALT 128 IU/L (normal values 10–40 IU/l); Lactate-dehydrogenase 4390 IU/L (normal<500 IU/L). Serologic test for toxoplasmosis, cytomegalovirus, EBV, HIV, hepatitis, herpesvirus were negative.\n\nBone marrow analysis revealed the presence of 15% of cells with morphological aspect of medium-size lymphocytes with agranular cytoplasm and irregular shaped nuclei with nucleoli.\n\nThe flow cytometric immunophenotyping analysis of the bone marrow cells was positive for CD3 bright, TCR alpha-beta, CD2, CD16, CD56 and negative for CD4, CD8, CD5 and CD20.\n\nTCR gene arrangement was studied by PCR analysis on marrow sample and showed clonal restriction of αβ chain [9]. Cytogenetic analysis revealed a normal karyotype.\n\nA liver biopsy depicted an abnormal lymphocytic infiltrate CD3 positive, CD 4 and CD 8 negative and with the same TCR αβ clonal restriction pattern (Fig. 1).\n\nA computed tomography (CT) was made for completing the work-up and showed enlarged liver and a massive splenomegaly with compressive picture on the stomach and with stenosis of splenic vein and dislocation of the kidney. Cerebrospinal fluid analysis was negative. All these findings were diagnostic of hepatosplenic αβ T cell lymphoma, stage IV B.\n\nThe patient was started on induction chemotherapy containing cyclophosphamide, vincristine, etoposide, doxorubicin and prednisone (CHOEP) plus central nervous (CNS) prophylaxis with methotrexate and steroid. After the first cycle the patient׳s clinical picture did not improved, with persisting hepato-splenomegaly and liver dysfunction; therefore, we decided to intensify the treatment protocol with the Hyper-C-HIDAM regimen (cyclophosphamide 300 mg/m2 days 1–3 plus high-dose cytarabine 2 g/m2 bid days 1–3 and methotrexate 2000 mg/m2 for 24 h of continuous infusion). After three courses a partial remission (PR) was achieved, with reduction of spleen size but persistence of neoplastic marrow involvement. During the fourth course of Hyper-C-HIDAM the patient was submitted to peripheral blood stem cell (PBSC) mobilization, with a yield of 6.8×106/kg. In October 2012, a high-dose conditioning therapy (FEAM) was begun with fotemustine (150 mg/m2 −7, −6), etoposide (100 mg2/m2 −5, −4, −3, −2), cytarabine (200 mg2/m2 −5, −4, −3, −2) and melphalan (140 mg/m2 −1), followed by reinfusion of autologous PBSC (3.40 CD34+ cells×106/kg).\n\nOn day 30 after autoSCT the patient underwent a clinical and laboratoristic restaging: while total body positron emission tomography (PET) pointed out a complete response with the normalization of the hepato-splenomegaly, the bone marrow aspirate revealed the persistence of an abnormal lymphoid population with the same immunophenotypic profile (7% of cells).\n\nConsidering the disease persistence, a decision was made to perform an allogeneic stem cells transplant with a non myeloabtive conditioning (NMA). Since the patient had neither sibling nor voluntary donors it was established to carry out a HLA-haploidentical SCT from his daughter. Unfortunately, just a week before starting the preparative regimen, lymphoma progressed with an increasing splenomegaly, worsening of pancytopenia and increasing of the pathologic lymphoid cells in the marrow (70% of cells). Having evidence of the lymphoma׳s refractoriness and considering the patient׳s young age we re-scheduled our initial program towards a myeloablative conditioning regimen containing thiotepa (5 mg/kg −6, −5 days), Busulphan (3.2 mg/kg −5, −4, −3 days) and Fludarabine (30 mg/m2 −7, −6, −5, −4 days), with reinfusion of 2.66×106/kg of CD 34+ bone marrow stem cells.\n\nGraft versus host disease prophylaxis included tacrolimus, mycophenolate mofetil and post transplant cyclophosfamide (50 mg/kg on days +3 and +4) as previously proposed by Baltimora׳s group.\n\nEngraftment post SCT was achieved successfully with complete recovery of hematologic blood count cells at day +18. Chimerism evaluation at day +28 revealed full donor chimerism, which was confirmed also at days +60 and +90, with contemporary demonstration of immunophenotipic complete remission at bone marrow aspirate. Patient did not show any sign of acute graft versus host disease (GVDH). The only one acute complication was an episode of hemorrhagic cystitis secondary to BK virus reactivation, successfully treated with cidofovir. Six months after transplant, during tapering of immunosuppression, limited chronic GVHD of skin and eyes developed, requiring a brief course of steroid plus UV-B applications; calcineurin inhibitors were substituted with low dose rapamycin.\n\nAfter a follow up of 18 months patient is in good clinical conditions, in persisting complete remission as established both by PET and CT scan. Moreover the TCR αβ molecular analysis shows an oligoclonal pattern fully distinct from which manifested during the disease (Fig. 2).\n\n3 Discussion\nIn this paper, we report the experience on a patient affected by a αβ variant of hepatosplenic T cell lymphoma, with rapid progression after autologous stem cell transplant and successfully rescued with a haploidentical transplant. Some important considerations might come up from our report.\n\nFirst, the clinical course of the disease confirmed the dismal outcome of this subtype of lymphoma with conventional chemotherapy.\n\nWe started with a CHOP regimen but after the first cycle we had to shift the therapeutic approach towards a salvage regimen. We administered four cycles of hyper-C-HiDAM protocol, a therapeutic scheme containing hyperfractionated cyclophosphamide plus high-doses of Ara-C and methotrexate [10] followed by autoSCT. This approach is reported being effective for patients with aggressive NHL refractory to first-line anthracycline-containing regimens. A partial remission was obtained at the end of the program. However, as previously reported in PTCL [11,12], only the achievement of complete remission after induction therapy is a strong predictor of long term survival; thus, in this category of patients with a high risk of disease recurrence the general recommendation is to proceed rapidly to an allogeneic transplant. Unfortunately the major problem is related to the aggressiveness of the underlying disease, that does not allow to have enough time to find a suitable donor and to proceed to transplantation.\n\nConsidering the disease׳s aggressiveness and the lack of related or unrelated full match HLA donor; we decided to proceed anyway using the haploidentical daughter, despite the very few cases reported on the literature about the haplo transplants in this particular subtype of lymphoma.\n\nHistorically, alloSCT from HLA-haploidentical relatives has been limited by an unacceptably high non-relapse mortality, due to high rates of graft rejection and GVHD [13].\n\nT-cell depletion of the donor graft represented a step forward in the haplo setting, but it required a high level of expertise in laboratory techniques [14].