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"abstract": "Tardive dyskinesia (TD) is a hyperkinetic movement disorder that results from exposure to dopamine receptor antagonists and/or first- and second-generation antipsychotics. While cessation of the offending agent(s) through early detection is recommended, TD symptoms may be irreversible and require further treatment. Deutetrabenazine is approved by the Food and Drug Administration for treatment of persistent TD. Irreversible orofacial dyskinesia, a common affliction in TD, can progress to severe oropharyngeal dysphagia requiring alternate means of nutrition and medication delivery. Enteral administration of crushed deutetrabenazine has not been studied, and its use to treat TD in patients who cannot take medications by mouth has not been reported previously.\n\n\n\nA 38-year-old female patient with a history of bipolar I disorder and TD secondary to atypical antipsychotic exposure developed worsening athetosis, hyperkinesia, and severe orofacial dyskinesia after initiation of ziprasidone. The patient had no improvement after discontinuation of atypical antipsychotics and required percutaneous endoscopic gastrostomy (PEG) placement for nutrition due to persistent aspiration and inability to tolerate oral nutrition. Despite a lack of information regarding administration of crushed deutetrabenazine tablets via PEG, that form of therapy was initiated and resulted in improvement of TD symptoms without noticeable adverse effects.\n\n\n\nTD can result in significant orofacial dyskinesia with impaired delivery of needed medications and nutrition. We describe a case in which a patient with severe TD and orofacial dyskinesia experienced improvement of symptoms with use of crushed deutetrabenazine. Larger studies to further evaluate use of crushed deutetrabenazine for treatment of TD are needed.",
"affiliations": "West Virginia University School of Pharmacy, Morgantown, WV, and WVU Medicine Ruby Memorial Hospital, Morgantown, WV.;Department of Medicine, Section of General Internal Medicine, West Virginia University School of Medicine, Morgantown, WV.;Department of Pharmacy, WVU Medicine Ruby Memorial Hospital, Morgantown, WV.",
"authors": "Wietholter|Jon P|JP|;Sizemore|Jenna|J|;Piechowski|Kara|K|",
"chemical_list": "D014150:Antipsychotic Agents; D013607:Tablets; C000609690:deutetrabenazine; D013747:Tetrabenazine",
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/zxaa205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "77(18)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "deutetrabenazine; drug administration; orofacial dyskinesia; percutaneous endoscopic gastrostomy; tardive dyskinesia",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D005260:Female; D005774:Gastrostomy; D006801:Humans; D012720:Severity of Illness Index; D013607:Tablets; D000071057:Tardive Dyskinesia; D013747:Tetrabenazine",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1477-1481",
"pmc": null,
"pmid": "32761113",
"pubdate": "2020-09-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Crushing deutetrabenazine for treatment of tardive dyskinesia in a patient with severe orofacial symptoms: A case report.",
"title_normalized": "crushing deutetrabenazine for treatment of tardive dyskinesia in a patient with severe orofacial symptoms a case report"
} | [
{
"companynumb": "US-PFIZER INC-2020318328",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZIPRASIDONE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Non-Aspergillus invasive mould infections (IMIs) are associated with devastating morbidity and mortality rates and are increasingly diagnosed in immunocompromised hosts. The aim of this study was to describe the epidemiology and outcomes of non-Aspergillus IMIs at a university hospital in San Diego, California, USA. A retrospective chart review of the medical records of all patients with cultures growing non-Aspergillus moulds at the microbiology laboratory in the Center for Academic Laboratory Medicine, Department of Pathology, University of California, San Diego (UCSD) Health between mid-2014 and mid-2017 (3-year period) was performed. A total of 23 cases of non-Aspergillus IMI were identified, including 10 cases of mucormycosis, 8 cases of lomentosporiosis and 5 cases of fusariosis. Antifungal susceptibility testing was performed for 14 isolates, and 10/11 Fusarium and Lomentospora isolates had minimum inhibitory concentrations (MICs) of >16 µg/mL for voriconazole and/or posaconazole. Overall 180-day mortality was significantly lower among those who received combination antifungal therapy than among those who received single-agent therapy [3/13 (23%) vs. 9/10 (90%); P = 0.003]. In conclusion, Lomentospora prolificans (35% of non-Aspergillus IMIs) and Fusarium spp. (22%) accounted for high proportions of non-Aspergillus IMIs during the study period. Non-Aspergillus IMIs were detected in patients with various underlying diseases and were associated with high mortality rates, which was significantly lower in those who received antifungal combination therapy.",
"affiliations": "Department of Medicine, University of California, San Diego, San Diego, CA, USA. Electronic address: jjenks@ucsd.edu.;Department of Medicine, University of California, San Diego, San Diego, CA, USA; Department of Pathology, University of California, San Diego, San Diego, CA, USA.;Department of Internal Medicine, Excellence Center for Medical Mycology (ECMM), University Hospital Cologne, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.;Department of Internal Medicine, Excellence Center for Medical Mycology (ECMM), University Hospital Cologne, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.;Department of Internal Medicine, Excellence Center for Medical Mycology (ECMM), University Hospital Cologne, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; Clinical Trials Centre Cologne (ZKS Köln), University of Cologne, Cologne, Germany.;Department of Medicine, University of California, San Diego, San Diego, CA, USA.;Department of Medicine, University of California, San Diego, San Diego, CA, USA; Department of Medicine, Medical University of Graz, Graz, Austria. Electronic address: mhoenigl@ucsd.edu.",
"authors": "Jenks|Jeffrey D|JD|;Reed|Sharon L|SL|;Seidel|Danila|D|;Koehler|Philipp|P|;Cornely|Oliver A|OA|;Mehta|Sanjay R|SR|;Hoenigl|Martin|M|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijantimicag.2018.08.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-8579",
"issue": "52(5)",
"journal": "International journal of antimicrobial agents",
"keywords": "Epidemiology; Fusarium solani; Mucormycosis; Scedosporiosis; Scedosporium; Zygomycosis",
"medline_ta": "Int J Antimicrob Agents",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents; D001203:Ascomycota; D002140:California; D004359:Drug Therapy, Combination; D005260:Female; D005670:Fusarium; D006801:Humans; D000072742:Invasive Fungal Infections; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009090:Mucorales; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9111860",
"other_id": null,
"pages": "706-712",
"pmc": null,
"pmid": "30099056",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": "18458135;24118322;18694953;18212101;27744310;22653819;23716556;18558882;22000355;20218877;16110792;28497502;27365388;16511748;18936190;29750016;29544767;24479848;27085727;24548001",
"title": "Rare mould infections caused by Mucorales, Lomentospora prolificans and Fusarium, in San Diego, CA: the role of antifungal combination therapy.",
"title_normalized": "rare mould infections caused by mucorales lomentospora prolificans and fusarium in san diego ca the role of antifungal combination therapy"
} | [
{
"companynumb": "US-PFIZER INC-2018352442",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "To investigate the efficacy of pembrolizumab plus lenvatinib as a second-line or later-line therapy in women with advanced or recurrent uterine carcinosarcoma (UCS).\nA single-institution pharmacy database was queried for women with advanced or recurrent UCS who were prescribed concurrent pembrolizumab and lenvatinib. Patient demographic, oncologic, and immunotherapy outcomes data were recorded. Univariate analysis summarized progression-free survival (PFS) and overall survival (OS).\nSeven patients with advanced or recurrent UCS were treated with combination pembrolizumab and lenvatinib, with a median age of 63.0 years. The majority had stage III or IV disease (n = 6, 85.7%) and had failed two or more lines of therapy (n = 7, 100.0%), and a minority were MMR deficient (n = 1, 14.3%) or PD-L1+ (n = 1, 14.3%). No partial or complete responses were observed. The median PFS was 2.6 months (95% CI, 0.9-11.2 months), and the median OS was 2.8 months (95% CI, 2.4-NE).\nIn this small, retrospective series, we demonstrate that pembrolizumab and lenvatinib combination therapy may not be highly active in UCS and may be associated with similar PFS and OS as traditional cytotoxic regimens. Further study is warranted to assess the efficacy of this regimen in more targeted cohorts of women with advanced or recurrent UCS.",
"affiliations": "Department of Obstetrics, Gynecology, Women's Health Institute, Cleveland Clinic, Desk A81, 9500 Euclid Avenue, Cleveland, OH 44195, United States.;Division of Gynecologic Oncology, Obstetrics, Gynecology, Women's Health Institute, Cleveland Clinic, Desk A81, 9500 Euclid Avenue, Cleveland, OH 44195, United States.;Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, United States.;Department of Pathology, Cleveland Clinic, Cleveland, OH 44195, United States.;Division of Gynecologic Oncology, Obstetrics, Gynecology, Women's Health Institute, Cleveland Clinic, Desk A81, 9500 Euclid Avenue, Cleveland, OH 44195, United States.;Division of Gynecologic Oncology, Obstetrics, Gynecology, Women's Health Institute, Cleveland Clinic, Desk A81, 9500 Euclid Avenue, Cleveland, OH 44195, United States.",
"authors": "Hunt|Jonathan T|JT|;Chambers|Laura M|LM|;Yao|Meng|M|;Joehlin-Price|Amy|A|;Debernardo|Robert|R|;Rose|Peter G|PG|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gore.2021.100840",
"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789\nElsevier\n\nS2352-5789(21)00144-2\n10.1016/j.gore.2021.100840\n100840\nCase Reports and Case Series\nLenvatinib plus pembrolizumab in patients with advanced or recurrent uterine carcinosarcoma\nHunt Jonathan T. huntj2@ccf.org\na⁎\nChambers Laura M. b\nYao Meng c\nJoehlin-Price Amy d\nDebernardo Robert b\nRose Peter G. b\na Department of Obstetrics, Gynecology, Women's Health Institute, Cleveland Clinic, Desk A81, 9500 Euclid Avenue, Cleveland, OH 44195, United States\nb Division of Gynecologic Oncology, Obstetrics, Gynecology, Women's Health Institute, Cleveland Clinic, Desk A81, 9500 Euclid Avenue, Cleveland, OH 44195, United States\nc Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, United States\nd Department of Pathology, Cleveland Clinic, Cleveland, OH 44195, United States\n⁎ Corresponding author. huntj2@ccf.org\n24 7 2021\n8 2021\n24 7 2021\n37 1008407 4 2021\n18 7 2021\n21 7 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHighlights\n\n• No partial or complete responses to pembrolizumab and lenvatinib therapy were observed in advanced or recurrent UCS.\n\n• Median PFS and OS following pembrolizumab and lenvatinib therapy is similar to traditional cytotoxic regimens.\n\n• Pembrolizumab and lenvatinib therapy was only used in patients who had failed two or more lines of therapy.\n\nObjective(s)\n\nTo investigate the efficacy of pembrolizumab plus lenvatinib as a second-line or later-line therapy in women with advanced or recurrent uterine carcinosarcoma (UCS).\n\nMethods\n\nA single-institution pharmacy database was queried for women with advanced or recurrent UCS who were prescribed concurrent pembrolizumab and lenvatinib. Patient demographic, oncologic, and immunotherapy outcomes data were recorded. Univariate analysis summarized progression-free survival (PFS) and overall survival (OS).\n\nResults\n\nSeven patients with advanced or recurrent UCS were treated with combination pembrolizumab and lenvatinib, with a median age of 63.0 years. The majority had stage III or IV disease (n = 6, 85.7%) and had failed two or more lines of therapy (n = 7, 100.0%), and a minority were MMR deficient (n = 1, 14.3%) or PD-L1+ (n = 1, 14.3%). No partial or complete responses were observed. The median PFS was 2.6 months (95% CI, 0.9–11.2 months), and the median OS was 2.8 months (95% CI, 2.4-NE).\n\nConclusions\n\nIn this small, retrospective series, we demonstrate that pembrolizumab and lenvatinib combination therapy may not be highly active in UCS and may be associated with similar PFS and OS as traditional cytotoxic regimens. Further study is warranted to assess the efficacy of this regimen in more targeted cohorts of women with advanced or recurrent UCS.\n\nKeywords\n\nUterine carcinosarcoma\nPembrolizumab\nLenvatinib\n==== Body\n1 Introduction\n\nUterine carcinosarcomas (UCS) account for less than 5% of endometrial cancers (EC), yet this aggressive variant has a poor prognosis accounting for 15% of uterine cancer deaths (Siegel et al., 2014, Brooks et al., 2004, Cimbaluk et al., 2007). Studies have demonstrated that women diagnosed with uterine carcinosarcomas have significantly worse survival compared to those with high-grade endometrioid, serous, or clear cell carcinomas (Zhang et al., 2015). Despite recent molecular studies suggesting that the sarcomatous element is secondary to metaplasia of the carcinomatous component, prognosis remains much bleaker than other histologic sub-types (Gotoh et al., 2019, Cherniack et al., 2017, Zhao et al., 2016). In a large retrospective analysis of over 900 women with UCS from the United States and Japan, patients with a high-grade carcinoma and heterologous sarcoma had a 5-year progression-free survival (PFS) of 34%, those with a high-grade carcinoma and homologous sarcoma had a 5-year PFS of 46%, and those with a low-grade carcinoma and homologous sarcoma had a 5-year PFS of 60% (Matsuo et al., 2016).\n\nThe primary management for UCS involves a multi-modality approach, typically including cytotoxic chemotherapy and surgery in the setting of operable tumors, with complete cytoreduction associated with improved overall survival (Harano et al., 2016). GOG 261 demonstrated that the combination of carboplatin with paclitaxel was associated with better PFS (16 vs 12 months; HR 0.73, p < .01) and OS (37 vs 29 months; HR 0.87, p < .01) compared with ifosfamide with paclitaxel in women with advanced or recurrent UCS (Powell et al., 2019). Unfortunately, in the setting of second-line and later-line therapies, median response rate to cytotoxic therapy is less than 10% with median PFS of approximately two months (Matsuzaki et al., 2021). Collectively, these studies demonstrate that new therapeutic approaches for women with recurrent UCS are urgently needed.\n\nThe KEYNOTE-146 study by Makker et al. was a single-arm, open-label, multicenter trial that enrolled 108 patients with metastatic EC (Makker et al., 2020). In this trial, combination therapy comprising pembrolizumab and lenvatinib demonstrated an impressive response rate of 38% with a PFS of 7.4 months and overall survival of 16.7 months, with many patients experiencing durable responses to treatment (Makker et al., 2020). Although women with UCS were not enrolled in this trial, many believe UCS shares tumor biology with serous carcinomas, which made up 32.4% of the KEYNOTE-146 study population (Makker et al., 2020, Menczer et al., 2005, Vitale et al., 2017, Livasy et al., 2006, Emoto et al., 2004). Understanding the biologic activity of this regimen in women with UCS is essential to improving oncologic outcomes in women. The objective of this study was to report preliminary data for efficacy of pembrolizumab and lenvatinib combination therapy with advanced or recurrent UCS in a retrospective single institution cohort study.\n\n2 Methods\n\n2.1 Study design\n\nThe study is an Institutional Review Board approved, single-institution retrospective case series including all women with advanced or recurrent uterine carcinosarcomas treated with combination therapy with pembrolizumab and lenvatinib at the Cleveland Clinic. The institution’s pharmacy database was queried for patients with concurrent prescriptions for pembrolizumab and lenvatinib, and those with a diagnosis of uterine carcinosarcoma confirmed on final surgical pathology were included. Consent for use of patient health information was obtained prior to starting the study.\n\n2.2 Data collection\n\nPatient demographics were extracted from the electronic medical record, including age, race, body mass index (kg/m2), Eastern Cooperative Oncology Group (ECOG) performance status score prior to start of immunotherapy, and medical comorbidities. Oncologic variables included stage, primary cancer treatment, route of initial surgery, prior lines of treatment, PD-L1 status (positive, negative, or unknown), and MMR status (proficient, deficit, or unknown). PD-L1 status was defined as positive if there was membranous staining in at least 1% of viable tumor cells. Immunotherapy variables included start and end date, number of cycles, reason for discontinuation, radiological response using the Immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) criteria, whether the patient required dose reduction or steroids during immunotherapy, progression or recurrence date, last follow-up, current status, and date of death (Seymour et al., 2017). All data was collected and stored securely in a RedCAP database (Harris et al., 2019, Harris et al., 2009).\n\n2.3 Statistical analysis\n\nContinuous variables were reported using medians and interquartile range. Categorical factors and ordinal variables were described as frequencies and percentages. For right censored PFS and OS, time to progression or death was defined as the difference in months from immunotherapy start date to progression date or death date. Kaplan-Meier plot was created for PFS and OS. Statistical analysis was performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC).\n\n3 Results\n\n3.1 Patient demographics and oncologic characteristics\n\nSeven eligible patients with advanced or recurrent uterine carcinosarcoma were treated with combination pembrolizumab and lenvatinib at the Cleveland Clinic. Patient demographics are displayed in Table 1. The median age at the start of immunotherapy was 63.0 years (IQR 58.0, 64.0 years). The majority of patient had stage III or IV disease (85.7%), an ECOG score of 0 or 1 (71.4%), and comorbid hypertension (57.1%). All patients had undergone cytoreductive surgery followed by adjuvant chemotherapy (42.9%) or adjuvant chemoradiation (57.1%). Pembrolizumab and lenvatinib was the third line of treatment for most included patients (71.4%), with zero instances of being used as a second-line therapy. Few tumors were known to be MMR deficient (14.3%) or PD-L1 positive (14.3%).Table 1 Patient and oncologic characteristics.\n\nVariable\tN = 7\t\nAge\t63.0 [58.0, 64.0]\t\n\n\n\t\nRace\t\nWhite\t3 (42.9)\t\nBlack\t4 (57.1)\t\n\n\n\t\nBMI\t27.0 [19.0, 29.0]\t\n\n\n\t\nECOG Score\t\n0\t4 (57.1)\t\n1\t1 (14.3)\t\n2\t2 (28.6)\t\n\n\n\t\nMedical Comorbidities\t\nHTN\t4 (57.1)\t\nHLD\t3 (42.9)\t\nDM\t2 (28.6)\t\nVTE\t1 (14.3)\t\nPVD\t1 (14.3)\t\nPulmonary Disease\t1 (14.3)\t\nRenal Disease\t0 (0.00)\t\n\n\n\t\nStage\t\nI\t1 (14.3)\t\nIII\t4 (57.1)\t\nIV\t2 (28.6)\t\n\n\n\t\nPrimary Cancer Treatment\t\nSurgery + Chemotherapy\t3 (42.9)\t\nSurgery + Chemotherapy + Radiotherapy\t4 (57.1)\t\n\n\n\t\nNumber of Prior Lines of Therapy\t\n2\t5 (71.4)\t\n3\t1 (14.3)\t\n4\t1 (14.3)\t\n\n\n\t\nPrior Bevacizumab\t\nYes\t2 (28.6)\t\nNo\t5 (71.4)\t\n\n\n\t\nMMR Status\t\nMMR proficient\t6 (85.7)\t\nMMR deficient\t1 (14.3)\t\n\n\n\t\nPD-L1 Status\t\nPositive\t1 (14.3)\t\nNegative\t6 (85.7)\t\nBMI, body mass index; ECOG, Eastern Cooperative Oncology Group; HTN, hypertension; HLD, hyperlipidemia; DM, diabetes mellitus; VTE, venous thromboembolic disease; PVD, peripheral vascular disease; CKD, chronic kidney disease.\n\nStatistics presented as Median [P25, P75], N (column %).\n\n3.2 Oncologic outcomes\n\nStarting lenvatinib dose ranged from 10 mg to 20 mg, with a starting mean dose of 16 mg/day (standard deviation, 4.0). Only two of seven patients (28.6%) required lenvatinib dose reductions for treatment-related AEs, with a final mean dose of 14.3 mg/day (standard deviation, 5.3). Treatment-related AEs requiring dose reduction in this series included poor appetite leading to hospitalization for failure to thrive in one patient, and plantar-palmar erythrodysesthesia syndrome and mucositis in the other. No patients discontinued treatment due to treatment-related toxicity.\n\nThe median follow-up duration for the cohort was 2.8 months (IQR 2.4, 9.9 months). Imaging was typically performed every 3 cycles while receiving pembrolizumab and lenvatinib combination therapy, unless otherwise clinically indicated. No complete or partial responses were observed. Disease progression was noted in 5 patients (71.4%), while 1 patient achieved stable disease followed by progression (14.3%) and the other achieved stable disease without progression (14.3%). PFS was 2.6 months (95% CI, 0.9–11.2 months) with 6-month progression free survival of 28.6% (95% CI, 0.0, 62.0). Furthermore, OS was 2.8 months (95% CI, 2.4-NE) with 6-month overall survival of 42.9% (6.2, 79.5) (Table 2, Fig. 1).Table 2 Oncologic outcomes.\n\nVariable\tN = 7\t\nCycles of Immunotherapy\t\n2\t2 (28.6)\t\n3\t1 (14.3)\t\n4\t2 (28.6)\t\n6\t1 (14.3)\t\n16\t1 (14.3)\t\n\n\n\t\nReason for Stopping Immunotherapy*\t\nProgression\t6 (100.0)\t\n\n\n\t\nResponse (iRECIST)\t\nProgression\t5 (71.4)\t\nStable disease followed by progression\t1 (14.3)\t\nStable disease\t1 (14.3)\t\n\n\n\t\nLenvatinib Starting Dose\t\n20 mg\t3 (42.9)\t\n14 mg\t3 (42.9)\t\n10 mg\t1 (14.3)\t\n\n\n\t\nLenvatinib Dose Reductions\t\nYes\t2 (28.6)\t\nNo\t5 (71.4)\t\n\n\n\t\nSteroids During Immunotherapy\t\nYes\t2 (28.6)\t\nNo\t5 (71.4)\t\n\n\n\t\nCurrent Status\t\nAlive with disease\t2 (28.6)\t\nDead of disease\t5 (71.4)\t\n\n\n\t\nCurrently on Immunotherapy\t\nYes\t1 (14.3)\t\nNo\t6 (85.7)\t\n\n\n\t\nFollow-up Duration (months)\t2.8 [2.4, 9.9]\t\niRECIST, immunotherapy response evaluation criteria in solid tumors.\n\nStatistics presented as Median [P25, P75], N (column %).\n\n*Data not available for all subjects. Patients stopped immunotherapy N = 6.\n\nFig. 1 Kaplan-Meier plot for progression-free survival and overall survival of patients with advanced or recurrent uterine carcinosarcoma receiving pembrolizumab and lenvatinib combination therapy.\n\n4 Discussion\n\nThe prognosis of women diagnosed with UCS is quite dismal, with a median overall survival of 23 months, which is significantly worse than women diagnosed with other EC histologies including high-grade endometrioid, serous, or clear cell carcinomas (Zhang et al., 2015, Matsuzaki et al., 2021). The standard management according to National Comprehensive Cancer Network (NCCN) guidelines in women with UCS is surgical management followed by a combination of adjuvant platinum-based chemotherapy with or without radiotherapy (NCCN Clinical Practice Guidelines in Oncology, n.d, Matsuo et al., 2017). Unfortunately, despite upfront multi-modality therapy, even women with early-stage UCS have high risk for recurrence and death from their disease (Matsuzaki et al., 2021). There is a significant, unmet need to advance therapeutic options for women with recurrent uterine carcinosarcoma (see Table 3).Table 3 Patient details.\n\nID\tStage\tMMR\tPDL1\tPrior lines\t# Cycles\tiRECIST\tPFS (m)\tOS (m)\t\n1\tIV\tMMRp\tPDL1-\t2\t4\tProgression\t3.3\tDead of disease at 9.9 months\t\n2\tIII\tMMRp\tPDL1-\t2\t2\tProgression\t0.9\tDead of disease at 2.8 months\t\n3\tIV\tMMRd\tPDL1+\t2\t2\tProgression\t1.6\tDead of disease at 2.4 months\t\n4\tIII\tMMRp\tPDL1-\t2\t4\tProgression\t2.6\tDead of disease at 2.8 months\t\n5\tIII\tMMRp\tPDL1-\t4\t3\tProgression\t1.9\tDead of disease at 2.1 months\t\n6\tIII\tMMRp\tPDL1-\t3\t6\tStable\t–\tAlive with disease at 4.4 months\t\n7\tI\tMMRp\tPDL1-\t2\t16\tStable then progression\t11.2\tAlive with disease at 12.6 months\t\nMMRp, mismatch repair proficient; MMRd, mismatch repair deficient; PFS, progression-free survival; OS, overall survival.\n\nThe KEYNOTE-146 study was a promising turn of events in the treatment of recurrent EC, with pembrolizumab and lenvatinib combination therapy generating an overall response rate of 38.0% (Makker et al., 2020). Notably, women with UCS were not included in this trial. Given the similarities of UCS with other EC high-risk histologies, pembrolizumab and lenvatinib was considered as a novel approach for improving outcomes in the previously treated UCS population, but data was limited to inform its efficacy. To this end, in this small, retrospective series of women with advanced or recurrent UCS, we demonstrate that pembrolizumab and lenvatinib combination therapy has limited efficacy with no complete or partial responses, and a 28.6% rate of stable disease.\n\nIn our cohort of women with advanced or recurrent UCS who underwent pembrolizumab and lenvatinib combination therapy, the median PFS and OS were 2.6 months and 2.8 months, respectively. In a pooled analysis of studies by Matsuzaki et al. of women undergoing salvage chemotherapy for uterine carcinosarcoma, second-line and later-line therapies demonstrated a median response rate of only 5.5% and median PFS of approximately 2 months (Matsuzaki et al., 2021). Our findings suggest a similar PFS compared to prior historical studies, and no objective radiographic response among a series of seven patients.\n\nInterestingly, PD-L1 status was negative in the majority of patients (85.7%). Given recent studies demonstrating PD-L1 expression in 58% of UCS, this cohort of patients does not follow the expected distribution of PD-L1 status, and therefore these findings may not be generalizable to all patients (Engerud et al., 2020). The majority of patients were also MMR-proficient (85.7%). Further study is needed to understand how UCS response to pembrolizumab and lenvatinib combination therapy is impacted by the tumor’s immunohistochemical signature.\n\nAn important consideration with pembrolizumab and lenvatinib combination therapy is patient tolerability and toxicity. The KEYNOTE-146 study reported a 62.9% rate of dose reductions of lenvatinib for treatment-related adverse effects (AEs) with a mean dose intensity of lenvatinib of 14.4 mg/day (standard deviation, 4.3) (Makker et al., 2020). In contrast, in our series, only two of seven patients (28.6%) required dose reductions for treatment-related AEs, with a final mean dose of lenvatinib of 14.3 mg/day (standard deviation, 5.3). No patients discontinued treatment due to treatment-related toxicity, although this must be interpreted in the context of four of seven patients (57.1%) dying within three months of treatment initiation. Although five of seven patients discontinued therapy within four cycles (71.4%), recent studies show that all-grade immune-related adverse events present within 8.4 weeks of initiation of PD-1 and PD-L1 inhibitors, and within the first 2 months of initiation of lenvatinib therapy (Haddad et al., 2017, Tang et al., 2021). Toxicity appears not to bias the response rate of this case series more than that seen in larger trials. Despite this, it is essential that patients are adequately counselled regarding the side effect profile of this regimen, in light of the poor efficacy, prior to starting treatment.\n\nThere are several significant limitations to consider in the interpretation of our results. Primarily, our findings are limited by the small sample size, including only seven patients with previously treated UCS, without a control cohort who received an alternative line of therapy. Similarly, given the retrospective nature, all prior treatment lines were at the discretion of the primary gynecologic oncologist, as well as the starting dose of lenvatinib and the approach taken towards dose reduction and steroid administration. Notably, in the KEYNOTE-146 study, 51.1% patients received only one prior line of treatment, 38.3% patients received two prior lines of treatment, and 10.6% patients received three or more prior lines of treatment (Makker et al., 2020). Our cohort of women included 0.0% with only one prior line of treatment, and 28.6% with three or more prior lines of treatment, representative of a more heavily-pretreated population. Despite a higher number of prior lines, only two of the seven patients (28.6%) had previously received bevacizumab. Such a trend in number of prior lines of treatment shifts the focus towards more aggressive or refractory tumor biologies, and therefore introduces a bias towards a worse response rate and PFS. Further study is needed to determine whether this regimen would be more active in patients earlier in their disease recurrence.\n\nDespite these limitations, our study is of the first to report the limited activity of pembrolizumab and lenvatinib combination therapy in women with advanced and recurrent UCS and contributes relevant, timely information to the literature. Our single institution, retrospective data suggest that pembrolizumab and lenvatinib combination therapy is not highly active in UCS and is associated with similar PFS and OS as similar traditional cytotoxic regimens. Further study is warranted to assess the efficacy of this regimen in more targeted cohorts of women with advanced or recurrent UCS.\n\nAuthor contribution\n\nJH, LC, and PR conceived of the idea and designed the study. MY performed the computations. AJP obtained and evaluated archived tumor for PD-L1 and MMR status. JH wrote the manuscript with support from LC, RD, PR.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nAcknowledgments\n\nNone.\n==== Refs\nReferences\n\nBrooks S.E. Zhan M. Cote T. Baquet C.R. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989–1999 Gynecol. Oncol. 93 2004 204 208 10.1016/j.ygyno.2003.12.029 15047237\nCherniack A.D. Shen H. Walter V. Stewart C. Murray B.A. Bowlby R. Hu X. Ling S. Soslow R.A. Broaddus R.R. Zuna R.E. Robertson G. Laird P.W. Kucherlapati R. Mills G.B. Akbani R. Ally A. Auman J.T. Balasundaram M. Balu S. Baylin S.B. Beroukhim R. Bodenheimer T. Bogomolniy F. Boice L. Bootwalla M.S. Bowen J. Broaddus R. Brooks D. Carlsen R. Cho J. Chuah E. Chudamani S. Cibulskis K. Cline M. Dao F. David M. Demchok J.A. Dhalla N. Dowdy S. Felau I. Ferguson M.L. Frazer S. Frick J. Gabriel S. Gastier-Foster J.M. Gehlenborg N. Gerken M. Getz G. Gupta M. Haussler D. Hayes D.N. Heiman D.I. Hess J. Hoadley K.A. Hoffmann R. Holt R.A. Hoyle A.P. Huang M. Hutter C.M. Jefferys S.R. Jones S.J.M. Jones C.D. Kanchi R.S. Kandoth C. Kasaian K. Kerr S. Kim J. Lai P.H. Lander E. Lawrence M.S. Lee D. Leraas K.M. Leshchiner I. Levine D.A. Lichtenberg T.M. Lin P. Liu J. Liu W. Liu Y. Lolla L. Lu Y. Ma Y. Maglinte D.T. Marra M.A. Mayo M. Meng S. Meyerson M. Mieczkowski P.A. Moore R.A. Mose L.E. Mungall A.J. Mungall K. Naresh R. Noble M.S. Olvera N. Parker J.S. Perou C.M. Perou A.H. Pihl T. Radenbaugh A.J. Ramirez N.C. Rathmell W.K. Roach J. Robertson A.G. Sadeghi S. Saksena G. Salvesen H.B. Schein J.E. Schumacher S.E. Sheth M. Shi Y. Shih J. Simons J.V. Sipahimalani P. Skelly T. Sofia H.J. Soloway M.G. Sougnez C. Sun C. Tam A. Tan D. Tarnuzzer R. Thiessen N. Thorne L.B. Tse K. Tseng J. Van Den Berg D.J. Veluvolu U. Verhaak R.G.W. Voet D. von Bismarck A. Wan Y. Wang Z. Wang C. Weinstein J.N. Weisenberger D.J. Wilkerson M.D. Winterhoff B. Wise L. Wong T. Wu Y. Yang L. Zenklusen J.C. (Julia) Zhang J. Zhang H. Zhang W. chun Zhu J. Zmuda E. Zhang J. Integrated molecular characterization of uterine carcinosarcoma Cancer Cell 31 2017 411 423 10.1016/j.ccell.2017.02.010 28292439\nCimbaluk D. Rotmensch J. Scudiere J. Gown A. Bitterman P. Uterine carcinosarcoma: immunohistochemical studies on tissue microarrays with focus on potential therapeutic targets Gynecol. Oncol. 105 2007 138 144 10.1016/j.ygyno.2006.11.001 17175012\nEmoto M. Charnock-Jones D.S. Licence D.R. Ishiguro M. Kawai M. Yanaihara A. Saito T. Hachisuga T. Iwasaki H. Kawarabayashi T. Smith S.K. Localization of the VEGF and angiopoietin genes in uterine carcinosarcoma Gynecol. Oncol. 95 2004 474 482 10.1016/j.ygyno.2004.08.042 15581949\nEngerud H. Berg H.F. Myrvold M. Halle M.K. Bjorge L. Haldorsen I.S. Hoivik E.A. Trovik J. Krakstad C. High degree of heterogeneity of PD-L1 and PD-1 from primary to metastatic endometrial cancer Gynecol. Oncol. 157 2020 260 267 10.1016/j.ygyno.2020.01.020 31973911\nGotoh O. Sugiyama Y. Takazawa Y. Kato K. Tanaka N. Omatsu K. Takeshima N. Nomura H. Hasegawa K. Fujiwara K. Taki M. Matsumura N. Noda T. Mori S. Clinically relevant molecular subtypes and genomic alteration-independent differentiation in gynecologic carcinosarcoma Nat. Commun. 10 2019 10.1038/s41467-019-12985-x\nHaddad R.I. Schlumberger M. Wirth L.J. Sherman E.J. Shah M.H. Robinson B. Dutcus C.E. Teng A. Gianoukakis A.G. Sherman S.I. Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes Endocrine 56 2017 121 128 10.1007/s12020-017-1233-5 28155175\nHarano K. Hirakawa A. Yunokawa M. Nakamura T. Satoh T. Nishikawa T. Aoki D. Ito K. Ito K. Nakanishi T. Susumu N. Takehara K. Watanabe Y. Watari H. Saito T. Optimal cytoreductive surgery in patients with advanced uterine carcinosarcoma: a multi-institutional retrospective study from the Japanese gynecologic oncology group Gynecol. Oncol. 141 2016 447 453 10.1016/j.ygyno.2016.04.004 27072806\nHarris P.A. Taylor R. Thielke R. Payne J. Gonzalez N. Conde J.G. Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support J. Biomed. Inform. 42 2009 377 381 10.1016/j.jbi.2008.08.010 18929686\nHarris P.A. Taylor R. Minor B.L. Elliott V. Fernandez M. O’Neal L. McLeod L. Delacqua G. Delacqua F. Kirby J. Duda S.N. The REDCap consortium: building an international community of software platform partners J. Biomed. Inform. 95 2019 103208 10.1016/j.jbi.2019.103208\nLivasy C.A. Reading F.C. Moore D.T. Boggess J.F. Lininger R.A. EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma Gynecol. Oncol. 100 2006 101 106 10.1016/j.ygyno.2005.07.124 16157366\nMakker V. Taylor M.H. Aghajanian C. Oaknin A. Mier J. Cohn A.L. Romeo M. Bratos R. Brose M.S. DiSimone C. Messing M. Stepan D.E. Dutcus C.E. Wu J. Schmidt E.V. Orlowski R. Sachdev P. Shumaker R. Herraez A.C. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer J. Clin. Oncol. 38 2020 2981 2992 10.1200/JCO.19.02627 32167863\nMatsuo K. Takazawa Y. Ross M.S. Elishaev E. Podzielinski I. Yunokawa M. Sheridan T.B. Bush S.H. Klobocista M.M. Blake E.A. Takano T. Matsuzaki S. Baba T. Satoh S. Shida M. Nishikawa T. Ikeda Y. Adachi S. Yokoyama T. Takekuma M. Fujiwara K. Hazama Y. Kadogami D. Moffitt M.N. Takeuchi S. Nishimura M. Iwasaki K. Ushioda N. Johnson M.S. Yoshida M. Hakam A. Li S.W. Richmond A.M. Machida H. Mhawech-Fauceglia P. Ueda Y. Yoshino K. Yamaguchi K. Oishi T. Kajiwara H. Hasegawa K. Yasuda M. Kawana K. Suda K. Miyake T.M. Moriya T. Yuba Y. Morgan T. Fukagawa T. Wakatsuki A. Sugiyama T. Pejovic T. Nagano T. Shimoya K. Andoh M. Shiki Y. Enomoto T. Sasaki T. Fujiwara K. Mikami M. Shimada M. Konishi I. Kimura T. Post M.D. Shahzad M.M. Im D.D. Yoshida H. Omatsu K. Ueland F.R. Kelley J.L. Karabakhtsian R.G. Roman L.D. Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma Ann. Oncol. 27 2016 1257 1266 10.1093/annonc/mdw161 27052653\nMatsuo K. Machida H. Ragab O.M. Takiuchi T. Pham H.Q. Roman L.D. Extent of pelvic lymphadenectomy and use of adjuvant vaginal brachytherapy for early-stage endometrial cancer Gynecol. Oncol. 144 2017 515 523 10.1016/j.ygyno.2016.12.012 28017306\nMatsuzaki S. Klar M. Matsuzaki S. Roman L.D. Sood A.K. Matsuo K. Uterine carcinosarcoma: contemporary clinical summary, molecular updates, and future research opportunity Gynecol. Oncol. 160 2021 586 601 10.1016/j.ygyno.2020.10.043 33183764\nMenczer J. Kravtsov V. Levy T. Berger E. Glezerman M. Avinoach I. Expression of c-kit in uterine carcinosarcoma Gynecol. Oncol. 96 2005 210 215 10.1016/j.ygyno.2004.09.045 15589603\nNCCN Clinical Practice Guidelines in Oncology, n.d. https://www.nccn.org/professionals/physician_gls/default.aspx (accessed March 24, 2021).\nPowell M.A. Filiaci V.L. Hensley M.L. Huang H.Q. Moore K.N. Tewari K.S. Copeland L.J. Secord A.A. Mutch D.G. Santin A. Richards W. Warshal D.P. Spirtos N.M. Disilverstro P. Ioffe O. Miller D.S. A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I) in chemotherapy-naive patients with stage I-IV, persistent or recurrent carcinosarcoma of the uterus or ovary: an NRG Oncology trial J. Clin. Oncol. 37 2019 5500 10.1200/jco.2019.37.15_suppl.5500\nSeymour L. Bogaerts J. Perrone A. Ford R. Schwartz L.H. Mandrekar S. Lin N.U. Litière S. Dancey J. Chen A. Hodi F.S. Therasse P. Hoekstra O.S. Shankar L.K. Wolchok J.D. Ballinger M. Caramella C. de Vries E.G.E. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics Lancet Oncol. 18 2017 e143 e152 10.1016/S1470-2045(17)30074-8 28271869\nSiegel R. Ma J. Zou Z. Jemal A. Cancer statistics, 2014, CA Cancer J. Clin. 64 2014 9 29 10.3322/caac.21208\nTang S.Q. Tang L.L. Mao Y.P. Li W.F. Chen L. Zhang Y. Guo Y. Liu Q. Sun Y. Xu C. Ma J. The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: a pooled analysis of 23 clinical trials and 8,436 patients Cancer Res. Treat. 53 2021 339 354 10.4143/CRT.2020.790 33171025\nVitale S.G. Laganà A.S. Capriglione S. Angioli R. Lucia V. Rosa L. Lopez S. Valenti G. Sapia F. Sarpietro G. Butticè S. Tuscano C. Fanale D. Tropea A. Rossetti D. Target therapies for uterine carcinosarcomas: current evidence and future perspectives Mdpi. Com. 2017 10.3390/ijms18051100\nZhang C. Hu W. Jia N. Li Q. Hua K. Tao X. Wang L. Feng W. Uterine carcinosarcoma and high-risk endometrial carcinomas Int. J. Gynecol. Cancer 25 2015 629 636 10.1097/IGC.0000000000000350 25633654\nZhao S. Bellone S. Lopez S. Thakral D. Schwab C. English D.P. Black J. Cocco E. Choi J. Zammataro L. Predolini F. Bonazzoli E. Bi M. Buza N. Hui P. Wong S. Abu-Khalaf M. Ravaggi A. Bignotti E. Bandiera E. Romani C. Todeschini P. Tassi R. Zanotti L. Odicino F. Pecorelli S. Donzelli C. Ardighieri L. Facchetti F. Falchetti M. Silasi D.A. Ratner E. Azodi M. Schwartz P.E. Mane S. Angioli R. Terranova C. Quick C.M. Edraki B. Bilgüvar K. Lee M. Choi M. Stiegler A.L. Boggon T.J. Schlessinger J. Lifton R.P. Santin A.D. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition Proc. Natl. Acad. Sci. USA 113 2016 12238 12243 10.1073/pnas.1614120113 27791010\n\n",
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"issue": "37()",
"journal": "Gynecologic oncology reports",
"keywords": "Lenvatinib; Pembrolizumab; Uterine carcinosarcoma",
"medline_ta": "Gynecol Oncol Rep",
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"title": "Lenvatinib plus pembrolizumab in patients with advanced or recurrent uterine carcinosarcoma.",
"title_normalized": "lenvatinib plus pembrolizumab in patients with advanced or recurrent uterine carcinosarcoma"
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"abstract": "The carcinoid syndrome is rare but it is associated with carcinoid heart disease in more than a half of the cases. Carcinoid heart disease is typically characterised by morphological and functional modifications of right-sided valves. Its aetiology is probable multifactorial but serotonin appears to play a key role in the development of this valvular disease. Unlike gastrointestinal neuroendocrine tumours, ovarian neuroendocrine tumours can present with carcinoid syndrome and carcinoid heart disease in the absence of liver metastases; such ovarian neuroendocrine tumours are a unique clinical entity. The additional burden of cardiac impairment in these patients represents a significant reduction in survival. Early recognition and surgical valve replacement before advanced heart failure is established may improve the clinical outcome. We report the case of a woman with an ovarian neuroendocrine tumour and highly symptomatic carcinoid heart disease who was submitted to tumour resection followed by valvuloplasty. She demonstrated an outstanding clinical improvement and has remained free of tumour and symptomatology.",
"affiliations": "Serviço de Endocrinologia. Instituto Português de Oncologia de Lisboa Francisco Gentil. Lisboa. Portugal.;Department of Pathology. John Radcliffe Hospital. Oxford. United Kingdom. United Kingdom.;Department of Cardiology. Milton Keynes Hospital. Buckinghamshire. United Kingdom.;Oxford Centre for Diabetes, Endocrinology and Metabolism. Churchill Hospital. Oxford. United Kingdom.",
"authors": "Simões-Pereira|Joana|J|;Wang|Lai Mun|LM|;Kardos|Attila|A|;Grossman|Ashley|A|",
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"keywords": "Carcinoid Heart Disease; Carcinoid Tumor; Carcinoma, Neuroendocrine; Ovarian Neoplasms",
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"title": "Carcinoid Syndrome and Carcinoid Heart Disease as Manifestations of Non-Metastatic Ovarian Neuroendocrine Tumour.",
"title_normalized": "carcinoid syndrome and carcinoid heart disease as manifestations of non metastatic ovarian neuroendocrine tumour"
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"abstract": "Methadone has a long and successful history in the treatment of opioid addiction. In recent years, it has become popular again--as potent and inexpensive analgesic in patients with chronic pain. Since methadone has been used fatalities have been reported. In our study all methadone-associated deaths in Zurich from 1998 to 2007 were analysed. Most of the 146 detected deaths of the past 10 years occurred during substitution programmes or illicit intake of methadone while only three of them could be attributed to methadone used as an analgesic. Noticeable in our study was the high percentage of cases of combined drug intoxication (76%). The most frequent co-intoxicants were alcohol and cocaine. Mortalities attributed to methadone intoxication alone were a rare finding and could only be detected in five cases of deceased who had received methadone maintenance treatment. The aim of our study is to assess the trends in the number and nature of methadone-related fatalities in Zurich during the last 19 years. For this purpose a previous study from Zurich (1989-1997) was included, whereby a very long observation period and large number of cases resulted.",
"affiliations": "Institute of Legal Medicine, University of Basel, Pestalozzistr. 22, 4056, Basel, Switzerland. patrick.laberke@bs.ch",
"authors": "Laberke|Patrick Johannes|PJ|;Bartsch|Christine|C|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D001569:Benzodiazepines; D002423:Cause of Death; D002492:Central Nervous System Depressants; D003042:Cocaine; D000431:Ethanol; D005260:Female; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008691:Methadone; D008875:Middle Aged; D009294:Narcotics; D058850:Opiate Substitution Treatment; D017678:Sex Distribution; D019966:Substance-Related Disorders; D013405:Suicide; D013557:Switzerland",
"nlm_unique_id": "9101456",
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"title": "Trends in methadone-related deaths in Zurich.",
"title_normalized": "trends in methadone related deaths in zurich"
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"abstract": "In recent years, the hepatotoxic potential of thiopurines, in particular 6-thioguanine (6-TG) has been discussed in literature. However, cirrhosis was exceptionally reported. We report the case of a 56-year-old woman with ileocaecal Crohn's disease treated with azathioprine. After taking azathioprine (2 mg/kg daily) for four years, she underwent surgical treatment for acute intestinal obstruction. In peroperative, we noticed a cirrhotic liver. A surgical biopsy was performed and the diagnosis of cirrhosis was confirmed. Autoimmune and viral liver diseases were ruled out by laboratory parameters. Therefore, Azathioprine is believed to be the causative actor for inducing liver cirrhosis. Thus, treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle.",
"affiliations": "Department of Gastroenterology, Sahloul Sousse, Tunisia.;Department of Gastroenterology, Sahloul Sousse, Tunisia.;Department of Gastroenterology, Sahloul Sousse, Tunisia.;Department of Gastroenterology, Sahloul Sousse, Tunisia.;Department of Gastroenterology, Sahloul Sousse, Tunisia.;Department of Gastroenterology, Sahloul Sousse, Tunisia.",
"authors": "Trabelsi|Aida Ben Slama|AB|;Hamami|Eya|E|;Souguir|Ahlem|A|;Ksiaa|Mehdi|M|;Ajmi|Salem|S|;Jmaa|Ali|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
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"doi": "10.11604/pamj.2014.17.174.3018",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-17-17410.11604/pamj.2014.17.174.3018Case ReportSuspected azathioprine induced liver cirrhosis: an unusual side effect Trabelsi Aida Ben Slama 1&Hamami Eya 1Souguir Ahlem 1Ksiaa Mehdi 1Ajmi Salem 1Jmaa Ali 11 Department of Gastroenterology, Sahloul Sousse, Tunisia& Corresponding author: Aida Ben Slama Trabelsi, Department of Gastroenterology, Sahloul Sousse, Tunisia07 3 2014 2014 17 17425 6 2013 05 3 2014 © Aida Ben Slama Trabelsi et al.2014The Pan African Medical Journal - ISSN 1937-8688. 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 work is properly cited.In recent years, the hepatotoxic potential of thiopurines, in particular 6-thioguanine (6-TG) has been discussed in literature. However, cirrhosis was exceptionally reported. We report the case of a 56-year-old woman with ileocaecal Crohn's disease treated with azathioprine. After taking azathioprine (2 mg/kg daily) for four years, she underwent surgical treatment for acute intestinal obstruction. In peroperative, we noticed a cirrhotic liver. A surgical biopsy was performed and the diagnosis of cirrhosis was confirmed. Autoimmune and viral liver diseases were ruled out by laboratory parameters. Therefore, Azathioprine is believed to be the causative actor for inducing liver cirrhosis. Thus, treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle.\n\nAzathioprineCrohn′s diseasehepatotoxicityliver cirrhosis\n==== Body\nIntroduction\nNowadays, thiopurines (azathioprine (AZA) and mercaptopurine (6 MP)) are the most commonly used immunomodulatory drugs for managing patients with inflammatory bowel disease (IBD)[1]. They are among the pharmacological agents with the greatest potential to cause adverse reactions. The side-effects of thiopurines can be divided into dose independent or “allergic/idiosyncratic” and dose-dependent events. Hepatic toxicity is believed to be a dose independent side effect of AZA. In recent years the hepatotoxic profile of thiopurines has been recognised. Most hepatic lesions described are vascular, such as peliosis hepatis, veno-occlusive disease, perisinusoidal fibrosis, hepatoportal sclerosis, and nodular regenerative hyperplasia. Even after long term treatment, most series report a rate of hepatic abnormalities of between 3 and 10%, which are usually limited to abnormal liver function tests and minor changes seen on liver biopsy specimens. The occurrence of side-effects, however, is a major drawback in the use of AZA or MP[1]. Cirrhosis is an exceptional complication of thiopurine drugs; only one case was reported in literature [2]. We report a rare case of liver cirrhosis in a Crohn′s disease patient associated with AZA therapy and we try to do a review of the literature regarding this complication.\n\nPatient and observation\nA 56 year old woman was followed, for 20 years, for ileocaecal Crohn disease complicated with stenosis. A corticosteroid pulse therapy was administered to induce remission. In 2000, a surgical treatment consisting of an ileocaecal resection was performed due to an acute intestinal obstruction caused by the terminal ileum stenosis. During surgery, liver was macroscopically normal. In the post-operative, Budesonide therapy was immediately initiated. The disease remained quiescent and regular laboratory controls including serum transaminases were normal. In 2006, the patient was treated with AZA in doses of 2mg/kg/j. She remained free of endoscopic and clinical recurrence until 2010 when she underwent reoperation for adhesions bowel obstruction. She had a new resection of the ileum. At laparotomy, the liver was macroscopically fibrosed. A surgical hepatic biopsy specimen was taken for histological examination and confirmed liver cirrhosis. Liver function tests were normal. Viral liver diseases were ruled out by laboratory parameters. Autoimmune diseases of the liver are also unlikely in the absence of autoantibodies. Then, AZA therapy (4 years) was believed to be the causative factor of cirrhosis.\n\nDiscussion\nThe thiopurine drugs such as AZA and 6-MP represent an effective and widely used immunosuppressant in the therapeutic armamentarium of IBD. They can induce and maintain remission of Crohn's disease (CD) and ulcerative colitis (UC), and have steroid-sparing effects in patients with steroid-dependent IBD [3, 4]. However, their therapeutic role is disputable because of toxicity. Up to 25% of patients may be unable to continue the drug due to side effects. The incidence of hepatotoxicity associated with thiopurine use is reported between 0% and 32% [5]. Many of the symptoms of hepatotoxicity can be nonspecific and can be confused with a flare-up of inflammatory bowel disease. As well, the subtype resulting in portal hypertension can occur without biochemical abnormalities. Thiopurine-induced hepatotoxicity can be grouped into three syndromes: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury (with resultant raised portal pressures, veno-occlusive disease, or peliosis hepatis, perisinusoidal fibrosis and nodular regenerative hyperplasia) [6].\n\nAZA and 6-MP are metabolized into active and inactive metabolites by the same enzymatic cascade. AZA is a pro-drug that is converted to 6-MP via a nonenzymatic metabolic pathway and its imidazole derivative by glutathione in the liver. Then, 6-MP enters cells and is subject to 3 competing enzymatic pathways [7]. It may be activated via a multi-step enzymatic pathway to produce the active metabolites, the 6-thioguanine nucleotides (6-TGNs). 6-MP is also metabolized bythiopurine methyl transferase (TPMT) to 6-methylmercaptopurine (6-MMP) or by xanthine oxidase to 6-thiouric acid [7]. Several metabolites have been held responsible for induction of adverse events. Many studies have shown that hepatotoxicity seems to be related to the accumulation of methylated metabolites such as 6-MMP [2, 8]. The enzyme TPMT is the key enzyme in the metabolic pathway: patients with very high TPMT activity are resistant to thiopurine drugs due to shunting of 6-MP away from 6 TGN towards over production of 6-MMP [8, 9], and at the risk of hepatotoxicity due to high 6-MMP concentrations[10].\n\nIn our case, high TPMT activity cannot be the mechanism of hepatotoxicity. Indeed, azathioprine was effective in maintaining remission in our patient at a dose of 2mg / kg / day. The hypothesis that high 6-TGN levels are hepatotoxic may provide an explanation why our patient developed liver cirrhosis. The higher occurrence of histological liver abnormalities during 6-TG treatment in comparison with AZA or 6-mercaptopurine (6-MP) may be explained by the significantly higher levels of 6-TGN reached by 6-TG [2].\n\nConclusion\nThis case illustrates the potential toxicity of AZA, highlights the need to monitor liver function tests in patients treated with thiopurine, and identifies the need for additional research focused on the mechanism of thiopurine-induced hepatic injury in patients treated with thiopurines for inflammatory bowel disease. Cirrhosis may be an exceptional complication of thiopurine drugs. Knowledge of such side effect could justify the routine use of abdominal ultrasound in monitoring patients on thiopurine as liver function tests may be normal.\n\nCompeting interests\nThe authors declare no competing interest.\n\nAuthors’ contributions\nAll th eauthors have contributed to this case in ways that conform to ICMJE authorship criteria. All the authors have read and approved the final version of the manuscript.\n==== Refs\nReferences\n1 Markowitz J Grancher K Kohn N Daum F Immunomodulatory therapy for pediatric inflammatory bowel disease: changing patterns of use, 1990-2000 Am J Gastroenterol. 2002 97 4 928 32 12003428 \n2 Boer NKH Mulder CJJ Van Bodegraven AA Myelotoxicity and hepatotoxicity during azathioprine therapy Neth J Med. 2005 63 11 444 6 16397313 \n3 Pearson DC May GR Fick GH Sutherland LR Azathioprine and 6-mercaptopurine in Crohn ‘s disease: A meta-analysis Ann Intern Med. 1995 123 2 132 142 7778826 \n4 Fraser AG Orchard TR Jewell DP The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review Gut. 2002 50 4 485 489 11889067 \n5 Lowry PW Franklin CL Weaver AL Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease Gut. 2001 49 5 665 70 11600469 \n6 Gisbert JP González-Lama Y Maté J Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review Am J Gastroenterol. 2007 102 7 1518 27 17391318 \n7 Macdonald A Omega-3 fatty acids as adjunctive therapy in Crohns disease Gastroenterol Nurs. 2006 29 295 301 16974165 \n8 Cuffari C Dassopoulos T Turnbough L Thompson RE Bayless TM Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease Clin Gastroenterol Hepatol. 2004 2 5 410 417 15118980 \n9 Kiefer K El-Matary W 6 Mercaptopurine as an Alternative to Azathioprine in Azathioprine-induced Hepatoxicity Inflamm Bowel Dis. 2009 15 2 318 18989893 \n10 Gastal GR Moreira S Noble CF Ferreira LE França PH Pinho M Toxicity of azathioprine: why and when: Analysis of the prevalence of polymorphism in Joinville, SC, Brazil Arq Gastroenterol. 2012 49 2 130 4 22767000\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "17()",
"journal": "The Pan African medical journal",
"keywords": "Azathioprine; Crohn′s disease; hepatotoxicity; liver cirrhosis",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D001379:Azathioprine; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008103:Liver Cirrhosis; D008875:Middle Aged",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "174",
"pmc": null,
"pmid": "25392720",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11600469;11889067;12003428;15118980;22767000;16397313;16974165;17391318;18989893;7778826",
"title": "Suspected azathioprine induced liver cirrhosis: an unusual side effect.",
"title_normalized": "suspected azathioprine induced liver cirrhosis an unusual side effect"
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"companynumb": "TN-MYLANLABS-2015M1026102",
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"occurcountry": "TN",
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"activesubstancename": "BUDESONIDE"
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"abstract": "A 29-year-old woman with past medical history of hypertension was referred to our hospital for the evaluation of kidney dysfunction (serum creatinine 1.0 mg/dL), proteinuria (0.54 g/gCre), and microscopic hematuria. Renal biopsy before the first pregnancy was supportive for benign nephrosclerosis with no evidence of vasculitis. After her second pregnancy and delivery when she was 32 years old, she developed proteinuria of 3.2 g/gCre, hematuria, and elevated serum creatinine level of 2.6 mg/dL. Second renal biopsy revealed necrotizing glomerulonephritis and her serum MPO-ANCA was positive, leading to the diagnosis of MPA/renal-limited vasculitis (RLV). Interestingly, frozen preserved serum from 4 years earlier also tested positive for MPO-ANCA. Despite intensive treatment, hemodialysis was required 10 years later due to progressive deterioration of renal function. At that time, she developed pericarditis, bloody cardiac tamponade, and pulmonary alveolar hemorrhage, resulting in a diagnosis of systemic vasculitis MPA. She received living donor kidney transplantation at the age of 44 years, after which serum creatinine has been stable around 1.1 mg/dL without proteinuria or hematuria and MPO-ANCA has remained negative. The association of vasculitis with pregnancy and delivery is not well documented, especially in patients with MPA. Here, we report this MPO-ANCA positive woman developing MPA necrotizing glomerulonephritis after her second pregnancy and a 20-year clinical course.",
"affiliations": "Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan. yoichi-o-s@hotmail.co.jp.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Department of Pathology, Toranomon Hospital, Tokyo, Japan.;Department of Pathology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.;Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, 105-8470, Japan.",
"authors": "Oshima|Yoichi|Y|http://orcid.org/0000-0003-1908-6329;Suwabe|Tatsuya|T|;Marui|Yuji|Y|;Hayami|Noriko|N|;Hasegawa|Eiko|E|;Yamanouchi|Masayuki|M|;Hiramatsu|Rikako|R|;Sumida|Keiichi|K|;Kawada|Masahiro|M|;Sekine|Akinari|A|;Mizuno|Hiroki|H|;Oguro|Masahiko|M|;Hoshino|Junichi|J|;Sawa|Naoki|N|;Ishii|Yasuo|Y|;Fujii|Takeshi|T|;Ohashi|Kenichi|K|;Takaichi|Kenmei|K|;Ubara|Yoshifumi|Y|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-018-0342-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "7(2)",
"journal": "CEN case reports",
"keywords": "Delivery; MPO-ANCA; Microscopic polyangiitis; Necrotizing glomerulonephritis; Pregnancy",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000328:Adult; D019268:Antibodies, Antineutrophil Cytoplasmic; D005260:Female; D005921:Glomerulonephritis; D006801:Humans; D016030:Kidney Transplantation; D055953:Microscopic Polyangiitis; D009336:Necrosis; D011247:Pregnancy; D011248:Pregnancy Complications; D011507:Proteinuria; D006435:Renal Dialysis; D056647:Systemic Vasculitis; D016896:Treatment Outcome",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "274-281",
"pmc": null,
"pmid": "29869147",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15521377;26934300;27733943;8777855;25841802;2383088;23045170;24223652;9746391;23401494;21183452;12597314;16901958;23810690;19395136;15806479;3574116;25272233;24429174;26373560;14671064;20130479;21555869;20616173;21798892;3827345;22162518;23549081",
"title": "Microscopic polyangiitis necrotizing glomerulonephritis associated with pregnancy: case with a 20-year clinical course and review of the literature.",
"title_normalized": "microscopic polyangiitis necrotizing glomerulonephritis associated with pregnancy case with a 20 year clinical course and review of the literature"
} | [
{
"companynumb": "PHHY2018JP147816",
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"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Pituitary and adrenal insufficiency must not be overlooked when weaning patients down from high-dose steroids. Prednisolone can be used as glucocorticoid replacement therapy, with most patients needing 3-4 mg once daily.",
"affiliations": "Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism Imperial College London London UK.;Endocrinology Imperial College Healthcare NHS Trust London UK.;Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism Imperial College London London UK.;Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism Imperial College London London UK.",
"authors": "Choudhury|Sirazum|S|https://orcid.org/0000-0003-2429-005X;Machenahalli|Pratibha|P|;Tan|Tricia|T|;Meeran|Karim|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2132",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2132CCR32132Case ReportCase ReportsInadvertent treatment of hypoadrenalism with prednisolone in pemphigus: A case report CHOUDHURY et al.Choudhury Sirazum https://orcid.org/0000-0003-2429-005Xs.choudhury@imperial.ac.uk \n1\n\n2\nMachenahalli Pratibha \n3\nTan Tricia \n1\n\n2\n\n3\nMeeran Karim \n1\n\n3\n\n1 \nSection of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism\nImperial College London\nLondon\nUK\n\n2 \nDepartment of Clinical Biochemistry\nImperial College Healthcare NHS Trust\nLondon\nUK\n\n3 \nEndocrinology\nImperial College Healthcare NHS Trust\nLondon\nUK\n* Correspondence\n\nSirazum Choudhury, Section of Investigative Medicine, Imperial College London, London, UK.\n\nEmail: s.choudhury@imperial.ac.uk\n08 4 2019 5 2019 7 5 10.1002/ccr3.2019.7.issue-5987 989 21 1 2019 04 3 2019 14 3 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nPituitary and adrenal insufficiency must not be overlooked when weaning patients down from high‐dose steroids. Prednisolone can be used as glucocorticoid replacement therapy, with most patients needing 3‐4 mg once daily.\n\nadrenal insufficiencyglucocorticoid replacementhypoadrenalismprednisolone source-schema-version-number2.0component-idccr32132cover-dateMay 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:10.05.2019\n\n\nChoudhury \nS \n, \nMachenahalli \nP \n, \nTan \nT \n, \nMeeran \nK \n. Inadvertent treatment of hypoadrenalism with prednisolone in pemphigus: A case report . Clin Case Rep . 2019 ;7 :987 –989 . 10.1002/ccr3.2132\n==== Body\n1 INTRODUCTION\nA 49‐year‐old male with hypopituitarism and pemphigus receiving 10‐30 mg prednisolone had unexpected improvement and was weaned to 4 mg but no lower due to tiredness and nausea. This experience highlights that the prednisolone dose required for adrenal replacement is 3‐4 mg daily, and hypothalamo‐pituitary‐adrenal failure should not be overlooked in patients on steroids.\n\nThe gradual reduction of prednisolone dosage in a patient with pituitary failure is an experiment that is never knowingly undertaken, because of the appropriate fear of an Addisonian crisis. As a consequence, there is an absence of good data on the minimum dose of prednisolone that can be used as a replacement.\n\nThis case highlights a patient who inadvertently became aware of his own glucocorticoid requirement. During this process, he has highlighted that once‐daily prednisolone is a convenient option for steroid replacement therapy, and that the doses required for adequate replacement are lower than previously thought. This case has changed local practice, and we now use prednisolone 2‐4 mg once daily and titrate the dose against a prednisolone level in patients with adrenal insufficiency.\n\n2 CASE REPORT\nA 49‐year‐old bus driver presented in November 2000 with features of acromegaly. An MRI scan demonstrated a large (2.0 × 2.0 × 0.5 cm) pituitary adenoma. His growth hormone levels were 14.8‐16.4 mU/L and were not suppressible with glucose. His IGF1 was 191 nmol/L (reference range: 13‐64 nmol/L), prolactin 6557 mU/L, testosterone 2 nmol/L, and cortisol uninterpretable given long‐term high‐dose prednisolone therapy for long‐standing pemphigus vulgaris. He was treated with a transsphenoidal hypophysectomy in January 2001 and external beam pituitary radiotherapy in October 2001. In the same year, he was discovered to be thyrotoxic, secondary to a toxic adenoma, which was treated with radioactive iodine. He has never required thyroid replacement therapy, and his current thyroid function tests 18 years later reveal that he is euthyroid (TSH 2.69 mU/L; free T4 10.6 pmol/L; free T3 3.5 pmol/L). He was noted to be osteopenic on a DEXA scan in 2004, prompting treatment with alendronate 70 mg weekly. Subsequent DEXA scans have demonstrated osteoporosis due to a combination of testosterone deficiency and long‐term high‐dose prednisolone treatment. Over the years, the patient was treated with cabergoline and later, octreotide in 2003, for excess levels of growth hormone and IGF‐1. These treatments were stopped in 2004, when his growth hormone level was found to be suppressed and the radiotherapy had clearly worked. Since 2001, he has required exogenous testosterone.\n\nThe patient had a pre‐existing diagnosis of pemphigus vulgaris which was treated with long‐term prednisolone, at doses no lower than 10 mg for over 15 years, and azathioprine 125 mg daily. His cortisol reserve was never assessed as it was thought unlikely that he would ever come off his high‐dose prednisolone. The patient reported that his skin “started burning” when the dose of prednisolone was ever reduced below 10 mg. He stayed on prednisolone for at least another 10 years and was regularly reviewed by the dermatologists.\n\nUnexpectedly, by August 2014, the patient's pemphigus had undergone complete remission. He was very slowly weaned down on prednisolone according to a standard dermatological protocol (reduction by 1 mg every 2 months, with regular review for resurgence of skin inflammation), with a view to stopping completely. By October 2015, the patient had come off azathioprine completely and was taking prednisolone 3 mg daily, on which he was well. Unaware that the prednisolone served as glucocorticoid replacement, the patient continued to wean down to 2 mg, on which he experienced severe lethargy, and then 1 mg, on which he started vomiting, although he never had a salt‐losing Addisonian crisis. He independently up‐titrated the prednisolone to 4 mg once daily. A short synacthen test was performed in May 2016, the results of which were suggested that recovery of the cortisol axis is unlikely (cortisol at T = 0: <20 nmol/L; T = 30: 59 nmol/L; T = 60: 79 nmol/L).\n\nIn August 2017, an 8‐hour trough level prednisolone measurement of 18 µg/L (target range: 15‐25 µg/L) confirmed that his appropriate replacement dose is 4 mg once daily.\n\nThe patient remains well on 4 mg prednisolone daily and will continue on this indefinitely. This patient's experience confirms recent evidence that the dose required for adequate replacement is far less than the 7.5 mg traditionally quoted. If prednisolone is to be used as replacement glucocorticoid, we recommend a starting dose of 3‐4 mg daily.1\n\n\n3 DISCUSSION\nIt is well known that patients with adrenal insufficiency should be given adequate steroid cover, especially at times of intercurrent illness. This is ingrained into doctors across all specialities given the lethal consequences of under‐replacement. Patients who do not receive adequate treatment are at risk of adrenal crises, presenting with vomiting, diarrhea, abdominal pain, lethargy, hypotension, hypoglycemia, and electrolyte dysregulation. Because of this, most patients are over‐replaced, and there are little data on the minimum dose of steroid required. Patients with pituitary failure have an intact adrenal gland and have normal regulation of aldosterone, and thus are not at risk of a salt‐losing crisis. Instead, when cortisol‐deficient, they develop exhaustion and eventually vomiting, but no life‐threatening salt‐losing crises.\n\nOur evidence base for the dose of hydrocortisone replacement is poor. The average dose used as replacement has fallen from an average of 30 mg hydrocortisone daily to 20 mg daily, and the actual required dose is probably even lower than this. Although short‐term extra hydrocortisone may be lifesaving, chronic minor excess of replacement contributes to side effects such as osteoporosis.\n\nThe Endocrine Society Clinical Practice Guidelines endorse prednisolone as an alternative steroid for glucocorticoid replacement therapy.2 Taken only once a day, it is more convenient than hydrocortisone therapy and better mimics the normal cortisol day profile.\n\nThe association of high‐dose prednisolone with adverse metabolic outcomes such as osteoporosis has hindered wider adoption as a primary replacement therapy. This association is however based on studies in which prednisolone was used at doses in the order of 5‐7.5 mg daily for replacement, and much larger doses for immunosuppression.3 There is now evidence that prednisolone is more potent than previously thought and that a lower dose in the order of 2‐4 mg is in fact more appropriate.4, 5\n\n\n4 CONCLUSION\nSince this patient illustrated the safety of once‐daily prednisolone, we have changed to using prednisolone once daily as our first‐line glucocorticoid replacement therapy in patients with Addison's disease as well as (secondary) pituitary hypoadrenalism. We now have over 100 patients, who are currently treated with low‐dose (2‐4 mg) prednisolone as steroid replacement therapy.1 Those with adrenal failure also start on fludrocortisone 100 µg daily. Having developed a sensitive and reliable in‐house prednisolone assay, we have observed that there is variability in prednisolone metabolism between patients. We are able to tailor doses to each individual, using an 8‐hour trough measurement aiming for a level of 15‐25 µg/L. The majority of daily maintenance doses are between 2 and 4 mg once daily, with no observed adrenal crises thus far.\n\nClinicians hold a clear association between hypoadrenalism and hydrocortisone, meaning that steroid replacement therapy is less likely to be overlooked than with prednisolone. As the number of patients taking prednisolone for hypoadrenalism increases, it is important that this same association is entrained to prevent replacement therapy being inadvertently withheld.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nSC and PM: was responsible for the initial draft of this manuscript. KM and TT: have reviewed this manuscript and made edits to the text. SC, PM, TT and KM: have approved the final manuscript. All authors have contributed equally. KM: is the named physician who is responsible for this patient's care.\n\nACKNOWLEDGMENTS\nNil.\n==== Refs\nREFERENCES\n1 \n\nSmith \nD \n, \nPrabhudev \nH \n, \nChoudhury \nS \n, \nMeeran \nK \n. Prednisolone has the same cardiovascular risk profile as hydrocortisone in glucocorticoid replacement . Endocr Connect . 2017 ;6 (8 ):766 ‐772 .29018153 \n2 \n\nBornstein \nSR \n, \nAllolio \nB \n, \nArlt \nW \n, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline . J Clin Endocrinol Metab . 2016 ;101 (2 ):364 ‐389 .26760044 \n3 \n\nJodar \nE \n, \nValdepenas \nMP \n, \nMartinez \nG \n, \nJara \nA \n, \nHawkins \nF \n. Long‐term follow‐up of bone mineral density in addison's disease . Clin Endocrinol (Oxf) . 2003 ;58 (5 ):617 ‐620 .12699444 \n4 \n\nWilliams \nEL \n, \nChoudhury \nS \n, \nTan \nT \n, \nMeeran \nK \n. Prednisolone replacement therapy mimics the circadian rhythm more closely than other glucocorticoids . J Appl Lab Med . 2016 ;1 (2 ):152 ‐161 .\n5 \n\nCaldato \nMC \n, \nFernandes \nVT \n, \nKater \nCE \n. One‐year clinical evaluation of single morning dose prednisolone therapy for 21‐hydroxylase deficiency . Arq Bras Endocrinol Metabol . 2004 ;48 (5 ):705 ‐712 .15761542\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "7(5)",
"journal": "Clinical case reports",
"keywords": "adrenal insufficiency; glucocorticoid replacement; hypoadrenalism; prednisolone",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
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"pages": "987-989",
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"pmid": "31110731",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports",
"references": "12699444;15761542;26760044;29018153",
"title": "Inadvertent treatment of hypoadrenalism with prednisolone in pemphigus: A case report.",
"title_normalized": "inadvertent treatment of hypoadrenalism with prednisolone in pemphigus a case report"
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"abstract": "There are limited data on clinical profile of adolescent patients with Budd-Chiari syndrome (BCS). We studied clinical, radiological, thrombophilia profile and treatment outcomes in adolescent patients with BCS.\n\n\nMETHODS\nForty-three consecutive patients of BCS with onset of symptoms during adolescence (10-19 years) were enrolled in the study. 129 randomly selected adult patients with BCS and 36 children with BCS formed the two control groups. The clinical history, physical examination, laboratory tests, thrombophilic disorders, radiological features and treatment outcomes of adolescents were compared to adults and children.\n\n\nRESULTS\nIn adolescents, ascites (25/43 vs. 110/129, p = 0.0004) and thrombophilic disorders (16/43 vs. 93/129 p < 0.0001) were less frequent than adults. More adolescents (14/43) presented with hepatomegaly alone without ascites than adults (9/129, p < 0.001) or children (1/36, p = 0.005). Adolescents had lower Clichy scores [3.75 (1.2)] than adults [4.72 (1.3), p < 0.0001) or children [4.43 (1.7), p = 0.041]. JAK-2 V617F mutation was the most common thrombophilic disorder in adolescents (5/43) and more common than children (0/36, p = 0.043). Response to therapy was better in adolescents (74.4%) than children (52.8%, p = 0.038), but similar to adults (63.56%, p = 0.13).\n\n\nCONCLUSIONS\nDuring adolescence, patients with BCS present less commonly with ascites and may present with hepatomegaly alone. JAK-2 V617F mutation is the most common thrombophilic disorder during adolescence; though thrombophilic disorders are less common in adolescents than adults. Response to therapy is similar to adults, but better than children.",
"affiliations": "Department of Gastroenterology, KEM Hospital and Seth GS Medical College, Multistory Building, 11th floor, Parel, Mumbai, Maharashtra, 400012, India. drakashshukla@yahoo.com.;Department of Gastroenterology, KEM Hospital and Seth GS Medical College, Multistory Building, 11th floor, Parel, Mumbai, Maharashtra, 400012, India.;Department of Gastroenterology, KEM Hospital and Seth GS Medical College, Multistory Building, 11th floor, Parel, Mumbai, Maharashtra, 400012, India.;Department of Gastroenterology, KEM Hospital and Seth GS Medical College, Multistory Building, 11th floor, Parel, Mumbai, Maharashtra, 400012, India.;Department of Gastroenterology, KEM Hospital and Seth GS Medical College, Multistory Building, 11th floor, Parel, Mumbai, Maharashtra, 400012, India.;Department of Gastroenterology, KEM Hospital and Seth GS Medical College, Multistory Building, 11th floor, Parel, Mumbai, Maharashtra, 400012, India.;Department of Gastroenterology, KEM Hospital and Seth GS Medical College, Multistory Building, 11th floor, Parel, Mumbai, Maharashtra, 400012, India.;Department of Gastroenterology, KEM Hospital and Seth GS Medical College, Multistory Building, 11th floor, Parel, Mumbai, Maharashtra, 400012, India.",
"authors": "Shukla|Akash|A|http://orcid.org/0000-0001-7718-9452;Bhatt|Pratin|P|;Gupta|Deepak Kumar|DK|;Modi|Tejas|T|;Patel|Jatin|J|;Gupte|Amit|A|;Meshram|Megha|M|;Bhatia|Shobna|S|",
"chemical_list": "C507924:JAK2 protein, human; D053614:Janus Kinase 2",
"country": "United States",
"delete": false,
"doi": "10.1007/s12072-018-9880-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1936-0533",
"issue": "12(6)",
"journal": "Hepatology international",
"keywords": "Anticoagulation therapy; Hepatic vein outflow tract obstruction; Pediatric liver disease; Portal hypertension; Trans-jugular intrahepatic porto-systemic shunt",
"medline_ta": "Hepatol Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001201:Ascites; D006502:Budd-Chiari Syndrome; D002648:Child; D005260:Female; D006529:Hepatomegaly; D006801:Humans; D053614:Janus Kinase 2; D008297:Male; D008487:Medical History Taking; D009154:Mutation; D010808:Physical Examination; D012720:Severity of Illness Index; D019851:Thrombophilia",
"nlm_unique_id": "101304009",
"other_id": null,
"pages": "560-566",
"pmc": null,
"pmid": "29971683",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": "19652186;8309360;17719087;24225289;25003745;17645565;9794901;27465349;8006900;12971957;23884647;11592594;27218672;25609002;11584361;14768004;10847443;9884387;20373079;11953980;14332054;14531919;19915494;19468728",
"title": "Budd-Chiari syndrome has different presentations and disease severity during adolescence.",
"title_normalized": "budd chiari syndrome has different presentations and disease severity during adolescence"
} | [
{
"companynumb": "IN-CIPLA LTD.-2018IN23906",
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"occurcountry": "IN",
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"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the incidence and risk factors for thromboembolic events (TE) and febrile neutropenia (FN) in patients receiving systemic chemotherapy for early breast cancer (EBC).\n\n\nMETHODS\n325 patients received FEC75, FEC100-T or ECaP for EBC in 2013.\n\n\nRESULTS\nTE occurred in 7.4% and FN in 19.1% of patients. Risk factors for TE were: central venous catheter (p = 0.011). Risk factors for FN were: FEC100-T treatment versus FEC75 and ECaP (p ≤ 0.001); lower pre-treatment neutrophil count (p = 0.009) and poorer performance status (p = 0.012). Two patients died from treatment-related toxicities.\n\n\nCONCLUSIONS\nIn real-world experience, the majority of patients completed adequate treatment, despite significant complications.",
"affiliations": "Breast Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom.;Breast Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Institute of Cancer Research, London, United Kingdom.;Breast Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Institute of Cancer Research, London, United Kingdom.;Research and Development Department, The Royal Marsden NHS Foundation Trust, London, United Kingdom.;Breast Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom.;Breast Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom.;Breast Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom. Electronic address: alistair.ring@rmh.nhs.uk.",
"authors": "Redana|S|S|;Sharp|A|A|;Lote|H|H|;Mohammed|K|K|;Papadimitraki|E|E|;Capelan|M|M|;Ring|A|A|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.breast.2016.07.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-9776",
"issue": "30()",
"journal": "Breast (Edinburgh, Scotland)",
"keywords": "Adjuvant chemotherapy; Early breast cancer (EBC); Febrile neutropenia; Neoadjuvant chemotherapy; Thromboembolic events; Treatment related toxicity",
"medline_ta": "Breast",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D018275:Carcinoma, Lobular; D017024:Chemotherapy, Adjuvant; D064146:Chemotherapy-Induced Febrile Neutropenia; D003520:Cyclophosphamide; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D015994:Incidence; D008408:Mastectomy; D015412:Mastectomy, Segmental; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D017239:Paclitaxel; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D012307:Risk Factors; D021701:Sentinel Lymph Node Biopsy; D020521:Stroke; D043823:Taxoids; D013923:Thromboembolism; D020246:Venous Thrombosis",
"nlm_unique_id": "9213011",
"other_id": null,
"pages": "13-18",
"pmc": null,
"pmid": "27569021",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rates of major complications during neoadjuvant and adjuvant chemotherapy for early breast cancer: An off study population.",
"title_normalized": "rates of major complications during neoadjuvant and adjuvant chemotherapy for early breast cancer an off study population"
} | [
{
"companynumb": "GB-ACCORD-049806",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
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... |
{
"abstract": "The aim of this 12-month, observational study was to compare the effects of switching daily teriparatide (TPTD) to oral bisphosphonates (BP) therapy or denosumab (DMAb) therapy in patients with primary osteoporosis. Patients [n = 78; 71 postmenopausal women and seven men; mean age 76.3 (64-94) years; mean duration of prior daily TPTD therapy 20.1 (6-24) months] were allocated to either the (1) \"switch-to-BP\" group [n = 36; weekly alendronate 35 mg (n = 19), weekly risedronate 17.5 mg (n = 12), monthly minodronate 50 mg (n = 5)]; or (2) \"switch-to-DMAb\" group (n = 42; 60 mg sc every 6 months) based on each physicians' decision. Changes in bone mineral density (BMD) and serum bone turnover markers were monitored every 6 months. No significant difference was observed in baseline clinical characteristics between the groups. After 12 months, the increase in BMD was significantly greater in the switch-to-DMAb group compared to the switch-to-BP group: lumbar spine (6.2 vs. 2.6 %; P < 0.01), total hip (4.2 vs. 1.1 %; P < 0.05), and femoral neck (3.5 vs. 1.4 %; P < 0.05). In addition, the patients in the switch-to-DMAb group showed a significant decrease compared to those in the switch-to-BP group in TRACP-5b (-55.8 vs. -32.8 %; P < 0.01) and ucOC (-85.5 vs. -65.0 %; P < 0.001), while no significant difference was observed in PINP (-67.5 vs. -62.1 %). Switching daily TPTD to DMAb significantly increased BMD and decreased bone resorption marker compared to switching to oral BP at 12 months, and thus may provide an effective sequential treatment option after daily TPTD treatment.",
"affiliations": "Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. k-ebina@umin.ac.jp.;Department of Rheumatology, National Hospital Organization, Osaka Minami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka, 586-8521, Japan.;Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.;Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.;Department of Orthopaedic Surgery, Japan Community Health Care Organization, Osaka Hospital, 4-2-78 Fukushima Ward, Osaka, 586-8521, Japan.;Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.;Department of Orthopaedic Surgery, North Osaka Police Hospital, 1-2-2 Muroyama, Ibaraki, Osaka, 567-0052, Japan.;Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.",
"authors": "Ebina|Kosuke|K|;Hashimoto|Jun|J|;Kashii|Masafumi|M|;Hirao|Makoto|M|;Kaneshiro|Shoichi|S|;Noguchi|Takaaki|T|;Tsukamoto|Yasunori|Y|;Yoshikawa|Hideki|H|",
"chemical_list": "D015415:Biomarkers; D004164:Diphosphonates; D019379:Teriparatide; D000069448:Denosumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00774-015-0731-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0914-8779",
"issue": "35(1)",
"journal": "Journal of bone and mineral metabolism",
"keywords": "Daily teriparatide; Denosumab; Oral bisphosphonates; Primary osteoporosis",
"medline_ta": "J Bone Miner Metab",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D015519:Bone Density; D000069448:Denosumab; D004164:Diphosphonates; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis; D019379:Teriparatide",
"nlm_unique_id": "9436705",
"other_id": null,
"pages": "91-98",
"pmc": null,
"pmid": "26762133",
"pubdate": "2017-01",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "17014384;18505369;18767928;22836585;9108485;24646104;23147574;23812464;24141036;17501665;23203733;25524021;25403903;24368586;20872215;12110442;23045165;18214569;23124653;26097648;24275677;26303222;20839290;25369992;25082556;25684625",
"title": "The effects of switching daily teriparatide to oral bisphosphonates or denosumab in patients with primary osteoporosis.",
"title_normalized": "the effects of switching daily teriparatide to oral bisphosphonates or denosumab in patients with primary osteoporosis"
} | [
{
"companynumb": "JP-ALLERGAN-1709469US",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Mucorales is an order of angioinvasive fungi that classically infects immunocompromised patients. As an aerogenous pathogen, it most frequently causes disease of the lungs and paranasal sinuses. Gastrointestinal mucormycosis represents a particularly rare site of infection. This case report describes the complicated presentation of ileocecal mucormycosis in an immunocompromised orthotopic heart transplant recipient. The diagnosis was made status-post ileocolonic resection, and the patient was promptly started on liposomal amphotericin B and micafungin. Unfortunately, the patient ultimately succumbed to disseminated infection. In this study, we review the epidemiology, the presenting features of gastrointestinal mucormycosis, and emphasize the prompt initiation of therapy on suspected disease.",
"affiliations": "Department of Surgery, University of Virginia Health System, Charlottesville, VA.;Department of Surgery, West Virginia University School of Medicine, Morgantown, WV.",
"authors": "Hoang|Sook|S|;Sestito|Michael|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.0000000000000699",
"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253\nWolters Kluwer Maryland, MD\n\nACGCR-20-1186\n10.14309/crj.0000000000000699\n00027\nCase Report\nColon\nA Rare Presentation of Ileocecal Mucormycosis in a Heart Transplant Recipient\nHoang Sook MD 1\nSestito Michael MD 2mps8bt@virginia.edu\n\n1 Department of Surgery, University of Virginia Health System, Charlottesville, VA\n2 Department of Surgery, West Virginia University School of Medicine, Morgantown, WV\nCorrespondence: Sook C Hoang, MD (sh7je@virginia.edu).\n11 2021\n24 11 2021\n8 11 e0069913 10 2020\n21 6 2021\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nABSTRACT\n\nMucorales is an order of angioinvasive fungi that classically infects immunocompromised patients. As an aerogenous pathogen, it most frequently causes disease of the lungs and paranasal sinuses. Gastrointestinal mucormycosis represents a particularly rare site of infection. This case report describes the complicated presentation of ileocecal mucormycosis in an immunocompromised orthotopic heart transplant recipient. The diagnosis was made status-post ileocolonic resection, and the patient was promptly started on liposomal amphotericin B and micafungin. Unfortunately, the patient ultimately succumbed to disseminated infection. In this study, we review the epidemiology, the presenting features of gastrointestinal mucormycosis, and emphasize the prompt initiation of therapy on suspected disease.\n\nOPEN-ACCESSTRUE\n==== Body\npmcINTRODUCTION\n\nMucorales is an order of filamentous fungi that are ubiquitous in the environment.1 It acts as an opportunistic pathogen implicated in a host of human diseases collectively known as mucormycosis. As an aerogenous pathogen, it is believed to be introduced to the host through inhalation of sporangiospores primarily. Not surprisingly then, its primary sites of infectivity tend to be the lungs and paranasal sinuses (and by extension, orbit, and cerebrum).2 In this study, we describe a rare case of ileocolic mucormycosis in a young but severely immunocompromised patient.\n\nCASE REPORT\n\nOur patient is a 25-year-old man who was admitted after an episode of ventricular fibrillation. His medical history was significant for dilated cardiomyopathy requiring a heart transplant at 3 years of age and a second orthotropic heart transplant at 24 years old. His post-transplant course was complicated by cardiac arrest requiring extracorporeal membrane oxygenation with eventual permanent pacemaker placement, percutaneous endoscopic gastrostomy tube, and end-stage renal failure. In addition, in the setting of immunosuppression with neutropenia, he has had a complex infectious disease history including chronic sternal dehiscence containing Pseudomonas aeruginosa, Coryneform Gram-negative rods, and Candida spp. Given the proximity of the infection to his sternum and concern for osteomyelitis, before admission, he was being treated with a 6-week course of intravenous cefepime and vancomycin administered as an outpatient. He had also started on an extended 6- to 12-month course of oral voriconazole to treat the Candida spp. cultured from debrided mediastinal tissue. Because of concern for drug-associated arrhythmia, voriconazole was stopped at admission. This was replaced by micafungin for continued treatment of Candida spp. Of note, his immunosuppression regimen included tacrolimus and low-dose prednisone. He had previously been prescribed mycophenolate, but this was discontinued before admission in the setting of fungal infections. His immunosuppressant dosages were titrated to be within therapeutic range.\n\nEarly in his hospital course, he was intermittently febrile with a leukocytosis of 23 k/uL which was initially attributed to P. aeruginosa ventilator-associated pneumonia. Given his immunocompromised state, a noncontrast computed tomography (CT) scan was obtained on hospital day (HD) 7, demonstrating inflammatory changes of the cecum and ascending colon (Figure 1). These findings were initially believed to be multifactorial, including ischemia after recent ventricular fibrillation arrest and bowel edema from cardiogenic shock. Supportive management was used. On HD 12, the patient developed increasing abdominal distension with decreased stool output, and a repeat abdominal CT demonstrated persistent inflammatory changes and a new onset of dilated small bowel loops with a transition point at the ileocecal valve. This was consistent with a partial small bowel obstruction. Because the patient was critically ill with multiple ongoing medical issues, the surgical team recommended conservative management. This included percutaneous endoscopic gastrostomy tube decompression, serial abdominal examinations, abdominal x-rays every 2–3 days, and transitioning enteral nutrition to total parenteral nutrition. Likewise, endoscopic evaluation was initially deferred because of his tenuous clinical status.\n\nFigure 1. Pelvic and abdominal computed tomography with findings suggestive of inflammatory changes to the cecum and moderate abdominal ascites.\n\nDespite these measures, the obstruction did not resolve, and the patient remained persistently febrile. A colonoscopy was ultimately performed on HD 22 which showed large ulcerations of the cecum and ascending colon and a severe angulated stricture of the ileocecal valve which was not traversable endoscopically (Figure 2). Biopsies of the cecum and ileocecal valve were performed, but pathologic results were not available at that time. Immediately after the colonoscopy, the patient developed worsening abdominal distension. An abdominal CT showed a large-volume pneumoperitoneum, and he was taken to the operating room for an urgent exploratory laparotomy. Intraoperatively, 2 large perforations associated with necrotic bowel were identified at the terminal ileum. An ileocolic resection with extended right colectomy, long Hartmann pouch, and end ileostomy was performed. Gross inspection of the remaining bowel appeared viable. Final surgical pathology yielded transmural ischemic infarction with large fungal hyphae of variable morphology consistent with gastrointestinal mucormycosis (Figure 3). He was started on liposomal amphotericin B. Of note, micafungin was continued primarily to treat Candida mediastinitis and not mucormycosis because echinocandins have not been found to be an effective treatment for Mucorales species.\n\nFigure 2. Photographic images of the colonoscopy. (A) Large deep ulcerations surrounded by friable mucosa are visible in the cecum, and (B) scattered and discontinuous shallow ulcerations are seen extending to the hepatic flexure.\n\nFigure 3. Histologic images taken from the ileocolic resection. (A) Intermediate-power image demonstrating abundant hyphal forms (red arrows) in necrotic debris on the serosal surface of the cecum and (B) high-power image of hyphae within a vessel (blue arrows) surrounded by acute inflammation.\n\nOn the postoperative day 16/HD 38, he experienced a sudden drop in hemoglobin from 7.5 to 6.1 g/dL and frank blood through his ileostomy. CT angiography demonstrated active extravasation from the midjejunum along with several segments of worsening bowel wall thickening. Mesenteric angiography, however, did not demonstrate active bleeding, and therapeutic embolization could not be performed. Over the next 3 days, the patient's clinical status gradually worsened with increasing lactic acidosis, hypothermia, and requirements for blood pressure support. An ileoscopy was performed on postoperative day 18/HD 40 which showed necrotic, ulcerated ileum spanning 40%–50% of luminal circumference consistent with disseminated fungal infection (Figure 4). At that time, further surgical debridement was deemed unlikely to benefit the patient. Palliative measures were implemented, and our patient ultimately died the following day.\n\nFigure 4. Photographic images of the ileoscopy. (A) Diffusely necrotic and ulcerated ileum near end ileostomy and (B) necrotic and deeply ulcerated segment of more proximal ileum involving approximately 40%–50% of the bowel.\n\nDISCUSSION\n\nMucormycosis is classically diagnosed in immunocompromised patients with common risk factors, including diabetes mellitus, hematopoietic stem cell and solid organ transplantation, glucocorticoid therapy, and intravenous drug use.1,3,4 In a comprehensive retrospective review of 929 published cases, Roden et al reported infection patterns based on-site, including rhino-orbital-cerebral 39%, pulmonary 24%, cutaneous 19%, isolated cerebral 9%, gastrointestinal 7%, and generalized disseminated 3%.4 These patterns were similar when comparing sites of infection, specifically in the solid organ transplantation and hematopoietic stem cell population.5,6 In a 2020 case report by Poyuran et al, the authors identified only 8 adult cases of mucormycosis localized to the cecum or ileocecal junction reported in the literature.7\n\nClinical manifestations of gastrointestinal mucormycosis are nonspecific and include abdominal pain, distension, vomiting, fever, diarrhea, and melena.3 The presenting feature of ileocecal infection is often peritonitis after gastrointestinal perforation, as seen in our case after endoscopy.7,8 The gastrointestinal variant of mucormycosis tends to be fulminant with a mortality estimated to be 85%.4 In fact, antemortem diagnosis is only made in about 25% of cases.9\n\nThus, given a vague clinical picture but a life-threatening course, the clinician must maintain a high index of suspicion to make a timely diagnosis. This is essential because early initiation of treatment, a combination of surgery and antifungal therapy, offers the best chance of survival. Mucorales spp. are highly vasculotropic, leading to thrombosis and necrosis of the infected organ.6,10 Surgical debridement not only removes devitalized tissue but is also believed to improve penetration of subsequent antifungal therapy.1,3 The need for early initiation of antifungal therapy is perhaps best exemplified in a study by Chamilos et al who demonstrated a 2-fold increase in mortality when the administration of amphotericin B was delayed beyond 6 days after the diagnosis of zygomycosis was made.11 In our case, therapy was initiated as soon as the diagnosis became apparent; however, given the patient's protracted hospital course, it is likely that this infection had been present for much longer.\n\nIn summary, we present a 25-year-old heart transplant recipient who developed an extremely rare but highly fatal ileocecal mucormycosis. Despite our best efforts, the patient succumbed of this angioinvasive infection. We would like to emphasize keeping mucormycosis, of any site, high on the differential for immunocompromised populations to achieve the most optimal chance of survival.\n\nDISCLOSURES\n\nAuthor contributions: S. Hoang reviewed the literature and revised the manuscript for intellectual content. M. Sestito wrote the manuscript and reviewed the literature. S. Hoang is the article guarantor.\n\nAcknowledgments: The authors thank the Department of Pathology of the University of Virginia for providing histologic images essential to the diagnosis of this patient.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n\n1. Eucker J Sezer O Graf B Possinger K . Mucormycoses. Mycoses. 2001;44 :253–60.11714058\n2. Thomson SR Bade PG Taams M Chrystal V . Gastrointestinal mucormycosis. Br J Surg. 1991;78 :952–4.1913115\n3. Spellberg B . Gastrointestinal mucormycosis: An evolving disease. Gastroenterol Hepatol (NY). 2012;8 :140–2.\n4. Roden MM Zaoutis TE Buchanan WL Epidemiology and outcome of zygomycosis: A review of 929 reported cases. Clin Infect Dis. 2005;41 :634–53.16080086\n5. Singh N Aguado JM Bonatti H Zygomycosis in solid organ transplant recipients: A prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis. 2009;200 :1002–11.19659439\n6. Park BJ Pappas PG Wannemuehler KA Invasive non-aspergillus mold infections in transplant recipients, United States, 2001-2006. Emerg Infect Dis. 2011;17 :1855–64.22000355\n7. Poyuran R Dharan BS Sandhyamani S Narasimhaiah D . Mucormycosis-induced ileocecal perforation: A case report and review of literature. J Postgrad Med. 2020;66 :48–50.31929312\n8. Law W Lo OS . Ileocolonic mucormycosis in adult immunocompromised patients: A surgeon's perspective. World J Gastroenterol. 2010;16 :1165–70.20205292\n9. Petrikkos G Skiada A Lortholary O Roilides E Walsh TJ Kontoyiannis DP . Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012;54 (Suppl 1 ):S23–34.22247442\n10. Karanth M Taniere P Barraclough J Murray JA . A rare presentation of zygomycosis (mucormycosis) and review of the literature. J Clin Pathol. 2005;58 :879–81.16049294\n11. Chamilos G Lewis RE Kontoyiannis DP . Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis. 2008;47 :503–9.18611163\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "8(11)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e00699",
"pmc": null,
"pmid": "34840999",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": "16049294;18611163;19659439;16080086;22247442;11714058;22485085;22000355;31929312;1913115;20205292",
"title": "A Rare Presentation of Ileocecal Mucormycosis in a Heart Transplant Recipient.",
"title_normalized": "a rare presentation of ileocecal mucormycosis in a heart transplant recipient"
} | [
{
"companynumb": "US-Accord-246918",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "Many patients with psychiatric conditions undergo bariatric surgery. The Roux-en-Y gastric bypass (RYGB) procedure alters medication pharmacokinetic properties and may have significant impact on drug response. Our report is the first to describe atypical antipsychotic therapeutic drug monitoring in patients who have undergone RYGB. The first patient is a 53-year-old female with a stable psychiatric condition undergoing a laparoscopic RYGB. Her medications prior and following the procedure include bupropion, fluvoxamine, lurasidone, methylphenidate, oxcarbazepine, and verapamil. A concentration steady-state lurasidone concentration obtained prior to the procedure was 20 ng/mL and returned at 8.1 ng/mL, 29 days after surgery. The second patient is a 42-year-old female psychiatric inpatient who had previously undergone an RYGB procedure. Medications on admission included phenytoin, oxcarbazepine, risperidone, and venlafaxine. The patient was believed to be a good candidate for a long-acting antipsychotic and paliperidone was chosen. After concentration-steady-state on 6 mg oral paliperidone, a 23.5-hour trough level was drawn. The patient was noted to be improved on the oral paliperidone, the paliperidone long-acting injection was given, and the patient was discharged. After discharge, the paliperidone concentration returned very low at 1.1 ng/mL. We describe the contributions of drug-drug interactions, medication release mechanisms, and food coadministration that may have affected our therapeutic drug monitoring. Our therapeutic drug monitoring results need to be replicated prior to use in the general population but suggest that oral extended-release drug formulations are particularly poor choices and that nonoral antipsychotic formulations may be preferred in some patients who have undergone RYBG.",
"affiliations": "Skaggs School of Pharmacy, College of Health Professions & Biomedical Sciences, 307078University of Montana, Missoula, MT, USA.;Department of Psychiatry, 3279Providence St. Patrick Hospital, Missoula, MT, USA.;Department of Psychiatry, 3279Providence St. Patrick Hospital, Missoula, MT, USA.;Department of Psychiatry, 3279Providence St. Patrick Hospital, Missoula, MT, USA.",
"authors": "McGrane|Ian R|IR|https://orcid.org/0000-0002-9889-7260;Salyers|Laura A|LA|;Molinaro|Jason R|JR|;Munjal|Robert C|RC|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190020905467",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "34(3)",
"journal": "Journal of pharmacy practice",
"keywords": "Roux-en-Y gastric bypass; antipsychotic; bariatric surgery; lurasidone; paliperidone; therapeutic drug monitoring",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D016903:Drug Monitoring; D005260:Female; D015390:Gastric Bypass; D006801:Humans; D010535:Laparoscopy; D008875:Middle Aged; D009767:Obesity, Morbid",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "503-506",
"pmc": null,
"pmid": "32067562",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Roux-en-Y Gastric Bypass and Antipsychotic Therapeutic Drug Monitoring: Two Cases.",
"title_normalized": "roux en y gastric bypass and antipsychotic therapeutic drug monitoring two cases"
} | [
{
"companynumb": "US-TEVA-2021-US-1931407",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe D-SPIRIT registry is designed to investigate the safety and effectiveness of dabigatran etexilate in patients with atrial fibrillation in routine clinical practice.\n\n\nMETHODS\nD-SPIRIT is the first national, multicenter, prospective, observational, postmarketing registry that investigates the usage of dabigatran in real life. A total of 326 noveloral anticoagulant-eligible patients with atrial fibrillation who have been taking dabigatran etexilate therapy for stroke prevention at least 6 months from 9 different centers were enrolled into the registry. Patients were followed up for 2 years to evaluate the effectiveness and safety of the treatment. All adverse clinical events including bleeding, thromboembolic events, stroke, systemic embolism, transient ischemic attack, myocardial infarction, and all-cause death were recorded.\n\n\nRESULTS\nThe mean age was 71.1±9.6 years, and 57.4% of the study participants were female. The mean CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack [TIA], vascular disease, age 65-74 years, sex category) score was 3.4±1.6. The cumulative adverse clinical events rate was 6.30% per year. The rate for embolic events including TIA, ischemic stroke, and peripheral embolism was 1.26% per year. The rate for major bleeding was 2.20% per year, and the mortality rate was 0.94% per year.\n\n\nCONCLUSIONS\nThis registry obtained an important overview of the current safety and effectiveness of the dabigatran etexilate in Turkey. Our results indicate similar rates of thromboembolic and bleeding events with pivotal phase 3 trial and other real-life registries. However, rate of undertreatment usage of dabigatran etexilate in real life was found to be considerable.",
"affiliations": "Department of Cardiology, Başkent University School of Medicine, İzmir, Turkey.;Department of Cardiology, Karşıyaka State Hospital, İzmir, Turkey.;Department of Cardiology, Karşıyaka State Hospital, İzmir, Turkey.;Department of Cardiology, Karşıyaka State Hospital, İzmir, Turkey.;Department of Cardiology, Akhisar Mustafa Kirazoğlu State Hospital, Manisa, Turkey.;Department of Cardiology, Central Hospital, İzmir, Turkey.;Department of Cardiology, Menemen State Hospital, İzmir, Turkey.;Department of Cardiology, Tepecik Training and Research Hospital, İzmir, Turkey.;Department of Cardiology, İzmir Medical Park Hospital, İzmir, Turkey.;Department of Cardiology, İzmir Medical Park Hospital, İzmir, Turkey.;Department of Cardiology, Central Hospital, İzmir, Turkey.;Department of Cardiology, Kemalpaşa State Hospital, İzmir, Turkey.;Department of Cardiology, Karşıyaka State Hospital, İzmir, Turkey.;Department of Cardiology, Başkent University School of Medicine, İzmir, Turkey.;Department of Biostatistics, Ege University, İzmir, Turkey.;Center for Drug Research and Development and Pharmacokinetic Applications, Ege University, İzmir, Turkey.",
"authors": "Altın|Cihan|C|;Topaloğlu|Caner|C|;Çetin|Nurullah|N|;Dalgıç|Onur|O|;Yavuz|Veysel|V|;Alioğlu|Emin|E|;Bilgin|Nazile|N|;Ekmekçi|Cenk|C|;Pekel|Nihat|N|;Özpelit|Mehmet Emre|ME|;Tunçer|Eşref|E|;Türkoğlu|Ebru İpek|Eİ|;Tülüce|Kamil|K|;Kocabaş|Umut|U|;Yüksel|Kıvanç|K|;Türk|Uğur Önsel|UÖ|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5543/tkda.2021.07734",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-5169",
"issue": "49(8)",
"journal": "Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir",
"keywords": null,
"medline_ta": "Turk Kardiyol Dern Ars",
"mesh_terms": null,
"nlm_unique_id": "9426239",
"other_id": null,
"pages": "630-640",
"pmc": null,
"pmid": "34881702",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dabigatran for stroke prevention in real life in a sample of population from Turkey: D-SPIRIT registry.",
"title_normalized": "dabigatran for stroke prevention in real life in a sample of population from turkey d spirit registry"
} | [
{
"companynumb": "TR-BoehringerIngelheim-2022-BI-108249",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE"
},
"drugadd... |
{
"abstract": "Acute hepatotoxicity secondary to infliximab can occur with or without autoimmunity. A growing body of infliximab drug-induced liver injury cases without autoantibody formation is emerging. Nearly all other reported cases occur after at least three doses. This suggests infliximab may have a direct cytotoxic effect on the liver. We report a case of drug-induced liver injury resulting after an initial dose of infliximab.",
"affiliations": "Department of Gastroenterology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889.;Department of Internal Medicine, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889.;Department of Gastroenterology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889.",
"authors": "Cheng|Fong-Kuei F|FK|;Bridges|Edward E|EE|;Betteridge|John D|JD|",
"chemical_list": "D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.7205/MILMED-D-14-00485",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-4075",
"issue": "180(6)",
"journal": "Military medicine",
"keywords": null,
"medline_ta": "Mil Med",
"mesh_terms": "D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D003093:Colitis, Ulcerative; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008297:Male; D008889:Military Personnel; D014481:United States",
"nlm_unique_id": "2984771R",
"other_id": null,
"pages": "e723-4",
"pmc": null,
"pmid": "26032391",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced liver injury from initial dose of infliximab.",
"title_normalized": "drug induced liver injury from initial dose of infliximab"
} | [
{
"companynumb": "US-JNJFOC-20150608026",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nWe aimed to test a novel method of delivery of chloral hydrate (CH) sedation in ventilated critically ill young children.\n\n\nMETHODS\nChildren < 12 years old, within 72 hours of admission, who were ventilated, receiving enteral tube-feeds, with intermittent CH ordered were enrolled after signed consent. Patients received a CH loading-dose of 10 mg/kg enterally, then a syringe-pump enteral infusion at 5 mg/kg/hour, increasing to a maximum of 9 mg/kg/hour. Cases were compared to historical controls matched for age group and Pediatric Risk of Mortality score (PRISM) category, using Fisher's exact test and the t test. The primary outcome was feasibility, defined as the use of an enteral CH continuous infusion without discontinuation attributable to a pre-specified potential harm.\n\n\nRESULTS\nThere were 21 patients enrolled, at age 11.4 (12.1) months, with bronchiolitis in 10 (48%), a mean Pediatric Logistic Organ Dysfunction (PELOD) score of 6.2 (5.2), and having received enteral CH continuous infusion for 4.5 (2.2) days. Infusion of CH was feasible in 20/21 (95%; 95% CI 76-99%) patients, with one (5%) adverse event of duodenal ulcer perforation on day 3 in a patient with croup receiving regular ibuprofen and dexamethasone. The CH infusion dose (mg/kg/h) on day 2 (n = 20) was 8.9 (IQR 5.9, 9), and on day 4 (n = 11) was 8.8 (IQR 7, 9). Days to titration of adequate sedation (defined as ≤ 3 PRN doses/shift) was 1 (IQR 0.5, 2.5), and hours to awakening for extubation was 5 (IQR 2, 9). Cases (versus controls) had less positive fluid balance at 48 h (-2 (45) vs. 26 (46) ml/kg, p = 0.051), and a decrease in number of PRN sedation doses from 12 h pre to 12 hours post starting CH (4.7 (3.3) to 2.6 (2.8), p = 0.009 versus 2.9 (3.9) to 3.4 (5), p = 0.74). There were no statistically significant differences between cases and controls in inotrope scores, signs or treatment of withdrawal, or PICU days.\n\n\nCONCLUSIONS\nDelivering CH by continuous enteral infusion is feasible, effective, and may be associated with less positive fluid balance. Whether there is a risk of duodenal perforation requires further study.",
"affiliations": "Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stollery Children's Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta, T6G 2B7, Canada. ari.joffe@ahs.ca.;Department of Nursing, Division of Pediatric Critical Care Medicine, Stollery Children's Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta, T6G 2B7, Canada.;Department of Nursing, Division of Pediatric Critical Care Medicine, Stollery Children's Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta, T6G 2B7, Canada.;Department of Pharmacy, Division of Pediatric Critical Care Medicine, Stollery Children's Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta, T6G 2B7, Canada.;Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stollery Children's Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta, T6G 2B7, Canada.;Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stollery Children's Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta, T6G 2B7, Canada.",
"authors": "Joffe|Ari R|AR|;Hogan|Jessica|J|;Sheppard|Cathy|C|;Tawfik|Gerda|G|;Duff|Jonathan P|JP|;Garcia Guerra|Gonzalo|G|",
"chemical_list": "D006993:Hypnotics and Sedatives; D002697:Chloral Hydrate",
"country": "England",
"delete": false,
"doi": "10.1186/s13054-017-1879-7",
"fulltext": "\n==== Front\nCrit CareCritical Care1364-85351466-609XBioMed Central London 187910.1186/s13054-017-1879-7ResearchChloral hydrate enteral infusion for sedation in ventilated children: the CHOSEN pilot study Joffe Ari R. 780 2485435ari.joffe@ahs.ca 14Hogan Jessica Jessica.hogan@ahs.ca 2Sheppard Cathy cathy.sheppard@ahs.ca 2Tawfik Gerda Gerda.tawfik@ahs.ca 3Duff Jonathan P. jon.duff@ahs.ca 1Garcia Guerra Gonzalo gonzalo.guerra@ahs.ca 11 0000 0004 0633 3703grid.416656.6Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stollery Children’s Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta T6G 2B7 Canada 2 0000 0004 0633 3703grid.416656.6Department of Nursing, Division of Pediatric Critical Care Medicine, Stollery Children’s Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta T6G 2B7 Canada 3 0000 0004 0633 3703grid.416656.6Department of Pharmacy, Division of Pediatric Critical Care Medicine, Stollery Children’s Hospital and University of Alberta, 8440 112 Street, Edmonton, Alberta T6G 2B7 Canada 4 4-546 Edmonton Clinic Health Academy, 11405 87 Avenue, Edmonton, Alberta T6G 1C9 Canada 26 11 2017 26 11 2017 2017 21 29029 8 2017 30 10 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nWe aimed to test a novel method of delivery of chloral hydrate (CH) sedation in ventilated critically ill young children.\n\nMethods\nChildren < 12 years old, within 72 hours of admission, who were ventilated, receiving enteral tube-feeds, with intermittent CH ordered were enrolled after signed consent. Patients received a CH loading-dose of 10 mg/kg enterally, then a syringe-pump enteral infusion at 5 mg/kg/hour, increasing to a maximum of 9 mg/kg/hour. Cases were compared to historical controls matched for age group and Pediatric Risk of Mortality score (PRISM) category, using Fisher’s exact test and the t test. The primary outcome was feasibility, defined as the use of an enteral CH continuous infusion without discontinuation attributable to a pre-specified potential harm.\n\nResults\nThere were 21 patients enrolled, at age 11.4 (12.1) months, with bronchiolitis in 10 (48%), a mean Pediatric Logistic Organ Dysfunction (PELOD) score of 6.2 (5.2), and having received enteral CH continuous infusion for 4.5 (2.2) days. Infusion of CH was feasible in 20/21 (95%; 95% CI 76–99%) patients, with one (5%) adverse event of duodenal ulcer perforation on day 3 in a patient with croup receiving regular ibuprofen and dexamethasone. The CH infusion dose (mg/kg/h) on day 2 (n = 20) was 8.9 (IQR 5.9, 9), and on day 4 (n = 11) was 8.8 (IQR 7, 9). Days to titration of adequate sedation (defined as ≤ 3 PRN doses/shift) was 1 (IQR 0.5, 2.5), and hours to awakening for extubation was 5 (IQR 2, 9). Cases (versus controls) had less positive fluid balance at 48 h (-2 (45) vs. 26 (46) ml/kg, p = 0.051), and a decrease in number of PRN sedation doses from 12 h pre to 12 hours post starting CH (4.7 (3.3) to 2.6 (2.8), p = 0.009 versus 2.9 (3.9) to 3.4 (5), p = 0.74). There were no statistically significant differences between cases and controls in inotrope scores, signs or treatment of withdrawal, or PICU days.\n\nConclusions\nDelivering CH by continuous enteral infusion is feasible, effective, and may be associated with less positive fluid balance. Whether there is a risk of duodenal perforation requires further study.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s13054-017-1879-7) contains supplementary material, which is available to authorized users.\n\nKeywords\nChloral hydrateIntensive care unitsPediatricMechanical ventilationModerate sedationDepartment of Pediatrics, University of AlbertaSEED GrantJoffe Ari R. issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nSedation in the pediatric intensive care unit (PICU) is an essential part of management of the critically ill child receiving mechanical ventilation. Sedation facilitates safe therapeutic and diagnostic procedures, ensures patient comfort, reduces distress in the child and as a result also reduces parental anxiety [1, 2]. Ensuring adequate sedation in the PICU is often a challenge, requiring multiple drugs, delaying extubation, and resulting in drug withdrawal and delirium [1–5]. Over-sedation is associated with hypotension, fluid administration, and inability to assess underlying neurological status, any of which can delay extubation and PICU discharge [1–3]. Conversely, under-sedation is associated with anxiety, fear, and discomfort, and can lead to losing vascular lines and invasive airways [1, 2]. A recent consensus guideline on sedation and analgesia in critically ill children recommended the early use of enteral sedative agents [6].\n\nChloral hydrate (CH) is an enteral sedative/hypnotic drug that has been used for decades for sedation in children [7, 8]. It is common practice to administer CH in repetitive doses to maintain prolonged sedation in children during mechanical ventilation [6, 9–12]. A survey on the use of sedatives in the PICU in the USA found that 45% of intensivists used CH frequently or routinely; > 60% responded that they used CH for long-term sedation [9]. A survey of Canadian pediatric intensivists found that CH was among the most frequently used sedative medications [12]. A previous study has shown the greater efficacy of oral sedatives such as CH compared to midazolam, a sedative frequently given in the PICU [13]. A recent study including 343 PICU patients who received CH for a median of 6 days at a dose of 134.4 (SD 83.2) mg/kg/day found that CH was associated with similar rates of adverse reactions (mainly desaturation and hypotension) as other sedatives used in the PICU [14].\n\nOur anecdotal observation was that patients often are initially over-sedated following a dose of CH, but are then under-sedated before the next dose is due; a continuous enteral infusion of CH may blunt this fluctuation in sedation level, with a lower total dose and fewer adverse effects. In addition, continuous enteral infusion of CH may result in dose-sparing of other sedatives that have a higher potential for adverse effects, delayed awakening, and withdrawal, including benzodiazepines and opioids [1–4]. We hypothesized that a novel, simple, and low-cost method of delivering enteral CH, continuous enteral infusion, is feasible as a sedative infusion in critically ill children. We also hypothesized that continuous enteral infusion of CH is associated with important patient outcomes including lower opioid and benzodiazepine requirements, and improved outcomes in fluid balance, ventilator days, inotropic support, and harms in the PICU.\n\nMethods\nEthics approval\nThis study was approved by the Health Research Ethics Board of the University of Alberta (Pro00035544). All case patients had their parent or legal guardian sign informed consent to participation.\n\nStudy design\nThis is a prospective cohort study of enteral infusion of CH. Eligibility criteria were the following: admitted to the PICU at Stollery Children’s Hospital; PICU admission for < 72 h; mechanically ventilated; ≥ 44 weeks post-conceptional age up to 12 years of age; CH sedation ordered by the treating PICU team; and enteral feeding tube delivering feeds at any rate by nasogastric, nasojejunal, gastric, or gastrojejunal tube. Exclusion criteria were any of the following: weight <3 kg; contraindication to the use of the gastrointestinal tract to receive oral medication; short gut syndrome; known gastric or duodenal ulcer; severe liver dysfunction defined by INR >2 and lactate >2 mmol/L; severe renal dysfunction (defined by needing dialysis); or allergy to CH.\n\nThe intervention patients (CHOSEN cohort) were compared to a matched historical control group (control cohort) of patients that received intermittent CH in the year prior to the intervention. These historical controls were matched for age (<1 year or 1–5 years) and Pediatric Risk of Mortality (PRISM) score (<10 or 10–20) to intervention patients. In the historical controls, baseline was considered the time that CH was ordered by the attending physician. The historical controls met the same eligibility criteria, and were identified retrospectively through a pharmacy database by determining patients who had CH removed from the on-site PICU computerized dispensing system. Because many patients who had CH sedation in the PICU were not tracked through this system, to have enough patients to match, these controls were from periods both before and after the CHOSEN cohort was completed.\n\nStudy procedures\nA CHOSEN order sheet with instructions on dosing and using the infusion pump (for safety, programmed with hard dosing limits, and to require confirmation that infusion was given enterally) was used (Additional file 1). CHOSEN patients were to receive a loading dose of CH 10 mg/kg enterally, followed by a CH enteral infusion by syringe pump at 5 mg/kg/h Y-infused into the feeding tube with the feeds. The CH infusion could be increased up to a maximum of 9 mg/kg/h enterally. As there was no published information on continuous CH dosing, this dosing algorithm was based on our experience that intermittent CH in our PICU was usually ordered at doses of 15–30 mg/kg every 3 hours as required (prn). Each increment in the enteral CH infusion was by 1 mg/kg/h following a loading dose of 3 mg/kg, and could occur no more frequently than hourly. If the patient was over-sedated for at least 4 h without any prn medications, the other sedation medications being used were to be decreased at the attending medical team’s discretion prior to considering decreasing the CH infusion by 1–2 mg/kg/h up to every 3 h. When decreasing CH infusion in anticipation of extubation, the instruction was to decrease the CH infusion rate by half at 6 h prior to extubation, and to stop the CH infusion 3 h prior to extubation. Prior to the study, we tested an in vitro infusion of CH mixed with commonly used PICU feeding formulas infused at low rates to maximize the chance of tube blockage, and found no tube blockage after more than 24 h.\n\nClinical data were recorded from the patient chart onto a case report form with pre-specified definitions for all variables (Additional file 2). Baseline variables included demographics (age, sex, weight, diagnostic category, surgery category), and severity of illness measures (inotrope score, PRISM score, and Pediatric Logistic Organ Dysfunction (PELOD) score) [15–17]. Outcome variables from baseline included: sedation needs (rescue prn sedation doses per day for days 1–7; time to titration of adequate sedation defined as ≤ 3 prn sedation doses per 12-h shift; total daily dose (prn and infusion) of CH, benzodiazepine, opioid, and dexmedetomidine for days 1–7); time to awakening on discontinuation or lowering of sedation infusions in preparation for extubation, defined as awake enough for extubation to occur; fluid balance at 24 h and 48 h, in ml/kg; ventilator hours; and PICU length of stay in days. Potential harms were pre-specified to include: feeding tube blockage requiring tube replacement; gastrointestinal bleeding requiring transfusion of at least 10 ml/kg packed red blood cells; new or worsened seizures treated with anticonvulsant; new or worsened ventricular dysrhythmia requiring treatment; feed intolerance defined as feeds being held for > 3 h; or failed extubation due to excessive remaining sedative effect (e.g., hypoventilation, or excessive secretions).\n\nStatistics\nThere are no previous studies of CH enteral infusion. The primary outcome is feasibility, defined as the use of an enteral CH continuous infusion without discontinuation attributable to a pre-specified potential harm (see above for definition) or lack of adequate sedation. Assuming that CH infusion would be feasible in at least 75% of CHOSEN patients, we estimated that a sample size of 32 patients would be needed to estimate the feasibility within 15% of the true feasibility rate with 95% confidence. This was calculated as follows: n=1.96/0.152π1−π, \n\n\nwhere n is the number of patients needed, π is the proportion of patients in whom the CH infusion is expected to be feasible (=0.75), and 0.15 is the maximum discrepancy between the study sample feasibility and the population feasibility with a certainty of 95%. The main pre-specified secondary outcomes are: number of prn doses of sedation per day and their change from pre CH to post CH, time to titration to adequate sedative effect, time to awakening on discontinuation or lowering of sedation infusions, and fluid balance at 48 h. Descriptive summary measures including mean (standard deviation, SD) and median (interquartile range, IQR) were used as appropriate. The Student t test and chi-square analysis, as appropriate, were used to explore the differences between and within groups (enteral CH infusion vs. historical controls) in the secondary outcomes.\n\nResults\nDescription of cohorts\nFrom June 2013 to May 2014 there were 140 patients screened and 30 patients eligible for the study; 7 patients were not approached (1 whose family did not speak English, 1 who was apprehended by social services, and 5 who were not approached because there were no research staff available), 2 patients declined consent, and 21 patients were prospectively enrolled into the CHOSEN group. The historical controls were retrospectively identified patients from February to December 2012 and August 2014 to May 2016. Most baseline variables for CHOSEN cases and historical controls were similar, except that the controls included cardiac surgical patients (5 (24%) vs. 0%, p = 0.048), some patients that had non-invasive mechanical ventilation (3 (14%) vs. 0%, p = 0.23), and fewer patients with the diagnosis of bronchiolitis (4 (19%) vs. 10 (48%), p = 0.10) and with medical illness (13 (62%) vs. 18 (86%), p = 0.16) (Table 1). All patients were < 6 years old, mostly infants, and with moderate severity of illness as measured by inotrope score, PRISM, and PELOD scores (Table 1).Table 1 Baseline variables for cases and controls\n\nVariable\tCHOSEN (n = 21)\tControls (n = 21)\t\np value\t\nAge (months)\t11.4 (12.1)\t14.0 (19.6)\t0.61\t\n7 (IQR 3, 18)\t9 (IQR 5, 13)\t\nAge category (<1; 1–5; 6–12 years)\t13; 8; 0\t16; 4; 1\t0.27\t\nWeight (kg)\t8.6 (3.6)\t8.3 (5.5)\t0.87\t\n8.9 (IQR 5.5, 11.2)\t7 (IQR 4.6, 9.8)\t\nGender male\t15 (71%)\t11 (52%)\t0.34\t\nCardiac surgical\t0\t5 (24%)a\n\t0.048\t\nGeneral surgical\t4 (19%)\t5 (24%)\t0.99\t\nMedical\t18 (86%)\t13 (62%)\t0.16\t\nBronchiolitis\t10 (48%)\t4 (19%)\t0.10\t\nInotrope used\t2 (10%)\t2 (10%)\t0.99\t\nEpinephrine or norepinephrine used\t2 (10%)\t2 (10%)\t0.99\t\nInotrope score\t0.5 (1.5)\t1.1 (4.4)\t0.52\t\nAbsolute inotrope scores\t5, 5\t4, 20\t\nLactate measured\t19\t21\t0.49\t\nLactate (mmol/L)\t0.7 (0.2)\t1.0 (0.6)\t0.02\t\nCreatinine measured\t15\t17\t0.72\t\nCreatinine (umol/L)\t21 (5)\t21 (10)\t0.81\t\nPRISM\t2.5 (2.3)\t3.0 (2.5)\t0.48\t\n3 (0, 5)\t3 (1, 5)\t\nPELOD\t6.2 (5.2)\t6.5 (5.0)\t0.88\t\n2 (1, 11)\t10 (1, 11)\t\nInvasive ventilation\t21 (100%)\t18 (86%)b\n\t0.23\t\nData given as n (%), or mean (SD), or median (IQR). Comparisons by Fisher’s exact test and t test, as appropriate. PELOD pediatric logistic organ dysfunction score, PRISM pediatric risk of mortality score\n\n\nacongenital heart disease were: atrial septal defect (n = 1); tetralogy of Fallot (n = 2); other (n = 1)\n\n\nbThree control patients had only non-invasive ventilation used\n\n\n\n\nPrimary outcome\nThe CH enteral infusion was feasible in all 21 (100%) CHOSEN patients using the original definition of feasibility: use of an enteral CH continuous infusion without discontinuation attributable to a pre-specified potential harm or lack of adequate sedation. Patients were on CH enteral infusion for 4.5 (SD 2.2) days, and 4.4 (IQR 2.3, 6.7) days (Table 2); the highest infusion dose on day 1 and 2 was 6.4 (SD 1.0) and 7.4 (SD 2.3) mg/kg/h (Table 3). There was one serious adverse event in a 16-month-old girl with croup due to parainfluenza virus, who was intubated and ventilated and treated with dexamethasone every 6 h (q6h) and ibuprofen q6h for 3 days prior to developing a perforated duodenal ulcer that required laparotomy and Graham patch. This event was thought possibly related to the enteral CH infusion by the medical team; as this was a potential harm, the CH enteral infusion was feasible in 20/21 (95%; 95% adjusted Wald CI 76–99%). There was one death among patients in the historical control group (5%) and no deaths in the CHOSEN group.Table 2 Outcomes in cases and controls\n\nOutcome\tCHOSEN (n = 21)\tControls (n = 21)\t\np value\t\nDays on study\t\n\t4.5 (2.2)\t-\t-\t\n\t4.4 (IQR 2.3, 6.7)\t\nPrimary outcomes\t\n Pre-defined feasibility\t21/21 (100%)\t-\t-\t\n Any pre-specified adverse effecta\n\t0\t0\t-\t\n SAEb\n\t1 (5%)\t0\t0.99\t\n Mortality in PICU\t0\t1 (5%)\t0.99\t\n Post-hoc feasiblity\t20/21 (95%)\t20/21 (95%)\t0.99\t\nMain secondary outcomes\t\n Days to titration of adequate sedation\t1.4 (1.3)\t0.9 (1.3)\t0.22\t\n1 (IQR 0.5, 2.5)\t0.5 (IQR 0, 1.3)\t\n Hours to awakening\tN = 19\tN = 18\t0.80\t\n8.1 (8.4)\t8.8 (8.5)\t\n5 (IQR 2, 9)\t8 (IQR 1, 13)\t\n Fluid balance, 48 h (ml/kg)\t−2 (45)\t26 (46)\t0.051\t\n−7 (IQR −30, 25)\t19 (IQR −4, 59)\t\n Number of prn sedation doses from 12 h pre to 12 h post baseline\t4.7 (3.3) to 2.6 (2.8)\t2.9 (3.9) to 3.4 (5.0)\t0.009/0.74\t\nOther secondary outcomes\t\n Ventilator hours\t125 (84)\t258 (363)\t0.12\t\n106 (IQR 54, 162)\t129 (IQR 63, 191)\t\n PICU days\t9.8 (7.6)\t16.8 (21.7)\t0.17\t\n8.5 (IQR 5, 13)\t8 (IQR 5.5, 12)\t\n Extubation information\t\n Propofol used as bridge to extubation\t13 (62%)\t6 (29%)\t0.06\t\n Failed extubation due to sedation\t0/21\t0/19\t-\t\n Post-extubation withdrawal syndrome\t\n Signs of withdrawal\t9/20 (45%)\t8/19 (42%)\t0.99\t\n Enteral narcotic started within 48 h\t3 (15%)\t4 (22%)\t0.99\t\n Enteral BDZ started within 48 h\t4 (19%)\t2 (11%)\t0.66\t\n Enteral clonidine started within 48 h\t3 (15%)\t2 (11%)\t0.99\t\n Withdrawal score 48 h after extubation\tN = 12/21 (57%)\tN = 14/21 (67%)\t0.53\t\n4.3 (3.3)\t2.3 (2.5)\t0.10\t\nFluid balance, 24 h (ml/kg)\t5 (32)\t24 (31)\t0.06\t\n3 (IQR −17, 32)\t21 (IQR −3, 49)\t\nData given as n (%), mean (SD), or median (IQR). Comparisons by Fisher’s exact test and t test or paired t test, as appropriate. PICU pediatric intensive care unit, BDZ benzodiazepine, SAE serious adverse event, prn as required\n\n\naPre-specified adverse effects were defined as any of: feeding tube blockage, GI bleeding, new/worse seizure, feed intolerance, or new/worse ventricular dysrhythmia\n\n\nbChloral hydrate infusion was feasible on day 1 to 7, except for one patient on day 3 due to the SAE (duodenal perforation; see text)\n\n\nTable 3 Sedation used during the 7 days of study in patient cases and controls\n\nVariable\tGroup\tDay 1\tDay 2\tDay 3\tDay 4\tDay 5\tDay 6\tDay 7\t\nDoses of sedation given prn (excluding chloral hydrate) (number of doses (SD))\t\n Total\tCHOSEN\t\nN = 21 (12 h)\t\nN = 20\t\nN = 17\t\nN = 12\t\nN = 8\t\nN = 7\t\nN = 5\t\n2.6 (2.8)\t3.5 (3.5)\t3.5 (4.7)\t2.6 (2.2)\t4.5 (3.3)\t4.7 (4.8)\t4.8 (3.9)\t\nControl\t\nN = 21 (12 h)\t\nN = 20\t\nN = 14\t\nN = 10\t\nN = 6\t\nN = 4\t\nN = 3\t\n3.4 (5.0)\t2.4 (2.9)\t2.4 (3.5)\t3.0 (3.1)\t1.8 (1.7)\t2.3 (1.5)\t1.0 (1.0)\t\n\np value\t0.54\t0.29\t0.45\t0.72\t0.10\t0.35\t0.16\t\nDescription of chloral hydrate dosing (mg/kg/day; and mg/kg/h infusion)\t\n Total chloral dose given\tCHOSEN\t\nN = 21\t\nN = 20\t\nN = 17\t\nN = 11\t\nN = 8\t\nN = 7\t\nN = 5\t\n116 (50)\t160 (50)\t138 (84)\t140 (81)\t152 (74)\t143 (91)\t134 (86)\t\nControl\t\nN = 21\t\nN = 20\t\nN = 14\t\nN = 10\t\nN = 6\t\nN = 4\t\nN = 3\t\n38 (34)\t42 (49)\t37 (34)\t75 (117)\t64 (43)\t40 (32)\t33 (29)\t\n\np value\t<0.001\t<0.001\t<0.001\t0.15\t0.02\t0.03\t0.06\t\n Highest chloral infusion rate\tCHOSEN\t6.4 (1.0)\t7.4 (2.3)\t7.2 (2.1)\t7.7 (2.0)\t6.6 (2.7)\t6.7 (3.3)\t6.4 (2.7)\t\n7 (IQR 5, 9)\t8.9 (IQR 5.9, 9)\t8 (IQR 5.6, 9)\t8.8 (IQR 7, 9)\t7.1 (IQR 4, 9)\t8.8 (IQR 3.3, 9)\t5.2 (IQR 2.5, 9)\t\nInotrope requirements while on chloral hydrate (inotrope score (SD))\t\n Highest inotrope score\tCHOSEN\t\nN = 21\t\nN = 20\t\nN = 17\t\nN = 12\t\nN = 8\t\nN = 7\t\nN = 5\t\n0.5 (1.5)\t0.9 (2.3)\t1.1 (3.3)\t1.3 (3.7)\t1.8 (3.9)\t1.1 (3.0)\t1.0 (2.2)\t\nControl\t\nN = 21\t\nN = 20\t\nN = 14\t\nN = 11\t\nN = 6\t\nN = 4\t\nN = 3\t\n1.5 (4.6)\t0.7 (1.7)\t0.6 (1.6)\t0.9 (3.0)\t1.0 (2.4)\t1.0 (2.0)\t0 (0)\t\n\np value\t0.37\t0.76\t0.67\t0.75\t0.69\t0.94\t0.48\t\n On inotropes (absolute score)\tCHOSEN\t3/21 (14%)\t3/20(15%)\t2/17(12%)\t2/12(17%)\t2/8(25%)\t1/7 (14%)\t1/5(20%)\t\n1,5,5,\t5,5,8\t5,13\t5,11\t3,11\t8\t5\t\nControl\t3/21 (14%)\t3/20 (15%)\t2/14 (14%)\t1/11 (9%)\t1/6 (17%)\t1/4 (25%)\t0\t\n3, 8, 20\t4, 5, 5\t4, 5\t10\t6\t4\t\nUse of other sedation infusions (number/patients on study; dose (SD))\t\n Morphine (mcg/kg/h)\tCHOSEN\t21/21\t20/20\t15/17\t10/12\t6/8\t6/7\t4/5\t\n49 (17)\t45 (18)\t40 (20)\t33 (18)\t36 (19)\t33 (21)\t40 (22)\t\nControl\t12/21\t11/20\t8/14\t6/11\t5/6\t4/4\t2/3\t\n36 (19)\t36 (21)\t36 (21)\t37 (24)\t34 (17)\t30 (18)\t10 (0)\t\n\np value\t0.001\t0.001\t0.10\t0.19\t0.99\t0.99\t0.99\t\n0.06\t0.26\t0.70\t0.73\t0.87\t0.80\t0.14\t\n Midazolam (mcg/kg/min)\tCHOSEN\t16/21\t17/20\t9/17a\n\t6/12\t3/8\t3/7\t1/5\t\n2.1 (0.9)\t1.6 (0.7)\t1.7 (0.6)\t1.6 (0.9)\t1.3 (0.8)\t2.7 (2.1)\t2\t\nControl\t8/21\t7/20\t6/14\t4/11\t2/6\t2/4\t1/3\t\n2.3 (1.5)\t2.5 (1.7)\t2.6 (2.0)\t3.0 (2.2)\t1.5 (0.7)\t1.5 (0.7)\t1\t\n\np value\t0.03\t0.003\t0.72\t0.68\t0.99\t0.99\t0.99\t\n0.68\t0.07\t0.34\t0.18\t0.82\t0.52\t0.99\t\nData given as n (%), mean (SD), or median (IQR). Comparisons by Fisher’s exact and t test or paired t test, as appropriate\n\n\naThere was a statistically significant decrease in proportion of patients on midazolam infusion between day 2 and day 3 in the CHOSEN group (p = 0.03 by chi-square) but not in the control group (p = 0.64)\n\n\n\n\nMain secondary outcomes\nThe number of prn doses of sedation required by patients in the CHOSEN arm decreased from 4.7 doses (SD 3.3) 12 h pre CH infusion to 2.6 doses (SD 2.8) 12 h post CH infusion (p = 0.009); there was no change in the historical control patients (p = 0.74). The time to titration to adequate sedative effect and time to awakening on discontinuation or lowering of sedation infusions did not differ between the CHOSEN and historical control groups (Table 2). The fluid balance at 48 h was − 2 (SD 45) ml/kg in the CHOSEN group vs. 26 (SD 46) ml/kg in historical controls, p = 0.051. The use of morphine and midazolam infusions was less on day 1 and 2 in the historical controls (vs. CHOSEN patients), but not different from days 3–7, and the dose of these infusions when used was similar (Table 3). The proportion of patients on midazolam infusion between days 2 and 3 reduced in the CHOSEN group (from 17/20 (85%) to 9/17 (53%), p = 0.03) but not in the historical controls (from 7/20 (35%) to 6/14 (43%), p = 0.64) (Table 3).\n\nOther secondary outcomes\nOther outcomes examined are shown in Tables 2, 3 and Additional file 3: Tables S1 and S2. Ventilator hours and PICU length of stay was lower in the CHOSEN group vs. the historical controls, but not statistically significantly so (p = 0.12 and 0.17). No patient in either group failed extubation due to excessive sedation effect. There were no significant differences in post-extubation withdrawal measures, including signs of withdrawal, or enteral narcotic, benzodiazepine, or clonidine started within 48 h of extubation. The use of midazolam and narcotic infusions from 24 h pre extubation to 24 h post extubation significantly dropped in CHOSEN patients (from 11/21 (52%) to 2/21 (10%) on midazolam, p = 0.003; and from 21 (100%) to 12 (57%) on narcotic, p = 0.001), but not in historical controls (p = 0.22 and 0.12) (Additional file 3: Table S1). The use of narcotic infusion dropped further between 24 h post extubation to 48 h post extubation in CHOSEN patients (to 5/21 (24%), p = 0.03), but not in historical controls (p = 0.33) (Additional file 3: Table S1). Use of inotropes and inotrope scores did not differ between the groups. Detailed information on sedation variables are given in Additional file 3: Table S2.\n\nDiscussion\nIn this study we tested a novel low-cost method of delivery of the commonly used sedative medication CH in PICU patients. The main findings of this study include the following. First, continuous enteral infusion of CH was feasible in 95% of patients, used for a mean of 4.5 (SD 2.2) days. The time to titration of adequate sedation was short (mean 1.4 (SD 1.3) days). Second, continuous enteral infusion of CH was effective, associated with a statistically significant reduction in the number of prn doses of sedation from 12 h pre baseline to 12 h post baseline, and in the use of midazolam infusions between day 2 and 3 of ventilation. This reduction did not occur in the historical controls group. The doses used for continuous CH enteral infusion on days 1–3 were usually from 5–9 mg/kg/h, providing the first dose-finding information of which we are aware. Third, continuous infusion of enteral CH was associated with a lower positive fluid balance at 48 h compared to historical controls. Other patient important outcomes were not statistically different between groups, including ventilator hours, PICU length of stay, measures of drug withdrawal after extubation, hours to awakening on weaning of sedation, and inotrope scores. There was a statistically significant decrease in the use of midazolam and narcotic infusions in the 24–48 h after extubation in the group on continuous enteral infusion of CH, but not in the historical controls. Finally, there was one possible SAE comprising a punctate discrete duodenal perforation in a 16-month-old patient with croup who had been treated with regular dexamethasone and ibuprofen for 3 days in the group on continuous enteral infusion of CH.\n\nThere are some concerns with this study that warrant discussion. First, the matching process was sub-optimal, and there were clinically significant imbalances at baseline between the CHOSEN and retrospectively identified historical control groups (such as numbers of patients with congenital heart disease, bronchiolitis, non-invasive ventilation, and medical reasons for admission). In fact, we do not suggest the use of continuous CH enteral infusion in patients without a protected airway, such as those having non-invasive ventilation. These baseline imbalances are also reflected in the statistically significantly lower use of morphine and midazolam infusions in the first and second day of the study (Table 3), and in the wide SD of ventilator hours and PICU days (Table 2) in the historical control group. We believe that these imbalances reduced the ability to detect differences in outcomes between the CHOSEN and historical control groups. For this reason, we emphasize the difference within groups in number of prn doses of sedation between 12 h pre baseline to 12 h post baseline, in use of midazolam infusion for sedation between day 2 and 3 of the study, and in use of midazolam and narcotic infusions between 24 h pre extubation to 24 h post-extubation. In addition, the lack of difference in measures of drug withdrawal post extubation between groups (Table 2) was present even though there was the imbalance in the proportion of patients on narcotic and midazolam infusion 24 h pre extubation (lower in the historical control group; Additional file 3: Table S1). Thus, the differences between the CHOSEN and historical control groups should be considered to reflect the minimal efficacy of the continuous enteral infusion of CH.\n\nSecond, the SAE of a punctate discrete duodenal perforation in the first part of the duodenum was considered possibly related to the continuous enteral infusion of CH (the tip of the feeding tube was at the junction of the 2nd and 3rd part of the duodenum). This is not a common complication in previously well children admitted to the PICU. The product monograph for CH lists gastric irritation as an adverse effect, and suggests CH be avoided in patients with gastritis, esophagitis, or gastric or duodenal ulcer; in overdose the product monograph states that gastric necrosis, perforation, gastrointestinal hemorrhage and esophageal stricture have also been reported [8, 18, 19]. Thus, the local research ethics board defined this SAE as being within “expected” adverse events. The patient had risk factors for a duodenal ulcer including being treated with regular dexamethasone and ibuprofen without gastrointestinal bleeding prophylaxis. A recent review suggests that proton pump inhibitors are indicated in patients taking systemic corticosteroids and concomitant non-steroidal anti-inflammatory drugs, due to the higher risk of peptic ulcers [20]. Further experience with continuous infusion of enteral CH will be necessary in order to determine whether this serious adverse event was likely attributable to the CHOSEN intervention.\n\nThere are limitations to this study. First, the small sample size comprising 21 patients in each group, all from a single center, limit the conclusions that can be made. This sample size was smaller than the calculated sample size of 32 patients that would be required to estimate feasibility as 75% with narrow 95% confidence intervals. The study was stopped before more patients were recruited due to funding constraints. The continuous enteral CH infusion was found to be feasible in 95%, with wide 95% adjusted Wald CI 76–99%. Second, the imbalance in baseline characteristics between the CHOSEN and historical control groups was discussed above. We believe that this would mean that the results of the study reflect the minimal efficacy of continuous infusion of enteral CH. Third, there was no protocol for sedation management, acceptable depth of sedation, or for scoring of the level of sedation. In addition, no serum levels or pharmacodynamic investigations were done to direct therapy. Nevertheless, this study reflects the management of sedation based upon the bedside team’s best judgement in a center that did not use sedation scoring. Fourth, there was multiple statistical testing without correction of p values. This problem was mitigated by pre-specifying the four main secondary outcomes as reported, with the other outcomes considered as exploratory findings in this pilot study. Finally, one might wonder why we have not implemented CH enteral infusion as standard practice in our PICU. This pilot project was considered a research study, and not a quality improvement project, and thus we wanted to await peer-reviewed publication of the results before implementing this as a standard practice (which many members of the PICU staff have requested).\n\nThere are some strengths of this study. We tested a novel, simple, and low-cost intervention with a safe drug that is commonly used for sedation in PICU. This novel method of delivery of CH by continuous enteral infusion was found to be feasible and effective. By specifying the primary and main secondary outcomes, we limited the amount of multiple statistical testing thus improving the reliability of the statistical results. Finally, this pilot study provides information that will allow for sample size estimation for future randomized studies of this intervention.\n\nConclusions\nDelivering CH as a continuous enteral infusion is feasible, effective, and may be associated with less positive fluid balance. This small pilot trial does not allow definitive conclusions about the relative efficacy of continuous enteral infusion of CH on other outcomes including ventilator days, PICU days, vasoactive support, or drug withdrawal, although there was no signal of any adverse effect on these outcomes. Whether there is a risk of duodenal perforation as occurred in one patient in this study requires further study.\n\nAdditional files\n\nAdditional file 1: The study physician orders and instructions for administering enteral chloral hydrate infusion. (PDF 1548 kb)\n\n \nAdditional file 2: The CHOSEN study case report form. (DOCX 229 kb)\n\n \nAdditional file 3: Supplementary tables for the CHOSEN study results. Table S1. Detailed information on sedation from 24 h prior to 48 h after extubation. Table S2. More details of the sedation given on day 1 to 7 of study in cases and controls. (DOCX 25 kb)\n\n \n\n\nAbbreviations\nCHChloral hydrate\n\nIQRInterquartile range\n\nPELODPediatric Logistic Organ Dysfunction score\n\nPICUPediatric intensive care unit\n\nPRISMPediatric Risk of Mortality score\n\nprnas required\n\nSDStandard deviation\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1186/s13054-017-1879-7) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis study was supported by a SEED Grant from the Department of Pediatrics at the University of Alberta. The funding agency had no role in design and conduct of the study; analysis or interpretation of data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nARJ analyzed the data, and wrote the first draft of the manuscript. JH and CS acquired the data. All authors (ARJ, JH, CS, GT, JPD, and GG) made substantial contributions to conception and design of the study, interpretation of the data, revising the manuscript critically for important intellectual content, and had final approval of the version to be published. Each author (ARJ, JH, CS, GT, JPD, and GG) participated sufficiently in the work to take public responsibility for the content of the publication, and agree to be accountable for all aspects of the work.\n\nEthics approval and consent to participate\nThis study was approved by the Health Research Ethics Board of the University of Alberta (Pro00035544). All case patients had their parent or legal guardian sign informed consent to participation.\n\nConsent for publication\nNot applicable.\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. Tobias JD Sedation and analgesia in pediatric intensive care units Paediatric Drugs 1999 1 109 26 10.2165/00128072-199901020-00004 10937446 \n2. 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Hudson: Lexi-Comp; 2005. pp. 279−81.\n9. Rhoney DH Murry KR National survey on the use of sedatives and neuromuscular blocking agents in the pediatric intensive care unit Pediatr Crit Care Med 2002 3 2 129 33 10.1097/00130478-200204000-00007 12780981 \n10. Playfor SD Thomas DA Choonara I Sedation and neuromuscular blockade in paediatric intensive care: a review of current practice in the UK Paediatr Anaesth 2003 13 147 51 10.1046/j.1460-9592.2003.00989.x 12562488 \n11. Jenkins IA Playfor SD Bevan C Davies G Wolf AR Current United Kingdom sedation practice in pediatric intensive care Paediatr Anaesth 2007 17 675 83 10.1111/j.1460-9592.2006.02180.x 17564650 \n12. Garcia Guerra G Joffe AR Cave D Duff J Duncan S Sheppard C Tawfik G Hartling L Jou H Vohra S Team SWA the Canadian Critical Care Trials Group Survey of sedation and analgesia practice among Canadian pediatric critical care physicians Pediatr Crit Care Med 2016 17 823 30 10.1097/PCC.0000000000000864 27467012 \n13. Parkinson L Hughes J Gill A Billingham I Ratcliffe J Choonara I A randomized controlled trial of sedation in the critically ill Paediatr Anaesth 1997 7 405 10 10.1046/j.1460-9592.1997.d01-109.x 9308065 \n14. Martinbiancho JK Carvalho PR Trotta Ede A Schweiger AP Rau R Moreira LB Evidence of safety of chloral hydrate for prolonged sedation in PICU in a tertiary teaching hospital in southern Brazil Eur J Clin Pharmacol 2009 65 1253 8 10.1007/s00228-009-0694-8 19669738 \n15. Gaies MG Gurney JG Yen AH Napoli ML Gajarski RJ Ohye RG Charpie JR Hirsch JC Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass Pediatr Crit Care Med 2010 11 234 8 10.1097/PCC.0b013e3181b806fc 19794327 \n16. Pollack MM Patel KM Ruttimann UE PRISM III: an updated Pediatric Risk of Mortality score Crit Care Med 1996 24 5 743 52 10.1097/00003246-199605000-00004 8706448 \n17. Leteurtre S Martinot A Duhamel A Proulx F Grandbastien B Cotting J Gottesman R Joffe A Pfenninger J Hubert P Lacroix J Leclerc F Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicenter study Lancet 2003 362 9379 192 7 10.1016/S0140-6736(03)13908-6 12885479 \n18. Pharmascience Inc pms-Chloral Hydrate prescribing information 1998 Montreal Pharmascience Inc 1 8 \n19. Monograph CPA Repchinsky C Chloral hydrate Compendium of pharmaceutical and specialties (CPS): the Canadian drug reference for health professionals 2010 Ottawa Canadian Pharmacists Association 525 6 \n20. Jones MG Tsega S Cho HJ Inappropriate prescription of proton pump inhibitors in the setting of steroid use: a teachable moment JAMA Internal Med 2016 176 5 594 5 10.1001/jamainternmed.2016.0603 27065299\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1364-8535",
