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{
"abstract": "A 59-year-old man, with a background of multiply relapsed myeloma, presented with a 3-week history of confusion, short-term memory impairment and behavioural changes. CT head showed bilateral white matter changes and numerous, large lytic lesions of the skull vault. MRI brain revealed multiple areas of hyperintensity on T2-weighted sequences which did not enhance (many of which showed diffusion restriction) unexpectedly bringing progressive multifocal leukoencephalopathy (PML) into the differential. Initial cerebrospinal fluid studies were largely unremarkable, aside from a mildly elevated protein; cultures were negative. PCR for the John Cunningham (JC) virus was positive. Considering the patient's medical history and rapidily progressive symptoms, a palliative approach was adopted, with the patient dying 14 days later. We present this case as an example of PML in a patient with multiple myeloma, highlighting the need to consider this diagnosis in an enlarging population of heavily treated, severely immunocompromised, patients.",
"affiliations": "Core Medical Trainee, NHS Fife, Kirkaldy, UK.;Foundation Year Doctor, NHS Fife, Kirkaldy, UK.;Haematology, NHS Fife, Kirkaldy, UK ioannis.koutsavlis@nhs.net.;Haematology, NHS Fife, Kirkaldy, UK.",
"authors": "Knight|Kathryn|K|;Chien|Siobhan|S|;Koutsavlis|Ioannis|I|;Campbell|Victoria|V|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-233552",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(3)",
"journal": "BMJ case reports",
"keywords": "haematology (drugs and medicines); malignant disease and immunosuppression",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000970:Antineoplastic Agents; D016026:Bone Marrow Transplantation; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D014182:Transplantation, Autologous",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32205382",
"pubdate": "2020-03-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy following five lines of therapy and three autologous bone marrow transplants for multiple myeloma.",
"title_normalized": "progressive multifocal leukoencephalopathy following five lines of therapy and three autologous bone marrow transplants for multiple myeloma"
} | [
{
"companynumb": "GB-BAXTER-2020BAX011434",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBarbiturates and benzodiazepines are the first-line anticonvulsants for neonatal seizures. However, in immature brains, those drugs may lead to paradoxical neuronal excitation.\n\n\nMETHODS\nA patient with benign familial neonatal epilepsy developed epileptic encephalopathy after massive doses of phenobarbital that were followed by a continuous infusion of midazolam on postnatal day 3. Electroencephalography revealed rhythmic delta activity in clusters with migrating epileptic foci. After discontinuation of both drugs, the patient's consciousness promptly improved and her electroencephalography normalized on postnatal day 5.\n\n\nRESULTS\nThis baby developed persistent electroencephalographic seizures due to massive doses of phenobarbital and midazolam.\n\n\nCONCLUSIONS\nClinicians should be aware of this anticonvulsant-induced paradoxical neuronal excitation and the uncoupling phenomenon, especially in individuals with benign familial neonatal epilepsy, who have low seizure thresholds.",
"affiliations": "Department of Pediatrics and Child Neurology, Oita University Faculty of Medicine, Oita, Japan. Electronic address: tmaeda@oita-u.ac.jp.;Department of Pediatrics and Child Neurology, Oita University Faculty of Medicine, Oita, Japan.;Department of Pediatrics and Child Neurology, Oita University Faculty of Medicine, Oita, Japan.;Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for the Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan.;Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for the Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan.;Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan; Central Research Institute for the Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan.;Department of Pediatrics and Child Neurology, Oita University Faculty of Medicine, Oita, Japan.",
"authors": "Maeda|Tomoki|T|;Shimizu|Miki|M|;Sekiguchi|Kazuhito|K|;Ishii|Atsushi|A|;Ihara|Yukiko|Y|;Hirose|Shinichi|S|;Izumi|Tatsuro|T|",
"chemical_list": "D018757:GABA Modulators; D008874:Midazolam; D010634:Phenobarbital",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0887-8994",
"issue": "51(2)",
"journal": "Pediatric neurology",
"keywords": "amplitude-integrated electroencephalography; benign familial neonatal epilepsy; midazolam; paradoxical exacerbation; phenobarbital; uncoupling phenomenon",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D004569:Electroencephalography; D020936:Epilepsy, Benign Neonatal; D005260:Female; D018757:GABA Modulators; D006801:Humans; D008874:Midazolam; D010634:Phenobarbital; D012640:Seizures",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "259-61",
"pmc": null,
"pmid": "25079576",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Exacerbation of benign familial neonatal epilepsy induced by massive doses of phenobarbital and midazolam.",
"title_normalized": "exacerbation of benign familial neonatal epilepsy induced by massive doses of phenobarbital and midazolam"
} | [
{
"companynumb": "JP-RANBAXY-2014RR-84793",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of spontaneous non-traumatic bilateral rupture of the Achilles tendons following ciprofloxacin treatment. A 54-year-old man presented with spontaneous Achilles tendon rupture on the left side, tendinitis and partial tear on the right side following few days of treatment with ciprofloxacin 500 mg twice daily and long-term treatment with prednisolon 10 mg once daily. This rare side effect caused by concurrent treatment with steroids and ciprofloxacin should be kept in mind. Any signs of tendinitis following this treatment should arouse the physicians' suspicion towards ciprofloxacin.",
"affiliations": "Ortopædkirurgisk Afdeling, Herlev Hospital. pasha.attarzadeh@gmail.com",
"authors": "Attarzadeh|Amir Pasha|AP|;Ryge|Camilla|C|",
"chemical_list": "D000890:Anti-Infective Agents; D005938:Glucocorticoids; D002939:Ciprofloxacin; D011239:Prednisolone",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "175(39)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000125:Achilles Tendon; D000890:Anti-Infective Agents; D002939:Ciprofloxacin; D004359:Drug Therapy, Combination; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D012421:Rupture; D052256:Tendinopathy; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": "2264-5",
"pmc": null,
"pmid": "24063715",
"pubdate": "2013-09-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral rupture of the Achilles tendons after treatment with ciprofloxacin.",
"title_normalized": "bilateral rupture of the achilles tendons after treatment with ciprofloxacin"
} | [
{
"companynumb": "DK-HORIZON-PRE-0157-2016",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nStatin-induced lung injury (SILI) is an uncommon but serious complication of statins. The clinical features and outcome of patients with SILI vary widely. Clinical data relevant to diagnosis and outcome of patients with SILI were investigated in this study.\n\n\nMETHODS\nFour cases of SILI diagnosed at our institute and 12 cases reported in the English literature from 1995 to 2010 were studied. The patients were further divided into favourable and unfavourable outcome groups and compared.\n\n\nRESULTS\nCompared with the 12 previously reported cases, fever (p=0.008) and consolidation (p=0.027) were more common and duration of statin treatment was significantly shorter (p=0.030) in our patients. Foamy alveolar macrophages in bronchoalveolar lavage fluid (BALF) were found in our four patients. Patients with cough (p=0.024), fever (p=0.026) and alveolar infiltrates (p=0.036), especially ground-glass opacity (GGO) (p=0.001) shown on thoracic high-resolution CT (HRCT), had a favourable outcome. Conversely, those with fibrosis shown on HRCT (p=0.008) had an unfavourable outcome. Stepwise logistic regression analysis demonstrated that cough (p=0.011), fever (p=0.005), and alveolar infiltrates (p=0.017), GGO (p<0.001) and fibrosis (p=0.002) shown on thoracic HRCT were independent factors affecting the outcome of SILI.\n\n\nCONCLUSIONS\nFor patients with SILI, pulmonary phospholipidosis, as shown by foamy alveolar macrophages in BALF, may be valuable in diagnosis, and clinical symptoms and thoracic HRCT findings are of value in predicting the outcome.",
"affiliations": "Department of Chest Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.",
"authors": "Huang|Li-Kuo|LK|;Tsai|Ming-Ji|MJ|;Tsai|Han-Chen|HC|;Chao|Heng-Sheng|HS|;Lin|Fang-Chi|FC|;Chang|Shi-Chuan|SC|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/postgradmedj-2011-130209",
"fulltext": "\n==== Front\nPostgrad Med JPostgrad Med JpostgradmedjpmjPostgraduate Medical Journal0032-54731469-0756BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 23043128postgradmedj-2011-13020910.1136/postgradmedj-2011-1302091506Original ArticleStatin-induced lung injury: diagnostic clue and outcome Huang Li-Kuo 1Tsai Ming-Ji 1Tsai Han-Chen 2Chao Heng-Sheng 13Lin Fang-Chi 13Chang Shi-Chuan 141 Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan2 Respiratory Care Unit, Department of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan3 School of Medicine, National Yang-Ming University, Taipei, Taiwan4 Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, TaiwanCorrespondence to Dr Shi-Chuan Chang, Department of Chest Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, scchang@vghtpe.gov.tw1 2013 5 10 2012 89 1047 14 19 14 3 2012 28 7 2012 3 9 2012 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2012This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcodeBackground\nStatin-induced lung injury (SILI) is an uncommon but serious complication of statins. The clinical features and outcome of patients with SILI vary widely. Clinical data relevant to diagnosis and outcome of patients with SILI were investigated in this study.\n\nMethod\nFour cases of SILI diagnosed at our institute and 12 cases reported in the English literature from 1995 to 2010 were studied. The patients were further divided into favourable and unfavourable outcome groups and compared.\n\nResults\nCompared with the 12 previously reported cases, fever (p=0.008) and consolidation (p=0.027) were more common and duration of statin treatment was significantly shorter (p=0.030) in our patients. Foamy alveolar macrophages in bronchoalveolar lavage fluid (BALF) were found in our four patients. Patients with cough (p=0.024), fever (p=0.026) and alveolar infiltrates (p=0.036), especially ground-glass opacity (GGO) (p=0.001) shown on thoracic high-resolution CT (HRCT), had a favourable outcome. Conversely, those with fibrosis shown on HRCT (p=0.008) had an unfavourable outcome. Stepwise logistic regression analysis demonstrated that cough (p=0.011), fever (p=0.005), and alveolar infiltrates (p=0.017), GGO (p<0.001) and fibrosis (p=0.002) shown on thoracic HRCT were independent factors affecting the outcome of SILI.\n\nConclusions\nFor patients with SILI, pulmonary phospholipidosis, as shown by foamy alveolar macrophages in BALF, may be valuable in diagnosis, and clinical symptoms and thoracic HRCT findings are of value in predicting the outcome.\n\nspecial-featureunlocked\n==== Body\nIntroduction\nPulmonary drug toxicity is an increasing cause of acute and chronic lung diseases. Many drugs can cause adverse pulmonary reactions, and establishing a diagnosis of drug-induced lung injury is difficult because the clinical, radiological and physiological findings are often non-specific.\n\nStatins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are initially used to decrease plasma low-density lipoprotein cholesterol and reduce the risk of adverse cardiovascular events and death.1 Although statins seem safe and well tolerated clinically, major adverse effects such as hepatotoxicity and myotoxicity have been reported.2\n3\n\nIn 1995, lung injury, an uncommon but potentially fatal complication of statin use, was first reported by Hill and co-investigators.4 Several cases of lung injury caused by different statins were subsequently reported.5–11 Using the database from the US Food and Drug Administration adverse event reporting system, as of June 2007, Fernandez and colleagues reported that interstitial lung disease (ILD), comprising a group of disorders with similar pathological findings including cellular infiltration, scarring and/or architectural disruption of the pulmonary parenchyma involving alveolar lining cells, small and large airways, endothelial basement membranes and occasionally the pleura, was found in 0.01–0.4% of patients who had statin-induced adverse events.12 Recently, Xu et al13 reported a positive correlation between statin use and ILD in the cohort of smokers in the COPDGene Study, with 38% of subjects with ILD taking statins compared with 27% of subjects without ILD.\n\nHowever, clinical features and outcomes of reported patients with statin-induced lung injury (SILI) vary widely. In this study, we reviewed and analysed the clinical data of 16 patients with SILI: 12 patients reported in the English literature and four patients whose condition was diagnosed at our institute. The clinical data relevant to the outcome were explored. In addition, the role of bronchoalveolar lavage (BAL) in diagnosing SILI was investigated.\n\nMethods\nPatients with SILI diagnosed at our institute\nThe four patients with SILI diagnosed at our institute met the following criteria for presumed drug-induced lung injury caused by statins: (1) treatment with statins (rosuvastatin, n=3; atorvastatin, n=1); (2) newly developed pulmonary lesions presenting as ILD on the imaging studies after statin treatment; (3) other causes of lung diseases extensively excluded clinically; (4) obvious clinical and radiological improvement after discontinuation of statins.12\n14 Because of severe lung injury, rechallenge with statins was not performed. However, one patient (case 1) experienced increased dyspnoea 1 week after inadvertent re-administration of rosuvastatin prescribed by a physician with no knowledge of the patient's history of SILI.\n\nPatients with SILI reported in the English literature\nArticles related to SILI published in English from 1 January 1995 to 31 December 2010 were searched for using PubMed and the keywords ‘statins’ or ‘HMG-CoA reductase inhibitors’ in combination with the terms ‘pneumonitis’, ‘lung injury/toxicity’, ‘pulmonary toxicity/injury’ or ‘interstitial lung disease’. Relevant articles were selected and reviewed in detail, including the references of each article. Because of limited information, case reports and case series were included. Finally, 12 cases selected from six English articles were included in this study.4–9\n\nData collection\nThe clinical data of 16 patients with SILI were reviewed and analysed. The role of BAL in diagnosing SILI and the factors affecting the outcome of the patients were explored. The outcome was favourable when resolution of clinical symptoms or regression of lung lesions was found after discontinuation of statins and/or treatment with steroids. The outcome was unfavourable when worsening of clinical symptoms or death occurred irrespective of discontinuation of statins and/or treatment with steroids.\n\nStatistical analysis\nThe data were expressed as mean and SD or case number. Two group comparisons of continuous data were made using the Mann–Whitney U test. Comparisons of categorical data between two groups were performed using the χ2 test and/or Fisher exact test when appropriate. Independent factors for the outcome were assessed by stepwise logistic regression analysis. Statistical significance was defined as p<0.05 (two-tailed). Statistical analysis was performed using SPSS V.15.0.\n\nResults\nClinical data of the four patients with SILI diagnosed at our institute\nFour cases of SILI were diagnosed at our institute during the period 1 January 2006 to 31 December 2010. The demographic and clinical data are summarised in table 1. All four patients were male, aged 41–85 years (mean±SD, 67.5±20.7 years). Rosuvastatin was administered in three patients, and atorvastatin in one. The duration of statin treatment ranged from 0.33 to 12 months (mean±SD, 4.0±5.4 months). All patients presented with dyspnoea and fever, and two of them also complained of a dry cough. Thoracic high-resolution CT (HRCT) showed diffusely bilateral ground-glass opacity (GGO) in four patients, consolidations in three, minimal bilateral pleural effusions in two, and interstitial infiltrates predominantly in the upper lungs in one. Restrictive ventilatory impairment was noted in two of the three patients who underwent pulmonary function testing, and diffusing capacity for carbon monoxide (DLCO) had decreased significantly in all three patients. Lung biopsy—transbronchial or open—was not performed in our patients because of impaired renal function, compromised cardiopulmonary function and reluctance of the patients. Instead, diagnostic BAL was performed in all four patients. Microbiological culture of BAL fluid (BALF) yielded no growth for all four patients. The cellular profile of BALF varied: a neutrophilic pattern in case 2, a mixed pattern with increased lymphocytes and eosinophils in case 3, and predominance of alveolar macrophages in cases 1 and 4. Of note, a foamy appearance of the majority of alveolar macrophages (figure 1) which stained positive for Sudan black (figure 2) was found in all four cases. The four patients were managed with immediate withdrawal of statins and administration of prednisolone (0.5 mg/kg body weight per day or methylprednisolone in bioequivalent dose), and all of them improved clinically. Marked resolution of lung lesions, as evidenced by chest radiogram and/or thoracic HRCT, was found in two patients at 1 month, in one patient by chest radiogram at 2.5 months, and in a further patient by chest radiogram at 9 months.\n\nTable 1 Demographic and clinical data of four patients with statin-induced lung injury diagnosed at our institute\n\nVariable\tCase 1\tCase 2\tCase 3\tCase 4\t\nAge, years\t41\t61\t85\t83\t\nStatin/daily dose, mg\tRosuvastatin/10\tRosuvastatin/10\tAtorvastatin/5\tRosuvastatin/5\t\nDuration of treatment, months\t0.33\t12\t1.75\t2\t\nClinical symptoms\tDyspnoea, fever, cough\tDyspnoea, fever\tDyspnoea, fever, cough\tDyspnoea, fever\t\nHRCT findings\tG\tG, C, P\tG, C, I, P\tG, C\t\nBronchoalveolar lavage fluid\t\n Celluar profile, % (M/L/N/E)\t94.5/2.5/3/0\t74/4/22/0\t58.5/33/2.5/6\t94.5/4.5/1/0\t\n Foamy macrophages\t+\t+\t+\t+\t\n Sudan black smear\t+\t+\t+\t+\t\nPulmonary function testing\t\n Spirometry\tNot done\tRestrictive\tNormal\tRestrictive\t\n DLCO, % of predicted\tNot done\t44\t44\t39\t\nLaboratory findings*\t\n ALT/AST\t33/63\tNot done\t24/36\t33/23\t\n CK\t240\tNot done\t79\t10\t\n CRP\t69.2\t4.39\t4.99\t25.5\t\nTreatment\t\n Discontinuation of statin\t+\t+\t+\t+\t\n Steroid/daily dose, mg\tPrednisolone/45\tPrednisolone/30\tMethylprednisolone/24\tPrednisolone/30\t\nOutcome\tResolution\tResolution\tResolution\tResolution\t\n*ALT (reference, 0–40 U/l), AST (reference, 5–45 U/l), CK (reference, 27–168 U/l), CRP (reference, 0–0.5 mg/l).\n\nALT, alanine aminotransferase; AST, aspartate aminotransferase; C, consolidation; CK, creatinine kinase; CRP, C-reactive protein; DLCO, carbon monoxide diffusing capacity; E, eosinophil; G, ground-glass opacities; HRCT, high-resolution CT; I, interstitial opacities; L, lymphocyte; M, macrophage; N, neutrophil; P, pleural changes.\n\nFigure 1 Riu's stain smear of bronchoalveolar lavage fluid shows a foamy appearance of the alveolar macrophages (arrows) (original magnification ×400).\n\nFigure 2 Sudan black-stained smear of bronchoalveolar lavage fluid showing positive staining of alveolar macrophages (arrows) (original magnification ×400).\n\nClinical data of the 16 studied subjects\nSixteen cases of SILI including four cases diagnosed at our institute and 12 reported cases selected from English articles were investigated. Simvastatin was the most common statin reported to cause lung injury, found in six cases. The time from the start of statin treatment to the onset of lung injury varied widely, ranging from 0.25 to 120 months (mean±SD, 34.3±34.9 months). Cardiovascular disease was the most common underlying comorbidity, found in 14 of 16 patients. Dyspnoea, cough and fever were the most common presenting symptoms.\n\nRadiological features of the 16 studied subjects\nAlveolar infiltrates shown on thoracic HRCT were found in 11 patients (68.8%). GGO was the main finding in nine of these 11 patients. Six patients presented with varying degrees of fibrosis, and pleural changes including effusion and pleural thickening were seen in three patients.\n\nResults of pulmonary function testing of the 16 studied subjects\nThe results of pulmonary function testing showed a restrictive ventilatory defect in six of 10 patients studied. Hypoxaemia was found in all six patients undergoing arterial blood gas analysis. Marked reduction of DLCO was found in all 13 patients studied, and the values of DLCO measured in 12 patients ranged from 14% to 46% (mean±SD, 35.8±10.5%) of normal predicted value.\n\nHistopathology of the 16 studied subjects\nLung biopsy was performed in nine patients. The reported main histopathological findings in eight of the nine patients were as follows: fibrosis in three, non-specific interstitial pneumonitis (NSIP) in two, diffuse alveolar damage in two, and hypersensitivity pneumonitis in one. The histopathological findings were non-diagnostic in the remaining patient. Of note, a foamy appearance of the alveolar macrophages, type II pneumocytes and interstitial histiocytes was found and documented as heterogeneous intralysosomal lamellar inclusions in the cytoplasm of these cells under an electron microscope, highly suggestive of pulmonary phospholipidosis, in one patient.8\n\nManagement and outcome of the 16 studied subjects\nStatins were discontinued and steroids were administered in 15 of the 16 patients. Clinical or radiological improvement was noted in 10 patients, who were classified in the favourable outcome group. Of the remaining six patients with unfavourable outcome, two had slowly progressive disease complicated by persistent dyspnoea. Four patients died from respiratory or cardiac failure, including the patient receiving continuous simvastatin treatment.9\n\nComparison between our four patients and the 12 previously reported patients\nComparisons of clinical features between our four patients and the 12 patients reported in the English literature are shown in table 2. The duration of statin treatment was significantly shorter (4.0±5.4 vs 41.0±36.0 months, p=0.030) and fever more common in our patients (4/4 vs 2/12, p=0.008). Of note, most alveolar macrophages in the BALF of our four patients were found to be foamy in appearance and stained positive with Sudan black. However, no morphological change in alveolar macrophages was mentioned in six of the 12 reported patients undergoing BAL. In addition, consolidation was more common in our patients (3/4 vs 1/12, p=0.027).\n\nTable 2 Comparisons between patients with statin-induced lung injury diagnosed at our institute and reported in the English literature\n\nVariable\tOur patients (N=4)\tReported patients (N=12)\tp Value\t\nAge, years\t67.5±20.7\t69.7±8.8\t0.953\t\nGender (male/female)\t4/0\t7/5\t0.181\t\nDuration of statin treatment, months\t4.0±5.4\t41.0±36.0\t0.030\t\nSymptoms\t\n Dyspnoea\t4 (100.0)\t11 (91.7)\t0.750\t\n Cough\t2 (50.0)\t7 (58.3)\t0.608\t\n Fever\t4 (100.0)\t2 (16.7)\t0.008\t\nLaboratory findings\t\n Leucocytosis\t1/4 (25.0)\t1/2 (50.0)\t0.600\t\n Elevated CK level\t1/3 (33.3)\t2/3 (66.7)\t0.500\t\n Impaired LFT\t1/3 (33.3)\t2/2 (100.0)\t0.300\t\nHRCT findings\t\n Alveolar infiltrates\t4 (100.0)\t7 (58.3)\t0.181\t\n Consolidation\t3 (75.0)\t1 (8.3)\t0.027\t\n GGO\t4 (100.0)\t5 (41.7)\t0.069\t\n Unspecified\t0 (0)\t2 (16.7)\t0.550\t\n Interstitial infiltrates\t1 (25.0)\t1 (8.3)\t0.450\t\n Fibrosis\t0 (0)\t6 (50.0)\t0.115\t\n Pleural changes\t2 (50.0)\t1 (8.3)\t0.136\t\nSpirometry\t\n Restrictive\t2/3 (66.7)\t4/7 (57.1)\t0.667\t\n Obstructive\t0/3 (0)\t3/7 (42.9)\t0.292\t\nDLCO, % of predicted\t42.3±2.9\t33.7±11.3\t0.373\t\nBALF cytology\t\n Foamy macrophages\t4/4 (100.0)\t0/6 (0)\t0.005\t\n Neutrophils, > 3%\t1/4 (25.0)\t4/6 (66.7)\t0.262\t\n Lymphocytes, > 20%\t1/4 (25.0)\t1/6 (16.7)\t0.667\t\n Eosinophils, > 0.5%\t1/4 (25.0)\t4/6 (66.7)\t0.044\t\nData are expressed as mean±SD or n (%).\n\nBALF, bronchoalveolar lavage fluid; CK, creatinine kinase; DLCO, carbon monoxide diffusion capacity; GGO, ground glass opacity; HRCT, high-resolution CT; LFT, liver function test.\n\nComparisons between favourable and unfavourable outcome groups\nComparisons of demographic and clinical data between 10 patients with favourable outcome and six patients with unfavourable outcome are summarised in table 3. Cough (p=0.024) and fever (p=0.026) were more common in the patients with favourable outcome. The findings of thoracic HRCT appeared to be of value in predicting the outcome of patients. Alveolar infiltrates (p=0.036), in particular GGO (p=0.001), were more common in the patients with favourable outcome. In contrast, fibrosis (p=0.008) was more common in the patients with unfavourable outcome. After stepwise logistic regression analysis, cough (OR=0.050, 95% CI 0.050 to 0.706, p=0.011), fever (OR=0.040, 95% CI 0.187 to 0.855, p=0.005), and alveolar infiltrates (OR=0.056, 95% CI 0.004 to 0.805, p=0.017), GGO (OR=0.100, 95% CI 0.016 to 0.642, p<0.001) and fibrosis (OR=45.0, 95% CI 2.287 to 885.601, p=0.002) shown on HRCT were independent factors affecting the outcome of patients with SILI.\n\nTable 3 Comparisons between patients with statin-induced lung injury with favourable and unfavourable outcome\n\nVariable\tFavourable outcome (N=10)\tUnfavourable outcome (N=6)\tp Value (univariable)\tp Value (multivariable)\t\nAge, years\t65.6±13.4\t75.0±6.3\t0.147\t\t\nGender, M/F\t8/2\t3/3\t0.242\t\t\nDuration of statin treatment, months\t32.2±31.0\t31.0±44.3\t0.958\t\t\nSymptoms\t\n Dyspnoea\t9 (90.0)\t6 (100.0)\t0.625\t\t\n Cough\t8 (80.0)\t1 (16.7)\t0.024\t0.011\t\n Fever\t6 (60.0)\t0 (0.0)\t0.026\t0.005\t\nLaboratory findings\t\n Leucocytosis\t2 (20.0)\t3 (50.0)\t0.714\t\t\n Elevated CK\t2/4 (50.0)\t1/2 (50.0)\t0.600\t\t\n Impaired LFT\t2/4 (50.0)\t1/1 (100.0)\t0.600\t\t\nHRCT findings\t\n Alveolar infiltrates\t9 (90.0)\t2 (16.7)\t0.036\t0.017\t\n Consolidation\t4 (40.0)\t0 (0.0)\t0.115\t< 0.001\t\n GGO\t9 (90.0)\t0 (0.0)\t0.001\t0.002\t\n Unspecified\t0 (0.0)\t2 (16.7)\t0.125\t\t\n Interstitial infiltrates\t2 (20.0)\t0 (0.0)\t0.375\t\t\n Fibrosis\t1 (10.0)\t5 (83.3)\t0.008\t\t\n Pleural changes\t3 (30.0)\t0 (0.0)\t0.214\t\t\nSpirometry\t\n Restrictive\t4/7 (57.1)\t2/3 (67.7)\t0.667\t\t\n Obstructive\t2/7 (28.6)\t1/3 (33.3)\t0.708\t\t\n Normal\t1/7 (14.3)\t0/3 (0.0)\t0.383\t\t\nDLCO, % of predicted\t35.3±10.3\t37.3±13.3\t0.600\t\t\nLung biopsy\t\n Fibrosis\t2/5 (40.0)\t2/3 (66.7)\t0.500\t\t\n HP\t1/5 (20.0)\t0/3 (0.0)\t0.625\t\t\n NSIP\t2/5 (40.0)\t0/3 (0.0)\t0.357\t\t\n DAD\t0/5 (0.0)\t2/3 (66.7)\t0.107\t\t\nBALF cytology\t\n Foamy macrophages\t4/8 (50.0)\t0/2\t0.333\t\t\n Neutrophils, >3%\t3/8 (37.5.)\t2/2\t0.467\t\t\n Lymphocytes, >20%\t2/8\t0/2\t0.622\t\t\n Eosinophils, >0.5%\t3/8\t2/2\t0.071\t\t\nData are expressed as mean±SD or n (%).\n\nBALF, bronchoalveolar lavage fluid; CK, creatinine kinase; DAD, diffuse alveolar damage; DLCO, carbon monoxide diffusion capacity; GGO, ground glass opacity; HP, hypersensitivity pneumonitis; HRCT, high-resolution CT; LFT, liver function test; NSIP, non-specific interstitial pneumonitis.\n\nDiscussion\nOur results indicate that pulmonary phospholipidosis, as evidenced by a foamy appearance of alveolar macrophages in BALF, may be of value in diagnosing SILI, as shown in our four cases. Furthermore, the clinical symptoms and findings on HRCT may be of value in predicting the outcome of patients with SILI.\n\nThe duration between drug initiation and onset of respiratory symptoms varied widely, ranging from 0.25 to 120 months (mean±SD, 34.3±34.9 months) in the 16 patients studied. Compared with the 12 patients reported in the English literature, the duration of statin treatment was significantly shorter in our four patients, as shown in table 2. This can be explained in part by the clinical experience and high index of suspicion of SILI of our team. Of more importance, foamy appearance of most alveolar macrophages in BALF which showed positive Sudan black staining in the cytological smear used to detect pulmonary phospholipidosis was found in our four patients. This finding may be of value in diagnosing SILI because pulmonary phospholipidosis may be the representative pathological pattern of lung injury caused by statin because foamy appearance of macrophages, type II pneumocytes and interstitial histiocytes demonstrated on lung biopsy was reported in a patient with statin-induced fibrotic non-specific interstitial pneumonitis (NSIP).8\n\nPulmonary phospholipidosis is neither diagnostic nor pathognomonic for SILI, and can be induced by a variety of drugs and chemicals15\n16 including a well-studied anti-arrhythmic agent, amiodarone.17\n18 However, a foamy appearance of most alveolar macrophages in BALF may help narrow the list of differential diagnoses for a patient with ILD and aid the diagnosis of SILI in the appropriate clinical setting. Furthermore, the findings may be of clinical importance because SILI is a serious adverse pulmonary reaction with high morbidity (6/16, 37.5%) and mortality (4/16, 25%) as shown in this study (table 2).\n\nOur results indicate that the patients with clinical symptoms of cough and/or fever had a favourable outcome. It may be that the presence of such acute symptoms prompts the patient to seek medical help and avoid delay in diagnosis and treatment. However, these clinical symptoms, in addition to thoracic radiological findings, may mimic pulmonary infection and confuse physicians who are unaware of SILI.\n\nThe main findings of thoracic HRCT were alveolar infiltrates, in particular GGO, and varying degrees of fibrosis in SILI, which were similar to the radiological features described in previous reports.12\n13 These image findings have limited value in the diagnosis of drug-induced lung injury,19–21 but may affect the patient's outcome. Patients with alveolar infiltrates, in particular GGO, had a favourable outcome. In contrast, those with fibrosis had an unfavourable outcome. These results are consistent with previous studies on the prognostic role of thoracic HRCT in interstitial pneumonitis, including NSIP and idiopathic pulmonary fibrosis.22\n23 These studies suggested that inflammatory (GGO/consolidation) predominant findings were indicative of a better outcome, whereas fibrotic (reticular/honeycombing) predominant findings were suggestive of a worse prognosis. Further studies with larger numbers of subjects are needed to address the role of thoracic HRCT in predicting the outcome of patients with SILI.\n\nThis study had some limitations. First, the number of patients studied was inadequate because of the stringent selection criteria and limited cases reported in the English literature. Limited cases may confer potential error and bias. Second, pathological findings characteristic of pulmonary phospholipidosis were not obtained in our four patients because lung biopsy was not performed because of compromised cardiopulmonary function and reluctance of the patients. Third, SILI might be underdiagnosed because of the unusually prolonged duration of statin treatment and low index of suspicion of the physicians. Fourth, the patients enrolled in this study may have varying degrees of severity, and therefore conclusions must be drawn with caution. Fifth, the morphological changes in alveolar macrophages in BALF of the patients with SILI were not addressed in previous reports. Sixth, the risk factors for statin-associated ILD, including cigarette smoking, occupational dust exposure and hydrophilicity of statins, could not be evaluated because of incomplete clinical information drawn from previous reports and limited case number. However, the results of the present study may be of clinical relevance. Pulmonary phospholipidosis, as shown by morphological changes in alveolar macrophages in BALF, may be of value in diagnosing SILI and thereby avoiding delay in treatment. In addition, our results indicate that some clinical data may be relevant to the outcome of the patients. To our knowledge, this is the first study to investigate these issues in patients with SILI.\n\nIn summary, the duration of statin treatment varies widely in patients with SILI, and the clinical features of the disease are protean. A high index of suspicion and the presence of pulmonary phospholipidosis, shown by a foamy appearance of the majority of alveolar macrophages which stain positive for Sudan black, may be of considerable value in diagnosing SILI. Clinical symptoms of cough and fever and thoracic HRCT findings of alveolar infiltrates, GGO and fibrosis are of value in predicting the outcome of SILI. Further studies with larger populations are needed to clarify these issues.\nMain messages\nStatin-induced lung injury (SILI) is an uncommon but serious pulmonary complication. The clinical features and outcome of patients with SILI vary widely.\n\nFoamy appearance of the majority of alveolar macrophages showing positive Sudan black staining in bronchoalveolar lavage fluid may be of value in the diagnosis of SILI, especially after exclusion of other possible causal agents and entities.\n\nThe high-resolution CT (HRCT) findings in SILI are non-specific, but may be of prognostic value. Alveolar infiltrates, especially ground-glass opacity, indicate favourable outcome, while fibrosis shown on HRCT suggests unfavourable outcome.\n\n\nCurrent research questions\nWhat is the underlying mechanism of statin-induced lung injury (SILI)?\n\nAre there any risk factors for the occurrence of SILI?\n\nHow can physicians become more aware of SILI in their clinical practice?\n\n\nKey references\nLantuejoul S, Brambilla E, Brambilla C, et al. Statin-induced fibrotic nonspecific interstitial pneumonia. Eur Respir J 2002;19:577–80.\n\nFernandez AB, Karas RH, Alsheikh-Ali AA, et al. Statins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports. Chest 2008;134:824–30.\n\nXu JF, Washko GR, Nakahira K, et al. Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Am J Respir Crit Care Med 2012;185:547–56.\n\nSchmitz G, Grandl M. Endolysosomal phospholipidosis and cytosolic lipid droplet storage and release in macrophages. Biochim Biophys Acta 2009;1791:524–39.\n\n\n\nContributors: LKH and SCC were jointly responsible for the conception, design of the study and preparation of the manuscript. LKH, MJT, HSC, FCL and SCC were responsible for performing bronchoscopy, retrieving the specimen, and analysing the cytological results. LKH was responsible for collection of the data. HCT was responsible for statistical analysis of the data. SCC was responsible for conducting the processing of the study and preparation of the final manuscript.\n\nCompeting interests: None.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nOpen Access:This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) 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/3.0/\n==== Refs\nReferences\n1 Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) . JAMA \n2001 ;285 :2486 –97 11368702 \n2 Bellosta S Paoletti R Corsini A \nSafety of statins: focus on clinical pharmacokinetics and drug interact . Circulation \n2004 ;109 (Suppl 1 ):III50 –7 15198967 \n3 Farmer JA Torre-Amione G \nComparative tolerability of the HMG-CoA reductase inhibitors . Drug Saf \n2000 ;23 :197 –213 11005703 \n4 Hill C Zeitz C Kirkham B \nDermatomyositis with lung involvement in a patient treated with simvastatin . Aust N Z J Med \n1995 ;25 :745 –6 8770347 \n5 De Groot RE Willems LN Dijkman JH \nInterstitial lung disease with pleural effusion caused by simvastatin . J Intern Med \n1996 ;239 :361 –3 8774391 \n6 Sridhar MK Abdulla A \nFatal lupus-like syndrome and ARDS induced by fluvastatin (letter) . Lancet \n1998 ;352 :114 9672281 \n7 Liebhaber MI Wright RS Gelberg HJ \nPolymyalgia, hypersensitivity pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a report of ten cases . Chest \n1999 ;115 :886 –9 10084510 \n8 Lantuejoul S Brambilla E Brambilla C \nStatin-induced fibrotic nonspecific interstitial pneumonia . Eur Respir J \n2002 ;19 :577 –80 11936540 \n9 Walker T McCaffery J Steinfort C \nPotential link between HMG-CoA reductase inhibitor (statin) use and interstitial lung disease . MJA \n2007 ;186 :91 –4 17223772 \n10 Veyac G Cellerin L Jolliet P \nA case of interstitial lung disease with atorvastatin (Tahor) and a review of the literature about these effects observed under statins . Therapie \n2006 ;61 :57 –67 (In French English abstract )16792155 \n11 Liscoët-Loheac N André N Couturaud F \nHypersensitivity pneumonitis in a patient taking pravastatin (in French) . Rev Mal Respir \n2001 ;18 (4 Pt \n1 ):426 –8 11547251 \n12 Fernandez AB Karas RH Alsheikh-Ali AA \nStatins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports . Chest \n2008 ;134 :824 –30 18689579 \n13 Xu JF Washko GR Nakahira K \nStatins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation . Am J Respir Crit Care Med \n2012 ;185 :547 –56 22246178 \n14 Flieder DB Travis WD \nPathologic characteristics of drug-induced lung disease . Clin Chest Med \n2004 ;25 :37 –45 15062595 \n15 Costabel U Uzaslan E Guzman J \nBronchoalveolar lavage in drug-induced lung disease . Clin Chest Med \n2004 ;25 :25 –35 15062594 \n16 Schmitz G Grandl M \nEndolysosomal phospholipidosis and cytosolic lipid droplet storage and release in macrophages . Biochim Biophys Acta \n2009 ;1791 :524 –39 19146988 \n17 Israël-Biet D Venet A Caubarrère I \nBronchoalveolar lavage in amiodarone pneumonitis: cellular abnormalities and their relevance to pathogenesis . Chest \n1987 ;91 :214 –21 3802932 \n18 Chang CL Chern MS Chang SC \nAmiodarone toxicity in a patient with simultaneous involvement of cornea, thyroid gland, and lung . Am J Med Sci \n2000 ;320 :64 –8 10910375 \n19 Rossi SE Erasmus JJ McAdams HP \nPulmonary drug toxicity: Radiologic and pathologic manifestations . RadioGraphics \n2000 ;20 :1245 –59 10992015 \n20 Cleverley JR Screaton NJ Hiorns MP \nDrug-induced lung disease: high-resolution CT and histological findings . Clin Radiol \n2002 ;57 :292 –9 12014876 \n21 Ryu JH Daniels CE Hartman TE \nDiagnosis of interstitial lung diseases . Mayo Clin Proc \n2007 ;82 :976 –86 17673067 \n22 Screaton NJ Hiorns MP Lee KS \nSerial high resolution CT in non-specific interstitial pneumonia: prognostic value of the initial pattern . Clin Radiol \n2005 ;60 :96 –104 15642299 \n23 Flaherty KR Thwaite EL Kazerooni EA \nRadiological versus histological diagnosis in UIP and NSIP: survival implications . Thorax \n2003 ;58 :143 –8 12554898\n\n",
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"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008168:Lung; D055370:Lung Injury; D016676:Macrophages, Alveolar; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D013624:Taiwan; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
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"title": "Statin-induced lung injury: diagnostic clue and outcome.",
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"abstract": "Sporotrichosis is an infection caused by a dimorphic fungus of the Sporothrix schenckii complex. Host immunity is an important factor in the clinical manifestations of the disease. Deeply immunocompromised individuals, especially those infected with the Human Immunodeficiency Virus (HIV) and T CD4 counts < 350 cells/ul lymphocytes, may present with the systemic form of sporotrichosis. This report describes a case of disseminated sporotrichosis caused by S. brasiliensis in a patient with advanced AIDS. The skin, lungs, bones and central nervous system were affected. Medical treatment involved the administration of amphotericin B, terbinafine, itraconazole and posaconazole. Posaconazole was associated with the best clinical response and clearing of the fungus from the central nervous system.",
"affiliations": "Fundação Oswaldo Cruz - Fiocruz, Universidade Grande Rio, Rio de Janeiro, RJ Brazil.;Fundação Oswaldo Cruz - Fiocruz, Universidade Grande Rio, Rio de Janeiro, RJ Brazil.;Fundação Oswaldo Cruz - Fiocruz, Universidade Grande Rio, Rio de Janeiro, RJ Brazil.;Fundação Oswaldo Cruz - Fiocruz, Universidade Grande Rio, Rio de Janeiro, RJ Brazil.;Fundação Oswaldo Cruz - Fiocruz, Universidade Grande Rio, Rio de Janeiro, RJ Brazil.;Fundação Oswaldo Cruz - Fiocruz, Universidade Grande Rio, Rio de Janeiro, RJ Brazil.;Fundação Oswaldo Cruz - Fiocruz, Universidade Grande Rio, Rio de Janeiro, RJ Brazil.",
"authors": "Paixão|Ariane Gomes|AG|;Galhardo|Maria Clara Gutierrez|MCG|;Almeida-Paes|Rodrigo|R|;Nunes|Estevão Portela|EP|;Gonçalves|Marcelo Luiz Carvalho|MLC|;Chequer|Gisele Larias|GL|;Lamas|Cristiane da Cruz|CDC|",
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"doi": "10.1186/s12981-015-0051-1",
"fulltext": "\n==== Front\nAIDS Res TherAIDS Res TherAIDS Research and Therapy1742-6405BioMed Central London 5110.1186/s12981-015-0051-1Case ReportThe difficult management of disseminated Sporothrix brasiliensis in a patient with advanced AIDS Paixão Ariane Gomes aricapaixao@hotmail.com Galhardo Maria Clara Gutierrez maria.clara@ini.ipec.fiocruz.br Almeida-Paes Rodrigo rodrigo.paes@ipec.fiocruz.br Nunes Estevão Portela estevao.nunes@ipec.fiocruz.br Gonçalves Marcelo Luiz Carvalho marcelo.carvalho@ipec.fiocruz.br Chequer Gisele Larias gisele.chequer@ini.fiocruz.br Lamas Cristiane da Cruz cristianelamas@gmail.com Fundação Oswaldo Cruz - Fiocruz, Universidade Grande Rio, Rio de Janeiro, RJ Brazil 7 5 2015 7 5 2015 2015 12 1619 8 2014 3 3 2015 © Paixão et al.; licensee BioMed Central. 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. 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.Sporotrichosis is an infection caused by a dimorphic fungus of the Sporothrix schenckii complex. Host immunity is an important factor in the clinical manifestations of the disease. Deeply immunocompromised individuals, especially those infected with the Human Immunodeficiency Virus (HIV) and T CD4 counts < 350 cells/ul lymphocytes, may present with the systemic form of sporotrichosis. This report describes a case of disseminated sporotrichosis caused by S. brasiliensis in a patient with advanced AIDS. The skin, lungs, bones and central nervous system were affected. Medical treatment involved the administration of amphotericin B, terbinafine, itraconazole and posaconazole. Posaconazole was associated with the best clinical response and clearing of the fungus from the central nervous system.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12981-015-0051-1) contains supplementary material, which is available to authorized users.\n\nKeywords\nSporotrichosisAIDSAmphotericin BPosaconazoleissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nSporotrichosis may be an acute or chronic infection caused by a dimorphic fungus of the Sporothrix schenckii complex [1] generally located in cutaneous and sub-cutaneous tissue, often associated with lymphatic involvement. The fungus can disseminate to bones, lungs and central nervous system, especially in immunosuppressed patients [2-6]. Recent publications have drawn attention to the possibility of dissemination related to fungal virulence factors, as is the case for S. brasiliensis [7].\n\nThe disease usually manifests as isolated cases or outbreaks related to specific occupational exposure; however, recently, it has reached epidemic proportions in some parts of Latin America, India [8] and Northeastern China [9]. The clinical, demographic and epidemiologic features vary within regions. The disease affects predominantly tropical and subtropical regions, being the most prevalent subcutaneous mycosis in South America. In Brazil, it is the most common cutaneous mycosis, and, in the Rio de Janeiro metropolitan area, it has been considered an epidemic zoonosis since the 1990s [2]. In this area, sporotrichosis occurs mostly via transmission from infected cats to humans, and genotypic analysis has shown that samples isolated from the Rio de Janeiro epidemic have a high genetic similarity. This finding is suggestive of a common niche, as S. brasiliensis is the species most frequently found in the city and in its surroundings [2,7]. Currently, this species is considered the most virulent of the Sporothrix schenckii complex [10]. On the other hand, the immune system of the host is an important factor that contributes to the different forms of the disease [11-14]. HIV co-infection clearly modifies the clinical consequences of the disease because T CD4 lymphocytes play an important role in the control of this mycosis. HIV infection aggravates sporotrichosis, with a higher incidence of severe disseminated cases and a higher number of hospitalizations and deaths [15]. The classical presentation of sporotrichosis is polymorphic lesions in the skin and sub-cutaneous tissue, compromising the adjoining lymphatics. The most affected cutaneous sites are those where the skin is most exposed to the environment. The incubation period is on average three weeks from the inoculation date.\n\nThe most frequent clinical form is the lymphocutaneous form, followed by the cutaneous form and the disseminated form. This report details a case of disseminated sporotrichosis in an HIV-positive female patient with advanced HIV immunosuppression.\n\nClinical case\nLSC, a 20- year- old female from Campos dos Goytacases (41°19’28”W), a city in the rural part of the state of Rio de Janeiro ( 274 km from Rio de Janeiro city), was diagnosed HIV positive in March 2011. She was a student and single. Due to the lack of laboratory resources in the patient’s hometown, CD4 and viral load were not collected at the time of diagnosis, and zidovudine (AZT), lamivudine, lopinavir and ritonavir were prescribed six months later due to progressive weight loss and fatigue.\n\nOn January 2012, the patient was scratched by her cat on the left hand, where the first polymorphic lesions (vegetative, nodular, ulcerous and crusty) appeared on the skin, spreading afterwards. Because of the severe skin condition, the patient was admitted on April 2012 to the Ferreira Machado Hospital in Campos dos Goytacases where she received deoxycholate amphotericin B (AMB) and itraconazole 600 mg/day, in addition to the antiretroviral therapy. A total dose dose of 2,05 g AMB was given along the 45 days of hospitalization. She showed no improvement in her condition and was therefore transferred to a referral Infectious Diseases hospital.\n\nOn June 2012, the patient was transferred to the Institute of Clinical Research (ICR) Evandro Chagas/FIOCRUZ (IPEC) due to the difficulty in managing the spreading polymorphic skin lesions associated with a wasting syndrome, severe protein-caloric malnutrition and the worsening of her general condition (Figure 1A, B).Figure 1 \nPhotographs on admission to IPEC/FIOCRUZ on June, 2012. Polymorphic Sporotrichosis Lesions.\n\n\n\nInitial exams at the ICR showed macrocytic anemia (hemoglobin 10,3 g/dl; hematocrit 31,1%, MCV 105); leukocytosis 18110 mm3 with 10% band forms; C reactive protein of 32.48 mg/dl (reference level < 0.5), CD4 111 cells/mm3 (11,65%); CD8 605 cells/mm3 (63,75%); and a viral load of 92 copies/mm3. Cultures from blood, cerebrospinal fluid (CSF), induced sputum, urine and secretions from skin lesions were performed using Sabouraud, Mycosel and BHI-Agar and resulted positive for Sporothrix spp. A subsequent partial sequencing of the calmodulin gene showed that the isolate was actually S. brasiliensis. Plain radiographs and computed tomography (CT) scans showed osteolytic lesions, possibly due to fungal invasion. A bone biopsy was not performed because there was no local facility available for this type of procedure; moreover, given the results of all other exams, the biopsy was considered to be invasive and unnecessary (Figure 2A, B). At first, treatment with amphotericin B deoxycholate (1 mg/Kg/day; patient’s weight was 45 Kg) was maintained, and later on, it was substituted for a liposomal formulation. On July 16, 2012, treatment with itraconazole 200 mg/day was resumed and terbinafine 250 mg/day was associated. The patient had been taking zidovudine, lamivudine, lopinavir and ritonavir, but AZT was changed to abacavir due to severe anemia detected on August 2012. Skin lesions improved slowly and gradually, probably as a result of the antifungal and antiretroviral treatment and the weekly sessions of cryotherapy, which went on for 18 months (Figure 3A, B, C, D). The patient also presented an improvement in general condition with a weight gain of 6 Kg. She was able to stand and walk with assistance following weeks of intensive physiotherapy.Figure 2 \nPlain radiographs of hands (A) and lower limbs (B) showing osteolytic lesions (on June 2012, admission to IPEC).\n\n\nFigure 3 \nEvolution of the skin lesions after treatment. Evolution of the skin lesions.\n\n\n\nHowever, even with the general improvement and triple antifungal therapy with liposomal AMB, itraconazole and terbinafine, S. brasiliensis still grew in CSF that was collected up to October 2012, despite the fact the patient had no neurological symptoms. Because of the difficulty in sterilizing the CSF, on September 2012, terbinafine and itraconazole were stopped and posaconazole was prescribed at the dose of 800 mg/day [16,17], still associated with deoxycholate AMB. The administration of posaconazole was continuous but the AMB was not, as deep intravenous access was difficult and increases in serum creatinine occurred. The fungal susceptibility testing (Additional file 1) was done with the M38A2 method and CLSI 2008 standards on the S. brasiliensis isolated from the skin, sputum and CSF. The test results showed good sensitivity to terbinafine and voriconazole, intermediate sensitivity to AMB, and low sensitivity to itraconazole and ketoconazole. Posaconazole was not tested because there were no cut offs defined for this fungus; instead, its sensitivity was determined by comparing it to previous reports of S. brasiliensis isolates [18].\n\nMycological surveillance was performed monthly, and the first sterile CSF was seen on November 2012, a month after starting treatment with posaconazole. CSF sterility was documented until October 2013, despite the progressive cytological and biochemical changes seen in CSF (Additional file 1). The inflammatory changes led to the suspicion of meningeal tuberculosis or immune reconstitution syndrome, and empirical therapy with rifampin, isoniazid, pyrazinamide and ethambutol was given for 28 days and associated with dexamethasone (8 mg IV tds) for 14 days. At this point, the patient presented a CD4 cell count of 304 (11%) and a viral load < 40 copies/ml (Additional file 1).\n\nDuring October 2013, the patient presented confusion, headache and nystagmus. Repeat brain CT scans showed exudative hydrocephalus, hypodensity of the white substance adjacent to the lateral ventricles, compatible with cerebrospinal fluid transudation, cortical sulci deletion and intense meningeal enhancement (Figure 4). Concurrently, CSF culture on November 4, 2013, was positive for S. brasiliensis. The patient was given a ventriculoperitoneal shunt (VPS) at the Bonsucesso General Hospital on October 22, 2013, with significant improvement of the neurological status. Approximately two months after placement of the CSF shunt, the patient once again presented with the same neurological symptoms and signs: CT scans showed recurrence of the hydrocephalus (Figure 5A, B) and an organized intrahepatic CSF collection, which indicated obstruction of the shunt (Figure 6A, B). On January 2014, the patient was given a new shunt replacement, and a few hours after the procedure, she passed away from an undetermined cause.Figure 4 \nBrain CT Scan on October 2013 showing exudative hydrocephalus.\n\n\nFigure 5 \nBrain CT scan on January 2014, showing intraventricular shunt in place and hydrocephalus.\n\n\nFigure 6 \nAbdomen CT Scan, January 2014, showing infrahepatic fluid collection (CSF).\n\n\n\n\nDiscussion\nA severe case of S. brasiliensis disseminated sporotrichosis in a young female HIV-positive patient from Rio de Janeiro State in Brazil is presented. The severity of the case is shown by the isolation of the strain S. brasiliensis from cultures of the skin, sputum, blood and central nervous system, and the probable fungal osteomyelitis present radiologically. Virulence studies in a mouse infection model have shown that S. brasiliensis is significantly more lethal and results in higher fungal burdens compared to S. schenckii as well as other examined Sporothrix spp. Recently this species was also associated to aggressive and atypical cases [10,19].\n\nSeverity was also related to the poor clinical and mycological response to itraconazole and amphotericin B (the latter in high dose) during many months. Although itraconazole has been shown to treat S. schenkii complex adequately in a cohort of patients from the Rio de Janeiro metropolitan area [20], the strain isolated from our patient was itraconazole resistant. This finding raises the point that the itraconazole resistance found over time in strains in Rio de Janeiro could be related to the use of itraconazole to treat sick cats, which are the main source of S. brasiliensis. In this specific case, the patient had received itraconazole for 45 days at the time the first isolates were submitted for fungal sensitivity testing, which results showed itraconazole resistance.\n\nThe use of a combination of antifungals has not been described for treating sporotrichosis; however, for other mycosis such as chromoblastomycosis, this combination has been of clinical benefit [21]. In vitro synergy was observed with the combination of terbinafine and itraconazole against one isolate of C. carrionii, and no antagonism was observed when amphotericin B was combined with terbinafine or itraconazole against agents of chromoblastomycosis [21]. Weekly cryotherapy sessions occurred for a long period and resulted in the improvement of infiltrated cutaneous lesions, therefore favoring the skin penetration by antifungal agents.\n\nPosaconazole is a modern azole and was chosen based on its good sensitivity profile to S. schenckii (and recently to S. brasiliensis) and its good penetration in bone and in the central nervous system [22,23]. Posaconazole showed both in vitro and in vivo action against a wide variety of fungi, including the rare and resistant ones. Several case reports describe success in the treatment of refractory fungal diseases or in patients who are unable to tolerate other drugs. Additionally, posaconazole can be given orally and is well tolerated [16]. Although the profile of voriconazole susceptibility in our isolates pointed us to a good sensitivity, based on previous studies that showed high MIC values in S. schenckii, associated with a lack of clinical studies, we decided not to use it, preferring posaconazole. In the present report, the use of posaconazole for two months coincided with fungal clearance from bi-monthly CSF cultures and a sustained response for 10 months.\n\nIt is not clear why the patient relapsed. It may be that posaconazole absorption was erratic, as has been suggested in other reports [24], and levels in CSF may have not been sufficient to suppress fungal growth. Alternatively, the isolate may have become resistant. These seem to be the most likely reasons because immune response had significantly improved at the time relapse occurred.\n\nThis case illustrates how serious sporotrichosis-HIV coinfection is and the need for frequent mycological surveillance, especially in cases where the central nervous system is involved. Also S. brasiliensis may present resistance to antifungals and is a virulent species.\n\nConclusions\nS. brasiliensis sporotrichosis and HIV coinfection is a serious condition. Treatment is an unresolved issue, but posaconazole seems to be an effective drug. There is need for frequent mycological surveillance, especially in cases where the central nervous system is involved. More studies are needed in order to confirm the benefit of posaconazole treatment in S. brasiliensis infections.\n\nConsent\nWritten informed consent was obtained from the patient for the publication of this report and any accompanying images.\n\nAdditional file\nAdditional file 1: Table A. Profile of antifungal susceptibility using different strains of S. brasiliensis. Table B. Evolution of CSF patterns in the patient with Sporotrichosis and HIV. Table C. Results of cultures, CD4 cell count and treatment in a patient with disseminated sporotrichosis and HIV infection. \n\n\n\nAbbreviations\nAMBAmphotericin B\n\nAZTZidovudine\n\nCSFCerebrospinal fluid\n\nCTComputed tomograph\n\nHIVHuman Immunodeficiency Virus\n\nICRInstitute of Clinical Research\n\nVPSventriculoperitoneal shunt\n\nAriane Gomes Paixão, Maria Clara Gutierrez Galhardo, Rodrigo de Almeida Paes, Estevão Portela Nunes, Marcelo Luiz Carvalho Gonçalves, Gisele Larias Chequer and Cristiane da Cruz Lamas contributed equally to this work.\n\nAuthors’ contributions\n\nPaixão and Lamas, wrote the case report and did the reviews; Almeida Paes and Galhardo contributed to the mycological data and to the discussion; Nunes, Gonçalves and Chequer contributed to the general outline of the case report.\n==== Refs\nReferences\n1. Marimon R Cano J Gené J Sutton DA Kawasaki M Guarro J Sporothrix brasiliensis, S. globosa, and S. mexicana, three new Sporothrix species of clinical interest J Clin Microbiol 2007 3 198 206 \n2. Schubach A Barros MB Wanke B Epidemic sporotrichosis Curr Opin Infect Dis 2008 21 2 129 133 10.1097/QCO.0b013e3282f44c52 18317034 \n3. Freitas DFS de Siqueira Hoagland B do Valle ACF Fraga BB de Barros MB de Oliveira Schubach A Sporotrichosis in HIV-infected patients: report of 21 cases of epidemic/endemic cat-transmitted sporotrichosis in Rio de Janeiro Brazil Med Mycol 2012 50 2 170 178 10.3109/13693786.2011.596288 \n4. Hardman S Stephenson I Jenkins DR Wiselka MJ Johnson EM Disseminated Sporothrix schenckii in a patient with AIDS J Infect 2005 51 e73 e77 10.1016/j.jinf.2004.07.001 16230207 \n5. Bustamante B Lama RJ Mosquera C Soto L Sporotrichosis in human immunodeficiency virus infected peruvian patients Infect Dis Clin Pract 2009 17 78 83 10.1097/IPC.0b013e31818add36 \n6. Silva-Vergara ML de Camargo ZP Silva PF Abdalla MR Sgarbieri RN Rodrigues AM Case report: disseminated Sporothrix brasiliensis infection with endocardial and ocular involvement in an HIV-infected patient Am J Trop Med Hyg 2012 86 477 480 10.4269/ajtmh.2012.11-0441 22403321 \n7. Almeida-Paes R de Oliveira MME Freitas DFS Do Valle ACF Zancopé-Oliveira RM Gutierrez-Galhardo MC Sporotrichosis in Rio de Janeiro, Brazil: Sporothrix brasiliensis is associated with atypical clinical presentations PLoS Negl Trop Dis 2014 8 9 e3094 10.1371/journal.pntd.0003094 25233227 \n8. Devi KR Devi MU Singh TN Devi KS Sharma SS Singh LR Emergence of sporotrichosis in Manipur Indian J Med Microbiol 2006 24 216 219 16912444 \n9. Song Y Li S-S Zhong S-X Liu Y-Y Yao L Huo S-S Report of 457 sporotrichosis cases from Jilin province, northeast China, a serious endemic region J Eur Acad Dermatol Venereol 2013 27 313 318 10.1111/j.1468-3083.2011.04389.x 22176524 \n10. Arrillaga-Moncrieff I Capilla J Mayayo E Marimon R Mariné M Gené J Different virulence levels of the species of Sporothrix in a murine model Clin Microbiol Infect 2009 15 651 655 10.1111/j.1469-0691.2009.02824.x 19624508 \n11. Penn CC Goldstein E Bartholomew WR Sporothrix schenckii meningitis in a patient with AIDS Clin Infect Dis 1992 15 741 743 10.1093/clind/15.4.741 1420699 \n12. Donabedian H O'Donnell E Olszewski C MacArthur RD Budd N Disseminated cutaneous and meningeal sporotrichosis in an AIDS patient Diagn Microbiol Infect Dis 1994 18 111 115 10.1016/0732-8893(94)90075-2 8062528 \n13. Edwards C Reuther WL 3rd Greer DL Disseminated osteoarticular sporotrichosis: treatment in a patient with acquired immunodeficiency syndrome South Med J 2000 93 803 806 10.1097/00007611-200093080-00013 10963514 \n14. Al-Tawfiq JA Wools KK Disseminated sporotrichosis and Sporothrix schenckii fungemia as the initial presentation of human immunodefiency virus infection Clin Infect Dis 1998 26 1403 1406 10.1086/516356 9636870 \n15. Freitas DF Do Valle ACF Da Silva MB Campos DP Lyra MR De Souza RV Sporotrichosis: an emerging neglected opportunistic infection in HIV-infected patients in Rio de Janeiro, Brazil PLoS Negl Trop Dis 2014 8 8 e3110 10.1371/journal.pntd.0003110 25166475 \n16. Kauffman CA Bustamante B Chapman SW Pappas PG Clinical Practice Guidelines for the Management of Sporotrichosis: 2007 Update by the Infectious Diseases Society of America Clin Infect Dis 2007 45 10 1255 1265 10.1086/522765 17968818 \n17. Borba-Santos LP, Rodrigues AM, Gagini TB, Fernandes GF, Castro R, de Camargo ZP, et al. Susceptibility of Sporothrix brasiliensis isolates to amphotericin B, azoles, and terbinafine. Med Mycol. 2014; 13. [Epub ahead of print]\n18. Galhardo MC De Oliveira RM Valle AC A Paes Rde Silvatavares PM Monzon A Molecular epidemiology and antifungal susceptibility patterns of Sporothrix schenckii isolates from a cat-transmitted epidemic of sporotrichosis in Rio de Janeiro Brazil Med Mycol 2008 46 2 141 151 10.1080/13693780701742399 \n19. Orofino-Costa R Unterstell N Carlos Gripp A de Macedo PM Brota A Dias E Pulmonary cavitation and skin lesions mimicking tuberculosis in a HIV negative patient caused by Sporothrix brasiliensis Med Mycol Case Rep 2013 2 65 71 10.1016/j.mmcr.2013.02.004 24432220 \n20. de Lima Barros MB Schubach AO De Vasconcellos Carvalhaes De Oliveira R Martins EB Teixeira JL Wanke B Treatment of cutaneous sporotrichosis with itraconazole–study of 645 patients Clin Infect Dis 2011 52 12 e200 e206 10.1093/cid/cir245 21628477 \n21. Queiroz-Telles F, Esterre P, Perez-Blanco M, Vitale RG, Salgado CG, Bonifaz A. Chromoblastomycosis: an overview of clinical manifestations, diagnosis and treatment. Med Mycol. 2009 Feb;47(1):3–15.\n22. Ottonelli Stopiglia CD, Magagnin CM, Castrillón MR, Mendes SD, Heidrich D, Valente P, et al. Antifungal susceptibilities and identification of species of the Sporothrix schenckii complex isolated in Brazil. Med Mycol. 2014 Jan;52(1):56–64.\n23. Rodrigues AM de Hoog GS de Cássia Pires D Brihante RS Sidrim JJ Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis BMC Infectious Dis 2014 14 219 10.1186/1471-2334-14-219 \n24. Gross BN Ihorst G Jung M Wäsch R Engelhardt M Posaconazole therapeutic drug monitoring in the real-life setting: a single-center experience and review of the literature Pharmacotherapy 2013 33 10 1117 1125 23864486\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1742-6405",
"issue": "12()",
"journal": "AIDS research and therapy",
"keywords": "AIDS; Amphotericin B; Posaconazole; Sporotrichosis",
"medline_ta": "AIDS Res Ther",
"mesh_terms": null,
"nlm_unique_id": "101237921",
"other_id": null,
"pages": "16",
"pmc": null,
"pmid": "25949269",
"pubdate": "2015",
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"references": "16912444;18317034;25166475;16230207;8062528;25233227;1420699;9636870;23964828;24432220;21859385;17968818;18324493;10963514;17687013;22176524;19624508;22403321;25394542;21628477;19085206;23864486;24755107",
"title": "The difficult management of disseminated Sporothrix brasiliensis in a patient with advanced AIDS.",
"title_normalized": "the difficult management of disseminated sporothrix brasiliensis in a patient with advanced aids"
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"abstract": "To raise awareness of cefotetan-induced hemolytic anemia, a known rare but serious side effect that occurred in 5 patients at our medical center.\nFive cases of cefotetan-induced hemolytic anemia, which presented over the period of a single year at our center, are described. In each case, hemolytic anemia was confirmed by testing for the presence of anti-cefotetan antibodies. Each case occurred approximately 1 to 2 weeks following exposure to the drug. All five patients survived. A brief review of drug-induced immune hemolytic anemia (DIIHA) is also discussed.\nDIIHA may be difficult to distinguish from other causes of hemolytic anemia, but should be included in the differential in patients exposed to medications associated with DIIHA. Once suspected, antibody testing should be performed, and once diagnosed, further exposure should be avoided.",
"affiliations": "Cedars Sinai Medical Center, Los Angeles, CA, USA.;Department of Pharmacy, Cedars Sinai Medical Center, Los Angeles, CA, USA.;Department of Pharmacy, Cedars Sinai Medical Center, Los Angeles, CA, USA.;Center for Drug Policy, Partners Healthcare, Somerville, MA, USA.;Department of Pharmacy, Cedars Sinai Medical Center, Los Angeles, CA, USA.;Division of Transfusion Medicine, Department of Pathology, Cedars Sinai Medical Center, Los Angeles, CA, USA.",
"authors": "Lim|Kathlyn|K|https://orcid.org/0000-0001-7915-2397;Tran|Hai|H|;Hirai-Yang|Angela|A|;Vakil|Niyati|N|;Marks|Gregory|G|;Klapper|Ellen|E|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015313:Cefotetan",
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"issue": "32(6)",
"journal": "Journal of pharmacy practice",
"keywords": "cefotetan; cephalosporins; cephamycins; drug-induced hemolytic anemia; hemolytic anemia",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000743:Anemia, Hemolytic; D000900:Anti-Bacterial Agents; D015313:Cefotetan; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "679-682",
"pmc": null,
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"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cefotetan-Induced Hemolytic Anemia: Case Series and Review.",
"title_normalized": "cefotetan induced hemolytic anemia case series and review"
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"abstract": "Atonic seizures are typically observed in younger children with Lennox-Gastaut syndrome and have been rarely described in adults. Herein we present a case of the adolescent-onset drug-resistant focal epilepsy in a 31-year-old woman with focal atonic seizures originating in the left posterior temporoparietal area and manifesting without aura with abrupt impairment of consciousness and slow falling down. According to the video-EEG monitoring, the seizure began with the medium amplitude spikes principally at T5 area evolving onto the left centroparietal area, which was immediately followed by the diffuse suppression of the background EEG activity. The underlying mechanism might be related to high-frequency electrical stimulation of the negative motor areas within the inferior frontal gyrus or anterior to the supplementary sensorimotor area.",
"affiliations": "Epilepsy Center, TMG Asaka Medical Center, Asaka, Saitama, Japan.;Epilepsy Center, TMG Asaka Medical Center, Asaka, Saitama, Japan; Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical Center, Asaka, Saitama, Japan; Department of Neurosurgery, Medical Center East, Tokyo Women's Medical University, Tokyo, Japan. Electronic address: kubota.yuichi@twmu.ac.jp.;Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical Center, Asaka, Saitama, Japan.;Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.;Epilepsy Center, TMG Asaka Medical Center, Asaka, Saitama, Japan.",
"authors": "Nagino|Naoto|N|;Kubota|Yuichi|Y|;Nakamoto|Hidetoshi|H|;Ito|Susumu|S|;Oguni|Hirokazu|H|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.clineuro.2021.106776",
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"journal": "Clinical neurology and neurosurgery",
"keywords": "Focal atonic seizure; Focal epilepsy; Negative motor area; Video-EEG monitoring",
"medline_ta": "Clin Neurol Neurosurg",
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"pages": "106776",
"pmc": null,
"pmid": "34192624",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Focal atonic seizures originated in the posterior temporoparietal area: A case report.",
"title_normalized": "focal atonic seizures originated in the posterior temporoparietal area a case report"
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"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-01109",
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"abstract": "BACKGROUND\nA proportion of deliberate self-poisoning (DSP) patients present repeatedly to the emergency department (ED). Understanding the characteristics of frequent DSP patients and their presentation is a first step to implementing interventions that are designed to prevent repeated self-poisoning.\n\n\nMETHODS\nAll DSP presentations to three networked Australian ED's were retrospectively identified from the ED electronic medical record and hospital scanned medical records for 2011. Demographics, types of drugs ingested, emergency department length of stay and disposition for the repeat DSP presenters were extracted and compared to those who presented once with DSP in a one year period. Logistic regression was used to analyse repeat versus single DSP data.\n\n\nRESULTS\nThe study determined 755 single presenters and 93 repeat DSP presenters. The repeat presenters contributed to 321 DSP presentations. They were more likely to be unemployed (61.0% versus 39.9%, p = 0.008) and have a psychiatric illness compared to single presenters (36.6% versus 15.5%, p < 0.001). Repeat presenters were less likely to receive a toxicology consultation (11.5% versus 27.3%, p < 0.001) and were more likely to abscond from the ED (7.5% versus 3.4%, p = 0.004). Repeat presenters were more likely to ingest paracetamol and antipsychotics than single presenters. The defined daily dose for the most common antipsychotic ingested, quetiapine, was less in the repeat presenter group (median 1.9 [IQR: 1.3-3.5]) compared with the single presenter group (4 [1.4-9.5]), (OR 0.85, 95% CI 0.74-0.99).\n\n\nCONCLUSIONS\nPatients who present repeatedly to the ED with DSP have pre-existing disadvantages, with increased likelihood of being unemployed and having a mental illness. These patients are also more likely to have health service inequities given the greater likelihood to abscond from the ED and lower likelihood of receiving toxicology consultation for their DSP. Early recognition of repeat DSP patients in the ED may facilitate the development of individualised care plans with the aim to reduce repeat episodes of self-poisoning and subsequent risk of successful suicide.",
"affiliations": "Monash Emergency, Dandenong Hospital, Monash Health, David Street, Dandenong, Victoria, Australia. andis.graudins@monashhealth.org.",
"authors": "Martin|Catherine A|CA|;Chapman|Rose|R|;Rahman|Asheq|A|;Graudins|Andis|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1471-227X-14-21",
"fulltext": "\n==== Front\nBMC Emerg MedBMC Emerg MedBMC Emergency Medicine1471-227XBioMed Central 1471-227X-14-212514869210.1186/1471-227X-14-21Research ArticleA retrospective descriptive study of the characteristics of deliberate self-poisoning patients with single or repeat presentations to an Australian emergency medicine network in a one year period Martin Catherine A 12cathy.martin@monashhealth.orgChapman Rose 12rose.chapman@monashhealth.orgRahman Asheq 12asheq.rahman@monashhealth.orgGraudins Andis 234andis.graudins@monashhealth.org1 School of Nursing, Midwifery and Paramedicine, Australian Catholic University, Victoria Parade, Fitzroy, Victoria, Australia2 Monash Emergency, Dandenong Hospital, Monash Health, David Street, Dandenong, Victoria, Australia3 School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia4 Monash Clinical Toxicology and Addiction Medicine Service, Monash Health, David Street, Dandenong, Victoria, Australia2014 23 8 2014 14 21 21 25 2 2014 13 8 2014 Copyright © 2014 Martin et al.; licensee BioMed Central Ltd.2014Martin et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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\nA proportion of deliberate self-poisoning (DSP) patients present repeatedly to the emergency department (ED). Understanding the characteristics of frequent DSP patients and their presentation is a first step to implementing interventions that are designed to prevent repeated self-poisoning.\n\nMethods\nAll DSP presentations to three networked Australian ED’s were retrospectively identified from the ED electronic medical record and hospital scanned medical records for 2011. Demographics, types of drugs ingested, emergency department length of stay and disposition for the repeat DSP presenters were extracted and compared to those who presented once with DSP in a one year period. Logistic regression was used to analyse repeat versus single DSP data.\n\nResults\nThe study determined 755 single presenters and 93 repeat DSP presenters. The repeat presenters contributed to 321 DSP presentations. They were more likely to be unemployed (61.0% versus 39.9%, p = 0.008) and have a psychiatric illness compared to single presenters (36.6% versus 15.5%, p < 0.001). Repeat presenters were less likely to receive a toxicology consultation (11.5% versus 27.3%, p < 0.001) and were more likely to abscond from the ED (7.5% versus 3.4%, p = 0.004). Repeat presenters were more likely to ingest paracetamol and antipsychotics than single presenters. The defined daily dose for the most common antipsychotic ingested, quetiapine, was less in the repeat presenter group (median 1.9 [IQR: 1.3-3.5]) compared with the single presenter group (4 [1.4-9.5]), (OR 0.85, 95% CI 0.74-0.99).\n\nConclusion\nPatients who present repeatedly to the ED with DSP have pre-existing disadvantages, with increased likelihood of being unemployed and having a mental illness. These patients are also more likely to have health service inequities given the greater likelihood to abscond from the ED and lower likelihood of receiving toxicology consultation for their DSP. Early recognition of repeat DSP patients in the ED may facilitate the development of individualised care plans with the aim to reduce repeat episodes of self-poisoning and subsequent risk of successful suicide.\n==== Body\nBackground\nDeliberate self-poisoning (DSP) is a common cause for frequent presentations to the emergency department (ED), placing an increased burden on the ED [1]. Self-poisoning is the most common method of deliberate self-harm [2]. Presentation with DSP is often perceived negatively by staff involved in the treatment of these patients [3]. Staff attitudes and the patient’s ED experience have been shown to influence the patient’s decision to stay for treatment [4]. A poor ED experience may also exacerbate repeated self-harm behaviour [4]. In addition, an adverse experience may influence whether the patient seeks medical assistance for future self-harm [4]. These findings are significant considering that repeat self-poisoning behaviour results in an increased risk of subsequent successful suicide [5,6].\n\nIn an era of increasing demand on the ED [7] and introduction of efficiency initiatives such as the 4-hour rule [8], understanding and describing frequent presenters is an important first step towards development and implementation of strategies to reduce re-attendances. Therefore, the aim of this study was to examine presentations to three Australian ED’s, in a one-year period by repeat DSP status. Characteristics examined were 1) patient characteristics, including age, gender, employment and psychiatric history; 2) presentation characteristics, including length of stay (LOS) data and disposition from the ED; 3) ED interventions with occurrence of psychiatric and toxicological consultations; and 4) type and amount of medications taken in the DSP.\n\nMethods\nThis study was a retrospective chart review of DSP presentations to Monash Health’s three emergency departments from January 1st 2011 to December 31st 2011. Ethical approval for the study was obtained from Monash Health Human Research and Ethics Committee and Australian Catholic University. The definition of DSP was based on National Institute for Health and Clinical Excellence (NICE) definition of self-harm where self-harm is defined as ‘any act of self-poisoning or self-injury carried out by an individual irrespective of motivation’ [4]. Repeat poisoning presentations (RPP) were defined as greater than one presentation with DSP in 2011 to any of the three ED’s. A single presentation in 2011, following an episode of DSP, was termed single poisoning presentation (SPP).\n\nA search of the Monash Health’s emergency department electronic database (SYMPHONY Version 2.29, Ascribe plc, Bolton, UK) was conducted to identify DSP presentations. Patients were included if aged ≥ 18 years presenting to Monash Health’s three EDs in 2011 with a presenting complaint of 1) Mental Health involuntary assessment required, 2) Mental Health voluntary requesting treatment or self-harm, 3) overdose/ingestion/poison/toxic exposure were included. The triage notes of each presentation were then screened and those deemed as accidental, recreational and non-DSP presentations were removed. This included presentations requesting psychiatric help or presentations for irrational/disturbed behaviour. Each DSP patient identified from the initial screening then had all their ED presentations in 2011 examined in Scanned Medical Records (SMR) for any missed DSP presentations. Emergency and hospital information about each DSP presentation was obtained from Monash Health SMR. This was then entered into a clinical database specifically designed for toxicology data acquisition. The database included information about the patient’s demographics, previous psychiatric history, toxins taken and amounts, admission and discharge dates, toxicology and psychiatric consults, critical care required, ventilation support required, discharge outcome and follow-up.\n\nAge, employment, and marital status were determined at the index visit. The index visit was defined as the first presentation with DSP to the ED in 2011. The unemployed group included those patients who had identified themselves as unemployed or were on a disability support pension. These items were categorised together as a disability support pension may represent “hidden unemployment” [9]. Employement status distribution was analysed by repeat status. A secondary analysis was also undertaken where patients were categorised into unemployed and ‘other’. ‘Other’ was defined as either being either a student, employed, retired or undertaking home duties. Marital status was categorised into married/de facto relationship or single (single/widowed/separated/divorced).\n\nPrevious psychiatric history was obtained from emergency Enhanced Crisis Assessment Treatment Team (ECATT) or psychiatric notes from SMR. A person was deemed to have a previous psychiatric illness if they had documented personality disorder, bipolar affective disorder or schizophrenia.\n\nLOS was determined for 1) patients discharged home from the ED, 2) total hospital LOS for patients admitted to a general ward without requiring critical care stay (time spent in ED and general ward stay) and 3) total hospital stay for patients who required critical care stay (time spent in ED, critical care ward and general ward stay). LOS in the ED was defined as the time spent in ED and short stay unit (observation area of the ED) and was determined as the time recorded on arrival to the ED and discharge time from the ED. Patients staying overnight in ED short-stay/observation unit were considered non-admitted patients. LOS for patients admitted to the hospital was determined from SMR as ED arrival time to the time of discharge from the hospital documented in the patients’ medical records. If no discharge time was documented then 1400 hrs was entered into the clinical database. This time was chosen as it was the median discharge time determined for patients discharged from hospital wards with a documented discharge time.\n\nDrugs ingested were categorised into major drug classes. The most common specific agents in each drug class were also examined. Drugs were described by presentation, that is, what percentage of presentations involved ingestion of a particular class of medication. Daily defined dose (DDD) was determined from the Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) index 2014 World Health Organisation Collaborating Centre for Drug Statistics Methodology website [10]. Comparison of DDD between RPP and SPP was undertaken. A separate analysis of the DDD was also undertaken for patients with multiple frequent DSP presentations to the ED compared with SPP. Multiple frequent DSP attendance was defined as five or more presentations with DSP in 2011 [11].\n\nSummary categorical statistics are expressed as number (percentage). Continuous data were examined for normality using the Shapiro-Wilk and Shapiro-Francia tests. Summary continuous statistics are expressed as mean ± standard deviation if normally distributed or median [inter-quartile range (IQR)] if not. Univariate logistic regression was used to analyse the relationship between all potential predictor variables and the binary outcome variable, RPP versus SPP. The effect size was described as odds ratio (OR) and 95% confidence interval (CI). Statistical significance was considered if the 95% CI included the value one. Hosmer-Lemeshow goodness of fit test was used to assess fit of logistic regression model. Variables were also examined for frequency of missing data. Except for LOS missing data, where single imputation was performed as explained above, complete case analysis was used to handle missing data [12]. Data analysis was performed using Stata version 12 (Stata Corporation, TX, USA).\n\nResults\nPresentations of DSP\nA total of 1076 DSP presentations were identified for 2011 (see Figure 1). The majority of these presentations were SPP patient presentations (n = 755, 89.0%) in 2011; whereas 93 RPP patients (11.0%) contributed to 321 presentations (see Table 1). The RPP frequency ranged from 2 to 31 presentations, with a median number of 2 [IQR: 2-3] presentations. Sixty-four patients presented twice; 26 patients presented 3 to 9 times, which contributed to 116 presentations and three patients contributed to 77 presentations in 2011. Forty-two percent of the SPP’s ingested more than one toxin in the DSP, whereas 45% of the RPP group ingested more than one toxin (OR 1.13, 95% CI: 0.65-1.98).\n\nFigure 1 Flowchart summarizing how DSP presentations to the ED in 2011 were determined. DSP: deliberate self-poisoning, ED: Emergency Department, SMR: Scanned Medical Records.\n\nTable 1 Characteristics of patients presenting with deliberate self-poisoning in 2011\n\n \tSPP\tRPP\tOR\n¥\n\t95% CI\n¥\n\t\nNumber\t755\t93\t \t \t\nAge\t35.0 [23.7-45.0]\t37.0 [26.1-43.6]\t0.99\t0.98-1.01\t\nFemale\t485 (64.2)\t60 (64.5)\t1.10\t0.70-1.72\t\nMarital Status\t \t \t \t \t\nMarried/ Defacto\t274 (39.4)\t30 (32.6)\t1.13\t0.47-1.18\t\nSingle€\t422 (60.6)\t62 (67.4)\t \t \t\nEmployment\t \t \t1.17§\t0.97-1.41§\t\nEmployed\t237 (40.7)\t22 (28.6)\t \t \t\nStudent\t50 (8.6)\t3 (3.9)\t \t \t\nUnemployed\t232 (39.9)\t47 (61.0)\t \t \t\nRetired/Pensioner\t20 (3.4)\t0 (0)\t \t \t\nHome duties\t43 (7.4)\t5 (6.5)\t \t \t\nUnemployedδ\t232 (39.9)\t47 (61.0)\t2.36\t1.45-3.85\t\nPsychiatric history£\t120 (15.5)\t34 (36.6)\t3.05\t1.92-4.85\t\nData presented as number (%) or median [inter-quartile range]. ¥Univariate logistic regression test of SPP versus; €Single includes widows/separated/divorced; §Statistical test of employment distribution; δStatistical test of unemployed versus ‘others’; £Psychiatric history includes personality disorder, bipolar affective disorder or schizophrenia. SPP: Single poisoning presentation, RPP: Repeat poisoning presentation.\n\nCharacteristics of DSP patients\nNo difference was found in the distribution of employment status between the RPP and SPP groups, however when the patients were categorised into unemployed and ‘other’ the RPP patients were more likely to be unemployed than the SPP group (OR 2.36, 95% CI: 1.45-3.85). The RPP patients were more likely to have a previous diagnosis of personality disorder, bipolar affective disorder or schizophrenia than SPP patients (OR 3.05, 95% CI: 1.92-4.85). Although median age was not statistically different between the SPP and RPP groups the RPP group were all younger than 60 years of age (see Table 1).\n\nTable 2 shows that RPP patients were more likely to abscond from the ED and were less likely to have received a Toxicology consultation for their acute poisoning presentation.\n\nTable 2 Characteristics of ED disposition, consultations and length of stay\n\n \tSPP\tRPP\tOR\n¥\n\t95% CI\n¥\n\t\nNumber\t755\t321\t \t \t\nED Disposition\t \t \t \t \t\nHome\t453 (60.0)\t187 (58.3)\t0.89\t0.64-1.23\t\nICU/HDU/CCU\t54 (7.2)\t18 (5.6)\t0.77\t0.44-1.34\t\nVentilated\t37 (4.9)\t8 (2.5)\t0.50\t0.23-1.08\t\nGeneral ward\t86 (11.4)\t40 (12.5)\t1.11\t0.74-1.65\t\nMental Health\t99 (13.1)\t38 (11.8)\t0.90\t0.60-1.34\t\nInvoluntary\t32 (4.2)\t13 (4.1)\t0.95\t0.49-1.84\t\nAbsconded\t26 (3.4)\t24 (7.5)\t2.28\t1.28-4.05\t\nSelf-discharge\t25 (3.3)\t12 (3.7)\t1.13\t0.56-2.28\t\nOther\t12 (1.6)\t2 (0.6)\tNT\t \t\nConsultations\t \t \t \t \t\nPsychiatric consult\t457 (60.5)\t193 (60.1)\t0.98\t0.75-1.28\t\nToxicology consult\t205 (27.3)\t37 (11.5)\t0.35\t0.24-0.51\t\nLOS\t \t \t \t \t\nED€ (hours)\t6.5 [4.4-10.8]\t7.2 [4.3-12.6]\t1.02\t0.99-1.06\t\nNon critical care admission§ (days)\t1.9 [1.3-3.8]\t1.8 [1.6-2.8]\t0.85\t0.70-1.04\t\nCritical care admissionδ (days)\t2.6 [1.8-3.9]\t4.8 [2.5-5.9]\t1.15\t1.01-1.31\t\nData presented as number (%) or median [interquartile range]. ¥Univariate logistic regression test of SPP versus RPP; €LOS in ED for patients discharged home from ED. §Total hospital LOS, including ED for patients admitted to a general ward; δTotal hospital LOS for patients requiring a critical care admission (CCCU/ICU/HDU), includes ED and ward stay post critical care.. SPP: Single poisoning presentation, RPP: Repeat poisoning presentation, ICU: Intensive care unit, HDU: High dependency unit, CCU: Coronary care unit, DSP: Deliberate self-poisoning, LOS: Length of stay, ED: Emergency department includes short-stay area, NT: Not tested.\n\nLength of stay\nAlthough not statistically different, the ED LOS for patients who were discharged home from the ED tended to be higher in the RPP group (Table 2). The total hospital stay for patients requiring critical care admission was higher in the RPP group compared with the SPP group (OR 1.15, 95% CI: 1.10-1.31). One patient in the RPP group contributed to three critical care stays.\n\nType and amount of medication used in DSP\nAs a group, benzodiazepines were the most commonly reported toxicant ingested in DSP in 2011 for both the SPP and RPP groups (see Table 3). Diazepam was the most commonly ingested benzodiazepine in both groups but the RPP group had higher DSP presentations associated with diazepam than the SPP group (OR 1.66, 95% CI 1.23-2.25). RPP’s were more likely to ingest paracetamol than SPP patients (OR 1.37, 95% CI: 1.03-1.84) and less likely to take antidepressants (OR 0.64, 95% CI: 0.47-0.88) in overdose. Co-ingestion with alcohol during DSP was high and similar for both groups. Although not statistically different, the RPP patients tended to have a higher number of overdose presentations associated with antipsychotic agents. Quetiapine was the most common antipsychotic ingested for both groups. However, RPP patients more commonly ingested quetiapine for DSP (OR 1.63, 95% CI: 1.06-2.50). Interestingly, the median ingested DDD was lower in the RPP group than for SPP group (median 1.9 [IQR: 1.3-3.5] versus 4 [1.4-9.5], OR 0.85 95% CI: 0.74-0.99) (see Table 4). There was no significant difference in reported median DDD ingested between the two groups for any of the other classes of medications.\n\nTable 3 Comparison of drugs ingested by class for single and repeat presenters\n\nDrug Class\tMost common specific agents in class\tSPP\n€\npresentations (N = 752)\tRPP\n€\npresentations (N = 315)\tOR\n¥\n\t95% CI\n¥\n\t\nBenzodiazepines\t \t296 (39.4)\t135 (42.9)\t1.12\t0.85-1.46\t\n \tDiazepam\t146 (19.4)\t90 (28.6)\t1.66\t1.23-2.25*\t\n \tTemazepam\t74 (9.8)\t24 (7.6)\t0.76\t0.47-1.22\t\n \tAlprazolam\t64 (8.5)\t21 (6.7)\t0.76\t0.46-1.28\t\nAlcohol (Beverage)\t \t245 (32.5)\t95 (30.0)\t0.89\t0.67-1.19\t\nParacetamol\t \t179 (23.8)\t96 (30.5)\t1.37\t1.03-1.84*\t\nAntidepressants\t \t217 (28.9)\t65 (20.6)\t0.64\t0.47-0.88*\t\nSSRI£\t \t89 (11.8)\t20 (6.3)\t0.51\t0.31-0.84*\t\nEscitalopram/Sertraline\t51 (6.8)\t15 (4.8)\t0.69\t0.38-1.24\t\nSNRI\tVenlafaxine/Desvenlafaxine/Duloxetine§\t47 (6.3)\t19 (6.0)\t0.96\t0.56-1.67\t\nTCA\t \t39 (5.2)\t7 (2.2)\tNT\t \t\nAntipsychotics\t \t99 (13.2)\t55 (17.5)\t1.40\t0.97-2.00\t\n \tQuetiapine\t60 (8.0)\t39 (12.4)\t1.63\t1.06-2.50*\t\n \tOlanzapine\t11 (1.5)\t7 (2.2)\tNT\t \t\nNSAIDs\t \t81 (10.8)\t30 (9.5)\t0.87\t0.56-1.36\t\nOther drugs\t \t266 (35.4)\t100 (31.8)\t0.85\t0.64-1.12\t\n \tOpioids\t61 (8.1)\t11 (3.5)\t0.41\t0.21-0.79*\t\n \tZolpidem/Zopiclone\t32 (4.3)\t13 (4.1)\t0.97\t0.50-1.87\t\nData presented as number (%). ¥Univariate logistic regression test of SPP versus RPP, €Data missing: three for single presenters and 6 for repeat presenters, information either not in scanned medical records or described as unknown, *Significant difference, £Data presented for all SSRI and the three most common ingested, §Only these SNRI’s ingested in DSP. SPP: Single poisoning presentation, RPP: Repeat poisoning presentation, OR: Odds ratio, CI: Confidence interval, SSRI: Serotonin-specific reuptake inhibitor, SNRI: Serotonin–norepinephrine reuptake inhibitor, TCA: Tricyclic antidepressants, NSAID: Non-steroidal anti-inflammatory, NT: Not tested. Note: frequencies add up to greater than 100% as DSP may be associated with more than one toxin.\n\nTable 4 Comparison of amount of drug ingested for single and repeat deliberate self-poisoning presenters defined by daily dose of drug (DDD)\n\n \tN\tSPP\tN\tRPP\tOR\n¥\n\t95% CI\n¥\n\t\nBenzodiazepine\t217\t6 [4-14]\t101\t10 [5-16]\t1.01\t1.00-1.02\t\nDiazepam\t103\t6 [3-15]\t68\t10 [4.4-15]\t1.02\t0.99-1.05\t\nTemazepam\t67\t5.5 [3-10]\t20\t5.5 [2.8-12.3]\t0.99\t0.91-1.08\t\nAlprazolam\t35\t10 [5-20]\t13\t24 [20-32]\t1.01\t1.00-1.03\t\nParacetamol\t162\t2.2 [1.3-4.4]\t85\t3.3 [1.7-5.0]\t1.06\t0.98-1.15\t\nAntidepressant\t147\t15 [6-28]\t42\t20 [10-32]\t1.01\t0.99-1.02\t\nSSRI\t100\t15 [7-28]\t25\t20 [10-25]\t1.01\t0.99-1.02\t\nAntipsychotic\t61\t4.5 [1.8-10.5]\t39\t3 [1.3-5]\t0.98\t0.93-1.03\t\nQuetiapine\t40\t4 [1.4-9.5]\t26\t1.9 [1.3-3.5]\t0.85\t0.74-0.99*\t\nAnticonvulsant\t25\t4.5 [1.3-13.3]\t12\t7.3 [3.3-12.8]\t1.00\t0.92-1.09\t\nData presented as median [interquartile range]. ¥Univariate logistic regression test of SPP versus RPP, *Statistically significant. N: Number, SPP: Single poisoning presentation, RPP: Repeat poisoning presentation, OR: Odds ratio, CI: Confidence interval.\n\nFrequent DSP attenders\nA separate analysis for those with five or more DSP presentations in 2011 showed that these patients took more DDDs of Paracetamol compared to SPP patients (median 3.8 [IQR: 2.6-6] versus 2.2 [IQR: 1.3-4.4]; OR 1.14, 95% CI: 1.04-1.25).\n\nInpatient mortality from DSP\nThere were no inpatient deaths as a result of DSP during the study period.\n\nMissing data\nThe majority of variables examined had none or few missing data points as data is collected for key performance indicators for the ED. Variables with the most missing data included marital status (6.8%), employment status (19.6%), toxicology consultation (12.9%) and psychiatric consultations (23.2%). For the variables marital status and employment, the majority of missing data occurred in the SPP group.\n\nDiscussion\nThis study confirms the results of a number of previous studies examining DSP repeat presenters observing that, this patient group was more likely to be unemployed and have a mental health illness compared to those presenting only once [13,14]. This study found that RPP patients were more likely to be disadvantaged in other ways such as, they were more likely to abscond before care was completed and less likely to have a toxicology assessment even though similar doses of drug were ingested for most classes of medication. A similar severity of poisoning in both patient groups is suggested by the fact that ingested drug dose for most toxins was similar and the frequency of ICU admission was also not significantly different.\n\nThe proportion of DSP patients with recurrent presentations in the same year in this study was similar to that reported in other studies [14-17]. However, two studies reported higher re-presentation proportions [13,18]. One of these reported that 21% of DSP patients had recurrent presentations; however this was a retrospective study with a study period of ten years, which may have influenced the result [13]. The other study reported that 18% of DSP patients re-presented. The difference in representation proportion may be due to the prospective nature of the study as DSP patients, who met the study inclusion criteria, were consented to be followed over time [18].\n\nSimilar to our study, previous studies have also found that RPP patients were more likely to be unemployed [13,18,19], single [14], live alone [20], or have a psychiatric history [13,18,19]; particularly personality disorder or schizophrenia [19] than SPP patients.\n\nGender and age differences in RPP patients have been less consistent in previous studies, with two studies finding no gender influence on RPP behaviour [15,16]. However, two other studies found the opposite, with female gender being a significant factor in RPP behaviour [13,14]. Additionally, we found no association with age and RPP status. This is consistent with another Australian study [14]. Other studies have noted that RPP patients tended to be older than SPP patients [15,19]. It is possible that there are geographical and cultural differences between studies. For example, the catchment area of the present study included a large proportion of people born overseas [21]. However, it was beyond the scope of this study to examine this further.\n\nThis study also found no difference between SPP and RPP patients in their disposition from the ED. However, an older study of self-poisoning found that RPP patients were less likely to be admitted to a hospital ward than SPP patients [15]. As RPP patients had lower triage category scores than SPP patients the authors hypothesised that RPP patients were less sick and hence less likely to be admitted.\n\nDifferences in length of stay between SPP and RPP groups have not been well characterised. A study undertaken in 1999 examined hospital LOS of the index visit for the RPP group versus the SPP group. It was found that the RPP group had statistically significant longer hospital LOS than the SPP group, but the authors felt the difference was not clinically significant [14]. Our study found that RPPs had a significantly longer LOS if critical care admission was required. However, the number of critical care admissions in the RPP group was not large and one patient contributed to three critical care admissions. In older studies of DSP patients, the proportion of patients admitted to hospital was considerably greater than in this study and other more contemporary studies. A study from 20 years ago reported that 70% of all DSP patients were admitted to an in-patient bed [16], which was considerably higher than in the present study. The lower in-patient admission rate may reflect the current practice of utilising ED short stay or observation units for patients with projected short lengths of stay (<48 hours) as is often the case with DSP patients.\n\nVery few studies have examined whether the characteristics of toxicants ingested by SPP or RPP patients vary. In a retrospective study that examined the characteristics of patients presenting with DSP to a South Korean ED over a nine year period; the authors found that RPP patients were more likely to ingest sedatives or antidepressants whereas SPP patients tended to use sedatives or analgesics [13]. In an Australian study, the RPP characteristics for patients presenting to a Victorian hospital over a two-year period between 1993 and 1994 were examined. Those with greater than one presentation with DSP tended to take a single drug in the overdose compared to those that presented once [15]; this was not the case in this present study. However, similar to the current study, paracetamol overdose was higher in the RPP group. In another Australian study the class of drug ingested at the index visit in SPP and RPP patients was examined within one year period [14]. Benzodiazepines were most commonly ingested followed by paracetamol in both groups. In the RPP group, the third most common drug class was antipsychotics, whereas for the SPP group it was antidepressants [14]. This observation parallels the results of our study. Our study shows that RPP had higher use of quetiapine associated DSP but the ingested dose was lower in this group. Repeat DSP is often associated with pre-existing mental health conditions, such as schizophrenia and bipolar affective disorder [19], which allows easier access to antipsychotic prescription medication such as quetiapine. Concerns about the trend of increased rates of quetiapine prescribing and ambulance call outs associated with quetiapine use in recent years have been raised in Australia [22]. This study also reveals that although there was no significant difference in overall benzodiazepine ingestion between the two groups, the RPP group had statistically higher use of diazepam. This may reflect greater access to this drug in recurrent presenters.\n\nAlthough there are methodological differences and over a decade has lapsed between this current study and the two previous Australian studies, they all show that the top four classes of drugs used in DSP, excluding alcohol, are benzodiazepine, paracetamol, antidepressants and antipsychotics [14,15]. The impulsivity associated with DSP [23] may explain why paracetamol was the second most common ingested medication for patients who had repeated presentations following DSP in this current study.\n\nThis study confirms the results of other studies that alcohol co-ingestion is common in patients with DSP [1,23]. This current study found no difference in frequency of alcohol co-ingestion between the two groups, however, we did not examine chronic alcohol use as a predictor for RPP.\n\nWe recently reported that ED nursing and medical staff felt empathy towards DSP patients who presented once but frustration towards DSP patients who presented repeatedly [24,25]. The association of psychosocial history, unemployment and psychiatric illness, and more frequent absconding behaviour from the ED may result in staff feeling that they are dealing with patients who are difficult to manage, do not take responsibility for their actions, and do not want help. This finding is especially significant for those patients who re-present on numerous occasions. Many of the RPP patients were considered to be attention seeking, taking up resources and some staff queried whether the ED was the right place for these patients [24,25]. The sub-analysis of the most frequent DSP attenders suggested that the severity of poisoning was similar to the single presenters. For those that ingested paracetamol the ingested dose was greater in the frequent repeat presenters, with a median DDD of 3.8. This is within the range of expected toxic ingested dose requiring antidote treatment [26]. This suggests risk assessment in the ED is important in this group.\n\nThe ED has an important role in the recognition of patients at risk of recurrent self-poisoning and re-presentation to hospital. Detection of patients at risk of re-harming may allow the implementation of evidence based interventions designed to reduce this phenomenon. This may include measures such as frequent postcards sent to DSP patients, telephone follow up, or follow up in self-harm clinics once discharged [27]. An increase in the severity of repeat DSP is associated with increased risk of future suicide completion [28]. As a result, a database of DSP patient presentations could identify those in the RPP group. Coupled with regular multidisciplinary clinical meetings, this would facilitate the development and implementation of specific care plans for patients.\n\nThe retrospective nature of this study meant that we were reliant on the integrity of the medical record data. The variables marital and employment status, documentation of toxicology and psychiatric consult, all had high levels of missing data, which may have biased the results. Variables regarding the type and amount of medications used in DSP episodes were not collected for some patients, such as those with altered conscious state, which may also have influenced the results. We used the ED presenting diagnosis to determine self-poisoning presentations and may have missed some patients presenting with DSP. Also, we only examined repeat presentations in a one year period and some patients in the single presentation group may have re-presented beyond the boundaries of the study time-frame. Patients may have presented to other hospital networks during the study period, which means that patients identified as single presentations may actually be recurrent presenters. While there were no in-hospital deaths in this cohort, we did not analyse coroner’s data to assess for completed suicide following DSP in the community. Variables that may have helped to explain repeater behaviour were not collected for this study. These included previous DSP episodes, drug and alcohol history, and associated self-injury with the DSP. Therefore, further empirical studies investigating those patients who present to the ED following repeated DSP presentations are required.\n\nConclusion\nOur study provides more contemporary information regarding the characteristics of patients who present with repeated self-poisoning in an Australian setting. This patient group has pre-existing disadvantages, with increased likelihood of being unemployed and having a pre-existing mental health problem. They are also more likely to have health service inequities given the greater likelihood to abscond from the ED and lower likelihood of receiving toxicology consultation for their poisoning. However, repeat presenters had a similar severity of DSP as determined by frequency of critical care admission and similar doses and classes of drug ingested compared to single presenters. ED staff are well placed to facilitate the development and implementation of evidence based intervention and specific care plans for these patients.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nCM carried out data input, statistical analysis and interpretation of data; and drafting and revising manuscript. RC conceived the study and participated in data interpretation, drafting and revising manuscript. AG carried out data input, and participated in data interpretation, drafting and revising manuscript. AR carried out drafting and revising manuscript. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-227X/14/21/prepub\n\nAcknowledgements\nThe authors wish to acknowledge the assistance of Ian Denney with regard to the formatting of the figure used in this article.\n==== Refs\nHendrix L Verelst S Desruelles D Gillet JB Deliberate self-poisoning: characteristics of patients and impact on the emergency department of a large university hospital EMJ 2013 30 1 e9 10.1136/emermed-2011-201033 22328636 \nGunnell D Bennewith O Peters TJ House A Hawton K The epidemiology and management of self-harm amongst adults in England J Public Health 2005 27 67 73 10.1093/pubmed/fdh192 \nSaunders KE Hawton K Fortune S Farrell S Attitudes and knowledge of clinical staff regarding people who self-harm: a systematic review J Affect Disord 2012 139 205 216 10.1016/j.jad.2011.08.024 21925740 \nNational Institute for Clinical Excellence Self-harm: The short-term physical and psychological management and secondary prevention of self-harm in primary and secondary care National Clinical Practice Guideline Number 16 2004 Level 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT: National Institute for Health and Clinical Excellence \nCrandall C Fullerton-Gleason L Aguero R LaValley J Subsequent suicide mortality among emergency department patients seen for suicidal behavior Acad Emerg Med 2006 13 435 442 10.1111/j.1553-2712.2006.tb00322.x 16531601 \nSuominen K Isometsa E Suokas J Haukka J Achte K Lonnqvist J Completed suicide after a suicide attempt: a 37-year follow-up study Am J Psychiatr 2004 161 562 563 10.1176/appi.ajp.161.3.562 14992984 \nLowthian JA Curtis AJ Jolley DJ Stoelwinder JU McNeil JJ Cameron PA Demand at the emergency department front door: 10-year trends in presentations Med J Aust 2012 196 128 132 10.5694/mja11.10955 22304608 \nMason S Weber EJ Coster J Freeman J Locker T Time patients spend in the emergency department: England’s 4-hour rule-a case of hitting the target but missing the point? Ann Emerg Med 2012 59 341 349 10.1016/j.annemergmed.2011.08.017 22088495 \nCai L Gregory B Unemployment duration and inflows onto the disability support pension program: evidence from FaCS LDS data Aust Econ Rev 2005 38 233 252 10.1111/j.1467-8462.2005.00371.x \nAnatomical Therapeutic Chemical/ Defined Daily Dose (ATC/DDD) index 2014 World Health Organisation Collaborating Centre for Drug Statistics Methodology http://www.whocc.no/atc_ddd_index/ \nLocker TE Baston S Mason SM Nicholl J Defining frequent use of an urban emergency department Emerg Med J 2007 24 398 401 10.1136/emj.2006.043844 17513534 \nGroenwold RH Donders AR Roes KC Harrell FE JrMoons KG Dealing with missing outcome data in randomized trials and observational studies Am J Epidemiol 2012 175 210 217 10.1093/aje/kwr302 22262640 \nOh SH Park KN Jeong SH Kim HJ Lee CC Deliberate self-poisoning: factors associated with recurrent self-poisoning Am J Emerg Med 2011 29 908 912 10.1016/j.ajem.2011.03.015 21641159 \nCarter GL Whyte IM Ball K Carter NT Dawson AH Carr VJ Fryer J Repetition of deliberate self-poisoning in an Australian hospital-treated population Med J Aust 1999 170 307 311 10327971 \nTaylor DM Cameron PA Eddey D Recurrent overdose: patient characteristics, habits, and outcomes J Accid Emerg Med 1998 15 257 261 10.1136/emj.15.4.257 9681311 \nBoyes AP Repetition of overdose: a retrospective 5-year study J Adv Nurs 1994 20 462 468 10.1111/j.1365-2648.1994.tb02382.x 7963051 \nPrescott K Stratton R Freyer A Hall I Le Jeune I Detailed analyses of self-poisoning episodes presenting to a large regional teaching hospital in the UK Br J Clin Pharmacol 2009 68 260 268 10.1111/j.1365-2125.2009.03458.x 19694747 \nRiedi G Mathur A Seguin M Bousquet B Czapla P Charpentier S Genestal M Cailhol L Birmes P Alcohol and repeated deliberate self-harm: preliminary results of the French cohort study of risk for repeated incomplete suicides Crisis 2012 33 358 363 22759664 \nMorton MJ Prediction of repetition of parasuicide: with special reference to unemployment Int J Soc Psychiatry 1993 39 87 99 10.1177/002076409303900202 8340216 \nJames IP Self-poisoning and alcohol Lancet 1972 2 1260 1261 4117758 \nAustralian Bureau of Statistics http://www.censusdata.abs.gov.au/census_services/getproduct/census/2011/quickstat/0 \nHeilbronn C Lloyd B McElwee P Eade A Lubman DI Trends in quetiapine use and non-fatal quetiapine-related ambulance attendances Drug Alcohol Rev 2013 32 405 411 10.1111/dar.12028 23350582 \nDir AL Karyadi K Cyders MA The uniqueness of negative urgency as a common risk factor for self-harm behaviors, alcohol consumption, and eating problems Addict Behav 2013 38 2158 2162 10.1016/j.addbeh.2013.01.025 23454879 \nChapman R Martin C Perceptions of Australian emergency staff towards patients presenting with deliberate self-poisoning: a qualitative perspective Int Emerg Nurs 2014 doi: 10.1016/j.ienj.2014.03.002 \nMartin C Chapman R A mixed method study to determine the attitude of Australian emergency health professionals towards patients who present with deliberate self-poisoning Int Emerg Nurs 2014 22 98 104 10.1016/j.ienj.2013.09.002 24207085 \nDaly FFS Fountain JS Murray L Graudins A Buckley NA Guidelines for the management of paracetamol poisoning in Australia and New Zealand – explanation and elaboration MJA 2008 188 296 301 18312195 \nCarter GL Clover K Whyte IM Dawson AH D’Este C Postcards from the EDge: 5-year outcomes of a randomised controlled trial for hospital-treated self-poisoning Br J Psychiatry 2013 202 372 380 10.1192/bjp.bp.112.112664 23520223 \nCarter G Reith DM Whyte IM McPherson M Repeated self-poisoning: increasing severity of self-harm as a predictor of subsequent suicide Br J Psychiatry 2005 186 253 257 10.1192/bjp.186.3.253 15738507\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-227X",
"issue": "14()",
"journal": "BMC emergency medicine",
"keywords": null,
"medline_ta": "BMC Emerg Med",
"mesh_terms": "D000328:Adult; D001315:Australia; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D054624:Health Status Disparities; D054625:Healthcare Disparities; D006801:Humans; D007902:Length of Stay; D016015:Logistic Models; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D013406:Suicide, Attempted; D014478:Unemployment",
"nlm_unique_id": "100968543",
"other_id": null,
"pages": "21",
"pmc": null,
"pmid": "25148692",
"pubdate": "2014-08-23",
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"references": "23520223;17513534;19694747;15738507;22304608;22759664;8340216;21925740;14992984;23350582;15564277;18312195;22328636;4117758;22088495;23454879;9681311;21641159;16531601;22262640;7963051;10327971;24207085;24768529",
"title": "A retrospective descriptive study of the characteristics of deliberate self-poisoning patients with single or repeat presentations to an Australian emergency medicine network in a one year period.",
"title_normalized": "a retrospective descriptive study of the characteristics of deliberate self poisoning patients with single or repeat presentations to an australian emergency medicine network in a one year period"