\n\nRecently, the Baltimora and Seattle groups have pioneered a method to selectively deplete alloreactive cells in vivo by administering high doses of cyclophosphamide immediately post haplo-transplant (PT/Cy) after a nonmyeloablative conditioning regimen. This approach resulted in a very low NRM, due to low incidences of GVHD and infectious complications [15]. In the previous years several studies [16–18] have confirmed the encouraging results of the haploidentical PT/Cy strategy. This alternative source with haploidentical donor is growing as a valid alternative option if a matched related donor is not rapidly available.\n\nAt the beginning our strategy was to follow the Baltimora׳s original scheme; however, given the very fast disease progression, we decided to change the type of pre-transplant conditioning therapy. We chose a myeloablative regimen with Thiotepa, Bufulsano and Fludarabine, in an attempt to achieve a better disease control in a patient with a well established refractory malignancy [19].\n\nAllogeneic transplantation with myeloablative conditioning in peripheral T-cell lymphoma is a potentially curative option [20], but it is associated with a high treatment-related mortality (TRM), in particular after a failed autoSCT [21].Our patient at the time of transplant was in a relatively young age, in good clinical conditions, and without significative comorbidities (Sorror score 0), despite disease progression and previous treatment.\n\nFor that reason, our primary objective was to provide maximal tumor cytoreduction using a myeloablative preparation regimen containing high doses of Thiotepa and Busulphan in order to obtain a better disease control. The efficacy of this treatment was proved by the demonstration of complete remission at the day +60 (no spleen and liver activity on PET scan and the absence of marrow monoclonal infiltrate).\n\nFinally, as previously reported [22] in other subtypes of peripheral T cell lymphomas, the persistence of complete remission after allografting corroborates the perception that a graft-versus-T cell lymphoma effect may play a role in the curative potential of alloSCT.\n\nFocusing on the clinical history of the patient, we observed a rapid disease progression few weeks after conventional chemotherapy and also after autologous transplant; on the contrary we did not reveal any sign of any molecular relapse after more than one year of follow-up post haploidentical transplant, as demonstrated by the oligoclonal TCR pattern.\n\nIn conclusion, this report confirms that management of HSTCL refractory to conventional chemotherapy is still challenging. Some evidence suggested that haploidentical-SCT can activate an effective graft-versus lymphoma also in chemoresistant disease. This approach could offer a valid and safety alternative strategy in patients with neither a HLA-matched sibling or unrelated donor.\n\nConflict of interest\nNone of the authors has to declare a conflict of interest.\n\nFig. 1 Liver biopsy demonstrating a monomorphic, mostly intrasinusoidal, lymphoid infiltrate (arrow) composed of small to medium size cells (H&E stain, 500×).\n\nFig. 2 PCR analysis of TCRβ gene rearrangement using BIOMED-2 protocol. Genescan clonality profiles of bone marrow aspirates at diagnosis (A) and after allogeneic stem cells transplantation (B). Clonal products (arrows) at diagnosis are no more visible at follow up after allogeneic transplantion and a different oligoclonal pattern emerge.\n==== Refs\nReferences\n1 Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990 Leukemia 14 2000 991 997 10865963 \n2 Belhadj K. Reyes F. Farcet J.P. Hepatosplenic γδ T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients Blood 102 2003 4261 4269 12907441 \n3 Chalmers A.W. Katz D.A. Miller I.J. Gregory S.A. Successful treatment of hepatosplenic T-cell lymphoma with ESHAP followed by autologous stem cell transplant Clin Adv Hematol Oncol 11 2013 109 113 23598914 \n4 Voss M.H. Lunning M.A. Maragulia J.C. Intensive induction chemotherapy followed by early high-dose therapy and hematopoietic stem cell transplantation results in improved outcome for patients with hepatosplenic T-cell lymphoma: a single institution experience Clin Lymphoma Myeloma Leuk 13 2013 8 14 23107915 \n5 Dodero A. Spina F. Narni F. Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus-lymphoma effect Leukemia 26 2012 520 526 21904377 \n6 Konuma T. Ooi J. Takahashi S. Allogeneic stem cell transplantation for hepatosplenic gammadelta T-cell lymphoma Leuk Lymphoma 48 2007 630 632 17454612 \n7 Falchook G.S. Vega F. Dang N.H. Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment Ann Oncol 20 2009 1080 1085 19237479 \n8 Sakai R. Fujisawa S. Fujimaki K. Long-term remission in a patient with hepatosplenic gammadelta T cell lymphoma after cord blood stem cell transplantation following autologous peripheral blood stem cell transplantation Bone Marrow Transplant 37 2006 537 538 16415891 \n9 Van Dongen J.J. Langerak A.W. Brüggemann M. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the Biomed-2 Concerted Action BMH4-CT98-3936 Leukemia 2003 2257 2317 14671650 \n10 Todeschini G. Tecchio C. Pasini F. Hyperfractionated cyclophosphamide with high-doses of arabinosylcytosine and methotrexate (HyperCHiDAM Verona 897) Cancer 104 2005 555 560 15959910 \n11 Corradini P. Tarella C. Zallio F. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation Leukemia 20 2006 1533 1538 16871285 \n12 d’Amore F. Relander T. Lauritzsen G.F. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01 J Clin Oncol 30 2012 3093 3099 22851556 \n13 Powles R.L. Morgenstern G.R. Kay H.E. Mismatched family donors for bone-marrow transplantation as treatment for acute leukaemia Lancet 1 1983 612 615 6131300 \n14 Aversa F. Tabilio A. Terenzi A. Successful engraftment of T-cell-depleted haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum Blood 1 84 1994 3948 3955 7524753 \n15 Luznik L. O’Donnell P.V. Fuchs E.J. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation Semin Oncol 39 2012 683 693 23206845 \n16 Kanakry J.A. Kasamon Y.L. Gocke C.D. Outcomes of related donor HLA-identical or HLA-haploidentical allogeneic blood or marrow transplantation for peripheral T cell lymphoma Biol Blood Marrow Transplant 19 2013 602 606 23370119 \n17 Bashey A. Zhang X. Sizemore C.A. T cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosfamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplant J Clin Oncol 1 31 2013 1310 1316 23423745 \n18 Solomon S.R. Sizemore C.A. Sanacore M. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high risk hematologic malignancies who lack conventional donors in well tolerated and produces excellent relapse-free survival Biol Blood Marrow Transplant 18 2012 1859 1866 22863841 \n19 Raiola A.M. Dominietto A. Ghiso A. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning Biol Blood Marrow Transplant 19 2013 117 122 22940057 \n20 Le Gouill S. Milpied N. Buzyn A. Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Société Francaise de Greffe de Moëlle et de Thérapie Cellulaire J Clin Oncol 10 26 2008 2264 2271 18390969 \n21 Tsai T. Goodman S. Saez R. Allogeneic bone marrow transplantation in patients who relapse after autologous transplantation Bone Marrow Transplant 20 1997 859 863 9404927 \n22 He S. Roberts A. Ritchie D. Graft-versus-lymphoma effect in progressive hepatosplenic gamma/delta T-cell lymphoma Leuk Lymphoma 48 2007 1448 1450 17613781\n\n",
