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"abstract": "A complete case example of a fatal 2,4-dinitrophenol (DNP) overdose involving a 23-year-old male is described. Included are details of not only the patient's presentation symptoms and treatment, but also the subsequent findings of the coronial investigation process including the autopsy, post-mortem computed tomography (PMCT) scanning and toxicological analysis and results. The patient presented with elevated temperature, heart rate and blood pressure. Multiple treatments were conducted to counteract these symptoms, however the patient died approximately 1.5 hours after hospital admission and some 4.5 hours after the DNP was initially consumed. Autopsy revealed the presence of cardiovascular disease that was contributory to death and post-mortem computed tomography showed evidence of decompositional intravascular gas in the neck, head, face, lower abdomen, heart and hepatic systems. Toxicological analysis was completed by protein precipitation with methanol and subsequent instrumental analysis by LC/MS/MS in negative ion mode. The antemortem blood specimen showed the presence of tadalafil, two anabolic steroids and a DNP concentration of 110 mg/kg which is consistent with other reported DNP fatalities. Despite the small amount of time between the antemortem specimen collection and death, the DNP concentration identified in the femoral blood post-mortem specimen was comparably low (5.5 mg/kg). DNP concentrations also reduced during an extended period of specimen storage prior to analysis indicating some instability in biological specimens even when refrigerated or frozen. DNP was found to be distributed primarily in the aqueous tissues (blood, vitreous, bile) rather than solid matrices (liver, kidney, muscle).",
"affiliations": "Queensland Health Forensic and Scientific Services, Queensland, Australia. Electronic address: andrew.griffiths@health.qld.gov.au.;Queensland Health Forensic and Scientific Services, Queensland, Australia; The University of Queensland, Queensland, Australia; Bond University, Queensland, Australia.;Queensland Health Forensic and Scientific Services, Queensland, Australia; The University of Queensland, Queensland, Australia.;Queensland Health Forensic and Scientific Services, Queensland, Australia; Princess Alexandra Hospital, Queensland, Australia.",
"authors": "Griffiths|A|A|;Milne|N|N|;Ong|B|B|;Watkins|T|T|",
"chemical_list": "D019440:Anti-Obesity Agents; D005740:Gases; D019297:2,4-Dinitrophenol",
"country": "England",
"delete": false,
"doi": "10.1016/j.jflm.2021.102148",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-928X",
"issue": "79()",
"journal": "Journal of forensic and legal medicine",
"keywords": "2,4-Dinitrophenol (DNP); Death; Hyperthermia; Overdose; Post-mortem; Stability",
"medline_ta": "J Forensic Leg Med",
"mesh_terms": "D019297:2,4-Dinitrophenol; D019440:Anti-Obesity Agents; D001646:Bile; D003324:Coronary Artery Disease; D062787:Drug Overdose; D005740:Gases; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal; D011180:Postmortem Changes; D000081013:Suicide, Completed; D014057:Tomography, X-Ray Computed; D014822:Vitreous Body; D055815:Young Adult",
"nlm_unique_id": "101300022",
"other_id": null,
"pages": "102148",
"pmc": null,
"pmid": "33706128",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "2,4-Dinitrophenol overdose - Everything old is new again.",
"title_normalized": "2 4 dinitrophenol overdose everything old is new again"
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"companynumb": "AU-BAUSCH-BL-2021-034102",
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"abstract": "Since the onset of the COVID-19 pandemic, several cardiovascular manifestations have been described. Among them, venous thromboembolism (VTE) seems to be one of the most frequent, particularly in intensive care unit patients. We report two cases of COVID-19 patients developing acute pulmonary embolism (PE) after discharge from a first hospitalization for pneumonia of moderate severity.\nTwo patients with positive RT-PCR test were initially hospitalized for non-severe COVID-19. Both received standard thromboprophylaxis during the index hospitalization and had no strong predisposing risk factors for VTE. Few days after discharge, they were both readmitted for worsening dyspnoea due to PE. One patient was positive for lupus anticoagulant.\nWorsening respiratory status in COVID-19 patients must encourage physicians to search for PE since SARS-CoV-2 infection may act as a precipitant risk factor for VTE. Patients may thus require more aggressive and longer thromboprophylaxis after COVID-19 related hospitalization.",
"affiliations": "Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.;Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.;Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.;Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.;Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.;Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.;Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.;Pôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital 67091, Strasbourg Cedex, France.",
"authors": "Kanso|Mohamad|M|0000-0001-9604-8866;Cardi|Thomas|T|0000-0001-5381-5332;Marzak|Halim|H|;Schatz|Alexandre|A|0000-0002-1477-8329;Faucher|Loïc|L|0000-0002-7334-4184;Grunebaum|Lélia|L|;Morel|Olivier|O|;Jesel|Laurence|L|",
"chemical_list": null,
"country": "England",
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"doi": "10.1093/ehjcr/ytaa449",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119 Oxford University Press \n\n10.1093/ehjcr/ytaa449\nytaa449\nCase Series\nOther\nAcademicSubjects/MED00200\nDelayed pulmonary embolism after COVID-19 pneumonia: a case report\nhttp://orcid.org/0000-0001-9604-8866Kanso Mohamad http://orcid.org/0000-0001-5381-5332Cardi Thomas Marzak Halim http://orcid.org/0000-0002-1477-8329Schatz Alexandre http://orcid.org/0000-0002-7334-4184Faucher Loïc Grunebaum Lélia Morel Olivier Jesel Laurence \nPôle d'Activité Médico-Chirurgicale Cardiovasculaire, Hôpitaux Universitaires de Strasbourg, 1 Place de l’Hôpital 67091, Strasbourg Cedex, France\nTimothy C Tan Handling Editor Rafael Vidal-Perez Editor Sylvia Krupickova Editor Max Sayers Editor Vassilios Parisis Memtsas Editor Corresponding author. Tel: +33 3 695 51064, Fax: +33 3 695 51788, Email: mohamad.kanso@chru-strasbourg.fr\n12 2020 \n24 11 2020 \n24 11 2020 \n4 6 1 4\n02 5 2020 18 5 2020 4 11 2020 4 11 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground \nSince the onset of the COVID-19 pandemic, several cardiovascular manifestations have been described. Among them, venous thromboembolism (VTE) seems to be one of the most frequent, particularly in intensive care unit patients. We report two cases of COVID-19 patients developing acute pulmonary embolism (PE) after discharge from a first hospitalization for pneumonia of moderate severity. \n\nCase summary \nTwo patients with positive RT-PCR test were initially hospitalized for non-severe COVID-19. Both received standard thromboprophylaxis during the index hospitalization and had no strong predisposing risk factors for VTE. Few days after discharge, they were both readmitted for worsening dyspnoea due to PE. One patient was positive for lupus anticoagulant. \n\nDiscussion \nWorsening respiratory status in COVID-19 patients must encourage physicians to search for PE since SARS-CoV-2 infection may act as a precipitant risk factor for VTE. Patients may thus require more aggressive and longer thromboprophylaxis after COVID-19 related hospitalization.\n\nCOVID-19SARS-CoV-2Venous thromboembolismPulmonary embolismLupus anticoagulantCase report\n==== Body\nLearning points\nA deterioration in respiratory status in COVID-19 patients associated with increased D-dimer level must encourage physicians to search for pulmonary embolism.\n\nCOVID-19 patients may require more aggressive and longer thromboprophylaxis after hospital admission since SARS-CoV-2 could be a precipitant factor for venous thromboembolism.\n\nThere may be a potential role of lupus anticoagulant in the pro-thrombotic state in COVID-19 patients.\n\n\n\n\nIntroduction\nOn 11 March 2020, The World Health Organization (WHO) declared the onset of the COVID-19 pandemic; the disease caused by the novel coronavirus, SARS-CoV-2.\n\nSince then, several reports have been published on the cardiovascular implications of this emerging disease.1 Among them, venous thromboembolism (VTE) appears to be a frequent complication2 particularly in patients hospitalized for severe acute respiratory distress syndrome.3,4 In this observation, we report two cases of COVID-19 male patients developing acute pulmonary embolism (PE) after a first hospitalization for pneumonia of moderate severity. To the best of our knowledge, no cases of pulmonary embolism (PE) occurring secondly after a first hospitalization for COVID-19 non-severe infection have been described yet.\n\nTimeline\nTime\tEvents\t\n\nPatient 1\n\t\n22 March 2020\tFirst symptoms: fever and myalgia\t\n25 March 2020\tFirst hospitalization for the severe respiratory syndrome. RT-PCR testing and computed tomography (CT) scan confirmed COVID-19 pneumonia. Treatment with ceftriaxone, hydroxychloroquine, and enoxaparin. Negative lupus anticoagulant (LA) testing.\t\n3 April 2020\tDischarge with no treatment after the progressive withdrawal of oxygen.\t\n5 April 2020\tRehospitalization for rapidly worsening dyspnoea. Second CT scan showing more extensive pneumonia lesions and pulmonary embolism. Positive LA testing.\t\n21 April 2020\tDischarge on vitamin K antagonist\t\n\nPatient 2\n\t\t\n15 March 2020\tFirst symptoms: fever, dry cough, and myalgia\t\n19 March 2020\tFirst hospitalization for dyspnoea. Positive RT-PCR testing for SARS-CoV-2 but no lesions on CT scan. Thromboprophylaxis with enoxaparin.\t\n25 March 2020\tDischarge with no treatment.\t\n29 March 2020\tRehospitalization for new-onset dyspnoea (New York Heart Association III). Second CT scan showed subpleural ground-glass opacifications and pulmonary embolism. No LA was found.\t\n7 April 2020\tDischarge on apixaban.\t\nCase presentations \nPatient 1\nPatient 1, aged 68, with history of heavy smoking (60 pack-year) and hypercholesterolaemia presented with polypnoea (22 cycle/min) and low oxygen saturation in room air of 88% after 3 days of fever and myalgia. Physical examination demonstrated coarse crackles in both lower lung fields. Reverse transcription-polymerase chain reaction (RT-PCR) testing on nasopharyngeal swab was positive for SARS-Cov-2. A low-dose computed tomography (CT) scan on the first admission showed peripheral ground-glass opacifications with underlying centrilobular emphysema lesions with an extension of COVID lesions estimated to 10–25% of lung parenchyma (Figure 1A). The baseline electrocardiogram (ECG) was normal. A modest lymphopenia was present [750/mm³, referential range (RR) 1000–4000/mm³] with increased values of C-reactive protein (CRP) (41 mg/L, RR < 4 mg/L) and D-dimer (1040 µg/L, RR < 500 µg/L). Brain natriuretic peptide (BNP) and troponin I levels were normal. Lupus anticoagulant (LA) testing was negative. The arterial blood gas on nasal cannula 8 L/min showed PaO2 60 mmHg, PCO2 37 mmHg, and SaO2 90%. Based on these findings, treatments with low molecular weight heparin (LMWH), enoxaparin 40 mg once a day, ceftriaxone, and hydroxycholoroquine were started. The following day, oxygen flow was increased to 15 L/min and delivered on a non-rebreather mask. After 8 days, the clinical status improved, and the patient was discharged home after progressive oxygen weaning.\n\nFigure 1 Serial chest computed tomography scans of Patient 1. (A) Low dose computed tomography scan on the first hospitalization showing peripheral ground-glass opacifications with underlying centrilobular emphysema lesions. (B) High resolution computed tomography scan (lung window) on readmission showing an increase in infectious lesions of ground-glass opacifications with an extension of 30% of lung parenchyma with predominant consolidation in the lower lobes. (C) Computed tomography angiography showing filling defect (arrow) in the right pulmonary artery and its right superior lobe divisions. \n\nForty-eight hours after discharge, he presented with rapidly worsening dyspnoea and severe hypoxaemia. D-dimer level was high (>20 000 µg/L), and Troponin I and BNP remained normal. A second chest CT evidenced worsening infectious lesions (Figure 1B) with an extension of 30% and filling defects in the right pulmonary artery and its right superior lobe divisions diagnostic for pulmonary embolism (Figure 1C). Unfractionated heparin was then started and switched after 48 h to LMWH twice a day. A second LA testing was positive. Vitamin K antagonist treatment with warfarin was initiated. A second LA test was planned after 3 months to decide whether anticoagulation should be discontinued or not. The patient was advised to consult his cardiologist one month after discharge.\n\nPatient 2\nPatient 2, aged 62, was referred for dyspnoea after 5 days of fever, dry cough, and myalgia. He had a history of dilated cardiomyopathy with mildly reduced ejection fraction (42%) and several cardiovascular risk factors (smoking, hypertension, type 2 diabetes mellitus, and hypercholesterolaemia). The physical examination did not demonstrate any abnormalities on admission. No crackles had been detected on lung auscultation. RT-PCR testing on nasopharyngeal swab was positive for SARS-Cov-2. A low-dose CT scan was initially normal (Figure 2A). The baseline ECG showed sinus tachycardia. C-reactive protein was mildly increased (peak value of 20 mg/L) with no leucocytosis. No troponin, BNP, or D-dimer tests were performed during the index hospitalization. Despite subnormal arterial blood gas on room air on admission (PaO2 of 73 mmHg, PCO2 of 42 mmHg, SO2 of 95%), the patient received low flow nasal oxygen (1 L/min) for 2 days. Enoxaparin 40 mg once a day during the hospital stay of 5 days was the sole treatment.\n\nFigure 2 Serial chest computed tomography scans of Patient 2. (A) Low dose computed tomography scan on the first hospitalization showing normal lung parenchyma. (B) High resolution computed tomography scan (lung window) on readmission showing multiple subpleural ground-glass opacifications. (C) Computed tomography angiography showing filling defects (arrow) in the left inferior lobar artery branch.\n\nFour days after discharge, he was referred for a worsened dyspnoea (New York Heart Association III). A second CT scan showed multiple subpleural ground-glass opacifications and a filling defect diagnostic for pulmonary embolism in the left inferior lobe (Figure 2B and C). Four chamber view of the heart by CT angiography showed normal right ventricle size and cardiac biomarkers were not elevated [troponin I 10 ng/L (RR< 57 ng/L) and BNP 25 ng/L (RR <100 ng/L)]. A bedside echocardiography evidenced a left ventricle ejection fraction around 40% with normal right ventricle size and pressures. Inflammation markers were increased [CRP 95 mg/L and fibrinogen 7.16 g/L (RR 2–4 g/L)]. D-dimer level, measured 48 h after initiation of LMWH therapy, was normal (430 µg/L). Lupus anticoagulant was not detected, and the patient was switched to apixaban. The planned anticoagulation duration was 3 months and the patient was advised to consult his cardiologist one month after discharge.\n\nDiscussion\nWe describe two cases of COVID-19 patients presenting with post-hospital discharge acute pulmonary embolism despite adequate thromboprophylaxis in a non-intensive care unit setting. Despite the absence of major predisposing risk factors for venous thromboembolism (VTE), the administration of a weight-adjusted thromboprophylaxis during hospitalization and the absence of severe inflammatory syndrome, PE occurred and was associated with a worsening of CT lung injuries. In one case, LA could be evidenced by questioning about the correct anticoagulant treatment and its duration. To the best of our knowledge, no reports of acute pulmonary embolism (PE) after discharge from the hospital have been described yet in non-intensive care unit patients.\n\nThe novel Coronavirus Disease outbreak is a global public health challenge. Since the first cases of SARS-CoV-2 were detected in Wuhan, China,5 more than 2 500 000 confirmed cases and 175 000 deaths have been documented worldwide.6 COVID-19-induced interstitial pneumonia leading potentially to acute respiratory distress syndrome (ARDS) and multi-organ failure is in the spotlight of all medical teams as it often triggers transfer of patients in intensive care units. Recently, it has been evidenced that SARS-CoV-2 could predispose patients to increased thrombotic disease in the venous and arterial circulations.7 Severe inflammation, hypoxia, endothelial dysfunction, platelet activation and stasis particularly in intensive care unit patients could explain this pro-thrombotic state. Very recently, in a ARDS population, 16.7% of PE were diagnosed and 88.7% of those patients had positive LA.4 Llitjos et al. observed that the systematic screening by complete duplex ultrasound in 26 intensive care unit patients showed a peripheral VTE prevalence of 67%.8\n\nInterestingly, in the two cases described here, thrombotic events occurred 13–14 days from the onset of COVID-19 symptoms, at home after a first non-intensive care unit hospitalization and in patients clinically recovered.\n\nThere were no clinical signs of severe pneumonia, fever nor major inflammatory syndrome when PE occurred. Interestingly, both patients evidenced an increased extension of the peripheral ground-glass opacifications when PE was diagnosed despite a clear clinical improvement before discharge. Thromboprophylaxis during first hospital stay was effective but stopped after discharge. Several reports confirmed that attention should be paid to venous thromboembolism prophylaxis in COVID patients during hospitalization9 but no recommendations existed regarding routine post-hospital discharge thromboprophylaxis, recommended agent and/or duration.\n\nOur case report suggests the potential role of SARS-CoV-2 as a major precipitant factor for VTE. Some acute viral infections are known to be associated with LA which are often transient, but can persist and lead to thromboembolic complications by various mechanisms including the release of membrane microparticles and the exposure of pro-thrombotic phospholipids.10 Although the significance of these antibodies is not well established yet, COVID-19-induced LA could favour the highly frequent thrombo-embolic events in this population and should be systematically tested. COVID-19 patients may thus require longer and more aggressive VTE prophylaxis after discharge. The type of anticoagulant treatment after pulmonary embolism may be adapted according to the presence of COVID-19-induced LA, taking into consideration that oral direct anticoagulants are contraindicated in case of LA in the general population.\n\nSince COVID-19 patients are at high risk of developing PE, a sudden deterioration in respiratory status associated with high level of D-dimers must draw attention to progressive radiographic deterioration on CT and/or pulmonary embolism occurrence.\n\nLead author biography\nDr Mohamad Kanso is a cardiologist in Strasbourg University Hospital, Strasbourg, France. He graduated from the Cardiovascular Medicine, University of Strasbourg, in 2018 and is actually training in interventional electrophysiology. \n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patients in line with COPE guidance. \n\n\nConflict of interest: none declared.\n\n\nFunding: This work was supported by GERCA (Groupe pour l'Enseignement, la prévention et la Recheche Cardiologique en Alsace). \n\nSupplementary Material\nytaa449_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences \n1 \nDriggin E Madhavan MV Bikdeli B Chuich T Laracy J Bondi-Zoccai G \nCardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic\n. J Am Coll Cardiol 2020 ;75 :2352–2371 .32201335 \n2 \nKlok FA , Kruip MJHA , van der Meer NJM , Arbous MS , Gommers D , Kant KM \net al\nIncidence of thrombotic complications in critically ill ICU patients with COVID-19\n. Thromb Res 2020 ;191 :145 –147\n.32291094 \n3 \nPoissy J , Goutay J , Caplan M , Parmentier E , Duburcq T , Lassalle F \net al\nPulmonary embolism in COVID-19 patients: awareness of an increased prevalence\n. Circulation 2020 ;142 :184 –186\n.32330083 \n4 \nHelms J , Tacquard C , Severac F , Leonard-Lorant I , Ohana M , Delabranche X , et al CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). \nHigh risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study\n. Intensive Care Med 2020 ;46 :1089 –1098\n.32367170 \n5 \nZhu N , Zhang D , Wang W , Li X , Yang B , Song J \net al\nA novel coronavirus from patients with pneumonia in China, 2019\n. N Engl J Med 2020 ;382 :727 –733\n.31978945 \n6 Coronavirus disease 2019 (COVID-19) Situation Report – 94 [Internet]. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200423-sitrep-94-covid-19.pdf? sfvrsn=b8304bf0_4 (23 April 2020).\n7 \nBikdeli B , Madhavan MV , Jimenez D , Chuich T , Dreyfus I , Driggin E \net al\nCOVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up\n. J Am Coll Cardiol 2020 ;75 :2950 –2973\n.32311448 \n8 \nLlitjos J-F , Leclerc M , Chochois C , Monsallier J-M , Ramakers M , Auvray M \net al\nHigh incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients\n. J Thromb Haemost 2020 ;18 :1743 –1746\n.32320517 \n9 \nWang T , Chen R , Liu C , Liang W , Guan W , Tang R \net al\nAttention should be paid to venous thromboembolism prophylaxis in the management of COVID-19\n. Lancet Haematol 2020 ;7 :e362 –e363\n.32278361 \n10 \nAbdel-Wahab N , Talathi S , Lopez-Olivo MA , Suarez-Almazor ME. \nRisk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis\n. Lupus 2018 ;27 :572 –583\n.28945149\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "4(6)",
"journal": "European heart journal. Case reports",
"keywords": "COVID-19; Case report; Lupus anticoagulant; Pulmonary embolism; SARS-CoV-2; Venous thromboembolism",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "33447717",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "31978945;32320517;32201335;32367170;28945149;32291094;32311448;32330083;32278361",
"title": "Delayed pulmonary embolism after COVID-19 pneumonia: a case report.",
"title_normalized": "delayed pulmonary embolism after covid 19 pneumonia a case report"
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"abstract": "BACKGROUND\nIn this case report, we present a preterm newborn with persistent lactic acidosis who received total parenteral nutrition (TPN) that lacked thiamine.\n\n\nMETHODS\nA 28-week-old, 750 g female infant was born with an Apgar score of 8 at the 5th minute. Umbilical cord blood gas levels, including lactate level, were normal, and she was admitted to our neonatal intensive care unit (NICU). Achieving full enteral feeding was not possible due to gastric residues and abdominal distention, making the patient dependent on TPN during the first 2 weeks of life. An insidious increase in lactic acid levels and uncompensated metabolic acidosis were apparent from the 23rd day of life. Severe metabolic acidosis was persistent despite massive doses of bicarbonate. The acidosis resolved dramatically within 6 h when the patient was administered with thiamine.\n\n\nCONCLUSIONS\nAlthough TPN is life saving in the NICU, meticulous attention must be paid to provide all essential macro- and micro-nutrients.",
"affiliations": "Department of Pediatrics, Division of Neonatology, T.C. Sağlık Bakanlığı-Marmara Üniversitesi Pendik Eğitim ve Araştırma Hastanesi, Fevzi Çakmak Mah. Mimar Sinan Cad. Üstkaynarca, Pendik, Istanbul 3489, Turkey, Phone: +90 216 625 45 45/0 533 351 83 45, Fax: +90 216 657 06 95.;Department of Pediatrics, Division of Neonatology, Marmara University Faculty of Medicine, Istanbul, Turkey.;Department of Pediatrics, Division of Neonatology, Marmara University Faculty of Medicine, Istanbul, Turkey.;Division of Nutrition and Metabolism, Department of Pediatrics, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.;Department of Pediatrics, Division of Neonatology, Marmara University Faculty of Medicine, Istanbul, Turkey.;Department of Pediatrics, Division of Neonatology, Marmara University Faculty of Medicine, Istanbul, Turkey.",
"authors": "Ozdemir|Hulya|H|;Bilgen|Hulya|H|;Alp Unkar|Zeynep|Z|;Kiykim|Ertugrul|E|;Memisoglu|Asli|A|;Ozek|Eren|E|",
"chemical_list": "D013831:Thiamine",
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"doi": "10.1515/jpem-2017-0554",
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"issn_linking": "0334-018X",
"issue": "31(6)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": "preterm; severe lactic acidosis; thiamine deficiency",
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D000140:Acidosis, Lactic; D005260:Female; D005865:Gestational Age; D006801:Humans; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D007363:Intensive Care Units, Neonatal; D010289:Parenteral Nutrition, Total; D012720:Severity of Illness Index; D013831:Thiamine; D013832:Thiamine Deficiency",
"nlm_unique_id": "9508900",
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"pages": "693-695",
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"pmid": "29715193",
"pubdate": "2018-06-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe lactic acidosis in an extremely low birth weight infant due to thiamine deficiency.",
"title_normalized": "severe lactic acidosis in an extremely low birth weight infant due to thiamine deficiency"
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"abstract": "To report the clinical outcome of a patient with ocular cicatricial pemphigoid, treated with adrenocorticotropic hormone gel.\nA 75-year-old female with a biopsy proven ocular cicatricial pemphigoid (OCP) presented with bilateral conjunctival inflammation, fornix shortening, subepithelial fibrosis and corneal scarring. The patient was previously treated with topical steroids, topical cyclosporine and lubricating drops, and had undergone several amniotic membrane transplants due to recurrent corneal erosions. Once OCP diagnosis was established, the patient was started on oral corticosteroids (60 mg daily). In order to wean the patient off from systemic steroids, other immunomodulatory agents had been tried, including mycophenolate mofetil (1000 mg twice daily) and methotrexate (up to 25 mg weekly). However, none of these agents adequately controlled the ocular surface inflammation, and the patient experienced bilateral progressive cicatrization and corneal decompensation, as well as the development of side effects from the systemic corticosteroids, methotrexate and mycophenolate mofetil therapies. Treatment with twice weekly subcutaneous adrenocorticotropic hormone (ACTH) gel was initiated, along with tapering of systemic corticosteroids. During the 19 months treatment period, the patient demonstrated significant improvement in the ocular surface inflammation, visual acuity was stable and no significant adverse effects were observed. Systemic corticosteroids dosage was successfully reduced from 10 mg/day to none at last follow up.\nACTH gel has shown to be an effective and safe treatment option for chronic, refractory and progressive ocular inflammatory disease. To the best of our knowledge, this is the first case report of a patient with OCP, treated successfully with ACTH gel. This case report may encourage ophthalmologists to employ ACTH gel in the management of OCP.",
"affiliations": "Metropolitan Eye Research and Surgery Institute, Palisades Park, NJ, USA.;Metropolitan Eye Research and Surgery Institute, Palisades Park, NJ, USA.",
"authors": "Sharon|Yael|Y|;Chu|David S|DS|",
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"country": "United States",
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"doi": "10.1016/j.ajoc.2018.03.018",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(17)30291-810.1016/j.ajoc.2018.03.018Brief reportAdrenocorticotropic hormone analogue as novel treatment regimen in ocular cicatricial pemphigoid Sharon Yael yael@mersieye.coma∗Chu David S. aba Metropolitan Eye Research and Surgery Institute, Palisades Park, NJ, USAb Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Newark, NJ, USA∗ Corresponding author. yael@mersieye.com20 3 2018 6 2018 20 3 2018 10 264 267 29 9 2017 12 3 2018 19 3 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report the clinical outcome of a patient with ocular cicatricial pemphigoid, treated with adrenocorticotropic hormone gel.\n\nObservations\nA 75-year-old female with a biopsy proven ocular cicatricial pemphigoid (OCP) presented with bilateral conjunctival inflammation, fornix shortening, subepithelial fibrosis and corneal scarring. The patient was previously treated with topical steroids, topical cyclosporine and lubricating drops, and had undergone several amniotic membrane transplants due to recurrent corneal erosions. Once OCP diagnosis was established, the patient was started on oral corticosteroids (60 mg daily). In order to wean the patient off from systemic steroids, other immunomodulatory agents had been tried, including mycophenolate mofetil (1000 mg twice daily) and methotrexate (up to 25 mg weekly). However, none of these agents adequately controlled the ocular surface inflammation, and the patient experienced bilateral progressive cicatrization and corneal decompensation, as well as the development of side effects from the systemic corticosteroids, methotrexate and mycophenolate mofetil therapies. Treatment with twice weekly subcutaneous adrenocorticotropic hormone (ACTH) gel was initiated, along with tapering of systemic corticosteroids. During the 19 months treatment period, the patient demonstrated significant improvement in the ocular surface inflammation, visual acuity was stable and no significant adverse effects were observed. Systemic corticosteroids dosage was successfully reduced from 10 mg/day to none at last follow up.\n\nConclusions and importance\nACTH gel has shown to be an effective and safe treatment option for chronic, refractory and progressive ocular inflammatory disease. To the best of our knowledge, this is the first case report of a patient with OCP, treated successfully with ACTH gel. This case report may encourage ophthalmologists to employ ACTH gel in the management of OCP.\n\nKeywords\nAdrenocorticotropic hormoneOcular cicatricial pemphigoidClinical outcome\n==== Body\n1 Introduction\nOcular cicatricial pemphigoid (OCP) is a specific entity in a group of chronic inflammatory mucocutaneous blistering conditions, called mucous membrane pemphigoid.1 The disease is characterized by scarring and shrinkage of the conjunctiva as well as in extraocular mucous membranes, such as the oral mucosa, esophagus, larynx, and skin.1,2 The disease commonly affects females with an average age of onset of 65 years.3 OCP is diagnosed by linear antibody and complement deposition at the epithelial basement membrane of the involved mucosa. The earliest clinical finding is a chronic, recurrent, papillary conjunctivitis. Recurrent attacks of conjunctival inflammation can lead to destruction of goblet cells, lacrimal gland ductule obstruction, entropion, trichiasis and corneal abrasions, vascularization and ulceration. Progressive cicatrization is common, as well as remissions and exacerbations periods with therapy.\n\nTreatment for the majority of OCP patients utilizes systemic immunomodulatory therapies in order to prevent cicatrization. Systemic treatments include corticosteroids, and steroid-sparing agents, such as cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate (MTX), and diaminodiphenylsulfone (dapsone).4, 5, 6, 7 Usually, monotherapy with corticosteroids, along with its adverse events, is not sufficient to produce long-term remission, nor able to achieve an adequate level of sustained immunosuppression in OCP patients. Furthermore, the later the stage of disease upon initiation of therapy, the more likely it will progress and not respond to therapy. However, the use of steroid-sparing medications also carries potential risks and side effects. Cyclophosphamide can cause leukopenia, anemia, bone marrow suppression, and bladder carcinoma.2 Common side effects of mycophenolate mofetil are nausea, diarrhea, abdominal pain, fever and anemia. MTX may cause hepatotoxicity, pneumonitis, pulmonary fibrosis, pancytopenia, and malignancy. In some patients with reluctant disease, immunomodulatory treatments, such as intravenous immunoglobulin (IVIg) and rituximab, have shown some success.8,9\n\nAdrenocorticotropic hormone (ACTH) is a member of a group of molecules called melanocortins (MCs), derived from the precursor proopiomelanocortin (POMC) and endogenously produced in the hypothalamic-pituitary pathway. ACTH acts primarily to stimulate and regulate steroids production. ACTH has recently been shown to have anti-inflammatory effects beyond endogenous steroid production.10,11\n\nACTH gel was approved by the United States Food and Drug Administration (FDA) in 1952 for a variety of autoimmune and inflammatory conditions. ACTH gel is indicated for severe acute and chronic allergic and inflammatory ocular processes including keratitis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis and anterior segment inflammation.12 It also has shown efficacy in various systemic inflammatory diseases including systemic lupus erythematosus,13 multiple sclerosis,14 nephrotic syndrome,15 infantile spams,16 dermatomyositis, and polymyositis.17\n\nTo the best of our knowledge, treatment of ocular cicatricial pemphigoid with ACTH gel has never been reported. In this case report, we describe the clinical course and outcome of a patient with ocular cicatricial pemphigoid, treated with ACTH gel.\n\n2 Case report\nA 75-year-old woman was referred in April, 2015 due to chronic conjunctival redness, foreign body sensation, irritation and blurred vision in both eyes. She had previously been treated with topical steroids, topical cyclosporine (0.05%) and frequent use of lubricating eye drops. The patient had undergone amniotic membrane transplants in both eyes due to persistent corneal epithelial defects. She has a history of open-angle glaucoma, exudative age-related macular degeneration and cataract surgery in her right eye. The best corrected visual acuity (BCVA) was counting fingers (CF) in both eyes at the time of initial presentation. Slit-lamp examination revealed trichiasis, conjunctival injection, fornix shortening and subconjunctival fibrosis, as well as corneal scarring in both eyes. Serology testing was performed in order to exclude other infectious and autoimmune diseases and was negative. Ocular cicatricial pemphigoid (OCP) was confirmed using conjunctival biopsy with direct immunofluorescence testing of the conjunctiva. Based on the clinical findings, her disease was graded as stage 3.18\n\nThe patient was started on oral corticosteroids (prednisone 60 mg daily). Following initiation of oral corticosteroids, there was interval improvement in the ocular surface inflammation in both eyes. However, the patient developed multiple side effects attributed to systemic steroids including nervousness, moon facies, fatigue, ecchymoses, joint pain, swelling, and muscle weakness. In order to wean the patient off from systemic corticosteroids, initiation of immunomodulatory therapy was planned.\n\nMycophenolate mofetil was started (1000 mg twice daily), however, the patient had discontinued treatment after two months due to severe fatigue and persistent conjunctival inflammation after gradually tapering systemic corticosteroids dose. Methotrexate (MTX) was then initiated (15 mg weekly) and systemic corticosteroids were slowly tapered. After three months of MTX therapy, recurrence of bilateral conjunctival inflammation was observed and corneal ulcer had developed in the left eye. Methotrexate dose was increased to 30 mg weekly and the corneal ulcer was treated with topical antibiotics until resolved. However, the patient was still experiencing active conjunctival inflammation, recurrent corneal epithelial defects and systemic side effects from increasing MTX dose. These side effects included anemia, poor appetite, nausea, abdominal pain, skin rash, hair loss, recurrent urinary tract infections and was hospitalized due to pneumonia. Adalimumab and rituximab were suggested as alternative options, however, were not initiated because of denial for coverage for OCP by her insurance.\n\nThe patient was started on twice weekly subcutaneous H.P. Acthar® Gel (repository corticotropin injection; Mallinckrodt Pharmaceuticals, St. Louis, MO), (80 units/ml), in June, 2016. On ocular examination, BCVA was CF in her right eye and hand motion (HM) in her left eye. Slit-lamp examination revealed active disease, characterized by conjunctival injection in both eyes. Following initiation of ACTH gel, MTX dose was gradually decreased, as well as the systemic corticosteroids. The patient remained under adequate control with ACTH gel and MTX. The conjunctiva remained scarred, but was no longer inflamed (Fig. 1). Following 6 months of treatment with ACTH gel, the patient had cataract surgery and penetrating keratoplasty (PKP) in her left eye, due to corneal scarring and vascularization that affected her vision.Fig. 1 Anterior segment photograph of both eyes under ACTH gel treatment. Right eye with corneal haze and vascularization (A), as well as inferior fornix shortening and subepithelial scarring, without active inflammation (B). Left eye with corneal scarring and vascularization (C), inferior fornix shortening and subepithelial scarring, without active inflammation (D).\n\nFig. 1\n\nOn March, 2017, nine months after ACTH gel was started, the patient stopped treatment for 3 months (due to loss of coverage) and immediately flared up upon treatment cessation. Visual acuity in the left eye has decreased from 20/100 to CF and conjunctival inflammation was observed in both eyes. Corneal graft rejection and ulceration were noted in the left eye (as shown in Fig. 2), both of which subsided after resuming ACTH gel, but had left a scar in the corneal graft. PKP was later performed in the right eye as well, due to visually significant corneal scarring. On the last follow-up, after 19 months of treatment with ACTH gel, the BCVA was CF in the right eye and 20/200 in the left eye, no signs of inflammation were observed and corneal grafts were stable in both eyes. MTX was maintained on 25 mg weekly dose, and was well tolerated. The patient did not develop any side effects to ACTH gel treatment, and is being continued on ACTH gel and MTX regimen, with good compliance and sufficient control of the disease.Fig. 2 Anterior segment photograph of the left eye, previously underwent penetrating keratoplasty with clear corneal graft, and on ACTH gel treatment (A). The patient stopped ACTH gel for 3 months and immediately flared up upon treatment cessation, with corneal graft rejection and ulceration (B).\n\nFig. 2\n\n3 Discussion\nOCP is a devastating autoimmune blistering disease that frequently involves the conjunctiva and causes progressive scarring. Although the exact mechanism remains unknown, the pathogenesis includes circulating autoantibodies that bind to antigens within the basement membrane and activate the complement cascade, with further recruitment of inflammatory cells and cytokine secretion. The release of cytokines results in cytotoxic destruction of the conjunctival membrane, bulla formation and fibroblast activation with later progression to mucosal scarring. In the conjunctiva, recurrent inflammation causes loss of goblet cells and obstruction of lacrimal gland ductules, leading to aqueous and mucous tear abnormalities. These tear abnormalities, along with conjunctival scarring at the eyelid margin and mechanical trauma from eyelid changes, further cause corneal epithelial damage.19 The clinical course and severity of OCP is variable. Without treatment, the disease progresses in up to 75% of patients.20 Treatment of OCP is challenging; topical and subconjunctival agents are used only as an adjunctive measure with systemic immunomodulatory treatments, since they are ineffective in controlling and halting disease progression.6,21\n\nACTH induces cortisol production as well as stimulating anti-inflammatory processes by targeting melanocortin receptors present on immune cells.10 Melanocortin receptors are expressed on a range of immune cells throughout the body, including T cells, macrophages, B cells, monocytes, neutrophils, and mast cells. Studies addressing the anti-inflammatory effects of α-melanocyte-stimulating hormone (α-MSH), a part of the melanocortin family, focus on the suppressive effect of the peptide on expression of pro-inflammatory cytokines.22\n\nH.P Acthar Gel is an injectable formulation consisting of ACTH analogue. Since there are no guidelines regarding the recommended dosage for treatment of ocular diseases, we use a dose of 80 units/ml, administered subcutaneously twice weekly, as indicated for other FDA approved systemic diseases.12 Although ACTH gel is approved by the FDA for a wide range of ophthalmologic indications, it is rarely used for either of these indications, due to a lack of data and the high cost of treatment. Possible adverse effects are related primarily to its steroidogenic action and include increased susceptibility to infection or reactivation of latent infection, fluid retention, altered electrolyte balance, increase in blood glucose, systemic hypertension, behavioral and mood changes, weight gain, and cushingoid features, among others.12 In our case, the patient experienced multiple side effects from systemic corticosteroids, yet did not develop any of these side effects while on ACTH gel treatment.\n\nIn the current case, we reported the clinical course of a patient with progressive OCP, refractory and/or intolerant to several immunomodulatory agents. Initiation of ACTH gel treatment resulted in significant improvement of the conjunctival inflammation as well as of the patients' symptoms. ACTH gel provided adequate control and the disease remained inactive while the systemic corticosteroids dose was successfully tapered. A flare-up that occurred during treatment was attributed to ACTH gel treatment cessation, and resolved upon resuming treatment.\n\n4 Conclusions\nOCP can be challenging to treat, due to persistent inflammatory processes that cause progressive scarring and subsequent complications. Treatment is further complicated by the development of side effects to various therapies. According to our experience with ACTH gel treatment in a patient with OCP for more than a year, it may play a role in the management of patients with OCP. Better understanding the physiological and pharmacological mechanisms of action of ACTH gel and involvement of the melanocortin system, is necessary in order to establish its role. ACTH gel may be repurposed for new indications in the ophthalmology field, including OCP, as it appears to be safe and can be used as long-term treatment option for patients with chronic ocular inflammatory diseases.\n\nPatient consent\nThe study and data accumulation were carried out with approval from the appropriate Institutional Review Board (IRB).\n\nFunding\nFinancial interest: This study was funded in part by Mallinckrodt Pharmaceuticals as a medical writing grant (#3840).\n\nConflicts of interest\nThe following authors have no financial disclosures: Dr. Yael Sharon.\n\nDr. David S. Chu serves as a consultant for Mallinckrodt Pharmaceuticals, AbbVie, Aldeyra Therapeutics, Allakos Inc., and Santen Pharmaceuticals.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements\nNone.\n==== Refs\nReferences\n1 Schmidt E. Zillikens D. Pemphigoid diseases Lancet 381 9863 2013 320 332 23237497 \n2 Kirzhner M. Jakobiec F.A. Ocular cicatricial pemphigoid: a Review of clinical features, immunopathology, differential diagnosis, and current management Semin Ophthalmol 26 4-5 2011 270 277 21958173 \n3 Foster C.S. Cicatricial pemphigoid Trans Am Ophthalmol Soc 84 1986 527 663 http://www.ncbi.nlm.nih.gov/pubmed/3296406 Accessed August 10, 2017 3296406 \n4 Thorne J.E. Woreta F.A. Jabs D.A. Anhalt G.J. Treatment of ocular mucous membrane pemphigoid with immunosuppressive Drug therapy Ophthalmology 115 12 2008 2146 2152 e1 18930554 \n5 Saw V.P.J. Dart J.K.G. Rauz S. Immunosuppressive therapy for ocular mucous membrane pemphigoid strategies and outcomes Ophthalmology 115 2 2008 253 261 e1 17655931 \n6 Neff A.G. Turner M. Mutasim D.F. Treatment strategies in mucous membrane pemphigoid Therapeut Clin Risk Manag 4 3 2008 617 626 http://www.ncbi.nlm.nih.gov/pubmed/18827857 Accessed September 16, 2017 \n7 Queisi M.M. Zein M. Lamba N. Meese H. Foster C.S. Update on ocular cicatricial pemphigoid and emerging treatments Surv Ophthalmol 61 3 2016 314 317 26708362 \n8 Sami N. Letko E. Androudi S. Daoud Y. Foster C.S. Ahmed A.R. Intravenous immunoglobulin therapy in patients with Ocular–Cicatricial pemphigoid Ophthalmology 111 7 2004 1380 1382 15234140 \n9 Foster C.S. Chang P.Y. Ahmed A.R. Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid Ophthalmology 117 5 2010 861 869 20045562 \n10 Montero-Melendez T. ACTH: the forgotten therapy Semin Immunol 27 3 2015 216 226 25726511 \n11 Getting S.J. Targeting melanocortin receptors as potential novel therapeutics Pharmacol Ther 111 1 2006 1 15 16488018 \n12 Full Prescribing Information HP Acthar Gel (Repository Corticotropin Injection) 2015 www.acthar.com/pdf/acthar-pi.pdf https://www.acthar.com/ Accessed August 8, 2017 \n13 Fiechtner J.J. Montroy T. Treatment of moderately to severely active systemic lupus erythematosus with adrenocorticotropic hormone: a single-site, open-label trial Lupus 23 9 2014 905 912 24795067 \n14 Simsarian J. Saunders C. Smith M. Five-day regimen of intramuscular or subcutaneous self-administered adrenocorticotropic hormone gel for acute exacerbations of multiple sclerosis: a prospective, randomized, open-label pilot trial Drug Des Dev Ther 5 2011 381 \n15 Madan A. Mijovic-Das S. Stankovic A. Teehan G. Milward A.S. Khastgir A. Acthar gel in the treatment of nephrotic syndrome: a multicenter retrospective case series BMC Nephrol 17 2016 37 27036111 \n16 Baram T.Z. Mitchell W.G. Tournay A. Snead O.C. Hanson R.A. Horton E.J. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study Pediatrics 97 3 1996 375 379 http://www.ncbi.nlm.nih.gov/pubmed/8604274 Accessed June 27, 2017. 8604274 \n17 Levine T. Treating refractory dermatomyositis or polymyositis with adrenocorticotropic hormone gel: a retrospective case series Drug Des Dev Ther 6 2012 133 \n18 Foster C.S. Cicatricial pemphigoid Trans Am Ophthalmol Soc 84 1986 527 663 http://www.ncbi.nlm.nih.gov/pubmed/3296406 Accessed March 11, 2018 3296406 \n19 Ahmed M. Zein G. Khawaja F. Foster C.S. Ocular cicatricial pemphigoid: pathogenesis, diagnosis and treatment Prog Retin Eye Res 23 6 2004 579 592 15388075 \n20 Mondino B.J. Cicatricial pemphigoid and erythema multiforme Ophthalmology 97 7 1990 939 952 http://www.ncbi.nlm.nih.gov/pubmed/2199891 Accessed August 10, 2017 2199891 \n21 Elder M.J. Bernauer W. Leonard J. Dart J.K. Progression of disease in ocular cicatricial pemphigoid Br J Ophthalmol 80 4 1996 292 296 http://www.ncbi.nlm.nih.gov/pubmed/8703876 Accessed August 10, 2017 8703876 \n22 Brzoska T. Luger T.A. Maaser C. Abels C. Böhm M. α-Melanocyte-Stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo , and future perspectives for the treatment of immune-mediated inflammatory diseases Endocr Rev 29 5 2008 581 602 18612139\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "10()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Adrenocorticotropic hormone; Clinical outcome; Ocular cicatricial pemphigoid",
"medline_ta": "Am J Ophthalmol Case Rep",
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"pages": "264-267",
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"pubdate": "2018-06",
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"references": "23237497;2199891;24795067;26708362;25726511;21958173;3296406;16488018;8604274;18612139;20045562;18827857;21792296;17655931;8703876;18930554;15388075;27036111;22787386;15234140",
"title": "Adrenocorticotropic hormone analogue as novel treatment regimen in ocular cicatricial pemphigoid.",
"title_normalized": "adrenocorticotropic hormone analogue as novel treatment regimen in ocular cicatricial pemphigoid"
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"abstract": "Molar pregnancies have been associated with hyperthyroidism and hypertensive disorders. Coexisting molar and fetal pregnancies, which are very rare, have an even higher risk of complications.\nWe describe a case of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with a molar pregnancy. A 36-year-old patient at 13 weeks gestation with a coexisting molar pregnancy presented with headache, nausea, and vomiting. She was found to have hypertension, hyperthyroidism, and hyponatremia. The hyponatremia was further assessed with an isotonic saline challenge which resulted in a diagnosis of SIADH. The patient underwent dilation and curettage and her hyponatremia resolved. She later developed gestational trophoblastic neoplasia.\nA molar pregnancy can present with unusual associated conditions, such as SIADH. Hyponatremia in a patient with molar pregnancy may be mistakenly attributed to other side effects of trophoblastic tissue (hyperthyroidism, pre-eclampsia, or hyperemesis gravidarum). Hyponatremia in a patient with a molar pregnancy warrants evaluation for SIADH.",
"affiliations": "University of Kansas, School of Medicine, Kansas City, KS 66160, USA.;University of Kansas, Department of Obstetrics and Gynecology, Kansas City, KS 66160, USA.;University of Kansas, Department of Obstetrics and Gynecology, Kansas City, KS 66160, USA.",
"authors": "Mickelsen|Riley|R|https://orcid.org/0000-0002-5918-3580;French|Valerie|V|https://orcid.org/0000-0003-2380-7520;Amaya|Stephanie|S|https://orcid.org/0000-0003-1588-7209",
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"doi": "10.1210/jendso/bvab129",
"fulltext": "\n==== Front\nJ Endocr Soc\nJ Endocr Soc\njes\nJournal of the Endocrine Society\n2472-1972\nOxford University Press US\n\n34458655\n10.1210/jendso/bvab129\nbvab129\nCase Reports\nAcademicSubjects/MED00250\nHydatidiform Mole With Coexisting Fetus and Syndrome of Inappropriate Antidiuretic Hormone Secretion: A Case Report\nhttps://orcid.org/0000-0002-5918-3580\nMickelsen Riley 1rmickelsen@kumc.edu\n\nhttps://orcid.org/0000-0003-2380-7520\nFrench Valerie 2\nhttps://orcid.org/0000-0003-1588-7209\nAmaya Stephanie 2\n1 University of Kansas, School of Medicine, Kansas City, KS 66160, USA\n2 University of Kansas, Department of Obstetrics and Gynecology, Kansas City, KS 66160, USA\nCorrespondence: Riley Mickelsen, University of Kansas Medical Center, Department of Obstetrics and Gynecology, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. Email: rmickelsen@kumc.edu.\n01 10 2021\n25 7 2021\n25 7 2021\n5 10 bvab12906 4 2021\n21 7 2021\n26 8 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.\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-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nContext\n\nMolar pregnancies have been associated with hyperthyroidism and hypertensive disorders. Coexisting molar and fetal pregnancies, which are very rare, have an even higher risk of complications.\n\nCase Description\n\nWe describe a case of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with a molar pregnancy. A 36-year-old patient at 13 weeks gestation with a coexisting molar pregnancy presented with headache, nausea, and vomiting. She was found to have hypertension, hyperthyroidism, and hyponatremia. The hyponatremia was further assessed with an isotonic saline challenge which resulted in a diagnosis of SIADH. The patient underwent dilation and curettage and her hyponatremia resolved. She later developed gestational trophoblastic neoplasia.\n\nConclusions\n\nA molar pregnancy can present with unusual associated conditions, such as SIADH. Hyponatremia in a patient with molar pregnancy may be mistakenly attributed to other side effects of trophoblastic tissue (hyperthyroidism, pre-eclampsia, or hyperemesis gravidarum). Hyponatremia in a patient with a molar pregnancy warrants evaluation for SIADH.\n\nmole\npregnancy\nSIADH\nhyponatremia\n==== Body\npmcComplete hydatidiform mole with a coexisting fetus (CHMCF) is extremely rare, with an estimated incidence rate of 1 in 22 000 to 100 000 gestations and only 244 cases reported in the literature over the past 40 years [1]. CHMCF pregnancies have a higher risk of complications compared with normal twin pregnancies and single molar pregnancies. The most commonly reported complications include pre-eclampsia, intrauterine fetal demise, and preterm delivery. The incidence of maternal complications in 1 study was 81%, with hyperthyroidism reported in 23% and pre-eclampsia in 14% of cases [1]. Hyponatremia or syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with CHMCF pregnancies has not been reported. CHMCF pregnancies are often terminated due to these increased risks, with live births occurring in 37% to 50% of reported cases [1, 2]. Cases associated with more favorable outcomes are those with lower human chorionic gonadotropin (hCG) and the absence of pregnancy-induced hypertension, hyperthyroidism, or hyperemesis gravidarum, which are likely related to less molar growth [2].\n\nWe report our experience with the management of a molar pregnancy with coexisting single living uterine pregnancy and associated complications, including SIADH. The patient provided written informed consent for publication of this report and accompanying images.\n\nCase\n\nA 36-year-old woman, gravida 2 para 0, presented to the emergency department complaining of 6 weeks of headache, nausea, and vomiting, with acute worsening of the headache 1 day before presentation. The patient was 13 weeks pregnant by intrauterine insemination, and her obstetrician recently referred her for a high-risk consultation for coexisting molar pregnancy and expanding bilateral ovarian cysts seen on ultrasound. Her past medical history included an ectopic pregnancy managed with methotrexate 8 months prior, polycystic ovarian syndrome, gastroesophageal reflux disease, hypertriglyceridemia, and morbid obesity (body mass index of 40 kg/m2). Transabdominal ultrasound confirmed the diagnosis of a molar pregnancy in the upper uterine segment and single living pregnancy measuring 13 weeks 0 days gestational age in the lower uterine segment, seen in Fig. 1. Additionally, her ovaries were enlarged with multiple theca-lutein cysts.\n\nFigure 1. An ultrasound image demonstrating heterogenous appearance of the uterine endometrium within the mid and upper uterine segments. Numerous internal cystic spaces are seen.\n\nFurther evaluation revealed: (1) severe range hypertension (blood pressures 147-178/88-106 mmHg); (2) hyperthyroidism (free thyroxine 3.3 ng/dL, thyrotropin < 0.01 mcU/mL); and (3) hyponatremia (sodium 127 mmol/L). She received 1 dose of hydralazine 10 mg intravenously, followed by daily nifedipine XL 60 mg for her hypertension. Her hyperthyroidism was treated with daily methimazole 10 mg. Her thyroid ultrasound revealed a multinodular goiter, all sub-centimeter except for 1 larger nodule in the right mid-thyroid lobe.\n\nHypotonic, hyponatremia was noted on the patient’s labs on admission with a serum osmolality of 261 mOsm/kg and sodium level of 127 mmol/L. Clinically, the patient was euvolemic without lower extremity edema. Her urine output was normal at 828 mL over 24 hours. Urine osmolality was elevated at 394 mOsm/kg on the second day of admission. Isovolemic hypotonic hyponatremia was noted with an elevated urine osmolality and no signs of hypothyroidism or glucocorticoid deficiency. In conjunction with the finding of hyperthyroidism and hypertension, her clinicians suspected SIADH. Typically in SIADH, urine sodium is > 30 mmol/L, whereas this patient’s urine sodium level was < 10 mmol/L [3]. This level of urine sodium is more commonly seen in hyponatremia due to low effective arterial blood volume such as heart failure, dehydration, and third spacing. The labs relevant to the hyponatremia workup are listed in Table 1.\n\nTable 1. Serum and urine laboratory values relevant to hyponatremia during the patient’s admission\n\nLab\tDay 1\tDay 2\tDay 3\tDay 4\tDay 5 surgery date\tDay 6\tDay 7\tDay 8\t\nSerum Na (mmol/L)\t127\t128\t126\t123\t124\t127\t136\t136\t\n\t\t128\t126\t\t122\t133\t132\t\t\n\t\t\t\t\t125\t137\t136\t\t\n\t\t\t\t\t125\t132\t\t\t\nSerum osmolality (mOsmol/kg)\t261\t264\t263\t257\t256\t262\t280\t280\t\n\t\t265\t\t\t253\t275\t272\t\t\n\t\t\t\t\t259\t282\t281\t\t\n\t\t\t\t\t261\t273\t\t\t\n\t\t\t\t\t259\t\t\t\t\nUrine Na (mmol/L)\t\t<10\t11\t12\t18\t\t\t\t\nUrine osmolality (mOsm/kg)\t\t394\t370\t332\t331\t\t\t\t\nBlood pressure\nrange\t(143-162) /(79-101)\t(139-143)/(82-86)\t(150-155)/(85-95)\t(136-154)/(79/86)\t(136-168)/(84-92)\t(144-159)/85-92)\t(144-151)/ (84/92)\t(135-144)/(79-82)\t\nMedications\tNifedipine 60 mg XL, Hydralazine 10 mg IV\tNifidipine 60 mg XL\tNifidipine 60 mg XL\tNifidipine 60 mg XL Atenolol 25 mg\tLisinopril 10 mg Nifidipine 90 mg XL\tLisinopril 10 mg Nifidipine 90 mg XL\tLisinopril 10 mg Nifidipine 0 mg XL\tLisinopril 10 mg Nifidipine 90 mg XL\t\n\nThe etiology of the hyponatremia remained unclear on the third day of admission and the patient did not have other symptoms to point to a cause of low effective arterial blood volume. Therefore, the patient underwent an isotonic saline challenge to help differentiate between hypovolemic and euvolemic hyponatremia. This was performed by checking a basic metabolic profile and urine sodium, creatinine, and osmolality before and after 1 L of isotonic saline. In hypovolemic hyponatremia, a rise in serum sodium is expected. In SIADH, isotonic saline may worsen hyponatremia [3]. The patient’s lab values changed as follows: serum sodium decreased from 126 to 123 mmol/L, urine sodium rose from 11 to 12 mmol/L, urine creatinine decreased from 114 to 110 mg/dL, and urine osmolality decreased from 370 to 332 mOsm/kg. Because her low serum sodium decreased further and urine osmolality rose with isotonic saline, the patient was diagnosed with SIADH.\n\nThe patient received counseling about these findings and complications associated with molar pregnancies. An induced abortion was recommended to prevent maternal morbidity and mortality. Dilation and suction curettage of the pregnancy was planned. The patient received 100 mcg buccal misoprostol the morning of the procedure. Preoperatively, the patient was hypertensive and tachycardic. She received atenolol due to concerns for thyrotoxicosis. The patient’s preoperative hemoglobin had decreased to 7.6 g/dL from 9.9 g/dL on admission. The patient underwent dilation and suction curettage and was given 1 unit packed red blood cells intraoperatively. Total blood loss was 1 L. Pathology reported the products of conception with a complete hydatidiform mole.\n\nThe patient was admitted to the medical intensive care unit postoperatively to monitor her hyponatremia. She was transferred to a medical-surgical floor 2 days later. Her hemoglobin further decreased to 6.7 g/dL 2 days after surgery, so she received 1 L blood transfusion. The patient’s hyponatremia was treated with free water restriction. She did not appear volume overloaded on exam. Her serum sodium reached a nadir of 122 mmol/L on the day of the procedure. Postoperatively, her sodium levels trended upwards and remained stable in the 132-137 mmol/L range until discharge.\n\nThe patient remained hypertensive so lisinopril 10 mg was added to the nifedipine 90 mg XL. She was discharged on both medications until a blood pressure check appointment 1 week later. Her total T3 remained elevated at 218 ng/dL postoperatively. Per endocrinology’s recommendations, the patient remained on methimazole 10 mg daily until her hCG dropped below 100 000 U/L, and atenolol 10 mg daily to keep her heart rate within normal limits. She was discharged on postoperative day 3.\n\nWhen the patient initially presented to the emergency department, her hCG was 1 927 240 U/L. The first and second week following the dilation and curettage, the hCG trended downward to a nadir of 39 908 U/L. Three weeks postoperatively, her hCG increased to 54 930 U/L, prompting a referral to gynecologic oncology. At this time, transvaginal ultrasound showed 5 cm thickening of the endometrium and she was diagnosed with Stage 1, World Health Organization score 4 invasive molar pregnancy. She was treated with 6 cycles of dactinomycin. Her hCG level plateaued around 5000 U/L and her therapy transitioned to EMA-CO chemotherapy. She completed 6 cycles of EMA-CO chemotherapy and her hCG levels have since remained at 1 U/L. Her hCG is being checked monthly at the time of writing this case report. The patient’s serum sodium levels have remained within normal limits in the several months since the dilation and suction curettage.\n\nDiscussion\n\nWe present a rare case of hyponatremia with a molar pregnancy. We found no reported cases of SIADH in association with molar pregnancy with a literature search using PubMed, Embase, and Web of Science in July 2020 using the search terms hydatidiform mole, SIADH, hyponatremia.\n\nPregnancy normally results in a mild decrease in serum osmolality by 10 mOsm/kg and serum sodium by 5 mEq/L [4]. This patient, however, presented with a serum osmolality 19 mOsm/kg below normal range and serum sodium 10 mEq/L below the normal limit. One explanation for this finding could be extreme hypertension causing renal secretion of antidiuretic hormone (ADH). Hypertension and constricted renal afferent vessels may cause the juxtaglomerular cells in the kidney to sense a decrease in blood volume and renal perfusion. In response, prorenin is secreted and the renin-angiotensin-aldosterone system is activated. Angiotensin II stimulates the release of ADH from the posterior pituitary. ADH, in turn, acts on the collecting duct of the kidney to increase water reabsorption, which can result in hyponatremia via a dilutional effect [5].\n\nHydatidiform moles are associated with hormonal imbalances, including hyperthyroidism, caused by the high levels of hCG which has the same alpha subunit as thyrotropin (thyroid stimulating hormone, TSH). There has been a case report of trophoblastic tissue producing leptin, disrupting caloric homeostasis [6]. Therefore, it is also reasonable that a molar pregnancy could also alter sodium and water homeostasis via increasing ADH levels.\n\nSerum hCG is also known to reduce the osmotic threshold for ADH release. In a study by Davison et al, participants given different doses of intramuscular hCG had proportional decreases in osmotic thresholds for release of ADH. This study also presented a molar pregnancy case in which the thresholds for ADH secretion remained decreased until 6 weeks post-evacuation of the mole, which was the same time hCG levels diminished [7]. An extremely elevated hCG due to a molar pregnancy, as seen in the presented case, could have also resulted in a decreased osmotic threshold leading to inappropriate ADH secretion.\n\nWhile mild hyponatremia is often asymptomatic, moderate to severe hyponatremia can present with cognitive side effects including confusion, vomiting, seizures, and impaired consciousness [8]. Treating hyponatremia that has been present for 2 or more days has risks, as cells have adapted to their new environment. Raising serum sodium too quickly can result in osmotic demyelination syndrome resulting in neurologic symptoms including coma, locked-in syndrome, and quadriparesis. For this reason, it is recommended that serum sodium is only increased 8-10 mmol/L per day [3]. First-line treatment for chronic hyponatremia is fluid restriction of less than 1 L per day. Fluid restriction is effective in 59% of patients with SIADH, with decreased response seen in patients with urine sodium > 130 mmol/L and urine osmolality > 500 mOsm/kg [9].\n\nThere have been case reports of hypovolemia and SIADH in the setting of pre-eclampsia, with the average gestational age at presentation of 33 weeks [10]. Hyponatremia in association with pre-eclampsia has been reported to be associated with a greater risk of obstetric complications including eclampsia, placenta abruption, preterm delivery, and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), although these associations have not been reproduced in all studies [10]. It has been postulated that SIADH in these instances is due to both hypovolemia and placental secretion of ADH [11]. There has also been a case report of a patient with polycystic ovarian syndrome undergoing ovulation induction who developed hyponatremia and was found to have acute intermittent porphyria. This case is similar to our patient’s history, although our patient was several weeks remote from ovulation induction [12].\n\nThis case illustrates SIADH as a possible side effect of molar or CHMCF pregnancies. The SIADH improved after the removal of the molar tissue and fluid restriction. Because patients often have severe symptoms from other side effects of the trophoblastic tissue (hyperthyroidism, pre-eclampsia, or hyperemesis gravidarum), hyponatremia may be mistakenly attributed to other symptoms rather than evaluated for SIADH.\n\nAcknowledgments\n\nFinancial Support: None.\n\nAbbreviations\n\nADH antidiuretic hormone\n\nCHMCF complete hydatidiform mole with a coexisting fetus\n\nhCG human chorionic gonadotropin\n\nSIADH syndrome of inappropriate antidiuretic hormone secretion\n\nAdditional Information\n\nDisclosures: The authors have nothing to disclose.\n\nData Availability\n\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n1. Zilberman SharonN, MaymonR, MelcerY, JauniauxE. Obstetric outcomes of twin pregnancies presenting with a complete hydatidiform mole and coexistent normal fetus: a systematic review and meta-analysis. BJOG. 2020;127 (12 ):1450-1457.32339446\n2. SuksaiM, SuwanrathC, Kor-AnantakulO, et al. Complete hydatidiform mole with co-existing fetus: predictors of live birth. Eur J Obstet Gynecol Reprod Biol. 2017;212 :1-8.28301807\n3. HoornEJ, ZietseR. Diagnosis and treatment of hyponatremia: compilation of the guidelines. J Am Soc Nephrol. 2017;28 (5 ):1340-1349.28174217\n4. PazhayattilGS, RastegarA, BrewsterUC. Approach to the diagnosis and treatment of hyponatremia in pregnancy. Am J Kidney Dis. 2015;65 (4 ):623-627.25542410\n5. CuzzoB, PadalaSA, LappinSL. Vasopressin (Antidiuretic Hormone, ADH), in StatPearls. Treasure Island (FL): StatPearls Publishing LLC.; 2020.\n6. SagawaN, MoriT, MasuzakiH, OgawaY, NakaoK. Leptin production by hydatidiform mole. Lancet. 1997;350 (9090 ):1518-1519.\n7. DavisonJM, ShiellsEA, PhilipsPR, LindheimerMD. Serial evaluation of vasopressin release and thirst in human pregnancy. Role of human chorionic gonadotrophin in the osmoregulatory changes of gestation. J Clin Invest. 1988;81 (3 ):798-806.3343339\n8. HenryDA. In the clinic: hyponatremia. Ann Intern Med. 2015;163 (3 ):ITC1-IT19.\n9. WinzelerB, LengsfeldS, NigroN, et al. Predictors of nonresponse to fluid restriction in hyponatraemia due to the syndrome of inappropriate antidiuresis. J Intern Med. 2016;280 (6 ):609-617.27481546\n10. PowelJE, RosenthalE, RomanA, ChasenST, BerghellaV. Preeclampsia and low sodium (PALS): a case and systematic review. Eur J Obstet Gynecol Reprod Biol. 2020;249 :14-20.32344245\n11. HinksonL, ArmbrustR, MöllerA, HenrichW. Case report of severe maternal hyponatremia complicating preeclampsia. J Matern Fetal Neonatal Med. 2018;31 (14 ):1948-1949.28514932\n12. WangJG, GuarnacciaM, WeissSF, SauerMV, ChoiJM. Initial presentation of undiagnosed acute intermittent porphyria as a rare complication of ovulation induction. Fertil Steril. 2006;86 (2 ):462.e1-462.e3.\n\n",
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"issn_linking": "2472-1972",
"issue": "5(10)",
"journal": "Journal of the Endocrine Society",
"keywords": "SIADH; hyponatremia; mole; pregnancy",
"medline_ta": "J Endocr Soc",
"mesh_terms": null,
"nlm_unique_id": "101697997",
"other_id": null,
"pages": "bvab129",
"pmc": null,
"pmid": "34458655",
"pubdate": "2021-10-01",
"publication_types": "D002363:Case Reports",
"references": "32339446;25542410;3343339;9388403;28174217;26237763;28514932;32344245;28301807;27481546;16769059",
"title": "Hydatidiform Mole with Coexisting Fetus and Syndrome of Inappropriate Antidiuretic Hormone Secretion: A Case Report.",
"title_normalized": "hydatidiform mole with coexisting fetus and syndrome of inappropriate antidiuretic hormone secretion a case report"
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"abstract": "Quality of life (QOL) and patient-reported outcomes (PROs) assessments in immunodeficiency patients, including those with chronic severe neutropenia conditions, are imperative to determining modifiable health-related features to optimize care. We present the largest study to date of QOL in those with chronic severe neutropenia conditions with further evaluation of patient provider satisfaction and patient-reported outcome measures. Subjects completed electronic surveys assessing QOL, PROs, and patient provider satisfaction. There is a significantly negative impact of a chronic severe neutropenia disorder on QOL, fatigue, physical function, cognitive function and pain in adult patients when compared to controls. Children with a chronic neutropenia condition had comparable QOL to controls, but reported fewer depressive symptoms, improved mobility, and stronger self-reported peer relationships. Adults had worse scores for QOL, depression and fatigue when compared to children. Adult and pediatric chronic severe neutropenia patients or their caregivers felt that their medical provider was compassionate, trustworthy, and accessible. However, less than 50% of adult patients agreed their clinician had excellent expertise in white blood cell disorders. Chronic neutropenia complexly affect QOL and PROs. An analysis of these parameters allows for targeted interventions to improve patient psychosocial, physical and neurocognitive health.",
"affiliations": "Department of Pediatrics, University of Michigan, 1500 E. Medical Center Drive, D4202 Medical Professional Building, Ann Arbor, MI, 48109-5718, USA. tmich@med.umich.edu.;Department of Internal Medicine, Brigham and Women's Hospital, Boston, MA, USA.;Center for Human Growth and Development, University of Michigan, Ann Arbor, MI, USA.;Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Pediatrics, University of Michigan, 1500 E. Medical Center Drive, D4202 Medical Professional Building, Ann Arbor, MI, 48109-5718, USA.",
"authors": "Michniacki|Thomas F|TF|http://orcid.org/0000-0001-8919-5243;Merz|Lauren E|LE|;McCaffery|Harlan|H|;Connelly|James A|JA|;Walkovich|Kelly|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-021-03089-8",
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"issn_linking": "0925-5710",
"issue": "113(5)",
"journal": "International journal of hematology",
"keywords": "Granulocyte colony-stimulating factor; Medical provider satisfaction; Neutropenia; Patient reported outcomes; Quality of life",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D002648:Child; D003863:Depression; D005221:Fatigue; D005260:Female; D006801:Humans; D008297:Male; D009503:Neutropenia; D000071066:Patient Reported Outcome Measures; D011788:Quality of Life",
"nlm_unique_id": "9111627",
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"pages": "735-743",
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"references": "1722310",
"title": "Quality of life and patient-reported outcomes in chronic severe neutropenia conditions.",
"title_normalized": "quality of life and patient reported outcomes in chronic severe neutropenia conditions"
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"abstract": "The greater understanding of pathophysiology and behavior of systemic vasculitis, together with the development of therapeutic regimens with increasingly better safety and efficacy profiles, dramatically changed the prognosis of patients diagnosed with these clinical entities. Recently, the use of rituximab in the treatment of patients with ANCA-associated vasculitis in randomized clinical trials showed an important alternative in selected cases, especially patients refractory or intolerant to standard therapy with cyclophosphamide and corticosteroids. This article presents the report of seven cases of systemic vasculitis successfully treated with rituximab.",
"affiliations": "Faculdade de Medicina, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil.;Serviço de Reumatologia, Hospital Universitário Lauro Wanderley, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil.;Serviço de Reumatologia, Hospital Universitário Lauro Wanderley, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil.;Serviço de Reumatologia, Hospital Universitário Lauro Wanderley, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil; Curso de Medicina, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil; Departamento de Medicina Interna, Centro de Ciências Médicas, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil.;Serviço de Reumatologia, Hospital Universitário Lauro Wanderley, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil; Curso de Medicina, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil; Departamento de Medicina Interna, Centro de Ciências Médicas, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil.;Serviço de Reumatologia, Hospital Universitário Lauro Wanderley, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil; Curso de Medicina, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil; Departamento de Medicina Interna, Centro de Ciências Médicas, Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brasil. Electronic address: eutiliafreire@hotmail.com.",
"authors": "da Silva|Leonardo Sales|LS|;de Campos|Karla Valéria Miranda|KV|;de Melo|Ana Karla Guedes|AK|;de Brito|Danielle Christinne Soares Egypto|DC|;Braz|Alessandra Sousa|AS|;Freire|Eutilia Andrade Medeiros|EA|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D000069283:Rituximab; D003520:Cyclophosphamide",
"country": "Brazil",
"delete": false,
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"fulltext": null,
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"issn_linking": "0482-5004",
"issue": "55(6)",
"journal": "Revista brasileira de reumatologia",
"keywords": "Granulomatose com poliangeíte; Granulomatosis with polyangiitis; Microscopic polyangiitis; Poliangeíte microscópica; Poliarterite nodosa; Polyarteritis nodosa; Rituximab; Rituximabe; Systemic vasculitides; Vasculites sistêmicas",
"medline_ta": "Rev Bras Reumatol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D000069283:Rituximab; D014657:Vasculitis; D055815:Young Adult",
"nlm_unique_id": "0404256",
"other_id": null,
"pages": "531-5",
"pmc": null,
"pmid": "26318692",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rituximab as an alternative for patients with severe systemic vasculitis refractory to conventional therapy: report of seven cases and literature review.",
"title_normalized": "rituximab as an alternative for patients with severe systemic vasculitis refractory to conventional therapy report of seven cases and literature review"
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"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-113201",
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"activesubstancename": "CYCLOPHOSPHAMIDE"
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"abstract": "Brain tumors are the most common solid tumor in childhood, and astrocytomas account for the largest proportion of these tumors. Increasing sophistication in genetic testing has allowed for the detection of specific mutations within tumor subtypes that may represent targets for individualized tumor treatment. The mitogen-activating protein kinase (MAPK) pathway and, more specifically, BRAF mutations have been shown to be prevalent in pediatric pilocytic astrocytomas and may represent one such area to target. Herein, the authors describe 2 cases of inoperable, chemotherapy-resistant pediatric pilocytic astrocytomas with a documented response to trametinib, an MAPK pathway inhibitor. While these cases were not treated in the setting of a clinical trial, their data support further ongoing clinical trial investigation to evaluate the safety and efficacy of this agent in pediatric low-grade gliomas.",
"affiliations": "Departments of 1 Neurosurgery.;Departments of 1 Neurosurgery.;Radiation Oncology.;Pathology, and.;Pediatric Hematology/Oncology, University of Minnesota, Minneapolis, Minnesota.",
"authors": "Miller|Catherine|C|;Guillaume|Daniel|D|;Dusenbery|Kathryn|K|;Clark|H Brent|HB|;Moertel|Christopher|C|",
"chemical_list": "D000970:Antineoplastic Agents; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib",
"country": "United States",
"delete": false,
"doi": "10.3171/2016.9.PEDS16328",
"fulltext": null,
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"issn_linking": "1933-0707",
"issue": "19(3)",
"journal": "Journal of neurosurgery. Pediatrics",
"keywords": "BRAF mutation; CNS = central nervous system; MAPK = mitogen-activating protein kinase; MAPK pathway; astrocytoma; oncology; pediatric; trametinib",
"medline_ta": "J Neurosurg Pediatr",
"mesh_terms": "D000970:Antineoplastic Agents; D001254:Astrocytoma; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006801:Humans; D007029:Hypothalamic Neoplasms; D007223:Infant; D019574:Optic Nerve Neoplasms; D009929:Organ Size; D011728:Pyridones; D011744:Pyrimidinones; D016896:Treatment Outcome",
"nlm_unique_id": "101463759",
"other_id": null,
"pages": "319-324",
"pmc": null,
"pmid": "28009226",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Report of effective trametinib therapy in 2 children with progressive hypothalamic optic pathway pilocytic astrocytoma: documentation of volumetric response.",
"title_normalized": "report of effective trametinib therapy in 2 children with progressive hypothalamic optic pathway pilocytic astrocytoma documentation of volumetric response"
} | [
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"companynumb": "US-ASPEN PHARMA TRADING LIMITED US-AG-2017-004402",
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"activesubstance": {
"activesubstancename": "THIOGUANINE ANHYDROUS"
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... |
{
"abstract": "To assess sperm production and aneuploidy in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) before and after treatments.\n\n\n\nMulticenter, prospective, longitudinal study of lymphoma patients analyzed before treatment and after 3, 6, 12, and 24 months.\n\n\n\nUniversity hospitals.\n\n\n\nForty-five HL and 13 NHL patients were investigated before and after treatment. Treatment regimens were classified in two groups: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without (±) radiotherapy, and CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)/MOPP-ABV (mechlorethamine, oncovin, procarbazine, prednisone-doxorubicin, bleomycin, vinblastine). A control group of 29 healthy men was also studied.\n\n\n\nSemen analyses and aneuploidy study by FISH were performed at each time point.\n\n\n\nComparison of mean sperm characteristics and percentage of sperm aneuploidy rates before and after treatment.\n\n\n\nBefore treatment, HL and NHL men had altered semen characteristics and higher sperm aneuploidy rates (median 0.76 [interquartile range 0.56-0.64]) than the control group (0.54 [0.46-0.74]). After treatment, sperm production was significantly lowered 3 and 6 months after ABVD ± radiotherapy or CHOP/MOPP-ABV. After ABVD ± radiotherapy, the aneuploidy rate increased significantly only at 3 months, and values obtained 1 or 2 years later were lower than pretreatment values. In contrast, in the CHOP/MOPP-ABV treatment group, semen characteristics and aneuploidy rate did not return to normal levels until 2 years after treatment.\n\n\n\nLymphoma itself has consequences on sperm aneuploidy frequency before treatment. Moreover, lymphoma treatments have deleterious effects on sperm chromosomes related to treatment type and time since treatment. Patient counseling is essential concerning the transient but significant sperm aneuploidy induced by lymphoma and its treatments.",
"affiliations": "Université Grenoble-Alpes, Institut National de la Santé et de la recherche Médicale (INSERM) U-1029, Grenoble, France; Laboratoire d'Aide à la Procréation-CECOS, Centre Hospitalier Universitaire (CHU) de Grenoble, Grenoble, France.;Université de Toulouse III; Groupe de Recherche en Fertilité Humaine (EA 3694, Human Fertility Research Group), Toulouse, France.;Université Grenoble-Alpes, Institut National de la Santé et de la recherche Médicale (INSERM) U-1029, Grenoble, France; Laboratoire d'Aide à la Procréation-CECOS, Centre Hospitalier Universitaire (CHU) de Grenoble, Grenoble, France.;Université Grenoble-Alpes, Institut National de la Santé et de la recherche Médicale (INSERM) U-1029, Grenoble, France; Laboratoire d'Aide à la Procréation-CECOS, Centre Hospitalier Universitaire (CHU) de Grenoble, Grenoble, France.;Université Grenoble-Alpes, Institut National de la Santé et de la recherche Médicale (INSERM) U-1029, Grenoble, France; Laboratoire d'Aide à la Procréation-CECOS, Centre Hospitalier Universitaire (CHU) de Grenoble, Grenoble, France.;Département d'Histologie-Embryologie, Biologie de la Reproduction/CECOS, Site Port-Royal, Paris Centre University Hospitals, Paris, France; Federation Française des CECOS, Paris, France.;Federation Française des CECOS, Paris, France; Service d'Histologie, Biologie de la Reproduction-CECOS, Hôpital Tenon, Paris, France.;Federation Française des CECOS, Paris, France; Assistance Médicale à la Procréation, CECOS, CHU Estaing, Clermont-Ferrand, France; Laboratoire Génétique Reproduction et Développement, GReD, UMR CNRS 6293, INSERM U1103, Université d'Auvergne, Faculté de Médecine, Clermont-Ferrand, France.;Université de Toulouse III; Groupe de Recherche en Fertilité Humaine (EA 3694, Human Fertility Research Group), Toulouse, France; Federation Française des CECOS, Paris, France; CECOS, Groupe d'activité de médecine de la reproduction, CHU Toulouse, Toulouse, France.;Université de Toulouse III; Groupe de Recherche en Fertilité Humaine (EA 3694, Human Fertility Research Group), Toulouse, France; Federation Française des CECOS, Paris, France; CECOS, Groupe d'activité de médecine de la reproduction, CHU Toulouse, Toulouse, France.;Federation Française des CECOS, Paris, France; Service de Biologie de la Reproduction-CECOS CHU de Rennes, Rennes, France; INSERM U-1085- Institut Recherche Santé Environnement Travail (IRSET), Université de Rennes, Rennes, France.;Federation Française des CECOS, Paris, France; Laboratoire de Biologie de la Reproduction-CECOS, Hôpital La Conception, Marseille, France.;Federation Française des CECOS, Paris, France; Unité de BDR - CECOS, Pole de Biologie, CHU Côte de Nacre, Caen, France.;Federation Française des CECOS, Paris, France; CECOS Biologie de la Reproduction, CHU Rouen, and EA 4308 Gamétogenèse et Qualité du Gamète, Université de Rouen, Rouen, France.;Université Grenoble-Alpes, Institut National de la Santé et de la recherche Médicale (INSERM) U-1029, Grenoble, France; Laboratoire d'Aide à la Procréation-CECOS, Centre Hospitalier Universitaire (CHU) de Grenoble, Grenoble, France; Federation Française des CECOS, Paris, France.;Université de Toulouse III; Groupe de Recherche en Fertilité Humaine (EA 3694, Human Fertility Research Group), Toulouse, France; Federation Française des CECOS, Paris, France; CECOS, Groupe d'activité de médecine de la reproduction, CHU Toulouse, Toulouse, France. Electronic address: bujan.l@chu-toulouse.fr.",
"authors": "Martinez|Guillaume|G|;Walschaerts|Marie|M|;Le Mitouard|Marine|M|;Borye|Remi|R|;Thomas|Claire|C|;Auger|Jacques|J|;Berthaut|Isabelle|I|;Brugnon|Florence|F|;Daudin|Myriam|M|;Moinard|Nathalie|N|;Ravel|Célia|C|;Saias|Jacqueline|J|;Szerman|Ethel|E|;Rives|Nathalie|N|;Hennebicq|Sylviane|S|;Bujan|Louis|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.fertnstert.2016.10.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0015-0282",
"issue": "107(2)",
"journal": "Fertility and sterility",
"keywords": "Hodgkin; non-Hodgkin lymphoma; sperm aneuploidy; sperm chromosomes; treatment side effects",
"medline_ta": "Fertil Steril",
"mesh_terms": "D000782:Aneuploidy; D000971:Antineoplastic Combined Chemotherapy Protocols; D016022:Case-Control Studies; D059248:Chemoradiotherapy; D005602:France; D006689:Hodgkin Disease; D006785:Hospitals, University; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008137:Longitudinal Studies; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D011446:Prospective Studies; D012307:Risk Factors; D055101:Semen Analysis; D013091:Spermatogenesis; D013094:Spermatozoa; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0372772",
"other_id": null,
"pages": "341-350.e5",
"pmc": null,
"pmid": "27810161",
"pubdate": "2017-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Impact of Hodgkin or non-Hodgkin lymphoma and their treatments on sperm aneuploidy: a prospective study by the French CECOS network.",
"title_normalized": "impact of hodgkin or non hodgkin lymphoma and their treatments on sperm aneuploidy a prospective study by the french cecos network"
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"abstract": "BACKGROUND\nBrain is one of the most common target organ of lung cancer metastasis, while descriptions of intraventricular carcinomatosis could hardly be found among previous cases. To date no cases from lung adenocarcinoma have been reported in the literature.\n\n\nMETHODS\nWe report here a case of multiple intraventricular metastases from lung adenocarcinoma with EGFR G719X mutation. This 64-year-old woman was referred to our hospital with complaints of dizziness and vomiting. Target therapy with afatinib was initiated and the lesions in both lung and brain achieved good partial responses.\n\n\nCONCLUSIONS\nThis case report revealed a phenomenon of rare intraventricular metastasis from lung cancer, which should be carefully distinguished from primary ventricular tumors. Compared to brain parenchyma metastasis, intraventricular lesions would cause more severe symptoms which may be rapidly progressive. Target therapy could become a potential option in such patients with non-drugresistant EGFR mutations.",
"affiliations": "Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China.;Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China.;Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China. wnrainbow@126.com.;Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China. bc7878@sohu.com.",
"authors": "Kong|Chen|C|;Zhou|Dan|D|;Wu|Ning|N|;Bai|Chong|C|",
"chemical_list": "D000970:Antineoplastic Agents; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "England",
"delete": false,
"doi": "10.1186/s12890-020-1168-0",
"fulltext": "\n==== Front\nBMC Pulm Med\nBMC Pulm Med\nBMC Pulmonary Medicine\n1471-2466 BioMed Central London \n\n1168\n10.1186/s12890-020-1168-0\nCase Report\nMultiple intraventricular metastases from lung adenocarcinoma with EGFR G719X mutation: a case report\nKong Chen Zhou Dan Wu Ning wnrainbow@126.com Bai Chong bc7878@sohu.com grid.411525.60000 0004 0369 1599Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China \n11 5 2020 \n11 5 2020 \n2020 \n20 13523 1 2020 27 4 2020 © The Author(s). 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nBrain is one of the most common target organ of lung cancer metastasis, while descriptions of intraventricular carcinomatosis could hardly be found among previous cases. To date no cases from lung adenocarcinoma have been reported in the literature.\n\nCase presentation\nWe report here a case of multiple intraventricular metastases from lung adenocarcinoma with EGFR G719X mutation. This 64-year-old woman was referred to our hospital with complaints of dizziness and vomiting. Target therapy with afatinib was initiated and the lesions in both lung and brain achieved good partial responses.\n\nConclusions\nThis case report revealed a phenomenon of rare intraventricular metastasis from lung cancer, which should be carefully distinguished from primary ventricular tumors. Compared to brain parenchyma metastasis, intraventricular lesions would cause more severe symptoms which may be rapidly progressive. Target therapy could become a potential option in such patients with non-drugresistant EGFR mutations.\n\nKeywords\nCase reportIntraventricular metastasesLung adenocarcinomaTyrosine kinase inhibitorhttp://dx.doi.org/10.13039/501100003399Science and Technology Commission of Shanghai Municipality134119a0302Bai Chong http://dx.doi.org/10.13039/501100007054Second Military Medical University2017JZ05Bai Chong issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nUp to 50% of pulmonary carcinoma patients would develop brain metastases throughout their clinical courses, and 10–25% of them have brain metastases at the time of initial diagnosis [1–3]. Adenocarcinoma is the most common subtype of lung cancer in women. Although lung cancer can theoretically disseminate to ventricles, no case of isolated intraventricular metastasis of lung adenocarcinoma has been reported in the literature. Here, we present this unique case of a Chinese woman who was confirmed as late stage lung adenocarcinoma with intraventricular metastases without parenchyma lesions and had a good response to target therapy with Epidermal Growth Factor Receptor- tyrosine kinase inhibitor (EGFR-TKI).\n\nCase presentation\nA sixty-four-year-old Chinese woman, with a ten-year history of diabetes and hypertension, presented with serious dizziness and vomiting in a month.\n\nPositron emission tomography (PET) performed in October 2017 indicated a nodular lesion in left upper lung with diffuse bilateral lung metastases (Fig. 1a) and multiple intraventricular masses. Magnetic resonance imaging (MRI) of brain showed a mass at the posterior horn of the right lateral ventricle and the IV ventricle, respectively. T1 brain MRI sequences showed isointense lesions with heterogeneous enhancement on contrast and T2 brain MRI sequences showed hyperintense masses, remarkable dilation and hydrocephalus of upper cerebral ventricle and parenchyma edema around encephalocoele. No obvious involvement of brain parenchyma was found (Fig. 2a).\nFig. 1 CT scans of chest during different period of treatment a Chest CT scan showed a 1 cm × 1 cm irregular nodule in the upper lobe of left lung, with diffuse bilateral pulmonary metastases. b Bilateral nodules evidently shrunk after treatment with afitinib for 3 months. c Lesions of lung progressed after ten months of targeted therapy\n\nFig. 2 MRI of brain during different periods of treatment a Contrast-enhanced MRI of brain showed heterogeneously enhancing lesions at the posterior horn of the right lateral ventricle and the IV ventricle, with upper ventricle hydrocephalus and edema of the surrounding parenchyma. T2FLAIR showed slightly higher signal of the masses. b Intraventricular lesions and surrounding area of edema observably shrunk with restored ventricular dilatation after 3-month treatment with afitinib. c Masses in the brain remain stable after 10-month treatment while lesions of lung progressed\n\n\n\nLung adenocarcinoma was histopathologically diagnosed by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA). Afatinib, a second generation Epidermal Growth Factor Receptor- tyrosine kinase inhibitor (EGFR-TKI) was administered at a dose of 30 mg qd due to EGFR mutation in exon 18 (G719X). The symptoms of the patient improved significantly within one month and most of the daily activities were affordable. Reevaluation after three-month treatment showed partial remission in both lung and brain lesions (Figs. 1b and 2b). Repeated computed tomography (CT) of chest after ten months’ treatment in September 2018 showed bilateral pulmonary nodules increased and enlarged, while intracerebral lesions remained stable (Figs. 1c and 2c). Severe headache and dizziness reoccurred half a month later and the symptoms aggravated rapidly afterwards. The patient eventually died with an overall survival of 12 months.\n\nDiscussion and conclusions\nIntraventricular neoplasms account for less than 1% of intracranial neoplasms [4], which were mostly described in primary central nervous system malignant tumors, such as choroid plexus papilloma, carcinoma, ependymoma, subependymoma, subependymal giant cell astrocytoma, central neurocytoma and meningioma. Metastasis shares about 2% of all intraventricular neoplasms [5]. Intraventricular metastasis from a carcinoma occurs even rare (0.9–4.6% of all brain metastases) [6]. The most common intraventricular metastases from epithelial malignancies include renal [5, 6], lung [1], colon carcinomas and melanoma.\n\nIt has been widely recognized that brain metastases frequently occur in the early course of lung cancer, especially in small cell lung cancer (SCLC) [7]. Among all the brain metastases, parenchymal metastasis is the most common way, whereas its prognosis is poor. Intraventricular metastasis from lung cancer was rarely reported. Surgical management of lateral-ventricle metastases at the University of Texas M. D. Anderson Cancer Center was reported in 2010 [4]. Among the 29 cases reported, 22 had single or multiple intraventricular lesions without synchronous intraparenchymal metastases and only 2 of them were diagnosed as lung cancer. Esther Una [8] reported the first case of intraventricular metastasis developed from a man with SCLC in 2012. Another case of intraventricular metastases from SCLC presented with irregular thickening around edges of lateral ventricles and fourth ventricle in MRI images was reported by Hao Chen [9]. Saraj K. Singh [10] introduced a case of pulmonary squamous cell carcinoma with intraventricular metastases which had been misdiagnosed as meningioma before surgery. In our case, unique metastatic form of bulky masses in ventricles without involvement of brain parenchyma was shown in a patient with lung adenocarcinoma.\n\nThe lateral ventricles are the most common sites of intraventricular metastases due to the abundant vascular supply of choroid plexus [11]. It is difficult to distinguish intraventricular metastases from primary central nervous system tumors, especially choroid plexus papilloma and meningioma, given the brain MRI screenings merely. Choroid plexus papilloma is a slow-growing benign tumor originated from choroid plexus epithelial cells in ventricles, which is more common in children under 10 years old. It predominantly locates in the lateral ventricles and the fourth ventricle, 50 and 40% respectively, with potential of malignant transformation into choroid plexus carcinoma. Typical imaging findings consist of clear boundary of mass with equal or low T1WI, equal or slightly higher T2WI. Choroid plexus tumors are able to secrete plenty of cerebrospinal fluid, which cause obstructive or communicating hydrocephalus, resulting in the symptoms of intracranial hypertension such as dizziness and vomiting. Surgical resection is the only proven treatment. In respect to meningioma, the peak age range of it is 30–60 years [11]. Most meningiomas are found in the atria of the lateral ventricles and less commonly in the third and fourth ventricles [12]. On MRI, lesions are usually well-defined, iso- to hypointense on T1WI, and iso- to hyperintense on T2WI. In this case, the elder female patient does not belong to the high incidence group of these primary central nervous system diseases. Despite the overlap of imaging findings with these diseases, metastasis is the first diagnosis to be considered due to the underlying pulmonary malignancy.\n\nAfatinib, a second generation EGFR-TKI, was approved by the U.S. FDA for metastatic NSCLC with uncommon non-drugresistant EGFR mutations, such as L861Q, G719X, and S768I. Afatinib can achieve half maximal inhibitory concentration (IC50) against EGFR mutation in the cerebrospinal fluid [13] so that theoretically it can create an inhibitory effect on intraventricular metastases from lung cancer with minimal adverse effects. Molecular analysis indicated EGFR mutation (G719X) in this patient and both lesions in bilateral lungs and brain showed significant improvement after treatment with afatinib, which supported that the intraventricular lesions were metastatic disseminations of lung adenocarcinoma. However, it is a pity that on account of the severe dizziness and vomiting, the patient refused to accept lumbar puncture or surgery for intracranial histological tests.\n\nThe described case adds pulmonary adenocarcinoma to the possible origin of an intraventricular cerebral metastasis. Furthermore, whether the patient has brain metastases or not, afatinib may be a potential option for patient with uncommon mutations of EGFR.\n\nAbbreviations\nMRIMagnetic Resonance Imaging\n\nEBUS-TBNAEndobronchial Ultrasound Transbronchial Needle Aspiration\n\nTKITyrosine Kinase Inhibitor\n\nEGFRGrowth Factor Receptor\n\nPETPositron Emission Tomography\n\nCTComputed Tomography\n\nSCLCSmall Cell Lung Cancer\n\nIC50Half Maximal Inhibitory Concentration\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNing Wu and Chong Bai contributed equally to this work.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nThe work presented here was carried out in collaboration between all authors. NW prepared all the data from the patient. CK drafted the manuscript. DZ collected all the data. CB and NW critically revised the manuscript. All authors have contributed to, seen and approved the manuscript.\n\nFunding\nThe work of figure editing and the charge of article processing was supported by Shanghai Science and Technology Commission Program (134119a0302) and the Program of Second Military Medical University (2017JZ05).\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\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 any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Ulahannan D Khalifa J Faivre-Finn C Lee SM Emerging treatment paradigms for brain metastasis in non-small-cell lung cancer: an overview of the current landscape and challenges ahead Ann Oncol 2017 28 2923 2931 10.1093/annonc/mdx481 29045549 \n2. Schouten Leo J Joost R Huveneers Hans AM Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma Cancer. 2002 94 2698 2705 10.1002/cncr.10541 12173339 \n3. Barnholtz-Sloan Jill S Sloan Andrew E Davis Faith G Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan Detroit Cancer surveillance system J Clin Oncol 2004 22 2865 2872 10.1200/JCO.2004.12.149 15254054 \n4. Hassaneen W Suki D Salaskar AL Surgical management of lateral-ventricle metastases: report of 29 cases in a single-institution experience J Neurosurg 2010 112 1046 1055 10.3171/2009.7.JNS09571 19663549 \n5. Sava I Sava A Şapte E Intraventricular metastatic clear cell renal carcinoma Romanian J Morphol Embryol 2013 54 447 450 \n6. Raila FA Bottoms WT Jr Fratkin JD Solitary choroid plexus metastasis from a renal cell carcinoma South Med J 1998 19 1159 1162 10.1097/00007611-199812000-00013 \n7. Aizer Ayal A Lee EQ Brain Metastases Neurol Clin 2018 6 557 577 10.1016/j.ncl.2018.04.010 \n8. Uña E. Intraventricular metastases from small cell carcinoma of the lung. BMJ Case Rep. 2012. 10.1136/bcr.12.2011.5440.\n9. Chen H, Raza HK, Shi HJ, et al. A rare case of small cell carcinoma of lung with intraventricular metastasis. Br J Neurosurg. 2017. 10.1080/02688697.2017.1327020.\n10. Singh SK Agarwal H Singh P Intraventricular metastasis mimicking meningioma Surg Neurol Int 2018 9 149 10.4103/sni.sni_68_18 30105143 \n11. Smith AB Smirniotopoulos JG Horkanyne-Szakaly I From the radiologic pathology archives: intraventricular neoplasms: radiologic-pathologic correlation Radiographics 2013 33 21 43 10.1148/rg.331125192 23322825 \n12. Muly S Liu S Lee R MRI of intracranial intraventricular lesions Clin Imaging 2018 52 226 239 10.1016/j.clinimag.2018.07.021 30138862 \n13. Ma CH Huang CJ Tang DJ Afatinib for advanced non-small cell lung Cancer in a case with an uncommon epidermal growth factor receptor mutation (G719A) identified in the cerebrospinal fluid Front Oncol 2019 9 628 10.3389/fonc.2019.00628 31396478\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2466",
"issue": "20(1)",
"journal": "BMC pulmonary medicine",
"keywords": "Case report; Intraventricular metastases; Lung adenocarcinoma; Tyrosine kinase inhibitor",
"medline_ta": "BMC Pulm Med",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000970:Antineoplastic Agents; D001932:Brain Neoplasms; D066246:ErbB Receptors; D005091:Exons; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009154:Mutation; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100968563",
"other_id": null,
"pages": "135",
"pmc": null,
"pmid": "32393286",
"pubdate": "2020-05-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30138862;12173339;23322825;23771097;9853731;31396478;30105143;30072071;28497995;15254054;29045549;19663549",
"title": "Multiple intraventricular metastases from lung adenocarcinoma with EGFR G719X mutation: a case report.",
"title_normalized": "multiple intraventricular metastases from lung adenocarcinoma with egfr g719x mutation a case report"
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"abstract": "Malignant peripheral nerve sheath tumor (MPNST) in the thorax is an extremely rare disease, and half of all cases of MPNST are associated with neurofibromatosis type I. Sporadic intrathoracic MPNST is difficult to diagnose and treat. Because of the rarity of intrathoracic MPNST, the optimal method of diagnosis and the efficacy of chemotherapy are unknown. Herein, we present a case of inoperable mediastinal MPNST, in which the diagnosis was immunohistochemically made by the loss of H3K27me3 expression in a transbronchial needle biopsy specimen. The patient showed a good response to doxorubicin plus ifosfamide chemotherapy. The present case highlights that MPNST should be included in the differential diagnosis of non-posterior mediastinum thoracic lesions, and that appropriate diagnosis and treatment for intrathoracic MPNST should be considered in patients with a thoracic mass.",
"affiliations": "Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Anesthesiology and Resuscitology, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan.",
"authors": "Seno|Noriko|N|;Fukushima|Toshirou|T|;Gomi|Daisuke|D|;Kobayashi|Takashi|T|;Sekiguchi|Nodoka|N|;Matsushita|Hidehiro|H|;Ozawa|Takesumi|T|;Tsukahara|Yoshiko|Y|;Mamiya|Keiko|K|;Koizumi|Tomonobu|T|0000-0002-5182-0960;Sano|Kenji|K|",
"chemical_list": "D006657:Histones; D004317:Doxorubicin; D007069:Ifosfamide",
"country": "Singapore",
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"doi": "10.1111/1759-7714.12498",
"fulltext": "\n==== Front\nThorac CancerThorac Cancer10.1111/(ISSN)1759-7714TCAThoracic Cancer1759-77061759-7714John Wiley & Sons Australia, Ltd Melbourne 10.1111/1759-7714.12498TCA12498Case ReportCase ReportsSuccessful treatment with doxorubicin and ifosfamide for mediastinal malignant peripheral nerve sheath tumor with loss of H3K27me3 expression Thoracic MPSNT response to chemotherapyN. Seno et al.Seno Noriko \n1\n\n2\nFukushima Toshirou \n1\nGomi Daisuke \n1\nKobayashi Takashi \n1\nSekiguchi Nodoka \n1\nMatsushita Hidehiro \n1\nOzawa Takesumi \n1\nTsukahara Yoshiko \n3\nMamiya Keiko \n1\nKoizumi Tomonobu http://orcid.org/0000-0002-5182-0960tomonobu@shinshu-u.ac.jp \n1\nSano Kenji \n4\n\n1 \nDepartment of Comprehensive Cancer Therapy\nShinshu University School of Medicine\nMatsumoto\nJapan\n\n2 \nDivision of Hematology, Department of Internal Medicine\nShinshu University School of Medicine\nMatsumoto\nJapan\n\n3 \nDepartment of Anesthesiology and Resuscitology\nShinshu University School of Medicine\nMatsumoto\nJapan\n\n4 \nDepartment of Laboratory Medicine\nShinshu University School of Medicine\nMatsumoto\nJapan\n* Correspondence\n\nTomonobu Koizumi, Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, 3‐1‐1 Asahi, Matsumoto, Nagano 390‐8621, Japan.\n\nTel: +81 263 37 2554\n\nFax: +81 263 37 3302\n\nEmail: tomonobu@shinshu-u.ac.jp\n06 9 2017 11 2017 8 6 10.1111/tca.2017.8.issue-6720 723 12 7 2017 01 8 2017 03 8 2017 © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Malignant peripheral nerve sheath tumor (MPNST) in the thorax is an extremely rare disease, and half of all cases of MPNST are associated with neurofibromatosis type I. Sporadic intrathoracic MPNST is difficult to diagnose and treat. Because of the rarity of intrathoracic MPNST, the optimal method of diagnosis and the efficacy of chemotherapy are unknown. Herein, we present a case of inoperable mediastinal MPNST, in which the diagnosis was immunohistochemically made by the loss of H3K27me3 expression in a transbronchial needle biopsy specimen. The patient showed a good response to doxorubicin plus ifosfamide chemotherapy. The present case highlights that MPNST should be included in the differential diagnosis of non‐posterior mediastinum thoracic lesions, and that appropriate diagnosis and treatment for intrathoracic MPNST should be considered in patients with a thoracic mass.\n\nChemotherapydoxorubicinifosfamidemediastinal tumor source-schema-version-number2.0component-idtca12498cover-dateNovember 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:03.11.2017\n==== Body\nIntroduction\nMalignant peripheral nerve sheath tumors (MPNST), also called malignant schwannomas or neurofibrosarcomas, account for approximately 5–10% of all soft tissue sarcomas, and 50% of MPNST cases are associated with neurofibromatosis type I (NF‐1).1, 2, 3 Although MPNST commonly develops in the extremities, head, and neck, intrathoracic MPNST is extremely rare.2, 3, 4, 5, 6, 7 Most benign neurogenic tumors in the thorax develop in the posterior mediastinum, but MPNST has been reported to arise in various thoracic spaces, including the non‐posterior mediastinum and chest wall, as well as the posterior mediastinum.4, 5, 6, 7, 8 Because of the rarity of intrathoracic MPNST, the optimal method of diagnosis and the efficacy of chemotherapy for advanced intrathoracic MPNST are unknown.9, 10, 11, 12\n\n\nWe encountered a case of locally advanced inoperable MPNST mainly involving the middle mediastinum. The patient was treated with doxorubicin plus ifosfamide chemotherapy, and a partial response was obtained. Herein, we describe a rare case of intrathoracic MPNST focusing on the diagnosis and chemotherapy, along with a review of the relevant literature.\n\nCase report\nA 64‐year‐old woman was referred to our hospital because of a gradually progressing cough and abnormality on chest radiography. Chest radiography (Fig 1a) and computed tomography (CT) (Fig 2a) revealed a large middle mediastinal mass measuring 100 mm on the right side, compressing the trachea. Bronchoscopic examination was performed, and histological findings by endobronchial ultrasound‐guided transbronchial needle aspiration revealed oval to spindle‐shaped cells with hyperchromatic and pleomorphic nuclei arranged in dense cellular fascicles (Fig 3). Immunohistochemical analysis showed that the tumor cells were negative for AE1/AE3, S‐100 protein, α‐smooth muscle actin, desmin, vimentin, myogenin, STAT6, p40, and TTF‐1. In addition, Ki‐67 showed 30–40% positivity and loss of H3K27me3 (rabbit monoclonal C36B11, Cell Signaling Technology, Ltd., Danvers, MA, USA) expression. These findings confirmed a diagnosis of MPNST, although S‐100 immunostaining was negative.13 Positron emission tomography with fluorodeoxyglucose‐computed tomography (FDG‐PET/CT) revealed positive accumulation of FDG in the mediastinal mass (maximum standardized uptake value 16.1), but other organs were negative. As the mediastinal tumor was considered to be locally advanced and unresectable, the patient was treated with chemotherapy containing doxorubicin and ifosfamide (AI therapy: a total of 5 mg/m2 of ifosfamide and 60 mg/m2 doxorubicin were administered intravenously on days 1–2, and 40 mg of dexamethasone on days 1–3). A partial response was achieved after four cycles of AI therapy and in total six cycles of AI therapy were performed. Chest radiograph and CT results after chemotherapy are shown in Figures 1b and 2b, respectively. The tumor size was remarkably reduced. The major adverse effect of the chemotherapy was grade 4 neutropenia. Although febrile neutropenia was observed during the first cycle of AI chemotherapy, it was well controlled by the administration of G‐CSF and antibiotics. However, the patient presented with progressive disease two months after the cessation of chemotherapy. A total of 60 Gy of thoracic radiotherapy was performed and the disease remained stable for three months after the radiotherapy.\n\nFigure 1 Chest radiography (a) before and (b) after six cycles of doxorubicin and ifosfamide chemotherapy.\n\nFigure 2 Chest computed tomography (a) before and (b) after six cycles of doxorubicin and ifosfamide chemotherapy.\n\nFigure 3 Histological findings by endobronchial ultrasound‐guided transbronchial needle aspiration revealed oval to spindle‐shaped cells with hyperchromatic and pleomorphic nuclei arranged in dense cellular fascicles (a ×40, b ×100). (c) There was a loss of H3K27me3 (rabbit monoclonal C36B11) expression.\n\nDiscussion\nWe present a case of advanced intrathoracic MPNST located in the non‐posterior mediastinum. In general, neurogenic tumors develop mainly in the posterior mediastinum.4 However, MPNST primarily located in the pulmonary parenchyma may be pleural‐based, hilar, or closely associated with large bronchovascular bundles. Thus, intrathoracic MPNST can involve various sites, including the anterior or middle mediastinum and chest wall.4, 5, 6, 7, 8 As such, intrathoracic MPNST should be included as a differential diagnosis of aggressive masses in the mediastinum, especially in a sporadic setting.\n\nSporadic intrathoracic MPNST may be quite difficult to diagnosis because of its rarity and diverse morphologic features. Loss of H3K27me3 expression is considered an important diagnostic marker for MPNST, especially in differential diagnosis with neurofibroma. Loss of H3K27me3 expression is not always a specific marker for MPNST, but is related to poorer survival in patients with MPNST.13 A combination of S‐100 and cytokeratin staining with smooth muscle antigen is also useful for differential diagnosis for MPNST.1, 2, 3, 4, 5, 6 However, examination of H3K27me3 immunohistochemistry can help with the diagnosis and prognosis of MPNST.13\n\n\nThe patient in our case was treated with AI chemotherapy and showed a partial response. Kroep et al. summarized the data of 12 pooled clinical trials of first‐line chemotherapy for soft tissue sarcoma and reported that MPNST showed similar response (21%) and progression‐free survival (17 weeks) rates to chemotherapy compared to other soft tissue sarcomas (22% and 16 weeks, respectively).9 Although not statistically significant, AI therapy tended to show the best response and progression‐free survival rates in these studies. Indeed, our patient exhibited a good response to AI therapy. Thus, AI therapy is one of the active chemotherapy regimens available to treat this disease at present.\n\nSurgery with wide margins is considered the only procedure to improve the prognosis of MPNSTs; however, previous studies have reported that intrathoracic MPNSTs are larger than when they occur at other sites, and spread with invasion or encasement into adjacent mediastinal structures.4, 5, 6, 7, 8 Thus, it is speculated that non‐surgically treated or inoperable subjects may be included among cases of intrathoracic MPNST, as in the present case.\n\nSeveral case reports have demonstrated the efficacy of neoadjuvant chemotherapy followed by surgery for advanced MPNST.10, 11, 12 However, no information is available regarding the efficacy of neoadjuvant chemotherapy for advanced intrathoracic MPNST. The resectability of the remaining tumor after chemotherapy may be an important issue in patients with locally advanced intrathoracic MPNST. Unfortunately, the residual tumor after chemotherapy in the present case remained inoperable because of the involvement of large vessels. Further clinical experience and data regarding therapeutic outcomes of intrathoracic MPNST are required.\n\nIn conclusion, we describe a case of sporadic intrathoracic MPNST mainly involving the middle mediastinum that responded to ifosfamide plus doxorubicin chemotherapy. Sporadic intrathoracic MPNSTs are extremely rare in clinical practice. MPNSTs should be considered in the differential diagnosis of a large, elongated intrathoracic mass. Clinicians should be aware of this disease entity, and the accumulation of additional therapeutic experience is necessary.\n\nDisclosure\nNo authors report any conflict of interest.\n==== Refs\nReferences\n1 \n\nDucatman \nBS \n, \nScheithauer \nBW \n, \nPiepgras \nDG \n, \nReiman \nHM \n, \nIlstrup \nDM \n. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases . Cancer \n1986 ; 57 : 2006 –21 .3082508 \n2 \n\nKing \nAA \n, \nDebaun \nMR \n, \nRiccardi \nVM \n, \nGutmann \nDH \n. Malignant peripheral nerve sheath tumors in neurofibromatosis 1 . Am J Med Genet \n2000 ; 93 : 388 –92 .10951462 \n3 \n\nZou \nC \n, \nSmith \nKD \n, \nLiu \nJ \n\net al\nClinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome . Ann Surg \n2009 ; 249 : 1014 –22 .19474676 \n4 \n\nBoland \nJM \n, \nColby \nTV \n, \nFolpe \nAL \n. Intrathoracic peripheral nerve sheath tumors‐a clinicopathological study of 75 cases . Hum Pathol \n2015 ; 46 : 419 –25 .25595633 \n5 \n\nChao \nBH \n, \nStogner‐Underwood \nKA \n, \nKiev \nJ \n, \nSmith \nTJ \n. Intrathoracic malignant peripheral nerve sheath tumor in neurofibromatosis 1 . J Clin Oncol \n2008 ; 26 : 2216 –8 .18445849 \n6 \n\nRalli \nM \n, \nSingh \nS \n, \nHasija \nS \n, \nVerma \nR \n. Intrathoracic malignant peripheral nerve sheath tumor: Histopathological and immunohistochemical features . Iran J Pathol \n2015 ; 10 : 74 –8 .26516330 \n7 \n\nKalra \nB \n, \nKingsley \nPA \n, \nBedi \nHS \n, \nKwatra \nKS \n, \nNegi \nP \n. Malignant peripheral nerve sheath tumor of the anterior mediastinum: A rare presentation . Rare Tumors \n2014 ; 6 : 5528 .25568746 \n8 \n\nKamran \nSC \n, \nShinagare \nAB \n, \nHoward \nSA \n\net al\nIntrathoracic malignant peripheral nerve sheath tumors: Imaging features and implications for management . Radiol Oncol \n2013 ; 47 : 230 –8 .24133387 \n9 \n\nKroep \nJR \n, \nOuali \nM \n, \nGelderblom \nH \n\net al\nFirst‐line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histological soft tissue sarcoma subtypes and as a prognostic factor for MPNST: An EORTC soft tissue and bone sarcoma group study . Ann Oncol \n2011 ; 22 : 207 –14 .20656792 \n10 \n\nMoretti \nVM \n, \nCrawford \nEA \n, \nStaddon \nAP \n, \nLackman \nRD \n, \nOgilvie \nCM \n. Early outcomes for malignant peripheral nerve sheath tumor treated with chemotherapy . Am J Clin Oncol \n2011 ; 34 : 417 –21 .20838322 \n11 \n\nMinagawa \nT \n, \nShioya \nR \n, \nSato \nC \n\net al\nAdvanced epithelioid malignant peripheral nerve sheath tumor showing complete response to combined surgery and chemotherapy: A case report . Case Rep Oncol Med \n2011 ; 2011 : 705345 .22606446 \n12 \n\nMasui \nF \n, \nYokoyama \nR \n, \nSoshi \nS \n, \nBeppu \nY \n, \nAsanuma \nK \n, \nFujii \nK \n. A malignant peripheral nerve‐sheath tumour responding to chemotherapy . J Bone Joint Surg Br \n2004 ; 86 : 113 –5 .14765877 \n13 \n\nCleven \nAH \n, \nSannaa \nGA \n, \nBriaire‐de Bruijn \nI \n\net al\nLoss of H3K27 tri‐methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival . Mod Pathol \n2016 ; 29 : 582 –90 .26990975\n\n",
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"issn_linking": "1759-7706",
"issue": "8(6)",
"journal": "Thoracic cancer",
"keywords": "Chemotherapy; doxorubicin; ifosfamide; mediastinal tumor",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D015536:Down-Regulation; D004317:Doxorubicin; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones; D006801:Humans; D007069:Ifosfamide; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D009442:Neurilemmoma; D016896:Treatment Outcome",
"nlm_unique_id": "101531441",
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"pubdate": "2017-11",
"publication_types": "D002363:Case Reports",
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"title": "Successful treatment with doxorubicin and ifosfamide for mediastinal malignant peripheral nerve sheath tumor with loss of H3K27me3 expression.",
"title_normalized": "successful treatment with doxorubicin and ifosfamide for mediastinal malignant peripheral nerve sheath tumor with loss of h3k27me3 expression"
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"abstract": "OBJECTIVE\nSince the outbreak of COVID-19, concerns have been raised as to whether inflammatory bowel disease (IBD) patients under biologic therapy may be more susceptible to the disease. This study aimed to determine the incidence and outcomes of COVID-19 in a large cohort of IBD patients on biologic therapy.\n\n\nMETHODS\nThis observational retrospective multicenter study collected data about COVID-19 in IBD patients on biologic therapy in Italy, between February and May 2020. The main end-points were (i) to assess both the cumulative incidence and clinical outcome of COVID-19, according to different biologic agents and (ii) to compare them with the general population and a cohort IBD patients undergoing non-biologic therapies.\n\n\nRESULTS\nAmong 1816 IBD patients, the cumulative incidence of COVID-19 was 3.9 per 1000 (7/1816) with a 57% hospitalization rate and a 29% case-fatality rate. The class of biologic agents was the only risk factor of developing COVID-19 (P = 0.01). Non-gut selective agents were associated with a lower incidence of COVID-19 cases, related symptoms, and hospitalization (P < 0.05). Compared with the general population of Lombardy, an overall lower incidence of COVID-19 was observed (3.9 vs 8.5 per 1000, P = 0.03). Compared with 565 IBD patients on non-biologic therapies, a lower rate of COVID-19 symptoms was observed in our cohort (7.5% vs 18%, P < 0.001).\n\n\nCONCLUSIONS\nCompared with the general population, IBD patients on biologic therapy are not exposed to a higher risk of COVID-19. Non-gut selective agents are associated with a lower incidence of symptomatic disease, supporting the decision of maintaining the ongoing treatment.",
"affiliations": "Gastroenterology Unit, ASST Fatebenefratelli-Sacco, L. Sacco University Hospital, Department of Biochemical and Clinical Sciences, University of Milan, Milan, Italy.;Gastroenterology Unit, ASST Fatebenefratelli-Sacco, L. Sacco University Hospital, Department of Biochemical and Clinical Sciences, University of Milan, Milan, Italy.;Gastroenterology Unit, ASST Fatebenefratelli-Sacco, L. Sacco University Hospital, Department of Biochemical and Clinical Sciences, University of Milan, Milan, Italy.;Gastroenterology Unit, ASST Fatebenefratelli-Sacco, L. Sacco University Hospital, Department of Biochemical and Clinical Sciences, University of Milan, Milan, Italy.;Gastroenterology Unit, ASST Fatebenefratelli-Sacco, L. Sacco University Hospital, Department of Biochemical and Clinical Sciences, University of Milan, Milan, Italy.;Gastroenterology Unit, ASST Rhodense, Rho Hospital, Rho, Italy.;Gastroenterology Unit, ASST Rhodense, Rho Hospital, Rho, Italy.;ASST Ovest Milanese, Legnano Hospital, Legnano, Italy.;Gastroenterology and Endoscopy Unit, IRCCS Ca' Granda Ospedale Maggiore Policlinico Foundation, Milan, Italy.;Gastroenterology and Endoscopy Unit, IRCCS Ca' Granda Ospedale Maggiore Policlinico Foundation, Milan, Italy.;UOC Gastroenterology and Digestive Endoscopy, ASST Bergamo Est, Seriate, Bergamo, Italy.;ASST Sette Laghi, Gastroenterology and Endoscopy Unit, Circolo Hospital and Macchi Foundation, Varese, Italy.;ASST Sette Laghi, Gastroenterology and Endoscopy Unit, Circolo Hospital and Macchi Foundation, Varese, Italy.;ASST Sette Laghi, Gastroenterology and Endoscopy Unit, Circolo Hospital and Macchi Foundation, Varese, Italy.;Gastroenterology and Endoscopy Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy.;Gastroenterology and Endoscopy Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy.;Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.;Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.;Gastroenterology Unit, IRCCS Policlinico San Donato Research Hospital, Milan, Italy.;Gastroenterology Unit, IRCCS Policlinico San Donato Research Hospital, Milan, Italy.;Gastroenterology Unit, Spedali Civili Hospital, Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy.;Rheumatology Unit, ASST-Fatebenefratelli L. Sacco University Hospital, University of Milan, Milan, Italy.;Gastroenterology and Endoscopy Unit, IRCCS Ca' Granda Ospedale Maggiore Policlinico Foundation, Milan, Italy.;Gastroenterology Unit, ASST Fatebenefratelli-Sacco, L. Sacco University Hospital, Department of Biochemical and Clinical Sciences, University of Milan, Milan, Italy.",
"authors": "Ardizzone|Sandro|S|;Ferretti|Francesca|F|https://orcid.org/0000-0002-6445-0954;Monico|Maria Camilla|MC|;Carvalhas Gabrielli|Anna Maria|AM|;Carmagnola|Stefania|S|;Bezzio|Cristina|C|;Saibeni|Simone|S|;Bosani|Matteo|M|;Caprioli|Flavio|F|;Mazza|Stefano|S|;Casini|Valentina|V|;Cortelezzi|Claudio Camillo|CC|;Parravicini|Marco|M|;Cassinotti|Andrea|A|;Cosimo|Paola|P|;Indriolo|Amedeo|A|;Di Sabatino|Antonio|A|;Lenti|Marco Vincenzo|MV|;Pastorelli|Luca|L|;Conforti|Francesco|F|;Ricci|Chiara|C|;Sarzi-Puttini|Piercarlo|P|;Vecchi|Maurizio|M|;Maconi|Giovanni|G|https://orcid.org/0000-0003-0810-4026",
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"doi": "10.1111/jgh.15591",
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"issn_linking": "0815-9319",
"issue": "36(11)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "Biologic therapy; COVID-19; Inflammatory bowel disease; SARS-CoV-2",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": null,
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "3050-3055",
"pmc": null,
"pmid": "34159648",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lower incidence of COVID-19 in patients with inflammatory bowel disease treated with non-gut selective biologic therapy.",
"title_normalized": "lower incidence of covid 19 in patients with inflammatory bowel disease treated with non gut selective biologic therapy"
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"companynumb": "IT-NOVARTISPH-NVSC2022IT046580",
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"abstract": "Contraceptive implant devices are relatively safe devices, but complications arise when implants become nonpalpable, and cannot be safely removed. In this case report, we describe the location of an implant in the subfascial plane of the upper arm, the diagnostic imaging findings we encountered during the workup, and the procedure necessary to remove it. We demonstrated that if the device is in close proximity to the fascia, it may be difficult to distinguish from the fascia on magnetic resonance imaging. Nonetheless, fluoroscopy and ultrasound easily distinguished the device from the surrounding tissue and allowed localization intraoperatively.",
"affiliations": "Department of Orthopedics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.;Department of Radiology, Jackson Memorial Hospital-University of Miami, Miami, FL, USA.;Ross University School of Medicine, Miramar, FL, USA.;Central Magnetic Imaging South, 4860 SW 72nd Ave, Miami, FL, USA.;Department of Orthopedics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.",
"authors": "Kong|Adrian C|AC|;Alfonso|Matthew N|MN|;Pineda|Dimas E|DE|;Thorpe|Michael S|MS|;Miki|Roberto A|RA|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.radcr.2021.09.051",