"issue": "21(1)",
"journal": "Critical care (London, England)",
"keywords": "Chloral hydrate; Intensive care units; Mechanical ventilation; Moderate sedation; Pediatric",
"medline_ta": "Crit Care",
"mesh_terms": "D000416:Alberta; D002648:Child; D002675:Child, Preschool; D002697:Chloral Hydrate; D015331:Cohort Studies; D016292:Conscious Sedation; D004750:Enteral Nutrition; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D007223:Infant; D008297:Male; D010865:Pilot Projects; D011446:Prospective Studies; D012121:Respiration, Artificial",
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"pmid": "29178963",
"pubdate": "2017-11-26",
"publication_types": "D016428:Journal Article",
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"title": "Chloral hydrate enteral infusion for sedation in ventilated children: the CHOSEN pilot study.",
"title_normalized": "chloral hydrate enteral infusion for sedation in ventilated children the chosen pilot study"
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"abstract": "OBJECTIVE\nTo evaluate the efficacy and safety of celecoxib versus placebo in the prevention and treatment of colorectal polyposis in children with familial adenomatous polyposis (FAP).\n\n\nMETHODS\nIn this Phase III, double-blind, randomized, placebo-controlled, multicenter trial patients aged 10-17 years with FAP were randomized to celecoxib (16 mg/kg/day) or placebo for up to 5 years. Patients underwent annual assessments, including colonoscopies, to detect the time from randomization to the earliest occurrence of ≥20 polyps (>2 mm in size) or colorectal malignancy. The study was terminated early due to low rate of observed endpoints combined with a lower than expected enrollment rate. Descriptive results are provided.\n\n\nRESULTS\nOf 106 randomized patients, 55 were treated with celecoxib (mean age 12.6 years; 52.7% female) and 51 were given placebo (mean age 12.2 years; 54.9% female). Disease progression (≥20 polyps, >2 mm in size) was observed in seven (12.7%) and 13 (25.5%) patients, respectively. The median time to disease progression was 2.1 years in the celecoxib group and 1.1 years for placebo. No patient developed colorectal cancer. The rate of adverse events (AEs) was similar in both groups (75.5% and 72.9%, respectively). Three patients in the celecoxib group (none in the placebo group) experienced serious AEs.\n\n\nCONCLUSIONS\nIn children with FAP, celecoxib was a well-tolerated treatment that was associated with a lower rate of colorectal polyposis and a longer time to disease progression compared with placebo. Due to the low rate of observed endpoints, the long-term impact of these results could not be ascertained.",
"affiliations": "Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA.;Department of Surgery, St Mark's Hospital and Academic Institute, Middlesex, UK.;Global Clinical Affairs.;Global Clinical Affairs.;Global Medical Affairs, Pfizer Inc., New York, NY.;Global Clinical Affairs.;Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Burke|Carol A|CA|;Phillips|Robin|R|;Berger|Manuela F|MF|;Li|Chunming|C|;Essex|Margaret Noyes|MN|;Iorga|Dinu|D|;Lynch|Patrick M|PM|",
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"country": "New Zealand",
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"doi": "10.2147/CEG.S121841",
"fulltext": "\n==== Front\nClin Exp GastroenterolClin Exp GastroenterolClinical and Experimental GastroenterologyClinical and Experimental Gastroenterology1178-7023Dove Medical Press 10.2147/CEG.S121841ceg-10-177Original ResearchChildren’s International Polyposis (CHIP) study: a randomized, double-blind, placebo-controlled study of celecoxib in children with familial adenomatous polyposis Burke Carol A 1Phillips Robin 2Berger Manuela F 3Li Chunming 3Essex Margaret Noyes 4Iorga Dinu 3Lynch Patrick M 5\n1 Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA\n2 Department of Surgery, St Mark’s Hospital and Academic Institute, Middlesex, UK\n3 Global Clinical Affairs\n4 Global Medical Affairs, Pfizer Inc., New York, NY\n5 Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USACorrespondence: Carol A Burke, Department of Gastroenterology and Hepatology, Cleveland Clinic, Desk A 31, 9500 Euclid Avenue, Cleveland, OH 44195, USA, Tel +1 216 444 6864, Fax +1 216 444 6305, Email burkec1@ccf.org2017 19 7 2017 10 177 185 © 2017 Burke et al. This work is published and licensed by Dove Medical Press Limited2017The 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.Objective\nTo evaluate the efficacy and safety of celecoxib versus placebo in the prevention and treatment of colorectal polyposis in children with familial adenomatous polyposis (FAP).\n\nMethods\nIn this Phase III, double-blind, randomized, placebo-controlled, multicenter trial patients aged 10–17 years with FAP were randomized to celecoxib (16 mg/kg/day) or placebo for up to 5 years. Patients underwent annual assessments, including colonoscopies, to detect the time from randomization to the earliest occurrence of ≥20 polyps (>2 mm in size) or colorectal malignancy. The study was terminated early due to low rate of observed endpoints combined with a lower than expected enrollment rate. Descriptive results are provided.\n\nResults\nOf 106 randomized patients, 55 were treated with celecoxib (mean age 12.6 years; 52.7% female) and 51 were given placebo (mean age 12.2 years; 54.9% female). Disease progression (≥20 polyps, >2 mm in size) was observed in seven (12.7%) and 13 (25.5%) patients, respectively. The median time to disease progression was 2.1 years in the celecoxib group and 1.1 years for placebo. No patient developed colorectal cancer. The rate of adverse events (AEs) was similar in both groups (75.5% and 72.9%, respectively). Three patients in the celecoxib group (none in the placebo group) experienced serious AEs.\n\nConclusion\nIn children with FAP, celecoxib was a well-tolerated treatment that was associated with a lower rate of colorectal polyposis and a longer time to disease progression compared with placebo. Due to the low rate of observed endpoints, the long-term impact of these results could not be ascertained.\n\nKeywords\nchemopreventionclinical trialadenomacolorectal\n==== Body\nIntroduction\nFamilial adenomatous polyposis (FAP) is an autosomal dominant disease occurring in ~1 in 13,000 births.1 FAP is caused by a germline mutation in the adenomatous polyposis coli (APC) gene. A recent study reported that the mean age of onset of colorectal polyps in children with FAP was 13.4 years and 60% of children harbored >50 polyps at the time of diagnosis.2 If left untreated, polyposis invariably progresses, with a near certainty of patients developing colorectal cancer by the fifth decade of life if colectomy is not performed.3\n\nThe standard management of FAP is by surgical intervention and involves prophylactic total colectomy and ileorectal anastomosis (IRA), or proctocolectomy and ileal pouch anal anastomosis (IPAA) with postoperative endoscopic surveillance and polypectomy. Neither the timing of this surgery nor the procedure itself has been standardized in pediatric patients with FAP.4 Factors such as the presence of symptoms, polyp burden, psychosocial implications, and physical maturity, to name a few, must be considered before the decision to carry out this surgery is made.\n\nAlthough surgery is effective in the prevention of colon cancer, it comes with a risk of mortality and postoperative complications.5,6 Moreover, surgery does not prevent the development of rectal or ileal pouch polyposis. In one long-term follow-up study, 7/34 (21%) children treated with an IRA required proctectomy for either rectal cancer or advanced rectal polyposis, and 2/7 (29%) FAP patients treated with IPAA had postoperative pouch polyposis within one decade of surgery.7 Another study in patients who had undergone IPAA for FAP 10 years previously found that 42% of patients had developed adenoma of the pouch.8\n\nThe use of chemoprevention for FAP has been reviewed previously.9 The goal of this therapy is to prevent, or lead to the regression of, colorectal adenomas and to prevent postoperative recurrence. If shown to be well tolerated and associated with long-term effectiveness in children, chemoprevention may delay the timing of, or alter the approach to, surgical intervention and may decrease the need for endoscopic intervention.\n\nFollowing observations that gene expression of cyclooxygenase-2 (COX-2) is upregulated in many premalignant lesions such as colorectal adenomas,10,11 COX-2 selective inhibition has been considered as a potential chemopreventive strategy for treating FAP. A short-duration, randomized, placebo-controlled trial of celecoxib in children with FAP demonstrated a significant reduction in colorectal polyp burden compared with placebo;4 however, due to the short duration of that study, conclusions cannot be drawn on long-term efficacy and safety of celecoxib for FAP.\n\nThe objective of the present study was to assess the efficacy and safety of celecoxib versus placebo in children with FAP over a 5-year treatment duration.\n\nMethods\nTrial design\nThis was a Phase III, double-blind, randomized, placebo-controlled, multicenter trial in children with FAP. The study was designed to compare efficacy and safety of celecoxib versus placebo for the treatment of colorectal polyposis over a 5-year treatment period. The protocol and informed consent documents were reviewed and approved by an Institutional Review Board or Independent Ethics Committee at each participating study center (see the “Supplementary materials” and “Acknowledgments” sections), written assent was obtained from patients and written informed consent was obtained from parents prior to performing any study-related procedures. The trial was performed in accordance with the protocol, the International Conference on Harmonisation Good Clinical Practice guidelines, and applicable local regulatory requirements and laws.\n\nThe multinational clinical study was conducted at 18 centers located in 13 countries.\n\nParticipants and interventions\nA total of 200 eligible patients with FAP from multiple international centers were to be randomly assigned in a 1:1 ratio to receive either celecoxib (up to 16 mg/kg/day) or matching placebo for up to 5 years. Celecoxib was administered based on patients’ weight as follows: body weight 25.0–37.5 kg, dosage 200 mg BID; 37.6–50.0 kg, 300 mg BID; >50.0 kg, 400 mg BID. The dose was adjusted based on body weight at return visits according to the protocol.\n\nA central Internet/telephone system was used to assign each patient a randomization number. Randomization was carried out in block size of 4 and was stratified by center, age (≥12 vs <12 years), and FAP phenotype (negative vs positive).\n\nThe study comprised patients aged 10–17 years (inclusive). Patients were required to have either a deleterious APC gene mutation, based on central genetic testing, including a non-attenuated genotype or an attenuated genotype and a personal history of colorectal adenomas plus a first-degree relative with colectomy, colorectal cancer, or >100 adenomas by the age of 40; or if no gene mutation was detected in the family, a personal history of >2 adenomas and a parent with the FAP phenotype, as stated earlier. Patients were required to have <20 polyps of >2 mm at baseline colonoscopy that had to be completely excised, to render the colon free of polyps >2 mm in size before administration of study drug.\n\nOther inclusion criteria were negative pregnancy test and willingness to use effective birth control among female patients, abstention from use of other non-steroidal anti-inflammatory drugs (NSAIDs), intact colon, and normal blood tests.\n\nKey exclusion criteria were sensitivity to COX-2 selective NSAIDs, recent use of NSAIDs or oral adrenocorticosteroid, the need for concurrent use of fluconazole or lithium, and active peptic ulcer.\n\nAll patients underwent baseline colonoscopy under anesthesia, according to standard local practice, with complete excision of all polyps >2 mm in size in eligible patients. At a Month 6 visit, patients underwent physical and laboratory examination and safety monitoring. At annual visits, colonoscopies were performed to assess the number and size of colorectal polyps, with complete excision for all patients who developed <20 colorectal polyps (>2 mm in size). Histologic assessment of biopsied polyps was collected if available. Telephone monitoring was carried out at least every 3 months.\n\nStudy endpoints\nThe primary endpoint was the time to disease progression, defined as the time from randomization to the earliest occurrence of the following events:\nappearance of ≥20 polyps (>2 mm in size) at any colo-noscopy during the study;\n\ndiagnosis of colorectal malignancy.\n\n\n\nSecondary endpoints included\nthe time from randomization to treatment failure, where treatment failure was defined as:\nearliest occurrence of ≥20 polyps (>2 mm in size) at colonoscopy,\n\ncolorectal malignancy, or\n\ntreatment-related dropout (insufficient clinical response, disease progression, death, adverse events [AEs], treatment-related laboratory abnormalities, patient no longer willing to participate in the study, and other reasons related to treatment);\n\n\n\nthe weighted total number of colorectal polyps (>2 mm in size) diagnosed over Years 1–5 cumulatively, which was calculated as the sum of polyps over the 5 years divided by the number of colonoscopies the patient had during the study;\n\nthe polyp burden, defined as the sum of the largest diameters of all polyps (>2 mm in size) detected at each colonoscopy over the 5 years, divided by the number of colonoscopies the patient had during the study.\n\n\n\nSafety endpoints were based on investigator-reported AEs, serious adverse events (SAEs), laboratory measurements, and physical examinations. AEs were coded according to criteria from the Medical Dictionary for Regulatory Activities, version 16.1.\n\nData analysis\nThe sample size calculation for this study was originally based on the primary endpoint and the assumption that the hazard rates (HRs) for patients treated with placebo and celecoxib were 0.37942 and 0.24079, respectively. A total of 152 events would have been needed to show that the celecoxib group was superior to the placebo group (HR=1.576) at a significance level of 0.05 and with 80% power. Interim efficacy analyses were planned at increments of ~30 primary endpoint events.\n\nIn November 2012, the Data Safety Monitoring Board recommended that the trial be stopped if the 6-month enrollment rate was <10 patients, if the pooled observed HR was <0.16 events/person-year, or if there were any safety concerns. The first two conditions were met and the trial was terminated on October 31, 2013.\n\nDue to early study termination, only descriptive statistics were analyzed and presented. The interim analysis that was originally planned was not conducted.\n\nEndpoints were assessed in the intent-to-treat (ITT) population, consisting of all patients who were randomized (with study drug assignment designated according to initial randomization), regardless of whether patients received any study drug or received a different drug from that to which they were randomized.\n\nSafety was assessed in all patients who received at least one dose of study medication, with treatment assignments designated according to the actual study treatment received.\n\nResults\nPatient disposition\nPatients were recruited between September 2006 and October 2013 from centers in Belgium, Czech Republic, Hong Kong, Hungary, Israel, Italy, Slovakia, South Africa, Spain, Sweden, Ukraine, the UK, and the US. Of 305 patients screened for eligibility, 106 were randomized into the study: 55 to the celecoxib group and 51 to the placebo group (ITT population, Figure 1). Of those randomized, 53 (96.4%) patients received treatment with celecoxib and 48 (94.1%) patients received placebo (safety population); 64 patients were from the US, 35 were from Europe, and 7 were from Hong Kong, Israel, and South Africa.\n\nOut of the 106 randomized patients, 85 were still active in 2013, when the study was terminated. The other 21 patients were discontinued prior to 2013, as follows: 2 in 2009, 3 in 2010, 5 in 2011, and 11 in 2012. Discontinuations were considered related to study drug treatment (treatment failure or related AE resulting in discontinuation) occurred for nine (16.4%) patients in the celecoxib group (three patients for AEs, six patients for treatment failure) and 11 (21.6%) patients in the placebo group (all due to treatment failure). Compliance with medication, assessed by medication counts and patient diary, was similar between the groups.\n\nBaseline characteristics\nThe two arms of the study were balanced with respect to baseline characteristics; most patients were aged ~12 years and were white, and there were slightly more females than males in both groups (Table 1).\n\nOngoing coexisting medical conditions were reported in 37 (67.3%) patients in the celecoxib group and 28 (54.9%) in the placebo group. The most common of these were nervous system disorders (16 patients in the celecoxib group vs 15 in the placebo group), immune system disorders (13 vs 9, respectively), and psychiatric disorders (11 vs 10, respectively). The majority of patients’ mutation location was exon 15 (n=65), with equal numbers (n=12) having mutations at exons 10–14 and exons 5–8, and fewer at exon 9 (n=4) and exons 1–4 (n=2). An additional 11 patients had other mutations.\n\nStudy endpoints\nAmong those who were treated (safety population), the median duration of treatment was 23.0 months for patients in the celecoxib group and 25.5 months for those in the placebo group. In the ITT population, 20 patients met the primary endpoint (development of ≥20 polyps >2 mm in size) during the study, seven (12.7%) of 55 patients in the celecoxib group and 13 (25.5%) of 51 in the placebo group. The median time to disease progression was 2.1 years in the celecoxib group and 1.1 years for placebo. None of the patients developed a colorectal malignancy. The cumulative rate of patients reaching the primary endpoint over the 5-year follow-up period (appearance of ≥20 polyps that are >2 mm in size) is shown in Figure 2.\n\nA similar proportion of patients met the secondary endpoint (14 in each group), which compared the time from randomization to treatment failure (including development of ≥20 polyps [>2 mm in size], diagnosis of colorectal malignancy, and treatment-related dropout). The median time to treatment failure was 2.0 years in the celecoxib group and 1.1 years for placebo. Treatment-related dropout occurred in 14 (25.5%) patients in the celecoxib group and 12 (23.5%) patients in the placebo group.\n\nThe weighted total number of colorectal polyps (>2 mm in size) diagnosed over Years 1–5 cumulatively is shown in Table 2. The mean (standard deviation) polyp burden in the celecoxib and placebo groups was 4.1 (1.68) and 4.3 (1.61) mm, respectively.\n\nSafety\nThe number of AEs and treatment-related AEs were similar in the two treatment groups (Table 3). Of the six patients in the celecoxib group who discontinued treatment due to AEs, three were considered to have had treatment-related AEs. The most common AEs, occurring in >10% patients in a group, were headache, abdominal pain, vomiting, and nausea (Table 4).\n\nThree patients in the celecoxib group experienced SAEs during the treatment period (depression, pneumonia, and periorbital cellulitis secondary to sinusitis); none were considered to be related to the study drug. No patients in the placebo group experienced SAEs. One patient in the celecoxib treatment group reported SAEs after completion of treatment that were considered by the investigator and sponsor as related to the study drug treatment. These were Escherichia sepsis, maternal exposure, and delivery of a premature baby. Despite taking oral contraceptives, this patient became pregnant during the study and gave birth, prematurely, ~9 months after study visit 3 (Year 1). Treatment with the study drug had been discontinued ~1 month previously. The infant died 11 days later.\n\nThe incidence of specific laboratory abnormalities and shifts of baseline values from normal levels was comparable between the treatment groups.\n\nDiscussion\nThis Phase III randomized, double-blind, placebo-controlled celecoxib trial is one of the largest studies to assess the efficacy and safety of chemoprevention in children with FAP. The study endpoint, progression of polyposis to ≥20 polyps >2 mm in size in 1 year, was determined to be of clinical significance and of prudent safety by a consensus of investigators before the study was incepted. Fewer children with FAP who received 16 mg/kg/day doses of celecoxib reached the primary endpoint than patients who received placebo. Furthermore, celecoxib was associated with a slower rate of disease progression compared with placebo, with the time to disease progression being on average 1 year longer for patients who received celecoxib than those who received placebo. No patients in either group developed colorectal cancer during the study and celecoxib was generally well tolerated. However, the long-term impact of celecoxib on colorectal polyposis in children with FAP is unknown, because the study was terminated early due to the low occurrence of disease progression observed over the course of the study.\n\nThe results of this study, while limited by early termination, are valuable to clinicians and patients. Delaying disease progression in FAP is important as it affords a potential opportunity for children and parents to delay the timing for colectomy. Elective surgery is usually undertaken at an age of 16–20 years;12 however, the optimal timing has not been determined.4 Decisions about the timing of surgery should take into account psychosocial factors so as to minimize disruption to the child’s personal development. In some cases, delaying surgery so that it causes the least disruption to educational or work activities is necessary.12 After IPAA, there is usually a permanent effect on the patient’s bowel function, and in some cases sexual function can be altered.3 It is therefore important that patients are educated in advance about the possible quality of life changes post-surgery so that their expectations can be managed.3\n\nAlthough the use of COX-2 selective and nonselective NSAIDs as potential adjunctive therapies for patients with FAP who have undergone prophylactic surgery has been recommended,13 the application of these treatments in a pediatric population has not been rigorously tested. The Children’s International Polyposis (CHIP) trial was designed to provide long-term efficacy and safety data on celecoxib for the reduction of the number of polyps in children with FAP. The ages of patients in this trial were representative of the age at which screening is carried out in children with polyposis.14 The study of chemoprevention in children with FAP is important for clinical practice, where early intervention may lead to slower progression of polyposis, which may translate to improved outcomes such as a delay in surgery or fewer polypectomies. Earlier studies of chemoprevention in FAP with NSAIDs focused predominantly on adult populations15–18 and found them to be useful adjuncts to endoscopy.\n\nPrevious trials4,15 and cohort studies19 have provided some evidence for the efficacy of celecoxib in FAP, but they were limited by both small sample size and relatively short duration. In a Phase I dose-escalation study in 18 children, three cohorts of patients received celecoxib at sequential doses of 4, 8, or 16 mg/kg/day, or placebo for 3 months. The number of polyps increased in the placebo and 4 mg/kg celecoxib groups by a median (range) of 17.5 (−5 to 63) and 5.5 (2–17) polyps, respectively. In patients treated with celecoxib at 8 and 16 mg/kg doses, there was a median decrease in the number of polyps by −7.0 (−2 to −16) and −17.5 (−2 to −48), respectively (p=0.011), confirming a dose-dependent response with celecoxib in FAP.4\n\nThe chemopreventive attributes of celecoxib have also been evaluated in a short-term study of adults.15 In this trial, a 6-month treatment period was selected, based on previous studies with sulindac, an NSAID that acts on both COX-1 and COX-2 enzymes and has also been shown to reduce the number and size of colorectal polyps.16,17 In total, 77 patients with FAP received 400 mg celecoxib twice daily or placebo. In the active treatment group, there was a significant 28% reduction in the mean number of colorectal polyps (p=0.003) and a 31% reduction in polyp burden (p=0.001), compared with placebo.15\n\nAlthough NSAIDs are very commonly used drugs, long-term use at relatively high doses has been associated with increases in gastrointestinal and cardiovascular risk.20 As a result, there is a need to assess the relative long-term risks and benefits of celecoxib in different clinical settings, including patients with or without vascular disease and in those with adenomas;21 few studies have investigated the long-term effects of NSAIDs in children. The Adenoma Prevention with Celecoxib trial examined the efficacy and safety of celecoxib for preventing sporadic colorectal adenoma in >2,000 adults who were at high risk for colorectal cancer. Celecoxib was an effective agent in the trial but could not be recommended because of potential cardiovascular AEs.18 A 5-year follow-up of the trial noted that cardiovascular AEs were particularly associated with a history of atherosclerotic heart disease.22 It is not clear whether there are specific populations who may benefit from adenoma prevention with a COX-2 selective NSAID.\n\nBecause FAP is incurable and associated with substantial morbidity and tumor-related mortality, a safe and effective agent to manage the disease is desperately needed. Understanding of the utility of chemoprevention in the colorectum of patients with FAP has progressed over the last 40 years, due to several studies that have shown a short-term benefit of NSAIDs on polyp burden.4,5–17 Despite this, the search continues for a chemopreventive agent that is both effective and nontoxic. This study, despite being terminated prematurely, determined that at a median of 2 years of treatment there was a 50% reduction in the number of pediatric patients who met the primary outcome of disease progression in the celecoxib arm compared with patients in the placebo arm. Although it was not possible to confirm the statistical significance of celecoxib’s efficacy, the safety results indicate that celecoxib was a well-tolerated treatment in this population of children with FAP.\n\nSupplementary materials\nAll Institutional Review Boards and Independent Ethics Committees for sites that screened patients are listed below:\nCliniques Universitaires Commission d'Ethique Biomedi-cale Hospitalo- Facultaire, Bruxelles, Belgium\n\nEticka komise pro Multicentricka klinicka hodnoceni Fakultni nemocnice v Motole, Praha, Czech Republic\n\nJoint Chinese University of Hong Kong.-New Territories East Cluster Clinical Research Ethics Committee. Prince of Whales Hospital, Shatin, Hong Kong\n\nJoint Chinese University of Hong Kong –New Territories East Cluster Clinical Research Ethics Committee. Prince of Whales Hospital, Shatin, Hong Kong\n\nInstitutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster, Queen Mary Hospital, Hong Kong\n\nEgeszsegugyi Tudomanyos Tanacs Klinikai Farmakologiai Etikai Bizottsaga, Budapest, Hungary\n\nRambam Medical Center Helsinki Committee, Haifa, Israel\n\nHelsinki Committee, Rabin Medical Center, Beilinson Campus, Petach Tikvah, Israel\n\nBaruch Padeh Medical Center, Poriya Helsinki Committee, Lower Galilee, Israel\n\nThe Helsinki Committee Tel Aviv Sourasky Medical Center Sourasky MC, Tel Aviv, Israel\n\nComitato Etico, Istituto Regina Elena, Roma, Italy\n\nComitato Etico Locale per la Sperimentazione Clinica dei Medicinali, Siena, Italy\n\nEticka komisia DFNsP BA, Detska fakultna nemocnica s poliklinikou, Bratislava. Slovakia\n\nUniversity of Cape Town, Health Sciences Faculty, Research Ethics Committee, Cape Town, South Africa\n\nHospital Clinico San Carlos Comite Etico de Investigacion Clinica Ciudad Universitaria, Madrid, Spain\n\nRegionala etikprovningsnamnden i Stockholm, Stockholm, Sweden\n\nCentral Committee for Ethics Issues of Ministry of Health Care of Ukraine, Donetsk Regional Children Clinical Hospital, Local Ethics Committee, Donetsk, Ukraine\n\nCentral London REC 1, Northwick Park Hospital, London, UK\n\nNRES Committee London, Health Research Authority National Research Ethics\n\nUniversity of Texas MD Anderson Cancer Center, Houston, TX, USA\n\nMemorial Sloan Kettering Cancer Center Institutional Review Board, New York, NY, USA\n\nCase Western Reserve University School of Medicine, Cancer Institutional Review Board, Cleveland, OH, USA\n\nInstitutional Review Board of the Cleveland Clinic, Cleveland, OH, USA\n\nUniversity of Nebraska Medical Center Institutional Review Board, Omaha, NE, USA\n\nChildren’s Hospital Institutional Review Board, Omaha, NE, USA\n\nUniversity of Utah Institutional Review Board, East Salt Lake City, UT, USA\n\nUniversity of Utah Institutional Review Board, East Salt Lake City, UT, UA\n\nVanderbilt University Institutional Review Board, South Nashville, TN, USA\n\nUniversity of Michigan IRB-MED, Ann Arbor, MI, USA\n\nUniversity of Michigan IRB-MED, Ann Arbor, MI, USA\n\nRush University Medical Center, IRB Department, Chicago, IL, USA\n\nCincinnati Children's Hospital Medical Center Institutional Review Board, Cincinnati, OH, USA\n\nWestern Institutional Review Board, SW Olympia, WA, USA\n\nHuman Research Subjects Protection Office (HRSPO) Office, UPR Medical Sciences Campus, San Juan, Puerto Rico\n\n\n\nAcknowledgments\nThe study was sponsored by Pfizer. Editorial support was provided by K Bradford of PAREXEL and Joshua Fink of Engage Scientific Solutions and was funded by Pfizer. The authors gratefully acknowledge the study site investigators – Belgium: Prof Etienne Sokal, Cliniques Universitaires Saint-Luc/Pediatrie Generale, Brussels; Prof Catharina Dhooge and Dr Peeters Marc, Universitair Ziekenhuis Gent/Pediatrische Hematologie-Oncologie en Stamceltransplantatie, Ghent; Czech Republic: Dr Jiri Nevoral, Fakultni Nemocnice Motol, Prague; Hong Kong: Prof Simon Siu-Man Ng, The Chinese University of Hong Kong; Dr Judy Ho, Queen Mary Hospital; Hungary: Dr Tunde Kristof, Endomedix Diagnosztikai Kozpont-Miskolc; Israel: Prof Ron Shaoul, Meyer Children’s Hospital, Haifa; Prof Raanan Shamir, Schneider Children’s Medical Center of Israel, Petah Tikva; Dr Avi On, The Baruch Padeh Medical Center, Poriya; Dr Shlomi Cohen, Dana Children’s Hospital, Tel Aviv; Italy: Dr Vittoria Stigliano, Polo Oncologico Istituto Regina Elena, Rome; Dr Giorgio Frosini, Policlinico Le Scotte, Siena; Puerto Rico: Dr Marcia Cruz-Correa, Puerto Rico Clinical and Translational Research, Rio Piedras; Slovakia: Dr Iveta Cierna, Detska Klinika, Bratislava; South Africa: Dr Paul A Goldberg, Groote Schuur Hospital, Cape Town; Spain: Dr Pedro Perez Segura, Hospital Clinico San Carlos, Madrid; Sweden: Dr Jan Bjork and Dr Rolf Hultcrantz, Karolinska University Hospital, Stockholm; Ukraine: Prof Ivan P Zhurylo, Regional Children’s Clinical Hospital, Donetsk; UK: Dr Susan Katherine Clark, St Mark’s Hospital, Middlesex; USA: Dr Patrick Michael Lynch, University of Texas, Houston, TX; Dr Jose Gaston Guillem, Memorial Sloan Kettering Cancer Center, New York, NY; Dr Carol Ann Burke and Dr James Church, Cleveland Clinic, Cleveland, OH; Dr Ruben Eloy Quiros-Tejeira and Dr Thomas Attard, University of Nebraska Medical Center, Omaha, NB; Dr William D Jackson, Primary Children’s Medical Center, Salt Lake City, UT; Dr Timothy M Geiger and Dr Wise Paul, Vanderbilt University Medical Center, Nashville, TN; Dr Danielle Kim Turgeon and Dr Stephen Gruber, University of Michigan Health System, Ann Arbor, MI; Dr Marc Isadore Brand, Rush University Medical Center, Chicago, IL; Dr Ajay Kaul, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.\n\nDisclosure\n\nPML has received research support and has served on steering committees for Pfizer. He has also served on external advisory panels and speakers bureau for Myriad Genetics. RP has received research support and has served on steering committees for Pfizer. CAB has served on steering committees for Pfizer and has received research support from Pfizer, Salix, and Cancer Prevention Pharmaceuticals. MB, CL, MNE, and DI are employees of, and hold stock and/or stock options in, Pfizer. ClinicalTrials.gov identifier: NCT00585312. The authors report no other conflicts of interest in this work.\n\nFigure 1 Patient disposition.\n\nNote: *Includes “Does not meet entrance criteria” and “Protocol violation”.\n\nAbbreviation: ITT, intent-to-treat.\n\nFigure 2 Time to disease progression (ITT population).\n\nNote: Event defined as the appearance of >20 polyps that are >2 mm in size or diagnosis of colorectal malignancy.\n\nAbbreviation: ITT, intent-to-treat.\n\nTable 1 Baseline patient characteristics (ITT population)\n\n\tCelecoxib (n=55)\n\tPlacebo (n=51)\n\t\nFemale\tMale\tTotal\tFemale\tMale\tTotal\t\nSex, n (%)\t29 (52.7)\t26 (47.3)\t55\t28 (54.9)\t23 (45.1)\t51\t\nAge\t\n Mean (SD)\t12.4 (2.3)\t12.8 (2.0)\t12.6 (2.2)\t12.0 (1.7)\t12.4 (2.0)\t12.2 (1.8)\t\n Range\t10–17\t10–17\t10–17\t10–15\t10–17\t10–17\t\nRace, n (%)\t\n White\t26 (89.7)\t20 (76.9)\t46 (83.6)\t21 (75.0)\t19 (82.6)\t40 (78.4)\t\n Black\t1 (3.4)\t1 (3.8)\t2 (3.6)\t0\t2 (8.7)\t2 (3.9)\t\n Asian\t0\t1 (3.8)\t1 (1.8)\t0\t1 (4.3)\t1 (2.0)\t\n Other\t2 (6.9)\t4 (15.4)\t6 (10.9)\t7 (25.0)\t1 (4.3)\t8 (15.7)\t\nAbbreviations: ITT, intent-to-treat; SD, standard deviation.\n\nTable 2 Total number of colorectal polyps (>2 mm in size) detected at annual colonoscopies findings (ITT population)\n\n\tCelecoxib (n=55)\tPlacebo (n=51)\t\nYear 1\t\n N\t27\t30\t\n Mean (SD)\t3.0 (2.68)\t8.1 (7.32)\t\n Median\t2.0\t6.0\t\nYear 2\t\n N\t21\t25\t\n Mean (SD)\t8.8 (6.63)\t13.7 (10.51)\t\n Median\t6.0\t11.0\t\nYear 3\t\n N\t16\t14\t\n Mean (SD)\t13.4 (11.31)\t22.3 (11.74)\t\n Median\t10.0\t20.0\t\nYear 4\t\n N\t8\t7\t\n Mean (SD)\t18.6 (17.65)\t36.4 (22.50)\t\n Median\t11.5\t32.0\t\nYear 5\t\n N\t2\t2\t\n Mean (SD)\t30.5 (21.92)\t46.5 (34.65)\t\n Median\t30.5\t46.5\t\nYears 1–5 cumulatively\t\n N\t33\t36\t\n Mean (SD)\t4.3 (3.58)\t8.6 (7.12)\t\n Median\t3.0\t7.0\t\nAbbreviations: ITT, intent-to-treat; SD, standard deviation.\n\nTable 3 Patients with AEs (safety population)*\n\n\tCelecoxib, n (%) (n=53)\n\tPlacebo, n (%) (n=48)\n\t\nAll causes\tTreatment related\tAll causes\tTreatment related\t\nTotal AEs observed\t270\t43\t226\t43\t\nPatients with any AE\t40 (75.5)\t18 (34.0)\t35 (72.9)\t15 (31.3)\t\nPatients with serious AEs\t3 (5.7)\t0\t0\t0\t\nPatients with severe AEs\t5 (9.4)\t1 (1.9)\t3 (6.3)\t0\t\nPatients permanently discontinued study due to AEs\t3 (5.7)\t0\t0\t0\t\nPatients permanently discontinued treatment due to AEs\t6 (11.3)\t4 (7.5)\t1 (2.1)\t1 (2.1)\t\nPatients with dose reduction or temporary discontinuation due to AEs\t19 (35.8)\t4 (7.5)\t12 (25.0)\t2 (4.2)\t\nNotes:\n\n* Includes data up to 30 days after last dose of study drug. Except for the number of AEs, patients were counted only once per treatment in each row. Relationship of SAEs is displayed according to the investigator’s assessment.\n\nAbbreviations: AE, adverse event; SAE, serious adverse event.\n\nTable 4 AEs occurring in ≥10% of patients per group (safety population)\n\n\tCelecoxib, n (%) (n=53)\tPlacebo, n (%) (n=48)\t\nHeadache\t16 (30.2)\t14 (29.2)\t\nAbdominal pain\t9 (17.0)\t10 (20.8)\t\nVomiting\t9 (17.0)\t9 (18.8)\t\nNausea\t8 (15.1)\t8 (16.7)\t\nCough\t8 (15.1)\t6 (12.5)\t\nAbdominal discomfort\t9 (17.0)\t4 (8.3)\t\nOropharyngeal pain\t6 (11.3)\t5 (10.4)\t\nDiarrhea\t6 (11.3)\t4 (8.3)\t\nFatigue\t6 (11.3)\t4 (8.3)\t\nNasopharyngitis\t6 (11.3)\t4 (8.3)\t\nUpper respiratory tract infection\t4 (7.5)\t9 (18.8)\t\nInfluenza\t6 (11.3)\t1 (2.1)\t\nSeasonal allergy\t2 (3.8)\t5 (10.4)\t\nAbbreviation: AEs, adverse events.\n==== Refs\nReferences\n1 Bisgaard ML Fenger K Bulow S Niebuhr E Mohr J Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate Hum Mutat 1994 3 121 125 8199592 \n2 Kennedy RD Potter DD Moir CR El-Youssef M The natural history of familial adenomatous polyposis syndrome: a 24 year review of a single center experience in screening, diagnosis, and outcomes J Pediatr Surg 2014 49 82 86 24439586 \n3 Half E Bercovich D Rozen P Familial adenomatous polyposis Orphanet J Rare Dis 2009 4 22 19822006 \n4 Lynch PM Ayers GD Hawk E The safety and efficacy of celecoxib in children with familial adenomatous polyposis Am J Gastroenterol 2010 105 1437 1443 20234350 \n5 Bulow C Vasen H Jarvinen H Bjork J Bisgaard ML Bulow S Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis Gastroenterology 2000 119 1454 1460 11113066 \n6 Kirchhoff P Clavien PA Hahnloser D Complications in colorectal surgery: risk factors and preventive strategies Patient Saf Surg 2010 4 5 20338045 \n7 Booij KA Mathus-Vliegen EM Taminiau JA Evaluation of 28 years of surgical treatment of children and young adults with familial adenomatous polyposis J Pediatr Surg 2010 45 525 532 20223315 \n8 Friederich P de Jong AE Mathus-Vliegen LM Risk of developing adenomas and carcinomas in the ileal pouch in patients with familial adenomatous polyposis Clin Gastroenterol Hepatol 2008 6 1237 1242 18848811 \n9 Kim B Giardiello FM Chemoprevention in familial adenomatous polyposis Best Pract Res Clin Gastroenterol 2011 25 607 622 22122775 \n10 Eberhart CE Coffey RJ Radhika A Giardiello FM Ferrenbach S DuBois RN Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas Gastroenterology 1994 107 1183 1188 7926468 \n11 Sinicrope FA Lemoine M Xi L Reduced expression of cyclooxygenase 2 proteins in hereditary nonpolyposis colorectal cancers relative to sporadic cancers Gastroenterology 1999 117 350 358 10419916 \n12 Tudyka VN Clark SK Surgical treatment in familial adenomatous polyposis Ann Gastroenterology 2012 25 201 206 \n13 Vasen HF Moslein G Alonso A Guidelines for the clinical management of familial adenomatous polyposis (FAP) Gut 2008 57 704 713 18194984 \n14 National Comprehensive Cancer Network Clinical practice guidelines in oncology. Genetic/familial high-risk assessment: colorectal version 2 2014 Available from: nccn.org/professionals/physician_gls/f_guidelines.asp Accessed July 25, 2014 \n15 Steinbach G Lynch PM Phillips RK The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis N Engl J Med 2000 342 1946 1952 10874062 \n16 Rigau J Pique JM Rubio E Planas R Tarrech JM Bordas JM Effects of long-term sulindac therapy on colonic polyposis Ann Intern Med 1991 115 952 954 1659272 \n17 Giardiello FM Hamilton SR Krush AJ Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis N Engl J Med 1993 328 1313 1316 8385741 \n18 Bertagnolli MM Eagle CJ Zauber AG Celecoxib for the prevention of sporadic colorectal adenomas N Engl J Med 2006 355 873 884 16943400 \n19 Huang K Gutierrez LP Bulow S Clinical characteristics and outcomes in familial adenomatous polyposis patients with a long-term treatment of celecoxib: a matched cohort study Fam Cancer 2011 10 303 308 21359561 \n20 Bhala N Emberson J Merhi A Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials Lancet 2013 382 769 779 23726390 \n21 Wang D DuBois RN The role of COX-2 in intestinal inflammation and colorectal cancer Oncogene 2010 29 781 788 19946329 \n22 Bertagnolli MM Eagle CJ Zauber AG Five-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial Cancer Prev Res (Phila) 2009 2 310 321 19336730\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7023",
"issue": "10()",
"journal": "Clinical and experimental gastroenterology",
"keywords": "adenoma; chemoprevention; clinical trial; colorectal",
"medline_ta": "Clin Exp Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101532800",
"other_id": null,
"pages": "177-185",
"pmc": null,
"pmid": "28765715",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "20234350;19946329;19336730;20223315;11113066;20338045;18848811;16943400;21359561;8385741;10874062;10419916;24714154;24439586;23726390;7926468;8199592;22122775;19822006;18194984;1659272",
"title": "Children's International Polyposis (CHIP) study: a randomized, double-blind, placebo-controlled study of celecoxib in children with familial adenomatous polyposis.",
"title_normalized": "children s international polyposis chip study a randomized double blind placebo controlled study of celecoxib in children with familial adenomatous polyposis"
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{
"companynumb": "GB-PFIZER INC-2012274222",
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"occurcountry": "GB",
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"activesubstancename": "CELECOXIB"
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{
"abstract": "Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.",
"affiliations": "Medical Research Council and Kwazulu Research Institute for TB and HIV (K-RITH), Durban, South Africa Alex.Pym@k-rith.org.;Division of Medical Physiology and Dept of Science and Technology/National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research and Medical Research Council Centre for Tuberculosis Research, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.;Tuberculosis Dept, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumour Research Institute, Beijing, China.;Clinical HIV Research Unit, Dept of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.;Tartu University Lung Hospital, Tartu, Estonia.;Chest Disease Institute, Ministry of Public Health, Nonthaburi, Thailand.;Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russia.;Janssen Infectious Diseases BVBA, Beerse, Belgium.;Janssen Research & Development LLC, Titusville, NJ, USA.;Janssen Research & Development LLC, Titusville, NJ, USA.;Janssen Infectious Diseases BVBA, Beerse, Belgium.;Janssen Infectious Diseases BVBA, Beerse, Belgium.;Janssen Infectious Diseases BVBA, Beerse, Belgium.;Janssen Infectious Diseases BVBA, Beerse, Belgium.;Janssen Infectious Diseases BVBA, Beerse, Belgium.;Janssen Research & Development LLC, Titusville, NJ, USA.",
"authors": "Pym|Alexander S|AS|;Diacon|Andreas H|AH|;Tang|Shen-Jie|SJ|;Conradie|Francesca|F|;Danilovits|Manfred|M|;Chuchottaworn|Charoen|C|;Vasilyeva|Irina|I|;Andries|Koen|K|;Bakare|Nyasha|N|;De Marez|Tine|T|;Haxaire-Theeuwes|Myriam|M|;Lounis|Nacer|N|;Meyvisch|Paul|P|;Van Baelen|Ben|B|;van Heeswijk|Rolf P G|RP|;Dannemann|Brian|B|;|||",
"chemical_list": "D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline",
"country": "England",
"delete": false,
"doi": "10.1183/13993003.00724-2015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0903-1936",
"issue": "47(2)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents; D064687:Diarylquinolines; D054908:Extensively Drug-Resistant Tuberculosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant; D055815:Young Adult",
"nlm_unique_id": "8803460",
"other_id": null,
"pages": "564-74",
"pmc": null,
"pmid": "26647431",
"pubdate": "2016-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis.",
"title_normalized": "bedaquiline in the treatment of multidrug and extensively drug resistant tuberculosis"
} | [
{
"companynumb": "NVSC2019ZA036453",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOFAZIMINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nTumor chemotherapy could weaken the immune system of patients, which might enhance the body sensitivities to the exogenous pathogens, among which the hepatitis B virus (HBV) infection should be concerned because of the higher chances of infection and the severe outcomes, especially in East Asia. The titer level of hepatitis B surface antibody (HBsAb) higher than 10 IU/L is considered to offer immunocompetent individuals adequate protection. However, whether this level is enough to the tumor patients during chemotherapy remains unclear.\nA 58-year-old female lymphoma patient was admitted to our hospital for asthenia, nausea, vomiting, and abnormal liver function lasting over 1 week and diagnosed as acute hepatitis B. The patient just finished a course of chemotherapy with CHOP regimen and had recent record (78.61 IU/L) of HBsAb positive. The only risk of infection we could found was that the patient had received blood transfusion shortly after chemotherapy from a donor who was recovering from an asymptomatic acute HBV infection.\n\n\nMETHODS\nThe patient was administered with entecavir and glycyrrhizic acid agent, and then the disease was resolved successfully with hepatitis B surface antigen serological conversion.\n\n\nCONCLUSIONS\nTumor chemotherapy might have weakened the immune system of the patient and enhanced the body sensitivities to hepatitis B virus, then led to the infection. We concluded that HBsAb-positive status, at least \"weakly positive,\" might not enough to provide protection for tumor patients on chemotherapy though this level was enough for health individuals and donors recuperating from subclinical acute hepatitis B might be another potential risk of HBV infection.",
"affiliations": "Liver Disease Diagnosis and Treatment Center, Bethune International Peace Hospital Orthopedic Research Institute, the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.",
"authors": "Kang|Fu-Biao|FB|;Wang|Ling|L|;Sun|Dian-Xing|DX|",
"chemical_list": "D000998:Antiviral Agents; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; C413685:entecavir; D014750:Vincristine; D006147:Guanine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000008518",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29095312MD-D-17-0377310.1097/MD.0000000000008518085184900Research ArticleClinical Case ReportHepatitis B virus infection in an HBsAb-positive lymphoma patient who received chemotherapy A case reportKang Fu-Biao MD, PhDa∗Wang Ling MDbSun Dian-Xing MDaAlkhiary. Wael a Liver Disease Diagnosis and Treatment Center, Bethune International Peace Hospitalb Orthopedic Research Institute, the Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.∗ Correspondence: Fu-Biao Kang, Liver Disease Diagnosis and Treatment Center, Bethune International Peace Hospital, Shijiazhuang, Hebei, People's Republic of China (e-mail: kangfb@hotmail.com).11 2017 03 11 2017 96 44 e851818 6 2017 28 9 2017 12 10 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nRationale:\nTumor chemotherapy could weaken the immune system of patients, which might enhance the body sensitivities to the exogenous pathogens, among which the hepatitis B virus (HBV) infection should be concerned because of the higher chances of infection and the severe outcomes, especially in East Asia. The titer level of hepatitis B surface antibody (HBsAb) higher than 10 IU/L is considered to offer immunocompetent individuals adequate protection. However, whether this level is enough to the tumor patients during chemotherapy remains unclear.\n\nPatient concerns:\nA 58-year-old female lymphoma patient was admitted to our hospital for asthenia, nausea, vomiting, and abnormal liver function lasting over 1 week and diagnosed as acute hepatitis B. The patient just finished a course of chemotherapy with CHOP regimen and had recent record (78.61 IU/L) of HBsAb positive. The only risk of infection we could found was that the patient had received blood transfusion shortly after chemotherapy from a donor who was recovering from an asymptomatic acute HBV infection.\n\nIntervention:\nThe patient was administered with entecavir and glycyrrhizic acid agent, and then the disease was resolved successfully with hepatitis B surface antigen serological conversion.\n\nLessons:\nTumor chemotherapy might have weakened the immune system of the patient and enhanced the body sensitivities to hepatitis B virus, then led to the infection. We concluded that HBsAb-positive status, at least “weakly positive,” might not enough to provide protection for tumor patients on chemotherapy though this level was enough for health individuals and donors recuperating from subclinical acute hepatitis B might be another potential risk of HBV infection.\n\nKeywords\nchemotherapyhepatitis B surface antigenshepatitis BlymphomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nTumor chemotherapy can weaken the immune system of patients, which not only induces the reactivation of latent infections, such as tuberculosis bacteria, hepatitis B virus, and cytomegalovirus, but also enhances the body sensitivities to the exogenous pathogens.[1–3] Different antitumor drugs have different influence mechanisms to the immune system, including myelosuppression, cytotoxicity, and antiproliferation and apoptosis-induced effects. The hepatitis B virus (HBV) infection is an issue that should be concerned during and after tumor chemotherapy, one reason is the higher chances of HBV infection in tumor patients, especially in East Asia, and another reason lies in the fact that HBV infection in immune compromised patients may lead to severe outcomes, such as liver failure.[1,4] Several studies have indicated that the tumor patients undergoing chemotherapy with inactive HBV infection, which is defined as negative or low virus load and normal liver enzyme could develop active viral replication and liver function damage.[2] The same findings even could be seen in patients with single hepatitis B core antibody (HBcAb) positive.[3] Tumor chemotherapy may impress the specific antiviral immune response and disrupt the balance of immune system and HBV. Studies found that common chemotherapy drugs, such as cyclophosphamide and prednisone, could suppress the HBV specific humoral and cellular immunity via different mechanisms.[5–6] Based on above, the risk of HBV infection is greatly increased during and after tumor chemotherapy. This is why the tumor patients undergoing chemotherapy were listed as one of high risk groups in the guidelines of China and world health organization and were recommended to accept prophylactic injection of HBV vaccine and monitor the antibody level to maintain effective immune protection.[7–8]\n\n2 Case presentation\nHere we report a 58-year-old Chinese woman with lymphoma was admitted to our hospital for asthenia, nausea, vomiting, and abnormal liver function lasting over 1 week. On admission, her serology was found to be positive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), negative for hepatitis B surface antibody (HBsAb) and negative for antibodies of hepatitis C virus, hepatitis A virus, hepatitis E virus, and human immunodeficiency virus. Her serum blood hepatitis B virus-deoxyribonucleic acid (HBVDNA) concentration was 2.05 × 106 copies/mL (limit of detection by polymerase chain reaction: 500 copies/mL). Her alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) levels were 581 U/L (normal 0–45 U/L), 324 U/L (normal 0–37U/L), and 38.4 μmol/L (normal 0–19.1 μmol/L), respectively. Her albumin, globulin, α-fetoprotein, and complete blood counts were all within the upper limits of normal. The enhanced computed tomography scan of the upper abdomen showed no abnormal imaging result. Based on typical clinical findings and previous history, the patient was diagnosed as acute hepatitis B. Then, the patient was administered for antiviral treatment with entecavir (0.5 mg daily) and glycyrrhizic acid agent. After 4 weeks’ treatment, her serum ALT and AST levels were decreased to almost normal limits and the HBVDNA concentration fell below detectable levels (500 copies/mL). Six weeks after entecavir therapy initiation, the patient presented E antigen serological conversion and her HBsAg disappeared after 9 weeks. Twelve weeks after treatment, her hepatitis B surface antibody (HBsAb) was tested for positive and then stopped entecavir administration (Fig. 1).\n\nFigure 1 Time courses of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatitis B virus-deoxyribonucleic acid (HBVDNA) levels, and hepatitis B serological markers (HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb). The time admitted to the hospital was considered as 0 week.\n\nIt's worth noting that the patient had been vaccinated against hepatitis B 8 years ago and had reliable records of HBsAb positive. The latest test for HBsAb was nearly 8 weeks before hospitalization, when she was preparing to receive tumor chemotherapy. The exact titer was 78.6 IU/L, far more 7 times than 10 IU/L, the level which should provide enough protection and no need for revaccination according to the guidelines or position papers from the United States, China and World Health Organization (WHO).[7–9] In addition, her HBcAb and hepatitis B e antibody (HBeAb) levels were found to be negative, which suggested that HBsAb positive result was probably not to the result from postinfection immunity but vaccination.\n\nAbout 4 months ago, the patient was diagnosed as diffuse large B-cell lymphoma and then received the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) regimen. Significant side effects included anorexia, hair loss, and decreased leukocytes and platelets, whereas liver enzyme and bilirubin remained normal all the time. Symptomatic hepatitis B virus infection appears about 4 weeks after the chemotherapy ends. Calculating based on the patient's medical history and the incubation period of hepatitis B virus infection, the time point when she required the infection should be during the chemotherapy or in a very short time after it. Then, we decided to investigate her medical history in details even earlier from her latest HBsAb tested positive. According to her narration, she rested at home most of the time without suspect contact and injury. No invasive manipulation was executed during this period. Only one platelet unit was transfused for improvement of thrombocytopenia during the course of chemotherapy, about 5 weeks before the patient developed obvious acute hepatitis related symptoms. The donor's tests were recorded as bellows: normal liver function, weakly positive for HBsAb (6.82 IU/L), and negative for HBsAg, HBcAb, and HBeAb.\n\nWe then found the blood donor and asked for another investigation about 12 weeks after donating. The donor is a 28-year-old unmarried healthy male who had no history of hepatitis B and was not received hepatitis B virus vaccination. Like before, liver function test was normal and HBVDNA concentration was lower than the detectable limit (500 copies/mL). Surprisingly, obvious changes were found in serological markers of HBV, including HBsAb (255.82 IU/L), which was much higher than that tested 12 weeks ago, weakly positive HBcAb and positive HBeAb, which were all negative before blood donating. Based on above data, we concluded that the donor should be an asymptomatic acute HBV infected person and were recovering when he donated blood 12 weeks ago.\n\n3 Discussion\nCyclophosphamide and doxorubicin are all nonspecific cell cycle antineoplastic drugs, which can interact with or inhibit intracellular DNA and RNA and block the proliferation of cells.[10] Quick proliferative cells, including tumor cells and marrow cells and immune cells are more sensitive to this kind of drugs. Vincristine can inhibit microtubule assembly and induce tubulin self-association into coiled spiral aggregates, which are prone to influencing the same kinds of fast dividing cells as cyclophosphamide. Prednisone, as a kind of glucocorticoids, is thought to have a general suppressive effect on immunity, especially on specific cellular and humoral immune responses.[6] Interestingly, however, The HBV serological protective marker HBsAb had been found much higher than 10 IU/mL before the patient accepted the chemotherapy, which is considered to have full protective effect on hepatitis B virus. Because of the retrospective analysis, we couldn’t understand if the HBsAb titer of this patient declined after chemotherapy. To evaluate whether tumor chemotherapy could exert influence on the level of antibody, we selected 5 diffuse large B-cell lymphoma patients with HBsAb positive, detected the antibody levels before and after they underwent chemotherapy with CHOP regimen. The small-sample study and the case report above were approved by the International Review Board of Bethune International Peace Hospital. Both written and oral consents were obtained before the patients were rolled, and relevant data provided to the researchers were anonymized. Surprisingly, no obvious changes of HBsAb levels were found before and after chemotherapy (Fig. 2A). We also detected HBsAg epitope-specific cytotoxic T lymphocyte (CTL) responses by enzyme-linked immunospot assay (ELISPOT), which were achieved by patients’ peripheral blood mononuclear cells (PBMCs) incubated with HBV S region peptide 335–343 (WLSLLVPFV, 20 μg/mL), recombinant human interleukin-2 (rhIL-2, 50IU/mL) along with proper concentrations of rhIL-7 and rhIL-15 for 48 hours. Results showed that dramatic drops of epitope-specific CTL responses could be found after tumor chemotherapy ended (Fig. 2B). In theory, chemotherapy drugs above can inhibit both innate and specific immune responses. But for the intracellular microorganisms, such as hepatitis B virus, specific cellular immunity may play a key role in keeping the virus from invading and replicating.[11] This may explain why tumor patients receiving chemotherapy are prone to be infected with hepatitis B virus. For the tumor patients undergoing chemotherapy, HBsAb level beyond 10 IU/mL might not be used as security criteria and could not provide adequately protective effect.\n\nFigure 2 The effects of chemotherapy on HBV specific humoral and cellular immune responses in HBsAb-positive diffuse large B-cell lymphoma patients. A, The changes of HBsAb titers (IU/mL) in lymphoma patients before and after chemotherapy (n = 5). B, ELISPOT data showing the number of IFN-γ SFCs per million peripheral blood mononuclear cells (PBMCs) on stimulation with HBV S region peptide 335–343 (WLSLLVPFV, 20 μg/mL), recombinant human interleukin-2 (rhIL-2, 50IU/mL) along with proper concentrations of rhIL-7 and rhIL-15 for 48 hours in lymphoma patients before and after chemotherapy (n = 5). P values are shown.\n\nIn the retrospective investigation, we highly doubt that this patient's HBV infection was from a blood donor who was recuperating from subclinical HBV infection, for the patient received the donor's platelets because of chemotherapy induced thrombocytopenia. Interestingly, the donor showed HBsAb weakly positive and liver function normal before blood donating, whereas when we investigated after 6 weeks dramatic increase of HBsAb titer was marked and HBcAb and HBeAb both turned positive. We concluded that the donor suffered from subclinical HBV infection might still carry a tiny amount of HBV virus in the peripheral blood though HBsAg serological convention had occurred. We usually think that the risk of HBV infection via blood transfusion mainly come from the window period of donors.[12] Although this case hinted that the recovery stage of acute HBV infection might be regarded as occult HBV infection and be another dangerous period to the blood donors. Occult HBV infection is very easily misdiagnosed because of HBsAg negative, even along with HBsAb positive. The higher requirements should be put forward to screen blood donors, especially for the immune compromised recipients, such as tumor patients receiving chemotherapy.\n\nThough the weak HBsAb titer might be not enough to provide protection for tumor patients on chemotherapy, the effective protection level of HBsAb remains uncertain. Additional case reports and detailed mechanisms will be needed in the future.\n\n4 Conclusions\nThe case reported here demonstrated that tumor chemotherapy with the CHOP regimen might have weakened the immune system of this lymphoma patient and enhanced the body sensitivities to hepatitis B virus, then led to the infection, though she had a reliable record of HBsAb positive. We concluded that HBsAb-positive status, at least “weakly positive,” might not enough to provide protection for tumor patients on chemotherapy though this level was enough for health individuals. This case also suggested that the blood from donors recuperating from subclinical acute hepatitis B might still be infectious and cannot easily be screened though general serological methods before donation. This period might be another potential risk of transfusion transmitted HBV infection besides “window phase.”\n\nAbbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, CTL = cytotoxic T lymphocyte, ELISPOT = enzyme-linked immunospot assay, HBcAb = hepatitis B core antibody, HBeAg = hepatitis B e antigen, HBsAb = hepatitis B surface antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HBVDNA = hepatitis B virus-deoxyribonucleic acid, PBMCs = peripheral blood mononuclear cells, TBIL = total bilirubin.\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n[1] Yeo W Chan PK Zhong S \nFrequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors . J Med Virol \n2000 ;62 :299 –307 .11055239 \n[2] Voican CS Mir O Loulergue P \nHepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment . Ann Oncol \n2016 ;27 :2172 –84 .27803003 \n[3] Papadopoulos N Deutsch M Manolakopoulos S \nEfficacy of prophylactic antiviral therapy and outcomes in HBsAg-negative, anti-HBc-positive patients receiving chemotherapy: a real-life experience . Eur J Gastroenterol Hepatol \n2017 ;29 :56 –60 .27669175 \n[4] Li HR Huang JJ Guo HQ \nComparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy . J Viral Hepat \n2011 ;18 :877 –83 .21054683 \n[5] Shurlygina AV Mel’nikova EV Trufakin VA \nChronodependent effect of interleukin-2 on mouse spleen cells in the model of cyclophosphamide immunosuppression . Bull Exp Biol Med \n2015 ;158 :471 –4 .25708328 \n[6] Ashwell JD Lu FW Vacchio MS \nGlucocorticoids in T cell development and function . Annu Rev Immunol \n2000 ;18 :309 –45 .10837061 \n[7] Hou JL lai W \nThe guideline of prevention and treatment for chronic hepatitis B: a 2015 update . Zhonghua Gan Zang Bing Za Zhi \n2015 ;23 :888 –905 .26739464 \n[8] U.S. Public Health Service . Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis . MMWR Recomm Rep \n2001 ;50 :1 –52 .\n[9] WHO Publication . Hepatitis B vaccines: WHO position paper--recommendations . Vaccine \n2010 ;28 :589 –90 .19896455 \n[10] Rinaldi L Perini P Calabrese M \nCyclophosphamide as second-line therapy in multiple sclerosis: benefits and risks . Neurol Sci \n2009 ;30 :S171 –173 .19882369 \n[11] Guidotti LG Isogawa M Chisari FV \nHost-virus interactions in hepatitis B virus infection . Curr Opin Immunol \n2015 ;36 :61 –6 .26186123 \n[12] Allain JP Cox L \nChallenges in hepatitis B detection among blood donors . Curr Opin Hematol \n2011 ;18 :461 –6 .21912252\n\n",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000998:Antiviral Agents; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006147:Guanine; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D008223:Lymphoma; D008875:Middle Aged; D011239:Prednisolone; D065227:Transfusion Reaction; D014750:Vincristine",
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"pubdate": "2017-11",
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"title": "Hepatitis B virus infection in an HBsAb-positive lymphoma patient who received chemotherapy: A case report.",
"title_normalized": "hepatitis b virus infection in an hbsab positive lymphoma patient who received chemotherapy a case report"
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"abstract": "Acute respiratory distress syndrome remains the main cause of death among people with COVID-19. Although many immunomodulatory and antiviral drug therapies have been tested, the only effective therapy against severe COVID-19 pneumonia among the general population is a regimen of high-dose corticosteroids for cases of severe associated inflammation. In solid-organ transplant recipients with long-term immunosuppression, data on disease presentation and evolution are scarce, and the benefit of high-dose corticosteroids remains uncertain for cases of severe COVID-19 pneumonia. Here, we report 2 cases of COVID-19-related acute respiratory distress syndrome that occurred in lung transplant recipients in March and April 2020, respectively. Both cases of acute respiratory distress syndrome occurred in patients with long-term azithromycin treatment prescribed to prevent chronic allograft dysfunction. Acute respiratory distress syndrome was associated with severe inflammation and was cured after early administration of high-dose corticosteroids in both cases, with progressive and complete resolution of lung lesions evidenced on thoracic computed tomography scan. Our findings support the benefit of early high-dose corticosteroids in COVID-19-related acute respiratory distress syndrome with hyperinflammation in patients with long-term immunosuppression such as lung transplant recipients.",
"affiliations": "From the Service de Transplantation Pulmonaire et Centre de Compétence de la Mucoviscidose, Foch Hospital, Suresnes, France.",
"authors": "Brugiere|Olivier|O|;Neuville|Mathilde|M|;Le Balch|Pierre|P|;Le Tulzo|Yves|Y|;Brun|Anne-Laure|AL|;Hamid|Abdulmonem|A|;Beaumont|Laurence|L|;Roux|Antoine|A|;Jouneau|Stéphane|S|;Parquin|François|F|",
"chemical_list": "D008775:Methylprednisolone",
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"issue": "19(7)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
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"mesh_terms": "D000086382:COVID-19; D005260:Female; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D011183:Postoperative Complications; D012074:Remission Induction; D012128:Respiratory Distress Syndrome",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "COVID-19 in Lung Transplant Recipients: 2 Cases With Acute Respiratory Distress Syndrome Successfully Treated With High-Dose Corticosteroids.",
"title_normalized": "covid 19 in lung transplant recipients 2 cases with acute respiratory distress syndrome successfully treated with high dose corticosteroids"
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"abstract": "BACKGROUND\nBipartite combined oesophageal tumours are an exceedingly rare entity and much less is known about the natural history of these tumours following curative surgery. The authors present a case of a bipartite combined oesophageal tumour comprising of sarcomatoid carcinoma and small cell carcinoma with early postoperative recurrence.\n\n\nMETHODS\nA 63-year-old Chinese male with a smoking history presents with hemoptysis on a background of dysphagia and odynophagia for 1 month. An endoscopic evaluation found an exophytic oesophageal tumour with contact bleeding for which biopsy of this lesion returned as a malignant high-grade tumour where immunohistochemistry staining was unable to establish the lineage of the tumour. Differential diagnoses include sarcomatoid carcinoma and malignant undifferentiated sarcoma. With the provisional diagnosis of a high-grade oesopheageal sarcoma, the patient underwent minimally invasive McKeown's oesophagectomy. Final histological assessment was pT1bN0 with two histological types of malignancy within a single tumour-70% poorly differentiated spindle cell squamous carcinoma and small cell carcinoma. He was planned for adjuvant chemotherapy in view of the small cell carcinoma component after the resolution of the postoperative infective collections. A computed tomographic scan performed 4 months postoperatively demonstrated metastasis to the lung, pleura, thoracic nodes and liver. Biopsy of the largest lung nodule confirmed small cell neuroendocrine carcinoma with features similar to the small cell carcinoma component in the prior oesophagectomy specimen. He was thereafter initiated on palliative chemotherapy aimed at three weekly carboplatin and etoposide aimed at a total of 4 cycles with peglasta support. Etoposide was stopped during the first cycle due to asymptomatic bradycardia. The regime was then converted to carboplatin with irinotecan for 5 cycles. Repeat computed tomographic scan performed 3 weeks after the completion of chemotherapy showed a complete response of lung and liver metastasis and no evidence of local recurrence or distant metastasis.\n\n\nCONCLUSIONS\nThe management of bipartite combined oesophageal tumours should be guided by its more aggressive component. Bipartite combined oesophageal tumours with a small cell carcinoma component are believed to demonstrate aggressive tumour biology likened to that of primary oesophageal small cell carcinoma. Preoperative confirmation of a combined tumour may be challenging, and biopsy results may only yield one of the two components. The more aggressive component is usually a small cell carcinoma, for which the mainstay of therapy is platinum-based chemotherapy rather than surgery.",
"affiliations": "Department of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore. nicholette.goh@mohh.com.sg.;Department of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore.;Department of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore.;Department of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore.;Department of Pathology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore.;Department of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore.;Department of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore.",
"authors": "Goh|Nicholette|N|http://orcid.org/0000-0002-0379-9001;Yeo|Danson Xue Wei|DXW|;Amitbhai|Sanghvi Kaushal|SK|;Aung|Myint Oo|MO|;Ho|Yong Howe|YH|;Koura|Aaryan Nath|AN|;Rao|Jaideepraj|J|",
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"doi": "10.1186/s12957-019-1623-7",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 162310.1186/s12957-019-1623-7Case ReportA rare case of bipartite combined tumour of the oesophagus http://orcid.org/0000-0002-0379-9001Goh Nicholette nicholette.goh@mohh.com.sg 1Yeo Danson Xue Wei danson_xw_yeo@ttsh.com.sg 1Amitbhai Sanghvi Kaushal sanghvi_ka@ttsh.com.sg 1Aung Myint Oo myint_oo_aung@ttsh.com.sg 1Ho Yong Howe yong_howe_ho@ttsh.com.sg 2Koura Aaryan Nath koura_aaryan_nath@ttsh.com.sg 1Rao Jaideepraj jaideepraj_rao@ttsh.com.sg 11 grid.240988.fDepartment of General Surgery, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore 2 grid.240988.fDepartment of Pathology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, Singapore 6 5 2019 6 5 2019 2019 17 7918 3 2019 23 4 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\nBipartite combined oesophageal tumours are an exceedingly rare entity and much less is known about the natural history of these tumours following curative surgery. The authors present a case of a bipartite combined oesophageal tumour comprising of sarcomatoid carcinoma and small cell carcinoma with early postoperative recurrence.\n\nCase presentation\nA 63-year-old Chinese male with a smoking history presents with hemoptysis on a background of dysphagia and odynophagia for 1 month. An endoscopic evaluation found an exophytic oesophageal tumour with contact bleeding for which biopsy of this lesion returned as a malignant high-grade tumour where immunohistochemistry staining was unable to establish the lineage of the tumour. Differential diagnoses include sarcomatoid carcinoma and malignant undifferentiated sarcoma. With the provisional diagnosis of a high-grade oesopheageal sarcoma, the patient underwent minimally invasive McKeown’s oesophagectomy. Final histological assessment was pT1bN0 with two histological types of malignancy within a single tumour—70% poorly differentiated spindle cell squamous carcinoma and small cell carcinoma. He was planned for adjuvant chemotherapy in view of the small cell carcinoma component after the resolution of the postoperative infective collections. A computed tomographic scan performed 4 months postoperatively demonstrated metastasis to the lung, pleura, thoracic nodes and liver. Biopsy of the largest lung nodule confirmed small cell neuroendocrine carcinoma with features similar to the small cell carcinoma component in the prior oesophagectomy specimen. He was thereafter initiated on palliative chemotherapy aimed at three weekly carboplatin and etoposide aimed at a total of 4 cycles with peglasta support. Etoposide was stopped during the first cycle due to asymptomatic bradycardia. The regime was then converted to carboplatin with irinotecan for 5 cycles. Repeat computed tomographic scan performed 3 weeks after the completion of chemotherapy showed a complete response of lung and liver metastasis and no evidence of local recurrence or distant metastasis.\n\nConclusion\nThe management of bipartite combined oesophageal tumours should be guided by its more aggressive component. Bipartite combined oesophageal tumours with a small cell carcinoma component are believed to demonstrate aggressive tumour biology likened to that of primary oesophageal small cell carcinoma. Preoperative confirmation of a combined tumour may be challenging, and biopsy results may only yield one of the two components. The more aggressive component is usually a small cell carcinoma, for which the mainstay of therapy is platinum-based chemotherapy rather than surgery.\n\nKeywords\nOesophageal cancerSmall cell carcinomaCombined tumoursissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nBipartite combined oesophageal tumours are an exceedingly rare entity. Five-year survival for squamous cell carcinomas and adenocarcinomas of the oesophagus post-curative surgery is only 20–25% [1]. Much less is known about the natural history of combined tumours of the oesophagus. The authors present a case of a bipartite combined oesophageal tumour comprising of sarcomatoid carcinoma and small cell carcinoma with early postoperative recurrence.\n\nCase report\nOur patient is a 63-year-old Chinese male presenting with hemoptysis on a background of dysphagia and odynophagia for 1 month prior. He is a heavy smoker of 40 pack-years, has a history of hypertension and hyperlipidemia, and has not had any prior endoscopies. Physical examination was unremarkable. Given the presenting complaint of hemoptysis, a computed tomographic scan of his thorax was performed, revealing a polypoidal intraluminal soft tissue density in the upper third of the oesophagus (Fig. 1a, b).Fig. 1 a, b Computed tomographic scan of the chest demonstrating soft tissue mass in the upper third of the oesophagus (coronal and transverse cuts)\n\n\n\nAn endoscopic evaluation found an exophytic oesophageal tumour with contact bleeding situated 23–30 cm from the incisors (Fig. 2). Biopsy of this lesion revealed necrotic material and fragments of tumour tissue, for which the latter composed of polygonal to spindle cells associated with a fascicular arrangement in some areas. There was also significant mitotic activity and marked nuclear pleomorphism. Immunohistochemical staining for the tumour returned negative for S-100, HMB45, AE 1/3, Cam5.2, desmin, smooth muscle actin, caldesmon, CD117 and DOG-1. The pathological conclusion for the tumour biopsy was that of a malignant high-grade tumour for which the lineage could not be established given the limited tissue. Possible differential diagnoses include sarcomatoid carcinoma and malignant undifferentiated sarcoma. Further computed tomographic scans done for the staging of the malignancy did not reveal any metastasis. Preoperative lung function tests were normal, and there was no broncho-oesophageal fistula on bronchoscopy.Fig. 2 Endoscopic photograph of oesophageal tumour\n\n\n\nWith the provisional diagnosis of a high-grade oesopheageal sarcoma, the patient underwent minimally invasive McKeown’s oesophagectomy. Intraoperative findings were that of an upper oesophageal tumour (Fig. 3) without invasion into the airway or great vessels. The locoregional lymph nodes were not enlarged.Fig. 3 Resected specimen of minimally invasive McKeown’s oesophagectomy\n\n\n\nExamination of the specimen revealed an 11.5 × 5.3 cm polypoid mid-oesophageal tumour invading into the submucosa with clear resection margins. The tumour consisted of two histological types of malignancy within a single tumour—70% poorly differentiated spindle cell squamous carcinoma (Fig. 4) and small cell carcinoma (Fig. 5). On immunohistochemical staining, the nests of small cell carcinoma were positive for cytokeratin AE1/3 and cytoplasmic staining for the neuroendocrine marker synaptophysin. In contrast, the malignant spindle cells of the sarcomatoid carcinoma are negative for cytokeratin AE1/3 (Fig. 6). Lymphovascular invasion was negative, and none of the three lymph nodes excised were involved by malignancy. The pathological staging of the tumour was pT1bN0.Fig. 4 The oesophageal tumour is predominantly a sarcomatoid carcinoma composed of malignant spindle cells with overlying squamous cell carcinoma in situ (arrow). Original magnification × 100\n\nFig. 5 Nests of small cell carcinoma with scant cytoplasm are distributed among the malignant spindle cells with pleomorphic nuclei and ample eosinophilic cytoplasm. Original magnification × 200\n\nFig. 6 Nests of small cell carcinoma are positive for cytokeratin AE1/3 (arrows). Original magnification × 200\n\n\n\nPostoperative recovery was complicated by pneumonia with a right-sided pleural effusion. The pleural effusion was drained under radiological guidance, and mediastinal collections were conservatively managed with antibiotics. He was planned for adjuvant chemotherapy in view of the small cell carcinoma component after the resolution of the postoperative infective collections.\n\nA repeat computed tomographic scan of the thorax 3 months postoperatively to monitor for resolution of the infective collections revealed bilateral lung subcentimetre nodules. Interval repeat scan a month later demonstrated metastasis to the lung, pleura, thoracic nodes, and liver for which a biopsy of the largest lung nodule confirmed small cell neuroendocrine carcinoma. Immunohistochemical staining was positive for synaptophysin and chromogranin, with features similar to the small cell carcinoma component of the tumour in the prior oesophagectomy specimen. There were no squamous or spindle cell components seen in the lung biopsy. He had not received the intended adjuvant chemotherapy regime, and in light of the new metastasis, he was initiated on palliative chemotherapy aimed at three weekly carboplatin and etoposide aimed at a total of 4 cycles with peglasta support. Etoposide was stopped during the first cycle due to asymptomatic bradycardia. The regime was then converted to carboplatin with irinotecan for 5 cycles. Repeat computed tomographic scan performed 3 weeks after the completion of chemotherapy showed a complete response of lung and liver metastasis and no evidence of local recurrence or distant metastasis.\n\nDiscussion\nCombined tumours are part of an uncommon group of neoplasms that consist of more than one cell population. Other similar types of neoplasms include collision tumours and composite tumours. Collision tumours are inherently different from combined tumours in that they have two distinct cell populations originating from topographically separate sites, developing in juxtaposition without any or only minimal areas of intermingling [2, 3]. On the other hand, composite tumours which are characterised by two divergent lineages originate from the same neoplastic clonal proliferation [4].\n\nThe majority of oesophageal combined carcinomas are associated with small cell carcinoma, and a combination with squamous cell carcinoma is the most common [2]. It is postulated that these combined tumours arise from pluripotent cells present in the squamous epithelium or ducts of the submucosal glands, leading to a heterogenous differentiation within a single tumour [5–7]. According to the World Health Organization histological classification of tumours of the digestive system [8], oesophageal tumours can be broadly divided into epitheal, non-epithelial and secondary tumours, for which both spindle cell (squamous) carcinoma and small cell carcinoma are distinct entitites under epithelial tumours. Spindle cell carcinomas, also coined carcinosarcomas, are a rare variant of squamous cell carcinomas with a sarcomatoid spindle cell component. Macroscopically, these tumours demonstrate a polypoid growth pattern. On microscopic examination, most specimens show a gradual transition between carcinomatous and sarcomatous components [8].\n\nSmall cell carcinomas are considered to be poorly differentiated endocrine carcinomas and are described to be indistinguishable from its counterpart in the lung in terms of histological, immunohistochemical and clinical features [9]. Given the rarity of the combined oesophageal tumours, the biological behaviour of these neoplasms is not well established. Previously, Tadashi et. al [10] described that the small cell carcinoma component of combined oesophageal tumours confers extremely aggressive tumour biology and suggest that these tumours be managed as per primary small cell carcinomas.\n\nIn our patient, an endoscopically acquired biopsy of the tumour was that of a malignant high-grade tumour of unknown lineage, while imaging suggested a sarcomatoid carcinoma or malignant undifferentiated sarcoma.\n\nInitial management of the patient was based on that of an undifferentiated sarcoma. Despite resection with clear magins, our patient unfortunately developed early metastatic recurrence just 4 months postoperatively. Oesophageal sarcomas are extremely rare, and literature pertaining to their management is limited. A preoperative PET scan was not performed as it is not the standard of care for sarcomas [11]. En bloc oesophagectomy with radical lymphadenectomy is the recommended option for oesophageal sarcomas and is associated with a significant survival advantage [12]. Nonetheless, long-term survival tends to be poor with a high rate of local and metastatic recurrance [13].\n\nIn a small case series of three combined oesophageal tumours, Tadashi et al. [10] described the aggressive nature of the tumour with all three patients developing metastatic tumour recurrence soon after oesophagectomy and subsequent demise. Two of the three patients received postoperative adjuvant chemotherapy with a cisplatin-based regime. Metastatic recurrence was diagnosed 1 to 10 months postoperatively. Similar to our patient, the histology of the metastatic deposits in lymph nodes and skin was small cell carcinoma—supporting the postulation that the small cell component was responsible for its aggressive behaviour.\n\nAnother case series of two combined oesophageal tumours [2] demonstrates the poor prognosis of tumours with small cell component. These cases had confirmed small cell component on initial endoscopic biopsy, and thus, surgery was not considered. Both were stage II disease and received cisplatin-based chemotherapy and radiation but died of metastatic disease 7 and 15 months, respectively, after presentation. Hosokawa et al. [14] described five patients who underwent only oesophagectomy with curative intent, and all patients developed early relapse with a median survival of 7 months.\n\nPostoperative 5-year survival rate was significantly lower in patients with small cell carcinoma compared to patients with squamous cell carcinoma, and the presence of lymph nodal metastasis was a significant determinant [15]. Recurrence in resected primary oesophageal cancers of either squamous cell carcinoma or adenocarcinoma was detected in about 45 to 50% of patients within the first postoperative year [16–18], and the median time to developing recurrence was 12 months with no difference between squamous cell carcinoma and adenocarcinoma [16]. This is in contrast to patients with oesophageal small cell carcinoma who have a median survival time of 11–18 months following surgery [18, 19]. Situ et al. [18] found that regional lymph node involvement was the only significant prognostic factor for survival after surgical resection of oesopahgeal small cell carcinoma.\n\nPrimary oesophageal small cell carcinoma itself is a rare entity, and there are no strong recommendations for the optimal treatment regime. At present, treatment for localised disease is centred around systemic chemotherapy with the consideration of local treatment such as radiotherapy. The platinum-based chemotherapy regime would consist of etoposide plus platinum such as cisplastin or carboplatin—which is also the standard regimen for small cell carcinoma of the lung [2, 20–24]. Chemotherapy is well-established for the management of small cell lung cancer [25, 26], and extra-pulmonary small cell carcinoma is chemosensitive as well [27, 28]. Chemotherapy alone is recognised to improve survival in oesophageal small cell carcinoma [29], with further survival benefit with concurrent chemoradiotherapy for limited disease [15, 30, 31]. With the high frequency of early systemic relapse after local treatment and chemosensitivity of extra-pulmonary small cell carcinoma, chemotherapy has been the cornerstone of treatment of oesophageal small cell carcinoma. Our patient was also initiated on the same chemotherapy regimen.\n\nFor patients with metastatic small cell carcinoma of the oesophagus, small studies with limited data have shown longer survival with palliative chemotherapy [20, 23, 25]. On the other hand, oesophagectomy or radiotherapy alone is not recommended in insolation due to poor outcomes and should be combined with adjuvant or neoadjuvant platinum-based chemotherapy [20, 22]. The median survival of primary small cell carcinoma is about 8 months in patients with limited disease and 3 months in patients with extensive disease [22].\n\nConclusion\nThe management of bipartite combined oesophageal tumours should be carried out in accordance with its more aggressive component. Bipartite combined oesophageal tumours with a small cell carcinoma component are believed to possess aggressive tumour biology likened to that of primary oesophageal small cell carcinoma. Preoperative confirmation of a combined tumour may be challenging, and biopsy results may only yield one of the two components. The more aggressive component is usually a small cell carcinoma, for which the mainstay of therapy is platinum-based chemotherapy rather than surgery.\n\nAcknowledgements\nNot applicable\n\nFunding\nNot applicable\n\nAvailability of data and materials\nNot applicable\n\nAuthors’ contributions\nNG and YXWD reviewed and described the patient’s data, clinical features, treatment and outcomes; analysed the latest literature available including all previous cases in the field; and wrote the manuscript. HYH performed the pathohistological analyses and also contributed to the writing of the manuscript. JR was the main attending overseeing the care of this patient. All authors reviewed and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable\n\nConsent for publication\nCompleted consent form for participation is available from the corresponding author on reasonable request.\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. Mariette C Factors predictive of complete resection of operable esophageal cancer: review of 746 patients Gastroenterol Clin Biol 2002 26 5 454 462 12122354 \n2. Terada T Maruo H Esophageal combined carcinomas: immunohistochemical and molecular genetic studies World J Gastroenterol 2012 18 13 1545 1551 10.3748/wjg.v18.i13.1545 22509088 \n3. Spagnolo DV Heenan PJ Collision carcinoma at the esophagogastric junction: report of two cases Cancer 1980 46 12 2702 2708 10.1002/1097-0142(19801215)46:12<2702::AID-CNCR2820461228>3.0.CO;2-M 7448709 \n4. Nakata S Primary pulmonary collision cancer consisting of large cell carcinoma and adenocarcinoma Ann Thorac Surg 2005 80 1 340 342 10.1016/j.athoracsur.2003.12.053 15975404 \n5. Nishimaki T Composite tumor of the esophagus with tripartite differentiation Dig Dis Sci 1997 42 5 1041 1046 10.1023/A:1018897321851 9149060 \n6. Ugras S Primary composite tumour with bipartite differentiation of the esophagus Acta Chir Belg 2000 100 1 39 43 10776528 \n7. Ho KJ Small cell carcinoma of the esophagus: evidence for a unified histogenesis Hum Pathol 1984 15 5 460 468 10.1016/S0046-8177(84)80081-7 6327495 \n8. Hamilton SR Aaltonen LA World Health Organization Classification of Tumours 2000 Lyon Pathology and Genetics of Tumours of the Digestive System \n9. Tennvall J Johansson L Albertsson M Small cell carcinoma of the oesophagus: a clinical and immunohistopathological review Eur J Surg Oncol 1990 16 2 109 115 1691109 \n10. Tadashi T Esophageal composite carcinoma with tripartite differentiation: clinicopathological analysis of three cases Esophagus 2005 2 2 91 96 10.1007/s10388-005-0039-3 \n11. Becher S Oskouei S PET imaging in sarcoma Orthop Clin North Am 2015 46 3 409 15, xi 10.1016/j.ocl.2015.03.001 26043054 \n12. Wu GX A population-based examination of the surgical outcomes for patients with esophageal sarcoma Ann Surg Oncol 2015 22 Suppl 3 S1310 S1317 10.1245/s10434-015-4815-6 26310279 \n13. Mege D, et al. Surgical management of esophageal sarcoma: a multicenter European experience. Dis Esophagus. 2018;(3):31. https://academic.oup.com/dote/article-abstract/31/3/dox146/4850444?redirectedFrom=fulltext.\n14. Hosokawa A Small cell carcinoma of the esophagus. Analysis of 14 cases and literature review Hepatogastroenterology 2005 52 66 1738 1741 16334769 \n15. Lv J Primary small cell carcinoma of the esophagus J Thorac Oncol 2008 3 12 1460 1465 10.1097/JTO.0b013e31818e1247 19057273 \n16. Lou F Esophageal cancer recurrence patterns and implications for surveillance J Thorac Oncol 2013 8 12 1558 1562 10.1097/01.JTO.0000437420.38972.fb 24389438 \n17. Mariette C Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease Cancer 2003 97 7 1616 1623 10.1002/cncr.11228 12655517 \n18. Situ D Surgical treatment for limited-stage primary small cell cancer of the esophagus Ann Thorac Surg 2013 95 3 1057 1062 10.1016/j.athoracsur.2012.11.014 23333059 \n19. Chen SB Treatment and prognosis of limited disease primary small cell carcinoma of esophagus Dis Esophagus 2011 24 2 114 119 10.1111/j.1442-2050.2010.01112.x 21040151 \n20. Hudson E Small cell oesophageal carcinoma: an institutional experience and review of the literature Br J Cancer 2007 96 5 708 711 10.1038/sj.bjc.6603611 17299393 \n21. Brenner B Small-cell carcinomas of the gastrointestinal tract: a review J Clin Oncol 2004 22 13 2730 2739 10.1200/JCO.2004.09.075 15226341 \n22. Casas F Primary small cell carcinoma of the esophagus: a review of the literature with emphasis on therapy and prognosis Cancer 1997 80 8 1366 1372 10.1002/(SICI)1097-0142(19971015)80:8<1366::AID-CNCR2>3.0.CO;2-D 9338459 \n23. Doherty MA McIntyre M Arnott SJ Oat cell carcinoma of esophagus: a report of six British patients with a review of the literature Int J Radiat Oncol Biol Phys 1984 10 1 147 152 10.1016/0360-3016(84)90421-8 6321409 \n24. Ku GY Small-cell carcinoma of the esophagus and gastroesophageal junction: review of the Memorial Sloan-Kettering experience Ann Oncol 2008 19 3 533 537 10.1093/annonc/mdm476 17947223 \n25. Agra Y Chemotherapy versus best supportive care for extensive small cell lung cancer Cochrane Database Syst Rev 2003 4 CD001990 \n26. Girling DJ Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party Lancet 1996 348 9027 563 566 10.1016/S0140-6736(96)02005-3 8774567 \n27. Lester JF Hudson E Barber JB Bladder preservation in small cell carcinoma of the urinary bladder: an institutional experience and review of the literature Clin Oncol (R Coll Radiol) 2006 18 8 608 611 10.1016/j.clon.2006.06.009 17051951 \n28. Levenson RM Jr Small cell carcinoma presenting as an extrapulmonary neoplasm: sites of origin and response to chemotherapy J Natl Cancer Inst 1981 67 3 607 612 6268879 \n29. Van Der Gaast A Chemotherapy as treatment of choice in extrapulmonary undifferentiated small cell carcinomas Cancer 1990 65 3 422 424 10.1002/1097-0142(19900201)65:3<422::AID-CNCR2820650308>3.0.CO;2-Y 1688727 \n30. Law SY Small cell carcinoma of the esophagus Cancer 1994 73 12 2894 2899 10.1002/1097-0142(19940615)73:12<2894::AID-CNCR2820731204>3.0.CO;2-M 8199985 \n31. Vos B Small cell carcinoma of the esophagus: a multicentre Rare Cancer Network study Dis Esophagus 2011 24 4 258 264 10.1111/j.1442-2050.2010.01133.x 21073624\n\n",
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"issue": "17(1)",
"journal": "World journal of surgical oncology",
"keywords": "Combined tumours; Oesophageal cancer; Small cell carcinoma",
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D018288:Carcinoma, Small Cell; D002296:Carcinosarcoma; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011183:Postoperative Complications; D011379:Prognosis",
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"title": "A rare case of bipartite combined tumour of the oesophagus.",
"title_normalized": "a rare case of bipartite combined tumour of the oesophagus"
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"abstract": "Men who receive bone-targeted therapy for metastatic prostate cancer are at increased risk of osteonecrosis of the jaw (ONJ). Development of ONJ has been associated with the administration of bone-targeted therapies in association with other risk factors. ONJ can be distressing for a patient because it can cause pain, risk of jaw fracture, body image disturbance, difficultly eating, and difficulty maintaining good oral hygiene. The aim of this article is to report results of an audit of prior assessment by oral and maxillofacial surgeons (OMFS) before initiation of bone-targeted therapies and whether it may reduce the risk of ONJ in patients receiving bone-targeted therapies for advanced cancers.",
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"authors": "Turner|Bruce|B|;Ali|Sacha|S|;Pati|Jhumur|J|;Nargund|Vinod|V|;Ali|Enamul|E|;Cheng|Leo|L|;Wells|Paula|P|",
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"title": "Retrospective Audit: Does Prior Assessment by Oral and Maxillofacial Surgeons Reduce the Risk of Osteonecrosis of The Jaw in Patients Receiving Bone-Targeted Therapies for Metastatic Cancers to the Skeleton?--Part II.",
"title_normalized": "retrospective audit does prior assessment by oral and maxillofacial surgeons reduce the risk of osteonecrosis of the jaw in patients receiving bone targeted therapies for metastatic cancers to the skeleton part ii"
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"abstract": "Nivolumab is a feasible therapy option in patients with advanced non-small cell lung cancer (NSCLC) who progress on first-line treatment. However, there is limited information about an overlapping toxicity of PD-1 inhibitors when administered following thoracic radiotherapy (TRT). Three of 25 patients with advanced NSCLC were treated with palliative or curative intent. Nivolumab was initiated as second or third-line therapy after TRT for recurrent or progressive disease. All 3 patients developed grade 3 pneumonitis at some point during nivolumab therapy. Herein, we describe 3 cases of pneumonitis in patients with NSCLC started on nivolumab following TRT. Imaging analysis was strongly consistent with heterogenous lung parenchyma changes in the irradiated lung volume receiving a total dose of 15-20 Gy. Pulmonary toxicity was manageable; however, interruption of immunotherapy was necessary.",
"affiliations": "Department of Radiation Oncology, University Hospital, LMU Munich.;Department of Radiation Oncology, University Hospital, LMU Munich.;Department of Radiation Oncology, University Hospital, LMU Munich.;Department of Radiation Oncology, University Hospital, LMU Munich.;Department of Radiation Oncology, University Hospital, LMU Munich.;Department of Radiation Oncology, University Hospital, LMU Munich.",
"authors": "Manapov|Farkhad|F|;Roengvoraphoj|Olarn|O|;Dantes|Maurice|M|;Marschner|Sebastian|S|;Li|Minglun|M|;Eze|Chukwuka|C|",
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"title": "Pneumonitis in Irradiated Lungs After Nivolumab: A Brief Communication and Review of the Literature.",
"title_normalized": "pneumonitis in irradiated lungs after nivolumab a brief communication and review of the literature"
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"abstract": "Today, direct oral anticoagulants (DOAC) are widely used alternatives to Vitamin-K antagonists (VKA). Women of reproductive age may become pregnant during anticoagulation and, while VKA carry an embryotoxic potential, the risk of DOAC embryopathy is unknown. As a result, some patients elect to terminate pregnancy for fear of DOAC embryotoxicity. To assess the risk of DOAC embryopathy, we reviewed cases of DOAC exposure in pregnancy collected from physicians, literature and pharmacovigilance systems of drug authorities and manufacturers. A total of 357 reports including duplicates were available from which 233 unique cases could be identified. Information on pregnancy outcome was available in only 137/233 cases (58.8 %): 67 live births (48.9 %); 31 miscarriages (22.6 %); 39 elective pregnancy terminations (28.5 %). In 93 cases (39.9 %) no outcome data were available (including 3 cases of ongoing pregnancy). Of the 137 pregnancies with reported outcomes, seven showed abnormalities (5.1 %) of which three (2.2 %) could potentially be interpreted as embryopathy: live birth with facial dysmorphism; miscarriage in week 10 with limb abnormality; elective pregnancy termination due to a foetal cardiac defect in a woman who had to terminate a previous pregnancy due to Fallot tetralogy. Within its limitations (small numbers, incomplete outcome data) our results do not indicate that DOAC exposure in pregnancy carries a high risk of embryopathy or that DOAC exposure per se should be used to direct patient counselling towards pregnancy termination. Pregnancy outcome data are inconsistently captured in pharmacovigilance databases indicating the strong need for a more robust system of reporting.",
"affiliations": "Jan Beyer-Westendorf, Center for Vascular Medicine and Department of Medicine III, Division of Angiology University Hospital \"Carl Gustav Carus\", Technische Universität Dresden, Fetscherstrasse 74; 01307 Dresden, Germany, Tel.: +49 351 4583659, Fax: +49 531 4584359, E-mail: jan.beyer@uniklinikum-dresden.de.",
"authors": "Beyer-Westendorf|Jan|J|;Michalski|Franziska|F|;Tittl|Luise|L|;Middeldorp|Saskia|S|;Cohen|Hannah|H|;Abdul Kadir|Rezan|R|;Arachchillage|Deepa Jayakody|DJ|;Arya|Roopen|R|;Ay|Cihan|C|;Marten|Sandra|S|",
"chemical_list": "D000925:Anticoagulants",
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"mesh_terms": "D000022:Abortion, Spontaneous; D000925:Anticoagulants; D001777:Blood Coagulation; D005260:Female; D006801:Humans; D050498:Live Birth; D011247:Pregnancy; D011256:Pregnancy Outcome",
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"title": "Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting.",
"title_normalized": "pregnancy outcome in patients exposed to direct oral anticoagulants and the challenge of event reporting"
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"abstract": "A 48-year-old male patient requiring extracorporeal membrane oxygenation (ECMO) support for hypoxaemic respiratory failure failed to achieve therapeutic anticoagulation with bivalirudin after continuous dose escalations, and continued to have recurrent fibrin stranding in the circuit over a 6-day course of treatment. Suspecting bivalirudin resistance, the patient was transitioned to argatroban and achieved a therapeutic response in less than 24 hours. The case describes the challenges of anticoagulation in ECMO supported patients. The interplay between bivalirudin metabolism, renal replacement therapy, and immunological effects leading to a heparin-like-effect, inflammatory mediators, and thrombotic burdens may all impact the clinical effect during bivalirudin therapy. The structural biochemistry of thrombin and bivalirudin likely plays a role in the presented patient's successful response to argatroban. Bivalirudin may fail at achieving therapeutic anticoagulation in patients with genetic thrombin mutations or structural defects that alter the binding pockets at the thrombin exosites.",
"affiliations": "Anesthesiology, Mayo Clinic Florida, Jacksonville, Florida, USA berlioz.beric@mayo.edu.;Critical Care, Mayo Clinic Florida, Jacksonville, Florida, USA.;Critical Care, Mayo Clinic Florida, Jacksonville, Florida, USA.;Critical Care, Mayo Clinic Florida, Jacksonville, Florida, USA.",
"authors": "Berlioz|Beric|B|;Kaseer|Haya S|HS|http://orcid.org/0000-0003-3556-8141;Sanghavi|Devang K|DK|;Guru|Pramod K|PK|",
"chemical_list": "D000925:Anticoagulants; D006629:Hirudins; D010446:Peptide Fragments; D010875:Pipecolic Acids; D011994:Recombinant Proteins; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban; C074619:bivalirudin",
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"mesh_terms": "D000925:Anticoagulants; D001120:Arginine; D003131:Combined Modality Therapy; D004351:Drug Resistance; D015199:Extracorporeal Membrane Oxygenation; D006629:Hirudins; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments; D010875:Pipecolic Acids; D011994:Recombinant Proteins; D012131:Respiratory Insufficiency; D013449:Sulfonamides",
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"title": "Bivalirudin resistance in a patient on veno-venous extracorporeal membrane oxygenation with a therapeutic response to argatroban.",
"title_normalized": "bivalirudin resistance in a patient on veno venous extracorporeal membrane oxygenation with a therapeutic response to argatroban"
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"abstract": "Immunotherapy is an effective new approach in the treatment of many malignancies. However, pancreatic ductal adenocarcinoma (PDAC) does not usually respond to immunotherapy. We discuss the case of a patient with metastatic microsatellite instability-high PDAC who had a prolonged response to single-agent pembrolizumab for almost 3 years.",
"affiliations": "Section of Medical Oncology, Division of Hematology/Oncology/Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.;Section of Medical Oncology, Division of Hematology/Oncology/Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.;Section of Medical Oncology, Division of Hematology/Oncology/Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.;Section of Medical Oncology, Division of Hematology/Oncology/Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.",
"authors": "Guedikian|Annie A|AA|;Randall|Megan E|ME|;Sharko|Anita|A|;Leslie|William T|WT|",
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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\n10.1159/000519181\ncro-0014-1414\nCase Report\nA Patient with Metastatic Microsatellite Instability-High Pancreatic Ductal Adenocarcinoma with a Prolonged Response to Single-Agent Pembrolizumab\nGuedikian Annie A.\nRandall Megan E.\nSharko Anita\nLeslie William T. *\nSection of Medical Oncology, Division of Hematology/Oncology/Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA\n*William T. Leslie, William_Leslie@rush.edu\nSep-Dec 2021\n27 9 2021\n27 9 2021\n14 3 14141417\n2 8 2021\n22 8 2021\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.\nImmunotherapy is an effective new approach in the treatment of many malignancies. However, pancreatic ductal adenocarcinoma (PDAC) does not usually respond to immunotherapy. We discuss the case of a patient with metastatic microsatellite instability-high PDAC who had a prolonged response to single-agent pembrolizumab for almost 3 years.\n\nKeywords\n\nMetastatic pancreatic ductal adenocarcinoma\nMismatch repair deficiency\nMicrosatellite instability\nProgrammed cell death protein 1 inhibitor\n==== Body\npmcIntroduction\n\nMetastatic pancreatic ductal adenocarcinoma (PDAC) is associated with a 5-year survival rate of 3% and a median overall survival on the order of months [1, 2]. Immunotherapy continues to be explored as a potential treatment option in pancreatic tumors with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). The FDA approval for the anti-PD-1 monoclonal antibody pembrolizumab stems from a pivotal phase II clinical trial that demonstrated the efficacy of PD-1 inhibition in 12 different dMMR cancer types, with objective radiographic responses in 53% of patients and complete responses in 21% of patients [3]. This trial included 8 patients (9%) with MSI-H PDAC: 2 patients had a complete response, 3 had a partial response, and 1 had stable disease, with a response rate of 62% in PDAC. Although the MSI-H/dMMR phenotype is rare in PDAC (0.8%) [4], the American Society of Clinical Oncology practice guidelines recommend routine testing for MSI-H or dMMR and treatment with pembrolizumab as the second-line therapy for patients testing positive for MSI-H or dMMR [5]. The National Comprehensive Cancer Network guidelines also recommend MSI and/or MMR testing in patients with locally advanced or metastatic PDAC and treatment with pembrolizumab only for MSI-H or dMMR tumors [6]. Long-term outcomes of treatment remain uncertain. We present a case of a patient with metastatic PDAC and an MSI-H phenotype who had a prolonged response to single-agent pembrolizumab.\n\nCase Report/Case Presentation\n\nThe patient is a 64-year-old female who was diagnosed with metastatic PDAC in March of 2017. She initially presented with weight loss, nausea, and abdominal pain. Imaging showed a large 7-cm invasive cystic pancreas mass with metastases to nearby lymph nodes. A biopsy showed invasive moderately differentiated adenocarcinoma. She received 8 cycles of FOLFIRINOX from March 2017 to July 2017, and a subsequent PET/CT showed a near-complete response. She had developed hematological toxicities including neutropenia, anemia, and thrombocytopenia, and the treatment regimen was changed to gemcitabine and paclitaxel in December 2017.\n\nIn March 2018, a CT scan showed disease progression as evidenced by extension of the primary pancreatic head mass, retroperitoneal lymphadenopathy, and an enlarged left paratracheal lymph node. Genomic testing was performed which revealed that the tumor was MSI-H with loss of MLH1 and PMS2. She began treatment with pembrolizumab every 3 weeks starting in March 2018. Just 2 months later, CT imaging showed a decrease in the size of the primary pancreatic tumor as well as the thoracic and abdominal lymphadenopathy, consistent with a treatment response. Follow-up CT scans in May 2019 continued to show sustained response to treatment. The patient continued to receive pembrolizumab for the next 34 months. She tolerated the treatment with no significant side effects.\n\nIn January 2021, imaging demonstrated slight progression and severe narrowing of the superior mesenteric vein. The patient had received 44 cycles of pembrolizumab by this time, and pembrolizumab was discontinued. The patient then enrolled in a protocol at the University of Chicago in March 2021 using an anti-CD137 monoclonal antibody.\n\nDiscussion/Conclusion\n\nPDAC is characterized by a low tumor mutational burden which results in poor response to immunotherapies [7]. However, a small subset of PDAC patients with dMMR have an accelerated accumulation of random mutations resulting in high levels of microsatellite instability [8]. The high mutation burden results in the synthesis of mutation-associated neoantigens presented by major histocompatibility complex class I molecules. This attracts cytotoxic T lymphocytes to the tumor microenvironment via T-cell receptor engagement with major histocompatibility complex [9]. However, T cells can be inactivated by binding of the PD-1/PD-L1 complex between T cells and tumor cells. Blockade of the PD-1-PD-L1 interaction with a monoclonal anti-PD-1 antibody such as pembrolizumab results in T-cell activation and destruction of the tumor [10]. While MSI-H/dMMR is rare in PDAC, our case demonstrates that this treatment approach can be highly effective in these patients. Currently, several clinical trials involving patients with MSI-H status are recruiting PDAC patients to assess the role of immunotherapy in the treatment of PDAC patients with MSI-H tumors [11].\n\nStatement of Ethics\n\nThis study was acknowledged by the Rush University Medical Center Non-Human Subject Research Committee, and ethical approval was not required. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nThis study did not receive funding.\n\nAuthor Contributions\n\nAnnie A. Guedikian contributed to literature review and manuscript writing. Megan E. Randall contributed to conception of the work, drafting the manuscript and revising it critically, and final approval for the version to be published. Anita Sharko contributed to conception of the work, reviewing the manuscript, and revising it critically. William T. Leslie contributed to conception of the work, drafting the manuscript and revising it critically, and final approval for the version to be published.\n\nData Availability Statement\n\nAll data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.\n\nAcknowledgment\n\nThe authors would like to acknowledge their patient who is a strong and resilient cancer survivor.\n==== Refs\nReferences\n\n1 Siegel RL Miller KD Jemal A Cancer statistics, 2016 CA Cancer J Clin 2019 Jan 66 (1) 7 30\n2 Tas F Sen F Keskin S Kilic L Yildiz I Prognostic factors in metastatic pancreatic cancer: older patients are associated with reduced overall survival Mol Clin Oncol 2013 1 (4) 788 92 24649248\n3 Le DT Durham JN Smith KN Wang H Bartlett BR Aulakh LK Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade Science 2017 357 409 13 28596308\n4 Hu ZI Shia J Stadler ZK Varghese AM Capanu M Salo-Mullen E Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations Clin Cancer Res 2018 24 (6) 1326 36 29367431\n5 Sohal DPS Kennedy EB Khorana A Copur MS Crane CH Garrido-Laguna I Metastatic pancreatic cancer: ASCO clinical practice guideline update J Clin Oncol 2018 36 2545 56 29791286\n6 Tempero MA Malafa MP Chiorean EG Czito B Scaife C Narang AK Pancreatic adenocarcinoma, version 1.2019 J Natl Compr Canc Netw 2019 17 202 10 30865919\n7 Yarchoan M Hopkins A Jaffee EM Tumor mutational burden and response rate to PD-1 inhibition N Engl J Med 2017 377 (25) 2500 1 29262275\n8 Lee V Murphy A Le DT Diaz LA Jr Mismatch repair deficiency and response to immune checkpoint blockade Oncologist 2016 Oct 21 (10) 1200 11 27412392\n9 Eso Y Seno H Current status of treatment with immune checkpoint inhibitors for gastrointestinal, hepatobiliary, and pancreatic cancers Therap Adv Gastroenterol 2020 13 1756284820948773\n10 Dudley JC Lin MT Le DT Eshleman JR Microsatellite instability as a biomarker for PD-1 blockade Clin Cancer Res 2016 Feb 22 (4) 813 20 26880610\n11 Schizas D Charalampakis N Kole C Economopoulou P Koustas E Gkotsis E Immunotherapy for pancreatic cancer: a 2020 update Cancer Treat Rev 2020 Jun 86 102016 32247999\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(3)",
"journal": "Case reports in oncology",
"keywords": "Metastatic pancreatic ductal adenocarcinoma; Microsatellite instability; Mismatch repair deficiency; Programmed cell death protein 1 inhibitor",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1414-1417",
"pmc": null,
"pmid": "34720950",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26880610;30865919;24649248;29367431;26742998;29262275;27412392;29791286;28596308;32247999;32913444",
"title": "A Patient with Metastatic Microsatellite Instability-High Pancreatic Ductal Adenocarcinoma with a Prolonged Response to Single-Agent Pembrolizumab.",
"title_normalized": "a patient with metastatic microsatellite instability high pancreatic ductal adenocarcinoma with a prolonged response to single agent pembrolizumab"
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"abstract": "A 74-year-old man with peripheral neuropathy due to diabetes presented with deliberate ingestion of 450 mg of pregabalin (PBG) over a period of 8 hours followed by altered mental status. A bedside electroencephalogram was performed to rule out nonconvulsive status epilepticus, which showed continuous triphasic waves (TWs) with slow background activity. He recovered after 48 hours of stopping PBG, and his repeat electroencephalogram after 72 hours did not show any TWs. We present a rare case of PBG-induced TWs thereby highlighting the extent of the etiologic spectrum of TWs and discussing the literature related to this association.",
"affiliations": "*Department of Neurology, and †Department of Nephrology, Narayana Health City, Bangalore, India.",
"authors": "Parekh|Mihir|M|;Dash|Gopal Krishna|GK|;Ahamed|Isthiaque|I|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000069583:Pregabalin",
"country": "United States",
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"issue": "40(5)",
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"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D018712:Analgesics, Non-Narcotic; D001927:Brain Diseases; D058256:Brain Waves; D006801:Humans; D008297:Male; D000069583:Pregabalin",
"nlm_unique_id": "7607910",
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"pubdate": "2017",
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"title": "Pregabalin Toxicity Manifesting as Reversible Encephalopathy With Continuous Triphasic Waves in Electroencephalogram.",
"title_normalized": "pregabalin toxicity manifesting as reversible encephalopathy with continuous triphasic waves in electroencephalogram"
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"abstract": "OBJECTIVE\nThe use of quetiapine as a drug to treat various substance use disorders as well as a drug of abuse is examined.\n\n\nCONCLUSIONS\nQuetiapine's effectiveness in treating schizophrenia and bipolar disorder is well-known; however, growing evidence has indicated that it may be useful in the treatment of various substance use disorders. Small-scale studies have been conducted to investigate the potential benefit of quetiapine in patients dependent on alcohol, cocaine, and amphetamines. The results of these two studies provide some evidence that quetiapine may benefit patients diagnosed with a mental illness who are also dependent on cocaine, amphetamines, or both, though more rigorous studies are needed. An unforeseen use of antipsychotics, specifically quetiapine, as drugs of abuse has emerged. Since antipsychotics are not classified as controlled substances, the majority of clinicians may not consider the diversion of antipsychotics for recreational purposes, but evidence of this is increasing, particularly in incarcerated individuals. Intravenous quetiapine abuse was first reported in the literature in 2005. Although most cases of quetiapine abuse have been reported in the correctional setting, inappropriate quetiapine use within the community has been documented. Thus far, all of the documented cases have involved patients with a prior history of substance abuse. Clinicians must be cognizant of the potential for quetiapine as a treatment for substance use disorders and as a drug of abuse.\n\n\nCONCLUSIONS\nQuetiapine is a promising treatment for substance use disorders alone or combined with other psychiatric diagnoses, such as bipolar disorder and schizophrenia. Quetiapine abuse has also been documented, particularly in the correctional setting.",
"affiliations": "University College of Pharmacy, Kingston, RI, USA.",
"authors": "Hanley|Michael J|MJ|;Kenna|George A|GA|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D013287:Illicit Drugs; D000069348:Quetiapine Fumarate",
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"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000437:Alcoholism; D019969:Amphetamine-Related Disorders; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D019970:Cocaine-Related Disorders; D003987:Dibenzothiazepines; D006801:Humans; D013287:Illicit Drugs; D000069348:Quetiapine Fumarate; D012559:Schizophrenia; D019966:Substance-Related Disorders",
"nlm_unique_id": "9503023",
"other_id": null,
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"pmid": "18359967",
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"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Quetiapine: treatment for substance abuse and drug of abuse.",
"title_normalized": "quetiapine treatment for substance abuse and drug of abuse"
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"abstract": "This article describes a case of continuous dentoalveolar neuropathic pain in which relief was obtained following repeated administration of intravenous infusions of a subanesthetic dose of ketamine. A 50-year-old female presented in 2006 with a 1-year history of constant sharp pain in the gingiva surrounding the maxillary left second premolar and second molar rated as 10/10 on a pain intensity scale. After multiple systemic medications failed to adequately manage the patient's pain, partial pain reduction was obtained (4/10) with daily use of methadone 50 mg in combination with application of a topical compound including lidocaine, amitriptyline, and carbamazepine to the affected area as needed. In July 2012, for reasons unrelated to the neuropathic pain condition, the patient underwent extraction of the maxillary right second premolar under intravenous sedation. Initially, a subanesthetic dose of ketamine was added to the sedation regimen for postoperative pain management; however, due to subsequent improvement of the dentoalveolar neuropathic pain, repeated intravenous infusions were recommended for further pain management. The patient's neuropathic pain condition was successfully managed by a total of five intravenous ketamine infusions repeated over a 4-year period of time. The patient's daily use of methadone was progressively reduced and finally discontinued. This case suggests a possible role for intravenous infusions of subanesthetic doses of ketamine as an adjuvant management option in patients suffering from intractable dentoalveolar continuous neuropathic pain conditions.",
"affiliations": null,
"authors": "Moreno-Hay|Isabel|I|;Lindroth|John|J|",
"chemical_list": "D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.11607/ofph.2023",
"fulltext": null,
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"issn_linking": null,
"issue": "32(2)",
"journal": "Journal of oral & facial pain and headache",
"keywords": null,
"medline_ta": "J Oral Facial Pain Headache",
"mesh_terms": "D001641:Bicuspid; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004368:Dry Socket; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine; D008875:Middle Aged; D008963:Molar; D009437:Neuralgia; D014098:Toothache",
"nlm_unique_id": "101624698",
"other_id": null,
"pages": "e22-e27",
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"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Continuous Dentoalveolar Neuropathic Pain Response to Repeated Intravenous Ketamine Infusions: A Case Report.",
"title_normalized": "continuous dentoalveolar neuropathic pain response to repeated intravenous ketamine infusions a case report"
} | [
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"abstract": "The development of inhibitors against factor VIII (FVIII) concentrates represents a significant treatment complication for hemophilia. Immune tolerance induction (ITI) therapy eradicates inhibitors in 60-80% of patients, resulting in a normal FVIII response. This article, based on presentations at the 6th International Coagulation Meeting, held in Barcelona, Spain, in September 2017, provides an overview of management approaches for patients with inhibitors and briefly tabulates four cases of ITI therapy (first-line or rescue ITI therapy in pediatric and adult patients) with successful outcomes. Switching FVIII product from recombinant FVIII to plasma-derived FVIII/VWF concentrate may be helpful in eradicating inhibitors. The rate of decline of inhibitor titer in the initial stages of ITI therapy is a good indicator of the success or failure of therapy, although prognostic biomarkers are needed. The development of the bispecific monoclonal antibody emicizumab, which was recently shown to reduce bleeding in inhibitor patients, offers a potential alternative therapeutic option. However, the benefits of inhibitor eradication, including a wider choice of cheaper therapeutic products for preventing and treating bleeds, suggest that at least one attempt of ITI therapy should be offered to patients who develop inhibitors.",
"affiliations": "Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy, elena.santagostino@policlinico.mi.it.;Hemostasis and Thrombosis Center, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California, USA.;HZRM - Haemophilia Centre Rhein-Main, Mörfelden-Walldorf, Germany.;Hematology Department, Hospital Universitario La Paz, Autónoma University, IdiPaz, Madrid, Spain.;Division of Hematology/Oncology, Department of Pediatrics and Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.",
"authors": "Santagostino|Elena|E|;Young|Guy|G|;Escuriola Ettingshausen|Carmen|C|;Jimenez-Yuste|Victor|V|;Carcao|Manuel|M|",