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"journal": "Leukemia research reports",
"keywords": "Haploidentical-SCT; Hepatosplenic T-cell lymphoma; TCR rearrangement; αβ T-lymphocytes",
"medline_ta": "Leuk Res Rep",
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"title": "Successful HLA haploidentical myeloablative stem cell transplantation for aggressive hepatosplenic alpha/beta (αβ) T-cell lymphoma.",
"title_normalized": "successful hla haploidentical myeloablative stem cell transplantation for aggressive hepatosplenic alpha beta t cell lymphoma"
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"abstract": "A 75-year-old man having dementia and lifestyle related diseases developed a lobar intracerebral hemorrhage (LICH) in the left parietal and a small cerebellar infarction in the left occipital lobe. Many micro bleeds (MB) due to cerebral amyloid angiopathy (CAA) in the subcortical areas and multiple vascular stenosis were also found by MRI and MRA. He developed herpes zoster in his buttocks on day 6 of hospitalization and complicated with varicella zoster virus (VZV) meningitis with positive for VZV-DNA in the cerebrospinal fluid. Subsequently, LICHs occurred in the left frontal lobe and in the right parietal lobe for a short period of time and died on the day 18. We speculated that the repeating hemorrhages was primarily caused by VZV vasculopathy and additionally the subcortical MBs increased the hemorrhagic risk. The relationship between VZV vasculopathy and CAA should be studied in the future.",
"affiliations": "Department of Neurology, Brain Attack Center, Ota Memorial Hospital.;Department of Neurology, Brain Attack Center, Ota Memorial Hospital.;Department of Neurology, Brain Attack Center, Ota Memorial Hospital.;Department of Neurology, Brain Attack Center, Ota Memorial Hospital.;Department of Neurology, Brain Attack Center, Ota Memorial Hospital.;Department of Neurology, Brain Attack Center, Ota Memorial Hospital.",
"authors": "Takeshita|Jun|J|;Nomura|Eiichi|E|;Takemaru|Makoto|M|;Himeno|Takahiro|T|;Shimoe|Yutaka|Y|;Kuriyama|Masaru|M|",
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"keywords": "atherosclerosis; cerebral amyloid angiopathy; hemorrhagic risk; lobar intracerebral hemorrhage; varicella zoster virus vasculopathy",
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000368:Aged; D016657:Cerebral Amyloid Angiopathy; D002543:Cerebral Hemorrhage; D018450:Disease Progression; D017809:Fatal Outcome; D005625:Frontal Lobe; D006562:Herpes Zoster; D006801:Humans; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008297:Male; D010296:Parietal Lobe; D012008:Recurrence; D020293:Vasculitis, Central Nervous System",
"nlm_unique_id": "0417466",
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"title": "Rapidly deteriorated lobar intracerebral hemorrhages: possible association of varicella zoster virus-vasculopathy.",
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"abstract": "The sympathetic nervous system plays an important role in arrhythmogenesis in arrhythmogenic right ventricular cardiomyopathy (ARVC). Sudden cardiac death commonly occurs during exertion, and β-blockers are associated with a reduction in arrhythmia burden. Bilateral cardiac sympathetic denervation (BCSD) has been shown to reduce implantable cardioverter-defibrillator (ICD) shocks in patients with structural heart disease and refractory ventricular tachycardia (VT); however, data in ARVC are sparse.\n\n\n\nThe purpose of this study was to evaluate the role of BCSD in patients with ARVC and refractory VT.\n\n\n\nConsecutive patients with ARVC who underwent BCSD because of refractory VT were included. Number of ICD shocks, sustained VT episodes, VT storm, and antiarrhythmic therapy were assessed and compared before and after the intervention. VT-free survival rate, death, and heart transplantation were also evaluated.\n\n\n\nEight patients with ARVC (mean age 32 ± 20 years; 3 men [38%]) underwent sympathectomy for recurrent VT. All patients failed catheter ablation, and 50% had a desmosomal mutation identified. Procedural complications included neuropathic pain, paravertebral venous plexus injury, and pneumothorax. Over a mean follow-up of 1.9 ± 0.9 years, 5 patients (63%) had no VT recurrence. BCSD significantly reduced the number of ICD shocks or sustained VT compared with 1-year pre-BCSD (mean 12.6 ± 18.2 and median 6.5 [interquartile range 4.5-10.5] pre-BCSD vs 0.9 ± 1.4 and 0 [interquartile range 0-1.5] post-BCSD; P = .011). Most of the patients (88%) were on β-blocker therapy alone at the end of follow-up. One patient underwent heart transplantation because of heart failure, and no deaths occurred.\n\n\n\nBCSD may be an effective option for patients with ARVC and refractory ventricular arrhythmia who have failed conventional treatment modalities.",
"affiliations": "Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: fassis1@jhmi.edu.;Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Cardiac Surgery, PennState Health Milton S. Hershey Medical Center, Hershey, Pennsylvania.",
"authors": "Assis|Fabrizio R|FR|;Krishnan|Aravind|A|;Zhou|Xun|X|;James|Cynthia A|CA|;Murray|Brittney|B|;Tichnell|Crystal|C|;Berger|Ronald|R|;Calkins|Hugh|H|;Tandri|Harikrishna|H|;Mandal|Kaushik|K|",
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"doi": "10.1016/j.hrthm.2019.01.019",
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"issue": "16(7)",
"journal": "Heart rhythm",
"keywords": "Arrhythmogenic right ventricular dysplasia/cardiomyopathy; Cardiac sympathetic denervation; ICD shocks; Refractory ventricular tachycardia; Sympathectomy; Ventricular tachycardia recurrence",
"medline_ta": "Heart Rhythm",
"mesh_terms": "D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D011183:Postoperative Complications; D012189:Retrospective Studies; D015996:Survival Rate; D013562:Sympathectomy; D017180:Tachycardia, Ventricular",
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"pubdate": "2019-07",
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"references": null,
"title": "Cardiac sympathectomy for refractory ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy.",
"title_normalized": "cardiac sympathectomy for refractory ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy"