"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433\nElsevier\n\nS1930-0433(21)00701-9\n10.1016/j.radcr.2021.09.051\nCase Report\nNexplanon removal from intramuscular implantation in biceps: case report\nKong Adrian C. MS akong004@med.fiu.edu\na⁎\nAlfonso Matthew N. MD b\nPineda Dimas E. BS c\nThorpe Michael S. MD d\nMiki Roberto A. MD ae\na Department of Orthopedics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA\nb Department of Radiology, Jackson Memorial Hospital-University of Miami, Miami, FL, USA\nc Ross University School of Medicine, Miramar, FL, USA\nd Central Magnetic Imaging South, 4860 SW 72nd Ave, Miami, FL, USA\ne Miki & Alfonso Hand & Upper Extremity Center, 9035 Sunset Dr #203, Miami, FL, USA\n⁎ Corresponding author. akong004@med.fiu.edu\n22 10 2021\n12 2021\n22 10 2021\n16 12 39733976\n6 7 2021\n20 9 2021\n20 9 2021\nPublished by Elsevier Inc. on behalf of University of Washington.\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/).\nContraceptive implant devices are relatively safe devices, but complications arise when implants become nonpalpable, and cannot be safely removed. In this case report, we describe the location of an implant in the subfascial plane of the upper arm, the diagnostic imaging findings we encountered during the workup, and the procedure necessary to remove it. We demonstrated that if the device is in close proximity to the fascia, it may be difficult to distinguish from the fascia on magnetic resonance imaging. Nonetheless, fluoroscopy and ultrasound easily distinguished the device from the surrounding tissue and allowed localization intraoperatively.\n\nKeywords\n\nContraceptive implant\nNexplanon\nSubfascial implant removal\nComplication\nEtonogestrel\n==== Body\npmcIntroduction\n\nImplantable contraceptive devices have become more common in recent years [1]. Sold under brand name Nexplanon and Implanon (Merck & Co, Whitehouse Station, NJ), the device in this report is a rod-shaped, etonogestrel eluting implant [2,3]. They last for up to three years, offering long-acting reversible contraception in women. The implants are normally inserted subdermally, in the medial side of the upper arm, just proximal to the medial epicondyle. Retrieval complications are rare occurrences seen in rods inserted too deeply or those that migrated and cannot be palpated under the skin [4,5]. In this case report, we describe the location of an implant in the subfascial plane of the upper arm, the diagnostic imaging findings we encountered during the workup, and the procedure necessary to remove it. We demonstrated that if the device is in close proximity to the fascia, it may be difficult to distinguish from the fascia on magnetic resonance imaging. Nonetheless, fluoroscopy and ultrasound easily distinguished the device from the surrounding tissue and allowed localization intraoperatively.\n\nCase report\n\nA 21-year-old female with a history of a Nexplanon implant in her left arm for 3 years, presented to our office for implant removal. She was referred by her obstetrician because they were unable to localize the device in the subcutaneous tissue. During the visit, the device was localized by ultrasound in the upper arm (Fig. 1). However, the preoperative ultrasound was unable to provide sufficient details to determine the exact location of the device in relation to other anatomic landmarks. Upon communication with the implant device company, we determined that it could be localized via fluoroscopy, ultrasound, and MRI. We found that the device could be visualized by 2 out of 3 methods. In our patient, the implant was not identified on preoperative MRI, in all sequences used, irrespective of the imaging plane (Fig. 2). The patient was scheduled for surgery under local anesthesia with sedation due to the deep nature of the device. Fluoroscopy and ultrasound guidance were used intraoperatively to localize the device (Fig. 3). An incision site was marked using fluoroscopy and ultrasound. An incision was made over the device. Blunt dissection was performed to the level of the fascia (Fig. 4). The fascia was divided, and the device was found to be directly below the fascia of the biceps brachii muscle (Fig. 5). The device was removed (Fig. 6). Final fluoroscopy images demonstrated complete removal of the implant (Fig. 7).Fig. 1 The Nexplanon implant can be seen as a linear echogenic shadowing structure measuring approximately 4 cm in length in close proximity to the bicep's fascia.\n\nFig 1 –\n\nFig. 2 Pre-operative MRI, axial plane, of the upper arm. The implant was unable to be discriminated from other anatomic landmarks.\n\nFig 2 –\n\nFig. 3 Pre-operative fluoroscopy image localizing the device. The Nexplanon can be seen parallel to the humerus in the lower part of the image.\n\nFig 3 –\n\nFig. 4 Intraoperative photograph showing device below the bicep's fascia.\n\nFig 4 –\n\nFig. 5 Intraoperative photograph of the device after splitting the fascia and pulling the device out of the wound.\n\nFig 5 –\n\nFig. 6 Clinical photograph of the device that was removed. A photograph of the explanted Nexplanon.\n\nFig 6 –\n\nFig. 7 Post-operative fluoroscopy image demonstrating complete removal of the device.\n\nFig 7 –\n\nDiscussion\n\nImplanon and Nexplanon (Merck & Co, Whitehouse Station, NJ) are devices inserted in the upper arm to release etonogestrel slowly over three years. In general, removal is an office procedure that requires minimal effort. The devices are normally palpable on exam and do not require imaging for localization [6]. However, an implant that has migrated, or inserted too deeply, may be non–palpable on examination. In these cases, the device may be localized by imaging methods. Both devices can be visualized by MRI and ultrasound [7]. Nexplanon, unlike Implanon, was modified to contain barium sulfate, making it radiopaque, and visible on radiography or fluoroscopy [3]. This radiopaque feature was designed to facilitate better localization during insertion and removal. Removal complications still occur despite modifications [4]. In one clinical trial, they reported 5.3% adverse reactions [8]. The most common complication was fibrosis around the implant removal site (4.4%) [8]. Nerve injury involving the medial antebrachial cutaneous nerve has also been reported [9]. In more complicated cases, orthopedic surgeons and hand surgeons may be called in due to the proximity to important anatomic structures such as the median nerve, ulnar nerve, and brachial artery. Contraceptive implant embolization into the pulmonary vasculature have also been reported. If previously discussed methods do not localize the device in the arm, chest radiograph or computed tomography (CT) should be considered for possible central embolization [10].\n\nIn this specific case, the device could not be palpated because it had been placed or migrated into a subfascial location. We were able to locate the Nexplanon device on fluoroscopy and ultrasound. Interestingly, the preoperative MRI did not localize the device due to the close proximity to the fascia of the biceps. We have provided images of the appearance of the device on ultrasound and fluoroscopy in the hopes of helping other surgeons in a similar situation to recognize the device on those imaging modalities.\n\nPatient Consent\n\nPer the local Institutional Review Board consent was exempt due to this being the case of research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimen with the information being recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.\n\nCompeting Interests: The 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==== Refs\nReferences\n\n1 Kavanaugh ML Jerman J Finer LB Changes in use of long-acting reversible contraceptive methods among U.S. women Obstet Gynecol 126 5 2015 917 927 10.1097/AOG.0000000000001094 26444110\n2 Implanon (etonogestrel implant) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2019. http://www.merck.com/product/usa/pi_circulars/i/implanon/implanon_pi.pdf\n3 Nexplanon (etonogestrel) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2019. https://www.merck.com/product/usa/pi_circulars/n/nexplanon/nexplanon_pi.pdf\n4 Pillai M Gazet AC Griffiths M Continuing need for and provision of a service for non-standard implant removal J Fam Plann Reprod Health Care 40 2 2014 126 132 10.1136/jfprhc-2013-100619 24081828\n5 Chevreau J Krief D Abou Arab O Zitoun M Foulon A Sergent F Factors associated with removal difficulties of etonogestrel-containing contraceptive implants (Nexplanon ®) Eur J Obstet Gynecol Reprod Biol 224 2018 81 84 10.1016/j.ejogrb.2018.03.019 29554605\n6 Shulman LP Gabriel H Management and localization strategies for the nonpalpable implanon rod Contraception 73 4 2006 325 330 10.1016/j.contraception.2005.10.009 16531160\n7 Merki-Feld GS Brekenfeld C Migge B Keller PJ Nonpalpable ultrasonographically not detectable Implanon rods can be localized by magnetic resonance imaging Contraception 63 6 2001 325 328 10.1016/S0010-7824(01)00209-8 11672555\n8 Mommers E Blum G-F Gent TG Peters KP Sørdal TS Marintcheva-Petrova M Nexplanon, a radiopaque etonogestrel implant in combination with a next-generation applicator: 3-year results of a noncomparative multicenter trial Am J Obstet Gynecol 207 5 2012 388.e1 388.e6 10.1016/j.ajog.2012.08.002 22939402\n9 Brown M Britton J Neuropathy associated with etonogestrel implant insertion Contraception 86 5 2012 591 593 10.1016/j.contraception.2012.05.014 22770789\n10 Wilcox KK. Turcer F Soltes GD Shin DS Endovascular retrieval of contraceptive implant embolized to pulmonary artery Radiol Case Rep 13 6 2018 1285 1288 30275923\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "16(12)",
"journal": "Radiology case reports",
"keywords": "Complication; Contraceptive implant; Etonogestrel; Nexplanon; Subfascial implant removal",
"medline_ta": "Radiol Case Rep",
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"title": "Nexplanon removal from intramuscular implantation in biceps: case report.",
"title_normalized": "nexplanon removal from intramuscular implantation in biceps case report"
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"abstract": "Relapsed or refractory acute lymphoblastic leukemia represents a major challenge in low- and middle-income countries where new therapies are not easily accessible. Combinations of cost-effective drugs should be considered as a bridge for hematopoietic stem cell transplantation. We retrospectively analyzed pediatric and adolescent and young adult patients who received reinduction with a protocol based on l-asparaginase, doxorubicin, vincristine, dexamethasone, and bortezomib (BZ). Fifteen patients were included. Total complete response (CR) was achieved by nine of 15 patients (60%); five patients achieved CR with negative minimal residual disease, two achieved complete morphological response (CR), and two complete morphological response without platelet recovery. Eleven patients (73%) were not hospitalized and 10 (66%) did not require any blood component transfusions. There were no cases of serious toxicity or mortality. Nine patients (60%) underwent transplant. Five-year overall survival was 40%. This BZ-based protocol is effective and safe when administered as an outpatient regimen and feasible in a low resource setting.",
"affiliations": "Hematology Service, Facultad de Medicina y Hospital Universitario \"Dr. José Eleuterio González\", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.;Hematology Service, Facultad de Medicina y Hospital Universitario \"Dr. José Eleuterio González\", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.;Hematology Service, Facultad de Medicina y Hospital Universitario \"Dr. José Eleuterio González\", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.;Hematology Service, Facultad de Medicina y Hospital Universitario \"Dr. José Eleuterio González\", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.;Hematology Service, Facultad de Medicina y Hospital Universitario \"Dr. José Eleuterio González\", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.;Hematology Service, Facultad de Medicina y Hospital Universitario \"Dr. José Eleuterio González\", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.;Hematology Service, Facultad de Medicina y Hospital Universitario \"Dr. José Eleuterio González\", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.",
"authors": "Colunga-Pedraza|Julia E|JE|;González-Llano|Oscar|O|;González-Martinez|Carlos Eugenio|CE|;Gómez-Almaguer|David|D|;Yáñez-Reyes|José Miguel|JM|;Jiménez-Antolinez|Valentine|V|;Colunga-Pedraza|Perla R|PR|0000-0002-9937-439X",
"chemical_list": "D000069286:Bortezomib",
"country": "United States",
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"issn_linking": "1545-5009",
"issue": "67(5)",
"journal": "Pediatric blood & cancer",
"keywords": "bortezomib; pediatric; precursor cell lymphoblastic leukemia-lymphoma; relapse; young adult",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000069286:Bortezomib; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008800:Mexico; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101186624",
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"pages": "e28241",
"pmc": null,
"pmid": "32159276",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outpatient low toxic regimen with bortezomib in relapsed/refractory acute lymphoblastic leukemia in pediatrics and AYA patients: Single-center Mexican experience.",
"title_normalized": "outpatient low toxic regimen with bortezomib in relapsed refractory acute lymphoblastic leukemia in pediatrics and aya patients single center mexican experience"
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"abstract": "Cytomegalovirus (CMV) can cause severe disease including colitis, pneumonitis, and less commonly encephalitis, in profoundly immunocompromised individuals. CNS imaging findings are nonspecific and diagnosis is made by identifying CMV in cerebral spinal fluid through PCR testing or cell culture. Early initiation of antiviral therapy is key with an overall poor outcome. Here we present a patient with newly diagnosed AIDS and pneumocystis jiroveci pneumonia who was febrile and remained encephalopathic for the first 6 weeks of his admission despite treatment and extensive work up for encephalopathy. Ultimately, he was diagnosed with CMV encephalitis and radiculitis and failed to improve significantly. This case is important because of multiple points (1) the uncommon presentation of CMV encephalitis/radiculitis occurring over 1 month into a hospitalization; (2) in the era of highly active antiretroviral therapy (HAART) severe complications of AIDS are rarely seen by newer generations of physicians and are not typically thought of; (3) the difficulties in evaluating altered mental status and weakness in an intubated patient receiving sedation. In immunosuppressed patients on mechanical ventilation, early evaluation with LP should be considered when altered mental status and fever of unclear etiology are present.",
"affiliations": "Department of Internal Medicine, University of Rochester Medical Center, USA.;Division of Infectious Diseases, University of Rochester Medical Center, USA.;Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, USA.",
"authors": "Newcomb|Geoffrey|G|0000-0002-8356-4818;Mariuz|Peter|P|;Lachant|Daniel|D|0000-0003-3441-8264",
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"doi": "10.1155/2019/8067648",
"fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi 10.1155/2019/8067648Case ReportCMV Encephalitis/Radiculitis: The Difficulty in Diagnosing in an Intubated Patient http://orcid.org/0000-0002-8356-4818Newcomb Geoffrey geoffnewcomb7@gmail.com\n1\nMariuz Peter \n2\nhttp://orcid.org/0000-0003-3441-8264Lachant Daniel \n3\n\n1Department of Internal Medicine, University of Rochester Medical Center, USA\n2Division of Infectious Diseases, University of Rochester Medical Center, USA\n3Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, USAAcademic Editor: Joel Starkopf\n\n2019 18 2 2019 2019 80676484 12 2018 29 1 2019 5 2 2019 Copyright © 2019 Geoffrey Newcomb et al.2019This 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.Cytomegalovirus (CMV) can cause severe disease including colitis, pneumonitis, and less commonly encephalitis, in profoundly immunocompromised individuals. CNS imaging findings are nonspecific and diagnosis is made by identifying CMV in cerebral spinal fluid through PCR testing or cell culture. Early initiation of antiviral therapy is key with an overall poor outcome. Here we present a patient with newly diagnosed AIDS and pneumocystis jiroveci pneumonia who was febrile and remained encephalopathic for the first 6 weeks of his admission despite treatment and extensive work up for encephalopathy. Ultimately, he was diagnosed with CMV encephalitis and radiculitis and failed to improve significantly. This case is important because of multiple points (1) the uncommon presentation of CMV encephalitis/radiculitis occurring over 1 month into a hospitalization; (2) in the era of highly active antiretroviral therapy (HAART) severe complications of AIDS are rarely seen by newer generations of physicians and are not typically thought of; (3) the difficulties in evaluating altered mental status and weakness in an intubated patient receiving sedation. In immunosuppressed patients on mechanical ventilation, early evaluation with LP should be considered when altered mental status and fever of unclear etiology are present.\n==== Body\n1. Introduction\nCytomegalovirus (CMV) is a member of the Herpesviridae family and often causes a self-limiting infection in immunocompetent individuals [1], while it can cause more severe disease including colitis, pneumonitis, and less commonly encephalitis, in profoundly immunocompromised patients [2]. In HIV/AIDS CMV resulting in disease most commonly occurs when CD4+ counts are less than 50 cells/ml [3] and most frequently presents as retinitis or gastrointestinal disease (esophagitis, colitis), while encephalitis or radiculopathies are uncommon [4]. CNS imaging findings are nonspecific [5], and diagnosis is made by identifying CMV in cerebral spinal fluid through PCR testing or cell culture. Once identified, antiviral therapy, with ganciclovir, foscarnet, or cidofovir should be initiated [6]. Survival after CNS CMV disease is poor [4, 6], with most data reported before anti-retroviral therapy.\n\n2. Case Report\nA 65-year-old male with hypertension and atrial fibrillation was admitted to the University of Rochester Medical Center with fever, chest pain, and dyspnea. A CT Chest angiogram revealed bilateral ground-glass opacities with mediastinal lymphadenopathy and no embolic disease. He was admitted to the general medicine service and was treated for community-acquired pneumonia with ceftriaxone and doxycycline. His fevers persisted for the first three days. On hospital day 6 his antimicrobial therapy was broadened to vancomycin, piperacillin-tazobactam, and azithromycin due to worsening hypoxia and was continued for 10 days. He was found to be HIV positive with a RNA level greater than 500,000 copies/ml and a CD4 count of 15. On hospital day 9 he required intubation for worsening hypoxia. He underwent bronchoscopy with bronchoalveolar lavage (BAL) with pneumocystis jiroveci identified on PCR testing and microscopy and CMV was identified on viral cell culture. Sulfamethoxazole/trimethoprim and glucocorticoid therapy was empirically started and he completed 21 days of therapy.\n\nOn hospital day 23 he was extubated. Due to increasing lethargy he was reintubated on hospital day 27 for airway protection. After intubation he developed intermittent fevers for 25 days with altered mental status. Vancomycin and piperacillin-tazobactam were restarted. An initial work up for encephalopathy was performed with normal ammonia (18 μmol/L), normal CT head with and without contrast, and negative evaluation for infection including blood, urine, tracheal aspirate, and stool cultures. An electroencephalogram was performed and showed moderate encephalopathy without epileptiform abnormalities. Highly active antiretroviral therapy (HAART) with elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was started on hospital day 33 after HIV genotype testing returned. There was concern for drug fever from dexmedetomidine and piperacillin-tazobactam and both drugs were discontinued on hospital day 32 and 37. After no improvement in fevers a MRI of the head with and without contrast was performed on hospital day 37 and showed acute infarcts in the bilateral thalami, right parietal lobe, and right basal ganglia. Neurology felt it was embolic phenomena from atrial fibrillation. He also developed persistent, nonbloody loose stools with negative bacterial and parasite stool studies so serum CMV PCR was checked on hospital day 43 showing 2,623,108 IU/mL. With new nuchal rigidity on exam and right lower extremity weakness a lumbar puncture was performed on hospital day 44 after another head CT was normal. Spinal fluid analysis was consistent with encephalitis and CSF PCR for CMV DNA was positive (Table 1). After serum CMV PCR positivity returned ganciclovir was started on hospital day 47. MRI imaging of the cervical, thoracic, and lumbar spine showed extensive linear leptomeningeal enhancement along the lower spinal cord, conus medullaris, and roots of the cauda equine with thickening of the roots concerning for radiculomyelitis (Figure 1). At this point his mental status remained poor with quadriparesis and flaccid paraplegia. He underwent tracheostomy on hospital day 50.\n\nSerum CMV DNA PCR and HIV RNA PCR were checked weekly to monitor treatment efficacy, and both decreased significantly on treatment (Table 2). No further lumbar punctures were performed. He received 30 days of IV ganciclovir 469mg twice daily before decreasing to IV ganciclovir 469mg daily after two consecutive weeks of undetectable serum CMV DNA PCR, hospital day 76. He received IV ganciclovir daily for 85 days total, before switching to oral valganciclovir 900mg daily. The serum HIV RNA PCR continued to decline and was 49 copies/mL on hospital day 128 (96 days after initiation of HAART therapy). He remained on mechanical ventilation and was able to move his upper extremities with assistance and could answer simple questions. He never regained function in his lower extremities. After minimal improvement he opted to stop mechanical ventilation and passed away on hospital day 147.\n\n3. Discussion\nThis case report highlights the uncommon and rare presentation of CMV encephalitis and radiculitis, the limited data on treatment and prognosis in the HAART era, and the difficulties in evaluating altered mental status, fever, and extremity weakness in an intubated immunosuppressed patient.\n\nCMV infection usually causes asymptomatic disease in immunocompetent individuals [1]. Severe CMV disease (colitis, pneumonitis, and encephalitis) is typically seen in profound immunodeficiency states including solid organ transplantation [2], bone marrow transplantation [7], and advanced AIDS [8] with CD4 counts less than 50 cells/μL [3]. Although plasma quantitative CMV PCR is commonly measured in immunocompromised patients, its role in establishing CMV end-organ damage is unclear. The majority of individuals are exposed to CMV in their lifetime [4] and therefore testing for CMV PCR in peripheral blood is not always indicative of disease activity or severity [5]. According to the most recent NIH and CDC guidelines, blood assays to detect CMV DNA or antigen are not recommended for diagnosis of CMV end-organ disease because of their poor positive predictive value. CMV neurologic disease is diagnosed on the basis of a compatible clinical syndrome and the presence of CMV in CSF or brain tissue, most often evaluated with PCR. Initiating anti-CMV therapy should therefore be reserved until definitive diagnosis is established [6]. CMV encephalitis in AIDS is extremely uncommon with identification rates of ~2% of patients prior to the advent of HAART therapy [9]. With a decrease in AIDS, opportunistic infections are not frequently encountered by younger physicians and are thought of less commonly.\n\nDisseminated CMV in the central nervous system can present with meningitis, encephalitis, or radiculopathies. Symptoms typically include altered mental status, delirium, confusion, weakness, or urinary retention [10]. Imaging with CT and MRI can have variable findings and in some instances can be normal [11]. Currently, diagnosis is made by identifying CMV in cerebral spinal fluid with PCR testing [12, 13]. Arribas et al. reported that AIDS patients with CSF CMV DNA molecules greater than 103 per 8 μL had severe CMV disease [14]. Once identified, treatment should be initiated, though the regimen of choice is controversial because there are no prospective trials evaluating antiviral therapy for CMV encephalitis. Given the poor outcomes in many patients with CMV-related neurologic disease, some experts recommend initiation of both IV ganciclovir and IV foscarnet [6]; however, there are significant toxicities associated with these medications (anemia, neutropenia, thrombocytopenia, nausea, diarrhea and renal dysfunction) and thus benefits and risks of therapy must be considered. The recommendation for dual therapy has been extrapolated from a randomized trial that found patients with relapsed CMV retinitis had better outcomes with the use of dual therapy as compared to those who received monotherapy with either of these agents [15]. Cidofovir has also been used [12]. Although immune reconstitution inflammatory syndrome (IRIS) causing worsening neurologic disease is a concern the optimal timing of starting HAART in AIDS patients with CMV encephalitis is unknown and has not been studied. Given the poor prognosis even in treated patients, therapy should be started as soon as the diagnosis is made. Time to clinical improvement without HAART is variable and can take as long as two months after starting antiviral therapy [16]. Duration of induction therapy varies between 2-6 weeks and should be continued until neurologic and virologic improvement is seen, after which maintenance therapy is initiated. Survival after diagnosis of neurologic CMV is poor [10]. Prior to HAART the median survival was 4.6 weeks from time of symptom onset [17] and in hospital mortality 38% [18]. There is no data on CMV encephalitis outcomes and management strategies in the HAART era.\n\nAltered mental status/delirium is a common finding in patients in the intensive care unit and associated with increase hospital stay and mortality [19]. There are multiple etiologies including neurologic (stroke or seizure), infectious (sepsis, meningitis, encephalitis), temperature dysregulation (hyperthermia/hypothermia), metabolic (renal or liver dysfunction), medication (benzodiazepine), withdrawal (alcohol), hypoxia/hypercarbia, heart failure, or delirium [20]. Up to 80% of mechanically vented patients experience delirium [20]. Typically, a noncontrasted head CT is performed and abnormalities are found only a quarter of the time [21]. Infectious etiologies outside of the broad culturing (tracheal aspirate, blood, and urine culture) should always be considered in the work up of alerted mental status in an intubated immunosuppressed patient including lumbar puncture.\n\nIn our case report, we discuss the unique presentation of a patient with AIDS initially presenting with pneumocystis pneumonia and subsequently diagnosed with CMV encephalitis and radiculitis 6 weeks into his hospital stay after having persistent mental status changes and weakness while on mechanical ventilation. In the intubated immunosuppressed patient, broad differentials should be considered, including infectious etiologies, in patients with persistent altered mental status, fever, or weakness. Early recognition and initiation of therapy are key in improving outcomes of CMV in the central nervous system.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nFigure 1 Sagittal view of MR lumbar spine T1 FLAIR depicting significant leptomeningeal enhancement and thickening of nerve roots (arrows).\n\nTable 1 Results from lumbar puncture.\n\nCSF\tResults\t\nColor\tColorless\t\n\n\n\t\nNucleated Cells per μL\t70\t\n\n\n\t\nRBC per μL\t20\t\n\n\n\t\nPolymorphonuclear cells %\t89\t\n\n\n\t\nLymphocytes %\t7\t\n\n\n\t\nGlucose (mg/dL)\t96\t\n\n\n\t\nProtein (mg/dL)\t272\t\n\n\n\t\nAerobic Culture\tNo growth\t\n\n\n\t\nGram Stain\tNo organisms\t\n\n\n\t\nFungus Culture\tNo growth\t\n\n\n\t\nCMV DNA PCR (IU/mL)\t>1.88x108\t\n\n\n\t\nEBV DNA PCR (IU/mL)\t5,100\t\n\n\n\t\nCryptococcal Antigen\tNegative\t\n\n\n\t\nHSV Types 1 & 2 (copies/mL)\t6,900 (HSV 2)\t\n\n\n\t\nVaricella Zoster DNA\tNegative\t\n\n\n\t\nWest Nile Virus RNA\tNegative\t\nTable 2 PCR and CD4 count.\n\nHospital Day\t\n \t8\t9\t43\t51\t54\t56\t63\t69\t70\t76\t77\t84\t87\t130\t\n\n\n\t\nCMV PCR\t \t \t2,623,108\t223,152\t \t33,296\t538\t \t<137\t \t \t \t \t \t\n\n\n\t\nHIV PCR\t563,644\t \t \t \t390\t \t \t \t139\t \t172\t \t166\t49\t\n\n\n\t\nCD4 Count\t \t15\t \t \t \t16\t \t26\t \t23\t \t34\t \t39\n==== Refs\n1 Schottstedt V. Blumel J. Burger R. Human cytomegalovirus (HCMV)-revised Transfusion Medicine and Hemotherapy 2010 37 6 365 375 10.1159/000322141 2-s2.0-78649756516 21483467 \n2 Ramanan P. Razonable R. R. Cytomegalovirus infections in solid organ transplantation: a review Journal of Infection and Chemotherapy 2013 45 3 260 271 10.3947/ic.2013.45.3.260 2-s2.0-84887560446 \n3 Jacobson M. A. O’Donnell J. J. Porteous D. Brodie H. R. Feigal D. Mills J. Retinal and gastrointestinal disease due to cytomegalovirus in patients with the acquired immune deficiency syndrome: prevalence, natural history, and response to ganciclovir therapy QJM: An International Journal of Medicine 1988 67 3 473 486 10.1093/oxfordjournals.qjmed.a068213 2-s2.0-0023764692 \n4 Staras S. A. S. Dollard S. C. Radford K. W. Flanders W. D. Pass R. F. Cannon M. J. Seroprevalence of cytomegalovirus infection in the United States, 1988–1994 Clinical Infectious Diseases 2006 43 9 1143 1151 10.1086/508173 2-s2.0-33750128821 17029132 \n5 Zurlo J. J. O'Neill D. Polis M. A. Lack of clinical utility of cytomegalovirus blood and urine cultures in patients with HIV infection Annals of Internal Medicine 1993 118 1 12 17 2-s2.0-0027434720 10.7326/0003-4819-118-1-199301010-00003 8093214 \n6 Panel on opportunistic infections in HIV-infected adults and adolescents Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV MEdicine Association of the Infectious Diseases Society of America 2017 http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf \n7 Bhat V. Joshi A. Sarode R. Chavan P. Cytomegalovirus infection in the bone marrow transplant patient World Journal of Transplantation 2015 5 4 287 291 10.5500/wjt.v5.i4.287 26722656 \n8 Spector S. A. Hsia K. Crager M. Pilcher M. Cabral S. Stempien M. J. Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and survival in advanced AIDS Journal of Virology 1999 73 8 7027 7030 2-s2.0-0032795495 10400803 \n9 Gallant J. E. Moore R. D. Richman D. D. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine The Journal of Infectious Diseases 1992 166 6 1223 1227 2-s2.0-0026479981 10.1093/infdis/166.6.1223 1358986 \n10 Anders H. Goebel F. D. Neurological manifestations of cytomegalovirus infection in the acquired immunodeficiency syndrome International Journal of STD & AIDS 1999 10 3 151 159 10.1258/0956462991913817 10340195 \n11 Smith A. B. Smirniotopoulos J. G. Rushing E. J. Central nervous system infections associated with human immunodeficiency virus infection: radiologicpathologic correlation RadioGraphics 2008 28 7 2033 2058 10.1148/rg.287085135 2-s2.0-58149392585 19001657 \n12 Maschke M. Kastrup O. Diener H.-C. CNS manifestations of cytomegalovirus infections: diagnosis and treatment CNS Drugs 2002 16 5 303 315 10.2165/00023210-200216050-00003 2-s2.0-0036105486 11994020 \n13 Steiner I. Budka H. Chaudhuri A. Viral encephalitis: a review of diagnostic methods and guidelines for management European Journal of Neurology 2005 12 5 331 343 10.1111/j.1468-1331.2005.01126.x 2-s2.0-17144426931 15804262 \n14 Arribas J. R. Clifford D. B. Fichtenbaum C. J. Commins D. L. Powderly W. G. Storch G. A. Level of cytomegalovirus (CMV) DNA in cerebrospinal fluid of subjects with AIDS and CMV infection of the central nervous system The Journal of Infectious Diseases 1995 172 2 527 531 2-s2.0-0028984537 10.1093/infdis/172.2.527 7622897 \n15 Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The cytomegalovirus retreatment trial. The studies of ocular complications of AIDS research group in collaboration with the AIDS clinical trials group Archives of Ophthalmology 1996 114 1 23 33 10.1001/archopht.1996.01100130021004 2-s2.0-9044238842 8540847 \n16 Kim Y. S. Hollander H. Polyradiculopathy due to cytomegalovirus: report of two cases in which improvement occurred after prolonged therapy and review of the literature Clinical Infectious Diseases 1993 17 1 32 37 10.1093/clinids/17.1.32 2-s2.0-0027196239 8394748 \n17 Holland N. R. Power C. Mathews V. P. Glass J. D. Forman M. McArthur J. C. Cytomegalovirus encephalitis in acquired immunodeficiency syndrome (AIDS) Neurology 1994 44 3 (Pt 1) 507 514 10.1212/WNL.44.3_Part_1.507 2-s2.0-0028327561 8145923 \n18 Silva C. A. Oliveira A. C. Vilas-Boas L. Fink M. C. Pannuti C. S. Vidal J. E. Neurologic cytomegalovirus complications in patients with AIDS: retrospective review of 13 cases and review of the literature Revista do Instituto de Medicina Tropical de São Paulo 2010 52 6 305 310 10.1590/S0036-46652010000600004 21225213 \n19 Bleck T. P. Smith M. C. Pierre-Louis S. J.-C. Jares J. J. Murray J. Hansen C. A. Neurologic complications of critical medical illnesses Critical Care Medicine 1993 21 1 98 103 2-s2.0-0027439418 10.1097/00003246-199301000-00019 8420739 \n20 Hayhurst C. J. Pandharipande P. P. Hughes C. G. Intensive care unit delirium: a review of diagnosis, prevention, and treatment Anesthesiology 2016 125 6 1229 1241 10.1097/ALN.0000000000001378 2-s2.0-84991491427 27748656 \n21 Chokshi F. H. Sadigh G. Carpenter W. Kang J. Duszak R. Khosa F. Altered mental status in ICU patients: diagnostic yield of noncontrast head CT for abnormal and communicable findings Critical Care Medicine 2016 44 12 e1180 e1185 10.1097/CCM.0000000000002005 2-s2.0-84980320165 27488219\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6420",
"issue": "2019()",
"journal": "Case reports in critical care",
"keywords": null,
"medline_ta": "Case Rep Crit Care",
"mesh_terms": null,
"nlm_unique_id": "101598416",
"other_id": null,
"pages": "8067648",
"pmc": null,
"pmid": "30911420",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10340195;10400803;11994020;1358986;15804262;17029132;19001657;21225213;21483467;24396627;26722656;27488219;27748656;2854894;7622897;8093214;8145923;8394748;8420739;8540847",
"title": "CMV Encephalitis/Radiculitis: The Difficulty in Diagnosing in an Intubated Patient.",
"title_normalized": "cmv encephalitis radiculitis the difficulty in diagnosing in an intubated patient"
} | [
{
"companynumb": "US-MYLANLABS-2020M1005668",
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"activesubstancename": "GANCICLOVIR"
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... |
{
"abstract": "Talaromyces (Penicillium) marneffei (T. marneffei) is an important pathogenic thermally dimorphic fungus in Southeast Asia that leads to a life-threatening systemic mycosis in immunodeficient hosts, especially in AIDS patients. With the increasing AIDS epidemic, the number of patients with T. marneffei infections in mainland China has increased rapidly in recent years. The infection can be life-threatening in people with immunodeficiencies, such as HIV, organ transplantations, autoimmune diseases, and malignant tumors. Here, we present a disseminated T. marneffei infection case in a renal transplant recipient successfully treated with voriconazole followed by itraconazole. We describe the patient's clinical progression from onset symptoms to recovery and review the additional 14 published cases with T. marneffei infections in renal transplant recipients. In addition, we discuss the route of infection and treatment strategies of T. marneffei. Our data suggest that patients with kidney transplantations in T. marneffei infection-endemic areas should presume the possibility of infection and initiate appropriate antifungal treatment.",
"affiliations": "Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.;Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.;Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Department of Pharmacy Practice, College of Pharmacy and Health Sciences, Western New England University, Springfeld, MA 01119, USA.;Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.;Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China. Electronic address: dengsxy@sina.com.",
"authors": "Li|Yunfei|Y|;Tang|Mimi|M|;Sun|Shusen|S|;Hu|Qin|Q|;Deng|Sheng|S|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2021.101214",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "32(1)",
"journal": "Journal de mycologie medicale",
"keywords": "Itraconazole; Kidney transplant recipient; Recovery; Tacrolimus; Talaromyces marneffei; Voriconazole",
"medline_ta": "J Mycol Med",
"mesh_terms": null,
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "101214",
"pmc": null,
"pmid": "34763148",
"pubdate": "2021-10-28",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful treatment of Talaromyces marneffei infection in a kidney transplant recipient with voriconazole followed by itraconazole for the first time.",
"title_normalized": "successful treatment of talaromyces marneffei infection in a kidney transplant recipient with voriconazole followed by itraconazole for the first time"
} | [
{
"companynumb": "CN-PBT-004366",
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"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
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{
"abstract": "We report a case of a previously fit woman who presented at 26 weeks into her fourth pregnancy with a dry cough. Following a nasopharyngeal swab, she was diagnosed with a pertussis infection, and treated with antibiotics. A chest X-ray showed right atrial dilatation and an echocardiogram was scheduled outpatient. However, after re-presenting with worsening cough and dyspnoea, an inpatient echocardiogram was performed which suggested elevated pulmonary pressures with significant tricuspid regurgitation, as confirmed by subsequent cardiac catheterisation. She had an elective caesarean section at 34 weeks and underwent repeat right heart catheterisation which revealed persistent, and likely pre-existing, pulmonary arterial hypertension. This case highlights the importance of thorough assessment of non-obstetric symptoms in pregnancy in formulating alternative differentials, even after a diagnosis has been made, to prevent potentially life-threatening conditions from being missed. It also shows that although often associated, respiratory and cardiac causes may coexist separately.",
"affiliations": "Obstetrics and Gynaecology, KK Women's and Children's Hospital, Singapore tiffany.wong@mohh.com.sg.;Maternal Fetal Medicine, KK Women's and Children's Hospital, Singapore.;Department of Cardiology, National Heart Centre Singapore, Singapore.;Maternal Fetal Medicine, KK Women's and Children's Hospital, Singapore.",
"authors": "Wong|Tiffany Tuck Chin|TTC|http://orcid.org/0000-0002-1912-253X;Ng|Yang Huang Grace|YHG|;Yan|Limin|L|;Wright|Ann|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(9)",
"journal": "BMJ case reports",
"keywords": "hypertension; obstetrics and gynaecology; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002585:Cesarean Section; D004452:Echocardiography; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D011247:Pregnancy; D014262:Tricuspid Valve Insufficiency; D014917:Whooping Cough",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34493555",
"pubdate": "2021-09-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Whooping cough complicating pulmonary hypertension in pregnancy.",
"title_normalized": "whooping cough complicating pulmonary hypertension in pregnancy"
} | [
{
"companynumb": "SG-SLATE RUN PHARMACEUTICALS-22SG000908",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"drugadditiona... |
{
"abstract": "Limited data are available on the use of dialysis to treat cyanide or thiocyanate intoxication. This report describes the case of a 65-year-old woman with renal insufficiency who had development of thiocyanate toxicity secondary to a nitroprusside infusion. A rapid decline in her blood thiocyanate level was observed in response to initiation of continuous venovenous hemodiafiltration.",
"affiliations": "Department of Medicine, Division of Nephrology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Nessim|Sharon J|SJ|;Richardson|Robert M A|RM|",
"chemical_list": "D013861:Thiocyanates; D009599:Nitroprusside; C031760:thiocyanate",
"country": "United States",
"delete": false,
"doi": "10.1097/01.mat.0000227670.39719.ec",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-2916",
"issue": "52(4)",
"journal": "ASAIO journal (American Society for Artificial Internal Organs : 1992)",
"keywords": null,
"medline_ta": "ASAIO J",
"mesh_terms": "D000368:Aged; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007262:Infusions, Intravenous; D009599:Nitroprusside; D006435:Renal Dialysis; D051437:Renal Insufficiency; D013861:Thiocyanates; D016896:Treatment Outcome",
"nlm_unique_id": "9204109",
"other_id": null,
"pages": "479-81",
"pmc": null,
"pmid": "16883131",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Dialysis for thiocyanate intoxication: a case report and review of the literature.",
"title_normalized": "dialysis for thiocyanate intoxication a case report and review of the literature"
} | [
{
"companynumb": "CA-PFIZER INC-2019405449",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM THIOSULFATE"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nThe incidence of hepatitis B virus (HBV) recurrence after liver transplantation (LT) has been reduced by prophylaxis with hepatitis B immunoglobulin (HBIG) and nucleoside analogs, but the factors associated with HBV recurrence are unclear. The aim of this study was to determine the risk factors associated with HBV recurrence after living donor LT (LDLT).\n\n\nMETHODS\nA retrospective review was performed for 45 patients (28 male and 17 female; median age, 54 years) who underwent LDLT for HBV-related liver disease and were followed up for at least 6 months between October 1996 and June 2013. The virological data, tumor burden, antiviral therapy and immunosuppressive therapy were evaluated and compared between the HBV recurrence ad non-recurrence groups.\n\n\nRESULTS\nSeven of the 45 patients (15.6%) developed post-LT HBV recurrence. The median interval between LDLT and HBV recurrence was 23.7 months (range, 0.8-35.9). Three of the seven patients (42.9%) developed recurrence after cessation of HBIG, and three (42.9%) were cases with hepatocellular carcinoma (HCC) recurrence after LDLT. The remaining case underwent transplantation from a donor with positive hepatitis B surface antigen. Based on the univariate and multivariate analyses, HBIG cessation (hazard ratio [HR], 20.17; 95% confidence interval [95% CI], 2.091-194.593; P = 0.009) and HCC recurrence (HR, 30.835; 95% CI, 3.132-303.593; P = 0.003) were independent risk factors for HBV recurrence after LDLT.\n\n\nCONCLUSIONS\nIn LDLT patients, cessation of HBIG and HCC recurrence were risk factors associated with HBV recurrence, so careful monitoring for serological HBV markers is needed in patients with these factors.",
"affiliations": "Medicine and Biosystemic Science, Fukuoka, Japan.;Medicine and Biosystemic Science, Fukuoka, Japan.;Department of Surgery and Science, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Kyushu University, Fukuoka, Japan.;Department of Surgery and Science, Kyushu University, Fukuoka, Japan.",
"authors": "Bae|Sung Kwan|SK|;Shimoda|Shinji|S|;Ikegami|Toru|T|;Yoshizumi|Tomoharu|T|;Harimoto|Norifumi|N|;Itoh|Shinji|S|;Soejima|Yuji|Y|;Uchiyama|Hideaki|H|;Shirabe|Ken|K|;Maehara|Yoshihiko|Y|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.12489",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "45(12)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "hepatitis B immunoglobulin; hepatitis B virus recurrence; hepatocellular carcinoma; living donor liver transplantation",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "1203-10",
"pmc": null,
"pmid": "25594259",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk factors for hepatitis B virus recurrence after living donor liver transplantation: A 17-year experience at a single center.",
"title_normalized": "risk factors for hepatitis b virus recurrence after living donor liver transplantation a 17 year experience at a single center"
} | [
{
"companynumb": "JP-GILEAD-2016-0194206",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADEFOVIR DIPIVOXIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but potentially lethal inherited arrhythmia syndrome induced by adrenergic stress. Due to the atypical clinical manifestations in early age, limited recognition and experience of pediatric cardiologists, and low awareness of the significance of genetic diagnosis in some underdeveloped areas in China, a delayed or missed diagnosis of CPVT in children is common and concerning.\nA 9-year and 3-month male child with recurrent exercise-induced syncope accompanied by convulsion was initially misdiagnosed as epilepsy since the first manifestation at the age of 3 years. Due to the identification of polymorphic ventricular premature beats, nonsustained ventricular tachycardia (VT), and supraventricular tachycardia, a cardiogenic etiology was established. The patient received a successive treatment by propafenone, amiodarone, a combination of amiodarone with metoprolol, and metoprolol alone for up to 6 years.\nGiven the poor response to conventional antiarrhythmics, excise-induced syncope, QRS morphology and a structurally normal heart, the diagnosis of CPVT was suspected, and ultimately confirmed by detection of polymorphic and bidirectional VT with degeneration into ventricular fibrillation during exercise testing. In addition, a heterozygous mutant of RYR2 at c.7580T > G was identified by genetic testing.\n\n\nMETHODS\nDue to the unavailability of flecainide in China and the refusal of implantable cardioverter defibrillator implantation by his parents, this patient continued to be treated with oral metoprolol.\n\n\nRESULTS\nUnfortunately, the effect was unfavorable during 4 months outpatient follow-up.\n\n\nCONCLUSIONS\nCPVT should be suspected in young patients with a normal baseline electrocardiogram (EKG), a structurally normal heart and polymorphic and/or bidirectional ventricular tachycardia induced by exercise or emotional stress. Exercise and genetic testing is essential and significant for a timely and accurate diagnosis of CPVT. The current study firstly reported a case with CPVT associated with a mutant of RYR2 at c.7580T > G in children.",
"affiliations": "Department of Pediatrics, West China Second University Hospital, Sichuan University The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China.",
"authors": "Duan|Hongyu|H|;Lu|Yongyi|Y|;Yan|Song|S|;Qiao|Lina|L|;Hua|Yimin|Y|;Li|Yifei|Y|;Zhou|Kaiyu|K|;Wang|Chuan|C|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel; D011405:Propafenone; D008790:Metoprolol; D000638:Amiodarone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000010368",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29668588MD-D-17-0422010.1097/MD.0000000000010368003686200Research ArticleClinical Case ReportA delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia with a mutant of RYR2 at c.7580T>G for 6 years in a 9-year-old child Duan Hongyu MDabLu Yongyi MBacYan Song MBacQiao Lina MD, PhDacHua Yimin MD, PhDabcLi Yifei MDabZhou Kaiyu MD, PhDabc∗Wang Chuan MDab∗Elshmaa. Manal a Department of Pediatrics, West China Second University Hospital, Sichuan Universityb The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan Universityc Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China.∗ Correspondence: Kaiyu Zhou and Chuan Wang, Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, 3rd Section, South Renmin Road, Chengdu, Sichuan 610041, China (e-mails: kaiyuzhou313@163.com; 805101396@qq.com).4 2018 20 4 2018 97 16 e03687 7 2017 29 1 2018 7 3 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but potentially lethal inherited arrhythmia syndrome induced by adrenergic stress. Due to the atypical clinical manifestations in early age, limited recognition and experience of pediatric cardiologists, and low awareness of the significance of genetic diagnosis in some underdeveloped areas in China, a delayed or missed diagnosis of CPVT in children is common and concerning.\n\nPatient concerns:\nA 9-year and 3-month male child with recurrent exercise-induced syncope accompanied by convulsion was initially misdiagnosed as epilepsy since the first manifestation at the age of 3 years. Due to the identification of polymorphic ventricular premature beats, nonsustained ventricular tachycardia (VT), and supraventricular tachycardia, a cardiogenic etiology was established. The patient received a successive treatment by propafenone, amiodarone, a combination of amiodarone with metoprolol, and metoprolol alone for up to 6 years.\n\nDiagnoses:\nGiven the poor response to conventional antiarrhythmics, excise-induced syncope, QRS morphology and a structurally normal heart, the diagnosis of CPVT was suspected, and ultimately confirmed by detection of polymorphic and bidirectional VT with degeneration into ventricular fibrillation during exercise testing. In addition, a heterozygous mutant of RYR2 at c.7580T > G was identified by genetic testing.\n\nInterventions:\nDue to the unavailability of flecainide in China and the refusal of implantable cardioverter defibrillator implantation by his parents, this patient continued to be treated with oral metoprolol.\n\nOutcomes:\nUnfortunately, the effect was unfavorable during 4 months outpatient follow-up.\n\nLessons:\nCPVT should be suspected in young patients with a normal baseline electrocardiogram (EKG), a structurally normal heart and polymorphic and/or bidirectional ventricular tachycardia induced by exercise or emotional stress. Exercise and genetic testing is essential and significant for a timely and accurate diagnosis of CPVT. The current study firstly reported a case with CPVT associated with a mutant of RYR2 at c.7580T > G in children.\n\nKeywords\ncatecholaminergic polymorphic ventricular tachycardiachildrendelayed diagnosisRYR2OPEN-ACCESSTRUE\n==== Body\n1 Introduction\nCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by syncope and cardiac arrest occurring in children and young adults with morphologically normal hearts and normal baseline electrocardiograms (EKGs). Cardiac events are induced by sympathetic activation and physiological release of catecholamine during physical or emotional stress.[1] The hallmark sign of CPVT manifests as ectopic beats, bigeminy, and polymorphic or bidirectional ventricular tachycardia (VT).[1] Patients with CPVT typically present to medical attention most frequently during childhood or early adolescence, and the mean age at first symptom is 10 years.[1,2] It belongs to a group of inheritable disorders termed as “channelopathies,” caused by gene mutations encoding channel-proteins responsible for calcium homeostasis in cardiomyocytes.[3] Two main genetic variants have been identified as causative factors for CPVT: RyR2, encoding the cardiac ryanodine receptor; CASQ2, encoding cardiac calsequestrin.[2,3] Therefore, genetic testing is always quite essential and important to unveil the diagnosis for those cases with a clinical suspicion of CPVT, such as syncope occurring during exercise or the young children with genotype-positive family histories.\n\nAlthough it is a rare disease, with a prevalence estimated at 1:10,000 in population, early and prompt recognition of CPVT is clinically substantial due to its high mortality rate of up to 50% in severely affected untreated patients by the age of 20 years.[1] However, it is always difficult to establish a timely and accurate diagnosis due to a normal cardiac imaging, unremarkable baseline EKG, and commonly misattributed syncope episodes, thus leaving the patients untreated and exposed to arrhythmic risk. Children with CPVT are usually more severely affected than adults. The clinical presentations of affected individuals with younger age are more atypical in comparison with the older ones, some of whom even experience sudden unexpected death.[4] In addition, due to the limited recognition and experience of pediatric cardiologists and low awareness of the significance of genetic testing in the accurate diagnosis of CPVT in some underdeveloped areas in China, a delayed or missed diagnosis of CPVT in children is always more common and concerning. Here we reported 1 substantially delayed diagnosis of CPVT with RYR2 7850T>G mutant for up to 6 years since the symptom onset at the young age of 3 years old, aiming to share some experience and improve the recognition of CPVT for the pediatric cardiologists, particularly in developing countries.\n\n2 Case report\nThe case was a 9-year and 3-month male child, who experienced recurrent episodes of syncope accompanied by convulsion, was misdiagnosed as epilepsy since the first manifestation at the age of 3 years. Exercise-induced syncope followed by generalized tonic-clonic spasms had been noted since symptom onset. However, there was no positive family history of sudden cardiac death (SCD), seizure, pregnancy loss, and neonatal death. He was admitted to our pediatric cardiovascular department for the first time because of being unresponsive to 3 months of the antiepileptic treatment (sodium valproate, 20 mg/kg per day). On arrival, he was clear, afebrile, no tachycardia, no tachypnea, no hypotension (blood pressure: 90/47 mm Hg), and no hypoxia (SpO2: 97%). The vital signs were stable, and no positive findings were identified by physical examination.\n\nBlood routine, blood electrolytes, blood glucose, blood gas analysis, myocardial troponin, autoantibody, antistreptolysin O, acute phase protein, and thyroid function were unremarkable. Liver function test and creatinine level were also normal. Computed tomography and magnetic resonance imaging (MRI) of brain without enhancement did not reveal any intracranial hemorrhages, ischemic changes, or space-occupying lesions. Electroencephalogram detected no epileptiform discharge. Chest X-rays showed a mildly increased cardiothoracic ratio (0.53). The echocardiography detected mild mitral and tricuspid valve regurgitation without other remarkable findings. A 12-lead EKG showed sinus bradycardia (heart rate [HR]: 45 bpm), normal atrioventricular and intraventricular conduction and normal QT interval (corrected QT interval [QTc]: 435 ms). Repeated 24-h Holter monitoring demonstrated polymorphic ventricular premature beats (VPBs) (bigeminy and trigeminy), nonsustained VT, and supraventricular tachycardia (SVT). Regrettably, due to the lack of knowledge about CPVT, exercise stress testing was not undergone to further explore the underlying etiology resulting in arrhythmia. Oral administration of propafenone (15 mg/kg per day) was initiated, and the patient was discharged, taking periodic outpatient follow-up. However, it was proved to be noneffective after more than 2 years of follow-up. At the age of 5 years and 11 months, he was hospitalized again in our department because of more severe episodes of exercise-induced syncope and convulsion. At this time, sinus bradycardia (58 bpm), polymorphic VTs, and VPBs (trigeminy and bigeminy) on EKGs became more prominent. For the echocardiography, mildly dilated left ventricle with normal systolic function was noted. Thus, propafenone was discontinued, and oral amiodarone (loading dose: 15 mg/kg per day; maintenance dose: 5 mg/kg per day) was prescribed. Yet he was refractory to the amiodarone therapy, and experienced recurrent arrhythmic events at exercise or emotional stress during outpatient flow-up. Based on phases of QT interval prolongation (QTc 460–475 ms) observed on Holter monitoring, dose of amiodarone was gradually tapered. At the third admission, the patient received a combination of amiodarone (3 mg/kg per day) with metoprolol (initial dose: 0.4 mg/kg per day; maximal dose: 2 mg/kg per day), and subsequently metoprolol alone due to phases of QT prolongation. However, the effects seemed discouraging as well. On account of the excise-induced syncope, QRS morphology, a structurally normal heart, poor response to conventional antiarrhythmics (propafenone, amiodarone, and metoprolol) (Fig. 1) and a review of the literature, an increased clinical suspicion of CPVT was initiated, and exercise testing was performed. Encouragingly, on exercise testing, polymorphic VPB (bigeminy and couplets), polymorphic and bidirectional VT with degeneration into ventricular fibrillation were detected during exercise (Fig. 2). In light of the above findings, a clinical diagnosis of CPVT was established.\n\nFigure 1 The syncope episodes per year since initiation of antiarrhythmic treatment.\n\nFigure 2 Electrocardiographic manifestations on exercise testing for this patient. (A) The baseline EKG characterized by sinus bradycardia (HR, 46 bpm), normal atrioventricular and intraventricular conduction and normal QT interval (QTc 438 ms); (B–E) during exercise, starting with bigeminal ventricular premature beats and polymorphic couplets (B), nonsustained polymorphic and bidirectional ventricular tachycardia developed (C and D), ending with degeneration into ventricular fibrillation (E); (F) ventricular arrhythmia was reverted to sinus rhythm after exercise termination. HR = heart rate, QTc = corrected QT interval.\n\nBased on the sequencing analysis, a heterozygous mutant of RYR2 at c.7580T>G had been identified, where nucleotide 7580 changed from T (Thymine) to G (Guanine) in exon 50, while his parents and sibling were wild types (Fig. 3). As RYR2 mutant might also be associated with arrhythmogenic right ventricular dysplasia (ARVD), we reviewed the clinical manifestations and related examinations (such as cardiac MRI) and excluded the possibility of ARVD. Because mutation of RYR2 gene was the most frequent variant of CPVT, the diagnosis was ultimately confirmed genetically up to 6 years later since the symptom onset at the young age of 3 years old.\n\nFigure 3 The results of genetic sequencing that indicated a newly single mutant of RYR2 at c.7580T>G in absence of parents’ and sibling's findings.\n\nAccording to 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of SCD,[3] this patient continued to be treated with oral metoprolol (maximal tolerated dose: 3 mg/kg per day). Unfortunately, the effect was unfavorable during 4 months follow-up (Fig. 1). As the recommended flecainide[3] is unavailable in our country, implantable cardioverter defibrillator (ICD) therapy was suggested. Nevertheless, his parents refused to have an ICD implantation due to the economic factor and the possible related complications. This patient continued to be treated with oral metoprolol and followed up in our outpatient department.\n\n3 Discussion\nCPVT is one of the most lethal cardiac channelopathies, which mainly occurs during children or early adolescents.[2] However, the recognition and diagnosis are clinically challenging attributed to normal resting EKGs, and a structurally normal heart. Since CPVT-related syncope might be associated with convulsion, children are likely to be initially misdiagnosed as a noncardiogenic entity (such as epilepsy), especially for the patients younger than 8 years,[5] which is in consistence with the condition of the case reported in the present study. In this case, the presenting symptom was attributed to arrhythmic conditions according to the positive findings on Holter recording during the first admission, when antiepileptic drug was found to be ineffective. Notably, in spite of the arrhythmia refractory to conventional therapy, it took such a long time to gain enough clinical suspicion of CPVT and then specific tests were performed. The difficulty to recognize CPVT patients was reported by Roston et al, who found in a study on 226 CPVT patients that the establishment of diagnosis was approximately 2 years after the first symptomatic episode.[6] In addition, more than 60% of patients received a missed diagnosis at the initial evaluation.[5]\n\nAccording to current guidelines,[3] the clinical diagnosis of CPVT is based on the documented polymorphic VT induced by adrenergic stimuli, that is, emotions or exercise, in patients in absence of any other structural or electrical cardiac abnormality. The bidirectional VT (characterized by a 180° beat-to-beat rotation of the ectopic QRS complexes) detected at exercise testing is another highly specific sign of CPVT. Despite the often unremarkable baseline EKGs present in CPVT patients, some features, such as sinus bradycardia, SVT, and phases of QT prolongation, detected in the present case, may help the pediatricians to identify affected individuals. First, most CPVT patients demonstrate a prominent sinus bradycardia in resting EKG, which may be a consequence of the diastolic calcium leakage from the ryanodine receptor, resulted from either RyR2 or CASQ2 mutations.[7] Second, supraventricular arrhythmias, consisting of isolated atrial premature beat, SVT, and bursts of atrial fibrillation, are common in CPVT.[1] In addition, prominent U waves, dynamic in their appearance, are often found in CPVT patients, whose genesis and significance are not yet fully clarified. Finally, although a rare phenomenon, QT prolongation has been recently described in subjects with CPVT.[8]RYR2 gene mutation, which was detected in 6% of unrelated, genotype-negative long QT syndrome referrals, was hypothesized as responsible for arrhythmogenic after depolarizations of bradycardia-related acquired long QT syndrome.[9,10] These findings suggest that CPVT may be under-recognized among affected individuals because of a missed diagnosis. Thus, a diagnosis of “atypical long QT syndrome” may warrant suspicion of CPVT and the genetic analysis of RYR2, if the standard gene screen for long QT syndrome is negative. However, as the phases of QT prolongation in this case became present in the process of amiodarone treatment, it was unclear whether this phenomenon was directly related to the suffering disease or it was drug-induced.\n\nCPVT is recognized as a genetic disease associated with pathogenic variants of calcium handling genes. Therefore, genetic testing is significant for diagnosis confirmation, particularly in atypical cases or asymptomatic carriers. To date, 6 disease-causing genes have been identified, and the inheritance patterns may be autosomal dominant (RyR2, KCNJ2, CALM1, and CALM2) or recessive (CASQ2 and TRDN). According to the current guidelines,[3] genetic testing was performed to this case, revealing a pathogenic mutation of RyR2 gene occurred in the patient. RyR2 variant is the most frequent form of CPVT, responsible for up to 60% of the cases.[10] RyR2 is a large channel-protein, located within the sarcoplasmic reticulum, which is a pivotal component of calcium homeostasis and associated excitation-contraction coupling in the cardiomyocyte.[11] Genetic alterations in the RyR2 gene increase spontaneous diastolic calcium release from the sarcoplasmic reticulum, produce delayed after depolarization, and thereby trigger life-threatening ventricular arrhythmias under catecholaminergic stimulation.[11] Since RYR2 mutations may be a cause of adrenergically mediated idiopathic ventricular fibrillation,[12] we postulated that the ventricular fibrillation triggered by exercise testing might be in such instance, which was very rare in other CPVT cases. In addition, it was reported that patients with RyR2 CPVT became symptomatic earlier, remained symptomatic despite being treated, and was at higher risk of cardiac events in males,[2] which is consistent with the clinical features of this case. Moreover, as the new mutant on RYR2 c.7580T>G found in our study could result in the alteration of encoded amino acid sequence, we hypothesized that the altered physiologically important conformation of RYR2 protein would render the channel more sensitive to stimuli, leading to channel dysfunction. The new mutant might shed some light on the understanding of RYR2 function and its roles in CPVT if it could be further confirmed in more clinical samples and unraveled through structure-function analysis.\n\nUnfortunately, the missed and delayed diagnosis of the patient contributed to his recurrent arrhythmogenic episode. According to current guidelines,[3] preventive and therapeutic strategies in this case were based on close follow-up, extreme sport restriction, reduction in exposure to stressful situations, and pharmacological treatment with beta-blockers. Remarkably, up to one-third of CPVT patients, even with appropriate use of beta-blockers, may experience recurrent cardiac events or manifest persistence of complex arrhythmias at exercise stress testing.[10] Considering that the parents of the patient refused ICD implantation, compliance with exercise restriction and medical therapy should be emphasized to prevent recurrent cardiac events. Meanwhile, flecainide, showing direct RYR2 blocking properties,[13] might be purchased from abroad. In addition, it is well known that renal sympathetic nerve (RSN) plays an important role in modulation of central sympathetic activity. RSN activation could increase cardiac and systemic sympathetic activity and promote the incidence of ventricular arrhythmias, suggesting renal sympathetic denervation (RSD) may be a potential alternative treatment modality for VT and it has been proved to be effective in several case reports and series.[14] Recently, Aksu et al[15] reported a case of successful catheter-based RSD in a 44-year-old man diagnosed with CPVT unresponsive to medical therapy and endocardial ablation procedure. This technique may be an alternative strategy in patients who refused ICD implantation like the present case. Nevertheless, to our knowledge, the efficacy of RSD in management of CPVT has merely been explored in adult patients, while no trials of RSD therapy have been described in children. Based on complexity of this procedure and less well-established evidence to qualify its efficacy in pediatric patients, RSD was not suggested to his parents in our study.\n\n4 Conclusions\nCPVT is a rare but potentially lethal inherited arrhythmia syndrome induced by adrenergic stress. A delay to diagnosis is substantial due to the low awareness and recognition of the condition and ignorance about the importance of genetic testing, which remain challenges to overcome in the future, particularly in developing countries. In despite of a normal baseline EKG and structurally normal heart, a more thorough clinical history, some features in baseline EKGs (e.g., sinus bradycardia, SVT, and phases of QT prolongation) and polymorphic and/or bidirectional VT induced by exercise or emotional stress can increase clinical suspicion. Exercise testing is essential in making the diagnosis of CPVT. Importantly, Genetic testing is a significant tool for a timely and accurate diagnosis of CPVT. The current study firstly reported a case with CPVT associated with a newly identified mutant of RYR2 at c.7580T>G in children.\n\nAuthor contributions\nData curation: Song Yan.\n\nFormal analysis: Hongyu Duan.\n\nMethodology: Yongyi Lu, Yifei Li.\n\nSupervision: Yimin Hua, Kaiyu Zhou.\n\nValidation: Lina Qiao.\n\nWriting – original draft: Chuan Wang.\n\nAbbreviations: ARVD = arrhythmogenic right ventricular dysplasia, BP = blood pressure, CPVT = catecholaminergic polymorphic ventricular tachycardia, CT = computed tomography, EKG = electrocardiogram, HR = heart rate, ICD = implantable cardioverter defibrillator, MRI = magnetic resonance imaging, QTc = corrected QT interval, RSD = renal sympathetic denervation, RSN = renal sympathetic nerve, SCD = sudden cardiac death, SVT = supraventricular tachycardia, VPB = ventricular premature beat, VT = ventricular tachycardia.\n\nHD and YL contributed equally to this article.\n\nWe thank the funding supporters [National Natural Science Foundation of China (No. 81602817, No. 81741026, and No. 81571515), Science-technology Support Plan Projects in Sichuan province (No. 2016FZ0088, and No. 2017SZ0117). The authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Leenhardt A Lucet V Denjoy I \nCatecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients . Circulation \n1995 ;91 :1512 –9 .7867192 \n[2] Priori SG Napolitano C Memmi M \nClinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia . Circulation \n2002 ;106 :69 –74 .12093772 \n[3] Priori SG Blomström-Lundqvist C Mazzanti A \n2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC) . Eur Heart J \n2015 ;36 :2793 –867 .26320108 \n[4] Hayashi M Denjoy I Extramiana F \nIncidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia . Circulation \n2009 ;119 :2426 –34 .19398665 \n[5] Kawata H Ohno S Aiba T \nCatecholaminergic polymorphic ventricular tachycardia (CPVT) associated with ryanodine receptor (RyR2) gene mutations—long-term prognosis after initiation of medical treatment . Circ J \n2016 ;80 :1907 –15 .27452199 \n[6] Roston TM Vinocur JM Maginot KR \nCatecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry . Circ Arrhythm Electrophysiol \n2015 ;8 :633 –42 .25713214 \n[7] Neco P Torrente AG Mesirca P \nParadoxical effect of increased diastolic Ca(2+) release and decreased sinoatrial node activity in a mouse model of catecholaminergic polymorphic ventricular tachycardia . Circulation \n2012 ;126 :392 –401 .22711277 \n[8] Tanaka Y Kawabata M Scheinman MM \nCatecholaminergic polymorphic ventricular tachycardia with QT prolongation . Pacing Clin Electrophysiol \n2015 ;38 :1499 –502 .26256814 \n[9] Tester DJ Kopplin LJ Will ML \nSpectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing . Heart Rhythm \n2005 ;2 :1099 –105 .16188589 \n[10] Imberti JF Underwood K Mazzanti A \nClinical challenges in catecholaminergic polymorphic ventricular tachycardia . Heart Lung Circ \n2016 ;25 :777 –83 .26948768 \n[11] Lanner JT \nRyanodine receptor physiology and its role in disease . Adv Exp Med Biol \n2012 ;740 :217 –34 .22453944 \n[12] van der Werf C Wilde AA \nCatecholaminergic polymorphic ventricular tachycardia: from bench to bedside . Heart \n2013 ;99 :497 –504 .23390049 \n[13] Watanabe H Chopra N Laver D \nFlecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans . Nat Med \n2009 ;15 :380 –3 .19330009 \n[14] Huang B Scherlag BJ Yu L \nRenal sympathetic denervation for treatment of ventricular arrhythmias: a review on current experimental and clinical findings . Clin Res Cardiol \n2015 ;104 :535 –43 .25596725 \n[15] Aksu T Güler TE Özcan KS \nRenal sympathetic denervation assisted treatment of electrical storm due to polymorphic ventricular tachycardia in a patient with cathecolaminergic polymorphic ventricular tachycardia . Turk Kardiyol Dern Ars \n2017 ;45 :441 –9 .28694398\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(16)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D002648:Child; D016757:Death, Sudden, Cardiac; D057210:Delayed Diagnosis; D004562:Electrocardiography; D005080:Exercise Test; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008790:Metoprolol; D009154:Mutation; D005082:Physical Exertion; D011405:Propafenone; D019837:Ryanodine Receptor Calcium Release Channel; D013575:Syncope; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e0368",
"pmc": null,
"pmid": "29668588",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27452199;23390049;25713214;19398665;26256814;28694398;25596725;22711277;26948768;16188589;19330009;26320108;7867192;12093772;22453944",
"title": "A delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia with a mutant of RYR2 at c.7580T>G for 6 years in a 9-year-old child.",
"title_normalized": "a delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia with a mutant of ryr2 at c 7580t g for 6 years in a 9 year old child"
} | [
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"companynumb": "CN-MYLANLABS-2018M1054619",
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"activesubstance": {
"activesubstancename": "METOPROLOL"
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"abstract": "OBJECTIVE\nThis study was carried out to determine the maternal (including thromboembolic and hemorrhagic complications) and fetal outcomes (including miscarriage, stillbirth, baby death, and live birth) in women with mechanical heart valves managed with therapeutic doses of unfractionated heparin (UFH) versus enoxaparin during pregnancy.\n\n\nMETHODS\nThis is a prospective comparative, nonrandomized study. Pregnant women with mechanical heart valves presenting to high-risk pregnancy unit of Benha University Hospital, Egypt were treated with UFH 15,000 U/12 h versus enoxaparin (Clexane) 1 mg/kg SC/12 h during pregnancy and the results were analyzed.\n\n\nRESULTS\n40 pregnant women were included in the study. In 20 pregnant women, anticoagulation was with UFH, and 20 pregnant women received enoxaparin. One (3 %) thrombotic complication occurred with enoxaparin treatment. Noncompliance or subtherapeutic levels contributed to this outcome in this case. Antenatal hemorrhage occurred in 4 (10 %) and postpartum hemorrhagic complications in 5 (12.5 %) pregnancies. Of the 32 pregnant women who continued after 20 weeks' gestation, 100 % (17/17) of the women taking predominantly UFH had a surviving infant compared with 93 % (14/15) of the women taking primarily enoxaparin (p = 0.25). One intrauterine fetal death occurred in the enoxaparin group. There was no significant difference in the live birth rates between the two groups (p = 0.31).\n\n\nCONCLUSIONS\nCompliance with therapeutic dose of UFH during pregnancy in women with mechanical heart valves is associated with a low risk of valve thrombosis and good fetal outcomes, but meticulous monitoring is essential.",
"affiliations": "Benha Faculty of Medicine and Benha University Hospital, Benha University, Egypt, El Qulyobia Governorate, El Sadat Street, Benha City, Egypt.;Benha Faculty of Medicine and Benha University Hospital, Benha University, Egypt, El Qulyobia Governorate, El Sadat Street, Benha City, Egypt.;Benha Faculty of Medicine and Benha University Hospital, Benha University, Egypt, El Qulyobia Governorate, El Sadat Street, Benha City, Egypt.",
"authors": "Khader|Khalid Abd Aziz Mohamad|KA|;Saad|Ahmed Samy|AS|;Abdelshafy|Mohammed|M|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s13224-015-0678-9",
"fulltext": null,
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"issn_linking": "0975-6434",
"issue": "66(5)",
"journal": "Journal of obstetrics and gynaecology of India",
"keywords": "Enoxaparin; Pregnancy; Prosthetic heart valves; Thromboembolism; UFH",
"medline_ta": "J Obstet Gynaecol India",
"mesh_terms": null,
"nlm_unique_id": "0374763",
"other_id": null,
"pages": "321-6",
"pmc": null,
"pmid": "27486276",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": "12142189;18574280;8636556;16053950;16875962;11777507;15793047;16966122;11568791;10647757;15467581;17599871;1636585;15821823;3947472;15543433;18042775;14712967;17251669;15804785;6985765;12628941;7934533;15467905",
"title": "Pregnancy Outcome in Women with Mechanical Prosthetic Heart Valves Treated with Unfractionated Heparin (UFH) or Enoxaparin.",
"title_normalized": "pregnancy outcome in women with mechanical prosthetic heart valves treated with unfractionated heparin ufh or enoxaparin"
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"abstract": "BACKGROUND\nDaclizumab is a monoclonal antibody directed against the alpha chain of the interleukin 2 receptor. We review our experience with the use of daclizumab in liver transplant recipients.\n\n\nMETHODS\nThirty-two patients were given daclizumab as induction therapy in the setting of hepatic transplantation. Seven of these patients were enrolled in a pilot study to determine the efficacy of daclizumab in conjunction with corticosteroids and mycophenolate mofetil without the initial use of calcineurin inhibitors (CI). The remaining 25 patients received daclizumab, mycophenolate mofetil, and steroids, with the institution of CI generally within the first postoperative week. The majority of these patients (n = 17) had some degree of renal insufficiency.\n\n\nRESULTS\nThe pilot study was halted after the first seven patients were enrolled because of an unacceptably high rate of rejection (7/7 = 100%). The patients outside of this pilot study, however, had a much lower rate of rejection (36%). The incidence and severity of rejection correlated with the delay in institution of CI. The described dosing schedule resulted in subtherapeutic daclizumab levels in liver transplant recipients.\n\n\nCONCLUSIONS\nDaclizumab used in liver transplant recipients without any CI was ineffective and can potentially lead to steroid-resistant rejection. The dosing regimen used in renal transplant recipients is most likely insufficient for liver transplant patients. However, daclizumab can be used safely in patients with preexisting or postoperative renal dysfunction in conjunction with low doses of CI given within the first week postoperatively.",
"affiliations": "Department of Surgery, University of California, San Francisco 94143, USA.",
"authors": "Hirose|R|R|;Roberts|J P|JP|;Quan|D|D|;Osorio|R W|RW|;Freise|C|C|;Ascher|N L|NL|;Stock|P G|PG|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D065095:Calcineurin Inhibitors; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D000077561:Daclizumab; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/00007890-200001270-00019",
"fulltext": null,
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"issn_linking": "0041-1337",
"issue": "69(2)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D065095:Calcineurin Inhibitors; D002648:Child; D000077561:Daclizumab; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D015994:Incidence; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D010865:Pilot Projects; D011446:Prospective Studies; D051437:Renal Insufficiency; D016559:Tacrolimus",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "307-11",
"pmc": null,
"pmid": "10670644",
"pubdate": "2000-01-27",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Experience with daclizumab in liver transplantation: renal transplant dosing without calcineurin inhibitors is insufficient to prevent acute rejection in liver transplantation.",
"title_normalized": "experience with daclizumab in liver transplantation renal transplant dosing without calcineurin inhibitors is insufficient to prevent acute rejection in liver transplantation"
} | [
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"companynumb": "US-ROCHE-1884857",
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"activesubstancename": "SIROLIMUS"
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"abstract": "We report the first case of hypotensive episodes associated with intravenous (IV) azithromycin. This is a potentially fatal adverse drug reaction (ADR), with the risk of irreversible end-organ damage, and therefore must be recognized and treated immediately. In our case, the reaction was successfully managed by immediate cessation of the azithromycin infusion. It is important for clinicians to be aware of this ADR as azithromycin is a commonly prescribed medication worldwide.",
"affiliations": "Department of Respiratory Medicine The Alfred Hospital Melbourne Victoria Australia.;Department of Respiratory Medicine The Alfred Hospital Melbourne Victoria Australia.;Department of Respiratory Medicine The Alfred Hospital Melbourne Victoria Australia.;Department of Respiratory Medicine The Alfred Hospital Melbourne Victoria Australia.;Department of Respiratory Medicine The Alfred Hospital Melbourne Victoria Australia.",
"authors": "Wong|Jeffrey|J|https://orcid.org/0000-0003-4270-405X;Munsif|Maitri|M|;O'Hehir|Robyn|R|;Hew|Mark|M|;Dabscheck|Eli|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/rcr2.464",
"fulltext": "\n==== Front\nRespirol Case RepRespirol Case Rep10.1002/(ISSN)2051-3380RCR2Respirology Case Reports2051-3380John Wiley & Sons, Ltd Chichester, UK 10.1002/rcr2.464RCR2464Case ReportCase ReportsHypotensive episodes associated with azithromycin infusion: a potentially fatal adverse drug reaction Hypotensive episodes with azithromycinJ. Wong et al.Wong Jeffrey https://orcid.org/0000-0003-4270-405X\n1\nMunsif Maitri \n1\nO'Hehir Robyn \n1\nHew Mark \n1\nDabscheck Eli e.dabscheck@alfred.org.au \n1\n\n1 \nDepartment of Respiratory Medicine\nThe Alfred Hospital\nMelbourne\nVictoria\nAustralia\n* Correspondence\n\nEli Dabscheck, Department of Respiratory Medicine, The Alfred Hospital, Level 2, 55 Commercial Road, Melbourne, VIC 3004, Australia. E‐mail: e.dabscheck@alfred.org.au\n05 8 2019 10 2019 7 7 10.1002/rcr2.v7.7e0046430 5 2019 23 6 2019 24 6 2019 © 2019 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of RespirologyThis 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.We report the first case of hypotensive episodes associated with intravenous (IV) azithromycin. This is a potentially fatal adverse drug reaction (ADR), with the risk of irreversible end‐organ damage, and therefore must be recognized and treated immediately. In our case, the reaction was successfully managed by immediate cessation of the azithromycin infusion. It is important for clinicians to be aware of this ADR as azithromycin is a commonly prescribed medication worldwide.\n\nAntibioticsazithromycinhypotensionpneumonia source-schema-version-number2.0component-idrcr2464cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:05.08.2019\n\n\nWong , J \n, \nMunsif , M \n, \nO'Hehir , R \n, \nHew , M \n, \nDabscheck , E \n. (2019 ) Hypotensive episodes associated with azithromycin infusion: a potentially fatal adverse drug reaction . Respirology Case Reports , 7 (7 ), ;e00464. 10.1002/rcr2.464 \n\n\n\nAssociate Editor: Tow Keang Lim\n==== Body\nIntroduction\nWe report the first case of hypotensive episodes associated with intravenous (IV) azithromycin administration. It is a potentially fatal complication and must be recognized and treated immediately.\n\nCase Report\nA 64‐year old male Caucasian ex‐smoker with a 9‐year history of severe interstitial lung disease (ILD) presented with dyspnoea. Blood tests showed elevated inflammatory markers, and chest imaging demonstrated a new bilateral infiltrate consistent with the diagnosis of severe community‐acquired pneumonia. He was prescribed daily IV azithromycin of 500 mg and IV ceftriaxone of 1 g and was admitted to the ward.\n\nHis past medical history included well‐controlled type 1 diabetes mellitus and psoriasis. He had no prior known drug allergies. On multiple previous admissions, the patient had received ceftriaxone and piperacillin/tazobactam (Tazocin) without complications.\n\nOn the medical ward, he became hypotensive with a drop of blood pressure from 100/70 to 60/30 mmHg. His oxygen saturation dropped from 97 to 60%, and he became tachypnoeic (26 breaths/min), peripherally cyanotic, and unresponsive with a Glasgow Coma Scale (GCS) score of 3. The patient spontaneously regained consciousness after 20 s without adrenaline use. His GCS returned to 15 within 5 min. After the episode, the patient reported feeling warm, flushed, sweaty, and nauseated. There was no associated laryngeal angioedema, rash, or fever during this episode. He was admitted to the intensive care unit (ICU) for further evaluation.\n\nSerum troponins, sputum analysis, viral polymerase chain reaction (PCR), chest X‐ray, ventilation‐perfusion (V/Q) scan, and duplex ultrasound of the lower limbs were all unremarkable. The electrocardiogram (ECG) performed at the time of the episode and as a repeat ECG showed no arrhythmias; however, corrected QT interval (QTc) was slightly prolonged on both occasions (QTc = 471 and 491 ms, respectively). His blood glucose level was high (15.1 mmol/L); serum urea, electrolyte, and creatinine (UECs) showed mild acute kidney injury (Creatinine 114 μmol/L, estimated glomerular filtration rate 59 mL/min); and liver function tests (LFTs) were mildly deranged (Albumin = 31 g/L, alanine aminotransferase = 63 U/L, gamma‐glutamyl transferase = 229 U/L, alkaline phosphatase = 214 U/L). Serial serum tryptase measurements were within the normal limits on three occasions (immediate, 2 h, and 24‐h).\n\nOver the course of 2 days in the ICU on the monitor, he experienced two further hypotensive episodes. Only after the third episode did his medical team realize that all episodes had occurred during the azithromycin infusion, with resolution immediately upon infusion cessation. Azithromycin was then discontinued, with no subsequent recurrences. Telemetry throughout ICU admission showed no evidence of any arrhythmias.\n\nDiscussion\nThere have been no reported cases of immediate hypotensive episodes with IV azithromycin infusion in the literature. Azithromycin is widely prescribed for severe community‐acquired pneumonia. The most common adverse effects with azithromycin (both oral and IV) are gastrointestinal side effects such as nausea, diarrhoea, and abdominal pain 1, followed by hepatotoxicity 2, and QT prolongation leading to sudden cardiac death (SCD) 3.\n\nThe hypotensive episodes are likely an adverse drug reaction (ADR) following azithromycin infusion. This does not constitute a typical drug‐induced anaphylactic reaction as there was no angioedema, limited respiratory impairment beyond slight tachypnoea, and no mucocutaneous involvement. The reactions were self‐resolving without the use of adrenaline and did not cause an elevation in serial serum tryptase measurements. Drug‐induced anaphylaxis is usually associated with elevated serum tryptase. The reaction was not due to the ceftriaxone infusion as the patient had received ceftriaxone on multiple previous admissions without complications, and there was no clear temporal relationship as opposed to azithromycin.\n\nAccording to the current literature, azithromycin use has not been shown to cause hypotensive episodes. However, three studies concluded that there is an increased risk of hypotension or shock with the co‐prescription of calcium‐channel blockers and macrolide antibiotics, specifically erythromycin and clarithromycin but not azithromycin 4, 5, 6. In our case, the patient was not on any concurrent antihypertensive medications.\n\nA meta‐analysis on macrolides and cardiovascular risk showed that azithromycin use is 3.4 times more likely to cause SCD or ventricular tachyarrhythmias (VTA) 3. In our case, there were no abnormal findings on ECG.\n\nA few case reports have also outlined Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome in adults 7 and children 8, 9 upon azithromycin administration. However, in our case, there was no mucocutaneous involvement and no accompanying peripheral eosinophilia.\n\nIn summary, we report the first case of hypotensive episodes following an infusion of IV azithromycin. It is important to recognize that hypotension could result from the administration of a commonly prescribed antibiotic. It is a potentially life‐threatening condition that may lead to irreversible organ dysfunction and death if left untreated. The current consensus guidelines in managing an ADR is to immediately cease its administration, and that exact management was sufficient for our patient without requiring other measures such as adrenaline. We would like to emphasize the lessons learnt from our experience to recognize a potentially serious ADR. The awareness of this potential drug reaction could hopefully benefit future clinical practice worldwide.\n\nDisclosure Statement\nAppropriate written informed consent was obtained for publication of this case report and accompanying images.\n==== Refs\nReferences\n1 \n\nZuckerman \nJM \n. 2004 \nMacrolides and ketolides: azithromycin, clarithromycin, telithromycin . Infect. Dis. Clin. North Am. \n18 :621 –649 xi‐.15308279 \n2 \n\nMartinez \nMA \n, \nVuppalanchi \nR \n, \nFontana \nRJ \n, et al. 2015 \nClinical and histologic features of azithromycin‐induced liver injury . Clin. Gastroenterol. Hepatol. \n13 :369.e3 –76.e3 .25111234 \n3 \n\nCheng \nYJ \n, \nNie \nXY \n, \nChen \nXM \n, et al. 2015 \nThe role of macrolide antibiotics in increasing cardiovascular risk . J. Am. Coll. Cardiol. \n66 :2173 –2184 .26564594 \n4 \n\nGandhi \nS \n, \nFleet \nJL \n, \nBailey \nDG \n, et al. 2013 \nCalcium‐channel blocker‐clarithromycin drug interactions and acute kidney injury . JAMA \n310 :2544 –2553 .24346990 \n5 \n\nWright \nAJ \n, \nGomes \nT \n, \nMamdani \nMM \n, et al. 2011 \nThe risk of hypotension following co‐prescription of macrolide antibiotics and calcium‐channel blockers . CMAJ \n183 :303 –307 .21242274 \n6 \n\nCalcium channel blockers+macrolides \n: 2012 elderly patients hospitalised for low blood pressure. Prescrire Int 21 :182 . PMID: 22852287.\n7 \n\nSriratanaviriyakul \nN \n, \nNguyen \nLP \n, \nHenderson \nMC \n, et al. 2014 \nDrug reaction with eosinophilia and systemic symptoms syndrome (DRESS) syndrome associated with azithromycin presenting like septic shock: a case report . J Med Case Reports \n8 :332 .\n8 \n\nBauer \nKA \n, \nBrimhall \nAK \n, and \nChang \nTT \n. 2011 \nDrug reaction with eosinophilia and systemic symptoms (DRESS) associated with azithromycin in acute Epstein‐Barr virus infection . Pediatr. Dermatol. \n28 :741 –743 .22010986 \n9 \n\nSchmutz \nJL \n, and \nTrechot \nP \n. 2013 \nDRESS associated with azithromycin in a child . Ann. Dermatol. Venereol. \n140 :75 .23328369\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-3380",
"issue": "7(7)",
"journal": "Respirology case reports",
"keywords": "Antibiotics; azithromycin; hypotension; pneumonia",
"medline_ta": "Respirol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101631052",
"other_id": null,
"pages": "e00464",
"pmc": null,
"pmid": "31406576",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "15308279;21242274;22010986;22852287;23328369;24346990;25111234;25297051;26564594",
"title": "Hypotensive episodes associated with azithromycin infusion: a potentially fatal adverse drug reaction.",
"title_normalized": "hypotensive episodes associated with azithromycin infusion a potentially fatal adverse drug reaction"
} | [
{
"companynumb": "AU-EPIC PHARMA LLC-2019EPC00237",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null... |
{
"abstract": "High-dose intensification and autologous stem-cell transplantation (ASCT) is widely used to consolidate patients with non-Hodgkin's lymphoma (NHL), who have reached a stage of minimal residual disease. However, patients with persisting marrow and/or blood involvement and those who fail peripheral blood hemopoietic progenitor mobilization are excluded from ASCT. For such patients with no available graft to infuse, we developed 15 years ago, before the anti-CD20 monoclonal antibody therapeutic era, the use of the BEAM pretransplant regimen followed only by the administration of three cytokines (erythropoietin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor). We report here on the long-term follow-up of 33 patients treated with this approach. In all, 33 NHL patients underwent the BEAM (carmustine, VP-16, cytosine-arabinoside, melphalan) followed by the administration of the three cytokines from January 1994-2000. A backup marrow, albeit infiltrated by tumor cells, had been collected earlier and stored in all. A total of 30 patients (91%) recovered normal hematopoiesis. In total, 32 patients (97%) recovered neutrophils (>500/microl) at a median of 19 days and 30 patients (91%) recovered platelets (>20,000/microl) at a median of 26 days. Age, richness of backup graft and blood-hemoglobin level at intensification had an impact on the time for hematopoietic recovery (P=0.014, P=0.014, P=0.048). The median follow-up was 62 months. Five patients died from toxicity related to the procedure. Eight patients relapsed and died. A total of 20 patients (61%) are alive, 16 (49%) in complete remission. A 5-year disease-free survival was 52+/-9%, relapse incidence 35+/-16%, mortality due to the procedure 12+/-12% and overall survival 61+/-10%. The BEAM regimen is not myeloablative. The BEAM+3CK procedure is a feasible therapeutic option that has shown efficacy in poor risk NHL patients who were not eligible for autografting because of persisting marrow/blood tumor contamination, or poor hemopoietic progenitor harvesting. It is unclear today whether some of these patients would have cleared their marrow/peripheral blood with the additional use of anti-CD20 treatment, thereby making the classical approach (BEAM followed by the infusion of a clean autograft) feasible.",
"affiliations": "Department of Hematology and Cell Therapy, Hôpital Saint Antoine, Paris, France. jean-philippe.laporte@sat.ap-hop-paris.fr <jean-philippe.laporte@sat.ap-hop-paris.fr>",
"authors": "Laporte|J Ph|JP|;Yeshurun|M|M|;Fouillard|L|L|;Labopin|M|M|;Cailliot|C|C|;Lesage|S|S|;Isnard|F|F|;Najman|A|A|;Gorin|N-C|NC|",
"chemical_list": "D003561:Cytarabine; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008558:Melphalan; D002330:Carmustine",
"country": "England",
"delete": false,
"doi": "10.1038/sj.leu.2403427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-6924",
"issue": "18(10)",
"journal": "Leukemia",
"keywords": null,
"medline_ta": "Leukemia",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine; D003561:Cytarabine; D004359:Drug Therapy, Combination; D004921:Erythropoietin; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D015996:Survival Rate; D013997:Time Factors",
"nlm_unique_id": "8704895",
"other_id": null,
"pages": "1717-21",
"pmc": null,
"pmid": "15295607",
"pubdate": "2004-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A long-term follow-up of 33 patients with non-Hodgkin's lymphoma who received the BEAM high-dose intensification regimen with cytokine support only and no transplant.",
"title_normalized": "a long term follow up of 33 patients with non hodgkin s lymphoma who received the beam high dose intensification regimen with cytokine support only and no transplant"
} | [
{
"companynumb": "FR-PFIZER INC-2018148805",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Brivaracetam is a new antiepileptic drug with limited data in children. The objective of this study was to assess the efficacy/tolerability of brivaracetam. This is a retrospective chart review of children/adolescents with refractory epilepsy treated with brivaracetam from 2016 to 2018. The primary outcome was seizure reduction (decrease in seizure frequency >50%). Twenty-three patients were identified. Mean age at initiation was 12.5 years. Fourteen were females. Epilepsy was focal in 11, generalized in 6, and mixed in 3. Average dose was 3.9 mg/kg/d. The mean duration of treatment was 8.2 months. Eight had greater than 50% decrease in seizure frequency, of which 7 had focal epilepsy, and 1 had Lennox-Gastaut/mixed epilepsy. Two had drowsiness and 3 behavioral complaints. One experienced tingling and dizziness. Our retrospective review suggests that brivaracetam is an effective therapy for refractory focal epilepsy in children older than 4 years of age.",
"affiliations": "Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.;Department of Neurology, Hahnemann University Hospital, Drexel University College of Medicine, Philadelphia, PA, USA.;Department of Neurology, Hahnemann University Hospital, Drexel University College of Medicine, Philadelphia, PA, USA.;Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.;Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.;Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.;Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.;Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.;Section of Neurology, St. Christopher's Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.",
"authors": "McGuire|Sara|S|0000-0002-9745-6252;Silva|Gustavo|G|;Lal|Darshan|D|;Khurana|Divya S|DS|;Legido|Agustin|A|;Hasbani|Daphne|D|;Carvalho|Karen S|KS|;Melvin|Joseph|J|;Valencia|Ignacio|I|",
"chemical_list": "D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam",
"country": "United States",
"delete": false,
"doi": "10.1177/0883073819879276",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "35(2)",
"journal": "Journal of child neurology",
"keywords": "adolescents; brivaracetam; children; pediatrics; refractory epilepsy",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D011760:Pyrrolidinones; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "102-105",
"pmc": null,
"pmid": "31617449",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and Efficacy of Brivaracetam in Pediatric Refractory Epilepsy: A Single-Center Clinical Experience.",
"title_normalized": "safety and efficacy of brivaracetam in pediatric refractory epilepsy a single center clinical experience"
} | [
{
"companynumb": "US-UCBSA-2019048643",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nEarly detection of postoperative infectious complications (IC) is crucial after Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). The aim of this study was to evaluate the predictive role of early postoperative inflammatory biomarkers level for the detection of postoperative IC.\n\n\nMETHODS\na retrospective study was performed including 199 patients treated with complete CRS/HIPEC for PC from various primary origins from September 2012 to January 2021. Patients were monitored by a routine measurement of inflammatory biomarkers (CRP, leukocytes, neutrophils, lymphocytes, neutrophile-to-lymphocyte ratio and platelets-to-lymphocyte ratio). Inflammatory biomarkers were compared between patients with vs without IC.\n\n\nRESULTS\nIC occurred for 68 patients (34.2%). CRP values were significantly higher in patients with IC on POD 3, 5 and 7 (CRP = 166 mg/L [128-244], 155 mg/L [102-222] and 207 mg/L [135-259], respectively). The CRP on POD7, with a cut-off value of 100 mg/L, was an excellent predictor of postoperative IC (AUC = 90.1%). The CRP on POD 5, with a cut-off value of 90 mg/L, was a good predictor of postoperative IC (AUC = 83.2%). NLR values were significantly higher in patients with IC on POD 3, 5 and 7. NLR on POD 5 and 7 higher than 9.7 and 6.3, respectively, were fair predictors (AUC = 70.8 and 79.6, respectively).\n\n\nCONCLUSIONS\nCRP levels between POD3 and 7 are the best predictors of postoperative IC after CRS/HIPEC. The presence of postoperative IC should be suspected in patients with CRP higher than 140 mg/L, 90 mg/L or 100 mg/L on PODs 3, 5 or 7.",
"affiliations": "Department of Digestive and Endocrine Surgery, University Hospital of Reims, Reims, France; University of Champagne Ardenne, France. Electronic address: klamroun@chu-reims.fr.;Department of Digestive and Endocrine Surgery, University Hospital of Reims, Reims, France; University of Champagne Ardenne, France.;Department of Pharmacology and Toxicology, University Hospital of Reims, Reims, France; University of Champagne Ardenne, France.;Department of Digestive and Endocrine Surgery, University Hospital of Reims, Reims, France; University of Champagne Ardenne, France.;Department of Digestive Oncology, University Hospital of Reims, Reims, France; University of Champagne Ardenne, France.;Department of Digestive and Endocrine Surgery, University Hospital of Reims, Reims, France; University of Champagne Ardenne, France.;Department of Digestive and Endocrine Surgery, University Hospital of Reims, Reims, France; University of Champagne Ardenne, France.",
"authors": "Amroun|Koceila|K|;Scholer|Vincent|V|;Djerada|Zoubir|Z|;Renard|Yohann|Y|;Bouche|Olivier|O|;Rhaiem|Rami|R|;Kianmanesh|Reza|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.ejso.2021.09.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0748-7983",
"issue": null,
"journal": "European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology",
"keywords": "Cytoreductive surgery; Inflammatory biomarkers; Postoperative complications; Prediction",
"medline_ta": "Eur J Surg Oncol",
"mesh_terms": null,
"nlm_unique_id": "8504356",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34565632",
"pubdate": "2021-09-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Inflammatory biomarkers to predict postoperative infectious complications after cytoreductive surgery and HIPEC for peritoneal carcinomatosis.",
"title_normalized": "inflammatory biomarkers to predict postoperative infectious complications after cytoreductive surgery and hipec for peritoneal carcinomatosis"
} | [
{
"companynumb": "FR-AMGEN-FRASP2022081742",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": "4",
... |
{
"abstract": "In patients receiving pelvic irradiation for gynecological or genitourinary malignancies, urinary diversion is sometimes required for complete resection of malignancies or treatment of urological complications by irradiation. We report our attempts to promote healing and prevent complications by urinary diversion using a transverse colon conduit in cases in which urinary reconstruction was performed with irradiated lower abdominal organs such as small intestine or distal ureters. Between 2008 and 2012, 9 patients with pelvic irradiation received transverse colon conduit urinary diversion. Six patients received diversion for genitourinary complications, while 3 patients received complete resection of pelvic malignancies. Colostomy formation and lithotripsy of vesical stones were simultaneously performed in 4 cases. Wallace method was adopted for ureterointestinal anastomosis. There was no operative mortality. Although acute pyelonephritis, ileus, wound dehiscence and pelvic abscess formation were seen as postoperative complications, all but two improved without any additional procedure. Cases of pelvic abscess or wound dehiscence were treated by abscess drainage. In observation periods, no patients required urinary stent placement and none suffered from defecation problems. We think that transverse colon conduit can be a viable option for patients with pelvic irradiation history, affording them reasonable quality of life postoperatively.",
"affiliations": "The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Hyogo Collage of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.;The Department of Urology, Kyoto University Graduate School of Medicine.",
"authors": "Matsui|Yoshiyuki|Y|;Kanematsu|Akihiro|A|;Negoro|Hiromitsu|H|;Kobayashi|Takashi|T|;Terada|Naoki|N|;Sugino|Yoshio|Y|;Yamasaki|Toshinari|T|;Inoue|Takahiro|T|;Kamba|Tomomi|T|;Yoshimura|Koji|K|;Ogawa|Osamu|O|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "60(8)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000328:Adult; D000368:Aged; D044684:Colon, Transverse; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010388:Pelvis; D011471:Prostatic Neoplasms; D011878:Radiotherapy; D001749:Urinary Bladder Neoplasms; D014547:Urinary Diversion; D014594:Uterine Neoplasms",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "365-70",
"pmc": null,
"pmid": "25179985",
"pubdate": "2014-08",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Urinary diversion in patients treated with pelvic irradiation: transverse colon conduit revisited.",
"title_normalized": "urinary diversion in patients treated with pelvic irradiation transverse colon conduit revisited"
} | [
{
"companynumb": "JP-ROCHE-1465035",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Atypical femoral fracture (AFF) associated with bisphosphonate (BP) use is common, and its pathophysiology is considered to involve severely suppressed bone turnover. Surgical results following AFF fixation have not been optimal, with some cases resulting in delayed union or nonunion. Regarding bone healing, glucocorticoid (GC) has similar properties to BP. We investigated the surgical results of AFF fixation in both users of BP and GC, especially with regard to intraoperative fracture reduction. We included 12 AFFs in 11 patients with a follow-up over one year who all took GC for autoimmune disease and BP for management of GC-induced osteoporosis. Their mean age was 62 years and 10 patients were female. Six fractures were located in the subtrochanteric region of the femur and six were in the diaphysis. Intramedullary nails were used to treat all fractures. Union rate was recorded, and the status of the reduction immediately after the operation was analyzed. Four of the 12 cases developed nonunion, and three of them required additional surgery. The relationship between alignment, cortical continuity, fracture gap, and bone union was not significant. In the nonunion cases, cortical continuity on the anteroposterior and lateral views were never confirmed. Even if cortical continuity in either of the views was there, the two limbs resulted in nonunion. One third of the patients with AFF secondary to long-term BP and GC use developed nonunion despite their fracture reductions being acceptable. We consider strict reduction should be needed for these cases with disadvantage condition to bone union.",
"affiliations": "Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.",
"authors": "Nishino|Tomofumi|T|;Hyodo|Kojiro|K|;Matsumoto|Yukei|Y|;Yanagisawa|Yohei|Y|;Yoshizawa|Tomohiro|T|;Yamazaki|Masashi|M|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.jor.2019.11.044",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0972-978X",
"issue": "19()",
"journal": "Journal of orthopaedics",
"keywords": "Atypical femoral fracture; Bisphosphonate; Fracture reduction; Glucocorticoid; Surgical results",
"medline_ta": "J Orthop",
"mesh_terms": null,
"nlm_unique_id": "101233220",
"other_id": null,
"pages": "143-149",
"pmc": null,
"pmid": "32025122",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "15598694;15750687;28249967;24275891;24789301;14630836;25150344;21610533;10733048;22371548;24950251;21726859;18354114;10088839;11708295;15243759;20842676;20125175;19499274;6707031;24643097;23351871;23604648;23712442;27026435",
"title": "Surgical results of atypical femoral fractures in long-term bisphosphonate and glucocorticoid users - Relationship between fracture reduction and bone union.",
"title_normalized": "surgical results of atypical femoral fractures in long term bisphosphonate and glucocorticoid users relationship between fracture reduction and bone union"
} | [
{
"companynumb": "JP-TEVA-2020-JP-1213936",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "A 48-year-old woman was admitted to our hospital with a lump in her left breast. She was diagnosed with synchronous papillary thyroid carcinoma and breast ductal carcinoma. The patient underwent four cycles of neoadjuvant chemotherapy with epirubicin and cyclophosphamide, and one cycle of docetaxel. She then underwent left breast mastectomy and radical resection of thyroid cancer (total thyroidectomy and bilateral central group [levels VI and VII] lymph node dissection) at the same time. She was administered three cycles of chemotherapy with docetaxel and radiotherapy. The patient had no metastasis in the follow-up period. A literature search was performed to characterize the epidemiology, etiology, management, and prognosis of this condition. We speculate that hormone treatment could be a probable pathogenesis of synchronous breast and thyroid cancers.",
"affiliations": "Department of Thyroid and Breast Surgery, Baoan Central Hospital of Shenzhen (Fifth Affiliated Hospital of Shenzhen University), Shenzhen City, Guangdong Province, China.;Department of General Surgery, Shenzhen University General Hospital, Shenzhen University, Shenzhen City, Guangdong Province, China.;Cancer Center and Research Institute, Clinical and Translational Research, University of Mississippi Medical Center, Guyton Research Building, 2500 North State Street, Starkville, MS, USA.",
"authors": "Kong|Heng|H|https://orcid.org/0000-0003-2028-2028;Chen|JiXin|J|;Tang|Shou-Ching|SC|",
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"doi": "10.1177/0300060520948710",
"fulltext": "\n==== Front\nJ Int Med Res\nJ. Int. Med. Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n10.1177/0300060520948710\n10.1177_0300060520948710\nCase Report\nSynchronous papillary thyroid carcinoma and breast ductal carcinoma\nhttps://orcid.org/0000-0003-2028-2028Kong Heng 12 Chen JiXin 2 Tang Shou-Ching 3 \n1 Department of Thyroid and Breast Surgery, Baoan Central Hospital of Shenzhen (Fifth Affiliated Hospital of Shenzhen University), Shenzhen City, Guangdong Province, China\n\n2 Department of General Surgery, Shenzhen University General Hospital, Shenzhen University, Shenzhen City, Guangdong Province, China\n\n3 Cancer Center and Research Institute, Clinical and Translational Research, University of Mississippi Medical Center, Guyton Research Building, 2500 North State Street, Starkville, MS, USA\nHeng Kong, Department of Thyroid and Breast Surgery, Baoan Central Hospital of Shenzhen (Fifth Affiliated Hospital of Shenzhen University), No. 233 Xixiang section of Guangshen Avenue, Baoan District, Shenzhen City, Guangdong 518102, P.R. China. Email: generaldoc@126.com\n31 8 2020 \n8 2020 \n48 8 030006052094871015 3 2020 20 7 2020 © The Author(s) 20202020SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).A 48-year-old woman was admitted to our hospital with a lump in her left breast. She was diagnosed with synchronous papillary thyroid carcinoma and breast ductal carcinoma. The patient underwent four cycles of neoadjuvant chemotherapy with epirubicin and cyclophosphamide, and one cycle of docetaxel. She then underwent left breast mastectomy and radical resection of thyroid cancer (total thyroidectomy and bilateral central group [levels VI and VII] lymph node dissection) at the same time. She was administered three cycles of chemotherapy with docetaxel and radiotherapy. The patient had no metastasis in the follow-up period. A literature search was performed to characterize the epidemiology, etiology, management, and prognosis of this condition. We speculate that hormone treatment could be a probable pathogenesis of synchronous breast and thyroid cancers.\n\nBreastthyroidsynchronous cancerendocrine hormonechemotherapymastectomytypesetterts2\n==== Body\nIntroduction\nBreast cancer and thyroid cancer are two of the most common malignancies that occur in women. Synchronous carcinoma of the breast and thyroid can occur.1 The pathogenesis of breast and thyroid cancers is complex, and most of the patients are women. The breast and thyroid are hormone-responsive organs and are subject to hypothalamus–pituitary–glandular axis regulation.2,3 Therefore, endocrine changes and exogenous hormone drugs can lead to the onset of synchronous breast and thyroid cancers. We report here the clinical data of a case of breast cancer complicated by thyroid cancer. Primary synchronous breast and thyroid cancers might occur with long-term use of endocrine hormone treatment. Endogenous hormone levels could be one of the causes of synchronous breast and thyroid cancers.\n\nCase report\nA 48-year-old woman was admitted to our hospital in March 2018 with a lump in her left breast. On a physical examination in the outpatient service, we found a lesion that was approximately 8 × 7 cm in size in the upper outer quadrant of the left breast with occasional bloody nipple discharge. Some abnormally enlarged lymph nodes were observed in the left axilla (Figure 1).\n\nFigure 1. Ultrasound showing a left breast nodule and abnormally enlarged axillary lymph nodes. (a, b) A hypoechoic nodule with a size of 80 × 70×30 mm was observed on ultrasound. The shape of the nodule is irregular and the boundary is unclear. Color Doppler flow imaging shows blood flow signals inside of the hypoechoic zone. (c) A number of abnormally enlarged lymph nodes can be seen in the left axilla. The boundary of the lymph nodes is clear. These lymph nodes are hypoechoic with no lymphatic structure. A small amount of blood flow signal can be seen.\n\nA biopsy specimen of the left nodule showed invasive ductal carcinoma and scirrhous type cancer of the breast (cT3NxM0). Estrogen and progesterone receptors were positive, but human epidermal growth factor receptor 2 (HER2) was negative in immunohistochemical staining. The Ki-67 labeling index was 60%. At the same time, ultrasound imaging showed a 20 × 22 ×27-mm hypoechoic nodule of Thyroid Imaging Reporting and Data System category 4 in the left thyroid. Fine needle aspiration biopsy of a thyroid nodule showed papillary thyroid carcinoma (cT2NxM0, stage I) (Figure 2).\n\nFigure 2. (a) An ultrasound image shows a 20 × 22×27-mm hypoechoic nodule in the left thyroid. (b) Fine needle aspiration biopsy shows papillary thyroid carcinoma.\n\nDuring routine examinations, transvaginal ultrasound showed a hypoechoic area in the muscle layer of her uterus (Figure 3). She was diagnosed with uterine fibroids. Her history of disease included adenomyosis and dysfunctional uterine bleeding. She had continuous androgen, estrogen, and progesterone treatment for her gynecological diseases for longer than 5 years. She did not have any family history of papillary thyroid or breast cancer. The patient did not receive external beam radiation to the neck region. She did not know whether she had thyroiditis because she had not been examined before admission. She was not diagnosed with thyroiditis during preoperative laboratory tests in this hospitalization. She underwent endometrial scraping surgery 30 years previously because of uterine functional bleeding and adenomyosis.\n\nFigure 3. Transvaginal ultrasound shows a hypoechoic area in the muscle layer of the patient’s uterus. (a) The shape of the uterus is full and the shape is irregular. A hypoechoic area can be seen in the muscle layer of the right side. The size of the area is 76 × 71×57 mm. (b) The boundary is clear and the inner echo is uneven. The uterine intimal thickness is approximately 15 mm.\n\nThe patient was diagnosed with breast cancer and thyroid cancer. Her breast cancer was in the advanced stage and luminal B type. She was treated with neoadjuvant chemotherapy of epirubicin 100 mg/m2 and cyclophosphamide 600 mg/m2, followed by docetaxel 100 mg/m2 every 21 days. She had four cycles of chemotherapy with epirubicin and cyclophosphamide and then one treatment with docetaxel. Clinical responses in the breast and lymph nodes were assessed by ultrasound after five cycles of neoadjuvant chemotherapy. Ultrasound results were classified as stable disease by RECIST1.1.4 Clinicians decided to undergo surgical treatment combined with the patient’s wishes. In March 2019, she underwent modified radical mastectomy and radical resection of thyroid cancer (total thyroidectomy and bilateral central group [levels VI and VII] lymph node dissection). A histopathological examination showed that the lesion was invasive ductal carcinoma (Figure 4a) with lymph node metastasis (12/21) (pT3N3aM0, stage IIIc). Immunostaining results were positive for estrogen and progesterone receptors, but negative for HER2. The Ki-67 labeling index was 10%. The thyroid specimen showed a papillary thyroid carcinoma, with a classical subtype (Figure 4b), right central regional lymph node metastasis (1/9), and no left central regional lymph node metastasis (0/3) (pT2N1M0, stage I).\n\nFigure 4. Postoperative pathological results. (a) Left breast infiltrative ductal carcinoma. (b) Left papillary thyroid carcinoma.\n\nAfter surgery, the patient accepted the remaining three cycles of chemotherapy, endocrine therapy, and radiation. She has already finished chemotherapy and radiation. Currently, she is still on endocrine therapy. She had no metastasis and no postoperative complications in the 2-year follow-up period.\n\nDiscussion\nThe breast and thyroid are hormone-dependent organs. Once endocrine changes occur in the body, glandular diseases increase.5 The mammary gland is a target organ for many hormones. Estrogen and progestin are closely related to the incidence of breast cancer.6 The ratio of estrogen receptor-positive breast cancer is approximately 75% in all subtypes of breast cancer.7 Estrogen and progestin can activate transformation of breast cells and proliferation and invasion of estrogen receptor-positive breast cancer cells.8 An increasing amount data have shown that thyroid tissue also contains estrogen and progestin receptors.9 Estrogen and progestin can promote proliferation of thyroid cells and carcinogenesis of differentiated thyroid carcinoma.10 Estrogen receptor can be further divided into two subtypes as estrogen receptor α and β.11 The expression rate of estrogen receptor α and progestin receptor is significantly higher in papillary thyroid carcinoma than in other types of thyroid tumors.12\n\nBreast tissue also has receptors of thyroid-stimulating hormone, which alone or in combination with estrogen can promote the onset of breast cancer.13,14 Levels of thyroid-stimulating hormone are associated with the onset of primary thyroid cancer.15,16 Thyrotropin, thyroxin, and thyroid antibodies also promote the occurrence and development of primary thyroid cancer and breast cancer.17,18 This could be one mechanism of synchronous thyroid and breast carcinoma occurring.\n\nIn our case, the patient was diagnosed with synchronous thyroid and breast carcinoma. She had continuous intramuscular injection of androgen, estrogen, and progesterone for dysfunctional uterine bleeding and adenomyosis for longer than 5 years. Unfortunately, no doctor reminded her to be screened for breast and thyroid cancer. She visited a doctor when her nipples showed a neoplasm in France 1 month before admission to our hospital. Therefore, her breast illness was terminal as soon as it was discovered. A histopathological examination confirmed that her breast cancer was pT3N3aM0, stage IIIc. In view of positive estrogen and progesterone receptors in breast cancer tissue and long-term use of hormone drugs, we speculate that the synchronous thyroid and breast carcinoma in our case was due to long-term use of hormone drugs. More research on this subject is required to confirm this association.\n\nThe findings in our case suggest that clinicians should be careful when endocrine hormone treatment is used for a long time in any patient. Discussion should be carried out on whether endocrine hormones should be used in a large dose and for a long time, so that we can reduce or avoid the risk of patients suffering from breast and thyroid cancers.\n\nIn summary, long-term use of exogenous estrogen may increase the occurrence of thyroid and breast cancers. For patients who have to use exogenous estrogen to treat other systemic diseases, such as conditions of the uterus, regular screening of the breast and thyroid should be emphasized. Physicians should pay attention to the occurrence of thyroid cancer and breast cancer in this type of patient.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nEthics statement\nThis study was approved by the Human and Animal Ethics Review Board of Baoan Central Hospital of Shenzhen (Shenzhen, China) (reference number: A20200019). We obtained verbal consent for publication of this case report from the patient.\n\nFunding\nThis work was supported by the National Natural Science Foundation of China (grant no: 61802267), the Shenzhen Council for Scientific and Technological Innovation (grant nos: JCYJ20160429182058044 and JCYJ20190813100801664), Guangdong medical scientific and technological research funding (grant no: A2017251), and the Natural Science Foundation of Shenzhen University General Hospital (grant no: SUGH2018QD051).\n\nORCID iD\nHeng Kong https://orcid.org/0000-0003-2028-2028\n==== Refs\nReferences\n1 Tori M Shimo T Yoshidome K. \nNovel operative approach to double primary cancers of the breast and thyroid and its effects on cosmesis and the accuracy of follow-up examinations\n. Asian J Endosc Surg \n2018 ; \n11 : 185 –188\n. DOI: 10.1111/ases.12426.29869842 \n2 Aluclu MA Sen S Cevik M. \nAssociation between plasma kisspeptin levels and adolescent gynecomastia\n. Afr J Paediatr Surg \n2016 ; \n13 : 136 –139\n.27502882 \n3 Fisher DA. \nHypothyroxinemia in premature infants: is thyroxine treatment necessary?\n\nThyroid \n1999 ; \n9 : 715 –720\n.10447019 \n4 Gebhart G Lamberts LE Wimana Z , et al\nMolecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial\n. Ann Oncol \n2016 ; \n27 : 619 –624\n.26598545 \n5 Hardefeldt PJ Eslick GD Edirimanne S. \nBenign thyroid disease is associated with breast cancer: a meta-analysis.\n\nBreast Cancer Res Treat \n2012 ; \n133 : 1169 –1177\n.22434524 \n6 Gadducci A Biglia N Sismondi P , et al\nBreast cancer and sex steroids: critical review of epidemiological, experimental and clinical investigations on etiopathogenesis, chemoprevention and endocrine treatment of breast cancer.\n\nGynecol Endocrinol \n2005 ; \n20 : 343 –360\n.16019385 \n7 Patel HK Bihani T. \nSelective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment.\n\nPharmacol Ther \n2018 : \n186 : 1 –24\n.29289555 \n8 Pasqualini JR Chetrite GS. \nRecent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer.\n\nJ Steroid Biochem Mol Biol \n2005 ; \n93 : 221 –236\n.15860265 \n9 Liu J Chen G Meng XY , et al\nSerum levels of sex hormones and expression of their receptors in thyroid tissue in female patients with various types of thyroid neoplasms.\n\nPathol Res Pract \n2014 ; \n210 : 830 –835\n.25305147 \n10 Fernandez-Pol JA. \nModulation of EGF receptor protooncogene expression by growth factors and hormones in human breast carcinoma cells\n. Crit Rev Oncog \n1991 ; \n2 : 173 –185\n.1677274 \n11 Giani C Fierabracci P Bonacci R , et al\nRelationship between breast cancer and thyroid disease: relevance of autoimmune thyroid disorders in breast malignancy\n. J Clin Endocrinol Metab \n1996 ; \n81 : 990 –994\n.8772562 \n12 Sandeep TC Strachan MW Reynolds RM , et al\nSecond primary cancers in thyroid cancer patients: a multinational record linkage study.\n\nJ Clin Endocrinol Metab \n2006 ; \n91 : 1819 –1825\n.16478820 \n13 López-Fontana CM Sasso CV Maselli ME , et al\nExperimental hypothyroidism increases apoptosis in dimethylbenzanthracene-induced mammary tumors\n. Oncol Rep \n2013 ; \n30 : 1651 –1660\n.23912381 \n14 Turken O NarIn Y DemIrbas S , et al\nBreast cancer in association with thyroid disorders.\n\nBreast Cancer Res \n2003 ; \n5 : R110 –R113\n.12927040 \n15 Haugen BR. \n2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: what is new and what has changed?\n\nCancer \n2017 ; \n123 : 372 –381\n.27741354 \n16 Kuo JH Chabot JA Lee JA. \nBreast cancer in thyroid cancer survivors: An analysis of the Surveillance, Epidemiology, and End Results-9 database.\n\nSurgery \n2016 ; \n159 : 23 –29\n.26522696 \n17 Shi XZ Jin X Xu P , et al\nRelationship between breast cancer and levels of serum thyroid hormones and antibodies: a meta-analysis.\n\nAsian Pac J Cancer Prev \n2014 ; \n15 : 6643 –6647\n.25169502 \n18 Arer İM Yabanoğlu H Kuş M , et al\nRetrospective analysis of patients with synchronous primary breast and thyroid carcinoma\n. Eur J Breast Health \n2018 ; \n14 : 80 –84\n. DOI: 10.5152/ejbh.2018. 3853.29774315\n\n",
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"issue": "48(8)",
"journal": "The Journal of international medical research",
"keywords": "Breast; chemotherapy; endocrine hormone; mastectomy; synchronous cancer; thyroid",
"medline_ta": "J Int Med Res",
"mesh_terms": "D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D002291:Carcinoma, Papillary; D005260:Female; D006801:Humans; D008408:Mastectomy; D008875:Middle Aged; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms; D013965:Thyroidectomy",
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"title": "Synchronous papillary thyroid carcinoma and breast ductal carcinoma.",
"title_normalized": "synchronous papillary thyroid carcinoma and breast ductal carcinoma"
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"abstract": "The efficacy and safety of high-dose chemotherapy with tandem autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in a multicenter clinical study of patients with advanced multiple myeloma. Eligible patients (n = 40) were consecutively enrolled in the phase I/II study and received 2-4 cycles of vincristine-adriamycin-dexamethasone regimen. The responding patients underwent PBSC harvesting following high-dose cyclophosphamide and filgrastim administration. The first auto-PBSCT (n = 32) following high-dose melphalan (200 mg/m(2)) was performed within 2 months of PBSC harvesting; the second auto-PBSCT (n = 28) was scheduled 3-6 months later. Treatment-related mortality was 2.5% (n = 1) throughout the protocol. Grade 4 nonhematologic toxicity occurred in 12.5 and 14.3% of the first and second auto-PBSCT patients, respectively. All but one patient (who died) achieved hematopoietic recovery. For the 28 patients completing the second auto-PBSCT, the results were favorable with a response rate of 65% (complete response rate = 27.5%, n = 11); the five-year progression-free survival and overall survival were 20.3 and 66.5%, respectively. In conclusion, high-dose chemotherapy with tandem auto-PBSCT is feasible and safe with a favorable response rate in treating advanced multiple myeloma in Japan.",
"affiliations": "Division of Hematology, Department of Internal Medicine, National Hospital Organization Okayama Medical Center, 1711-1 Tamasu, Kitaku, Okayama, 701-1192, Japan. kazusuna@pop12.odn.ne.jp.;Division of Hematology/Oncology, Okayama University Medical School, Okayama, Japan.;Department of Internal Medicine, Nishigunma National Hospital, Shibukawa, Gunma, Japan.;Department of Hematology/Oncology, Institute for Rad. Biology and Medicine, Hiroshima University, Hiroshima, Japan.;Department of Hematology, Oita Prefectural Hospital, Oita, Japan.;Division of Hematology, St. Mary's Hospital, Kurume, Fukuoka, Japan.;Hematology Division, Department of Medicine, Hyogo Cancer Center, Akashi, Hyogo, Japan.;Department of Internal Medicine, Yamada Red Cross Hospital, Ise, Mie, Japan.;Department of Hematology, Harasanshin Hospital, Fukuoka, Japan.;Division of Hematology/Oncology, Kumamoto City Hospital, Kumamoto, Japan.;Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan.;Department of Internal Medicine, Kure Kyosai Hospital, Kure, Hiroshima, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Internal Medicine, Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuyama, Hiroshima, Japan.;Division of Blood Transfusion, Tottori University Hospital, Yonago, Tottori, Japan.;Medical Corporation Kouryokai CPC Clinic, Kagoshima, Japan.;Department of Hematology, International Medical Center of Japan, Tokyo, Japan.;Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.;Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.",
"authors": "Sunami|Kazutaka|K|;Shinagawa|Katsuji|K|;Sawamura|Morio|M|;Sakai|Akira|A|;Saburi|Yoshio|Y|;Imamura|Yutaka|Y|;Mizuno|Ishikazu|I|;Tamaki|Shigehisa|S|;Kamimura|Tomohiko|T|;Tsuda|Hiroyuki|H|;Gondo|Hisashi|H|;Hino|Norihiko|N|;Shimazaki|Chihiro|C|;Miyata|Akira|A|;Tajima|Fumihito|F|;Takemoto|Yoshinobu|Y|;Miwa|Akiyoshi|A|;Chou|Takaaki|T|;Harada|Mine|M|",
"chemical_list": "D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin",
"country": "Japan",
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"doi": "10.1007/s12185-009-0445-8",