"chemical_list": "D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D019774:Blood Coagulation Factor Inhibitors; C000608208:emicizumab; C078147:F8 protein, human; D005169:Factor VIII",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000495454",
"fulltext": null,
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"issn_linking": "0001-5792",
"issue": "141(3)",
"journal": "Acta haematologica",
"keywords": "Factor VIII concentrate; Hemophilia; Immune tolerance induction; Inhibitors; Von Willebrand factor",
"medline_ta": "Acta Haematol",
"mesh_terms": "D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D019774:Blood Coagulation Factor Inhibitors; D003226:Congresses as Topic; D005169:Factor VIII; D006467:Hemophilia A; D006801:Humans; D007108:Immune Tolerance",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "151-155",
"pmc": null,
"pmid": "30783066",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Inhibitors: A Need for Eradication?",
"title_normalized": "inhibitors a need for eradication"
} | [
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"activesubstancename": "HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX"
... |
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"abstract": "The correction of severe hyponatraemia is complicated by practical and theoretical limitations of formulae used to predict response to treatment, and random errors in the measurement of sodium concentration. We report the case of an elderly woman with a symptomatic serum sodium concentration of 93 mmol/l. Correction of serum sodium unintentionally exceeded conventional targets but, as in the majority of such cases, there were no neurological sequelae.",
"affiliations": "John Radcliffe Adult Intensive Care Unit and Oxford Kidney Unit, Oxford University Hospitals NHS Trust, Oxford, UK.",
"authors": "MacEwen|Clare|C|;Watkinson|Peter|P|",
"chemical_list": "D000959:Antihypertensive Agents; D049993:Sodium Chloride Symporter Inhibitors",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000339101",
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"issn_linking": "1660-2110",
"issue": "120(4)",
"journal": "Nephron. Clinical practice",
"keywords": null,
"medline_ta": "Nephron Clin Pract",
"mesh_terms": "D000369:Aged, 80 and over; D000959:Antihypertensive Agents; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D006973:Hypertension; D007010:Hyponatremia; D049993:Sodium Chloride Symporter Inhibitors",
"nlm_unique_id": "101159763",
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"references": null,
"title": "Pitfalls in the management of severe hyponatraemia.",
"title_normalized": "pitfalls in the management of severe hyponatraemia"
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{
"abstract": "Carcinosarcoma of the kidney and renal pelvis (CSKP) is a rare and highly-aggressive malignancy characterized by rapid progression and widespread metastases. To date, few studies describe the natural history of the disease. We present a patient placed on pembrolizumab therapy for suspected metastatic colon cancer. The patient was found to have a right renal mass with caval extension on surveillance and ultimately underwent radical surgery revealing carcinosarcoma with positive PD-L1 expression with no evidence of recurrence to date. To our knowledge, this is the first case describing PD-L1 expression in CSKP and presents a novel pathway for future treatment algorithms.",
"affiliations": "University of Toledo Department of Urology and Renal Transplantation, Toledo, OH, United States.;University of Toledo Department of Urology and Renal Transplantation, Toledo, OH, United States.;University of Toledo Department of Urology and Renal Transplantation, Toledo, OH, United States.;RoMIUS Institute of Northwest Ohio, Toledo, OH, United States.;RoMIUS Institute of Northwest Ohio, Toledo, OH, United States.",
"authors": "Raghavan|Ashwin M|AM|;Giffen|Zane C|ZC|;Irwin|Patrick M|PM|;Mostafa|Hesham I|HI|;Buck|Bradley J|BJ|",
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"doi": "10.1016/j.eucr.2020.101261",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30149-2\n10.1016/j.eucr.2020.101261\n101261\nOncology\nPD-L1 pathway as a novel target in carcinosarcoma of the kidney and renal pelvis\nRaghavan Ashwin M. ashwin.raghavan@utoledo.edua∗ Giffen Zane C. a Irwin Patrick M. a Mostafa Hesham I. b Buck Bradley J. b a University of Toledo Department of Urology and Renal Transplantation, Toledo, OH, United States\nb RoMIUS Institute of Northwest Ohio, Toledo, OH, United States\n∗ Corresponding author. University of Toledo Department of Urology and Renal Transplantation, 3000 Arlington Ave., Toledo, OH, 43614-2598, Department of Urology. ashwin.raghavan@utoledo.edu\n23 5 2020 \n11 2020 \n23 5 2020 \n33 10126130 4 2020 17 5 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Carcinosarcoma of the kidney and renal pelvis (CSKP) is a rare and highly-aggressive malignancy characterized by rapid progression and widespread metastases. To date, few studies describe the natural history of the disease. We present a patient placed on pembrolizumab therapy for suspected metastatic colon cancer. The patient was found to have a right renal mass with caval extension on surveillance and ultimately underwent radical surgery revealing carcinosarcoma with positive PD-L1 expression with no evidence of recurrence to date. To our knowledge, this is the first case describing PD-L1 expression in CSKP and presents a novel pathway for future treatment algorithms.\n\nHighlights\n• PD-1 inhibitors offer a novel approach to patients with renal carcinosarcoma.\n\n• Unusual presentation as locally invasive disease with tumor thrombus.\n\n• Biphasic histopathology with aggressive clinical course.\n\n\n\nKeywords\nCarcinosarcomaOncologyPembrolizumabImmunotherapyRadical nephrectomy\n==== Body\nIntroduction\nCarcinosarcoma of the kidney and renal pelvis (CSKP) is a rare and highly-aggressive malignancy of both epithelial and mesenchymal origin. It is characterized by both rapid progression and widespread metastases portending a poor prognosis. To date, there have been few studies in the literature describing the disease, its natural history, and optimal treatment guidelines, with most cancers poorly responsive to chemoradiation. Pembrolizumb, a PD-1 inhibitor has shown promise in preliminary trials involving intermediate-poor risk metastatic renal cell carcinoma as well as carcinosarcoma of other tissues. We present a patient with previously colonic adenocarcinoma placed on pembrolizumab therapy following local recurrence after surgical therapy. The patient was found to have a right renal mass on surveillance imaging and interval development of renal vein and IVC involvement. The patient ultimately underwent radical nephrectomy with caval thrombectomy almost 1.5 years following initial discovery and histologic examination revealed high-grade undifferentiated carcinoma with chondromyxoid sarcomatoid elements consistent with carcinosarcoma. Tumor was found to be positive for PD-L1 expression. To our knowledge, this is the first case describing PD-L1 expression in CSKP with evidence of survival benefit and presents as a novel pathway for future treatment algorithms.\n\nCase presentation\nOur patient is a 66-year-old Caucasian male who was found to have a right renal mass on positron emission topography (PET-CT) for surveillance of known stage III colonic adenocarcinoma. Patient had previously undergone left hemicolectomy with development of local recurrence at the right pelvic sidewall and an additional pelvic mass, thought to be an enlarged lymph node. This encasing mass was found to be causing right ureteral obstruction. Patient underwent resection of this mass in conjunction with a Hartmann's procedure with end-colostomy. Histopathology showed evidence of moderately differentiated adenocarcinoma consistent with local recurrence of primary colonic malignancy, however the right pelvic mass/node was found to be a high-grade sarcomatoid lesion. At the time, this was thought to be a dedifferentiated component of patient's primary colon cancer. The patient underwent seven total cycles of targeted chemotherapy as well as palliative radiation therapy. Follow-up at completion of the patient's chemoradiation regimen showed enlarging retroperitoneal lymph nodes, however further treatment was deferred due to stable carcinoembryonic antigen (CEA) levels used to monitor disease progression. Subsequent PET-CT imaging showed interval growth in these retroperitoneal nodes with worsening right-sided hydronephrosis and discovery of an enlarging right renal mass.\n\nThe patient was seen by urology and underwent biopsy of the renal mass, having been previously started on pembrolizumab therapy due to concern for metastatic colon cancer. Renal biopsy showed poorly differentiated neoplasm favoring sarcomatoid renal cell carcinoma. A decision was made to pursue a right radical nephrectomy. The patient underwent preoperative staging with magnetic resonance (MR) angiogram showing malignant replacement of a majority of the right renal parenchyma with tumor thrombus extending to the renal vein ostia (Fig. 1). There was no definitive inferior vena cava (IVC) extension noted.Fig. 1 MRA abdomen showing heterogeneous tumor replacing most of the right renal parenchyma with focal invasion of the renal vein to the confluence of the renal vein ostia and IVC.\n\nFig. 1\n\nThe patient underwent a right radical nephrectomy with caval thrombectomy. Tumor thrombus was found to be limited to the confluence of the renal vein and IVC. Histologic examination revealed high-grade undifferentiated carcinoma with chondromyxoid sarcomatoid elements (Fig. 2) diffusely positive for GATA 3 on immunohistochemistry (IHC) indicative of urothelial origin (Fig. 3). Specimen was subsequently sent for PD-L1 expression testing which was 30% positive on tissue analysis. Final tumor stage was pT3cN0M0. The patient underwent an otherwise unremarkable postoperative course and as of a year postoperatively has been disease free while maintained on pembrolizumab therapy.Fig. 2 H&E stain showing sarcomatoid variant of urothelial cell carcinoma of renal pelvis with myxoid features at 100x magnification.\n\nFig. 2Fig. 3 GATA 3 IHC of tumor cells indicating urothelial origin.\n\nFig. 3\n\nDiscussion\nCarcinosarcoma of the kidney and renal pelvis (CSKP) is an extremely rare biphasic malignancy consisting of both epithelial and mesenchymal components. It has been sparsely described in the literature with fewer than 30 documented studies, mostly case reports and pathologic analyses. Within these studies, even fewer describe localized carcinosarcoma of the kidney and no study to our knowledge describes tumor thrombus extension to the renal vein or IVC. This malignancy tends to present as high-grade advanced disease and portends a poor prognosis. In a cohort of 43 patients selected from a SEER database with CSKP, there was a median cancer-specific survival (CSS) of 6 months and 1-year CSS of 30.2%.1 Nephrectomy and chemoradiation have been used independently or in conjunction with limited results – surgical resection traditionally has offered the longest survival benefit.\n\nThe definitive histopathologic etiology of this disease remains to be fully characterized and is somewhat controversial. There are, however, two leading theories. The monoclonal theory (divergence hypothesis) describes a common pluripotent progenitor that differentiates into separate epithelial and mesenchymal cell lines.2 Conversely, the multiclonal theory (convergence hypothesis) postulates separate stem cell lines that coalesce as part of a “collision event”, giving rise to individual sarcomatous and carcinomatous elements within a single tumor.\n\nBased on our patient's overall clinical course, there is evidence to suggest CSKP may be an immunogenic malignancy and respond to checkpoint inhibition targeting the programmed cell death 1 (PD-1) protein, which has been demonstrated in advanced renal cell carcinoma. Pembrolizumab and nivolumab in combination therapy have shown improvements in overall and progression-free survival over traditional tyrosine kinase inhibitors (e.g., Sunitinib) in phase III studies involving intermediate-poor risk metastatic renal cell carcinoma and are now recommended as preferred regimens in the most recent National Comprehensive Cancer Network (NCCN) guidelines.3 Additionally, there is evidence that pembrolizumab monotherapy shows benefit in intermediate-poor risk disease with overall objective response rate of 38% with median progression-free survival of 8.7 months in a cohort of 110 patients in a recent KEYNOTE-427 phase III trial.4 Pembrolizumab and nivolumab have also shown short-term tumor control of multi-focal metastatic ovarian carcinosarcoma, another rare and aggressive malignancy with similar histopathologic etiology, indicating a further need for studies evaluating their efficacy in management of this disease process.5\n\nConclusion\nCarcinosarcoma of the kidney and renal pelvis is a rare, highly-aggressive malignancy that usually presents as late-stage disease with no optimal treatment regimen. PD-1 inhibitors present as a potentially novel treatment option for these malignancies. Future research is need to characterize response to immunotherapy and optimal treatment regimens.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Wang Jue Wang Fen W. Kessinger Anne The natural history and outcomes of the patients with carcinosarcoma involving kidney and renal pelvis Adv Urology 2011 2011 693964 10.1155/2011/693964 \n2 Dong Biao Zhang Jian-Jian Chen Chao Diagnosis and treatment of carcinosarcoma of the renal pelvis: a Case report. Oncology Lett 8 1 2014 467 469 10.3892/ol.2014.2145 \n3 Motzer Robert J. Tannir Nizar M. McDermott David F. Nivolumab plus ipilimumab versus Sunitinib in advanced renal-cell carcinoma N Engl J Med 378 14 2018 1277 1290 10.1056/NEJMoa1712126 29562145 \n4 McDermott David F. Lee Jae-Lyun Szczylik Cezary 871PKEYNOTE-427 cohort A: pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (CcRCC) Ann Oncol 29 suppl l_8 2018 10.1093/annonc/mdy283.080 \n5 Dal Molin Graziela Z. Abrahão Carina M. Coleman Robert L. Response to pembrolizumab in a heavily treated patient with metastatic ovarian carcinosarcoma Gynecol Oncol Res Pract 5 6 18 Aug. 2018 10.1186/s40661-018-0063-3\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "33()",
"journal": "Urology case reports",
"keywords": "Carcinosarcoma; Immunotherapy; Oncology; Pembrolizumab; Radical nephrectomy",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101261",
"pmc": null,
"pmid": "32489894",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": "21785585;24959298;29562145;30147940",
"title": "PD-L1 pathway as a novel target in carcinosarcoma of the kidney and renal pelvis.",
"title_normalized": "pd l1 pathway as a novel target in carcinosarcoma of the kidney and renal pelvis"
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"abstract": "Although induction immunochemotherapy including high-dose cytarabine and rituximab followed by high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R-High-CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20-65 years. Patients received 1 cycle of R-High-CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R-High-CHOP/CHASER. Primary endpoint was 2-year progression-free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38-65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty-five patients completed ASCT. Two-year PFS was 77% (80% CI 68-84), which met the primary endpoint. Five-year PFS and overall survival were 52% (95% CI 34-68%) and 71% (95% CI 51-84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R-High-CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.",
"affiliations": "Department of Hematology and Oncology, Kasugai Municipal Hospital, Kasugai, Japan.;Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan.;JCOG Data Center, National Cancer Center, Tokyo, Japan.;Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.;Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.;Department of Hematology, National Kyushu Cancer Center, Fukuoka, Japan.;Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.;Department of Hematology, Hyogo Cancer Center, Akashi, Japan.;Center for Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Hematology, Kumamoto University Hospital, Kumamoto, Japan.;Department of Hematology, Gunma University Hospital, Maebashi, Japan.;Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Hematology, Tohoku University Hospital, Sendai, Japan.;First Department of Internal Medicine, Ehime University Graduate School of Medicine, Toon, Japan.;Department of Hematology, Hamamatsu University School of Medicine, Hamamatsu, Japan.;Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.;Department of Hematology, Akita University Graduate School of Medicine and Faculty of Medicine, Akita, Japan.;Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.;Division of Hematology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan.;Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Hematology, Saitama Cancer Center, Saitama, Japan.;Department of Hematology, NTT Medical Center Tokyo, Shinagawa-ku, Tokyo, Japan.;Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.;Department of Hematology, Tokyo Medical University, Tokyo, Japan.;Department of Hematology, Shiga General Hospital, Moriyama City, Japan.;Department of Hematology, Chiba Cancer Center, Chiba, Japan.;Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.;Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.;Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.;Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan.;Foundation for Promotion of Cancer Research, Tokyo, Japan.;Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan.",
"authors": "Ogura|Michinori|M|;Yamamoto|Kazuhito|K|;Morishima|Yasuo|Y|;Wakabayashi|Masashi|M|;Tobinai|Kensei|K|;Ando|Kiyoshi|K|;Uike|Naokuni|N|;Kurosawa|Mitsutoshi|M|;Gomyo|Hiroshi|H|;Taniwaki|Masafumi|M|;Nosaka|Kisato|K|;Tsukamoto|Norifumi|N|;Shimoyama|Tatsu|T|;Fukuhara|Noriko|N|;Yakushijin|Yoshihiro|Y|;Ohnishi|Kazunori|K|;Miyazaki|Kana|K|;Sawada|Kenichi|K|;Takayama|Nobuyuki|N|;Hanamura|Ichiro|I|;Nagai|Hirokazu|H|;Kobayashi|Hirofumi|H|;Usuki|Kensuke|K|;Kobayashi|Naoki|N|;Ohyashiki|Kazuma|K|;Utsumi|Takahiko|T|;Kumagai|Kyoya|K|;Maruyama|Dai|D|;Ohmachi|Ken|K|;Matsuno|Yoshihiro|Y|;Nakamura|Shigeo|S|;Hotta|Tomomitsu|T|;Tsukasaki|Kunihiro|K|;|||",
"chemical_list": "D000951:Antigens, Neoplasm; D003561:Cytarabine; D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D008558:Melphalan; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/cas.13719",
"fulltext": "\n==== Front\nCancer SciCancer Sci10.1111/(ISSN)1349-7006CASCancer Science1347-90321349-7006John Wiley and Sons Inc. Hoboken 10.1111/cas.13719CAS13719Original ArticleOriginal ArticlesClinical ResearchR‐High‐CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY OGURA et al.Ogura Michinori magnoliamic@me.com \n1\n\n2\nYamamoto Kazuhito \n3\nMorishima Yasuo \n3\nWakabayashi Masashi \n4\nTobinai Kensei \n5\nAndo Kiyoshi \n6\nUike Naokuni \n7\nKurosawa Mitsutoshi \n8\nGomyo Hiroshi \n9\nTaniwaki Masafumi \n10\nNosaka Kisato \n11\nTsukamoto Norifumi \n12\nShimoyama Tatsu \n13\nFukuhara Noriko \n14\nYakushijin Yoshihiro \n15\nOhnishi Kazunori \n16\nMiyazaki Kana \n17\nSawada Kenichi \n18\nTakayama Nobuyuki \n19\nHanamura Ichiro \n20\nNagai Hirokazu \n21\nKobayashi Hirofumi \n22\nUsuki Kensuke \n23\nKobayashi Naoki \n24\nOhyashiki Kazuma \n25\nUtsumi Takahiko \n26\nKumagai Kyoya \n27\nMaruyama Dai \n5\nOhmachi Ken \n6\nMatsuno Yoshihiro \n28\nNakamura Shigeo \n29\nHotta Tomomitsu \n30\nTsukasaki Kunihiro \n31\nJapan Clinical Oncology Group‐ Lymphoma Study Group (JCOG‐LSG) \n1 \nDepartment of Hematology and Oncology\nKasugai Municipal Hospital\nKasugai\nJapan\n\n2 \nDepartment of Hematology and Oncology\nNagoya Daini Red Cross Hospital\nNagoya\nJapan\n\n3 \nDepartment of Hematology and Cell Therapy\nAichi Cancer Center Hospital\nNagoya\nJapan\n\n4 \nJCOG Data Center\nNational Cancer Center\nTokyo\nJapan\n\n5 \nDepartment of Hematology\nNational Cancer Center Hospital\nTokyo\nJapan\n\n6 \nDepartment of Hematology and Oncology\nTokai University School of Medicine\nIsehara\nJapan\n\n7 \nDepartment of Hematology\nNational Kyushu Cancer Center\nFukuoka\nJapan\n\n8 \nDepartment of Hematology\nNational Hospital Organization Hokkaido Cancer Center\nSapporo\nJapan\n\n9 \nDepartment of Hematology\nHyogo Cancer Center\nAkashi\nJapan\n\n10 \nCenter for Molecular Diagnostics and Therapeutics\nKyoto Prefectural University of Medicine\nKyoto\nJapan\n\n11 \nDepartment of Hematology\nKumamoto University Hospital\nKumamoto\nJapan\n\n12 \nDepartment of Hematology\nGunma University Hospital\nMaebashi\nJapan\n\n13 \nDepartment of Medical Oncology\nTokyo Metropolitan Cancer and Infectious Diseases Center\nKomagome Hospital\nTokyo\nJapan\n\n14 \nDepartment of Hematology\nTohoku University Hospital\nSendai\nJapan\n\n15 \nFirst Department of Internal Medicine\nEhime University Graduate School of Medicine\nToon\nJapan\n\n16 \nDepartment of Hematology\nHamamatsu University School of Medicine\nHamamatsu\nJapan\n\n17 \nDepartment of Hematology and Oncology\nMie University Graduate School of Medicine\nTsu\nJapan\n\n18 \nDepartment of Hematology\nAkita University Graduate School of Medicine and Faculty of Medicine\nAkita\nJapan\n\n19 \nSecond Department of Internal Medicine\nKyorin University School of Medicine\nTokyo\nJapan\n\n20 \nDivision of Hematology\nDepartment of Internal Medicine\nAichi Medical University\nNagakute\nJapan\n\n21 \nDepartment of Hematology\nNational Hospital Organization Nagoya Medical Center\nNagoya\nJapan\n\n22 \nDepartment of Hematology\nSaitama Cancer Center\nSaitama\nJapan\n\n23 \nDepartment of Hematology\nNTT Medical Center Tokyo\nShinagawa‐ku\nTokyo\nJapan\n\n24 \nDepartment of Hematology\nSapporo Hokuyu Hospital\nSapporo\nJapan\n\n25 \nDepartment of Hematology\nTokyo Medical University\nTokyo\nJapan\n\n26 \nDepartment of Hematology\nShiga General Hospital\nMoriyama City\nJapan\n\n27 \nDepartment of Hematology\nChiba Cancer Center\nChiba\nJapan\n\n28 \nDepartment of Surgical Pathology\nHokkaido University Hospital\nSapporo\nJapan\n\n29 \nDepartment of Pathology\nNagoya University School of Medicine\nNagoya\nJapan\n\n30 \nFoundation for Promotion of Cancer Research\nTokyo\nJapan\n\n31 \nDepartment of Hematology\nNational Cancer Center Hospital East\nKashiwa\nJapan\n* Correspondence: Michinori Ogura, Department of Hematology and Oncology, Kasugai Municipal Hospital, Kasugai, Japan (magnoliamic@me.com).28 7 2018 9 2018 109 9 10.1111/cas.2018.109.issue-92830 2840 27 3 2018 19 6 2018 23 6 2018 © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Although induction immunochemotherapy including high‐dose cytarabine and rituximab followed by high‐dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R‐High‐CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20‐65 years. Patients received 1 cycle of R‐High‐CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R‐High‐CHOP/CHASER. Primary endpoint was 2‐year progression‐free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38‐65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty‐five patients completed ASCT. Two‐year PFS was 77% (80% CI 68‐84), which met the primary endpoint. Five‐year PFS and overall survival were 52% (95% CI 34‐68%) and 71% (95% CI 51‐84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R‐High‐CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.\n\nautologous stem cell transplantationcytarabinehigh‐dose chemotherapymantle cell lymphomarituximabNational Cancer Center Research and Development Fund23‐A‐1623‐A‐1726‐A‐429‐A‐3Ministry of Health, Labour and Welfare Grants‐in‐Aid for Cancer Research16‐620S‐120S‐6Health and Labour Sciences Research Grants for Clinical Cancer Research19‐2722‐29 source-schema-version-number2.0component-idcas13719cover-dateSeptember 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.7.1 mode:remove_FC converted:06.09.2018\n\n\nOgura \nM \n, \nYamamoto \nK \n, \nMorishima \nY \n, et al. R‐High‐CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY . Cancer Sci . 2018 ;109 :2830 –2840 . 10.1111/cas.13719 \n\n\n\n\nFunding information\n\n\nThis work was supported in part by the National Cancer Center Research and Development Fund (grant numbers 23‐A‐16, 23‐A‐17, 26‐A‐4, 29‐A‐3); and by the Ministry of Health, Labour and Welfare Grants‐in‐Aid for Cancer Research (grant numbers 16‐6, 20S‐1, 20S‐6), and Health and Labour Sciences Research Grants for Clinical Cancer Research (grant numbers 19‐27, 22‐29)\n\nClinical Trial registration: UMIN Clinical Trials Registration number: UMIN000001220\n==== Body\nAbbreviations\nASCTautologous hematopoietic stem cell transplantation\n\nCHASERcyclophosphamide, high‐dose cytarabine, dexamethasone, etoposide, and rituximab\n\nCHOPcyclophosphamide, doxorubicin, vincristine, and prednisone\n\nCIconfidence interval\n\nCPAcyclophosphamide\n\nCRcomplete response\n\nGELAGroupe d'Etude des Lymphomes de l'Adulte\n\nHDAChigh‐dose cytarabine\n\nHDChigh‐dose chemotherapy\n\nJCOG‐LSGJapan Clinical Oncology Group ‐ Lymphoma Study Group\n\nLEEDmelphalan, CPA, etoposide and dexamethasone\n\nLYSALymphoma Study Association\n\nMCLmantle cell lymphoma\n\nMIPImantle cell lymphoma international prognostic index\n\nMIPI‐cmodified combination of the Ki‐67 index and MIPI\n\nNHLnon‐Hodgkin lymphoma\n\nOSoverall survival\n\nORRoverall response rate\n\nPBSCperipheral blood stem cell\n\nPFSprogression‐free survival\n\nPSperformance status\n\nRrituximab\n\nR‐DHAPrituximab, dexamethasone, HDAC and cisplatin\n\nWHOWorld Health Organization\n\n1 INTRODUCTION\nMantle cell lymphoma (MCL) is a well‐recognized B‐cell lymphoma subtype that accounts for approximately 5% of all patients with NHL.1 The clinical course of MCL ranges from indolent to aggressive, with a poor prognosis and a median OS of about 3‐5 years with conventional chemotherapy.2, 3 The prognosis when using conventional chemoimmunotherapy remains poor. Two‐year PFS of 30% was reported in a phase II study of MCL patients treated with 6 cycles of rituximab, an anti‐CD20 antibody, and CHOP chemotherapy.4\n\n\nHowever, a randomized phase III study by the European MCL Network that compared myeloablative radiochemotherapy followed by ASCT with interferon‐α (IFN‐α) maintenance during the first remission after a CHOP‐like regimen demonstrated significant superiority of ASCT, with PFS of 45% in younger patients aged 65 years or less in patients with advanced‐stage MCL.5 Promising approaches to improving CR rate before ASCT, as well as PFS and OS, include modified induction therapy with HDAC‐based chemotherapy regimens and rituximab. These strategies are based on clinical studies in which the addition of rituximab to an HDAC‐containing regimen was reported to ensure tumor depletion in vivo while allowing the collection of PBSC with conserved engraftment capability that was devoid of tumor cells.6, 7\n\n\nA phase II MCL‐2 study by the Nordic Lymphoma Group including HDAC and rituximab prior to stem cell mobilization, followed by HDC and ASCT, demonstrated an excellent ORR (96%), with a CR rate of 56%, and PFS of 70% and OS of 70% after 6 years.8 Similar promising results were also reported in another phase II study of an induction regimen with R‐CHOP and R‐DHAP followed by ASCT, which was conducted by GELA.9 This regimen of 6 cycles of alternating R‐CHOP/R‐DHAP followed by consolidative HDC with ASCT resulted in a superior PFS compared with the regimen of 6 cycles of R‐CHOP followed by consolidative HDC with ASCT reported for a randomized phase III study by the European Mantle Cell Network (European MCL Network).10 Recently, rituximab maintenance after ASCT was shown to improve event‐free survival, PFS, and OS in younger patients with MCL in a randomized phase III study by LYSA.11 Thus, HDC with ASCT after intensive immunochemotherapy using rituximab and HDAC as first‐line treatment, followed by rituximab maintenance, appears to be the only current therapy that might improve the outcomes of younger patients with untreated advanced MCL.10, 11, 12 However, there was no established regimen for induction and HDC when the present study was planned.\n\nWe developed the R‐High‐CHOP/cyclophosphamide, high‐dose cytarabine, dexamethasone, etoposide, and rituximab (CHASER) regimen as an induction therapy, and LEED therapy as HDC. One cycle of the R‐High‐CHOP regimen was incorporated to enhance MCL tumor reduction. CHASER and CHASE were originally developed for both salvage therapy without a platinum agent to avoid renal toxicity and for in vivo efficacy of purging of B‐cell lymphoma cells during harvesting of autologous PBSC.13, 14 Based on promising data from a small pilot study of R‐High‐CHOP/CHASER/LEED in newly diagnosed MCL in a single institute of the Aichi Cancer Center (data not shown), we conducted a phase II study (JCOG0406) of this regimen using a new induction procedure comprising R‐High‐CHOP/CHASER13, 14 with rituximab and HDAC followed by HDC (LEED therapy) with ASCT.\n\n2 MATERIALS AND METHODS\n2.1 Trial information\nThis trial was a multi‐institutional phase II study conducted by JCOG‐LSG. The study protocol was approved by the Protocol Review Committee of JCOG and by the respective institutional review boards.\n\nWritten, informed consent was obtained from each patient before enrolment in accordance with the Declaration of Helsinki. The trial is registered with the UMIN Clinical Trials Registry (UMIN000001220).\n\n2.2 Eligibility criteria\nEligibility criteria included the following: newly pathologically diagnosed with MCL according to the WHO classification 2001;15 positive staining for cyclin D1 in the nucleus of lymphoma cells; positive for CD5 and CD20 on lymphoma cells by flow cytometry or by immunohistochemistry; age between 20 and 65 years; ECOG performance status (PS) of 0, 1, or 2; clinical stage II with bulky disease, stages III or IV according to the Ann Arbor staging system; lymphoma cells in peripheral blood ≤10 000/μL; no involvement of the central nervous system; at least 1 measurable lymphomatous lesion; no previous history of chemotherapy, radiation therapy, IFN, and/or antibody therapy; adequate organ function; and written, informed consent. Patients were excluded if they had a history of glaucoma, uncontrollable diabetes mellitus, uncontrollable hypertension, hepatitis B virus surface antigens or antibodies to hepatitis C virus, interstitial pneumonia, severe bacterial infection, or another active neoplasm.\n\n2.3 Treatment\nThe R‐High‐CHOP/CHASER regimen comprised 1 cycle of R‐High CHOP consisting of 1500 mg/m2 CPA and 75 mg/m2 doxorubicin followed by 3 cycles of CHASER consisting of 1200 mg/m2 CPA on day 3, 2 g/m2 cytarabine on days 4 and 5, 100 mg/m2 etoposide on days 3‐5, 40 mg/body weight dexamethasone on days 1, 3‐5 and 15, and 375 mg/m2 rituximab on days 1 and 15 (Figure 1). HDC in LEED therapy consisting of 130 mg/m2 melphalan, 60 mg/kg CPA, 500 mg/m2 etoposide, and 40 mg/body dexamethasone was started on day 36‐49 of the last CHASER therapy. PBSC were harvested after the 2nd cycle of CHASER, and further harvesting was added after the 3rd CHASER cycle if the number of PBSC was less than 4 × 106 cells/kg. Although the recommended number of harvested CD34‐positive cells was ≥4 × 106 cells/kg, patients obtaining ≥2 × 106 cells/kg could proceed to HDT with ASCT. Patients received sulfamethoxazole‐trimethoprim from induction therapy until 6 months after ASCT to prevent opportunistic infections caused by Pneumocystis jirovecii.\n\nFigure 1 Study design. Ara‐C, cytarabine; CPA, cyclophosphamide; CR, complete response; Dexa, dexamethasone; DXR, doxorubicin; ETP, etoposide; L‐PAM, melphalan; MCL, mantle cell lymphoma; PBSCT, peripheral blood stem cell transplantation; PD, progression of disease; PR, partial response; PS, performance status; PSL, prednisolone; SD, stable disease; VCR, vincristine\n\n2.4 Central pathology review\nA central pathology review was carried out as previously reported.16 Antigens routinely examined by immunohistochemistry included CD3, CD5, CD10, CD20, cyclin D1, SOX‐11, Ki‐67, and cyclin D1. Four hematopathologists reviewed the pathology specimens and classified them according to the WHO classification system 2001.15 The diagnosis by the central pathology review committee was used in this article.\n\n2.5 Mantle cell lymphoma international prognostic index (MIPI) and modified combination of the Ki‐67 index and MIPI (MIPI‐c)\nPatients were classified into low‐risk, intermediate‐risk, and high‐risk groups based on the 4 prognostic factors (age, PS, lactate dehydrogenase [LDH], and leukocyte count) according to MIPI.17 Patients were classified into low‐risk, low‐intermediate risk, high‐intermediate risk, and high‐risk groups according to MIPI‐c.18\n\n\n2.6 Response and toxicity criteria\nTumor assessments were carried out on all target lesions identified at baseline by PET and CT scans after R‐High‐CHOP/CHASER and after LEED therapy completion (day 50‐63 after ASCT). In patients in CR after LEED therapy, tumor assessment was done every 6 months for 2 years and, thereafter, every year for the next 3 years. Tumor response was determined by the Revised Response Criteria for Malignant Lymphoma 2007.19 Toxicities were evaluated according to the NCI Common Terminology Criteria for Adverse Events version 3.0.\n\n2.7 Statistical analysis and endpoints\nPrimary endpoint was 2‐year PFS. Planned sample size was 45, with an expected 2‐year PFS of 50%, a threshold of 30%, 1‐sided α of 10%, and power of 90% based on the results of conventional chemotherapy4 and toxicities of R‐high‐CHOP/CHASER/LEED (M. Ogura, unpublished data, 2000).\n\nSecondary endpoints were ORR, CR rate, proportion of CR and ORR after induction therapy, PFS, 5‐year PFS, OS, 2‐year OS, 5‐year OS, and toxicity. OS was calculated from the date of registration until death as a result of any cause or censored at the last follow‐up date. PFS was calculated from the date of registration to the date of relapse or progression, death as a result of any cause, or censored at the date of the last follow up. CR rate and ORR (CR + PR) and 95% CI were estimated by an exact binomial method. OS and PFS were estimated according to the Kaplan‐Meier method, and CI were estimated by Greenwood's formula. These analyses were carried out using SAS release 9.2 (SAS Institute, Cary, NC, USA).\n\n3 RESULTS\n3.1 Patient characteristics\nPrimary analysis of JCOG0406 was conducted in December 2014 (data cut‐off date was June 2014). Forty‐five patients were enrolled from 25 institutions between June 2008 and June 2012. Clinical characteristics of all enrolled patients are shown in Table 1. There were no ineligible patients. There were 41 men and 4 women, and median age was 59 years. PS was 0 or 1 for the vast majority (98%) of eligible patients. All patients had stage III (5/45) or stage IV (40/45) disease. Distribution of risk according to MIPI and MIPI‐c is shown in Table 1. Supplementary analyses of 44 patients whose formalin‐fixed paraffin‐embedded tissue blocks were available at the institution were conducted in June 2016 (data cut‐off date was June 2015).\n\nTable 1 Characteristics of patients in the present study (N = 45)\n\n\tN\t%\t\nGender\t\nFemale/Male\t4/41\t9/91\t\nAge (years)\t\nMedian\t59\t\t\nRange\t38‐65\t\t\nPS\t\n0/1/2\t38/6/1\t85/13/2\t\nClinical stage\t\nII bulky/III/IV\t0/5/40\t0/11/89\t\nCentral pathological review\t\nMCL\t45\t100\t\nInternational prognostic index (IPI)a\n\t\nL/LI/HI/H\t8/17/17/2\t18/39/39/4\t\nMantle cell lymphoma IPI (MIPI)a\n\t\nL/Int/H\t28/14/2\t64/32/4\t\nMIPI‐ca\n\t\nL/LI/HI/H\t21/13/8/2\t48/30/18/4\t\nSOX‐11a\n\t\nPositive/negative\t43/1\t98/2\t\nBulky mass, tumor size (cm)\t\nSize <5 cm\t29\t64\t\n5 cm ≤ Size < 10 cm\t7\t16\t\nSize ≥10 cm\t9\t20\t\nExtranodal lesions\t\n0‐1\t19\t42\t\n≥2\t26\t58\t\nBone marrow involvementa\n\t36\t82\t\nPB involvementa\n\t19\t43\t\na In IPI, MIPI, MIPI‐c, SOX11, and involvement of lymphoma cells in bone marrow and peripheral blood, the total number of patients was 44.\n\nH, high‐risk; HI, high‐intermediate risk; Int, intermediate‐risk; L, low‐risk; LI, low‐intermediate risk; MCL, mantle cell lymphoma; PB, peripheral blood; PS, performance status.\n\nJohn Wiley & Sons, Ltd3.2 Feasibility\nFlowchart of the clinical course of enrolled patients is shown in Figure 2. All 45 enrolled patients received R‐High‐CHOP, among whom 40 patients completed R‐High‐CHOP followed by 3 cycles of CHASER, and 5 patients did not (Figure 2). Although all 40 patients who completed the R‐High‐CHOP/CHASER induction therapy achieved CR or PR, 5 of these 40 patients did not receive high‐dose LEED therapy with ASCT because of insufficient harvest of auto‐PBSC in 4 patients and an adverse event in 1 patient. Therefore, 35 patients received high‐dose LEED therapy with ASCT. PBSC were harvested in 43 of 45 patients because induction therapy was discontinued at less than 2 cycles as a result of disease progression or patient's refusal in 1 case each. In 43 patients, median number of harvested PBSC was 3.80 (range 0.40‐38.40) × 106/kg cells. In 36 patients, ≥2 × 106/kg cells PBSC were harvested, whereas in 7 patients, less than 2 × 106/kg cells PBSC were harvested. Percentage of successfully collected PBSC was 84%. In 2 of 7 patients with insufficient harvest of auto‐PBSC, additional harvests were carried out outside the protocol, and they received high‐dose LEED therapy with ASCT. These 2 patients were finally judged as having protocol treatment.\n\nFigure 2 Flowchart of clinical course. Auto‐PBSCH, autologous peripheral blood stem cell harvest; PD, progression of disease\n\n3.3 Responses\nResponses of the 45 enrolled patients are shown in Table 2. ORR and CR rates after R‐High‐CHOP/CHASER induction therapy were 95.6% (95% CI 84.9‐99.5%) and 82.2% (95% CI 68.0‐92.0%), respectively. ORR and CR rates in all 45 patients after induction and LEED therapy were 77.8% (95% CI 62.9‐88.8%) and 71.1% (95% CI 55.7‐83.6%), respectively.\n\nTable 2 Rate of response to therapy\n\n\tInduction therapy\tHigh‐dose therapy (LEED)\t\nORR\tCR rate\tORR\tCR rate\t\nN\t43\t37\t35\t32\t\n% (/45a)\t95.6%\t82.2%\t77.8%\t71.1%\t\n% (/35b)\t–\t–\t100%\t91.4%\t\na N = 45: number of enrolled patients.\n\nb N = 35: number of patients who received ASCT.\n\nCR, complete response; LEED, melphalan, cyclophosphamide, etoposide and dexamethasone; ORR, overall response rate; ‐, not applicable.\n\nJohn Wiley & Sons, Ltd3.4 Progression‐free survival\nMedian follow‐up time for all enrolled patients was 3.7 years in the primary analysis. Two‐year PFS as the primary endpoint of all enrolled patients was estimated to be 77.3% (lower boundary of 80% CI 68.0%, which exceeded the threshold of 30%, and 95% CI 61.9‐87.1%), which met the primary endpoint (Figure 3A). PFS at 5 years was estimated to be 52.2% (95% CI 33.8‐67.8). PFS at 5 years for patients with low‐risk (N = 28), intermediate‐risk (N = 14), and high‐risk (N = 2) disease according to MIPI was 59.9% (95% CI 37.4‐76.6%), 51.6% (95% CI 21.6‐75.1%), and 0%, respectively (Figure 3B). PFS at 5 years for patients with low‐risk (N = 21), low‐intermediate risk (N = 13), high‐intermediate risk (N = 8), and high‐risk (N = 2) disease according to MIPI‐c was 66.2% (95% CI 38.4‐83.8%), 44.0% (95% CI 16.8‐68.4%), 58.3% (95% CI 18.0‐84.4%), and 0%, respectively (Figure 3C). PFS rates at 5 years for patients who received LEED therapy followed by ASCT (n = 35) and for patients who did not receive LEED therapy followed by ASCT for any reason including harvesting failure of PBSC (n = 10) were 54.8% (95% CI 33.0‐72.1%) and 42.2% (95% CI 11.1‐71.3%), respectively.\n\nFigure 3 Kaplan‐Meier curves of progression‐free survival (PFS) (A) of all 45 enrolled patients, and Kaplan‐Meier curves of PFS according to risk stratified by MIPI (n = 44) (B) and by MIPI‐c (n = 44) (C). MIPI, mantle cell lymphoma international prognostic index; MIPI‐c, modified combination of the Ki‐67 index and MIPI\n\n3.5 Overall survival\nOverall survival of all 45 enrolled patients is shown in Figure 4A. Eleven patients died (7 died of MCL, 3 died of secondary malignancy [1 acute myelogenous leukemia (AML), 1 adult T‐cell leukemia/lymphoma (ATL), and 1 diffuse large B‐cell lymphoma (DLBCL)]), and 1 died after postprotocol treatment). OS at 2 years and 5 years was estimated to be 91% (95% CI 77.7‐96.5%) and 71.0% (95% CI 50.9‐84.1%), respectively. Subgroup analysis of OS according to MIPI and MIPI‐c is shown in Figure 4B,C, respectively. OS rates at 5 years for patients who received LEED therapy followed by ASCT (n = 35) and for patients who did not receive LEED therapy followed by ASCT for any reason including harvesting failure of PBSC (n = 10) were 71.9% (95% CI 47.4‐86.4%) and 67.5% (95% CI 29.1‐88.3%), respectively.\n\nFigure 4 Kaplan‐Meier curves of overall survival (OS) (A) of all 45 enrolled patients, and Kaplan‐Meier curves of OS according to risk stratified by MIPI (n = 44) (B) and MIPI‐c (n = 44) (C). MIPI, mantle cell lymphoma international prognostic index; MIPI‐c, modified combination of the Ki‐67 index and MIPI\n\n3.6 Toxicity\nAll 45 treated patients were evaluated for toxicity (Table 3). The most common grade 4 toxicities were hematological; the percentage of patients with grade 4 neutropenia and thrombocytopenia was 80% and 0% in R‐High‐CHOP, 91% and 89% in CHASER, and 94% and 77% in LEED, respectively. There were no grade 4 nonhematological or nonlaboratory toxicities during the entire protocol treatment. In R‐High‐CHOP therapy, 1 grade 4 increased alanine aminotransferase (ALT) was observed, and grade 3 increased aspartate aminotransferase (AST) and hyponatremia were observed in 1 patient each. All of these adverse events were reversible.\n\nTable 3 Toxicity (N = 45) in all protocol treatments\n\nCTCAE 3.0\tG1\tG2\tG3\tG4\t% G3‐4\t\nLeukocytes\t0\t0\t1\t44\t100%\t\nHemoglobin\t0\t3\t27\t14\t91.1%\t\nPlatelets\t1\t0\t4\t40\t97.8%\t\nNeutrophils\t0\t0\t0\t45\t100%\t\nHypoalbuminemia\t27\t17\t0\t–\t0%\t\nBilirubin\t20\t5\t0\t0\t0%\t\nAST\t25\t6\t3\t0\t6.7%\t\nALT\t23\t12\t4\t1\t11.1%\t\nGGT\t15\t12\t2\t0\t4.7%\t\nCholesterol\t19\t1\t0\t0\t0%\t\nCreatinine\t10\t0\t0\t0\t0%\t\nHypernatremia\t11\t0\t0\t0\t0%\t\nHyponatremia\t38\t–\t2\t0\t4.4%\t\nHyperkalemia\t16\t1\t0\t0\t0%\t\nHypokalemia\t27\t–\t9\t1\t22.2%\t\nHypercalcemia\t1\t0\t0\t0\t0%\t\nHypocalcemia\t18\t7\t0\t0\t0%\t\nALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, common terminology criteria for adverse events; G, grade; GGT, gamma‐glutamyl transpeptidase; ‐, not applicable.\n\nJohn Wiley & Sons, LtdIn CHASER therapy, grade 4 hypokalemia was observed in 1 patient, and grade 3 hyponatremia and hypokalemia were observed in 1 and 3 patients, respectively. All of these adverse events were reversible.\n\nIn LEED therapy, grade 4 hypokalemia was observed in 1 patient, and grade 3 increased AST, increased ALT, hyponatremia, and hypokalemia were observed in 2, 3, 1, and 5 patients, respectively. All of these adverse events were reversible. In the present study, 3 types of opportunistic infection were observed in 5 patients, including grade 3 Pneumocystis pneumonia in 2 patients, grade 3 cytomegalovirus infection in 2 patients, and grade 3 adenovirus cystitis in 2 patients; one patients had cytomegalovirus infection followed by adenovirus cystitis, sequentially. Treatment‐related death occurred in 1 patient as a result of brain DLBCL after the development of Epstein Barr (EB) virus‐positive post‐transplantation lymphoproliferative disorder (PTLD) on day 159 after ASCT. Secondary malignancies including AML, prostate cancer, DLBCL, and ATL developed in 1 patient each. Incidence of secondary malignancies was 8.9% (95% CI 2.5‐21.2%).\n\n3.7 Pathological characteristics\nA central review of the pathological diagnosis was carried out for 45 enrolled patients, and all were confirmed as having cyclin D1‐positive MCL, although 1 patient was diagnosed as having CD5‐negative MCL. Although CD5 positivity was defined as an eligibility criterion in this study, the Central Pathology Review Committee decided that this patient was pathologically eligible, as CD5 negativity was not unequivocally confirmed by other techniques, including flow cytometry.\n\n4 DISCUSSION\nThis phase II study showed that treatment of untreated younger MCL patients with R‐High‐CHOP/CHASER followed by LEED HDC with ASCT resulted in high ORR and CR rates with durable PFS and OS and acceptable toxicity profiles. These results show that this regimen of R‐High‐CHOP/CHASER/LEED with ASCT can now be considered a standard treatment option in this population.\n\nIn the present study, PFS with the R‐High‐CHOP/CHASER/LEED with ASCT regimen was comparable with that reported for other regimens containing rituximab and HDAC followed by consolidative HDC with ASCT.8, 9, 10 Addition of both HDAC and rituximab (MCL2 study) dramatically improved the PFS (4‐year PFS of 73% and 6‐year PFS of 66%) compared to the PFS (4‐year PFS of 37%) with previous MCL‐1 protocol treatments.8, 20 The 5‐year event‐free survival in the GELA phase II study of 3 cycles of R‐CHOP and 3 cycles of R‐DHAP followed by ASCT was 64%.9 In the randomized phase III study by the European MCL Network, the 5‐year PFS in the experimental arm of 6 cycles of the alternating R‐CHOP/R‐DHAP regimen followed by consolidative HDC with ASCT and the control arm of 6 cycles of R‐CHOP followed by consolidative HDC with ASCT was 65% and 44%, respectively.10 The present results provide further data to support the treatment approach used in these prior studies. Combined with the present data, the present findings strongly suggest that HDAC‐based high‐dose consolidation therapy followed by ASCT has dramatically improved the prognosis of MCL compared with the prognosis reported with conventional immunochemotherapy such as R‐CHOP21 or with consolidative ASCT after a CHOP‐like regimen.5 Therefore, HDAC‐based high‐dose consolidation therapy followed by ASCT should be considered a standard treatment strategy for frontline treatment of younger MCL patients.\n\nRecently, rituximab maintenance after ASCT was reported to improve event‐free survival, PFS, and OS in younger patients with MCL.11 PFS at 4 years was 83% in the rituximab maintenance group versus 64% in the observation group (P < .001), and OS was 89% vs 80% (P = 0.04), respectively. In this study, no patients received rituximab maintenance, and PFS and OS at 4 years were almost the same as in the observation group. It is likely that adding rituximab maintenance to our regimen will improve outcomes further.\n\nIn order that as many patients as possible can proceed to ASCT, it is important to achieve CR or PR after the induction chemotherapy before ASCT. In the present study, ORR and CR rates after R‐High‐CHOP/CHASER induction therapy were 95.6% (95% CI 84.9‐99.5%) and 82.2% (95% CI 68.0‐92.0%), respectively. In the Nordic MCL‐2 study, ORR and CR rates including uncertain CR were 96.3% and 54.4%, respectively.8 In the GELA phase II study, ORR and CR rates after induction therapy were 95% and 57%, respectively.9 In the European MCL Network phase III study, ORR and the CR including unconfirmed CR rate after alternating R‐CHOP/R‐DHAP were 94% and 55%, respectively.10 In a phase III LYSA study to evaluate the usefulness of rituximab maintenance treatment, induction therapy was 4 cycles of R‐DHAP (6.7% of patients received an additional 3 cycles of R‐CHOP), and ORR and CR rates were 94% and 74% (including 34% with unconfirmed CR), respectively.11 Thus, the high CR rate of 82.2% in the present study is notable. Recently, retrospective data of a nationwide study of MCL in Japan were reported.22 In that study, 501 patients with newly diagnosed MCL with a median age of 67 (range 22‐90) years treated with rituximab‐containing therapy between 1992 and 2012 were analyzed. PFS and OS at 5 years were 25% and 60%, respectively. These results are lower than in the present study (PFS of 52% and OS of 71% at 5 years). Although comparison is difficult, the most probable reason for these differences might be differences in the study populations: The median age was 67 years in the nationwide retrospective study and 59 years in the present study, and 48% of patients received R‐CHOP without ASCT in the retrospective nationwide study, whereas all patients in the present study received treatment with the intent of ASCT.\n\nIn the present study, 22.2% of all enrolled patients did not receive ASCT, whereas in the Nordic MCL‐2 study 6.8% of all 160 eligible patients did not proceed to the high‐dose regimen because of toxicity or patient refusal.8 Five of the present 10 patients did not proceed to ASCT due only to insufficient harvest. In 7 of all 43 harvested patients, collected PBSC did not reach the threshold number of stem cells per protocol (≥2 × 106 CD34‐positive cells per kg body weight). Thus, the percentage of PBSC collected was 84%.\n\nAccording to the protocol, auto‐PBSC were harvested during the second CHASER and, if necessary, during the third CHASER, to avoid contamination of harvested auto‐PBSC with MCL cells. As highly efficient harvest of auto‐PBSC was observed during the first CHASER (data not shown), it is possible that a greater number of patients may proceed to ASCT if the harvest of auto‐PBSC is initiated during the first CHASER. Possibility that the harvest of auto‐PBSC in the early period of intensive induction chemotherapy may result in a highly efficient harvest was suggested in a recent phase II study.23 In that randomized phase II study by the Southwest Oncology Group that compared HyperCVAD/MA with rituximab and bendamustine with rituximab (S1106 study), stem cell collection was planned and carried out after the 3rd of 4 HyperCVAD/MA cycles. The R‐HyperCVAD/MA arm was prematurely closed as a result of failure of stem cell collection and/or delay of therapy because of hematological toxicity.23 Percentage (84%) of collected PBSC in the present study was higher than that (66%) reported in the alternating R‐CHOP/R‐DHAP regimen in the European MCL Network phase III study.10 PFS and OS at 5 years for patients who received LEED therapy followed by ASCT were relatively higher than those for patients who did not receive LEED therapy followed by ASCT for any reason, although the comparison is difficult because of the small sample size and because it was a subset analysis according to outcome.\n\nOnly 5 of the 45 eligible patients in the present study did not complete induction chemotherapy (R‐High CHOP/CHASER) because of toxicity (N = 3), disease progression (N = 1), or refusal (N = 1). These proportions were much lower than the reported 29% of patients who did not complete the planned 6 or 8 HyperCVAD/MA cycles,23 and the reported 63% of patients who did not complete the planned 4 HyperCVAD/MA cycles with 3 deaths during therapy in a phase II study by Gruppo Italiano Studio Linfomi,24 but was comparable to the 3% of such patients reported in the Nordic MCL‐2 study8 and the 6.7% of such patients reported in the GELA study.9\n\n\nOur R‐High‐CHOP/CHASER/LEED therapy was well tolerated. The nonrelapse mortality of 4.4% (2/45), which included 1 case with ATL who was a HTLV type‐1 carrier and developed acute type ATL after the completion of the protocol treatment, and 1 case with DLBCL as PTLD, is comparable with that reported in the Nordic MCL‐2 study (5%).8 Apart from these 2 secondary malignancies, 2 secondary malignancies including AML and latent prostatic carcinoma developed after postprotocol treatment. Although a patient who developed latent prostatic carcinoma completed protocol treatment including ASCT, a patient who developed AML did not receive LEED therapy followed by ASCT. The cause of these 2 secondary malignancies is difficult to determine, especially with respect to the relationship with protocol treatment, because they developed following postprotocol treatment. No grade 2 or greater increased creatinine levels occurred during any of the treatment cycles, because R‐High‐CHOP/CHASER/LEED therapy does not contain any platinum agents. In contrast, 8.3% (N = 5; 3 patients with grade 3 or 4) of 60 enrolled patients developed renal insufficiency in the GELA study during which they were treated with DHAP using cisplatin.9\n\n\nIn the present study, opportunistic infections including cytomegalovirus infection, adenovirus cystitis and Pneumocystis pneumonia were observed in 5 patients. Although the patients recovered from these infections, routine monitoring of the number of peripheral CD4+ lymphocytes was essential because intensive immunochemotherapy caused severe lymphocytopenia. After encouraging all participating institutions to do this examination, no further opportunistic infections were reported. In the present study, 22.2% of patients developed grade 3 or 4 hypokalemia. Grade 4 hypokalemia developed in 1 patient after both induction therapy and LEED high‐dose therapy. The most likely reason for hypokalemia may have been the frequent use of diuretics for increased body weight as a result of the considerable volume of infusion fluid for CHASER and LEED therapy.\n\nRecently, Hoster et al reported that a modified MIP1 that combines the Ki‐67 index with MIPI (MIPI‐c) provided a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in routine clinical practice.18 In the present study, a very good OS at 5 years of 95.2% (95%CI 70.7‐99.3%) in low‐risk group (N=21), and a very poor OS of 0% in high‐risk group (N=2) were also observed when risk group was stratified according to MIPI‐c.\n\nLast, the incorporation of new molecular targeted drugs into the current standard regimens is an attractive approach to improving the efficacy of treatment strategies for MCL patients. It has been reported that Bruton's tyrosine kinase inhibitors and phosphoinositide 3‐kinase inhibitors showed high efficacy in relapsed or refractory MCL patients.25 Further improvements of our regimen, including more efficient harvest of auto‐PBSC and/or incorporation of promising new molecular targeting agents, are important future goals.\n\nIn conclusion, R‐High‐CHOP/CHASER including HDAC and rituximab followed by LEED HDC with ASCT showed a high CR rate and durable PFS and OS in patients aged 65 years or younger with newly diagnosed advanced MCL. This regimen compares favorably with other regimens including HDAC, rituximab, and HDC with ASCT and can now be considered a standard treatment option for newly diagnosed younger patients with MCL.\n\nCONFLICTS OF INTEREST\nK.Y. has received research funding from AbbVie, ARIAD Pharmaceuticals, Celgene, Chugai, Eisai, Gilead Sciences, MSD, Novartis, Ono, Solasia Pharma, and Takeda. K.To. has received research funding from Abbvie, Ono, Eisai, GlaxoSmithKline, Janssen Celgene, Chugai, Pharmaceuticals, Mundipharma, Novartis, Pharmaceutical, SERVIER, and Takeda; and honoraria from Celgene, Chugai, Eisai, HUYA, Bioscience, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Mundipharma, Ono Pharmaceutical, Takeda, and Zenyaku Kogyo; and advisory remuneration from Celgene. K.A. has received research funding from KyowaHakko‐Kirin and Takeda. T.S. has received honoraria from KyowaHakko‐Kirin and Takeda. N.Ta. has received honoraria from Takeda. I.H. has received honoraria from Bristol‐Meyers‐Squibb and Celgene; and research funding from Bristol‐Meyers‐Squibb, KyowaHakko‐Kirn, and Chugai. H.N. has received honoraria from Takeda, Chugai Pharma, and Mundipharma; and research funding from Bayer Yakuhin, Takeda, Abbvie, Chugai Pharma, Janssen, Mundipharma, Celgene, AstraZeneca, Ono, Bristol‐Myers‐Squibb, Gilead Sciences, and Otsuka. K.U. has received research funding from Astellas, Kyowahakko‐Kirin, and Daiichi Sankyo; and honoraria from Novartis. K. Ohya received research funding from Ono Pharmaceutical, Chugai, Bristol‐Meyers‐Squibb, Kyowahakko‐Kirin, and Janssen; and honoraria from Novartis and Celgene. D.M. has received honoraria from Takeda, Janssen, Eisai, Biomedis International, Celgene, Kyowa Hakko Kirin, Fujifilm, Ono Pharmaceutical, Mundipharma International, Chugai Pharma, MSD, and Zenyaku Kogyo; and research funding from Takeda, Janssen, Eisai, Biomedis International, Celgene, Kyowa Hakko Kirin, Fujifilm, Ono Pharmaceutical, Mundipharma International, Chugai Pharma, MSD, Zenyaku Kogyo, GlaxoSmithKline, Abbvie, Astellas Pharma, Amgen Astellas, BioPharma, Otsuka, Novartis, Nippon Boehringer Ingelheim, Pfizer, Solasia Pharma, and AstraZeneca. S.Na. has received research funding from Chugai and Kyowahakko‐Kirin. T.H. has received advisory remuneration from SymBio. K.Tu has received research funding from Chugai Pharma, Mundipharma, Celgene, and Takeda. M.O., Y.Mo., M.W., N.U., M.K., H.G., M.T., K.No., N.Tsu., N.F., Y.Y., K.Ohni., K.Mi, K.S., H.K., N.K., T.U., K.K., K. Ohma. and Y.Ma. have no conflicts of interest to declare.\n\nACKNOWLEDGMENTS\nThe authors are grateful to the pathologists Dr Koichi Ohshima and Dr Naoya Nakamura for their support with the Central Pathology Review, to Dr Satoko Shimada for immunohistochemical analysis of SOX11 and Ki‐67, and to the members of the JCOG Data Center and JCOG Operations Office for their support in preparing the manuscript (Dr Kenichi Nakamura and Dr Kenichi Miyamoto), data management (Ms Yuko Watanabe), and oversight of study management (Dr Haruhiko Fukuda).\n==== Refs\nREFERENCES\n1 \n\nSchmidt \nC \n, \nDreyling \nM \n. Therapy of mantle cell lymphoma: current standards and future strategies . Hematol Oncol Clin North Am . 2008 ;22 :953 ‐963 .18954745 \n2 \n\nFisher \nRI \n, \nDahlberg \nS \n, \nNathwani \nBN \n, et al. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa‐associated lymphoid tissue and monocytoid B‐cell subcategories): a Southwest Oncology Group study . Blood . 1995 ;85 :1075 ‐1082 .7849295 \n3 \n\nYatabe \nY \n, \nSuzuki \nR \n, \nTobinai \nK \n, et al. Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1‐positive MCL and cyclin D1‐negative MCL‐like B‐cell lymphoma . Blood . 2000 ;95 :2253 ‐2261 .10733493 \n4 \n\nHoward \nOM \n, \nGribben \nJG \n, \nNeuberg \nDS \n, et al. Rituximab and CHOP induction therapy for newly diagnosed mantle‐cell lymphoma: molecular complete responses are not predictive of progression‐free survival . J Clin Oncol . 2002 ;20 :1288 ‐1294 .11870171 \n5 \n\nDreyling \nM \n, \nLenz \nG \n, \nHoster \nE \n, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression‐free survival in mantle‐cell lymphoma: results of a prospective randomized trial of the European MCL Network . Blood . 2005 ;105 :2677 ‐2684 .15591112 \n6 \n\nMagni \nM \n, \nDi Nicola \nM \n, \nDevizzi \nL \n, et al. Successful in vivo purging of CD34‐containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion . Blood . 2000 ;96 :864 ‐869 .10910898 \n7 \n\nVoso \nMT \n, \nPantel \nG \n, \nWeis \nM \n, et al. In vivo depletion of B cells using a combination of high‐dose cytosine arabinoside/mitoxantrone and rituximab for autografting in patients with non‐Hodgkin's lymphoma . Br J Haematol . 2000 ;109 :729 ‐735 .10929022 \n8 \n\nGeisler \nCH \n, \nKolstad \nA \n, \nLaurell \nA \n, et al. Long‐term progression‐free survival of mantle cell lymphoma after intensive front‐line immunochemotherapy with in vivo‐purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group . Blood . 2008 ;112 :2687 ‐2693 .18625886 \n9 \n\nDelarue \nR \n, \nHaioun \nC \n, \nRibrag \nV \n, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte . Blood . 2013 ;121 :48 ‐53 .22718839 \n10 \n\nHermine \nO \n, \nHoster \nE \n, \nWalewski \nJ \n, et al. Addition of high‐dose cytarabine to immunochemotherapy before autologous stem‐cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open‐label, phase 3 trial of the European Mantle Cell Lymphoma Network . Lancet . 2016 ;388 :565 ‐575 .27313086 \n11 \n\nLe Gouill \nS \n, \nThieblemont \nC \n, \nOberic \nL \n, et al. Rituximab after autologous stem‐cell transplantation in mantle‐cell lymphoma . N Engl J Med . 2017 ;377 :1250 ‐1260 .28953447 \n12 \n\nCheah \nCY \n, \nSeymour \nJF \n, \nWang \nML \n. Mantle cell lymphoma . J Clin Oncol . 2016 ;34 :1256 ‐1269 .26755518 \n13 \n\nOgura \nM \n, \nKagami \nY \n, \nTaji \nH \n, et al. Pilot phase I/II study of new salvage therapy (CHASE) for refractory or relapsed malignant lymphoma . Int J Hematol . 2003 ;77 :503 ‐511 .12841390 \n14 \n\nOki \nY \n, \nOgura \nM \n, \nKato \nH \n, et al. Phase II study of a salvage regimen using cyclophosphamide, high‐dose cytarabine, dexamethasone, etoposide, and rituximab in patients with relapsed or refractory B‐cell non‐Hodgkin's lymphoma . Cancer Sci . 2008 ;99 :179 ‐184 .17991293 \n15 \n\nJaffe \nES \n, \nHarris \nNL \n, \nStein \nH \n, et al. World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues , 3rd edn \nLyon : IARC Press ; 2001 .\n16 \n\nOgura \nM \n, \nItoh \nK \n, \nIshizawa \nK \n, et al. Phase II study of ABV (doxorubicin with increased dose, bleomycin and vinblastine) therapy in newly diagnosed advanced‐stage Hodgkin lymphoma: Japan Clinical Oncology Group study (JCOG9705) . Leuk Lymphoma . 2013 ;54 :46 ‐52 .22712838 \n17 \n\nHoster \nE \n, \nDreyling \nM \n, \nKlapper \nW \n, et al. A new prognostic index (MIPI) for patients with advanced‐stage mantle cell lymphoma . Blood . 2008 ;111 :558 ‐565 .17962512 \n18 \n\nHoster \nE \n, \nRosenwald \nA \n, \nBerger \nF \n, et al. Prognostic value of Ki‐67 Index, cytology, and growth pattern in mantle‐cell lymphoma: results from randomized trials of the European Mantle Cell Lymphoma Network . J Clin Oncol . 2016 ;34 :1386 ‐1394 .26926679 \n19 \n\nCheson \nBD \n, \nPfistner \nB \n, \nJuweid \nME \n, et al. Revised response criteria for malignant lymphoma . J Clin Oncol . 2007 ;25 :579 ‐586 .17242396 \n20 \n\nAndersen \nNS \n, \nPedersen \nL \n, \nElonen \nE \n, et al. Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant . Eur J Haematol . 2003 ;71 :73 ‐80 .12890145 \n21 \n\nLenz \nG \n, \nDreyling \nM \n, \nHoster \nE \n, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long‐term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG) . J Clin Oncol . 2005 ;23 :1984 ‐1992 .15668467 \n22 \n\nChihara \nD \n, \nAsano \nN \n, \nOmachi \nK \n, et al. Prognostic model for mantle cell lymphoma in the rituximab era: a nationwide study in Japan . Br J Haematol . 2015 ;170 :657 ‐668 .25953436 \n23 \n\nChen \nR \n, \nLi \nH \n, \nBernstein \nSH \n, et al. RB but not R‐HCVAD is a feasible induction regimen prior to auto‐HCT in frontline MCL: results of SWOG Study S1106 . Br J Haematol . 2017 ;176 (5 ):759 ‐769 .27992063 \n24 \n\nMerli \nF \n, \nLuminari \nS \n, \nIlariucci \nF \n, et al. Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicenter trial from Gruppo Italiano Studio Linfomi . Br J Haematol . 2012 ;156 :346 ‐353 .22145911 \n25 \n\nWang \nML \n, \nRule \nS \n, \nMartin \nP \n, et al. BTK with ibrutinib in relapsed or refractory mantle‐cell lymphoma . N Engl J Med . 2013 ;369 :507 ‐516 .23782157\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1347-9032",
"issue": "109(9)",
"journal": "Cancer science",
"keywords": "autologous stem cell transplantation; cytarabine; high-dose chemotherapy; mantle cell lymphoma; rituximab",
"medline_ta": "Cancer Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003561:Cytarabine; D003907:Dexamethasone; D018572:Disease-Free Survival; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D014182:Transplantation, Autologous; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "101168776",
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"pages": "2830-2840",
"pmc": null,
"pmid": "29957865",
"pubdate": "2018-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "26755518;22145911;29957865;23782157;17962512;28953447;7849295;15591112;27313086;12841390;10929022;22712838;18954745;25953436;11870171;18625886;10733493;17991293;26926679;22718839;12890145;17242396;10910898;27992063;15668467",
"title": "R-High-CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY.",
"title_normalized": "r high chop chaser leed with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma jcog0406 study"
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"abstract": "Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.",
"affiliations": "Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Yawkey 9 East, 55 Fruit Street, Boston, MA, 02114, USA, chhedam@mskcc.org.",
"authors": "Chheda|Milan G|MG|;Wen|Patrick Y|PY|;Hochberg|Fred H|FH|;Chi|Andrew S|AS|;Drappatz|Jan|J|;Eichler|April F|AF|;Yang|Daniel|D|;Beroukhim|Rameen|R|;Norden|Andrew D|AD|;Gerstner|Elizabeth R|ER|;Betensky|Rebecca A|RA|;Batchelor|Tracy T|TT|",
"chemical_list": "D010880:Piperidines; D011799:Quinazolines; D020123:Sirolimus; C452423:N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine",
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"issue": "121(3)",
"journal": "Journal of neuro-oncology",
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"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010880:Piperidines; D011799:Quinazolines; D020123:Sirolimus",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "627-34",
"pmc": null,
"pmid": "25503302",
"pubdate": "2015-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "10561324;11523724;10688254;12183421;12499271;14638850;2358840;15758009;16012795;15905307;15998902;16299247;16443950;17409986;17432710;17872411;18936474;19075262;19332730;19562254;21282542;22137795;22206795;22588883;23095881;23099652;23261661",
"title": "Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study.",
"title_normalized": "vandetanib plus sirolimus in adults with recurrent glioblastoma results of a phase i and dose expansion cohort study"
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"companynumb": "US-PFIZER INC-2016090188",
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"abstract": "The selective α1-adrenergic antagonist prazosin has been shown in multiple studies to be effective in targeting trauma-related nightmares in posttraumatic stress disorder. There are limited data regarding the effectiveness of another selective α1-adrenergic antagonist terazosin for the treatment of trauma-related nightmares. We present 4 cases in which terazosin was effectively used to treat nightmares as a second-line agent after prazosin failure. Further studies are needed to validate terazosin as an alternative to prazosin for the treatment of posttraumatic stress disorder-related nightmares.",
"affiliations": "James A. Haley Veterans' Hospital, Tampa, FL.",
"authors": "Nirmalani-Gandhy|Anjali|A|;Sanchez|Deborah|D|;Catalano|Glenn|G|",
"chemical_list": "D000317:Adrenergic alpha-Antagonists; C041226:Terazosin; D011224:Prazosin",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000077",
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"issn_linking": "0362-5664",
"issue": "38(3)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000317:Adrenergic alpha-Antagonists; D000368:Aged; D004325:Dreams; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011224:Prazosin; D011569:Psychiatric Status Rating Scales; D013313:Stress Disorders, Post-Traumatic; D016896:Treatment Outcome",
"nlm_unique_id": "7607910",
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"pmc": null,
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"references": null,
"title": "Terazosin for the treatment of trauma-related nightmares: a report of 4 cases.",
"title_normalized": "terazosin for the treatment of trauma related nightmares a report of 4 cases"
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"companynumb": "US-APOTEX-2015AP015573",
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"activesubstancename": "HYDROCHLOROTHIAZIDE\\LISINOPRIL"
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"abstract": "There is growing evidence for inflammation as a cause and/or consequence of seizures in epilepsy as certain inflammatory biomarkers are elevated. Interleukin (IL)-6, with pro-inflammatory and epileptogenic effects, can perpetuate seizures. Clinical and experimental data support its involvement in acute refractory situations, with some cases responding to treatment with tocilizumab, a humanized monoclonal antibody against the IL-6 receptor. We describe 2 pediatric cases of refractory epilepsy with an abrupt debut responding to tocilizumab. Advances in the knowledge of inflammatory biomarkers involved in epilepsy and the targeted treatment could have important benefits, especially in cases that are refractory to usual treatments.",
"affiliations": "Department of Neuropediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Member of the Clinical Group linked (GCV14/ER/6) to the Networked Biomedical Research Centre for Rare Diseases (CIBERER), Carlos III Health Institute, Madrid, Spain.;Department of Neuropediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain. Electronic address: mjimenezl@salud.madrid.org.;Department of Neuropediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Member of the Clinical Group linked (GCV14/ER/6) to the Networked Biomedical Research Centre for Rare Diseases (CIBERER), Carlos III Health Institute, Madrid, Spain.;Video-EEG monitoring Unit, Neurophysiology Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Department of Clinical Genetics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Department of Neuropediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Member of the Clinical Group linked (GCV14/ER/6) to the Networked Biomedical Research Centre for Rare Diseases (CIBERER), Carlos III Health Institute, Madrid, Spain.;Department of Neuropediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Member of the Clinical Group linked (GCV14/ER/6) to the Networked Biomedical Research Centre for Rare Diseases (CIBERER), Carlos III Health Institute, Madrid, Spain.",
"authors": "Cantarín-Extremera|Verónica|V|;Jiménez-Legido|María|M|;Duat-Rodríguez|Anna|A|;García-Fernández|Marta|M|;Ortiz-Cabrera|Nelmar Valentina|NV|;Ruiz-Falcó-Rojas|María Luz|ML|;González-Gutiérrez-Solana|Luis|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000091042:Reelin Protein; C000717127:RELN protein, human; C502936:tocilizumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jneuroim.2019.577142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5728",
"issue": "340()",
"journal": "Journal of neuroimmunology",
"keywords": "Epilepsy; FIRES/NORSE; Interleukin (IL)-6; Neuroinflammation; RELN; Tocilizumab",
"medline_ta": "J Neuroimmunol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6; D008297:Male; D019947:Receptors, Interleukin-6; D000091042:Reelin Protein; D013226:Status Epilepticus",
"nlm_unique_id": "8109498",
"other_id": null,
"pages": "577142",
"pmc": null,
"pmid": "31935626",
"pubdate": "2020-03-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: Experience in two patients.",
"title_normalized": "tocilizumab in pediatric refractory status epilepticus and acute epilepsy experience in two patients"
} | [
{
"companynumb": "ES-PFIZER INC-2020095184",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
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... |
{
"abstract": "Giant cell glioblastoma (GCG) is a rare subtype of classic glioblastoma multiforme with favorable prognosis and little is known about its metastatic potential. We hereby present a unique case of GCG in a 7-year-old child who developed spinal and spinal leptomeningeal metastasis during adjuvant therapy. She succumbed to it in spite of salvage therapy.",
"affiliations": "Department of Radiation Oncology, Dr. BRA IRCH, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, Dr. BRA IRCH, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, Dr. BRA IRCH, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, VMMC and Safdarjung Hospital, New Delhi, India.;Department of Radiation Oncology, Dr. BRA IRCH, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Biswas|Rituparna|R|;Gupta|Subhash|S|;Haresh|K P|KP|;Halder|Anirban|A|;Rath|G K|GK|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jcvjs.JCVJS_39_18",
"fulltext": "\n==== Front\nJ Craniovertebr Junction SpineJ Craniovertebr Junction SpineJCVJSJournal of Craniovertebral Junction & Spine0974-82370976-9285Medknow Publications & Media Pvt Ltd India JCVJS-9-20210.4103/jcvjs.JCVJS_39_18Case ReportGiant cell glioblastoma with spinal and spinal leptomeningeal metastasis in a child: A rare presentation of a rare tumor Biswas Rituparna Gupta Subhash Haresh KP Halder Anirban 1Rath GK Department of Radiation Oncology, Dr. BRA IRCH, All India Institute of Medical Sciences, New Delhi, India1 Department of Radiation Oncology, VMMC and Safdarjung Hospital, New Delhi, IndiaAddress for correspondence: Dr. Subhash Gupta, Department of Radiation Oncology, Dr. BRA IRCH, All India Institute of Medical Sciences, New Delhi, India. E-mail: drsubhash_oncologist@yahoo.inJul-Sep 2018 9 3 202 204 Copyright: © 2018 Journal of Craniovertebral Junction and Spine2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Giant cell glioblastoma (GCG) is a rare subtype of classic glioblastoma multiforme with favorable prognosis and little is known about its metastatic potential. We hereby present a unique case of GCG in a 7-year-old child who developed spinal and spinal leptomeningeal metastasis during adjuvant therapy. She succumbed to it in spite of salvage therapy.\n\nGiant cellglioblastomaleptomeningeal metastasissalvage therapy\n==== Body\nINTRODUCTION\nMalignant gliomas including glioblastoma multiforme (GBM) are extremely rare in children as compared to the adult population.[1] Giant cell glioblastoma (GCG) is a rare subgroup of GBM, which constitutes around 5% of all GBMs and hence immensely uncommon among the pediatric population.[2] Due to rarity of the cases, natural history of the entity is not well understood. It has been hypothesized that GCG has a better outcome and higher survival rates than GBM. However, it does not hold true in our index case, hence making this case unique.\n\nCASE REPORT\nAn otherwise well, 7-year-old girl presented with generalized seizures, left-sided limb weakness, nausea and vomiting of short duration. Neurological examination revealed the power of 3/5 in both left upper and lower limbs. General and other systemic examinations were unremarkable. Contrast-enhanced magnetic resonance imaging (CEMRI) brain showed a 45 mm × 45 mm × 60 mm[3] lobulated, infiltrating, heterogeneously enhancing solid cystic mass (hypointense on T1, hyperintense on T2, and heterogeneous contrast enhancement of solid component) in the right posterior frontal, anterior temporoparietal lobe, and right basal ganglia with significant perilesional edema causing midline shift [Figure 1]. She underwent right frontotemporal craniotomy and near-total resection of the tumor. Histopathology was suggestive of GBM, giant cell variant, and the WHO Grade IV. Tumor cells were immunopositive for glial fibrillary acidic protein and p53 while negative for isocitrate dehydrogenase-1; MIB-1 labeling index was 45%–50%. Adjuvant concurrent chemoradiation with daily oral temozolomide (TMZ = 75 mg/m2) during radiation therapy followed by six cycles of adjuvant TMZ (150–200 mg/m2, day 1–5; per oral; every 28 days) was planned. A radiation dose of 60 Gy in 30 fractions over 6 weeks by three-dimensional conformal radiotherapy was delivered. After completion of the first cycle of adjuvant TMZ, she suddenly developed upper backache and paraparesis. CEMRI brain and spine were performed which revealed a residual mass in the right temporal lobe (2.1 cm × 1.6 cm × 1.3 cm) [Figure 2] with intradural extramedullary lesion at D3–D4 level causing severe cord compression (2.6 cm × 1.47 cm × 1.05 cm) with fine nodular leptomeningeal enhancement in dorso-lumbar spinal cord, dorsal, and ventral cauda equina nerve roots suggestive of leptomeningeal drop metastases [Figure 3]. She was administered palliative radiotherapy of 20 Gy in five fractions over 1 week to the spinal metastatic site (D2–D5 level) and was started on intrathecal methotrexate (10 mg) weekly. Unfortunately, she succumbed to death after 3 weeks.\n\nFigure 1 Contrast-enhanced magnetic resonance imaging brain showing lobulated, infiltrating, heterogeneously enhancing solid cystic mass in the right posterior frontal, anterior temporo-parietal lobe and right basal ganglia with significant perilesional edema causing midline shift; (a) T1 axial view, (b) T1 postcontrast axial view, (c) T1 sagittal view, (d) T1 coronal view, (e) T2 axial view, (f) T2 flair axial view\n\nFigure 2 Contrast-enhanced magnetic resonance imaging brain showing a residual mass in right temporal lobe; (a) T2 sagittal view, (b) T2 coronal view, (c) T1 axial view\n\nFigure 3 Contrast-enhanced magnetic resonance imaging spine showing intradural extramedullary lesion at D3–D4 level causing severe cord compression with fine nodular leptomeningeal enhancement in dorsal spinal cord; (a) T1 postcontrast sagittal view, (b) T1 postcontrast coronal view, (c) T2 sagittal view\n\nDISCUSSION\nGCG, defined as glioblastoma with predominance of giant cells, is a very infrequent tumor and is often considered as a variant of GBM, classified as Grade IV tumor as per the WHO classification, although they might be considered as intermediate between Grade III and Grade IV gliomas as they are prognostically better in terms of survival than the Grade IV GBM. Previously termed as monstrocellular tumor due to the large size of its cells, the glial origin of these tumors has now been confirmed on electron microscopy and immunohistochemistry.[34] It usually occurs in adults and rarely presents in the pediatric age group. To the best of our knowledge, since 1952, <100 cases in the pediatric age group have been reported in the literature.[5] GCG predominates subcortically in the temporal and parietal lobes, but they infrequently originate in the cerebellum, the lateral ventricles, the optic chiasm, and the spinal cord. The lesion can be multifocal and spinal leptomeningeal metastases, and extraneural metastases have rarely been reported.[6] Our patient presented with right fronto-temporoparietal mass with the development of spinal and spinal leptomeningeal metastases during adjuvant therapy which is extremely rare in GCG, and no other case has been reported in the literature in this population. GCGs do not differ much in the clinical presentation from the classical GBM, although the duration of symptoms may be short. Similarly, the child in our case presented with symptoms of short duration. GCG is generally well circumscribed and homogeneous but may progress to infiltrative and heterogeneous mass lesion. Magnetic resonance (MR) may disclose a contrast-enhancing heterogeneous mass, with solid and cystic areas, hypointense on T1-weighted sequences, hyperintense on T2-weighted sequences surrounded by edema, as in our case. The addition of MR spectroscopy, diffusion-weighted imaging, and perfusion imaging to routine MRI may offer clues that allow for a better differential diagnosis between glioblastomas, the giant cell variety included, and other pathologies.[7] The surgical management is still uncertain due to the rarity of this cases but is known that gross total tumor resection treatment and adjuvant radiotherapy can improve survival rate from 5 to 13 months, similarly to GBM patients.[1] Combination radiation with TMZ represents the optimum adjuvant paradigm to delay tumor progression for patients presenting with GCG.[8] Our patient was treated with near-total tumor resection followed by concurrent chemoradiotherapy with TMZ followed by adjuvant TMZ. Unfortunately, during adjuvant therapy, she developed spinal and spinal leptomeningeal metastases which led to her early demise in spite of salvage therapy with local radiation and intrathecal methotrexate.\n\nCONCLUSION\nGCG is very rare in the pediatric age group, but when the diagnosis is confirmed, it offers a better prospect for such patients because of prolonged survival than classic GBM patients. Nevertheless, the clinical presentation and the biological features of the tumor, despite the giant cell morphology, should be well taken into account since a sinister course is also a possibility.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Valle-Folgueral JM Mascarenhas L Costa JA Vieira F Soares-Fernandes J Beleza P Giant cell glioblastoma: Review of the literature and illustrated case Neurocirugia (Astur) 2008 19 343 9 18726045 \n2 Palma L Celli P Maleci A Di Lorenzo N Cantore G Malignant monstrocellular brain tumours. A study of 42 surgically treated cases Acta Neurochir (Wien) 1989 97 17 25 2718792 \n3 Hadfield MG Silverberg SG Light and electron microscopy of giant-cell glioblastoma Cancer 1972 30 989 96 4342859 \n4 Kawano H Kubota T Sato K Goya T Arikawa S Wakisaka S Immunohistochemical study of giant cell in glioblastoma Clin Neuropathol 1995 14 118 23 7606897 \n5 Kleihues P Cavenee WK World Health Organisation classification of tumours: Pathology and genetics of tumours of the nervous system 2000 Lyon IARC Press 40 1 \n6 Chang CC Kuwana N Ito S Koike Y Kitamura H Spinal leptomeningeal metastases of giant cell glioblastoma associated with subarachnoid haemorrhage: Case report J Clin Neurosci 2001 8 56 9 11148082 \n7 Demir MK Hakan T Akinci O Berkman Z Primary cerebellar glioblastoma multiforme Diagn Interv Radiol 2005 11 83 6 15957093 \n8 Oh T Rutkowski MJ Safaee M Sun MZ Sayegh ET Bloch O Survival outcomes of giant cell glioblastoma: Institutional experience in the management of 20 patients J Clin Neurosci 2014 21 2129 34 25037316\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0974-8237",
"issue": "9(3)",
"journal": "Journal of craniovertebral junction & spine",
"keywords": "Giant cell; glioblastoma; leptomeningeal metastasis; salvage therapy",
"medline_ta": "J Craniovertebr Junction Spine",
"mesh_terms": null,
"nlm_unique_id": "101536746",
"other_id": null,
"pages": "202-204",
"pmc": null,
"pmid": "30443141",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "2718792;7606897;25037316;15957093;18726045;4342859;11148082",
"title": "Giant cell glioblastoma with spinal and spinal leptomeningeal metastasis in a child: A rare presentation of a rare tumor.",
"title_normalized": "giant cell glioblastoma with spinal and spinal leptomeningeal metastasis in a child a rare presentation of a rare tumor"
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"abstract": "Brivaracetam (BRV) is the latest approved antiepileptic drug and acts as a synaptic vesicle protein 2A ligand. The aim of the present study was to evaluate the efficacy and tolerability of BRV in the clinical setting.\n\n\n\nRetrospective, observational multicentre study.\n\n\n\nWe retrospectively collected clinical data of patients who received BRV in 10 epilepsy centres using a questionnaire that was answered by the reporting neurologist.\n\n\n\nData of 615 epilepsy patients treated with BRV were included in the study.\n\n\n\nEfficacy regarding seizure frequency and tolerability of BRV were evaluated. Descriptive statistics complemented by X2 contingency tests and effect sizes were performed.\n\n\n\nOverall, 44% of the patients had a decreased, 38% a stable and 18% an increased seizure frequency. 17% of patients achieved seizure freedom after initiation of BRV. The seizure frequency decreased in 63% of 19 patients with BRV monotherapy. 27% reported adverse effects, but only 10% of patients with monotherapy. Brivaracetam was significantly more often associated with decreased seizure frequency in levetiracetam (LEV) naïve patients (p=0.012), but BRV also led to a decreased seizure frequency in 42% of patients who had been treated with LEV before, including 17% of patients who were completely seizure free. Adverse effects under LEV improved in 62% and deteriorated in 2% of patients after the switch to BRV. At latest follow-up (mean±SD = 26.3±6.5 months), 68% were still on BRV.\n\n\n\nThe present study shows that results of the phase III studies on BRV match data from real life clinical settings. Brivaracetam seems to be a useful alternative in patients who have suffered adverse effects while taking LEV.",
"affiliations": "Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany hattemer@med.uni-marburg.de.;Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.;Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.;Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany.;Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.;Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.;Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.;Epilepsy Center Greifswald and Department of Neurology, Ernst-Moritz-Arndt-University, Greifswald, Germany.;Epilepsy Center Greifswald and Department of Neurology, Ernst-Moritz-Arndt-University, Greifswald, Germany.;Epilepsy Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.;Epilepsy Center Erlangen, Department of Neurology, University of Erlangen, Erlangen, Germany.;Epilepsy Center Tuebingen, Department of Neurology, University Hospital Tuebingen, Tuebingen, Germany.;Epilepsy Center Mainz, Department of Neurology, Johannes Gutenberg-University Mainz, Mainz, Germany.;Department of Neurology, University of Münster, Münster, Germany.;Sächsisches Epilepsiezentrum Radeberg gGmbH, Kleinwachau, Germany.;Hospital Center of Luxembourg, Luxembourg, Luxembourg.;Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.;Epilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany.",
"authors": "Menzler|Katja|K|0000-0001-8289-480X;Mross|Peter Michael|PM|;Rosenow|Felix|F|;Schubert-Bast|Susanne|S|0000-0003-1545-7364;Willems|Laurent Maximilian|LM|0000-0001-8226-1674;Zahnert|Felix|F|;Immisch|Ilka|I|;Fuest|Sven|S|;von Podewils|Felix|F|;Kunz|Rhina|R|;Hirsch|Martin|M|;Mueller|Tamara|T|;Marquetand|Justus|J|;Winter|Yaroslav|Y|;Langenbruch|Lisa|L|;Cicanic|Michal|M|;Beyenburg|Stefan|S|;Strzelczyk|Adam|A|;Knake|Susanne|S|",
"chemical_list": "D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam",
"country": "England",
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"doi": "10.1136/bmjopen-2019-030746",
"fulltext": "\n==== Front\nBMJ OpenBMJ OpenbmjopenbmjopenBMJ Open2044-6055BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bmjopen-2019-03074610.1136/bmjopen-2019-030746NeurologyOriginal Research15061713First clinical postmarketing experiences in the treatment of epilepsies with brivaracetam: a retrospective observational multicentre study http://orcid.org/0000-0001-8289-480XMenzler Katja 1Mross Peter Michael 1Rosenow Felix 123http://orcid.org/0000-0003-1545-7364Schubert-Bast Susanne 234http://orcid.org/0000-0001-8226-1674Willems Laurent Maximilian 2Zahnert Felix 1Immisch Ilka 1Fuest Sven 1von Podewils Felix 5Kunz Rhina 5Hirsch Martin 6Mueller Tamara 7Marquetand Justus 8Winter Yaroslav 9Langenbruch Lisa 10Cicanic Michal 11Beyenburg Stefan 12Strzelczyk Adam 123Knake Susanne 13\n1 \nEpilepsy Center Hessen, Department of Neurology, Philipps-University Marburg, Marburg, Germany\n\n2 \nEpilepsy Center Frankfurt Rhine-Main, Department of Neurology, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt am Main, Germany\n\n3 \nCenter for Personalized Translational Epilepsy Research (CePTER)\n\n4 \nDepartment of Child Neurology, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany\n\n5 \nEpilepsy Center Greifswald and Department of Neurology, Ernst-Moritz-Arndt-University, Greifswald, Germany\n\n6 \nEpilepsy Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany\n\n7 \nEpilepsy Center Erlangen, Department of Neurology, University of Erlangen, Erlangen, Germany\n\n8 \nEpilepsy Center Tuebingen, Department of Neurology, University Hospital Tuebingen, Tuebingen, Germany\n\n9 \nEpilepsy Center Mainz, Department of Neurology, Johannes Gutenberg-University Mainz, Mainz, Germany\n\n10 \nDepartment of Neurology, University of Münster, Münster, Germany\n\n11 \nSächsisches Epilepsiezentrum Radeberg gGmbH, Kleinwachau, Germany\n\n12 \nHospital Center of Luxembourg, Luxembourg, Luxembourg\nCorrespondence to Dr Katja Menzler; hattemer@med.uni-marburg.de2019 4 11 2019 9 11 e03074609 4 2019 20 9 2019 26 9 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/.Objectives\nBrivaracetam (BRV) is the latest approved antiepileptic drug and acts as a synaptic vesicle protein 2A ligand. The aim of the present study was to evaluate the efficacy and tolerability of BRV in the clinical setting.\n\nDesign\nRetrospective, observational multicentre study.\n\nSetting\nWe retrospectively collected clinical data of patients who received BRV in 10 epilepsy centres using a questionnaire that was answered by the reporting neurologist.\n\nParticipants\nData of 615 epilepsy patients treated with BRV were included in the study.\n\nPrimary and secondary outcome measures\nEfficacy regarding seizure frequency and tolerability of BRV were evaluated. Descriptive statistics complemented by X2 contingency tests and effect sizes were performed.\n\nResults\nOverall, 44% of the patients had a decreased, 38% a stable and 18% an increased seizure frequency. 17% of patients achieved seizure freedom after initiation of BRV. The seizure frequency decreased in 63% of 19 patients with BRV monotherapy. 27% reported adverse effects, but only 10% of patients with monotherapy. Brivaracetam was significantly more often associated with decreased seizure frequency in levetiracetam (LEV) naïve patients (p=0.012), but BRV also led to a decreased seizure frequency in 42% of patients who had been treated with LEV before, including 17% of patients who were completely seizure free. Adverse effects under LEV improved in 62% and deteriorated in 2% of patients after the switch to BRV. At latest follow-up (mean±SD = 26.3±6.5 months), 68% were still on BRV.\n\nConclusions\nThe present study shows that results of the phase III studies on BRV match data from real life clinical settings. Brivaracetam seems to be a useful alternative in patients who have suffered adverse effects while taking LEV.\n\nbrivaracetammonotherapylevetiracetamadverse eventsefficacytolerabilityspecial-featureunlocked\n==== Body\nStrengths and limitations of this study\nThis study extends our knowledge about the efficacy and tolerability of brivaracetam (BRV) beyond phase III studies into real life clinical settings.\n\nThe inclusion of patients of 10 epilepsy centres results in a large number of 615 patients.\n\nThe study provides data on the efficacy and tolerability of BRV as off-label monotherapy, where sufficient clinical data are lacking so far.\n\nDue to the real life clinical setting and the retrospective analysis, data were not collected in a systematic way, for example, seizure frequency and side effects rely on the patient history, comedication was not kept stable and the follow-up period was variable.\n\nThese limitations in the study design only allow for descriptive statistics and very limited statistical tests, as more elaborate statistical analyses would overstress the data.\n\nIntroduction\nEpilepsy is a common neurological disorder, affecting about 0.7% of the general population.1 Up to 30% of epilepsy patients continue to have seizures despite adequate medication with currently available antiepileptic drugs (AED).2 The high prevalence of pharmacoresistant epilepsy exposes the need to develop new AED. Also, AED with minimal side effects are required, as tolerability is the most important factor influencing adherence.3 4\n\n\nBrivaracetam (BRV) is a new AED approved in patients aged 16 or above for the add-on treatment of focal-onset seizures, with or without secondary generalisation.5 Like levetiracetam (LEV), brivaracetam acts as a synaptic vesicle protein 2A ligand with a 15 to 30 times higher binding potential than LEV.6\n\n\nA pooled analysis of three phase III studies revealed a reduction in seizure frequency of 18.5% (50 mg/day), 24.4% (100 mg/day) and 24.0% (200 mg/day) over placebo and a ≥50% responder rate of 43.2% (50 mg/day), 39.5% (100 mg/day) and 37.8% (200 mg/day). Among patients treated with BRV, 68.0% reported adverse events (AE) as compared with 62.1% of patients taking placebo, mainly somnolence, dizziness, headache and fatigue.6\n\n\nThe aim of the present study was to evaluate the effectiveness and tolerability of BRV in the postmarketing period to evaluate if the reduction in seizure frequency and adverse events reported in the phase III studies can be extended into the clinical setting. Also, the proportion of patients still on BRV at latest follow-up was calculated.\n\nMethods\nIn this retrospective, observational multicentre study, data from epilepsy patients who received BRV anytime between February 2016 (approval of this AED in Germany) and October 2018 and had at least one follow-up visit were collected in 10 different epilepsy centres in Germany and Luxemburg. All German speaking epilepsy centres were asked for participation via email using the monthly letter from the German International League Against Epilepsy chapter.\n\nWe used a questionnaire that was answered by the reporting neurologist using medical records of the patients. We collected baseline data on age, sex, duration of epilepsy, aetiology, seizure frequency, dose and titration of BRV, current treatment with other AED, as well as psychiatric comedication. Due to the similar modes of action, previous treatment with LEV and side effects during treatment with LEV were also recorded.\n\nAt each site, we also collected follow-up data. We documented the time period between initiation of BRV and the latest follow-up while still on BRV. A minimum follow-up period of 3 months was required. The recorded data at follow-up included seizure frequency, AE, possible changes of adverse events during previous treatment with LEV and discontinuation of BRV together with the corresponding reasons.\n\nRegarding seizure outcome, the seizure frequency was determined from the medical history of the patients at the time of introduction of BRV and latest follow-up while still on treatment. Information on seizure frequency was considered unreliable if information on seizure frequency was not documented in the patients’ charts or patients could not report the number of seizures. If information on seizure frequency was missing, patients were excluded from the analysis of this parameter, but these patients were still included in the analysis of adverse events or proportion of patients still on BRV. The follow-up period was variable and the seizure frequencies reported ranged from less than once a month to more than 1000 a month. Also, in several patient charts a range of seizure frequencies like four to eight seizures per month was documented. We therefore decided to only report broad categories including complete seizure freedom and stable, increased or decreased seizure frequency. Any changes in seizure frequency were interpreted as increase or decrease, no minimum percentage of increase or decrease was required. In our opinion any more detailed analysis would suggest an accuracy that is not in the data.\n\nChanges in seizure frequency and adverse events as well as the proportion of patients still taking BRV at latest follow-up were evaluated in the whole group of patients. In addition, subgroups of LEV naïve patients and patients who had been treated with LEV before were analysed separately due to the similar mode of action of BRV and LEV that might influence the efficacy or tolerability. Also, a subgroup of patients with off-label use of BRV in monotherapy was analysed separately.\n\nStatistical analysis was performed using the Statistical Package for Social Science (SPSS, IBM) V.24. The analysis focused primarily on descriptive statistics that were complemented by X2 contingency tests and effect sizes (Cramer’s V).\n\nIn this manuscript we followed the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for the reporting of observational studies.\n\nPatient and public involvement statement\nPatients were not involved in this retrospective data analysis.\n\nResults\nPatient characteristics\nData from 615 patients were collected in 10 epilepsy centres. Three hundred and four patients (49%) were male, 311 patients (51%) were female. The mean age was 40.8±17.0 (mean±SD) years.\n\nInformation on epilepsy duration was available in 589 patients. The mean duration of epilepsy was 21.0±14.6 (mean±SD) years. The median seizure frequency of 600 patients was 5 (range 0 to 1000) per month. The sample included 25 patients with genetic generalised epilepsy.\n\nSixty patients (10%) had psychiatric medication as an indicator of psychiatric comorbidity.\n\nThe mean follow-up was 26.3±6.5 months.\n\nPatient characteristics and number of patients included in each analysis are presented in table 1.\n\nTable 1 Patient characteristics and number of patients included in the analysis\n\nParameter\tN\t%*\t\n\nInitial daily dose of BRV\n\t610\t\t\n\nInformation on previous treatment with LEV\n\t\n600\n\t\t\nNo previous treatment with LEV\t73\t22%\t\nPrevious treatment with LEV\t527\t88%\t\n Direct switch from LEV to BRV\n\t\n237\n\t\n40%\n\t\n Slow switch from LEV to BRV\n\t\n50\n\t\n8%\n\t\n LEV discontinued before initiation of BRV therapy\n\t\n116\n\t\n19%\n\t\n No information how the switch was performed\n\t\n124\n\t\n21%\n\t\n\nEfficacy analysis\n\t\n514\n\t\t\nDecreased seizure frequency including seizure free\t226\t44%\t\n Seizure free\n\t\n89\n\t\n17%\n\t\nStable seizure frequency\t194\t38%\t\nIncreased seizure frequency\t94\t18%\t\n\nEfficacy analysis in patients on BRV monotherapy\n\t\n19\n\t\t\nDecreased seizure frequency including seizure free\t12\t63%\t\n Seizure free\n\t\n11\n\t\n58%\n\t\nStable seizure frequency\t4\t21%\t\nIncreased seizure frequency\t3\t16%\t\n\nEfficacy analysis in patients pretreated with LEV\n\t\n441\n\t\t\nDecreased seizure frequency including seizure free\t184\t42%\t\n Seizure free\n\t\n75\n\t\n17%\n\t\nStable seizure frequency\t167\t38%\t\nIncreased seizure frequency\t90\t20%\t\n\nEfficacy analysis in LEV naïve patients\n\t\n73\n\t\t\nDecreased seizure frequency including seizure free\t42\t58%\t\n Seizure free\n\t\n14\n\t\n19%\n\t\nStable seizure frequency\t27\t37%\t\nIncreased seizure frequency\t4\t5%\t\n\nAnalysis of tolerability\n\t\n615\n\t\t\nPatients with AE on BRV treatment\t169\t27%\t\nPatients without AE on BRV treatment\t446\t73%\t\n\nPatients with AE on previous LEV treatment\n\t\n268\n\t\t\nImprovement after switch to BRV\t168\t63%\t\nPersistence after switch to BRV\t93\t35%\t\nAggravation after switch to BRV\t7\t2%\t\n\nAetiology\n\t\n615\n\t\t\nStructural\t312\t51%\t\nCryptogenic\t159\t26%\t\nGenetic\t39\t6%\t\nMetabolic\t1\t0%\t\nImmunological\t6\t1%\t\nPost-infectious\t4\t1%\t\nNo information\t94\t15%\t\n*Percent in relation to the number of patients included in this analysis, printed in bold letters, italics: subgroup of the above-mentioned group.\n\nAE, adverse events; BRV, brivaracetam; LEV, levetiracetam.\n\nTreatment scheme\nThe 610 patients with documented initial dose of BRV were treated with a median daily dose of 100 mg BRV (range 25 to 400 mg). In 590 patients, BRV was introduced as add-on anticonvulsant therapy with a median of 2 (range 1 to 6) other AED. Twenty-two patients were started on a monotherapy with BRV. In three patients concomitant AED were not documented.\n\nA total of 527 patients (86% of the whole sample) had been treated with LEV before. Seventy-three patients (12% of the whole sample) were LEV naïve. There were no statistical differences between both groups regarding sex (χ²=0.217, p=0.64, n=600), age (t (596)=−0.26, p=0.79) or duration of epilepsy (t (569)=−0.95, p=0.92), both samples fulfilled equality criteria. In 15 patients (2%) information on previous LEV therapy was not provided. Of the patients who had been treated with LEV, 237 (45% of the whole sample) were switched to BRV directly and 50 (9% of the whole sample) were switched slowly. In 116 patients (22% of the whole sample) BRV was introduced with a delay after LEV had been discontinued. In the other 124 patients (24% of the whole sample) the switch from LEV to BRV was not further described.\n\nIn 116 patients without current LEV therapy, an AED other than LEV was discontinued slowly in exchange for BRV. In one patient, another AED was discontinued simultaneously with the switch from LEV to BRV.\n\nEfficacy\nOf the 514 patients with reliably documented seizures, 226 (44%) had a decreased seizure frequency, 194 (38%) an unchanged and 94 patients (18%) an increased seizure frequency.\n\nIn the 19 of 22 patients with BRV monotherapy and sufficient information on seizure outcome, 12 (63%) improved, four (21%) had no change and three (16%) deteriorated.\n\nOf the patients who had been treated with LEV before, changes in seizure frequency after introduction of BRV were reliably documented in 441 patients. One hundred and eighty-four of these patients (42%) had a decreased, 167 (38%) a stable and 90 (20%) an increased seizure frequency (figure 1).\n\nFigure 1 Seizure outcome with brivaracetam(BRV) at latest follow-up for patients who had taken levetiracetam(LEV) before (light grey), LEV naïve patients (dark grey) and patients on BRV monotherapy.\n\nSeizures improved in 42 (58%), remained stable in 27 (37%) and deteriorated in four (5%) of the 73 patients who were LEV naïve.\n\nComplete seizure freedom could be achieved in 89 (17%) patients of the total sample, in 75 (17%) of the patients with previous LEV treatment, in 14 (19%) of the LEV naïve patients and in 11 (58%) of the patients on BRV monotherapy.\n\nAn increase of seizure frequency was significantly more often observed in patients with previous LEV treatment compared with those patients who were LEV naïve (χ²=9.341, p=0.002, n=514). A reduction of seizure frequency was significantly more often observed in patients who were LEV naïve compared with patients pretreated with LEV (χ²=6.355, p=0.012, n=514). These relationships are featured by a small effect size (Cramer’s V=0.13 – 0.11). No significant difference was found between these two groups regarding the proportion of patients with unchanged seizure frequencies (χ²=0.21, p=0.85, n=514) or patients who achieved seizure freedom (χ²=0.206, p=0.65, n=514).\n\nRegarding subgroups in aetiology, three groups could be identified for statistical analysis with 312 (51% of the whole sample) patients suffering from structural, 159 (26%) from cryptogenic and 39 (6%) from genetic epilepsies. No significant difference was found between these three groups regarding seizure frequency reduction (χ²=1.434, p=0.48, n=510) or seizure freedom (χ²=1.549, p=0.46, n=510).\n\nTolerability\nOverall, 169 of all patients (27%) reported AE. A significant dose dependent relationship (χ²=23.35, p=0.016, n=610) with a small effect size (Cramer’s V=0.19) was observed (table 2).\n\nTable 2 Relationship between dose of BRV and AE\n\nDose (mg)\tPatients without AE\tPatients with AE\t\n25\t0\t1\t\n50\t60\t16\t\n75\t1\t4\t\n80\t1\t0\t\n100\t161\t70\t\n120\t1\t0\t\n125\t2\t0\t\n150\t37\t23\t\n200\t155\t53\t\n250\t6\t0\t\n300\t15\t1\t\n400\t2\t1\t\nN\t441\t169\t\nAE, adverse event; BRV, brivaracetam.\n\nThe most common AE are summarised in figure 2. Only 2 of 20 patients (10%) with BRV monotherapy reported AE, one headache and one loss of appetite. Eleven of the 60 patients with psychiatric comedication (18%) reported behavioural AE like depression, aggressiveness, irritability, fear or hallucinations or deterioration of their symptoms, six patients (10%) reported non-behavioural AE like dizziness, sleep disturbances, tiredness, weight changes or headache. There were no reports of attempted suicide.\n\nFigure 2 Number of patients with adverse events during therapy with brivaracetam(BRV).\n\nTwo hundred and sixty-eight patients (51% of the 527 patients on previous LEV treatment) had reported AE while taking LEV, 106 behavioural and 34 non-behavioural AE. In 128 patients, the LEV-associated AE were not further specified. After switching to BRV, these AE persisted in 93 (35%) and were aggravated in seven (2%) of the 268 patients. However, 168 patients (63%) reported an improvement of previous LEV-associated AE. On the other hand, 60 patients (23%) without AE under treatment with LEV had AE when treated with BRV, 11 (4%) behavioural and 18 (7%) non-behavioural AE. In 31 (12%) the AE were not further specified.\n\nRetention\nOverall, the proportion of patients still on BRV after a mean follow-up of 26.3±6.5 (mean±SD) months was 68%. One hundred and ninety-nine of the 615 patients (32%) discontinued BRV after 6.8±5.2 (mean±SD) months. The reasons for discontinuation were an increase in seizure frequency in 34 (17%) or lack of improvement of seizure frequency in 43 (22%) of these 199 patients. In 77 patients (39%), BRV was discontinued due to AE and in four patients (2%) to both, lack of efficacy and AE. In 42 of the 199 patients (21%), the discontinuation had other reasons or the reason was not further specified.\n\nIn patients on BRV monotherapy, eight patients (36%) discontinued BRV after 13.4±7.6 (mean±SD) months. The proportion of patients still taking BRV after 27.5±6.4 (mean±SD) months was 64%.\n\nDiscussion\nThe present multicentre study evaluated the effectiveness and tolerability of BRV in daily clinical practice. We could show that BRV is an effective and well tolerated AED and can also be effective in patients who had been treated with LEV before, even though the proportion of patients with reduced seizure frequency was significantly lower in these patients compared with LEV naïve patients. Adverse events during treatment with LEV improved in the majority of patients after the switch to BRV. Brivaracetam was also effective and well tolerated when given in monotherapy. The proportion of patients still taking BRV at latest follow-up (mean±SD = 26.3±6.5 months) was 68%.\n\nEfficacy\nOverall, our results show improved seizure control in 44% of the patients. Several phase III studies evaluating the effect of BRV showed ≥50% responder rates of 27.3% to 32.7% (BRV 50 mg), 36.0% to 38.9% (BRV 100 mg) and 37.8% (BRV 200 mg).7–9 These prospective, placebo-controlled studies had strict inclusion and exclusion criteria like a frequency of at least eight partial onset seizures in the 8 week baseline period and comedication was kept stable. Data were thoroughly collected during predefined follow-up visits and allow for a sophisticated and reliable statistical analysis. On the other hand it remains unclear if results of this special group of patients can be transferred to the heterogeneous patient collective and circumstances of every day clinical practice. The strength of the present study is that patients with all types of epilepsy and any seizure frequency as well as simultaneous changes in other AED were included. Therefore, the present study confirms findings of phase III studies in the clinical setting.\n\nOur results are in line with an earlier multicentre postmarketing study on a smaller group of 262 patients, which showed a responder rate of 40.5% after a shorter follow-up period of 6 months.10\n\n\nDue to the similar mode of action of LEV and BRV6 the benefit of BRV for patients who have been treated with LEV before is of special interest. In the three phase III studies on BRV, concomitant LEV use was either limited to 20%7 9 of the patient population or patients who had taken LEV within the last 90 days were excluded.8 However, these studies point to an effect of BRV even in patients who have previously taken LEV, possibly with a slightly lower responder rate.7–9 11 12 Our data show that BRV is significantly less effective in patients who have been treated with LEV, but BRV still leads to seizure reduction in 42% of these patients and there is no significant difference in the proportion of patients who become seizure free compared with patients who are LEV naïve. Even though the efficacy was lower than in LEV naïve patients, brivaracetam might therefore be a treatment option even for patients who have been treated with LEV before.\n\nWe also included a subsample of patients with BRV monotherapy. A recently published study reports on two phase III studies which were terminated after a high drop-out rate of about 40%.13 Sufficient data on efficacy and tolerability of BRV monotherapy are therefore lacking. The present results on a limited number of patients with BRV monotherapy show a reduction of seizure frequency in more than half of the patients and a low rate of AE. Further studies on safety and tolerability are therefore warranted.\n\nTolerability\nA pooled analysis of the three phase III studies reports drug-related AE of 47.0% (50 mg/day), 39.9% (100 mg/day) and 43.6% (200 mg/day).6 Our results support these findings and even show a slightly lower rate of AE in the clinical setting. This lower number might however be due to the retrospective study design and lack of systematic documentation of adverse events in the present study and should therefore be interpreted with caution. Interestingly, the number of behavioural AE and deterioration of psychiatric condition was low (18%) in patients with psychiatric medication, an indicator for psychiatric comorbidities. Brivaracetam therefore appears to be a treatment option even in those patients seemingly at higher risk for psychiatric adverse events.\n\nIncluding all patients who had been treated with LEV before and experienced AEs we could show an improvement of LEV-associated AEs during the treatment with BRV in 63% of 268 patients. In a pooled analysis of patients who switched to BRV due to behavioural AE during treatment with LEV, 27 out of 29 patients (93%) had a clinically meaningful reduction in behavioural AE as rated by the physician.12 The small number of 29 patients, strict inclusion criteria allowing only an immediate switch and the stable comedication in this earlier study might explain the higher percentage of patients in whom AE improved after the switch to BRV. The improvement of LEV-associated AE in 62% of patients in the present study is however in line with results of another study, where 44 out of 57 patients (77%) had a clinically meaningful reduction of overall AE and 24 out of 36 (67%) of behavioural AE after switching from LEV to BRV.14 A switch to BRV might therefore be a treatment option for patients with LEV-associated AE.\n\nConcusions and limitations\nIn this multicentre study on postmarketing experiences with BRV in clinical settings, BRV seemed to be an easy to use, easy to switch and well tolerated new antiepileptic drug with more than 60% of patients still taking BRV even after a follow-up period of more than 2 years. Brivaracetam also appears to be effective and well tolerated when given as monotherapy and might even be a treatment option for patients with psychiatric comorbidities or those who failed LEV treatment. We observed a weak relationship between BRV dose and adverse events. However, this result should be interpreted with caution as sample sizes in some dose subgroups were small.\n\nThis study is a multicentre retrospective study. Data were collected by questionnaires that were answered by the reporting neurologist using patient charts. Therefore, limitations of this study include missing data, data that were not collected in a systematic way, variable follow-up intervals and changes in comedication. On the other hand, the group of patients is representative for the group of patients treated with BRV in the clinical setting as all patients treated with BRV and a follow-up period of at least 3 months were included in the 10 participating centres. Another limitation of this retrospective study is the lack of a control-group receiving placebo. Due to these limitations of the study results are mainly presented in a descriptive manner to avoid overinterpretation of the results.\n\nSupplementary Material\nReviewer comments\n Author's manuscript\n We thank Isabel Steinig for her help with preparing the data from Frankfurt.\n\nContributors: KM: analysis and interpretation of the data, writing of the manuscript. PMM: acquisition of data, analysis and interpretation of the data. FR: acquisition of data, revision of the manuscript. SSB: acquisition of data, revision of the manuscript. LMW: acquisition of data, revision of the manuscript. FZ: acquisition of data, revision of the manuscript. Il: acquisition of data, revision of the manuscript. SF: acquisition of data, revision of the manuscript. FvP: acquisition of data, revision of the manuscript. RK: acquisition of data, revision of the manuscript. MH: acquisition of data, revision of the manuscript. TM: acquisition of data, revision of the manuscript. JM: acquisition of data, revision of the manuscript. YW: acquisition of data, revision of the manuscript. LL: acquisition of data, revision of the manuscript. MC: acquisition of data, revision of the manuscript. SB: acquisition of data, revision of the manuscript. AS: acquisition of data, revision of the manuscript. SK: study concept and design, analysis and interpretation of the data, revision of the 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: KM has received honoraria as advisory board member from Eisai and UCB. FR has received personal fees from Bayer-Vital, Cerbomed, Eisai, Hexal and Sandoz, personal fees and support for continuing medical education activities from Desitin, Novartis, Shire and UCB Pharma and grants from DFG (German Research Foundation) and the European Union. SS-B reports personal fees from UCB, Eisai, Desitin Pharma, LivaNova, Bial, Novartis and Zogenix outside of the submitted work. FVP reports industry-funded travel with support of Desitin Arzneimittel, UCB Pharma, Eisai Pharma and BIAL, obtained honoraria for speaking engagements from Desitin Arzneimittel, UCB Pharma, Eisai Pharma and BIAL and was part of a speaker’s bureau of Desitin Arzneimittel, UCB Pharma and BIAL. RK reports industry-funded travel with support of Eisai Pharma and Desitin Arzneimittel. MH has received honoraria for lectures from pharmaceutical companies (Eisai, UCB) and research support for participation in clinical trials and registries from Medtronic, Cyberonics and Precisis. TM has received travel expenses for attending a meeting from UCB Pharma. YW received travel grants and honoraries for lectures from UCB Pharma, BIAL, Eisai, Bayer and Novartis, which were not related to the publication. LL has received lecture honoraria from Eisai. MC has received travel expenses for attending meetings from Desitin and Zogenix. AS reports personal fees and/or grants from Desitin Arzneimittel, Eisai, GW Pharma, LivaNova, Medtronic, Sage Therapeutics, UCB Pharma and Zogenix. SK reports honoraria for speaking engagements from Desitin and UCB as well as educational grants from AD Tech, Desitin Arzneimittel, Eisai, GW, Medtronic, Novartis, Siemens and UCB.\n\nPatient consent for publication: Not required.\n\nEthics approval: The study was approved by local ethic committees.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: Data are available upon reasonable request.\n==== Refs\nReferences\n1 \nHirtz D , Thurman DJ , Gwinn-Hardy K , et al \nHow common are the \"common\" neurologic disorders? \nNeurology \n2007 ;68 :326 –37 . 10.1212/01.wnl.0000252807.38124.a3 \n17261678 \n2 \nKwan P , Brodie MJ \nEarly identification of refractory epilepsy . N Engl J Med Overseas Ed \n2000 ;342 :314 –9 . 10.1056/NEJM200002033420503 \n\n3 \nWilby J , Kainth A , Hawkins N , et al \nClinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation . Health Technol Assess \n2005 ;9 :1 –157 . 10.3310/hta9150 \n\n4 \nChung S , Wang N , Hank N \nComparative retention rates and long-term tolerability of new antiepileptic drugs . Seizure \n2007 ;16 :296 –304 . 10.1016/j.seizure.2007.01.004 \n17267243 \n5 \nStrzelczyk A , Klein KM , Willems LM , et al \nBrivaracetam in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus . Expert Rev Clin Pharmacol \n2016 ;9 :637 –45 . 10.1586/17512433.2016.1156529 \n26891946 \n6. \nBen-Menachem E , Mameniškienė R , Quarato PP , et al \nEfficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies . Neurology \n2016 ;87 :314 –23 . 10.1212/WNL.0000000000002864 \n27335114 \n7 \nRyvlin P , Werhahn KJ , Blaszczyk B , et al \nAdjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial . Epilepsia \n2014 ;55 :47 –56 . 10.1111/epi.12432 \n24256083 \n8 \nKlein P , Schiemann J , Sperling MR , et al \nA randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures . Epilepsia \n2015 ;56 :1890 –8 . 10.1111/epi.13212 \n26471380 \n9 \nBiton V , Berkovic SF , Abou-Khalil B , et al \nBrivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial . Epilepsia \n2014 ;55 :57 –66 . 10.1111/epi.12433 \n24446953 \n10 \nSteinig I , von Podewils F , Möddel G , et al \nPostmarketing experience with brivaracetam in the treatment of epilepsies: a multicenter cohort study from Germany . Epilepsia \n2017 ;58 :1208 –16 . 10.1111/epi.13768 \n28480518 \n11 \nAsadi-Pooya AA , Sperling MR , Chung S , et al \nEfficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: a post-hoc study . Epilepsy Res \n2017 ;131 :70 –5 . 10.1016/j.eplepsyres.2017.02.007 \n28279891 \n12 \nYates SL , Fakhoury T , Liang W , et al \nAn open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam . Epilepsy Behav \n2015 ;52 :165 –8 . 10.1016/j.yebeh.2015.09.005 \n26432008 \n13 \nArnold S , Badalamenti V , Diaz A , et al \nConversion to brivaracetam monotherapy for the treatment of patients with focal seizures: two double-blind, randomized, multicenter, historical control, phase III studies . Epilepsy Res \n2018 ;141 :73 –82 . 10.1016/j.eplepsyres.2018.02.005 \n29486396 \n14 \nZahnert F , Krause K , Immisch I , et al \nBrivaracetam in the treatment of patients with Epilepsy-First clinical experiences . Front Neurol \n2018 ;9 :38\n10.3389/fneur.2018.00038 \n29467714\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2044-6055",
"issue": "9(11)",
"journal": "BMJ open",
"keywords": "adverse events; brivaracetam; efficacy; levetiracetam; monotherapy; tolerability",
"medline_ta": "BMJ Open",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D011760:Pyrrolidinones; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101552874",
"other_id": null,
"pages": "e030746",
"pmc": null,
"pmid": "31690606",
"pubdate": "2019-11-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "29467714;27335114;17261678;26471380;17267243;29486396;28480518;15842952;24256083;26891946;26432008;24446953;28279891;10660394",
"title": "First clinical postmarketing experiences in the treatment of epilepsies with brivaracetam: a retrospective observational multicentre study.",
"title_normalized": "first clinical postmarketing experiences in the treatment of epilepsies with brivaracetam a retrospective observational multicentre study"
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"abstract": "Nontuberculous mycobacteria represent an uncommon but important cause of infection of the musculoskeletal system. Such infections require aggressive medical and surgical treatment, and cases are often complicated by delayed diagnosis. We retrospectively reviewed all 14 nonspinal cases of nontuberculous mycobacterial musculoskeletal infections treated over 6 years by orthopedic surgeons at a university-affiliated tertiary referral center. All patients required multiple antimicrobial agents along with aggressive surgical treatment; 13 of 14 patients ultimately achieved cure. Four patients required amputation to control the infection. Half these patients were immunosuppressed by medications or other medical illness when they sought care at the referral center. Six cases involved joint prostheses; all ultimately required hardware removal and placement of an antimicrobial spacer for eradication of infection. Our findings highlight the importance of vigilance for nontuberculous mycobacterial musculoskeletal infection, particularly in patients who are immunosuppressed or have a history of musculoskeletal surgery.",
"affiliations": null,
"authors": "Goldstein|Noah|N|;St Clair|J Benjamin|JB|;Kasperbauer|Shannon H|SH|;Daley|Charles L|CL|;Lindeque|Bennie|B|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "United States",
"delete": false,
"doi": "10.3201/eid2406.181041",