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"abstract": "BACKGROUND The normalization of serum lactate levels in a patient with non-syndromic mitochondrial disorder due to the m.3243A>G mitochondrial DNA (mtDNA) variant has not been previously reported. CASE REPORT A 57-year-old woman was diagnosed with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to the m.3243A>G variant, with low heteroplasmy rates (31%), at age 50. The initial manifestations were short stature, migraine, and diabetes. With progression of the disease, multisystem involvement developed, affecting the brain (stroke-like episode, mild cognitive impairment), eyes (pigmentary retinopathy), ears and the vestibular system (impaired hearing, tinnitus, imbalance, drop attacks, vertigo), intestines (constipation, distended abdomen, gastro-esophageal reflux, gastroparesis), and the muscles (muscle weakness). The gastrointestinal involvement was most prominent and most significantly lowered the patient's quality of life. The diabetes was well controlled with an insulin pump. Recurrent, acute deteriorations responded favorably to L-arginine. Owing to lifestyle and diet changes 2 years after diagnosis (start of art classes, increase in spin biking to 22.5 km 3 times per week, travel to Hawaii, adherence to low-carbohydrate high-protein diet), the patient managed to lower elevated serum lactate levels to largely normal values. CONCLUSIONS Gastrointestinal compromise may be the prominent manifestation of the m.3243A>G variant, lifestyle and diet changes may lower serum lactate in m.3243A>G carriers, and low heteroplasmy rates of the m.3243A>G variant in scarcely affected tissues do not exclude pathogenicity.",
"affiliations": "Neurological Department, Landstrasse Clinic, Messerli Institute, Vienna, Austria.",
"authors": "Finsterer|Josef|J|",
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"doi": "10.12659/AJCR.930175",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n33867519\n10.12659/AJCR.930175\n930175\nArticles\nLifestyle Changes Normalize Serum Lactate Levels in an m.3243A>G Carrier\nFinsterer Josef ABCDE\nNeurological Department, Landstrasse Clinic, Messerli Institute, Vienna, Austria\nCorresponding Author: Josef Finsterer, e-mail: fifigs1@yahoo.de\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n19 4 2021\n22 e930175-1e930175-5\n01 12 2020\n04 3 2021\n15 3 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 57-year-old\n\nFinal Diagnosis: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)\n\nSymptoms: Fatigue • gastrointestinal\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Neurology\n\nObjective:\n\nChallenging differential diagnosis\n\nBackground:\n\nThe normalization of serum lactate levels in a patient with non-syndromic mitochondrial disorder due to the m.3243A>G mitochondrial DNA (mtDNA) variant has not been previously reported.\n\nCase Report:\n\nA 57-year-old woman was diagnosed with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) due to the m.3243A>G variant, with low heteroplasmy rates (31%), at age 50. The initial manifestations were short stature, migraine, and diabetes. With progression of the disease, multisystem involvement developed, affecting the brain (stroke-like episode, mild cognitive impairment), eyes (pigmentary retinopathy), ears and the vestibular system (impaired hearing, tinnitus, imbalance, drop attacks, vertigo), intestines (constipation, distended abdomen, gastro-esophageal reflux, gastroparesis), and the muscles (muscle weakness). The gastrointestinal involvement was most prominent and most significantly lowered the patient’s quality of life. The diabetes was well controlled with an insulin pump. Recurrent, acute deteriorations responded favorably to L-arginine. Owing to lifestyle and diet changes 2 years after diagnosis (start of art classes, increase in spin biking to 22.5 km 3 times per week, travel to Hawaii, adherence to low-carbohydrate high-protein diet), the patient managed to lower elevated serum lactate levels to largely normal values.\n\nConclusions:\n\nGastrointestinal compromise may be the prominent manifestation of the m.3243A>G variant, lifestyle and diet changes may lower serum lactate in m.3243A>G carriers, and low heteroplasmy rates of the m.3243A>G variant in scarcely affected tissues do not exclude pathogenicity.\n\nKeywords:\n\nMELAS Syndrome\nMitochondria\nMitochondrial Proton-Translocating ATPases\n==== Body\nBackground\n\nThe m.3243A>G variant is one of the most common point mutations of mitochondrial DNA (mtDNA) [1]. The m.3243A>G variant is located within the mtDNA gene MT-TL1, which encodes the mitochondrial transfer ribonucleic acid (tRNA) leucine-1. Generally, tRNAs help assemble protein building blocks (amino acids) into functioning proteins. Leucine tRNA specifically attaches to the amino acid leucine and inserts it into the appropriate locations in the growing protein during protein assembly. The variant m.3243A>G manifests phenotypically in a broad spectrum of diseases. The most well-known phenotype is mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. In 80% of the cases, MELAS is due to the variant m.3243A>G [1]. More rarely, the m.3243A>G variant manifests as maternally inherited diabetes and deafness syndrome, myoclonic epilepsy with ragged red fiber syndrome, Leigh syndrome, progressive external ophthalmoplegia, or MELAS/Kearns-Sayre overlap syndrome [2]. In addition to these syndromic phenotypes, the variant m.3243A>G manifests with non-syndromic phenotypes, which do not fit to any of the more than 50 mitochondrial syndromes. Although gastrointestinal involvement is known in m.3243A>G carriers [3], predominant gastrointestinal compromise and normalization of serum lactate levels have not been reported in non-syndromic m.3243A>G carriers. This report presents a case of a woman with mitochondrial encephalopathy, lactic acidosis, and MELAS syndrome due to the m.3243A>G variant. This study was approved by the institutional review board.\n\nCase Report\n\nThe patient was a 57-year-old woman, with a height of 155 cm and weight of 56 kg, who was diagnosed with MELAS at the age of 50 years. The initial manifestations of MELAS were a short stature since early childhood and migraine since age 17 years. When the patient was between 20 and 35 years of age, she had recurrent lower urinary tract infections, which were repeatedly treated with ciprofloxacin (800 mg/day for 3 days). During her only pregnancy at age 30, she experienced gestational diabetes. Additionally, she experienced postpartum depression and transient weakness of the lower legs, after epidural anesthesia for Cesarean section, which was conducted in the absence of clinical indications for deep venous thrombosis or nerve injury. Since pregnancy, she had symptoms of a distended abdomen. Starting at age 38, she developed progressive impaired hearing, and diabetes was diagnosed, which was treated with metformin (up to 2000 mg/day). Starting at age 40, she began experiencing recurrent episodes of hearing loss, left ear tinnitus, imbalance, drop attacks, and occasional vertigo, which were interpreted as Meniere’s disease. Since age 42, she had intermittent dysphagia. At age 48, an episode of depression developed following the deaths of her mother and brother. Insulin treatment was added to the metformin regimen at age 49 years. At age 50, sudden-onset weakness of the left upper