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"abstract": "This study retrospectively evaluated the effectiveness of pulmonary vasodilator therapy with bosentan (n = 14) and/ or sildenafil (n = 23) in 34 patients with a functionally single ventricle. Vasodilator therapy was initiated before the Fontan procedure in 18 patients and after the procedure in 16 patients. The reasons for vasodilator treatment included high pulmonary artery pressure or pulmonary vascular resistance (n = 8), high central venous pressure after the Fontan or bidirectional Glenn procedure (n = 7), and ventilatory impairment (n = 8). In the 11 patients who underwent right heart catheterization before and after the initiation of therapy, the mean pulmonary artery pressure decreased significantly from 19.5 ± 5.5 mmHg to 14.3 ± 3.0 mmHg (P = 0.023) and the transpulmonary pressure gradient decreased significantly from 10.9 ± 4.6 mmHg to 7.2 ± 3.3 mmHg (P = 0.046). Of the 18 patients who started vasodilator therapy before the Fontan procedure, 10 survived surgery, 4 are awaiting surgery, 3 had not been evaluated for the Fontan procedure at the end of the study period, and 1 died of heart failure after discontinuing bosentan therapy. There were no deaths among the patients who started therapy after the Fontan procedure. Two of the 14 patients receiving bosentan discontinued treatment because of adverse effects (hepatic dysfunction and increased serum brain natriuretic peptide level). Bosentan or sildenafil therapy is usually safe and may contribute to reducing pulmonary vascular resistance in patients with a functionally single ventricle before and after a Fontan type operation.",
"affiliations": "Department of Pediatric Cardiology, Sakakibara Heart Institute.",
"authors": "Park|In-Sam|IS|",
"chemical_list": "D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D014665:Vasodilator Agents; D000077300:Bosentan",
"country": "Japan",
"delete": false,
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"issue": "56 Suppl()",
"journal": "International heart journal",
"keywords": null,
"medline_ta": "Int Heart J",
"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D000077300:Bosentan; D006328:Cardiac Catheterization; D002648:Child; D002675:Child, Preschool; D065128:Endothelin Receptor Antagonists; D005260:Female; D018729:Fontan Procedure; D006352:Heart Ventricles; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D013449:Sulfonamides; D014665:Vasodilator Agents; D055815:Young Adult",
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "S26-30",
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"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy of pulmonary vasodilator therapy in patients with functionally single ventricle.",
"title_normalized": "efficacy of pulmonary vasodilator therapy in patients with functionally single ventricle"
} | [
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"companynumb": "JP-ACTELION-A-CH2015-115196",
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{
"abstract": "A 6-year-old child developed heparin-induced thrombocytopenia while on extracorporeal life support. Hours after a difficult transition from heparin to argatroban for anticoagulation therapy, the child underwent heart transplantation. Intraoperative management was plagued with circuit thrombus formation while on cardiopulmonary bypass and subsequent massive hemorrhage after bypass. We review the child's anticoagulation management, clinical challenges encountered, and review current literature related to the use of argatroban in pediatric cardiac surgery.",
"affiliations": "Seattle Children's Hospital, Seattle, WA, USA University of Washington School of Medicine, Seattle, WA, USA gregory.latham@seattlechildrens.org.;Seattle Children's Hospital, Seattle, WA, USA.;Seattle Children's Hospital, Seattle, WA, USA.;Seattle Children's Hospital, Seattle, WA, USA.;Seattle Children's Hospital, Seattle, WA, USA University of Washington School of Medicine, Seattle, WA, USA.;Seattle Children's Hospital, Seattle, WA, USA University of Washington School of Medicine, Seattle, WA, USA.",
"authors": "Latham|Gregory J|GJ|;Jefferis Kirk|Christa|C|;Falconer|Amy|A|;Dickey|Renee|R|;Albers|Erin L|EL|;McMullan|David Michael|DM|",
"chemical_list": "D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D010875:Pipecolic Acids; D011994:Recombinant Proteins; D013449:Sulfonamides; D006493:Heparin; D001120:Arginine; C031942:argatroban; C074619:bivalirudin",
"country": "United States",
"delete": false,
"doi": "10.1177/1089253215624766",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1089-2532",
"issue": "20(2)",
"journal": "Seminars in cardiothoracic and vascular anesthesia",
"keywords": "HIT; anticoagulants; bivalirudin; cardiopulmonary bypass; children; coagulation; coagulopathy; congenital heart disease; hemorrhage; thrombosis",
"medline_ta": "Semin Cardiothorac Vasc Anesth",
"mesh_terms": "D000991:Antithrombins; D001120:Arginine; D002315:Cardiopulmonary Bypass; D002648:Child; D005078:Exchange Transfusion, Whole Blood; D015199:Extracorporeal Membrane Oxygenation; D016027:Heart Transplantation; D006493:Heparin; D006629:Hirudins; D006801:Humans; D008297:Male; D010446:Peptide Fragments; D010875:Pipecolic Acids; D011994:Recombinant Proteins; D013449:Sulfonamides; D013921:Thrombocytopenia",
"nlm_unique_id": "9807630",
"other_id": null,
"pages": "168-74",
"pmc": null,
"pmid": "26721808",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Challenging Argatroban Management of a Child on Extracorporeal Support and Subsequent Heart Transplant.",
"title_normalized": "challenging argatroban management of a child on extracorporeal support and subsequent heart transplant"
} | [
{
"companynumb": "US-WATSON-2016-10778",
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"activesubstancename": "HEPARIN SODIUM"
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... |
{
"abstract": "BACKGROUND\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare disease which can cause severe morbidity and mortality. The aim of this study is to evaluate the clinical manifestation and course of DRESS syndrome.\n\n\nMETHODS\nWe conducted a retrospective analysis of prospectively collected data in 45 patients with DRESS syndrome diagnosed between September 2009 and August 2011.\n\n\nRESULTS\nThe most common causative drug group was antibiotics (n=13, 28.9%), followed by anticonvulsants (n=12, 26.7%), antituberculosis drugs (n=6, 13.3%), non-steroidal anti-inflammatory drugs (n=4, 8.9%), undetermined agents (n=4, 8.9%), allopurinol (n=3, 6.7%), and others (n=3, 6.7%). The latency period ranged from 2 to 120 days, with a mean of 20.2 ± 24.3 days. The longest latency period was noted for the antituberculosis drug group, at 46.5 ± 29.9 days. Eosinophilia in peripheral blood examination was noted in 35 subjects (77.8%). Atypical lymphocytosis was noted in 16 patients (35.6%), and thrombocytopenia in seven patients (15.6%). Hepatic involvement was noted in 39 (86.7%) study patients, kidney in eight (17.8%), lung in four (8.9%), and central nervous system in one (2.3%). Systemic corticosteroids were administered to 10 patients (22.2%). Forty-three patients (95.6%) showed complete recovery, while two patients had poor outcomes.\n\n\nCONCLUSIONS\nDRESS syndrome was not more uncommon than generally recognised. Antibiotics were the most frequently implicated drug group, followed by anticonvulsants. Most patients with this disease showed a better clinical outcome than that which had been generally expected.",
"affiliations": "Department of Internal Medicine, College of Medicine, Dong-A University, Busan, Republic of Korea.;Department of Internal Medicine, College of Medicine, Dong-A University, Busan, Republic of Korea.;Department of Pharmacy, Dong-A University Hospital, Busan, Republic of Korea.;Department of Internal Medicine, College of Medicine, Dong-A University, Busan, Republic of Korea. Electronic address: skleeai@dau.ac.kr.;Department of Dermatology, College of Medicine, Dong-A University, Busan, Republic of Korea.;Department of Pathology, College of Medicine, Dong-A University, Busan, Republic of Korea.;Department of Internal Medicine, College of Medicine, Dong-A University, Busan, Republic of Korea.;Department of Internal Medicine, College of Medicine, Dong-A University, Busan, Republic of Korea.",
"authors": "Nam|Y H|YH|;Park|M R|MR|;Nam|H J|HJ|;Lee|S K|SK|;Kim|K H|KH|;Roh|M S|MS|;Um|S-J|SJ|;Son|C-H|CH|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000485:Allergens; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000995:Antitubercular Agents",
"country": "Singapore",
"delete": false,
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"issue": "43(1)",
"journal": "Allergologia et immunopathologia",
"keywords": "Anticonvulsants; Drug hypersensitivity; Eosinophilia",
"medline_ta": "Allergol Immunopathol (Madr)",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000485:Allergens; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D000995:Antitubercular Agents; D063926:Drug Hypersensitivity Syndrome; D004802:Eosinophilia; D005260:Female; D006801:Humans; D007668:Kidney; D008099:Liver; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0370073",
"other_id": null,
"pages": "19-24",
"pmc": null,
"pmid": "24388810",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug reaction with eosinophilia and systemic symptoms syndrome is not uncommon and shows better clinical outcome than generally recognised.",
"title_normalized": "drug reaction with eosinophilia and systemic symptoms syndrome is not uncommon and shows better clinical outcome than generally recognised"
} | [
{
"companynumb": "PHHY2015KR071384",
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"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
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"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nAcquired hemophilia A is a rare autoimmune disease with clinically often significant bleeding diathesis resulting from circulating autoantibodies inhibiting coagulation factor VIII. Half of acquired hemophilia A cases are associated with an underlying disorder, such as autoimmune diseases, cancer, or use of certain drugs, or occur during pregnancy and in the postpartum period. In the other half, no underlying cause is identified. An association of acquired hemophilia A with plasma cell neoplasm seems to be extremely rare.\n\n\nMETHODS\nWe describe a case of a 77-year-old Swiss Caucasian man who was diagnosed with acquired hemophilia A and smoldering multiple myeloma as an underlying cause. Acquired hemophilia A was treated with prednisolone, cyclophosphamide, and immunoadsorption. Extensive workup revealed a plasma cell neoplasm as the only disorder associated with or underlying the acquired hemophilia A. For long-term control of acquired hemophilia A, we considered treatment of the plasma cell neoplasm necessary, and a VRD (bortezomib, lenalidomide, and dexamethasone) regimen was initiated. Due to multiple complications, VRD was reduced to VRD-lite after two cycles. After nine cycles of induction therapy and five cycles of consolidation therapy, the patient is in complete remission of his acquired hemophilia A and very good partial remission of the plasma cell neoplasm. We conducted a literature review to identify additional cases of this rare association and identified 15 other cases. Case descriptions, including the sequence of occurrence of acquired hemophilia A and plasma cell neoplasm , treatment, evolution, and outcome are presented.\n\n\nCONCLUSIONS\nOur case, together with 15 other cases described in the literature, underscore the possibility of plasma cell neoplasm as an underlying cause of acquired hemophilia A. Physicians should consider including protein electrophoresis, immunofixation, and analysis of free light chains in laboratory diagnostics when treating a patient with acquired hemophilia A. The occurrence of excessive and unexplained bleeding in patients diagnosed with plasma cell neoplasm should raise suspicion of secondary acquired hemophilia A and trigger the request for coagulation tests, particularly in patients treated with immunomodulatory drugs such as thalidomide or lenalidomide. Additionally, early intervention with immunoadsorption can be lifesaving in cases with high-titer factor VIII inhibitors, especially when surgical interventions are necessary.",
"affiliations": "Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland. katarzynaaleksandra.jalowiec@insel.ch.;Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.;Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.;Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.;Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.;Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.;Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.;Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.",
"authors": "Jalowiec|Katarzyna A|KA|http://orcid.org/0000-0003-3284-8308;Andres|Martin|M|;Taleghani|Behrouz Mansouri|BM|;Musa|Albulena|A|;Dickenmann|Martina|M|;Angelillo-Scherrer|Anne|A|;Rovó|Alicia|A|;Kremer Hovinga|Johanna A|JA|",
"chemical_list": "D013792:Thalidomide; D005169:Factor VIII; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02505-7",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2505\n10.1186/s13256-020-02505-7\nCase Report\nAcquired hemophilia A and plasma cell neoplasms: a case report and review of the literature \nhttp://orcid.org/0000-0003-3284-8308Jalowiec Katarzyna A. katarzynaaleksandra.jalowiec@insel.ch Andres Martin Taleghani Behrouz Mansouri Musa Albulena Dickenmann Martina Angelillo-Scherrer Anne Rovó Alicia Kremer Hovinga Johanna A. grid.5734.50000 0001 0726 5157Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland \n30 10 2020 \n30 10 2020 \n2020 \n14 20610 10 2019 17 8 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\nAcquired hemophilia A is a rare autoimmune disease with clinically often significant bleeding diathesis resulting from circulating autoantibodies inhibiting coagulation factor VIII. Half of acquired hemophilia A cases are associated with an underlying disorder, such as autoimmune diseases, cancer, or use of certain drugs, or occur during pregnancy and in the postpartum period. In the other half, no underlying cause is identified. An association of acquired hemophilia A with plasma cell neoplasm seems to be extremely rare.\n\nCase presentation\nWe describe a case of a 77-year-old Swiss Caucasian man who was diagnosed with acquired hemophilia A and smoldering multiple myeloma as an underlying cause. Acquired hemophilia A was treated with prednisolone, cyclophosphamide, and immunoadsorption. Extensive workup revealed a plasma cell neoplasm as the only disorder associated with or underlying the acquired hemophilia A. For long-term control of acquired hemophilia A, we considered treatment of the plasma cell neoplasm necessary, and a VRD (bortezomib, lenalidomide, and dexamethasone) regimen was initiated. Due to multiple complications, VRD was reduced to VRD-lite after two cycles. After nine cycles of induction therapy and five cycles of consolidation therapy, the patient is in complete remission of his acquired hemophilia A and very good partial remission of the plasma cell neoplasm. We conducted a literature review to identify additional cases of this rare association and identified 15 other cases. Case descriptions, including the sequence of occurrence of acquired hemophilia A and plasma cell neoplasm , treatment, evolution, and outcome are presented.\n\nDiscussion and conclusions\nOur case, together with 15 other cases described in the literature, underscore the possibility of plasma cell neoplasm as an underlying cause of acquired hemophilia A. Physicians should consider including protein electrophoresis, immunofixation, and analysis of free light chains in laboratory diagnostics when treating a patient with acquired hemophilia A. The occurrence of excessive and unexplained bleeding in patients diagnosed with plasma cell neoplasm should raise suspicion of secondary acquired hemophilia A and trigger the request for coagulation tests, particularly in patients treated with immunomodulatory drugs such as thalidomide or lenalidomide. Additionally, early intervention with immunoadsorption can be lifesaving in cases with high-titer factor VIII inhibitors, especially when surgical interventions are necessary.\n\nKeywords\nAcquired hemophilia AMultiple myelomaSoldering multiple myelomaPlasma cell diseasesBleeding diathesisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAcquired hemophilia A (AHA) is a rare autoimmune disease with a clinically significant bleeding diathesis, resulting from circulating autoantibodies inhibiting coagulation factor VIII (FVIII). The incidence is estimated to be 1–1.5 cases per 1 million population, and AHA is most often encountered in elderly patients. Half of AHA cases are associated with an underlying disorder, such as autoimmune diseases, cancer, use of certain drugs, or occur during pregnancy, and in the postpartum period. In the other half, no underlying cause is identified (idiopathic AHA). Typically, bleeding is located in the skin, mucosa, or soft tissues, and, in contrast to congenital hemophilia, joint bleeding is rare. Mortality in AHA is increased, particularly in elderly patients and in patients with underlying malignancies. Despite frequent bleeding complications and complications of immunosuppressive therapy, the primary cause of death in AHA is the underlying disease [1].\n\nManagement of AHA is based on four pillars: (1) avoidance of procedures that may induce bleeding, (2) control of bleeding, (3) inhibitor eradication, and (4) treatment of the underlying disease. The mainstays of bleeding management are bypassing agents, such as activated prothrombin complex concentrates (aPCCs) and recombinant activated factor VII (rFVIIa). More recently, recombinant porcine FVIII, which lacks complete sequence homology with human FVIII, has become available. Different strategies, such as immunosuppression with steroids alone or in combination with cyclophosphamide, immunoglobulins, rituximab, plasma exchange, and immunoadsorption, are in use for inhibitor elimination and eradication and, with that, restoration of FVIII clotting activity [1].\n\nHematological malignancies may be associated with or may be the underlying cause of AHA. Among these malignancies, lymphoproliferative disorders are most common. An association of AHA with plasma cell neoplasm (PCN) seems to be extremely rare and to represent only 14% of AHA cases associated with a hematological malignancy [2]. We describe a case of a 77-year-old man who presented with AHA and smoldering multiple myeloma as an underlying cause.\n\nCase presentation\nA 77-year-old Swiss Caucasian man was admitted to a peripheral hospital due to a compartment syndrome of his left calf following a minor trauma (Fig. 1a). A large (13 × 8 × 0.6 cm) isolated calf hematoma was documented on ultrasound, but the patient’s further physical evaluation was unremarkable. At admission, anticoagulant therapy with apixaban, prescribed for atrial fibrillation, was interrupted. The patient’s family and personal history were negative for hematological diseases. Two months earlier, the patient had undergone an uneventful colonoscopy with polypectomy initiated because of melena. No coagulation tests were available from that time. Despite two surgical interventions, the bleeding into the calf persisted. Six days after initial admission, AHA was suspected, and the patient was transferred to our hospital.\nFig. 1 Findings in our patient. a Presentation of compartment syndrome following surgery. b Plasma cells on bone marrow aspirate\n\n\n\nThe results of the patient’s laboratory evaluation revealed a prolonged activated partial thromboplastin time (aPTT; 119 s; reference range 25.0–36.0 s), and FVIII:C of 2% in the presence of a high-titer FVIII inhibitor of 102 Bethesda units (BU)/ml confirmed the diagnosis of AHA. Additional diagnostic workup revealed an IgG kappa paraprotein of 9.2 g/L as well as a slightly reduced hemoglobin of 106 g/L. The patient’s albumin corrected serum calcium was 2.38 mmol/L, serum creatinine 103 μmol/L, β2-microglobulin 3.0 mg/L, lactate dehydrogenase 301 U/L, free light chains kappa 41.1 mg/L and lambda 10.9 mg/L, and free light chain ratio of 3.77. Magnetic resonance imaging excluded multiple myeloma defining focal bone lesions. A subsequent bone marrow biopsy showed infiltration of clonal plasma cells of 15% (Fig. 1b). Conventional cytogenetic analysis was not performed; however, microarray-based comparative genomic hybridization revealed hyperdiploidy with trisomy 3, 4, 5, 9, 11, and 21, whereas the result of fluorescence in situ hybridization was negative for MYC, IGH rearrangement, and 17p. Apart from a smoldering myeloma, no other diseases potentially underlying the AHA were identified.\n\nTreatment with prednisolone (1 mg/kg body weight) and cyclophosphamide (150 mg/day) was started the day of presentation at our hospital. Because of imminent compartment syndrome and potential need of further surgical interventions, immunoadsorption was started according to the modified Bonn Malmö protocol [3] to rapidly deplete the FVIII inhibitor. Altogether, we performed seven immunoadsorption sessions processing approximately two total patient plasma volumes per session over the next 13 days. Within 1 month, aPTT and FVIII:C had normalized, whereas the inhibitor titer had significantly decreased but was still detectable (1.04 BU/ml).\n\nInsertion of a central venous catheter for immunoadsorption, as well as the bone marrow biopsy, were done under substitution with rFVIIa (NovoSeven; Novo Nordisk, Plainsboro, NJ, USA). One to three doses of 90 μg/kg body weight were applied. Wound healing at the calf was delayed, and due to skin necrosis, surgical revision became necessary. At that time, the patient’s aPTT had already normalized, and substitution with rFVIIa was not needed.\n\nLack of complete remission of AHA prompted us to initiate a VRD (bortezomib, lenalidomide, dexamethasone) regimen to treat the patient’s smoldering myeloma. After two cycles, the FVIII inhibitor had further declined to 0.31 BU/ml. The monoclonal immunoglobulin was still detectable by immune fixation but no longer quantifiable. Subsequently, treatment intensity was reduced to a VRD-lite regimen [4] because of thrombocytopenia, mild polyneuropathy, and signs of congestive heart failure. During follow-up, no further bleeding occurred. After nine cycles of induction therapy and five cycles of consolidation therapy with the VRD-lite regimen, the patient is in complete remission of his AHA and in very good partial remission of his PCN (Table 1, patient 16).\nTable 1 Characteristics of patients with association of AHA and plasma cell neoplasms – a systematic review\n\nPatient no.\tAuthor, year [reference]\tSex\tAge (years)\tDiagnosed first\tBleeding\tFVIII:C (%)\tFVIII inhibitor (BU/ml)\tHemostatic treatment\tTreatment AHA inhibitor eradication\tAHA outcome\tParaprotein\tTreatment PCN\tPCN outcome\tAlive/died\t\n1\tGlueck et al., 1965 [5]\tM\t70\tPCN\tMC, RT\tNA\tNA\tNA\tC\tNA\tNA\tNA\tNA\tNA\t\n2\tLoftus et al., 1994 [6]\tF\t58\tPCN\tMC, A\t8\t36\tFVIII, pFVIII\tS, C\tBleeding continued\tLambda light chain\tM\tNA\tDied of intra-abdominal bleeding\t\n3\tStricker et al., 1994a [7]\tM\t52\tPCN\tI\t2\t17.8\tFVIII, plasma\tS, PEX\tNormal APTT and FVIII:C\tKappa light chain\tIFN-α, ASCT\tCR\tDied of sudden cardiac death\t\n4\tSallah et al., 2000 [8]\tF\t58\tAHA\tMC\t< 1\t28\tpFVIII, APCC\tS, PEX\tInhibitor persisted\tNA\tM\tDied\tDied of acute renal failure/hemorrhage\t\n5\tHolme et al., 2005 [9]\tM\t58\tAHA\tI\t6\t20\tAPCC\tS, C\tNA\tNA\tNA\tPR\tAlive\t\n6\tSari et al. 2009 [10]\tF\t43\tAHA\tI\t6\t10\tNo treatment\tNo treatment\tNormal coagulation\tIgG kappa\tVinOD, ASCT\tCR\tNA\t\n7\tDecaux et al. 2009 [11]\tF\t44\tPCN\tMC\t6\t29\trFVIIa\tR\tNA\tIgA kappa\tNA\tNA\tNA\t\n8\tMuzaffar et al. [12]\tM\t65\tPCN\tPE, HA\t< 5\t9.5\tAPCC, plasma\tIVIG, R\tFVIII:C 22%, no FVIII inhibitor\tLambda light chain\tVTD\tCR\tAlive\t\n9\tSaburi et al. 2015a [13]\tF\t67\tPCN\tNA\t2\t4.9\tNo treatment\tS, C\tNormal APTT, FVIII inhibitor 4.85 BU/ml\tNA\tVD, LCD\tCR\tNA\t\n10\tRoss et al. [14]\tF\t64\tAHA\tMC, HP\t17\t5\trFVIIa\tS\tNormal coagulation\tIgM kappa\tVTD\tNA\tNA\t\n11\tInnao et al. [15]\tM\t67\tPCN\tNA\t28\tNA\tFVIII\tNo treatment\tNormal coagulation\tIgG kappa, kappa light chain\tVMP, ASCT\tCR\tAlive\t\n12\tBrás, et al. [16]\tM\t87\tPCN\tMC, IM\t1.4\t18.4\tAPPC\tS, C, B\tNormal APTT, FVIII:C 36%, FVIII inhibitor 0.8 BU/ml\tIgG kappa\tMTP, VD\tPR\tNA\t\n13\tNapolitano et al. 2017 [17]\tF\t59\tAHA\tMC, HA, A\t12\t70\trFVIIa, APCC\tS, R\tNormal coagulation\tIgG lambda\tVMP\tCR\tAlive\t\n14\tKawashima et al. 2018 [18]\tM\t52\tPCN\tIM\t17\t1\trFVIIa\tNo treatment\tNormal coagulation\tIgA kappa\tVD, VCD, VTD, LD, ASCT, allo-HCT\tCR\tNA\t\n15\tSourdeau et al. 2019 [19]\tM\t78\tPCN\tST\t< 1\t19\tNA\tNA\tNA\tNA\tVCD\tNA\tNA\t\n16\tOur patient\tM\t77\tAHA\tIM\t2\t102\trFVIIab\tS, C, IA\tNormal APTT, normal FVIII\tIgG kappa\tVRD, RD\tVGPR\tAlive\t\nAbbreviation: AHA acquired hemophilia, PCN plasma cell neoplasm, NA not available, n.d. not done\n\nBleeding: MC mucocutaneous bleeding (epistaxis, gingiva, soft tissue, gastro-intestinal, gynecological), I iatrogenic (postoperative, after biopsy or dental procedure), A intra-abdominal, HA hemarthrosis, PE pericardial bleeding, HP hemoptysis, RT retinal bleeding, IM intramuscular\n\nHemostatic treatment: rFVIIa recombinant activated factor VII, aPCC activated prothrombin complex concentrate, FVIII factor VIII (human plasma or recombinant), pFVIII porcine factor VIII, plasma fresh frozen plasma or cryoprecipitate\n\nOther treatment: allo-HCT allogenic stem cell transplantation, ASCT autologous stem cell transplantation, C cyclophosphamide, CR complete remission, D dexamethasone, IA immunoadsorption, INF-a interferon alpha, IVIG intravenous immunoglobulin, L lenalidomide, M melphalan, O doxorubicin, P prednisone, PEX plasma exchange, PR partial remission, R Rituximab, S steroids, T thalidomide, V bortezomib, Vin vincristine, VGPR very good partial remission\n\naAHA considered a side effect of plasma cell disease treatment (discussed in text)\n\nbHemostatic treatment only for interventions (bone marrow biopsy, surgery)\n\n\n\nDiscussion and conclusions\nTo further elucidate this rare association of AHA and PCN, we reviewed the published literature in PubMed using the following search terms: “hemophilia,” “inhibitor,” “factor VIII,” “myeloma,” “plasma cell disorder” or “neoplasm,” “smoldering myeloma,” “MGUS,” “monoclonal gammopathy,” and “paraprotein.” Our search identified 15 further cases. Case descriptions, including the sequence of occurrence of AHA and PCN, treatment, evolution, and outcome, are provided in Table 1.\n\nWe found nine male and seven female patients diagnosed with AHA and PCN. Their median age at diagnosis of AHA was 61.5 (range 43–87) years. Soft tissue bleeding was the most common type of bleeding (7 of 16 patients; 43%), in line with other reports [1]. The patients’ median FVIII inhibitor titer was 18.7 BU/ml (range 1–102 BU/ml; no data available for two patients). AHA was diagnosed after excessive postintervention hemorrhage in two patients and in one patient following life-threatening pericardial bleeding and hemarthrosis. AHA with active bleeding was the presenting sign and preceded PCN diagnosis in six cases (38%) (Table 1, cases 4, 5, 6, 10, 13, and 16), whereas in the other cases, PCN was diagnosed first. In three of the latter cases, AHA was considered to have occurred secondary to multiple myeloma treatment. The implicated drugs were interferon alpha, lenalidomide, and thalidomide. Information on the type of paraprotein was available in 11 cases, but no particular immunoglobulin type or clonal light-chain was discernible.\n\nHemostatic treatment with bypassing agents was necessary in 11 cases. Their median FVIII inhibitor titer was 19.2 (range 1–70) BU/ml, whereas the three patients who did not need hemostatic treatment had FVIII inhibitor titers of 4.85, 10, and 102 BU/ml, respectively. This underscores the fact that FVIII inhibitor titers in AHA do not necessarily correlate with the severity of the bleeding manifestations. Our patient received rFVIIa only prophylactically before catheter insertion and bone marrow biopsy. Under immunoadsorption, a rapid increase of FVIII clotting activity reaching safe levels was observed, and further treatment with bypassing products was not necessary.\n\nInhibitor eradication was attempted with steroids alone (n = 4) or in combination with cyclophosphamide (n = 5), with cyclophosphamide alone (n = 1), and with rituximab (n = 3). Plasma exchange and immunoadsorption to remove FVIII antibodies were performed in two and one patient (our patient), respectively. Given the long observation period of 55 years, different therapy regimens were used to treat the underlying PCN in the 16 cases (details are given in Table 1). At the time of reporting, 13 patients were alive, whereas two of the three patients who died, died of bleeding complications. Information on the outcome of AHA and/or PCN was available for nine of 13 survivors: six had normal coagulation tests, and FVIII activity was mildly reduced in two. PCN was in complete or partial remission in seven and two cases, respectively. One patient (case 7 in Table 1) had a spontaneous remission of his FVIII inhibitor without any treatment.\n\nIn summary, our patient’s case, together with the 15 other cases described in the literature, underscores the possibility of PCN as an underlying cause of AHA. Serum and urine protein electrophoresis is not (everywhere) part of standard workup of AHA, and underreporting of this association is possible or even likely. Accordingly, physicians should consider including protein electrophoresis, immunofixation, and analysis of free light chains in laboratory diagnostics when treating a patient with AHA. The occurrence of excessive and unexplained bleeding in patients diagnosed with PCN should raise the suspicion of secondary AHA and trigger the request for coagulation tests, particularly in patients treated with immunomodulatory drugs such as thalidomide or lenalidomide. Whether PCN treatment alone can control AHA in these cases remains an open question; 11 of 16 (69%) of the reported cases received treatment for both diseases.\n\nIn our experience, early intervention with immunoadsorption can be lifesaving in cases with high FVIII inhibitor titers, especially in patients requiring a surgical intervention. The modified Bonn Malmö protocol [3] is useful to guide AHA therapy that includes immunoadsorption.\n\nAbbreviations\nAIntra-abdominal\n\nAHAAcquired hemophilia\n\naPCCActivated prothrombin complex concentrate\n\nASCTAutologous stem cell transplant\n\nCCyclophosphamide\n\nCRComplete remission\n\nDDexamethasone\n\nFVIIIFactor VIII\n\nHAHemarthrosis\n\nHCTAllogeneic stem cell transplant\n\nHPHemoptysis\n\nIIatrogenic\n\nIAImmunoadsorption\n\nIMIntramuscular\n\nIFNInterferon\n\nIVIGIntravenous immunoglobulin\n\nLLenalidomide\n\nMMelphalan\n\nMCMucocutaneous bleeding\n\nn.d.Not done\n\nNANot available\n\nODoxorubicin\n\nPprednisone\n\nPCNPlasma cell neoplasm\n\nPEPericardial bleeding\n\nPEXPlasma exchange\n\npFVIIIPorcine factor VIII\n\nPRPartial remission\n\nRRituximab\n\nrFVIIaRecombinant activated factor VII\n\nRTRetinal bleeding\n\nSSteroids\n\nTThalidomide\n\nVBortezomib\n\nVGPRVery good partial remission\n\nVinVincristine\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank the patient for providing consent for publication.\n\nAuthors’ contributions\nKAJ analyzed and interpreted the patient data regarding hematological diseases and conducted the systematic review of the literature. MA, BMT, AM, MD, and AAS reviewed and corrected the manuscript. KAJ, AR, and JAKH were major contributors in the writing of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNo funding.\n\nAvailability of data and materials\nNot applicable. All data are included in the article.\n\nEthics approval and consent to participate\nThis study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.\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. Kruse-Jarres R Acquired hemophilia A: updated review of evidence and treatment guidance Am J Hematol 2017 92 7 695 705 10.1002/ajh.24777 28470674 \n2. Franchini M Acquired factor VIII inhibitors in oncohematology: a systematic review Crit Rev Oncol Hematol 2008 66 3 194 199 10.1016/j.critrevonc.2007.12.004 18243727 \n3. Zeitler H Treatment of acquired hemophilia by the Bonn-Malmo protocol: documentation of an in vivo immunomodulating concept Blood. 2005 105 6 2287 2293 10.1182/blood-2004-05-1811 15542586 \n4. O’Donnell EK A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma Br J Haematol 2018 182 2 222 230 10.1111/bjh.15261 29740809 \n5. Glueck HI Hong R A circulating anticoagulant in gamma-1A-multiple myeloma: its modification by penicillin J Clin Invest 1965 44 11 1866 1881 10.1172/JCI105294 5843717 \n6. Loftus LS Arnold WN Acquired hemophilia in a patient with myeloma West J Med 1994 160 2 173 176 8160473 \n7. Stricker RB Barlogie B Kiprov DD Acquired factor VIII inhibitor associated with chronic interferon-alpha therapy J Rheumatol 1994 21 2 350 352 8182649 \n8. Sallah S Nguyen NP Abdallah JM Hanrahan LR Acquired hemophilia in patients with hematologic malignancies Arch Pathol Lab Med 2000 124 5 730 734 10782157 \n9. Holme PA Brosstad F Tjønnfjord GE Acquired haemophilia: management of bleeds and immune therapy to eradicate autoantibodies Haemophilia 2005 11 5 510 515 10.1111/j.1365-2516.2005.01136.x 16128896 \n10. Sari I Multiple myeloma presenting with acquired factor VIII inhibitor Int J Hematol 2009 90 2 166 169 10.1007/s12185-009-0363-9 19551464 \n11. Decaux O Guillet B Millet A Acquired hemophilia associated with smoldering myeloma: demonstration that the monoclonal gammopathy acts as the factor VIII inhibitor [abstract] Blood. 2009 114 22 1307 10.1182/blood.V114.22.1307.1307 \n12. Muzaffar J Rituximab and intravenous immunoglobulin (IVIG) for the management of acquired factor VIII inhibitor in multiple myeloma: case report and review of literature Int J Hematol 2012 95 1 102 106 10.1007/s12185-011-0968-7 22170228 \n13. Saburi M Development of acquired hemophilia A during treatment of multiple myeloma with lenalidomide [in Japanese] Rinsho Ketsueki 2015 56 5 496 500 26062672 \n14. Ross C Management of acquired haemophilia bleed in the backdrop of multiple myeloma Indian J Hematol Blood Transfus 2015 31 1 151 153 10.1007/s12288-013-0266-z 25548464 \n15. Innao V Disappearance of acquired hemophilia a after complete remission in a multiple myeloma patient Turk J Haematol 2017 34 2 184 185 10.4274/tjh.2016.0146 28077343 \n16. Brás GP Pinto RJ Carvalho MM Fernandes SP Andrade JJ Guimarães JE Bortezomib: Potential Key Role in the Treatment of Multiple Myeloma-Related Acquired Hemophilia A Semin Thromb Hemost 2017 43 1 109 112 27992938 \n17. Napolitano M Acquired haemophilia in cancer: a systematic and critical literature review Haemophilia. 2018 24 1 43 56 10.1111/hae.13355 28960809 \n18. Kawashima I Combined coagulopathy can induce both hemorrhagic and thrombotic complications in multiple myeloma Intern Med 2018 57 22 3303 3306 10.2169/internalmedicine.0915-18 29984746 \n19. Sourdeau E Acquired hemophilia A associated with bullous pemphigoid and multiple myeloma: a case report Ann Biol Clin (Paris) 2019 77 2 179 183 30882350\n\n",
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"journal": "Journal of medical case reports",
"keywords": "Acquired hemophilia A; Bleeding diathesis; Multiple myeloma; Plasma cell diseases; Soldering multiple myeloma",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D005169:Factor VIII; D006467:Hemophilia A; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D009101:Multiple Myeloma; D010954:Plasmacytoma; D013792:Thalidomide",
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"title": "Acquired hemophilia A and plasma cell neoplasms: a case report and review of the literature.",
"title_normalized": "acquired hemophilia a and plasma cell neoplasms a case report and review of the literature"
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"abstract": "OBJECTIVE\nThe renal safety of cisplatin-based chemotherapy has not been investigated in patients with urothelial carcinoma of the upper urinary tract (UUT-UC) who retain a solitary kidney after nephroureterectomy. This study aimed to assess and compare the renal safety and efficacy of gemcitabine-cisplatin (GP) and gemcitabine-carboplatin (GC) in these patients.\n\n\nMETHODS\nThe medical records of patients diagnosed with urothelial carcinoma at the Sun Yat-Sen University Cancer Center between January 2005 and December 2015 were retrospectively reviewed. The creatinine clearance (CrCl) and estimated glomerular filtration rate (eGFR) were used to assess renal function and were calculated using different formulas.\n\n\nRESULTS\nA total of 71 patients were enrolled in this study; 48 patients were on GP, and 23 were on GC. The renal function indicators (CrCl and eGFR) were all significantly lower after GP chemotherapy than at baseline, a phenomenon that was not observed in the GC group. Severe nephrotoxicities (SNTs) were reported in 12 patients on GP (25%) and zero on GC. SNT risk factors included a more than 20% decrease in eGFR after one GP cycle and the presence of diabetes (all p < 0.05). Among patients treated with first-line palliative chemotherapy (n = 32), GC (n = 13) patients had an ORR of 46.2%, which was not significantly different from GP patients (36.8%, n = 19), whereas GC patients tended to have a shorter OS than GP patients (9.2 vs. 29 months, p = 0.200).\n\n\nCONCLUSIONS\nOur results confirm that GP has an adverse impact on the renal function of patients with UUT-UC who retain a solitary kidney, but it can be safely administered to the majority of these patients without inducing SNT. In specific patients, GC is an alternative to GP that has comparable efficacy and favourable renal toxicity.",
"affiliations": "State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.;Section of Cancer Genomics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA.;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China. jiangwq@sysucc.org.cn.;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, 510060, Guangdong, People's Republic of China. shiyx@sysucc.org.cn.",
"authors": "Sun|Peng|P|;Xue|Cong|C|;Li|Li-Ren|LR|;Shao|Cui|C|;An|Xin|X|;Thomas|Ried|R|;Yang|Wei|W|;Deng|Ying-Fei|YF|;Jiang|Wen-Qi|WQ|;Shi|Yan-Xia|YX|",
"chemical_list": "D003841:Deoxycytidine; D003404:Creatinine; C056507:gemcitabine; D016190:Carboplatin; D002945:Cisplatin",
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"keywords": "Carboplatin; Chemotherapy; Cisplatin; Gemcitabine; Solitary kidney; Urothelial carcinoma of upper urinary tract (UUT-UC)",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D044466:Asians; D016190:Carboplatin; D002295:Carcinoma, Transitional Cell; D002945:Cisplatin; D003404:Creatinine; D003841:Deoxycytidine; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D012189:Retrospective Studies; D012307:Risk Factors; D014516:Ureteral Neoplasms",
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"title": "The renal safety and efficacy of combined gemcitabine plus cisplatin and gemcitabine plus carboplatin chemotherapy in Chinese patients with a solitary kidney after nephroureterectomy.",
"title_normalized": "the renal safety and efficacy of combined gemcitabine plus cisplatin and gemcitabine plus carboplatin chemotherapy in chinese patients with a solitary kidney after nephroureterectomy"
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"abstract": "A 61-year-old woman developed multiple and clustered eruptive epidermoid cysts at the site of treatment of a basal cell carcinoma located on her nose with imiquimod 5% cream (5 times/week for 6 weeks). Clearing was achieved after topical treatment with tretinoin 0.025% cream (1 application/day for 1 month).",
"affiliations": "Dermatology Clinic, University of Catania, Catania, Italy.",
"authors": "Nasca|Maria Rita|MR|;De Pasquale|Rocco|R|;Micali|Giuseppe|G|",
"chemical_list": "D000634:Aminoquinolines; D000970:Antineoplastic Agents; D000077271:Imiquimod",
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"title": "Multiple and clustered eruptive epidermoid cysts following treatment with topical imiquimod.",
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"abstract": "Electroconvulsive therapy (ECT) is the most effective treatment for therapy-refractory depression. Usually, prior antidepressant medication will be continued during ECT. However, the seizure threshold may be influenced by psychotropic drugs. We report a patient who received right unilateral ECT under concomitant treatment with bupropion, a selective noradrenaline- and dopamine-reuptake inhibitor. After the fourth session, a focal status epilepticus occurred, which was pharmacoresistant for the duration of 12 days. We assume that the induction of a status may be facilitated by a lowering of the seizure threshold due to bupropion. An evaluation of drug therapy and control of EEG before and during ECT are recommended, especially when the drug treatment has an influence on the seizure threshold.",
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"authors": "Dersch|R|R|;Zwernemann|S|S|;Voderholzer|U|U|",
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"publication_types": "D002363:Case Reports; D016422:Letter",
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"title": "Partial status epilepticus after electroconvulsive therapy and medical treatment with bupropion.",
"title_normalized": "partial status epilepticus after electroconvulsive therapy and medical treatment with bupropion"
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"abstract": "BACKGROUND\nAdenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib.\n\n\nMETHODS\nA 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al. All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases.\n\n\nCONCLUSIONS\nWe present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.",
"affiliations": "Institute of Pathology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany. alexander.quaas@uk-koeln.de.;Department of Hepato- and Gastroenterology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Department of Visceral Surgery, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Department of Oncology and Hematology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Institute of Pathology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Department of Hepato- and Gastroenterology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Department of Hepato- and Gastroenterology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Department of Hepato- and Gastroenterology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Department of Visceral Surgery, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Department of Visceral Surgery, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Institute of Neuropathology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Institute of Pathology, University of Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.;Institute of Pathology, University of Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.;Department of Radiology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Department of Nuclear-Medicine, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Institute of Pathology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Institute of Pathology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Institute of Pathology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.;Institute of Pathology, University of Cologne, Kerpener Strasse 62, 50937, Cologne, Germany.",
"authors": "Quaas|A|A|http://orcid.org/0000-0002-3537-6011;Waldschmidt|D|D|;Alakus|H|H|;Zander|T|T|;Heydt|C|C|;Goeser|T|T|;Daheim|M|M|;Kasper|P|P|;Plum|P|P|;Bruns|C|C|;Brunn|A|A|;Roth|W|W|;Hartmann|N|N|;Bunck|A|A|;Schmidt|M|M|;Göbel|H|H|;Tharun|L|L|;Buettner|R|R|;Merkelbach-Bruse|S|S|",
"chemical_list": "D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016190:Carboplatin; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1186/s12876-018-0803-1",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 2985527580310.1186/s12876-018-0803-1Case ReportTherapy susceptible germline-related BRCA 1-mutation in a case of metastasized mixed adeno-neuroendocrine carcinoma (MANEC) of the small bowel http://orcid.org/0000-0002-3537-6011Quaas A. 0049-221-4785257alexander.quaas@uk-koeln.de 19Waldschmidt D. dirk.waldschmidt@uk-koeln.de 4Alakus H. hakan.alakus@uk-koeln.de 29Zander T. thomas.zander@uk-koeln.de 39Heydt C. carina.heydt@uk-koeln.de 1Goeser T. tobias.goeser@uk-koeln.de 4Daheim M. mathias.daheim@uk-koeln.de 4Kasper P. philipp.kasper@uk-koeln.de 4Plum P. Patrick.plum@uk-koeln.de 2Bruns C. christiane.bruns@uk-koeln.de 2Brunn A. anna.brunn@uk-koeln.de 5Roth W. wilfried.roth@unimedizin-mainz.de 6Hartmann N. nils.hartmann@unimedizin-mainz.de 6Bunck A. anne.bunck@uk-koeln.de 7Schmidt M. matthias.schmidt@uk-koeln.de 8Göbel H. heike.goebel@uk-koeln.de 1Tharun L. lars.tharun@uk-koeln.de 1Buettner R. reinhard.buettner@uk-koeln.de 1Merkelbach-Bruse S. sabine.merkelbach-bruse@uk-koeln.de 11 0000 0000 8580 3777grid.6190.eInstitute of Pathology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 2 0000 0000 8580 3777grid.6190.eDepartment of Visceral Surgery, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 3 0000 0000 8580 3777grid.6190.eDepartment of Oncology and Hematology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 4 0000 0000 8580 3777grid.6190.eDepartment of Hepato- and Gastroenterology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 5 0000 0000 8580 3777grid.6190.eInstitute of Neuropathology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 6 0000 0001 1941 7111grid.5802.fInstitute of Pathology, University of Mainz, Langenbeckstraße 1, 55131 Mainz, Germany 7 0000 0000 8580 3777grid.6190.eDepartment of Radiology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 8 0000 0000 8580 3777grid.6190.eDepartment of Nuclear-Medicine, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany 9 Gastrointestinal Cancer Group Cologne, Cologne, Germany 31 5 2018 31 5 2018 2018 18 7521 10 2017 23 5 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\nAdenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib.\n\nCase presentation\nA 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al.\n\nAll liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases.\n\nConclusion\nWe present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.\n\nKeywords\nSmall bowel mixed adeno-neuroendocrine carcinoma (MANEC)BRCA1 mutationGermline-relatedPARP-inhibitionPersonalized treatmentissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nSmall bowel carcinomas are rare and account only for 0.5% of all cancers. The 5 year overall survival rates for patients with small-bowel adenocarcinoma is 34.9%. To best of our knowledge no valid prognostic or survival data exist to the mixed adeno-neuroendocrine carcinoma (MANEC)-subtype of the small bowel. There is a strong need for a more effective and personalized systemic treatment option in carcinoma of the small bowel. Most recently Schrock, A et al. [1] described molecular alterations in a very large cohort of 317 small bowel carcinomas. According to this study microsatellite-instability (MSI) was present in 7,6% and are characterized by the following mutations like KRAS (53,6%), APC (26,8%), CDKN2A (14,5%), SMAD4 (17,4%) and BRAF (9,1% but only 10% of these have the typical V600E mutation) as well as ERBB2 mutation in 8,2% of the analysable tumors.\n\nThe most important pathway in DNA double strand break (DNA-dbs.) repair is homologous recombination (HR). The HR pathway is dependent on different proteins including BRCA1 and BRCA2 and others (e.g. MNR complex, CtIP, MRE11, RAD51, ATM, H2AX, PALB2, RPA, RAD52) [2, 3].\n\nEffective DNA repair is essential to maintain DNA integrity – so BRCA1/2 deficient cells show a high degree of chromosomal instability which increases the risk of malignant transformation [4, 5]. Germline mutations of BRCA1/2 (gBRCA-mut) were described in carcinoma of the ovary in 5–18% and in some other solid malignant tumors including breast carcinoma, pancreatic carcinoma and less frequent in prostate carcinoma. It became apparent that BRCA mutations also occur in sporadic carcinomas and these tumors respond to Poly (ADP-ribose) polymerase- (PARP) inhibition. The full significance of somatic BRCA mutations as a biomarker for the prediction of therapeutic response to PARP inhibition is not entirely clear but ovarian cancer patients with a somatic BRCA mutation are equally likely to benefit from treatment with PARP inhibitors as those with a germline mutation of BRCA. Some authors suggest to perform somatic BRCA testing in routine clinical diagnostics of all advanced tumors, which are potentially amenable to PARP inhibitors [3, 6–11].\n\nEach BRCA variant was classified according to the established IARC classification. This classification ranges from class 1 variants (not pathogenic or of no clinical significance) via class 2 (likely not pathogenic or of no clinical significance), class 3 (uncertain), class 4 (likely pathogenic) to class 5 variants (definitively pathogenic) according to different databases (compare: BRCA mutation database: http://arup.utah.edu/database/BRCA/orClinVardatabase:http://www.ncbi.nlm.nih.gov/clinvar/ or Universal mutation database BRCA share: http://www.umd.be/BRCA1/).\n\nParallel sequencing\nTumor areas were marked on H&E-stained tissue slides by a pathologist (AQ) and DNA was extracted from corresponding unstained 10 μm thick slides by manual macrodissection. After proteinase K treatment, the DNA was automatically purified using the Maxwell 16 FFPE Tissue LEV DNA Purification Kit (Promega, Madison, USA) on the Maxwell 16 Instrument (Promega) following the manufacturers’ protocol. The DNA concentration was measured using a real-time qPCR-based method.\n\nBy parallel sequencing, all tumor manifestations were analyzed for BRCA1 and BRCA2 mutation and were further analyzed using a panel of 12 other genes resulting altogether in a total of 452 amplicons. Additionally, in these tumor manifestations microsatellite status was checked using five different mononucleotide markers: BAT25, BAT26, NR-21, NR-22 and NR-27 [12].\n\nIsolated DNA (10 ng each) was amplified with the Human BRCA1 and BRCA2 GeneRead DNAseq Targeted Panel V2 (Qiagen, Hilden, Germany) or with a customized GeneRead DNAseq Alignment and annotation was done using a modified version of a previously described method [13]. Resulting BAM files were visualized using the Integrative Genomics Viewer (IGV; http://www.broadinstitute.org/igv/, Cambridge; USA). A 5% cutoff for variant calls was used and results were only interpreted if the coverage was > 200×.\n\nHistopathological findings\nThe primary MANEC of the ileum showed two different tumor components: One gland-forming adenocarcinoma-component including PAS-positive mucins in the tumor cell cytoplasm or gland lumina as well as a solid tumor forming neuroendocrine carcinoma-component showing a strong and diffuse immunohistochemical positivity for synatophysin and to a lesser content chromogranin A as well (Fig. 1). The tumor infiltrated the subserosal tissue of the ileum and presented with vessel invasion including a single regional lymph node metastasis. Both, the brain and liver metastasis showed the adenocarcinoma-component.Fig. 1 a Primary MANEC of the ileum (HE, 2,5×) showing the gland-forming adenocarcinoma-component (left side) as well as the solid forming neuroendocrine carcinoma component (right side); b the gland forming adenocarcinoma showing PAS-positive mucins in gland lumina (PAS, 20×); c the solid growth-pattern of the neuroendocrine carcinoma component (HE, 20×); d Immunohistochemistry using an antibody against synaptophysin – diffuse and strong positivity of all tumor cells in the neuroendocrine-carcinoma component (synaptophysin, 5×); e Immunohisto-chemistry using an antibody against chromogranin A – more patchy positivity in the neuroendocrine-carcinoma component (chromogranin A, 5×) f1 Metastasis in liver and f2 in the brain, both formed by the adenocarcinoma component (HE, 10× and 20×)\n\n\n\nCase presentation\nWe describe the case of a 74-year old man presented to our hospital due to a liver tumor in the segments II and III as well as satellite metastatic lesions in the right liver lobe. After taken a liver biopsy from the tumor the diagnosis of an adenocarcinoma was established and interpreted as an unresectable cholangiocarcinoma, initially lacking the information of the primary tumor in the small intestine. The patient was treated with a mono-chemotherapy of Gemcitabine ((1000 mg/qm d1–8) 12/2015–03/2016) followed by selective internal radiotherapy (SIRT) analogous to the SIRCCA study protocol (ClinicalTrials.gov Identifier: NCT02807181). Because of anemia and poor general condition the administration of cisplatin was withheld. In the further course of treatment an additional tumor site in the ileum was detected and progression with cerebral metastasis occurred. The ileum tumor and one brain metastasis were removed. The ileum tumor was classified as a mixed adeno-neuroendocrine carcinoma (MANEC). Tumor manifestations in the liver and in the brain could be characterized as metastases from the adenocarcinoma component (Fig. 1).\n\nIn the further course we patient was treated with capecitabine (500 mg 2–0-2, 5d/week) 05–09/2016). This treatment finally failed 4 months later and all liver metastases showed progression. The treatment failure was the reason to analyze the tumor-DNA for molecular alterations using two panels of 14 genes including BRCA 1 and BRCA 2 (452 amplicons in total; compare versions below). We verified the same BRCA1 mutation (c.3700_3704delGTAAA p.V1234Qfs*8) with a very high allele frequency up to 96% in all locations using ultra deep sequencing in the formalin-fixed paraffin embedded material (Fig. 2). According to different databases (UMD, ARUP, ClinVar) this BRCA1 mutation was classified as pathogenic (class 5). The MANEC was microsatellite stable. The mutational hot spots of all other analyzed genes (KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA and BRCA2) were wild type.Fig. 2 BRCA deletion (BRCA1: c.3700_3704delGTAAA; p.V1234Qfs*8) as visualized by the IGV (integrative genomics viewer; www.broadinstitute.org/igv/)\n\n\n\nAccording to the encouraging experiences using combined platin-based chemotherapy and PARP-inhibitors in BRCA-mutated ovarian carcinomas the molecular results have been the trigger for the personalized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the PARP1-inhibitor olaparib analogous to the treatment protocol of Oza et al. [14] following a bridging therapy with capecitabine (olaparib 200 mg capsules twice daily, administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m2, administered intravenously on day 1) and carboplatin (4 mg/mL per min) in total five cycles for the following 4 months.\n\nAll tumor manifestations demonstrated with a significant tumor regression in the MINT analysis and Ga-68-Dotatate PET-CT after 3 months of treatment (mind analysis Table 1 and Ga-68-Dotatate PET-CT Fig. 3) – and the persistent highly necrotic liver metastasis of 6 cm could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases (compare time table, Table 2).Table 1 Response to personalized treatment (including olaparib): MINT analysisTumor showed significant regression under personalized treatment approach using olaparib, carboplatin and paclitaxel (data shown before and 3 months after initialization of personalized treatment)\n\nFig. 3 Response to personalized treatment (including olaparib): Ga-68 Dotatate PET/CT. Upper row (May 2016) demonstrating an 8 cm tumor in the left liver lobe below physiologic liver uptake and a SRS-positive brain metastasis. Lower row: (Nov 2016): Follow-up PET/CT with tumor shrinkage to 6 cm and disappearance of the brain metastasis\n\nTable 2 Time table\n\nTime period\tTherapy\t\n12.2015\tPat. presented with liver and brain metastases.\t\n12.2015–03.2016\tGemcitabine mono 1000 mg/qm d1–8 15 and selective internal radiotherapy (SIRT) analogous to the SIRCCA study protocol.Excision of the tumor in the ileum and one brain metastasis (02.2016)\t\n05.2016–09.2016\tCapecitabine 500 mg (2–0-2, 5d/week)\t\n12.09.16\t1. Cycle: Olaparib (200 mg capsules twice daily, administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m2, administered intravenously on day 1) and carboplatin (4 mg/mL per min)\t\n04.10.2016\t2. Cycle: Olaparib (200 mg capsules twice daily, administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m2, administered intravenously on day 1) and carboplatin (4 mg/mL per min)\t\n31.10.2016\t3. Cycle: Olaparib (100 mg capsules twice daily (reduced dosage), administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m2, administered intravenously on day 1) and carboplatin (4 mg/mL per min)\t\n05.12.2016\t4. Cycle: Olaparib (100 mg capsules twice daily (reduced dosage), administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m2, administered intravenously on day 1) and carboplatin (4 mg/mL per min)\t\n09.01.2017\t5. Cycle: Olaparib (100 mg capsules twice daily (reduced dosage), administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m2, administered intravenously on day 1) and carboplatin (4 mg/mL per min)\t\n02.2017\tliver metastases could be removed\t\n12.2017\tLast CT-scan staging: still no further tumor manifestations/still no metastasis\t\n\n\nDiscussion and conclusion\nTo the best of our knowledge this is the first description of pathogenic and treatable germline-related BRCA1 mutation in mixed adeno-neuroendocrine carcinoma (MANEC) of the small bowel. There was no known personal history of a previous malignant tumor. Nevertheless, the high allele frequency of the BRCA1 mutation in all tumor manifestations suggested a germline background. Consequently, we tested histologically tumor-free ileum mucosa and were able to detect the same BRCA1 mutation with an allele frequency of 48%. This finding clearly identifies the mutation as germline and a deletion of the wild type BRCA1 allele in the tumor. The homogeneous distribution of BRCA1 mutated tumor cells in the primary tumor and in the different metastasis analyzed here suggests a clonal origin and a causative role of this second hit. Even though a gBRCA1 mutation could be a marker for prostate cancer we did not find any indications for prostate cancer [7].\n\nAccording to treatment protocols established in BRCA mutated ovarian carcinomas we successfully applied combined chemotherapy of carboplatin, paclitaxel and the PARP1-inhibitor olaparib. Initially, we assumed a somatic background of the BRCA1 mutation in our treated patient, because there was no known personal history of a prior malignant tumor in the 74 year-old man. The germline background of the BRCA1 mutated small bowel carcinoma (like in ovarian adenocarcinoma) is especially promising for a successful combination therapy using platinum-based chemotherapy and a PARP inhibitor (e.g. Olaparib). It has to be questioned whether the somatic pathogenic BRCA mutation itself is the main predictor of an effective PARP inhibition [3].\n\nBeyond BRCA1/2 somatic mutations or the promoter methylation of BRCA some other alterations are potential markers of an effective PARP inhibition (like microsatellite-instable cancers with MRE11-dominant negative mutations, PTEN deficiency, ATM mutation and FANCF promoter methylation) [15].\n\nAdditionally, first evidence came up that gBRCA mutated ovarian carcinoma are sensitive to therapies using immune-checkpoint inhibition most likely due to its higher mutational load compared to wild type ovarian carcinoma [16]. It remains to be shown whether our BRCA mutated MANEC also benefit from immune-checkpoint inhibition as an additional future treatment option.\n\nOur findings are remarkable in many ways: Here we provide first evidence of a therapy susceptible BRCA1 mutation in a metastasized mixed adeno-neuroendocrine carcinoma (MANEC) of small bowel.\n\nThe germline background of our patient was unexpected because he is a 74-year old man with no previously known tumor burden. Currently, there is increasing evidence that the first germline associated tumor manifestation (e.g. endometrial carcinoma in Lynch syndrome) may occur beyond the sixth decade of living which means that we should be aware of the familiar background in tumors of older patients as well [17].\n\nAbbreviations\nBRCA1Breast cancer gene 1\n\nMANECMixed adeno-neuroendocrine carcinoma\n\nPARPPoly (ADP-ribose) polymerase\n\nAvailability of data and materials\nThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAQ, DW and CB were responsible for study concept and design. AQ, DW, TG, MD, CB, AB, WR, NH, MS and LT were responsible for acquisition of data. AQ, AB, CH and MS were responsible for analyses and interpretation of data. AQ and SM were responsible for writing of the manuscript. TZ was responsible for critical revision of the manuscript. HA, TZ, CH, PK, PP, HG, LT and SB were responsible technical or material support. CH, RB and SM were responsible for study supervision. All authors have fully read the manuscript and have approved the accuracy and completeness of the content of all parts of the manuscript and assume responsibility for it.\n\nEthics approval and consent to participate\nProcedures were followed as outlined in accordance with ethical standards formulated in the Helsinki Declaration 1975 (and revised in 1983). Informed consent was obtained prior to participation in this study with approval by the Ethics Committee at the University Hospital, Cologne (reference number: 13–091). This approval was necessary due to gene analysis made in this study.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images, and is available on request.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Schrock AB, Devoe CE, McWilliams R, Sun J, Aparicio T, Stephens PJ, Ross JS, Wilson R, Miller VA, Ali SM, et al. Genomic profiling of small-bowel adenocarcinoma. JAMA Oncol. 2017;3(11):1546–53.\n2. Lupo B Trusolino L Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited Biochim Biophys Acta 2014 1846 1 201 215 25026313 \n3. Moschetta M George A Kaye SB Banerjee S BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer Ann Oncol 2016 27 8 1449 1455 10.1093/annonc/mdw142 27037296 \n4. Hoeijmakers JH Genome maintenance mechanisms for preventing cancer Nature 2001 411 6835 366 374 10.1038/35077232 11357144 \n5. Levy-Lahad E Friedman E Cancer risks among BRCA1 and BRCA2 mutation carriers Br J Cancer 2007 96 1 11 15 10.1038/sj.bjc.6603535 17213823 \n6. Yuan W Zhang Z Dai B Wei Q Liu J Liu Y Liu Y He L Zhou D Whole-exome sequencing of duodenal adenocarcinoma identifies recurrent Wnt/beta-catenin signaling pathway mutations Cancer 2016 122 11 1689 1696 10.1002/cncr.29974 26998897 \n7. O'Sullivan CC Moon DH Kohn EC Lee JM Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-associated and BRCA-like solid tumors Front Oncol 2014 4 42 24616882 \n8. Ledermann J Harter P Gourley C Friedlander M Vergote I Rustin G Scott CL Meier W Shapira-Frommer R Safra T Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial Lancet Oncol 2014 15 8 852 861 10.1016/S1470-2045(14)70228-1 24882434 \n9. Hennessy BT Timms KM Carey MS Gutin A Meyer LA Flake DD 2nd Abkevich V Potter J Pruss D Glenn P Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer J Clin Oncol 2010 28 22 3570 3576 10.1200/JCO.2009.27.2997 20606085 \n10. Pennington KP Walsh T Harrell MI Lee MK Pennil CC Rendi MH Thornton A Norquist BM Casadei S Nord AS Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas Clin Cancer Res 2014 20 3 764 775 10.1158/1078-0432.CCR-13-2287 24240112 \n11. Ashworth A A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair J Clin Oncol 2008 26 22 3785 3790 10.1200/JCO.2008.16.0812 18591545 \n12. Nardon E, Glavac D, Benhattar J, Groenen PJ, Hofler G, Hofler H, Jung A, Keller G, Kirchner T, Lessi F, et al. A multicenter study to validate the reproducibility of MSI testing with a panel of 5 quasimonomorphic mononucleotide repeats.\n13. Peifer M Fernandez-Cuesta L Sos ML George J Seidel D Kasper LH Plenker D Leenders F Sun R Zander T Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer Nat Genet 2012 44 10 1104 1110 10.1038/ng.2396 22941188 \n14. Oza AM Cibula D Benzaquen AO Poole C Mathijssen RH Sonke GS Colombo N Spacek J Vuylsteke P Hirte H Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial Lancet Oncol 2015 16 1 87 97 10.1016/S1470-2045(14)71135-0 25481791 \n15. Murai J Huang SY Das BB Renaud A Zhang Y Doroshow JH Ji J Takeda S Pommier Y Trapping of PARP1 and PARP2 by clinical PARP inhibitors Cancer Res 2012 72 21 5588 5599 10.1158/0008-5472.CAN-12-2753 23118055 \n16. Higuchi T Flies DB Marjon NA Mantia-Smaldone G Ronner L Gimotty PA Adams SF CTLA-4 blockade synergizes therapeutically with PARP inhibition in BRCA1-deficient ovarian Cancer Cancer Immunol Res 2015 3 11 1257 1268 10.1158/2326-6066.CIR-15-0044 26138335 \n17. Mills AM Liou S Ford JM Berek JS Pai RK Longacre TA Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer Am J Surg Pathol 2014 38 11 1501 1509 10.1097/PAS.0000000000000321 25229768\n\n",
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"issue": "18(1)",
"journal": "BMC gastroenterology",
"keywords": "BRCA1 mutation; Germline-related; PARP-inhibition; Personalized treatment; Small bowel mixed adeno-neuroendocrine carcinoma (MANEC)",
"medline_ta": "BMC Gastroenterol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D019313:BRCA1 Protein; D001932:Brain Neoplasms; D016190:Carboplatin; D018278:Carcinoma, Neuroendocrine; D018095:Germ-Line Mutation; D006801:Humans; D007078:Ileal Neoplasms; D008113:Liver Neoplasms; D008297:Male; D017239:Paclitaxel; D000067856:Poly(ADP-ribose) Polymerase Inhibitors",
"nlm_unique_id": "100968547",
"other_id": null,
"pages": "75",
"pmc": null,
"pmid": "29855275",
"pubdate": "2018-05-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23118055;26138335;22941188;20606085;28617917;24882434;18591545;27037296;17213823;24240112;25481791;26998897;25026313;24616882;25229768;21051996;11357144",
"title": "Therapy susceptible germline-related BRCA 1-mutation in a case of metastasized mixed adeno-neuroendocrine carcinoma (MANEC) of the small bowel.",
"title_normalized": "therapy susceptible germline related brca 1 mutation in a case of metastasized mixed adeno neuroendocrine carcinoma manec of the small bowel"
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"abstract": "Attempted murder by repeated poisoning is quite rare. The authors describe the case of a 62-year-old man who was admitted to an intensive care unit (ICU) for neurological disturbances complicated by inhalation pneumopathy. He presented a loss of consciousness while his wife was visiting him at the ICU (H0). Forty-eight hours later (H48), police officers apprehended the patient's wife pouring a liquid into his fruit salad at the hospital. Toxicological analyses of a blood sample and the infusion equipment (H0), as well as the fruit salad and its container (H48), confirmed the attempted poisoning with cyamemazine (H0) and hydrochloric acid (H48). In order to evaluate the anteriority of poisonings, hair analysis was requested and the medical records of the 6 previous months were also examined. Two 6-cm brown hair strands were sampled and the victim's medical record was seized in order to determine the treatments he had been given during the previous six months. Segmental hair testing on two 6-cm brown hair was conducted by GC-MS, LC-DAD and LC-MS/MS (0-2/2-4/4-6 cm; pg/mg). Haloperidol (9200/1391/227), amitriptyline (7450/1850/3260), venlafaxine (332/560/260), that had never been part of the victim's treatment were detected, as well as some benzodiazepines (alprazolam, bromazepam, nordazepam); cyamemazine was also detected in all the segments (9960/1610/2367) though only a single dose administration was reported in the medical records. The toxicological analyses performed at H0 and H48 confirmed the homicide attempts in the ICU. In addition, comparison of the results in hair analysis with the medical records confirmed repeated poisoning attempts over the previous six months, and thus explain the origin of the disorders presented by the victim. This case serves to remind us that repeated attempted murder can be difficult to diagnose and that hair analysis can be an effective way to detect such attempts.",
"affiliations": "AP-HM, Hôpital de la Timone, Service de Médecine Légale, Marseille, France.;Aix Marseille Univ, CNRS, EFS, ADES, Marseille, France.;AP-HM, Hôpital de la Timone, Service de Médecine Légale, Marseille, France.;Laboratoire TOXLAB, 75018 Paris, France.;Laboratoire TOXLAB, 75018 Paris, France.;AP-HM, Hôpital de la Timone, Service de Médecine Légale, Marseille, France; Aix Marseille Univ, CNRS, EFS, ADES, Marseille, France.;AP-HM, Hôpital de la Timone, Service de Médecine Légale, Marseille, France; Aix Marseille Univ, INSERM, INMED, Marseille, France. Electronic address: apelissier@ap-hm.fr.",
"authors": "Baillif-Couniou|Valérie|V|;Bartoli|Christophe|C|;Sastre|Caroline|C|;Chèze|Marjorie|M|;Deveaux|Marc|M|;Léonetti|Georges|G|;Pélissier-Alicot|Anne-Laure|AL|",
"chemical_list": "D002424:Caustics; D010640:Phenothiazines; D011619:Psychotropic Drugs; D001569:Benzodiazepines; D000639:Amitriptyline; D000069470:Venlafaxine Hydrochloride; C028457:cyamemazine; D006220:Haloperidol; D006851:Hydrochloric Acid",
"country": "England",
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"doi": "10.1016/j.jflm.2018.01.001",
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"issn_linking": "1752-928X",
"issue": "54()",
"journal": "Journal of forensic and legal medicine",
"keywords": "Hair analysis; Poisoning; Repeated attempted murder; Toxicological analysis",
"medline_ta": "J Forensic Leg Med",
"mesh_terms": "D000639:Amitriptyline; D001569:Benzodiazepines; D002424:Caustics; D002853:Chromatography, Liquid; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006197:Hair; D006220:Haloperidol; D006708:Homicide; D006801:Humans; D006851:Hydrochloric Acid; D008297:Male; D008875:Middle Aged; D010640:Phenothiazines; D011619:Psychotropic Drugs; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "101300022",
"other_id": null,
"pages": "82-86",
"pmc": null,
"pmid": "29331713",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Repeated attempted homicide by administration of drugs documented by hair analysis.",
"title_normalized": "repeated attempted homicide by administration of drugs documented by hair analysis"
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"activesubstancename": "HYDROXYZINE HYDROCHLORIDE"
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"abstract": "Metformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity.\n\n\n\nHere, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes.\n\n\n\nParent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients.\n\n\n\nThese results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.",
"affiliations": "Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.;Department of Pediatric Inpatient Medicine, University of Utah and Primary Children's Hospital, Salt Lake City, Utah.;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.;University of California Davis School of Medicine, Sacramento, California.;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.;Fundación Valle del Lili, Clinical Research Center, Cali, Colombia.;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.;Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.",
"authors": "Biag|Hazel Maridith B|HMB|0000-0003-1786-5847;Potter|Laura A|LA|;Wilkins|Victoria|V|;Afzal|Sumra|S|;Rosvall|Alexis|A|;Salcedo-Arellano|Maria Jimena|MJ|0000-0002-2412-9146;Rajaratnam|Akash|A|;Manzano-Nunez|Ramiro|R|0000-0001-7444-9634;Schneider|Andrea|A|0000-0002-4674-7244;Tassone|Flora|F|;Rivera|Susan M|SM|;Hagerman|Randi J|RJ|0000-0001-5029-8448",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1002/mgg3.956",
"fulltext": "\n==== Front\nMol Genet Genomic MedMol Genet Genomic Med10.1002/(ISSN)2324-9269MGG3Molecular Genetics & Genomic Medicine2324-9269John Wiley and Sons Inc. Hoboken 10.1002/mgg3.956MGG3956Original ArticleOriginal ArticlesMetformin treatment in young children with fragile X syndrome BIAG et al.Biag Hazel Maridith B. https://orcid.org/0000-0003-1786-5847\n1\n\n2\nhbbiag@ucdavis.edu Potter Laura A. \n1\n\n2\nWilkins Victoria \n3\nAfzal Sumra \n1\n\n2\nRosvall Alexis \n4\nSalcedo‐Arellano Maria Jimena https://orcid.org/0000-0002-2412-9146\n1\n\n2\nRajaratnam Akash \n1\n\n5\nManzano‐Nunez Ramiro https://orcid.org/0000-0001-7444-9634\n6\nSchneider Andrea https://orcid.org/0000-0002-4674-7244\n1\n\n2\nTassone Flora \n1\n\n7\nRivera Susan M. \n1\n\n8\n\n9\nHagerman Randi J. https://orcid.org/0000-0001-5029-8448\n1\n\n2\n\n1 \nMedical Investigation of Neurodevelopmental Disorders (MIND) Institute\nUniversity of California Davis Medical Center\nSacramento\nCalifornia\n\n2 \nDepartment of Pediatrics\nUniversity of California Davis Medical Center\nSacramento\nCalifornia\n\n3 \nDepartment of Pediatric Inpatient Medicine\nUniversity of Utah and Primary Children’s Hospital\nSalt Lake City, Utah\n\n4 \nUniversity of California Davis School of Medicine\nSacramento\nCalifornia\n\n5 \nCase Western Reserve University School of Medicine\nCleveland\nOhio\n\n6 \nFundación Valle del Lili\nClinical Research Center\nCali\nColombia\n\n7 \nDepartment of Biochemistry and Molecular Medicine\nUniversity of California Davis Medical Center\nSacramento\nCalifornia\n\n8 \nDepartment of Psychology\nUniversity of California Davis\nDavis\nCalifornia\n\n9 \nNeurocognitive Development Lab\nCenter for Mind and Brain\nDavis\nCalifornia\n* Correspondence\n\nHazel Maridith B. Biag, MIND Institute UCDMC, 2825 50th Street, Sacramento, California 95817.\n\nEmail: hbbiag@ucdavis.edu\n14 9 2019 11 2019 7 11 10.1002/mgg3.v7.11e95621 6 2019 07 8 2019 © 2019 UC Davis MIND Institute. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nBackground\nMetformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity.\n\nMethods\nHere, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes.\n\nResults\nParent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients.\n\nConclusion\nThese results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.\n\nFMR1fragile X syndromemetformintargeted treatmentstranslational medicineDepartment of Health and Human Services Administration for Children and Families90DD05069MIND Institute Intellectual and Developmental Disabilities Research CenterU54 HD079125Azrieli FoundationNational Center for Advancing Translational Sciences and National Institutes of HealthUL1 TR001860 source-schema-version-number2.0component-idmgg3956cover-dateNovember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:03.11.2019\n\n\nBiag \nHMB \n, \nPotter \nLA \n, \nWilkins \nV \n, et al. Metformin treatment in young children with fragile X syndrome . Mol Genet Genomic Med . 2019 ;7 :e956\n10.1002/mgg3.956\n==== Body\n1 INTRODUCTION\nFragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and is typically diagnosed between 2 and 3 years of age at the time language delays and behavioral manifestations emerge (Bailey, Cody Hazlett, Roberts, & Wheeler, 2011). It is caused by a trinucleotide repeat expansion of CGG in the promoter region of Fragile X Mental Retardation‐1 (FMR1, OMIM: 309550) gene, leading to methylation, transcriptional silencing, and the absence or deficiency of fragile X mental retardation protein (FMRP).\n\nMetformin was originally FDA‐approved for its effects in lowering blood glucose levels in patients with type 2 diabetes (T2D). It is safe and effective at doses up to 1,000 mg twice a day in children 10–16 years old with T2D (Jones, Arslanian, Peterokova, Park, & Tomlinson, 2002). Because its mechanism of action does not directly stimulate insulin, metformin is unlikely to lead to hypoglycemic episodes (Bodmer, Meier, Krahenbuhl, Jick, & Meier, 2008; Bolen, Feldman, Vassy, &, Feldman, & Vassy&&, 22007). Metformin has since expanded to the treatment of obesity and overeating in children and adults with and without T2D (Anagnostou et al., 2016; Klein, Cottingham, Sorter, Barton, & Morrison, 2006; Muzar, Lozano, Kolevzon, & Hagerman, 2016; Park, Kinra, Ward, White, & Viner, 2009). For patients who are nonobese, metformin has been effective in glycemic control (Ong, Molyneaux, Constantino, Twigg, & Yue, 2006). In FXS, overeating is commonly associated with psychiatric comorbidities including anxiety and obsessive‐compulsive behaviors. Also, the Prader‐Willi‐phenotype (PWP) of FXS is found in less than 10% of children with FXS. The FXS‐PWP is associated with hyperphagia, morbid obesity, delayed puberty, and lowered cytoplasmic FMRP interacting protein (CYFIP1, OMIM: 606322) expression (Muzar et al., 2016; Nowicki et al., 2007). The common use of atypical antipsychotics in children with FXS further increases their risk for obesity. Treatment with metformin showed clinical improvement in eating behaviors and weight loss in those with and without FXS‐PWP and is now recommended for the treatment of obesity in FXS (Dy et al., 2018).\n\nRecent research in animal models of FXS has demonstrated that metformin, a T2D medication, can rescue both behavioral and cognitive features of FXS. In the Drosophila FXS model, metformin rescued abnormalities of circadian rhythm and memory problems (Monyak et al., 2017). In the FMR1 knock out (KO) mouse, metformin rescued many deficits including: social deficits, seizures, macroorchidism, and was also seen to improve extracellular signal regulated kinase (ERK) signaling, eukaryotic translation initiation factor 4e (EIF4E, OMIM: 133440) phosphorylation, and matrix metalloproteinase 9 (MMP9, OMIM: 120361) overexpression (Esfahanian et al., 2012; Gantois et al., 2017; Gantois, Popic, Khoutorsky, & Sonenberg, 2018). Upregulation of MMP9 has been shown to interfere with synaptic maturation and plasticity in both the FMR1 KO mouse (Bilousova et al., 2009; Rotschafer, Trujillo, Dansie, Ethell, & Razak, 2012) and in patients with FXS (AlOlaby et al., 2017; Dziembowska & Wlodarczyk, 2012). Metformin has been shown to lower MMP9 levels via reduction of EIF4E phosphorylation which promotes translation of a subset of mRNAs including MMP9 (Gantois et al., 2017, 2018; Hoeffer et al., 2012; Li et al., 2017; Muzar et al., 2016). These developments have led to the off‐label clinical use of metformin in patients with FXS. The first seven cases of patients ages 4–60 years old treated clinically demonstrated improvements on the Aberrant Behavior Checklist‐Community (ABC‐C), language, and conversational skills per parent report (Dy et al., 2018). The growing interest of metformin as a feasible alternative for this population led to the initiation of a controlled trial of metformin for individuals with FXS between the ages of 6–25 years old (NCT03479476). In addition, a smaller open label trial of metformin is also underway for those 10–40 years old with FXS (NCT03722290).\n\nPrevious studies have suggested that targeted treatments may work best for young children with FXS (Berry‐Kravis et al., 2017; Greiss Hess et al., 2016; Leigh et al., 2013). Furthermore, recent research in the FMR1 KO mouse shows that correction of key disruptions in neuronal development during the critical period in young animals results in restoration of synaptic development, produces a long‐lasting rescue of somatosensory circuit function, and normalizes differentially expressed proteins (He et al., 2017). Such findings indicate a critical period of development during which targeted interventions may have significant and durable effects on developmental trajectory and outcomes in FXS. These data suggest that metformin would have a significant benefit in young children with FXS; here we describe nine boys between 2 and 7 years old with FXS who underwent off‐label clinical treatment with metformin for a period of at least 3 months. It is important to emphasize that represented here are individual cases of young children with FXS treated clinically with metformin, not an open‐label trial; therefore, there is no specified protocol homogenizing the sample.\n\n2 MATERIALS AND METHODS\nPatients were seen clinically at the Fragile X Treatment and Research Center at the MIND Institute at the University of California, Davis Health for management of FXS. All patients had a full mutation FXS documented via FMR1 (GenBank: NG_007529.2) DNA testing. Laboratory studies were attempted pre‐ treatment whenever possible and included fasting glucose, a chemistry panel, and HbA1c. When available, copies of previous FXS testing, including FMR1 methylation status, were also obtained from caregivers or patient records with permission. Post‐treatment laboratory studies were collected in many cases at patients’ primary care locations and were therefore not available to report here. All families signed an institutional review board‐approved consent form for research involving the blood work and developmental testing and gave consent for publication of their clinical case histories.\n\nParents completed the ABC‐C and reported on behavior and symptoms pre‐ and post‐metformin treatment. The ABC‐C was scored using the FXS algorithm (Sansone et al., 2012). The ABC‐C is a 58‐item global behavior checklist implemented for the measurement of treatment effects in individuals with ID; a factor analysis of the ABC‐C specifically in FXS generated a 6‐factor structure: irritability, lethargy, stereotypy, hyperactivity, inappropriate speech, and social avoidance (Berry‐Kravis et al., 2017). Higher subscale scores are correlated with more severe aberrant behavior; therefore, a decrease in the scores across each domain is indicative of an improvement of that behavior. Length of time between pre‐ and post‐treatment ABC‐C administration ranged from 1 to 7 months due to the natural variability in duration of clinical follow‐up and caregiver report.\n\nDevelopmental testing was administered pre‐ and post‐treatment for six of the nine subjects using the Mullen scales of early learning (MSEL) (Mullen, 1995). The MSEL includes four domains: fine motor, receptive language, expressive language, and visual reception, all of which have age equivalent scores generated. In place of the early learning composite (ELC) score, which is an age‐normed standard score generated from the aforementioned domains, a global development age (GDA) score was used. The GDA averages the age equivalents across the four domains (Roberts et al., 2009) and thus provides a consistent metric that can be utilized as a measurement for improvement in this report. For one of the subjects, pre‐treatment age equivalent scores from three of the four domains from the Bayley Scales of Infant and Toddler Development (Bayley, 2006) were used in place of pre‐treatment MSEL data, which was not available. The moderate correlation between the two developmental tests is reported in the MSEL test manual (Farmer, Golden, & Thurm, 2016; Mullen, 1995). Due to the clinical nature of this study, there is variability in the pre‐ and post‐testing time points for the MSEL among the cases which ranges from 7 to 26 months after pre‐treatment testing.\n\nStatistical analyses of pre‐ and post‐treatment ABC‐C and developmental testing scores are presented in median and interquartile ranges. They were done in Stata 14 utilizing a nonparametric test “signrank.” Stata command tests the equality of matched pairs of observations by using the Wilcoxon matched‐pairs signed‐ranks test and generates p‐values (Wilcoxon, 1945). The null hypothesis is that both distributions are the same. A pre‐specified significance level of p < .05 was assumed. Additionally, using MSEL age equivalent scores, mean linear slopes in all subscales and GDA were generated using the individual trajectories per patient. The slope was then compared to m = 0.48, the experimentally determined expected rate of developmental gains seen in children with FXS (Bailey Jr., Hatton, & Skinner, 1998).\n\n3 RESULTS\n3.1 Case 1\nPatient 1 is a 4‐year, 2‐month‐old boy diagnosed with FXS at 9 months of age due to missed motor milestones and delayed babbling. He was adopted at birth and lives with his adoptive family. His birth weight was 3.6 kg and he had respiratory distress requiring immediate treatment. He was diagnosed with neonatal pneumonia, requiring a 7‐day Neonatal Intensive Care Unit stay. He sat alone at 8 months and took steps at 13 months. With the intention of improving speech, at 12 months he was started on sertraline but with limited results; his first words were spoken at 16 months, with very slow progress in language thereafter. He had tympanostomy tubes placed at age 2 without significant improvement in language. He has a history of awakening multiple times per night for a total of 2–4 hr. Behaviorally, he is generally a “happy and social child with mild anxiety.”\n\nOn examination at age 2 years, typical physical features of FXS were observed, and baseline laboratory findings were normal (see Table 1). He was started on metformin at 25 mg of the liquid form that is 100 mg/ml at dinner, and his dose was gradually increased to 200 mg twice a day (bid) over 1 year (see Table 1). After initiation of metformin, his sleep disturbance resolved, only occasionally awakening once for roughly 30 min. Two weeks after initiation, he went from stacking 3–4 blocks to stacking a tower of 11 or more blocks; within a few more weeks, he began building more complex structures comprised of different size blocks. He showed marked improvement in self‐help and motor activities, including toilet training, clearing the table and loading the dishwasher, brushing his own teeth, dressing independently, and learning how to make toast. His preschool teachers, who were unaware of metformin treatment, told his mother that “it's like something just clicked or he just woke up. He's a whole different kid.”\n\nPatient 1’s ABC‐C composite score improved on metformin (see Table 2). With respect to language acquisition, he had 10–20 verbal words and 20 signs at the time of initiation. Six months later, he demonstrated use of 60–80 words, including several 2‐word phrases and 100 signs, and his mother reports that his cognitive skills have significantly improved as well. He tolerated all medication increases with only minor self‐limited diarrhea for 1–2 days. Fasting blood glucose has remained stable at all doses. He is tolerating his current dose without problems.\n\nTable 1 Summary of all nine cases\n\nCase/Age at initiation/sex\tDiagnoses\tFamily history\tPhysical features\tCGG repeats\tMethylation status\t\nFMR1 mRNA expression level\tPre‐Tx laboratory findings\tMetformin dose\tOther medications\t\nCase 1. 2‐year‐old, male\tFXS\tAdopted; family history unknown\tBroad forehead, epicanthal folds, hyperextensible joints to 90 degrees, double jointed thumbs, slight hypospadias, 4 ml testicular volume\t320, 490, 790, 1,280\tMethylation mosaicism with a full mutation methylated in ~67% of the cells\t0.18 (±0.001)\tHbA1c: 5.0, FBS: 84\t25 mg QD increased gradually over 1 year to 200 mg BID (31.01 mg kg−1 day−1)\tSertraline 2.5 mg, folic acid 5 mg, N‐acetyl cysteine, melatonin, probiotic, vitamins C, D & E\t\nCase 2. 4‐year‐old, male\tFXS, ASD, OSA and CSA\tMother (carrier, 99 CGG repeats), maternal grandmother (carrier, no FXTAS)\tLess than 6 ml testicular volume, small umbilical hernia, finger joints hyperextensible with MP extension to 90 degrees, single palmar crease, bilaterally, flat feet, bilaterally\t>200\tFull\tNone\tHbA1c: 4.9, FBS: 92\t50 mg at dinner increased after 1 week to 50 mg BID. Increased after 6 months to 100 mg BID (12.91 mg kg−1 day−1)\tClonidine (0.05 mg qHS, 0.025 mg in the morning), melatonin 1.5 mg qHS, omega‐3, folic acid\t\nCase 3. 6‐year‐old, male\tFXS, epilepsy\tMaternal grandfather (carrier, FXTAS)\tHeterochromia on the right eye, fingers hyperextensible, DTRs 1+ bilaterally on UE\t470\tFull\tNone\tHbA1c: 5.3, FBS: 86\t50 mg at dinner increased to 50 mg BID (5.62 mg kg−1 day−1)\tSertraline 4 mg QD, minocycline 25 mg QD, guanfacine 0.5 mg BID, oxcarbazepine300 mg BID, melatonin 0.25 mg qHS\t\nCase 4. 4‐year‐old, male\tFXS, ASD\tMother (carrier, 77 CGG repeats), maternal grandfather (carrier, 65 repeats), maternal great‐grandmother (carrier), 2 aunts (carriers), 2 cousins (carriers. 77 and 75 CGG repeats, respectively).\tForehead is broad, ears are prominent with cupping bilaterally. Finger joints are hyperextensible with MP extension to 90 degrees. Thumbs are double jointed, feet are completely flat with mild pronation. 4 ml testicular volume\t550\tFull\tNone\tNot Available\t50 mg BID increased after 3 months to 100 mg BID (10.75 mg kg−1 day−1)\tSertraline 5 mg QD, guanfacine 50 mg BID\t\nCase 5. 7‐year‐old, male\tFXS, ASD, ADHD, seizures, cleft lip S/P repair\tMother (carrier)\tCleft lip repair on the left, 3 ml testicular volume\t350. 510, 860\tMethylation mosaicism with a full mutation methylated in >95% of the cells\t0.12 (±0.004)\tHbA1c: 5.4, NF glucose: 102\t500 mg QD at dinner increased after 6 months to 500 mg BID (44.26 mg kg−1 day−1)\tClonidine 0.1 mg TID, clonidine 0.2 mg qHS, adderall 2.5 mg TID, oxcarbazepine 420 mg BID, CBD tincture 0.3 ml, melatonin 10 mg qHS\t\nCase 6. 4‐year‐old, male\tFXS, ASD\tMother (carrier)\tMildly prominent ears, prominent forehead, decreased tone, transverse palmar crease on right palm, bridged palmar crease on left palm, hyperextensible finger joints\t380, 650\tMethylation mosaicism with a full mutation methylated in >95% of the cells\t0.18 (±0.03)\tHbA1c: 4.7, FBS: 87\t50 mg QD at dinner increased after 1 week to 50 mg BID (6.85 mg kg−1 day−1)\tSertraline 2.5 mg QD, lithium orotate 2.5 mg QD, methyl Folate 4 mg QD, vayarin 1 capsule QD, multivitamin with folate QD, fish oil QD, melatonin QD\t\nCase 7. 2‐year‐old, male\tFXS\tMother (carrier), maternal grandmother (carrier), 2 maternal great‐aunts (carriers), 6 maternal cousins (carriers)\tMildly hyperextensible joints in his fingers and hands, flat feet, low tone in his ankles/core.\t480\tFull\tNone\tHbA1c: 4.8, FBS: 78\t50 mg BID increased after 5 months to 150 mg BID (20.27 mg kg−1 day−1)\tSertraline 2.5 mg QD, melatonin 1 mg qHS, multivitamin with folate QD, fish oil QD\t\nCase 8. 3‐year‐old, male\tFXS, ASD\tMother (carrier)\tLong face with high forehead, high palate, large prominent ears, 3 ml testicular volume, flat feet bilaterally with mild pronation\t430, 560,800\tMethylation mosaicism with a full mutation methylated in ~94% of the cells\tNone\tHbA1c: 5.1, FBS: 77\t50 mg at dinner increased after 1–2 weeks to 50 mg BID (6.38 mg kg−1 day−1)\tSertraline 1.25 mg QD\t\nCase 9. 4‐year old, male\tFXS\tMother (carrier)\tProminent ears, bilateral tympanostomy tubes present, mild epicanthal folds bilaterally, hyperextensible fingers, flat feet\t360, 520, 660, 860\tFull\tNone\tFBS: 80\t50 mg QD gradually increased to 150 mg BID (16.67 mg kg−1 day−1)\tSertraline 5.0 mg QD\t\nAbbreviations: ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; BID, two times a day; CBD, cannabidiol; CSA, central sleep apnea; DTRs, deep tendon reflexes; FBS, fasting blood sugar; FMR1 (GenBank: NG_007529.2), fragile X mental retardation 1; FXS, fragile X syndrome; FXTAS, fragile X with tremors and ataxia syndrome; MP, metacarpophalangeal; NF, non‐fasting; OSA, obstructive sleep apnea; Pre‐Tx, pre‐treatment with metformin; QD, once daily; qHS, at hour of sleep; S/P, status post; TID, three times a day; UE, upper extremity.\n\nJohn Wiley & Sons, LtdTable 2 Aberrant Behavior Checklist‐Community (ABC‐C)—prior to metformin treatment and after 1–8 months of treatment\n\nAberrant Behavior Checklist‐Community\t\n \tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\tCase 7\tCase 8\tCase 9\t\nBaseline\tAfter 4 mos.\tBaseline\tAfter 4 mos.\tBaseline\tAfter 3 mos.\tBaseline\tAfter 3 mos.\tBaseline\tAfter 7 mos.\tBaseline\tAfter 1 mos.\tBaseline\tAfter 8 mos.\tBaseline\tAfter 7 mos.\tBaseline\tAfter 6 mos.\t\nABC‐C composite score\t15\t7\t109\t39\t29\t20\t32\t28\t113\t59\t22\t20\t33\t48\t67\t59\t62\t51\t\nI. Irritability\t8\t3\t32\t12\t12\t8\t4\t6\t40\t19\t5\t3\t14\t17\t21\t25\t29\t22\t\nII. Lethargy\t1\t0\t20\t4\t1\t0\t4\t3\t23\t12\t0\t0\t0\t1\t11\t5\t0\t0\t\nIII. Stereotypy\t2\t0\t11\t5\t0\t0\t4\t4\t10\t5\t2\t0\t2\t1\t9\t6\t9\t8\t\nIV. Hyperactivity\t4\t4\t29\t13\t13\t9\t16\t12\t29\t14\t12\t11\t17\t27\t22\t16\t17\t14\t\nV. Inappropriate speech\t0\t0\t6\t2\t2\t2\t0\t0\t9\t8\t3\t6\t0\t2\t4\t6\t7\t7\t\nVI. Social avoidance\t0\t0\t11\t3\t1\t1\t4\t3\t2\t1\t0\t0\t0\t0\t0\t1\t0\t0\t\nJohn Wiley & Sons, Ltd3.2 Case 2\nPatient 2 is a 6‐year, 1‐month‐old boy diagnosed with FXS at the age of 2 years 7 months after parental concern regarding developmental delays. He was born at term and weighed 3.2 kg. He sat alone at 9 months, walked at 19 months, and fed himself and said his first word at 3 years. Past medical history includes reflux since infancy as well as more than 10 episodes of acute otitis media (OM), prompting placement of his first set of pressure equalization (PE) tubes at 3 years, 11 months. After a possible seizure at 7 months, patient 2’s EEG and MRI were normal; no further seizure‐like episodes have occurred since. Once his parents noted loud snoring and brief pauses in breathing, a diagnosis of obstructive and central sleep apnea was made and an adenoidectomy was performed.\n\nBehaviorally, patient 2 chews on things, babbles to himself, and hand flaps when he is excited or anxious. His eye contact is poor with his peers but better with adults; he is hyperactive and engages in perseverative behavior, such as repetitively pouring liquids.\n\nAfter diagnosis, patient 2 was evaluated for an individualized education program and started school where he is receiving speech, occupational, and physical therapy. At 4 years, he initiated metformin at a dose of 50 mg bid which was gradually increased to 100 mg bid (see Table 1). His pre‐ and post‐metformin ABC‐C scores demonstrate an overall decrease across all measured behaviors (see Table 2). Since starting metformin, he has also made progress in expressive language, specifically in expanding his vocabulary. Although baseline MSEL testing was not available for comparison, a post‐treatment MSEL at 58 months yielded age equivalent scores (in months) of 25 for visual reception, 27 for fine motor, 18 for receptive language, and 15 for expressive language, with an ELC of 49. His parents reported no significant side effects aside from loose stools, which resolved spontaneously within two days of metformin initiation.\n\n3.3 Case 3\nPatient 3 is an 8‐year, 6‐month‐old boy with a normal birth history. However, significant developmental delays and hypotonia led to a FXS diagnosis at 18 months. Due to severe anxiety, at 3.5 years he was treated with sertraline, which was beneficial. Attention deficit hyperactivity disorder symptoms emerged at 3 years, and he began guanfacine a year later. The stimulant methylphenidate was introduced at 5 years with beneficial effects on hyperactivity and short attention span. Past medical history includes intermittent exotropia and mild astigmatism, two episodes of OM, and occasional constipation. He currently receives physical, occupational, and speech‐language therapy.\n\nAt the age of 6 years, 7 months, patient 3 initiated metformin at a starting dose of 50 mg at dinner and increased to 50 mg bid without any side effects (see Table 1). He experienced initial improvement in behavior, but after one month he suffered a generalized seizure in the early morning with tonic‐clonic movements and was taken to the ER. An MRI revealed grey matter heterotopias and a possible cortical abnormality of the posterior cingulate gyrus; furthermore, an EEG showed spike wave discharges that were diffusely dispersed throughout the reading. ER laboratory reports showed a normal glucose. At this time, he was started on oxcarbazepine for treatment of his seizures. Due to the occurrence of a second generalized seizure 1 week later, metformin was discontinued.\n\nPatient 3 exhibited an overall improvement across all measurements on the ABC‐C before metformin discontinuation (see Table 2). Likewise, developmental testing shows an overall improvement pre‐ and post‐metformin (see Table 3). Within the first month of his treatment with metformin, patient 3’s parents reported gains in his language and cognition; specifically, his mother noted more complex language, thoughts, and statements from him. One year later, he continues on oxcarbazepine without seizures.\n\nTable 3 Mullen Scales of Early Learning (MSEL)—prior to metformin treatment and after 7–26 months of treatment\n\nDevelopmental testing—Mullen (age equivalent in months)\t\n \tCase 1\tCase 3\tCase 6\tCase 7\tCase 8\tCase 9\t\n \tBaselinea 22 mos.\tPost 30 mos.\tBaseline 63 mos.\tPost 89 mos.\tBaseline 34 mos.\tPost 47 mos.\tBaseline 23 mos.\tPost 31 mos.\tBaseline 46 mos.\tPost 53 mos.\tBaseline 30 mos.\tPost 50 mos.\t\nVisual reception\tNA\t27\t30\t40\t38\t40\t15\t25\t50\t52\t18\t29\t\nFine motor\t13\t21\t20\t23\t29\t30\t18\t21\t26\t27\t21\t27\t\nReceptive language\t19\t27\t36\t36\t32\t36\t10\t17\t31\t36\t24\t33\t\nExpressive language\t16\t17\t42\t53\t21\t29\t7\t14\t18\t27\t22\t48\t\nEarly learning Composite\t75\t70\t52\t55\t61\t61\t54\t54\t63\t62\t61\t61\t\nGlobal development age scoreb\n\tUTG\t23\t32\t38\t30\t33.75\t12.5\t19.25\t31.25\t35.5\t21.25\t34.25\t\nAbbreviations: NA, not administered; UTG, unable to generate.\n\na Baseline testing scores taken from Bayley Scales of Infant and Toddler Development, 3rd edition.\n\nb Global developmental age was calculated based on the average age equivalents of the Mullen subscales.\n\nJohn Wiley & Sons, Ltd3.4 Case 4\nPatient 4 is a 6‐year‐old boy born via emergency C‐section due to premature labor at 33 weeks gestation; his mother had partial placental abruption. Developmentally he sat at 6.5 months, crawled at 12 months, walked at 12.5 months, and began speaking at 3 years. Patient 4 exhibits some hand flapping when excited, tactile defensiveness, and anxiety in new situations. Past medical history includes recurrent OM treated with PE tube placement, gastroesophageal reflux disease (GERD), milk intolerance, chronic rhinitis, partial adenoidectomy, and two episodes each of bronchiolitis and croup before 12 months.\n\nPatient 4 began metformin at 4 years, 1 month (see Table 1). His pre‐treatment MSEL was performed at a chronological age of 39 months and yielded age equivalent scores (in months) of 23 for visual reception, 24 for fine motor, 28 for receptive language, and 14 for expressive language, with an ELC of 54. Follow‐up testing post‐treatment was not obtained. Since initiating metformin, his vocabulary has increased from 2 words to about 40 words. His mother notes improvement in gross motor function, particularly proprioception and ability to imitate actions on command. She reports that metformin treatment has “unlocked” him, noting “he now has a general increased connectedness to [family] and others around him that he didn't have before.” His creative and independent play have soared, and he is now initiating play with his brother and dogs. Mother attributes these gains to metformin because of minimal to no therapy since initiation, aside from continuing to attend his ongoing applied behavior analysis (ABA) sessions.\n\nPatient 4's only reported side effect is increased verbalization of frustration when he does not get his way. Indeed, on the ABC‐C, he exhibited a slight increase in irritability but an overall decrease across all other behaviors except stereotypy, which remained constant (see Table 2).\n\n3.5 Case 5\nPatient 5 is an 9‐year, 3‐month‐old boy who was diagnosed at 2 years with FXS. Mother had a normal pregnancy until 41 weeks when an emergency C‐section was performed for fetal distress. At 3 months, patient 5 underwent surgery for the repair of cleft lip and recovered well. He crawled at 10 months, walked at 18 months, and spoke a few words at 2 years; however, emergence of more words was delayed until approximately 5 years, with phrasing at 6 years. Due to recurrent OM, PE tubes were placed at 2 years and again at 4 years. He has also been diagnosed with autism spectrum disorder (ASD).\n\nAt 5 years old he was found seizing in his bedroom with a grand mal seizure. For several days afterwards, he was less verbal and off balance but he gradually recovered. An MRI at the time showed mildly dilated ventricles with a somewhat thin corpus callosum, and an EEG demonstrated right‐sided slowing and spike wave discharges. He began levetiracetam but discontinued due to increased aggression and other behavioral problems and instead started oxcarbazepine. On oxcarbazepine, patient 5 continued to have staring spells that were often associated with projectile emesis and falling to the ground; these partial motor seizures occurred once or twice a week.\n\nBehaviorally, patient 5 was very aggressive, hitting his parents and his grandparents. He had echolalia and sensitivity to noises and touch, and he engaged in both hand flapping and hand biting. Overall, he was very hyperactive, perseverative, and anxious.\n\nAt 7 years, patient 5 started metformin at a dose of 500 mg at dinner and increased to 500 mg bid a few months later (see Table 1). His pre‐treatment MSEL was performed at a chronological age of 93 months and yielded age equivalent scores (in months) of 27 for visual reception, 20 for fine motor, 23 for receptive language, and 18 for expressive language, with an ELC of 49. Follow‐up testing post‐treatment was not yet obtained. Since initiation of metformin, he has not experienced any seizures or seizure‐like symptoms. He is now able to eat at normal frequencies rather than continuously throughout the day. Behaviorally, his parents report improvement in irritability, hyperactivity, anxiety, tantrums, and aggression. His communication has also improved to the extent that he is now able to engage in a two‐way conversation with multiple exchanges. Previously, his mother had constant complaints from school teachers about his behavior, but after metformin initiation she has received consistently positive feedback. The only side effect he has experienced is intermittent loose stools.\n\n3.6 Case 6\nPatient 6 is a 5‐year, 4‐month‐old boy born via C‐section due to breech presentation at 35 weeks and weighing 2.6 kg. He had mild jaundice and was treated with phototherapy for 12 hr before being discharged 4 days later. Past medical history includes reflux treated with omeprazole in the first year. He sat at 9 months, never crawled, and walked at 15 months. He said his first words at 24 months and when seen pre‐treatment at 34 months he could combine 2 words (see Table 3). At 47 months, he was diagnosed with ASD.\n\nPatient 6’s behavior at 34 months included excessive chewing, shyness, perseveration, hyperactivity, and a short attention span. He had mild sleeping problems and occasional tantrums but was not aggressive. Ongoing interventions included ABA, speech and language, in home, and physical therapy.\n\nPatient 6 was started on metformin at an initial dose of 50 mg at dinner and then increased to bid after 1 week (see Table 1). Although his initial response to metformin was positive (see Table 2), after 4 months increased hyperactivity and anxiety, decreased attention, and language regression were observed. Metformin was discontinued and the aforementioned problems subsequently resolved.\n\n3.7 Case 7\nPatient 7 is a 3‐year, 11‐month‐old boy diagnosed with FXS at 16 months due to delayed communication milestones and a positive family history (see Table 1). He was born at term via normal spontaneous delivery without complications and weighed 4.6 kg. He sat independently at 6 months, took his first steps at 14.5 months, and said his first word at 15 months. At 15 months a diagnosis of Global Developmental Delay was made. At 20 months patient 7 was started on sertraline, and parents observed some improvement in self‐regulation and a reduction in separation anxiety (see Table 1).\n\nBehaviorally, patient 7 is a social child who arm‐flaps when excited. He experiences mild to moderate separation and performance anxiety. He has significant verbal and nonverbal communication delays and difficulty with imitation. Prior to metformin initiation, he could express himself using 3–5 verbal words and 15 signs, and he stacked approximately 3–4 blocks.\n\nAt 26 months patient 7 started taking 50 mg of metformin bid, and over the following 5 months his dose was gradually increased up to 150 mg bid. Over time he has shown dose‐dependent improvement across multiple areas of development, including language acquisition (see Table 3). Six months after initiation, he demonstrated use of 30 verbal words and 25–30 signs, including some combinations of 2–3 words and signs together. His therapists have noted improvements in his sustained attention, listening, focus, ability to imitate, and the speed with which he learns new words and signs. He is now stacking interlocking blocks greater than 15, and his family reports increased engagement in pretend play. He more regularly performs self‐help activities and daily tasks, such as dressing himself, picking up toys, throwing away trash, putting his dirty clothes in the hamper, and independently washing his hands. Behaviorally, his family has noted a significant increase in hyperactivity and impulsivity over the last four months, the former of which is reflected in his ABC‐C composite scores (see Table 2).\n\nOverall, patient 7 tolerated all metformin dose increases fairly well. Besides the increase in hyperactivity and impulsivity, his only side effect was an increase in frequency of nightly awakenings upon initiation and with each subsequent increase in dose, but sleep returned to normal within 2 weeks each time.\n\n3.8 Case 8\nPatient 8 is a 5‐year, 7‐month‐old who boy was diagnosed with FXS at 22 months. His mother had a normal pregnancy, but delivery via C‐section was delayed 1 week due to lack of progression. At birth he weighed 3.8 kg and was tongue‐tied; his tongue was clipped the next day without sequelae. He sat independently at 6 months, crawled at 8 months, and walked independently at 9 months. Significant language delay and behaviors such as hand flapping, poor eye contact, and tactile defensiveness prompted evaluation and ASD was diagnosed at 18 months. He subsequently enrolled in an early intervention preschool with expertise in ASD, speech and language therapy, and occupational therapy. He had reflux as an infant with significant vomiting and poor weight gain but since stabilizing on a paleo diet, he has had less reflux but still suffers occasional diet‐related constipation. He was started on sertraline at 25 months with a positive response (see Table 1).\n\nOn examination at 3 years, he was hyperactive and impulsive, demonstrating poor eye contact. He could only verbalize single words such as “bye‐bye” or 2‐word combinations such as “big dog” or “black dog” (see Table 3). His mother reported that he would play chase games with other children but would not socially interact with them.\n\nAt 46 months he started on metformin at 50 mg at dinner and increased to 50 mg bid after a few weeks; he tolerated the dose increase well. Initially, he had some soft stools but no diarrhea. He is no longer aggressive, although he continues to have poor eye contact, hand flapping, and biting. Since metformin initiation, he has been eating more and maintains a healthy weight. He exhibited an overall decrease across all measurements on the ABC‐C (see Table 2) and no cognitive decline on follow‐up developmental testing (see Table 3).\n\n3.9 Case 9\nPatient 9 is a 5‐year, 3‐month‐old boy born at term via C‐section after a pregnancy complicated by gestational diabetes. His developmental milestones included sitting at 8 months, crawling at 13 months, and walking at 16 months. He was diagnosed with FXS at 26 months of age and started on sertraline with a positive response in language development (see Table 1). Behaviorally, patient 9 hand flaps when excited and occasionally bites his fingers. He is social, making good eye contact, and often complimenting others and asking questions. He can be inattentive and hyperactive at times. He exhibits tantrums, irritability, and aggression (sometimes hitting and pushing people or objects). Past medical history includes seasonal eczema and three episodes of OM with PE tubes placed at 2 years, which led to a dramatic improvement in his language. However, by 3 years his mother noticed an increase in dysfluency and stuttering.\n\nHe began metformin at 4 years, initially taking 50 mg at dinner and gradually increasing to 150 mg bid. Since initiation, he has exhibited improved language development: increased vocabulary and he now uses full sentences and carries out reciprocal conversations. His mother reports that he more frequently attempts and succeeds at problem solving without looking to others for help. Furthermore, he has made progress in his social development and is more regularly seeking interactions with his peers for longer periods of time. He has experienced some loose stools and occasionally complains of stomach aches, but he continues to have a good appetite and overall tolerates metformin well.\n\nPatient 9’s follow‐up developmental testing reflects improvement across all areas but most notably expressive language (see Table 3). His ABC‐C showed a decrease across all subscales except for inappropriate speech and social avoidance, which remained static (Table 2).\n\n3.10 Statistical results\nStatistical analysis on the ABC‐C pre‐ and post‐treatment for all nine cases yielded a statistically significant (p < .05) improvement in two of the six factors: lethargy and stereotypy (Table 5). These findings differentiate this cohort from others in previous observational studies that saw an increase in these two factors over time (Hustyi, Hall, Jo, Lightbody, & Reiss, 2014). Analyses on the Mullen results were performed for at least five of the nine cases; p‐values (p < .05) suggest a statistically significant effect in all subscales and the global developmental age. Additionally, for all patients with both pre‐ and post‐treatment developmental testing data available, mean linear slope trajectories were calculated (Table 4). Among the MSEL subscales, the rate of growth for receptive and expressive language—0.56 and 0.77, respectively, exceeded previously published literature estimating a rate of growth with 0.48 in this population (Bailey Jr. et al., 1998); in a larger sample size, this finding might indicate accelerated gains that could be attributable to metformin, but given the small sample size and noncontrolled nature of the treatment, no definitive conclusions can be drawn except that no regression was observed.