"fulltext": "\n==== Front\nEmerg Infect Dis\nEmerging Infect. Dis\nEID\nEmerging Infectious Diseases\n1080-6040\n1080-6059\nCenters for Disease Control and Prevention\n\n31107224\n18-1041\n10.3201/eid2506.181041\nSynopsis\nSynopsis\nNontuberculous Mycobacterial Musculoskeletal Infection Cases from a Tertiary Referral Center, Colorado, USA\nNontuberculous Mycobacterial Musculoskeletal Infection Cases from a Tertiary Referral Center, Colorado, USA\nNontuberculous Mycobacterial Infections\nGoldstein Noah 1\nSt. Clair J. Benjamin 1\nKasperbauer Shannon H.\nDaley Charles L.\nLindeque Bennie\nUniversity of Colorado, Aurora, Colorado, USA (N. Goldstein, J.B. St. Clair, S.H. Kasperbauer, B. Lindeque);\nUniversity of Chicago, Chicago, Illinois, USA (J.B. St. Clair);\nNational Jewish Health, Denver, Colorado, USA (S.H. Kasperbauer, C.L. Daley)\nAddress for correspondence: Bennie Lindeque, University of Colorado, 12631 E 17th Ave, Academic Office 1, Rm 4602, Mailstop B202, Aurora, CO 80045, USA; email: bennie.lindeque@ucdenver.edu\n6 2019\n25 6 10751083\nEarly identification and aggressive treatment are crucial for patients with these infections.\n\nNontuberculous mycobacteria represent an uncommon but important cause of infection of the musculoskeletal system. Such infections require aggressive medical and surgical treatment, and cases are often complicated by delayed diagnosis. We retrospectively reviewed all 14 nonspinal cases of nontuberculous mycobacterial musculoskeletal infections treated over 6 years by orthopedic surgeons at a university-affiliated tertiary referral center. All patients required multiple antimicrobial agents along with aggressive surgical treatment; 13 of 14 patients ultimately achieved cure. Four patients required amputation to control the infection. Half these patients were immunosuppressed by medications or other medical illness when they sought care at the referral center. Six cases involved joint prostheses; all ultimately required hardware removal and placement of an antimicrobial spacer for eradication of infection. Our findings highlight the importance of vigilance for nontuberculous mycobacterial musculoskeletal infection, particularly in patients who are immunosuppressed or have a history of musculoskeletal surgery.\n\nKeywords:\n\nnontuberculous mycobacteria\nMycobacterium\nmusculoskeletal diseases\nprosthesis-related infections\nosteomyelitis\ninfectious arthritis\ntuberculosis and other mycobacteria\nantimicrobial resistance\nColorado\nUnited States\n==== Body\nNontuberculous mycobacteria (NTM) are opportunistic pathogens found in soil and water and are the sources of an increasing number of infections and illness (1,2). Multiple recent studies have recognized this temporal trend of increasing annual prevalence of NTM disease; current prevalence is estimated at 2.6%–10% annually (1–4). NTM cause a broad range of clinical manifestations, depending on the immune competency of the host. Pulmonary disease is most common and is often seen in immunocompetent hosts. It is difficult to estimate the prevalence of extrapulmonary NTM infection in the United States because no system of national surveillance and reporting exists as for tuberculosis. Reported laboratory isolation data indicate that extrapulmonary disease may comprise up to one quarter of all NTM infections, although the best estimates are based on data that are 1–3 decades old. Data from the mid-1990s estimated the overall US incidence of NTM infection at 1.0%–1.8%, with ≈5% of isolates reported to the Centers for Disease Control and Infection at that time being of extrapulmonary origin. A population-based record review in Oregon that used data gathered during 2005–2006 found ≈22% of isolates originating from nonpulmonary specimens. Data from North Carolina gathered during 2006–2010 showed 16%–23% of total isolates originating from extrapulmonary specimens (5–7). Skin and soft tissue infections represent most extrapulmonary NTM disease, whereas bone and joint disease is less common. With increasing immunosuppression, NTM is more likely to manifest as disseminated disease, possibly including bone and joint involvement.\n\nPrevious case reports and series of NTM musculoskeletal infections have focused on the demographics, diagnosis, and treatment of patients with these difficult-to-manage infections (8–24). Patients were often immunocompetent persons who contracted an NTM disease after direct inoculation via traumatic skin puncture (25–28). In a series of 29 cases from South Korea, all patients required surgical intervention in addition to antimicrobial drugs; 3 patients failed to respond despite aggressive treatment, and an additional 4 were lost to follow-up. Of note, only 20 of the patients in this series received NTM-specific antimicrobial therapy; the remainder were treated with empirical antimicrobial therapy. A series of 28 cases of M. marinum musculoskeletal infections found that 93% of cases involved fingers or hands and 87% were related to aquatic exposure; two thirds progressed from cutaneous to invasive infection. Most cases were managed with multiple antimycobacterial agents in addition to surgery, and the series reported a 75% cure rate and 25% loss to follow-up. A study of 8 cases of prosthetic joint infection (PJI) caused by rapidly growing mycobacteria found that the median interval from prosthesis implantation to infection was 312 weeks and that all patients required either resection and explantation of infected prostheses or chronic suppressive antimicrobial therapy.\n\nIn these series, infections occurred throughout the musculoskeletal system but were particularly common in the hands and spine. Identification of NTM as the causative agent was often delayed due to the indolent course of the infection and lack of appropriate diagnostic testing. Once identified, the infections could be treated effectively with a combination of debridement and conventional antimycobacterial chemotherapy.\n\nWe reviewed all cases of nonspinal NTM musculoskeletal infection treated at the University of Colorado Hospital (UCH; Aurora, CO, USA) over a 6-year period by a multidisciplinary team of providers at UCH and National Jewish Health (NJH; Denver, CO, USA), a renowned center for mycobacterial research and treatment that receives referrals for difficult-to-treat NTM infections from across the United States. Our aim was to describe the clinical characteristics and treatment outcomes of patients with NTM musculoskeletal infections.\n\nMaterials and Methods\n\nStudy Design\n\nWe performed a retrospective study of patients with nonspinal NTM musculoskeletal infections treated at UCH during 2009–2015. The management of each case was directed by an orthopedic surgeon and infectious disease physicians at UCH and NJH. For patients with positive culture results at UCH, mycobacterial speciation and susceptibility data were identified by ARUP Laboratories (https://www.aruplab.com) using DNA sequencing or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.\n\nCase Ascertainment\n\nWe identified all cases of nonspinal NTM musculoskeletal infections treated by orthopedic surgeons at UCH during the study period using a registry of NTM musculoskeletal infections. We omitted spinal cases because they are handled by a different department at UCH and so were not part of the surgeons’ personal registry. We reviewed the medical records of patients after approval from the Institutional Review Board.\n\nData Collection\n\nWe performed our review of the medical records using a standardized case report form. We collected demographic characteristics and data on concurrent conditions, laboratory values, surgical intervention, antimycobacterial chemotherapy, and outcomes.\n\nLiterature Review\n\nWe searched the Medline database to identify case reports and reviews of NTM musculoskeletal infections. We used both the PubMed and Ovid access tools.\n\nResults\n\nPatient Characteristics\n\nOf the 14 patients in our series, 7 were receiving immunosuppressive medications at arrival, and 5 of those had chronic autoimmune disease. Twelve patients were referred from NJH. No predisposing host factor was identified for 6 patients. (Table 1).\n\nTable 1 Demographics of patients in retrospective study of nontuberculous mycobacterial musculoskeletal infections, Colorado, USA*\n\nPatient no.\tAge, y/sex\tImmunocompromising conditions\tInciting or predisposing factor(s)\tTime to symptom onset, mo\tReason care sought\tTime from symptom onset to diagnosis, mo\tDiagnostic procedure, source of microbiologic diagnosis\t\n1\t55/M\tHistory of lymphoma, pseudogout, oral steroid use\tSteroid injection, left ankle\tUNK\tOsteomyelitis, septic arthritis\t12\tTissue sample from ankle debridement\t\n2\t53/F\tNone\tPedicure\t0\tSynovitis, osteomyelitis, cellulitis\t4\tUNK; diagnosis at another hospital\t\n3\t48/F\tNone\tSecond THA\tUNK\tPJI\tUNK\tThigh fluid sampled during I&D\t\n4\t45/M\tNone\tAKA\t1\tDraining wound at stump\t2\tSample of fluid draining from AKA stump\t\n5\t64/F\tNone\tCarpal tunnel release\t0\tTenosynovitis, septic arthritis\t8\tSynovial fluid obtained during excision of synovitis\t\n6\t69/F\tDiabetes mellitus\tTHA\t6\tPJI\t9\tSynovial biopsy obtained during explantation\t\n7\t23/F\tSystemic lupus erythematosus, oral steroids, hydroxyl-chloroquine, mycophenolate mofetil\tAvascular necrosis, ankle fusion\t3\tSeptic arthritis, osteomyelitis, skin abscesses\t1\tUNK; diagnosis at another hospital\t\n8\t57/F\tPolymyositis, oral steroids, azathioprine, rituximab, methotrexate\tACL repair, arthroscopy, steroid injection\tUNK\tSeptic arthritis\tUNK\tAspirate of left knee and right hip\t\n9\t76/M\tNonspecific autoimmune disease, oral steroids\tCalcium pyrophosphate deposition disease, TKA\t0\tPJI\t2\tUNK; diagnosis at another hospital\t\n10\t58/M\tNone\tTrauma, steroid injection\t12\tSeptic arthritis\t19\tUNK; diagnosis at another hospital\t\n11\t77/F\tRheumatoid arthritis, prednisone, azathioprine\tTKA\t300\tPJI\t12\tSynovial biopsy obtained during placement of antimicrobial spacer\t\n12\t83/M\tMalnutrition, prednisone\tTKA\t168\tPJI\t8\tTissue obtained during TKA revision\t\n13\t49/F\tNone\tTKA (revision)\t14\tPJI\t2\tUNK; diagnosis at another hospital\t\n14\t24/F\tCrohn’s disease, infliximab\tFailed IV\t0\tCellulitis, abscess\t7\tSkin biopsy\t\n*AKA, above-knee amputation; I&D, irrigation and debridement; PJI, prosthetic joint infection, THA, total hip arthroplasty; TKA, total knee arthroplasty; UNK, unknown.\n\nClinical Presentation and Diagnosis\n\nThe patients had a wide array of sites of infection when they sought care at UCH (5 knee, 2 hip, 1 thigh, 1 hand, 1 foot, 1 elbow, 3 with disseminated disease at multiple sites). The diagnosis at arrival was most commonly PJI (n = 6); the next most common diagnoses included septic arthritis (n = 5), osteomyelitis (n = 3), tendon sheath infection (n = 2), skin abscess (n = 2), cellulitis (n = 2), and surgical-wound infection (n = 1). Several patients had complex local infections with multiple concurrent tissue diagnoses; case-patients 1, 7, and 8 had disseminated disease at multiple sites. Each patient had undergone >1 prior procedure at the site of infection, including 6 patients with infected prostheses, 4 with other surgical procedures, 2 with steroid injection, 1 with a failed intravenous (IV) placement, and 1 with a cosmetic pedicure. The median interval from symptom onset to diagnosis was 7.5 months (range 1–19 months).\n\nOf 10 patients tested, the median erythrocyte sedimentation rate (ESR) was above the upper limit of normal (ULN) in 7 patients (70%) at arrival (ULN 15 mm/h in men, 20 mm/h in women). C-reactive protein level was elevated in 4/14 patients (29%) (ULN 10.0 mg/L). Blood leukocyte count was elevated in 2/14 patients (14%) (ULN 10.1 × 104 cells/μL). All 3 laboratory tests were within reference limits in 1 patient, and both C-reactive protein and leukocyte levels were within reference limits in an additional 2 patients without ESR data.\n\nPJIs\n\nSix patients arrived with PJI at the knee (4 patients) and hip (2 patients). The interval from prosthesis implantation to symptom onset ranged from the immediate aftermath of implantation to 25 years postimplantation; median duration was 6 months. Infected hardware was removed in all patients with PJI; the median period from symptom onset to explantation was 8.5 months (range <3–16 months). After explantation, 2-stage revision was undertaken, first with implantation of a temporary articulating prosthesis prepared with 1 g of antimicrobial-loaded polymethylmethacrylate bone cement, with drug selection based on sensitivity testing. This preparation, called an antimicrobial spacer, was subsequently replaced with a permanent prosthesis after several months without evidence of recurrent infection. Medication-loaded bone cement was also used for patients requiring intramedullary nailing. Patients with PJI were also treated with amikacin-containing calcium sulfate beads implanted within the surgical bed (1 g of amikacin per 10 cc packet of calcium sulfate mixture). These antimicrobial beads were used at initial explantation or when the antimicrobial spacer was replaced with a permanent prosthesis at the discretion of the surgeon as needed to fill dead space from aggressive debridement or the infection itself. The precise amount of amikacin used is not always clearly reflected in the surgical record; however, in our series, use of up to 5 g of amikacin has been recorded. Amikacin is used for its activity against mycobacteria and its ability to integrate with the calcium sulfate material to form beads. Such amikacin-laden beads were also used in 2 other patients with extensive soft-tissue involvement. A seventh patient with septic arthritis of her native knee (case-patient 8) underwent a total knee arthroplasty that was insufficient to eradicate the infection and ultimately required subsequent 2-stage revision.\n\nSurgical Treatment\n\nAll patients required surgical treatment for control of infection, and all but 1 patient were ultimately cured by combined medical and surgical treatment. Seven patients had >1 procedure at outside hospitals before seeking treatment at UCH. Case-patients 4 and 5 required only a single surgical procedure at UCH for control of infection. Case-patients 6 and 12 underwent planned 2-stage revision and required no further surgeries. The remaining 10 case-patients had initial procedures at UCH that were intended to definitively treat infection but proved unsuccessful. Surgical treatment at UCH consisted of aggressive debridement of infected bone and soft tissue, as well as explantation of any infected hardware with 2-stage revision of infected prostheses. Four patients with infections involving the knee also required placement of intramedullary nails coated with antibiotic-loaded cement (case-patients 9, 10, 11, and 13). The median interval from initial diagnostic or therapeutic procedure to definitive surgical treatment was 14 months (range 4–52 months) in the patients who required multiple procedures. One patient with disseminated M. abscessus (case-patient 1) required a debridement of the femur, partial claviculectomy, synovectomy of an ankle and a knee, and a fasciectomy. The patient with disseminated M. massiliense in the setting of chronic immunosuppressive therapy (case-patient 7) required >12 procedures including multiple debridements and soft tissue excisions, removal of infected ankle fusion hardware, and osteotomy and arthrotomy of an infected elbow with extensive use of antimicrobial beads and bone cement. A patient with M. intracellulare infection disseminated to the left knee and right hip (case-patient 8) required multiple irrigations and debridements, total knee arthroplasty with antimicrobial spacer, and subsequent implantation of a tumor prosthesis. One patient with M. fortuitum infection (case-patient 5) had a debridement and eventually required amputation of her hand. One patient had cellulitis and abscess formation caused by M. marinum (case-patient 14) requiring a wide excision of the soft tissue around her elbow. One patient with a hip-prosthetic infection caused by M. abscessus (case-patient 3) required hemipelvectomy due to the progressive spread of the infection despite >1 year of intravenous therapy, prosthetic hip explantation, and multiple debridements (Table 2).\n\nTable 2 Surgical treatment of patients with nontuberculous mycobacterial musculoskeletal infections, Colorado, USA*\n\nPatient no.\tSite\tPrevious surgeries\tSymptom onset to first surgery, mo\tSurgeries for control of infection at UCH\tTime between surgeries, mo\tFirst visit to definitive procedure, mo\tLength of follow-up, mo\t\nFirst procedure(s)\tDefinitive procedure\t\n1\tMultiple joints†\tMultiple I&Ds, below-knee amputation\tUNK\tI&D, excision of soft-tissue masses, debridement, synovectomy, amikacin bead implantation\tWide excision of right calf\t36\t22\t7\t\n2\tLeft foot\tDebridement, amputation L 5th toe, nodule excision\t2\tDebridement of dorsum of left foot\tExcisional debridement of left foot\t17\t14\t60\t\n3\tLeft hip (PJI)\tUNK\tUNK\tDebridement and polyethylene exchange\tHemi-pelvectomy\t31\t38\t14\t\n4\tLeft thigh\tNone\t18\tNA\tAbove-knee amputation stump revision\tNA\t14\t1\t\n5\tRight hand\tNone\t9\tNA\tAmputation of right hand and forearm\tNA\t3\t37\t\n6\tRight hip (PJI)\tNone\t9\tResection arthroplasty, tobramycin cement spacer\tRevision THA\t4\t6\t49\t\n7\tMultiple joints‡\tI&D\t1\tHardware removal, I&D, amikacin bead implantation, arthrotomy and osteotomy with amikacin cement, soft-tissue excisions\tExcisional debridement of left forearm and right foot with amikacin bead placement§\t51\t51\t2\t\n8\tLeft knee, right hip\tNone\tUNK\tI&D, amikacin cement spacer\tTKA with tumor prosthesis, gentamicin cement, amikacin beads\t7\t8\t48\t\n9\tLeft knee (PJI)\tExplant with antimicrobial spacer, I&D\t4\tI&D, explantation, tobramycin spacer, intramedullary nail with tobramycin cement, revision of spacer\tRevision TKA with tobramycin cement and amikacin beads\t20\t12\t20\t\n10\tLeft knee\tArthroscopic meniscectomy, synovial biopsy, aspirations, arthroscopic synovectomy\t2\tRadical synovectomy, amikacin bead implantation, resection arthroplasty, knee-spanning intramedullary nail with tobramycin cement\tTKA with tumor prosthesis and tobramycin cement\t40\t12\t4\t\n11\tRight knee (PJI)\tNone\t12\tExplantation, amikacin spacer, I&D, intramedullary nail with amikacin cement\tRevision TKA with gentamicin cement and amikacin beads\t7\t11\t17\t\n12\tLeft knee (PJI)\tI&D, polyethylene exchange\t0\tExplantation, gentamicin cement spacer\tRevision TKA with tobramycin cement and amikacin beads\t12\t5\t20\t\n13\tRight knee (PJI)\tExplant, I&D, antimicrobial spacers\t3\tRevision TKA, I&D, intramedullary nail with amikacin cement\tRevision TKA with amikacin cement and amikacin beads\t14\t6\t1\t\n14\tRight elbow\tNone\t8\tWide excision of right forearm, nodule excision\tWide excision of right forearm\t4\t10\t47\t\n*I&D, irrigation and debridement; NA, not applicable; PJI, prosthetic joint infection, THA, total hip arthroplasty; TKA, total knee arthroplasty; UNK, unknown.\n†Infection was present in patient’s left thigh and knee, and right talus, ankle joint, and subtalar joint.\n‡Infection was present in patient’s left elbow, buttock, forearm, calf, right ankle and thigh, and both feet. \n§Because this patient is in treatment for chronic disseminated infection, definitive procedure is defined as the most recent surgical procedure.\n\nHistopathology and Microbiology\n\nThe species of NTM responsible for the musculoskeletal infection was known or identified in each patient. All patients had tissue specimens taken for culture during their procedure(s) at UCH. Eight patients had microbiologic diagnoses of NTM infection before transfer to UCH, and 6 of these patients were culture-negative at the time of surgery at UCH (case-patients 1, 2, 4, 8, 9, and 13). Antimicrobial therapy was initiated at outside hospitals in 6 of the 8 patients who came to UCH with established microbiologic diagnoses; the other 2 patients were referred directly to infectious diseases specialists at UCH, NJH, or both for treatment.\n\nSeven patients were infected with a rapidly growing mycobacterial species, whereas the remaining 7 were infected with slowly growing species (Table 1). Ten patients had intraoperative biopsy specimens demonstrating granuloma formation, but only 2 of these had evidence of acid-fast bacilli on direct microscopy. Eight of 14 patients had intraoperative cultures that grew NTM, with speciation consistent with prior data when available. All patients had visual evidence of infection at the time of operation. One patient who had M. marinum worked at a pet store that sold fish and aquariums and frequently submerged her hands and arms in the water, and her infection originated at a failed IV site. In the 5 patients with M. avium complex, 3 had speciation available that identified M. intracellulare.\n\nAntimicrobial Treatment\n\nAll patients were treated with combination antimycobacterial chemotherapy (Table 3) determined on the basis of antimicrobial drug sensitivities (Appendix Table) and recommendations from NJH. Thirteen of 14 patients were receiving antimycobacterial therapy at the time of surgery based on previous culture and drug susceptibility test results. Antimicrobial therapy was not administered around the time of surgery for case-patient 7 because of adverse effects from these medications.\n\nTable 3 Microbiology and antimicrobial treatment of patients with nontuberculous mycobacterial musculoskeletal infections, Colorado, USA*\n\nPatient no.\tSpecies\tOral therapy (duration, mo)\tIntravenous therapy (duration, mo)\tTotal duration of therapy, mo\tTime from last surgery to cessation of antimicrobial therapy, mo\tOutcome\t\n1\tM. abscessus\tAzithromycin (24)\tTigecycline + amikacin + imipenem (24)\t24\t0\tCured\t\n2\tM. abscessus\tAzithromycin + linezolid (6)\tAmikacin + imipenem (6)\t6\t0\tCured\t\n3\tM. abscessus\tAzithromycin + clofazimine (20)\tImipenem + amikacin (15)\t20\t0\tCured\t\n4\tM. abscessus\tAzithromycin + clofazimine (14)\tCefoxitin + amikacin (8)\t14\t0\tCured\t\n5\tM. fortuitum\tMoxifloxacin (2)\tImipenem (2)\t2\t1\tCured\t\n6\tM. fortuitum\tDoxycycline + ciprofloxacin + trimethoprim/ sulfamethoxazole (5)\tAmikacin (3)\t5\t3\tCured\t\n7\tM. massiliense\tAzithromycin, linezolid (4)\tCefoxitin, tigecycline, linezolid, amikacin, azithromycin (4)\t4†\tNA\tTreatment failure\t\n8\tM. intracellulare\tAzithromycin + ethambutol + rifabutin (14)\tAmikacin (8)\t14\t1\tCured\t\n9\tMAC, speciation unavailable\tAzithromycin + clofazimine + ethambutol + rifampin (39)\tAmikacin (2)\t39\t11\tCured\t\n10\tM. intracellulare\tAzithromycin + rifampin + clofazimine + ethambutol (27)\tAmikacin (5)\t27\t7\tCured\t\n11\tM. intracellulare\tAzithromycin + moxifloxacin + ethambutol (9)\tNone\t9\t5\tCured\t\n12\tMAC, speciation unavailable\tAzithromycin + ethambutol + rifampin (7)\tNone\t7\t3\tCured\t\n13\tM. gordonae\tAzithromycin + trimethoprim/ sulfamethoxazole + ethambutol (16)\tAmikacin (2)\t16\t2\tCured\t\n14\tM. marinum\tAzithromycin + ciprofloxacin (14)\tImipenem (10)\t14\t10\tCured\t\n*All bacteria are Mycobacterium spp. MAC, Mycobacterium avium complex. \n†Patient elected to discontinue antimicrobial treatment after experiencing intolerable side effects from multiple medications, despite ongoing disseminated infection.\n\nAmikacin-related toxicity occurred in 3 patients. Ototoxicity occurred in 2 patients: case-patient 1 reported hearing loss after 9 months of parenteral amikacin and within 1 month of implantation of amikacin beads, and case-patient 6 experienced tinnitus after 3 months of parenteral amikacin. Kidney injury occurred in case-patient 7 after 3 months of parenteral amikacin and 1 month after implantation of amikacin beads (creatinine level increased from 0.71 to 2.37 mg/dL). Tigecycline was also discontinued in case-patient 7 due to intractable nausea and vomiting within 2 days of initiation, and cefoxitin was discontinued due to fever within 3 days of treatment. Clofazimine also caused intractable nausea and vomiting upon initiation in this patient and was discontinued after 1 month. Apart from case-patient 1, who experienced permanent hearing loss, toxicity resolved with discontinuation of medications. Two patients with M. avium complex infection did not receive amikacin due to history of C. difficile infection (case-patients 10 and 11).\n\nThe median duration of antimicrobial chemotherapy was 14 months (range 2–39 months). Among the 7 patients with rapidly growing NTM, the median duration was 6 months. The median duration was longer in patients with slow-growing NTM, at 14 months. Twelve patients received injectable antimicrobial drugs as part of their treatment regimen, whereas 2 patients had oral therapy alone. The median duration of therapy with injectable agents was 5 months; rapidly growing strains were treated for a median of 6 months and slow-growing strains for a median of 5 months. The median duration of antimicrobial drug therapy after definitive surgery was 2 months. Patients infected with slow-growing NTM received a more protracted course of postoperative antimicrobial therapy, with a median duration of 5 months, compared with <1 month in patients infected with rapidly growing strains.\n\nOutcomes\n\nDuring the follow-up period after surgical intervention (median duration 20 months, range 1–60 months), 13/14 patients did not develop clinical or microbiological relapse and were cured. One (case-patient 7) had clinical and microbiological relapse and was deemed to have failed treatment; the first relapse occurred 2 months after the first surgery to control the infection. The relapse, a disseminated infection distant from the original surgical site, was a likely result of the patient receiving multiple immunosuppressive medications to control systemic lupus erythematosus. She required 12 surgical procedures within the first year and subsequently required ≈1 procedure/year for control of chronic disseminated infection over the next 3 years, primarily in the form of debridement and excision of soft tissue mass. Of note, this patient chose to forgo antimicrobial therapy after the first 4 months of treatment because of intolerable side effects from multiple medications. Two instances of microbiologic relapse were documented for this patient.\n\nDiscussion\n\nWe present a series of cases of NTM musculoskeletal infections requiring surgical intervention and antimycobacterial chemotherapy that were managed at UCH and NJH over a 6-year period. NTM musculoskeletal infections have been reported in the literature sporadically due to their rare occurrence; 2 previous case series documented 29 cases over 13 years in South Korea (27) and 8 cases of PJI by NTM over 4 decades at the Mayo Clinic in the United States (26). In a 6-year period, we have identified 14 case-patients treated at our institutions with unique characteristics, in comparison to previous studies (25–28). Specifically, the cases we report indicate the importance of a low threshold for suspicion and testing for NTM in any patient who has an unidentified musculoskeletal infection, particularly with evidence of granuloma formation on pathology. Furthermore, for all of our case-patients, NTM infections developed at the site of a prior procedure (prosthetic joint or other intervention), raising the concept of early culture for mycobacteria in conjunction with or after negative results from conventional bacterial culture.\n\nOne of the most notable findings from the 3 previous case series studying NTM musculoskeletal infections was that, in all studies, the overwhelming majority of the patients were immunocompetent (26–28). In contrast, half the patients in our study were immunosuppressed as a result of either an underlying medical condition or a medication used to treat rheumatologic disease. While this may be a manifestation of the relationship between UCH and NJH, our report highlights the importance of hypervigilance for possible NTM in immunocompromised patients with musculoskeletal infections. The most severely immunocompromised patients in our series (case-patients 1, 7, and 8) had disseminated infection. Immunocompromised patients with a history of musculoskeletal surgery should receive a mycobacterial workup as a component of their care.\n\nAnother crucial aspect of our case series is the observation that 10/14 cases occurred at the site of a previous musculoskeletal surgery and 6 of these cases involved a joint prosthesis. Moreover, all 14 cases were preceded by an invasive procedure at the initial site of infection. In all but 3 of our surgery-associated cases, the onset of symptoms occurred >3 months after the preceding surgical procedure, suggesting hematogenous spread, possibly due to transient mycobacteremia, with seeding of surgically altered tissue as the likely mechanism of inoculation. This mechanism is particularly likely in case-patients 1, 7, 8, 11, and 12, which comprise 3 cases of disseminated infection in severely immunocompromised patients and 2 late prosthetic joint infections with more than a decade between initial prosthetic joint surgery and eventual infection. The previous report from South Korea noted a minority of periprosthetic infections, but most cases were related to trauma or iatrogenic injections rather than surgery (27).\n\nThe report from the Mayo Clinic focused on PJIs but noted only 8 cases over 4 decades (26). A recent series of 6 cases of chronic trauma– or intervention-related joint infection not responding to empiric therapy reported no cases of periprosthetic NTM infection (29). Our relatively rapid accumulation of surgery-related cases over a 6-year period is due to the relationship between UHC and NJH and NJH’s high volume of NTM cases; we cannot generalize this trend to the general US population, given the unique referral characteristics of our patient population. It is possible that improvements in detection and identification of NTM infections may contribute to this increased case volume, as has been suggested to explain the increasing incidence and prevalence of pulmonary NTM (30). Regardless, infections in our study were more likely to occur at the site of a previous orthopedic surgery and in >4 cases led to severe complications requiring partial or full amputation, with 1 patient requiring hemipelvectomy. Three of these patients were infected with M. abscessus and 1 with M. fortuitum. M. abscessus is highly drug resistant and therefore responds poorly to antimicrobial therapy. It is difficult to ascertain if these amputations could have been avoided with earlier diagnosis and aggressive surgical therapy. In several cases, patients with long delays in diagnosis ultimately required amputation; almost one third of patients in our series required amputation.\n\nGiven the importance in identifying NTM musculoskeletal infections in the immunocompromised or those with prior surgery, it is unfortunate that our data did not identify more substantial diagnostic criteria based upon inflammatory markers. Whereas the ESR in our patients was usually elevated, the C-reactive protein and leukocyte counts were typically normal. The patient who failed treatment had one of the highest ESRs in our patient group, nearly double the median value of 38 at intake, perhaps because of her chronic autoimmune condition.\n\nAll patients had positive mycobacterial cultures at time of initial diagnosis. Thirteen of 14 patients were receiving mycobacterial therapy at the time of surgery at our institution and only half of them were persistently positive for mycobacterial growth despite ongoing symptoms and intraoperative observation of sinus tract formation and suppuration. We are familiar with this phenomenon, and therefore do not require a positive culture to define failure of therapy. If a patient has ongoing signs of infection while receiving effective antimicrobial drugs (based on drug sensitivity testing), then they need more aggressive resection of infected tissue. The 3 patients with PJI and rapidly growing NTM infection all required prolonged courses of IV and oral antimicrobial therapy. One of the 3 patients with M. avium complex–related PJI also required 2 months of concomitant IV amikacin. All patients with PJIs required explantation of the infected hardware followed by antimicrobial spacer placement for >3 months in addition to ongoing postoperative oral or intravenous antimicrobial therapy to achieve a successful outcome. In >5 cases, microbiologic diagnosis of mycobacterial infection was only confirmed during the initial surgical intervention, and in each of these cases, prior or subsequent surgeries were required for ultimate control of infection. Ultimately, the fact that 10/14 cases required multiple surgeries for control of infection with long intervals from onset of symptoms and initial seeking of care to identification of the infectious agent and finally definitive surgical treatment underscores the need for early identification and aggressive treatment of NTM infection.\n\nAppendix\n\nAdditional information about nontuberculous mycobacterial musculoskeletal infections, Colorado, USA.\n\nDr. Goldstein is a graduate of the University of Colorado School of Medicine, Aurora, CO. He will begin his residency in psychiatry at the University of North Carolina in July 2019.\n\nSuggested citation for this article: Goldstein N, St. Clair JB, Kasperbauer SH, Daley CL, Lindeque B. Nontuberculous mycobacterial musculoskeletal infection cases from a tertiary referral center, Colorado, USA. 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Breda L, de Michele G, Nozzi M, De Sanctis S, Di Marzio D, Chiarelli F. Non-tuberculous mycobacterial osteomyelitis: an unusual cause of hip pain in immunocompetent children. Rheumatol Int. 2009;29 :1487–9. 10.1007/s00296-009-0844-4 19156420\n14. Wang S-X, Yang C-J, Chen Y-C, Lay C-J, Tsai C-C. Septic arthritis caused by Mycobacterium fortuitum and Mycobacterium abscessus in a prosthetic knee joint: case report and review of literature. Intern Med. 2011;50 :2227–32. 10.2169/internalmedicine.50.5610 21963746\n15. Garcia DC, Sandoval-Sus J, Razzaq K, Young L. Vertebral osteomyelitis caused by Mycobacterium abscessus. BMJ Case Rep. 2013;2013 (aug07 1 ):cr2013009597. 10.1136/bcr-2013-009597 23925676\n16. Suy F, Carricajo A, Grattard F, Cazorla C, Denis C, Girardin P, et al. Infection due to Mycobacterium thermoresistibile: a case associated with an orthopedic device. J Clin Microbiol. 2013;51 :3154–6. 10.1128/JCM.00925-13 23843483\n17. Bakhsh WR, Mesfin A. 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Disseminated Mycobacterium avium complex infection in a child with partial dominant interferon gamma receptor 1 deficiency in India. J Clin Immunol. 2015;35 :459–62. 10.1007/s10875-015-0173-1 26054576\n22. Silva JT, López-Medrano F, Fernández-Ruiz M, San-Juan R, Ruiz-Cano MJ, Delgado JF, et al. Mycobacterium abscessus pulmonary infection complicated with vertebral osteomyelitis in a heart transplant recipient: case report and literature review. Transpl Infect Dis. 2015;17 :418–23. 10.1111/tid.12381 25816889\n23. Wood BR, Buitrago MO, Patel S, Hachey DH, Haneuse S, Harrington RD. Mycobacterium avium complex osteomyelitis in persons with human immunodeficiency virus: case series and literature review. Open Forum Infect Dis. 2015;2 :ofv090. 10.1093/ofid/ofv090 26180837\n24. Kuntz M, Seidl M, Henneke P. Osteomyelitis because of Mycobacterium xenopi in an immunocompetent child. Pediatr Infect Dis J. 2016;35 :110–3.26418244\n25. Marchevsky AM, Damsker B, Green S, Tepper S. The clinicopathological spectrum of non-tuberculous mycobacterial osteoarticular infections. J Bone Joint Surg Am. 1985;67 :925–9. 10.2106/00004623-198567060-00015 4019542\n26. Eid AJ, Berbari EF, Sia IG, Wengenack NL, Osmon DR, Razonable RR. Prosthetic joint infection due to rapidly growing mycobacteria: report of 8 cases and review of the literature. Clin Infect Dis. 2007;45 :687–94. 10.1086/520982 17712751\n27. Park JW, Kim YS, Yoon JO, Kim JS, Chang JS, Kim JM, et al. Non-tuberculous mycobacterial infection of the musculoskeletal system: pattern of infection and efficacy of combined surgical/antimicrobial treatment. Bone Joint J. 2014;96-B :1561–5. 10.1302/0301-620X.96B11.33427 25371475\n28. Johnson MG, Stout JE. Twenty-eight cases of Mycobacterium marinum infection: retrospective case series and literature review. Infection. 2015;43 :655–62. 10.1007/s15010-015-0776-8 25869820\n29. Gundavda MK, Patil HG, Agashe VM, Soman R, Rodriques C, Deshpande RB. Nontuberculous mycobacterial infection of the musculoskeletal system in immunocompetent hosts. Indian J Orthop. 2017;51 :205–12. 10.4103/0019-5413.201718 28400668\n30. Johnson MM, Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis. 2014;6 :210–20.24624285\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1080-6040",
"issue": "25(6)",
"journal": "Emerging infectious diseases",
"keywords": "Colorado; Mycobacterium; United States; antimicrobial resistance; infectious arthritis; musculoskeletal diseases; nontuberculous mycobacteria; osteomyelitis; prosthesis-related infections; tuberculosis and other mycobacteria",
"medline_ta": "Emerg Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents; D003120:Colorado; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009140:Musculoskeletal Diseases; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D016459:Prosthesis-Related Infections; D062486:Public Health Surveillance; D012189:Retrospective Studies; D063189:Symptom Assessment; D062606:Tertiary Care Centers; D055815:Young Adult",
"nlm_unique_id": "9508155",
"other_id": null,
"pages": "1075-1083",
"pmc": null,
"pmid": "31107224",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "23843483;8676110;9670366;25040696;21963746;25371475;26997636;25544922;21724552;422622;17277290;25869820;22312016;23925676;17712751;28400668;26180837;26418244;20538958;25816889;25664190;24624285;4019542;8163823;25153815;7058374;26054576;19911942;19156420;28817307",
"title": "Nontuberculous Mycobacterial Musculoskeletal Infection Cases from a Tertiary Referral Center, Colorado, USA.",
"title_normalized": "nontuberculous mycobacterial musculoskeletal infection cases from a tertiary referral center colorado usa"
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"abstract": "The presence of multiple primary tumors (MPT) in a single patient has been identified with an increasing frequency. A critical issue is to establish if the second tumor represents an independent primary cancer or a metastasis. Therefore, the assessment of MPT clonal origin might help understand the disease behavior and improve the management/prognosis of the patient.Herein, we report a 73-year-old male smoker who developed 2 primary lung cancers (adenocarcinoma and squamous cell carcinoma) and a malignant peritoneal mesothelioma (PM).Whole exome sequencing (WES) of the 3 tumors and of germline DNA was performed to determine the clonal origin and identify genetic cancer susceptibility.Both lung cancers were characterized by a high mutational rate with distinct mutational profiles and activation of tumor-specific pathways. Conversely, the PM harbored a relative low number of genetic variants and a novel mutation in the WT1 gene that might be involved in the carcinogenesis of nonasbestos-related mesothelioma. Finally, WES of the germinal DNA displayed several single nucleotide polymorphisms in DNA repair genes likely conferring higher cancer susceptibility.Overall, WES did not disclose any somatic genetic variant shared across the 3 tumors, suggesting their clonal independency; however, the carcinogenic effect of smoke combined with a deficiency in DNA repair genes and the patient advanced age might have been responsible for the MPT development. This case highlights the WES importance to define the clonal origin of MPT and susceptibility to cancer.",
"affiliations": "Lung Cancer Unit, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova Centre for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milan Department of Internal Medicine and Medical Specialties (DIMI), Università di Genova IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova Department of Pathology, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro and Department of Health Sciences, Università di Genova, Genova, Italy.",
"authors": "Vanni|Irene|I|;Coco|Simona|S|;Bonfiglio|Silvia|S|;Cittaro|Davide|D|;Genova|Carlo|C|;Biello|Federica|F|;Mora|Marco|M|;Rossella|Valeria|V|;Dal Bello|Maria Giovanna|MG|;Truini|Anna|A|;Banelli|Barbara|B|;Lazarevic|Dejan|D|;Alama|Angela|A|;Rijavec|Erika|E|;Barletta|Giulia|G|;Grossi|Francesco|F|",
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"country": "United States",
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"doi": "10.1097/MD.0000000000005447",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 27902597MD-D-16-0255410.1097/MD.0000000000005447054475700Research ArticleClinical Case ReportWhole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma A case reportVanni Irene MSaCoco Simona PhDa∗Bonfiglio Silvia PhDbCittaro Davide PhDbGenova Carlo MDacBiello Federica MDaMora Marco MDdRossella Valeria MSbDal Bello Maria Giovanna PhDaTruini Anna MSacBanelli Barbara PhDeLazarevic Dejan PhDbAlama Angela PhDaRijavec Erika MDaBarletta Giulia MDaGrossi Francesco MDaBombardiere. Sergio Gonzalez a Lung Cancer Unit, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genovab Centre for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, Milanc Department of Internal Medicine and Medical Specialties (DIMI), Università di Genova IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genovad Department of Pathology, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genovae Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro and Department of Health Sciences, Università di Genova, Genova, Italy.∗ Correspondence: Simona Coco, Lung Cancer Unit, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, L.go R. Benzi 10, 16132 Genova, Italy (e-mail: simona.coco@hsanmartino.it).12 2016 02 12 2016 95 48 e544712 4 2016 30 8 2016 28 10 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Supplemental Digital Content is available in the text\n\nAbstract\nThe presence of multiple primary tumors (MPT) in a single patient has been identified with an increasing frequency. A critical issue is to establish if the second tumor represents an independent primary cancer or a metastasis. Therefore, the assessment of MPT clonal origin might help understand the disease behavior and improve the management/prognosis of the patient.\n\nHerein, we report a 73-year-old male smoker who developed 2 primary lung cancers (adenocarcinoma and squamous cell carcinoma) and a malignant peritoneal mesothelioma (PM).\n\nWhole exome sequencing (WES) of the 3 tumors and of germline DNA was performed to determine the clonal origin and identify genetic cancer susceptibility.\n\nBoth lung cancers were characterized by a high mutational rate with distinct mutational profiles and activation of tumor-specific pathways. Conversely, the PM harbored a relative low number of genetic variants and a novel mutation in the WT1 gene that might be involved in the carcinogenesis of nonasbestos-related mesothelioma. Finally, WES of the germinal DNA displayed several single nucleotide polymorphisms in DNA repair genes likely conferring higher cancer susceptibility.\n\nOverall, WES did not disclose any somatic genetic variant shared across the 3 tumors, suggesting their clonal independency; however, the carcinogenic effect of smoke combined with a deficiency in DNA repair genes and the patient advanced age might have been responsible for the MPT development. This case highlights the WES importance to define the clonal origin of MPT and susceptibility to cancer.\n\nKeywords\nclonal originmesotheliomamultiple lung cancerstumor susceptibilitywhole exome sequencingOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe incidence of multiple primary tumors (MPT) during an individual's lifetime is increasing, mainly due to the advent of accurate cancer secondary prevention programs and the increase of life expectancy for cancer patients. The development of multiple primary lung cancers (MPLC) is an uncommon event, although the improvement in the diagnostic tests and novel therapies able to influence survival after the first diagnosis of cancer have led to an incidence peak that has grown up to 20% over the past 10 years.[1,2] A correct understanding whether the second tumor is an independent primary lesion or a metastasis is fundamental for an adequate therapeutic management of these patients. Currently, the main criteria for defining the lineage of multiple unrelated intrapulmonary tumors compared with metastatic lesions are based on pathological and clinical assessments.[3,4] To date, several studies have described MPLC cases,[1] but most of them have analyzed a limited number of genetic markers, resulting in a low accuracy and limited ability to establish cancers clonality.[5,6] Next generation sequencing (NGS) is a recent technology that can contribute to understanding the molecular mechanisms underlying tumor development by screening the whole DNA mutational profile.[7–10] Recently, Murphy et al[11] applied the NGS approach to define the lineage of MPLC, demonstrating how genomic rearrangements were able to distinguish MPLC from metastatic lesions; however, the authors did not evaluate somatic and germinal mutational profiles. Once established that MPLC are primary and independent tumors, understanding the intrinsic genetic susceptibility to develop multiple cancers during the lifetime is crucial; indeed, those subjects with high predisposition might be enrolled in prevention programs and benefit from personalized follow-ups. Herein, we report an interesting case of a patient that developed 2 primary histologically distinct lung tumors and a malignant PM after 6 years. WES allowed us to deeply screen the 3 tumors, in order to identify a mutational signature specific for each malignancy and to establish the clonal origin of cancers. Concomitantly, the sequencing of normal genomic DNA (gDNA) allowed the identification of germline genetic variants potentially correlated with an individual risk of developing multiple cancers.\n\n2 Case report\nWe describe the case of a Caucasian male patient with a medical history of heavy smoking habit (100 pack-years), chronic obstructive pulmonary disease (COPD), and no exposure to asbestos. Before being referred to our unit, the patient was initially followed and treated in a different institution; hence, part of the patient's oncologic history was retrospectively retraced when he came to our attention (Fig. 1). In January 2009, the patient, aged 73 years, was subjected to a chest X-ray as preoperative examination for minor surgery with the incidental detection of a suspicious opacity in the left lower lobe. The subsequent diagnostic work-up confirmed a high-risk lesion in the left lower lobe; in addition, the computed tomography (CT) scan identified a smaller lesion in the right upper lobe (22 mm), which was considered an indeterminate lung nodule due to its morphologic characteristics, along with unspecific micro-nodules in the same lung. As the position of the pulmonary findings and the structural lung alterations caused by COPD prevented the collection of bioptic samples, the decision of approaching the left lung lesion with surgery and periodically evaluate the evolution of the indeterminate nodule was taken. Hence, the patient underwent left lung lower lobe segmental resection in April 2009, with postoperative diagnosis of stage IB lung adenocarcinoma (ADC) with solid and glandular patterns and foci of mucus secretion (Fig. 2A). The immunohistochemistry (IHC) analysis revealed positivity for TTF-1, consistently with the diagnosis of a lung primary tumor. The postoperative pathological staging was pT2a, G3, Nx, Mx.\n\nFigure 1 Timeline of oncologic history of the patient. Dashed line means the time of each diagnostic examination (red box) or surgical intervention (violet); Light green, dark green, and dark/light blue boxes report the ADC, SCC, and PM evolution, respectively. Yellow box describes the pharmacological treatment.\n\nFigure 2 Hematoxylin and eosin stained images of ADC (A), SCC (B), and PM (C) (Original magnification 40x). Immunohistochemistry of PM reported a positive staining for Calretinin (D), CK-7 (E), and CK5&6 (F), whereas a negative staining for TFF-1 (G) and p63 (H) (Original magnification 40x).\n\nThe indeterminate nodule in the right upper lobe remained stable until September 2010, when an increase of its maximum diameters from 22 to 33 mm was reported; a positron emission tomography (PET) scan showed fluorodeoxyglucose (FDG) uptake limited to the right upper lobe lesion (SUV max: 6.2). Following this finding, the lesion was considered a metastasis of the original ADC and subsequently the patient received chemotherapy with carboplatin (AUC2), which was discontinued after 2 cycles for thrombocytopenia. During the subsequent assessments, the pulmonary lesion was substantially stable until November 2011, when a significant dimensional increase was observed. A subsequent PET-scan confirmed the right lung lesion as the only clearly detectable active site of disease (SUV max: 12.6, increased from the previous examination), while no distant metastases were identified; therefore, surgery with potential curative intent for oligo-metastatic disease was proposed. Hence, in January 2012, the patient underwent right upper lobectomy and radical lymphadenectomy with postoperative diagnosis of keratinizing and moderately differentiated squamous cell carcinoma (SCC) of the lung with positivity for p63 at IHC (pT2a G2 pN0 Mx, stage IB) (Fig. 2B). Although the clinical presentation could initially suggest a possible correlation between the 2 lung lesions, the IHC led to define 2 histologically distinct primary lung tumors. After surgery, the patient did not receive further treatments. In February 2014, metabolically active gastric lymphadenopathies and ascites were detected during follow-up, although no suspicious lesions were identified with esophagogastroduodenoscopy. Between October 2014 and January 2015, diffuse nodulations within the abdomen, morphologically compatible with peritoneal carcinomatosis, and a new lesion in the middle lobe of the right lung were identified. In February 2015, the patient was referred to our institution (Lung Cancer Unit; IRCCS AOU San Martino - IST, Genova, Italy), wherein he underwent biopsy of an easily accessible abdominal lesion located at the level of the right iliac fossa. At microscopic examination, the specimen was consistent with several small fibrous fragments diffusely infiltrated by an epitheliomorphic neoplasm composed of atypical cells, ranging from middle to large dimension, with well-represented eosinophilic cytoplasm, sometimes microvacuolated, and large nuclei, with prominent eosinophilic nucleoli; rare “hobnail cells” were identified and the neoplastic elements were arranged in solid nests, ribbons, and papillary structures. At IHC, expression of CK7, CK5&6, calretinin, and WT-1 was detected in neoplastic cells, whereas no expression of CK20, p63, MOC-31, TTF-1, and napsin-A was reported (Fig. 2C–H). On the basis of the morphology and the IHC pattern, the diagnosis of epithelioid PM was posed and, subsequently, the patient received chemotherapy with pemetrexed (500 mg/m2), which was discontinued after 2 cycles due to poor tolerance. Then, the patient experienced progressive worsening of clinical conditions and died in March 2015. Relevant images from CT-scans collected throughout the clinical history of the patients have been reported in Fig. 3.\n\nFigure 3 Relevant figures from CT-scans collected throughout the patient's clinical history. The arrows indicate lesions of interest. Notably, as the patient could not provide CT-scans performed before April 2009 in a different Institution, pictures of the lung adenocarcinoma located in the left lower lobe are not available. (A) CT-scan picture showing the SCC located in the right upper lobe in September 2010, before being treated with carboplatin-based chemotherapy; (B) CT-scan picture showing the same tumor (SCC) as in November 2011, progressing after carboplatin-based chemotherapy and periodical follow-up; (C) CT-scan picture showing diffuse abdominal lesions of PM.\n\nIn order to understand whether ADC, SCC, and PM were unrelated cancers or shared a common clonal evolution, WES analysis was performed on the 3 tumors by HiSeq 2500 sequencer (Illumina Inc, San Diego, CA, USA) as already described.[12] Simultaneously, the WES of germinal gDNA obtained from peripheral blood was performed to subtract the germline background for the identification of somatic variants (see text, Supplemental Content 1, which illustrates samples processing and WES analysis).[12–15] For this analysis, the ADC and the SCC samples were collected from stored surgical specimens (acquired during potentially curative surgery), while the PM sample derived from the tissue collected during the abdominal biopsy.\n\nWe firstly extracted the somatic mutational signature from all the tumors according to base substitutions, as already described by Alexandrov et al.[8] This analysis displayed a predominance of C>A transversions in both lung cancers (ADC and SCC) (Fig. 4A), corresponding to a specific cancer signature related to tobacco consumption.[8] In contrast, the PM did not exhibit any specific mutational signature, probably as a consequence of the few observed somatic variants (Fig. 4A). Then, we found that each tumor reported a specific set of somatic variants (358, 405, 28 in ADC, SCC, and PM, respectively; Fig. 4B; See Table, Supplemental Content 2A, Supplemental Content 2B, and Supplemental Content 2C, which list all somatic mutations found in ADC, SCC, and PM, respectively), which were not shared across the 3 tumors. Both ADC and SCC showed lung tumor hotspot mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC; http://cancer.sanger.ac.uk/cosmic) database and described in lung cancers: EHHADH (COSM5247826), KRAS (COSM512), OR4K2 (COSM1515038), and TP53 (COSM6549) in ADC; KIAA1324L (COSM396629), NFE2L2 (COSM396629), PEG3 (COSM5284477), POM121L12 (COSM393793), and WAC (COSM5311283) in SCC. Moreover, both histotypes carried mutations associated with potential therapeutic targets (FLT3 and HGF in ADC; MTOR in SCC), or in a predictor of resistance to EGFR tyrosine kinase inhibitors (KRAS in ADC).\n\nFigure 4 (A) Specific mutational signature for ADC, SCC, and PM according to the base substitutions.[8] The substitution types are showed on the horizontal axis, whereas the percentages of base substitutions are displayed on the vertical axis. (B) Mutational profile of somatic (ADC, SCC, and PM) and germline (PB) gene variants divided in single nucleotide variant (SNV), multiple nucleotide variant (MNV), and INDEL. Each type of mutation was subdivided into exon or non-exon (intergenic regions, downstream and upstream regions, 5′UTR/3′UTR regions, splice regions, and intron regions) variants. “Stop gained”: variant causes a stop codon; “Start_Stop lost”: variant causes start codon to be mutated into a nonstart codon or variant causes stop codon to be mutated into a nonstop codon, respectively; “Splice region variant”: variant affective putative (Lariat) branch point from U12 splicing machinery, located in the intron; “Sequence Feature”: unknown/any extent of continuous biological sequence.\n\nThe enrichment analysis using Reactome 2015 (http://amp.pharm.mssm.edu/Enrichr/) also showed that different pathways were deregulated in ADC and SCC. Specifically, ADC was enriched with altered genes belonging to the MAPK pathway (p.Gly12Phe KRAS; c.∗76delC MAP2K; c.∗30C>T MAP3K4), whereas the mutations observed in SCC mostly affected genes involved in collagen modification, in extracellular matrix organization (p.His1331Gln ADAMTS3; p.Phe486Ser COL19A1; p.Ala75fs LOX; c.93 + 567C>A SPP1; p.Pro947Ser LAMB1; p.Met688Ile A2M), and in the meiotic synapsis pathway (p.Ser1801Gly ATR; p.Gln1747Glu DIDO1; c.1961 + 53A>T SUN1; c.17542-41A>C SYNE1). Conversely, the PM did not display COSMIC mutations or pathways associated with the carcinogenesis, probably due to the low number of somatic mutations (28); however, among these mutations, we identified 3 novel variants including 2 frameshift variants (p.Glu673fs BAP1; p.Glu1595fs SETD2) and a missense variant (p.Ser71Phe WT1).\n\nGermline analysis was also performed in order to discover genetic variants potentially linked to cancer predisposition. Germinal gDNA sequencing identified a total of 31,608 genetic variants of which 15,790 and 15,818 occurred in exons and nonexons regions, respectively (Fig. 4B). In particular, 49% (7784/15,790) of the exon variants showed a high/moderate effect on the protein, whereas the 66% (10,397/15,818) of nonexon variants potentially modified the protein regulation based on effect prediction of SnpEff tool (http://snpeff.sourceforge.net).\n\nAs pathway analysis did not disclose enrichment pathways linked to tumor susceptibility, we focused on genes related to DNA repair or associated with cancer predisposition. The analysis identified 74 genetic variants in 59 genes related to DNA repair/cancer predisposition. Specifically, 21 out of 74 genetic variants have already been described to confer a high risk of cancer development and 7 of them were homozygous (rs3760413, EME1; rs26279, MSH3; rs8305, POLI; rs373572, RAD18; rs462779, REV3L; rs25487, XRCC1; rs1143634, IL1B) (Table 1). Finally, we found 5 single nucleotide polymorphisms (SNPs) (rs1948, CHRNB4; rs1051730, CHRNA3; rs16969968, CHRNA5; rs4950, CHRNB3; rs5320, DBH) involved in the etiology of the nicotine dependence (Table 1).\n\nTable 1 Single nucleotide polymorphisms associated with tumor susceptibility and nicotine dependence.\n\n3 Discussion\nHere, we describe an infrequent case of a patient who developed 2 histological distinct intrapulmonary tumors and a PM after 6 years. WES of the 3 tumors was performed to establish a clonal relationship. Although both lung ADC and SCC showed a similar mutational signature, characterized by a prominence of C>A substitutions, they did not share common somatic variants. Interestingly, the signature characterized by C>A mutations has been associated with smoke exposure in several cancers including lung ADC and SCC[8]; indeed, cigarettes contain a complex mixture of carcinogenic agents and these compounds could interact with DNA leading to the accumulation of somatic mutations. Recently, Warth et al[6] analyzed a set of synchronous primary lung tumors demonstrating that clonally independent ADC and SCC tumors were mainly identified in heavy smoker patients. These data support the association between extensive smoking and the development of the 2 clonally unrelated lung tumors occurred in our case. Across 358 altered genes in the ADC, we found 6 (KRAS, MAP2K1, MGAM, NF1, PPP3CA, and TP53) of 38 genes significantly mutated in a cohort of 660 lung ADC.[16] Of note, mutation in PPP3CA co-occurred with an activating KRAS mutation (COSM512) as already described by Campbell et al.[16] In addition, the mutation in the MGAM gene has been also observed in a comprehensive genome-wide characterization by Cancer Genome Atlas Research Network among 18 genes found significantly mutated in 230 lung ADC tumors.[17] Across the 405 SCC-mutated genes, we found only 1 gene (NFE2L2) of 20 genes recurrent mutated in 484 lung SCC tumors[16]; moreover, mutations in NFE3L2 gene have also been identified in 34% of 178 lung SCC tumors profiled by Cancer Genome Atlas Research Networt.[18]\n\nFurthermore, both lung tumors showed a specific gene signature linked to distinct pathways of activation. Specifically, the ADC harbored mutations in genes involved in EGFR signaling pathway, such as 2 novel genetic variants in the 3’UTR regions of MAP3K4 and MAP2K1 genes, and a hotspot mutation in the KRAS codon 12; as it is known, the EGFR signaling pathway is one of the most frequently altered pathways in this histology.[19] On the contrary, the SCC carried several mutations in genes involved in the extracellular matrix organization, a pathway often deregulated in cancer.[20] In particular, we found a novel frameshift deletion (c.221delC; p.Ala75fs) leading to a potential LOX protein destruction. LOX downmodulation has been found in SCC and its lack has been shown to induce the extracellular matrix disorganization leading to tumor development.[21] Furthermore, in addition to being potentially involved in tumor development, some of the affected genes that were observed in this case might also play a relevant role in a targeted therapy approach in patients affected by lung cancer, possibly reducing sensitivity to currently registered agents or eventually representing potential targets for drugs that might become available for lung cancer in future. Although it is still unclear whether KRAS mutations are actually associated with resistance to EGFR inhibitors in lung cancer,[22] aberrations of HGF signal are apparently involved in resistance to anti-EGFR and anti-VEGF targeted therapies.[23] Contrarily, FLT-3 and mTOR might represent potentially actionable targets, as the former is sensitive to drugs such as dovitinib, while the latter is sensitive to everolimus.[24]\n\nConversely, in PM, the distribution of base substitutions did not match any specific mutational signature, probably as a consequence of a relatively limited number of observed mutations (28 variants in PM vs >350 in the lung cancer lesions). Peritoneal mesothelioma is an extremely rare tumor and our sequencing data were in accordance with a previous study in which the authors performed WES on 7 PM finding a low mutational rate and BAP1 as the most altered gene.[25] We also found an insertion in BAP1, potentially associated with a loss-of-function, and a deletion changing the reading frame in SETD2, a gene found altered in malignant pleural mesothelioma.[26] In addition, we detected a novel mutation in the WT1 transactivation domain (NM_000378.4; c.212C>T; p.Ser71Phe). Mutated WT1 has been already described in mesothelioma; interestingly, Park et al[27] reported a patient with PM that harbored a point mutation within the transactivation domain of WT1 gene, demonstrating that this variant conferred an activation of its transcriptional role. However, the authors did not find any WT1 mutations in a further set of 32 asbestos-related mesothelioma patients, thus concluding that the WT1 pathway could be involved in the malignant transformation of nonasbestos-related mesothelioma. These data suggest that the p.Ser71Phe WT1 mutation might be implicated in the PM carcinogenesis process through the WT1 downstream pathway activation. Indeed, the mutation serine-71-phenylalanine (p.Ser71Phe) in WT1 gene is a nonconservative mutation that alters the properties of the protein by replacing the small and polar serine with the large and bulky side chain of a phenylalanine.\n\nAccording to the previous data and excluding a common lineage across the 3 tumors, we hypothesized that this patient could have an intrinsic predisposition to develop MPT. Indeed, the germinal gDNA sequencing showed that more than half of the variants were potentially associated with protein alterations. Notably, the analysis identified 21 genetic variants that were already described; of these, 62% were related to increased lung cancer risk. Among such variants, the association of the p.Glu589Lys in EXO1 gene (rs1047840) with cigarette smoking has been described as conferring a significantly increased lung cancer risk, with a reported odds ratio equal to 1.72.[28]\n\nTo the best of our knowledge, this is the first study that investigates the whole exome mutational profile of 3 MPT aimed at defining the clonal origin of the tumor lesions and also the germline assets in order to discover an individual genetic susceptibility to cancer predisposition. Our data support the hypothesis that the development of the 3 tumors was clonally independent, as they do not share a common mutational profile; however, we could not exclude the presence of mutations in regulatory regions, omitted by WES. The patient also carried several SNPs involved in nicotine dependence and DNA repair. The carcinogenic effects of tobacco smoke together with both a DNA repair deficiency and the advanced age of the patient may have led to a high mutation rate in the lung cancer lesions. It is also known that chemotherapy might affect the mutational status of eukaryote cells.[29] Despite the only 2 cycles of carboplatin, considering the interval between treatment and SCC tumor collection (about 14 months), we cannot exclude the mutagenic effect induced by carboplatin.\n\nOn the contrary, the low number of somatic mutations in PM suggests that its development is mainly caused by onset of mutations in driver genes (BAP1 and SETD2) and that other mechanisms, such as microRNA deregulation, might be involved.[30] In addition, the novel missense mutation in WT1 gene may also explain the PM development regardless of asbestos exposure.\n\nIn conclusion, this study underlines how the germline assets could influence the cancer predisposition and how future WES studies on patients with MPT should be directed toward the genetic variants identification leading to cancer susceptibility. Our findings highlight the power of WES analysis in screening the mutational landscapes of patient with MPT in order to define the clonal feature and identify novel potential molecular targets for treatment.\n\nSupplementary Material\nSupplemental Digital Content\n Supplementary Material\nSupplemental Digital Content\n Supplementary Material\nSupplemental Digital Content\n Supplementary Material\nSupplemental Digital Content\n Acknowledgment\nWe kindly thank Drs Cristina Bruzzo and Zita Cavalieri for technical support (IRCCS AOU San Martino – IST, Genova, Italy), and Dr Gabriele Bucci for bioinformatics support (IRCCS San Raffaele Scientific Institute, Milan, Italy).\n\nAbbreviations: ADC = adenocarcinoma, COPD = chronic obstructive pulmonary disease, CT = computed tomography, Genomic DNA = gDNA, IHC = immunohistochemistry, MNV = multiple nucleotide variant, MPLC = multiple primary lung cancers, MPT = multiple primary tumors, NGS = next generation sequencing, PET = positron-emission tomography, PM = peritoneal mesothelioma, SCC = squamous cell carcinoma, SNP = single nucleotide polymorphism, SNV = single nucleotide variant, WES = whole exome sequencing.\n\nIV, SC, and SB contributed equally to this work.\n\nFunding/support: The present study was supported by “Italian Ministry of Health” (GR 2011–12; 02350922; SC).\n\nThe authors have no conflicts of interests to disclose.\n\nWritten informed consent was obtained from the patient to perform the molecular analysis and public the content.\n\nSupplemental Digital Content is available for this article.\n==== Refs\nReferences\n[1] Xue X Liu Y Pan L \nDiagnosis of multiple primary lung cancer: a systematic review . J Int Med Res \n2013 ;41 :1779 –87 .24265329 \n[2] Lee YC Park YJ Gang SJ \nRepeated occurrence of second primary lung cancer at different sites in trachea: a case report . Medicine \n2015 ;94 :e770 .25929917 \n[3] Martini N Melamed MR \nMultiple primary lung cancers . J Thorac Cardiovasc Surg \n1975 ;70 :606 –12 .170482 \n[4] Antakli T Schaefer RF Rutherford JE \nSecond primary lung cancer . Ann Thorac Surg \n1995 ;59 :863 –6 .7695410 \n[5] Girard N Ostrovnaya I Lau C \nGenomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers . Clin Cancer Res \n2009 ;15 :5184 –90 .19671847 \n[6] Warth A Macher-Goeppinger S Muley T \nClonality of multifocal nonsmall cell lung cancer: implications for staging and therapy . Eur Respir J \n2012 ;39 :1437 –42 .22075483 \n[7] Lawrence MS Stojanov P Polak P \nMutational heterogeneity in cancer and the search for new cancer-associated genes . Nature \n2013 ;499 :214 –8 .23770567 \n[8] Alexandrov LB Nik-Zainal S Wedge DC \nSignatures of mutational processes in human cancer . Nature \n2013 ;500 :415 –21 . Erratum in: Nature. 2013;502:258. Imielinsk, Marcin [corrected to Imielinski, Marcin] .23945592 \n[9] Beltran H Eng K Mosquera JM \nWhole-exome sequencing of metastatic cancer and biomarkers of treatment response . JAMA Oncol \n2015 ;1 :466 –74 .26181256 \n[10] Coco S Truini A Vanni I \nNext generation sequencing in non-small cell lung cancer: new avenues toward the personalized medicine . Curr Drug Targets \n2015 ;16 :47 –59 .25495923 \n[11] Murphy SJ Aubry MC Harris FR \nIdentification of independent primary tumors and intrapulmonary metastases using DNA rearrangements in non-small-cell lung cancer . J Clin Oncol \n2014 ;32 :4050 –8 .25385739 \n[12] Bonfiglio S Vanni I Rossella V \nPerformance comparison of two commercial human whole-exome capture systems on formalin-fixed paraffin-embedded lung adenocarcinoma samples . BMC Cancer \n2016 ;16 :692 .27578032 \n[13] Li H Durbin R \nFast and accurate long-read alignment with Burrows-Wheeler transform . Bioinformatics \n2010 ;26 :589 –95 .20080505 \n[14] Chiang C Layer RM Faust GG \nSpeedSeq: ultra-fast personal genome analysis and interpretation . Nat Methods \n2015 ;12 :966 –8 .26258291 \n[15] Cingolani P Platts A Wang le L \nA program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3 . Fly (Austin) \n2012 ;6 :80 –92 .22728672 \n[16] Campbell JD Alexandrov A Kim J \nDistinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas . Nat Genet \n2016 ;48 :607 –16 .27158780 \n[17] Cancer Genome Atlas Research Network . Comprehensive molecular profiling of lung adenocarcinoma . Nature \n2014 ;511 :543 –50 . Erratum in: Nature. 2014;514:262 .25079552 \n[18] Cancer Genome Atlas Research Network . Comprehensive genomic characterization of squamous cell lung cancers . Nature \n2012 ;489 :519 –25 . Erratum in: Nature. 2012;491:288 .22960745 \n[19] Ding L Getz G Wheeler DA \nSomatic mutations affect key pathways in lung adenocarcinoma . Nature \n2008 ;455 :1069 –75 .18948947 \n[20] Lu P Weaver VM Werb Z \nThe extracellular matrix: a dynamic niche in cancer progression . J Cell Biol \n2012 ;196 :395 –406 .22351925 \n[21] Payne SL Hendrix MJ Kirschmann DA \nParadoxical roles for lysyl oxidases in cancer: a prospect . J Cell Biochem \n2007 ;10 :1338 –54 .\n[22] Roberts PJ Stinchcombe TE \nKRAS mutation: should we test for it, and does it matter? \nJ Clin Oncol \n2013 ;31 :1112 –21 .23401440 \n[23] Raghav KP Gonzalez-Angulo AM Blumenschein GR Jr \nRole of HGF/MET axis in resistance of lung cancer to contemporary management . Transl Lung Cancer Res \n2012 ;1 :179 –93 .25806180 \n[24] Reungwetwattana T Dy GK \nTargeted therapies in development for non-small cell lung cancer . J Carcinog \n2013 ;12 :22 .24574860 \n[25] Alakus H Yost SE Woo B \nBAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma . J Transl Med \n2015 ;13 :122 .25889843 \n[26] Bueno R Stawiski EW Goldstein LD \nComprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations . Nat Genet \n2016 ;48 :407 –16 .26928227 \n[27] Park S Schalling M Bernard A \nThe Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma . Nat Genet \n1993 ;4 :415 –20 .8401592 \n[28] Hsu NY Wang HC Wang CH \nLung cancer susceptibility and genetic polymorphisms of Exo1 gene in Taiwan . Anticancer Res \n2009 ;29 :725 –30 .19331228 \n[29] Szikriszt B Póti Á Pipek O \nA comprehensive survey of the mutagenic impact of common cancer cytotoxics . Genome Biol \n2016 ;17 :99 .27161042 \n[30] Truini A Coco S Alama A \nRole of microRNAs in malignant mesothelioma . Cell Mol Life Sci \n2014 ;71 :2865 –78 .24562347\n\n",
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"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D002294:Carcinoma, Squamous Cell; D059472:Exome; D016162:Genes, Wilms Tumor; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008654:Mesothelioma; D009154:Mutation; D009378:Neoplasms, Multiple Primary; D010534:Peritoneal Neoplasms; D012907:Smoking",
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"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23770567;23401440;27578032;20080505;25079552;26928227;170482;22075483;22351925;7695410;25929917;24562347;25806180;27158780;19671847;24265329;18948947;22728672;27161042;25385739;17471532;26181256;25495923;23945592;25889843;8401592;26258291;22960745;19331228;24574860",
"title": "Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma: A case report.",
"title_normalized": "whole exome sequencing of independent lung adenocarcinoma lung squamous cell carcinoma and malignant peritoneal mesothelioma a case report"
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"abstract": "OBJECTIVE\nWe evaluated the outcomes of liver transplantation (LT) in pediatric and adult patients with biliary atresia (BA). We focused on bowel perforation after LT (BPLT) as the most common surgical complication and analyzed its risk factors.\n\n\nMETHODS\nThis was a retrospective analysis of 70 BA patients who underwent LT. The patients were divided into three groups according to the timing of LT: within the first year of age (Group A), between 1 and 12 years of age (Group B), and after 12 years of age (Group C). The outcomes of LT and the clinical presentations of BPLT were compared. The surgical variables of patients with and without BPLT were analyzed to assess the risk factors.\n\n\nRESULTS\nThe timing of LT did not affect patient survival. The incidence of BPLT was significantly higher in Group C. In Group C, BPLT progressed to severe peritonitis. No cases of BPLT-associated mortality were observed. A multivariate analysis revealed that a prolonged operative time for LT was an independent risk factor (p = 0.03).\n\n\nCONCLUSIONS\nThe clinical course after transplantation was complicated after adolescence. BPLT should be strongly suspected and relaparotomy should be performed in a timely manner for patients undergoing LT after adolescence.",
"affiliations": "Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. matsuura@pedsurg.med.kyushu-u.ac.jp.;Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.",
"authors": "Yanagi|Yusuke|Y|;Matsuura|Toshiharu|T|;Hayashida|Makoto|M|;Takahashi|Yoshiaki|Y|;Yoshimaru|Koichiro|K|;Esumi|Genshirou|G|;Taguchi|Tomoaki|T|",
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"doi": "10.1007/s00383-016-4008-9",
"fulltext": "\n==== Front\nPediatr Surg IntPediatr. Surg. IntPediatric Surgery International0179-03581437-9813Springer Berlin Heidelberg Berlin/Heidelberg 400810.1007/s00383-016-4008-9Original ArticleBowel perforation after liver transplantation for biliary atresia: a retrospective study of care in the transition from children to adulthood Yanagi Yusuke Matsuura Toshiharu 81-92-642-5573matsuura@pedsurg.med.kyushu-u.ac.jp Hayashida Makoto Takahashi Yoshiaki Yoshimaru Koichiro Esumi Genshirou Taguchi Tomoaki 0000 0001 2242 4849grid.177174.3Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan 23 11 2016 23 11 2016 2017 33 2 155 163 25 10 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nWe evaluated the outcomes of liver transplantation (LT) in pediatric and adult patients with biliary atresia (BA). We focused on bowel perforation after LT (BPLT) as the most common surgical complication and analyzed its risk factors.\n\nMethods\nThis was a retrospective analysis of 70 BA patients who underwent LT. The patients were divided into three groups according to the timing of LT: within the first year of age (Group A), between 1 and 12 years of age (Group B), and after 12 years of age (Group C). The outcomes of LT and the clinical presentations of BPLT were compared. The surgical variables of patients with and without BPLT were analyzed to assess the risk factors.\n\nResults\nThe timing of LT did not affect patient survival. The incidence of BPLT was significantly higher in Group C. In Group C, BPLT progressed to severe peritonitis. No cases of BPLT-associated mortality were observed. A multivariate analysis revealed that a prolonged operative time for LT was an independent risk factor (p = 0.03).\n\nConclusion\nThe clinical course after transplantation was complicated after adolescence. BPLT should be strongly suspected and relaparotomy should be performed in a timely manner for patients undergoing LT after adolescence.\n\nKeywords\nBowel perforationLiver transplantationBiliary atresiaissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2017\n==== Body\nIntroduction\nBiliary atresia (BA) is the most common surgical cause of chronic cholestasis in children. If left untreated, progressive liver cirrhosis leads to death from hepatic failure, visceral bleeding and sepsis within the first years of life [1, 2]. Kasai portoenterostomy (KPE) [3] has improved the outcome of BA, particularly when it is performed during the first 90 days of life [4–6]. Some patients who attain satisfactory biliary drainage after KPE will reach adolescence without liver transplantation (LT). However, LT remains the ultimate surgery for BA and two-third of BA patients will require LT due to the progression of chronic liver disease [5, 7]. Many reports that have investigated the outcomes of LT for BA have evaluated the patients in childhood [8–11]. More than 50 years have passed since Kasai introduced KPE in 1959 [3]; thus in some cases, patients reached adulthood with their native liver [12, 13]. However, the outcomes of performing LT for BA posterior to childhood have not well discussed [14–16].\n\nComplications after LT are common and result in significant mortality among BA patients [8–11]. Bowel perforation is associated with high rates of morbidity and mortality (2.5–20 and 30–50%, respectively) [17]. Previous studies reported that the risk factors for bowel perforation after liver transplantation (BPLT) included the pre-LT model for end-stage liver disease (MELD) score [18], a prolonged operative time for LT (duration of hepatectomy) [17, 19], previous laparotomy [11, 19–22], young age [23, 24], intra-abdominal bleeding requiring relaparotomy, early portal vein thrombosis[19], the use of high doses of steroids in immunosuppressive therapy [25] and cytomegalovirus infection [26].\n\nWe evaluated the outcomes of LT in pediatric and adult BA patients and then focused on BPLT as the most common surgical complication after LT for BA in our department. The incidence, clinical presentations, risk factors, and outcomes of BPLT after LT for BA were investigated.\n\nPatients and methods\nAmong the 92 LTs performed in 90 recipients at the Department of Pediatric Surgery in Kyushu University from October 1996 to February 2015, 70 (76.1%) were performed for BA. The other etiologies of liver failure included fulminant hepatic failure (n = 8; 8.7%), hepatoblastoma (n = 3; 3.3%), Alagille syndrome (n = 2; 2.2%), congenital absence of the portal vein and liver graft failure (n = 2; 2.2%) and one case (1.1%) each of Wilson’s disease, Primary sclerosing cholangitis, carbamoyl phosphate synthetase I deficiency, citrullinemia and hepatic failure due to familial hemophagocytic lymphohistiocytosis.\n\nWe performed a retrospective analysis of the 70 pediatric and adult BA patients who underwent LT at our department. The records were examined for the details of BPLT, the patient’s clinical status before and after LT, and the surgical variables that were possibly associated with BPLT.\n\nThe patients were divided into three groups according to the age at LT. The patients who required LT within the first year of life were classified into Group A. Then the patients who required LT later were divided at 12 years of age according to the categorization of the score for end-stage liver disease. The patients who required LT at between 1 and 12 years of age and after 12 years of age were classified into Groups B and C, respectively. First, the surgical variables and outcomes of LT were compared among the three groups. Next, the details of BPLT were analyzed among three groups. Finally, the clinical status of the patients before and after LT and the surgical variables that were possibly associated with bowel perforation after LT were analyzed in patients with and without BPLT to identify the surgical risk factors. We defined the duration between skin incision and removal of recipient’s native liver as the duration of hepatectomy. The severity of liver disease was determined using the pediatric end-stage liver disease (PELD) score in groups A and B and the MELD score in Group C.\n\nLTs were performed under the approval from the Ethics and Indications Committee of Kyushu University. During LT, biliary reconstruction was performed using Roux-en Y hepaticojejunostomy in all cases. In all cases, immunosuppression was achieved using steroids and calcineurin inhibitors (tacrolimus or cyclosporine). Tacrolimus and cyclosporine were started at a dosage of 0.1 mg/kg/day and 5 mg/kg/day, respectively, and were adjusted based on the trough level. Methylprednisolone was progressively tapered from 3 mg/kg/day at day 1 to 0.75 mg/kg/day at day 10, and 0.3 mg/kg/day at day 30. Acute rejection was treated with steroid pulse therapy (methylprednisolone 10–20 mg/kg/day for 3 days). All of the patients received intravenous ceftriaxone or tazobactam/piperacillin for 7 days for bacterial prophylaxis and micafungin for 14 days for fungal prophylaxis.\n\nThe data are expressed as the median and interquartile range (IQR). All statistical analyses were performed using the JMP® 11 software program (SAS Institute Inc., Cary, NC, USA). The comparisons among three groups were performed using Tukey’s wholly significant difference (WSD) test. The Kruskal–Wallis test was used to analyze the variance among the three groups. The Steel–Dwass test was used for nonparametric multiple comparisons of data among the three groups. Mann–Whitney‘s U test and Fisher’s exact test were used for the univariate analyses. A logistic regression model was used to perform a multivariate analysis. In the multivariate analysis, a variance inflation factor (VIF) of >5 was applied to exclude multicollinearity. p values of <0.05 were considered to indicate statistical significance and p values of <0.1 were considered to indicate moderate significance.\n\nResults\nSixty-eight living donor and two deceased donor LTs were performed for 70 BA patients. The ages of the patients at LT ranged from 5 months to 33 years (median 4.6 years).\n\nThe patient characteristics and the outcomes of liver transplantation\nThe patient characteristics and the surgical outcomes were assessed according to the period of life. There were no statistically significant differences in the numbers of patients in each group (Groups A, B and C). Table 1 shows the patient characteristics and the surgical outcomes of Groups A, B and C. Factors that were significant on the Kruskal–Wallis test (p < 0.05) were subjected to the Steel–Dwass test; the results are summarized in Table 2. The body weight at LT increased significantly with an increase in age. The number of previous laparotomies in Group C was significantly higher than that in Group A. Six cases involved pulmonary complications. The incidence of pulmonary complications in the BA patients increased as their age increased. The PELD or MELD scores of the patients in Group A were significantly higher in comparison to Groups B and C. There was a significant decrease in the ratio of graft volume (GV)/standard liver volume (SLV) as the patients’ age category increased. The operative time for LT and the duration of hepatectomy were significantly longer in Group C. No significant differences were observed in the cold ischemic time, the duration of portal clamping or the blood loss volume.Table 1 The patient characteristics and the surgical variables in the different age groups\n\n\tGroup A\tGroup B\tGroup C\t\np value\t\nNumber of patients\t23\t23\t24\t\t\nAge at LT (years)\t0.8 (0.6–0.9)\t4.2 (1.8–7.4)\t20.5 (13.7–25.6)\t<0.01\t\nBody weight at LT (kg)\t6.3 (6.1–7.4)\t15.0 (9.8–20.6)\t50.4 (44.5–59.6)\t<0.01\t\nPrevious laparotomy (times)\t1.0 (1.0–1.0)\t1.0 (1.0–2.0)\t2.0 (1.0–2.0)\t<0.01\t\nPELD or MELD score\t19 (14–19)\t5.5 (−1.5 to 16.3)\t10.0 (8.0–18.0)\t<0.01\t\nHepatopulmonary precomplications\t\nn = 0\t\nn = 2\t\nn = 4\t0.15\t\nType of graft\tRd-LLS (n = 5)\tRd-LLS (n = 1)\tLLS (n = 2)\t\t\nLLS (n = 17)\tLLS (n = 16)\tLeft (n = 11)\t\nLeft (n = 1)\tLeft (n = 6)\tRight (n = 9)\t\n\t\tWhole (n = 2)\t\nGV/SLV (%)\t94.6 (82.9–101.9)\t68.2 (52.0–79.5)\t44.6 (36.5–49.2)\t<0.01\t\nOperative time for LT (h:min)\t12:22 (10:51–15:15)\t12:55 (10:39–14:28)\t15:17 (12:56–18:46)\t<0.05\t\nDuration of hepatectomy (h:min)\t3:43 (3:15–4:33)\t4:48 (4:02–5:33)\t6:32 (5:31–7:42)\t<0.01\t\nCold ischemic time (h:min)\t1:50 (1:32–2:32)\t1:04 (0:47–2:57)\t1:59 (1:16–3:22)\t<0.05\t\nDuration of portal clamping (h:min)\t2:34 (1:59–3:17)\t1:53 (1:31–2:35)\t1:44 (1:06–3:12)\t0.15\t\nBlood loss volume (ml/kg)\t78.3 (50.6–98.9)\t50.5 (39.6–148.1)\t107.1 (51.9–148.4)\t0.47\t\nPosttransplant complications\tBP (n = 4)\tBP (n = 1)\tBP (n = 8)\t0.04\t\nPVT (n = 2)\tPVT (n = 3)\tPVT (n = 2)\tNS\t\nBiliary stricture (n = 2)\tBiliary stricture (n = 1)\tBiliary stricture (n = 2)\tNS\t\nIntra-abdominal\tIntra-abdominal\t\t\t\nhemorrhage (n = 2)\themorrhage (n = 1)\t–\tNS\t\nHAT (n = 2)\t–\tHAT (n = 1), HAA (n = 1)\tNS\t\nHVS (n = 1)\tHVS (n = 1)\t–\tNS\t\nIleus (n = 1)\t–\t–\tNS\t\nDuration of hospitalization after LT (days)\t39 (28–94)\t55 (50–71)\t48.5 (30.6–61.8)\t0.06\t\nThe data are expressed as the median and interquartile range: median (IQR)\n\nGroup A: The patients who required LT within the first year of life. Group B: The patients who required LT at between 1 and 12 years of age. Group C: The patients who required LT at after 12 years of age\n\n\nLT liver transplantation, PELD pediatric end-stage liver disease, MELD model for end-stage liver disease, GV/SLV the graft volume/standard liver volume ratio, LLS left lateral segment, Rd-LLS reduced left lateral segment, BP bowel perforation, PVT portal vein thrombosis, HAT hepatic artery thrombosis, HAA hepatic artery aneurysm, HVS hepatic vein stenosis, NS not significant\n\n\nTable 2 The outcomes of the nonparametric multiple comparisons among the three groups using the Steel–Dwass test\n\n\tA–B\tB–C\tC–A\t\nAge at LT\t\np < 0.01\t\np < 0.01\t\np < 0.01\t\nBody weight at LT\t\np < 0.01\t\np < 0.01\t\np < 0.01\t\nPrevious laparotomy\t\np = 0.37\t\np = 0.12\t\np < 0.01\t\nPELD or MELD score\t\np < 0.01\t\np = 0.14\t\np < 0.01\t\nGV/SLV\t\np < 0.01\t\np < 0.01\t\np < 0.01\t\nOperative time for LT\t\np = 0.90\t\np < 0.05\t\np < 0.05\t\nDuration of hepatectomy\t\np < 0.05\t\np < 0.01\t\np < 0.01\t\nCold ischemic time\t\np < 0.05\t\np < 0.1\t\np = 0.94\t\nA–B: The comparison between Groups A and B. B–C: The comparison between Groups B and C. C–A: The comparison between Group C and A\n\n\nLT liver transplantation, PELD pediatric end-stage liver disease, MELD model for end-stage liver disease, GV/SLV the graft volume/standard liver volume ratio\n\n\n\n\nA patient suffered from bowel perforation after LT (BPLT) due to posttransplantation lymphoproliferative disorder (PTLD) [27]. The patient was a 10-month-old girl who suffered two bowel perforations at the ileum and the transverse colon on days 94 and 394 after transplantation, respectively. To discuss the early surgical complications after LT, we excluded this case. Bowel perforation (n = 13) was the most common posttransplantation complication to require surgical treatment, followed by portal vein complications (n = 7), bile duct complications (n = 5), hepatic artery complications (n = 4), intra-abdominal hemorrhage requiring relaparotomy (n = 3), hepatic vein complications (n = 2), and intestinal obstruction (n = 1). Groups A, B and C included 4 (18.2%), 1 (4.3%) and 6 (24.0%) patients with BPLT, respectively. With regard to the number of BPLT cases that required relaparotomy, since two patients in Group C suffered from bowel perforation twice, the incidence in Group C (8 perforations in 24 LTs) was significantly higher than that in Group B. There were no significant differences in the incidence rates of other surgical complications among the three groups. The duration of hospital stay after LT in Groups A, B and C was 39 (28–94) days, 55 (50–71) days and 48.5 (30.6–61.8) days, respectively (p = 0.06). The long-term survival did not differ to a statistically significant extent among the three groups. The Kaplan–Meier survival curves are shown in Fig. 1.Fig. 1 The Kaplan–Meier curves for the survival rates of patients in Groups A, B and C. Group A: The patients who required LT within the first year of age. Group B: The patients who required LT at between 1 and 12 years of age. Group C: The patients who required LT at after 12 years of age\n\n\n\n\nThe details of bowel perforation after LT\nNext, we focused on BPLT as the most common surgical complication after LT for BA in our department. Excluding the case of PTLD, BPLT occurred as an early complication after LT in 15.9% of the patients (11 patients in 69 LTs). The median age of the patient with BPLT was 12.3 (0.9–14.5) years. The details of BPLT were assessed for each of the age groups. Figure 2 shows the ages of BA patients who underwent LT for BA and those who developed BPLT. Table 3 compares the characteristics of the BPLT cases among the three groups. The median time between transplantation and bowel perforation of the 11 BPLT cases was 9 (7.0–15.0) days. The median times in Groups A, B and C were 8 (7.0–13.5) days, 9 days and 11.0 (6.3–16.5) days, respectively (p = 0.95). The sites of perforation in Group A were localized around the liver (stomach, n = 1; duodenum, n = 1; jejunum, n = 2), while those in Groups B and C were located throughout the abdominal cavity (Roux-en Y limb, n = 2; ileum, n = 5; transverse colon, n = 2). Bowel perforation occurred at ten sites where adhesiotomy was performed during LT. The causes of bowel perforation at Roux-en Y limbs in two cases were ruptured sutures at the site of fixation of the Roux-en Y limb to the peritoneum. These were caused by strong traction due to stiff adhesion. The other cause in Group A was an injury to the jejunum that occurred during the placement of the nasoenteric tube in LT. One patient required steroid pulse therapy prior to BPLT due to acute rejection. One patient required relaparotomy for intestinal obstruction and steroid pulse therapy for acute rejection prior to BPLT. Cytomegalovirus infection was not observed before BPLT. Two patients in Group C had two episodes of bowel perforation. These patients had pulmonary complications associated with BA such as hepatopulmonary syndrome or pulmonary hypertension. Reperforation was observed at 2 days from the first episode in both cases; however, the site of reperforation was different from first sites.Fig. 2 The ages of the patients who underwent liver transplantation for biliary atresia. Group A: The patients who required LT within the first year of age. Group B: The patients who required LT at between 1 and 12 years of age. Group C: The patients who required LT at after 12 years of age. LT liver transplantation, BA biliary atresia, BP bowel perforation\n\n\nTable 3 The details of the cases of bowel perforation after liver transplantation\n\n\tBPLT in Group A\tBPLT in Group B\tBPLT in Group C\t\nNumber of BP\t4\t1\t8 (in 6 patients)\t\nTime between LT and BP\t8 (7–13.5) days\t9 days\t11.0(6.3–16.5) days\t\nSites of BP\tStomach (n = 1)\nDuodenum (n = 1)\nJejunum (n = 2)\tRoux-en-Y limb (n = 1)\tRoux-en-Y limb (n = 1)\nIleum (n = 5)\nTransverse colon (n = 2)\t\nClinical presentation\tAbdominal distention, tachycardia\tAbdominal tenderness\tAbdominal tenderness\t\nDiagnostic findings of BP\tFree gas on abdominal CT\tDetection of bowel contents\tDetection of bowel contents\t\nOperative procedures\tSingle-layer closure (n = 4)\tSingle layer closure (n = 1)\tSingle layer closure (n = 2)\nResection and anastomosis (n = 3)\nEnterostomy (n = 3)\t\nThe data are expressed as the median and interquartile range: median (IQR)\n\nGroup A: The patients who required LT within the first year of age. Group B: The patients who required LT at between 1 and 12 years of age. Group C: The patients who required LT at after 12 years of age\n\n\nLT liver transplantation, BP bowel perforation, BPLT bowel perforation after liver transplantation\n\n\n\n\nThe common clinical manifestations of bowel perforation in Group A were abdominal distention and tachycardia, while patients in Groups B and C most frequently presented with abdominal tenderness. Nine cases (69.2%) had fever at the time of bowel perforation. An elevated white blood cell count and serum C-reactive protein level was observed in 11 cases (84.6%), however, the patients were immunosuppressed. Most of the patients in Groups B and C were diagnosed through the detection of the bowel contents, which were obtained from an intra-abdominal drain or surgical sites. On the other hand, the abdominal fluid sampled from the intra-abdominal drains of the patients in Group A was serous due to upper gastrointestinal perforation and bowel perforation was diagnosed by the identification of free gas on abdominal CT. The operative procedures included single layer closure [n = 7: stomach, duodenum and ileum (n = 1), jejunum and Roux-en Y limb (n = 2)], segmental enteral resection and primary anastomosis (n = 3: all at the ileum) and enterostomy [n = 3: ileum (n = 1), transverse colon (n = 2)]. Aggressive surgery was required for the treatment of severe peritonitis due to lower gastrointestinal perforation in Group C. After the operation, all of the patients were treated with broad-spectrum antibiotics intravenously and immunosuppressive therapy was moderated; however, no patients suffered from acute rejection. All patients survived BPLT; however, two patients in Group A died from portal vein thrombosis. There was no significant difference in the duration of hospitalization after LT in the patients with and without bowel perforation [median, 50.0 (30.0–56.0) days vs. 51.0 (34.0–71.5) days, respectively; p = 0.37].\n\nThe univariate analysis of the clinical status of the patients before and after LT, and the surgical variables of the patients with and without bowel perforation after LT\nTo analyze the surgical risk factors for BPLT, the clinical status of the patients before and after LT, and the surgical variables that were possibly associated with BPLT were compared in patients with and without bowel perforation. Table 4 shows a summary of the comparative data. The median age and body weight at LT in the patients with BPLT were 12.3 (0.9–14.5) years and 23.9 (7.5–55.2) kg, respectively. All but one patient underwent KPE as the primary operative procedure for BA. Only one patient underwent LT as the primary operative procedure for BA. The median number of previous laparotomies and PELD/MELD score were 1.0 (1.0–1.0) times and 13.0 (9.0–19.0) times, respectively. The hepatopulmonary precomplications were observed in 18.1% of the patients with BPLT and in 6.9% of the patients without BPLT, respectively. The mean ratio of graft volume (GV)/standard liver volume (SLV) in the patients with BPLT was 44.6% (36.5–88.6%). The median operative time for LT was 14 h 51 min (13 h 07 min–18 h 05 min); the median duration of hepatectomy was 4 h 38 min (4 h 07 min–6 h 27 min); the median cold ischemic time was 1 h 48 min (1 h 04 min–2 h 11 min); and the median duration of portal clamping was 2 h 05 min (1 h 08 min–2 h 49 min). The median ratio of blood loss volume/body weight in the patients with BPLT was 51.7 (29.7–141.0) ml/kg. There was a moderate significant difference in the GV/SLV ratio (p = 0.07) and in the operative time for LT (p = 0.09).Table 4 The comparative analysis of the clinical status of the patients before and after liver transplantation and the surgical variables associated with bowel perforation after liver transplantation\n\n\tBPLT (+)\tBPLT (−)\t\np value\t\nNumber of patients\t11\t58\t–\t\nAge at LT (years)\t12.3 (0.9–14.5)\t3.9 (1–14.5)\t0.70\t\nBody weight at LT (kg)\t23.9 (7.5–55.2)\t15.0 (6.7–33.2)\t0.35\t\nPrevious laparotomy (times)\t1.0 (1.0–1.0)\t1.0 (1.0–2.0)\t0.31\t\nPELD or MELD score\t13.0 (9.0–19.0)\t15.0 (6.3–20.0)\t0.90\t\nHepatopulmonary precomplications\t2 (18.1%)\t4 (6.9%)\t0.24\t\nGV/SLV (%)\t44.6 (36.5–88.6)\t72.9 (48.1–91.4)\t<0.1\t\nOperative time for LT (h:min)\t14:51 (13:07–18:05)\t12:59 (11:00–15:30)\t<0.1\t\nDuration of hepatectomy\t4:38 (4:07–6:27)\t4:49 (3:37–6:33)\t0.85\t\nCold ischemic time (h:min)\t1:48 (1:04–2:11)\t1:43 (1:00–3:00)\t0.67\t\nDuration of portal clamping (h:min)\t2:05 (1:08–2:49)\t2:08 (1:26–3:09)\t0.76\t\nBlood loss volume (ml/kg)\t51.7 (29.7–141.0)\t93.7 (45.0–141.1)\t0.22\t\nThe data are expressed as the median and interquartile range: median (IQR)\n\n\nBPLT bowel perforation after liver transplantation, LT liver transplantation, PELD pediatric end-stage liver disease, MELD model for end-stage liver disease, GV/SLV the graft volume/standard liver volume ratio\n\n\n\n\nThe multivariate analysis of the risk factors for bowel perforation after LT\nNext, we investigated the independent risk factors for BPLT. Among the factors that were included in the univariate analyses, the body weight at LT was not included in the multivariate analysis, because the body weight at LT was highly correlated with GV/SLV and the ratio of blood loss volume/body weight (VIF >10). Both the duration of hepatectomy and portal clamping time were components of the operative time for LT; however, their VIF values were <3 and they were, therefore, included. The significant factors included a prolonged operative time for LT (p = 0.03). No significant difference was observed in the age at LT, previous laparotomy, PELD or MELD score, the incidence of hepatopulmonary precomplications, the GV/SLV ratio, the duration of hepatectomy, the cold ischemic time, the duration of portal clamping, or the blood loss volume (Table 5).Table 5 The outcomes of the multivariate logistic regression analysis\n\n\tOdds ratio\t95% confidence interval\t\np value\t\nAge at LT\t1.01\t0.86–1.18\t0.86\t\nPrevious laparotomy\t0.68\t0.12–1.94\t0.49\t\nPELD/MELD score\t1.06\t0.94–1.25\t0.34\t\nHepatopulmonary precomplications\t3.96\t0.24–65.1\t0.31\t\nGV/SLV\t0.96\t0.90–1.02\t0.18\t\nOperative time for LT\t1.46 (per 1-h increment)\t1.03–2.21\t\n0.03\n\t\nDuration of hepatectomy\t0.57\t0.23–1.24\t0.16\t\nCold ischemic time\t0.65\t0.23–1.24\t0.13\t\nDuration of portal clamping\t0.55\t0.15–1.41\t0.24\t\nBlood loss volume\t1.00\t0.98–1.00\t0.63\t\n\nLT liver transplantation, GV/SLV the graft volume/standard liver volume ratio\n\nBold value represent statistical significance (p < 0.05)\n\n\n\n\nDiscussion\nThe timing of LT for BA has remained controversial. In a retrospective cohort study of 347 pediatric patients, it was reported that the patients who were underwent KPE and required LT after the first year of age showed better patient and graft survival than those who required LT within the first year of age [11]. Although some BA patients reached adulthood with their native livers, there has been limited evidence of the impact of LT on the outcome of patients who reach adulthood after KPE. Uchida et al. [15] reported that the outcome of LT in adult BA patients was significantly poorer in comparison to pediatric patients. They noted that the rates of post-transplant intestinal perforation, intra-abdominal bleeding requiring relaparotomy and biliary leakage were significantly higher in adult patients. The cumulative 5- and 10-year survival rates were 70 and 56% in adult patients, respectively. In contrast, those in pediatric patients were 87 and 81%, respectively. On the other hand, Sampedro et al. [14] and Kyoden et al. [16] reported that the outcomes of LT were satisfactory in adult BA patients. They concluded that LT can be performed safely in adult patients. In this study, with respect to the preoperative statuses of the patients, the number of previous laparotomies and the coexistence of pulmonary precomplications were higher in Group C. The PELD/MELD scores in Group A were significantly higher in comparison to Groups B and C. This is probably because the indication for LT was portal hypertension or repeated cholangitis with relatively mild liver damage. Since almost all LT patients who were treated in our department underwent living donor LT, the GV/SLV decreased as the age at LT increased. Regarding the intraoperative outcomes, the operative time for LT and the duration of hepatectomy were significantly longer in Group C. This result indicates that prolonged adhesiotomy was required due to severe intra-abdominal adhesion in Group C; thus, the incidence of BPLT was higher in Group C. However, satisfactory patient survival was achieved in all three groups.\n\nComplications after LT are relatively common in BA patients and result in significant mortality [28, 29]. Bowel perforation is a noteworthy complication that occurs after LT in BA patients [8–11]. The incidence of this complication after pediatric LT is reported to be 6.4–20% [17, 19–23]. In the present study, bowel perforation was the most common surgical complication after LT. The incidence in the present study was relatively high (15.9%)—probably because the study population included greater numbers of adolescent and adult patients than children. Various etiologies of BPLT were reported [17–26]. One possible cause is thermal injury to the bowel during LT. In most BA patients, KPE was performed before LT and intra-abdominal adhesion was severe. Thus, we need to perform adhesiotomy carefully and gently when performing LT for BA patients. Previous studies reported that previous laparotomy and a prolonged operative time for LT were risk factors; this suggests that difficult adhesiotomy and thermal injury due to electrocautery were etiologies of BPLT. Although the number of previous laparotomies was not identified as a risk factor for BPLT in the present study, most sites of bowel perforation were observed where adhesiotomy had been performed during LT. Interestingly, the sites of perforation were observed in different locations in the patients in Group A (around the liver) and those in Groups B and C (throughout the abdominal cavity). This result indicates that KPE caused adhesion around the liver in Group A, while repeated cholangitis and multiple laparotomy caused adhesions throughout the abdominal cavity in groups B and C. Bowel injuries in the lower abdomen occurred during adhesiotomy, not only for hepatectomy but also for the construction of Roux-en Y hepaticojejunostomy in Group C. Ruptured sutures at the fixation of the Roux-en Y limb to the peritoneum due to strong traction occurred in two cases. Following these results, we usually make a Roux-en Y limb of 30 cm through the antecolic route in KPE to prevent difficult adhesiotomy and a short limb in LT. Moreover, we place adhesion barriers (Seprafilm®, Kaken Pharmaceutical Co., Ltd, Japan) around the liver at the end of KPE. Further studies will be necessary to establish the utility of these procedures in preventing this complication. The results of the present study suggested that Seprafilm® did not have a significant effect in the prevention of BPLT (p = 1.0, data not shown). This result indicated that the cause of adhesion was not only KPE but also the cholangitis that occurred after the Seprafilm® was resorbed. Recent studies have shown laparoscopic portoenterostomy for BA to have equivalent outcomes to open portoenterostomy [30–33]. Because laparoscopic portoenterostomy can decrease adhesion, further studies are necessary to evaluate its benefit in LT. Because laparoscopic portoenterostomy can decrease adhesion, further studies to evaluate its benefit to LT are required. Development of new surgical devices is also required to perform adhesiotomy safely and quickly.\n\nPulmonary complications are well recognized in chronic liver disease. The development of portal hypertension is fundamental in the pathogenesis [34]. The incidence of pulmonary complications in BA patients increased as the age of patients increased in the present study. It was reported that pulmonary complications were a risk factor for surgical complications (including infection, biliary complications, portal vein thrombosis and bowel perforation) after LT [35–37]. Multiple perforation was only observed in the patients with pulmonary complications in this study. In addition to these two cases, a patient in Group C suffered from multiple bowel perforations following splenectomy before LT. Although pulmonary complications did not show strong statistical power because of the small sample size of the present study, pulmonary complications remain a risk factor for BPLT.\n\nIn our cases, fever or the elevation of inflammatory marker levels was observed in most patients, despite the patients being immunosuppressed. Bowel perforation was suggested to have triggered the severe immune response and distressed the patients. Because the sites of perforation in Group C were localized in the lower tract, peritonitis was relatively severe, even if the diagnosis was immediate. Aggressive operations, such as segmental enteral resection and primary anastomosis or enterostomy were, therefore, indicated for most of the patients in Group C. Xiong et al. [38] reported that among adults with BPLT, the patients who had severe abdominal cavity contamination tended to die despite undergoing enterostomy. Thus, an early diagnosis may ensure better survival. While the rate of mortality due to bowel perforation after pediatric LT is reported to be 30–50% [17], we did not encounter any cases of BPLT-associated mortality in the present study. Timely laparotomy and aggressive operations seemed to prevent deaths due to this life-threatening complication in our department.\n\nAs in previous reports [17, 19], a prolonged operative time for LT was found to be an independent risk factor for BPLT in a multivariate analysis with logistic regression in the present study. This result also suggests that severe intra-abdominal adhesion is a risk factor for BPLT because the duration of adhesiotomy had a strong impact on the operative time for LT. While a prolonged operative time for LT was identified as an independent risk factor, the duration of hepatectomy did not differ to a statistically significant extent. This is also depended on the duration of adhesiotomy. A possible reason for this difference is that adhesiotomy was performed not only during hepatectomy but also during Roux-en Y hepaticojejunostomy construction. In two cases of bowel perforation, the perforation occurred due to the rapture of sutures at the site of fixation of the Roux-en Y limb to the peritoneum. Although thermal injury due to electrocautery was not the etiology, adhesiotomy for the construction of Roux-en Y hepaticojejunostomy took a long time in these two cases. Thus, a prolonged operative time for LT showed strong statistical power. In this point, we must be careful until the end of the operation, even if a longer operative time is required.\n\nIn summary, the timing of LT did not affect patient survival after LT for BA. However, the incidence of BPLT was significantly higher in patients who were older than 12 years of age. Furthermore, these patients suffered from more severe peritonitis, which required aggressive surgery. The patients who required LTt after 12 years of age showed a potentially higher risk of BPLT because they required longer operations due to severe adhesion throughout the abdominal cavity and the coexistence of pulmonary complications. Since the clinical course after transplantation was complicated after adolescence, LT should be performed, as early as possible for patients who are diagnosed with progressive liver disease after KPE. Patients who undergo LT after adolescence, should be carefully observed to allow for an immediate diagnosis of BPLT and timely laparotomy should be performed to treat this lethal complication. The population of the present study was small. Thus, further studies are necessary to clarify the optimal timing of LT for BA patients.\n\nAbbreviations\nBABiliary atresia\n\nKPEKasai portoenterostomy\n\nLTLiver transplantation\n\nBPLTBowel perforation after liver transplantation\n\nPTLDPosttransplantation lymphoproliferative disorder\n\nPELDPediatric end-stage liver disease\n\nMELDModel for end-stage liver disease\n\nGV/SLVThe ratio of graft volume/standard liver volume\n\nThis retrospective study was performed according to the Ethical Guidelines for Clinical Research published by the Ministry of Health, Labor and Welfare of Japan on July 30, 2003 (revised 2008) and complies with the Helsinki Declaration of 1964 (revised 2008). All parents or guardians of the infants in this study gave informed consent prior to their inclusion in this study.\n\nAcknowledgements\nThe authors declare no conflicts of interest in association with the present study. 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Utterson EC Shepherd RW Sokol RJ Biliary atresia:clinical profiles, risk factors, and outcomes of 755 patients listed for liver transplantation J Pediatr 2005 147 180 185 10.1016/j.jpeds.2005.04.073 16126046 \n29. McDiarmid SV Anand R Martz K Millis MJ Mazariegos G A multivariate analysis of pre-, peri-, and post-transplant factors affecting outcome after pediatric liver transplantation Ann Surg 2011 254 145 154 10.1097/SLA.0b013e31821ad86a 21606838 \n30. Chan KW Lee KH Tsui SY Laparoscopic versus open Kasai portoenterostomy in infant with biliary atresia: a retrospective review on the 5-year native liver survival Pediatr Surg Int 2012 28 1109 1113 10.1007/s00383-012-3172-9 22987040 \n31. Sun X Diao M Wu X Cheng W Ye M Li L A prospective study comparing laparoscopic and conventional Kasai portoenterostomy in children with biliary atresia J Pediatr Surg 2016 51 374 378 10.1016/j.jpedsurg.2015.10.045 26589186 \n32. Nakamura H Koga H Cazares J Comprehensive assessment of prognosis after laparoscopic portoenterostomy for biliary atresia Pediatr Surg Int 2016 32 109 112 10.1007/s00383-015-3820-y 26520656 \n33. Lishuang M Zhen C Guoliang Q Laparoscopic portoenterostomy versus open portoenterostomy for the treatment of biliary atresia: a systematic review and meta-analysis of comparative studies Pediatr Surg Int 2015 31 261 269 10.1007/s00383-015-3662-7 25627699 \n34. Machicao VI Balakrishnan M Fallon MB Pulmonary complications in chronic liver disease Hepatology 2014 59 1627 1637 10.1002/hep.26745 24089295 \n35. Uemoto S Inomata Y Egawa H Effects of hypoxemia on early postoperative course of liver transplantation in pediatric patients with intrapulmonary shunting Transplant 1997 63 407 414 10.1097/00007890-199702150-00014 \n36. Egawa H Kasahara M Inomata Y Long-term outcome of living related liver transplantation for patients with intrapulmonary shunting and strategy for complications Transplantation 1999 67 712 717 10.1097/00007890-199903150-00012 10096527 \n37. Urahashi T Mizuta K Sanada Y Pediatric living donor liver transplantation for biliary atresia with hepatopulmonary syndrome: the gift of a second win Pediatr Surg Int 2011 27 817 821 10.1007/s00383-011-2866-8 21331580 \n38. Xiong J You S He XS Gut perforation after orthotopic liver transplantation in adults World J Gastroenterol 2007 13 2125 2128 10.3748/wjg.v13.i14.2125 17465460\n\n",
"fulltext_license": "CC BY",
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"issue": "33(2)",
"journal": "Pediatric surgery international",
"keywords": "Biliary atresia; Bowel perforation; Liver transplantation",
"medline_ta": "Pediatr Surg Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001656:Biliary Atresia; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007416:Intestinal Perforation; D016031:Liver Transplantation; D008297:Male; D011183:Postoperative Complications; D012189:Retrospective Studies; D012307:Risk Factors; D060305:Transition to Adult Care; D016896:Treatment Outcome; D055815:Young Adult",
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"pubdate": "2017-02",
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"title": "Bowel perforation after liver transplantation for biliary atresia: a retrospective study of care in the transition from children to adulthood.",
"title_normalized": "bowel perforation after liver transplantation for biliary atresia a retrospective study of care in the transition from children to adulthood"
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"abstract": "Background Recurrent malignancy of the skull base poses a treatment challenge due to a lack of treatment options and potential for damage to surrounding structures. Methods Case report of two patients with recurrent nasopharyngeal carcinoma (NPC) of skull base previously treated with adjuvant chemoradiotherapy using intensity-modulated radiation therapy (IMRT). Results In both cases, the recurrent tumor was treated with endoscopic surgical resection and intraoperative cesium-131 (Cs-131) interstitial brachytherapy (IBT). Total dose delivered to tumor bed was 57 and 60 Gy, respectively. With a half- life of 9 days, the majority of the radiation dose had been delivered within the first 40 days following implant and there have been no treatment-related complications reported. Conclusion Intraoperative Cs-131 IBT is a feasible adjuvant treatment option for patients with recurrent malignancies of the skull base. These are the first known cases of Cs-131 IBT used for recurrent NPC.",
"affiliations": "Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.;Department of Radiation Oncology-Head and Neck Cancer, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.;Department of Neurosurgery-Neuro-Oncologic and Stereotactic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.;Department of Neurosurgery-Neuro-Oncologic and Stereotactic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States.",
"authors": "Savard|Corey|C|;Epps|Gregory|G|;Ad|Voichita Bar|VB|;Curry|Joseph|J|;Evans|James J|JJ|;Farrell|Christopher J|CJ|;Nyquist|Gurston|G|;Luginbuhl|Adam|A|",
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"fulltext": "\n==== Front\nJ Neurol Surg RepJ Neurol Surg Rep10.1055/s-00000182Journal of Neurological Surgery Reports2193-63582193-6366Georg Thieme Verlag KG Stuttgart · New York 10.1055/s-0039-1687848180023Case ReportCesium-131 Interstitial Brachytherapy for Recurrent Malignancies of Skull Base Savard Corey 1Epps Gregory 2Ad Voichita Bar 3Curry Joseph 2Evans James J. 4Farrell Christopher J. 4Nyquist Gurston 2Luginbuhl Adam 21 Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States2 Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States3 Department of Radiation Oncology–Head and Neck Cancer, Thomas Jefferson University, Philadelphia, Pennsylvania, United States4 Department of Neurosurgery–Neuro-Oncologic and Stereotactic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United StatesAddress for correspondence Corey Savard, BS Sidney Kimmel Medical College, Thomas Jefferson University925 Chestnut Street, 6th Floor, Philadelphia, PA 19147United StatesCorey.savard@jefferson.edu4 2019 09 4 2019 80 2 e23 e26 20 12 2018 20 2 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground\n Recurrent malignancy of the skull base poses a treatment challenge due to a lack of treatment options and potential for damage to surrounding structures.\n\n\n\nMethods\n Case report of two patients with recurrent nasopharyngeal carcinoma (NPC) of skull base previously treated with adjuvant chemoradiotherapy using intensity-modulated radiation therapy (IMRT).\n\n\n\nResults\n In both cases, the recurrent tumor was treated with endoscopic surgical resection and intraoperative cesium-131 (Cs-131) interstitial brachytherapy (IBT). Total dose delivered to tumor bed was 57 and 60 Gy, respectively. With a half- life of 9 days, the majority of the radiation dose had been delivered within the first 40 days following implant and there have been no treatment-related complications reported.\n\n\n\nConclusion\n Intraoperative Cs-131 IBT is a feasible adjuvant treatment option for patients with recurrent malignancies of the skull base. These are the first known cases of Cs-131 IBT used for recurrent NPC.\n\n\nKeywords\ncesium-131interstitialbrachytherapynasopharyngeal carcinomarecurrent\n==== Body\nIntroduction\n\nPatients with recurrent malignancy at the skull base pose are a re-treatment challenge. During the course of treatment for skull base malignancies, intensity-modulated radiation therapy (IMRT) provides the backbone of definitive or adjuvant therapy. In the recurrent setting, surgery may be possible. Reirradiation with external beam source remains controversial due to additive toxicity.\n1\nCesium-131 (Cs-131) is a radioactive isotope with favorable dosimetric properties for interstitial brachytherapy (IBT). The mean energy of Cs-131 is low and the half-life is 9.7 days, leading to a reduced exposure to the patient, treating providers, and families.\n2\n3\nThe Cs-131 IBT radiation dose is prescribed at a depth of 0.5 to 1 cm; the rapid dose fall limits the dose to surrounding tissues and decreases treatment related side effects. The Cs-131 seeds are permanently implanted intraoperatively, eliminating use of catheters required for delivery of high-dose rate (HDR) brachytherapy. Special radiation safety precautions, shielding, or extended hospital care, seen with previous forms of brachytherapy, are generally not necessary\n2\n. These properties give Cs-131 major benefits over previously used isotopes\n125\nI and\n192\nIr in head and neck IBT. In this case series, we present the feasibility, utility, and dosimetry of Cs-131 IBT for recurrent skull base tumor in previously irradiated cases. These are the first known cases of Cs-131 IBT use for the treatment of recurrent nasopharyngeal carcinoma (NPC).\n\n\nCase 1\nA 65-year-old Asian male presented with an erosive mass in the nasopharynx consistent with EBV-encoded small RNA positive (EBER) NPC extending into the cavernous sinus and staged as IIIb. The patient was treated with definitive combined chemoradiation. Definitive IMRT was delivered to the nasopharynx and at-risk cervical lymph nodes to a total dose of 70 Gy, using 2 Gy daily, 5 days per week concurrently with cisplatin. He also received sequential adjuvant chemotherapy with cisplatinum and 5-flourouracil (5-FU). However, cisplatinum was discontinued due to side effects of persistent neutropenia and bilateral sensorineural hearing loss. In its place, the patient received three cycles of a reduced dose carboplatin and 5-FU.\n\nThree years later, the patient presented with symptoms and imaging concerning for local recurrence of NPC. Biopsy showed fragments of recurrent NPC, nonkeratanizing-undifferentiated type (World Health Organization [WHO] type 3) with strong nuclear staining in-situ hybridization for EBER. The patient underwent endoscopic nasopharyngectomy with reconstruction with a pediculed nasal septal flap.\n\n\nFour months after this operation, imaging revealed a recurrent 2.5 × 2.0 cm lobulated tissue mass in the skull base. Upon review by the multidisciplinary tumor board, therapeutic treatment was decided to include surgical resection and IBT with Cs-131 intraoperative implants. A preoperative computed tomography (CT) scan (\nFig. 1A\n) was used to plan the placement of the cesium seeds and expected dose.\n\n\nFig. 1 \nCase 1 (\nA\n) Preoperative dose planning axial CT. (\nB\n) Vicryl mesh with suture containing cesium brachytherapy seeds used in both cases 1 and 2. (\nC\n) Postoperative CT scans with dosimetry curves. CT, computed tomography.\n\n\nPrimary surgical intervention consisted of a resection of the lateral sphenoid, posterior maxilla extending to the foramen rotundum superiorly and resection of the pterygoid plates inferiorly. Reconstruction and Cs-131 strand implantation was staged and undertaken the following day utilizing a left temperoparietal fascia flap, and infratemporal fossa approach to left nasopharyngeal tumor resection defect with endoscopic placement of brachytherapy to the at-risk surgical bed. Coverage and stabilization of the Cs-131 strand was achieved utilizing the left temporoparietal fascia flap.\n\n\nBrachytherapy preimplant plan was performed by the radiation oncology team using a Vicryl mesh (\nFig. 1B\n), which contained brachytherapy seeds, two strands of three seeds, for a total of six Cs-131 seeds. The mesh was sutured endoscopically to the skull base and nasopharynx followed by its coverage using a tunneled temporoparietal fascia flap. Pathology confirmed recurrent CK5/6+ and EBER+ NPC involving dense connective tissue and bone in left nasopharynx and skull base. The radiation dose prescribed consisted of a total dose of 57 Gy at 5mm depth with majority of the dose delivered over the first 40 days. Six seeds of Cs-131 with an activity of 2.7 mCi were used for IBT for this case.\n\n\n\nPost-operative CT scans performed within 24 hours postimplant (\nFig. 1C\n) showed placement of the seeds in the resection bed and verified doses of radiotherapy.\n\n\nHe is currently 9 months out from surgery with no signs of recurrent disease. His post treatment positron emission tomography (PET) scan and MRI demonstrate no evidence of metabolically active metastasis or recurrent disease. He will be closely followed-up in the coming months.\n\nCase 2\n\nA 34-year-old man presenting with right sided nasal obstruction and epistaxis was found to have a large nasopharyngeal mass with biopsy-proven EBER+, nonkeratanizing undifferentiated NPC with extension into right pterygopalatine fossa, stage III. He underwent a PET–CT which showed no distant metastasis and started on definitive combined chemoradiation. Definitive IMRT consisted of a total dose of 70 Gy, using a 2 Gy daily, 5 days per week regiment to the nasopharynx and at-risk cervical lymph nodes. He also received sequential adjuvant chemotherapy with cisplatinum at 100 mg/m\n2\ndose over 21 days.\n\n\n\nFollowing the completion of his adjuvant chemoradiation, he underwent surveillance MRI and PET–CT at 8 and 12 weeks post treatment which were negative for local recurrence, metabolically active malignancy, or distant metastatic disease. Despite negative imaging results, there was persistent swelling in the right superior nasopharynx 4 months following completion of adjuvant therapy. This area was biopsied and found to be persistent EBER positive, nonkeratanizing undifferentiated NPC. Upon review in the multidisciplinary clinic, therapeutic treatment was decided to proceed with surgical resection and IBT with Cs-131 intraoperative implants. A preoperative CT (\nFig. 2A\n) scan was used for the Cs-131 preimplant plan.\n\n\nFig. 2 \nCase 2 (\nA\n) Preoperative dose planning axial CT, (\nB\n) intraoperative endoscopic image of mesh and synthetic dura, (\nC\n) intraoperative endoscopic image of nasal septal flap covering mesh, (\nD\n) postoperative CT scans with dosimetry curves. CT, computed tomography.\n\n\n\nSurgical resection involved an endoscopic transnasal approach to the cranial base with posterior septectomy and resection of neoplastic tissue of nasopharynx along clivus and skull base. Following confirmation of negative margins, reconstruction was planned to incorporate placement of Cs-131 seeds and a left sided vascularized pediculed nasal septal flap. Cs-131 seeds were prepared by radiation oncology team using a Vicryl mesh (\nFig. 1B\n). It contained three separate strands of three seeds each, for a total of nine Cs-131 seeds. Following resection, bony skull base remained exposed. To separate the mesh from the bony skull base and reduce the risk of osteoradionecrosis, a folded piece of 1 × 3 inch Dura Repair was sutured to the mesh.\n\n\n\nThe mesh and synthetic dura (\nFig. 2B\n) were endoscopically placed, covering the resection bed. The nasal septal flap (\nFig. 2C\n) was rotated to cover the bony cranial base along the clivus and middle cranial fossa and to entirely cover the cesium seeds. Final pathology confirmed persistent EBER positive, nonkeratanizing undifferentiated NPC resected to negative margins.\n\n\n\nThe prescribed radiation dose was 60 Gy at 5 mm depth with the majority being delivered over the first 40 days. Nine seeds of Cs-131 with an activity of 2.7 mCi were used for this IBT. Postoperative CT scans (\nFig. 2D\n) showed placement of the seeds in the resection bed and the post implant radiotherapy plan.\n\n\nThe patient is currently being followed with serial imaging and physical exams without evidence of recurrence.\n\nDiscussion\n\nTumors of the skull base are particularly challenging for clinicians. The density of high-risk structures at the skull base and incredible topography for tumor spread leads to incomplete resection and a poor prognosis. Due to previous treatments including chemoradiotherapy, the therapeutic options available are often limited. Reirradiation has the potential to cause cerebrovascular accidents, carotid rupture, skin necrosis, and spinal cord damage. Chemotherapy given as single-modality treatment for these patients has a limited benefit\n1\n. The theoretical benefit of IBT, as an adjunct to total resection, is improved control of malignancy via targeted delivery of irradiation to the tumor bed. The dosimetric properties of Cs-131 previously outlined make it ideally suited for IBT at the skull base, significantly reducing the radiation dose to the surrounding critical normal structures, and the risk of radiation-related side effects.\n\n\nConsidering the skull base has limited soft tissue and difficult access, stabilization of the cesium seeds poses a significant challenge. Migration of the radioisotope seeds may reduce the effectiveness of the therapy and increase the dose to normal structures causing unintended toxicities. Migration of the seeds into the aerodigestive tract could result in additional procedures necessary to retrieve the seeds or may cause damage to the mucosa. The use of mesh containing the Cs-131 seeds and adequate surgical techniques to stabilize the implant may eliminate the risks of these severe complications.\n\nReconstruction needs to be considered to support the seeds if placed in a nondependent position. Soft tissue membranes may also be needed to protect critical structures, such as the carotid, cranial nerves, or bones from direct contact with the Cs-131 seeds. Given these concerns, a synthetic dura was used as a protective buffer in case 2. Careful consideration was taken to ensure the dose dependent distance of the Cs-131 seeds to the at-risk surgical bed was optimized for treatment effect while limiting the risk of osteoradionecrosis.\n\nConclusion\nIn conclusion, this case report highlights the first ever use of a novel approach to targeted intraoperative radiation therapy by using Cs-131 permanent interstitial implant in the previously radiated recurrent malignancies at the skull base.\n\nConflict of Interest None declared.\n\nFinancial Disclosure\nThe authors have indicated they have no financial relationships relevant to this article to disclose.\n==== Refs\nReferences\n1 Kupferman M E Morrison W H Santillan A A The role of interstitial brachytherapy with salvage surgery for the management of recurrent head and neck cancers Cancer 2007 109 10 2052 2057 17407106 \n2 Parashar B Wernicke A G Pavese A Cesium-131 permanent seed brachytherapy: dosimetric evaluation and radiation exposure to surgeons, radiation oncologists, and staff Brachytherapy 2011 10 06 508 513 21640663 \n3 Armpilia C I Dale R G Coles I P Jones B Antipas V The determination of radiobiologically optimized half-lives for radionuclides used in permanent brachytherapy implants Int J Radiat Oncol Biol Phys 2003 55 02 378 385 12527051\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2193-6358",
"issue": "80(2)",
"journal": "Journal of neurological surgery reports",
"keywords": "brachytherapy; cesium-131; interstitial; nasopharyngeal carcinoma; recurrent",
"medline_ta": "J Neurol Surg Rep",
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"nlm_unique_id": "101601540",
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"pages": "e23-e26",
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"pmid": "30972273",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": "12527051;17407106;21640663",
"title": "Cesium-131 Interstitial Brachytherapy for Recurrent Malignancies of Skull Base.",
"title_normalized": "cesium 131 interstitial brachytherapy for recurrent malignancies of skull base"
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"abstract": "A patient with underlying Hashimoto's thyroiditis developed amiodarone-induced thyrotoxicosis type 1 that was successfully treated using methimazole in combination with potassium iodide. A 35-year-old woman admitted for perinatal care of twin-to-twin transfusion syndrome was given amiodarone for 7 days for paroxysmal ventricular contraction following pulseless ventricular tachycardia 1 day after delivery. She developed thyrotoxicosis one month after the discontinuation of amiodarone therapy and was negative for thyroid-stimulating hormone receptor antibody. An increased peak velocity of the superior thyroid artery suggested amiodarone-induced thyrotoxicosis type 1. Her thyroid function recovered after combination therapy with methimazole and potassium iodide.",
"affiliations": "Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Japan.;Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Japan.;Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Japan.;Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Japan.;Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Japan.;Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Japan.;Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Japan.",
"authors": "Katoh|Daisuke|D|;Yoshino|Hiroshi|H|;Ikehara|Kayoko|K|;Kumashiro|Naoki|N|;Uchino|Hiroshi|H|;Tsuboi|Kumiko|K|;Hirose|Takahisa|T|",
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"doi": "10.2169/internalmedicine.2179-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3155475010.2169/internalmedicine.2179-18Case ReportSuccessful Treatment of Amiodarone-induced Thyrotoxicosis Type 1 in Combination with Methimazole and Potassium Iodide in a Patient with Hashimoto's Thyroiditis Katoh Daisuke 1Yoshino Hiroshi 1Ikehara Kayoko 1Kumashiro Naoki 1Uchino Hiroshi 1Tsuboi Kumiko 1Hirose Takahisa 1\n1 Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, JapanCorrespondence to Dr. Daisuke Katoh, daisuke.kato@med.toho-u.ac.jp\n\n26 9 2019 1 2 2020 59 3 383 388 25 9 2018 15 7 2019 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A patient with underlying Hashimoto's thyroiditis developed amiodarone-induced thyrotoxicosis type 1 that was successfully treated using methimazole in combination with potassium iodide. A 35-year-old woman admitted for perinatal care of twin-to-twin transfusion syndrome was given amiodarone for 7 days for paroxysmal ventricular contraction following pulseless ventricular tachycardia 1 day after delivery. She developed thyrotoxicosis one month after the discontinuation of amiodarone therapy and was negative for thyroid-stimulating hormone receptor antibody. An increased peak velocity of the superior thyroid artery suggested amiodarone-induced thyrotoxicosis type 1. Her thyroid function recovered after combination therapy with methimazole and potassium iodide. \n\namiodaroneamiodarone-induced thyrotoxicosiscolor flow Doppler sonographymethimazolepotassium iodide\n==== Body\nIntroduction\nAmiodarone-induced thyrotoxicosis (AIT) type 1, a form of iodine-induced hyperthyroidism, typically develops in patients with underlying Graves' disease or nodular goiter (1). The onset timing of AIT type 1 has been reported to be a median three months after beginning amiodarone therapy (2). Antithyroid drugs in the presence of a 4- to 6-week course of sodium perchlorate are recommended for the treatment of AIT type 1, but higher doses (e.g., 40-60 mg/day of methimazole) and longer periods of treatment are often needed (3,4). Because AIT type 1 is very rare in iodine-sufficient areas, such as Japan, the clinical course of such cases has been rarely described (5-7).\n\nWe herein report a case of AIT type 1 in a patient with underlying Hashimoto's thyroiditis that developed one month after the discontinuation of amiodarone treatment and was successfully resolved with methimazole (15 mg/day) in combination with potassium iodide.\n\nCase Report\nA 35-year-old woman with a history of Hashimoto's thyroiditis was referred to our hospital for perinatal care of a monochorionic diamniotic twin pregnancy at 24 weeks and 5 days of gestation. She had been euthyroid before her pregnancy [free thyroxin (FT4) 1.1 ng/dL, free triiodothyronine (FT3) 2.5 pg/mL, thyroid-stimulating hormone (TSH) 1.72 μIU/mL, anti-thyroglobulin antibody (TgAb) 138 IU/mL, and anti-thyroperoxidase antibody (TPOAb) >1,300 IU/mL at the diagnosis of Hashimoto's thyroiditis (28 years old)]. She was started on 50 μg L-thyroxine per day at 4 weeks of gestation as her TSH level was >2.5 μIU/mL (FT4 1.2 ng/dL, FT3 2.4 pg/mL, and TSH 3.91 μIU/mL) (8), and she was euthyroid during her pregnancy with a maintenance dose of 200 μg L-thyroxine per week. She was also diagnosed with gestational diabetes at seven weeks of gestation, and her blood glucose levels were well controlled after starting basal and bolus insulin therapy. She denied any family history of thyroid disorders. Her iodine intake during hospitalization was thought to be comparable to that of other healthy Japanese people.\n\nFetoscopic laser photocoagulation of communicating vessels was performed for twin-to-twin transfusion syndrome (TTTS) at 25 weeks of gestation. Frequent paroxysmal ventricular contractions (PVCs) including bigeminy were observed during and after the procedure, and X-ray the next day showed cardiomegaly, pulmonary congestion and minor pleural effusion. Echocardiography showed normal left ventricular contraction. Based on the diagnosis of heart failure and possible Mirror syndrome (9), noninvasive positive pressure ventilation and medical therapy including bisoprolol tape 1 mg, intravenous furosemide and lidocaine were started. Her heart failure was resolved, so these treatments were stopped within a week. However, given that the symptomatic PVCs, including bigeminy but not ventricular tachycardia (VT), continued throughout the pregnancy, she started taking mexiletine at 27 weeks of pregnancy and switched to propranolol at 32 weeks, continuing this regimen until delivery; however, this ultimately failed to resolve her PVCs.\n\nShe delivered healthy twin male babies at 34 weeks and 2 days (1,745 g and 1,767 g) by planned Caesarean section, and L-thyroxine was discontinued after delivery because she had been euthyroid before her pregnancy. She developed sustained pulseless VT with transient loss of consciousness at one day after delivery. Immediate cardiac resuscitation with chest compression and the use of a cardiac defibrillator restored her to a sinus rhythm. A temporary pacemaker was inserted the same day to maintain an increased heart rate in order to suppress the PVCs that triggered VT. She was also started on amiodarone intravenously with a loading dose (125 mg over 10 minutes, 300 mg over 6 hours and 450 mg over 18 hours on the first day; 600 mg over 24 hours on the second and third days, and 400 mg/day thereafter), but the PVCs were soon resolved, so the amiodarone was stopped one week later.\n\nAt 36 days after delivery, she was found to have thyrotoxicosis on a thyroid function test (Fig. 1). On an examination, the patient was afebrile, her blood pressure was 92/56 mmHg and her pulse rate was 82/min. Her thyroid gland was soft and had neither increased in size nor was tender; no nodules were palpable. There were no symptoms or signs of Graves' ophthalmopathy. During a careful interview, she reported palpitation and breathlessness on exacerbation, although she initially thought these were normal physiological responses after delivery. She also had mild diarrhea one week before she was diagnosed with thyrotoxicosis. She was initially suspected of having developed painless thyroiditis because of its high incidence among women two to four months after delivery (10,11), especially in those with underlying Hashimoto's thyroiditis. However, color flow Doppler sonography (CFDS) at 38 days after delivery showed an increased peak velocity of the superior thyroid artery (66.2 cm/s in the right and 47.3 cm/s in the left) (Fig. 2), findings that were not compatible with painless thyroiditis. In addition, repeated thyrotropin receptor antibody (TRAb) tests were negative (Table), suggesting that AIT type 1 rather than Graves' disease or painless thyroiditis was the most likely diagnosis. No nodules were detected in her thyroid glands, which suggested that autonomously functioning thyroid nodules or toxic multinodular goiter were unlikely. She was therefore started on 15 mg of methimazole and 50 mg of potassium iodide, the latter of which was increased to 100 mg 1 week later (Fig. 1).\n\nFigure 1. The clinical state and hormone concentration in the patient. FT3: free triiodothyronine, FT4: free thyroxine, KI: potassium iodide, MMI: methimazole, TSH: thyroid-stimulating hormone\n\nFigure 2. Ultrasound images of the thyroid and the measurement of the peak systolic velocity of the superior thyroid artery. (a) Ultrasound showed diffuse enlargement of the thyroid gland with nonuniform echogenicity without nodular lesions. The estimated volume of the thyroid calculated by the ellipsoid formula was 19.1 mL. (b) Doppler imaging showed no marked increase in the vascularity in the right or left thyroid glands. (c) Color flow Doppler sonography showed an increased peak velocity of the superior thyroid artery (66.2 cm/s in the right and 47.3 cm/s in the left).\n\nTable. Laboratory Findings\n\nOn admission\t\tReference range\t\t6 days after admission\t\tReference range\t\nWBC\t\t6.8×103\t/μL\t\t3.3-8.6×103\t\tThyroglobulin\t\t0.96\tng/mL\t\t<32.7\t\nHb\t\t12.7\tg/dL\t\t11.6-14.8\t\tTgAb\t\t75.5\tIU/mL\t\t<28\t\nPlt\t\t22.4×104\t/μL\t\t15.8-34.8×104\t\tTPOAb\t\t93.0\tIU/mL\t\t<16\t\nAST\t\t19\tIU/L\t\t13-30\t\t\t\nALT\t\t10\tIU/L\t\t7-23\t\t90 days after admission\t\tReference range\t\nALP\t\t234\tIU/L\t\t106-322\t\tTRAb\t\t<0.80\tIU/L\t\t<2\t\nLDH\t\t219\tIU/L\t\t124-222\t\tTSAb\t\t100\t%\t\t<120\t\nCK\t\t54\tIU/L\t\t41-153\t\t\nBUN\t\t10\tmg/dL\t\t8-20\t\t\nCr\t\t0.51\tmg/dL\t\t0.46-0.79\t\t\nTP\t\t6.4\tg/dL\t\t6.6-8.1\t\t\nAlb\t\t2.8\tg/dL\t\t4.1-5.1\t\t\nNa\t\t139\tmEq/L\t\t138-145\t\t\nK\t\t3.8\tmEq/L\t\t3.6-4.8\t\t\nCRP\t\t0.2\tmg/dL\t\t0.0-0.2\t\t\nFree T3\t\t2.25\tpg/mL\t\t2.26-4.15\t\t\nFree T4\t\t1.14\tng/dL\t\t1.01-1.67\t\t\nTSH\t\t0.4\tμIU/mL\t\t0.32-4.12\t\t\t\t\t\t\t\t\nAlb: albumin, ALP: alkaline phosphatase, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CK: creatine kinase, Cr: creatinine, CRP: C-reactive protein, Hb: hemoglobin, K: potassium, LDH: lactate dehydrogenase, Na: sodium, Plt: platelet, T3: triiodothyronine, T4: thyroxine, TgAb: anti-thyroglobulin antibody, TP: total protein, TPOAb: anti-thyroperoxidase antibody, TRAb: anti-TSH receptor antibody, TSH: thyroid-stimulating hormone, WBC: white blood cell count\n\nAt five weeks after starting these drugs, her FT4 and FT3 levels returned to the normal range or below, and both palpitation and breathlessness disappeared, at which point the potassium iodide and methimazole dosages were reduced. Potassium iodide was stopped at 9 weeks, and methimazole was stopped at 12 weeks, since she displayed hypothyroidism after 5 weeks of the treatment. After 25 μg L-thyroxine per day was started, she remained euthyroid.\n\nDiscussion\nAmiodarone, a benzofuranic iodine-rich anti-arrhythmic drug, is widely used to treat ventricular and atrial arrhythmia (1). However, it causes thyroid dysfunction, including both hyper- and hypothyroidism, in 15-20% of cases (1,12). There are two types of AIT: type 1, a form of increased synthesis of thyroid hormone that often develops in patients with underlying nodular goiter or Graves' disease; and type 2, a form of destructive thyroiditis (4,13). AIT type 1 frequently develops in iodine-deficient areas, whereas AIT type 2 develops in iodine-sufficient areas (3,4,13). Uchida et al. reported that AIT develops in 6% of amiodarone-treated Japanese patients, all of whom are classified as AIT type 2 (7). Since AIT type 1 is very rare in Japan, the clinical course has rarely been described in detail. This is the first case report of AIT type 1 that developed in a patient with underlying Hashimoto's thyroiditis. The present case suggests important clinical points concerning the management of AIT type 1 in terms of its diagnosis and treatment.\n\nDifferentiating the two types of AIT is crucial because the treatment approach differs between the two types; however, such differentiation is sometimes difficult, since some patients may have an overlapping condition of both types (3,14). Given the onset of thyrotoxicosis after delivery in the present case, painless thyroiditis, which often develops 2-4 months after delivery, and Graves' disease, which often develops 4-10 months after delivery, were other differential diagnoses (10,11). The 24-h radioactive iodine uptake is helpful for differentiating mild Graves' disease (increased uptake) from painless thyroiditis (decreased uptake) (15). A thyroid ultrasound is also a useful non-invasive examination; Graves' disease is often associated with hypervascularity in the thyroid gland with an increased systolic blood-flow velocity in the superior thyroid artery, whereas painless thyroiditis does not show hypervascularity (16). Hypervascularity in the thyroid gland is also shown in AIT type 1 while being absent in AIT type 2 (17). In the present case, CFDS was useful for differentiating AIT type 1 from painless thyroiditis. At a cut-off value of 43 cm/s for the average peak systolic blood-flow velocity in the superior thyroid artery, the sensitivity and specificity for discriminating Graves' disease from painless thyroiditis have been reported to be 0.87 and 1.00, respectively (16). Therefore, in the present case, AIT type 1 rather than painless thyroiditis or Graves' disease was the most likely diagnosis based on the combination of negative TRAb findings and an increased peak velocity of the superior thyroid artery (66.2 cm/s in the right and 47.3 cm/s in the left).\n\nThe urinary iodine concentration has been reported to be useful for differentiating destructive thyroiditis from Graves' disease (18). In the present case, however, it was not tested because elevated urine iodine excretion after amiodarone treatment negates its diagnostic value (18,19). Although the FT3/FT4 ratio also has been reported to be helpful for differentiating painless thyroiditis from Graves' disease (20), the present patient's severe comorbid conditions, including lethal arrhythmia and heart failure, would have modified the FT3/FT4 ratio in this case.\n\nAntithyroid drugs with a 4- to 6-week course of sodium perchlorate are recommended as the treatment of most cases of AIT type 1, but a higher dose of antithyroid drugs (e.g., 40-60 mg/day of methimazole) and longer periods of treatment are often needed (3,4). Oral glucocorticoids are recommended as the first-line treatment for AIT type 2 (3,4). Sodium perchlorate, which decreases the iodine uptake to the thyroid, has synergetic therapeutic effects with antithyroid drugs on AIT type 1 (3). However, sodium perchlorate is not available in Japan. Potassium iodide has also been used to treat hyperthyroidism, especially when rapid clinical or biochemical improvement is required (e.g., in patients with thyroid storm or before urgent thyroidectomy) (15). Inorganic iodide suppresses thyroid hormone secretion (21). In addition, excess iodine has inhibitory effects on iodine organification in the thyroid, known as the Wolff-Chaikoff effect (12). Combination therapy of antithyroid drugs with potassium iodide has been reported to achieve euthyroid status for patients with Graves' disease more effectively and rapidly than antithyroid drugs alone (22). Such combination therapy can also be applied to AIT type 1, as in the present case. To our knowledge, this is the first report of AIT type 1 successfully being treated with methimazole in combination with potassium iodide. Because the rapid restoration of the thyroid function was necessary in order to prevent lethal arrythmia in the present case, combination therapy was immediately started, although painless thyroiditis, for which no medication is usually required, was not completely excluded.\n\nThyroid function tests are recommended before amiodarone therapy and at three- to four-months intervals during treatment because amiodarone-induced thyroid dysfunction is not a rare condition (23). The onset time is short (median 3 months) in AIT type 1 after the beginning of amiodarone, whereas it is long (median 30 months) in AIT type 2 (2). However, after starting amiodarone, sooner or more frequent tests need to be considered when a patient has a history of thyroid diseases, since the present case developed thyrotoxicosis shortly (one month) after the discontinuation of amiodarone treatment with minimal symptoms. A careful medical interview or a physical examination is needed to diagnose AIT, as bed rest and the beta-blocking effects of amiodarone may mask palpitations and tachycardia caused by hyperthyroidism (1), which often worsen during physical activities.\n\nOne possible mechanism underlying the development of AIT type 1 with underlying Hashimoto's thyroiditis in this case is that she discontinued L-thyroxine after delivery, which can alter the iodine uptake to the thyroid gland, while also starting to take the high-iodine-content drug amiodarone for ventricular arrhythmia; this enhanced the total iodine uptake to her thyroid gland, resulting in increased thyroid hormone synthesis. The 24-h radioactive iodine uptake might have been useful for proving this hypothesis, but it was not assessed in the present case because the continued administration of the anti-thyroid drug was necessary in order to prevent hyperthyroidism-induced heart sensitivity or lethal arrhythmia.\n\nOne limitation of this report is that the diagnosis of AIT type 1 was made based on the combination of ultrasound findings and negative TRAb results without the uptake of 24-h radioactive iodine. However, the diagnosis and classification of AIT is often challenging, as demonstrated by the heterogeneous responses of expert thyroidologists to recent surveys (24,25). Only one definite AIT type 1 case, diagnosed based on the combination of ultrasound and the 24-h radioactive iodine uptake findings, has been reported in Japan to date (6); many other AIT cases have been reported as either AIT type 2 or possible mixed type (type 1 and type 2) (5,6). To our knowledge, this is the first case report of AIT type 1 with positive antibodies related to Hashimoto's thyroiditis.\n\nIn conclusion, we experienced a rare case of AIT type 1 in a patient with underlying Hashimoto's thyroiditis successfully treated using methimazole in combination with potassium iodide. This case demonstrates two clinical important issues. First, the careful monitoring of thyroid hormones along a medical interview and a physical examination are necessary in patients with an underlying thyroid condition (not only Graves' disease or nodular goiter but also Hashimoto's thyroiditis) who start amiodarone therapy. Second, potassium iodide in combination with antithyroid drugs might be an effective treatment for AIT type 1 in countries where sodium perchlorate is not available.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nNaoki Kumashiro: Honoraria, Novo Nordisk Pharma, Takeda Pharmaceutical and Sanofi. Takahisa Hirose: Honoraria, Sanofi, Eli Lilly Japan, Novo Nordisk Pharma, Takeda Pharmaceutical, MSD, Sumitomo Dainippon Pharma, Novartis Pharma, Nippon Boehringer Ingelheim, Ono Pharmaceutical, AstraZeneca, Daiichi Sankyo, Mitsubishi Tanabe Pharma and Kissei Pharmaceutical; Research funding, Ono Pharmaceutical and Mitsubishi Tanabe Pharma.\n==== Refs\n1. \nBasaria S , Cooper DS \nAmiodarone and the thyroid . Am J Med \n118 : 706 -714 , 2005 .15989900 \n2. \nTomisti L , Rossi G , Bartalena L , Martino E , Bogazzi F \nThe onset time of amiodarone-induced thyrotoxicosis (AIT) depends on AIT type . Eur J Endocrinol \n171 : 363 -368 , 2014 .24935933 \n3. \nBartalena L , Bogazzi F , Chiovato L , Hubalewska-Dydejczyk A , Links TP , Vanderpump M \n2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction . Eur Thyroid J \n7 : 55 -66 , 2018 .29594056 \n4. \nBogazzi F , Bartalena L , Martino E \nApproach to the patient with amiodarone-induced thyrotoxicosis . J Clin Endocrinol Metab \n95 : 2529 -2535 , 2010 .20525904 \n5. \nSato K , Miyakawa M , Eto M , et al \nClinical characteristics of amiodarone-induced thyrotoxicosis and hypothyroidism in Japan . Endocr J \n46 : 443 -451 , 1999 .10503998 \n6. \nSato K , Omi Y , Kodama H , et al \nDifferential diagnosis and appropriate treatment of four thyrotoxic patients with Graves' disease required to take amiodarone due to life-threatening arrhythmia . Intern Med \n47 : 757 -762 , 2008 .18421194 \n7. \nUchida T , Kasai T , Takagi A , et al \nPrevalence of amiodarone-induced thyrotoxicosis and associated risk factors in Japanese patients . Int J Endocrinol \n2014 : 534904 , 2014 .25053942 \n8. \nAlexander EK , Pearce EN , Brent GA , et al \n2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum . Thyroid \n27 : 315 -389 , 2017 .28056690 \n9. \nBraun T , Brauer M , Fuchs I , et al \nMirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome . Fetal Diagn Ther \n27 : 191 -203 , 2010 .20357423 \n10. \nAmino N , Tada H , Hidaka Y \nPostpartum autoimmune thyroid syndrome: a model of aggravation of autoimmune disease . Thyroid \n9 : 705 -713 , 1999 .10447018 \n11. \nIde A , Amino N , Kang S , et al \nDifferentiation of postpartum Graves' thyrotoxicosis from postpartum destructive thyrotoxicosis using antithyrotropin receptor antibodies and thyroid blood flow . Thyroid \n24 : 1027 -1031 , 2014 .24400892 \n12. \nCohen-Lehman J , Dahl P , Danzi S , Klein I \nEffects of amiodarone therapy on thyroid function . Nat Rev Endocrinol \n6 : 34 -41 , 2010 .19935743 \n13. \nMartino E , Bartalena L , Bogazzi F , Braverman LE \nThe effects of amiodarone on the thyroid . Endocr Rev \n22 : 240 -254 , 2001 .11294826 \n14. \nKhan A , Puttanna A , Raskauskiene D \nAmiodarone-induced thyrotoxicosis: type 1 or type 2? \nBMJ Case Rep \n2014 : 2014 .\n15. \nCooper DS \nHyperthyroidism . Lancet \n362 : 459 -468 , 2003 .12927435 \n16. \nHiraiwa T , Tsujimoto N , Tanimoto K , Terasaki J , Amino N , Hanafusa T \nUse of color Doppler ultrasonography to measure thyroid blood flow and differentiate graves' disease from painless thyroiditis . Eur Thyroid J \n2 : 120 -126 , 2013 .24783050 \n17. \nBogazzi F , Bartalena L , Brogioni S , et al \nColor flow Doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis . Thyroid \n7 : 541 -545 , 1997 .9292940 \n18. \nSugimoto T , Momotani N , Iino S , Ito K \n[Clinical significance of the measurement of the urinary concentration of iodine in differentiating silent thyroiditis from Graves' disease] . Nihon Naibunpi Gakkai Zasshi (Jpn J Endocrinol) \n70 : 1083 -1092 , 1994 (in Japanese, Abstract in English).\n19. \nGiovacchini G , Giovanella L , Haldemann A , Staub U , Fuchsel FG , Koch P \nPotentiometric measurement of urinary iodine concentration in patients with thyroid diseases with and without previous exposure to non-radioactive iodine . Clin Chem Lab Med \n53 : 1753 -1760 , 2015 .25803080 \n20. \nShigemasa C , Abe K , Taniguchi S , et al \nLower serum free thyroxine (T4) levels in painless thyroiditis compared with Graves' disease despite similar serum total T4 levels . J Clin Endocrinol Metab \n65 : 359 -363 , 1987 .3110204 \n21. \nWartofsky L , Ransil BJ , Ingbar SH \nInhibition by iodine of the release of thyroxine from the thyroid glands of patients with thyrotoxicosis . J Clin Invest \n49 : 78 -86 , 1970 .5409810 \n22. \nTakata K , Amino N , Kubota S , et al \nBenefit of short-term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves' disease . Clin Endocrinol \n72 : 845 -850 , 2010 .\n23. \nTrip MD , Wiersinga W , Plomp TA \nIncidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism . Am J Med \n91 : 507 -511 , 1991 .1951413 \n24. \nAhmed S , Van Gelder IC , Wiesfeld AC , Van Veldhuisen DJ , Links TP \nDeterminants and outcome of amiodarone-associated thyroid dysfunction . Clin Endocrinol \n75 : 388 -394 , 2011 .\n25. \nRaghavan RP , Taylor PN , Bhake R , et al \nAmiodarone-induced thyrotoxicosis, an overview of UK management . Clin Endocrinol \n77 : 936 -937 , 2012 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(3)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "amiodarone; amiodarone-induced thyrotoxicosis; color flow Doppler sonography; methimazole; potassium iodide",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D013956:Antithyroid Agents; D005260:Female; D050031:Hashimoto Disease; D006801:Humans; D008713:Methimazole; D011193:Potassium Iodide; D013971:Thyrotoxicosis; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "383-388",