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"issn_linking": "0925-5710",
"issue": "90(5)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D003907:Dexamethasone; D004317:Doxorubicin; D006801:Humans; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D015996:Survival Rate; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "9111627",
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"pages": "635-642",
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"pmid": "19936876",
"pubdate": "2009-12",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "17606443;15761019;15287913;5818682;16525139;11806971;6137651;14695409;8611448;3304465;8971391;9864146;10713623;18302711;12542490;9753033;8649495;16782727;16330437;9787148;1182674;9404921;9028309;1350228;11908738;17485707;12736280;7581098;9850028",
"title": "Phase I/II study of tandem high-dose chemotherapy with autologous peripheral blood stem cell transplantation for advanced multiple myeloma.",
"title_normalized": "phase i ii study of tandem high dose chemotherapy with autologous peripheral blood stem cell transplantation for advanced multiple myeloma"
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"abstract": "We designed a multicenter, phase Ib dose-escalation trial of carfilzomib with bendamustine and rituximab in patients with relapsed/refractory non-Hodgkin lymphoma (NCT02187133) in order to improve the response rates of this difficult-to-treat population. Chemoimmunotherapy with bendamustine and rituximab has shown activity in a variety of lymphomas, and proteasome inhibitors have demonstrated pre-clinical synergy and early clinical activity in this population. The objectives were to determine the maximum tolerated dose of carfilzomib and the preliminary efficacy of this combination.\n\n\n\nThe protocol followed a 3+3 design of carfilzomib dose escalation combined with standard doses of bendamustine and rituximab. Patients were treated for up to 6 cycles with an interim positron emission tomography/computed tomography after cycle 3.\n\n\n\nTen patients were treated on the dose-escalation phase. The study was terminated at a carfilzomib dose of 56 mg/m2, and the maximum tolerated dose was not reached. The most common grade 3/4 adverse event was thrombocytopenia. There was 1 dose-limiting toxicity observed, grade 3 febrile neutropenia, and there were no treatment-related deaths. The overall response rate was 40% (complete response rate, 30%), with a median duration of response of 12 months and a median progression-free survival of 2.1 months.\n\n\n\nCarfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for patients with relapsed/refractory non-Hodgkin lymphoma. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options.",
"affiliations": "Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.;Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.;Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.;Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.;Department of Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.;Department of Medicine, Division of Hematology/Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA.;Atara Biotherapeutics Inc, Thousand Oaks, CA.;Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.;Department of Medicine, Division of Hematology/Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA.;Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.;Gilead Sciences, Daly City, CA.;Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.;Department of Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.;Department of Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.;Department of Medicine, Division of Hematology/Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA.;Department of Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.;Department of Medicine, Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA. Electronic address: charalambos.andreadis@ucsf.edu.",
"authors": "Kambhampati|Swetha|S|;Fakhri|Bita|B|;Ai|Weiyun Z|WZ|;Kaplan|Lawrence D|LD|;Tuscano|Joseph M|JM|;Wieduwilt|Matthew J|MJ|;Sudhindra|Akshay|A|;Cavallone|Erika|E|;Reiner|Jesika|J|;Aoun|Charlie|C|;Castillo|Miguel|M|;Martinelli|Michelle|M|;Ta|Teresa|T|;Le|Diem|D|;Padilla|Michelle|M|;Crawford|Erika|E|;Andreadis|Charalambos B|CB|",
"chemical_list": null,
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"doi": "10.1016/j.clml.2020.12.020",
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"issn_linking": "2152-2669",
"issue": "21(3)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Mantle cell lymphoma; Proteasome inhibitor; Refractory lymphoma; Relapsed lymphoma",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": null,
"nlm_unique_id": "101525386",
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"pages": "139-146",
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"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Carfilzomib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma: A Phase I Trial.",
"title_normalized": "carfilzomib in combination with bendamustine and rituximab in patients with relapsed or refractory non hodgkin lymphoma a phase i trial"
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"companynumb": "US-CELLTRION INC.-2021US001336",
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"activesubstancename": "CARFILZOMIB"
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{
"abstract": "A 48-year-old male with history of schizoaffective disorder on clozapine presented with chest pain, dyspnea, and new left bundle branch block. He underwent coronary angiography, which revealed no atherosclerosis. The patient's workup was unrevealing for a cause for the cardiomyopathy and thus it was thought that clozapine was the offending agent. The patient was taken off clozapine and started on guideline directed heart failure therapy. During the course of hospitalization, he was also discovered to have a left ventricular (LV) thrombus for which he received anticoagulation. To our knowledge, this is the first case report of clozapine-induced cardiomyopathy complicated by a LV thrombus.",
"affiliations": "Department of Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, ND 58102, USA.;Department of Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, ND 58102, USA.;Department of Cardiology, Sanford Health, Fargo, ND 58102, USA.;Department of Psychiatry and Behavioral Science, University of North Dakota School of Medicine and Health Sciences, Fargo, ND 58102, USA.",
"authors": "Malik|Shahbaz A|SA|;Malik|Sarah|S|;Dowsley|Taylor F|TF|;Singh|Balwinder|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/835952",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2015/835952Case ReportLeft Ventricular Thrombus as a Complication of Clozapine-Induced Cardiomyopathy: A Case Report and Brief Literature Review Malik Shahbaz A. \n1\nMalik Sarah \n1\nDowsley Taylor F. \n2\nSingh Balwinder \n3\n\n*\n1Department of Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, ND 58102, USA2Department of Cardiology, Sanford Health, Fargo, ND 58102, USA3Department of Psychiatry and Behavioral Science, University of North Dakota School of Medicine and Health Sciences, Fargo, ND 58102, USA*Balwinder Singh: balwinder.singh@med.und.eduAcademic Editor: Tayfun Sahin\n\n2015 18 11 2015 2015 8359522 7 2015 7 11 2015 Copyright © 2015 Shahbaz A. Malik et al.2015This 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.A 48-year-old male with history of schizoaffective disorder on clozapine presented with chest pain, dyspnea, and new left bundle branch block. He underwent coronary angiography, which revealed no atherosclerosis. The patient's workup was unrevealing for a cause for the cardiomyopathy and thus it was thought that clozapine was the offending agent. The patient was taken off clozapine and started on guideline directed heart failure therapy. During the course of hospitalization, he was also discovered to have a left ventricular (LV) thrombus for which he received anticoagulation. To our knowledge, this is the first case report of clozapine-induced cardiomyopathy complicated by a LV thrombus.\n==== Body\n1. Introduction\nClozapine is the most effective antipsychotic agent available for use in treatment resistant schizophrenia [1]. Despite its efficacy, the drug has been associated with serious adverse effects such as fatal agranulocytosis and cardiovascular complications (such as myocarditis and dilated cardiomyopathy) [1]. The former is monitored with the help of regular laboratory testing and by enrolling patients in the clozapine registry. However, the cardiovascular side effects still elude early detection. We present this case of dilated, nonischemic cardiomyopathy found in a patient taking clozapine to help bring this potential and gravely morbid complication to light, hopefully, increasing awareness among practitioners.\n\n2. Case Presentation\nA 48-year-old Caucasian male presented to the emergency department (ED) via local ambulance service, with complaints of new onset chest pain and shortness of breath with activity for past two weeks. The chest pain was present all over the chest, described as a “heavy sensation,” and had significantly improved by the time he arrived to the ED with some residual “achiness.” The pain was nonpleuritic and did not vary with postural changes. He denied any fevers, chills, cough, hemoptysis, calf tenderness, or leg swelling. He had no history of recent viral illnesses, infections, or long distance travel and no family history for premature coronary heart disease or sudden cardiac death. He had no prior reported history of coronary artery disease (CAD). He did have a history of schizoaffective disorder for which he was on aripiprazole (15 mg daily), lamotrigine (200 mg daily), benztropine (1 mg 3 times a day), and clozapine (100 mg twice a day). He had no history of smoking or recreational drug use.\n\nHistory at the time of presentation was limited due to patient's psychiatric condition, as the patient would answer questions in a bizarre fashion.\n\nHis vitals in the ED revealed a heart rate of 101 beats/min, blood pressure of 95/58 mmHg, and weight of 160 lbs, and saturation was 95% on room air. Positive findings on physical examination were elevated jugular venous pulsations, fine crackles at bilateral lung bases. Cardiovascular exam revealed a regular rhythm, elevated rate, and normal heart tones without any obvious S3. Pulses were palpable and symmetrical in bilateral upper and lower extremities with no peripheral edema. The patient was alert, oriented to self and time, only. On mental status examination, his thought process was tangential.\n\nA 12-lead electrocardiogram showed sinus tachycardia of 103 beats/min and a new onset left bundle branch block (LBBB), with prolonged corrected QT interval (QTc) of 497 ms; there were no ST segment or T-wave changes. Point-of-care troponin and subsequent cardiac troponin I were both within normal range. Remaining laboratory and biochemical findings are reported in the Table 1.\n\nChest X-ray showed significant cardiomegaly along with prominent pulmonary vascular markings consistent with pulmonary edema. Due to his complaints of chest pain and shortness of breath along with finding of new LBBB, the patient was taken immediately to the cardiac catheterization laboratory and loaded with aspirin en route. Coronary angiography revealed an essentially normal coronary anatomy with no significant lesions or evidence of occlusive CAD. Ramus intermedius was identified. Left ventricular angiogram showed an ejection fraction (EF) of 15%. Left ventricle end diastolic pressure (LVEDP) was significantly elevated at 35 mm Hg (normal 6–12 mm Hg).\n\nThe patient was admitted to the intensive care unit (ICU) and initiated on dobutamine at 5 mcg/kg body weight/min for inotropic support. Transthoracic echocardiogram (TTE) revealed an EF of 10% with severe diffuse hypokinesis, normal left ventricular wall thickness, with evidence of elevated left atrial pressures along with markedly dilated left and right atria. Mild-to-moderate mitral regurgitation was reported. Pulmonary artery systolic pressure was elevated at 69 mm Hg. No pericardial effusion was identified. Inferior vena cava (IVC) was markedly dilated as well, showing <50% variation with breathing. Table 2 shows the results from the multiple echocardiography measurements during hospitalization.\n\nHe was initially started on diuresis with intravenous (IV) furosemide 40 mg daily that was increased to twice daily the next day. With diuresis the patient's weight gradually came down to 153 lbs (nadir at the time of discharge) and he improved symptomatically. On day 3, he was switched to per oral (PO) furosemide 40 mg daily. He initially required vasopressor support while being diuresed but was later weaned off it on day 6. Furosemide was decreased to 20 mg PO daily at that point and he was initiated on low dose metoprolol succinate at 12.5 mg daily. Lisinopril 2.5 mg daily was added on day 7. Metoprolol was increased to 25 mg daily on day 9, but lisinopril dose could not be increased further on account of blood pressures remaining in the low-normal range. Repeat TTE did not reveal any change in EF. His vitals stabilized and he started ambulating with physical therapy.\n\nGiven the relatively young age of the patient, absence of viral prodromal symptoms, unremarkable coronary angiogram excluding an ischemic etiology, normal cardiac enzymes excluding active cardiac myonecrosis, iron studies not suggestive of any iron overload condition to explain the patient's dilated cardiomyopathy, and absence of other risk factors to explain the cause for the profoundly low EF, clozapine was thought to be possible culprit of the cardiomyopathy.\n\nReview of outside medical records indicated that the patient was on clozapine due to “command hallucinations to harm himself.” Going through the clozapine registry, it was ascertained that the patient had been on 300 mg a day of clozapine (200 mg at bedtime and 100 mg in the morning) since June 2010. For unknown reasons, the dose was decreased to 200 mg a day (100 mg in the morning, 100 mg at bedtime) a few weeks prior to hospitalization. Consult liaison (CL) psychiatry team was consulted to assist in treatment planning. Given the possibility of clozapine-induced cardiomyopathy CL team tapered and discontinued clozapine. On day 7, aripiprazole was increased to 30 mg daily (admitted on 15 mg daily); lamotrigine was continued at 200 mg daily. Benztropine was later discontinued. On day 10, he was initiated on PO olanzapine 5 mg at bedtime and titrated to 10 mg on day 15.\n\nKidney function and hematological laboratory values remained essentially unchanged throughout the course of the hospitalization. No cardiac arrhythmias were observed during the stay. Cardiac rehabilitation was initiated during hospitalization; his functional status gradually improved during stay. Repeat TTE at three weeks showed an EF of approximately 10% but now with a new large, echogenic, mobile, mass which measured 26 mm × 20 mm on the basal inferoseptal wall. This was representative of a LV mural thrombus. The patient's mitral regurgitation also looked worse, based on echocardiographic assessment. He was immediately started on parenteral anticoagulation with low molecular weight heparin (enoxaparin) 80 mg twice daily and then started on oral warfarin. Parenteral anticoagulation was continued until the international normalized ratio (INR) level reached a therapeutic range of greater than 2.\n\nCardiothoracic surgery was consulted in order to obtain an opinion in regard to the patient's mitral regurgitation. The risks of surgery for mitral valve repair outweighed the benefit in their opinion and thus no surgery was recommended. A repeat TTE on day 33 showed the size of the LV thrombus had decreased to approximately 19 mm × 13 mm (Table 2). Mitral regurgitation remained the same. During all this time, his vitals remained stable.\n\n3. Outcome and Follow-Up\nThe patient improved clinically and by the end of the hospitalization course, his dyspnea improved and he was able to walk over thousand feet with cardiac rehabilitation and physical therapy. He was discharged on day 37, on metoprolol succinate at 25 mg daily, lisinopril 2.5 mg daily, and warfarin. Furosemide was switched to torsemide 20 mg daily on the day of discharge. In terms of the patient's psychiatric medications, he was sent home on aripiprazole 30 mg daily, lamotrigine 200 mg daily, and olanzapine 10 mg. He was scheduled to follow-up with an outpatient primary care provider, cardiologist, and a psychiatrist on discharge. The patient continues to follow with cardiology regularly with not much improvement in ejection fraction at three months of follow-up. This has prompted consideration for cardiac resynchronization therapy, in the near future.\n\n4. Discussion\nIn this report, we described a case of a young male with schizoaffective disorder with no prior history of coronary heart disease presenting with a new onset heart failure and cardiomyopathy. Hypertensive heart disease and genetic and toxic etiologies were ruled out on the basis of the patient's medical history and physical examination. History was also negative for the use of chemotherapeutic agents (notably anthracyclines) or other medications such as antiretroviral drugs, phenothiazines, or chloroquine that could have led to the development of cardiomyopathy. Ischemic cause was excluded based on coronary angiography, whereas infectious and metabolic etiologies were ruled out based on laboratory analyses. In the absence of any other obvious cause for the patient's cardiomyopathy, clozapine was considered the culprit and the medication was discontinued. The patient's case was complicated by a LV thrombus. LV thrombi are an uncommon yet known complication of anterior wall transmural myocardial infarctions (10%) [2]. Furthermore, severe mitral regurgitation has been thought to have a protective role in LV thrombus formation in patients with reduced ejection fraction [3]. Thus, to our knowledge, this is the first case report of cardiomyopathy related to clozapine that was further complicated by an LV thrombus, despite presence of mitral regurgitation. It is unclear whether clozapine itself could be implicated in the thrombus formation, as there have been reports of possible association of clozapine with venous thromboembolic phenomenon [4]. However, it is just as likely that the thrombus was related to poor LV function and the cardiomyopathy itself.\n\nSchizophrenia is currently understood as a psychiatric illness with progressive clinical, neuropsychological, neurophysiological, and neurostructural deterioration [5]. It typically involves recurrent or chronic psychosis. It has been ranked by the World Health Organization as one of the top ten illnesses contributing to the global burden of disease [6]. Approximately 1% of the world's adult population suffers from schizophrenia [7]. Clozapine is the treatment of choice for patients with treatment resistant schizophrenia [8–10]. For patients with schizophrenia, it is the only antipsychotic agent with a demonstrated significant reduction in suicidality and it usually produces few or no extrapyramidal symptoms (such as tardive dyskinesia or dystonia caused by typical antipsychotics) [4, 11]. Despite its efficacy, the drug has been associated with serious adverse effects such as fatal agranulocytosis and toxic megacolon and cardiovascular complications including myocarditis and dilated cardiomyopathy. As a result, it is not considered a first-line treatment and is reserved for patients with treatment resistant schizophrenia/schizoaffective disorder [12–14].\n\nCharacteristics of patients with clozapine-induced cardiomyopathy were detailed in a systematic review from 2014, which included reviewing data from 26 cases of clozapine-induced cardiomyopathy [15]. They reported a mean age of 33.5 years, a mean dose of 360 mg, and average time to symptoms onset of 14.4 months and most commonly reported echocardiographic findings as being reduced ejection fraction with global dysfunction [15]. Specific mention of dilated cardiomyopathy was in 39% of individual case reports per the systematic review [15]. Approximately 80% of clozapine treated patients in whom cardiomyopathy was reported were less than 50 years of age, according to a manufacturer adverse event database [16].\n\nThe incidence of dilated cardiomyopathy in the general population has been reported to be 7.5–10.0 per 100,000 population [17]. A recent cohort study performed in Australia describes the incidence of clozapine-induced myocarditis and cardiomyopathy to be 3.88% and 4.65% (or 2.26 per 100 patient years), respectively [18]. The rate of cardiomyopathy in clozapine treated patients in the US was shown to be 8.9 per 100,000 person-years according to national databases reporting adverse drug effects [19]. On the other hand, the incidence of clinically severe clozapine-induced cardiomyopathy was reported as 51.5 per 100,000 patient-years [20]. Time to onset of clozapine-induced cardiomyopathy has varied between reports. One case report noted it at 3 weeks [21]. Another case report detailed the discovery on postmortem exam after the patient had been on clozapine for 4 years [22]. A case series described three men developing symptoms secondary to severe left ventricular dysfunction from clozapine use on average one year before diagnosis [23]. The clinical manifestations of clozapine-induced cardiomyopathy range from subclinical presentation [24] to fulminant pulmonary edema and cardiogenic shock [25, 26]. Common presenting symptoms include shortness of breath, palpitations, cough, fatigue, chest pain, and sometimes atypical symptoms such as worsening psychiatric mental status [27, 28]. Diagnosis of clozapine-induced cardiomyopathy has typically been on clinical exam, electrocardiography, and echocardiography. There are two reports in literature detailing the diagnosis on postmortem examination [22, 29].\n\nMechanism of association of clozapine with cardiomyopathy is still elusive and lacks consensus in the literature. Cardiomyopathy is not as closely related to other antipsychotics as it is to clozapine [20]. One hypothesis suggests that there may be a direct toxicity similar to anthracycline-induced cardiomyopathy [25]. Second explanation is that cardiomyopathy may evolve from clozapine associated myocarditis. Some authors have suggested that exposure to prior antipsychotics, illicit drugs, or alcohol may plays a factor [13].\n\nTreatment of clozapine-induced cardiomyopathy involves cessation of the drug [15]. Guideline directed therapy for heart failure should be instituted [15]. Other treatment goals include prevention of additional cardiac injury related to recreational drug such as alcohol and amphetamines. Alternative antipsychotics such as olanzapine have been used in most other cases [15]. Several reports have noted that there was an improvement in cardiac function on echocardiogram after cessation of clozapine [15, 20]. However, an interesting case report suggested efficacy of beta blockers in association with an angiotensin-converting enzyme inhibitor to decrease the risk of cardiac deterioration and possibility of resuming drug in patients with psychiatric symptoms refractory to other antipsychotics [30]. In general, patients with an ejection fraction of <25% at the time of diagnosis have a poor prognosis including the highest risk of mortality with limited recovery [15]. Patients with an ejection fraction of 25–40% generally show significant improvement [15]. Patients with an ejection fraction of >40% usually show near complete recovery of cardiac function at 6 months, after cessation of clozapine and with normal heart failure treatment [15]. It should be noted that one study demonstrated that 80% of patients withdrawn from clozapine for medical reasons developed a psychotic relapse [31]. Therefore, clozapine cessation should be done under supervision of a psychiatrist and appropriate alternative medication should be substituted to prevent relapse.\n\nConflict of Interests\nNone of the authors have any disclosures or conflict of interests.\n\nTable 1 Laboratory and biochemical analyses.\n\nLaboratory parameters (units)\tPatient's results (reference range)\t\nComplete blood count\t \t\n White cell count (K/μL)\t8.2 (4–11)\t\n Hemoglobin (g/dL)\t13.1 (13.5–17.5)\t\n Hematocrit (%)\t38.3 (40–50)\t\n MCV (fL)\t83.6 (80–98)\t\n Platelet count (K/μL)\t175 (normal 140–400)\t\nChemistry\t \t\n Serum glucose (mg/dL)\t126 (70–100)\t\n Sodium (mEq/L)\t140 (135–145)\t\n Potassium (mEq/L)\t3.5 (3.5–5.3)\t\n Chloride (mEq/L)\t104 (99–110)\t\n Magnesium (mg/dL)\t1.9 (1.8–2.4)\t\n BUN (mg/dL)\t16 (6–22)\t\n Creatinine (mg/dL)\t1.2 (0.8–1.3)\t\n Total bilirubin (mg/dL)\t1.9 (0.2–1.2)\t\n Alanine aminotransferase (AST) (U/L)\t6 (0–55)\t\n Aspartate aminotransferase (AST) (U/L)\t12 (0–35)\t\n Alkaline phosphatase (U/L)\t73 (30–150)\t\nIron studies\t \t\n Total iron (mcg/dL)\t30 (65–175)\t\n Iron saturation (%)\t10 (20–50)\t\n Ferritin (ng/mL)\t88 (21–275)\t\n Total iron binding capacity (mcg/dL)\t307 (250–400)\t\nCardiac markers\t \t\n Troponin (ng/mL)\t0.01 (0.00–0.08)\t\n Troponin I (ng/mL)\t0.019 (0.00–0.028)\t\n Creatine kinase (CK) (U/L)\t48 (30–200)\t\nTable 2 Echocardiography measurements during hospitalization demonstrating left ventricle dysfunction.\n\nParameter\tDay 1\tDay 6\tDay 14\tDay 21\tDay 33\t\nLeft ventricular ejection fraction (%)\t10\t10\t10\t10\t10\t\nLeft ventricular internal diameter (end diastolic) mm (millimeter)\t82\t81\t79\t73\t73\t\nLeft ventricular internal diameter (end systolic) mm (millimeter)\t75\t70\t73.8\t70\t68\t\nPeak E/A ratio (early-to-late ventricular filling ratio of mitral flow)\t1.66\t—\t—\t—\t—\t\nDeceleration time (of mitral E wave) ms (meters per second)\t124\t—\t—\t—\t—\t\nPulmonary artery peak systolic pressure in millimeter mercury\t69\t65\t57\t64\t72\t\nLeft ventricle thrombus in millimeter × millimeter\t—\t—\t \t26 × 20\t19 × 13\n==== Refs\n1 Nielsen J. Damkier P. Lublin H. Taylor D. Optimizing clozapine treatment Acta Psychiatrica Scandinavica 2011 123 6 411 422 10.1111/j.1600-0447.2011.01710.x 2-s2.0-79955956495 21534935 \n2 Kalra A. Jang I.-K. Prevalence of early left ventricular thrombus after primary coronary intervention for acute myocardial infarction Journal of Thrombosis and Thrombolysis 2000 10 2 133 136 10.1023/a:1018710425817 2-s2.0-0033760728 11005935 \n3 Kalaria V. G. Passannante M. R. Shah T. Modi K. Weisse A. B. Effect of mitral regurgitation on left ventricular thrombus formation in dilated cardiomyopathy American Heart Journal 1998 135 2 215 220 10.1016/s0002-8703(98)70084-5 2-s2.0-0031911002 9489967 \n4 Walker A. M. Lanza L. L. Arellano F. Rothman K. J. Mortality in current and former users of clozapine Epidemiology 1997 8 6 671 677 10.1097/00001648-199710000-00010 2-s2.0-0030778896 9345668 \n5 Vera I. Rezende L. Molina V. Sanz-Fuentenebro J. Clozapine as treatment of first choice in first psychotic episodes. What do we know? Actas Españolas de Psiquiatría 2012 40 5 281 289 2-s2.0-84872012410 23076611 \n6 Murray C. Lopez A. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020 1996 Cambridge, Mass, USA Harvard University Press \n7 Voruganti L. Cortese L. Oyewumi L. Cernovsky Z. Zirul S. Awad A. Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side-effect profile and impact on quality of life Schizophrenia Research 2000 43 2-3 135 145 10.1016/s0920-9964(99)00154-1 2-s2.0-0034674458 10858632 \n8 Kane J. Honigfeld G. Singer J. Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine Archives of General Psychiatry 1988 45 9 789 796 10.1001/archpsyc.1988.01800330013001 2-s2.0-0023812652 3046553 \n9 Kane J. M. Treatment-resistant schizophrenic patients Journal of Clinical Psychiatry 1996 57 supplement 9 35 40 2-s2.0-0029825886 8823348 \n10 Lewis S. W. Barnes T. R. E. Davies L. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia Schizophrenia Bulletin 2006 32 4 715 723 10.1093/schbul/sbj067 2-s2.0-33748768220 16540702 \n11 Hennen J. Baldessarini R. J. Suicidal risk during treatment with clozapine: a meta-analysis Schizophrenia Research 2005 73 2-3 139 145 10.1016/j.schres.2004.05.015 2-s2.0-12144282766 15653256 \n12 Coulter D. M. Bate A. Meyboom R. H. B. Lindquist M. Edwards I. R. Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study British Medical Journal 2001 322 7296 1207 1209 10.1136/bmj.322.7296.1207 2-s2.0-0035912544 11358771 \n13 Wehmeier P. M. Heiser P. Remschmidt H. Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapine Journal of Clinical Pharmacy and Therapeutics 2005 30 1 91 96 10.1111/j.1365-2710.2004.00616_1.x 2-s2.0-21244440442 15659009 \n14 Wooltorton E. Antipsychotic clozapine (Clozaril): myocarditis and cardiovascular toxicity Canadian Medical Association Journal 2002 166 9 1185 1186 2-s2.0-0036257674 12000254 \n15 Alawami M. Wasywich C. Cicovic A. Kenedi C. A systematic review of clozapine induced cardiomyopathy International Journal of Cardiology 2014 176 2 315 320 10.1016/j.ijcard.2014.07.103 2-s2.0-84922407443 25131906 \n16 Fontana P. G. Sümegi B. Association of Clozaril (Clozapine) with Cardiovascular Toxicity 2002 Dorval, Canada Novartis Pharmaceuticals Canada \n17 Friman G. Wesslen L. Fohlman J. Karjalainen J. Rolf C. The epidemiology of infectious myocarditis, lymphocytic myocarditis and dilated cardiomyopathy European Heart Journal 1995 16 36 41 10.1093/eurheartj/16.suppl_O.36 8682098 \n18 Youssef D. L. 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Optimizing treatment with clozapine Journal of Clinical Psychiatry 1998 59 supplement 3 44 48 2-s2.0-0031980134 9541338\n\n",
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"issue": "2015()",
"journal": "Case reports in cardiology",
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"medline_ta": "Case Rep Cardiol",
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"nlm_unique_id": "101576452",
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"pages": "835952",
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"pmid": "26664756",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "10858632;12000254;3046553;15659009;18178706;11005935;26400457;15653256;15643098;18433662;16540702;9489967;18520789;9541338;11485134;20931297;23076611;15555025;9345668;11463031;21534935;10584719;8792945;25332789;8823348;12075045;11358771;25131906;8682098",
"title": "Left Ventricular Thrombus as a Complication of Clozapine-Induced Cardiomyopathy: A Case Report and Brief Literature Review.",
"title_normalized": "left ventricular thrombus as a complication of clozapine induced cardiomyopathy a case report and brief literature review"
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"abstract": "We report a case of paradoxical worsening of tuberculous chorioretinitis after initiation of anti-tuberculous therapy (ATT). The patient had left panuveitis with tuberculous chorioretinitis and was started on systemic ATT and oral steroids a week later. However, he developed paradoxical worsening 2 months after initiation of therapy. He was continued on ATT, oral steroids and intravitreal amikacin with resolution of the chorioretinal lesion subsequently. Ocular tuberculosis often poses a diagnostic challenge, and clinicians should be aware of the possibility of paradoxical worsening despite appropriate ATT. Clinicians should strongly consider starting oral steroids concurrently with ATT when managing ocular tuberculosis.",
"affiliations": "Department of Ophthalmology, Tan Tock Seng Hospital, Singapore, 308433 Singapore.;Department of Ophthalmology, Tan Tock Seng Hospital, Singapore, 308433 Singapore.;Department of Ophthalmology, Tan Tock Seng Hospital, Singapore, 308433 Singapore.",
"authors": "Siantar|Rosalynn Grace|RG|;Ho|Su Ling|SL|;Agrawal|Rupesh|R|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s12348-015-0052-1",
"fulltext": "\n==== Front\nJ Ophthalmic Inflamm InfectJ Ophthalmic Inflamm InfectJournal of Ophthalmic Inflammation and Infection1869-5760Springer Berlin Heidelberg Berlin/Heidelberg 5210.1186/s12348-015-0052-1Letter to the EditorParadoxical worsening of tuberculous chorioretinitis in a Chinese gentleman Siantar Rosalynn Grace rosalynn.g.siantar@gmail.com Ho Su Ling su_ling_ho@ttsh.com.sg Agrawal Rupesh rupeshttsh@gmail.com Department of Ophthalmology, Tan Tock Seng Hospital, Singapore, 308433 Singapore 9 7 2015 9 7 2015 2015 5 2118 4 2015 26 6 2015 © Siantar et al. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.We report a case of paradoxical worsening of tuberculous chorioretinitis after initiation of anti-tuberculous therapy (ATT). The patient had left panuveitis with tuberculous chorioretinitis and was started on systemic ATT and oral steroids a week later. However, he developed paradoxical worsening 2 months after initiation of therapy. He was continued on ATT, oral steroids and intravitreal amikacin with resolution of the chorioretinal lesion subsequently. Ocular tuberculosis often poses a diagnostic challenge, and clinicians should be aware of the possibility of paradoxical worsening despite appropriate ATT. Clinicians should strongly consider starting oral steroids concurrently with ATT when managing ocular tuberculosis.\n\nKeywords\nOcular tuberculosisChorioretinitisParadoxical worseningSteroidsissue-copyright-statement© The Author(s) 2015\n==== Body\nCorrespondence/findings\nIntroduction\nTuberculosis (TB), caused by Mycobacterium tuberculosis, can cause multi-systemic granulomatous inflammation, most commonly in the pulmonary system. Although ocular involvement is relatively uncommon, it is still a well-known extrapulmonary manifestation [1]. It often poses a diagnostic challenge to ophthalmologists, and management should be prompt as it can sight saving. The commonest manifestation of ocular tuberculosis is in the uveal tract and usually presents as a posterior uveitis, of which choroidal tuberculomas are the commonest [1]. With anti-tuberculous therapy (ATT), posterior uveitis is expected to resolve within 4 to 6 weeks [1]. We report a rare case of paradoxical worsening of ocular TB after initiation of ATT.\n\nReport\nA 50-year-old man with past medical history of diabetes mellitus presented with 1 week history of left eye blurring of vision and mild discomfort. His Snellen visual acuity was 6/7.5 in the right eye and 6/15 in the left eye. Anterior segment examination revealed signs of uveitis with multiple keratic precipitates, anterior chamber cells 1+ and retrolental cells 2+. Fundus examination showed significant vitritis, vasculitis and a well defined yellowish-white chorioretinal lesion superior to the macula (Fig. 1a, b). Anterior and posterior segment examination of the right eye was normal. He underwent a vitreous tap which identified mycobacterial DNA via polymerase chain reaction (PCR). The PCR test was the Probetec DTB assay (Becton Dickinson), and the gene sequences targeted were IS6110 and 16S rRNA. His Mantoux test measured 25 mm and chest X-ray was clear. Full blood count revealed lymphocytosis, and other systemic investigations including HIV and syphilis were negative. The working diagnosis was that of a left eye panuveitis with tuberculous chorioretinitis, and he was started on ATT (6 months course of oral rifampicin, isoniazid and ethambutol) by the infectious disease specialist. He was subsequently started on oral prednisolone 40 mg a week later. Fundus fluorescein angiogram (Fig. 2a–c) revealed non-perfusion peripheral to the choroidal lesion representing a branch retinal vein occlusion, and he underwent a sectoral panretinal photocoagulation. In the third month of treatment, the patient was noted to have clinical deterioration with decrease in visual acuity to hand movement and progression of the chorioretinal lesion to the macula (Fig. 3). He underwent a repeat vitreous tap for which mycobacterial DNA PCR was now negative and received a dose of intravitreal amikacin 0.4 mg/0.1 ml. The patient was continued on systemic oral ATT and steroids, and the lesion slowly resolved, becoming smaller in size and developing fibrosis and later scarring. The patient’s final visual acuity at last follow-up was 6/120. The patient has given consent for the report to be published.Fig. 1 \na, b Fundus photos of left eye showing vitritis, vasculitis and chorioretinitis superior to the macula\n\nFig. 2 Fundus fluorescein angiography in early (a), mid (b) and late (c) phases showing non-perfusion peripheral to area of chorioretinitis\n\nFig. 3 Fundus photo of the left eye showing progression of chorioretinitis to the macula\n\n\n\nDiscussion\nIn systemic tuberculosis, paradoxical worsening has been described as worsening of intracranial tuberculoma, meningeal disease, tuberculous meningeal radiculitis, pleural effusion and abdominal tuberculosis [1]. Paradoxical worsening after antibiotic therapy has been described in other conditions and is termed Jarisch-Herxheimer reaction (JHR) when associated with the treatment of secondary syphilis, manifesting with systemic symptoms such as fever, headache and sweating [2].\n\nIsolated intraocular JHR has been previously reported in treatment of ocular syphilis with rapid visual loss [3]. Worsening after initial therapy has also been described in other conditions such as Whipple’s disease [4] and Lyme disease [5].\n\nThe pathogenesis of paradoxical worsening in tuberculosis is not well understood. Proposed mechanisms include release of mycobacterial antigens after ATT and delayed hypersensitivity [1]. It can clinically manifest as rapid worsening of vitritis and chorioretinitis and has been reported to have good response to the addition of oral steroid [6–8] (Fig. 4).Fig. 4 Diagrammatic representation of clinical course of ocular tuberculosis\n\n\n\nIn a case series published by Hamade et al. [9], 20 patients with presumed ocular tuberculosis treated with ATT only had complete resolution with no complication. On the other hand, although paradoxical worsening of ocular tuberculosis after treatment with ATT is rare, there have been a few cases reported so far [6–8, 10]. Interestingly, in a case series of 110 patients published by Gupta et al. [11], 14 % of patients with tubercular serpiginous-like choroiditis had continued progression while on treatment. One patient was on corticosteroids only, while the rest were on ATT and corticosteroids when they were observed to have continued progression. They were managed with increased immunosuppression either with increased dosage of corticosteroids or other immunosuppressants such as azathioprine, and these patients subsequently achieved clinical resolution. These studies demonstrate variability in response of ocular TB to different treatment regimes and highlight a need for future studies with a larger population of ocular tuberculosis to better evaluate the ideal treatment regime of ATT with or without adjunctive systemic steroids.\n\nOur patient developed paradoxical worsening despite already being on oral steroid and ATT. In our case, oral steroid was initiated 1 week after the initiation of ATT. This is unique among other reported cases where steroid was only added to the treatment regime after development of ocular paradoxical worsening or started concurrently with ATT [11]. It is important to highlight that rifampicin, which is usually part of the standard regimen of ATT, may reduce bioavailability of prednisolone by 66 % [12]. This should be taken into consideration in order to achieve the therapeutic dose of systemic steroids in such patients. The benefit of starting oral steroids concurrently with ATT remains to be seen and needs further studies.\n\nConclusion\nOcular tuberculosis often poses a diagnostic and management challenge. Clinicians should be aware of the possibility of paradoxical worsening of ocular tuberculosis despite initiating ATT and consider starting systemic oral steroids concurrently and at the right dosage when managing ocular tuberculosis.\n\nAbbreviations\nATTanti-tubercular therapy\n\nDNAdeoxyribonucleic acid\n\nHIVhuman immunodeficiency virus\n\nJHRJarisch-Herxheimer reaction\n\nPCRpolymerase chain reaction\n\nTBtuberculosis\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nRGS, SLH and RA wrote the main manuscript text. All authors read and approved the final manuscript.\n\nAuthors’ information\n\nRGS (MBBS) is a first year Ophthalmology resident. SLH (MB, BCh BAO, FRCS (Edinburgh)) is a Senior Consultant Ophthalmologist. RA (MBBS, FRCS (Glasg)) is a Consultant Ophthalmologist. They are all working at the Department of Ophthalmology, Tan Tock Seng Hospital, Singapore.\n==== Refs\nReferences\n1. Gupta V Gupta A Rao NA Intraocular tuberculosis—an update Surv Ophthalmol 2007 52 6 561 587 10.1016/j.survophthal.2007.08.015 18029267 \n2. Anonymous Jarisch-Herxheimer reaction (editorial) BMJ 1967 i 384 \n3. Fathilah J Choo MM The Jarisch–Herxheimer reaction in ocular syphilis Med J Malays 2003 58 3 437 439 \n4. Playford RJ Schulenburg E Herrington CS Hodgson HJ Whipple’s disease complicated by a retinal Jarisch-Herxheimer reaction: a case report Gut 1992 33 1 132 134 10.1136/gut.33.1.132 1371261 \n5. Karma A Mikkila H Ocular manifestations and treatment of Lyme disease Curr Opin Ophthalmol 1996 7 7 12 10.1097/00055735-199606000-00002 10163463 \n6. Cheung CMG Chee SP Jarisch-Herxheimer reaction: paradoxical worsening of tuberculosis chorioretinitis following initiation of antituberculous therapy Eye (Lond) 2009 23 6 1472 1473 10.1038/eye.2008.204 18600241 \n7. Neunhoffer H Gold A Hoerauf H Herbort C Heiligenhaus A Zimmermann O Feltgen N Isolated ocular Jarisch-Herxheimer reaction after initiating tuberculostatic therapy in a child Int Ophthalmol 2014 34 675 677 10.1007/s10792-013-9848-x 24022644 \n8. Rathinam SR Lalitha P Paradoxical worsening of ocular tuberculosis in HIV patients after antiretroviral therapy Eye 2007 21 667 668 17139273 \n9. Hamade IH Tabbara KF Complications of presumed ocular tuberculosis Acta Ophthalmol (Copenh) 2010 88 905 909 10.1111/j.1755-3768.2009.01579.x \n10. Yilmaz T Selcuk E Polat N Mutlu K Choroidal tuberculoma showing paradoxical worsening in a patient with military TB Ocul Immunol Inflamm 2015 23 1 97 99 10.3109/09273948.2014.943350 25140405 \n11. Gupta V Bansal R Gupta A Continuous progression of tubercular serpiginous-like choroiditis after initiating antituberculosis treatment Am J Ophthalmol 2011 152 857 863 10.1016/j.ajo.2011.05.004 21794847 \n12. McAllister WA Thompson PJ Al-Habet SM Rogers HJ Rifampicin reduces effectiveness and bioavailability of prednisolone Br Med J (Clin Res Ed) 1983 286 6369 923 925 10.1136/bmj.286.6369.923\n\n",
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"abstract": "The benefits afforded by tocilizumab (TCZ) in patients with adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA) have been described in previous studies. However, few reports have evaluated severe hypersensitivity reactions (HSRs) to TCZ in patients with AOSD or SJIA. We describe three instances of TCZ-induced anaphylactic reactions in AOSD/SJIA patients, and review relevant prior reports on patients with various rheumatic diseases. Two of our cases exhibited shock and cardiovascular collapse; TCZ was discontinued in all three cases. All events occurred within 20 min of TCZ infusion, after at least three prior infusions, indicating an IgE-mediated mechanism and previous sensitization to TCZ. In all three cases, mild HSRs had been observed about 1 month before the anaphylactic events, but pre-medication with antihistamines and corticosteroids failed to prevent anaphylaxis. All three cases had active AOSD or SJIA disease, and were refractory to other immunosuppressive agents. It is essential to be aware that severe anaphylaxis to TCZ can develop in patients with active refractory AOSD or SJIA, and to be cautious when medicating certain patients. Anaphylaxis is a serious condition that can be fatal; TCZ infusion should not be re-challenged via pre-medication in patients who exhibited mild HSRs before TCZ without desensitization.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.;Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.;Divison of Rheumatology, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Hospital Boramae Medical Center, Seoul, South Korea.;Department of Rheumatology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, South Korea. nakhada@naver.com.",
"authors": "Park|Eun Hye|EH|http://orcid.org/0000-0002-6813-4182;Lee|Eun Young|EY|http://orcid.org/0000-0001-6975-8627;Shin|Kichul|K|http://orcid.org/0000-0002-6749-7598;Kim|Hyoun-Ah|HA|http://orcid.org/0000-0003-2609-3367",
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"title": "Tocilizumab-induced anaphylaxis in patients with adult-onset Still's disease and systemic juvenile idiopathic arthritis: a case-based review.",
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"abstract": "We report two patients with primary cardiac sarcomas. The first patient was admitted for dyspnea on exertion secondary to congestive heart failure. She was later diagnosed with intimal pleomorphic sarcoma involving the right ventricular outflow tract extending into the pulmonary artery, which was further complicated by metastasis to the lung. The second patient was admitted for left-sided weakness secondary to a right frontal lobe ischemic stroke. The patient was later diagnosed with left atrial intimal pleomorphic sarcoma, which was further complicated by metastasis to the small bowel and right femur.",
"affiliations": "Department of Internal Medicine, Atlantic Health System, Overlook Medical Center, NJ 07901, USA.;Department of Internal Medicine, Atlantic Health System, Overlook Medical Center, NJ 07901, USA.;Department of Internal Medicine, Atlantic Health System, Overlook Medical Center, NJ 07901, USA.;Division of Cardiology, Atlantic Health System, Overlook Medical Center, 99 Beauvoir Ave, Summit, NJ 07901, USA.;Division of Cardiology, Atlantic Health System, Overlook Medical Center, 99 Beauvoir Ave, Summit, NJ 07901, USA.",
"authors": "Alam|Loba|L|;Agrawal|Kavita|K|;Kankanala|Vijaya|V|;Fishberg|Robert|R|;Powell|David|D|",
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"fulltext": "\n==== Front\nCardiol Res\nCardiol Res\nElmer Press\nCardiology Research\n1923-2829 1923-2837 Elmer Press \n\n10.14740/cr1029\nCase Report\nPrimary Cardiac Undifferentiated High-Grade Intimal Pleomorphic Sarcoma: A Case Series Report\nA Case Series Report of PCSAlam Loba ac Agrawal Kavita a Kankanala Vijaya a Fishberg Robert b Powell David b a Department of Internal Medicine, Atlantic Health System, Overlook Medical Center, NJ 07901, USA\nb Division of Cardiology, Atlantic Health System, Overlook Medical Center, 99 Beauvoir Ave, Summit, NJ 07901, USA\nc Corresponding Author: Loba Alam, Department of Internal Medicine, Atlantic Health System, Overlook Medical Center, 99 Beauvoir Ave, Summit, NJ 07901, USA. Email: alamloba@gmail.com\n4 2020 \n10 3 2020 \n11 2 129 133\n3 2 2020 15 2 2020 Copyright 2020, Alam et al.2020This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.We report two patients with primary cardiac sarcomas. The first patient was admitted for dyspnea on exertion secondary to congestive heart failure. She was later diagnosed with intimal pleomorphic sarcoma involving the right ventricular outflow tract extending into the pulmonary artery, which was further complicated by metastasis to the lung. The second patient was admitted for left-sided weakness secondary to a right frontal lobe ischemic stroke. The patient was later diagnosed with left atrial intimal pleomorphic sarcoma, which was further complicated by metastasis to the small bowel and right femur.\n\nImagingCardiac magnetic resonanceEchocardiographyComputed tomographyThrombusCancer\n==== Body\nIntroduction\nPrimary cardiac sarcomas (PCSs) are extremely rare with only a few cases reported in the literature. About 25% of primary cardiac tumors are malignant, and of those 75% are sarcomas [1]. Radiologic similarities to benign myxomas/thrombus make PCSs a diagnostic challenge. Clinical presentations of PCSs include cerebrovascular accident, pulmonary embolism (PE), valvular dysfunctions, arrhythmias, and congestive heart failure. Imaging modalities such as transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), cardiovascular magnetic resonance imaging (CMR), positron emission tomography (PET), and computed tomography (CT) can provide initial information about the tumor location, size and the need for surgery. Chemotherapy and immunotherapy are based on histologic subtype of the tumor. Here we report two cases of undifferentiated PCSs, its diagnostic dilemmas and therapeutic challenges.\n\nCase Reports\nCase 1\nA 79-year-old female with past medical history of hypertension and hyperlipidemia presented with progressively worsening dyspnea on exertion and dry cough for 1 month. Electrocardiogram (ECG) showed normal sinus rhythm and left axis deviation. TTE revealed a large mobile echodensity in the right ventricular outflow tract (RVOT) measuring 6 × 2 cm (Fig. 1a, b). The peak RVOT velocity was elevated at 4.2 m/s, consistent with significant RVOT obstruction. The right ventricle was mildly enlarged and hypokinetic. CT angiogram of the chest showed intraluminal mass in the RVOT extending into the right pulmonary artery, with smaller filling defects in the distal segmental branches (Fig. 2a, b).\n\nFigure 1 Case 1: TTE demonstrating large mobile, well circumscribed echo-density in the right ventricular outflow tract (RVOT) measuring 6 × 2 cm. TTE: transthoracic echocardiogram.\n\nFigure 2 (a) Case 1: CT angiogram demonstrating large intraluminal mass centered in the RVOT. (b) Large eccentric mural thrombus in right main pulmonary artery with smaller filling defects in the distal segmental branches. CT: computed tomography; RVOT: right ventricular outflow tract.\n\nDifferential diagnosis\nBased on the clinical scenario, pulmonary thromboembolism was a possibility, and the patient was started on heparin infusion. However, the patient’s dyspnea on exertion could also have been attributed to RVOT obstruction which is rarely reported in the setting of PE. Furthermore, the well circumscribed appearance of the mass on TTE was more characteristic of a tumor. In addition, the right ventricular remodeling with global hypokinesis was consistent with right ventricular pressure overload rather than the characteristic McConnell’s sign seen in PE.\n\nDiagnostic workup/interventions\nFurther workup included a cardiac magnetic resonance imaging (MRI) which showed an enhancing RVOT mass concerning for sarcoma or other malignancies. PET scan revealed these lesions to be hypermetabolic, increasing suspicion for malignancy. The decision was made for surgical resection of the mass. The patient underwent an incomplete surgical resection of the cardiac mass with positive tumor margins. Pathology confirmed undifferentiated intimal pleomorphic sarcoma with 90% tumor infiltrating immune cells positive for programmed death-ligand 1 (PD-L1). Postoperative complications included cardiogenic shock and acute kidney injury from which patient recovered and underwent physical rehabilitation. She was started on immunotherapy with pembrolizumab to target PD-L1+ tumor cells.\n\nPatient outcome\nAlthough the patient was clinically improving, a 4-month follow-up of chest CT revealed a new solid 12 mm right suprahilar pulmonary nodule concerning for metastatic disease. The decision was made to monitor the patient clinically with continued course of pembrolizumab immunotherapy and interval follow-up imaging. Further advancement in her disease or symptomatology would require consideration for a multidisciplinary treatment approach including surgical resection if appropriate, combined with chemotherapy and/or radiation therapy.\n\nCase 2\nA 55-year-old female with past medical history of hypertension presented with left-sided weakness after sustaining a fall. Physical examination revealed decreased motor strength and sensation on the left side. ECG showed new evidence of atrial fibrillation. CT head and MRI head confirmed a right frontal lobe ischemic stroke. Evaluation for the source of embolism included a TTE which demonstrated a 2.1 × 1.2 cm mass attached to the intraatrial septum just adjacent to the anterior mitral annulus (Fig. 3a).\n\nFigure 3 (a) Case 2: TTE demonstrating mass attached to the intraatrial septum adjacent to anterior mitral annulus. (b) Atrial tumor cross section. (c) Pleomorphic, spindle-shaped cells with hyper-chromatic nuclei and prominent mitotic figures. TTE: transthoracic echocardiogram.\n\nDifferential diagnosis\nAlthough the location was atypical, a presumptive diagnosis of left atrial myxoma was made. Myxomas are the most common benign cardiac tumors typically affecting middle aged women. It can occur in either atria but are most commonly attached to the fossa ovalis of the left atrium.\n\nDiagnostic workup/interventions\nThe decision was made for surgical excision of the mass. The patient underwent resection of the mass with a bovine atrial patch repair. Pathology revealed pleomorphic, spindle-shaped cells with hyperchromatic nuclei and prominent mitotic figures consistent with high-grade intimal pleomorphic sarcoma with positive tumor margins (Fig. 3b, c). Immunophenotyping was positive for murine double minute 2 (MDM2) amplification. The patient underwent local radiotherapy with CyberKnife procedure given the positive tumor margin and no metastatic disease. She was followed-up closely with serial PET/CT and TTE every 3 months.\n\nPatient outcome\nUnfortunately, 20 months later the patient presented with small bowel obstruction and pathologic right femur fracture secondary to metastases. Pathology of metastatic lesions were consistent with initial intimal tumor. TEE, CMR and PET/CT revealed recurrence of tumor in the left atrium (Fig. 4a-d). The patient was started on palliative chemotherapy with doxorubicin and olaratumab to target local tumor recurrence and metastasis. Unfortunately, the patient expired 3 years after the initial diagnosis.\n\nFigure 4 (a) Case 2: TEE demonstrating recurrence of mobile heterogenous echodense mass in left atrium at 20-month interval. (b) Hypermetabolic left atrial lesion on PET/CT. (c) Mass adjacent to anterior mitral leaflet (and prolapses into left ventricle) on CMR. (d) Mass within the left atrium on CMR. TEE: transesophageal echocardiogram; PET/CT: positron emission tomography/computed tomography; CMR: cardiovascular magnetic resonance imaging.\n\nDiscussion\nPrimary cardiac sarcomas are extremely rare neoplasms arising from mesenchymal cells. We present two female patients with undifferentiated intimal pleomorphic sarcoma, previously named malignant fibrous histiocytoma. Intimal pleomorphic sarcomas have a female predominance, with mean presenting age of 47, and involve the posterior wall of the left atrium in > 80% of reported cases [2]. The most common reported symptom of undifferentiated intimal pleomorphic sarcomas includes dyspnea (74%), followed by chest pain and palpitations (40%) [2]. Embolic phenomena have also been reported in organs including brain, lungs, bones, and adrenal glands [2]. Presenting symptoms of primary cardiac sarcomas depend on the location and the size of the tumor rather than the tumor histology. Left heart sarcomas are broad based and abnormally located which differentiates them from myxomas, and commonly present with dyspnea on exertion due to congestive heart failure from obstruction of intracardiac blood flow [3]. Right heart tumors are bulkier and exophytic in nature, commonly presenting with non-specific symptoms [3].\n\nDue to the rareness of primary cardiac sarcomas and consequent lack of randomized controlled trials, no standard treatment protocol has been established. Currently, in addition to surgical resection, two trends are at the frontier of cardiac sarcoma treatment: molecular agents that target genomic alterations and immunotherapy that target immune mediated cancer cells. Based on tumor pathology, our patients demonstrated two different molecular tumor subtypes: case 1 had PD-L1+ tumor cells, and case 2 had MDM2+ amplification. PD-L1 is a key immune checkpoint protein that plays a significant role in sarcomagenesis [4]. Upregulation of PD-L1 is associated with increased tumor aggressiveness [4]. PD-L1+ sarcomas can be targeted with single agent immunotherapy such as pembrolizumab, as seen in our first case.\n\nMDM2 is a proto-oncogene, which is one of the most frequently mutated genes in cardiac intimal sarcomas [5]. Upregulation of MDM2 results in loss of p53-dependent activities, such as apoptosis and cell cycle arrest. There are no established guidelines for chemotherapy targeting MDM2. Newer agent such as olaratumab, a monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR)-α, combined with doxorubicin has limited data to show drug efficacy against soft tissue sarcomas [6].\n\nThe overall prognosis of malignant primary cardiac tumors remains poor despite early detection and surgical resection [7]. Patients who receive multimodality treatment with any combination of surgery, chemotherapy, immunotherapy, and radiation have better outcome compared to any single treatment modality alone [8, 9]. Adjuvant treatment needs to be individualized based on the patient’s clinical course and depends on residual disease after initial surgical resection and specific tumor variants.\n\nLearning objectives\nThere are several learning objectives involved in this study: 1) Left heart sarcomas are broad based and commonly located along the posterior wall of the left atrium, while right heart sarcomas are bulkier and exophytic in nature; 2) Left heart sarcomas commonly present with dyspnea on exertion due to congestive heart failure from obstruction of intracardiac blood flow, and right heart sarcomas commonly present with non-specific symptoms; 3) Multimodality imaging including TTE/TEE, PET, cardiac CT and cardiac MRI can characterize benign versus malignant primary cardiac tumors based on tumor invasion across tissue planes, associated effusions and lymphadenopathy, and visible metastasis; 4) Prompt referral to experienced centers for multidisciplinary approach to surgical resection combined with adjuvant chemotherapy, immunotherapy and radiotherapy can improve outcome; 5) Advancements and better understanding of tumor immunologic and molecular markers can further improve targeted treatment plan in the future.\n\nConclusions\nNon-specific presentations, rarity, and radiologic similarity to benign myxoma or thrombus makes PCSs a diagnostic challenge preoperatively. Advanced imaging modalities (TTE/TEE, CMR, PET/CT) can identify tumors as malignant based on characteristics such as tumor invasion across tissue planes, associated effusions and lymphadenopathy, or visible metastasis. Advanced imaging is further helpful in demonstrating tumor location and staging, anticipating complications, and planning surgical interventions. With promising advancements and better understanding of targeted adjuvant therapies, clinicians may find hope for improved long-term prognosis.\n\nWe thank Dr. Gregg Rosner from the Division of Cardiology, Columbia University, for his valuable insights on cardiac sarcoma management.\n\nFinancial Disclosure\nNone to declare.\n\nConflict of Interest\nThere are no conflicts of interest associated with this manuscript.\n\nInformed Consent\nInformed consents were obtained from each patient.\n\nAuthor Contributions\nLoba Alam, Kavita Agrawal, Vijaya Kankanala contributed to conception and design of the study, and acquisition of the data. Robert Fishberg and David Powell were involved in analysis and interpretation of data, and contributed to drafting and revising the article.\n\nData Availability\nThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\n\nAbbreviations\nPCSprimary cardiac sarcoma\n\nTTEtransthoracic echocardiogram\n\nTEEtransesophageal echocardiogram\n\nCMRcardiovascular magnetic resonance imaging\n\nCTcomputed tomography\n\nPETpositron emission tomography\n\nRVOTright ventricular outflow tract\n\nPD-L1programmed death-ligand 1\n\nMDM2murine double minute 2\n==== Refs\nReferences\n1 Hudzik B Miszalski-Jamka K Glowacki J Lekston A Gierlotka M Zembala M Polonski L et al Malignant tumors of the heart Cancer Epidemiol 2015 39 5 665 672 10.1016/j.canep.2015.07.007 26239627 \n2 Maleszewski JJ Bois MC Bois JP Young PM Stulak JM Klarich KW Neoplasia and the heart: pathological review of effects with clinical and radiological correlation J Am Coll Cardiol 2018 72 2 202 227 10.1016/j.jacc.2018.05.026 29976295 \n3 Simpson L Kumar SK Okuno SH Schaff HV Porrata LF Buckner JC Moynihan TJ Malignant primary cardiac tumors: review of a single institution experience Cancer 2008 112 11 2440 2446 10.1002/cncr.23459 18428209 \n4 Zheng C You W Wan P Jiang X Chen J Zheng Y Li W et al Clinicopathological and prognostic significance of PD-L1 expression in sarcoma: A systematic review and meta-analysis Medicine (Baltimore) 2018 97 25 e11004 10.1097/MD.0000000000011004 29923984 \n5 Oliner JD Saiki AY Caenepeel S The role of MDM2 amplification and overexpression in tumorigenesis Cold Spring Harb Perspect Med 2016 6 6 a026336 10.1101/cshperspect.a026336 27194168 \n6 Pender A Jones RL Olaratumab: a platelet-derived growth factor receptor-alpha-blocking antibody for the treatment of soft tissue sarcoma Clin Pharmacol 2017 9 159 164 10.2147/CPAA.S130178 29270033 \n7 Elbardissi AW Dearani JA Daly RC Mullany CJ Orszulak TA Puga FJ Schaff HV Survival after resection of primary cardiac tumors: a 48-year experience Circulation 2008 118 14 Suppl S7 15 10.1161/CIRCULATIONAHA.107.783126 18824772 \n8 Ramlawi B Leja MJ Abu Saleh WK Al Jabbari O Benjamin R Ravi V Shapira OM et al Surgical treatment of primary cardiac sarcomas: review of a single-institution experience Ann Thorac Surg 2016 101 2 698 702 10.1016/j.athoracsur.2015.07.087 26476808 \n9 Abu Saleh WK Ramlawi B Shapira OM Al Jabbari O Ravi V Benjamin R Durand JB et al Improved outcomes with the evolution of a neoadjuvant chemotherapy approach to right heart sarcoma Ann Thorac Surg 2017 104 1 90 96 10.1016/j.athoracsur.2016.10.054 28189277\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "11(2)",
"journal": "Cardiology research",
"keywords": "Cancer; Cardiac magnetic resonance; Computed tomography; Echocardiography; Imaging; Thrombus",
"medline_ta": "Cardiol Res",
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"title": "Primary Cardiac Undifferentiated High-Grade Intimal Pleomorphic Sarcoma: A Case Series Report.",
"title_normalized": "primary cardiac undifferentiated high grade intimal pleomorphic sarcoma a case series report"
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"abstract": "BACKGROUND\nDengue fever is the commonest mosquito-borne illness in the tropics and subtropics. Renal transplantation is one of the ever expanding modes of treatment of end-stage renal disease. Hepatitis B is a common infection in South and East Asia, but rare in Sri Lanka. Here we describe a recipient of a renal transplant with a stable graft, on antiviral treatment for hepatitis B infection, developing dengue superinfection and entering a complex clinical course. To the best of our knowledge this is the first report of such a case.\n\n\nMETHODS\nA 59-year-old Sri Lankan woman developed acute renal failure and needed dialysis support; she had upper gastrointestinal bleeding that needed transfusions, pancytopenia, and a prolonged phase of thrombocytopenia. She eventually recovered from illness, and her renal functions returned to baseline levels. The differences in presentation, signs, symptoms, and mortality of renal transplant recipients infected with dengue fever from the general population are discussed, with possible reasons for altered presentation.\n\n\nCONCLUSIONS\nDengue superinfection in transplant recipients with hepatitis B infection can lead to management difficulties. The recovery can be slow as seen from this case, with prolonged thrombocytopenia.",
"affiliations": "Department of Nephrology, Teaching Hospital, Jaffna, Sri Lanka. rangamw2003@yahoo.com.;University Medical Unit, Teaching Hospital, Karapitiya, Galle, Sri Lanka.;Department of Clinical Medicine, Faculty of Medicine, University of Colombo, 8 Kyinsey Road, Colombo, Sri Lanka.",
"authors": "Weerakkody|Ranga Migara|RM|;Palangasinghe|Dhammika Randula|DR|;Wijewickrama|Eranga Sanjeewa|ES|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 179010.1186/s13256-018-1790-0Case ReportDengue fever in a kidney transplant recipient with complicated clinical course: a case report Weerakkody Ranga Migara rangamw2003@yahoo.com 1Palangasinghe Dhammika Randula dhammika27@yahoo.com 2Wijewickrama Eranga Sanjeewa erangasw@gmail.com 31 0000 0004 0493 4054grid.416931.8Department of Nephrology, Teaching Hospital, Jaffna, Sri Lanka 2 University Medical Unit, Teaching Hospital, Karapitiya, Galle, Sri Lanka 3 0000000121828067grid.8065.bDepartment of Clinical Medicine, Faculty of Medicine, University of Colombo, 8 Kyinsey Road, Colombo, Sri Lanka 1 9 2018 1 9 2018 2018 12 2605 2 2018 3 8 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDengue fever is the commonest mosquito-borne illness in the tropics and subtropics. Renal transplantation is one of the ever expanding modes of treatment of end-stage renal disease. Hepatitis B is a common infection in South and East Asia, but rare in Sri Lanka. Here we describe a recipient of a renal transplant with a stable graft, on antiviral treatment for hepatitis B infection, developing dengue superinfection and entering a complex clinical course. To the best of our knowledge this is the first report of such a case.\n\nCase presentation\nA 59-year-old Sri Lankan woman developed acute renal failure and needed dialysis support; she had upper gastrointestinal bleeding that needed transfusions, pancytopenia, and a prolonged phase of thrombocytopenia. She eventually recovered from illness, and her renal functions returned to baseline levels. The differences in presentation, signs, symptoms, and mortality of renal transplant recipients infected with dengue fever from the general population are discussed, with possible reasons for altered presentation.\n\nConclusions\nDengue superinfection in transplant recipients with hepatitis B infection can lead to management difficulties. The recovery can be slow as seen from this case, with prolonged thrombocytopenia.\n\nKeywords\nDengue feverRenal transplantHepatitis BAcute kidney injuryPancytopeniaissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nDengue fever (DF) is the commonest mosquito-borne illness in the tropics and subtropics. Many outbreaks have had devastating results over many years. In the majority of sufferers, DF is a subclinical infection, and in a minority, it presents with hemorrhagic manifestations. Solid organ transplant recipients have displayed a spectrum of clinical manifestations similar to their non-transplant counterparts. Immunosuppressive treatment plays a part in relatively less complications in transplant recipients than in their non-transplant counterparts, although fatal outcomes had been reported [1–4]. The course of the illness can be prolonged, in the form of: thrombocytopenia; unusual complications, such as graft dysfunction; or uncommon complications, like acute colitis [3, 5]. The occurrence of hepatorenal dysfunction in DF is being increasingly reported among previously healthy patients [6, 7] and, as a result, there is a novel enthusiasm on the pathogenesis of the disease.\n\nHepatitis B is an important, challenging infection among renal transplant recipients, although it is very rare among Sri Lankans due to safe blood products and immunization. The prevalence among patients with a renal transplant is estimated to approximately 0.1–0.4% [8]. There are no statistics about the Sri Lankan population, but in the authors’ experience, it is extremely rare. Here we report a case of DF in a post kidney transplant patient in a background of chronic active hepatitis B infection. Information on confirmed cases of DF among solid organ transplant recipients in the literature is limited, with very few fatalities; most of the fatalities occurring during the immediate post transplant period [2, 4]. Complete recovery of a post liver transplant recipient with DF was reported locally [9]. To the best of our knowledge this is the first reported case of DF in a post kidney transplant patient with chronic active hepatitis B infection.\n\nCase presentation\nA 59-year-old Sri Lankan woman, recipient of an ABO matched, living donor kidney transplant performed in 1997, presented with a 3-day history of fever, a fall, mild headache, arthralgia, myalgia, abdominal pain, and progressive drowsiness. She was on tenofovir, azathioprine 75 mg daily, and prednisolone 5 mg daily. She denied respiratory, bowel, or urinary symptoms. We did not find a contact history of fever. She did not have any seizures during the illness. Her primary renal disease was membranous glomerulopathy diagnosed in 1989. She had diabetes and developed end-stage disease in 1996 and was commenced on hemodialysis. She received a transplant in 1997 and enjoyed an uncomplicated post-transplant period with creatinine values between 84 and 104 umol/L (50–110), and an excellent quality of life.\n\nIn 2013, she presented with progressive abdominal distension due to ascites and with stigmata of liver disease and was diagnosed as having cirrhosis. She was diagnosed as having hepatitis B infection, where the viral load was in the order of log 9, and renal function was within normal range. Serology for hepatitis C and human immunodeficiency virus (HIV) was negative. Therapy was initiated with lamivudine, but an inadequate response led to replacement with tenofovir 330 mg daily, which brought down the viral loads to order of log 2. She was very compliant in all her medications and did not have major adverse effects to any of her medications.\n\nOn examination she was drowsy, with Glasgow Coma Scale (GCS) of 12/15, and had flapping tremors. She was pale, anicteric, and was well hydrated. No skin rashes, cutaneous bleeding, or neck stiffness was noted. Her abdomen was soft on examination and tenderness noted in right iliac fossa overlying the graft. Her respiratory system and cardiovascular system examinations were clinically normal. Optic fundi were normal except for background diabetic retinopathy. Capillary blood sugar on admission was 7.7 mmol/L. Her initial investigations revealed pancytopenia on day 3 of the illness with hemoglobin (Hb) of 78 g/L (120–160), white cell count of 3.7 × 109/L (3.5–12), and platelet count of 52 × 109 /L (150–400). Blood picture showed normochromic normocytic red cells with reduced count, mild to moderate rouleaux formation, normal white cell count with hypersegmented and toxic-looking neutrophils. Severe thrombocytopenia was confirmed on the blood picture. We did not find any evidence of microangiopathic hemolytic anemia. Her C-reactive protein (CRP) level on admission was 108 mg/dL (< 6). Urine analysis showed 4–6 pus cells and 2–4 red cells, but no proteinuria. Serum creatinine was raised to 630 umol/L, from a background of 96 umol/L, checked 2 weeks ago on her routine clinic visit. Her serum creatinine phosphokinase level was normal. Urine and blood cultures were negative on day 3 of the illness. Non-contrast computed tomography (CT) of her brain was normal and a hip X-ray did not show evidence of any fracture. An ultrasound scan of her abdomen showed swollen kidney, with preserved corticomedullary demarcation, raising suspicions of acute renal parenchymal disease. She had no splenomegaly ultrasonically and portal vein diameter was 1.7 cm. She did not have oligo-anuria at that time. She developed metabolic acidosis, and with rising potassium levels, we decided to start renal replacement. Dengue non-structural protein 1 (NS1) antigen (day 2) was positive, but other viral studies such as cytomegalovirus and Epstein–Barr virus were negative. Subsequent blood counts revealed progressive decline in platelet and white cell counts. She developed an upper gastrointestinal (GI) bleed on day 6 (Hb, 52 g/L) and was supported with blood. From day 3 onward, of the illness, we empirically treated her with intravenously administered ceftriaxone for a suspected bacterial infection owing to her high CRP. Azathioprine and tenofovir were temporarily withheld due to possible marrow suppression and orally administered steroids doses were increased from 7.5 mg to 30 mg daily. Dengue IgM and IgG on day 6 were positive. Blood and urine cultures were sterile. Free fluid in the hepatorenal pouch was demonstrated on day 6 of the illness where she entered the critical phase. The lowest platelet count recorded was 5 × 109/L. Her conscious level gradually improved and she was fully alert by day 5. She was never oligo-anuric during the period of illness. Upper GI endoscopy revealed portal gastropathy, antral gastritis, and non-bleeding small esophageal varices. We reintroduced tenofovir from day 5 onward. We had already taken her off azathioprine, but pancytopenia persisted. Intravenously administered ceftriaxone 1 g twice daily was continued up to 14 days, until CRP returned to normal. Her fluid management was monitored clinically, rather than according to the National Dengue guidelines, due to acute kidney injury (AKI). She was discharged on day 16 with creatinine normalized, but her liver enzymes and thrombocytopenia took 6 weeks to correct themselves. A review of this patient 12 weeks later revealed normal serum creatinine level and return of her blood counts to baseline. Figure 1 shows the case presentation in a timeline, while Fig. 2 describes the changes in the biochemical parameters. Table 1 describes pre-morbid, the most abnormal and convalescent values of important biochemical tests.Fig. 1 Case presentation in a timeline. GI gastrointestinal, HIV human immunodeficiency virus, NS1 non-structural protein 1\n\nFig. 2 Changes in biochemical parameters over the course of hospital stay. Hb hemoglobin, Plt platelets, WCC white cell count\n\nTable 1 Summary of laboratory investigations\n\nTest\tUnits\tReference\tPre-illness\tMost abnormal\tDay#\tDischarge\tFollow up\t\nPotassium\tumol/L\t3.5–5.1\t4.1\t6.3\t2\t3.3\t4.0\t\nCRP\tumol/L\t< 6\t< 6\t> 192*\t2\t6\t< 6\t\nESR\tmm/hour\t< 20\t24\t128\t2\t60\t12\t\nAlbumin\tmg/dL\t35–50\t4.0\t2.8\t7\t3.9\t4.7\t\nALT\tIU\t< 40\t27\t116\t10\t67\t28\t\nAST\tIU\t< 40\t40\t267\t10\t160\t39\t\nALT alanine aminotransferase, AST aspartate aminotransferase, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Day# number of days after admission to the hospital, Pre-illness the most recent value before contracting the illness, Follow up is after 84 days, *CRP was measured using dilution method, and levels more than 32 times dilution expressed as > 192\n\n\n\nDiscussion\nDF occurs in outbreaks and has become the most widespread and important mosquito-borne illness in Sri Lanka, as well as in South and East Asia. It is mostly an asymptomatic or self-limiting infection; it has the ability to cause high morbidity and mortality. Although uncommon, complications like pericardial effusion, AKI, and acute colitis were reported with DF [1, 5, 10]. Despite high prevalence, DF is a rarely reported disease among patients who have had solid organ transplants. Similar to the non-transplant population, DF follows a benign course in most recipients of renal transplants. Severe dengue infection is rare [1, 10], but commoner than in non-transplant population [11]. The effects may be related to the relative balance between immunosuppression reducing the risk for antibody-enhanced complications, and reduced clearance of the viremia. Diminished T cell response can lead to atypical presentations in a transplant recipient [3, 4, 6]. Similar to the non-transplant population, early recognition will help to prevent or minimize complications. A systematic review by Weerakkody et al. showed that physical signs and symptoms differ from the general population [11]. Studies had shown that approximately 8.9% mortality was associated with dengue infection among renal transplant recipients [11]. In some cases mortality is a direct effect of bleeding [2], while others were due to secondary causes (for example, sepsis, type 1 respiratory failure) [7, 8].\n\nOur patient had a prolonged period of thrombocytopenia running up to 16 days. Prolonged thrombocytopenia is a recognized feature of DF in patients with a renal transplant [1, 10]. Our patient had normal renal functions for 19 years post transplant up to this illness. The common causes of graft failure would be rejection, pyelonephritis, allograft nephropathy, and hepatorenal syndrome in this patient. Her urine analysis and sterile culture are not supportive of pyelonephritis, but high CRP and swollen allograft during imaging makes it a possibility. DF is known to cause renal dysfunction, sometimes to the extent of needing renal replacement [1, 3, 4]. However, elevated CRP is a known association with severe DF [12, 13]. We did not pursue a renal biopsy in the face of severe bleeding risk and rapid improvement in renal functions. Pre-renal AKI was also unlikely because she was not dehydrated and she never became oligo-anuric. Rejection is unlikely, given the spontaneous recovery without anti-rejection medication. Hepatorenal syndrome is a very likely cause, but oligo-anuria is the norm rather than an exception. DF as the cause for her AKI remains the plausible explanation. This patient had severe AKI which needed dialysis, but had a complete recovery of renal function of the allograft.\n\nSeveral factors could have contributed to the pancytopenia in this patient, including azathioprine, tenofovir, acute viral illness, and chronic liver cells disease; however, normal blood counts before the febrile illness make this diagnosis unlikely. Leukopenia and thrombocytopenia are well-recognized features of DF, including the population of transplant recipients [1]. A fall in Hb and packed cell volume instead of the usual hemoconcentration during the critical phase can be associated with gut bleeding. However, true aplastic anemia has been described with DF, and some of these cases have been attributed to hemophagocytic syndrome [14] and others to bone marrow suppression [15, 16]. Our patient did not undergo a bone marrow biopsy; hence, it is impossible to differentiate bone marrow pathology from a peripheral pathology. However, a very low reticulocyte index of 0.2% indicated that the former is more likely. Aplastic anemia reported with dengue had been treated with intravenously administered immunoglobulins, steroids, and cyclosporine [15, 16]. Our patient was already on immunosuppressives; hence, the aplastic crisis could have become self-limited with the medications she was already receiving.\n\nThis patient was a particularly difficult case to manage due to multiple comorbidities such as cirrhosis, hepatitis B infection, acute renal failure which needed dialysis, pancytopenia, and immunosuppression. Management guidelines are not available on patients with such a complex clinical picture due to the rarity of the combinations of the disease. Accurate clinical assessment and objective-guided fluid management made management of this patient a success.\n\nConclusion\nManagement of dengue in patients with comorbidities could be difficult. Dengue can cause severe allograft dysfunction, but it is reversible at least in many cases.\n\nAbbreviations\nAKIAcute kidney injury\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nDFDengue fever\n\nGCSGlasgow Coma Scale\n\nGIGastrointestinal\n\nHbHemoglobin\n\nHIVHuman immunodeficiency virus\n\nNS1Non-structural protein 1\n\nAcknowledgements\nWe would like to acknowledge all the staff of the Medical Intensive Care Unit, National Hospital of Sri Lanka, in the help they have given in managing this patient.\n\nAuthors’ contributions\nRMW has headed the nephrology management, and wrote the manuscript. DRP was involved in medical management of dengue and helped in writing the manuscript. ESW is the supervising clinician, and has critically appraised the manuscript. All three authors have read and agree with the contents of the manuscript.\n\nConsent for publication\nWritten informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Azevedo LS Carvalho DB Matuck T Alvarenga MF Morgado L Magalhaes I Dengue in renal transplant patients: a retrospective analysis Transplantation 2007 84 6 792 794 10.1097/01.tp.0000280547.91617.25 17893614 \n2. Maia SH Brasil IR Esmeraldo Rde M Ponte CN Costa RC Lira RA Severe dengue in the early postoperative period after kidney transplantation: two case reports from hospital Geral de Fortaleza Rev Soc Bras Med Trop 2015 48 6 783 785 10.1590/0037-8682-0205-2015 26676509 \n3. Nasim A Anis S Baqi S Akhtar SF Baig-Ansari N Clinical presentation and outcome of dengue viral infection in live-related renal transplant recipients in Karachi Pakistan Transpl Infect Dis 2013 15 5 516 525 23890225 \n4. Prasad N Bhadauria D Sharma RK Gupta A Kaul A Srivastava A Dengue virus infection in renal allograft recipients: a case series during 2010 outbreak Transpl Infect Dis 2012 14 2 163 168 10.1111/j.1399-3062.2011.00699.x 22212524 \n5. Park SB Ryu SY Jin KB Hwang EA Han SY Kim HT Acute colitis associated with dengue fever in a renal transplant recipient Transplant Proc 2008 40 7 2431 2432 10.1016/j.transproceed.2008.07.037 18790257 \n6. Jain PK Sharma AK Agarwal N Siddiqi MZ Pawal P Gaba R A prospective clinical study of incidence of hepatorenal and hematological complications in dengue fever and management of symptomatic bleed in bundelkhand region of northern India with fresh whole blood J Infect Dis Immun 2011 3 7 124 133 \n7. Lima EQ Gorayeb FS Zanon JR Nogueira ML Ramalho HJ Burdmann EA Dengue haemorrhagic fever-induced acute kidney injury without hypotension, haemolysis or rhabdomyolysis Nephrol Dial Transplant 2006 22 11 3322 3326 10.1093/ndt/gfm431 \n8. Kalia H Fabrizi F Martin P Hepatitis B virus and renal transplantation Transplantation 2011 25 3 102 109 10.1016/j.trre.2011.02.001 \n9. Weerakkody RM Palangasinghe DR Dalpatadu KPC Rankothkumbura JP Cassim MRN Karunanayake P Dengue fever in a liver-transplanted patient: a case report J Med Case Rep 2014 8 378 10.1186/1752-1947-8-378 25412699 \n10. Renaud CJ Manjit K Pary S Dengue has a benign presentation in renal transplant patients: a case series Nephrology (Carlton) 2007 12 3 305 307 10.1111/j.1440-1797.2007.00785.x 17498128 \n11. Weerakkody RM Patrick JA Sheriff MH Dengue fever in renal transplant patients: a systematic review of literature BMC Nephrol 2017 18 1 15 10.1186/s12882-016-0428-y 28086881 \n12. Bodinayake CK, Weerarathna TP, Liyanage PLGC, LS Basnayake, editors. Value of C-reactive protein in assessing adverse outcomes of dengue fever. Annual Scientific Sessions; 2004. http://www.ruh.ac.lk/research/academic_sessions/2004_mergepdf/80-81.PDF. Accessed 25 Feb 2018.\n13. Chen CC Lee IK Liu JW Huang SY Wang L Utility of C-reactive protein levels for early prediction of dengue severity in adults Biomed Res Int 2015 2015 936062 26247033 \n14. Jain D Singh T Dengue virus related hemophagocytosis: a rare case report Hematology 2008 13 5 286 288 10.1179/102453308X316095 18854091 \n15. Albuquerque PL Silva Júnior GB Diógenes SS Silva HF Travel Med Infect Dis 2009 7 2 118 112 10.1016/j.tmaid.2009.01.001 19237145 \n16. Ramzan MPS Sachdeva A Post-dengue fever severe aplastic anemia: a rare association Hematol Oncol Stem Cell Ther 2012 5 2 122 124 10.5144/1658-3876.2012.122 22828377\n\n",
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"issn_linking": "1752-1947",
"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "Acute kidney injury; Dengue fever; Hepatitis B; Pancytopenia; Renal transplant",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000998:Antiviral Agents; D003715:Dengue; D005260:Female; D006509:Hepatitis B; D006521:Hepatitis, Chronic; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008875:Middle Aged; D011788:Quality of Life; D015163:Superinfection; D013921:Thrombocytopenia",
"nlm_unique_id": "101293382",
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"title": "Dengue fever in a kidney transplant recipient with complicated clinical course: a case report.",
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"abstract": "BACKGROUND\nIn the United States, cocaine is a commonly used drug of abuse. It is also a recognized contributing factor for both hemorrhagic and ischemic strokes. However, cocaine-induced basilar artery thrombosis has rarely been reported in the literature.\n\n\nMETHODS\nOur patient was a 51-year-old African American woman with a history of polysubstance abuse who presented to the emergency department for acute behavior changes. Later, during admission, she had a dramatic decrease in motor strength in all extremities and a positive Babinski reflex bilaterally. The results of her toxicology reports were positive for cocaine; in addition, results of magnetic resonance angiography and magnetic resonance imaging were consistent with acute thrombosis and subsequent infarction of the basilar artery. Her mental status improved, but she was only able to communicate via movements of her eyes.\n\n\nCONCLUSIONS\nOur patient developed locked-in syndrome after use of cocaine. Given the prevalence of its use in the United States, cocaine use should be included among the potential causes of locked-in syndrome.",
"affiliations": "Division of Pulmonary & Critical Care Medicine, University of Maryland School of Medicine, 110 S. Paca Street, Baltimore, MD, 21201, USA. oali@som.umaryland.edu.;Division of Internal Medicine, University of Maryland Midtown Campus, 827 Linden Avenue, Baltimore, MD, 21201, USA.;Division of Internal Medicine, University of Maryland Midtown Campus, 827 Linden Avenue, Baltimore, MD, 21201, USA.;Division of Internal Medicine, University of Maryland Midtown Campus, 827 Linden Avenue, Baltimore, MD, 21201, USA.;Division of Pulmonary & Critical Care Medicine, University of Maryland School of Medicine, 110 S. Paca Street, Baltimore, MD, 21201, USA.;Division of Internal Medicine, University of Maryland Midtown Campus, 827 Linden Avenue, Baltimore, MD, 21201, USA.;Division of Pulmonary, Critical Care & Sleep Medicine, University of Maryland School of Medicine, 110 S. Paca Street, Baltimore, MD, 21201, USA.",
"authors": "Ali|Osman|O|;Bueno|Mark G|MG|;Duong-Pham|Trinh|T|;Gunawardhana|Nuwan|N|;Tran|Dena H|DH|;Chow|Robert D|RD|;Verceles|Avelino C|AC|",
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"doi": "10.1186/s13256-019-2278-2",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 227810.1186/s13256-019-2278-2Case ReportCocaine as a rare cause of locked-in syndrome: a case report Ali Osman 410.328.8141oali@som.umaryland.edu 1Bueno Mark G. markbu@auamed.net 2Duong-Pham Trinh trinhd@auamed.net 2Gunawardhana Nuwan nuwang@auamed.net 2Tran Dena H. dena.tran@som.umaryland.edu 1Chow Robert D. rchow@umm.edu 2Verceles Avelino C. avercele@medicine.umaryland.edu 31 0000 0001 2175 4264grid.411024.2Division of Pulmonary & Critical Care Medicine, University of Maryland School of Medicine, 110 S. Paca Street, Baltimore, MD 21201 USA 2 Division of Internal Medicine, University of Maryland Midtown Campus, 827 Linden Avenue, Baltimore, MD 21201 USA 3 0000 0001 2175 4264grid.411024.2Division of Pulmonary, Critical Care & Sleep Medicine, University of Maryland School of Medicine, 110 S. Paca Street, Baltimore, MD 21201 USA 19 11 2019 19 11 2019 2019 13 33725 1 2019 27 9 2019 © The Author(s). 2019Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nIn the United States, cocaine is a commonly used drug of abuse. It is also a recognized contributing factor for both hemorrhagic and ischemic strokes. However, cocaine-induced basilar artery thrombosis has rarely been reported in the literature.\n\nCase presentation\nOur patient was a 51-year-old African American woman with a history of polysubstance abuse who presented to the emergency department for acute behavior changes. Later, during admission, she had a dramatic decrease in motor strength in all extremities and a positive Babinski reflex bilaterally. The results of her toxicology reports were positive for cocaine; in addition, results of magnetic resonance angiography and magnetic resonance imaging were consistent with acute thrombosis and subsequent infarction of the basilar artery. Her mental status improved, but she was only able to communicate via movements of her eyes.\n\nConclusion\nOur patient developed locked-in syndrome after use of cocaine. Given the prevalence of its use in the United States, cocaine use should be included among the potential causes of locked-in syndrome.\n\nKeywords\nBasilar arteryCocaine-related disordersMagnetic resonance imagingQuadriplegiaLocked-in syndromeissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nAccording to the National Survey on Drug Use and Health (NSDUH), cocaine is the second most popular recreational drug in the United States behind marijuana. The NSDUH reported in 2008 that 36.7 million people in the United States had used cocaine during their lifetime [1]. In 2012, the NSDUH found that nearly 4.7 million Americans aged 12 or older reported using cocaine in the past year, and almost 38 million Americans reported ever using cocaine in their lifetime [2].\n\nLocked-in syndrome (LIS) is a rare manifestation of stroke and is typically challenging for clinicians to diagnose, taking an average of 78 days to uncover [3]. The syndrome is characterized by the following findings: paralysis of the limbs and oral structures, cranial nerve deficits, and intact consciousness with retention of cognitive function and vertical eye movement [4]. The first contemporary description of the syndrome was published in 1941 by Cairns and associates [5]. In 1966, Plum and Posner coined the term locked-in syndrome in their description of a similar case [6]. LIS results from a lesion affecting the corticospinal, corticobulbar, and corticopontine tracts of the ventral pons, with the most common cause of LIS being embolism or thrombosis of the basilar artery [7]. The second most common cause of LIS is hemorrhage or head trauma [8]. The diagnosis of LIS requires a combination of physical examination abnormalities and confirmatory findings based on neuroimaging using magnetic resonance imaging (MRI) with diffusion-weighted imaging or magnetic resonance angiography (MRA) [9].\n\nAlthough cocaine use is a well-documented contributing factor in both ischemic and hemorrhagic strokes [10, 11], few cases have been reported in the medical literature describing cocaine as a potential cause of LIS [12]. The mechanism by which cocaine can induce a stroke is not entirely understood. In general, cocaine is thought to work at the presynaptic junction of sympathetic neurons to inhibit the reuptake of noradrenaline, dopamine, and 5-hydroxytryptamine. Cocaine-induced strokes are ischemic in nature, likely due to vasospasm of the cerebral arteries caused by excess neurotransmitters at the synaptic cleft [13]. In addition, cocaine may promote thromboemboli through enhanced platelet aggregation and potentiated endothelial dysfunction [13].\n\nIn this case report, we expand the literature and describe an extension of the time frame for onset of cocaine-induced LIS symptoms. Additionally, we review updated reports and proposed pathophysiology of cocaine-induced LIS.\n\nCase presentation\nA 51-year-old African American woman with a limited medical history significant for depression and polysubstance abuse was brought to our emergency department by her boyfriend because of her bizarre behavior, nonsensical communication, and listlessness. As per her boyfriend, the patient was seen inhaling cocaine on the night prior to admission to the hospital. Owing to her altered mental status, her history was obtained from her boyfriend and sister and was limited because of their limited knowledge of the patient’s previous health issues. However, upon further questioning, it was discovered that the patient’s family history was significant for maternal chronic kidney disease, diabetes mellitus, and hypertension. Furthermore, it was revealed that the patient was unemployed, used tobacco, had substance abuse issues specifically with cocaine and heroin, and had abstained from alcohol use for over 10 years. The patient’s initial vital signs were significant for a body temperature of 36.7 °C, heart rate of 60–70 beats/minute, blood pressure of 113/73 mmHg, and respiratory rate of 20 breaths/minute. Her initial physical examination revealed that she was an awake and alert obese African American woman appearing to be her stated age, was confused and very agitated, and was not following commands. She had intact corneal and pupillary reflexes and clear lung sounds. She had regular heart sounds with no murmurs, rubs, or gallops and had a soft nontender abdomen. Additionally, the result of her neurological examination was negative for muscle rigidity, nystagmus, or diffuse hyperhidrosis. However, her examination revealed generalized confusion and agitation. Her pupils were round but sluggishly reactive to light bilaterally. She opened her eyes upon command and moved all four extremities spontaneously, withdrawing appropriately to noxious stimuli, and she exhibited dysarthria.\n\nThe result of her urine toxicology was positive for cocaine, opiates, and benzodiazepines. The results of her laboratory studies were unremarkable, with the exception of a potassium level of 3.1 mEq/L. After blood cultures were drawn, empirical intravenous vancomycin and cefepime were initiated for possible encephalomeningitis. The findings of initial unenhanced computed tomography (CT) of the brain were negative for any acute changes. Etomidate and rocuronium were administered for the patient’s agitation, and she was intubated and started on a propofol infusion.\n\nOn day 3 of admission, when the patient had been weaned off sedation and paralytic therapy, she demonstrated decorticate posturing, intact gag and cough reflex, positive Babinski reflexes bilaterally, and intact pupillary reflexes. The patient’s motor strength was dramatically decreased in both upper and lower extremities. She was obtunded, unable to follow commands, and opened her eyes spontaneously. On day 4 of admission, she was minimally responsive to commands and was able to communicate only with vertical eye movements. Repeat noncontrast CT showed hyperdensity in the basilar artery, suggestive of occlusion due to thrombosis, which was not present in the initial CT findings (Fig. 1). Findings of lumbar puncture with cerebrospinal fluid examination and electroencephalography (EEG) were unremarkable. MRI showed large foci of abnormally restricted vessels of the brainstem with recent infarction, occurring bilaterally with no observed hemorrhage (Fig. 2). MRA revealed complete loss of flow-related signal within the distal basilar artery (Fig. 3).\nFig. 1 Axial computed tomography of the patient’s head without contrast from February 7, 2015. Image at the level of the brainstem demonstrates a hyperdense basilar artery (orange arrow), which in the appropriate clinical setting is concerning for occlusion of the basilar artery due to thrombosis. Also, note that the pons (red arrow) is slightly decreased in attenuation compared with the surrounding brain parenchyma, concerning for ischemia. This finding is slightly more prominent on the left side\n\n\nFig. 2 Magnetic resonance imaging of the patient’s brain without contrast from February 9, 2015. A large focus of abnormal restricted diffusion is demonstrated in the brainstem (red arrow), consistent with recent infarction. This primarily affects the cranial aspect of the pons, possibly extending into the midbrain. This is a bilateral finding, with more extensive involvement on the left. This is concordant with findings from computed tomography of the patient’s head on February 7, 2015. Mild associated mass effect and swelling are present at this time\n\n\nFig. 3 Magnetic resonance angiogram without contrast from February 9, 2015. Complete loss of flow-related signal is noted within the distal basilar artery (orange arrow). In contrast, bilateral symmetric flow-related signal in normal-appearing right and left internal cerebral arteries (red arrows) is seen\n\n\n\nTracheostomy and a percutaneous gastrostomy tube were placed, and supportive care with rehabilitation was initiated. The patient died 2 weeks later of suspected aspiration; however, no autopsy was performed, because her family declined the option.\n\nDiscussion\nIn this report, we present a case of a 51-year-old woman with a history cocaine abuse who presented to the emergency department for acute behavior changes and was found to have basilar artery thrombosis. Given that few case reports in the literature have described basilar artery thrombosis due to cocaine use, the definitive diagnosis of basilar artery occlusion due to cocaine use may be challenging. Specifically, delayed basilar artery thrombosis due to cocaine use has not been reported previously in the literature. In our patient’s case, we report delayed onset of symptoms and imaging confirmation of basilar artery thrombosis on day 4 of hospitalization.\n\nLIS is a rare neurological disorder characterized by relatively intact cognitive function with preserved awareness and consciousness, but with quadriplegia and inability to speak. According to Smith and Delargy, there are three clinical subcategories of LIS [7]. A patient with classic LIS has quadriplegia and anarthria with preserved consciousness and vertical eye movements. Incomplete LIS is similar to the classic form, but voluntary movements can supplement the presence of vertical eye movements. Total LIS describes a patient who is unable to communicate and has total immobility but retains full consciousness. Our patient’s presentation is consistent with classic LIS because she was able to communicate with vertical eye movements but was fully immobile. She was awake and alert, and her pupils were equally round and reactive to light. Though her corneal reflexes were intact and her vertical eye movement was preserved, she lacked any horizontal eye movements. She had facial plegia and the inability to move any extremities. Furthermore, her lower limbs partially withdrew in response to plantar stimulation. She exhibited bilateral positive Babinski reflexes and absent patellar and Achilles reflexes throughout.\n\nPatients with LIS may be able to communicate with others by moving their eyes or sending blinking messages. Depending on the level of the lesion, vertical eye and upper eyelid movements may not be affected [6]. Furthermore, some patients with incomplete LIS can retain peripheral sensation and proprioception, move certain facial muscles, or control some or all of the extraocular muscles. Aphonia results, due not to the paralysis of the vocal cords but rather to the lack of coordination between breathing and voice, which prevents the voluntary production of sound [14].\n\nInjury to the pons is often due to tissue loss resulting from lack of blood flow, usually from an infarct due to thrombosis or stroke. Other causes of LIS include hemorrhage, infection, loss of myelin, tumors, and certain disorders such as polymyositis or amyotrophic lateral sclerosis [4, 8]. However, due to limited literature, use of cocaine is often not included in the differential diagnosis of LIS.\n\nLIS can be difficult to diagnose because it may mimic loss of consciousness or loss of respiratory control. Recommended brain imaging tests include MRI with close attention to the pons and MRA for thrombosis in the arteries of the brainstem, which can help confirm the diagnosis of LIS in the appropriate clinical scenario and to rule out injuries elsewhere in the brain. Furthermore, an EEG can demonstrate sleep-wake patterns consistent with the apparent inability to physically move [15]. Because these patients lack the ability to execute standard motor responses, such as withdrawal from pain, testing often is conducted through the communication of the patient by blinking or vertical eye movement, which was demonstrated by our patient.\n\nIn cases of confirmed cocaine-induced thrombotic or thromboembolic stroke, the main aim is to establish reperfusion therapy within the standard window of time. However, in cases involving posterior cerebral circulation outside the standard time window, intra-arterial thrombolysis and mechanical retrieval thrombectomy may be suggested. Vallée et al. and MacEwen et al. described successful thrombosis identification and intra-arterial thrombolysis and aspiration within 30 hours of symptom onset in patients with basilar artery thrombosis induced by cocaine [16, 17]. In both case reports, the patients were young, had no reported significant medical history, and were not comatose at initial presentation. In such patients, intra-arterial thrombolysis with or without mechanical thrombectomy can be considered as a therapeutic option. However, MRI diffusion-weighted and perfusion-weighted imaging should be performed prior to thrombolysis or thrombectomy in order to determine ischemic penumbra and identify salvageable tissue [18]. As reported by Alqahtani et al. [12], no endovascular attempt was performed in a 75-year-old man with LIS, owing to the size of the stroke, hemorrhagic conversation, and poor neurological status. As in our patient’s case, the patient’s negative initial findings on imagining combined with late presentation of irreversible neurological symptoms suggested that further interventions would be unsuccessful.\n\nConclusion\nWe suggest that the usual clinical manifestations of LIS can result from cocaine use and, importantly, that cocaine use should be included among the potential causes of LIS. This case report illustrates the need for routine investigation by obtaining a urine toxicology screen for all patients with altered mental status and the importance of awareness of the serious complications of cocaine use.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nOA, MGB, TDP, NG, and DHT collected data, performed the literature search, and wrote and edited the manuscript. RDC and ACV performed the literature search and wrote and edited the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone to declare.\n\nAvailability of data and materials\nNot applicable.\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 any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Substance Abuse Mental Health Services Administration (SAMHSA) Results from the 2007 National Survey on Drug Use and Health: National Findings. Office of Applied Studies, NSDUH Series H-34, DHHS Publication No. SMA 08-4343 2008 Rockville SAMHSA, Office of Applied Studies 15 29 \n2. Substance Abuse Mental Health Services Administration (SAMHSA) Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-46, HHS Publication No. (SMA) 13-4795 2013 Rockville SAMHSA, Office of Applied Studies 15 29 \n3. León-Carrión J van Eeckhout P del Rosario Domínguez-Morales M Pérez-Santamaría FJ The locked-in syndrome: a syndrome looking for a therapy Brain Inj 2002 16 7 571 582 10.1080/02699050110119781 12119076 \n4. Al-Sardar H Grabau W Locked-in syndrome caused by basilar artery ectasia Br Geriatr Soc 2002 31 481 482 \n5. Cairns H Oldfield RC Pennybacker JB Akinetic mutism with an epidermoid cyst of the third ventricle Brain 1941 64 273 290 10.1093/brain/64.4.273 \n6. Plum F Posner J The diagnosis of stupor and coma 1980 3 Philadelphia F.A. Davis \n7. Smith E Delargy M Locked-in syndrome BMJ. 2005 330 7488 406 409 10.1136/bmj.330.7488.406 15718541 \n8. Wyllie A.H. Kerr J.F.R. Currie A.R. Cell Death: The Significance of Apoptosis International Review of Cytology 1980 251 306 \n9. Kotchoubey B Lotze M Instrumental methods in the diagnostics of locked-in syndrome Restor Neurol Neurosci 2013 31 1 25 40 23168499 \n10. Yoon SH Zuccarello M Rapoport RM Acute cocaine induces endothelin-1-dependent constriction of rabbit basilar artery Endothelium 2007 14 137 139 10.1080/10623320701421644 17578707 \n11. Su J Li J Li W Altura BT Altura BM Cocaine induces apoptosis in cerebral vascular muscle cells: potential roles in strokes and brain damage Eur J Pharmacol 2003 482 61 66 10.1016/j.ejphar.2003.09.056 14660005 \n12. Alqahtani SA Burger K Potolicchio S Cocaine-induced acute fatal basilar artery thrombosis: report of a case and review of the literature Am J Case Rep 2015 16 393 397 10.12659/AJCR.894565 26109011 \n13. Treadwell SD Robinson TG Cocaine use and stroke Postgrad Med J. 2007 83 389 394 10.1136/pgmj.2006.055970 17551070 \n14. Fager S Beukelman D Karantounis R Jakobs T Use of safe-laser access technology to increase head movements in persons with severe motor impairments: a series of case reports Augment Altern Commun 2006 22 3 222 229 10.1080/07434610600650318 17114165 \n15. Jacome DE Morilla-Pastor D Unreactive EEG: pattern in locked-in syndrome Clin Electroencephalogr 1990 21 1 31 36 10.1177/155005949002100112 2297946 \n16. MacEwen C Ward M Buchan A A case of cocaine-induced basilar artery thrombosis Nat Clin Pract Neurol 2008 4 11 622 626 10.1038/ncpneuro0879 18679392 \n17. Vallée JN Crozier S Guillevin R Acute basilar artery occlusion treated by thromboaspiration in a cocaine and ecstasy abuser Neurology 2003 61 839 841 10.1212/WNL.61.6.839 14504335 \n18. Albers GW Expanding the window for thrombolytic therapy in acute stroke: the potential role of acute MRI for patient selection Stroke 1999 30 2230 2237 10.1161/01.STR.30.10.2230 10512933\n\n",
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"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Basilar artery; Cocaine-related disorders; Locked-in syndrome; Magnetic resonance imaging; Quadriplegia",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D001488:Basilar Artery; D003042:Cocaine; D019970:Cocaine-Related Disorders; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007238:Infarction; D020767:Intracranial Thrombosis; D000080422:Locked-In Syndrome; D018810:Magnetic Resonance Angiography; D008875:Middle Aged; D000066553:Problem Behavior; D001405:Reflex, Babinski",
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"pubdate": "2019-11-19",
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"title": "Cocaine as a rare cause of locked-in syndrome: a case report.",
"title_normalized": "cocaine as a rare cause of locked in syndrome a case report"
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"activesubstancename": "COCAINE HYDROCHLORIDE"
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"abstract": "BACKGROUND\nPancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action.\n\n\nMETHODS\nA total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR).\n\n\nRESULTS\nThe confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank).\n\n\nCONCLUSIONS\nThe combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.",
"affiliations": "Medical Clinic II, University Hospital Frankfurt, Frankfurt/Main, Germany. Electronic address: l.bergmann@em.uni-frankfurt.de.;Medical Clinic II, University Hospital Frankfurt, Frankfurt/Main, Germany.;Klinik für Hämatologie und Onkologie, Märkische Kliniken Lüdenscheid, Lüdenscheid, Germany.;Department of Oncology and Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Germany.;Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt/Main, Germany.;Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland.;Onkologische Schwerpunktpraxis, Heidelberg, Germany.;Medizinische Klinik, Klinikum Nürnberg Nord, Nürnberg, Germany.;Hämatologie, Onkologie, Klinische Immunologie, Robert-Bosch-Krankenhaus, Stuttgart, Germany.;Medizinisches Versorgungszentrum Onkologie, Charité - Campus Virchow-Klinikum, Berlin, Germany.;Onkologische Schwerpunktpraxis, Groß-Gerau, Germany.;CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria.;Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.;Department of Nursing and Health, University of Applied Sciences of the Saarland, Saarbruecken, Germany.;Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.;Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.",
"authors": "Bergmann|L|L|;Maute|L|L|;Heil|G|G|;Rüssel|J|J|;Weidmann|E|E|;Köberle|D|D|;Fuxius|S|S|;Weigang-Köhler|K|K|;Aulitzky|W E|WE|;Wörmann|B|B|;Hartung|G|G|;Moritz|B|B|;Edler|L|L|;Burkholder|I|I|;Scheulen|M E|ME|;Richly|H|H|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D003841:Deoxycytidine; C056507:gemcitabine; D000077210:Sunitinib",
"country": "England",
"delete": false,
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"issn_linking": "0959-8049",
"issue": "51(1)",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Combination; Gemcitabine; Pancreatic cancer; Sunitinib",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D021441:Carcinoma, Pancreatic Ductal; D003841:Deoxycytidine; D005060:Europe; D005260:Female; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011758:Pyrroles; D000077210:Sunitinib; D016896:Treatment Outcome",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "27-36",
"pmc": null,
"pmid": "25459392",
"pubdate": "2015-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A prospective randomised phase-II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV.",
"title_normalized": "a prospective randomised phase ii trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer a study of the cesar central european society for anticancer drug research ewiv"
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"abstract": "BACKGROUND\nVery little is known about the pharmacokinetics of chemotherapeutic agents in patients also being treated with continuous ambulatory peritoneal dialysis. We sought to evaluate the pharmacokinetics of cisplatin and 5-fluorouracil in plasma and peritoneal dialysate in a patient being treated for esophageal adenocarcinoma.\n\n\nMETHODS\nA single patient with esophageal adenocarcinoma and on peritoneal dialysis for end-stage renal disease was treated with cisplatin 25 mg/m(2) on day 1 of weeks 1 and 5 and continuous infusional 5-fluorouracil 1000 mg/m(2)/day on days 1-4 of weeks 1 and 5 along with daily radiation therapy. Intense plasma and dialysate sampling was performed during the week 5 administration, followed by quantitation of platinum by atomic absorption spectrophotometry and 5-fluorouracil by LC-MS/MS.\n\n\nRESULTS\nFollowing systemic administration, clearance of ultrafilterable (active) platinum over the first 6 h was 20.8 L/h, which is lower than previously reported clearance levels of ultrafilterable platinum. Total platinum AUC was 131 μg h/mL, also higher than an AUC previously reported for total platinum in patients with normal renal function. Platinum-related material was detected in the peritoneal cavity, but this is likely inactive. 5-Fluorouracil penetrated the intraperitoneal cavity, but the contribution of peritoneal dialysis to drug clearance was negligible at 0.072 %.\n\n\nCONCLUSIONS\nAdministration of intravenous cisplatin and 5-fluorouracil chemotherapy to a patient treated with continuous ambulatory peritoneal dialysis is feasible, but clearance in dialysate is nominal, thus suggesting that dose reduction is indicated for cisplatin. Systemic drug administration results in limited intraperitoneal penetration of 5-fluorouracil and inactive platinum species.",
"affiliations": "University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, 11100 Euclid Avenue, Lakeside 1200, Cleveland, OH, USA. jennifer.eads@uhhospitals.org.;Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.;Division of Nephrology and Hypertension, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.;Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.;Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.;University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, 11100 Euclid Avenue, Lakeside 1200, Cleveland, OH, USA.",
"authors": "Eads|Jennifer R|JR|;Beumer|Jan H|JH|;Negrea|Lavinia|L|;Holleran|Julianne L|JL|;Strychor|Sandra|S|;Meropol|Neal J|NJ|",
"chemical_list": "D000970:Antineoplastic Agents; D015314:Dialysis Solutions; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-015-2939-9",
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"issn_linking": "0344-5704",
"issue": "77(2)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "5-Fluorouracil; Cisplatin; Peritoneal dialysis; Pharmacokinetics",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D059248:Chemoradiotherapy; D002945:Cisplatin; D015314:Dialysis Solutions; D004938:Esophageal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007676:Kidney Failure, Chronic; D010530:Peritoneal Dialysis; D013053:Spectrophotometry",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "333-8",
"pmc": null,
"pmid": "26687170",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "9614438;10894879;20437796;18840986;12556954;8960474;11395577;16306860;20084400;16044967;16394300;10235156;15151521;11081567;14630685;18085512;11103248;18191389;21789133;11181662",
"title": "A pharmacokinetic analysis of cisplatin and 5-fluorouracil in a patient with esophageal cancer on peritoneal dialysis.",
"title_normalized": "a pharmacokinetic analysis of cisplatin and 5 fluorouracil in a patient with esophageal cancer on peritoneal dialysis"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201602008",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Peripheral neuropathy (PN) is an important toxicity that limits the use of bortezomib (Btz). Attempts to reduce PN have included its subcutaneous (SC) administration.\n\n\n\nWe retrospectively analyzed 307 patients with newly diagnosed multiple myeloma from a single Chinese center, receiving Btz-based regimens administered either via SC injection (SC group, n = 167) or intravenous (IV) infusion (IV group, n = 140). The efficacy and safety of Btz administration via SC and IV were then compared.\n\n\n\nMost baseline characteristics were similar between these 2 groups. A lower frequency of adverse events, especially grade ≥ 3 PN (P = .002), was observed in the SC group compared with the IV group. The estimated median Btz dosage when PN developed was higher (20.8 mg/m2 vs. 15.6 mg/m2), and fewer patients reduced or discontinued Btz owing to adverse events in the SC group compared with the IV group. The overall response rate (≥ partial response [PR]) was comparable (94.8% vs. 96.2%). However, patients in the IV group required fewer cycles to achieve PR, whereas a larger proportion of patients in the IV group achieved ≥ very good PR. After a median follow-up of 23 months (range, 1-84 months), no significant difference in median progression-free survival (not arrived vs. 33.0 ± 2.735 months) and overall survival (not arrived vs. 56.0 months) was noted.\n\n\n\nSC Btz is associated with better tolerance; however, IV administration achieves a faster and deeper response in Chinese patients with newly-diagnosed multiple myeloma.",
"affiliations": "State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China; Department of Medical Oncology, Jerome Lipper Center for Multiple Myeloma Research, Lebow Institute for Myeloma Therapeutics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;Department of Hematology, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.;Department of Medical Oncology, Jerome Lipper Center for Multiple Myeloma Research, Lebow Institute for Myeloma Therapeutics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA.;Department of Medical Oncology, Jerome Lipper Center for Multiple Myeloma Research, Lebow Institute for Myeloma Therapeutics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA.;Department of Medical Oncology, Jerome Lipper Center for Multiple Myeloma Research, Lebow Institute for Myeloma Therapeutics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China.;Department of Medical Oncology, Jerome Lipper Center for Multiple Myeloma Research, Lebow Institute for Myeloma Therapeutics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA. Electronic address: Nikhil_Munshi@dfci.harvard.edu.;State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academic Medical Science and Peking Union Medical College, Tianjin, China. Electronic address: qiulg@ihcams.ac.cn.",
"authors": "Xu|Yan|Y|;Deng|Shuhui|S|;Mao|Xuehan|X|;An|Gang|G|;Li|Zengjun|Z|;Wang|Yafei|Y|;Fulciniti|Mariateresa|M|;Ho|Matthew|M|;Lin|Jianhong|J|;Sui|Weiwei|W|;Liu|Wei|W|;Zou|Dehui|D|;Yi|Shuhua|S|;Huang|Wenyang|W|;Liu|Hong|H|;Lv|Rui|R|;Li|Jian|J|;Wang|Tingyu|T|;Du|Chenxing|C|;Munshi|Nikhil C|NC|;Qiu|Lugui|L|",
"chemical_list": "D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2018.03.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "18(6)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Bortezomib; Intravenous administration; Multiple myeloma; Response; Subcutaneous administration",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D010523:Peripheral Nervous System Diseases; D000077982:Progression-Free Survival; D012189:Retrospective Studies; D016019:Survival Analysis",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "422-430",
"pmc": null,
"pmid": "29625927",
"pubdate": "2018-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "25773856;20739431;24171961;21146205;17690257;22193964;26240224;21507715;16754936;28655599;18615002;24974945;12171876;22689676;25840597;25096796;22422823;23091109;23018466;15953001;15461622;18768528;12826635;27882113;16855634;25875484;24861981;24941833;26425561;25413901;20823406;28684379",
"title": "Tolerance, Kinetics, and Depth of Response for Subcutaneous Versus Intravenous Administration of Bortezomib Combination in Chinese Patients With Newly Diagnosed Multiple Myeloma.",
"title_normalized": "tolerance kinetics and depth of response for subcutaneous versus intravenous administration of bortezomib combination in chinese patients with newly diagnosed multiple myeloma"
} | [
{
"companynumb": "CN-TAKEDA-2018MPI004281",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAlthough tumor necrosis factor inhibitors (TNFi) might be expected to protect against nonalcoholic fatty liver disease (NAFLD), we have seen patients who appeared to develop NAFLD during TNFi treatment. We aimed to explore risk factors for this TNFi complication in a case-control study.\n\n\nMETHODS\nWe reviewed clinic records at our VA hospital to identify patients with inflammatory diseases who developed aminotransferase elevations during TNFi therapy and who had liver biopsies showing NAFLD. These patients were matched with patients in each of three control groups: (i) inflammatory disease controls: patients on TNFi treatment with normal aminotransferase levels, (ii) nonalcoholic steatohepatitis (NASH) controls: patients with biopsy-proven NASH with no other inflammatory disease, and (iii) healthy controls. Genotyping was performed for PNPLA3, a gene predisposing to NASH.\n\n\nRESULTS\nWe identified eight cases (five steatohepatitis, three steatosis); elevated aminotransferase levels were first observed 1-63 months into TNFi therapy (average 12 months). TNFi therapy was stopped in five patients, whose aminotransferase levels then normalized within 2-8 months. There were no significant differences between cases and inflammatory disease controls in the frequency of features of metabolic syndrome. Cases had more methotrexate exposure than inflammatory controls (50 vs. 12.5%, P=0.28). PNPLA3 genotyping revealed mutations in 75% of cases, 38% of inflammatory controls, 88% of NASH controls, and 63% of healthy controls (P=NS).\n\n\nCONCLUSIONS\nOur findings suggest that NAFLD can be a side effect of TNFi therapy, and that methotrexate exposure and PNPLA3 gene mutations might be risk factors. Further studies are needed to determine how TNFi causes NAFLD and to confirm these risk factors.",
"affiliations": "aDivision of Gastroenterology and Hepatology bDivision of Rheumatology cDepartment of Pathology, VA North Texas Healthcare System dDivision of Digestive and Liver Diseases eDivision of Rheumatology fDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.",
"authors": "Feagins|Linda A|LA|;Flores|Avegail|A|;Arriens|Cristina|C|;Park|Christina|C|;Crook|Terri|T|;Reimold|Andreas|A|;Brown|Geri|G|",
"chemical_list": "D001685:Biological Factors; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D000637:Transaminases",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "27(10)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D001685:Biological Factors; D001706:Biopsy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D000637:Transaminases; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "1154-60",
"pmc": null,
"pmid": "26148245",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10484010;11438497;21381068;21175232;24283931;22422493;15915461;23333219;15571584;20414788;17553036;16793841;19521405;16201116;24082887;17979620;11078773;16899321;16287793;21038418;21351214;15565570;22416768;18820647;12540784;15447754;18321606;18384521;22488764;18000721",
"title": "Nonalcoholic fatty liver disease: a potential consequence of tumor necrosis factor-inhibitor therapy.",
"title_normalized": "nonalcoholic fatty liver disease a potential consequence of tumor necrosis factor inhibitor therapy"
} | [
{
"companynumb": "US-AMGEN-USASP2015135152",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "Pulmonary hypertension due to left heart disease (PH-LHD) frequently complicates heart failure with reduced ejection fraction (HFrEF). Specific therapies for PH have not offered an advantage in patients with PH-LHD. The combined angiotensin receptor blocker-neprilysin inhibitor (ARNI), sacubitril/valsartan, is a novel therapy that can increase levels of natriuretic peptides (NPs). The resulting action on natriuresis and vasodilation may play an important role in the reduction of pulmonary pressures. Here, we report how the use of ARNI in two patients with HFrEF has resulted in an improvement in PH and, consequently, in clinical status and prognosis. <Learning objective: Sacubitril/valsartan (ARNI) is the newest neurohormonal agent approved for therapy in heart failure with reduced ejection fraction (HFrEF). Pulmonary hypertension (PH) due to left heart disease (PH-LHD) is frequent in patients with HFrEF and is associated with a reduced functional class and poor prognosis. The use of ARNI has been associated with a relevant reduction in pulmonary pressures in two cases of PH-LHD.>.",
"affiliations": "Department of Cardiology, Ospedale Mater Salutis, Legnago, Italy.;Department of Cardiology, Ospedale Mater Salutis, Legnago, Italy.;Department of Cardiology, Ospedale Mater Salutis, Legnago, Italy.;Department of Cardiology, Ospedale Mater Salutis, Legnago, Italy.",
"authors": "De Simone|Vincenzo|V|;Guarise|Paola|P|;Zanotto|Gabriele|G|;Morando|Giorgio|G|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2019.08.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "20(5)",
"journal": "Journal of cardiology cases",
"keywords": "Heart failure; Pulmonary artery pressures; Sacubitril/valsartan; Systolic dysfunction",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "187-190",
"pmc": null,
"pmid": "31719942",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports",
"references": "27931609;18380534;22240126;20693169;22509435;19934029;30093137;26508169;30545968",
"title": "Reduction in pulmonary artery pressures with use of sacubitril/valsartan.",
"title_normalized": "reduction in pulmonary artery pressures with use of sacubitril valsartan"
} | [
{
"companynumb": "IT-AUROBINDO-AUR-APL-2019-103415",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nRecent reports have shown that hepatitis E virus (HEV) infection can become chronic in solid-organ transplant recipients, but few studies have systematically investigated the clinical consequences of this chronic HEV infection in solid-organ transplant (SOT) recipients.\n\n\nMETHODS\nWe have undertaken an in-depth study of 6 chronic HEV-infected heart transplant recipients to gain further insight into the clinical, biochemical and virologic presentation of this disorder.\n\n\nRESULTS\nIn 6 patients (2.3%) chronic HEV infection, genotype 3, was identified. Immunosuppression in these patients was tacrolimus-based, combined with either everolimus or prednisolone and/or mycophenolate mofetil. Median follow-up after case detection was 26 months (range 21 to 40 months). All chronic HEV cases had elevated liver enzyme values. IgM antibodies at presentation were positive in 2 of 6 (33%) patients. Liver histology in 4 of 6 (67%) patients showed advanced fibrosis within 2 years after infection. One patient spontaneously cleared the HEV infection: 1 after dose reduction of immunosuppressive therapy and 3 during ribavirin therapy. One patient has yet to clear the virus and remains on ribavirin therapy.\n\n\nCONCLUSIONS\nChronic HEV infection in heart transplant (HTx) recipients may lead to rapid fibrosis of the liver. We advise additional HEV RNA screening in solid-organ transplant recipients with elevated liver enzymes, because antibody production is often delayed, as demonstrated in these patients. Dose reduction of immunosuppressive therapy should be the first intervention strategy to achieve viral clearance in chronic HEV-infected immunocompromised patients. Ribavirin treatment should be considered in cases of chronic HEV.",
"affiliations": "Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.",
"authors": "Koning|Ludi|L|;Pas|Suzan D|SD|;de Man|Robert A|RA|;Balk|Aggie H M M|AH|;de Knegt|Robert J|RJ|;ten Kate|Fiebo J|FJ|;Osterhaus|Albert D M E|AD|;van der Eijk|Annemiek A|AA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "32(1)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": null,
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D000328:Adult; D002908:Chronic Disease; D005260:Female; D016027:Heart Transplantation; D016751:Hepatitis E; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "78-85",