\n\nTable 4 Statistical Analysis of Mullen Scales of Early Learning\n\nMullen subscale\tPre‐metformina\n\tPost‐metformina\n\tSlopea\n,\nb\n\t\np‐value*\n\t\nVisual receptionc\n\t30 (18–38)\t40 (29–40)\t0.52\t.04\t\nFine motor\t20 (18–26)\t25 (21–27)\t0.34\t.02\t\nReceptive language\t27 (19–32)\t34 (27–36)\t0.56\t.03\t\nExpressive language\t19 (16–22)\t28 (17–48)\t0.77\t.02\t\nEarly learning composite score\t61 (54–63)\t61 (55–62)\tNA\t.5\t\nGlobal developmental agec\n,\nd\n\t30 (21.2–31.2)\t34.2 (33.7–35.5)\t0.52\t.04\t\na All values measured in median and interquartile range.\n\nb Rate of Growth.\n\nc Analysis with n = 5, all others were calculated with n = 6.\n\nd Global developmental age was calculated based on the average age equivalents of the Mullen subscales.\n\n* A pre‐specified significance level of p < .05 was assumed.\n\nJohn Wiley & Sons, LtdTable 5 Statistical Analysis for Aberrant Behavior Checklist‐Community\n\nABC‐C domain\tPre‐metformina\n\tPost‐metformina\n\t\np‐value*\n\t\nIrritability\t14 (8–29)\t12 (6–19)\t.1\t\nLethargy\t1 (0–11)\t1 (0–4)\t.04\t\nStereotypy\t4 (2–9)\t4 (0–5)\t.01\t\nHyperactivity\t17 (13–22)\t13 (11–14)\t.07\t\nSpeech\t3 (0–6)\t2 (2–6)\t.6\t\nSocial avoidance\t0 (0–2)\t1 (0–1)\t.2\t\nComposite score\t33 (29–67)\t39 (20–51)\t.06\t\nNote\nAll calculations were done with an n = 9.\n\na All values measured in median and interquartile range.\n\n* A pre‐specified significance level of p < .05. was assumed.\n\nJohn Wiley & Sons, Ltd4 DISCUSSION\nIn this study, we describe nine cases of young children with FXS between the ages of 2–7 years who were treated clinically with metformin with beneficial effects in language and some areas of aberrant behavior as measured by the ABC‐C, developmental testing, and parent reports (Tables 2 and 3). As is common in this population, all children described in this report were receiving interventions in the community or at school, including speech and language therapy, physical and occupational therapy, and special education support. Those with ASD were also receiving ABA.\n\nIn comparison to typically developing children (TDC), those with FXS have a significantly lower rate of development; because of this, their IQ is found to decrease over time (Wright‐Talamante et al., 1996). This observation can be attributed to the lack of FMRP, which is essential for synaptic plasticity and cognitive development. Those with FXS have significant deficits in abstract reasoning and higher symbolic language skills so the IQ decline increases in later childhood and adolescence; they neither lose skills nor regress but fall further behind TDC over time (Bailey Jr. et al., 1998; Hagerman et al., 1989; Hodapp et al., 1990; Lachiewicz, Gullion, Spiridigliozzi, & Aylsworth, 1987; Roberts et al., 2009). Although babies with FXS are usually quiet in the first year of life, behavioral problems including irritability, hyperactivity, and tantrums emerge in the second and third years of life, and sleep disturbances are common (Roberts, McCary, Shinkareva, & Bailey, 2016). Language is expected to improve somewhat in the early years even in those with FXS who have not received pharmacological or nonpharmacological intervention, but approximately 10% of children with FXS remain nonverbal by age 7 (Komesidou, Brady, Fleming, Esplund, & Warren, 2017).\n\nTreatment of children younger than 6 years of age has the potential of improving brain development in the absence of FMRP by reversing the upregulation of the mTORC1 and MEK‐ERK pathways and lowering the elevated MMP9 levels that are deleterious to synaptic development in FXS. Cognitive impairment is universally seen in males with the methylated full mutation due to the complete lack of FMRP. Counteracting the negative effects due to the lack of FMRP early in development has the potential to reverse the protein upregulation seen early on in FXS and prevent cognitive deficits before they are entrenched.\n\nThe parents of the children in this report were positive overall about metformin treatment; while there is a possibility that these impressions were due to a placebo response, per parent account there was demonstrated improvement in language acquisition rate and practical expressive ability. Parents noted gains not only in verbal and nonverbal communication but also in problem solving, motor abilities, and daily living skills. Behaviorally, tantrums and aggression were generally decreased, and improvement was observed in overall aberrant behavior as measured by the ABC‐C pre‐ and post‐treatment. The clinical treatment of the children in this report is not dissimilar to an open label treatment, and therefore bias can be introduced since the caregivers know that their child is being treated with a medication considered to be a potential targeted treatment for FXS. Informant based questionnaires, such as the ABC‐C, can introduce such bias and recall effects. A potential possibility for the improvement in scores is that increases in adaptive behavior with time along with the natural course of development may be responsible in part for decreases (or the perception thereof) in aberrant behavior; likewise, caregivers could be habituating to the severity of their child's behavior over time. Despite this, a longitudinal study with 124 children and adolescents with FXS demonstrated a significant decrease in hyperactivity and irritability over time (Hustyi et al., 2014). Not all children demonstrated an improvement on metformin. One patient (Case 7) had an increase in hyperactivity several months after metformin initiation, though this behavioral observation improved after discontinuation of treatment, it may also be unrelated since increased hyperactivity is expected in the developmental course of FXS in the early years of life (Grefer, Flory, Cornish, Hatton, & Roberts, 2016).\n\nSeizures are experienced by approximately 14% of male and 6% of female children with FXS and is often associated with a diagnosis of ASD. Seizures are more often partial, although generalized tonic‐clonic seizures may occur. Common age of seizure onset is in young and mid‐childhood (Berry‐Kravis et al., 2010). After one month on metformin, patient 3 experienced a seizure and despite subsequent initiation of the anticonvulsant oxcarbazepine, within 1 week a second episode occurred. Patient 3's MRI after the first episode revealed grey matter heterotopias, which have been previously reported in FXS (Moro et al., 2006) and likely constitute the cause of the seizures. Metformin was discontinued at the discretion of the attending physician; however, the only recognized association of metformin with the presentation of seizures and other neurological symptoms has been reported in those with vitamin B12 deficiency (Lee, Chang, Wu, Weng, & Chen, 2005; Naha, Dasari, Vivek, & Prabhu, 2012) that can be occasionally seen after treatment for more than 4 months (Langan & Goodbred, 2017). Patient 3’s complete blood count, comprehensive metabolic panel including blood glucose, and urinalysis results were unremarkable at baseline and at time of hospital discharge after the first episode of a seizure. Furthermore, no drug interaction is known to exist between metformin and oxcarbazepine.\n\nContrary to what was seen in patient 3, metformin has been reported as exhibiting beneficial effects in epilepsy such as decreasing seizure susceptibility, reducing seizure number and length, suppressing progression of seizures and ameliorating learning and memory impairments (Gantois et al., 2018; Mehrabi et al., 2018; Yang et al., 2017; Zhao et al., 2014). Metformin is also known to improve seizures in the mouse model of FXS (Gantois et al., 2017). Indeed, in one patient (Case 5) the partial motor seizures were improved with metformin. The most commonly reported side effect of treatment was self‐limited loose stools after initiation or subsequent dose increases. Thus, it is necessary to start at a low dose and increase dosage gradually until a maximum tolerated dose is reached. While the nine patients presented in this report demonstrate relative safety, further studies regarding safety are warranted. Close monitoring is recommended to detect any adverse behavioral changes that may accompany dose modification so that treatment can be discontinued if needed. In addition, further studies of young children treated with metformin should include careful monitoring for possible seizures and hyperarousal.\n\nThe results of this preliminary clinical treatment of children with FXS 2–7 years old indicate the potential of metformin as a targeted treatment for young patients with FXS as data suggests language and cognitive benefits with no regression.\n\n5 LIMITATIONS\nEven though certain p‐values may suggest statistical significance, it is important to address the limitations of our preliminary data. The material presented here are several clinical case reports, not an open‐label study, hence no specified protocol is used. This cohort was treated clinically so there is variability in the time points for data collection; therefore, it is difficult to differentiate between the influence of time on the effects of metformin seen and the natural developmental progression of each patient. The small number of patients is a limitation in terms of statistical analyses; the presented statistical values could be the result of a large random error. Therefore, interpretation of the results as definitively providing evidence of an effect when p < .05, or a lack thereof when p > .05, is not possible. While there are limitations to the conclusions which can be drawn from the data, there were positive effects seen while the patients were treated with metformin. Likewise, our findings support a biologically plausible hypothesis based on previous work by Gantois and colleagues (Gantois et al., 2017) where metformin was shown to improve outcomes among the FMR1 KO mouse model of FXS. Our preliminary data, although promising, suggests that only a controlled trial of metformin in young children (two and older) with FXS can ascertain the influence of the treatment in this population (Table 5). \n\nCONFLICTS OF INTEREST\nRJH has received funding from Zynerba, Ovid and the Azrieli Foundation for carrying out treatment studies in patients with fragile X syndrome. She has also consulted with Fulcrum, and Zynerba regarding treatment studies in the same population. FT received funds from Asuragen, Inc, Roche and Zynerba. The other authors declare no conflicts of interest.\n\nACKNOWLEDGMENTS\nThis research was partially supported by the Azrieli Foundation, the MIND Institute Intellectual and Developmental Disabilities Research Center (grant U54 HD079125), the National Center for Advancing Translational Sciences and National Institutes of Health (grant UL1 TR001860) and the Department of Health and Human Services Administration for Children and Families (grant 90DD05069). The authors thank Jane Roberts, PhD, for her invaluable comments on the manuscript.\n\nDATA AVAILABILITY STATEMENT\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n\nAlOlaby , R. R. \n, \nSweha , S. R. \n, \nSilva , M. \n, \nDurbin‐Johnson , B. \n, \nYrigollen , C. M. \n, \nPretto , D. \n, … \nTassone , F. \n (2017 ). Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome . Brain and Development , 39 (6 ), 483 –492 . 10.1016/j.braindev.2017.01.012 \n28242040 \n\n\nAnagnostou , E. \n, \nAman , M. G. \n, \nHanden , B. L. \n, \nSanders , K. B. \n, \nShui , A. \n, \nHolloway , J. A. \n, … \nVeenstra‐VanderWeele \nJ. \n (2016 ). Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder: A randomized clinical trial . JAMA Psychiatry , 73 (9 ), 928 –937 . 10.1001/jamapsychiatry.2016.1232 \n27556593 \n\n\nBailey , D. B. \n, \nCody Hazlett , H. \n, \nRoberts , J. E. \n, & \nWheeler , A. C. \n (2011 ). Early development in fragile X syndrome: Implications for developmental screening . International Review of Research in Developmental Disabilities , 40 , 75 –108 . 10.1016/b978-0-12-374478-4.00004-6 \n\n\n\nBailey , D. \nJr\n, \nHatton , D. \n, & \nSkinner , M. \n (1998 ). Early developmental trajectories of males with fragile X syndrome . American Journal on Mental Retardation , 103 (1 ), 29 –39 . 10.1352/0895-8017(1998)103<0029:EDTOMW>2.0.CO;2 \n9678228 \n\n\nBayley , N. \n (2006 ). Bayley scales of infant and toddler development–Third edition . San Antonio, TX : Harcourt Assessment .\n\n\nBerry‐Kravis , E. \n, \nHagerman , R. \n, \nVisootsak , J. \n, \nBudimirovic , D. \n, \nKaufmann , W. E. \n, \nCherubini , M. \n, … \nCarpenter , R. L. \n (2017 ). Arbaclofen in fragile X syndrome: Results of phase 3 trials . Journal of Neurodevelopmental Disorders , 9 , 3 \n10.1186/s11689-016-9181-6 \n28616094 \n\n\nBerry‐Kravis , E. \n, \nRaspa , M. \n, \nLoggin‐Hester , L. \n, \nBishop , E. \n, \nHoliday , D. \n, & \nBailey , D. B. \n (2010 ). Seizures in fragile X syndrome: Characteristics and comorbid diagnoses . American Journal on Intellectual and Developmental Disabilities , 115 (6 ), 461 –472 . 10.1352/1944-7558-115.6.461 \n20945999 \n\n\nBilousova , T. V. \n, \nDansie , L. \n, \nNgo , M. \n, \nAye , J. \n, \nCharles , J. R. \n, \nEthell , D. W. \n, & \nEthell , I. M. \n (2009 ). Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model . Journal of Medical Genetics , 46 (2 ), 94 –102 . 10.1136/jmg.2008.061796 \n18835858 \n\n\nBodmer , M. \n, \nMeier , C. \n, \nKrahenbuhl , S. \n, \nJick , S. S. \n, & \nMeier , C. R. \n (2008 ). Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: A nested case‐control analysis . Diabetes Care , 31 (11 ), 2086 –2091 . 10.2337/dc08-1171 \n18782901 \n\n\nBolen , S. \n, \nFeldman , L. \n, \nVassy , J. \n, \nWilson , L. \n, \nYeh , H. C. \n, \nMarinopoulos , S. \n, … \nBrancati , F. L. \n (2007 ). Systematic review: Comparative effectiveness and safety of oral medications for type 2 diabetes mellitus . Annals of Internal Medicine , 147 (6 ), 386 –399 . 10.7326/0003-4819-147-6-200709180-00178 \n17638715 \n\n\nDy , A. B. C. \n, \nTassone , F. \n, \nEldeeb , M. \n, \nSalcedo‐Arellano , M. J. \n, \nTartaglia , N. \n, & \nHagerman , R. \n (2018 ). Metformin as targeted treatment in fragile X syndrome . Clinical Genetics , 93 (2 ), 216 –222 . 10.1111/cge.13039 \n28436599 \n\n\nDziembowska , M. \n, & \nWlodarczyk , J. \n (2012 ). MMP9: A novel function in synaptic plasticity . International Journal of Biochemistry & Cell Biology , 44 (5 ), 709 –713 . 10.1016/j.biocel.2012.01.023 \n22326910 \n\n\nEsfahanian , N. \n, \nShakiba , Y. \n, \nNikbin , B. \n, \nSoraya , H. \n, \nMaleki‐Dizaji , N. \n, \nGhazi‐Khansari , M. \n, & \nGarjani , A. \n (2012 ). Effect of metformin on the proliferation, migration, and MMP‐2 and ‐9 expression of human umbilical vein endothelial cells . Mol Med Rep , 5 (4 ), 1068 –1074 . 10.3892/mmr.2012.753 \n22246099 \n\n\nFarmer , C. \n, \nGolden , C. \n, & \nThurm , A. \n (2016 ). Concurrent validity of the differential ability scales, second edition with the Mullen scales of early learning in young children with and without neurodevelopmental disorders . Child Neuropsychology , 22 (5 ), 556 –569 . 10.1080/09297049.2015.1020775 \n25833070 \n\n\nGantois , I. \n, \nKhoutorsky , A. \n, \nPopic , J. \n, \nAguilar‐Valles , A. \n, \nFreemantle , E. \n, \nCao , R. \n, … \nSonenberg , N. \n (2017 ). Metformin ameliorates core deficits in a mouse model of fragile X syndrome . Nature Medicine , 23 (6 ), 674 –677 . 10.1038/nm.4335 \n\n\n\nGantois , I. \n, \nPopic , J. \n, \nKhoutorsky , A. \n, & \nSonenberg , N. \n (2018 ). Metformin for treatment of fragile X syndrome and other neurological disorders . Annual Review of Medicine , 10.1146/annurev-med-081117-041238 \n\n\n\nGrefer , M. \n, \nFlory , K. \n, \nCornish , K. \n, \nHatton , D. \n, & \nRoberts , J. \n (2016 ). The emergence and stability of attention deficit hyperactivity disorder in boys with fragile X syndrome . Journal of Intellectual Disability Research , 60 (2 ), 167 –178 . 10.1111/jir.12226 \n26610738 \n\n\nGreiss Hess , L. \n, \nFitzpatrick , S. E. \n, \nNguyen , D. V. \n, \nChen , Y. \n, \nGaul , K. N. \n, \nSchneider , A. \n, … \nHagerman , R. J. \n (2016 ). A randomized, double‐blind, placebo‐controlled trial of low‐dose sertraline in young children with fragile X syndrome . Journal of Developmental and Behavioral Pediatrics , 37 (8 ), 619 –628 . 10.1097/dbp.0000000000000334 \n27560971 \n\n\nHagerman , R. J. \n, \nSchreiner , R. A. \n, \nKemper , M. B. \n, \nWittenberger , M. D. \n, \nZahn , B. \n, & \nHabicht , K. \n (1989 ). Longitudinal IQ changes in fragile X males . American Journal of Medical Genetics , 33 (4 ), 513 –518 . 10.1002/ajmg.1320330422 \n2596514 \n\n\nHe , C. X. \n, \nCantu , D. A. \n, \nMantri , S. S. \n, \nZeiger , W. A. \n, \nGoel , A. \n, & \nPortera‐Cailliau , C. \n (2017 ). Tactile defensiveness and impaired adaptation of neuronal activity in the Fmr1 knock‐out mouse model of autism . Journal of Neuroscience , 37 (27 ), 6475 –6487 . 10.1523/jneurosci.0651-17.2017 \n28607173 \n\n\nHodapp , R. M. \n, \nDykens , E. M. \n, \nHagerman , R. J. \n, \nSchreiner , R. \n, \nLachiewicz , A. M. \n, & \nLeckman , J. F. \n (1990 ). Developmental implications of changing trajectories of IQ in males with fragile X syndrome . Journal of the American Academy of Child and Adolescent Psychiatry , 29 (2 ), 214 –219 . 10.1097/00004583-199003000-00009 \n2324062 \n\n\nHoeffer , C. A. \n, \nSanchez , E. \n, \nHagerman , R. J. \n, \nMu , Y. \n, \nNguyen , D. V. \n, \nWong , H. \n, … \nTassone , F. \n (2012 ). Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome . Genes, Brain, and Behavior , 11 (3 ), 332 –341 . 10.1111/j.1601-183X.2012.00768.x \n\n\n\nHustyi , K. M. \n, \nHall , S. S. \n, \nJo , B. \n, \nLightbody , A. A. \n, & \nReiss , A. L. \n (2014 ). Longitudinal trajectories of aberrant behavior in fragile X syndrome . Research in Developmental Disabilities , 35 (11 ), 2691 –2701 . 10.1016/j.ridd.2014.07.003 \n25129200 \n\n\nJones , K. L. \n, \nArslanian , S. \n, \nPeterokova , V. \n, \nPark , J.‐S. \n, & \nTomlinson , M. \n (2002 ). Effect of metformin in pediatric patients with type 2 diabetes . Diabetes Care , 25 (1 ), 89 –94 .11772907 \n\n\nKlein , D. J. \n, \nCottingham , E. M. \n, \nSorter , M. \n, \nBarton , B. A. \n, & \nMorrison , J. A. \n (2006 ). A randomized, double‐blind, placebo‐controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents . American Journal of Psychiatry , 163 (12 ), 2072 –2079 . 10.1176/ajp.2006.163.12.2072 \n17151157 \n\n\nKomesidou , R. \n, \nBrady , N. C. \n, \nFleming , K. \n, \nEsplund , A. \n, & \nWarren , S. F. \n (2017 ). Growth of expressive syntax in children with fragile X syndrome . Journal of Speech, Language, and Hearing Research , 60 (2 ), 422 –434 . 10.1044/2016_jslhr-l-15-0360 \n\n\n\nLachiewicz , A. M. \n, \nGullion , C. M. \n, \nSpiridigliozzi , G. A. \n, & \nAylsworth , A. S. \n (1987 ). Declining IQs of young males with the fragile X syndrome . American Journal of Mental Retardation , 92 (3 ), 272 –278 .3426837 \n\n\nLangan , R. C. \n, & \nGoodbred , A. J. \n (2017 ). Vitamin B12 deficiency: Recognition and management . American Family Physician , 96 (6 ), 384 –389 .28925645 \n\n\nLee , M. \n, \nChang , H. S. \n, \nWu , H. T. \n, \nWeng , H. H. \n, & \nChen , C. M. \n (2005 ). Intractable epilepsy as the presentation of vitamin B deficiency in the absence of macrocytic anemia . Epilepsia , 46 (7 ), 1147 –1148 . 10.1111/j.1528-1167.2005.66204.x \n16026570 \n\n\nLeigh , M. J. \n, \nNguyen , D. V. \n, \nMu , Y. \n, \nWinarni , T. I. \n, \nSchneider , A. \n, \nChechi , T. \n, … \nHagerman , R. J. \n (2013 ). A randomized double‐blind, placebo‐controlled trial of minocycline in children and adolescents with fragile x syndrome . Journal of Developmental and Behavioral Pediatrics , 34 (3 ), 147 –155 . 10.1097/DBP.0b013e318287cd17 \n23572165 \n\n\nLi , W. D. \n, \nLi , N. P. \n, \nSong , D. D. \n, \nRong , J. J. \n, \nQian , A. M. \n, & \nLi , X. Q. \n (2017 ). Metformin inhibits endothelial progenitor cell migration by decreasing matrix metalloproteinases, MMP‐2 and MMP‐9, via the AMPK/mTOR/autophagy pathway . International Journal of Molecular Medicine , 39 (5 ), 1262 –1268 . 10.3892/ijmm.2017.2929 \n28339020 \n\n\nMehrabi , S. \n, \nSanadgol , N. \n, \nBarati , M. \n, \nShahbazi , A. \n, \nVahabzadeh , G. \n, \nBarzroudi , M. \n, … \nGolab , F. \n (2018 ). Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy . Metabolic Brain Disease , 33 (1 ), 107 –114 . 10.1007/s11011-017-0132-z \n29080083 \n\n\nMonyak , R. E. \n, \nEmerson , D. \n, \nSchoenfeld , B. P. \n, \nZheng , X. \n, \nChambers , D. B. \n, \nRosenfelt , C. \n, … \nJongens , T. A. \n (2017 ). Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model . Molecular Psychiatry , 22 (8 ), 1140 –1148 . 10.1038/mp.2016.51 \n27090306 \n\n\nMoro , F. \n, \nPisano , T. \n, \nBernardina , B. D. \n, \nPolli , R. \n, \nMurgia , A. \n, \nZoccante , L. \n, … \nGuerrini , R. \n (2006 ). Periventricular heterotopia in fragile X syndrome . Neurology , 67 (4 ), 713 –715 . 10.1212/01.wnl.0000230223.51595.99 \n16924033 \n\n\nMullen , E. M. \n (1995 ). Mullen scales of early learning: AGS Edition . Minneapolis, MN : Pearson (AGS) .\n\n\nMuzar , Z. \n, \nLozano , R. \n, \nKolevzon , A. \n, & \nHagerman , R. J. \n (2016 ). The neurobiology of the Prader‐Willi phenotype of fragile X syndrome . Intractable and Rare Diseases Research , 5 (4 ), 255 –261 . 10.5582/irdr.2016.01082 \n27904820 \n\n\nNaha , K. \n, \nDasari , S. \n, \nVivek , G. \n, & \nPrabhu , M. \n (2012 ). Vitamin B(1)(2) deficiency: An unusual cause for recurrent generalised seizures with pancytopaenia . BMJ Case Reports , 2012 , 10.1136/bcr-2012-006632 \n\n\n\nNowicki , S. T. \n, \nTassone , F. \n, \nOno , M. Y. \n, \nFerranti , J. \n, \nCroquette , M. F. \n, \nGoodlin‐Jones , B. \n, & \nHagerman , R. J. \n (2007 ). The Prader‐Willi phenotype of fragile X syndrome . Journal of Developmental & Behavioral Pediatrics , 28 (2 ), 133 –138 . 10.1097/01.DBP.0000267563.18952.c9 \n17435464 \n\n\nOng , C. R. \n, \nMolyneaux , L. M. \n, \nConstantino , M. I. \n, \nTwigg , S. M. \n, & \nYue , D. K. \n (2006 ). Long‐term efficacy of metformin therapy in nonobese individuals with type 2 diabetes . Diabetes Care , 29 (11 ), 2361 –2364 . 10.2337/dc06-0827 \n17065668 \n\n\nPark , M. H. \n, \nKinra , S. \n, \nWard , K. J. \n, \nWhite , B. \n, & \nViner , R. M. \n (2009 ). Metformin for obesity in children and adolescents: A systematic review . Diabetes Care , 32 (9 ), 1743 –1745 . 10.2337/dc09-0258 \n19502540 \n\n\nRoberts , J. E. \n, \nMankowski , J. B. \n, \nSideris , J. \n, \nGoldman , B. D. \n, \nHatton , D. D. \n, \nMirrett , P. L. \n, … \nBailey , D. B. \nJr\n (2009 ). Trajectories and predictors of the development of very young boys with fragile X syndrome . Journal of Pediatric Psychology , 34 (8 ), 827 –836 . 10.1093/jpepsy/jsn129 \n19074489 \n\n\nRoberts , J. E. \n, \nMcCary , L. M. \n, \nShinkareva , S. V. \n, & \nBailey , D. B. \nJr\n (2016 ). Infant development in fragile X syndrome: Cross‐syndrome comparisons . Journal of Autism and Developmental Disorders , 46 (6 ), 2088 –2099 . 10.1007/s10803-016-2737-1 \n26864160 \n\n\nRotschafer , S. E. \n, \nTrujillo , M. S. \n, \nDansie , L. E. \n, \nEthell , I. M. \n, & \nRazak , K. A. \n (2012 ). Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of Fragile X Syndrome . Brain Research , 1439 , 7 –14 . 10.1016/j.brainres.2011.12.041 \n22265702 \n\n\nSansone , S. M. \n, \nWidaman , K. F. \n, \nHall , S. S. \n, \nReiss , A. L. \n, \nLightbody , A. \n, \nKaufmann , W. E. \n, … \nHessl , D. \n (2012 ). Psychometric study of the aberrant behavior checklist in fragile X syndrome and implications for targeted treatment . Journal of Autism and Developmental Disorders , 42 (7 ), 1377 –1392 . 10.1007/s10803-011-1370-2 \n21972117 \n\n\nWilcoxon , F. \n (1945 ). Individual comparisons by ranking methods . Biometrics Bulletin , 1 (6 ), 80 –83 . 10.2307/3001968 \n\n\n\nWright‐Talamante , C. \n, \nCheema , A. \n, \nRiddle , J. E. \n, \nLuckey , D. W. \n, \nTaylor , A. K. \n, & \nHagerman , R. J. \n (1996 ). A controlled study of longitudinal IQ changes in females and males with fragile X syndrome . American Journal of Medical Genetics , 64 (2 ), 350 –355 . 10.1002/(sici)1096-8628(19960809)64:2<350:aid-ajmg23>3.0.co;2-d \n8844079 \n\n\nYang , Y. \n, \nZhu , B. \n, \nZheng , F. \n, \nLi , Y. \n, \nZhang , Y. \n, \nHu , Y. \n, & \nWang , X. \n (2017 ). Chronic metformin treatment facilitates seizure termination . Biochemical and Biophysical Research Communications , 484 (2 ), 450 –455 . 10.1016/j.bbrc.2017.01.157 \n28137587 \n\n\nZhao , R. R. \n, \nXu , X. C. \n, \nXu , F. \n, \nZhang , W. L. \n, \nZhang , W. L. \n, \nLiu , L. M. \n, & \nWang , W. P. \n (2014 ). Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole‐induced kindling in mice . Biochemical and Biophysical Research Communications , 448 (4 ), 414 –417 . 10.1016/j.bbrc.2014.04.130 \n24802403\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2324-9269",
"issue": "7(11)",
"journal": "Molecular genetics & genomic medicine",
"keywords": "\nFMR1\n; fragile X syndrome; metformin; targeted treatments; translational medicine",
"medline_ta": "Mol Genet Genomic Med",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D005600:Fragile X Syndrome; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D065886:Neurodevelopmental Disorders; D011379:Prognosis",
"nlm_unique_id": "101603758",
"other_id": null,
"pages": "e956",
"pmc": null,
"pmid": "31520524",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "27556593;23572165;30365357;9678228;29080083;11772907;18835858;27904820;2596514;19502540;22948998;17638715;21972117;28339020;28436599;25129200;26610738;28504725;22268788;24802403;28607173;17065668;27090306;16026570;17435464;16924033;28616094;20945999;8844079;3426837;19074489;28242040;2324062;18782901;26864160;22265702;28925645;25833070;28219082;22326910;27560971;28137587;17151157;31520524;22246099",
"title": "Metformin treatment in young children with fragile X syndrome.",
"title_normalized": "metformin treatment in young children with fragile x syndrome"
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-08232",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "SERTRALINE HYDROCHLORIDE"
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{
"abstract": "To report the findings of unilateral cystoid macular edema (CME) associated with bilateral sub-foveal hyperreflectivity in a patient previously diagnosed with breast cancer and treated with docetaxel and cyclophosphamide.\nA 69-year-old female on docetaxel and cyclophosphamide chemotherapy treatment for breast cancer developed blurry vision 20 days after initiation of therapy. Ophthalmic examination revealed reduced visual acuity with bilateral retinal pigment epithelium mottling and annular sub-foveal thickening in the left eye. Optical coherence tomography (OCT) showed cystoid macular changes in the right eye and central sub-macular hyperreflectivity of outer layers in both eyes. Six-months after discontinuation of therapy, OCT findings remained unchanged and visual acuity did not improve.\nCME may occur in patients taking taxanes, but this finding associated with sub-macular hyperreflectivity of the outer layers in diagnostic testing has never been reported before. Sub-macular deposits found in this patient may be responsible for decreased vision and did not respond to cessation of therapy.",
"affiliations": "Louisiana State University (LSU) School of Medicine, New Orleans, LA, USA.;Louisiana State University (LSU) School of Medicine, New Orleans, LA, USA.",
"authors": "Torrado|Laura A|LA|;Fivgas|George D|GD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100995",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30310-8\n10.1016/j.ajoc.2020.100995\n100995\nCase Report\nUnilateral cystoid macular edema and bilateral subfoveal hyperreflectivity following docetaxel chemotherapy: A case report\nTorrado Laura A. gfivga@lsuhsc.edua1 Fivgas George D. ab∗ a Louisiana State University (LSU) School of Medicine, New Orleans, LA, USA\nb The Retina Center, 7777 Hennessy Blvd, Suite 3000. Baton Rouge, LA, 70808, USA\n∗ Corresponding author. LSU Department of Ophthalmology, Retina Division, The Retina Center, 7777 Hennessy Blvd, Suite 3000 Baton Rouge, LA, 70808, USA1 Department of Ophthalmology, Retina Division. 533 Bolivar Street, Room 451B. New Orleans, LA 70112.\n\n\n13 12 2020 \n12 2020 \n13 12 2020 \n20 10099525 10 2019 14 10 2020 15 11 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report the findings of unilateral cystoid macular edema (CME) associated with bilateral sub-foveal hyperreflectivity in a patient previously diagnosed with breast cancer and treated with docetaxel and cyclophosphamide.\n\nObservations\nA 69-year-old female on docetaxel and cyclophosphamide chemotherapy treatment for breast cancer developed blurry vision 20 days after initiation of therapy. Ophthalmic examination revealed reduced visual acuity with bilateral retinal pigment epithelium mottling and annular sub-foveal thickening in the left eye. Optical coherence tomography (OCT) showed cystoid macular changes in the right eye and central sub-macular hyperreflectivity of outer layers in both eyes. Six-months after discontinuation of therapy, OCT findings remained unchanged and visual acuity did not improve.\n\nConclusionsand importance\nCME may occur in patients taking taxanes, but this finding associated with sub-macular hyperreflectivity of the outer layers in diagnostic testing has never been reported before. Sub-macular deposits found in this patient may be responsible for decreased vision and did not respond to cessation of therapy.\n\nKeywords\nDocetaxelCystoid macular edemaSubfoveal hyperreflectivityOcular toxicity\n==== Body\n1 Introduction\nDocetaxel is an antineoplastic agent of the taxane class of drugs used for the treatment of several types of tumors.1, 2, 3 Cystoid macular edema (CME) is a well-known complication of therapy and to our knowledge there are no reports of bilateral outer layer hyperreflectivity on Spectral Domain Optical Coherence Tomography (SDOCT) associated with this chemotherapeutic agent. We present a patient with breast cancer who developed unilateral CME and bilateral outer retinal layer hyperreflectivity during combination chemotherapy with docetaxel and cyclophosphamide.\n\n1.1 Case report\nA 69-year-old female was referred to our clinic with a two-month history of blurry vision in both eyes. The patient was diagnosed with recurrent breast cancer seven months prior. She was treated with excisional surgery and started on chemotherapy with docetaxel and cyclophosphamide 20 days before the development of symptoms.\n\nHer past medical history is significant for breast carcinoma diagnosed 19 years ago treated with radical mastectomy and reconstruction, chemotherapy and radiotherapy, hypothyroidism and hypercholesterolemia. Past ocular history is significant for cataract surgery in the right eye followed by vitrectomy for macular hole repair at an outside facility. Family history is non-contributory.\n\nHer exam revealed a best corrected visual acuity (BCVA) of 20/50 in the right eye and 20/40 in the left eye. Intraocular pressures were 19 mmHg in the right eye and 17 mmHg in the left eye. Her external ocular exam, anterior segment, and vitreous were normal bilaterally. The fundus exam was notable for macular drusen and retinal pigment epithelial (RPE) mottling centrally in both eyes and annular sub-foveal RPE thickening in the left eye (Fig. 1A, Fig. 1B-A and 1-B), with slight hyper autofluorescence surrounding the fovea (Fig. 2A, Fig. 2B-A and 2-B) in fundus autofluorescence (FAF). Spectral Domain Optical Coherence Tomography (SDOCT) showed central sub-macular hyperreflectivity of the outer layers (between the ellipsoid zone and Retinal Pigment epithelium) with disruption of the ellipsoid band in both eyes and fine CME in the right eye (Fig. 3A, Fig. 3B-A and 3-B). Fluorescein Angiography (FA) revealed a couple of focal non-leaking hyperfluorescent spots temporal to the fovea in the right eye, probably due to residual defects from prior macular hole surgery eyes, and a nummular central hyperfluorescent area in the left eye (Fig. 4A, Fig. 4B-A and 4-B).Fig. 1A Fundus photo of the right eye showing macular drusen and RPE mottling centrally.\n\nFig. 1AFig. 1B Fundus photo of the left eye showing macular drusen and annular sub-foveal retinal pigment epithelium thickening.\n\nFig. 1BFig. 2A Autofluorescence photo of the right eye showing mild hyper autofluorescence on the edge of soft drusen surrounding the fovea.\n\nFig. 2AFig. 2B Autofluorescence photo of the left eye showing mild hyper autofluorescence on the edge of soft drusen surrounding the fovea.\n\nFig. 2BFig. 3A SD-OCT of the right eye, showing blunted foveal contour, drusen, retinal nerve fiber layer dissociation following vitrectomy and internal limiting membrane stripping for macular hole repair, fine nasal cystoid macular edema (arrowhead) and central sub-macular hyperreflectivity between the RPE and ellipsoid zone. (arrow).\n\nFig. 3AFig. 3B SD-OCT of the left eye, showing presence of foveal contour and central sub-macular hyperreflectivity of the outer layers (arrow).\n\nFig. 3BFig. 4A FA of the right eye showing a couple of hyperfluorescent spots superotemporal to the fovea and stippling in central macula with no leakage in late stages, due to residual defect from macular hole surgery.\n\nFig. 4AFig. 4B FA of the left eye showing nummular central hypofluorescent area with no leakage.\n\nFig. 4B\n\nThe patient was started on oral acetazolamide for taxane-induced CME in the right eye and scheduled for follow-up. One month later, the patient's symptoms subjectively improved but no change was noted on SDOCT or BCVA. Her oncologist was contacted and since she had only one more cycle of chemotherapy remaining, the decision was made to continue with the current treatment and to follow-up after completion. Six-months after completion of chemotherapy no improvement in BCVA or SD-OCT was seen.\n\n2 Discussion\nDocetaxel-induced CME is a known but rare complication of therapy first reported by Teitelbaum et al., in 2003.2 Since then, 7 case reports can be found in the literature, some of them associated with taxane use alone but others associated with the use of other medications such as gemcitabine and hydroxicloroquine. 4, 5, 6, 7, 8. And a couple of cases associated with retinitis pigmentosa and fluid retention syndrome.1,9\n\nPatients present with a non-leaking form of CME, characterized by macular cystoid changes on exam and normal filling of the choroidal and retinal vessels without evidence of leakage on FA.3, 6, 10 The pathophysiology remains unclear, but a couple of theories being postulated include1 dysfunction in the cytoskeleton of the RPE with an intact choroid-pigment epithelium border and2 toxicity to Muller cells with subsequent fluid accumulation and subclinical leakage of extracellular fluid.1,6\n\nIn all case reports, regardless of concurrent chemotherapy, complete resolution of edema has been accomplished within 4–10 weeks of taxane cessation.3 Although most cases resolve spontaneously, several authors have used systemic or topical carbonic anhydrase inhibitors, topical anti-inflammatory agents, or intravitreal bevacizumab to accelerate resolution or when taxane therapy cannot be discontinued.3,5\n\nOur patient presented with CME in the right eye associated with bilateral hyperreflective changes on SDOCT that didn't respond to cessation of therapy. Even though the presence of CME can be related to the history of previous macular surgery due to its subtle presentation and it's absence in the fellow eye, its association with bilateral hyperreflective deposits raises the question if the use of both medications in a patient with prior history of macular surgery increases the risk of retinal toxicity in patients undergoing chemotherapy.\n\nThe presence of subretinal deposits have been previously associated with a wide spectrum of clinical entities such as vitreomacular traction, adult-onset foveomacular dystrophies and cuticular and reticular drusen among others; and have been referred as acquired vitelliform lesions (AVL) 11. AVL can assume variable configurations and its etiology is likely disturbance of outer retinal-RPE structures and metabolism leading to accumulation of subretinal material 11. However, these lesions are rarely associated with soft drusen and usually show in FAF marked hyper autofluorescence, finding not seen in our patient. Nonetheless, outer layer hyperreflectivity associated with taxane and cyclophosphamide intake may be considered another clinical entity that may induce formation of AVL.\n\nThe use of combination chemotherapy and introduction of novel cancer agents has resulted in an increase of cases with chemotherapy-induced ocular toxicity. 4 When evaluating a patient, it is important to evaluate systemic disease, ocular history and concurrent treatment that may accelerate development of retinal toxicities. 4 It also seems reasonable to consider the length of treatment, dose of medication as well as the duration of CME in the final visual prognosis. 2\n\nEarly detection, and close ophthalmologic follow-up may allow prevention of chemotherapy-induced permanent ocular side effects. 4 Ophthalmologists and oncologists should work together and weigh risks and benefits of continuing chemotherapeutic treatment when ocular pathology or toxicity develop. 1\n\n3 Conclusion\nOuter retinal layer disruption and increased macular thickness has been a common finding on OCT in patients developing CME induced by taxanes, but no outer layer hyperreflectivity has ever been reported in the literature. Moreover, visual acuity returns to baseline in previous reports. Our patient presented with vision loss associated with unilateral CME and bilateral outer layer changes evidenced by hyper reflecivity on SDOCT. The origin of this finding is unknown, but it most likely related to drug toxicity or deposits in the retina. As well, there is possibly a synergistic effect exacerbated by cyclophosphamide use. In this case the CME cleared but the outer layer hyperreflectivity has been unchanged for 6 months following taxane cessation. Most importantly, the BCVA has not improved to baseline unlike previous reports.\n\n3.1 Patient consent\nConsent to publish the case report was verbally given by the patient. This report does not contain any personal information that could identify the patient.\n\nFunding\nNo funding or grant support.\n\nDisclosures\nThe authors have no financial or conflicting interests to disclose.\n\nAcknowledgments\nNone.\n==== Refs\nReferences\n1 Enzsoly A. Kammerer K. Nemeth J. Bilateral cystoid macular edema following docetaxel chemotherapy in a patient with retinitis pigmentosa: a case report BMC Ophthalmol 15 2015 32 25885440 \n2 Teitelbaum B.A. Tresley D.J. Cystic maculopathy with normal capillary permeability secondary to docetaxel Optom Vis Sci 80 2003 277 279 12692483 \n3 Hassall M.M. Andrew N.H. Single-eye trial of a topical carbonic anhydrase inhibitor versus intravitreal bevacizumab for the treatment of taxane drug-induced cystoid macula edema BMJ Case Rep 2016 10 2016 Apr 19 \n4 Shih C.H. Lee Y.C. Impaired retinal pigment epithelium in paclitaxel-induced macular edema: a case report Medicine (Baltim) 97 26 2018 Jun e11229 10.1097/MD.0000000000011229 Medicine (Baltimore). 2018. PMID: 29952984 Free PMC article \n5 Yokoe T. Fukada I. Kobayashi K. Cystoid macular edema during treatment with paclitaxel and bevacizumab in a patient with metastatic breast cancer: a case report and literature review 2017 Jul 11 Case Rep Oncol 10 2 2017 605 612 10.1159/000477897 eCollection 2017 May-Aug. PMID: 28868019 Free PMC article 28868019 \n6 Bassi E. Loizzi V. Furino C. Cystoid macular edema secondary to paclitaxel therapy for ovarian cancer: a case report Mol Clin Oncol 7 2 2017 Aug 285 287 10.3892/mco.2017.1296 Epub 2017 Jun 21 28781803 \n7 Valeshabad A.K. Mieler W.F. Setlur V. Posterior segment toxicity following gemcitabine and docetaxel chemotherapy Optom Vis Sci 92 5 2015 e110 e113 25822016 \n8 Elhusseiny A.M. Relhan N. Smiddy W.E. Docetaxel-induced maculopathy possibly potentiated by concurrent hydroxychloroquine use Am J Ophthalmol Case Rep 16 2019 Sep 26 100560 10.1016/j.ajoc.2019.100560 eCollection 2019 Dec. PMID: 31650088 Free PMC article \n9 Telander D.G. Sarraf D. Cystoid macular edema with docetaxel chemotherapy and the fluid retention syndrome Semin Ophthalmol 22 3 2007 151 153 17763235 \n10 Joshi M.M. Garretson B.R. Paclitaxel maculopathy Arch Ophthalmol 125 5 2007 709 710 17502517 \n11 Freund K.B. Laud K. Lima L.H. Spaide R.F. Zweifel S. Yannuzzi L.A. Acquired Vitelliform Lesions: correlation of clinical findings and multiple imaging analyses Retina 31 2011 13 25 21102371\n\n",
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"journal": "American journal of ophthalmology case reports",
"keywords": "Cystoid macular edema; Docetaxel; Ocular toxicity; Subfoveal hyperreflectivity",
"medline_ta": "Am J Ophthalmol Case Rep",
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"pubdate": "2020-12",
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"title": "Unilateral cystoid macular edema and bilateral subfoveal hyperreflectivity following docetaxel chemotherapy: A case report.",
"title_normalized": "unilateral cystoid macular edema and bilateral subfoveal hyperreflectivity following docetaxel chemotherapy a case report"
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"abstract": "BACKGROUND\nThe systemic inflammation is associated with clinical outcome and mortality in chronic obstructive pulmonary disease (COPD) patients. To investigate the effects of tiotropium (Tio) and/or budesonide/formoterol (Bud/Form) on systemic inflammation biomarkers in stable COPD patients of group D, a randomized, open-label clinical trial was conducted.\n\n\nMETHODS\nEligible participants (n = 324) were randomized and received either Tio 18ug once daily (group I), Bud/Form 160/4.5ug twice daily (group II), Bud/Form 320/9ug twice daily (group III), or Tio 18ug once daily with Bud/Form 160/4.5ug twice daily (group IV) for 6 months. Systemic inflammation biomarkers were measured before randomization and during the treatment, including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), serum amyloid A (SAA), tumor necrosis factor-α (TNF-α), fibrinogen (Fib), and white blood cell (WBC).\n\n\nRESULTS\nAfter 6-month treatment, CRP levels in group II, group III and group IV changed by a median (interquartile range) of -1.25 (-3.29, 1.18) mg/L, -1.13 (-2.55, 0.77) mg/L, and -1.56 (-4.64, 0.22) mg/L respectively, all of which with statistical differences compared with group I. In addition, there were no treatment differences in terms of IL-8, SAA, TNF-α, Fib and WBC levels.\n\n\nCONCLUSIONS\nA long-term treatment with Bud/Form alone or together with Tio can attenuate circulating CRP levels in COPD patients of group D, compared with Tio alone.",
"affiliations": "Department of Respiratory Medicine, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.;Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China.;Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China.;Department of Respiratory Medicine, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.;Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China.;Department of Respiratory Medicine, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.",
"authors": "Lin|Yi-Hua|YH|;Liao|Xi-Ning|XN|;Fan|Li-Li|LL|;Qu|Yue-Jin|YJ|;Cheng|De-Yun|DY|;Shi|Yong-Hong|YH|",
"chemical_list": "D015415:Biomarkers; D001993:Bronchodilator Agents; D019819:Budesonide; D002097:C-Reactive Protein; D000068759:Formoterol Fumarate",
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"doi": "10.1371/journal.pone.0183300",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0183300PONE-D-16-47556Research ArticleMedicine and Health SciencesPulmonologyChronic Obstructive Pulmonary DiseaseBiology and Life SciencesImmunologyImmune ResponseInflammationMedicine and Health SciencesImmunologyImmune ResponseInflammationMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsInflammationMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsInflammationBiology and Life SciencesBiochemistryBiomarkersBiology and Life SciencesPhysiologyPhysiological ProcessesRespirationInhalationMedicine and Health SciencesPhysiologyPhysiological ProcessesRespirationInhalationMedicine and Health SciencesInflammatory DiseasesBiology and Life SciencesBiochemistryProteinsC-Reactive ProteinsBiology and Life SciencesBiochemistryGlycobiologyGlycoproteinsFibrinogenBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsBiology and Life SciencesCell BiologyCellular TypesAnimal CellsImmune CellsWhite Blood CellsBiology and Life SciencesImmunologyImmune CellsWhite Blood CellsMedicine and Health SciencesImmunologyImmune CellsWhite Blood CellsLong-term treatment with budesonide/formoterol attenuates circulating CRP levels in chronic obstructive pulmonary disease patients of group D Bud/form attenuates CRP levels in COPD patients of group DLin Yi-Hua ConceptualizationData curationFormal analysisWriting – original draftWriting – review & editing12Liao Xi-Ning InvestigationMethodologyProject administration2Fan Li-Li InvestigationMethodologyProject administration2Qu Yue-Jin InvestigationMethodologyProject administrationSoftware1Cheng De-Yun ConceptualizationSupervisionValidationWriting – review & editing2Shi Yong-Hong ConceptualizationSupervisionValidationWriting – review & editing1*1 \nDepartment of Respiratory Medicine, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China2 \nDepartment of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, ChinaTashkin Donald EditorUCLA, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: shiyonghong_XMU@163.com23 8 2017 2017 12 8 e01833005 12 2016 31 7 2017 © 2017 Lin et al2017Lin et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nThe systemic inflammation is associated with clinical outcome and mortality in chronic obstructive pulmonary disease (COPD) patients. To investigate the effects of tiotropium (Tio) and/or budesonide/formoterol (Bud/Form) on systemic inflammation biomarkers in stable COPD patients of group D, a randomized, open-label clinical trial was conducted.\n\nMethods\nEligible participants (n = 324) were randomized and received either Tio 18ug once daily (group I), Bud/Form 160/4.5ug twice daily (group II), Bud/Form 320/9ug twice daily (group III), or Tio 18ug once daily with Bud/Form 160/4.5ug twice daily (group IV) for 6 months. Systemic inflammation biomarkers were measured before randomization and during the treatment, including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), serum amyloid A (SAA), tumor necrosis factor-α (TNF-α), fibrinogen (Fib), and white blood cell (WBC).\n\nResults\nAfter 6-month treatment, CRP levels in group II, group III and group IV changed by a median (interquartile range) of -1.25 (-3.29, 1.18) mg/L, -1.13 (-2.55, 0.77) mg/L, and -1.56 (-4.64, 0.22) mg/L respectively, all of which with statistical differences compared with group I. In addition, there were no treatment differences in terms of IL-8, SAA, TNF-α, Fib and WBC levels.\n\nConclusions\nA long-term treatment with Bud/Form alone or together with Tio can attenuate circulating CRP levels in COPD patients of group D, compared with Tio alone.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nChronic obstructive pulmonary disease (COPD) is one of the leading causes of disability and death worldwide. It is the fourth most common cause of death in the world[1], and it is predicted to rise to the third place by the year of 2020[2].Increasing studies have shown that COPD is not only a respiratory inflammatory condition[3], but also a mild chronic systemic inflammation accompanied by many extrapulmonary manifestations[4]. Several biomarkers of systemic inflammation have been proved to be directly associated with COPD, including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), serum amyloid A (SAA), tumor necrosis factor-α (TNF-α), fibrinogen (Fib), and white blood cell (WBC). The systemic inflammation is also related with lung function, arterial oxygen tension, exercise capacity, degree of dyspnea, clinical outcome, risk of exacerbation, all-cause and COPD-related mortality[5–7]. Moreover, the systemic inflammation could increase the risk of major comorbidities in COPD, including cardiovascular disease, lung cancer, pneumonia, diabetes mellitus, depression, cachexia, skeletal muscle dysfunction and osteoporosis[8–10]. Take all the factors above into consideration, attenuating systemic inflammation might provide a potential method to improve health conditions and prognosis in COPD patients. Inhaled corticosteroid (ICS) +long-acting β2-agonist (LABA) and/or long-acting anticholinergic agents (LAMA) reduce exacerbation risks and symptoms in COPD patients. Nevertheless, the effects of inhaled therapy on systemic inflammation in COPD are still controversial[11–14].\n\nMany clinical symptoms and a high risk of exacerbations were observed in COPD patients of group D[15], whose CRP values were significantly higher than those in the other three groups[16]. Thus, a clinical trial was conducted to investigate the effects of tiotropium (Tio) and/or budesonide/formoterol (Bud/Form) on systemic inflammation biomarkers in stable COPD patients of group D and improvements of symptoms and pulmonary function.\n\nMethods\nThis randomized, open-label study aimed to evaluate the effect of inhaled therapy on systemic inflammation biomarkers in stable COPD patients of group D over 6 months. The study protocol was in compliance with the Declaration of Helsinki and was approved by the ethical committee of GCP and biomedicine of West China Hospital of Sichuan University. Written informed consents were obtained from all subjects. The study was registered at http://www.chictr.org.cn/ (ChiCTR-IPR-14005619).\n\nStudy subjects\nOutpatients with a clinical diagnosis of stable COPD were recruited from Jan 2015 to Nov 2015 in the West China Hospital of Sichuan University, China. The inclusion criteria were as follows: confirmed COPD of group D by pulmonary physicians based on the 2011 GOLD guidelines[15], age ≥40 years, absence of exacerbations[15] for at least one month. Exclusion criteria: patients used LAMA, LABA, oral corticosteroid or ICS in the previous one month, with any infection in the previous one month before study entry, with proved prostatic hyperplasia, bladder neck stenosis or narrow angle glaucoma, with other clinically significant lung diseases or complications which were associated with increasing systemic inflammation (e.g. rheumatoid arthritis, hepatic diseases, renal diseases, cancer or tuberculosis).\n\nStudy design\nEligible participants were then randomly assigned (1:1:1:1) using a computer-generated randomization list to one of four arms: group I, Tio 18ug once daily by Handihaler (Boehringer Ingelheim Pharma, Ingelheim, Germany); group II, Bud/Form 160/4.5ug/dose (Symbicort Turbuhaler; AstraZeneca, Sweden) one inhalation twice daily; group III, Bud/Form 160/4.5ug/dose two inhalations twice daily; group IV, Tio 18ug once daily plus Bud/Form 160/4.5ug/dose one inhalation twice daily. All subjects were allowed to take Terbutaline (Bricasol pressurized metered-dose inhale; AstraZeneca, Wuxi, China) as reliever during the study period. No other bronchodilator was permitted to be used throughout the study. Considering life style modifications may have impacts on the level of systemic inflammation, specific instructions on risk-factor modifications were not given during the study, such as exercise training and smoking cessation.\n\nThe treatment duration was 6 months, with clinical visits at the end of the first month (visit 2), the third month (visit 3) and the sixth month (visit 4). During the treatment, subjects with any of the following conditions would be removed from the study: poor compliance (taking <80% or >120% of the dosage); combined with acute exacerbations; occurring serious adverse events; combined with any one of the above exclusion criteria.\n\nOutcome measurements\nDuring each visit, fasting blood samples were collected in the morning. The samples were stored at -80°C until analyzed with standard hospital assays in the central laboratory. Whole blood leukocyte counts were measured using Sysmex XE-2100 automated hematology analyzer (Sysmex Medical Electronics Co., Ltd, Japan). CRP levels were determined using high-sensitivity immunoturbidimetric assay (Beckman Coulter, Inc, USA). IL-6 levels were measured by electrochemiluminescence assay (Roche Diagnostics Co., Ltd, Switzerland). IL-8 and TNF-α levels were measured by chemiluminescence immunoassay, whereas SAA serum concentrations were determined by nephelometry assay (Siemens Medical Diagnostic Products Co., Ltd, Germany). Fibrinogen levels were measured using coagulation method (Sysmex Medical Electronics Co., Ltd, Japan). All samples were analyzed in duplicate.\n\nIn addition, at each visit, participants’ symptoms were evaluated according to the modified British medical Research Council (mMRC) dyspnea scale[17] and COPD assessment test (CAT)[18]. Besides, at visit 1, 3 and 4, spirometry was performed [19].\n\nStatistical analysis\nCRP was selected as the reference for calculation of the estimated sample size. It was assumed that the mean difference in the change of CRP level was 1.5 mg/L between groups with an SD of 3 mg/L[14], the level of significance was 0.05, the power of the test was 0.8, the lost follow-up rate was no more than 20%, and the calculated sample size was 80 per treatment group.\n\nAll statistical analysis was performed using IBM SPSS Statistics for Windows, version 19.0, Armonk, NY: IBM Corp. Analyses were conducted based on an intention-to-treat principle. Normally distributed data were described as mean ± standard deviations (SD), whereas non-normally distributed data were reported as medians (interquartile range, IQR) unless otherwise indicated.\n\nFor each visit of every group, changes from baseline in systemic inflammation biomarkers, lung function, and symptom scores were analyzed using paired t tests or Wilcoxon signed rank test, according to whether they meet the normal distribution.\n\nFor normally distributed variables, the differences of changes (post-treatment minus pre-treatment) of IL-8 levels, TNF-α levels, Fib levels, WBC levels, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and CAT scores between each groups were analyzed using an analysis of variance (ANOVA) model. And the least significance difference test was applied for pairwise comparison following ANOVA. For non-normally distributed variables, the differences of changes (post-treatment minus pre-treatment) of CRP levels, IL-6 levels, and SAA levels between each group were analyzed using Kruskal-Wallis test. And the Mann-Whitney U test applying for pairwise comparison was followed.\n\nResults\nA total of 324 subjects were eligible for randomization. Among them, 301 subjects (92.9%) completed the first visit after 1 month of treatment, 268 subjects (82.7%) completed the second visit after 3 months of treatment, and 256 subjects (79%) completed the third visit after 6 months of treatment (Fig 1). Baseline characteristics of the four groups were similar (Table 1).\n\n10.1371/journal.pone.0183300.g001Fig 1 Flow diagram of patients in the study.\nTio, tiotropium; Bud, budesonide; Form, formoterol; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; SAE, serious adverse events; PC, poor compliance.\n\n10.1371/journal.pone.0183300.t001Table 1 Baseline characteristics of the study subjects.\n\tGroup I(n = 83)\tGroup II(n = 79)\tGroup III(n = 80)\tGroup IV(n = 82)\tP\t\nMale (%)\t79.5\t69.6\t73.8\t74.4\t0.958\t\nAge (years)\t65.31±9.75\t65.27±9.57\t66.44±9.82\t63.45±9.90\t0.274\t\nNon smokers\t15\t16\t21\t19\t0.974\t\nPack-yearsδ\t30(10,40)\t30(10,42)\t25(5,40)\t30(3,40)\t0.668\t\nBMI(kg/m2)\t20.89±2.42\t21.44±2.16\t21.53±2.52\t21.92±2.75\t0.066\t\nDuration COPD yearsδ\t7(2, 15)\t7(1, 10)\t5(1.25, 10)\t5.5(1, 10)\t0.778\t\nExacerbations*δ\t2(1, 2)\t2(1,2)\t2(1, 2)\t1(1, 2)\t0.340\t\nHospitalizations*\t0.16±0.43\t0.22±0.47\t0.20±0.46\t0.15±0.39\t0.676\t\nFEV1 (L)\t0.88±0.34\t0.82±0.27\t0.93±0.27\t0.81±0.30\t0.709\t\nFEV1% predicted\t37.73±9.97\t39.08±10.78\t42.41±12.43\t34.12±12.85\t0.295\t\nFVC (L)\t2.21±0.72\t1.89±0.65\t2.21±0.65\t1.95±0.50\t0.369\t\nFEV1/FVC (%)\t40.11±7.29\t45.63±8.63\t43.59±8.32\t41.51±11.15\t0.325\t\nCor Pulmonale\t5\t8\t5\t3\t0.480\t\nComorbidities\t\t\t\t\t\t\n CVD\t6\t6\t6\t8\t0.944\t\n Hypertension\t5\t6\t7\t5\t0.909\t\n DM\t9\t5\t4\t5\t0.547\t\nmMRC\t\t\t\t\t0.574\t\n 1\t1\t0\t0\t1\t\t\n 2\t20\t26\t28\t20\t\t\n 3\t60\t49\t50\t56\t\t\n 4\t2\t4\t2\t5\t\t\nCAT score\t16.29±5.14\t16.15±4.74\t15.40±4.19\t15.77±4.91\t0.633\t\nCRP(mg/L)δ\t3.54(1.60, 5.32)\t3.90(2.97, 6.56)\t3.69(1.98, 5.21)\t4.20(2.36, 6.40)\t0.197\t\nIL-6(pg/mL)δ\t4.40(3.13, 7.29)\t4.50(3.09, 9.39)\t4.55(3.11, 8.61)\t5.34(3.06, 10.11)\t0.527\t\nIL-8(pg/mL)\t11.54±6.82\t10.99±5.61\t10.44±4.61\t11.41±5.84\t0.616\t\nSAA(mg/L)δ\t3.52(2.32, 10.00)\t4.06(2.32, 11.98)\t4.12(2.66, 7.37)\t4.46(2.42, 12.22)\t0.728\t\nTNF-α(pg/mL)\t10.39±3.19\t10.90±3.66\t10.73±3.60\t11.37±4.19\t0.391\t\nFib(g/L)\t3.58±0.90\t3.49±0.76\t3.50±0.84\t3.49±0.85\t0.898\t\nWBC(×109/L)\t6.67±1.66\t6.38±1.66\t6.30±1.62\t6.35±1.70\t0.477\t\nNeu%\t60.35±9.77\t60.79±8.95\t58.60±8.56\t59.21±9.84\t0.421\t\nLym%\t29.72±8.99\t28.85±7.60\t30.37±6.92\t30.78±8.98\t0.472\t\nGroup I: tiotropium 18ug once daily; Group II, budesonide/formoterol 160/4.5ug twice daily; Group III, budesonide/formoterol 320/9ug twice daily; Group IV, tiotropium 18ug once daily+ budesonide/formoterol 160/4.5ug twice daily.\n\nBMI: body mass index; COPD: chronic obstructive pulmonary disease;\n\n*: the number of exacerbations or hospitalizations in the preceding year;\n\nFEV1: forced expiratory volume in one second; FVC: forced vital capacity; CVD: cardiovascular disease; DM: Diabetes mellitus; mMRC: modified British medical Research Council dyspnoea scale; CAT: COPD assessment test; CRP: C-reactive protein; IL-6: interleukin-6; IL-8: interleukin-8; SAA: serum amyloid; TNF-α: tumour necrosis factor-α; Fib: fibrinogen; WBC: white blood cell; Neu: neutrophil; Lym: lymphocyte.\n\nData are shown as mean ± SD, unless indicated otherwise.\n\nδ: Nonormally distributed variables are shown as median (interquartile range).\n\nSystemic inflammation biomarkers\n(1) CRP\nGroup I: the median baseline CRP level was 3.54 mg/L. The median CRP levels of subjects who completed the second, third and fourth visit were 3.87 mg/L, 4.46 mg/L and 4.05 mg/L, respectively, none of which with statistical difference compared with the baseline level (Table 2). Group II: the median baseline CRP level was 3.90 mg/L. The median CRP levels of subjects who completed the second, third and fourth visit were 3.79 mg/L, 3.32 mg/L (compared with baseline, P<0.05) and 3.41 mg/L (compared with baseline, P<0.05), respectively (Table 3). Group III: the median baseline CRP level was 3.69 mg/L. The median CRP levels of subjects who completed the second, third and fourth visit were 3.16 mg/L, 3.08 mg/L and 3.10 mg/L, respectively, all of which with statistical differences compared with the baseline level (Table 4). Group IV: the median baseline CRP level was 4.20 mg/L. The median CRP levels of subjects who completed the second, third and fourth visit were 3.48 mg/L, 3.68 mg/L and 3.27 mg/L, respectively, all of which with statistical differences compared with the baseline level (Table 5).\n\n10.1371/journal.pone.0183300.t002Table 2 Changes in circulating biomarkers, pulmonary function and CAT scores of subjects in group I during six months of therapy.\n\tVisit 1\tVisit 2\tVisit 3\tVisit 4\t\nn\t83\t75\t68\t65\t\nCRP (mg/L) δ\t3.54(1.60, 5.32)\t3.87(2.33, 6.33)\t4.46(2.72, 7.46)\t4.05(2.75, 5.90)\t\nIL-6 (pg/mL) δ\t4.40(3.13, 7.29)\t4.57(3.09, 7.87)\t4.80(3.35, 8.12)\t4.94(3.44, 8.32)\t\nIL-8 (pg/mL)\t11.54±6.82\t10.15±4.78\t11.09±6.23\t10.37±4.83\t\nSAA (mg/L) δ\t3.52(2.32, 10.00)\t3.61(2.36, 7.96)\t3.84(2.36, 7.93)\t4.27(2.39, 10.99)\t\nTNF-α (pg/mL)\t10.39±3.19\t10.71±3.02\t10.77±3.13\t10.70±2.86\t\nFib (g/L)\t3.58±0.90\t3.50±0.94\t3.53±0.98\t3.48±0.89\t\nWBC (×109/L)\t6.67±1.66\t6.18±1.72\t6.28±1.75\t6.06±1.77*\t\nNeu (%)\t60.35±9.77\t61.77±9.20\t61.75±9.00\t62.10±8.50\t\nLym (%)\t29.72±8.99\t31.35±8.39\t31.22±8.27\t30.93±8.29\t\nFEV1 (L)\t0.88±0.34\tND\t1.02±0.23*\t1.00±0.22*\t\nFEV1% predicted\t37.73±9.97\tND\t41.66±9.96*\t41.28±10.25*\t\nFVC (L)\t2.21±0.72\tND\t2.37±0.58*\t2.33±0.54*\t\nFEV1/FVC (%)\t40.11±7.29\tND\t45.12±12.15\t45.02±12.32*\t\nCAT score\t16.29±5.14\t11.29±2.14*\t9.38±2.13*\t8.65±1.64*\t\nGroup I: tiotropium 18ug once daily group; CAT: COPD assessment test; Visit 1: at the beginning of therapy; Visit 2: at the end of 1 month-therapy; Visit 3: at the end of 3 month-therapy; Visit 4: at the end of 6 month-therapy.\n\n*: compared to baseline, P <0.05.\n\nCRP: C-reactive protein; IL-6: interleukin-6; IL-8: interleukin-8; SAA: serum amyloid; TNF-α: tumour necrosis factor-α; Fib: fibrinogen; WBC: white blood cell; Neu: neutrophil; Lym: lymphocyte; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; ND: not detected.\n\nData are shown as mean ± SD, unless indicated otherwise.\n\nδ: Nonormally distributed variables are shown as median (interquartile range).\n\n10.1371/journal.pone.0183300.t003Table 3 Changes in circulating biomarkers, pulmonary function and CAT scores of subjects in group II during six months of therapy.\n\tVisit 1\tVisit 2\tVisit 3\tVisit 4\t\nn\t79\t75\t70\t67\t\nCRP (mg/L) δ\t3.90 (2.97, 6.56)\t3.79(1.77, 6.32)\t3.32(1.44, 5.16)*\t3.41(1.16, 4.69)*\t\nIL-6 (pg/mL) δ\t4.50(3.09, 9.39)\t4.20(2.87, 6.51)\t3.99(2.43, 5.82)*\t3.64(2.37, 6.20)*\t\nIL-8 (pg/mL)\t10.99±5.61\t9.91±4.31\t9.78±3.76\t9.50±3.34\t\nSAA (mg/L) δ\t4.06(2.32, 11.98)\t3.52(2.18, 7.50)\t3.86(2.57, 7.79)\t3.89(2.70, 7.78)\t\nTNF-α (pg/mL)\t10.90±3.66\t10.51±4.21\t11.12±2.83\t11.36±3.14\t\nFib (g/L)\t3.49±0.76\t3.40±0.80\t3.20±0.67 *\t3.29±0.71\t\nWBC (×109/L)\t6.38±1.66\t6.71±1.67\t6.66±1.67\t6.43±1.71\t\nNeu (%)\t60.79±8.95\t60.34±9.30\t60.83±8.89\t62.35±8.56\t\nLym (%)\t28.85±7.60\t29.61±8.34\t28.78±8.11\t28.71±8.00\t\nFEV1 (L)\t0.82±0.27\tND\t0.98±0.19*\t0.98±0.18*\t\nFEV1% predicted\t39.08±10.78\tND\t42.13±10.75*\t41.99±10.99*\t\nFVC (L)\t1.89±0.65\tND\t2.27±0.60\t2.27±0.61\t\nFEV1/FVC (%)\t45.63±8.63\tND\t45.92±13.59\t46.32±14.10\t\nCAT score\t16.15±4.74\t12.07±3.02*\t10.01±2.76*\t9.70±2.22*\t\nGroup II: budesonide/formoterol 160/4.5ug twice daily group; CAT: COPD assessment test; Visit 1: at the beginning of therapy; Visit 2: at the end of 1 month-therapy; Visit 3: at the end of 3 month-therapy; Visit 4: at the end of 6 month-therapy.\n\n*: compared to baseline, P <0.05.\n\nCRP: C-reactive protein; IL-6: interleukin-6; IL-8: interleukin-8; SAA: serum amyloid; TNF-α: tumour necrosis factor-α; Fib: fibrinogen; WBC: white blood cell; Neu: neutrophil; Lym: lymphocyte; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; ND: not detected.\n\nData are shown as mean ± SD, unless indicated otherwise.\n\nδ: Nonormally distributed variables are shown as median (interquartile range).\n\n10.1371/journal.pone.0183300.t004Table 4 Changes in circulating biomarkers, pulmonary function and CAT scores of subjects in group III during six months of therapy.\n\tVisit 1\tVisit 2\tVisit 3\tVisit 4\t\nn\t80\t77\t66\t64\t\nCRP (mg/L) δ\t3.69(1.98, 5.21)\t3.16(2.08, 4.10)*\t3.08(1.83, 3.78)*\t3.10(1.80, 3.86)*\t\nIL-6 (pg/mL) δ\t4.55(3.11, 8.61)\t3.72(2.48, 6.54)*\t3.70(2.63, 4.98)\t3.35(2.39, 5.43)*\t\nIL-8 (pg/mL)\t10.44±4.61\t9.32±4.55\t10.40±5.41\t9.86±5.16\t\nSAA (mg/L) δ\t4.12(2.66, 7.37)\t3.84(2.42, 7.44)\t4.55(2.78, 8.33)\t4.21(2.47, 8.47)\t\nTNF-α (pg/mL)\t10.73±3.60\t10.77±3.26\t10.91±2.50\t11.28±2.77\t\nFib (g/L)\t3.50±0.84\t3.37±0.83\t3.23±0.61\t3.22±0.78\t\nWBC (×109/L)\t6.30±1.62\t6.64±1.64\t6.59±1.66\t6.23±1.65\t\nNeu (%)\t58.60±8.56\t60.04±9.72\t60.32±9.72\t59.75±10.32\t\nLym (%)\t30.37±6.92\t29.57±8.47\t29.38±8.58\t29.25±9.11\t\nFEV1 (L)\t0.93±0.27\tND\t1.06±0.27*\t1.08±0.26*\t\nFEV1% predicted\t42.41±12.43\tND\t42.10±11.98*\t42.67±12.02*\t\nFVC (L)\t2.21±0.65\tND\t2.23±0.52\t2.31±0.53*\t\nFEV1/FVC (%)\t43.59±8.32\tND\t49.68±14.98*\t50.68±15.09*\t\nCAT score\t15.40±4.19\t9.95±2.05*\t9.02±2.57*\t8.72±2.14*\t\nGroup III, budesonide/formoterol 320/9ug twice daily group; CAT: COPD assessment test; Visit 1: at the beginning of therapy; Visit 2: at the end of 1 month-therapy; Visit 3: at the end of 3 month-therapy; Visit 4: at the end of 6 month-therapy.\n\n*: compared to baseline, P <0.05.\n\nCRP: C-reactive protein; IL-6: interleukin-6; IL-8: interleukin-8; SAA: serum amyloid; TNF-α: tumour necrosis factor-α; Fib: fibrinogen; WBC: white blood cell; Neu: neutrophil; Lym: lymphocyte; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; ND: not detected.\n\nData are shown as mean ± SD, unless indicated otherwise.\n\nδ: Nonormally distributed variables are shown as median (interquartile range).\n\n10.1371/journal.pone.0183300.t005Table 5 Changes in circulating biomarkers, pulmonary function and CAT scores of subjects in group IV during six months of therapy.\n\tVisit 1\tVisit 2\tVisit 3\tVisit 4\t\nn\t82\t74\t64\t60\t\nCRP (mg/L) δ\t4.20(2.36, 6.40)\t3.48(2.56, 5.48)*\t3.68(2.68, 5.21)*\t3.27(2.05, 4.53)*\t\nIL-6 (pg/mL) δ\t5.34(3.06, 10.11)\t4.47(3.11, 7.57)*\t3.94(2.80, 7.27)*\t4.00(2.60, 6.94)*\t\nIL-8 (pg/mL)\t11.41±5.84\t9.87±4.29\t9.94±3.57\t10.46±3.17\t\nSAA (mg/L) δ\t4.46(2.42, 12.22)\t4.19(2.29, 7.86)\t4.16(2.34, 7.80)\t5.21(3.67, 8.93)\t\nTNF-α (pg/mL)\t11.37±4.19\t10.96±2.99\t11.87±3.19\t12.10±3.70\t\nFib (g/L)\t3.49±0.85\t3.29±0.84\t3.20±0.80\t3.32±0.72\t\nWBC (×109/L)\t6.35±1.70\t6.51±1.63\t6.39±1.68\t6.11±1.68\t\nNeu (%)\t59.21±9.84\t58.89±8.70\t58.69±8.88\t58.77±9.37\t\nLym (%)\t30.78±8.98\t30.91±7.83\t31.20±8.19\t30.90±8.75\t\nFEV1 (L)\t0.81±0.30\tND\t1.07±0.20*\t1.08±0.20*\t\nFEV1% predicted\t34.12±12.85\tND\t44.36±12.22*\t45.01±12.04*\t\nFVC (L)\t1.95±0.50\tND\t2.41±0.65*\t2.45±0.68*\t\nFEV1/FVC (%)\t41.51±11.15\tND\t46.83±12.96*\t46.85±12.72*\t\nCAT score\t15.77±4.91\t9.32±2.47*\t8.48±2.49*\t7.93±1.65*\t\nGroup IV, tiotropium 18ug once daily+ budesonide/formoterol 160/4.5ug twice daily group; CAT: COPD assessment test; Visit 1: at the beginning of therapy; Visit 2: at the end of 1 month-therapy; Visit 3: at the end of 3 month-therapy; Visit 4: at the end of 6 month-therapy.\n\n*: compared to baseline, P <0.05.\n\nCRP: C-reactive protein; IL-6: interleukin-6; IL-8: interleukin-8; SAA: serum amyloid; TNF-α: tumour necrosis factor-α; Fib: fibrinogen; WBC: white blood cell; Neu: neutrophil; Lym: lymphocyte; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; ND: not detected.\n\nData are shown as mean ± SD, unless indicated otherwise.\n\nδ: Nonormally distributed variables are shown as median (interquartile range).\n\nAfter 3-month and 6-month treatment, CRP level in Group II changed by a median (IQR) of -1.21 (-2.91, 1.19) mg/L and -1.25 (-3.29, 1.18) mg/L, respectively, both of which with statistical differences compared with group I. After 3-month and 6-month treatment, CRP level in Group III changed by a median (IQR) of -0.94 (-2.42, 0.82) mg/L and -1.13 (-2.55, 0.77) mg/L, respectively, both of which with statistical differences compared with group I. After 1-month, 3-month and 6-month treatment, CRP level in Group IV changed by a median (IQR) of -1.14 (-3.40, 0.96) mg/L, -1.30 (-3.39, 0.76) mg/L and -1.56 (-4.64, 0.22) mg/L, respectively, all of which with statistical differences compared with group I (Figs 2–4).\n\n10.1371/journal.pone.0183300.g002Fig 2 Treatment differences in terms of A) CRP, B) IL-6, and C) CAT Score after 1 month of therapy.\nGroup I: tiotropium 18ug once daily; Group II, budesonide/formoterol 160/4.5ug twice daily; Group III, budesonide/formoterol 320/9ug twice daily; Group IV, tiotropium 18ug once daily+ budesonide/formoterol 160/4.5ug twice daily; CRP: C-reactive protein; IL-6: interleukin-6; CAT: COPD assessment test.\n\n10.1371/journal.pone.0183300.g003Fig 3 Treatment differences in terms of A) CRP, B) IL-6, C) FEV1 and D) CAT Score after 3 months of therapy.\nGroup I: tiotropium 18ug once daily; Group II, budesonide/ formoterol 160/4.5ug twice daily; Group III, budesonide/formoterol 320/9ug twice daily; Group IV, tiotropium 18ug once daily+budesonide/formoterol 160/4.5ug twice daily; CRP: C-reactive protein; IL-6: interleukin-6; FEV1: forced expiratory volume in one second; CAT: COPD assessment test.\n\n10.1371/journal.pone.0183300.g004Fig 4 Treatment differences in terms of A) CRP, B) IL-6, C) FEV1 and D) CAT Score after 6 months of therapy.\nGroup I: tiotropium 18ug once daily; Group II, budesonide/ formoterol 160/4.5ug twice daily; Group III, budesonide/formoterol 320/9ug twice daily; Group IV, tiotropium 18ug once daily+budesonide/formoterol 160/4.5ug twice daily; CRP: C-reactive protein; IL-6: interleukin-6;FEV1: forced expiratory volume in one second; CAT: COPD assessment test.\n\n(2) IL-6\nGroup I: the median baseline IL-6 level was 4.40 pg/mL. The median IL-6 levels of subjects who completed the second, third and fourth visit were 4.57 pg/mL, 4.80 pg/mL and 4.94 pg/mL, respectively, none of which with statistical difference compared with the baseline level (Table 2). Group II: the median baseline IL-6 level was 4.50 pg/mL. The median IL-6 levels of subjects who completed the second, third and fourth visit were 4.20 pg/mL, 3.99 pg/mL (compared with baseline, P<0.05) and 3.64 pg/mL (compared with baseline, P<0.05), respectively (Table 3). Group III: the median baseline IL-6 level was 4.55 pg/mL. The median IL-6 levels of subjects who completed the second, third and fourth visit were 3.72 pg/mL(compared with baseline, P<0.05), 3.70 pg/mL and 3.35 pg/mL(compared with baseline, P<0.05), respectively (Table 4). Group IV: the median baseline IL-6 level was 5.34 pg/mL. The median IL-6 levels of subjects who completed the second, third and fourth visit were 4.47 pg/mL, 3.94 pg/mL and 4.00 pg/mL, respectively, all of which with statistical differences compared with the baseline level (Table 5).\n\nAfter 1-month, 3-month and 6-month treatment, IL-6 level in Group IV changed by a median (IQR) of -0.93 (-5.13, 0.60) pg/mL, -1.14 (-5.37, 0.66) pg/mL and -1.50 (-5.56, 0.08) pg/mL, respectively, all of which with statistical differences compared with group I (Figs 2–4).\n\n(3) The levels of IL-8, SAA, TNF-α, Fib and WBC of each group did not change significantly (shown in Tables 2–5).\n\nPulmonary function\nFEV1 of each group increased significantly after inhaled treatment (Tables 2–5). After 3-month and 6-month treatment, the mean increase of FEV1 in group IV was more than the other three groups (Figs 3 and 4).\n\nCAT score\nCAT scores of each group decreased significantly after inhaled treatment (Tables 2–5). After 1-month treatment, the mean decrease of CAT scores in group IV was more prominent than the other three groups (Fig 2). After 3-month treatment, the mean decrease of CAT scores in group IV was more notably than group II and group III (Fig 3). After 6-month treatment, the mean decrease of CAT score in group I and IV was more distinct than group II and group III (Fig 4).\n\nDiscussion\nThis is the first randomized (not double blinded) clinical trial to compare the effects of Tio and/or Bud/Form on systemic inflammation in stable COPD patients of group D. The study showed that a long-term treatment with Bud/Form alone or with Tio reduced circulating CRP levels in COPD patients of group D, while treatment with Tio alone did not. This result is similar to previous trials conducted by Sin et al [11]and Tang et al[14], which also showed that ICS and/or LABA reduced circulating level of CRP in COPD patients. These findings may explain the data of a cross-sectional study conducted by Pinto-Plata et al which showed that CRP levels were lower in users of ICS than in non-users in stable moderate-to-very severe COPD patients[12].\n\nHowever, unlike our report, serum levels of CRP or IL-6 did not significantly change in inhaled fluticasone alone or in combination with salmeterol after 4 weeks of treatment[13]. Several important factors may facilitate to explain the discrepancies. First, the treatment duration was much longer (6 months vs. 4 weeks), which might lead to different outcomes. In our study, the changes of CRP levels were not significantly different at 1 month between Bud/Form group and Tio group. However, the levels of CRP were significantly reduced in Bud/Form alone or with Tio groups after 3-month and 6-month therapy. Therefore, the attenuation of underlying systemic inflammation by Bud/Form may be a progressive and lasting process. Second, different medications might also be an important factor accounting for this difference. In vitro experiments demonstrated that β 2-agonists varied in their suppressive effects on activated neutrophils[20]. Last, our participants did not take any corticosteroids prior to the study, which might eliminate the effects of corticosteroids on baseline systemic inflammation.\n\nThe origin of systemic inflammation in COPD is unclear. One potential explanation was that, somehow, pulmonary inflammation was “spilling over” into the systemic circulation[21]. Considering budesonide could attenuate the release and expression of IL-6 and IL-8 in bronchial epithelial cells[22] and block the release of cytokines and MMPs in COPD lung fibroblasts[23], it’s plausible that Bud/Form reduced systemic inflammation through attenuating airway and pulmonary inflammation in COPD. In addition, as IL-6 is a major signaling cytokine for CRP expression and other acute-phase proteins by hepatocytes[24], it’s possible that Bud/Form downregulated IL-6 production in the airways[22], which then reduced CRP expression by the liver. Moreover, Bud/Form could be absorbed systemically and then directly affected the hepatocytes. This might help to explain why the declines of CRP levels were accompanied with varying degrees of declines in IL-6 levels in our study.\n\nAlthough the precise mechanism remained unknown, the finding of our study, which showed the intervention effect of Bud/Form on circulating CRP levels in COPD patients of group D, might have important clinical significance. COPD is a highly heterogeneous disease. There are significant differences in treatment options for patients with different clinical manifestations and severities. COPD patients of group D have many symptoms and a high risk of exacerbations. The first choice of therapy is ICS+LABA and/or LAMA[25]. But the guideline did not specify when an alternative monotherapy, and when the combination of medication[25]. The results of this study showed that, a long-term treatment with Bud/Form alone or with Tio can reduce circulating levels of CRP in COPD patients of group D compared with treatment with Tio alone. Since not all COPD patients have elevated systemic markers of inflammation[26], for those COPD patients with systemic inflammation in group D, Bud/Form might be a more appropriate choice.\n\nInterestingly, all ICS-containing treatments reduced CRP levels 3 months after initiation of therapy, but only the combination of the Bud/Form with Tio significantly reduced CRP levels compared with Tio alone at 1 month, suggesting a modifying influence of the LAMA. These findings might explain the data of Cazzola M et al [27], which showed that adding Tio to ICS may provide benefits in symptomatic patients with severe-to-very severe stable COPD.\n\nReducing systemic inflammation in patients with COPD might have potential important clinical implications. It’s widely accepted that systemic inflammation is a key factor connecting COPD with its comorbidities[28–31]. And there is consistent evidence that these comorbiditie have a greater negative impact on the life qualities, exacerbation and mortality of COPD patients[32]. Therefore, reducing systemic inflammation might reduce the complications of COPD and then improve the prognosis of patients. Further follow-up cohort studies with larger samples would help to determine it.\n\nNotably, although Bud/Form alone or with Tio reduced circulating CRP levels in COPD patients in our study, none of the four inhalation treatments showed the effect of intervening other systemic inflammation biomarkers including IL-8, SAA, TNF-α, Fib and WBC. Moreover, even after 6 months of treatment, the median values of CRP were all higher than 3mg/L in our study. And Previous population-based studies have reported the average CRP values were lower than 2.5 mg/L in adults who were 40 years of age [33, 34]. It meant that after 6 months of inhalation treatment, the CRP levels in COPD patients of group D might still be higher than non-COPD population. All of these findings suggested that Bud/Form could attenuate CRP levels in COPD patients of group D only to a limited extent and might be insufficient to restore it to the normal range. Therefore, further researches are needed to seek for the treatment of intervening systemic inflammation in patients with COPD.\n\nBesides, the dosage of Bud/Form should also be highlighted for its value in clinical practice. An independent study showed that in Chinese patients with moderate to very severe COPD, fixed combination treatment with Bud/Form(160/4.5μg, two inhalations twice daily) resulted in clinically meaningful improvements in lung function, health-related quality-of-life, and COPD symptoms[35]. In our study, however, there was no statistical difference between the two treatments, Bud/Form (160/4.5μg, one inhalation twice daily) and Bud/Form (160/4.5μg two inhalations twice daily), in terms of the improvements in lung function, reducing symptoms and systemic inflammation. This result suggested that, for Chinese COPD patients of group D, increasing the dosage of Bud/Form (160/4.5μg, one inhalation twice daily) from one inhalation to two inhalations might not be helpful to increase the therapeutic effect. Considering the increase of the dosage adds the economic burden and increases the incidence of drug-related adverse events for patients[36, 37], the treatment of Bud/Form (160/4.5μg, one inhalation twice daily) could be considered for Chinese COPD patients of group D. More large-scale and long-term clinical trials should be conducted to confirm the result.\n\nAlthough we see promising effect of Bud/Form attenuating circulating CRP levels in COPD patients of group D, there are some limitations in our present study. First, placebo treatment was not chosen for a control group. Since the subjects in our study were COPD patients of group D with obvious clinical symptoms and high risks, taking placebo alone was definitly improper for the ethical considerations. Second, interventions were open to participants, which was prone to introduce bias into the study. And the results of the CAT could have been biased by the non- blinded study design. However, the researchers who evaluated systemic inflammation biomarker levels and pulmonary functions were blind to the treatment. Besides, the data acquisition and data analysis were relatively independent. In this way, the generation of subjective bias was reduced. Third, the specificity of selected inflammation markers was not prominent enough, which were susceptible to be interfered by other diseases or factors. Therefore, we adopted strict exclusion criteria. Fourth, inflammatory biomarkers were not measured from lung samples due to ethical considerations and technical constraints, thus we could not further explore the possible origin of systemic inflammation and the mechanisms of drug intervention in COPD. In addition, there was lack of detailed screening for comorbidities. In our study, the establishment of comorbidities was based on patients’ history report, which might lead to missed diagnosis. For this reason, we did not further assess the relationship between systemic inflammation and comorbidities. Finally, the relationship between the treatment and acute exacerbation was not evaluated due to the relatively small number of cases and short follow-up period.\n\nIn summary, our clinical trial demonstrated that a long-term treatment with Bud/Form alone or with Tio can reduce circulating CRP levels in stable COPD patients of group D compared with treatment with Tio alone. The results highlighted the choice of individual therapy for COPD patients of group D. Longterm, large-scale, multicenter studies are needed in the future to determine whether Bud/Form can modify the progressive nature of chronic obstructive pulmonary disease.\n\nSupporting information\nS1 File CONSORT checklist.\n(DOC)\n\nClick here for additional data file.\n\n S2 File Trial protocol in Chinese.\n(DOCX)\n\nClick here for additional data file.\n\n S3 File Trial protocol in English.\n(DOCX)\n\nClick here for additional data file.\n\n S4 File The data in the trial.\n(RAR)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Kochanek K , Xu J , Murphy S , AM M and Kung H . Deaths: preliminary data for 2009 . Natl Vital Stat Rep . 2011 ; 54 : 1 –51 .\n2 Murray CJ and Lopez AD . Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study . The Lancet . 1997 ; 349 : 1498 –1504 .\n3 Hogg JC , Chu F , Utokaparch S , Woods R , Elliott WM , Buzatu L , et al\nThe nature of small-airway obstruction in chronic obstructive pulmonary disease . N Engl J Med . 2004 ; 350 : 2645 –2653 . doi: 10.1056/NEJMoa032158 \n15215480 \n4 Gan W , Man S , Senthilselvan A and Sin D . Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis . Thorax . 2004 ; 59 : 574 –580 . doi: 10.1136/thx.2003.019588 \n15223864 \n5 De Torres J , Cordoba-Lanus E , Lopez-Aguilar C , de Fuentes MM , de Garcini AM , Aguirre-Jaime A , et al\nC-reactive protein levels and clinically important predictive outcomes in stable COPD patients . Eur Respir J . 2006 ; 27 : 902 –907 . doi: 10.1183/09031936.06.00109605 \n16455829 \n6 Garcia-Rio F , Miravitlles M , Soriano JB , Munoz L , Duran-Tauleria E , Sanchez G , et al\nSystemic inflammation in chronic obstructive pulmonary disease: a population-based study . Respir Res . 2010 ; 11 : 63 \ndoi: 10.1186/1465-9921-11-63 \n20500811 \n7 Dahl M , Vestbo J , Lange P , Bojesen SE , Tybjærg-Hansen A and Nordestgaard BG . C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease . Am J Respir Crit Care Med . 2007 ; 175 : 250 –255 . doi: 10.1164/rccm.200605-713OC \n17053205 \n8 Thomsen M , Dahl M , Lange P , Vestbo J and Nordestgaard BG . Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease . Am J Respir Crit Care Med . 2012 ; 186 : 982 –988 . doi: 10.1164/rccm.201206-1113OC \n22983959 \n9 Reid MB and Li Y-P . Tumor necrosis factor-α and muscle wasting: a cellular perspective . Resp Res . 2001 ; 2 : 269 .\n10 Liang B and Feng Y . The association of low bone mineral density with systemic inflammation in clinically stable COPD . Endocrine . 2012 ; 42 : 190 –195 . doi: 10.1007/s12020-011-9583-x \n22198912 \n11 Sin DD , Lacy P , York E and Man SP . Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease . Am J Respir Crit Care Med . 2004 ; 170 : 760 –765 . doi: 10.1164/rccm.200404-543OC \n15229100 \n12 Pinto-Plata VM , Mullerova H , Toso JF , Feudjo-Tepie M , Soriano JB , Vessey RS , et al\nC-reactive protein in patients with COPD, control smokers and non-smokers . Thorax . 2006 ; 61 : 23 –28 . doi: 10.1136/thx.2005.042200 \n16143583 \n13 Sin DD , Man SF , Marciniuk DD , Ford G , FitzGerald M , Wong E , et al\nThe effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease . Am J Respir Crit Care Med . 2008 ; 177 : 1207 –1214 . doi: 10.1164/rccm.200709-1356OC \n18310480 \n14 Tang YJ , Wang K , Yuan T , Qiu T , Xiao J , Yi Q , et al\nSalmeterol/fluticasone treatment reduces circulating C-reactive protein level in patients with stable chronic obstructive pulmonary disease . Chinese Med J (English Edition) . 2010 ; 123 : 1652 –1657 .\n15 GOLD Executive Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (Revised 2011). 2012. http://www.goldcopd.com.\n16 Lin YH , Wang WY , Hu SX and Shi YH . Serum C-reactive protein level in COPD patients stratified according to GOLD 2011 grading classification . Pak J Med Sci . 2016 ; 32 (6 ). https://doi.org/10.12669/pjms.326.10905\n17 Bestall JC , Paul EA , Garrod R , Garnham R , Jones PW and Wedzicha JA . Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease . Thorax . 1999 ; 54 : 581 –586 . 10377201 \n18 Jones PW , Harding G , Berry P , Wiklund I , Chen WH and Kline Leidy N . Development and first validation of the COPD Assessment Test . Eur Respir J . 2009 ; 34 : 648 –654 . doi: 10.1183/09031936.00102509 \n19720809 \n19 Quanjer PH , Tammeling GJ , Cotes JE , Pedersen OF , Peslin R and Yernault JC . Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society . Eur Respir J Suppl . 1993 ; 16 : 5 –40 . 8499054 \n20 Anderson R , Theron AJ , Steel HC , Durandt C , Tintinger GR and Feldman C . The beta-2-adrenoreceptor agonists, formoterol and indacaterol, but not salbutamol, effectively suppress the reactivity of human neutrophils in vitro . Mediators Inflamm . 2014 ; 2014 : 105420 \ndoi: 10.1155/2014/105420 \n24733958 \n21 Agusti AG , Noguera A , Sauleda J , Sala E , Pons J and Busquets X . Systemic effects of chronic obstructive pulmonary disease . Eur Respir J . 2003 ; 21 : 347 –360 . 12608452 \n22 von Scheele I , Larsson K and Palmberg L . Budesonide enhances Toll-like receptor 2 expression in activated bronchial epithelial cells . Inhal Toxicol . 2010 ; 22 : 493 –499 . doi: 10.3109/08958370903521216 \n20388003 \n23 Wang X , Nelson A , Weiler ZM , Patil A , Sato T , Kanaji N , et al\nAnti-inflammatory effects of budesonide in human lung fibroblast are independent of histone deacetylase 2 . J Inflamm Res . 2013 ; 6 : 109 –119 . doi: 10.2147/JIR.S43736 \n24062615 \n24 Heinrich PC , Castell JV and Andus T . Interleukin-6 and the acute phase response . Biochem J . 1990 ; 265 : 621 \n1689567 \n25 Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (Updated 2013). 2013. http://www.goldcopd.com.\n26 Vestbo J , Agusti A , Wouters EF , Bakke P , Calverley PM , Celli B , et al\nShould we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team . Am J Respir Crit Care Med . 2014 ; 189 : 1022 –1030 . doi: 10.1164/rccm.201311-2006PP \n24552242 \n27 Cazzola M , Ando F , Santus P , Ruggeri P , Di Marco F , Sanduzzi A , et al\nA pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD . Pulm Pharmacol Ther . 2007 ; 20 : 556 –561 . doi: 10.1016/j.pupt.2006.06.001 \n16914336 \n28 Decramer M and Janssens W . Chronic obstructive pulmonary disease and comorbidities . Lancet Respir Med . 2013 ; 1 : 73 –83 . doi: 10.1016/S2213-2600(12)70060-7 \n24321806 \n29 Cavailles A , Brinchault-Rabin G , Dixmier A , Goupil F , Gut-Gobert C , Marchand-Adam S , et al\nComorbidities of COPD . Eur Respir Rev . 2013 ; 22 : 454 –475 . doi: 10.1183/09059180.00008612 \n24293462 \n30 Putcha N , Puhan MA , Hansel NN , Drummond MB and Boyd CM . Impact of co-morbidities on self-rated health in self-reported COPD: an analysis of NHANES 2001–2008 . COPD . 2013 ; 10 : 324 –332 . doi: 10.3109/15412555.2012.744963 \n23713595 \n31 Thomsen M , Ingebrigtsen TS , Marott JL , Dahl M , Lange P , Vestbo J , et al\nInflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease . JAMA . 2013 ; 309 : 2353 –2361 . doi: 10.1001/jama.2013.5732 \n23757083 \n32 McGarvey LP , John M , Anderson JA , Zvarich M and Wise RA . Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee . Thorax . 2007 ; 62 : 411 –415 . doi: 10.1136/thx.2006.072348 \n17311843 \n33 Pradhan AD , Manson JE , Rossouw JE , Siscovick DS , Mouton CP , Rifai N , et al\nInflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study . JAMA . 2002 ; 288 : 980 –987 . 12190368 \n34 Stork S , Feelders RA , van den Beld AW , Steyerberg EW , Savelkoul HF , Lamberts SW , et al\nPrediction of mortality risk in the elderly . Am J Med . 2006 ; 119 : 519 –525 . doi: 10.1016/j.amjmed.2005.10.062 \n16750966 \n35 Zhong N , Zheng J , Wen F , Yang L , Chen P , Xiu Q , et al\nEfficacy and safety of budesonide/formoterol via a dry powder inhaler in Chinese patients with chronic obstructive pulmonary disease . Curr Med Res Opin . 2012 ; 28 : 257 –265 . doi: 10.1185/03007995.2011.636420 \n22046961 \n36 Tashkin DP , Rennard SI , Martin P , Ramachandran S , Martin UJ , Silkoff PE , et al\nEfficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease . Drugs . 2008 ; 68 : 1975 –2000 . 18778120 \n37 Rennard SI , Tashkin DP , McElhattan J , Goldman M , Ramachandran S , Martin UJ , et al\nEfficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease . Drugs . 2009 ; 69 : 549 –565 . doi: 10.2165/00003495-200969050-00004 \n19368417\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "12(8)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001993:Bronchodilator Agents; D019819:Budesonide; D002097:C-Reactive Protein; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0183300",
"pmc": null,
"pmid": "28832630",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "19368417;24062615;23757083;12608452;17311843;9167458;22198912;24293462;19720809;22983959;16914336;12190368;28083044;16455829;18778120;16750966;10377201;15229100;18310480;11686894;24552242;23713595;17053205;15223864;22878278;8499054;20819623;24321806;15215480;20388003;25073815;1689567;20500811;16143583;22046961;24733958",
"title": "Long-term treatment with budesonide/formoterol attenuates circulating CRP levels in chronic obstructive pulmonary disease patients of group D.",
"title_normalized": "long term treatment with budesonide formoterol attenuates circulating crp levels in chronic obstructive pulmonary disease patients of group d"
} | [
{
"companynumb": "CN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-050084",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TIOTROPIUM BROMIDE MONOHYDRATE"
... |
{
"abstract": "OBJECTIVE\nChronic myeloid leukemia (CML) is a rare malignancy in kidney transplant (KT) recipients. Although dasatinib is the first-line treatment for CML, it has inhibitory activity against CYP3A4; this might increase the blood concentration of tacrolimus (administered to KT patients for immune suppression). Furthermore, tacrolimus can also increase blood concentrations of dasatinib through P-glycoprotein inhibition.\n\n\nMETHODS\nHere, we report a case of sustained molecular remission of CML with prolonged first-line dasatinib therapy in a KT recipient being treated with tacrolimus. A 61-year-old woman developed CML-chronic phase (CML-CP) 38 months post KT. Her maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Considering the potential drug interaction with tacrolimus, dasatinib was administered at a low dose of 50 mg/day. Her immune status was evaluated regularly by assessing the mixed lymphocyte reaction (MLR) using an intracellular carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling technique; immunosuppressive therapy was adjusted accordingly.\n\n\nRESULTS\nThe patient achieved complete hematologic remission (CHR) after 1 month of dasatinib treatment. Six months after dasatinib treatment, she achieved a major molecular response. During the observation period, neither antibody-mediated nor acute cellular rejection were encountered in the patient. She remained in CHR with a major molecular response 12 months after the diagnosis of CML-CP.\n\n\nCONCLUSIONS\nData obtained from immune monitoring assays using CFSE-MLR helped us to successfully manage a KT recipient with CML-CP being treated with dasatinib. Drug-drug interactions are a key consideration while designing treatment regimens; such strategies would ensure that drug-drug interactions do not negatively affect the treatment outcomes.",
"affiliations": "Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: ideken@hiroshima-u.ac.jp.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.",
"authors": "Yamane|Hiroaki|H|;Ide|Kentaro|K|;Tanaka|Asuka|A|;Hashimoto|Shinji|S|;Nagoshi|Hisao|H|;Tahara|Hiroyuki|H|;Ohira|Masahiro|M|;Seidakhmetov|Akhmet|A|;Marlen|Doskali|D|;Tanaka|Yuka|Y|;Ohdan|Hideki|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D000069439:Dasatinib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.06.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(2)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000069439:Dasatinib; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D012074:Remission Induction; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "600-603",
"pmc": null,
"pmid": "31733802",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Chronic Myeloid Leukemia With Dasatinib After Kidney Transplantation: A Case Report.",
"title_normalized": "successful treatment of chronic myeloid leukemia with dasatinib after kidney transplantation a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2019528738",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect.",
"affiliations": "Division of Metabolic Disorders, CHOC Children's Hospital, Orange, CA 92868, USA; Department of Human Genetics, University of California Los Angeles, CA 90095, USA.;Division of Metabolic Disorders, CHOC Children's Hospital, Orange, CA 92868, USA.;Division of Metabolic Disorders, CHOC Children's Hospital, Orange, CA 92868, USA.;Charles E. Schmidt College of Medicine, Boca Raton, FL 33431, USA.;Department of Radiology, Memorial Healthcare System, Hollywood, FL 33021, USA.;Division of Metabolic Disorders, CHOC Children's Hospital, Orange, CA 92868, USA; Department of Pediatrics, University of California Irvine, Orange, CA 92868, USA.;Division of Metabolic Disorders, CHOC Children's Hospital, Orange, CA 92868, USA; Department of Pediatrics, University of California Irvine, Orange, CA 92868, USA.;Division of Neurology, CHOC Children's Hospital, Orange, CA, 92868, USA; Department of Pediatrics, University of California Irvine, Orange, CA 92868, USA.;Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.;Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.;Illumina Inc., San Diego, CA 92122, USA.;Charles E. Schmidt College of Medicine, Boca Raton, FL 33431, USA; Division of Genetics, Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA.;Division of Metabolic Disorders, CHOC Children's Hospital, Orange, CA 92868, USA; Department of Pediatrics, University of California Irvine, Orange, CA 92868, USA. Electronic address: jabdenur@choc.org.",
"authors": "Simon|Mariella T|MT|;Eftekharian|Shaya S|SS|;Stover|Alexander E|AE|;Osborne|Aaron F|AF|;Braffman|Bruce H|BH|;Chang|Richard C|RC|;Wang|Raymond Y|RY|;Steenari|Maija R|MR|;Tang|Sha|S|;Hwu|Paul Wuh-Liang|PW|;Taft|Ryan J|RJ|;Benke|Paul J|PJ|;Abdenur|Jose E|JE|",
"chemical_list": "D024101:Mitochondrial Proteins; D008780:Methyltransferases; C532992:NDUFAF5 protein, human; D042967:Electron Transport Complex I",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ymgme.2018.11.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1096-7192",
"issue": "126(1)",
"journal": "Molecular genetics and metabolism",
"keywords": "Complex I; Hyponatremia; Leigh syndrome; Mitochondrial disease; NDUFAF5; Splicing",
"medline_ta": "Mol Genet Metab",
"mesh_terms": "D000293:Adolescent; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D042967:Electron Transport Complex I; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease; D008297:Male; D008780:Methyltransferases; D028361:Mitochondrial Diseases; D024101:Mitochondrial Proteins; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012867:Skin; D000073359:Whole Exome Sequencing; D000073336:Whole Genome Sequencing; D055815:Young Adult",
"nlm_unique_id": "9805456",
"other_id": null,
"pages": "53-63",
"pmc": null,
"pmid": "30473481",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21734595;24089531;27535533;27626371;20571988;21607760;29429571;27499296;29581464;28771251;22019594;28797839;18805359;27226634;8602753;27696015;17985265;20858599;29654708;9810562;10066162;28853723;18940309;19542079;18501715;27986404;23313708;19339519;15794176;22972949;27720676",
"title": "Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes.",
"title_normalized": "novel mutations in the mitochondrial complex i assembly gene ndufaf5 reveal heterogeneous phenotypes"
} | [
{
"companynumb": "US-LUNDBECK-DKLU2057929",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VIGABATRIN"
},
"drugadditional": null,
... |
{
"abstract": "Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) is used for selected gastrointestinal carcinomas. We report a case of ventricular tachycardia during HIPEC with cisplatin that persisted as long as the chemotherapy solution remained in the intra-abdominal cavity. We hypothesise that high plasma levels of cisplatin with concomitant low magnesium levels caused the arrhythmia.",
"affiliations": "Department of Anaesthesiology and Critical Care Medicine, Tuebingen University Hospital, Tuebingen, Germany.",
"authors": "Thix|C A|CA|;Königsrainer|I|I|;Kind|R|R|;Wied|P|P|;Schroeder|T H|TH|",
"chemical_list": "D000970:Antineoplastic Agents; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2044.2009.05993.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2409",
"issue": "64(10)",
"journal": "Anaesthesia",
"keywords": null,
"medline_ta": "Anaesthesia",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007263:Infusions, Parenteral; D010534:Peritoneal Neoplasms; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "0370524",
"other_id": null,
"pages": "1134-6",
"pmc": null,
"pmid": "19735407",
"pubdate": "2009-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ventricular tachycardia during hyperthermic intraperitoneal chemotherapy.",
"title_normalized": "ventricular tachycardia during hyperthermic intraperitoneal chemotherapy"
} | [
{
"companynumb": "DE-WEST-WARD PHARMACEUTICALS CORP.-DE-HIK-2009-00063",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"dru... |
{
"abstract": "Antimuscarinics are first-line medication for management of overactive bladder with solifenacin being commonly prescribed. Angioedema is the swelling of mucosa and submucosal tissue. There are no published case reports of drug-induced angioedema involving solifenacin. We report a case of a 41-year-old man with spinal cord injury who presented with oedema of face, lips, tongue and associated pruritic urticaria after taking 5 mg of solifenacin. All other possible causes including food allergy, insect bite, hereditary angioedema, use of NSAIDs, ACE inhibitors and antibiotics were ruled out. The temporal association between solifenacin and angioedema and complete resolution of symptoms after discontinuing the drug suggest that solifenacin was the most probable cause of angioedema in our patient.",
"affiliations": "Physical Medicine & Rehabilitation, Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, Pakistan umeryounassp@gmail.com.;Physical Medicine & Rehabilitation, Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, Pakistan.;Physical Medicine & Rehabilitation, Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, Pakistan.;Physical Medicine & Rehabilitation, Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, Pakistan.",
"authors": "Younas|Umer|U|http://orcid.org/0000-0001-5402-2983;Shafiq|Omar|O|;Mansoor|Sahibzada Nasir|SN|;Khalil|Muhammad Tawab|MT|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/postgradmedj-2020-138375",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-5473",
"issue": null,
"journal": "Postgraduate medical journal",
"keywords": "adverse events; rehabilitation medicine",
"medline_ta": "Postgrad Med J",
"mesh_terms": null,
"nlm_unique_id": "0234135",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33452148",
"pubdate": "2021-01-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Solifenacin-induced acute urticaria and angioedema: a rare adverse effect.",
"title_normalized": "solifenacin induced acute urticaria and angioedema a rare adverse effect"
} | [
{
"companynumb": "PK-Graviti Pharmaceuticals Private Limited-2130017",
"fulfillexpeditecriteria": "2",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SOLIFENACIN SUCCINATE"
},
... |
{
"abstract": "Chemotherapy-induced diarrhoea (CID) is a risk of antineoplastic regimens, often associated with 5-fluorouracil (5-FU), irinotecan and capecitabine. Current treatment guidelines for CID include the use of loperamide and octreotide but do not account for other therapies, including budesonide. Small case reports have shown benefit with budesonide in CID secondary to 5-FU and irinotecan, but there is no literature base addressing budesonide use in CID secondary to capecitabine. We describe a case of a patient with severe capecitabine-induced diarrhoea that was refractory to guideline based therapy but resolved with the use of budesonide.",
"affiliations": "Internal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA John.n.shumar.mil@mail.mil.;Gastroenterology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.;Pathology and Laboratory Services, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.;Gastroenterology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.",
"authors": "Shumar|John|J|http://orcid.org/0000-0001-8913-6139;Junga|Zachary|Z|;Johnson|Jeptha T|JT|;Goldkind|Lawrence|L|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D005938:Glucocorticoids; D019819:Budesonide; D000069287:Capecitabine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231544",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(11)",
"journal": "BMJ case reports",
"keywords": "colon cancer; drugs: gastrointestinal system; gastroenterology; gastrointestinal system; pathology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D019819:Budesonide; D000069287:Capecitabine; D003967:Diarrhea; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D012004:Rectal Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31791985",
"pubdate": "2019-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16020959;15254061;21789126;24947412;18351341;22412841;20844880;24744571;10586346;27157244;8899106;23107827;11350878;9849491",
"title": "Treatment-resistant severe capecitabine-induced diarrhoea resolved with oral budesonide.",
"title_normalized": "treatment resistant severe capecitabine induced diarrhoea resolved with oral budesonide"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-06339",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"... |
{
"abstract": "We report a case of transient sixth nerve palsy after systemic administration of bevacizumab. Two days after systemic administration of bevacizumab in conjunction with gemcitabine and carboplatin in a 67-year-old woman with recurrent primary ovarian cancer, the patient developed sixth nerve palsy. After bevacizumab was stopped, the complete left sixth nerve palsy resolved spontaneously over the course of 3 months. This is the first reported case of bevacizumab-induced cranial sixth nerve palsy in the treatment of gynecologic malignancy.",
"affiliations": "Gynecology Oncology Division, Mount Sinai School of Medicine, New York, USA.;Gynecology Oncology Division, Mount Sinai School of Medicine, New York, USA.;Gynecology Oncology Division, Mount Sinai School of Medicine, New York, USA.",
"authors": "Momeni|Mazdak|M|;Veras|Laura|L|;Zakashansky|Konstantin|K|",
"chemical_list": "D003841:Deoxycytidine; D000068258:Bevacizumab; C056507:gemcitabine; D016190:Carboplatin",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.12129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-7555",
"issue": "12(1)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": null,
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D020434:Abducens Nerve Diseases; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D016190:Carboplatin; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "e196-8",
"pmc": null,
"pmid": "24188139",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bevacizumab-induced transient sixth nerve palsy in ovarian cancer: A case report.",
"title_normalized": "bevacizumab induced transient sixth nerve palsy in ovarian cancer a case report"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US02411",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Melioidosis is a tropical infection that is increasingly being reported from South India. It is frequently observed in patients with diabetes mellitus, chronic ethanol consumption and chronic kidney disease (CKD). It presents commonly with pneumonia, deep seated abscesses or osteoarticular infections. Cardiac complications are very rare with endocarditis being reported in very few patients. We report the first case of endocarditis in melioidosis in India. Although infections are common in patients with CKD, melioidosis at the time of diagnosis of CKD has never been reported in the past. Our patient had multiple liver abscesses and endocarditis, and responded well to a 6 week course of ceftazidime and doxycycline, with the latter being continued for 20 weeks.",
"affiliations": "Department of Internal Medicine, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India.;Department of Nephrology, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India.;Department of Cardiology, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India.;Department of Microbiology, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India.;Department of Infectious Diseases, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India.",
"authors": "Krishnamoorthy|Adhiti|A|;Fernando|Edwin|E|;Dorairaj|Prabhakar|P|;Thimmaiah|Akshith|A|;Kumar|D Suresh|DS|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_185_19",