"pmc": null,
"pmid": "31554750",
"pubdate": "2020-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12927435;22578004;15989900;21535072;25349184;18421194;7859888;24400892;11294826;1951413;20525904;28056690;25053942;9292940;10503998;24935933;24783050;3110204;19935743;29594056;20357423;25803080;19912243;10447018;5409810",
"title": "Successful Treatment of Amiodarone-induced Thyrotoxicosis Type 1 in Combination with Methimazole and Potassium Iodide in a Patient with Hashimoto's Thyroiditis.",
"title_normalized": "successful treatment of amiodarone induced thyrotoxicosis type 1 in combination with methimazole and potassium iodide in a patient with hashimoto s thyroiditis"
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"abstract": "OBJECTIVE\nTo examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders.\n\n\nMETHODS\nPatients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks.\n\n\nRESULTS\nOf the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment.\n\n\nCONCLUSIONS\nOnly 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703.",
"affiliations": "Case Western Reserve University. robert.findling@uhhospitals.org",
"authors": "Findling|Robert L|RL|;Johnson|Jacqueline L|JL|;McClellan|Jon|J|;Frazier|Jean A|JA|;Vitiello|Benedetto|B|;Hamer|Robert M|RM|;Lieberman|Jeffrey A|JA|;Ritz|Louise|L|;McNamara|Nora K|NK|;Lingler|Jacqui|J|;Hlastala|Stefanie|S|;Pierson|Leslie|L|;Puglia|Madeline|M|;Maloney|Ann E|AE|;Kaufman|Emily Michael|EM|;Noyes|Nancy|N|;Sikich|Linmarie|L|",
"chemical_list": "D011619:Psychotropic Drugs; D001569:Benzodiazepines; D011388:Prolactin; D018967:Risperidone; D000077152:Olanzapine; D008972:Molindone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaac.2010.03.013",
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"issn_linking": "0890-8567",
"issue": "49(6)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": null,
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D000293:Adolescent; D017109:Akathisia, Drug-Induced; D001569:Benzodiazepines; D002648:Child; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008134:Long-Term Care; D008297:Male; D008972:Molindone; D000077152:Olanzapine; D011388:Prolactin; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders; D011619:Psychotropic Drugs; D012307:Risk Factors; D018967:Risperidone; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D015430:Weight Gain; D055815:Young Adult",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "583-94; quiz 632",
"pmc": null,
"pmid": "20494268",
"pubdate": "2010-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "18794207;16172203;17606657;18374841;3616518;11434484;17015810;7111598;2574607;17667476;18439263;17667477",
"title": "Double-blind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) study.",
"title_normalized": "double blind maintenance safety and effectiveness findings from the treatment of early onset schizophrenia spectrum teoss study"
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"abstract": "Calcium channel blockers are highly protein-bound medications frequently used in the management of hypertension. Overdose results in severe hypotension and is the fourth most common cause of toxicity-related deaths in the United States. Management is mostly supportive, with currently no standard role for targeted drug removal. The protein-bound nature of these medications presents the option of utilizing albumin dialysis for their removal and for the reversal of associated shock.\nWe present two cases of life-threatening intentional amlodipine overdoses successfully treated with albumin dialysis. Both patients experienced profound distributive shock in the setting of preserved cardiac contractility that was refractory to maximal vasoactive agent support.\nAfter initiation of albumin dialysis, the patients showed rapid hemodynamic improvement and were able to be weaned off vasopressor support.\nThese cases demonstrate the safety and efficacy of albumin dialysis in the management of near-fatal calcium channel blocker overdoses related to amlodipine and offer an additional therapeutic option apart from conventional supportive care. Importantly, these cases were not associated with impaired cardiac contractility, thereby making venoarterial extracorporeal membrane oxygenation a less preferable option. Furthermore, this therapeutic benefit of albumin dialysis can potentially be extended to the management of toxicity related to other highly protein-bound drugs and toxins.",
"affiliations": "Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA.;Emory Center for Critical Care, Emory University, Atlanta, GA.;Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA.;Emory Center for Critical Care, Emory University, Atlanta, GA.;Emory Center for Critical Care, Emory University, Atlanta, GA.;Emory Center for Critical Care, Emory University, Atlanta, GA.",
"authors": "Connor-Schuler|Randi L|RL|;Carr|Jennifer M|JM|;Reaven|Matthew S|MS|;Bridgman|Bob T|BT|;Patel|Deepa M|DM|;Subramanian|Ram M|RM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/CCE.0000000000000120",
"fulltext": "\n==== Front\nCrit Care Explor\nCrit Care Explor\nCC9\nCritical Care Explorations\n2639-8028\nWolters Kluwer Health\n\n00001\n10.1097/CCE.0000000000000120\nCase Report\nThe Efficacy of Albumin Dialysis in the Reversal of Refractory Vasoplegic Shock Due to Amlodipine Toxicity\nConnor-Schuler Randi L. MD 1\nCarr Jennifer M. MS 2\nReaven Matthew S. MD 1\nBridgman Bob T. PharmD 2\nPatel Deepa M. MD 2\nSubramanian Ram M. MD 2\n1 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA.\n2 Emory Center for Critical Care, Emory University, Atlanta, GA.\nFor information regarding this article, E-mail: rmsubra@emory.edu\n6 2020\n05 6 2020\n2 6 e0120Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.\n2020\nThis is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nObjectives:\n\nCalcium channel blockers are highly protein-bound medications frequently used in the management of hypertension. Overdose results in severe hypotension and is the fourth most common cause of toxicity-related deaths in the United States. Management is mostly supportive, with currently no standard role for targeted drug removal. The protein-bound nature of these medications presents the option of utilizing albumin dialysis for their removal and for the reversal of associated shock.\n\nDesign and Subjects:\n\nWe present two cases of life-threatening intentional amlodipine overdoses successfully treated with albumin dialysis. Both patients experienced profound distributive shock in the setting of preserved cardiac contractility that was refractory to maximal vasoactive agent support.\n\nInterventions and Results:\n\nAfter initiation of albumin dialysis, the patients showed rapid hemodynamic improvement and were able to be weaned off vasopressor support.\n\nConclusions:\n\nThese cases demonstrate the safety and efficacy of albumin dialysis in the management of near-fatal calcium channel blocker overdoses related to amlodipine and offer an additional therapeutic option apart from conventional supportive care. Importantly, these cases were not associated with impaired cardiac contractility, thereby making venoarterial extracorporeal membrane oxygenation a less preferable option. Furthermore, this therapeutic benefit of albumin dialysis can potentially be extended to the management of toxicity related to other highly protein-bound drugs and toxins.\n\nalbumin dialysis\namlodipine\ncalcium channel blocker\ncontinuous renal replacement therapy\ntoxicology\nvasoplegia\nOPEN-ACCESSTRUE\n==== Body\nAccording to the National Poison Data System, calcium channel blocker (CCB) toxicity was the fourth highest cause of toxicity-related deaths in 2016, accounting for over 5% of fatal exposures (1). Non-dihydropyridine CCB (e.g., verapamil, diltiazem) toxicity can cause negative inotropic and chronotropic effects, in particular, resulting in life-threatening cardiogenic shock. Typical therapies are supportive, aimed to temporize hemodynamic derangements until inherent elimination can occur. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is an additional therapeutic option in this context. In contrast, dihydropyridine CCB (e.g., amlodipine) toxicity is predominantly associated with systemic vasodilation and less cardiac depression, thereby resulting in distributive shock; in this setting, VA-ECMO has not traditionally been used given preserved cardiac function.\n\nAmlodipine is a long-acting dihydropyridine CCB that is 98% protein bound with a terminal elimination half-life of 40–50 hours (2). Given the highly protein-bound nature of amlodipine, extracorporeal removal using albumin dialysis is a mechanistically attractive option to reverse refractory vasoplegia due to its toxicity. We present two cases of refractory shock secondary to amlodipine overdose that were successfully treated with albumin dialysis using the Molecular Adsorbent Recirculating System (MARS) (Baxter Inc., Deerfield, IL).\n\nCASE 1\n\nA 47-year-old male status post liver transplant for autoimmune hepatitis few years before presented to the emergency department (ED) following an intentional overdose of 145 mg of amlodipine. He was hemodynamically stable on arrival to the ED, and laboratory values were unremarkable. Upon admission to the ICU, however, the patient developed sudden profound shock with an abrupt drop in systolic blood pressure from 140 to 50 mm Hg. Electrocardiography demonstrated sinus tachycardia at 120 beats/min. A transthoracic echo (TTE) demonstrated preserved cardiac contractility with an ejection fraction (EF) of 60%.\n\nVasopressors were rapidly uptitrated, including norepinephrine, epinephrine, and vasopressin, and he was intubated given his instability. Poison control was consulted, and the patient was given the following additional therapies: glucagon 10 mg followed by multiple 5-mg doses, four 250-mL doses of 20% fat emulsion, calcium gluconate infusion at 1.5 g/hr, hydrocortisone 100 mg followed by 50 mg every 6 hours, and uptitration of an insulin infusion to 1 U/kg/hr with concurrent dextrose infusion to maintain euglycemia (Fig. 1A). The patient was unable to tolerate higher doses of the insulin infusion due to persistent hypokalemia and hypoglycemia even with maximal glycemic support and potassium repletion efforts. Despite these interventions, the patient remained hemodynamically unstable with a mean arterial pressure (MAP) of less than 65 mm Hg.\n\nFigure 1. Graphs depicting vasopressor dosing in the two patients over time (hours), with the timing for initiation and termination of albumin dialysis noted. MARS = Molecular Adsorbent Recirculating System.\n\nHepatology and nephrology services were consulted, and MARS with continuous renal replacement therapy (CRRT) were started within 6 hours of admission. Two hours after initiation, the MARS circuit clotted; however, once flow in the circuit was restored, the patient’s hemodynamics improved rapidly, and vasopressors were able to be weaned off within 20 hours of initiation. The patient was ultimately extubated and transferred out of the ICU on day 3 of hospitalization and suffered no lasting organ dysfunction.\n\nCASE 2\n\nA 39-year-old woman with a medical history of hypertension and prior stroke with residual right-sided deficits presented to an outside ED hemodynamically stable following an intentional overdose of 600 mg of amlodipine and 400 mg of lisinopril. Poison control was contacted, and she was given activated charcoal, glucagon, and IV fluids, and was admitted to the ICU for monitoring.\n\nUpon arrival to the ICU at the outside hospital, the patient became acutely hypotensive and was intubated given her instability. Cardiac workup revealed sinus tachycardia on electrocardiography and preserved EF on TTE. Vasopressors were quickly uptitrated, including norepinephrine, epinephrine, vasopressin, and angiotensin II. She was given a total of 16 g of calcium gluconate divided over multiple doses, two 150-mg doses of methylene blue, three 50-mg doses of hydrocortisone, and a total of 770 mL of 20% fat emulsion divided over three doses. An insulin infusion was also started and rapidly uptitrated to 6 U/kg/hr with concurrent dextrose infusion to maintain euglycemia (Fig. 1B). She had a metabolic acidosis that continued to worsen and was started on a bicarbonate drip and CRRT with nephrology consultation.\n\nDespite these interventions, the patient continued to be profoundly hypotensive with MAPs in the 40s with a worsening acidosis and rising lactate. She was then transferred to our ICU for MARS therapy on hospital day 2. After beginning MARS, vasopressors and adjunctive therapies were weaned within hours, and the patient was ultimately stabilized. She was discharged on hospital day 12 without any lasting organ dysfunction.\n\nDISCUSSION\n\nThe MARS is the most common form of albumin dialysis and has typically been used to remove endogenous hepatic toxins as a treatment for hepatic encephalopathy, or as a bridge to recovery or liver transplant in acute or acute on chronic liver failure. MARS involves an initial dialysate of 600 mL of 16% albumin solution that recirculates through a MARS dialysis membrane, a CRRT membrane, charcoal filter, and anion exchanger (Fig. 2A). This albumin-enriched dialysate combined with a larger membrane pore size permits the removal of larger molecules up to 50 kDa that cannot be cleared by conventional hemodialysis, allowing removal of both water soluble substances such as ammonia, and larger albumin-bound toxins such as endogenous benzodiazepines, nitric oxide, and bilirubin from the patient’s blood (Fig. 2B). The albumin effluent derived from the MARS dialysis membrane then gets sequentially dialyzed across a conventional CRRT membrane that removes water soluble toxins, and then passes through a activated charcoal filter and anion exchange column that remove protein-bound toxins.\n\nFigure 2. A, Details of the Molecular Adsorbent Recirculating System (MARS) circuit, which involves a dialysate of albumin solution that passes through a MARS dialysis membrane and then subsequently via a CRRT membrane, charcoal filter, and anion exchanger. B, Diagram of the MARS membrane, which illustrates the albumin dialysate, and the passage of both water soluble low molecular weight and larger albumin-bound toxins across the membrane. TBG = thyroxine-binding globulin. Reproduced with permission from Baxter.\n\nAlso, in a nonhepatic context, MARS has been used efficaciously in cases of overdose of highly protein-bound CCBs such as amlodipine, verapamil, and diltiazem, with noted decrease in vasopressor requirements within several hours of initiation (3–6). Such cases have noted a decrease in the half-life elimination and a drop in serum levels of these medications with the use of MARS, indicating enhanced elimination through albumin dialysis (3, 5). However, one study by Gerard et al (4) did not demonstrate a significant amount of amlodipine in the dialysate, instead suggesting direct enhanced elimination may not be the only mechanism leading to hemodynamic improvements in these patients.\n\nPublished case reports of MARS in the context of liver failure may provide insight into potential other mechanisms of hemodynamic improvement apart from drug elimination. These reports in patients with hepatic failure have demonstrated increases in MAP and systemic vascular resistance following a single MARS session (7–9). This improvement in systemic hemodynamics is postulated to be due to MARS’ ability to act as a scavenger for endogenous vasoactive substances, such as nitric oxide. MARS removes plasma nitric oxide that is bound to albumin as S-nitrosothiol, with studies documenting a 50% decrease in nitric oxide levels in a single session (9, 10). MARS has also been shown to decrease free radical production, reduce oxidative stress, and eliminate pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-8 (9, 11).\n\nIn our cases, amlodipine levels in the serum or dialysate were not measured; the absence of these data raises the question whether our observed hemodynamic improvements were primarily due to exogenous clearance of amlodipine or elimination of endogenous vasoactive substances. Nevertheless, in our extensive experience with the use of MARS in liver failure patients, we have not observed a demonstrable hemodynamic benefit related to the potential elimination of endogenous vasoactive substances, and therefore, we would postulate that MARS in the context of our cases is working predominantly by removing drug. In future studies, analyzing both serum and dialysate levels of toxins may be beneficial as we continue exploring the potential use of MARS in managing critical toxicologic overdoses.\n\nIn the context of CCB toxicity, non-dihydropyridine CCBs typically act on calcium channels in the myocardium causing negative inotropy, and dihydropyridine CCBs act on the calcium channels in the vasculature causing vasoplegia. However, in cases of massive overdose, these medications can spread overwhelmingly throughout serum and tissue, losing this difference in receptor affinity; as such, either type of CCB subclass could potentially result in cardiogenic and/or vasoplegic shock (12). Therefore, it is critical to perform echocardiographic assessment of cardiac function in all cases of CCB toxicity to consider VA-ECMO is the setting of refractory cardiogenic shock (13). In this case series, our patients had preserved cardiac function, thereby making VA-ECMO a less preferable option. VA-ECMO is expensive, labor intensive, and prone to complications, including hemorrhage, thrombosis, stroke, and limb ischemia (14). In cases of CCB toxicity resulting primarily in vasoplegic shock, MARS provides a novel therapeutic strategy that can be life-saving in the setting of refractory shock.\n\nMARS is generally considered a safe modality in critically ill patients. The blood flow rate is 180 mL/min, which should result in less hemodynamic instability than would be seen with conventional hemodialysis. Potential side effects include metabolic derangements if citrate is used as an anticoagulant, and unintentional medication elimination. If citrate is used as an anticoagulant, attention should be given to following calcium levels, and adjustments can be made to the citrate solution and/or dialysate flow rates. With respect to unintended medication elimination, MARS can remove protein-bound medications used in the critical care setting, including antibiotics (such as piperacillin/tazobactam, meropenem, moxifloxacin, and ceftriaxone), therapeutic antidotes such as N-acetylcysteine, and sedatives such as fentanyl and midazolam; these medications may require increased dosing or frequency to avoid subtherapeutic levels (15–19).\n\nCCB toxicity is increasingly common and is a major cause of overdose-related deaths. The mainstay of treatment is typically supportive, with a consideration for VA-ECMO typically in cases of refractory cardiogenic shock due to CCB toxicity. Our cases demonstrate the remarkable efficacy of albumin dialysis with the MARS system in reversing refractory distributive shock in the setting of dihydropyridine toxicity by utilizing the protein-bound nature of the medication; therefore, this alternative therapeutic strategy should be considered in the management of this form of CCB toxicity. Furthermore, this case series highlights the potential application of albumin dialysis in the treatment of toxicologic emergencies related to other highly protein-bound drugs and toxins.\n\nACKNOWLEDGMENT\n\nWe acknowledge and thank our Surgical/Transplant ICU nursing colleagues for their passion and dedication towards establishing our albumin dialysis program.\n\nThe authors have disclosed that they do not have any potential conflicts of interest.\n==== Refs\nREFERENCES\n\n1. Gummin DD Mowry JB Spyker DA 2017 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 35th annual report. Clin Toxicol (Phila). 2018; 21 :1–203\n2. Meredith PA Elliott H Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet. 1992; 22 :22–31 1532771\n3. Pichon N Dugard A Clavel M Extracorporeal albumin dialysis in three cases of acute calcium channel blocker poisoning with life-threatening refractory cardiogenic shock. Ann Emerg Med. 2012; 59 :540–544 21862178\n4. Gerard L Galloy AC Capron A Mixed amlodipine/valsartan overdose treated by the Molecular Adsorbent Recirculating System (MARSTM). Clin Toxicol (Phila). 2015; 53 :573–577 26006182\n5. Pichon N François B Chevreuil C Albumin dialysis: A new therapeutic alternative for severe diltiazem intoxication. Clin Toxicol (Phila). 2006; 44 :195 196 16615682\n6. Belleflamme M Hantson P Gougnard T Survival despite extremely high plasma diltiazem level in a case of acute poisoning treated by the molecular-adsorbent recirculating system. Eur J Emerg Med. 2012; 19 :59–61 22223131\n7. Laleman W Wilmer A Evenepoel P Effect of the Molecular Adsorbent Recirculating System and Prometheus devices on systemic hemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure. Crit Care. 2006; 10 :R108 16859530\n8. Donati G Piscaglia F Colì L Acute systemic, splanchnic and renal haemodynamic changes induced by Molecular Adsorbent Recirculating System (MARS) treatment in patients with end-stage cirrhosis. Aliment Pharmacol Ther. 2007; 26 :717–726 17697205\n9. Guo LM Liu JY Xu DZ Application of molecular adsorbents recirculating system to remove NO and cytokines in severe liver failure patients with multiple organ dysfunction syndrome. Liver Int. 2003; 23 Suppl 3 16–20 12950956\n10. Stadlbauer V Krisper P Aigner R Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure. Crit Care. 2006; 10 :R169 17156425\n11. Sen S Ratnaraj N Davies NA Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS). Epilepsia. 2003; 44 :265–267 12558586\n12. Chakraborty R Hamilton R Calcium Channel Blocker Toxicity. 2020 Treasure Island, FL: StatPearls Publishing Available at: https://www.ncbi.nlm.nih.gov/books/NBK537147/. Accessed March 28, 2020\n13. St-Onge M Dubé PA Gosselin S Treatment for calcium channel blocker poisoning: A systematic review. Clin Toxicol (Phila). 2014; 52 :926–944 25283255\n14. Zangrillo A Landoni G Biondi-Zoccai G A meta-analysis of complications and mortality of extracorporeal membrane oxygenation. Crit Care Resusc. 2013; 15 :172–178 23944202\n15. Ruggero M Argento A Heavner M Molecular Adsorbent Recirculating System (MARS) removal of piperacillin/tazobactam in a patient with acetaminophen-induced acute liver failure. Transpl Infect Dis. 2013; 15 :214–218 23279615\n16. Peszynski P Majcher-Peszynska J Klammt S Removal of albumin bound drugs in albumin dialysis (MARS)—A new liver support system. ASAIO J. 2000; 46 :239\n17. Sen S Ytrebø LM Rose C Albumin dialysis: A new therapeutic strategy for intoxication from protein-bound drugs. Intensive Care Med. 2004; 30 :496–501 14735236\n18. Roth GA Sipos W Höferl M The effect of the Molecular Adsorbent Recirculating System on moxifloxacin and meropenem plasma levels. Acta Anaesthesiol Scand. 2013; 57 :461–467 23237505\n19. Wittebole X Hantson P Use of the Molecular Adsorbent Recirculating System (MARSTM) for the management of acute poisoning with or without liver failure. Clin Toxicol (Phila). 2011; 49 :782–793 22077243\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2639-8028",
"issue": "2(6)",
"journal": "Critical care explorations",
"keywords": "albumin dialysis; amlodipine; calcium channel blocker; continuous renal replacement therapy; toxicology; vasoplegia",
"medline_ta": "Crit Care Explor",
"mesh_terms": null,
"nlm_unique_id": "101746347",
"other_id": null,
"pages": "e0120",
"pmc": null,
"pmid": "32695989",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "12558586;22077243;14735236;16859530;26006182;23237505;17156425;30576252;16615682;12950956;23279615;23944202;21862178;1532771;22223131;17697205;25283255",
"title": "The Efficacy of Albumin Dialysis in the Reversal of Refractory Vasoplegic Shock Due to Amlodipine Toxicity.",
"title_normalized": "the efficacy of albumin dialysis in the reversal of refractory vasoplegic shock due to amlodipine toxicity"
} | [
{
"companynumb": "US-ACCORD-194062",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": null,
"drug... |
{
"abstract": "A 24+5-week preterm neonate with a severe scalp lesion was admitted to the neonatal intensive care unit (NICU) after caesarean section due to maternal chorioamnionitis (MC). An Arabin pessary had been inserted in addition to a previous cervical cerclage due to cervix insufficiency at 21+5 weeks of pregnancy (wp). At 23+5 wp, preterm rupture of membranes was evidenced. Both devices were kept to provide fetal viability. On 24+4 wp, she developed MC. Urgent caesarean section was performed. Transvaginal manual manipulation was required during the procedure. On NICU, she presented severe shock which required high-dose vasopressors and blood products. Following surgical repair, a bilateral grade IV intracranial haemorrhage was evidenced. Subsequently, it was agreed to withdraw life support. We hypothesise that MC and local infection could have acted as predisposing factors, with the presence of a pessary in the setting causing uterine contractions and its manipulation acting as a precipitating factor.",
"affiliations": "NICU, General University Hospital of Castellon, Castellon de la Plana, Spain aperezi@uv.es.;NICU, General University Hospital of Castellon, Castellon de la Plana, Spain.;NICU, General University Hospital of Castellon, Castellon de la Plana, Spain.;NICU, General University Hospital of Castellon, Castellon de la Plana, Spain.",
"authors": "Pérez-Iranzo|Antonio|A|;Olaya Alamar|Vicente|V|;Mira Ferrer|Luz M|LM|;Nos Colom|Andrea|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236375",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "gynaecology and fertility; infections; neonatal intensive care; obstetrics; paediatric surgery; skin",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017809:Fatal Outcome; D005260:Female; D005734:Gangrene; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases; D007511:Ischemia; D012535:Scalp",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33419746",
"pubdate": "2021-01-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe ischaemic gangrene of scalp in an extreme preterm: a fatal case of combined aetiology.",
"title_normalized": "severe ischaemic gangrene of scalp in an extreme preterm a fatal case of combined aetiology"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-285646",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"d... |
{
"abstract": "Pancreatic liposarcoma is a malignant tumor originated from the pancreas mesenchymal tissue and mostly presented in skin, subcutaneous, periosteum, and long bone on both sides. Both conventional chemotherapy and radiotherapy have limited efficacy and poor prognosis for advanced pancreatic liposarcoma. Here, we reported a case of advanced pancreatic liposarcoma and reviewed the literature specific for liposarcoma of the pancreas and discuss the emerging options of treatment. The patient was treated with apatinib and a cross-line rescue therapy combined with paclitaxel after progressive disease. The therapeutic effect of the combination regimen has been evaluated. Apatinib is an oral tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor-2 (VEGFR-2), which has dual effects of anti-angiogenesis and anti-tumor cell proliferation. To our knowledge, this is the first case to report the successful use of apatinib for advanced pancreatic liposarcoma.",
"affiliations": "a Department of Oncology , Cancer Center of People's Liberation Army, General Hospital of Shenyang, Military Region , Shenyang , P.R. China.;b Department of Clinical Pharmacy , Shenyang Pharmaceautical University , Shenyang , P.R. China.;a Department of Oncology , Cancer Center of People's Liberation Army, General Hospital of Shenyang, Military Region , Shenyang , P.R. China.;a Department of Oncology , Cancer Center of People's Liberation Army, General Hospital of Shenyang, Military Region , Shenyang , P.R. China.;a Department of Oncology , Cancer Center of People's Liberation Army, General Hospital of Shenyang, Military Region , Shenyang , P.R. China.;b Department of Clinical Pharmacy , Shenyang Pharmaceautical University , Shenyang , P.R. China.;b Department of Clinical Pharmacy , Shenyang Pharmaceautical University , Shenyang , P.R. China.;a Department of Oncology , Cancer Center of People's Liberation Army, General Hospital of Shenyang, Military Region , Shenyang , P.R. China.",
"authors": "Han|Tao|T|;Luan|Yuting|Y|;Xu|Ying|Y|;Yang|Xiaodan|X|;Li|Jing|J|;Liu|Ran|R|;Li|Qing|Q|;Zheng|Zhendong|Z|",
"chemical_list": "D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C553458:apatinib",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2017.1345394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "18(9)",
"journal": "Cancer biology & therapy",
"keywords": "Apatinib; liposarcoma; paclitaxel; pancreatic cancer; prognosis",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D015415:Biomarkers; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008080:Liposarcoma; D010190:Pancreatic Neoplasms; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "635-639",
"pmc": null,
"pmid": "28678611",
"pubdate": "2017-09-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "18276084;23714556;25115417;25609980;25901099;7370927;28477272;14501502;25722109;18029845;19149759;12802520;20927579;14990633;26864131;26917971;16891463;21154746;16437699;28969086;3075107;21463120;28061477;21751200;26020064;539669",
"title": "Successful treatment of advanced pancreatic liposarcoma with apatinib: A case report and literature review.",
"title_normalized": "successful treatment of advanced pancreatic liposarcoma with apatinib a case report and literature review"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1075997",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Bendamustine, an alkylating agent with cytotoxic properties, has been increasingly employed in the treatment of chronic lymphocytic leukemia (CLL) either as a single agent or combination with rituximab. Although rarely reported, they can potentially cause hypersensitivity reactions with serious consequences. The objective of the case report was to offer a safe and effective bendamustine desensitization protocol to patients with a hypersensitivity reaction to this drug. We report a case of a patient with a CLL who developed a type IV hypersensitivity reaction to bendamustine and who was successfully treated by drug desensitization. A 51-year-old man with CLL was started on chemotherapy with bendamustin-rituximab developed a type IV hypersensitivity reaction 3 days later. A desensitization protocol was developed for the second cycle of bendamustine. This protocol was well tolerated, and no hypersensitivity reaction was observed. The desensitization protocol allowed us to continue the treatment, and to achieve a favorable response of the CLL. Patients with a hypersensitivity reaction to bendamustine can safely receive bendamustine by our rapid desensitization protocol.",
"affiliations": "Departments of Internal Medicine.;Department of Pharmacy, University of the Sciences, Philadelphia College of Pharmacy, Philadelphia, Pennsylvania, USA.;Pharmacy.;Hemato-Oncology, Mercy Catholic Medical Center, Darby.",
"authors": "Shikdar|Sufana|S|;Totton|David|D|;Turco|Thomas|T|;Rachshtut|Michael|M|",
"chemical_list": "D000069283:Rituximab; D000069461:Bendamustine Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000660",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "29(8)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000069461:Bendamustine Hydrochloride; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D000069283:Rituximab",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "814-816",
"pmc": null,
"pmid": "29877929",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Presentation and management of the delayed type of hypersensitivity reaction with bendamustine.",
"title_normalized": "presentation and management of the delayed type of hypersensitivity reaction with bendamustine"
} | [
{
"companynumb": "US-TEVA-2018-US-959759",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report a case of anaphylactoid reaction in a woman after initial exposure to verteporfin and to alert physicians of this potentially life-threatening reaction.\n\n\nMETHODS\nInterventional case report.\n\n\nMETHODS\nAn 80-year-old woman who was found to have exudative age-related macular degeneration on clinical examination and fluorescein angiography underwent treatment with verteporfin photodynamic therapy (PDT). Thirty minutes after verteporfin PDT infusion, the patient experienced throat constriction, swelling of her hands, and severe shortness of breath. She received immediate intravenous treatment with methylprednisolone, diphenhydramine, and famotidine and was admitted for observation.\n\n\nRESULTS\nThe patient's symptoms resolved, and she experienced no long-term side effects related to PDT. Routine noninvasive pulse oximetry, however, did result in finger discoloration and superficial burn. Evaluation revealed that her symptoms were noncardiac in origin.\n\n\nCONCLUSIONS\nVerteporfin can result in an anaphylactoid reaction. Treating physicians should be advised of possible photosensitizing reactions once the patient has received verteporfin PDT.",
"affiliations": "California Vitreoretinal Center, Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, USA.",
"authors": "Doshi|Amish B|AB|;Moshfeghi|Darius M|DM|;Jack|Robert L|RL|",
"chemical_list": "D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin; D015738:Famotidine; D004155:Diphenhydramine; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajo.2005.05.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "140(5)",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000369:Aged, 80 and over; D000707:Anaphylaxis; D004155:Diphenhydramine; D004359:Drug Therapy, Combination; D015738:Famotidine; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008268:Macular Degeneration; D008775:Methylprednisolone; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "936-7",
"pmc": null,
"pmid": "16310483",
"pubdate": "2005-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anaphylactoid reaction after verteporfin therapy.",
"title_normalized": "anaphylactoid reaction after verteporfin therapy"
} | [
{
"companynumb": "US-BAUSCH-SYM-2013-09625",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "Bronchopulmonary dysplasia (BPD) is the leading cause of long-term respiratory morbidity in newborns who require respiratory support at birth. BPD is a multifactorial disorder, and infants are frequently subjected to treatment with multiple pharmacologic agents of dubious efficacy and questionable safety, including diuretics, bronchodilators, corticosteroids, anti-reflux medications, and pulmonary vasodilators. These agents, with narrow therapeutic indices, are widely used despite the lack of an evidence base, and some may do more harm than good. It is incumbent on the clinician to establish a risk:benefit ratio and to avoid drugs that have little efficacy and a high rate of toxicity.",
"affiliations": "Division of Neonatal-Perinatal Medicine, Department of Pediatrics, C.S. Mott Children's Hospital, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: smdonnmd@med.umich.edu.",
"authors": "Donn|Steven M|SM|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D001993:Bronchodilator Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.siny.2017.08.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1744-165X",
"issue": "22(5)",
"journal": "Seminars in fetal & neonatal medicine",
"keywords": "Bronchodilators; Bronchopulmonary dysplasia; Corticosteroids; Diuretics; Gastroesophageal reflux; Newborn; Vasoactive agents",
"medline_ta": "Semin Fetal Neonatal Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D001993:Bronchodilator Agents; D001997:Bronchopulmonary Dysplasia; D019317:Evidence-Based Medicine; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D016896:Treatment Outcome",
"nlm_unique_id": "101240003",
"other_id": null,
"pages": "354-358",
"pmc": null,
"pmid": "28807545",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Bronchopulmonary dysplasia: Myths of pharmacologic management.",
"title_normalized": "bronchopulmonary dysplasia myths of pharmacologic management"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK029946",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUTICASONE PROPIONATE"
},
"d... |
{
"abstract": "OBJECTIVE\nThere is no consensus on how to successfully treat medication-related osteonecrosis of the jaws (MRONJ). We report here on the application of piezoelectric bone surgery to treat MRONJ in combination with antibiotherapy and on its possible benefit.\nA cohort of 18 consecutive patients has been treated for MRONJ; they involved 20 sites, 15 in the mandible, and five in the maxilla. Surgical removal of the necrotic areas and debridement was performed with a powerful piezoelectric surgery device (max 90 W) in combination with antibiotherapy.\n\n\nRESULTS\nAll patients healed and obtained a complete soft tissue closure within 1 month. No recurrence of the symptoms was observed during the present follow-up (10-54 months).\n\n\nCONCLUSIONS\nWe hypothesize that healing of all treated sites might have resulted from the synergic effect of bone ablation, biofilm alteration, and antibiotic administration. Biofilm alteration might have permitted a better access of antibiotics to the involved germs. These encouraging results warrant further studies on the use of ultrasonic surgery to treat MRONJ patients in order to confirm or refute the hypothesized effect.",
"affiliations": "Odontology Biotechnology Laboratory, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy. corblus@gmail.com.;Department of Odontostomatology, Hospital Sacro Cuore di Gesù, Gallipoli, Lecce, Italy.;Odontology Biotechnology Laboratory, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy.;Odontology Biotechnology Laboratory, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy.",
"authors": "Blus|Cornelio|C|;Giannelli|Giulio|G|;Szmukler-Moncler|Serge|S|;Orru|Germano|G|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10006-016-0597-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-1550",
"issue": "21(1)",
"journal": "Oral and maxillofacial surgery",
"keywords": "Bacterial biofilm; Biphosphonate-related osteonecrosis of the jaw; MRONJ; Piezosurgery; Surgical management; Surgical treatment; Ultrasonic bone surgery",
"medline_ta": "Oral Maxillofac Surg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D059745:Piezosurgery; D016896:Treatment Outcome; D059708:Ultrasonic Surgical Procedures",
"nlm_unique_id": "101319632",
"other_id": null,
"pages": "41-48",
"pmc": null,
"pmid": "27924427",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "17397320;12202673;22054203;26515735;15197804;22000426;24044030;17482847;21176870;17172949;19371809;25234529;23751458;9626201;26795450;20452252;23161050;25414052;17524535;27179556;18371101;11208851;20360666;22698292;20664837;17092230;23899163;18355603;19797556;21763050;15173273;22336489;26713306;24141714;19371819;20674411;15803271;20425090;19371813;20333419;4575867;19143020;26659615;12966493",
"title": "Treatment of medication-related osteonecrosis of the jaws (MRONJ) with ultrasonic piezoelectric bone surgery. A case series of 20 treated sites.",
"title_normalized": "treatment of medication related osteonecrosis of the jaws mronj with ultrasonic piezoelectric bone surgery a case series of 20 treated sites"
} | [
{
"companynumb": "PHHY2018IT055742",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "1",
"... |
{
"abstract": "Epidermodysplasia verruciformis (EV) is a genodermatosis characterized by widespread and persistent cutaneous lesions caused by beta-papillomaviruses. Rare cases of acquired EV-like eruption associated with beta-papillomavirus infection have been reported in immunosuppressed patients. We report a case of acquired EV-like eruption in an immunosuppressed patient with adult T-cell leukemia. The cutaneous lesions clinically resembled pityriasis versicolor and exhibited the typical histological features of EV, but in some areas of the same biopsy specimen characteristic homogeneous intracytoplasmic inclusion bodies were observed. Although beta-papillomavirus was not detected by highly sensitive polymerase chain reaction, a putative novel type of gamma-papillomavirus was identified. This is the first documentation of an association between EV-like eruption and gamma-papillomavirus infection.",
"affiliations": "Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. kazkawai@m2.kufm.kagoshima-u.ac.jp",
"authors": "Kawai|Kazuhiro|K|;Egawa|Nagayasu|N|;Kiyono|Tohru|T|;Kanekura|Takuro|T|",
"chemical_list": "D004279:DNA, Viral",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000235743",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "219(3)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dermatology",
"mesh_terms": "D001706:Biopsy; D004279:DNA, Viral; D003937:Diagnosis, Differential; D004819:Epidermodysplasia Verruciformis; D052689:Gammapapillomavirus; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D008297:Male; D008875:Middle Aged; D030361:Papillomavirus Infections; D016133:Polymerase Chain Reaction; D012867:Skin",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "274-8",
"pmc": null,
"pmid": "19696474",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epidermodysplasia-verruciformis-like eruption associated with gamma-papillomavirus infection in a patient with adult T-cell leukemia.",
"title_normalized": "epidermodysplasia verruciformis like eruption associated with gamma papillomavirus infection in a patient with adult t cell leukemia"
} | [
{
"companynumb": "JP-PFIZER INC-2017432311",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "A subset of children who receive a liver and/or kidney transplant develop de novo inflammatory bowel disease-like chronic intestinal inflammation, not explained by infection or medications, following transplant. We have conducted a single-center, retrospective case series describing the unique clinical and histologic features of this IBD-like chronic intestinal inflammation following solid organ transplant. At our center, nine of 327 kidney or liver recipients developed de novo IBD following transplant (six liver, two kidney, one liver-kidney). Most children presented with prolonged hematochezia and diarrhea and were treated with aminosalicylates. At time of diagnosis, five were not currently using mycophenolate mofetil for transplant immunosuppression. Histologic and endoscopic findings at IBD diagnosis included inflammation, ulcerations, granulomas, and chronic colitis. Since diagnosis, no patients have required surgical intervention, or escalation to biologic therapy, nor developed stricturing or perianal disease. In this case series, de novo post-transplant IBD developed in 4% of pediatric liver and/or kidney recipients; however, it often does not fit the classic patterns of Crohn's disease or ulcerative colitis.",
"affiliations": "Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Benioff Children's Hospital San Francisco, University of California San Francisco, San Francisco, CA, USA.;School of Medicine, University of California San Francisco, San Francisco, CA, USA.;Department of Pathology, University of California San Francisco, San Francisco, CA, USA.;Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Benioff Children's Hospital San Francisco, University of California San Francisco, San Francisco, CA, USA.;Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Benioff Children's Hospital San Francisco, University of California San Francisco, San Francisco, CA, USA.",
"authors": "Fernandes|Melissa A|MA|;Braun|Hillary J|HJ|;Evason|Kim|K|;Rhee|Sue|S|;Perito|Emily R|ER|",
"chemical_list": "D007166:Immunosuppressive Agents; D010131:Aminosalicylic Acid",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12835",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(1)",
"journal": "Pediatric transplantation",
"keywords": "colitis; diarrhea; immunosuppression; solid organ transplant",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D010131:Aminosalicylic Acid; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D007249:Inflammation; D015212:Inflammatory Bowel Diseases; D016030:Kidney Transplantation; D017093:Liver Failure; D016031:Liver Transplantation; D008297:Male; D051437:Renal Insufficiency; D012189:Retrospective Studies",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27862714",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": "17524953;17631020;9404958;16911498;26048916;25981516;26209893;16790037;16968516;17904915;18043034;19098859;24813518;18708022;19715523",
"title": "De novo inflammatory bowel disease after pediatric kidney or liver transplant.",
"title_normalized": "de novo inflammatory bowel disease after pediatric kidney or liver transplant"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP010991",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
"drugadditional... |
{
"abstract": "31 years old female with a history of contact dermatitis, eczema, allergic rhinitis, pernicious anemia, alopecia areata and latent tuberculosis was treated concurrently with methotrexate along with isoniazid and pyridoxine. Five months into the therapy she developed acute onset jaundice progressing into fulminant liver failure with altered mentation and worsening liver function tests. Extensive workup including serological and histopathological evaluation revealed drug-induced liver injury as the etiology of her liver failure and she underwent a successful orthotropic liver transplant. On post-transplant follow-up at four months, she was noted to have an allergic reaction consisting of a perioral rash and swelling (without anaphylaxis) after receiving a kiss from her significant other who had just eaten a peanut butter chocolate. She denied any history of allergic reaction to peanuts prior to the transplant. Percutaneous skin testing revealed immediate hypersensitivity to peanut, hazelnut, and pecan believed to be acquired newly post-transplant. Further investigation revealed that the organ donor had a documented history of systemic anaphylaxis from the peanut allergy and a positive peanut-specific IgE level. Also, another parallel solid organ recipient (lung transplant) from the same organ donor experienced a serious anaphylactic reaction after peanut exposure. This is a case of food (peanut) allergy transfer from the donor to the recipient after the liver transplant. This case highlights the importance of incorporating known donor allergies as a part of pre-transplant screening, given the potentially serious consequences from the transfer of allergies to a previously anergic recipient.",
"affiliations": "Department of Medicine, Division of Gastroenterology and Hepatology, University of Arizona College of Medicine, Tucson, AZ, USA. Electronic address: avin.aggarwal@hotmail.com.;Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, USA.;Department of Medicine, Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, University of Arizona College of Medicine, Tucson, AZ, USA.;Department of Medicine, Division of Gastroenterology and Hepatology, University of Arizona College of Medicine, Tucson, AZ, USA.;Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA.;Department of Medicine, Division of Gastroenterology and Hepatology, University of Arizona College of Medicine, Tucson, AZ, USA.",
"authors": "Aggarwal|Avin|A|;Balogun|Rilwan|R|;Carr|Tara F|TF|;Desai|Archita P|AP|;Jie|Tun|T|;Pan|Jen-Jung|JJ|",
"chemical_list": "D000888:Antibodies, Anti-Idiotypic; D007073:Immunoglobulin E",
"country": "Mexico",
"delete": false,
"doi": "10.1016/j.aohep.2018.10.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "18(3)",
"journal": "Annals of hepatology",
"keywords": "Acquired food allergy; IgE transfer; Rash in transplant recipient; Solid organ transplant; Transplant-acquired allergy",
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000328:Adult; D000888:Antibodies, Anti-Idiotypic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007073:Immunoglobulin E; D016031:Liver Transplantation; D021183:Peanut Hypersensitivity; D012882:Skin Tests; D014019:Tissue Donors; D066027:Transplant Recipients",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "508-513",
"pmc": null,
"pmid": "31031165",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transfer of peanut allergy from donor to recipient after liver transplant.",
"title_normalized": "transfer of peanut allergy from donor to recipient after liver transplant"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-215584",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "We report four cases of ceftriaxone-associated biliary pseudolithiasis. All cases were treated conservatively without cholecystectomy or endoscopic retrograde cholangiopancreatography. Because conservative treatment is the preferred treatment, clinicians should be aware that biliary pseudolithiasis is possible in patients who have abdominal pain associated with gallbladder stones on imaging. Regardless of whether we are treating adults or children, it is necessary to check for a history of ceftriaxone treatment before symptom onset.",
"affiliations": "Department of Surgery, Japanese Red Cross Gifu Hospital.",
"authors": "Niwa|Masao|M|;Tochii|Koya|K|",
"chemical_list": "D002443:Ceftriaxone",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.113.281",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "113(2)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D015746:Abdominal Pain; D000368:Aged; D000369:Aged, 80 and over; D002443:Ceftriaxone; D003937:Diagnosis, Differential; D005260:Female; D042882:Gallstones; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "281-8",
"pmc": null,
"pmid": "26853988",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Four cases of ceftriaxone-associated biliary pseudolithiasis.",
"title_normalized": "four cases of ceftriaxone associated biliary pseudolithiasis"
} | [
{
"companynumb": "JP-ROCHE-1719664",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Pheochromocytoma is an uncommon tumor that originates in the adrenal medulla or in other paraganglia of the sympathetic nervous system. If a hypertensive crisis occurs during general anesthesia in incidental or untreated pheochromocytoma, it is a life-threatening event with a mortality rate of about 80%. Anesthetic drugs such as pancuronium, atracurium, and metoclopromide can exacerbate the potentially lethal cardiovascular effects of catecholamines. We report a case of a patient with pheochromocytoma who display abrupt increases in systolic arterial pressure and plasma norepinephrine following rocuronium administration. This case indicates the possible involvement of elevated sympathetic nervous system to a catecholamine crisis triggered by rocuronium in pheochromocytoma.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Korea. nextphil2@freechal.com.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Korea. nextphil2@freechal.com.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Korea. nextphil2@freechal.com.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Korea. nextphil2@freechal.com.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Korea. nextphil2@freechal.com.",
"authors": "Jeong|Cheol Won|CW|;Lee|Hyung Gon|HG|;Kim|Woong Mo|WM|;Shin|Seung Heon|SH|;Bae|Hong Beom|HB|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4097/kjae.2009.57.2.249",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2005-6419",
"issue": "57(2)",
"journal": "Korean journal of anesthesiology",
"keywords": "Catecholamine; Hypertensive crisis; Pheochoromocytoma; Rocuronium",
"medline_ta": "Korean J Anesthesiol",
"mesh_terms": null,
"nlm_unique_id": "101502451",
"other_id": null,
"pages": "249-253",
"pmc": null,
"pmid": "30625868",
"pubdate": "2009-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Was a hypertensive crisis in a patient with pheochromocytoma caused by rocuronium?: A case report.",
"title_normalized": "was a hypertensive crisis in a patient with pheochromocytoma caused by rocuronium a case report"
} | [
{
"companynumb": "KR-PFIZER INC-2019019729",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Treatment of aggressive pituitary tumors may be challenging. Temozolomide (TMZ) is a promising agent when conventional treatment methods fail. We present three patients with aggressive pituitary tumors with atypical morphology, who were resistant to conventional treatments and treated with TMZ. First case had a somatotroph adenoma, second a corticotroph adenoma, and the third a macroprolactinoma. We also reviewed the literature reporting TMZ efficacy in somatotroph, corticotroph and mammotroph tumors of pituitary. TMZ, 150-200 mg/m2 for 5 days in 28 days schedule was given to all patients. Among our patients, even though only the case of macroprolactinoma had a favorable response to TMZ treatment, both radiological and hormonal recurrences occurred 30 months after cessation of TMZ treatment. Then TMZ treatment was applied again. Cases of somatotroph and corticotroph adenomas had progressed under TMZ treatment and patients were lost due to mass effect of the tumor. Review of the literature demonstrated 67.3%, 60% and 26.7% overall response rates to the TMZ treatment in prolactinoma, corticotropinoma and somatostatinoma cases, respectively. There is still need to define response criteria uniformly to TMZ treatment in aggressive pituitary tumors and duration of response should be reported for reliable evaluation of results.",
"affiliations": "Ankara University Faculty of Medicine, Department of Endocrinology and Metabolism.",
"authors": "Aydoğan|Berna İmge|Bİ|;Ünlütürk|Uğur|U|;Emral|Rıfat|R|;Güllü|Sevim|S|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5137/1019-5149.JTN.20216-17.1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1019-5149",
"issue": null,
"journal": "Turkish neurosurgery",
"keywords": null,
"medline_ta": "Turk Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "9423821",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28608351",
"pubdate": "2017-05-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Course of Aggressive Somatotroph, Corticotroph and Mammotroph Tumors under Temozolomide; Report of Three Cases and Review of the Literature.",
"title_normalized": "course of aggressive somatotroph corticotroph and mammotroph tumors under temozolomide report of three cases and review of the literature"
} | [
{
"companynumb": "PHHY2018TR110000",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PASIREOTIDE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Trazodone is used as an antidepressant in doses between 150 and 600 mg. At lower doses, it is commonly used to treat insomnia. There are few case reports about confusional symptoms as an undesirable side effect of this drug. We report a case of a patient who presented with delirium after prescription of trazodone 100 mg. She required hospitalisation but, shortly after discontinuation of trazodone, the symptoms disappeared without antipsychotic medication. Seven months after the episode, the patient remains asymptomatic.",
"affiliations": "Department of Psychiatry and Mental Health, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal. Electronic address: atpereira89@gmail.com.;Department of Psychiatry and Mental Health, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.;Department of Psychiatry and Mental Health, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.;Department of Psychiatry and Mental Health, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.",
"authors": "Pereira|Ana Teresa|AT|;Mota|Diana|D|;Ribeiro|Lúcia|L|;Rodrigues|José Daniel|JD|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D014196:Trazodone",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.rcp.2018.10.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2530-3120",
"issue": "49(3)",
"journal": "Revista Colombiana de psiquiatria (English ed.)",
"keywords": "Adverse effects; Delirio; Delirium; Efectos adversos; Insomnia; Insomnio; Mental disorders; Trastornos mentales; Trazodona; Trazodone",
"medline_ta": "Rev Colomb Psiquiatr (Engl Ed)",
"mesh_terms": "D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D003693:Delirium; D005260:Female; D006760:Hospitalization; D006801:Humans; D014196:Trazodone",
"nlm_unique_id": "101778593",
"other_id": null,
"pages": "199-201",
"pmc": null,
"pmid": "32888664",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Trazodone-induced delirium: case report.",
"title_normalized": "trazodone induced delirium case report"
} | [
{
"companynumb": "PT-ALVOGEN-2020-ALVOGEN-114397",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUSPIRONE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Complement activation plays an important role in the pathogenesis of atypical hemolytic uremic syndrome. Eculizumab is a monoclonal antibody that blocks complement activity and has been approved for use in the treatment of atypical hemolytic uremic syndrome (HUS). Less well appreciated is the role of complement in Shiga toxin-induced HUS (Shiga toxin producing Escherichia coli [STEC]-HUS). To a limited extent, eculizumab has been used off label in patients with severe STEC-HUS with neurological involvement. Through a systematic search of available databases, we identified 16 reports describing the use of eculizumab in STEC-HUS (eight case reports/series, seven retrospective studies, and one prospective cohort study). All studies described its use in severe STEC-HUS with neurological or multiorgan dysfunction; none were randomized or blinded. Four studies used the control groups. Although the overall quality of evidence is low, some published studies showed positive clinical improvement after treatment with eculizumab in severe STEC-HUS with progressive neurological involvement.",
"affiliations": "Department of Pediatric Hematology Oncology and BMT, Cleveland Clinic Children's, Cleveland, Ohio.;Center for Pediatric Nephrology, Cleveland Clinic Children's, Cleveland, Ohio.;Department of Pediatric Hematology Oncology and BMT, Cleveland Clinic Children's, Cleveland, Ohio.",
"authors": "Mahat|Upendra|U|0000-0001-7272-0988;Matar|Raed Bou|RB|;Rotz|Seth J|SJ|0000-0003-2896-1113",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C481642:eculizumab",
"country": "United States",
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"doi": "10.1002/pbc.27913",
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"issn_linking": "1545-5009",
"issue": "66(11)",
"journal": "Pediatric blood & cancer",
"keywords": "E. coli; STEC-HUS; Shiga toxin; complement; eculizumab",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D017326:Clinical Trials, Phase III as Topic; D003167:Complement Activation; D004311:Double-Blind Method; D004927:Escherichia coli Infections; D005544:Forecasting; D006331:Heart Diseases; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D009422:Nervous System Diseases; D056687:Off-Label Use; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D054323:Shiga-Toxigenic Escherichia coli",
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"pages": "e27913",
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"pmid": "31286658",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Use of complement monoclonal antibody eculizumab in Shiga toxin producing Escherichia coli associated hemolytic uremic syndrome: A review of current evidence.",
"title_normalized": "use of complement monoclonal antibody eculizumab in shiga toxin producing escherichia coli associated hemolytic uremic syndrome a review of current evidence"
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"abstract": "We report a case of a 28-year-old man with angiosarcoma of the spleen and liver metastases. The aim of this paper is to underline the importance of planned splenectomy in these patients even if they have metastatic disease, and to propose an intensive chemotherapy regimen consisting of anthracyclines, ifosfamide and mesna with G-CSF support.",
"affiliations": "Divisione di Oncologia Medica, Centro di Riferimento Oncologico, IRCCS, Istituto Nazionale Tumori, Aviano, Italy.",
"authors": "Rupolo|M|M|;Berretta|M|M|;Buonadonna|A|A|;Stefanovski|P|P|;Bearz|A|A|;Bertola|G|G|;Canzonieri|V|V|;Morassut|S|S|;Frustaci|S|S|",
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"journal": "Tumori",
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"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D006394:Hemangiosarcoma; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D010166:Palliative Care; D011788:Quality of Life; D013156:Splenectomy; D013160:Splenic Neoplasms",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "439-43",
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"pmid": "11989602",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Metastatic angiosarcoma of the spleen. A case report and treatment approach.",
"title_normalized": "metastatic angiosarcoma of the spleen a case report and treatment approach"
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"abstract": "BACKGROUND\nPrimary intracranial neuroendocrine tumors are exceedingly rare, with few cases in the literature. We present a case of a primary neuroendocrine carcinoma of the pineal gland, which is the second that has ever been reported.\n\n\nMETHODS\nA 53-year-old male patient presented with vomiting, weakness, and headaches. Imaging revealed a lesion in the pineal region, which was surgically resected. This mass was characterized by histology as a neuroendocrine carcinoma, given the presence of neuroendocrine markers and cytokeratin markers with absence of a primary lesion elsewhere on imaging.\n\n\nCONCLUSIONS\nThere are currently no guidelines on the management of primary intracranial neuroendocrine tumors. In this case, the patient underwent surgical resection and craniospinal radiotherapy. He subsequently received one cycle of chemotherapy with temozolomide, an alkylating agent, but he unfortunately did not tolerate treatment. A multidisciplinary decision was made along with the patient and his family to focus on palliative care. Eighteen months after the initial presentation, disease recurred in the patient's neck. The patient underwent resection to control the metastases, with a plan to follow with radiotherapy and chemotherapy. Unfortunately, the patient became unwell and died at 21 months after initial diagnosis. This demonstrates a need for continued research and reporting on this uncommon disease entity.",
"affiliations": "Faculty of Medicine, Memorial University, 105-78 Thorburn Road, St. John's, NL, A1B3T4, Canada. ascheng@mun.ca.;Discipline of Laboratory Medicine (Neuropathology), Memorial University Faculty of Medicine, St. John's, Canada.;Discipline of Oncology (Radiation Oncology), Memorial University Faculty of Medicine, St. John's, Canada.;Department of Radiology, Memorial University Faculty of Medicine, St. John's, Canada.;Department of Surgery (Neurosurgery), Memorial University Faculty of Medicine, St. John's, Canada.;Discipline of Oncology (Medical Oncology), Memorial University Faculty of Medicine, St. John's, Canada.",
"authors": "Cheng|Angela|A|http://orcid.org/0000-0002-4386-148X;Barron|Jane|J|;Holmes|Oliver|O|;Bartlett|Peter|P|;Jenkins|Gregory|G|;Seal|Melanie|M|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s12883-021-02351-0",
"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377\nBioMed Central London\n\n2351\n10.1186/s12883-021-02351-0\nCase Report\nPrimary neuroendocrine tumor of the pineal gland: a case report\nhttp://orcid.org/0000-0002-4386-148X\nCheng Angela ascheng@mun.ca\n\n1\nBarron Jane 2\nHolmes Oliver 3\nBartlett Peter 4\nJenkins Gregory 5\nSeal Melanie 6\n1 grid.25055.37 0000 0000 9130 6822 Faculty of Medicine, Memorial University, 105-78 Thorburn Road, St. John’s, NL A1B3T4 Canada\n2 grid.25055.37 0000 0000 9130 6822 Discipline of Laboratory Medicine (Neuropathology), Memorial University Faculty of Medicine, St. John’s, Canada\n3 grid.25055.37 0000 0000 9130 6822 Discipline of Oncology (Radiation Oncology), Memorial University Faculty of Medicine, St. John’s, Canada\n4 grid.25055.37 0000 0000 9130 6822 Department of Radiology, Memorial University Faculty of Medicine, St. John’s, Canada\n5 grid.25055.37 0000 0000 9130 6822 Department of Surgery (Neurosurgery), Memorial University Faculty of Medicine, St. John’s, Canada\n6 grid.25055.37 0000 0000 9130 6822 Discipline of Oncology (Medical Oncology), Memorial University Faculty of Medicine, St. John’s, Canada\n20 8 2021\n20 8 2021\n2021\n21 32315 4 2021\n12 8 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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.\nIntroduction\n\nPrimary intracranial neuroendocrine tumors are exceedingly rare, with few cases in the literature. We present a case of a primary neuroendocrine carcinoma of the pineal gland, which is the second that has ever been reported.\n\nCase presentation\n\nA 53-year-old male patient presented with vomiting, weakness, and headaches. Imaging revealed a lesion in the pineal region, which was surgically resected. This mass was characterized by histology as a neuroendocrine carcinoma, given the presence of neuroendocrine markers and cytokeratin markers with absence of a primary lesion elsewhere on imaging.\n\nConclusions\n\nThere are currently no guidelines on the management of primary intracranial neuroendocrine tumors. In this case, the patient underwent surgical resection and craniospinal radiotherapy. He subsequently received one cycle of chemotherapy with temozolomide, an alkylating agent, but he unfortunately did not tolerate treatment. A multidisciplinary decision was made along with the patient and his family to focus on palliative care. Eighteen months after the initial presentation, disease recurred in the patient’s neck. The patient underwent resection to control the metastases, with a plan to follow with radiotherapy and chemotherapy. Unfortunately, the patient became unwell and died at 21 months after initial diagnosis. This demonstrates a need for continued research and reporting on this uncommon disease entity.\n\nKeywords\n\nNeuroendocrine carcinoma\nPineal gland\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nNeuroendocrine tumors (NETs) are a heterogeneous and uncommon group of tumors. They are composed of cells that contain dense core granules, hence the prefix ‘neuro’, and have secretory abilities, described by the term ‘endocrine’. While circulating biomarkers such as chromogranin A (CgA) and neuron specific enolase (NSE) can increase with the presence of a NET, the measurement of these peptides is not recommended for screening as they are unspecific markers and can be elevated due to other clinical conditions. For instance, CgA can be elevated in patients that are taking a proton pump inhibitor or in those with renal insufficiency, while NSE can be raised due to the presence of small-cell lung carcinoma [1]. Therefore, diagnosis requires tissue biopsy and the presence of neuroendocrine markers such as CgA, NSE, and synaptophysin on histological examination. The most common anatomical origins of these tumors are along the gastrointestinal tract and within the bronchopulmonary segments. Rarely, these tumors can occur intracranially, with nine reported cases of primary origin in this site [2–9]. Pineal gland origin is even less common, with only one previous case having been reported [2]. Pineal region tumors, given their proximity to the cerebral aqueduct, can lead to obstruction of cerebrospinal fluid (CSF) outflow, resulting in downstream effects such as hydrocephalus. To our knowledge, this is the second case that has been reported of a neuroendocrine carcinoma originating in the pineal region.\n\nCase presentation\n\nClinical summary\n\nA previously healthy 53-year-old male was admitted to hospital after presenting with a five-day history of intractable vomiting, generalized weakness, and ataxia. Additionally, he reported that he had been experiencing severe headaches. The patient had an unremarkable medical history, with hypertension as his only medical condition. On physical examination, he appeared lethargic and was frequently retching and vomiting. The only neurological findings were bilateral papilledema and impaired upward and downward gaze. Due to the patient’s condition, his gait could not be safely assessed. Computed tomography (CT) and magnetic resonance imaging (MRI) scans revealed hydrocephalus secondary to an outflow obstruction of the third ventricle. The obstructing mass measured 2.5 cm × 3 cm × 3.2 cm and appeared hyperdense, demonstrating enhancement with contrast. It was centred in the pineal region and had central calcification. There was mass effect on the adjacent midbrain. The midbrain was edematous, possibly indicating invasion. The remainder of the brain appeared normal (Fig. 1A, B). Fig. 1 Pre-operative axial radiological images of the brain. A Computed tomography scan demonstrating the neoplasm in the pineal region with central calcification. B Magnetic resonance imaging scan demonstrating the neoplasm within the pineal region\n\nThe patient underwent endoscopic biopsy and endoscopic third ventriculostomy (ETV). An external ventricular drain (EVD) was placed due to moderate tumor bleeding during the biopsy. This drain was then weaned and removed on post-operation day three after a CT head showed improvement in the patient’s hydrocephalus. After the biopsy was reported as a malignancy, we offered the patient surgical resection of the tumor. We performed a craniotomy through the occipital bone. A supracerebellar, infratentorial approach was used to achieve a subtotal resection.\n\nThe patient developed a communicating hydrocephalus while recovering after the resection, requiring an EVD. The EVD became blocked twice, requiring reinsertion of the drain. The second time the drain blocked, the patient became drowsy, prompting us to place a permanent ventriculoperitoneal shunt. A ventriculoperitoneal shunt was not placed during the resection surgery as the non-communicating hydrocephalus was adequately treated with the ETV.\n\nHistological analysis of the biopsied and resected tumor tissues presented a diagnostic challenge, given the rarity of primary neuroendocrine tumors of the pineal gland. The initial differential diagnosis included pineal parenchymal tumors, such as a pineoblastoma, as well as metastatic neuroendocrine carcinoma. The tissue was evaluated by four external pathologists, as well as a local Neuropathologist, and diagnosed as a neuroendocrine carcinoma based on the cytokeratin and synaptophysin positivity. Positron emission tomography-computed tomography (PET/CT) demonstrated fluorodeoxyglucose (FDG) avidity in the pineal gland with no evidence of another primary site, strongly suggesting that this was a primary neuroendocrine carcinoma of the pineal gland. It is worth mentioning that PET/CT revealed a small incidentaloma –without FDG avidity – in the upper pole of the left kidney suggestive of renal cell carcinoma (RCC).\n\nDuring his hospitalization, the patient was found to have hypercalcemia and elevated parathyroid hormone (PTH). Consultation with an Endocrinologist revealed that he had primary hyperparathyroidism. Two months after his initial presentation, the patient had lost 24 kg, and was unable to speak or sit up in bed but retained the ability to move all limbs independently. At that time, the patient’s performance status was Eastern Cooperative Oncology Group (ECOG) 4 and he was not a candidate for further therapy. After discussions with the patient and his family, the patient was transferred home for palliative care.\n\nOver the subsequent months, the patient’s condition improved significantly. He was reassessed and treated with craniospinal radiation in two phases (5400 cGy in 30 fractions to the residual enhancing tumor and resection cavity, and 3600 cGy in 20 fractions to the craniospinal axis). Post-radiation, the plan was to administer systemic therapy with palliative intent to slow disease progression and maintain quality of life. Approximately 8 months after his initial presentation, the patient’s performance status improved to ECOG-2 and he received his first cycle of chemotherapy (temozolomide 150 mg/m2 given orally daily for 5 days of a planned 28-day cycle). Unfortunately, he did not tolerate the drug well and was admitted to hospital for 5 weeks. Systemic therapy was discontinued. The patient recovered at home, and it was decided, in consultation with the patient and family, that surveillance would be the preferred approach.\n\nEighteen months after his initial presentation, the patient developed a rapidly growing lesion on his posterior neck that tripled in size over 2 months. MRI showed at least four enhancing lesions in the soft tissue of the neck (Fig. 2). The lesion that was clinically palpable measured 56 mm × 35 mm × 55 mm and was located left of the midline of the posterior neck (Fig. 2A). The second lesion was in the left posterior neck at level Vb, measuring 16 mm × 17 mm × 17 mm (Fig. 2B). The third lesion was located on the right posterior neck at level Vb, measuring 22 mm × 18 mm × 20 mm (Fig. 2C). The fourth lesion was paraesophageal on the left at level VI, measuring 10 mm × 18 mm (Fig. 2D). The smaller lesions were likely lymph node metastases. A biopsy of the largest lesion was performed, and histology was highly suggestive of a metastatic lesion from the original pineal tumor. The treatment plan at this time was local resection, followed by radiation to control the metastases and potential platinum-based chemotherapy. The clinically palpable neck mass was surgically excised from the soft tissue 3 months after it was initially identified. Unfortunately, the patient became unwell prior to starting radiation and died 21 months after his initial diagnosis (Table 1). Fig. 2 Four magnetic resonance images demonstrating metastatic disease throughout the soft tissue of the patient’s neck. A The clinically palpable lesion is shown located left of the midline of the posterior neck. B A lesion is shown located in the left posterior neck at level Vb. C A lesion is shown located in the right posterior neck at level Vb. D A lesion is shown located on the left side of the paraesophageal region at level VI\n\nTable 1 Timeline showcasing the relevant events from episode of care\n\nPast medical history: Hypertension\t\nDate\tSummary\tDiagnostic Testing\tIntervention\t\nJanuary 2018\tPatient presented with five-day history of vomiting, weakness, balance difficulties, and headaches.\tCT head: aggressive pineal tumor with hydrocephalus.\tStarted on IV steroids and transported to tertiary care centre.\t\nJanuary 2018\tPatient experiencing symptoms of hydrocephalus.\t\tThird ventriculostomy, biopsy of the pineal tumor, and insertion of external ventricular drain and ICP monitor.\t\nFebruary 2018\tPatient experienced minimal symptom relief from drain placement.\t\tSurgical subtotal resection of the pineal tumor for symptom relief.\t\nMarch 2018\tPatient continued to experience symptoms from hydrocephalus.\tCT head: hydrocephalus.\tVentriculoperitoneal shunt placed.\t\nMarch 2018\tPatient assessed by Medical Oncology and Radiation Oncology. The patient was ECOG-4 at that time.\n\nIncidental hyperparathyroidism and hypercalcemia discovered after Endocrinology consultation.\n\n\tPET-CT: no evidence of FDG-avid neoplasia elsewhere in body. Small renal lesion noted.\tNo systemic intervention or radiotherapy at that time due to patient’s performance status.\t\nApril 2018\tThe patient remained in ECOG-4. The patient and family wished to return home.\t\tDiscussion held with patient and family. Decision for the patient to return to his community hospital for palliative care.\t\nMay 2018\tThe patient’s condition improved significantly during rehabilitation to ECOG-2.\t\tPatient discharged from community hospital.\t\nJune 2018\tPatient reassessed by Radiation Oncology.\tMRI head and spine: enlargement of pineal tumor. No evidence of drop metastases within spinal column.\t\t\nJuly 2018\tRadiation regimen of 54 cGy in 30 fractions to primary tumor and resection cavity. 3600 cGy in 20 fractions to craniospinal axis.\t\t\t\nJuly 2018\tPatient reassessed by Medical Oncology. Discussion held with the patient and family members about the role of systemic therapy with palliative intent.\t\tThe patient was provided with information about temozolomide and capecitabine. Systemic therapy planned for post-radiation.\t\nSeptember 2018\tRadiotherapy completed. The patient started temozolomide alone based on ECOG, but experienced significant toxicity, resulting in hospital admission.\tMRI head and spine: residual tumor slightly decreased in size post-radiotherapy.\tFurther chemotherapy held.\t\nDecember 2018\tPatient reassessed by Medical Oncology.\tMRI head: slight decrease in size of residual tumor with stable edema and hydrocephalus.\tNo further systemic therapy at this time. Continued surveillance. Referral to Palliative Care for best supportive care.\t\nMarch, April 2019\tRoutine follow-ups with Radiation Oncology.\tMRI head: stable residual tumor size.\t\t\nJune 2019\tPatient noticed posterior neck swelling.\tBiopsy: metastatic disease.\n\nMRI cervical spine: at least four enhancing lesions.\n\n\tBiopsy of neck mass performed.\t\nJuly 2019\tPatient reassessed by Medical Oncology and Radiation Oncology. Planned for radiotherapy to control metastatic disease with possible platinum-based chemotherapy post-radiation.\t\t\t\nAugust 2019\tPatient became unwell before radiotherapy attempted.\t\tNo radiation due to decline in performance status. .\t\nSeptember 2019\tThe patient’s condition deteriorated and was admitted to hospital for palliative care, where he later died.\t\t\t\nAbbreviations: CT Computed tomography, IV Intravenous, ICP Intracranial pressure, ECOG Eastern Cooperative Oncology Group, MRI Magnetic resonance imaging\n\nPathology findings\n\nThe gross total pineal tumor was soft, tan, and hemorrhagic. Microscopic examination of the biopsied and resected tissues from the pineal region revealed that they were similar in composition, and both included a highly cellular neoplasm composed of primitive-looking round cells with finely dispersed granular chromatin, indistinct nucleoli, and scanty cytoplasm (Fig. 3A). The cells were arranged in diffuse sheets and trabeculae. There were focal papillary arrangements and vague rosettes. Mitotic activity was brisk with 20 per 10 high power fields. Atypical mitotic forms were also seen. Immunohistochemistry was performed and the tumor cells were strongly positive for synaptophysin, neuron specific enolase (NSE), cytokeratin (CK) 8/18, CK AE1/AE3, and CK CAM 5.2 (Fig. 3B, C, D). There was focal positivity for chromogranin, S100, and neurofilament (NF). There was no staining for PTH, epithelial membrane antigen (EMA), CK 7, CK 20, thyroid transcription factor-1 (TTF-1), glial fibrillary acidic protein (GFAP), and microtubule associated protein 2 (MAP2). Integrase interactor 1 (INI1) nuclear staining was intact. The Ki67 index was estimated to be 60–70%. Fig. 3 Photomicrographs of the tumor tissue. A The tumor consists of uniform round cells arranged in diffuse sheets and trabeculae. Cells contain minimal cytoplasm and indistinct nucleoli. B Immunohistochemistry. Tumor cells stain positive for CK 8/18. C Immunohistochemistry. Tumor cells stain positive for NSE. D Immunohistochemistry. Tumor cells stain positive for synaptophysin\n\nThe slides were scanned using the Leica Aperio AT2 scanner and viewed with the Leica eSlideManager software. The images were acquired at a magnification of 20X and resolution of 0.50uM/pixel. No digital enhancements or adjustments were performed on any of these images.\n\nDiscussion and conclusions\n\nNETs arise from Kulchitsky cells, a type of enterochromaffin cell mostly located in the gastrointestinal and bronchopulmonary tracts, resulting in a propensity for tumours in these locations. However, many epithelial cells and their progenitors can exhibit neuroendocrine differentiation and therefore, although less frequently, NETs can originate in various anatomical regions. In this report, we described a patient with a primary neuroendocrine carcinoma of the pineal gland.\n\nDiagnostic approach\n\nIn this case, the diagnosis of a primary neuroendocrine carcinoma was based on thorough review of pathology and imaging with PET-CT.\n\nPathology\n\nBased on the dual expression of neuroendocrine markers and cytokeratin markers on the resected and biopsied tissue, the diagnosis favoured a neuroendocrine carcinoma. This was supported by histological review by four external pathologists. The World Health Organization (WHO) currently does not include neuroendocrine tumors in its description of pineal tumors [10]. Instead, the WHO describes two main categories of pineal tumours: pineal parenchymal tumours (PPT) [including the pineocytomas, pineal parenchymal tumor of intermediate differentiation, and pineoblastomas] and papillary tumors of the pineal region (PTPR) [10]. Histologically, PPTs are characteristically positive for NSE and synaptophysin, while PTPR demonstrate papillary features and keratin reactivity (CK AE1/AE3, CK 18, CAM 5.2). Intriguingly, there is a reported case of a pineal tumour that was biopsied and subsequently resected at a later date, in which the biopsied tissue was histologically similar to a PPT, while the resected tissue had features of a PTPR [11]. The authors suggest that this phenomenon occurred because the tumor was transitioning from a PPT to a PTPR. It is also feasible that this finding resulted from a sampling error. Another possibility is that this tumor was actually a neuroendocrine carcinoma, as the presence of neuroendocrine markers along with cytokeratin positivity is consistent with a neuroendocrine carcinoma. Our case, along with this case by Cohan et al. highlights the gaps in the current WHO pineal tumor classification guidelines.\n\nDiagnostic imaging\n\nThe PET/CT showed no primary lesion other than the pineal gland. As mentioned, a possible RCC was incidentally found, but this was unlikely to be the primary site due to the lack of FDG avidity.\n\nTreatment approach\n\nThe patient underwent subtotal resection of the tumor and craniospinal radiation with a plan to administer systemic therapy post-radiation. Initially, the plan was to treat with capecitabine and temozolomide chemotherapy in combination as there is existing evidence demonstrating the effectiveness of this doublet in the treatment of advanced NETs [12]. Furthermore, both agents have shown activity in central nervous system tumours [13, 14]. However, given the patient’s performance status, he received temozolomide alone. Temozolomide was selected because it is an alkylating agent that crosses the blood brain barrier, with a proven efficacy against primary central nervous system tumours, such as gliomas [14]. Platinum-based treatment was ruled out at this point, as the patient was not systemically well enough to receive doublet therapy. Unfortunately, the patient did not tolerate the temozolomide. Treatment with capecitabine and temozolomide in combination would have provided valuable insight into the efficacy and tolerability of treating rare intracranial NETs. The only systemic therapy regimens previously published for this type of intracranial tumour were cisplatin and etoposide with and without sunitinib, or single agent temozolomide.\n\nFrom a Radiation Oncology perspective, this was a remarkable case given the pattern of disease recurrence. As this disease entity is exceedingly rare, there were no pre-existing standards for radiotherapy. Knowing that this was a high-grade tumor, we treated the patient with craniospinal irradiation, which is standard for pineoblastomas, another high-grade pineal tumor. The treatment focuses on the craniospinal axis, along with a boost to the intracranial cavity, and does not involve radiation to the surgical scar and dermis (Fig. 4A, B, C). Unexpectedly, the marginal failure involved the soft tissues in the surgical site outside of the radiation field and the patient developed lymphadenopathy in his neck. In the future, we would strongly consider including the surgical tract all the way to the epidermis in the 3600 cGy volume to prevent a marginal failure. It is unclear whether including lymph node levels in the neck would prevent a locoregional failure. Fig. 4 Images demonstrating the radiation field. A Axial head view, with 5400 cGy volume. B Coronal head view, with 5400 cGy volume. C Sagittal body view with 3600 cGy volume and dose colourwash. The arrow indicates the low dose region and surgical tract where the disease recurred\n\nIntracranial primary neuroendocrine tumors in the literature\n\nThere are few instances in the literature of intracranial NETs, either as primary occurrences or metastases from other sites [2]. We identified eight published case reports of primary intracranial NETs [2–9] (Table 2) including primaries near the pituitary, along the meninges, in the pineal gland, and intraventricularly [2–9]. Patients in these case reports either underwent surgical resection or excisional biopsy only [2–9]. In four of these cases, treatment included systemic therapy and three of these patients also received radiation therapy [2, 3, 8, 9]. In the previously reported case of a primary neuroendocrine tumor of the pineal gland, a chemotherapy regimen of cisplatin, etoposide, and sunitinib was administered, along with craniospinal radiation, and the patient died 26 months following their diagnosis [2]. In the case of a primary intraventricular neuroendocrine carcinoma, cisplatin and etoposide were used as systemic therapy, along with intensity-modulated radiation therapy [8]. That patient tolerated therapy and was followed for 5 years, experiencing no recurrence until 10 years later [8]. During treatment of recurrence, the patient experienced worsening issues related to her ventriculoperitoneal shunt secondary to hydrocephaly and died due to complications [8]. This highlights the importance of ongoing and long-term surveillance post-remission in cases of primary intracranial NETs. In one of these cases, multiple primary intracranial NETs were found in a single patient. This patient underwent surgical resection of the largest lesion, followed by whole brain and tumor bed radiation, and systemic therapy using temozolomide resulting in decrease in tumor volume and no recurrence at the 10-month follow-up [9]. Table 2 Published cases of intracranial neuroendocrine tumors of primary origin\n\nSource\tIntracranial Location\tAge (y.)\tSex\tTreatment\tOverall survival\tCause of death\t\nHakar et al.\tPineal parenchyma\t35\tFemale\tSubtotal resection\n\nCisplatin, etoposide, sunitinib\n\nCraniospinal irradiation\n\n\tDied 26 months following diagnosis\tCancer progression\t\nLiu et al.\tSella/hypothalamic\t39\tFemale\tResection\tDied three months following diagnosis\tCancer progression, too unwell to receive radiotherapy\t\nLiu et al.\tAnterior cranial fossa\t40\tFemale\tResection\tAt time of publication, patient alive, but undisclosed timeline\t-\t\nReed et al.\tIntraventricular, third ventricle\t34\tFemale\tResection\n\nIntensity modulated radiation therapy\n\nCisplatin and etoposide\n\n\tFollowed for five years with no recurrence\n\nRecurrence 10 years after initial diagnosis, died 2 months after\n\n\tComplications of hydrocephalus secondary to recurrence\t\nIbrahim et al.\tSkull base, level of jugular foramen\t29\tFemale\tMonthly somatostatin injections\n\nPatient declined radiotherapy\n\n\tFollowed for one year with stable disease\t-\t\nHood et al.\tLeft cavernous sinus\t61\tFemale\tSubtotal resection\n\nFractionated external beam radiation therapy\n\n\tFollowed for 7.5 years with stable disease\t-\t\nDeshaies et al.\tDural-based, compressing right frontal lobe\t79\tFemale\tResection\n\nOctreotide\n\n\tDied 6 weeks after diagnosis\tUnknown complications\t\nCao et al.\tMultiple lesions, left parietal convexity, right occipital parietal convexity, left frontal convexity, left cerebral falx, right temporal lobe\t56\tFemale\tResection of three lesions\n\nWhole brain and tumor bed radiotherapy\n\nTemozolomide with recombinant human endostatin\n\n\tFollowed for 10 months with stable disease\t-\t\nPorter et al.\tRight cerebellopontine angle of posterior fossa\t62\tMale\tSubtotal resection\tAt time of publication, 5-year survival\t-\t\nOur study\tPineal parenchyma\t53\tMale\tSubtotal resection\n\nTemozolomide\n\nCraniospinal irradiation\n\n\tDied 18 months after diagnosis\tCancer progression\t\n\nMetastatic intracranial neuroendocrine tumors\n\nMetastatic intracranial NETs are also quite uncommon. There are few reported cases of brain metastases occurring in patients with NETs of non-lung, gastroenteropancreatic, or bronchopulmonary origin, with an estimated incidence of 1.5–5% [15]. In one study of patients with NETs and brain metastases, lung was noted to be the most frequent primary disease site [16]. As such, there are recommendations for MRI of the head of part of the metastatic workup in patients with primary carcinoma of the lung [15]. In patients with single brain metastases, surgery is indicated with a palliative role [15]. Systemic therapy is typically chosen based on the tumor origin and biology [15]. In those with multiple intracranial metastases, external beam irradiation is indicated and can be combined with surgery [15]. Palliative radiation was the most common treatment type found in a cohort of 51 patients with secondary intracranial neuroendocrine disease [16]. In patients with brain metastases, median survival is less than 10 months with a 1-year survival rate of < 40% [15]. Given the difference in prognosis and treatment indications between primary and secondary disease, there is value in performing a thorough metastatic work-up to establish tumor origin.\n\nPatient perspective\n\nUnfortunately, the patient died before being able to write about his experience with this disease and his care. His partner had provided written consent for publication.\n\nConclusion\n\nIn conclusion, intracranial NETs are an uncommon entity and those arising in the pineal gland are exceedingly rare. There is limited evidence pertaining to the care of affected patients published in the literature. We report on a case of NET of the pineal gland to contribute to research in this area and ultimately improve health care delivery for patients with these tumours. Although uncommon, NETs should be considered in the differential diagnosis of intracranial lesions.\n\nAbbreviations\n\nNET Neuroendocrine tumor\n\nCgA Chromogranin A\n\nNSE Neuron specific enolase\n\nCSF Cerebrospinal fluid\n\nCT Computed tomography\n\nMRI Magnetic resonance imaging\n\nEVD External ventricular drain\n\nETV Endoscopic third ventriculostomy\n\nPET/CT Positron emission tomography-computed tomography\n\nFDG Fluorodeoxyglucose\n\nRCC Renal cell carcinoma\n\nPTH Parathyroid hormone\n\nECOG Eastern Cooperative Oncology Group\n\nCK Cytokeratin\n\nNF Neurofilament\n\nEMA Epithelial membrane antigen\n\nTTF-1 Thyroid transcription factor 1\n\nGFAP Glial fibrillary acidic protein\n\nMAP 2 Microtubule associated protein 2\n\nINI1 Integrase interactor 1\n\nPPT Parenchymal pineal tumor\n\nPTPR Papillary tumor of pineal region\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nLiterature review, writing and formatting of manuscript: A.C. Conception of report, supervising overall project, writing and review of Medical Oncology contribution: M.S. Writing and review of Pathology contribution, provided histological figures: J.B. Writing and review of Radiation Oncology contribution, provided radiation figures: O.H. Writing and review of Radiology contribution, provided imaging figures: P.B. Writing and review of Neurosurgery contribution: G.J. Review of final manuscript: All authors. The author(s) read and approved the final manuscript.\n\nFunding\n\nThe authors declare that they received no funding for this research.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nAs this was a single case study, ethics approval was not required. This was confirmed by the Newfoundland and Labrador Health Research and Ethics Board.\n\nConsent for publication\n\nThe patient’s next-of-kin provided written consent for publication.\n\nCompeting interests\n\nThe 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. Tzontcheva A Neuroendocrine tumors – laboratory diagnosis J Med Biochem 2010 29 4 254 264 10.2478/v10011-010-0028-5\n2. Hakar M Chandler JP Bigio EH Mao Q Neuroendocrine carcinoma of the pineal parenchyma. The first reported case J Clin Neurosci 2017 35 68 70 10.1016/j.jocn.2016.09.024 27742368\n3. Reed CT Duma N Halfdanarson T Buckner J Primary neuroendocrine carcinoma of the brain BMJ Case Rep 2019 12 9 e230582 10.1136/bcr-2019-230582 31537610\n4. Ibrahim M Yousef M Bohnen N Eisbruch A Parmar H Primary carcinoid tumor of the skull base: case report and review of the literature J Neuroimaging 2010 20 4 390 392 10.1111/j.1552-6569.2008.00317.x 19021842\n5. Liu H Wang H Qi X Yu C Primary intracranial neuroendocrine tumor: two case reports World J Surg Oncol 2016 14 1 138 10.1186/s12957-016-0887-4 27138163\n6. Porter DG Chakrabarty A McEvoy A Intracranial carcinoid without evidence of extracranial disease Neuropathol Appl Neurobiol 2000 26 3 298 300 10.1046/j.1365-2990.2000.00257.x 10886688\n7. Hood B Bray E Bregy A Primary carcinoid tumor of the cavernous sinus World Neurosurg 2014 81 1 202.e9 202.13 10.1016/j.wneu.2013.06.009\n8. Deshaies EM Adamo MA Qian J DiRisio D A carcinoid tumor mimicking an isolated intracranial meningioma. Case report J Neurosurg 2004 101 5 858 860 10.3171/jns.2004.101.5.0858 15540927\n9. Cao J Xu W Du Z Pathologic progression, possible origin, and management of multiple primary intracranial neuroendocrine carcinomas World Neurosurg 2017 106 1054.e13 1054.e17 10.1016/j.wneu.2017.07.053\n10. Nakazato Y Jouvet A Scheithauer BW Tumours of the pineal region WHO classification of Tumours of the central nervous system 2007 4 Geneva WHO Press 121 130\n11. Cohan JN Moliterno JA Mok CL Lavi E Boockvar JA Pineal parenchymal tumor of intermediate differentiation with papillary features: a continuum of primary pineal tumors? J Neuro-Oncol 2011 101 2 301 306 10.1007/s11060-010-0242-5\n12. Lu Y Zhao Z Wang J Lv W Lu L Fu W Li W Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: a meta-analysis Medicine (Baltimore) 2018 97 41 e12784 10.1097/MD.0000000000012784 30313101\n13. Ekenel M Hormigo AM Peak S DeAngelis LM Abrey LE Capecitabine therapy of central nervous system metastases from breast cancer J Neuro-Oncol 2007 85 2 223 227 10.1007/s11060-007-9409-0\n14. Friendman HS Kerby T Calvert H Temozolomide and treatment of malignant glioma Clin Can Res 2000 6 7 2585 2597\n15. Pavel M Grossman A Arnold R Perren A Kaltsas G Steinmüller T de Herder W Nikou G Plöckinger U Lopes JM Sasano H Buscombe J Lind P O'Toole D Oberg K Palma de Mallorca Consensus Conference Participants ENETS consensus guidelines for the Management of Brain, cardiac and ovarian metastases from neuroendocrine tumors Neuroendocrinology. 2010 91 4 326 332 10.1159/000287277 20453466\n16. Krug S Teupe F Michl P Gress TM Rinke A Brain metastases in patients with neuroendocrine neoplasms: risk factors and outcome BMC Cancer 2019 19 1 362 10.1186/s12885-019-5559-7 30991982\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "21(1)",
"journal": "BMC neurology",
"keywords": "Case report; Neuroendocrine carcinoma; Pineal gland",
"medline_ta": "BMC Neurol",
"mesh_terms": "D001932:Brain Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D018358:Neuroendocrine Tumors; D010870:Pineal Gland; D010871:Pinealoma",
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"pubdate": "2021-08-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Primary neuroendocrine tumor of the pineal gland: a case report.",
"title_normalized": "primary neuroendocrine tumor of the pineal gland a case report"
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"abstract": "We present a case of a 38+1 weeks pregnant patient (G1P0) with a proven COVID-19 infection, who was planned for induction of labour because of pre-existent hypertension, systemic lupus erythematosus, respiratory problem of coughing and mild dyspnoea without fever during the COVID-19 pandemic in March 2020. To estimate the risk of vertical transmission of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) during labour and delivery, we collected oropharyngeal, vaginal, urinary, placental and neonatal PCRs for SARS-CoV-2 during the period of admission. All PCRs, except for the oropharyngeal, were negative and vertical transmission was not observed. Labour and delivery were uncomplicated and the patient and neonate were discharged the next day. We give a short overview of the known literature about SARS-CoV-2-related infection during pregnancy, delivery and outcome of the neonate.",
"affiliations": "Department of Obstetrics and Gynaecology, Reinier de Graaf Gasthuis, Delft, Zuid-Holland, The Netherlands.;Department of Obstetrics and Gynaecology, Reinier de Graaf Gasthuis, Delft, Zuid-Holland, The Netherlands.;Department of Obstetrics and Gynaecology, Reinier de Graaf Gasthuis, Delft, Zuid-Holland, The Netherlands.;Department of Paediatrics, Subdivision Infectious Diseases and Immunology, Erasmus Medical Center - Sophia, Rotterdam, The Netherlands.;Division of Neonatology, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Obstetrics and Gynaecology, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands s.schoenmakers@erasmusmc.nl.",
"authors": "Grimminck|Koen|K|;Santegoets|Lindy Anne Maria|LAM|;Siemens|Frederike Charlotte|FC|;Fraaij|Pieter Leendert Alex|PLA|;Reiss|Irwin Karl Marcel|IKM|;Schoenmakers|Sam|S|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
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"doi": "10.1136/bcr-2020-235581",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2020-235581\n10.1136/bcr-2020-235581\nNew Disease\n1506\n2474\n1520\n1334\n349\n1332\n276\n192\n1330\nCase reportNo evidence of vertical transmission of SARS-CoV-2 after induction of labour in an immune-suppressed SARS-CoV-2-positive patient\nGrimminck Koen 1 Santegoets Lindy Anne Maria 1 Siemens Frederike Charlotte 1 Fraaij Pieter Leendert Alex 23 Reiss Irwin Karl Marcel 4 Schoenmakers Sam 5 1 Department of Obstetrics and Gynaecology, Reinier de Graaf Gasthuis, Delft, Zuid-Holland, The Netherlands\n2 Department of Paediatrics, Subdivision Infectious Diseases and Immunology, Erasmus Medical Center - Sophia, Rotterdam, The Netherlands\n3 Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands\n4 Division of Neonatology, Erasmus Medical Center, Rotterdam, The Netherlands\n5 Department of Obstetrics and Gynaecology, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands\nCorrespondence to Dr Sam Schoenmakers; s.schoenmakers@erasmusmc.nl\n2020 \n30 6 2020 \n13 6 e23558114 6 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY. Published by BMJ.2020https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.We present a case of a 38+1 weeks pregnant patient (G1P0) with a proven COVID-19 infection, who was planned for induction of labour because of pre-existent hypertension, systemic lupus erythematosus, respiratory problem of coughing and mild dyspnoea without fever during the COVID-19 pandemic in March 2020. To estimate the risk of vertical transmission of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) during labour and delivery, we collected oropharyngeal, vaginal, urinary, placental and neonatal PCRs for SARS-CoV-2 during the period of admission. All PCRs, except for the oropharyngeal, were negative and vertical transmission was not observed. Labour and delivery were uncomplicated and the patient and neonate were discharged the next day. We give a short overview of the known literature about SARS-CoV-2-related infection during pregnancy, delivery and outcome of the neonate.\n\nmaterno-fetal medicinepregnancypneumonia (infectious disease)infectious diseasesglobal healthspecial-featureunlocked\n==== Body\nBackground\nThe pandemic, COVID-19, caused by the novel coronavirus SARS-CoV-2, originating from the Wuhan region of China, has spread rapidly throughout the world, including the Netherlands.1 2 COVID-19 pneumonia is a highly infectious disease and the ongoing outbreak has been declared a global public health emergency.1 In the Netherlands, the first COVID-19 patient was confirmed on the 27 February 2020. By the end of March 2020 in the Netherlands, 10 866 infected persons have been identified, of whom 3483 have been admitted to a hospital, more than 800 are currently admitted to an Intensive Care Unit (ICU) and 771 people died after COVID-19 confirmed infection.3\n\nDue to the adaptive physiological and anatomical changes combined with the immunosuppressive state of pregnancy, pregnant women, in general, are prone for airway pathogens and pneumonia.4\n\nLittle is known about COVID-19 and pregnancy. So far, worldwide results have shown that clinical characteristics as well as CT imaging results of COVID-19 infection in pregnant women seem to be similar to non-pregnant adults.5 6 With the recent outbreak of the Zika virus in mind, we should be aware that new viruses can cross the placenta and cause congenital disease.7 So far, there seems to be limited evidence for vertical transmission of SARS-CoV-2 in pregnant patients.5 8 Schwartz et al described no vertical transmission in 38 pregnant women with COVID-19 and their neonates using PCR analyses.9 Unlike previous Middle East Respiratory Syndrome (MERS) and SARS infections in pregnant women, limited maternal deaths have been ascribed to COVID-19.9 10\n\nWith this case report, we aim to contribute to the evidence of the absence of transplacental and intrauterine transmission of SARS-CoV-2. We hereby report the outcome, management and investigation into the vertical transmission of a COVID-19 infection in a pregnant woman with pre-existent hypertension and systemic lupus erythematosus (SLE).\n\nCase presentation\nIn March 2020, a 31-year-old patient, G1P0, amenorrhea of 38+1 weeks, was scheduled for induction of labour because of pre-existent hypertension combined with a stable SLE with normal kidney function. Tests for Sjogrens Syndrome antibodies (SSA and SSB) were negative. The patient used methyldopa, prednisolone and azathioprine as prescribed medication. To reduce the risk of pre-eclampsia, acetylsalicylic acid was prescribed according to local protocol until 36 weeks of pregnancy.11 Fetal biometry was within normal range throughout pregnancy (antenatal ultrasounds for fetal biometrical parameters were performed at 28, 30, 34 and 36 weeks of gestation) with a continuous estimated fetal weight around the 16th percentile.\n\nDue to the development of the progressive problem of coughing, the patient contacted our outpatient clinic before the scheduled induction of labour. Her history mentioned the daily use of prednisolone for SLE, did not reveal recent fever or having visited a known high-risk COVID-19 region or came in contact with people with a confirmed SARS-CoV-2 infection. After consulting the microbiologist, a PCR for SARS-CoV-2 was performed following the national protocol by collecting an oropharyngeal sample. The following day the result of the test was positive. To prevent further potential maternal respiratory distress, we decided to proceed with the scheduled induction of labour.\n\nAfter a multidisciplinary consultation, the patient was admitted into an isolated zone on the delivery ward, following national and local COVID-19 guidelines.\n\nOn admission, physical examination revealed a temperature of 37.2°C, heart rate of 82 beats/min, blood pressure of 141/88 mm Hg, transcutaneous saturation of 99% by a FiO2 0.21, with a respiratory rate of 12 breaths/min. Lung auscultation revealed no abnormal breath sounds. Laboratory findings were normal with a C-reactive protein of 14 mg/L, leucocytes of 6.5×109/L, haemoglobin of 119.2 g/L, thrombocytes of 192×109/L, neutrophils of 5.63×109/L, lymphocytes of 0.22×109/L, monocytes of 0.59×109/L, creatinine of 38 µmol/L, estimated Glomerular Filtration Rate (eFGR) of >90 mL/min, uric acid of 0.18 mmol/L, Alanine aminotransferase (ALAT) of 20 U/L and Lactate dehydrogenase (LDH) of 203 U/L. After vaginal examination, a Foley catheter with 50cc of sterile water was placed intracervical to induce labour after which the patient went into labour. The patient received epidural analgesia to prevent maternal exhaustion and to have epidural access for extra analgesia in case of an emergency situation. Hereafter, the membranes were artificially broken and clear amniotic fluid was drained. Augmentation of labour by the administration of oxytocin was performed following local protocol until sufficient contractions (3–4 per 10 min) were established.12 A corticosteroid stress dose scheme was started following local protocol (100 mg in 30 min continued by 8.3 mg/hour until 8 hours post partum) because of the long-term systemic use of prednisolone with possible suppression of the hypothalamic–pituitary–adrenal axis.13 Two hours after artificial rupture of membranes, she progressed to 8 cm of dilation with the fetal head presenting at fetal station −3. We observed normal fetal heart tracing with stable maternal haemodynamic and respiratory parameters. One hour later the patient progressed into the second stage of labour. After 20 min, she delivered a daughter with an Apgar score of 9/10 at 5 and 10 min, respectively, an arterial umbilical pH level of 7.19 and a birth weight of 2880 g (30th percentile). The third stage of labour proceeded without complications.\n\nThere was a normal neonatal transitional phase after delivery, with no abnormal findings at physical examination. Antenatal SSA and SSB antibodies were tested negative and no signs of congenital abnormalities were noted. The neonate shared the room with both parents. Parents were advised to minimise physical contact during the symptomatic period with coughing, dyspnoea and/or a temperature above 38°C. During any physical contact within this period, the mother was advised to wear a surgical mask and surgical gloves to prevent transmission of SARS-CoV-2. Our patient bottle fed the neonate.\n\nTo be able to assess different anatomical compartments capable of viral shedding and different moments of possible vertical transmission during pregnancy and delivery, PCRs for SARS-CoV-2 were sampled. Prior to and directly after artificial rupture of membranes, the fornix posterior of the vagina was sampled, while a sample of catheter urine was collected during delivery. Post partum, both the maternal and the fetal side of the placenta were sampled in addition to an oropharyngeal PCR sample of the neonate. We were unable to collect a breastmilk sample. For the results, see table 1.\n\nTable 1 PCR sampling for COVID-19 during different stages of labour\n\nSwab\tDate\tTime\tCOVID-19\t\nMaternal oropharyngeal\t19-03-2020\t09:00, at the outpatient clinic\tPositive\t\nVaginal swab before rupture of membranes\t20-03-2020\t18:00\tNegative\t\nVaginal swab after rupture of membranes\t20-03-2020\t22:30\tNegative\t\nMaternal urinary swab of catheter urine\t20-03-2020\t23:00\tNegative\t\nPlacental swab maternal side\t20-03-2020\t23:45\tNegative\t\nPlacental swab fetal side\t20-03-2020\t23:45\tNegative\t\nNeonatal oropharyngeal swab\t21-03-2020\t00.30\tNegative\t\nTwelve hours after delivery the patient was discharged from the hospital in good health and advised to stay isolated at home while being symptomatic for at least 14 days or until 24 hours had passed without problems.\n\nOutcome and follow-up\nBy using PCR samples for SARS-CoV-2 at different times and from different anatomical regions during delivery, we demonstrate no evidence of vertical transmission of SARS-CoV-2 after vaginal birth in an immune-suppressed SARS-CoV-2 positive patient with pre-existing hypertension and SLE. All PCR samples which could indicate vertical transmission (vaginal, maternal urine, maternal and fetal side of the placenta, oropharynx of the neonate) were tested negative. One week after delivery the patient still reported coughing and episodes of mild dyspnoea. There were no signs of neonatal infection with SARS-CoV-2. Four-week post partum, all maternal COVID-19-related symptoms were gone and there were no signs of a neonatal COVID-19 infection.\n\nDiscussion\nWe report a term, prelabour, immuno-suppressed pregnant women with pre-existent hypertension and SLE who tested positive for SARS-CoV-2 and gave birth to a healthy female neonate. There was no evidence of transplacental or intrapartum transmission of SARS-CoV-2 following induction of labour in combination with administration of high doses of corticosteroids. An uneventful induction of labour, delivery, postpartum and postnatal course was observed.\n\nDuring the course of the COVID-19 infection, several decisions had to be made based on the, at that moment, sparse available literature about COVID-19 and delivery. First, we decided to continue with the scheduled induction of labour, since she was at term with only mild respiratory symptoms, but at risk for respiratory insufficiency because of her immunocompromised state and the concomitant SARS-CoV-2 infection. Because of a lack of evidence of contra-indication for corticosteroids in patients with COVID-19 without respiratory insufficiency balanced against the known risk of an adrenal crisis without supportive therapy, we decided to provide our patient with a stress scheme of corticosteroids during the induction of labour.14 Due to the immunosuppressive medication during pregnancy and delivery, we argued for a possible higher risk of vertical transmission. The transplacental viral transmission was suggested by Dong et al because of the detection of elevated neonatal IgM and IgG antibodies directly post partum.15 This suggests vertical transmission and fetal infection since IgM antibodies cannot be transferred over the placenta. However, the reliability of IgM assays has been questioned.16 Depending on the routes and mechanism of intrauterine infection, further risk assessment can be made. If the transplacental transmission can occur, follow-up of fetal development after infection should be recommended. Viral shedding in diverse anatomical compartments (vaginal discharge, faeces, urine, amniotic fluid and haematogenous/placenta) could lead to fetal or neonatal infection during pregnancy, labour or delivery with possible consequences for the mode of delivery. The limited evidence of vertical transmission is comforting, but it is important to determine if and how, at which moments and in which situations, vertical transmission can occur. This will allow adequate advice for patients at risk and shared decision-making concerning delivery mode, antenatal and postnatal follow-up.\n\nRoyal College of Obstetricians and Gynaecologists (RCOG) guidelines recommend not to separate mother and child, with a maternal confirmed COVID-19 infection but to make use of adequate personal protective measurements to prevent transmission.17 Mother and child were discharged the next day to minimise the risk of spreading SARS-CoV-2 by shortening the hospital time. We provided strict instructions about COVID-19-related symptoms and when to contact the hospital. To identify the routes of and risks for possible vertical transmission during pregnancy and delivery, we advise to collect PCR samples for SARS-CoV-2 of different anatomical regions and at different time points during pregnancy and delivery. Immunoglobulins against SARS-CoV-2 should be tested for in maternal and neonatal blood as well as in breast milk after maternal infection.\n\nImportantly, even less is known about the consequences of infection with COVID-19 in the first and second trimester of pregnancy. Recommendations are made to follow-up pregnant patients with COVID-19 because of the possible risk of abortion, premature delivery and fetal growth restriction as seen with other viral infections in the first and second trimester.18–20\n\nLearning points\nOur case shows an uncomplicated vaginal birth in a patient with pre-existent hypertension and systemic lupus erythematosus (SLE) using long-term corticosteroids without signs of vertical transmission of SARS-CoV-2.\n\nThe physical stress of vaginal birth did not influence dyspnoea and/or saturation levels in an immune-suppressed patient with pre-existent hypertension and SLE.\n\nIn the absence of an obstetric or maternal contraindication, vaginal birth in COVID-19 patient’s wild mild respiratory symptoms can and should be considered.\n\nWith personal protection measurements in place, COVID-19-positive mother and child should not be separated during the postpartum period. These measures may be sufficient to avoid horizontal transmission of the newborn as seen in our case.\n\nTo interpret the vertical transmission of SARS-CoV-2, PCR samples for and immunoglobulins against SARS-CoV-2 should be included in the medical workup of pregnant women suspected for or with a confirmed COVID-19 infection. The same workup should be done for the newborn within the first few hours after birth.\n\nContributors: KG: patient care, reporting, data acquisition, analysis and interpretation, conception and design, discuss planning. LAMS: supervised clinically, reporting. FCS: patient care, in lead of crisis management during delivery, supervised clinically, acquisition of data, reporting. PLAF: supervised, reporting, interpretation of data. IKMR: supervised, reporting, interpretation of data. SS: supervised the case report, planning, reporting and data analysis.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 World Health Organisation , 2020 Available: www.who.int [Accessed 29 Mar 2020 ].\n2 Zhu N , Zhang D , Wang W , et al \nA novel coronavirus from patients with pneumonia in China, 2019\n. N Engl J Med \n2020 ;382 :727 –33\n. 10.1056/NEJMoa2001017 31978945 \n3 Dutch national guideline. RIVM\n, 2020 Available: https://www.rivm.nl/nieuws/actuele-informatie-over-coronavirus [Accessed 29 Mar 2020 ].\n4 Rigby FB , Pastorek JG \nPneumonia during pregnancy\n. Clin Obstet Gynecol \n1996 ;39 :107 –19\n. 10.1097/00003081-199603000-00011 8635293 \n5 Chen H , Guo J , Wang C , et al \nClinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records\n. Lancet \n2020 ;395 :809 –15\n. 10.1016/S0140-6736(20)30360-3 32151335 \n6 Wen R , Sun Y , Xing Q-S , et al \nA patient with SARS-CoV-2 infection during pregnancy in Qingdao, China\n. J Microbiol Immunol Infect \n2020 ;53 :499 –500\n. 10.1016/j.jmii.2020.03.004 32198004 \n7 ACOG COMMITTEE OPINION, Number 784 \nManagement of patients in the context of Zika virus\n. Obstetrics & Gynecology \n2019 ;134 :655 –7\n. 10.1097/AOG.0000000000003400 \n8 Zeng L , Xia S , Yuan W , et al \nNeonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China\n. JAMA Pediatr \n2020 . 10.1001/jamapediatrics.2020.0878 . [Epub ahead of print: 26 Mar 2020].\n9 Schwartz DA \nAn analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes\n. Arch Pathol Lab Med \n2020 . 10.5858/arpa.2020-0901-SA . [Epub ahead of print: 17 Mar 2020].\n10 Hantoushzadeh S , Shamshirsaz AA , Aleyasin A , et al \nMaternal death due to COVID-19\n. Am J Obstet Gynecol \n2020 \n10.1016/j.ajog.2020.04.030 \n11 Dutch guideline for the prevention of pre-eclampsia en foetal growth restriction. NVOG\n, 2020 Available: https://www.nvog.nl/wp-content/uploads/2019/10/NVOG-module-Acetylsalicylzuur-okt-2019.pdf [Accessed 29 Mar 2020 ].\n12 Dutch guideline for induction of labour. NVOG\n, 2020 Available: https://www.nvog.nl/wp-content/uploads/2017/12/Inductie-van-de-baring-1.0-20-09-2006.pdf [Accessed 29 Mar 2020 ].\n13 Hamrahian AH \nMd. UpToDate\n, 2020 Available: https://www.uptodate.com/contents/the-management-of-the-surgical-patient-taking-glucocorticoids?search=SLE%20pregnancy&topicRef=7998&source=see_link [Accessed 29 Mar 2020 ].\n14 Cascella M , Rajnik M , Cuomo A , et al \nFeatures, Evaluation and Treatment Coronavirus (COVID-19); StatPearls [Internet . Treasure Island (FL : StatPearls Publishing , 2020 .\n15 Dong L , Tian J , He S , et al \nPossible vertical transmission of SARS-CoV-2 from an infected mother to her newborn\n. JAMA \n2020 . 10.1001/jama.2020.4621 . [Epub ahead of print: 26 Mar 2020].\n16 Kimberlin DW , Stagno S \nCan SARS-CoV-2 infection be acquired in utero?: more definitive evidence is needed\n. JAMA \n2020 ;26 . 10.1001/jama.2020.4868 . [Epub ahead of print: 26 Mar 2020].\n17 RCOG guideline on COVID-19 in pregnancy. RCOG\n. Available: https://www.rcog.org.uk/globalassets/documents/guidelines/2020-05-13-coronavirus-covid-19-infection-in-pregnancy.pdf [Accessed 13 May 2020 ].\n18 John C \nCoronavirus disease 2019 (COVID-19) and pregnancy: what obstetricians need to know; Journal Pre-proof, to appear in\n. Am J Obstet Gynecol \n2020 .\n19 Chen D , Yang H , Cao Y , et al \nExpert consensus for managing pregnant women and neonates born to mothers with suspected or confirmed novel coronavirus (COVID-19) infection\n. Int J Gynaecol Obstet \n2020 .\n20 Jiao J \nUnder the epidemic situation of COVID-19, should special attention to pregnant women be given?\n\nJ Med Virol \n2020 ;17 . 10.1002/jmv.25771 . [Epub ahead of print: 17 Mar 2020].\n\n",
"fulltext_license": "CC BY",
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"issue": "13(6)",
"journal": "BMJ case reports",
"keywords": "global health; infectious diseases; materno-fetal medicine; pneumonia (infectious disease); pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D006973:Hypertension; D016867:Immunocompromised Host; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D007751:Labor, Induced; D034721:Mastocytosis, Systemic; D058873:Pandemics; D011024:Pneumonia, Viral; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D000086402:SARS-CoV-2",
"nlm_unique_id": "101526291",
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"pmid": "32606133",
"pubdate": "2020-06-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32215579;32215598;32151335;32196655;32181904;32360108;8635293;32215581;31441819;31978945;32180426;32198004",
"title": "No evidence of vertical transmission of SARS-CoV-2 after induction of labour in an immune-suppressed SARS-CoV-2-positive patient.",
"title_normalized": "no evidence of vertical transmission of sars cov 2 after induction of labour in an immune suppressed sars cov 2 positive patient"
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"abstract": "Marijuana is the most commonly used illicit drug. In young children, there are relatively few reports in the literature of acute marijuana intoxication. Here, we describe the case of a previously healthy 2-year-old girl who presented with clinical seizures. A urine toxicology screen showed elevated levels of tetrahydrocannabinol. The source of the drug was not identified. After a short stay in the hospital, the patient fully recovered with only supportive measures. In this report, we also summarize all domestic and international cases of marijuana intoxication in children younger than 6 years, in conjunction with the number of exposures in children of similar age identified by the US National Poison Data System. This report highlights what is becoming a more common problem. As cannabis continues to be decriminalized across the United States with its increasingly diverse modes of delivery, the potential for accidental exposure in infants and young children also rises. Clinicians should now routinely consider marijuana intoxication in children who present with acute neurological abnormalities.",
"affiliations": "From the University of Rochester School of Medicine and Dentistry, Rochester, NY.;Department of Pediatrics.;Department of Pediatrics.;Department of Pediatrics.",
"authors": "Boadu|Osei|O|;Gombolay|Grace Y|GY|;Caviness|Verne S|VS|;El Saleeby|Chadi M|CM|",
"chemical_list": "D013759:Dronabinol",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001420",
"fulltext": null,
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"issn_linking": "0749-5161",
"issue": "36(6)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D002188:Cannabis; D013759:Dronabinol; D004435:Eating; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D007223:Infant; D008404:Massachusetts; D020258:Neurotoxicity Syndromes",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e349-e354",
"pmc": null,
"pmid": "29406477",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Intoxication From Accidental Marijuana Ingestion in Pediatric Patients: What May Lie Ahead.",
"title_normalized": "intoxication from accidental marijuana ingestion in pediatric patients what may lie ahead"
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"activesubstancename": "LORAZEPAM"
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"abstract": "Doxorubicin plus cyclophosphamide followed by paclitaxel is a common adjuvant treatment for high-risk breast cancer. It has been associated with pulmonary toxicity in several case reports. We describe three patients in whom interstitial pneumonitis developed immediately after the first paclitaxel exposure and worsened clinically over time. All reported dyspnoea, fever and progressive respiratory distress. Imaging revealed diffuse bilateral pulmonary infiltrates. Other causes of respiratory failure were excluded with laboratory work-up, imaging, biopsy studies and results of antibiotic treatment. The respiratory decline was reversed only after administration of high-dose steroids, an empirical treatment previously reported to be beneficial in similar cases. Although chemotherapy using concomitant or sequential drugs may make identification of the toxic agent difficult, we noted a clear temporal relationship between exposure to paclitaxel and the development of pulmonary toxicity. Furthermore, according to the available literature, it is less likely that a respiratory decline would be caused by either cyclophosphamide or trastuzumab. In conclusion, clinicians should be aware of the potentially life-threatening risk of pulmonary toxicity following paclitaxel treatment. If paclitaxel is halted early and the patient has good lung reserve, pulmonary toxicity can be reversed with high-dose steroid administration.",
"affiliations": "a Department of Internal Medicine D , Rabin Medical Center , Petach Tikva , Israel.;c Department of Oncology , Assaf Harofeh Medical Center, Affiliated with Tel Aviv University , Zerifin , Israel.;b Sackler Faculty of Medicine , Tel Aviv University , Tel Aviv , Israel.;a Department of Internal Medicine D , Rabin Medical Center , Petach Tikva , Israel.;e Institute of Oncology , Davidoff Center, Rabin Medical Center , Petach Tikva , Israel.;a Department of Internal Medicine D , Rabin Medical Center , Petach Tikva , Israel.",
"authors": "Bielopolski|Dana|D|;Evron|Ella|E|;Moreh-Rahav|Osnat|O|;Landes|Michal|M|;Stemmer|Salomon M|SM|;Salamon|Francis|F|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1179/1973947815Y.0000000029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-009X",
"issue": "29(2)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Breast cancer; Paclitaxel; Pneumonitis; Pulmonary toxicity",
"medline_ta": "J Chemother",
"mesh_terms": "D000328:Adult; D000972:Antineoplastic Agents, Phytogenic; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D011014:Pneumonia; D011379:Prognosis",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "113-117",
"pmc": null,
"pmid": "25978147",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Paclitaxel-induced pneumonitis in patients with breast cancer: case series and review of the literature.",
"title_normalized": "paclitaxel induced pneumonitis in patients with breast cancer case series and review of the literature"
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"companynumb": "IL-MYLANLABS-2017M1029702",
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"activesubstancename": "PACLITAXEL"
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... |
{
"abstract": "Heparin is commonly used in clinical practice for the prevention and treatment of various thrombotic conditions. Its use can be associated with bleeding which can range from minor to life threatening. Non-traumatic causes of breast haematoma are very rare. We report a case of spontaneous bleeding into the breast in a female patient who was anticoagulated with heparin.\nAnticoagulant use can be associated with the adverse effect of bleeding at various sites.Physicians should be cautious of such bleeding which can occur at unsuspected sites.Our patient developed spontaneous breast haematoma after unfractionated heparin anticoagulation, and was successfully managed with cessation of anticoagulation, protamine, desmopressin and blood transfusion.",
"affiliations": "Department of Nephrology, Hypertension and Transplant Medicine, Augusta University Medical Center, Augusta, GA, USA.;Department of Nephrology, Hypertension and Transplant Medicine, Augusta University Medical Center, Augusta, GA, USA.;Department of Transplant Surgery, Augusta University Medical Center, Augusta, GA, USA.",
"authors": "Gani|Imran|I|;Kapoor|Rajan|R|;Saeed|Muhammad|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_001735",
"fulltext": null,
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"issn_linking": "2284-2594",
"issue": "7(9)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Thrombosis; anticoagulation; breast haematoma; heparin",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001735",
"pmc": null,
"pmid": "32908833",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "10758200;11836541;23507668;28261775",
"title": "Spontaneous Breast Haematoma after Heparin Anticoagulation.",
"title_normalized": "spontaneous breast haematoma after heparin anticoagulation"
} | [
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"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
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{
"abstract": "Acute Myelogenous Leukemia (AML) is an aggressive hematologic malignancy that cause by abnormal proliferation and accumulation of hematopoietic progenitor cells. A 37-year-old woman referred to oncologic clinic with a self-detected mass and pain in her left breast. The stage of tumor was ΙΙΙA. She was treated with the combination of anthracycline and cyclophosphamide for four courses, followed by four courses of paclitaxel with trastuzumab for one year. After 18 months of the first treatment for breast cancer, her bone marrow biopsy was compatible with AML-M2. Here, we are reporting a young woman case with breast cancer that developed AML malignancy during short interval of therapy.",