"pmc": null,
"pmid": "23260707",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical implications of chronic hepatitis E virus infection in heart transplant recipients.",
"title_normalized": "clinical implications of chronic hepatitis e virus infection in heart transplant recipients"
} | [
{
"companynumb": "NL-BAUSCH-BL-2019-023011",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "1... |
{
"abstract": "Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse reaction caused mostly by medication. Early diagnosis is important as initiation of supportive treatment and avoidance of drug is of prime importance. A young male presented with an erythematous rash after taking diclofenac for pain. Polarized dermoscopy revealed milky globules on a uniform reddish background sparing the follicles, which confirmed the diagnosis of AGEP.",
"affiliations": "Department of Skin and VD, Patna Medical College & Hospital, Patna, Bihar, India.;Skinnocence: The Skin Clinic, Gurgaon, India.;First Department of Dermatology, Aristotle University, Thessaloniki, Greece.",
"authors": "Jha|Abhijeet K|AK|;Sonthalia|Sidharth|S|;Lallas|Aimilios|A|",
"chemical_list": null,
"country": "Austria",
"delete": false,
"doi": "10.5826/dpc.0702a07",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-9381",
"issue": "7(2)",
"journal": "Dermatology practical & conceptual",
"keywords": "acute generalized exanthematous pustulosis; dermoscopy; milky globules",
"medline_ta": "Dermatol Pract Concept",
"mesh_terms": null,
"nlm_unique_id": "101585990",
"other_id": null,
"pages": "35-36",
"pmc": null,
"pmid": "28515991",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": "21743852;11168761;26775791;15767024;11679003;24819755;1832534",
"title": "Non-follicular milky globules-dermoscopy saves the day.",
"title_normalized": "non follicular milky globules dermoscopy saves the day"
} | [
{
"companynumb": "IN-BION-006338",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC POTASSIUM"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nMultimodality treatments combining radiotherapy, immune therapy and/or targeted therapy are under heavy investigation. Promising data from clinical trials are emerging, nevertheless unexpected interactions and adverse events should not be overlooked.\n\n\nMETHODS\nHere we present a case study of a patient with metastatic colon adenocarcinoma treated sequentially with a chemotherapy/targeted therapy combination, immune checkpoint inhibitors and ultra-hypofractionated radiotherapy. After radiation treatment, the patient developed extensive posterior abdominal wall wounds coinciding with regression of the irradiated metastatic tumour mass and marked elevation of the inflammation parameters.\n\n\nCONCLUSIONS\nThis case represents an unusual fatal wound complication after palliative ultra-hypofractionated radiotherapy. Further research into synergistic effects of sequential radiotherapy and anti-angiogenesis therapy may provide an advantage in anticipating severe sequelae.",
"affiliations": "Department of Oncology, KU Leuven, Leuven, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium. cedric.draulans@uzleuven.be.;Department of Radiation Oncology, Ghent University Hospital and Ghent University, Ghent, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium.;Department of Radiation Oncology, University Hospitals Leuven, Leuven, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium.;Department of Oncology, KU Leuven, Leuven, Belgium. karin.haustermans@uzleuven.be.",
"authors": "Orazem|Miha|M|;Draulans|Cédric|C|http://orcid.org/0000-0002-1267-7874;Spaas|Mathieu|M|;Van Cutsem|Eric|E|;Debecker|Marina|M|;De Meerleer|Gert|G|;Tejpar|Sabine|S|;Dekervel|Jeroen|J|;Haustermans|Karin|K|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01399-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(4)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Anti-angiogenesis; Case report; Complication; Immune checkpoint inhibition; Radiotherapy",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D003131:Combined Modality Therapy; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1121-1125",
"pmc": null,
"pmid": "33844128",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31021390;30982687;30518410;15908660;17442997;26765102;28056412;26433823;32047000;33096027;31269983;19482548;23677405;26068491;20189257",
"title": "A fatal wound complication following sequential anti-angiogenesis, immune checkpoint inhibition and ultra-hypofractionated radiotherapy.",
"title_normalized": "a fatal wound complication following sequential anti angiogenesis immune checkpoint inhibition and ultra hypofractionated radiotherapy"
} | [
{
"companynumb": "BE-PFIZER INC-202101093759",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "4",
... |
{
"abstract": "We report a patient presented with recurrent pericardial effusion caused by drug-induced systemic lupus Erythematosus (SLE) following mitral valve repair. The surgery was complicated by hemiparesis and convulsion in early postoperative period. The patient had been received carbamazepine for a paroxysmal seizure that occurred following mitral valve repair. The post operative computed tomography showed embolic stroke and its sequel (seizure) that treated with carbamazepine. In the 3rd month of follow-up, however, hemiparesis recovered by physiotherapy but carbamazepine was not discontinued as by request of neurologist. In the 6th month of surgery, the patient admitted by dyspnea and massive pericardial effusion that treated by subxiphoid drainage. This event was re occurred in two times in a short time frame and each event treated by surgical approach. The serologic exam in the last admission revealed drug-induced lupus erythematosus. The carbamazepine as an anti convulsive drug has been described to cause LE like disease in multiple case reports. Laboratory exam exhibited the possibility of carbamazepine-induced lupus in our case, with the extremely rare presentation of recurrent massive pericardial effusion.",
"affiliations": "Department of Anesthesiology, Imam Ali Hospital, Kermanshah University of Medicine, Kermanshah, Iran.;Department of Cardiac Surgery, Imam Ali Hospital, Kermanshah University of Medicine, Kermanshah, Iran.;Department of Cardiac Surgery, Imam Ali Hospital, Kermanshah University of Medicine, Kermanshah, Iran.;Department of Cardiac Surgery, Imam Ali Hospital, Kermanshah University of Medicine, Kermanshah, Iran.",
"authors": "Haydari|Aghigh|A|;Sabzi|Feridoun|F|;Dabiri|Samsam|S|;Poormotaabed|Alireza|A|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-6025",
"issue": "55(9)",
"journal": "Acta medica Iranica",
"keywords": "Drug-induced type; Lupus erythematosus; Pericardial effusion",
"medline_ta": "Acta Med Iran",
"mesh_terms": "D000328:Adult; D006348:Cardiac Surgical Procedures; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008943:Mitral Valve; D010490:Pericardial Effusion; D012640:Seizures; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "14540050R",
"other_id": null,
"pages": "597-601",
"pmc": null,
"pmid": "29202555",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-Induced by Systemic Lupus Erythematosus Presenting as Recurrent Pericardial Effusion After Mitral Valve Repair.",
"title_normalized": "drug induced by systemic lupus erythematosus presenting as recurrent pericardial effusion after mitral valve repair"
} | [
{
"companynumb": "IR-JUBILANT CADISTA PHARMACEUTICALS-2017JUB00443",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"dru... |
{
"abstract": "To describe the long-term outcomes of patients with lymphoma in the CNS treated with rituximab, temozolomide and high-dose methotrexate without consolidation therapy.\nA retrospective cohort study of 46 consecutive patients with primary CNS lymphoma (PCNSL, 27 patients) or secondary CNS involvement of diffuse large B-cell lymphoma (DLBCL, 19 patients) who were treated with rituximab on day 1 in combination with high-dose methotrexate (days 1 and 15) and temozolomide (days 1-5) in 28-day cycles without further consolidation.\nMedian follow-up was 21.2 months. Patients received a median of five cycles (range 1-15). Median overall survival (OS) was 26 months and median progression-free survival was 8.6 months. At 3 years, 37% of patients were alive and without evidence of disease. The patients with PCNSL had a significantly higher response rates (ORR 81 vs 47%; p = 0.015) and longer median OS (55.3 vs 4.8 months; p < 0.01) than those with secondary CNS DLBCL. Toxicities were mild and manageable.\nThe rituximab, temozolomide and methotrexate regimen is an effective therapy for patients with PCNSL without the toxicities typically associated with consolidation therapy.",
"affiliations": "Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, 2 West Pavilion, Philadelphia, PA 19104, USA.;Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI 53226, USA.;Department of Pharmacy, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, 2 West Pavilion, Philadelphia, PA 19104, USA.;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, 2 West Pavilion, Philadelphia, PA 19104, USA.;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, 2 West Pavilion, Philadelphia, PA 19104, USA.;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, 2 West Pavilion, Philadelphia, PA 19104, USA.;Division of Hematology/Oncology & the Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, 2 West Pavilion, Philadelphia, PA 19104, USA.;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, 2 West Pavilion, Philadelphia, PA 19104, USA.",
"authors": "Nagle|Sarah J|SJ|;Shah|Nirav N|NN|;Ganetsky|Alex|A|;Landsburg|Daniel J|DJ|;Nasta|Sunita D|SD|;Mato|Anthony|A|;Schuster|Stephen J|SJ|;Reshef|Ran|R|;Tsai|Donald E|DE|;Svoboda|Jakub|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/ijh-2017-0020",
"fulltext": "\n==== Front\nInt J Hematol OncolInt J Hematol OncolIJHInternational Journal of Hematologic Oncology2045-13932045-1407Future Medicine Ltd London, UK 10.2217/ijh-2017-0020Research ArticleLong-term outcomes of rituximab, temozolomide and high-dose methotrexate without consolidation therapy for lymphoma involving the CNS Nagle, Shah, Ganetsky et al.RTM for CNS lymphomaNagle Sarah J \n1\nShah Nirav N \n2\nGanetsky Alex \n3\nLandsburg Daniel J \n1\nNasta Sunita D \n1\nMato Anthony \n1\nSchuster Stephen J *\n1\nReshef Ran \n4\nTsai Donald E \n1\nSvoboda Jakub \n1\n\n1 Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, 2 West Pavilion, Philadelphia, PA 19104, USA\n2 Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI 53226, USA\n3 Department of Pharmacy, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA\n4 Division of Hematology/Oncology & the Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA*Author for correspondence: Tel.: +1 215 964 7244; Fax: +1 215 615 5887; @stephen.schuster@uphs.upenn.edu12 2017 26 1 2018 6 4 113 121 22 6 2017 16 10 2017 26 1 2018 © 2018 Future Medicine Ltd2018This work is licensed under a Creative Commons Attribution 4.0 License\nAim:\nTo describe the long-term outcomes of patients with lymphoma in the CNS treated with rituximab, temozolomide and high-dose methotrexate without consolidation therapy.\n\nPatients & methods:\nA retrospective cohort study of 46 consecutive patients with primary CNS lymphoma (PCNSL, 27 patients) or secondary CNS involvement of diffuse large B-cell lymphoma (DLBCL, 19 patients) who were treated with rituximab on day 1 in combination with high-dose methotrexate (days 1 and 15) and temozolomide (days 1–5) in 28-day cycles without further consolidation.\n\nResults:\nMedian follow-up was 21.2 months. Patients received a median of five cycles (range 1–15). Median overall survival (OS) was 26 months and median progression-free survival was 8.6 months. At 3 years, 37% of patients were alive and without evidence of disease. The patients with PCNSL had a significantly higher response rates (ORR 81 vs 47%; p = 0.015) and longer median OS (55.3 vs 4.8 months; p < 0.01) than those with secondary CNS DLBCL. Toxicities were mild and manageable.\n\nConclusion:\nThe rituximab, temozolomide and methotrexate regimen is an effective therapy for patients with PCNSL without the toxicities typically associated with consolidation therapy.\n\nKeywords: \nhigh-dose methotrexateprimary CNS lymphomasecondary CNS lymphomatemozolomidetreatment\n==== Body\nNon-Hodgkin's lymphoma (NHL) can involve the CNS either as the sole area of disease or as a secondary spread of systemic disease. Primary CNS lymphoma (PCNSL) is a rare variant of NHL that involves the brain, leptomeninges, eyes or spinal cord without evidence of systemic disease [1]. It represents approximately 4% of newly diagnosed primary CNS tumors and 4–6% of all extranodal lymphomas [2,3]. Secondary involvement of the CNS by lymphoma presents heterogeneously with the most common manifestations being leptomeningeal disease and parenchymal brain involvement. Approximately 2–5% of patients with aggressive NHL develop involvement of the CNS at some point during their disease course [4–6].\n\nRapid control of CNS involvement by lymphoma is necessary to prevent significant neurologic morbidity. Standard immunochemotherapy regimens used in the treatment of systemic NHL are ineffective at controlling disease in the CNS since most of these agents do not penetrate through the blood–brain barrier [7]. There is no consensus on optimal therapy for PCNSL or secondary CNS involvement by diffuse large B-cell lymphoma (DLBCL), but National Comprehensive Cancer Network guidelines recommend a high-dose methotrexate-based regimen in eligible patients [8]. As the recommendations are broad, there is significant variation in clinical practice.\n\nIntravenous methotrexate (MTX), given at sufficiently high doses to penetrate the CNS is the most active single agent against PCNSL and should be the backbone of induction therapy in most patients [9–11]. However, while high-dose methotrexate (HD-MTX)-based regimens are effective for induction therapy, the majority of patients with PCNSL who achieve a complete response (CR) will relapse [12]. Optimal consolidation therapy in this population has not been established.\n\nHistorically, whole-brain radiation therapy (WBRT) has been used for consolidation therapy in patients with PCNSL. However, while WBRT has been shown to improve progression-free survival (PFS), it does not improve overall survival (OS) compared with induction chemotherapy alone [13–15]. Additionally, there can be a high incidence of neurotoxicity and cognitive decline with consolidation radiation [16]. More recently, several groups have attempted to substitute WBRT consolidation with either high-dose chemotherapy with autologous stem cell transplant (HDT/ASCT) or nonmyeloablative chemotherapy (such as etoposide and cytarabine) [17–23]. These consolidation options can be associated with significant toxicity, especially in older patients with comorbidities.\n\nSince 2009, we have used a prolonged course of the combination of rituximab, temozolomide and HD-MTX (RTM) without further consolidation to treat patients with PCNSL and secondary involvement of the CNS by DLBCL. Although it is clear that PCNSL and secondary involvement of the CNS by DLBCL are different entities in terms of biology, clinical history and outcome, we have chosen to present data for both in this manuscript as clinicians might be tempted to treat them the same based on their physical location. Here we report the results of our approach to these patient populations.\n\nMaterials & methods\nStudy design\nWe conducted a retrospective cohort study of consecutive patients with PCNSL or secondary CNS DLBCL who were treated with the RTM regimen at the Hospital of the University of Pennsylvania. The study was approved by the institutional review board of the University of Pennsylvania.\n\nPatients\nAdult patients (18 years of age and older) were identified using a pharmacy database of patients who received HD-MTX, rituximab and temozolomide for PCNSL or secondary CNS DLBCL between 1 January 2009 and 31 December 2014. This would include almost all patients with CNS lymphoma treated during that time frame at our institution as RTM was our standard treatment regimen. To be included in the analysis, patients must have had documented lymphoma in their CNS (via biopsy or cerebrospinal fluid cytology). Patients were excluded if they received prior therapy for PCNSL or if they had prior CNS-directed therapy for active CNS involvement of DLBCL. Patients were also excluded if they had received radiation or HDT/ASCT as consolidation after frontline RTM for their lymphoma.\n\nChemotherapy regimen\nPatients were treated with rituximab 375 mg/m2 on day 1 in combination with HD-MTX 8 g/m2 (days 1 and 15) and temozolomide 150 mg/m2 (days 1–5) in 28-day cycles. HD-MTX was administered with leucovorin rescue. It was adjusted for creatinine clearance (Supplementary Table 1) and other toxicities (i.e., transaminitis, infection, poor performance status). Once a complete response (CR) was achieved, the day 15 MTX was omitted from subsequent cycles. Based on the protocol originally described in New Approaches to Brain Tumor Therapy (NABTT) 96–07, treatment was continued for 12 months unless there was disease progression or significant adverse events without further consolidation. Growth factor support was not mandatory and used at the discretion of the treating physician. Standard antimicrobial prophylaxis with fluconazole and antiviral antibiotics was used in all patients.\n\nResponse & toxicity assessment\nInitial response assessment was performed after one or two cycles of RTM with MRI of the brain or cerebrospinal fluid (CSF) cytology, where appropriate. Clinical response in the CNS was graded using the criteria from the International Workshop to Standardize Baseline Evaluation and Response Criteria for Primary CNS Lymphoma [24]. Toxicities were assessed and recorded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4 [25].\n\nOS was defined as the time from initiation of therapy to last follow-up or death from any cause. PFS was calculated from initiation of therapy to disease progression or last follow-up.\n\nStatistical analysis\nDescriptive and survival analyses using the Kaplan–Meier methodology were performed (STATA version 13; Stata Corp, TX, USA). A log-rank test was utilized to compare OS and PFS between patient groups. For the primary outcome of OS, we performed a univariate Cox proportional hazard analysis to evaluate the association of each variable on OS. All tests were two sided and a p-value of <0.05 was considered statistically significant.\n\nResults\nPatient characteristics\nWe identified 46 consecutive patients with PCNSL or secondary CNS DLBCL who received RTM at our institution between 1 January 2009 and 31 December 2014. 27 (59%) patients had PCNSL and 19 (41%) patients had secondary CNS DLBCL. The median age at diagnosis was 61 years (range: 21–85 years). The baseline characteristics at diagnosis are presented in Table 1. No patients received further consolidation chemotherapy or radiation therapy.\n\nTable 1. \nBaseline patient characteristics.\n\nCharacteristic\tNumber of patients\t%\t\nAge at diagnosis:\t \t \t\n\t\n– >60 years\t25\t54\t\n\t\n– ≤60 years\t21\t46\t\n\t\nGender:\t \t \t\n\t\n– Male\t23\t50\t\n\t\n– Female\t23\t50\t\n\t\nDisease:\t \t \t\n\t\n– PCNSL\t27\t59\t\n\t\n– Secondary CNS DLBCL\t19\t41\t\n\t\nCycles of RTM received:\t \t \t\n\t\n– 1–2\t16\t35\t\n\t\n– 3–5\t9\t20\t\n\t\n– 6–9\t7\t15\t\n\t\n– ≥10\t14\t30\t\n\t\nBest response to therapy:\t \t \t\n\t\n– CR\t26\t56\t\n\t\n– PR\t11\t24\t\n\t\n– SD\t5\t11\t\n\t\n– PD\t4\t9\t\nCR: Complete response; DLBCL: Diffuse large B-cell lymphoma; PCNSL: Primary central nervous system lymphoma; PD: Progressive disease; PR: Partial response; RTM: Combination of rituximab, temozolomide and high-dose methotrexate; SD: Stable disease.\n\nOutcomes for the entire cohort\n57% of patients achieved CR and 10.9% achieved partial response (PR) for an overall response rate (ORR) of 67.4%. The ORR in PCNSL was 81% versus 47.4% in secondary CNS DLBCL (p = 0.015). In patients achieving CR, the median time to best response was 2 months (two cycles). The patients received a median of five cycles (range 1–15) of RTM. Therapy was discontinued due to disease progression in 17 patients (seven [26%] PCNSL and ten [53%] secondary CNS DLBCL). Therapy was discontinued in five (11%) additional patients due to acute kidney injury (AKI, three patients), pulmonary toxicity (one patient) and infection (one patient).\n\nFor the entire cohort, the median OS was 26 months and median PFS was 8.6 months (Figure 1A & B). Compared with secondary CNS DLBCL, patients with PCNSL had a significantly longer median OS (55.3 vs 4.8 m; p < 0.01; see Figure 1C). PFS was also significantly longer for patients with primary versus secondary CNS DLBCL (22 vs 2 months; p = 0.02). The 4-year OS for the entire cohort was 44% (95% CI: 0.288–0.589). The 4-year PFS was 29% (95% CI: 0.153–0.45). Univariate cox proportional analysis demonstrated that sex and age did not impact OS. However, patients who were in a CR or PR after two cycles of RTM had a significantly improved OS compared with those who had stable disease (SD) or progressive disease (PD) at that time point (hazard ratio [HR]: 0.12; 95% CI: 0.05–0.29; p < 0.01; Figure 2 & Table 2).\n\nFigure 1. \nOverall and progression-free survival.\n\n\n(A) Overall survival of the entire cohort; (B) progression-free survival of the entire cohort; (C) overall survival by disease (primary versus secondary CNS lymphoma); and (D) progression-free survival by disease (primary versus secondary CNS lymphoma).\n\nFigure 2. \nOutcomes by response after two cycles of rituximab, temozolomide and high-dose methotrexate (RTM).\n\n\n(A) Overall survival by response after two cycles of RTM. (B) Progression free survival by response after two cycles of RTM.\n\nCR: Complete response; PD: Progressive disease; PR: Partial response; SD: Stable disease.\n\nTable 2. \nOverall survival hazard ratios.\n\nVariable\tHR\tp-value\t95% CI\t\nSex (female)\t0.87\t0.72\t0.39–1.91\t\n\t\nNot achieved CR\t10.84\t<0.001\t4.21–27.91\t\n\t\nAge >60\t1.43\t0.38\t0.64–3.20\t\n\t\nCR/PR after two cycles\t0.12\t<0.01\t0.05–0.29\t\nCR: Complete response; HR: Hazard ratio; PR: Partial response.\n\nPrimary CNS lymphoma\n27 (59%) patients had PCNSL and received RTM as their initial treatment. Patients received a median of seven cycles of RTM (range 2–15 cycles). Best response to therapy in this group was as follows: 19 (70%) patients had a CR, three (11%) patients had PR, three (11%) patients had SD and two (7%) patients had PD. The overall response rate in this patient cohort was 81%.\n\nAt 3 years, 16 of the 27 patients with PCNSL were alive (59%; 95% CI: 0.388–0.776). Out of the 16 patients with PCNSL, four patients had active disease (14%; 95%CI: 0.042–0.337); 12 patients had no evidence of active disease (44%; 95% CI: 0.255–0.647). The 4-year OS was 59% (95% CI: 0.373–0.761) and the 4-year PFS was 38% (95% CI: 0.178–0.582).\n\nCNS lymphoma secondary to DLBCL\n19 (41%) patients had secondary CNS DLBCL and all had an isolated relapse in the CNS after prior systemic therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Patients received a median of two cycles of RTM (range 1–13 cycles). Best CNS response to therapy in this group was as follows: seven (37%) patients had CR, two (11%) patients had PR, one (5%) patient had SD and nine (47%) patients had PD. The ORR for patients with secondary CNS DLBCL was 47%. Ultimately, 15 of 19 (79%) patients had documented evidence of PD in the CNS. Two of these patients additionally had evidence of systemic progression.\n\nSix of the 19 patients were alive at 3 years (31%; 95% CI: 0.1291–0.5225). One of the 19 patients was alive with active disease; the remainder were alive without active disease. The 4-year OS was 25% (95% CI: 0.086–0.462) and the 4-year PFS was 18% (95% CI: 0.038–0.396).\n\nToxicity\nOf the entire cohort, 33 (72%) patients developed an adverse event. This resulted in a dose decrease in 29 (63%) patients and termination of therapy in five (11%) patients. Toxicities included AKI, transaminitis, neutropenic sepsis, lung injury and mucositis. 20 patients (43%) developed AKI, with 95% of them requiring a dose decrease and three ultimately resulting in cessation of therapy. Transaminitis developed in seven (15%) patients, with 57% requiring a dose decrease and none resulting in termination of therapy. Four (9%) patients developed sepsis and therapy was discontinued in one (2%) patient as a result. One patient developed pulmonary toxicity and one patient developed mucositis. No patient deaths were considered to be treatment related. Adverse events resolved in all patients other than one patient with pulmonary toxicity who remained with persistent abnormalities on chest imaging but without clinical symptomatology. Complete toxicity data can be seen in Table 3. Given this was a retrospective analysis, effects of the chemotherapy on cognitive functions could not be assessed.\n\nTable 3. \nToxicities.\n\nToxicity\tNumber of patients\t%\t\nAcute kidney injury:\t \t \t\n\t\n– Grade 1\t5\t11\t\n\t\n– Grade 2\t12\t26\t\n\t\n– Grade 3\t3\t7\t\n\t\nTransaminitis:\t \t \t\n\t\n– Grade 2\t1\t2\t\n\t\n– Grade 3\t6\t13\t\n\t\nNeutropenic sepsis:\t \t \t\n\t\n– Grade 4\t4\t9\t\n\t\nMucositis†\t1\t2\t\n\t\nPneumonitis†\t1\t2\t\n\n†Unable to be graded.\n\nDiscussion\nWe evaluated 46 consecutive patients treated at our institution between 2009 and 2014 with CNS involvement of their lymphoma who received RTM. 27 patients had PCNSL and 19 patients had secondary CNS lymphoma. The ORR for the entire cohort was 67%. At 3 years, 37% of patients (12 patients with PCNSL and five patients with secondary CNS lymphoma) were alive without evidence of disease. The 4-year OS for the entire cohort was 44%; it was 59% in the PCNSL cohort and 25% in the secondary CNS lymphoma cohort. The regimen was well tolerated.\n\nTherapy for PCNSL often involves both methotrexate-based induction and further consolidation therapies. However, the original NABTT 96–07 study which established methotrexate monotherapy as the standard for PCNSL utilized 12 months of continuous methotrexate treatment with no consolidation. Since that time, clinicians have attempted to improve upon those results by adding other agents to methotrexate induction or incorporating a variety of consolidation therapies. The addition of rituximab to cytotoxic chemotherapy has been found to be safe and effective for PCNSL [26–28]. Studies have shown that consolidation with WBRT results in a median survival of 36–60 months [9,29,30]. However, recurrent or progressive disease is common and there is a substantial risk of late neurotoxicity particularly in patients older than 60 years. More recent data have suggested that HDT/ASCT is associated with high rates of remission. Several prospective Phase II trials and multicenter retrospective studies have reported high rates of long-term disease control [17,19,22,23,31,32]. However, this strategy is reserved for younger patients without comorbidities and generally these studies included only patients with PCNSL. Nonmyeloablative consolidation chemotherapy with cytarabine and etoposide is a feasible option in patients who achieve remission with induction therapy resulting in a median PFS of 4 years with a 4-year OS estimated at 65% [21]. However, this approach can be associated with significant toxicities including cytopenias, febrile neutropenia and death.\n\nOptimal consolidation for older adults who achieve remission with induction chemotherapy has not been established. WBRT in patients older than 60 years is associated with the greatest risk of neurotoxicity including incontinence, gait instability and memory disturbances [33]. Additionally, this population often has a worse performance status compared with younger patients, which increases toxicity and limits their ability to tolerate HDT/ASCT and nonmyeloablative chemotherapy.\n\nGiven the small numbers of PCNSL patients and the difficulty in running clinical trials in this area, almost none of these newer therapeutic regimens have been tested in comparative trials. While consensus exists that induction consists of HD-MTX-based chemotherapy combinations, the optimal consolidation strategy and whether consolidation is even needed has not been established. Widely used consolidation strategies include WBRT, HDT/ASCT or nonmyeloablative chemotherapy, which add to the toxicity of high-dose methotrexate induction with unclear benefit. In this study, we present an alternative treatment strategy with the prolonged course of RTM, similar to that used in NABTT 96–07, without further consolidation [12].\n\nOur results suggest that a prolonged course of RTM without consolidation therapy is a favorable treatment strategy for patients with PCNSL. This regimen is associated with improved ORR (81 vs 66%) and similar 4-year OS (59 vs 65%) as treatment regimens that use cytarabine and etoposide consolidation, but with less toxicity. This suggests that patients who respond initially to the combination of RTM may not need aggressive consolidation therapy such as etoposide and cytarabine, HDT/ASCT or WBRT. The RTM regimen may be a desirable option, particularly in patients who cannot tolerate HDT/ASCT or nonmyeloablative chemotherapy. Early response assessment can prognosticate patients. Patients who achieved CR within two cycles of therapy have an improved OS as compared with those who had only PR.\n\nLogic would suggest that more is better and that by adding aggressive consolidation therapy to methotrexate-based induction, results would improve. However, in recent protocols that utilize consolidation steps, the number of high dose methotrexate cycles is reduced compared with that originally described in NABTT 96–07, which planned for year-long continuous methotrexate therapy. Whether reducing the number of methotrexate cycles in exchange for aggressive consolidation with WBRT, alternative chemotherapy or HDT/ASCT provides benefit and is worth the toxicity remains to be seen. Our study suggests there is substantial benefit in prolonged RTM induction without consolidation therapy in patients with PCNSL. This option may be especially useful in patients who would not otherwise tolerate consolidation therapy.\n\nSecondary CNS DLBCL is associated with an extremely poor prognosis and a low likelihood of long-term survival [4]. In this study, the patients with relapsed DLBCL involving the CNS did not respond as well to RTM and despite CNS-directed therapy, all patients who had PD progressed in the CNS. This poor response in the CNS may represent a different biology and aggressive nature of the disease. Better treatment options need to be developed for this population.\n\nThe study has several limitations. It is a single institution retrospective cohort study and data were obtained via chart abstraction. Given it was not a prospective clinical trial, variations in dosing and scheduling occurred. Complete toxicity data may have been missing and other toxicities were not graded. Despite these potential limitations, we show that RTM without consolidation is a reasonable first-line treatment strategy for patients with PCNSL.\n\nConclusion\nIn conclusion, we show that a prolonged course of RTM without consolidation is a favorable first-line treatment strategy for patients with PCNSL. It is associated with low rate of treatment discontinuation due to toxicity and its efficacy is within the range of previously described approaches that are frequently too toxic in older patients or those with comorbidities. Patients tolerated the therapy well, and those with toxicities to high-dose methotrexate were able to continue therapy with dose reductions and no long-term sequela. Early response assessment after two cycles of therapy was able to predict patients who would have improved OS. Future prospective studies are needed to validate these findings.\n\nFuture perspective\nAlthough the field of oncology is rapidly advancing over the recent years, CNS lymphoma has moved at a slower pace. Our paper brings up the issue of optimal initial therapy. There are currently multiple induction regimens available with multiple consolidation options afterward. However, unlike other areas in oncology where a standard of care has been established through the process of methodical comparative trials, the CNS lymphoma area is almost devoid of comparative trials. The cause of this of course is the rarity of the cancer type in combination with the lack of funding. As such, it is very unclear what optimal therapy in 2017 is for primary CNS lymphoma. Looking forward there is real need for large-scale collaborative comparative clinical to sort out optimal induction and consolidation steps. This issue is made even more urgent by the coming wave of newer novel agents, which have started to appear in the systemic lymphoma arena and will soon come into use for CNS lymphomas, further complicating treatment options. While currently confusion reigns and art may be as important as science for a clinician operating in this area, I believe the future is bright with a host of new options that once sorted out will ultimately lead to better outcomes for patients with CNS lymphoma.\n\nSummary points\nManagement of patients with primary CNS lymphoma (PCNSL) and those with secondary CNS involvement by diffuse large B-cell lymphoma (DLBCL) is challenging.\n\nThis is a retrospective cohort study of 46 patients with PCNSL (27 patients) or secondary CNS DLBCL (19 patients) who were treated with rituximab on day 1 in combination with high-dose methotrexate (days 1 and 15) and temozolomide (days 1–5) in 28-day cycles without further consolidation.\n\nFor the entire cohort, median overall survival (OS) was 41.8 months and median progression-free survival was 8.6 months.\n\nAt 3 years, 33% of patients were alive and without evidence of disease.\n\nThe patients with PCNSL had a significantly longer median OS than those with secondary CNS DLBCL.\n\nPatients who were in a complete or partial response after two cycles of rituximab, temozolomide and methotrexate had an improved OS compared with those who had stable or progressive disease.\n\nAcute toxicities included acute kidney injury, transaminitis, sepsis, mucositis and lung injury, but there were no long-term adverse effects of this regimen.\n\nThe rituximab, temozolomide and methotrexate regimen without consolidation is an effective therapy for patients with PCNSL without the toxicities typically associated with consolidation therapy.\n\nSupplementary Material\nClick here for additional data file.\n\n \nSupplementary data\n\n\nTo view the supplementary data that accompany this paper, please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/ijh-2017-0020\n\n\n\nFinancial & competing interests disclosure\n\n\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\n\nEthical conduct of research\n\n\nThe study was approved by the institutional review board of the University of Pennsylvania.\n==== Refs\nReferences\nPapers of special note have been highlighted as: • of interest\n\n1 Ferreri AJ Abrey LE Blay JY Summary statement on primary central nervous system lymphomas from the eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002 J. Clin. Oncol. 21 12 2407 2414 2003 12805341 \n2 Hoffman S Propp JM McCarthy BJ Temporal trends in incidence of primary brain tumors in the United States, 1985–1999 Neuro. 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Oncol. 18 1 149 157 2007 17018708 \n7 Mead GM Bleehen NM Gregor A A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy Cancer 89 6 1359 1370 2000 11002232 \n8 Network NCC Clinical Practice Guidelines in Oncology: Central Nervous System Cancers www.nccn.org/professionals/physician_gls/pdf/cns_blocks.pdf \n9 Ferreri AJ Reni M Villa E Therapeutic management of primary central nervous system lymphoma: lessons from prospective trials Ann. Oncol. 11 8 927 937 2000 11038028 \n10 Joerger M Huitema AD Krahenbuhl S Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: a pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial Br. J. Cancer. 102 4 673 677 2010 20125159 \n11 Kasenda B Schorb E Fritsch K Finke J Illerhaus G Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma – a long-term follow-up study Ann. Oncol. 26 3 608 611 2015 25725080 \n12 Batchelor T Carson K O'Neill A Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96–07 J. Clin. Oncol. 21 6 1044 1049 2003 12637469 • This Phase II study showed that high-dose methotrexate is associated with a moderate amount of activity and a radiographic response rate of 74% in patients with primary CNS lymphoma (PCNSL).\n\n\n13 DeAngelis LM Seiferheld W Schold SC Fisher B Schultz CJ 93–10 RTOGS Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10 J. Clin. Oncol. 20 24 4643 4648 2002 12488408 \n14 Thiel E Korfel A Martus P High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a Phase III, randomised, non-inferiority trial Lancet Oncol. 11 11 1036 1047 2010 20970380 \n15 Korfel A Thiel E Martus P Randomized Phase III study of whole-brain radiotherapy for primary CNS lymphoma Neurology 84 12 1242 1248 2015 25716362 \n16 Correa DD DeAngelis LM Shi W Thaler H Glass A Abrey LE Cognitive functions in survivors of primary central nervous system lymphoma Neurology 62 4 548 555 2004 14981169 \n17 Illerhaus G Muller F Feuerhake F Schafer AO Ostertag C Finke J High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system Haematologica 93 1 147 148 2008 18166803 \n18 Colombat P Lemevel A Bertrand P High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter Phase II study of the GOELAMS group Bone Marrow Transplant 38 6 417 420 2006 16951691 • 25 patients with PCNSL were treated with methotrexate-based chemotherapy followed by high-dose therapy and autologous stem cell transplant with an objective response rate of 84%.\n\n\n19 Omuro A Correa DD DeAngelis LM R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma Blood 125 9 1403 1410 2015 25568347 • Single-center Phase II study of patients treated with rituximab, methotrexate, procarbazine and vincristine (R-MPV) followed by high-dose chemotherapy and autologous stem cell transplant; 2-year progression-free survival (PFS) and overall survival (OS) were 81%.\n\n\n20 Kiefer T Hirt C Spath C Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hamatologie und Onkologie Ann. Oncol. 23 7 1809 1812 2012 22115927 \n21 Rubenstein JL Hsi ED Johnson JL Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202) J. Clin. Oncol. 31 25 3061 3068 2013 23569323 • 44 patients with PCNSL were treated with induction methotrexate, temozolomide and rituximab (MT-R) followed by consolidation with eloposide plus cytarabine (EA); the 2-year PFS was 57%.\n\n\n22 Illerhaus G Marks R Ihorst G High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma J. Clin. Oncol. 24 24 3865 3870 2006 16864853 \n23 Kasenda B Schorb E Fritsch K Finke J Illerhaus G Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma – a long-term follow-up study Ann. Oncol. 23 10 2670 2675 2012 22473593 \n24 Abrey LE Batchelor TT Ferreri AJ Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma J. Clin. Oncol. 23 22 5034 5043 2005 15955902 \n25 US Department of Health and Human Services, NIH, NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 May 28 2019 https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf \n26 Shah GD Yahalom J Correa DD Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma J. Clin. Oncol. 25 30 4730 4735 2007 17947720 \n27 Masaki Y Miki M Sun Y High-dose methotrexate with R-CHOP therapy for the treatment of patients with primary central nervous system lymphoma Int. J. Hematol. 93 6 720 726 2011 21573892 \n28 Enting RH Demopoulos A DeAngelis LM Abrey LE Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide Neurology 63 5 901 903 2004 15365145 \n29 Ferreri AJ Reni M Pasini F A multicenter study of treatment of primary CNS lymphoma Neurology 58 10 1513 1520 2002 12034789 \n30 Shibamoto Y Ogino H Suzuki G Primary central nervous system lymphoma in Japan: changes in clinical features, treatment, and prognosis during 1985–2004 Neuro. Oncol. 10 4 560 568 2008 18559969 \n31 Abrey LE Moskowitz CH Mason WP Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis J. Clin. Oncol. 21 22 4151 4156 2003 14615443 \n32 Montemurro M Kiefer T Schuler F Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkol Ann. Oncol. 18 4 665 671 2007 17185743 \n33 Abrey LE DeAngelis LM Yahalom J Long-term survival in primary CNS lymphoma J. Clin. Oncol. 16 3 859 863 1998 9508166\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-1393",
"issue": "6(4)",
"journal": "International journal of hematologic oncology",
"keywords": "high-dose methotrexate; primary CNS lymphoma; secondary CNS lymphoma; temozolomide; treatment",
"medline_ta": "Int J Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101600758",
"other_id": null,
"pages": "113-121",
"pmc": null,
"pmid": "30302232",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
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"title": "Long-term outcomes of rituximab, temozolomide and high-dose methotrexate without consolidation therapy for lymphoma involving the CNS.",
"title_normalized": "long term outcomes of rituximab temozolomide and high dose methotrexate without consolidation therapy for lymphoma involving the cns"
} | [
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"companynumb": "US-FRESENIUS KABI-FK201803833",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "TEMOZOLOMIDE"
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"abstract": "OBJECTIVE\nPatients with acute myelogenous leukemia or myelodysplastic syndrome undergoing induction chemotherapy are at increased risk of invasive fungal infection due to prolonged, severe neutropenia. Due to this risk, national guidelines recommend invasive fungal infection prophylaxis in this population until the resolution of neutropenia. Although posaconazole has demonstrated superiority over fluconazole and itraconazole, there is limited evidence for voriconazole for invasive fungal infection prophylaxis in this population. Even less data are available comparing posaconazole and voriconazole directly. The study objective was to investigate the efficacy and safety of delayed-release posaconazole tablets versus voriconazole for primary invasive fungal infection prophylaxis. The primary outcome was rate of discontinuation of either agent. Secondary outcomes included specific rates of discontinuation due to adverse events and drug-drug interactions, rates of breakthrough invasive fungal infection, and 30-day and 100-day mortality rates.\n\n\nMETHODS\nThis was a retrospective cohort study of adult patients admitted to NYU Langone Health between 1 January 2014 and 31 August 2017 and initiated on invasive fungal infection prophylaxis during induction or reinduction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome.\n\n\nRESULTS\nIn total, 77 patients were included in the study: 43 using posaconazole delayed-release tablets and 34 using oral voriconazole. In the posaconazole group, 30% of patients (n = 13) discontinued therapy for any reason compared with 35% (n = 12) of patients in the voriconazole group (p = 0.64). A higher percentage of patients in the voriconazole group discontinued due to adverse events (6 patients, 18% vs. 1 patient, 2%, p = 0.04). Mortality rates at 30 and 100 days were similar between both groups. No breakthrough invasive fungal infections was noted in either group.\n\n\nCONCLUSIONS\nOverall, discontinuations for any reason were similar in patients taking both posaconazole delayed-release and oral voriconazole. Both posaconazole delayed-release tablets and oral voriconazole appear to be effective at preventing invasive fungal infection in acute myelogenous leukemia and myelodysplastic syndrome patients undergoing induction chemotherapy, although posaconazole may be more tolerable.",
"affiliations": "Department of Pharmacy, New York University Langone Health, New York, NY, USA.;Department of Pharmacy, New York University Langone Health, New York, NY, USA.;Department of Pharmacy, New York University Langone Health, New York, NY, USA.;Department of Pharmacy, New York University Langone Health, New York, NY, USA.;Department of Pharmacy, New York University Langone Health, New York, NY, USA.",
"authors": "Phillips|Kynlon|K|;Cirrone|Frank|F|;Ahuja|Tania|T|;Siegfried|Justin|J|;Papadopoulos|John|J|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218806975",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(2)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Acute myelogenous leukemia; myelodysplastic syndrome; posaconazole; voriconazole",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D000072742:Invasive Fungal Infections; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "398-403",
"pmc": null,
"pmid": "30319061",
"pubdate": "2019-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Posaconazole versus voriconazole as antifungal prophylaxis during induction therapy for acute myelogenous leukemia or myelodysplastic syndrome.",
"title_normalized": "posaconazole versus voriconazole as antifungal prophylaxis during induction therapy for acute myelogenous leukemia or myelodysplastic syndrome"
} | [
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"companynumb": "US-009507513-1810USA013392",
"fulfillexpeditecriteria": "2",
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"activesubstancename": "POSACONAZOLE"
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{
"abstract": "Programmed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors.\nThis was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records.\nThe final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (<1%) experienced suspected PD-L1-related AKI. The PD-L1-related AKI occurred a median of 99 days after starting therapy. All patients concurrently received another medication known to cause acute interstitial nephritis (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or antibiotics) at the time of the suspected PDL1-related AKI.\nAlthough AKI is common in patients receiving PD-L1 therapy, the incidence of suspected PD-L1-related AKI is low (<1%) and may be less common when compared to other classes of ICIs. This cohort provides further validation that other drugs associated with acute interstitial nephritis may be involved in the pathogenesis of ICI-related AKI.",
"affiliations": "Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.;Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.",
"authors": "Seethapathy|Harish|H|;Zhao|Sophia|S|;Strohbehn|Ian A|IA|;Lee|Meghan|M|;Chute|Donald F|DF|;Bates|Halla|H|;Molina|Gabriel E|GE|;Zubiri|Leyre|L|;Gupta|Shruti|S|;Motwani|Shveta|S|;Leaf|David E|DE|;Sullivan|Ryan J|RJ|;Rahma|Osama|O|;Blumenthal|Kimberly G|KG|;Villani|Alexandra-Chloe|AC|;Reynolds|Kerry L|KL|;Sise|Meghan E|ME|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ekir.2020.07.011",
"fulltext": "\n==== Front\nKidney Int Rep\nKidney Int Rep\nKidney International Reports\n2468-0249 Elsevier \n\nS2468-0249(20)31376-0\n10.1016/j.ekir.2020.07.011\nClinical Research\nIncidence and Clinical Features of Immune-Related Acute Kidney Injury in Patients Receiving Programmed Cell Death Ligand-1 Inhibitors\nSeethapathy Harish 1 Zhao Sophia 1 Strohbehn Ian A. 2 Lee Meghan 2 Chute Donald F. 1 Bates Halla 1 Molina Gabriel E. 3 Zubiri Leyre 3 Gupta Shruti 4 Motwani Shveta 4 Leaf David E. 4 Sullivan Ryan J. 3 Rahma Osama 5 Blumenthal Kimberly G. 6 Villani Alexandra-Chloe 6 Reynolds Kerry L. 37 Sise Meghan E. msise@partners.org1∗7 1 Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA\n2 Department of Medicine, Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA\n3 Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA\n4 Department of Medicine, Division of Renal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA\n5 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA\n6 Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA\n∗ Correspondence: Meghan Sise, 165 Cambridge Street Suite 302, Boston, Massachusetts 02114, USA. msise@partners.org7 Equal contribution/co-supervised.\n\n\n21 7 2020 \n10 2020 \n21 7 2020 \n5 10 1700 1705\n4 2 2020 21 6 2020 14 7 2020 © 2020 International Society of Nephrology. Published by Elsevier Inc.2020International Society of NephrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nProgrammed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte−associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors.\n\nMethods\nThis was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records.\n\nResults\nThe final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (<1%) experienced suspected PD-L1–related AKI. The PD-L1–related AKI occurred a median of 99 days after starting therapy. All patients concurrently received another medication known to cause acute interstitial nephritis (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or antibiotics) at the time of the suspected PDL1-related AKI.\n\nConclusion\nAlthough AKI is common in patients receiving PD-L1 therapy, the incidence of suspected PD-L1–related AKI is low (<1%) and may be less common when compared to other classes of ICIs. This cohort provides further validation that other drugs associated with acute interstitial nephritis may be involved in the pathogenesis of ICI-related AKI.\n\nGraphical abstract\nKeywords\nacute interstitial nephritisacute kidney injuryimmune checkpoint inhibitorimmune-related adverse eventsPD-L1 inhibitors\n==== Body\nAcute interstitial nephritis (AIN) has been increasingly recognized as an important immune-related adverse event (irAE) that may complicate treatment with immune checkpoint inhibitor (ICI) therapy.1, 2, 3, 4 In a recently published study, we determined the incidence of sustained AKI to be 8% in patients receiving ICIs, with suspected ICI-related AKI occuring in 3% of patients.4 Other meta-analyses summarizing clinical trial data have estimated ICI-related AKI to occur in 1.4%–2.2% of patients receiving CTLA-4 or PD-1 monotherapy, and up to 4.9%% of patients receiving combination CTLA-4/PD-1 therapy.2,5\n\nPD-L1 inhibitors, including atezolizumab, durvalumab, and avelumab, are a relatively new class of ICIs approved for multiple new cancer indications, and their use is rapidly increasing.6 Because they are a relatively new class of ICIs, clinical experience with these agents is limited. Prior studies evaluating AKI in patients on checkpoint inhibitors have included a very limited number (<40) of patients receiving PD-L1 inhibitors.1,2,4 Clinical trials have shown that the rate of hypothyroidism and pneumonitis are lower in patients receiving PD-L1 inhibitors than other ICI classes.7 It is not known whether this lower risk extends to nephrotoxicity as well. Hence, we sought to define the incidence, etiology, and clinical features of AKI in a large, unselected cohort of patients receiving PD-L1 inhibitors.\n\nMethods\nWe performed a retrospective cohort study of all patients who received a PD-L1 inhibitor (durvalumab, atezolizumab, or avelumab) as first-line therapy for advanced malignancies from 2017 to 2018 at Mass General Brigham (Boston, MA) to evaluate changes in kidney function from baseline up to 1 year. The Research Patient Data Repository at Partners Healthcare System was used to collect data on baseline demographics, comorbidities, medications, and laboratory studies. Baseline use of medications known to be associated with acute interstitial nephritis (AIN), such as proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), and antibiotics, was defined by active prescriptions at the ICI start date. AKI was defined by a ≥1.5-fold rise in creatinine from baseline, and staged by Kidney Disease: Improving Global Outcomes (KDIGO) criteria.8 Sustained AKI was defined as AKI that lasted >48 hours; all cases were chart reviewed for etiology by 2 nephrologists (HS, MES), with a third (SG) available for disagreement. The etiology of sustained AKI was divided into the following: (i) suspected PD-L1–related AKI diagnosed by a kidney biopsy, or subspecialist determination with corticosteroid treatment, or unexplained sustained AKI occurring simultaneously with another irAE without an alternative cause for AKI identified; (ii) hemodynamic AKI (prerenal azotemia or acute tubular necrosis); (iii) obstruction; or (iv) AKI of undetermined cause if insufficient diagnostic workup was pursued. Detailed review of electronic medical records was used to obtain clinical information on all patients with sustained AKI. Death date was determined by manual chart review or was assumed at the time of last encounter for patients enrolled in hospice.\n\nBaseline characteristics were described using means and SDs for continuous variables and counts and percentages for categorical variables. Descriptive analyses are reported for suspected PD-L1–related AKI, given the small number of events. The Institutional Review Board approved this study and waived the need for informed consent.\n\nResults\nBetween 1 January 2017 and 31 December 2018, a total of 607 patients were started on a PD-L1 inhibitor (Figure 1). Five patients were excluded because they did not have a baseline or a follow-up creatinine measurement within the 12-month follow-up period, and 3 patients were excluded because they were on hemodialysis at the time of PD-L1 initiation. In total, 599 patients had adequate creatinine measurements and were included in this study. The mean age was 65 (SD: 13) years, 50% were male, and 92% were white. The mean baseline creatinine value was 1.0 (SD: 0.3) mg/dl; 99 (17%) had an estimated glomerular filtration rate of <60 ml/min per 1.73 m2. Underlying malignancy types and individual PD-L1 inhibitors prescribed are shown in Table 1.Figure 1 Patient flow and acute kidney injury (AKI) outcomes among patients treated with programmed death ligand-1 (PD-L1) inhibitors. Overall, 17% of the included cohort developed AKI. ∗Among patients with transient AKI (lasting <48 hours), 36 (53%) occurred in outpatients; the majority did not have creatinine measurements immediately repeated, but it normalized by the following clinic visit (mean: 14 days, SD: 9 days until next check). Among those with AKI that was confirmed to have been sustained AKI, lasting for >48 hours, the etiology and Kidney Disease: Improving Global Outcomes (KDIGO) severity stage are shown. ∗∗Of the 9 patients with KDIGO grade 3 AKI, 4 patients had progressive kidney failure and died during the hospital stay, and none underwent renal replacement therapy. ATN, acute tubular necrosis; SCr, serum creatinine.\n\nTable 1 Baseline characteristics of patients receiving PD-L1 inhibitor therapy\n\nCharacteristic\tAll patientsa\tNo sustained AKI\tSustained AKI\tPD-L1 inhibitor–related AKI\t\nMean ± SD or n (%)\t\nPatients, n\t599\t563\t36\t5\t\nAge, yr\t65 ± 13\t63 ± 14\t63 ± 12\t65 ± 12\t\nBaseline creatinine, mg/dl\t1.0 ± 0.3\t1.0 ± 0.3\t1.0 ± 0.3\t1.0 ± 0.3\t\neGFR, ml/min\t88 ± 26\t89 ± 26\t82 ± 26\t80 ± 20\t\nMale\t298 (50)\t281 (50)\t17 (47)\t2 (40)\t\nFemale\t301 (50)\t282 (50)\t19 (53)\t3 (60)\t\nRace\t\t\t\t\t\n White\t554 (92)\t521 (92)\t33 (91)\t5 (100)\t\n Black\t16 (3)\t15 (3)\t1 (3)\t0\t\n Asian\t11 (2)\t10 (2)\t1 (3)\t0\t\n Other/unknown\t18 (3)\t17 (3)\t1 (3)\t0\t\nCirrhosis\t7 (1)\t7 (1)\t0\t0\t\nHypertension\t242 (40)\t229 (41)\t13 (36)\t2 (40)\t\nDiabetes\t113 (19)\t103 (18)\t10 (28)\t0\t\nBaseline medications\t\t\t\t\t\n PPIb\t210 (35)\t192 (34)\t18 (50)b\t1 (20)\t\n H2 blockers\t113 (19)\t104 (18)\t9 (25)\t0\t\n NSAIDs\t103 (17)\t95 (17)\t8 (22)\t1 (20)\t\n Allopurinol\t12 (2)\t11 (2)\t1 (3)\t0\t\n ACEI/ARB\t135 (23)\t128 (23)\t7 (19)\t0\t\nBaseline kidney function, eGFR group\t\t\t\t\t\n <60 ml/min per 1.73 m2\t99 (17)\t92 (16)\t7 (19)\t1 (20)\t\n 60−90 ml/min per 1.73 m2\t208 (35)\t192 (34)\t16 (44)\t3 (60)\t\n >90 ml/min per 1.73 m2\t292 (49)\t179 (50)\t13 (36)\t1 (20)\t\nPD1 inhibitor type\t\t\t\t\t\n Atezolizumab\t347 (58)\t322 (57)\t25 (69)\t4 (80)\t\n Avelumab\t99 (16)\t93 (17)\t6 (17)\t0\t\n Durvalumab\t153 (26)\t148 (26)\t5 (14)\t1 (20)\t\nMalignancy\t\t\t\t\t\n Thoracic\t255 (43)\t244 (43)\t11 (31)\t2 (40)\t\n Genitourinary\t117 (19)\t106 (19)\t11 (31)\t3 (60)\t\n Gynecological\t67 (11)\t61 (11)\t6 (17)\t0\t\n Gastrointestinal\t64 (11)\t61 (11)\t3 (8)\t0\t\n Breast\t38 (6)\t36 (6)\t2 (5)\t0\t\n Other\t58 (10)\t55 (10)\t3 (8)\t0\t\nACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate, NSAID, nonsteroidal anti-inflammatory drug; PD1, programmed cell death 1 receptor; PD-L1, programmed cell death ligand 1.\n\na Baseline characteristics for ‘All patients’ are shown as a percentage of the overall cohort (N = 599). For the outcomes, sustained AKI and immune checkpoint inhibitor−related AKI, the percentage of events in each subgroup is presented. The first sustained AKI event was specified as the outcome for each patient. Comorbid conditions, including hypertension and cirrhosis, were determined by International Classification of Diseases Ninth or Tenth Revision codes appearing at least twice in the electronic medical record. Diagnosis of diabetes was determined by either a hemoglobin A1c ≥ 6.5% or by prescription of a glucose-lowering medication and a diagnosis code for diabetes. Other than race being unknown in a few patients, there were no missing demographic or comorbidities data.\n\nb In univariable models comparing demographic and clinical characteristics of patients who experienced “sustained AKI” vs. those who did not, only baseline proton pump inhibitor exposure (0.05) was significant at a P value of <0.10. This was included in the multivariable model for “sustained AKI” along with other clinically important variables that were determined a priori to be exposures of interest.\n\n\n\nIn total, 104 patients (17%) experienced AKI within the 1-year follow-up period, of whom 68 had transient AKI (lasting ≤48 hours) and the other 36 had sustained AKI (Figure 1). Baseline characteristics of patients with and without sustained AKI are shown in Table 1. Use of PPIs was more common among patients who developed sustained AKI.\n\nHemodynamic AKI (including prerenal azotemia and acute tubular necrosis) was the most common cause of sustained AKI, occurring in 23 patients (64% of sustained AKI). Urinary tract obstruction occurred in 5 patients (14% of sustained AKI), suspected PD-L1 inhibitor−related AKI occurred in 5 (14% of sustained AKI), and the etiology of sustained AKI had an undetermined cause in 3 (8% of sustained AKI). De-identified case summaries of all 36 patients with sustained AKI are shown in Supplementary Table S1. The overall incidence and severity stages of sustained AKI for the individual PD-L1 inhibitor types are shown in Figure 2.Figure 2 Overall incidence of all acute kidney injury (AKI), sustained AKI, and programmed death ligand-1 (PD-L1)–related AKI in patients receiving atezolizumab, durvalumab, and avelumab. Among the 347 patients who received atezolizumab, 64 patients (18%) experienced any AKI, 25 (7%) had sustained AKI, and 4 (1%) had PD-L1–related AKI. Among the 153 patients who received durvalumab, 21 (14%) experienced any AKI, 5 (3%) had sustained AKI, and 1 (1%) experienced PD-L1–related AKI. Among the 99 patients who received avelumab, 19 (19%) experienced any AKI, 6 (6%) had sustained AKI, and none had PD-L1–related AKI.\n\n\n\nThe overall incidence of PD-L1–related AKI was <1% of the overall cohort; the rate per 100 person-years was 1.2 (95% confidence interval: 0.5–3.0). The presence of AIN was confirmed by biopsy in 1 of the 5 cases. The clinical features of the 5 patients are summarized in Table 2. Three of the 5 patients (60%) with suspected PD-L1–related AKI had a concurrent extrarenal irAE. Urinalysis was obtained in 3 patients with suspected PD-L1–related AKI; each had leukocyturia (>5 white blood cells per high-power field), including the patient with biopsy-proven AIN. None had hematuria or proteinuria (all ≤1+ on urinary dipstick). None had eosinophilia (<500 cells/μl). The median latency period from PD-L1 initiation to suspected PD-L1–related AKI was 99 days (interquartile range: 3–79 days). All patients were receiving a concomitant medication known to cause AIN (PPIs, NSAIDS, or antibiotics) at the time of suspected PD-L1–related AKI. The PD-L1 inhibitors were permanently discontinued in all 5 patients. Three patients received high-dose steroids (≥0.5 mg/kg per day in prednisone equivalents) tapered over 6 to 10 weeks; 2 of these patients experienced remission, whereas the third patient had persistently elevated creatinine. One patient transitioned to hospice without steroid treatment. The final patient had PD-L1 permanently discontinued with resolution of AKI. Only 1 patient was re-challenged with a different class of drug, a PD-1 inhibitor (nivolumab) 11 months after PD-L1–related AKI; that patient did not experience recurrent AKI.Table 2 Clinical characteristics of patients with suspected PD-L1–related AKI\n\nAge/race/sex\tCancer type\tPD-L1 drug type\tTime to AKI, mo\tKDIGO AKI stage\tConcurrent AIN-associated medications\tConcurrent irAE\tKidney biopsy\tSteroids\tOutcome\tRe-challenge\t\n65 WF\tSCLC\tAtezolizumab\t2\t1\tPPI\tHypothyroidism\tNo\tNo\tTransitioned to hospice and died\tNo\t\n65 WF\tRCC\tAtezolizumab\t6\t2\tPPI, NSAIDs, amoxicillin\tColitis\tNo\tYes\tPartial recovery but not to baseline\tNo\t\n50 WM\tBladder cancer\tAtezolizumab\t8\t1\tCiprofloxacin\t0\tYes (AIN)\tYes\tNo recovery\tNo\t\n65 WM\tBladder cancer\tAtezolizumab\t4\t3\tLevofloxacin\t0\tNo\tYes\tFull recovery to baseline\tNo\t\n55 WF\tNSCLC\tDurvalumab\t4\t1\tSAIDs\tImmune-related cytopenias\tNo\tNo\tFull recovery to baseline\tYes\nNivolumab 11 mo later without recurrence of AKI\t\nAIN, acute interstitial nephritis; AKI, acute kidney injury; irAE, immune-related adverse event; NSAIDs, nonsteroidal anti-inflammatory drugs; NSCLC, non–small cell lung cancer; PD-L1, programmed cell death receptor ligand 1; PPI, proton pump inhibitor; RCC, renal cell cancer; SCLC, small cell lung cancer; WF, white female; WM, white male.\n\n\n\nOverall, the 1-year mortality in the cohort was high: 311 patients (52%) died. Of the patients with sustained AKI, mortality was 58%, and the median time to death after sustained AKI in those 21 patients was 10 days (interquartile range: 3–79 days). However, only 1 of the 5 patients (20%) with suspected PD-L1–related AKI died within 12 months.\n\nDiscussion\nThis is the largest cohort study evaluating kidney function in patients receiving PD-L1 inhibitors, the most recently approved class of ICIs used to treat advanced malignancies. Because durvalumab, avelumab, and atezolizumab were approved only in 2016 to 2017, prior studies describing AKI in patients receiving these drugs have been extremely limited. We found a lower incidence of suspected PD-L1–related AKI than in prior reports; those studies predominantly included patients on CTLA-4 inhibitors (ipilimumab) and PD-1 inhibitors (pembrolizumab and nivolumab; Figure 3).2,4,5 Our findings support recent pooled analyses of clinical trial data suggesting that irAEs may be lower in patients receiving PD-L1 inhibitors compared to other ICIs; this may be due to the selective blockade of the PD-L1 and not the PD-L2 ligand; sparing of the PD-1/PD-L2 interaction may be important for immune tolerance in certain organs.9, 10, 11 Although the number of cases of PD-L1–related AKI was small, the clinical features of suspected PD-L1–related AKI appear to be consistent with those in prior studies of patients with PD-1 and CTLA-4–related AKI; the majority had concomitant irAEs, and the mean onset was approximately 3 months after ICI initiation.2,4,12 In this study, all patients with suspected PD-L1–related AKI were on medications associated with AIN at the time of diagnosis, which strengthens the evidence that use of other concomitant medications associated with AIN may trigger nephritis in patients treated with ICIs. Drug-hapten–specific T-cell responses that drive type 4 hypersensitivity reactions affecting the skin and kidneys are regulated by PD-1/PDL-1 pathways; ICIs may inadvertently lead to activation of T cells that have previously been primed to a drug.13 Further research is needed to identify whether drug-specific T-cells are activated in patients with ICI-nephritis, and to determine whether minimizing exposure to potential AIN drugs that act as haptens can lower the rate of ICI-related AKI and other irAEs.14,15Figure 3 Incidence of programmed death ligand-1 (PD-L1)–related acute kidney injury (AKI) compared to historical estimates of cytotoxic T-lymphocyte−associated protein 4 (CTLA-4), programmed cell death 1 receptor (PD-1), and CTLA-4/PD-1 combination therapy–related AKI. The incidence of immune checkpoint inhibitor (ICI)–related AKI from clinical trial data was gathered in 2 meta-analyses (Cortazar et al.2 [2016] and Manohar et al.5 [2019]) and 1 observational real-world study (Seethapathy et al.4 [2019]). The incidence of CTLA-4–related AKI was 2% in Cortazar et al. and 4.8% in Seethapathy et al. The incidence of PD-1 related AKI was 1.9% in Cortazar et al., 2.2% in Manohar et al., and 2.3% in Seethapathy et al. The incidence of ICI-AKI with combination CTLA-4 and PD-1 therapy was 4.9% from Cortazar et al. In comparison, the incidence of PD-L1–related AKI was 0.8% in our study.\n\n\n\nSimilar to AKI in patients on other ICIs, the most likely etiology of sustained AKI in patients receiving PD-L1 inhibitors was hemodynamic AKI (prerenal azotemia or acute tubular necrosis). This cohort also had a substantial fraction of AKI due to urinary obstruction; this is likely explained by the higher prevalence of urothelial cancers in this cohort. This highlights the importance of full diagnostic workup, including imaging and kidney biopsy when needed to exclude alternative etiologies, in order to prevent a misdiagnosis of ICI-related AKI that could lead to unnecessary delays of future PD-L1 doses or corticosteroid treatment, both of which could compromise treatment of the underlying cancer.16,17\n\nOur study has several limitations. The generalizability of this study may be reduced, given the limited racial diversity in this cohort. In addition, we may have underestimated the frequency of AKI if patients had AKI events managed at hospitals outside of our healthcare network. The retrospective nature of data collection and small number of cases limited our ability to phenotype all cases of sustained AKI; misdiagnosis of even a few cases could have significantly influence on the calculations of PD-L1–related AKI incidence. Finally, only 1 patient with PD-L1–related AKI underwent a kidney biopsy; thus, we were not able to exclude alternative pathologic lesions explaining AKI. However, other studies have shown that AIN is found in >90% of biopsied patients, and the absence of proteinuria in our patients argues against less common glomerular diseases leading to AKI.\n\nOncologists and nephrologists should be aware that PD-L1–related AKI may be less common than in patients treated with PD-1 or CTLA-4 inhibitors. Future multicenter studies are needed to precisely determine the incidence and predictors of PD-L1–related AKI, as well as to identify noninvasive biomarkers of ICI-AKI to enable more precise diagnosis.\n\nDisclosure\nKGB reports spouse employment at Devoted Health, royalties from UptoDate, and has served as a scientific consultant to Persistent Systems. DEL received research support from BioPorto Diagnostics. RS receives research support from Merck and Amgen. He serves as a consultant or on advisory boards of Merck, Amgen, Array, Novartis, Genentech, Replimmune, and Compugen. MES receives research support from Gilead and EMD-Serono and has served on advisory boards of Merck, Gilead, and Abbvie. LZ serves as a consultant to Merck. OR receives research support from Merck. He serves as a speaker for activities supported by educational grants from BMS and Merck and is a consultant for Merck, Celgene, Five Prime, GSK, GFK, Defined Health INC, Roche/Genentech, Puretech, Imvax, Leerink, and PRMA Consulting. In addition, he has a patent pending (“Methods of Using Pembrolizumab and Trebananib”). SG has served on an advisory board for AstraZeneca and is a Scientific Coordinator for the ASCEND trial sponsored by GlaxoSmithKline. SM reports salary from UpToDate. All the other authors declared no competing interests.\n\nSupplementary Material\nSupplementary File (PDF)\n \n\nSupplementary File (PDF)\n\nTable S1. De-identified case summaries of patients with sustained AKI.\n==== Refs\nReferences\n1 Mamlouk O. Selamet U. Machado S. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience J Immunother Cancer 7 2019 2 30612580 \n2 Cortazar F.B. Marrone K.A. Troxell M.L. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors Kidney Int 90 2016 638 647 27282937 \n3 Shirali A.C. Perazella M.A. Gettinger S. Association of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients Am J Kidney Dis 68 2016 287 291 27113507 \n4 Seethapathy H. Zhao S. Chute D.F. The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors Clin J Am Soc Nephrol 14 2019 1692 1700 31672794 \n5 Manohar S. Kompotiatis P. Thongprayoon C. Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis Nephrol Dial Transplant 34 2019 108 117 29762725 \n6 Akinleye A. Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics J Hematol Oncol 12 2019 92 31488176 \n7 Baxi S. Yang A. Gennarelli R.L. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis BMJ 360 2018 2018 2019 \n8 Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO clinical practice guideline for acute kidney injury Kidney Int Suppl 2 2012 \n9 Khunger M. Rakshit S. Pasupuleti V. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials Chest 152 2017 271 281 28499515 \n10 Xiao Y. Yu S. Zhu B. RGMb is a novel binding partner for PD-l2 and its engagement with PD-l2 promotes respiratory tolerance J Exp Med 211 2014 943 959 24752301 \n11 Wang P.F. Chen Y. Song S.Y. Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis Front Pharmacol 18 2017 730 \n12 Cortazar F.B. Kibbelaar Z.A. Glezerman I.G. Clinical features and outcomes of immune checkpoint inhibitor-associated AKI: a multicenter study J Am Soc Nephrol 31 2020 435 446 31896554 \n13 Gibson A. Faulkner L. Lichtenfels M. the effect of inhibitory signals on the priming of drug hapten−specific t cells that express distinct V β receptors J Immunol 199 2017 1223 1237 28687658 \n14 Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy Am J Clin Dermatol 19 2018 345 361 29256113 \n15 Naidoo J. Page D.B. Li B.T. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies Ann Oncol 26 2015 2375 2391 26371282 \n16 Faje A.T. Lawrence D. Flaherty K. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma Cancer 124 2018 3706 3714 29975414 \n17 Hughes M.S. Molina G.E. Chen S.T. Budesonide treatment for microscopic colitis from immune checkpoint inhibitors J Immunother Cancer 7 2019 1 10 30612589\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-0249",
"issue": "5(10)",
"journal": "Kidney international reports",
"keywords": "PD-L1 inhibitors; acute interstitial nephritis; acute kidney injury; immune checkpoint inhibitor; immune-related adverse events",
"medline_ta": "Kidney Int Rep",
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"pages": "1700-1705",
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"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
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"title": "Incidence and Clinical Features of Immune-Related Acute Kidney Injury in Patients Receiving Programmed Cell Death Ligand-1 Inhibitors.",
"title_normalized": "incidence and clinical features of immune related acute kidney injury in patients receiving programmed cell death ligand 1 inhibitors"
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"abstract": "BACKGROUND\nRefractory gastrointestinal bleeding (GIB) secondary to gastrointestinal vascular malformations (GIVM) such as gastrointestinal angiodysplasia (GIAD) and gastric antral vascular ectasia (GAVE) remains challenging to treat when endoscopic therapy fails. Recently thalidomide has been suggested as a treatment option for refractory GIB.\n\n\nOBJECTIVE\nTo determine the outcome of patients treated with thalidomide for refractory GIB due to GIVM.\n\n\nMETHODS\nIRB approved, single center, retrospective review of electronic medical records from January 2012 to November 2018. Patients age > 18 years old, who had > 3 episodes of GIB refractory to medical or endoscopic therapy, and who had been treated with thalidomide for at least 3 mo were included. The primary endpoint was recurrence of GIB 6 mo after initiation of thalidomide.\n\n\nRESULTS\nFifteen patients were included in the study, all with significant cardiac, hepatic, or renal comorbidities. The cause of GIB was GIAD in 10 patients and GAVE in 5 patients. Two patients were lost to follow up. Of the 13 patients followed, 38.5% (n = 5) had no recurrent GIB or transfusion requirement after treatment with thalidomide. Furthermore, 84.6% (n = 11) of patients had a reduction in transfusion requirements and hospitalizations for GIB. Thalidomide was discontinued in 2 patients due to cost (n = 1) and medication interaction (n = 1). Reported adverse reactions included fatigue (n = 3), neuropathy (n = 2), dizziness (n = 1), and constipation (n = 1). Six patients died during follow up due to unknown cause (n = 4) and sepsis (n = 2).\n\n\nCONCLUSIONS\nThalidomide appears to be an effective treatment for refractory GIB due to GIAD or GAVE in a Western population with significant comorbidities.",
"affiliations": "Department of Medicine, Washington University School of Medicine, St. Louis, MO 63108, United States.;Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States. chen330@wustl.edu.",
"authors": "Bayudan|Alexis Mae|AM|;Chen|Chien-Huan|CH|",
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"country": "United States",
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"doi": "10.12998/wjcc.v8.i15.3218",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960 Baishideng Publishing Group Inc \n\njWJCC.v8.i15.pg3218\n10.12998/wjcc.v8.i15.3218\nRetrospective Study\nThalidomide for refractory gastrointestinal bleeding from vascular malformations in patients with significant comorbidities\nBayudan Alexis Mae Department of Medicine, Washington University School of Medicine, St. Louis, MO 63108, United States\n Chen Chien-Huan Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States. chen330@wustl.edu\n Author contributions: Chen CH designed the research; Bayudan AM performed database generation; all authors performed statistical analysis and wrote the paper. Both authors approved the final version.\n\nCorresponding author: Chien-Huan Chen, MD, PhD, Professor, Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Ave, Box 8124, St. Louis, MO 63110, United States. chen330@wustl.edu\n\n\n6 8 2020 \n6 8 2020 \n8 15 3218 3229\n8 2 2020 15 6 2020 15 7 2020 ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.2020This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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.BACKGROUND\nRefractory gastrointestinal bleeding (GIB) secondary to gastrointestinal vascular malformations (GIVM) such as gastrointestinal angiodysplasia (GIAD) and gastric antral vascular ectasia (GAVE) remains challenging to treat when endoscopic therapy fails. Recently thalidomide has been suggested as a treatment option for refractory GIB.\n\nAIM\nTo determine the outcome of patients treated with thalidomide for refractory GIB due to GIVM.\n\nMETHODS\nIRB approved, single center, retrospective review of electronic medical records from January 2012 to November 2018. Patients age > 18 years old, who had > 3 episodes of GIB refractory to medical or endoscopic therapy, and who had been treated with thalidomide for at least 3 mo were included. The primary endpoint was recurrence of GIB 6 mo after initiation of thalidomide.\n\nRESULTS\nFifteen patients were included in the study, all with significant cardiac, hepatic, or renal comorbidities. The cause of GIB was GIAD in 10 patients and GAVE in 5 patients. Two patients were lost to follow up. Of the 13 patients followed, 38.5% (n = 5) had no recurrent GIB or transfusion requirement after treatment with thalidomide. Furthermore, 84.6% (n = 11) of patients had a reduction in transfusion requirements and hospitalizations for GIB. Thalidomide was discontinued in 2 patients due to cost (n = 1) and medication interaction (n = 1). Reported adverse reactions included fatigue (n = 3), neuropathy (n = 2), dizziness (n = 1), and constipation (n = 1). Six patients died during follow up due to unknown cause (n = 4) and sepsis (n = 2).\n\nCONCLUSION\nThalidomide appears to be an effective treatment for refractory GIB due to GIAD or GAVE in a Western population with significant comorbidities.\n\nVascular malformationThalidomideRefractory gastrointestinal bleedingGastric antral vascular ectasiaAngiodysplasia\n==== Body\nCore tip: Gastrointestinal vascular malformations (GIVM) consist of several types such as gastrointestinal angiodysplasias (GIAD) and gastric antral vascular ectasias (GAVE). Refractory gastrointestinal bleeding secondary to GIVM such as GIAD and GAVE remains challenging to treat when endoscopic therapy fails. Thalidomide appears to be an effective treatment for refractory gastrointestinal bleeding due to GIAD or GAVE in a Western population with significant comorbidities.\n\nINTRODUCTION\nGastrointestinal vascular malformations (GIVM) consist of several types such as gastrointestinal angiodysplasias (GIAD) and gastric antral vascular ectasias (GAVE). The pathogenesis of vascular malformations remains unclear, but is thought to be due to an imbalance of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), and anti-angiogenic properties leading to neovascularization[1]. In vitro studies have also demonstrated hypoxic conditions leading to increased expression of hypoxia-inducible-factor-1-α (HIF-1α) and HIF-2α, which upregulate VEGF and participate in the formation of GIVM[2]. Patients with GIVM can present with overt gastrointestinal bleeding (GIB) or iron deficiency anemia (IDA) due to chronic occult blood loss, and can be associated with significant morbidity and mortality.\n\nGIAD are abnormal, dilated, tortuous vessels within the mucosal and submucosal layers and are the most common GIVM seen throughout the gastrointestinal tract. GIAD can account for up to 40% of occult GIB episodes[3]. Several chronic conditions have been associated with GIAD such as aortic stenosis, which can cause an acquired von Willbrand disease leading to increased GIB, also known as Heyde’s Syndrome. GIAD has also been shown to increase risk of GIB in patients with left ventricular assist devices (LVAD) as well as chronic renal failure.\n\nGAVE is generally found in patients with chronic illnesses, such as liver disease, connective tissue diseases, and chronic renal failure. Bleeding from GAVE accounts for 4% of upper GIB and is commonly found in women. Endoscopically, GAVE appears as either punctate lesions throughout the stomach or as red lesions radiating from the pylorus in stripes, known as “watermelon stomach”. Generally, it is found in the antrum with rare presentations in the proximal stomach. Histologically, GAVE is characterized by vascular ectasia of mucosal capillaries, focal thrombosis, spindle cell proliferation, and fibrinolysis.\n\nEndoscopic therapy primarily with argon plasma coagulation (APC) is the mainstay of treatment for GIVM. However, GIVM refractory to endoscopic treatment is common and medications such as octreotide[7], tranexamic acid[8,9], hormonal therapy (estrogen-progesterone)[10], and thalidomide[8,11-23] have all been studied in the management of recurrent GIB refractory to endoscopic therapy.\n\nThalidomide, known to have antiangiogenic properties by suppressing VEGF, has been shown in several studies (Table 1) to be a promising treatment option for refractory GIB from GIVM[11-22]. However, only one randomized control trial has been reported by Ge et al[8] in a Chinese population in 2011. In addition, this study has an extensive exclusion criteria, such as comorbidities of cardiac, pulmonary, liver, renal, hematologic, and rheumatologic disorders; history of thromboembolic disease; or patient on antiplatelet agent or anticoagulation. Given that patients with recurrent GIB from GIVM are frequently elderly with several comorbidities, it is unclear whether the results of this study can be extrapolated to other patient populations. Whereas there are several reported case series on the effects of thalidomide on patient with cirrhosis or LVAD[13,20-22], many other studies excluded patients with significant comorbidities (Table 1). We therefore decided to conduct a retrospective study of thalidomide in treating refractory GIB from GIVM in a Western population with significant comorbidities at a tertiary medical center.\n\nTable 1 Studies evaluating the effect of thalidomide on treating gastrointestinal vascular malformations\n\nRef.\tNo. patients\tPatient population\tTreatment\tFollow-up\tResults\t\nHeidt et al[18], 2006\t1\tvon-Willebrand's disease type II-a\t100 mg daily\t11 mo\tCase report. Recurrent bleed within 2 wk of starting, at 11 months no further bleeding episodes. No side effects. Rebleeding upon cessation and with decreased dose\t\nDabak et al[15], 2007\t3\tExcluded: HIV positive on treatment. History of seizure disorder. Pregnant or lactating females. Patient with nonmalignant disease (congestive heart failure, uncontrolled infection, etc.). History of noncompliance\tThalidomide 100 mg daily and increased every 2 wk by 100 mg up to 400 mg daily\t250 d\tProspective study. 2/3 patients had responded to thalidomide with decrease transfusion requirements starting at 12 wk of study drug initiation. 1/3 stopped due to lack of response. 1/3 had side effects and dose reduced to 50 mg daily\t\nKamalaporn et al[19], 2009\t7\tExcluded: Severe medical conditions, such as heart or liver disease\t50 mg daily, increased by 50 mg weekly up to 200 mg daily for 6 mo\t12 mo\tCase series. Response to treatment in 3/6 with no blood transfusions at 6 months. 4/7 discontinued thalidomide because of side effects. Upon cessation of thalidomide, of the response group: 1 maintained response with no transfusion for 2 mo, then 1 unit every 4 wk. 1 required 2 u every 3-4 wk, 1 passed from diabetes complications\t\nGe et al[10], 2011\t55\tExcluded: Cirrhotic or portal gastropathy. Severe comorbidities of cardiac, pulmonary, renal, liver, hematological, rheumatologic, or uncontrollable diabetes mellitus or hypertension. History of severe bilateral peripheral neuropathy or seizure activity, thromboembolic disease, known thalidomide or iron allergy. Treatment with ASA, NSAID, antiplatelet, anticoagulant, or Chinese medications, gingko, echinacea, or immunomodulators. Pregnant or lactating. Undergoing cancer therapy via chemotherapy or radiation\tThalidomide 25 mg four times daily vs ferrous succinate 100 mg four times daily. Both for 4 mo\t39 mo (8-52)\tProspective, randomized, parallel control trial. Effective response rate of decrease bleed > 50% first year of follow-up period in thalidomide 71.4% vs iron supplementation response 3.7% (P < 0.001). Secondary endpoints of rates of bleeding cessation, blood transfusion, overall hospitalization, and hospitalization for bleeding demonstrated thalidomide was more effective. Level of VEGF significantly reduced in thalidomide group (P < 0.001). Minor side effects reported in thalidomide group\t\nGarrido Serrano et al[17], 2012\t19\tCirrhosis\tThalidomide 200 mg daily for 4 mo\t4 mo\tProspective study. Mean hemoglobin before thalidomide 7 g/dL, after 2 mo 9 g/dL and at end of 4 mo 10 g/dL. Side effects included HE (2/19), sensitive axonal polyneuropathy (1/19) which resolved after withdrawal of thalidomide\t\nRay et al[20], 2014\t1\tLVAD\t50 mg twice daily\t12 mo\tCase report. No further bleeding after starting thalidomide and remained on warfarin. No reported side effects\t\nBond et al[12], 2015\t1\tCutaneous T-cell lymphoma\t100 mg daily\t6 mo\tCase report. No further bleeding episodes at 6 mo. Side effects of dizziness and unsteadiness\t\nDraper et al[23], 2015\t8\tLVAD\t50 mg twice daily increased by 50 mg weekly up to 200 mg daily\tNot included\tCase series. No recurrence of bleeding 5/8, reduced bleeding 2/8. Death 1/8 within 1 wk of starting due to sepsis. Side effects in 2/8\t\nChen et al[14], 2016\t80\tExcluded: Cirrhotic or portal hypertension gastropathy. Severe cardiac, pulmonary, renal, liver, pancreas, hematological, or rheumatologic comorbidities, uncontrolled diabetes mellitus or hypertension, or renal insufficiency without hemodialysis or peritoneal dialysis. Severe bilateral peripheral neuropathy or seizure, thromboembolic disease. Known thalidomide allergy, treatment with any systemic or oral topical corticosteroids, NSAID, any putative immunomodulators, or antiangiogenic agents. Pregnant or lactating. Alcohol and/or drug abuse. Poor compliance\tThalidomide 25 mg four times a day for 4 mo\t42.6 mo (12-120)\tRetrospective study. In first year of follow-up, overall response rate was 77.5% (62/80) with 41.3% (33/80) achieving complete cessation. Overall response rate of 79.5% (62/78). Adverse effects in 60% with serious effects in 31.3% (25/80)\t\nChan et al[13], 2017\t4\tLVAD\t50 mg daily\t11.4 mo (7-24)\tCase series. No further bleeding. When medications stopped, recurrence of bleeding, with restart of medication and cessation of bleeding\t\nDuarte et al[16], 2017\t1\tGlanzmann's thrombasthenia\t50 mg daily, after 15 d increased to 100 mg daily\t6 mo\tCase report. Recurrent bleeding at 5 mo, requiring transfusions. Thalidomide suspended at 5 mo. Death due to sepsis and hemorrhage\t\nSeng et al[21], 2017\t11\tLVAD\tThalidomide 50 mg daily\t186 d (3-512 d)\tRetrospective study. Resolution of bleeding in 90.9% (10/11). Discontinued in 6 (63.6%) due to resolution of bleeding (n = 4) or side effects (n = 2), with GIB recurring in 4 of these patients. Adverse effects in 5/11 patients including pump thrombosis (n = 2) leading to death. 4/11 died during the study with 1 from continued bleeding and 1 from septic shock\t\nNSAID: Non-steroidal anti-inflammatory; ASA: Aspirin; HE: Hepatic encephalopathy; LVAD: Left ventricular assist device; GIB: Gastrointestinal bleeding.\n\nMATERIALS AND METHODS\nStudy population\nThis is a retrospective study of patients diagnosed with GIVM at the Division of Gastroenterology, Washington University Medical Center/Barnes-Jewish Hospital, from January 2012 to November 2018 who were treated with thalidomide. The institutional review board at Washington University in St. Louis, Missouri approved the study.\n\nInclusion criteria\nAged ≥ 18 years old; male and post-menopausal females; > 3 episodes of GIB with > 1 episode of refractory bleeding; documented vascular malformation (either GIAD or GAVE) on either upper endoscopy (esophagogastroduodenoscopy) or colonoscopy and if bleeding was not initially found, subsequent balloon enteroscopy or capsule endoscopy; and treated with thalidomide for at least 3 months. Refractory bleeding was defined as recurrent bleeding requiring > 2 transfusions after failing 2 treatments with endoscopic therapy using APC or medical therapies, such as octreotide, estrogen, or aminocaproic acid. Exclusion criteria: Patients with other causes of GIB, patients with allergy to thalidomide, women who were pregnant or lactating, and pre-menopausal women.\n\nThalidomide treatment\nAll of the patients included in this study were prescribed thalidomide (Thalomid®) by a single certified provider (Chen CH) according to the Thalomid Risk Evaluation and Mitigation Strategy (REMS) program of Celgene (NJ, United States). Patients were started on thalidomide for more than 3 episodes of GIB requiring blood transfusion with recurrent GIB after failing at least two treatments with endoscopic therapy or medical therapy. Patients were started on thalidomide 50 mg twice daily or 100 mg once daily. This initial dose was increased or decreased depending on patient’s response and ability to tolerate the medication. During the treatment period, patients were monitored by phone every 4 wk and in the outpatient clinic every 3 to 6 mo. Complete blood count and comprehensive metabolic panel were monitored every 3 to 6 mo.\n\nIn the event of an adverse side effect, thalidomide was temporarily or permanently discontinued depending on the severity of the side effect and the patient’s tolerability. During treatment with thalidomide, adjunct therapy such as blood transfusions or repeat endoscopic treatment were performed as necessary at the discretion of treating physicians. Transfusion was given to patients when hemoglobin level fell below 7.0 g/dL. Patients were continued on antiplatelet or anticoagulation or iron supplementation if they were taking it prior to initiation of thalidomide.\n\nData collection\nData collected from electronic medical records included patient’s demographics, medical history, comorbidities, medications, number of hospitalizations, endoscopic treatment, and number of blood transfusions.\n\nAssessment\nThe primary endpoint was to assess the recurrence of GIB 6 mo after the initiation of thalidomide. The secondary endpoints were the number of hospitalizations, blood transfusion requirements, and endoscopic treatments. A bleeding recurrence was defined as a GIB episode with hemoglobin level less than 7.0 g/dL resulting in a blood transfusion. All bleeding episodes of the patients studied were due to GIVM. Patients were encouraged to keep in close contact with patient care coordinators to update the team on their progress, possible side effects from thalidomide, and any bleeding episodes requiring blood transfusions or hospitalizations that occurred in between office visits.\n\nRESULTS\nA total of 15 patients were included in this study. Table 2 details the demographic and clinical characteristics of patients included in this study. Mean age was 69 (range: 58-83) years old. There were 6 women (40%) and 9 men (60%). Eleven patients were Caucasian (73.3%) and four patients were African American (26.7%). Body mass index median was 28.6 (range: 21-48). All patients in this study had multiple comorbidities. Six patients had cirrhosis (n = 5) or non-cirrhotic portal hypertension; Child-Pugh class A (n = 2), class B (n = 3). Three had end stage renal disease (ESRD) on hemodialysis, 3 had chronic kidney disease, stage 3 (n = 2), stage 5 (n = 1). Three had a LVAD, 10 had hypertension, 5 had diabetes, 1 had myelodysplastic syndrome (MDS) and non-Hodgkin’s lymphoma, 1 had polyclonal gammopathy, 2 had aortic stenosis, and 1 had hereditary hemorrhagic telangiectasias.\n\nTable 2 Patient characteristics\n\nPatient\tAge\tSex\tComorbidities\tCause of GIB\tPrior failed treatments\tIron supplementation\tComments\t\n1\t58\tM\tLVAD\tGIAD\tOctreotide\t\t\t\n2\t67\tF\tESRD\tGIAD\t\tSodium ferric gluconate\tAspirin\t\n3\t70\tM\tLVAD\tGIAD\tOctreotide\tFerrous sulfate\tWarfarin\t\n4\t61\tF\tCirrhosis\tGIAD\t\tFerrous sulfate\t\t\n5\t81\tM\tLVAD\tGIAD\tOctreotide\tFerrous sulfate\tAspirin, warfarin\t\n6\t83\tM\tCAD, AS, AAA, CVA\tGIAD\tOctreotide, estrogen\tPolysaccharide iron\tAspirin, cilostazol, plavix\t\n7\t72\tM\tHepatoportal sclerosis\tGAVE\t\t\t\t\n8\t69\tF\tPolyclonal gammopathy\tGIAD\t\t\t\t\n9\t70\tF\tESRD, HHT\tGIAD\tOctreotide\tFerrous sulfate\t\t\n10\t62\tM\tCirrhosis\tGAVE\t\tFerrous fumarate\t\t\n11\t58\tM\tCirrhosis, CHF, ESRD\tGAVE\tOctreotide\tFerrous sulfate\t\t\n12\t64\tF\tCirrhosis, MDS, NHL\tGAVE\t\t\t\t\n13\t80\tF\tAS\tGIAD\t\t\t\t\n14\t74\tM\tNSCLC, AFIB, MDS\tGIAD\t\t\tLost to follow-up\t\n15\t68\tM\tAFIB, CHF, Cirrhosis\tGAVE\t\t\tAspirin, warfarin, lost to follow-up\t\nLVAD: Left ventricular assist device; ESRD: End stage renal disease; CAD: Coronary artery disease; AS: Aortic stenosis; AAA: Abdominal aortic aneurysm; CVA: Cerebrovascular accident; HHT: Hereditary hemorrhagic telangiectasia; CHF: Congestive heart failure; MDS: Myelodysplastic syndrome; NHL: Non-Hodgkin lymphoma; NSCLC: Non-small cell lung cancer; AFIB: Atrial fibrillation; GIAD: Gastrointestinal angiodysplasia; GAVE: Gastric antral vascular ectasia.\n\nThe cause of GIB was GIAD in 10 patients (66.6%) and GAVE in 5 patients (33.3%). Prior to treatment with thalidomide, 6 patients were previously treated with octreotide, 1 treated with estrogen, and 1 treated with aminocaproic acid. All patients received at least two treatments of APC before starting thalidomide, except for one whose source of bleeding was not reachable via endoscopy. All patients prior to the initiation of thalidomide had anemia with average hemoglobin level of 7.9 g/dL. Five patients were on iron supplement when referred to our care and 3 patients with iron deficiency were not on iron supplement. Eight patients continued with iron supplementation after initiation of thalidomide treatment. Five patients remained on antiplatelet or anticoagulation such as aspirin, warfarin, clopidogrel, or cilostazol. Two patients discontinued thalidomide: One due to cost and another due to drug interaction with methadone, after being treated with thalidomide for 17 mo and 3 mo respectively. Two other patients were lost to follow up.\n\nDuring the one year prior to starting thalidomide, of the 13 patients who remained in the study, the mean number of hospital admissions for GIB was 5.46 (range, 1-20 admissions), the mean number of packed red blood cell (PRBC) transfusions was 31 units (range, 8-99 units) and the mean number of endoscopic treatments was 4.54 (range, 0-12 endoscopic treatments).\n\nThalidomide was started at either 50 mg twice daily or 100 mg once daily. Ultimately the dose of thalidomide ranged from 50 mg to 200 mg daily, titrating to patients’ response and tolerability. The average duration of treatment on thalidomide was 28 mo (range, 3-45 mo).\n\nOf the 13 patients followed (range 3-45 mo), 9 patients had GIAD and 4 patients had GAVE. GIAD were located in the gastric fundus (n = 1), duodenum (n = 3), jejunum (n = 5), ileum (n = 1), and hepatic flexure of colon (n = 1). After initiation of thalidomide treatment for 6 mo, 5 patients (38.5%) met our primary endpoint with no recurrent GIB episodes during follow-up (Figure 1). Of these 5 patients, 2 had an LVAD and GIAD, 2 had cirrhosis and GAVE, and 1 had cirrhosis and GIAD. Another 6 patients (46.2%) had both marked reduction in transfusion requirements and hospitalizations for GIB (Figure 1 and Table 3). Two patients had increased transfusion after treatment with thalidomide for 3 and 30 mo. The requirement of endoscopic treatments decreased in 11 patients (84.6%) after the initiation of treatment. Of the 11 patients who responded favorably to treatment, the effect of thalidomide could be observed after 3 mo of treatment. Significant reduction of GIVM could be seen during follow-up endoscopies, as demonstrated in a patient with GAVE who underwent esophagogastroduo-denoscopy 3 and 8 mo after treatment with thalidomide (Figure 2).\n\nFigure 1 Units of packed red blood cell transfused before and after initiation of thalidomide.\n\nFigure 2 Endoscopic pictures of gastric antral vascular ectasia before and after treatment with thalidomide. A: Gastric antral vascular ectasia (GAVE) with visible bleeding prior to initiation of thalidomide; B: GAVE 3 mo after initiation of thalidomide; C: GAVE 8 mo after initiation of thalidomide.\n\nTable 3 The effect of thalidomide treatment on refractory gastrointestinal bleeding due to vascular malformation\n\nPatient\tDuration of treatment (mo)\tRecurrence of bleeding after 6 mo\tNumber of hospitalizations due to GIB\tUnits RBC transfused\tNumber of endoscopic treatments (APC)\tComments\t\n1 yr before thalidomide\tAfter starting thalidomide\t1 yr before thalidomide\tAfter starting thalidomide\t1 yr before thalidomide\tAfter starting thalidomide\t\n1\t6\tNo\t2\t0\t21\t0\t2\t0\t\t\n2\t19\tYes\t4\t1\t8\t12\t3\t1\tSide effect of fatigue and dizziness\t\n3\t45\tNo\t2\t0\t20\t0\t1\t0\tSide effect of neuropathy\t\n4\t14\tNo\t1\t0\tWeekly transfusion\t0\t6\t0\tSide effect of fatigue and constipation. Death\t\n5\t44\tYes\t5\t1\t14\t4\t4\t1\tSide effect of neuropathy. Death, Sepsis\t\n6\t17\tYes\t6\t5\tBiweekly transfusion\t4\t3\t2\tStopped due to cost. Death\t\n7\t24\tYes\t9\t3\t33\t9\t4\t10\tDeath\t\n8\t30\tYes\t1\t2\t2\t8\t2\t1\tSide effect of fatigue\t\n9\t28\tYes\t17\t8\t48\t32\t12\t1\tDeath\t\n10\t3\tNA\t1\t0\t3\t0\t1\t0\tStopped due to drug interaction\t\n11\t25\tNo\t20\t1\t65\t3\t12\t1\tDeath, Sepsis\t\n12\t6\tNo\t2\t0\t99\t0\t9\t4\tSide effect of neutropenia\t\n13\t3\tNA\t1\t1\t12\t16\t1\t1\t\t\nGIB: Gastrointestinal bleeding; APC: Argon plasma coagulation; RBC: Red blood cell; NA: Not available.\n\nAll 4 patients who remained on anticoagulation or antiplatelet therapy, including 2 with an LVAD, had a significant decrease in GIB as demonstrated by a decreased transfusion requirements and hospitalizations. Additionally, all 4 patients with cirrhosis had a marked decrease in hospitalizations, blood transfusions, and endoscopic treatments. The 3 patients with ESRD on dialysis and 3 patients with chronic kidney disease all showed improvement in transfusion requirements after treatment.\n\nReported adverse reactions were documented in 6 of the 13 patients (46%), including fatigue (n = 3), neuropathy (n = 2), constipation (n = 1), and dizziness (n = 1). Worsening neutropenia was observed in a patient with concurrent MDS, with stabilization of white blood cell counts after a dose reduction of thalidomide from 100 mg to 50 mg daily. GIB did not recur after this dose reduction. Six patients died during the follow-up period of this study. Five patients died while on thalidomide due to causes unrelated to recurrent GIB and one patient died from unknown causes after discontinuing thalidomide due to cost. All patients who died while taking thalidomide had been treated for over 1 year. Of the 5 patients who died while taking thalidomide, 2 died from complications due to sepsis, 1 sustained a traumatic fall and passed away in hospice, and 2 died from unknown causes.\n\nDISCUSSION\nThis retrospective study aimed to examine the effect of thalidomide on refractory GIB due to GIVM. Our results demonstrated that thalidomide appears to be an effective medical therapy for this very challenging patient population. Five out of 13 patients (38.5%) followed in our study had no recurrent GIB after treatment with thalidomide, while overall 11 out of 13 patients (86.4%) had decrease in recurrence of GIB, hospitalizations, blood transfusions and endoscopic therapies.\n\nPrevious studies and case reports have reported similar results with thalidomide in treating recurrent GIB from GIVM[8,10-22]. Whereas the only randomized controlled trial so far by Ge et al[10] from China found a response rate of 71.4%, patients with cardiac, pulmonary, hepatic, renal, and other comorbidities were excluded from the study. In a follow-up retrospective study by the same group with 80 patients, the response rate to thalidomide in patients with or without comorbidities was 76.7% and 78% respectively, although this study again excluded patients with severe comorbidities such as cirrhosis and severe cardiac and renal conditions[14]. Therefore, it is unclear whether these results could be applied to other patient populations with significant comorbidities. Three previous case series of patients with an LVAD[13] and one case study of patients with liver cirrhosis[17] found thalidomide effective in treating refractory GIB patients with these comorbidities. The response rate in our study was 84.6%, comparable to other previous studies. The patients in our study represent the most challenging recurrent GIB patients we encounter in a tertiary referral medical center, as evidenced by their multiple comorbidities, and the average number of admissions (5.46) and transfusions (31 units of PRBC) one year before the initiation of thalidomide. Our study demonstrated that thalidomide remains an effective treatment for refractory GIB from GIVM in a Western population, including patients with severe comorbidities such as LVAD, cirrhosis, and ESRD on dialysis.\n\nAnticoagulation or antiplatelet agents are frequently discontinued in the setting of GIB. However, this increases the risk of thromboembolism especially in patients with significant cardiovascular comorbidities and patients with LVAD. Four of our patients continued their anticoagulation or antiplatelet agents such as warfarin, aspirin, clopidogrel, or cilostazol, and still responded favorably to thalidomide. Our results suggest that it may not be necessary to discontinue anticoagulation or antiplatelet agents in this group of patients with severe multiple comorbidities while on thalidomide. One patient with severe GAVE and platelet count < 30000/mL due to MDS received 99 units of PRBC in the one year before thalidomide treatment, and required no transfusion after treatment. More data is needed to determine whether correcting thrombocytopenia is necessary when treating GIVM with thalidomide.\n\nThalidomide is thought to inhibit angiogenesis by suppressing VEGF. In our study, the effects of thalidomide became apparent after about 3 mo of treatment, consistent with the observation of previous studies[15,17,19]. The interval between the initiation of thalidomide and the decrease of GIB likely reflects the time it takes to change the balance between anti- and pro- angiogenesis factors in the existing GIVM and suppressing new GIVM formation. The effectiveness of thalidomide in treating GIB from GIVM as shown in this and other studies suggests that we could potentially explore other angiogenesis inhibitors to treat GIVM.\n\nThe dose of thalidomide in previous studies ranged from 50 mg to 400 mg per day. Dosing and efficacy could possibly be related to a patient’s body mass index (BMI), as was suggested by Seng et al[20] where BMI median was 18. The initial dose of thalidomide in their study was 50 mg daily for all patients, whereas other studies typically used at least 100 mg daily[16,20]. In our study, the dose of thalidomide was started at 100 mg daily, with the final dosage ranged from 50 to 200 mg daily. The median BMI of our patients was 28. Seven of our patients improved on thalidomide 100 mg daily, whereas two patients did not see improvement of bleeding until the dose of thalidomide was increased to 150 and 200 mg daily, with a BMI of 28 and 48 respectively. Two non-responders in our study were treated with 200 mg daily with a BMI of 30, and 100 mg daily with BMI of 24. We do not see a clear association of dose, BMI, and effectiveness based on our data. Further study is needed to elucidate the relationship between the response to thalidomide and BMI.\n\nThe common side effects of thalidomide include drowsiness, fatigue, dizziness, neuropathy, skin rash, and constipation. The most common side effect reported in our study was fatigue (n = 3). Fatigue and dizziness were reported in one patient who mistakenly took double dose of thalidomide, and resolved once she went back to the prescribed dose. Neutropenia (n = 1) occurred in a patient with MDS, and resolved upon reducing the dose of thalidomide to 50 mg daily and without recurrence of GIB. Neuropathy was described in 2 patients, one of which had a history of parkinsonism and another with a history of diabetes. No thromboembolism was observed in our study, although the reported risk of thromboembolism associated with thalidomide is mainly seen in patients with multiple myeloma on chemotherapy. Five patients died while on thalidomide and one patient died after discontinuation of thalidomide due to cost. The cause of death does not appear to be associated with thalidomide (sepsis 2, fall 1) in 3 patients. The cause of death in 2 patients was unknown and therefore unclear if it is related to thalidomide.\n\nThe major limitations of this study are the limitations inherent with a retrospective study, such that we were not able to control for variables like the degree of IDA or whether patients were taking iron supplement. Another limitation is our small sample size (n = 15). Most of our patients with refractory GIB were elderly with limited income. Many patients could not receive treatment with thalidomide due to cost or lack of insurance coverage. Even more patients declined treatment with thalidomide due to concern of potential side effects in the context of their multiple comorbidities after reading the patient medical information from REMS. Nevertheless, our sample size is the second largest from the Western World in the literature. In addition, our primary and secondary outcomes were objective measures and less susceptible to reporting bias. With more data published on thalidomide in recurrent GIB, we may see improvement in its coverage or patients’ acceptance.\n\nIn conclusion, the treatment of patients with refractory GIB due to GIVM remains a daunting task with limited options. Our study suggests that thalidomide appears to be an effective treatment for refractory GIB due to GIAD or GAVE in a Western population with significant comorbidities such as LVAD, portal hypertension, and ESRD.\n\nARTICLE HIGHLIGHTS\nResearch background\nGastrointestinal vascular malformations (GIVM) consist of several types such as gastrointestinal angiodysplasias (GIAD) and gastric antral vascular ectasias (GAVE). GIAD are abnormal, dilated, tortuous vessels within the mucosal and submucosal layers and are the most common GIVM seen throughout the gastrointestinal tract. GAVE is generally found in patients with chronic illnesses, such as liver disease, connective tissue diseases, and chronic renal failure. Refractory gastrointestinal bleeding (GIB) secondary to GIVM remains challenging to treat when endoscopic therapy fails. Endoscopic therapy with argon plasma coagulation (APC) is the mainstay of treatment for GIVM. However, GIVM refractory to endoscopic treatment is common and medications such as octreotide, tranexamic acid, hormonal therapy such as estrogen-progesterone, and thalidomide have all been studied in the management of recurrent GIB refractory to endoscopic therapy. Thalidomide, known to have antiangiogenic properties by suppressing VEGF, has been suggested recently as a treatment option for refractory GIB.\n\nResearch motivation\nOnly one randomized control trial demonstrating the efficacy of thalidomide for treating refractory GIB due to GIVM has been published in 2011 in a Chinese population. However, the study had extensive exclusion criteria and it is unclear whether the results of the study can be extrapolated to other patient populations. We therefore decided to conduct a retrospective study of thalidomide in treating refractory GIB from GIVM in a Western population with significant comorbidities at a tertiary medical center.\n\nResearch objectives\nTo evaluate thalidomide as a treatment option for patients who suffer from refractory GIB due to GIVM.\n\nResearch methods\nSingle center, IRB approved, retrospective review of electronic medical records from January 2012 to November 2018. Patients age > 18 years old, who had > 3 episodes of GIB refractory to medical or endoscopic therapy and documented to be due to GIVM, and who had been treated with thalidomide for at least 3 months were included. Refractory bleeding was defined as recurrent bleeding requiring > 2 transfusions after failing 2 treatments with endoscopic therapy using APC or medical therapies, such as octreotide, estrogen, or aminocaproic acid. The primary endpoint was recurrence of GIB 6 mo after initiation of thalidomide. The secondary endpoints were the number of hospitalizations, blood transfusion requirements, and endoscopic treatments.\n\nResearch results\nFifteen patients were included in the study, all with significant cardiac, hepatic, or renal comorbidities. The cause of GIB was GIAD in 10 patients and GAVE in 5 patients. Two patients were lost to follow up. Of the 13 patients followed, 38.5% (n = 5) had no recurrent GIB or transfusion requirement after treatment with thalidomide. Furthermore, 84.6% (n = 11) of patients had a reduction in transfusion requirements and hospitalizations for GIB. Thalidomide was discontinued in 2 patients due to cost (n = 1) and medication interaction (n = 1). Reported adverse reactions included fatigue (n = 3), neuropathy (n = 2), dizziness (n = 1), and constipation (n = 1). Six patients died during follow up due to unknown cause (n = 4) and sepsis (n = 2).\n\nResearch conclusions\nOur results demonstrated that thalidomide appears to be an effective medical therapy for refractory GIB due to GIVM. The response rate in this study was 84.6%, comparable to other previous studies. The patients in our study represent the most challenging recurrent GIB patients in a tertiary referral medical center, as evidenced by their multiple comorbidities, and the average number of admissions (5.5) and transfusions (31 units of PRBC) one year before the initiation of thalidomide. Our study demonstrated that thalidomide remains an effective treatment for refractory GIB from GIVM in a Western population, including patients with severe comorbidities such as left ventricular assist device, cirrhosis, and end-stage renal disease on dialysis.\n\nResearch perspectives\nBased on the results of this study, future research should include prospective randomized control trial with a larger patient population so that we can examine the effect of thalidomide on each comorbidity with sufficient power.\n\nInstitutional review board statement: The study was reviewed and approved by the Washington University Institutional Review Board.\n\nInformed consent statement: As this is a retrospective study, all participants were waived of written informed consent by our IRB.\n\nConflict-of-interest statement: Both authors have no conflicts of interest.\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: February 8, 2020\n\nFirst decision: May 22, 2020\n\nArticle in press: July 15, 2020\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: United States\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): D, D\n\nGrade E (Poor): 0\n\nP-Reviewer: Ho CM, Lee J, Leontiadis GI S-Editor: Yan JP L-Editor: A E-Editor: Wang LL\n==== Refs\n1 Junquera F Saperas E de Torres I Vidal MT Malagelada JR Increased expression of angiogenic factors in human colonic angiodysplasia Am J Gastroenterol 1999 94 1070 1076 10201485 \n2 Feng N Chen H Fu S Bian Z Lin X Yang L Gao Y Fang J Ge Z HIF-1α and HIF-2α induced angiogenesis in gastrointestinal vascular malformation and reversed by thalidomide Sci Rep 2016 6 27280 27249651 \n3 Nardone G Compare D Martino A Rocco A Pharmacological treatment of gastrointestinal bleeding due to angiodysplasias: A position paper of the Italian Society of Gastroenterology (SIGE) Dig Liver Dis 2018 50 542 548 29610020 \n4 Draper KV Huang RJ Gerson LB GI bleeding in patients with continuous-flow left ventricular assist devices: a systematic review and meta-analysis Gastrointest Endosc 2014 80 435 446.e1 24975405 \n5 Chalasani N Cotsonis G Wilcox CM Upper gastrointestinal bleeding in patients with chronic renal failure: role of vascular ectasia Am J Gastroenterol 1996 91 2329 2332 8931412 \n6 Alkhormi AM Memon MY Alqarawi A Gastric Antral Vascular Ectasia: A Case Report and Literature Review J Transl Int Med 2018 6 47 51 29607305 \n7 Vuddanda V Jazayeri MA Turagam MK Lavu M Parikh V Atkins D Bommana S Yeruva MR Di Biase L Cheng J Swarup V Gopinathannair R Olyaee M Ivaturi V Natale A Lakkireddy D Systemic Octreotide Therapy in Prevention of Gastrointestinal Bleeds Related to Arteriovenous Malformations and Obscure Etiology in Atrial Fibrillation JACC Clin Electrophysiol 2017 3 1390 1399 29759670 \n8 Ge ZZ Chen HM Gao YJ Liu WZ Xu CH Tan HH Chen HY Wei W Fang JY Xiao SD Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation Gastroenterology 2011 141 1629 37.e1-4 21784047 \n9 Grooteman KV van Geenen EJM Drenth JPH Tranexamic acid in treatment-resistant chronic transfusion-dependent gastrointestinal angiodysplasia bleeding BMJ Case Rep 2017 2017 bcr2017221832 \n10 Tran A Villeneuve JP Bilodeau M Willems B Marleau D Fenyves D Parent R Pomier-Layrargues G Treatment of chronic bleeding from gastric antral vascular ectasia (GAVE) with estrogen-progesterone in cirrhotic patients: an open pilot study Am J Gastroenterol 1999 94 2909 2911 10520843 \n11 Bauditz J Effective treatment of gastrointestinal bleeding with thalidomide--Chances and limitations World J Gastroenterol 2016 22 3158 3164 27003992 \n12 Bond A Ahmed W Thalidomide for the treatment of angiodysplasia in a patient with acute upper.gastrointestinal haemorrhage BMJ Case Rep 2016 2016 bcr2015213522 \n13 Chan LL Lim CP Lim CH Tan TE Sim D Sivathasan C Novel Use of Thalidomide in Recurrent Gastrointestinal Tract Bleeding in Patients with Left Ventricular Assist Devices: A Case Series Heart Lung Circ 2017 26 1101 1104 28131776 \n14 Chen H Fu S Feng N Chen H Gao Y Zhao Y Xue H Zhang Y Li X Dai J Fang J Ge Z Bleeding recurrence in patients with gastrointestinal vascular malformation after thalidomide Medicine (Baltimore) 2016 95 e4606 27537596 \n15 Dabak V Kuriakose P Kamboj G Shurafa M A pilot study of thalidomide in recurrent GI bleeding due to angiodysplasias Dig Dis Sci 2008 53 1632 1635 17990111 \n16 Duarte BKL de Souza SM Costa-Lima C Medina SS Ozelo MC Thalidomide for the Treatment of Gastrointestinal Bleeding Due to Angiodysplasia in a Patient with Glanzmann's Thrombasthenia Hematol Rep 2017 9 6961 28670433 \n17 Garrido Serrano A León R Sayago M Márquez JL Thalidomide treatment in cirrhotic patients with severe anemia secondary to vascular malformations Dig Dis Sci 2012 57 1112 1113 22089255 \n18 Heidt J Langers AM van der Meer FJ Brouwer RE Thalidomide as treatment for digestive tract angiodysplasias Neth J Med 2006 64 425 428 17179574 \n19 Kamalaporn P Saravanan R Cirocco M May G Kortan P Kandel G Marcon N Thalidomide for the treatment of chronic gastrointestinal bleeding from angiodysplasias: a case series Eur J Gastroenterol Hepatol 2009 21 1347 1350 19730385 \n20 Ray R Kale PP Ha R Banerjee D Treatment of left ventricular assist device-associated arteriovenous malformations with thalidomide ASAIO J 2014 60 482 483 24830804 \n21 Seng BJJ Teo LLY Chan LL Sim DKL Kerk KL Soon JL Tan TE Sivathasan C Lim CP Novel use of low-dose thalidomide in refractory gastrointestinal bleeding in left ventricular assist device patients Int J Artif Organs 2017 40 636 640 28708213 \n22 Draper K Kale P Martin B Kelly Cordero R Ha R Banerjee D Thalidomide for treatment of gastrointestinal angiodysplasia in patients with left ventricular assist devices: case series and treatment protocol J Heart Lung Transplant 2015 34 132 134 25447569 \n23 Carrier M Le Gal G Tay J Wu C Lee AY Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis J Thromb Haemost 2011 9 653 663 21255254\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "8(15)",
"journal": "World journal of clinical cases",
"keywords": "Angiodysplasia; Gastric antral vascular ectasia; Refractory gastrointestinal bleeding; Thalidomide; Vascular malformation",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "3218-3229",
"pmc": null,
"pmid": "32874976",
"pubdate": "2020-08-06",
"publication_types": "D016428:Journal Article",
"references": "29759670;8931412;28708213;17179574;21255254;29607305;24830804;29610020;22089255;27537596;26791122;25447569;28670433;19730385;27249651;17990111;10520843;28131776;21784047;27003992;29092972;10201485;24975405",
"title": "Thalidomide for refractory gastrointestinal bleeding from vascular malformations in patients with significant comorbidities.",
"title_normalized": "thalidomide for refractory gastrointestinal bleeding from vascular malformations in patients with significant comorbidities"
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"companynumb": "US-BAYER-2021-151657",
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"occurcountry": "US",
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"activesubstancename": "ASPIRIN"
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"abstract": "BACKGROUND\nEwing sarcoma (ES) is the second most common bone tumor in children. Current chemotherapeutic regimens include high-dose anthracyclines and alkylating agents with significant variation in treatment length. The Memorial Sloan Kettering Cancer Center P6 regimen (MSKCC P6) treatment protocol is a highly aggressive regimen given over 21 weeks only. We present the outcome of ES patients treated in our center with this protocol over the last 15 years.\n\n\nMETHODS\nWe retrospectively analyzed data on the presentation, patient characteristics, treatment, and outcome of all ES patients treated according to the MSKCC P6 regimen from 1999 to 2014.\n\n\nRESULTS\nOf 48 patients, 37 (77%) presented with a nonmetastatic disease and 26 (54%) with tumor located in the extremities. The 5-year overall survival (OS) of the entire cohort was 55.9% ± 8%. Nonmetastatic disease conferred a better prognosis with a 5-year OS of 68.4% ± 8.5%. Patients with a nonmetastatic extremity tumor had the most favorable outcome with 5-year OS of 72.2% ± 9.8%.\n\n\nCONCLUSIONS\nThe outcome of ES patients after a short aggressive course of chemotherapy (the MSKCC P6 protocol), is comparable to that following other first-line treatment regimens in use, with potentially fewer long-term adverse events.",
"affiliations": "*Department of Pediatric Hematology-Oncology †Department of Oncology, Hadassah Hebrew-University Medical Center, Jerusalem, Israel.",
"authors": "Ben-Ami|Tal|T|;Waldman|Elisha|E|;Marc|Wygoda|W|;Weintraub|Michael|M|;Revel-Vilk|Shoshana|S|;Fried|Iris|I|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000456",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "38(1)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012512:Sarcoma, Ewing; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "38-42",
"pmc": null,
"pmid": "26670840",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ewing Sarcoma: A 15-Year Experience of a Single Center With the MSKCC P6 Treatment Protocol.",
"title_normalized": "ewing sarcoma a 15 year experience of a single center with the mskcc p6 treatment protocol"
} | [
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"companynumb": "IL-BAXTER-2016BAX004710",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
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"actiondrug": "5",
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"abstract": "We report a case of intracranial hypertension presenting with bradycardia as the only component of Cushing's triad in a patient on extracorporeal membrane oxygenation. A 41-year-old woman with recurrent driveline infections of HeartMate-II had sternotomy and debridement that was complicated by right ventricular failure requiring veno-arterial extracorporeal membrane oxygenation. Patient was comatose and acute onset of bradycardia occurred without any change in blood pressure or respiration. Computed tomography of brain demonstrated an uncal herniation from diffuse cerebral edema. Acute onset of bradycardia in comatose patients may be the sole component of Cushing's triad in laminar flow circulatory support.",
"affiliations": "Neurosciences Critical Care Division, Departments of Neurology, Anesthesiology, and Critical Care Medicine and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Anesthesia and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.",
"authors": "Cho|Sung-Min|SM|https://orcid.org/0000-0002-5132-0958;Kilic|Ahmet|A|;Dodd-O|Jeffrey M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0391398819893701",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-3988",
"issue": "43(6)",
"journal": "The International journal of artificial organs",
"keywords": "Cushing’s reflex; Extracorporeal membrane oxygenation; brain herniation; continuous flow pump",
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D000328:Adult; D001919:Bradycardia; D003480:Cushing Syndrome; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006333:Heart Failure; D006801:Humans",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "401-404",
"pmc": null,
"pmid": "31856638",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Incomplete Cushing's reflex in extracorporeal membrane oxygenation.",
"title_normalized": "incomplete cushing s reflex in extracorporeal membrane oxygenation"
} | [
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"companynumb": "US-DRREDDYS-USA/USA/20/0124614",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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"drugaddit... |
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"abstract": "/AIMS: Patients with neuromuscular disorders (NMDs), including many elderly, immunosuppressed, and disabled individuals, may have been particularly affected during the coronavirus disease 2019 (COVID-19) pandemic in Lombardy, a COVID-19 high-incidence area between February and May 2020. We aimed to evaluate the effects of the COVID-19 pandemic on the quality of life (QoL) and perceived disease burden of this group of patients.\n\n\n\nWe conducted a cross-sectional phone-based survey study between June 1 and June 14, 2020, on a sample of 240 NMD patients followed at our clinic in Milan, Italy. We asked about perceived NMD burden and QoL before and during the COVID-19 pandemic. We collected responses on access to outpatient care and ancillary services. We investigated the presence of symptoms suggestive of COVID-19 infection and confirmed cases.\n\n\n\nWe collected 205 responses: 53 patients (25.9%) reported a subjective worsening of the underlying NMD. QoL measures showed a significant worsening between pre and pandemic time frames (odds ratio, 2.14 95%; confidence interval, 1.82-2.51). Outpatient visits were postponed in more than half of cases (57.1%), with 104 patients (50.7%) experiencing a cancellation of scheduled diagnostic tests. 79 patients (38.5%) reported at least one symptom attributable to COVID-19 infection. Among the 10 patients tested with nasopharyngeal swabs, 6 tested positive and 3 died from respiratory failure, including 2 patients on corticosteroid/ immunosuppressive therapy.\n\n\n\nThe COVID-19 pandemic affected QoL and limited access to outpatient care and ancillary services of NMD patients in Lombardy between February and May 2020.",
"affiliations": "Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.;Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.;Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.;Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Scientific Direction, Clinical Trial Center, IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano Foundation, Milan, Italy.;Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.;Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.;Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.;Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Neuromuscular and Rare Diseases Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.;Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.;Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Milan, Italy.",
"authors": "Gagliardi|Delia|D|0000-0001-8460-938X;Costamagna|Gianluca|G|;Abati|Elena|E|;Mauri|Eleonora|E|;Brusa|Roberta|R|;Scudeller|Luigia|L|;Andreoli|Luca|L|;Citterio|Gaia|G|;Piccin|Eleonora|E|;Magri|Francesca|F|;Meneri|Megi|M|;Velardo|Daniele|D|0000-0003-1837-2788;Sciacco|Monica|M|;Bresolin|Nereo|N|;Corti|Stefania|S|;Comi|Giacomo Pietro|GP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/mus.27378",