limb, slurred speech, blurred vision, and tandem gait occurred, and were interpreted as a stroke-like episode. Cerebral magnetic resonance imaging (MRI), carried out within 6 h after onset, showed T1-hyperintensity of the globus pallidum bilaterally and the left posterior thalamus, but no stroke-like lesion was detected. Additionally, there were some non-specific, subcortical T2-hyperintense spots. The patient’s lactate level was elevated, but L-arginine was not given. At age 51 years, pigmentary retinopathy (“speckled pigment” maculopathy) was diagnosed, and a genetic work-up revealed the common MELAS mutation m.3243A>G in MT-TL1, with a heteroplasmy rate of 31% in buccal mucosa cells. Two other mtDNA variants, m.5084A>G in MT-ND2 and m.16362T>C in the D-loop, with heteroplasmy rates of 9% and 4%, respectively, were additionally detected. A muscle biopsy was not carried out. Instead, a second genetic test revealed the m.3243A>G variant, but in the blood lymphocytes, with a heteroplasmy rate of 14%. MELAS was diagnosed, and a mitochondrial cocktail was prescribed. The metformin was discontinued.\n\nSince the first episode, the patient experienced recurrent episodes of slurred speech, imbalance, and left-sided weakness, lasting between a few minutes and a few hours, which always resolved with intravenous L-arginine. At age 52 years, the patient had recurrence of a distended abdomen and constipation, and gastro-esophageal reflux disease (GERD) and gastroparesis were diagnosed. Laxatives helped little, and probiotics were ineffective. Transient sinus tachycardia was recorded on an electrocardiogram (telemetry). Changes in lifestyle (start of art classes, increase in spin biking to 22.5 km 3 times per week, travel to Hawaii, and daughter moving out of state for new job) and adherence to a low-carbohydrate, protein-rich diet resulted in the normalization of the patient’s serum lac-tate level (Figure 1). A cerebral MRI at age 53 years was unchanged from previous findings. The patient started recognizing weakness of the left lower leg upon exercising. Since age 54 years, the patient’s creatine-kinase level had been slightly but constantly elevated. A cerebral computed tomography scan at age 57 years showed marked bilateral basal ganglia calcification. She had multiple allergies, including milk, corn, pork, lobster, mussels, monosodium glutamate, preservatives, sulfites, nitrates, pollen, ragweed, trees, grass, dust, mold, many chemicals, perfumes, cosmetics, and many drugs, particularly antibiotics. Her last medication included insulin in a pump, antihistamines, potassium, and magnesium. Additionally, she was taking liquid ubiquinol, citrulline, taurine, vitamin B complex (riboflavin, vitamin B12), vitamin D3, alpha-lipoic acid, nicotinamide riboside, and N-acetyl-cysteine. The patient was on a low-carbohydrate (30 g to 50 g daily) diet for diabetes and ate protein-rich food, healthy fats, and medium-chain triglyceride oil. She tolerated soft foods and liquids better than she did solid foods. A clinical neurologic exam at age 57 years revealed mildly delayed recall, hypoacusis, mild dysarthria, microphonia, and weakness of the left deltoid (M4+), left hip flexors (M4), and left plantar flexors (M4+).\n\nThe patient’s family history was positive for suspected mitochondrial disorder; however, none of the index patient’s relatives had been genetically tested (Figure 2). Her daughter’s history included hypoacusis, migraine, attention deficit disorder, and a depressive episode. Her mother had mononucleosis, hypothyroidism, arterial hypertension, 1 stillbirth, and gallstones and died at 72 years of age from pancreatitis, which had been attributed to the gallstones (Figure 2). The grandmother from the mother’s side had Parkinsonism and died at age 69 years. The index patient had 1 sister and 2 brothers (Figure 2). One brother had a history of severe mononucleosis, bipolar disorder, psychosis, several suicide attempts, and alcohol and drug misuse. At age 48 years, the brother was diagnosed with multiple sclerosis. He died from cardiopulmonary arrest at 53 years of age, but an autopsy was not performed. The other brother was healthy, as was the sister, who had a history of smoking and alcohol abuse. The index patient’s mother had 7 siblings. An 88-year-old sister of the mother had mild memory impairment, hypoacusis, Brown-Sequard syndrome, and arthritis. One brother of the mother presumably died from a heart attack at 45 years of age. He had a history of alcohol abuse, smoking, and arterial hypertension. An 84-year-old sister had prediabetes since age 80 years, atrial fibrillation, and a history of thyroidectomy because of malignancy. One brother drank alcohol and smoked, developed diabetes, hypoacusis, and heart failure, and died at 84 years of age. A 79-year-old brother was exposed to Agent Orange during the Vietnam War, which caused long-term pulmonary compromise. A 77-year-old brother had psychosis and had also been exposed to Agent Orange in Vietnam. A 74-year-old sister of the mother was healthy. Among 3 cousins of the index patient (children of the 84-year-old aunt), a 60-year-old woman had Hashimoto’s disease, Graves’ disease, and a hip replacement; a 58-year-old woman had anosognosia and a history of smoking and alcohol and drug misuse; and a 52-year-old man had an intestinal carcinoid (Figure 2).\n\nDiscussion\n\nThe presented patient is interesting for the non-syndromic, multisystem nature of the phenotype, normalization of serum lactate upon lifestyle and diet changes, predominant gastrointestinal manifestations, and the low heteroplasmy rate of the variant, which was responsible for the phenotype.\n\nThe phenotype was definitively non-syndromic because it did not fulfill the Japanese or Hirano criteria for diagnosing MELAS [4,5]. The patient never experienced an MRI-confirmed stroke-like episode. The phenotype was too broad for diagnosing maternally inherited diabetes and deafness syndrome. Myoclonic epilepsy with ragged red fiber syndrome was excluded upon the absence of myoclonic epilepsy [6], and there were no typical diagnostic features allowing the diagnosis of Kearns-Sayre syndrome.\n\nThere was definitively multisystem involvement in the patient, as the variant manifested in the brain (migraine, basal ganglia calcification), eyes (pigmentary retinopathy), ears and vestibular system (hypoacusis, tinnitus, nausea, vertigo), endocrine organs (diabetes, short stature), intestines (dysphagia, nausea, vomiting, gastroparesis, bloating, GERD, constipation, distended abdomen), and muscles (myopathy, creatine-kinase elevation). Whether there was also involvement of the immune system remains speculative, but the patient’s multiple allergies and the recurrent urinary tract infections suggest it.