"fulltext": "\n==== Front\nIndian J Nephrol\nIndian J Nephrol\nIJN\nIndian Journal of Nephrology\n0971-4065\n1998-3662\nWolters Kluwer - Medknow India\n\nIJN-30-416\n10.4103/ijn.IJN_185_19\nCase Report\nChallenges in Management of Disseminated Melioidosis with Endocarditis in a Patient with Chronic Kidney Disease\nKrishnamoorthy Adhiti\nFernando Edwin 1\nDorairaj Prabhakar 2\nThimmaiah Akshith 3\nKumar D. Suresh 4\nDepartment of Internal Medicine, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India\n1 Department of Nephrology, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India\n2 Department of Cardiology, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India\n3 Department of Microbiology, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India\n4 Department of Infectious Diseases, Mehta Multispecialty Hospital Pvt. Ltd., Chennai, Tamil Nadu, India\nAddress for correspondence: Dr. Edwin Fernando, Plot No. 1623, 9th Main Road, Ramnagar South, Madipakkam, Chennai - 600 091, Tamil Nadu, India. E-mail: nephroeddy@gmail.com\nNov-Dec 2020\n09 10 2020\n30 6 416419\n28 5 2019\n30 6 2019\nCopyright: © 2020 Indian Journal of Nephrology\n2020\nThis is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nMelioidosis is a tropical infection that is increasingly being reported from South India. It is frequently observed in patients with diabetes mellitus, chronic ethanol consumption and chronic kidney disease (CKD). It presents commonly with pneumonia, deep seated abscesses or osteoarticular infections. Cardiac complications are very rare with endocarditis being reported in very few patients. We report the first case of endocarditis in melioidosis in India. Although infections are common in patients with CKD, melioidosis at the time of diagnosis of CKD has never been reported in the past. Our patient had multiple liver abscesses and endocarditis, and responded well to a 6 week course of ceftazidime and doxycycline, with the latter being continued for 20 weeks.\n\nMelioidosis\nchronic kidney disease\nliver abscess\nendocarditis\n==== Body\nIntroduction\n\nMelioidosis is an emerging infectious disease of major public health importance, which has been increasingly reported from South India over the last decade. It has been frequently observed in patients with diabetes, alcoholism and renal failure. Its presentation varies from an acute fulminant septicemia to a chronic granuomatous disease.[1] We describe a case of disseminated melioidosis in a young girl, who presented with multiple liver abscesses at the time of diagnosis of Chronic Kidney Disease (CKD) stage 5. The infection was complicated by endocarditis that further protracted the course of the patient.\n\nCase Description\n\nA 16 year old girl, who was premorbidly asymptomatic, presented to our emergency department with high-grade intermittent fever, loose stools and abdominal pain for 4 weeks duration. Examination was significant for pallor, pedal edema and right hypochondrial tenderness. Initial investigations were significant for severe renal failure [creatinine = 13.3 mg/dL, urea = 178 mg/dL], severe anemia [hemoglobin = 6.3 g/dL] and neutrophilic leucocytosis [total counts = 13,600 with 80% polymorphs] [Table 1]. Imaging (with computed tomography (CT) and ultrasound) revealed bilateral contracted kidneys (7.5 and 6 cm – right and left respectively) and urinalysis was normal. She was thus diagnosed with CKD-stage 5, probably due to chronic interstitial nephritis and was initiated on hemodialysis for the same.\n\nTable 1 Investigations at the time of admission\n\nInvestigation\tResult\t\nHemoglobin\t6.3g%\t\nPacked cell volume\t19.8%\t\nRBC count\t2.22 million/mm3\t\nTotal leucocyte count\t13600 cells/mm3\t\nDifferential count\t80% polymorphs, 18% lymphocytes, 2% eosinophils\t\nPlatelet count\t1.92 lakhs/mm3\t\nESR (60 min)\t95 mm\t\nCreatinine\t13.3 mg/dL\t\nUrea\t178mg/dL\t\nSodium\t132 meq/L\t\nPotassium\t4.6 meq/L\t\nChloride\t101 meq/L\t\nBicarbonate\t14 meq/L\t\nRandom blood glucose\t84mg/dL\t\nTotal bilirubin\t0.2mg/dL\t\nTotal protein\t5.8g/dL\t\nAlbumin\t3.2g/dL\t\nGlobulin\t2.6g/dL\t\nSGOT (ALT)\t82 U/L\t\nSGPT (AST)\t16 U/L\t\nAlkaline phosphatase\t116 U/L\t\nBlood-borne viral screen (HIV, HbsAg, HCV)\tNegative\t\nRBC: Red blood cell; ESR: Erythrocyte sedimentation rate; SGOT: Serum glutamic-oxaloacetic transaminase; ALT: Alanine aminotransferase; AST: Aspartate transaminase; HCV: Hepatitis C virus\n\nImaging also detected the presence of multiple liver abscesses (measuring 63 × 35 mm in the superior aspect of the right lobe, 43 × 40 mm in the inferior aspect of the right lobe, and 80 × 55 mm in the left lobe) [Figure 1]. Given the history of loose stools and the background of recently diagnosed CKD (which made her an immunocompromised host), the possibility of pyogenic liver abscess was considered, with the gram-negative enteric organisms being implicated. She was hence initiated on parenteral broad-spectrum antibiotics (piperacillin + tazobactam and metronidazole) after blood cultures. Possible sources of portal pyemia were looked for with the help of colonoscopy and contrast CT imaging. Source control in the form of drainage of liver abscesses was also done, but the fever persisted. Although the blood cultures were negative, pus aspirated from the liver abscess grew Burkholderia pseudomallei. They were identified by the presence of wrinkled medium-sized colonies with metallic sheen on Mac Conkey agar [Figure 2]. She was diagnosed with melioidosis and switched over to ceftazidime (1g IV 8th hourly) and oral cotrimoxazole (double strength, twice a day).\n\nFigure 1 Plain CT imaging of the abdomen showing centrally hypoattenuating lesion in the right lobe measuring 63 × 35 mm\n\nFigure 2 Pus aspirated from the liver abscess cultured on Mac Conkey agar. Growth of Burkholderia pseudomalleii evident by the colonies with “metallic sheen”\n\nHowever, fever persisted and multiple blood cultures done subsequently were also found to be sterile. Repeat imaging of the chest and abdomen did not reveal any new focus of infection. However, echocardiogram detected the presence of vegetations on the mitral valve [Figure 3] and the diagnosis was revised into disseminated melioidosis with endocarditis. Therefore, it was decided to increase the dose of ceftazidime (to 2g IV 8th hourly) and extend the intensive phase of treatment to 6 weeks. Her fever settled over the subsequent 4 days and she continued to remain afebrile throughout the course of hospitalization.\n\nFigure 3 Transthoracic echocardiogram showing two vegetations attached to the atrial aspect of the posterior mitral leaflet measuring 4 × 1 mm and 6 × 2 mm\n\nOne week after initiation of treatment, her potassium levels started rising despite alternate day hemodialysis and a potassium-free diet. Cotrimoxazole was thought to be the culprit drug and it was switched to oral doxycycline (100mg twice daily). Subsequently, her potassium levels stabilized and eradication phase with doxycycline was planned for a total of 20 weeks.\n\nThe patient was followed up subsequently after 3 months and was found to have significant clinical improvement with near-total resolution of systemic symptoms. Repeat imaging revealed clearance of the vegetation and significant decrease in size of the liver abscesses. She has been advised to continue eradication therapy with doxycycline. She continues to be on thrice weekly schedule of hemodialysis.\n\nDiscussion\n\nMelioidosis is an infection that is endemic to South East Asia and Northern Australia.[2] There has been an increase in reports of Meloidosis from South India in the past decade, probably owing to increase in awareness that translates into higher index of clinical suspicion and improved diagnostic methods.[13]\n\nMelioidosis is caused by the Gram-negative bacterium, Burkholderia pseudomalleii. It is a saprophytic organism that favours moist clay soils. Inhalation (rather than inoculation or ingestion) of aerosolized dust has been implicated in acquisition of infection in most cases. Our patient belonged to an agricultural family from rural south India (Karaikudi). Most cases reported had an occupational history of exposure to soil.[2]\n\nAlthough melioidosis is more common among males, there has been a study that noted female preponderance among the patients with end stage renal disease.[4] Poorly controlled diabetes mellitus, chronic ethanol consumption and CKD have been frequently reported as risk factors. Other comorbidities reported include thalassemia, sickle cell anemia, liver disease, steroid use, chronic obstructive pulmonary disease and tuberculosis. The effect of these risk factors on neutrophil function has been implicated in the pathogenesis of melioidosis.[5]\n\nThe manifestations of the disease are protean. The disease has been usually observed in two forms: localized melioidosis (where the involvement is confined to a single organ like septic arthritis or deep-seated visceral abscess) and disseminated melioidosis (with multi-system involvement).[5] Pulmonary involvement is common in the acute presentation and often the patients tend to present with septicemia, whereas the chronic forms may be either localized in the form of visceral abscesses (splenic, hepatic, prostatic) or osteoarticular infections (septic arthritis or osteomyelitis), or may be disseminated with multifocal involvement.[1] In patients with CKD 5 requiring dialysis, the presentation was frequently acute and the presence of bacteremia was more common.[4]\n\nIsolation of the bacterium from pus, body fluids or blood is the gold standard in diagnosis of melioidosis.[6] The organism shows bipolar staining on Gram stain and has a typical “safety pin” appearance. Growth on blood agar and Mac Conkey agar reveal smooth wrinkled colonies with a metallic sheen. Selective media like Ashdown agar medium have a better yeild.[7]\n\nThe management of melioidosis is divided into 2 phases: the initial shorter intensive phase (which lasts for 2 weeks) and the subsequent longer eradication phase (which lasts for 20 weeks). Ceftazidime, carbapenems (imipenem and meropenem) and to a lesser extent amoxicillin clavulanate are the preferred options for the initial phase of treatment.[2] Ceftazidime is the only drug with mortality benefit in melioidosis and doses upto 2g 6th hourly can be given.[8] Cotrimoxazole and Doxycycline (either or both) constitute the eradication therapy for most patients, although the former seems to have a higher efficacy with lower relapse rates.[9] As the organism is intrinsically resistant to a wide range of antibiotics (third-generation cephalosporins, penicillins, rifamycins, aminoglycosides, and to a lesser extent quinolones and macrolides), choice of initial antibiotic is vital in patients with suspected melioidosis.\n\nRelapse has been reported in 13%-23% of patients, 6-8 months after successful treatment completion.[2] Risk factors for relapse appear to be poor compliance, multifocal involvement, initial presentation with a severe disease and shorter eradication period.[9]\n\nCardiac involvement is uncommon in melioidosis with pericardial effusion being more frequently encountered. There are very few case reports on endocarditis in melioidosis across the globe.[101112] Almost all the patients reported are males and had risk factors in the form of chronic ethanol consumption or chronic obstructive pulmonary disease. Two such patients had further complications in the form of cerebral infarcts.[1012] This is the first case report of endocarditis in melioidosis in India, to the best of our knowledge.\n\nThere are no existing guidelines on the treatment of melioid endocarditis, with most of the knowledge regarding the same, originating from case reports and case series. As our organism was resistant to aminoglycoside, we did not consider adding it to the existing regime, which had been earlier attempted with aminoglycoside susceptible strains.[11] A 6 week course of high-dose ceftazidime or carbapenem along with cotrimoxazole or doxycycline seem to constitute the intensive phase of treatment in these patients.\n\nConclusion\n\nMelioidosis as the first presentation of CKD has not been reported in the past and our case is unique in this aspect. It is a disease with high case fatality rate and hence a high degree of clinical suspicion is required for early diagnosis. Ceftazidime or carbapenem may be a good choice for initial antibiotic in patients suspected with melioidosis. Endocarditis requires prolongation of the intensive phase of treatment to 6 weeks. Good compliance and completion of the eradication phase needs to be ensured to prevent relapse.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\nAcknowledgement\n\nThe authors would like to acknowledge their radiologist, Dr. Anand for his significant contribution towards the patient.\n==== Refs\n1 Koshy M Jagannati M Ralph R Victor P David T Sathyendra S Clinical manifestations, antimicrobial drug susceptibility patterns, and outcomes in melioidosis cases, India Emerg Infect Dis 2019 25 316 20 30666953\n2 Cheng AC Currie BJ Melioidosis: Epidemiology, pathophysiology, and management Clin Microbiol Rev 2005 18 383 416 15831829\n3 Saravu K Mukhopadhyay C Vishwanath S Valsalan R Docherla M Vandana KE ' Melioidosis in southern India: Epidemiological and clinical profile Southeast Asian J Trop Med Public Health 2010 41 401 9 20578524\n4 Chalmers RMS Majoni SW Ward L Perry GJ Jabbar Z Currie BJ Melioidosis and end-stage renal disease in tropical northern Australia Kidney Int 2014 86 867 70 25360487\n5 Gopalakrishnan R SureshKumar D Thirnunarayanan MA Ramasubramanian V Melioidosis: An emerging Infection in India J Assoc Physicians India 2013 61 612 4 24772696\n6 Mukhopadhyay C Shaw T Varghese GM Dance DA Melioidosis in South Asia (India, Nepal, Pakistan, Bhutan and Afghanistan) Trop Med Infect Dis 2018 3 pii: E51\n7 Gilad J Schwartz D Amsalem Y Clinical features and laboratory diagnosis of infection with the potential bioterrorism agents burkholderia mallei and burkholderia pseudomallei Int J Biomed Sci 2007 3 144 52 23675037\n8 White NJ Dance DA Chaowagul W Wattanagoon Y Wuthiekanun V Pitakwatchara N Halving of mortality of severe melioidosis by ceftazidime Lancet Lond Engl 1989 2 697 701\n9 Limmathurotsakul D Chaowagul W Chierakul W Stepniewska K Maharjan B Wuthiekanun V Risk factors for recurrent melioidosis in northeast Thailand Clin Infect Dis Off Publ Infect Dis Soc Am 2006 43 979 86\n10 Piyasiri LB Wickramasinghe SA Lekamvasam VC Corea EM Gunarathne R Priyadarshana U Endocarditis in melioidosis Ceylon Med J 2016 61 192 3 28078837\n11 Sia T Podin Y Chuah TB Wong JS Melioidosis: An unusual cause of infective endocarditis: A case report Eur Heart J-Case Rep 2018 2 yty055 31020134\n12 Abdulla MC Alungal J Melioidosis with endocarditis and massive cerebral infarct Ital J Med 2015 10 55\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "30(6)",
"journal": "Indian journal of nephrology",
"keywords": "Melioidosis; chronic kidney disease; endocarditis; liver abscess",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "416-419",
"pmc": null,
"pmid": "33840962",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "20578524;16983608;25360487;23675037;31020134;30274447;2570956;15831829;24772696;30666953;28078837",
"title": "Challenges in Management of Disseminated Melioidosis with Endocarditis in a Patient with Chronic Kidney Disease.",
"title_normalized": "challenges in management of disseminated melioidosis with endocarditis in a patient with chronic kidney disease"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-278657",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
... |
{
"abstract": "Modafinil is a non-amphetamine stimulant that is prescribed for narcolepsy-associated sleepiness as well as reported off-licence uses among university students looking to improve wakefulness and focus. There is limited information in the medical literature about supratherapeutic modafinil dosage, symptomatology and management of overdose. We report a case of a healthy 32-year-old man who was found unconscious, having vomited, with an empty modafinil blister strip. At the emergency department, he presented with reduced Glasgow Coma Scale and prolonged episodes of vomiting. This acute presentation was conservatively managed in the intensive care unit. Antibiotics were also given for a suspected aspiration pneumonia. CT of the head showed cerebral oedema and biochemistry investigations revealed hyponatraemia. Result aetiology was unclear, however, it has been theorised to be secondary to a sizeable modafinil overdose.",
"affiliations": "Brain Injury Rehabilitation Unit, North Bristol NHS Trust, Bristol, Avon, UK rohan.kandasamy@gmail.com.;Medical Student, University of Exeter Medical School, Exeter, Devon, UK.;Brain Injury Rehabilitation Unit, North Bristol NHS Trust, Bristol, Avon, UK.",
"authors": "Kandasamy|Rohan Oliver|RO|;Kaminskaite|Viktorija|V|;May|Felix|F|http://orcid.org/0000-0003-4773-790X",
"chemical_list": "D000697:Central Nervous System Stimulants; D000077408:Modafinil",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-234530",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(7)",
"journal": "BMJ case reports",
"keywords": "coma and raised intracranial pressure; drug misuse (including addiction); drugs: CNS (not psychiatric); poisoning; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001929:Brain Edema; D000697:Central Nervous System Stimulants; D062787:Drug Overdose; D006801:Humans; D007010:Hyponatremia; D008297:Male; D000077408:Modafinil",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32624486",
"pubdate": "2020-07-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hyponatraemia and cerebral oedema due to a modafinil overdose.",
"title_normalized": "hyponatraemia and cerebral oedema due to a modafinil overdose"
} | [
{
"companynumb": "GB-TEVA-2020-GB-1815024",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MODAFINIL"
},
"drugadditional": "3",
... |
{
"abstract": "Venous thromboembolism is one of the complications in patients prescribed antipsychotic medications. Neuroleptic malignant syndrome (NMS) is a rare side effect of antipsychotic medications in this population. In this case, a young patient, who presented with NMS after a recent start of antipsychotic medications, had developed a pulmonary embolism despite standard of care measures of venous thromboprophylaxis and early mobilization. A low threshold of VTE suspicion and effective preventive measures are both required in order to avoid this preventable complication in this population.",
"affiliations": "Department of Medicine, Al Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia.",
"authors": "Almegren|Mosaad|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2018.7753",
"fulltext": "\n==== Front\nHematol RepHRHematology Reports2038-83222038-8330PAGEPress Publications, Pavia, Italy 10.4081/hr.2018.7753Case ReportPulmonary embolism in a patient with neuroleptic malignant syndrome Almegren Mosaad Department of Medicine, Al Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi ArabiaCollege of Medicine, Al Imam Mohammad Ibn Saud Islamic University, P.O. Box 7544, Othman Bin Affan road, Al Nada Riyadh, Kingdom of Saudi Arabia. +966112037100 - +966112037108. mosaad966@gmail.comConflict of interest: the author declares no potential conflict of interest.\n\n12 12 2018 06 11 2018 10 4 775321 5 2018 16 11 2018 ©Copyright M. Almegren , 20182018Licensee PAGEPress, ItalyThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.Venous thromboembolism is one of the complications in patients prescribed antipsychotic medications. Neuroleptic malignant syndrome (NMS) is a rare side effect of antipsychotic medications in this population. In this case, a young patient, who presented with NMS after a recent start of antipsychotic medications, had developed a pulmonary embolism despite standard of care measures of venous thromboprophylaxis and early mobilization. A low threshold of VTE suspicion and effective preventive measures are both required in order to avoid this preventable complication in this population.\n\nKey words\nPulmonary embolismneuroleptic malignant syndromeantipsychoticFunding: none.\n==== Body\nIntroduction\nNeuroleptic malignant syndrome (NMS) is a rare but serious psychiatric emergency condition classically found in patients who have started taking antipsychotic medications. It was first described in 1960.1 NMS has been recognized and described since that time especially with the increasing use of antipsychotic medications. Early recognition and diagnosis of NMS is critical for the management of this psychiatric emergency. Antipsychotic medications are a known risk for venous thromboembolism (VTE).2 In this paper, a case of pulmonary embolism in a patient diagnosed with NMS that was triggered by recently started atypical antipsychotic medications is described.\n\nCase Report\nA 29-year-old Caucasian male was admitted to the hospital for altered mental status in the form of abnormal behavior, mutism, and confusion, associated with diaphoresis, rigidity, and difficulty walking. He was started on quetiapine 100 mg daily and risperidone 2 mg daily for substance induced psychosis four days prior to this admission but no previous history of catatonia. On physical examination he had a temperature of 37.2 C (98.9 F), heart rate was 115 beats/minute, blood pressure was 133/79 mm/Hg, respiratory rate was 18/min, and oxygen saturation was 97% in room air. He was lying in the bed and was conscious but not oriented. He had more diffuse rigidity in the lower limbs, however reflexes were not elicitable due to diffuse rigidity. The rest of his systemic examination was normal. He had a hemoglobin of 158 g/L (135-175 g/L), white blood count 11.1×109/L (4-11×109/L), platelet 226×109/L (150-450 ×109/L), and creatinine kinase 3792 U/L (30-300 U/L). Serum electrolytes level, blood urea nitrogen, and creatinine were normal. The urine analysis and urine for the toxicology screen was negative. A computed tomography (CT) brain scan was normal.\n\nA diagnosis of NMS was made. Quetiapine and risperidone were discontinued immediately. He was started on diazepam 15 mg orally three times daily, bromocriptine 2.5 mg orally twice daily, intravenous fluid, and pharmacological thromboprophylaxis with enoxaparin 40 mg once daily. On day 1 of hospital admission, he had improved and was mobile with help of a physiotherapist. On day 3, he was oriented, communicating normally, and fully mobile with a gradual improvement in his creatinine kinase. However, he complained of one episode of a small amount of hemoptysis. D-dimer was requested due to suspicion of pulmonary embolism (PE); it was 3.96 ug/ml. A CT pulmonary angiography scan showed filling defects at the left main pulmonary artery, left lobar, segmental, and subsegmental branches (Figure 1). The patient was started on enoxaparin (1 mg/kg twice daily) and warfarin in order to achieve a therapeutic international normalized ratio. Doppler ultrasound of the lower limbs excluded deep vein thrombosis. He was treated with warfarin for three months for a provoked pulmonary embolism without complications.\n\nDiscussion\nNMS is a psychiatric emergency characterized by a change in mental status, fever, rigidity, and autonomic instability.3 The incidence rate is 0.01-3% of patients treated with antipsychotics and has a 5-10% mortality rate.4,5 The cause of NMS is unknown; dopamine receptor blockade, however, plays a central role in the pathogenesis that is responsible for the symptoms and signs of NMS. The onset usually develops within 24 h to 30 days after administration of antipsychotic medications.6\n\nVenous thromboembolism (VTE) is the third most common cause of vascular death following myocardial infarction and stroke.7 Thromboprophylaxis is highly recommended in patients at high risk for venous thrombosis. Immobilization, surgery, leg fractures, pregnancy, and cancer are all well known risk factors for VTE.7 Several observational studies and case reports have shown an association between antipsychotic medications and VTE.2 Immobilization and physical restraint were the most important provoking factors for the VTE in this population.2 In a case control study, antipsychotic medications increased the risk of VTE by 3.5-fold.8 In another case control study of 25,532 patients, those who had been prescribed antipsychotic medications in the last two years had a 32% higher risk of VTE compared to nonusers.9 The relationship between antipsychotic medications and VTE was also evaluated in a meta-analysis of seven case control studies that showed double the risk of VTE in antipsychotic users when compared with the controls.10 NMS might be an underestimated risk factor for VTE in psychiatric patients. In another case report, pharmacological prophylaxis did not prevent an extensive deep vein thrombosis from developing in a patient diagnosed with NMS.11 In a recent case report, Reilly et al. reported a case of PE in a 49-year-old male with NMS despite pharmacological thromboprophylaxis.12\n\nIn this case, the patient developed a significant pulmonary embolism despite the use of enoxaparin (40 mg) as thromboprophylactic agent during admission and early mobility with an assistant on the first day and complete and independent mobility on the third day of admission. Antipsychotic medications were less likely to have been the cause of PE in this case as the medications were only started four days prior to hospital admission. It appears that NMS was the major provoking factor for this patient’s VTE during his hospitalization.\n\nConclusions\nThe usual measures of VTE prevention (such as pharmacological prophylaxis and early mobilization) failed to protect against PE in this patient. Further measures should be considered in VTE prevention of patients with NMS, including higher doses or frequencies of pharmacological prophylaxis or a combination of mechanical and pharmacological measures.\n\nFigure 1. A CT pulmonary angiography scan showed filling defects at the left main pulmonary artery, left lobar, segmental, and subsegmental branches.\n==== Refs\nReferences\n1. Delay J Pichot P Lemperiere T \nA non-phenothiazine and non-reserpine major neuroleptic, haloperidol, in the treatment of psychoses . Ann Med Psychol (Paris) \n1960 ;118 :145 -52 .13815606 \n2. Nester EGV Verbrugger W Leyer M. \nDeep vein thrombosis and pulmonary emboli in psychiatric settings . European J Psy \n2009 ;23 :19 -30 .\n3. Caroff SN \nThe neuroleptic malignant syndrome . J Clin Psychiatry \n1980 ; 4179 -83 .\n4. Jeffrey R Strawn MD Paul E \nNeuroleptic malignant syndrome . Am J of Psy \n2007 ; 164 :6 , 870 -876 .\n5. Modi S Dharaiya D Schultz L. Varelas P \nNeuroleptic Malignant Syndrome: Complications, Outcomes, and Mortality . Neurocrit Care \n2016 ;24 :97 -103 .26223336 \n6. Caroff SN Mann SC \nNeuroleptic malignant syndrome . Psychopharmacol Bull \n1988 ;24 :25 -9 .3290944 \n7. Kearon C Kahn SR Agnelli G \nAntithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition) . Chest . 2008 ;133 :454S -5S .18574272 \n8. Lacut K Le Gal G Couturaud F \nAssociation between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case–control study . Fundam Clin Pharm \n2007 ;21643 -50 .\n9. Parker C Coupland C Hippisley-Cox J. \nAntipsychotic drugs and risk of venous thromboembolism: Nested case-control study . BMJ \n2010 ;341 :c4245 20858909 \n10. Zhang R Dong L Shao F \nAntipsychotics and venous thromboembolism risk: A meta-analysis . Pharmacopsych \n2011 ;44 :183 -8 .\n11. Mathew JC Pillai U Lacasse A. \nExtensive Deep Venous Thrombosis in a Patient with Neurolept Malignant Syndrome despite Being on Prophylaxis . Case Rep Psychiatry \n2011 :258172 .22937401 \n12. Reilly TJ Cross S Taylor DM \nNeuroleptic malignant syndrome following catatonia: Vigilance is the price of antipsychotic prescription . SAGE Open Med Case Rep \n2017 ;5 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2038-8322",
"issue": "10(4)",
"journal": "Hematology reports",
"keywords": "Pulmonary embolism; antipsychotic; neuroleptic malignant syndrome",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "7753",
"pmc": null,
"pmid": "30631408",
"pubdate": "2018-11-06",
"publication_types": "D016428:Journal Article",
"references": "13815606;17541044;18034665;18574272;20858909;21739416;22937401;26223336;28491312;3290944;6101595",
"title": "Pulmonary embolism in a patient with neuroleptic malignant syndrome.",
"title_normalized": "pulmonary embolism in a patient with neuroleptic malignant syndrome"
} | [
{
"companynumb": "SA-ACCORD-108590",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",
"drug... |
{
"abstract": "We report a case of hepatotoxicity following the introduction of two drugs to treat a 81 years old man. The presence of liver alterations following the introduction of a new drug must suggest an adverse drug reaction. Manifestations of adverse drug reactions are often non-specific. Thus, the most important problem in assessing adverse drug reactions is establishing whether there is a causal association between the suspected drug and the untoward clinical event. The use of the Naranjo score could help the clinician to assess the probability of a causal relationship between a drug and the suspected adverse drug reaction.",
"affiliations": "Service de Gériatrie, Hôpital de Nivelles.;Service de Gériatrie, CHU Saint-Pierre.;Service de Gériatrie, CHU Saint-Pierre.;Service d'Oncologie médicale, Institut Jules Bordet, ULB.",
"authors": "El Kahi|C|C|;Martinet|V|V|;Praet|J P|JP|;Pepersack|T|T|",
"chemical_list": "D000493:Allopurinol",
"country": "Belgium",
"delete": false,
"doi": "10.30637/2018.17-018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-3639",
"issue": "39(3)",
"journal": "Revue medicale de Bruxelles",
"keywords": "Adverse drug event; Allopurinol; Hepatotoxicity",
"medline_ta": "Rev Med Brux",
"mesh_terms": "D000369:Aged, 80 and over; D000493:Allopurinol; D056486:Chemical and Drug Induced Liver Injury; D064420:Drug-Related Side Effects and Adverse Reactions; D015577:Geriatric Assessment; D005853:Geriatrics; D006801:Humans; D008297:Male; D019338:Polypharmacy",
"nlm_unique_id": "8003474",
"other_id": null,
"pages": "164-165",
"pmc": null,
"pmid": "29964389",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare case of hepatotoxicity in geriatrics.",
"title_normalized": "a rare case of hepatotoxicity in geriatrics"
} | [
{
"companynumb": "BE-JNJFOC-20180910920",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nEndometrial cancer with hematogenous metastases can be treated with chemotherapy. We present a case of spontaneous pneumothorax that occurred when a solitary pulmonary endometrial metastatic lesion was treated with paclitaxel plus carboplatin.\n\n\nMETHODS\nA 38-year-old female had stage II endometrial endometrioid adenocarcinoma. Solitary bilateral pulmonary metastases developed after primary treatment. Complete remission accompanied by a right spontaneous pneumothorax occurred during chemotherapy with paclitaxel plus carboplatin.\n\n\nCONCLUSIONS\nRapid shrinkage of a pulmonary space-occupying tumor sometimes causes rare but life-threatening spontaneous pneumothoraces. We report the first case of a spontaneous pneumothorax after using paclitaxel plus carboplatin in the treatment of endometrial cancer.",
"affiliations": "Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medicine, Nursing and Management College, Taipei, Taiwan. Electronic address: cremaster4471@gmail.com.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan.",
"authors": "Chen|Jen-Ruei|JR|;Yang|Yuh-Cheng|YC|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-4559",
"issue": "53(2)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "carboplatin; endometrial cancer; paclitaxel; pulmonary metastases; spontaneous pneumothorax",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D018269:Carcinoma, Endometrioid; D016889:Endometrial Neoplasms; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D017239:Paclitaxel; D011030:Pneumothorax; D012074:Remission Induction",
"nlm_unique_id": "101213819",
"other_id": null,
"pages": "245-7",
"pmc": null,
"pmid": "25017278",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous pneumothorax after intensive chemotherapy in endometrial cancer: a rare complication.",
"title_normalized": "spontaneous pneumothorax after intensive chemotherapy in endometrial cancer a rare complication"
} | [
{
"companynumb": "PHHY2014TW094514",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nTo present our preliminary experience on intravitreal administration of an anti-tumor necrosis factor (TNF) monoclonal antibody for neovascular age-related macular degeneration (AMD).\n\n\nMETHODS\nProspective, noncomparative series of 3 patients previously treated with an anti-vascular endothelial growth factor agent.\n\n\nMETHODS\nTwo intravitreal injections of 0.05 ml containing infliximab were administered in the first (1 and 2 mg, 2 months apart), second (2 mg each, 2 months apart), and third patient (2 mg each, 3 months apart). Best-corrected visual acuity (BCVA) and central foveal thickness (CFT) were monthly assessed for up to 7 months.\n\n\nRESULTS\nIn the first patient, BCVA increased from 20/200 to 20/100 and CFT decreased from 462 to 386 microm, 2 months after the first injection. The condition was further improved after the second injection (BCVA, 20/40; CFT, 210 microm), but recurrence occurred 7 months post-baseline. In the second patient, BCVA increased from 20/200 to 20/70 and CFT decreased from 512 to 420 and 184 microm, 2 and 4 months post-baseline, respectively. In the third patient, clinical improvement was documented after the first injection. A second injection attributable to recurrence resulted in improvement of BCVA from 20/100 to 20/30 and decrease of CFT from 388 to 282 microm, 2 months after the second injection.\n\n\nCONCLUSIONS\nThese findings, although insufficient to consider \"off-label\" treatment with intravitreal infliximab, provide in vivo evidence of a pathogenetic link of locally produced and/or acting TNF to neovascular AMD. A randomized study of consecutive intravitreal injections of infliximab for AMD may be warranted.",
"affiliations": "Attikon University Hospital, 2nd Department of Ophthalmology, University of Athens, Athens, Greece. patheo@med.uoa.gr",
"authors": "Theodossiadis|Panagiotis G|PG|;Liarakos|Vasilios S|VS|;Sfikakis|Petros P|PP|;Vergados|Ioannis A|IA|;Theodossiadis|George P|GP|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajo.2008.12.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "147(5)",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D020256:Choroidal Neovascularization; D005260:Female; D005584:Fovea Centralis; D006801:Humans; D000069285:Infliximab; D007267:Injections; D008268:Macular Degeneration; D008297:Male; D011446:Prospective Studies; D041623:Tomography, Optical Coherence; D014409:Tumor Necrosis Factor-alpha; D014792:Visual Acuity; D014822:Vitreous Body",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "825-30, 830.e1",
"pmc": null,
"pmid": "19211094",
"pubdate": "2009-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degeneration.",
"title_normalized": "intravitreal administration of the anti tumor necrosis factor agent infliximab for neovascular age related macular degeneration"
} | [
{
"companynumb": "GR-ROCHE-2232554",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is frequently reported in the literature; however, its pathophysiology has not been fully elucidated to date. We herein describe a case of MTX-LPD that occurred after long-term treatment with oral MTX in a 67-year-old Japanese woman with rheumatoid arthritis (RA) who presented with generalized lymphadenopathy of the neck. The patient had been diagnosed with RA 24 years earlier, and had been on oral MTX for 20 years. The patient noticed a mass on her neck, which prompted a visit to our hospital. The mass was confirmed as diffuse large B-cell lymphoma by biopsy. MTX treatment was discontinued, which resulted in a reduction in the size of the mass and improvement of the patient's symptoms. Therefore, clinicians must be aware of MTX-LPD as a differential diagnosis for patients with rheumatological conditions on long-term MTX therapy presenting with signs and symptoms suggestive of lymphoma.",
"affiliations": "Department of Orthopedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan.;Department of Orthopedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan.",
"authors": "Hashimoto|Kazuhiko|K|;Akagi|Masao|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2018.1675",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "9(3)",
"journal": "Molecular and clinical oncology",
"keywords": "elderly; long-term oral administration; methotrexate-associated lymphoproliferative disorder; rheumatoid arthritis",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "293-296",
"pmc": null,
"pmid": "30155252",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": "16508929;23560463;17117491;23823018;24499448;1787499;28264816;28380678;24515570;21933041;27523005;12010788;27846761;29855173;26328653;15160955;25593236;17654684",
"title": "Lymphoproliferative disorder in an elderly rheumatoid arthritis patient after longterm oral methotrexate administration: A case report.",
"title_normalized": "lymphoproliferative disorder in an elderly rheumatoid arthritis patient after longterm oral methotrexate administration a case report"
} | [
{
"companynumb": "JP-ACCORD-070777",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BUCILLAMINE"
},
"drugadditional": "1",
"drug... |
{
"abstract": "OBJECTIVE\nBased on the interpersonal theory of suicide, pain habituation that occurs with injection substance use may raise risk for a suicide attempt. The current study tested whether injection substance use, relative to painless routes of substance administration, was related to greater risk for suicide attempts. We also assessed whether this risk was specific to suicide attempts and not suicidal ideation or suicide plans.\n\n\nMETHODS\nData on 2095 substance-using adolescents aged 12-17 who endorsed clinically significant depression symptoms and answered questions on suicidal thoughts and behavior were drawn from the 2004-2011 National Survey on Drug Use and Health, a nationally representative household survey. Logistic regression analyses were conducted to assess the associations between injection substance use and suicidal ideation, plans, and attempts.\n\n\nRESULTS\nInjection substance use was associated with suicide attempts (OR = 3.02, 95% CI = 1.75-5.23) but not ideation or plans. These findings were not accounted for by sex, age, race/ethnicity, family income, abuse and dependence symptoms, and depression symptoms. Among ideators, injection substance use was associated with suicide attempts (OR = 2.92, 95% CI = 1.58-5.06), but not plans. Among suicide planners, injection substance use was associated with suicide attempts (OR = 5.16, 95% CI = 1.88-14.17).\n\n\nCONCLUSIONS\nConsistent with the interpersonal theory of suicide, adolescent injection drug use was associated with specific risk for suicide attempts but not ideation or planning. Hence, consideration of the manner in which adolescents use substances is important in evaluating suicide risk in this population.",
"affiliations": "Adolescent Mood and Behavior Program, Emma Pendleton Bradley Hospital, United States; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States. Electronic address: richard_liu@brown.edu.;Health Services Research Program, Emma Pendleton Bradley Hospital, United States; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States; Department of Health Services, Policy, and Practice, Public Health Program of Brown University, United States.;Adolescent Mood and Behavior Program, Emma Pendleton Bradley Hospital, United States; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States.",
"authors": "Liu|Richard T|RT|;Case|Brady G|BG|;Spirito|Anthony|A|",
"chemical_list": "D013287:Illicit Drugs",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3956",
"issue": "56()",
"journal": "Journal of psychiatric research",
"keywords": "Adolescents; Epidemiology; Interpersonal theory of suicide; Substance use; Suicide",
"medline_ta": "J Psychiatr Res",
"mesh_terms": "D000293:Adolescent; D002648:Child; D003863:Depression; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D007267:Injections; D008297:Male; D008606:Mental Processes; D008960:Models, Psychological; D015999:Multivariate Analysis; D012306:Risk; D012959:Socioeconomic Factors; D019966:Substance-Related Disorders; D059020:Suicidal Ideation; D013406:Suicide, Attempted",
"nlm_unique_id": "0376331",
"other_id": null,
"pages": "65-71",
"pmc": null,
"pmid": "24853457",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Injection drug use is associated with suicide attempts but not ideation or plans in a sample of adolescents with depressive symptoms.",
"title_normalized": "injection drug use is associated with suicide attempts but not ideation or plans in a sample of adolescents with depressive symptoms"
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"abstract": "Buprenorphine is a potent partial opioid agonist that is analyzed in urine to (i) monitor adherence to maintenance or detoxification therapy and (ii) detect illicit use. Buprenorphine analysis is commonly conducted on urine by immunoassay, but is subject to cross-reactivity from other drugs/drug metabolites, including morphine, codeine and dihydrocodeine. This study reports false-positive buprenorphine analysis [Thermo Fisher Scientific cloned enzyme donor immunoassay (CEDIA)] in patients who denied unauthorized buprenorphine use prior to sampling, but who had been prescribed amisulpride. In two cases, confirmatory analysis by liquid chromatography-tandem mass spectrometry was negative (<0.5 µg/L) for buprenorphine and metabolites and positive for amisulpride. Although the cross-reactivity of amisulpride and sulpiride in the CEDIA buprenorphine assay is low (estimated at 0.003 and 0.002%, respectively), it remains a significant consideration given the likely high concentrations of these compounds in urine relative to the low cutoff of the buprenorphine assay. Neither amisulpride nor sulpiride was listed as potential sources of interference on the CEDIA data sheet when this work was performed. These findings highlight the importance of confirming immunoassay-positive buprenorphine results using a more selective analytical technique.",
"affiliations": "Toxicology Unit, Department of Clinical Biochemistry, King's College Hospital, London, UK.",
"authors": "Birch|M A|MA|;Couchman|L|L|;Pietromartire|S|S|;Karna|T|T|;Paton|C|C|;McAllister|R|R|;Marsh|A|A|;Flanagan|R J|RJ|",
"chemical_list": "D002047:Buprenorphine; D013469:Sulpiride; D000077582:Amisulpride",
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"issue": "37(4)",
"journal": "Journal of analytical toxicology",
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"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D000077582:Amisulpride; D002047:Buprenorphine; D002851:Chromatography, High Pressure Liquid; D005189:False Positive Reactions; D006801:Humans; D007118:Immunoassay; D007124:Immunoenzyme Techniques; D008297:Male; D015813:Substance Abuse Detection; D013469:Sulpiride",
"nlm_unique_id": "7705085",
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"publication_types": "D016428:Journal Article",
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"title": "False-positive buprenorphine by CEDIA in patients prescribed amisulpride or sulpiride.",
"title_normalized": "false positive buprenorphine by cedia in patients prescribed amisulpride or sulpiride"
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"abstract": "Cryptococcus neoformans infections occur mostly in immunodeficient individuals, being the most common opportunistic fungal central nervous system (CNS) infection in HIV seropositive patients. Moreover, other conditions affecting host immunity, such as hematologic malignancies, organ transplantation and immunosuppressive drugs are implicated as risk factors. The authors present a case of a 48-year-old male with Hodgkin Lymphoma for 26 years and submitted to several lines of treatment, diagnosed with cryptococcal meningitis while on therapy with brentuximab. The patient presented with positive cerebral spinal fluid (CSF) cryptococcal antigen plus positive blood cultures. He was put under induction antifungal treatment with liposomal amphotericin B and flucytosine, as well as corticosteroid therapy with dexamethasone with headache improvement and a favorable clinical evolution. There are no reported cases of cryptococcal meningoencephalitis under CD30-directed monoclonal antibody. Furthermore, this case illustrates the risk of Cryptococcus neoformans infection in immunocompromising conditions other than HIV, underlining the need of considering this differential diagnosis when physicians face an opportunistic neuroinfection.",
"affiliations": "Medical Oncology Department, Instituto Português Oncologia de Coimbra Francisco Gentil E. P. E., Coimbra, Portugal.;Onco-Hematology Department, Instituto Português de Oncologia do Porto, Porto, Portugal.;Medical Oncology Department, Instituto Português Oncologia de Coimbra Francisco Gentil E. P. E., Coimbra, Portugal.;Onco-Hematology Department, Instituto Português de Oncologia do Porto, Porto, Portugal.;Onco-Hematology Department, Instituto Português de Oncologia do Porto, Porto, Portugal.",
"authors": "Cunha Pereira|Tatiana|T|0000-0002-0527-7039;Rb-Silva|Rita|R|0000-0002-1422-0974;Félix Soares|Rita|R|;Domingues|Nelson|N|;Mariz|José|J|",
"chemical_list": "D000935:Antifungal Agents; D003907:Dexamethasone; D000079963:Brentuximab Vedotin; D000666:Amphotericin B; D005437:Flucytosine",
"country": "England",
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"doi": "10.12688/f1000research.24816.2",
"fulltext": "\n==== Front\nF1000Res\nF1000Res\nF1000Research\nF1000Research\n2046-1402 F1000 Research Limited London, UK \n\n10.12688/f1000research.24816.2\nCase Report\nArticles\nCase Report: Cryptococcal meningitis in Hodgkin’s Lymphoma patient receiving brentuximab-vedotin therapy\n[version 2; peer review: 2 approved]\n\nCunha Pereira Tatiana ConceptualizationWriting – Original Draft Preparationhttps://orcid.org/0000-0002-0527-7039a1 Rb-Silva Rita Writing – Review & Editinghttps://orcid.org/0000-0002-1422-09742 Félix Soares Rita Writing – Review & Editing1 Domingues Nelson SupervisionWriting – Review & Editing2 Mariz José Writing – Review & Editing2 \n1 Medical Oncology Department, Instituto Português Oncologia de Coimbra Francisco Gentil E. P. E., Coimbra, Portugal\n\n2 Onco-Hematology Department, Instituto Português de Oncologia do Porto, Porto, Portugal\na tatiana.cunhapereira@gmail.comNo competing interests were disclosed.\n\n\n12 8 2020 \n2020 \n9 6876 8 2020 Copyright: © 2020 Cunha Pereira T et al.2020This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nCryptococcus neoformans infections occur mostly in immunodeficient individuals, being the most common opportunistic fungal central nervous system (CNS) infection in HIV seropositive patients. Moreover, other conditions affecting host immunity, such as hematologic malignancies, organ transplantation and immunosuppressive drugs are implicated as risk factors.\n\n The authors present a case of a 48-year-old male with Hodgkin Lymphoma for 26 years and submitted to several lines of treatment, diagnosed with cryptococcal meningitis while on therapy with brentuximab. The patient presented with positive cerebral spinal fluid (CSF) cryptococcal antigen plus positive blood cultures. He was put under induction antifungal treatment with liposomal amphotericin B and flucytosine, as well as corticosteroid therapy with dexamethasone with headache improvement and a favorable clinical evolution.\n\n There are no reported cases of cryptococcal meningoencephalitis under CD30-directed monoclonal antibody. Furthermore, this case illustrates the risk of\nCryptococcus neoformans infection in immunocompromising conditions other than HIV, underlining the need of considering this differential diagnosis when physicians face an opportunistic neuroinfection.\n\nC. neoformansBrentuximab-vedotinHodgkin LymphomaMeningitisThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\nAs suggested by the peer review reports, grammar corrections have been made in this new version.\n==== Body\nLearning points\nCryptococcal meningitis is a common opportunistic central nervous system (CNS) infection among HIV-positive patients. However, it also affects HIV seronegative patients.\n\nEvery immunocompromising condition must be assessed and considered a risk factor for an opportunistic fungal meningoencephalitis. A therapeutic agent affecting host immunity, such as with CD30-directed monoclonal antibody, may predispose to opportunistic infections.\n\nCryptococcal meningitis diagnosis may be challenging in cases presenting negative cerebral spinal fluid (CSF) cultures, but cryptococcal polysaccharide antigen titers in CSF correlate with fungal burden.\n\nBackground\nCryptococcus species have a major predilection for the lungs with potential to spread further, mainly through continuity or through hematogenic and lymphoid pathways, with possible penetration through the blood-brain barrier and CNS involvement\n1–\n4.\n\n\nCryptococcus neoformans infections occur mostly in immunodeficient individuals, being the most common opportunistic CNS infection in HIV-positive patients, counting up to 1 million new infections annually worldwide\n3,\n4. It also occurs in transplant recipients, patients with hematological malignancies, as well as patients receiving immunosuppressive medications\n1,\n2,\n4.\n\nThis case reports an opportunistic CNS infection in a patient with Hodgkin Lymphoma under brentuximab after multiple lines of treatment for over 20 years, including an allogenic stem cell transplantation. Despite being reported as a common fungal infection in HIV-patients, neuroinfections in patients under CD30-directed monoclonal antibody therapy or other drugs besides immunosuppressants are a rare occurrence.\n\nCase presentation\nA 48-year-old Caucasian male presented at the outpatient clinic in May 2019 with holocranial headache, more intense at occipital level, lasting for 6 days, with increasing intensity over the last couple of hours, associated with photophobia and vomiting.\n\nThe patient was diagnosed in 1993 with Classic Hodgkin Lymphoma, nodular sclerosis subtype, stage IVB, achieving complete remission after first line chemotherapy. Since then, the patient suffered several relapses and underwent radiotherapy, one autologous bone marrow transplant in 1998, as well as an allogenic stem cell transplant in 2001, followed by several lines of chemotherapy. From October 2018 to this episode, the patient was taking brentuximab due to a hepatic hilar lesion. Sequencial imaging assessments showed a large left infratentorial arachnoid cystic lesion that was being monitored. (\nFigure 1).\n\nFigure 1. Head computed tomography (CT) scan revealing a large left extra-axial cystic lesion that was being monitored before current symptomatology.\nAt first evaluation, the patient was conscious and aware, hemodynamic stable and subfebrile, presenting general tremors and limited cervical mobility.\n\nBlood workup revealed elevated C-reactive protein with 73.2 mg/L (normal range under 5 mg/L), without other abnormalities.\n\nA head computed tomography (CT) scan showed the pre-existing cystic lesion in the left cerebellopontine angle with a slight right brainstem deviation, without associated edema (\nFigure 2A), confirmed by magnetic resonance imaging (\nFigure 2B). The case was discussed with the Neurosurgery Department and a lumbar puncture was postponed as it was considered a high-risk procedure. The patient started antibiotics with ceftriaxone (2 g q12h) and ampicillin. (2g q4h) At day 4, blood cultures came back positive for\nCryptococcus neoformans sensitive to Posaconazole, Amphotericin B and Itraconazole, so that patient started Liposomal Amphotericin B (3mg/kg id) and Flucytosine (100 mg/kg per day orally in four divided doses) for 14 days and low dose corticosteroid therapy (4 mg per day). There was a progressive improvement of the symptoms and patient was discharged after 19 days with prescription of Fluconazole (400mg per day).\n\nFigure 2. Head computed tomography (CT) scan showed the pre-existing cystic lesion in the left cerebellopontine angle with a slight right brainstem deviation, without associated edema (\n2A), as confirmed by magnetic resonance imagining (MRI) (\n2B).\n\nAfter one month of treatment, a ventricular puncture was performed and normal pressure cerebrospinal fluid (CSF) revealed glucose consumption and elevated levels of proteins (\nTable 1), as well as positivity for cryptococcal polysaccharide capsular antigen. Follow-up lumbar punctures were performed to assess CSF characteristics and cryptococcal antigen assessment. Patient was kept under consolidation therapy with Fluconazole for 10 weeks with a favorable clinical evolution, as well as decreasing levels of protein and nucleated cells count as seen in\nTable 1. Patient maintains close surveillance under regular appointments at the Onco-Haematology Clinic. However, headache complaints increased in intensity shortly after dexamethasone discontinuation with an intermittent pattern. Patient died in another hospital about 8 months after the meningitis diagnosis due to a cardiovascular event.\n\nTable 1. Cerebrospinal fluid profile evolution throughout treatment.\nCSF – Cerebrospinal fluid. LP – Lumbar puncture. NV – Normal value.\n\nLP date\t27-06-2019\t17-07-2019\t31-07-2019\t16-09-2019\t\nCharacteristic\t\n\nAppearance\n\tClear\tClear\tClear\tClear\t\n\nNucleated cells count\n\t104/μL\t43/μL\t35/μL\t5/μL\t\n\nGlucose\n\n\n(NV: 2.8 – 4.4 mmol/L)\n\t2,3 mmol/L\t3.1 mmol/L\t3,4 mmol/L\t3,3 mmol/L\t\n\nProtein level\n\n\n(NV: 150 – 450 mg/L)\n\t838 mg/L\t583 mg/L\t529 mg/L\t544 mg/L\t\n\nCSF culture\n\tNegative\tNegative\tNegative\tNegative\t\n\nCryptococcus neoformans\n\n\nantigen\n\tPositive\tPositive\tPositive\tPositive\t\nDiscussion\nCryptococcal meningitis accounts for up to 1 million new infections annually, mainly affecting HIV-positive patients. Other immunocompromising conditions such as organ transplantation, hematologic malignancies and immunosuppressive drugs constitutes other relevant risk factors to these opportunistic fungi CNS infections\n1–\n4.\n\nIn a recent review of\nCryptococcus neoformans infections in patients with cancer, 82% corresponded to patients with haematological malignancies and from these patients, approximately 54% had lymphoma\n5.\n\nThe patient presented several conditions affecting host immunity due to several previous lines of treatment for over 25 years. However, Cryptococcus species were not considered the etiological agent for a possible opportunistic neuroinfection, emphasizing the need for an initial lumbar puncture to exclude fungal agents. This procedure was not possible at first evaluation and it delayed the start of antifungal therapy.\n\nAlthough there are many published case reports of Cryptococcosis in patients with lymphoma, this is the first reported case of Cryptococcal neuroinfection in a patient with Hodgkin’s Lymphoma treated with CD-30-directed monoclonal antibody.\n\nConsent\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient prior to their death.\n\nData availability\nUnderlying data\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n10.5256/f1000research.28541.r69298\nReviewer response for version 2\nSchmalzle Sarah A. 1Referee \n1 Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA\n\nCompeting interests: No competing interests were disclosed.\n\n\n23 9 2020 \nCopyright: © 2020 Schmalzle SA2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 2recommendationapproveNo new comments.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nInfectious disease, HIV, cryptococcosis, Group A Strep\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.27380.r68025\nReviewer response for version 1\nSchmalzle Sarah A. 1Referee \n1 Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA\n\nCompeting interests: No competing interests were disclosed.\n\n\n30 7 2020 \nCopyright: © 2020 Schmalzle SA2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapprove-with-reservationsThis is a clinically relevant case report as it is purportedly the first report in a patient being treated with a particular immunosuppressive monoclonal Ab. \n\n There are several minor language and grammatical improvements to be made that will strengthen and clarify the report. It should have an additional round of editing by a native English speaker. Examples: \nHIV-positive should be 'people living with HIV'.\n\nAbstract: 'fungi central nervous system..' should be fungal.\n\nBrentuximab should be in lower case throughout. It is not explained with it is 'brentuximab-vedotin' in keywords but 'brentuximab' elsewhere.\n\nEnd of abstract - opportunist should be opportunistic. \n\nThis sentence needs an English language revision: \"However, these fungi neuroinfection affects HIV seronegative patients.\" \n\nBackground - it is not accurate to say crypto has a predilection for the lungs. The lungs are the route of entry, but this is a neurotropic pathogen. \n\n'penetration into' should be 'penetration through'.\n\nCase presentation: \"over the last couple hours\" should be \"over the last couple of hours\" or \"over the last several hours\".\n\nThe use of 'under' to describe being prescribed a treatment is not commonly how this is stated in the US. Try \"treated with\" or \"on treatment for ___ with ___\".\n\nAlso not common to say patients are admitted at the outpatient clinic. Patients are seen or evaluated at a clinic, but admitted to a hospital. \n\nThis sentence also needs to be revised for proper grammar/syntax. \"Throughout image assessments, a large left infratentorial arachnoid cystic lesion was being monitored.\".\n\nSusceptibilities are not commonly reported in Crypto case reports. There is not known resistance and generally all therapy is empiric.\n\nCorticotherapy should be corticosteroid therapy.\n\nThis needs to be reworded for clarity: \"However, Cryptococcus species were not considered the etiological agent for a CNS infection, emphasizing the need for an initial lumbar puncture to exclude fungal agents when approaching opportunist neuroinfection. This was not possible at first evaluation in this case which delayed antifungal therapy.\"\n\n\n\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nInfectious disease, HIV, cryptococcosis, Group A Strep\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\n10.5256/f1000research.27380.r66704\nReviewer response for version 1\nRoque Adriana 12Refereehttps://orcid.org/0000-0003-4194-9119 \n1 Clinical Hematology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal\n\n2 Faculty of Medicine, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra Institute for Clinical and Biomedical Research (iCBR), Coimbra, Portugal\n\nCompeting interests: No competing interests were disclosed.\n\n\n20 7 2020 \nCopyright: © 2020 Roque A2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapproveI think that this is an interesting report that claims for attention to rare infections in patients under immunotherapy and other novel therapies, especially when they are more difficult to diagnose (due to the location and the infectious agent).\n\n This report provides a concise and informative history of the case, mainly focus on the difficulties of the process.\n\n I consider that it would be important to provide information about the previous therapeutics that the patient had received, including the transplantation conditioning regimen, as well as the development of graft versus host disease (GvHD) and GvHD therapeutics, because it can help to explain the subjacent immunosuppression state. Another helpful information is to understand if Hodgkin lymphoma was under control at the time of CNS infection presentation.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nPartly\n\nReviewer Expertise:\n\nHematology, Hematology-oncology\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n==== Refs\n1 \nLi SS Mody CH :\nCryptococcus.\n\nProc Am Thorac Soc. \n2010 ;7 (3 ):186 –96\n.\n10.1513/pats.200907-063AL \n20463247 \n2 \nBeardsley J Sorrell TC Chen SCA :\nCentral nervous system cryptococcal infections in non-HIV infected patients.\n\nJ Fungi (Basel). \n2019 ;5 (3 ):71 .\n10.3390/jof5030071 \n\n31382367 \n3 \nGóralska K Blaszkowska J Dzikowiec M :\nNeuroinfections caused by fungi.\n\nInfection. \n2018 ;46 (4 ):443 –59\n.\n10.1007/s15010-018-1152-2 \n\n29785613 \n4 \nMazlarz EK Perfect JR :\nCryptococcosis.\n\nInfect Dis Clin North Am. \n2016 ;30 (1 ):179 –206\n.\n10.1016/j.idc.2015.10.006 \n\n26897067 \n5 \nSchmalzle SA Buchwald UK Gilliam BL :\n\nCryptococcus neoformans infection in malignancy.\n\nMycoses. \n2016 ;59 (9 ):542 –52\n.\n10.1111/myc.12496 \n26932366\n\n",
"fulltext_license": "CC BY",
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"keywords": "Brentuximab-vedotin; C. neoformans; Hodgkin Lymphoma; Meningitis",
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"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D000079963:Brentuximab Vedotin; D003455:Cryptococcus neoformans; D003907:Dexamethasone; D005437:Flucytosine; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal; D008875:Middle Aged; D009894:Opportunistic Infections",
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"title": "Case Report: Cryptococcal meningitis in Hodgkin's Lymphoma patient receiving brentuximab-vedotin therapy.",
"title_normalized": "case report cryptococcal meningitis in hodgkin s lymphoma patient receiving brentuximab vedotin therapy"
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"abstract": "Metastatic pancreatic adenocarcinoma confers a poor prognosis. Even with recent advances in the treatment of this disease with the introduction of two modestly effective chemotherapy regimens, complete responses are still very rare. Moreover, there are no published data on how to further manage the patients who achieve a sustained remission following treatment. Herein, we report the case of a patient with metastatic pancreatic adenocarcinoma who achieved a complete response lasting for more than three years after receiving induction chemotherapy with FOLFIRINOX followed by maintenance with FOLFIRI.",
"affiliations": "Department of Medical Oncology, University Hospital of Heraklion, Voutes, P.O. Box 1352, Heraklion, 71110 Crete, Greece.;Department of Medical Oncology, University Hospital of Heraklion, Voutes, P.O. Box 1352, Heraklion, 71110 Crete, Greece.;Olympion General Clinic, Volou & Meilichou, 26443 Patra, Greece.;Department of Medical Oncology, University Hospital of Heraklion, Voutes, P.O. Box 1352, Heraklion, 71110 Crete, Greece.;Department of Medical Oncology, University Hospital of Heraklion, Voutes, P.O. Box 1352, Heraklion, 71110 Crete, Greece.",
"authors": "Nikolaou|Christos|C|;Matikas|Alexios|A|;Papavasilopoulou|Maria|M|;Mavroudis|Dimitris|D|;Vamvakas|Lampros|L|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2015/659624Case ReportProlonged Complete Response in a Patient with Metastatic Pancreatic Adenocarcinoma after FOLFIRINOX Chemotherapy and Maintenance with FOLFIRI Nikolaou Christos \n1\nMatikas Alexios \n1\nPapavasilopoulou Maria \n2\nMavroudis Dimitris \n1\nVamvakas Lampros \n1\n\n*\n1Department of Medical Oncology, University Hospital of Heraklion, Voutes, P.O. Box 1352, Heraklion, 71110 Crete, Greece2Olympion General Clinic, Volou & Meilichou, 26443 Patra, Greece*Lampros Vamvakas: vamvakasla@yahoo.grAcademic Editor: Jose I. Mayordomo\n\n2015 21 5 2015 2015 65962427 2 2015 10 5 2015 Copyright © 2015 Christos Nikolaou 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.Metastatic pancreatic adenocarcinoma confers a poor prognosis. Even with recent advances in the treatment of this disease with the introduction of two modestly effective chemotherapy regimens, complete responses are still very rare. Moreover, there are no published data on how to further manage the patients who achieve a sustained remission following treatment. Herein, we report the case of a patient with metastatic pancreatic adenocarcinoma who achieved a complete response lasting for more than three years after receiving induction chemotherapy with FOLFIRINOX followed by maintenance with FOLFIRI.\n==== Body\n1. Introduction\nPrimary adenocarcinoma of the pancreas is the eighth most common cancer and fourth leading cause of cancer-related death in the United States; the vast majority of newly diagnosed patients will eventually die of the disease [1]. Even when amenable to “curative” surgery, most patients eventually relapse. Despite recent advances, metastatic pancreatic cancer remains a devastating disease and carries a grim prognosis, with less than 1% of patients surviving for more than 5 years [1].\n\nUntil 2011, monotherapy with gemcitabine was the standard of care leading to an overall survival (OS) of approximately 6 months and a one-year survival rate of less than 20%; objective radiographic responses were rare [2]. Gemcitabine has been combined with a variety of cytotoxic and targeted agents, such as oxaliplatin [3], capecitabine [4, 5], 5-fluorouracil [6], irinotecan [7], and erlotinib [8]. However, the improvement in OS has been either statistically or clinically insignificant. In 2011, the results of the ACCORD 11 trial were published, which showed that the combination of 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) produced superior response rate, progression-free survival (PFS), and OS compared to single agent gemcitabine [9]. More recently, the combination of gemcitabine plus nanoparticle albumin bound paclitaxel (nab-paclitaxel) was also shown to be superior in terms of OS compared to gemcitabine [10]. Despite the aforementioned advances, almost all patients with metastatic pancreatic cancer eventually die of progressive disease, underscoring the clearly unmet need of curative therapy and the lack of data on how to best sequence existing active regimens when treating these patients.\n\nIn this case report, we present the case of a 51-year-old man with lung metastases from pancreatic adenocarcinoma who achieved a complete response after initial chemotherapy with FOLFIRINOX followed by maintenance chemotherapy with irinotecan, leucovorin, and 5-fluorouracil (FOLFIRI) and who has not yet recurred after 3 years from the initial diagnosis of metastatic disease. We propose this approach for highly selected patients with sustained responses to chemotherapy.\n\n2. Case Presentation\nA 51-year-old male patient with a medical history of type II diabetes and a smoking history of over 30 pack-years presented with a 2-month history of worsening epigastric pain, jaundice, and weight loss of approximately 10 kg. Physical examination was otherwise unremarkable. An abdominal computed tomography (CT) scan revealed a mass at the head of the pancreas with a maximal diameter of 2.4 cm which caused dilatation of the pancreatic and biliary tract. Further testing revealed markedly elevated levels of CA 19-9 tumor marker exceeding 12000 U/mL (normal range: 0–37 U/mL). Subsequent staging with chest CT and abdominal magnetic resonance imaging (MRI) showed absence of metastases and the patient underwent a Whipple procedure. The pathology exam was diagnostic of a primary pancreatic adenocarcinoma with a maximal diameter of 3.2 cm, with perivascular and perineural invasion. Four out of seven excised peripancreatic lymph nodes were positive for metastatic disease and all surgical margins were negative. According to the American Joint Committee on Cancer (AJCC) staging system, pathologic stage was pT2N1M0, stage II.\n\nThe patient's recovery was uneventful. Postsurgery CT scans showed no evidence of metastatic or residual disease and CA 19-9 tumor marker levels were 1203 U/mL. Adjuvant chemotherapy with gemcitabine 1000 mg/m2 on days 1, 8, and 15 on 28-day cycles was started 2.5 months after surgery, with a plan of administering 6 cycles. After completing 2 cycles, a gradual increase of CA 19-9 levels was noted and new imaging was performed. New multiple bilateral pulmonary nodules as well as para-aortic lymph nodes and one new liver lesion were shown, findings consistent with metastatic disease. On physical examination the patient remained asymptomatic, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0. A palpable left supraclavicular lymph node approximately 1.5 cm in diameter was noted. CA 19-9 levels were increased to over 12000 U/mL.\n\nFirst-line chemotherapy with the combination of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 given as a bolus followed by 2400 mg/m2 given as a 46-hour continuous infusion, every 2 weeks (FOLFIRINOX), was initiated. After 4 administrations of chemotherapy a gradual decrease of CA 19-9 levels to 550 U/mL was evident, while the left supraclavicular lymph node was no longer palpable. Imaging revealed a partial response of the pulmonary nodes and a complete response of the para-aortic lymph nodes and liver lesion (Figure 1). After 4 more administrations (8 cycles in total) the patient attained a complete response which he maintained after seven months of FOLFIRINOX chemotherapy despite dose reductions due to hematologic toxicity. Because of worsening neurotoxicity caused by oxaliplatin which peaked at grade 3 and taking into account the absence of published data regarding the optimal management of this patient, maintenance chemotherapy with FOLFIRI was commenced. Due to sustained complete remission on reimaging studies, the patient completed a total of two years of chemotherapy and discontinued treatment due to steatohepatitis with grade 1 transaminitis probably caused by irinotecan. Eight months after treatment discontinuation he remained alive and in complete radiographic and biochemical remission.\n\n3. Discussion\nIn spite of the use of more active combination regimens, complete responses are a rare occurrence in metastatic pancreatic cancer; in the ACCORD 11 trial, there was only one complete response among the 171 patients who received FOLFIRINOX (0.6%) [9]. Published case series propose total gross resection for locally advanced pancreatic cancer following dramatic responses from first-line chemotherapy [11, 12]. Complete radiological or pathologic complete responses after neoadjuvant FOLFIRINOX are rare but well documented in this setting [13–15]; these patients may have a better prognosis compared to those who experience lesser responses [16]. However, there is no published literature on how to best treat the rare patient with distant metastases who achieves a sustained partial or complete response, due to the rarity of such cases [17]. Current guidelines support the continuation of intensive chemotherapy until disease progression or unacceptable toxicities, as was the case with our patient [18]. Also, the role of Positron Emission Tomography (PET and PET/CT) scan in the initial staging of pancreatic cancer is controversial and there are no data to support its use in the metastatic setting [19].\n\nTaking into account the absence of measurable disease after achieving a complete response and grade 3 neurotoxicity which affected our patient's activities of daily living and his unwillingness to stop treatment altogether, we proposed omitting oxaliplatin and continue with FOLFIRI. To our knowledge, this is the first published report of maintenance FOLFIRI after initial response to FOLFIRINOX in a patient with pancreatic cancer. How much benefit the patient actually derived from FOLFIRI cannot be determined, especially in light of the modest activity of irinotecan in metastatic pancreatic cancer [20].\n\nIn recent years, the traditional approach of distinct chemotherapy lines when treating metastatic solid tumors is being challenged in favor of a continuum of care paradigm where periods of intensive chemotherapy are followed by less toxic maintenance strategies. Whether such an approach can be successfully implemented in the treatment of metastatic pancreatic cancer remains to be seen in future trials. In addition, the optimal sequence of active regimens and whether surgical excision of metastatic sites in patients who exhibit significant response to systemic treatment has a role in the treatment strategy are questions that also remain unanswered, although the feasibility of the latter strategy has been demonstrated in case reports [21].\n\nIn conclusion, we present the case of a patient with prolonged complete response after initial chemotherapy with FOLFIRINOX and maintenance with FOLFIRI. Until data from prospective randomized trials are available and taking into account the absence of any relevant published literature, case reports and retrospective case series may offer a guide on how to treat the selected population of long-term (i.e., more than two years) survivors with metastatic pancreatic cancer.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflict of Interests\nThe authors report no financial interests or potential conflict of interests.\n\nFigure 1 CT scan, axial images, at the same level, at the beginning of the therapy (a), after three cycles of chemotherapy (b) showing partial response (PR), and after the seventh cycle (c) in competence with complete response (CR). Yellow arrows indicate the pulmonary nodules (first two images) that are easily recognized at the first scan, are faintly differentiable at the following, and have disappeared at the final. In the remaining images, arrows indicate the pathologic mediastinal lymph node (third image) and the liver lesion.\n==== Refs\n1 Siegel R. Ma J. Zou Z. Jemal A. Cancer statistics, 2014 CA—Cancer Journal for Clinicians 2014 64 1 9 29 10.3322/caac.21208 2-s2.0-84892805731 \n2 Burris H. A. III Moore M. J. Andersen J. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial Journal of Clinical Oncology 1997 15 6 2403 2413 2-s2.0-8244254377 9196156 \n3 Louvet C. Labianca R. Hammel P. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial Journal of Clinical Oncology 2005 23 15 3509 3516 10.1200/JCO.2005.06.023 2-s2.0-20644464360 15908661 \n4 Cunningham D. Chau I. Stocken D. D. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer Journal of Clinical Oncology 2009 27 33 5513 5518 10.1200/jco.2009.24.2446 2-s2.0-73949135518 19858379 \n5 Herrmann R. Bodoky G. Ruhstaller T. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group Journal of Clinical Oncology 2007 25 16 2212 2217 10.1200/jco.2006.09.0886 2-s2.0-34250180939 17538165 \n6 Berlin J. D. Catalano P. Thomas J. P. Kugler J. W. Haller D. G. Benson A. B. III Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: eastern Cooperative Oncology Group trial E2297 Journal of Clinical Oncology 2002 20 15 3270 3275 10.1200/jco.2002.11.149 2-s2.0-0036682041 12149301 \n7 Stathopoulos G. P. Syrigos K. Aravantinos G. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer British Journal of Cancer 2006 95 5 587 592 10.1038/sj.bjc.6603301 2-s2.0-33748297529 16909140 \n8 Moore M. J. Goldstein D. Hamm J. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group Journal of Clinical Oncology 2007 25 15 1960 1966 10.1200/jco.2006.07.9525 2-s2.0-34249933404 17452677 \n9 Conroy T. Desseigne F. Ychou M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer The New England Journal of Medicine 2011 364 19 1817 1825 10.1056/nejmoa1011923 2-s2.0-79955921754 21561347 \n10 von Hoff D. D. Ervin T. Arena F. P. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine The New England Journal of Medicine 2013 369 18 1691 1703 10.1056/nejmoa1304369 2-s2.0-84886741654 24131140 \n11 Hosein P. J. Macintyre J. Kawamura C. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma BMC Cancer 2012 12, article 199 10.1186/1471-2407-12-199 2-s2.0-84861465672 \n12 Peddi P. F. Lubner S. McWilliams R. Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma Journal of the Pancreas 2012 13 5 497 501 2-s2.0-84866378244 22964956 \n13 Valeri S. Borzomati D. Nappo G. Perrone G. Santini D. Coppola R. Complete pathological response after FOLFIRINOX for locally advanced pancreatic cancer. The beginning of a new era? Case report and review of the literature Pancreatology 2014 14 5 425 430 10.1016/j.pan.2014.07.002 25278312 \n14 Turner K. Sandri G. B. L. Boucher E. Complete radiological response of an initially locally advanced unresectable pancreatic cancer to chemoradiotherapy using FOLFIRINOX regimen: report of a case Clinics and Research in Hepatology and Gastroenterology 2015 39 2 e29 e31 10.1016/j.clinre.2014.08.011 25288453 \n15 Hartlapp I. Müller J. Kenn W. Complete pathological remission of locally advanced, unresectable pancreatic cancer (LAPC) after intensified neoadjuvant chemotherapy Onkologie 2013 36 3 123 125 10.1159/000348527 2-s2.0-84875162527 23486001 \n16 Wang H. Zhao Q. Rashid A. Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with a better prognosis Annals of Diagnostic Pathology 2012 16 1 29 37 10.1016/j.anndiagpath.2011.08.005 2-s2.0-84856019443 22050964 \n17 Shakir A. R. A near-complete response to treatment with gemcitabine plus nab-paclitaxel in a patient with metastatic pancreatic cancer and poor performance status: a case report Case Reports in Oncology 2014 7 3 711 717 10.1159/000368346 25493084 \n18 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Pancreatic Adenocarcinoma, Version 2.2014, 2014, http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf \n19 Izuishi K. Yamamoto Y. Sano T. Takebayashi R. Masaki T. Suzuki Y. Impact of 18-fluorodeoxyglucose positron emission tomography on the management of pancreatic cancer Journal of Gastrointestinal Surgery 2010 14 7 1151 1158 10.1007/s11605-010-1207-x 2-s2.0-78649688880 20443074 \n20 Wagener D. J. T. Verdonk H. E. R. Dirix L. Y. Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study Annals of Oncology 1995 6 2 129 132 2-s2.0-0028839053 7786820 \n21 Iida T. Nakabayashi Y. Okui N. Shiba H. Otsuka M. Yanaga K. Successful management of metachronous liver metastasis after pancreaticoduodectomy for pancreatic ductal carcinoma using hepatectomy and chemotherapy: a case report Anticancer Research 2014 34 5 2417 2420 24778053\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2015()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "659624",
"pmc": null,
"pmid": "26090249",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "25288453;12149301;24778053;21561347;22964956;24131140;25278312;20443074;22050964;25493084;19858379;17538165;15908661;16909140;24399786;17452677;23486001;7786820;9196156;22642850",
"title": "Prolonged Complete Response in a Patient with Metastatic Pancreatic Adenocarcinoma after FOLFIRINOX Chemotherapy and Maintenance with FOLFIRI.",
"title_normalized": "prolonged complete response in a patient with metastatic pancreatic adenocarcinoma after folfirinox chemotherapy and maintenance with folfiri"
} | [
{
"companynumb": "GR-SA-2015SA094439",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "Maraviroc-intensified antiretroviral therapy (ART) may be associated with cognitive benefits.\n\n\n\nTherapy-naive, cognitively asymptomatic, HIV-positive individuals were randomly allocated on a 1 : 1 basis to standard ART (Arm1: tenofovir-emtricitabine and atazanavir/ritonavir) or maraviroc intensified ART (Arm2: abacavir-lamivudine and darunavir/ritonavir/maraviroc). Over 48 weeks, detailed assessments of cognitive function tests were undertaken and cerebral metabolites measured using proton magnetic resonance spectroscopy. Our primary endpoint was mean change in cognitive function across treatment arms with factors associated with cognitive function changes also assessed.\n\n\n\nOf 60 individuals randomized (30 Arm1 and 30 Arm2), 58 were men and 44 of white ethnicity. Treatment groups had similar disease characteristics including overall mean (SD) baseline CD4 cell count 428 (209) and 414 (229) cells/μl, Arms1 and 2, respectively. At week 48, plasma HIV RNA was less than 50 copies/ml in 55 of 56 of those completing study procedures. Cognitive function improved over 48 weeks [mean change z-score (SD) 0.16 (0.09) Arm1 and 0.25 (0.08) Arm2, P = 0.96 for differences between study arms]. A greater increase in frontal grey matter N-acetyl aspartate/creatine ratio was observed in Arm1 [ratio change of 0.071 (SD 0.16)] versus Arm2 [change -0.097 (SD 0.18), P = 0.009], although this was not associated with changes in cognitive function (P = 0.17).\n\n\n\nMaraviroc-intensified ART had no demonstrable benefit on cognitive function in individuals initiating ART. Greater improvement in neuronal metabolites (N-acetyl aspartate/creatine) was observed with standard ART. Future work should focus on maraviroc-intensified ART in individuals with cognitive impairment.",
"affiliations": "Division of Infectious Diseases, Department of Medicine.;Imperial Clinical Trials Unit, School of Public Health, Imperial College London.;St. Thomas' Hospital, London.;Brighton and Sussex University Hospital, Brighton.;King's College Hospital.;Division of Infectious Diseases, Department of Medicine.;Imperial Clinical Trials Unit, School of Public Health, Imperial College London.;St. Thomas' Hospital, London.;Department of Pharmacology, University of Liverpool, Liverpool.;Birmingham Heartlands Hospital, Birmingham, UK.;Imperial Clinical Trials Unit, School of Public Health, Imperial College London.;Division of Infectious Diseases, Department of Medicine.",
"authors": "Mora-Peris|Borja|B|;Bouliotis|George|G|;Ranjababu|Kulasegaram|K|;Clarke|Amanda|A|;Post|Frank A|FA|;Nelson|Mark|M|;Burgess|Laura|L|;Tiraboschi|Juan|J|;Khoo|Saye|S|;Taylor|Steve|S|;Ashby|Deborah|D|;Winston|Alan|A|",
"chemical_list": "D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D000077592:Maraviroc",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000001786",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "32(8)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D015526:AIDS Dementia Complex; D000328:Adult; D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D023241:Antiretroviral Therapy, Highly Active; D001923:Brain Chemistry; D005260:Female; D015658:HIV Infections; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D000077592:Maraviroc; D016896:Treatment Outcome",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "1007-1015",
"pmc": null,
"pmid": "29438199",
"pubdate": "2018-05-15",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Changes in cerebral function parameters with maraviroc-intensified antiretroviral therapy in treatment naive HIV-positive individuals.",
"title_normalized": "changes in cerebral function parameters with maraviroc intensified antiretroviral therapy in treatment naive hiv positive individuals"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1008863",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATAZANAVIR SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "Thrombosis in the neonatal population is rare, but increasing. Its incidence and management are not well understood.\n\n\n\nTo investigate the incidence, associated factors, and management of thrombosis in the neonatal intensive care unit (NICU) population.\n\n\n\nWe performed a retrospective cohort study of infants admitted to a Pediatrix Medical Group-affiliated NICU from 1997 through 2015. We determined the prevalence of venous and arterial thrombosis, and assessed demographic characteristics and known risk factors. Categorical variables were compared with the Pearson χ2 test and continuous variables with Wilcoxon rank-sum tests. Stepwise logistic regression was used to identify associated factors. The primary outcome was incidence of thrombosis. Secondary analyses investigated correlations between clinical and demographic characteristics and thrombosis.\n\n\n\nAmong 1 158 755 infants, we identified 2367 (0.20%) diagnosed with thrombosis. In a multivariable regression analysis, prematurity, male sex, congenital heart disease, sepsis, ventilator support, vasopressor receipt, central venous catheter, invasive procedures, and receipt of erythropoietin were associated with increased risk of thrombosis, while Black race and Hispanic ethnicity were associated with reduced risk. The majority of infants diagnosed with thrombosis (73%) received no anticoagulation, but anticoagulant use in infants with thrombosis was higher than those without (27% versus 0.2%, P < .001). Thrombosis in infants was associated with higher mortality (11% versus 2%, P < .001) and longer hospital stays (57 days, [interquartile range (IQR) 28--100] versus 10 days, [IQR 6--22], P < .001).\n\n\n\nIn the largest national study to date, we found that thrombosis in NICU patients is associated with prematurity, low birth weight, sepsis, and invasive procedures.",
"affiliations": "Duke University School of Medicine, Durham, NC, USA.;Duke University School of Medicine, Durham, NC, USA.;Department of Surgery, Duke University Medical Center, Durham, NC, USA.;Department of Surgery, Duke University Medical Center, Durham, NC, USA.;Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.;Division of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.;Mednax, Sunrise, FL, USA.;Division of Pediatric Surgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA.",
"authors": "Robinson|Victoria|V|;Achey|Meredith A|MA|0000-0003-4539-8422;Nag|Uttara P|UP|;Reed|Christopher R|CR|;Pahl|Kristy S|KS|;Greenberg|Rachel G|RG|;Clark|Reese H|RH|;Tracy|Elisabeth T|ET|0000-0003-3459-2772",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jth.15144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-7836",
"issue": "19(2)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "anticoagulants; critical care; infant; intensive care units; neonatal; premature; thrombosis",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D007902:Length of Stay; D008297:Male; D012189:Retrospective Studies; D013927:Thrombosis",
"nlm_unique_id": "101170508",
"other_id": null,
"pages": "400-407",
"pmc": null,
"pmid": "33075167",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thrombosis in infants in the neonatal intensive care unit: Analysis of a large national database.",
"title_normalized": "thrombosis in infants in the neonatal intensive care unit analysis of a large national database"
} | [
{
"companynumb": "US-AMGEN-USASP2020204510",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ERYTHROPOIETIN"
},
"drugadditional": null,
... |
{
"abstract": "Leflunomide is an immunosuppressant drug used in rheumatoid arthritis and psoriatic arthritis. This product may cause rare but serious interstitial lung disease that appear at the beginning of treatment. This is why leflunomide should be prescribed and monitored in hospital. We present the case of a 71 years old woman who presented a pleuro-pericarditis with an increase of CA 125 during a treatment with leflunomide. This is the second case reported in the literature. The outcome was favorable after discontinuation of leflunomide.",
"affiliations": "Service de pneumologie, hôpital Clavary, BP 53149, 06135 Grasse cedex, France; Centre de soins de suite et de rééducation « La Maison du Mineur », 577, avenue Henri-Giraud, 06141 Vence, France. Electronic address: f.vandenbos@maisondumineur.com.;Service de pneumologie, hôpital Clavary, BP 53149, 06135 Grasse cedex, France.;Service de pneumologie, hôpital Clavary, BP 53149, 06135 Grasse cedex, France.;Service de gérontologie et de rhumatologie, hôpital Clavary, BP 53149, 06135 Grasse cedex, France.",
"authors": "Vandenbos|F|F|;Figueredo|M|M|;Tarhini|A|A|;Ribière|J|J|",
"chemical_list": "D018501:Antirheumatic Agents; D007555:Isoxazoles; D000077339:Leflunomide",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0761-8417",
"issue": "71(1)",
"journal": "Revue de pneumologie clinique",
"keywords": "Leflunomide; Léflunomide; Pericarditis; Pleural effusion; Pleurésie; Psoriatic arthritis; Péricardite; Rhumatisme psoriasique",
"medline_ta": "Rev Pneumol Clin",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007555:Isoxazoles; D000077339:Leflunomide; D010493:Pericarditis; D010998:Pleurisy",
"nlm_unique_id": "8406312",
"other_id": null,
"pages": "57-9",
"pmc": null,
"pmid": "25457216",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pleuro-pericarditis developed under a leflunomide therapy.",
"title_normalized": "pleuro pericarditis developed under a leflunomide therapy"
} | [
{
"companynumb": "PHHY2015FR029609",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Routine HIV-1 antiretroviral drug resistance testing for patients failing NNRTI-based regimens is not recommended in resource-limited settings. Therefore, surveys are required to monitor resistance profiles in patients failing ART.\n\n\n\nA cross-sectional survey was conducted amongst patients failing NNRTI-based regimens in the public sector throughout South Africa. Virological failure was defined as two consecutive HIV-1 viral load results >1000 RNA copies/mL. Pol sequences were obtained using RT-PCR and Sanger sequencing and submitted to Stanford HIVdb v7.0.1.\n\n\n\nA total of 788 sequences were available for analysis. Most patients failed a tenofovir-based NRTI backbone (74.4%) in combination with efavirenz (82.1%) after median treatment duration of 36 months. K103N (48.9%) and V106M (34.9%) were the most common NNRTI mutations. Only one-third of patients retained full susceptibility to second-generation NNRTIs such as etravirine (36.5%) and rilpivirine (27.3%). After M184V/I (82.7%), K65R was the most common NRTI mutation (45.8%). The prevalence of K65R increased to 57.5% in patients failing a tenofovir regimen without prior stavudine exposure. Cross-resistance to NRTIs was often observed, but did not seem to affect the predicted activity of zidovudine as 82.9% of patients remained fully susceptible to this drug.\n\n\n\nThe introduction of tenofovir-based first-line regimens has dramatically increased the prevalence of K65R mutations in the HIV-1-infected South African population. However, most patients failing tenofovir-based regimens remained fully susceptible to zidovudine. Based on these data, there is currently no need to change either the recommended first- or second-line ART regimens in South Africa.",
"affiliations": "Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa kim.steegen@nhls.ac.za.;National Health Laboratory Service, Johannesburg, South Africa.;Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa.;National Health Laboratory Service, Johannesburg, South Africa.;National Health Laboratory Service, Johannesburg, South Africa.;Department of Internal Medicine, Klerksdorp Tshepong Hospital Complex, Klerksdorp, South Africa.;Center for Global Health and Development, Boston University School of Public Health, Boston, MA, USA.;Right to Care, Johannesburg, South Africa.;Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa.;Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, South Africa.",
"authors": "Steegen|K|K|;Bronze|M|M|;Papathanasopoulos|M A|MA|;van Zyl|G|G|;Goedhals|D|D|;Variava|E|E|;MacLeod|W|W|;Sanne|I|I|;Stevens|W S|WS|;Carmona|S|S|",
"chemical_list": "D044966:Anti-Retroviral Agents; D054302:pol Gene Products, Human Immunodeficiency Virus",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkw358",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "72(1)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044966:Anti-Retroviral Agents; D003430:Cross-Sectional Studies; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013019:South Africa; D017211:Treatment Failure; D019562:Viral Load; D055815:Young Adult; D054302:pol Gene Products, Human Immunodeficiency Virus",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "210-219",
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"pmid": "27659733",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "HIV-1 antiretroviral drug resistance patterns in patients failing NNRTI-based treatment: results from a national survey in South Africa.",
"title_normalized": "hiv 1 antiretroviral drug resistance patterns in patients failing nnrti based treatment results from a national survey in south africa"
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"abstract": "To investigate the uptake, safety and efficacy of docetaxel chemotherapy in hormone-naïve metastatic prostate cancer (mPC) in the first year of use outside of a clinical trial.\n\n\n\nPatients in the West of Scotland Cancer Network with newly diagnosed mPC were identified from the regional multidisciplinary team meetings and their treatment details were collected from electronic patient records. The rate of febrile neutropenia, hospitalisations, time to progression, and overall survival were compared between those patients who received docetaxel and androgen-deprivation therapy (ADT), or ADT alone using survival analysis.\n\n\n\nOf the 270 eligible patients, 103 received docetaxel (38.1%). 35 patients (34%) were hospitalised and there were 17 episodes of febrile neutropenia (16.5%). Two patients (1.9%) died within 30 days of chemotherapy. Patients who received ADT alone had an increased risk of progression (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.27-3.25; log-rank test, P = 0.002) and had an increased risk of death (HR 5.88, 95% CI: 2.52-13.72; log-rank test, P = 0.001) compared to the docetaxel group. The risk of febrile neutropenia was nine-times greater if chemotherapy was started within 3 weeks of ADT initiation (95% CI: 1.22-77.72; P = 0.032).\n\n\n\nDocetaxel chemotherapy in hormone-naïve mPC has significant toxicities, but has a similar effect on time to progression and overall survival as seen in randomised trials. Chemotherapy should be started at ≥3 weeks after ADT.",
"affiliations": "The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;University Hospital Ayr, Ayr, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.;The Beatson West of Scotland Cancer Centre, Glasgow, UK.",
"authors": "Rulach|Robert J|RJ|0000-0002-3148-0647;McKay|Stephen|S|;Neilson|Sam|S|;White|Lillian|L|;Wallace|Jan|J|;Carruthers|Ross|R|;Lamb|Carolynn|C|;Cascales|Almudena|A|;Marashi|Husam|H|;Glen|Hilary|H|;Venugopal|Balaji|B|;Sadoyze|Azmat|A|;Sidek|Norma|N|;Russell|J Martin|JM|;Alhasso|Abdulla|A|;Dodds|David|D|;Laskey|Jennifer|J|;Jones|Robert J|RJ|;MacLeod|Nicholas|N|",
"chemical_list": "D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D007987:Gonadotropin-Releasing Hormone; D011239:Prednisolone; D017430:Prostate-Specific Antigen",
"country": "England",
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"doi": "10.1111/bju.14025",
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"issn_linking": "1464-4096",
"issue": "121(2)",
"journal": "BJU international",
"keywords": "#PCSM; #ProstateCancer; docetaxel; hormone-naïve; metastatic; real world",
"medline_ta": "BJU Int",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D064147:Febrile Neutropenia; D007987:Gonadotropin-Releasing Hormone; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011239:Prednisolone; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D015996:Survival Rate; D043823:Taxoids; D013997:Time Factors",
"nlm_unique_id": "100886721",
"other_id": null,
"pages": "268-274",
"pmc": null,
"pmid": "28940952",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer.",
"title_normalized": "real world uptake safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer"
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"abstract": "We report a case of acute onset of ulcerative colitis (UC) during chemoradiotherapy in a patient with anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma. A 46-year-old male patient with an abnormal chest shadow was referred to our hospital. He was diagnosed with lung adenocarcinoma, clinical stage T1aN3M0 and stage IIIB. Concurrent chemoradiotherapy was selected for his initial therapy. After two cycles of cisplatin and vinorelbine administration, he experienced persistent diarrhoea and anorexia. Findings of the colonoscopy revealed a pancolitis type of UC. After discontinuation of chemotherapy, oral administration of mesalazine was initiated. The development of UC during chemotherapy is very rare and only a few case reports have been published. Although adverse events are rare, it is very important to assess the colitis precisely by performing a colonoscopy when protracted abdominal pain is experienced by the patient, along with diarrhoea or bloody stool during chemotherapy.",
"affiliations": "Division of Respiratory Medicine National Hospital Organization Kyoto Medical Center Kyoto Japan.;Division of Gastroenterology National Hospital Organization Kyoto Medical Center Kyoto Japan.;Division of Clinical Pathology National Hospital Organization Kyoto Medical Center Kyoto Japan.;Division of Radiation Oncology National Hospital Organization Kyoto Medical Center Kyoto Japan.;Division of Respiratory Medicine National Hospital Organization Kyoto Medical Center Kyoto Japan.",
"authors": "Fujita|Kohei|K|0000-0002-6902-9085;Mizumoto|Yoshinori|Y|;Moriyoshi|Koki|K|;Araki|Norio|N|;Mio|Tadashi|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/rcr2.288",
"fulltext": "\n==== Front\nRespirol Case RepRespirol Case Rep10.1002/(ISSN)2051-3380RCR2Respirology Case Reports2051-3380John Wiley & Sons, Ltd Chichester, UK 10.1002/rcr2.288RCR2288Case ReportCase ReportsAcute onset of ulcerative colitis during chemoradiotherapy for anaplastic lymphoma kinase‐positive lung adenocarcinoma Ulcerative colitis during chemoradiotherapyK. Fujita et al.Fujita Kohei http://orcid.org/0000-0002-6902-9085kfujita-oka@umin.ac.jp \n1\nMizumoto Yoshinori \n2\nMoriyoshi Koki \n3\nAraki Norio \n4\nMio Tadashi \n1\n\n1 \nDivision of Respiratory Medicine\nNational Hospital Organization Kyoto Medical Center\nKyoto\nJapan\n\n2 \nDivision of Gastroenterology\nNational Hospital Organization Kyoto Medical Center\nKyoto\nJapan\n\n3 \nDivision of Clinical Pathology\nNational Hospital Organization Kyoto Medical Center\nKyoto\nJapan\n\n4 \nDivision of Radiation Oncology\nNational Hospital Organization Kyoto Medical Center\nKyoto\nJapan\n* Correspondence\n\nKohei Fujita, Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, 1‐1 Fukakusa‐Mukaihata‐Cho, Fushimi‐Ku, Kyoto, 612‐8555, Japan. E‐mail: kfujita-oka@umin.ac.jp\n22 12 2017 2 2018 6 2 10.1002/rcr2.v6.2e0028802 11 2017 08 11 2017 18 11 2017 © 2017 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 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.We report a case of acute onset of ulcerative colitis (UC) during chemoradiotherapy in a patient with anaplastic lymphoma kinase (ALK)‐positive lung adenocarcinoma. A 46‐year‐old male patient with an abnormal chest shadow was referred to our hospital. He was diagnosed with lung adenocarcinoma, clinical stage T1aN3M0 and stage IIIB. Concurrent chemoradiotherapy was selected for his initial therapy. After two cycles of cisplatin and vinorelbine administration, he experienced persistent diarrhoea and anorexia. Findings of the colonoscopy revealed a pancolitis type of UC. After discontinuation of chemotherapy, oral administration of mesalazine was initiated. The development of UC during chemotherapy is very rare and only a few case reports have been published. Although adverse events are rare, it is very important to assess the colitis precisely by performing a colonoscopy when protracted abdominal pain is experienced by the patient, along with diarrhoea or bloody stool during chemotherapy.\n\nChemoradiotherapychemotherapylung adenocarcinomanon‐small cell lung cancerulcerative colitis source-schema-version-number2.0component-idrcr2288cover-dateFebruary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:07.01.2018\n\n\nFujita , K. \n, \nMizumoto , Y. \n, \nMoriyoshi , K. \n, \nAraki , N. \n and \nMio , T. \n (2018 ) Acute onset of ulcerative colitis during chemoradiotherapy for anaplastic lymphoma kinase‐positive lung adenocarcinoma . Respirology Case Reports , 6 (2 ), e00288. doi: 10.1002/rcr2.288.\n\n\nAssociate Editor: James Ho\n==== Body\nIntroduction\nCytotoxic chemotherapy can cause various adverse effects involving the mucosa of the gastrointestinal tract. Ischaemic and pseudomembranous enterocolitis are well‐known cytotoxic drug‐induced enterocolitis 1, 2. Although drug‐induced enterocolitis is a common phenomenon, ulcerative colitis (UC) is a very rare condition and only a few cases have been reported previously 3, 4.\n\nHere, we discuss a case of acute onset UC during chemoradiotherapy in a patient with anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer.\n\nCase Report\nA 46‐year‐old male patient with an abnormal chest shadow was referred to our hospital. He had no obvious history of gastrointestinal diseases. Positron emission tomography‐computed tomography (PET‐CT) studies revealed a high uptake of fluorodeoxyglucose (FDG) in the small nodules of the right upper lobe, and bilateral mediastinal and right hilar lymphadenopathy (Fig. 1A, B). Specimens obtained by endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS TBNA) of the mediastinal lymph node showed adenocarcinoma harbouring the ALK fusion gene (Fig. 1C–E). The clinical stage of his carcinoma was T1aN3M0 and stage IIIB. Concurrent chemoradiotherapy was selected for his initial therapy. After two cycles of cisplatin and vinorelbine administration, he experienced persistent diarrhoea and anorexia. Supportive care using digestive drugs had poor efficacy for treating his symptoms. Results were negative for the presence of the Clostridium difficile (C. difficile) toxin and culture. Before consolidation chemotherapy, he underwent a complete colonoscopy, which revealed oedematous thickening of the bowel wall with ulceration and erythema (Fig. 2A–D). Findings of the colonoscopy suggested a pancolitis type of UC. Histopathology of the mucosa specimens showed distortion of the crypts with diffuse infiltration of inflammatory cells (Fig. 2E). He was diagnosed clinically and pathologically with UC.\n\nFigure 1 (A, B) Positron emission tomography‐computed tomography scan imaging showed high uptake of fluorodeoxyglucose (FDG) in the small nodules of the right upper lobe, bilateral mediastinal and right hilar lymphadenopathy, and absence of FDG uptake in the bowels. (C–E) Specimens taken by endobronchial ultrasound‐guided transbronchial needle aspiration showed the aggregation of atypical oval cell with abundant chromatin with positive‐staining cam 5.2 (C, 200×) and napsin A (D, 200×), suggesting adenocarcinoma. Tumour tissue also showed positive staining of anaplastic lymphoma kinase immunohistochemistry (E, 200×).\n\nFigure 2 (A–D) Colonoscopy showed diffuse mucosal oedema, redness and petechial haemorrhagic lesions from hepatic flexure to rectum (200×, A, hepatic flexure; B, splenic flexure; C, sigmoid colon; D, rectum). (E) Biopsy specimens taken by colonoscopy revealed distortion of the architecture of colonic crypts including inflammatory cells (200×). Tissue also included crypt abscess (yellow circle).\n\nAlthough radiotherapy was continued, concurrent chemotherapy was discontinued after he was diagnosed with UC. The oral administration of mesalazine was initiated. After 2 months of administration of mesalazine, his digestive symptoms remitted and a second colonoscopy revealed that his UC improved. At the time of UC remission, his tumour slightly increased in size. Because his tumour harboured the ALK fusion gene, we administered an oral ALK inhibitor, alectinib as a second line therapy. We started with 300 mg/day of alectinib for the first 2 weeks and then dosed up to 600 mg/day. Administration of 600 mg/day has been effective in maintaining a response after the tumour recurrence.\n\nDiscussion\nChemotherapy‐induced colitis is common with use of cytotoxic anticancer agents including fluoropyrimidines, irinotecan, methotrexate, docetaxel, vinorelbine and cisplatin 1, 2. Vinorelbine is also known to have venous toxicity and often causes cutaneous ulcers. Although various mechanisms are proposed for chemotherapy‐induced colitis, including increased intestinal permeability, early onset anticholinergic effects and mesenteric vascular insufficiency, precise mechanisms are different for every drug.\n\nThe colitis in patients receiving chemotherapeutic agents is usually divided into three types including: neutropenic colitis, ischaemic colitis and C. difficile‐associated colitis 2. In our case, there was no evidence of compromised neutropenic status during chemoradiotherapy. After diarrhoea occurred, we confirmed the negative results of the C. difficile toxin and culture. A high possibility of ischaemic colitis remained. We also obtained typical images of UC during the colonoscopy and the pathology of the intestinal mucosa indicated evidence of UC. UC as an adverse effect of cytotoxic chemotherapy is a very rare condition. Previously, only two case reports have demonstrated UC during cytotoxic chemotherapy. One case was a patient with lung cancer whose UC was induced by bevacizumab therapy and the other case was a patient with breast cancer whose UC was induced by the therapy of a combination of capecitabine and trastuzumab 3, 4.\n\nAlthough precise mechanisms underlying the causes of UC are unknown, some mechanisms were speculated. In patients receiving bevacizumab, anti‐angiogenesis activity of bevacizumab may have played an important role 4. Previously, therapy with a combination of docetaxel and vinorelbine for breast cancer was associated with exacerbation of intestinal toxicity 1. In the present case, we also used cisplatin in addition to vinorelbine, and therefore, additive toxicity may have been induced. Intestinal mucosa vasculopathy associated with vinorelbine might affect the development of UC.\n\nAlthough our patient did not have a colonoscopy before concurrent chemoradiotherapy, UC likely did not exist before the treatment for the following reasons. First, our patient had no history of abdominal pains, diarrhoea or bloody stool. A faecal occult blood test was also negative before the treatment. Because the UC of this patient was a pancolitis type, the patient was unlikely to remain free of symptoms. Second, baseline PET‐CT apparently showed no FDG uptake in bowel, which can support the notion that there was no pre‐existing UC. Third, previous reports suggested that cytotoxic chemotherapy can remit activity of UC 5. If UC existed before the diagnosis of lung cancer, chemotherapy would have inhibited the symptoms.\n\nIn conclusion, we encountered a rare case of UC during chemoradiotherapy. Although this rare complication occurred in a patient with a rare type of lung cancer with ALK translocation, it is very important to assess the patient to determine the type of colitis by colonoscopy when the patient experiences protracted abdominal pain, diarrhoea or bloody stool during chemotherapy.\n\nAcknowledgments\nWe thank Drs. Osamu Kanai, Misato Okamura and Koichi Nakatani for their helpful support in patient care.\n\nDisclosure Statement\nAppropriate written informed consent was obtained for publication of this case report and accompanying images.\n==== Refs\nReferences\n1 \n\nIbrahim \nNK \n, \nSahin \nAA \n, \nDubrow \nRA \n, et al. 2000 \nColitis associated with docetaxel‐based chemotherapy in patients with metastatic breast cancer . Lancet \n355 (9200 ):281 –283 .10675076 \n2 \n\nZeino \nZ \n, \nSisson \nG \n, and \nBjarnason \nI \n. 2010 \nAdverse effects of drugs on small intestine and colon . Best Pract. Res. Clin. Gastroenterol. \n24 (2 ):133 –141 .20227027 \n3 \n\nKatada \nY \n, \nNakano \nM \n, \nIshii \nY \n, et al. 2011 \nA case of ulcerative colitis associated with chemotherapy for breast cancer . Prog. Dig. Endosc. \n79 (2 ):96 –97 [In Japanese, English abstract available].\n4 \n\nTanaka \nM \n, \nIshii \nH \n, \nAzuma \nK \n, et al. 2015 \nUlcerative colitis in a patient with non‐small‐cell lung cancer receiving bevacizumab . Invest. New Drugs \n33 (5, 5 ):1133 .26280212 \n5 \n\nAxelrad \nJE \n, \nFowler \nSA \n, \nFriedman \nS \n, et al. 2012 \nEffects of cancer treatment on inflammatory bowel disease remission and reactivation . Clin. Gastroenterol. Hepatol. \n10 (9 ):1021 –1027.e1 .22732273\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "6(2)",
"journal": "Respirology case reports",
"keywords": "Chemoradiotherapy; chemotherapy; lung adenocarcinoma; non‐small cell lung cancer; ulcerative colitis",
"medline_ta": "Respirol Case Rep",
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"nlm_unique_id": "101631052",
"other_id": null,
"pages": "e00288",
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"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": "22732273;20227027;10675076;29321932;26280212",
"title": "Acute onset of ulcerative colitis during chemoradiotherapy for anaplastic lymphoma kinase-positive lung adenocarcinoma.",
"title_normalized": "acute onset of ulcerative colitis during chemoradiotherapy for anaplastic lymphoma kinase positive lung adenocarcinoma"
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"abstract": "Although crizotinib shows marked antitumor activity in anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancer (NSCLC) patients, all treated patients ultimately develop resistance to this drug. Isolated central nervous system failure without progression at extracranial sites is a common progression pattern in ALK rearrangement-positive NSCLC patients treated with crizotinib. Here, we report the success of crizotinib combined with whole-brain radiotherapy in an ALK rearrangement-positive NSCLC patient who developed leptomeningeal carcinomatosis and progression of multiple brain metastases. Additionally, we focused on the mechanism involved by examining the plasma and cerebrospinal fluid concentrations of crizotinib in the present case.",
"affiliations": "Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Oncology, Pharmaceutical Care and Sciences, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.",