"fulltext": "\n==== Front\nMuscle Nerve\nMuscle Nerve\n10.1002/(ISSN)1097-4598\nMUS\nMuscle & Nerve\n0148-639X\n1097-4598\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n34296433\n10.1002/mus.27378\nMUS27378\nClinical Research Article\nClinical Research Articles\nImpact of COVID‐19 on the quality of life of patients with neuromuscular disorders in the Lombardy area, Italy\nGagliardi et al.\nGagliardi Delia MD https://orcid.org/0000-0001-8460-938X\n1 2\nCostamagna Gianluca MD 1 2\nAbati Elena MD 1 2\nMauri Eleonora MD 2\nBrusa Roberta MD 2\nScudeller Luigia MD 3\nAndreoli Luca MD 1\nCitterio Gaia MD 1\nPiccin Eleonora MD 1\nMagri Francesca MD 2\nMeneri Megi MD, PhD 2\nVelardo Daniele MD https://orcid.org/0000-0003-1837-2788\n2\nSciacco Monica MD, PhD 4\nBresolin Nereo MD 1 2\nCorti Stefania MD, PhD 1 2 stefania.corti@unimi.it\n\nComi Giacomo Pietro MD 1 2 4 giacomo.comi@unimi.it\n\n1 Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section University of Milan Milan Italy\n2 Neurology Unit IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico Milan Italy\n3 Scientific Direction, Clinical Trial Center IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano Foundation Milan Italy\n4 Neuromuscular and Rare Diseases Unit IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico Milan Italy\n* Correspondence\nStefania Corti, Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.\nEmail: stefania.corti@unimi.it\nGiacomo Pietro Comi, Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, Neurology Unit, Neuromuscular and Rare Diseases Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.\nEmail: giacomo.comi@unimi.it\n\n03 8 2021\n10 2021\n03 8 2021\n64 4 10.1002/mus.v64.4 474482\n15 7 2021\n29 8 2020\n18 7 2021\n© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nIntroduction:/Aims\n\nPatients with neuromuscular disorders (NMDs), including many elderly, immunosuppressed, and disabled individuals, may have been particularly affected during the coronavirus disease 2019 (COVID‐19) pandemic in Lombardy, a COVID‐19 high‐incidence area between February and May 2020. We aimed to evaluate the effects of the COVID‐19 pandemic on the quality of life (QoL) and perceived disease burden of this group of patients.\n\nMethods\n\nWe conducted a cross‐sectional phone‐based survey study between June 1 and June 14, 2020, on a sample of 240 NMD patients followed at our clinic in Milan, Italy. We asked about perceived NMD burden and QoL before and during the COVID‐19 pandemic. We collected responses on access to outpatient care and ancillary services. We investigated the presence of symptoms suggestive of COVID‐19 infection and confirmed cases.\n\nResults\n\nWe collected 205 responses: 53 patients (25.9%) reported a subjective worsening of the underlying NMD. QoL measures showed a significant worsening between pre and pandemic time frames (odds ratio, 2.14 95%; confidence interval, 1.82–2.51). Outpatient visits were postponed in more than half of cases (57.1%), with 104 patients (50.7%) experiencing a cancellation of scheduled diagnostic tests. 79 patients (38.5%) reported at least one symptom attributable to COVID‐19 infection. Among the 10 patients tested with nasopharyngeal swabs, 6 tested positive and 3 died from respiratory failure, including 2 patients on corticosteroid/ immunosuppressive therapy.\n\nDiscussion\n\nThe COVID‐19 pandemic affected QoL and limited access to outpatient care and ancillary services of NMD patients in Lombardy between February and May 2020.\n\naccess to care\nCOVID‐19\nimmunosuppression\nneuromuscular disorders\nquality‐of‐life\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:07.07.2022\nGagliardi D , Costamagna G , Abati E , et al. Impact of COVID‐19 on the quality of life of patients with neuromuscular disorders in the Lombardy area, Italy. Muscle & Nerve. 2021;64 (4 ):474‐482. 10.1002/mus.27378 34296433\n\nDelia Gagliardi and Gianluca Costamagna contributed equally to the work.\n\nStefania Corti and Giacomo Pietro Comi contributed equally to the work.\n==== Body\npmcAbbreviations\n\nADLs activities of daily living\n\nALS amyotrophic lateral sclerosis\n\nCI confidence interval\n\nCIDP chronic inflammatory demyelinating polyneuropathy\n\nCOVID‐19 coronavirus disease 2019\n\nIQR interquartile range\n\nMG myasthenia gravis\n\nMMN multifocal motor neuropathy\n\nMNDs motor neuron diseases\n\nMRC Medical Research Council\n\nNIV non‐invasive ventilation\n\nNM necrotizing myopathy\n\nNMDs neuromuscular disorders\n\nOPMD oculopharyngeal muscular dystrophy\n\nOR odds ratio\n\nPEG percutaneous endoscopic gastrostomy\n\nQoL quality of life\n\nSARS‐CoV‐2 severe acute respiratory syndrome coronavirus 2\n\n1 INTRODUCTION\n\nIndividuals with hereditary or acquired neuromuscular disorders (NMDs), including many elderly, immunosuppressed, and disabled patients, represent a concern for neurologists during the coronavirus disease 2019 (COVID‐19) pandemic. In parallel, the crisis has forced the postponement of millions of visits and has prompted the rapid implementation of at‐distance approaches. All these efforts have been critical to mitigating the burden of infection during the first phase of the pandemic, but they have had consequences on the quality of life (QoL) and well‐being of patients who have been infected or have been required to practice strict preventative measures. 1 , 2 , 3\n\nAlthough some articles on NMD patients and their management during the COVID‐19 pandemic have been published, 4 , 5 , 6 issues regarding this subgroup remain unsolved. (1) Some patients with NMDs may be at higher risk to develop a severe severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection due to the involvement of respiratory muscles and chronic use of immunosuppressive therapies, 7 , 8 but definitive data on infected NMD patients are still lacking. 9 (2) The health crisis has forced the dismantling of traditional health care services, 10 the postponement of in‐person visits, 11 and the rapid implementation of at‐distance approaches, but its impact at a population level is still unclear. (3) National authorities have imposed strict preventive measures, including prolonged home isolation, with uncertain consequences on the QoL of individuals with chronic debilitating diseases.\n\nTo answer these questions, we assessed the QoL and the burden of SARS‐CoV‐2 infection of NMDs patients followed up at our NMD Centre in Milan, Lombardy, one of the SARS‐CoV‐2 worst‐hit regions worldwide. 12 Particularly, we aimed at evaluating whether and how the COVID‐19 pandemic has affected patients' QoL and has had an impact on the provision of care following healthcare reorganization. Moreover, we have provided a detailed description of patients with a confirmed or suspected diagnosis of COVID‐19, evaluating factors (eg, neuromuscular deficits, ongoing chronic treatment) potentially impacting the clinical course and the outcome of the infection.\n\n2 METHODS\n\nWe conducted a cross‐sectional phone‐based survey study between June 1 and June 14, 2020, among a sample of patients followed up at our NMD clinic in Milan, Italy. We included patients with consecutive sampling. Participants were both new and follow‐up NMD patients who attended the clinic consecutively between February 1, 2019, and May 31, 2020. Inclusion criteria were: age 18 y or older and resident in Lombardy. Exclusion criteria included an undiagnosed NMD. All participants provided informed consent. Demographics were obtained from our institutional electronic records according to local regulations. The institutional review board of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico approved the study. Patients were contacted between 9 am and 7 pm. Non‐respondents were re‐contacted up to three times within a week at different times of the day. In case of bedridden, tracheostomized, or severely cognitively impaired patients (five in total) caregivers were interviewed. All data used for analysis were aggregated to ensure patients' anonymity.\n\n2.1 Survey\n\nThe survey was divided into four sections (supplemental material): Demographics and comorbidities: some data were retrieved from clinical records.\n\nPerceived disease burden and QoL before the pandemic: improvement, stability or worsening of patients' perception of NMD compared to that before the pandemic (February 2020) was retrospectively assessed. Perceived QoL was assessed using a 5‐point Likert‐type scale focusing on six items: sleep, appetite, pain, mood, employment satisfaction, and social relationships. Likert‐type scale grading ranged from 1 (low burden) to 5 (high burden).\n\nPerceived disease burden and QoL during the pandemic: evaluation of subjective changes of NMD burden and QoL between February 20th (first SARS‐CoV‐2 confirmed case in Italy) and the day of the interview.\n\nSuspected and confirmed COVID‐19 cases: findings related to contacts with confirmed cases, presence of symptoms attributable to COVID‐19, results of nasopharyngeal swabs, and serological testing were obtained. Management and outcome of confirmed cases were further investigated.\n\n2.2 Demographics\n\nAge, sex, diagnosis, and disease duration were retrieved from the clinical records. Information on the use of immunosuppressants and steroid therapies were retrieved from the survey (question 10 to 13, supplemental material). Patients receiving oral steroids were on long‐term therapy with low dose (≤7.5 mg prednisone equivalent a day) and medium‐dose (>7.5 mg, but ≤30 mg prednisone equivalent a day) corticosteroids. 13\n\n2.3 Functional status\n\nPatient functional status was assessed by asking about activities of daily living (ADLs) (bathing, personal hygiene, toileting, dressing, self‐feeding, and transferring), respiratory support, presence of dysphagia, and ambulation (question 5 to 8, in the Supporting Information Material, which is available online).\n\n2.4 Statistical analysis\n\nMean ± SD are reported for continuous variables. Relative frequencies, percentages as well as medians with interquartile ranges (IQR) are presented for categorical variables.\n\nTo assess the effect of the pandemic period on perceived disease burden and QoL items, we employed multilevel mixed ordinal regression models, with “patient” as random effect and “timing” as fixed effect; these models take into account within‐patient correlation and do not require further adjustment of p‐value. We fitted a cumulative model of items, thus estimating a common effect of the pandemic on perceived disease burden and on the underlying trait “QoL,” and a model with timing interacting with individual items, to assess whether the pandemic had a different effect on some of the individual QoL items. The reference timing was February 2020. To explore potential differences in subgroups, further models were fitted adding an interaction term between timing and each subgroup. The association of clinical features (age, sex, disease duration, independent ambulation, respiratory support, dysphagia, inflammatory disease, and steroid and immunosuppressive therapy) with changes in perceived disease burden and QoL during the pandemic period was also assessed.\n\nStatistical analyses were performed using GraphPad (Prism) version 8.3.1 and STATA version 16.0 (Stata Corporation, College Station, Texas, USA).\n\n3 RESULTS\n\nWe contacted 240 out of 350 patients followed at our neuromuscular center and received 205 phone responses, resulting in a response rate of 85%; 110 undiagnosed patients under investigation for a possible NMD condition were excluded from the survey. Three patients out of 205 had died from COVID‐19 infection, and 1 patient was unable to perform the survey due to a language barrier, resulting in 201 complete responses.\n\n3.1 Demographic and clinical features\n\nOur sample consisted of eight subgroups of NMDs, including myositis (dermatomyositis, necrotizing myositis [NM], polymyositis, inclusion body myositis, and overlap myositis with rheumatoid arthritis) myasthenia gravis (MG), metabolic myopathies, muscular dystrophies, congenital myopathies, motor neuron disorders (MNDs), immune‐mediated neuropathies (chronic inflammatory demyelinating polyneuropathy [CIDP], multifocal motor neuropathy [MMN], and anti‐MAG neuropathies), and other neuropathies (diabetic, toxic, and hereditary).\n\nThe mean age of respondents was 61.7 ± 16.2 y (range 21–90). Male and female sexes were equally distributed, except for congenital myopathies, immune‐mediated neuropathies, and MNDs. Demographic and clinical features are listed in Table 1. Comorbidities and functional disease status (dependence in ADLs, respiratory support, dysphagia, ambulation) are summarized in Supporting Information Table SS1. Hypertension and obesity‐related comorbidities were the most represented.\n\nTABLE 1 Demographic and clinical features of patients with neuromuscular disorders\n\n\tTotal (n = 205)\tMyositis (n = 44–21.5%)\tMyasthenia gravis (n = 44–21.5%)\tMetabolic myopathies (n = 24–11.7%)\tMuscular dystrophies (n = 27–13.2%)\tCongenital myopathies (3–1.4%)\tMNDs (n = 30–14.6%)\tImmune‐mediated neuropathies (n = 9–4.4%)\tOther neuropathies (n = 24–11.7%)\t\nAge, y (mean ± SD)\t61.7 ± 16.2\t62.2 ± 16.1\t68.4 ± 14.3\t55.8 ± 16.6\t50 ± 14.7\t57 ± 19.7\t66.1 ± 10.2\t65.3 ± 16.2\t61.1 ± 19.2\t\nSex, n (%)\t\nFemale\t103 (50.2)\t29 (65.9)\t23 (52.3)\t12 (50)\t10 (37)\t3 (100)\t12 (40)\t6 (66.7)\t8 (33.3)\t\nDisease duration, y (mean ± SD)\t11.4 ± 11.6\t7.8 ± 7\t9.5 ± 8.9\t18 ± 13.2\t14.4 ± 13.1\t31 ± 15.1\t4.7 ± 3.6\t12.9 ± 10.4\t17.1 ± 17\t\nSteroid therapy, n (%)\t\nMedium dose\t23 (11.2)\t11 (25)\t8 (18.2)\t‐\t‐\t‐\t1 (3.3)\t2 (22.2)\t1 (4.2)\t\nLow dose\t33 (16.1)\t15 (34.1)\t14 (31.8)\t‐\t‐\t‐\t‐\t2 (22.2)\t2 (8.3)\t\nImmunosuppressants, n (%)\t34 (16.6)\t22 (50)\t9 (20.4)\t‐\t1 (3.7)\t‐\t‐\t2 (22.2)\t‐\t\nSteroid + immunosuppressant, n (%)\t20 (9.8)\t13 (29.5)\t5 (11.4)\t‐\t‐\t‐\t‐\t2 (22.2)\t‐\t\nNote: Immune‐mediated neuropathies included 5 CIDP, 2 MMN, and 2 anti‐MAG neuropathies. Myositis included 7 dermatomyositis, 15 necrotizing myositis, 12 polymyositis, 8 inclusion body myositis, and 2 overlap myositis with rheumatoid arthritis.\n\nAlmost half of the patients were on maintenance therapy with corticosteroid or immunosuppressive drugs including patients with myositis, MG, and immune‐mediated neuropathies (Table 1). Approximately 10% of patients were taking both steroids and immunosuppressive drugs.\n\n3.2 Perceived disease burden and QoL before and during the pandemic\n\n3.2.1 Perceived disease burden\n\nPerceived disease burden was derived from questions 14, 15, and 22 (Supporting Information Material); 71.2% of patients did not experience any changes concerning their NMD during the COVID‐19 pandemic, while 25.9% reported a subjective worsening of the disease burden. Perceived disease burden showed a significant worsening between February 2019 and May 2020 (odds ratio [OR] 3.75; 95% confidence interval [CI], 2.29–6.13, p < .001). No significant change was observed during the COVID‐19 pandemic between February 2020 and May 2020 (OR 1.42; 95% CI 0.89–2.26; P = .140). Independent ambulation, inflammatory disease (myositis, MG, and immune‐mediated neuropathies), and steroid therapy were associated with perceived disease burden worsening during the pandemic (Table 2). In the same timeframe, respiratory support and dysphagia were inversely associated with subjective worsening of NMD burden.\n\nTABLE 2 Association between perceived disease burden during pandemic period and clinical features\n\n\tUnivariable\t\t\nReference = February 2020\t\nCovariates\tOR [95%CI]\tP‐value\t\nAge (ref = average age)\t0.99 [0.96–1.02]\t.391\t\nFemale sex (ref = F)\t1.37 [0.54–3.46]\t.502\t\nDisease duration (ref = 1 y)\t1.00 [0.96–1.04]\t.931\t\nIndependent ambulation (ref = no)\t3.80 [1–43‐10.08]\t.007\t\nRespiratory support (ref = no)\t0.08 [0.02–0.38]\t.002\t\nDysphagia (ref = no)\t0.21 [0.07–0.62]\t.004\t\nInflammatory disease (ref = no)\t16.43 [5.91–45.66]\t<.001\t\nSteroid therapy (ref = no)\t14.08 [4.36–45.52]\t<.001\t\nImmunosuppressive therapy (ref = no)\t1.23 [0.33–4.59]\t.761\t\nNMD subgroup (ref = myositis)\t\nMyasthenia gravis\t0.95 [0.20–4.55]\t.949\t\nMetabolic myopathies\t0.06 [0.01–0.43]\t.005\t\nMuscular dystrophies\t0.04 [0.01–0.24]\t<.001\t\nCongenital myopathies\t0.11 [0.00–4.55]\t.248\t\nMNDs\t0.03 [0.01–0.15]\t<.001\t\nImmune‐mediated neuropathies\t0.95 [0.07–13.42]\t.971\t\nOther neuropathies\t0.19 [0.03–1.14]\t.070\t\nNote: Bold values indicate significant p‐values (p < 0.05)\n\nTaking into account the different NMD categories, perceived disease burden was significantly worsened in patients with metabolic myopathies, muscular dystrophies, and MNDs compared to myositis (Table 2).\n\n3.2.2 QoL\n\nQoL item scores collectively significantly worsened between pre‐pandemic (February 2020) and pandemic (May 2020) timeframes (OR 2.14; 95% CI, 1.82–2.51; P < .001). When analyzing QoL item scores individually, we found a statistically significant risk of worsening for employment satisfaction and social relationships (Table 3). No significant differences were found considering the various NMD subgroups (Table 4). Age, sex, disease duration, independent ambulation, respiratory support, steroid, and immunosuppressive therapy did not significantly modify the impact on QoL (Table 4), while having an inflammatory disease was directly associated with QoL worsening during the COVID‐19 pandemic.\n\nTABLE 3 QoL items between pre‐ and post‐pandemic timeframes\n\nQoL items\tOR [95%CI]\tPvalue\t\nFebruary 2020\t\nBaseline (ref = appetite)\t1.00\t\t\nPain\t1.89 [1.27–2.83]\t.002\t\nWork\t2.96 [1.75–5.01]\t<.001\t\nSocial relationships\t1.63 [1.10–2.41]\t.015\t\nSleep\t3.90 [2.64–5.76]\t<.001\t\nMood\t3.89 [2.65–5.72]\t<.001\t\nMay 2020\t\nAppetite (ref = Feb 2020)\t1.54 [1.04–2.30]\t.033\t\nMay 2020\t\nPain\t0.80 [0.46–1.40]\t.430\t\nWork\t4.42 [2.14–9.10]\t<.001\t\nSocial relationships\t4.35 [2.52–7.52]\t<.001\t\nSleep\t0.94 [0.55–1.61]\t.816\t\nMood\t1.33 [0.78–2.27]\t.289\t\nNotes: The odds ratios refer to the probability of a 1 unit decrease of each item score (and 1 unit increase of pain score) compared to appetite at February 2020 (top), of appetite at May 2020 compared to February 2020 (mid), and of each item score compared to the change in appetite from February to May 2020 (bottom). Bold values indicate significant p‐values (p < 0.05)\n\nTABLE 4 Association between QoL item scores (cumulative trait) during the pandemic period and clinical features\n\nCovariates\tUnivariable\t\t\nOR [95%CI]\tP‐value\t\nAge (ref = average age)\t1.00 [0.99–1.01]\t.510\t\nFemale sex (ref = F)\t0.85 [0.62–1.17]\t.321\t\nDisease duration (ref = 1 y)\t1.00 [0.98–1.01]\t.801\t\nIndependent ambulation (ref = no)\t1.34 [0.95–1.88]\t.095\t\nRespiratory support (ref = no)\t0.69 [0.40–1.18]\t.177\t\nDysphagia (ref = no)\t0.80 [0.55–1.15]\t.229\t\nInflammatory disease (ref = no)\t1.49 [1.08–2.05]\t.014\t\nSteroid therapy (ref = no)\t1.42 [0.99–2.03]\t.059\t\nImmunosuppressive therapy (ref = no)\t1.32 [0.85–2.06]\t.212\t\nNMD subgroup (ref = myositis)\t\nMyasthenia gravis\t1.09 [0.67–1.79]\t.728\t\nMetabolic myopathies\t0.61 [0.43–1.09]\t.094\t\nMuscular dystrophies\t0.65 [0.37–1.15]\t.138\t\nCongenital myopathies\t2.23 [0.63–7.81]\t.212\t\nMNDs\t0.73 [0.43–1.24]\t.244\t\nImmune‐mediated neuropathies\t1.70 [0.75–3.83]\t.201\t\nOther neuropathies\t0.91 [0.52–1.59]\t.734\t\nNote: Bold values indicate significant p‐values (p < 0.05)\n\nRelative frequencies of responses for each QoL item are reported in Figure 1. Medians and IQR of pre‐and post‐pandemic scores for each NMD subgroup are reported in Supporting Information Table SS2.\n\nFIGURE 1 QoL changes before and during the COVID‐19 pandemic. As regards the quality of life, sleep (A), appetite (B), pain (C), mood (D), employment (E), and social relationships (F) were ranked on a 1‐ to 5‐point Likert‐type scale. The histograms represent the frequencies of patients according to the score assigned to each item. Yellow columns, rates during the pre‐pandemic period; blue columns, rates during the pandemic period\n\n3.3 Outpatient caring, ancillary services, and physiotherapy\n\nThe COVID‐19 outbreak may have affected outpatient care and ancillary services, favoring at‐distance approaches. We asked our patients about the delay or cancellation of on‐site visits and diagnostic tests. Outpatient clinical visits were postponed in 117 cases (57.1%), while telemedicine visits were scheduled in only 9 cases (4.4%). Consistent with this, 104 patients (50.7%) could not undergo their scheduled diagnostic tests due to the COVID‐19 emergency.\n\nOf 205 patients, 87 (42.4%) were regularly performing physical therapy before the onset of the COVID‐19 epidemic; 66 of them (75.9%) experienced a suspension or a frequency reduction of these sessions between February and May; 22 out of 66 patients (33.3%) reported a subjective worsening of the underlying NMD during the pandemic period.\n\n3.4 Patients with symptoms attributable to suspected or definite COVID‐19 infection\n\nOverall, 79 patients (38.5%) reported at least one symptom potentially suggestive of COVID‐19 infection between February and the end of May. In our cohort, a total of 10 nasopharyngeal swabs were administered. Only eight (10%) of the symptomatic patients received a nasopharyngeal swab, with positive results confirmed by two repeated tests in six patients.\n\nConsidering confirmed cases (Table 5), all patients presented typical symptoms of COVID‐19. Three out of six patients were hospitalized. They all showed signs of hypoxemic respiratory failure secondary to SARS‐CoV‐2 and received respiratory support. Patient 1 was on low‐dose corticosteroid maintenance therapy. Patient 5 was on medium‐dose corticosteroid therapy (30 mg), and she had received an infusion of rituximab, 1 g, 1.5 mo before. During the infection, patient 2 received a higher dose of steroids (from 17.5 to 25 mg daily) while maintaining azathioprine. All the hospitalized patients died due to respiratory failure.\n\nTABLE 5 Patients with confirmed COVID‐19 infection\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\t\nDiagnosis\tAChR‐Ab MG\tAChR‐Ab MG\tCIDP\tOPMD\tSRP‐Ab NM\tBMD\t\nAge, y\t88\t61\t50\t80\t85\t32\t\nSex\tMale\tMale\tFemale\tMale\tFemale\tMale\t\nDisease duration, y\t8\t1\t26\t9\t0.5\t12\t\nComorbidities\tHypertension, previous stroke\t‐\tHypertension, obesity/dyslipidemia\t‐\tHypertension, obesity/dyslipidemia\t‐\t\nBaseline respiratory impairment\tNo\tNo\tNo\tNo\tYes\tNo\t\nPrednisone, mg\t2.5\t17.5\t‐\t‐\t75\t‐\t\nImmunosuppressant\t‐\tAzathioprine 150 mg daily\t‐\t‐\tRituximab 1 g (last infusion 1.5 mo before the infection)\t‐\t\nChest X‐ray findings\tPneumonia\tNot done\tInterstitial pneumonia\tFocal opacity + lung interstitial thickening\tMultifocal interstitial pneumonia, pleural effusion\tUnremarkable\t\nHospital admission\tYes\tNo\tNo\tYes\tYes\tNo\t\nTherapy for COVID‐19\tNot available\tParacetamol\tHQC, LMWH, azithromycin\tParacetamol, levofloxacin\tHQC, antiviral (lopinavir/ritonavir), Vancomycin\tParacetamol\t\nRespiratory support\tNIV\tNo\tNo\tOxygen therapy\tNIV\tNo\t\nOutcome\tDeath from respiratory failure\tFull recovery\tFull recovery\tDeath from respiratory failure\tDeath from respiratory failure\tFull recovery\t\nAbbreviations: Ab, antibodies; AChR, acetylcholine receptor; BMD, Becker muscular distrophy; HQC, hydroxychloroquine; LMWH, low molecular weight heparin; SRP, signal recognition particle.\n\nPatients 2 and 3 reported a subjective worsening of neuromuscular symptoms following recovery from the infection, with increased fatigability and worsened distal weakness, respectively.\n\n4 DISCUSSION\n\nBased on our survey, we found that the SARS‐CoV‐2 pandemic in Italy had an overall negative impact on access to visits, ancillary services, and QoL of our NMD patients regarding social relationships, mood, employment satisfaction, sleep, appetite, and pain.\n\nAs regards QoL, we observed a worsening in all the items evaluated in our survey. Different studies have assessed the QoL of residents in COVID‐19 worst‐hit areas, 14 patients with neurological diseases, 1 , 15 and individuals with suspected COVID‐19 infection. 2 In all these studies, the pandemic had an overall negative impact on the QoL of the respondents. For instance, among 40 patients with Alzheimer disease in Spain, 30% of them reported a worsening of their health status during a 5‐wk lockdown period. 1 Also in low‐risk areas, the COVID‐19 pandemic affected physical activity and QoL during the first wave, as reported in a study on NMD patients in Sicily. 15 In our cohort, employment satisfaction and social relationships were particularly affected. The fact that our patients come from Lombardy, where authority‐appointed isolation measures were stricter compared with other parts of Italy, may have played a role. We did not observe significant differences in terms of QoL worsening among the various NMD subgroups, likely due to the heterogeneous and relatively small sample of patients and the short follow‐up.\n\nIn our cohort, the perceived disease burden did not significantly change during the pandemic outbreak. However, patients with an inflammatory NMD and taking corticosteroids presented an increased risk of perceived disease burden worsening. Decreased access to outpatient care and in‐person therapy adjustments may have affected patients' perception of their disease burden. Respiratory support, dysphagia, and dependent ambulation were associated with reduced perceived disease burden. It could be speculated that patients with more disabling NMDs, such as amyotrophic lateral sclerosis (ALS), may show disease‐related behavioural changes, including apathy and lower awareness of clinical worsening, 16 , 17 possibly leading to bias in self‐rating.\n\nThe literature on the clinical course of NMD patients with COVID‐19 infection is scant. A small case series of five patients with MG and COVID‐19 showed high variability of disease severity and outcome. 4 Three of them developed severe respiratory failure following the infection and required intubation or high‐flow oxygen, whereas two had a milder disease course. Four of them had a favorable outcome. A patient with MG (patient 1) required non‐invasive ventilation (NIV) during hospitalization and eventually died from respiratory failure. Patient 1 did not present with previous respiratory involvement. However, older age (88 y), a predictor of mortality in COVID‐19, 18 may have played a role in this case. In some MG patients, COVID‐19 may directly induce a myasthenic crisis. 5 , 19 Although an exacerbation of the underlying disease cannot be excluded in patient 1, our MG patient who recovered from the infection (patient 2) had milder symptoms and did not experience a flare of the underlying disease.\n\nThe fatal outcome observed in patient 4, who suffered from oculopharyngeal muscular dystrophy (OPMD), was likely due to respiratory impairment and old age.\n\nReferring to immunosuppressive therapies, the need for therapy dosage reduction vs. discontinuation in NMD patients is uncertain 7 and large systematic studies on the outcome of infected immunosuppressed patients still lack. Preliminary systematic reviews do not report a significantly increased mortality or risk for a severe disease course in immunosuppressed patients with COVID‐19. 9 , 20 Our cohort includes a limited number of patients with inflammatory diseases (44 inflammatory myositis and 9 immune‐mediated neuropathies) from which to draw conclusions on the impact of immunosuppression in infected NMD patients. The need for discontinuing immunosuppressive therapy during COVID‐19 infection for NMD will require further clinical studies.\n\nIt is still unclear how the isolation measures have affected the QoL of patients in different regions worldwide, particularly for those with chronic debilitating diseases. In addition, how the underlying NMDs and immunosuppression affect the COVID‐19 disease course remains unanswered. On the other hand, it is essential to assess whether COVID‐19 infection may prompt exacerbation of the underlying NMD in these patients. Studies investigating both pathogenic mechanisms of COVID‐19 infection and comprehensive systematic analysis involving large cohorts will help to clarify these questions.\n\nThis study has limitations. Despite a satisfactory response rate (85%), our survey reached only a fraction of our patients. Symptoms and medical conditions were self‐reported and likely limited by the availability of home thermometers as well as patients' recall and literacy. Since at the planning stage we could not anticipate the number of patients we would be able to enroll, we did not perform sample size calculations. The study size was based on patients' availability to participate; our results should be viewed as exploratory and hypothesis‐generating, rather than confirmatory. The use of an unvalidated Likert scale represents another limitation. Further, reported clinical worsening lacked an objective assessment using standardized scales (e.g. Medical Research Council [MRC] scale for muscle; 6‐minute walk test; five times sit to stand test). However, surveys are a simple and quick tool to reach people at distance and have been used to assess QoL and disease burden of NMD patients in the past. 21 , 22\n\nWith our survey, we showed that the COVID‐19 pandemic impaired some aspects of QoL and affected access to outpatient care and ancillary services, with limited use of at‐distance alternatives, of NMD patients in a COVID‐19 high‐incidence area. Given the possibility of cyclical outbreaks of the infection, it will be important to offer alternatives to in‐person care, redefine access to ancillary services and provide new approaches to support patients with chronic NMDs and their caregivers.\n\nCONFLICT OF INTEREST\n\nNone of the authors has any conflict of interest to disclose.\n\nAUTHOR CONTRIBUTIONS\n\nDr. D. Gagliardi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs D. Gagliardi and G. Costamagna contributed equally and share the first authorship. Conception and design of the work: Delia Gagliardi. Acquisition, analysis and interpretation of data for the work: Delia Gagliardi, Gianluca Costamagna, Elena Abati, Eleonora Mauri, Roberta Brusa, Luigia Scudeller, Luca Andreoli, Gaia Citterio, Eleonora Piccin. Drafting of the manuscript: Gianluca Costamagna, Delia Gagliardi, Elena Abati. Critical revision of the manuscript for important intellectual content: Francesca Magri, Megi Meneri, Daniele Velardo, Stefania Corti, Giacomo Pietro Comi. Final approval of the version to be published: Monica Sciacco, Nereo Bresolin, Stefania Corti, Giacomo Pietro Comi.\n\nETHICAL PUBLICATION STATEMENT\n\nWe confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\n\nSupporting information\n\nAppendix S1. Supporting Information\n\nClick here for additional data file.\n\nTable S1. Comorbidities and functional status of patients with neuromuscular disorders\n\nClick here for additional data file.\n\nTable S2. Quality of life before and after the pandemic across various NMD groups.\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nThe authors thank Associazione Amici del Centro Dino Ferrari for its support. This study was funded by Italian Ministry of Health, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico Ricerca Corrente 2020 to NB and GPC. Open Access Funding provided by Universita degli Studi di Milano within the CRUI‐CARE Agreement.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 Beatriz Lara B , Carnes A , Dakterzada F , Benitez I , Piñol‐Ripoll G . Neuropsychiatric symptoms and quality of life in Spanish Alzheimer's disease patients during COVID‐19 lockdown. Eur J Neurol. 2020;27 :1744‐1747. 10.1111/ene.14339 32449791\n2 Nguyen HC , Nguyen MH , Do BN , et al. People with suspected COVID‐19 symptoms were more likely depressed and had lower health‐related quality of life: the potential benefit of health literacy. J Clin Med. 2020;9 (4 ):965. 10.3390/jcm9040965\n3 Galea S , Merchant RM , Lurie N . The mental health consequences of COVID‐19 and physical distancing: the need for prevention and early intervention. JAMA Intern Med. 2020;180 (6 ):817‐818. 10.1001/jamainternmed.2020.1562 32275292\n4 Guidon AC , Amato AA . COVID‐19 and neuromuscular disorders. Neurology. 2020;94 (22 ):959‐969. 10.1212/WNL.0000000000009566 32284362\n5 Anand P , Slama MCC , Kaku M , et al. COVID‐19 in patients with myasthenia gravis. Muscle Nerve. 2020;62 :254‐258. 10.1002/mus.26918 32392389\n6 Costamagna G , Abati E , Bresolin N , Comi GP , Corti S . Management of patients with neuromuscular disorders at the time of the SARS‐CoV‐2 pandemic. J Neurol. 2020;268 :1580‐1591. 10.1007/s00415-020-10149-2 32804279\n7 International MG/COVID‐19 Working Group , Jacob S , Muppidi S , et al. Guidance for the management of myasthenia gravis (MG) and Lambert‐Eaton myasthenic syndrome (LEMS) during the COVID‐19 pandemic. J Neurol Sci. 2020;412 :116803. 10.1016/j.jns.2020.116803 32247193\n8 Solé G , Salort‐Campana E , Pereon Y , et al. Guidance for the care of neuromuscular patients during the COVID‐19 pandemic outbreak from the French rare health care for Neuromuscular Diseases Network. Rev Neurol. 2020;176 (6 ):507‐515. 10.1016/j.neurol.2020.04.004 32354651\n9 Minotti C , Tirelli F , Barbieri E , Giaquinto C , Donà D . How is immunosuppressive status affecting children and adults in SARS‐CoV‐2 infection? A systematic review. J Infect. 2020;81 :e61‐e66. 10.1016/j.jinf.2020.04.026\n10 Bersano A , Pantoni L . The impact of SARS‐Cov‐2 pandemic on stroke care: a warning message. Eur J Neurol. 2020;27 :1781‐1782. 10.1111/ene.14394 32526074\n11 Mauri E , Abati E , Musumeci O , et al. Italian Association of Myology . Estimating the impact of COVID‐19 pandemic on services provided by Italian neuromuscular centers: an Italian Association of Myology survey of the acute phase. Acta Myol. 2020;39 (2 ):57‐66. 10.36185/2532-1900-008.32904925\n12 Carrara C , Cappelletti L , Portalupi V . A view from the front line of the COVID‐19 war. Kidney Int. 2020;98 (1 ):10‐11. 10.1016/j.kint.2020.04.018 32451077\n13 Buttgereit F , Silva JAPD , Boers M , et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis. 2002;61 :718‐722. 10.1136/ard.61.8.718 12117678\n14 Zhang Y , Ma ZF . Impact of the COVID‐19 pandemic on mental health and quality of life among local residents in Liaoning Province, China: a cross‐sectional study. Int J Environ Res Public Health. 2020;17 (7 ):2381. 10.3390/ijerph17072381\n15 di Stefano V , Battaglia G , Giustino V , et al. Significant reduction of physical activity in patients with neuromuscular disease during COVID‐19 pandemic: the long‐term consequences of quarantine. J Neurol. 2020;268 :20‐26. 10.1007/s00415-020-10064-6 32661716\n16 Strong MJ , Abrahams S , Goldstein LH , et al. Amyotrophic lateral sclerosis ‐ frontotemporal spectrum disorder (ALS‐FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18 (3‐4 ):153‐174. 10.1080/21678421.2016.1267768 28054827\n17 Consonni M , Telesca A , Dalla Bella E , Bersano E , Lauria G . Amyotrophic lateral sclerosis patients' and caregivers' distress and loneliness during COVID‐19 lockdown. J Neurol. 2021;268 :420‐423. 10.1007/s00415-020-10080-6 32696342\n18 Leung C . Risk factors for predicting mortality in elderly patients with COVID‐19: a review of clinical data in China. Mech Ageing Dev. 2020;188 :111255. 10.1016/j.mad.2020.111255 32353398\n19 Delly F , Syed MJ , Lisak RP , Zutshi D . Myasthenic crisis in COVID‐19. J Neurol Sci. 2020;414 :116888. 10.1016/j.jns.2020.116888 32413767\n20 Gao Y , Chen Y , Liu M , Shi S , Tian J . Impacts of immunosuppression and immunodeficiency on COVID‐19: a systematic review and meta‐analysis. J Infect. 2020;81 :e93‐e95. 10.1016/j.jinf.2020.05.017\n21 Orcesi S , Ariaudo G , Mercuri E , et al. A new self‐report quality of life questionnaire for children with neuromuscular disorders: presentation of the instrument, rationale for its development, and some preliminary results. J Child Neurol. 2014;29 (2 ):167‐181. 10.1177/0883073813511859 24352162\n22 Burns TM , Graham CD , Rose MR , Simmons Z . Quality of life and measures of quality of life in patients with neuromuscular disorders. Muscle Nerve. 2012;46 :9‐25. 10.1002/mus.23245 22644588\n\n",
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"keywords": "COVID-19; access to care; immunosuppression; neuromuscular disorders; quality-of-life",
"medline_ta": "Muscle Nerve",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000086382:COVID-19; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009468:Neuromuscular Diseases; D011788:Quality of Life; D011795:Surveys and Questionnaires",
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"title": "Impact of COVID-19 on the quality of life of patients with neuromuscular disorders in the Lombardy area, Italy.",
"title_normalized": "impact of covid 19 on the quality of life of patients with neuromuscular disorders in the lombardy area italy"
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"abstract": "Wunderlich syndrome is a rare condition characterised by acute spontaneous non-traumatic renal haemorrhage into the subcapsular and perirenal spaces. Our case of anti-GAD65-associated autoimmune encephalitis (AE), aged 30 years, developed this complication following use of enoxaparin and was managed by selective glue embolisation of subsegmental branches of right renal cortical arteries. Our case had opsoclonus as one of the clinical manifestations, which has till now been described in only two patients of this AE. This patient received all forms of induction therapies (steroids, plasmapheresis, intravenous immunoglobulin and rituximab) following which she had good improvement in her clinical condition. The good response to immunotherapy is also a point of discussion as this has been rarely associated with anti-GAD65 AE.",
"affiliations": "Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, Delhi, India.;Neurology, All India Institute of Medical Sciences, New Delhi, India animeshdas05@gmail.com.;Neurology, All India Institute of Medical Sciences, New Delhi, India.;Neurology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Gomathy|Saranya B|SB|;Das|Animesh|A|http://orcid.org/0000-0002-0507-1866;Pandit|Awadh Kishor|AK|;Srivastava|Achal Kumar|AK|http://orcid.org/0000-0002-4590-7947",
"chemical_list": "D017984:Enoxaparin",
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"journal": "BMJ case reports",
"keywords": "interventional radiology; neurology (drugs and medicines)",
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"mesh_terms": "D004660:Encephalitis; D017984:Enoxaparin; D005260:Female; D006801:Humans; D020363:Limbic Encephalitis; D015835:Ocular Motility Disorders; D035583:Rare Diseases",
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"title": "Enoxaparin-induced Wunderlich syndrome in a young patient with anti-GAD 65-associated opsoclonus and limbic encephalitis: a rare complication in a rare disease.",
"title_normalized": "enoxaparin induced wunderlich syndrome in a young patient with anti gad 65 associated opsoclonus and limbic encephalitis a rare complication in a rare disease"
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"abstract": "We report a case of invasive dermatophytosis mimicking vasculitis. A patient consulted the Department of Dermatology, Zealand University Hospital, Roskilde, Denmark for the assessment of violaceous/erythematous lesions thought to be vasculitis. She had prior to this been treated with the immunosuppressive drug teriflunomid. Due to the lesion's erythematous scaling boarder invasive dermatophytosis was suspected. By using direct microscopy a mycological diagnosis was confirmed. We underline the utility of direct microscopy in the diagnosis.",
"affiliations": "Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.;Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.;Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.;Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.",
"authors": "Bouazzi|Dorra|D|;Fabricius|Susanne|S|;Jemec|Gregor Be|GB|;Saunte|Ditte Marie Lindhardt|DML|",
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"country": "Netherlands",
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"doi": "10.1016/j.mmcr.2019.10.008",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(19)30086-710.1016/j.mmcr.2019.10.008Case ReportInvasive dermatophytosis mimicking vasculitis Bouazzi Dorra Dob@regionsjaelland.dkab∗Fabricius Susanne abJemec Gregor BE. abSaunte Ditte Marie Lindhardt aba Department of Dermatology, Zealand University Hospital, Roskilde, Denmarkb Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark∗ Corresponding author. Department of Dermatology, Zealand University Hospital, Roskilde Health Sciences Faculty, University of Copenhagen, Sygehusvej 5, DK-4000, Roskilde, Denmark. Dob@regionsjaelland.dk31 10 2019 12 2019 31 10 2019 26 67 68 4 9 2019 14 10 2019 27 10 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a case of invasive dermatophytosis mimicking vasculitis. A patient consulted the Department of Dermatology, Zealand University Hospital, Roskilde, Denmark for the assessment of violaceous/erythematous lesions thought to be vasculitis. She had prior to this been treated with the immunosuppressive drug teriflunomid. Due to the lesion's erythematous scaling boarder invasive dermatophytosis was suspected. By using direct microscopy a mycological diagnosis was confirmed. We underline the utility of direct microscopy in the diagnosis.\n\nKeywords\nVasculitisInvasive dermatophytosisFungal infectionTrichophyton rubrumUlcer\n==== Body\n1 Introduction\nThe clinical presentation of vasculitis can range from cutaneous vasculitis to life threating internal organ involvement [1]. Several conditions can mimic the presentation of vasculitis and the range of differential diagnosis is therefore broad [1]. One differential diagnosis is invasive dermatophytosis, which is associated with immunodeficiency. A tool that can be used in making the diagnosis is direct microscopy. We report a case of invasive dermatophytosis mimicking vasculitis in an immunocompromised patient and underline the practical utility of direct microscopy in the diagnosis.\n\n2 Case\nA 55-year old woman known with multiple sclerosis and onychomycosis consulted the Department of Dermatology, Zealand University Hospital, Roskilde, Denmark, for the assessment of lesions thought to represent vasculitis (day 0). She had a one year history of scaly, itching sores on the lower right leg. The lesions were exacerbated during treatment with clobetasolpropionate under zinkoxide bandage. The patient had been treated with the immunosuppressive drug teriflunomid for multiple sclerosis for two years.\n\nA physical examination revealed scaly violaceous/erythematous skin with sharply demarcated lesions primarily on the right foot and anterior aspect on the lower right leg (Fig. 1). Deep <1 cm diameter ulcers were also observed.Fig. 1 Violaceous, haemorrhagic and scaly erythematous skin with deep sores. Right foot.\n\nFig. 1\n\nDue to the ulcers the patient was referred for vasculitis, but because of erythematous scaling border of the lesions, dermatophytosis was suspected as a differential diagnosis. Direct microscopy was performed using blanchophor and fluorescence microscopy and showed numerous hyphae (day 0) (Fig. 2). A skin scraping was performed for further mycological examination. The patient was started on a combination of oral terbinafine 250 mg daily combined with topically terbinafine (day 0) for the treatment of tinea incognito due to the usage of teriflunomid and clobetasolpropionate.Fig. 2 Direct microscopy revealing numerous hyphae.\n\nFig. 2\n\nLaboratory investigations including PCR confirmed a mycological diagnosis and revealed a growth of Trichophyton (T.) rubrum (day +2). PCR diagnostics were performed by Statens Serum Institut (SSI) using an in house PCR [6] Treatment assessment (day + 30) revealed improvement and no growth of T. rubrum.\n\n3 Discussion\nDermatophytes are fungal pathogens that infect the keratinized layers of the skin, hair and nails [3]. T. rubrum is one of the most prevalent species [4]. Invasive dermatophytosis is a rare condition in which dermatophytes invade the deep dermis or internal organs [2,5]. It can present in two clinical forms: Majocchi's granuloma and deep dermatophytosis. A biopsy for histopathology is often required to differentiate between Majocchis granuloma/deep dermatophytosis.\n\nOne clue to the diagnosis of invasive dermatophytosis is the presence of associated typical superficial dermatophytosis lesions. Our patient had clinical signs of tinea pedis and onychomycosis. Furthermore, invasive dermatophytosis is typically unilateral whereas vasculitis is often bilateral.\n\nIn a review by Boral et al. [5] of 33 published cases of Majocchis granuloma 6/33 (17%) of the cases received immunosuppressive therapy, 6/33 (17%) systemically prednisolone and 18/33 (55%) topical corticosteroid treatment, respectively.\n\nTo the best of our knowledge, this is the first report of invasive dermatophytosis mimicking vasculitis. In our case direct microscopy was used to confirm a mycological diagnosis, thus confirming that it is still a highly useful bedside tool that should be used as a first step to help guide the use of other often more time-consuming diagnostic procedures.\n\nFunding statement\nNone.\n\nDeclaration of competing interest\nThe authors have the following conflicts of interests to declare: GB Jemec has received honoraria from AbbVie, Coloplast, Pfizer, Pierre Fabre, Inflarx, MSD, Novartis and UCB for participation on advisory boards, and grants from Abbvie, Leo Pharma, Novartis, Janssen-Cilag, Regeneron, UCB, and Sanofi for participation as an investigator, and received speaker honoraria from AbbVie, Galderma, and Leo Pharma. DMLS was paid as a consultant for advisory board meeting by AbbVie, Janssen, Sanofi and received speaker's honoraria and/or received grants from the following companies: Bayer, Abbvie, Desitin, Pfizer, Galderma, Astellas, Novartis and Leo Pharma during the last 5 years.\n\nAcknowledgments\nWe wish to thank Unit of Mycology, Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark for performing the PCR analysis.\n==== Refs\nReferences\n1 Suresh E. Diagnostic approach to patients with suspected vasculitis Postgrad. Med. J. 82 2006 483 488 16891436 \n2 Warycha M.A. Leger M. Tzu J. Kamino H. Stein J. Deep dermatophytosis caused by Trichophyton rubrum Dermatol. Online J. 17 2011 21 22031647 \n3 Hay R.J. Baran R. Deep dermatophytosis: rare infections or common, but unrecognised, complications of lymphatic spread? Curr. Opin. Infect. Dis. 17 2004 77 79 15021044 \n4 Matsuzaki Y. Ota K. Sato K. Nara S. Yagushi T. Nakano H. Sawamura D. Deep pseudocystic dermatophytosis caused by Trichophyton rubrum in a patient with myasthenia gravis Acta Derm. Venereol. 93 3 2013 May 358 359 22949072 \n5 Boral H. Durdu M. Ilkit M. Majocchi's granuloma: current perspectives. 1 Infect. Drug Resist. 11 2018 May 22 751 760 eCollection 2018 29861637 \n6 Brillowska-Dabrowska A. Nielsen S.S. Nielsen H.V. Arendrup M.C. Optimized 5-hour multiplex PCR test for the detection of tinea unguium: performance in a routine, PCR laboratory Med. Mycol. 48 6 2010 Sep 828 831 PubMed PMID: 20105101 20105101\n\n",
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"journal": "Medical mycology case reports",
"keywords": "Fungal infection; Invasive dermatophytosis; Trichophyton rubrum; Ulcer; Vasculitis",
"medline_ta": "Med Mycol Case Rep",
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"publication_types": "D002363:Case Reports",
"references": "22949072;22031647;29861637;20105101;15021044;16891436",
"title": "Invasive dermatophytosis mimicking vasculitis.",
"title_normalized": "invasive dermatophytosis mimicking vasculitis"
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"abstract": "BACKGROUND\nExtramedullary plasma cell dyscrasias are rare.\n\n\nMETHODS\nWe report a case of a 56-year-old male Caucasian hemodialysis patient with cutaneous plasmacytoma. The diagnosis was made a few months after surgical removal of his renal graft due to chronic rejection. Investigations for the presence of an associated myeloma were negative. He underwent local radiotherapy with complete resolution of the skin lesion.\n\n\nCONCLUSIONS\nNephrologists should be aware that the frequency of post-transplant lymphoproliferative disorders is increasing in the dialysis population, especially in those previously or currently treated with immunosuppressive drugs.",
"affiliations": "Department of Nephrology, Ospedale Civile Maggiore, Verona - Italy. hrfabbia@tin.it",
"authors": "Fabbian|F|F|;Tessari|G|G|;Colato|C|C|;Cavallini|L|L|;Martino|F|F|;Ortalda|V|V|;Loschiavo|C|C|;Lupo|A|A|;Maschio|G|G|",
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"journal": "The International journal of artificial organs",
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"mesh_terms": "D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010954:Plasmacytoma; D006435:Renal Dialysis; D012878:Skin Neoplasms; D013997:Time Factors",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Cutaneous plasmacytoma in a hemodialysis patient.",
"title_normalized": "cutaneous plasmacytoma in a hemodialysis patient"
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"abstract": "Therapies of complementary and alternative medicine (CAM) are used increasingly in paediatric oncology. We present and discuss the influence of supportive mistletoe therapy on factors, such as quality of life, physical ability and performance, and course of disease based on the case of a female patient diagnosed at age 18 with metastasised neuroblastoma, which responded insufficiently to chemotherapy.",
"affiliations": "Klinik für Kinder- und Jugendmedizin, Friedrich-Schiller-Universität Jena, Jena, Germany.;Research and Development, Helixor Heilmittel GmbH, Rosenfeld, Germany.;Medical Science, Helixor Heilmittel GmbH, Rosenfeld, Germany.;Klinik für Kinder- und Jugendmedizin, Friedrich-Schiller-Universität Jena, Jena, Germany.",
"authors": "Kaestner|Jens|J|;Schlodder|Dietrich|D|;Preussler|Christfried|C|;Gruhn|Bernd|B|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; C000602513:helixor A",
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"doi": "10.1136/bcr-2018-227652",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepbmjcrbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2018-22765210.1136/bcr-2018-227652Unexpected Outcome (Positive or Negative) Including Adverse Drug Reactions15061525Case ReportSupportive mistletoe therapy in a patient with metastasised neuroblastoma Kaestner Jens 1Schlodder Dietrich 2Preussler Christfried 3Gruhn Bernd 1\n1 \nKlinik für Kinder- und Jugendmedizin, Friedrich-Schiller-Universität Jena, Jena, Germany\n\n2 \nResearch and Development, Helixor Heilmittel GmbH, Rosenfeld, Germany\n\n3 \nMedical Science, Helixor Heilmittel GmbH, Rosenfeld, Germany\nCorrespondence to Dr Christfried Preussler, cpreussler@helixor.de2019 31 3 2019 31 3 2019 12 3 e22765228 2 2019 © BMJ Publishing Group Limited 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Therapies of complementary and alternative medicine (CAM) are used increasingly in paediatric oncology. We present and discuss the influence of supportive mistletoe therapy on factors, such as quality of life, physical ability and performance, and course of disease based on the case of a female patient diagnosed at age 18 with metastasised neuroblastoma, which responded insufficiently to chemotherapy.\n\ncomplementary medicinecancer interventionpaediatric oncologyspecial-featureunlocked\n==== Body\nBackground\nNeuroblastoma (NB) is a malignant disease that develops in certain types of nerve tissue, such as the sympathetic nerve trunk, adrenal medulla or other tissue in the sympathetic nervous system. With about 1.1 cases per 100 000 children, it is the most frequent extracranial solid tumour of childhood. Because NB is an embryonal tumour, the median age of patients at diagnosis is approximately 2 years. Less than 5 per cent of newly diagnosed children are over the age of 10.1\n\nThe initial symptoms of NB depend on the tumour location and are often vague. They can include visible or palpable swelling on the neck or abdomen, bone pain, weight loss and changes in the skin or around the eyes. Many diagnoses occur unexpectedly during routine paediatric check-ups or exams involving other concerns.\n\nThe course of disease can vary widely among individuals and depends largely on risk factors as well as the level of tumour infiltration, patient age, and molecular genetic alterations (N-Myc amplification) and chromosome 1 mutations (1 p deletion, 1 p imbalance or loss of heterozygosity of the 1 p chromosomal arm) in tumour cells. At the time of diagnosis, about one-half of all the patients present with some form of metastasis, typically occurring in the bone or bone marrow, lymph nodes, liver, skin and, less frequently, in the CNS or lung.2\n\nStandard treatment includes surgical removal of the tumour elements, chemotherapy, and radiation and administration of metaiodobenzylguanidine (MIBG) with a radioactive tracer for internal targeted radiation therapy of the NB tumour. MIBG is an organic compound that is structurally related to norepinephrine. When attached to radioactive iodine, it can be used to treat neuroendocrine tumours as well as for nuclear medicine and molecular imaging.\n\nHigh-risk patients may additionally require myeloablative high-dose chemotherapy followed by autologous stem cell transplantation. This form of therapy should always be administered in a paediatric oncology setting in controlled therapy-optimisation trials.\n\nAlongside such vital standard therapies, complementary oncological procedures are also administered in the treatment of childhood cancer. Among parents surveyed in a large population-based study, which was conducted in cooperation with the German Childhood Cancer Registry and included 1595 children with malignant tumours, 35% of respondents stated that their child’s course of treatment included complementary and alternative therapies (CAM). Anthroposophic medicine, including mistletoe therapy, was an option used by 26.7% of CAM users. In terms of effect on the disease, 63% of the parents had a positive opinion of CAM.3\n\nMedicinal products made from white-berry mistletoe (Viscum album L.) have been clinically administered in cancer patients since 1917. The products are registered in several European countries and number among the most frequently administered forms of CAM in oncological treatment.4 Both their biologically active substances (mistletoe lectin, viscotoxins, oligosaccharides and polysaccharides, and polyphenols and flavonoids) and their pharmacological effects, such as apoptosis induction via the mitochondrial pathway, and immunomodulation and DNA protection in lymphocytes, are well documented (see5 for an overview).\n\nIn a review of numerous clinical studies, 21 prospective randomised trials that involved the administration of oncological mistletoe therapy satisfied the strict criteria established by Cochrane.4 In 14 out of 16 studies that examined quality of life, mistletoe therapy was linked to a positive influence on quality of life and a better tolerance of chemotherapy. Moreover, a recent study also demonstrated a significant impact of mistletoe therapy on survival of cancer patients.6 This result is supported by previous series of studies, though their methodological quality is notably weaker.7\n\nAll of the above trials involved the treatment of adult cancer patients. In paediatric settings, we can draw on decades of experience in administering V. album L. to children in specialised anthroposophic hospitals during or after standard therapy.8 There are also some individual case reports detailing impressive developments in the course of disease.9–11 Yet, there is still a lack of formal clinical trials on mistletoe therapy in paediatric cancer.\n\nGiven the above situation, a prospective, multicentre randomised phase IV trial was conducted with 340 children diagnosed with 14 different tumour entities (including NB). The trial was designed to test an anthroposophic supportive care concept consisting of the mistletoe product Helixor A, seven additional basic medicines and a defined ‘when required’ medication, administered during the intensive phase of a polychemotherapy regimen. Alongside the Charité Berlin as the main trial site, the university hospital in Jena (Universitätsklinikum Jena) and 10 additional university hospitals participated in the trial. No negative interactions with the standard oncological treatment could be observed. While the researchers did not find any significant differences in terms of a reduced toxicity of standard therapy, the supportive therapy did appear to have a positive influence on quality of life and performance.12 13\n\nThe following case report on supportive mistletoe therapy in an NB patient is intended to supplement current knowledge on mistletoe therapy in the treatment of aggressive tumours in children and adolescent patients. It was prepared following the CARE guidelines.14\n\nCase presentation\nFamily history\nNo known family history of malignant disease.\n\nMedical history\nThe symptoms of the female patient began in November 2009, at age 18. She was experiencing increasing pain in the thoracolumbar region and sacrum with intermittent pain radiating into the left leg. MRI revealed an intraspinal tumour at Th10 as well as multiple bone metastases along the spinal column with a pathological fracture of the fifth lumbar vertebra.\n\nIn the neurosurgery hospital where the patient was first admitted, an open biopsy was performed at the fifth lumbar vertebra. Because the patient presented with an ataxic gait after surgery, a second operation was performed in early January 2010 with a resection of the intraspinal tumour portion at Th10. Due to pronounced spinal instability, corset application and use of a wheelchair were necessary after surgery. The patient was transferred to a hospital specialised in paediatric and adolescent medicine for further diagnosis and therapy.\n\nFindings on admission\nOn admission, the patient presented with a poor general condition (Karnofsky index 40%), pre-existing arterial hypertonia and increasing bone pain. Lab results showed elevated levels of tumour markers LDH and NSE. A urine sample revealed an increase in the catecholamine decomposition products homovanillic acid (HVA) and vanillylmandelic acid (VMA), as well as moderate thrombocytopenia (85 000/µL). In addition to pronounced skeletal metastases, MRI for staging displayed a fibrous para-aortic mass near the aorta descendens. Skeletal scintigraphy showed generalised bone metastases with osteoplastic changes (spine, shoulder joints, both scapulae, sacroiliac joint, hip joints, ischium on both sides as well as the right mid-femur) and osteolytic lesions at the 11th thoracic and the 4th lumbar vertebra. A biopsy of the iliac crest confirmed a bone marrow infiltration by blast cells.\n\nInvestigations\nDue to the histology of the vertebral tumour biopsies and the immunohistochemical marker configuration without molecular-genetic verification of a specific translocation, the patient was given a preliminary diagnosis of a primitive neuroectodermal tumour (PNET). A guideline-compliant chemotherapy (I3VA protocol containing ifosfamide, vincristine and actinomycin D, and CEV protocol containing carboplatine, etoposide and vincristine) in accordance with the CWS guidance for patients with stage IV metastatic disease was initiated.\n\nTreatment\nDuring the first two courses of chemotherapy, there was further deterioration in the patient’s general condition with the need for complete immobilisation and increased pain medication. The patient also suffered from pronounced intestinal symptoms including abdominal pain, constipation, nausea and recurrent bilious vomiting over several weeks. Since the initial diagnosis, the patient had lost almost 20 kilograms of body weight.\n\nIn the same month, the histology lab revised the diagnosis in favour of an extended, regressively transformed, poorly differentiated, stroma-poor stage IV NB. An assessment of the 1 p and N-Myc status was not possible. The diagnosis was supported by the sustained increase in NB-typical tumour markers HVA and VMA in the patient’s urine, an elevated NSE blood serum level, and a bone scan revealing an uptake of MIBG by all tumour clusters, indicating catecholamine-producing tumours. On the basis of the revised diagnosis, the patient’s chemotherapy regimen was adjusted in March 2010 in accordance with the NB2004 trial protocol for the treatment of NB. Due to the presence of haematogenic metastases, the patient was assigned to the high risk (HR) group.\n\nThe new chemotherapy regimen resulted in an impressive and continuous improvement in the patient’s general condition and in her pain levels and mobility. After two courses, she was able to walk short distances on crutches.\n\nNevertheless, imaging performed during therapy showed the continued presence of extended tumour foci. Following consultation with the principal investigator of the NB trial, two further chemotherapy courses (N8), as well as MIBG therapy, were administered as additive therapy. Subsequently, in October 2010, myeloablative high-dose chemotherapy was administered, along with an autologous stem cell transplantation, in accordance with the NB2004 HR trial protocol.\n\nStill, after 3 months of treatment, imaging did not indicate any tumour regression. Both MRI and MIBG scintiscan showed no significant changes. Due to these findings, the decision was made in January 2011 to initiate an innovative form of chemotherapy (sirolimus, irinotecan, dasatinib and temozolomide) in line with the RIST HGG trial protocol. The patient was also started on bisphosphonate therapy with zoledronate every 4 weeks.\n\nThe patient had a poor tolerance to the new chemotherapy regimen. She often complained of nausea and vomiting. She also contracted multiple infections during the neutropenic phases, which required inpatient treatment with systemic antibiotics. Because subsequent diagnostic imaging in April 2011 showed only a minor tumour regression on the bone scan and no relevant changes in the MRI, chemotherapy was discontinued at the patient’s request.\n\nCourse of disease after beginning anthroposophic supportive therapy\nIn April 2011, the patient began a regimen of anthroposophic supportive therapy, which has shown its value in the previously mentioned randomised multicentre phase IV trial.13 The therapy concept, in this case, revolved around the subcutaneous injection of the mistletoe product Helixor A, with an initial dose of 1.25 mg (0.25 mL Helixor A 5 mg). The patient was given biweekly injections of gradually increasing doses, as per standard practice, up to 12.5 mg (0.25 mL Helixor A 50 mg). During this time, the patient experienced a significant increase in physical and subjective well-being. She regained her stamina to accomplish everyday activities, and even sports, such as cycling, were once again possible. The patient felt well and her symptoms had disappeared. She was able to complete her schooling in summer 2012 and start a university degree programme in psychology in October 2012.\n\nIn regular examinations (MRI and MIBG scintiscan) from April 2011 to July 2012, the patient’s tumour foci initially remained constant in size. In December 2012, however, both the scintiscan and the MRI showed new tumour growth in the left proximal humerus, the second right rib, on the angulus inferior scapulae, and in the right iliac wing. Yet, the patient did not report any pain or restrictions. Diagnostic imaging in March and May 2013 showed an enlargement of the lesion in the left proximal humerus while the other tumour foci remained unchanged. Urine samples also showed elevated levels of the tumour markers HVA and VMA. On the basis of the patient’s good general condition and the only remaining innovative therapy options, the treating physicians decided, together with the patient, to continue zoledronate therapy every 4 weeks, which had been initiated in January 2011. Radiation therapy for the bone metastases, with the goal of improving bone stability, was discussed as an option, but not initiated at this point in time.\n\nThe patient regained her normal weight. She continued to receive regular biweekly subcutaneous injections of 12.5 mg Helixor A. The patient showed regularly local reactions to the injections, with redness at the injection site measuring 2–5 cm, which can be interpreted as an immunological response. About every 4–6 weeks, it was necessary to reduce the dose to 5 mg Helixor A, since the preceding local reaction to 12.5 mg was too strong. Mistletoe therapy continued to be administered in this form until February 2014.\n\nOutcome and follow-up\nThe clinical course described above represents the time between the initial diagnosis in 2009 and 2013, for which exact data is available. Meanwhile, additional metastases have appeared, which were treated with conventional oncological therapies and supportive approaches. From June to July 2017, the patient received radiation therapy for soft tissue metastasis in the left temporal bone. A progressive bone metastasis in the left humerus/scapula area was treated with radiation therapy in January 2018. Radiation therapy for bone metastasis in the left lower jaw occurred in May 2018. Due to her positive experiences in the past, the patient resumed mistletoe therapy with Helixor A, previously discontinued in February 2014, in June 2018.\n\nThe clinical course is shown in figure 1. The patient still attends the university and will soon graduate with a master’s degree.\n\nFigure 1 Treatment and course of the disease. HR, high risk; MIBG, metaiodobenzylguanidine; NB, neuroblastoma; PNET, primitive neuroectodermal tumour.\n\nDiscussion\nSince the onset of NB, the patient was treated using several different chemotherapy trial protocols with varying degrees of success.Two courses of chemotherapy according to CWS guidance and the initial PNET diagnosis, with a dramatic deterioration in general condition.\n\nAfter the revised diagnosis, a switch to the NB2004 trial protocol with an impressive improvement.\n\nDue to extended and persisting tumour foci, two additional courses of chemotherapy with additive MIBG therapy.\n\nSubsequently myeloablative high-dose chemotherapy with autologous stem cell transplantation.\n\nDue to the lack of tumour response, an innovative new chemotherapy according to the RIST HGG regimen was initiated but discontinued after 3 months due to insufficient response and poor tolerance. Bisphosphonate therapy, which had been initiated simultaneously, was continued.\n\n\n\nThe focus of the subsequently initiated anthroposophic supportive therapy was treated with the mistletoe product Helixor A, derived from the host tree fir.\n\nDuring this treatment, the patient experienced a significant improvement in her health condition and physical ability and even the complete disappearance of symptoms, so that she could successfully resume her schooling, which had been interrupted by the disease. One year later, although the bone metastases had progressed, this development occurred, surprisingly, without any complaints or symptoms and without any impairment to the patient’s general condition.\n\nObservations of a discrepancy between good subjective well-being and the objective status of the tumour are not seldom in conjunction with mistletoe therapy. An improvement in quality of life is the most well-documented effect of mistletoe therapy in various studies and medical reports. Especially the following aspects of quality of life have been positively influenced by mistletoe therapy: cancer-related fatigue, sleep, exhaustion, energy, ability to work, nausea, vomiting and body weight, as well as pain, emotional well-being, depression, anxiety and concentration difficulties.15 The first symptoms in this list (from energy to pain) were the most prominent in our patient and they quickly improved during treatment with mistletoe. Most impressive was the stabilisation of the patient’s weight, after an initial weight loss of 20 kg.\n\nAdolescent and adult patients with NB have a less favourable prognosis than younger patients, regardless of their N-Myc status.2 16 In addition, the presence of haematogenous metastasis already at first diagnosis is a further prognostic disadvantage.\n\nGiven this poor prognosis and the patient’s insufficient response to chemotherapy regimens, the course of disease outlined above can be considered surprisingly positive. Although the preceding courses of chemotherapy, which were at least temporarily effective after switching to the NB trial protocol, were certainly mainly responsible for the long-term stable course of disease, the significant improvement in quality of life and even freedom from symptoms, and full recovery of performance can be attributed primarily to mistletoe therapy due to the coincidence with this treatment. This is especially the case since this improvement did not co-occur with a regression of the tumour, but remained present even after new tumour growth was established.\n\nThis observation reinforces the significance of mistletoe therapy as a supportive treatment in oncology, which is primarily intended to restore well-being and performance during and following conventional therapy. With regard to children and adolescents, the effectiveness of this therapy as an element of oncological treatment, rehabilitation and aftercare should be tested in a clinical study with an appropriate number of patients focusing on mistletoe therapy, as the multicentre study,13 cited at multiple junctures above, only allowed statements about the overall supportive concept proven involving mistletoe therapy but not about mistletoe therapy itself.\n\nThe need to account for the quality of life of young patients and potential long-term consequences of conventional therapies is increasingly finding its way into current discussions. Mistletoe therapy is capable of making an important contribution in these areas.\n\nPatient’s perspective\nIn late 2009, I discovered that I was ill, and was diagnosed with neuroblastoma. The diagnosis was followed by about 17 months of treatment, which included chemotherapy, high-dosage chemotherapy and a stem cell transplantation. I had extreme bone pain because of the tumours and was not able to leave my hospital bed for about 4 months. Afterwards, I still could only get around in a wheelchair or walk very short distances on crutches. Slowly, the pain subsided and I became slightly more mobile, but the side effects from chemotherapy were getting worse and worse. Nausea, loss of appetite and irritated mucous membranes were just a few.\n\nIn May 2011, the therapy was discontinued without full recovery. This was also when I started mistletoe therapy. I also began a very long and somewhat painful physiotherapy process. And I noticed improvements, almost weekly, in my condition. Gradually, I could walk longer distances and I even started driving again. Then I decided to go back to school, finish the 12th grade and attend the university. Even though I stopped chemotherapy, the tumour had not grown, and the pain in my bones was completely gone. In September 2011, I went to physical therapy in the Black Forest, where I started to do sports—very carefully, so that I would not damage my spine. But that did not stop me from climbing, testing my balance on the high-rope course or going on day trips with other patients to the surrounding countryside. I had regained the energy to enjoy everyday life without needing to take regular breaks. That would have been unimaginable just 6 months ago. As soon as I got back home, I was taking dance and vocal lessons in order to keep up with the other pupils in a musical performance in fall 2012. At school, I also had my first positive experiences and successes and my whole life felt like it was almost back to normal. I fit in with the ‘normal’ kids again. I returned to my regular study habits and graduated on time with my classmates in summer of 2012. And I took full advantage of the time I had before the university started in the fall. That meant spending four more weeks in physical therapy, where an extensive sports programme was waiting for me. Immediately after my return, I was off for a 2-week vacation. An entire day of sightseeing and walking through the city was no problem; I could also tolerate large crowds and tight spaces without becoming exhausted. Plus, I did not contract any colds or infections. After vacation, I moved to Leipzig to start studying psychology here in October 2012. I bike to university every day and do not have any limitations that make me different from the other students.\n\nLearning points\nInitial chemotherapy induced regression of neuroblastoma (NB) but also reduction of quality of life.\n\nSignificant increase in physical and subjective well-being could be achieved after beginning of mistletoe therapy in a patient with NB.\n\nQuality of life could be preserved for a long time even after recurrence of progression of the disease.\n\nTo the best of our knowledge, this is the first documented case of a significant improvement in quality of life induced by supportive mistletoe therapy of a patient suffering from NB.\n\nThe authors thank Sandra Fuchs, Dr Michael Schink, Sabine Rieger and Bruni Diemer for support.\n\nContributors: BG guided the patient’s therapy. Both BG and JK were attending physicians, provided the medical data and supported the production of the manuscript. DS supplemented and reviewed the manuscript. CP guided and managed the development of the manuscript. Each author approved the final manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nPatient consent for publication: Obtained.\n==== Refs\nReferences\n1 \nConte M , De Bernardi B , Milanaccio C , et al \nMalignant neuroblastic tumors in adolescents . Cancer Lett \n2005 ;228 (1-2 ):271 –4 . 10.1016/j.canlet.2005.02.048 \n15916849 \n2 \nFischer M , Oberthür A , von Schweinitz D , et al \nDas Neuroblastom . Der Onkologe \n2005 ;11 :1054 –64 . 10.1007/s00761-005-0929-y \n\n3 \nLaengler A , Spix C , Seifert G , et al \nComplementary and alternative treatment methods in children with cancer: A population-based retrospective survey on the prevalence of use in Germany . Eur J Cancer \n2008 ;44 :2233 –40 . 10.1016/j.ejca.2008.07.020 \n18809313 \n4 \nHorneber M , Bueschel G , Huber R , et al \nMistletoe therapy in oncology . Cochrane Database Syst Rev \n2008 ;92 \n10.1002/14651858.CD003297.pub2 \n\n5 \nKienle GS , Kiene H \nDie Mistel in der Onkologie. Fakten und konzeptionelle Grundlagen . Stuttgart New York : Schattauer , 2003 .\n6 \nTröger W , Galun D , Reif M , et al \nViscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival . Eur J Cancer \n2013 ;49 :3788 –97 . 10.1016/j.ejca.2013.06.043 \n23890767 \n7 \nStumpf C , Rieger S , Fischer IU , et al \nVergleich der Überlebenszeit bei Patienten mit verschiedenen Tumorentitäten - Retrospektive Untersuchung zur Wirksamkeit von Misteltherapie vs. Daten eines Tumorregisters : Scheer R , Alban S , Becker H , Die Mistel in der Tumortherapie 2 . Essen : KVC Verlag , 2009 :427 –40 .\n8 \nLängler A , Kameda G , Seifert G \nAlternative und komplementäre Behandlungsmethoden in der Kinderonkologie - ein Überblick . Deutsche Zeitschrift für Onkologie \n2007 ;39 :100 –6 . 10.1055/s-2007-985976 \n\n9 \nLenard HG , Engelbrecht V , Janssen G , et al \nComplete remission of a diffuse pontine glioma . Neuropediatrics \n1998 ;29 :328 –30 . 10.1055/s-2007-973589 \n10029356 \n10 \nSeifert G , Laengler A , Tautz C , et al \nResponse to subcutaneous therapy with mistletoe in recurrent multisystem Langerhans cell histiocytosis . Pediatr Blood Cancer \n2007 ;48 :591 –2 . 10.1002/pbc.20649 \n16261597 \n11 \nSeifert G , Rutkowski S , Jesse P , et al \nAnthroposophic supportive treatment in children with medulloblastoma receiving first-line therapy . J Pediatr Hematol Oncol \n2011 ;33 :e105 –e108 . 10.1097/MPH.0b013e31820946d3 \n21368673 \n12 \nCalaminus G , Längler A , Henze G , et al \nQuality of Life (QoL) in children and adolescents with paediatric malignancies under anthroposophic supportive treatment . Phytomedicine \n2015 ;22 :S18 –S19 . 10.1016/j.phymed.2015.05.035 \n\n13 \nSeifert G , Henze G , Calaminus G , et al \nEvaluation of an anthroposophic supportive treatment intervention (ASTI) in children with malignant diseases during intensive chemotherapy . Phytomedicine \n2015 ;22 (Suppl. 1 ):S18 \n10.1016/j.phymed.2015.05.034 \n\n14 \nRiley DS , Barber MS , Kienle GS , et al \nCARE guidelines for case reports: explanation and elaboration document . J Clin Epidemiol \n2017 ;89 :218 –35 . 10.1016/j.jclinepi.2017.04.026 \n28529185 \n15 \nKienle GS , Kiene H \nReview article: Influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: a systematic review of controlled clinical studies . Integr Cancer Ther \n2010 ;9 :142 –57 . 10.1177/1534735410369673 \n20483874 \n16 \nCastel V , Villamón E , Cañete A , et al \nNeuroblastoma in adolescents: genetic and clinical characterisation . Clin Transl Oncol \n2010 ;12 :49 –54 . 10.1007/s12094-010-0466-z \n20080471\n\n",
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"mesh_terms": "D000203:Activities of Daily Living; D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic; D001859:Bone Neoplasms; D001932:Brain Neoplasms; D004522:Educational Status; D005260:Female; D006801:Humans; D009447:Neuroblastoma; D008517:Phytotherapy; D010936:Plant Extracts; D011788:Quality of Life; D016896:Treatment Outcome",
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"abstract": "Purpose: To describe subclinical chorioretinal lesions revealed by indocyanine green angiography (ICGA) and their evolution under systemic treatment in tubulointerstitial nephritis and uveitis (TINU) patients.Methods: Retrospective case series of three patients with TINU syndrome. Choroidal and retinal involvement were assessed by fluorescein angiography (FA) and ICGA.Results: Three patients were analyzed. FA demonstrated hot disc, associated in two cases with retinal vascular leakage, and ICGA revealed subclinical chorioretinal dots in all three cases. Given the presence of posterior uveitis and deterioration of kidney function, asystemic treatment by oral methylprednisolone was started. Persistence of retinal and choroidal inflammations under systemic corticosteroids required association with immunosuppressive agent to control the disease activityConclusion: Multimodal imaging and more precisely ICGA is useful to assess subclinical choroidal inflammation and monitor treatment response in TINU syndrome. Immunosuppression needs to be revised and adapted when uveitis and/or kidney function are unresponsive to systemic steroidsAbbreviations: TINU: tubulointerstitial nephritis and uveitis; TIN: tubulointerstitial nephritis; ACE: angiotensin-converting enzyme; RF: rheumatoid factor; Uβ2M: urinary β-2microglobulin; AMPPE: acute multifocal placoid pigment epitheliopathy; FA: fluorescein angiography; ICGA: indocyanine green angiography; CT: computed tomography.",
"affiliations": "Department of Ophthalmology, CHU St-Pierre, Université Libre de Bruxelles, Brussels, Belgium.;Department of Ophthalmology, CHU St-Pierre, Université Libre de Bruxelles, Brussels, Belgium.;Department of Ophthalmology, Hôpital Brugmann, Université Libre de Bruxelles, Brussels, Belgium.;Department of Nephrology and Dialysis, Hôpital Brugmann, Université Libre de Bruxelles, Brussels, Belgium.;Department of Pediatric Nephrology, Hôpital Universitaire des Enfants - Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.;Department of Pediatrics, CHU St-Pierre, Université Libre de Bruxelles, Brussels, Belgium.;Department of Ophthalmology, Hôpital Universitaire des Enfants - Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.;Department of Ophthalmology, CHU St-Pierre, Université Libre de Bruxelles, Brussels, Belgium.",
"authors": "Scifo|Lisa|L|;Willermain|François|F|;Postelmans|Laurence|L|;Pozdzik|Agnieszka|A|;Lolin Sekelj|Ksenija|K|;Zampieri|Monalisa|M|;de Jong|Casper|C|;Makhoul|Dorine|D|",
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"keywords": "Tubulointerstitial nephritis; immunosuppression; inflammation; uveitis",
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"title": "Subclinical Choroidal Inflammation Revealed by Indocyanine Green Angiography in Tubulointerstitial Nephritis and Uveitis Syndrome.",
"title_normalized": "subclinical choroidal inflammation revealed by indocyanine green angiography in tubulointerstitial nephritis and uveitis syndrome"
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"abstract": "BACKGROUND\nAcute purulent bacterial pericarditis is of rare occurrence in this modern antibiotic era. Primary involvement of the pericardium without evidence of underlying infection elsewhere is even rarer. It is a rapidly progressive infection with high mortality. We present an extremely rare case of acute purulent bacterial pericarditis in an immunocompetent adult patient with no underlying chronic medical conditions.\n\n\nMETHODS\nA 33-year-old previously healthy white man presented with the complaints of chest pain and dyspnea. He was diagnosed as having acute pericarditis and was discharged home on indomethacin. Over a period of 2 weeks, his symptoms worsened gradually and he was readmitted to our hospital. He was found to have large pericardial effusion with cardiac tamponade. An urgent pericardiocentesis was done with drainage of 550 ml of purulent material. Cultures grew Streptococcus intermedius confirming the diagnosis of acute purulent bacterial pericarditis. No other focus of infection was identified on imaging workup suggesting primary infection of the pericardium. His clinical course was complicated by development of constrictive pericarditis for which he underwent surgical pericardiectomy. He received a total of 7 weeks of intravenously administered antibiotics with complete clinical recovery.\n\n\nCONCLUSIONS\nAcute purulent bacterial pericarditis, although rare, should always be kept in mind as a possible cause of pericarditis. Early recognition and prompt intervention are important for a successful outcome.",
"affiliations": "Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mail Stop 1150, Toledo, Ohio, 43614, USA. mohammad.khan2@utoledo.edu.;Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mail Stop 1150, Toledo, Ohio, 43614, USA.;Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mail Stop 1150, Toledo, Ohio, 43614, USA.;Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mail Stop 1150, Toledo, Ohio, 43614, USA.;Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mail Stop 1150, Toledo, Ohio, 43614, USA.;Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mail Stop 1150, Toledo, Ohio, 43614, USA.",
"authors": "Khan|Mohammad Saud|MS|http://orcid.org/0000-0001-5055-3226;Khan|Zubair|Z|;Banglore|Bhavana Siddegowda|BS|;Alkhoury|Ghattas|G|;Murphy|Laura|L|;Georgescu|Claudiu|C|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 157010.1186/s13256-018-1570-xCase ReportPrimary purulent bacterial pericarditis due to Streptococcus intermedius in an immunocompetent adult: a case report http://orcid.org/0000-0001-5055-3226Khan Mohammad Saud mohammad.khan2@utoledo.edu 1Khan Zubair zubair.khan@utoledo.edu 1Banglore Bhavana Siddegowda bhavana.banglore@utoledo.edu 12Alkhoury Ghattas ghattas.alkhoury@utoledo.edu 1Murphy Laura laura.murphy@utoledo.edu 12Georgescu Claudiu claudiu.georgescu@utoledo.edu 131 0000 0004 0628 5895grid.411726.7Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Mail Stop 1150, Toledo, Ohio 43614 USA 2 0000 0004 0628 5895grid.411726.7Department of Cardiovascular Medicine, University of Toledo Medical Center, Toledo, Ohio USA 3 0000 0004 0628 5895grid.411726.7Department of Infectious Diseases, University of Toledo Medical Center, Toledo, Ohio USA 5 2 2018 5 2 2018 2018 12 2724 10 2017 10 1 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAcute purulent bacterial pericarditis is of rare occurrence in this modern antibiotic era. Primary involvement of the pericardium without evidence of underlying infection elsewhere is even rarer. It is a rapidly progressive infection with high mortality. We present an extremely rare case of acute purulent bacterial pericarditis in an immunocompetent adult patient with no underlying chronic medical conditions.\n\nCase presentation\nA 33-year-old previously healthy white man presented with the complaints of chest pain and dyspnea. He was diagnosed as having acute pericarditis and was discharged home on indomethacin. Over a period of 2 weeks, his symptoms worsened gradually and he was readmitted to our hospital. He was found to have large pericardial effusion with cardiac tamponade. An urgent pericardiocentesis was done with drainage of 550 ml of purulent material. Cultures grew Streptococcus intermedius confirming the diagnosis of acute purulent bacterial pericarditis. No other focus of infection was identified on imaging workup suggesting primary infection of the pericardium. His clinical course was complicated by development of constrictive pericarditis for which he underwent surgical pericardiectomy. He received a total of 7 weeks of intravenously administered antibiotics with complete clinical recovery.\n\nConclusions\nAcute purulent bacterial pericarditis, although rare, should always be kept in mind as a possible cause of pericarditis. Early recognition and prompt intervention are important for a successful outcome.\n\nKeywords\nPrimary bacterial pericarditisAcute purulent pericarditisStreptococcus intermediusCardiac tamponadeissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nBacterial pericarditis is a rapidly progressive infection with high mortality. It is rare in the modern antibiotic era and the majority of cases occur in immunocompromised individuals or in individuals with underlying disease of the pericardium [1, 2]. Bacterial pericarditis usually occurs as a secondary infection by contiguous spread from surrounding intrathoracic focus of infection or by hematogenous spread from distant focus of infection [2, 3]. Primary involvement of the pericardium without evidence of underlying infection elsewhere is very rare. We present a case of a 33-year-old immunocompetent previously healthy adult patient who was diagnosed as having primary purulent acute bacterial pericarditis caused by Streptococcus intermedius.\n\nCase presentation\nA 33-year-old white man presented to our hospital with sudden onset pleuritic chest pain and dyspnea of 1 day’s duration. The chest pain started when he was lifting a heavy trash bag and described the pain as sharp, constant, and radiating to his back. He also complained of diffuse body aches and chills but denied any fever, cough, hemoptysis, or weight loss. He denied any history of dental caries, recent travel, or exposure to sick contacts. He had no significant past medical history and was not taking any routine medications. He smoked half a pack of cigarettes a day for the past 10 years and denied any alcohol or illicit drug use. He worked as a waste collector in a garbage disposal firm.\n\nAt the time of presentation, he was: alert; oriented in time, place, and person; afebrile with a temperature of 37.06 °C (98.7 °F); tachycardic (heart rate of 110 beats/minute); and tachypneic (respiratory rate of 18/minute) with a blood pressure of 126/78 mmHg. An oral examination revealed normal dentition. A cardiopulmonary examination showed normal S1 and S2 with no murmurs and clear lung fields to auscultation bilaterally. An abdominal examination revealed a soft, non-tender abdomen with no organomegaly. A neurological examination showed intact cranial nerves and sensory system, and his muscle strength was 5/5 in all limbs with normal tone. Deep tendon reflexes were normal. An initial laboratory workup showed mild leukocytosis with white blood cell (WBC) count of 13,700 cells/mm3, elevated inflammatory markers of erythrocyte sedimentation rate (ESR) 48 mm/hour and C-reactive protein (CRP) 84 mg/dl, and moderately elevated serum transaminases of aspartate aminotransferase (AST) 634 U/L and alanine aminotransferase (ALT) 326 U/L. A basic metabolic panel was within normal limits. Three sets of cardiac enzymes done 8 hours apart were normal. An electrocardiogram was obtained which showed sinus tachycardia and diffuse ST segment elevations. A chest radiograph showed normal bilateral lung fields and normal cardiac silhouette. Computed tomography (CT) of his chest (Fig. 1) ruled out aortic dissection but showed pericardial effusion. A transthoracic echocardiogram showed normal left ventricular systolic function with ejection fraction of 55% and a small pericardial effusion with no signs of tamponade physiology.Fig. 1 Axial computed tomography scan of chest showing pericardial effusion\n\n\n\nHe was diagnosed as a case of acute pericarditis with minimal pericardial effusion. He was discharged home on indomethacin and was asked to follow up in the out-patient clinic. Two weeks later, when he was seen in our out-patient clinic, he complained of worsening dyspnea and chest pain. He was readmitted to hospital and an urgent transthoracic echocardiogram was obtained, which showed moderate to large pericardial effusion and tamponade physiology with right ventricular diastolic collapse and dilated inferior vena cava (Fig. 2). An emergency pericardiocentesis was done and approximately 550 ml of purulent pericardial fluid was drained. The pericardial fluid was sent for culture, cell analysis, and cytology. Pericardial fluid WBC count was 15,376 cells/mm3 with 98% segmented neutrophils. A Gram stain of the pericardial fluid showed Gram-positive cocci in chains. He was started on broad-spectrum antibiotics with intravenously administered vancomycin (dosed on trough concentration) and piperacillin-tazobactam (3.375 g every 8 hours). Pericardial fluid cultures grew alpha hemolytic streptococci which were characterized as S. intermedius by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF MS). S. intermedius was susceptible to penicillin and ceftriaxone. Anaerobic, fungal, and acid-fast bacilli cultures were negative. Pericardial fluid cytology was also negative for any malignant cells. Extensive workup with CT abdomen, CT chest, urine analysis, urine culture, and blood culture to look for source of infection failed to identify any other focus of infection. Human immunodeficiency virus (HIV) and tuberculosis QuantiFERON testing were negative. Antibiotics were deescalated to intravenously administered ceftriaxone (2 g every 24 hours) as per culture sensitivity.Fig. 2 Transthoracic echocardiogram (four chamber view) showing pericardial effusion with presence of internal septations\n\n\n\nHis hospital course was complicated with the development of a pulmonary embolism for which he was started on an intravenously administered heparin infusion. However, within a few days of starting heparin, there was a steady decline in his platelets count. Heparin-induced thrombocytopenia (HIT) was suspected and heparin infusion was stopped. Our patient was started on argatroban infusion at a rate of 140 mcg/minute. HIT antibodies and serotonin release assay were sent which came back positive. He was subsequently transitioned to orally administered warfarin with target international normalized ratio (INR) range of 2 to 3. However, with the course of time, he did not have complete resolution of symptoms with persistence of chest pain and dyspnea. Hemodynamic and echocardiographic features were consistent with development of constrictive pericarditis. Surgical pericardiectomy with median sternotomy approach was performed which revealed thickened pericardium (Fig. 3). He reported improvement in his symptoms after pericardiectomy. He was discharged home in a stable condition and received a total of 7 weeks of intravenously administered ceftriaxone. Six months post-discharge he reported complete resolution of his symptoms. A repeat echocardiography was normal and showed resolution of pericardial effusion.Fig. 3 Gross pathological specimen of pericardium after pericardiectomy\n\n\n\nDiscussion\nWe report a case of primary purulent acute bacterial pericarditis in an immunocompetent previously healthy adult patient caused by S. intermedius. Our patient presented with symptoms of dyspnea and chest pain, which gradually progressed over the course of 2 weeks. He was found to have large purulent pericardial effusion with cardiac tamponade and was managed with emergent pericardiocentesis and intravenously administered antibiotics. Further, the disease course was complicated with development of constrictive pericarditis, which was successfully managed with pericardiectomy. Acute pericarditis can be caused by a wide variety of etiologies, which can be infectious or noninfectious [4]. Possible causes include connective tissue disorders, malignancies, radiation, cardiac injury, uremia, and infections (including viral, bacterial, and fungal etiologies) [4, 5]. In a majority of cases (80 to 90%), the cause of pericarditis is not identified [5, 6]. These cases are considered to be idiopathic, most likely due to an undetected underlying virus [5, 6]. Bacterial pericarditis is a rare cause of acute pericarditis in the modern antibiotic era. The reported incidence is < 1% of all cases of pericarditis [7, 8]. The most common organisms implicated are Streptococci, Staphylococci, Haemophilus, and Mycobacterium tuberculosis [3, 9].\n\nBacterial pericarditis usually occurs as a secondary infection by contiguous spread from surrounding intrathoracic infection, including extension from pulmonary, myocardial, and subdiaphragmatic site of infection or by hematogenous dissemination from a distant infection elsewhere in the body [2, 3]. Among these, direct extension from lung or pleura (pneumonia and pleural empyema) accounts for the majority of cases [3, 10]. Very rarely, it can occur as a primary infection without evidence of underlying infection elsewhere. The common predisposing conditions for bacterial pericarditis are immunosuppression, malignancies, preexisting pericardial effusion, alcoholism, uremia, chest trauma, cardiac and thoracic surgery, and insertion or use of catheters for draining pericardial fluid [9, 10]. Purulent pericarditis is a serious manifestation of bacterial pericarditis characterized by the presence of frank pus in the pericardial cavity. It is an acute fulminant disease with rapid progression. It is associated with high mortality and a large number of cases are identified after death [2]. If not identified and treated promptly the mortality rates can be as high as 100% [11]. Even with treatment, the rate of complications and death is high, with the mortality rate approaching 40% [3, 9]. Death is most likely secondary to cardiac tamponade, constriction, and sepsis [3, 9].\n\nClinical recognition of bacterial pericarditis can be difficult as classical manifestations of acute pericarditis such as chest pain, pericardial friction rub, and pulsus paradoxus may be absent and a patient may present with nonspecific signs and symptoms of infection. Fever is present in almost all of the patients [3]. Chest pain, which can be pleuritic or nonpleuritic, is seen in 25 to 37% of patients [3, 10]. Pericardial friction rub and pulsus paradoxus are seen in less than 50% of patients [3, 10]. Laboratory workup may show evidence of systemic inflammation with leukocytosis, and elevated CRP and ESR [9]. Elevated troponins are seen in approximately 50% of cases [12]. Chest radiograph usually shows cardiomegaly with abnormal cardiac silhouette. Pulmonary infiltrates, pleural effusion, and mediastinal widening may be identified as well [9]. Electrocardiogram findings of acute pericarditis are present in a majority of patients; however, in 10 to 35% of cases findings may be normal [9, 10]. Echocardiogram is the most sensitive test and shows presence of fluid in the pericardial cavity in almost all the patients. However, it is not possible to differentiate purulent fluid collections from other causes of acute pericarditis based on echocardiogram alone. If purulent pericarditis is suspected an urgent pericardiocentesis should be performed for diagnostic and therapeutic indications and fluid should be sent for cell count, Gram stain, culture, and fungal and acid-fast stain. If tuberculous pericarditis is suspected, then performing polymerase chain reaction and adenosine deaminase activity assays on fluid increase the diagnostic yield [13]. Medical therapy includes immediate initiation of broad-spectrum antibiotics with antistaphylococcal agent and an aminoglycoside, which can be followed by 4 weeks of bactericidal antibiotic as per culture and sensitivities. For critically ill patients the empiric antibiotic should include vancomycin, third generation cephalosporin, and a fluoroquinolone [9]. Surgical pericardiectomy is indicated in selected patients with incomplete resolution and complications of the disease.\n\nOur case is an extremely rare case of primary purulent acute bacterial pericarditis in a previously healthy adult individual with no immunocompromising or chronic medical condition, caused by S. intermedius. S. intermedius is a member of the Streptococcus anginosus group. The S. anginosus group (also called Streptococcus milleri group) is a subgroup of viridans streptococci that includes three streptococcal species: S. anginosus, S. intermedius, and Streptococcus constellatus. Although these organisms are a part of normal commensal of oral cavity, gastrointestinal tract, and genitourinary tract, they are capable of causing various pyogenic infections and abscess formation [14]. They have been associated with abscess formation in the liver, abdomen, brain, and lung but rarely cause purulent pericarditis.\n\nFrom a search of the medical literature, we identified a total of 22 cases of bacterial pericarditis caused by S. anginosus (milleri) group from 1984 to 2017 [3, 15–34]. Out of these, five cases were attributed to S. intermedius [18, 28, 31, 34]. To the best of our knowledge, this is the sixth reported case of bacterial pericarditis caused by S. intermedius. In our case, the source of S. intermedius infection was unclear and development of pericarditis was spontaneous without evidence of any other infective focus elsewhere. S. intermedius is a part of normal microbial flora of human oral cavity as discussed earlier. We believe that the most likely etiology of infection in our case was transient bacteremia from a mucosal breach in our patient’s oral cavity with hematogenous spread and seeding of bacteria in pericardial cavity leading to purulent pericarditis.\n\nConclusions\nAcute purulent bacterial pericarditis, although rare, should always be kept in mind as a possible cause of pericarditis. As this disease has a rapidly progressive fulminant course, early recognition and prompt intervention are critical for a successful outcome.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received for this study.\n\nAvailability of data and materials\nDatasets used and/or analyzed for this study have been included in this published article.\n\nAuthors’ contributions\nStudy concept and design: MSK and ZK. Acquisition of data: MSK, ZK, BSB, GA, LM, and CG. Drafting of the manuscript: MSK and ZK. Critical revision of manuscript for important intellectual content: all authors. All authors read and approved the final manuscript.\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 any accompanying images. Copies of the written consent are available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests regarding the publication of this paper.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hall IP Purulent pericarditis Postgrad Med J 1989 65 765 444 8 10.1136/pgmj.65.765.444 2690043 \n2. Klacsmann PG Bulkley BH Hutchins GM The changed spectrum of purulent pericarditis: an 86 year autopsy experience in 200 patients Am J Med 1977 63 5 666 73 10.1016/0002-9343(77)90150-4 930941 \n3. Sagrista-Sauleda J Purulent pericarditis: review of a 20-year experience in a general hospital J Am Coll Cardiol 1993 22 6 1661 5 10.1016/0735-1097(93)90592-O 8227835 \n4. Lange RA Hillis LD Clinical practice Acute pericarditis. N Engl J Med. 2004 351 21 2195 202 10.1056/NEJMcp041997 15548780 \n5. Little WC Freeman GL Pericardial disease Circulation 2006 113 12 1622 32 10.1161/CIRCULATIONAHA.105.561514 16567581 \n6. LeWinter MM Clinical practice. Acute pericarditis N Engl J Med. 2014 371 25 2410 6 10.1056/NEJMcp1404070 25517707 \n7. Imazio M Indicators of poor prognosis of acute pericarditis Circulation 2007 115 21 2739 44 10.1161/CIRCULATIONAHA.106.662114 17502574 \n8. Leoncini G Primary and secondary purulent pericarditis in otherwise healthy adults Interact Cardiovasc Thorac Surg 2006 5 5 652 4 10.1510/icvts.2006.131912 17670671 \n9. Pankuweit S Bacterial pericarditis: diagnosis and management Am J Cardiovasc Drugs 2005 5 2 103 12 10.2165/00129784-200505020-00004 15725041 \n10. Rubin RH Moellering RC Jr Clinical, microbiologic and therapeutic aspects of purulent pericarditis Am J Med 1975 59 1 68 78 10.1016/0002-9343(75)90323-X 1138554 \n11. Keersmaekers T Elshot SR Sergeant PT Primary bacterial pericarditis Acta Cardiol 2002 57 5 387 9 10.2143/AC.57.5.2005459 12405580 \n12. Bonnefoy E Serum cardiac troponin I and ST-segment elevation in patients with acute pericarditis Eur Heart J 2000 21 10 832 6 10.1053/euhj.1999.1907 10781355 \n13. Mayosi BM Burgess LJ Doubell AF Tuberculous pericarditis Circulation 2005 112 23 3608 16 10.1161/CIRCULATIONAHA.105.543066 16330703 \n14. Whiley RA Streptococcus intermedius , Streptococcus constellatus , and Streptococcus anginosus (the Streptococcus milleri group): association with different body sites and clinical infections J Clin Microbiol 1992 30 1 243 4 1734062 \n15. Reder RF Purulent pericarditis caused by Streptococcus anginosus -constellatus Mt Sinai J Med 1984 51 3 295 7 6611499 \n16. Akashi K Purulent pericarditis caused by Streptococcus milleri Arch Intern Med 1988 148 11 2446 7 10.1001/archinte.1988.00380110088018 3190375 \n17. Hirata K Asato H Maeshiro M A case of effusive constrictive pericarditis caused by Streptococcus milleri Jpn Circ J 1991 55 2 154 8 10.1253/jcj.55.154 2020085 \n18. Muto M Streptococcus milleri infection and pericardial abscess associated with esophageal carcinoma: report of two cases Hepatogastroenterology 1999 46 27 1782 4 10430344 \n19. Snyder RW Braun TI Purulent pericarditis with tamponade in a postpartum patient due to group F streptococcus Chest 1999 115 6 1746 7 10.1378/chest.115.6.1746 10378580 \n20. Marchal LL Detollenaere M De Baere HJ Streptococcus milleri , a rare cause of pericarditis; successful treatment by pericardiocentesis combined with parenteral antibiotics Acta Clin Belg 2000 55 4 222 4 10.1080/17843286.2000.11754300 11036681 \n21. Berek Z Group-F streptococcal pleuro-pericarditis in a mesothelioma patient after dental surgery (case report) Acta Microbiol Immunol Hung 2001 48 2 147 50 10.1556/AMicr.48.2001.2.3 11233692 \n22. Salazar Gonzalez JJ Sanchez-Rubio Lezcano J Merchante Garcia P Purulent pericarditis with pneumopericardium caused by Streptococcus milleri Rev Esp Cardiol 2002 55 8 861 10.1016/S0300-8932(02)76715-8 12199982 \n23. Kaufman J Esophageal-pericardial fistula with purulent pericarditis secondary to esophageal carcinoma presenting with tamponade Ann Thorac Surg 2003 75 1 288 9 10.1016/S0003-4975(02)04168-1 12537238 \n24. Tomkowski WZ Effectiveness of intrapericardial administration of streptokinase in purulent pericarditis Herz 2004 29 8 802 5 10.1007/s00059-004-2655-4 15599678 \n25. Kabra R Bacterial pericarditis due to group F streptococci as a complication of esophagomediastinal fistula Ann Thorac Surg 2005 79 6 2132 4 10.1016/j.athoracsur.2004.01.001 15919326 \n26. Tokuyasu H Purulent pericarditis caused by the Streptococcus milleri group: a case report and review of the literature Intern Med 2009 48 12 1073 8 10.2169/internalmedicine.48.2109 19525602 \n27. Li Q Purulent pericarditis caused by a bad tooth Eur Heart J 2013 34 11 862 10.1093/eurheartj/eht008 23344978 \n28. Presnell L A child with purulent pericarditis and Streptococcus intermedius in the presence of a pericardial teratoma: an unusual presentation J Thorac Cardiovasc Surg 2014 147 3 e23 4 10.1016/j.jtcvs.2013.11.025 24373623 \n29. Tachjian A Purulent pericarditis after transbronchial biopsy Can J Cardiol 2014 30 10 1250 e19 21 10.1016/j.cjca.2014.04.013 \n30. Takayama T Esophageal cancer with an esophagopericardial fistula and purulent pericarditis Intern Med 2013 52 2 243 7 10.2169/internalmedicine.52.8673 23318856 \n31. Tigen ET Giant purulent pericarditis with cardiac tamponade due to Streptococcus intermedius rapidly progressing to constriction Echocardiography 2015 32 8 1318 21 10.1111/echo.12919 25735951 \n32. Maves RC Pyogenic pericarditis and cardiac tamponade due to Streptococcus anginosus in a combat theater Open Forum Infect Dis 2017 4 1 ofw267 28470013 \n33. Hindi Z Rare purulent cardiac tamponade caused by Streptococcus constellatus in a young immunocompetent patient: case report and review of the literature Am J Case Rep. 2016 17 855 9 10.12659/AJCR.900904 27847383 \n34. Denby KJ Byrne RD Gomez-Duarte OG Streptococcus intermedius : an unusual case of purulent pericarditis Case Rep Infect Dis. 2017 2017 5864694 28932608\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "Acute purulent pericarditis; Cardiac tamponade; Primary bacterial pericarditis; Streptococcus intermedius",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D002305:Cardiac Tamponade; D002637:Chest Pain; D018450:Disease Progression; D004417:Dyspnea; D006801:Humans; D007121:Immunocompetence; D008297:Male; D010490:Pericardial Effusion; D010492:Pericardiectomy; D020519:Pericardiocentesis; D010493:Pericarditis; D013290:Streptococcal Infections; D034367:Streptococcus intermedius; D016896:Treatment Outcome",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "27",
"pmc": null,
"pmid": "29397796",
"pubdate": "2018-02-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10781355;2020085;17502574;15919326;19525602;23318856;1734062;28470013;930941;10378580;12405580;24373623;16567581;15599678;16330703;12199982;2690043;11036681;12537238;25735951;11233692;15725041;1138554;3190375;27847383;10430344;15548780;8227835;23344978;25517707;25138484;28932608;17670671;6611499",
"title": "Primary purulent bacterial pericarditis due to Streptococcus intermedius in an immunocompetent adult: a case report.",
"title_normalized": "primary purulent bacterial pericarditis due to streptococcus intermedius in an immunocompetent adult a case report"
} | [
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"companynumb": "US-IROKO PHARMACEUTICALS LLC-US-I09001-18-00021",
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{
"abstract": "OBJECTIVE\nDespite the lack of safety data, chlorhexidine gluconate (CHG) is an antiseptic with broadspectrum coverage often used in neonatal intensive care units (NICUs). Adverse skin reactions, most commonly burns, have been reported after the use of CHG. Preserving skin integrity in preterm infants is vital in the prevention of sepsis, excessive water loss, hypothermia, and renal failure.\n\n\nMETHODS\nThis is a case report of two incidents of significant skin burning in extremely low birth weight (ELBW) infants who were treated with CHG for the purposes of umbilical cord sterilization prior to umbilical line placement.\n\n\nMETHODS\nThis case report of burns associated with CHG in one infant weighing 610 g at birth and a second infant weighing 600 g at birth.\n\n\nRESULTS\nCHG does have a strong association with causing skin burns in the ELBW population; however, wiping the solution off of the skin seems to reduce injury.",
"affiliations": null,
"authors": "Kutsch|Jennifer|J|;Ottinger|Daniele|D|",
"chemical_list": "D000891:Anti-Infective Agents, Local; D003879:Dermatologic Agents; C010882:chlorhexidine gluconate; D002710:Chlorhexidine",
"country": "United States",
"delete": false,
"doi": "10.1891/0730-0832.33.1.19",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-0832",
"issue": "33(1)",
"journal": "Neonatal network : NN",
"keywords": "chlorhexidine burns; neonatal skin care",
"medline_ta": "Neonatal Netw",
"mesh_terms": "D000891:Anti-Infective Agents, Local; D002057:Burns, Chemical; D002710:Chlorhexidine; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D014472:Umbilicus",
"nlm_unique_id": "8503921",
"other_id": null,
"pages": "19-23",
"pmc": null,
"pmid": "24413032",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neonatal skin and chlorhexidine: a burning experience.",
"title_normalized": "neonatal skin and chlorhexidine a burning experience"
} | [
{
"companynumb": "US-BECTON DICKINSON-2016BDN00342",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "CHLORHEXIDINE"
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{
"abstract": "Vulvovaginal graft-versus-host disease (GVHD) is an underdiagnosed and poorly recognized complication of hematopoietic stem cell transplantation (HSCT). Previous studies have reported findings restricted to predominantly adult populations. We report a case series of pediatric and young adult vulvovaginal GVHD, which was identified in 19 patients (median age, 11.8 years; range, 2.4 to 21.9 years) out of a total 302 female patients who underwent transplantation over an 8-year period at a pediatric HSCT center. The majority of patients had concomitant nongenital GVHD; only 1 patient had isolated vulvovaginal GVHD. The median time from bone marrow transplantation to diagnosis of vulvovaginal GVHD was 30 months (range, 2.3 to 97.5 months). A high percentage of the patients in our series were without vulvar or vaginal symptoms (n = 8; 42%), even though 17 patients (89%) presented with grade 3 disease based on current adult grading scales. Vulvar examination findings most frequently included interlabial and clitoral hood adhesions (89%), loss of architecture of the labia minora or clitoral hood (42%), and skin erosions or fissures (37%). Only 5 patients underwent a speculum exam, none of whom had vaginal GVHD. Examination findings of primary ovarian insufficiency (POI) can overlap with those of GVHD, and 6 patients (32%) in our cohort were diagnosed with POI. Only 1 patient was on systemic hormone replacement therapy at the time of vulvovaginal GVHD diagnosis. The majority of patients (n = 16) were treated with topical steroid therapy, with a median time to response of 43 days. Five patients (26%) had a complete response to therapy, and 10 patients (53%) had a partial response. This case series provides valuable insight into pediatric and young adult vulvovaginal GVHD and highlights the need for increased screening for vulvar disease in this population.",
"affiliations": "Division of Pediatric and Adolescent Gynecology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Stephanie.cizek@gmail.com.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Pediatric and Adolescent Gynecology, Washington University School of Medicine, St Louis, Missouri.",
"authors": "Cizek|Stephanie M|SM|;El-Bietar|Javier|J|;Rubinstein|Jeremy|J|;Dandoy|Christopher|C|;Wallace|Gregory H|GH|;Nelson|Adam|A|;Khandelwal|Pooja|P|;Myers|Kasiani C|KC|;Hoefgen|Holly R|HR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2019.07.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "25(12)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "GVHD; Gynecology; Pediatric; Survivorship; Vaginal; Vulvar",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D064591:Allografts; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D010049:Ovarian Diseases; D014623:Vaginal Diseases; D014845:Vulvar Diseases; D055815:Young Adult",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "2408-2415",
"pmc": null,
"pmid": "31325588",
"pubdate": "2019-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Pediatric and Young Adult Vulvovaginal Graft-versus-Host Disease.",
"title_normalized": "pediatric and young adult vulvovaginal graft versus host disease"
} | [
{
"companynumb": "NVSC2020US003258",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "A 57-year-old man was admitted with pruritus and jaundice following treatment for fatigue with the herbal medicine Hochuekkito. The patient was prescribed prednisolone and ursodeoxycholic acid, but he developed progressive cholestasis that required intravenous methylprednisolone pulse therapy. After treatment with plasma exchange for prolonged prothrombin time, the patient recovered; however, his liver function deteriorated because of liver injury induced by trimethoprim-sulfamethoxazole for pneumocystis pneumonia. After reduction of trimethoprim-sulfamethoxazole, his liver function almost returned to normal by day 130 of admission. It has remained normal for 10 months since then. Therefore, when prescribing Hochuekkito, the possibility of drug-induced liver injury should be taken in account.",
"affiliations": "Department of Gastroenterology, Itabashi Chuo Medical Center.",
"authors": "Negishi|Ryoju|R|;Ichikawa|Takeshi|T|;Tawa|Yoshiyuki|Y|;Fujimura|Akira|A|;Tanaka|Sayo|S|;Tenmoku|Akira|A|;Akazawa|Kimika|K|;Kanno|Masataka|M|;Sasaki|Hiroshi|H|;Okubo|Sae|S|;Machida|Nobuaki|N|;Fukuda|Yuh|Y|;Oi|Itaru|I|;Fujino|Masayuki A|MA|",
"chemical_list": "D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; C402943:bu-zhong-yi-qi-tang",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "111(6)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D004365:Drugs, Chinese Herbal; D006501:Hepatic Encephalopathy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010936:Plant Extracts",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "1149-56",
"pmc": null,
"pmid": "24898495",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Liver injury and hepatic encephalopathy induced by the herbal medicine Hochuekkito.",
"title_normalized": "liver injury and hepatic encephalopathy induced by the herbal medicine hochuekkito"
} | [
{
"companynumb": "PHHY2014JP089494",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": n... |
{
"abstract": "Systemic adenovirus infection in the immunocompromised host is often fatal and therapeutic options are limited. We report an infant with acute lymphoblastic leukemia who developed disseminated adenovirus infection while lymphopenic during maintenance chemotherapy 6 months following a bout of adenoviral diarrhea. His serum adenoviral load peaked at 35 million copies/mL and was associated with pancytopenia and hepatic injury. Treatment with cidofovir was effective although associated with mild renal injury. The patient recovered fully and completed chemotherapy for infant acute lymphoblastic leukemia.",
"affiliations": "Departments of *Pediatrics ‡Pathology †Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.",
"authors": "Alcamo|Alicia M|AM|;Pinchasik|Dawn E|DE|;Mo|Jun Qin|JQ|;Grimley|Michael S|MS|;O'Brien|Maureen M|MM|",
"chemical_list": "D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000224",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000258:Adenovirus Infections, Human; D000998:Antiviral Agents; D000077404:Cidofovir; D003596:Cytosine; D006801:Humans; D016867:Immunocompromised Host; D007223:Infant; D008297:Male; D063065:Organophosphonates; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D015996:Survival Rate",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e178-81",
"pmc": null,
"pmid": "25089608",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Disseminated Adenovirus Infection in an Infant With Acute Lymphoblastic Leukemia.",
"title_normalized": "successful treatment of disseminated adenovirus infection in an infant with acute lymphoblastic leukemia"
} | [
{
"companynumb": "US-GILEAD-2015-0150271",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROBENECID"
},
"drugadditional": null,
... |
{
"abstract": "Giant cell granuloma (GCG) of the jaw is a rare disease with high morbidity. Various treatment options have been discussed in the past. Since 2010, a pharmaceutical therapy with denosumab seems to have been successful for giant cell tumors of the femur. The authors hypothesized the equally successful use of denosumab for GCGs of the jaws.\n\n\n\nIn the present retrospective cohort study, 5 patients with large GCGs of the jaws were treated with denosumab with a follow-up of 25 to 49 months. Frequent clinical follow-ups and a radiologic follow-up were performed and systematically analyzed.\n\n\n\nAll patients showed a curative treatment response and complete metabolic resolution of the GCGs under treatment with denosumab.\n\n\n\nA brief review of the relevant literature and a detailed evaluation of current cases led to the conclusion that denosumab therapy should be considered a therapeutic option for large central GCGs of the jaws. The results of this study suggest denosumab is a successful treatment option. A treatment length no shorter than 12 months is recommended and monitoring of treatment response can be well managed by positron-emission tomographic computed tomography or magnetic resonance imaging.",
"affiliations": "Private Practice and Visiting Consultant, Cantonal Hospital Winterthur, Winterthur, Switzerland. Electronic address: marius.bredell@gesicht.ch.;Consultant, Department of Oncology, University Hospital of Zurich, Zurich, Switzerland.;Consultant, Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.;Professor and Head of Department, Department of Craniomaxillofacial and Oral Surgery, University Hospital of Zurich, Zurich, Switzerland.;Consultant, Department of Craniomaxillofacial and Oral Surgery, University Hospital of Zurich, Zurich, Switzerland.;Resident, Department of Craniomaxillofacial and Oral Surgery, University Hospital of Zurich, Zurich, Switzerland.",
"authors": "Bredell|Marius|M|;Rordorf|Tamara|T|;Kroiss|Sabine|S|;Rücker|Martin|M|;Zweifel|Daniel Fritz|DF|;Rostetter|Claudio|C|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2017.09.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "76(4)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D050071:Bone Density Conservation Agents; D002675:Child, Preschool; D054893:Cone-Beam Computed Tomography; D000069448:Denosumab; D005260:Female; D006101:Granuloma, Giant Cell; D006801:Humans; D007571:Jaw Diseases; D008297:Male; D011862:Radiography, Panoramic; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "775-784",
"pmc": null,
"pmid": "29035698",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Denosumab as a Treatment Alternative for Central Giant Cell Granuloma: A Long-Term Retrospective Cohort Study.",
"title_normalized": "denosumab as a treatment alternative for central giant cell granuloma a long term retrospective cohort study"
} | [
{
"companynumb": "CH-MYLANLABS-2018M1035946",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CALCITONIN SALMON"
},
"drugadditional": null,... |
{
"abstract": "Gingival overgrowth (GO) includes gingival enlargement and hyperplasia and may be induced by certain drugs, including calcium channel blockers (CCBs), particularly first-generation CCBs. However, to date, only few cases of GO induced by second- or third-generation CCBs have been reported. The present study reports on a case of a 48-year-old diabetic male who was admitted to the First Hospital of Jilin University (Changchun, China) due to poor blood glucose control. This patient was diagnosed with GO. Review of the patient's medical history revealed diagnoses of type 2 diabetes and hypertension, as well as the use of felodipine, a second-generation CCB, to control hypertension. The hypertensive drugs were replaced and the new drugs helped the patient control his blood glucose levels. Additionally, the patient was instructed on methods he could use to improve his oral hygiene, including rinsing of the teeth following each meal and increasing the frequency of tooth brushing per day. After 3 months, the clinical symptoms of GO were relieved. The relevant literature was also reviewed to gain an improved understanding of the correlation between GO and CCBs, as well as diabetes and poor oral hygiene.",
"affiliations": "Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.;Department of Developmental and Behavior Pediatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.;Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.;Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.;Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.;Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.",
"authors": "Sun|Lin|L|;Wang|Chengxin|C|;Xi|Shugang|S|;Zhou|Tong|T|;Wang|Guixia|G|;Gang|Xiaokun|X|",
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"doi": "10.3892/etm.2019.7376",