\n\nNormalization of the patient’s serum lactate values were achieved by avoiding physical and psychological stress and by the strict adherence to a low-carbohydrate, protein-rich diet. Although serum lactate levels occasionally slightly increased thereafter, they never reached values that were as high as before. Explanations other than lifestyle changes for lowering the patient’s serum lactate level could include ramping up the mitochondrial cocktail the patient received since age 50 at age 53 and improved control of her diabetes with insulin. It is also conceivable that repeated L-arginine infusions had a lactate-lowering effect. Discontinuation of metformin was excluded as a cause of lactate normalization because it had happened 1 year earlier. Nevertheless, it has been reported that carriers of the m.3243A>G variant require a non-stressful life, discontinuation of mitochondrion-toxic drugs, ketogenic-like diet, and a clean environment [7].\n\nGastrointestinal involvement is not uncommon in carriers of the m.3243A>G variant and has been previously reported [3,8,9]. Gastrointestinal involvement was the phenotypic feature that most significantly affected our patient’s quality of life. She had the feeling of a lump in her throat when swallowing and was afraid that hard food might get stuck. She had recurrent nausea and progressive dysphagia since age 50. However, she had no pseudo-obstruction, as has been previously reported [10]. She reported some relief from dysphagia from pureeing food and the use of stool softeners. However, probiotics, antacids, antiflatulent agents, and polyethylene glycol were ineffective. Gastrointestinal involvement was attributed to affection of smooth muscle cells rather than to autonomic neuropathy because no other clinical manifestations of an autonomic involvement were found. The patient’s diabetes was well controlled. A brainstem/cerebellar lesion was excluded as the cause of nausea or dysphagia by MRI. Lactic acidosis was excluded because the patient’s serum lactate values were largely within normal limits beyond age 52.\n\nWhether the variant m.3243A>G was truly responsible for the phenotype remains speculative; however, low heteroplasmy rates detected in blood and buccal mucosa are not unusual and can nonetheless explain the phenotype. Low heteroplasmy rates of 14% and 31% can be explained by investigations of scarcely affected tissues. Most likely, heteroplasmy rates would be higher if more severely affected tissues, such as gastrointestinal smooth muscle cells, myocytes, beta cells, or cochlear cells, were investigated. Whether the 2 variants additionally detected played a pathogenic role in this patient remains speculative. Variant m.5084A>G in MT-ND2 has not been previously reported as pathogenic. Variant m.16362T>C in the D-loop is regarded as a variant of unknown significance. Nonetheless, these variants may have modified the phenotypic expression of the m.3243A>G mutation.\n\nThere were some limitations to the study. None of the affected or unaffected family members were genetically tested and the mtDNA copy number was not determined. A further limitation is that the index patient had never undergone a muscle biopsy or electroencephalogram recordings. An additional limitation is that cerebral MRIs were not always immediately carried out in the acute stage of a clinical deterioration.\n\nConclusions\n\nThis case shows that gastrointestinal compromise may be the prominent manifestation of the m.3243A>G variant, serum lactate may normalize upon changes in lifestyle and diet, and low heteroplasmy rates of the m.3243A>G variant in scarcely affected tissues do not exclude pathogenicity.\n\nFigure 1. Serum lactate values over 5 years showing improvement upon changes in the patient’s lifestyle and diet at the end of 2014.\n\nFigure 2. Pedigree of the family of the index patient, with possibly affected family members.\n\nConflicts of Interest\n\nNone.\n==== Refs\nReferences:\n\n1. El-Hattab AW Almannai M Scaglia F MELAS. 2001 Feb 27 [updated 2018 Nov 29] Adam MP Ardinger HH Pagon RA GeneReviews® [Internet] Seattle (WA) University of Washington, Seattle 1993–2020 http://www.ncbi.nlm.nih.gov/books/NBK1233/\n2. Finsterer J Zarrouk-Mahjoub S The heart in m.3243A>G carriers Herz 2018 45 4 356 61 30128910\n3. Pickett SJ Grady JP Ng YS Phenotypic heterogeneity in m.3243A>G mitochondrial disease: The role of nuclear factors Ann Clin Transl Neurol 2018 5 333 45 29560378\n4. Yatsuga S Povalko N Nishioka J MELAS: A nationwide prospective cohort study of 96 patients in Japan Biochim Biophys Acta 2012 1820 619 24 21443929\n5. Hirano M Ricci E Koenigsberger MR Melas: An original case and clinical criteria for diagnosis Neuromuscul Disord 1992 2 125 35 1422200\n6. Finsterer J Zarrouk-Mahjoub S Shoffner JM MERRF Classification: Implications for diagnosis and clinical trials Pediatr Neurol 2018 80 8 23 29449072\n7. Yee ML Wong R Datta M Mitochondrial disease: An uncommon but important cause of diabetes mellitus Endocrinol Diabetes Metab Case Rep 2018 2018 18 0091\n8. Finsterer J Zarrouk-Mahjoub S Gastrointestinal involvement in m.3243A>G-associated MELAS Intern Med 2018 57 769 70 29151527\n9. de Laat P Zweers HE Knuijt S Dysphagia, malnutrition and gastrointestinal problems in patients with mitochondrial disease caused by the m3243A>G mutation Neth J Med 2015 73 30 36 26219939\n10. Ng YS Feeney C Schaefer AM Pseudo-obstruction, stroke, and mitochondrial dysfunction: A lethal combination Ann Neurol 2016 80 686 92 27453452\n\n",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D004272:DNA, Mitochondrial; D005260:Female; D000081942:Heteroplasmy; D006801:Humans; D007773:Lactates; D008019:Life Style; D017241:MELAS Syndrome; D008875:Middle Aged; D028361:Mitochondrial Diseases; D009154:Mutation; D011788:Quality of Life",
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"pubdate": "2021-04-19",
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"title": "Lifestyle Changes Normalize Serum Lactate Levels in an m.3243A>G Carrier.",
"title_normalized": "lifestyle changes normalize serum lactate levels in an m 3243a g carrier"
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"abstract": "OBJECTIVE\nLenalidomide has significant single-agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). We demonstrated that lenalidomide can be safely combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone); this new combination is known as R2CHOP. The goal of this phase II study was to evaluate the efficacy of this combination in newly diagnosed DLBCL.\n\n\nMETHODS\nEligible patients were adults with newly diagnosed untreated stages II to IV CD20(+) DLBCL. Patients received lenalidomide 25 mg orally per day on days 1 through 10 with standard-dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry and classified as germinal center B-cell (GCB) versus non-GCB in the R2CHOP patients and 87 control patients with DLBCL from the Lymphoma Database who were treated with conventional R-CHOP.\n\n\nRESULTS\nIn all, 64 patients with DLBCL were enrolled, and 60 were evaluable for response. The overall response rate was 98% (59 of 60) with 80% (48 of 60) achieving complete response. Event-free survival and overall survival (OS) rates at 24 months were 59% (95% CI, 48% to 74%) and 78% (95% CI, 68% to 90%), respectively. In R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% versus 64% (P < .001) and 46% versus 78% (P < .001) in non-GCB DLBCL versus GCB DLBCL, respectively. In contrast, there was no difference in 24-month PFS or OS for R2CHOP patients on the basis of non-GCB and GCB subtype (60% v 59% [P = .83] and 83% v 75% [P = .61] at 2 years, respectively).\n\n\nCONCLUSIONS\nR2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide appears to mitigate a negative impact of non-GCB phenotype on patient outcome.",