"authors": "Okawa|Sachi|S|;Shibayama|Takuo|T|;Shimonishi|Atsushi|A|;Nishimura|Jun|J|;Ozeki|Taichi|T|;Takada|Kenji|K|;Kayatani|Hiroe|H|;Minami|Daisuke|D|;Sato|Ken|K|;Fujiwara|Keiichi|K|;Yonei|Toshiro|T|;Sato|Toshio|T|;Suno|Manabu|M|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000492150cro-0011-0777Case ReportSuccess of Crizotinib Combined with Whole-Brain Radiotherapy for Brain Metastases in a Patient with Anaplastic Lymphoma Kinase Rearrangement-Positive Non-Small-Cell Lung Cancer Okawa Sachi aShibayama Takuo a*Shimonishi Atsushi aNishimura Jun aOzeki Taichi aTakada Kenji aKayatani Hiroe aMinami Daisuke aSato Ken aFujiwara Keiichi aYonei Toshiro aSato Toshio aSuno Manabu baDepartment of Respiratory Medicine, National Hospital Organization Okayama Medical Center, Okayama, JapanbDepartment of Oncology, Pharmaceutical Care and Sciences, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan*Takuo Shibayama, Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center, 1711-1 Tamasu Kita-ku, Okayama 701-1192 (Japan), E-Mail shibayamat@okayamamc.jpSep-Dec 2018 29 11 2018 29 11 2018 11 3 777 783 17 7 2018 17 7 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Although crizotinib shows marked antitumor activity in anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancer (NSCLC) patients, all treated patients ultimately develop resistance to this drug. Isolated central nervous system failure without progression at extracranial sites is a common progression pattern in ALK rearrangement-positive NSCLC patients treated with crizotinib. Here, we report the success of crizotinib combined with whole-brain radiotherapy in an ALK rearrangement-positive NSCLC patient who developed leptomeningeal carcinomatosis and progression of multiple brain metastases. Additionally, we focused on the mechanism involved by examining the plasma and cerebrospinal fluid concentrations of crizotinib in the present case.\n\nKeywords\nALK rearrangement-positive NSCLCLeptomeningeal carcinomatosisCentral nervous system failureCrizotinibWhole-brain radiotherapyBlood-brain barrier permeability\n==== Body\nIntroduction\nThe echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) oncogene fusion is present in 4–5% of non-small-cell lung cancers (NSCLCs) [1, 2]. Although crizotinib, an inhibitor of ALK tyrosine kinase, shows marked antitumor activity in ALK rearrangement-positive NSCLC patients, all treated patients ultimately develop resistance to this drug [3].\n\nIsolated central nervous system (CNS) failure, defined as a CNS relapse without progression at extracranial sites, is a common progression pattern, besides systemic progression, in ALK rearrangement-positive NSCLC patients treated with crizotinib [4]. Extracranial tumors are considered to remain sensitive to crizotinib in patients who develop isolated CNS failure, and the continuation of crizotinib treatment beyond CNS progression has been reported in ALK rearrangement-positive NSCLC patients in whom CNS metastasis was well controlled with radiotherapy [5]. Here, we report the success of crizotinib combined with whole-brain radiotherapy (WBRT), which was performed owing to nonapproval of alectinib or ceritinib in Japan at the time, in an ALK rearrangement-positive NSCLC patient who developed leptomeningeal carcinomatosis (LM) and progression of multiple brain metastases.\n\nCase Report\nA 60-year-old male never-smoker presented to our hospital with back pain. Chest radiography revealed a mass lesion in the left lower lobe of the lung with left pleural effusion (Fig. 1a). Computed tomography of the chest/abdomen showed mediastinal lymph node swelling, pulmonary lymphangitic carcinomatosis, and right adrenal metastasis (Fig. 1b). Magnetic resonance imaging (MRI) revealed multiple, small, diffuse asymptomatic metastases of the brain (Fig. 1c), and bone scintigraphy showed multiple bone metastases. Transbronchial biopsy and cytological examination of the pleural effusion indicated adenocarcinoma of the lung, and he was finally diagnosed with adenocarcinoma of the lung (clinical stage IV, T4N2M1b) in May 2013.\n\nAlthough chemotherapy with docetaxel and cisplatin was administered, the disease progressed. As a biopsy specimen revealed EML4-ALK rearrangement on both fluorescence in situ hybridization and immunohistochemistry during the first-line chemotherapy, he was administered crizotinib (250 mg twice daily) in July 2013. However, it was discontinued for a short time owing to grade 3 acute hepatic dysfunction and was later restarted at a dose of 200 mg twice daily. Two months after the initiation of crizotinib, the adrenal and brain metastases as well as the pulmonary mass, lymphangitic carcinomatosis, and pleural effusion regressed markedly.\n\nThree months after regression, he complained of severe headache. MRI of the brain revealed progression of brain metastases (Fig. 2a), and cerebrospinal fluid (CSF) cytology from a lumbar puncture was positive for malignant cells. Isolated central nervous system failure was observed without progression at extracranial sites. He received WBRT (30 Gy) and continued to receive crizotinib, but the dose was increased to 250 mg twice daily after the initiation of WBRT. Three weeks later, the metastatic brain tumors regressed (Fig. 2b), and CSF cytology was negative for malignant cells (Fig. 2). His severe headache was well controlled, and, therefore, he was followed up at the outpatient clinic.\n\nHis plasma and CSF were examined thrice at 1-week intervals to evaluate the effect of crizotinib combined with WBRT. Plasma was collected at around 5 h after crizotinib administration, according to a previous report [6]. The concentration of crizotinib was measured using a validated high-performance liquid chromatography with tandem mass spectrometry [7]. The crizotinib concentrations in the plasma and CSF were measured at 4 time points (1 before and 3 after the initiation of WBRT at 1-week intervals). The plasma concentrations of crizotinib were 136.6 ng/mL (0.31 μmol/L) before WBRT, and 133.4 ng/mL (0.30 μmol/L), 176.7 ng/mL (0.40 μmol/L), and 286.1 ng/mL (0.64 μmol/L) after the initiation of WBRT. Additionally, the CSF concentrations of crizotinib were lower than the quantification limit before WBRT and at 1 time point after the initiation of WBRT and were 6.2 ng/mL (0.014 μmol/L) and 6.3 ng/mL (0.014 μmol/L) at the remaining 2 time points, with a CSF-to-plasma ratio of 0.035 and 0.022 at the last 2 time points (Table 1).\n\nIsolated CNS failure was noted 6 months later. Although he received intrathecal methotrexate and cytarabine, followed by intravenous pemetrexed, the disease continued to progress, and 4 months after the second CNS failure, he died.\n\nDiscussion\nWe reported the success of crizotinib combined with WBRT in an ALK rearrangement-positive NSCLC patient who developed LM and progression of multiple brain metastases. Isolated CNS failure is a common progression pattern in ALK rearrangement-positive NSCLC patients treated with crizotinib [4]. Costa et al. [6] reported that the most likely reason for isolated CNS failure is incomplete penetration of the blood-brain barrier (BBB) by crizotinib. In their report, after completing 2 weeks of WBRT, crizotinib was restarted at a dose of 250 mg twice daily, and 2 weeks later, the plasma and CSF concentrations of crizotinib were found to be 237 ng/mL (0.53 μmol/L) and 0.616 ng/mL (0.0014 μmol/L), respectively, with a CSF-to-plasma ratio of 0.0026. The plasma concentration of crizotinib in our case was similar to the one in this previous report; however, the CSF-to-plasma ratio of 0.022 in our case was almost 10 times higher than that in this previous report. Additionally, in our case, crizotinib was effective not only for extracranial systemic control but also for LM, which is contrary to the finding in this previous case report.\n\nA previous study showed that fractionated brain irradiation increased the BBB permeability in a murine model, allowing transport across the BBB [8]. In our case, although the CSF concentration of crizotinib was lower than the quantification limit at 1 week after initiating WBRT, the concentration increased to 6.2 and 6.3 ng/mL at 2 and 3 weeks, respectively, after initiating WBRT, indicating that the transport of crizotinib across the BBB increased owing to destruction of the BBB by WBRT. Therefore, in our case, crizotinib continuation was effective for LM because the destruction of the BBB with WBRT resulted in a high concentration of crizotinib in the CSF.\n\nAlthough treatment approaches for LM are present, such as intrathecal or systemic chemotherapy and whole-brain irradiation, a standard treatment approach has not been established. Johung et al. [9] reported that patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (stereotactic radiosurgery and/or WBRT) and tyrosine kinase inhibitors have prolonged survival. On the other hand, there have been conflicting reports on the use of crizotinib for CNS metastasis [10, 11, 12], and the mechanism involved has not yet been fully understood. Therefore, the selection of a treatment approach for LM in ALK rearrangement-positive NCLSC patients with CNS metastasis is difficult.\n\nSince the second-generation ALK tyrosine kinase inhibitor alectinib was approved in 2014, high-dose alectinib has shown to be active against CNS failure after crizotinib treatment for NSCLCs [13]. According to recent findings, alectinib rather than crizotinib should be considered for ALK rearrangement-positive NCLSC patients with CNS metastasis. On the other hand, rearrangements of the c-ros oncogene 1, receptor tyrosine kinase (ROS1) gene, which has shown to be associated with favorable antitumor activity to crizotinib, are reported in 1–2% of lung adenocarcinomas. Zhang et al. [14] reported success in a case receiving crizotinib combined with palliative operation and radiation therapy for the treatment of ROS1-positive lung adenocarcinoma with symptomatic brain metastases. If crizotinib concentrations in the CSF can be monitored as in the present case, crizotinib combined with WBRT could be an optional strategy for ROS1-positive NCLSC patients with CNS metastasis. Although there are quite a few cases of ROS1-positive lung cancer, it is unclear why crizotinib can be effective against CNS metastasis. Therefore, further investigation is required to reveal the mechanisms involved.\n\nIn conclusion, we presented the successful treatment with crizotinib combined with WBRT in an ALK rearrangement-positive NSCLC patient who developed LM and progression of multiple brain metastases.\n\nStatement of Ethics\nAll procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\n\nDisclosure Statement\nAll authors declare that they have no conflicts of interest.\n\nAcknowledgment\nThe authors thank the patient for consenting to plasma and CSF sampling for research purposes as well as providing written informed consent for the publication of this case report.\n\nFig. 1 Radiographic findings on admission. Chest radiography (a), chest computed tomography (b), and contrast-enhanced brain magnetic resonance imaging (c) show a mass lesion in the left lower lobe of the lung with left pleural effusion, pulmonary lymphangitic carcinomatosis, and multiple brain metastases.\n\nFig. 2 Treatment schedule, cerebrospinal fluid (CSF) cytology, and magnetic resonance (MR) imaging findings. CFS cytology was negative for malignant cells at 3 weeks after crizotinib (250 mg twice daily) combined with whole-brain radiotherapy (WBRT; 30 Gy). a Brain MR image obtained before treatment shows a single brain metastatic lesion. b Brain MR image obtained 3 weeks after the initiation of WBRT shows a decrease in size of the metastatic lesion.\n\nTable 1 Crizotinib concentrations in the plasma and cerebrospinal fluid\n\n\tDate of collection\t\n\tOctober 8\tOctober 18\tOctober 25\tNovember 1\t\nPlasma concentration, ng/mL\t136.6\t133.4\t176.7\t286.1\t\nCerebrospinal fluid concentration, ng/mL\tND\tND\t006.2\t006.3\t\nND, not detected because the concentration was lower than the quantification limit.\n==== Refs\nReferences\n1 Soda M Choi YL Enomoto M Takada S Yamashita Y Ishikawa S Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer Nature 2007 8 448 (7153) 561 6 17625570 \n2 Takeuchi K Choi YL Soda M Inamura K Togashi Y Hatano S Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts Clin Cancer Res 2008 10 14 (20) 6618 24 18927303 \n3 Kwak EL Bang YJ Camidge DR Shaw AT Solomon B Maki RG Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer N Engl J Med 2010 10 363 (18) 1693 703 20979469 \n4 Camidge DR Bang YJ Kwak EL Iafrate AJ Varella-Garcia M Fox SB Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study Lancet Oncol 2012 10 13 (10) 1011 9 22954507 \n5 Takeda M Okamoto I Nakagawa K Clinical impact of continued crizotinib administration after isolated central nervous system progression in patients with lung cancer positive for ALK rearrangement J Thorac Oncol 2013 5 8 (5) 654 7 23584297 \n6 Costa DB Kobayashi S Pandya SS Yeo WL Shen Z Tan W CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib J Clin Oncol 2011 5 29 (15) e443 5 21422405 \n7 Yamazaki S Skaptason J Romero D Vekich S Jones HM Tan W Prediction of oral pharmacokinetics of cMet kinase inhibitors in humans: physiologically based pharmacokinetic model versus traditional one-compartment model Drug Metab Dispos 2011 3 39 (3) 383 93 21098644 \n8 Yuan H Gaber MW Boyd K Wilson CM Kiani MF Merchant TE Effects of fractionated radiation on the brain vasculature in a murine model: blood-brain barrier permeability, astrocyte proliferation, and ultrastructural changes Int J Radiat Oncol Biol Phys 2006 11 66 (3) 860 6 17011458 \n9 Johung KL Yeh N Desai NB Williams TM Lautenschlaeger T Arvold ND Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis J Clin Oncol 2016 1 34 (2) 123 9 26438117 \n10 Isozaki H Yasugi M Takigawa N Hotta K Ichihara E Taniguchi A A new human lung adenocarcinoma cell line harboring the EML4-ALK fusion gene Jpn J Clin Oncol 2014 10 44 (10) 963 8 25170107 \n11 Kinoshita Y Koga Y Sakamoto A Hidaka K Long-lasting response to crizotinib in brain metastases due to EML4-ALK-rearranged non-small-cell lung cancer BMJ Case Rep 2013 9 2013 sep10 1 bcr-2013-200867 \n12 Maillet D Martel-Lafay I Arpin D Pérol M Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement J Thorac Oncol 2013 4 8 (4) e30 1 23486270 \n13 Gadgeel SM Gandhi L Riely GJ Chiappori AA West HL Azada MC Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study Lancet Oncol 2014 9 15 (10) 1119 28 25153538 \n14 Zhang M Nie L Zhang J [Crizotinib Treatment Combined with Resection and Whole-brain Radiation Therapy in A ROS1 Rearranged Lung Adenocarcinoma with Brain Metastasis: Case Report and Literature Review] Zhongguo Fei Ai Za Zhi 2016 8 19 (8) 525 9 27561802\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "11(3)",
"journal": "Case reports in oncology",
"keywords": "ALK rearrangement-positive NSCLC; Blood-brain barrier permeability; Central nervous system failure; Crizotinib; Leptomeningeal carcinomatosis; Whole-brain radiotherapy",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "777-783",
"pmc": null,
"pmid": "30627092",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "17011458;17625570;18927303;20979469;21098644;21422405;22954507;23486270;23584297;24022905;25153538;25170107;26438117;27561802",
"title": "Success of Crizotinib Combined with Whole-Brain Radiotherapy for Brain Metastases in a Patient with Anaplastic Lymphoma Kinase Rearrangement-Positive Non-Small-Cell Lung Cancer.",
"title_normalized": "success of crizotinib combined with whole brain radiotherapy for brain metastases in a patient with anaplastic lymphoma kinase rearrangement positive non small cell lung cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2019029499",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "BEAM with BCNU is commonly used for conditioning treatment followed by autologous stem cell transplantation (ASCT). However, pulmonary toxicity and availability issues associated with BCNU prompted us to evaluate bendamustine-replacing BCNU (BeEAM). We analyzed 39 lymphoma patients receiving BeEAM conditioning with 200 mg/m2 bendamustine at days -7 and -6. The median duration until neutrophil recovery was 11 days, and 15 days for platelet recovery (>20 g/L). The most common grade 3/4 non-hematologic toxicities comprised mucosal side effects (27 pts.). Pulmonary toxicity was observed in one patient (2.5%), and one patient died of septic complications. The CR rate increased from 33% to 74% 100 days after ASCT. After a median follow-up of 18.5 months, progression and death each occurred in 11 patients (28%). Median progression-free and overall survival at 2 years were 69% and 72%. Our data suggest that BeEAM conditioning using bendamustine is safe and results in promising survival rates.",
"affiliations": "Department of Medical Oncology, University Hospital Bern, 3010, Berne, Switzerland.;Department of Medical Oncology, University Hospital Bern, 3010, Berne, Switzerland.;Department of Hematology, University Hospital Bern, Berne, Switzerland.;Department of Hematology, University Hospital Bern, Berne, Switzerland.;Department of Pediatric Hemato-Oncology, Inselspital, University Hospital Bern, Berne, Switzerland.;Institute of Pathology, University of Bern, Berne, Switzerland.;Department of Oncology, Kantonsspital, Lucerne, Switzerland.;Department of Oncology, Kantonsspital, Fribourg, Switzerland.;Department of Oncology, Kantonsspital, Solothurn, Switzerland.;Department of Oncology, Regionalspital, Thun, Switzerland.;Department of Medical Oncology, University Hospital Bern, 3010, Berne, Switzerland. thomas.pabst@insel.ch.",
"authors": "Gilli|Stefanie|S|;Novak|Urban|U|;Taleghani|Behrouz Mansouri|BM|;Baerlocher|Gabriela M|GM|;Leibundgut|Kurt|K|;Banz|Yara|Y|;Zander|Thilo|T|;Betticher|Daniel|D|;Egger|Thomas|T|;Rauch|Daniel|D|;Pabst|Thomas|T|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D000069461:Bendamustine Hydrochloride; D002330:Carmustine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-016-2900-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "96(3)",
"journal": "Annals of hematology",
"keywords": "Autologous; BCNU; BeEAM; Beam; Bendamustine; Chemotherapy; High dose; Lymphoma; Prognosis; Stem cell; Survival; Transplantation",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D000069461:Bendamustine Hydrochloride; D002330:Carmustine; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "421-429",
"pmc": null,
"pmid": "28011985",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "BeEAM conditioning with bendamustine-replacing BCNU before autologous transplantation is safe and effective in lymphoma patients.",
"title_normalized": "beeam conditioning with bendamustine replacing bcnu before autologous transplantation is safe and effective in lymphoma patients"
} | [
{
"companynumb": "CH-ACCORD-047090",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Essentials Risk factors of bleeding in adult immune thrombocytopenia are not known. This multicenter study assessed risk factors of bleeding at immune thrombocytopenia onset. Platelet count thresholds associated with bleeding were < 20 × 109 L-1 and < 10 × 109 L-1 . Exposure to anticoagulants was a major risk factor of severe bleeding.\n\n\n\nBackground The aim of this cross-sectional study was to assess risk factors for bleeding in immune thrombocytopenia (ITP) adults, including the determination of platelet count thresholds. Methods We selected all newly diagnosed ITP adults included in the Cytopénies Auto-immunes Registre Midi-PyrénéEN (CARMEN) register and at the French referral center for autoimmune cytopenias. The frequencies of any bleeding, mucosal bleeding and severe bleeding (gastrointestinal, intracranial, or macroscopic hematuria) at ITP onset were assessed. Platelet count thresholds were assessed by the use of receiver operating characteristic curves. All potential risk factors were included in logistic regression models. Results Among the 302 patients, the frequencies of any, mucosal and severe bleeding were 57.9%, 30.1%, and 6.6%, respectively. The best discriminant threshold of platelet count for any bleeding was 20 × 109 L-1 . In multivariate analysis, factors associated with any bleeding were platelet count (< 10 × 109 L-1 versus ≥ 20 × 109 L-1 , odds ratio [OR] 48.2, 95% confidence interval [CI] 20.0-116.3; between 10 × 109 L-1 and 19 × 109 L-1 versus ≥ 20 × 109 L-1 , OR 5.2, 95% CI 2.3-11.6), female sex (OR 2.6, 95% CI 1.3-5.0), and exposure to non-steroidal anti-inflammatory drugs (NSAIDs) (OR 4.8, 95% CI 1.1-20.7). A low platelet count was also the main risk factor for mucosal bleeding. Exposure to anticoagulant drugs was associated with severe bleeding (OR 4.3, 95% CI 1.3-14.1). Conclusions Platelet counts of < 20 × 109 L-1 and < 10 × 109 L-1 were thresholds for major increased risks of any and mucosal bleeding. Platelet count, female sex and exposure to NSAIDs should be considered for assessment of the risk of any bleeding. Exposure to anticoagulant drugs was a major risk factor for severe bleeding.",
"affiliations": "Service de Médecine Interne, Salle Le Tallec, Centre Hospitalier Universitaire de Toulouse-Purpan, Toulouse, France.;Service de Médecine Interne, CHU Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Centre de Référence des Cytopénies Auto-Immunes de l'adulte, Université Paris-Est-Créteil, Créteil, France.;Centre d'Investigation Clinique 1436, Axe Pharmacoépidémiologie, Centre Hospitalier Universitaire de Toulouse-Purpan, Toulouse, France.;Service de Médecine Interne, CHU Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Centre de Référence des Cytopénies Auto-Immunes de l'adulte, Université Paris-Est-Créteil, Créteil, France.;Service de Médecine Interne, Institut Universitaire du Cancer de Toulouse - Oncopôle, Toulouse, France.;Centre d'Investigation Clinique 1436, Axe Pharmacoépidémiologie, Centre Hospitalier Universitaire de Toulouse-Purpan, Toulouse, France.;Inserm U1048 (I2MC), CHU de Toulouse and Université Toulouse III, Toulouse, France.;Service de Médecine Interne, Institut Universitaire du Cancer de Toulouse - Oncopôle, Toulouse, France.;Service de Médecine Interne, CHU Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Centre de Référence des Cytopénies Auto-Immunes de l'adulte, Université Paris-Est-Créteil, Créteil, France.;Service de Médecine Interne, CHU Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Centre de Référence des Cytopénies Auto-Immunes de l'adulte, Université Paris-Est-Créteil, Créteil, France.;Service de Médecine Interne, Institut Universitaire du Cancer de Toulouse - Oncopôle, Toulouse, France.;Service de Médecine Interne, Salle Le Tallec, Centre Hospitalier Universitaire de Toulouse-Purpan, Toulouse, France.",
"authors": "Piel-Julian|M-L|ML|;Mahévas|M|M|;Germain|J|J|;Languille|L|L|;Comont|T|T|;Lapeyre-Mestre|M|M|;Payrastre|B|B|;Beyne-Rauzy|O|O|;Michel|M|M|;Godeau|B|B|;Adoue|D|D|;Moulis|G|G|0000-0001-9953-4640;|||",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D017367:Serotonin Uptake Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1111/jth.14227",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-7836",
"issue": "16(9)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "epidemiology; hemorrhage; idiopathic thrombocytopenic purpura; platelet count; risk factors",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D019540:Area Under Curve; D015897:Comorbidity; D003430:Cross-Sectional Studies; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D012372:ROC Curve; D012307:Risk Factors; D017367:Serotonin Uptake Inhibitors; D012720:Severity of Illness Index",
"nlm_unique_id": "101170508",
"other_id": null,
"pages": "1830-1842",
"pmc": null,
"pmid": "29978544",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults.",
"title_normalized": "risk factors for bleeding including platelet count threshold in newly diagnosed immune thrombocytopenia adults"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1031686",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDespite not being licensed for the treatment of infantile hemangiomas (IH) in infants younger than 5 weeks or older than 5 months, propranolol is often used in these age groups to prevent or to treat potentially severe complications. The objective of the present study was to review the experience of 8 Italian pediatric and dermatologic centers regarding propranolol treatment for IH started before 5 weeks or after 5 months of age.\n\n\nMETHODS\nWe retrospectively reviewed the records of patients followed up for IH, on propranolol treatment started before 5 weeks or after 5 months of age, and collected information on sociodemographic data, treatment indications, IH involution, IH relapse, and treatment side effects.\n\n\nRESULTS\nA total of 343 patients were enrolled; 15 were started on propranolol before 5 weeks (group 1), 328 were started after 5 months of age (group 2). The most frequent indications were permanent aesthetical disfigurement (91.8%) and function threatening complications (42.6%). In most cases, the treatment was effective. The involution was partial in 67.7% of patients. In 11.8% of cases a relapse was observed. No relapse was observed in group 1. Treatment complications were reported in 15.8% of children, most frequently sleep disorders (6.6%), followed by irritability (5.1%) and diarrhea (2.2%). Only a case of mild constipation was observed in group 1.\n\n\nCONCLUSIONS\nThe safety and effectiveness profile of propranolol in infants younger than 5 weeks or older than 5 months may be acceptable. Taking in account propranolol's potential in preventing severe complications, further studies should assess the acceptability of propranolol treatment, especially in the <5-week age group .",
"affiliations": "Pediatric Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.;Multifactorial and Complex Disease Research Area, Bambino Gesù Children's Hospital IRCCS, Viale Baldelli 41, 00146, Rome, Italy. f.gesualdo@gmail.com.;Pediatric Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.;Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy.;Angioma Center, Cardiovascular Department, Gaslini Children's Research Institute, Genoa, Italy.;Dermatology Clinic, Parma University Hospital, Parma, Italy.;Division of Dermatology, Department of of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.;Pediatric Cardiology Unit, Anna Meyer Children's Hospital, Florence, Italy.;Pediatric Cardiology Unit, Anna Meyer Children's Hospital, Florence, Italy.;Pediatric Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.;Pediatric Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.;Pediatric Emergency Department, Ospedale dell'Angelo Ulss12, Venice, Italy.;Angioma Center, Cardiovascular Department, Gaslini Children's Research Institute, Genoa, Italy.",
"authors": "El Hachem|Maya|M|;Gesualdo|Francesco|F|http://orcid.org/0000-0002-9087-4398;Diociaiuti|Andrea|A|;Berti|Irene|I|;Vercellino|Nadia|N|;Boccaletti|Valeria|V|;Neri|Iria|I|;Porcedda|Giulio|G|;Greco|Antonella|A|;Carnevale|Claudia|C|;Oranges|Teresa|T|;Cutrone|Mario|M|;Dalmonte|Pietro|P|",
"chemical_list": "D011433:Propranolol",
"country": "England",
"delete": false,
"doi": "10.1186/s13052-017-0357-9",
"fulltext": "\n==== Front\nItal J PediatrItal J PediatrItalian Journal of Pediatrics1824-7288BioMed Central London 35710.1186/s13052-017-0357-9ResearchSafety and effectiveness of oral propranolol for infantile hemangiomas started before 5 weeks and after 5 months of age: an Italian multicenter experience El Hachem Maya may.elhachem@opbg.net 1http://orcid.org/0000-0002-9087-4398Gesualdo Francesco +39 0668592852f.gesualdo@gmail.com 2Diociaiuti Andrea andrea.diociaiuti@opbg.net 1Berti Irene irene.berti@burlo.trieste.it 3Vercellino Nadia NadiaVercellino@gaslini.org 4Boccaletti Valeria valeria.boccaletti@gmail.com 5Neri Iria iria.neri@aosp.bo.it 6Porcedda Giulio giulio.porcedda@meyer.it 7Greco Antonella antonella.greco@meyer.it 7Carnevale Claudia claudia.carnevale@opbg.net 1Oranges Teresa teresa.oranges@gmail.com 1Cutrone Mario mario.cutrone@ulss12.ve.it 8Dalmonte Pietro pietro.dalmonte@fastwebnet.it 41 0000 0001 0727 6809grid.414125.7Pediatric Dermatology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy 2 0000 0001 0727 6809grid.414125.7Multifactorial and Complex Disease Research Area, Bambino Gesù Children’s Hospital IRCCS, Viale Baldelli 41, 00146 Rome, Italy 3 0000 0004 1760 7415grid.418712.9Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste, Italy 4 Angioma Center, Cardiovascular Department, Gaslini Children’s Research Institute, Genoa, Italy 5 grid.411482.aDermatology Clinic, Parma University Hospital, Parma, Italy 6 0000 0004 1757 1758grid.6292.fDivision of Dermatology, Department of of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy 7 0000 0004 1757 8562grid.413181.ePediatric Cardiology Unit, Anna Meyer Children’s Hospital, Florence, Italy 8 0000 0004 1757 5003grid.459845.1Pediatric Emergency Department, Ospedale dell’Angelo Ulss12, Venice, Italy 19 4 2017 19 4 2017 2017 43 4017 1 2017 8 4 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDespite not being licensed for the treatment of infantile hemangiomas (IH) in infants younger than 5 weeks or older than 5 months, propranolol is often used in these age groups to prevent or to treat potentially severe complications. The objective of the present study was to review the experience of 8 Italian pediatric and dermatologic centers regarding propranolol treatment for IH started before 5 weeks or after 5 months of age.\n\nMethods\nWe retrospectively reviewed the records of patients followed up for IH, on propranolol treatment started before 5 weeks or after 5 months of age, and collected information on sociodemographic data, treatment indications, IH involution, IH relapse, and treatment side effects.\n\nResults\nA total of 343 patients were enrolled; 15 were started on propranolol before 5 weeks (group 1), 328 were started after 5 months of age (group 2). The most frequent indications were permanent aesthetical disfigurement (91.8%) and function threatening complications (42.6%).\n\nIn most cases, the treatment was effective. The involution was partial in 67.7% of patients. In 11.8% of cases a relapse was observed. No relapse was observed in group 1. Treatment complications were reported in 15.8% of children, most frequently sleep disorders (6.6%), followed by irritability (5.1%) and diarrhea (2.2%). Only a case of mild constipation was observed in group 1.\n\nConclusion\nThe safety and effectiveness profile of propranolol in infants younger than 5 weeks or older than 5 months may be acceptable. Taking in account propranolol's potential in preventing severe complications, further studies should assess the acceptability of propranolol treatment, especially in the <5-week age group .\n\nissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nInfantile hemangiomas (IHs) are the most common benign neoplasms in infancy [1–5]. The natural history of IHs is characterized by an onset within the first weeks of life, followed by a proliferative phase with rapid growth, generally lasting until 5 months of age; in some cases, the proliferative phase may last up to 10-11 months [6].\n\nAbout 90% of IHs spontaneously regress, partially or completely, within the 7th year of life (usually between the 3rd and the 6th year) [2, 7, 8]. In 10-15% of cases, a treatment is required, with the following indications: life threatening complications, function threatening complications, ulceration not responding to local treatments, pain and potential permanent disfigurement [6, 9–15].\n\nOral propranolol has been repeatedly demonstrated as the first-choice drug for IH and, at present, is available in several countries with a specific indication for pediatric patients [6, 16, 17].\n\nThe treatment is highly effective (up to 96-98% after 6 months) and has an optimal safety profile, with a low incidence of adverse events, such as sleep disorders, diarrhea, cold extremities, irritability, hypotension, bradycardia, bronchospasm and hypoglycemia. Symptomatic hypotension and bradycardia are very rare [17–19]. All side effects are usually transient and only in few cases a definitive treatment discontinuation is required [20].\n\nAccording to international consensus recommendations and to the drug’s summary of product characteristics (SmPC), oral propranolol should be administered in infants between 5 weeks and 5 months of age, for a duration shorter than 6 months [6]. Nevertheless, peculiar clinical pictures may exist, in which an off-label treatment could be required or suggested.\n\nThe aim of our study was to describe the experience of 8 Italian pediatric and dermatologic centers in the off-label use of oral propranolol for the treatment of IH, starting earlier than 5 weeks or later than 5 months of age, in terms of treatment indications, effectiveness and side effects.\n\nMethods\nStudy design and population\nThis is a multicenter, retrospective cohort study that was conducted in the Pediatric Units and Pediatric Dermatology Units of 8 major Italian metropolitan hospitals.\n\nWe retrospectively reviewed the records of patients followed up for IH in the participating centers between June, 2008 and June, 2015, who had been treated with oral propranolol started before 5 weeks or after 5 months of age, and who had discontinued the treatment for at least one month. The following data were collected: sociodemographic data; risk factors for IH; IH therapy (indication, dose, therapy duration); treatment effectiveness (involution at treatment end, relapse); treatment complications (including irritability, nightmares, cold extremities, diarrhea, hypoglycemia, hypotension).\n\nData were collected in a dedicated database.\n\nThe study was approved by the Ethical Committee of the Bambino Gesù Children’s Hospital.\n\nStatistical analysis\nData were described as means and SD or medians and range or proportions and CI, as appropriate. Age is expressed in months, and was corrected to 40 weeks of gestational age for preterm infants.\n\nStata 13 was used for the statistical analysis.\n\nResults\nStudy population\nWe enrolled a total of 343 patients. Characteristics of the study population are presented in Table 1.Table 1 Sociodemographic characteristics and IH risk factors\n\n\tStart <5 weeks (N = 15)\tStart >5 months (N = 328)\tTotal (N = 343)\t\nFemale sex (N, %)\t10 (66.7)\t232 (71)\t242 (70.8)\t\nAge at treatment start (median, range)\t0.8 (0-1.1)\t9 (5-90.7)\t8.7 (0-90.7)\t\nAge at treatment end (median, range)\t10 (7.3-15.2)\t16.1 (8.6-107.1)\t16 (7.3-107.1)\t\nTreatment duration (median, range)\t9.5 (6.3-14.5)\t6.8 (0.5-20)\t6.8 (0.5-20)\t\nPreterm (N, %)\t8 (53.3)\t49 (14.9)\t57 (16.6)\t\nRisk factors (N, %)\t9 (60)\t73 (22.3)\t82 (24)\t\n twins\t3 (20)\t16 (4.8)\t19 (5.5)\t\n IVF\t1 (6.7)\t2 (0.6)\t3 (0.9)\t\n family history of IE\t0 (0)\t9 (2.7)\t9 (2.6)\t\n amniocentesis\t1 (6.7)\t15 (4.6)\t16 (4.7)\t\n villocentesis\t2 (13.3)\t10 (3)\t12 (3.5)\t\n pre-eclampsia or placenta praevia\t2 (13.3)\t12 (3.7)\t14 (4)\t\n\n\n\nA total of 242 (70.8%) were female.\n\nFifteen patients (4.3%) were started on oral propranolol before 5 weeks of age; 328 patients (96%) had started the treatment after 5 months of age.\n\nMedian age at treatment start was 0.8 months in the subgroup of patients starting the therapy before 5 weeks of age (range 0-1.1 months) and 9 months in the subgroup of patients starting the therapy after 5 months (range 5-90.7 months).\n\nMedian treatment duration was 9.5 months (range 6.3-14.5 months) among patients starting the therapy before 5 weeks of age and 6.8 months (range 0.5-20 months) in those starting the therapy after 5 months. A patient was treated with propranolol for 2 weeks only, waiting to be treated surgically. Despite the short interval between the treatment start and the surgical intervention, the clinicians decided to treat the patient anyway, in order to reduce the IH's vascularization and the consequent risk for an intraoperative hemorrhage.\n\nA total of 57 children (16.6%) were born preterm. The proportion of preterms among patients starting the treatment before 5 weeks of age was high (53%).\n\nAt least one risk factor among those recognized in the medical literature [6, 21] and listed in Table 1 was identified in 82 patients (24%), most commonly twin pregnancy (5.5%), amniocentesis (4.7%) and pre-eclampsia or placenta previa (4%). Risk factors were reported in a high proportion (60%) of patients starting the treatment before 5 weeks and in 22.3% of patients starting the treatment after 5 months. Twin pregnancy was the most common risk factor in both groups.\n\nTreatment indications and dosages\nTreatment indications are reported in Table 2.Table 2 Treatment indications\n\n\tStart <5 weeks (N = 15)\tStart >5 months (N = 328)\tTotal (N = 343)\t\nLife threatening complications\t2 (13)\t4 (1.2)\t6 (1.8)\t\nFunction threatening complications\t5 (66.7)\t136 (41.4)\t146 (42.6)\t\nPermanent esthetical disfigurement\t13 (86.7)\t302 (92.1)\t315 (91.8)\t\nUlceration\t3 (20)\t8 (2.4)\t11 (3,2)\t\nPain\t2 (13.3)\t4 (1.2)\t6 (1.8)\t\n\n\n\nIn both groups, the most frequent indications to treatment with propranolol was potential permanent aesthetical disfigurement, followed by function threatening complications. Other indications accounted for less than 5% in the subgroup started on propranolol after 5 months of age. On the other hand, among infants starting the treatment before 5 weeks, life threatening, ulceration and pain were reported in a total of 5 patients (1/3 of the subgroup). Of the subgroup of 6 patients with a life threatening indication, the following localizations were reported: laryngeal (3 patients), liver (3 patients), and hemithorax (1 patient). All patients started on propranolol before 5 weeks of age for life threatening complications had a liver hemangiomatosis.\n\nMedian therapeutic dosage was 2 mg/Kg daily (range 1-3). A proportion of 54% patients had a dosage between 1.8 and 2.2 mg/Kg. As per protocol, children <5 weeks were started on a lower dosage and progressively adjusted.\n\nEffectiveness and safety\nIn most cases, the treatment was effective, although the involution at the end of the treatment was partial in 2/3 of patients, in both groups (Table 3).Table 3 Effectiveness and safety\n\n\tStart <5 weeks (N = 15)\tStart >5 months (N = 328)\tTotal (N = 343)\t\nInvolution\t\n complete\t2 (13.3)\t77 (23.9)\t79 (23.4)\t\n almost complete\t3 (20)\t17 (5.3)\t20 (5.9)\t\n partial\t10 (66.7)\t218 (67.7)\t228 (67.7)\t\n absent\t0\t10 (3.1)\t10 (3)\t\nRelapse\t1 (6.7)\t39 (12)\t40 (11.8)\t\nTreatment complications\t1 (6.7)\t52 (15.9)\t53 (15.5)\t\n irritability\t0\t17 (5.4)\t17 (5.12)\t\n sleep disorders\t0\t22 (6.8)\t22 (6.6)\t\n cold extremities\t0\t2 (0.6)\t2 (0.6)\t\n diarrhoea\t0\t10 (3.1)\t10 (2.9)\t\n hypoglicemia\t0\t1 (0.3)\t1 (0.3)\t\n hypotension\t0\t4 (1.3)\t4 (1.2)\t\n\n\n\nAmong the 15 patients started on propranolol before 5 weeks, an involution was seen in all patients (complete: 2 patients; almost complete: 3 patients; partial: 10 patients).\n\nAmong patients started on propranolol after 5 months, a complete or almost complete involution at treatment end was observed in 23.9% and 5.3%, respectively. Only in 3% of cases no involution was observed.\n\nRelapse was infrequent among patients started on treatment before 5 weeks (recorded in 1 patient only). Twelve patients in the older group had a relapse.\n\nTreatment complications were reported in 15.8% of children, mostly children started on propranolol after 5 months of age.\n\nIn this group, the most frequent complications were sleep disorders (6.8%), followed by irritability (5.4%) and diarrhea (3.1%). Cold extremities, hypoglycemia, hypotension and wheezing were observed in a very low proportion of cases. All the described cases of hypoglicemia and hypotension were asymptomatic. A severe complication was reported in a child started on propranolol at 12 months of age for a wide IH of the back, with a high risk of ulceration. The patient had a cardiac arrest after 40 days of treatment, during a respiratory tract infection.\n\nAmong patients starting the treatment before 5 weeks of age, only a case of mild constipation was observed.\n\nDiscussion\nWith the present descriptive study, we show that the off-label use of oral propranolol for IHs in infants, with treatment start before 5 weeks or after 5 months of age, may have an acceptable profile of effectiveness and safety.\n\nBased on the only randomized controlled trial (RCT) available in the literature [19], the indications for oral propranolol in infants suggest a treatment start between 5 weeks and 5 months.\n\nOff-label use of propranolol after 5 months of age is frequent and already described in the literature [22].\n\nAs a matter of fact, despite children with an IH requiring treatment should be started on oral propranolol within the first 2-3 months of age, referral to dermatology centers may be late (after 5 months), due to a scarce knowledge of the therapeutic option of propranolol, and of its safety and efficacy, among general pediatricians. Moreover, despite the regression of IH is usually spontaneous after 1 year of age, sometimes complications may be severe and waiting for a spontaneous involution may cause irreversible functional and aesthetical damage. In infants referred to pediatric dermatology centers after 5 months of age, propranolol, through its pro-apoptotic properties, may promote and accelerate the involution of the lesion, thus reducing the risk of permanent damages.\n\nOn the other hand, a treatment start before 5 weeks of age is less frequently reported. Although very rarely, IHs may actually pose a risk of severe and possibly irreversible complications at birth or within the first 5 weeks of life, thus justifying an early treatment start, with an indication of life or function threatening complications, eg. laryngeal hemangiomas impairing the breathing dynamic, periorbital hemangiomas entailing a risk of amblyopia and liver hemangiomas impairing the hemodynamics, with a high risk of cardiac failure. When starting the treatment before 5 weeks, special precautions should be carefully taken, accordingly to consensus guidelines [6, 23]: hospitalization at treatment start and during dose adjustment, low initial dose, continuous monitoring of blood pressure and heart rate for the first week, follow up visits every 2-4 weeks.\n\nThe experience of the major Italian pediatric and dermatologic centers reported in the present article confirms an acceptable profile of the drug in terms of effectiveness, safety and prevention of IH-related complications in children younger than 5 weeks and older than 5 months.\n\nEffectiveness was very high. Any improvement (including partial, almost complete and complete involution) was reported in 97% of the study population. The authors of a systematic review published in 2013 and including 41 articles on propranolol treatment for IH reported a mean response rate of 98% (ranging from 82% to 100%), which is consistent with our figures. Nevertheless, according to this review, rebound growth and adverse events were more frequent compared to our population (rebound growth = 17% compared to 11.8% in our population; adverse events = 30% compared to 15.8% in our population) [24].\n\nIn a recent article on propranolol safety, the reported complication rate was lower (8.8%) compared to our figures [25]. The reason of this lower proportion of treatment complications is probably due to the fact that the authors assessed the causality using a standardized protocol [26].\n\nIn our population, 15 children were started on propranolol before 5 weeks of age, mainly due to life-threatening complications, ulceration and pain. In this group, risk factors were highly represented, especially preterm birth and twin pregnancy. Efficacy was high, as involution of the lesion was observed in all cases started on treatment before 5 weeks, and only one case of relapse was described, in a child treated for a parotideal IH. Parotideal IHs are known to exhibit an extended growth phase during the second and third year of life. This could explain the frequent relapse at treatment discontinuation [19, 27]. As a matter of fact, the low proportion of relapse in this subgroup may be related to the fact that the treatment duration was always longer than 6 months (median 9.5 months). The SmPC suggests a treatment duration shorter than 6 months. However, our data suggest that the safety and effectiveness of a longer treatment duration in terms of reduction of relapse may be convenient and should be further investigated. Moreover, no side effect of the treatment was observed in this subgroup, apart from a mild case of constipation. We believe that the extreme accuracy of the management of these very young infants, with slow dosage increase and continuous monitoring of vital signs, has strongly contributed to the prevention of side effects.\n\nAmong the subgroup of patients started on propranolol after 5 months of age, treatment complications were reported in 16% of cases, mainly including sleep disorders and irritability. One severe adverse event was reported: a cardiac arrest during a respiratory tract infection in a child that had been treated for 40 days. The child suffered from breath-holding spells and was dehydrated due to the infection. Cardiac adverse events potentially related to propranolol therapy have been previously reported in the literature [25], and one case of cardiac arrest in an infant on propranolol with bronchiolitis has been described [28]. Based on these observations, parents should be carefully trained to recognize symptoms of a respiratory infection and advised to immediately discontinue treatment if a respiratory infection occurs, as previously reported [23].\n\nThe present study has several limitations, mainly with regards to its design. First of all, we did not compare our results with those obtained from a retrospective cohort of controls started on propranolol between 5 weeks and 5 months of age. Nevertheless, our results were in line with the figures reported in the literature. Moreover, causality of side effects has not been investigated with a standardized protocol, and this may have impaired our estimates, probably through an overestimation of the frequency of side effects. Finally, the subgroup of infants started on propranolol before 5 weeks of age was relatively small, and this may have affected the precision and generalizability of our estimates.\n\nConclusion\nIn conclusion, we report an acceptable profile of effectiveness and safety for the off-label use of propranolol in infants, with figures that are comparable to those reported in the literature, with regard to involution, relapse and complications. In particular, relapse and complication rates in children started on propranolol at an age younger than 5 weeks were even lower than those reported for other age groups. Despite this subgroup of patient was relatively small, this finding suggests that a closely monitored therapy start may contribute to a higher safety profile in these very young infants. On the other hand, the late start of propranolol after 5 months of age is often due to the late referral of patients by family pediatricians, which are still not aware of the availability of propranolol therapy for IH. With the aim of resolving this cultural gap, in Italy, the Italian Society for the Study of Vascular Anomalies (SISAV) and the Italian Society of Pediatric Dermatology (SIDerP) promoted educational courses dedicated to pediatricians and dermatologists for the management of IHs.\n\nFinally, based on our observations, additional RCTs are needed to validate the use of propranolol, especially in the <5-week age group, in order to reduce IH-related complications, which may be severe and irreversible.\n\nFunding\nNo funding.\n\nAvailability of data and materials\nThe datasets generated during and/or analysed during the current study are not publicly available due to hospital research policy. Aggregate analyses different from those presented in the article are however available on reasonable request to the corresponding author.\n\nAuthors’ contributions\nMEA, FG and AD wrote the article; IB and NV conceived the study; AG, CC and TO contributed to patient enrolment and data management; VB, IN, GP and MC critically revised the article; PD revised the article and gave the final consent to publication. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent to publication\nNot applicable.\n\nEthics approval and consent to participate\nThe publication of this study was approved by the Bambino Gesù Children’s Hospital Ethical Committee (protocol n.1278_OPBG_2016). Data were acquired retrospectively, therefore no consent was asked to parents of included patients.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hoornweg MJ Smeulders MJ van der Horst CM Prevalence and characteristics of haemangiomas in young children Ned Tijdschr Geneeskd 2005 149 44 \n2. Dickison P Christou E Wargon O A prospective study of infantile hemangiomas with a focus on incidence and risk factors Pediatr Dermatol 2011 28 6 10.1111/j.1525-1470.2011.01568.x 21070347 \n3. Leaute-Labreze C Prey S Ezzedine K Leaute-Labreze C Prey S Ezzedine K Infantile haemangioma: Part I. pathophysiology, epidemiology, clinical features, life cycle and associated structural abnormalities J Eur Acad Dermatol Venereol 2011 25 11 \n4. Hoornweg MJ Smeulders MJ Ubbink DT van der Horst CM The prevalence and risk factors of infantile haemangiomas: A case-control study in the dutch population Paediatr Perinat Epidemiol. 2012 26 2 10.1111/j.1365-3016.2011.01214.x 22150701 \n5. Munden A Butschek R Tom WL Marshall JS Poeltler DM Krohne SE Prospective study of infantile haemangiomas: Incidence, clinical characteristics and association with placental anomalies Br J Dermatol 2014 170 4 10.1111/bjd.12804 24443908 \n6. Hoeger PH Harper JI Baselga E Bonnet D Boon LM Ciofi Degli Atti M Treatment of infantile haemangiomas: recommendations of a european expert group Eur J Pediatr 2015 174 7 10.1007/s00431-015-2570-0 \n7. Luu M Frieden IJ Haemangioma: Clinical course, complications and management Br J Dermatol. 2013 169 1 10.1111/bjd.12436 \n8. Puttgen KB Diagnosis and management of infantile hemangiomas Pediatr Clin North Am. 2014 61 2 10.1016/j.pcl.2013.11.010 \n9. Chamlin SL Haggstrom AN Drolet BA Baselga E Frieden IJ Garzon MC Multicenter prospective study of ulcerated hemangiomas J Pediatr 2007 151 6 10.1016/j.jpeds.2007.04.055 17586181 \n10. Hermans DJ Boezeman JB Van de Kerkhof PC Rieu PN Van der Vleuten CJ Differences between ulcerated and non-ulcerated hemangiomas, a retrospective study of 465 cases Eur J Dermatol. 2009 19 2 \n11. Bauland CG Luning TH Smit JM Zeebregts CJ Spauwen PH Untreated hemangiomas: Growth pattern and residual lesions Plast Reconstr Surg. 2011 127 4 10.1097/PRS.0b013e318208d2ac 21548187 \n12. Horii KA Drolet BA Frieden IJ Baselga E Chamlin SL Haggstrom AN Prospective study of the frequency of hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas Pediatr Dermatol. 2011 28 3 10.1111/j.1525-1470.2011.01420.x \n13. Bosemani T Puttgen KB Huisman TA Tekes A Multifocal infantile hepatic hemangiomas--imaging strategy and response to treatment after propranolol and steroids including review of the literature Eur J Pediatr. 2012 171 7 10.1007/s00431-011-1671-7 \n14. Chen TS Eichenfield LF Friedlander SF Infantile hemangiomas: An update on pathogenesis and therapy Pediatrics. 2013 131 1 10.1542/peds.2012-1128 23277318 \n15. Vredenborg AD Janmohamed SR de Laat PC Madern GC Oranje AP Multiple cutaneous infantile haemangiomas and the risk of internal haemangioma Br J Dermatol. 2013 169 1 10.1111/bjd.12229 \n16. Leaute-Labreze C Dumas de la Roque E Hubiche T Boralevi F Thambo JB Taieb A Propranolol for severe hemangiomas of infancy N Engl J Med. 2008 358 24 10.1056/NEJMc0708819 \n17. Drolet BA Frommelt PC Chamlin SL Haggstrom A Bauman NM Chiu YE Initiation and use of propranolol for infantile hemangioma: Report of a consensus conference Pediatrics 2013 131 1 10.1542/peds.2012-1691 23277318 \n18. Haggstrom AN Drolet BA Baselga E Chamlin SL Garzon MC Horii KA Prospective study of infantile hemangiomas: Clinical characteristics predicting complications and treatment Pediatrics 2006 118 3 10.1542/peds.2006-0413 \n19. Leaute-Labreze C Hoeger P Mazereeuw-Hautier J Guibaud L Baselga E Posiunas G A randomized, controlled trial of oral propranolol in infantile hemangioma N Engl J Med. 2015 372 8 10.1056/NEJMoa1404710 \n20. Sans V de la Roque ED Berge J Grenier N Boralevi F Mazereeuw-Hautier J Propranolol for severe infantile hemangiomas: Follow-up report Pediatrics. 2009 124 3 10.1542/peds.2008-3458 \n21. Leaute-Labreze C Infantile hemangiomas: The revolution of beta-blockers Rev Prat. 2014 64 10 \n22. Vivas-Colmenares GV Bernabeu-Wittel J Alonso-Arroyo V de Cardenas JA M Fernandez-Pineda I Effectiveness of propranolol in the treatment of infantile hemangioma beyond the proliferation phase Pediatr Dermatol. 2015 32 3 10.1111/pde.12520 \n23. Stillo F Baraldini V Dalmonte P El Hachem M Mattassi R Vercellio G Vascular anomalies guidelines by the italian society for the study of vascular anomalies (SISAV) Int Angiol 2015 34 2 Suppl 1 1 45 26159424 \n24. Marqueling AL Oza V Frieden IJ Puttgen KB Propranolol and infantile hemangiomas four years later: A systematic review Pediatr Dermatol 2013 30 2 \n25. Prey S Voisard JJ Delarue A Lebbe G Taieb A Leaute-Labreze C Safety of propranolol therapy for severe infantile hemangioma JAMA 2016 315 4 10.1001/jama.2015.13969 \n26. Begaud B Evreux JC Jouglard J Lagier G Imputation of the unexpected or toxic effects of drugs. actualization of the method used in france Therapie 1985 40 2 \n27. Brandling-Bennett HA Metry DW Baselga E Lucky AW Adams DM Cordisco MR Infantile hemangiomas with unusually prolonged growth phase: A case series Arch Dermatol. 2008 144 12 10.1001/archderm.144.12.1632 \n28. Saidi W Zaouali A Saihi N Mokni S Denguezli M Nouira R Cardiorespiratory arrest following bronchiolitis in a child treated with propranolol for hemangioma Ann Dermatol Venereol. 2014 141 8 9\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1720-8424",
"issue": "43(1)",
"journal": "Italian journal of pediatrics",
"keywords": null,
"medline_ta": "Ital J Pediatr",
"mesh_terms": "D000284:Administration, Oral; D000367:Age Factors; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006391:Hemangioma; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D061214:Patient Safety; D011433:Propranolol; D012189:Retrospective Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101510759",
"other_id": null,
"pages": "40",
"pmc": null,
"pmid": "28424095",
"pubdate": "2017-04-19",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": "23421718;21460670;22234480;24641194;18550886;23701395;25721095;16950977;22324502;23266916;19706583;16285361;25693013;19075148;23266923;21995808;21569112;26159424;19106042;4002188;18035154;25665327;24636652;25209817;26813215;26021855;23405852;21517952",
"title": "Safety and effectiveness of oral propranolol for infantile hemangiomas started before 5 weeks and after 5 months of age: an Italian multicenter experience.",
"title_normalized": "safety and effectiveness of oral propranolol for infantile hemangiomas started before 5 weeks and after 5 months of age an italian multicenter experience"
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"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
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"abstract": "OBJECTIVE\nTreatment of secondary CNS dissemination in patients with aggressive lymphomas remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment for secondary CNS lymphoma based on encouraging experiences with high doses of antimetabolites in primary CNS lymphoma and with rituximab plus high-dose sequential chemoimmunotherapy (R-HDS) in relapsed aggressive lymphoma.\n\n\nMETHODS\nHIV-negative patients with aggressive B-cell lymphoma and secondary CNS involvement at diagnosis or relapse, age 18 to 70 years, and Eastern Cooperative Oncology Group performance status ≤ 3 were enrolled and treated with high-doses of methotrexate and cytarabine, followed by R-HDS (cyclophosphamide, cytarabine, and etoposide) supported by autologous stem-cell transplantation (ASCT). Treatment included eight doses of rituximab and four doses of intrathecal liposomal cytarabine. The primary end point was 2-year event-free survival; the planned accrual was 38 patients.\n\n\nRESULTS\nThirty-eight patients were enrolled; CNS disease was detected at presentation in 16 patients. Toxicity was usually hematologic and manageable, with grade 4 febrile neutropenia in 3% of delivered courses and grade 4 nonhematologic toxicity in 2% of delivered courses. Four patients died because of toxicity. Autologous stem cells were successfully collected in 24 (89%) of 27 patients (median, 10 × 10(6)/kg); 20 patients underwent ASCT. Complete response was achieved in 24 patients (complete response rate, 63%; 95% CI, 48% to 78%). At a median follow-up of 48 months, 17 patients remained relapse free, with a 2-year event-free survival rate of 50% ± 8%. At 5 years, 16 patients were alive, with a 5-year overall survival rate of 41% ± 8% for the whole series and 68% ± 11% for patients who received transplantation. Systemic (extra-CNS) and/or meningeal disease did not affect outcome.\n\n\nCONCLUSIONS\nThe combination of high doses of antimetabolites, R-HDS, and ASCT is feasible and effective in patients age 18 to 70 years old with secondary CNS lymphoma, and we propose it as a new standard therapeutic option.",
"affiliations": "Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy. ferreri.andres@hsr.it.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.;Andrés J.M. Ferreri, Giovanni Donadoni, Marta Bruno-Ventre, Andrea Assanelli, Marco Foppoli, Giovanni Citterio, Federico Caligaris-Cappio, and Fabio Ciceri, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute; Massimo Di Nicola, Istituto Nazionale dei Tumori, Milano; Maria Giuseppina Cabras and Alessandro Fanni, Hospital Businco, Cagliari; Caterina Patti and Antonino Mulè, Hospital \"V. Cervello,\" Palermo; Michael Mian, Ospedale di Bolzano, Bolzano; Renato Zambello, Azienda Ospedaliera di Padua, University of Padua, Padua; Corrado Tarella, Azienda Ospedaliera Ordine Mauriziano-Umberto I, University of Turín, Turín; Alfonso M. D'Arco, Polo Oncologico Nocera-Pagani, Nocera Inferiore; and Gianluca Doa, Azienda Ospedaliera di Nuoro, Nuoro, Italy.",
"authors": "Ferreri|Andrés J M|AJ|;Donadoni|Giovanni|G|;Cabras|Maria Giuseppina|MG|;Patti|Caterina|C|;Mian|Michael|M|;Zambello|Renato|R|;Tarella|Corrado|C|;Di Nicola|Massimo|M|;D'Arco|Alfonso M|AM|;Doa|Gianluca|G|;Bruno-Ventre|Marta|M|;Assanelli|Andrea|A|;Foppoli|Marco|M|;Citterio|Giovanni|G|;Fanni|Alessandro|A|;Mulè|Antonino|A|;Caligaris-Cappio|Federico|F|;Ciceri|Fabio|F|",
"chemical_list": "D000963:Antimetabolites",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2015.61.1236",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "33(33)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000963:Antimetabolites; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy; D016393:Lymphoma, B-Cell; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018570:Risk Assessment; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "3903-10",
"pmc": null,
"pmid": "26282634",
"pubdate": "2015-11-20",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "High Doses of Antimetabolites Followed by High-Dose Sequential Chemoimmunotherapy and Autologous Stem-Cell Transplantation in Patients With Systemic B-Cell Lymphoma and Secondary CNS Involvement: Final Results of a Multicenter Phase II Trial.",
"title_normalized": "high doses of antimetabolites followed by high dose sequential chemoimmunotherapy and autologous stem cell transplantation in patients with systemic b cell lymphoma and secondary cns involvement final results of a multicenter phase ii trial"
} | [
{
"companynumb": "IT-PFIZER INC-2016420508",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nPresentation of the risk of psychosis induced by the treatment of adrenal crisis with high doses of hydrocortisone.\n\n\nMETHODS\nA case analysis in the context of the literature.\n\n\nRESULTS\nThere are reported psychoses in the patients with adrenal hypofunction and hyperfunction. Psychoses following implementation of substitution with small doses of corticosteroids due to adrenal insufficiency were also observed. The hypereactivity of the glucocorticoid receptor is supposed mechanism. We have not found any description of psychosis connected with steroid administration in adrenal crisis. We present a case of 55 years old female, so far mentally healthy with untreated adrenocortical insufficiency secondary to radiotherapy of pituitary adenoma (prolactinoma) performed 3 years ago. She was admitted to the hospital because of acute adrenal crisis provoked by infection. In the fourth day of treatment with intravenous Hydrocortisone (up to 400mg/24 hours) there occurred acute psychosis with hallucinations, delusions and life-threatening behaviours. The patient was admitted to the psychiatric inpatient unit. Following 3 days of treatment with haloperidol, and decreasing the steroid dosage - the psychosis disappeared, without recurrence, despite of discontinuation of haloperidol.\n\n\nCONCLUSIONS\nThe case focuses attention on the risk of psychosis connected with the treatment of the adrenal crisis with high doses of Hydrocortisone. Because of the risk of psychiatric complications, the patients treated with high doses of corticosteroids, require an evaluation of risk factors for mental disturbances, and safety precautions in cooperation of endocrinologist and psychiatrist.",
"affiliations": "Kliniczny Oddział Psychiatryczny i IV Klinika Psychiatrii IPiN w Szpitalu Bielańskim w Warszawie.;Kliniczny Oddział i Klinika Endokrynologii CMKP w Szpitalu Bielańskim w Warszawie.;Kliniczny Oddział Psychiatryczny i IV Klinika Psychiatrii IPiN w Szpitalu Bielańskim w Warszawie.",
"authors": "Brykalski|Jan|J|;Papierska|Lucyna|L|;Załuska|Maria|M|",
"chemical_list": "D005938:Glucocorticoids; D006854:Hydrocortisone",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2674",
"issue": "49(4)",
"journal": "Psychiatria polska",
"keywords": "acute psychosis; adrenal crisis; glucocorticosteroids",
"medline_ta": "Psychiatr Pol",
"mesh_terms": "D000309:Adrenal Insufficiency; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006854:Hydrocortisone; D007239:Infections; D008875:Middle Aged; D010911:Pituitary Neoplasms; D011618:Psychotic Disorders; D011878:Radiotherapy; D016896:Treatment Outcome",
"nlm_unique_id": "0103314",
"other_id": null,
"pages": "673-81",
"pmc": null,
"pmid": "26488344",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute psychosis in the course of treatment of acute adrenal crisis with hydrocortisone in the patient with secondary adrenal insufficiency - a case study.",
"title_normalized": "acute psychosis in the course of treatment of acute adrenal crisis with hydrocortisone in the patient with secondary adrenal insufficiency a case study"
} | [
{
"companynumb": "PL-ACTAVIS-2015-21270",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAdenovirus is a frequent cause of mild self-limiting upper respiratory tract infection, gastroenteritis, and conjunctivitis. Severe or fatal infection mostly occurs in newborn, elderly or immunocompromised persons.\n\n\nMETHODS\nFatal adenovirus pneumonia in three immunocompetent adults was identified. The clinical data and virological findings were reported from patients. Additional review of recently recorded fatal patients with adenovirus infection was carried out.\n\n\nRESULTS\nThe patients presented with sudden onset respiratory distress that progressed rapidly to respiratory failure and death. Human adenovirus (HAdV)-55 was detected in both nasopharyngeal aspirates and serum samples in all three cases, and moreover detected in lung, liver, and kidney in one case. In another case, remarkably elevated aspartate aminotransferase, alanine transaminase, and lactate dehydrogenase were identified. Three HAdV-55 strains were isolated and genome sequencing revealed a high similarity with other strains from mild infection.\n\n\nCONCLUSIONS\nFatal infection with HAdv-55 might occur in otherwise healthy adults. Diagnosis of adenovirus infection should be considered in patients with severe pneumonia yielding negative bacterial culture and presenting no response to antibiotic therapy.",
"affiliations": "a From the Department of Clinical Laboratory , General Hospital of Beijing Military Region , Beijing , PR China.;b General Hospital of PLA , Beijing , PR China.;c State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology , Beijing , PR China.;c State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology , Beijing , PR China.;d School of Public Health, Peking University , Beijing , PR China.;c State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology , Beijing , PR China.;b General Hospital of PLA , Beijing , PR China.;c State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology , Beijing , PR China.;e PLA 307 Hospital , Beijing , PR China.;c State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology , Beijing , PR China.;c State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology , Beijing , PR China.;c State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology , Beijing , PR China.",
"authors": "Zhang|Shu-Yan|SY|;Luo|Yan-Ping|YP|;Huang|Dou-Dou|DD|;Fan|Hang|H|;Lu|Qing-Bin|QB|;Wo|Ying|Y|;Chen|Gang|G|;Zhang|Xiao-Ai|XA|;Li|Yan|Y|;Tong|Yi-Gang|YG|;Cao|Wu-Chun|WC|;Liu|Wei|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/23744235.2015.1055585",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-4243",
"issue": "48(1)",
"journal": "Infectious diseases (London, England)",
"keywords": "Human adenovirus; death; epidemiology; pneumonia; respiratory tract infection",
"medline_ta": "Infect Dis (Lond)",
"mesh_terms": "D000258:Adenovirus Infections, Human; D000260:Adenoviruses, Human; D000328:Adult; D002681:China; D017809:Fatal Outcome; D006801:Humans; D007121:Immunocompetence; D008297:Male; D010802:Phylogeny; D011024:Pneumonia, Viral; D012131:Respiratory Insufficiency; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "101650235",
"other_id": null,
"pages": "40-7",
"pmc": null,
"pmid": "26465201",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fatal pneumonia cases caused by human adenovirus 55 in immunocompetent adults.",
"title_normalized": "fatal pneumonia cases caused by human adenovirus 55 in immunocompetent adults"
} | [
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"companynumb": "CN-PFIZER INC-2016231536",
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"abstract": "We have recently reported on our experience with C-X-C-motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT) in multiple myeloma and acute leukemia. Methods: Six patients with heavily pretreated relapsed diffuse large B-cell lymphoma (3 men, 3 women; aged, 54 ± 8 y) underwent CXCR4-directed RLT in combination with conditioning chemotherapy and allogeneic stem cell transplantation. In 2 patients, radioimmunotherapy targeting CD20 or CD66 was added to enhance antilymphoma activity. Endpoints were incidence and severity of adverse events, progression-free survival, and overall survival. Results: RLT and additional radioimmunotherapy were well tolerated, without any acute adverse events or changes in vital signs. Successful engraftment was recorded after a median of 11 d (range, 9-13 d). Of the 4 patients who were available for follow-up (one patient died of CNS aspergillosis 29 d after RLT and another of sepsis in aplasia 34 d after RLT), CXCR4-directed RLT resulted in a partial response in two (both treated with additional radioimmunotherapy) and a mixed response in the remaining two. The response duration was rather short-lived, with a median progression-free survival of 62 d (range, 29-110 d) and a median overall survival of 76 d (range, 29-334 d). Conclusion: CXCR4-directed RLT (in combination with additional radioimmunotherapy) is feasible as a conditioning regimen before allogeneic stem cell transplantation in diffuse large B-cell lymphoma.",
"affiliations": "Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany lapa_c@ukw.de.;Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.;Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.;Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.;Department of Nuclear Medicine, University Hospital Dresden, Dresden, Germany.;Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.;Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.;Department of Nuclear Medicine, University Hospital Dresden, Dresden, Germany.;Division of Hematology and Medical Oncology, Department of Internal Medicine II, Universitätsklinikum Würzburg, Würzburg, Germany; and.;Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.;Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany.;Division of Hematology and Medical Oncology, Department of Internal Medicine II, Universitätsklinikum Würzburg, Würzburg, Germany; and.",
"authors": "Lapa|Constantin|C|;Hänscheid|Heribert|H|;Kircher|Malte|M|;Schirbel|Andreas|A|;Wunderlich|Gerd|G|;Werner|Rudolf A|RA|;Samnick|Samuel|S|;Kotzerke|Jörg|J|;Einsele|Hermann|H|;Buck|Andreas K|AK|;Wester|Hans-Jürgen|HJ|;Grigoleit|Götz Ulrich|GU|",
"chemical_list": "C527276:CXCR4 protein, human; D008024:Ligands; D019718:Receptors, CXCR4",
"country": "United States",
"delete": false,
"doi": "10.2967/jnumed.118.210997",
"fulltext": null,
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"issn_linking": "0161-5505",
"issue": "60(1)",
"journal": "Journal of nuclear medicine : official publication, Society of Nuclear Medicine",
"keywords": "CXCR4; DLBCL; chemokine receptors; lymphoma; radioligand therapy",
"medline_ta": "J Nucl Med",
"mesh_terms": "D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008024:Ligands; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011874:Radiometry; D019718:Receptors, CXCR4; D012449:Safety; D033581:Stem Cell Transplantation; D016896:Treatment Outcome",
"nlm_unique_id": "0217410",
"other_id": null,
"pages": "60-64",
"pmc": null,
"pmid": "29777009",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Feasibility of CXCR4-Directed Radioligand Therapy in Advanced Diffuse Large B-Cell Lymphoma.",
"title_normalized": "feasibility of cxcr4 directed radioligand therapy in advanced diffuse large b cell lymphoma"
} | [
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"abstract": "Clinical studies suggest that the antiepileptic drug (AED) brivaracetam (BRV) is associated with fewer behavioral and psychiatric adverse events (AEs) compared with levetiracetam (LEV) in treating epilepsy. There are, however, few comparative studies of treatment-emergent AEs between patients on BRV with preexisting psychiatric or behavioral comorbidities to those without. Our study compared longer-term tolerability over a 26-month period between these patient groups and assessed the overall efficacy of BRV as add-on therapy. Patients with intellectual disabilities in whom the prevalence of epilepsy is higher, are often excluded from randomized controlled trials, and our study further assessed comparative effectiveness between this patient group and those with normal range intellect. We collected prospective data on 134 patients prescribed add-on BRV for epilepsy at a tertiary UK center over a 26-month period. All patients had previously received LEV. Sixty-three patients were on LEV at the start of the data collection period. Levetiracetam was withdrawn and switched to BRV in 39 patients because of inefficacy and 24 patients because of behavioral or psychiatric side effects. Seventy-three patients (54%) had a preexisting psychiatric or behavioral disorder compared with 64 patients (46%) without. The retention rate at last follow-up [mean: 11 months (0.5-26 months)] was 60% in the psychiatric/behavioral disorders group versus 67% in those without (p = 0.68). Forty-one patients had diagnosed intellectual disabilities. The retention rate was 66% in this group versus 62% in patients without intellectual disabilities (p = 0.36). The commonest treatment-emergent AEs were somnolence (26%), aggression (23%), and depression (9%). There were similar frequencies reported for these specific events across the groups. The proportion with a 50% responder rate was 29% in patients with focal epilepsy and 47% in patients with generalized and combined focal and generalized epilepsies. However, fifteen patients (11%) reported increased seizure activity leading to withdrawal of treatment. This study showed evidence that BRV may be an effective adjunctive therapy in patients with drug-resistant focal or generalized epilepsies whose seizures have previously not responded or tolerated LEV therapy. We demonstrated a higher incidence of treatment-emergent AEs leading to lower retention rates compared with previous studies across all patient groups. There were, however, no significant differences in tolerability between patients with preexisting psychiatric or behavioral comorbidities, or intellectual disability to those without.",
"affiliations": "Department of Neurology, Leeds Teaching Hospitals, Leeds, United Kingdom. Electronic address: engchuan.foo@nhs.net.;Department of Neurology, Leeds Teaching Hospitals, Leeds, United Kingdom.;Department of Neurology, Leeds Teaching Hospitals, Leeds, United Kingdom.;Department of Neurology, Leeds Teaching Hospitals, Leeds, United Kingdom.;Department of Neurology, Leeds Teaching Hospitals, Leeds, United Kingdom.;Department of Neurology, Leeds Teaching Hospitals, Leeds, United Kingdom.",
"authors": "Foo|Eng Chuan|EC|;Geldard|Jo|J|;Peacey|Caroline|C|;Wright|Elizabeth|E|;Eltayeb|Khalid|K|;Maguire|Melissa|M|",
"chemical_list": "D000927:Anticonvulsants; D011760:Pyrrolidinones; D000077287:Levetiracetam; C482793:brivaracetam",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2019.106505",
"fulltext": null,
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"issn_linking": "1525-5050",
"issue": "99()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Brivaracetam; Epilepsy; Intellectual disability; Levetiracetam; Psychiatric adverse event; Treatment-emergent adverse events",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D001526:Behavioral Symptoms; D015897:Comorbidity; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial; D004829:Epilepsy, Generalized; D005260:Female; D006801:Humans; D008607:Intellectual Disability; D000077287:Levetiracetam; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D011446:Prospective Studies; D011760:Pyrrolidinones; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "106505",
"pmc": null,
"pmid": "31493736",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Adjunctive brivaracetam in focal and generalized epilepsies: A single-center open-label prospective study in patients with psychiatric comorbidities and intellectual disability.",
"title_normalized": "adjunctive brivaracetam in focal and generalized epilepsies a single center open label prospective study in patients with psychiatric comorbidities and intellectual disability"
} | [
{
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{
"abstract": "This case report describes an unusual case of late-onset larynx angioedema after ranibizumab intravitreal injection. A 72-year-old female patient presented to our clinic for decreased vision; right eye (RE) fundoscopy and optical coherence tomography (OCT) revealed mild chorioretinal atrophy and choroidal neovascularization with subretinal fluid. A ranibizumab injection was planned in the RE, with standard pretreatment with daily oral administration of betamethasone, cetirizine, and ranitidine because her medical history revealed two adverse drug reactions (ADRs) to contrast media (CM). Despite the premedication, 2 h after injection, the patient referred throat closing sensation and dyspnea that resolved within few hours by betamethasone 4 mg intramuscular injection, without further reoccurrence. In occasion of the second intravitreal injection, video rhinofibrolaryngoscopy revealed subglottic edema that resolved within few hours by betamethasone 4 mg intramuscular injection. This report suggests that, even in cases of intravitreal injection, patients with history of allergy, despite the anti-allergic treatment, should be hospitalized to detect late onset of such a life-threatening complication.",
"affiliations": "Department of Medicine, Surgery and Dentistry, \"Scuola Medica Salernitana,\" University of Salerno, Salerno, Italy.;Department of Medicine, Surgery and Dentistry, \"Scuola Medica Salernitana,\" University of Salerno, Salerno, Italy.;Department of Medicine, Surgery and Dentistry, \"Scuola Medica Salernitana,\" University of Salerno, Salerno, Italy.;Department of Medicine, Surgery and Dentistry, \"Scuola Medica Salernitana,\" University of Salerno, Salerno, Italy.;Department of Medicine, Surgery and Dentistry, \"Scuola Medica Salernitana,\" University of Salerno, Salerno, Italy.",
"authors": "De Bernardo|Maddalena|M|https://orcid.org/0000-0003-4566-0064;Stellato|Cristiana|C|;Rosa|Nicola|N|;De Pascale|Ilaria|I|;Salzano|Francesco Antonio|FA|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D005938:Glucocorticoids; D001623:Betamethasone; D000069579:Ranibizumab",
"country": "England",
"delete": false,
"doi": "10.1177/2058738420929173",
"fulltext": "\n==== Front\nInt J Immunopathol Pharmacol\nInt J Immunopathol Pharmacol\nIJI\nspiji\nInternational Journal of Immunopathology and Pharmacology\n0394-6320 2058-7384 SAGE Publications Sage UK: London, England \n\n32820959\n10.1177/2058738420929173\n10.1177_2058738420929173\nCase Report\nA case of late-onset larynx angioedema after ranibizumab intravitreal injection: Ranibizumab-related angioedema\nhttps://orcid.org/0000-0003-4566-0064De Bernardo Maddalena Stellato Cristiana Rosa Nicola De Pascale Ilaria Salzano Francesco Antonio Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno, Italy\nMaddalena De Bernardo, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Via S Allende, Baronissi, Salerno 84081, Italy. Email: mdebernardo@unisa.it\n21 8 2020 \nJan-Dec 2020 \n34 205873842092917313 5 2019 21 4 2020 © The Author(s) 20202020SAGE 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 (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).This case report describes an unusual case of late-onset larynx angioedema after ranibizumab intravitreal injection. A 72-year-old female patient presented to our clinic for decreased vision; right eye (RE) fundoscopy and optical coherence tomography (OCT) revealed mild chorioretinal atrophy and choroidal neovascularization with subretinal fluid. A ranibizumab injection was planned in the RE, with standard pretreatment with daily oral administration of betamethasone, cetirizine, and ranitidine because her medical history revealed two adverse drug reactions (ADRs) to contrast media (CM). Despite the premedication, 2 h after injection, the patient referred throat closing sensation and dyspnea that resolved within few hours by betamethasone 4 mg intramuscular injection, without further reoccurrence. In occasion of the second intravitreal injection, video rhinofibrolaryngoscopy revealed subglottic edema that resolved within few hours by betamethasone 4 mg intramuscular injection. This report suggests that, even in cases of intravitreal injection, patients with history of allergy, despite the anti-allergic treatment, should be hospitalized to detect late onset of such a life-threatening complication.\n\nadverse drug reactionangioedemaintravitreal injectionranibizumabsubglottic edemaUniversità degli Studi di Salernohttps://doi.org/10.13039/501100007065FARBcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nExudative maculopathies are one of the most sight-threatening complications worldwide. Current trends of treatment suggest the use of intravitreal anti-vascular endothelial growth factor (VEGF) as the first-line therapy and, due to the increasing number of patients affected and the need of repeated treatments, in clinical routine they are often treated as outpatients.1 We report a case of late-onset larynx angioedema in a patient with history of allergy that underwent ranibizumab intravitreal injection, which to the best of our knowledge has not been previously described.\n\nCase report\nA 72-year-old woman was referred to our clinic for decreased vision in the right eye (RE). The subject provided a written informed consent for information and images, in accordance with the Declaration of Helsinki. Her medical history revealed two adverse drug reactions (ADRs) with contrast media (CM) injection, which occurred with submandibular and neck swelling, loss of voice, dyspnea, and fainting episode; no other symptoms and signs were present. The second ADR occurred despite patient’s premedication with oral corticosteroids ad histamine blockers, but in both cases, adverse events were solved treating her with intramuscular corticosteroids.\n\nThe patient regularly assumed an angiotensin-converting enzyme (ACE) inhibitor/diuretic combination (perindopril 5 mg/indapamide 1.25 mg) plus a beta blocker (bisoprolol 1.25 mg) as hypertension therapy over the past several years, without ADRs occurrence. The ocular anamnesis revealed the presence of severe myopia, retinal detachment in the left eye (LE) treated with surgery, and cataract surgery in both eyes, with no ADRs reported. Her best-corrected visual acuity was 20/70 RE and 20/20 LE; RE fundoscopy and optical coherence tomography (OCT) revealed mild chorioretinal atrophy and choroidal neovascularization (CNV) with subretinal fluid (Figure 1). The diagnosis of myopic CNV was entertained and ranibizumab injection was planned.\n\nFigure 1. Fundus photography and OCT image of the right eye.\n\nPremedication regimen with oral corticosteroid and antihistamines (betamethasone, cetirizine, ranitidine) was performed. The patient received intravitreal injection of ranibizumab in pre-filled syringe (containing a single dose of 0.05 mL solution); 2 h after injection, the patient referred throat closing sensation and dyspnea, treated and resolved with an intramuscular injection of betamethasone (one dose of 4 mg), without further reoccurrence.\n\nAfter this event, the patient underwent lidocaine 4% eye drops instillation and skin and fornix disinfection with povidone–iodine 5% solution, without ranibizumab injection, to determine whether the symptoms were related to preoperative preparation or ranibizumab injection; no reaction was detected in the following 3 h and in the days after discharge. The second injection of ranibizumab, preceded by the same premedication regimen, was followed by an extended period of observation in the hospital. The patient experienced the same symptoms; she underwent video rhinofibrolaryngoscopy (RFL), which revealed a subglottic edema. The patient was treated with betamethasone 4 mg intramuscular injection and the subglottic edema resolved in few hours, without further reoccurrence (Figure 2(a)–(d)).\n\nFigure 2. (a) Rhinofibrolaryngoscopy (RFL) before treatment showing a very light edema of the subglottic region. (b) RFL 10 min after the ophthalmological procedure showed an unmodified picture of the subglottic region. (c) RFL 1 h after the injection showing a clearly visible edema under the right true vocal cord, whereas the contralateral was unchanged. (d) 150 min after the injection, RFL showed a marked edema with a significant increase under the right true vocal cord.\n\nDiscussion\nOnly two cases of hypersensitivity reactions (HRs) to intravitreal injection of bevacizumab were described.2,3 In the first case, angioedema and conjunctival chemosis developed 50 min after the injection, which resolved within 48 h with intravenous methylprednisolone and diphenhydramine.2 In the second case, the patient developed dyspnea 5 min after the first and even after the second injection, despite pretreatment with cetirizine and diphenhydramine. After another injection with ranibizumab, the patient experienced throat tightness and coughing. Therefore, he was shifted to verteporfin and photodynamic therapy.3\n\nIn our case report, angioedema and its timing of onset (at the end of the 2-h time frame considered immunoglobulin E (IgE) mediated by World Allergy Organization (WAO) definition) are still potentially compatible with a type 1 HR, taking into account the implemented premedication regimen. However, the same clinical presentation previously occurred twice, with longer time lag (~6 h), following CM administration, which frequently triggers non-allergic hypersensitivity reaction (NAHR).4 Indeed, the patient carried several risk factors potentially relevant in the HR to ranibizumab: female sex, previous HR to CM, cardiovascular conditions, use of beta blocker and ACE inhibitors, which can trigger severe facial and laryngeal angioedema.5\n\nDifferentiation between allergic and NAHR is difficult due to superimposable timing and clinical manifestations; specificity and sensitivity of skin prick test for ranibizumab are yet to be established.6 However, desensitization protocols can successfully deliver monoclonals in patients experiencing HRs. Premedication with corticosteroids and H1-antihistamines is useful mainly for NAHRs5 although may not prevent IgE-dependent anaphylaxis.7–9 In these patients, alternative anti-VEGF monoclonals could be cau-tiously administered.2\n\nIn conclusion, this report documents endoscopically the localization of laryngeal swelling, and suggests that even in cases of intravitreal injection, patients with history of allergy, despite the anti-allergic treatment, should be hospitalized to detect late onset of such a life-threatening complication.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Ethical approval to report this case was obtained from Cometico Campania Sud, Italy (prot. no. 16544).\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the FARB, University of Salerno.\n\nInformed consent: Written informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iD: Maddalena De Bernardo \nhttps://orcid.org/0000-0003-4566-0064\n==== Refs\nReferences\n1 \nWiesinger K Reinelt P Ennemoser A , et al (2017 ) What can anti-VEGF therapy achieve in clinical routine?: Effectiveness of anti-VEGF therapy in patients with macular diseases in clinical routine on 1492 eyes in Austria\n. Ophthalmologe \n114 : 639 –645\n.27815675 \n2 \nMeredith GG Schkade PA Joondeph BC (2017 ) Allergic reaction upon intravitreal administration of anti-vascular endothelial growth factor agents\n. Retinal Cases & Brief Reports \n13 : 287 –289\n.\n3 \nToklu Y Sarac O Berk S , et al (2012 ) Angioedema after intravitreal bevacizumab injection\n. Cutaneous and Ocular Toxicology \n31 : 85 –86\n.22309281 \n4 \nRubio M Bousquet PJ Demoly P (2010 ) Update in drug allergy: Novel drugs with novel reaction patterns\n. Current Opinion in Allergy and Clinical Immunology \n10 : 457 –462\n.20706115 \n5 \nJohansson SG Bieber T Dahl R , et al (2004 ) Revised nomenclature for allergy for global use: Report of the nomenclature review committee of the world allergy organization, October 2003\n. Journal of Allergy and Clinical Immunology \n113 : 832 –836\n.15131563 \n6 \nBrockow K Garvey LH Aberer W , et al (2013 ) Skin test concentrations for systemically administered drugs—An ENDA/EAACI drug allergy interest group position paper\n. Allergy \n68 : 702 –712\n.23617635 \n7 \nSolensky R Khan DA Bernstein IL , et al (2010 ) Drug allergy: An updated practice parameter\n. Annals of Allergy, Asthma, & Immunology \n105 : 259 –273\n.\n8 \nDe Bernardo M Rosa N (2018 ) Comment on “Invasive and noninvasive means of measuring intracranial pressure: A review”\n. Physiological Measurement \n39 : 058001 .29767627 \n9 \nDe Bernardo M Vitiello L Rosa N (2019 ) Optic nerve ultrasonography to predict increased intracranial pressure in idiopathic intracranial hypertension\n. Neuroradiology Journal \n32 : 227 –228\n30793659\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0394-6320",
"issue": "34()",
"journal": "International journal of immunopathology and pharmacology",
"keywords": "adverse drug reaction; angioedema; intravitreal injection; ranibizumab; subglottic edema",
"medline_ta": "Int J Immunopathol Pharmacol",
"mesh_terms": "D000368:Aged; D000799:Angioedema; D020533:Angiogenesis Inhibitors; D001623:Betamethasone; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007273:Injections, Intramuscular; D058449:Intravitreal Injections; D007819:Laryngeal Edema; D000069579:Ranibizumab; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8911335",
"other_id": null,
"pages": "2058738420929173",
"pmc": null,
"pmid": "32820959",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "15131563;22309281;20706115;30793659;29767627;23617635;27815675;28301410",
"title": "A case of late-onset larynx angioedema after ranibizumab intravitreal injection: Ranibizumab-related angioedema.",
"title_normalized": "a case of late onset larynx angioedema after ranibizumab intravitreal injection ranibizumab related angioedema"
} | [
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"companynumb": "IT-TEVA-2021-IT-1879407",
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"activesubstancename": "BISOPROLOL"
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{
"abstract": "Although opioid maintenance therapy (OMT) is currently recommended for pregnant opioid-dependent women, potential effects on children's long-term development are still largely unknown. The current study assessed the long-term cognitive development of children born to women in OMT. Particularly, children's decision-making performance was assessed with a child-friendly version of the Iowa Gambling Task. Using a prospective longitudinal design, a cohort of children was followed from birth to middle childhood. Data were collected in Norway between 2005 and 2017. Participants included 41 children (aged 9-11 years), 20 of whom had histories of prenatal methadone or buprenorphine exposure. Background data were collected from personal interviews and medical records in 2005-2006. Children's affective decision-making was assessed in 2016-2017. Results showed no main effect of group on the net scores in the gambling task, F(1, 39) = 1.44, p = 0.24, η2 = 0.04, demonstrating no group differences in decision-making performance. A main effect of group was found on sensitivity to punishment, with children in the control group choosing the doors with the infrequent, but high punishment more often compared to children in the OMT group, F(1, 39) = 4.90, p = 0.03, η2 = 0.11. No main effect of group on decision-making speed was found, although results showed a significant interaction effect between group and gain, F(1, 8,194) = 4.09, p = 0.04, η2 = 0.001. Children prenatally exposed to opioids were found to have normal decision-making performance on an affective decision-making task and were able to consider future consequences when making decisions.",
"affiliations": "Department of Psychology, Inland Norway University of Applied Sciences, Lillehammer, Norway.;Cognitive Developmental Research Unit, Department of Psychology, University of Oslo, Oslo, Norway.",
"authors": "Carolien|Konijnenberg|K|https://orcid.org/0000-0001-5732-5488;Annika|Melinder|M|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1111/sjop.12743",
"fulltext": null,
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"issn_linking": "0036-5564",
"issue": "62(4)",
"journal": "Scandinavian journal of psychology",
"keywords": "Iowa Gambling Task; Methadone; buprenorphine; decision-making; opioid maintenance therapy; prenatal opioid exposure",
"medline_ta": "Scand J Psychol",
"mesh_terms": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D002648:Child; D002657:Child Development; D003071:Cognition; D003657:Decision Making; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone; D009664:Norway; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies",
"nlm_unique_id": "0404510",
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"pages": "529-536",
"pmc": null,
"pmid": "34037260",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Affective decision-making in children prenatally exposed to opioids.",
"title_normalized": "affective decision making in children prenatally exposed to opioids"
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"activesubstancename": "BUPRENORPHINE"
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"abstract": "An 80-year-old woman was diagnosed with miliary tuberculosis. Laboratory findings showed marked thrombocytopenia (3000/μl). Immune thrombocytopenia (ITP) was diagnosed because platelet transfusion was ineffective, and bone marrow puncture demonstrated a normal number of megakaryocytes. Anti-tuberculosis treatment was started promptly, followed by prednisolone 20 mg. However, the platelet count did not increase. The effect of high-dose intravenous immunoglobulin was temporary. She was not responded to prednisolone, and eltrombopag 12.5 mg was added. The eltrombopag dose was increased by 12.5 mg every two weeks. When the eltrombopag dose reached 50 mg, the thrombocytopenia improved sufficiently (44,000/μl). She didn't have any severe bleeding and thrombotic complications. The treatment of tuberculosis went well and there was no side effect of anti-tuberculosis treatment. Eltrombopag can be a useful treatment for ITP due to tuberculosis.",
"affiliations": "Department of Respiratory Medicine, National Hospital Organization Higashi-ohmi General Medical Center, 255 Gochi, Higashi-ohmi, Shiga, 527-8505, Japan.;Department of Respiratory Medicine, National Hospital Organization Higashi-ohmi General Medical Center, 255 Gochi, Higashi-ohmi, Shiga, 527-8505, Japan.",
"authors": "Wada|Hiroshi|H|;Sakashita|Takuto|T|",
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"country": "England",
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"doi": "10.1016/j.rmcr.2020.101320",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30534-7\n10.1016/j.rmcr.2020.101320\n101320\nCase Report\nA case of immune thrombocytopenia due to miliary tuberculosis effectively treated with eltrombopag\nWada Hiroshi hwada@belle.shiga-med.ac.jp∗ Sakashita Takuto Department of Respiratory Medicine, National Hospital Organization Higashi-ohmi General Medical Center, 255 Gochi, Higashi-ohmi, Shiga, 527-8505, Japan\n∗ Corresponding author. National Hospital Organization Higashi-ohmi General Medical Center, 255 Gochi, Higashi-ohmi, Shiga, 527-8505, Japan. hwada@belle.shiga-med.ac.jp\n09 12 2020 \n2020 \n09 12 2020 \n31 10132022 8 2020 7 12 2020 7 12 2020 © 2020 Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).An 80-year-old woman was diagnosed with miliary tuberculosis. Laboratory findings showed marked thrombocytopenia (3000/μl). Immune thrombocytopenia (ITP) was diagnosed because platelet transfusion was ineffective, and bone marrow puncture demonstrated a normal number of megakaryocytes. Anti-tuberculosis treatment was started promptly, followed by prednisolone 20 mg. However, the platelet count did not increase. The effect of high-dose intravenous immunoglobulin was temporary. She was not responded to prednisolone, and eltrombopag 12.5 mg was added. The eltrombopag dose was increased by 12.5 mg every two weeks. When the eltrombopag dose reached 50 mg, the thrombocytopenia improved sufficiently (44,000/μl). She didn't have any severe bleeding and thrombotic complications. The treatment of tuberculosis went well and there was no side effect of anti-tuberculosis treatment. Eltrombopag can be a useful treatment for ITP due to tuberculosis.\n\nKeywords\nTuberculosisImmune thrombocytopeniaEltrombopag\n==== Body\n1 Introduction\nImmune thrombocytopenia (ITP) is characterized by thrombocytopenia due to an autoimmune mechanism. Various infectious and non-infectious conditions can be considered as factors causing ITP.\n\nIt is considered very rare that tuberculosis is associated with secondary ITP, though no prospective study investigating the prevalence of secondary ITP due to tuberculosis has been reported [1]. Many secondary ITP cases due to tuberculosis are usually treated with anti-tuberculosis treatment and corticosteroids, resulting in an increase of platelets from some days to 3 months [1]. Some cases of refractory ITP that required high-dose intravenous immunoglobulin (IVIG) have been reported [2]. However, there have been only one report of ITP due to tuberculosis that eltrombopag, thrombopoietin receptor agonist (TPO-RA), was administered [3].\n\nWe report a case of secondary ITP due to miliary tuberculosis in which anti-tuberculosis treatment and prednisolone had no effect, IVIG had only temporary and limited effects, and a gradual additional increase of eltrombopag seemed to be effective and safe.\n\n2 Case report\nAn 80-year-old woman presented with a 1-month history of fever and appetite loss. Her chest computed tomography (CT) showed multiple miliary nodular shadows and some small cavitary lesions in all lung fields bilaterally (Fig. 1). Acid-fast bacteria staining of sputum was smear-positive, and tuberculosis was demonstrated in polymerase chain reaction (PCR) testing. The patient was diagnosed as having miliary tuberculosis and pulmonary tuberculosis. She was referred to our hospital and admitted to the isolation ward. She had mild mental retardation and a past history of an ovarian cyst.Fig. 1 Chest CT on admission.\n\nChest CT shows multiple miliary nodular shadows and some small cavitary legions in all lung fields bilaterally. The arrows indicate some small cavitary lesions.\n\nFig. 1\n\nOn examination, her height was 152.1 cm, her weight was 42.0 kg, her temperature was 36.5 °C, her blood pressure was 115/74 mmHg, her pulse rate was 91 beats/min, and her oxygen saturation was 93%. She had anemic conjunctivae and purpura of the right inguinal region and left elbow joint, but no enlarged lymph nodes.\n\nChest and abdominal examinations showed no specific findings. Laboratory findings showed a normal white blood cell count, anemia (Hb 7.1 g/dl), marked thrombocytopenia (Plt 3000/μL), and elevated CRP (Table 1). Coagulation, liver function, and renal function tests were normal. There was no elevation of bilirubin, urinary urobilinogen. The urine and blood cultures for acid-fast bacteria were negative. Standard anti-tuberculosis treatment (isoniazid 300 mg, rifampicin 450 mg, ethambutol 500 mg, pyrazinamide 1200 mg) was started, along with platelet transfusion after bone marrow puncture at the time of admission. There was no increase of platelets (9000/μL) despite transfusion of 10 units of platelets for two days. In her myelogram, total nucleated cell counts were normal (184,750/μL), differential counts of granulocyte and erythroblast were normal, the megakaryocyte counts were almost normal (111/μL) and no blastoid cells were found. Bone marrow findings showed normal hematopoietic capacity and some epithelioid granulomas with caseating necrosis (Fig. 2). Acid-fast bacteria staining and culture of bone marrow were both negative. Immune thrombocytopenia (ITP) was diagnosed on the basis of the lack of efficacy of platelet transfusion and normal hematopoietic capacity. Anemia improved after transfusion 2 units of RCC. Anti-Helicobacter pylori (HP) antibody, anti-nuclear antibody, and hepatitis C antibody were all negative. Platelet-associated IgG was positive (53.9 ng/107 cells). Therefore, it was considered that the thrombocytopenia was secondary ITP due to miliary tuberculosis.Table 1 Laboratory findings on admission.\n\nTable 1Hematology\tBiochemistry\t\nWBC\t6530\t/μL\tTP\t7.3\tg/dL\t\nNeutrophils\t68.9\t%\tAlbumin\t2.3\tg/dL\t\nLymphocytes\t24.8\t%\ttotal birilubin\t0.8\tmg/dL\t\nMonocytes\t5.5\t%\tAST\t31\tIU/L\t\nEosinophils\t0.6\t%\tALT\t15\tIU/L\t\nBasophils\t0.2\t%\tLDH\t294\tIU/L\t\nHematocrit\t23.8\t%\tALP\t276\tIU/L\t\nHemoglobin\t7.1\tg/dL\tCK\t20\tU/L\t\nRBC\t25,10,000\t/μL\tAMY\t49\tU/L\t\nPlatelets\t4000\t/μL\tBUN\t16\tmg/dL\t\n\t\t\tCRE\t0.93\tmg/dL\t\nCoagulation\t\t\tUA\t5.4\tmg/dL\t\nProthrombin time\t11.6\tsec\tCa\t8.2\tmg/dL\t\nAPTT\t40\tsec\tNa\t137\tmEq/dL\t\nFibrinogen\t161\tmg/dl\tK\t3.4\tmEq/dL\t\nD-dimer\t11.4\tμg/mL\tCl\t102\tmEq/dL\t\nSerology\tCRP\t2.67\tmg/dL\t\nantinuclear antibody\t＜40\tliter\tHbA1c\t4.9\t%\t\nHepatitis C antibody\tnegative\t\t\t\t\t\nanti H.pyroli antibody\t5.4\tIU/mL\tPT-IgG\t53.9\tng/107 cells\t\nRBC: red blood cell, ESR: erythrocyte sedimentation rate, TP: total protein.\n\nAST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, CK: creatine phosphokinase.\n\nAMY: amylase, BUN: blood urea nitrogen, CRE: creatinine, CRP: C reactive protein.\n\nAPTT: Activated partial thromboplastin time, PT-IgG: platelet associated immunoglobulin G.\n\nFig. 2 Histopathological findings of bone marrow (hematoxylin-eosin stain × 100).\n\nHistopathological findings of bone marrow from the right iliac crest show normal bone marrow and some epithelioid granuloma with caseating necrosis. The arrow indicates the caseating necrosis. The arrowheads indicate epithelioid cells. The circles indicate some epithelioid granuloma.\n\nAcid-fast bacteria staining and culture of bone marrow were both negative.\n\nFig. 2\n\nThere was no increase of platelets despite initiation of prednisolone 20 mg on the third day. High-dose IVIG (20,000 mg/day, 476 mg/kg) was given for 5 days because anti-tuberculosis drugs and prednisolone 20 mg were ineffective. Laboratory findings showed temporary improvement of the platelet counts (56,000/μL) on the day 11, but the platelet counts dropped to less than 10,000/μL again in several days. Eltrombopag 12.5 mg, recommended initial dose in Japan, was then added on day 17. However, no platelet increase was achieved, and the eltrombopag dose was then increased by 12.5 mg every two weeks. After prednisolone 20 mg was given for 4 weeks, the dose of prednisolone was decreased to 10 mg for three weeks. Sufficient elevation of the platelets (44,000/μL) was seen when the dose of eltrombopag reached 50 mg on day 65 (Fig. 3). The patient had no bleeding complications and no thrombotic diseases during hospitalization. During the treatment of tuberculosis, the major side effects, including liver dysfunction and rash, were not observed. The respiratory condition gradually improved in the initial two weeks. The drug sensitivity test for Mycobacterium tuberculosis showed that it was sensitive to all anti-tuberculosis drugs. The anti-tuberculosis drugs were decreased to the two drugs isoniazid and rifampicin on day 68. The sputum smear staining showed negative conversion at 5 weeks. A chest X-ray showed improvement of the miliary nodular shadows. She was discharged to her house on day 71. It was planned to give the patient standard anti-tuberculosis treatment for an extra 3 months (total 9 months) because of steroid use and the presence of miliary tuberculosis.Fig. 3 Clinical course.\n\nThis figure shows the clinical course and changes in hemoglobin and platelet counts.\n\nThe red line shows hemoglobin (Hb). The blue line shows the platelets (PLT). IVIG: intravenous immunoglobulin therapy. INH: isoniazid. RFP: Rifampicin. EB: ethambutol. PZA: pyrazinamide.\n\nFig. 3\n\n3 Discussion\nThis present case demonstrates that additional eltrombopag can be an effective and practical treatment in secondary ITP due to tuberculosis not responded to prednisolone and anti-tuberculosis treatment. This is important information for physicians because secondary ITP due to tuberculosis is considered a treatable disorder that responds to corticosteroids, and anti-tuberculosis treatment.\n\nHer thrombocytopenia is existing in the diagnosis of tuberculosis and she didn't have concurrent medication. Bone marrow involvement with tuberculosis is conceivable as a reason for thrombocytopenia, because she had caseating granuloma in her bone marrow. However, the diagnosis in the present case was ITP, considering that platelet transfusion was not effective, and there was no decrease of megakaryocytes, normal hematopoietic capacity in her bone marrow. In our view, bone marrow involvement of tuberculosis didn't contribute much to thrombocytopenia clinically. We think she didn't suffer from Evan's syndrome in the absence of hemolysis and improvement of anemia by transfusion. We ruled out hemophagocytic lymphohistiocytosis (HLH) because of no splenomegaly, fibrinogen 161 mg/dl (more than 150 mg/dl), and no HLH in the bone marrow findings. Moreover, we ruled out Disseminated intravascular coagulation because of normal prothrombin time (11.6 sec), activated partial thromboplastin time (40 sec), fibrinogen, that is no hypercoagulable condition.\n\nWe ultimately diagnosed her as ITP due to tuberculosis because she didn't have connective tissue disease and other infectious diseases due to ITP. The platelet counts were marked low value, and the patient presented with severe anemia. She had subcutaneous bleeding without apparent wet purpura. But we couldn't completely rule out wet purpura including gastrointestinal bleeding at the admission because we didn't know the progression of anemia. Therefore, we considered the necessity of treating ITP.\n\nNo established standard therapy for ITP due to tuberculosis has been recognized. Weber et al. reported a case and a review of secondary ITP due to tuberculosis. Anti-tuberculosis treatment and corticosteroids are effective in many cases. High-dose IVIG is sometimes used with corticosteroids. The prognosis of ITP due to tuberculosis is generally good. Weber et al. concluded that early diagnosis and initiation of treatment for tuberculosis should be given the highest priority to reduce the use of immunosuppressants, transfusion, and the risk of hemorrhage [1]. There are 4 new case reports of ITP due to tuberculosis after Weber's report [[4], [5], [6], [7]]. Considering 50 cases and 4 cases, most cases obtain platelets response using anti-tuberculosis treatment, corticosteroid and IVIG. Time from treatment initiation until platelets recovery varies from some days to a few months. No severe fetal bleeding occurred in the clinical course [1,[4], [5], [6], [7]].\n\nAnti-tuberculosis treatment combined with high-dose IVIG were reported to be safe and effective for ITP due to tuberculosis. The effect of high-dose IVIG was obtained in a few days [8,9]. In the present case, an early increase of platelets was seen with high-dose IVIG, but it was not sustained.\n\nThe standard first-line treatment for primary ITP is mainly corticosteroids. At least 80% of patients with ITP showed an initial response to corticosteroids. Intravenous immunoglobulin is often used when a rapid rise in the platelet count is desired [10]. There are several second-line treatments for corticosteroid-resistant ITP. TPO-RA, splenectomy, and rituximab are recommended, and the choice of these second line treatments should be based on the individual situation [11].\n\nIn adults, the treatments of secondary ITP differ depending on the underlying disease. Corticosteroids and splenectomy are less effective in secondary than in primary ITP [12]. Secondary ITP with infectious diseases has no tendency to remit spontaneously, although the severity of the thrombocytopenia may parallel the stage of the infectious disease [13]. Patients with HCV infection and immune thrombocytopenia have been reported to have a greater than 50% platelet response to corticosteroids [13,14]. In Rajan's report, of the seven patients treated with prednisone, four (55.7%) responded, and six developed elevations of hepatic transaminases of two times greater than pretreatment levels while receiving prednisone [15]. In patients with HIV infection, antiretroviral therapy is the first-line and most effective treatment [13,14]. In addition, HIV-associated thrombocytopenia is generally responsive to the therapies used in classical ITP [13]. In H pylori-infected ITP patients, eradication therapy obtains an overall response in 52.7% of patients [13]. However, prolonged corticosteroid usage has a potential adverse effect on the underlying infection [14].\n\nEltrombopag is an oral TPO-RA and works on the stem cells and megakaryocytes and increases platelet counts. Eltrombopag is positioned as the second-line therapy for adult primary ITP [14]. The RAISE study demonstrated that eltrombopag had more efficacy in previously treated ITP than placebo over a 6-month period [16]. The EXTEND study demonstrated that eltrombopag had infrequent important adverse events [17]. The role of eltrombopag in secondary ITP is not established. Gonzalez-Lopez et al. reported the use of eltrombopag for secondary ITP in clinical practice. In their report, of 87 secondary ITP patients who had been treated with eltrombopag, 44 (51%) had a platelet response, including 40 (46%) with complete response. The median time to platelet response was 15 days (95% confidence interval, 7–28 days), and the platelet response rate was significantly lower in lymphoproliferative disorders than in autoimmune diseases and infectious diseases. Forty-three patients (49.4%) experienced adverse events (mainly grade 1–2), the most common being hepatobiliary laboratory abnormalities. Eltrombopag is effective and well-tolerated in unselected patients with ITP secondary to both immune and infectious disorders [12]. But there has been only one report in which eltrombopag was administered for ITP due to tuberculosis. In Surana's case, high dose dexamethasone and anti-rh0 immunoglobulin were minimal transit response, and the administration of eltrombopag 50 mg led to the rapid response of platelets [3].\n\nIn the present case, prednisolone 20mg is too low because prednisolone 0.5mg/kg is a small dose as the treatment of ITP and the effect of prednisolone decreases under combination with rifampicin inducing cytochrome p450 3A4 (CYP3A4). We placed maximum priority on tuberculosis treatment. We had to start prednisolone early because we evaluate the patient had bleeding tendency. But we worried the deterioration of tuberculosis and considered she might resolve with tuberculosis treatment alone. Therefore, we decided to use low dose prednisolone.\n\nA low dose of prednisolone may be one of the reasons that anti-tuberculosis treatment and prednisolone were not effective for ITP due to tuberculosis. In adults with newly diagnosed ITP, the ASH guideline panel suggests either prednisone (0.5–2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days) as the corticosteroid for initial therapy [6]. In the treatment of secondary ITP due to tuberculosis, the most important aim is curing tuberculosis. We didn't use high-dose and long-term corticosteroids and administered eltrombopag early to avoid that tuberculosis got worse. We initiated 12.5 mg of eltrombopag and increased the dose every two weeks according to package insert in Japan.\n\nDhibar DP et al. claimed IV pulse of methylprednisolone along with anti-tuberculosis treatment might be given after judging the risk and benefit in resource constraint settings [18]. We think eltrombopag should be used in only patients with strong bleeding tendency and resistant to anti-tuberculosis treatments and corticosteroids. Anti-tuberculosis treatment and prednisolone could be useful in many cases. We should wait with using only anti-tuberculosis treatment and prednisolone until recovery of platelets in resource constraint settings.\n\nThere are some possibilities that may explain why it took a long time to increase platelet counts in the present case. First, the dose of prednisolone may have been too low. Second, the initial dose of eltrombopag may have been too low. Third, the anti-tuberculosis treatment takes time to have an effect on ITP independently from eltrombopag. We don't know eltrombopag was effective for ITP due to tuberculosis alone, but low dose prednisolone, anti-tuberculosis treatment and early administered eltrombopag resulted in the increase of platelets and no influence for tuberculosis treatment. Although the recommended initial dose of eltrombopag is 12.5 mg in Japan, the higher initial dose may be better.\n\nEltrombopag was effective for ITP due to tuberculosis in which anti-tuberculosis treatment, corticosteroids, and high-dose IVIG were ineffective. There were no major or minor side effects. We prefer to avoid immunosuppressants for anti-tuberculosis treatment and corticosteroids-resistant ITP due to tuberculosis. In such cases, additional eltrombopag can be a useful and safe option.\n\nIn our view, corticosteroids and anti-tuberculosis treatment should be used in combination, in the treatment of ITP due to tuberculosis. If this is not effective, eltrombopag should be administered early in the treatment of ITP due to tuberculosis. These treatments can be an effective and safe treatment without negative impact on tuberculosis treatment. It is strongly expected that additional cases using eltrombopag in secondary ITP cases due to tuberculosis are reported. In conclusion, the second case in which additional eltrombopag was effective for an elderly woman with ITP due to miliary tuberculosis not responded to prednisolone and anti-tuberculosis treatment was described. Eltrombopag may have an advantage in ITP secondary to tuberculosis in which anti-tuberculosis treatment, corticosteroids and high-dose IVIG are ineffective.\n\nDeclaration of competing interest\nThe authors state that they have no conflict of interest to declare.\n\nAcknowledgements\nThe authors would like to thank Dr Masaki Iwasa of the Department of Hematology of Shiga University of Medical Science for advice about hematological examination.\n==== Refs\nReferences\n1 Weber S.F. Bélard S. Rai S. Immune thrombocytopenia secondary to tuberculosis: a case and review of literature Int. J. Tubercul. Lung Dis. 21 4 2017 466 470 \n2 Akyildiz B. Uzel N. Yanni D. Immune thrombocytopenic purpura associated with pulmonary tuberculosis Turk. J. Pediatr. 51 2009 271 274 19817271 \n3 Sunara A.P. Shelgikar K.M. Melinkeri S. Immune Thrombocytopenia (ITP): A Rare Association of Lymphnode Tuberculosis. J Assoc Physicians India vol. 62 2014 74 76 Jan; \n4 Rama Krishna M. Gottam U.S. Mahendra N. Disseminated tuberculosis with sever immune thrombocytopenia Feb Respir. Med. Case Rep. 25 27 2019 10.1016/j.rmcr.2019.02.013 100812, PMID: 30949428; PMCID: PMC6430074 \n5 Nasa P. Juneja D. Sehra S. Immune thrombocytopenic purpura in a patient with disseminated tuberculosis: an unusual presentation Int. J. Mycobacteriol. 8 1 2019 107 109 10.4103/ijmy.ijmy_169_18.PMID:30860190 Jan-Mar 30860190 \n6 Panda S. Meher L.K. Dalai S.P. A case of immune thrombocytopenic purpura secondary to pulmonary tuberculosis J. Clin. Diagn. Res. 10 10 2019 OD12 OD13 10.7860/JCDR/2016/21365.8726 Epub 2016 Oct 1. PMID: 27891382; PMCID: PMC5121720 \n7 Lugito N.P.H. Lorens J.O. Kwenandar J. Kurniawan A. The dilemma in a case of immune thrombocytopenia in a patient with human immunodeficiency virus on antituberculosis treatment for miliary pulmonary tuberculosis Oxf. Med. Case Rep. 11 2019 486 489 10.1093/omcr/omz119.PMID:31844534 PMCID: PMC6902628 \n8 Tsuro K. Kojima H. Mitoro A. Immune thrombocytopenic purpura associated with pulmonary tuberculosis Intern. Med. 45 11 2006 739 742 16819256 \n9 Ghobrial M.W. Aobornoz M.A. Immune thrombocytopenia: a rare presenting manifestation of tuberculosis Am. J. Hematol. 67 2 2001 139 143 11343388 \n10 Kistanguri G. McCrae K.R. Immune thrombocytopenia Hematol. Oncol. Clin. N. Am. 27 3 2013 495 520 \n11 Neunert C. Terrell D.R. Arnold D.R. American Society of Hematology 2019 guidelines for immune thrombocytopenia Blood Adv. 3 23 2019 3829 3866 31794604 \n12 González-López T.J. Alvarez-Roman M. Pascual C. Use of eltrombopag for secondary immune thrombocytopenia in clinical practice Br. J. Haematol. 178 6 2017 959 970 28573819 \n13 Stasi R. Therapeutic strategies for hepatitis- and other infection-related immune thrombocytopenias Semin. Hematol. 46 1 Suppl 2 2009 S15 S25 19245929 \n14 Stasi R. Willis F. Shannon M.S. Infectious causes of chronic immune thrombocytopenia Hematol. Oncol. Clin. N. Am. 23 6 2009 1275 1297 \n15 Rajan S.K. Espina B.M. Liebman H.A. Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura Br. J. Haematol. 129 6 2005 818 824 15953010 \n16 Cheng G. Saleh M.N. Marcher C. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomized, phase 3 trial Lancet 29 9763 2011 393 402 377 \n17 Wong R.S.M. Saleh M.N. Khelif A. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study Blood 130 23 2017 2527 2536 29042367 \n18 Dhibar D.P. Sahu K.K. Dhir V. Immune thrombocytopenia as a presenting manifestation of tuberculosis- challenge in resource constraint settings J. Clin. Diagn. Res. 10 10 2016 OD01 OD02\n\n",
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"issn_linking": "2213-0071",
"issue": "31()",
"journal": "Respiratory medicine case reports",
"keywords": "Eltrombopag; Immune thrombocytopenia; Tuberculosis",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
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"pages": "101320",
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"pubdate": "2020",
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"title": "A case of immune thrombocytopenia due to miliary tuberculosis effectively treated with eltrombopag.",
"title_normalized": "a case of immune thrombocytopenia due to miliary tuberculosis effectively treated with eltrombopag"