"affiliations": "Dept. of Hematology, Oncology, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.;Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.",
"authors": "Payandeh|Mehrdad|M|;Khodarahmi|Reza|R|;Sadeghi|Masoud|M|;Sadeghi|Edris|E|",
"chemical_list": null,
"country": "Iran",
"delete": false,
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"fulltext": "\n==== Front\nIran J Cancer PrevIran J Cancer PrevIJCPIranian Journal of Cancer Prevention2008-23982008-2401Cancer Research Center, Shahid Beheshti University of Medical Sciences IJCP-08-125Case ReportAppearance of Acute Myelogenous Leukemia (AML) in a Patient with Breast Cancer after Adjuvant Chemotherapy: Case Report and Review of the Literature Payandeh Mehrdad 1Khodarahmi Reza 2Sadeghi Masoud 3Sadeghi Edris 31 Dept. of Hematology, Oncology, Kermanshah University of Medical Sciences, Kermanshah, Iran2 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran3 Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, IranCorresponding Author:\nMasoud Sadeghi, MSc;\nDegree in Biochemistry\nTel: (+91) 8338428221\nEmail: sadeghi_mbrc@yahoo.comMar-Apr 2015 8 2 125 128 07 2 2015 22 2 2015 © 2014 Cancer Research Center, Shahid Beheshti University of Medical Sciences2014This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.Acute Myelogenous Leukemia (AML) is an aggressive hematologic malignancy that cause by abnormal proliferation and accumulation of hematopoietic progenitor cells. A 37-year-old woman referred to oncologic clinic with a self-detected mass and pain in her left breast. The stage of tumor was ΙΙΙA. She was treated with the combination of anthracycline and cyclophosphamide for four courses, followed by four courses of paclitaxel with trastuzumab for one year. After 18 months of the first treatment for breast cancer, her bone marrow biopsy was compatible with AML-M2.\nHere, we are reporting a young woman case with breast cancer that developed AML malignancy during short interval of therapy.\n\nAcute myelogenous leukemiaCyclophosphamidePaclitaxel\n==== Body\nIntroduction\nBreast cancer is the most frequent malignancy among women that can be a leading cause of death through middle-aged women [1]. Adjuvant chemotherapy, commonly Include alkylating agents and anthracyclines [1], improves survival rate in operable breast cancer but treatment-induced Acute Myelogenous Leukemia (AML) is now widely regarded as an important concern of survivors [2]. Numerous studies have reported an increased risk of AML after treatment of breast cancer (Table 1). The aim of this study is to evaluate the treatment agents for breast cancer and their effect on risk of AML Expression.\n\nCase Report\nIn April 2009, a 37-Year-old woman referred to oncologic clinic in Kermanshah, Iran with a self-detected mass and pain in her left breast. The pathology report of biopsy confirmed invasive ductal carcinoma, with Immunohistochemical (IHC)-based Estrogen Receptor (ER) and Progesterone Receptor (PR) positive results. P53 was also negative, and Ki67 was positive in 50% of tumor cells. Furthermore, Human Epidermal Growth Factor Receptor 2 (Her-2) was Three positive. The stage of tumor was ΙΙΙA. The status of patient in sentinel lymph node biopsy, bone scan and Computerized Tomography (CT) scan of abdomen and pelvis were normal. She was consulted about radical modified left breast mastectomy axillary dissection, and then her therapy was started with the combination of anthracycline and cyclophosphamide for four courses, followed by four courses of paclitaxel with trastuzumab for one year (17 courses of trastuzumab). Due to node-positive, she was treated in follow up with irradiation on site of surgery and left axillary area. After 18 months of the first treatment for breast cancer, she referred again to our clinic with gingival hyperplasia complaints. Peripheral blood analyses indicated WBC count more than 40000/µL with immature (blasts) cells. Her bone marrow biopsy according to FAB (French-American-British) classification was compatible with AML-M2. She was treated with diagnosis of Leukemia as a secondary cancer with 7+3 regiment that lead to complete remission and continued by two extra courses of high dose Ara-C. She had a full match sibling donor for allogeneic transplant, but unfortunately she rejected procedure of bone morrow transplantation. She died with relapse of AML after six months of last consolidation.\n\nDiscussion\nAML is an aggressive hematologic cancer that is characterized by accumulation of immature myelogenous cells in the blood and bone marrow [3] that cause by abnormal proliferation and accumulation of hematopoietic progenitor cells, and is one of the most common malignancies in adults [4]. According to FAB classification, subtypes of AML are M0 to M7 [5]. Many studies (listed in table 1) as well as other reports [6, 7] have reported the incidence of leukemia as a complication of adjuvant chemotherapy or radiotherapy for breast cancer. In these studies, increased risk of AML has been especially reported for treated cases with cyclophosphamide and anthracyclines and paclitaxel. In majority of these cases, AML was developed after two or more years of starting chemotherapy for breast cancer and also the age of patients was between 36 to 69 years. Table 1 also shows that majority of patients with breast cancer develop AML-M2. In this study, the young aged patient diagnoses with AML-M2 in a short period of interval. She was a case of Her-2 positive breast cancer and so treated with trastuzumab for one year + irradiation on site of surgery and left axillary area and also treated with cyclophosphamide and anthracyclines and paclitaxel. Adjuvant chemotherapy for breast cancer has been shown to make an increase in the risk of secondary malignancies such as AML. As indicated in table 1, irradiation and cyclophosphamide appear to be suspects of secondary AML incidence. Since paclitaxel is by itself leukemogenic, its effect may be augmented by carboplatin (REF). The interval between the alkylating agent exposure and the development of AML is usually 5 to 7 years (60-84 months).\n\nConclusion\nThere is a strongly possibility that addition of paclitaxel-therapy to irradiation and cyclophosphamide will reduce interval period between two malignancies (breast cancer and AML).\n\nAcknowledgments\nThere is no acknowledgment.\n\n\nConflicts of Interest\n\n\nThe authors had no conflict of interest.\n\n\nAuthors’ Contribution\n\n\nMehrdad Payandeh: Analysis of study \n\nReza Khodarahmi: Edition \n\nMasoud Sadeghi: Corresponding author \n\nEdris sadeghi: Edition.\n\nTable 1 Case reports about acute myelogenous leukemia (AML) and its subtypes after breast cancer\n\nReference\tsubtypes\tAge\tInterval (month)\tTreatment between two malignancies\t\n8\tM2\t56\t~53\tcyclophosphamide, methothrexate,\nfluorouracil, radiation, tamoxifene\t\nThe present study\tM2\t37\t18\tanthracycline\n, cyclophosphamide,\npaclitaxel,\ntrastuzumab, irradiation\t\n9\tM2\t42\t36\tmitoxanthrone. cyclophosphamide,\n5-fluorouracil, vincristine, radiotherapy\t\n9\tM2\t39\t48\tmitoxanthrone, cyclophosphamide,\n5-fluorouracil, vincristine, tamoxifen, radiotherapy\t\n9\tM2\t62\t108\tcyclophosphamide, methothrexate,\n5-fluorouracil, mitomycin, mitoxanthrone, etoposide, cisplatin,\nradiotherapy\t\n10\tM2\t39\t31\t5- fluorouracil, epirubicin, cyclophosphamide,\nradiotherapy\n\t\n10\tM2\t44\t28\tdocetaxel, doxorubicin, cyclophosphamide,\nlapatinib, radiotherapy, herceptin, tamoxifen\n\t\n11\tM2\t42\t48\tepirubicin,\npaclitaxel,\ncyclophosphamide, 5-fluorouracil, radiation therapy, tamoxifene\t\n12\tM3\t51\t71\tdoxorubicin, cyclophosphamide,\ndocetaxel, leuprorelin, tamoxifen, radiation therapy with (89) Sr\ninjection\t\n13\tM3\t36\t24\tmedroxyprogesterone acetate, tamoxifen,\nradiotherapy\t\n14\tM3\t43\t9\t-\t\n15\tM3\t69\t10\tcyclophosphamide, doxorubicin,\npaclitaxel\t\n16\tM5\t56\t36\tradical mastectomy, radiotherapy,\nadriamycin, cyclophosphamide, oral anti-estrogen therapy\t\n17\tM5\t37\t36\tadriamycin, cyclophosphamide,\nradiotherapy\t\n18\tM5\t59\t168\toral cyclophosphamide, methotrexate, 5-\nfluorouracil, radiation, Tamoxifen\t\n19\tM4\t54\t36\tpaclitaxel, radiotherapy\t\n20\t-\t50\t48\talkylating agents, antitumor antibiotics,\nvincristine,\netoposide, teniposide, Paclitaxel, gemcitabine\n==== Refs\nREFERENCES\n1 Valentini CG Fianchi L Voso MT Caira M Leone G Pagano L Incidence of acute myeloid leukemia after breast cancer. Mediterr J Hematol Infect Dis . 2011 3 1 e2011069 22220266 \n2 Beadle G Baade P Fritschi L Acute myeloid leukemia after breast cancer: a population-based comparison with hematological malignancies and other cancers. Ann Oncol. 2009 20 1 103 9 18647961 \n3 Lamba G Zaidi SK Luebbers K Verschraegen C Stein GS Rosmarin A Epigenetic Landscape of Acute Myelogenous Leukemia-Moving Toward Personalized Medicine. J Cell Biochem. 2014 115 10 1669 72 24905899 \n4 Liu Q Liu N Zang S Liu H Wang P Ji C Tumor Suppressor DYRK1A Effects on Proliferation and Chemoresistance of AML Cells by Downregulating c-Myc. PLoS One. 2014 9 6 e98853 24901999 \n5 Daraki A Zachaki S Koromila T Diamantopoulou P Pantelias GE Sambani C The G⁵¹⁶T CYP2B6 germline polymorphism affects the risk of acute myeloid leukemia and is associated with specific chromosomal abnormalities. PLoS One. 2014 9 2 e88879 24586425 \n6 Takagi H Ichigo S Matsunami K Takagi H Ikeda T Murase T Occurrence of myelodysplastic syndrome during paclitaxel- and carboplatin-based chemotherapy for recurrent ovarian cancer: Case report. Open Journal of Obstetrics and Gynecology. 2013 3 2 232 4 \n7 Vay A Kumar S Seward S Semaan A Schiffer CA Munkarah AR Therapy-related myeloid leukemia after treatment for epithelial ovarian carcinoma: an epidemiological analysis. Gynecol Oncol. 2011 123 3 456 60 21855120 \n8 Weldon CB Jaffe BM Kahn MJ Therapy-induced leukemias and myelodysplastic syndromes after breast cancer treatment: an underemphasized clinical problem. Ann Surg Oncol. 2002 9 8 738 44 12374656 \n9 La Starza R Sambani C Crescenzi B Matteucci C Martelli MF Mecucci C AML1/MTG16 fusion gene from a t(16;21)(q24;q22) translocation in treatment-induced leukemia after breast cancer. Haematologica. 2001 86 2 212 3 11224496 \n10 Chalayer E Tavernier-Tardy E Clavreul G Bay JO Cornillon J Carcinomatosis lymphangitis and pleurisy after allo-SCT in two patients with secondary leukemia after breast cancer. Bone Marrow Transpl. 2012 47 1 155 6 \n11 Manola KN Georgakakos VN Margaritis D Stavropoulou C Panos C Kotsianidis I Disruption of the ETV6 gene as a consequence of a rare translocation (12;12)(p13;q13) in treatment-induced acute myeloid leukemia after breast cancer. Cancer Genet Cytogenet. 2008 180 1 37 42 18068531 \n12 Utsu Y Aotsuka N Masuda S Matsuura Y Wakita H Atypical onset of therapy-related acute promyelocytic leukemia after combined modality therapy including (89)Sr for metastatic breast cancer. Rinsho Ketsueki. 2013 54 8 759 63 24005436 \n13 Ono M Watanabe T Shimizu C Hiramoto N Goto Y Yonemori K Therapy-related acute promyelocytic leukemia caused by hormonal therapy and radiation in a patient with recurrent breast cancer. Jpn J Clin Oncol. 2008 38 8 567 70 18617535 \n14 Bhattacharyya M Chatterjee T Panigrahi I Kannan M Choudhry VP Mahapatra M Therapy-related acute promyelocytic leukemia after treatment of carcinoma breast--a case report. Indian J Pathol Microbiol. 2006 49 2 251 4 16933728 \n15 Kurian S Hogan TF Bleigh OC Dowdy YG Merghoub T Pandolfi PP Atypical t(15;17)(q13;q12) in a patient with all-trans retinoic acid refractory secondary acute promyelocytic leukemia: a case report and review of the literature. Cancer Genet Cytogenet. 2002 138 2 143 8 12505260 \n16 Gabriel IH Abdalla SH Ryley S Bain BJ Case 34: acute leukemia in a patient with a previous history of breast cancer. Leuk Lymphoma. 2007 48 2 403 5 17325903 \n17 Yonal I Hindilerden F Ozcan E Palanduz S Aktan M The co-presence of deletion 7q, 20q and inversion 16 in therapy-related acute myeloid leukemia developed secondary to treatment of breast cancer with cyclophosphamide, doxorubicin, and radiotherapy: a case report. J Med Case Rep. 2012 6 67 22339850 \n18 Asleson AD Morgan V Smith S Velagaleti GV Amplification of the RARA gene in acute myeloid leukemia: significant finding or coincidental observation? Cancer Genet Cytogenet. 2010 202 1 33 7 20804918 \n19 Saito M Mori A Irie T Tanaka M Morioka M Therapy-related acute myeloid leukemia with 11q23 abnormality due to paclitaxel coexisting with bone marrow metastasis of breast cancer. Rinsho Ketsueki. 2009 50 3 192 6 19352087 \n20 Arends J Urger C Excellent response to gemcitabine in a massively pre-treated woman with extensive cutaneous involvement after recurrence of breast cancer. Invest New Drugs. 2001 19 1 93 100 11291839\n\n",
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"title": "Appearance of Acute Myelogenous Leukemia (AML) in a Patient with Breast Cancer after Adjuvant Chemotherapy: Case Report and Review of the Literature.",
"title_normalized": "appearance of acute myelogenous leukemia aml in a patient with breast cancer after adjuvant chemotherapy case report and review of the literature"
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"abstract": "Pheochromocytoma in pregnancy is rare (1 in 50,000 full term pregnancies). Recognition of the condition is central to improving outcome (maternal and foetal mortality is reduced from 58% and 56%, respectively to 2% and 11-15%, respectively). An antenatal patient in third trimester diagnosed as pheochromocytoma has been described. Diagnosis of pheochromocytoma was confirmed by urinary VMA levels and demonstration of right adrenal mass on ultrasound. A multidisciplinary approach was used and the patient received antihypertensives for 10 days. Vaginal delivery was conducted under epidural analgesia and the patient was kept under close surveillance. She delivered a healthy baby girl weighing 2.5 kg. The intrapartum and the postpartum period were uneventful. Adrenalectomy was done at 6 weeks postpartum. Using multidisciplinary approach and individualised management decreases both maternal and foetal morbidity and mortality. Selected multigravidae cases and those with previous history of short uncomplicated labour, may be considered for vaginal delivery under epidural analgesia and with back up facilities available to manage hypertensive crisis.",
"affiliations": "Department of Obstetrics and Gynaecology, VMMC and Safdarjang Hospital, New Delhi.;Department of Obstetrics and Gynaecology, VMMC and Safdarjang Hospital, New Delhi.;Department of Obstetrics and Gynaecology, VMMC and Safdarjang Hospital, New Delhi.;Surgery, LNJP Hospital, New Delhi.;Surgery, LNJP Hospital, New Delhi.",
"authors": "Kapoor|Garima|G|;Salhan|Sudha|S|;Sarda|Nivedita|N|;Sarda|A K|AK|;Aggarwal|Deepika|D|",
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"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000315:Adrenalectomy; D000328:Adult; D036861:Delivery, Obstetric; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D010673:Pheochromocytoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome",
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"pubdate": "2013-04",
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"title": "Phaeochromocytoma in pregnancy: safe vaginal delivery, is it possible?",
"title_normalized": "phaeochromocytoma in pregnancy safe vaginal delivery is it possible"
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"abstract": "Isotretinoin, a drug used for moderate to severe acne, has been repeatedly associated with various psychiatric complications, although a definitive causal relationship has not been established to date. This case report describes a 25-year-old male who developed obsessive-compulsive disorder at the age of 23 years following isotretinoin treatment for acne (10-20 mg/day) since the age of 16 years. Although standard treatment for obsessive-compulsive disorder caused mood swings, the combination of fluvoxamine 300 mg/day and olanzapine 15 mg/day significantly improves the clinical picture. Although rare, severe adulthood psychiatric complications may occur following isotretinoin treatment, requiring management which is individually tailored to the patient.",
"affiliations": "Department of Neuroscience, Section of Psychiatry, University of Genoa, Genoa, Italy. dott.fornaro@gmail.com",
"authors": "Fornaro|Michele|M|",
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"journal": "Neuropsychiatric disease and treatment",
"keywords": "fluvoxamine; isotretinoin; obsessive-compulsive disorder; olanzapine; treatment",
"medline_ta": "Neuropsychiatr Dis Treat",
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"pages": "719-22",
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"title": "Obsessive-compulsive disorder with bipolar diathesis following isotretinoin therapy remitting upon treatment with olanzapine and fluvoxamine.",
"title_normalized": "obsessive compulsive disorder with bipolar diathesis following isotretinoin therapy remitting upon treatment with olanzapine and fluvoxamine"
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"abstract": "Diabetes mellitus is a leading cause of nephropathy and end-stage renal disease. However, diabetic nephropathy during pregnancy in patients with normal glomerular filtration rate and subsequent progression to end-stage renal disease has not been well studied.\nThis report presents two patients with poorly controlled type 1 diabetes mellitus who had diabetic nephropathy with preserved estimated glomerular filtration rate (Case 1: 117 mL/min/1.73m2; Case 2: 79 mL/min/1.73m2) and shared a similar clinical course, with glomerular filtration rates decreasing by approximately one-half during pregnancy and progression to end-stage renal disease within the first year postpartum. Both women had a long history of type 1 diabetes: 18 years and 24 years for case 1 and case 2 respectively. The first patient's course of pregnancy was complicated by difficult-to-control blood glucose and hypertension with subsequent preeclampsia. The second patient's course of pregnancy was complicated by difficult-to-control blood sugars and preterm labor resulting in classical cesarean delivery at 24 weeks. Both patients had renal biopsies shortly after delivery as their renal function continued to worsen postpartum. Both kidney biopsies demonstrated advanced diabetic nephropathy changes and ultimately required chronic renal replacement therapy within 7-9 months postpartum.\nComprehensive family planning discussions with women who have diabetic nephropathy should include the risks of renal disease progression, even in those patients with preserved renal function at the time of conception.",
"affiliations": "UConn Health Division of Nephrology, 263 Farmington Ave, Farmington, CT 06030, USA.;UConn Health Division of Nephrology, 263 Farmington Ave, Farmington, CT 06030, USA.;UConn Health Division of Maternal Fetal Medicine, 263 Farmington Ave, Farmington, CT 06030, USA.;UConn Health Division of Maternal Fetal Medicine, 263 Farmington Ave, Farmington, CT 06030, USA.;Hartford Hospital Division of Maternal Fetal Medicine, 80 Seymour St, Hartford, CT 06106, USA.;UConn Health Division of Nephrology, 263 Farmington Ave, Farmington, CT 06030, USA.",
"authors": "Attique|Hassan Bin|HB|;Phachu|Deep|D|;Loza|Alexandra|A|;Campbell|Winston|W|;Hammer|Erica|E|;Elali|Ibrahim|I|",
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"doi": "10.1016/j.crwh.2021.e00326",
"fulltext": "\n==== Front\nCase Rep Womens Health\nCase Rep Womens Health\nCase Reports in Women's Health\n2214-9112\nElsevier\n\nS2214-9112(21)00044-8\n10.1016/j.crwh.2021.e00326\ne00326\nArticle\nDiabetic nephropathy in pregnancy: Report of two cases progressing to end-stage renal disease within one year postpartum\nAttique Hassan Bin a\nPhachu Deep a\nLoza Alexandra b\nCampbell Winston b\nHammer Erica c\nElali Ibrahim ielali@uchc.edu\na⁎\na UConn Health Division of Nephrology, 263 Farmington Ave, Farmington, CT 06030, USA\nb UConn Health Division of Maternal Fetal Medicine, 263 Farmington Ave, Farmington, CT 06030, USA\nc Hartford Hospital Division of Maternal Fetal Medicine, 80 Seymour St, Hartford, CT 06106, USA\n⁎ Corresponding author at: University of Connecticut Health Center, Division of Nephrology, 263 Farmington Avenue, CT 06032, USA. ielali@uchc.edu\n14 5 2021\n7 2021\n14 5 2021\n31 e0032629 4 2021\n7 5 2021\n11 5 2021\n© 2021 Published by Elsevier B.V.\n2021\n\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/).\nBackground\n\nDiabetes mellitus is a leading cause of nephropathy and end-stage renal disease. However, diabetic nephropathy during pregnancy in patients with normal glomerular filtration rate and subsequent progression to end-stage renal disease has not been well studied.\n\nCases\n\nThis report presents two patients with poorly controlled type 1 diabetes mellitus who had diabetic nephropathy with preserved estimated glomerular filtration rate (Case 1: 117 mL/min/1.73m2; Case 2: 79 mL/min/1.73m2) and shared a similar clinical course, with glomerular filtration rates decreasing by approximately one-half during pregnancy and progression to end-stage renal disease within the first year postpartum. Both women had a long history of type 1 diabetes: 18 years and 24 years for case 1 and case 2 respectively. The first patient's course of pregnancy was complicated by difficult-to-control blood glucose and hypertension with subsequent preeclampsia. The second patient's course of pregnancy was complicated by difficult-to-control blood sugars and preterm labor resulting in classical cesarean delivery at 24 weeks. Both patients had renal biopsies shortly after delivery as their renal function continued to worsen postpartum. Both kidney biopsies demonstrated advanced diabetic nephropathy changes and ultimately required chronic renal replacement therapy within 7–9 months postpartum.\n\nConclusion\n\nComprehensive family planning discussions with women who have diabetic nephropathy should include the risks of renal disease progression, even in those patients with preserved renal function at the time of conception.\n\nHighlights\n\n• Diabetic nephropathy carries a high risk for renal disease progression.\n\n• Diabetics with nephropathy need counseling on risk of kidney disease progression.\n\n• Diabetic women should be started on kidney-protective medications postpartum.\n\nKeywords\n\nType 1 diabetes mellitus\nDiabetic nephropathy\nEnd-stage renal disease\nPreterm premature rupture of membranes\nHemodialysis\nPeritoneal dialysis\nCase report\n==== Body\n1 Introduction\n\nDiabetic nephropathy (DN) is a well-known micro-vascular complication of type 1 diabetes (T1DM) and a major cause of end-stage renal disease (ESRD) [[1], [2], [3]]. The incidence of pregnancy-associated complications in patients with DN is well established, but the rate of DN progression after pregnancy has not been adequately studied [4]. Although a definitive diagnosis of DN can be made only with a renal biopsy, DN can be identified clinically with a persistent urinary albumin-to-creatinine ratio ≥ 30 mg/gCr and/or sustained reduction in GFR < 60 mL/min along with the assessment of clinical features, such as diabetes duration, diabetic control, and presence of microvascular damage such as diabetic retinopathy [15]. This report presents two cases of young women with uncontrolled T1DM and evidence of DN but relatively preserved renal function before pregnancy. Both suffered progressive renal decline requiring chronic renal replacement therapy within the first one year postpartum.\n\n2 Case 1\n\nA 36-year-old multiparous Hispanic woman with T1DM (diagnosed at age 18) and hypertension presented to a nephrology clinic at 12 weeks of gestation after she was found to have nephrotic range proteinuria of 7.6 g, and measured creatinine clearance (CCr) of 104 mL/min on 24-h urine collection. Her serum creatinine (SCr) at that time was 0.8 mg/dl. One month before her pregnancy, SCr was 0.61 mg/dL with an estimated glomerular filtration rate (eGFR) of 117 mL/min/1.73m2 based on the chronic kidney disease epidemiology collaboration equation (CKD-EPI), and urine dipstick demonstrated 2–3+ proteinuria.\n\nThroughout the remainder of her pregnancy, her diabetes remained uncontrolled with a hemoglobin A1c (HbA1c) of 10.1% despite the up-titration of her initial insulin regimen (Levemir 15 units in the morning and 12 units in the afternoon; Humalog: 6 units with breakfast, 7 units with lunch and 20 units with dinner). She continued to have glycosuria of more than 1000 mg/dL on multiple occasions. She was started on labetalol 200 mg twice daily at the beginning of pregnancy for elevated blood pressure. Her blood pressure ranged from 140 to 158 mmHg systolic and from 80 to 98 mmHg diastolic. Her antihypertensive regimen was escalated to labetalol 300 mg twice daily, nifedipine extended-release 60 mg daily and furosemide 80 mg twice daily. Despite these changes, her hypertension remained poorly controlled, with blood pressures ranging from 130 to 184 mmHg systolic and from 68 to 120 mmHg diastolic until delivery. She was also started on aspirin 81 mg daily around 12 weeks of gestation to reduce her risk of preeclampsia.\n\nShe presented to the hospital at 36 weeks and 0 days of gestation with contractions and was noted to have very high blood pressure, at 170–180 mmHg systolic and 90–100 mmHg diastolic, which was treated with intravenous labetalol. At that time, her SCr was 1.3 mg/dL along with a protein-creatinine ratio of 17 g/gCr. Given her uncontrolled hypertension and proteinuria, she was admitted for superimposed preeclampsia with severe features. Labor induction was initiated with misoprostol for cervical ripening and magnesium sulfate was administered. Shortly after administration of misoprostol, fetal heart rate decelerations were noted, which prompted an urgent cesarean delivery and bilateral tubal ligation. She delivered a viable female infant of low birth weight, 2095 g, yet appropriate for gestational age with Apgar scores of 8 and 9. She remained on magnesium sulfate for 24 h postpartum and blood pressure control was ultimately achieved with amlodipine 10 mg daily, carvedilol 25 mg twice daily, lisinopril 30 mg daily and bumetanide 3 mg daily.\n\nOne month after delivery, the patient's SCr had decreased to 1.1 mg/dL, with an eGFR (CKD-EPI) of 65 mL/min/1.73m2 and an albumin-creatinine ratio of 9 g/gCr. Given her proteinuria and elevated SCr during her pregnancy, she underwent a renal biopsy, which showed advanced DN (Fig. 1, Fig. 2, Fig. 3, Fig. 4). Renal function gradually declined. At 3 months postpartum SCr was 1.6 mg/dL, and by 8 months had risen to 4.3 mg/d L. Table 1 outlines the progression of the patient's estimated renal function and proteinuria. 24-h urine collection at that time revealed CCr of 12.4 mL/min with 20 g of proteinuria. She was diagnosed with ESRD, defined as a GFR of less than 15 mL/min, and was started on hemodialysis.Fig. 1 PAS stain. Glomerulus showing centrilobular nodular sclerosis. Capillary loops around the nodules are patent. The arteriole shows hyaline arteriolosclerosis.\n\nFig. 1\n\nFig. 2 PAS stain. Three glomeruli showing advanced global sclerosis.\n\nFig. 2\n\nFig. 3 Elastic trichrome stain. The photo shows endocapillary insudative deposits at 10 to 12 o'clock.\n\nFig. 3\n\nFig. 4 PAS stain. Glomerulus showing advanced global sclerosis. A nodular character to the glomerular lobules is still appreciable.\n\nFig. 4\n\nTable 1 Renal function summary table.\n\nTable 1Case 1\tBaseline\tDuring Pregnancy: 12 weeks of gestation\tAfter Pregnancy: 1 month postpartum\tTime to ESRD: 8 months postpartum\t\nCreatinine\t0.61 mg/d L\t0.8 mg/d L\t1.1 mg/dl L\t4.3 mg/d L\t\nProteinuria\t2+ to 3+ proteinuria\t7.6 g\tACR – 9 g/g\t20 g\t\neGFR (CKD-EPI)/CCr\teGFR −117 mL/min/1.73m2\tCCr - 104 mL/min\teGFR - 65 mL/min/1.73m2\tCCr - 12.4 mL/min\t\n\n\n\t\nCase 2\tBaseline\tDuring Pregnancy: 10 weeks of gestation\tAfter Pregnancy: 1 month postpartum\tTime to ESRD: 9.5 months postpartum\t\nCreatinine\t0.96 mg/dL\t1.3 mg/dl\t1.9 mg/dL\t6 mg/dL\t\nProteinuria\t2+ proteinuria\t9.4 g\t7.5 g\t10 g\t\neGFR (CKD-EPI)/CCr\teGFR - 79 mL/min/1.73 m2\tCCr - 73 mL/min\tCCr - 28 mL/min\tCCr - 9 mL/min\t\neGFR - estimated glomerular filtration rate, ESRD – end stage renal disease, CCr – creatinine clearance, ACR – albumin-to-creatinine ratio.\n\n3 Case 2\n\nA 32-year-old Hispanic nulliparous woman with T1DM (diagnosed at age 8) and hypertension was referred by a primary care clinic to an obstetrical care provider at 10 weeks of gestation with poor glycemic control. She had a history of non-adherence with her home insulin regimen (NPH insulin: 5 units in the morning; 12 units in the afternoon, Humalog insulin: 5 units three times daily before meals). Her HbA1c was 9.9% at that time. She had previously been diagnosed with diabetic retinopathy requiring laser phototherapy. She was taking lisinopril for her hypertension but was transitioned to labetalol 200 mg twice daily shortly after conception. At 10 weeks and 2 days of gestation, the patient was admitted to the hospital for optimization of poor glycemic control and blood pressure. On admission, fasting blood glucose levels were noted to be around 300 mg/dL and her 2-h post-prandial glucose levels were around 400 mg/dL. Her SCr was 1.3 mg/dL and 24-h urine collection resulted in a CCr of 73 mL/min and 9.4 g of protein. Before pregnancy, her baseline SCr was 0.96 mg/dL with an eGFR (CKD-EPI) of 79 mL/min/1.73 m2, and 2+ proteinuria on urine dipstick. She was evaluated by endocrinology and her insulin regimen was further optimized with improvement in her glycemic control. She was started on aspirin 81 mg daily to reduce her preeclampsia risk and her labetalol was increased to 400 mg twice daily with good control at the time of discharge.\n\nDuring pregnancy, her spot albumin-creatinine ratio was reported as 5 g/gCr. Her peak SCr rose to 1.8 mg/dL with an eGFR (CKD-EPI) of 37 mL/min/1.73m2. Her blood pressure remained well controlled on her new dose of labetalol, consistently ranging from 94 to 137 mmHg systolic and from 58 to 81 mmHg diastolic. Urinalysis documented glucosuria up to 250 mg/dL. At 22 weeks and 2 days of gestation, she presented to the hospital with vaginal leakage of fluid and was diagnosed with a previable premature rupture of membranes. An ultrasound scan documented a singleton fetus in breech presentation with an estimated fetal weight of 492 g and anhydramnios. Maternal-fetal medicine and neonatology were consulted. The patient was extensively counseled regarding her prognosis; however, she wished to continue the pregnancy. There was no clinical evidence of labor or intraamniotic infection. She received a course of betamethasone and completed a course of latency antibiotics. The patient remained stable without evidence of intraamniotic infection or preterm labor until 24 weeks and 2 days of gestation, when she was noted to have a fever of 101.2 °F. She began experiencing painful contractions. The patient was started on a magnesium sulfate infusion for fetal neuroprotection and a rescue dose of betamethasone was administered. The fetal heart rate tracing was initially reassuring for gestational age; however, a few hours later minimal variability and recurrent variable decelerations were noted. A decision was made to proceed with cesarean delivery for non-reassuring fetal status, suspected intraamniotic infection, and breech presentation. The patient underwent an uncomplicated classical cesarean delivery of a viable 500 g male infant with Apgar scores of 1, 6, and 7. The patient's postpartum course was uncomplicated and she was discharged home on postoperative day 4. The infant was admitted to the neonatal intensive care unit for 8 months before being discharged home.\n\nOne month postpartum, SCr was 1.9 mg/dL and 24-h urine collection resulted in a CCr of 28 mL/min and 7.5 g of protein. Over the following 9 months, her blood pressure ranged from 123 to 180 mmHg systolic and from 88 to 98 mmHg diastolic, for which her anti-hypertensive regimen was changed from labetalol to amlodipine 5 mg daily, losartan 25 mg daily, and torsemide 10 mg daily. At 5 months postpartum, her SCr was 2.7 mg/dLand by 7 months had increased to 5.1 mg/dL. A kidney biopsy was consistent with advanced DN (Fig. 5, Fig. 6, Fig. 7, Fig. 8). By nine and half months postpartum, SCr had worsened to 6 mg/dL and 24-h urine collection resulted in a CCr of 9 mL/min with 10 g of proteinuria. She was diagnosed with ESRD and started on peritoneal dialysis.Fig. 5 PAS stain. Three glomeruli are globally sclerosed. There is severe tubular atrophy/interstitial fibrosis.\n\nFig. 5\n\nFig. 6 PAS stain. Global glomerular sclerosis/obsolescence with many endocapillary insudative/hyalinosis ‘deposits’.\n\nFig. 6\n\nFig. 7 PAS stain. Hyaline arteriolosclerosis.\n\nFig. 7\n\nFig. 8 PAS stain. Non-globally sclerosed glomerulus showing centrilobular nodular sclerosis lesion (2 o'clock) with peripheral patent capillary loops.\n\nFig. 8\n\n4 Discussion\n\nDiabetic nephropathy is a major cause of ESRD in patients with T1DM. The physiological burdens of pregnancy, such as insulin resistance, glomerular hyper-filtration, and increase in proteinuria, are plausible mechanisms contributing to a potential decline in renal function in an already compromised kidney [[1], [2], [3], [4]].\n\nWomen with DN can be considered as a group of patients with the highest propensity for worse pregnancy-associated outcomes. For example, rates of preeclampsia are noted to be 35–64% in patients with DN and 9–17% in diabetic women without DN, compared with 7% in women with lupus nephritis [5,6]. Other adverse pregnancy outcomes include small for gestational age (15–39%), preterm delivery <37 weeks (73–77%), and cesarean delivery (70–100%).\n\nPrior literature has suggested that patients with DN and relatively preserved renal function do not experience faster progression of kidney disease as a consequence of pregnancy [7]. Rossing et al. investigated the long-term impact of pregnancy on the progression of DN in 93 patients with TIDM over a 16-year follow-up. They compared ever-pregnant and never-pregnant women who received similar medical therapy and who had similar baseline degrees of renal function at the start of the study. At the end of the follow-up, 35% (95% CI:17–53) of the ever-pregnant women had died while 19% (95% CI: 7–39) had developed ESRD, whereas 34% (95% CI:23–45) of the never-pregnant women had died while 24% (95% CI,14–34) had developed ESRD. This suggests that pregnancy neither altered the time course of renal disease nor increased the likelihood of developing ESRD [9].\n\nPre-existing vascular disease generally portends a higher risk of preeclampsia (35–64%) and it is considered an established complication in DN [7,8]. However, nephrotic-range proteinuria with preserved GFR and rapid progression to ESRD post-pregnancy has not been well documented [9]. Previous studies showed no increased risk of overt DN or ESRD in women with preserved GFR at conception, and proteinuria generally returns to baseline postpartum [10].\n\nThe 2 patients presented in this case report fit the criteria for early-stage CKD (including SCr < 1.4 mg/dL, CCr of >70 mL/min or CKD Stage I/II) with favorable long-term renal outcomes as compared with moderate to severe CKD (SCr >1.4 mg/dL, CCr <70 mL/min or CKD Stage III/IV/IV) [7]. However, both patients experienced an accelerated decline in renal function as well as worsening proteinuria leading to ESRD postpartum. The difficulties in controlling their blood pressure and blood glucose during pregnancy likely played a major role in progression of their renal disease.\n\nSeveral studies have shown significantly worse outcomes in diabetic ESRD patients than in non-diabetic patients, with one study demonstrating a 1.9 times higher risk of death compared with non-diabetics over 28-month follow-up [11]. Of the two patients presented in this case report, one has died of diabetes-related complications. Patients with T1DM and DN experience large variations in disease manifestation, ranging from rapid progression of preserved renal function to ESRD within 2–3 years versus progression over 20–40 years. Patients with rapid decline are termed “fast decliners” and usually have higher HbA1c levels and proteinuria [12]. There is a higher rate of fetal malformations with higher HbA1c levels and the clinical data suggest that women with HbA1c greater than 10% should be recommended to avoid conception [13].\n\nEven as renal failure develops, the kidneys have the ability to compensate and there may be significant kidney fibrosis unaccompanied by measurable changes in GFR [14]. Patients with preserved GFR and DN manifested only by proteinuria might mask the risk of progression to severe kidney disease and possibly even ESRD. In the absence of non-invasive tools to evaluate underlying disease burden, aggressive glycemic and blood pressure control serve as the only proven modalities to slow renal disease progression postpartum.\n\nSince kidney fibrosis is a key component of the final common pathway leading to ESRD, several attempts have been made to utilize non-invasive imaging to measure the degree of kidney fibrosis. A recent study demonstrated the ability to use magnetic resonance elastography (MRE) combined with magnetic resonance arterial kidney blood flow to predict decreasing renal cortical tissue perfusion, without the need for intravenous contrast; the results correlated with increasing fibrosis on renal biopsy [14]. In patients at risk of disease progression, non-invasive determination of the degree of renal fibrosis burden before apparent reductions in GFR could allow for more accurate renal evaluations without the need for renal biopsy.\n\nAside from better glycemic and blood pressure control, reducing activation of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been clearly shown to be beneficial in slowing the progression of diabetic nephropathy. Although contraindicated in pregnancy due to their effects on the fetus, these medications should be initiated postpartum [15]. Many of these agents, however, have been noted in very small quantities in breast milk [16]. Enalapril is often the preferred option since it has the most published data supporting its use. One study calculated the level of infant exposure to enalapril as 0.16% of the maternal weight-adjusted dose [16]. Given the clinically demonstrated benefit of RAAS blockade, a risk/benefit discussion regarding their usage should be held during breastfeeding period.\n\n5 Conclusion\n\nDespite a preserved GFR at the time of conception, poorly controlled risk factors can result in the rapid progression of DN to ESRD. Additional studies with a larger sample size are needed to understand the nature of the disease behavior in this subpopulation. Furthermore, new non-invasive screening tools that assess underlying fibro-sclerotic disease burden can provide valuable information regarding risk of disease progression.\n\nContributors\n\nHassan Bin Attique was involved in patient care and writing the manuscript.\n\nDeep Phachu was involved in patient care and writing the manuscript.\n\nAlexandra Loza assisted in writing and revising the manuscript.\n\nWinston Campbell assisted in writing and revising the manuscript.\n\nErica Hammer assisted in writing and revising the manuscript.\n\nIbrahim Elali finalized the manuscript.\n\nFunding\n\nNo funding from an external source supported the publication of this case report.\n\nPatient Consent\n\nPatient consent was obtained for case description and images.\n\nProvenance and Peer Review\n\nThis case report was peer reviewed.\n\nConflict of Interest\n\nThe authors declare that they have no conflict of interest regarding the publication of this case report.\n==== Refs\nReferences\n\n1 Andersen A.R. Christiansen J.S. Andersen J.K. Kreiner S. Deckert T. Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study Diabetologia 25 6 1983 496 501 6363177\n2 Krolewski A.S. Warram J.H. Christlieb A.R. Busick E.J. Kahn C.R. The changing natural history of nephropathy in type I diabetes Am. J. Med. 78 5 1985 785 794 3993659\n3 Selby J.V. Fitz-Simmons S.C. Newman J.M. Katz P.P. Sepe S. Showstack J. The natural history and epidemiology of diabetic nephropathy JAMA 263 14 1990 1954 2179596\n4 Miodovnik M. Rosenn B.M. Khoury J.C. Grigsby J.L. Siddiqi T.A. Does pregnancy increase the risk for development and progression of diabetic nephropathy? Am. J. Obstet. Gynecol. 174 4 1996 1180 1191 8623845\n5 Bramham K. Diabetic nephropathy and pregnancy Semin. Nephrol. 37 4 2017 P362 369\n6 Lightstone L. Hladunewich M.A. Lupus nephritis and pregnancy: concerns and management Semin. Nephrol. 37 4 2017 P347 353\n7 Hladunewich M.A. Melamad N. Bramham K. Pregnancy across the spectrum of chronic kidney disease Kidney Int. 89 5 2016 995 1007 27083278\n8 Maternal C.E. Fleming K. Acolet D. Diabetes in Pregnancy: Are We Providing The Best Care?, Findings of a National Enquiry 2007 CEMACH\n9 Rossing K. Jacobsen P. Hommel E. Mathiesen E. Svenningsen A. Rossing P. Parving H.-H. Pregnancy and progression of diabetic nephropathy Diabetologia 45 1 2002 36 41 11845221\n10 Khoury J.C. Miodovnik M. LeMasters G. Sibai B. Pregnancy outcome and progression of diabetic nephropathy. What’s next? J. Matern. Fetal Neonatal Med. 11 4 2002 238 244 12375677\n11 Soleymanian T, Kokabeh Z, Ramaghi R, Mahjoub A, Argani H. Clinical outcomes and quality of life in hemodialysis diabetic patients versus non-diabetics. J. Nephropathol.\n12 Krolewski A.S. Skupien J. Rossing P. Warram J.H. Fast renal decline to end-stage renal disease: an unrecognized feature of nephropathy in diabetes Kidney Int. 91 6 2017 1300 1311 28366227\n13 Glinianaia S.V. Tennant P.W.G. Bilous R.W. Rankin J. Bell R. Bell R. HbA 1c and birthweight in women with pre-conception type 1 and type 2 diabetes: a population-based cohort study Diabetologia 55 2012 3193 3203 23015260\n14 Brown R.S. Sun M.R.M. Stillman I.E. Russell T.L. Rosas S.E. Wei J.L. The utility of magnetic resonance imaging for noninvasive evaluation of diabetic nephropathy Nephrol. Dial. Transplant. 2020 10.1093/ndt/gfz066\n15 Umanath K. Lewis J.B. Update on diabetic nephropathy: core curriculum 2018 Am. J. Kidney Dis. 71 6 2018 P884 895\n16 Kearney L. Wright P. Fhadil S. Thomas M. Postpartum Cardiomyopathy and Considerations for Breastfeeding Card Fail Rev 4 2 2018 Aug 112 118 30206487\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "31()",
"journal": "Case reports in women's health",
"keywords": "Case report; Diabetic nephropathy; End-stage renal disease; Hemodialysis; Peritoneal dialysis; Preterm premature rupture of membranes; Type 1 diabetes mellitus",
"medline_ta": "Case Rep Womens Health",
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"pmid": "34195020",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "31329940;11845221;27083278;3993659;29398179;2179596;30206487;28491858;8623845;28711073;28366227;23015260;28711075;6363177;12375677",
"title": "Diabetic nephropathy in pregnancy: Report of two cases progressing to end-stage renal disease within one year postpartum.",
"title_normalized": "diabetic nephropathy in pregnancy report of two cases progressing to end stage renal disease within one year postpartum"
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"abstract": "The association between acute lymphoblastic leukemia (ALL), non-Langerhans cell histiocytosis (non-LCH), and hemophagocytic lymphohistiocytosis (HLH), to the best of our knowledge, has not been published to date. Juvenile xanthogranuloma (JXG), as a type of non-LCH, is usually a benign disease limited to the skin. Systemic involvement is rarely reported. The present case report describes a 15-year-old boy diagnosed with disseminated JXG involving skin and bone marrow concurrent with severe symptoms of HLH during ALL therapy. Examination of immunoglobulin heavy chain genes in B-cell precursor leukemic blasts and histiocytes in the skin and bone marrow revealed identical rearrangements, confirming clonal relationship between both diseases. Implementation of corticosteroids, vinblastine, etoposide, cyclosporine, and tocilizumab resulted in partial skin lesion resolution with no improvement of bone marrow function; therefore, hematopoietic stem cell transplantation (HSCT) was eventually performed. The patient's hematological and general status has improved gradually; however, remarkable recovery of skin lesions was observed after empirical antitubercular therapy. Mycobacterium spp. infection should be considered as a possible secondary HLH trigger. Triple association of ALL, non-LCH, and HLH highlights heterogeneity of histiocytic disorders and possible common origin of dendritic and lymphoid cells.",
"affiliations": "Department of Pediatric Oncology and Hematology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.;Department of Pediatric Oncology and Hematology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.;Department of Oncology and Hematology, University Children's Hospital of Krakow, Krakow, Poland.;Department of Pediatric Oncology and Hematology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.;Department of Clinical Immunology and Transplantation, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.;Department of Clinical Immunology and Transplantology, Stem Cell Transplant Center, University Children's Hospital of Krakow, Jagiellonian University Medical College, Krakow, Poland.;Department of Clinical Immunology and Transplantology, Stem Cell Transplant Center, University Children's Hospital of Krakow, Jagiellonian University Medical College, Krakow, Poland.;Department of Pathology, University Children's Hospital of Krakow, Krakow, Poland.;Department of Biochemistry, University Children's Hospital of Krakow, Krakow, Poland.;Student Scientific Group of Pediatric Oncology and Hematology, Jagiellonian University Medical College, Krakow, Poland.;Department of Pediatric Oncology and Hematology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.",
"authors": "Pawińska-Wa Sikowska|Katarzyna|K|;Cwiklinska|Magdalena|M|;Wyrobek|Elzbieta|E|;Balwierz|Walentyna|W|;Bukowska-Strakova|Karolina|K|;Dluzniewska|Agnieszka|A|;Gozdzik|Jolanta|J|;Drabik|Grazyna|G|;Rygielska|Monika|M|;Stepien|Konrad|K|;Skoczen|Szymon|S|",
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"doi": "10.3389/fonc.2020.00921",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00921\nOncology\nCase Report\nDisseminated Juvenile Xanthogranuloma and Hemophagocytic Lymphohistiocytosis Developed During Treatment of Acute Lymphoblastic Leukemia: Case Report\nPawińska-Wa̧sikowska Katarzyna 12 Cwiklinska Magdalena 12 Wyrobek Elzbieta 2 Balwierz Walentyna 12 Bukowska-Strakova Karolina 3 Dluzniewska Agnieszka 4 Gozdzik Jolanta 4 Drabik Grazyna 5 Rygielska Monika 6 Stepien Konrad 7 Skoczen Szymon 12* 1Department of Pediatric Oncology and Hematology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland\n2Department of Oncology and Hematology, University Children's Hospital of Krakow, Krakow, Poland\n3Department of Clinical Immunology and Transplantation, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland\n4Department of Clinical Immunology and Transplantology, Stem Cell Transplant Center, University Children's Hospital of Krakow, Jagiellonian University Medical College, Krakow, Poland\n5Department of Pathology, University Children's Hospital of Krakow, Krakow, Poland\n6Department of Biochemistry, University Children's Hospital of Krakow, Krakow, Poland\n7Student Scientific Group of Pediatric Oncology and Hematology, Jagiellonian University Medical College, Krakow, Poland\nEdited by: Shimin Hu, University of Texas MD Anderson Cancer Center, United States\n\nReviewed by: Habibe Kurt, Brown University, United States; Mina Luqing Xu, Yale University, United States\n\n*Correspondence: Szymon Skoczen szymon.skoczen@uj.edu.plThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n\n03 7 2020 \n2020 \n10 92114 2 2020 11 5 2020 Copyright © 2020 Pawińska-Wa̧sikowska, Cwiklinska, Wyrobek, Balwierz, Bukowska-Strakova, Dluzniewska, Gozdzik, Drabik, Rygielska, Stepien and Skoczen.2020Pawińska-Wa̧sikowska, Cwiklinska, Wyrobek, Balwierz, Bukowska-Strakova, Dluzniewska, Gozdzik, Drabik, Rygielska, Stepien and SkoczenThis 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.The association between acute lymphoblastic leukemia (ALL), non-Langerhans cell histiocytosis (non-LCH), and hemophagocytic lymphohistiocytosis (HLH), to the best of our knowledge, has not been published to date. Juvenile xanthogranuloma (JXG), as a type of non-LCH, is usually a benign disease limited to the skin. Systemic involvement is rarely reported. The present case report describes a 15-year-old boy diagnosed with disseminated JXG involving skin and bone marrow concurrent with severe symptoms of HLH during ALL therapy. Examination of immunoglobulin heavy chain genes in B-cell precursor leukemic blasts and histiocytes in the skin and bone marrow revealed identical rearrangements, confirming clonal relationship between both diseases. Implementation of corticosteroids, vinblastine, etoposide, cyclosporine, and tocilizumab resulted in partial skin lesion resolution with no improvement of bone marrow function; therefore, hematopoietic stem cell transplantation (HSCT) was eventually performed. The patient's hematological and general status has improved gradually; however, remarkable recovery of skin lesions was observed after empirical antitubercular therapy. Mycobacterium spp. infection should be considered as a possible secondary HLH trigger. Triple association of ALL, non-LCH, and HLH highlights heterogeneity of histiocytic disorders and possible common origin of dendritic and lymphoid cells.\n\nacute lymphoblastic leukemianon-Langerhans cell histiocytosishemophagocytic lymphohistiocytosisjuvenile xanthogranulomacase report\n==== Body\nBackground\nHistiocytoses are proliferative disorders of cells derived from dendritic cells or macrophages that occur predominantly in children. Recently, the Histiocyte Society prepared a revised classification system of histiocytoses, on the basis of clinical, genetic, and histologic features. In this classification, the histiocytic disorders are grouped into five categories: Langerhans-related (L), cutaneous and mucocutaneous non-Langerhans histiocytoses (C), malignant histiocytoses (M), Rosai–Dorfman disease (R), and hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (H) (1).\n\nDendritic cells, monocytes, and macrophages belong to the mononuclear phagocyte system, whereas the term “histiocytes” refers to macrophages found in various tissues throughout the body (2).\n\nJuvenile xanthogranuloma (JXG) is a benign proliferative histiocytic cell disorder of early childhood, and the most common form of non-Langerhans cell histiocytosis (non-LCH). JXG typically manifests in the skin as spontaneously regressing nodules, localized on the trunk, scalp, face, and extremities. Most patients with JXG have only cutaneous symptoms; rarely is extracutaneous manifestation observed, for example, bone marrow and bone involvement (3). JXG cases associated with leukemia are uncommon. There are single reports on JXG coexistence with juvenile myelomonocytic leukemia, T-cell and B-cell lymphoblastic leukemia, and acute monocytic leukemia, as well as neurofibromatosis type 1 (4–7).\n\nHLH is a severe, life-threatening complication of infectious, rheumatoid, autoimmune, or malignant disease. It is caused by hyperreaction of T lymphocyte or macrophages, causing a cytokine storm manifested by fever, hepatosplenomegaly, lymphadenopathy, neurologic signs, or multiorgan failures (1, 8).\n\nTo the best of our knowledge, concomitant non-LCH with secondary HLH is unique in children being treated for acute lymphoblastic leukemia (ALL). Hence, we report on 15-year-old boy diagnosed with both disseminated JXG and severe secondary HLH with enteral enteropathy during the intensive treatment of ALL who was successfully treated with allogeneic hematopoietic stem cell transplantation (HSCT) followed by empirical antitubercular therapy.\n\nCase Presentation\nA 15-year-old boy was referred to University Children's Hospital of Krakow, Department of Oncology and Hematology, in December 2016, because of progressive pallor, bone pain, and upper respiratory tract infection. Physical examination revealed general lymphadenopathy and no hepatosplenomegaly. At admission, severe anemia (hemoglobin level of 6.0 g/dl), leukopenia (white blood cell count of 3.4 × 109/L), and thrombocytopenia (platelet count 45 × 109/L) were found, prompting a bone marrow examination. Bone marrow biopsy revealed 81% of lymphoblasts presenting expression of CD45, CD19, CD22, and CD10; thus, the diagnosis was pre-B-cell precursor ALL (pre-B-ALL). A normal male karyotype (46, XY) was found in the bone marrow cytogenetic analysis. None of the prognostic genetic abnormalities such as BCR-ABL, MLL-AF4, and ETV6-RUNX1 were found in leukemic cells. Cerebrospinal fluid examination revealed no lymphoblasts, and the patient was classified as CSN1 status.\n\nThe treatment according to ALL IC-BFM 2009 protocol was started, beginning with cytoreductive prednisone prophase and methotrexate intrathecally. Good response to glucocorticoids was seen. Induction therapy (Protocol IA) was continued afterwards with prednisolone, vincristine, and daunorubicin once per week with four total doses each and Escherichia coli-derived l-asparaginase with eight total doses and methotrexate intrathecally. Bone marrow aspiration on day 15 revealed no blasts (M1 bone marrow) and minimal residual disease (MRD) of 0.05%, indicating a good response to therapy. According to treatment protocol, the patient was ultimately stratified to intermediate risk group. Further treatment according to Protocol IB was continued: four blocks of cytarabine, cyclophosphamide, oral mercaptopurine, and intrathecal methotrexate. During the induction phase, apart from short-term pancytopenia, the patient did not present major toxicities of induction therapy. Complete remission with negative MRD (<0.01%) was achieved on day 78 (at the end of induction).\n\nAt the beginning of consolidation, in March 2017, the patient was admitted to our department because of unexplained fever lasting 3 days. On physical examination at admission, disseminated, single, pearly yellow nodules localized on the face, trunk, and extremities (Figure 1); bruises; and significant hepatosplenomegaly were found. Complete blood count revealed severe pancytopenia with hemoglobin level of 6.0 g/dl, leukocytes count of 1.2 × 109/L, and platelet count of 13 × 109/L. Owing to suspicion of pending relapse, bone marrow biopsy was performed. Bone marrow examination confirmed persistent complete remission with negative MRD of <0.01%; however, an increased number of histiocytes with hemophagocytosis (Figures 2, 3) was seen in bone marrow. Flow cytometric analysis of bone marrow cells revealed abnormal population of cells presenting SSChigh and high expression of CD45, CD64, CD14, and CD33, evaluated as macrophages (16% of all nucleated cells). Bone marrow core biopsy was not performed owing to low platelet count and poor coagulation functions not responding to substitution treatment.\n\nFigure 1 Multiple papulonodular skin lesions with predilection for cheeks.\n\nFigure 2 Histiocyte proliferation in the bone marrow of patient in remission of acute lymphoblastic leukemia (ALL); magnification, ×1,000.\n\nFigure 3 Hemophagocytosis in bone marrow; magnification, ×1,000.\n\nBecause remission of ALL was confirmed, we started to explore other causes of pancytopenia. Firstly, the patient underwent infectious disease screening. Blood tests revealed elevated C-reactive protein (CRP) (44 mg/dl), with a low procalcitonin level. Blood and urine cultures, as well as viral panel testing for cytomegalovirus (CMV), Epstein–Barr virus (EBV), human herpes virus 6 (HHV6), HIV, parvovirus B19 (PVB19), hepatitis C virus (HCV), hepatitis B virus (HBV), hepatitis A virus (HAV), and herpes simplex virus (HSV), were negative, as were screening examinations for autoimmune and rheumatoid markers.\n\nWithin the next several days, the general status of the patient deteriorated, high-grade fever persisted, and hepatomegaly and splenomegaly progressed. Severe hypoproteinemia (30 g/L), hypoalbuminemia (16 g/L), and hypofibrinogenemia (0.6 g/L) was observed. Additionally, an elevated level of ferritin (1,850 μg/L) and CD25 level [soluble interleukin (IL)-2 receptor-−6,541 U/ml) were found. Cytotoxic tests of NK cells revealed their reduced activity (6%, normal range 9.9–26.1%). Finally, based on clinical manifestation (fever and splenomegaly) and laboratory tests (pancytopenia, hypofibrinogenemia, hemophagocytosis in bone marrow, high ferritin, and low activity of NK cells), the diagnosis was HLH according to HLH-2004 trial diagnostic criteria (9).\n\nConsidering the probability of secondary HLH with malignancy in the patient, extensive investigations for pathogens were carried out; however, none of the infectious triggers (bacterial, viral, fungal, or parasitic) were found at that time. In the diagnosis of primary HLH, defect in SH2D1A was excluded.\n\nAdditionally, owing to the appearance of new skin lesions on the face, trunk, and extremities of the patient, we decided to biopsy the nodules. Skin biopsy revealed diffuse infiltration by histiocytes expressing CD45 and CD68 but negative for CD1a, langerin, and S100 (Figure 4); thus, JXG was recognized. Furthermore, the DNA was extracted from the initial ALL bone marrow smears, with the bone marrow specimen showing histiocytic proliferation and current histiocytic lesions in the skin. The BIOMED-2-primer was used to amplify the immunoglobulin heavy chain gene. The PCR products were analyzed by capillary electrophoresis. There were predominant monoclonal amplifications of 305, 239, and 104 bp found in the bone marrow cells. Identical products were detectable in the histiocytic lesion of the skin, which finally proved clonal relationship between both diseases. No lymphoblasts were found in the skin biopsy.\n\nFigure 4 Skin biopsy revealed diffuse infiltration by histiocytes positive for CD45 and CD68 and negative for S100 and CD1a. Hematoxylin–eosin stain; magnification, ×10.\n\nDespite intensive supportive therapy, patient's status deteriorated gradually. Serious enteral enteropathy with extremely low protein (23 g/L) and albumin (11 g/L) levels resulted in considerable peripheral edemas and hydrothorax. Because the patient stayed in complete remission of ALL with negative MRD status, further therapy according to ALL IC-BFM 2009 was ceased, and treatment, based on HLH 2004 protocol, was introduced. At the beginning, methylprednisolone and etoposide were given; however, no improvement was seen. Thus, cyclosporine and vinblastine were added after 2 weeks. Owing to remarkable fluid retention, cyclosporine was stopped eventually. The patient still needed everyday transfusion of red blood cells, platelet, and plasma concentrates, as well as intravenous immunoglobulin supply. He was fed by gastric feeding tube and then by jejunal tube to fulfill caloric requirements.\n\nIn the beginning of April, the patient started to complain about bone pain of left scapula and upper extremities. MRI scan showed bone structure alterations of left clavicula, scapula, and humerus. However, biopsy of the lesion was not done owing to the poor general status of the patient, low platelet count, and persistent coagulation abnormalities.\n\nDespite multidrug, intensive therapy, there was no improvement, neither in patient status nor in bone marrow function or skin lesions. Progression of hepatosplenomegaly was observed. Moreover, the patient developed additional side effects of steroids, such as diabetes, hypertension, and adrenal insufficiency.\n\nAdditionally, laboratory findings showed prominent pancytopenia, significantly elevated serum ferritin level, reduced fibrinogen level, and persistent hemophagocytosis in bone marrow. Looking for another treatment modalities of HLH, we decided to apply tocilizumab (IgG anti-IL-6 receptor). Once tocilizumab was given, a slow although unequivocal improvement of skin manifestation was seen. Increase of protein and fibrinogen levels, along with decrease of ferritin concentration, were achieved. Unfortunately, no change in blood parameters and features of hemophagocytosis in bone marrow were observed.\n\nFinally, a total of five tocilizumab doses were given. Because there was no further improvement, the patient was planned to have HSCT. In August 2017, the allogeneic HSCT from matched sibling donor was performed. Patient received treosulfan, fludarabine, thiotepa, and alemtuzumab as a part of his conditioning. Since day 15, reconstitution of leukocyte count > 1 × 109/L has been observed; neutrophils count > 0.5 × 109/L since day 17; and platelet count > 50 × 109/L since day 65 after HSCT. General and nutritional status of the patient gradually improved; however, some nodules on the skin of the face, trunk, and extremities were still present. One month after HSCT, the patient was discharged home. Ten days later, he was admitted to the hospital again owing to severe herpetic mucositis (WHO grade III). Because he started complaining of chest wall pain on the left side, X-ray was performed, and left side pleuritis was found. The pleura was punctured, and fluid examinations revealed high protein concentration and leukocytosis with presence of lymphocytes and macrophages. HHV6 PCR tests were positive, whereas aerobic and anaerobic bacterial, mycologic, and mycobacteria cultures, from both fluid and blood, were negative. Mycobacterium tuberculosis DNA by PCR test was not detected in pleural fluid.\n\nDespite negativity of tests, still, atypical mycobacterial infection was suspected in our patient, as he had been treated with immunosuppressive therapy. Therefore, we decided to introduce antitubercular agents on an empirical basis. Once isoniazid and rifampicin were given, remarkable regression of all skin lesions was observed. Gradual increase of platelet number was also seen within the next weeks. The patient continued with antitubercular drug therapy for further 6 months. Currently, 2 years after HSCT, the patient's general health status is good, in continuous remission of ALL, HLH, and JXG.\n\nDiscussion of the Underlying Pathophysiology and Significance of the Case\nWe report on a unique case of coexistence of disseminated JXG and HLH in a 15-year-old boy in remission of pre-B-ALL. According to our knowledge, there are several reports in the literature of concurrent existence of LCH and childhood leukemia. Rarely do patients with acute myeloid leukemia (AML) develop subsequent LCH. The more often pattern is ALL preceding the diagnosis of LCH and AML succeeding it. AML after LCH is probably secondary neoplasm triggered by chemotherapeutic agents used in LCH therapy (4–7, 10).\n\nThe association between ALL and histiocytic disorders has been investigated. Several articles have shown that LCH and ALL share the same mutations or had the same T-cell receptor or immunoglobulin rearrangement, which proves clonal relationship between them (8, 9, 11). Some papers report on RAS and CDKN2A mutations detected in ALL cases, which subsequently developed histiocytosis (8, 9).\n\nImportantly, in our case, presence of identical genome alterations in both ALL and histiocytosis confirms that the latter is not the secondary malignancy caused by DNA damage owing to chemotherapeutic agents used for ALL treatment. Identical immunoglobulin heavy chain gene alterations detected in non-LCH and ALL, as well as short time of onset of histiocytosis (3 months) after initial ALL diagnosis in our patient, proves the common genetic origin in both. The association might be also related to suspected common progenitor cell defect of dendritic and lymphoid precursor (12). Unfortunately, we did not perform the whole exome sequencing (WES) analysis of B-ALL and non-LCH cells, which would be crucial for definitive estimation of clonal character of those two entities in the current case report.\n\nFor the future studies, the existence of common genetic background with specific molecular alterations brings opportunity for addition of molecular targeted therapies in patients usually resistant to conventional therapies (13, 14).\n\nThe association of ALL and HLH is more often reported, because secondary forms of HLH usually occur during different forms of immune system alterations, including malignancy, iatrogenic suppression induced by chemotherapeutic agents, HSCT, or infections (15).\n\nIn our patient, HLH could be malignancy or infection induced, even though we did not manage to prove infection trigger. HHV6 infection was documented, although it has been reported to be extremely rare as an HLH trigger (16). Moreover, HHV6 infection was detected late in our patient, after HSCT, and it is rather unlikely that it caused secondary HLH in this case.\n\nThe possible trigger of secondary HLH could be Mycobacterium tuberculosis. Tuberculosis is known as a great mimicker, owing to its diverse range of clinical manifestations, which make diagnosis difficult. Zhang et al. reported a study on adults with tuberculosis who had secondary HLH, with no underlying diseases. All patients manifested fever; additionally, half of them presented with skin rash, which was presented in different forms (17).\n\nFurthermore, M. tuberculosis can induce Th1-mediated cytotoxicity, as well as can activate macrophages and NK cells, releasing more cytokines [IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF)], leading to tuberculosis and HLH symptoms (17, 18).\n\nIn HLH, excessive immune reaction leads to cytokine storm; thus, patients manifest a high level of IFN-γ, TNF-α, macrophage CSF (M-CSF), and ILs, including IL-1, IL-6, and IL-18. All those markers are responsible for diversity of clinical picture in HLH (15, 17–19).\n\nTherefore, targeting specific cytokines might be an attractive therapeutic approach in HLH patients. Indeed, IL-6 is one of the contributors to the pathogenesis of HLH, which has been shown to induce defective expression of perforin and decreased NK cell cytotoxic activity (20, 21). Therapy with tocilizumab, targeting IL-6, helps to regulate the immune response in the course of HLH by diminishing inappropriate macrophage activation (20). The patient status improved after tocilizumab partially; however, he still presented with profound and persistent pancytopenia, which may suggest that IL-6 might not have a central role in the pathogenesis of HLH.\n\nMoreover, ongoing ALL therapy, immunosuppression, and infections could induce overlapping histiocytes proliferation non-LCH and HLH in our patient. Triple association of ALL, non-LCH, and HLH highlights the heterogeneity of histiocytic disorders.\n\nConcluding Remarks\nDiversity of non-Langerhans histiocytosis manifestation and severity of its course with systemic involvement in patient with malignancy make diagnosis and treatment highly challenging. Careful search for microorganism colonization/infection should be always performed especially in cases with concomitant HLH, considering mycobacterial infections as a possible trigger.\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nKP-W, MC, EW, and SS contributed to case report concept and design. KP-W, MC, and KS wrote a section of the manuscript. KP-W, MC, EW, KB-S, AD, JG, GD, and MR performed diagnostic tests and collected relevant clinical data. WB, KS, and SS critically revised the article. All authors were responsible for the integrity and accuracy of the data and approved the submitted version.\n\nConflict of Interest\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 would like to thank Prof. Gunnar Cario (Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany) for opinion and advice on diagnosis and therapy of our patient; and Prof. Wolfgang Klapper (Institute of Pathology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany) for his expert review of the pathology specimens.\n==== Refs\nReferences\n1. Emile JF Abla O Fraitag S Horne A Haroche J Donadieu J . Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages\n. Blood. (2016 ) 27 :2672 –81\n. 10.1182/blood-2016-01-690636 26966089 \n2. Guilliams M Ginhoux F Jakubzick C Naik SH Onai N Schraml BU \nDendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny\n. Nat Rev Immunol. (2014 ) 14 :571 –8\n. 10.1038/nri3712 25033907 \n3. Janssen D Harms D . Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the Kiel pediatric tumor registry\n. Am J Surg Pathol. (2005 ) 29 :21 –8\n. 10.1097/01.pas.0000147395.01229.06 15613853 \n4. Chiou CC Wang PN Yang LC Kuo TT Hong HS . Disseminated xanthogranulomas associated with adult T-cell leukaemia/lymphoma: a case report and review the association of haematologic malignancies\n. J Eur Acad Dermatol Venereol. (2007 ) 21 :532 –5\n. 10.1111/j.1468-3083.2006.02013.x 17373983 \n5. Shoo BA Shinkai K McCalmont TH Fox LP . Xanthogranulomas associated with hematologic malignancy in adulthood\n. J Am Acad Dermatol. (2008 ) 59 :488 –93\n. 10.1016/j.jaad.2008.03.046 18538449 \n6. Perez-Becker R Szczepanowski M Leuschner I Janka G Gokel M Imschweiler T . An aggressive systemic juvenile xanthogranuloma clonally related to a preceding T-cell acute lymphoblastic leukemia\n. Pediatr Blood Cancer. (2011 ) 56 :859 –62\n. 10.1002/pbc.22756 20848640 \n7. Shin HT Harris MB Orlow SJ . Juvenile myelomonocytic leukemia presenting with features of hemophagocytic lymphohistiocytosis in association with neurofibromatosis and juvenile xanthogranulomas\n. J Pediatr Hematol Oncol. (2004 ) 26 :591 –5\n. 10.1097/01.mph.0000135282.39550.99 15342987 \n8. Kato M Seki M Yoshida K Sato Y Oyama R Arakawa M . Genomic analysis of clonal origin of Langerhans cell histiocytosis following acute lymphoblastic leukemia\n. Br J Hematol. (2016 ) 175 :161 –75\n. 10.1111/bjh.13841 26537828 \n9. Henter JI Horne A Arico M Egeler RM Filipovich AH Imashuku S . HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis\n. Pediatr Blood Cancer. (2007 ) 48 :124 –31\n. 10.1002/pbc.21039 16937360 \n10. Raj A Bendon R Moriarty T Suarez C Bertolone S . Langerhans cell histiocytosis following childhood acute lymphoblastic leukemia\n. Am J Hematol. (2001 ) 68 :284 –86\n. 10.1002/ajh.10004 11754419 \n11. Bleeke M Johann P Gröbner S Alten J Cario G Schäfer H . Genome-wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients\n. Pediatr Blood Cancer. (2020 ) 6 :e28074 . 10.1002/pbc.28074 31737984 \n12. Maly E Przyborska M Rybczynska A Konatkowska B Nowak J Januszkiewicz D . Juvenile xanthogranuloma with clonal proliferation in the bone marrow\n. J Pediatr Hematol Oncol. (2012 ) 34 :222 –5\n. 10.1097/MPH.0b013e31823321ca 22217493 \n13. Skoczen S Stepien K Krzysztofik M Luszawska T Hnatko-Kołacz M Korostynski M . Genetic profile and clinical implications of hepatoblastoma and neuroblastoma coexistance in a child\n. Front Oncol. (2019 ) 9 :230 . 10.3389/fonc.2019.00230 31019896 \n14. Skoczen S Stepien K Mlynarski W Centkowski P Kwiecinska K Korostynski M \nGenetic signature of acute lymphoblastic leuekmia and Netherton Syndrome Co-incidence - first report in the literature\n. Front Oncol. (2020 ) 9 :1477 \n10.3389/fonc.2019.01477 32010610 \n15. Strenger V Merth G Lackner H Aberle SW Kessler H Seidel MG . Malignancy and chemotherapy induced hemphagocytic lymphohistiocytosis in children and adolescent - a single center experience of 20 years\n. Ann Hematol. (2018 ) 97 :989 –98\n. 10.1007/s00277-018-3254-4 29411124 \n16. Eliassen E Krueger G Luppi M Ablashi D . Lymphoproliferative syndromes associated with human herpesvirus-6A and human herpesvirus-6B\n. Mediterr J Hematol Infect Dis. (2018 ) 10 :e2018035 . 10.4084/mjhid.2018.035 29755712 \n17. Zhang Y Liang G Qin H Li Y Zeng H \nTuberculosis-associated hemophagocytic lymphohistiocytosis with initial presentation of fever of unknown origin in a general hospital - an analysis of 8 clinical cases\n. Medicine (Baltimore). (2017 ) 96 :e6575 \n10.1097/MD.0000000000006575 28422850 \n18. Créput C Galicier L Buyse S Azoulay E . Understanding organ dysfunction in hemophagocytic lymphohistiocytosis\n. Intens Care Med. (2008 ) 34 :1177 –87\n. 10.1007/s00134-008-1111-y 18427781 \n19. Mazodier K Marin V Novick D Farnarier C Robitail S Schleinitz N . Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome\n. Blood. (2005 ) 106 :3483 –9\n. 10.1182/blood-2005-05-1980 16020503 \n20. Cifaldi L Prencipe G Caiello I Bracaglia C Locatelli F De Benedetti F . Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome\n. Arthritis Rheumatol. (2015 ) 67 :3037 –46\n. 10.1002/art.39295 26251193 \n21. Grom A Horne C De Benedetti F . Macrophage activation syndrome in the era of biologic therapy\n. Nat Rev Rheumatol. (2016 ) 12 :259 –68\n. 10.1038/nrrheum.2015.179 27009539\n\n",
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"journal": "Frontiers in oncology",
"keywords": "acute lymphoblastic leukemia; case report; hemophagocytic lymphohistiocytosis; juvenile xanthogranuloma; non-Langerhans cell histiocytosis",
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"title": "Disseminated Juvenile Xanthogranuloma and Hemophagocytic Lymphohistiocytosis Developed During Treatment of Acute Lymphoblastic Leukemia: Case Report.",
"title_normalized": "disseminated juvenile xanthogranuloma and hemophagocytic lymphohistiocytosis developed during treatment of acute lymphoblastic leukemia case report"
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"abstract": "Sofosbuvir/velpatasvir (SOF/VEL) is expected to be highly effective, even in patients with decompensated liver cirrhosis. However, portal hypertension can be problematic after achieving a sustained viral response (SVR), especially in patients with hepatic encephalopathy (HE) associated with large portal-systemic shunt. Although balloon-occluded retrograde transvenous obliteration (BRTO) is a useful option, whether BRTO or SOF/VEL therapy should be initially performed in patients with a poor liver function reserve is controversial. We herein report a case of refractory HE caused by decompensated liver cirrhosis due to hepatitis C virus (HCV) classified as Child-Pugh class C that was treated by BRTO after SVR with SOF/VEL. A 64-year-old woman with HCV-associated decompensated cirrhosis developed refractory HE. Dynamic contrast-enhanced computed tomography (CT) revealed large portal-systemic shunt. We treated the patient with 12 weeks of SOF/VEL, and she achieved SVR. Although the serum albumin level, edema, and ascites were improved, intractable HE remained. Her general condition had been improved after SVR, so HE was suspected to have been caused by portal-systemic shunting. We, therefore, treated the patient by BRTO. On dynamic contrast-enhanced CT, partial obstruction of the shunt vessel was confirmed after BRTO. Thereafter, her serum ammonia level rapidly improved, and HE did not recur. Interventional radiology such as BRTO following SOF/VEL therapy may be a useful option even in patients with decompensated HCV-associated cirrhosis accompanied by portal-systemic shunt.",
"affiliations": "Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.;Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan. kakizaki@gunma-u.ac.jp.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.",
"authors": "Takakusagi|Satoshi|S|;Shimizu|Megumi|M|;Yokoyama|Yozo|Y|;Kizawa|Kazuko|K|;Marubashi|Kyoko|K|;Kosone|Takashi|T|;Sato|Ken|K|;Kakizaki|Satoru|S|http://orcid.org/0000-0003-0224-7093;Takagi|Hitoshi|H|;Uraoka|Toshio|T|",
"chemical_list": "D002219:Carbamates; D006576:Heterocyclic Compounds, 4 or More Rings; C000604171:velpatasvir; D000069474:Sofosbuvir",
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"issue": "13(6)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Balloon occluded retrograde transvenous obliteration; Decompensated cirrhosis; Hepatitis C; Sustained viral response",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D021721:Balloon Occlusion; D002219:Carbamates; D005260:Female; D016174:Hepacivirus; D006501:Hepatic Encephalopathy; D006526:Hepatitis C; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D008103:Liver Cirrhosis; D008875:Middle Aged; D000069474:Sofosbuvir; D016896:Treatment Outcome",
"nlm_unique_id": "101477246",
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"pages": "1303-1309",
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"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis C virus-associated decompensated liver cirrhosis with refractory hepatic encephalopathy successfully treated by balloon-occluded retrograde transvenous obliteration after sofosbuvir/velpatasvir.",
"title_normalized": "hepatitis c virus associated decompensated liver cirrhosis with refractory hepatic encephalopathy successfully treated by balloon occluded retrograde transvenous obliteration after sofosbuvir velpatasvir"
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"abstract": "BACKGROUND\nLung cancer is the most common cause of cancer-related deaths globally. Metastatic disease is often found at the time of initial diagnosis in the majority of lung cancer patients. However, colonic metastases are rare. This report describes an uncommon case of colonic metastasis from lung adenocarcinoma.\n\n\nMETHODS\nA 64-year-old female presented to her gastroenterologist for progressively worsening abdominal pain and constipation. Exploratory colonoscopy revealed a large rectosigmoid mass resulting in near total rectal occlusion. Her specialist recommended she immediately go to her regional hospital for further workup. On admission, she complained of continued abdominal pain and constipation. Notably, she had a past medical history of non-small cell lung cancer (T1bN3M0 stage IIIB), diagnosed 1 year prior. She was thought to be in remission following radiation and immunotherapy with pembrolizumab. Upon hospital admission, she underwent an urgent colostomy, ileocecectomy and anastomosis, and rectosigmoid mass resection with tissue sampling. Pathology confirmed the diagnosis of colonic metastasis from primary lung adenocarcinoma. Treatment was with systemic chemotherapy followed by localized radiation to the pelvic region was started. She did not respond well to these therapies. Subsequent imaging showed refractory tumor growth in the pelvic region. Treatment could not be completed due to the patient experiencing a debilitating stroke, and she was transitioned to hospice care.\n\n\nCONCLUSIONS\nClinicians should have a low threshold for intestinal investigation and considerations for colonic metastasis when patients with a history of primary lung cancer have abdominal symptoms.",
"affiliations": "Department of Internal Medicine, University of Kansas School of Medicine, 2817 N Tallgrass St, Wichita, KS, 67226, USA. nparker6@kumc.edu.;Department of Internal Medicine, University of Kansas School of Medicine, 1010 N Kansas St, Wichita, KS, 67214, USA.;Department of Internal Medicine, University of Kansas School of Medicine, 1010 N Kansas St, Wichita, KS, 67214, USA.;Department of Anatomical and Clinical Pathology, Wesley Medical Center, 550 N. Hillside St, Wichita, KS, 67214, USA.",
"authors": "Parker|N A|NA|http://orcid.org/0000-0002-5519-7758;McBride|C|C|;Forge|J|J|;Lalich|D|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12957-019-1611-y",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 161110.1186/s12957-019-1611-yCase ReportBowel obstruction caused by colonic metastasis of lung adenocarcinoma: a case report and literature review http://orcid.org/0000-0002-5519-7758Parker N. A. nparker6@kumc.edu 1McBride C. cmcbride@kumc.edu 2Forge J. jforge2@kumc.edu 2Lalich D. Daniel.Lalich@wesleymc.com 31 0000 0001 2106 0692grid.266515.3Department of Internal Medicine, University of Kansas School of Medicine, 2817 N Tallgrass St, Wichita, KS 67226 USA 2 0000 0001 2106 0692grid.266515.3Department of Internal Medicine, University of Kansas School of Medicine, 1010 N Kansas St, Wichita, KS 67214 USA 3 0000 0004 0484 8703grid.413812.dDepartment of Anatomical and Clinical Pathology, Wesley Medical Center, 550 N. Hillside St, Wichita, KS 67214 USA 8 4 2019 8 4 2019 2019 17 6320 1 2019 29 3 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.Introduction\nLung cancer is the most common cause of cancer-related deaths globally. Metastatic disease is often found at the time of initial diagnosis in the majority of lung cancer patients. However, colonic metastases are rare. This report describes an uncommon case of colonic metastasis from lung adenocarcinoma.\n\nCase presentation\nA 64-year-old female presented to her gastroenterologist for progressively worsening abdominal pain and constipation. Exploratory colonoscopy revealed a large rectosigmoid mass resulting in near total rectal occlusion. Her specialist recommended she immediately go to her regional hospital for further workup. On admission, she complained of continued abdominal pain and constipation. Notably, she had a past medical history of non-small cell lung cancer (T1bN3M0 stage IIIB), diagnosed 1 year prior. She was thought to be in remission following radiation and immunotherapy with pembrolizumab. Upon hospital admission, she underwent an urgent colostomy, ileocecectomy and anastomosis, and rectosigmoid mass resection with tissue sampling. Pathology confirmed the diagnosis of colonic metastasis from primary lung adenocarcinoma. Treatment was with systemic chemotherapy followed by localized radiation to the pelvic region was started. She did not respond well to these therapies. Subsequent imaging showed refractory tumor growth in the pelvic region. Treatment could not be completed due to the patient experiencing a debilitating stroke, and she was transitioned to hospice care.\n\nConclusions\nClinicians should have a low threshold for intestinal investigation and considerations for colonic metastasis when patients with a history of primary lung cancer have abdominal symptoms.\n\nKeywords\nColonic metastasisPrimary lung cancerNon-small cell lung cancerissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nNon-small cell lung carcinoma (NSCLC) accounts for the majority of all lung cancer cases. Metastatic disease is often present at the time of diagnosis, regardless of primary lung cancer type [1–4]. However, colonic metastases are rare. The exact prevalence of large bowel metastasis is difficult to determine. Asymptomatic colonic metastasis has an incidence of approximately 12% based on autopsy studies [5–10]. Symptomatic colonic metastasis infrequently occurs [5, 6, 8, 11–14]. Clinicians should have a high index of suspicion and a low threshold for intestinal tract investigation when primary lung cancer patients present with abdominal symptoms.\n\nCase report\nA 64-year-old female was referred to the hospital by her gastroenterologist after a same-day colonoscopy revealed a large rectosigmoid mass resulting in near total rectal occlusion. She had a past medical history of tobacco smoking and NSCLC (T1bN3M0 stage IIIB), diagnosed 1 year prior (Fig. 1). She was thought to be in remission following radiation and immunotherapy with pembrolizumab.Fig. 1 Chest X-ray and computed tomography showed a tumor in the left lung field. a CXR showed a round mass in the left upper lung field. b CT coronal image demonstrated the mass anteriorly within the left upper lobe. c CT scan revealed a 3.4 × 3.1 cm left upper lobe pulmonary mass lesion most compatible with primary lung cancer. d CT scan showed abnormal left hilar and mediastinal adenopathy (arrow) suggestive of metastatic nodal involvement\n\n\n\nOn admission, she complained of progressively worsening abdominal pain and constipation. Vital signs and measurements were unremarkable. Physical examination was primarily benign. Notable laboratory findings only included elevated carcinoembryonic antigen of 4.2 ng/dL. Computerized tomography (CT) imaging showed a severe colonic stool burden and a soft tissue left upper lobe lung mass consistent with patient’s NSCLC history. A single large soft tissue mass with possible mucosal invasion in the rectosigmoid colon was noted (Fig. 2). She underwent urgent diagnostic laparoscopy that was quickly converted to open exploratory laparotomy due to numerous bowel-to-bowel and bowel-to-anterior abdominal wall adhesions. At that time, a rectal mass appeared to be invading into the small bowel. Ultimately, colostomy, ileocecectomy and anastomosis, and rectosigmoid mass resection with tissue sampling were performed. She tolerated the procedure well, and her immediate postoperative course was uneventful.Fig. 2 Imaging showed a tumor in the left lung field and sigmoid colon. a Chest CT revealed a residual soft tissue mass anteriorly within the left upper lobe measuring approximately 2.0 × 1.7 cm without appreciable adenopathy (not shown) consistent with the patient’s known history of lung cancer. b Abdomen and pelvic CT showed a soft tissue mass with approximate 5.0 × 4.7 cm dimensions within sigmoid colon (arrow) at 15 cm from the anal orifice. A sigmoid mass with extrinsic features and mucosal involvement can be seen contributing to marked narrowing of the sigmoid colon, but allowed contrast to pass through area of narrowing\n\n\n\nRectosigmoid mass biopsies revealed positivity for high-grade NSCLC and favored metastatic poorly differentiated adenocarcinoma of lung origin. Hematoxylin and eosin (H&E) staining showed rectosigmoid mass tissue exhibiting extensive necrosis, focal mucosal involvement, and negativity for regional lymph node carcinoma. Also, normal appearing colonic glandular cells were surrounded by atypical cells infiltrating the colonic stroma. To evaluate these high-grade and poorly differentiated malignant changes further, properly controlled routine immunohistochemical (IHC) stains for cytokeratin 7 (CK7), thyroid transcription factor-1 (TTF-1), Napsin-A, epithelial specific antigen/EpCAM (Moc-31), Ber-EP4, p63, cytokeratin 5 or 6 (CK5, CK6), caudal type homeobox 2 (CDX2), and cytokeratin 20 (CK20) were performed not only based on the patient’s age, gender, and past medical history, but also her recent clinical, radiologic, and operative findings. Additional properly controlled IHC stains for leukocyte common antigen (CD45), melanoma antigen recognized by T cells (MART-1), gross cystic disease fluid protein 15 (GCDFP-15), estrogen receptor (ER), synaptophysin, neural-cell adhesion molecule (NCAM/CD56), and chromogranin were performed due to the unusual presentation and nature of the case. The malignant cells exhibited strong positive immunoreactivity for CK7, and positive TTF-1 Napsin-A, Moc-31, and Ber-EP4, while showing only minimal focal staining for p63 and cytokeratin 5 or 6 (CK5, CK6). The tumor was negative for CDX2, CK20, CD45, MART-1, GCDFP-15, ER, synaptophysin, NCAM/CD56, and chromogranin (Fig. 3). Mucicarmine staining was equivocal for intra-cytoplasmic mucin. This IHC staining profile (strongly positive CK7 and positive TTF-1/Napsin-A with negative CDX2/CK20) supported metastatic adenocarcinoma of lung origin, rather than primary colorectal adenocarcinoma. This hypothesis was supported by numerous colonic and regional lymph node samples lacking malignant carcinoma cells and properly controlled IHC stains of right colon and ileum biopsy cells exhibiting negative immunoreactivity for CK7, TTF-1 Napsin-A, Moc-31, and Ber-EP4.Fig. 3 The pathology specimen demonstrated metastatic lung adenocarcinoma of the colon. (H&E stain, × 40). The carcinoma cells were positive for CK7, TTF-1, and Napsin-A, but negative CK20 and CDX2 (× 40)\n\n\n\nHer postoperative course was uneventful, and she was discharged home. The patient was started on systemic chemotherapy with carboplatin and pemetrexed followed by radiation to the pelvic region for metastatic NSCLC. She did not tolerate chemoradiation therapy well. During the treatment period, she developed considerable pelvic pain resulting in a significant performance status decline. She also experienced multiple prolonged hospitalizations due to infections. Subsequent positron emission tomography–CT (PET-CT) scans suggested refractory pelvic tumor growth. Additional radiation for palliation of pain by reducing pelvic tumor size was determined reasonable. However, the patient experienced a debilitating stroke and was transitioned to hospice care.\n\nDiscussion\nThe most common NSCLC metastatic site is bone (34%), followed by lungs (32%), brain (28%), adrenal glands (17%), liver (13%), and extrathoracic lymph nodes (9%) [15]. Colonic metastasis is uncommon with an incidence of 0.1% [16]. Although metastasis to the colon from lung cancer is uncommon, the phenomenon has been reported [5–56]. Most commonly, the small intestine develops metastatic lesions [5]. This could be due to the enhanced potential of small bowel malignancies to cause serious complications such as perforation, obstruction, or bleeding [5, 6]. Only 44 unique case reports of lung cancer metastasizing to the colon have been published globally (Table 1) [5, 10, 13, 17–56]. The pathological diagnosis in 20 of the 44 cases (45%) was squamous cell carcinoma (SqCC) [13, 17–35]. Twelve lung adenocarcinomas (27%) and five small cell lung carcinomas (SCC, 11%) were confirmed as primary origins [5, 10, 36–44, 46–49, 52]. Large-cell carcinoma of the lung was reported in three cases (7%) [10, 50, 51]. Four cases (9%) confirmed colonic metastasis from other primary lung histopathologic cell types such as sarcomatoid, pleomorphic, and unknown [53–56]. SqCC had a higher propensity for colonic metastasis [13, 17–35]. Lung adenocarcinoma had the second highest potential for colonic metastasis [10, 36–44, 52]. Abdominal pain due to intestinal tract obstruction was the most frequent initial clinical symptom of metastatic colon cancer from primary malignant lung neoplasms [19, 25, 29, 32, 33, 37, 38, 40, 43, 44, 52, 53]. Bloody stool due to either melena or hematochezia was also a common chief complaint [5, 10, 17, 31, 35, 48, 56]. Diagnosis of metastatic lung cancer to the colon by incidental polyp discovery occurs infrequently [10, 18, 42, 55]. Metastatic colonic neoplasms of lung origin can also present initially with non-bloody diarrhea, encopresis, and hyponatremia [20, 36, 39]. Metastatic lung SqCC and SCC to the colon were associated more with serious complications such as perforation, hemorrhage, and intussusception [13, 22, 47, 49, 51]. Lung cancer manifesting as colonic metastasis is rare, and thus cited remotely in case reports. Broad interpretations based on such isolated events should be taken into consideration.Table 1 Clinical presentations of patients with colonic metastasis, historically (1988–2016)\n\nCase report\tCell type\tSymptomatology\t\nAzevedo et al. [30]\tSqCC\tObstruction\t\nCarroll et al. [20]\tSqCC\tDiarrhea\t\nCedres et al. [29]\tSqCC\tAbdominal pain\t\nFranco et al. [31]\tSqCC\tBloody stool\t\nGateley et al. [22]\tSqCC\tHemorrhage\t\nGitt et al. [13]\tSqCC\tPerforation\t\nHabesoglu et al. [19]\tSqCC\tAbdominal pain\t\nHirasaki et al. [17]\tSqCC\tBloody stool\t\nLou et al. [32]\tSqCC\tAbdominal pain\t\nMa et al. [33]\tSqCC\tAbdominal pain\t\nRouhanimanesh et al. [34]\tSqCC\tObstruction\t\nSakai et al. [25]\tSqCC\tAbdominal pain\t\nStinchcombe et al. [18]\tSqCC\tIncidental polyp\t\nWegener et al. [35]\tSqCC\tBloody stool\t\nYuyuan Y. [26]\tSqCC\tObstruction\t\nAl-Tarakji et al. [39]\tADC\tEncopresis\t\nCeretti et al. [41]\tADC\tObstruction\t\nHsing et al. [40]\tADC\tAbdominal pain\t\nHuang et al. [37]\tADC\tAbdominal pain\t\nMiyazaki et al. [38]\tADC\tAbdominal pain\t\nOno et al. [52]\tADC\tAbdominal pain\t\nPezzuto et al. [36]\tADC\tHyponatremia\t\nPozzato et al. [44]\tADC\tAbdominal pain\t\nRossi et al. [10]\tADC, LCC\tPolyp, bloody stool\t\nWeng et al. [43]\tADC\tAbdominal pain\t\nXue et al. [42]\tADC\tIncidental polyp\t\nJohnson et al. [48]\tSCC\tBloody stool\t\nPolak et al. [49]\tSCC\tPerforation\t\nYang et al. [5]\tSCC\tBloody stool\t\nZhidong et al. [47]\tSCC\tPerforation\t\nGoh et al. [51]\tLCC\tHemorrhage\t\nChen et al. [53]\tO\tAbdominal pain\t\nLin et al. [54]\tO\tIntussusception\t\nBastos et al. [56]\tU\tBloody stool\t\nMyoteri et al. [55]\tU\tIncidental polyp\t\nParticular case reports have been excluded from tabulation due to accessibility and non-English language barriers for symptomatology information only [21, 23, 27, 28, 45, 46, 50]\n\nSqCC squamous cell carcinoma, ADC adenocarcinoma, SCC small cell carcinoma, LCC large cell carcinoma, O other: sarcomatoid or pleomorphic, U unknown\n\n\n\nInitial diagnosis of colonic metastasis of lung carcinoma is challenging since its incidence has been reported sporadically. The phenomenon is being reported more frequently due to the recent higher rates of lung cancer in women, increased availability and utilization of endoscopic examinations, and advancements in IHC staining [9]. Details regarding colonic metastasis in terms of typical symptomatology remain sparse. Colonic metastasis of lung carcinoma can present as an incidental polyp, with bloody stool, or by significant bowel obstruction, such as with our patient.\n\nHistological examination, in correlation with clinical findings, remains the gold standard for diagnosis. IHC stains such as TTF-1, CDX2, CK7, and CK20 help distinguish metastatic lung carcinoma from primary colonic cancer [10, 25]. The immunostaining profile of our patient (strongly positive CK7 and positive TTF-1 with negative CDX2/CK20) supported that her rectosigmoid tumor causing near-total rectal occlusion was metastatic adenocarcinoma of lung origin, rather than primary colorectal adenocarcinoma [57–59].\n\nEarly detection could be expedited by fecal occult blood testing [56]. This test is generally fast and inexpensive. As a result, stool testing is sufficient in terms of early evaluation and workup, especially in patients with abdominal symptoms and a known history of cancer [17]. PET-CT scans can diagnose asymptomatic colonic metastasis from lung carcinoma [5, 8, 18]. In contrast to conventional CT and endoscopy, PET-CT can determine if an intestinal neoplasm is of primary or secondary tumor origins. However, it is unable to establish an intestinal tumor’s specific histopathologic cell type.\n\nAverage survivability of patients with primary lung carcinoma, from the time of diagnosis of colonic metastasis to death, varies widely. Moreover, small and large bowel metastasis outcome data are often aggregated. The 5-year survival rate for stage IV metastatic NSCLC is approximately 10% [60]. Our patient initially received pembrolizumab before the discovery of colonic metastasis. Pembrolizumab is a novel and well-researched cancer immunotherapy most commonly used for tumors that are unresectable, recurrent, or metastatic [61]. Until recently, pembrolizumab has been recommended as a second-line agent. Combination chemotherapy with platinum-based pemetrexed and carboplatin is the first-line treatment for advanced NSCLC [62]. Trends are now focusing on tumor genotype-specific characteristics and in favor of earlier use of immunotherapeutic agents such as pembrolizumab. In a recent open-label phase III trial involving patients with advanced NSCLC, pembrolizumab was associated with significantly longer progression-free and overall survival [61–63]. Also, pembrolizumab was associated with fewer adverse events compared to platinum-based chemotherapy [61–63]. Before our patient’s initial presentation with symptomatic rectal occlusion, it was reported she did not tolerate pembrolizumab therapy well due to medication side effects.\n\nAll forms of intestinal metastasis of lung carcinoma are considered a late-stage complication of the disease. Average survival following the discovery of colonic metastasis to death has been reported to be approximately 2 months [5, 10, 56]. However, the range of survival after the diagnosis of colonic metastasis from primary lung carcinoma has been found to vary greatly [5, 7–14, 17–57]. Outcomes are based on chief complaints at the time of initial presentation and subsequent surgical intervention [5, 6, 11, 14, 15, 52, 53]. Perforation, obstruction, or hemorrhage have been associated with less favorable outcomes [6, 11, 19, 22, 48, 52, 53]. Early detection and surgical intervention have been postulated to improve survival [25]. Furthermore, longer survival times have been observed in patients that underwent palliative surgical resection of the metastatic site [8, 10–25], as with our patient.\n\nConclusion\nColonic metastasis should be considered when patients have abdominal symptoms and a history of primary lung cancer. Expedited intestinal tract investigation should be done to allow for early detection and treatment. Findings can initially be subtle and isolated, such as a single polyp, bloody stool, or obstruction. Symptoms can be dismissed as a primary gastrointestinal process such as ulcers or colitis. Fecal occult blood testing, PET-CT scans, and endoscopy are clinically useful for establishing a diagnosis. However, histological examination confirms the diagnosis. Many previous case reports of this phenomenon present aggregate data from the small bowel and large bowel metastasis of lung carcinoma. More reports on colonic metastasis of lung carcinoma are required to clarify clinical features and outcomes. Ultimately, early detection and surgical intervention have been thought to improve survival.\n\nAbbreviations\nCD45Leukocyte common antigen\n\nCDX2Caudal type homeobox 2\n\nCK20Cytokeratin 20\n\nCK5/6Cytokeratin 5 or 6\n\nCK7Cytokeratin 7\n\nCTComputerized tomography\n\nEREstrogen receptor\n\nGCDFP-15Gross cystic disease fluid protein 15\n\nH&EHemotoxylin and eosin\n\nIHCImmunohistochemical\n\nMART-1Melanoma antigen recognized by T cells\n\nMoc-31Epithelial specific antigen/EpCAM\n\nNCAM/CD56Neural-cell adhesion molecule\n\nNSCLCNon-small cell lung carcinoma\n\nPD-L1Programmed death-ligand 1\n\nPET-CTPositron emission tomography–CT\n\nSqCCSquamous cell carcinoma\n\nTTF-1Thyroid transcription factor-1\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nThe material supporting the conclusion of this review has been included within the article.\n\nAuthors’ contributions\nNP performed data collection and wrote manuscript. DL facilitated in pathology image access and interpretation. CM, JF, and DL participated in the editing of the manuscript. All authors have read and approved of the manuscript.\n\nEthics approval and consent to participate\nThe data collection on the patient had been approved by the local Ethical Committee.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/ relative of the patient.\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. 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Huang YM Hsieh TY Chen JR Chien HP Chang PH Wang CH Huang JS Gastric and colonic metastases from primary lung adenocarcinoma: A case report and review of the literature Oncol Lett 2012 4 517 520 10.3892/ol.2012.778 22970049 \n38. Miyazaki K Satoh H Sekizawa K Metastasis to appendix from lung adenocarcinoma Int J Gastrointest Cancer 2005 36 59 60 10.1385/IJGC:36:1:059 16227637 \n39. Al-Tarakji M, et al. Rare occurrence of metastasis from lung cancer to the anus: case report and review of the literature. World J Surg Oncol. 2016;14(157).\n40. Hsing CT Gastrointestinal metastasis from a primary adenocarcinoma of the lung presenting with acute abdominal pain Korean J Gastroenterol 2012 59 5 382 385 10.4166/kjg.2012.59.5.382 22617534 \n41. Ceretti AP Goi G Barabino M De Nicola E Strada D Bislenghi G Opocher E Colonic metastasis from primary carcinoma of the lung. Case report Ann Ital Chir 2011 82 229 232 21780567 \n42. Xue XY Colonic metastasis from primary lung adenocarcinoma: case report and review of the literature Med Oncol 2012 29 2 644 647 10.1007/s12032-011-9954-4 21516483 \n43. Weng MW Wang HC Chiou JC Lin SL Lai RS Colonic metastasis from a primary adenocarcinoma of the lung presenting with acute abdominal pain: a case report Kaohsiung J Med Sci 2010 26 1 40 44 10.1016/S1607-551X(10)70007-3 20040472 \n44. Pozzato Paolo Salerno Angela Cancellieri Alessandra Ventrucci Maurizio Colonic metastasis from a primary adenocarcinoma of the lung presenting with acute abdominal pain Digestive and Liver Disease 2012 44 6 e11 10.1016/j.dld.2011.12.007 22293127 \n45. Ahn SE Lee HL Lee OY Yoon BC Choi HS Hahm JS Park SW Colonic metastasis from primary lung adenocarcinoma Korean J Gastroenterol 2009 53 2 121 125 19237839 \n46. Jianguo S Xiufeng Z Qingmei J A case report of rectal metastasis of small cell lung cancer Chin J Cancer Prev Treat 2000 7 369 \n47. 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Ettinger DS Wood DE Aisner DL Non-small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology J Natl Compr Cancer Netw 2017 15 4 504 535 10.6004/jnccn.2017.0050 \n62. Reck M Rodriguez-Abreu D Robinson AG Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer N Engl J Med 2016 375 1823 1833 10.1056/NEJMoa1606774 27718847 \n63. Garon EB Rizvi NA Hui R Pembrolizumab for the treatment of non-small-cell lung cancer N Engl J Med 2015 372 2018 2028 10.1056/NEJMoa1501824 25891174\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-7819",
"issue": "17(1)",
"journal": "World journal of surgical oncology",
"keywords": "Colonic metastasis; Non-small cell lung cancer; Primary lung cancer",
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D003110:Colonic Neoplasms; D005260:Female; D006801:Humans; D007415:Intestinal Obstruction; D008175:Lung Neoplasms; D008875:Middle Aged; D011379:Prognosis",
"nlm_unique_id": "101170544",
"other_id": null,
"pages": "63",
"pmc": null,
"pmid": "30961608",
"pubdate": "2019-04-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Bowel obstruction caused by colonic metastasis of lung adenocarcinoma: a case report and literature review.",
"title_normalized": "bowel obstruction caused by colonic metastasis of lung adenocarcinoma a case report and literature review"
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"companynumb": "US-009507513-1904USA010431",
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"abstract": "OBJECTIVE\nTo estimate the number of acetaminophen overdose-related emergency department (ED) visits and hospitalizations in the United States, characterize these by intentionality, age, and gender, and compare the strengths and limitations of the utilized databases.\n\n\nMETHODS\nWe used data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) and the National Electronic Injury Surveillance System (NEISS) to estimate the number of relevant ED visits in the United States between 2000 and 2007, and the National Hospital Discharge Survey (NHDS) to estimate the number of relevant hospitalizations in the United States between 1991 and 2006. National estimates and their standard errors were calculated using information provided in each database. We used the standard United States population in 2000 to calculate age-adjusted rates.\n\n\nRESULTS\nWe estimate an annual average of 44,348 (NHAMCS, 2000-2007) or 78,414 (NEISS, 2006-2007) acetaminophen overdose-related ED visits and 33,520 (NHDS, 2000-2006) hospitalizations. For 2000-2006 we calculated an age-adjusted rate of 13.9 acetaminophen overdose-related hospitalizations per 100,000 US population, with the highest rate (15.7) occurring from 2005 to 2006. Between 1991 and 2006, there was no decrease noted in hospitalizations for intentional or unintentional overdoses. The majority of overdoses reported in NEISS (69.8%) and NHDS (74.2%) were classified as intentional (suicides or suicidal gestures), whereas in NHAMCS, intentionality was evenly distributed.\n\n\nCONCLUSIONS\nOur results suggest that acetaminophen overdose, both intentional and unintentional, remains a significant public health concern. With an understanding of their methodological characteristics and limitations, these national databases can be useful tools to characterize acetaminophen overdose-related ED visits and hospitalizations.",
"affiliations": "Division of Epidemiology, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. angelika.manthripragada@fda.hhs.gov",
"authors": "Manthripragada|Angelika D|AD|;Zhou|Esther H|EH|;Budnitz|Daniel S|DS|;Lovegrove|Maribeth C|MC|;Willy|Mary E|ME|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "England",
"delete": false,
"doi": "10.1002/pds.2090",
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"issue": "20(8)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": null,
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D018712:Analgesics, Non-Narcotic; D002648:Child; D016208:Databases, Factual; D004636:Emergency Service, Hospital; D005260:Female; D019538:Health Care Surveys; D006760:Hospitalization; D006801:Humans; D008297:Male; D011159:Population Surveillance; D013406:Suicide, Attempted; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "819-26",
"pmc": null,
"pmid": "21294217",
"pubdate": "2011-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Characterization of acetaminophen overdose-related emergency department visits and hospitalizations in the United States.",
"title_normalized": "characterization of acetaminophen overdose related emergency department visits and hospitalizations in the united states"
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"companynumb": "US-JNJFOC-20161013175",
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"actiondrug": "5",
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"activesubstancename": "ACETAMINOPHEN"
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... |
{
"abstract": "OBJECTIVE\nThe prevalence of sickle cell disease (SCD) in Spain is markedly inferior compared with other European and Mediterranean countries. However, the diagnosis of new patients with SCD is expected to increase. In this multicenter retrospective study, we analyze the hematopoietic stem cell transplantation (HSCT) results obtained in Spain.\n\n\nMETHODS\nForty-five patients who underwent a matched sibling donor (MSD) HSCT between 1999 and 2018 were included. Primary endpoint was event-free survival (EFS), and secondary endpoints included acute and chronic graft-versus-host disease (GvHD) and overall survival (OS).\n\n\nRESULTS\nBone marrow was the most frequent stem cell source (93.3%). Most patients received a conditioning regimen based on busulfan and cyclophosphamide (69%). Cumulative incidence of grade III-IV acute GvHD and chronic GvHD was 6.8% (95% CI: 2.3%-20.1%) and 5.4% (95% CI: 1.38%-19.9%), respectively. EFS and overall survival (OS) at 3 years post-HSCT were 89.4% (95% CI: 73.9%-95.9%) and 92.1% (95% CI: 77.2%-97.4%), respectively. All patients aged ≤ 5 presented 100% EFS and OS.\n\n\nCONCLUSIONS\nAn early referral to HSCT centers should be proposed early in life, before severe complications occur. MSD HSCT should be considered a curative option for all patients aged ≤ 5 years and for older pediatric patients who present complications derived from the disease.",
"affiliations": "Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.;Department of Pediatric Hematology and Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.;Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.;Department of Pediatric Hematology and Oncology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.;Department of Hematology, Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Department of Pediatric Hematology and Oncology, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.;Department of Pediatric Hematology and Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.",
"authors": "Benítez-Carabante|María Isabel|MI|https://orcid.org/0000-0002-5366-8384;Beléndez|Cristina|C|;González-Vicent|Marta|M|;Alonso|Laura|L|https://orcid.org/0000-0002-7835-1594;Uría-Oficialdegui|María Luz|ML|;Torrent|Monserrat|M|;Pérez-Hurtado|José María|JM|;Fuster|José Luis|JL|;Cela|Elena|E|;Díaz-de-Heredia|Cristina|C|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13566",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "106(3)",
"journal": "European journal of haematology",
"keywords": "children; hematopoietic stem cell transplantation (HSCT); sickle cell disease (SCD)",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000755:Anemia, Sickle Cell; D002648:Child; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D008297:Male; D012189:Retrospective Studies; D012720:Severity of Illness Index; D035781:Siblings; D013030:Spain; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "408-416",
"pmc": null,
"pmid": "33296531",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Matched sibling donor stem cell transplantation for sickle cell disease: Results from the Spanish group for bone marrow transplantation in children.",
"title_normalized": "matched sibling donor stem cell transplantation for sickle cell disease results from the spanish group for bone marrow transplantation in children"
} | [
{
"companynumb": "ES-OTSUKA-2020_033131",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "We describe hypersensitivity to polyethylene glycols (PEGs), with cross-reactivity to a structural analog, polysorbate 80, in a 69-year-old patient with perioperative anaphylaxis and subsequent, severe anaphylactic reactions to unrelated medical products. PEGs and PEG analogs are prevalent in the perioperative setting, contained in a wide range of products seldom suspected of causing hypersensitivity reactions and thus rarely documented in surgical/anesthetic records. We suggest routine testing for PEGs after perioperative anaphylaxis because exposure to these polymers often is significant. Comprehensive brand name documentation on the anesthetic chart of all product exposures is central to identifying the responsible allergen.",
"affiliations": "From the Danish Anaesthesia Allergy Centre, Allergy Clinic, Copenhagen University Hospital, Gentofte, Hellerup, Denmark.",
"authors": "Wenande|Emily|E|;Kroigaard|Mogens|M|;Mosbech|Holger|H|;Garvey|Lene H|LH|",
"chemical_list": "D000485:Allergens; D000777:Anesthetics; D011092:Polyethylene Glycols",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000126",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-7237",
"issue": "4(5)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000368:Aged; D000485:Allergens; D000707:Anaphylaxis; D000777:Anesthetics; D003429:Cross Reactions; D004342:Drug Hypersensitivity; D020199:Hematoma, Subdural, Acute; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "61-4",
"pmc": null,
"pmid": "25730412",
"pubdate": "2015-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Polyethylene glycols (PEG) and related structures: overlooked allergens in the perioperative setting.",
"title_normalized": "polyethylene glycols peg and related structures overlooked allergens in the perioperative setting"
} | [
{
"companynumb": "DK-TEVA-594639ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFUROXIME"
},
"drugadditional": null,
"dr... |
{
"abstract": "Betamethasone is widely used to enhance fetal lung maturation in case of threatened preterm labour. Fetal heart rate variability is one of the most important parameters to assess in fetal monitoring, since it is a reliable indicator for fetal distress.\n\n\n\nTo describe the effect of betamethasone on fetal heart rate variability, by applying spectral analysis on non-invasive fetal electrocardiogram recordings.\n\n\n\nProspective cohort study.\n\n\n\nPatients that require betamethasone, with a gestational age from 24 weeks onwards.\n\n\n\nFetal heart rate variability parameters on day 1, 2, and 3 after betamethasone administration are compared to a reference measurement.\n\n\n\nFollowing 68 inclusions, 12 patients remained with complete series of measurements and sufficient data quality. During day 1, an increase in absolute fetal heart rate variability values was seen. During day 2, a decrease in these values was seen. All trends indicate to return to pre-medication values on day 3. Normalised high- and low-frequency power show little changes during the study period.\n\n\n\nThe changes in fetal heart rate variability following betamethasone administration show the same pattern when calculated by spectral analysis of the fetal electrocardiogram, as when calculated by cardiotocography. Since normalised spectral values show little changes, the influence of autonomic modulation seems minor.",
"affiliations": "Department of Obstetrics and Gynaecology, Máxima Medical Centre, Veldhoven, The Netherlands. Electronic address: kimverdurmen@live.nl.;Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.;Department of Obstetrics and Gynaecology, Máxima Medical Centre, Veldhoven, The Netherlands.;Department of Obstetrics and Gynaecology, Máxima Medical Centre, Veldhoven, The Netherlands.;Department of Obstetrics and Gynaecology, Máxima Medical Centre, Veldhoven, The Netherlands.;MMC Academy, Máxima Medical Centre, Veldhoven, The Netherlands.;Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.;Department of Obstetrics and Gynaecology, Máxima Medical Centre, Veldhoven, The Netherlands.;Department of Obstetrics and Gynaecology, Máxima Medical Centre, Veldhoven, The Netherlands; Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.",
"authors": "Verdurmen|Kim M J|KMJ|;Warmerdam|Guy J J|GJJ|;Lempersz|Carlijn|C|;Hulsenboom|Alexandra D J|ADJ|;Renckens|Joris|J|;Dieleman|Jeanne P|JP|;Vullings|Rik|R|;van Laar|Judith O E H|JOEH|;Oei|S Guid|SG|",
"chemical_list": "D001623:Betamethasone",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.earlhumdev.2018.02.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0378-3782",
"issue": "119()",
"journal": "Early human development",
"keywords": "Betamethasone; Corticosteroid; Fetal electrocardiogram; Fetal heart rate variability",
"medline_ta": "Early Hum Dev",
"mesh_terms": "D001341:Autonomic Nervous System; D001623:Betamethasone; D004562:Electrocardiography; D005260:Female; D006340:Heart Rate, Fetal; D006801:Humans; D007752:Obstetric Labor, Premature; D011247:Pregnancy; D012016:Reference Values",
"nlm_unique_id": "7708381",
"other_id": null,
"pages": "8-14",
"pmc": null,
"pmid": "29505915",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The influence of betamethasone on fetal heart rate variability, obtained by non-invasive fetal electrocardiogram recordings.",
"title_normalized": "the influence of betamethasone on fetal heart rate variability obtained by non invasive fetal electrocardiogram recordings"
} | [
{
"companynumb": "NL-MYLANLABS-2018M1048063",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIFEDIPINE"
},
"drugadditional": "3",
... |
{
"abstract": "The subject of the work included 41 cases of death in which amphetamine was involved as the direct or indirect cause. Identification and determination of xenobiotics in blood samples collected from post-mortem cases were performed by high-performance liquid chromatography coupled with tandem mass spectrometry with electrospray ionisation (HPLC-ESI-MS-MS). Only for two cases was the cause of death amphetamine poisoning. In most of the investigated cases the death was caused by poisoning due to complex amphetamine and other psychoactive substances (e.g. opiates, benzodiazepines, cocaine). In other cases, multi-organ damage (fall from a height, traffic accident), a puncture wound and wound incised, drowning, or asphyxiation by hanging were reported. It can be explained as risky, murderous, or suicidal actions of people who were under the influence of amphetamines. The presented paper focuses on the interpretation of amphetamine concentration in blood samples from the perspective of direct or indirect cause of death.",
"affiliations": "Karol Kula, Chair and Department of Forensic Medicine, Jagiellonian University Medical College, Grzegórzecka 16, 31-531 Krakow, Poland, e-mail: karol.kula@uj.edu.pl.",
"authors": "Kula|K|K|;Rojek|S|S|;Maciów-Głąb|M|M|;Kopacz|P|P|;Kłys|M|M|",
"chemical_list": "D000697:Central Nervous System Stimulants; D000661:Amphetamine",
"country": "Poland",
"delete": false,
"doi": "10.5114/amsik.2014.47746",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0324-8267",
"issue": "64(2)",
"journal": "Archiwum medycyny sadowej i kryminologii",
"keywords": null,
"medline_ta": "Arch Med Sadowej Kryminol",
"mesh_terms": "D000661:Amphetamine; D001237:Asphyxia; D001344:Autopsy; D000697:Central Nervous System Stimulants; D062787:Drug Overdose; D006708:Homicide; D006801:Humans; D013405:Suicide",
"nlm_unique_id": "1260766",
"other_id": null,
"pages": "76-101",
"pmc": null,
"pmid": "25574941",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Medico-legal aspect of amphetamine-related deaths.",
"title_normalized": "medico legal aspect of amphetamine related deaths"
} | [
{
"companynumb": "PL-ARBOR PHARMACEUTICALS, LLC-PL-2017ARB000997",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHETAMINE SULFATE"
},
... |
{
"abstract": "Delayed onset heparin induced thrombocytopenia (HIT), is characterized by a late nadir due to persistent platelet-activating IgG antibodies. It typically begins or worsens 5 or more days after heparin is discontinued with complications such as thrombosis up to 3 weeks after exposure to heparin.1-3 In 50% of cases, the platelet count can decrease to very low numbers (<20 000/μL), which is not usual for typical HIT. Here we report 2 cases of post-operative delayed onset HIT manifesting as severe thrombocytopenia that persisted despite cessation of heparin and initiation of argatroban. Key Clinical Question: Is intravenous immunoglulin beneficial in severe refractory delayed-onset HIT?",
"affiliations": "Department of Internal Medicine Medstar Washington Hospital Center Washington DC USA.;Department of Hematology/Oncology Medstar Washington Hospital Center Washington DC USA.;Department of Internal Medicine Medstar Washington Hospital Center Washington DC USA.;Department of Hematology/Oncology Medstar Washington Hospital Center Washington DC USA.;Department of Hematology/Oncology Medstar Washington Hospital Center Washington DC USA.;Department of Hematology/Oncology Medstar Washington Hospital Center Washington DC USA.",
"authors": "Doucette|Kimberley|K|;DeStefano|Christin B|CB|;Jain|Natasha A|NA|;Cruz|Allan L|AL|;Malkovska|Vera|V|;Fitzpatrick|Kelly|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/rth2.12009",
"fulltext": "\n==== Front\nRes Pract Thromb HaemostRes Pract Thromb Haemost10.1002/(ISSN)2475-0379RTH2Research and Practice in Thrombosis and Haemostasis2475-0379John Wiley and Sons Inc. Hoboken 10.1002/rth2.12009RTH212009Case ReportOnline‐only ArticlesCase ReportTreatment of refractory delayed onset heparin‐induced thrombocytopenia after thoracic endovascular aortic repair with intravenous immunoglobulin (IVIG) Doucette Kimberley MSc, MDkimberley.doucette@medstar.net \n1\nDeStefano Christin B. MD\n2\nJain Natasha A. MD\n1\nCruz Allan L. MD\n2\nMalkovska Vera MD\n2\nFitzpatrick Kelly MD\n2\n\n1 \nDepartment of Internal Medicine\nMedstar Washington Hospital Center\nWashington\nDC\nUSA\n\n2 \nDepartment of Hematology/Oncology\nMedstar Washington Hospital Center\nWashington\nDC\nUSA\n* Correspondence\n\nKimberley Doucette, Department of Internal Medicine, Medstar Washington Hospital Center, Washington, DC, USA.\n\nEmail: kimberley.doucette@medstar.net\n19 6 2017 7 2017 1 1 10.1002/rth2.2017.1.issue-1134 137 01 2 2017 05 5 2017 © 2017 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\n\nEssentials\n\nDelayed‐onset heparin‐induced thrombocytopenia can lead to severe thrombocytopenia in the setting of recent major vascular surgery.\n\nIntravenous immunoglobulin (IVIG) can be used as a supplementary treatment when platelet count fails to improve with conventional treatment.\n\nWhen platelet counts are severely low, benefits of using IVIG can outweigh the risks of thromboembolic events.\n\n\n\n\n\n\n\nDelayed onset heparin induced thrombocytopenia (HIT), is characterized by a late nadir due to persistent platelet‐activating IgG antibodies. It typically begins or worsens 5 or more days after heparin is discontinued with complications such as thrombosis up to 3 weeks after exposure to heparin.1–3 In 50% of cases, the platelet count can decrease to very low numbers (<20 000/μL), which is not usual for typical HIT. Here we report 2 cases of post‐operative delayed onset HIT manifesting as severe thrombocytopenia that persisted despite cessation of heparin and initiation of argatroban. Key Clinical Question: Is intravenous immunoglulin beneficial in severe refractory delayed‐onset HIT?\n\nheparinimmunoglobulins, intravenousthrombocytopeniathrombosis source-schema-version-number2.0component-idrth212009cover-dateJuly 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:25.07.2018\n\n\nDoucette \nK \n, \nDeStefano \nCB \n, \nJain \nNA \n, \nCruz \nAL \n, \nMalkovska \nV \n, \nFitzpatrick \nK \n. Treatment of refractory delayed onset heparin‐induced thrombocytopenia after thoracic endovascular aortic repair with intravenous immunoglobulin (IVIG) . Res Pract Thromb Haemost . 2017 ;1 :134 –137 . 10.1002/rth2.12009\n==== Body\n1 INTRODUCTION\nPatients with type II immune mediated heparin‐induced thrombocytopenia (HIT) develop antibodies to platelet factor 4 (PF4) and develop a clinical syndrome characterized by a drop in platelet count and a prothrombotic state causing venous or arterial thrombosis.1, 2 Delayed‐onset HIT is usually suspected when the platelet count fall begins after stopping heparin. Delayed‐onset HIT is also suspected with worsening thrombocytopenia after heparin cessation and is considered an “autoimmune‐like HIT”.3, 4, 5, 6 The platelet count nadir usually occurs between 10 and 17 days post‐immunizing heparin exposure. In some cases, the thrombocytopenia can persist for several weeks. It is commonly reported after major surgical interventions.4, 6, 7 These patients are typically challenging to manage due to the persistence of their HIT antibodies and as such, their platelets remain low, leaving them at risk of thrombotic and bleeding complications. It is postulated that trauma and the inflammatory state prime an immune response toward the immunogenic cationic PF4+ anionic heparin complex.8 HIT commonly occurs postoperatively, likely due to the combined effect of the release of PF4 from activated platelets during surgery and the concomitant administration of heparin.6 As such, vascular and cardiac patients have higher rates of platelet factor‐4 heparin antibody seroconversion and HIT after large intraoperative doses of therapeutic heparin or prophylactic post‐operative heparin.2, 9, 10, 11 This case series aims to identify whether there is an indication for IVIG in patients with prolonged and severe thrombocytopenia not responding to conventional HIT treatments.\n\n2 CASE 1\nA 49‐year‐old female presented with acute new onset severe bilateral claudication and occluded bilateral popliteal and tibioperoneal arteries with a large thrombus along the anterior wall of the proximal to mid‐descending thoracic aorta. Heparin at 18 units/kg/hour was started and she underwent successful thromboembolectomies of both lower extremities and thoracic endovascular aortic aneurysm repair (TEVAR) with stent graft placement. Her arterial thrombi were thought to be precipitated by multiple risk factors, including the use of combined oral contraceptive pills, and heterozygosity for the prothrombin gene PG20210 mutation.\n\nOn hospital day 8, the patient's platelet count dropped from 243 000/μL to 122 000/μL with a positive clinical 4T score of 6. Heparin was stopped and an argatroban drip was started. Heparin‐induced antiplatelet antibodies and PF4 antibodies ELISA screen were positive at 2.79 OD and 95‐97% SRA at 0.1 and 0.5 IU/mL UFH, respectively. Despite changing heparin to argatroban, platelets continued to decline. The worsening thrombocytopenia despite being having stopped heparin suggested a diagnosis of delayed onset HIT. Intravenous immunoglobulin 1 g/kg/day and methylprednisolone 1 g/kg/day were given on days 11 and 12, when platelet count fell to 11 000/μL. On day 12, the patient was found to have a symptomatic catheter associated non‐occlusive right internal jugular deep vein thrombosis. The central catheter was not heparin coated.\n\nPlatelet count recovered to 81 000/μL on day 14, but began to decline again the following day (Figure 1). Repeat HIT studies on day 15 remained strongly positive by ELISA with an optic density of 3.14 and SRA of 91 and 100% with 0.1 and 0.5 IU/mL UFH, respectively. Repeat computed tomography angiography on day 15 showed an aortic endograft thrombus. Platelets nadired at 5000/μL on day 18, but recovered after another dose of IVIG, reaching 150 000/μL at discharge on day 20 (Figure 1).\n\nFigure 1 Platelet count trend with interventions versus days post heparin initiation for both cases\n\n3 CASE 2\nAn 84‐year‐old female presenting with acute chest and back pain was found to have a large descending aortic aneurysm with impending rupture. She underwent a TEVAR. Prophylactic unfractionated heparin was started. On postoperative day (POD) 9, the platelet count dropped to 81 000/μL. HIT was diagnosed with a 4T score of 7, positive HIT ELISA with an optical density of 2.805, and a positive SRA with 100% serotonin release at 0.1 and 0.5 IU/mL UFH. Heparin was discontinued and argatroban initiated. She was subsequently found to have new deep venous thromboses in the right internal jugular and right posterior tibial veins.\n\nThe platelet count continued to decline despite avoidance of heparin products. A platelet count of 31 000/μL triggered testing for DIC, which showed hyperfibrinolysis. A workup, performed 12 hours after holding argatroban, revealed a low fibrinogen level of 75 mg/dL and normal activity of factors VII, VIII and X. Mixing studies were negative, thus excluding the presence of a factor inhibitor. Due to intermittent epistaxis and hemoptysis, she received 2 units of fresh frozen plasma on POD 17. On POD 19, platelets nadired at 16 000/μL. Given this severe thrombocytopenia and prior bleeding manifestations, she was started on a 5‐day course of IVIG (1 g/kg/day) and methylprednisolone (1 g/kg/day) (Figure 1). Due to persistently low platelets (Figure 1), repeat HIT studies were performed on POD 22, revealing an optical density of 2.46 and positive SRA with 100% serotonin release at 0.1 and 0.5 IU/mL UFH. Her platelets began to recover by POD 26, at which time argatroban was switched to fondaparinux (off label treatment for HIT). Platelets further rose to above 100 000 upon follow‐up, one week later.\n\n4 DISCUSSION\n4.1 Clinical presentation of delayed HIT\nSevere thrombocytopenia is not typically seen in HIT, however it has been described in 50% of patients with delayed onset HIT.6 In these cases, platelet counts will usually recover slowly. There are also persistently high titers of platelet‐activating IgG induced by heparin as seen in this case (up to 20 days after heparin administration).6, 7 In a published case‐series of such patients, there was greater heparin‐dependent and independent platelet activation at serial dilutions seen in cases than in control patients with typical HIT. These delayed onset HIT patients were also found to have more thrombosis and other complications including disseminated intravascular coagulation (25% of cases).7 The strong activation of platelets seen in serologic testing even in the absence of therapeutic heparin is a characteristic feature of delayed onset HIT.5, 6 Although our laboratory did not perform serotonin release functional assays in the absence of heparin, our suspicion of delayed onset HIT remained elevated due to persistent HIT that worsened after heparin cessation.\n\n4.2 IVIG in the setting of delayed onset HIT\nAs soon as HIT is suspected, heparin should be discontinued and an alternative anticoagulant should be initiated. Alternative agents include direct thrombin inhibitors, namely argatroban and bivalirudin.12, 13 Guidance on the utilization of IVIG with HIT is scant; however, there are several reports of it being associated with successful results. Many of the published cases in the literature interestingly involve severe thrombocytopenia (below 25 000/μL) that was refractory to conventional therapy4, 9, 14, 15, 16, 17, which is suspicious for delayed onset HIT. Of particular interest, in 2014, Warkentin and Sheppard described a case where IVIG was used in a second lifetime episode of HIT after cardiac surgery with subsequent improvement in platelet counts after two rounds of IVIG, similar to our first case.9\n\n\nWe experienced success with using IVIG/methylprednisolone for delayed onset HIT, when platelet count severely dropped to below 20 000/μL during the postoperative period. Platelet counts began to improve the subsequent day, with one of our patients requiring additional IVIG after platelet count dropped again, due to persistence of antibodies. Case 1 did experience a catheter‐associated thrombosis and aortic endograft thrombosis after IVIG was initially infused. However, it is unclear whether these were recognized adverse reactions to IVIG versus HIT. Otherwise, we found no additional adverse reactions to systemic IVIG. Our cases support the growing evidence that IVIG is a helpful supplemental treatment to increase platelet count and interfere with activation of heparin‐PF4 antibodies in cases of severe persistent HIT, also supported through in vitro analyses.4, 18, 19 In these cases, the benefits of IVIG outweigh the thromboembolic risks. Methylprednisolone may also have provided a benefit, difficult to distinguish from IVIG.\n\n5 CONCLUSION\nFurther studies should investigate IVIG as an additional treatment to aid recovery of platelets when bleeding risk is high and while awaiting recovery from severe thrombocytopenia as a result of delayed onset HIT. Biologically, there is some interest in proposing IVIG as the treatment of delayed HIT due to persistent platelet‐activating IgG antibodies as the underlying cause, as was presumed in these cases. However, cases should be selected cautiously since IVIG can also increase thromboembolic risk.\n\nAUTHOR CONTRIBUTIONS\nK. Doucette: primary author, writing and interpretation. C.B. Destefano: writing, interpretation and editing. N.A. Jain: interpretation and editing. A.L. Cruz: interpretation editing. V. Malkovska: interpretation and editing. K. Fitzpatrick: interpretation and editing.\n\nRELATIONSHIP DISCLOSURES\nNone of the authors have any disclosures relevant to this paper.\n==== Refs\nREFERENCES\n1 \n\nWarkentin \nTE \n. Heparin‐induced thrombocytopenia: pathogenesis and management . Br J Haematol \n2003 ;121 :535 –55 .12752095 \n2 \n\nWarkentin \nTE \n, \nKelton \nJG \n. A 14‐year study of heparin‐induced thrombocytopenia . Am J Med \n1996 ;101 :502 –7 .8948273 \n3 \n\nRice \nL \n, \nAttisha \nWK \n, \nDrexler \nA \n, \nFrancis \nJL \n. Delayed‐onset heparin‐induced thrombocytopenia . Ann Intern Med \n2002 ;136 :210 –5 .11827497 \n4 \n\nTvito \nA \n, \nBakchoul \nT \n, \nRowe \nJM \n, \nGreinacher \nA \n, \nGanzel \nC \n. Severe and persistent heparin‐induced thrombocytopenia despite fondaparinux treatment . Am J Hematol \n2015 ;90 :675 –8 .25683147 \n5 \n\nWarkentin \nTE \n, \nGreinacher \nA \n. Management of heparin‐induced thrombocytopenia . Curr Opin Hematol \n2016 ;23 :462 –70 .27380556 \n6 \n\nKopolovic \nI \n, \nWarkentin \nTE \n. Progressive thrombocytopenia after cardiac surgery in a 67‐year‐old man . CMAJ \n2014 ;186 :929 –33 .24756626 \n7 \n\nWarkentin \nTE \n, \nKelton \nJG \n. Delayed‐onset heparin‐induced thrombocytopenia and thrombosis . Ann Intern Med \n2001 ;135 :502 –6 .11578153 \n8 \n\nLubenow \nN \n, \nHinz \nP \n, \nThomaschewski \nS \n, et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin‐induced thrombocytopenia . Blood \n2010 ;115 :1797 –803 .19965682 \n9 \n\nWarkentin \nTE \n, \nSheppard \nJA \n. Serological investigation of patients with a previous history of heparin‐induced thrombocytopenia who are reexposed to heparin . Blood \n2014 ;123 :2485 –93 .24516044 \n10 \n\nPouplard \nC \n, \nMay \nMA \n, \nIochmann \nS \n, et al. Antibodies to platelet factor 4‐heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low‐molecular‐weight heparin: clinical implications for heparin‐induced thrombocytopenia . Circulation \n1999 ;99 :2530 –6 .10330384 \n11 \n\nSelleng \nS \n, \nSelleng \nK \n, \nWollert \nHG \n, et al. Heparin‐induced thrombocytopenia in patients requiring prolonged intensive care unit treatment after cardiopulmonary bypass . J Thromb Haemost \n2008 ;6 :428 –35 .18088340 \n12 \n\nGreinacher \nA \n. Heparin‐induced thrombocytopenia . J Thromb Haemost \n2009 ;7 (suppl 1 ):9 –12 .19630757 \n13 \n\nWarkentin \nTE \n, \nPai \nM \n, \nSheppard \nJI \n, \nSchulman \nS \n, \nSpyropoulos \nAC \n, \nEikelboom \nJW \n. Fondaparinux treatment of acute heparin‐induced thrombocytopenia confirmed by the serotonin‐release assay: a 30‐month, 16‐patient case series . J Thromb Haemost \n2011 ;9 :2389 –96 .21883878 \n14 \n\nFrame \nJN \n, \nMulvey \nKP \n, \nPhares \nJC \n, \nAnderson \nMJ \n. Correction of severe heparin‐associated thrombocytopenia with intravenous immunoglobulin . Ann Intern Med \n1989 ;111 :946 –7 .2510573 \n15 \n\nGrau \nE \n, \nLinares \nM \n, \nOlaso \nMA \n, \nRuvira \nJ \n, \nSanchis \nJ \n. Heparin‐induced thrombocytopenia–response to intravenous immunoglobulin in vivo and in vitro . Am J Hematol \n1992 ;39 :312 –3 .1553962 \n16 \n\nWinder \nA \n, \nShoenfeld \nY \n, \nHochman \nR \n, \nKeren \nG \n, \nLevy \nY \n, \nEldor \nA \n. High‐dose intravenous gamma‐globulins for heparin‐induced thrombocytopenia: a prompt response . J Clin Immunol \n1998 ;18 :330 –4 .9793825 \n17 \n\nPadmanabhan \nA \n, \nJones \nCG \n, \nPechauer \nSM \n, et al. Intravenous immunoglobulin for treatment of severe refractory heparin‐induced thrombocytopenia . Chest \n2017 \n10.1016/j.chest.2017.03.050 .\n18 \n\nGreinacher \nA \n, \nLiebenhoff \nU \n, \nKiefel \nV \n, \nPresek \nP \n, \nMueller‐Eckhardt \nC \n. Heparin‐associated thrombocytopenia: the effects of various intravenous IgG preparations on antibody mediated platelet activation–a possible new indication for high dose i.v. IgG . Thromb Haemost \n1994 ;71 :641 –5 .8091393 \n19 \n\nLei \nBZ \n, \nShatzel \nJJ \n, \nSendowski \nM \n. Rapid and durable response to intravenous immunoglobulin in delayed heparin‐induced thrombocytopenia: a case report . Transfusion \n2017 ;57 :919 –23 .27943368\n\n",