"affiliations": "Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL. nowakowski.grzegorz@mayo.edu.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.;Grzegorz S. Nowakowski, Betsy LaPlant, William R. Macon, Garth D. Nelson, Carrie A. Thompson, David J. Inwards, Ivana N. Micallef, Patrick B. Johnston, Luis F. Porrata, Stephen M. Ansell, Thomas M. Habermann, and Thomas E. Witzig, Mayo Clinic, Rochester, MN; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, BC, Canada; Craig B. Reeder, Mayo Clinic, Scottsdale, AZ; and James M. Foran and Candido E. Rivera, Mayo Clinic, Jacksonville, FL.",
"authors": "Nowakowski|Grzegorz S|GS|;LaPlant|Betsy|B|;Macon|William R|WR|;Reeder|Craig B|CB|;Foran|James M|JM|;Nelson|Garth D|GD|;Thompson|Carrie A|CA|;Rivera|Candido E|CE|;Inwards|David J|DJ|;Micallef|Ivana N|IN|;Johnston|Patrick B|PB|;Porrata|Luis F|LF|;Ansell|Stephen M|SM|;Gascoyne|Randy D|RD|;Habermann|Thomas M|TM|;Witzig|Thomas E|TE|",
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"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "33(3)",
"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; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011241:Prednisone; D011379:Prognosis; D000069283:Rituximab; D013792:Thalidomide; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "251-7",
"pmc": null,
"pmid": "25135992",
"pubdate": "2015-01-20",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study.",
"title_normalized": "lenalidomide combined with r chop overcomes negative prognostic impact of non germinal center b cell phenotype in newly diagnosed diffuse large b cell lymphoma a phase ii study"
} | [
{
"companynumb": "US-JNJFOC-20150114300",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A subset of patients with high-grade glioma and brain metastases who are treated with bevacizumab develop regions of marked and persistent restricted diffusion that do not reflect recurrent tumor. Here, we quantify the degree of restricted diffusion and the relative cerebral blood volume (rCBV) within these regions of bevacizumab-related imaging abnormality (BRIA) in order to facilitate differentiation of these lesions from recurrent tumor. Six patients with high-grade glioma and two patients with brain metastases who developed regions of restricted diffusion after initiation of bevacizumab were included. Six pre-treatment GBM controls were also included. Restriction spectrum imaging (RSI) was used to create diffusion maps which were co-registered with rCBV maps. Within regions of restricted diffusion, mean RSI values and mean rCBV values were calculated for patients with BRIA and for the GBM controls. These values were also calculated for normal-appearing white matter (NAWM). RSI values in regions of restricted diffusion were higher for both BRIA and tumor when compared to NAWM; furthermore RSI values in BRIA were slightly higher than in tumor. Conversely, rCBV values were very low in BRIA-lower than both tumor and NAWM. However, there was only a trend for rCBV values to be higher in tumor than in NAWM. When evaluating areas of restricted diffusion in patients with high-grade glioma or brain metastases treated with bevacizumab, RSI is better able to detect the presence of pathology whereas rCBV is better able to differentiate BRIA from tumor. Thus, combining these tools may help to differentiate necrotic tissue related to bevacizumab treatment from recurrent tumor.",
"affiliations": "Department of Radiology, University of California, San Diego, 200 West Arbor Drive, MC 0834, San Diego, CA, 92103-0834, USA, nfarid@ucsd.edu.",
"authors": "Farid|Nikdokht|N|;Almeida-Freitas|Daniela B|DB|;White|Nathan S|NS|;McDonald|Carrie R|CR|;Kuperman|Joshua M|JM|;Almutairi|Abdulrahman A|AA|;Muller|Karra A|KA|;VandenBerg|Scott R|SR|;Kesari|Santosh|S|;Dale|Anders M|AM|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-014-1583-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "120(3)",
"journal": "Journal of neuro-oncology",
"keywords": null,
"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001810:Blood Volume; D001921:Brain; D001932:Brain Neoplasms; D002560:Cerebrovascular Circulation; D004058:Diffusion; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005910:Glioma; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D055420:Perfusion Imaging; D066127:White Matter",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "539-46",
"pmc": null,
"pmid": "25135423",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19720927;23814264;21149667;20035366;23169482;11415902;22977022;23799286;22538078;22229249;18987829;10030650;23578667;20187195;21393407;19944768;22820413;23139079;19628627",
"title": "Combining diffusion and perfusion differentiates tumor from bevacizumab-related imaging abnormality (bria).",
"title_normalized": "combining diffusion and perfusion differentiates tumor from bevacizumab related imaging abnormality bria"
} | [
{
"companynumb": "US-ROCHE-1499938",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Hyperthyroidism affects approximately 1.2% of the population and its routine treatment includes antithyroid drugs (ATDs), radioiodine and surgery. Management of patients with resistance or contraindications to ATDs who require thyroidectomy may be challenging. We present the experience of our department in preparing thyrotoxic patients for life-saving thyroidectomy by using therapeutic plasma exchange (TPE) with albumin: one patient with Graves' disease and previous history of agranulocytosis and cholestatic jaundice after ATDs and two patients with amiodarone-induced thyrotoxicosis. Five to six TPEs were applied to each patient resulting in a decrease of fT3 by 57% to 83%, fT4 by 21% to 60% and decrease/normalization of total thyroid hormones. All patients underwent surgery successfully. In case of drug-resistant thyrotoxicosis or contraindications to ATDs, TPE can be a valuable tool in preparing patients for surgery. Albumin used as a replacement fluid appears to be effective in ameliorating clinical and laboratory symptoms of thyrotoxicosis.",