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"abstract": "OBJECTIVE\nThe development of oral chemotherapy (OC) has led to the recent establishment of multidisciplinary programmes involving pharmacists. We evaluated the utility of our local programme for detecting potential interactions with OCs, particularly drug-drug interactions (DDIs) and herbal-drug interactions (HDIs).\n\n\nMETHODS\nWe performed a single-centre retrospective descriptive study of patients on OC attending a pharmaceutical consultation (PC) during a seven-month period. These consultations included the use of various complementary tools/databases to search for interactions.\n\n\nRESULTS\nWe analysed 308 treatments taken by 42 consecutive patients. Fifty-four potential interactions with OCs were detected in 26% (n = 79) of the treatments taken by patients: 46 DDIs (32 minor, 12 major, 2 contraindicated) and eight HDIs. Five interventions associated with interactions were suggested by pharmacists during the consultations (4 were taken into account by oncologists). The total mean time spent on each PC for an individual patient was 80 minutes (36 minutes of preparation, 44 minutes with the patient).\n\n\nCONCLUSIONS\nThis pilot study highlights the importance of studying interactions in such patients, and of the expertise of pharmacists for detecting interactions, which were found in more than one in four treatment lines. The further development of such activities, which already take up considerable amounts of time, is therefore warranted.",
"affiliations": "Department of Pharmacy, Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Assistance Publique, Hôpitaux de Paris, Paris, France.;Department of Pharmacy, Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Assistance Publique, Hôpitaux de Paris, Paris, France.;Department of Pharmacy, Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Assistance Publique, Hôpitaux de Paris, Paris, France.;Department of Pharmacy, Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Assistance Publique, Hôpitaux de Paris, Paris, France.;Department of Medical Oncology, Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Assistance Publique, Hôpitaux de Paris, Paris, France.;Department of Medical Oncology, Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Assistance Publique, Hôpitaux de Paris, Paris, France.;Department of Pharmacy, Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Assistance Publique, Hôpitaux de Paris, Paris, France.;Department of Pharmacy, Hôpital Européen Georges Pompidou, Hôpitaux Universitaires Paris Ouest, Assistance Publique, Hôpitaux de Paris, Paris, France.",
"authors": "Lachuer|Célia|C|https://orcid.org/0000-0002-0963-8110;Perrin|Germain|G|;Chastel|Aymeric|A|;Aboudagga|Hail|H|;Thibault|Constance|C|;Delanoy|Nicolas|N|;Caudron|Eric|E|;Sabatier|Brigitte|B|",
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"issue": "30(3)",
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"medline_ta": "Eur J Cancer Care (Engl)",
"mesh_terms": "D003430:Cross-Sectional Studies; D004347:Drug Interactions; D006801:Humans; D004364:Pharmaceutical Preparations; D010595:Pharmacists; D010865:Pilot Projects; D012017:Referral and Consultation; D012189:Retrospective Studies",
"nlm_unique_id": "9301979",
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"pages": "e13396",
"pmc": null,
"pmid": "33340189",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pharmaceutical consultation to detect drug interactions in patients treated with oral chemotherapies: A descriptive cross-sectional study.",
"title_normalized": "pharmaceutical consultation to detect drug interactions in patients treated with oral chemotherapies a descriptive cross sectional study"
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"drugaddition... |
{
"abstract": "Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.",
"affiliations": "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Pathology, St. Mary's Hospital, Madison, Wisconsin, USA.;Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Gleue|Casey A|CA|https://orcid.org/0000-0002-3144-6318;Shah|Kabeer|K|;Wentworth|Ashley|A|;Bridges|Alina|A|",
"chemical_list": "D000631:Aminopyridines; D002227:Carbazoles; D018797:Cell Cycle Proteins; D007769:Lactams; D008869:Microtubule-Associated Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C415585:EML4 protein, human; D012697:Serine Endopeptidases; C582670:alectinib; C000590786:lorlatinib",
"country": "United States",
"delete": false,
"doi": "10.1111/cup.13911",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": "48(3)",
"journal": "Journal of cutaneous pathology",
"keywords": "anaplastic lymphoma kinase inhibitor; drug reaction; granulomatous; sarcoidal",
"medline_ta": "J Cutan Pathol",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000368:Aged; D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D001706:Biopsy; D002227:Carbazoles; D018797:Cell Cycle Proteins; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006099:Granuloma; D006801:Humans; D007769:Lactams; D008869:Microtubule-Associated Proteins; D009367:Neoplasm Staging; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D012507:Sarcoidosis; D012697:Serine Endopeptidases; D012867:Skin; D028761:Withholding Treatment",
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "425-428",
"pmc": null,
"pmid": "33128468",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cutaneous sarcoid-like drug reaction caused by an anaplastic lymphoma kinase inhibitor.",
"title_normalized": "cutaneous sarcoid like drug reaction caused by an anaplastic lymphoma kinase inhibitor"
} | [
{
"companynumb": "US-PFIZER INC-202101442643",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LORLATINIB"
},
"drugadditional": "1",
... |
{
"abstract": "Sorafenib, a multiple kinase inhibitor, has been established as first-line standard systemic chemotherapy for patients with advanced hepatocellular carcinoma (HCC). We encountered a patient with combined hepatocellular and cholangiocarcinoma (CHC) who achieved complete remission in response to sorafenib treatment. A 58-year old man with hepatitis C virus (HCV)-induced liver cirrhosis was diagnosed with CHC in segments 6th and 7th of the liver and underwent partial surgical resection. Three months later, CHC recurred as metastases at multiple intrahepatic sites, lymph nodes, and bones, making surgery impossible. Treatment with sorafenib was initiated at 400 mg b.i.d., later reduced to 400 mg/day. After 6 months of sorafenib administration, he no longer showed abnormal uptake on fluorodeoxyglucose positron emission tomography. He was continued on sorafenib for 2.5 years, but later discontinued due to adverse events. He has shown no evidence of tumor recurrence more than 1 year after sorafenib discontinuation. His HCV was eradicated by direct-acting antivirals, and he remains in good health.",
"affiliations": "Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan. tajikazu@med.u-toyama.ac.jp.;Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Gastroenterology, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.",
"authors": "Futsukaichi|Yuka|Y|;Tajiri|Kazuto|K|http://orcid.org/0000-0002-2373-8601;Kobayashi|Saito|S|;Nagata|Kohei|K|;Yasumura|Satoshi|S|;Takahara|Terumi|T|;Minemura|Masami|M|;Yasuda|Ichiro|I|",
"chemical_list": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D047428:Protein Kinase Inhibitors; D000077157:Sorafenib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-018-0918-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "12(2)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Cirrhosis; Combined hepatocellular-cholangiocarcinoma; Hepatitis C virus; Sorafenib; Systemic chemotherapy",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D018281:Cholangiocarcinoma; D019698:Hepatitis C, Chronic; D006801:Humans; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D047428:Protein Kinase Inhibitors; D012074:Remission Induction; D000077157:Sorafenib",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "128-134",
"pmc": null,
"pmid": "30374884",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "12913082;15466206;18152860;18284443;18650514;19935794;21253326;21331764;21748296;24294517;24712771;2578078;26571380;27064257;27783997;28480073;28529557;28852525;29085491;29486800;29856900",
"title": "Combined hepatocellular-cholangiocarcinoma successfully treated with sorafenib: case report and review of the literature.",
"title_normalized": "combined hepatocellular cholangiocarcinoma successfully treated with sorafenib case report and review of the literature"
} | [
{
"companynumb": "JP-BAYER-2018-008270",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"... |
{
"abstract": "Fluoroquinolones (FQs) and extended-spectrum cephalosporins (ESCs) are associated with higher risk of Clostridioides difficile infection (CDI). Decreasing the unnecessary use of FQs and ESCs is a goal of antimicrobial stewardship. Understanding how prescribers perceive the risks and benefits of FQs and ESCs is needed.\n\n\n\nWe conducted interviews with clinicians from 4 hospitals. Interviews elicited respondent perceptions about the risk of ESCs, FQs, and CDI. Interviews were audio recorded, transcribed, and analyzed using a flexible coding approach.\n\n\n\nInterviews were conducted with 64 respondents (38 physicians, 7 nurses, 6 advance practice providers, and 13 pharmacists). ESCs and FQs were perceived to have many benefits, including infrequent dosing, breadth of coverage, and greater patient adherence after hospital discharge. Prescribers stated that it was easy to make decisions about these drugs, so they were especially appealing to use in the context of time pressures. They described having difficulty discontinuing these drugs when prescribed by others due to inertia and fear. Prescribers were skeptical about targeting specific drugs as a stewardship approach and felt that the risk of a negative outcome from under treatment of a suspected bacterial infection was a higher priority than the prevention of CDI.\n\n\n\nPrescribers in this study perceived many advantages to using ESCs and FQs, especially under conditions of time pressure and uncertainty. In making decisions about these drugs, prescribers balance risk and benefit, and they believed that the risk of CDI was acceptable in compared with the risk of undertreatment.",
"affiliations": "Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.;Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.;Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.;Division of Infectious Diseases, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.;Department of Infectious Diseases, Rochester General Hospital, Rochester, New York.;Center for Community Health and Prevention, University of Rochester Medical Center, Rochester, New York.;Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia.;Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, AtlantaGeorgia.;Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, AtlantaGeorgia.;Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.",
"authors": "Szymczak|Julia E|JE|0000-0002-3230-8670;Muller|Brandi M|BM|;Shakamuri|Nikitha Shankar|NS|;Hamilton|Keith W|KW|;Gerber|Jeffrey S|JS|;Laguio-Vila|Maryrose|M|;Dumyati|Ghinwa K|GK|;Fridkin|Scott K|SK|;Guh|Alice Y|AY|;Reddy|Sujan C|SC|;Lautenbach|Ebbing|E|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D024841:Fluoroquinolones",
"country": "United States",
"delete": false,
"doi": "10.1017/ice.2020.183",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-823X",
"issue": "41(8)",
"journal": "Infection control and hospital epidemiology",
"keywords": null,
"medline_ta": "Infect Control Hosp Epidemiol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000082682:Clostridioides; D016360:Clostridioides difficile; D003015:Clostridium Infections; D003428:Cross Infection; D024841:Fluoroquinolones; D006801:Humans; D010465:Perception",
"nlm_unique_id": "8804099",
"other_id": null,
"pages": "914-920",
"pmc": null,
"pmid": "32468967",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Prescriber perceptions of fluoroquinolones, extended-spectrum cephalosporins, and Clostridioides difficile infection.",
"title_normalized": "prescriber perceptions of fluoroquinolones extended spectrum cephalosporins and clostridioides difficile infection"
} | [
{
"companynumb": "US-JNJFOC-20201002854",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report ocular side effects after inadvertent intracameral injection of a high dose of cefuroxime.\n\n\nMETHODS\nNineteen eyes of 19 patients were seen in our eye department 1 week after the referring surgeon had injected an erroneous dose of intracameral cefuroxime (12.5 mg/0.1 mL in 14 patients, Group A, and 10 mg/0.1 mL in 5 patients, Group B) at the end of a cataract surgery. A complete ophthalmic examination was performed postoperatively.\n\n\nRESULTS\nEight patients (42.10%) exhibited ocular side effects. One patient (Group A) developed a noninfectious panuveitis. One case (Group B) had a serous macular detachment. Five patients (4 from Group A and 1 from Group B) showed a disruption of the ellipsoid layer with temporary/permanent drop in visual acuity. One patient presented with color alteration (Group A), but electrodiagnostic studies did not reveal any significant alterations.\n\n\nCONCLUSIONS\nAnterior and posterior inflammation has been described after intracameral injection of high dose of cefuroxime. In this study, 10 mg to 12.5 mg of intracameral cefuroxime is shown to be, principally, toxic to the retina with transient or permanent retinal changes on optical coherence tomography which correlate with visual outcomes postoperatively. Protocols to avoid dilution errors should be available in theaters during cataract surgery where such commercial preparations are not available.",
"affiliations": "Torbay Hospital-South Devon Healthcare NHS Foundation Trust, Torquay, United Kingdom.",
"authors": "Kamal-Salah|Radua|R|;Osoba|Olayinka|O|;Doyle|Edward|E|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002444:Cefuroxime",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000577",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "13(3)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002444:Cefuroxime; D005260:Female; D006801:Humans; D056965:Injections, Intraocular; D008297:Male; D019300:Medical Errors; D008875:Middle Aged; D015864:Panuveitis; D012163:Retinal Detachment; D014786:Vision Disorders",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "269-272",
"pmc": null,
"pmid": "28301414",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "OCULAR TOXICITY AFTER INADVERTENT INTRACAMERAL INJECTION OF HIGH DOSE OF CEFUROXIME DURING CATARACT SURGERY: A CASE SERIES.",
"title_normalized": "ocular toxicity after inadvertent intracameral injection of high dose of cefuroxime during cataract surgery a case series"
} | [
{
"companynumb": "FI-ALKEM LABORATORIES LIMITED-FI-ALKEM-2019-05960",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFUROXIME AXETIL"
},
... |
{
"abstract": "The type I cryoglobulins (CGs) account for 10-15% of all cryoglobulins and are found in patients with hematological disorders. We here describe the largest series of seven cases of type I cryoglobulinemia associated with multiple myeloma (MM) and provide a detailed review of the literature associated with this disorder, with the aim of improving the future diagnosis and therapeutic management of this rare disease. Six of the cases in our series were men aged 28-69 years, and most of the subject patients had an immunoglobulin G (IgG) monoclonal component and stage I indolent MM that manifested as cryoglobulin-related symptoms. The patients were all karyotypically normal. Clinical manifestations in this group were: skin lesions (five cases, 71.4%), rheumatologic failure (four cases, 57.1%), neurological abnormalities (two cases, 28.6%), mixed cutaneous/rheumatologic/renal defects (one case, 14.3%) and one case in which the cryoglobulinemia was asymptomatic. Two patients experienced acute renal failure but underwent a full recovery following treatment for MM. We conclude from our analysis that treatment approaches for severe type I cryoglobulinemia should involve plasmapheresis at the onset to achieve a rapid control of the CG-related symptoms, and that specific MM treatments should be introduced also at an early stage to avoid cryoglobulinemia relapse. In this context, bortezomib and lenalidomide are potentially the most effective therapeutic agents.",
"affiliations": "Rheumatology Department, Cochin Hospital, Paris, France.",
"authors": "Payet|Judith|J|;Livartowski|Joël|J|;Kavian|Niloufar|N|;Chandesris|Olivia|O|;Dupin|Nicolas|N|;Wallet|Nadège|N|;Karras|Alexandre|A|;Salliot|Carine|C|;Suarez|Felipe|F|;Avet-Loiseau|Hervé|H|;Alyanakian|Marie Alexandra|MA|;Nawakil|Chadi Al|CA|;Park|Sophie|S|;Tamburini|Jé|J|;Roux|Christian|C|;Bouscary|Didier|D|;Sparsa|Laetitia|L|",
"chemical_list": "D007074:Immunoglobulin G; D007075:Immunoglobulin M",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2012.671481",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "54(4)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D003449:Cryoglobulinemia; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009336:Necrosis; D009367:Neoplasm Staging; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "767-77",
"pmc": null,
"pmid": "22385269",
"pubdate": "2013-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Type I cryoglobulinemia in multiple myeloma, a rare entity: analysis of clinical and biological characteristics of seven cases and review of the literature.",
"title_normalized": "type i cryoglobulinemia in multiple myeloma a rare entity analysis of clinical and biological characteristics of seven cases and review of the literature"
} | [
{
"companynumb": "PHHY2015FR007388",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
"drug... |
{
"abstract": "Nongestational ovarian choriocarcinoma (NGOC) accounts for <1% of ovarian germ cell tumors and may develop into the rare and fatal complication of choriocarcinoma syndrome. We reported a case of a 12-year-old girl with NGOC that metastasized to the lungs, retroperitoneal lymph nodes and brain. On day 2 of chemotherapy with actinomycin D and etoposide, choriocarcinoma syndrome developed due to a massive pulmonary hemorrhage, presenting as acute respiratory distress syndrome. The patient received mechanical ventilation and multimodal support and completed two cycles of an actinomycin D and etoposide regimen with intubation. After the patient's acute respiratory distress syndrome was under control, she received 9 cycles of more intensive chemotherapy regimens and achieved complete remission. An exploratory laparotomy with salpingo-oophorectomy confirmed ovarian choriocarcinoma. The patient remained disease-free at a 3-month follow-up visit. In conclusion, appropriate management consisting of multimodal support and timely, sequential and intensive chemotherapy is effective for NGOC complicated with choriocarcinoma syndrome. Stating with mild regimens would probably reduce the risk of choriocarcinoma syndrome, or at least lessen its severity. To our knowledge, we presented the first report of NGOC-related choriocarcinoma syndrome.",
"affiliations": "Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, China; Department of Obstetrics and Gynecology, The Sencond Hospital of Hebei Medical University, Shijiazhuang, China.;Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, China. Electronic address: lileigh@163.com.;Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, China.",
"authors": "Peng|Hongfa|H|;Li|Lei|L|;Bi|Yalan|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.currproblcancer.2020.100539",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-0272",
"issue": "44(4)",
"journal": "Current problems in cancer",
"keywords": "Acute respiratory distress syndrome; Chemotherapy; Choriocarcinoma syndrome; Nongestational ovarian choriocarcinoma",
"medline_ta": "Curr Probl Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002822:Choriocarcinoma; D019468:Disease Management; D005260:Female; D006801:Humans; D009373:Neoplasms, Germ Cell and Embryonal; D010051:Ovarian Neoplasms; D011379:Prognosis",
"nlm_unique_id": "7702986",
"other_id": null,
"pages": "100539",
"pmc": null,
"pmid": "31987522",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Successful management of nongestational ovarian choriocarcinoma complicated with choriocarcinoma syndrome: A case report and a literature review.",
"title_normalized": "successful management of nongestational ovarian choriocarcinoma complicated with choriocarcinoma syndrome a case report and a literature review"
} | [
{
"companynumb": "CN-BAXTER-2020BAX003208",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "Recent large use of magnesium in the obstetric population should incite anesthesiologists to control its side effects and drugs interactions. We report a case of a 30-year-old woman, with severe preeclampsia and HELLP syndrome, receiving sulfate magnesium and nicardipine, who underwent a cesarean section under general anesthesia. She developed a prolonged and deep neuromuscular blockade, which was antagonized three hours later with neostigmine. In case of therapeutic hypermagnesaemia, non-depolarizing relaxants must be used in reduced doses, and at increased time intervals, with appropriate neuromuscular monitoring.",
"affiliations": "Obstetric and Pediatric Intensive Care Unit, University Hospital Hassan II, Fez, Morocco.;Obstetric and Pediatric Intensive Care Unit, University Hospital Hassan II, Fez, Morocco.;Obstetric and Pediatric Intensive Care Unit, University Hospital Hassan II, Fez, Morocco.",
"authors": "Berdai|Mohamed Adnane|MA|;Labib|Smael|S|;Harandou|Mustapha|M|",
"chemical_list": "D009388:Neostigmine; D008278:Magnesium Sulfate; D009529:Nicardipine",
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2016.25.5.6616",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-25-510.11604/pamj.2016.25.5.6616Case ReportProlonged neuromuscular block in a preeclamptic patient induced by magnesium sulfate Berdai Mohamed Adnane 1&Labib Smael 1Harandou Mustapha 11 Obstetric and Pediatric Intensive Care Unit, University Hospital Hassan II, Fez, Morocco& Corresponding author: Mohamed Adnane Berdai, Obstetric and Pediatric Intensive Care Unit, University Hospital Hassan II, Fez, Morocco14 9 2016 2016 25 518 3 2015 19 8 2015 © Mohamed Adnane Berdai et al.2016The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Recent large use of magnesium in the obstetric population should incite anesthesiologists to control its side effects and drugs interactions. We report a case of a 30-year-old woman, with severe preeclampsia and HELLP syndrome, receiving sulfate magnesium and nicardipine, who underwent a cesarean section under general anesthesia. She developed a prolonged and deep neuromuscular blockade, which was antagonized three hours later with neostigmine. In case of therapeutic hypermagnesaemia, non-depolarizing relaxants must be used in reduced doses, and at increased time intervals, with appropriate neuromuscular monitoring.\n\nMagnesium sulfatenon depolarizing relaxantspregnancyneuromuscular block\n==== Body\nIntroduction\nMagnesium sulfate is widely used in preeclampsia patients to prevent and to treat seizures. It is also used as a tocolytic agent and for labour analgesia. However, its potentiating effects on non depolarizing neuromuscular blocking agents should be taken in consideration, especially in obstetric patients. We report the case of prolonged neuromuscular blockade after cesarean section in a patient receiving magnesium and nicardipine.\n\nPatient and observation\nA 30-year-old woman, primigravida, at 33 weeks of pregnancy, with unremarkable medical history. She presented to the hospital with complains of headache and epigastric pain. The patient weighted 60 kg, was conscious, her blood pressure was 160/110 mmHg, pulse of 120/min, and respiratory rate of 16/min, no edema was present. Blood cell count revealed a hemoglobin level of 11 g/dl, platelet count of 31000 cells/ml, coagulation test and kidney function tests were normal, liver function tests showed L-aspartate aminotransferase level at 231 IU/l (N<40), L-alanine aminotransferase at 114 IU/l (N<45), proteinuria was mild (600 mg/24h). We concluded to the diagnosis of pregnancy induced severe preeclampsia associated with incomplete HELLP syndrome. An intravenous infusion of magnesium sulfate was given with a 4 g loading dose perfused in 30 minutes and continued at 1 g/hour. Nicardipine was selected as the antihypertensive drug (2 mg/h). Due to continuing symptoms of headache and epigastric pain, elevated blood pressure (175/123 mmHg), and severe thrombocytopenia; decision of emergency delivery was made and was undertaken by caesarean section. Regional anesthesia wasn't appropriate because of severe thrombocytopenia, We performed then general anesthesia. Standard monitoring was used. After 3 minutes of preoxygenation, anesthesia was induced with propofol 150 mg and vecuronium 6 mg. Oral endotracheal tube was inserted without difficulty 100 seconds after muscle relaxant administration. Anesthesia was maintained with isoflurane (1-1.2 MAC), 50% nitrous oxide in oxygen, and fentanyl 150 µg after delivery of the baby. At this time, she received 35 mg/kg of amoxicillin plus clavulanic acid as antibioprophylaxy. The end-tidal CO2 was maintained at 36-38 mmHg. During surgery, blood loss was estimated at 800 ml, we transfused one unit of packed red blood cells. The cesarean section ended uneventfully at 40 min postinduction. The patient received then magnesium sulfate 1g/h and nicardipine 1 mg/h. Due to the context of severe preeclampsia and HELLP syndrome, the patient was shifted to the intensive care unit of the obstetric department for close observation and extubation. At admission, she was unconscient, with blood pressure at 150/110 mmHg and pulse of 128/min, the urine output was 2.1 ml/kg/j. One hour after the end of surgery, we noted the absence of awakening signs. In order to search neurological complication of preeclampsia, we realized a cerebral tomodensitometry which was normal. Three hours later, we suspected a prolonged neuromuscular blockade, so, we administrated 40 µg/kg of neostigmine and 20 µg/kg of atropine. Five minutes later, we noted the reappearance of coughing and swallowing reflexes, and in 10 minutes, the patient executed verbal orders. Therefore, she was successfully extubated without any residual neuromuscular blockade. Liver and hematologic biological abnormalities were progressively corrected. On the third postoperative day, the patient was discharged.\n\n\nConsent: Written 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\nDiscussion\nMagnesium sulfate is nowadays established as the treatment of choice for the prevention and control of eclamptic convulsions [1], It can also be used at caesarean delivery to attenuate hypertensive response to tracheal intubation, and can be indicated for fetal neuroprotection in preterm labour, and as a tocolytic agent [2]. Magnesium can also be administrated as an adjunct for labour analgesia or postoperative pain relief, its administration reduces postoperative pain and opioid consumption [3]. With this recent large use of magnesium in the obstetric population, a parturient has a greater likelihood of hypermagnesaemia. In this situation, clinicians should take in consideration the interaction of this ion with muscles relaxants. In fact, magnesium suppresses acetylcholine transmission by blocking the calcium channel at the motor endplate, and by decreasing pre-synaptic release of acetylcholine [2]. Magnesium alone can produce neuromuscular blockade at serum levels above 5 mmol/l, hence the use of loss of patellar reflexes as a clinical monitor for magnesium toxicity [4]. As result of diminishing muscle fiber excitability and reducing the amplitude of endplate potential, magnesium potentiates induced neuromuscular blockade by nondepolarizing neuromuscular blocker [5]. In our case, neuromuscular monitoring wasn't available, and due to pre-eclampsia context, we suspected initially a neurological complication. The diagnosis was rectified later by suspecting an interaction of magnesium and vecuronium which would result in such severe prolongation of neuromuscular blockade. This diagnosis of prolonged neuromuscular blockade was based on its reversibility by using anti-cholinesterase. Several case reports have highlighted the potential for clinical difficulties with non-depolarizing muscle relaxants in obstetric patients with therapeutic hypermagnesaemia. Yoshida et al. reported prolonged ventilatory support in two parturients receiving vecuronium following administration of magnesium for preeclampsia and tocolysis [6]. The magnesium potentiates the action of all non-depolarizing neuromuscular blockers; the speed of onset of pancuronium and atracurium are increased by administration of magnesium, and the duration of the neuromuscular block induced by rocuronium is prolonged [7]. The onset and duration of neuromuscular blockade produced by suxamethonium is not potentiated in hypermagnesemic states. However, magnesium may reduce the fasciculations seen on induction of the neuromuscular block [2]. In our case, we used vecuronium as a myorelaxant for intubation and maintaining neuromuscular blockade during cesarean section, because it was the only disponible myorelaxant agent. Fuchs-Buder et al. demonstrate that magnesium, administered before vecuronium, accelerated the onset, intensified and prolonged neuromuscular block, and concluded that monitoring of neuromuscular function and reduction in dose of vecuronium are required when using these two drugs in combination [8]. There are case reports describing maternal neuromuscular blockade in concomitant administration of magnesium and calcium channel blockers. Even if, this interaction in pregnant woman is rare and not formally proved, it may be a possible [9], we believe that neuromuscular monitoring in this context is indicated. In patients who had received intravenous magnesium, the speed of recovery after antagonizing a vecuronium-induced neuromuscular blockade with neostigmine is decreased by approximately 30%, thus, this attenuation is mainly a result of slower spontaneous recovery and not decreasing response to neostigmine [10]. Unlike cholinesterase inhibitors, sugammadex encapsulates steroidal muscle relaxants. It causes a rapid and complete reversal of the neuromuscular blockade. Administration of magnesium before induction of anesthesia had no effect on the ability of recommended doses of sugammadex to reverse neuromuscular blockade [11].\n\nConclusion\nWhere relaxants are to be used in a magnesium treated patient with obstetric condition, non-depolarizing agents must be used in reduced doses, and at increased time intervals. The neuromuscular monitoring in this context is essential. Concomitant administration of calcium channel blockers can also potentiate neuromuscular blockade, caution is advised when these agents are combined.\n\nCompeting interests\nThe authors declare no conflicts of interest.\n\nAuthors’ contributions\nAll authors were involved in patient´s care and manuscript preparation.\n==== Refs\nReferences\n1 Altman D Carroli G Duley L Farrell B Moodley J Neilson J Smith D Magpie Trial Collaboration Group Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial The Lancet. 2002 359 9321 1877 90 \n2 Dean C Douglas J Magnesium and the obstetric anaesthetist Int J Obstet Anesth. 2013 22 1 52 63 23182610 \n3 De Oliveira GS Castro-Alves LJ Khan JH McCarthy RJ Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials Anesthesiology. 2013 119 1 178 90 23669270 \n4 James MFM Magnesium in obstetric anesthesia Int J Obstet Anesth. 1998 7 2 115 23 15321229 \n5 Fisher DM Clinical pharmacology of neuromuscular blocking agents Am J Health Syst Pharm. 1999 56 11 Suppl 1 S4 9 \n6 Yoshida A Itoh Y Nagaya K Takino K Sugawara J Murakami T Okamura K Takahashi M Prolonged relaxant effects of vecuronium in patients with deliberate hypermagnesemia: time for caution in caesarean section J Anesth. 2006 20 1 33 5 16421674 \n7 Kussman B Shorten G Uppington J Comunale ME Administration of magnesium sulphate before rocuronium: effects on speed of onset and duration of neuromuscular block Br J Anaesth. 1997 79 1 122 4 9301400 \n8 Fuchs-Buder T Wilder-Smith O Borgeat A Tassonyi E Interaction of magnesium sulphate with vecuronium-induced neuromuscular block Br J Anaesth. 1995 74 4 405 9 7734259 \n9 Wu QA Ye YQ Neuromuscular blockade after therapy with magnesium sulfate and amlodipine Eur J Obstet Gynecol Reprod Biol. 2010 149 2 225 231 \n10 Fuchs-Buder T Ziegenfuss T Lysakowski K Tassonyi E Antagonism of vecuronium-induced neuromuscular block in patients pretreated with magnesium sulphate: Dose-effect relationship of neostigmine Br J Anaesth. 1999 82 1 61 5 10325838 \n11 Czarnetzki C Tassonyi E Lysakows C Elia N Tramer MR Efficacy of Sugammadex for the Reversal of Moderate and Deep Rocuronium-induced Neuromuscular Block in Patients Pretreated with Intravenous Magnesium: a Randomized Controlled Trial Anesthesiology. 2014 121 1 59 67 24608361\n\n",
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"journal": "The Pan African medical journal",
"keywords": "Magnesium sulfate; neuromuscular block; non depolarizing relaxants; pregnancy",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D002585:Cesarean Section; D005260:Female; D017359:HELLP Syndrome; D006801:Humans; D008278:Magnesium Sulfate; D009388:Neostigmine; D019148:Neuromuscular Blockade; D009529:Nicardipine; D011225:Pre-Eclampsia; D011247:Pregnancy",
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"title": "Prolonged neuromuscular block in a preeclamptic patient induced by magnesium sulfate.",
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"abstract": "BACKGROUND\nIn addition to its direct cytotoxic effects, radiation therapy renders tumor cells more susceptible to T cell-mediated cytotoxicity by modulating cell surface molecules involved in antigen presentation. The purpose of the present study was to determine the benefit of combined 89Sr radiation and dendritic cell (DC) vaccine therapy in bone metastasis patients.\n\n\nMETHODS\nPatients were treated with intravenous 89Sr at a dose of 40 μCi/kg of body weight on the first day after the peripheral blood mononuclear cell collection. Seven days later, patients received DCs once a week for 6 weeks. The first three vaccines were administered by intravenous infusion, and the last three vaccines were administered by 24-point intradermal injection. Clinical response was evaluated by the number of bone metastatic foci demonstrated on bone scintigraphy; cell-mediated cytotoxicity response was evaluated by delayed-type hypersensitivity (DTH) reaction. All treatment-related toxicities including vaccine-induced fever and 89Sr-associated hematological toxicity were carefully monitored.\n\n\nRESULTS\nTwenty-six patients with histologically diagnosed with primary cancers and multiple bone metastases demonstrated on bone scintigraphy were studied. The overall survival rate was 58.3%. The total positive DTH rate was 50%. The efficiency rate for pain relief was 60% (6/10), for quantity of life was 80%, and for clinic responses was 90%. Out of 10 cases, the Grade 1 or 2 of hematological depression in 4, erythema in 1, and fever in 7 were observed.\n\n\nCONCLUSIONS\nThe study has important implications for that combined 89Sr radiation, and DC vaccine therapy can benefit cancer patients with bone metastasis.",
"affiliations": "Department of Molecule Imaging and Nuclear Medicine in Diagnosis and Treatment, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.",
"authors": "Liu|J|J|;Li|J|J|;Fan|Y|Y|;Chang|K|K|;Yang|X|X|;Zhu|W|W|;Wu|X|X|;Pang|Yan|Y|",
"chemical_list": "D019496:Cancer Vaccines; D013326:Strontium Radioisotopes; C025700:strontium chloride; D013324:Strontium",
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"issue": "184(2)",
"journal": "Irish journal of medical science",
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"mesh_terms": "D000368:Aged; D001859:Bone Neoplasms; D019496:Cancer Vaccines; D003131:Combined Modality Therapy; D003713:Dendritic Cells; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed; D008297:Male; D008875:Middle Aged; D059408:Pain Management; D011788:Quality of Life; D013324:Strontium; D013326:Strontium Radioisotopes; D015996:Survival Rate; D016896:Treatment Outcome",
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"title": "Concurrent dendritic cell vaccine and strontium-89 radiation therapy in the management of multiple bone metastases.",
"title_normalized": "concurrent dendritic cell vaccine and strontium 89 radiation therapy in the management of multiple bone metastases"
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"abstract": "Background: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder characterized by rapidly progressive dementia. Growing evidence suggests that antidepressant usage was associated with dementia. Given the commonality of depression in CJD, it is necessary to investigate the effect of antidepressants on CJD. Methods: First, we report a case of sporadic CJD (sCJD) with depression where the condition worsened rapidly after using a serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant. Second, a systematic literature survey was conducted to investigate the effect of antidepressants on the survival time of sCJD patients with depression. Thirteen cases plus our case were included for qualitative analysis. Twelve subjects were included in the Kaplan-Meier survival and Cox regression analysis. Finally, we provide a postulation of pathophysiological mechanism in CJD. Results: The median survival time of all patients was 6.0 months, of which patients with SNRIs were significantly shorter than those with first-generation antidepressants (2.0 vs. 6.0 months; log rank, P = .008) and relatively shorter than those with nonselective serotonin reuptake inhibitors (SSRIs; 4.0 vs. 6.0 months; log rank, P = .090). In comparison with first-generation antidepressants, the use of SNRIs [hazard ratio (HR), 23.028; 95% confidence interval (CI), 1.401 to 378.461; P = .028] remained independently associated with shorter survival time. Conclusions: The use of antidepressants, especially SNRIs, was associated with a shorter survival time of sCJD patients. The possible changes in neurotransmitters should be emphasized. Scientifically, this study may provide insights into the mechanism of CJD. Clinically, it may contribute to the early diagnosis of CJD.",
"affiliations": "Department of Neurology, The First Hospital of China Medical University, Shenyang, China.;Department of Neurology, The First Hospital of China Medical University, Shenyang, China.;Department of Neurology, The First Hospital of China Medical University, Shenyang, China.;Department of Neurology, The First Hospital of China Medical University, Shenyang, China.;Department of Neurology, The First Hospital of China Medical University, Shenyang, China.;Department of Neurology, The First Hospital of China Medical University, Shenyang, China.;Department of Neurology, The First Hospital of China Medical University, Shenyang, China.",
"authors": "Liang|Yifan|Y|;Li|Yan|Y|;Wang|Huibin|H|;Cheng|Xi|X|;Guan|Meiting|M|;Zhong|Shanshan|S|;Zhao|Chuansheng|C|",
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"doi": "10.3389/fpsyt.2019.00297",
"fulltext": "\n==== Front\nFront PsychiatryFront PsychiatryFront. PsychiatryFrontiers in Psychiatry1664-0640Frontiers Media S.A. 10.3389/fpsyt.2019.00297PsychiatryCase ReportDoes the Use of Antidepressants Accelerate the Disease Progress in Creutzfeldt–Jakob Disease Patients With Depression? A Case Report and A Systematic Review Liang Yifan Li Yan Wang Huibin Cheng Xi Guan Meiting Zhong Shanshan Zhao Chuansheng \n*\nDepartment of Neurology, The First Hospital of China Medical University, Shenyang, ChinaEdited by: Yi Yang, First Affiliated Hospital of Jilin University, China\n\nReviewed by: Michael X. Zhu, University of Texas Health Science Center at Houston, United States; Yan-Jiang Wang, Third Military Medical University, China\n\n*Correspondence: Chuansheng Zhao, cszhao@cmu.edu.cn\nThis article was submitted to Mood and Anxiety Disorders, a section of the journal Frontiers in Psychiatry\n\n03 5 2019 2019 10 29704 10 2018 16 4 2019 Copyright © 2019 Liang, Li, Wang, Cheng, Guan, Zhong and Zhao2019Liang, Li, Wang, Cheng, Guan, Zhong and ZhaoThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground: Creutzfeldt–Jakob disease (CJD) is a fatal neurodegenerative disorder characterized by rapidly progressive dementia. Growing evidence suggests that antidepressant usage was associated with dementia. Given the commonality of depression in CJD, it is necessary to investigate the effect of antidepressants on CJD.\n\n\nMethods: First, we report a case of sporadic CJD (sCJD) with depression where the condition worsened rapidly after using a serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant. Second, a systematic literature survey was conducted to investigate the effect of antidepressants on the survival time of sCJD patients with depression. Thirteen cases plus our case were included for qualitative analysis. Twelve subjects were included in the Kaplan–Meier survival and Cox regression analysis. Finally, we provide a postulation of pathophysiological mechanism in CJD.\n\n\nResults: The median survival time of all patients was 6.0 months, of which patients with SNRIs were significantly shorter than those with first-generation antidepressants (2.0 vs. 6.0 months; log rank, P = .008) and relatively shorter than those with nonselective serotonin reuptake inhibitors (SSRIs; 4.0 vs. 6.0 months; log rank, P = .090). In comparison with first-generation antidepressants, the use of SNRIs [hazard ratio (HR), 23.028; 95% confidence interval (CI), 1.401 to 378.461; P = .028] remained independently associated with shorter survival time.\n\n\nConclusions: The use of antidepressants, especially SNRIs, was associated with a shorter survival time of sCJD patients. The possible changes in neurotransmitters should be emphasized. Scientifically, this study may provide insights into the mechanism of CJD. Clinically, it may contribute to the early diagnosis of CJD.\n\ndepressionCreutzfeldt–Jakob diseaseantidepressantneurotransmitterssleep wake disorders\n==== Body\nIntroduction\nDepression is common in the elderly. Its prevalence rate is as high as 11.19%, and this increases progressively with worsening cognitive impairment (1). The presence of depression is an acknowledged risk factor for dementia (2); it can even double the risk for Alzheimer’s disease (AD) (3, 4). Many reasons lie behind the prescription of antidepressant drugs, which increased dramatically from 1999 to 2014 (5). However, some studies have questioned whether antidepressants confer any benefits in terms of cognitive decline (6–9). Recently, a meta-analysis indicated that antidepressant usage was associated with AD/dementia (10). Tricyclic antidepressants (TCA) may be associated with a reduced risk (11) or no risk of dementia (12) for depressed patients, whereas nonselective serotonin reuptake inhibitors (SSRIs) antidepressant drugs, including monoamine oxidase (MAO) inhibitors, and serotonin and noradrenaline reuptake inhibitors (SNRIs) have been reported to possess an intermediate risk (11–13).\n\nCreutzfeldt–Jakob disease (CJD), a fatal neurodegenerative disorder characterized by rapidly progressive dementia, is divided into the sporadic (sCJD), familial (fCJD), variant (vCJD), and iatrogenic (iCJD) subtypes (14). sCJD accounts for the majority, i.e., 85% of all CJD cases, with an annual worldwide incidence of one to two cases/million population (15). Although rare, the overall mortality rate of sCJD has been increasing since 1993 (16). There is no effective treatment for CJD, so it is important to identify modifiable risk factors for CJD and to delay disease progression. Psychiatric manifestations are often the first symptoms to appear in vCJD. Recent studies have shown that they are also more prevalent in sCJD than previously thought. Most commonly, these are exhibited as depression in 16%–37% of cases (17–19). While treatment of the psychiatric symptoms with hypnotics, anxiolytics, or antipsychotic drugs may offer relief to CJD patients, it appears that antidepressant drugs are ineffective (19). As is the case in some other dementias, the implication is that antidepressants may also fail to benefit CJD patients.\n\nHere, we report a case of sCJD in which depression was the first symptom, and the condition worsened rapidly after the administration of an SNRI antidepressant. Subsequently, a systematic review of the literature was undertaken to explore the characteristics of sCJD patients with depressive symptoms as well as the effect of treatment with antidepressants on sCJD. This report aims to provide novel insights into the underlying causes and treatment of CJD and dementia.\n\nCase Report\nMs. S was a 63-year-old female with no previous medical or psychiatric history. In July 2017, she presented with dizziness, weakness, chronic shoulder pain, and high blood pressure. She informed her family that she felt helpless and sick. The preliminary examination revealed nothing but multiple lacunar infarcts in brain magnetic resonance imaging (MRI) scans. On September 17, 2017, she exhibited anhedonia, fear, anxiety, impatience, and a propensity to cry after being annoyed with others. She was examined in the psychiatric unit of the local hospital. Her value on the Self-rating Depression Scale (SDS) was 53.75, which pointed to mild depression, whereas on the Hastgawa Dementia Scale (HDS), she scored 13.0, which suggested probable dementia (education: primary school). The memory quotient (MQ) of Wechsler Memory Scale (WMS) was 59. Her sleep was normal. She was diagnosed with depression, and sertraline 50 mg/day was prescribed. Her symptoms nonetheless worsened with insomnia, garrulity, irritability, and gait imbalance. Her memory function deteriorated, and she became disoriented. The psychiatrist changed the antidepressant drug to venlafaxine 75 mg/day on October 8, 2017. However, instead of improving, the condition rapidly worsened. Her speech became hypophonic and monotonous with a paucity of content. She was sleepy during the day and sometimes burst into tears. Her arms curled up, indicating panic. She developed psychomotor retardation, responded poorly to questions, experienced visual hallucination, and suffered from a rigid posture with paroxysmal myoclonus and an inability to walk. The changes in her symptoms were initially considered to be side effects of venlafaxine. Two weeks later, she had deteriorated further and was unable to talk, exhibiting dysphagia and suffering from urinary incontinence. The symptoms did not improve after the withdrawal of the antidepressant. An assessment of her electroencephalogram (EEG) revealed generalized slow activity (\nFigure 1A\n). She was then transferred to the neurologic ward of our hospital where the following neurological findings were detected: akinetic mutism (AM), normal muscle strength, increased muscle tension, brisk tendon reflexes, and unresponsive pathologic reflexes. We performed a hematology screen for endocrine, metabolic, autoimmune, neoplastic, and infectious diseases, which were all negative. Cerebrospinal fluid (CSF) studies, including a paraneoplastic, an autoimmune antibody panel, and a tubercular, fungal antibody survey were also negative. Fluid-attenuated inversion recovery (FLAIR) of the brain MRI showed hyperintensities in the bilateral frontal lobe, corona radiate, and near the anterior and posterior horns of the lateral ventricle (\nFigure 2A\n). Diffusion-weighted imaging (DWI) showed hyperintensities in the bilateral caudate nucleus and putamen (\nFigure 2B\n). A diagnosis of CJD was considered. One week after admission, the second EEG was performed, revealing partially periodic sharp wave complexes (PSWC; \nFigure 1B\n). No gene mutations associated with genetic CJD were found, but methionine homozygotes were detected at codon 129 of the prion protein gene. The final diagnosis was probable sCJD according to the diagnostic criteria for sCJD (20, 21). Antibiotics, antiviral, and corticosteroid therapies had been tried since admission, but none of them worked. Ultimately, she was discharged from the hospital.\n\nFigure 1 Electroencephalogram (EEG) (A) on October 26, 2017 showed generalized slow activity. The second EEG (B) on November 2, 2017 showed partially periodic sharp wave complexes (PSWC).\n\nFigure 2 Brain magnetic resonance imaging magnetic. Fluid-attenuated inversion recovery (A) showed hyperintensities in the bilateral frontal lobe, corona radiate, and near the anterior and posterior horns of the lateral ventricle. Diffusion-weighted imaging (B) showed hyperintensities in the bilateral caudate nucleus and putamen on November 1, 2017.\n\nMethods\nSearch Strategy and Study Selection\nWe searched PubMed, EMBASE, and PsycINFO up to May 2018 for previous cases using the key words “Creutzfeldt–Jakob disease AND depression.” The reports were restricted to those published and unpublished in English and those including human subjects. The inclusion criteria were as follows: case reports, case series, previous literature reviews, or systematic reviews describing sCJD patients with depression as the first symptom and receiving the treatment for depression. The CJD patients had to meet the WHO or 2009 Consortium diagnostic criteria for definite or probable sCJD (20, 21). To minimize confounders, such as the effect of other medications on outcomes, the included cases were those in which depression was the only symptom diagnosed initially. Two authors independently decided on the selection.\n\nData Extraction\nThe data extracted included study name, study characteristics, patient characteristics, and the duration, institutional care, symptoms, examinations, treatments, and diagnosis of distinct phases. The duration of CJD patients was divided into three phases based on the main symptoms. The first phase was the prodromal phase, with mental manifestations; the second phase was the intermediate phase, with progressive dementia, myoclonus, psychiatric disorder, pyramidal signs, and extrapyramidal performance; the third phase was the late phase, with incontinence, AM, coma, or decorticate rigidity. If an article did not distinguish between the duration of the second and third phases, we utilized a value of half of the total duration of the two periods as their respective durations. Data were graded by two authors independently according to the Oxford Centre for Evidence-Based Medicine levels of evidence (22).\n\nStatistical Analysis\nA systematic analysis was performed. Categorical variables were described using proportions and continuous variables using medians and interquartile range (IQR). A Kaplan–Meier survival analysis was conducted in those patients for whom we had data on the three-phase duration and the use of antidepressants. Antidepressants were categorized into three classes, SSRIs, newer non-SSRI antidepressants (mostly SNRIs), and first-generation antidepressants (mostly TCA) according to the Anatomical Therapeutical Chemical (ATC) classification system (World Health Organization, 1999). The log rank test was used to compare the survival distributions of different groups. Finally, a multivariate Cox regression analysis with Enter was undertaken to determine the predictors of survival. Due to the small number of cases, we considered only three factors: gender, age, and antidepressant type. The model with a significant score test and a smaller deviance in likelihood ratio test will be preferred. Significance was set at P < .05 (two-sided test). Statistical analysis was completed using SPSS v17.0 (SPSS Inc., Chicago, IL, USA).\n\nResults\nStudy Identification and Characteristics\nThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed (23). The PRISMA flow diagram is depicted in eFigure in the Supplementary Material. In our literature search, we identified 13 cases from 12 articles that met our inclusion criteria for qualitative analysis (24–35). Subsequently, 11 cases from 10 articles were included for qualitative analysis (24–26, 28, 30–35). With the addition of our case, a total of 12 subjects could be included in the Kaplan–Meier survival and multivariate Cox regression analysis.\n\nThe characteristics and evidence levels of the 14 cases published from 1993 to 2017 are shown in eTable in the Supplementary Material. All included articles were case reports. The age of all subjects was 58.8 (55.5–61.5) years with 11 (79%) being female. After administration of antidepressants, only 1 case out of 13 (8%) showed improved depressive symptoms.\n\nSurvival Time of Sporadic Creutzfeldt–Jakob Disease Patients with Different Antidepressants\nA Kaplan–Meier survival curve for all of the sCJD patients who had used antidepressants is shown in \nFigure 3\n. The median survival time of all of the cases was 6.0 months. The cumulative incidences with survival times less than 3, 6, and 12 months were 30.0%, 90.0%, and 100%, respectively. All of the patients died within 1 year after onset.\n\nFigure 3 The Kaplan–Meier survival curves for sCJD patients with antidepressants. (A) Survival time for all patients. (B) Survival time for patients stratified according to the type of antidepressant. X-axis represents survival time (months) and Y-axis represents survival probability. sCJD = sporadic Creutzfeldt–Jakob disease; SNRIs = serotonin and noradrenaline reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors. aReferred to first-generation antidepressants.\n\nThe use of antidepressants in 12 cases is as follows: 3 (25%) were given SNRIs (1 censored), 4 (33%) were administered SSRIs (2 censored), and 5 (42%) were treated with first-generation antidepressants. The median survival times for cases with SNRIs, SSRIs, and first-generation antidepressants were 2.0, 4.0, and 6.0 months, respectively. The median survival time of patients with SNRIs was significantly shorter than those treated with first-generation antidepressants (log rank, P = .008) and relatively shorter than those with SSRIs (log rank, P = .090). Furthermore, the median survival time of patients receiving SSRIs was nonsignificantly shorter than those with the first-generation antidepressants (log rank, P = .615).\n\nPredictors of Survival Time in Sporadic Creutzfeldt–Jakob Disease Patients With Depression\nThe Cox regression model including age and antidepressant types (\nTable 1\n) was preferred (likelihood ratio test, deviance = 25.469; score test, P = .043). Compared to first-generation antidepressants, the use of SNRIs [hazard ratio (HR), 23.028; 95% confidence interval (CI), 1.401 to 378.461; P = .028] remained independently associated with significantly shorter survival time in sCJD patients with depression.\n\nTable 1 Cox regression analysis of survival time in sCJD patients with depression.\n\nFactors\tUnadjusted\tAdjusted\na\n\n\t\n\tHR (95% CI)\t\nP\n\tHR (95% CI)\t\nP\n\t\nAge\t1.015 (0.947–1.087)\t.677\t1.042 (0.955–1.136)\t.354\t\nAntidepressants\tNA\t.103\tNA\t.086\t\nSNRIs\t15.665 (1.215–201.884)\t.035*\t23.028 (1.401–378.461)\t.028*\t\nSSRIs\t1.432 (0.256–8.018)\t.683\t2.689 (0.295–24.498)\t.380\t\nFirst-generation antidepressants (reference)\tNA\tNA\tNA\tNA\t\nsCJD, sporadic Creutzfeldt–Jakob disease; HR, hazard ratio; C, confidence interval; NA, not applicable (outcome not investigated); SNRIs, serotonin and noradrenaline reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.\n\na Adjusted for age and antidepressant types.\n\n*P < .05.\n\nDiscussion\nSince depression is one of the most common global mental health conditions, the use of antidepressant drugs has increased dramatically with almost half of the prescriptions being for some off-label indication (36). However, our investigation revealed that almost none of the sCJD patients experienced any relief of their depressive symptoms after the antidepressant treatment. Furthermore, the median survival time of sCJD patients receiving SNRI therapy was shorter than the average survival of sCJD patients (2.3 vs. 4.6–17.4 months) (16). Thus, antidepressants do not seem to have any beneficial effect on sCJD patients with depression, a finding consistent with previous clinical studies not only on sCJD patients but also those with dementia (10, 19). Likewise, the efficacy characteristics of antidepressants indicate that antidepressants appear to display relatively poor efficacy in people older than 65 years (37). Based on the neurotransmitter receptor hypothesis of antidepressant drugs, the amount of neurotransmitter changes rapidly after an antidepressant is administered. But the clinical effects appear only weeks later (usually 6–12 weeks) (37). Due to the rapid progress of the disease, sCJD patients often use antidepressants for only a brief period. Therefore, the drugs usually cannot achieve clinical efficacy but are instead likely to exert unwanted side effects.\n\nThe question arises as to why patients with sCJD receiving antidepressants seem to deteriorate faster. Since antidepressants mainly alter neurotransmitter levels, we postulate that this deterioration must be related to these changes. Several independent lines of evidence support this postulation. sCJD resembles the degenerative dementias. Studies of AD, the best-known of the degenerative dementias, have proved that the accumulations of β-amyloid (Aβ) and tau proteins damage neurons and synapses, whereas the change in neurotransmitters such as acetylcholine (ACh) occurs at the initial stage (38). Similarly, the cause of sCJD neuropathological changes has also proved to be a reversible process, such as synaptic or neuronal dysfunction (39). Interestingly, patients with sCJD also have higher concentrations of Aβ and tau proteins in their serum and CSF (40, 41). Aβ may be propagated in a prion-like manner (42, 43). Similar observations have been made for tau (44). Because sCJD and AD share these common features (45), perhaps we can also attempt to delay the progress of sCJD by regulating the level of neurotransmitters. Furthermore, the typical lesions in MRI and histologic appearance in sCJD consist of cortical, basal ganglia, and cerebellum (46, 47). It was observed that the clinical target areas in the brainstem of prion-infected mice were the locus coeruleus, the nucleus of the solitary tract, and the pre-Bötzinger complex (48). These brain areas are exactly those in which the neuronal cell bodies generating neurotransmitters are mainly located or the areas innervated by their axonal projections.\n\nHow do these neurotransmitters modulate disease progression? According to our study, the survival period of sCJD patients is related to the type of antidepressants. By analyzing the pharmacological characteristics, we postulate that elevations in 5-hydroxytryptamine (5-HT) and norepinephrine (NE) may worsen the condition, although the sedative effects mediated by anti-histamine (HA), anti-ACh, and blockade of α-1 adrenoceptors may contribute to the relief of symptoms. Acute stimulation of the 5-HT can produce symptoms similar to sCJD (37). Neurotransmitters exist in many brain areas, but which area plays the key role? When SSRI treatment is initiated, the concentrations of 5-HT are elevated to a much greater extent at the somatodendritic area located in the midbrain raphe, rather than in the brain areas where the axons terminate (37). Therefore, SSRIs may exert more significant effects on the brainstem in patients with sCJD. However, the pathological changes in sCJD do not occur in the brainstem but rather in the projection pathways of neurotransmitters, such as cortical, basal ganglia, and cerebellum. This raises the question of how changes in the brainstem’s neurotransmitter activities affect other brain areas. Taking into account the symptoms (such as myoclonus that occurs at night, AM) of patients with sCJD, we postulate that one pathway through which brainstem’s neurotransmitter activities trigger cognitive impairment encountered in sCJD patients may be through its disruption of sleep centers in the brainstem. AM is a disorder caused by damage to the ascending reticular activating system (ARAS) centered on the brainstem. Arousal is regulated by ARAS, which is influenced in large part by five key neurotransmitters: HA, dopamine (DA), NE, 5-HT, and ACh. Changes in these neurotransmitters can cause sleep disorders, i.e., rapid eye movement (REM) sleep without atonia (RSWA), and nonrapid eye movement (NREM) sleep disruption. Clinical studies have shown that SSRIs and SNRIs are associated with a higher prevalence of RSWA (49), explained in part by the theories about REM sleep initiation that advocate for a double switch model, possibly triggered by neurons located in the brainstem (50). Sleep disorders can cause many symptoms similar to sCJD, such as psychiatric symptoms (fear, anger, aggressive behavior, etc.), increased muscle tone, and most notably, cognitive impairment. For example, REM sleep behavior disorder (RBD) is by far the strongest clinical predictor of onset of neurodegenerative diseases (51). The presence of RBD in Parkinson’s disease (PD) is associated with higher risk of cognitive decline (52). The reduced NREM slow-wave activity (SWA) generation was associated with impaired hippocampus-dependent memory consolidation (53). The Aβ burden in the medial prefrontal cortex correlates significantly with the severity of impairment in NREM SWA generation (53). Even one night of sleep deprivation could result in a significant increase in Aβ burden in the brain (54). Thus, the dual excitatory effects of 5-HT and NE may exacerbate the sleep deprivation encountered in sCJD patients, causing a cascading effect and then triggering cognitive impairment.\n\nWhy is the effect of neurotransmitters so rapid in sCJD patients? One reason may be the pathological overactivity of the brain’s serotonergic system in this disease. This hypothesis is supported by the evidence that the mean tryptophan hydroxylase (TPH)-positive cell size was significantly greater and cells were more intensely stained in CJD compared to controls (55). This may result in an increase in release of 5-HT. Coupled with the cascade effect of neurotransmitters, the actual effects may be amplified. The increase in 5-HT also reduced the release of DA in the prefrontal zone by negative feedback regulation (37). The reduction of DA may cause some symptoms similar to sCJD, such as cognitive impairment and apathy. Another reason could be that synapses in sCJD may be more vulnerable. The pathological features of CJD indicate that the vacuole in the cytoplasm is the cystic dilation of neurons and necrosis of the necrotic membrane. The cell membrane damage of CJD seems to be more serious than AD, where amyloid plaques form outside the neurons and neuron fibers entangle within the neurons. Damage to the synaptic membrane leads to a decrease in neurotransmitter receptors. In response to this change, the remaining receptors may be in a hypersensitivity state, or the number of receptors may increase (37), which may further enhance the effects of neurotransmitters such as 5-HT.\n\nMany of the families of patients with sCJD complain of the delay in diagnosis and the plethora of misdiagnoses (56). Expediating a sCJD diagnosis is of great significance. Almost half of patients were misdiagnosed first as “psychiatric patients” (57). Consequently, it is very important for psychiatrists to consider CJD among the possible differential diagnoses in elderly patients. Our investigation suggests that it may be helpful to use imaging such as functional MRI and positron emission computed tomography (PET) to detect earlier changes in patients with sCJD.\n\nOf course, our study has some limitations. First, the number of available cases is too small, and in many cases, the description of psychiatric symptoms and details of the antidepressants were inadequate. Second, because case reports tend to report exceptional situations, there is inevitably some bias. However, we think it is a reasonable approach to study CJD by undertaking case analysis or studies of one single individual. Due to the rapid progression of CJD, studies on population samples often overlook certain unique changes.\n\nInvestigations into sCJD have mainly focused on autopsy-based pathology, but little is known about neurophysiological changes. We hope this study will draw attention to the depressive symptoms of sCJD patients and the underlying neurophysiological mechanisms.\n\nConclusions\nThe use of antidepressants was associated with a shorter survival time of sCJD patients, especially the use of SNRIs. The possible neurotransmitter changes may be due to a pathophysiological mechanism in CJD. Functional imaging and use of the polysomnogram to detect earlier changes in sCJD patients may be worth trying.\n\nEthics Statement\nThis case study was carried out in accordance with the recommendations of the Ethical Committee of China Medical University. The case study has been approved by the Ethics Committee of China Medical University. The subject gave written informed consent in accordance with the Declaration of Helsinki. Written informed consent was also obtained from each patient for the publication of this case report.\n\nAuthor Contributions\nCZ 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. CZ and YLia contributed to the study concept and design. YLi contributed to the case report. YLia, YLi, MG, and SZ contributed to the acquisition, analysis, or interpretation of data. YLia, HW, and XC drafted the manuscript. CZ conducted the critical revision of the manuscript for important intellectual content. All authors performed the statistical analysis.\n\nFunding\nThis work was supported by The Liaoning Province Key Research and Development Project Critical Project (no. 2017225005, CZ), The Shenyang Municipal Bureau of Science and Technology International Exchange and Cooperation Project (no. 17-129-6-00, CZ), and China Medical University High-level Innovation Team Training Plan (no. 2017CXTD02, CZ).\n\nConflict of Interest Statements\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\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00297/full#supplementary-material\n\n\nClick here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n1 \nSteffens DC Fisher GG Langa KM Potter GG Plassman BL \nPrevalence of depression among older Americans: the Aging, Demographics and Memory Study . Int Psychogeriatr (2009 ) 21 :879–88. 10.1017/S1041610209990044 \n\n2 \nWHO \nDementia . Fact sheet [Updated December 2017]. Geneva, Switzerland : World Health Organization (2017 ). Available at www.who.int/mediacentre/factsheets/fs362/en/\n\n3 \nCaraci F Copani A Nicoletti F Drago F \nDepression and Alzheimer’s disease: neurobiological links and common pharmacological targets . Eur J Pharmacol (2010 ) 626 :64 –71 . 10.1016/j.ejphar.2009.10.022 \n19837057 \n4 \nMasters MC Morris JC Roe CM \n“Noncognitive” symptoms of early Alzheimer disease: a longitudinal analysis . Neurology (2015 ) 84 :617–22. 10.1212/WNL.0000000000001238 \n\n5 \nPratt LA Brody DJ Gu Q \nAntidepressant use among persons aged 12 and over: United States, 2011–2014 . NCHS Data Brief, no. 283 . Hyattsville, MD : National Center for Health Statistics (2017 ). Available at https://www.cdc.gov/nchs/data/databriefs/db283.pdf\n\n6 \nDawes SE Palmer BW Meeks T Golshan S Kasckow J Mohamed S \nDoes antidepressant treatment improve cognition in older people with schizophrenia or schizoaffective disorder and comorbid subsyndromal depression . Neuropsychobiology (2012 ) 65 :168–72. 10.1159/000331141 \n\n7 \nKessing LV Forman JL Andersen PK \nDo continued antidepressants protect against dementia in patients with severe depressive disorder . Int Clin Psychopharmacol (2011 ) 26 :316–22. 10.1097/YIC.0b013e32834ace0f \n\n8 \nRosenberg PB Mielke MM Han D Leoutsakos JS Lyketsos CG Rabins PV \nThe association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer’s disease . Int J Geriatr Psychiatry (2012 ) 27 :1248–57. 10.1002/gps.3769 \n\n9 \nÅrdal G Hammar Å \nIs impairment in cognitive inhibition in the acute phase of major depression irreversible? Results from a 10-year follow-up study . Psychol Psychother (2011 ) 84 :141–50. 10.1348/147608310X502328 \n\n10 \nMoraros J Nwankwo C Patten SB Mousseau DD \nThe association of antidepressant drug usage with cognitive impairment or dementia, including Alzheimer disease: A systematic review and meta-analysis . Depress Anxiety (2017 ) 34 :217–26. 10.1002/da.22584 \n\n11 \nLee CW Lin CL Sung FC Liang JA Kao CH \nAntidepressant treatment and risk of dementia: a population-based, retrospective case–control study . J Clin Psychiatry (2016 ) 77 :117–22. 10.4088/JCP.14m09580 \n\n12 \nKessing LV Søndergård L Forman JL Andersen PK \nAntidepressants and dementia . J Affect Disord (2009 ) 117 :24–9. 10.1016/j.jad.2008.11.020 \n\n13 \nWang C Gao S Hendrie HC Kesterson J Campbell NL Shekhar A \nAntidepressant use in the elderly is associated with an increased risk of dementia . Alzheimer Dis Assoc Disord (2016 ) 30 :99 –104 . 10.1097/WAD.0000000000000103 \n26295747 \n14 \nLadogana A Puopolo M Croes EA Budka H Jarius C Collins S \nMortality from Creutzfeldt–Jakob disease and related disorders in Europe, Australia, and Canada . Neurology (2005 ) 64 :1586–91. 10.1212/01.WNL.0000160117.56690.B2 \n\n15 \nMead S Stumpf MP Whitfield J Beck JA Poulter M Campbell T \nBalancing selection at the prion protein gene consistent with prehistoric kurulike epidemics . Science (2003 ) 300 :640–3. 10.1126/science.1083320 \n\n16 \nChen C Dong XP \nEpidemiological characteristics of human prion diseases . Infect Dis Poverty (2016 ) 5 :47 . 10.1186/s40249-016-0143-8 \n27251305 \n17 \nKrasnianski A Bohling GT Harden M Zerr I \nPsychiatric symptoms in patients with sporadic Creutzfeldt–Jakob disease in Germany . J Clin Psychiatry (2015 ) 76 :1209–15. 10.4088/JCP.13m08915 \n\n18 \nRabinovici GD Wang PN Levin J Cook L Pravdin M Davis J \nFirst symptom in sporadic Creutzfeldt–Jakob disease . Neurology (2006 ) 66 :286–7. 10.1212/01.wnl.0000196440.00297.67 \n\n19 \nWall CA Rummans TA Aksamit AJ Krahn LE Pankratz VS \nPsychiatric manifestations of Creutzfeldt–Jakob disease: a 25-year analysis . J Neuropsychiatry Clin Neurosci (2005 ) 17 :489–95. 10.1176/jnp.17.4.489 \n\n20 \nWHO \nHuman transmissible spongiform encephalopathies . Wkly Epidemiol Rec (1998 ) 73 :361–5.\n21 \nZerr I Kallenberg K Summers DM Romero C Taratuto A Heinemann U \nUpdated clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease . Brain (2009 ) 132 :2659–68. 10.1093/brain/awp191 \n\n22 \nOCEBM Levels of Evidence Working Group \nThe Oxford 2011 levels of evidence . Oxford, England : Oxford Centre for Evidence-Based Medicine (2016 ). Available at www.cebm.net/index.aspx?o=5653\n\n23 \nMoher D Liberati A Tetzlaff J Altman DG \nPreferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . Ann Intern Med (2009 ) 151 :264–9. 10.7326/0003-4819-151-4-200908180-00135 \n\n24 \nAzorin JM Donnet A Dassa D Gambarelli D \nCreutzfeldt–Jakob disease misdiagnosed as depressive pseudodementia . Compr Psychiatry (1993 ) 34 :42–4. 10.1016/0010-440X(93)90034-2 \n\n25 \nGoetz KL Price TR \nElectroconvulsive therapy in Creutzfeldt–Jakob disease . Convuls Ther (1993 ) 9 :58 –62 .11941194 \n26 \nGonzález-Duarte A Medina Z Balaguer RR Calleja JH \nCan prion disease suspicion be supported earlier? Clinical, radiological and laboratory findings in a series of cases . Prion (2011 ) 5 :201–7. 10.4161/pri.5.3.16187 \n\n27 \nGrande I Fortea J Gelpi E Flamarique I Udina M Blanch J \nAtypical Creutzfeldt–Jakob disease evolution after electroconvulsive therapy for catatonic depression . Case Rep Psychiatry (2011 ) 2011 :791275. 10.1155/2011/791275 \n22937408 \n28 \nJardri R DiPaola C Lajugie C Thomas P Goeb JL \nDepressive disorder with psychotic symptoms as psychiatric presentation of sporadic Creutzfeldt–Jakob disease: a case report . Gen Hosp Psychiatry (2006 ) 28 :452–4. 10.1016/j.genhosppsych.2006.05.005 \n\n29 \nJiang TT Moses H Gordon H Obah E \nSporadic Creutzfeldt–Jakob disease presenting as major depression . South Med J (1999 ) 92 :807–8. 10.1097/00007611-199908000-00012 \n\n30 \nMilanlioglu A Ozdemir PG Cilingir V Ozdemir O \nCatatonic depression as the presenting manifestation of Creutzfeldt–Jakob disease . J Neurosci Rural Pract (2015 ) 6 :122 . 10.4103/0976-3147.143220 \n25552870 \n31 \nMuayqil T Siddiqi ZA \nSporadic Creutzfeldt–Jakob disease with worsening depression and cognition . Can J Neurol Sci (2007 ) 34 :464–6. 10.1017/S031716710000737X \n\n32 \nOnofrj M Fulgente T Gambi D Macchi G \nEarly MRI findings in Creutzfeldt–Jakob disease . J Neurol (1993 ) 240 :423–6. 10.1007/BF00867355 \n\n33 \nPower B Trivedi D Samuel M \nWhat psychiatrists should know about sporadic Creutzfeldt–Jakob disease . Australas Psychiatry (2012 ) 20 :61–6. 10.1177/1039856211430145 \n\n34 \nWang YT Wu CL \nProbable sporadic Creutzfeldt–Jakob disease mimicking a catatonic depression in an elderly adult . Psychogeriatrics (2017 ) 17 (6 ):524–5. 10.1111/psyg.12264 \n\n35 \nYang HY Huang SS Lin CC Lan TH Chan CH \nIdentification of a patient with sporadic Creutzfeldt–Jakob disease in a psychiatric ward . Psychiatry Clin Neurosci (2013 ) 67 :280–1. 10.1111/pcn.12049 \n\n36 \nWong J Motulsky A Abrahamowicz M Eguale T Buckeridge DL Tamblyn R \nOff-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system . BMJ (2017 ) 356 :j603 . 10.1136/bmj.j603 \n\n37 \nStahl SM \nStahl’s essential psychopharmacology: neuroscientific basis and practical applications . 4th ed \nNew York : Cambridge University Press (2014 ).\n38 \nWang L Benzinger TL Su Y Christensen J Friedrichsen K Aldea P \nEvaluation of tau imaging in staging Alzheimer disease and revealing interactions between β-amyloid and tauopathy . JAMA Neurol (2016 ) 73 :1070–7. 10.1001/jamaneurol.2016.2078 \n\n39 \nSoto C Satani N \nThe intricate mechanisms of neurodegeneration in prion diseases . Trends Mol Med (2011 ) 17 :14 –24 . 10.1016/j.molmed.2010.09.001 \n20889378 \n40 \nThompson AGB Luk C Heslegrave AJ Zetterberg H Mead SH Collinge J \nNeurofilament light chain and tau concentrations are markedly increased in the serum of patients with sporadic Creutzfeldt–Jakob disease, and tau correlates with rate of disease progression . J Neurol Neurosurg Psychiatry (2018 ) 89 (9 ):955–61. 10.1136/jnnp-2017-317793 \n\n41 \nLeitão MJ Baldeiras I Almeida MR Ribeiro MH Santos AC Ribeiro M \nCSF Tau proteins reduce misdiagnosis of sporadic Creutzfeldt–Jakob disease suspected cases with inconclusive 14-3-3 result . J Neurol (2016 ) 263 :1847–61. 10.1007/s00415-016-8209-x \n\n42 \nFrontzek K Lutz MI Aguzzi A Kovacs GG Budka H \nAmyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt–Jakob disease after dural grafting . Swiss Med Wkly (2016 ) 146 :w14287. 10.4414/smw.2016.14287 \n26812492 \n43 \nJucker M Walker LC \nNeurodegeneration: amyloid-β pathology induced in humans . Nature (2015 ) 525 :193–4. 10.1038/525193a \n\n44 \nAlonso AD Beharry C Corbo CP Cohen LS \nMolecular mechanism of prion-like tau-induced neurodegeneration . Alzheimers Dement (2016 ) 12 :1090–7. 10.1016/j.jalz.2015.12.014 \n\n45 \nDebatin L Streffer J Geissen M Matschke J Aguzzi A Glatzel M \nAssociation between deposition of beta-amyloid and pathological prion protein in sporadic Creutzfeldt–Jakob disease . Neurodegener Dis (2008 ) 5 :347–54. 10.1159/000121389 \n\n46 \nFragoso DC Gonçalves FAL Pacheco FT Barros BR Aguiar LI Nunes RH \nImaging of Creutzfeldt–Jakob disease: imaging patterns and their differential diagnosis . Radiographics (2017 ) 37 :234–57. 10.1148/rg.2017160075 \n\n47 \nLiberski PP \nSpongiform change—an electron microscopic view . Folia Neuropathol (2004 ) 42 \nSuppl B :59 –70 .\n48 \nMirabile I Jat PS Brandner S Collinge J \nIdentification of clinical target areas in the brainstem of prion-infected mice . Neuropathol Appl Neurobiol (2015 ) 41 :613–30. 10.1111/nan.12189 \n\n49 \nLee K Baron K Soca R Attarian H \nThe prevalence and characteristics of REM sleep without atonia (RSWA) in patients taking antidepressants . J Clin Sleep Med (2016 ) 12 :351–5. 10.5664/jcsm.5582 \n\n50 \nPeever J Luppi PH Montplaisir J \nBreakdown in REM sleep circuitry underlies REM sleep behavior disorder . Trends Neurosci (2014 ) 37 :279–88. 10.1016/j.tins.2014.02.009 \n\n51 \nIranzo A Molinuevo JL Santamaría J Serradell M Martí MJ Valldeoriola F \nRapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study . Lancet Neurol (2006 ) 5 :572–7. 10.1016/S1474-4422(06)70476-8 \n\n52 \nVendette M Gagnon JF Décary A Massicotte-Marquez J Postuma RB Doyon J \nREM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia . Neurology (2007 ) 69 :1843–9. 10.1212/01.wnl.0000278114.14096.74 \n\n53 \nMander BA Marks SM Vogel JW Rao V Lu B Saletin JM \nβ-Amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation . Nat Neurosci (2015 ) 18 :1051–7. 10.1038/nn.4035 \n\n54 \nShokri-Kojori E Wang GJ Wiers CE Demiral SB Guo M Kim SW \nβ-Amyloid accumulation in the human brain after one night of sleep deprivation . Proc Natl Acad Sci U S A (2018 ) 115 :4483–8. 10.1073/pnas.1721694115 \n\n55 \nFraser E McDonagh AM Head M Bishop M Ironside JW Mann DM \nNeuronal and astrocytic responses involving the serotonergic system in human spongiform encephalopathies . Neuropathol Appl Neurobiol (2003 ) 29 :482–95. 10.1046/j.1365-2990.2003.00486.x \n\n56 \nPaterson RW Torres-Chae CC Kuo AL Ando T Nguyen EA Wong K \nDifferential diagnosis of Jakob–Creutzfeldt disease . Arch Neurol (2012 ) 69 :1578–82. 10.1001/2013.jamaneurol.79 \n\n57 \nAbudy A Juven-Wetzler A Zohar J \nThe different faces of Creutzfeldt–Jacob disease CJD in psychiatry . Gen Hosp Psychiatry (2014 ) 36 :245–8. 10.1016/j.genhosppsych.2014.02.002\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-0640",
"issue": "10()",
"journal": "Frontiers in psychiatry",
"keywords": "Creutzfeldt–Jakob disease; antidepressant; depression; neurotransmitters; sleep wake disorders",
"medline_ta": "Front Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101545006",
"other_id": null,
"pages": "297",
"pmc": null,
"pmid": "31130883",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10456721;11941194;12690204;14507340;15883321;16387988;16434680;16781987;16903142;16950387;17984452;18062457;18349519;19138799;19519984;19622511;19773352;19837057;20889378;21869605;21876440;22357679;22374884;22456094;22903853;22937408;23229042;23683161;24630894;24673896;25311251;25552870;25589671;25938948;26030850;26295747;26354478;26446247;26812492;26845268;27126544;27251305;27357003;27454922;28029715;28076012;28228380;28378508;29155679;29487167;29632177;8410083;8425391",
"title": "Does the Use of Antidepressants Accelerate the Disease Progress in Creutzfeldt-Jakob Disease Patients With Depression? A Case Report and A Systematic Review.",
"title_normalized": "does the use of antidepressants accelerate the disease progress in creutzfeldt jakob disease patients with depression a case report and a systematic review"
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"companynumb": "CN-BAUSCH-BL-2019-021006",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
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"abstract": "According to the ARISTOTLE trial, apixaban was superior to warfarin because it was associated with fewer strokes, systemic embolism, and bleeding. Hemopericardium was one of the major bleeding events reported in this trial. However, the percentage of patients that developed hemopericardium was not stated in the trial results. We present a case of hemopericardium in an 80-year-old man admitted for dyspnea, cough, and lower extremity edema. He was recently diagnosed with paroxysmal atrial fibrillation and started on apixaban for stroke prevention. Prior to admission, he was taking metoprolol succinate and amiodarone for atrial fibrillation. His symptoms resolved after undergoing successful pericardiocentesis. Although hemopericardium is a rare side effect associated with the use of non-vitamin K oral anticoagulants (NOACs), we suspect that a drug-drug interaction between apixaban and amiodarone (via the cytochrome p450 system and p-glycoprotein efflux pumps), the patient's advanced age, and borderline creatinine are possible risk factors.",
"affiliations": "Internal Medicine, Creighton University School of Medicine, Phoenix, USA.;Internal Medicine, Creighton University School of Medicine, Phoenix, USA.;Internal Medicine, Creighton University School of Medicine, Phoenix, USA.",
"authors": "Olagunju|Abdulbaril|A|;Khatib|Mohammad|M|;Palermo-Alvarado|Frances|F|",
"chemical_list": null,
"country": "United States",
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"doi": "10.7759/cureus.13486",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13486\nCardiology\nEmergency Medicine\nInternal Medicine\nA Possible Drug-Drug Interaction Between Eliquis and Amiodarone Resulting in Hemopericardium\nMuacevic Alexander\nAdler John R\nOlagunju Abdulbaril 1\nKhatib Mohammad 1\nPalermo-Alvarado Frances 1\n1 Internal Medicine, Creighton University School of Medicine, Phoenix, USA\nAbdulbaril Olagunju ab.dapoola@gmail.com\n22 2 2021\n2 2021\n13 2 e1348622 2 2021\nCopyright © 2021, Olagunju et al.\n2021\nOlagunju et al.\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/51575-a-possible-drug-drug-interaction-between-eliquis-and-amiodarone-resulting-in-hemopericardium\nAccording to the ARISTOTLE trial, apixaban was superior to warfarin because it was associated with fewer strokes, systemic embolism, and bleeding. Hemopericardium was one of the major bleeding events reported in this trial. However, the percentage of patients that developed hemopericardium was not stated in the trial results.\n\nWe present a case of hemopericardium in an 80-year-old man admitted for dyspnea, cough, and lower extremity edema. He was recently diagnosed with paroxysmal atrial fibrillation and started on apixaban for stroke prevention. Prior to admission, he was taking metoprolol succinate and amiodarone for atrial fibrillation. His symptoms resolved after undergoing successful pericardiocentesis.\n\nAlthough hemopericardium is a rare side effect associated with the use of non-vitamin K oral anticoagulants (NOACs), we suspect that a drug-drug interaction between apixaban and amiodarone (via the cytochrome p450 system and p-glycoprotein efflux pumps), the patient's advanced age, and borderline creatinine are possible risk factors.\n\nhemorrhage\npericardium\neffusion\neliquis\namiodarone\ncytochrome p450\np-glycoprotein\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nApixaban is a non-vitamin K oral anticoagulants (NOACs) in the same class as rivaroxaban, endoxaban, and dabigatran. It is licensed in the United States for the prevention of stroke in nonvalvular atrial fibrillation and venous thromboembolism [1]. Although it was associated with a greater reduction in the rate of stroke and a lower rate of bleeding compared to warfarin in the ARISTOTLE trial, it was associated with an increased risk of major bleeding (including hemopericardium) defined using the International Society on Thrombosis and Hemostasis (ISTH) criteria; at an incident rate of 2.13% per year [2,3]. However, the percentage of hemopericardium compared to other bleeding sites was not included in the trial results [2,3]. Hemopericardium is the accumulation of blood in the pericardial space [4]. This could lead to life-threatening hemodynamic compromise, cardiac tamponade depending on the rate and volume of blood accumulation [4]. Reported causes are infection (especially tuberculosis), metastasis of malignant cells to the pericardium, thoracic aortic dissection, cardiac surgery, acute myocardial infarction, trauma, pericarditis, and bleeding diathesis [3]. We present a case of hemopericardium in a patient taking apixaban for paroxysmal atrial fibrillation.\n\nCase presentation\n\nAn 80-year-old male with a past medical history of paroxysmal atrial fibrillation, heart failure with preserved ejection fraction, chronic obstructive pulmonary disease, tobacco dependence, benign essential hypertension, and stage 3 chronic kidney disease presented to the emergency department (ED) with shortness of breath, orthopnea, increasing lower extremity edema, and cough of two weeks' duration. The cough was productive with white sputum and worse in the supine position. He denied hemoptysis, chest pain, fever, chills, night sweat, weight loss, nausea, and vomiting. His paroxysmal atrial fibrillation was diagnosed two weeks prior when he was admitted and treated for COPD exacerbation and cellulitis of the right shin. He converted to sinus rhythm after receiving 20mg IV diltiazem. Based on his CHA2DS2VASc score of 4, he was discharged home with 5mg twice a day (BID) of apixaban and metoprolol succinate 12.5mg BID for rate control; he was also started on amiodarone 200mg daily outpatient. A transthoracic echocardiogram before discharge revealed a normal ejection fraction of 62% with grade 2 diastolic dysfunction (Figure 1).\n\nFigure 1 Parasternal long-axis view of the patient's baseline echocardiogram did not show pericardial effusion.\n\nOn presentation to the ED, he was tachypneic with a respiratory rate of 32 breaths per minute and oxygen saturation of 91% on room air, his heart rate was 77 beats per minute and blood pressure was 114/78mmHg. Physical examination was remarkable for jugular venous distention, distant heart sounds, and 3+ bilateral lower extremity edema up to his shins. Abnormal laboratory findings on admission were hemoglobin of 10.8g/dL (his baseline is 12g/dL), creatinine of 1.67mg/dL (his baseline is 1.42mg/dL), glomerular filtration rate (GFR) of 40mL/min (his baseline is 50mL/min), blood urea nitrogen (BUN) of 31mg/dL, INR of 3.0, and N-terminal brain natriuretic peptide (NT-BNP) of 729pg/mL. Electrocardiogram revealed sinus rhythm with premature ventricular contraction, no low QRS voltage or electrical alternans (Figure 2). The chest radiograph was remarkable for an enlarged cardiac silhouette, new bibasilar airspace opacities, and small bilateral pleural effusion (Figure 3). A limited bedside echocardiogram was remarkable for a large pericardial effusion with fibrinous material noted in the effusion, an excessive respiratory variation of the mitral and tricuspid inflow velocities, a dilated inferior vena cava (IVC) with a diameter >2.1cm, and <50% respiratory collapse estimating a right atrial pressure of 15mmHg. There was no collapse of the right ventricle (Figure 4).\n\nFigure 2 Electrocardiogram unremarkable for low QRS voltage or electrical alternans.\n\nFigure 3 Chest radiograph remarkable for enlarged cardiac silhouette, new bibasilar airspace opacities, and small bilateral pleural effusion.\n\nFigure 4 Parasternal long-axis view on echocardiogram remarkable for a large pericardial effusion.\n\nHe immediately received 50 units/kg of prothrombin complex concentrate to reverse the effect of apixaban and urgent pericardiocentesis was performed. There was 600mL of frank blood initially drained and an additional 200mL was drained by the end of the following day via the pericardial drain. The pericardial fluid was sent for cytology, acid fast bacilli (AFB) culture, stain, fungal culture, gram stain, and bacterial culture. A repeat echocardiogram a day after pericardiocentesis revealed complete evacuation of the effusion. Although the pericardiocentesis led to an improvement in his shortness of breath and orthopnea, he required diuresis with 20mg of furosemide for complete resolution. The pericardial drain was removed on day 3 of admission and he was discharged the following day.\n\nCytology of the pericardial fluid revealed numerous red blood cells, lymphocytes, neutrophils, and benign mesothelial cells. There were no malignant cells. There were no organisms on gram stain and bacterial culture was negative after five days. No organisms were noted on the AFB stain; AFB culture remained negative after five weeks. Fungal culture remained negative after four weeks. \n\nDiscussion\n\nThe absence of malignant cells in the pericardial effusion, negative cultures, and stains makes apixaban a possible cause of hemopericardium in this patient. Drug-drug interaction with amiodarone, the patient's advanced age, and borderline creatinine might explain this finding. \n\nApixaban has a half-life of 12 hours [5]; approximately 25% is eliminated indirectly into bile as hydroxylated-O-demethyl apixaban after metabolism by the cytochrome p450 system, particularly CYP3A4 [6]. About 25%-27% is eliminated directly by the kidney and the rest is secreted directly into bile and excreted into feces via the p-glycoprotein efflux pump [6,7]. Amiodarone is a known inhibitor of CYP3A4 and the p-glycoprotein efflux pump [7-11]. It likely increased the half-life of apixaban in this patient and possibly contributed to the hemopericardium. Interestingly, about 11.4% of the patients in the ARISTOTLE trial received amiodarone [12]. In addition, according to a post-hoc analysis of the ARISTOTLE trial, a retrospective study of p-glycoprotein inhibitors and apixaban, the bleeding outcomes were not statistically significant when compared to patients taking apixaban alone [10].\n\nThe patient's advanced age and stage 3 chronic kidney disease could have also predisposed to hemopericardium. Perhaps a dose reduction to 2.5mg BID upon initiation of amiodarone might have prevented this. However, there are no guideline recommendations that back this up. Based on the apixaban dosing guidelines, the 2.5mg BID dosing should be used in patients with two of three criteria which are age, weight, and creatinine of at least 80 years, 60kg, and 1.5mg/dL, respectively [13]. Our patient’s weight of 72.6kg and baseline creatinine of 1.42mL/min at the time of apixaban initiation meant that the patient met only one of the three criteria. Perhaps the impact of age on the likelihood of bleeding is independent of the presence of the other two criteria.\n\nConclusions\n\nThis is a very unusual case of hemopericardium because both amiodarone and apixaban are commonly prescribed together. A drug-drug interaction between apixaban and amiodarone could have increased the risk of bleeding in this patient via inhibition of the cytochrome p450 system and p-glycoprotein efflux pumps. In addition, the patient's age of 80 years and borderline creatinine of 1.42mg/dL might have also predisposed him to bleeding.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Overview of the new oral anticoagulants Arterioscler Thromb Vasc Biol Yeh C Hogg K Weitz J 1056 1065 35 2015 25792448\n2 Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med Granger C AlexanderJ AlexanderJ McMurray J 981 992 365 2011 21870978\n3 First reported case series in the United States of hemopericardium in patients on apixaban HeartRhythm Case Rep Sablani N Garg J Hasan B Patel R Martinez M 82 84 4 2018 29876295\n4 A rare case of idiopathic hemorrhagic pericardial effusion presenting as cardiac tamponade 102020 2019 https://doi.org/10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A3534\n5 Spontaneous hemorrhagic pericardial and pleural effusion in a patient receiving apixaban Cardiol Res Cinelli M Uddin A Duka I Soomro A Tamburrino F Ghavami F Lafferty J 249 252 10 2019 31413784\n6 Apixaban: a clinical pharmacokinetic and pharmacodynamic review Clin Pharmacokinet Byon W Garonzik S Boyd R Frost C 1265 1279 58 2019 31089975\n7 Potential drug-drug interactions with direct oral anticoagulants in elderly hospitalized patients Ther Adv Drug Saf Forbes H Polasek T 319 328 8 2017 29593860\n8 A rare case of spontaneous cardiac tamponade induced by concomitant use of rivaroxaban and amiodarone Case Rep Cardiol Oladiran O Segal J Nwosu I Nazir S 1 4 2018 2018\n9 Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: a systematic review Thromb Res Li A Li M Crowther M Vazquez S 240 245 194 2020 33213849\n10 Drug interactions with apixaban: a systematic review of the literature and an analysis of VigiBase, the World Health Organization database of spontaneous safety reports Pharmacol Res Perspect Fernandez S Lenoir C Samer C Rollason V 647 8 2020\n11 Physicians beware: direct oral anticoagulants do interact with some commonly used drugs Hematologist Linkins L 1 15 2018\n12 Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial J AM Coll Cardiol Flaker G Lopes D Hylek E 1541 1550 64 2014 25301455\n13 Apixaban (eliquis) for stroke prevention in atrial fibrillation Am Fam Physician Beck R King W 672 675 89 2014 https://www.aafp.org/afp/2014/0415/p672.html 24784127\n\n",
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"keywords": "amiodarone; cytochrome p450; effusion; eliquis; hemorrhage; p-glycoprotein; pericardium",
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"title": "A Possible Drug-Drug Interaction Between Eliquis and Amiodarone Resulting in Hemopericardium.",
"title_normalized": "a possible drug drug interaction between eliquis and amiodarone resulting in hemopericardium"
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"abstract": "Coronary artery disease (CAD), the major reason of deaths worldwide is generally known as a disease of the elderly, however it is grasping the youth too. The most common etiology of young CAD is lifestyle changes, smoking, and development of other comorbid conditions such as diabetes and hypertension at an early age. There has been an upward trend in youngsters regarding consciousness about their body build and thus use of various protein supplements and anabolic steroids for faster results. The present case reports a young patient presenting with severe retrosternal left-sided chest pain for 15-20 min to the emergency department. His electrocardiogram was suggestive of acute anterolateral wall ST segment elevation myocardial infarction for which he underwent urgent coronary angiography and percutaneous coronary intervention. His personal history revealed a significant use of steroids, proteins, and other supplements in supraphysiological doses for instant body building efforts without any other significant past medical, surgical, or family history. He showed good recovery and was strongly recommended to stop steroids and protein supplements. In conclusion, supraphysiological doses of protein supplements, anabolic steroids, and other nutritional products bear a risk factor for CAD. <Learning objective: This is evident from the case report that excessive supplements use by body builders for immediate mass gain and performance enhancement may lead to adverse cardiovascular complications. This is mostly prescribed by peer groups or untrained gym professionals without judging their adverse effects so we recommend a detailed history for steroid use and protein supplements in young patients presenting with acute myocardial infarction without other significant risk factors and need for counselling for use of such substances.>.",
"affiliations": "Department of Cardiovascular Disease, Mayo Clinic, Rochester, MN, USA.;Department of Cardiology, QRG Health City, Faridabad, Haryana, India.",
"authors": "Jain|Vaibhav|V|;Goel|Gajinder|G|",
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"issue": "21(4)",
"journal": "Journal of cardiology cases",
"keywords": "AMI, acute myocardial infarction; Acute myocardial infarction; BCAA, branched-chain amino acid; Bodybuilder; CAD, coronary artery disease; LVH, left ventricular hypertrophy; MI, myocardial infarction; PCI, percutaneous coronary intervention; Protein supplements; STEMI, ST segment elevation myocardial infarction; Steroids; TSH, thyroid stimulating hormone; TXA2, thromboxane A2",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "134-136",
"pmc": null,
"pmid": "32256860",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": "27839839;24970969;11849669;23067914;15660036;25045293;7758179;18388062;11175645",
"title": "Acute myocardial infarction in young newbie bodybuilder using multiple steroid and protein supplements.",
"title_normalized": "acute myocardial infarction in young newbie bodybuilder using multiple steroid and protein supplements"
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-03202",
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"abstract": "BACKGROUND\nHypercoagulability can lead to thromboembolic events that are a life-threatening complication of nephrotic syndrome (NS). Conventional anticoagulants are first-line treatment in the presence of demonstrated thrombosis in NS. Direct-acting oral anticoagulants (DOACs) have provided useful alternatives for the prevention and treatment of thromboembolic events.\nA 59-year-old male developed lower limbs deep vein thrombosis (DVT) during the early course of NS but presented poor response to oral therapeutic doses of rivaroxaban. The decision was made to switch from rivaroxaban to heparin and subsequently bridged to warfarin. The patient presented significant clinical symptom improvement.\n\n\nMETHODS\nNS with Lower limbs DVT.\n\n\nMETHODS\nRivaroxaban was discontinued and switch to heparin and subsequently bridged to warfarin.\n\n\nRESULTS\nVenography result of both lower limb vein showed the venous wall was smooth without obvious stenosis or obstruction. Edema of the patient's lower limbs gradually improved and disappeared.\n\n\nCONCLUSIONS\nThe existing published data on the application of DOACs in NS are limited. DOACs have an immediate anticoagulant effect and have demonstrated safety and efficacy and required no routine monitoring, however, application of these agents in NS likely requires further investigation before widespread adoption.",
"affiliations": "Department of Pharmacy, the Second Affiliated Hospital of Chongqing Medical University.;Department of Vascular Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.;Department of Vascular Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.;College of Pharmacy, Chongqing Medical University.;Department of Pharmacy, the Second Affiliated Hospital of Chongqing Medical University.;Department of Pharmacy, the Second Affiliated Hospital of Chongqing Medical University.",
"authors": "Li|Yan|Y|;Chen|Yikuan|Y|;Qi|Xiaotong|X|;Hu|Bangqin|B|;Du|Qingqing|Q|;Qian|Yan|Y|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D000069552:Rivaroxaban",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000016585",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31374026MD-D-19-0065310.1097/MD.0000000000016585165854200Research ArticleClinical Case ReportPoor response to rivaroxaban in nephrotic syndrome with acute deep vein thrombosis A case reportLi Yan BSabChen Yikuan PhDcQi Xiaotong PhDcHu Bangqin BSbDu Qingqing PhDa∗Qian Yan BSa∗A. N/ a Department of Pharmacy, the Second Affiliated Hospital of Chongqing Medical Universityb College of Pharmacy, Chongqing Medical Universityc Department of Vascular Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.∗ Correspondence: Qingqing Du, Department of Pharmacy, the Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing 400010, China (e-mail: Dorothydu@hospital.cqmu.edu.cn); Yan Qian, Department of Pharmacy, the Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing 400010, China (e-mail: 300861@hospital.cqmu.edu.cn).8 2019 02 8 2019 98 31 e1658524 1 2019 23 5 2019 02 7 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-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:\nHypercoagulability can lead to thromboembolic events that are a life-threatening complication of nephrotic syndrome (NS). Conventional anticoagulants are first-line treatment in the presence of demonstrated thrombosis in NS. Direct-acting oral anticoagulants (DOACs) have provided useful alternatives for the prevention and treatment of thromboembolic events.\n\nPatient concerns:\nA 59-year-old male developed lower limbs deep vein thrombosis (DVT) during the early course of NS but presented poor response to oral therapeutic doses of rivaroxaban. The decision was made to switch from rivaroxaban to heparin and subsequently bridged to warfarin. The patient presented significant clinical symptom improvement.\n\nDiagnosis:\nNS with Lower limbs DVT.\n\nInterventions:\nRivaroxaban was discontinued and switch to heparin and subsequently bridged to warfarin.\n\nOutcomes:\nVenography result of both lower limb vein showed the venous wall was smooth without obvious stenosis or obstruction. Edema of the patient's lower limbs gradually improved and disappeared.\n\nLessons:\nThe existing published data on the application of DOACs in NS are limited. DOACs have an immediate anticoagulant effect and have demonstrated safety and efficacy and required no routine monitoring, however, application of these agents in NS likely requires further investigation before widespread adoption.\n\nKeywords\nanticoagulationhypercoagulabilitynephrotic syndromerivaroxabanOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nDeep venous thrombosis (DVT) is a significant complication associated with nephrotic syndrome (NS). The incidence of thromboembolism is approximately 25% in adult patients with NS.[1] The exact pathophysiology of thrombogenesis in NS is complex and remains inconclusive. Thrombosis in NS may arise from leakage of high-molecular-weight proteins in addition to albumin leading to a hypercoagulability, increased synthesis of factors promoting thrombosis, platelet activation, and aggregation, activation of the coagulation system (ie, factor V, factor VIII, von Willebrand factor, fibrinogen), or decreased endogenous anticoagulants (ie, antithrombin III, protein C, protein S, tissue factor pathway inhibitor).[2,3] Conventional anticoagulants are first-line treatment in the presence of demonstrated thrombosis. Here we report a patient who developed lower limbs DVT during the early course of NS but presented poor treatment on oral therapeutic doses of rivaroxaban.\n\n2 Case report\nApproval for the study by the local institution review board was not required because it was a case report. The patient provided a written informed consent for the publication of his clinical data. A 59-year-old male was admitted to our hospital with an approximately 12-hour history of swelling pain of left lower limb. Two months previously, he had presented with both lower limbs’ edema. Ten days before admission, he had been diagnosed with NS in another hospital but refused a kidney biopsy. Then he was treated with 60 mg/day of prednison and 50 mg of dipyridamole 3 times a day. He had a 40-year tobacco history and 10-year erosive gastritis history but no family history of notable illness.\n\nPhysical examination on admission revealed the following: height 160 cm, weight 69 kg, blood pressure 130/80 mmHg, heart rate 70 beats/min with a regular rhythm, respiration rate 18/min, and temperature 36.5°C. Left lower limb moderate nonpitting edema was observed. There was no rash, hyperpigmentation, or anabrosis. The rest of the physical examination was unremarkable.\n\nThe patient's laboratory test results are shown in Table 1. Urine sediment analysis revealed massive proteinuria. Twenty-four-hour urine protein excretion was 2660 mg. Albumin was significantly lower than normal. The lipid panel revealed total cholesterol, triglyceride, and low-density lipoprotein were high. Initial d-dimer and fibrin/fibrinogen degradation products remarkably increased. Prothrombin time, prothrombin time-international normalized ratio, and activated partial thromboplastin time (APTT) were all normal. Vascular ultrasound showed thrombus of left lower limb vein but no definite abnormality of right lower limb vein (Fig. 1A). And we performed venography of left lower limb vein. The results showed DVT, with total thrombosis of the left common iliac vein and popliteal veins (Fig. 1B). Therefore, we performed balloon dilatation and catheter-directed thrombolysis. And a recyclable inferior vena cava filter was placed. Then thrombolytic therapy with urokinase and anticoagulation therapy with rivaroxaban were initiated. After operation, the patient had a high fever and temperature was 39.2°C. Complete blood count showed white blood cell count 21.24 × 109 cells/L, the percent of neutrophile granulocyte 95.3%. Biochemical examination revealed procalcitonin 9.6800 ng/mL. The result of blood culture was Acinetobacter baumannii. So antibacterial treatment with meropenem was initiated. On day 3, because the patient was diagnosed with catheter-associated bacterial infection, he removed the thrombolytic catheter and performed iliac vein stent placement. But on day 10, we performed venography of left lower limb vein and inferior vena cava and the results showed thrombosis of inferior vena cava (Fig. 1E). On day 12, emission computed tomography (ECT) examination revealed fresh thrombosis of deep vein in both lower extremities (Fig. 1D). However, bilateral pulmonary perfusion imaging showed no pulmonary embolism. The patient presented no significant clinical symptom improvement and then switched from rivaroxaban to heparin. APTT levels were monitored for dose adjustments so that APTT reached and maintained 1.5 to 2.5 times of normal value. On day 17, venography result of both lower limb vein showed the venous wall was smooth without obvious stenosis or obstruction. Edema of the patient's lower limbs gradually improved and disappeared. The patient was subsequently bridged to warfarin for discharge and continued receiving treatment with glucocorticoids. The clinical course of the patient is shown in Figure 2.\n\nTable 1 Laboratory test results of the patient.\n\nFigure 1 Imageological examination results of the patient. (A) Vascular ultrasound. (B) Venography of left lower limb before thrombolysis and anticoagulation (day 1). (C) Venography of left lower limb after thrombolysis and anticoagulation (day 3). (D) emission computed tomography. (E) Venography of inferior vena cava (day 10); (F) Venography of inferior vena cava (day 15). LEIA = left external iliac artery, LEIV = left external iliac vein.\n\nFigure 2 The clinical course. CDT = catheter-directed thrombolysis, ST = systemic thrombolysis.\n\n3 Discussion\nHypercoagulability associated with NS can lead to arterial and venous thromboembolism. The management of thrombosis in NS is not clearly established because of the lack of large randomized trials and guidelines.[4] Conventional anticoagulation remains the standard therapy in the presence of demonstrated thrombosis. At present, the anticoagulants are mainly divided into parenteral anticoagulants and oral anticoagulants. Parenteral anticoagulants include heparin and low-molecular-weight heparins which bind to and potentiate the effects of antithrombin III.[5] Oral anticoagulants include vitamin K antagonists (warfarin) and direct-acting oral anticoagulants (DOACs): direct-acting factors Xa and IIa inhibitors. Warfarin inhibits vitamin K-dependent clotting factors II, VII, IX, and X as well as protein C and S. Owing to its multiple drug and food interactions, the safety, efficacy, and compliance of warfarin have been affected.[4] This has prompted the development of DOACs that target key clotting factors Xa and IIa. Rivaroxaban, the first of the DOACs to be FDA approved for both prevention and treatment of venous thromboembolism, is an oral, direct-acting factor Xa inhibitor that is highly protein-bound (90%–95%) in vitro in humans, serum albumin being the main binding component. It is metabolized by CYP3A4 and is the substrate of P-glycoprotein.[6] Therefore it may interact with medications that affect these pathways if coadministered. Because of its predictable pharmacokinetic properties, a rapid onset of action, rivaroxaban has fixed dosing and requires no routine coagulation monitoring.[7] Although DOACs may simplify thromboembolism prophylaxis in NS and might obviate the need for concern about heparin resistance because of antithrombin urinary losses, whether the pharmacokinetics and pharmacodynamics of these agents are altered in NS is unknown.\n\nIn the case reported here, the patient was initially diagnosed with NS and started on conventional corticosteroid therapy with prednisone and antiplatelet therapy with dipyridamole. But DVT occurred 10 days after the diagnosis of NS. Treatment of venous thromboembolism in patients with NS is similar to that in patients without NS.[8] Then thrombolytic therapy with urokinase and anticoagulation therapy with rivaroxaban were adopted. While on anticoagulation with rivaroxaban, ECT examination revealed fresh thrombosis of deep vein in right lower extremities. Venography results showed thrombosis of inferior vena cava. As a result, the patient switched from rivaroxaban to heparin and subsequently bridged to warfarin. In general it is thought that for medications that are highly protein-bound, urinary loss of albumin in NS could lead to higher free drug levels and potential toxicity.[9] However it is likely that high protein-binding could lead to urinary losses of the drug. There is a report that high protein-binding of rivaroxaban can lead to increased plasma clearance of the drug in NS which led to treatment failure.[10] Or the initial high proportion of free drugs is metabolized and excreted freely, accelerating the release of the binding part and shortening the half-life. This may cause the concentration required for thrombus treatment to fall below the threshold during dosing interval, leading to poor treatment.[11] Whether this means that anticoagulation with rivaroxaban in NS requires routine monitoring of serum drug concentrations is uncertain. Compensatory increase in hepatic production secondary to hypoallbuminemia leads to increased activity of clotting factors in NS.[3] Rivaroxaban is a direct factor Xa inhibitor. Increased factor levels can make anticoagulants ineffective, which results in treatment failure. Whether this means that the efficacy and bleeding risk of rivaroxaban will depend on the factor Xa levels and whether factor Xa levels should be used to guide anticoagulant therapy in NS are currently unclear. After the admission of 2 days, the patient developed catheter-associated bacterial infection and the result of blood culture was Acinetobacter baumannii. Bacterial sepsis induces systemic thrombosis triggered by microbial endotoxin or exotoxin and subsequently releases inflammatory cytokines from monocytes. Hemostatic disorders mediated by tissue factor responses to tumor necrosis factor and interleukin 1 (IL-1) and 6 (IL-6) at the cell surface may lead to hypercoagulability.[12] Clinically, significant infection-induced coagulation activation can be observed in 30% to 50% of patients with gram-negative sepsis.[13] Hypercoagulability owing to infection in this patient may have increased the difficulty of treatment and prolonged the course of the disease. There is a report that high-dose meropenem inhibits CYP2C19 and CYP3A4.[14] So high-dose meropenem can potentially change the exposure of rivaroxaban metabolized by CYP3A4. But this patient was on conventional-dose meropenem; there may be no drug interaction between meropenem and rivaroxaban. Normalization of albumin levels is important because it lowers the level of clotting factors, making anticoagulation more effective. Decreased albumin levels of this patient potentially led to poor treatment during anticoagulation. Therefore, the treatment of NS is crucial to the prevention and treatment of thrombosis.\n\n4 Conclusion\nThromboembolism is a frequent life-threatening complication of NS. Antithrombotic therapy is important in preventing and treating acute and recurrent thromboembolism. We reported the case of a patient with NS in whom an oral factor Xa inhibitor, rivaroxaban, had poor therapeutic effect in treating acute DVT. Although DOACs have an immediate anticoagulant effect and have demonstrated safety and efficacy and required no routine monitoring, the existing published data on the application of these agents in NS are limited. Many uncertainties remain, such as whether dosing and monitoring should be based on serum factor Xa levels to guide therapy in NS, whether high protein-binding leads to urinary losses of active agent, and whether anticoagulation with rivaroxaban in NS requires routine monitoring of serum drug concentrations. Application of DOACs in NS likely requires further investigation before widespread adoption.\n\nAcknowledgment\nThe authors thank all participants for their supports and participation.\n\nAuthor contributions\nData curation: Yikuan Chen, Xiaotong Qi.\n\nWriting – review & editing: Yan Li, Bangqin Hu, Qingqing Du, Yan Qian.\n\nAbbreviations: APTT = activated partial thromboplastin time, DOACs = direct-acting oral anticoagulants, DVT = deep vein thrombosis, ECT = emission computed tomography, FDP = fibrin/fibrinogen degradation products, INR = prothrombin time-international normalized ratio, LDL = low-density lipoprotein, NS = nephrotic syndrome, PT = prothrombin time, TC = total cholesterol, TG = triglyceride.\n\nThis work was supported by Young Talents Nursery Foundation of the second affiliated Hospital of Chongqing Medical University and Chongqing Social Work and People's Livelihood Security Science and Technology Innovation Project Fund (No. cstc2017shmsA130041). The authors declare that they have no conflict of interest.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Kerlin BA Ayoob R Smoyer WE \nEpidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease . Clin J Am Soc Nephrol \n2012 ;7 :513–20 .22344511 \n[2] Singhal R Brimble KS \nThromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management . Thromb Res \n2006 ;118 :397–407 .15990160 \n[3] Chen G Liu H Liu F \nA glimpse of the glomerular milieu: from endothelial cell to thrombotic disease in nephrotic syndrome . Microvasc Res \n2013 ;89 :1–6 .23851046 \n[4] Barbano B Gigante A Amoroso A \nThrombosis in nephrotic syndrome . Semin Thromb Hemost \n2013 ;39 :469–76 .23625754 \n[5] Garcia DA Baglin TP Weitz JI \nParenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines . Chest \n2012 ;141 :e24S–43S .22315264 \n[6] Mueck W Stampfuss J Kubitza D \nClinical pharmacokinetic and pharmacodynamic profile of rivaroxaban . Clin Pharmacokinet \n2014 ;53 :1–6 .23999929 \n[7] Gonsalves WI Pruthi RK Patnaik MM \nThe new oral anticoagulants in clinical practice . Mayo Clin Proc \n2013 ;88 :495–511 .23639500 \n[8] Al-Azzawi HF Obi OC Safi J \nNephrotic syndrome-induced thromboembolism in adults . Int J Crit Illn Inj Sci \n2016 ;6 :85–8 .27308257 \n[9] Bernard DB \nExtrarenal complications of the nephrotic syndrome . Kidney Int \n1988 ;33 :1184–202 .3404817 \n[10] Basu A Jain S Patel D \nFailure of anticoagulation in a case of nephrotic syndrome with recurrent thromboembolism . Chest \n2015 ;148 :983A.\n[11] Reynolds ML Nachman PH Mooberry MJ \nRecurrent venous thromboembolism in primary membranous nephropathy despite direct Xa inhibitor therapy . J Nephrol \n2019 ;32 :669–72 .30421320 \n[12] Piotr P Maria Z Zofia T \nPlasma markers of hypercoagulability in patients with serious infections and risk of septic shock . Clin Appl Thromb Hemost \n2002 ;8 :225–30 .12361199 \n[13] Levi M \nInfection and inflammation and the coagulation system . Cardiovasc Res \n2003 ;60 :26–39 .14522404 \n[14] Mahmoudi M Brenner T Hatiboglu G \nSubstantial impairment of voriconazole clearance by high-dose meropenem in a patient with renal failure . Clin Infect Dis \n2017 ;65 :1033–6 .28505263\n\n",