"fulltext": "\n==== Front\nExp Ther MedExp Ther MedETMExperimental and Therapeutic Medicine1792-09811792-1015D.A. Spandidos 10.3892/etm.2019.7376ETM-0-0-7376ArticlesFelodipine-associated gingival overgrowth in a type 2 diabetic patient: A case report and literature review Sun Lin 1Wang Chengxin 2Xi Shugang 1Zhou Tong 1Wang Guixia 1Gang Xiaokun 11 Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China2 Department of Developmental and Behavior Pediatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. ChinaCorrespondence to: Dr Guixia Wang or Dr Xiaokun Gang, Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 71 Xinmin Road, Changchun, Jilin 130021, P.R. China, E-mail: gwang168_1@163.com, E-mail: insightful@126.com5 2019 13 3 2019 13 3 2019 17 5 3399 3402 11 8 2018 04 2 2019 Copyright: © Sun et al.2019This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Gingival overgrowth (GO) includes gingival enlargement and hyperplasia and may be induced by certain drugs, including calcium channel blockers (CCBs), particularly first-generation CCBs. However, to date, only few cases of GO induced by second- or third-generation CCBs have been reported. The present study reports on a case of a 48-year-old diabetic male who was admitted to the First Hospital of Jilin University (Changchun, China) due to poor blood glucose control. This patient was diagnosed with GO. Review of the patient's medical history revealed diagnoses of type 2 diabetes and hypertension, as well as the use of felodipine, a second-generation CCB, to control hypertension. The hypertensive drugs were replaced and the new drugs helped the patient control his blood glucose levels. Additionally, the patient was instructed on methods he could use to improve his oral hygiene, including rinsing of the teeth following each meal and increasing the frequency of tooth brushing per day. After 3 months, the clinical symptoms of GO were relieved. The relevant literature was also reviewed to gain an improved understanding of the correlation between GO and CCBs, as well as diabetes and poor oral hygiene.\n\ncalcium channel blockerfelodipinedrug-induced gingival overgrowth\n==== Body\nIntroduction\nGingival overgrowth (GO), which usually occurs at the upper and lower anterior teeth, includes gingival enlargement and hyperplasia. GO is characterized by a change in the color of the gingiva, bleeding upon probing, compromised appearance of the teeth, and difficulties regarding mastication, deglutition and speech (1–5). The pathogenesis of GO is thought to be multifactorial, involving inflammation, malignancy (e.g., oral cavity tumor or other solid tumor type), systemic diseases and undesired effects associated with systemic administration of certain drugs (6,7). GO that occurs via the latter mechanism is referred to as drug-induced gingival overgrowth (DIGO) and has a prevalence of 3–20% (8). To date, >20 drugs have been reported to be associated with DIGO, including anti-convulsants (e.g., phenytoin), immunosuppressants (e.g., cyclosporine A) and calcium channel blockers (CCBs, e.g., nifedipine and verapamil) (9–22). CCBs are administered to treat various cardiac diseases, including hypertension, angina pectoris and certain arrhythmias (e.g., supraventricular tachycardia) and exert their effect on voltage-dependent Ca2+ channels in smooth muscles (23), subsequently promoting a higher concentration of extracellular calcium and decreasing the level of intracellular calcium. The changes in calcium concentrations inside and outside of cells affect the activation of collagenase and processes involved in apoptosis (24–26). Therefore, CCBs have an important role in the initiation and progression of tissue overgrowth.\n\nCCBs are primarily divided into three categories: Phenylalkylamine derivatives (e.g., verapamil), benzothiazepine derivatives (e.g., diltiazem) and substitute dihydropyridines (e.g., nifedipine, amlodipine, felodipine, isradipine, nicardipine, nimodipine, oxodipine, nisodipine and nitrendipine) (23). Nifedipine, as a first-generation dihydropyridine, has been widely used in the management of cardiac diseases, including hypertension. In the mid-1980s, Lombardi et al (27) first reported on a case of GO caused by nifedipine. Since then, further cases of GO linked to the use of nifedipine have been reported. The incidence of nifedipine-induced GO varies among different studies, ranging from 14–83% (28). Compared to the first-generation CCBs, the involvement of second- and third-generation dihydropyridines, including felodipine and amlodipine, in the pathogenesis of DIGO has been less frequently reported. One study reported on incidence of amlodipine-induced GO of 1.4–3.3% (8). Felodipine was first reported to cause DIGO in 1991 (27), and Fay et al (4) reported on one case of felodipine-associated GO in a patient with type 2 diabetes, whose histological characteristics of GO were similar to those in DIGO and withdrawal of felodipine almost fully resolved the GO. The present study reports on a case of GO that was attributed to felodipine treatment. To the best of our knowledge, the present study is the first to report on felodipine-induced GO in a Chinese patient with type 2 diabetes.\n\nCase report\nA 48-year-old man from Jilin Province in the northeast region of China presented at the Endocrinology Department of the First Clinical Hospital of Jilin University (Changchun, China) with the chief complaint of poor blood glucose control lasting for nearly 3 days. The patient denied a family history of hypertension and diabetes mellitus but admitted that his blood pressure had been high for 4 years, with a peak blood pressure of 180/100 mmHg. Various anti-hypertensive drugs had been used to control his blood pressure but had a poor efficiency. The patient had a history of diabetes of ~1 year. Aside from diet control, he did not take any medications or insulin to control his blood glucose levels and monitored his fingertip blood glucose regularly. At 3 days prior to presentation, his fingertip blood glucose were 14 mmol/l and glycated hemoglobin (HbA1c) levels were 8.4%, which prompted him to visit our department. On physical examination, the patient had a body temperature of 36.5°C, heart rate of 88 beats/min, respiratory rate of 20 breaths/min and blood pressure of 160/100 mmHg. He was well developed and moderately nourished with a body mass index of 26.2 kg/m2. His skin and sclera had no yellow staining. The trachea was in the midline and the thyroid was not enlarged. No abnormal breath or heart sound was noted on auscultation. No abdominal positive signs were identified. Routine examination indicated the following: Normal liver and kidney function, fasting blood glucose of 7.9 mmol/l, blood potassium of 3.1 mmol/l (normal range, 3.5–5.3 mmol/l), carbon dioxide binding capacity of 35.6 mmol/l (normal range, 22–30 mmol/l) and no abnormalities in electrocardiogram and chest X-ray. Abdominal computed tomography indicated slight hyperplasia of the bilateral adrenal grands and thick insides and thin outsides of limbs. No retinopathy or diabetic peripheral neuropathy was observed.\n\nOn physical examination, GO was identified. The patient had mild gingival soreness when chewing hard foods, but did not have any difficulties with mastication. Review of the patient's medical history revealed the use of oral medicines to control hypertension. He had started taking a combination of irbesartan, an angiotensin II receptor antagonist, and felodipine ~4 years previously, but after ~6 months on this medication, he discontinued irbesartan due to the increasing incidence of hypopiesia. Since then, he had taken only felodipine for ~3.5 years. He mentioned that GO first occurred 8 months previously while he was using felodipine. Oral examination revealed a mouth opening index of III and GO throughout all quadrants, which was particularly pronounced under the dental papilla (Fig. 1). In addition, the gums bled when probed. All teeth were dark brown due to poor oral hygiene. Based on the patient's medical history and consultation with a dental professional, it is likely that GO in this patient was caused by felodipine. Therefore, felodipine was first replaced with a combination of spironolactone (a diuretic) and terazosin (an α-receptor blocker) to control the hypertension. It was then proposed that the patient retains his original dietary habits combined with the use of metformin (a hypoglycemic drug) to reduce blood glucose levels. Finally, the patient was instructed on methods to improve his oral hygiene, including rinsing of the teeth after each meal and increasing the frequency of tooth brushing per day. At the 3-month follow-up, the patient had a blood pressure ranging from 130/85 to 140/90 mmHg, fasting blood glucose of 7–8 mmol/l and postprandial blood glucose of 9–10 mmol/l. The level of HbA1c had decreased to 7.5%. Although the GO had not been completely eliminated, the symptoms of tooth soreness disappeared after the triggers of GO were eliminated (Fig. 2).\n\nDiscussion\nFelodipine was first reported to cause DIGO in 1991 (27). However to the best of our knowledge, felodipine-induced GO in a Chinese patient with diabetes mellitus has not been previously reported. The present study reports on one case of felodipine-associated GO in a type 2 diabetic patient.\n\nAlthough it is well established that CCBs are associated with the development of GO, the exact underlying mechanisms remain to be fully elucidated. Inflammatory as well as non-inflammatory pathways have been indicated to be involved in CCB-induced GO (28). The non-inflammatory pathway includes the upregulation of keratinocyte growth factor, which promotes epithelial cell growth in the oral cavity and matrix synthesis around gingival connected tissues. Such increased matrix synthesis leads to defective collagenase activity attributed to the reduced uptake of folic acid, thereby resulting in the accumulation of connective tissue and development of GO (28).\n\nOn the other hand, the inflammatory pathway also has an important role in the interaction between drugs and fibroblasts (28). First, the higher drug concentration in crevicular gingival fluid, which was identified to be up to 292-fold of that detected in serum, may have direct toxic effects. This drug-induced inflammation causes an upregulation of the levels of several cytokine factors, including fibroblast growth factor-2, transforming growth factor-β1, interleukin-6 (IL-6), IL-1B and platelet derived growth factor-β to generate excessive fibroblasts, which contributes to the development of fibrotic gingival hyperplasia (28,29). In addition, the pro-inflammatory cytokines released from inflammatory corpuscles participate in inflammation-associated local cellular events, including mast cell migration, fibroblast proliferation, as well as an increase in extracellular matrix synthesis and decrease in degradation. These processes may create a vicious cycle to promote the pathogenesis of DIGO. Mechanistically, the CCB-induced fluctuation in intra- and extra-cellular calcium levels is mediated via inflammatory signaling (30). It has been reported that a high intracellular free Ca2+ concentration potentiates the activity of growth factors and cell cycle regulators, and thus, promotes cell proliferation and collagen synthesis (30).\n\nApart from certain drugs, GO has been reported to be associated with other factors, including diabetes. For instance, Van Dis et al (31) reported on four cases of hyperplastic gingival enlargement in diabetes mellitus patients and Fay et al (4) reported one case of felodipine-influenced GO in a patient with uncontrolled type 2 diabetes mellitus. Hence, diabetes mellitus may be regarded as one of the contributing factors to the development of GO, particularly CCB-induced GO. The exact mechanisms by which hyperglycemia contributes to the development of GO remain elusive. It may be speculated that hyperglycemia is associated with an elevated local inflammatory response, which may have a role in the pathogenesis of GO. Furthermore, the clinical manifestations in previously reported cases of GO included erythematous and edematous hyperplastic gingival tissues, numerous food sediments and severe periodontitis (32,33), all of which were accompanied by poor oral hygiene (34). Therefore, it may be reasoned that the poor gingival hygienic conditions of the present case served as another contributing factor to DIGO (35). However, how these contributing factors act synergistically remains elusive.\n\nThe case of the present study had been diagnosed with type 2 diabetes 1 year previously and had experienced poor blood glucose control for 3 days. GO occurred at 8 months prior to the patient's presentation at the department of Endocrinology and Metabolism of the First Hospital of Jilin University, and after the replacement of the angiotensin II receptor antagonist with the CCB felodipine. In addition, his gingival hygienic condition was poor. Of note, the degree of severity of GO, drug dosage and the occurrence time of DIGO were similar to those of a previous case reported by Fay et al (4), except for the controlled diabetes mellitus. Hence, it may be concluded that the gingival hygienic status may be regarded as a major promoting factor for felodipine-induced DIGO. As mentioned above, hyperglycemia is likely to be another contributing factor.\n\nPreviously, Fay et al (4) and Khzam et al (35) suggested that surgery and application of antibiotics should be considered as the second choice for treating DIGO. Indeed, upon revision of the medication strategy for the present case, i.e., replacement of the CCB with a diuretic, the symptoms of gingival soreness were relieved and GO had been partially eliminated within 3 months. Therefore, removal of the causative factors, including the improvement of oral hygiene, control of blood glucose levels, and most importantly, replacement of the CCB with a different appropriate anti-hypertensive drug, reduced the clinical symptoms and prevented the recurrence of lesions. Indeed, the clinical significance of the present case is that a simple change of the dihydropyridine drug in combination with improvements in the patient's health care (i.e., controlling diabetes and oral hygiene) permitted the avoidance of surgical intervention.\n\nA literature search did not provide any studies that linked angiotensin II receptor antagonists to the pathogenesis of GO and this possibility was therefore excluded. The present case had recurrent hypokalemia and adrenal hyperplasia. After a series of endocrine system examinations, the patient was determined to have adrenal hyperplasia. In combination with the presence of gingival hyperplasia in the present case, the treatment was switched to aldosterone antagonist spironolactone combined with terazosin anti-hypertensive drug in order to control blood pressure and hypokalemia. From the start of the new treatment, the patient's blood pressure was under control. Trazosin and spironolactone are not known to be associated with drug-induced gingival hyperplasia. The patient was advised to return periodically for follow-up with regard to adrenal hyperplasia and associated endocrine hormone levels.\n\nThe limitations of the present case report should be acknowledged. For instance, the local concentration of CCB and glucose around the gingival tissue was not determined and no histological examination was performed. Furthermore, the glucose levels in blood vs. gingival interstitial fluid were not compared, and changes in the gingival tissues by histological examination prior to and following treatment were not determined. These changes may be investigated in further intensive studies.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe present study was sponsored by Jilin Province Science and Technology Development Plan Project (grant nos. 20160623092TC-03 and 20180623083TC-03).\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nGW and XG contributed a lot to the design of the study and revision of the manuscript. LS and CW wrote the first draft of the manuscript. TZ and SX edited this manuscript and interpreted the data. LS, CW and XG contributed a lot to the acquisition of the data as well as the revision of the final draft. All authors have approved the submitted version and agreed to be accountable for all aspects of the manuscript.\n\nEthics approval and consent to participate\nThe present study was approved by the Ethics Committee of the First Hospital of Jilin University (Changchun, China).\n\nPatient consent for publication\nThe patient provided written informed consent for the publication of his data and images in the present study.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. At presentation, all of the patient's teeth were dark brown due to poor oral hygiene. Oral examination revealed a mouth opening index of III and gingival overgrowth throughout all quadrants that was particularly pronounced under the dental papilla.\n\nFigure 2. The quality of the patient's teeth was improved after 3 months under the new treatment, although the gingival overgrowth had not been completely eliminated.\n==== Refs\nReferences\n1 Nyska A Shemesh M Tal H Dayan D Gingival hyperplasia induced by calcium channel blockers: Mode of action Med Hypotheses 43 115 118 1994 10.1016/0306-9877(94)90061-2 7990738 \n2 Lafzi A Farahani RM Shoja MA Amlodipine-induced gingival hyperplasia Med Oral Patol Oral Cir Bucal 11 E480 E482 2006 17072250 \n3 Joshi S Bansal S A rare case report of amlodipine-induced gingival enlargement and review of its pathogenesis Case Rep Dent 2013 138248 2013 24024043 \n4 Fay AA Satheesh K Gapski R Felodipine-influenced gingival enlargement in an uncontrolled type 2 diabetic patient J Periodontol 76 1217 2005 10.1902/jop.2005.76.7.1217 16018768 \n5 Sucu M Yuce M Davutoglu V Amlodipine-induced massive gingival hypertrophy Can Fam Physician 57 436 437 2011 21490356 \n6 Hallmon WW Rossmann JA The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts Periodontol 2000 21 176 196 1999 10.1111/j.1600-0757.1999.tb00175.x 10551182 \n7 Seymour RA Thomason JM Ellis JS The pathogenesis of drug-induced gingival overgrowth J Clin Periodontol 23 165 175 1996 10.1111/j.1600-051X.1996.tb02072.x 8707974 \n8 Ono M Tanaka S Takeuchi R Matsumoto H Okada H Yamamoto H Makiyama Y Hirayama T Sakamaki T Fujii A Akimoto Y Prevalence of Amlodipine-induced Gingival Overgrowth Int J Oral-Med Sci 9 96 100 2010 10.5466/ijoms.9.96 \n9 Hassell TM Gilbert GH Phenytoin sensitivity of fibroblasts as the basis for susceptibility to gingival enlargement Am J Pathol 112 218 223 1983 6881288 \n10 Casetta I Granieri E Desiderá M Monetti VC Tola MR Paolino E Govoni V Calura G Phenytoin-induced gingival overgrowth: A community-based cross-sectional study in Ferrara, Italy Neuroepidemiology 16 296 303 1997 10.1159/000109700 9430129 \n11 Brunsvold M Tomasovic J Ruemping D The measured effect of phenytoin withdrawal on gingival hyperplasia in children ASDC J Dent Child 52 417 421 1985 3864798 \n12 Rateitschak-Plüss EM Hefti A Lörtscher R Thiel G Initial observation that cyclosporin-A induces gingival enlargement in man J Clin Periodontol 10 237 246 1983 10.1111/j.1600-051X.1983.tb01272.x 6575979 \n13 Pisanty S Rahamim E Ben-Ezra D Shoshan S Prolonged systemic administration of cyclosporin A affects gingival epithelium J Periodontol 61 138 141 1990 10.1902/jop.1990.61.2.138 2313531 \n14 Daly CG Resolution of cyclosporin A (CsA)-induced gingival enlargement following reduction in CsA dosage J Clin Periodontol 19 143 145 1992 10.1111/j.1600-051X.1992.tb00453.x 1602038 \n15 Barak S Engelberg IS Hiss J Gingival hyperplasia caused by nifedipine. Histopathologic findings J Periodontol 58 639 642 1987 10.1902/jop.1987.58.9.639 3477631 \n16 Romanos GE Schröter-Kermani C Hinz N Herrmann D Strub JR Bernimoulin JP Extracellular matrix analysis of nifedipine-induced gingival overgrowth: Immunohistochemical distribution of different collagen types as well as the glycoprotein fibronectin J Periodontal Res 28 10 16 1993 10.1111/j.1600-0765.1993.tb01044.x 8426277 \n17 Miranda J Brunet L Roset P Berini L Farré M Mendieta C Prevalence and risk of gingival enlargement in patients treated with nifedipine J Periodontol 72 605 611 2001 10.1902/jop.2001.72.5.605 11394395 \n18 Pernu HE Oikarinen K Hietanen J Knuuttila M Verapamil-induced gingival overgrowth: A clinical, histologic, and biochemic approach J Oral Pathol Med 18 422 425 1989 10.1111/j.1600-0714.1989.tb01576.x 2585306 \n19 Miller CS Damm DD Incidence of verapamil-induced gingival hyperplasia in a dental population J Periodontol 63 453 456 1992 10.1902/jop.1992.63.5.453 1527689 \n20 Mehta AV Chidambaram B O'Riordan AC Verapamil-induced gingival hyperplasia in children Am Heart J 124 535 536 1992 10.1016/0002-8703(92)90630-E 1636605 \n21 Giustiniani S Robustelli della Cuna F Marieni M Hyperplastic gingivitis during diltiazem therapy Int J Cardiol 15 247 249 1987 10.1016/0167-5273(87)90322-6 3583463 \n22 Fattore L Stablein M Bredfeldt G Semla T Moran M Doherty-Greenberg JM Gingival hyperplasia: A side effect of nifedipine and diltiazem Spec Care Dentist 11 107 109 1991 10.1111/j.1754-4505.1991.tb00828.x 1887359 \n23 Godfraind T Calcium channel blockers in cardiovascular pharmacotherapy J Cardiovasc Pharmacol Ther 19 501 515 2014 10.1177/1074248414530508 24872348 \n24 Godfraind T Mechanisms of action of calcium entry blockers Fed Proc 40 2866 2871 1981 7308497 \n25 Soward AL Vanhaleweyk GL Serruys PW The haemodynamic effects of nifedipine, verapamil and diltiazem in patients with coronary artery disease. A review Drugs 32 66 101 1986 10.2165/00003495-198632010-00004 2874975 \n26 Bose T Cieślar-Pobuda A Wiechec E Role of ion channels in regulating Ca2+ homeostasis during the interplay between immune and cancer cells Cell Death Dis 6 e1648 2015 10.1038/cddis.2015.23 25695601 \n27 Lombardi T Fiore-Donno G Belser U Di Felice R Felodipine-induced gingival hyperplasia: A clinical and histologic study J Oral Pathol Med 20 89 92 1991 10.1111/j.1600-0714.1991.tb00896.x 2016700 \n28 Thomas P Tolstoy R Duraisingh L Amlodipine induced gingival hyperplasia: A case report Int J Basic Clin Pharmacol 805 807 2015 (In Chinese) 10.18203/2319-2003.ijbcp20150396 \n29 Gong Y Lu J Ding X Yu Y Effect of adjunctive roxithromycin therapy on interleukin-1β, transforming growth factor-β1 and vascular endothelial growth factor in gingival crevicular fluid of cyclosporine A-treated patients with gingival overgrowth J Periodontal Res 49 448 457 2014 10.1111/jre.12123 23947915 \n30 Matsumoto H Takeuchi R Ono M Akimoto Y Kobayashi N Fujii A Drug-induced gingival overgrowth and its tentative pharmacotherapy Jpn Dent Sci Rev 46 11 16 2010 10.1016/j.jdsr.2009.09.001 \n31 Van Dis ML Allen CM Neville BW Erythematous gingival enlargement in diabetic patients: A report of four cases J Oral Maxillofac Surg 46 794 798 1988 10.1016/0278-2391(88)90192-9 3045273 \n32 Padmanabhan S Dwarakanath CD Severe gingival enlargement associated with aggressive periodontitis J Indian Soc Periodontol 17 115 119 2013 10.4103/0972-124X.107486 23633785 \n33 Agrawal AA Gingival enlargements: Differential diagnosis and review of literature World J Clin Cases 3 779 788 2015 10.12998/wjcc.v3.i9.779 26380825 \n34 Reali L Zuliani E Gabutti L Schönholzer C Marone C Poor oral hygiene enhances gingival overgrowth caused by calcineurin inhibitors J Clin Pharm Ther 34 255 260 2009 10.1111/j.1365-2710.2008.01000.x 19646074 \n35 Khzam N Bailey D Yie HS Bakr MM Gingival enlargement induced by felodipine resolves with a conventional periodontal treatment and drug modification Case Rep Dent 2016 1095927 2016 27034854\n\n",
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"title": "Felodipine-associated gingival overgrowth in a type 2 diabetic patient: A case report and literature review.",
"title_normalized": "felodipine associated gingival overgrowth in a type 2 diabetic patient a case report and literature review"
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"abstract": "Pulmonary hypertension during pregnancy carries high mortality rate. The relatively long-acting, specific pulmonary vasodilator treprostinil has been used to improve survival in these parturients. Slow uptitration is performed in most cases, and rapid titration has not been reported in the postpartum period.\n\n\n\nWe retrospectively reviewed 17 pregnant patients with severe pulmonary arterial hypertension who were treated with intravenous treprostinil in our institution between 2014 and 2016. Patients' demographic characteristics, etiology, functional status, mode of delivery, anesthetic administration, medical therapy, echocardiographic and hemodynamic measurements, subsequent clinical course, and maternal-fetal outcomes were assessed. The a priori primary outcome is maternal mortality in this study.\n\n\n\nRapid titration of intravenous treprostinil was initiated at 1.25 ng/kg/min and increased to effective dose of 10 ng/kg/min by 1.25-2.5 ng/kg/min every 3 hours. In the next 24 hours, we adjusted the dosage to a median maximum dose of 15 ng/kg/min (interquartile range, 15-20 ng/kg/min) over a median uptitration period of 34 hours (interquartile range, 24-41 hours) for 17 parturients with severe pulmonary hypertension. Treprostinil was weaned off by 0.50-1.25 ng/kg/min every 3 hours in 94.3 ± 42.4 hours. Fifteen patients survived to discharge, and only 2 patients died of pulmonary hypertensive crisis (maternal mortality rate, 11.7%). No treprostinil infusion-related postpartum complication was observed.\n\n\n\nOur experience suggested that rapid uptitration of intravenous treprostinil combined with oral sildenafil in the postpartum period may be a safe and effective approach for these very sick parturients with severe pulmonary hypertension.",
"affiliations": "From the Departments of Surgical Intensive Care Medicine.;Anesthesia.;From the Departments of Surgical Intensive Care Medicine.;From the Departments of Surgical Intensive Care Medicine.;From the Departments of Surgical Intensive Care Medicine.;From the Departments of Surgical Intensive Care Medicine.;Obstetric Medicine, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing AnZhen Hospital, Capital Medical University, Beijing, China.;Anesthesia.;Department of Anesthesiology, Jewish Hospital, Louisville, Kentucky.;From the Departments of Surgical Intensive Care Medicine.",
"authors": "Wang|Tengke|T|;Lu|Jiakai|J|;Li|Qiang|Q|;Chen|Yao|Y|;Ye|Qing|Q|;Gao|Jie|J|;Yang|Dong|D|;Zhao|Liyun|L|;Huang|Jiapeng|J|;Zhang|Jinglan|J|",
"chemical_list": "D000959:Antihypertensive Agents; D011464:Epoprostenol; C427248:treprostinil",
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"title": "Rapid Titration of Intravenous Treprostinil to Treat Severe Pulmonary Arterial Hypertension Postpartum: A Retrospective Observational Case Series Study.",
"title_normalized": "rapid titration of intravenous treprostinil to treat severe pulmonary arterial hypertension postpartum a retrospective observational case series study"
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"abstract": "Schizophrenia is a chronic relapsing and remitting disorder associated with significant impairments in social and vocational functioning and a shortened lifespan, and it is a disabling psychiatric brain syndrome whose phenotype is characterized by three core symptom domains: positive symptoms, such as delusions and hallucinations, negative symptoms, which include lack of motivation and social withdrawal, and cognitive impairment. Moreover, patients with schizophrenia have severe problems with personal and social relations which affect their quality of life. Antipsychotic medications in conjunction with psychosocial interventions can help patients achieve recovery. Here are described three clinical cases of schizophrenic patients treated with cariprazine for inadequate response to a previous treatment. The purpose of this clinical series is to give useful information for the use of cariprazine in clinical practice.",
"affiliations": "Kliniken Essen-Mitte, Klinik für Psychiatrie, Psychotherapie, Psychosomatik und Suchtmedizin, Essen, Germany.",
"authors": "Aubel|Thomas|T|",
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"doi": "10.2147/NDT.S315653",
"fulltext": "\n==== Front\nNeuropsychiatr Dis Treat\nNeuropsychiatr Dis Treat\nndt\nneurodist\nNeuropsychiatric Disease and Treatment\n1176-6328\n1178-2021\nDove\n\n315653\n10.2147/NDT.S315653\nCase Series\nCariprazine: Patients with Treatment-Resistant Schizophrenia\nAubel\nAubel\nAubel Thomas 1\n1 Kliniken Essen-Mitte, Klinik für Psychiatrie, Psychotherapie, Psychosomatik und Suchtmedizin, Essen, Germany\nCorrespondence: Thomas Aubel Kliniken Essen-Mitte, Klinik für Psychiatrie, Psychotherapie, Psychosomatik und Suchtmedizin, Henricistraße 92, Essen, 45136, GermanyTel +4920117430005 Email T.Aubel@kem-med.com\n14 7 2021\n2021\n17 23272332\n14 4 2021\n08 7 2021\n© 2021 Aubel.\n2021\nAubel.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nSchizophrenia is a chronic relapsing and remitting disorder associated with significant impairments in social and vocational functioning and a shortened lifespan, and it is a disabling psychiatric brain syndrome whose phenotype is characterized by three core symptom domains: positive symptoms, such as delusions and hallucinations, negative symptoms, which include lack of motivation and social withdrawal, and cognitive impairment. Moreover, patients with schizophrenia have severe problems with personal and social relations which affect their quality of life. Antipsychotic medications in conjunction with psychosocial interventions can help patients achieve recovery. Here are described three clinical cases of schizophrenic patients treated with cariprazine for inadequate response to a previous treatment. The purpose of this clinical series is to give useful information for the use of cariprazine in clinical practice.\n\nKeywords\n\ncariprazine\nschizophrenia\nparanoid schizophrenia\nnegative symptoms\nresistant schizophrenia\nantipsychotics\n==== Body\nIntroduction\n\nSchizophrenia is a severe, chronic mental condition that requires long-term treatment.1 It is a heterogeneous mental disorder, with no single pathognomonic symptom or presentation, characterized by a constellation of signs and symptoms that are divided into three core symptom domains: positive, negative, and cognitive. Pharmacologic therapy is a central part of schizophrenia management and antipsychotics are the first-line medication for this psychiatric disorder.\n\nCariprazine is a new D3/D2 partial agonist antipsychotic with preferential binding to D3 receptors2,3 (Table 1) and its efficacy in the treatment of schizophrenia has been demonstrated by several trials.4–11 Due to its specific profile, cariprazine is expected to predominately control negative symptoms, but its long-term efficacy in the prevention of disease relapse has been demonstrated as well.8 Common side effects include motor symptoms, restlessness and GI symptoms, albeit it is generally considered to be well tolerated. As of today, the number of novel treatments targeting schizophrenia is increasing.12 Cariprazine has the potential to be of additional value, thanks to its unique receptor profile and its good tolerability. Its beneficial effects have recently also been reported outside of schizophrenia.13Table 1 Binding Affinities of Cariprazine and the Clinical Properties of the Receptors. Cariprazine Shows High Affinity for D3, D2 and 5-HT1A Receptors, Moderate Affinity for 5-HT2A and H1 Receptors and Low Affinity for 5-HT2C and α1A Receptors\n\nReceptor\tAction2,21\tAffinity22\tKi Value (nM)23\tPharmacodynamic Effects24\t\nD3\tPartial agonist\tHigh (<10 nM)\t0.085\tAntipsychotic (including negative symptoms)\t\nD2L\tPartial agonist\tHigh (<10 nM)\t0.49\tAntipsychotic\t\nD2S\tPartial agonist\tHigh (<10 nM)\t0.69\tAntipsychotic\t\n5-HT1A\tPartial agonist\tHigh (<10 nM)\t3.0\tAntidepressant\t\n5-HT2A\tAntagonist\tModerate (10–100 nM)\t19.0\tAnti-EPS\t\nH1\tAntagonist\tModerate (10–100 nM)\t23.0\tAnxiolytic, anti-insomnia\t\n5-HT2C\tAntagonist\tLow (>100 nM)\t134\tAntidepressant\t\nα1A\tAntagonist\tLow (>100 nM)\t155\tAntihypertensive\t\n\nThe efficacy of Cariprazine in treatment-refractory schizophrenia remains to be systematically investigated. Here we report three clinical cases of schizophrenia patients who responded to cariprazine after inadequate responses to previous treatments. The first two cases fulfill the expert consensus of treatment-refractory schizophrenia, defined as failure to two attempts of adequate antipsychotic medical treatment, whereas the third case describes a patient at high risk of a treatment-refractory course of disease.14\n\nCase 1: Cariprazine Replaces Electroconvulsive Therapy (ECT) for the Treatment of Negative Symptoms of Paranoid Schizophrenia\n\nThis case report describes a successful switch to cariprazine in a patient with paranoid schizophrenia (ICD10), after multiple medication changes and electroconvulsive therapy failed to adequately control positive, as well as negative symptoms.\n\nThe patient is a 59-year-old lady, early retired, married with no children. Eldest of three children, at the age of 16 the patient was affected by her parent’s separation and the subsequent suicide of her father. In age 30, she was first diagnosed with paranoid schizophrenia whose chief complaint at that time was avolition. Between 1990 and 2002, the patient had three severe episodes of disease exacerbation each one requiring inpatient treatment for several months. Leading complaints were pronounced negative symptoms with severe psychomotor retardation and delusional thoughts, like the feeling of being observed by the neighbors. She received various drug treatments and suffered sometimes severe somatic complications, such as pulmonary embolism after deep vein thrombosis. Neither the combination therapy of flupentixol 10 mg, mirtazapine 45 mg, and lorazepam 1.5 mg for 4 weeks nor olanzapine 20 mg, aripiprazole 15 mg, haloperidol 10 mg, mirtazapine 45 mg, and lorazepam 6mg for 6 weeks were able to effectuate significant improvements in her negative and delusional symptoms. After her psychomotor drive deteriorated further and the patient became progressively bedridden, ECT was performed. After 5 courses of ECT there was no adequate treatment response and the patient, who was now fully bedridden, suffered subsequently from deep vein thrombosis, pulmonary artery embolism and infarct pneumonia. After a drug pause and intravenous treatment with lorazepam 3×2 mg daily, there was a switch to risperidone, starting at 2×0.5 mg and later increased to 2×1 mg daily, which did not result in any significant improvement either. Psychomotor drive remained massively reduced with continued bedriddenness.\n\nCariprazine was initiated with a starting dose of 1.5 mg daily, increased to 3 mg daily after three days and to 4.5 mg daily after two weeks while risperidone was tapered to 2×0.5 mg daily and eventually discontinued. The patient tolerated the medication well and her symptoms improved significantly. After 4.5 months of treatment, the patient did not experience any more delusions and psychomotor drive. Negative symptoms were significantly improved, and the patient was discharged.\n\nFour weeks after discharge, the patient, now on cariprazine 4.5 mg daily and rivaroxaban 20 mg daily for prevention of deep vein thrombosis, was mentally stable and took care of her household independently.\n\nCase 2: Cariprazine for Paranoid Schizophrenia with Pronounced Negative Symptoms\n\nThis case report presents the successful medication switch from olanzapine/clozapine to cariprazine in a 31-year-old patient suffering from severe paranoid schizophrenia.\n\nThe 31-year-old patient was initially diagnosed with paranoid-hallucinatory schizophrenia (ICD10) in 2010. At that time, he experienced predominantly severe negative symptoms and psychomotor retardation. The patient lived by himself and failed repeatedly to complete his studies due to the disease. His social contacts were limited to his mother and his two older siblings; there was no family history of mental illness. His past psychiatric history included five severe episodes, each lasting for several months, characterized by acute psychotic symptoms, severe drive disorders, flattening of the formal thought disorders, and leading to several inpatient stays.\n\nThe patient was first prescribed olanzapine 10-0-10 mg in 2010. After an attempt to reduce the dose to 2.5 mg daily in 2013, he experienced a relapse which required weeks of inpatient treatment and a subsequent dose increase to 20 mg/daily. After olanzapine discontinuation on his own account, we attempted to switch to clozapine 50-50-100 mg per day. In 2015, he was admitted with an acute psychotic symptom exacerbation after he discontinued his medication again. He was then administered clozapine under the supervision of the hospital nursing staff. In 2018, the patient stopped taking clozapine again and was admitted to the hospital. Clozapine was started once again, but eventually combined with amisulpride up to 300 mg/daily amid a massive decompensation and gradually persistent negative symptoms. Symptoms did not improve and his drive remained reduced.\n\nIn 2019, we initiated a treatment attempt with cariprazine in addition to the existing combination therapy of clozapine and amisulpride. Initial starting dose of cariprazine was 1.5 mg daily, which was increased to 3 mg daily after three days. We could subsequently taper off and discontinue amisulpride, whilst continuously administering clozapine 100 mg daily. After 2 months of remission of psychotic symptoms we can reduce clozapine to 75 mg. As the patient reported a significant improvement in psychomotor drive and mood, we increased cariprazine dosage to 4.5 mg daily and further reduced clozapine to 50 mg daily. Our aim was mono therapy. In September 2019, the patient was in complete remission and clozapine could be discontinued and he eventually registered for the final study exam.\n\nCase 3: Acute Treatment and Desired Switch to Cariprazine\n\nThis case report describes the use of cariprazine in a patient with acute psychotic decompensation. Cariprazine was initiated upon the patient’s own request. A rapid updosing scheme was used, as the patient wanted to be discharged from the hospital quickly.\n\nThis was a 32-year-old male patient from Sudan. He has been living in Germany for two years, he lived alone and worked as a doctor in a neurological rehabilitation clinic. He had previously worked as a resident in a psychiatric clinic for 6 months but had quit due to working conditions. The patient reported having had psychotic episodes as early as 17 during military service. However, these had not been further evaluated and he himself had attributed them to an underlying iron deficiency anemia.\n\nThe patient was diagnosed with paranoid schizophrenia (ICD10) in 2018. Since the first psychotic symptoms had occurred at 17 years of age, an even longer duration of illness can be assumed. He suffered other psychotic episodes in 2018 and 2019, in September 2018 after consumption of cannabis on the previous day. He experienced recurrent paranoid episodes with ideas of reference and persecutory delusions, and he was also increasingly suspicious. There were no formal thought disorders. His main concern, however, was his increasingly impaired concentration, which made working very difficult for him. Head MRI from August 2018 reported mild cortical atrophy as well as microangiopathic lesions and a small uncharacteristic lesion on the right temporomesial side without signs of space occupation.\n\nMost recently, the patient presented to our emergency room with paranoid ideas that had been present for three days. At time of admission, he was alert, oriented to person, place and time, friendly. He was in a euthymic mood with intermittent suicidal thoughts but no suicide attempt. Moreover, he was able to agree to therapy.\n\nPatient was admitted to the open inpatient ward for a psychotic disorder and took part in a multimodal therapy concept with individual and group psychological therapies. Pharmacological therapy consisted in risperidone 1 mg twice a day increased to 2 mg twice a day during treatment. Therapy was switched to aripiprazole 10 mg with simultaneous reduction to 0.5 mg risperidone on patient’s request. After discussing treatment options with this medically knowledgeable patient, cariprazine was initiated at 1.5 mg/day (day 1), while aripiprazole 10 mg and risperidone 0.5 mg were discontinued, and gradually increased to 3 mg (day 2) and 4.5 mg (day 3). Cariprazine was very well tolerated with complete resolution of psychotic symptoms and improvement in cognitive performance, concentration, and alertness. No recurrence of akathisia developed while on aripiprazole nor other forms of agitation were reported. The patient remained on 4.5 mg cariprazine and he was able to resume work in the clinic as a resident with no complaint of any impairment of his performance and psychotic symptoms no longer occurred.\n\nDiscussion\n\nSchizophrenia is a chronic and disabling disorder, characterized by heterogeneous positive and negative symptom constellations.15 While positive symptoms reflect an excess or distortion of normal function (eg, delusions, hallucinations, disorganized behavior), negative symptoms refer to a diminution or absence of normal behaviors related to motivation and interest (eg, avolition, anhedonia, asociality) or expression (eg, blunted affect, alogia).16\n\nSchizophrenia requires lifelong treatment, even when symptoms have subsided. Treatment with medications and psychosocial therapy can help manage the condition and, in some cases, hospitalization may be needed.\n\nCariprazine is a new atypical antipsychotic approved by the European Medicines Agency for the management of schizophrenia.17 Cariprazine acts as a D2 and D3 receptor partial agonist with a higher affinity for the D3 receptor, which differs from current antipsychotics.18 In addition to potent partial agonist activity at D3 and D2 receptors, cariprazine also acts as an antagonist at the serotonin 5-HT2B receptors, a partial agonist at 5-HT1A receptors, and shows lower or negligible affinity at other receptors, including noradrenergic, histaminergic, and cholinergic receptors.11\n\nClinical results to date from several schizophrenia trials clearly demonstrated that cariprazine is effective and well tolerated. Cariprazine was significantly more effective than placebo for the treatment of acute schizophrenia in all symptom domains.4–7 Moreover, a clinical trial supported the efficacy of cariprazine in the treatment of predominant negative symptoms. Patients given cariprazine had a greater improvement in negative symptoms of schizophrenia than did patients given risperidone. Patients receiving cariprazine also had a greater improvement in functioning, suggesting that improvement in negative symptoms translated to improved community functioning for these patients.9 Furthermore, open-label extension studies support the long-term safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia10,11 reinforcing the findings observed in the double-blind studies. In addition, in the relapse prevention study8 long-term cariprazine treatment was significantly more effective than placebo for relapse prevention in patients with schizophrenia.\n\nIn our experience, a targeted medical approach with cariprazine, combined with behavioral interventions, is a promising treatment option even after multiple previous medical treatments have failed. In the first case, the therapeutic breakthrough was achieved with the switch to cariprazine. After increasing the cariprazine dosage to 4.5 mg/day, the patient showed a significant improvement in her symptoms within a few weeks. Eventually psychomotor drive and negative symptoms further improved. Cariprazine was well tolerated and risperidone was discontinued. After 4.5 months of treatment, the patient was free of delusional symptoms and was able to be discharged. In the second patient cariprazine finally brought the hoped-for treatment success. Cariprazine was administered at starting dose of 1.5 mg in combination with clozapine and after three days increased to 3 mg and then to 4.5 mg. After the patient’s symptoms improved, the combined treatment with cariprazine and clozapine was continued as an outpatient. Within only 2 months, the symptoms improved significantly, and clozapine could be reduced and then discontinued. The last case describes long-standing, severe paranoid-hallucinatory schizophrenia with pronounced negative symptoms where a switch to cariprazine led to a treatment success in combination with psychological therapies. Cariprazine was initiated, upon patient’s own request, at 1.5 mg/day, increased to 3 mg on day 2 and to 4.5 mg on day 3. The treatment was excellently tolerated, and the symptoms subsided quickly. Patient remained on cariprazine 4.5 mg and was able to resume work in the clinic as a resident and to achieve and maintain a satisfactory lifestyle.\n\nConclusion\n\nCariprazine is a new antipsychotic effective in the treatment of schizophrenia and thanks to its peculiar receptor profile with a D2/D3 partial agonist and high D3 affinity it is effective on the entire spectrum of symptoms of schizophrenia.19,20 The cases described highlight several problems of real-life schizophrenia management and show the beneficial effect of cariprazine in patients with an inadequate response to a previous medication. A tailored approach can be a therapeutic breakthrough for the treatment of patients with schizophrenia.\n\nConsent for Publication\n\nKliniken Essen-Mitte, Klinik für Psychiatrie, Psychotherapie, Psychosomatik und Suchtmedizin ethics committee approved the clinical cases publication and Informed consent was obtained from the patients.\n\nDisclosure\n\nDr. Thomas Aubel has received honoraria for scientific talks and participation in advisory boards from Janssen-Cilag, Lundbeck, Otsuka Pharma, Servier, Lilly and Recordati Pharma. Recordati provided financial support for the writing of the manuscript.\n==== Refs\nReferences\n\n1. Mueser KT, McGurk SR. Schizophrenia. Lancet. 2004;363 (9426 ):2063–2072. doi:10.1016/S0140-6736(04)16458-1 15207959\n2. Kiss B, Horváth A, Némethy Z, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010;333 (1 ):328–340. doi:10.1124/jpet.109.160432 20093397\n3. Girgis RR, Slifstein M, D’Souza D, et al. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO. Psychopharmacology (Berl). 2016;233 (19–20 ):3503–3512. doi:10.1007/s00213-016-4382-y 27525990\n4. Durgam S, Litman RE, Papadakis K, et al. Cariprazine in the treatment of schizophrenia: a proof-of-concept trial. Int Clin Psychopharmacol. 2016;31 (2 ):61–68. doi:10.1097/YIC.0000000000000110 26655732\n5. Durgam S, Starace A, Li D, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a Phase II, randomized clinical trial. Schizophr Res. 2014;152 (2–3 ):450–457. doi:10.1016/j.schres.2013.11.041 24412468\n6. Durgam S, Cutler AJ, Lu K, et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, Phase 3, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry. 2015;76 (12 ):e1574–82. doi:10.4088/JCP.15m09997 26717533\n7. Kane JM, Zukin S, Wang Y, et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an international, phase III clinical trial. J Clin Psychopharmacol. 2015;35 (4 ):367–373. doi:10.1097/JCP.0000000000000346 26075487\n8. Durgam S, Earley W, Li R, et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. Schizophr Res. 2016;176 (2–3 ):264–271. doi:10.1016/j.schres.2016.06.030 27427558\n9. Németh G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017;389 (10074 ):1103–1113. doi:10.1016/S0140-6736(17)30060-0 28185672\n10. Durgam S, Greenberg WM, Li D, et al. Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: results from a 48-week, single-arm, Open-Label Extension Study. Psychopharmacology (Berl). 2017;234 (2 ):199–209. doi:10.1007/s00213-016-4450-3 27807604\n11. Cutler AJ, Durgam S, Wang Y, et al. Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-Year Open-Label Study. CNS Spectr. 2018;23 (1 ):39–50. doi:10.1017/S1092852917000220 28478771\n12. Orsolini L, De Berardis D, Volpe U. Up-to-date expert opinion on the safety of recently developed antipsychotics. Expert Opin Drug Saf. 2020;19 (8 ):981–998. Epub 2020 Jul 21. PMID: 32657173. doi:10.1080/14740338.2020.1795126 32657173\n13. De Berardis D, Vellante F, Fornaro M, et al. Rapid improvement of obsessive-compulsive disorder associated with schizophrenia with cariprazine add-on in a subject under paliperidone long-acting injection: a case report. Int Clin Psychopharmacol. 2020;35 (2 ):113–118. PMID: 32004167. doi:10.1097/YIC.0000000000000284 32004167\n14. Potkin SG, Kane JM, Correll CU, et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr. 2020;6 (1 ). doi:10.1038/s41537-019-0090-z\n15. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 2015;1 (1 ):15067. doi:10.1038/nrdp.2015.67 27189524\n16. Correll CU, Schooler NR. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat. 2020;16 :519–534. doi:10.2147/NDT.S225643 32110026\n17. European Medicines Agency Reagila Assessment Report. 2017. Available from: https://www.ema.europa.eu/en/documents/assessment-report/reagila-epar-public-assessment-report_en.pdf. Accessed 79, 2021.\n18. Stahl SM. Mechanism of action of cariprazine. CNS Spectr. 2016;21 (2 ):123–127. doi:10.1017/S1092852916000043 26956157\n19. Chhatlani A, Farheen SA, Setty MJ, et al. Use of cariprazine in psychiatric disorders: a systematic review. Ann Clin Psychiatry. 2018;30 (4 ):326–334.30372510\n20. Citrome L. Cariprazine for the treatment of schizophrenia: a review of this dopamine D3-preferring D3/D2 receptor partial agonist. Clin Schizophr Relat Psychoses. 2016;10 (2 ):109–119. doi:10.3371/1935-1232-10.2.109 27440212\n21. Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. 1996.\n22. De Deurwaerdère P. Cariprazine: Newdopamine biased agonist for neuropsychiatric disorders. Drugs Today (Barc). 2016;52 (2 ):97–110. doi:10.1358/dot.2016.52.2.2461868 27092339\n23. Ki values have been taken from the PDSD Ki database. Available from: https://pdsp.unc.edu/databases/pdsp.php. Accessed 79, 2021.\n24. Frankel JS, Schwartz TL. Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole. Ther Adv Psychopharmacol. 2017;7 (1 ):29–41. doi:10.1177/2045125316672136 28101322\n\n",
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"issn_linking": "1176-6328",
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"journal": "Neuropsychiatric disease and treatment",
"keywords": "antipsychotics; cariprazine; negative symptoms; paranoid schizophrenia; resistant schizophrenia; schizophrenia",
"medline_ta": "Neuropsychiatr Dis Treat",
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"nlm_unique_id": "101240304",
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"pages": "2327-2332",
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"pmid": "34285492",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32110026;15207959;26655732;27092339;20093397;26956157;26075487;27427558;27440212;30372510;27189524;28101322;31911624;32657173;27807604;26717533;28478771;28185672;27525990;32004167;24412468",
"title": "Cariprazine: Patients with Treatment-Resistant Schizophrenia.",
"title_normalized": "cariprazine patients with treatment resistant schizophrenia"
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"abstract": "BACKGROUND\nAbatacept (ABA) is a fusion receptor protein containing the CTLA-4 domain that prevents the activation of naïve T cells by binding the CD80 and CD86 molecules expressed on the surface of dendritic cells, indicated for the treatment of moderate to severe rheumatoid arthritis (RA). There is still little evidence concerning the safety of ABA in RA patients with positive serology for hepatitis virus B (HBV) infection.\n\n\nMETHODS\nWe report the case of a HBV infection reactivation in an ABA-treated male RA patient. The patient (caucasian race, 66-year-old) was diagnosed with RA in Novembre 2010 and in December 2010 he started a treatment with prednisone plus subcutaneous methotrexate. In October 2011, an anti-TNF agent (golimumab) was added but soon discontinued due to an adverse event. At baseline, screening for HBV markers showed a positivity for HBcAb and HBeAb IgG, being HBsAg, HBsAb, HBcAb IgM, HBeAg and HBV DNA negative. Serum amino-transferase (AST and ALT) levels were within the normal range. In January 2012 he was swapped to intravenous treatment with ABA 750 mg/month, that allowed the achievement of a good clinical response and the permanent discontinuation of corticosteroids. In November 2013, laboratory reports showed that he was positive for HBcAb but negative for the remaining HBV markers, and had a slightly increased AST level and, in December 2013, he became HBV DNA positive (326 IU/mL). In January 2014, his HBV DNA levels had further increased and ABA was stopped while maintaining MTX. He started lamivudine 100 mg/day in January 2014. After 1 month of lamivudine, his HBV DNA levels became undetectable (<10 IU/mL) and liver function was normal although RA had been reactivated (DAS28 5.53). Treatment with ABA was therefore resumed with the achievement of a good response after 6 months. The patient is currently being treated with lamivudine 100 mg/day, i.v. ABA 750 mg/month, and MTX 15 mg/week, with a good response (DAS28 2.27 in October 2015), and constantly monitored without any further evidence of HBV infection reactivation.\n\n\nCONCLUSIONS\nAlthough there are still few reports in literature, we suggest caution in HBV- occult carriers RA patients undergoing a treatment with abatacept.",
"affiliations": "Rheumatology Unit, University Hospital \"Luigi Sacco\", Via GB Grassi 74, 20157, Milan, Italy. talotta1@virgilio.it.;Rheumatology Unit, University Hospital \"Luigi Sacco\", Via GB Grassi 74, 20157, Milan, Italy.;Rheumatology Unit, University Hospital \"Luigi Sacco\", Via GB Grassi 74, 20157, Milan, Italy.",
"authors": "Talotta|Rossella|R|;Atzeni|Fabiola|F|;Sarzi Puttini|Piercarlo|P|",
"chemical_list": "D018501:Antirheumatic Agents; D000998:Antiviral Agents; D015415:Biomarkers; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D019259:Lamivudine; D000069594:Abatacept; D008727:Methotrexate",
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"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 6010.1186/s40360-016-0060-2Case ReportReactivation of occult hepatitis B virus infection under treatment with abatacept: a case report Talotta Rossella +390239043351talotta1@virgilio.it Atzeni Fabiola +390239043351atzeni.fabiola@hsacco.it Sarzi Puttini Piercarlo +390239043351sarzi.piercarlo@hsacco.it Rheumatology Unit, University Hospital “Luigi Sacco”, Via GB Grassi 74, 20157 Milan, Italy 21 4 2016 21 4 2016 2016 17 1723 12 2015 23 3 2016 © Talotta et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAbatacept (ABA) is a fusion receptor protein containing the CTLA-4 domain that prevents the activation of naïve T cells by binding the CD80 and CD86 molecules expressed on the surface of dendritic cells, indicated for the treatment of moderate to severe rheumatoid arthritis (RA). There is still little evidence concerning the safety of ABA in RA patients with positive serology for hepatitis virus B (HBV) infection.\n\nCase Presentation\nWe report the case of a HBV infection reactivation in an ABA-treated male RA patient. The patient (caucasian race, 66-year-old) was diagnosed with RA in Novembre 2010 and in December 2010 he started a treatment with prednisone plus subcutaneous methotrexate. In October 2011, an anti-TNF agent (golimumab) was added but soon discontinued due to an adverse event. At baseline, screening for HBV markers showed a positivity for HBcAb and HBeAb IgG, being HBsAg, HBsAb, HBcAb IgM, HBeAg and HBV DNA negative. Serum amino-transferase (AST and ALT) levels were within the normal range. In January 2012 he was swapped to intravenous treatment with ABA 750 mg/month, that allowed the achievement of a good clinical response and the permanent discontinuation of corticosteroids. In November 2013, laboratory reports showed that he was positive for HBcAb but negative for the remaining HBV markers, and had a slightly increased AST level and, in December 2013, he became HBV DNA positive (326 IU/mL). In January 2014, his HBV DNA levels had further increased and ABA was stopped while maintaining MTX. He started lamivudine 100 mg/day in January 2014. After 1 month of lamivudine, his HBV DNA levels became undetectable (<10 IU/mL) and liver function was normal although RA had been reactivated (DAS28 5.53). Treatment with ABA was therefore resumed with the achievement of a good response after 6 months. The patient is currently being treated with lamivudine 100 mg/day, i.v. ABA 750 mg/month, and MTX 15 mg/week, with a good response (DAS28 2.27 in October 2015), and constantly monitored without any further evidence of HBV infection reactivation.\n\nConclusions\nAlthough there are still few reports in literature, we suggest caution in HBV- occult carriers RA patients undergoing a treatment with abatacept.\n\nKeywords\nAbataceptHepatitis BReactivationRheumatoid arthritisissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThe treatment of rheumatoid arthritis (RA) includes many biologic drugs blocking different steps of the inflammatory cascade. Abatacept (ABA) is a fusion receptor protein containing the CTLA-4 domain that prevents the activation of naïve T-cells by binding CD80 and CD86 expressed on the surface of dendritic cells [1]. Abatacept, with or without methotrexate (MTX), is approved for treating moderate to severe RA in patients refractory to previous disease modifying anti-rheumatic drugs (DMARDs) and anti- TNF drugs.\n\nEvidences show the safety of ABA in RA patients with positive serology for hepatitis virus (HBV) infection [2], and there are few reports of HBV reactivation. We observed a case of HBV infection reactivation in a Caucasian male patient affected by RA treated with ABA.\n\nCase presentation\nThe patient, 66 years old, was diagnosed with RA in November 2010 according to the new European League Against Rheumatisms (EULAR)/American College of Rheumatology (ACR) 2010 criteria [3]. At baseline clinical examination showed 23 swollen joints and 26 tender joints, increased values of Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP) and of Rheumatoid Factor (RF) (15 mg/L) and anti-citrullinated peptides antibodies (ACPA). Complete blood count, serum amino-transferases and creatinine were within the range of normality. X-rays of both hands and feet showed juxta articular osteoporosis but no bone erosions.\n\nIn December 2010 he started a treatment with prednisone 5 mg/day plus subcutaneous MTX 10 mg/week, which was increased up to 15 mg/week in February 2011. Due to persistent disease activity (DAS28 = 4.16), in October 2011 the patient was considered candidate to a biologic agent according to the Italian guidelines and therefore a screening for opportunistic infections was required [4]. Tuberculosis screening assessed by interferon-gamma release assay (IGRA) proved negative. Thorax X-rays showed no pleural or pulmonary lesion. Hepatitis screening showed a positivity for HBcAb IgG and HBeAb IgG, while HBsAg, HBsAb, HBcAb IgM, HBeAg and HCV-Ab were negative. HBV DNA was negative (<20 IU/mL), AST and ALT value were within the normal range (20 and 27 IU/L respectively). In November 2011 a therapy with golimumab 50 mg every month was started, but it was permanently discontinued after three weeks due to adverse effects (cough and tachycardia). In January 2012 the patient was swapped to a treatment with abatacept (ABA) e.v. 750 mg monthly. At baseline DAS28 was 4.85; CRP value was 19 mg/L (normal values < 1 mg/L), ESR 21 mm (normal values < 27 mm), AST 18 IU/L (normal values < 40 IU/L) and ALT 30 IU/L (normal values < 40 IU/L).\n\nHBV DNA, AST and ALT were evaluated every three months, and remained within the normal range. The response to ABA therapy was good with DAS28 achieving the score of 2.31 after 3 months. The patient maintained a clinical remission at the follow-up visits despite the tapering and the definitive discontinuation of corticosteroids.\n\nHowever, in November 2013 laboratory reports showed a positivity in HBcAb with a negativity in the remaining HBV serologic markers (HBsAg, HBcAb, HBeAg, HBeAb, HCV-Ab) and a mild increase in the value of AST (41 IU/L). Furthermore, in December 2013 HBV DNA turned positive with a level of 326 IU/mL (normal range <20 IU/mL). In January 2014, a subsequent control of HBV-DNA revealed a further increase up to 1416 IU/mL. ABA was then stopped maintaining MTX, and the patient referred to a hepatologist. A liver examination by means of abdominal ultrasound was done, resulting into normal findings. However, since January 2014 a treatment with lamivudine 100 mg/day was started.\n\nAfter 1 month of lamivudine, HBV DNA became undetectable (<10 IU/mL) and liver functionality was normal (AST 29 IU/L, ALT 38 IU/L); on the contrary CRP values were greatly increased (42.4 mg/L) and RA reactivated (DAS28 = 5.53); therefore the treatment with ABA was reintroduced. The patient experimented a rapid benefit on the rheumatic symptoms reaching a good EULAR response after 3 months. In April 2014 liver functionality was good (AST 29 IU/L, ALT 31 IU/L), HBV-DNA was <10 IU/mL and an assessment through Fibroscan showed an index of stiffness of 3.9 kPA.\n\nThe patient is currently treated with lamivudine 100 mg/day, i.v. abatacept 750 mg every month and MTX 15 mg/week with a good response (DAS28 = 2.27 in October 2015). Figure 1 illustrates the time-course of DAS28, AST, ALT and HBV DNA levels.Fig. 1 Time-course of DAS28, AST, ALT and HBV DNA levels. DAS28: Disease Activity Score (28 Joints); AST: ASpartate aminotransferase; ALT: ALanine aminotransferase; HBV DNA: Hepatitis B Virus DNA\n\n\n\nConclusions\nThe association between ABA and HBV infection is still unclear. Germanidis et al. [5] reported the case of a elderly RA woman who developed an active HBV hepatitis after 1 year of treatment with ABA. The patient was concomitantly treated with prednisone 10 mg/day and leflunomide 20 mg/day, perhaps favouring the viral reactivation. Our patient did not need concomitant treatment with prednisone because the RA disease activity was persistently low under ABA treatment (DAS28 < 2.6).\n\nOther authors reported a case of HBV reactivation in an occult carrier receiving ABA as first biologic line for RA [6]. In this case a treatment with tenofovir 300 mg/day was started and ABA was permanently discontinued. A recent “real life” Italian study was carried on 72 RA patients with concomitant HBV infection, treated with ABA plus steroids and conventional Disease Modifying Anti-Rheumatic Drugs (DMARDs). Among them, 21 were occult carriers who received prophylaxis with lamivudine only in 9 cases. No viral reactivation was detected in a 24 months follow-up period, underlining a safe profile of ABA during HBV infection, also without applying antiviral prophylaxis [7]. However, in our experience, a treatment with a biologic agent inducing a peripheral tolerance could favour the progression of HBV infection in an occult carrier. The concomitant use of corticosteroids may represent an aggravating factor, whereas the use of methotrexate may be helpful in preventing the immune-mediated damage to HBV-infected hepatocytes [8]. Therefore, HBV DNA and serum levels of AST and ALT should be periodically monitored in occult carriers. In case of HBV reactivation patients can be successfully treated with antiviral agents while continuing the treatment with ABA [9]. In conclusion, reports remain still isolated in literature and, according to our experience, this is the first case of HBV reactivation under ABA in our cohort of RA patients (n.9) affected by occult HBV infection.\n\nConsent\nWritten informed consent for publication of the clinical details was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nAbbreviations\nABAabatacept\n\nACPAanti-citrullinated peptides antibodies\n\nACRAmerican College of Rheumatology\n\nCRPC-reactive protein\n\nDAS28disease activity score (28 Joint)\n\nDMARDsdisease modifying anti-rheumatic drugs\n\nESRerythrocyte sedimentation rate\n\nEULAREuropean League Against Rheumatisms\n\nHBVhepatitis B virus\n\nIGRAinterferon-gamma release assay\n\nMTXmethotrexate\n\nRArheumatoid arthritis\n\nRFrheumatoid factor\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contribution\n\nRT conceived the study and drafted the manuscript. AF participated in the design of the study and drafted the manuscript. PCSP participated in the design and coordination of the study. All authors read and approved the final manuscript.\n\nWe acknowledge all the physicians at Rheumatology Unit of the University Hospital \"Luigi Sacco\" who allowed us to have access to the patient's source documents.\n==== Refs\nReferences\n1. Vital EM Emery P Abatacept in the treatment of rheumatoid arthritis Ther Clin Risk Manag 2006 2 4 365 75 10.2147/tcrm.2006.2.4.365 18360649 \n2. Padovan M, Lanciano E, Epis O, Mathieu A, Erba G, Ciani L, et al. Safety of Abatacept in rheumatoid arthritis with chronic hepatitis B virus infection. Abstract 356 ACR 2013.\n3. Smolen JS Landewé R Breedveld FC Dougados M Emery P Gaujoux-Viala C EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs Ann Rheum Dis 2010 69 6 964 75 10.1136/ard.2009.126532 20444750 \n4. Caporali R Conti F Alivernini S Atzeni F Seriolo B Cutolo M Italian Society for Rheumatology. Recommendations for the use of biologic therapy in rheumatoid arthritis: update from the Italian Society for Rheumatology I. Efficacy Clin Exp Rheumatol 2011 29 3 Suppl 66 S7 14 21906423 \n5. Germanidis G Hytiroglou P Zakalka M Settas L Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept J Hepatol 2012 56 6 1420 1 10.1016/j.jhep.2011.10.011 22127282 \n6. Fanouriakis A Vassilopoulos D Repa A Boumpas DT Sidiropoulos P Hepatitis B reactivation following treatment with abatacept in a patient with past hepatitis B virus infection Rheumatology (Oxford) 2014 53 1 195 6 10.1093/rheumatology/ket221 23771951 \n7. Padovan M, Filippini M, Tincani A, Lanciano E, Bruschi E, Epis O et al. Safety of abatacept in rheumatoid arthritis with serological evidence of past or present hepatitis B virus infection. Arthritis Care Res (Hoboken). 2015 Nov.\n8. López-Serrano P de la Fuente BE Alonso EC Pérez-Calle JL Rodríguez CF Hepatitis B and immunosuppressive therapies for chronic inflammatory diseases: When and how to apply prophylaxis, with a special focus on corticosteroid therapy World J Hepatol 2015 7 3 539 47 10.4254/wjh.v7.i3.539 25848477 \n9. Kim PS Ho GY Prete PE Furst DE Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B Arthritis Care Res (Hoboken) 2012 64 8 1265 8 22392695\n\n",
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"keywords": "Abatacept; Hepatitis B; Reactivation; Rheumatoid arthritis",
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"mesh_terms": "D000069594:Abatacept; D000368:Aged; D018501:Antirheumatic Agents; D000998:Antiviral Agents; D001172:Arthritis, Rheumatoid; D058345:Asymptomatic Infections; D015415:Biomarkers; D004279:DNA, Viral; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D006510:Hepatitis B Antibodies; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D007262:Infusions, Intravenous; D019259:Lamivudine; D008297:Male; D008727:Methotrexate; D016896:Treatment Outcome; D014775:Virus Activation",
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"abstract": "We observed a case over 25 years of relapsing-remitting schizophrenic spectrum disorder, varying regarding the main symptomatology between more depressive or more schizoaffective or rather typical schizophrenic syndrome. Diseased phases were repeatedly accompanied by minor skin lesions, which were initially classified as mixed tissue disorder. Psychotic phases were waxing-waning over years. During one later relapse, skin involvement was severe, classified to likely represent an allergic reaction to psychopharmaca; this generalized exanthema remitted rapidly with cortisone treatment and azathioprine. Under continued azathioprine and low dose neuroleptics, the patient remitted completely, appearing psychiatrically healthy for 16 years. When azathioprine was set off due to pregnancy, an extraordinary severe relapse of schizophrenia like psychosis accompanied by most severe skin lesions developed within a few weeks, then requiring 2 years of psychiatric inpatient treatment. Finally, a diagnosis of systemic lupus erythematodes plus neuropsychiatric lupus was made. A single CSF sample in 2013 showed suspicious biomarkers, matching with CSF cytokine profiling in schizophrenic and affective spectrum disorder patients and indicated mild neuroinflammation. Complex immune suppressive treatment was reinitiated short after relapse, but was only partially successful. However, surprisingly the psychosis and skin lesions remitted (in parallel) when belimumab was given (add-on). The very details of this complicated, long-term disease course are discussed also with regard to general ideas, in particular with respect to the question if this case of seemingly comorbid schizophrenia with minor autoimmunity signs represented a case of one emerging autoimmune disorder with variant manifestations systemically and within the CNS, though atypically with predominant appearance as a schizophrenia spectrum disorder.",
"affiliations": "Department of Psychiatry and Psychotherapy II, University Ulm/Bezirkskrankenhaus Guenzburg, Guenzburg, Germany.;Department of Dermatology and Allergology, University Hospital Ulm, Ulm, Germany.;Sektion Experimentelle Anaesthesiologie, University Hospital Ulm, Ulm, Germany.;Department of Psychiatry and Psychotherapy II, University Ulm/Bezirkskrankenhaus Guenzburg, Guenzburg, Germany.",
"authors": "Mack|Axel|A|;Pfeiffer|Christiane|C|;Schneider|E Marion|EM|;Bechter|Karl|K|",
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"doi": "10.3389/fpsyt.2017.00131",
"fulltext": "\n==== Front\nFront PsychiatryFront PsychiatryFront. PsychiatryFrontiers in Psychiatry1664-0640Frontiers Media S.A. 10.3389/fpsyt.2017.00131PsychiatryCase ReportSchizophrenia or Atypical Lupus Erythematosus with Predominant Psychiatric Manifestations over 25 Years: Case Analysis and Review Mack Axel 1*Pfeiffer Christiane 2Schneider E. Marion 3Bechter Karl 1*1Department of Psychiatry and Psychotherapy II, University Ulm/Bezirkskrankenhaus Guenzburg, Guenzburg, Germany2Department of Dermatology and Allergology, University Hospital Ulm, Ulm, Germany3Sektion Experimentelle Anaesthesiologie, University Hospital Ulm, Ulm, GermanyEdited by: Gretchen Hermes, Yale University, United States\n\nReviewed by: Bernhard J. Mitterauer, Volitronics-Institute for Basic Research Psychopathology and Brain Philosophy, Austria; Armando D’Agostino, Università degli Studi di Milano, Italy\n\n*Correspondence: Axel Mack, mack.axel@gmx.de; Karl Bechter, karl.bechter@bkh-guenzburg.deSpecialty section: This article was submitted to Schizophrenia, a section of the journal Frontiers in Psychiatry\n\n27 7 2017 2017 8 13112 12 2016 07 7 2017 Copyright © 2017 Mack, Pfeiffer, Schneider and Bechter.2017Mack, Pfeiffer, Schneider and BechterThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.We observed a case over 25 years of relapsing–remitting schizophrenic spectrum disorder, varying regarding the main symptomatology between more depressive or more schizoaffective or rather typical schizophrenic syndrome. Diseased phases were repeatedly accompanied by minor skin lesions, which were initially classified as mixed tissue disorder. Psychotic phases were waxing–waning over years. During one later relapse, skin involvement was severe, classified to likely represent an allergic reaction to psychopharmaca; this generalized exanthema remitted rapidly with cortisone treatment and azathioprine. Under continued azathioprine and low dose neuroleptics, the patient remitted completely, appearing psychiatrically healthy for 16 years. When azathioprine was set off due to pregnancy, an extraordinary severe relapse of schizophrenia like psychosis accompanied by most severe skin lesions developed within a few weeks, then requiring 2 years of psychiatric inpatient treatment. Finally, a diagnosis of systemic lupus erythematodes plus neuropsychiatric lupus was made. A single CSF sample in 2013 showed suspicious biomarkers, matching with CSF cytokine profiling in schizophrenic and affective spectrum disorder patients and indicated mild neuroinflammation. Complex immune suppressive treatment was reinitiated short after relapse, but was only partially successful. However, surprisingly the psychosis and skin lesions remitted (in parallel) when belimumab was given (add-on). The very details of this complicated, long-term disease course are discussed also with regard to general ideas, in particular with respect to the question if this case of seemingly comorbid schizophrenia with minor autoimmunity signs represented a case of one emerging autoimmune disorder with variant manifestations systemically and within the CNS, though atypically with predominant appearance as a schizophrenia spectrum disorder.\n\nmild encephalitisneuroinflammationchronic schizophreniaautoimmune encephalitisautoimmune diseasesneuropsychiatric lupus erythematosuslupus erythematosussystemic\n==== Body\nIntroduction\nSchizophrenia is understood as a partly heritable brain disease, recent interesting findings showing alleles of the complement component C4 genes play a role in both in the CNS and the immune system (1). Autoimmune diseases and severe infections are associated with a later increased risk of schizophrenia and other psychiatric disorders (2, 3). The relative risk of schizophrenia for an individual with a history of autoimmune disease in themselves or in their family is elevated by about 45%. Inversely schizophrenia is associated with a nearly 50% elevated lifetime prevalence of autoimmune diseases (4).\n\nWe observed a case of a female patient with a 25-year psychiatric history, her disease beginning at the age of 24. As the medical records show, the diagnosis was changing several times, from depression (bipolar disorder hypothesized) to schizoaffective to schizophrenic disorder, this was the predominating diagnosis over disease cause. Besides psychiatric process, the disease course in this patient was atypical, as her psychotic phases were often accompanied by appearance of minor non-specific skin lesions on the trunk and limbs. It has been suggested that there might be an autoimmune process; however, she did not fulfill any criteria for a defined autoimmune disorder. During one particular psychotic relapse she developed severe skin efflorescences, which were treated with cortisone and later azathioprine. Under this regimen skin improved rapidly and surprisingly after this particular inpatient treatment, the patient remained psychiatrically well with few exceptions over many years. Sixteen years later, this patient became pregnant and azathioprine had been set off because of possible teratogenic side effects. Soon, after discontinuing azathioprine, she rapidly relapsed and for the first time the criteria of an established autoimmune disorder, systemic lupus erythematosus (SLE), were fulfilled and could be even extended to neuropsychiatric lupus erythematosus (NPSLE).\n\nThe question discussed in this single case, is whether the patient suffered from the two unrelated disorders of schizophrenia and SLE, or an atypical course of a not clearly defined autoimmune disorder with early predominant psychiatric and late neuropsychiatric manifestations, with minor systemic manifestations and late fulfilling criteria of SLE/NPSLE.\n\nBackground\nIn previous CSF studies, we accumulated evidence of minor neuroinflammation and immune activation in large subgroups of both schizophrenic and affective disorders (5). These findings were recently confirmed by others (6). In addition we recently found high CSF cytokines, especially at IL-8 in each patient (7), also increased CSF neopterin (8). All these findings supported the recently updated mild encephalitis (ME) hypothesis (9). Also epidemiological studies are well compatible with ME hypothesis, in that infections and autoimmune disorders are additive risk factors for a spectrum of severe psychiatric disorders (3). Discrete features of neuroinflammation are seen in a variety of CNS disorders, including degenerative diseases like Alzheimer’s disease, where neuroinflammation seems to represent a disease escalating factor (10). Most interesting is that in single case studies of acute psychosis, despite normal magnetic resonance imaging scans of the brain and normal CSF and without detection of CNS autoantibodies, there was nevertheless proof of mild neuroinflammation in the cortex biopsy (11). These findings point to the difficulties in detecting mild inflammatory processes and show the limitations of available diagnostic methods including CSF diagnostics (12).\n\nThe study was approved by the ethics committee of the University of Ulm (the patient gave written informed consent to publication) was to gain a better insight into possible relationships between a seemingly primary psychiatric disorder and a poorly defined autoimmune process. By using a careful retrospective analysis of an unusual case with a long-standing disease course and considerable available clinical material, the possibility of a unifying diagnosis over the disease course, against the established assumption of two separate disorders (schizophrenia and autoimmune disorder) was tested.\n\nFamily History\nWithin the framework of the patient’s sixth hospitalization, the suspicious family history for both psychiatric and autoimmune disorders became apparent: both parents and the maternal grandmother suffered from a longtime depression with several psychiatric hospitalizations; the grandmother committed suicide. The patient’s only sibling has a schizophrenic disorder as well as Crohn’s disease.\n\nRetrospective Case Analysis of 25 Years\nIn 1989, a 24-year-old woman suffering from severe depression (ICD-10 F32.3) with predominant loss of interest, hypersomnia, feelings of guilt, and worthlessness and diminished ability to concentrate was hospitalized in our clinic for the first time. The physical findings were unremarkable except slight anemia, increased blood sedimentation rate and positive rheumatoid factor. Besides the psychiatric symptomatology no signs of autoimmunity were registered. The patient was treated successfully with a combination of pimozide, flupentixol, and amitriptyline and released after 3 months inpatient stay in good mental condition.\n\nDuring 1990, now 25 years old, the patient again demonstrated emerging anxiety, thought disorder (derailment and thought blocking), disorganized speech and for the first time acoustic hallucinations (commenting voices) and initially catatonic stupor. In the required second psychiatric hospital stay she showed slight leukopenia and hypochromic microcytic anemia. One month after hospitalization some non-specific skin manifestations on her chest and back appeared. Internal and dermatological consultancies happened, tissue samples were made, but neither serological nor histopathological results could name the disorder. Now the differential diagnosis of collagenosis was considered and further blood testing was undertaken. For the first time, antinuclear antibodies (ANA) tested positive. Bone marrow examinations showing no hematological disorder, brain MRI exposed no cerebral pathology. There was no evidence of infection, electrolyte disturbances or metabolic derangements. Established criteria of a defined autoimmune disorder were not fulfilled and therefore no immune suppressive therapy was started. With a combination of bromperidol and clorazepate, she distanced from productive psychotic content. During the cause, more depressive symptoms developed, tranylcypromine were added. The patient was dismissed in acceptable mental status.\n\nIn 1993, a third severe relapse occurred requiring hospitalization again. Main symptoms were restlessness, anxiety and extensive productive psychotic symptoms. One month after hospitalization, additional symptoms of severe maculopapular exanthema on the trunk and limbs appeared. This was diagnosed as a Stevens–Johnson syndrome and thought to be caused by the psychopharmacological drugs, propyphenazone ergotamine or acetylsalicylic acid (her own headache medication). The patient was transferred to the internal medicine department, where high-dose cortisone (100 mg/day) was initiated, 11 days later the exanthema had remitted, and patient was transferred back to the psychiatric ward. Cortisone was gradually phased out until the patient was discharged from the hospital. A few months later, in outpatient treatment the patient attempted suicide during a psychotic episode and was readmitted to the hospital. Clinical examination now demonstrated speckled exanthema on her chest, which was rapidly progressing, then confluating and spreading over the limbs (see Figure 1). Blood testing showed high ANA Titer and for the first time autoantibodies against Ro/SSA and La/SSB (see Table 1). In October 1993, an atypical collagenosis was hypothesized. Under this assumption, prednisolone was administered for over 6 months. During this period, skin and psychosis improved, though some symptoms continued to fluctuate.\n\nFigure 1 Skin manifestations of the patient in April 1993, hypothesized as Stevens–Johnson Syndrome.\n\nTable 1 Exemplary serological immunoinflammatory markers of the patient over last 25 years.\n\n\tTreatment\tST (no. 1)\tAMB\tST (no. 2)\tST (no. 3)\tST (no. 4)\tAMB\tST (no. 5)\tST (no. 6)\tAMB\tST (no. 7)\tST (no. 8)\tST (no. 9)\t\n\t\t\n\tPeriod of time\t14.04.–23.06.1989\t01.01.2000\t15.02.–11.07.1990\t11.03.–27.07.1990\t20.08.1993–30.03.1994\t20.02.1995\t11.06.1996–12.06.1997\t19.07.–25.09.2004\t30.09.2008–30.04.2009\t01.02.201020.02.2011\t29.05.2012–03.05.2013\t29.05.–13.12.2013\t03.01.–06.05.2014\t\nLaboratory marker\tReference range/unit\t\nLeukocytes\t4.0–10.0 × 103/μL\tNormal\tNormal\t3.3\t3.4\tNDA\t4.9\t3.88\t4.9\tNDA\tNDA\t2.8\t2.1\t2,8\t\nHemoglobin\t12.0–16.0 g/dl\tNormal\tNormal\t11.2\t12.2\tNDA\t17.3\t12.3\t13.0\tNDA\tNDA\t11.0\t11.3\t11.5\t\nESR\t<10/20 mm\t38/76\t29/64\t26/54\tNDA\t33/65\t56/60\t18/55\t19/46\t14/33\t14/35\tNDA\tNDA\t17/39\t\nAlpha 2 macroglobulin\t7.4–12.6 rel%\tHigh\tNDA\tNDA\tNDA\tNDA\t9.1\t8.1\tNDA\tNDA\tNDA\tNDA\t13.2\tNDA\t\nGamma-globulin\t8.0–15.8 rel%\t25.4\tNDA\tNDA\tNDA\tNDA\t24.4\t19.5\tNDA\tNDA\tNDA\tNDA\t10.8\tNDA\t\n\t\nANA\t\t<1:80 Titer\tNegative\tNegative\tNDA\tNDA\t1:10,240\t1:2,400\t1:10,000\t1:1,200\t1:9,600\tNDA\tNDA\t1:2,560\t1:2,560\t\nAnti-dsDNA\t<10 or <100 U/ml\tNDA\tNegative\t62\tNDA\t<40\t<3\tNDA\t10\t<2\t<3\tNDA\t<0.5\tNDA\t\nAnticentromere\t<7 U/ml\tNDA\tNDA\tNDA\tNDA\tNegative\tNDA\tNDA\tNegative\tNDA\tNDA\tNDA\t<0.4\tNDA\t\nAnti-histone AB\t<25 U/ml\tNDA\tNDA\tNDA\tNDA\tNegative\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t\nAnti-Jo-1-AB\t<7 U/ml\tNDA\tNDA\tNDA\tNDA\tNegative\tNDA\tNDA\tNegative\tNDA\tNDA\tNDA\t<0.3\tNDA\t\nAnti-U1-RNP-AB\t<25 U/ml\tNDA\tNDA\tNDA\tNDA\tNegative\tNDA\tNDA\tNegative\tNDA\tNDA\tNDA\t0.3\tNDA\t\nAnti-Scl-70-AB\t<25 U/ml\tNDA\tNDA\tNDA\tNDA\tNegative\tNDA\tNDA\tNegative\tNDA\tNDA\tNDA\t<0.4\tNDA\t\nAnti-Smith-AB\t<25 U/ml\tNDA\tNDA\tNDA\tNDA\tNegative\tNDA\tNDA\tNegative\tNDA\tNDA\tNDA\t0.3\tNDA\t\nAnti-SSA/Ro-AB\tNegative U/ml\tNDA\tNDA\tNDA\tNDA\t182.5\tNDA\tNDA\t4.4\tNDA\tNDA\tNDA\t>240.0\t>240.0\t\nAnti-SSB/La-AB\tNegative U/ml\tNDA\tNDA\tNDA\tNDA\t117.5\tNDA\tNDA\t2.0\tNDA\tNDA\tNDA\t2.5\tNDA\t\n\t\nRheumatoid factor\t<20 IU/ml\tPositive\t112\t176\tNDA\t48.4\tNDA\tNDA\t44\tNDA\tNDA\tNDA\tNDA\tNDA\t\nAnti-CCP-AB\t<7 U/ml\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t\n\t\naPL-AB\tLupus anticoagulant\t<1.08 (Ratio)\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t\nAnti-cardiolipin-AB\tMPL-U/ml\tNDA\tNegative\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNegative\t\nβ2-Glycoprotein 1-AB\t<7 U/ml\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t\nAntiphosphatidylserine-AB\t<10 IU/ml\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t\n\t\nComplement component 3\t0.90–1.70 g/l\tLow\tNormal\tNDA\tNDA\t1.13\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t0,89\t1,03\t\nComplement component 4\t0.11–0.34 g/l\tNDA\tNormal\tNDA\tNDA\t0.18\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t0.18\t0,25\t\n\t\nANCAs\tc-ANCA\t1:<10\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t1:<10\tNDA\tNDA\tNDA\tNDA\tNDA\t\np-ANCA\t1:<10\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\tNDA\t1:<10\tNDA\tNDA\tNDA\tNDA\tNDA\t\nLaboratory marker and reference range/unit: AB, antibody; ANA, antinuclear antibody; CCP, (anti) citrullinated protein antibodies; DsDNA, double stranded deoxyribonucleic acid; ESR, erythrocyte sedimentation rate; aPL, antiphospolipid (antibody); ANCA, antineutrophil cytoplasmic antibodies.\n\nTreatment: ST, stationary treatment (number of hospitalization in brackets); AMB, ambulatory treatment.\n\nNDA, no data available; green, pathologically elevated; red, pathologically elevated.\n\nSurprising Remission Under Azathioprine Treatment for Almost 16 Years\nIn the time period between 1994 and 1996 no severe problems were stated, according to the patient’s own evaluation “skin and mind came to rest.” However, in June 1996 another relapse of psychosis occurred: she presented initially symptoms of thought disorder, delusional ideas, paranoia, depersonalization and later acoustic hallucinations. Thioridazine, fluphenazine, and diazepam were added. In the course, fluphenazine was reduced and because of emerging comorbid depressive symptoms and affective instability, amitriptyline and later lithium was added. Because of suspected drug-induced leukopenia, fluphenazine was replaced by olanzapine. Skin eruptions on the trunk followed psychiatric symptoms about 5 months later. Another therapy trial with prednisolone was initiated, with worsening of her skin and mental status, so that treatment on a protected psychiatric ward became necessary. CSF examination ruled out any brain infection, however, did show unspecific inflammation. A diagnosis of mixed connective tissue disorder was then made. Azathioprine (Imurek®) was prescribed, starting in January 1997 and continued for nearly 16 years. About 2 weeks after the start of azathioprine, the exanthema regressed and prednisolone was tapered out. As the psychiatric symptoms gradually improved, with a complex psychopharmacological treatment including lithium, olanzapine, amitriptyline, the patient was discharged from hospital. Azathioprine was reduced from 100 to 50 mg future years. Because of her good mental health, olanzapine and amitriptyline were gradually reduced but maintained until 2004. Lithium was phased out in subsequent 2 years. Under this treatment the patient remained stable with regard to mental status and skin status for nearly 16 years (except for one exception in 2004). After release she was in psychiatric and sporadic rheumatologic supervision. Interim, she married a second time. She chose early retirement but was able to work part-time in a fashion store. The ambulatory protocols in this time noted occasionally social anxieties, but predominant an “emotionally and psychologically stable” status.\n\nIn 2004, a brief hospitalization became necessary, because of restlessness and affective tension, probably as a consequence of life events (suicide attempt of her mother and sister and the sisters diagnosis schizophrenic disorder). During inpatient stay, acoustic hallucinations were noted and quetiapine was added next to amitriptyline, olanzapine, and azathioprine. She was released after 2 months in good condition and was mentally stable for another 8 years.\n\nSevere Relapse after Discontinuance of Azathioprine\nIn 2012, because of pregnancy, the patient decided together with the gynecologist to stop azathioprine medication immediately, balancing the teratogenic potential versus the need for continuing azathioprine. Shortly after, the pregnancy was terminated at the request of the patient, but azathioprine was still left out. As a result, an unexpected and dramatic change in the overall health status of the patient reoccurred. Within 4 weeks the patient developed signs of restlessness, insomnia and mania, all symptoms rapidly deteriorating further to a full blown psychosis, and again requiring hospitalization in May 2012. She soon developed progressive disorganized behavior, thought disorder overall incoherence and paranoid ideation. The initial therapy was undergoing a continual adjustment, including benperidol (stopped because of side effects), later fluphenazine, quetiapine, asenapine, and because of depressive symptoms trimipramine and amitriptyline. Finally, a combination of risperidone, olanzapine, chlorprothixene, and valproate was given. Electroconvulsive therapy was tried. Besides psychotropic medication, cortisone and azathioprine were restarted from the beginning. Exactly 19 days after admission, an exanthema appeared on her cleavage and upper back. Simultaneously, the patient reported to suffer from light sensitivity and arthralgia. ANA titer and antibodies against SSA–Ro were rising, C3 complement was low (compare Table 1). Severe skin eruptions were constantly treated in the department of Dermatology, at Ulm University.\n\nIn January 2013, the disease fulfilled the criteria of subacute cutaneous lupus erythematosus (psychosis, discoid lesions, photosensitivity, leukopenia, and ANA titer). Despite immediate resumption of immune suppression, the clinical situation was unchanged if not worsening. Because of self injurious behavior she was taken to the protected ward for weeks, partly medical restraint become necessary. Subsequently, instead of azathioprine, mycophenolate mofetil (CellCept® 3 g/day) was prescribed. Nevertheless, there was little therapeutic success to be observed. In March 2013, additionally even the scalp and face were affected by skin lesions. After 10 months of inpatient stay, the patient agreed to another CSF examination, which showed oligoclonal IgG bands (compare Tables 2 and 3). There were no neuronal antibodies. Also levels of tumor necrosis factor (TNF)-α and SCDs 25 were increased in the blood and elevated biomarkers in CSF were found (compare Table 2). The results of CSF examination now justified a diagnosis of NPSLE in accordance with established criteria (12–15).\n\nTable 2 Plasma cytokines and CSF cytokines (red framed) of the patient in 2011–2015 based on research done by Prof. Dr. E. Marion Schneider, Experimental Anesthesiology Section, University Clinic Ulm, 89075 Ulm, Germany.\n\n\t29.03.2011\t18.06.2012\t26.06.2012\t10.12.2012\t12.03.2013\t15.03.2013\t09.04.2013\t23.05.2013\t13.06.2013\t13.06.2013 (CSF)\t21.01.2015\tUnit\t\nEPO\t\t5.55\t6.39\t11.00\t7.03\t10.20\t21.10\t3.74\t15.50\t\t5.77\tmU/ml\t\nIL-10\t0.96\t0.92\t0.47\t0.48\t2.20\t3.85\t1.41\t0.88\t0.00\t2.64\t6.91\tpg/ml\t\nIL-1β\t4.40\t2.12\t3.44\t1.85\t1.98\t0.92\t1.68\t0.43\t38.70\t1.08\t3.98\tpg/ml\t\nIL-6\t0.28\t0.62\t0.215\t4.77\t3.40\t2.33\t3.11\t0.94\t131.00\t8.41\t1.34\tpg/ml\t\nIL-8\t16.80\t4.63\t1.61\t7.70\t18.20\t11.60\t6.84\t6.45\t8.84\t53.70\t4.47\tpg/ml\t\nTNF-α\t23.60\t8.05\t8.90\t15.30\t18.50\t19.60\t15.80\t9.93\t14.90\t7.26\t24.40\tpg/ml\t\nsCD25\t588.00\t603.00\t591.00\t421.00\t865.00\t986.00\t1,422.00\t1,246.0\t1,126.00\t1.32\t849.00\tU/ml\t\nLBP\t7.70\t5.15\t7.11\t4.34\t11.80\t11.80\t9.23\t9.04\t4.06\t0.76\t3.41\tng/ml\t\nFerritin\t53.20\t79.60\t77.00\t59.20\t163.00\t160.00\t65.00\t17.80\t14.50\t3.23\t124.00\tng/ml\t\nNormal range: erythropoietin (EPO) <30 mU/ml; IL-10 <3–15 pg/ml; IL-1β <1–3 pg/ml; IL-6 <6–10 pg/ml; IL-8 <70.0 pg/l; tumor necrosis factor (TNF)-α <3–15 pg/ml; sCD25 = 200–500 U/ml (adult); plasma ferritin <50 ng/ml; lipopolysaccharide binding protein (LBP) <15 μg.\n\nTable 3 CSF parameters in our patients sample (13 June 2013).\n\nCells\t\n\t\nCSF leukocytes, 1/μl\tCSF erythrocytes, 0/μl\t\n\t\nProteins\t\n\t\n\tCSF\tSerum\tQ (CSF/serum) <103\t\nTotal protein\t320 mg/l\t\t\t\nAlbumin\t169.00 mg/l\t40.7 g/l\t4.2\t\nIgG\t26.0 mg/l\t11.2 g/l\t2.3\t\nIgA\t1.77 mg/l\t1.63 g/l\t1.1\t\nIgM\t<0.142 mg/l\t0.604 g/l\t<0.2\t\n\t\nOligoclonal IgG in CSF with additional identical bands in CSF and serum\t\n\t\nLactate\t1.4 mmol/l\t\nOvercoming Therapy Resistance with Monoclonal Antibody Therapy\nBecause of therapy resistance for more than 1 year and the initial diagnoses of SCLE with NPSLE, actual immune suppressive therapy was reconsidered, and intravenous therapy with the monoclonal antibody belimumab (Benlysta®) was started as an add-on treatment to the previous therapy (see Figure 2). Gradually, the patient improved over the next 2 months in every aspect and was discharged in December 2013. However, 2 weeks later she again attempted suicide by drug intoxication, requiring treatment in the intensive care unit, where all psychiatric and immune suppressive treatments were stopped. Eight weeks later, severe skin eruptions again emerged. In spite of hydroxychloroquine (Quensyl® 400 mg/day) being prescribed now, the skin eruptions worsened further, and psychiatric hospitalization was again required because of her severe psychosis relapse. Subsequently belimumab was restarted again. With the combination of mycophenolate mofetil (1,000 mg/day), hydroxychloroquine (400 mg/day), urbason (2 mg/day), and belimumab (10 mg kg/bodyweight per cycle) a rapid remission was achieved. Both, psychotic symptoms and skin manifestations improved in parallel. An attempt at pausing hydroxychloroquine was discarded because of repeated erupting skin manifestations. The patient was discharged from hospital treatment in an acceptable clinical status. During the next continuous outpatient treatment months she improved to full remission in psychosis and skin manifestations.\n\nFigure 2 Timeline of the development of the disease, the severity of the skin lesons and immunotherapeutic treatments over time. Abbreviations and explanations: 1well documentated, specific cutaneous, and mucosal lesions; 2except for topical application; 3/4methylprednisolone/mycophenolate mofetil was paused due to a suicide attempt. (A–G) period of stationary treatment: (A) 14.04.–23.06.89; (B) 15.02.–11.07.90; (C) 11.03.–27.07.90; (D) 20.08.93–30.03.94; (E) 11.06.96–12.06.97; (F) 19.07.–25.09.2004; (G) 29.05.12–03.05.13; (H) 29.05.–13.12.1; (I) 03.01.–30.04.14 and 01.05.–06.05.14.\n\nFollowing dismissal, she remained clinically stable with a complex of psychopharmacological and immune suppressive medications (for details see Figure 2).\n\nDiscussion\nWe conducted a detailed analysis case study of a patient with schizophrenia in regard to the question of whether autoimmunity and schizophrenia were unrelated comorbid disorders, or whether both disorders could be interpreted as a unified disorder, representing in fact the varied manifestations of an atypical course of SLE, predominantly with psychiatric symptoms and accompanying skin manifestations most over the time. The latter hypothesis was plausible from a first look because of concurrent minor autoimmune signs and findings with the psychotic phases. To assume indeed a unifying disease hypothesis, we need, however, more arguments. The following points support the unifying perspective:\nGood clinical improvement of skin and psyche under short time corticosteroids in 1993 with repeated relapses after corticosteroids was discontinued.\n\nRepeated temporal parallelism of the appearance of skin manifestations and psychiatric manifestations consistently over the disease course of 25 years.\n\nSome temporal relationship between high titer of autoimmune/inflammatory markers and antinuclear antibodies to the severity of psychiatric symptoms.\n\nStriking temporal parallelism of improvement of most severe psychiatric and skin manifestations with complex immune suppression during the last severe relapse.\n\nClose temporal relationship between longtime full remission under azathioprine medication, followed by the most severe relapse ever after discontinuance. In addition, there is a plausible delay of a few weeks after discontinuance of azathioprine and onset of first psychotic symptoms.\n\nDemonstration of mild neuroinflammation by CSF analysis during the most severe disease phase, when fulfilling criteria of SCLE, fulfilling thus criteria of NPSLE, the latter appearing as an acute severe schizophreniform psychosis.\n\nSuspicious family history with both severe psychiatric [depression in both parents (ICD F 33.3); sister with depression and paranoid schizophrenia (ICD-10 F20.0, F32.2)] and autoimmune disorders [sister with Crohn’s disease (ICD-10 K50.1)].\n\nUnnoticed autoimmune signs were retrospectively assessed with a newly developed questionnaire [details in Ref. (16), in review], yet detected in the prepsychotic phase repeated arthralgia and swelling of limbs and fingers, which happened in our patient.\n\nClinical improvement of psychosis repeatedly seemed associated with immune or anti-inflammatory therapies, including lithium with immune suppressive reactions.\n\nTemporal relationship of increasing serum cytokines, especially TNF-α, during the most severe psychotic relapse and uniquely elevated CSF cytokines fitting to observations in schizophrenic patients (see Table 2; see below).\n\n\n\nBecause our patient rejected repeatedly CSF diagnostics, there is only a single CSF sample with cytokine profiling. The sampling was done in June 2013, during a phase of severe psychotic symptoms. In this CSF sample, we found suspicious biomarkers (compare Table 2): chemokine IL-8 was selectively higher than in the corresponding serum samples, other CSF cytokines were marginally elevated, TNF-α was not increased. These results match with CSF and serum cytokine profiling in schizophrenic and affective spectrum disorder patients (7). The presence of oligoclonal bands in CSF, few of them also in serum (compare Table 3), indicates in agreement with established criteria (13, 14) neuroinflammation, here overall mild and such was found in small groups of patients with affective and schizophrenic spectrum disorders in several studies (5, 6).\n\nWe conclude from our case analysis of 25 years disease course, that our case represented an atypical case of autoimmune disorder, lately diagnosed as LE, beginning with a focus on the CNS, explaining the variant psychiatric Syndrome from variant autoimmune-inflammatory disease activity. We could only partially define the apparently variant disease activity and only partially detect the immune inflammatory pathomechanisms involved. Overall the case represents a prototype of what was preliminary defined and hypothesized as ME. Cases with incomplete diagnostic autoimmune disorders over years, which later may develop a classified autoimmune disorder, are well-known, for example, presenting with mixed tissue disorder years before (17–20). Comparable cases of NPSLE were not described according to our knowledge. Our many arguments to assume an atypical case of remitting relapsing, or chronic when without immune suppressive treatment, NPSLE may be strong, though proof is missing: there were no definite, in part from circumstantial reasons, signs of neuroinflammation by imaging or CSF analysis in the early course. However, such was not unexpected from many arguments (9) and in rare single cases of schizophrenic syndromes with normal or quite normal CSF, nevertheless brain biopsy demonstrated mild inflammation (11, 21). We did not find neuronal antibodies, but this does not argue against our conclusion, cases with brain biopsy proven ME described by Najjar et al. (11) did also not demonstrate neuronal autoantibodies. We had not the opportunity to take a brain biopsy. On the other hand, we had the advantage of a long-term observation including several time periods of immune suppressive treatment, given from somewhat only partially established diagnostic criteria, detecting in retrospect a rather plausible if not clear evidence of positive treatment effects from immune suppression, which continues up to the time point of writing this paper. In sum, our arguments appear to represent strong arguments in total, to interpret our case as an atypical course of NPSLE from the beginning focused on the CNS.\n\nWith this case several difficult scientific and ethical questions had to be considered: After remission of the debated severe skin disease, thought to represent an allergic reaction to pharmaca or an undefined autoimmune disorder, also the possibility of a unified autoimmune disorder, as discussed in this paper, was considered by author Karl Bechter and discussed with the patient, though by majority of psychiatric doctors in our hospital rather held implausible. The patient was clearly informed about these scientific uncertainties and the novelty of the hypothesis of mild neuroinflammation to possibly causally underlie the psychotic disorder, held by Karl Bechter. The question of a relative indication of long-term treatment with azathioprine was evaluated independently by specialist in internal medicine (Dr. Peter Müller), with the result that long time azathioprine was justified (defined as relative indication) by the case history and because of continued mild leukopenia. With this informed knowledge the patient preferred to be treated with azathioprine as documented and the psychopharmacological medication to be reduced. The patient continued to visit Drs. Karl Bechter and Peter Müller, all over the respective years reported, though visiting Karl Bechter only sporadically but continuous over many years with remitted psychiatric syndrome but immediately with incipient relapse after set off of azathioprine.\n\nDifficulties in Diagnosing Autoimmune Disorders in Psychiatric Patients\nPsychiatric symptoms are rarely reported as an initial and isolated feature of SLE (22), in spite of many patients having the feeling that psychiatric symptoms occurred before they were diagnosed with SLE. However, central inflammation does not always coincide with systemic signs. Tests on mice suggest that NPSLE is not always a complication of SLE and can occur in absence of systemic autoimmunity (23). This supports the importance that early CSF diagnostics are done in longtime psychiatric patients. The European League Against Rheumatism emphasizes the increased risk of neuropsychiatric manifestations in SLE and requests early diagnostics including CSF examination in neuropsychiatric patients (even if only to exclude CNS infections) (24).\n\nIn our case, there was a delay of 4 years between initial psychiatric symptoms and first noticed mild skin manifestations. Accompanying systemic signs are maybe misinterpreted or remain undiagnosed, in our case even the established criteria of lupus were fulfilled only late in the course. This case shows the difficulties in establishing a diagnosis of common autoimmune disorders such as SLE, by regarding criteria like those of the American College of Rheumatology (ACR)-97 or Systemic Lupus International Collaborating Criteria (SLICC)-12. Our patient never had any further neuropsychiatric symptoms like seizures or neuropathy. No cerebrovascular accidents were noticed. Missing manifestations or incomplete laboratory markers create major uncertainties for clinicians. The general problem of incomplete criteria is known in autoimmune disorders, the diagnosis of mixed tissue disorder, a respective phenomenon, number of cases later being diagnosed with classical autoimmune disorders (19). Also atypical courses in other organ systems, e.g., with visceral focus have been described (25).\n\nConclusion\nPsychosis as the initial or predominant manifestation of SLE over years is an unusual course of the disease presented here. If our conclusion is correct, that indeed we observed one disorder with manifestations in different organ systems, there is an apparent need for improved diagnostic instruments and methods. For better detection of unnoticed clinical signs we recently developed a questionnaire called “FAISF” [(16), in review]. Another problem is, as our case strikingly demonstrates, that even known signs and minor findings of autoimmunity do not usually allow a definitive diagnosis of the defined autoimmune disorder, as established for example by the ACR or the SLICC. This problem of sub diagnostic cases has also been recognized in rheumatology.\n\nA careful analysis of our case with 25 years disease including actual and previous material, clearly suggests that this case of seemingly comorbid schizophrenia with minor autoimmunity signs represented a case of one emerging autoimmune disorder with variant manifestations systemically and within the CNS, though atypically with predominant appearance as a schizophrenia spectrum disorder. We do not exclude, that more such cases exist, but were certainly inappropriately understood. This case demonstrates the therapeutic potential if detected in an early phase and treated appropriately including with immunosuppressive options. The consequences of our perspective would likely include psychoimmunological aspects in psychiatric routine examinations. Recommendations should be developed including clinical signs and findings.\n\nAuthor Contributions\nAM—collecting data and summary of the patient. CP and KB—treatment of the patient. EMS—CSF analysis, serum analysis, and cytokine profiling.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nThe authors thank Dr. Peter Müller, Kreiskliniken Günzburg, for his continued cooperation. The authors also thank the Margarete-Ammon-Stiftung, München, for continued financial support for research on mild neuroinflammation.\n\nFunding. 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JAMA Psychiatry (2013 ) 70 (8 ):812 –20 .10.1001/jamapsychiatry.2013.1111 23760347 \n4 Eaton WW Byrne M Ewald H Mors O Chen CY Agerbo E \nAssociation of schizophrenia and autoimmune diseases: linkage of Danish national registers . Am J Psychiatry (2006 ) 163 :521 –8 .10.1176/appi.ajp.163.3.521 16513876 \n5 Bechter K Reiber H Herzog S Fuchs D Tumani H Maxeiner HG . Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction . J Psychiatr Res (2010 ) 44 (5 ):321 –30 .10.1016/j.jpsychires.2009.08.008 19796773 \n6 Endres D Perlov E Baumgartner A Hottenrott T Dersch R Stich O \nImmunological findings in psychotic syndromes: a tertiary care hospital’s CSF sample of 180 patients . Front Hum Neurosci (2015 ) 10 (9 ):476 10.3389/fnhum.2015.00476 \n7 Maxeiner H-G Schneider M Kurfiss S-T Brettschneider J Tumani H Bechter K . Cerebrospinal fluid and serum cytokine profiling to detect immune control of infectious and inflammatory neurological and psychiatric diseases . Cytokine (2014 ) 69 :62 –7 .10.1016/j.cyto.2014.05.008 25022963 \n8 Kuehne LK Reiber H Bechter K Hagberg L Fuchs D \nCerebrospinal fluid neopterin is brain-derived and not associated with blood-CSF barrier dysfunction in non-inflammatory affective and schizophrenic spectrum disorders . J Psychiatr Res (2013 ) 47 (10 ):1417 –22 .10.1016/j.jpsychires.2013.05.027 23790260 \n9 Bechter K . Updating the mild encephalitis hypothesis of schizophrenia . Prog Neuropsychopharmacol Biol Psychiatry (2013 ) 42 :71 –91 .10.1016/j.pnpbp.2012.06.019 22765923 \n10 Schwartz M Deczkowska A . Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation . Trends Immunol (2016 ) 37 (10 ):668 –79 .10.1016/j.it.2016.08.001 27616557 \n11 Najjar S Pearlman D Devinsky O Najjar A Nadkarni S Butler T \nNeuropsychiatric autoimmune encephalitis without VGKC-complex, NMDAR, and GAD autoantibodies: case report and literature review . Cogn Behav Neurol (2013 ) 26 (1 ):36 –49 .10.1097/WNN.0b013e31828b6531 23538571 \n12 Bechter K \nCSF diagnostics in psychiatry – present status – future projects . Neurol Psychiatry Brain Res (2016 ) 22 (2 ):69 –74 .10.1016/j.npbr.2016.01.008 \n13 Reiber H Peter JB \nCerebrospinal fluid analysis – disease-related data patterns and evaluation programs . J Neurol Sci (2001 ) 184 :101 –22 .10.1016/S0022-510X(00)00501-3 11239944 \n14 Wildemann B Oschmann P Reiber H \nLaboratory Diagnosis in Neurology . Stuttgart : Thieme Verlag (2010 ).\n15 Reiber H \nCerebrospinal fluid immunoglobulin data compilation and knowledge-based interpretation. Diagnostic patterns in neurology and psychiatry . Arq Neuro Psiquiatr (2016 ) 74 :4 10.1590/0004-282X20160044 \n16 Mack A \nFamiliäre Häufung von Depressionen und Psychosen: Eine biographisch medizinische Detailanalyse von autoimmunen und infektiösen Faktoren in einer Familie [Dissertation] . University Ulm Faculty of Medicine, University Ulm (2016 ).\n17 Fantò M Salemi S Socciarelli F Bartolazzi A Natale GA Casorelli I \nA case of subacute cutaneous lupus erythematosus in a patient with mixed connective tissue disease: successful treatment with plasmapheresis and rituximab . Case Rep Rheumatol (2013 ) 2013 :4 10.1155/2013/857694 \n18 Mosca M Tani C Bombardieri S . A case of undifferentiated connective tissue disease: is it a distinct clinical entity? \nNat Clin Pract Rheumatol (2008 ) 4 :328 –32 .10.1038/ncprheum0799 18414458 \n19 Swaak AJ van de BH Smeenk RJ Manger K Kalden JR Tosi S \nIncomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR standing committee on international clinical studies including therapeutic trials (ESCISIT) . Rheumatology (Oxford) (2001 ) 40 (1 ):89 –94 .10.1093/rheumatology/40.1.89 11157147 \n20 Akiyama Y Suzuki T Tanaka M Kobayashi K Kagiri T Ishibashi T \nA case of mixed connective tissue disease developed into overlap syndrome of progressive systemic sclerosis, systemic lupus erythematosus, polymyositis and Sjögren’s syndrome . Arerugi (1990 ) 39 (6 ):542 –7 .2222196 \n21 Najjar S Pearlman D Zagzag D Golfinos J Devinsky O . Glutamic acid decarboxylase autoantibody syndrome presenting as schizophrenia . Neurologist (2012 ) 18 :88 –91 .10.1097/NRL.0b013e318247b87d 22367838 \n22 van Dam AP Wekking EM Oomen HA de Jong J Swaak AJG Smeenk RJT \nPsychiatric symptoms before systemic lupus erythematosus is diagnosed . Rheumatol Int (1994 ) 14 :57 –62 .10.1007/BF00300248 7824836 \n23 Stock AD Wen J Doerner J Herlitz LC Gulinello M Putterman C . Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice . J Neuroinflammation (2015 ) 12 :205 .10.1186/s12974-015-0423-4 26546449 \n24 Bertsias GK Ioannidis JPA Aringer M Bollen E Bombardieri S Bruce IN \nEULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs . Ann Rheum Dis (2010 ) 69 :2074 –82 .10.1136/ard.2010.130476 20724309 \n25 Fabio G Carraba M Hu C Florian M Besana C \nDramatic development of severe SLE in a patient with incomplete disease . Rheumatol Int (2005 ) 25 :543 –7 .10.1007/s00296-004-0550-1 15662528\n\n",
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"title": "Schizophrenia or Atypical Lupus Erythematosus with Predominant Psychiatric Manifestations over 25 Years: Case Analysis and Review.",
"title_normalized": "schizophrenia or atypical lupus erythematosus with predominant psychiatric manifestations over 25 years case analysis and review"
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"abstract": "Emergency department (ED) procedural sedation and analgesia is widely and routinely performed; serious complications are rare. We describe the first reported case of aspiration during procedural sedation in the ED. Although our patient required endotracheal intubation and critical care admission, there was no adverse long-term outcome. Given that there were no apparent predisposing factors, we believe it is crucial for emergency physicians to routinely anticipate the possibility of such a complication during each sedation event.",
"affiliations": "Department of Emergency Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. kwcheung@dal.ca",
"authors": "Cheung|Ka Wai|KW|;Watson|Mary-Lynn|ML|;Field|Simon|S|;Campbell|Samuel G|SG|",
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"title": "Aspiration pneumonitis requiring intubation after procedural sedation and analgesia: a case report.",
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"abstract": "BACKGROUND\nDurvalumab is a programmed cell death ligand 1 (PD-L1) inhibitor indicated for stage III, unresectable non-small cell lung cancer (NSCLC) consolidation therapy following concurrent platinum-based chemoradiation based on results of the PACIFIC trial. Safety data of durvalumab demonstrates an increased risk of immune-related adverse effects (irAEs), most notably pneumonitis. Pneumonitis is a serious and potentially fatal complication of immunotherapy. It is important to investigate the incidence of pneumonitis in clinical practice to evaluate the generalizability of published data. The objective of this study is to assess and characterize real-world incidence of pneumonitis in patients with NSCLC receiving durvalumab.\n\n\nMETHODS\nThis retrospective study included patients who were initiated on durvalumab for unresectable stage III NSCLC from February 2018 through November 2019. The data analysis utilized descriptive statistics to determine the incidence of pneumonitis associated with durvalumab.\n\n\nRESULTS\nOf the 83 patients who were evaluated, 21 patients (25.3%) experienced pneumonitis, with 5 cases (6%) being grade 3/4. Seven patients were re-challenged with durvalumab, while 14 patients permanently discontinued durvalumab. There were no clearly identifiable risk factors leading to an increased incidence of pneumonitis.\n\n\nCONCLUSIONS\nThe results of this study indicate that real-world incidence of pneumonitis in stage III NSCLC patients receiving durvalumab consolidation therapy is congruent with the incidence reported in the PACIFIC trial.",
"affiliations": "Department of Pharmacy, Section of Oncology, Yale New Haven Hospital, New Haven, CT. Electronic address: Jessica.LeClair@ynhh.org.;Department of Pharmacy, Section of Oncology, Yale New Haven Hospital, New Haven, CT.;Department of Clinical Medicine, Section of Medical Oncology, School of Medicine, Yale University, New Haven, CT.;Department of Pharmacy, Section of Oncology, Yale New Haven Hospital, New Haven, CT.",
"authors": "LeClair|Jessica N|JN|;Merl|Man Yee|MY|;Cohenuram|Michael|M|;Luon|Darren|D|",
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"abstract": "BACKGROUND Drug-induced immune hemolytic anemia (DIIHA) is a rare condition that may result from the administration of an antibiotic, most notably the cephalosporin class, commonly used in both the adult and pediatric populations. A delay in recognition by a provider may lead to continuation of the offending agent and possibly result in fatal outcomes. CASE REPORT We report the case of a 65-year-old woman on ceftriaxone infusions after being diagnosed with acute mitral valve endocarditis 3 weeks prior, which presented with severe anemia and bilateral transient vision loss. Being a Jehovah's Witness, the patient refused blood product transfusions and was managed with alternative therapies. The etiology of the symptoms was suspected to be a hemolytic anemia directly related to her ceftriaxone infusions. CONCLUSIONS This report demonstrates the importance of close vigilance while prescribing drugs known to cause hemolytic anemia. Although rare, drug-induced immune hemolytic anemia caused by ceftriaxone may be a potentially fatal condition, but with early recognition and withdrawal of the offending agent, successful treatment may ensue. Serological tests should be utilized to obtain a definitive diagnosis.",
"affiliations": "Graduate Medical Education, Arnot Ogden Medical Center, Elmira, USA.;Graduate Medical Education, Arnot Ogden Medical Center, Elmira, USA.",
"authors": "Tasch|James|J|;Gonzalez-Zayaz|Pedro|P|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005296:Ferrous Compounds; D006397:Hematinics; C020748:ferrous sulfate; D000068817:Epoetin Alfa; D002443:Ceftriaxone; D005492:Folic Acid; D014805:Vitamin B 12",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2842853210.12659/AJCR.903507903507ArticlesCeftriaxone-Induced Hemolytic Anemia in a Jehovah’s Witness Tasch James AEFGonzalez-Zayaz Pedro EGGraduate Medical Education, Arnot Ogden Medical Center, Elmira, NY, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: James Tasch, e-mail: jtasch@ah.arnothealth.org2017 21 4 2017 18 431 435 23 1 2017 17 2 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 65\n\nFinal Diagnosis: Ceftriaxone induced immune hemolytic anemia\n\nSymptoms: Blindness • fatigue\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Hematology\n\nObjective:\nUnusual clinical course\n\nBackground:\nDrug-induced immune hemolytic anemia (DIIHA) is a rare condition that may result from the administration of an antibiotic, most notably the cephalosporin class, commonly used in both the adult and pediatric populations. A delay in recognition by a provider may lead to continuation of the offending agent and possibly result in fatal outcomes.\n\nCase Report:\nWe report the case of a 65-year-old woman on ceftriaxone infusions after being diagnosed with acute mitral valve endocarditis 3 weeks prior, which presented with severe anemia and bilateral transient vision loss. Being a Jehovah’s Witness, the patient refused blood product transfusions and was managed with alternative therapies. The etiology of the symptoms was suspected to be a hemolytic anemia directly related to her ceftriaxone infusions.\n\nConclusions:\nThis report demonstrates the importance of close vigilance while prescribing drugs known to cause hemolytic anemia. Although rare, drug-induced immune hemolytic anemia caused by ceftriaxone may be a potentially fatal condition, but with early recognition and withdrawal of the offending agent, successful treatment may ensue. Serological tests should be utilized to obtain a definitive diagnosis.\n\nMeSH Keywords:\nAnemia, HemolyticCeftriaxoneJehovah’s Witnesses\n==== Body\nBackground\nDrug-induced immune hemolytic anemia (DIIHA) is a rare but potentially life-threatening disorder that should be considered if a patient develops hemolysis under drug treatment [1]. DIIHA occurs in approximately 1 in 1 million people, but is likely underdiagnosed despite its potential lethality [2]. Second- and third-generation cephalosporins, especially cefotetan and ceftriaxone, are increasingly associated with severe, sometimes fatal, immune hemolytic anemia [3]. The first case of fatal ceftriaxone-induced immune hemolytic anemia (CIIHA) was reported by Garratty et al. in 1991 [4,5]. Estimates of fatality in CIIHA are reported as high as 40% [5–7]. DIIHA should be classified as involving either drug-dependent (DDAB) or drug-independent antibodies (DIAB) to more appropriately treat the condition. When involving DDAB, hemolysis typically appears within 2 weeks of starting the causative drug with the patient developing a progressive anemia [2]. Cessation of the offending agent is standard treatment, along with blood product transfusions for symptomatic anemia.\n\nCase Report\nA 64-year-old white woman presenting with complaints of recent transient bilateral vision loss was found to be severely anemic upon arrival to the emergency department. She described her new-onset vision changes as a complete vision loss during which she saw pitch black for a few hours. She stated this occurred immediately after the last 2–3 sessions of her daily intravenous ceftriaxone infusions, as she was being treated for a recent group B streptococcal bacteremia with associated acute endocarditis. She stated her vision loss would improve within a few hours when she would get home and lay down. Over the past 2 weeks, she had noted an increase in fatigue, which worsened with even minimal exertion and was associated with mild shortness of breath. At the time of presentation, she denied chest pain, hemoptysis, hematochezia, change in stool, fever, chills, abdominal pain with associated nausea/vomiting/diarrhea, and urinary symptoms. She denied any recent falls or trauma.\n\nPast medical/surgical history included right-sided breast cancer status post right mastectomy with reconstruction with latissimus dorsi myocutaneous flap, diastolic congestive heart failure, mild aortic stenosis, hypertension, sciatica, and a recent hospitalization (discharged about 3 weeks prior) for group B streptococcal bacteremia with associated acute endocarditis, which was deemed most likely to be a result from a urinary tract infection (UTI). Past social history included being a Jehovah’s Witness. She denied any alcohol, tobacco, or recreational drug use. Past family history included a father with history of lung cancer and mother with unspecified liver cirrhosis. For her previous hospitalization (roughly 3 weeks prior), she presented with complaints of low back pain and foul smelling urine for 2 days. She was found to be febrile at 105.1°F (40°C), tachycardic, and hypotensive. After proper fluid hydration of 30 cc/kg, she was started on pressor support. She was started empirically on vancomycin and ceftriaxone for a likely urinary tract infection, with the urine culture eventually reporting as no growth. Cerebrospinal fluid studies were negative. Blood cultures ×2 grew group B streptococcus. No obvious source of the bacteremia was found, but was hypothesized to be due to a UTI. Ultimately, her lactic acidosis/septic shock resolved within 48 hours, but due to continued leukocytosis, a transesophageal echocardiogram (TEE) was obtained, which revealed a medium-sized, 8.6 mm (L)×7.3 mm (W), irregular vegetation on the anterior leaflet of the mitral valve (Figure 1). She was discharged home with plans for intravenous infusion of ceftriaxone 2 grams IV daily for a total of a 6-week course with ESR, CRP, CMP, and CBC scheduled every Monday, which followed infectious disease recommendations.\n\nFor her current admission, the patient’s initial vitals were blood pressure 108/62 mmHg, heart rate 91, respirations 18, temperature 99.3°F (37°C), and oxygen saturation 96% on room air. Primary exam revealed a pale, well-developed, alert, and oriented female in no acute distress, lying flat in bed. Cardiac exam revealed a +3/6 systolic murmur without radiation to the carotid arteries. Rectal exam was unremarkable, with stool Hemoccult-negative. No splinter hemorrhages were appreciated on nail beds. Head, ears, eyes, nose, throat (HEENT)/neck/pulmonary/abdomen/skin/neurological exams were all grossly unremarkable. An initial electrocardiogram (EKG) was unremarkable. Chest x-ray revealed a right-sided PICC in proper placement, but was otherwise unremarkable. A computer tomography (CT) scan of the head revealed moderate diffuse cerebral volume loss with chronic microvascular ischemic changes. CT abdomen/pelvis revealed a large right-sided pleural effusion and incidental cholelithiasis, but otherwise unremarkable with no retroperitoneal hematoma.\n\nLaboratory assessments on admission were as follows: white blood cell count (WBC) 5.8; hemoglobin/hematocrit (Hgb/Hct) 6.0/17.0; platelets 560; reticulocyte count 12.4%; sodium 129; potassium 3.8; chloride 100; carbon dioxide 23; blood urea nitrogen (BUN) 13; creatinine 0.7; alkaline phosphatase 71; total bilirubin 1.5; aspartate transaminase (AST) 38; alanine transaminase (ALT) 17; lactate dehydrogenase (LDH) 348; haptoglobin 101; direct coombs positive including positivity for both IgG and C3d; activated partial thromboplastin time 24.4; pro-time 13.8; INR 1.2; lactic acid 0.9; and an overall negative urinalysis. Blood cultures were negative. Peripheral blood smear revealed lymphocyte 45%, monocyte 48%, eosinophil 6%, basophil 1%, nucleated red blood cell 10%, +2 anisocytosis, and polychromasia (Figure 2).\n\nThe patient was admitted to a telemetry floor for her symptomatic, likely hemolytic, anemia. Our infectious disease service was consulted, who recommended a change from ceftriaxone to vancomycin due to a likely ongoing drug-induced immune hemolytic anemia. The patient adamantly refused blood products and requested to be treated conservatively. She was started on daily 325 mg ferrous sulfate, daily 1 mg folic acid, and 1000 mcg intramuscular vitamin B12 injections for 7 days. A prednisone taper was initiated, starting at 40 mg daily (starting hospital day 2) for 4 days and then decreasing by 5 mg until off. Epoetin Alfa was initiated on hospital day 2 at 4000 units subcutaneous scheduled every other day. The dose was increased to 8000 units on hospital day 6, 10 000 units on hospital day 8, and 12 000 units on hospital day 10. The patient’s Hgb eventually plateaued at 5.7 and slowly improved with the cessation of ceftriaxone.\n\nOutcome and follow-up\nFigure 3 shows the gradual improvement in hemoglobin (Hgb) throughout the second hospital stay and post-hospital stay. The patient’s severe anemia was successfully treated conservatively and she was safely discharged to home with assistance from family. The patient finished her outpatient antibiotic course of intravenous vancomycin and continues to follow up on a routine basis. The multiple episodes of transient vision loss, which the patient suffered prior to admission, never returned and were explained as being directly related to her severe anemia; i.e., ischemic optic neuropathy.\n\nDiscussion\nThe patient was determined to have a subacute, progressive hemolytic anemia due to her infusions of ceftriaxone. It was concluded that her type of anemia was due to an extravascular hemolysis due to the presence of spherocytes/lack of red blood cell fragments on smear, positive DAT, increase in serum LDH, and absence of urine hemoglobin. The patient’s normal haptoglobin points away from an intravascular hemolysis and may be due to the progressive nature of the anemia. Normal haptoglobin levels may be present in extravascular hemolysis. In the United States, ceftriaxone appears to be the second most common drug causing DIIHA [6,8]. A positive DAT is the most reliable laboratory finding in DIIHA [2].\n\nFor clinical management of a DIIHA, it is useful to categorize the involved antibody as drug-dependent (DDAB) or drug-independent (DIAB) [2]. Ceftriaxone, along with other cephalosporin antibiotics, are most commonly associated with DDAB formation [2,9]. Extravascular hemolysis may result from the production of non-complement-activating, drug-dependent antibodies (DDAB) [10]. DDAB-related hemolysis usually demonstrates a positive DAT and a negative elution, which may be performed to characterize the antibody coating the RBCs [2]. The DAT was positive in our patient, with both IgG and C3d positivity. Unfortunately, there was no elution completed on our patient, which in retrospect may have been helpful in clarifying the final diagnosis. Another possibility would have been to have an immunohematology laboratory, which specializes in DDAB detection, confirm the presence or absence of specific anti-ceftriaxone antibodies.\n\nFor drug-dependent hemolysis, cessation of the drug (usually cefotetan, ceftriaxone, or piperacillin) is critical and this is equally true for drug-independent hemolysis, but because of the true autoantibody in drug-independent hemolysis, patients should additionally be treated as for warm antibody autoimmune hemolytic anemia (WAIHA) (i.e., with steroids, IVIG, and/ or plasma exchange) [2,8]. It was decided to initiate intravenous steroids in the patient due to the lack of contraindication and possibility of benefit in that WAIHA could not be ruled out secondary to the lack of antibody analysis. Differentiation between DIIHA and WAIHA can be fairly challenging. The only reliable confirmation of DDAB-mediated DIIHA over WAIHA requires testing the patient’s serum after drug cessation and clearance of any circulating drug or drug-antibody complexes, indicated by a clear decrease in serologic reactivity [2]. There is no need at the present time for this continued testing in the patient due to the lack of DDAB verification during the acute event. Retrospectively, confirmation of the presence of DDAB should be been sought.\n\nMost cases of WAIHA are idiopathic, with no direct cause found. It is usually associated with splenomegaly, severe anemia, fever, and jaundice, and is mostly associated with extravascular hemolysis [11]. Our patient did not have splenomegaly, fever, or jaundice, but did have spherocytes and polychromatophilicred cells on the repeat blood smear completed on hospital day 4. Hemolysis associated with ceftriaxone typically appears within 2 weeks of starting the drug and presents with progressive anemia [2], which exactly fits the clinical picture of our patient, leading to the conclusion that this case was likely a DIIHA, specifically a CIIHA. This again can only be concluded with a relative amount of certainty in that the serological evaluation was limited and therefore not allowing for a definitive diagnosis.\n\nThe differential diagnosis initially included G6PD deficiency, which was deemed doubtful due to the standard timing of G6PD presentation being 2–4 days after initial drug ingestion, as well as the lack of red blood cells fragments or “bite” cells on peripheral smear. Acute transfusion reaction could easily have been eliminated from the list of differential diagnosis in our patient. Infectious etiology, with the patient’s recent (3 weeks prior) endocarditis history, was initially debated as the cause of the acute hemolysis. It is important to mention that the only positive blood cultures documented were the initial set during the initial hospitalization, which grew group B streptococcus. The presence of fragmented erythrocytes (on smear) suggests mechanical destruction of the RBCs [12], even regarding a native heart valve. There were no RBC fragments seen on smear, and with the clinical picture pointing toward an extravascular hemolysis, an infectious cause was considered unlikely.\n\nConclusions\nThe presented case highlights the importance of close vigilance while prescribing drugs known to cause hemolytic anemia. Most published cases to date involving CIIHA are in children [13] and most include blood product transfusions as the standard of treatment. The presented case is very unique in that this patient with severe hemolytic anemia was a Jehovah’s Witness and was able to be successfully treated without blood product transfusion. In retrospect, further antibody evaluation should have been sought, which would have eliminated the need to speculate on the definitive diagnosis.\n\nWe thank David Lester for providing assistance with publication searches. We thank Dr Terry Lenhardt, M.D., Ph.D. for his support in obtaining blood smear images. We also thank Dr Jerry Pudusseri, DO for his time and assistance in providing TEE images.\n\nCompeting Interests\n\nNone.\n\nFigure 1. (A, B) These 2 transesophageal echocardiogram (TEE) images show the vegetation on the anterior leaflet of the mitral valve. The vegetation was not seen on the standard 2-D transthoracic echocardiogram (TTE).\n\nFigure 2. This blood smear demonstrates the presence of numerous spherocytes (smaller, more dense cells), abundant immature reticulocytes (larger cells with significant central pallor), and the lack of schistocytes or “bite” cells.\n\nFigure 3. This graph depicts the patient’s Hgb levels from her first hospitalization through the post second hospitalization outpatient followup. Hgb measured in g/dL. (*) designates day 1 of cessation of ceftriaxone and transition to vancomycin. Solid bar designates hospitalization 1 and dotted bar designates hospitalization 2.\n==== Refs\nReferences:\n1. Mayer B Bartolmäs T Yürek S Salama A Variability of findings in drug-induced immune haemolytic anaemia: Axperience over 20 years in a single centre Transfus Med Hemother 2015 42 5 333 39 26696803 \n2. Pierce A Nester T Education Committee of the Academy of Clinical Laboratory Physicians and Scientists: Pathology consultation on drug-induced hemolytic anemia Am J Clin Pathol 2011 136 1 7 12 21685026 \n3. Arndt PA Leger RM Garratty G Serology of antibodies to second- and third-generation cephalosporins associated with immune hemolytic anemia and/ or positive direct antiglobulin tests Transfusion 1999 39 11–12 1239 46 10604252 \n4. Garratty G Postoway N Schwellenbach J McMahill PC A fatal case of ceftriaxone (Rocephin)-induced hemolytic anemia associated with intravascular immune hemolysis Transfusion 1991 31 2 176 49 1825363 \n5. Garratty G Immune hemolytic anemia caused by drugs Expert Opin Drug Saf 2012 11 4 635 42 22502777 \n6. Arndt PA Leger RM Garratty G Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune hemolytic anemia Transfusion 2012 52 3 602 12 21880048 \n7. Neuman G Boodhan S Wurman I Ceftriaxone-induced immune hemolytic anemia Ann Pharmacother 2014 48 12 1594 604 25163809 \n8. Garratty G Immune hemolytic anemia associated with drug therapy Blood Rev 2010 24 4–5 143 50 20650555 \n9. Guleria VS Sharma N Amitabh S Nair V Ceftriaxone-induced hemolysis Indian J Pharmacol 2013 45 5 530 31 24130395 \n10. Garbe E Andersohn F Bronder E Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study Br J Haematol 2011 154 5 644 53 21749359 \n11. Packman CH The clinical pictures of autoimmune hemolytic anemia Transfus Med Hemother 2015 42 5 317 24 26696800 \n12. Huang HL Lin FC Hung KC Hemolytic anemia in native valve infective endocarditis: A case report and literature review Jpn Circ J 1999 63 5 400 3 10943622 \n13. Imam SN Wright K Bhoopalam N Choudhury A Hemolytic anemia from ceftriaxone in an elderly patient: A case report J Am Med Dir Assoc 2008 9 8 610 11 19083297\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "18()",