"affiliations": "Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.;Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.;Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.;Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.;Department of Colorectal, General and Oncological Surgery, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.;Department of Endocrine Oncology and Nuclear Medicine, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.;Department of Endocrine Oncology and Nuclear Medicine, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.;Department of Nephrology and Internal Medicine, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.;Department of Nephrology and Internal Medicine, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.;Department of Nephrology and Internal Medicine, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.;Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw, Poland.",
"authors": "Tańska|Kamila|K|https://orcid.org/0000-0002-2120-1368;Leszczyńska|Dorota|D|;Glinicki|Piotr|P|;Kapuścińska|Renata|R|;Szczepkowski|Marek|M|;Dedecjus|Marek|M|;Stachlewska-Nasfeter|Elżbieta|E|;Brym|Izabela|I|;Żelek|Tomasz|T|;Daniewska|Dorota|D|;Gietka-Czernel|Małgorzata|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21866",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "36(3)",
"journal": "Journal of clinical apheresis",
"keywords": "albumin; life-saving thyroidectomy; plasma exchange; thyrotoxicosis",
"medline_ta": "J Clin Apher",
"mesh_terms": null,
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "496-498",
"pmc": null,
"pmid": "33340148",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Therapeutic plasma exchange with albumin as a valuable method of preparing thyrotoxic patients for a life-saving thyroidectomy.",
"title_normalized": "therapeutic plasma exchange with albumin as a valuable method of preparing thyrotoxic patients for a life saving thyroidectomy"
} | [
{
"companynumb": "PL-B.BRAUN MEDICAL INC.-2105852",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": n... |
{
"abstract": "Erythema multiforme (EM)-like erythema nodosum leprosum (ENL) is a rare atypical presentation, and its late appearance after the completion of multidrug therapy (MDT) is unusual. We describe the case of a lepromatous leprosy patient who after the completion of MDT presented to us with late EM-like ENL and was found to be resistant to rifampicin. We discuss the implications of this finding and the potential role of resistant bacilli in causing reactions with atypical presentations.",
"affiliations": "Department of Dermatology and STDs, Dr. RML Hospital and PGIMER, New Delhi, India.;Department of Dermatology and STDs, Dr. RML Hospital and ABVIMS, New Delhi, India.;Department of Dermatology and STDs, Dr. RML Hospital and ABVIMS, New Delhi, India.;Department of Dermatology and STDs, Dr. RML Hospital and ABVIMS, New Delhi, India.;Department of Dermatology and STDs, Dr. RML Hospital and ABVIMS, New Delhi, India.;Department of Pathology, Dr. RML Hospital and ABVIMS, New Delhi, India.;Research Scientist, Stanley Browne Laboratory, The Leprosy Mission Community Hospital, New Delhi, India.;Research Scientist, Stanley Browne Laboratory, The Leprosy Mission Community Hospital, New Delhi, India.",
"authors": "Sardana|Kabir|K|;Kulhari|Anita|A|;Mathachan|Sinu Rose|SR|;Khurana|Ananta|A|;Bansal|Prekshi|P|;Ahuja|Arvind|A|;Lavania|Mallika|M|;Ahuja|Madhvi|M|",
"chemical_list": "D007917:Leprostatic Agents; D012293:Rifampin",
"country": "Netherlands",
"delete": false,
"doi": "10.4103/ijmy.ijmy_26_20",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2212-5531",
"issue": "9(2)",
"journal": "International journal of mycobacteriology",
"keywords": "Erythema multiforme like; erythema nodosum leprosum; leprosy; multibacillary; multidrug therapy; real-time PCR; resistance; steroids",
"medline_ta": "Int J Mycobacteriol",
"mesh_terms": "D000328:Adult; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D004892:Erythema Multiforme; D004893:Erythema Nodosum; D006801:Humans; D007917:Leprostatic Agents; D007918:Leprosy; D008297:Male; D009167:Mycobacterium lepraemurium; D012293:Rifampin; D013997:Time Factors",
"nlm_unique_id": "101615660",
"other_id": null,
"pages": "226-228",
"pmc": null,
"pmid": "32474551",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Late leprosy reaction presenting as erythema multiforme-like erythema nodosum leprosum with underlying rifampicin resistance and its potential implications.",
"title_normalized": "late leprosy reaction presenting as erythema multiforme like erythema nodosum leprosum with underlying rifampicin resistance and its potential implications"
} | [
{
"companynumb": "IN-SA-2020SA155106",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Adrenocortical carcinoma is a rare tumour with high malignancy and poor prognosis. This tumour is rarely diagnosed in the reproductive age. Complete surgical resection is the only curative treatment for adrenal cancer in all stages. After surgery adjuvant chemotherapy is required. Mitotane is the most important drug in adrenal cancer chemotherapy. Mitotane's mode of action is not entirely explained. Animal studies have shown that the substance exerts a direct cytotoxic effect on the cells of the adrenal cortex. This activity is selective, progressive and affects only the zona reticularis and fasciculata of the adrenal cortex. Mitotane inhibits cortisol synthesis by disrupting the chain of cholesterol. It has been suggested, that mitotane also affects the peripheral metabolism of steroids, especially of transcortin (CBG). This results in an increase of CBG blood concentration and a reduction of the amount of free hormones.",
"affiliations": "3rd Chair and Department of Gynecology Medical University in Lublin, Jaczewskiego 8, 20-954, Lublin, Poland. piotr.szkodziak@gmail.com.",
"authors": "Szkodziak|Piotr Robert|PR|;Czuczwar|Piotr|P|;Woźniak|Sławomir|S|;Szkodziak|Filip|F|;Paszkowski|Tomasz|T|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D016912:Levonorgestrel; D008939:Mitotane",
"country": "Poland",
"delete": false,
"doi": "10.5603/GP.a2017.0104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-0011",
"issue": "88(10)",
"journal": "Ginekologia polska",
"keywords": "LNG-IUD; adjuvant therapy; adrenocortical carcinoma; levonorgestrel-releasing intrauterine device; menorrhagia; mitotane",
"medline_ta": "Ginekol Pol",
"mesh_terms": "D000306:Adrenal Cortex Neoplasms; D018268:Adrenocortical Carcinoma; D000328:Adult; D018931:Antineoplastic Agents, Hormonal; D017024:Chemotherapy, Adjuvant; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007436:Intrauterine Devices, Medicated; D016912:Levonorgestrel; D008595:Menorrhagia; D008939:Mitotane",
"nlm_unique_id": "0374641",
"other_id": null,
"pages": "576-577",
"pmc": null,
"pmid": "29192420",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of a levonorgestrel-releasing intrauterine device for menorrhagia treatment during adjuvant therapy of adrenocortical carcinoma with mitotane.",
"title_normalized": "use of a levonorgestrel releasing intrauterine device for menorrhagia treatment during adjuvant therapy of adrenocortical carcinoma with mitotane"
} | [
{
"companynumb": "PL-LABORATOIRE HRA PHARMA-2054949",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MITOTANE"
},
"drugadditional": null,... |
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