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"issue": "98(31)",
"journal": "Medicine",
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"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000925:Anticoagulants; D006801:Humans; D008297:Male; D008875:Middle Aged; D009404:Nephrotic Syndrome; D000069552:Rivaroxaban; D019851:Thrombophilia; D020246:Venous Thrombosis; D014859:Warfarin",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Poor response to rivaroxaban in nephrotic syndrome with acute deep vein thrombosis: A case report.",
"title_normalized": "poor response to rivaroxaban in nephrotic syndrome with acute deep vein thrombosis a case report"
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"abstract": "BACKGROUND\nDirect comparisons between lamivudine plus bPIs and lamivudine plus dolutegravir as maintenance strategies in virologically-suppressed HIV positive patients are lacking.\n\n\nMETHODS\nTime to treatment discontinuation (TD) and virological failure (VF) were compared in a cohort of HIV+ patients on a virologically-effective ART starting lamivudine with either darunavir/r, atazanavir/r or dolutegravir. Changes in laboratory parameters were also evaluated.\n\n\nRESULTS\nFour-hundred-ninety-four patients were analyzed (170 switching to darunavir/r, 141 to atazanavir/r, 183 to dolutegravir): median age was 49 years, with 8 years since ART start. Groups differed for age, HIV-risk factor, time since HIV-diagnosis and on ART, previous therapy and reasons for switching. Estimated proportions free from TD at week 48 and 96 were 79.8 and 48.3% of patients with darunavir/r, 87.0 and 70.9% with atazanavir/r, and 88.2 and 82.6% with dolutegravir, respectively (p < 0.001). Calendar years, HIV-risk factor, higher baseline cholesterol and an InSTI-based previous regimen predicted TD, whereas lamivudine+dolutegravir therapy and previous tenofovir use were protective. VF was the cause of TD in 6/123 cases with darunavir/r, 4/97 with atazanavir/r and 3/21 with dolutegravir. Other main reasons for TD were: toxicity (43.1% with darunavir/r, 39.2% with atazanavir/r, 52.4% with dolutegravir), further simplification (36.6% with darunavir/r, 30.9% with atazanavir/r, 14.3% with dolutegravir). Incidence of VF did not differ among study groups (p = 0.747). No factor could predict VF. Lipid profile improved in the dolutegravir group, whereas renal function improved in the bPIs groups.\n\n\nCONCLUSIONS\nIn real practice, a switch to lamivudine+dolutegravir showed similar efficacy but longer durability than a switch to lamivudine+bPIs.",
"affiliations": "Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Infectious Diseases Unit, Siena University Hospital, Viale Mario Bracci, 53100, Siena, Italy.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Infectious Diseases Unit, Siena University Hospital, Viale Mario Bracci, 53100, Siena, Italy.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.;Infectious Diseases Unit, Siena University Hospital, Viale Mario Bracci, 53100, Siena, Italy. andrea.deluca@unisi.it.;Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy.",
"authors": "Borghetti|Alberto|A|;Lombardi|Francesca|F|;Gagliardini|Roberta|R|;Baldin|Gianmaria|G|;Ciccullo|Arturo|A|;Moschese|Davide|D|;Emiliozzi|Arianna|A|;Belmonti|Simone|S|;Lamonica|Silvia|S|;Montagnani|Francesca|F|;Visconti|Elena|E|;De Luca|Andrea|A|;Di Giambenedetto|Simona|S|",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D019259:Lamivudine; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; C562325:dolutegravir; D019438:Ritonavir; D000069454:Darunavir",
"country": "England",
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"doi": "10.1186/s12879-018-3666-8",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 366610.1186/s12879-018-3666-8Research ArticleEfficacy and tolerability of lamivudine plus dolutegravir compared with lamivudine plus boosted PIs in HIV-1 positive individuals with virologic suppression: a retrospective study from the clinical practice Borghetti Alberto al.bor86@gmail.com 1Lombardi Francesca francesca.lombardi@gmail.com 1Gagliardini Roberta roberta_gagliardini@yahoo.it 2Baldin Gianmaria gian.baldin@gmail.com 1Ciccullo Arturo arturo.ciccullo@gmail.com 1Moschese Davide davide.moschese@gmail.com 1Emiliozzi Arianna ariannaemiliozzi@gmail.com 1Belmonti Simone s.belmonti@yahoo.it 1Lamonica Silvia silvia.lamonica@libero.it 1Montagnani Francesca francesca.montagnani@unisi.it 2Visconti Elena elena.visconti@policlinicogemelli.it 1De Luca Andrea 0039-0577586347andrea.deluca@unisi.it 2Di Giambenedetto Simona Simona.DiGiambenedetto@unicatt.it 11 0000 0001 0941 3192grid.8142.fInstitute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Policlinico Gemelli, Rome, Italy 2 0000 0004 1759 0844grid.411477.0Infectious Diseases Unit, Siena University Hospital, Viale Mario Bracci, 53100 Siena, Italy 17 1 2019 17 1 2019 2019 19 5913 1 2018 28 12 2018 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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\nDirect comparisons between lamivudine plus bPIs and lamivudine plus dolutegravir as maintenance strategies in virologically-suppressed HIV positive patients are lacking.\n\nMethods\nTime to treatment discontinuation (TD) and virological failure (VF) were compared in a cohort of HIV+ patients on a virologically-effective ART starting lamivudine with either darunavir/r, atazanavir/r or dolutegravir. Changes in laboratory parameters were also evaluated.\n\nResults\nFour-hundred-ninety-four patients were analyzed (170 switching to darunavir/r, 141 to atazanavir/r, 183 to dolutegravir): median age was 49 years, with 8 years since ART start. Groups differed for age, HIV-risk factor, time since HIV-diagnosis and on ART, previous therapy and reasons for switching.\n\nEstimated proportions free from TD at week 48 and 96 were 79.8 and 48.3% of patients with darunavir/r, 87.0 and 70.9% with atazanavir/r, and 88.2 and 82.6% with dolutegravir, respectively (p < 0.001). Calendar years, HIV-risk factor, higher baseline cholesterol and an InSTI-based previous regimen predicted TD, whereas lamivudine+dolutegravir therapy and previous tenofovir use were protective. VF was the cause of TD in 6/123 cases with darunavir/r, 4/97 with atazanavir/r and 3/21 with dolutegravir. Other main reasons for TD were: toxicity (43.1% with darunavir/r, 39.2% with atazanavir/r, 52.4% with dolutegravir), further simplification (36.6% with darunavir/r, 30.9% with atazanavir/r, 14.3% with dolutegravir). Incidence of VF did not differ among study groups (p = 0.747). No factor could predict VF.\n\nLipid profile improved in the dolutegravir group, whereas renal function improved in the bPIs groups.\n\nConclusions\nIn real practice, a switch to lamivudine+dolutegravir showed similar efficacy but longer durability than a switch to lamivudine+bPIs.\n\nKeywords\nHIVAntiretroviral therapyMaintenance therapyDual therapyLamivudineDolutegravirAtazanavir/ritonavirDarunavir/ritonavirissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nCombination antiretroviral therapy (ART) has dramatically decreased the incidence of AIDS-defining events in the HIV-infected population [1]. International guidelines [2, 3] recommend a prompt initiation of ART independently from CD4 cell count in order to reduce morbidity and mortality associated with HIV infection. Conversely, even if non-AIDS defining events are reduced by the immediate initiation of ART [4] the beneficial effects of long-term therapy on the burden of some non-AIDS related conditions (such as cardiovascular disease) remain to be established. Mathematical models [5] forecast that, in the next few decades, age-related comorbidities will become increasingly relevant in the management of HIV-infected individuals, especially due to an increased burden of cardiovascular diseases, diabetes and chronic kidney disease. Moreover, the indication to treat all HIV-infected patients regardless of their CD4 counts [4] raises the issue of the long-term treatment-related toxicities, such as those related to nucleoside reverse transcriptase inhibitors, NRTIs [6], and patients’ adherence [7]. Finally, the increasing prevalence of HIV infection, the improved life expectancy of the infected population, and the increased projected lifetime healthcare costs also prompt the need for new treatment paradigms [8].\n\nAfter achieving a stable virological suppression, treatment simplification with two-drugs regimens is a switch strategy considered by both US [2] and European [3] guidelines in order to manage or prevent ART toxicity or in case of comorbidities, drug-drug interactions, or when treatment simplification is required. Among these strategies, lamivudine plus boosted protease inhibitors (bPIs) are supported by the most robust evidence [9–13]. However, due to the impact of bPIs on the metabolic profile [9–13] and the potential for drug-drug interactions of boosting agents [14], new treatment options are under investigation. Recent observational studies [15–17] and a pilot study [18] suggest that switching to lamivudine plus dolutegravir could be a feasible option, overcoming some disadvantages of bPIs. The virological efficacy of this combination, that also emerged in naïve patients [19], and the protective effect of the M184I/V mutation on the emergence of resistance mutations against dolutegravir [20], makes it a potential option in highly treatment-experienced patients with a long history of HIV disease and previous virological failures to NRTIs but not to integrase strand transfer inhibitors (InSTIs).\n\nSo far, direct comparisons between lamivudine plus bPIs and lamivudine plus dolutegravir as maintenance strategies in virologically-suppressed HIV positive patients are lacking. Therefore, we aimed to compare the virological efficacy, safety and durability of lamivudine plus either atazanavir/ritonavir (r), darunavir/r or dolutegravir in clinical practice.\n\nMethods\nThree groups of ART-treated HIV-positive adult (≥ 18 years) patients, followed-up in a single clinical center, starting a two-drug regimen with lamivudine plus either atazanavir/r, darunavir/r or dolutegravir in a period ranging from 2008 to 2017 were retrospectively evaluated. Switching to a dual regimen was driven by current toxicity issues or need for prevention of future toxicities, and all patients had undetectable viral load at the time of regimen initiation (HIV-RNA < 50 copies/mL). Due to increasing knowledge about treatment toxicities and a greater availability of different treatment choices over time, reasons for beginning a lamivudine-based dual regimen changed in different study periods. In order to observe these changes, no exclusion criteria were selected about study population, with the exception of hepatitis B surface antigen-positive serostatus. The choice of this criterion was mainly driven by the possibility of finding patients who could inadvertently have had their three drug-regimens switched to lamivudine-based dual therapy without checking HBsAg serostatus and that could subsequently have undergone treatment discontinuation at the time of serological test availability.\n\nData analyzed in the present study were selected from an internal observational database, which collects main clinical and demographic characteristics of every patient who gave informed consent to personal data record since the time of HIV diagnosis. The creation of the database was approved by the “Fondazione Policlinico Gemelli” Ethics Committee (protocol number: 10978/15).\n\nMain outcomes measures were time free from treatment discontinuation (TD, i.e. interruption of one or both study drugs or intensification of study regimen) and time free from virological failure (VF, as defined by 2 consecutive HIV-RNA ≥50 copies/mL or a single HIV-RNA ≥1000 copies/mL), estimated by the Kaplan-Meier method and compared between groups by the log-rank test. The follow up was censored at TD, death, loss to follow-up, or last available clinical data (until April 30, 2017), whichever occurred first. For the VF analysis, TD was used as an additional censoring criterion. Predictors of TD and VF were evaluated by Cox regression.\n\nSecondary endpoints were the evaluation and comparison of changes in CD4 count, blood lipids and estimated glomerular filtration rate (eGFR, according to MDRD study equation) at different times (baseline, week 24 and 48) by using generalized linear models for repeated measures. Predictors of changes were identified by linear regression analysis.\n\nResults\nFour-hundred-ninety-four patients were eligible for the analysis: 170 started lamivudine plus darunavir/r, 141 lamivudine plus atazanavir/r and 183 lamivudine plus dolutegravir. Overall, 348 (70.4%) were male, with 49 years of median age, 12 years since HIV diagnosis and 8 years on ART. Characteristics of the study population are summarized in Table 1.Table 1 Characteristics of study population at baseline (N = 484)\n\nVariables\tDarunavir/r N = 170\tAtazanavir/r N = 141\tDolutegravir N = 183\t\np\n\t\nAge*\t48 (40–54)\t48 (43–53)\t51 (43–57)\t0.008\t\nMale sex\t126 (74.1)\t95 (67.4)\t127 (69.4)\t0.399\t\nCaucasians\t157 (92.4)\t136 (96.5)\t164 (89.6)\t0.165\t\nHIV risk factor\t0.043\t\n Heterosexual\t74 (43.5)\t68 (48.2)\t83 (45.4)\t\t\n MSM\t84 (49.4)\t49 (34.8)\t80 (43.7)\t\t\n IDUs\t11 (6.5)\t24 (17.0)\t19 (10.4)\t\t\n Other\t1 (0.6)\t0\t1 (0.5)\t\t\nCDC stage C\t48 (28.2)\t34 (24.1)\t53 (29.0)\t0.592\t\nHCV positive serostatus\t18 (10.6)\t25 (17.7)\t26 (14.2)\t0.193\t\nNadir CD4 count (cells/μL)*\t219 (64–311)\t194 (62–293)\t194 (64–284)\t0.741\t\nZenith HIV-RNA (log10 copies/mL)*\t4.90 (4.36–5.40)\t5.02 (4.48–5.39)\t4.93 (4.34–5.40)\t0.687\t\nCD4 count at baseline (cells/μL)*\t617 (484–793)\t616 (509–786)\t630 (500–800)\t0.671\t\nYears since HIV diagnosis*\t9 (5–17)\t11 (4–18)\t14 (8–20)\t< 0.001\t\nYears on antiretroviral therapy*\t8 (3–14)\t7 (3–13)\t12 (5–18)\t< 0.001\t\nPrevious virological failure\t91 (53.5)\t78 (55.3)\t94 (51.4)\t0.775\t\nPrevious M184 V resistance mutation\t22 (12.9)\t17 (12.1)\t16 (8.7)\t0.419\t\nYears of viral suppression at baseline*\t5 (2–8)\t4 (2–7)\t8 (4–11)\t< 0.001\t\nPrevious regimen:\t< 0.001\t\n 2NRTI + bPI\t80 (47.1)\t125 (88.7)\t14 (7.7)\t\n 2NRTI + NNRTI\t20 (11.8)\t4 (2.8)\t34 (18.6)\t\n 2NRTI + INI\t24 (14.1)\t1 (0.7)\t32 (17.5)\t\nTwo-drug regimen\t34 (20.0)\t8 (5.7)\t99 (54.1)\t\n - Lamivudine plus bPI\t32 (18.8)\t8 (5.7)\t89 (48.6)\t\n - bPI plus NNRTI, InSTI or MVC\t2 (1.2)\t0 (0)\t6 (3.3)\t\n - Other regimen\t0 (0)\t0 (0)\t4 (2.2)\t\nOther\t12 (7.1)\t3 (2.1)\t4 (2.2)\t\nTDF in previous regimen\t97 (57.1)\t119 (84.4)\t65 (35.5)\t< 0.001\t\nReasons for switch to dual regimen:\t< 0.001\t\n Simplification\t86 (50.6)\t100 (70.9)\t57 (31.1)\t\n Dyslipidemia\t8 (4.7)\t7 (5.0)\t60 (32.8)\t\n GI toxicity\t4 (2.4)\t2 (1.4)\t13 (7.1)\t\n Liver toxicity\t11 (6.5)\t0\t4 (2.2)\t\n Renal toxicity\t28 (16.5)\t12 (8.5)\t15 (8.2)\t\n Bone toxicity\t3 (1.8)\t3 (2.1)\t12 (6.6)\t\n CNS toxicity\t1 (0.6)\t0\t3 (1.6)\t\n Other toxicity\t14 (8.2)\t4 (2.8)\t7 (3.8)\t\n DDI\t2 (1.2)\t0\t6 (3.3)\t\n Other\t13 (7.6)\t13 (9.2)\t6 (3.3)\t\n Years on previous regimen*\t2 (1–4)\t3 (1–5)\t2 (1–3)\t0.530\t\nStudy period:\t< 0.001\t\n 2008–2013\t37 (21.8)\t88 (62.4)\t0\t\n 2013–2014\t91 (53.5)\t33 (23.4)\t0\t\n 2014–2015\t34 (20.0)\t12 (8.5)\t77 (42.1)\t\n 2015–2017\t8 (4.7)\t8 (5.7)\t106 (57.9)\t\nNote: bPI boosted protease inhibitor, TDF tenofovir, MVC maraviroc, GI gastrointestinal, CNS central nervous system, DDI drug-drug interaction\n\n*Continuous variables (interquantile range)\n\n\n\nOver 333.2 patient-years follow-up (PYFU) there were 123 discontinuations in the darunavir/r group (incidence rate, IR, 36.9 per 100 PYFU), 97 over 461.1 PYFU (21.0 per 100 PFU) in the atazanavir/r group and 21 over 189.1 PYFU (11.1 per 100 PYFU) in the dolutegravir group. Estimated probabilities of remaining free from TD at week 48 and 96 were, respectively, 79.8% (95% confidence interval, CI, 73.7–85.9%) and 48.3% (95% CI 40.7–55.9%) with darunavir/r, 87.0% (95% CI 81.3–92.7%) and 70.9% (95% CI, 63.3–78.5%) with atazanavir/r, 88.2% (95% CI 82.9–93.5%) and 82.6% (95% CI 74.4–90.8%) with dolutegravir (log-rank p < 0.001). Between-group comparisons showed a significant difference between darunavir/r and atazanavir/r (p < 0.001) and between darunavir/r and dolutegravir (p < 0.001), but no differences between atazanavir/r and dolutegravir (p = 0.252; see Fig. 1). Considering that a not negligible proportion of the patients switching to lamivudine and darunavir and, above all, to lamivudine and dolutegravir were already on a dual regimen (mostly lamivudine-based), a secondary analysis excluding these patients on a previous dual therapy was performed. Also in this case, the probability of remaining on lamivudine plus dolutegravir at 48 weeks (89.0, 95% CI 81.5–96.5%) and 96 weeks (76.3, 95% CI 52.4–100.0%) was higher compared to the probability of remaining with lamivudine and darunavir/r (82.1, 95% CI 75.6–88.6% at week 48; 40.6, 95% CI 40.6–57.8% at week 96; log-rank p = 0.040), but not with lamivudine and atazanavir/r (88.6, 95% CI 83.1–94.1% at week 48; 72.5, 95% CI 64.7–80.3% at week 96; log-rank p = 0.745).Fig. 1 Estimated proportions surviving without TD divided by regimen type (log-rank p < 0.001)\n\n\n\nAfter adjusting for baseline factors that were significantly different among groups, calendar period of regimen initiation (2015 or later versus 2013 and before), HIV-risk factor (injecting drug use versus heterosexual contacts), higher baseline cholesterol and the use of a InSTI-based three-drug regimen before switch (versus a bPI-based three-drug regimen) were associated with TD, whereas dolutegravir use (versus bPIs), switch from tenofovir (versus other backbones) and duration of the previous regimen were protective factors (see Table 2). When considering the two-drug regimens separately in the same multivariate model, dolutegravir was independently associated with a lower hazard of discontinuation when compared with both darunavir/r (aHR: 0.15, 95% CI 0.08–0.27; p < 0.001) and atazanavir/r (aHR: 0.19, 95% CI 0.10–0.39; p < 0.001).Table 2 Predictors of TD. Univariable and multivariable Cox regression\n\nVariables\tHR (95% CI)\t\np\n\taHR (95% CI)\t\np\n\t\nAge (per 10 years more)\t1.03 (0.91–1.15)\t0.675\t1.04 (0.91–1.19)\t0.565\t\nHIV risk factor:\t\n Heteosexual\tRef\t\tRef\t\t\n MSM\t1.14 (0.87–1.50)\t0.358\t1.25 (0.93–1.68)\t0.143\t\n IDUs\t1.39 (0.93–2.08)\t0.112\t1.75 (1.13–2.70)\t0.011\t\n Other\t1.72 (0.24–12.38)\t0.590\t0.84 (0.11–6.73)\t0.870\t\nPrevious regimen:\t\n 2NRTI + bPI\tRef\t\tRef\t\t\n 2NRTI + NNRTI\t1.09 (0.65–1.81)\t0.754\t1.13 (0.66–1.93)\t0.662\t\n 2NRTI + InSTI\t1.87 (1.21–2.90)\t0.005\t2.16 (1.30–3.60)\t0.003\t\n Two-drug regimen\t1.15 (0.79–1.67)\t0.466\t0.64 (0.37–1.10)\t0.103\t\n Other\t1.43 (0.79–2.59)\t0.233\t0.84 (0.41–1.71)\t0.631\t\nSwitch from TDF-containing regimen\t0.72 (0.54–0.95)\t0.019\t0.59 (0.39–0.88)\t0.010\t\nReasons for switch to dual regimen:\t\n Simplification\tRef\t\tRef\t\t\n Dyslipidemia\t0.71 (0.41–1.21)\t0.207\t0.74 (0.40–1.36)\t0.332\t\n GI toxicity\t1.04 (0.42–2.56)\t0.929\t1.12 (0.43–2.87)\t0.820\t\n Liver toxicity\t2.18 (1.14–4.16)\t0.019\t1.50 (0.71–3.17)\t0.286\t\n Renal toxicity\t1.17 (0.76–1.78)\t0.475\t1.14 (0.73–1.80)\t0.565\t\n Bone toxicity\t1.45 (0.60–3.62)\t0.405\t1.12 (0.3–2.91)\t0.813\t\n CNS toxicity\t1.21 (0.17–8.71)\t0.849\t1.94 (0.25–14.87)\t0.524\t\n Other toxicity\t2.98 (1.83–4.84)\t< 0.001\t2.16 (1.27–3.70)\t0.005\t\n DDI\t2.24 (0.71–7.09)\t0.169\t1.82 (0.54–6.12)\t0.330\t\n Other\t1.37 (0.84–2.25)\t0.207\t1.25 (0.74–2.13)\t0.408\t\nTime on previous regimen (per 1 year more)\t0.98 (0.92–1.04)\t0.547\t0.92 (0.85–0.99)\t0.021\t\neGFR at baseline (per 10 mL/min/1.73 m more)\t1.06 (1.00–1.11)\t0.039\t1.05 (0.99–1.11)\t0.102\t\nTotal cholesterol at baseline (per 10 mg/dL more)\t1.03 (1.00–1.06)\t0.058\t1.04 (1.01–1.07)\t0.012\t\nYears on antiretroviral therapy\t1.01 (0.99–1.03)\t0.208\t1.01 (0.99–1.04)\t0.330\t\nStudy period:\t\n 2008–2013\tRef\t\tRef\t\t\n 2013–2014\t2.04 (1.44–2.87)\t< 0.001\t1.98 (1.37–2.88)\t< 0.001\t\n 2014–2015\t2.25 (1.47–3.43)\t< 0.001\t4.88 (3.00–7.94)\t< 0.001\t\n 2015–2017\t2.18 (1.20–3.97)\t< 0.001\t8.45 (4.12–17.31)\t< 0.001\t\nStudy treatment with Dolutegravir (versus bPIs)\t0.50 (0.31–0.80)\t0.004\t0.15 (0.08–0.28)\t< 0.001\t\nNote: bPI boosted protease inhibitor, TDF tenofovir, GI gastrointestinal, CNS central nervous system, DDI drug-drug interaction, eGFR estimated glomerular filtration rate\n\n\n\nReasons for TD varied among groups (p < 0.001). With darunavir/r, 6 (4.9%) interruptions were due to VF, 53 (43.1%) to toxicity (35 cases of dyslipidemia, 11 cases of gastro-intestinal toxicity, 1 case of renal toxicity and 1 of neurological toxicity, 5 of unspecified patients intolerance), 45 (36.6%) due to further simplification, 7 (5.7%) due to drug interactions and 12 (9.8%) due to other/unknown reasons. With atazanavir/r discontinuations occurred for VF in 4 (4.1%) cases, toxicity in 38 (39.2%) (10 dyslipidemia, 1 gastro-intestinal toxicity, 15 liver toxicity, 9 renal toxicity, 3 other or unspecified toxicity), simplification in 30 (30.9%), drug interactions in 8 (8.2%), other/unknown reasons in 17 (17.5%). With dolutegravir, reasons for TD were VF in 3 (14.3%) cases, toxicity in 11 (52.4%) (3 gastro-intestinal toxicity, 1 liver toxicity, 6 neuropsychological toxicity, 1 unspecified intolerance), simplification in 3 (14.3%) and unspecified reasons in 4 (19.0%).\n\nVF occurred in 11 patients over 319.2 PYFU (IR 3.5 per 100 PYFU) with darunavir/r, with estimated probabilities of remaining free from VF of 95.4% (95% CI 92.1–98.7) and 92.5% (95% CI 88.0–97.0) at week 48 and 96, respectively. Ten VF over 441 PYFU (IR 2.3 per 100 PYFU) occurred with atazanavir/r, with estimated probabilities of remaining free from VF of 96.1% (95% CI 92.8–99.4) and 95.1% (95% CI 91.2–99.0) at week 48 and 96, respectively. With dolutegravir, 5 VF occurred over 188 PYFU (IR 2.7 per 100 PYFU): the estimated probabilities of remaining free from VF were 97.5% (95% CI 94.8–100) and 94.5% (95% CI 89.6–99.4) at week 48 and 96, respectively. No difference in the time to VF was detected among study groups (log-rank p = 0.747). Potential exposure variables associated to VF were analyzed: nor immunological parameters (baseline and nadir CD4+ count), nor viral factors (especially zenith HIV-RNA or the presence of M184 V/I at historical genotypes), nor HCV coinfection, time since HIV diagnosis and years of exposure to antiretrovirals, could predict an increased risk of VF.\n\nOf 494 patients, 341 had week 24 and 48 follow-up CD4 counts, 295 total cholesterol (TC) and HDL, 362 triglycerides, 369 eGFR. At baseline, groups differed for eGFR levels only, these were slightly higher in the dolutegravir group (p < 0.001).\n\nAbsolute CD4 counts significantly increased in all groups from baseline to 48 weeks (mean + 54 cells/μL; within-groups effect test-p < 0.001), with no significant changes in CD4/CD8 ratio. No differences among groups were seen at different time points (between-groups effect test-p = 0.530) and no time-group interaction was found (p = 0.477). A previous AIDS-event (versus none, mean difference in change − 3.40 cells/μL, 95% CI -5.09; − 1.71; p < 0.001) and baseline CD4 count (per 100 cells/μL higher, mean difference in change: − 98.41 cells/μL, 95% CI -98.72; − 98.11; p < 0.001) independently predicted CD4 change at week 48, after adjusting for type of dual regimen and nadir CD4 count.\n\nA decrease in TC/HDL ratio emerged with lamivudine plus dolutegravir (− 0.39 at week 24, p < 0.001; − 0.33 at week 48, p = 0.001) compared with lamivudine plus bPIs (time-group interaction-effect test-p = 0.006): the differences in mean change in TC/HDL between dolutegravir and atazanavir/r (− 0.50; p = 0.047) and between dolutegravir and darunavir/r (− 0.53; p = 0.012) were significant only at week 24. The use of dolutegravir (versus bPIs, mean difference in change: -0.32, 95% CI -0.61; − 0.02; p = 0.036) and baseline TC/HDL values (per 1 unit higher, mean difference in change: -0.43, 95% CI -0.51; − 0.35; p < 0.001) predicted a decreased TC/HDL at week 48, after adjusting for use of cholesterol-lowering therapy after baseline, time to start of cholesterol-lowering therapy, previous tenofovir use and cumulative time on ART.\n\nDespite a greater use of triglycerides-lowering therapies since or after baseline in the bPIs groups compared with dolutegravir group (p = 0.003), triglycerides only decreased in the latter (mean change from baseline − 32 mg/dL at week 24, p < 0.001; − 36 mg/dL at week 48, p < 0.001), with a significant time-group interaction (p < 0.001). The difference in mean change of triglycerides between dolutegravir and both bPIs emerged at both week 24 (p < 0.001) and week 48 (p = 0.003). Baseline triglycerides values (per 1 mg/dL higher, mean difference in change: − 0.43 mg/dL, 95% CI -0.50; − 0.36; p < 0.001) and the use of dolutegravir (versus bPIs, mean difference in change: − 25.13 mg/dL, 95% -42.43; − 7.82; p = 0.005) independently predicted a decrease in triglycerides at week 48, whereas previous tenofovir use (versus other backbones, mean difference in change: + 25.90 mg/dL, 95% CI + 9.42; + 40.38; p = 0.002) predicted their increase, independently from the start and time to start of a triglycerides-lowering therapy, history of myocardial infarction and cumulative time on ART.\n\nEstimated GFR improved in the bPIs groups (mean change + 5 mL/min/1.73 m2, p = 0.005 at week 48 with darunavir/r; + 3 mL/min/1.73 m2 at week 48, p = 0.028 with atazanavir/r), with a significant time-group interaction (p < 0.001). The eGFR decreased in the first 24 weeks of dolutegravir use (mean change − 13 mL/min/1.73 m2, p < 0.001) and stabilized thereafter. Age (per 10 years older, mean difference in change: − 4.34 mL/min/1.73 m2, 95% CI -5.93, − 2.76; p < 0.001), baseline eGFR (per 1 mL/min/1.73 m2 higher, mean difference in change: − 0.39 mL/min/1.73 m2, 95% CI -0.45; − 0.33; p < 0.001) and the use of dolutegravir (versus bPIs, mean difference in change: − 12.88 mL/min/1.73 m2, 95% CI -16.97; − 8.79; p < 0.001) were negatively associated with the change in eGFR at 48 weeks, after adjusting for anti-HCV positive serostatus, previous use of tenofovir, cumulative time on ART and PIs and duration of virologic suppression at baseline.\n\nDiscussion\nA recent meta-analysis on lamivudine plus bPIs in patients with stable viral suppression confirmed the non-inferior virological efficacy of these strategies compared with standard three-drug regimens [21]. However, due to the increasing prevalence of comorbid conditions (especially cardiovascular and metabolic disorders) of people aging with HIV and to issues related to drug interactions, dual therapies with bPIs have lost part of their role as maintenance therapies in favor of more tolerable dual regimens. Particularly, two randomized trials about the use of rilpivirine and dolutegravir in patients who achieved viral control found no differences in the virological efficacy of this strategy when compared to standard therapy [22] and strongly support its role as a maintenance therapy. However, dietary constriction and some important drug interactions could represent a limit of this strategy, that would not be present by using the combination of lamivudine plus dolutegravir. In a randomized pilot clinical trial [23], this strategy was also non-inferior to continuation of standard three-drug maintenance therapy. Due to its favorable metabolic profile, the lack of major toxicities and the low projected costs, if ongoing trials will confirm its efficacy, the combination of lamivudine plus dolutegravir could change the management of HIV-infection in next years, as two systematic review on this subject also evidenced [24, 25].\n\nBesides randomized trials, assessing the feasibility of lamivudine plus dolutegravir in clinical practice, especially in comparison with the other approved lamivudine-based simplification strategies, is of paramount importance. In our cohort lamivudine-based two-drug therapies in HIV-positive patients with suppressed HIV-RNA showed a good virological efficacy: the cumulative incidence of VF was less than 3.5 per 100 PYFU, without differences among study groups. This finding is in agreement with previous trials [10, 12, 13] and observational studies [15, 17, 18], including the preliminary data on lamivudine plus dolutegravir showing its high virological efficacy and good tolerability. In a multicenter cohort [15] of 110, virologically-suppressed patients on first line therapy, only one had a pre-defined VF; another cohort study, including 27 heavily treatment-experienced, virologically-suppressed patients [18], did not detect any VF after 96 weeks, despite the presence of M184 V mutation in 63% of the study population; finally, an Italian study [17] on 94 treatment-experienced patients on stable cART and virological suppression, switching to lamivudine plus dolutegravir, did not observe VF after 24 weeks of follow-up. In line with these reports, our results confirm the efficacy of lamivudine plus dolutegravir in different clinical contexts.\n\nHere, for the first time, we present how the efficacy of different lamivudine-based dual therapies may impact in clinical practice. Findings from the dolutegravir group are reassuring but should be interpreted with caution, given that more than half of patients were already on a previous lamivudine-based dual regimen, suggesting that this was a selected sample of patients (however, the exclusion of patients switching from a previous dual regimen did not seem to affect the results of the main analysis). Moreover, follow-up time of patients on dolutegravir were shorter than follow-up of patients on lamivudine plus PIs: at week 96, only 14 patients with dolutegravir were still on study, compared with 74 on darunavir/r and 88 on atazanavir/r, indicating the reduced reliability of data after the first 48 weeks of treatment for lamivudine plus dolutegravir.\n\nThe main reason for TD was drug-related toxicity in all groups, but our data seem to underline an overall better tolerability of dolutegravir. Indeed, dolutegravir-treated group was independently associated with a lower discontinuation risk as compared with both darunavir/r- and atazanavir/r-treated groups. However, a series of possible study bias should be considered before drawing conclusions: some baseline characteristics also related to TD, namely the injecting drug use as a HIV-risk factor, the presence of dyslipidemia, and the previous regimen, were statistically different among groups. Patients switching from an InSTI-based regimen were at higher risk of TD. As previously found in a multicenter cohort study [11], this result could be ascribed to a worse tolerability and worse metabolic profile of bPIs as compared with InSTI. Of note, patients on lamivudine and darunavir/r mainly switched from a Insti-based three-drug regimen, and this could have emphasized the worsening of blood lipids commonly seen after switch to a PI-based regimen.\n\nConversely, tenofovir discontinuation was protective against TD, likely reflecting a loss of renal or bone toxicity, as observed in previous trials [10, 13], or a higher patients’ satisfaction with a less-drug regimen compared with standard three-drug regimens, that in our cohort mostly included tenofovir disoproxil fumarate. Almost 85% of patients on lamivudine plus atazanavir/r (compared with 57% of patients on lamivudine plus darunavir/r) were on a previous TDF-containing regimen and this could also have affected the lower rate of discontinuation of atazanavir/r compared to darunavir/r.\n\nInterestingly, more recent study calendar periods were increasingly associated to the risk of TD, indicating a higher propensity to change, presumably related to the availability of more alternative regimens during more recent years. Considering the more recent introduction of dolutegravir and the shorter follow-up of patients on lamivudine and dolutegravir compared with patients on lamivudine plus PIs, prospective studies are needed to fully assess the durability of this strategy over time, especially in comparison with newer treatment strategies.\n\nBlood lipids profile significantly improved after switching to lamivudine plus dolutegravir: the use of dolutegravir was associated with a reduction of TC/HDL ratio and triglycerides at week 48, independently from baseline values, use of lipid-lowering therapy and a previous tenofovir-containing regimen. Renal function apparently declined in the dolutegravir group at week 24 but stabilized thereafter, whereas an increase in eGFR was observed in the bPIs groups, independently from a previous tenofovir use, as already reported in the ATLAS-M trial [10]. These findings can be explained by the loss of interaction between bPIs and tenofovir disoproxil fumarate, that seems to accelerate the eGFR decline [26], more than the single effect of tenofovir withdrawal. It is also known that dolutegravir can lead to an initial non progressive increase in serum creatinine by inhibiting the renal organic cation transporter 2 (OCT2) [27], which could have further increased the difference in eGFR changes among study groups.\n\nConclusions\nTo our knowledge this is the first observational study aiming to compare the durability of lamivudine-based two-drug regimens. Further strengths of our study are represented by the large sample size, the relatively long median follow-up time (1.6 years) and the lack of exclusion criteria that could have had an impact on efficacy of dual regimens (e.g., zenith HIV-RNA > 100.000 copies/mL, nadir CD4 count< 200 cells/μL). Of course, our study has important limitations, particularly in relation to its retrospective design and the lack of randomization, that hamper direct evaluation of differences among lamivudine-based dual regimens and that precluded to interpret the global efficacy of these simplification strategies. The different characteristics of study groups at baseline, partly explained by the different periods of enrolment, lead to the emergence of several important confounders: although we used multivariate models to address these issues, the strength and the generalization of our conclusions are limited.\n\nKeeping that in mind, our study adds further proof that lamivudine plus dolutegravir could represent a potential optimization strategy in virologically-suppressed patients. The improvement of the blood lipids profile can be considered another advantage of this strategy: given the increased frequency of age-related comorbidities in the HIV-infected population, lamivudine plus dolutegravir could play an important role in the next years to reduce cardiovascular diseases in this setting. Longer follow-up studies are needed to verify this hypothesis.\n\nAbbreviations\nARTCombination antiretroviral therapy\n\nbPIsBoosted protease inhibitors\n\neGFRestimated glomerular filtration rate\n\nInSTIsIntegrase strand transfer inhibitors\n\nNRTIsNucleoside reverse transcriptase inhibitors\n\nOCT2Organic cation transporter 2\n\nTCTotal cholesterol\n\nTDTreatment discontinuation\n\nVFVirological failure\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo external funding was received to conduct this study.\n\nAvailability of data and materials\nThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAB, SDG and ADL designed the study, analyzed the data and finalized the drafting of the paper. RG, GB and AC gave contribution in study design, literature search and article drafting. FL, DM, AE, SB, SLM, FM and EV were responsible for data collection and made a substantial contribution in analyzing and interpreting the data, as well as in drafting the manuscript. AB, SDG, ADL, RG, GB, AC, FL, DM, AE, SB, SLM, FM and EV critically read, revised and approved the final version of the manuscript, took part sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.\n\nEthics approval and consent to participate\nThe study received approval by the “Fondazione Policlinico Gemelli” Ethics Committee (protocol number: 10978/15), and every patient signed an informed consent before data collection.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nAB reports non-financial support from Bristol Myers Squibb, personal fees from Gilead Sciences, non-financial support from ViiV Healthcare, outside the submitted work. RG reports travel grants from Gilead and from Janssen-Cilag, outside the submitted work. FM reports non-financial support from Angelini, and a contract research from Novartis Vaccine and Diagnostics S.r.l., outside the submitted work. EV reports personal fees from Merck Sharp and Dohme. ADL reports grants and personal fees from Gilead, personal fees from Bristol-Myers Squibb, grants and personal fees from ViiV, personal fees from Abbvie, personal fees from Janssen, grants and personal fees from Merck Sharp and Dohme, outside the submitted work. ADL also declares to be member of the editorial board (Associate Editor) of BMC Infectious Diseases. SDG reports personal fees from Bristol-Myers Squibb, personal fees from Gilead Sciences, personal fees from Boehringer Ingelheim, personal fees from Janssen-Cilag, personal fees from GlaxoSmithKline, outside the submitted work. All other authors have nothing to disclose.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Broder S The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic Antivir Res 2010 85 1 1 18 10.1016/j.antiviral.2009.10.002 20018391 \n2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. . (Updated 17 October 2017. Accessed on 22 Aug 2017). Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.\n3. EACS Guidelines version 8.2, January 2017. Available at http://www.eacsociety.org/files/guidelines_9.0-english.pdf.\n4. Lundgren JD Babiker AG Gordin F Emery S Grund B Sharma S Avihingsanon A Cooper DA Fatkenheuer G Llibre JM Initiation of antiretroviral therapy in early asymptomatic HIV infection N Engl J Med 2015 373 9 795 807 10.1056/NEJMoa1506816 26192873 \n5. Smit M, Cassidy R, Cozzi-Lepri A, et al. Quantifying the future clinical burden of an ageing HIV positive population in Italy. a mathematical modelling study. HIV Drug Therapy. 23–26 October 2016, Glasgow, UK. Abstract P156.\n6. Margolis AM Heverling H Pham PA Stolbach A A review of the toxicity of HIV medications J Med Toxicol 2014 10 1 26 39 10.1007/s13181-013-0325-8 23963694 \n7. Langebeek N Gisolf EH Reiss P Vervoort SC Hafsteinsdottir TB Richter C Sprangers MA Nieuwkerk PT Predictors and correlates of adherence to combination antiretroviral therapy (ART) for chronic HIV infection: a meta-analysis BMC Med 2014 12 142 10.1186/s12916-014-0142-1 25145556 \n8. Nakagawa F Miners A Smith CJ Simmons R Lodwick RK Cambiano V Lundgren JD Delpech V Phillips AN Projected lifetime healthcare costs associated with HIV infection PLoS One 2015 10 4 e0125018 10.1371/journal.pone.0125018 25901355 \n9. Arribas JR Girard PM Landman R Pich J Mallolas J Martinez-Rebollar M Zamora FX Estrada V Crespo M Podzamczer D Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial Lancet Infect Dis 2015 15 7 785 792 10.1016/S1473-3099(15)00096-1 26062880 \n10. Di Giambenedetto S Fabbiani M Quiros Roldan E Latini A D'Ettorre G Antinori A Castagna A Orofino G Francisci D Chinello P Treatment simplification to atazanavir/ritonavir + lamivudine versus maintenance of atazanavir/ritonavir + two NRTIs in virologically suppressed HIV-1-infected patients: 48 week results from a randomized trial (ATLAS-M) J Antimicrob Chemother 2017 72 4 1163 1171 28093483 \n11. Fabbiani M Di Giambenedetto S Poli A Borghetti A Castagna A Mondi A Galizzi N Maillard M Gori A Cauda R Simplification to a dual regimen with darunavir/ritonavir plus lamivudine or emtricitabine in virologically-suppressed HIV-infected patients J Infect 2016 73 6 619 623 10.1016/j.jinf.2016.08.011 27575581 \n12. Perez-Molina JA Rubio R Rivero A Pasquau J Suarez-Lozano I Riera M Estebanez M Palacios R Sanz-Moreno J Troya J Simplification to dual therapy (atazanavir/ritonavir + lamivudine) versus standard triple therapy [atazanavir/ritonavir + two nucleos(t)ides] in virologically stable patients on antiretroviral therapy: 96 week results from an open-label, non-inferiority, randomized clinical trial (SALT study) J Antimicrob Chemother 2017 72 1 246 253 10.1093/jac/dkw379 27629070 \n13. Pulido F, Ribera E, Lagarde M, Perez-Valero I, Palacios R, Iribarren JA, Payeras A, Domingo P, Sanz J, Cervero M, et al. Dual therapy with darunavir and ritonavir plus lamivudine versus triple therapy with darunavir and ritonavir plus tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine for maintenance of HIV-1 viral suppression: randomised, open label, non-inferiority DUAL-GESIDA 8014-RIS-EST45 trial. Clin Infect Dis. 2017;65(12):2112–18.\n14. Marzolini C Gibbons S Khoo S Back D Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications J Antimicrob Chemother 2016 71 7 1755 1758 10.1093/jac/dkw032 26945713 \n15. Joly V, Burdet C, Landman R, et al. Promising results of dolutegravir + lamivudine maintenance in ANRS 167 LAMIDOL Trial. 24th Conference on Retroviruses and Opportunistic Infections. 13–16 February 2017, Seattle, WA, USA. Abstract 458.\n16. Kelly SG Nyaku AN Taiwo BO Two-drug treatment approaches in HIV: finally getting somewhere? Drugs 2016 76 5 523 531 10.1007/s40265-016-0553-8 26886135 \n17. Maggiolo F Gulminetti R Pagnucco L Digaetano M Benatti S Valenti D Callegaro A Ripamonti D Mussini C Lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients BMC Infect Dis 2017 17 1 215 10.1186/s12879-017-2311-2 28302065 \n18. Reynes J, Meftah N, Tuaillon E, et al. Dual regimen with Dolutegravir and Lamivudine maintains virologic suppression even in heavily treatment experienced HIV-infected patients: 96 weeks results from maintenance DOLULAM study. 9th IAS Conference on HIV Science. 23–26 July 2017, Paris, France. Abstract MOPEB0322. .\n19. Cahn P, Rolòn MJ, Figueroa MI, et al. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: 48 week results of the PADDLE trial. 21st International AIDS Conference. 18–22 July 2016, Durban, South Africa. Abstract FRAB0104LB.\n20. Oliveira M Ibanescu RI Pham HT Brenner B Mesplede T Wainberg MA The M184I/V and K65R nucleoside resistance mutations in HIV-1 prevent the emergence of resistance mutations against dolutegravir AIDS 2016 30 15 2267 2273 10.1097/QAD.0000000000001191 27367488 \n21. J.A. Perez-Molina, F. Pulido, S. Di Gianbenedetto, et al. Individual patient data meta-analysis of randomized controlled trials of dual therapy with a boosted protease inhibitor plus lamivudine for maintenance of virological suppression Gesida study 9717. EACS - 16th European AIDS Conference, 25–27 October 2017, Milan, Italy. Abstract PS1/1.\n22. Llibre JM Hung C Brinson C Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies Lancet 2018 391 10123 839 849 10.1016/S0140-6736(17)33095-7 29310899 \n23. Taiwo BO, Marconi VC, Berzins B, et al. Dolutegravir plus lamivudine maintain HIV-1 suppression through week 48 in a pilot randomized trial. Clin Infect Dis. 2017;26 [Epub ahead of print].\n24. Rossetti B, Montagnani F, De Luca A. Current and emerging two-drug approaches for HIV-1 therapy in ART-naïve and ART-experienced, virologically suppressed patients. Expert Opin Pharmacother 2018 Apr 20:1–26.\n25. Soriano V Fernandez-Montero JV Benitez-Gutierrez L Dual antiretroviral therapy for HIV infection Expert Opin Drug Saf 2017 16 8 923 932 10.1080/14740338.2017.1343300 28621159 \n26. Bagnis CI, Stellbrink HJ. Protease inhibitors and renal function in patients with HIV infection: a systematic review. Infect Dis Ther. 2015;4(1):15–50.\n27. Shah BM, Schafer JJ, Desimone JA, Jr. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2014, 34(5):506–520.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "19(1)",
"journal": "BMC infectious diseases",
"keywords": "Antiretroviral therapy; Atazanavir/ritonavir; Darunavir/ritonavir; Dolutegravir; Dual therapy; HIV; Lamivudine; Maintenance therapy",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate; D015331:Cohort Studies; D000069454:Darunavir; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D006679:HIV Seropositivity; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012189:Retrospective Studies; D019438:Ritonavir; D000068698:Tenofovir; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "59",
"pmc": null,
"pmid": "30654739",
"pubdate": "2019-01-17",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "20018391;23963694;24347095;25145556;25567681;25901355;26062880;26192873;26886135;26945713;27367488;27575581;27629070;28093483;28302065;28621159;29020293;29293895;29310899;29676935;30085184",
"title": "Efficacy and tolerability of lamivudine plus dolutegravir compared with lamivudine plus boosted PIs in HIV-1 positive individuals with virologic suppression: a retrospective study from the clinical practice.",
"title_normalized": "efficacy and tolerability of lamivudine plus dolutegravir compared with lamivudine plus boosted pis in hiv 1 positive individuals with virologic suppression a retrospective study from the clinical practice"
} | [
{
"companynumb": "IT-JNJFOC-20190238484",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "We present a 23-year-old female patient who developed bilateral, multifocal CSCR three months after BMT and two months after developing GvHD. At the time of diagnosis, her medications included cyclosporine and high-dose oral steroid for GvHD. CSCR resolved quickly after the resolution of GvHD, along with rapid tapering of steroids and restoration of emotional wellbeing. Rapid tapering of systemic steroids under close monitoring of a hematologist in the setting of resolved mild GvHD may facilitate prompt resolution of CSCR.",
"affiliations": "a South Australian Institute of Ophthalmology, Royal Adelaide Hospital , Adelaide , South Australia.;a South Australian Institute of Ophthalmology, Royal Adelaide Hospital , Adelaide , South Australia.;a South Australian Institute of Ophthalmology, Royal Adelaide Hospital , Adelaide , South Australia.",
"authors": "Ng|Soo Khai|SK|;Durkin|Shane|S|;Gilhotra|Jagjit S|JS|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "England",
"delete": false,
"doi": "10.3109/08820538.2013.874473",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0882-0538",
"issue": "30(5-6)",
"journal": "Seminars in ophthalmology",
"keywords": "Bone marrow transplant; central serous chorioretinopathy; cortiscosteroid; graft versus host disease",
"medline_ta": "Semin Ophthalmol",
"mesh_terms": "D016026:Bone Marrow Transplantation; D056833:Central Serous Chorioretinopathy; D016572:Cyclosporine; D003967:Diarrhea; D005076:Exanthema; D005260:Female; D005451:Fluorescein Angiography; D005938:Glucocorticoids; D006086:Graft vs Host Disease; D006801:Humans; D007166:Immunosuppressive Agents; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult",
"nlm_unique_id": "8610759",
"other_id": null,
"pages": "432-4",
"pmc": null,
"pmid": "24506577",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rapid Resolution of Graft-versus-Host-Disease-Related Central Serous Chorioretinopathy.",
"title_normalized": "rapid resolution of graft versus host disease related central serous chorioretinopathy"
} | [
{
"companynumb": "PHHY2016AU018166",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "We adopted ABVD chemotherapy with risk-adapted radiation therapy (RT) as first-line therapy for children, adolescents and young adults with Hodgkin lymphoma (HL) in British Columbia in 2004.\n\n\n\nPatients ≤ 25 years diagnosed from 2004 to 2013 with all stages of HL who received ABVD as initial therapy were included.\n\n\n\nAmong 55 children (age < 18 year) and 154 young adults (18-25 year), there were no significant differences among age groups for sex, histologic subtype, tumour bulk, B symptoms, prognostic risk groups or treatment received. The rates of complete response, partial response and progressive disease were 84%, 7% and 10% for children and 95%, 4% and 1% for young adults (P=0.01), respectively. Treatment failures in children all occurred within one year of completion, while 8/21 (38%) relapses in young adults occurred later (P=0.04). With a median follow-up of 66 months the 5-year progression-free (PFS) and overall survival (OS) were 85 ± 3% and 97 ± 1%, respectively. For limited stage disease, PFS was 90 ± 7% for children and 93 ± 3% for young adults (P=0.65); OS was 100% for both. For advanced stage patients, PFS and OS were also similar for the children and young adults (77 ± 7% versus 81 ± 4%; P=0.38 and OS 90 ± 6% versus 97 ± 2%; P=0.17). The rate of consolidative RT was low (21%) and did not differ between age groups.\n\n\n\nABVD is an effective treatment in children, adolescents and young adults with HL. Children were less likely to achieve complete response and demonstrated earlier relapses compared to young adults. RT may be omitted for the majority of patients while maintaining excellent 5-year OS.",
"affiliations": "Division of Paediatric Hematology/Oncology/Bone Marrow Transplantation, British Columbia Children's Hospital.;British Columbia Cancer Agency, Centre for Lymphoid Cancer.;British Columbia Cancer Agency, Centre for Lymphoid Cancer.;British Columbia Cancer Agency, Department of Radiation Oncology, University of British Columbia, Vancouver, Canada.;Division of Paediatric Hematology/Oncology/Bone Marrow Transplantation, British Columbia Children's Hospital.",
"authors": "Marr|K C|KC|;Connors|J M|JM|;Savage|K J|KJ|;Goddard|K J|KJ|;Deyell|R J|RJ|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdx005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "28(4)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "ABVD; Hodgkin lymphoma; adolescent; paediatric; young adult",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D059248:Chemoradiotherapy; D002648:Child; D003606:Dacarbazine; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D012189:Retrospective Studies; D016896:Treatment Outcome; D014747:Vinblastine; D055815:Young Adult",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "849-854",
"pmc": null,
"pmid": "28327925",
"pubdate": "2017-04-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12436452;19231160;20625128;17242396;27470081;19738111;25901426;20734400;27269949;26855007;11986425;16735704;25311218;21774708;22149921;20159818;15837968;16172458;21054151;22271480;21037086;16818852;5121694;10999813",
"title": "ABVD chemotherapy with reduced radiation therapy rates in children, adolescents and young adults with all stages of Hodgkin lymphoma.",
"title_normalized": "abvd chemotherapy with reduced radiation therapy rates in children adolescents and young adults with all stages of hodgkin lymphoma"
} | [
{
"companynumb": "CA-FRESENIUS KABI-FK201706058",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis is a case report of a 51 year old male with marked splenomegaly, basophilia, severe thrombocytopenia, anemia and high SFKL phosphorylation downstream of Bcr-Abl, investigated for association of the e6a2 BCR-ABL fusion gene and marked basophilia. The treatment strategy implications in patients with Philadelphia positive CML are described.\n\n\nMETHODS\nRT-PCR and sequencing were carried out on the peripheral blood leukocytes to detect the type of BCR-ABL transcript. The BCR-ABL mutational status was assessed using sequencing of the RT-PCR products. The in vitro test of sensitivity to TKIs was based on detecting inhibited phosphorylation of the Crkl and Phospho-Src family kinases (SFK, Tyr416) using immunodetection.\n\n\nRESULTS\nThe cytogenetics revealed 90% of Ph+ (Philadelphia) cells in the bone marrow aspirate with no additional clonal chromosomal abnormalities at diagnosis. This correlated with an accelerated phase of the CML. Sequencing analysis of reverse transcribed and PCR amplified BCR-ABL transcript revealed a rare e6a2 fusion, with no evidence for Bcr-Abl kinase domain mutation. Western blot analysis showed high phosphorylation (activation) of Crkl and the Src family of kinases (P-SFK). In vitro test of sensitivity of the patients' leukemic cells to imatinib demonstrated sensitivity of Bcr-Abl tyrosine kinase to imatinib, as assessed by a decrease in phosphorylated Crkl and the disappearance of P-SFK, suggesting that P-Src reflects only the Bcr-Abl-dependent Src activity. The initial treatment strategy was reduced imatinib and search for an unrelated hematopoietic stem cell donor (according to the ELN recommendations). The patient was allografted with peripheral stem cells from an HLA- identical male donor but on day +70 graft failure occurred. He was allografted again with the peripheral stem cells from an HLA-identical female donor, engrafted on day +15 and showed 100% donor chimerism with no evidence of the e6a2 BCR-ABL fusion transcript on day +30.\n\n\nCONCLUSIONS\nThe clinical disease course in patients with the rare e6a2 BCR-ABL transcript variant is aggressive. This may be the result of increased kinase activity due to partial loss of the guanine exchange factor/dbl-like domain which mediates the interaction with several Ras-like G-proteins involved in cell proliferation, signal transduction, and cytoskeletal organization. For the above reasons, these patients should receive stem cell transplant immediately after a short course of treatment with imatinib/ dual Src/Abl kinase inhibitor or they should be registered in clinical trials with experimental agents.",
"affiliations": "Department of Hemato-Oncology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic. peter.rohon@centrum.cz",
"authors": "Rohon|Peter|P|;Divoka|Martina|M|;Calabkova|Lenka|L|;Mojzikova|Renata|R|;Katrincsakova|Beata|B|;Rusinakova|Zuzana|Z|;Lapcikova|Anna|A|;Raida|Ludek|L|;Faber|Edgar|E|;Jarosova|Marie|M|;Divoky|Vladimir|V|;Indrak|Karel|K|",
"chemical_list": null,
"country": "Czech Republic",
"delete": false,
"doi": "10.5507/bp.2011.030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1213-8118",
"issue": "155(2)",
"journal": "Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia",
"keywords": null,
"medline_ta": "Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub",
"mesh_terms": "D001491:Basophils; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D050596:Oncogene Fusion; D010677:Philadelphia Chromosome; D033581:Stem Cell Transplantation",
"nlm_unique_id": "101140142",
"other_id": null,
"pages": "187-90",
"pmc": null,
"pmid": "21804629",
"pubdate": "2011-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Identification of e6a2 BCR-ABL fusion in a Philadelphia-positive CML with marked basophilia: implications for treatment strategy.",
"title_normalized": "identification of e6a2 bcr abl fusion in a philadelphia positive cml with marked basophilia implications for treatment strategy"
} | [
{
"companynumb": "CZ-MYLANLABS-2020M1016229",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "This case study documents a 13-year-old female who presented to our intensive inpatient chronic pain rehabilitation program with complex regional pain syndrome (CRPS) of her left leg, which was significantly interfering with her normal daily functioning. She participated in a full day of traditional interdisciplinary therapies, including physical and occupational therapy for 3 hours daily. As assistive equipment was altered or weaned her physical mobility, balance, and tremors worsened and/or increased. As she began advancing her legs more independently (versus requiring physical assist), she demonstrated more variable functional strength and stability, inconsistent balance reactions, and a more unsteady gait pattern. The team was treating her according to her incoming CRPS diagnosis; however, as treatment progressed, her physical and psychological presentation seemed more aligned with diagnostic criteria of functional neurologic symptom disorder (FND). Staff then treated according to the FND diagnosis resulting in successful long-term outcomes. The clinical impact from this case study includes highlighting the commonalities between CPRS and FND clinically, discussing treatment suggestions depending on the diagnosis, and emphasizing key components of family/patient education.",
"affiliations": null,
"authors": "Kempert|Heidi|H|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.3233/PRM-200700",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1874-5393",
"issue": "14(1)",
"journal": "Journal of pediatric rehabilitation medicine",
"keywords": "Complex regional pain syndrome; case study; functional neurologic symptom disorder; occupational therapy; physical therapy",
"medline_ta": "J Pediatr Rehabil Med",
"mesh_terms": "D000293:Adolescent; D002648:Child; D020918:Complex Regional Pain Syndromes; D005260:Female; D006801:Humans; D007866:Leg; D009788:Occupational Therapy; D010372:Pediatrics",
"nlm_unique_id": "101490944",
"other_id": null,
"pages": "113-120",
"pmc": null,
"pmid": "33720859",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical overlap of functional neurologic symptom disorder and complex regional pain syndrome in pediatrics: A case report.",
"title_normalized": "clinical overlap of functional neurologic symptom disorder and complex regional pain syndrome in pediatrics a case report"
} | [
{
"companynumb": "US-APOTEX-2021AP039424",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": "3",
... |
{
"abstract": "Background Although rare, familial hypertriglyceridemia can cause acute and life-threatening complications in pregnancy. Cases The first patient's pregnancy was complicated by multiple admissions for pancreatitis due to hypertriglyceridemia and noncompliance with gemfibrozil. In her second pregnancy, she was compliant with gemfibrozil and only experienced pancreatitis episodes toward the end of pregnancy. The second patient had diabetes mellitus and familial hypertriglyceridemia. She required multiple hospitalizations for diabetic ketoacidosis secondary to insulin noncompliance. In both pregnancies, she was compliant with gemfibrozil and had no complications related to hypertriglyceridemia. Conclusion Treatment with gemfibrozil in pregnancies complicated by hypertriglyceridemia may prevent complications without adverse maternal or fetal effects and could be considered in treating pregnant patients with severe hypertriglyceridemia. These cases also demonstrate the importance of medication compliance in the prevention of poor outcomes.",
"affiliations": "Department of Women's Health, Arrowhead Regional Medical Center, Colton, California.;Department of Women's Health, Arrowhead Regional Medical Center, Colton, California.;Department of Women's Health, Arrowhead Regional Medical Center, Colton, California.;Department of Women's Health, Arrowhead Regional Medical Center, Colton, California.",
"authors": "Cao|Suzanne|S|;Dao|NhuChi|N|;Roloff|Kristina|K|;Valenzuela|Guillermo J|GJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0038-1676832",
"fulltext": "\n==== Front\nAJP RepAJP Rep10.1055/s-00000169AJP Reports2157-69982157-7005Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. 3059184210.1055/s-0038-1676832180063Case ReportPregnancies Complicated by Familial Hypertriglyceridemia: A Case Report Cao Suzanne DO, MPH1Dao NhuChi DO1Roloff Kristina DO, MPH1Valenzuela Guillermo J. MD, MBA11 Department of Women's Health, Arrowhead Regional Medical Center, Colton, CaliforniaAddress for correspondence Suzanne Cao, DO, MPH Department of Women's Health, Arrowhead Regional Medical Center400 N Pepper Ave., Colton, CA 92324suzcao@gmail.com10 2018 26 12 2018 8 4 e362 e364 06 11 2018 14 11 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground\n Although rare, familial hypertriglyceridemia can cause acute and life-threatening complications in pregnancy.\n\n\n\nCases\n The first patient's pregnancy was complicated by multiple admissions for pancreatitis due to hypertriglyceridemia and noncompliance with gemfibrozil. In her second pregnancy, she was compliant with gemfibrozil and only experienced pancreatitis episodes toward the end of pregnancy. The second patient had diabetes mellitus and familial hypertriglyceridemia. She required multiple hospitalizations for diabetic ketoacidosis secondary to insulin noncompliance. In both pregnancies, she was compliant with gemfibrozil and had no complications related to hypertriglyceridemia.\n\n\n\nConclusion\n Treatment with gemfibrozil in pregnancies complicated by hypertriglyceridemia may prevent complications without adverse maternal or fetal effects and could be considered in treating pregnant patients with severe hypertriglyceridemia. These cases also demonstrate the importance of medication compliance in the prevention of poor outcomes.\n\n\nKeywords\nfamilial hypertriglyceridemiapancreatitisgemfibrozilpreterm deliveryfetal demise\n==== Body\nThere are few cases of familial hypertriglyceridemia, and its management during pregnancy reported in the literature.\n1\n2\nFamilial hypertriglyceridemia is an autosomal dominant disorder associated with moderate elevations in the serum triglyceride concentration (200–500 mg/dL). Patients are heterozygous for inactivating mutations of the lipoprotein lipase gene. They are at a risk of pathological levels of triglycerides (>1,000 mg/dL) when they are exposed to exacerbating conditions such as pregnancy, hormone replacement therapy, and uncontrolled diabetes. During pregnancy, there is an increase in triglyceride and total cholesterol levels, which are mediated by estrogen, progesterone, and human placental lactogen.\n3\nThe risk of pancreatitis is increased when triglyceride levels are above 500 mg/dL.\n4\nTriglycerides break down into free fatty acids by pancreatic lipase and can lead to lipotoxicity and acute pancreatitis. Hypertriglyceridemia during pregnancy may be responsible for 56% of the pancreatitis cases in contrast with 1–4% in the nonpregnant state.\n5\n\n\n\nAcute pancreatitis is associated with poor pregnancy outcomes including preterm delivery, fetal distress, fetal demise, pancreatic necrosis, and electrolyte abnormalities.\n6\n7\n8\nOther maternal complications of hypertriglyceridemia include hyperviscosity syndrome, preeclampsia, and an increased likelihood of the development of hyperlipoproteinemia in the future.\n9\n10\n11\nFetal effects include macrosomia and pancreatitis-related complications such as preterm delivery and demise.\n12\n\n\nWe report four pregnancies between two patients complicated by familial hypertriglyceridemia.\n\nCase Presentation\nCase 1\n\nThe patient is a 21-year-old G2P0Ab1 with a history of four prior hospital admissions for pancreatitis prior to this pregnancy. The patient presented at 13\n6/7\nweeks-gestation with upper abdominal pain. Laboratory values demonstrated a lipase of 744U/L and triglycerides of 2,281 mg/dL, and she was admitted for acute pancreatitis. Her treatment was managed by a multidisciplinary team consisting of obstetricians, maternal fetal medicine specialists, internal medicine specialists, and a registered dietician. The patient was hospitalized for 5 days, and recovered with supportive care and was discharged with fish oil. At 18\n2/7\nweeks, she was readmitted for acute pancreatitis with a lipase of 197U/L and triglycerides of 4,206 mg/dL. She admitted to noncompliance with her prescribed medication. The patient was admitted to the intensive care unit for possible hemorrhagic and/or necrotic pancreatitis. The patient was treated conservatively and recovered with fish oil, gemfibrozil 600 mg orally twice a day, and supportive care. She was readmitted at 26\n1/7\nweeks for acute pancreatitis with a lipase of 731U/L and triglycerides of 2,633 mg/dL, underwent similar treatment, and again was noted to be noncompliant with medications. She then presented at 30\n5/7\nweeks in preterm labor with a cervical dilation of 4 cm. The patient's preterm labor eventually arrested and she was subsequently discharged home. She returned at 32\n5/7\nweeks with preterm premature rupture of membranes and delivered vaginally a male infant weighing 2,190 g with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. The patient self-discontinued her gemfibrozil after delivery.\n\n\nThe following year, the patient became pregnant again. She had prenatal care elsewhere but was admitted to our hospital for acute pancreatitis at 13 weeks of gestation with a lipase of 298U/L and triglycerides of 2,616 mg/dL and was restarted on gemfibrozil 600 mg orally twice a day. She was readmitted again at 16 weeks of gestation for recurrent pancreatitis, and again noted she did not take the gemfibrozil as prescribed. Following this hospital discharge, she was compliant with her gemfibrozil and did not have another episode of pancreatitis until 32 weeks of gestation. She was subsequently admitted again at 33 and 35 weeks for pancreatitis and intractable abdominal pain. Delivery at 35 weeks was recommended due to her intractable pain from recurrent pancreatitis. She underwent induction of labor and delivered vaginally a male infant weighing 2,530 g with Apgar scores of 7 and 8 at 1 and 5 minutes, respectively. The patient was seen for a postpartum visit and was lost to follow-up thereafter.\n\nCase 2\n\nThe patient is a 22-year-old G3P0Ab2 with familial hypertriglyceridemia and diabetes mellitus since childhood. She was previously on niacin and gemfibrozil but self-discontinued prior to pregnancy. She had prenatal care elsewhere but was admitted to our hospital at 28\n0/7\nweeks gestation due to diabetic ketoacidosis (DKA) from insulin noncompliance. Her hemoglobin A1C was noted to be 7.6%. Her treatment was managed with a multidisciplinary team (obstetricians, maternal fetal medicine, internal medicine, and a registered dietician). Her insulin regimen was adjusted and she was started on gemfibrozil 600 mg orally twice a day. She left against medical advice but reported compliance with all medications at scheduled outpatient visits. She then presented at 35\n2/7\nweeks complaining of decreased fetal movement and had a biophysical profile of 2. The patient delivered through cesarean section a male infant weighing 2,995 g with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Patient had an uncomplicated postoperative course and was discharged home with insulin and gemfibrozil. However, she failed to follow up postpartum.\n\n\n\nSeven months later, the patient presented in DKA and was found to be 15\n2/7\nweeks pregnant. Her hemoglobin A1C was 8.3% on admission. She was on insulin and niacin, which was being managed by her primary care provider. During her admission, the niacin was discontinued and she was prescribed gemfibrozil 600 mg orally twice a day. She presented again at 27 weeks gestation in DKA triggered by a viral upper respiratory infection. Laboratory studies demonstrated a triglyceride level of 1,422 mg/dL and a normal lipase. At 29 weeks of gestation, the fetus was found to have mild ascites and a complex congenital heart anomaly on ultrasound (interrupted aortic arch), and she received fetal lung maturity steroids. At 34 weeks of gestation, she presented with possible preterm premature rupture of membranes and was transferred to another facility capable of fetal cardiothoracic intervention. She suffered a fetal demise within 3 days due to the complex congenital heart anomaly. She stated medication compliance throughout her entire pregnancy.\n\n\nDiscussion\n\nThis case report is significant because it demonstrates that compliance with gemfibrozil decreased the frequency of acute pancreatitis. Prevention of pancreatitis in hypertriglyceridemia is critical because it is associated with decreased placental perfusion, fetal distress, and contractions, leading to significant morbidity. Historically, pancreatitis was associated with significant maternal and fetal mortality, up to 20% for both. However, this has improved with improved diagnosis and early intervention.\n13\n14\n\n\n\nThere are no practice guidelines for the treatment of hypertriglyceridemia during pregnancy, with most recommendations coming from case reports. Wong et al proposed a hierarchical management strategy that includes a multidisciplinary team management and a low-fat and low-glycemic carbohydrate diet with nutritional support (replacement of omega 3 fatty acids and midchain triglycerides as needed), with care to avoid essential fatty acid deficiency. If patients are still refractory, consider hospitalization for parenteral nutrition or intravenous insulin therapy, fibrate use after the first trimester, and plasmapheresis.\n12\n\n\n\nTriglyceride-lowering medication such as niacin and gemfibrozil are often discontinued since their safety during pregnancy has not been established. Niacin supplementation is present in prenatal vitamins and has not been associated with adverse effects.\n15\nHowever, the use of niacin in lipid-lowering doses has not been studied. Gemfibrozil has been evaluated in rats and rabbits for effects on the various phases of the reproductive process. Rats and rabbits received dosages up to 200 mg/kg during organogenesis without any reported teratogenic effects.\n16\nSeveral case reports demonstrate the successful use of gemfibrozil during pregnancy without any fetal harm.\n9\nTo date, there are no epidemiology studies published on the congenital effects in infants whose mothers were treated with gemfibrozil during pregnancy. In the preceding cases, the fetal heart anomaly was likely associated with the patient's diabetes. All the other fetuses demonstrated no anomalies on ultrasound or on physical examination after delivery.\n\n\nIn the four pregnancies presented, there were significant complications. The first patient was noncompliant with gemfibrozil and required hospitalizations throughout her first pregnancy. However, when she was compliant during her second pregnancy, she experienced clusters of admissions at the beginning of the pregnancy when she was restarting her medication and toward the end of her pregnancy, late preterm. This highlights how pregnancy can exacerbate triglyceride levels. The second patient was noncompliant with her insulin and was admitted for DKA on several occasions during her first pregnancy. She was compliant during her second pregnancy and only experienced DKA early on and during a viral infection. She remained compliant with her gemfibrozil and did not experience any episodes of acute pancreatitis during either pregnancy. These examples stress the importance of medication compliance in the prevention of complications associated with hypertriglyceridemia, especially during pregnancy due to the increased morbidity and mortality for both mother and fetus.\n\nThe four presented cases contribute to the scant literature on hypertriglyceridemia and pregnancy. Treatment with gemfibrozil in pregnancies complicated by hypertriglyceridemia may prevent complications without adverse maternal or fetal effects, contributing to the paucity of safety literature. Therefore, it is reasonable to recommend diet and lipid-lowering medication as a first-line treatment for hypertriglyceridemia during pregnancy. These cases highlight the importance of patient education and compliance in the prevention of maternal and fetal complications and poor outcomes.\n\nAcknowledgments\nNone.\n\nConflicts of Interest The authors declare no conflict of interest regarding the publication of this article.\n==== Refs\nReferences\n1 Glueck C J Christopher C Mishkel M A Tsang R C Mellies M J Pancreatitis, familial hypertriglyceridemia, and pregnancy Am J Obstet Gynecol 1980 136 06 755 761 7355961 \n2 De Chalain T M Michell W L Berger G M Hyperlipidemia, pregnancy and pancreatitis Surg Gynecol Obstet 1988 167 06 469 473 3187871 \n3 Brizzi P Tonolo G Esposito F Lipoprotein metabolism during normal pregnancy Am J Obstet Gynecol 1999 181 02 430 434 10454696 \n4 Gupta N Ahmed S Shaffer L Cavens P Blankstein J Severe hypertriglyceridemia induced pancreatitis in pregnancy Case Rep Obstet Gynecol 2014 2014 485493 24995138 \n5 Chang C C Hsieh Y Y Tsai H D Yang T C Yeh L S Hsu T Y Acute pancreatitis in pregnancy Zhonghua Yi Xue Za Zhi (Taipei) 1998 61 02 85 92 9532870 \n6 Wilkinson E J Acute pancreatitis in pregnancy: a review of 98 cases and a report of 8 new cases Obstet Gynecol Surv 1973 28 05 281 303 4614151 \n7 Ghio A Bertolotto A Resi V Volpe L Di Cianni G Triglyceride metabolism in pregnancy Adv Clin Chem 2011 55 133 153 22126027 \n8 Scherer J Singh V P Pitchumoni C S Yadav D Issues in hypertriglyceridemic pancreatitis: an update J Clin Gastroenterol 2014 48 03 195 203 24172179 \n9 Goldberg A S Hegele R A Severe hypertriglyceridemia in pregnancy J Clin Endocrinol Metab 2012 97 08 2589 2596 22639290 \n10 Gallos I D Sivakumar K Kilby M D Coomarasamy A Thangaratinam S Vatish M Pre-eclampsia is associated with, and preceded by, hypertriglyceridaemia: a meta-analysis BJOG 2013 120 11 1321 1332 23859707 \n11 Shenhav S Gemer O Schneider R Harats D Segal S Severe hyperlipidemia-associated pregnancy: prevention in subsequent pregnancy by diet Acta Obstet Gynecol Scand 2002 81 08 788 790 12174168 \n12 Wong B Ooi T C Keely E Severe gestational hypertriglyceridemia: a practical approach for clinicians Obstet Med 2015 8 04 158 167 27512474 \n13 Montgomery W H Miller F C Pancreatitis and pregnancy Obstet Gynecol 1970 35 04 658 664 5438159 \n14 Eddy J J Gideonsen M D Song J Y Grobman W A O'Halloran P Pancreatitis in pregnancy Obstet Gynecol 2008 112 05 1075 1081 18978108 \n15 Saadi H F Kurlander D J Erkins J M Hoogwerf B J Severe hypertriglyceridemia and acute pancreatitis during pregnancy: treatment with gemfibrozil Endocr Pract 1999 5 01 33 36 15251700 \n16 Fitzgerald J E Petrere J A de la Iglesia F A Experimental studies on reproduction with the lipid-regulating agent gemfibrozil Fundam Appl Toxicol 1987 8 04 454 464 3475229\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2157-7005",
"issue": "8(4)",
"journal": "AJP reports",
"keywords": "familial hypertriglyceridemia; fetal demise; gemfibrozil; pancreatitis; preterm delivery",
"medline_ta": "AJP Rep",
"mesh_terms": null,
"nlm_unique_id": "101569862",
"other_id": null,
"pages": "e362-e364",
"pmc": null,
"pmid": "30591842",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": "10454696;12174168;15251700;18978108;22126027;22639290;23859707;24172179;24995138;27512474;3187871;3475229;4614151;5438159;7355961;9532870",
"title": "Pregnancies Complicated by Familial Hypertriglyceridemia: A Case Report.",
"title_normalized": "pregnancies complicated by familial hypertriglyceridemia a case report"
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-197764",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMFIBROZIL"
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"abstract": "Chronic hepatitis C (HCV) virus infection may be associated with several non-hepatic manifestations, mainly driven by chronic immune stimulation, such as mixed cryoglobulinemia and Non-Hodgkin's Lymphoma. This association has been proved by several meta-analyses and some interventional studies demonstrating that antiviral treatment may be effective in inducing HCV-associated lymphoma regression. The recent advent of direct acting antivirals (DAAs) in the therapeutic armamentarium of HCV infection made possible treatment of patients with advanced liver disease. Here we report on a rare association of a cirrhotic patient with HCV and Waldenström's Macroglobulinemia with severe cryoglobulinemia, who had already failed an interferon-based antiviral regimen, whose haematologic disease was ameliorated by HCV eradication following treatment with sofosbuvir and simeprevir with ribavirin, and where successful treatment was accompanied also by consistent improvement in liver function and parameters of portal hypertension.",
"affiliations": "Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Internal Medicine and Oncology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Internal Medicine and Oncology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Pathology Unit, Department of Surgical Sciences, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.;Gastroenterology Unit, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, University of Genoa, Genoa, Italy.",
"authors": "Crespi|Mattia|M|;Demarzo|Maria Giulia|MG|;Brunacci|Matteo|M|;Pellegatta|Gaia|G|;Ferrando|Fabio|F|;Ballestrero|Alberto|A|;Grillo|Federica|F|;Savarino|Vincenzo|V|;Giannini|Edoardo G|EG|",
"chemical_list": "D000998:Antiviral Agents; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "Mexico",
"delete": false,
"doi": "10.5604/01.3001.0012.7208",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "17(6)",
"journal": "Annals of hepatology",
"keywords": "Cirrhosis; Haematology; Outcome; Portal hypertension",
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000998:Antiviral Agents; D001707:Biopsy, Needle; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D019698:Hepatitis C, Chronic; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis; D008875:Middle Aged; D012720:Severity of Illness Index; D000069616:Simeprevir; D000069474:Sofosbuvir; D016896:Treatment Outcome; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "1072-1077",
"pmc": null,
"pmid": "30600285",
"pubdate": "2018-10-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Improvement in Waldenström's Macroglobulinemia after Successful Treatment of HCV with Direct-acting Antivirals.",
"title_normalized": "improvement in waldenstr m s macroglobulinemia after successful treatment of hcv with direct acting antivirals"
} | [
{
"companynumb": "IT-KADMON PHARMACEUTICALS, LLC-KAD201905-000356",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2A"
},
... |
{
"abstract": "The recent interferon-free direct-acting antiviral (DAA) regimens have very good safety and efficacy profiles and are highly recommended for kidney transplant (KT) recipients with chronic hepatitis C (CHC).\nAll KT recipients with CHC followed at our hospital and who received therapy with the current DAAs were included. At the baseline visit, demographic, clinical and laboratory variables before and after KT, as well as at the commencement of DAAs, at the end of antiviral therapy and the end of follow up, were recorded, including assessment of glomerular filtration rate (eGFR). The changes in eGFR (DGFR) between baseline and end of therapy (1st period), and between end of therapy and end of follow up (2nd period), were evaluated.\nTwelve KT recipients were retrospectively evaluated: 2 had received antiviral therapy in the past; 4 (33.3%) patients had genotype 1 and 3 (25%) genotype 4 CHC. The median stiffness was 11.9 kPa (range 5-16.8), while 5 patients, none with decompensated cirrhosis, had stiffness >12.5 kPa. Eight patients received a sofosbuvir-containing antiviral regimen (Group 1) and 4 patients received an antiviral regimen without sofosbuvir (Group 2). Eleven (91.7%) patients achieved a sustained virological response (SVR). One patient discontinued DAAs early after treatment and did not achieve SVR. Otherwise, DAAs were well tolerated and no rejection episode was recorded. The DGFRs in the 1st period and 2nd period did not differ significantly between Group 1 and Group 2 patients.\nIn this real-world study of KT recipients with CHC, the high efficacy and clinically acceptable tolerability of DAAs were confirmed.",
"affiliations": "Nephrology Department and Transplantation Unit, Laiko Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;First Department of Internal Medicine, Medical School of National and Kapodistrian University, Athens, Greece.;Nephrology Department and Transplantation Unit, Laiko Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Nephrology Department and Transplantation Unit, Laiko Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;National and Kapodistrian University of Athens, Faculty of Nursing P. & A. Kyriakou Children's Hospital.;Nephrology Department and Transplantation Unit, Laiko Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Nephrology Department and Transplantation Unit, Laiko Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Darema|Maria|M|;Cholongitas|Evangelos|E|;Filiopoulos|Vassilis|V|;Marinaki|Smaragdi|S|;Pavlopoulou|Ioanna D|ID|;Tsoubou|Ioanna|I|;Boletis|John N|JN|;Papatheodoridis|George V|GV|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.20524/aog.2020.0481",
"fulltext": "\n==== Front\nAnn Gastroenterol\nAnn Gastroenterol\nAnnals of Gastroenterology\n1108-7471 1792-7463 Hellenic Society of Gastroenterology Greece \n\nAnnGastroenterol-33-285\n10.20524/aog.2020.0481\nOriginal Article\nEfficacy and safety of new direct-acting antivirals in kidney transplant recipients with chronic hepatitis C: a single-center study\nDarema Maria a* Cholongitas Evangelos b* Filiopoulos Vassilis a Marinaki Smaragdi a Pavlopoulou Ioanna D. c Tsoubou Ioanna a Boletis John N. a Papatheodoridis George V. d a Nephrology Department and Transplantation Unit, Laiko Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece\nb First Department of Internal Medicine, Medical School of National and Kapodistrian University, Athens, Greece\nc National and Kapodistrian University of Athens, Faculty of Nursing P. & A. Kyriakou Children’s Hospital\nd Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Athens, Greece\n\nCorrespondence to: George V. Papatheodoridis, MD, PhD, Director of Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital of Athens, 17 Agiou Thoma street, 11527 Athens, Greece, e-mail: gepapath@med.uoa.gr* These two authors contributed equally to this work and both should be considered as first author\n\n\nMay-Jun 2020 \n14 4 2020 \n33 3 285 292\n17 11 2019 03 3 2020 Copyright: © Hellenic Society of Gastroenterology2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThe recent interferon-free direct-acting antiviral (DAA) regimens have very good safety and efficacy profiles and are highly recommended for kidney transplant (KT) recipients with chronic hepatitis C (CHC).\n\nMethods\nAll KT recipients with CHC followed at our hospital and who received therapy with the current DAAs were included. At the baseline visit, demographic, clinical and laboratory variables before and after KT, as well as at the commencement of DAAs, at the end of antiviral therapy and the end of follow up, were recorded, including assessment of glomerular filtration rate (eGFR). The changes in eGFR (DGFR) between baseline and end of therapy (1st period), and between end of therapy and end of follow up (2nd period), were evaluated.\n\nResults\nTwelve KT recipients were retrospectively evaluated: 2 had received antiviral therapy in the past; 4 (33.3%) patients had genotype 1 and 3 (25%) genotype 4 CHC. The median stiffness was 11.9 kPa (range 5-16.8), while 5 patients, none with decompensated cirrhosis, had stiffness >12.5 kPa. Eight patients received a sofosbuvir-containing antiviral regimen (Group 1) and 4 patients received an antiviral regimen without sofosbuvir (Group 2). Eleven (91.7%) patients achieved a sustained virological response (SVR). One patient discontinued DAAs early after treatment and did not achieve SVR. Otherwise, DAAs were well tolerated and no rejection episode was recorded. The DGFRs in the 1st period and 2nd period did not differ significantly between Group 1 and Group 2 patients.\n\nConclusion\nIn this real-world study of KT recipients with CHC, the high efficacy and clinically acceptable tolerability of DAAs were confirmed.\n\nKidney transplantationhepatitis Cdirect-acting antiviralschronic hepatitis Ckidney\n==== Body\nIntroduction\nIt is estimated that 5-15% of kidney transplant (KT) recipients have chronic hepatitis C (CHC), associated with poor patient and graft survival after KT [1]. In particular, CHC after organ transplantation usually has a more aggressive course due to the necessary immunosuppressive therapy, as well as the more frequent development of post-transplant diabetes mellitus, cardiovascular disease and HCV-associated glomerulonephritis, while there is an increased risk of post-transplant lymphoproliferative disorders [2,3]. In the era before direct-acting antivirals (DAAs), there was hardly any therapeutic option for CHC in KT recipients, as interferon-based therapy, with or without ribavirin (RBV), was usually not recommended, or was even contraindicated because of the low rates of sustained virological response (SVR) and the high risk for the development of steroid-resistant acute allograft rejection [3]. After 2014, the introduction of DAAs in the treatment of CHC has changed the landscape dramatically, as interferon-free and RBV-free oral DAA combinations given for a few weeks can achieve very high cure rates (>95% SVR), while having excellent tolerability and safety profile even in immunocompromised patients [2,3].\n\nCurrently, DAA combinations represent the standard therapeutic option for the treatment of all CHC subgroups, including those with renal dysfunction or KT. All current DAAs are eliminated mainly through the liver, except for sofosbuvir eliminated through the kidney and may be associated with an unfavorable safety profile in patients who have at least moderate-to-severe renal impairment [4]. Thus, sofosbuvir—and consequently its co-formulations, sofosbuvir/ledipasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir—are not recommended for use in patients who have an estimated glomerular filtration rate (eGFR) lower than 30 mL/min [4], although in the very recently updated guidelines of the American Association for the Study of Liver Diseases (AASLD), a daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) is considered as an option in this specific group of patients [5]. On the other hand, caution is required regarding the potential drug-drug interactions between immunosuppressive agents and DAAs in the KT setting, since calcineurin inhibitors (CNIs: tacrolimus and cyclosporine) and mammalian target of rapamycin inhibitors (sirolimus and everolimus) are substrates of cytochrome P450 and P-glycoprotein [6]. In fact, some DAAs should not be used and some others should be used with caution in combination with specific immunosuppressive drugs (e.g., protease inhibitors with cyclosporine, given the elevations in cyclosporine concentrations) [6]. The aim of the present study was to evaluate the efficacy, tolerability and safety of DAAs in KT recipients followed in a single center in Greece.\n\nPatients and methods\nWe included all KT recipients with CHC followed at our hospital who received therapy with the current DAAs. All KT recipients with positive antibodies against hepatitis C (anti-HCV) before transplantation were reassessed after KT with anti-HCV and serum HCV RNA to confirm the HCV infection. In patients with detectable serum HCV RNA, HCV genotype determination and baseline laboratory tests were performed. The choice of antiviral regimen was based on the availability of DAAs at the time of evaluation in relation to the HCV genotype and viral load, previous antiviral therapy, liver disease severity, eGFR, co-morbidities and co-medications.\n\nCommercially available enzyme immunoassays were used for the detection of anti-HCV, while serum HCV RNA levels were determined by a commercially available quantitative polymerase chain reaction (PCR) assay. HCV genotype was also determined by a commercially available assay. Evaluation of liver severity was classified into the following subgroups: fibrosis stage F0-F1, F2, F3 and F4, and decompensated cirrhosis. The diagnosis of fibrosis stage F0-F4 was based on liver stiffness measurements (LSM) using 2-dimensional real-time shear-wave elastography (2D-SWE) performed by experienced operators according to the current guidelines (evaluation of the right lobe of the liver through the intercostal spaces with the fasting patient in the supine position). The Aixplorer ultrasound system (Supersonic Imagine S.A., Aix-en-Provence, France) with an abdominal 3.5 MHz curved array probe was used, as recommended. Ten reliable LSM were obtained from each patient, and the mean values were calculated. The standard deviation (SD) was <20% of the mean value of LSM. The recipients with reliable liver stiffness measurements of <7.0, 7.0-9.0, 9.1-12.5 and >12.5 kPa were considered to have fibrosis stage F0-F1, F2, F3 and F4, respectively. The diagnosis of decompensated cirrhosis was based on the presence of ascites, episodes of variceal bleeding, encephalopathy or non-obstructive jaundice diagnosed by clinical and/or radiological signs.\n\nAt the baseline visit, demographic and clinical variables were recorded: (a) before KT: duration of hemodialysis and indication for KT; and (b) after KT: rejection episodes, concomitant diseases (e.g., diabetes mellitus, arterial hypertension, hyperlipidemia, cardiovascular events) and immunosuppressive therapy, including dosage and blood concentrations of CNIs and everolimus, dosage of mycophenolate mofetil (MMF) and steroids.\n\nIn addition, several laboratory parameters were tested, including hematocrit, hemoglobin, white blood count, platelet count, serum creatinine (sCr), and aminotransferases (aspartate [AST] and alanine [ALT]). Renal function was assessed by eGFR calculated with the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) sCr-based formula. Evaluation of renal function was performed at baseline (initiation of DAAs), at the end of antiviral therapy and at the end of follow up. The changes in eGFR (DGFR) between baseline and end of therapy (1st period), and between end of therapy and end of follow up (2nd period) were also evaluated.\n\nAfter the commencement of DAA therapy, all patients were followed every month and whenever clinically indicated, with or without laboratory evaluation. Adverse events and their management were recorded. At the end of therapy, clinical and laboratory re-evaluation was performed, with measurement of aminotransferases, serum HCV RNA, and renal function based on sCr and eGFR. SVR was evaluated at 3 months after stopping DAAs (SVR12) and was considered to have been achieved when serum HCV RNA was undetectable by PCR. Patients with serum HCV RNA undetectable at the end of treatment, but detectable subsequently, were considered as relapsed responders, while patients with detectable serum HCV RNA at the end of treatment were classified as non-responders.\n\nThe study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was not supported by any external institution or agency. Informed consent was obtained from all participants before DAAs were initiated.\n\nStatistical analysis\nContinuous variables were represented as mean ± standard deviation (if normally distributed) or median with interquartile range (if non-normally distributed). Categorical variables were expressed as frequencies or percentages. Comparisons of parameters between patients were performed using Student’s t- or Mann-Whitney U tests, as appropriate, for continuous variables, and a corrected chi-square test for categorical variables. Chronic kidney disease was defined as eGFR<60 mL/min/1.73 m2. A P-value <0.05 was considered to be statistically significant. Statistical analysis was conducted using SPSS software (IBM SPSS v.24.0 (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp.).\n\nResults\nPatient characteristics\nOur study was a case series of 12 KT recipients with CHC (6 male, age 57±12 years) who received therapy with DAAs. Table 1 depicts their baseline features. Six (50%) patients had known CHC before KT, but only 2 (16.6%) had received antiviral therapy in the past. One patient with CHC genotype 4 had used pegylated interferon and RBV before KT, and another patient with CHC genotype 4 had received sofosbuvir plus RBV after KT. Both cases had discontinued antiviral therapy shortly after its initiation, because of adverse events (anemia/leukopenia and anemia, respectively). A total of 4 (33.3%) patients were infected with genotype 1 (3 with 1b and 1 with 1a), 3 (25%) with genotype 4, and 2 with genotype 3 (16.7%), whereas the genotype was unknown in 3 (25%) patients. The median baseline serum HCV RNA was 3.68×106 IU/mL in the study population. The median stiffness was 11.9 (range 5-16.8) kPa and 5 patients had stiffness >12.5 kPa, i.e., had fibrosis F4 (cirrhosis) based on elastography. None of the patients had evidence of decompensated cirrhosis. At the commencement of DAA administration, 9 (75%) patients were under triple immunosuppressive therapy with CNIs plus MMF and methylprednisolone, 2 (16.7%) patients were under a combination of everolimus and methylprednisolone (1 with tacrolimus and 1 with MMF), while 1 (8.3%) patient was receiving no immunosuppressive agent. Regarding comorbidities, 12 (100%) patients had arterial hypertension, 6 (50%) diabetes mellitus, and 6 (50%) coronary artery disease (Table 1).\n\nTable 1 Baseline characteristics of 12 kidney transplant (KT) recipients with chronic hepatitis C (CHC) who received antiviral therapy with direct acting antivirals (DAAs)\n\nTherapy with DAAs\nTherapy with DAAs was initiated at a median of 189 (range: 1-339) months after KT. One patient started antiviral therapy after the diagnosis of acute cholestatic hepatitis C confirmed by liver biopsy at 20 months after KT. Eleven patients were treated for 12 weeks and 1 patient received therapy for 16 weeks. Eight patients received a sofosbuvir-containing antiviral regimen (Group 1) and 4 patients received an antiviral regimen without sofosbuvir (Group 2). In Group 1 patients, sofosbuvir was given with ledipasvir (n=3; 1 patient had received sofosbuvir plus RBV after KT), velpatasvir (n=2) and daclatasvir (n=3; 1 patient had received pegylated interferon plus RBV before KT). RBV was added in 1 patient with genotype 3 treated with sofosbuvir plus daclatasvir. In Group 2, 2 patients received the combination of elbasvir/grazoprevir and 2 the combination of ombitasvir/paritaprevir/ritonavir plus dasabuvir (3D regimen; together with RBV in 1 patient).\n\nEleven (91.7%) patients achieved SVR with undetectable serum HCV RNA at 12 weeks after the end of therapy. These 11 patients were followed for a median 30 (range: 3-49) months after the end of therapy and all remained in good clinical condition with undetectable serum HCV RNA. SVR was not achieved in only one patient (8.3%) treated with 3D plus RBV who discontinued DAAs early after treatment onset because of a serious adverse event (Table 2).\n\nTable 2 Characteristics of antiviral therapy with direct acting antivirals (DAAs) in kidney transplant (KT) recipients with chronic hepatitis C (CHC)\n\nSafety profile of DAAs\nInterestingly, no significant changes were observed between baseline and 12 weeks after the end of therapy regarding proteinuria (218.8±53.6 vs. 358.5±69.4 mg/24h, P=0.49), serum phosphate (3.25±0.48 vs. 3.09±0.65 mg/dL, P=0.51), calcium (9.74±0.88 vs. 9.71±0.69 mg/dL, P=0.93), sodium (139.2±3.43 vs. 138.66±2.42 mmol/L, P=0.68), potassium (4.3±0.41 vs. 4.27±0.42 mmol/L, P=0.84) or uric acid (7.97±1.42 vs. 8.3±2.41 mg/dL, P=0.69).\n\nThe only serious adverse event was observed in the patient treated with the 3D plus RBV combination, who developed drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, resulting in permanent withdrawal of DAAs. The DRESS syndrome was attributed to the DAA therapy, since no other medication was changed or added during the last months in this patient. After DAA discontinuation, the patient received appropriate symptomatic management and improved rapidly, but he refused to take any other DAA regimen.\n\nIn the remaining 11 patients, therapy with DAAs was generally well tolerated. Only mild non-specific adverse events were reported (e.g., fatigue, headache, diarrhea) in 4 patients. All these mild adverse events were of short duration and required no specific therapeutic manipulation, treatment discontinuation or hospitalization. No patient received a blood transfusion during antiviral therapy, while 4 patients under erythropoietin before therapy continued the same erythropoietin dosage during and after DAA therapy (Table 2).\n\nThe dosages and levels of immunosuppressive agents did not change significantly during treatment with DAAs in all but 1 patient who received 3D therapy and had to decrease the dosage of cyclosporine. Otherwise, CNIs and everolimus trough levels were measured more frequently during DAAs therapy, but no other change was required. No rejection episode was recorded (Table 2).\n\nSubgroup analysis at baseline and changes during antiviral therapy\nThe patients (n=8) who received a sofosbuvir-containing regimen (Group 1), compared to those (n=4) who received a regimen without sofosbuvir (Group 2), were more frequently under CNI-based immunosuppression (7/8 or 87.5% vs. 1/4 or 25%, P=0.03) and had better renal function at baseline (sCr: 1.2±0.2 vs. 1.8±0.3, P=0.028; eGFR: 58±16 vs. 35±6, P=0.007), end of therapy (sCr: 1.2±0.3 vs. 2.1±0.6, P=0.05; eGFR: 59±19 vs. 32±8, P=0.007), and end of follow up (sCr: 1.2±0.3 vs. 3.0±1.3, P=0.016; eGFR: 55±21 vs. 23±10, P=0.017). However, the changes in eGFR between baseline and end of therapy (1st period), and between end of therapy and end of follow up (2nd period), did not differ significantly between Group 1 and Group 2 patients (P=0.15 and P=0.073, respectively) (Table 3). Finally, the patients (n=5) who showed improvement in eGFR (DGFR>0) in the 1st period, compared to those without improvement (n=7), had significantly better renal function at the end of follow up (eGFR: 67.7±18 vs. 38.5±11, P=0.028).\n\nTable 3 Characteristics of patients under sofosbuvir-based and non–sofosbuvir-based antiviral therapy in kidney transplant (KT) recipients with chronic hepatitis C (CHC) at baseline and during antiviral therapy\n\nRegarding aminotransferases, AST remained unchanged between baseline and end of therapy, regardless of antiviral (regimen with or without sofosbuvir) or immunosuppressive therapy (CNIs vs. non-CNI-based therapy). In contrast, ALT levels decreased in the total cohort (P=0.05) and in the subgroup of patients who received a sofosbuvir-containing regimen (P=0.031) (Table 3).\n\nDiscussion\nCurrently, only few studies in the literature, most of which included relatively small numbers of patients, have focused on KT recipients with CHC treated with DAAs (Table 4) [7-26]. In our study, 11 (91.7%) of 12 patients achieved SVR under DAA combination therapy. Notably, RBV was given in only 2 (16.7%) patients and the vast majority (11/12 or 91.7%) of the KT recipients received 12 weeks of antiviral therapy. The only treatment failure was observed in 1 patient who developed DRESS syndrome shortly after 3D plus RBV initiation, leading to premature discontinuation of therapy. Thus, HCV eradication was achieved in all (11/11 or 100%) patients who received the full antiviral regimen. Our findings confirm previous studies from other centers (Table 4) that DAAs are highly effective in KT recipients, offering SVR rates comparable to those achieved in the non-transplant setting and therefore representing major progress in the elimination of HCV infection in this setting.\n\nTable 4 Studies of direct acting antivirals (DAAs) for treatment of hepatitis C virus infection in kidney transplant recipients\n\nImportantly, DAAs in our cohort showed a satisfactory safety profile and were usually well-tolerated, since withdrawal of antiviral therapy was recorded only in the patient who developed DRESS syndrome, possibly attributable to the 3D plus RBV combination. No further serious clinical or laboratory adverse event and/or even transient discontinuation of DAAs was observed. It should be mentioned that all adverse events were non-specific, such as fatigue and headache, and of mild severity, requiring no specific therapeutic manipulation. Interestingly, no rejection episode was recorded during antiviral therapy or until the end of the 12-week follow up, while adjustment of immunosuppression was needed in only 1 KT recipient. In that patient, high levels of cyclosporine were measured during antiviral therapy with the 3D combination and the cyclosporine dosage was reduced, with no further consequences for patient or graft outcome. Thus, changes in immunosuppressive drugs were rather infrequent during DAA therapy in our cohort, although antiviral regimens with protease inhibitors were used in another 3 patients. Contradictory data have been reported on this issue: some studies recorded no need for significant changes in the dosage of immunosuppressive drugs, with stable immunosuppression levels during DAA therapy [17,18,20-22], while in other studies [9,19] a high proportion of patients were reported to require dose adjustment (Table 4). Nevertheless, in accordance with current guidelines, more frequent monitoring of immunosuppressive drug levels is recommended during and after the end of DAA therapy to avoid drug toxicity and/or rejection episodes. In the same context, development of anemia was not reported in our KT recipients under RBV, possibly reflecting careful escalation of the RBV dosage and close laboratory monitoring. Finally, since we performed a real-world study, all the patients in our cohort had comorbidities and were receiving several other drugs, usually related with components of metabolic syndrome. However, no evidence of clinically significant drug–drug interactions was observed, since no adjustments in co-medications were needed during DAA therapy.\n\nIn our cohort, most of the KT recipients (n=8, or 66.6%) received a sofosbuvir-containing regimen. Sofosbuvir was given in combination with daclatasvir, ledipasvir and velpatasvir, reflecting the evolution of antiviral regimens according to the guidelines and the availability of DAAs in Greece during recent years. Although our cohort was small, no difference in the effectiveness and safety profile was observed among the different sofosbuvir-containing regimens. In addition, literature studies have shown that sofosbuvir might have a negative impact on eGFR, particularly in high-risk patients, such as KT recipients and/or patients under CNIs [3]. In our cohort, patients treated with a sofosbuvir-containing regimen had baseline mean eGFR 58±16 mL/min and they were more frequently under CNI-based immunosuppression (7/8 or 87.5%). Interestingly, their median DGFR while receiving the sofosbuvir-containing regimen was 0 (range: -13 – 15) indicating that sofosbuvir had an overall neutral renal safety profile in these patients. On the other hand, antiviral regimens without sofosbuvir were given to recipients with renal dysfunction at baseline (mean eGFR: 35±6 mL/min) who were more frequently under everolimus-based immunosuppression (3/4 or 75%). Interestingly, eGFR worsened in Group 2 patients, under a sofosbuvir-free DAA regimen, i.e., DAAs with a theoretically more favorable renal profile (Table 3). However, this group had pre-existing renal dysfunction and the decline in GFR could not be attributed to DAA administration. Nevertheless, in both Group 1 and 2 patients there was no change in eGFR during either the 1st (between baseline and end of therapy) or the 2nd (between end of therapy and end of follow up) period (Table 3), confirming previous studies that DAAs do not adversely affect renal function in KT recipients (Table 4). In addition, DGFR was not associated with the type of immunosuppression used during antiviral therapy or the presence of comorbidities, such as diabetes mellitus or arterial hypertension (data not shown).\n\nFinally, regarding liver function tests, all patients had AST and ALT within normal ranges (<40 IU/L) at baseline; thus, only minor changes in aminotransferase levels were observed at the end of antiviral therapy and after hepatitis C eradication. Only ALT levels significantly decreased from baseline to the end of therapy in the total cohort (P=0.05) and in the subgroup of patients who received a sofosbuvir-containing regimen (from 18.5±6 to 16.5±5 IU/L, P=0.031) (Table 3).\n\nOur study is not without limitations, since it was a small observational single-center study that included only Caucasian patients. Nevertheless, although only 12 patients were included in our study, most studies in the literature were characterized by a small sample size (Table 4). Moreover, we were not able to evaluate more sensitive markers of renal dysfunction, such as neutrophil gelatinase-associated lipocalin, before and after DAA therapy. Nevertheless, it was a real-world study of KT recipients with several comorbidities and co-medications, and therefore patients at high risk for drug–drug interactions, in whom DAA therapy showed high efficacy and clinically acceptable tolerability, with only a few non-specific adverse events.\n\nSummary Box\nWhat is already known:\n\n\nIn the era before direct-acting antivirals (DAAs), there was almost no therapeutic option for chronic hepatitis C (CHC) in kidney transplant (KT) recipients\n\nSince 2014, interferon-free and ribavirin-free oral DAA combinations given for a few weeks can achieve very high cure rates, with excellent tolerability and safety profile\n\nCurrently, DAA combinations represent the standard therapeutic option for the treatment of all CHC subgroups, including KT recipients\n\n\n\n\nWhat the new findings are:\n\n\nIn our study of KT recipients with CHC, DAAs showed a satisfactory safety profile and were usually well-tolerated\n\nOur findings confirmed that DAAs are highly effective in KT recipients\n\nA sofosbuvir-containing regimen had an overall neutral renal safety profile in this group of patients\n\n\n\n\nConflict of Interest: None\n\nLaiko Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Medical School of National and Kapodistrian University, Athens, Greece; National and Kapodistrian University of Athens, P. and A. Kyriakou Children’s Hospital, Athens, Greece\n==== Refs\n1 Morales JM Fabrizi F Hepatitis C and its impact on renal transplantation Nat Rev Nephrol 2015 11 172 182 25643666 \n2 Pipili C Ilonidis G Cholongitas E Hepatitis C virus and kidney:a strong association with different clinical aspects Liver Int 2011 31 1071 1080 21745269 \n3 Cholongitas E Pipili C Papatheodoridis GV Interferon-free regimens in patients with hepatitis C infection and renal dysfunction or kidney transplantation World J Hepatol 2017 9 180 190 28217256 \n4 Cholongitas E Papatheodoridis GV Sofosbuvir:a novel oral agent for chronic hepatitis C Ann Gastroenterol 2014 27 331 337 25332066 \n5 HCV Guidance:Recommendations for testing, managing, and treating hepatitis C [Accessed 27 March 2020] Available at: https://www.hcvguidelines.org/unique-populations/renal-impairment \n6 Chute DF Chung RT Sise ME Direct-acting antiviral therapy for hepatitis C virus infection in the kidney transplant recipient Kidney Int 2018 93 560 567 29325996 \n7 Gendia M Lampertico P Alfieri CM Impact of hepatitis C virus and direct acting antivirals on kidney recipients:a retrospective study Transpl Int 2019 32 493 501 30580473 \n8 Kawagishi N Nakamura A Takayama T Haga I Safety of direct-acting antiviral therapy for renal function in post-kidney transplant patients infected with hepatitis C virus and a 100% 12-week sustained virologic response:a single-center study Ther Apher Dial 2020 24 184 188 31290282 \n9 Musialik J Kolonko A Kwiecień K Owczarek AJ Więcek A Effectiveness and safety of sofosbuvir-based therapy against chronic hepatitis C infection after successful kidney transplantation Transpl Infect Dis 2019 21 e13090 30972854 \n10 El Maghrabi HM Elmowafy AY Donia AF Treatment of chronic hepatitis C infection among Egyptian kidney transplant recipients:a pilot study Exp Clin Transplant 2019 17 62 67 30777525 \n11 Özer Etik D Suna N Öcal S Successful treatment with direct-acting antiviral agents of hepatitis C in patients with end-stage renal disease and kidney transplant recipients Exp Clin Transplant 2019 17 52 58 30719954 \n12 Duerr M Schrezenmeier EV Lehner LJ A prospective study of daclatasvir and sofosbuvir in chronic HCV-infected kidney transplant recipients BMC Nephrol 2019 20 36 30717681 \n13 Weigert A Querido S Carvalho L Hepatitis C virus eradication in kidney transplant recipients:a single-center experience in Portugal Transplant Proc 2018 50 743 745 29661427 \n14 Xue Y Zhang LX Wang L Li T Qu YD Liu F Efficacy and safety of sofosbuvir and daclatasvir in treatment of kidney transplantation recipients with hepatitis C virus infection World J Gastroenterol 2017 23 5969 5976 28932089 \n15 Saxena V Khungar V Verna EC Safety and efficacy of current direct-acting antiviral regimens in kidney and liver transplant recipients with hepatitis C:Results from the HCV-TARGET study Hepatology 2017 66 1090 1101 28504842 \n16 Goel A Bhadauria DS Kaul A Experience with direct acting anti-viral agents for treating hepatitis C virus infection in renal transplant recipients Indian J Gastroenterol 2017 36 137 140 28345112 \n17 Beinhardt S Al Zoairy R Ferenci P DAA-based antiviral treatment of patients with chronic hepatitis C in the pre- and postkidney transplantation setting Transpl Int 2016 29 999 1007 27203857 \n18 Lin MV Sise ME Pavlakis M Efficacy and safety of direct acting antivirals in kidney transplant recipients with chronic hepatitis C virus infection PLoS One 2016 11 e0158431 27415632 \n19 Fernández I Muñoz-Gómez R Pascasio JM Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C J Hepatol 2017 66 718 723 28039098 \n20 Huang H Tang H Deng H Treatment of chronic hepatitis C viral infection with sofosbuvir and daclatasvir in kidney transplant recipients Transpl Infect Dis 2019 21 e13018 30369001 \n21 Zhang J Sun W Lin J Long-term follow-up of HCV infected kidney transplant recipients receiving direct-acting antiviral agents:a single-center experience in China BMC Infect Dis 2019 19 645 31324230 \n22 Sawinski D Kaur N Ajeti A Successful treatment of hepatitis C in renal transplant recipients with direct-acting antiviral agents Am J Transplant 2016 16 1588 1595 26604182 \n23 Moreno A Fernandez A Vivancos MJ Real life safety and efficacy of IFN/RBV-free, full-dose SOF-based therapy in kidney transplanted patients J Hepatol 2016 64 S745 \n24 El-Halawany H Qureshi K Treatment of chronic hepatitis C after deceased donor renal transplantation with direct acting antiviral regimens:interim data J Hepatol 2016 64 S785 S786 \n25 Colombo M Aghemo A Liu H Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis c virus genotype 1 or 4 infection:a randomized trial Ann Intern Med 2017 166 109 117 27842383 \n26 Kamar N Marion O Rostaing L Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation Am J Transplant 2016 16 1474 1479 26587971\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7471",