"journal": "The American journal of case reports",
"keywords": "Anemia, Hemolytic; Ceftriaxone; Jehovah's Witnesses",
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D000743:Anemia, Hemolytic; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D004697:Endocarditis, Bacterial; D000068817:Epoetin Alfa; D005260:Female; D005296:Ferrous Compounds; D005492:Folic Acid; D006397:Hematinics; D006801:Humans; D033221:Jehovah's Witnesses; D014805:Vitamin B 12",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "431-435",
"pmc": null,
"pmid": "28428532",
"pubdate": "2017-04-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19083297;26696800;10604252;1825363;21880048;24130395;22502777;21749359;21685026;20650555;10943622;26696803;25163809",
"title": "Ceftriaxone-Induced Hemolytic Anemia in a Jehovah's Witness.",
"title_normalized": "ceftriaxone induced hemolytic anemia in a jehovah s witness"
} | [
{
"companynumb": "US-ROCHE-1944826",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": "1",
"drug... |
{
"abstract": "OBJECTIVE\nTo assess the prevalence of false-positive meningeal contrast enhancement in patients with solid tumors who were undergoing chemotherapy.\n\n\nMETHODS\nA total of 2572 magnetic resonance imaging (MRI) examinations of the brain were retrospectively evaluated by two readers for the presence of pathological meningeal contrast enhancement conspicuous for neoplastic meningitis. These patients either had malignant melanoma, breast or lung cancer, or lymphoma. The reference standards were cerebrospinal fluid cytology results and follow-up MRI. In cases with pathological contrast enhancement that decreased upon follow-up and non-malignant cytology, the enhancement pattern was further described as pial or dural, local or diffuse, or supra- or infra-tentorial. Moreover, the underlying therapy regimes were assessed.\n\n\nRESULTS\nThe final study cohort included 78 patients (51 females, median age 57 years), of which 11 patients (14.1%) had a repeated non-malignant cytology ('pseudomeningeosis'). In one case, this finding, a granular pleocytosis, was attributed to previous radiotherapy. Of the remaining patients, seven were receiving multimodal, immunotherapy-based therapy regimens. Patients with unsuspicious cytology had a predominantly supratentorial distribution pattern in comparison to patients with neoplastic meningitis.\n\n\nCONCLUSIONS\nThe overall prevalence of the presence of false-positive meningeal contrast enhancement is low (< 1%) and not associated with specific imaging patterns. We hypothesize that there is a possible relationship between immunotherapy and 'pseudomeningeosis'. Therefore, in all cases with suspected neoplastic meningitis, the cerebrospinal fluid should be analyzed to confirm the diagnosis, especially in patients undergoing immunotherapy.",
"affiliations": "Institute of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany. georghomann@web.de.;Diagnostic and Interventional Radiology, Eberhard Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.;Department of Neurosurgery and Interdisciplinary Division of Neurooncology, Eberhard Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.;Department of Dermatology, Eberhard Karls University Tuebingen, Liebermeisterstr. 25, 72076, Tuebingen, Germany.;Diagnostic and Interventional Radiology, Eberhard Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.;Diagnostic and Interventional Neuroradiology, Eberhard Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.;Diagnostic and Interventional Neuroradiology, Eberhard Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.",
"authors": "Bier|Georg|G|http://orcid.org/0000-0002-1034-5681;Klumpp|Bernhard|B|;Roder|Constantin|C|;Garbe|Claus|C|;Preibsch|Heike|H|;Ernemann|Ulrike|U|;Hempel|Johann-Martin|JM|",
"chemical_list": "D003287:Contrast Media",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00234-019-02215-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3940",
"issue": "61(7)",
"journal": "Neuroradiology",
"keywords": "Contrast-enhancement; False positive reactions; Immunotherapy; Magnetic resonance imaging; Meningeal carcinomatosis",
"medline_ta": "Neuroradiology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003287:Contrast Media; D003430:Cross-Sectional Studies; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D055756:Meningeal Carcinomatosis; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "1302751",
"other_id": null,
"pages": "775-782",
"pmc": null,
"pmid": "31001647",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "10525979;16386866;16632315;16707725;17374867;18485616;18795275;19479865;19965290;2086737;21358101;21373901;23447136;24453817;2594181;26264063;26427830;27333363;28039364;28106152;28271869;28945858;29341936;29880440;29983829;6895713;8232877;843571",
"title": "Meningeal enhancement depicted by magnetic resonance imaging in tumor patients: neoplastic meningitis or therapy-related enhancement?",
"title_normalized": "meningeal enhancement depicted by magnetic resonance imaging in tumor patients neoplastic meningitis or therapy related enhancement"
} | [
{
"companynumb": "DE-ROCHE-2350081",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nIn Hong Kong, most patients with hepatitis C virus (HCV) have either genotype 6a or 1b infection.\n\n\nOBJECTIVE\nTo evaluate the efficacy and safety of sofosbuvir with ribavirin in treatment-naïve patients in Hong Kong with HCV genotype 1 or 6.\n\n\nMETHODS\nIn an open-label study, patients were randomised to sofosbuvir 400 mg once daily plus ribavirin 1000-1200 divided twice daily for 12 (n = 10), 16 (n = 11) or 24 (n = 10) weeks. The primary endpoint was the percentage of patients with HCV RNA < LLOQ (lower limit of quantification, 25 IU/mL) 12 weeks after cessation of therapy (SVR12).\n\n\nRESULTS\nAll 31 patients (20 HCV genotype 1 and 11 genotype 6) had HCV RNA < LLOQ by Week 4 of treatment and at their last on-treatment visit. SVR12 rates were high in all treatment groups: 100% (10/10) for 12 weeks, 100% (11/11) for 16 weeks and 90% (9/10) for 24 weeks of therapy. The only patient who did not reach SVR12 had genotype 1 HCV and relapsed at post-treatment Week 4. Sofosbuvir with ribavirin was generally well tolerated. The most common adverse events were malaise (13%) and upper respiratory tract infection (13%), followed by anaemia (10%). No patients experienced serious adverse events. One patient discontinued treatment at Week 16 because of an adverse event. The event, upper respiratory tract infection, was not considered treatment related by the investigator. This subject achieved SVR12.\n\n\nCONCLUSIONS\nThe all-oral regimen sofosbuvir plus ribavirin is effective in treatment-naïve patients in Hong Kong with genotype 1 or 6 HCV.\n\n\nBACKGROUND\nNCT02021643.",
"affiliations": "Queen Mary Hospital, Hong Kong, China.;Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.;Queen Mary Hospital, Hong Kong, China.;Gilead Sciences Inc., Foster City, CA, USA.;Gilead Sciences Inc., Foster City, CA, USA.;Gilead Sciences Inc., Foster City, CA, USA.;Gilead Sciences Inc., Foster City, CA, USA.;Gilead Sciences Inc., Foster City, CA, USA.;Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.",
"authors": "Lai|C L|CL|;Wong|V W-S|VW|;Yuen|M F|MF|;Yang|J C|JC|;Knox|S J|SJ|;Mo|H|H|;Han|L L|LL|;Brainard|D M|DM|;Chan|H L Y|HL|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D012313:RNA; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.1111/apt.13429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "43(1)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006723:Hong Kong; D006801:Humans; D008297:Male; D008875:Middle Aged; D012313:RNA; D012254:Ribavirin; D000069474:Sofosbuvir; D016896:Treatment Outcome",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "96-101",
"pmc": null,
"pmid": "26503414",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sofosbuvir plus ribavirin for the treatment of patients with chronic genotype 1 or 6 hepatitis C virus infection in Hong Kong.",
"title_normalized": "sofosbuvir plus ribavirin for the treatment of patients with chronic genotype 1 or 6 hepatitis c virus infection in hong kong"
} | [
{
"companynumb": "HK-BAUSCH-BL-2016-000250",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nHuman leukocyte antigen (HLA) has been recognized as the most important genetic risk factor for severe cutaneous adverse drug reactions (SCARs) caused by certain drugs. However, cumulated observations suggest the presence of genetic risk factors for SCARs other than drug-specific HLA. We aimed to identify a common genetic risk factor of SCARs across multiple drugs.\n\n\nMETHODS\nWe performed 2 independent genome-wide association studies (GWASs). A total of 68 and 38 subjects with a diagnosis of SCAR were enrolled in each GWAS. Their allele frequencies were compared to those of healthy subjects in Korea.\n\n\nRESULTS\nNo single nucleotide polymorphism (SNP) with genome-wide significance was found in either GWAS. We next selected and annotated the 200 top-ranked SNPs from each GWAS. These 2 sets of annotated genes were then entered into the web interface of ConsensusPathDB for a pathway-level analysis. The Fas signaling pathway was significantly over-represented in each gene set from the 2 GWASs.\n\n\nCONCLUSIONS\nOur observations suggest that the Fas signaling pathway may be a common genetic risk factor for SCARs across multiple drugs.",
"affiliations": "Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea.;Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea.;Department of Dermatology, Dongguk University Ilsan Hospital, Goyang, Korea.;Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.;Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.",
"authors": "Park|Heung Woo|HW|https://orcid.org/0000-0002-6970-3228;Kim|Sang Heon|SH|;Chang|Yoon Seok|YS|;Kim|Sang Hoon|SH|;Jee|Young Koo|YK|;Lee|Ai Young|AY|;Jang|In Jin|IJ|;Park|Hae Sim|HS|https://orcid.org/0000-0003-2614-0303;Min|Kyung Up|KU|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4168/aair.2018.10.5.555",
"fulltext": "\n==== Front\nAllergy Asthma Immunol ResAllergy Asthma Immunol ResAAIRAllergy, Asthma & Immunology Research2092-73552092-7363The Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease 10.4168/aair.2018.10.5.555Original ArticleThe Fas Signaling Pathway Is a Common Genetic Risk Factor for Severe Cutaneous Drug Adverse Reactions Across Diverse Drugs https://orcid.org/0000-0002-6970-3228Park Heung-Woo 12Kim Sang-Heon 3Chang Yoon-Seok 4Kim Sang-Hoon 5Jee Young-Koo 6Lee Ai-Young 7Jang In-Jin 8https://orcid.org/0000-0003-2614-0303Park Hae-Sim 9Min Kyung-Up 121 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.2 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.3 Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea.4 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.5 Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea.6 Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea.7 Department of Dermatology, Dongguk University Ilsan Hospital, Goyang, Korea.8 Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.9 Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.Correspondence to Heung-Woo Park, MD, PhD. Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: +82-2-2072-0699, Fax: +82-2-742-3291, guinea71@snu.ac.kr9 2018 09 7 2018 10 5 555 561 06 2 2018 25 5 2018 01 6 2018 Copyright © 2018 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease2018The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory DiseaseThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nHuman leukocyte antigen (HLA) has been recognized as the most important genetic risk factor for severe cutaneous adverse drug reactions (SCARs) caused by certain drugs. However, cumulated observations suggest the presence of genetic risk factors for SCARs other than drug-specific HLA. We aimed to identify a common genetic risk factor of SCARs across multiple drugs.\n\nMethods\nWe performed 2 independent genome-wide association studies (GWASs). A total of 68 and 38 subjects with a diagnosis of SCAR were enrolled in each GWAS. Their allele frequencies were compared to those of healthy subjects in Korea.\n\nResults\nNo single nucleotide polymorphism (SNP) with genome-wide significance was found in either GWAS. We next selected and annotated the 200 top-ranked SNPs from each GWAS. These 2 sets of annotated genes were then entered into the web interface of ConsensusPathDB for a pathway-level analysis. The Fas signaling pathway was significantly over-represented in each gene set from the 2 GWASs.\n\nConclusions\nOur observations suggest that the Fas signaling pathway may be a common genetic risk factor for SCARs across multiple drugs.\n\nDrugStevens-Johnson syndrometoxic epidermal necrolysisgenome-wide association studyFas signaling pathway\n==== Body\nINTRODUCTION\nSevere cutaneous adverse drug reactions (SCARs) characterized by an acute inflammatory reaction of the skin and mucous membranes are very rare, but sometimes fatal.1 SCARs include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS).1 Thus far, human leukocyte antigen (HLA) has been recognized as the most important genetic risk factor for SCARs caused by certain drugs.2 However, we reported that only 20% of carriers of the HLA-B*58:01 allele experienced an allopurinol-induced SCAR.3 Similarly, the risk of carbamazepine-induced hypersensitivity was 26% in carriers of HLA-A*31:01 in a European population.4 These observations suggest the presence of genetic risk factors for SCARs other than drug-specific HLA. The purpose of this study was to identify common genetic risk factors of SCARs in addition to drug-specific HLA. Cases of SCAR induced by various drugs were collected and a genome-wide association study (GWAS) was performed. As previously mentioned, drug-specific HLA is believed to be the strongest risk factor for SCAR. Therefore, it is possible that genetic variants with modest effects on SCAR are not captured in a GWAS. To overcome this problem, we used the gene set-based approach, which increases the likelihood of identifying the biological pathway involved by utilizing enrichment tools.5\n\nMATERIALS AND METHODS\nWe performed 2 independent GWASs in 2008 (the first) and 2012 (the second). All subjects with SCAR were enrolled by the Adverse Drug Reaction Research Group, Korea. Each study was approved by the Institutional Review Board of the Seoul National University Hospital (H-0506-150-011 and C-1111-100-387) and informed consent was obtained from all study participants.\n\nStudy subjects and phenotype definitions\nSJS, SJS/TEN overlap and TEN were diagnosed according to the range of detached surface area (< 10%, 10%–30% and > 30%, respectively).67 DRESS was defined when a subject met at least five of the following criteria: development of a maculopapular rash more than 3 weeks after starting a limited number of drugs, prolonged clinical symptoms for 2 weeks after discontinuation of the causative drug, fever (> 38°C), liver abnormalities or other organ involvement, leukocyte abnormalities such as leukocytosis (>11 × 109 cells/L), atypical lymphocytosis (> 5%), or eosinophilia (>1.5 × 109 cells/L), lymphadenopathy, and human herpes virus 6 reactivation.8 All clinical evaluations were performed by allergy specialists with more than 10 years of experience in drug allergy consultation. A drug was classified as a cause of SCAR when it satisfied the grade of ‘certain’ or ‘probable’ on the World Health Organization-Uppsala Monitoring Center causality assessment system.9 Characteristics of subjects with SCAR are shown in Table 1. Control subjects were selected from a publicly available database to provide a 4:1 match with the case subjects. All control subjects were healthy Koreans and were genotyped on the same chip in each GWAS.\n\nTable 1 Characteristics of SCAR subjects\nCharacteristic\tFirst GWAS (n = 68)\tSecond GWAS (n = 38)\t\nMale\t35 (51.5)\t35 (51.5)\t\nAge (yr)\t49.8 ± 16.8\t52 ± 19.2\t\nPhenotype\t\t\t\n\tSJS/Overlap*/TEN/DRESS\t14 (20.6)/12 (17.6)/4 (5.9)/38 (55.9)\t7 (18.4)/6 (15.8)/4 (10.5)/21 (55.3)\t\nCausative drug\t\t\t\n\tAllopurinol\t13 (19.1)\t5 (13.2)\t\n\tCarbamazepine\t18 (26.5)\t3 (7.9)\t\n\tAnti-epileptics except carbamazepine\t7 (10.3)†\t6 (15.8)¶\t\n\tAcetaminophen\t3 (4.4)\t3 (7.9)\t\n\tNSAID\t6 (8.8)‡\t12 (31.5)**\t\n\tBeta-lactam antibiotics\t7 (10.3)§\t9 (23.7)††\t\n\tOthers\t14 (20.6)∥\t-\t\nData are shown as number (%) or mean ± standard deviation.\n\nSCAR, severe cutaneous adverse drug reaction; GWAS, genome-wide association study; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DRESS, drug rash with eosinophilia and systemic symptom; NSAID, non-steroidal anti-inflammatory drug.\n\n*SJS/TEN overlap syndrome; †Including phenytoin (3), valproic acid (2), and lamotrigine (2); ‡Including ibuprofen (4) and mefenamic acid (2); §Including ceftezole (2), cefaclor (2), piperacillin (1), cefazolin (1), and cefpiramide (1); ∥Including anti-tuberculosis medication (6), oriental herbal medication (3), vancomycin (2), sulfasalazine (1), pantoprazole (1), and propylthiouracil (1); ¶Including phenytoin (5) and lamotrigine (1); **Including ibuprofen (6), loxoprofen (3), and mefenamic acid (3); ††Including amoxicillin (2), cefaclor (2), cefbuperazone (1), cefixime (1), cefoxitin (1), cephradine (1), and meropenem (1).\n\nGenotyping\nDNA of subjects included in the first GWAS was genotyped on the Affymetrix 500K Chip (Affymetrix, Santa Clara, CA, USA). DNA of subjects included in the second GWAS was genotyped on the Affymetrix Axiom® Genome-Wide East Asian Ancestry Chip. All single nucleotide polymorphisms (SNPs) that were included in the GWAS had a completion rate of >95%, a minor allele frequency of >0.05, and a Hardy-Weinberg equilibrium P value >0.0001.\n\nStatistical analysis\nAssociations between SNPs and the occurrence of SCAR were measured according to a linear regression model, as implemented in PLINK,10 using an additive genetic model. The regression models were adjusted for age and sex. SNPs with P values < 10−8 in the GWAS were considered genome-wide significant. For over-representation analysis, we selected and annotated the 200 top-ranked SNPs from both GWASs using the open-source software package NCBI2R in the statistical and graphical environment of R software (http://www.r-project.org). Only genes that harbored the SNP of interest were selected; 62 genes were identified from the first GWAS and 69 were identified from the second GWAS. Gene lists are provided in Supplementary Tables S1 and S2. The list of genes was then entered into the web interface of ConsensusPathDB (http://cpdb.molgen.mpg.de) for pathway-level interpretation. ConsensusPathDB is a meta-database that integrates different types of functional interactions from heterogeneous interaction data resources.11 To control for multiple tests, 0.05 was set as the limit of Q values, which were calculated using the false discovery rate method.\n\nRESULTS\nThe top-ranked SNP in the first GWAS was rs2327661 (P = 6.3 × 10−7) and that in the second GWAS was rs8180036 (P = 4.48 × 10−6). However, none of the SNP reached genome-wide significance. A list of the 200 top-ranked SNPs is provided in Supplementary Table S3 and the Manhattan plots each GWAS are presented in Supplementary Fig. S1. Over-representation analysis of the annotated gene sets by ConsensusPathDB identified 17 significant pathways in the first GWAS and 3 significant pathways in the second GWAS, see Tables 2 and 3. Interestingly, the Fas signaling pathway (the fourth ranked pathway in the first GWAS and the 1st ranked pathway in the second GWAS) was commonly found. Two genes (CASP10 and MAP3K7) in the gene set from the first GWAS and 3 genes (PTPN13, PRKDC and FADD) in the gene set from the second GWAS were significantly over-represented in the Fas signaling pathway, see Supplementary Table S4.\n\nTable 2 Pathway-based gene sets identified from the first GWAS\nP value\tQ value\tPathway\tSource\tOverlapped genes*\t\n0.00069918\t0.02407312\tPropanoate metabolism\tSMPDB\tACACA; ABAT\t\n0.00091873\t0.02407312\tIL-4 signaling pathway\tPID, BioCarta\tHLA-DRA; JAK1\t\n0.00109038\t0.02407312\tLeishmaniasis - Homo sapiens (human)\tKEGG\tHLA-DRA; MAP3K7; JAK1\t\n0.00144439\t0.02407312\tFas signaling pathway (cd95)\tPID, BioCarta\tCASP10; MAP3K7\t\n0.00244457\t0.02575628\tA tetrasaccharide linker sequence is required for GAG synthesis\tReactome\tVCAN; GPC5\t\n0.00263548\t0.02575628\tAlk in cardiac myocytes\tPID, BioCarta\tBMP7; MAP3K7\t\n0.00283319\t0.02575628\tThrombin signaling and protease-activated receptors\tPID, BioCarta\tPLCB1; MAP3K7\t\n0.00346684\t0.02636741\tIL-17 signaling pathway\tWikipathways\tMAP3K7; JAK1\t\n0.00346684\t0.02636741\tMucin type O-glycan biosynthesis - Homo sapiens (human)\tKEGG\tGALNTL6; WBSCR17\t\n0.00369144\t0.02636741\tPropanoate metabolism - Homo sapiens (human)\tKEGG\tACACA; ABAT\t\n0.00446835\t0.02978898\tToxoplasmosis - Homo sapiens (human)\tKEGG\tHLA-DRA; MAP3K7; JAK1\t\n0.00517687\t0.03235546\tFAS pathway and stress induction of HSP regulation\tWikipathways\tCASP10; MAP3K7\t\n0.00600657\t0.03533279\tBMP receptor signaling\tPID\tBMP7; MAP3K7\t\n0.00751491\t0.0417495\tProton pump inhibitor pathway, Pharmacodynamics\tPharmGKB\tPLCB1; AKAP2\t\n0.00816134\t0.04295442\tChondroitin sulfate/dermatan sulfate metabolism\tReactome\tVCAN; GPC5\t\n0.00917629\t0.04588144\tDownstream TCR signaling\tReactome\tHLA-DRA; MAP3K7\t\n0.00966203\t0.04600966\tHippo signaling pathway - Homo sapiens (human)\tKEGG\tBMP7; GLI2; CTNNA3\t\nInput options: 13 databases, minimum overlap with input list = 2 and P value cutoff = 0.01. Bold styled value means overlapped pathway.\n\nGWAS, genome-wide association study.\n\n*Overlapped genes between the input and database sets; bold denotes a common pathway identified from the first and second GWASs.\n\nTable 3 Pathway-based gene sets identified from the second GWAS\nP value\tQ value\tPathway\tSource\tOverlapped genes*\t\n0.00010214\t0.00423877\tFas signaling pathway (cd95)\tPID, BioCarta\tPTPN13; FADD; PRKDC\t\n0.00085642\t0.02369427\tG protein signaling pathways\tWikipathways\tPRKCH; PDE4B; PRKAR2B; PDE8B\t\n0.00214336\t0.03557973\tRepression of pain sensation by the transcriptional regulator, DREAM\tPID, BioCarta\tPRKAR2B; CREM\t\nInput options: 13 databases, minimum overlap with input list = 2 and P value cutoff = 0.01. Bold styled value means overlapped pathway.\n\nGWAS, genome-wide association study\n\n*Overlapped genes between the input and database sets; bold denotes a common pathway identified from the first and second GWASs.\n\nDISCUSSION\nPrevious GWASs have identified only SNPs located in the HLA region12 or SNPs in linkage disequilibrium with HLA alleles1314 as genetic risk factors for SCAR. In our study, causative drugs were diverse, and thus we could not adjust for the potential effects of the drug-specific HLA. Considering that the drug-specific HLA is believed to be the strongest genetic risk factor of SCAR, failure to adjust for its effects may partly explain why we did not detect any SNPs with genome-wide significance. It may be true that no single genetic variant confers an increased risk of SCAR greater than the drug-specific HLA. A gene set-based approach is widely used in genetic studies and has shown promising results. Likewise, we found that the gene sets annotated with the 200 top-ranked SNPs from t2 independent GWASs of SCAR induced by diverse drugs were commonly over-represented in the Fas signaling pathway. To the best of our knowledge, this is the first study to show that the Fas signaling pathway is a common genetic risk factor for SCAR across diverse drugs.\n\nOver-representation analysis statistically evaluates the fraction of genes in a particular pathway found among a set of genes (input).5 Over-representation analysis can be performed in ConsensusPathDB using gene sets and functional modules derived from incorporating pathway definitions provided by the source databases. For each predefined module, a P value is calculated based on the hypergeometric distribution, which reflects the significance of the observed overlap between the input gene list and the module's members compared to random expectations.15 If the input list is obtained from a case-control study, over-representation analysis may indicate pathways and functional sub-networks that are dysregulated in the disease state.\n\nThe Fas receptor (CD95) mediates apoptosis via the Fas-ligand (FasL), which is expressed on the surface of other cells. The Fas-FasL interaction plays an important role in the immune system and a lack of this interaction leads to autoimmunity.16 Fas-induced keratinocyte apoptosis plays a key role in the pathogenesis of SCAR.1718 Therefore, our observations suggest that the genetic susceptibility associated with the Fas signaling pathway may be a common (drug-non-specific) risk factor for the development of SCAR in conjunction with the drug-specific HLA, although detailed genetic mechanisms should be investigated in a future study.\n\nAlthough genome-wide significance was not reached, some SNPs mapped to NKAIN2 (Sodium/Potassium Transporting ATPase Interacting 2 gene) and ANGPT2 (Angiopoietin 2 gene) showed significant associations with SCAR both in 2 GWASs. NKAIN2 gene encodes a transmembrane protein that interacts with the beta subunit of a sodium/potassium-transporting ATPase. A previous report showed that a chromosomal translocation involving this gene was a cause of lymphoma.19 Angiopoietin 2 encoded by ANGPT2 is an antagonist of angiopoietin 1 and thus disrupts its vascular remodeling ability which may induce endothelial cell apoptosis.20 However, so far, there has been no report to show the association between SCAR or drug adverse reaction and NKAIN2 or ANGPT2. This finding may emphasize an importance of the gene-set based analysis, although further mechanistic studies need to be performed.\n\nThere are a few limitations to the present study. First, our genotyping platforms differed between the 2 GWASs and thus SNPs genotyped overlapped poorly, which increased the likelihood that SNPs that were significantly associated with SCAR were not genotyped across the studies. However, it is known that the probabilistic nature of imputed SNPs presents challenges when testing for association of those SNPs.21 Therefore, we used a gene-based approach instead of imputation of our SNP dataset. Secondly, a SNP was annotated to a gene when a gene harbored that SNP within its chromosomal region. A SNP located outside of a gene can be functionally relevant by affecting the expression of genes located adjacently or remotely.22 In addition, we selected only the 200 top-ranked SNPs for analysis. Therefore, it is possible that some functionally important genes were missed and thus not included in the over-representation analysis, which limited the identification of more significant pathways. Secondly, approximately half of the enrolled subjects (subjects with a diagnosis of DRESS) showed skin eruption rather than blister or detachment. The role of Fas-FasL in the pathogenesis of drug eruption is not clear. However, a previous report showed that overlapping expression of Fas and FasL is accompanied by apoptosis in fixed-drug eruption lesions.23 In addition, we found no difference between DRESS cases and all other cases in our over-representation analysis (data not shown). Thus, it is possible that the Fas signaling pathway plays its own role in the pathogenesis of eruption seen in subjects with DRESS. Another possible explanation is that prompt and intensive treatment may have stopped the progression from eruption to blister or detachment in the subjects enrolled in this study. Thirdly, a small number of patients with SCAR was also an important issue before generalizing our results. However, given that SCAR is a very rare event, our findings may provide investigators to prioritize variants for follow-up analysis. A pathway analysis based on the gene set is known to be particularly useful for pilot studies with small sample sizes.24\n\nIn conclusion, an over-representation analysis using gene sets from 2 independent GWASs of SCAR induced by diverse drugs identified the Fas signaling pathway as a significant and common pathway. Our observations suggest that the Fas signaling pathway may be a common genetic risk factor for SCARs across diverse drugs.\n\nDisclosure: There are no financial or other issues that might lead to conflict of interest.\n\nSUPPLEMENTARY MATERIALS\nSupplementary Table S1\nA total of 62 SNPs and their annotated genes in the first GWAS used for an over-representation analysis\n\n Supplementary Table S2\nA total of 69 SNPs and their annotated genes in the second GWAS used for an over-representation analysis\n\n Supplementary Table S3\nThe top-ranked 200 SNPs identified from the first and second GWAS\n\n Supplementary Table S4\nGenes significantly over-represented in the Fas signaling pathway\n\n Supplementary Fig. S1\nThe Manhattan plots of each GWAS. (A) The first GWAS. (B) The second GWAS.\n==== Refs\n1 Chung WH Wang CW Dao RL Severe cutaneous adverse drug reactions J Dermatol 2016 43 758 766 27154258 \n2 Pavlos R Mallal S Phillips E HLA and pharmacogenetics of drug hypersensitivity Pharmacogenomics 2012 13 1285 1306 22920398 \n3 Jung JW Song WJ Kim YS Joo KW Lee KW Kim SH HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency Nephrol Dial Transplant 2011 26 3567 3572 21393610 \n4 McCormack M Alfirevic A Bourgeois S Farrell JJ Kasperavičiūtė D Carrington M HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans N Engl J Med 2011 364 1134 1143 21428769 \n5 Khatri P Sirota M Butte AJ Ten years of pathway analysis: current approaches and outstanding challenges PLoS Comput Biol 2012 8 e1002375 22383865 \n6 Creamer D Walsh SA Dziewulski P Exton LS Lee HY Dart JK U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016 Br J Dermatol 2016 174 1194 1227 27317286 \n7 French LE Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding Allergol Int 2006 55 9 16 17075281 \n8 Shiohara T Iijima M Ikezawa Z Hashimoto K The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations Br J Dermatol 2007 156 1083 1084 17381452 \n9 World Health Organization, Uppsala Monitoring Centre The use of the WHO-UMC system for standardized case causality assessment Uppsala The Uppsala Monitoring Centre 2005 \n10 Purcell S Neale B Todd-Brown K Thomas L Ferreira MA Bender D PLINK: a tool set for whole-genome association and population-based linkage analyses Am J Hum Genet 2007 81 559 575 17701901 \n11 Kamburov A Wierling C Lehrach H Herwig R ConsensusPathDB--a database for integrating human functional interaction networks Nucleic Acids Res 2009 37 D623 D628 18940869 \n12 Génin E Schumacher M Roujeau JC Naldi L Liss Y Kazma R Genome-wide association study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Europe Orphanet J Rare Dis 2011 6 52 21801394 \n13 Ozeki T Mushiroda T Yowang A Takahashi A Kubo M Shirakata Y Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population Hum Mol Genet 2011 20 1034 1041 21149285 \n14 Tohkin M Kaniwa N Saito Y Sugiyama E Kurose K Nishikawa J A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients Pharmacogenomics J 2013 13 60 69 21912425 \n15 Kamburov A Pentchev K Galicka H Wierling C Lehrach H Herwig R ConsensusPathDB: toward a more complete picture of cell biology Nucleic Acids Res 2011 39 D712 D717 21071422 \n16 Brunner T Wasem C Torgler R Cima I Jakob S Corazza N Fas (CD95/Apo-1) ligand regulation in T cell homeostasis, cell-mediated cytotoxicity and immune pathology Semin Immunol 2003 15 167 176 14563115 \n17 French LE Trent JT Kerdel FA Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding Int Immunopharmacol 2006 6 543 549 16504917 \n18 Su SC Chung WH Cytotoxic proteins and therapeutic targets in severe cutaneous adverse reactions Toxins (Basel) 2014 6 194 210 24394640 \n19 Zhao SC Zhou BW Luo F Mao X Lu YJ The structure and function of NKAIN2-a candidate tumor suppressor Int J Clin Exp Med 2015 8 17072 17079 26770299 \n20 Augustin HG Koh GY Thurston G Alitalo K Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system Nat Rev Mol Cell Biol 2009 10 165 177 19234476 \n21 Marchini J Howie B Genotype imputation for genome-wide association studies Nat Rev Genet 2010 11 499 511 20517342 \n22 Westra HJ Franke L From genome to function by studying eQTLs Biochim Biophys Acta 2014 1842 1896 1902 24798236 \n23 Choi HJ Ku JK Kim MY Kang H Cho SH Kim HO Possible role of Fas/Fas ligand-mediated apoptosis in the pathogenesis of fixed drug eruption Br J Dermatol 2006 154 419 425 16445769 \n24 Kao PY Leung KH Chan LW Yip SP Yap MK Pathway analysis of complex diseases for GWAS, extending to consider rare variants, multi-omics and interactions Biochim Biophys Acta 2017 1861 335 353 27888147\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2092-7355",
"issue": "10(5)",
"journal": "Allergy, asthma & immunology research",
"keywords": "Drug; Fas signaling pathway; Stevens-Johnson syndrome; genome-wide association study; toxic epidermal necrolysis",
"medline_ta": "Allergy Asthma Immunol Res",
"mesh_terms": null,
"nlm_unique_id": "101518382",
"other_id": null,
"pages": "555-561",
"pmc": null,
"pmid": "30088374",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": "17075281;27154258;21912425;22383865;22920398;24798236;27888147;16504917;14563115;20517342;16445769;19234476;27317286;21428769;17381452;21393610;24394640;17701901;26770299;21801394;21071422;21149285;18940869",
"title": "The Fas Signaling Pathway Is a Common Genetic Risk Factor for Severe Cutaneous Drug Adverse Reactions Across Diverse Drugs.",
"title_normalized": "the fas signaling pathway is a common genetic risk factor for severe cutaneous drug adverse reactions across diverse drugs"
} | [
{
"companynumb": "KR-JNJFOC-20180928691",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Headache is a common symptom at the onset of acute ischemic cerebrovascular disease. Simultaneous development of migraine-like headache and stroke in the same patient makes it difficult to differentiate between migraine-induced stroke and migraine-like headache attributed to ischemic stroke. We report a case of a 34-year-old woman with no previous migraine history who presented with migraine-like headache, thought to be a first attack of migraine, and who developed brainstem infarction shortly after triptan administration. Magnetic resonance imaging revealed an acute pontine infarction, and CT angiography revealed occlusion of the basilar artery. A detailed etiological evaluation revealed no risk factor for ischemic stroke. We believe that the migraine-like headache was the first symptom of cerebral ischemia and that sumatriptan accelerated the development of the infarction. This case report emphasizes the importance of accurate diagnosis of migraine before using triptans. Secondary causes of migraine-like headache should be excluded, especially in patients with migraine-like headache for the first time.",
"affiliations": "Department of Neurology, Medical Faculty of Karadeniz Technical University, 61080 Trabzon, Turkey. sibelgazioglu@hotmail.com",
"authors": "Gazioglu|Sibel|S|;Boz|Cavit|C|;Ozmenoglu|Mehmet|M|",
"chemical_list": "D058825:Serotonin 5-HT1 Receptor Agonists; D018170:Sumatriptan",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-011-0651-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "33(1)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": null,
"medline_ta": "Neurol Sci",
"mesh_terms": "D000328:Adult; D020526:Brain Stem Infarctions; D005260:Female; D006801:Humans; D008881:Migraine Disorders; D058825:Serotonin 5-HT1 Receptor Agonists; D018170:Sumatriptan; D014715:Vertebrobasilar Insufficiency",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "125-8",
"pmc": null,
"pmid": "21681368",
"pubdate": "2012-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7909130;20816453;15883306;11903526;15781820;7738564;8453456;7482645;19545252;11874390;18479417;2538194;14979299;15853772;16426269;20827380;18600300;19330285;17661873",
"title": "Basilar artery occlusion in migraine-like headache: a possible triggering effect of sumatriptan.",
"title_normalized": "basilar artery occlusion in migraine like headache a possible triggering effect of sumatriptan"
} | [
{
"companynumb": "TR-RANBAXY-2011RR-50539",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 26-year-old man with no medical history was admitted to the hospital for evaluation of his change in mental status. He was noted to be agitated at work and had difficulty walking for 2 days before being brought in to the ED by his family. According to his uncle, the patient had been complaining of a headache and pain with urination for approximately 1 week. He was born in Guerrero, Mexico (a small farm town), and moved to Los Angeles, California, in 2008.",
"affiliations": "Division of Pulmonary and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, CA.;Division of Pulmonary and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, CA.;Division of Pulmonary and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, Torrance, CA. Electronic address: charles.lanks@gmail.com.",
"authors": "Correa|Vanessa|V|;Vintch|Janine|J|;Lanks|Charles|C|",
"chemical_list": "D004269:DNA, Bacterial",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2017.08.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "152(6)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000328:Adult; D004269:DNA, Bacterial; D003937:Diagnosis, Differential; D053159:Dysuria; D006261:Headache; D006801:Humans; D006849:Hydrocephalus; D008279:Magnetic Resonance Imaging; D008297:Male; D009163:Mycobacterium bovis; D012611:Scrotum; D014389:Tuberculosis, Male Genital",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e147-e150",
"pmc": null,
"pmid": "29223275",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 26-Year-Old Man From Mexico With Headaches, Dysuria, and a Right Scrotal Mass.",
"title_normalized": "a 26 year old man from mexico with headaches dysuria and a right scrotal mass"
} | [
{
"companynumb": "US-BAYER-2018-009977",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Interstitial lung disease (ILD) with dermatomyositis often requires intensive immunosuppressive therapy. Here, we report two cases of pulmonary alveolar proteinosis (PAP) in dermatomyositis with ILD. One case was secondary PAP, and the other was autoimmune PAP positive for the anti-granulocyte macrophage-colony-stimulating factor antibody. PAP arose during immunosuppressive therapy and symptoms ceased by attenuating immunosuppression. Exacerbation of pulmonary lesions during intensive immunosuppressive therapy may distinguish PAP from worsening ILD and attenuating immunosuppression should be considered.",
"affiliations": "a Department of Rheumatology and Clinical Immunology.;a Department of Rheumatology and Clinical Immunology.;b Department of Respiratory Medicine Graduate School of Medicine , Kyoto University , Sakyo-ku, Kyoto , Japan.;a Department of Rheumatology and Clinical Immunology.;a Department of Rheumatology and Clinical Immunology.;a Department of Rheumatology and Clinical Immunology.;a Department of Rheumatology and Clinical Immunology.;c Department of Respiratory Medicine , Kyorin University School of Medicine , Mitaka , Japan , and.;d Bioscience Medical Research Center , Niigata University , Chuoku, Niigata , Japan.;a Department of Rheumatology and Clinical Immunology.",
"authors": "Imura|Yoshitaka|Y|;Yukawa|Naoichiro|N|;Handa|Tomohiro|T|;Nakashima|Ran|R|;Murakami|Kosaku|K|;Yoshifuji|Hajime|H|;Ohmura|Koichiro|K|;Ishii|Haruyuki|H|;Nakata|Koh|K|;Mimori|Tsuneyo|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
"country": "England",
"delete": false,
"doi": "10.3109/14397595.2016.1153443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "28(4)",
"journal": "Modern rheumatology",
"keywords": "Dermatomyositis; Granulocyte macrophage–colony-stimulating factor; Immunosuppression; Pulmonary alveolar proteinosis",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D003882:Dermatomyositis; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D008875:Middle Aged; D011649:Pulmonary Alveolar Proteinosis",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "724-729",
"pmc": null,
"pmid": "26872621",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of autoimmune and secondary pulmonary alveolar proteinosis during immunosuppressive therapy in dermatomyositis with interstitial lung disease.",
"title_normalized": "two cases of autoimmune and secondary pulmonary alveolar proteinosis during immunosuppressive therapy in dermatomyositis with interstitial lung disease"
} | [
{
"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2018EDE000250",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"d... |
{
"abstract": "BACKGROUND\nMycobacterium tuberculosis disease may occur after treatment of latent TB infection (LTBI). Prompted by a case of reactivation TB disease in a solid organ transplant (SOT) recipient who received LTBI treatment, we reviewed the literature to examine outcomes, adverse effects, resistance, and treatment choices of tuberculosis after LTBI therapy.\n\n\nMETHODS\nMEDLINE and Web of Science from inception to 5/2019 were reviewed using key words \"latent tuberculosis infection\" and \"SOT\" or \"transplantation.\" The search yielded nine cases, 41 cohort studies and six randomized controlled trials (RCT).\n\n\nRESULTS\nCohort and RCT demonstrated significant reduction in TB disease among transplanted patients who received LTBI therapy; only 56/2651 (2.1%) SOT patients developed TB after LTBI therapy. Adverse drug reactions occurred in 149/1148 (12.9%) and 73/641 (11.4%) of cohort and RCT patients, respectively. Among liver recipients, 56/266 (21%) developed side effects, of which half (29/56, 51.8%) was INH-related. There was no reported INH resistance.\n\n\nCONCLUSIONS\nLatent TB infection treatment is efficacious in SOT recipients at risk of TB disease. However, tuberculosis may still occur despite LTBI treatment. Hepatotoxicity associated with LTBI therapy is infrequent, although more commonly observed among liver recipients.",
"affiliations": "Section of Infectious Diseases, Department of Medicine, Philippine General Hospital, University of the Philippines, Manila, Philippines.;Division of Infectious Diseases, Department of Medicine, The William J Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic College of Medicine and Sciences, Rochester, MN, USA.;Division of Infectious Diseases, Department of Medicine, The William J Von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic College of Medicine and Sciences, Rochester, MN, USA.",
"authors": "Abad|Cybele Lara R|CLR|https://orcid.org/0000-0002-5183-8239;Deziel|Paul J|PJ|;Razonable|Raymund R|RR|https://orcid.org/0000-0001-5248-0227",
"chemical_list": "D000995:Antitubercular Agents; D007166:Immunosuppressive Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13178",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nMycobacterium tuberculosis\n; latent TB; solid organ transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D054242:Emigrants and Immigrants; D005002:Ethiopia; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D055985:Latent Tuberculosis; D009169:Mycobacterium tuberculosis; D016377:Organ Transplantation; D016032:Randomized Controlled Trials as Topic; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13178",
"pmc": null,
"pmid": "31541575",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment of latent TB Infection and the risk of tuberculosis after solid organ transplantation: Comprehensive review.",
"title_normalized": "treatment of latent tb infection and the risk of tuberculosis after solid organ transplantation comprehensive review"
} | [
{
"companynumb": "PHHY2019US228192",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "Uremic pruritus is one of the most prevalent and bothersome dermatologic symptoms in patients with end-stage renal disease. Some studies suggest a possible neuropathic cause of uremic pruritus. Gabapentin, an anticonvulsant, may control pruritus with neuropathic origin. The objectives of this study were to assess the efficacy of gabapentin in reducing pruritus scores of patients with uremic pruritus and evaluate its safety among dialysis patients. Meta-analysis of randomized controlled trials, using gabapentin as treatment for uremic pruritus among hemodialysis patients was included and analyzed using Review Manager Version 5.1.4 software. Seven out of 17 screened articles were included, with a total of 315 participants. Meta-analysis of the incidence of improved pruritus scores after treatment from four studies (n = 171) showed that treatment with gabapentin decreased the severity of uremic pruritus as compared to the placebo (risk ratio = 0.18; 95% confidence interval: 0.09, 0.33; I2 = 4%: P =< 0.00001). Six studies (n = 290) presented with incidence of adverse drug events such as dizziness, drowsiness, and somnolence. In the pooled analysis, treatment with gabapentin was associated with a higher incidence of adverse drug events compared to the comparator drugs, but the results were not significant (risk ratio = 1.3, 95% confidence interval: 0.81, 2.11; P = 0.28, I2 = 37%). The results of this systematic review suggest that gabapentin is efficacious and safe in improving uremic pruritus among dialysis patients.",
"affiliations": "Section of Dermatology, Department of Medicine, University of the Philippines, Philippine General Hospital, Manila, Philippines.;Section of Dermatology, Department of Medicine, University of the Philippines, Philippine General Hospital, Manila, Philippines.;Section of Dermatology, Department of Medicine, University of the Philippines, Philippine General Hospital, Manila, Philippines.",
"authors": "Eusebio-Alpapara|Kathleen May V|KMV|https://orcid.org/0000-0001-9856-7985;Castillo|Rochelle L|RL|https://orcid.org/0000-0002-1704-9420;Dofitas|Belen L|BL|https://orcid.org/0000-0001-5494-9455",
"chemical_list": "D000077206:Gabapentin; D014508:Urea",
"country": "England",
"delete": false,
"doi": "10.1111/ijd.14708",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "59(4)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D004244:Dizziness; D000077206:Gabapentin; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic; D011537:Pruritus; D016032:Randomized Controlled Trials as Topic; D006435:Renal Dialysis; D012720:Severity of Illness Index; D012867:Skin; D000077260:Sleepiness; D016896:Treatment Outcome; D014508:Urea; D014511:Uremia",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "412-422",
"pmc": null,
"pmid": "31777066",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review",
"references": null,
"title": "Gabapentin for uremic pruritus: a systematic review of randomized controlled trials.",
"title_normalized": "gabapentin for uremic pruritus a systematic review of randomized controlled trials"
} | [
{
"companynumb": "IR-ALKEM LABORATORIES LIMITED-IR-ALKEM-2020-01285",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"druga... |
{
"abstract": "Cerebral hemiatrophy syndromes can present with variable neurological symptoms. In childhood epilepsy, mental retardation and neuropsychiatric disorders are common while in adults movement disorders, such as highly asymmetric parkinsonism or hemidystonia as well as neuropsychiatric problems have been reported.\nHere, we present three adult patients with features that expand the clinical spectrum and give an overview of the most common clinical signs associated with this rare condition.\nAll three patients had prominent neuropsychiatric symptoms such as mood swings and increased irritability. Furthermore, one patient developed hemichorea which can be a rare presentation of cerebral hemiatrophy.\nCerebral hemiatrophy syndromes are a heterogeneous group of disorders that may also present with neuropsychiatric symptoms or hemichorea.",
"affiliations": "Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Molecular Neuroscience and Reta Lila Weston Institute for Neurological Studies University of London London United Kingdom.;Department of Molecular Neuroscience and Reta Lila Weston Institute for Neurological Studies University of London London United Kingdom.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.;Department of Neurology Innsbruck Medical University Innsbruck Austria.",
"authors": "Reiter|Eva|E|;Heim|Beatrice|B|;Scherfler|Christoph|C|;Mueller|Christoph|C|;Nocker|Michael|M|;Ndayisaba|Jean-Pierre|JP|;Loescher|Wolfgang|W|;Seppi|Klaus|K|;Lees|Andrew J|AJ|;Warner|Thomas|T|;Poewe|Werner|W|;Wenning|Gregor K|GK|;Djamshidian|Atbin|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/mdc3.12301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2330-1619",
"issue": "3(4)",
"journal": "Movement disorders clinical practice",
"keywords": "apomorphine; cerebral hemiatrophy syndrome; hemichorea; imaging; neuropsychiatric symptoms",
"medline_ta": "Mov Disord Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101630279",
"other_id": null,
"pages": "382-388",
"pmc": null,
"pmid": "30713929",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "10029885;10631651;10830421;11784827;11889248;15277660;16633341;16914408;17846160;17869142;17938368;19097182;19169186;20399008;20721918;20945435;21106830;2125535;21284039;22173950;22301321;2234429;22821557;23618490;23986429;25945281;2929271;3352904;7191439;7194980;7994517;8559423;8794514;9553851",
"title": "Clinical Heterogeneity in Cerebral Hemiatrophy Syndromes.",
"title_normalized": "clinical heterogeneity in cerebral hemiatrophy syndromes"
} | [
{
"companynumb": "AT-GLENMARK PHARMACEUTICALS INC, USA.-2016GMK024159",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROPINIROLE HYDROCHLORIDE"
},
... |
{
"abstract": "Tumor necrosis factor α antagonists are increasingly used to treat inflammatory and autoimmune disorders and are associated with increased risk of active tuberculosis. Diagnosis of active tuberculosis in patients taking tumor necrosis factor α antagonists can be challenging owing to increased incidence of extrapulmonary manifestations and false-negative results on current available diagnostic tests. We present a case of a young woman on infliximab for ulcerative colitis who presented with disseminated tuberculosis. As part of a research study, we performed flow cytometric immune profiling, which has previously not been reported in patients with active tuberculosis taking tumor necrosis α antagonists. The flow cytometry results were within the positive thresholds for tuberculosis infection. Flow cytometric immune profiling may be a valid diagnostic tool for patients taking tumor necrosis factor α antagonists.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Immunology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Immunology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.",
"authors": "Pennington|Kelly|K|;Sasieta|Humberto C|HC|;Ramos|Guiherme P|GP|;Erskine|Courtney L|CL|;Van Keulen|Virginia P|VP|;Peikert|Tobias|T|;Escalante|Patricio|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1179547617724776",
"fulltext": "\n==== Front\nClin Med Insights Case RepClin Med Insights Case RepICRspicrClinical Medicine Insights. Case Reports1179-5476SAGE Publications Sage UK: London, England 10.1177/117954761772477610.1177_1179547617724776ICR-0042243Case ReportFlow Cytometric Immune Profiling in Infliximab-Associated Tuberculosis Pennington Kelly 1Sasieta Humberto C 1Ramos Guiherme P 2Erskine Courtney L 3Van Keulen Virginia P 3Peikert Tobias 1Escalante Patricio 141 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA2 Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA3 Division of Immunology, Department of Medicine, Mayo Clinic, Rochester, MN, USA4 Mayo Clinic Center for Tuberculosis, Mayo Clinic, Rochester, MN, USAPatricio Escalante, Department of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. Email: Escalante.patricio@mayo.edu24 8 2017 2017 10 117954761772477628 3 2017 13 7 2017 © The Author(s) 20172017SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page(https://us.sagepub.com/en-us/nam/open-access-at-sage).Tumor necrosis factor α antagonists are increasingly used to treat inflammatory and autoimmune disorders and are associated with increased risk of active tuberculosis. Diagnosis of active tuberculosis in patients taking tumor necrosis factor α antagonists can be challenging owing to increased incidence of extrapulmonary manifestations and false-negative results on current available diagnostic tests. We present a case of a young woman on infliximab for ulcerative colitis who presented with disseminated tuberculosis. As part of a research study, we performed flow cytometric immune profiling, which has previously not been reported in patients with active tuberculosis taking tumor necrosis α antagonists. The flow cytometry results were within the positive thresholds for tuberculosis infection. Flow cytometric immune profiling may be a valid diagnostic tool for patients taking tumor necrosis factor α antagonists.\n\nTumor necrosis factor alpha antagonistsactive tuberculosisinflammatory bowel diseaseflow cytometrycover-dateJanuary-December 2017\n==== Body\nIntroduction\nTumor necrosis factor α antagonists (TNFAs) are increasingly used to treat connective tissue diseases and inflammatory bowel disease. Tumor necrosis factor α antagonists are associated with a high incidence of active tuberculosis (TB) that can reactivate despite chemoprophylaxis on some reports.1 The role of tumor necrosis factor α (TNF-α) in the immune response to Mycobacterium tuberculosis (MTB) is important but not entirely clear. In animal models, it appears to play a significant role in disease containment and granuloma formation2–4; which may explain the increased risk of patients on TNFA to develop TB, including disseminated disease.\n\nMoreover, current diagnostic tests, tuberculin skin testing and interferon gamma release assays, have false-negative results in immunosuppressed patients5,6 and cannot distinguish between active and latent TB infections.6 Combinatorial immunoassay profiling using flow cytometric (FC) detection of co-expression of surface markers CD25 (interleukin 2α receptor) and CD134 (a TNF-α receptor superfamily member) can identify antigen-specific effector CD4+ and CD8+ T-cell activation in latent TB infection (LTBI), and early studies suggest that it can distinguish between unexposed subjects, untreated subjects with LTBI, and treated patients with LTBI.7 This diagnostic strategy has not been used in active TB or in immunosuppressed patients receiving TNFA. We present a case of a patient on infliximab for ulcerative colitis who presented with disseminated TB. As part of a research study, we performed FC immune profiling.\n\nCase Report\nA 19-year-old US-born college student with a past medical history significant for ulcerative colitis treated with infliximab for the past 3 years and negative tuberculin skin test at initiation of TNFA was evaluated for a 3-month history of fever, night sweats, weight loss, productive cough, and abdominal pain. Several weeks prior to evaluation, she was treated for community-acquired pneumonia with azithromycin without symptomatic improvement. She was additionally treated with a short course of ciprofloxacin and prednisone for possible ulcerative colitis exacerbation without improvement. She had no known TB exposure including prior travel to endemic TB areas.\n\nPhysical examination revealed an afebrile woman in mild distress. Vital signs were notable for mild hypoxia (Spo2 = 92% on room air). She had no palpable lymphadenopathy. Bilateral rhonchi were present on pulmonary auscultation. Remainder of physical examination was unremarkable.\n\nLaboratory evaluation revealed a normal complete blood count and inflammatory markers. Human immunodeficiency virus (HIV) testing was negative. QuantiFERON-TB Gold in-Tube (QFT) test was positive (2.62 IU/mL). Transbronchial lung biopsy and bronchoalveolar lavage showed acid-fast bacilli, and subsequent cultures grew pan-sensitive MTB. Computed tomography of the chest, abdomen, and pelvis revealed miliary pulmonary pattern, patchy nodular infiltrates, and mediastinal lymphadenopathy with peritoneal and omental involvement (Figure 1). She did well after completion of 6 months of anti-TB therapy.\n\nFigure 1. Bilateral diffuse miliary nodular infiltrates with mediastinal and bilateral hilar adenopathy.\n\nFC Immunoprofiling\nIn addition to the clinical QFT test, peripheral blood mononuclear cells (PBMCs) were analyzed by FC as part of a research study. This research study was approved by Mayo Clinic Institutional Review Board (Mayo IRB number 09-003253 00). Peripheral blood mononuclear cells were isolated by Ficoll-Paque separation from 40 mL of heparinized blood within 1 hour of collection and cryopreserved in liquid nitrogen until stimulation. Multiparameter antigen stimulation with costimulatory antibodies (MTB-purified protein derivatives (PPD), region of difference 1 (RD1) peptide antigen [ESAT-6/CFP-10 peptide mix or specific MTB antigens], positive and negative controls) was completed. The PBMC sample and antigens were incubated for 48 hours at 37°C and then stained with fluorescent dye–conjugated anti-CD3, anti-CD4, anti-CD8, anti-CD25, and anti-CD134 antibodies and isotype controls. About 2 × 105 cells were analyzed by fluorescence-activated cell sorting (FACS) (BD FACSCanto) and gated using FlowJo software and Kaluza FC software. Detailed methods have been reported previously.7\n\nCD25+CD134+ co-expression was detected on 0.34% and 0.84% of RD1 peptide and PPD-stimulated CD3+CD4+ T cells, respectively (Figure 2). In addition, upregulation of CD25+CD134+ was present on 0.26% and 0.59% of RD1 peptide and PPD-stimulated CD3+CD8+ T cells, respectively. These results were in the range of untreated LTBI associated with an increased risk of TB reactivation, as previously described,7 and suggest possible active TB infection in an immunosuppressed and symptomatic patient.\n\nFigure 2. Flow cytometric gating strategy for detection of percentage of activated T cells (CD3+CD4+ and CD3+CD8+) co-expressing CD25+CD134+ markers. (A) Viable lymphocyte gate using side and forward scatter, (B) gate on CD3+/CD4+, (C) CD3+CD4+/CD25+CD134+ co-expression after 48 hours incubation with an unstimulated sample, PPD, and ESAT-6/CFP-10 peptides mix (RD1 peptide antigen), (D) gate on CD3+/CD8+, (E) CD3+CD8+/CD25+CD134+ co-expression after 48 hours incubation with an unstimulated sample, PPD, and RD1 peptide antigen. Percentages (boxes) indicate the calculated distribution of CD25+CD134+ among CD3+CD4+ and CD3+CD8+ T cells after the subtraction of background (nil). FCS-A indicates forward scatter; PPD, purified protein derivatives; RD1, region of difference 1; SSC-A, side scatter.\n\nDiscussion\nTumor necrosis factor α antagonists are associated with an increased risk of development of active TB. Extrapulmonary TB and disseminated TB represent one-half and one-quarter, respectively, of TB cases in patients receiving TNFA leading to many atypical presentations.8 Moreover, current diagnostic tools, tuberculin skin tests and interferon gamma release assays, can be false negative in this population and do not distinguish between active and latent infections.5 The FC-based assays of T-cell markers could potentially provide an additional diagnostic tool to identify patients on TNFA with latent and active TB.9–11 Combinatorial interferon gamma release assays and FC assays assessing TB antigen–induced T-cell CD25 (interleukin-2 receptor α chain) and CD134 (TNF-α receptor superfamily member) co-expression were recently described as a method to risk stratify patients with LTBI.7 Furthermore, this strategy has been used to identify patients with LTBI with HIV co-infection.12 However, FC has not been used to clinically identify active TB, and the effects of TNFA on the FC detection of CD134 have not been described.\n\nOur patient was on infliximab for several months prior to presenting with a clear diagnosis of disseminated TB in an immunosuppressed host. Flow cytometric immune profiling was completed as a research tool to determine the feasibility of this strategy in immune compromised patients with active TB on TNFA therapy. The result demonstrated that this FC immune profiling strategy can detect antigen-specific T-cell activation in an immunosuppressed patient with disseminated TB receiving TNFA; however, further validation is warranted.\n\nThis case was reported at the September 2016 European Respiratory Society Meeting in London, England, as a poster presentation.\n\nPeer review:Two peer reviewers contributed to the peer review report. Reviewers’ reports totaled 243 words, excluding any confidential comments to the academic editor.\n\nFunding:The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by internal Mayo Clinic grants (The 2009 and 2011 Lucille Nelson Clinical Career Development Award in Pulmonary Research; the 2011 Mayo Clinic Center for Clinical and Translational Sciences (CCaTS) Career Transition Award; the 2012 Mayo Clinic CCaTS Novel Methodology Award; the 2014 Mayo Clinic Department of Medicine Career Development Time for Scholarly Physicians Award; and the 2010 Clinical Immunology and Immunotherapeutics Program Award (P.E.). This research was also supported by K23CA159391 (T.P.). Part of this project was also supported by Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). This paper’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or Mayo Clinic. No other financial or material support for this work was provided to the authors and participants.\n\nDeclaration of conflicting interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs. Escalante and Peikert and their institution have filed two patent applications related to immunodiagnostic laboratory methodologies for latent tuberculosis infection. To date, there has been no income or royalties associated with those filed patent applications. None of the authors have any other conflicts of interest to declare.\n\nAuthor Contributions: All authors contributed to the research and construction of this manuscript.\n==== Refs\nReferences\n1 \nSichletidis L Settas L Spyratos D Chloros D Patakas D \nTuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis . Int J Tuberc Lung Dis . 2006 ;10 :1127 –1132 .17044206 \n2 \nKisich KO Higgins M Diamond G Heifets L \nTumor necrosis factor alpha stimulates killing of Mycobacterium tuberculosis by human neutrophils . Infect Immun . 2002 ;70 :4591 –4599 .12117972 \n3 \nFlynn JL Chan J \nImmunology of tuberculosis . Annu Rev Immunol . 2001 ;19 :93 –129 .11244032 \n4 \nRoach DR Bean AG Demangel C France MP Briscoe H Britton WJ \nTNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection . J Immunol . 2002 ;168 :4620 –4627 .11971010 \n5 \nMenzies D Pai M Comstock G \nMeta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research . Ann Intern Med . 2007 ;146 :340 –354 .17339619 \n6 \nPai M Denkinger CM Kik SV et al \nGamma interferon release assays for detection of Mycobacterium tuberculosis infection . Clin Microbiol Rev . 2014 ;27 :3 –20 .24396134 \n7 \nEscalante P Peikert T Van Keulen VP et al \nCombinatorial immunoprofiling in latent tuberculosis infection. Toward better risk stratification . Am J Respir Crit Care Med . 2015 ;192 :605 –617 .26030344 \n8 \nKeane J Gershon S Wise RP et al \nTuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent . N Engl J Med . 2001 ;345 :1098 –1104 .11596589 \n9 \nAdekambi T Ibegbu CC Cagle S et al \nBiomarkers on patient T cells diagnose active tuberculosis and monitor treatment response . J Clin Invest . 2015 ;125 :1827 –1838 .25822019 \n10 \nSester U Fousse M Dirks J et al \nWhole-blood flow-cytometric analysis of antigen-specific CD4 T-cell cytokine profiles distinguishes active tuberculosis from non-active states . PLoS ONE . 2011 ;6 :e17813 .21423578 \n11 \nSauzullo I Scrivo R Mengoni F et al \nMulti-functional flow cytometry analysis of CD4+ T cells as an immune biomarker for latent tuberculosis status in patients treated with tumour necrosis factor (TNF) antagonists . Clin Exp Immunol . 2014 ;176 :410 –417 .24528189 \n12 \nHsu DC Zaunders JJ Plit M et al \nA novel assay detecting recall response to Mycobacterium tuberculosis: comparison with existing assays . Tuberculosis (Edinb) . 2012 ;92 :321 –327 .22542644\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-5476",
"issue": "10()",
"journal": "Clinical medicine insights. Case reports",
"keywords": "Tumor necrosis factor alpha antagonists; active tuberculosis; flow cytometry; inflammatory bowel disease",
"medline_ta": "Clin Med Insights Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101531893",
"other_id": null,
"pages": "1179547617724776",
"pmc": null,
"pmid": "28890660",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "11971010;11244032;26030344;22542644;17339619;17044206;12117972;25822019;24396134;11596589;24528189;21423578",
"title": "Flow Cytometric Immune Profiling in Infliximab-Associated Tuberculosis.",
"title_normalized": "flow cytometric immune profiling in infliximab associated tuberculosis"
} | [
{
"companynumb": "US-JNJFOC-20170404279",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nCapecitabine is an orally bioavailable prodrug of the chemotherapeutic agent, fluorouracil. Fluorouracil is converted to several active metabolites that induce a cytotoxic effect. Capecitabine toxicity can be life-threatening with a delayed presentation from ingestion. An oral antidote, uridine triacetate, exists but requires the administration of 20 total doses over a course of five days.\n\n\nMETHODS\nIn this report, we describe a case where timely coordination with a clinical toxicology laboratory was utilized to drive clinical decision making and management. Two children were brought to the emergency department shortly after suspected capecitabine ingestion.\nPatients were admitted to the hospital and started on uridine triacetate. Real-time comprehensive toxicology testing of the children's blood was used to rule out capecitabine toxicity and prevent several unnecessary days of hospitalization and doses of antidote. Patients were discharged safely.\n\n\nCONCLUSIONS\nReal-time comprehensive toxicology testing on a patient's blood may be a valuable resource in ruling out or confirming toxic exposure in accidental pediatric ingestion of chemotherapeutic agents like capecitabine when performed in a timely manner.",
"affiliations": "Department of Pharmacy Services, University of California, Davis, CA, USA.;Department of Emergency Medicine, 3989Baylor College of Medicine, Houston, TX, USA.;6152Kaiser Permanente, Oakland, CA, USA.;Department of Laboratory Medicine, University of California, San Francisco, CA, USA.;Department of Laboratory Medicine, University of California, San Francisco, CA, USA.;Department of Emergency Medicine, University of California, San Francisco, CA, USA.;Department of Emergency Medicine, University of California, San Francisco, CA, USA.",
"authors": "Gintjee|Thomas J|TJ|https://orcid.org/0000-0002-2170-140X;Goodnough|Robert|R|;Li|Kai|K|;Badea|Adina|A|;Lynch|Kara L|KL|;Garcia|Eddie|E|;Repplinger|Daniel|D|",
"chemical_list": "D000085:Acetates; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; C000609666:uridine triacetate; D000069287:Capecitabine; D014529:Uridine",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220906266",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(7)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Capecitabine; overdose; pediatric; toxicology",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000085:Acetates; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D002675:Child, Preschool; D006801:Humans; D008297:Male; D014529:Uridine",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1759-1761",
"pmc": null,
"pmid": "32089072",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Real-time comprehensive toxicology testing in the clinical management of accidental pediatric capecitabine ingestion.",
"title_normalized": "real time comprehensive toxicology testing in the clinical management of accidental pediatric capecitabine ingestion"
} | [
{
"companynumb": "US-ACCORD-174908",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nTo assess antenatal and early postnatal antecedents of attention problems identified by the Child Behavior Checklist in extremely preterm children.\n\n\nMETHODS\nIn a cohort of 826 children born between 23 and 27 weeks' gestation, we collected demographic, birth, and postnatal information. We then identified behavior problems by using parent ratings from the Child Behavior Checklist at 2 years' adjusted age. We created time-oriented logistic regression risk models to identify significant risk factors for attention problems and Diagnostic and Statistical Manual of Mental Disorders-compatible attention deficit/hyperactivity problems (ADHP(DSM)).\n\n\nRESULTS\nChildren were at increased risk of both attention problems if they were born to a woman who had no formal education beyond high school and/or a woman who was exposed to secondhand smoke. Recovery of a single organism from the placenta was associated with increased risk of an attention problem, and fetal stem vessel thrombosis and recovery of Mycoplasma species were associated with increased risk of ADHP(DSM). Infants of multifetal gestations were at reduced risk of both attention problems. The only postnatal risk factor for an attention problem was recovery of bacteria from a tracheal aspirate.\n\n\nCONCLUSIONS\nAmong extremely preterm infants, several potentially modifiable antenatal and perinatal antecedents are associated with increased risk for attention problems and ADHP(DSM) at 2 years adjusted age.",
"affiliations": "Division of Neonatology, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC.;Division of Neonatology, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC.;Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA.;Division of Pediatric Neurology, Department of Pediatrics, Boston University, Boston, MA.;Division of Maternal-Fetal Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA.;Division of Neonatology, Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC.;Division of Developmental Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA.;Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.;Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA.;Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA.",
"authors": "Downey|L Corbin|LC|;O'Shea|T Michael|TM|;Allred|Elizabeth N|EN|;Kuban|Karl|K|;McElrath|Thomas F|TF|;Warner|Diane D|DD|;Ware|Janice|J|;Hecht|Jonathan L|JL|;Onderdonk|Andrew|A|;Leviton|Alan|A|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "166(1)",
"journal": "The Journal of pediatrics",
"keywords": null,
"medline_ta": "J Pediatr",
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"title": "Antenatal and early postnatal antecedents of parent-reported attention problems at 2 years of age.",
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"abstract": "In the postrituximab era, approximately half of the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation with curative intent. The Bruton tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell of origin. We conducted a single-center phase 1 study evaluating dose-escalated ibrutinib, in a 3-by-3 design, in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose-limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level 3. Of the 20 patients evaluable for response, per modern International Conference on Malignant Lymphoma criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later-phase studies. This trial was registered at www.clinicaltrials.gov as #NCT02219737.",
"affiliations": "Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Molecular Imaging and Therapy Service, Department of Radiology, and.;Department of Epidemiology and Biostatistics, MSKCC, New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.;Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.",
"authors": "Sauter|Craig S|CS|0000-0002-5316-8785;Matasar|Matthew J|MJ|;Schoder|Heiko|H|;Devlin|Sean M|SM|;Drullinsky|Pamela|P|;Gerecitano|John|J|;Kumar|Anita|A|;Noy|Ariela|A|;Palomba|Maria L|ML|;Portlock|Carol S|CS|;Straus|David J|DJ|;Zelenetz|Andrew D|AD|;McCall|Susan J|SJ|;Miller|Shoshana T|ST|;Courtien|Amanda I|AI|;Younes|Anas|A|;Moskowitz|Craig H|CH|",
"chemical_list": "D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069283:Rituximab; D005047:Etoposide; D016190:Carboplatin; D000225:Adenine; D007069:Ifosfamide",
"country": "United States",
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"doi": "10.1182/blood-2017-08-802561",
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"issn_linking": "0006-4971",
"issue": "131(16)",
"journal": "Blood",
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"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D005047:Etoposide; D005260:Female; D006801:Humans; D007069:Ifosfamide; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D012074:Remission Induction; D000069283:Rituximab",
"nlm_unique_id": "7603509",
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"pages": "1805-1808",
"pmc": null,
"pmid": "29386196",
"pubdate": "2018-04-19",
"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": "28029326;14504078;20660832;25758829;26193343;25651427;23356514;7477169;21495023;14739217;24661044;25113771;25267740",
"title": "A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL.",
"title_normalized": "a phase 1 study of ibrutinib in combination with r ice in patients with relapsed or primary refractory dlbcl"
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"abstract": "Lidocaine is a cost-effective drug that is widely used for local and regional anesthesia. However, central nervous system (CNS) toxicity can occur when lidocaine is administered above the maximum recommended dose (approximately 4.5 mg/kg) or if lidocaine is injected intravascularly rather than administered locally. Systemic toxicity by lidocaine has been reported in several studies. However, psychotic reactions due to lidocaine have been rarely reported; furthermore, reports of lidocaine-related euphoria are very rare. We report a very rare case of euphoria caused by CNS toxicity that occurred during the local administration of lidocaine at the therapeutic dose. Therefore, anesthesiologists should be aware of the severe side effects of local anesthetics despite administering the appropriate dosage at the appropriate location. Future studies should investigate pharmacokinetics to determine the safety profile of local anesthetics.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju, Korea.;Department of Anesthesiology and Pain Medicine, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju, Korea.;Department of Anesthesiology and Pain Medicine, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju, Korea.;Department of Anesthesiology and Pain Medicine, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju, Korea.",
"authors": "Lee|Joo Yong|JY|0000-0002-2433-2937;Kim|Hyeon Tae|HT|0000-0002-3581-9767;Won|Jeong Moon|JM|0000-0002-5587-4595;Shin|Young Duck|YD|0000-0002-8373-8478",
"chemical_list": null,
"country": "New Zealand",
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"doi": "10.2147/JPR.S271535",
"fulltext": "\n==== Front\nJ Pain Res\nJ Pain Res\njpr\njpainres\nJournal of Pain Research\n1178-7090 Dove \n\n271535\n10.2147/JPR.S271535\nCase Report\nA Rare Case of Euphoria Caused by Lidocaine After an Erector Spinae Plane Block: A Case Report\nLee et alLee et alhttp://orcid.org/0000-0002-2433-2937Lee Joo Yong 1 http://orcid.org/0000-0002-3581-9767Kim Hyeon Tae 1 http://orcid.org/0000-0002-5587-4595Won Jeong Moon 1 http://orcid.org/0000-0002-8373-8478Shin Young Duck 1 1 Department of Anesthesiology and Pain Medicine, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju, Korea\nCorrespondence: Young Duck Shin; Hyeon Tae Kim Department of Anesthesiology and Pain Medicine, Chungbuk National University Hospital, 776, 1 Sunhwan-Ro, Seowon-Gu, Cheongju, Chungbuk28644, KoreaTel +82-43-269-6234; +82-43-269-6988Fax +82-43-272-0264 Email yydshin@naver.com; gskht@naver.com\n22 9 2020 \n2020 \n13 2329 2332\n14 7 2020 04 9 2020 © 2020 Lee et al.2020Lee et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nLidocaine is a cost-effective drug that is widely used for local and regional anesthesia. However, central nervous system (CNS) toxicity can occur when lidocaine is administered above the maximum recommended dose (approximately 4.5 mg/kg) or if lidocaine is injected intravascularly rather than administered locally. Systemic toxicity by lidocaine has been reported in several studies. However, psychotic reactions due to lidocaine have been rarely reported; furthermore, reports of lidocaine-related euphoria are very rare. We report a very rare case of euphoria caused by CNS toxicity that occurred during the local administration of lidocaine at the therapeutic dose. Therefore, anesthesiologists should be aware of the severe side effects of local anesthetics despite administering the appropriate dosage at the appropriate location. Future studies should investigate pharmacokinetics to determine the safety profile of local anesthetics.\n\nKeywords\neuphorialidocaineadverse effectsnerve blockNo fundingNo funding was received for this report.\n==== Body\nIntroduction\nLocal anesthetics account for 5–10% of all side effects reported for anesthetic drugs.1 Side effects include cardiovascular and central nervous system (CNS) toxicity due to blockage of cell membrane ion channels, peripheral nerve complications due to other effects of the drug or the vehicle, allergic reactions, and needle trauma or infection due to mechanical or other technical problems.1 The incidence of toxicity caused by local anesthetics occurs more often by accidental intravascular injection than by overdosage; nevertheless, the arterial blood concentration of the local anesthetic is an important factor in both cases.2\n\nA higher dosage of lidocaine in the stellate ganglion block and epidural block results in a higher blood concentration.3,4 Therefore, if local anesthetic-induced systemic toxicity occurs, overdosage should be considered during both intravascular administration and local administration. However, due to the lack of quality data, specific recommendations for the general maximum dose of lidocaine cannot be determined, and the manufacturer’s recommended dose varies from country to country.5 According to most manufacturer recommendations, the maximum lidocaine dose for local anesthesia and local nerve block is 300 mg for a patient weighing 70 kg (approximately 4.5 mg/kg).5\n\nFirst described by Forero et al6 in 2016 for thoracic neuropathic pain, the erector spinae plane block (ESPB) is a novel technique of interfascial plane block between the transverse process and the erector spinae muscle. The erector spinae muscle is highly vascularized,7 and during the ESPB procedure, a large surface area of the muscle comes into contact with local anesthetics.8 However, it has been reported that even with a dose of 0–3.72 mg/kg lidocaine, serum lidocaine concentrations did not reach the systemic toxicity range,9 and there are few reports of systemic toxicity symptoms due to local anesthetics used for ESPB.\n\nSide effects of lidocaine have been reported in several studies10–12 and have been known to occur during intravascular injection or overdosage.13 However, side effects, such as psychotic reactions, particularly euphoria, have rarely been reported. We report a rare case of euphoria caused by lidocaine after an ESPB.\n\nCase Report\nThis case was approved by the Chungbuk National University Hospital Clinical Research Review Committee (approval number 2020–04-010-001). The patient provided informed consent for the publication of this case report.\n\nA 48-year-old man (164 cm, 79 kg) visited the pain clinic for herpes zoster pain. The patient had blisters on the left flank area (left T6 area) that developed three days ago. The patient reported pain that was localized to his left flank (rated 5–7/10 on a numeric rating scale) accompanied by a burning and tingling sensation. The patient previously received a caudal block to treat back pain due to spondylolytic spondylolisthesis at L5/S1 and an adductor canal block to treat left knee pain with lidocaine; no side effects were observed during these procedures.\n\nAn ESPB was scheduled to treat the patient’s pain as the first treatment. The patient did not take any medication or addictive drug (such as cocaine) that may interact and potentially increase serum levels and potential for toxicity. The patient had no psychosis or other psychological disorders.\n\nAfter disinfection, the patient was placed in the prone position, and a 22-gauge quince needle was inserted under ultrasound guidance in plane towards the transverse process T6 level. We confirmed the needle location in the fascial plane between the transverse process and erector spinae muscle under ultrasound guidance. After confirming that blood was not aspirated, 10 mL of 1% lidocaine and 10 mL of normal saline was injected. Lidocaine was slowly injected in 5 mL increments at a rate of 1 mL every 3 seconds with a careful repetitive aspiration to avoid intravascular injection. The procedure was completed after confirming separation of the erector spinae muscles from the transverse process with a good caudal and cephalic spread.\n\nTwo minutes after the procedure, the patient began to laugh, saying inaccurately that he was feeling very good. We could not identify the cause of the patient’s symptoms except for the lidocaine injected into the erector spinae plane.\n\nThe patient’s vital signs (electrocardiogram, oxygen saturation, tidal CO2, etc) remained within the normal limit, and intubation and emergency kits were prepared. Except for slurred speech and euphoria, the patient had no neurological symptoms, such as numbness of the tongue or lip, lightheadedness, tinnitus, or visual disturbance. After 35 minutes, the patient’s neurological symptoms improved completely, and accurate communication was possible. Dermatomal coverage after the procedure with pinprick and/or cold test was not performed. The patient’s left flank pain decreased to a numerical rating scale score of 1–2/10 after ESPB and remained so for over 2 hours until discharge. He remembered exactly what was going on during and after the procedure. He said, “I seemed to be drunk. It was the most pleasant and happy feeling I have ever had.” The patient was observed for 2 hours, and after confirming that there were no neurological symptoms, he was discharged.\n\nDiscussion\nAmong the adverse events caused by CNS toxicity due to lidocaine, psychotic reactions have been previously reported.10–12 Symptoms of psychotic reactions were mainly mood changes, doom anxiety, hallucinations, and delusions,11 but euphoria has been rarely reported. Short-lasting euphoria after intravenous lidocaine administration was reported in a 42-year-old patient who was addicted to cocaine.12 Euphoria was also reported after administration of 35 mL of 2% lidocaine for axillary block and 50 mL of 1% lidocaine for local anesthesia.10 In both cases, euphoria occurred after intravenous administration with a high possibility of CNS toxicity or after administration of a dose higher than 300 mg of lidocaine.10,12 However, our case differs from these cases since euphoria occurred during the local, not intravascular administration of lidocaine and at a dose lower (10 mL of 1% lidocaine) than the maximum recommended dose. This suggests that CNS toxicity of local anesthetics may occur during local administration, even at doses lower than the known maximum dose. The characteristics of ESPB and the patient’s position can be considered as the reasons these side effects occurred with ESPB.\n\nAlthough randomized, controlled studies have not been performed yet, the efficacy of ESPB for acute herpes pain has been demonstrated in several studies.14,15 The mechanism of action is unclear, but it has been reported that the injected local anesthetic spreads through the costotransverse foramen to the external intercostal muscle and internal intercostal membrane,6 and interfacial injected local anesthetics spread through the costotransverse foramen and peripheral porous tissues to the intercostal and thoracic paravertebral spaces.16 Additionally, sensitivity depends on the integrity of A-gamma fibers (light touch), A-delta fibers (cold and pinprick), and C fibers (warmth and dull pain).17 Several studies reported that the analgesic effect of ESPB is due to a differential block mediated by non-myelinated C fibers rather than larger A-delta and A-gamma fibers.18,19\n\nElkoundi et al reported that plasma local anesthetic levels are expected to increase significantly when large amounts of local anesthetics are administered with ESP blockade.20 The peak plasma concentration of a local anesthetic is determined by the vascular supply-dependent rate of systemic absorption at the injection site and surface area contact with the local anesthetic injectate.21 When ESPB is performed, a large surface area comes into contact with local anesthetics.8 Furthermore, the erector spinae muscle is highly vascularized.7 Considering these mechanisms of ESPB and the blood supply of erector spinae musculature, lidocaine was likely rapidly absorbed over a large area in a short time, and the intramuscular or interfacial spread of the lidocaine may have caused a rapid increase in the level of lidocaine in the blood. Therefore, interfacial administration of local anesthetics could cause CNS toxicity to a greater degree than typical local administration. However, Caruso et al reported that serum lidocaine concentrations were below the systemic toxicity range, even with an injection of 0–3.72 mg/kg of lidocaine for ESPB in a study of 27 patients.9 In this regard, future pharmacokinetic studies of local anesthetics in ESPB are needed to determine their safety profile.\n\nAnother possible cause of euphoria was the patient’s position during the procedure. The concentration of local anesthetics reaching the brain depends on the ratio of cardiac output to the brain.2 The patient’s prone position during the procedure may have led to euphoria due to the increased cardiac output to the brain. Therefore, the patient’s prone position during the procedure could also be a factor that could affect CNS toxicity by local anesthetics.\n\nThe reported sequence of CNS toxicity symptoms after local anesthetic injection is numbness of the tongue, lightheadedness, tinnitus, visual disturbance, slurring of speech, muscular twitching, irrational conversation, unconsciousness, convulsion, coma, and apnea.2 Furthermore, medical professionals usually assess numbness of the tongue, tinnitus, and visual disturbance to evaluate CNS toxicity caused by local anesthetic. However, in our case, the first symptom was euphoria and slurring of speech. This indicates that symptoms of CNS toxicity may occur in a different order than that previously reported or even skip steps in this sequence. Thus, we speculate that any sequence, including the initial sequence of CNS toxicity symptoms, can be a predicting factor for a life-threatening situation such as seizure, coma, and respiratory arrest.\n\nThe limitation of our case report is that laboratory tests were not performed since the patient’s symptoms completely disappeared within 35 minutes after the procedure. Performing laboratory tests on patients before and after the procedure could help identify other factors that cause lidocaine-induced systemic toxicity. In this case, adrenaline was not added to lidocaine, but it is worth considering adding adrenaline to local anesthetics to avoid the side effects of local anesthetics. The addition of a small amount of adrenaline to a local anesthetic acts as a marker of intravascular absorption and significantly reduces the peak plasma concentration of the local anesthetic, reducing systemic toxicity.22\n\nConclusion\nIn summary, euphoria is a very rare side effect of systemic toxicity that can occur after lidocaine injection. The occurrence of this side effect with ESPB suggests that future pharmacokinetic studies are needed to determine the safety profile. Furthermore, the severe side effects of local anesthetics should be considered despite administering the appropriate dose at the appropriate location while avoiding intravascular administration. In addition, the patient’s position during the procedure may also cause unexpected side effects.\n\nAcknowledgments\nWe would like to thank Editage (www.editage.com) for English language editing.\n\nAuthor Contributions\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors declare that they have no competing interests for this work.\n==== Refs\nReferences\n1. McCaughey \nW . Adverse effects of local anaesthetics\n. Drug Saf . 1992 ;7 (3 ):178 –189\n. doi:10.2165/00002018-199207030-00003 1503666 \n2. Scott \nDB . Toxic effects of local anaesthetic agents on the central nervous system\n. Br J Anaesth . 1986 ;58 (7 ):732 –735\n. doi:10.1093/bja/58.7.732 3730224 \n3. Park \nHS , Chung \nCJ , Chin \nYJ . The plasma concentrations and systemic toxicity of lidocaine after maximal or supramaximal recommended doses of epidural administration\n. Korean J Pain . 1999 ;12 :36 –42\n.\n4. Song \nSO , Suh \nYH . Changes of plasma lidocaine concentrations after Stellate Ganglion Block according to volume-changes of 1% lidocaine\n. Korean J Pain . 2001 ;14 :26 –31\n.\n5. Weinberg \nL , Peake \nB , Tan \nC , Nikfarjam \nM . Pharmacokinetics and pharmacodynamics of lignocaine: a review\n. World J Anesthesiol . 2015 ;4 (2 ):17 –29\n. doi:10.5313/wja.v4.i2.17 \n6. Forero \nM , Adhikary \nSD , Lopez \nH , Tsui \nC , Chin \nKJ . The erector spinae plane block: a novel analgesic technique in thoracic neuropathic pain\n. Reg Anesth Pain Med . 2016 ;41 :621 –627\n. doi:10.1097/AAP.0000000000000451 27501016 \n7. Yue \nBY , le Roux \nCM , Corlett \nR , De La Harpe \nD , Richardson \nM , Ashton \nM . The arterial supply of the cervical and thoracic spinal muscles and overlying skin: anatomical study with implications for surgical wound complications\n. Clin Anat . 2013 ;26 (5 ):584 –591\n. doi:10.1002/ca.22139 22887027 \n8. Yang \nHM , Choi \nYJ , Kwon \nHJ , O \nJ , Cho \nTH , Kim \nSH . Comparison of injectate spread and nerve involvement between retrolaminar and erector spinae plane blocks in the thoracic region: a cadaveric study\n. Anaesthesia . 2018 ;73 (10 ):1244 –1250\n. doi:10.1111/anae.14408 30113699 \n9. Caruso \nTJ , Lin \nC , O’Connell \nC , et al. Systemic absorption of lidocaine from continuous erector spinae plane catheters after congenital cardiac surgery: a retrospective study\n. J Cardiothorac Vasc Anesth . 2020 ;S1053-0770(20)30502–4. doi:10.1053/j.jvca.2020.05.040 .\n10. Zeidan \nA , Baraka \nA . Is euphoria a side-effect of lidocaine?\n\nAnaesthesia . 2004 ;59 (12 ):1253 –1254\n. doi:10.1111/j.1365-2044.2004.04025.x \n11. Saravay \nSM , Marke \nJ , Steinberg \nMD , Rabiner \nCJ . “Doom anxiety” and delirium in lidocaine toxicity\n. Am J Psychiatry . 1987 ;144 (2 ):159 –163\n.3812782 \n12. Blanke \nJ , Wolstein \nJ , Paulus \nHJ . Euphoric effect of lidocaine\n. Psychiatr Prax . 1996 ;23 (2 ):90 –91\n.8657816 \n13. Becker \nDE , Reed \nKL . Local anesthetics: review of pharmacological considerations\n. Anesth Prog . 2012 ;59 (2 ):90 –102\n. doi:10.2344/0003-3006-59.2.90 22822998 \n14. Aydın \nT , Balaban \nO , Ahiskalioglu \nA , Alici \nHA , Acar \nA . Ultrasound-guided erector spinae plane block for the management of herpes zoster pain: observational study\n. Cureus . 2019 ;11 (10 ):e5891 .31772861 \n15. Tekin \nE , Ahiskalioglu \nA , Aydin \nME , Sengun \nE , Bayramoglu \nA , Alici \nHA . High-thoracic ultrasound-guided erector spinae plane block for acute herpes zoster pain management in emergency department\n. Am J Emerg Med . 2019 ;37 (2 ):375.e1–375.e3. doi:10.1016/j.ajem.2018.10.028 \n16. Adhikary \nSD , Bernard \nS , Lopez \nH , Chin \nKJ . Erector spinae plane block versus retrolaminar block: a magnetic resonance imaging and anatomical study\n. Reg Anesth Pain Med . 2018 ;43 (7 ):756 –762\n.29794943 \n17. Mackenzie \nRA , Burke \nD , Skuse \nNF , Lethlean \nAK . Fibre function and perception during cutaneous nerve block\n. J Neurol Neurosurg Psychiatry . 1975 ;38 (9 ):865 –873\n. doi:10.1136/jnnp.38.9.865 1185225 \n18. Chin \nKJ , Adhikary \nSD , Forero \nM . Understanding ESP and fascial plane blocks: a challenge to omniscience\n. Reg Anesth Pain Med . 2018 ;43 :807 –808\n. doi:10.1097/AAP.0000000000000857 30234844 \n19. Ford \nDJ , Raj \nPP , Singh \nP , Regan \nKM , Ohlweiler \nD . Differential peripheral nerve block by local anesthetics in the cat\n. Anesthesiology . 1984 ;60 :28 –33\n. doi:10.1097/00000542-198401000-00007 6691593 \n20. Elkoundi \nA , Balkhi \nH , Bensghir \nM , Baite \nA . Levobupivacaine plasma level between erector spinae plane block and thoracic paravertebral block\n. Reg Anesth Pain Med . 2020 ;rapm-2020-101406. doi:10.1136/rapm-2020-101406 \n21. Yasumura \nR , Kobayashi \nY , Ochiai \nR . A comparison of plasma levobupivacaine concentrations following transversus abdominis plane block and rectus sheath block\n. Anaesthesia . 2016 ;71 :544 –549\n. doi:10.1111/anae.13414 26945692 \n22. Karmakar \nMK , Ho \nAM , Law \nBK , Wong \nAS , Shafer \nSL , Gin \nT . Arterial and venous pharmacokinetics of ropivacaine with and without epinephrine after thoracic paravertebral block\n. Anesthesiology . 2005 ;103 (4 ):704 –711\n. doi:10.1097/00000542-200510000-00008 16192762\n\n",
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"title": "A Rare Case of Euphoria Caused by Lidocaine After an Erector Spinae Plane Block: A Case Report.",
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"drugadditional"... |
{
"abstract": "BACKGROUND\nStrokes secondary to acute internal carotid artery (ICA) occlusion are associated with an extremely poor prognosis. The best treatment approach in this setting is still unknown. The aim of our study was to evaluate the efficacy, safety, and outcomes of emergent surgical revascularization of acute extracranial ICA occlusion in patients with minor to severe ischemic stroke.\n\n\nMETHODS\nA retrospective analysis was performed using prospectively collected data of consecutive patients who underwent carotid thromboendarterectomy for symptomatic acute ICA occlusion during the period from January 2013 to December 2015. Primary outcomes were disability at 90 days assessed by the modified Rankin Scale (mRS) and neurological deficit at discharge assessed using the National Institute of Health Stroke Scale (NIHSS). Secondary outcomes were the recanalization rate, 30-day overall mortality, and any intracerebral bleeding.\n\n\nRESULTS\nDuring the study period, a total of 6 patients (5 men and 1 woman) with a median age of 64 years (range: 58-84 years) underwent emergent reconstruction for acute symptomatic ICA occlusion within a median of 5.4 hours (range: 2.9-12.0 hours) after symptoms onset. The median presenting NIHSS score was 10.5 points (range: 4-21). Before surgery, 4 patients (66.7%) had been treated by systemic recombinant tissue plasminogen activator lysis. The median time interval between initiation of intravenous thrombolysis and carotid thromboendarterectomy was 117.5 minutes (range: 65-140 minutes). Patency of the ICA was achieved in all patients. On discharge, the median NIHSS score was 2 points (range: 0-11 points). There was no postoperative intracerebral hemorrhage and zero 30-day mortality rate. At 3 months, 5 patients (83.3%) had a good clinical outcome (mRS ≤ 2).\n\n\nCONCLUSIONS\nPatients presenting with minor to severe ischemic stroke syndromes due to isolated extracranial ICA occlusion may benefit from emergent carotid revascularization. Thorough preoperative neuroimaging is essential to aid in selecting eligible candidates for acute surgical intervention.",
"affiliations": "1 Department of Surgery, University Hospital and Faculty of Medicine Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.;2 Department of Neurology, University Hospital and Faculty of Medicine Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.;1 Department of Surgery, University Hospital and Faculty of Medicine Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.;1 Department of Surgery, University Hospital and Faculty of Medicine Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.;3 Department of Radiology, University Hospital and Faculty of Medicine Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.;3 Department of Radiology, University Hospital and Faculty of Medicine Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.;4 1st Department of Internal Medicine-Cardioangiology, University Hospital and Faculty of Medicine Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic.",
"authors": "Gunka|Igor|I|;Krajickova|Dagmar|D|;Lesko|Michal|M|;Jiska|Stanislav|S|;Raupach|Jan|J|;Lojik|Miroslav|M|;Maly|Radovan|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1538574416674641",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-5744",
"issue": "51(4)",
"journal": "Vascular and endovascular surgery",
"keywords": "acute ischemic stroke; carotid artery occlusion; carotid endarterectomy; internal carotid artery; outcome; penumbra",
"medline_ta": "Vasc Endovascular Surg",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D015901:Angiography, Digital Subtraction; D002545:Brain Ischemia; D002343:Carotid Artery, Internal; D016893:Carotid Stenosis; D002533:Cerebral Angiography; D002560:Cerebrovascular Circulation; D000072226:Computed Tomography Angiography; D004185:Disability Evaluation; D004630:Emergencies; D016894:Endarterectomy, Carotid; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D055420:Perfusion Imaging; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D020521:Stroke; D015912:Thrombolytic Therapy; D013997:Time Factors; D061665:Time-to-Treatment; D016896:Treatment Outcome; D014654:Vascular Patency",
"nlm_unique_id": "101136421",
"other_id": null,
"pages": "176-182",
"pmc": null,
"pmid": "28424044",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Emergent Carotid Thromboendarterectomy for Acute Symptomatic Occlusion of the Extracranial Internal Carotid Artery.",
"title_normalized": "emergent carotid thromboendarterectomy for acute symptomatic occlusion of the extracranial internal carotid artery"
} | [
{
"companynumb": "CZ-ROCHE-1937642",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
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"drugadditional": "3",
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{
"abstract": "OBJECTIVE\nTopiramate (TPM), lamotrigine (LTG), and levetiracetam (LEV) are three new-generation antiepileptic drugs (AEDs) which have recently come into use in add-on therapy for refractory childhood epilepsy in Japan. The aim of this study was to evaluate their efficacy and tolerability, and to clarify the role of these three AEDs in childhood epilepsy therapy.\n\n\nMETHODS\nThree separate audits were conducted between July 2007 and July 2012. All patients studied had epilepsy refractory to other AEDs. Efficacy was confirmed if a patient became seizure-free or achieved > 50% reduction (50% responder rate: 50% RR) in seizure frequency for 12 months after starting add-on therapy.\n\n\nRESULTS\nA total of 55 children received TPM, 44 LTG, and 38 LEV. The 50% RR of partial epilepsy was 31.8% for LTG, 41.8% for TPM, and 52.6% for LEV. The 50% RR of generalized epilepsy was 28.6% for LTG, 26.7% for TPM, and 44.4% for LEV. The incidence of adverse events was 9.1% for LTG, 43.6% for TPM, and 15.8% for LEV.\n\n\nCONCLUSIONS\nLEV was the most effective of the three add-on therapies in refractory childhood epilepsy with partial and generalized onset. Regarding seizure-free, TPM was more effective than the other therapies, but it had many side effects. LTG tended to be more effective for generalized epilepsy, particularly idiopathic epilepsy, than partial epilepsy. We conclude that it is necessary to develop a treatment plan for pediatric epilepsies after considering the advantages and disadvantage of these new AEDs.",
"affiliations": null,
"authors": "Kato|Takeo|T|;Nakata|Masatoshi|M|;Ide|Minako|M|;Saito|Keiko|K|;Yoshida|Takeshi|T|;Awaya|Tomonari|T|;Heike|Toshio|T|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D000077287:Levetiracetam; D000077213:Lamotrigine; D010889:Piracetam",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-0831",
"issue": "47(5)",
"journal": "No to hattatsu = Brain and development",
"keywords": null,
"medline_ta": "No To Hattatsu",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D000069279:Drug Resistant Epilepsy; D005260:Female; D005632:Fructose; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam; D012189:Retrospective Studies; D000077236:Topiramate; D014227:Triazines",
"nlm_unique_id": "0215224",
"other_id": null,
"pages": "354-9",
"pmc": null,
"pmid": "26502652",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and tolerability of topiramate, lamotrigine, and levetiracetam in children with refractory epilepsy.",
"title_normalized": "efficacy and tolerability of topiramate lamotrigine and levetiracetam in children with refractory epilepsy"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-297157",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
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{
"abstract": "The treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has undergone several recent advancements, leading to an increased amount of treatment options for relapsed patients. The development of immunotherapies such as anti-CD19 chimeric antigen receptor(CAR) T cells and bispecific T-cell engagers has given clinicians therapeutic options with less expected toxicity when compared to standard re-induction chemotherapy. This is especially beneficial in patients with toxicities from their prior treatment. Along with this, the emergence of haploidentical hematopoietic cell transplantation (HCT) has increased opportunity for patients to receive HCT who may not have had an available matched donor. We present four patients who have received all of these therapies in different combinations to treat multiple relapses. Because of the success of achieving remission as well as decreasing toxicity, the patients are alive and well up to 15 y after the original B-ALL diagnosis, rendering this as a chronic disease for them.",
"affiliations": "Department of Pediatrics, University of Arizona, Tucson, Arizona, USA.;Department of Pediatrics, University of Arizona, Tucson, Arizona, USA.;Department of Pediatrics, University of Arizona, Tucson, Arizona, USA.",
"authors": "Pariury|Holly|H|;Truscott|Laurel|L|;Katsanis|Emmanuel|E|0000-0003-1466-6965",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/2162402X.2021.1956125",
"fulltext": "\n==== Front\nOncoimmunology\nOncoimmunology\nOncoimmunology\n2162-4011\n2162-402X\nTaylor & Francis\n\n10.1080/2162402X.2021.1956125\n1956125\nVersion of Record\nReport\nBrief Report\nHave CD19-directed immunotherapy and haploidentical hematopoietic cell transplantation transformed pediatric B-cell acute lymphoblastic leukemia into a chronic disease?\nH. PARIURY ET AL.\nONCOIMMUNOLOGY\nPariury Holly abc\nTruscott Laurel abc\nhttps://orcid.org/0000-0003-1466-6965\nKatsanis Emmanuel abcdef\na Department of Pediatrics, University of Arizona , Tucson, Arizona, USA\nb The University of Arizona Cancer Center , Tucson, Arizona, USA\nc Banner University Medical Center , Tucson, AZ, USA\nd Department of Immunobiology, University of Arizona , Tucson, Arizona, USA\ne Department of Medicine, University of Arizona , Tucson, Arizona, USA\nf Department of Pathology, University of Arizona , Tucson, Arizona, USA\nCONTACT Emmanuel Katsanis katsanis@peds.arizona.edu Department of Pediatrics, 1501 N. Campbell Ave., PO Box 245073, Tucson, AZ 85724-5073\n25 7 2021\n2021\n25 7 2021\n10 1 1956125Integra21 7 2021\nIntegra21 7 2021\n10 6 2021\n12 7 2021\n12 7 2021\n© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.\n2021\nThe Author(s)\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nABSTRACT\n\nThe treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has undergone several recent advancements, leading to an increased amount of treatment options for relapsed patients. The development of immunotherapies such as anti-CD19 chimeric antigen receptor(CAR) T cells and bispecific T-cell engagers has given clinicians therapeutic options with less expected toxicity when compared to standard re-induction chemotherapy. This is especially beneficial in patients with toxicities from their prior treatment. Along with this, the emergence of haploidentical hematopoietic cell transplantation (HCT) has increased opportunity for patients to receive HCT who may not have had an available matched donor. We present four patients who have received all of these therapies in different combinations to treat multiple relapses. Because of the success of achieving remission as well as decreasing toxicity, the patients are alive and well up to 15 y after the original B-ALL diagnosis, rendering this as a chronic disease for them.\n\nKEYWORDS\n\nacute lymphoblastic leukemia\nchronic\nCAR-T\nblinatumomab\nhematopoietic cell transplantation\n==== Body\nIntroduction\n\nIn the last 10 y, there have been significant advances in the treatment of B-cell precursor acute lymphoblastic leukemia (B-ALL). Blinatumomab, a bispecific T cell engager (BITE), engages CD3+ T cells directly to CD19+ targeted B-ALL cells. Blinatumomab was FDA approved for the treatment of B-ALL in December 2014 and has become an important component of cooperative group protocols and is widely used following relapse to successfully induce remission.1 In addition, anti-CD19 chimeric antigen receptor (CAR) T cells, FDA approved in July 2017, are commonly applied for relapsed B-ALL.2 They have been used effectively either as definitive treatment or as a bridge to allogeneic hematopoietic cell transplantation (allo-HCT).3 To date, these immunotherapies have been associated with decreased toxicity, diminished neutropenia and opportunistic infections, improving the patient’s performance status and therefore patient’s ability to receive further therapy when needed. Imatinib is a selective BCR-ABL tyrosine kinase inhibitor (TKI), while dasatinib is a dual BCR-ABL and Src family TKI. These agents have drastically improved the outcomes for patients with Philadelphia chromosome positive (Ph+ ALL) who previously were unlikely to be cured with chemotherapy alone.4\n\nDonor choice for allo-HCT has evolved as well. Matched related and unrelated allo-HCTs have been the standard of care for high-risk and relapsed B-ALL for half a century. However, in the last decade haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide (PT-CY) has proven to be a practical and reliable alternative approach. It is easily applicable by many transplant centers and readily available for most patients. Along with emerging therapeutic options, improved supportive care has led to reduced morbidities in patients.5 Herein, we present four patients who have benefited from these promising treatment modalities leading to repeated inductions of complete remissions (CR) and prolonged disease-free survival. Our cases illustrate that these therapeutic advances, in addition to improved supportive care, have altered the landscape of pediatric B-ALL transforming it into a chronic disease.\n\nWhile the definition of chronic disease varies across the literature and between medical organizations, common criteria typically include a prolonged, often perpetual, course of illness requiring ongoing medical attention and an associated functional impairment. In order to unify the definition and appropriately allocate resources within healthcare, it has been suggested to utilize the Merriam Webster definition of chronic, which is something that is “continuing and occurring again and again for a long time”.6 This definition specifies the need for ongoing monitoring and treatments with the goal of continued survival.\n\nCase series\n\nCase 1: BITE, UCBT, CAR-T, BITE, haplo-BMT\n\nPatient #1 was diagnosed with B-ALL at 1.6 y of age and developed an early isolated central nervous system relapse. He was treated according to the COG AALL 1331 protocol receiving reinduction followed by blinatumomab 15 μg/m2/24 hr for two cycles. He then proceeded to a four of six antigen-matched unrelated cord blood transplant (UCBT) in second complete remission (CR2) following conditioning with Busulfan Fludarabine and Melphalan. Unfortunately, he relapsed 2.5 months later.7 The patient was then enrolled into an anti-CD19 CAR-T cell trial (University of Washington) requiring three separate infusions which resulted in brief responses due to short-lived persistence of the infused T cells. He then was treated on a second CAR-T cell clinical trial (Children’s Hospital of Philadelphia) but failed to respond for the same reason. In addition to lack of persistence or exhaustion of CAR-T cells, failure to respond may be due to development of escape variants with loss of CD19 on B-ALL cells. After returning to our institution, he received reinduction chemotherapy for two weeks, and since his leukemia blasts remained CD19-positive, this was followed by a cycle of blinatumomab 15 μg/m2/24 hr, achieving again a minimal residual disease (MRD) negative remission. He quickly proceeded to a second transplant while in CR4 using his mother as the bone marrow donor. He received myeloablative conditioning comprising fractionated total body irradiation (f-TBI 200 cGy x 6) followed by fludarabine (FLU) 30 mg/m2 for four doses.8,9 PT-CY (50 mg/kg/dose) was infused on days +3 and +4 following a T-replete haplo-bone marrow transplant (BMT). He remains alive and disease-free for 4.9 y post-transplant (7.8 y since ALL diagnosis, Figure 1). This case underscores the utility of blinatumomab in treating relapsed refractory ALL even after failing anti-CD19 CAR-T cell therapy. It also highlights the advantage of having a readily available haploidentical donor to promptly move to HCT when a matched sibling donor is not available.Figure 1.\n\nCase 2: MMUD-BMT, BITE, haplo-BMT, CAR-T, haplo-CD34 +\n\nPatient # 2 was diagnosed in Mexico at age 13 y with B-ALL and presented to us during her third relapse at age of 20 y. After achieving a CR4 with four cycles of Hyper-CVAD (CY, vincristine, doxorubicin, dexamethasone) she was conditioned with CY, f-TBI (1200 cGy) and anti-thymocyte globulin and underwent a one antigen mismatched unrelated donor (MMUD)-BMT. She had a bone marrow relapse 2.8 y later and was reinduced with a two-week course of chemotherapy followed by blinatumomab 15 μg/m2/24 hr for 2 cycles, achieving an MRD negative CR5. She then underwent a T-replete haplo-BMT from her brother after conditioning with busulfan (BU), FLU and melphalan (MEL) followed by PT-CY.8,9 She again had a bone marrow relapse 1.2 y post-BMT. T cells were collected just prior to her 26th birthday and she received CAR-T cells (Tisagenlecleucel) following lymphodepleting chemotherapy. She then developed prolonged pancytopenia with an aplastic bone marrow requiring prolonged granulocyte colony-stimulating factor support and remained red cell and platelet dependent for over six months. As she continued to have full donor chimerism, she was rescued with CD34+ selected cells from a peripheral blood stem cell (PBSC) collection from her haploidentical donor (brother). At age 27.8 and remarkably 15 y since her original diagnosis she remains in remission with trilineage engraftment and normal counts but continues to have B cell aplasia.\n\nCase 3: BITE, MSD-HCT, CAR-T, haplo-BMT\n\nPatient # 3 presented with B-ALL when she was 2.3 y old and relapsed 13 months later. She was reinduced according to ALL-R3 protocol10 (dexamethasone, mitoxantrone, vincristine, peg-asparaginase) but failed to achieve remission having 24% bone marrow blasts at the end of re-induction chemotherapy. She was then treated with blinatumomab (15 μg/m2/24 hr) leading to an MRD negative CR2 after the initial cycle but with a detectable MRD of 0.04% after the second cycle. While off blinatumomab for two weeks her bone marrow blasts increased to 2.2% the day she began her HCT preparative regimen. She underwent a matched sibling donor (MSD) PBSC transplant following CY, f-TBI (1200 cGy) conditioning but not unexpectedly relapsed six months later. She was subsequently treated with CAR-T cells (Tisagenlecleucel). She continued to have B cell aplasia for 12 months and found to have a CD19+ bone marrow relapse just two months after recovery of her B cells. She once again received reinduction chemotherapy and achieved an MRD negative CR4. She then underwent a T-replete haplo-BMT from her mother following BU-FLU-MEL conditioning. She is now 7 y old and remains in remission at 1.1-y post haplo-BMT and 4.9 y since her original diagnosis. While this patient was clearly sensitive to both anti-CD19 immunotherapies, blinatumomab and CAR-T cells, she appeared to relapse as soon as exposure to these agents was waning. Her first transplant became possible following a remission achieved with blinatumomab, and CAR-T cell treatment allowed a prolonged interval between her first and second transplants (2.2 y) which we and others have shown to be associated with improved outcomes.11,12\n\nCase 4: BITE, haplo-BMT, haplo-HCT\n\nPatient # 4 was diagnosed with Ph+ B-ALL when he was 8.8 y old and was treated on COG protocol AALL0622 completing therapy after 2.5 y. He remained in remission for more than 7 y when he was found to have a bone marrow and central nervous system relapse after presenting with a facial palsy. Reinduction chemotherapy according to COG AALL1331 with addition of dasatinib induced an MRD-remission but was complicated by disseminated candidiasis. Due to his overwhelming fungemia, further myelosuppressive chemotherapy was prohibited and after a prolonged delay in therapy it was decided to treat him with blinatumomab and daily dasatinib. He received a total of five 28-day cycles of blinatumomab until his candidiasis had been adequately treated. He then proceeded to a T-replete haplo-BMT from his mother following BU-FLU-MEL conditioning. Unfortunately, he failed to engraft and was salvaged with a second haplo-HCT after receiving a single-day multiagent immunosuppressive conditioning with 200 cGy TBI followed by CY, FLU and alemtuzumab all given on day −1 with unmanipulated G-CSF mobilized PBSC from the same donor infused the following day.13 The proximal timing of alemtuzumab in this regimen allows for in vivo depletion of donor T cells without the need for graft manipulation or PT-CY. The patient engrafted promptly and remains alive and disease-free more for than 3 y from his second HCT and more than 11 y after his original diagnosis.\n\nMaterials and methods\n\nAll patients described in our series were treated according to Children’s Oncology Group protocols were indicated and/or received standard of care institutional HCT protocols at our center. Informed written consent was obtained for the COG protocols and prior to each HCT. The authors obtained approval by the University of Arizona IRB board, to review the cases reported.\n\nDiscussion\n\nDespite the advancing understanding of the role of molecular genetics in ALL and the incorporation of risk-adapted therapy upfront, 10–15% of pediatric and adolescent/young adult (AYA) patients with ALL experience a relapse.14 Historically, the outcomes of this patient population have been poor, with an event-free survival (EFS) of 30–50% in patients with first relapsed ALL in the pre CD19-directed immunotherapy era.15–17 While 51% of these individuals will achieve CR2, CR3 declined to 37% and CR4 to 31% with continued decrease in CR rates with each successive attempt.18 The 2-y EFS for patients with multiply relapsed disease is 10–40%, and strongly impacted by the total number of prior salvage attempts.16,18\n\nIn an effort to improve upon these trends, over the last 10 y, there have been significant advances in the treatment of relapsed and refractory (R/R) B-ALL which have been associated with more favorable toxicity profiles and an improved ability to achieve an MRD negative remission. More specifically, the increasing use of CD19-directed immunotherapy for early relapse, in addition to the efficacy and reliability of haplo-HCT with PT-CY, allowed patients with a previously dismal EFS to live longer lives with less long-term toxicity, and subsequently increased their ability and likelihood to pursue further therapy for subsequent relapses.8,9,19–23\n\nBlinatumomab has become an important tool to successfully induce remission in R/R B-ALL. The Children’s Oncology Group (COG) recently completed a prospective, multicenter, phase III trial of pediatric, AYA patients with R/R B-ALL in which patients (n = 208) were randomized to receive two blocks of standard chemotherapy or two 4-week cycles of blinatumomab following a single block of re-induction chemotherapy. For the 80% of patients that remained MRD positive post re-induction block 1, 21% went on to be MRD negative after one cycle of therapy in the chemotherapy only arm, compared to 79% of those in the blinatumomab arm. Similar results were seen with the subsequent block of therapy. Overall toxicity was substantially higher in the post-induction chemotherapy arm with 61% of patients developing a grade ≥3 infection and 21% of patients developing grade ≥3 sepsis, four of which died. In contrast, only 11% and 2% of patients on the blinatumomab arm developed a CTCAEv4 grade ≥3 infection and sepsis respectively, and there were no toxic deaths. For those in the blinatumomab arm, grade ≥3 cytokine release syndrome (CRS) and seizures were seen in ≤ 1% of patients. Other neurotoxicity was seen in 11–14% of blinatumomab receiving patients, however all incidents were transient.1 This study exemplifies how more targeted therapy is changing the landscape of relapsed ALL. The combination of fewer and less severe toxicities, superior MRD response, and more successful bridges to transplant not only leads to an improved survival in patients receiving blinatumomab for relapse, but also allows those patients whose disease will recur in the future to be in better condition with an improved performance status when undergoing future therapies.\n\nAnother valuable CD19-directed immunotherapy that is reshaping the way we think about patients with relapsed B-ALL is anti-CD19 CAR-T cells. A recent non-randomized phase II trial of the anti-CD19 CAR-T cell product, Tisagenlecleucel, demonstrated an MRD negative remission rate of 81% in pediatric and AYA patients with R/R B-ALL within 3 months of initial infusion. The EFS at 6 and 12 months was 73% and 50% respectively.2 Similar findings were demonstrated at the Children’s Hospital of Philadelphia, where 88% of patients obtained an MRD negative remission and 65% of patients remained in remission at 12 months without the addition of transplant. However, in the pediatric CAR-T cell trial at the Pediatric Oncology Branch/National Cancer Institute,75% of MRD negative patients proceeded to HCT. At 18 months, 62% of patients who bridged to HCT were leukemia free, compared to 14% of patients who did not proceed to HCT.3 While grade ≥3 events did occur in 73% of patients in phase II trial utilizing tisagenlecleucel, the incidence down trended to 17% between 2 and 12 months after infusion. Among these adverse events, the most concerning nonhematologic toxicities were CRS and neurologic events, however most of the events were mitigated with supportive care measures and in some cases, cytokine blockade and no cerebral edema were reported.2 Similar findings have been demonstrated in adults, with lower disease burden at time of the infusion being associated with a decreased incidence of CRS and neurotoxic events, and longer survival. Neither number of prior therapies nor previous transplantation correlated with toxic effects.24 The initial experience with anti-CD19 CAR-T cells in a real-world setting from Center for International Blood and Marrow Transplant Research was recently published.25 Of 511 patients from 73 centers, 410 patients had reported follow-up data with 255 being patients with ALL. With a median follow-up of 13.4 months in ALL patients, the CR was 85.5%. The 1-y duration of response, event-free survival, and overall survival (OS) rates were similar to previous clinical trials at 60.9%, 52.4%, and 77.2%, respectively. CRS grade ≥3 was lower (16%) than previous clinical trials as patients received CAR-T therapy earlier and with less disease burden. Similarly, neurotoxicity grade ≥3 was only seen in 9% of patients.25\n\nThe investigation and utilization of additional monoclonal antibody therapies targeting other B-ALL surface antigens such as CD22 with inotuzumab ozogamicin, a humanized monoclonal antibody-drug conjugate, have shown promising results.26 Targeting of B-ALL CD20 with rituximab or CD52 with alemtuzumab has mainly been investigated in adult B-ALL (Figure 2).27,28Along with antibody-directed immunotherapy, the development and incorporation of TKIs into B-ALL treatment regimens have altered the prognosis of Ph+ ALL patients dramatically from <25% to approximately 80%.29 Ph+ ALL patients had historically been treated with HSCT as <40% were curable with chemotherapy alone. In the long-term follow-up of imatinib used in addition to chemotherapy for patients with Ph+ ALL in the COG AALL0031 study, the 5-year disease-free survival was 70% in patients receiving imatinib plus chemotherapy compared to 65% in those receiving matched sibling HCT and 59% in those receiving MUD HCT.4 The emergence of TKIs has led to not only improved survival, but the potential for reserving HCT for patients in CR2.Figure 2.\n\nAllo-HCT can be curative for patients with high- risk ALL. However, identification of suitable human leukocyte antigen-matched donors remains a challenge, particularly for minority groups and patients of mixed race.30 T cell replete haplo-HCT with PT-CY has revolutionized the field of allo-HCT.31–33 Haplo-BMT with PT-CY has emerged as the most widely applied haplo-BMT regimen, as it eliminates the need to manipulate stem cell grafts in order to prevent graft-versus-host disease (GvHD).,34 PT-CY in haplo-BMT has been associated with relatively low rates of severe acute and chronic GvHD, graft rejection, and non-relapse mortality.21,35 Moreover, outcomes have been comparable to matched unrelated and, in some cases, matched sibling transplants.36–40 Other haplo-HCT approaches have also been successful such as depletion of αβ T-cell and B-cell depletion of the graft.41 The benefits of haploidentical are numerous, with arguably the most notable being that haplo-HCT extends donor availability to nearly all patients. Haplo-HCT offers additional advantages by circumventing the delays and costs associated with unrelated donor searches and hematopoietic stem cell procurement. Haplo-HCT, therefore, expedites transplantation in time-sensitive circumstances such as R/R B-ALL, potentially preventing relapses while awaiting an unrelated donor. Moreover, haploidentical familial donors, especially parents, are often eager to donate and readily available for not only the initial harvest, but also potential additional collections of bone marrow, PBSCs, or donor leukocyte infusions as was the case with our second patient whose post-CAR-T cell prolonged pancytopenia was salvaged by CD34+ stem cells from her haploidentical brother. Since implementing haplo-HCT at our institution more than 80% of our alternative donor HCTs for pediatric and AYA patients with hematologic malignancies have been haploidentical with about 20% of those being second transplants. We recently updated our results reporting 84% 2-y overall survival and 74% progression-free survival.8,9 Our three cases underscore the utility of haplo-HCT in salvaging patients failing CD19-directed immunotherapy and an initial non haplo-HCT.\n\nAlongside the advances of therapy for R/R B-ALL have come the remarkable improvements in supportive care for patients with leukemia with a focus on addressing some of the unique toxicities which have emerged in the CD19-directed immunotherapy era. The American Society for Transplantation and Cellular Therapy, for instance, has put forth comprehensive guidelines on the assessment, grading, and treatment of CRS and neurotoxicity associated with immune effector cell therapies, which has allowed for earlier recognition and more streamlined management of these toxicities.16,18 A second area of advancement which has had tremendous impact on the quality of life and outcomes of patients with acute leukemia is supportive care for infections. Multiply R/R patients and patients that are post-transplant are profoundly immunocompromised and have a high risk of severe infection, not only due to prolonged states of neutropenia, but also because the integrity of the gastrointestinal mucosa is often compromised by cytotoxic chemotherapy, and key features of serious infection may not be evident. This highlights the importance of maintaining a high clinical suspicion for infection as well as the critical need for antimicrobial prophylaxis in this patient population. While institutional practices will vary given local epidemiology and resistance rates, the IDSA/ASCO guidelines provide consensus recommendations with a goal of preventing opportunistic infections. They address the importance of antibacterial and antifungal prophylaxis during prolonged periods of neutropenia and provide guidelines on agent selection depending on the leukemia therapy being utilized.5,42 Our ability to optimize supportive care measurements throughout a patient’s multiply relapsed disease course plays a key role in their outcomes and ability to overcome the many toxicities that come with repeat exposure to cytotoxic chemotherapy, immunotherapy, and transplant alike.\n\nWhile the idea of B-ALL being a chronic disease may have at one point seemed absurd, the advent of T cell/antibody-engaging immunotherapy has revolutionized the treatment of patients with high-risk R/R B-ALL allowing bridging to HCT with good performance status, decreased organ co-morbidities and infection-free due to patients being relatively free of periods of prolonged neutropenia and advancements in supportive care. Moreover, the accessibility and reliability of haplo-HCT have made second transplants more feasible as was the case with our patients. All four of our patients are alive, obtaining their current remission (in three CR4 or greater) many years following their initial diagnosis and live high-functioning lives despite the chronicity of their disease. As a pediatric program, our report has focused on salvage treatment of B-ALL in young patients. Our findings may not be pertinent to older patients with B-ALL who inherently have a worse prognosis. Moreover, CAR-T cells have not yet been approved for B-ALL patients older than 25 y and myeloablative conditioning followed by haploidentical transplantation may not be an option for older adults with B-ALL.\n\nAcknowledgments\n\nThe authors would also like to thank the inpatient and outpatient nursing and other staff on the pediatric HCTT unit at Banner University Medical Center in Tucson, AZ, for their outstanding care of our patients.\n\nDisclosure of Conflicts of Interest\n\nThere are no conflicts of interest, financial or otherwise, involving any of the authors regarding the submission or publication of this manuscript.\n==== Refs\nReferences\n\n1. Brown PA, Ji L, Xu X, Devidas M, Hogan L, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Gore L, et al. A randomized phase 3 trial of Blinatumomab Vs. Chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs) Demonstrates Superior Efficacy and Tolerability of Blinatumomab: a Report from Children’s Oncology Group Study AALL1331. Blood. 2019;134 :LBA-1-LBA-1.\n2. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, et al. Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med. 2018;378 (5 ):439–7. doi:10.1056/NEJMoa1709866.29385370\n3. Pehlivan KC, Duncan BB, Lee DW. CAR-T cell therapy for acute lymphoblastic leukemia: transforming the treatment of relapsed and refractory disease. Curr Hematol Malig Rep. 2018;13 (5 ):396–406. doi:10.1007/s11899-018-0470-x.30120708\n4. Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Zheng HW, Davies SM, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: children’s oncology group study AALL0031. Leukemia. 2014;28 (7 ):1467–1471. doi:10.1038/leu.2014.30.24441288\n5. Cook J, Litzow M. Advances in supportive care for acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2020;15 (4 ):276–293. doi:10.1007/s11899-020-00585-2.32607955\n6. Bernell S, Howard SW. Use your words carefully: what is a chronic disease? Front Public Health. 2016;4 :159. doi:10.3389/fpubh.2016.00159.27532034\n7. Zeng Y, Katsanis E. Potential niche indications for blinatumomab as a bridge to hematopoietic cell transplantation. Bone Marrow Transplant. 2017;52 (12 ):1671–1673. doi:10.1038/bmt.2017.186.28920946\n8. Katsanis E, Sapp LN, Reid SC, Reddivalla N, Stea B. T-cell replete myeloablative haploidentical bone marrow transplantation is an effective option for pediatric and young adult patients with high-risk hematologic malignancies. Front Pediatr. 2020;8 :282. doi:10.3389/fped.2020.00282.32582591\n9. Katsanis E, Sapp LN, Varner N, Koza S, Stea B, Zeng Y. Haploidentical bone marrow transplantation with post-transplant cyclophosphamide/bendamustine in pediatric and young adult patients with hematologic malignancies. Biol Blood Marrow Transplant. 2018;24 (10 ):2034–2039. doi:10.1016/j.bbmt.2018.06.007.29908231\n10. Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376 (9757 ):2009–2017. doi:10.1016/S0140-6736(10)62002-8.21131038\n11. Menon NN, Jenkins LM, Cui H, Jenkins C, Anwer F, Yeager AM, Katsanis E. Factors associated with improved outcomes after second allogeneic hematopoietic cell transplantation for relapsed pediatric leukemia. Ann Hematol. 2016;95 (4 ):637–644. doi:10.1007/s00277-016-2599-9.26787415\n12. Naik S, Martinez C, Leung K, Sasa G, Nguyen NY, Wu MF, Gottschalk S, Brenner M, Heslop H, Krance R. Outcomes after second hematopoietic stem cell transplantations in pediatric patients with relapsed hematological malignancies. Biol Blood Marrow Transplant. 2015;21 (7 ):1266–1272. doi:10.1016/j.bbmt.2015.02.024.25765555\n13. Kanda J, Horwitz ME, Long GD, Gasparetto C, Sullivan KM, Chute JP, Morris A, Hennig T, Li Z, Chao NJ, et al. Outcomes of a 1-day nonmyeloablative salvage regimen for patients with primary graft failure after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47 (5 ):700–705. doi:10.1038/bmt.2011.158.21804612\n14. Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14 (6 ):e205–217. doi:10.1016/S1470-2045(12)70580-6.23639321\n15. Freyer DR, Devidas M, La M, Carroll WL, Gaynon PS, Hunger SP, Seibel NL. 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Sun W, Malvar J, Sposto R, Verma A, Wilkes JJ, Dennis R, Heym K, Laetsch TW, Widener M, Rheingold SR, et al. Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study. Leukemia. 2018;32 (11 ):2316–2325. doi:10.1038/s41375-018-0094-0.29728694\n19. McCurdy SR, Luznik L. How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide. Blood. 2019;134 (21 ):1802–1810. doi:10.1182/blood.2019001323.31751485\n20. McCurdy SR, Kanakry CG, Tsai HL, Kasamon YL, Showel MM, Bolanos-Meade J, Huff CA, Borrello I, Matsui WH, Brodsky RA, et al. II acute graft-versus-host disease and higher nucleated cell graft dose improve progression-free survival after HLA-Haploidentical transplant with post-transplant cyclophosphamide. Biol Blood Marrow Transplant. 2018;24 (2 ):343–352. doi:10.1016/j.bbmt.2017.10.023.29055682\n21. McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolanos-Meade J, Rosner GL, Kanakry CG, Perica K, Symons HJ, Brodsky RA, et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015;125 :3024–3031.25814532\n22. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, Armand P, Antin JH, Chen J, Devine SM, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126 (8 ):1033–1040. doi:10.1182/blood-2015-04-639831.26130705\n23. Kanakry CG, O’Donnell PV, Furlong T, De Lima MJ, Wei W, Medeot M, Mielcarek M, Champlin RE, Jones RJ, Thall PF, et al. Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014;32 (31 ):3497–3505. doi:10.1200/JCO.2013.54.0625.25267759\n24. Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, et al. Follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378 (5 ):449–459. doi:10.1056/NEJMoa1709919.29385376\n25. Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, Pulsipher MA, Phillips CL, Keating A, Frigault MJ, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4 (21 ):5414–5424. doi:10.1182/bloodadvances.2020003092.33147337\n26. Brown PA. Emerging therapeutic options in acute lymphoblastic leukemia. JNCCN. 2020 (18 ):1781–1784.\n27. Gorin NC, Isnard F, Garderet L, Ikhlef S, Corm S, Quesnel B, Legrand O, Cachanado M, Rousseau A, Laporte JP. Administration of alemtuzumab and G-CSF to adults with relapsed or refractory acute lymphoblastic leukemia: results of a phase II study. Eur J Haematol. 2013;91 :315–321.23738686\n28. Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, Chevallier P, Hunault M, Boissel N, Escoffre-Barbe M, et al. for G. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016;375 (11 ):1044–1053. doi:10.1056/NEJMoa1605085.27626518\n29. Jabbour E, O’Brien S, Konopleva M, Kantarjian H. New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia. Cancer. 2015;121 (15 ):2517–2528. doi:10.1002/cncr.29383.25891003\n30. Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, Hartzman R, Rizzo JD, Horowitz M, Confer D, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371 (4 ):339–348. doi:10.1056/NEJMsa1311707.25054717\n31. Brodsky RA, Luznik L, Bolanos-Meade J, Leffell MS, Jones RJ, Fuchs EJ. Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant. 2008;42 (8 ):523–527. doi:10.1038/bmt.2008.203.18622413\n32. So C, Mulanovich V, Rm S, UD B, Jiang Y, Bassett R, Sa W, Konopleva M, Fernandez-Vina M, Montes N, et al. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18 :1835–1844.22796535\n33. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, Morris LE, Bashey A. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012;18 :1859–1866.22863841\n34. Luznik L, Fuchs EJ. High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res. 2010;47 (1–3 ):65–77. doi:10.1007/s12026-009-8139-0.20066512\n35. Fuchs EJ. HLA-haploidentical blood or marrow transplantation with high-dose, post-transplantation cyclophosphamide. Bone Marrow Transplant. 2015;50 (Suppl 2 ):S31–36. doi:10.1038/bmt.2015.92.26039204\n36. Arcese W, Cerretti R, Sarmati L, Cudillo L, De Angelis G, Mariotti B, Bruno A, Mangione I, Rapanotti C, Andreani M, et al. Matched-pair analysis of transplant from haploidentical, unmanipulated bone marrow donor versus HLA identical sibling for patients with hematologic malignancies. Biol Blood Marrow Transplant. 2020;26 (6 ):1113–1118. doi:10.1016/j.bbmt.2020.02.005.32068095\n37. Bazarbachi A, Labopin M, Blaise D, Forcade E, Socie G, Berceanu A, Angelucci E, Bulabois CE, Kroger N, Rambaldi A, et al. Comparable outcomes of haploidentical transplant with TBF conditioning versus matched unrelated donor with fludarabine/busulfan conditioning for acute myeloid leukemia. Bone Marrow Transplant. 2021;56(3):622–634.\n38. Gagelmann N, Bacigalupo A, Rambaldi A, Hoelzer D, Halter J, Sanz J, Bonifazi F, Meijer E, Itala-Remes M, Markova M, et al. Haploidentical stem cell transplantation with posttransplant cyclophosphamide therapy vs other donor transplantations in adults with hematologic cancers: a systematic review and meta-analysis. JAMA Oncol. 2019;5(12):1739–1748. doi:10.1001/jamaoncol.2019.3541.\n39. Saglio F, Berger M, Spadea M, Pessolano R, Carraro F, Barone M, Quarello P, Vassallo E, Fagioli F. Haploidentical HSCT with post transplantation cyclophosphamide versus unrelated donor HSCT in pediatric patients affected by acute leukemia. Bone Marrow Transplant. 2021;56(3):586–595.\n40. Solh MM, Baron J, Zhang X, Bashey A, Morris LE, Holland HK, Solomon SR; Solh MM, Baron J, Zhang X, Bashey A, Morris LE, Holland HK, Solomon SR. Differences in graft-versus-host disease characteristics between haploidentical transplantation using post-transplantation cyclophosphamide and matched unrelated donor transplantation using calcineurin inhibitors. Biol Blood Marrow Transplant. 2020;26 (11 ):2082–2088. doi:10.1016/j.bbmt.2020.07.035.32745575\n41. Locatelli F, Merli P, Pagliara D, Li Pira G, Falco M, Pende D, Rondelli R, Lucarelli B, Brescia LP, Masetti R, et al. Outcome of children with acute leukemia given HLA-haploidentical HSCT after alphabeta T-cell and B-cell depletion. Blood. 2017;130 (5 ):677–685. doi:10.1182/blood-2017-04-779769.28588018\n42. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, et al. Grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25 (4 ):625–638. doi:10.1016/j.bbmt.2018.12.758.30592986\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2162-4011",