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"journal": "Research and practice in thrombosis and haemostasis",
"keywords": "heparin; immunoglobulins, intravenous; thrombocytopenia; thrombosis",
"medline_ta": "Res Pract Thromb Haemost",
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"pages": "134-137",
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"pubdate": "2017-07",
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"references": "28427966;25683147;19630757;8091393;19965682;9793825;24516044;1553962;12752095;27380556;21883878;18088340;24756626;10330384;11578153;27943368;8948273;11827497;2510573",
"title": "Treatment of refractory delayed onset heparin-induced thrombocytopenia after thoracic endovascular aortic repair with intravenous immunoglobulin (IVIG).",
"title_normalized": "treatment of refractory delayed onset heparin induced thrombocytopenia after thoracic endovascular aortic repair with intravenous immunoglobulin ivig"
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"abstract": "BACKGROUND\nDefinitive chemoradiotherapy (dCRT) using cisplatin plus 5fluorouracil (CF) with radiation is considered the standard treatment for unresectable locally advanced T4 esophageal squamous cell carcinoma (ESCC). Recently, induction chemotherapy has received attention as an effective treatment strategy.\n\n\nMETHODS\nWe report a successful case of a 59-year-old female with unresectable locally advanced T4 ESCC treated by two additional courses of chemotherapy with CF after induction chemotherapy with docetaxel, cisplatin and fluorouracil (DCF) followed by dCRT. Initial esophagogastroduodenoscopy (EGD) detected a type 2 advanced lesion located on the middle part of the esophagus, with stenosis. Computed tomography detected the primary tumor with suspected invasion of the left bronchus and 90° of direct contact with the aorta, and upper mediastinal lymph node metastasis. Pathological findings from biopsy revealed squamous cell carcinoma. We initially performed induction chemotherapy using three courses of DCF, but the lesion was still evaluated unresectable after DCF chemotherapy. Therefore, we subsequently performed dCRT treatment (CF and radiation). After dCRT, prominent reduction of the primary tumor was recognized but a residual tumor with ulceration was detected by EGD. Since the patient had some surgical risk, we performed two additional courses of CF and achieved a clinically complete response. After 14 mo from last administration of CF chemotherapy, recurrence has not been detected by computed tomography and EGD, and biopsy from the scar formation has revealed no cancer cells.\n\n\nCONCLUSIONS\nWe report successful case with tumor remnants even after DCF and subsequent dCRT, for whom a complete response was finally achieved with two additional courses of CF chemotherapy. Additional CF chemotherapy could be one radical treatment option for residual ESCC after treatment with induction DCF followed by dCRT to avoid salvage surgery, especially for high-risk patients.",
"affiliations": "Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan. myura@ncc.go.jp.;Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara 2591193, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Radiology, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgical Pathology, Hiratsuka City Hospital, Kanagawa 2540065, Japan.;Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan.",
"authors": "Yura|Masahiro|M|;Koyanagi|Kazuo|K|;Hara|Asuka|A|;Hayashi|Keita|K|;Tajima|Yuki|Y|;Kaneko|Yasushi|Y|;Fujisaki|Hiroto|H|;Hirata|Akira|A|;Takano|Kiminori|K|;Hongo|Kumiko|K|;Yo|Kikuo|K|;Yoneyama|Kimiyasu|K|;Tamai|Yoshifumi|Y|;Dehari|Reiko|R|;Nakagawa|Motohito|M|",
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"doi": "10.12998/wjcc.v9.i12.2801",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i12.pg2801\n10.12998/wjcc.v9.i12.2801\nCase Report\nUnresectable esophageal cancer treated with multiple chemotherapies in combination with chemoradiotherapy: A case report\nYura M et al. Unresectable ESCC treated by combination of chemotherapy and dCRT\nYura Masahiro Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan. myura@ncc.go.jp\n\nKoyanagi Kazuo Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara 2591193, Japan\n\nHara Asuka Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nHayashi Keita Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nTajima Yuki Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nKaneko Yasushi Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nFujisaki Hiroto Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nHirata Akira Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nTakano Kiminori Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nHongo Kumiko Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nYo Kikuo Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nYoneyama Kimiyasu Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nTamai Yoshifumi Department of Radiology, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nDehari Reiko Department of Surgical Pathology, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nNakagawa Motohito Department of Surgery, Hiratsuka City Hospital, Kanagawa 2540065, Japan\n\nAuthor contributions: Yura M and Koyanagi K wrote this paper; Nakagawa M reviewed the manuscript; Tamai Y planned and performed radiation therapy; Dehari R contributed to pathological diagnosis; and all other members equally contributed to medical treatment.\n\nCorresponding author: Masahiro Yura, MD, Doctor, Surgeon, Department of Surgery, Hiratsuka City Hospital, 1-19-1, Minamihara, Hiratsuka-shi, Kanagawa 2540065, Japan. myura@ncc.go.jp\n\n26 4 2021\n26 4 2021\n9 12 28012810\n27 8 2020\n2 1 2021\n5 3 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nDefinitive chemoradiotherapy (dCRT) using cisplatin plus 5fluorouracil (CF) with radiation is considered the standard treatment for unresectable locally advanced T4 esophageal squamous cell carcinoma (ESCC). Recently, induction chemotherapy has received attention as an effective treatment strategy.\n\nCASE SUMMARY\n\nWe report a successful case of a 59-year-old female with unresectable locally advanced T4 ESCC treated by two additional courses of chemotherapy with CF after induction chemotherapy with docetaxel, cisplatin and fluorouracil (DCF) followed by dCRT. Initial esophagogastroduodenoscopy (EGD) detected a type 2 advanced lesion located on the middle part of the esophagus, with stenosis. Computed tomography detected the primary tumor with suspected invasion of the left bronchus and 90° of direct contact with the aorta, and upper mediastinal lymph node metastasis. Pathological findings from biopsy revealed squamous cell carcinoma. We initially performed induction chemotherapy using three courses of DCF, but the lesion was still evaluated unresectable after DCF chemotherapy. Therefore, we subsequently performed dCRT treatment (CF and radiation). After dCRT, prominent reduction of the primary tumor was recognized but a residual tumor with ulceration was detected by EGD. Since the patient had some surgical risk, we performed two additional courses of CF and achieved a clinically complete response. After 14 mo from last administration of CF chemotherapy, recurrence has not been detected by computed tomography and EGD, and biopsy from the scar formation has revealed no cancer cells.\n\nCONCLUSION\n\nWe report successful case with tumor remnants even after DCF and subsequent dCRT, for whom a complete response was finally achieved with two additional courses of CF chemotherapy. Additional CF chemotherapy could be one radical treatment option for residual ESCC after treatment with induction DCF followed by dCRT to avoid salvage surgery, especially for high-risk patients.\n\nUnresectable esophageal cancer\nInduction docetaxel, cisplatin and fluorouracil\nChemoradiotherapy\nComplete response\nAdditional chemotherapy\nCase report\n==== Body\nCore Tip: Salvage surgery after definitive chemoradiotherapy (dCRT) for T4 esophageal cancer is associated with a high incidence of surgery-related death and severe complication. In the present study, we have described the successful case of an unresectable locally advanced T4 esophageal squamous cell carcinoma treated by additional cisplatin plus 5fluorouracil chemotherapy after induction docetaxel, cisplatin and fluorouracil followed by dCRT. This case suggests that additional cisplatin plus 5fluorouracil chemotherapy could be one radical treatment option for residual esophageal squamous cell carcinoma after induction docetaxel, cisplatin and fluorouracil followed by dCRT to avoid salvage surgery, especially for high-risk patients.\n\nINTRODUCTION\n\nEsophageal cancer is the sixth most common cause of cancer deaths worldwide, according to statistics presented in 2018[1]. Esophageal squamous cell carcinoma (ESCC) often invades adjacent vital organs such as the trachea, bronchus, lungs and aorta. Approximately 15% of incidents of ESCC are clinically diagnosed at the T4 stage[2]. Standard treatment for unresectable ESCC without distant metastasis is definitive chemoradiotherapy (dCRT) with cisplatin (CDDP) plus 5fluorouracil [(5FU), combination denoted cisplatin plus 5-FU (CF)], using a total irradiation dose of 50.4 or 60 Gy[3,4]. A study by the Japan Clinical Oncology Group (JCOG9516), a multicenter phase II trial, demonstrated the efficacy of dCRT using CF for unresectable ESCC and reported a complete response rate (CR) of 15% and a 3-year survival rate of 23%[5]. On the other hand, among patients who fail to achieve CR, salvage esophagectomy is the only modality left that offers a chance for long-term survival[6,7]. However, previous studies have reported that salvage surgery after dCRT is associated with a high incidence of surgery-related death (8%-10.2%)[6,8,9]. In addition, not only is the R0 resection rate after dCRT not high but also the prognosis for patients who have failed R0 resection is unfavorable[6,7,10,11].\n\nRecently, there has been hope that chemotherapy combined with docetaxel (DTX) is a useful treatment for ESCC. Neoadjuvant chemotherapy with DTX, CDDP and 5FU (DCF) has demonstrated potential, with a pathological CR rate of 17% for resectable stage II/III ESCC[12]. Furthermore, a prospective multicenter phase I/II study revealed that induction chemotherapy with DCF followed by chemoradiotherapy showed efficacy for unresectable locally advanced ESCC[13]. In the present case, induction chemotherapy with DCF followed by dCRT did not result in a CR for an initially unresectable locally advanced T4 ESCC, but a CR was finally achieved with two additional courses of CF chemotherapy. No recurrence has been observed for more than 14 mo while maintaining the quality of life after the last chemotherapy. Combination of these treatment could be a useful treatment option for unresectable T4 ESCC.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 59-year-old female had symptoms of dysphagia.\n\nHistory of present illness\n\nThe patient complained of dysphagia for a month and visited a former doctor. Esophagogastroduodenoscopy (EGD) was performed and a tumor suspected of esophageal cancer was found in the middle part of the esophagus. After that, she was introduced to our hospital for the purpose of detailed medical examination and treatment.\n\nHistory of past illness\n\nThe patient had a history of hypertension, was a hepatitis B virus carrier, and had experienced a brain stem hemorrhage with sensory paralysis. Her surgical history included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peri-arterial lymph node dissection to treat endometrial cancer (endometrial adenocarcinoma, pT1bN0M0) 7 years previously. Six courses of adjuvant chemotherapy (paclitaxel + carboplatin) were prescribed after surgery. Six years ago, a squamous cell carcinoma of the oral tongue (pT1, ly0, v0) was partially resected. She is also a smoker (Brinkman index 800; 20 cigarettes/day × 40 years).\n\nPersonal and family history\n\nNo family history to note.\n\nPhysical examination\n\nThere were no notable abnormal findings related to esophageal cancer on physical examination, and surgical scars during total hysterectomy were found in the lower abdomen.\n\nLaboratory examinations\n\nLaboratory data revealed a hemoglobin level of 12.9 g/dL, white blood cell count of 5700 cells/µL and platelet count of 339 × 103/μL. The creatinine level was 0.54 mg/dL, total bilirubin level 0.4 mg/dL, direct bilirubin level 0.1 mg/dL, glutamic oxaloacetic transaminase level 15 IU/L, glutamic pyruvate transaminase level 7 IU/L, albumin level 3.8 g/dL, and hemoglobin A1c level 6.1%. Tumor marker levels of the carcinoembryonic antigen was 9.2 ng/mL and squamous cell carcinoma antigen was 7.5 ng/mL.\n\nEchocardiography showed almost normal cardiac function with moderate tricuspid regurgitation. Pulmonary function examination revealed vital capacity, 102.0% of predicted; forced expiratory volume in 1 s, 79.1% of predicted; forced expiratory volume in 1 s, 1.78 L.\n\nImaging examinations\n\nEGD was performed and detected an advanced type 2 lesion on the middle part of the esophagus, with stenosis (Figure 1A). Computed tomography (CT) detected the primary tumor (40.7 mm × 30.7 mm) with suspected invasion of the main left bronchus (Figure 2A), 90° of direct contact with the aorta (Figure 3A). The upper mediastinal lymph node was swollen (10.16 mm × 8.02 mm) and was suspected to be metastasis to the right recurrent nerve lymph node (#106recR, Figure 4A), and no distant metastasis was detected.\n\nFigure 1 Endoscopic findings. A: Initial endoscopic findings detected type 2 tumor located on the middle part of the esophagus; B: After 3 courses of induction docetaxel, cisplatin and fluorouracil chemotherapy. Primary tumor volume decreased; C: After subsequent definitive chemoradiotherapy. Esophagogastroduodenoscopy findings showed a prominent reduction of the primary tumor, with ulceration; D: Fourteen months after additional 2 courses cisplatin plus 5fluorouracil chemotherapy. Primary lesion maintained clinically and pathologically complete response.\n\nFigure 2 Computed tomography findings showing level of left bronchus. A: Initial computed tomography findings suspected to invasion to the left bronchus; B: After 3 courses of induction docetaxel, cisplatin and fluorouracil. Shrinkage of the tumor size was recognized but invasion of the left bronchus was still suspected; C: After subsequent definitive chemoradiotherapy. Primary tumor volume decreased; D: Fourteen months after additional 2 courses of cisplatin plus 5fluorouracil chemotherapy. Primary tumor has maintained shrinkage.\n\nFigure 3 Computerized tomography findings showing level of aorta. A: Initial computed tomography findings suspected to 90° of direct contact with the aorta, which defined as invasion to the aorta; B: After 3 courses of induction docetaxel, cisplatin and fluorouracil. Shrinkage of the tumor size was recognized but invasion of the aorta was still suspected; C: After subsequent definitive chemoradiotherapy. Primary tumor volume decreased; D: Fourteen months after additional 2 courses of cisplatin plus 5fluorouracil chemotherapy. Primary tumor has maintained shrinkage.\n\nFigure 4 Computed tomography findings showing #106recR lymph node. A: Initial computed tomography findings suspected swollen lymph node (10.16 mm × 8.02 mm); B: After 3 courses of induction docetaxel, cisplatin and fluorouracil. Slightly shrinkage of the lymph node size (8.01 mm × 6.69 mm) was recognized; C: After subsequent definitive chemoradiotherapy. #106recR lymph node did not change in size (8.31 mm × 7.59 mm); D: After additional 2 courses of cisplatin plus 5fluorouracil chemotherapy. #106recR lymph node could not be detected (Orange arrow; 106recR lymph node).\n\nFINAL DIAGNOSIS\n\nBiopsies were taken, and the histological examination led to a diagnosis of a squamous cell carcinoma. The clinical diagnosis was esophageal cancer Mt circ cType2 cT4bN1 (#106recR) M0 cStageIVA according to the Union for International Cancer Control TNM Classification of Malignant Tumors, eighth edition[14]. The lymph node station was defined according to the Japanese Classification of Esophageal Cancer, 11th Edition[15].\n\nTREATMENT\n\nFirst, a gastrostomy was created using an endoscope for the possibility of total occlusion when the tumor grew.\n\nInduction chemotherapy with DCF\n\nFive days after creating the gastrostomy, induction chemotherapy consisted of intravenous administration of DTX on day 1; infusion of CDDP on day 1; and continuous intravenous administration of 5FU on days 1-5. Oral prophylactic antibiotics with ciprofloxacin (200 mg × 3/d) were administered on days 5-15. This regimen was repeated for three courses. The first course was administered with a full dose of DCF (DTX: 70 mg/m2, CDDP: 70 mg/m2, 5FU: 750 mg/m2); the patient experienced grade 4 neutropenia, for which we used granulocyte-colony stimulating factor. The second and third courses of DCF were administered with the −1 Level of dose (DTX: 55 mg/m2, CDDP: 55 mg/m2, 5FU: 600 mg/m2). After three courses of DCF, the CT findings showed shrinkage of the tumor size (36.6 mm × 30.5 mm) but invasion of the left bronchus (Figure 2B) and aorta (Figure 3B) was still suspected. Thus, the lesion was still evaluated as unresectable. The #106recR lymph node had slightly shrunk (8.01 mm × 6.69 mm; Figure 4B). EGD findings also showed a decrease in the primary tumor volume (Figure 1B), and evaluation of the clinical efficacy of the chemotherapy was defined to be stable disease according to the Response Evaluation Criteria in Solid Tumors criteria version 1.0.\n\nDefinitive chemoradiotherapy with CF\n\nAfter induction DCF therapy, dCRT with CF was performed, consisting of concurrently administered CDDP on days 1 and 28, and 5FU on days 1-4 and 28-31. The first and second courses of CF were administered with 55 mg/m2 of CDDP and 550 mg/m2 of 5FU. Radiotherapy consisted of 60 Gy with a daily dose of 2 Gy delivered with 10 MV Xrays. Three-dimensional treatment planning with a CT stimulator was used. The pretreatment gross tumor volume was determined via CT and EGD. The clinical target volume included the gross tumor volume and a craniocaudal margin of 2.4 cm around the primary tumor. Swollen lymph node (#106recR) was designated as gross tumor volume node. Prophylactic irradiation of mediastinal lymph node areas was performed (Figure 5). The maximum irradiation of the spinal cord was 43 Gy, and the volume of lungs exposed to 20 Gy was set at 17.1%. In the second course of CF, grade 4 neutropenia and grade 3 anorexia were observed. After dCRT, EGD findings showed a prominent reduction of the primary tumor, with ulceration (Figure 1C). The lesion was not stained by iodine staining, and the pink color sign was positive. CT findings showed shrinkage of the primary tumor (23.5 mm × 25.1 mm) (Figure 2C and Figure 3C), which was evaluated to be a partial response. The #106recR lymph node did not change in size (8.31 mm × 7.59 mm; Figure 4C). CT also revealed pulmonary embolism and deep vein thrombosis of the left popliteal vein. We began administering direct oral anticoagulant.\n\nFigure 5 Chemoradiation planning. A: Swollen lymph node (#106recR) was designated as gross tumor volume node; B and C: The clinical target volume included the gross tumor volume and a craniocaudal margin of 2.4 cm around the primary tumor.\n\nAdditional CF chemotherapy\n\nConsidering of the patient’s status and of complication risks of salvage surgery after dCRT, we performed two additional courses of CF treatment, consisting of concurrent administration of CDDP on days 1 and 28, and of 5FU on days 1-5 and 28-32. The first course of CF was administered 4 wk after last irradiation with 50 mg/m2 of CDDP and 500 mg/m2 of 5FU, while the second course was administered with 40 mg/m2 and 400 mg/m2, respectively. After this additional CF, CT findings revealed tumor shrinkage and wall thickening, which was considered to be the effect of radiotherapy.\n\n#106recR lymph node had significantly shrunk and not be detected (Figure 4D). EGD findings revealed a scarred and flattened primary lesion and biopsy found no cancer cells. Positron emission tomography showed no accumulation and viability of the primary tumor or any metastasis were not indicated.\n\nAdverse events\n\nOur present case experienced grade 4 neutropenia in the first course of full-dose induction DCF and the second course of dCRT and grade 3 thromboembolic event. Adverse events was defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0[16].\n\nOUTCOME AND FOLLOW-UP\n\nSix months later, CT showed no remarkable change, and gadolinium scintigraphy did not produce any findings suggestive of malignant accumulation. Fourteen months after the last chemotherapy, CT and EGD showed no recurrence and maintained clinical CR (Figures 1D, 2D and 3D).\n\nPathological examination and classification\n\nBefore treatment, biopsy from the primary tumor revealed squamous cell carcinoma (Figure 6A). Fourteen months after the last chemotherapy, biopsy from the scarred primary lesion revealed no cancer cells (Figure 6B).\n\nFigure 6 Pathological examination, biopsy from primary lesion. A: Initial biopsy from primary tumor revealed squamous cell carcinoma (× 10). A proliferation of large atypical cells with swollen deep-stained nuclei was observed. A squamous cell carcinoma with a tendency toward keratinization, intercellular bridges, necrosis, and large atypical cells with bizarre nuclei were evident; B: Fourteen months after additional 2 courses of cisplatin plus 5fluorouracil chemotherapy, primary lesion has maintained pathologically negative for cancer (× 20). There is a small infiltration of inflammatory cells, but no obvious evidence of malignant cells.\n\nDISCUSSION\n\nIn the present study, we have described the successful case of an unresectable locally advanced T4 ESCC treated by additional CF chemotherapy after induction DCF followed by dCRT. The most characteristic point of this case is that additional CF chemotherapy can be an alternative radical treatment of residual ESCC for salvage surgery after induction DCF followed by dCRT, especially in high-risk patients.\n\nThe standard treatment for unresectable ESCC without distant metastasis is dCRT with CF, using a total irradiation dose of 50.4 or 60 Gy[3,4]. Previous multicenter clinical trials of JCOG (JCOG9516, JCOG0303) with concurrent chemoradiotherapy with CF in patients with ESCC with cT4 tumor or M1 Lymph node showed a CR rate of 1.4%-15%[5,17]. Recently, two high-volume centers reported that the CR rate after dCRT was 22.4%-29%[7,11]. While, salvage esophagectomy may be chosen as the treatment of residual or recurrent tumors after dCRT if the tumor is resectable. However, salvage esophagectomy after dCRT is associated with a high incidence rate of severe postoperative complications (22.9%-29%) and surgery-related death (8.6%-10%)[6,11]. Although some studies conversely described that the surgery-related mortality rate was zero[7,10], this discrepancy may be due to selection bias; thus, the indication for salvage surgery needs to be carefully determined. The Esophageal Cancer Practice Guidelines 2017, edited by the Japan Esophageal Society, weakly recommended against performing salvage surgery for T4 ESCC patients showing residual disease after dCRT[3,4].\n\nBooka et al[7] reported from their experience of salvage surgery for T4 ESCC that the 5-year overall survival (OS) following a CR after dCRT, salvage esophagectomy, and chemotherapy or best supportive care groups were 83.0%, 51.6%, and 1.3%, respectively. In addition, in the salvage group, R1/R2 resection was a significantly poor prognostic factor, for which the 3-year OS was 0%. Okamura et al[6] reported their experience regarding the role of salvage surgery after dCRT in 35 patients; the 5-year OS was 5.7% and all patients with incomplete resection died within 2 years. Considering the results of these previous studies, incomplete resection in salvage surgery not only impairs quality of life but also fails to improve the prognosis. Therefore, we should select good candidates for salvage surgery after dCRT. Several studies have described the risk factors for incomplete resection: (1) Patients with a tumor in the upper thoracic esophagus were up to 50% more likely to undergo incomplete (R1/R2) resection[7]; and (2) Patients with a tumor evaluated T3 or deeper after dCRT were also up to 55.2% likely to undergo incomplete resection[6]. In our present case, the tumor was located on middle part of the esophagus and remnant tumor was estimated less than T2 after dCRT, therefore salvage surgery may have been the one option if the patient was adequately tolerated for surgery.\n\nRecently, induction chemotherapy has become another important treatment strategy for unresectable ESCC. Satake et al[13] conducted a phase I/II trial of induction chemotherapy with DCF followed by dCRT using CF with 60 Gy radiotherapy in patients with unresectable locally advanced ESCC. The CR rate was 39.4% and the 1- and 3-year OS rates were 78.8% and 40.4%, respectively, and 8 out of 33 patients underwent salvage surgery, with 5 patients achieving curative resection (62.5%; 5/8). Yokota et al[18] conducted a phase II trial of induction chemotherapy using DCF for patients with unresectable locally advanced ESCC. After induction chemotherapy, patients whose cancer was converted to being resectable received conversion surgery, and patients whose cancer remained unresectable received dCRT. The overall rate of R0 resection was 39.6% and the 1-year OS rate was 67.9% across all patients. Four of 17 patients (23.5%) who completed dCRT achieved a CR without conversion surgery.\n\nIn our present case, the lesion was evaluated to be stable disease and unresectable after three courses of induction DCF. However, after dCRT, prominent tumor volume reduction was observed and evaluated to be partial response. Satake et al[13] reported in their phase II study that of 13 patients who had no response after induction DCF, 2 achieved a clinical CR and 4 achieved a clinical partial response after subsequent dCRT. Thus, a shift in strategy to dCRT might also be effective for non-responders to induction DCF chemotherapy.\n\nThe most characteristic treatment strategy in this case is that we chose additional CF chemotherapy, not salvage surgery, for residual ESCC after induction DCF followed by dCRT, considering the patient’s status such as histories of endometrial cancer, tongue cancer, brainstem hemorrhage and hepatitis B virus. Although it is unknown whether additional CF is superior to salvage surgery, it was reported that salvage esophagectomy patients had a significantly worse OS rate than CR patients without surgery[7]. Thus, avoiding salvage surgery by combining additional chemotherapy after chemoradiation to achieve a CR may be useful treatment strategy. In fact, in this case, our patient has maintained a good quality of life and a CR for more than 14 mo. There is also no clear evidence of efficacy in additional chemotherapy after definitive chemoradiotherapy, however previous large-scale trials of dCRT for esophageal cancer included two courses of additional chemotherapy[19-22], therefore the Japanese guideline weakly recommend additional chemotherapy after dCRT[3]. We think that even after induction DCF and subsequent dCRT, additional CF could be useful treatment option to achieve definitive cure, especially for high-risk patients of salvage surgery.\n\nSome limitations of this study should be discussed. First, we initially chose induction DCF chemotherapy, however, it is unclear whether this is superior to dCRT, because there is a lack of direct comparative trials. Currently, the JCOG is conducting a phase III trial (JCOG1510) comparing induction chemotherapy using DCF followed by conversion surgery with dCRT in patients with unresectable locally advanced ESCC (UMIN000031165). Second, the observation period after the additional CF chemotherapy was only 14 mo, thus, we should continue to check for recurrence during additional follow-up visits.\n\nCONCLUSION\n\nWe report a successful case with tumor remnants even after docetaxel, cisplatin and fluorouracil followed by definitive chemoradiotherapy, for whom a complete response rate was finally achieved with two additional courses of CF chemotherapy. Especially for high-risk patients, additional CF chemotherapy could be one radical treatment option for residual esophageal squamous cell carcinoma after treatment with induction docetaxel, cisplatin and fluorouracil followed by definitive chemoradiotherapy to avoid salvage surgery.\n\nInformed consent statement: Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflict-of-interest statement: All authors declare no conflicts of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: August 27, 2020\n\nFirst decision: December 20, 2020\n\nArticle in press: March 5, 2021\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: Japan\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C\n\nGrade D (Fair): D\n\nGrade E (Poor): 0\n\nP-Reviewer: Cai ZZ, Li LW S-Editor: Zhang L L-Editor: A P-Editor: Wang LL\n==== Refs\n1 Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 394 424 30207593\n2 Tachimori Y Ozawa S Numasaki H Ishihara R Matsubara H Muro K Oyama T Toh Y Udagawa H Uno T Registration Committee for Esophageal Cancer of the Japan Esophageal Society Comprehensive Registry of Esophageal Cancer in Japan, 2010 Esophagus 2017 14 189 214 28725168\n3 Kitagawa Y Uno T Oyama T Kato K Kato H Kawakubo H Kawamura O Kusano M Kuwano H Takeuchi H Toh Y Doki Y Naomoto Y Nemoto K Booka E Matsubara H Miyazaki T Muto M Yanagisawa A Yoshida M Esophageal cancer practice guidelines 2017 edited by the Japan Esophageal Society: part 1 Esophagus 2019 16 1 24 30171413\n4 Kitagawa Y Uno T Oyama T Kato K Kato H Kawakubo H Kawamura O Kusano M Kuwano H Takeuchi H Toh Y Doki Y Naomoto Y Nemoto K Booka E Matsubara H Miyazaki T Muto M Yanagisawa A Yoshida M Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2 Esophagus 2019 16 25 43 30171414\n5 Ishida K Ando N Yamamoto S Ide H Shinoda M Phase II study of cisplatin and 5-fluorouracil with concurrent radiotherapy in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG)/Japan Clinical Oncology Group trial (JCOG9516) Jpn J Clin Oncol 2004 34 615 619 15591460\n6 Okamura A Hayami M Kozuki R Takahashi K Toihata T Imamura Y Mine S Watanabe M Salvage esophagectomy for initially unresectable locally advanced T4 esophageal squamous cell carcinoma Esophagus 2020 17 59 66 31595397\n7 Booka E Haneda R Ishii K Kawakami T Tsushima T Yasui H Onoe T Ogawa H Tsubosa Y Appropriate Candidates for Salvage Esophagectomy of Initially Unresectable Locally Advanced T4 Esophageal Squamous Cell Carcinoma Ann Surg Oncol 2020 27 3163 3170 32314159\n8 Tachimori Y Kanamori N Uemura N Hokamura N Igaki H Kato H Salvage esophagectomy after high-dose chemoradiotherapy for esophageal squamous cell carcinoma J Thorac Cardiovasc Surg 2009 137 49 54 19154902\n9 de Manzoni G Pedrazzani C Pasini F Bernini M Minicozzi AM Giacopuzzi S Grandinetti A Cordiano C Chemoradiotherapy followed by surgery for squamous cell carcinoma of the thoracic esophagus with clinical evidence of adjacent organ invasion J Surg Oncol 2007 95 261 266 17323341\n10 Takeuchi M Kawakubo H Mayanagi S Yoshida K Irino T Fukuda K Nakamura R Wada N Takeuchi H Kitagawa Y The Benefits of Docetaxel Plus Cisplatin and 5-Fluorouracil Induction Therapy in Conversion to Curative Treatment for Locally Advanced Esophageal Squamous Cell Carcinoma World J Surg 2019 43 2006 2015 30972432\n11 Sugawara K Yagi K Okumura Y Nishida M Aikou S Yamashita H Seto Y Long-term outcomes of multimodal therapy combining definitive chemoradiotherapy and salvage surgery for T4 esophageal squamous cell carcinoma Int J Clin Oncol 2020 25 552 560 31828451\n12 Hara H Tahara M Daiko H Kato K Igaki H Kadowaki S Tanaka Y Hamamoto Y Matsushita H Nagase M Hosoya Y Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma Cancer Sci 2013 104 1455 1460 23991649\n13 Satake H Tahara M Mochizuki S Kato K Hara H Yokota T Kiyota N Kii T Chin K Zenda S Kojima T Bando H Yamazaki T Iwasa S Honma Y Hamauchi S Tsushima T Ohtsu A A prospective, multicenter phase I/II study of induction chemotherapy with docetaxel, cisplatin and fluorouracil (DCF) followed by chemoradiotherapy in patients with unresectable locally advanced esophageal carcinoma Cancer Chemother Pharmacol 2016 78 91 99 27193097\n14 Brierley JD Gospodarowicz MK Wittekind C TNM classification of malignant tumors: International union against cancer. 8th ed. Oxford: Wiley, 2017\n15 Japan Esophageal Society Japanese Classification of Esophageal Cancer, 11th Edition: part I Esophagus 2017 14 1 36 28111535\n16 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0. November 27, 2017 [cited 4 March 2021]. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\n17 Shinoda M Ando N Kato K Ishikura S Kato H Tsubosa Y Minashi K Okabe H Kimura Y Kawano T Kosugi S Toh Y Nakamura K Fukuda H Japan Clinical Oncology Group Randomized study of low-dose vs standard-dose chemoradiotherapy for unresectable esophageal squamous cell carcinoma (JCOG0303) Cancer Sci 2015 106 407 412 25640628\n18 Yokota T Kato K Hamamoto Y Tsubosa Y Ogawa H Ito Y Hara H Ura T Kojima T Chin K Hironaka S Kii T Kojima Y Akutsu Y Matsushita H Kawakami K Mori K Nagai Y Asami C Kitagawa Y Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer Br J Cancer 2016 115 1328 1334 27811857\n19 Cooper JS Guo MD Herskovic A Macdonald JS Martenson JA Jr Al-Sarraf M Byhardt R Russell AH Beitler JJ Spencer S Asbell SO Graham MV Leichman LL Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group JAMA 1999 281 1623 1627 10235156\n20 Minsky BD Pajak TF Ginsberg RJ Pisansky TM Martenson J Komaki R Okawara G Rosenthal SA Kelsen DP INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose vs standard-dose radiation therapy J Clin Oncol 2002 20 1167 1174 11870157\n21 Kato K Muro K Minashi K Ohtsu A Ishikura S Boku N Takiuchi H Komatsu Y Miyata Y Fukuda H Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group (JCOG) Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for Stage II-III esophageal squamous cell carcinoma: JCOG trial (JCOG 9906) Int J Radiat Oncol Biol Phys 2011 81 684 690 20932658\n22 Ohtsu A Boku N Muro K Chin K Muto M Yoshida S Satake M Ishikura S Ogino T Miyata Y Seki S Kaneko K Nakamura A Definitive chemoradiotherapy for T4 and/or M1 Lymph node squamous cell carcinoma of the esophagus J Clin Oncol 1999 17 2915 2921 10561371\n\n",
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"journal": "World journal of clinical cases",
"keywords": "Additional chemotherapy; Case report; Chemoradiotherapy; Complete response; Induction docetaxel, cisplatin and fluorouracil; Unresectable esophageal cancer",
"medline_ta": "World J Clin Cases",
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"nlm_unique_id": "101618806",
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"pages": "2801-2810",
"pmc": null,
"pmid": "33969062",
"pubdate": "2021-04-26",
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"title": "Unresectable esophageal cancer treated with multiple chemotherapies in combination with chemoradiotherapy: A case report.",
"title_normalized": "unresectable esophageal cancer treated with multiple chemotherapies in combination with chemoradiotherapy a case report"
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"abstract": "OBJECTIVE\nTo report an association between central serous chorioretinopathy (CSCR) and exogenous testosterone therapy.\n\n\nMETHODS\nThis is a retrospective case series from two institutions. Patients who presented with fluorescein angiography and optical coherence tomography findings consistent with CSCR were included. All patients were concurrently being treated with exogenous testosterone therapy and lacked other known risk factors for CSCR.\n\n\nRESULTS\nNine patients presented with CSCR after beginning exogenous testosterone therapy. Two patients stopped therapy with resolution of symptoms and subretinal fluid.\n\n\nCONCLUSIONS\nExogenous testosterone may be an independent risk factor for the development of CSCR.",
"affiliations": "*Associated Retinal Consultants, Royal Oak, Michigan; †Department of Ophthalmology, Weill Cornell Medical College, New York, New York; and ‡Department of Ophthalmology, Oakland University William Beaumont School of Medicine, Beaumont Eye Institute, Royal Oak, Michigan.",
"authors": "Nudleman|Eric|E|;Witmer|Matthew T|MT|;Kiss|Szilard|S|;Williams|George A|GA|;Wolfe|Jeremy D|JD|",
"chemical_list": "D000728:Androgens; D004396:Coloring Agents; D013739:Testosterone; D007208:Indocyanine Green",
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"journal": "Retina (Philadelphia, Pa.)",
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"medline_ta": "Retina",
"mesh_terms": "D000328:Adult; D000728:Androgens; D056833:Central Serous Chorioretinopathy; D004396:Coloring Agents; D005451:Fluorescein Angiography; D006801:Humans; D007208:Indocyanine Green; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D013739:Testosterone; D041623:Tomography, Optical Coherence; D014786:Vision Disorders; D014792:Visual Acuity",
"nlm_unique_id": "8309919",
"other_id": null,
"pages": "2128-32",
"pmc": null,
"pmid": "24946102",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Central serous chorioretinopathy in patients receiving exogenous testosterone therapy.",
"title_normalized": "central serous chorioretinopathy in patients receiving exogenous testosterone therapy"
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"companynumb": "US-ABBVIE-15P-163-1360600-00",
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"abstract": "Histologic transformation of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors. However, the SCLC transformation has also been observed in non.\nmutant NSCLC. In these cases, whether SCLC initially co-exists with NSCLC or originates from initial NSCLC remains to be determined.\nWhole exome sequencing was performed on 10 samples from 5 patients with SCLC transformation from lung adenocarcinoma (LUAD), a main subtype of NSCLC. Somatic mutations and copy number variations (CNVs) were analyzed to explore the differences between initial LUAD and transformed SCLC, as well as the origin of transformed SCLC.\nAfter SCLC transformation, the mutation spectrum changed, with decreased C>T and increased C>A. Compared with initial LUAD, the CNV burden of transformed SCLC was greatly increased (39.0 vs. 61.1, Wilcoxon P=0.4). The higher the CNV burden of LUAD, the shorter the time to SCLC transformation was observed to be; and the higher the CNV burden of transformed SCLC, the shorter the overall survival (OS) after transformation. Clonal evolution analysis showed different clonal components between initial LUAD and transformed SCLC.\nThe transformation of LUAD into SCLC may be promoted by CNV events rather than mutational events. CNV burden was associated with the time to SCLC transformation and with the OS of patients following SCLC transformation. Transformed SCLC did not evolve directly from the initial LUAD but branched off from LUAD before the time of initial diagnosis.",
"affiliations": "National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Shanghai Tongshu Biotechnology Co., Ltd, Shanghai, China.;National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Precision Medicine Lung Cancer Center, Konkuk University Medical Center and Department of Pulmonary Medicine, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-Gu, Seoul, 05030 Republic of Korea.;Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;University of Colorado Anschutz Cancer Center, Aurora, CO, USA.;National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.",
"authors": "Xie|Tongji|T|;Li|Yan|Y|;Ying|Jianming|J|;Cai|Weijing|W|;Li|Junling|J|;Lee|Kye Young|KY|;Ricciuti|Biagio|B|;Pacheco|Jose|J|;Xing|Puyuan|P|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/tlcr-20-1278",
"fulltext": "\n==== Front\nTransl Lung Cancer Res\nTransl Lung Cancer Res\nTLCR\nTranslational Lung Cancer Research\n2218-6751\n2226-4477\nAME Publishing Company\n\n33489804\ntlcr-09-06-2428\n10.21037/tlcr-20-1278\nOriginal Article\nWhole exome sequencing (WES) analysis of transformed small cell lung cancer (SCLC) from lung adenocarcinoma (LUAD)\nXie Tongji 1\nLi Yan 1\nYing Jianming 1\nCai Weijing 2\nLi Junling 1\nLee Kye Young 3\nRicciuti Biagio 4 5\nPacheco Jose 6\nXing Puyuan 1\n1 National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;\n2 Shanghai Tongshu Biotechnology Co., Ltd, Shanghai, China;\n3 Precision Medicine Lung Cancer Center, Konkuk University Medical Center and Department of Pulmonary Medicine, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-Gu, Seoul, 05030 Republic of Korea;\n4 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;\n5 Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138 Bologna, Italy;\n6 University of Colorado Anschutz Cancer Center, Aurora, CO, USA\nContributions: (I) Conception and design: T Xie, P Xing; (II) Administrative support: J Li; (III) Provision of study materials or patients: P Xing, Y Li; (IV) Collection and assembly of data: J Ying; (V) Data analysis and interpretation: T Xie, W Cai; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.\n\nCorrespondence to: Puyuan Xing. Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No 17 Panjiayuan Nanli, Chaoyang district, Beijing 100021, China. Email: xingpuyuan@cicams.ac.cn.\n12 2020\n12 2020\n9 6 24282439\n15 10 2020\n23 12 2020\n2020 Translational Lung Cancer Research. All rights reserved.\n2020\nTranslational Lung Cancer Research.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.\nBackground\n\nHistologic transformation of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors. However, the SCLC transformation has also been observed in non-\n\nEGFR\n\nmutant NSCLC. In these cases, whether SCLC initially co-exists with NSCLC or originates from initial NSCLC remains to be determined.\n\nMethods\n\nWhole exome sequencing was performed on 10 samples from 5 patients with SCLC transformation from lung adenocarcinoma (LUAD), a main subtype of NSCLC. Somatic mutations and copy number variations (CNVs) were analyzed to explore the differences between initial LUAD and transformed SCLC, as well as the origin of transformed SCLC.\n\nResults\n\nAfter SCLC transformation, the mutation spectrum changed, with decreased C>T and increased C>A. Compared with initial LUAD, the CNV burden of transformed SCLC was greatly increased (39.0 vs. 61.1, Wilcoxon P=0.4). The higher the CNV burden of LUAD, the shorter the time to SCLC transformation was observed to be; and the higher the CNV burden of transformed SCLC, the shorter the overall survival (OS) after transformation. Clonal evolution analysis showed different clonal components between initial LUAD and transformed SCLC.\n\nConclusions\n\nThe transformation of LUAD into SCLC may be promoted by CNV events rather than mutational events. CNV burden was associated with the time to SCLC transformation and with the OS of patients following SCLC transformation. Transformed SCLC did not evolve directly from the initial LUAD but branched off from LUAD before the time of initial diagnosis.\n\nKeywords:\n\nNext generation sequencing (NGS)\nsingle nucleotide variants (SNVs)\ncopy number variation (CNV) burden\nclonal evolution analysis\nprognostic predictor\n==== Body\npmcIntroduction\n\nHistologic transformation of EGFR-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) represents a rare mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs), occurring in 3–14% of EGFR-mutant NSCLCs (1). The phenomenon of SCLC transformation in TKI-resistant EGFR-mutant cancers has been identified in small retrospective series and case reports (2-10). The transformation of NSCLC to SCLC has also occasionally been observed in EGFR wild type NSCLC (9,10), raising the question of whether SCLC initially co-exists with NSCLC or rather originates from initial NSCLC.\n\nSeveral studies have been conducted to elucidate this mechanism. For instance, Niederst et al. (11) demonstrated that while the original EGFR mutation was maintained in transformed cancers, the expression of the EGFR protein was significantly diminished after transformation, thus rendering the transformed tumors unresponsive to EGFR TKI therapy. However, the mechanisms underlying low expression of EGFR in SCLC remain unknown. Oser et al. (12) suggested that, since every transformed SCLC tumor sample in their study had retained its original EGFR-activating mutation, transformed SCLCs are not independent de-novo cancers but a transformed phenotype, which is in contrast with the hypothesis that patients had tumors with combined histology at the time of initial diagnosis, with the SCLC component becoming dominant over time, following treatment with EGFR TKIs. Lee et al. (13) showed that the SCLC clone branched off from the founder clone early, in some cases even before initial clinical cancer diagnosis, and that NSCLCs prone to transformation may show both tumor protein p53 (TP53) and RB1 inactivation at initial diagnosis. Consistently, retrospective analyses have shown that concurrent RB1 and TP53 alterations at baseline define a unique subset of EGFR-mutant NSCLCs at increased risk of SCLC transformation, and poor clinical outcomes (1,14). A recent study reported the association between SCLC transformation and the resistance to ROS TKIs in a patient with ROS1 fusion-positive (ROS1+) lung cancer (15), in which WES was performed in order to define the clonal evolution of the transformed SCLC. However, the tumor tissue from the initial or ROS TKI-resistant LUAD was insufficient for WES, so the WES based clonal evolution analysis of the transformed SCLC from the preceding LUAD was unavailable. According to the findings that while the ROS1 fusion was retained throughout the evolutionary trajectory, its expression was lost, and the ROS1 G2032R resistance mutation previously detected in the ROS TKI-resistant LUAD was not identified in the transformed SCLC, the authors deduced that the transformed SCLC and the preceding LUAD shared a common clonal origin and had an early divergence.\n\nAgainst this background, we aimed to explore the genomic similarities and differences between initial lung adenocarcinoma (LUAD), the most common subtype of NSCLC and transformed SCLC, and to investigate the origin of transformed SCLC using clonal evolution analysis.\n\nWe present the following article in accordance with the MDAR checklist (available at http://dx.doi.org/10.21037/tlcr-20-1278).\n\nMethods\n\nPatient samples and clinical characteristics\n\nFive patients with transformed SCLC from NSCLC who underwent lung biopsy at the Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College between November 2013 and January 2019, were selected for this study. The study was approved by the ethics committee of the Cancer Hospital of the Chinese Academy of Medical Sciences (No. 18-102/1680). Written informed consent was obtained from all study participants. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). Whole exome sequencing was performed on samples collected from each patient at the time of initial LUAD diagnosis and at the time of transformed SCLC diagnosis (Shanghai Tongshu Biotechnology Co., Ltd, Shanghai, China).\n\nWe selected previously reported patients in the Chinese LUAD cohort who did not transform to SCLC until death as controls for this study (16), and finally 16 patients were included. Whole exome sequencing has been performed on the tumor samples from these patients. The basic clinical information was listed in Table S1.\n\nDNA extraction\n\nWe performed DNA extraction from serial thick sections cut from tumor tissue samples and control sections. The invasive tumor content was estimated by pathologists, to ensure more than 50% of cells were tumor cells. The DNA was isolated from the FFPE using the DNeasy Blood and Tissue Kit (69504, QIAGEN, Venlo, Netherlands).\n\nEGFR mutation analysis\n\nEGFR mutations were analyzed based on the principle of the amplification refractory mutation system (ARMS). Briefly, resected tumor samples were fixed in 10% neutral buffered formalin and embedded in paraffin wax. Extracted DNA was used for PCR with the Mx3000PtM (Stratagene, La Jolla, USA) using the EGFR 29 Mutations Detection Kit (Amoy Diagnostics, Xiamen, China).\n\nWhole exome sequencing\n\nTargeted capture pulldown and exon-wide libraries were created from native DNA using the xGen® Exome Research Panel (Integrated DNA Technologies, Inc., Skokie, Illinois, US) and TruePrep DNA Library Prep Kit V2 for Illumina (#TD501, Vazyme, Nanjing, China), and paired-end sequence data were generated using Illumina HiSeq machines with an average sequencing depth of 150× for controls and 320× for tumor tissues. The sequence data were aligned to the human reference genome (NCBI build 37) using Burrows-Wheeler Aligner (BWA), and polymerase chain reaction (PCR) duplicates were sorted and removed using sambamba.\n\nVariant calling pipeline\n\nSingle nucleotide variants (SNVs), insertions, and deletions were detected using Strelka2 with default parameters. Variants and polymorphisms were annotated using the Ensembl Variant Effect Predictor (VEP). A minimum of 20 reads covering mutated region and 5 reads supporting the variant allele are required for somatic SNV/indel calling. In contrast, sequencing depth need to be ≥20×, and reads supporting the variant <5 at the same site in the normal control sample. Variants with MAF >1% in the ExAC, gnomAD, and esp6500 databases were filtered out as common germline variants.\n\nTumor mutation burden\n\nThe tumor mutation burden (TMB) of a tumor sample is calculated by the number of non-synonymous somatic mutations (single nucleotide variants and small insertions/deletions) per mega-base in coding regions. We defined the non-synonymous somatic mutations as follows: firstly, select the mutations that appeared within the consensus coding sequence region designed by the CDS project; secondly, remove variant with variant count <3, allele frequency <5% or total depth <25; at last, filter out synonymous and splice region mutations, and retain only nonsynonymous mutations (missense, nonsense, insertions and deletions mutations).\n\nCopy number variation analysis\n\nSomatic copy number variations (CNVs) were analyzed using FACETS, and the resulting CNVs were used in further analysis. Recurrent CNVs were identified with GISTIC2.0. Circos were plotted using RCircos.\n\nIntratumoral heterogeneity\n\nIntratumoral heterogeneity (ITH) was evaluated based on two characteristics of ITH, the number of clones forming the tumor (ITH index) and clonal diversity (Shannon diversity index, SDI), according to the methods described previously (17).\n\nClonal evolution analysis\n\nPyClone was used to cluster subclones inferred from SNVs. With the clustering results used as input, the optimal tree solutions were obtained with the iterative version of citup. Then, the fish plot and phylogenetic tree of each patient were constructed with timescape.\n\nStatistical analysis\n\nAll visualizations were generated in the R statistical environment (v3.6.0) using ggpubr, maftools, pheatmap, copynumber and VennDiagram packages. T-test was applied to continuous and normal distribution data; and wilcoxon rank-sum test was applied to discrete variable or non-normal distribution data. P<0.05 was considered as statistical significance.\n\nData availability\n\nThe data that support the findings of this study are openly available from the Sequence Read Archive (SRA) at https://www.ncbi.nlm.nih.gov/Traces/study/?acc=PRJNA622410. Our scripts are available at https://github.com/Chitanda-Satou/BioinformaticsScripts. All other data are available upon reasonable request.\n\nResults\n\nClinicopathological characteristics\n\nFive patients who were initially given a diagnosis of advanced LUAD with canonical EGFR-activating mutation and underwent EGFR TKI treatment to achieve a favorable response were selected. The clinical characteristics of these patients are summarized in Table 1. Two patients (patients 1 and 3) were excluded from further analysis. For patient 1, the quality of the WES data was poor due to the degradation of adenocarcinoma DNA; for patient 3, normal tissue was unavailable because of the patient’s death. The clinical history of the three patients included in this study is presented in Figure 1. EGFR mutations were determined through amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). All patients harbored EGFR mutations at the time of LUAD diagnosis and maintained the same EGFR mutation at the time of SCLC diagnosis. For patients 2, 4, and 5, the time to SCLC transformation was 40.9, 16.0, and 56.2 months, respectively, and the overall survival (OS) after transformation was 9.7, 8.5, and >14.5 months, respectively (Table 1).\n\nTable 1 Clinicopathologic characteristics of patients with SCLC transformation from LUAD\n\nPatient ID\tSex\tAge\tActive smoking\tInitial histology\t\tTransformed histology\tTreatment before Transformation\tTime (months)\t\nHistology\tEGFR mutation\tHistology\tEGFR mutation\tTime of SCLC transformation\tOS after transformation\tTotal OS\t\nP1\tFemale\t60\tNever\tLUAD\tEx19Del\t\tSCLC\tEx19Del\tChemotherapy, gefitinib, icotinib, afatinib\t42.7\t20.7\t63.4\t\nP2\tFemale\t70\tNever\tLUAD\tEx19Del\t\tSCLC\tEx19Del\tIcotinib, afatinib\t40.9\t9.7\t50.6\t\nP3\tMale\t48\t20 yr\tLUAD\tEx19Del\t\tSCLC\tEx19Del\tChemotherapy, erlotinib\t11.4\t27.3\t38.7\t\nP4\tFemale\t33\tNever\tLUAD\tEx18G719X\t\tSCLC\tEx18G719X\tChemotherapy, gefitinib, afatinib, bevacizumab\t16.0\t8.5\t24.5\t\nP5\tMale\t73\tNever\tLUAD\tEx19Del\t\tSCLC\tEx19Del\tGefitinib, afatinib\t56.2\t>14.5\tAlive\t\nSCLC, small cell lung cancer; LUAD, lung adenocarcinoma.\n\nFigure 1 Clinical history of three patients with transformed small cell lung cancers (SCLCs). The staining method is hematoxylin-eosin (H&E) staining and the magnification is ×400. The timelines show the points of lung adenocarcinoma (LUAD) and SCLC tissue acquisitions, and the treatment history of the patients. Numbers indicate time (in months) from the diagnosis of LUAD. The arrows in the computed tomography images indicate LUAD or SCLC masses. EGFR, epidermal growth factor receptor.\n\nMutational landscape of initial LUAD and transformed SCLC\n\nTumor samples obtained at the time of initial LUAD diagnosis and at the time of transformed SCLC diagnosis for each patient were subjected to WES with an average sequencing depth of 320×. Matched DNA from normal lung tissue was used as germline DNA control. The number of nonsynonymous somatic mutations per sample ranged from 106 to 468. The distribution of substitutions showed a strong preference for C>T transitions that is consistent with cytidine deamination.\n\nAfter SCLC transformation, the mutation spectrum changed, with a decrease in the median proportion of C>T, from 55.8% to 33.3%, and an increase in the median proportion of C>A, from 12.7% to 25.0% (Figure 2A). The mutation spectrum of LUAD with or without SCLC transformation were different (Figure S1A). After SCLC transformation, TMB in patient 2 decreased slightly, but TMB in patient 4 and 5 remained unchanged. The TMB of LUAD and SCLC was 9.7 and 6.1 in patient 2, 1.5 and 1.7 in patient 4, and 1.3 and 1.7 mutations per Mb in patient 5, respectively (Figure 2B). The median TMB of LUAD with SCLC transformation (1.5 mutations/Mb) was comparable to LUAD without SCLC transformation (1.3 mutations/Mb, Table S2). Eleven known lung cancer driver genes (18) were detected in patients with SCLC transformation, among which TP53 and EGFR had a high mutation frequency (Figure 2C). Fifteen known lung cancer driver genes were detected in LUAD without SCLC transformation (Figure S1B). Only two driver genes, TP53 and EGFR, were shared by LUAD with or without SCLC transformation.\n\nFigure 2 Mutational landscape of initial lung adenocarcinoma (LUAD) and transformed small cell lung cancer (SCLC). (A) The mutation spectrum changed after SCLC transformation. (B) The tumor mutation burden (TMB). (C) Altered known lung cancer driver genes in each sample. Each row represents a gene, each column represents a sample, and colors represent types of mutations.\n\nNext, we investigated the most frequently mutated genes in this cohort. As shown in Figure S2, no specific mutations were observed in the transformed SCLC samples. Examination of the alterations in key pathways of typical LUAD (19) (Figure S3A) and de novo SCLC (20) (Figure S3B) revealed that the genes involved in these pathways were rarely mutated except for several recurrently mutated genes (including TP53 and EGFR); however, CNVs were ubiquitous in these genes.\n\nCNV profiles of initial LUAD and transformed SCLC\n\nCompared with that of initial LUAD, the CNV burden of transformed SCLC was significantly elevated in patient 2 (39.0 vs. 94.9) and patient 5 (14.0 vs. 61.1), but it was slightly decreased in patient 4 (44.1 vs. 27.6) (Figure 3A). The median CNV burden of transformed SCLC was higher than that of initial LUAD (39.0 vs. 61.1, Wilcoxon P=0.4). However, the weighted genome instability index (wGII) (21) was comparable between initial LUAD and transformed SCLC (Figure 3B). As shown in Figure 3C, in patients 2 and 5, CNVs were widespread throughout the entire genome of transformed SCLC compared with the initial LUAD, but fewer CNVs were observed in patient 4. Known lung cancer driver genes affected by CNVs are presented in Figure S4. Compared with LUAD without SCLC transformation, the median CNV burden of initial LUAD with SCLC transformation was higher (39.0 vs. 21.5, Wilcoxon P=0.36, Table S2).\n\nFigure 3 Copy number variant (CNV) profiles showed significant alterations in transformed SCLC. The CNV burden (A) and the weighted genome instability index (wGII) (B) of each patient. (C) Circos plot represents the genome-wide distribution density of each sample (in clockwise order). The outer ring of the plot shows the chromosomes. The central ring shows the driver genes located in the altered regions. The inner ring exhibits the CNV amplifications (red) and deletions (blue). LUAD, lung adenocarcinoma; SCLC, small cell lung cancer.\n\nClonal evolution analysis\n\nInitial LUAD and transformed SCLC were found to share a small proportion of nonsynonymous mutations, and there were over 60% unique mutations (Figure S5). Four genes, TP53, mucin-17 (MUC17), EGFR, and pumilio RNA binding family member 1 (PUM1), were frequently mutated in both initial LUAD and transformed SCLC (Figure S2). The intratumoral heterogeneity (ITH) index (Figure 4A) and Shannon diversity index (SDI) (Figure 4B) of transformed SCLC were higher than those of initial LUAD. Histograms of CCF distribution also showed transformed SCLC to have a higher ITH index (Figure S6).\n\nFigure 4 Clonal evolution analysis. The intratumoral heterogeneity (ITH) index (A) and Shannon diversity index (SDI) (B) of transformed SCLC was higher than that of initial LUAD. (C) Fish plots constructed by timescape. Colors indicate different clones. Driver genes detected in the clones are shown. LUAD, lung adenocarcinoma; SCLC, small cell lung cancer.\n\nThe clonal evolution analysis showed that the clonal components of initial LUAD and transformed SCLC were different. In patient 2, the LUAD was mainly composed of clones 2, 3, and 5, while the SCLC was mainly composed of clones 4, 6, and 7 (Figure 4C). The LUAD of patient 4 was mainly composed of clones 0 and 4, while the SCLC was mainly composed of clones 0, 3, and 6 (Figure 4C). In patient 5, the LUAD was mainly composed of clones 6 and 7, and the SCLC was mainly composed of clones 0 and 4 (Figure 4C). As shown, the major clones in the transformed SCLC did not originate from the major clones in the LUAD; rather, they originated from subclones generated before diagnosis. In all the three cases, mutations in TP53 occurred early in the tumorigenesis, and mutations in EGFR occurred relatively late. Other driver genes detected in the clones varied between the patients. These results suggest that LUAD and transformed SCLC originate from the same clone but the transformed SCLC clones do not originate directly from the major clones of the initial LUAD.\n\nCNV burden is associated with the prognosis of patients with transformed SCLC\n\nFor the three patients (patient 5, 2, 4) in this study, the transformation time from LUAD to SCLC was 56.2, 40.9, and 16 months, and the CNV burden of LUAD was 14.0, 39.0, and 44.1, respectively (Table 1, Figure 5A). Together with the result that showed higher CNV burden of initial LUAD with SCLC transformation than LUAD without SCLC transformation (Table S2), these results suggested that the higher the CNV burden, the shorter the time to transformation into SCLC. The OS of the patient 5, 2 and 4 after SCLC transformation was >14.5, 9.7, and 8.5 months, with a CNV burden of SCLC of 61, 94.9, and 27.6, respectively (Table 1, Figure 5B). Because of the small sample size (N=3) whether CNV burden of transformed SCLC is prognostic remains to be determined.\n\nFigure 5 Copy number variant (CNV) burden was associated with the prognosis of patients with transformed SCLC. (A) The association between CNV burden and the time to SCLC transformation from LUAD. (B) The association between CNV burden and OS after transformation to SCLC. LUAD, lung adenocarcinoma; SCLC, small cell lung cancer.\n\nDiscussion\n\nTransformation from LUAD into SCLC is a rare event in patients with lung cancer, and occurs in approximately 3–7% of EGFR-mutant NSCLC treated with TKIs. In this study we investigated the genomic correlates of SCLC transformation from 3 cases of EGFR-mutant LUAD. Although limited by the small sample size, our analysis provided some important insights into the genetic characteristics of transformed SCLC from initial LUAD.\n\nC>T transitions were predominant in all three patients included in our analysis, all of whom were never-smokers. This finding is consistent with a previous study in which C>T transitions were found to be predominant in never-smokers and former light smokers with lung cancer, whereas a predominance of C>A transversions was observed in smokers (22). C>T transitions are resulted from the deamination of cytosine to uracil. A recent study suggested that activation-induced cytidine deaminase hypermutation could serve as an early predictor of SCLC transformation (14). In our study, C>T transitions were decreased in transformed SCLC, while C>A transversions were increased. Cancers with enrichment of C>T transitions have been reported to exhibit low levels of chromosomal alterations, and cancers with a preponderance of C>A transversions have been observed to have significantly more copy number gains (23), which is consistent with our findings. We also observed a significantly higher CNV burden in transformed SCLC than in initial LUAD in patients with increased C>A transversions and decreased C>T transitions. However, compared with that of initial LUAD, the wGII of transformed SCLC did not change, which allowed us to conclude that genome instability was not the cause of the increase in CNVs. Moreover, patients 2 and 5 had more DDR gene alterations in their transformed SCLC than patient 4 whose CNV burden did not increase after transformation to SCLC, which indicates that incorrect repair of DNA damage may be the source of increased CNVs (24). It is not clear whether the hypothetical mechanism of SCLC transformation for non-smokers is applicable to smokers.\n\nThe origin of SCLC subclones is a question still in need of investigation. Several studies have suggested that EGFR-mutant lung cancers that develop in alveolar type II cells might have the potential to transform into SCLC (25-27). Lee et al. suggested that EGFR TKI-resistant SCLCs may branch out early from the LUAD clones, even before EGFR TKI treatment (13). Our results were consistent with the findings of Lee et al., suggesting that SCLC diverges early from LUAD. We also found TP53 mutation to be an early event in both LUAD and SCLC, while EGFR mutation occurred later.\n\nIn previous studies, deactivation of TP53 and RB1 has been reported to occur in the majority of transformed SCLCs (13). In our study, all three cases harbored TP53 mutations in both LUAD and SCLC, and one of the cases harbored RB1 mutations. Moreover, CNV loss of RB1 occurred in all but one of six samples. However, accumulating experimental evidence has demonstrated that while dual inactivation of RB and p53 is essential for SCLC lineage transformation in EGFR-mutant LUAD, it is not sufficient to induce this transformation alone, which suggests that additional factors are required (11). A retrospective study described the clinical outcomes of patients with EGFR-mutant transformed SCLCs. Among 67 patients, all maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations identified in SCLC samples were TP53 (79%, 38/48), RB1 (58%, 18/31), and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) (27%, 14/52) (1). MYC amplification and PIK3CA mutation have been proposed to potentially cooperate with RB/p53 loss to facilitate transformation, and specific epigenetic regulators may also provide the appropriate context for lineage reprogramming to occur (13). Park et al. (28) reported that loss of RB and inactivation of p53 combined with expression of myristoylated AKT1 and overexpression of MYC and B-cell lymphoma 2 (BCL2), leads to the development of aggressive SCLC. In our study, in transformed SCLCs, 100% [6/6] of samples had TP53 mutations, 33.3% [2/6] of samples had RB1 mutations, and 33.3% [3/6] of samples had PIK3CA mutations. We attempted to explore the genetic features of transformed SCLC, but no common mutations were found among the 3 cases. Our failure to determine the genetic features of transformed SCLC may mainly be attributed to the number of patients in this study, which was too small to identify common features.\n\nThe results of previous studies indicate that transformed SCLC takes on many features of de novo SCLC, including inactivation of the tumor suppressors RB and p53 in nearly all cases, similar gene expression profiles, including reduced or absent EGFR expression, and heightened sensitivity to BCL-2 family inhibition (11,29). However, a systematic review showed that current treatment strategies derived from de novo SCLC seemed to be largely inefficacious for transformed SCLC (30). Another previous study showed that few de novo SCLCs harbored EGFR mutations (12). From these observations, transformed SCLC may be genetically different from de novo SCLC.\n\nFurthermore, we found that the CNV burden of initial LUAD with SCLC transformation was higher than LUAD without SCLC transformation. There was an association between CNV burden and the prognosis of patients with transformed SCLC. We observed that the higher the CNV burden in the initial LUAD, the shorter the transformation time to SCLC, and the higher CNV burden in the transformed SCLC, the shorter the OS after SCLC transformation. Nevertheless, the value of CNV burden in predicting SCLC transformation has not been studied. In future studies, we will employ transcriptome and epigenome analysis to elucidate the causal relations between increased CNV burden and SCLC transformation.\n\nIn conclusion, we demonstrated that the transformed SCLC did not evolve directly from the initial LUAD but branched off from LUAD early. The CNV burden was associated with the time to SCLC transformation and with the OS of patients after SCLC transformation.\n\nSupplementary\n\nThe article’s supplementary files as\n\n10.21037/tlcr-20-1278 10.21037/tlcr-20-1278 10.21037/tlcr-20-1278\n\nAcknowledgments\n\nWe thank all participating subjects for their kind cooperation in this study and appreciate the academic support from AME Lung Cancer Collaborative Group.\n\nFunding: This work was sponsored by Shanghai Tongshu Biotechnology Co., Ltd.\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by the ethics committee of the Cancer Hospital of the Chinese Academy of Medical Sciences (No. 18-102/1680). Written informed consent was provided by all participants. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).\n\nReporting Checklist: The authors have completed the MDAR reporting checklist. Available at http://dx.doi.org/10.21037/tlcr-20-1278\n\nData Sharing Statement: Available at http://dx.doi.org/10.21037/tlcr-20-1278\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-1278). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Marcoux N Gettinger SN O'Kane G EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. J Clin Oncol 2019;37 :278-85. 10.1200/JCO.18.01585 30550363\n2 Zakowski MF Ladanyi M Kris MG , Memorial Sloan-Kettering Cancer Center Lung Cancer OncoGenome Group. EGFR mutations in small-cell lung cancers in patients who have never smoked. 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"journal": "Translational lung cancer research",
"keywords": "Next generation sequencing (NGS); clonal evolution analysis; copy number variation (CNV) burden; prognostic predictor; single nucleotide variants (SNVs)",
"medline_ta": "Transl Lung Cancer Res",
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"title": "Whole exome sequencing (WES) analysis of transformed small cell lung cancer (SCLC) from lung adenocarcinoma (LUAD).",
"title_normalized": "whole exome sequencing wes analysis of transformed small cell lung cancer sclc from lung adenocarcinoma luad"
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"abstract": "An 81-year-old man was admitted with upper abdominal pain and weight loss. Esophagogastroduodenoscopy revealed a large tumor located from the gastric angle to the body. Histological analysis of a biopsy revealed a moderately differentiated adenocarcinoma. Computed tomography revealed metastases in the liver and lung and the patient was subsequently diagnosed with metastatic advanced gastric cancer. He was treated with chemotherapy using S-1 (80 mg/m2) and cisplatin (CDDP) (60 mg/m2). Twenty-two months after chemotherapy, the gastric tumor, and the nodules in the liver and lung, had disappeared. We subsequently diagnosed a clinical complete response. The patient was treated with further S-1 monotherapy for 7 months after complete response assessment. He has lived for more than 7 years since the initial diagnosis without recurrence. Chemotherapy using S-1 and CDDP may be a potent strategy for improving survival in elderly patients with advanced gastric cancer.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School.",
"authors": "Kawagoe|Tetsuro|T|;Maruki|Yuta|Y|;Nagoya|Hiroyuki|H|;Kosugi|Yuki|Y|;Akimoto|Teppei|T|;Yamawaki|Hiroshi|H|;Kodaka|Yasuhiro|Y|;Shimpuku|Mayumi|M|;Ueki|Nobue|N|;Futagami|Seiji|S|;Miyake|Kazumasa|K|;Iwakiri|Katsuhiko|K|",
"chemical_list": null,
"country": "Japan",
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"doi": "10.1272/jnms.83.199",
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"issue": "83(5)",
"journal": "Journal of Nippon Medical School = Nippon Ika Daigaku zasshi",
"keywords": null,
"medline_ta": "J Nippon Med Sch",
"mesh_terms": "D000369:Aged, 80 and over; D016145:Endoscopy, Digestive System; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D013274:Stomach Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100935589",
"other_id": null,
"pages": "199-202",
"pmc": null,
"pmid": "27890894",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical Complete Response from Chemotherapy in an Elderly Patient with Metastatic Gastric Cancer: A Case Report.",
"title_normalized": "clinical complete response from chemotherapy in an elderly patient with metastatic gastric cancer a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1059109",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nLittle is known regarding the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) efficacy and safety in the elderly.\n\n\nOBJECTIVE\nConsecutive patients (n = 53) with ALK-positive advanced non-small cell lung cancer treated with an ALK TKI were identified through internal databases of three cancer centers and divided into groups A (< 65 years old; n = 34) and B (≥65 years old; n = 19). Progression-free survival (PFS), ALK TKI safety and overall survival (OS) were assessed. Uni- and multivariate PFS and OS analyses were performed.\n\n\nRESULTS\nCrizotinib, ceritinib, and alectinib were administered in 94 and 100%, 35 and 31%, 38 and 52% of patients in groups A and B, respectively. The median PFS (months) was 5.4 (95% CI, 3.4-12.4) and 5.6 (95% CI, 2.5-14.7) with crizotinib (log-rank 0.0009, p = 0.9), 4.7 (95% CI, 1.0-11.5) and 23.0 (95% CI, 0.8-27.7) with ceritinib (log-rank 0.44, p = 0.5), and 21.2 (95% CI, 1.2 to not reached, NR) and 5.6 (95% CI, 0.5 to NR) with alectinib (log-rank 0.53, p = 0.5) in groups A and B, respectively. The median OS (months) comprised 29.8 (95% CI, 21.0 to NR) and 25.1 (95% CI, 10.8-53.6) in groups A and B, respectively (log-rank 0.57, p = 0.4). Age affected neither PFS nor OS. 19 and 37%, 50 and 40%, and 0 and 0% of patients in groups A and B, treated with crizotinib, ceritinib, and alectinib, respectively, developed high-grade adverse events. The treatment discontinuation rate was 9 and 21%, 16 and 60%, 0 and 0% with crizotinib, ceritinib, and alectinib in groups A and B, respectively.\n\n\nCONCLUSIONS\nIn the elderly, crizotinib, ceritinib, and alectinib treatments are associated with similar efficacy but different safety profiles; alectinib is associated with a lower rate of high-grade adverse events and a lower treatment discontinuation rate.",
"affiliations": "Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Cancer Institute, Soroka University Medical Center, Beer-Sheva, Israel.;Oncology Department, Meir Medical Center, Kfar Sava, Israel.;Oncology Department, Meir Medical Center, Kfar Sava, Israel.;Statistical Consulting Unit, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.;Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.;Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Thoracic Cancer Service, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel, elizabeth.dudnik1603@gmail.com.",
"authors": "Bedas|Aseel|A|;Peled|Nir|N|;Maimon Rabinovich|Natalie|N|;Mishaeli|Moshe|M|;Shochat|Tzippy|T|;Zer|Alona|A|;Rotem|Ofer|O|;Allen|Aaron M|AM|;Bar|Jair|J|;Dudnik|Elizabeth|E|;|||",
"chemical_list": "D000970:Antineoplastic Agents; D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C586847:ceritinib; C582670:alectinib",
"country": "Netherlands",
"delete": false,
"doi": "10.1159/000499086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-5270",
"issue": "42(5)",
"journal": "Oncology research and treatment",
"keywords": "ALK inhibitors; Alectinib; Anaplastic lymphoma kinase; Ceritinib; Crizotinib; Lung cancer",
"medline_ta": "Oncol Res Treat",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D002227:Carbazoles; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D010880:Piperidines; D000077982:Progression-Free Survival; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; D055815:Young Adult",
"nlm_unique_id": "101627692",
"other_id": null,
"pages": "275-282",
"pmc": null,
"pmid": "30955009",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and Safety of ALK Tyrosine Kinase Inhibitors in Elderly Patients with Advanced ALK-Positive Non-Small Cell Lung Cancer: Findings from the Real-Life Cohort.",
"title_normalized": "efficacy and safety of alk tyrosine kinase inhibitors in elderly patients with advanced alk positive non small cell lung cancer findings from the real life cohort"
} | [
{
"companynumb": "IL-ROCHE-2304655",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALECTINIB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "A 61-year old male was referred to the Ophthalmology department because of decreased bilateral visual acuity. The patient had metastatic pancreatic adenocarcinoma and was being treated with gemcitabine+nab-paclitaxel. On examination, the patient presented best corrected visual acuities of 4/20 and 2/20 in the right and left eye, respectively. The optical coherence tomography revealed bilateral severe macular edema. Macular edema was considered secondary to nab-paclitaxel and the drug was discontinued. Three months after drug discontinuation, the patient presented best corrected visual acuities of 20/20 and 16/20 in the right and left eye, respectively, and normal fundoscopy. Macular edema is a very rare side effect of taxanes, and the etiopathology is still unknown. Edema is usually reversible upon discontinuation of the offending agent. Clinicians should be aware of this adverse effect of taxanes, and a high index of clinical suspicion is essential for diagnosis.",
"affiliations": "Departamento de Oftalmologia. Unidade Local de Saúde Matosinhos. Senhora da Hora. Portugal.;Departamento de Oftalmologia. Unidade Local de Saúde Matosinhos. Senhora da Hora. Portugal.;Departamento de Oftalmologia. Unidade Local de Saúde Matosinhos. Senhora da Hora. Portugal.;Departamento de Oftalmologia. Unidade Local de Saúde Matosinhos. Senhora da Hora. Portugal.",
"authors": "Alves Pereira|Sara|S|;Vale|Carolina|C|;Moreira|Jorge|J|;Sampaio|Filipa|F|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.13421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": null,
"journal": "Acta medica portuguesa",
"keywords": "Albumin-Bound Paclitaxel/adverse effects; Albumins/adverse effects; Macular Edema/chemically induced; Paclitaxel/adverse effects; Pancreatic Neoplasms/drug therapy",
"medline_ta": "Acta Med Port",
"mesh_terms": null,
"nlm_unique_id": "7906803",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34287143",
"pubdate": "2021-07-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Macular Cystoid Edema Induced by Nab-Paclitaxel.",
"title_normalized": "macular cystoid edema induced by nab paclitaxel"
} | [
{
"companynumb": "PT-MYLANLABS-2021M1054492",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "1",
... |
{
"abstract": "Paradoxical embolism is a kind of important pathogenesis of cardiocerebrovascular diseases. In our case, radiofrequency current catheter ablation was accomplished successfully in a 15-year-old girl who had been experiencing supraventricular tachycardia for 6 months. She presented with abrupt onset of left hemiplegia and loss of consciousness on the first postoperative day. An urgent cerebral computed tomography showed a hyperdense right middle cerebral artery. Transthoracic echocardiogram examination revealed an atrial septal defect (ASD), with the diameter measuring 39 mm. The case highly suggests that the issue of ASD should be resolved by either closed or prompt anticoagulant therapy, especially for patients who are planned to receive catheter manipulation.",
"affiliations": "Cardiovascular Department, No 117 Hospital of Chinese People's Liberation Army, Hangzhou, Zhejiang.;Cardiovascular Department, No 117 Hospital of Chinese People's Liberation Army, Hangzhou, Zhejiang.;Cardiovascular Department, No 117 Hospital of Chinese People's Liberation Army, Hangzhou, Zhejiang. Electronic address: wdn20150901@sina.com.",
"authors": "Chen|Xiang|X|;Zhu|Zhijun|Z|;Wu|Danning|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2017.05.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "26(9)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Cerebral infarction; complication; embolism; radiofrequency ablation",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000293:Adolescent; D017115:Catheter Ablation; D002533:Cerebral Angiography; D000072226:Computed Tomography Angiography; D004452:Echocardiography; D004562:Electrocardiography; D019320:Embolism, Paradoxical; D005260:Female; D006344:Heart Septal Defects, Atrial; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D020766:Intracranial Embolism; D013614:Tachycardia, Paroxysmal; D013617:Tachycardia, Supraventricular; D015912:Thrombolytic Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "e189-e191",
"pmc": null,
"pmid": "28733121",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paradoxical Embolism in a Girl with Atrial Septal Defect After Paroxysmal Supraventricular Tachycardia Ablation.",
"title_normalized": "paradoxical embolism in a girl with atrial septal defect after paroxysmal supraventricular tachycardia ablation"
} | [
{
"companynumb": "CN-BAYER-2017-161447",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nFor patients with a history of drug hypersensitivity reaction (HSR) during anesthesia, strategies to minimize risk with subsequent anesthesia are unclear. Identification of the cause of HSR during anesthesia remains challenging.\n\n\nOBJECTIVE\nTo determine the success of a comprehensive allergy evaluation and management plan for patients with HSR during anesthesia, including identification of the causative agent and review of outcomes during subsequent anesthesia exposure.\n\n\nMETHODS\nWe performed chart reviews of patients referred for the evaluation of HSR during anesthesia between 2003 and 2012. Data collection included patient characteristics, signs/symptoms of HSR during anesthesia, and subsequent outcomes. Patients underwent comprehensive allergy evaluation including skin testing for identifying potential culprit agents, and the results were used to provide recommendations for any subsequent anesthesia.\n\n\nRESULTS\nOver the 10-year study period, 73 patients with HSR during anesthesia were referred for further evaluation. Thirteen patients (18%) had positive skin test results to a drug received during anesthesia. One patient with a positive skin test result was diagnosed with mastocytosis. The causative agents identified in these 13 patients included latex, β-lactam antibiotics, neuromuscular blockers, tetracaine, odansetron, and fentanyl. On follow-up, 47 of the 73 patients (64%) subsequently underwent procedures requiring anesthesia. Using our recommendations from evaluation and testing, 45 of these 47 patients (96%) successfully tolerated subsequent anesthesia. The 2 patients who developed recurrent HSR during anesthesia were later diagnosed with mast cell disorders.\n\n\nCONCLUSIONS\nOur comprehensive evaluation and management plan minimizes risk with subsequent anesthesia even when the cause of HSR could not be identified. Baseline tryptase levels may be helpful in this patient population to diagnose mast cell disorders.",
"affiliations": "Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA. Electronic address: aguyer@bidmc.harvard.edu.;Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.;Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.;Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.;Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.;Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.;Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.",
"authors": "Guyer|Autumn C|AC|;Saff|Rebecca R|RR|;Conroy|Michelle|M|;Blumenthal|Kimberly G|KG|;Camargo|Carlos A|CA|;Long|Aidan A|AA|;Banerji|Aleena|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "3(1)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Allergic reactions during anesthesia; Drug allergy; Drug hypersensitivity reaction; General anesthetics; Hypersensitivity reactions during anesthesia; Intraoperative anaphylaxis; Perioperative anaphylaxis; Tryptase",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000758:Anesthesia; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012882:Skin Tests",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "94-100",
"pmc": null,
"pmid": "25577625",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comprehensive allergy evaluation is useful in the subsequent care of patients with drug hypersensitivity reactions during anesthesia.",
"title_normalized": "comprehensive allergy evaluation is useful in the subsequent care of patients with drug hypersensitivity reactions during anesthesia"
} | [
{
"companynumb": "US-APOTEX-2015AP006488",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "A 24-year-old African American female (L.R.) with a history of smoking and gestational diabetes was diagnosed with Hodgkin lymphoma. She received multiple chemotherapies, including six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), followed by radiation therapy to left inguinal areas for a total of 30.6 Gy in 17 fractions; she obtained complete remission. Two years later, L.R. had disease relapse in the mediastinum and received two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin) followed by etoposide and ifosfamide. She then received BEAM (carmustine, etoposide, cytarabine, and melphalan) as a conditioning regimen and underwent autologous bone marrow transplant. Her post-transplant course was complicated by cytomegalovirus antigenemia, aspergillus pneumonia, and congestive heart failure with left ventricular ejection fraction (LVEF) of 20%-25%. She was treated with an ACE inhibitor (lisinopril) and a beta-blocker (carvedilol) with improvement of her LVEF to 30%-35%. A follow-up chest x-ray showed an increase in the size of the anterior mediastinal adenopathy suspicious for relapse of lymphoma, and at the same time she was also found to be 5 weeks pregnant. Given her cardiomyopathy, significant obesity, poorly controlled diabetes, and cancer recurrence, L.R. was advised by her gynecologist that the pregnancy was very high risk and might not be viable. The oncologists advised her to terminate the pregnancy within the first trimester, as she needed salvage radiotherapy treatment to the mediastinum and chemotherapy treatments that might endanger the fetus. However, the patient decided to continue with the pregnancy. A multidisciplinary team-which included a cardiologist, oncologist, high-risk obstetrician, pharmacist, and nurse practitioner-was then involved to provide care during the pregnancy. A social worker was also solicited to help with home and financial issues because L.R. was a single mother with a 2-year-old son. L.R. was treated with carvedilol and furosemide, with monthly cardiology clinical follow-up during the first and second trimesters, then every 2 weeks starting with the 28th week, and weekly thereafter until delivery. Between visits, she notified the clinic for symptoms of heart failure exacerbation and was seen as necessary. The possible in utero effects of both medications were discussed with the patient. L.R. had a normal uncomplicated pregnancy and delivered a 6-pound, 10-ounce healthy boy at 39 weeks via vaginal delivery and was discharged home 2 days later. A week after delivery, L.R. presented to the cardiology clinic in good spirits and was excited to show pictures of her newborn baby. She had no cardiac complaints and the repeat echocardiogram showed an unchanged LVEF of 30%-35%.",
"affiliations": "MD Anderson Cancer Center, Houston, Texas.;MD Anderson Cancer Center, Houston, Texas.;MD Anderson Cancer Center, Houston, Texas.;MD Anderson Cancer Center, Houston, Texas.",
"authors": "Fadol|Anecita P|AP|;Lech|Tara|T|;Bickford|Courtney|C|;Yusuf|Syed Wamique|SW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.6004/jadpro.2012.3.2.3",
"fulltext": "\n==== Front\nJ Adv Pract OncolJ Adv Pract OncolJADPROJournal of the Advanced Practitioner in Oncology2150-08782150-0886Harborside Press 25031933jadpro.v03.i02.pg85Review ArticleOncologyPregnancy in a Patient With Cancer and Heart Failure: Challenges and Complexities Fadol Anecita P. Fadol, PhD, RN, FNP-BC, FAANPLech Tara PharmDBickford Courtney PharmDYusuf Syed Wamique MBBS, FACCFrom MD Anderson Cancer Center, Houston, TexasCorrespondence to: Anecita Fadol, RN, PhD, Department of Cardiology, MD Anderson Cancer Center, 1515 Holcombe Boulevard #1451, Houston, TX 77030 E-mail: afadol@mdanderson.org\n\nMar-Apr 2012 1 3 2012 3 2 85 93 Copyright © 2012, Harborside Press2012This is an open-access article distributed under the terms of the\nCreative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original\nwork is properly cited and is for non-commercial purposes.\nA 24-year-old African American female (L.R.) with a history of smoking and gestational diabetes was diagnosed with Hodgkin lymphoma. She received multiple chemotherapies, including six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), followed by radiation therapy to left inguinal areas for a total of 30.6 Gy in 17 fractions; she obtained complete remission. Two years later, L.R. had disease relapse in the mediastinum and received two cycles of ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin) followed by etoposide and ifosfamide. She then received BEAM (carmustine, etoposide, cytarabine, and melphalan) as a conditioning regimen and underwent autologous bone marrow transplant. Her post-transplant course was complicated by cytomegalovirus antigenemia, aspergillus pneumonia, and congestive heart failure with left ventricular ejection fraction (LVEF) of 20%–25%. She was treated with an ACE inhibitor (lisinopril) and a beta-blocker (carvedilol) with improvement of her LVEF to 30%–35%. A follow-up chest x-ray showed an increase in the size of the anterior mediastinal adenopathy suspicious for relapse of lymphoma, and at the same time she was also found to be 5 weeks pregnant.\n\n\n\nGiven her cardiomyopathy, significant obesity, poorly controlled diabetes, and cancer recurrence, L.R. was advised by her gynecologist that the pregnancy was very high risk and might not be viable. The oncologists advised her to terminate the pregnancy within the first trimester, as she needed salvage radiotherapy treatment to the mediastinum and chemotherapy treatments that might endanger the fetus. However, the patient decided to continue with the pregnancy. A multidisciplinary team—which included a cardiologist, oncologist, high-risk obstetrician, pharmacist, and nurse practitioner—was then involved to provide care during the pregnancy. A social worker was also solicited to help with home and financial issues because L.R. was a single mother with a 2-year-old son.\n\n\n\nL.R. was treated with carvedilol and furosemide, with monthly cardiology clinical follow-up during the first and second trimesters, then every 2 weeks starting with the 28th week, and weekly thereafter until delivery. Between visits, she notified the clinic for symptoms of heart failure exacerbation and was seen as necessary. The possible in utero effects of both medications were discussed with the patient. L.R. had a normal uncomplicated pregnancy and delivered a 6-pound, 10-ounce healthy boy at 39 weeks via vaginal delivery and was discharged home 2 days later.\n\n\n\nA week after delivery, L.R. presented to the cardiology clinic in good spirits and was excited to show pictures of her newborn baby. She had no cardiac complaints and the repeat echocardiogram showed an unchanged LVEF of 30%–35%.\n==== Body\nThe advent of newer treatment modalities has led to an increasing number of cancer survivors, and the number of women who have received cancer therapy with potential cardiotoxic side effects is growing rapidly. As these women contemplate pregnancy, history of prior cancer therapies is critical in determining the risk of cardiac complications during pregnancy. Cardiomyopathy is an adverse effect of many chemotherapeutic agents (Yeh & Bickford, 2009). Chemotherapy-induced cardiomyopathy may manifest before and during pregnancy and poses complex therapeutic challenges as medications such as angiotensin-converting enzyme (ACE) inhibitors are contraindicated in pregnancy because of their teratogenic effects (Briggs, Freeman, & Yaffe, 2008).\n\n\n\nThere is a paucity of information to guide the clinician in the management of these high-risk patients, who need meticulous surveillance and follow-up throughout the course of the pregnancy. The purpose of this article is to describe the collaboration of a multidisciplinary team of health-care providers in the management of a successful pregnancy in a cancer patient with heart failure (HF).\n\n\nChemotherapy and Cardiotoxicity\n\nSeveral of the standard chemotherapy regimens recommended for the treatment of Hodgkin lymphoma are anthracycline-based. In clinical trials, anthracyclines have proven to be highly efficacious in the treatment of lymphoma. Their efficacy has been attributed to a clear dose-response relationship, with higher doses showing greater rates of remission and cure (Shan, Lincoff, & Young, 1996). However, higher cumulative anthracycline doses are associated with an increased incidence of adverse effects, such as cardiotoxicity, which often limits the further use of certain cancer therapies.\n\n\n\nAnthracyline-induced cardiotoxicity may be categorized into three distinct types: acute, early-onset chronic progressive, and late-onset chronic progressive (Grenier & Lipshultz, 1998; Lipshultz, Alvarez, & Scully, 2008; Yeh & Bickford, 2009). Acute cardiotoxicity occurs in < 1% of patients immediately after infusion of the anthracycline and may manifest as arrhythmias, acute pericarditis-myocarditis syndrome, or an acute, transient decline in myocardial contractility, which is usually reversible (Shan, Lincoff, & Young, 1996; Wouters, Kremer, Miller, Herman, & Lipschultz, 2005).\n\n\n\nThe early-onset chronic progressive form occurs in 1.6% to 2.1% of patients, during therapy or within the first year after treatment (Wouters et al., 2005; Yeh & Bickford, 2009). In a series of approximately 3,900 patients who received treatment with anthracyclines, heart failure occurred 0 to 231 days after the completion of anthracycline therapy (Von Hoff et al., 1979).\n\n\n\nIn contrast, late-onset anthracycline-induced cardiac abnormalities have been reported to occur much later, and may not become clinically evident until 10 to 20 years after the first dose of cancer treatment (Yeh & Bickford, 2009). Late-onset chronic progressive anthracycline-induced cardiotoxicity, which typically presents as dilated cardiomyopathy and can be progressive, occurs at least 1 year after completion of therapy in 1.6% to 5% of patients (Wouters et al., 2005; Yeh & Bickford, 2009).\n\n\n\nCardiotoxicity associated with anthracyclines is related to total cumulative dose. Studies that have looked at the cumulative probability of doxorubicin-induced heart failure have found that it occurs in 3% to 48% at doses of ranging from 400 to 700 mg/m2 (Von Hoff et al., 1979; Swain et al., 1997; Wouters et al., 2005). However, in a retrospective review of three trials, the incidence of HF was found to be 26% with cumulative doses of 550 mg/m2 (Swain, Whaley, & Ewer, 2003). Therefore, the maximum lifetime cumulative dose for doxorubicin is 400 to 550 mg/m2 (Wouters et al., 2005). In this case report, our patient received six cycles of ABVD that resulted in a total cumulative doxorubicin dose of 300 mg/m2.\n\n\n\nBesides total cumulative dose, risk factors for anthracycline toxicity include IV bolus administration; higher single doses; history of prior irradiation; use of other concomitant agents known to have cardiotoxic effects, such as cyclophosphamide, trastuzumab (Herceptin), and paclitaxel; female gender; underlying cardiovascular disease; age (both young and old); and increased length of time since anthracycline completion (Grenier & Lipshultz, 1998; Swain, Whaley, & Ewer, 2003; Lipshultz, Alvarez, & Scully, 2008; Yeh & Bickford, 2009).\n\n\n\nAlthough the cause of anthracycline-induced cardiotoxicity is probably multifactorial, free radical formation is generally acknowledged as the main mechanism (Yeh & Bickford, 2009). The semiquinone moiety of the doxorubicin increases oxygen radical activity thereby causing lipid peroxidation and cell injury (Shan, Lincoff, & Young, 1996). Other hypotheses include interference with topoisomerase II beta (Lyu et al., 2007; Yeh & Bickford, 2009), myocyte damage from calcium overload, adrenergic dysfunction, apoptosis, transcriptional changes in intracellular ATP production in cardiac myocytes, downregulation of mRNA expression for sarcoplasmic reticulum calcium-ATPase, which decreases cardiac contractility, and prolonged drug-related depression in cardiac glutathione peroxidase activity associated with mitochondrial DNA damage (Shan, Lincoff, & Young, 1996; Wouters et al., 2005; Yeh & Bickford, 2009).\n\n\nManagement of Pregnancy With Heart Failure and Cancer\n\nThe management of pregnancy in the concurrence of heart failure and cancer presents an enormous challenge to health-care providers. The physiologic changes that occur in a normal pregnancy are stressful to the cardiovascular system. During pregnancy, blood volume increases 45% to 50% and cardiac output rises 30% to 50% above baseline, peaking by the end of the second trimester and reaching a plateau until delivery (Howlett et al., 2010; Rimes, Gano, & Milbourne, 2008).\n\n\n\nCardiac disease complicates approximately 1% to 3% of pregnancies, with a maternal mortality rate of 10% to 15% (Gei & Hankins, 2001; Klein & Galan, 2004). The risk of maternal death is approximately 7% if the patient is in New York Heart Association (NYHA) functional class III or IV (Thorne, 2004). An LVEF of < 20%, presence of mitral regurgitation, right ventricular failure, atrial fibrillation, and systemic hypotension are other risk factors that can increase the risk for overt heart failure during pregnancy and may increase the risk of maternal death (Thorne, 2004).\n\n\n\nPatients with preexisting chemotherapy-induced left ventricular dysfunction during pregnancy should be closely monitored during the gestation period, at the time of delivery, and during the postpartum period (Howlett et al., 2010). Initial assessment should include a detailed history including cancer treatment history (chemotherapy and radiation therapy), review of systems including symptom assessment (i.e., orthopnea, paroxysmal nocturnal dyspnea, and weight gain), functional status, and baseline diagnostic tests (Table 1), which should be monitored closely on a regular basis (Howlett et al., 2010).\n\n\nTable 1 \nTable 1. Recommended Tests for Monitoring During Pregnancy\n\n\n\nThe hemodynamic changes that occur during pregnancy result in the development of several signs and symptoms that can mimic heart disease presentation. The normal symptoms of pregnancy can obscure the early signs and symptoms of heart failure exacerbation (Howlett et al., 2010). Manifestations of worsening heart failure that should prompt further investigation include chest pain, new-onset cough with dyspnea, increased jugular venous pressure/distention, new-onset diastolic murmur or systolic murmur (not considered physiologic), paroxysmal nocturnal dyspnea, pulmonary crackles or other adventitious breath sounds, and profound peripheral edema.\n\n\n\nEarly identification and intervention is crucial in preventing the worsening of heart failure. Because no specific criteria are available to differentiate subtle symptoms of heart failure from the normal course of pregnancy, health-care providers should maintain a high index of suspicion (Pearson et al., 2000). Careful and meticulous clinical assessment is necessary to distinguish the symptoms related to pregnancy vs. early-onset heart failure (Table 2).\n\n\nTable 2 \nTable 2. Cardiovascular Signs and Symptoms of Pregnancy vs. Worsening Heart Failure\n\n\n\nThe goals of management and medical therapy are generally similar to those in the general population with heart failure, but with careful consideration of the impact of pharmacologic therapy on the fetus.\n\n\nPharmacologic Management\n\nThe management of patients with heart failure is extremely complex; drug therapy must be tailored to fit the individual. There are many factors to consider when developing an adequate pharmacotherapeutic treatment plan, and decision-making can become increasingly more difficult during pregnancy. Patients ideally would remain on chronic therapies that have been shown to improve outcomes in heart failure; however, we must first evaluate the risk-benefit ratio of continuing each medication to minimize potential harm to the fetus. Table 3 highlights the medications currently prescribed for the treatment of heart failure and their associated risks to the unborn fetus. The following sections will take a closer look at each medication and review its evidence for use during pregnancy.\n\n\nTable 3 \nTable 3. Medications Approved for Heart Failure and Their Risk in Pregnancy\n\n\nACE Inhibitors and ARBs\n\nThe use of ACE inhibitors and angiotensin receptor blockers (ARBs) is well established in the treatment of heart failure in nonpregnant patients (The SOLVD Investigators, 1991; Granger et al., 2003). These drugs inhibit the renin-angiotensin aldosterone system, and as a result they decrease blood pressure, reduce afterload, and improve LV systolic function. ACE inhibitors have been shown to improve morbidity, mortality, and quality of life in many large-scale prospective clinical trials (The SOLVD Investigators, 1991; The CONSENSUS Trial Study Group, 1987). ARBs are generally recommended as an alternative to ACE inhibitors in cases where ACE inhibitors are not tolerated (Granger et al., 2003). Treatment with either therapy, however, must be discontinued during pregnancy. Both ACE inhibitors and ARBs are known teratogens, and their use during pregnancy is contraindicated (Briggs, Freeman, & Yaffe, 2008).\n\n\n\nUntil recently it was thought that the risks associated with these drugs—including anuria, oligohydramnios, fetal hypocalvaria (reduced size of the calvarial bones), intrauterine growth retardation, prematurity, and patent ductus arteriosus—were highest during the second and third trimesters, but recent studies have reported adverse fetal outcomes associated with first trimester use as well (Lavoratti et al., 1997; Flather et al., 2000; Alwan, Polifka, & Friedman, 2005; Briggs, Freeman, & Yaffe, 2008; Buhimschi & Weiner, 2009). Cooper and colleagues (2006) reported that 7.1% of infants exposed to ACE inhibitors in the first trimester had congenital malformation, which was 2.71 times higher than the infants with no exposure (risk ratio, 2.71; 95% confidence interval, 1.72 to 4.27). Given the significant fetal risks, ACE inhibitors and ARBs should not be used during pregnancy.\n\n\nBeta-Blockers\n\nBeta-blockers, such as metoprolol succinate and carvedilol, play an important role in the management of chronic heart failure patients. Beta-blockers reduced all-cause mortality and length of hospitalization in patients with heart failure (The MERIT-HF Study Group, 1999; Packer et al., 1996; Brophy, Joseph, & Rouleau, 2001). However, there is insufficient evidence to draw conclusions about the effects of beta-adrenoreceptor antagonists on perinatal outcome (Magee et al., 2007). The major concerns associated with these drugs are intrauterine growth retardation (IUGR), cardiorespiratory depression, bradycardia, hypoglycemia, and hypothermia (Ghanem & Movahed, 2008). Reports of these adverse effects are rare, and they are most often associated with atenolol (Butters, Kennedy, & Rubin, 1990).\n\n\n\nGiven the risk of IUGR associated with prolonged beta-blocker use, it is recommended that fetal growth be routinely monitored by ultrasound and that the mother’s hemodynamic status be closely observed (Howlett et al., 2010). There are thoughts that lower maternal blood pressures may increase the risk for developing IUGR; titration of these medications should be done slowly over time. Beta-blockers should be used very cautiously and are best avoided in cases of acutely decompensated heart failure in pregnant patients.\n\n\nLoop Diuretics\n\nLoop diuretics play an important role in the management of the edema and pulmonary congestion associated with heart failure, and are thought to be safe for use in pregnancy (Briggs, Freeman, & Yaffe, 2008). These drugs work by inhibiting the reabsorption of sodium and chloride in the ascending loop of Henle and in the distal renal tubule, leading to an increased excretion of water, sodium, chloride, magnesium, and calcium (Brunton, Lazo, & Parker, 2005). The overall net effect causes an increase in diuresis and a decrease in cardiac preload.\n\n\n\nWhile believed to be nonteratogenic, the risks and benefits of using these drugs throughout pregnancy must be considered. For example, diuretics have been shown to decrease placental perfusion and intravascular volume contraction (Carr, Gavrila, Brateng, & Easterling, 2007; Ghanem & Movahed, 2008; Newsstead-Angel & Gibson, 2009). Sibai, Grossman, & Grossman followed 21 patients in their first trimester currently taking diuretics prior to study enrollment. In order to compare outcomes, 10 patients were asked to discontinue treatment with their diuretic following enrollment. The findings showed that while initial plasma volumes were similar in the two groups, measurements at various stages of pregnancy showed decreased plasma volumes in the diuretic-treated group. However, there was no difference in perinatal outcomes between the two groups.\n\n\nAldosterone Antagonists\n\nAldosterone antagonists, such as spironolactone and eplerenone, compete with aldosterone for receptor sites in the distal renal tubules, increasing sodium chloride and water excretion while retaining potassium and hydrogen ions (Brunton, Lazo, & Parker, 2005). These drugs are beneficial in patients with congestive heart failure and prolong survival in patients with NYHA class III and IV heart failure (The RALES Investigators, 1996; Pitt et al., 1999). There are currently no data to support the use of aldosterone antagonists during pregnancy, and animal studies have reported feminization of the male fetus due to the antiandrogen effects of the drugs (Briggs, Freeman, & Yaffe, 2008; Newsstead-Angel & Gibson, 2009). There is one case report of a patient with Bartter’s syndrome who was treated with spironolactone 200 mg/day during three pregnancies, of which two boys were reported to have developed mild learning disabilities (Groves & Corenblum, 1995). Until more safety data have been established, it is recommended that aldosterone antagonists be avoided during pregnancy (Briggs, Freeman, & Yaffe, 2008; Newsstead-Angel & Gibson, 2009).\n\n\nHydralazine and Nitrates\n\nHydralazine is a centrally acting vasodilator. It causes direct vasodilation of arterioles and a decrease in systemic vascular resistance. When used in conjunction with nitrates, which are predominantly venodilators, it has been shown to provide symptomatic and mortality benefits particularly in certain populations of heart failure patients, such as African Americans (Taylor et al., 2004; Taylor et al., 2007). Both of these drugs have a record for safe and effective use in pregnancy without any evidence of teratogenicity and may serve as a good substitute for ACE inhibitors or ARBs in this patient population (Newstead-Angel & Gibson, 2009).\n\n\nDigoxin\n\nDigoxin has not been shown to improve mortality in the general population of heart failure patients; as a result, it is not a first-line agent in the management of heart failure (The Digitalis Investigation Group, 1997). It is instead used as adjunct therapy to improve exercise tolerance and increase cardiac contractility. It works via inhibition of the sodium/potassium ATPase pump in myocardial cells, causing an influx of calcium via the sodium-calcium exchange pump that ultimately leads to an increase in cardiac contractility (Briggs, Freeman, & Yaffe, 2008).\n\n\n\nDigoxin has historically been used in pregnant patients with heart failure as well as for the management of both maternal and fetal arrhythmias; it has been proven safe at all stages of pregnancy (Briggs, Freeman, & Yaffe., 2008). Some concerns, such as low birth weight and mental retardation, have arisen from anecdotal case reports (Widerhorn, Rubin, Frishman, & Elkayam, 1987), but overall, digoxin has been used with favorable results. Because of these pharmacokinetic alterations, serum levels may be checked periodically during the course of therapy in order to minimize the risk of toxicity while trying to achieve a therapeutic response (Widerhorn et al., 1987). This drug should be considered in pregnant women with heart failure who are still symptomatic despite adequate treatment with vasodilators and diuretic therapy.\n\n\nManagement During Delivery\n\nThe decision regarding timing and mode of delivery for these high-risk patients is generally based on obstetric indications. Early delivery is not required unless medical management is unsuccessful and the patient is hemodynamically unstable (Howlett et al., 2010). For most cardiac conditions, a normal vaginal delivery is the preferred mode of delivery for the mother, as it is associated with minimal blood loss, greater hemodynamic stability, avoidance of surgical stress, and less chance of postoperative infection and pulmonary complications than cesarean section (Thorne, 2004). Effective pain management is necessary to avoid tachycardia, which increases myocardial oxygen consumption. Cesarean delivery is reserved for indications such as fetal distress or failure to progress (Howlett et al., 2010).\n\n\n\nDuring delivery, maintenance of normal to low heart rate to decrease oxygen demand and prevention of large swings in blood pressure are imperative. Careful hemodynamic monitoring and fluid balance is obligatory and arterial and central venous pressure lines are recommended if cesarean section is chosen as a mode of delivery. Management in the intensive care unit is usually required due to the severity of the condition (Carlin & Alfirevic, 2010). Early critical care referral is essential for unstable and critically ill patients with pulmonary edema, hypoxia, mental obtundation, hypotension, refractory oliguria, or acidemia and may require Swan-Ganz monitoring, artificial ventilation, and inotropic support (Baughman, 2001).\n\n\nPostpartum Period\n\nSubsequent monitoring after delivery depends on response to treatment, and includes a follow-up echocardiogram in the first several weeks to evaluate left ventricular systolic function. If standard heart failure medical therapy is ineffective, more aggressive ventricular support such as the intra-aortic balloon counter pulsation or left ventricular assist device may be considered (Carlin & Alfirevic, 2010). In the absence of evidence-based guidelines for the management of cancer patients with heart failure, standard heart failure therapy recommended by clinical guidelines including diuretics, beta-blockers, ACE inhibitors, nitrates, hydralazine, and digoxin should be initiated (Carlin & Alfirevic, 2010). Careful attention must be paid to fetal safety and to excretion of drug (i.e., ACE inhibitors and beta-blockers) or drug metabolites during breastfeeding after delivery.\n\n\nImplications for Advanced Practice\n\nWith a growing number of cancer survivors at a childbearing age, advanced practitioners will increasingly come across cancer patients who are pregnant or contemplating pregnancy. These patients may present with many challenges that require a personalized approach to the management of the mother and the fetus. Health-care providers must educate themselves about the early signs and symptoms of worsening heart failure so that the treatment is initiated at an early stage. Advanced practitioners are often the patient’s main source of information within the health-care system; therefore, they need to be able to assist patients or refer them to appropriate services. Advanced practitioners should also evaluate patients’ psychosocial needs and encourage them to seek professional help when necessary (Rimes, Gano, & Milbourne, 2008). Working as a multidisciplinary team will help achieve the best possible outcome for mothers and their babies.\n\n\nConclusions\n\nPregnancy in cancer patients with preexisting heart disease should be managed by a multidisciplinary team of cardiologists, oncologists, obstetrician, perinatologists, anesthesiologists, advanced practitioners, nurses, and pharmacists. A collaborative effort is paramount during various stages of pregnancy and perinatal care; a successful outcome is possible, as documented in our case. It is important to realize that the treatment recommendations of pregnant patients with cancer will always rely on limited evidence. Each clinical situation is unique and requires a multidisciplinary approach. A registry will help establish guidelines for optimal management of pregnancy in cancer patients with heart failure.\n\n\nThe author has no relevant conflicts to disclose.\n==== Refs\n1 Alwan S. Polifka J. E. Friedman J. M. Angiotensin II receptor antagonist treatment during pregnancy Birth Defects Research Part A Clinical Molecular Teratology 2005 73(2) 123 130 \n2 Arnold J. M. Howlett J. G. Dorian P. Ducharme A. Giannetti N. Haddad H. White M. Canadian Cardiovascular Society Consensus Conference recommendations on heart failure update 2007: Prevention, management during intercurrent illness or acute decompensation, and use of biomarkers Canadian Journal of Cardiology 2007 23(1) 21 45 17245481 \n3 Baughman K. L. Peripartum cardiomyopathy Current Treatment Options in Cardiovascular Medicine 2001 3(6) 469 480 11696267 \n4 Briggs G. G. Freeman R. K. Yaffe S. J. Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2008 \n5 Brophy J. M. Joseph L. Rouleau J. L. Beta-blockers in congestive heart failure. A Bayesian meta-analysis Annals of Internal Medicine 2001 134(7) 550 560 11281737 \n6 Brunton L. Lazo J. S. Parker K. Goodman & Gilman’s The Pharmacological Basis of Therapeutics New York: McGraw-Hill. 2005 \n7 Buhimschi C. S. Weiner C. P. Medications in pregnancy and lactation: Part 2. Drugs with minimal or unknown human teratogenic effect Obstetrics and Gynecology 2009 113(2 pt 1) 417 432 19155916 \n8 Butters L. Kennedy S. Rubin P. C. Atenolol in essential hypertension during pregnancy British Medical Journal 1990 301(6752) 587 589 2242456 \n9 Carlin A. J. Alfirevic Z. Interventions for treating peripartum cardiomyopathy to improve outcomes for women and babies Cochrane Database of Systematic Reviews 2010 9 CD008589 \n10 Carr D. B. Gavrila D. Brateng D. Easterling T. R. Maternal hemodynamic changes associated with furosemide treatment Hypertension in Pregnancy 2007 26(2) 173 178 http://dx.doi.org/10.1080/10641950701204489 17469007 \n11 Cooper W. O. Hernandez-Diaz S. Arbogast P. G. Dudley J. A. Dyer S. Gideon P. S. Ray W. A. Major congenital malformations after first-trimester exposure to ACE inhibitors New England Journal of Medicine 2006 354(23) 2443 2451 16760444 \n12 Flather M. D. Yusuf S. Køber L. Peffer M. Hall A. Murray G. Braunwald E. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: A systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group Lancet 2000 355(9215) 1575 1581 10821360 \n13 Gei A. F. Hankins G. D. Cardiac disease and pregnancy Obstetrics and Gynecology Clinics of North America 2001 28(3) 465 512 11512497 \n14 Ghanem F. A. Movahed A. Use of antihypertensive drugs during pregnancy and lactation Cardiovascular Therapy 2008 26(1) 38 49 \n15 Granger C. B. McMurray J. J. Yusuf S. Held P. Michelson E. L Olofsson B. Swedberg K. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial Lancet 2003 362(9386) 772 776 13678870 \n16 Grenier M. A. Lipshultz S. E. Epidemiology of anthracycline cardiotoxicity in children and adults Seminars in Oncology 1998 25(4 suppl 10) 72 85 9768828 \n17 Groves T. D. Corenblum B. Spironolactone therapy during human pregnancy American Journal of Obstetrics and Gynecology 1995 172(5) 1655 1656 7755100 \n18 Howlett J. G. McKelvie R. S. Costigan J. Ducharme A. Estrella-Holder E. Ezekowitz J. A. Zeiroth S. The 2010 Canadian Cardiovascular Society guidelines for the diagnosis and management of heart failure update: Heart failure in ethnic minority populations, heart failure and pregnancy, disease management, and quality improvement/assurance programs Canadian Journal of Cardiology 2010 26(4) 185 202 20386768 \n19 Klein L. L. Galan H. L. Cardiac disease in pregnancy Obstetrics and Gynecology Clinics of North America 2004 31(2) 429 459 15200971 \n20 Lavoratti G. Seracini D. Fiorini P. Cocchi C. Materassi M. Donzelli G. Pela I. Neonatal anuria by ACE inhibitors during pregnancy Nephron 1997 76(2) 235 236 9200422 \n21 Lipshultz S. E. Alvarez J. A. Scully R. E. Anthracycline associated cardiotoxicity in survivors of childhood cancer Heart 2008 94(4) 525 533 18347383 \n22 Lyu Y. L. Kerrigan J. E. Lin C. P. Azarova A. M. Tsai Y. C. Ban Y. Liu L. F. Topoisomerase II beta mediated DNA double-strand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane Cancer Research 2007 67(18) 8839 8846 17875725 \n23 Magee L. A. von Dadelszen P. Chan S. Gafni A. Gruslin A. Helewa M. Hannah M. E. The Control of Hypertension In Pregnancy Study pilot trial BJOG: An International Journal of Obstetrics and Gynaecology 2007 114(6) 770 e13-e20 17516972 \n24 MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet 1999 353(9169) 2001 2007 10376614 \n25 Newsstead-Angel J. G. Gibson P. S. Cardiac drug use in pregnancy: Safety, effectiveness and obstetric implications Expert Review of Cardiovascular Therapy 2009 7(12) 1569 1580 19954319 \n26 Packer M. Bristow M. R. Cohn J. N. Colucci W. S. Fowler M. B. Gilbert E. M. Shusterman N. H. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure New England Journal of Medicine 1996 334(21) 1349 1355 8614419 \n27 Pearson G. D. Veille J.-C. Rahimtoola S. Hsia J. Oakley C. M. Hosenpud J. D. Baughman K. L. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review Journal of the American Medical Association 2000 283(9) 1183 1188 10703781 \n28 Pitt B. Zannad F. Remme W. J. Cody R. Castaigne A. Perez A. Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure New England Journal of Medicine 1999 341(10) 709 717 10471456 \n29 Resnik J. L. Hong C. Resnik R. Kazanegra R. Beede J. Bhalla V. Maisel A. Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women American Journal of Obstetrics and Gynecology 2005 193(2) 450 454 16098869 \n30 Rimes S. Gano J. Milbourne A. Care of the pregnant patient with cancer Oncology (Williston Park) 2008 22(8 suppl Nurse Ed) 13 22 19856566 \n31 Shan K. Lincoff A. M. Young J. B. Anthracycline-induced cardiotoxicity Annals of Internal Medicine 1996 125(1) 47 58 8644988 \n32 Sibai B. M. Grossman R. A. Grossman H. G. Effects of diuretics on plasma volume in pregnancies with long-term hypertension American Journal of Obstetrics and Gynecology 1984 150(7) 831 835 6507509 \n33 Swain S. M. Whaley F. S. Ewer M. S. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials Cancer 2003 97(11) 2869 2879 12767102 \n34 Swain S. M. Whaley F. S. Gerber M. C. Weisberg S. York M. Spicer D. Gams R. A. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer Journal of Clinical Oncology 1997 15(4) 1318 1332 9193323 \n35 Taylor A. L. Ziesche S. Yancy C. Carson P. D’Agostino R. Ferdinand K. Cohn J. N. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure New England Journal of Medicine 2004 351(20) 2049 2057 15533851 \n36 Taylor A. L. Ziesche S. Yancy C. W. Carson P. Ferdinand K. Taylor M. Cohn J. N. Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: Consistency across subgroups in the African-American Heart Failure Trial Circulation 2007 115(13) 1747 1753 17372175 \n37 The CONSENSUS Trial Study Group Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) New England Journal of Medicine 1987 316 1429 1435 2883575 \n38 The Digitalis Investigation Group The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group New England Journal of Medicine 1997 336(8) 525 533 9036306 \n39 The RALES Investigators Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]) American Journal of Cardiology 1996 78(8) 902 907 8888663 \n40 The SOLVD Investigators Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure New England Journal of Medicine 1991 325(5) 293 302 2057034 \n41 Thorne S. A. Pregnancy in heart disease Heart 2004 90(4) 450 456 15020530 \n42 Von Hoff D.D. Layard M. W. Basa P. Davis H. L. Jr. Von Hoff A. L. Rozencweig M. Muggia F. M. Risk factors for doxorubicin-induced congestive heart failure Annals of Internal Medicine 1979 91 710 717 496103 \n43 Widerhorn J. Rubin J. N. Frishman W. H. Elkayam U. Cardiovascular drugs in pregnancy Cardiology Clinics 1987 5(4) 651 674 2900070 \n44 Wouters K. A. Kremer L. C. Miller T. L. Herman E. H. Lipshultz S. E. Protecting against anthracycline-induced myocardial damage: A review of the most promising strategies British Journal of Haematology 2005 131(5) 561 578 16351632 \n45 Yeh E. T. Bickford C. L. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management Journal of the American College of Cardiology 2009 53(24) 2231 2247 19520246\n\n",
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"title": "Pregnancy in a patient with cancer and heart failure: challenges and complexities.",
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"abstract": "A 74-year-old man with end-stage renal failure secondary to diabetes received a living donor renal transplant (cytomegalovirus [CMV]-seropositive recipient from a CMV-seropositive donor). Computed tomography scan revealed a gallbladder with hemorrhage. On postoperative day 27, cholecystography revealed gallbladder perforation; he underwent an emergency operation. Histological examination of the gallbladder wall was positive for multiple viral inclusion bodies. We report a very rare case of both hemorrhagic and perforated CMV cholecystitis within a month following renal transplantation.",
"affiliations": "Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.",
"authors": "Imaoka|Yuki|Y|http://orcid.org/0000-0003-0882-5341;Ohira|Masahiro|M|;Ishiyama|Kohei|K|;Ide|Kentaro|K|;Kobayashi|Tsuyoshi|T|;Tahara|Hiroyuki|H|;Ohdan|Hideki|H|",
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"doi": "10.1111/tid.12733",
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"issue": "19(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "cytomegalovirus cholecystitis; gallbladder perforation; renal transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D003586:Cytomegalovirus Infections; D005705:Gallbladder Diseases; D006801:Humans; D016030:Kidney Transplantation; D008297:Male",
"nlm_unique_id": "100883688",
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"pages": null,
"pmc": null,
"pmid": "28605108",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Perforation of the gallbladder in a patient with acute cytomegalovirus cholecystitis shortly following renal transplantation.",
"title_normalized": "perforation of the gallbladder in a patient with acute cytomegalovirus cholecystitis shortly following renal transplantation"
} | [
{
"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2018EDE000223",
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{
"abstract": "Primary central nervous system (CNS) lymphomas account for 13-20% of the posttransplant lymphoproliferative disorders (PTLD) and rank among the most aggressive conditions. Reduction of immunosuppressive therapy should be mandatory to treat PTLD, but this is rarely used as the only therapy option. Chemotherapy regimens for PTLD involving the CNS most commonly include high-dose rituximab and high-dose methotrexate and/or cytarabine. The efficiency only of discontinuation of immunosuppressive therapy for PTLD does not exceed 5-10%, but there are no literature data on its efficiency for PTLD involving the CNS. The paper describes a clinical case of achieving long-term remission in a female patient with Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma involving the central nervous system, associated with immunosuppression after kidney transplantation from a related donor, in the absence of chemotherapy during immunosuppressive therapy discontinuation and transplantectomy.",
"affiliations": "National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.;National Research Center for Hematology, Ministry of Health of Russia, Moscow, Russia.",
"authors": "Gavrilina|O A|OA|;Troitskaya|V V|VV|;Zvonkov|E E|EE|;Parovichnikova|E N|EN|;Galstyan|G M|GM|;Biryukova|L S|LS|;Nesterenko|I V|IV|;Kovrigina|A M|AM|;Bazhenov|A V|AV|;Savchenko|V G|VG|;Savchenko|V G|VG|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Russia (Federation)",
"delete": false,
"doi": "10.17116/terarkh201789769-75",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-3660",
"issue": "89(7)",
"journal": "Terapevticheskii arkhiv",
"keywords": "diffuse large B-cell lymphoma involving the central nervous system; posttransplant lymphoproliferative diseases; kidney transplantation; immunosuppressive therapy",
"medline_ta": "Ter Arkh",
"mesh_terms": "D000328:Adult; D001921:Brain; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D016403:Lymphoma, Large B-Cell, Diffuse; D009392:Nephrectomy; D019635:Neurosurgical Procedures; D014057:Tomography, X-Ray Computed; D019737:Transplants; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "2984818R",
"other_id": null,
"pages": "69-75",
"pmc": null,
"pmid": "28766544",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "EBV-positive central nervous system lymphoproliferative disease associated with immunosuppression after organ transplantation: Long-term remission without chemotherapy.",
"title_normalized": "ebv positive central nervous system lymphoproliferative disease associated with immunosuppression after organ transplantation long term remission without chemotherapy"
} | [
{
"companynumb": "RU-MYLANLABS-2017M1082359",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Tumor necrosis factor (TNF) antagonists are the first-line treatment for many autoimmune diseases. However, they have been associated with reactivation of hepatitis B virus (HBV). We determined the rate of HBV reactivation and hepatotoxicity grade 3 or 4 (HT ≥3) in patients treated with an anti-TNF agent for an autoimmune disease.\n\n\n\nWe collected data from 8887 adult patients in the Kaiser Permanente Northern California database who began treatment with TNF antagonists for autoimmune diseases (dermatologic, rheumatologic, or gastrointestinal) from 2001 through 2010, followed through December 2012. We obtained data on HBV infection (52% of patients were screened for HBV before treatment), demographic features, comorbidities, and use of immunosuppressive agents. HBV reactivation was defined as 1 of the following: >1 log increase in HBV DNA, HBV DNA-positive when previously negative, HBV DNA >2000 IU/mL if no baseline level was available, or reverse seroconversion. HT ≥3 was defined according to the National Cancer Institute Common Toxicity Criteria. We performed multivariable logistic regression to identify factors associated with HT ≥3.\n\n\n\nTwenty-three patients tested positive for HB surface antigen (HBsAg) at baseline and 9 of these had HBV reactivation; of the 4267 patients with unknown HBV status at baseline, 2 had HBV reactivation. None of the 178 patients who were HBsAg negative and positive for the hepatitis B core antibody (anti-HBc+) had HBV reactivation. HBV reactivation occurred in 1/5 HBsAg+ patients who received prophylactic antiviral therapy and 8/18 who did not (P = .61). No one with HBV reactivation had liver failure. HT ≥3 occurred in 273 patients (2.7%), but only 3 cases were attributed to HBV. Cirrhosis was significantly associated with HT ≥3 (P < .001).\n\n\n\nIn a retrospective analysis of patients treated with TNF antagonists for autoimmune diseases, we found HBV reactivation in 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy. Patients should be screened for HBV infection before anti-TNF therapy; HBsAg+ patients should receive prophylactic antiviral therapy, but not HBsAg-negative, anti-HBc+ patients.",
"affiliations": "Department of Gastroenterology, Kaiser Permanente Northern California, Sacramento, California. Electronic address: mppauly@ucdavis.edu.;Division of Research, Kaiser Permanente Northern California, Sacramento, California.;Department of Gastroenterology, Kaiser Permanente Northern California, Sacramento, California.;Department of Gastroenterology, Kaiser Permanente Northern California, Sacramento, California.;Department of Hematology and Oncology, Kaiser Permanente Northern California, Sacramento, California.;Department of General Internal Medicine, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Internal Medicine and Gastroenterology, University of Michigan, Ann Arbor, Michigan.",
"authors": "Pauly|Mary Patricia|MP|;Tucker|Lue-Yen|LY|;Szpakowski|Jean-Luc|JL|;Ready|Joanna B|JB|;Baer|David|D|;Hwang|Jessica|J|;Lok|Anna S-F|AS|",
"chemical_list": "D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2018.04.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "16(12)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Hepatitis Flare; Immunosuppression; Prognostic Factor; Serology",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D001327:Autoimmune Diseases; D002140:California; D005260:Female; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha; D014775:Virus Activation",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1964-1973.e1",
"pmc": null,
"pmid": "29702293",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment With Tumor Necrosis Factor Antagonists.",
"title_normalized": "incidence of hepatitis b virus reactivation and hepatotoxicity in patients receiving long term treatment with tumor necrosis factor antagonists"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US23994",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": "3",
... |
{
"abstract": "We report the case of a 28-year-old male in rural Madagascar with iatrogenic hypotension induced by improper treatment of a normal grief response. The man lost both of his children in the spring of 2019 during a measles outbreak that infected at minimum 152,000 individuals on the island. After developing symptoms of chest pain, intermittent tachycardia, and widespread pain when he would think of his children in the weeks following their loss, he was prescribed gabapentin, lisinopril, and metoprolol by a general practice nurse. He subsequently developed dizziness, lightheadedness, and fatigue. After visiting Mada Clinics two weeks later, all medications were stopped, and the man's symptoms resolved. This case demonstrates the effects of a lack of available mental health care in Madagascar, a country with sixteen available psychiatrists for a rapidly expanding population of over 26 million people.",
"affiliations": "Mayo Clinic, Rochester, MN, USA.",
"authors": "Robinson|Kyle E|KE|https://orcid.org/0000-0003-3934-3206",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6661943",
"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X\n2090-6838\nHindawi\n\n10.1155/2021/6661943\nCase Report\nIatrogenic Hypotension Induced by the Improper Treatment of Normal Grief\nhttps://orcid.org/0000-0003-3934-3206\nRobinson Kyle E. robinson.kyle@mayo.edu\n\nMayo Clinic, Rochester, MN, USA\nAcademic Editor: Erik J nsson\n\n2021\n13 4 2021\n2021 666194329 12 2020\n7 4 2021\nCopyright © 2021 Kyle E. Robinson.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nWe report the case of a 28-year-old male in rural Madagascar with iatrogenic hypotension induced by improper treatment of a normal grief response. The man lost both of his children in the spring of 2019 during a measles outbreak that infected at minimum 152,000 individuals on the island. After developing symptoms of chest pain, intermittent tachycardia, and widespread pain when he would think of his children in the weeks following their loss, he was prescribed gabapentin, lisinopril, and metoprolol by a general practice nurse. He subsequently developed dizziness, lightheadedness, and fatigue. After visiting Mada Clinics two weeks later, all medications were stopped, and the man's symptoms resolved. This case demonstrates the effects of a lack of available mental health care in Madagascar, a country with sixteen available psychiatrists for a rapidly expanding population of over 26 million people.\n==== Body\n1. Introduction\n\nMadagascar is an East African Island nation with the world's seventh-lowest GDP per capita and 0.06 available psychiatrists per 100,000 population [1, 2]. This lack of psychiatric specialists not only prevents those with severe mental illness from obtaining specialized care but also correlates with a lack of mental health training in other practitioners and the absence of psychotropic medications from local pharmacies. Owing to this limited training and the difficulty in obtaining psychotropic medications, many practitioners in Madagascar treat the symptoms of psychiatric conditions with available medications, which are often better suited to somatic illnesses. In addition, vaccination rates in rural Madagascar are low, with a survey we conducted on 340 participants in the region of this case report demonstrating a measles vaccination rate of 30.6% (Figure 1).\n\nDuring a 2019 measles pandemic, at least 112,000 Malagasy individuals were infected, leading to the deaths of at minimum 1200 children [3]. Loss of family members and loved ones can trigger feelings of bereavement and grief, which often manifest themselves with physical symptoms. These symptoms can include physical pain, tightness, heaviness, and shortness of breath, as well as symptoms of anxiety or panic disorders [4]. Normal grief is defined as feelings of grief that diminish within six months of loss and present with preservation of the patient's ability to function in daily life. Normal grief does not require pharmacologic treatment [5]. However, owing to the physical symptoms encountered, inexperienced practitioners may prescribe unnecessary medications that cause financial and physical harm, thereby exacerbating the adverse effects of normal grief.\n\nWe herein report a case of iatrogenic hypotension induced by improper treatment of a normal grief response. In this case, the removal of all medications was effective in reversing the patient's symptoms. To the best of our knowledge, this is the first report of iatrogenic hypotension induced by improper treatment of a normal grief response.\n\n2. Case Presentation\n\nThe case was a 28-year-old male without past medical history who presented to Mada Clinics in early May 2019 with symptoms of dizziness, lightheadedness, and fatigue which made it difficult for him to maintain his rice farm. On physical exam, his blood pressure was recorded at 88/57, and upon taking a history, it was discovered that the man was taking gabapentin (900 mg/day), metoprolol (200 mg/day), and lisinopril (20 mg/day) prescribed to him by a general practice nurse for prior symptoms of intermittent chest pain, intermittent tachycardia, and widespread pain. The man lost both of his children that spring, with one child drowning in a river in February 2019, and the other child passing away in March 2019 from secondary pneumonia after contracting measles in late February 2019. He reported that in the weeks following the loss of his second child, he developed generalized full body pain along with feelings of chest pressure and a “racing heart” when he would think of his children. At that time, he was still able to carry out the normal daily work of maintaining his rice farm. The man reported that after starting the three-drug regimen of gabapentin, metoprolol, and lisinopril, his symptoms of pain and tachycardia were reduced; however, he was exhausting a significant portion of his income to afford the medications, and the side effects were making it difficult for him to complete his daily work. He subsequently presented to Mada Clinics, a nonprofit medical organization serving rural Northern Madagascar. With the exception of the aforementioned hypotension, his physical exam was otherwise normal. Suspecting that the man's original symptoms stemmed from a normal grief response, all medications were stopped, with subsequent resolution of his symptoms in the following weeks. The man did not return for his requested follow-up appointment. However, he was encountered by clinic staff while competing for his village soccer team in a regional tournament later that month where he reported resolution of all symptoms including lightheadedness, dizziness, fatigue, chest pain, generalized pain, and intermittent tachycardia.\n\n3. Discussion\n\nWe have described a case of iatrogenic hypotension induced by improperly treated grief, which stemmed from the loss of life encountered during a substantial measles outbreak on the island of Madagascar in the spring of 2019. Madagascar has between 1/225th to 1/500th the rate of psychiatrists encountered in North America and Western Europe [1]. Exacerbating the lack of mental health services available, childhood and infant mortality remain substantial in Madagascar, leading to perhaps higher rates of grief and bereavement than those encountered in countries with greater availability of mental health services [6]. Grief can present with various physical complaints, and it is important for practitioners to understand the numerous presentations of grief to prevent improper or unnecessary treatment. Unnecessary treatment can exacerbate the burdens of grief and, particularly in developing countries, add substantial financial hardship to the bereaved patient [7]. Greater mental health training for nursing staff may have prevented the harms experienced by the patient in this case report. Of note, in the 21 years that Mada Clinics has accepted volunteer physicians from around the world, they have not once received a volunteer psychiatrist. Psychiatrists could do much by sharing their knowledge and skills with practitioners in countries with undersupplied mental health systems. More data is needed to understand the ways in which mental health complaints are currently treated in rural Madagascar.\n\n4. Conclusion\n\nNormal grief is defined as feelings of grief that diminish within 6 months of loss and present with preservation of the patient's ability to function in daily life. Normal grief does not normally require pharmacologic treatment, and such treatment can lead to unnecessary hardship for patients [5].\n\nData Availability\n\nThe data used to support the findings of this study originated in written patient records kept by Mada Clinics, the details of which are included in the article. The data for the vaccine survey graph is available upon request.\n\nConflicts of Interest\n\nThe author declares that there are no conflicts of interest.\n\nFigure 1 Results of vaccination survey in rural Northwestern Madagascar. 69.4% of the population in this region remains unvaccinated for measles. Vaccination rates for other major infectious diseases remain similarly low.\n==== Refs\n1 WHO Mental Health Atlas Country Profile Madagascar World Health Organization December 2020, https://www.who.int/mental_health/evidence/atlas/profiles-2014/mdg.pdf?ua=1\n2 GDP per capita (Current US$) - Madagascar | Data December 2020, http://Data.worldbank.org, https://data.worldbank.org/indicator/NY.GDP.PCAP.CD?locations=MG\n3 Nimpa M. M. Andrianirinarison J. C. Sodjinou V. D. Measles outbreak in 2018-2019, Madagascar: epidemiology and public health implications The Pan African Medical Journal 2020 35 84 10.11604/pamj.2020.35.84.19630\n4 Gudmundsdottir M. Embodied grief: bereaved parents' narratives of their suffering body Omega (Westport) 2009 59 3 253 269 10.2190/OM.59.3.e 2-s2.0-70349490958 19791520\n5 Zisook S. Shear K. Grief and bereavement: what psychiatrists need to know World Psychiatry 2009 8 2 67 74 10.1002/j.2051-5545.2009.tb00217.x 2-s2.0-67651159266 19516922\n6 Sharp M. Kruse I. Health, Nutrition, and Population in Madagascar, 2000-09 2011 The World Bank 10.1596/978-0-8213-8538-8\n7 Kruk M. E. Goldmann E. Galea S. Borrowing and selling to pay for health care in low- and middle-income countries Health Affairs 2009 28 4 1056 1066 10.1377/hlthaff.28.4.1056 2-s2.0-67651224998 19597204\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6838",
"issue": "2021()",
"journal": "Case reports in psychiatry",
"keywords": null,
"medline_ta": "Case Rep Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101583308",
"other_id": null,
"pages": "6661943",
"pmc": null,
"pmid": "33936830",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "19516922;19597204;19791520;32537087",
"title": "Iatrogenic Hypotension Induced by the Improper Treatment of Normal Grief.",
"title_normalized": "iatrogenic hypotension induced by the improper treatment of normal grief"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP024871",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nSuicide is a major cause of premature mortality in patients with epilepsy. We aimed to identify the clinical correlates of suicide in these patients.\n\n\nMETHODS\nWe conducted a matched, case-control study based on a clinical case registry of epilepsy patients (n = 35,638) treated between January 1994 and December 2011 at an academic tertiary medical center in Seoul, Korea. Each epilepsy patient in the suicide group (n = 74) was matched with three epilepsy patients in the nonsuicide group (n = 222) by age, gender, and approximate time at first treatment. The clinical characteristics of the patients in both groups were then compared.\n\n\nRESULTS\nIn a univariate analysis, seizure frequency during the year before suicide, use of antiepileptic drug polytherapy, lack of aura before seizure, diagnosis of temporal lobe epilepsy, use of levetiracetam, psychiatric comorbidity, and use of antidepressants were all significantly higher in the suicide group than in the nonsuicide group. Multivariate analysis revealed that a high seizure frequency (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.04-10.2), a lack of aura before seizure (OR 4.0, 95% CI 1.7-9.3), temporal lobe epilepsy (OR 3.7, 95% CI 1.6-8.6), and use of levetiracetam (OR 7.6, 95% CI 1.1-53.7) and antidepressants (OR 7.2, 95% CI 1.5-34.1) were all associated with a higher probability of suicide.\n\n\nCONCLUSIONS\nPatients with temporal lobe epilepsy who experience seizures weekly or more frequently, experience a lack of aura, use levetiracetam, or take antidepressants are all at a higher risk of suicide and should be monitored closely.",
"affiliations": "Department of Psychology, Seoul National University, Seoul, Korea.;Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, U.S.A.;Department of Psychiatry, Asan Medical Center, College of Medicine University of Ulsan, Seoul, Korea.;Department of Psychiatry, Seoul National University, Seoul, Korea.;Department of Neurology, Asan Medical Center, College of Medicine University of Ulsan, Seoul, Korea.;Department of Psychology, Seoul National University, Seoul, Korea.;Department of Neurology, Asan Medical Center, College of Medicine University of Ulsan, Seoul, Korea.;Department of Neurology, Asan Medical Center, College of Medicine University of Ulsan, Seoul, Korea.;Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Park|Sung-Jin|SJ|;Lee|Hochang Benjamin|HB|;Ahn|Myung Hee|MH|;Park|Subin|S|;Choi|Eun Ju|EJ|;Lee|Hoon-Jin|HJ|;Ryu|Han Uk|HU|;Kang|Joong-Koo|JK|;Hong|Jin Pyo|JP|",
"chemical_list": "D000927:Anticonvulsants; D000928:Antidepressive Agents; D000077287:Levetiracetam; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.13226",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "56(12)",
"journal": "Epilepsia",
"keywords": "Aura; Levetiracetam; Seizure frequency; Temporal lobe epilepsy",
"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D000928:Antidepressive Agents; D016022:Case-Control Studies; D004827:Epilepsy; D004833:Epilepsy, Temporal Lobe; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam; D056910:Republic of Korea; D012307:Risk Factors; D013405:Suicide; D055815:Young Adult",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "1966-72",
"pmc": null,
"pmid": "26530473",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Identifying clinical correlates for suicide among epilepsy patients in South Korea: A case-control study.",
"title_normalized": "identifying clinical correlates for suicide among epilepsy patients in south korea a case control study"
} | [
{
"companynumb": "KR-UCBSA-2015038336",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Enterococci are an uncommon cause of CNS infection. A 20 month-old boy, diagnosed with hydrocephalus with ventriculoperitoneal shunt and history of lengthy hospitalization and use of wide spectrum antibiotics, was admitted to the pediatric intensive care unit diagnosed with ventriculitis. On the 14th day of empirical antibiotic therapy (vancomycin and meropenem) the child presented fever while the CSF sample culture evidenced vancomycin-resistant Enterococcus faecium. The patient received intravenous linezolid achieving cerebrospinal fluid sterilization.\n\n\nCONCLUSIONS\nIntravenous linezolid appears to be a safe and effective therapy for vancomycin-resistant enterococcus ventriculoperitoneal shunt infection.",
"affiliations": "Pediatric Intensive Care Unit, Department of Pediatrics, State Hospital of Diadema, Federal University of São Paulo, São Paulo, SP, Brazil. psls.nat@terra.com.br",
"authors": "da Silva|Paulo Sérgio Lucas|PS|;Monteiro Neto|Henrique|H|;Sejas|Lílian Márcia|LM|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "Brazil",
"delete": false,
"doi": "10.1590/s1413-86702007000200027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1413-8670",
"issue": "11(2)",
"journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases",
"keywords": null,
"medline_ta": "Braz J Infect Dis",
"mesh_terms": "D000081:Acetamides; D000890:Anti-Infective Agents; D002552:Cerebral Ventricles; D004660:Encephalitis; D016984:Enterococcus faecium; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D006849:Hydrocephalus; D007223:Infant; D000069349:Linezolid; D008297:Male; D023303:Oxazolidinones; D016896:Treatment Outcome; D020713:Vancomycin Resistance; D017287:Ventriculoperitoneal Shunt",
"nlm_unique_id": "9812937",
"other_id": null,
"pages": "297-9",
"pmc": null,
"pmid": "17625782",
"pubdate": "2007-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of vancomycin-resistant enterococcus ventriculitis in a child.",
"title_normalized": "successful treatment of vancomycin resistant enterococcus ventriculitis in a child"
} | [
{
"companynumb": "BR-PFIZER INC-2007UW19712",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Midostaurin is a multitargeted tyrosine kinase inhibitor approved by the Food and Drug Administration for FMS-related tyrosine kinase 3-positive acute myeloid leukemia in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation. The pharmacokinetics of midostaurin in the setting of severe renal impairment (creatinine clearance [CrCl] 15-29 mL/min utilizing Cockcroft-Gault method) and end-stage renal disease are unknown. Midostaurin is primarily metabolized by the liver through the CYP3A4 enzyme with fecal excretion accounting for 95% of the dose (4% recovered as unchanged drug). Only 5% of the parent drug is found in the urine. This is the first case report documenting the administration of midostaurin in two patients with end-stage renal disease on HD. Given the limited excretion of both active and inactive metabolites of midostaurin in the urine, one does not expect an increase in toxicity related to impaired drug excretion. Although this report describes the likely successful utilization of midostaurin, caution should be exercised when administering in patient populations with end organ disease. Medical history, concomitant comorbidities, and goals of therapy should be taken into account.",
"affiliations": "1 College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.;2 Division of Pharmacy, Rush University Medical Center, Chicago, IL, USA.;2 Division of Pharmacy, Rush University Medical Center, Chicago, IL, USA.;3 College of Pharmacy, Midwestern University, Downers Grove, IL, USA.",
"authors": "Tollkuci|Eris|E|;Seddon|Amanda|A|;Geswein|Laura|L|;Mulseh|Musa|M|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019311:Staurosporine; C059539:midostaurin",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218801067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Acute myeloid leukemia; FMS-related tyrosine kinase 3; end-stage renal disease; hemodialysis; midostaurin",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D006435:Renal Dialysis; D019311:Staurosporine",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1285-1288",
"pmc": null,
"pmid": "30253726",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Midostaurin administration in two hemodialysis patients.",
"title_normalized": "midostaurin administration in two hemodialysis patients"
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"abstract": "Peripheral facial nerve paralysis in children might be an alarming sign of serious disease such as malignancy, systemic disease, congenital anomalies, trauma, infection, middle ear surgery, and hypertension. The cases of 40 consecutive children and adolescents who were diagnosed with peripheral facial nerve paralysis at Baskent University Adana Hospital Pediatrics and Pediatric Neurology Unit between January 2010 and January 2013 were retrospectively evaluated. We determined that the most common cause was Bell palsy, followed by infection, tumor lesion, and suspected chemotherapy toxicity. We noted that younger patients had generally poorer outcome than older patients regardless of disease etiology. Peripheral facial nerve paralysis has been reported in many countries in America and Europe; however, knowledge about its clinical features, microbiology, neuroimaging, and treatment in Turkey is incomplete. The present study demonstrated that Bell palsy and infection were the most common etiologies of peripheral facial nerve paralysis.",
"affiliations": "Department of Pediatrics, Baskent University Faculty of Medicine, Adana, Turkey dryaseminozkale@gmail.com.;Division of Child Neurology, Department of Pediatrics, Baskent University Faculty of Medicine, Adana, Turkey.;Division of Child Neurology, Department of Pediatrics, Baskent University Faculty of Medicine, Adana, Turkey.;Department of Otolaryngology-Head and Neck Surgery, Baskent University Faculty of Medicine, Adana, Turkey.",
"authors": "Özkale|Yasemin|Y|;Erol|İlknur|İ|;Saygı|Semra|S|;Yılmaz|İsmail|İ|",
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"issue": "30(2)",
"journal": "Journal of child neurology",
"keywords": "Bell palsy; Lyme disease; child; peripheral facial nerve paralysis",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D005158:Facial Paralysis; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D010523:Peripheral Nervous System Diseases; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015898:Tomography Scanners, X-Ray Computed; D014421:Turkey",
"nlm_unique_id": "8606714",
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"pages": "193-9",
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"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
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"title": "Overview of pediatric peripheral facial nerve paralysis: analysis of 40 patients.",
"title_normalized": "overview of pediatric peripheral facial nerve paralysis analysis of 40 patients"
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"abstract": "BACKGROUND\nOesophageal submucosal hematoma is a rare perioperative complication. When this complication develops after endovascular surgery, which requires postoperative antiplatelet therapy, whether to stop antiplatelet therapy or not is controversial. If antiplatelet therapy is discontinued, the appropriate time to resume antiplatelet therapy is unclear.\n\n\nMETHODS\nA 75-year-old woman (height 134 cm, weight 37 kg) underwent flow diverter embolization for unruptured cerebral aneurysm under general anaesthesia. The patient received dual antiplatelet therapy before surgery and anticoagulation therapy intraoperatively. After surgery, the patient developed hematemesis and was diagnosed with oesophageal submucosal hematoma. Conservative treatment was initiated after discontinuing antiplatelet therapy, which was resumed 3 days after surgery. The patient showed good recovery even after the resumption of antiplatelet therapy.\n\n\nCONCLUSIONS\nIn our case, we successfully treated oesophageal submucosal hematoma developing after endovascular surgery with early resumption of postoperative antiplatelet therapy.",
"affiliations": "Department of Anesthesiology, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-Ku, Osaka-city, Osaka, 540-0006, Japan.;Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.;Department of Anesthesiology, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-Ku, Osaka-city, Osaka, 540-0006, Japan.;Department of Anesthesiology, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-Ku, Osaka-city, Osaka, 540-0006, Japan. shibuya.hiromi.np@mail.hosp.go.jp.",
"authors": "Takeyama|Eriko|E|http://orcid.org/0000-0003-1889-2062;Wada|Aiko|A|;Amano|Eizo|E|;Shibuya|Hiromi|H|",
"chemical_list": null,
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"doi": "10.1186/s40981-018-0222-x",
"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJA Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 22210.1186/s40981-018-0222-xCase ReportOesophageal submucosal hematoma after flow diverter embolization with favourable outcome treated by discontinuing postoperative antiplatelet therapy for only three days: a case report http://orcid.org/0000-0003-1889-2062Takeyama Eriko erk.aikawa@gmail.com 1Wada Aiko aikooo1129@gmail.com 2Amano Eizo shizuseijin87@bluesky.zaq.jp 1Shibuya Hiromi shibuya.hiromi.np@mail.hosp.go.jp 11 0000 0004 0377 7966grid.416803.8Department of Anesthesiology, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-Ku, Osaka-city, Osaka, 540-0006 Japan 2 0000 0004 0373 3971grid.136593.bDepartment of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, Osaka, 565-0871 Japan 8 1 2019 8 1 2019 12 2019 5 26 12 2018 26 12 2018 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nOesophageal submucosal hematoma is a rare perioperative complication. When this complication develops after endovascular surgery, which requires postoperative antiplatelet therapy, whether to stop antiplatelet therapy or not is controversial. If antiplatelet therapy is discontinued, the appropriate time to resume antiplatelet therapy is unclear.\n\nCase presentation\nA 75-year-old woman (height 134 cm, weight 37 kg) underwent flow diverter embolization for unruptured cerebral aneurysm under general anaesthesia. The patient received dual antiplatelet therapy before surgery and anticoagulation therapy intraoperatively. After surgery, the patient developed hematemesis and was diagnosed with oesophageal submucosal hematoma. Conservative treatment was initiated after discontinuing antiplatelet therapy, which was resumed 3 days after surgery. The patient showed good recovery even after the resumption of antiplatelet therapy.\n\nConclusions\nIn our case, we successfully treated oesophageal submucosal hematoma developing after endovascular surgery with early resumption of postoperative antiplatelet therapy.\n\nKeywords\nOesophageal submucosal hematomaEndovascular surgeryAntiplatelet therapyissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nOesophageal submucosal hematoma is a rare perioperative complication. There have been several reports of this complication after endovascular surgery, which requires perioperative antiplatelet therapy. For these cases, physicians have to treat patients considering both the management of haemorrhage associated with the oesophageal submucosal hematoma and the prevention of thromboembolic complications after endovascular treatment. We report a case of oesophageal submucosal hematoma after placement of a flow diverter, a new-generation endovascular device for unruptured cerebral aneurysm-associated long-term postoperative antiplatelet therapy to prevent thromboembolic complications. We treated the patient successfully by suspending the antiplatelet therapy temporally and resuming it 3 days after hematoma development. To the best of our knowledge, this is the first report of a patient with oesophageal submucosal hematoma resuming antiplatelet therapy after only 3 days of suspension.\n\nCase presentation\nA 75-year-old woman (height 134 cm, weight 37 kg) underwent flow diverter placement for an unruptured cerebral aneurysm under general anaesthesia. Her medical history and preoperative complications were unremarkable. Preoperative laboratory data were within normal limits, with no coagulation abnormalities. She received dual antiplatelet therapy with aspirin and clopidogrel beginning 10 days prior to surgery.\n\nAnaesthesia was induced with a target-controlled infusion of propofol (3.0 μg/ml) and fentanyl (50 μg). After administration of rocuronium (30 mg), tracheal intubation was performed uneventfully with a video laryngoscope (McGRATH MAC™), followed by smooth insertion of a gastric tube. The gastric tube was maintained without suction intraoperatively. Anaesthesia was maintained with target-controlled infusion of propofol and remifentanil 0.05–0.1 μg/kg/min with an inhaled oxygen concentration of 42% under standard monitoring, as well as direct radial artery pressure monitoring.\n\nHeparin (4000 units) was intravenously administered at the beginning of surgery. Activating clotting time was 159, 254, and 244 s before surgery, 15 min after starting surgery, and at the end of surgery, respectively. The operative approach was from the femoral artery. Surgery was performed without complications. Protamine was not administered at the end of surgery. Intraoperatively, the patients’ blood pressure remained at 80–120/40–50 mmHg and her heart rate remained at 55–65 beats/min with no acute hemodynamic changes.\n\nContinuous infusion of propofol and remifentanil were discontinued at the completion of surgery. The patient awakened 20 min after completion of surgery, and her systolic blood pressure increased to 150 mmHg. The gastric tube was removed without any abnormal findings, such as blood in the secretions. The tracheal tube was removed smoothly. Continuous infusion of argatroban was initiated at completion of surgery. The operation time was 97 min, and anaesthesia time was 172 min.\n\nDue to systolic blood pressure greater than 150 mmHg, continuous infusion of nicardipine was initiated to maintain systolic pressure below 140 mmHg after entering the recovery room. The patient started to complain of chest pain 90 min after entering the recovery room. At that time, her blood pressure was 155/77 mmHg and her pulse rate was approximately 70 bpm. The electrocardiogram was unremarkable, and blood biochemical haemostatic function testing showed no abnormal findings without prolonged activated partial thromboplastin time (120 s). She developed hematemesis 120 min after entering the recovery room. Her blood pressure and heart rate remained stable. Emergent computed tomography (CT) was performed. Although the vascular system was normal, expansion of the oesophagus was noted (Fig. 1). Due to a decrease in blood pressure to 90/47 mmHg and haemoglobin level from 11.7 to 8.7 g/dL, the patient was given fluid resuscitation and was transfused with 6 units of red blood cells and 6 units of fresh frozen plasma following CT examination. Considering the risk of tracheal aspiration, we performed tracheal intubation. Upper gastrointestinal endoscopy (UGE) was performed, and an oesophageal submucosal hematoma extending longitudinally on the right wall, 17 cm from the incisor, was noted. Because a narrowed lumen and oozing due to scope contact were recognised, observation was limited to the lower oesophagus (Fig. 2).Fig. 1 Computed tomography thoracic examination immediately after hematemesis. The thoracic oesophagus is dilated. The white arrow indicates the oesophagus\n\nFig. 2 Upper gastrointestinal endoscopy images after hematemesis. a The submucosal hematoma occupied the oesophagus. b, a Longitudinal extension of reddish or wine-coloured mucosal thickening (asterisk), obstructing the oesophagus, is seen from the cervical oesophagus to the thoracic oesophagus\n\n\n\nConservative treatment was initiated with the cessation of continuous infusion of argatroban and the planned postoperative antiplatelet therapy. CT performed 2 days postoperatively showed reduced dilation of the oesophagus, and thus, the tracheal tube was removed. A nasogastric tube was inserted 3 days after surgery without any abnormal findings, and antiplatelet therapy was resumed on the same day. The patient had no symptoms even after the resumption of antiplatelet therapy. UGE performed 11 days postoperatively showed that the submucosal hematoma was almost completely resolved, and solid food intake was resumed. The patient showed good recovery and was discharged 27 days after surgery.\n\nDiscussion\nOesophageal submucosal hematoma is a rare condition. The spontaneous type of oesophageal submucosal hematoma is considered to be caused by the rupture of blood vessels in the submucosal layer [1], as the result of a sudden increase in pressure induced by factors such as nausea and vomiting. It is also suggested that oesophageal submucosal hematoma is associated with bleeding tendency, such as antiplatelet or anticoagulant therapy [2]. Although reports of intraoperative oesophageal submucosal hematoma are rare, a few cases have been reported of this complication after endovascular surgery for unruptured cerebral aneurysms. Endovascular surgery requires perioperative antiplatelet therapy, which could be associated with the development of oesophageal submucosal hematoma. The prognosis of this complication is generally good, and approximately 90% of reported cases receiving antiplatelet therapy had been treated conservatively with cessation of postoperative antiplatelet therapy [3–9].\n\nThe flow diverter is a new-generation stent placed in the parent artery at the level of the aneurysm neck to disrupt inflow into the aneurysm sac and, thus, favour intra-aneurysm thrombosis. It is clinically used for large cerebral aneurysms that are difficult to treat with coil embolization. Conversely, long-term postoperative antiplatelet therapy is necessary to prevent severe thromboembolic complications, since a prolonged time period is required for aneurysm resolution. However, there are no clear criteria for drug selection, administration period, and short-term discontinuation of antiplatelet therapy due to haemorrhagic events.\n\nTherefore, oesophageal submucosal hematoma after flow diverter placement must be treated considering not only the risk of bleeding but also the possibility of thromboembolic complications.\n\nConsidering the risk of bleeding, the risk of potentially severe oesophageal submucosal hematoma should be considered. Although this complication often shows a good prognosis, cases of haemorrhagic shock associated with the onset of oesophageal submucosal hematoma have been reported [4]. In our case, the patient developed massive bleeding requiring transfusion. As the guideline for flow diverter use recommends cessation of antiplatelet therapy when a severe bleeding event occurs, discontinuation of antiplatelet therapy immediately after the development of this complication can be considered reasonable.\n\nAfter cessation of antiplatelet therapy, the optimum timing to resume treatment is a serious concern due to the possibility of thromboembolic complications. While there are no broadly accepted practice patterns addressing dual antiplatelet therapy in the flow diversion literature, the length and dose of antiplatelet therapy are reported to correlate with a decreased incidence of thrombotic and haemorrhagic events after flow diverter placement [10]. In our case, we diagnosed haemostasis at a relatively early stage by CT examination and resumed treatment 3 days after surgery. Even after the resumption of antiplatelet therapy, the patient did not show relapse of symptoms and had a favourable course. In almost every reported case treated conservatively, hematoma contraction has been confirmed by CT or upper gastrointestinal endoscopy within 4 to 7 days after onset. These reports may suggest that active bleeding stops at this time point and that resumption of antiplatelet therapy may be considered.\n\nIn conclusion, the risk of oesophageal submucosal hematoma development after endovascular surgery should be considered. When postoperative antiplatelet therapy is necessary, such as flow diversion, it may be beneficial to perform periodic reassessments for haemostasis or oesophageal submucosal hematoma, and early resumption of antiplatelet therapy may be considered with careful observation.\n\nAbbreviations\nCTComputed tomography\n\nUGEUpper gastrointestinal endoscopy\n\nAcknowledgements\nNone.\n\nFunding\nThis research did not receive any specific grant from agencies in the public, commercial, or not-for profit sectors.\n\nAvailability of data and materials\nThe datasets analysed in this article are included within article.\n\nAuthors’ contributions\nAW and HS provided anaesthetic care. ET and EA drafted the manuscript. All authors revised the manuscript critically and approved the final version for publication.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\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. Freeman AH Dickinson RJ Spontaneous intramural oesophageal haematoma Clin Radiol 1988 39 628 634 10.1016/S0009-9260(88)80076-X 3266591 \n2. Hong M Warum D Karamanian A Spontaneous intramural esophageal hematoma (IEH) secondary to anticoagulation and/or thrombolysis therapy in the setting of a pulmonary embolism: a case report J Radiol Case Rep 2013 7 1 10 23705034 \n3. Yamashita K Okuda H Fukushima H Arimura Y Endo T Imai K A case of intramural esophageal hematoma: complication of anticoagulation with heparin Gastrointest Endosc 2000 52 559 561 10.1067/mge.2000.108664 11023585 \n4. Ito S Iwata S Kondo I Iwade M Ozaki M Ishikawa T Esophageal submucosal hematoma developed after endovascular surgery for unruptured cerebral aneurysm under general anesthesia: a case report JA Clin Rep 2017 3 54 10.1186/s40981-017-0124-3 29457098 \n5. Fujimoto Y Shirozu K Shirozu N Akiyoshi K Nishimura A Kawasaki S Esophageal submucosal hematoma possibly caused by gastric tube insertion under general anesthesia A A Case Rep 2016 7 169 171 10.1213/XAA.0000000000000376 27467902 \n6. Chiu YH Chen JD Hsu CY How CK Yen DH Huang CI Spontaneous esophageal injury: esophageal intramural hematoma J Chin Med Assoc 2009 72 498 500 10.1016/S1726-4901(09)70416-2 19762321 \n7. Oe S Watanabe K Kume K Shibata M Hiura M Yoshikawa I Harada M A case of idiopathic gastroesophageal submucosal hematoma and its disappearance observed by endoscopy JUEOH 2014 1 123 128 \n8. Saito S Hosoya Y Kurashina K Yokoyama T Arai W Hyodo M Esophageal submucosal hematoma: a case report and review of the literature Esophagus 2005 2 3 155 159 10.1007/s10388-005-0049-1 \n9. Polat C Dervisoglu A Guven H Kaya E Malazgirt Z Danaci M Ozkan K Anticoagulant-induced intramural intestinal hematoma Am J Emerg Med 2003 21 208 211 10.1016/S0735-6757(02)42258-9 12811714 \n10. Skukalek SL Winkler AM Kang J Dion JE Cawley CM Webb A Effect of antiplatelet therapy and platelet function testing on hemorrhagic and thrombotic complications in patients with cerebral aneurysms treated with the pipeline embolization device: a review and meta-analysis J Neurointerv Surg 2016 8 58 65 10.1136/neurintsurg-2014-011145 25385746\n\n",
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"keywords": "Antiplatelet therapy; Endovascular surgery; Oesophageal submucosal hematoma",
"medline_ta": "JA Clin Rep",
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"pmid": "32025915",
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"title": "Oesophageal submucosal hematoma after flow diverter embolization with favourable outcome treated by discontinuing postoperative antiplatelet therapy for only three days: a case report.",
"title_normalized": "oesophageal submucosal hematoma after flow diverter embolization with favourable outcome treated by discontinuing postoperative antiplatelet therapy for only three days a case report"
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"abstract": "Negative pressure pulmonary oedema is well described in the literature as an uncommon but recognised complication of general anaesthe sia; negative pressure diffuse alveolar haemorrhage is a rarer consequence. We report a case of massive haemoptysis following elective general anaesthesia using a laryngeal mask airway device and sevoflurane anaesthetic maintenance. The patient had no obvious signs of laryngospasm or other cause of upper airway obstruction perioperatively. We explore the possibility that the haemoptysis was caused by clinically unapparent negative pressure generation, but also ask whether the anaesthetic agent should be considered as a culprit.",
"affiliations": "Anaesthetics, St Mary's Hospital, Paddington, London, UK.;Respiratory Medicine, St Mary's Hospital, Paddington, London, UK.",
"authors": "Mersh|Rebecca|R|;Ross|Clare|C|",
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"mesh_terms": "D000328:Adult; D018685:Anesthetics, Inhalation; D004452:Echocardiography; D006469:Hemoptysis; D006801:Humans; D017214:Laryngeal Masks; D008171:Lung Diseases; D055370:Lung Injury; D008297:Male; D008738:Methyl Ethers; D019106:Postoperative Hemorrhage; D011312:Pressure; D011650:Pulmonary Alveoli; D011654:Pulmonary Edema; D000077149:Sevoflurane; D014057:Tomography, X-Ray Computed",
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"title": "Postoperative diffuse alveolar haemorrhage: insidious negative pressure or sevoflurane induced?",
"title_normalized": "postoperative diffuse alveolar haemorrhage insidious negative pressure or sevoflurane induced"
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"abstract": "BACKGROUND\nPheochromocytoma is a tumor originating in the chromaffin cells. These tumors secrete catecholamines which act on target organs and cause hypertensive crises. They are rare during pregnancy, and a differential diagnosis must be carried out mainly with pregnancy-induced hypertension.\n\n\nMETHODS\nA 22-year-old patient in week 11.5 of pregnancy presented at the Hospital General Dr. Miguel Silva in Morelia, Michoacán with hypertension that had existed for more than two years with poor adherence to treatment. At the time of referral to our unit she presented a hypertensive crisis that had been unresponsive to all antihypertensive treatments. Following the establishment of a study protocol, a diagnosis of posterior left adrenal pheochromocytoma was made. After subsequent pharmacological treatment with alpha and beta blockers, a left adrenalectomy was performed. The patient did not require antihypertensive treatment following surgery. The histopathological report indicates the presence of a nodular and vascularized left adrenal gland weighing 25 g and measuring 5 x 4 x 3.5 cm. Gland consistency was soft, and the presence of cystic lesions in parenchymal tissue was noted. A yellowish-brown color and sponge-like appearance were also present. Such features support a diagnosis of pheochromocytoma. The pregnancy continued normally until week 32, when the patient presented to our department with active-phase preterm labor. A Cesarean section was performed with the delivery of a live female weighing 1400 gr. The infant is currently alive and well.\n\n\nCONCLUSIONS\nThus, it is important that obstetrician knows this disease and its management during pregnancy; so we present this case report.",
"affiliations": null,
"authors": "Merlos-Gutiérrez|Ana Laura|AL|;Martínez-García|Manuel|M|;Pérez-Martínez|Andrés|A|;Chávez-Martínez|Sareni|S|;Sereno-Coló|José Antonio|JA|",
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"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000315:Adrenalectomy; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D046110:Hypertension, Pregnancy-Induced; D010673:Pheochromocytoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D055815:Young Adult",
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"title": "Pheochromocytoma and pregnancy. A case report.",
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{
"abstract": "The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.",
"affiliations": "Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Bristol, BS8 2BN, UK.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, 5000, Australia.;Pathology Queensland and School of Medicine, University of Queensland, St Lucia, QLD, 4006, Australia.;Rajiv Gandhi Centre for Biotechnology, Thycaud Post, Poojappura, Thiruvananthapuram, Kerala, 695014, India.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Department of Medical Oncology, Hospital Universitario Virgen del Rocío, 41013, Sevilla, Spain.;Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, 28040, Madrid, Spain.;Department of Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, IBIMA, 29010, Málaga, Spain.;GEICAM, Spanish Breast Cancer Group, Madrid, 28703, Spain.;GEICAM, Spanish Breast Cancer Group, Madrid, 28703, Spain.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, 5000, Australia.;Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, 28040, Madrid, Spain.;Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. a.swarbrick@garvan.org.au.",
"authors": "Cazet|Aurélie S|AS|http://orcid.org/0000-0001-7075-8448;Hui|Mun N|MN|;Elsworth|Benjamin L|BL|;Wu|Sunny Z|SZ|;Roden|Daniel|D|;Chan|Chia-Ling|CL|;Skhinas|Joanna N|JN|;Collot|Raphaël|R|;Yang|Jessica|J|;Harvey|Kate|K|;Johan|M Zahied|MZ|;Cooper|Caroline|C|;Nair|Radhika|R|;Herrmann|David|D|http://orcid.org/0000-0002-9514-7501;McFarland|Andrea|A|;Deng|Niantao|N|;Ruiz-Borrego|Manuel|M|;Rojo|Federico|F|;Trigo|José M|JM|;Bezares|Susana|S|;Caballero|Rosalía|R|;Lim|Elgene|E|;Timpson|Paul|P|;O'Toole|Sandra|S|;Watkins|D Neil|DN|;Cox|Thomas R|TR|http://orcid.org/0000-0001-9294-1745;Samuel|Michael S|MS|http://orcid.org/0000-0001-7880-6379;Martín|Miguel|M|;Swarbrick|Alexander|A|",
"chemical_list": "D000813:Anilides; D001713:Biphenyl Compounds; C538724:HhAntag691; D011725:Pyridines; C561435:sonidegib; D000077143:Docetaxel",
"country": "England",
"delete": false,
"doi": "10.1038/s41467-018-05220-6",
"fulltext": "\n==== Front\nNat CommunNat CommunNature Communications2041-1723Nature Publishing Group UK London 522010.1038/s41467-018-05220-6ArticleTargeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer http://orcid.org/0000-0001-7075-8448Cazet Aurélie S. 123Hui Mun N. 1245Elsworth Benjamin L. 6Wu Sunny Z. 123Roden Daniel 123Chan Chia-Ling 12Skhinas Joanna N. 12Collot Raphaël 12Yang Jessica 12Harvey Kate 12Johan M. Zahied 78Cooper Caroline 9Nair Radhika 10http://orcid.org/0000-0002-9514-7501Herrmann David 123McFarland Andrea 12Deng Niantao 123Ruiz-Borrego Manuel 11Rojo Federico 12Trigo José M. 13Bezares Susana 14Caballero Rosalía 14Lim Elgene 12315Timpson Paul 123O’Toole Sandra 125Watkins D. Neil 12315http://orcid.org/0000-0001-9294-1745Cox Thomas R. 123http://orcid.org/0000-0001-7880-6379Samuel Michael S. 78Martín Miguel 16Swarbrick Alexander a.swarbrick@garvan.org.au 1231 0000 0000 9983 6924grid.415306.5Garvan Institute of Medical Research, Darlinghurst, NSW 2010 Australia 2 grid.410697.dThe Kinghorn Cancer Centre, Darlinghurst, NSW 2010 Australia 3 0000 0004 4902 0432grid.1005.4St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW 2010 Australia 4 grid.419783.0The Chris O’ Brien Lifehouse, Camperdown, NSW 2050 Australia 5 0000 0004 0385 0051grid.413249.9Royal Prince Alfred Hospital, Camperdown, NSW 2050 Australia 6 0000 0004 1936 7603grid.5337.2MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Bristol, BS8 2BN UK 7 0000 0000 8994 5086grid.1026.5Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA 5000 Australia 8 0000 0004 1936 7304grid.1010.0Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, SA 5000 Australia 9 0000 0000 9320 7537grid.1003.2Pathology Queensland and School of Medicine, University of Queensland, St Lucia, QLD 4006 Australia 10 0000 0001 0177 8509grid.418917.2Rajiv Gandhi Centre for Biotechnology, Thycaud Post, Poojappura, Thiruvananthapuram, Kerala 695014 India 11 0000 0000 9542 1158grid.411109.cDepartment of Medical Oncology, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain 12 grid.419651.eDepartment of Pathology, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain 13 grid.452525.1Department of Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, IBIMA, 29010 Málaga, Spain 14 grid.476406.7GEICAM, Spanish Breast Cancer Group, Madrid, 28703 Spain 15 0000 0000 9119 2677grid.437825.fSt Vincent’s Hospital, 2010 Darlinghurst, NSW Australia 16 0000 0001 2157 7667grid.4795.fDepartment of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, 28040 Madrid, Spain 24 7 2018 24 7 2018 2018 9 289718 2 2018 21 6 2018 © The Author(s) 2018Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.\n\nStromal cell recruitment, activation and crosstalk with cancer cells is poorly understood. Here, the authors demonstrate that cancer cell-derived Hedgehog ligand triggers stromal remodeling that in turn induces a cancer-stem-cell like, drug-resistant phenotype of nearby cancer cells while treatment with smoothened inhibitors reverses these phenotypes.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nCarcinogenesis draws many parallels with developmental biology. During development, dynamic interaction between stromal and epithelial cells drives patterning and function. Cell fate specification occurs through activation of transcriptional cascades in response to extracellular signals from developmental signaling pathways such as Hedgehog (Hh), Wnt, Notch, BMP (bone morphogenetic proteins), and FGF (fibroblast growth factor)1,2. These pathways direct developmental processes either by direct cell-to-cell contact or through secreted diffusible factors (paracrine signaling). They can act individually or in concert with each other. For example, the interaction between Hh and FGF signaling pathways has been shown to mediate tracheal and lung branching morphogenesis3. In mature, differentiated tissues, these pathways are quiescent but may be reactivated to drive repair and regeneration to maintain tissue homeostasis.\n\nMore specifically, the Hh developmental pathway is reactivated in a subset of cancers. Binding of Hh ligand to its receptor Patched (PTCH) enables Smoothened (SMO)-mediated translocation of Gli1 into the cell nucleus to drive the transcription of Hh target genes4. Mutations in Hh pathway components are oncogenic drivers in “Gorlin’s-like” cancers such as medulloblastoma and basal cell carcinoma where tumors rely on cell-autonomous Hh signaling5. Small molecule inhibitors of SMO (SMOi), Vismodegib and Sonidegib, are well-tolerated and clinically approved for the treatment of these lesions5. In contrast, many other solid tumors, including breast cancer, predominantly exhibit ligand-dependent pathway activation4–6. While Hh signaling is quiescent in the adult mammary gland, Hh ligand expression is reactivated in a subset of breast cancers, particularly the poor-prognosis triple negative breast cancer (TNBC) subtype6. Thirty percent of TNBCs exhibit paracrine Hh pathway signature, defined by high epithelial HH ligand expression in combination with high stromal GLI1 expression, which is associated with a greater risk of metastasis and breast cancer-specific death6.\n\nNeoplastic cells co-opt components of the tumor microenvironment (TME) to further their progression. The TME is a complex ecosystem comprising a myriad of neoplastic and nonmalignant cells embedded in a glycoprotein-rich extracellular matrix (ECM). Prominent cell types include the endothelium, cells of the immune system and cancer-associated fibroblasts (CAFs). In addition to its role as a physical scaffold to support tissue architecture, the ECM also functions as a signal transducer between the different TME cell types7. The stiffness of the ECM and the abundance of fibrillar collagen immediately adjacent to epithelial lesions provide mechanical signals that facilitate tumor development and progression8,9. Not surprisingly, the TME has emerged as a major determinant of cancer phenotype. In breast cancer, stromal metagenes, in particular those associated with ECM remodeling, strongly predict prognosis and response to chemotherapy10,11.\n\nWhile it is now apparent that Hh signals in a paracrine manner in animal models of TNBC6 and in isolated cancer stem cells (CSCs)12, a detailed study of the dynamic crosstalk within the TME is required to make clinical progress in integrating anti-stromal therapies into breast cancer treatment. Progress has been impeded by the field’s limited understanding of the mechanisms underlying tumor−stromal interactions, a limited repertoire of well-tolerated agents to target the TME, and an absence of predictive biomarkers for response to TME-directed therapies. In this study, we showed that CAFs are the primary stromal cells that respond to Hh ligand stimulation. Activated CAFs in turn provide a conducive environment for neoplastic cells to acquire a chemo-resistant stem-like phenotype. SMOi treatment sensitized tumors to docetaxel chemotherapy in mouse models and in patients from the EDALINE Phase I clinical trial, resulting in reduced metastatic burden and improved survival.\n\nResults\nHh-tumors are enriched for a reversible CSC-like phenotype\nTo investigate the mechanistic basis for Hh-dependent tumor growth and metastasis in TNBC, we used the murine M6 allograft model of low grade TNBC, in which transgenic Hh expression drives invasion, metastasis, and high-grade morphology6 (M6-Hh; Supplementary Fig. 1a). Treatment with the SMO inhibitor (SMOi) GDC-0449 (Vismodegib; 100 mg/kg/bid) slowed tumor growth, reduced metastatic burden and improved overall animal survival of M6-Hh tumors (Supplementary Fig. 1b–d). M6-Ctrl and M6-Hh monoculture cell viability were similar between vehicle and SMOi treatment and the expression of canonical Hh target genes Ptch, Gli1, and Hhip were downregulated in vivo but not in vitro, consistent with a paracrine requirement for Hh signaling as previously reported6,12,13 (Supplementary Fig. 1e–g). The effects of SMO inhibition on tumor growth and gene expression were not observed in control tumors lacking Hh expression (M6-Ctrl) or in benign adult mouse mammary gland (Supplementary Fig. 1b, g, h), reflecting on-target drug activities. Similar results were observed with the SMOi NVP-LDE-225 (Sonidegib; 80 mg/kg/day; Supplementary Fig. 1i, j).\n\nTo examine the transcriptional changes induced by Hh pathway activation in detail, we dissociated and analyzed freshly flow cytometry-sorted stromal and epithelial fractions of M6-Ctrl and M6-Hh tumors ± SMOi using RNA-Sequencing (RNA-Seq) (Fig. 1a). Differential gene expression analysis confirmed effective cellular fractionation, with Hh transgene expression restricted to the epithelial cell population while Hh target genes Ptch, Gli1, and Hhip expression were induced solely in the stromal fraction of M6-Hh tumors (Supplementary Data 1).Fig. 1 Malignant epithelial cells with increased self-renewal properties are located adjacent to the stroma of Hh-expressing cancers. a Scheme depicting the purification of epithelial and mixed stromal populations from disaggregated M6 murine tumor models. b Expression of genes significantly downregulated (blue) or upregulated (red) by RNA-Seq analysis (cut-off log2 (Fold Change) ≥ 2; vertical lines) in the epithelium of M6-Hh tumors compared to the epithelium of M6-Ctrl or M6-Hh tumors treated with the SMOi, GDC-0449 (100 mg/kg/bid), plotted against FDR values (horizontal lines indicate −log10 (FDR) > 2). Each symbol represents the transcriptome from five biological replicates per treatment group. c GSEA analysis reveals significant enrichment for genes encoding stemness and invasion in M6-Hh primary cells (FDR q value < 0.05). d Heat map showing relative CSC genes expression in the epithelium of M6-Hh tumors compared to M6-Ctrl and M6-Hh tumors + SMOi. Data show normalized row Z-score (n = 5 biological replicates for each treatment group). e Representative FACS dot plots showing the expression of CSC markers CD61 and CD29 within the EpCAM+/GFP+/CD24+ population of M6-Ctrl and M6-Hh tumors (n = 3 biological replicates per group). f Relative expression of key stemness genes in M6-Ctrl and M6-Hh whole tumors ± SMOi (100 mg/kg/bid). n = 3 biological replicates per treatment group; statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. g Kaplan−Meier and h tumor penetrance curves of mice injected with 250 primary M6-Ctrl (blue) or M6-Hh cells (violet); n = 10 biological replicates. Six tumors from the M6-Hh and two tumors from the M6-Ctrl models were detectable, respectively. Statistical significance was determined using log-rank test. i Primary M6-Ctrl and M6-Hh tumor cells were isolated by FACS and transplanted at various dilutions into recipient mice. Limiting dilution analysis demonstrating higher in vivo tumor-forming capacity in M6-Hh cells compared to M6-Ctrl cells. n = 10 mice per condition. j Representative images and quantification of CK6-progenitor and phospho-Histone H3-positive cancer cells at the tumor−stromal interface of M6 tumor models. Scale bars: 100 μm for CK6 and 200 μm for phospho-Histone H3. n = 3 biological replicates per treatment group. Statistical significance was determined using unpaired two-tailed Student’s t test; *P < 0.05; **P < 0.01. Bars represent mean ± s.e.m.\n\n\n\nIn the epithelial compartment, 67 genes were differentially expressed (>2-fold change, P < 0.001), with 60 upregulated and 7 downregulated genes in the neoplastic M6-Hh cells in comparison to M6-Ctrl or M6-Hh cells treated with SMOi. Transcriptional changes were robust and highly statistically significant (Fig. 1b). Hh expression in M6 cancer cells resulted in increased expression of stemness genes14 including Peg3 (>11-fold), Igfbp4 (>7-fold), and Thy1 (>4-fold), which were downregulated following SMO inhibition (Fig. 1b).\n\nGene set enrichment analysis (GSEA) and gene ontology (GO) analysis of the purified epithelial fraction highlighted enrichment for genes specifically and almost exclusively associated with mammary stemness and invasion, consistent with the morphologically undifferentiated phenotype previously observed in Hh-overexpressing tumors6 (Fig. 1c, d and Supplementary Data 1). To examine the CSC phenotype in greater detail, epithelial cells were profiled by flow cytometry. M6-Hh tumors had a higher proportion of CD61hi cells, previously shown to be a marker of mouse mammary CSCs15, within the EpCAM+CD24hiCD29+ cancer cell population (55.3% in M6-Hh tumors vs. 36.4% in M6-Ctrl tumors; Fig. 1e). M6-Hh tumors also had elevated expression of the stemness markers Id3, Gpc3, Thy1, Sox10, and Krt6, validating the RNA-Seq data (Fig. 1b, f). Following transplantation of low numbers of sorted primary M6-Hh and M6-Ctrl cells into naive recipients, tumors were detectable earlier, formed at a higher frequency and survival was shorter in the M6-Hh group (Fig. 1g, h). Limiting dilution assays16 were used to quantitate the impact of Hh signaling on tumor-initiating capacity. M6-Ctrl and M6-Hh tumor cells were isolated by FACS and transplanted at various dilutions. M6-Hh cells had significantly higher tumor-initiating capacity (1 in 435) compared with M6-Ctrl cells (1 in 1088; Fig. 1i). Importantly, the proliferation and expression of CSC markers were indistinguishable between M6-Ctrl and M6-Hh cells in monoculture, indicating that Hh expression in M6 cells does not regulate CSC properties in a cell-autonomous manner (Supplementary Fig. 1e).\n\nImmunohistochemical detection of the mammary progenitor marker cytokeratin 6 (CK6; product of the Krt6 gene)17 localized cells with a stem/progenitor signature specifically to the tumor−stromal interface (Fig. 1j). SMO inhibition reduced the expression of Id3, Gpc3, Thy1, Sox10, and Krt6 and significantly reduced the number of cells positive for CK6 and the mitotic marker phospho-Histone H3 at the tumor−stromal interface (Fig. 1f, j). These data demonstrate that paracrine Hh signaling results in the induction of a reversible stem-like phenotype preferentially at the tumor−stromal interface.\n\nHh-activated CAFs markedly remodel the ECM\nRNA-Seq analysis of the stromal fraction revealed 185 genes that were differentially expressed (>2-fold, P < 0.001), with 146 upregulated and 39 downregulated genes in the stroma of M6-Hh tumors compared to M6-Ctrl and M6-Hh tumor + SMOi (Supplementary Data 1). A number of genes were markedly upregulated by Hh signaling, in particular the growth factor gene Fgf5 at more than 290-fold, St8Sia2 (>40-fold) and Tspan11 (>4-fold; Fig. 2a). The large majority of gene expression changes in Hh-activated stroma returned to baseline following treatment with SMOi (Fig. 2a and Supplementary Data 1), suggesting that the stromal transcriptional changes are SMO-dependent and reversible.Fig. 2 Hh-activated stroma defines a novel transcriptional signature robustly associated with poor-prognosis in TNBC. a Expression of genes significantly downregulated (blue) or upregulated (red) (cut-off log2 (Fold Change) ≥ 2; vertical lines) in the stroma of M6-Hh tumors compared to the stroma of M6-Ctrl or M6-Hh tumors treated with SMOi (100 mg/kg/bid), plotted against FDR values (horizontal lines indicate −log10 (FDR) > 2). Each symbol represents the transcriptome of the stromal population from five biological replicates per treatment group. b RNA-Seq analysis reveals significant enrichment of GO groups related to ECM organization and production in M6-Hh tumor stroma (FDR q value < 0.05). c Heat maps demonstrating relative expression levels of gene-sets defined by RNA-Seq analysis. Genes highlighted in red represent those that are directly involved in ECM production. Data show normalized row Z-score (n = 5 biological replicates for each treatment group). d Kaplan−Meier curves of overall survival in unstratified breast cancer patients and in patients with basal, TNBC. Blue and red lines represent low and high Hh-stromal gene signature expression (HSGS), respectively. Statistical significance was determined using the Log-rank test; ***P < 0.001\n\n\n\nComparative GO and GSEA analysis revealed that the stromal fraction of M6-Hh tumors are highly enriched for genes encoding ECM processes (Fig. 2b, c), suggesting that a major influence of paracrine Hh activation on the tumor stroma is related to ECM production and remodeling18. Genes highly enriched in this set included collagens (Col2a1, Col3a1, Col4a1, Col9a1, Col11a1), ECM remodeling metallopeptidases (Mmp3, Mmp13, Mmp15, Adamts3, Adamts18), ECM glycoproteins (St8sia2, Rspo3, Lama5, Edil3, Thbs4) and cell adhesion molecules (Cldn3, Cldn7, Cldn1, Cdh2, Cdh15) (Fig. 2c). Interestingly, these ECM gene expression changes were not a consequence of changes in stromal cellular composition due to Hh pathway activation or long-term SMO inhibition. Immunohistochemical analysis did not reveal any difference between M6-Ctrl and M6-Hh tumors in terms of CAF, endothelial and innate immune cell abundance, regardless of treatment with SMOi (Supplementary Fig. 2a). This finding was confirmed using whole tumor qRT-PCR and flow cytometry analysis (Supplementary Fig. 2b, c).\n\nTo determine the prognostic value of the Hh-activated stromal gene signature (HSGS), we examined its impact on overall survival using The Cancer Genome Atlas (TCGA) breast invasive carcinoma cohort19. The HSGS was not predictive of patient outcome in the unstratified patient cohort (Fig. 2d) but was associated with significantly lower patient overall survival uniquely in the basal breast cancer subtype, where Hh ligand is most frequently overexpressed6 (Hazard ratio = 9.7 (1.9−48.2); P < 0.001; Fig. 2d).\n\nAccumulating evidence suggests that CAFs contribute to tumor growth upon Hh ligand activation12,20. However, the stroma of M6 tumors is composed of multiple cell types, any of which may be responsible for Hh-dependent gene expression changes. We used a single-cell RNA-sequencing (scRNA-Seq) approach to determine the cell population/s that respond to paracrine Hh signaling. The microfluidic 10× Chromium system was used to comprehensively profile gene expression at cellular resolution in thousands of cells isolated from freshly dissociated M6-Ctrl and M6-Hh tumors ± SMOi. In total, we compared 6064 FACS-isolated cells from M6-Ctrl tumors, 6200 cells from M6-Hh tumors, and 2686 single cells from M6-Hh tumor treated with SMOi.\n\nAs shown in Fig. 3a, unsupervised clustering analysis of 14,950 cells revealed populations of myeloid, neoplastic, endothelial, CAF and natural killer cells within the breast TME (Fig. 3a). Importantly, the upregulation of canonical Hh target genes Gli1, Ptch1, Ptch2, and Hhip and ECM genes such as Col4a1, Tspan11, St8sia2, and Tnfaip6 was observed exclusively in the CAF population of M6-Hh tumors (Fig. 3a), and not in the other stromal cell types. More specifically, the ECM signature detected in the stroma of Hh-expressing tumors via “bulk” RNA-Seq was driven by CAF gene expression (Figs. 2b, c, 3b). scRNA-Seq also confirmed the lack of autocrine Hh pathway activation within the neoplastic cells (Fig. 3a). Treatment with SMOi almost completely reversed the Hh-dependent gene expression changes observed in CAFs without affecting gene expression in the other stromal cell types (Fig. 3a; Supplementary Fig. 2d and Supplementary Data 2), highlighting the on-target activity of SMOi at the single-cell level.Fig. 3 Paracrine Hedgehog signaling at cellular resolution. a Freshly isolated M6-Ctrl (blue), M6-Hh (magenta) and M6-Hh tumors + SMOi (100 mg/kg/bid; pink violin plot) were captured using 10x Chromium technology and the Cell Ranger Single Cell Software Suite 2.0 was used to perform demultiplexing, barcode processing, and single-cell 3′gene counting. t-SNE plot shows the subcellular clusters present in the breast TME of M6 tumors. Unless stated, P values are highly significant (Supplementary Data 2). b Single-cell RNA-Seq analysis reveals significant enrichment of GSEA groups related to ECM organization and production specifically in the CAF population of M6-Hh tumors (ECM-related processes highlighted in red; FDR q value < 0.05)\n\n\n\nCoculture of primary CAFs with M6-Hh cells was sufficient to induce the expression of the Hh target genes Ptch2, Gli1, and Hhip in CAFs (Supplementary Fig. 3a, b) with concomitant upregulation of CSC markers Id3, Sox10, Itgb3, and Krt6b in M6-Hh cells (Supplementary Fig. 3a, c). Importantly, this stromal-epithelial malignant crosstalk was blocked by SMOi (Fig. 3a, Supplementary Fig. 3b, c). These data allow us to conclude that Hh signaling occurs solely in a paracrine manner in this murine model of TNBC and that CAFs are the therapeutic target of SMOi in TNBC.\n\nHh-dependent collagen remodeling promotes cancer stemness\nBulk and scRNA-Seq data suggested that stromal Hh-signaling drives collagen remodeling in the local ECM (Figs. 2b, c, 3), which is known to associate with breast cancer progression21. We employed second harmonic generation (SHG) microscopy, a sensitive label-free method for quantifying fibrillar collagen density and orientation in tissues22. SHG analysis revealed a ~3-fold increase in fibrillar collagen density at the tumor−stromal interface of Hh-expressing tumors (Fig. 4a), but not in the tumor center (data not shown). The increase in collagen abundance was confirmed by chromogenic staining using Picrosirius red (Fig. 4b). Further detailed analyses of the distribution and orientation of collagen fibers as described by Mayorca-Guiliani et al.23 and by Gray level co-occurrence matrix (GLCM) analysis24 revealed changes in texture and crosslinking of the ECM with linearization of collagen fibers adjacent to epithelial lesions in M6-Hh tumors, a hallmark of breast tumor growth and invasiveness8,23 (Fig. 4a). These features were ameliorated in M6-Hh tumors treated with SMOi (Fig. 4a), demonstrating an ongoing dependency on SMO activation.Fig. 4 High fibrillar collagen content resulting from Hh pathway activation promotes mechano-signaling and breast cancer stemness. a–d Concomitant expression analysis of collagen content and organization, integrin/focal adhesion activation and CSC-like characteristics at the tumor−stromal interface of M6 tumor models ± SMOi (100 mg/kg/bid; n = 3 biological replicates). a Representative multiphoton SHG imaging (scale bars: 100 μm) and quantitative analysis of collagen abundance. Statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. Corresponding graphs comparing fiber orientation (top right panel) and quantifying GLCM (bottom right panel). Unpaired two-tailed nonparametric Mann–Whitney U test was used for determining statistical significance across distributions. For GLCM analysis, statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. b Collagen I and III deposition detected and quantified by picrosirius red staining. Scale bars, 200 μm. Statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. c Representative immunofluorescence images and quantification of phospho-FAK and d CK6 expression. Scale bars, 100 μm. Statistical significance was determined using Kruskal−Wallis test. e M6-Ctrl and M6-Hh single cells were embedded and grown for 12 days in 3D Alginate IPNs containing increasing concentrations of collagen. Quantification of the number of colonies was normalized to the mean colony count in 0% collagen IPNs. n = 3 biological replicates with at least six technical replicates per condition. Statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. Representative phase contrast images of M6 colonies on polyacrylamide substrata after 12 days of culture. Scale bars: 100 μm. f Relative mRNA expression of the CSC markers Id3, Igtb3, and Krt6b in M6-Ctrl and M6-Hh cells cultured within 3D alginate-collagen I IPNs. n = 3 biological replicates with six technical replicates per experiment. Statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Bars represent mean ± s.e.m.\n\n\n\nSites of collagen deposition and crosslinking at the stromal−epithelial interface were also associated with increased epithelial phosphorylation and activation of focal adhesion kinase (FAK), a key signaling intermediate downstream of integrin receptors (Fig. 4c; Supplementary Fig. 4a). E-cadherin was used to mark the epithelial compartment (Fig. 4c, d; Supplementary Fig. 4). Increased phospho-FAK (pFAK) and CK6 expressions were observed to occur in the same regions of the M6-Hh tumors (Fig. 4d), linking fibrillar collagen content to FAK signaling and the acquisition of a stem-like phenotype in the neoplastic cells. Importantly, mechano-signaling and cancer stemness occurred primarily in dense collagen regions and were not observed in the core of M6-Hh tumors (Supplementary Fig. 4a, b).\n\nTo directly assess the sufficiency of collagen mechano-signaling to promote stemness, the clonogenic potential of M6-Ctrl and M6-Hh cells was assessed using three-dimensional cultures encapsulated within Alginate-Collagen I Inter-Penetrating Network (IPN) hydrogels. Alginates are widely used in bioengineering approaches as scaffolds25 and previous work has shown the successful application of IPNs for the study of fibroblast biology26 and the role of ECM biomechanics in the induction of malignant phenotypes in mammary epithelium27. In our experiments, biomechanical properties were precisely controlled through regulation of alginate gelation. The enrichment for fibrillar collagen in this in vitro model allowed the uncoupling of 3D environmental biomechanics from biochemistry, recapitulating the features of stromal collagen matrix deposition observed in Hh-expressing models. Increased content and presence of highly bundled fibrillar collagen significantly increased the clonogenic capacity of M6 cells, a functional surrogate for CSC activity, independently of Hh ligand expression (Fig. 4e). Furthermore, increasing collagen I abundance also increased expression of the stem cell markers Id3, Itgb3 (CD61) and Krt6 (CK6) (Fig. 4f). These data demonstrate that Hh-dependent stromal ECM remodeling is sufficient to foster a CSC phenotype.\n\nParacrine Hh-FGF5 axis also contributes to CSC plasticity\nTo identify additional mechanisms by which stromal signaling promotes the acquisition of a CSC phenotype, we turned our attention to Fgf5, which was strongly upregulated in Hh-activated stroma compared to controls (Fig. 2a, c and Supplementary Data 1 and 2). qRT-PCR analysis of whole tumors confirmed ~60-fold upregulation of Fgf5 mRNA in M6-Hh tumors, which was reversed upon SMOi treatment (Fig. 5a). Notably, a sole subset of Hh-activated CAFs exhibited robust Fgf5 expression at single-cell resolution (P = 9.16×10−12), reflecting the close spatial localization of these CAFs with M6-Hh cells (Fig. 5b). Fgf5 was not expressed by any of the other cell populations (Fig. 5b). Immunohistochemical analysis of phospho-FGFR revealed potent receptor activation in epithelial cells adjacent to M6-Hh tumor stroma, which was reversed upon SMOi treatment (Fig. 5c). To explore the role of FGF5 in the acquisition of the CSC phenotype, M6-Ctrl cells were treated with recombinant FGF5 protein in vitro and proliferation, stem cell marker expression and sphere-forming capacity were evaluated. FGF5 treatment led to an increase in proliferation under serum and growth factor deprivation (Supplementary Fig. 5a). Importantly, the stemness markers Id3 and Sox10 were also robustly upregulated (Fig. 5d) and primary and secondary sphere-forming capacity increased by ~3-fold (Fig. 5e and Supplementary Fig. 5b), suggesting a specific effect of FGF5 signaling on stemness.Fig 5 Hh-activated CAFs form a reversible, chemo-resistant CSC niche via FGF pathway activity. a RT-qPCR analysis of Fgf5 expression in M6 whole tumors. n = 3 biological replicates per treatment group with three technical replicates per assay. Statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. b Expression of Fgf5 at single-cell resolution in M6 tumor models. Freshly isolated M6-Ctrl (blue), M6-Hh (magenta), and M6-Hh tumors + SMOi (100 mg/kg/bid; violin dots) were captured using 10x Chromium technology. t-SNE plot represents the subcellular clusters present in the breast TME of M6 tumors. A sole subset of Hh-activated CAFs exhibits robust expression of Fgf5 in M6-Hh tumors. c Representative immunohistochemistry staining for phospho-FGFR on M6 tumors. Scale bars: 100 μm. Quantification of phospho-FGFR-positive cancer cells at the tumor−stromal interface. n = 4 biological replicates per treatment group; statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. d Relative mRNA expression of CSC markers Id3 and Sox10 in M6-Ctrl cells treated with DMSO (vehicle; blue) or recombinant FGF5 (red) in vitro. n = 3 biological replicates with three technical replicates per experiment; statistical significance was determined using unpaired two-tailed Student’s t test. e Primary and secondary tumorsphere formation of M6-Ctrl cells treated with DMSO (vehicle; blue) or recombinant FGF5 (red). Sphere Formation Efficiency (SFE) values in % are mean ± s.e.m.; n = 3 biological replicates with three technical replicates per tumorsphere assay. Representative phase contrast micrographs of M6-Ctrl spheres upon recombinant FGF5 stimulation. Scale bars: 100 μm. f Cell viability of M6-Ctrl and M6-Hh cells treated with indicated agents (n = 5 biological replicates with six technical replicates each). Statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d.; *P < 0.05; **P < 0.01; ***P < 0.001. Bars represent mean ± s.e.m.\n\n\n\nTo test whether the induction of sphere-forming capacity by FGF5 treatment was epigenetically stable or plastic, we tested the impact of addition or removal of FGF5 to primary and secondary sphere cultures. Increased sphere formation in response to FGF5 was observed in secondary cultures regardless of whether those cells were pre-treated with FGF5 during primary cultures (Fig. 5e and Supplementary Fig. 5b). Furthermore, removal of recombinant FGF5 decreased secondary sphere formation to levels comparable to those of cells never treated with FGF5 ligand (Fig. 5e and Supplementary Fig. 5b). Consistent with this result, treatment of spheres with a small molecule inhibitor of FGFR signaling (NVP-BGJ398) prevented FGF5-mediated tumorsphere formation in primary or secondary cultures (Supplementary Fig. 5c). These results demonstrate that stromal-derived FGF5 is sufficient to promote reversible transition to a CSC phenotype, rather than through the expansion of a subpopulation of CSC.\n\nThe CSC phenotype is associated with resistance to cytotoxic chemotherapy in TNBC28. To test whether the FGF-dependent increase in CSC alters the sensitivity of TNBC cells to chemotherapy, the efficacy of docetaxel was evaluated in M6 cell lines in vitro. Monocultures of M6-Hh cells did not display differential sensitivity to docetaxel when compared to M6-Ctrl cells as expected (Supplementary Fig. 5d). However, stimulation of M6-Ctrl and M6-Hh models with recombinant FGF5 ligand rescued these cells from docetaxel cytotoxicity (Fig. 5f). The FGFR inhibitor NVP-BGJ 398 abrogated drug resistance conferred by FGF5 (Fig. 5f). Similar results were observed in the human MDA-MB-231 cell line model of TNBC (Supplementary Fig. 5e). This result suggests that FGF5, released by Hh-activated CAFs, may create a “chemo-resistant niche” at the tumor−stromal interface of TNBC. It also suggests that targeting both tumor and stromal compartments with chemotherapeutic regimen and SMOi, respectively, may be an effectively therapeutic strategy.\n\nSMOi-combined therapy improves preclinical TNBC outcomes\nTo directly test these findings in more clinically relevant models, we turned our analysis to xenograft models of human TNBC. All three patient-derived xenograft (PDX) models tested were Hh ligand-positive as was the MDA-MB-231 cell line model (Supplementary Fig. 6a). We found convincing evidence of exclusive stromal-restricted Hh signaling and sensitivity to SMOi, using species-specific RT-PCR (Supplementary Fig. 6b, c). In addition, in vitro treatment of MDA-MB-231 cells with SMOi did not alter Hh target gene expression or proliferation (Supplementary Fig. 6d, e), consistent with the absence of SMO expression by these cells. The HCI-002 and MDA-MB-231 models were used for further studies, as they are well-accepted models of TNBC29.\n\nAnalyses of the ECM in HCI-002 xenografts by SHG and picrosirius red staining revealed abundant fibrillar collagen exclusively at the tumor−stromal interface (Fig. 6a, b). The collagen fibers were highly linearized and densely packed as depicted by orientation and GLCM analyses (Fig. 6a). Areas of high fibrillar collagen density were also associated with concomitant FAK phosphorylation and expression of the human CSC marker ALDH1 in the epithelial compartment, as highlighted by co-staining experiments (Fig. 6c). As observed in the transgenic model, collagen density and orientation, FAK phosphorylation and CSC marker expression were reduced following SMO inhibition (Fig. 6a–c).Fig. 6 Efficacy of long-term SMOi-combined therapy in preclinical models. a–c Concomitant expression analysis of collagen content and organization, integrin pathway activation and CSC-like characteristics at the tumor−stromal interface of the TNBC HCI-002 PDX model treated with vehicle (red) or the SMO inhibitor NVP-LDE225 (80 mg/kg/day; blue) (n = 5 biological replicates). a Representative imaging (scale bars: 100 μm) and quantitative analysis of collagen abundance (left panel). Statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. Corresponding graphs comparing fiber orientation (middle) and quantifying GLCM analysis (right panel) in the vehicle and SMOi-treated models. Unpaired two-tailed nonparametric Mann–Whitney U test was used for determining statistical significance across distributions. b Collagen I and III deposition detected and quantified by picrosirius red staining. Scale bars, 200 μm. Statistical significance was determined using unpaired two-tailed Student’s t test with equal s.d. c Representative immunofluorescence images and quantification of concomitant phospho-FAK (green) and the human CSC marker ALDH1 (red) expression in the HCI-002 model. The white arrows illustrate examples of co-staining within the epithelial population. Scale bars, 100 μm. n = 3 biological replicates. Statistical significance was determined using Kruskal−Wallis test. d–f TNBC HCI-002 PDX model treated with vehicle (blue), SMO inhibitor (NVP-LDE225; 80 mg/kg/day; magenta), chemotherapy (docetaxel; 15 mg/kg/week; dark orange) or NVP-LDE225 (80 mg/kg/day) + docetaxel (15 mg/kg/week; orange line) (n = 7 mice per treatment group). d Tumor growth curves. Statistical significance was determined using unpaired Student’s t test. e Percentage of mice with detectable metastases in the lung, liver, and axillary lymph node in each treatment group. Statistical significance was determined using the Fisher’s exact test. f Kaplan−Meier curves of mice overall survival of each treatment group. Statistical significance was determined using Log-rank test of NVP-LDE225 + docetaxel vs. docetaxel; *P < 0.05; ***P < 0.001; ****P < 0.0001. Bars on the graphs represent mean ± s.e.m.\n\n\n\nBased on these observations we predicted that SMOi would sensitize tumors to cytotoxic chemotherapy. HCI-002 PDX and MDA-MB-231 xenografts were then treated with SMOi ± docetaxel (Fig. 6d–f). Compared with vehicle treatment, either SMOi or docetaxel monotherapy slowed tumor growth and extended mice survival (Fig. 6d, f). However, the most robust and durable therapeutic effect occurred with combined therapy (Fig. 6d, f). Interestingly, the proportion of mice with metastatic disease at ethical endpoint (based on primary tumor size) was doubled in the docetaxel treated group, an observation previously made with paclitaxel in TNBC mouse models30 (Fig. 6e). Combination therapy reduced the frequency of mice with metastatic disease to below that seen in the vehicle control group, despite these mice being alive much longer compared to those in the other treatment groups. Similar therapeutic benefit was observed in MDA-MB-231 tumor-bearing mice treated with combination therapy in terms of tumor growth, overall survival, and histological changes (Supplementary Fig. 7a–d).\n\nWe then examined the impact of stromal Hh pathway inhibition on the histology of the tumor epithelial and stromal compartments. The proportion and number of stromal cells in the HCI-002 PDX model were unaffected by long-term SMOi and/or chemotherapy treatments (data not shown). SMOi had no inhibitory effect on the proliferation of human cancer cells across a range of doses (Supplementary Fig. 7e). Even in the context of docetaxel chemotherapy, Hh signaling was still stromally restricted (Supplementary Fig. 7f, g), arguing that SMOi does not sensitize cells to docetaxel via a cell-autonomous mechanism.\n\nClinical evaluation in the phase I clinical trial EDALINE\nThe promising preclinical study results led us to establish the EDALINE (GEICAM/2012-12) phase I trial of docetaxel in combination with SMOi (NVP -LDE225, Sonidegib) to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of this combined therapy in patients with metastatic TNBC. Twelve patients with prior standard of care chemotherapy treatments with taxanes and/or anthracyclines were enrolled. Detailed information on clinical trial design, patient and treatment characteristics are described in Supplementary Tables 1 and 2 and on ClinicalTrials.gov (Identifier: NCT02027376). Combination therapy was well-tolerated and the RP2D of Sonidegib 800 mg once daily in combination with Docetaxel 75 mg/m2 every 21 days was established. Clinical response was evaluated according to standard clinical trial RECIST31 (Response Evaluation Criteria in Solid Tumors) criteria version 1.1. One patient experienced a complete clinical response, defined as the disappearance of all target and non-target tumor lesions and the absence of new tumor lesions. As shown in Fig. 7a, the 54-year-old postmenopausal woman presented with metastatic disease in the lungs (red and blue arrows). Following eight cycles of combined therapy, the patient achieved complete clinical response, evident by the complete resolution of all her lung metastases on routine progress CT scan (Fig. 7a and Supplementary Tables 1 and 2). Two other patients experienced disease stabilization (Supplementary Tables 1 and 2).Fig. 7 Phase I clinical trial of docetaxel and SMO inhibitor, NVP-LDE225 (EDALINE) in patients with advanced TNBC. a Representative computed tomography (CT) images from a patient with complete radiological response. The 54-year-old postmenopausal woman was diagnosed with recurrent metastatic TNBC in the lungs with one measurable lesion on the right upper lobe (red arrow) and several nonmeasurable lesions (blue arrows). Therapeutic response was evaluated according to RECIST criteria version 1.1. The remaining structure seen in the right upper lobe corresponds to the azygos vein (violet arrow). b Representative HH and GLI1 immunostaining of treatment-naive tumor specimens from patients enrolled in the EDALINE trial. The left panel is representative of patients with high HPAS (characterized by high epithelial HH ligand and high stromal GLI1 expression) while the right panel represents low/intermediate epithelial HH and low stromal GLI1 expression. Scale bars: 100 μm. c Representative immunohistochemistry staining for phospho-FGFR, collagen deposition depicted by SHG imaging and concomitant phospho-FAK and ALDH1 stem cell marker expression in treatment-naive tumor specimens with high HPAS from the EDALINE trial. The left panel represents tissue derived from the patient who experienced a complete clinical response, the middle is from the patient with stable disease and the right panel represents tissue from the patient with high HPAS who progressed on the prescribed regimen. Scale bars: 100 μm. The white arrows illustrate examples of co-staining. d Graphical summary: Paracrine Hh signaling in TNBC drives a reversible stem-like, chemo-resistant phenotype via FGF signaling and ECM remodeling. CAFs represent the primary cells of the breast TME that respond to Hh ligand stimulation. Hh-activated CAFs enhance ECM collagen deposition and express FGF5 to establish a supportive niche for chemo-resistant cancer stem cell maintenance. This study strongly highlights a novel rational approach targeting both the tumor cells and their surrounding signaling support using SMO inhibitors to overcome chemoresistance in patients with TNBC\n\n\n\nTo assess if stromal Hh pathway activation determines clinical response, we evaluated epithelial HH ligand and stromal GLI1 expression in treatment naïve surgical tissue by immunochemistry. Only ten patient tumor samples were evaluable. Three out of ten tumors had high paracrine Hh Pathway Activation Signature (HPAS), characterized by high epithelial HH in combination with high stromal GLI1 expression (Fig. 7b and Supplementary Table 1). Of these, two patients experienced a clinical response whereas all patients with low HPAS expression had progressive metastatic disease on the prescribed treatment regimen (Supplementary Table 2). An additional patient experienced clinical benefit, but the status of Hh pathway activation was unknown as her tumor sample was not available for analysis (Supplementary Table 2).\n\nDownstream analysis of the effect of paracrine Hh signaling revealed moderate to high phospho-FGFR expression, high collagen deposition and fiber linearization in treatment-naive tumor specimens of the two responders with biopsy material available (Fig. 7c). This correlated with elevated phospho-FAK mechano-signaling and ALDH1-positive cells at the tumor−stromal interface (Fig. 7c). In contrast, the non-responder with high paracrine HPAS exhibited weak phospho-FGFR expression, low collagen content and minimal/no evidence of mechano-signaling and breast CSCs (Fig. 7c). While the small number of patients warrants caution, these additional tumor factors deserve further investigation in future clinical trials as adjunct biomarkers of therapeutic response for patient selection for anti-SMOi-based combination therapies in Hh-expressing TNBC.\n\nDiscussion\nIn certain settings, CSCs are responsible for metastasis to distant organs32–34 and are frequently enriched in residual tumors following chemotherapy35–37, reflecting a role in therapeutic resistance. The hierarchical model for CSC maintenance proposes that CSCs behave like tissue-resident physiological stem cells, self-renewing, and undergoing asymmetric divisions to generate differentiated progeny38. However, evidence from cell culture models has challenged the hierarchical CSC model, by suggesting that cancer cells can transition into a CSC state under specific culture conditions38–40. In support of this notion, we now demonstrate that stromal cues from Hh-activated CAFs, including FGF and fibrillar collagen-rich ECM, are capable of inducing and maintain a stem-like phenotype in TNBC cells in vivo. By combining a murine gain-of-function model, small molecule inhibitor studies in human xenografts with powerful in vitro systems, we have demonstrated the plastic characteristics of breast CSCs that can be successfully targeted using anti-stromal therapies, reducing metastatic growth and sensitizing to taxane chemotherapy.\n\nIncreased stromal collagen content correlates with stemness in the epidermis, both in the cancer and homeostatic contexts41,42. It also enhances CSC properties of breast cancer cells in vitro43. However, the impact of ECM collagen content and matrix mechanical properties on the biology of CSCs is not well defined. Our work provides new mechanistic insights, demonstrating that increased collagen density and fiber linearity at the tumor−stroma interface are associated with FAK activation and increased CSC number, dependent upon Hh paracrine signaling. Notably, we report a relationship between collagen abundance and clonogenicity in vitro and in vivo. Suppressing collagen production using SMO inhibitors was associated with decreased CK6+ and ALDH1+ CSCs, respectively, in both murine and human models of TNBC. Interestingly, recent data links mammographic fibrillar collagen density to breast cancer risk, raising the possibility that breast cancer progenitors in these patients may have expanded in response to a dense collagen matrix21,44,45. The precise mechanism controlling fibrillar collagen ECM remodeling in Hh-expressing tumors remains undetermined. Further mechanistic investigations are needed to determine if Hh induces the fibrillar collagen program in CAFs through direct regulation of collagen gene promoters via Gli1 or indirect interaction with other transcription factors, as shown in bone formation46.\n\nFGF signaling has been shown to drive malignant processes including stem cell self-renewal, multipotency, and therapeutic resistance47–50. In metastatic breast cancer, resistance to anticancer treatment is primarily due to FGFR gene amplification51. Here, we demonstrate a novel ligand-driven mechanism by which FGFR activation mediates both breast cancer stemness and chemoresistance, downstream of activation of the Hh signaling pathway. Importantly, our findings suggest that CAF targeting using small molecule inhibitors of SMO is sufficient to prevent FGF ligand signaling and may overcome resistance to chemotherapies. Interestingly, FGF5 has been reported to be upregulated in prostate CAFs relative to normal fibroblasts52, where it is also a target of Hh-Gli signaling. Thus this axis may be operational, and of therapeutic value, in tumor types beyond TNBC.\n\nWhich effects of CAFs on cancer stemness are mediated by direct cell−cell interactions, and which by secreted factors are still unknown. Moreover, how FGFR activation and high FAK mechano-signaling lead to the establishment of a stem-like phenotype remains to be determined, but they are associated in vitro and in vivo with upregulation of transcription factors previously implicated in mammary physiological and CSCs, including ID3 and SOX1048,53. The mechanisms underlying Id3 and Sox10 transcription are unknown. Id3 may be induced through Erk-EGR1 signaling, as observed in activated T cells, downstream of both FAK and FGFR54. Our data also reveal the cooperative activity of ECM remodeling and FGF signaling in driving malignancy and drug resistance, recapitulating the interaction seen between these pathways during development and wound healing55.\n\nImportantly, many elements of Hh paracrine signaling to CAFs are active during embryonic development in mammals, though have not previously been linked. Dhh is highly expressed in a subset of epithelial cells of the mammary end bud, an invasive and proliferative structure responsible for ductal elongation in the developing mouse mammary gland56. Consistent with our observation in TNBC, stromal but not epithelial Hh signaling is required for appropriate ductal morphogenesis57. A number of FGF ligands are secreted by mammary stromal cells, and activation of epithelial FGFR1/2 is required for mammary ductal elongation and stem cell activity58,59. In addition, mammary stromal fibroblasts secrete and remodel ECM components including collagens60. Similar to our results in neoplastic cells, increased collagen density and mechano-signaling via FAK is sufficient to inhibit mammary epithelial cell differentiation and increased clonogenic potential60. Thus the paracrine Hh signaling we observe in TNBC most likely represents the dysregulation and chronic activation of a process that is important for normal mammary ductal morphogenesis.\n\nUsing high-throughput single-cell RNA-sequencing, we demonstrate that CAFs are the only stromal cell type responding to Hh ligand, and that SMO inhibitors act “on-target” to reverse CAF gene expression changes induced by Hh signaling. Surprisingly, long-term (up to 3 months) daily treatment with SMOi did not alter the stromal cell composition of mammary tumors. This result contrasts markedly to that recently observed in pancreatic, colon and bladder cancer models, where chronic SMO inhibition was associated with marked changes in stromal cellular composition and shorter survival for mice receiving long-term SMOi treatment61–63. The basis for this difference is not known, but may be explained by the divergent epigenomics contexts of these cancer types, resulting in the evolution of distinct TMEs9. Alternately, differences in the origin or phenotype of CAFs64 in these endodermally derived tumors vs. ectodermally derived mammary carcinomas may be relevant.\n\nThe benefit from therapeutic targeting of CAFs is twofold. Firstly, we and others have provided evidence for the crucial role of CAFs in supporting CSC self-renewal and resistance to chemotherapy65–67. Therefore, targeting the CAF population and the subsequent abolition of the CAF−neoplastic cell interaction represent a practical strategy to improve cancer outcomes. Secondly, unlike neoplastic cells, CAFs have not been reported to exhibit genomic instability and are therefore less likely to acquire resistance to therapy over time, making them good targets for combination cancer therapies. Combined therapy with SMOi + docetaxel was well-tolerated by mice and humans, and effective in treating a proportion of women with metastatic disease who had previously failed on taxane chemotherapy, including one patient who experienced a complete response. While patient numbers are small, these remarkable results provide the first evidence to our knowledge for clinical benefit from a CAF-directed therapy. Treatment response in patients correlated with high levels of paracrine Hh signaling, FGFR activation and fibrillar collagen deposition, suggesting that the mechanism of action in patients may be consistent with that in mouse models. Hh, FGFR or collagen pathway activation may have value as predictive biomarkers of response to SMOi. Thirty percent of TNBCs show evidence of paracrine Hh pathway activity; SMO inhibitors could then represent therapeutics of interest for a significant number of women. Whilst phase I clinical trials are not designed nor powered to assess therapeutic efficacy, these data suggest an exciting new therapeutic strategy for drug-resistant or metastatic TNBC which should proceed to prospective assessment through Phase II clinical trials.\n\nMethods\nCell culture\nM6 murine mammary carcinoma cells derived from the C3(1)/SV40 Tag mouse model (gift from J. Green, NIH)68 were cultured as previously described6. The human triple negative breast cancer cell line MDA-MB-231 was obtained from the American Type Cell Culture Collection (ATCC) and grown in RPMI-1640 supplemented with 10% (v/v) fetal bovine serum (FBS; Gibco®). All cell lines were grown at 37 °C in a 5% CO2 incubator. Each cell line was characterized by short tandem repeat analysis profiling using the PowerPlexR 18D System (Promega) and tested for mycoplasma contamination (MycoAlertTM Mycoplasma Detection kit, Lonza). SMOi GDC-0449 (S1082, Selleckchem) and NVP-LDE225 (Novartis, Australia) were dissolved in DMSO to stock concentration of 10 mM. Docetaxel chemotherapy (McBeath, Australia) was diluted fresh (0.1 nM to 10 μM) with cell culture media. Recombinant FGF-5 (237-F5-050, R&D) was reconstituted at 10 μg/mL in PBS containing 1 μg/mL sodium heparin (H3149-50KU, Sigma-Aldrich) and 0.1% bovine serum albumin (A9418-10G, Sigma-Aldrich). NVP-BGJ 398, a potent and selective FGFR inhibitor (S2183, Selleckchem) was used at a concentration of 500 nM. All cell culture experiments involving SMOi (1 nM to 10 μM), NVP-BGJ 398 and chemotherapy (IC30) lasted 5 days and were performed in the presence of FBS. For cell viability assays, treatment of M6 cells with recombinant FGF-5 (150 ng/mL) in the absence of FBS lasted 5 days. Cell viability assays were carried out in 96-well plates (Corning® Life Sciences) and were determined by alamarBlue® reduction.\n\nTumor dissociation\nM6 tumors were processed into single-cell suspensions before limiting dilution assays, fluorescence-activated cell sorting (FACS) or flow cytometry analysis. Tumor dissociation into single-cell suspension was carried out using the MACS mouse Tissue Dissociation Kit (Miltenyi Biotec, Australia) in gentleMACS C tubes on the gentleMACS Dissociator (Miltenyi Biotec) according to the manufacturer’s recommended protocol. Briefly, up to 1.5 g of tissue was transferred into a gentleMACS C-Tube (Miltenyi Biotec) containing 2.35 mL of RPMI 1640 solution with 1× Penicillin/Streptomycin (Gibco). 100 μL of enzyme D, 50 μL of enzyme R and 12.5 μL of enzyme A were then added and the sample was processed by running the defined gentleMACS program m_impTumor_02 on the gentleMACS Dissociator. The sample was incubated for 40 min at 37 °C under continuous agitation and then processed using the gentleMACS program m_impTumour_03. The sample was resuspended in RPMI 1640 and filtered sequentially through 70 μm and 40 μm cell strainers (BD Falcon) and the resulting single-cell suspension was centrifuged at 300 × g for 7 min. Cells were then resuspended in 1× BD Pharm LyseTM lysing solution (555899, BD Biosciences) for 3 min at room temperature (RT) to lyse erythrocytes.\n\nFlow cytometry and FACS isolation\nCell sorting and flow cytometry experiments were performed at the Garvan Institute Flow Cytometry Facility. Flow cytometry was performed on a Becton Dickinson CantoII or LSRII SORP flow cytometer using BD FACSDIVA software, and the results were analyzed using Flowjo software (Tree Star Inc.). FACS experiments were performed on a FACS AriaII sorter using the BD FACSorter software. Full details of each commercial antibody used for flow cytometry and immunochemistry are described in Supplementary Table 3.\n\nSingle-cell suspensions of primary M6 tumors were incubated with anti-CD16/CD32 antibody (1:200, BD Biosciences) in FACS buffer (PBS containing salts, 2% FBS, 2% Hepes) to block nonspecific antibody binding.\n\nFor the next generation sequencing experiment, single-cell suspensions were then pelleted and resuspended in FACS buffer containing the anti-EpCAM-PerCP/Cy5.5 (1:500, BioLegend®, Clone: G8.8) for 20 min on ice. Cells were then washed twice in FACS buffer before being resuspended in FACS buffer containing DAPI (1:1000; Invitrogen) to discriminate dead cells. Stromal cells identified as DAPI-/GFP-/ EPCAM−and M6 cancer cells identified as DAPI−/ GFP+/EPCAM+ were collected from at least five tumor specimens per treatment group.\n\nFor the isolation of M6-Ctrl or M6-Hh cells for limiting dilution assays, cells were pelleted and resuspended in FACS buffer containing the following murine lineage markers (Lin+): anti-CD45-biotin (1:100; BD PharmingenTM, Clone: 30-F11); anti-CD31-biotin (1:40; BD PharmingenTM, Clone: 390), anti-TER119-biotin (1:80; BD PharmingenTM, Clone: TER119), and anti-BP1-biotin (1:50; Affymetrix eBiosciences, Clone: 6C3) for 20 min on ice. Cells were then pelleted and resuspended in FACS buffer containing streptavidin-APC-CyTM7 (1:400; BD PharmingenTM) and anti-EpCAM-PerCp/Cy5.5 (1:500, BioLegend®, Clone: G8.8), and incubated for 20 min on ice. Cells were then washed twice in FACS buffer before being resuspended in FACS buffer containing DAPI (1:1000; Invitrogen). Live primary M6 neoplastic cells were sorted based on their GFP+/EpCAM+/Lin− expression.\n\nFor the analysis of CSC properties, single-cell suspensions from M6 tumor models were incubated with the combination of the following murine lineage markers: anti-CD31-biotin (1:40), anti-CD45-biotin (1:100), anti-TER119-biotin (1:80), and anti-BP1-biotin (1:50) for 20 min on ice. Cells were then pelleted and resuspended in FACS buffer containing streptavidin-APC-CyTM7 (1:400) and the following epithelial stem cell markers: anti-CD24-PE (1:500; BD PharmingenTM, Clone: M1/69), anti-CD29-APC-Cy7 (1:100; BioLegend, Clone: HMβ1-1) and anti-CD61-APC (1:50; ThermoFisher), and incubated for 20 min on ice. Cells were then washed twice in FACS buffer before being resuspended in FACS buffer containing DAPI (Invitrogen).\n\nCoculture of primary cells\nPrimary M6 cells and CAFs derived from M6-Ctrl and M6-Hh tumors, respectively, were selected by FACS using the following cell surface markers: Epithelial cells: CD45−/CD31−/CD140a−/GP38−/EpCAM+/GFP+; CAFs: CD45−/CD31−/CD140a+/GP38+/EpCAM−/GFP−. After tumor dissociation, single cells were pelleted and resuspended in FACS buffer containing the following antibodies: anti-CD45-APC-eFluor®-780 (1:500; Affymetrix eBioscience, Clone: 30-F11), anti-CD31-biotin (1:100; BD PharmingenTM, Clone: 390), anti-CD140a-APC (1:100; BioLegend®, Clone: APA5), anti-Podoplanin-PE (1: 1,000, BioLegend®, Clone: 8.1.1) for 20 min on ice. After two washes with PBS, cells were then pelleted and resuspended in FACS buffer containing Brilliant Violet 421™ Streptavidin (1:400; BioLegend®), and incubated for 20 min on ice. Cells were then washed twice in FACS buffer before being resuspended in FACS buffer containing DAPI (Invitrogen) to discriminate dead cells. Different epithelial and CAF populations from at least three tumor specimens per treatment group were isolated and cultured into 100 mm culture dishes (Corning® LifeSciences) in DMEM supplemented with 10% (v/v) FBS, 50 μg/mL gentamycin and 1× antibiotic/antimycotic (15-240-096, Gibco®) in a 5% O2, 5% CO2 incubator at 37 °C. 105 M6 cells were added to the Petri dish when CAFs derived from the corresponding tumors have reached 70% confluency and the coculture assays lasted a total of 5 days.\n\nAnimals and surgery\nAll animal procedures were carried out in accordance with relevant national and international guidelines and according to the animal protocol approved by the Garvan/St Vincent’s Animal Ethics Committee (Animal ethics number 11/46). M6-Ctrl or M6-Hh (0.75×106 cells/10 μL) and MDA-MB-231 (1×106 cells/10 μL) transplants were carried out by surgical injection via direct visualization into the fourth mammary fat pads of pre-pubescent Rag−/− and NOD-scid IL2rγnull (NSG) mice, respectively.\n\nFor limiting dilution studies, single-cell suspensions of viable M6-Ctrl or M6-Hh tumor cells were prepared as described in the “Tumor dissociation” section. EpCAM+/GFP+/Lin− tumor cells, isolated by FACS, were transplanted in appropriate numbers into the fourth mammary fat pad of 3- to 4-week-old syngeneic Rag−/− mice and aged till ethical endpoint. Extreme limiting dilution analysis (ELDA16) software was used to calculate the tumor-propagating cell frequency.\n\nPDX tumor tissues, acquired from the laboratory of A. Welm29 were serially passaged as 2 mm3 fragments in the cleared fourth mammary fat pads of pre-pubescent NSG mice according to established protocols29. When tumors became palpable, they were measured three times weekly in a blinded manner using electronic calipers to monitor growth kinetics. Tumor volume was calculated using the formula (π/6) × length × width2. Upon reaching ethical or predefined experimental endpoints, mice were euthanized and primary tumor and any associated metastases were collected.\n\nIn vivo drug treatment experiments\nSMOi GDC-0449 (S1082, Selleckchem) and NVP-LDE225 (Novartis, Australia) were dissolved in 0.5% methylcellulose, 0.2% Tween® 80 (Sigma-Aldrich) and 0.5% methylcellulose, 0.5% Tween® 80, respectively, and then delivered by oral gavage (100 mg/kg/bid, GDC-0449; 80 mg/kg/day, NVP-LDE225). Chemotherapy (Docetaxel, McBeath Australia) was diluted in 5% dextrose then delivered by intraperitoneal injection (15 mg/kg/week). Tumor-bearing mice were randomly assigned into respective treatment groups once tumor volume reached 100 mm3 (n = 7–8 mice per group). Tumor growth was calculated for each individual tumor by normalizing to the tumor volume at day 0. In short-term studies examining the molecular and histological impact of Hh pathway activation and inhibition, mice were treated between 8 and 14 days then euthanized. At euthanasia, primary tumors were harvested and macroscopic metastatic lesions were scored. For the long-term therapeutic study, mice were treated to endpoint. Animals were excluded from overall survival analysis if they had to be sacrificed for poor body conditioning, unrelated to tumor size endpoint. Animal technicians, who were blinded to the experiment treatment groups, independently monitored the mice.\n\nNext generation sequencing\nWe isolated by FACS the stromal DAPI−/GFP−/EPCAM−and epithelial DAPI−/ GFP+/EPCAM+ cell fractions from at least five M6-Ctrl and M6-Hh tumor models treated with vehicle (0.5% methylcellulose, 0.2% Tween® 80) or with SMOi. RNA was isolated using the miRNeasy kit (Qiagen). For standard input samples, 1 μg of total RNA was used as input to the TruSeq RNA Sample Preparation Kit v2 (Illumina). The samples were prepared according to the manufacturer’s instructions, starting with the poly-A pulldown. The number of PCR cycles was reduced from 15 to 13, to minimize duplications. The samples were sequenced on the HiSeq2000 using v3 SBS reagents (Ramaciotti Centre for Genomics, University of New South Wales (UNSW)). Low-input RNA stromal samples were firstly amplified using the Ovation® RNA-Seq System V2 kit (4 ng of total RNA input; Nugen Integrated Sciences Pty. Ltd.) according to the manufacturer’s instructions. 1 μg of the cDNA was sheared with Covaris to fragment sizes of ~200 bp. The material was used as input to the TruSeq RNA Sample Preparation v2 kit, starting at the end-repair step. The number of PCR cycles was reduced from 15 to 10. All the samples were sequenced on the HiSeq2000 using v3 SBS reagents (Ramaciotti Centre for Genomics, University of New South Wales).\n\nBioinformatics and computational analysis\nAnalysis of the RNA-Sequencing data was conducted on the high-performance computing cluster at the Garvan Institute following a standard four-step approach, cleaning, aligning, counting, and differential expression with an additional normalization step. FASTQ files were quality checked using FastQC version 0.11.1 (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/) and FastQ Screen version 0.4.4 (http://www.bioinformatics.babraham.ac.uk/projects/fastq_screen/) then quality filtered using FastqMCF version 1.1.2 (https://code.google.com/p/ea-utils/wiki/FastqMcf) to remove low quality bases and adapter contamination. Filtered reads were then aligned to the mouse reference genome GRCm38/mm10 using STAR, version 2.4.0d . Feature counting was performed using HTSeq version 0.5.4p3 . Due to high levels of variation in the expression data between replicates, the RUV normalization procedure was implemented69. This aims to remove unwanted variation and produce more reliable pair-wise comparisons when calculating differential expression. In this instance, RUVr with a K of 3 was found to be the most effective method based on the suggested diagnostics, e.g. plots of P value distributions and PCA. Differential expression analysis was performed within the RUV analysis using edgeR70.\n\nSingle-cell RNA-Sequencing using the Chromium Platform\nM6 tumors were processed into single-cell suspensions as described previously. Sorted live single epithelial and stromal cells were loaded on a Chromium Single Cell Instrument (10× Genomics, Pleasanton, CA) to generate single-cell Gel Bead-in-Emulsion (GEMs). As per the manufacturer’s instructions, approximately ~7000 cells were loaded per channel for a target of ~4000 cells (10× Genomics). Two biological replicates were analyzed per sample. Single-cell RNA-Seq libraries were prepared using the Chromium Single Cell 30 Gel Bead and Library Kit (10× Genomics). Single-cell sequencing libraries were generated from sorted cells collected in parallel on the same Chromium Single Cell Chip and sequenced in multiplexed pairs to minimize experimental variability and any confounding batch effects. Single-cell libraries were sequenced using the Illumina NextSeq 500 system using the following parameters: pair-end sequencing with dual indexing, 26 cycles for Read1, 8 cycles for I7 Index Read and 98 cycles for Read2.\n\nThe Cell Ranger Single Cell Software v2.0 (10× Genomics) was used to process raw bcl files to perform sample demultiplexing, barcode processing and single-cell 3′ gene counting (https://software.10xgenomics.com/single-cell/overview/welcome). Reads were mapped to the mm10 mouse reference genome. The Cell Ranger aggregation pipeline was used to normalize the sequencing depths of multiple datasets (based on the proportion of mapped reads) to recompute a combined gene−cell barcode matrix.\n\nDownstream filtering and analysis of the raw gene−cell barcode matrix was performed using the Seurat v2.0 package in R71. The gene−cell barcode matrix was filtered based on number of genes detected per cell (any cells with less than 500 or more than 6000 genes per cell were filtered), a total number of unique molecular identifiers (UMIs) (any cells with UMIs > 50,000 were filtered) and a percentage of mitochondrial UMI counts (any cells with more than 10% of mitochondrial UMI counts were filtered). Altogether, in the combined five datasets, a total of 14,950 cells and 18,487 genes were analyzed. Based on an expression cut-off of 0.0125 and a dispersion cut-off of 0.5, a total of 2620 variable genes were selected for principal component analysis (PCA). A total of 91 significant principal components (determined using JackStraw in Seurat, P < 0.05) were used for clustering analysis and t-SNE projection. The classification of cell clusters was inferred using the following canonical markers: CAFs (Pdpn and Pdgfrb), epithelial cancer cells (Epcam), endothelial cells (Cd34 and Pecam1), macrophages/monocytes (Ptprc and Cd68), neutrophils (Ptprc and Csf3r), and natural killer cells (Ptprc and Ncr1). Differential gene expression analysis in Seurat was performed using the “bimod” likelihood-ratio test.\n\nGene set enrichment analysis\nGene-sets used in GSEA were extracted from version 3.1 and 4.0 of the Broad Institute’s Molecular Signatures Database (MSigDB) and extended with additional curated gene-sets from literature. All GSEA analyses were performed using a combined set of the c2, c5 and c6 from MSigDB plus additional curated sets that we identified in the literature.\n\nAssociation of gene signatures with clinical outcome\nA stringent mouse gene signature was derived through differential expression analysis of the stromal fraction of M6-Hh tumors in comparison to the stroma of M6-Ctrl or M6-Hh tumors treated with SMOi. The stromal mouse gene signature was then converted to human genes using NCBI homolog gene list v68 (http://www.ncbi.nlm.nih.gov/homologene). The converted gene list consists of 146 upregulated genes and 39 downregulated genes in the Hh-activated stromal population (Supplementary Data 1). The gene list was further assessed for survival analysis using the TCGA breast invasive carcinoma cohort. The processed TCGA data were downloaded from cBioPortal72 based on the TCGA study19. The gene signature score was defined by a weighted average method for each sample in the TCGA cohort. Survival curves were estimated using the Kaplan−Meier method, with overall survival used as the outcome metric.\n\nRNA isolation and quantitative RT-PCR experiments\nIndividual stromal CAFs and epithelial malignant M6 cancer cells were FACS-isolated as described above. For each fraction, between 1,000 and 50,000 cells were directly collected into QIAzol lysis reagent. Low-input RNA samples were then isolated using the miRNeasy Micro kit (Qiagen). All the other standard input RNA samples were isolated using the miRNeasy kit (Qiagen) and reverse transcribed with the Transcriptor First Strand cDNA Synthesis Kit (Roche Diagnostics). cDNA was synthesized from 0.5 to 2 μg of total RNA and diluted 1:10 before any further quantitative RT-PCR (qRT-PCR) analysis.\n\nqRT-PCR experiments were performed using either the Roche Universal Probe Library System on a Roche LightCycler480® (Roche LifeScience) or the TaqMan Gene Expression Assay (Applied Biosystems/Life Technologies) on an ABI Prism® 7900 HT Sequence Detection System (Perkin-Elmer Applied Biosystems). Primers, probes, and programs used for qRT-PCR analysis are listed in Supplementary Table 4. Relative mRNA expression levels were normalized to β-actin, GAPDH, or HPRT and quantification was performed using the comparative CT method described by Livak and Schmittgen73.\n\nHistological assays and analysis\nTissues were fixed in 10% neutral buffered formalin at 4 °C overnight then processed for paraffin embedding. For histological analysis, 4 μm tissue sections were stained with hematoxylin and eosin using standard methods. Immunohistochemical, immunofluorescence, and picrosirius red staining were performed on paraffin-embedded tissue sections using standard protocols. Full details of each antibody used and their relative staining protocols for immunochemistry are described in Supplementary Table 3.\n\nHistological analysis of the proliferative marker phospho-histone H3, ALDH-1, and the progenitor cell marker CK6 were carried out by digitizing entire images using the Aperio CS2 digital pathology slide scanner (Leica Biosystem) at ×20 magnification. Cells that stained positively for phospho-Histone H3, ALDH-1, or CK6 within a distance of 200 μm from CAFs at the tumor−stromal interface were then counted and averaged over at least five fields using the Aperio Imagescope software (Leica Biosystem). The limit of 200 μm reflects the well-established diffusional distance for Hh ligand in mammalian models74. Picrosirius red stain was analyzed as previously described75. Two specialist breast pathologists, who were blinded to the experiment treatment groups, independently scored the remaining IHC stains. Areas of necrosis were excluded for all analyses. The number of CD45+ cells in the peritumoral stroma and the number of CD31+ blood vessels were estimated and averaged over five high power fields (×40 magnification). Alpha-SMA was scored as the percentage of myofibroblabts in the tumor stroma at the whole tumor level. Tumor vs. stromal ratio was estimated on H&E sections.\n\nFor immunofluorescence staining, formalin-fixed paraffin-embedded (FFPE) sections on Superfrost+ glass slides (Thermo) were dewaxed and rehydrated, and antigen retrieval was performed by boiling for 12 min in 10 mM citrate buffer (pH 6.0) or 10 mM Tris-Cl (pH 9.0) in a pressure cooker (Supplementary Table 3). Following blocking with 10% goat serum, sections were incubated with the primary antibodies p(Tyr397)-FAK, CK6, ALDH1, E-cadherin at 4 °C for 18 h, washed in PBS and incubated with the appropriate secondary antibodies for 1 h. After washing in PBS, sections were incubated with 0.2 µg/mL DAPI in PBS for 5 min to label nuclei and mounted. Confocal fluorescence images were captured using an LSM 700 confocal scanning system (Carl Zeiss AV), with Zen 2011 (Black Edition) version 8.1.5.484 software. Images were processed using ImageJ (National Institutes of Health, Bethesda MD, USA) as previously described42. Two cell biologists from separate institutes, who were blinded to the treatment groups, independently scored the IF stains for CK6, ALDH1, and phospho-FAK.\n\nMicroscopy analyses of collagen deposition and organization\nFormalin-fixed, paraffin-embedded sections stained with hematoxylin and eosin and mounted in DPX (Sigma) were imaged using a ×20 1.0 NA objective on an upright fixed-stage two-photon laser scanning microscope system (Zeiss). The excitation source was a Ti:Sapphire femto-second laser cavity (Newport Mai Tai), coupled into an LSM 710 scan module. An excitation wavelength of 890 nm was used to collect SHG signal (435 ± 20 nm) from collagen. Maximum collagen coverage values derived from SHG signal (by depth (line graph) and at peak value (histogram inset)) was used as a measure of collagen abundance and density. Signal was acquired from three separate areas measuring 320 × 320 μm2 across each sample. Bright-field transmission images were co-acquired with SHG data.\n\nImageJ was used to calculate percentage area covered by SHG signal per image, after conversion to a binary image based upon a single manually determined threshold value applied across all images as previously described41. Results were expressed as medians, ranges, and quartiles across all datasets.\n\nStromal collagen fiber organization and crosslinking were assessed using GLCM24 analysis to characterize the texture of a sample and determine the correlation of the SHG signal within the matrix. The correlation plots represent the similarity in signal strength between pixels. A slower decay shows a more organized and correlated network of collagen fibers than in samples with a faster decay. GLCM analysis was performed in ImageJ.\n\nOrientation analysis was carried out as previously described23. Briefly, fiber orientation analysis was performed on SHG images using an in-house ImageJ macro where structure tensors were derived from the local orientation and isotropic properties of pixels that make up collagen fibrils. Within each input image, these tensors were evaluated for each pixel by computing the continuous spatial derivatives in the x and y dimensions using a cubic B-spline interpolation. From this, the local predominant orientation was obtained. The peak alignment (measured in degrees) of fibers was then determined, and the frequency of fiber alignment calculated.\n\nAlginate-Collagen I Inter-Penetrating Network hydrogels\nAlginate-Collagen I Inter-Penetrating Network (IPNs) hydrogels were generated from 1% sodium alginate mixed with either 20, 5 or 0% rat tail collagen I, plus 1% Matrigel. A standard guide describing cell encapsulation in alginate is available from ASTM International (ASTM F2315–11). Well-characterized alginates with high purity and G-block composition were used to prepare hydrogels with consistent mechanical properties for cell encapsulation. M6-Ctrl and M6-Hh single cells were encapsulated in 400 μm diameter beads before transferring to normal growth media. Colony-forming ability was assessed at days 5, 8, and 12.\n\nTumorsphere assays\nLow passage M6 cells grown to 70–80% confluency as adherent monolayer were trypsinized, quenched in normal culture media, washed three times with large volumes of calcium-magnesium-free PBS then passed through a 40 μm cell strainer to obtain a single-cell suspension. Cell number was determined using the Countess™ Automated Cell Counter (Invitrogen) then seeded in sphere-promoting culture at a density of 2.5×103 cells/mL in ultra low-adherent six-well plates (Corning® LifeSciences). Cells were grown at 37 °C in a 5% CO2 incubator. Primary sphere formation efficiency was determined after 5 days. Spheres larger than 40 μm were counted manually using a light microscope and automatically using the IncuCyte ZOOM® Live Cell System (Essen BioScience). Primary spheres were then collected by gentle centrifugation and washed with calcium-magnesium-free PBS prior to dissociation into single-cell suspension. Cell number was determined as above then seeded in triplicate at a density of 5×102 cells/mL in ultra low-adherent six-well plates. Secondary sphere formation efficiency was determined after 8 days. Sphere media was composed of DMEM/F12, 1% methylcellulose, 1× B27 supplement (17504-044, Invitrogen), and 4 μg/mL sodium heparin (H3149-50KU, Sigma-Aldrich). Tumorspheres were treated with 150 ng/mL recombinant FGF5 (237-F5-050, R&D Systems) and/or 500 nM FGFR inhibitor, NVP-BGJ 398 (S2183, Selleckchem). Sphere formation efficiency was calculated using the following formula: (Number of tumorspheres larger than 40 μm / Number of single cells seeded) × 100%.\n\nPatients\nPatients in this study were enrolled in the GEICAM/2012-12 (EDALINE) clinical trial (ClinicalTrials.gov Identifier: NCT02027376); a single-arm, open-label, phase I, 3 + 3 dose escalation study in which patients with TNBC were treated with the SMOi Sonidegib (LDE-225) in combination with docetaxel to determine the MTD and the Recommended Phase II Dose (RP2D), as the primary objective. Written informed consent was obtained from all patients and documented before performing any protocol-specific procedure. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines (ICH GCP), the Declaration of Helsinki and applicable local regulatory requirements and laws. The protocol was approved by the Institutional Review Board and the Ethics Committee of all the participating sites (Hospital General Universitario Gregorio Marañón, Hospital Universitario Clínico San Carlos, Complejo Hospitalario Universitario A Coruña, Hospital Universitario Virgen del Rocío, Hospital Universitario Virgen de la Victoria), according to the requirements of the Spanish regulations (GEICAM/2012-12; clinicaltrials.gov identifier: NCT02027376). Eligible patients, with no more than three previous lines of chemotherapy for metastatic disease were treated with 21-day cycles of intravenous docetaxel 75 mg/m2 on day 1 and oral Sonidegib administered at increasing doses of 400, 600, and 800 mg once daily (QD), until radiographic or symptomatic progression, unacceptable toxicity or withdrawal of the informed consent, whichever occurred first. All patients at each dose level completed at least two treatment cycles before being enrolled to the next Sonidegib dose level. Twelve patients were enrolled into the study and were treated as described above.\n\nClinical markers of therapeutic activity\nThe expression of Hedgehog ligand (HH) and GLI1 were examined by immunohistochemistry (IHC) from archived FFPE pretreatment primary breast tumors from patients enrolled in the EDALINE clinical trial. Pathologists, who were blinded to clinical parameters, carried out biomarker analysis. Two specialist breast pathologists independently calculated the Histo-score (Hscore) based on the percentage of stained cells (HH and GLI1 expression) and staining intensity on a predetermined scale (0: no staining to 3: strong), in the tumor epithelial cells (HH) and the tumor stroma (GLI1). Predefined cut-offs for high/low biomarker expression were established based on standard criteria (median Hscore for HH in tumor cells and intensity staining for GLI1 in the stroma).\n\nWe defined an HPAS predictive for clinical response to sonidegib (LDE-225) in combination with docetaxel as cases with both high HH expression in the tumor epithelium (HH Hscore > 150) and intense GLI1 expression in the tumor stroma.\n\nStatistical analysis\nAll statistical analyses were performed using GraphPad Prism 6.0c software (GraphPad Software). For all in vitro experiments, three or six technical replicates were analyzed for each experiment, and results are presented as the mean ± s.e.m. of three biological replicates. Quantitative analyses were carried out using unpaired two-tailed Student’s t test with equal standard deviation after confirming that the data met appropriate assumptions (normality, homogenous variance, and independent sampling). Seven to ten mice per treatment group were used for all in vivo experiments with SMOi treatment. Five mice per treatment group were utilized for RNA-Seq. For all RT-qPCR experiments, three technical replicates were analyzed for each experiment, and results are presented as the mean ± s.e.m. of three biological replicates. Subsequent statistical analyses of in vivo experiments were performed with either unpaired two-sided Student’s t tests or the Fisher’s exact test. Survival analysis was performed using the Log-rank (Mantel−Cox) test. A P value < 0.05 was considered statistically significant. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Estimation of variation within each group was determined by s.e.m. Sample size estimation was initially chosen by using power calculations for guidance (http://biomath.info/power/ttest.htm). Effect sizes were estimated at 30% for single agent arms, based on earlier data with single agent docetaxel and SMO inhibitors. With alpha = 0.05 and power = 0.9 and allowing for attrition of ~1 mouse/group, ≥7 mice per group were needed for all preclinical studies. For the Phase I clinical trial EDALINE, descriptive analysis on demographic and clinicopathological characteristics (age, visceral disease, number of involved sites, prior treatment, histologic tumor grade and Ki67), Hh biomarkers expression (HH and GLI1) and efficacy data to the combined therapy sonidegib with docetaxel were performed. The Chi-square test of Independence was assessed to examine the association between epithelial HH and stromal GLI1 expression and efficacy endpoints: best tumor response (complete or partial response, stable disease, progression disease, and Time to Progression (TTP)). TTP was defined as the time from treatment commencement until objective tumor progression (does not include deaths). Progression-free survival (PFS) was explored using Kaplan−Meier survival analysis. PFS was defined as the time from treatment commencement until disease progression or death. For mouse and clinical studies, specialists were blinded to the experiment treatment groups.\n\nData availability\nAll relevant data are available from the authors. All RNA-Sequencing files that support the findings of this study have been deposited in GEO with the accession code PRJNA369574. The RNA-Seq pipeline and the analysis scripts can be found on the respective websites: https://github.com/elswob/rna-seq-pipe and https://github.com/elswob/Hh.\n\nElectronic supplementary material\n\nSupplementary Information\n\n \nDescription of Additional Supplementary Files\n\n \nSupplementary Data 1\n\n \nSupplementary Data 2\n\n \n\n\nThese authors contributed equally: Aurélie S. Cazet, Mun N. Hui.\n\nElectronic supplementary material\n\nSupplementary Information accompanies this paper at 10.1038/s41467-018-05220-6.\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe would like to thank the following people for their assistance with this manuscript: Ms. Nicola Foreman and Ms. Breanna Fitzpatrick for animal handling; Ms. Alice Boulghourjian and Ms. Anaiis Zaratzian for tissue processing and IHC staining; Mr. Rob Salomon, Mr. Eric Lam, Mr. David Snowden, and Mrs. Vitri Dewi for their help with flow sorting; Ms. Natasha T. Pyne for SHG imaging; Ms. Stephanie Ketterer, Ms. Sylvia Pietkiewicz, and Ms. Natasha Sharma for their input; Dr. Kate Patterson for her help with the graphical summary as well as Mr Julien Charton for his help with the proofreading. This work was supported by funding from the National Health and Medical Research Council (NHMRC) of Australia, the McMurtrie family, Perpetual Trustees, the Estate of the late RT Hall and Novartis. A.S. is the recipient of a Career Development Award from the NHMRC. M.N.H. is a recipient of the following awards: 2013 Pfizer Australia Cancer Research Grant, Australia Postgraduate Award, Sydney Catalyst Top-Up Scholarship and Sydney Breast Cancer Foundation Fellowship. D.N.W. acknowledges the Petre Foundation. T.R.C. is the recipient of a New Investigator Award from the NHMRC. M.S. is supported by a Future Fellowship from the Australian Research Council and Project Grant funding from the NHMRC, the Cancer Council South Australia and the Royal Adelaide Hospital Research Fund. The Zeiss LSM710 two-photon system used for SHG analysis was purchased with assistance from the Health Service Charitable Gifts Board of South Australia. P.T. is the recipient of Len Ainsworth Research Fellowship. S.O.T. is supported by NBCF practitioner fellowship and also gratefully acknowledges the support of the Sydney Breast Cancer Foundation, the Tag family, Mr David Paradice, ICAP and the O’Sullivan family and the estate of the late Kylie Sinclair.\n\nAuthor contributions\nA.S. conceived the project and directed the study with input from all authors. A.S.C. optimized the tumor dissociation, flow sorting, RNA isolation of low-input samples before Next Generation Sequencing, conducted mouse experiments and treatment on the M6 model. M.N.H. conducted the long-term SMO-combined therapy experiments in human preclinical models, tumorsphere assays and image analysis. A.S.C. and M.N.H. interpreted the RNA-Seq data, performed the IHC staining, coculture assays, RT-PCR experiments and all cell culture-related work. B.L.E. analyzed the RNA-Seq datasets. D.R. and N.D. helped with survival analysis using TCGA data and other bioinformatics. C.C. generated cDNA from low-input RNA samples and helped with bioinformatics. A.S.C., S.W., C.C., and D.R. assisted with single-cell RNA-Seq analysis. R.C. and J.Y. performed qRT-PCR experiments. M.S. aided in the interpretation of the stromal RNA-Seq data. M.S., T.R.C., D.H. and P.T. performed SHG imaging and analysis. R.N. and A.F. helped with the xenograft experiments. S.O.T. and C.C. independently scored the IHC stains. T.R.C. and J.N.S. designed, performed and analyzed the alginate-bead experiments. M.R.-B., F.R., J.M.T., S.B., R.C. were involved in the acquisition and data analysis and interpretation of the Phase 1 clinical trial GEICAM EDALINE, designed and driven by M.M. F.R. performed the biomarkers analysis of the GEICAM EDALINE clinical trial. D.N.W. designed experiments, provided intellectual input. E.L. and M.M. provided intellectual input into the design and interpretation of clinical data and assisted in drafting the manuscript. A.S.C., M.N.H. and A.S. wrote the manuscript with input from all authors.\n\nCompeting interests\nNovartis funded a part of the study. The authors declare no other competing interests.\n==== Refs\nReferences\n1. Perrimon N Pitsouli C Shilo BZ Signaling mechanisms controlling cell fate and embryonic patterning Cold Spring Harb. Perspect. Biol. 2012 4 a005975 10.1101/cshperspect.a005975 22855721 \n2. Wiseman BS Werb Z Stromal effects on mammary gland development and breast cancer Science 2002 296 1046 1049 10.1126/science.1067431 12004111 \n3. Chuang PT Kawcak T McMahon AP Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung Genes Dev. 2003 17 342 347 10.1101/gad.1026303 12569124 \n4. Hui M The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy Breast Cancer Res. 2013 15 203 10.1186/bcr3401 23547970 \n5. 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Eisenhauer EA New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur. J. Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774 \n32. Malanchi I Interactions between cancer stem cells and their niche govern metastatic colonization Nature 2011 481 85 89 10.1038/nature10694 22158103 \n33. Lawson DA Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells Nature 2015 526 131 135 10.1038/nature15260 26416748 \n34. Pang R A subpopulation of CD26+cancer stem cells with metastatic capacity in human colorectal cancer Cell Stem Cell 2010 6 603 615 10.1016/j.stem.2010.04.001 20569697 \n35. Chen J A restricted cell population propagates glioblastoma growth after chemotherapy Nature 2012 488 522 526 10.1038/nature11287 22854781 \n36. Li X Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy J. Natl. Cancer Inst. 2008 100 672 679 10.1093/jnci/djn123 18445819 \n37. 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J. Pathol. 2013 183 930 937 10.1016/j.ajpath.2013.05.014 23830873 \n43. Pang MF Tissue stiffness and hypoxia modulate the integrin-linked kinase ILK to control breast cancer stem-like cells Cancer Res. 2016 76 5277 5287 10.1158/0008-5472.CAN-16-0579 27503933 \n44. Sherratt MJ McConnell JC Streuli CH Raised mammographic density: causative mechanisms and biological consequences Breast Cancer Res. 2016 18 45 10.1186/s13058-016-0701-9 27142210 \n45. McConnell JC Increased peri-ductal collagen micro-organization may contribute to raised mammographic density Breast Cancer Res. 2016 18 5 10.1186/s13058-015-0664-2 26747277 \n46. Alvero AB Stem-like ovarian cancer cells can serve as tumor vascular progenitors Stem Cells 2009 27 2405 2413 10.1002/stem.191 19658191 \n47. Spike BT A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer Cell Stem Cell 2012 10 183 197 10.1016/j.stem.2011.12.018 22305568 \n48. Dravis C Sox10 regulates stem/progenitor and mesenchymal cell states in mammary epithelial cells Cell Rep. 2015 12 2035 2048 10.1016/j.celrep.2015.08.040 26365194 \n49. Fillmore CM Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling Proc. Natl. Acad. Sci. USA 2010 107 21737 21742 10.1073/pnas.1007863107 21098263 \n50. Su SC CD10(+) GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness Cell 2018 172 841-+ 10.1016/j.cell.2018.01.009 29395328 \n51. Babina IS Turner NC Advances and challenges in targeting FGFR signalling in cancer Nat. Rev. Cancer 2017 17 318 332 10.1038/nrc.2017.8 28303906 \n52. Wilkinson SE Hedgehog signaling is active in human prostate cancer stroma and regulates proliferation and differentiation of adjacent epithelium Prostate 2013 73 1810 1823 10.1002/pros.22720 24105601 \n53. Lasorella A Benezra R Iavarone A The ID proteins: master regulators of cancer stem cells and tumour aggressiveness Nat. Rev. Cancer 2014 14 77 91 10.1038/nrc3638 24442143 \n54. Bain G Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade Nat. Immunol. 2001 2 165 171 10.1038/84273 11175815 \n55. Wilgus TA Growth factor-extracellular matrix interactions regulate wound repair Adv. Wound Care (New Rochelle) 2012 1 249 254 10.1089/wound.2011.0344 24527314 \n56. Kouros-Mehr H Werb Z Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis Dev. Dyn. 2006 235 3404 3412 10.1002/dvdy.20978 17039550 \n57. Lewis MT The Gli2 transcription factor is required for normal mouse mammary gland development Dev. Biol. 2001 238 133 144 10.1006/dbio.2001.0410 11783999 \n58. Lu P Ewald AJ Martin GR Werb Z Genetic mosaic analysis reveals FGF receptor 2 function in terminal end buds during mammary gland branching morphogenesis Dev. 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"fulltext_license": "CC BY",
"issn_linking": "2041-1723",
"issue": "9(1)",
"journal": "Nature communications",
"keywords": null,
"medline_ta": "Nat Commun",
"mesh_terms": "D000328:Adult; D000368:Aged; D000813:Anilides; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells; D011725:Pyridines; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms; D023041:Xenograft Model Antitumor Assays",
"nlm_unique_id": "101528555",
"other_id": null,
"pages": "2897",
"pmc": null,
"pmid": "30042390",
"pubdate": "2018-07-24",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer.",
"title_normalized": "targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer"
} | [
{
"companynumb": "AU-SA-2019SA130205",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
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{
"abstract": "A case of ibuprofen-associated meningitis is reported in a previously healthy 26-year-old woman. The association was substantiated with a rechallenge. She had no symptoms of rheumatoid factor and a positive antibody to the intranuclear antigen SS-A.",
"affiliations": "Department of Internal Medicine, University of North Carolina, Chapel Hill.",
"authors": "Ewert|B H|BH|",
"chemical_list": "D000974:Antibodies, Antinuclear; C035356:SS-A antibodies; D012217:Rheumatoid Factor; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": "10.1097/00000441-198905000-00010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "297(5)",
"journal": "The American journal of the medical sciences",
"keywords": null,
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000328:Adult; D000974:Antibodies, Antinuclear; D005260:Female; D006801:Humans; D007052:Ibuprofen; D008581:Meningitis; D008582:Meningitis, Aseptic; D012217:Rheumatoid Factor",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "326-7",
"pmc": null,
"pmid": "2785759",
"pubdate": "1989-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ibuprofen-associated meningitis in a woman with only serologic evidence of a rheumatologic disorder.",
"title_normalized": "ibuprofen associated meningitis in a woman with only serologic evidence of a rheumatologic disorder"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP017373",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional"... |
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