"issue": "10(1)",
"journal": "Oncoimmunology",
"keywords": "CAR-T; acute lymphoblastic leukemia; blinatumomab; chronic; hematopoietic cell transplantation",
"medline_ta": "Oncoimmunology",
"mesh_terms": "D001402:B-Lymphocytes; D002648:Child; D002908:Chronic Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction",
"nlm_unique_id": "101570526",
"other_id": null,
"pages": "1956125",
"pmc": null,
"pmid": "34367735",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "29385370;21193696;25765555;20385996;30120708;25814532;32582591;28588018;27626518;29385376;26039204;22796535;29728694;32968215;21804612;24441288;28920946;18622413;23738686;31621796;33020591;19841326;29055682;32745575;26787415;29908231;25891003;25267759;27532034;21131038;30592986;31751485;26130705;32607955;20066512;32068095;23639321;25054717;33147337;22863841",
"title": "Have CD19-directed immunotherapy and haploidentical hematopoietic cell transplantation transformed pediatric B-cell acute lymphoblastic leukemia into a chronic disease?",
"title_normalized": "have cd19 directed immunotherapy and haploidentical hematopoietic cell transplantation transformed pediatric b cell acute lymphoblastic leukemia into a chronic disease"
} | [
{
"companynumb": "US-AMGEN-USASP2021124384",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
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{
"abstract": "OBJECTIVE\nLaparoscopic management of nonobstetric acute abdominal pain in the third trimester of pregnancy remains controversial with limited data regarding procedure safety and feasibility. This study aimed to investigate the feasibility, immediate complications, and short-term outcomes of laparoscopic surgery at an advanced gestational age.\n\n\nMETHODS\nCase-series.\n\n\nMETHODS\nSheba Medical Center, a tertiary referral center.\n\n\nMETHODS\nPregnant women who underwent urgent laparoscopic surgery at 27 weeks of gestation and above.\n\n\nMETHODS\nEmergent laparoscopic surgery.\n\n\nRESULTS\nClinical data were retrospectively collected and analyzed. A telephone questionnaire was administered in cases of missing data. Clinical information obtained included detailed medical and obstetric history; preoperative, intraoperative, and postoperative data; complications; and pregnancy outcomes. Between January 2010 and July 2017, 12 patients underwent emergent laparoscopic surgeries during the third trimester of pregnancy. The gestational age at the time of the surgery ranged between 27 and 38 weeks. All women had singleton pregnancies. Laparoscopic surgeries included 7 appendectomies, 4 adnexal surgeries, and 1 diagnostic laparoscopy. No complications related to the access route for any of the 12 laparoscopic surgeries occurred. The laparoscopic surgical procedure was successfully completed in 11 patients; only 1 laparoscopic appendectomy for perforated acute appendicitis with purulent peritonitis at 30 weeks of gestation was converted to laparotomy because of a limited operative field. Two patients had preterm labor at 35 and 36 weeks of gestation, respectively. None of the women was complicated with intrauterine fetal demise or low Apgar scores.\n\n\nCONCLUSIONS\nOur results demonstrate that urgent laparoscopic surgeries in the third trimester of pregnancy are feasible and can be safely performed with minimal risk for the patient and fetus. Larger prospective studies are required to validate these recommendations.",
"affiliations": "Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (all authors).;Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (all authors). Electronic address: Hadeel.wattad@mail.huji.ac.il.;Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (all authors).;Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (all authors).;Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (all authors).",
"authors": "Cohen|Shlomo B|SB|;Watad|Hadel|H|;Shapira|Moran|M|;Goldenberg|Mordechai|M|;Mashiach|Roy|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jmig.2019.06.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1553-4650",
"issue": "27(4)",
"journal": "Journal of minimally invasive gynecology",
"keywords": "Adnexal surgery; Advanced pregnancy; Appendectomy; Laparoscopy; Pregnancy; Third trimester",
"medline_ta": "J Minim Invasive Gynecol",
"mesh_terms": null,
"nlm_unique_id": "101235322",
"other_id": null,
"pages": "909-914",
"pmc": null,
"pmid": "31271895",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Urgent Laparoscopic Surgeries during the Third Trimester of Pregnancy: A Case Series.",
"title_normalized": "urgent laparoscopic surgeries during the third trimester of pregnancy a case series"
} | [
{
"companynumb": "NVSC2020IL149647",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "We describe a rare case of hepatitis A virus (HAV) replication in feces despite presence of hepatitis A antibodies in an acute myeloid leukemia (AML) patient after transfusion with HAV contaminated platelets. The patient has been vaccinated against HAV years before the AML diagnosis. Transient infection and reshedding should thus be considered in antibody-positive hematological patients. Transfusion associated HAV transmission is rare, and little evidence exists on the clinical consequences and possible effect of treatment with immunoglobulin. Further reporting on fecal shedding despite antibodies are needed, as HAV antibody levels are used as course of action for post-exposure prophylaxis and infection control.",
"affiliations": "Virus & Microbiological Special Diagnostics, Statens Serum Institut, Copenhagen, Denmark. Electronic address: hvs@ssi.dk.;Department of Clinical Immunology, Blood Bank, Rigshospitalet, Copenhagen, Denmark.;Virus & Microbiological Special Diagnostics, Statens Serum Institut, Copenhagen, Denmark.;Department of Clinical Immunology, Blood Bank, Rigshospitalet, Copenhagen, Denmark.;Department of Hematology, Rigshospitalet, Copenhagen, Denmark.",
"authors": "Vestergaard|Hanne Thang|HT|;Harritshøj|Lene Holm|LH|;Midgley|Sofie Elisabeth|SE|;Ullum|Henrik|H|;Kampmann|Peter|P|",
"chemical_list": "D035922:Hepatitis A Antibodies; D022362:Hepatitis A Vaccines",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2018.01.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "24(9)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Hepatitis A shedding; Post-exposure prophylaxis; Transfusion transmission; Transient infection",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000328:Adult; D001803:Blood Transfusion; D005243:Feces; D005260:Female; D006506:Hepatitis A; D035922:Hepatitis A Antibodies; D022362:Hepatitis A Vaccines; D030041:Hepatitis A virus; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D056990:Post-Exposure Prophylaxis; D065227:Transfusion Reaction; D014611:Vaccination",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "766-768",
"pmc": null,
"pmid": "29490881",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transfusion transmission of hepatitis A virus with fecal shedding in a previously hepatitis A vaccinated recipient.",
"title_normalized": "transfusion transmission of hepatitis a virus with fecal shedding in a previously hepatitis a vaccinated recipient"
} | [
{
"companynumb": "DK-FRESENIUS KABI-FK201809815",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYTARABINE"
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... |
{
"abstract": "The objective is to evaluate the effectiveness of a spacing strategy of bDMARDs in a cohort of selected patients in disease remission or low-disease activity (LDA) without glucocorticoids affected with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). This was a single-centre study carried out on patients prospectively enrolled in the biologic Apulian registry. Patients whose disease was in remission or LDA without taking glucocorticoids during the previous 6 months and who had agreed to increase the time interval between bDMARD doses were included in this study. Demographic and clinical characteristics were recorded at baseline and at 3, 6 and 12 months of follow-up. Endpoint of the study was the survival of spacing doses in the time lag of the study. Failure of spacing was defined as the first flare of disease. Thirty-seven RA, 28 PsA and 20 axSpA patients underwent bDMARD spacing according to a local strategy. During the follow-up, 5 RA, 6 PsA and 4 axSpA patients had a joint flare, but further 5 PsA patients manifested a skin relapse. Global persistence was 86.5% for RA (MST = 41 (95% CI: 37-45) months) and 80% for axSpA patients (MST = 36 (95% CI: 31-42) months). PsA patients showed a lower persistence, being of 60.7% (MST = 30 (95% CI: 23-36) months) (log-rank test, p = 0.03). Dose reduction by spacing bDMARD doses may be a feasible approach in patients with persistent remission/LDA activity. However, PsA patients might have greater odds of spacing failure because of skin psoriasis relapse. Key Points • Spacing of bDMARDs may be a feasible strategy for some patients with rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis who achieve the target and withdrawn glucocorticoids. • Psoriatic arthritis patients showed lower persistence because of both articular and skin relapses.",
"affiliations": "Unit of Rheumatology, Department of Emergency and Organ Transplantation, University of Bari, P.zza G Cesare, 11 70124, Bari, Italy.;Unit of Rheumatology, Department of Emergency and Organ Transplantation, University of Bari, P.zza G Cesare, 11 70124, Bari, Italy.;Unit of Rheumatology, Department of Emergency and Organ Transplantation, University of Bari, P.zza G Cesare, 11 70124, Bari, Italy.;Unit of Rheumatology, Department of Emergency and Organ Transplantation, University of Bari, P.zza G Cesare, 11 70124, Bari, Italy.;Unit of Rheumatology, Department of Emergency and Organ Transplantation, University of Bari, P.zza G Cesare, 11 70124, Bari, Italy.;Unit of Rheumatology, Department of Emergency and Organ Transplantation, University of Bari, P.zza G Cesare, 11 70124, Bari, Italy.;Unit of Rheumatology, Department of Emergency and Organ Transplantation, University of Bari, P.zza G Cesare, 11 70124, Bari, Italy.;Unit of Rheumatology, Department of Emergency and Organ Transplantation, University of Bari, P.zza G Cesare, 11 70124, Bari, Italy. florenzo.iannone@uniba.it.",
"authors": "Fornaro|M|M|;Righetti|G|G|;Abbruzzese|A|A|;Lopalco|G|G|;Cacciapaglia|F|F|;Anelli|M G|MG|;Venerito|V|V|;Iannone|F|F|http://orcid.org/0000-0003-0474-5344",
"chemical_list": "D018501:Antirheumatic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-021-05728-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "40(9)",
"journal": "Clinical rheumatology",
"keywords": "Axial spondyloarthritis; Biologic disease-modifying antirheumatic drug; Psoriatic arthritis; Rheumatoid arthritis; Spacing",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D018501:Antirheumatic Agents; D015535:Arthritis, Psoriatic; D001172:Arthritis, Rheumatoid; D006801:Humans; D012008:Recurrence; D012042:Registries; D025241:Spondylarthritis; D016896:Treatment Outcome",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "3659-3665",
"pmc": null,
"pmid": "33864158",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": "22904612",
"title": "High disease relapse after bDMARD spacing in psoriatic arthritis compared to rheumatoid arthritis and axial spondyloarthritis patients: real-life data from BIOPURE registry.",
"title_normalized": "high disease relapse after bdmard spacing in psoriatic arthritis compared to rheumatoid arthritis and axial spondyloarthritis patients real life data from biopure registry"
} | [
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"companynumb": "IT-MYLANLABS-2021M1063047",
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"activesubstancename": "ADALIMUMAB"
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"abstract": "Hyponatremia is frequently seen in heart failure patients and has a high mortality rate. If not treated adequately, acute and chronic hyponatremia may worsen the prognosis of heart failure. Despite its high incidence in heart failure patients, other underlying conditions that possibly lead to the incidence of hyponatremia may be underestimated, thus making its treatment more difficult. In this case study, we describe a rare case of levetiracem-induced and tolvaptan-resistant hyponatremia.",
"affiliations": "Department of Cardiology, Süleyman Demirel University Faculty of Medicine, Isparta, Turkey. hatem_ari@hotmail.com.;Department of Cardiology, Süleyman Demirel University Faculty of Medicine, Isparta, Turkey.;Department of Cardiology, Süleyman Demirel University Faculty of Medicine, Isparta, Turkey.",
"authors": "Arı|Hatem|H|;Kahraman|Fatih|F|;Acaban|Murat Baver|MB|",
"chemical_list": "D000927:Anticonvulsants; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan; D000077287:Levetiracetam; D010889:Piracetam",
"country": "Turkey",
"delete": false,
"doi": "10.5543/tkda.2015.45735",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-5169",
"issue": "43(3)",
"journal": "Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir",
"keywords": null,
"medline_ta": "Turk Kardiyol Dern Ars",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004827:Epilepsy; D006333:Heart Failure; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam; D000077602:Tolvaptan",
"nlm_unique_id": "9426239",
"other_id": null,
"pages": "284-7",
"pmc": null,
"pmid": "25906002",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The first case of levetiracetam-induced and tolvaptan-resistant hyponatremia.",
"title_normalized": "the first case of levetiracetam induced and tolvaptan resistant hyponatremia"
} | [
{
"companynumb": "TR-ENDO PHARMACEUTICALS INC-2015-002081",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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"activesubstance": {
"activesubstancename": "CARVEDILOL"
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{
"abstract": "Electroconvulsive therapy (ECT), which has been in use for 75 years, is an important treatment for severe and treatment-resistant depression. Although it is acknowledged as the most effective acute treatment for severe mood and psychotic disorders, it remains controversial because of misperceptions about its use and lack of familiarity among health care professionals about modern ECT technique. The authors present an illustrative case of a patient for whom ECT is indicated. They review the basic and clinical science related to ECT's mechanism of action and discuss clinical issues in the administration of a course of ECT, including the consent process.",
"affiliations": "Departments of Psychiatry and Anesthesiology, Mount Sinai School of Medicine, NY, USA. charles.kellner@mssm.edu",
"authors": "Kellner|Charles H|CH|;Greenberg|Robert M|RM|;Murrough|James W|JW|;Bryson|Ethan O|EO|;Briggs|Mimi C|MC|;Pasculli|Rosa M|RM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1176/appi.ajp.2012.12050648",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-953X",
"issue": "169(12)",
"journal": "The American journal of psychiatry",
"keywords": null,
"medline_ta": "Am J Psychiatry",
"mesh_terms": "D003865:Depressive Disorder, Major; D004565:Electroconvulsive Therapy; D006801:Humans; D007258:Informed Consent; D016896:Treatment Outcome",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "1238-44",
"pmc": null,
"pmid": "23212054",
"pubdate": "2012-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": null,
"title": "ECT in treatment-resistant depression.",
"title_normalized": "ect in treatment resistant depression"
} | [
{
"companynumb": "US-MYLANLABS-2015M1046936",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ESCITALOPRAM OXALATE"
},
"drugadditional": nu... |
{
"abstract": "To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose-lowering regimens with differing risks of hypoglycaemia.\n\n\n\nData were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose-lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all-cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time-dependent covariable.\n\n\n\nThere were 6646 deaths in a total follow-up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95-1.12); sulphonylurea, aHR 1.11 (95% CI 0.99-1.25); insulin, aHR 1.47 (95% CI 1.25-1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94-1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13-1.35) and including insulin, aHR 1.28 (95% CI 1.18-1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all-cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia.\n\n\n\nThe pattern of mortality risk across the range of HbA1c differed by glucose-lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.",
"affiliations": "Institute of Population Medicine, School of Medicine, Cardiff University, Cardiff, UK.;Global Epidemiology, Pharmatelligence, Cardiff, UK.;Global Epidemiology, Pharmatelligence, Cardiff, UK.;Global Epidemiology, Pharmatelligence, Cardiff, UK.;MSD RBSC GmbH, Germany.;Merck & Co. Inc, Kenilworth, New Jersey.;Merck & Co. Inc, Kenilworth, New Jersey.;Diabetes and Endocrinology, University Hospital of Wales, Cardiff, UK.;Merck & Co. Inc, Kenilworth, New Jersey.",
"authors": "Currie|Craig J|CJ|0000-0002-6154-818X;Holden|Sarah E|SE|0000-0002-4315-5681;Jenkins-Jones|Sara|S|0000-0003-3836-8102;Morgan|Christopher Ll|CL|0000-0001-8796-7406;Voss|Bernd|B|;Rajpathak|Swapnil N|SN|;Alemayehu|Berhanu|B|;Peters|John R|JR|;Engel|Samuel S|SS|0000-0002-4439-6356",
"chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents",
"country": "England",
"delete": false,
"doi": "10.1111/dom.13155",
"fulltext": "\n==== Front\nDiabetes Obes MetabDiabetes Obes Metab10.1111/(ISSN)1463-1326DOMDiabetes, Obesity & Metabolism1462-89021463-1326Blackwell Publishing Ltd Oxford, UK 10.1111/dom.13155DOM13155Original ArticleOriginal ArticlesImpact of differing glucose‐lowering regimens on the pattern of association between glucose control and survival Currie et al.Currie Craig J. PhDhttp://orcid.org/0000-0002-6154-818Xcurrie@cardiff.ac.uk \n1\n\n2\nHolden Sarah E. PhDhttp://orcid.org/0000-0002-4315-5681\n2\nJenkins‐Jones Sara MSchttp://orcid.org/0000-0003-3836-8102\n2\nMorgan Christopher Ll MSchttp://orcid.org/0000-0001-8796-7406\n2\nVoss Bernd MD\n3\nRajpathak Swapnil N. MD\n4\nAlemayehu Berhanu DrPH\n4\nPeters John R. MD\n5\nEngel Samuel S. MDhttp://orcid.org/0000-0002-4439-6356\n4\n\n1 \nInstitute of Population Medicine, School of Medicine\nCardiff University\nCardiff\nUK\n\n2 \nGlobal Epidemiology, Pharmatelligence\nCardiff\nUK\n\n3 \nMSD RBSC GmbH\nGermany\n\n4 \nMerck & Co. Inc\nKenilworth\nNew Jersey\n\n5 \nDiabetes and Endocrinology\nUniversity Hospital of Wales\nCardiff\nUK\n* Correspondence\n\nCraig Currie, Institute of Population Medicine, School of Medicine, Cardiff University, Abton House, Wedal Road, Cardiff CF14 3QX, UK. Email: currie@cardiff.ac.uk\n08 12 2017 4 2018 20 4 10.1111/dom.2018.20.issue-4821 830 18 8 2017 16 10 2017 04 11 2017 © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Aims\nTo characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose‐lowering regimens with differing risks of hypoglycaemia.\n\nMethods\nData were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose‐lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all‐cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time‐dependent covariable.\n\nResults\nThere were 6646 deaths in a total follow‐up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95‐1.12); sulphonylurea, aHR 1.11 (95% CI 0.99‐1.25); insulin, aHR 1.47 (95% CI 1.25‐1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94‐1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13‐1.35) and including insulin, aHR 1.28 (95% CI 1.18‐1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all‐cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia.\n\nConclusions\nThe pattern of mortality risk across the range of HbA1c differed by glucose‐lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.\n\ndiabetesglucosehypoglycaemiamortalitysurvivalMerck Sharp and Dohme source-schema-version-number2.0component-iddom13155cover-dateApril 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:06.04.2018\n\n\nCurrie \nCJ \n, \nHolden \nSE \n, \nJenkins‐Jones \nS \n, et al. Impact of differing glucose‐lowering regimens on the pattern of association between glucose control and survival . Diabetes Obes Metab . 2018 ;20 :821 –830 . https://doi.org/10.1111/dom.13155\n29119713 \n\n\n\nFunding information Merck Sharp and Dohme\n==== Body\n1 INTRODUCTION\nTreatment guidelines for diabetes generally recommend therapeutic strategies that aim for normalization or near‐normalization of glucose control.1 These guidelines are based, in large part, on convincing evidence from the Diabetes Control and Complications Trial in type 1 diabetes and the UK Prospective Diabetes Study in type 2 diabetes, which demonstrated that improved glucose control reduced the risk of microvascular complications.2, 3\n\n\nWhilst reductions in macrovascular complications and mortality have been observed in long‐term follow‐up of intensively treated subjects in these studies,2, 4 data from subsequent randomized clinical trials suggested no benefit, or an increase in mortality with intensive glucose control.5, 6 Furthermore, observational studies generally report increased mortality in those with low glycated haemoglobin (HbA1c).7 Thus, the optimum target for glucose control in patients with diabetes remains uncertain. This uncertainty is further complicated because both randomized trials8, 9 and observational studies7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 26 have been unable to demonstrate a consistent pattern of association between levels of glucose control and adverse outcome, nor to explain why this may be the case.\n\nOne potentially influential explanation for an absence of improved survival in these studies, and the inconsistent pattern of association across the glucose control range relates to the impact of hypoglycaemia on cardiovascular event risk. Both randomized trials and observational studies included therapies that cause hypoglycaemia: primarily insulin and sulphonylureas; therefore, determination of optimal glucose control may be complicated by potentially competing influences of improved hyperglycaemia vs inducement of hypoglycaemia. Severe hypoglycaemia is associated with increased cardiovascular death and all‐cause mortality,23 but, in turn, hypoglycaemia is associated with other factors, for instance, exposure to exogenous insulin and, less often, sulphonylureas. The recent introduction of glucose‐lowering drugs that are not associated with hypoglycaemia provided an opportunity to dissect out these competing mechanisms. The aim of the present study was to characterize the risk of all‐cause mortality across the range of achieved HbA1c targets, and to determine whether this pattern varied in alternative regimens with differing risk of hypoglycaemia.\n\n2 MATERIALS AND METHODS\n2.1 Data source\nThis was a retrospective cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) linked, where available, to the Hospital Episode Statistics (HES). The CPRD is a proprietary data source containing clinically rich, pseudonymized data collected in a non‐interventional manner. These data include demographics, consultations, medical history, test results and prescriptions. The CPRD is broadly representative of the UK population and contains records from approximately 14 million people. No patient consent was required for this study.\n\n2.2 Patient selection\nPatients with type 2 diabetes were identified between January 2004 and December 2013, with follow‐up to January 2015. Only practices with research‐quality data were included. Patients were selected if they had been treated with glucose‐lowering therapy, prescribed as monotherapy or dual therapy in combination with metformin. A minimum wash‐in period of 1 year from the date of registration or the up‐to‐standard date for the practice was required in order to identify treatment initiation. The up‐to‐standard date is the date at which the practice is considered to have been supplying continuous high‐quality data suitable for research. The study index date was defined as the first exposure to a relevant regimen; a patient could potentially contribute more than one regimen to the study. Exclusion criteria included diagnosis of type 1 diabetes, <91 days’ follow‐up time, and absence of HbA1c observations during the follow‐up period.\n\n2.3 Treatment exposure\nSix cohorts were selected, a priori, to provide insight into the overall impact of lower HbA1c and to differentiate between treatments that have a higher or a lower risk of hypoglycaemia. Two treatment cohorts were composed of glucose‐lowering therapies with a low risk of hypoglycaemia: the metformin monotherapy group; and a composite group treated with metformin monotherapy and acarbose, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists, sodium‐glucose co‐transporter‐2 inhibitors or thiazolidinediones, as monotherapy or in combination with metformin. Four treatment cohorts comprised patients receiving glucose‐lowering therapies associated with a higher hypoglycaemia risk: sulphonylurea monotherapy; insulin monotherapy; a composite group of regimens comprising sulphonylureas and meglitinides prescribed as monotherapy or in combination with metformin but excluding insulin; and a composite group of regimens comprising sulphonylureas, meglitinides and insulin prescribed as monotherapy or with metformin. Treatment was considered to have been discontinued if there was a gap of >100 days between prescriptions for the same class of glucose‐lowering therapy. Patients were followed until the earliest of their date of death, date of regimen change, end of recorded data or the last prescription for the glucose‐lowering therapy of interest plus 90 days.\n\n2.4 Outcome\nThe outcome was all‐cause mortality.\n\n2.5 Achieved HbA1c categorization\nBased on the pattern of association elucidated in a previous study7 and treatment guidelines,1 the following glucose‐control categories were selected a priori: lower HbA1c, <7%; moderate HbA1c, ≥7% < 8.5%; high HbA1c, ≥8.5% < 9.5%; and very high HbA1c, ≥9.5%.\n\n2.6 Validation of the hypoglycaemia risk assumption\nTo validate that the prespecified treatment cohorts varied in hypoglycaemia risk as predicted, the hospital admission rate relating to hypoglycaemia was determined for each treatment cohort in those patients who were eligible for linkage to HES.\n\n2.7 Statistical methods\nCrude event rates were calculated for each treatment cohort and reported as events per 1000 person‐years of exposure. The relative rate was determined as the ratio of the respective crude event rates. Mid‐P confidence intervals (CIs)24 were calculated for the crude rates and the relative rate ratios. Time to and risk of death were evaluated using the Kaplan–Meier and multivariable Cox proportional hazards models.25 A significance level of .05 was chosen for this study. Unadjusted survival curves were compared using the log‐rank test. Day 0 was defined as index date plus 91 days. Based on their clinical rationale and past research,7 the following co‐variables were selected a priori and included in the multivariable models: age, gender, history of large vessel disease, Charlson morbidity index26, general practitioner contacts in the year prior to index date, smoking status, diabetes duration, systolic blood pressure, total cholesterol, and calendar year. The proportion of missing data was low (5% for total cholesterol [8464 patients], 2% for systolic blood pressure [3884 patients] and 0.2% for smoking status [350 patients]). Systolic blood pressure and total cholesterol were categorized into quartiles, plus a separate category for those with missing data, and patients with no smoking status were assumed to be non‐smokers.\n\nComparisons were made within each treatment cohort and not between cohorts. This is important because it eliminates glucose treatment indication bias in those on monotherapy. In the main analysis, achieved HbA1c was analysed as a mean, quarterly updated, time‐dependent co‐variable. Last observations carried forward and backwards were used to impute missing, post‐baseline values. HbA1c was also introduced into the models in the following ways in sensitivity analyses: non‐time‐dependently using mean HbA1c over follow‐up (theoretically violating the assumptions of survival models) and time‐dependently using a quarterly updated cumulative, mean value. The proportional hazards assumption was tested by examining the Pearson correlation between Schoenfeld residuals and the rank of survival time for cases that had progressed to death. Two‐sided P values are presented, and 95% CIs calculated for hazard ratios (HRs). We also report findings from an exploratory post hoc analysis, carried out to examine in more detail the structure of the association using deciles of HbA1c instead of the prespecified categories. Analyses were carried out using r‐v3.2.3 and spss‐v20.\n\nTo determine if the pattern of association between achieved HbA1c and mortality risk is the same in people with or without comorbidity, a subgroup analysis was conducted in those with a Charlson index of 1 (diabetes with no complications) and a Charlson index of ≥2 (diabetes with diabetic complications, diabetes plus non‐diabetic comorbidities or diabetes with diabetic complications plus non‐diabetic comorbidities).\n\n2.8 Ethical approval\nStudies using the CPRD are covered by ethics approval granted by the Trent Multicentre Research Ethics Committee (reference 05/MRE04/87). This study was granted CPRD Independent Scientific Advisory Committee approval on 23 February 2016, protocol number 16_007R2.\n\n3 RESULTS\n3.1 Study population\nAn attrition table detailing patient selection is provided in Table S1. There were 290 739 subjects with at least 1 diabetes glucose‐lowering therapy. Following exclusions, 131 315 patients were selected, with some participating in more than 1 treatment cohort and contributing more than 1 regimen to the composite treatment cohorts (number of periods of continuous therapy = 167 786). The treatment cohort with the fewest subjects was insulin monotherapy (n = 6827), and the largest was the composite cohort of regimens with a low risk of hypoglycaemia (n = 101 740; Table 1). Overall, there were 6646 deaths, with a corresponding total follow‐up of 374 591 years. The percentage of patients with a mean follow‐up HbA1c in the moderate category ranged from 42% for those prescribed metformin monotherapy (32 188 patients) to 46% for those prescribed regimens with a higher hypoglycaemia risk including insulin (30 363 patients). The percentage of patients with a mean follow‐up HbA1c in the lowest category ranged from 20% for those prescribed insulin monotherapy (1388 patients) to 47% for those prescribed metformin monotherapy (36 257 patients; Tables S2‐S7).\n\nTable 1 Baseline characteristics by glucose‐lowering regimen\n\nCharacteristic\tInsulin\tMetformin\tSulphonylureas\tRegimens with a low risk of hypoglycaemia\tRegimens with higher hypoglycaemia risk excluding insulin\tRegimens with higher hypoglycaemia risk including insulin\t\n\nN\n\t6827\t76 821\t14 834\t101 740\t50 094\t66 046\t\nMales, n (%)\t3819(56)\t43 985 (57)\t7675 (52)\t58 299 (57)\t29 213 (58)\t38 372 (58)\t\nAge at index, mean (SD), years\t66.3 (12.9)\t62.5 (12.4)\t69.7 (12.3)\t62.1 (12.2)\t65.3 (12.5)\t65 (12.5)\t\nDuration of diabetes, median (IQR), years\t7.5 (3‐12.9)\t0.5 (0‐3.1)\t2.6 (0.4 to 6.1)\t1.4 (0.1‐4.5)\t3.9 (1.4‐7.2)\t4.7 (1.7‐8.6)\t\nEver smoked, n (%)\t4063 (60)\t44 157 (57)\t8377 (56)\t58 559 (58)\t28 844 (58)\t38 343 (58)\t\nSerum creatinine, median (IQR), μmol/L\t99 (77‐143)\t82 (71‐95)\t91 (76‐119)\t82 (70‐95)\t84 (72‐100)\t85 (72‐102)\t\nBMI, mean (SD), kg/m2\n\t29.8 (6.6)\t32.4 (6.4)\t29.3 (6)\t32.6 (6.4)\t30.6 (6.1)\t30.7 (6.2)\t\nSystolic blood pressure, mean (SD), mmHg\t134.1 (18.5)\t137 (16.1)\t135.4 (17.4)\t136.5 (15.9)\t135.3 (16)\t135.2 (16.3)\t\nTotal cholesterol, mean (SD), mmol/L\t4.5 (1.4)\t4.9 (1.3)\t4.7 (1.3)\t4.8 (1.2)\t4.5 (1.2)\t4.5 (1.2)\t\nCharlson comorbidity index, median (IQR)\t3 (2‐5)\t2 (1‐3)\t3 (1‐4)\t2 (1‐3)\t2 (1‐3)\t2 (1‐3)\t\nPrior cancer, n (%)\t870 (13)\t5863 (8)\t1918 (13)\t7594 (7)\t4759 (10)\t6335 (10)\t\nPrior large vessel disease, n (%)\t2501 (37)\t15 173 (20)\t4537 (31)\t19 878 (20%)\t12 148 (24)\t17 216 (26)\t\nPrior vision problems, n (%)\t2982 (44)\t15 382 (20)\t4941 (33)\t23 102 (23)\t15 799 (32)\t22 633 (34)\t\nPrior microalbuminuria, n (%)\t720 (11)\t1738 (2)\t860 (6%)\t3352 (3)\t2960 (14)\t4598 (7)\t\nPrior renal, n (%)\t2482 (36)\t7888 (10)\t4066 (27)\t11 444 (11)\t9102 (18)\t13 193 (20)\t\nAbbreviations: BMI, body mass index; IQR, interquartile range.\n\n3.2 Baseline characteristics\nThe baseline characteristics varied by cohort (Table 1). For example, the youngest mean age at treatment initiation was in the composite cohort of regimens with a low risk of hypoglycaemia, with a mean age of 62.1 years. The oldest mean age was in those in the sulphonylurea monotherapy cohort, at 69.7 years. A summary of the baseline characteristics by treatment cohort is provided in Table 1; more detailed descriptions by HbA1c category are provided in Tables S2 to S7. There were differences between those with lower and moderate mean HbA1c values within the 6 cohorts. Age at treatment initiation was generally younger in those with moderate mean HbA1c, except for insulin monotherapy where those with moderate control vs lower control were older (67.3 vs 65.8 years; P = .001). Modifiable risk factors such as smoking status, blood pressure and total cholesterol concentration did not vary markedly between moderate and lower HbA1c categories. Patients in the lower HbA1c category had a shorter duration of diabetes.\n\n3.3 Crude admission rates for hypoglycaemia\nThe hospital admission rate for hypoglycaemia varied by treatment cohort. For example, the value for the insulin monotherapy cohort was 42.2 (95% CI 37.9‐46.5) admissions per 1000 person‐years of exposure. For the composite cohort of regimens with lower hypoglycaemia risk, this was 0.8 (95% CI 0.6‐0.9) admissions per 1000 person‐years of exposure (Figure S1). When compared with moderate control, the rate of admissions for hypoglycaemia was higher for those in the lower mean follow‐up HbA1c category treated with regimens defined a priori to have a high risk of hypoglycaemia. The rate of hypoglycaemia was also higher in those with very high mean follow‐up HbA1c treated with insulin monotherapy and regimens with a higher risk of hypoglycaemia including insulin.\n\n3.4 Crude mortality rates\nThe overall crude mortality rate was 17.7 deaths per 1000 person‐years of exposure. This differed between glucose‐lowering cohorts; the highest rate was in those treated with insulin monotherapy, with a crude rate of 53.5 deaths per 1000 person‐years, and the lowest rate was in the composite group of regimens with low risk of hypoglycaemia, with a crude rate of 13.5 deaths per 1000 person‐years (Table 2). The Kaplan–Meier survival curves by mean HbA1c categories, and by treatment cohort are shown in Figure 1. These showed that the rate of progression to death was more rapid for those with lower mean HbA1c vs moderate.\n\nTable 2 Frequency of deaths, total exposure and crude event rates by mean follow‐up HbA1c category\n\nParameter\tLower (<7%)\tModerate (≥7% and <8.5%)\tHigh (≥8.5% and <9.5%)\tVery high (≥9.5%)\tOverall\t\nMetformin\t\nNumber of deaths\t1708\t928\t49\t34\t2719\t\nPerson‐years of exposure\t104 268\t72 022\t6666\t3095\t186 051\t\nMean follow‐up, years\t2.88\t2.24\t1.25\t1.02\t2.42\t\nCrude event rate per 1000 person‐years (95% CI)\t16.4 (15.6‐17.2)\t12.9 (12.1‐13.7)\t7.4 (5.3‐9.4)\t11.0 (7.3‐14.7)\t14.6 (14.1‐15.2)\t\nCrude rate ratio\t1.27 (1.17‐1.38)\t1\t0.57 (0.42‐0.75)\t0.85 (0.6‐1.19)\t\t\nSulphonylureas\t\nNumber of deaths\t768\t505\t73\t29\t1375\t\nPerson‐years of exposure\t12 564\t11 899\t2214\t1147\t27 823\t\nMean follow‐up, years\t2.20\t1.90\t1.28\t1.03\t1.88\t\nCrude event rate per 1000 person‐years (95% CI)\t61.1 (56.8‐65.5)\t42.4 (38.7‐46.1)\t33.0 (25.4‐40.5)\t25.3 (16.1‐34.5)\t49.4 (46.8‐52)\t\nCrude rate ratio\t1.44 (1.29‐1.61)\t1\t0.78 (0.6‐0.99)\t0.60 (0.4‐0.85)\t\t\nInsulin\t\nNumber of deaths\t182\t389\t170\t108\t849\t\nPerson‐years of exposure\t2818\t7847\t3307\t1898\t15 870\t\nMean follow‐up, years\t2.03\t2.60\t2.33\t1.90\t2.32\t\nCrude event rate per 1000 person‐years (95% CI)\t64.6 (55.2‐74)\t49.6 (44.6‐54.5)\t51.4 (43.7‐59.1)\t56.9 (46.2‐67.6)\t53.5 (49.9‐57.1)\t\nCrude rate ratio\t1.30 (1.09‐1.55)\t1\t1.04 (0.86‐1.24)\t1.15 (0.92‐1.42)\t\t\nRegimens with a low hypoglycaemia risk\t\nNumber of deaths\t1928\t1128\t72\t41\t3169\t\nPerson‐years of exposure\t125 054\t93 951\t10 006\t4952\t233 962\t\nMean follow‐up, years\t2.81\t2.14\t1.21\t0.97\t2.30\t\nCrude event rate per 1000 person‐years (95% CI)\t15.4 (14.7‐16.1)\t12.0 (11.3‐12.7)\t7.2 (5.5‐8.9)\t8.3 (5.7‐10.8)\t13.5 (13.1‐14)\t\nCrude rate ratio\t1.28 (1.19‐1.38)\t1\t0.60 (0.47‐0.76)\t0.69 (0.5‐0.93)\t\t\nRegimens with a higher hypoglycaemia risk excluding insulin\t\nNumber of deaths\t1280\t959\t138\t64\t2441\t\nPerson‐years of exposure\t38 958\t49 927\t9691\t4760\t103 336\t\nMean follow‐up, years\t2.23\t2.17\t1.60\t1.32\t2.06\t\nCrude event rate per 1000 person‐years (95% CI)\t32.9 (31.1‐34.7)\t19.2 (18‐20.4)\t14.2 (11.9‐16.6)\t13.4 (10.2‐16.7)\t23.6 (22.7‐24.6)\t\nCrude rate ratio\t1.71 (1.57‐1.86)\t1\t0.74 (0.62‐0.88)\t0.70 (0.54‐0.9)\t\t\nRegimens with a higher hypoglycaemia risk including insulin\t\nNumber of deaths\t1504\t1444\t334\t195\t3477\t\nPerson‐years of exposure\t44 597\t68 873\t17 828\t9331\t140 628\t\nMean follow‐up, years\t2.21\t2.27\t1.87\t1.57\t2.13\t\nCrude event rate per 1000 person‐years (95% CI)\t33.7 (32‐35.4)\t21.0 (19.9‐22)\t18.7 (16.7‐20.7)\t20.9 (18‐23.8)\t24.7 (23.9‐25.5)\t\nCrude rate ratio\t1.61 (1.5‐1.73)\t1\t0.89 (0.79‐1.01)\t1.00 (0.86‐1.16)\t\t\nAbbreviation: CI, confidence interval.\n\nFigure 1 Kaplan–Meier survival curves by glucose‐lowering regimen. A, Metformin monotherapy. B, Regimens with a low hypoglycaemia risk. C, Sulphonylurea monotherapy. D, Insulin monotherapy. E, Regimens with a higher hypoglycaemia risk excluding insulin. F, Regimens with a higher hypoglycaemia risk including insulin. Black dashed line = lower glycated haemoglobin (HbA1c; <7%), black solid line = moderate HbA1c (≥7% and <8.5%), grey dashed line = high HbA1c (≥8.5% and <9.5%) and grey solid line = very high HbA1c (≥9.5%). The number next to each line is the mean age for each cohort\n\nThe crude death rate was consistently higher in patients in the lower mean HbA1c category than in those in the moderate mean HbA1c category across all 6 cohorts (Table 2). Patients in the composite cohort of regimens with a higher risk of hypoglycaemia excluding insulin had the highest relative increase in crude death rate between the lower and moderate mean HbA1c categories: relative rate ratio 1.71 (95% CI 1.57‐1.86). The lowest relative death rate between the lower and moderate mean HbA1c categories was in the metformin monotherapy cohort: 1.27 (95% CI 1.17‐1.38). The crude mortality rates are shown in Figures S2 and S3.\n\n3.5 Adjusted risk of death by HbA1c category\nIn the main analysis, the overall adjusted HRs (aHRs), compared with moderate HbA1c, for the lower, high and very high HbA1c categories were 1.16 (95% CI 1.06‐1.18), 1.18 (95% CI 1.07‐1.32) and 1.16 (95% CI 1.03‐1.32), respectively.\n\nFor metformin monotherapy and the composite cohort of regimens with a low risk of hypoglycaemia, there was no statistically significant difference in the risk of mortality between the lower and moderate HbA1c categories when HbA1c was modelled as a mean, quarterly updated, time‐dependent co‐variable (aHR 1.03 [95% CI 0.95‐1.12] and 1.02 [95% CI 0.94‐1.10], respectively); however, an increase in the risk of all‐cause mortality in the lower vs moderate HbA1c categories was observed in patients in the insulin monotherapy cohort (aHR 1.47 [95% CI 1.25‐1.72]) and in both composite cohorts of regimens with a higher hypoglycaemia risk, excluding and including insulin (aHR 1.24 [95% CI 1.13‐1.35] and 1.28 [95% CI 1.18‐1.37], respectively; Figure 2). The high and very high HbA1c categories were associated with a significantly increased risk of all‐cause mortality when compared with the moderate categories for patients in the metformin monotherapy cohort and in the composite group of regimens with a low risk of hypoglycaemia (results for the high and very high categories were aHR 1.37 [95% CI 1.09‐1.72] and 1.70 [95% CI 1.28‐2.26] for metformin, and aHR 1.27 [95% CI 1.04‐1.56] and 1.45 [95% CI 1.12‐1.89] for regimens with a lower‐risk of hypoglycaemia). The risk of all‐cause mortality was not significantly elevated in the high and very high categories for sulphonylurea monotherapy, insulin monotherapy and regimens with a higher risk of hypoglycaemia with the exception of the high HbA1c category for regimens with a higher risk of hypoglycaemia including insulin where the risk of all‐cause mortality was significantly elevated (aHR 1.13, 95% CI 1.00‐1.28, p=0.047). Sensitivity analyses were largely consistent with the primary analysis (Figure S2).\n\nFigure 2 Relative risk of death by glycated haemoglobin (HbA1c) category when HbA1c is modelled as a mean, quarterly updated, time‐dependent covariate. Data from alternative models are detailed in Figure S2. A, Metformin monotherapy. B, Regimens with a low hypoglycaemia risk. C, Sulphonylurea monotherapy. D, Insulin monotherapy. E, Regimens with a higher hypoglycaemia risk excluding insulin. F, Regimens with a higher hypoglycaemia risk including insulin. Vertical error bars represent the 95% confidence interval (CI) for adjusted hazard ratio (aHR) and the horizontal error bars represent the HbA1c range\n\n3.6 Adjusted risk of death stratified by HbA1c decile\nWhen analysed according to HbA1c deciles there was further structure in these data (Figures 3 and S3). There was a consistent pattern of a more specific, optimal HbA1c (7.03%‐7.27%). In all 6 cohorts there was an increased association with all‐cause mortality in the lowest decile compared with the nadir. At the highest decile of HbA1c, all treatment cohorts had elevated risk, and this achieved significance in those prescribed metformin monotherapy (aHR 2.01 [95% CI 1.53‐2.65]), regimens with a lower hypoglycaemia risk (aHR 1.77 [95% CI 1.38‐2.27]) and regimens with a higher hypoglycaemia risk, excluding (aHR 1.27 [95% CI 1.02‐1.57]) and including (aHR 1.22 [95% CI 1.03‐1.44]) insulin. This was not the case, however, for all high deciles of HbA1c. Sensitivity analyses were largely consistent with the primary analysis (Figure S3). A similar pattern of association between HbA1c and all‐cause mortality was observed in those patients with a baseline Charlson score of 1 and ≥2 prescribed regimens with a low hypoglycaemia risk or regimens with a higher hypoglycaemia risk including insulin (Figure S4).\n\nFigure 3 Relative risk of death by HbA1c decile when HbA1c is modelled as a mean, quarterly updated, time‐dependent covariate. Data from alternative models are detailed in Figure S3. A, Metformin monotherapy. B, Regimens with a low hypoglycaemia risk. C, Sulphonylurea monotherapy. D, Insulin monotherapy. E, Regimens with a higher hypoglycaemia risk excluding insulin. F, Regimens with a higher hypoglycaemia risk including insulin. Vertical error bars represent the 95% confidence interval (CI) for adjusted hazard ratio (aHR) and the horizontal error bars represent the glycated haemoglobin (HbA1c) range\n\n4 DISCUSSION\nPrevious studies in patients with type 2 diabetes have reported that the relationship between HbA1c, all‐cause mortality and other outcomes was not a direct association but better characterized by a J‐shaped, V‐shaped or U‐shaped association.7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22 In this study, we not only found that the pattern of association between differing levels of HbA1c and all‐cause mortality differed within specific glucose‐lowering regimens, but also that this pattern of association differed between differing glucose‐lowering regimens. When categorized by prespecified HbA1c ranges, lower HbA1c was associated with significantly increased mortality when compared with moderate levels of control, but only in those regimens that were associated with hypoglycaemia. In regimens associated with hypoglycaemia, there was either no elevation of mortality risk at higher levels of HbA1c at the conventional level of statistical significance, or a small increase in mortality risk was observed. In contrast, in those regimens not associated with hypoglycaemia there was no increase in mortality at the lower HbA1c range, but, as might be expected, there was an increase in mortality at higher levels. In itself this does not prove that hypoglycaemia is solely or even partially responsible for these observations; however, these findings do show persuasively that there were marked differences that need somehow to be explained.\n\nWithin the prespecified categories of HbA1c, patient numbers varied, with more people in the moderate control category. Thus, we performed a post hoc analysis by HbA1c deciles that revealed further structure in these data. The findings by HbA1c category masked more detailed differences in risk patterns between regimens. All regimens were associated with elevated mortality risk at the lowest decile of HbA1c. Sulphonylurea monotherapy and insulin monotherapy resulted in considerably elevated mortality risk at low HbA1c levels, but an increase was also seen with therapies that are not typically associated with hypoglycaemia. Insofar as low glucose levels may possibly be a consequence of disease‐related morbidity, these observations may suggest that the overall increase in mortality in patients with type 2 diabetes that has been previously described may be a function of the interplay between 2 recognized factors: hypoglycaemia induced by certain glucose‐lowering drugs, against a background of a generalized association of morbidity with reduced plasma glucose concentrations.\n\nIn contrast, at higher levels of HbA1c there was no clear elevation in mortality in people treated with regimens associated with increased hypoglycaemia. While the reasons for this observation remain unknown, one possibility is that the influence of hypoglycaemia‐related mortality extends throughout the entire HbA1c range, and confounds the ability to tease out the contribution of hyperglycaemia to mortality. This hypothesis is supported by the observations in patients treated with regimens with a low hypoglycaemia risk, where the expected increase in mortality was observed in higher HbA1c categories.\n\nIn terms of the association with all‐cause mortality, the optimal level of HbA1c in these analyses was consistently slightly above 7% in all regimens, although high levels of HbA1c were not always associated with increased risk of all‐cause mortality. Variability in these patterns between alternative regimens—whilst consistent with previous observational studies—helps explain why no single, consistent pattern has yet emerged. It is likely that the pattern of HbA1c association with adverse outcome varies by regimen, and if confirmed, this would be an important consideration.\n\nThese data may also help explain the lack of demonstrable mortality benefits in previous studies of intensive control such as the ACCORD5 and the VADT studies.5, 6 To the extent that an increase in mortality is associated with therapies that increase insulin availability in a non‐glucose‐dependent manner (eg, sulphonylureas and insulin), studies of intensive glucose‐lowering may be confounded by the competing influences of reversal of hyperglycaemia and risk of hypoglycaemia. The ORIGIN trial27 examined the outcome of low‐dose, basal insulin compared with standard care, and the insulin arm did not reduce either all‐cause mortality or cardiovascular mortality; however, patients in the insulin group received concomitant metformin—shown to markedly attenuate mortality risk in people treated with insulin, in particular at low doses28—and insulin was quite frequently used in the standard care arm. In a recent observational study characterizing the outcome of care of those exposed to metformin, where the outcome was major adverse cardiovascular events or all‐cause mortality, there was no evidence of increased adverse outcomes at low HbA1c levels.29 A further observational study in 2010 reported that there was no difference in all‐cause mortality across the HbA1c range, but this study was subject to immortal time bias and other limitations30.\n\nThe risk‐to‐benefit calculation in choosing between alternative glucose‐lowering drugs involves a complex balancing exercise between competing risks due to pleiotropic effects such as hypoglycaemia, hyperglycaemia, weight gain, renal disease, cancer‐related properties, haemodynamic changes, hyperlipidaemia and direct cardiovascular injury. Although there are no competing risks when analysing all‐cause mortality, the potential harms or benefits from these drugs may differentially influence microvascular and macrovascular outcomes and may impact differing patient phenotypes in differing ways. Intensive glucose control undoubtedly results in improved microvascular disease outcome, but, in the present study, we confirm that there is a serious downside risk that must be taken into account when HbA1c is lowered, particularly with therapies that are associated with an increased risk of hypoglycaemia.\n\nThese data and the study design had a number of strengths and limitations. The study included routine observations from a very large number of people, from a national, real‐world setting. There was no standardization of the timing of observations such as HbA1c. We believe that this will have introduced noise but not bias because there is inherent variability in the measurement and timing of glucose control in routine care. One general criticism of retrospective, observational studies is indication bias, that is, that patients are often treated differentially with differing drugs at differing doses in a non‐random way. Unusually, this was less of a concern here because the comparisons of the pattern of association between differing levels of HbA1c were only made in a statistical way within the same regimens and compared only differing levels of glucose control. However, it is also possible to examine the general patterns of association and determine that they differed markedly between the 6 regimens that were characterized. Nevertheless, multivariable models were used to account for recorded differences between HbA1c categories. HbA1c varies over time for many reasons. The time‐dependent statistical models helped account for this, but they remain statistical models. To increase confidence in our findings, we set out, a priori, to use various analytical approaches and to determine if our findings remained consistent. In the main, there was consistency between alternative approaches. There were differences in phenotype between groups, so the possibility of residual confounding is a consideration that needs to be borne in mind. There could be several reasons why treatment intensification was delayed in those with poor glucose control including clinical inertia, non‐compliance, age, comorbidities, or restricted access to care and there may therefore be underlying differences between patients across the HbA1c range that could not be fully adjusted for in our statistical model.\n\nIn summary, lower HbA1c was associated with increased mortality risk compared with moderate levels, especially with regimens that are associated with hypoglycaemia. High levels of HbA1c were consistently associated with the expected elevated mortality risk in those regimens that have a lower risk of hypoglycaemia. These data suggest that, in the individualization of glycaemic targets for patients, consideration needs to be given to the classes of glucose‐lowering therapy that are being used, with less aggressive targets in those patients who are being treated with therapies associated with hypoglycaemia. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia.\n\nSupporting information\n\nTable S1. Attrition table.\n\n\nTable S2. Baseline characteristics for metformin monotherapy by (a) mean follow‐up HbA1c category and (b) mean follow‐up HbA1c decile.\n\n\nTable S3. Baseline characteristics for sulfonylurea monotherapy by (a) mean follow‐up HbA1c category and (b) mean follow‐up HbA1c decile.\n\n\nTable S4. Baseline characteristics for insulin monotherapy by (a) mean follow‐up HbA1c category and (b) mean follow‐up HbA1c decile.\n\n\nTable S5. Baseline characteristics for regimens with a low hypoglycaemia risk by (a) mean follow‐up HbA1c category and (b) mean follow‐up HbA1c decile.\n\n\nTable S6. Baseline characteristics for regimens with a higher hypoglycaemia risk excluding insulin by (a) mean follow‐up HbA1c category and (b) mean follow‐up HbA1c decile.\n\n\nTable S7. Baseline characteristics for regimens with a higher hypoglycaemia risk including insulin by (a) mean follow‐up HbA1c category and (b) mean follow‐up HbA1c decile.\n\n\nFigure S1. Hospital admission rate for hypoglycaemia (a) by treatment cohort and (b) by treatment cohort and mean follow‐up HbA1c.\n\n\nFigure S2. Relative risk of death by HbA1c category using 5 alternative methods of risk estimation for (a) metformin monotherapy, (b) regimens with low hypoglycaemia risk, (c) sulfonylurea monotherapy, (d) insulin monotherapy, (e) regimens with higher hypoglycaemia risk (excluding insulin) and (f) regimens with higher hypoglycaemia risk (including insulin).\n\n\nFigure S3. Relative risk of death by HbA1c decile using 5 alternative methods of risk estimation for (a) metformin monotherapy, (b) regimens with low hypoglycaemia risk, (c) sulfonylurea monotherapy, (d) insulin monotherapy, (e) regimens with higher hypoglycaemia risk (excluding insulin) and (f) regimens with higher hypoglycaemia risk (including insulin).\n\n\nFigure S4 Relative risk of death in patients with low baseline morbidity (Charlson index of 1 due–diabetes) and a higher baseline morbidity (Charlson index >1) by HbA1c decile when HbA1c was modelled as a mean, quarterly updated, time‐dependent covariate (aHR, adjusted hazard ratio) for (a) regimens with a low risk of hypoglycaemia and (b) regimens with a higher risk of hypoglycaemia including insulin.\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThis study was supported by Merck Sharp and Dohme & Co. Employees of the sponsor contributed to this study as co‐authors, as detailed.\n\nConflict of interest\nAll authors have completed the unified competing interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that (1) C.J.C., S.E.H., S.J.J., C.Ll.M. are employed by, and C.J.C. is a director of Pharmatelligence, a research consultancy receiving funding from Merck for the submitted work; (2) B.V., S.N.R., B.A., and S.S.E. are employees of Merck (i.e. MSD outside of the US&Canada), the sponsor of the study. J.R.P. has no competing interests to declare.\n\nAuthor contributions\nAll co‐authors contributed to the study design. S.J.J. extracted these data. S.H. carried out the data analysis. All co‐authors jointly interpreted these data. C.J.C. wrote the first draft of the manuscript, and all co‐authors edited the manuscript.\n==== Refs\nREFERENCES\n1 \n\nInzucchi \nSE \n, \nBergenstal \nRM \n, \nBuse \nJB \n, et al. Management of hyperglycemia in type 2 diabetes: a patient‐centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) . Diabetes Care . 2012 ;35 :1364 ‐1379 .22517736 \n2 \nThe Diabetes Control and Complications Trial Research Group \n. The effect of intensive treatment of diabetes on the development and progression of long‐term complications in insulin‐dependent diabetes mellitus . N Engl J Med . 1993 ;329 :977 ‐986 .8366922 \n3 \n\nHolman \nRR \n, \nPaul \nSK \n, \nBethel \nMA \n, \nMatthews \nDR \n, \nNeil \nHA \n. 10‐year follow‐up of intensive glucose control in type 2 diabetes . N Engl J Med . 2008 ;359 :1577 ‐1589 .18784090 \n4 \n\nNathan \nDM \n, \nCleary \nPA \n, \nBacklund \nJY \n, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes . 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Lancet . 2009 ;373 :1765 ‐1772 .19465231 \n9 \n\nBoussageon \nR \n, \nBejan‐Angoulvant \nT \n, \nSaadatian‐Elahi \nM \n, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta‐analysis of randomised controlled trials . BMJ . 2011 ;343 :d4169 \nhttps://doi.org/10.1136/bmj.d4169.21791495 \n10 \n\nÖstgren \nCJ \n, \nSundström \nJ \n, \nSvennblad \nB \n, \nLohm \nL \n, \nNilsson \nPM \n, \nJohansson \nG \n. Associations of HbA1c and educational level with risk of cardiovascular events in 32,871 drug‐treated patients with type 2 diabetes: a cohort study in primary care . Diabet Med . 2013 ;30 :e170 ‐e177 .23350893 \n11 \n\nPaprott \nR \n, \nSchaffrath Rosario \nA \n, \nBusch \nMA \n, et al. Association between hemoglobin A1c and all‐cause mortality: results of the mortality follow‐up of the German National Health Interview and examination survey 1998 . Diabetes Care . 2015 ;38 :249 ‐256 .25414153 \n12 \n\nRiddle \nMC \n, \nAmbrosius \nWT \n, \nBrillon \nDJ \n, et al. Epidemiologic relationships between A1C and all‐cause mortality during a median 3.4‐year follow‐up of glycemic treatment in the ACCORD trial . Diabetes Care . 2010 ;33 :983 ‐990 .20427682 \n13 \n\nSelvin \nE \n, \nSteffes \nMW \n, \nZhu \nH \n, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults . N Engl J Med . 2010 ;362 :800 ‐811 .20200384 \n14 \n\nNichols \nGA \n, \nJoshua‐Gotlib \nS \n, \nParasuraman \nS \n. Glycemic control and risk of cardiovascular disease hospitalization and all‐cause mortality . J Am Coll Cardiol . 2013 ;62 :121 ‐127 .23665365 \n15 \n\nKontopantelis \nE \n, \nSpringate \nDA \n, \nReeves \nD \n, et al. Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study . Diabetologia . 2015 ;58 :505 ‐518 .25512005 \n16 \n\nPark \nC \n, \nGuallar \nE \n, \nLinton \nJA \n, et al. Fasting glucose level and the risk of incident atherosclerotic cardiovascular diseases . Diabetes Care . 2013 ;36 :1988 ‐1993 .23404299 \n17 \n\nMonami \nM \n, \nVitale \nV \n, \nLamanna \nC \n, et al. HbA1c levels and all‐cause mortality in type 2 diabetic patients: epidemiological evidence of the need for personalised therapeutic targets . Nutr Metab Cardiovasc Dis . 2013 ;23 :300 ‐306 .22633797 \n18 \n\nFagher \nK \n, \nLöndahl \nM \n. The impact of metabolic control and QTc prolongation on all‐cause mortality in patients with type 2 diabetes and foot ulcers . Diabetologia . 2013 ;56 :1140 ‐1147 .23404446 \n19 \n\nNicholas \nJ \n, \nCharlton \nJ \n, \nDregan \nA \n, \nGulliford \nMC \n. Recent HbA1c values and mortality risk in type 2 diabetes. Population‐based case‐control study . PLoS ONE . 2013 ;8 :e68008 .23861845 \n20 \n\nGrembowski \nD \n, \nRalston \nJD \n, \nAnderson \nML \n. Hemoglobin A1c, comorbid conditions and all‐cause mortality in older patients with diabetes: a retrospective 9‐year cohort study . Diabetes Res Clin Pract . 2014 ;106 :373 ‐382 .25151226 \n21 \n\nChiang \nHH \n, \nTseng \nFY \n, \nWang \nCY \n, et al. All‐cause mortality in patients with type 2 diabetes in association with achieved hemoglobin A1c, systolic blood pressure, and low‐density lipoprotein cholesterol levels . PLoS ONE . 2014 ;9 :e109501 .25347712 \n22 \n\nLi \nW \n, \nKatzmarzyk \nPT \n, \nHorswell \nR \n, \nWang \nY \n, \nJohnson \nJ \n, \nHu \nG \n. HbA1c and all‐cause mortality risk among patients with type 2 diabetes . Int J Cardiol . 2016 ;202 :490 ‐496 .26440458 \n23 \n\nZoungas \nS \n, \nPatel \nA \n, \nChalmers \nJ \n, et al. Severe hypoglycemia and risks of vascular events and death . N Engl J Med . 2010 ;363 :1410 ‐1418 .20925543 \n24 \n\nRothmann \nKJ \n, \nGreenland \nS \n, \nLash \nTL \n. Modern Epidemiology . 3rd ed. Philadelphia, PA : Lippincott Williams & Wilkins ; 2008 .\n25 \n\nKleinbaum \nDG \n, \nKlein \nM \n. Survival Analysis: A Self‐Learning Text . 2nd ed. New York : Springer ; 2005 .\n26 \n\nCharlson \nME \n, \nPompei \nP \n, \nAles \nKL \n, \nMackenzie \nCR \n. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation . J Chronic Dis . 1989 ;40 :373 ‐383 .\n27 \nThe ORIGIN Trial Investigators \n. Basal insulin and cardiovascular and other outcomes in dysglycemia . N Engl J Med . 2012 ;367 :319 ‐328 .22686416 \n28 \n\nHolden \nSE \n, \nJenkins‐Jones \nS \n, \nCurrie \nCJ \n. Association between insulin monotherapy versus insulin plus metformin and the risk of all‐cause mortality and other serious outcomes: a retrospective cohort study . PLoS ONE . 2016 ;11 :e0153594 .27152598 \n29 \n\nSvensson \nE \n, \nBaggesen \nLM \n, \nJohnsen \nSP \n, et al. Early glycemic control and magnitude of HbA1c reduction predict cardiovascular events and mortality: population‐based cohort study of 24,752 metformin initiators . Diabetes Care . 2017 ;40 :800 ‐807 .28404659 \n30 \n\nEeg‐Olofsson \nK \n, \nCederholm \nJ \n, \nNilsson \nPM \n, et al. New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR) . J Intern Med . 2010 ;268 :471 ‐482 .20804517\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1462-8902",
"issue": "20(4)",
"journal": "Diabetes, obesity & metabolism",
"keywords": "diabetes; glucose; hypoglycaemia; mortality; survival",
"medline_ta": "Diabetes Obes Metab",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose; D002318:Cardiovascular Diseases; D003924:Diabetes Mellitus, Type 2; D003925:Diabetic Angiopathies; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D006113:United Kingdom",
"nlm_unique_id": "100883645",
"other_id": null,
"pages": "821-830",
"pmc": null,
"pmid": "29119713",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "8366922;20427682;27152598;18539917;23404299;23665365;18784090;25512005;16371630;23350893;20925543;26440458;25347712;22686416;3558716;20110121;21791495;23404446;19465231;22517736;28404659;20804517;22633797;25151226;19092145;25414153;29119713;23861845;20200384",
"title": "Impact of differing glucose-lowering regimens on the pattern of association between glucose control and survival.",
"title_normalized": "impact of differing glucose lowering regimens on the pattern of association between glucose control and survival"
} | [
{
"companynumb": "GB-IMPAX LABORATORIES, LLC-2019-IPXL-00309",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nStudies conducted in recent years have reported promising results regarding the treatment of retinoblastoma with the intra-arterial use of melphalan. In the present study, we intended to report the results of intra-arterial chemotherapy with melphalan (IACT) in the treatment of newly diagnosed or relapsed-refractory retinoblastoma patients at the Department of Pediatric Oncology of Hacettepe University, Ankara, Turkey.\n\n\nMETHODS\nThis was a retrospective study of patients with intraocular retinoblastoma who were treated with IACT from December 2011 to May 2014. A total of 56 eyes of 46 consecutive patients (30 males and 16 females) were included in the study. Forty-four eyes received systemic chemotherapy upon diagnosis (systemic chemotherapy group, SCG), and 12 eyes were those of newly diagnosed patients (primary intra-arterial melphalan group, PIAG). The choice of the IACT dose was based on age. Tumor control and globe salvage with IACT were analyzed. Complete blood counts were examined 7 days after the IACT for systemic toxicity. Ocular toxicities such as proptosis, eyelid edema, ocular motility, and retinal and optic atrophy were assessed by an ocular oncologist with regular ophthalmologic examinations.\n\n\nRESULTS\nEnucleation was avoided overall in 66% (37/56) of the eyes, including 75% (9/12) in the PIAG and 64% (28/44) in the SCG patients. The 1-year enucleation-free survival rate was 56.7% at a median follow-up time of 11.9 months (range 0.27-27.6). IACT was administered in a total of 124 cycles (ranging from 1 to 7 cycles, mean 2.3). The responses were as follows: regression of the retinal tumor in 27 eyes and improvements in vitreous seeding in 5 of 15 eyes. The further treatment requirements after IACT were as follows: enucleation in 19 eyes (10 with vitreous seeding), radiotherapy in 3 eyes, systemic chemotherapy in 1 eye, and local therapy in 1 eye. No severe systemic side effects occurred. Transient swelling of the eyelids (22 patients), conjunctival chemosis (12 patients), upper eyelid ptosis (5 patients), redness over the frontal area (3 patients), limitation of ocular motility (3 patients) and mild proptosis (1 patient) were detected. Retinal pigment epithelial alterations (30 patients) and optic atrophy (3 patients) were seen in the late follow-up.\n\n\nCONCLUSIONS\nGlobe salvage and avoidance of radiotherapy may be achieved by IACT with limited toxicity. This treatment is efficient, repeatable and safe.",
"affiliations": "Department of Pediatric Oncology, Cancer Institute, Hacettepe University, Ankara, Turkey.",
"authors": "Akyüz|Canan|C|;Kıratlı|Hayyam|H|;Şen|Hilal|H|;Aydın|Burça|B|;Tarlan|Berçin|B|;Varan|Ali|A|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000439357",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-3755",
"issue": "234(4)",
"journal": "Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde",
"keywords": null,
"medline_ta": "Ophthalmologica",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D015353:Eye Enucleation; D005260:Female; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008297:Male; D008558:Melphalan; D009364:Neoplasm Recurrence, Local; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "0054655",
"other_id": null,
"pages": "227-32",
"pmc": null,
"pmid": "26368674",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intra-Arterial Chemotherapy for Retinoblastoma: A Single-Center Experience.",
"title_normalized": "intra arterial chemotherapy for retinoblastoma a single center experience"
} | [
{
"companynumb": "TR-GLAXOSMITHKLINE-TR2015GSK141656",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null... |
{
"abstract": "Although blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980's, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid-liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The Response Surface Methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography-mass spectrometry (GC-MS) with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidances (FDA). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid, and sensitive method. The analytical method was applied to thirty-one pericardial fluid samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.",
"affiliations": "Forensic Toxicology Service. Institute of Forensic Sciences. Faculty of Medicine, University of Santiago de Compostela. C/San Francisco s/n, 15782, Santiago de Compostela, Spain.;Forensic Toxicology Service. Institute of Forensic Sciences. Faculty of Medicine, University of Santiago de Compostela. C/San Francisco s/n, 15782, Santiago de Compostela, Spain.;Forensic Toxicology Service. Institute of Forensic Sciences. Faculty of Medicine, University of Santiago de Compostela. C/San Francisco s/n, 15782, Santiago de Compostela, Spain.;Forensic Toxicology Service. Institute of Forensic Sciences. Faculty of Medicine, University of Santiago de Compostela. C/San Francisco s/n, 15782, Santiago de Compostela, Spain.",
"authors": "Cabarcos-Fernández|P|P|;Tabernero-Duque|M J|MJ|;Álvarez-Freire|I|I|;Bermejo-Barrera|A M|AM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkab003",
"fulltext": "\n==== Front\nJ Anal Toxicol\nJ Anal Toxicol\njat\nJournal of Analytical Toxicology\n0146-4760\n1945-2403\nOxford University Press US\n\n33410888\n10.1093/jat/bkab003\nbkab003\nArticle\nAcademicSubjects/MED00305\nAcademicSubjects/SCI01040\nAcademicSubjects/SCI00030\nDetermination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid–Liquid Microextraction and Gas Chromatography–Mass Spectrometry\nCabarcos-Fernández P Forensic Toxicology Service, Institute of Forensic Sciences, Faculty of Medicine, University of Santiago de Compostela, C/San Francisco s/n, Santiago de Compostela, A Coruña 15782, Spain\n\nTabernero-Duque M J Forensic Toxicology Service, Institute of Forensic Sciences, Faculty of Medicine, University of Santiago de Compostela, C/San Francisco s/n, Santiago de Compostela, A Coruña 15782, Spain\n\nÁlvarez-Freire I Forensic Toxicology Service, Institute of Forensic Sciences, Faculty of Medicine, University of Santiago de Compostela, C/San Francisco s/n, Santiago de Compostela, A Coruña 15782, Spain\n\nBermejo-Barrera A M Forensic Toxicology Service, Institute of Forensic Sciences, Faculty of Medicine, University of Santiago de Compostela, C/San Francisco s/n, Santiago de Compostela, A Coruña 15782, Spain\n\n*Author to whom correspondence should be addressed. Email: pamela.cabarcos@usc.es\n3 2022\n07 1 2021\n07 1 2021\n46 2 146156\n01 9 2020\n23 11 2020\n22 11 2021\n03 1 2021\n24 2 2022\n© The Author(s) 2021. Published by Oxford University Press.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nAlthough blood is often used to detect and quantify the presence of drugs, there are some instances where samples obtained from other biological matrices, like pericardial fluid (PF), are necessary since adequate blood samples may not be available. PF is an epicardial transudate, which contains plasma components that include toxicological substances making this sample useful when blood samples are not available. This fluid is a well-preserved postmortem sample and can easily be collected in larger amounts without significant contamination, compared with other body fluids. Although studies involving PF began around the 1980s, the adequacy of such fluid as a biological matrix has been poorly investigated. Antidepressants are frequently detected in postmortem samples from forensic cases. Nowadays, they constitute some of the most commonly prescribed drugs worldwide. A total of seven antidepressants (venlafaxine, mirtazapine, olanzapine, paroxetine, sertraline, fluoxetine and citalopram) were evaluated in this study. A new extraction method involving dispersive liquid–liquid microextraction (DLLME) is presented in which chloroform and acetonitrile are determined to be the best extraction and dispersing solvents. The experimental design was achieved using StatGraphics 18. The response surface methodology enabled us to know the optimal volume for the two solvents used in the DLLME. The detection technique used was gas chromatography–mass spectrometry with electron impact ionization as ionization source. A temperature gradient has been used and the total chromatographic separation time was 19.43 min. Validation results met the international validation guidance (Food and Drug Administration (FDA)). Under the optimal condition, the method offered good validation parameters showing a new efficient, simple, rapid and sensitive method. The analytical method was applied to 31 PF samples. Twenty-one samples were positive with concentrations between 0.19 and 8.48 µg/mL. Venlafaxine and olanzapine were the antidepressants most frequently found.\n==== Body\npmcIntroduction\n\nDepression constitutes nowadays one of the most common mental disorders either as a major condition or as a neuropsychiatric symptom characteristic of several diseases. In fact, major depressive disorder is a chronic, prevalent and pervasive brain-based disorder that significantly incapacitates the person affected (1). It is estimated that more than 350 million people worldwide are currently diagnosed with such condition, being women more frequently affected than men (2). At its worst, depression may lead to suicide. Close to 800,000 people commit suicide each year, being the second leading cause of death in 15–29-year-olds (3).\n\nTricyclic antidepressants (TCAs) were discovered in the 1950s, but their significant side effects led to a sustained effort in search for more selective drugs. This leads to the discovery of serotonin reuptake inhibitors, some of which (fluoxetine, sertraline and citalopram) are very commonly prescribed as first-choice drugs to treat depression. In addition, newer antidepressants, such as mirtazapine and venlafaxine, do affect both the serotonin and norepinephrine systems within the central nervous system, without the associated anticholinergic and cardiovascular side effects of older drugs such as TCAs. Mirtazapine has a dual mode of action. It is noradrenergic and specific serotonergic antidepressant that acts by antagonizing the adrenergic α2-autoreceptors and α2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission (4). Venlafaxine is a phenylethylamine derivative. It is a serotonin norepinephrine re-uptake inhibitor. Venlafaxine was approved by the FDA (Food and Drug Administration) for the following conditions: major depression, generalized anxiety disorder, panic disorder and social phobia (5). Olanzapine is a second-generation antipsychotic neuroleptic or “atypical antipsychotic”. These medications have more receptor-binding targets than first-generation treatments (e.g., haloperidol) do and have complex pharmacologic mechanisms of action. Olanzapine has the most binding targets in its class, binding to 10 serotonin receptors, 4 dopamine receptors, 4 acetylcholine receptors, 4 α-adrenergic receptors, 1 histamine receptor and 2 different neurotransmitter transport receptors (6).\n\nWithin the forensic practice, it is important to investigate postmortem drug concentrations to discriminate whether the cause of death was due to intoxication, side effects of the undergoing treatment or lack of compliance. Urine and blood specimens are the main biological samples used in forensic autopsy cases, being peripheral blood the most used in postmortem research. Moreover, special care must be taken in the interpretation of the data when using postmortem blood samples as these concentrations may change due to several factors such as chemical/enzymatic degradation of substances, redistribution phenomena and postmortem diffusion from solid organs or gastric content, especially with cardiac blood since it is more affected by postmortem redistribution (7). However, it should be borne in mind that blood analysis will be always a fundamental and essential step since it enables one to know the toxicological status of the deceased at the time of death. In addition to blood or urine samples, one may consider pericardial fluid (PF) as a useful alternative matrix in cases where adequate peripheral blood samples cannot be obtained. The potential use of PF samples has been considered within relatively few reports (7–13). Previous studies showed good correlation with the drug concentrations in peripheral blood (8, 10, 14, 15). PF is a well-preserved postmortem material in cases without structural damage due to injury or medical intervention and can easily be collected in large amounts without significant contamination as it is contained within a tight compartment (pericardial sac), compared with other body fluids (13). With a volume of 15–35 mL, it is believed to be a transudate generated by the net result of the hydrostatic pressure and the osmotic gradient between plasma and PF. The composition of the normal human PF is difficult to define. The hematological and biochemical analyses of the PF show that the concentration of electrolytes and small molecules (urea, uric acid, glucose and creatinine) corresponds to an ultrafiltrate of plasma (7, 13).\n\nPrevious works using liquid–liquid extraction or solid phase extraction have been reported (7–9, 12). In particular, efforts were oriented towards the development of efficient and miniaturized sample preparation methods. Liquid-phase microextraction (LPME) was introduced according to this perspective. Dispersive liquid–liquid microextraction (DLLME) is one of the LPME methods and has attracted recent interest within the analytical chemists’ community (16). The method was introduced by Assadi and co-workers in 2006 (17). It is a simple and fast microextraction technique based upon the use of an appropriate extractant (an organic solvent with high density) and a disperser solvent with high miscibility in both extractant and aqueous phases. DLLME consists of two steps: (i) injection of an appropriate mixture of extracting and disperser solvents into an aqueous sample, containing the analytes. In this step, the extracting solvent is dispersed into the aqueous sample as very fine droplets and the analytes are enriched into it. After the formation of a cloudy solution, the surface area between the extracting solvent and the aqueous sample becomes very large, so the equilibrium state is quickly attained and, therefore, the extraction time is very short. In fact, this is the principal advantage of this method. (ii) Centrifugation of the cloudy solution, thereby obtaining a settled phase that is deposited at the bottom of a conical tube. Other advantages include simplicity of operation, rapidity, low cost, high recovery, high enrichment factor and environment benignity (18). Like the other analytical methods, DLLME has some disadvantages, which result from the requirements related to the organic extraction and disperser solvents. The extraction solvent used should have some special requirements, such as a density larger than water for simple separation of the extraction phase after centrifugation and to form a cloudy solution in the presence of the disperser solvent. The potential organic solvents meeting this requirement are limited since they are hazardous chemicals (such as halogenated hydrocarbons). It is precisely because of this the choice of the extraction solvent becomes the method’s primary limitation (16). According to detection techniques, several methods were used involving liquid chromatography as well as gas chromatography (7–9, 12).\n\nThe aim of this study was to develop a gas chromatography–mass spectrometry (GC–MS) method for the determination and quantification of antidepressants in PF using DLLME as a new extraction method. The validation of the method was carried out according to the guidelines of the FDA (19). The method was then applied to PF samples collected from deceased people.\n\nMaterial and Methods\n\nChemicals\n\nAcetonitrile and chloroform gradient grade solvents were purchased from Merck® (Madrid, Spain) and sodium chloride from Panreac® (Barcelona, Spain). Fluoxetine, venlafaxine, mirtazapine, sertraline, citalopram, olanzapine, paroxetine and proadifen (SKF), used as internal standard, were obtained from Cerilliant®. Distilled water was processed through a Milli-Q water system (Millipore, Bedford, MA, USA).\n\nMatrix collection\n\nTo carry out the validation procedure, antidepressant-free PF obtained from autopsies was used. For this purpose, a mixture of PF from deceased subjects was collected and stored at –20°C until use, following a previous peripheral blood and urine analysis that was negative to antidepressants.\n\nSample preparation\n\nPF used for validation was previously ultracentrifuged for 5 min at 14,000 rpm. Aliquots of 0.3 mL were used for analysis, collected in a glass tube and spiked with Proadifen (SKF) (20 µL Sol. 10 µg/mL). Then, it was diluted with water (1.1 mL) and 150 mg of NaCl was also added to facilitate analytes’ transition from aqueous phase to organic phase. This mixture was submited to the DLLME. After an experimental design using StatGraphics (StatGraphics Technologies, Inc.), the optimal conditions were as follows: 175 uL of chloroform and 750 uL of acetonitrile as the best extracting and disperser solvents, respectively. Both solvents were rapidly injected into the sample with a Pasteur pipette and the mixture was gently shaken. Then, the mixture was centrifuged, and the droplet formed was collected by a 100 µL syringe and transferred to an 8 mL glass tube. The organic solvent was evaporated under a stream of nitrogen in a heated aluminum block at 40°C (VLM GmbH, HP series). The dried residue was redissolved with 40 µL of methanol prior to injection of a 2 µL aliquot into the GC–MS system.\n\nInstrumentation\n\nChromatographic analyses were performed using an electron impact ionization gas chromatograph model 7890 B from Agilent Technologies® (Las Rozas, Spain) interfaced to a mass selective detector (MSD) model 5977 B, also from Agilent Technologies®. An HP5-MS capillary column (30 m × 250 µm i.d., 0.5 µm film thickness; Agilent Technologies®) with helium as carrier gas (1 mL/min) was used for the gas chromatographic separation. The injector temperature was set at 250°C and a purge time of 2 min was used. Samples were injected in the splitless mode. The following temperature program was applied: the initial temperature of the column was 100°C for 1 min, then ramped-up progressively at 35°C/min up to 220°C, held constant for 1 min, and then ramped-up again at 8°C/min up to 260°C and held for 2 min. Finally, the temperature was ramped-up at 5°C/min up to 280°C for 3 min. After that, the temperature was increased to 290°C for 5 min to clean the column. The total chromatographic separation time was 19.43 min, and the total run time was 24.43 min. The MSD was kept at 300°C, the ion source at 230°C and the quadrupole at 150°C.\n\nIdentification of compounds\n\nInitially, neat standards of all antidepressants were injected and analyzed using the full scan mode of the GC–MS, which scanned from 50 to 550 amu. Quantifier and qualifier ions used for each analyte were selected based on their abundances and mass-to-charge ratios (m/z). Because of their reproducibilities and lack of interference, high mass ions were selected whenever possible. The ions selected for each compound studied and the retention times are shown in Table I. Upon selection of ion, the mass spectrometry was run in selected ion monitoring mode (Figure 1).\n\nTable I. Retention Times and Ions Selected for Monitorization\n\nAnalyte\tQuantifier ion, m/z\tQualifier ions, m/z\tRetention time, min\t\nFluoxetine\t104\t148, 309\t7.78\t\nVenlafaxine\t58\t134, 179\t9.97\t\nMirtazapine\t195\t208, 245\t11.78\t\nSKF\t86\t99, 165\t12.30\t\nSertraline\t274\t276, 262\t13.55\t\nCitalopram\t58\t238, 324\t13.20\t\nParoxetine\t192\t138, 329\t16.09\t\nOlanzapine\t242\t229, 207\t18.50\t\n\nFigure 1. Extracted ionic chromatogram of all analytes.\n\nResults\n\nExperimental design\n\nTo find the best conditions for DLLME, 18 replicates were performed using a 2 × 4 factorial design with four factors: sample volume, water volume, extracting solvent volume and disperser solvent volume. The experimental design was achieved using Statgraphics 18. To make this design rotatable, for each factor, two axial points were chosen, and the runs were randomized to exclude the block effects. Response surface methodology (RSM) is a combination of mathematical and statistical techniques used to study the relationship between two or more responses that depend on several factors or independent variables. The final goal of RSM is to optimize responses determining the best conditions in the operation of the system. Our design of response surface was obtained using the statistical software StatGraphics (Figure 2).\n\nFigure 2. Response surface graph.\n\nValidation of the method\n\nValidation was achieved according to the FDA Guideline for Bioanalytical Method Validation (19). The suitability of the method for quantitative analysis was studied by testing selectivity, linearity and sensitivity, precision and accuracy and recovery.\n\nSelectivity\n\nSelectivity is the ability of an analytical method to differentiate and quantify the analyte in the presence of other components in the sample. It should confirm that the assay is free of potential interfering substances, include endogenous matrix components, metabolites, decomposition products and medication and other exogenous xenobiotics. The selectivity of the method was demonstrated by analyzing six blank PF samples (19). No interfering peaks were found at the retention time for all analytes (Figure 3).\n\nFigure 3. Chromatogram of a blank PF.\n\nLinearity\n\nStandard addition curves were obtained in six runs with the described method using drug-free control PF spiked with standard solutions to obtain the range of concentrations shown in Table II. The curves were obtained by fitting the ratio of the peak areas of analytes to that of IS versus concentrations. A linear response was observed in the studied range with a good correlation coefficient (higher than 0.99 in all cases). The sensitivity of the method was determined by calculation of the limit of detection (LOD) and the lower limit of quantification (LLOQ). LOD was determined by an empirical method that consists of analyzing a series of PF samples containing decreasing amounts of the analytes. LOD was the lowest concentration that presented a signal-to-noise ratio higher than 3 for at least three diagnostic ions for each substance. The LLOQ was the lowest concentration of analytes in a sample that can be determined with appropriate precision (20%) and accuracy (80–120%) (19) (Table II).\n\nTable II. LOD, Limit of Quantification and Calibration Results for the Antidepressants Studied\n\nAnalyte\tLOD (µg/mL)\tLLOQ (µg/mL)\tC. coef.\tRange of calibration (µg/mL)\t\nFluoxetine\t0.05\t0.2\t0.991\t0.2–10\t\nVenlafaxine\t0.01\t0.02\t0.991\t0.02–10\t\nMirtazapine\t0.01\t0.02\t0.997\t0.02–5\t\nSertraline\t0.005\t0.2\t0.992\t0.2–5\t\nCitalopram\t0.01\t0.04\t0.995\t0.04–5\t\nOlanzapine\t0.02\t0.2\t0.993\t0.2–10\t\nParoxetine\t0.2\t1\t0.997\t1–10\t\nC. coef., correlation coefficient.\n\nPrecision and accuracy\n\nThe accuracy of an analytical method describes the closeness of mean test results obtained by the method to the true value (concentration) of the analyte. The precision of an analytical method describes the closeness of individual measures of an analyte when the procedure is applied repeatedly to multiple aliquots of a single homogeneous volume of biological matrix. Precision and accuracy were determined by inter- and intra-day assay. Inter-day precision and accuracy were calculated by analyzing negative PF samples spiked with the antidepressants at three concentrations; the LLOQ, the upper limit of quantification and an intermediate level were assessed by analyzing five replicates each day in five different days for each level of concentration. Intra-day precision and accuracy were determined at three concentrations, by preparing and analyzing five replicates for each level on the same day. Precision, expressed as the coefficient of variation of the measured values, was expected to be less than 15% at all concentrations, except for the LLOQ for which 20% was acceptable. In the same way, accuracy was evaluated using the mean relative error (ME), which had to be less than 15% of the theoretical values at each concentration level except for the LLOQ, for which 20% was acceptable (19). Data presented in Table III (Supplementary Material) satisfied the international validation rules.\n\nTable III. Intra- and Inter-Day Precision and Accuracy (ME) of the Method\n\n\tIntra-day study (n = 5)\tInter-day study (n = 5)\t\nConcentrations (μg/mL)\tME (%)\tRSD (%)\tME (%)\tRSD (%)\t\nFluoxetine\t\n0.2\t17\t5\t14\t10\t\n5\t6\t5\t8\t4\t\n10\t6\t7\t1\t5\t\nVenlafaxine\t\n0.02\t18\t8\t14\t7\t\n5\t6\t3\t5\t3\t\n10\t2\t5\t1\t4\t\nMirtazapine\t\n0.02\t19\t3\t16\t6\t\n2.5\t11\t2\t6\t2\t\n5\t1\t4\t3\t6\t\nSertraline\t\n0.2\t17\t7\t18\t7\t\n2.5\t8\t5\t6\t3\t\n5\t2\t8\t1\t4\t\nCitalopram\t\n0.04\t17\t10\t13\t7\t\n2.5\t5\t4\t4\t3\t\n5\t1\t4\t2\t3\t\nParoxetine\t\n1\t13\t12\t13\t12\t\n5\t8\t15\t9\t12\t\n10\t14\t12\t1\t7\t\nOlanzapine\t\n0.2\t12\t14\t19\t5\t\n5\t14\t3\t9\t6\t\n10\t6\t3\t2\t7\t\nRSD: Relative Standard Deviation.\n\nRecovery\n\nThe recovery of an analyte is the detector response obtained from an amount of the analyte added to an extracted from the biological matrix, compared to the detector response obtained for the true concentration of the pure authentic standard (19). The recovery of the method was examined by comparing the analytical results for extracted samples at three levels of concentration (high, medium and low) five times within three days with theoretical concentration that represent 100% recovery. The data obtained demonstrates that the extraction procedure is particularly efficient, providing a recovery values ranged from 85 to 105% for all compounds. The results are shown in Table IV (Supplementary Material).\n\nTable IV. Intra and Inter-Day Accuracy (Analytical Recovery) of the Method\n\n\tIntra-day study (n = 5)\tInter-day study (n = 5)\t\nConcentrations (μg/mL)\tRecovery (%)\tRecovery (%)\t\nFluoxetine\t\n0.2\t98\t89\t\n5\t93\t91\t\n10\t94\t100\t\nVenlafaxine\t\n0.02\t92\t95\t\n5\t93\t95\t\n10\t98\t99\t\nMirtazapine\t\n0.02\t85\t94\t\n2.5\t89\t94\t\n5\t92\t97\t\nSertraline\t\n0.2\t97\t98\t\n2.5\t91\t94\t\n5\t98\t99\t\nCitalopram\t\n0.04\t93\t105\t\n2.5\t95\t96\t\n5\t99\t98\t\nParoxetine\t\n1\t93\t93\t\n5\t91\t91\t\n10\t94\t101\t\nOlanzapine\t\n0.2\t89\t89\t\n5\t85\t90\t\n10\t87\t98\t\n\nApplication to real cases\n\nThe developed method was used to analyze 31 real PF samples obtained from the Forensic Toxicology Service of the Institute of Forensic Sciences of Santiago de Compostela from cases including suicide, overdose or death from unknown causes. Some information is described in Table V. From the 31 cases, 21 were positive for at least one of the substances analyzed. Venlafaxine and olanzapine were the two antidepressants most frequently found in 12 and 4 cases, respectively. There were also positive cases for mirtazapine, fluoxetine, sertraline and citalopram. Three samples were positive for several compounds at the same time. Figures 4 and 5 show real cases analyzed in our laboratory with their corresponding mass spectra (Figures 6 and 7). One of them corresponds to a female whose cause of death was hanging after having consumed high amounts of several drugs and the other case belongs to a male poisoned by carbon monoxide.\n\nTable V. Real Cases\n\nCase no.\tAge\tSex\tSample\tCause of death\tGeneral information and treatment\tSubstance detected\t\n\t(years)\t\t\t\t\t[µg/mL]\t\n1\t82\tFemale\tBlood, urine and PF\tPulmonary embolism\tDepressive disorder\tMirtazapine [0.48]\t\n2\t83\tFemale\tBlood, urine and PF\tTraumatic brain injury\tDuloxetine, bromazepam, quetiapine, tramadol and metamizol\t–\t\n3\t42\tFemale\tBlood, urine and PF\tSuicide\tPsychiatric treatment for schizophrenia. Lormetazepam and paliperidone\tVenlafaxine [0.27]\t\n4\t32\tFemale\tBlood and PF\tSuicide\tDepressive disorder. Risperidone, benzodiazepines and olanzapine\tOlanzapine <LLOQ\t\n5\t56\tFemale\tBlood, urine and PF\tSuicide\tVenlafaxine and benzodiazepines\tVenlafaxine [3.44]\t\n6\t45\tMale\tBlood, urine, vitreous humor and PF\tSuicide\tPast history of drug abuse\tVenlafaxine [0.27]\t\n7\t52\tMale\tBlood, vitreous humor and PF\tAcute myocardial infarction\tDepressive disorder\t–\t\n8\t45\tMale\tBlood and PF\tPossible cardiac death\tParanoid Schizophrenia. Valproic acid\t–\t\n9\t60\tFemale\tBlood, urine, gastric content, hair, PF and nail\tSuicide\tKetazolam and bromazepam\tVenlafaxine [0.28]\t\n10\t67\tMale\tBlood, urine and PF\tChoking suffocation\tOlanzapine\tVenlafaxine [0.28] and olanzapine <LLOQ\t\n11\t37\tMale\tBlood, urine, bile, vitreous humor and PF\t–\tDrinker and smoker\t–\t\n12\t32\tMale\tBlood, urine and PF\tFall\tDepressive disorder. Haloperidol, olanzapine and flufenazine,\tVenlafaxine [0.27] and olanzapine [0.23]\t\n13\t64\tFemale\tBlood, urine, hair, vitreous humor, bile and PF\tMethanol poisoning\t–\t–\t\n14\t65\tMale\tBlood, urine, gastric content and PF\tSuspected suicide\tHeptaminol hidroclorure, sertraline\t–\t\n15\t83\tMale\tBlood, urine and PF\tSuicide\tPregabaline, carbamazepine, clonazepam and mirtazapine\tMirtazapine [0.19]\t\n16\t48\tMale\tBlood, urine and PF\tAdverse drug reaction\tFluoxetine, lormetazepam, lorazepam, alprazolam, clozapine, cocaine and dipotassium chlorazepate\tFluoxetine [0.63]\t\n17\t75\tFemale\tBlood, urine, gastric content and PF\tDrug overdose\tTramadol, ciclobenzaprine, ketazolam and lorazepam\tVenlafaxine [8.48]\t\n18\t70\tFemale\tBlood, urine and PF\tSuicide\tVenlafaxine and lorazepam\tVenlafaxine [0.81]\t\n19\t89\tFemale\tBlood, gastric content and PF\tPrevious depressive episodes\tLorazepam and olanzapine\tOlanzapine <LLOQ\t\n20\t75\tFemale\tBlood, urine and PF\tNatural\tAlprazolam, trazodone, venlafaxine and quietiapine\tVenlafaxine [0.95]\t\n21\t47\tFemale\tBlood, urine and PF\tNatural\tDepressive and personality disorder. Alprazolam and paroxetine\t–\t\n22\t56\tMale\tBlood, urine and PF\tCardiac death\t–\t–\t\n23\t35\tMale\tBlood, vitreous humor and PF\tChoking suffocation\tBenzodiacepines, topiramate, fluoxetine, paliperidone, quetiapine and mirtazapine\tMirtazapine [0.39] and fluoxetine [0.20]\t\n24\t36\tMale\tBlood, urine, vitreous humor and PF\tSuicide\tDepressive disorder\t–\t\n25\t61\tMale\tBlood, urine, vitreous humor and PF\tNatural\tBipolar disorder. Alcohol consumption. Benzodiacepines, pregabaline, sertraline and olanzapine\tSertraline [0.23]\t\n26\t86\tMale\tBlood, urine, vitreous humor and PF\tCarbon monoxide poisoning\tSertraline, trazodone and lorazepam\tSertraline [0.48]\t\n27\t73\tFemale\tBlood, urine, vitreous humor and PF\tSuffocation from airway occlusion\tBenzodiacepines and venlafaxine\tVenlafaxine [0.62]\t\n28\t60\tFemale\tBlood, urine and PF\tEmpyema\tAlcohol consumption. Mirtazapine, quetiapine and benzodiapcepines\tCitalopram [0.27]\t\n29\t40\tFemale\tBlood, vitreous humor and PF\tSuicide\tDepressive disorder. Venlafaxine, benzodiacepines, clomipramine and trazodone,\tVenlafaxine [3.84]\t\n30\t55\tFemale\tBlood, vitreous humor and PF\tNatural\t–\t–\t\n31\t52\tMale\tBlood, urine, vitreous humor and PF\tSuicide\tDepressive disorder\tVenlafaxine [0.33]\t\nPF, pericardial fluid.\n\nFigure 4. Chromatogram of a real sample (positive for venlafaxine).\n\nFigure 5. Chromatogram of a real sample (positive for sertraline).\n\nFigure 6. Venlafaxine mass spectra.\n\nFigure 7. Sertraline mass spectra.\n\nDiscussion\n\nThe present work aims to contribute toward the development of methods able to quantify the presence of antidepressants in samples of PF in cases where adequate blood samples may not be available. Previous literature reports comprise only a few articles where PF is used as a biological sample for the determination of drugs (7, 8, 15). The DLLME was one of the techniques used by several authors to extract antidepressants, but only one author determined the concentration of these compounds in PF (8, 16, 20–30). Most of the articles published so far used the DLLME technique coupled to another extraction method (16, 20, 22–24, 26, 27), but few papers have followed a similar method to ours (21, 25, 28–30). Most of them employed urine as the biological matrix (25, 28–30), while Lima et al. used water samples (21). Most of the published research dealt with TCAs as the particular drugs under study (16, 20, 25–27, 29, 30), and only two articles have employed GC–MS (22, 29).\n\nOn the grounds of the available evidence, it can be stated that drug concentrations in PF are mostly equivalent to those in peripheral blood (7–9, 31). In consequence, samples of PF can be considered as an alternative for drug quantification in cases where blood samples are not available. PF is usually available in quantities large enough, thus making it suitable for toxicological purposes. In addition, rather similar treatments and procedures to those customarily used for blood can be followed, a fact that constitutes an added advantage for the use of this particular fluid. Finally, as the PF is found within a closed compartment, contamination by microorganisms is less likely to occur (8) than in case of other samples.\n\nA set of experiments were carried out in the quest for an efficient antidepressant extraction procedure by varying several DLLME parameters as the quantity of water, salt amounts, types of extraction and disperser solvents and quantity of biological matrix used. With respect to the volume of sample used, our method uses 0.3 mL, while other authors employ larger volumes (7, 9, 31). The use of chloroform as extracting solvent and acetonitrile as disperser solvent was also determined by Fernández et al. in a study published in 2016 (23). Finally, the method here developed was fully validated with good results in accordance with the limits approved by the FDA. The developed method was used to determine 31 PF samples. The results confirmed the presence of venlafaxine in most cases (12 cases), followed by olanzapine (4 cases), mirtazapine (3 cases), fluoxetine and sertraline (2 cases) and citalopram (1 case). No positive cases for paroxetine have been found. Fernández et al. also found venlafaxine as the most frequently used antidepressant in his study (23). However, citalopram and mirtazapine were the two antidepressants most frequently detected in Leere et al.’s study (8) followed by venlafaxine and sertraline. In the study just referred to, venlafaxine was detected in six cases, having found within four of those cases drug concentrations above the therapeutic range. In addition, one of the cases here studied revealed the presence of extremely high concentrations. Paroxetine was also poorly detected (8). In our study, high concentrations of venlafaxine were also found in three cases. All antidepressants, except one, were found in concentrations above LLOQ. Of the four cases detected for olanzapine, three of them were detected at concentrations below LLOQ.\n\nIn view of the present results, we recommend that PF should be added to the list of biological samples used in a forensic laboratory. To conclude, it is worth remarking the increase in use of PF in toxicological practice as pointed out by Contreras et al. in their analysis of morphine and cocaine (11, 32).\n\nConclusions\n\nThe aim of the present article is to report on an optimized analytical method to determine antidepressants using PF as a biological matrix. Sample preparation based on DLLME was employed. An experimental design setup using StatGraphics 18 and 175 µL of chloroform and 750 µL of acetonitrile as the best quantities for the extracting and disperser solvents was employed. A gas chromatograph using HP5-MS capillary column was used for the separation, and a mass spectrometer was used for the identification. Analytes were identified by their retention times and mass spectra. The method provides high precision, accuracy and recovery within the linear range of detection. Therefore, our method was found to be specific, sensitive and selective enough for the routine analysis of antidepressants in PF and for the application of the method in forensic practice. In conclusion, we have shown the usefulness of PF samples in cases where adequate blood specimens cannot be made available. The existing literature regarding drug concentrations in PF is however scarce, so further studies are in order.\n\nSupplementary Material\n\nbkab003_Supp Click here for additional data file.\n\nSupplementary Data\n\nSupplementary Data is available at Journal of Analytical Toxicology online.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n\n1. Lee Y. , RosenblatJ.D., JungGooL., CarmonaN.E., SubramaniapillaiM., ShekotikhinaM., et al. (2018) Efficacy of antidepressants on measures of workplace functioning in major depressive disorder: a systematic review. Journal of Affective Disorders, 227 , 406–415. doi: 10.1016/j.jad.2017.11.003 29154157\n2. Rosenblat J.D. , KakarR., McIntyreR.S. (2016) The cognitive effects of antidepressants in major depressive disorder: a systematic review and meta-analysis of randomized clinical trials. 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Journal of Pharmaceutical and Biomedical Analysis, 124 , 189–197. doi: 10.1016/j.jpba.2016.02.041 26955756\n24. Akbar Alizadeh Nabil A. , NouriN., FarajzadehM.A. (2015) Determination of three antidepressants in urine using simultaneous derivatization and temperature-assisted dispersive liquid-liquid microextraction followed by gas chromatography-flame ionization detection. Biomedical Chromatography, 29 , 1094–1102. doi: 10.1002/bmc.3396 25516238\n25. Shamsipur M. , MirmohammadiM. (2014) High performance liquid chromatographic determination of ultra-traces of two tricyclic antidepressant drugs imipramine and trimipramine in urine samples after their dispersive liquid-liquid microextraction coupled with response surface optimization. Journal of Pharmaceutical and Biomedical Analysis, 100 , 271–278. doi: 10.1016/j.jpba.2014.08.008 25178259\n26. Ge D. , LeeH.K. (2013) Ionic liquid based dispersive liquid-liquid microextraction coupled with micro-solid phase extraction of antidepressant drugs from environmental water samples. Journal of Chromatography A, 1317 , 217–222. doi: 10.1016/j.chroma.2013.04.014 23639124\n27. Seidi S. , YaminiY., RezazadehM. (2013) Combination of electromembrane extraction with dispersive liquid-liquid microextraction followed by gas chromatographic analysis as a fast and sensitive technique for determination of tricyclic antidepressants. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences, 913–914 , 138–146. doi: 10.1016/j.jchromb.2012.12.008\n28. Huang S.W. , HsiehM.M., ChangS.Y. (2012) Sensitive determination of sertraline by capillary electrophoresis with dispersive liquid-liquid microextraction and field-amplified sample stacking. Talanta, 101 , 460–464. doi: 10.1016/j.talanta.2012.09.060 23158349\n29. Ito R. , UshiroM., TakahashiY., SaitoK., OokuboT., IwasakiY., et al. (2011) Improvement and validation the method using dispersive liquid-liquid microextraction with in situ derivatization followed by gas chromatography-mass spectrometry for determination of tricyclic antidepressants in human urine samples. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences, 879 , 3714–3720. doi: 10.1016/j.jchromb.2011.10.012 22035981\n30. Xiong C. , RuanJ., CaiY., TangY. (2009) Extraction and determination of some psychotropic drugs in urine samples using dispersive liquid-liquid microextraction followed by high-performance liquid chromatography. Journal of Pharmaceutical and Biomedical Analysis, 49 , 572–578. doi: 10.1016/j.jpba.2008.11.036 19135820\n31. Tominaga M. , MichiueT., IshikawaT., KawamotoO., OritaniS., IkedaK. (2013) Postmortem analyses of drugs in pericardial fluid and bone marrow aspirate. Journal of Analytical Toxicology, 37 , 423–429. doi: 10.1093/jat/bkt047 23852608\n32. Contreras M.T. , GonzálezM., GonzálezS., VenturaR., ValverdeJ.L., HernándezA.F., et al. (2007) Validation of a procedure for the gas chromatography--mass spectrometry analysis of cocaine and metabolites in pericardial fluid. Journal of Analytical Toxicology, 31 , 75–80. doi: 10.1093/jat/31.2.75 17536741\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0146-4760",
"issue": null,
"journal": "Journal of analytical toxicology",
"keywords": "Pericardial fluid; antidepressants; dispersive liquid-liquid microextraction; forensic toxicology, depression; postmortem samples",
"medline_ta": "J Anal Toxicol",
"mesh_terms": null,
"nlm_unique_id": "7705085",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33410888",
"pubdate": "2021-01-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Determination of Seven Antidepressants in Pericardial Fluid by Means of Dispersive Liquid-Liquid Microextraction (DLLME) and Gas Chromatography-Mass Spectrometry (GC/MS).",
"title_normalized": "determination of seven antidepressants in pericardial fluid by means of dispersive liquid liquid microextraction dllme and gas chromatography mass spectrometry gc ms"
} | [
{
"companynumb": "ES-ALLERGAN-2102956US",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditional": "4... |
{
"abstract": "BACKGROUND\nThe aim of this study was to assess the effect of high plasma levels of lomitapide and its main metabolite on ECG parameters.\n\n\nMETHODS\nIn this randomized five-way cross-over thorough QT study, 56 healthy subjects were enrolled. Study treatments were administered orally for 3 days in five separate periods in which subjects were dosed with (1) a single dose of 75 mg lomitapide on Day 1 followed by a single dose of 200 mg on Day 3; (2) ketoconazole 200 mg BID; (3) ketoconazole with a single dose of 75 mg lomitapide on Day 3; (4) a single dose of 400 mg moxifloxacin on Day 3 and (5) placebo.\n\n\nRESULTS\nSingle doses of 75 and 200 mg lomitapide alone or in combination with ketoconazole caused minor changes in the change-from-baseline QTcI (ΔQTcI), whereas moxifloxacin and ketoconazole caused an increase of ΔQTcI with a peak effect at 1 and 3 hours postdosing, respectively. The largest mean placebo-corrected ΔQTcI (ΔΔQTcI) for lomitapide did not exceed 3 ms (upper bound of 90% CI: 4.7 ms) at any time points postdosing. Ketoconazole caused mild QT prolongation with mean ΔΔQTcI of 5.9 and 6.5 ms at 2 and 3 hours postdosing, and exposure-response analysis demonstrated a significantly positive slope of 1.3 ms per μg/mL (90% CI: 1.0-1.7). Moxifloxacin met the criteria for assay sensitivity.\n\n\nCONCLUSIONS\nLomitapide does not have an effect on cardiac repolarization. The study's ability to detect small QTc changes was demonstrated with both moxifloxacin and ketoconazole.",
"affiliations": "iCardiac Technologies, Rochester, NY; Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden.",
"authors": "Darpo|Borje|B|;Ferber|Georg|G|;Zhou|Meijian|M|;Sumeray|Mark|M|;Sager|Philip|P|",
"chemical_list": "D058888:14-alpha Demethylase Inhibitors; D001372:Aza Compounds; C473731:BMS201038; D001562:Benzimidazoles; D024841:Fluoroquinolones; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; D007654:Ketoconazole; D000077266:Moxifloxacin",
"country": "United States",
"delete": false,
"doi": "10.1111/anec.12103",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1082-720X",
"issue": "18(6)",
"journal": "Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc",
"keywords": "QT/QTc; healthy volunteers; ketoconazole; lomitapide; thorough QT study",
"medline_ta": "Ann Noninvasive Electrocardiol",
"mesh_terms": "D058888:14-alpha Demethylase Inhibitors; D000293:Adolescent; D000328:Adult; D001372:Aza Compounds; D001562:Benzimidazoles; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate; D006801:Humans; D007654:Ketoconazole; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines; D012016:Reference Values; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D055815:Young Adult",
"nlm_unique_id": "9607443",
"other_id": null,
"pages": "577-89",
"pmc": null,
"pmid": "24118671",
"pubdate": "2013-11",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "18094216;20978278;19922536;21642470;17437965;18470755;2218183;14600288;15691222;21251129;21769821;20358443;9694927;21228407;19246722;21883386;20124517;16707406;15752381;16403073;20457587",
"title": "Lomitapide at supratherapeutic plasma levels does not prolong the Qtc interval--results from a TQT study with moxifloxacin and ketoconazole.",
"title_normalized": "lomitapide at supratherapeutic plasma levels does not prolong the qtc interval results from a tqt study with moxifloxacin and ketoconazole"
} | [
{
"companynumb": "SE-JNJFOC-20131207873",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOMITAPIDE MESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the CT enteroclysis (CTE)/enterography findings of patients with small-bowel mucosal damage induced by aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) and to compare these findings with the duration of drug use and endoscopic findings.\n\n\nMETHODS\nCTE findings of 11 patients (22 lesions) with drug-induced small-bowel damage were reviewed, including 8 NSAID users and 3 aspirin users. Three patients were short-term users (6 months or shorter) and eight were long-term users (3 years or longer). Nine patients also underwent videocapsule endoscopy (VCE) or double-balloon enteroscopy (DBE).\n\n\nRESULTS\nSmall-bowel abnormalities were visible in 8 of 11 patients (73%) on CTE. Multiple lesions were seen in five patients, including all short-term users. Lesions were classified into three types. Type 1 (mucosal patchy enhancement) was found in four of eight patients (50%, 12 lesions) all were short-term users. Small erosions with mild oedema/redness were shown by DBE. Type 2 (homogeneous hyperenhancement) was found in two of eight patients (25%, four lesions) who were long-term users. Large ulcers with marked oedema/redness were shown by DBE. Type 3 (stratification enhancement) was found in four of eight patients (50%, six lesions), both short-term and long-term users. Annular or large ulcers with strictures were shown by VCE or DBE.\n\n\nCONCLUSIONS\nOn CTE, Type 1 lesions in patients with mostly short-term aspirin or NSAID use, Type 2 lesions in patients with long-term use and Type 3 lesions in both types of patients were detected. CTE may have usefulness for the detection of mild damage.\n\n\nCONCLUSIONS\nSmall-bowel abnormalities owing to aspirin or NSAID present with three different patterns on CTE.",
"affiliations": "1 Department of Radiology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.",
"authors": "Kishi|T|T|;Shimizu|K|K|;Hashimoto|S|S|;Onoda|H|H|;Washida|Y|Y|;Sakaida|I|I|;Matsunaga|N|N|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "England",
"delete": false,
"doi": "10.1259/bjr.20140367",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1285",
"issue": "87(1044)",
"journal": "The British journal of radiology",
"keywords": null,
"medline_ta": "Br J Radiol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D053704:Capsule Endoscopy; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007410:Intestinal Diseases; D007421:Intestine, Small; D008297:Male; D008875:Middle Aged; D011859:Radiography; D012189:Retrospective Studies",
"nlm_unique_id": "0373125",
"other_id": null,
"pages": "20140367",
"pmc": null,
"pmid": "25348282",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": "10589566;15459329;17451567;16436815;15704047;16967238;15973225;18365915;12235339;22447355;15645405;20652705;1898566;10852655;17646455;15887101;10652913;10845479;9530396",
"title": "CT enteroclysis/enterography findings in drug-induced small-bowel damage.",
"title_normalized": "ct enteroclysis enterography findings in drug induced small bowel damage"
} | [
{
"companynumb": "PHHY2015JP150384",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "Germinotropic lymphoproliferative disorder (GLPD) is a poorly characterized lymphoproliferative entity, recently included in the World Health Organization classification of hematolymphoid neoplasms. The histological pattern of this disease comprises monotypic plasmablasts that involve the germinal centers of the lymphoid follicles (germinotrophism), forming confluent aggregates positive for both human herpes virus type 8 (HHV8) and Epstein-Barr virus. Currently, after 17 years of its first description, only 18 cases have been reported. In this article, we describe a case of a GLPD presenting in an immunocompetent 79-year-old woman with localized axillary lymphadenopathy, showing a prominent sinusoidal growth pattern, with no evidence of germinotrophism or extrasinusoidal spread. Stinking pleomorphism in tumor cells was also noted. An extension study has not revealed involvement of other groups of lymph nodes or extralymphoid sites. The patient is alive and has shown no relapse after 8 years follow-up (the longest follow-up reported period for this entity). This previously unrecognized pure sinusoidal growth pattern along with the striking pleomorphism in neoplastic cells closely mimics the appearance of an anaplastic large cell lymphoma. GLPD is not usually considered in such a setting, but it should be included in the differential diagnosis of sinusoidal proliferations. Our findings contribute to the expansion of the morphological spectrum of HHV8-associated lymphoproliferative lesions and aids in the characterization of the very infrequent GLPD entity.",
"affiliations": "Hospital Clinico Universitario of Valencia, University of Valencia, Valencia, Spain.;University Hospital of North Norway, Tromso, Norway.;Hospital de Sagunto, Sagunto, Valencia, Spain.;Hospital Clinico Universitario of Valencia, University of Valencia, Valencia, Spain.;Hospital de Sagunto, Sagunto, Valencia, Spain.;Hospital Clinico Universitario of Valencia, University of Valencia, Valencia, Spain.",
"authors": "Martinez-Ciarpaglini|Carolina|C|https://orcid.org/0000-0002-8797-2114;Valkov|Andrey|A|;Hurtado|Mercedes|M|;Agustí|Jaime|J|;Malave|Giomer|G|;Ferrández|Antonio|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1066896920921238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1066-8969",
"issue": "28(7)",
"journal": "International journal of surgical pathology",
"keywords": "Epstein-Barr virus; germinotrophism; human herpes virus; immunodeficiency; lymphoma",
"medline_ta": "Int J Surg Pathol",
"mesh_terms": "D000368:Aged; D020031:Epstein-Barr Virus Infections; D005260:Female; D006566:Herpesviridae Infections; D004854:Herpesvirus 4, Human; D019288:Herpesvirus 8, Human; D006801:Humans; D008198:Lymph Nodes; D016393:Lymphoma, B-Cell; D008232:Lymphoproliferative Disorders",
"nlm_unique_id": "9314927",
"other_id": null,
"pages": "804-811",
"pmc": null,
"pmid": "32423260",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intrasinusoidal HHV8-EBV-Positive Large B-Cell Lymphoma With Features of Germinotropic Lymphoproliferative Disorder.",
"title_normalized": "intrasinusoidal hhv8 ebv positive large b cell lymphoma with features of germinotropic lymphoproliferative disorder"
} | [
{
"companynumb": "ES-STRIDES ARCOLAB LIMITED-2020SP013552",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugaddit... |
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