"issue": "33(3)",
"journal": "Annals of gastroenterology",
"keywords": "Kidney transplantation; chronic hepatitis C; direct-acting antivirals; hepatitis C; kidney",
"medline_ta": "Ann Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101121847",
"other_id": null,
"pages": "285-292",
"pmc": null,
"pmid": "32382232",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "30717681;30719954;29325996;26604182;31290282;27203857;25643666;28217256;27842383;26587971;21745269;28039098;31324230;28932089;30369001;30972854;28504842;30777525;28345112;29661427;30580473;27415632;25332066",
"title": "Efficacy and safety of new direct-acting antivirals in kidney transplant recipients with chronic hepatitis C: a single-center study.",
"title_normalized": "efficacy and safety of new direct acting antivirals in kidney transplant recipients with chronic hepatitis c a single center study"
} | [
{
"companynumb": "GR-TEVA-2020-GR-1505161",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DASABUVIR"
},
"drugadditional": "1",
... |
{
"abstract": "Background The occurrence of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome before 20 weeks of gestation is rare. HELLP is a possible but rare syndrome in gestational surrogate pregnancies for surrogates with risk factors for development of preeclampsia. Case A 32-year-old patient with chronic hypertension and positive antinuclear antibody presented for prenatal care at 13 weeks and 1 day. She was a surrogate for the embryo of a 43-year-old couple. By 15 weeks she developed uncontrolled hypertension requiring hospitalization. She was expectantly managed until her condition deteriorated. At 16 weeks and 1 day she developed hemolysis, elevated liver enzymes, thrombocytopenia, and fetal demise. Conclusions HELLP syndrome is rare and carries a significant morbidity and mortality for the mother and fetus. Clinicians should encourage the surrogate to share her medical history with the embryo donor for appropriate counseling on pregnancy risks.",
"affiliations": "Department of Obstetrics and Gynecology and Section of Maternal-Fetal Medicine, Eastern Virginia Medical School, Norfolk, Virginia.;Department of Obstetrics and Gynecology and Section of Maternal-Fetal Medicine, Eastern Virginia Medical School, Norfolk, Virginia.",
"authors": "Myer|Emily|E|;Hill|James|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0035-1563389",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2157-7005",
"issue": "5(2)",
"journal": "AJP reports",
"keywords": "HELLP syndrome; gestational surrogate; in vitro fertilization; preeclampsia; previable",
"medline_ta": "AJP Rep",
"mesh_terms": null,
"nlm_unique_id": "101569862",
"other_id": null,
"pages": "e212-4",
"pmc": null,
"pmid": "26495187",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports",
"references": "17666652;22111023;17084396;21782350;12383328;9325513;16586230;15121574;24150027;23541404;10368474;12790854;24499757;24175873",
"title": "First Trimester Hemolysis, Elevated Liver Enzymes, Low Platelets Syndrome in a Surrogate Pregnancy.",
"title_normalized": "first trimester hemolysis elevated liver enzymes low platelets syndrome in a surrogate pregnancy"
} | [
{
"companynumb": "US-BAYER-2015-469283",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MAGNESIUM"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nInfective endocarditis (IE) due to gram-negative (GN) bacilli is uncommon. Although multi- and extensively-drug resistant (MDR/XDR) GN infections are emerging, very few data are available on IE due to these microrganisms.\n\n\nMETHODS\nIn this study, we describe the clinical characteristics, course and outcome of five contemporary, definite, MDR/XDR GNIE cases seen at our centre.\n\n\nRESULTS\nAll patients had been admitted to a hospital during the 6months before IE onset, 2 were on hemodialysis and 3 on intravenous medications. Three of the 5 cases were hospital-acquired. Intracardiac prosthetic devices were present in all cases (3 central venous lines, 2 prosthetic heart valves, 2 pacemakers). Mean Charlson comorbidity index was 5.8. Causative pathogens were XDR Pseudomonas aeruginosa (2 cases), XDR Acinetobacter baumannii, MDR Burkolderia cepacia and MDR Escherichia coli (1 case each). Concomitant pathogens with a MDR/XDR phenotype were isolated in 4 patients. Both valves and intracardiac devices and left and right sides of the heart were involved. The rate of complications was high. Antibiotic treatment hinged on the use of colistin, a carbapenem or both. Cardiovascular surgical procedures were performed in 3 patients. Despite aggressive therapeutic regimens, outcomes were poor. Clearance of bacteremia was obtained in 3 patients, in-hospital death occurred in 3 patients, only 1 patient survived during follow up.\n\n\nCONCLUSIONS\nMDR/XDR GN are emerging as a cause of IE in carriers of intracardiac prostheses with extensive healthcare contacts and multiple comorbidities. Resistant GNIE has a complicated course and shows a dismal prognosis.",
"affiliations": "Internal Medicine Section, Department of Cardiothoracic Sciences, University of Naples S.U.N., Monaldi Hospital, Naples, Italy. Electronic address: emanuele.durante@unina2.it.;Internal Medicine Section, Department of Cardiothoracic Sciences, University of Naples S.U.N., Monaldi Hospital, Naples, Italy.;Internal Medicine Section, Department of Cardiothoracic Sciences, University of Naples S.U.N., Monaldi Hospital, Naples, Italy.;Internal Medicine Section, Department of Cardiothoracic Sciences, University of Naples S.U.N., Monaldi Hospital, Naples, Italy.;Internal Medicine Section, Department of Cardiothoracic Sciences, University of Naples S.U.N., Monaldi Hospital, Naples, Italy.;Microbiology and Virology Unit, Monaldi Hospital, Naples, Italy.;Internal Medicine Section, Department of Cardiothoracic Sciences, University of Naples S.U.N., Monaldi Hospital, Naples, Italy.",
"authors": "Durante-Mangoni|Emanuele|E|;Andini|Roberto|R|;Agrusta|Federica|F|;Iossa|Domenico|D|;Mattucci|Irene|I|;Bernardo|Mariano|M|;Utili|Riccardo|R|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-6205",
"issue": "25(7)",
"journal": "European journal of internal medicine",
"keywords": "Anti-infective agents; Colistin; Heart valve prostheses; Nosocomial Infection; Prosthesis-related infections",
"medline_ta": "Eur J Intern Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D024901:Drug Resistance, Multiple, Bacterial; D004697:Endocarditis, Bacterial; D005260:Female; D005500:Follow-Up Studies; D006090:Gram-Negative Bacteria; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D015994:Incidence; D007558:Italy; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors",
"nlm_unique_id": "9003220",
"other_id": null,
"pages": "657-61",
"pmc": null,
"pmid": "24954705",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Infective endocarditis due to multidrug resistant gram-negative bacilli: single centre experience over 5 years.",
"title_normalized": "infective endocarditis due to multidrug resistant gram negative bacilli single centre experience over 5 years"
} | [
{
"companynumb": "IT-CUBIST PHARMACEUTICALS, INC.-2014CBST001326",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugaddi... |
{
"abstract": "Sulfonylureas, a potent stimulator of insulin release from pancreatic β cells, can cause hypoglycemia, which is apt to recur with a prolonged duration in elderly patients. Octreotide acetate, a long-acting somatostatin analogue, suppresses the secretion of insulin and is recognized as a possible treatment for sulfonylurea-induced hypoglycemia. However, there are few reports on its use in an actual clinical setting, especially in the elderly. We herein report a case in which subcutaneous injection of octreotide was effective for treating prolonged and recurrent hypoglycemia caused by sulfonylureas in an elderly man. An 89-year-old man was transported to the emergency department of our hospital for disturbance of consciousness in the morning. He had been treated for type 2 diabetes with 0.5 mg glimepiride, with the most recent HbA1c measurement being 5.7%. His plasma glucose level was low (22 mg/dL), and he was in a coma (Japan Coma Scale: 300). Under a diagnosis of hypoglycemic coma caused by sulfonylurea, we dripped 10% glucose solution and administered 50% glucose solution every 1 to 2 h through a peripheral vein, but his hypoglycemia recurred several times. Finally, 50 μg octreotide was subcutaneously injected. Thereafter, hypoglycemia did not recur, and additional injections of 50% glucose solution were not required. The same dose of octreotide was additionally administered after 8 h. In conclusion, the subcutaneous injection of octreotide can be an effective and safe method of treating prolonged hypoglycemia caused by sulfonylureas in the elderly.",
"affiliations": "Department of Internal Medicine, Hokuriku Central Hospital.;Department of Internal Medicine, Hokuriku Central Hospital.;Department of Internal Medicine, Hokuriku Central Hospital.",
"authors": "Nakaya|Masako|M|;Oka|Rie|R|;Miyamoto|Susumu|S|",
"chemical_list": "D001786:Blood Glucose; D013453:Sulfonylurea Compounds; D015282:Octreotide",
"country": "Japan",
"delete": false,
"doi": "10.3143/geriatrics.56.336",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9173",
"issue": "56(3)",
"journal": "Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics",
"keywords": "Hypoglycemia; Octreotide; Sulfonylurea; The elderly",
"medline_ta": "Nihon Ronen Igakkai Zasshi",
"mesh_terms": "D000279:Administration, Cutaneous; D000369:Aged, 80 and over; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D007003:Hypoglycemia; D008297:Male; D015282:Octreotide; D013453:Sulfonylurea Compounds; D016896:Treatment Outcome",
"nlm_unique_id": "7507332",
"other_id": null,
"pages": "336-342",
"pmc": null,
"pmid": "31366755",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of severe sulfonylurea-induced hypoglycemia by the subcutaneous administration of octreotide in an elderly patient with diabetes: A case report.",
"title_normalized": "successful treatment of severe sulfonylurea induced hypoglycemia by the subcutaneous administration of octreotide in an elderly patient with diabetes a case report"
} | [
{
"companynumb": "JP-INDOCO-000052",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GLIMEPIRIDE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Spinal cord haematoma, or haematomyelia, is a rare condition caused by several unusual disease processes. Traumatic events, such as spinal cord injury and surgery or procedures involving the spinal cord, are the most important causes of spinal cord haematoma. Rarely, it is associated with anticoagulation therapy. Irrespective of cause, spinal cord haematoma is considered a neurosurgical emergency and must be treated promptly in order to prevent neurological sequelae. The authors describe the case of a 69-year-old patient taking warfarin in the therapeutic range for a mechanic mitral valve, who developed chest pain with cervical and dorsal radiation, and experienced sudden paraparesis of the limbs. A CT of the spine confirmed haematomyelia. A high index of suspicion, prompt recognition and immediate intervention are essential to prevent major morbidity and mortality from intraspinal haemorrhage.\nThis article reports an unusual presentation of spontaneous spinal haematoma, imposing the careful elaboration of differential diagnoses, which is very important in internal medicine.The description of this low-incidence case allows the scientific community to assist in approaching patients with similar symptoms.The lack of studies about the etiology and treatment of spontaneous spinal haematoma underlines the need for further studies and research in the area in order to increase the scientific evidence on the approach of these patients.",
"affiliations": "Internal Medicine Department, Centro Hospitalar Cova da Beira, EPE, Covilhã, Portugal.;Internal Medicine Department, Centro Hospitalar Cova da Beira, EPE, Covilhã, Portugal.;Internal Medicine Department, Centro Hospitalar Cova da Beira, EPE, Covilhã, Portugal.;Internal Medicine Department, Centro Hospitalar Cova da Beira, EPE, Covilhã, Portugal.;Emergency Department, Centro Hospitalar Cova da Beira, Covilhã, Portugal.",
"authors": "Gomes|Patrícia A|PA|;Cernadas|Eduardo|E|;Sá|Juliana|J|;Brito|Helena|H|;Costa|Ricardo|R|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2018_000887",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2018_000887887-1-6564-1-10-20181211ArticlesSpontaneous Spinal Haemorrhage as a Complication of Oral Anticoagulant Therapy: A Case Report and Literature Review Gomes Patrícia A. 1Cernadas Eduardo 1Sá Juliana 1Brito Helena 1Costa Ricardo 2\n1 Internal Medicine Department, Centro Hospitalar Cova da Beira, EPE, Covilhã, Portugal\n2 Emergency Department, Centro Hospitalar Cova da Beira, Covilhã, Portugal2018 27 12 2018 5 12 00088714 10 2018 09 11 2018 © EFIM 20182018This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseSpinal cord haematoma, or haematomyelia, is a rare condition caused by several unusual disease processes. Traumatic events, such as spinal cord injury and surgery or procedures involving the spinal cord, are the most important causes of spinal cord haematoma. Rarely, it is associated with anticoagulation therapy. Irrespective of cause, spinal cord haematoma is considered a neurosurgical emergency and must be treated promptly in order to prevent neurological sequelae. The authors describe the case of a 69-year-old patient taking warfarin in the therapeutic range for a mechanic mitral valve, who developed chest pain with cervical and dorsal radiation, and experienced sudden paraparesis of the limbs. A CT of the spine confirmed haematomyelia. A high index of suspicion, prompt recognition and immediate intervention are essential to prevent major morbidity and mortality from intraspinal haemorrhage.\n\nLEARNING POINTS\nThis article reports an unusual presentation of spontaneous spinal haematoma, imposing the careful elaboration of differential diagnoses, which is very important in internal medicine.\n\nThe description of this low-incidence case allows the scientific community to assist in approaching patients with similar symptoms.\n\nThe lack of studies about the etiology and treatment of spontaneous spinal haematoma underlines the need for further studies and research in the area in order to increase the scientific evidence on the approach of these patients.\n\nHaematomyeliawarfarinlaminectomyepidural haematomaspinal haematomaspinal cord compressionmyelopathyspinal cord diseaseneurologic deficit\n==== Body\nINTRODUCTION\nSpinal cord spontaneous haematoma (SCSH) is a rare condition which can cause rapid and irreversible neurological impairment. The incidence is reported to be one per 100,000 population per year and represents 0.3–0.9% of all spinal cord lesions[1–7]. The main causes implicated in SCSH are traumatic injuries or complications of spinal medical procedures such as lumbar puncture or epidural anaesthesia. In a few cases, other aetiologies may be involved, such as vascular malformations of the spinal cord, clotting disorders, inflammatory and infectious myelitis, spinal tumours and syringomyelia. However, in 40–50% of cases no aetiological cause can be found and the condition is considered spontaneous[2, 8].\n\nPatients with intramedullary spinal cord haematomas may present with severe spinal pain and significant neurological findings consistent with the level of spinal cord involvement. Sudden spinal pain at the level of the lesion is the first manifestation of SCSH (85%) and presents in some cases with metameric radiation[9]. In 92% of patients, neurological impairment appears simultaneously or sometimes after the pain has started, manifesting as pure sensory syndrome, pure motor hemiparesis or sensorimotor stroke. In some series, neurological impairment started 3.5 hours after the pain had begun[9]. MRI with and without gadolinium is still the investigation of choice for early diagnosis. Successful outcomes depend on early diagnosis, aggressive, emergent surgical treatment and drainage of the haematoma.\n\nCASE DESCRIPTION\nThe authors describe the case of a 69-year-old patient who was admitted to the emergency department with a 6-hour history of epigastric pain without radiation and associated with acute cervical pain with lumbar radiation described as severe. The patient had previously been fitted with a mitral prosthetic valve and was being anticoagulated with warfarin. He denied nausea, vomiting, dyspnoea or other complaints. There was no recent history of trauma. During physical examination, the patient was found to be mildly anxious due to the pain. He was hypertensive with a blood pressure of 160/70 mmHg, heart rate of 70 bpm and a peripheral oxygen saturation of 98% without supplementation, and was afebrile. No relevant differential blood pressure between the arms and legs was observed. Cardiac, pulmonary, abdominal and vascular peripheral examinations were normal. There was no neurological impairment. The pain remained intense despite analgesia, including with morphine. The electrocardiogram and cardiac enzymes were normal. The echocardiogram was negative for valvular prosthetic dysfunction and for abnormalities of myocardial contraction. Blood analysis revealed a leucocyte count of 12,200/μl (normal: 4,000–10,000/μl) with 88.5% neutrophils, a haemoglobin of 15.9 g/dl (normal: 13.6–18.0 g/dl) and a platelet count of 189,000/μl (normal: 1,400,000–440,000/μl). Prothrombin time was 41.0 seconds, INR was 3.2 and D-dimers were 225.0 ng/ml (normal: 0–500 ng/ml). Creatinine was 0.77 mg/dl (normal: <0.9 mg/dl) and C-reactive protein was negative. A normal aortic angio-scan ruled out aortic disease.\n\nFour hours after admission, the patient experienced severe posterior thoracic pain without radiation and began to develop mild motor and sensory deficits in his lower extremities. Symptom severity rapidly progressed, and within 30 min the patient had paraparesis of the limbs (grade 2 in both legs), with bilateral sensory loss to the D1 dermatome level, with normal and symmetrical osteotendinous reflexes. The patient underwent an emergency medullar contrast CT scan which revealed a C5–D2 intracanalicular medullar haematoma (Figs. 1 and 2). At this point, the case was discussed with the neurosurgical team who decided on an emergency transfer to the reference centre for a decompression laminectomy. However, despite the prompt neurosurgical approach, the patient maintained paraparesis of the limbs after the procedure. After 2 months of physical rehabilitation with intensive physiotherapy, the patient achieved only minimal recovery, maintaining a high level of dependence in activities of daily living.\n\nDISCUSSION\nSpinal epidural haematomas were first described by Jackson in 1869[10] and first treated surgically by Bain in 1897[11]. The exact pathophysiology of SCSH is not clearly understood. Some authors maintain that the spontaneous haemorrhage is the result of increased intra-abdominal and intrathoracic pressure which is directly transmitted to the epidural venous plexus leading to rupture[12]. However, this suggestion is controversial because the absence of a valvular venous system at this level results in a low-pressure system. On the other hand, some authors believe that these ruptures have an arterial origin and are due rupture of the radicular arterioles which follow the course of the nerve roots, within the epidural space[13]. However in most case reports, no arterial rupture was seen when the haematoma was surgically removed[1,14]. SCSH usually affects patients between 40 and 80 years of age and has a male predominance (1.5 males for every female)[3,4]. Surgery and trauma are known risk factors for epidural haematomas, with other risk factors being less well-defined. Many authors suggest there is an association between SCSH and arteriovenous malformations, underlying coagulopathy, infectious and inflammatory medullar diseases and hypertension, while some reports indicate that 17–30% of SCSH is related to anticoagulant drug use. Other researchers have mentioned minor trauma, pregnancy, haemophilia and leukaemia as precipitating factors. In 40–60% of cases, there were no identifiable risk factors for haemorrhage[15–17]. In addition, a meta-analysis has suggested that individuals with hypertension do not have an increased risk of SCSH[17]. The cervicothoracic or thoracolumbar regions are the most frequent sites for SCSH with a posterior predominance. This is partly explained by the position of the anterior epidural veins which are anatomically supported by the posterior longitudinal ligament, associated with the fact that the posterior epidural plexus is larger than the ventral[15,16]. There may also be an area of minor resistance that is more susceptible to rupture with small changes in intravenous pressure[15]. The neurological deficits are related to both compression and a secondary inflammatory reaction[14].\n\nSCSHs have a wide spectrum of presentation ranging from radiculopathy to acute quadriplegia. Most patients present with severe back or neck pain, often with a radicular component[17]. The pain is usually followed by progressive motor or sensory deficits. Approximately 37% of patients present with complete sensorimotor deficits[8].\n\nMRI is currently the imaging modality of choice for SCSH diagnosis, with CT of the spinal cord an option if MRI is not possible[3,4,18]. MRI of the spinal cord performed within 24 hours of symptom onset typically shows the haematoma as isointense on T1-weighted images and hyperintense on T2-weighted images[15,17,19]. After 24 hours, the haematoma often appears hyperintense on both T1- and T2-weighted images[15,19]. Chronic haematomas are hypointense on both T1- and T2-weighted images[15]. Sometimes active bleeding into the haematoma will reveal a central area of enhancement when contrast is used.\n\nPrompt treatment is one of the best predictors of a good outcome, and is optimal when delivered within 12–36 hours of symptom onset[2,20–23]. The neurological status of the patient prior to operative intervention is the most important prognostic indicator of long-term outcome[16]. The duration of symptoms, the degree of medullar compression[24] and the metamere impaired (worst in cervical and thoracic areas) are also prognostic factors[25]. Prompt neurosurgical treatment is best performed within the first 12–24 hours of motor impairment, although when motor deficits are minor, it can be delayed for 48 hours[5,8,26]. Some authors suggest that a surgical approach offers no benefits when motor impairment has existed for over 36 hours. The treatment of choice for SCSH typically is a hemilaminectomy or a laminectomy followed by irrigation and debridement[19,27,28]. In the last few years, some case reports describing conservative treatment (control of symptoms and corticoid therapy) have been published[3,8,20]. In some cases, serial MRIs have shown the blood has been reabsorbed, in one case within 4 months[29,30]. Candidate patients for conservative measures are those without neurological symptoms or those who recovered spontaneously within the first few hours of symptom onset. In such patients, meticulous assessment is necessary in order to identify patients at risk of a poor prognosis.\n\nCONCLUSION\nThe rarity of this pathology increases the difficulty of examining underlying risk factors and further study is warranted. Physicians should be aware of the subtle signs of SCSH in the setting of minimal or no clear antecedent trauma and should initiate appropriate imaging and treatment. The authors hope with this case report to raise awareness of SCSH, especially in patients receiving anticoagulant therapy who complain of sudden and unexplained neck or back pain with acute myelopathy.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 CT medullary scan showing a posterior medullar haematoma at the C5–T2 level (red arrow)\n\nFigure 2 CT Medullar Scan showing posterior medullar hematoma at C5 level.\n==== Refs\nREFERENCES\n1 Lo CC Chen JY Lo YK Lai PH Lin YT Spontaneous spinal epidural hematoma: a case report and review of the literatures Acta Neurol Taiwan 2012 21 31 34 22879087 \n2 Paiva WS Amorim RL Rusafa E Taricco MA Bor-Seng-Shu E Figueiredo EG Idiopathic spinal epidural hematoma in patients with sudden paraplegia: a case report Rev Neurol 2008 46 540 542 18446696 \n3 Baek BS Hur JW Kwon KY Lee HK Spontaneous spinal epidural hematoma J Korean Neurosurg Soc 2008 44 40 42 19096655 \n4 Gundag M Hakan M Dogan K Kitis S Ozkan N Spontaneous resolution of paraparesis because of acute spontaneous thoracolumbar epidural hematoma Iran Red Crescent Med J 2012 14 574 577 23115720 \n5 Kim KT Cho DC Ahn SW Kang SH Epidural hematoma related with low-dose aspirin: complete recovery without surgical treatment J Korean Neurosurg Soc 2012 51 308 311 22792431 \n6 Yang SM Kang SH Kim KT Park SW Lee WS Spontaneous spinal epidural hematomas associated with acute myocardial infarction treatment Korean Circ J 2011 41 759 762 22259609 \n7 Nakanishi K Nakano N Uchiyama T Kato A Hemiparesis caused by cervical spontaneous spinal epidural hematoma: a report of 3 cases Adv Orthop 2011 2011 516382 \n8 Gopalkrishnan CV Dhakoji A Nair S Spontaneous cervical epidural hematoma of idiopathic etiology: case report and review of literature J Spinal Cord Med 2012 35 113 117 22333537 \n9 Munõz G Cuello J Rodriguez M Iglesias Mohedano I Dominguez Rubio R Hematoma espinal epidural espontaneo: estudio retrospectivo de una serie de 13 casos Neurología 2015 30 393 400 24839904 \n10 Jackson R A case of spinal apoplexy Lancet 1869 94 2392 5 6 \n11 Bain N A case of haematorrachis Br Med J 1897 2 1912 455 \n12 Bruyn GW Bosma NJ Handbook of clinical neurology Amsterdam North Holland Publishing 1976 \n13 Beatty RM Winston KR Spontaneous cervical epidural hematoma J Neurosurg 1984 61 143 148 6726389 \n14 Varela Rois P González García J Regueira Portas M Martínez Cueto P Azevedo González E Hematomas espinales: la apoplejía espinal Neurología 2010 25 96 103 20487709 \n15 Al-Mutair A Bednar DA Spinal epidural hematoma J Am Acad Orthop Surg 2010 18 494 502 20675642 \n16 Bhat KJ Kapoor S Watali YZ Spontaneous epidural hematoma of spine associated with clopidogrel: a case study and review of the literature Asian J Neurosurg 2015 10 54 25767588 \n17 Bakker NA Veeger NJ Vergeer RA Prognosis after spinal cord and cauda compression in spontaneous spinal epidural hematomas Neurology 2015 84 1894 1903 25862799 \n18 Dziedzic T Kunert P Krych P Management and neurological outcome of spontaneous spinal epidural hematoma J Clin Neurosci 2015 22 726 729 25677879 \n19 Kokubo R Kim K Sugawara A Nomura R Morimoto D Isu T Treatment of spontaneous spinal epidural hematoma No Shinkei Geka 2011 39 947 952 21972183 \n20 Zhong W Chen H You C Spontaneous spinal epidural hematoma J Clin Neurosci 2011 18 1490 1494 21920757 \n21 Torres A Acebes JJ Cabiol J Gabarros A López L Plans G Revisión de 22 casos de hematomas epidurales espinales. Factores pronósticos y manejo terapéutico Neurocirugía (Astur) 2004 15 353 359 15368025 \n22 Park J Lee JB Park JY Lim DJ Kim SD Chung YK Spinal cord infarction after decompressive laminectomy for spontaneous spinal epidural hematoma–case report Neurol Med Chir (Tokyo) 2007 47 325 327 17652921 \n23 Ko JI Kim T Jwa CS Jang JY Jeong KY Suh GJ Spontaneous spinal epidural hematoma presenting as Brown-Sequard syndrome Am J Emerg Med 2013 31 e3 4 \n24 Dimou J Jithoo R Morokoff A Spontaneous spinal epidural haematoma in a geriatric patient on aspirin J Clin Neurosci 2010 17 142 144 19914071 \n25 Haussmann O Kirsch E Radu E Mindermann Th Gratzl O Coagulopathy induced spinal intradural extramedullary haematoma: report of three cases and review of the literature Acta Neurochir (Wien) 2001 143 135 140 11459084 \n26 Morandi X Laurent R Emmanuel C Acute nontraumatic spinal subdural haematoma in three patients Spine 2001 26 547 551 \n27 Yabe H Ishii A Niikawa N Matsubayashi H Kakei M Kawakami M An elderly patient who developed spontaneous spinal epidural hematoma during warfarin therapy Intern Med 2012 51 1429 1432 22687856 \n28 Babayev R Ekşi MŞ Spontaneous thoracic epidural hematoma: a case report and literature review Childs Nerv Syst 2016 32 181 187 26033378 \n29 Tawk C El Hajj Moussa M Zgheib R Spontaneous epidural hematoma of the spine associated with oral anticoagulants: 3 case studies Int J Surg Case Rep 2015 13 8 11 26074484 \n30 Iwatsuki K Deguchi M Hirata H Spontaneously resolved recurrent cervical epidural hematoma in a 37-week primigravida Global Spine J 2015 5 e44 47 26430600 \n31 Yamao Y Takagi Y Kawauchi T Surgical management of recurrent spontaneous spinal epidural hematoma with 3 episodes Spine (Phila Pa 1976) 2015 40 E996 998 26323026\n\n",
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"keywords": "Haematomyelia; epidural haematoma; laminectomy; myelopathy; neurologic deficit; spinal cord compression; spinal cord disease; spinal haematoma; warfarin",
"medline_ta": "Eur J Case Rep Intern Med",
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"pages": "000887",
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"pmid": "30755993",
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"title": "Spontaneous Spinal Haemorrhage as a Complication of Oral Anticoagulant Therapy: A Case Report and Literature Review.",
"title_normalized": "spontaneous spinal haemorrhage as a complication of oral anticoagulant therapy a case report and literature review"
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"abstract": "A 67-year-old man was admitted to the emergency department about 5 h after deliberate self-poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 μg l-1 of Apixaban. The Cmax was observed 17 h after the intake (3654 μg l-1 ), about four times the classical Tmax value (median [range]: 4 h [2-4]). The Apixaban was then eliminated following a first order elimination with a calculated half-life of 10.8 h. The anti-Xa activity seems to be linearly related to concentration up to 4000 μg l-1 . This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake.",
"affiliations": "Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.;Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.;Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.;Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.;Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.;Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.;Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.;Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.;Department of Pharmacology and Toxicology, CHU Limoges, F-87000, Limoges, France.",
"authors": "Franck|Bénédicte|B|;Dulaurent|Sylvain|S|;El Balkhi|Souleiman|S|;Monchaud|Caroline|C|;Picard|Nicolas|N|;Couderc|Sylvain|S|;Marquet|Pierre|P|;Saint-Marcoux|Franck|F|;Woillard|Jean-Baptiste|JB|0000-0003-1695-0695",
"chemical_list": "D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; D013607:Tablets; C522181:apixaban",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13790",
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"mesh_terms": "D000368:Aged; D003863:Depression; D062787:Drug Overdose; D065427:Factor Xa Inhibitors; D006207:Half-Life; D006801:Humans; D008297:Male; D011720:Pyrazoles; D011728:Pyridones; D013607:Tablets",
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"title": "Self-poisoning with 60 tablets of Apixaban, a pharmacokinetics case report.",
"title_normalized": "self poisoning with 60 tablets of apixaban a pharmacokinetics case report"
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"abstract": "Histoplasma capsulatum variety capsulatum (H. capsulatum) is a thermally dimorphic fungus that is endemic to the Mississippi River and Ohio River valley regions. Of the hundreds of thousands of patients exposed to this fungus, less than 1% develop a severe illness most commonly manifesting as pulmonary disease. Septic arthritis from hematogenous seeding with H. capsulatum or from direct inoculation has been reported only rarely in the literature. The first case of septic arthritis of the shoulder due to H. capsulatum occurring in an immunocompromised patient, treated successfully with irrigation and debridement, systemic antifungals, and local delivery of amphotericin B with cement beads, is reported here. Importantly, the addition of local amphotericin B delivery by cement beads to conventional treatment likely led to clinical cure in this patient.",
"affiliations": "Department of Orthopedic Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.;Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.;Department of Orthopedic Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.;Division of Infectious Diseases, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. Electronic address: poorani-sekar@uiowa.edu.",
"authors": "Compton|Jocelyn|J|;Vander Voort|Wyatt|W|;Willey|Michael|M|;Sekar|Poorani|P|",
"chemical_list": "D000935:Antifungal Agents; D018501:Antirheumatic Agents; D000666:Amphotericin B; D008727:Methotrexate",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2018.09.023",
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"issue": "77()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Antifungals; Fungal arthritis; Histoplasma capsulatum; Rheumatoid arthritis; Septic arthritis",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000369:Aged, 80 and over; D000666:Amphotericin B; D000935:Antifungal Agents; D018501:Antirheumatic Agents; D001170:Arthritis, Infectious; D005260:Female; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D016867:Immunocompromised Host; D008727:Methotrexate; D009820:Ohio; D016896:Treatment Outcome",
"nlm_unique_id": "9610933",
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"title": "A case of Histoplasma capsulatum variety capsulatum septic arthritis successfully treated with surgery, systemic antifungals, and local amphotericin cement beads.",
"title_normalized": "a case of histoplasma capsulatum variety capsulatum septic arthritis successfully treated with surgery systemic antifungals and local amphotericin cement beads"
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"abstract": "OBJECTIVE\nCauda equina syndrome (CES) is a well-known complication of spinal and epidural anesthesia. Previous reports have implicated lidocaine, chloroprocaine, and procaine in its etiology, but not bupivacaine.\n\n\nMETHODS\nA 63-year-old man underwent transurethral resection of the prostrate for which he received bupivacaine with glucose intrathecally. Postoperative, he had difficulty in urination and defecation, and magnetic resonance imaging revealed spinal stenosis at the L1-L2 level. The second patient was a 70-year-old woman who underwent hip replacement surgery using a combined spinal-epidural technique. Postoperative, after 42 hours, when the epidural infusion of bupivacaine was stopped, the patient had difficulty in urination and defecation. No anatomical abnormality was found on magnetic resonance imaging.\n\n\nRESULTS\nThe two patients developed cauda equina syndrome following bupivacaine with glucose injected spinally, and bupivacaine without glucose injected in a combined spinal-epidural technique.\n\n\nCONCLUSIONS\nThis case report describes two cases of CES following the use of bupivacaine. The first patient had spinal stenosis which could explain this complication; however the explanation for CES in the second patient is uncertain and consequently speculative. We have discussed the possible contributing factors but believe that the etiology of CES in the second patient remains unknown.",
"affiliations": "Department of Anaesthesiology, Orebro Hospital Medical Center, Sweden.",
"authors": "Kubina|P|P|;Gupta|A|A|;Oscarsson|A|A|;Axelsson|K|K|;Bengtsson|M|M|",
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"issue": "22(5)",
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"mesh_terms": "D000368:Aged; D000767:Anesthesia, Epidural; D000775:Anesthesia, Spinal; D000779:Anesthetics, Local; D019645:Arthroplasty, Replacement, Knee; D002045:Bupivacaine; D002420:Cauda Equina; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010149:Pain, Postoperative; D010523:Peripheral Nervous System Diseases; D011183:Postoperative Complications; D011467:Prostate; D013130:Spinal Stenosis",
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"references": null,
"title": "Two cases of cauda equina syndrome following spinal-epidural anesthesia.",
"title_normalized": "two cases of cauda equina syndrome following spinal epidural anesthesia"
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"activesubstancename": "EPINEPHRINE"
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"abstract": "Anti-programmed cell death-1 receptor/programmed cell death-1 receptor ligand-directed therapies are transforming cancer care, with durable antitumor responses observed in multiple cancer types. Toxicities arising from therapy are autoimmune in nature and may affect essentially any organ system. The immunologic basis of such toxities is complex, with contributions from T-cell activation and autoantibody generation. Although less recognized, hypersensitivity reactions are also possible. Although most toxicities resolve with systemic corticosteroids, some require second-line immunosuppression. Furthermore, the safety of drug rechallenge is not well characterized, with variable rates of toxicity flares arising with re-exposure. Herein, we review toxicities of immune checkpoint inhibitor therapies, particularly focusing on issues that allergists/immunologists may clinically encounter, including interstitial nephritis, skin toxicity, and risks associated with immunotherapy rechallenge.",
"affiliations": "Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn. Electronic address: Douglas.b.johnson@vumc.org.;Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.;Department of Oncodermatology, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France.;Renal Division, Department of Internal Medicine, Massachusetts General Hospital, Boston, Mass.",
"authors": "Johnson|Douglas B|DB|;Jakubovic|Baruch D|BD|;Sibaud|Vincent|V|;Sise|Meghan E|ME|",
"chemical_list": "D060890:B7-H1 Antigen; D007155:Immunologic Factors; D061026:Programmed Cell Death 1 Receptor",
"country": "United States",
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"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Allergy; Anti–PD-1; Anti–PD-L1; Dermatitis; Immune-related adverse event; Nephritis; Rechallenge",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D060890:B7-H1 Antigen; D006801:Humans; D007155:Immunologic Factors; D007167:Immunotherapy; D009369:Neoplasms; D061026:Programmed Cell Death 1 Receptor",
"nlm_unique_id": "101597220",
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"pmid": "32599218",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": "30998826;20525992;25667295;27113507;31449902;27136138;31800340;29746230;29536852;29567210;29289977;30746132;31864416;30540342;32434790;30421306;31118078;28434648;32320734;29442540;28076863;31169866;31332390;29678394;31611368;27806233;30286224;31163011;31672794;29573850;31580492;32009131;26633184;30125216;32302769;29518427;27687304;32043780;31730012;26798465;29718308;29975414;26837003;30242316;32454097;30399387;31896554;27256570;24052222;30992053;27540850;31021392;28687658;31233857;28918974;26895621;29123955;31562797;29803289;29045547;32043028;29262275;29162153;26317459;29320654;31154457;28241095;31343665;30025829;26027431;24695685;31189043;31540935;31981081;30885563;31699151;27646942;29567705;31390169;32353870;31216228;30612580;30442497;30677306",
"title": "Balancing Cancer Immunotherapy Efficacy and Toxicity.",
"title_normalized": "balancing cancer immunotherapy efficacy and toxicity"
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"abstract": "Attention-deficit/hyperactivity disorder is commonly treated with amphetamines as first line therapy. Rare case reports have shown amphetamines are associated with open angle glaucoma. We report a rare case of a 14-year-old male who presented with bilateral acute angle closure presumed to be related to his use of lisdexamfetamine dimesylate (Vyvanse). The patient's medication was discontinued which resulted in complete resolution of angle closure.",
"affiliations": "Vanderbilt Eye Institute.;Vanderbilt Eye Institute.;Vanderbilt University Medical Center, Nashville, TN, Vanderbilt.;Vanderbilt University Medical Center, Nashville, TN, Vanderbilt.;Vanderbilt Eye Institute.",
"authors": "Davanian|Arash M|AM|;Fitzpatrick|John C|JC|;Tran|Duy P|DP|;Korducki|John P|JP|;Groth|Sylvia L|SL|",
"chemical_list": "D000697:Central Nervous System Stimulants; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine",
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"issue": "30(5)",
"journal": "Journal of glaucoma",
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"medline_ta": "J Glaucoma",
"mesh_terms": "D000293:Adolescent; D000697:Central Nervous System Stimulants; D002648:Child; D003913:Dextroamphetamine; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D000069478:Lisdexamfetamine Dimesylate; D008297:Male; D016896:Treatment Outcome",
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"title": "Bilateral Acute Angle Closure in a Pediatric Patient Taking Lisdexamfetamine Dimesylate (Vyvanse).",
"title_normalized": "bilateral acute angle closure in a pediatric patient taking lisdexamfetamine dimesylate vyvanse"
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"abstract": "Acute pericarditis generally follows a mild clinical course and is rarely fatal. Coronary vein involvement is rarely reported.\nWe report an autopsy case of cardiac tamponade from idiopathic myopericarditis due to coronary venous perforation under the triple antithrombotic therapy. A 69-year-old man was admitted to our hospital with abnormal findings on electrocardiography, bloody pericardial effusion, and mild elevation of troponin I. Oral anti-inflammatories were started and the patient followed a benign course. However, on hospital Day 5, he suddenly suffered cardiogenic shock with pulseless electric activity due to cardiac tamponade under the combination use of the dual antiplatelet drugs and an anticoagulant drug. He died despite intense medical treatment. Autopsy revealed cardiac tamponade caused by perforation in the coronary venous wall. To the best of our knowledge, this is the first description of fatal myopericarditis as a complication of coronary venous perforation.\nThe aetiology and mechanism remain unknown; however, we should take care for this rare complication in patients with acute myopericarditis and bloody effusion under the triple antithrombotic therapy.",
"affiliations": "Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.;Department of Pathology, Matsusaka Central Hospital, Kobo 102, Kawai-machi, Matsusaka, Mie 515-8566, Japan.;Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.",
"authors": "Takasaki|Akihiro|A|https://orcid.org/0000-0003-0641-6464;Okamoto|Ryuji|R|https://orcid.org/0000-0002-8067-398X;Sugimoto|Hiroko|H|;Dohi|Kaoru|K|https://orcid.org/0000-0002-5078-6326",
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"doi": "10.1093/ehjcr/ytab098",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n34124546\n10.1093/ehjcr/ytab098\nytab098\nCase Report\nOther\nAcademicSubjects/MED00200\nFatal myopericarditis complicated with coronary vein perforation under the triple antithrombotic therapy: a case report\nhttps://orcid.org/0000-0003-0641-6464\nTakasaki Akihiro 12\nhttps://orcid.org/0000-0002-8067-398X\nOkamoto Ryuji 1\nSugimoto Hiroko 3\nhttps://orcid.org/0000-0002-5078-6326\nDohi Kaoru 1\n1 Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan\n2 Department of Cardiology, Matsusaka Central Hospital, Kobo 102, Kawai-machi, Matsusaka, Mie 515-8566, Japan\n3 Department of Pathology, Matsusaka Central Hospital, Kobo 102, Kawai-machi, Matsusaka, Mie 515-8566, Japan\nAraiza-Garaygordobil Diego Handling Editor\nConte Edoardo Editor\nBegic Edin Editor\nTardo Daniel Editor\nThomson Ross Editor\nCorresponding author. Tel: +81-59-231-5015, Fax: +81-59-231-5201, Email: ryuji@clin.medic.mie-u.ac.jp\n4 2021\n24 4 2021\n24 4 2021\n5 4 ytab09808 11 2020\n25 11 2020\n26 2 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (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.com\n\nAbstract\n\nBackground \n\nAcute pericarditis generally follows a mild clinical course and is rarely fatal. Coronary vein involvement is rarely reported.\n\nCase summary \n\nWe report an autopsy case of cardiac tamponade from idiopathic myopericarditis due to coronary venous perforation under the triple antithrombotic therapy. A 69-year-old man was admitted to our hospital with abnormal findings on electrocardiography, bloody pericardial effusion, and mild elevation of troponin I. Oral anti-inflammatories were started and the patient followed a benign course. However, on hospital Day 5, he suddenly suffered cardiogenic shock with pulseless electric activity due to cardiac tamponade under the combination use of the dual antiplatelet drugs and an anticoagulant drug. He died despite intense medical treatment. Autopsy revealed cardiac tamponade caused by perforation in the coronary venous wall. To the best of our knowledge, this is the first description of fatal myopericarditis as a complication of coronary venous perforation.\n\nDiscussion \n\nThe aetiology and mechanism remain unknown; however, we should take care for this rare complication in patients with acute myopericarditis and bloody effusion under the triple antithrombotic therapy.\n\nCase report\nPericardial disease\nCoronary vein\nTriple antithrombotic therapy\n==== Body\nLearning points\n\nCoronary vein perforation is a rare complication of myopericarditis whilst on antithrombotic therapy, presenting as a haemorrhagic pericardial effusion.\n\nIntroduction\n\nAcute pericarditis generally follows a mild clinical course and is rarely fatal.1 Herein, a severe case of acute myopericarditis is reported presenting with blood pericardial effusion leading to uncontrollable cardiac dysfunction and death. Autopsy revealed perforation of the coronary vein due to acute inflammation. Although the underlying mechanisms remain unclear, this appears to represent the first description of fatal myopericarditis complicated by coronary vein perforation.\n\nTimeline\n\n\tPast history of percutaneous coronary intervention for angina pectoris, surgical resection of rectal cancer, and lung metastatic cancer\n\nMedications included low-dose aspirin, cilostazol, valsartan, and cilnidipine\n\n\t\nTwo weeks before admission\tAnterior chest discomfort+\t\nOne week before admission\tAsymptomatic, normal electrocardiography (ECG)\t\nOn admission\tAsymptomatic, pericardial friction rub +, ST-elevation in almost all leads in ECG\n\nC-reactive protein and troponin I were increased, at 2.97 mg/dL and 1995 pg/mL\n\nMild pericardial effusion with attenuation indicating blood constituent\n\nTreatment including aspirin (750 mg every 8 h) and colchicine (0.5 mg/day)\n\n\t\nThree days after admission\tParoxysmal atrial fibrillation+\n\nTreatment including rivaroxaban (15 mg/day): triple antithrombotic therapy+\n\n\t\nFive days after admission\tC-reactive protein and troponin I were reduced, at 0.44 mg/dL and 1718 pg/mL\n\nThe unchanged volume of pericardial effusion\n\nHe abruptly complained of severe chest discomfort and cardiogenic shock developed due to cardiac tamponade\n\nUrgent first and last pericardiocentesis was performed and confirmed haemorrhagic effusion\n\nHe died after bloody drainage and cardiac dysfunction were continued\n\n\t\nAutopsy\tThe oozing site led to the coronary sinus, perforation of the coronary vein\n\nChronic changes including mild fibrosis in pericardial and myocardial tissues around the perforated site\n\n\t\n\nCase presentation\n\nA 69-year-old man presented to our outpatient department complaining of anterior chest discomfort, which had intermittently continued for a week. Because the symptom was improving and blood testing and electrocardiography (ECG) showed no abnormalities, he returned home, and visited a doctor again 1 week later. He had a history of successful percutaneous coronary stenting for angina pectoris (10 years ago), surgical resection of rectal cancer (6 years ago), and lung metastatic cancer (5 years ago). Medications included low-dose aspirin (100 mg/day), cilostazol (200 mg/day), valsartan (80 mg/day), and cilnidipine (10 mg/day). He visited our outpatient department without any symptoms during the preceding week. However, auscultation revealed pericardial friction rub and ECG showed ST-elevation in I, II, III, aVF, and V2 to V6 leads (Figure 1A). Laboratory evaluation revealed elevated C-reactive protein (CRP) level of 2.97 mg/dL (normal, ≤0.30 mg/dL) and troponin I level of 1995 pg/mL (normal, ≤26.2 pg/mL). Creatine phosphokinase (CPK) was within normal limits. On admission, the patient showed no symptoms with a blood pressure of 133/84 mmHg, temperature of 35.0°C, heart rate of 68 b.p.m., respiratory rate of 15 breaths/min, and oxygen saturation of 98% in room air.\n\nFigure 1 (A) ST-T changes on electrocardiography on admission (Day 1). (B) Chest computed tomography demonstrates mild pericardial effusion (Day 1). (C) Perforation of the coronary vein is apparent in the inferior wall in the autopsied heart (arrow). Please note fragile tissue of the cardiac surface with many petechiae. (D–G) Site of perforation in the coronary vein in the pathological examination (arrowhead). (E, G) Magnification of the boxed area. (H) Infiltration of lymphocytes and (I) macrophages containing haemosiderin around the perforated site.\n\nTransthoracic echocardiography showed circumferential mild pericardial effusion without any findings of cardiac tamponade including swinging heart and diastolic collapse of right atria and ventricle (Video 1). Coronary angiography revealed no significant stenosis. Computed tomography (CT) also revealed mild pericardial effusion with attenuation of ∼60 Hounsfield units (HU), indicating blood constituent (Figure 1B). Acute pericarditis and pericardial effusion with minor injury in cardiac muscle were diagnosed. Treatment including aspirin (750 mg every 8 h) and colchicine (0.5 mg/day) was started according to pericardial disease management guidelines.2 On hospital Day 3, paroxysmal atrial fibrillation (AF) lasting 20 min was recognized, although the patient was asymptomatic. A regular dose (15 mg/day) of rivaroxaban was added to his medications.\n\nOn hospital Day 5, laboratory evaluation revealed that CRP and troponin I were reduced, at 0.44 mg/dL and 1718 pg/mL, respectively. However, the volume of pericardial effusion was unchanged on echocardiography. The patient abruptly complained of severe chest discomfort and cardiogenic shock developed, accompanied by systolic blood pressure of 50–59 mmHg and a heart rate of 155 b.p.m. of AF. He suffered cardiogenic shock with pulseless electric activity due to cardiac tamponade despite synchronized cardioversion. Urgent pericardiocentesis was performed and confirmed haemorrhagic effusion. Percutaneous cardiopulmonary support was introduced immediately, and intra-aortic balloon pumping was also started, because return of spontaneous circulation was not obtained.\n\nBloody drainage and cardiac dysfunction were continued. Despite extensive medical treatment including blood transfusion, heart rate, and blood pressure gradually decreased without any ventricular arrhythmia and the patient finally died 12 h after onset of cardiogenic shock.\n\nAutopsy revealed a drainage tube placed in the posterior side of the pericardial cavity and ∼690 mL of blood retained there. Culture and polymerase chain reaction yielded negative results for bacterial infection. The heart weighed 520 g and exhibited many petechiae on the fatty tissue of the inferoposterior wall. In addition, blood oozing was identified on manual compression (Figure 1C, Video 2). Because the oozing site led to the coronary sinus, perforation of the coronary vein was identified. Microscopically, the perforated site was confirmed in the coronary venous wall as expected (Figures 1D–G). Lymphocytic infiltration (Figure 1H), macrophages containing haemosiderin (Figure 1I) and mild fibrosis were detected in pericardial and myocardial tissues only around the perforated site. The coronary vein was considered to have been perforated a few days earlier based on the presence of fibrosis.\n\nDiscussion\n\nThe two major indicators of poor prognosis in acute pericarditis are reportedly the existence of cardiac tamponade and the failure of anti-inflammatory drugs.3 Indeed, the present case was accompanied by cardiac tamponade and failure of aspirin and colchicine treatment. It is important for us to be more careful when encountering such patients with acute pericarditis.\n\nComputed tomography on admission revealed mild pericardial effusion with 60 HU. Hounsfield units >30 in pericardial effusion has been reported to have a sensitivity of 100% and specificity of 70% for visceral or vascular rupture.4 Haemorrhagic pericardial effusion is caused by several diseases including cardiac rupture due to myocardial infarction or trauma, impending aortic rupture, iatrogenic injury of coronary artery and veins, which were excluded by the clinical history and the histological examination.\n\nIn the present case, the cause of death was identified as cardiac tamponade and dysfunction due to coronary venous perforation complicating myopericarditis.\n\nPericarditis and myocarditis share common aetiologies and overlap in daily clinical practice. According to European Society of Cardiology Task Force consensus, our patient met the criteria for pericarditis plus mild elevation of markers of myocardial damage without focal or diffuse impairment of left ventricular function on echocardiography, and we diagnosed ‘myopericarditis’.2 Damage to the myocardium was limited to within the surface area, with no elevation of CPK recognized during the clinical course and autopsy ruled out active myocarditis. Negative results from culture excluded the possibility of purulent pericarditis.\n\nThe use of rivaroxaban in addition to aspirin and cilostazol might have exacerbated damage to the coronary vein wall due to myopericarditis. However, no other common bleeding events such as gastrointestinal and/or subcutaneous bleeding were observed. It remains unclear whether we should or should not start anticoagulant drugs when paroxysmal AF is observed in patients with pericarditis and pericardial effusion with high HU in CT images.\n\nViral infections are among the most common causes of myopericarditis. Other mechanisms causing myopericarditis include connective tissue diseases, radiation-induced, drug-induced, or vaccine-associated diseases.2 Any preceding viral illness was not reported by the patient and blood tests showed no evidence of connective tissue diseases.\n\nThe patient had undergone low anterior resection due to rectal cancer 6 years earlier, thoracoscopic resection of metastases in the left lung inferior lobe followed by chemotherapy including bevacizumab (a vascular endothelial growth factor inhibitor) and radiofrequency ablation therapy 3 years earlier. Therefore, it is impossible to rule out the possibility completely that chemotherapy and radiofrequency ablation therapy had induced chronic inflammation in the pericardium or surface of the myocardium. Although coronary veins can be involved by pericardial metastatic cancer,5 the tumour cells were not identified histologically and cytologically. The thickening of the pericardium, which is an important sign of chronic radiation-induced pericarditis,6 was not recognized on chest CT image 3 months before the admission and not in autopsy specimen. Therefore, it is unlikely that coronary vein perforation was associated with chronic inflammatory response due to metastasis or radiation.\n\nCoronary venous perforation is an extremely rare entity and only several cases have been reported as a complication of catheterization and percutaneous coronary intervention.7 Perforation of the coronary vein was estimated to be induced by both inflammation of myopericarditis and the combined use of rivaroxaban, aspirin, and cilostazol.\n\nIn conclusion, our case presented with fatal myopericarditis (pericarditis plus minor cardiac muscle injury) complicated by coronary vein perforation. The aetiology and mechanisms underlying extensive focal damage to superficial tissue around the coronary vein remain unclear. It is important to take this rare complication into consideration when we see patients with pericarditis and uncontrollable cardiac tamponade and dysfunction due to bloody effusion under the triple antithrombotic therapy.\n\nLead author biography\n\nAkihiro Takasaki is a cardiologist at Mie University Hospital, Mie, Japan. He is currently undertaking a PhD with the Mie University, exploring familial hypercholesterolaemia using the Acute Coronary Registry data in Mie prefecture.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient's next of kin in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab098_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 Imazio M , BrucatoA, BarbieriA, FerroniF, MaestroniS, LigabueG et al Good prognosis for pericarditis with and without myocardial involvement: results from a multicenter, prospective cohort study. Circulation 2013;128 :42–49.23709669\n2 Adler Y , CharronP, ImazioM, BadanoL, Baron-EsquiviasG, BogaertJ, ESC Scientific Document Group et al 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: the task force for the diagnosis and management of pericardial diseases of the European Society of Cardiology (ESC). Endorsed by: the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015;36 :2921–2964.26320112\n3 Imazio M , CecchiE, DemichelisB, IernaS, DemarieD, GhisioA et al Indicators of poor prognosis of acute pericarditis. Circulation 2007;115 :2739–2744.17502574\n4 Rifkin RD , MernoffDB. Noninvasive evaluation of pericardial effusion composition by computed tomography. Am Heart J 2005;149 :1120–1127.15976797\n5 Thurber DL , EdwardsJE, AchorRW. Secondary malignant tumors of the pericardium. Circulation 1962;26 :228–241.14037856\n6 Cuomo JR , SharmaGK, CongerPD, WeintraubNL. Novel concepts in radiation-induced cardiovascular disease. World J Cardiol 2016;8 :504–519.27721934\n7 Nomura T , KikaiM, HoriY, YoshiokaK, KubotaH, MiyawakiD et al Bizarre sequela with cardiac venous perforation after percutaneous coronary intervention. JACC Cardiovasc Interv 2017;10 :e95–e96.28456698\n\n",
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"issue": "5(4)",
"journal": "European heart journal. Case reports",
"keywords": "Case report; Coronary vein; Pericardial disease; Triple antithrombotic therapy",
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"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
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"title": "Fatal myopericarditis complicated with coronary vein perforation under the triple antithrombotic therapy: a case report.",
"title_normalized": "fatal myopericarditis complicated with coronary vein perforation under the triple antithrombotic therapy a case report"
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"abstract": "The incidence of cutaneous and subcutaneous metastases from atypical laryngeal carcinoids is approximately 20%. However, the pathogenesis and natural history of, and prognostic factors for, the condition remain poorly understood. We reported a 54-year-old female presented with cutaneous and subcutaneous metastases from atypical laryngeal carcinoid. Laryngoscopy revealed a 0.5 × 1.5-cm reddish mass on the laryngeal surface of the epiglottis. Under general anesthesia, a biopsy sample was obtained via suspension laryngoscopy. Routine pathology revealed atypical laryngeal carcinoid. Immunohistochemical staining of the sections of primary tumor was positive for cytokeratin, chromogranin A, synaptophysin, hypoxia-inducible factor-1α, P53, and CD56. GLUT-1, p-Akt, and PI3K were negative. The Ki-67 index was 15%. Supraglottic laryngectomy and selective right-neck dissection were performed. After 6 months, the patient complained of pain in the right wall of the chest; multiple cutaneous and subcutaneous nodules were evident at that site and in the abdomen. An abdominal nodule was biopsied and pathology revealed that the atypical metastatic carcinoid had metastasized to both cutaneous and subcutaneous areas of the abdomen. Chemotherapy was then prescribed. Currently, the intrathecal drug delivery system remains in place. No local recurrence has been detected. Furthermore, we systematically reviewed clinical manifestations of the disease, pathogenesis, prognostic factors, and treatment. The metastasis rate (cutaneous and subcutaneous) was approximately 12.2%. Thirty patients (62.5%) with cutaneous and subcutaneous metastases exhibited contemporaneous lymph node invasion. The 3-, 5-, and 10-year survival rates were 44.0%, 22.0%, and 13.0%, respectively. The prognosis of patients with atypical laryngeal carcinoids was poor. Relevant prognostic factors included the level of p53, human papilloma virus status, certain hypoxic markers, and distant metastasis. No optimal treatment for such metastases has yet been defined.",
"affiliations": "From the Department of Anaesthesia (K-RW, Z-YF); Department of Otolaryngology (Y-JJ, S-HZ, Q-YW, Y-YB); Department of Pathology (H-TY); and State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, China (JF).",
"authors": "Wang|Kui-Rong|KR|;Jia|Yuan-Jing|YJ|;Zhou|Shui-Hong|SH|;Wang|Qin-Ying|QY|;Bao|Yang-Yang|YY|;Feng|Zhi-Ying|ZY|;Yao|Hong-Tian|HT|;Fan|Jun|J|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2688662910.1097/MD.0000000000002796027966000Research ArticleClinical Case ReportCutaneous and Subcutaneous Metastases From Atypical Laryngeal Carcinoids Case Report and Review of the LiteratureWang Kui-Rong PhDJia Yuan-Jing BMZhou Shui-Hong PhDWang Qin-Ying MMBao Yang-Yang MMFeng Zhi-Ying PhDYao Hong-Tian BMFan Jun MMLin. Yung-Song From the Department of Anaesthesia (K-RW, Z-YF); Department of Otolaryngology (Y-JJ, S-HZ, Q-YW, Y-YB); Department of Pathology (H-TY); and State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, China (JF).Correspondence: Shui-Hong Zhou, Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province 310003, China (e-mail: zhouyunzhoush@163.com).2 2016 18 2 2016 95 7 e27966 11 2015 4 12 2015 20 1 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nThe incidence of cutaneous and subcutaneous metastases from atypical laryngeal carcinoids is approximately 20%. However, the pathogenesis and natural history of, and prognostic factors for, the condition remain poorly understood. We reported a 54-year-old female presented with cutaneous and subcutaneous metastases from atypical laryngeal carcinoid. Laryngoscopy revealed a 0.5 × 1.5-cm reddish mass on the laryngeal surface of the epiglottis. Under general anesthesia, a biopsy sample was obtained via suspension laryngoscopy. Routine pathology revealed atypical laryngeal carcinoid. Immunohistochemical staining of the sections of primary tumor was positive for cytokeratin, chromogranin A, synaptophysin, hypoxia-inducible factor-1α, P53, and CD56. GLUT-1, p-Akt, and PI3K were negative. The Ki-67 index was 15%. Supraglottic laryngectomy and selective right-neck dissection were performed. After 6 months, the patient complained of pain in the right wall of the chest; multiple cutaneous and subcutaneous nodules were evident at that site and in the abdomen. An abdominal nodule was biopsied and pathology revealed that the atypical metastatic carcinoid had metastasized to both cutaneous and subcutaneous areas of the abdomen. Chemotherapy was then prescribed. Currently, the intrathecal drug delivery system remains in place. No local recurrence has been detected. Furthermore, we systematically reviewed clinical manifestations of the disease, pathogenesis, prognostic factors, and treatment. The metastasis rate (cutaneous and subcutaneous) was approximately 12.2%. Thirty patients (62.5%) with cutaneous and subcutaneous metastases exhibited contemporaneous lymph node invasion. The 3-, 5-, and 10-year survival rates were 44.0%, 22.0%, and 13.0%, respectively.\n\nThe prognosis of patients with atypical laryngeal carcinoids was poor. Relevant prognostic factors included the level of p53, human papilloma virus status, certain hypoxic markers, and distant metastasis. No optimal treatment for such metastases has yet been defined.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nLaryngeal neuroendocrine carcinomas (NECs) are rare, constituting <1% of all tumors of the larynx. Four histological subtypes are distinguished based on the extent of differentiation and cell size. Well and moderately differentiated NECs are termed typical and atypical carcinoids, respectively. Poorly differentiated NCLs are divided into small- and large-cell NECs.1,2 The most frequent laryngeal NEC is the atypical carcinoid, followed by small-cell NEC, carcinoid tumor, and large-cell NEC.3\n\nThe prognosis of laryngeal NEC varies by histopathological type.2 A meta-analysis of 436 patients with laryngeal NECs found that the 5-year disease-specific survival was 100% for patients with typical carcinoids, 53% for those with atypical carcinoids, and 19% for those with small-cell carcinomas. Prognostic factors included distant metastasis. An atypical carcinoid of the larynx is a more aggressive type of NEC, often associated with multiple distant metastases.4,5 Metastatic sites include the cervical and distant lymph nodes, lung, bones, skin, subcutaneous tissues, mediastinum, liver, heart, pancreas, diaphragm, peritoneum, gastrointestinal tract, prostate, breast, brain, dura mater, pleura, testicles, and muscles.4 Lymph node metastases are the most common (40%), followed by skin and subcutaneous metastases (20%), and metastases at other sites (40%).6–8 The prognoses of patients with atypical laryngeal carcinoids are relatively poor; the 5-year survival rate is approximately 50%. Death is usually caused by metastatic disease rather than local recurrence.4 Although the incidence of cutaneous and subcutaneous metastases from atypical laryngeal carcinoids is approximately 20%, few systematic analyses of clinical manifestations or treatment of such metastases have been reported. The precise means by which distant metastasis and local recurrence develop remain unclear, as do relevant prognostic factors.\n\nTo date, the only effective treatment appears to be surgery. The disease is refractory to chemotherapy, and any role for radiotherapy is controversial.9 Thus, new treatments are required to improve long-term survival. Targeted therapies have recently been used to treat other cancers,10,11 including NECs of other sites. Targets include vascular endothelial growth factor, platelet-derived growth factor, and the mammalian target of rapamycin; such treatments have improved the progression-free survival times of patients with pancreatic NEC, pulmonary large-cell-type NEC, and prostate NEC.12–14 However, no report on targeted therapy of laryngeal NEC has yet been described.\n\nOur previous study15 and additional work16 have shown that positron emission tomography/computed tomography (PET/CT) detected high-level uptake of [18F]-fluoro-2-deoxy-d-glucose (FDG) by laryngeal NECs, as is also true of other head-and-neck cancers.17–20 Many studies have found that FDG uptake is associated with overexpression of glucose transporter-1 (GLUT-1),20–23 which is associated with metastasis and poor prognosis of many human cancers.22,24,25 NECs also express high levels of GLUT-126–28 with certain biological consequences.26 We previously found that targeted inhibition of GLUT-1 decreased glucose uptake by, and inhibited proliferation of, Hep-2 cells,29 and enhanced the radiosensitivity of laryngeal carcinoma Hep-2 cells.30 Thus, we proposed that GLUT-1 targeting may be useful for the treatment of laryngeal NECs.\n\nHere, we report a patient exhibiting cutaneous and subcutaneous metastases from an atypical laryngeal carcinoid and review clinical manifestations, possible pathogenesis, prognostic factors, and treatments. We measured the levels of GLUT-1 mRNA and protein, and screened for human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein–Barr virus (EBV).\n\nCASE REPORT\nPresenting Concerns\nA 54-year-old female presented with a sore throat and radiating pain in the right ear lasting over 1 year in duration. She denied hoarseness, respiratory distress, dysphagia, and fever. Her past medical history included hypertension during the 3 years prior, blood pressure was controlled by oral irbesartan (10 mg, per day).\n\nClinical Findings\nLaryngoscopy revealed a 0.5 × 1.5-cm reddish mass on the laryngeal surface of the epiglottis (Figure 1). Movements of both vocal cords were normal. Magnetic resonance imaging (MRI) revealed a 0.8 × 1.3-cm lesion in the epiglottis. T1-weighted imaging was isointense; T2-weighted imaging hyperintense; and diffusion-weighted imaging of high signal intensity. The lesion underwent heterogeneous enhancement following administration of gadolinium-DTPA (Figure 2). However, the preoperative PET/CT was not done.\n\nFIGURE 1 Laryngoscopy revealed a 0.5 × 1.5-cm reddish mass on the laryngeal surface of the epiglottis.\n\nFIGURE 2 MRI revealed a 0.8 × 1.3-cm lesion in the epiglottis. T1-weighted imaging was isointense (A), but T2-weighted imaging was hyperintense (B). diffusion-weighted imaging exhibited high signal intensity (C). The apparant diffusion coefficient value was 0.741 × 10−3 mm2/s (D). The lesion exhibited heterogeneous enhancement (E). MRI = magnetic resonance imaging.\n\nThe institutional review board (IRB no.2015427) of The First Affiliated Hospital, College of Medicine, Zhejiang University (Hangzhou City, China) approved the present study. Written informed consent was obtained from the patient before inclusion.\n\nTherapeutic Focus and Assessment\nThe process of the patient received was listed in Table 1. Under general anesthesia, a biopsy sample was obtained via suspension laryngoscopy. Analysis of the frozen section suggested that only a small-cell tumor was present; therefore, it was necessary to immunohistochemically differentiate a myoepithelial tumor from an atypical carcinoma. Routine pathology revealed that the tumor cells were uniform in size, exhibited marked heteromorphy, had an eosinophilic cytoplasm, and were arranged into nests and cords containing prominent blood sinuses. Immunohistochemical staining of the sections of primary tumor was positive for cytokeratin, chromogranin A, synaptophysin, hypoxia-inducible factor-1α (HIF-1α), P53, and CD56. GLUT-1, p-Akt, and PI3K were negative. The Ki-67 index was 15% (Figure 3). These histopathological features confirmed the presence of an atypical carcinoid. On May 7th 2014, supraglottic laryngectomy and selective right-neck dissection were performed under general anesthesia (Figure 4). Postoperatively, the histopathological features of paraffin sections were confirmed to be those of an atypical carcinoid; the right cervical lymph nodes and the resection margin were negative. The pathological diagnosis was pT2N0M0. The postoperative course was uneventful; no surgical morbidity was evident. Postoperative radiotherapy was not scheduled.\n\nTABLE 1 Timeline\n\nFIGURE 3 Pathology revealed that the tumor cells were uniform in size, markedly heteromorphic with eosinophilic cytoplasm, and formed nests and cords containing prominent blood sinuses (A) (HE × 200). Immunohistochemical staining was positive for hypoxia-inducible factor-1α (HIF-1α) (B) and p53 (C) (EliVision, ×200).\n\nFIGURE 4 Surgical section revealed a reddish lesion in the laryngeal surface of the epiglottis.\n\nFollow-Up and Outcomes\nThe patient received regular monthly follow-ups. On October 9th 2014, PET/CT revealed no recurrence or distant metastasis. In November 2014, the patient complained of pain in the right wall of the chest; multiple cutaneous and subcutaneous nodules were evident at that site and in the abdomen (Figure 5). An abdominal nodule was biopsied and pathology revealed that the atypical metastatic carcinoid had metastasized to both cutaneous and subcutaneous areas of the abdomen. Chemotherapy was then prescribed (capecitabine, 100 mg orally/day and 150 mg orally/night, days 1–14; and temozolomide, 300 mg orally/day, days 2–5). However, even after 2 cycles of chemotherapy, the nodules did not shrink in size and, indeed, several new cutaneous and subcutaneous metastases developed. Pain was not resolved by chemotherapy but was relieved with oral oxycontin. Another chemotherapy regime was then prescribed (octreotide, 30 mg intramuscularly, 1 dose). However, this did not control the pain (scored using a visual analog scale as 6) from the multiple nodules. Pain was relieved with the aid of an intrathecal drug delivery system (ropivacaine, 4 mL + ketamine, 60 mg + morphine, 160 mg; maintenance dose, 6 mg/day). On May 20th 2015, MRI revealed a metastasis in the lumbar vertebrae. Hence, a new chemotherapeutic regime was prescribed (2 cycles: irinotecan, 350 mg/m2 by intravenous infusion); the nodules did not respond. Currently, the intrathecal drug delivery system remains in place. No local recurrence has been detected.\n\nFIGURE 5 Multiple cutaneous and subcutaneous nodules were evident in the right wall of the chest (A) and the abdomen (B).\n\nGLUT-1, HIF-1α, p-Akt, and PI3K mRNA levels of frozen tissues of primary tumor and precancerous lesion (laryngeal papilloma) as control were measured using real-time reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the expression of GLUT-1, p-Akt, and PI3K mRNA was higher in the atypical carcinoid than in precancerous lesion and in the laryngeal squamous cell carcinoma (Figure 6). GLUT-1, HIF-1α, p-Akt, and PI3K protein levels were analyzed using a BAC Protein Quantification Kit and Western blot analysis. The results showed that the expression of GLUT-1, p-Akt, and PI3K proteins was higher in the atypical carcinoid and in the laryngeal squamous cell carcinoma than in precancerous lesion; however, there is no difference in expression between in the atypical carcinoid and in the laryngeal squamous cell carcinoma (Figure 7). HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 59, and 68 types), CMV, and EBV DNAs were detected by quantitative fluorescence PCR. During the detection of HPV, H2O was used as a negative control and an immunodeficiency virus containing the target gene was the positive control. During the detection of CMV, a CMV-negative sample was the negative control and HCMV AD-169 standard strain was the positive control. During the detection of EBV, saline was the negative control and clinical isolates of the EB virus were the positive control. In all viral detection assays, samples from healthy controls were also included. The results revealed that HPV, CMV, and EBV DNAs were negative. Each primer sample was run in triplicate.\n\nFIGURE 6 RT-PCR showed that the expression of GLUT-1 (A), HIF-1α (B), p-Akt (C), and PI3K (D) mRNA were high than these in precancerous lesion and laryngeal squamous cell carcinoma. Akt = protein kinase B, GLUT-1 = glucose transporter-1, HIF-1α = hypoxia-inducible factor-1α, PI3K = phosphatidylinositol 3-kinase, RT-PCR = reverse transcription-polymerase chain reaction.\n\nFIGURE 7 Western blot analysis showed that the expression of GLUT-1, HIF-1α, p-Akt, and PI3K proteins were high than these in precancerous lesion and laryngeal squamous cell carcinoma. Akt = protein kinase B, GLUT-1 = glucose transporter-1, HIF-1α = hypoxia-inducible factor-1α, PI3K = phosphatidylinositol 3-kinase.\n\nDISCUSSION\nAn atypical laryngeal carcinoid is the most common nonsquamous cell carcinoma of the larynx. The tumor is aggressive and the prognosis relatively poor compared to a laryngeal carcinoid. However, the pathogenesis and natural history of, and prognostic factors for, the condition remain poorly understood.\n\nOnly 2 reports have explored HPV status in patients with laryngeal NECs.31,32 Giordano et al (2009)31 found no HPV DNA in a patient with a moderately differentiated laryngeal NEC (an atypical carcinoid). Halmos et al (2013)32 described 2 patients who were positive for the high-risk type of HPV (hrHPV) (1 atypical laryngeal carcinoid patient was positive for HPV 18, and 1 patient with a laryngeal small-cell NEC was positive for HPV 16). Both patients experienced relatively good outcomes compared to those of another 5 patients. It was therefore suggested that hrHPV involvement in laryngeal NECs may be associated with good prognoses. We also detected hrHPV in our current patient. We were the first to explore CMV and EBV DNA status in patients with laryngeal NECs. Such patients were negative for hrHPV, CMV, and EBV DNAs. Therefore, any relationship between laryngeal NEC and viral DNA positivity requires further investigations in larger numbers of patients.\n\nProtein p53 is prognostic in terms of the outcomes of patients with neuroendocrine tumors.33 Giordano et al (2009)31 reported p53 overexpression in a patient with a moderately differentiated laryngeal NEC (an atypical carcinoid). Chung et al (2004)34 found that 3 of 6 patients with moderately differentiated laryngeal NECs were p53-positive. McCluggage et al (1997)35 also reported that 3 atypical laryngeal carcinoid patients were p53-positive. Overholt et al (1995)36 found that 6 of 8 patients with laryngeal neuroendocrine neoplasms (including 2 atypical carcinoids) were p53-positive. The cited authors suggested that p53 mutation may be involved in the pathogenesis of atypical carcinoids.31,34–36 Our present patient is also p53-positive.\n\nHypoxic markers have been explored as possible prognostic factors for NECs, including atypical carcinoids. The markers explored include GLUT-1, HIF-1α, and proteins of the associated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway.26–28,37–39 Ozbudak et al (2009)26 found that GLUT-1 was expressed in approximately half of all pulmonary NEC patients, and such expression was associated with an increased risk of mortality. GLUT-1 expression is regulated by HIF-1α and the PI3K/Akt signaling pathway.39 Hafner et al (2012)37 found that the PI3K/AKT pathway was activated in patients with Merkel cell carcinoma and suggested that the pathway may represent a useful new therapeutic target. Kaira et al (2013)39 reported high-level immunohistochemical expression of GLUT-1, HIF-1α, and p-Akt in 34 patients with pulmonary NECs. In addition, FDG uptake was associated with the expression of GLUT-1, HIF-1α, VEGF, and CD34. The survival of patients positive for GLUT-1 was poorer than that of others.39 In our previous study, we found that GLUT-1, HIF-1α, PI3K, and p-Akt were overexpressed in 10 patients with sinonasal and laryngeal small-cell NECs by 80%, 50%, 40%, and 40%, respectively.27 Although the expression levels of GLUT-1, HIF-1α, PI3K, and p-Akt did not correlate with survival in a small patient series, 5 patients who died (100%) were positive for GLUT-1, and 2 (40%) for HIF-1α, PI3K, and p-Akt.27 Our present patient expressed high levels of GLUT-1, HIF-1α, PI3K, and p-Akt mRNAs and proteins, as revealed by real-time RT-PCR and Western blot analysis, respectively. Thus, we propose that targeting of hypoxic markers may effectively treat laryngeal NECs.\n\nAlthough the factors described above may influence pathogenesis and survival, the utilities of such molecular markers require further study. Clinicopathological factors prognostic of laryngeal NEC are well-understood; these include distant metastasis, a tumor diameter over 1 cm and tumor type.40,41 Patients with typical laryngeal carcinoids have relatively good prognoses. All atypical laryngeal carcinoids, small-cell NECs and large-cell NECs, are associated with poor outcomes.40 Of the latter 3 tumor types, atypical laryngeal carcinoid is the most common form of laryngeal NEC and exhibits a high rate (67%) of distant metastasis.42,43 Soga (2003)43 analyzed 11,842 cases with carcinoids and variant endocarinomas, and found 199 cases of atypical carcinoids in the larynx with a metastasis rate of 66.8%.43 Lymph node metastases were the most common (40%), followed by skin and subcutaneous metastases (20%) and metastases to other sites (40%).6–8\n\nEarly in 1991, Woodruff and Senie44 reported that survival was reduced when tumors triggered cutaneous and subcutaneous metastases. The cited authors reviewed 127 patients with atypical laryngeal carcinoids, 119 (94%) for whom follow-up data were available. Of these 119 patients, 22% developed skin or subcutaneous metastases.44 In 2005, Ferlito and Rinaldo45 searched the English language literature and found nearly 350 cases of atypical laryngeal carcinoids.44 As of 10 years later (in 2015), no further systematic review on this tumor type or metastases thereof has been reported. In the study described herein, we reviewed the English language literature using MEDLINE to run a PubMed/Web of Science search employing the keywords “neuroendocrine carcinoma or atypical carcinoid or moderately differentiated neuroendocrine carcinoma” with “head and neck or laryngeal or larynx” and “extrapulmonary neuroendocrine carcinoma.”\n\nGoldman et al reported the 1st case of atypical laryngeal carcinoid in 1969. The patient also exhibited widespread subcutaneous metastases. Since 2005, an additional 42 cases (including our present case) have been described (Table 2 ).9,32,41,46–55 Of these recent cases, 23 were males and 17 females; the genders of 2 were not specified. The male-to-female ratio was thus approximately 1.4:1, lower than those reported by Woodruff and Senie (1991)44 and Ferlito et al (2005, 2006).42,45 The mean age of the 42 patients was 61 years (range, 38–85 years), and disease incidence peaked in the 5th (12 patients, 28.6%) and 6th (13 patients, 30.9%) decades of life, unlike the data reported by Woodruff and Senie.44 Of all cases, 24 (57.1%) had histories of cigarette smoking. Of all tumors, 35 (83.3%) were located in the supraglottic area, 1 (2.4%) in the glottis, 1 (2.4%) in the subglottis, and 4 at undefined laryngeal sites. The main symptoms included sore throat (45.2%), dysphagia (40.5%), and hoarseness (23.8%). Of all patients, 35 (83.3%) received surgery (11 underwent neck dissection), and 10 (28.6%) were prescribed postoperative treatments. Three (7.1%) received radiotherapy alone and 3 (7.1%) received both chemotherapy and radiotherapy. One patient (2.4%) received chemotherapy only.\n\nTABLE 2 Data on 42 New Cases Described in the English Language Literature Since 2005\n\nTABLE 2 (Continued) Data on 42 New Cases Described in the English Language Literature Since 2005\n\nThe surgical procedures used included total and partial laryngectomy (7 cases were treated using CO2 lasers; the others underwent robotic partial laryngectomy48). As concluded by Woodruff and Senie (1991)44 and Ferlito et al (2005, 2006),42,45 surgery remains the mainstream treatment for atypical laryngeal carcinoid today. Recently, transoral robotic partial laryngectomy has become possible.48 The principal advantages of robotic partial laryngectomy (compared to the traditional open approaches) are preservation of laryngeal function and elimination of the need for permanent tracheostomy.48 However, such surgery is expensive and few hospitals have the sophisticated equipment required. Thus, CO2 laser treatment delivered under laryngomicroscopic guidance remains the principal surgical modality for the treatment of early-stage atypical laryngeal carcinoid patients.9,32,41,49,55\n\nFollow-up information was available for 39 (92.9%) of the 42 patients. Nineteen (48.7%) developed regional recurrences, 12 (30.8%) distant metastases, and 6 (15.4%) both cutaneous and subcutaneous metastases. Overall, 11 patients (28.2%) remained alive and free of disease; 16 41.0%) died from the disease, 2 (5.1%) died from other diseases, 8 (20.5%) were alive with disease, and 1 (2.6%) was lost to follow-up. The 5- and 10-year survival rates were 57.0% and 15.0%, respectively (Figure 8). The 5-year rate was similar to that reported by Woodruff and Senie (1991).44 However, the 10-year rate was lower than that reported by the cited authors.44 We found that neither the treatment modality used nor the development of local recurrence affected outcomes (both P values >0.05). The development of distant metastasis significantly (negatively) affected survival. The estimated mean survival time of patients with distant metastases was poorer than that of others (102.0 vs 41.3 months, P < 0.01).\n\nFIGURE 8 The 5- and 10-year survival rates of 39 patients diagnosed since our last review in 2005 were 57.0% and 15.0%, respectively.\n\nWe found that the rates of cutaneous and subcutaneous metastasis in these patients were lower (22%) than those reported by Woodruff and Senie (1991).44 We searched the English language literature for information on cutaneous and subcutaneous metastases in such patients. We found data on 48 such patients (including our present case) (Table 3 ).6,8,32,34–36,40,44,54,56,57 To the best of our knowledge, approximately 392 cases of atypical laryngeal carcinoids have been reported in the English language literature, combining the data of Ferlito et al42,45 with those of the present review. The frequency of metastasis in such patients is approximately 12.2%; this incidence may fall as more data accumulate. Thirty patients (62.5%) with such metastases exhibited contemporaneous lymph node invasion. Cutaneous and subcutaneous metastases were always accompanied by distant metastases to other sites, including bone, lung, heart, liver, gallbladder, pancreas, bowel, kidney, ureter, testis, thyroid, diaphragm, and rectus muscle. The principal symptom was pain. Of the 42 patients (87.5%) for whom follow-up data were available, the 3-, 5-, and 10-year survival rates were 44.0%, 22.0%, and 13.0%, respectively (Figure 9).\n\nTABLE 3 Data on 48 Patients Described in the English Language Literature With Cutaneous and Subcutaneous Metastases From Atypical Laryngeal Carcinoids\n\nTABLE 3 (Continued) Data on 48 Patients Described in the English Language Literature With Cutaneous and Subcutaneous Metastases From Atypical Laryngeal Carcinoids\n\nFIGURE 9 The 3-, 5-, and 10-year survival rates of patients described in the English language literature with cutaneous and subcutaneous metastases from atypical laryngeal carcinoids were 44.0%, 22.0%, and 13.0%, respectively.\n\nNo satisfactory treatment for cutaneous and subcutaneous metastases of atypical laryngeal carcinoids has yet been described. Descriptions of treatments are rare.6,36,40,4,56,58,59 In 1989, Ferlito and Friedmann proposed that painful skin/subcutaneous metastases should be treated surgically.44 van der Laan et al (2012) suggested that salvage surgery, including palliative metastasectomy, had an important role in the treatment of laryngeal NEC. In addition, the overall survival level was reasonable. The cited authors described 3 patients with atypical laryngeal carcinoids who developed cutaneous and subcutaneous metastases; 1 died of disease 74 months after primary treatment (total laryngectomy); 1 received miltefosine after metastasis was diagnosed and died of disease 28 months after primary treatment (horizontal laryngectomy); and 1 underwent total laryngectomy after metastasis was diagnosed and was alive with disease 26 months after primary treatment (supraglottic laryngectomy).41 Simpson et al (2009)7 reported on an 82-year-old patient who presented with multiple exquisitely tender skin lesions. The patient had undergone resection of an atypical laryngeal carcinoid 33 years prior, and 2 further endoscopic laser resections (with adjuvant radiotherapy) due to local recurrence 2 years prior. The multiple skin metastases were treated using a CO2 laser; palliation was effective. However, the patient died from unrelated causes 8 months after the final presentation.6 Overholt et al (1995)36 described a patient with skin metastases who underwent chemotherapy. The patient died of disease 26 months after primary treatment. It was thus suggested that chemotherapy was ineffective. Gripp et al (1995)58 used somatostatin to treat skin metastases from atypical laryngeal carcinoids. However, the drug was no better than other chemotherapies.58 Electrochemotherapy is useful to palliate cutaneous and subcutaneous metastases arising from some other malignant tumors.60 Such management included intravenous bleomycin (15,000 IU/m2); the electrodes were placed under general anesthesia. The overall response rate was 66.6%. Patients with less than 10 nodules and masses smaller than 2 cm in diameter benefited the most.60 In our present case, multiple cutaneous and subcutaneous metastases developed 6 months after supraglottic laryngectomy. The tested treatments were unsatisfactory. Pain was relieved only via intrathecal drug delivery.\n\nIn conclusion, atypical laryngeal carcinoids are rare, and the prognoses are poor. Prognostic factors include the level of p53, HPV status, certain hypoxic markers, and distant metastasis. The rate of development of cutaneous and subcutaneous metastases was 12.2%. No optimal treatment for such metastases has yet been defined.\n\nAcknowledgements\nThis research was supported by the National Natural Science Foundation of China (grant nos. 81172562 and 81372903).\n\nAbbreviations: CMV = cytomegalovirus, EBV = Epstein–Barr virus, FDG = [18F]-fluoro-2-deoxy-d-glucose, GLUT-1 = glucose transporter-1, HIF-1α = hypoxia-inducible factor-1α, HPV = human papilloma virus, NEC = neuroendocrine carcinomas, PET/CT = positron emission tomography/computed tomography, PI3K/Akt = phosphatidylinositol 3-kinase/protein kinase B.\n\nThe English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/3ocKWB.\n\nThis research was supported by the National Natural Science Foundation of China (grant nos. 81172562 and 81372903).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Barnes L \nBarnes L Eveson JW Reichart P Sidransky D \nNeuroendocrine tumours . Pathology and Genetics. Head and Neck Tumours. World Health Organization Classification of Tumours . Lyon : IARC Press ; 2005 \n135 –139 .\n2. van der Laan TP Plaat BE van der Laan BF \nClinical recommendations on the treatment of neuroendocrine carcinoma of the larynx: a meta-analysis of 436 reported cases . Head Neck \n2015 ; 37 :707 –715 .24596175 \n3. Ferlito A Lewis JS JrRinaldo A \nThe evolving management of laryngeal neuroendocrine carcinomas . Eur Arch Otorhinolaryngol \n2011 ; 268 :1247 –1248 .21681569 \n4. Ferlito A Rinaldo A \nThe spectrum of endocrinocarcinomas of the larynx . Oral Oncol \n2005 ; 41 :878 –883 .16154516 \n5. Ferlito A Barnes L Rinaldo A \nA review of neuroendocrine neoplasms of the larynx: update on diagnosis and treatment . J Laryngol Otol \n1998 ; 112 :827 –834 .9876371 \n6. Simpson LK Ostlere LS Harland C \nTreatment with carbon dioxide laser of painful skin metastases from a laryngeal neuroendocrine carcinoma . Clin Exp Dermatol \n2009 ; 34 :e873 –875 .20055852 \n7. Rosai J. \nRespiratory tract. Rosai and Ackerman's Surgical Pathology. 9th Ed. Elsevier , 2005 ; 1 :411 –12 .\n8. AL H K A K A \nPrimary laryngeal neuroendocrine carcinoma - a rare entity with deviant clinical presentation . J Clin Diagn Res \n2014 ; 8 :FD07 –8 .\n9. Kanazawa T Nokubi M Takeoda K \nAtypical carcinoid of the larynx and expressions of proteins associated with molecular targeted therapy . Auris Nasus Larynx \n2011 ; 38 :123 –126 .20580173 \n10. Liu JC Ridge JA Brizel DM \nCurrent status of clinical trials in head and neck cancer 2014 . Otolaryngol Head Neck Surg \n2015 ; 152 :410 –417 .25605695 \n11. Chen WH Lecaros RL Tseng YC \nNanoparticle delivery of HIF1 (siRNA combined with photodynamic therapy as a potential treatment strategy for head-and-neck cancer . Cancer Lett \n2015 ; 359 :65 –74 .25596376 \n12. Shida T Kishimoto T Furuya M \nExpression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors . Cancer Chemother Pharmacol \n2010 ; 65 :889 –893 .19657638 \n13. Volante M Birocco N Gatti G \nExtrapulmonary neuroendocrine small and large cell carcinomas: a review of controversial diagnostic and therapeutic issues . Hum Pathol \n2014 ; 45 :665 –673 .23806528 \n14. Vlachostergios PJ Papandreou CN \nTargeting neuroendocrine prostate cancer: molecular and clinical perspectives . Front Oncol \n2015 ; 5 :6 .25699233 \n15. Ying HF Bao YY Zhou SH \nSubmucosal small-cell neuroendocrine carcinoma of the larynx detected using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography: a case report and review of the literature . Oncol Lett \n2014 ; 8 :1065 –1069 .25120658 \n16. Miki K Orita Y Nose S \nNeuroendocrine carcinoma of the larynx presenting as a primary unknown carcinoma . Auris Nasus Larynx \n2012 ; 39 :98 –102 .21570790 \n17. Chun BJ Yoo IR Joo YH \nThe efficacy of 18F-FDG PET/CT imaging for extracapsular spread of the laryngeal squamous cell carcinoma . Head Neck \n2016 ; 38 :290 –293 .25327765 \n18. Roh JL Park JP Kim JS \n18Ffluorodeoxyglucose PET/CT in head and neck squamous cell carcinoma with negative neck palpation findings: a prospective study . Radiology \n2014 ; 271 :153 –161 .24475791 \n19. Zhao K Luo XM Zhou SH \n18F-fluorodeoxyglucose positron emission tomography/computed tomography as an effective diagnostic workup in cervical metastasis of carcinoma from an unknown primary tumor . Cancer Biother Radiopharm \n2012 ; 27 :685 –693 .22834634 \n20. Zhao K Yang SY Zhou SH \nFluorodeoxyglucose uptake in laryngeal carcinoma is associated with the expression of glucose transporter-1 and hypoxia-inducible-factor-1α and the phosphoinositide 3-kinase/protein kinase B pathway . Oncol Lett \n2014 ; 7 :984 –990 .24944654 \n21. van Berkel A Rao JU Kusters B \nCorrelation between in vivo 18F-FDG PET and immunohistochemical markers of glucose uptake and metabolism in pheochromocytoma and paraganglioma . J Nucl Med \n2014 ; 55 :1253 –1259 .24925884 \n22. Kobayashi M Kaida H Kawahara A \nThe relationship between GLUT-1 and vascular endothelial growth factor expression and 18F-FDG uptake in esophageal squamous cell cancer patients . Clin Nucl Med \n2012 ; 37 :447 –452 .22475893 \n23. Li SJ Guo W Ren GX \nExpression of Glut-1 in primary and recurrent head and neck squamous cell carcinomas, and compared with 2-[18F]fluoro-2-deoxy-D-glucose accumulation in positron emission tomography . Br J Oral Maxillofac Surg \n2008 ; 46 :180 –186 .18093707 \n24. Huang XQ Chen X Xie XX \nCo-expression of CD147 and GLUT-1 indicates radiation resistance and poor prognosis in cervical squamous cell carcinoma . Int J Clin Exp Pathol \n2014 ; 7 :1651 –1666 .24817962 \n25. Yamada T Uchida M Kwang-Lee K \nCorrelation of metabolism/hypoxia markers and fluorodeoxyglucose uptake in oral squamous cell carcinomas . Oral Surg Oral Med Oral Pathol Oral Radiol \n2012 ; 113 :464 –471 .22676927 \n26. Ozbudak IH Shilo K Tavora F \nGlucose transporter-1 in pulmonary neuroendocrine carcinomas:expression and survival analysis . Mod Pathol \n2009 ; 22 :633 –638 .19234439 \n27. Chai L Ying HF Wu TT \nClinical features and hypoxic marker expression of primary sinonasal and laryngeal small-cell neuroendocrine carcinoma: a small case series . World J Surg Oncol \n2014 ; 12 :199 .24980293 \n28. Song YS Lee WW Chung JH \nCorrelation between FDG uptake and glucose transporter type 1 expression in neuroendocrine tumors of the lung . Lung Cancer \n2008 ; 61 :54 –60 .18191496 \n29. Zhou SH Fan J Chen XM \nInhibition of cell proliferation and glucose uptake in human laryngeal carcinoma cells by antisense oligonucleotides against glucose transporter-1 . Head Neck \n2009 ; 31 :1624 –1633 .19441091 \n30. Yan SX Luo XM Zhou SH \nEffect of antisense oligodeoxynucleotides glucose transporter-1 on enhancement of radiosensitivity of laryngeal carcinoma . Int J Med Sci \n2013 ; 10 :1375 –1386 .23983599 \n31. Giordano G Corcione L Giordano D \nPrimary moderately differentiated neuroendocrine carcinoma (atypical carcinoid) of the larynx: a case report with immunohistochemical and molecular study . Auris Nasus Larynx \n2009 ; 36 :228 –231 .18617341 \n32. Halmos GB van der Laan TP van Hemel BM \nIs human papillomavirus involved in laryngeal neuroendocrine carcinoma? \nEur Arch Otorhinolaryngol \n2013 ; 270 :719 –725 .22699626 \n33. Erler BS Presby MM Finch M \nCD117, Ki-67, and p53 predict survival in neuroendocrine carcinomas, but not within the subgroup of small cell lung carcinoma . Tumour Biol \n2011 ; 32 :107 –111 .21058037 \n34. Chung JH Lee SS Shim YS \nA study of moderately differentiated neuroendocrine carcinomas of the larynx and an examination of non-neoplastic larynx tissue for neuroendocrine cells . Laryngoscope \n2004 ; 114 :1264 –1270 .15235358 \n35. McCluggage WG Cameron CH Arthur K \nAtypical carcinoid tumor of the larynx: an immunohistochemical, ultrastructural, and flow cytometric analysis . Ultrastruct Pathol \n1997 ; 21 :431 –438 .9273973 \n36. Overholt SM Donovan DT Schwartz MR \nNeuroendocrine neoplasms of the larynx . Laryngoscope \n1995 ; 105 :789 –794 .7630288 \n37. Hafner C Houben R Baeurle A \nActivation of the PI3K/AKT pathway in Merkel cell carcinoma . PLoS One \n2012 ; 7 :e31255 .22363598 \n38. Leung R Lang B Wong H \nAdvances in the systemic treatment of neuroendocrine tumors in the era of molecular therapy . Anticancer Agents Med Chem \n2013 ; 13 :382 –388 .23092266 \n39. Kaira K Murakami H Endo M \nBiological correlation of 18F-FDG uptake on PET in pulmonary neuroendocrine tumors . Anticancer Res \n2013 ; 33 :4219 –4228 .24122985 \n40. van der Laan TP van der Laan BF Plaat BE \nNeuroendocrine carcinoma of the larynx – an extraordinary malignancy with high recurrence rates and long survival: our experience in 11 patients . Clin Otolaryngol \n2012 ; 37 :63 –66 .22433139 \n41. Carić T Bilić M Bilić LK \nNeuroendocrine tumors of larynx – two case reports and literature review . Coll Antropol \n2012 ; 36 :173 –178 .23397781 \n42. Ferlito A Devaney KO Rinaldo A \nNeuroendocrine neoplasms of the larynx: advances in identification, understanding, and management . Oral Oncol \n2006 ; 42 :770 –788 .16815077 \n43. Soga J \nCarcinoids and their variant endocrinomas. An analysis of 11842 reported cases . J Exp Clin Cancer Res \n2003 ; 22 :517 –530 .15053292 \n44. Woodruff JM Senie RT \nAtypical carcinoid tumor of the larynx. A critical review of the literature . ORL J Otorhinolaryngol Relat Spec \n1991 ; 53 :194 –209 .1891252 \n45. Ferlito A Friedmann A \nReview of neuroendocrine carcinomas of the larynx . AnnOtol Rhinol Laryngol \n1989 ; 98 :780 –790 .\n46. Ferlito A Silver CE Bradford CR \nNeuroendocrine neoplasms of the larynx: an overview . Head Neck \n2009 ; 31 :1634 –1646 .19536850 \n47. Kumar PD Simha NV Sreenivas N \nAtypical carcinoid of larynx: a case study and a brief review . J Clin Diagn Res \n2014 ; 8 :KD03 –KD04 .\n48. Muderris T Bercin S Sevil E \nTransoral robotic surgery for atypical carcinoid tumor of the larynx . J Craniofac Surg \n2013 ; 24 :1996 –1999 .24220389 \n49. Davies-Husband CR Montgomery P Premachandra D \nPrimary, combined, atypical carcinoid and squamous cell carcinoma of the larynx: a new variety of composite tumour . J Laryngol Otol \n2010 ; 124 :226 –229 .19930775 \n50. Zhang M Zhou L Li C \nModerately differentiated neuroendocrine carcinoma of the larynx . Acta Otolaryngol \n2010 ; 130 :498 –502 .19883182 \n51. Seshamani M Einhorn E Mirza N \nAtypical carcinoid of the larynx and potential complications of the carcinoid syndrome: a case report . Ear Nose Throat J \n2009 ; 88 :E1 .19172557 \n52. Chung EJ Baek SK Kwon SY \nModerately differentiated euroendocrine carcinoma of the larynx . Clin Exp Otorhinolaryngol \n2008 ; 1 :217 –220 .19434271 \n53. Capelli M Bertino G Morbini P \nNeuroendocrine carcinomas of the upper airways: a small case series with histopathological considerations . Tumori \n2007 ; 93 :499 –503 .18038886 \n54. Gillenwater A Lewin J Roberts D \nModerately differentiated neuroendocrine carcinoma (atypical carcinoid) of the larynx: a clinically aggressive tumor . Laryngoscope \n2005 ; 115 :1191 –1195 .15995505 \n55. Chang KP Lee LY Yeh AR \nEndoscopic CO2 laser surgery for an atypical carcinoid tumor of the epiglottis masquerading as a supraglottic cyst . Head Neck \n2005 ; 27 :1004 –1007 .16114009 \n56. Machens A Holzhausen HJ Dralle H \nMinimally invasive surgery for recurrent neuroendocrine carcinoma of the supraglottic larynx . Eur Arch Otorhinolaryngol \n1999 ; 256 :242 –246 .10392299 \n57. Ereño C Lopez JI Sanchez JM \nAtypical carcinoid of larynx: presentation with scalp metastases . J Laryngol Otol \n1997 ; 111 :89 –91 .9292144 \n58. Gripp FM Risse EK Leverstein H \nNeuroendocrine neoplasms of the larynx. Importance of the correct diagnosis and differences between atypical carcinoid tumors and small-cell neuroendocrine carcinoma . Eur Arch Otorhinolaryngol \n1995 ; 252 :280 –286 .7576585 \n59. Watters GW Molyneux AJ \nAtypical carcinoid tumour of the larynx . J Laryngol Otol \n1995 ; 109 :455 –458 .7798009 \n60. Solari N Spagnolo F Ponte E \nElectrochemotherapy for the management of cutaneous and subcutaneous metastasis: a series of 39 patients treated with palliative intent . J Surg Oncol \n2014 ; 109 :270 –274 .24165992\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "95(7)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D002276:Carcinoid Tumor; D005260:Female; D006801:Humans; D007822:Laryngeal Neoplasms; D007830:Larynx; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012867:Skin; D012878:Skin Neoplasms",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e2796",
"pmc": null,
"pmid": "26886629",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "24959467;16114009;9273973;19657638;18093707;9292144;24596175;24165992;23983599;16154516;25605695;19441091;7576585;22699626;25386445;19234439;24925884;19434271;24980293;19536850;18038886;25699233;20055852;20580173;18191496;9876371;22834634;25120658;19172557;23092266;22433139;24475791;22676927;21570790;22475893;24944654;24817962;1891252;23806528;18617341;22363598;10392299;19883182;15995505;23397781;21058037;25327765;24122985;2552894;15053292;25596376;24220389;21681569;7630288;19930775;15235358;16815077;7798009",
"title": "Cutaneous and Subcutaneous Metastases From Atypical Laryngeal Carcinoids: Case Report and Review of the Literature.",
"title_normalized": "cutaneous and subcutaneous metastases from atypical laryngeal carcinoids case report and review of the literature"
} | [
{
"companynumb": "CN-ACCORD-039242",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Several treatment protocols for medication-related osteonecrosis of the jaw (MRONJ) have been published. Despite the efficacy of surgical therapy of approximately 90% as primary therapy, the role of other agents, such as drug administration, should not be underestimated. Based on previous experience with osteoradionecrosis, the association of pentoxifylline and tocopherol has shown encouraging results in MRONJ patients. Despite the need for long-term use of the combination, compliance has been good. However, studies in breast cancer patients revealed that pentoxifylline can require dose reduction or discontinuation due to nausea and epigastric pain. Cilostazol has been used as a substitute for pentoxifylline in peripheral artery disease. Herein we report a case in which cilostazol replaced pentoxifylline at a dose of 100mg, 2 times/day with tocopherol 500UI, 2 times/day, in a 77-year-old female patient that could not tolerate pentoxifylline for the management of MRONJ. After an uneventful 22 months of follow-up, a cone-beam computed tomography revealed complete bone formation and no signs of recurrence. Cilostazol may be a useful and safe alternative to pentoxifylline as part of MRONJ management protocols.",
"affiliations": "Postgraduate Student, Oral and Maxillofacial Surgeon, University of Sao Paulo, School of Dentistry, São Paulo, Brazil.;Resident, Oral and Maxillofacial Surgery, University of Sao Paulo Medical School Hospital, São Paulo, Brazil.;Chair of Department of Diagnostic Sciences and Oral Medicine, The University of Tennessee Health Science Center, Memphis, TN.;Professor, Oral and Maxillofacial Surgeon, University of Sao Paulo Medical School Hospital, São Paulo, Brazil. Electronic address: andcaroli@uol.com.br.",
"authors": "de Carvalho E|Façanha|F|;Bertotti|Maitê|M|;Migliorati|Cesar Augusto|CA|;Rocha|André Caroli|AC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2021.06.036",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "79(12)",
"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": null,
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "2499-2506",
"pmc": null,
"pmid": "34339622",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cilostazol and Tocopherol in the Management of Medication-Related Osteonecrosis of the Jaw: New Insights From a Case Report.",
"title_normalized": "cilostazol and tocopherol in the management of medication related osteonecrosis of the jaw new insights from a case report"
} | [
{
"companynumb": "BR-MYLANLABS-2021M1060694",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe efficacy of dolutegravir (DTG) has been demonstrated in 5 randomized studies in integrase inhibitor (INI)-naive adult populations. To date, a detailed safety review of DTG has not been provided in the literature.\n\n\nOBJECTIVE\nTo describe the safety and tolerability profile of DTG in adults based on 5 randomized, controlled trials and comparison with drugs in 3 major antiretroviral (ARV) classes.\n\n\nMETHODS\nSafety data from phase IIb/III/IIIb trials in ART-naive and ART-experienced, INI-naive adults were integrated.\n\n\nRESULTS\nIn 4 ART-naive (SPRING-1, SPRING-2, SINGLE, FLAMINGO) and 1 ART-experienced, INI-naive study (SAILING), 1,579 individuals received a DTG-containing regimen. The proportion of individuals from DTG treatment arms who withdrew due to adverse events (AEs) was low (≤2%) compared to raltegravir (RAL; 2% SPRING-2, 4% SAILING), efavirenz (EFV)-containing comparator arm (10% SINGLE), and darunavir + ritonavir (DRV/r; 4% FLAMINGO). The most frequently observed AEs (diarrhea, nausea, headache), typically grade 1 or 2 in severity, did not lead to study discontinuation. Psychiatric and nervous system disorders with DTG were comparable to RAL- and DRV/r-containing regimens and favorable to EFV-containing regimens. In hepatitis B and/or C coinfected ART-naive individuals, the incidence of transaminase elevations was lower with DTG versus RAL and EFV comparators, but was similar to DRV/r. In SAILING, transaminase elevations were more commonly observed with DTG, particularly in the setting of inadequate hepatitis B therapy or immune reconstitution. On DTG treatment, mild creatinine elevations occurred and stabilized early. Few cases of hypersensitivity reaction and/or severe rash were seen. Rates of these events were comparable to or lower than with RAL-, EFV-, and DRV/r-containing regimens.\n\n\nCONCLUSIONS\nThe safety profile for DTG 50 mg once daily in INI-naive individuals was comparable to RAL- and DRV/r-containing regimens and generally favorable compared with EFV-containing regimens.",
"affiliations": "GlaxoSmithKline, Stockley Park, UK.;GlaxoSmithKline, Research Triangle Park, NC, USA.;GlaxoSmithKline, Stockley Park, UK.;GlaxoSmithKline, Stockley Park, UK.;GlaxoSmithKline, Stockley Park, UK.;GlaxoSmithKline, Philadelphia, PA, USA.;ViiV Healthcare, Brentford, UK.;Holdsworth House Medical Practice, Sydney, Australia.;ViiV Healthcare, Brentford, UK.;ViiV Healthcare, Research Triangle Park, NC, USA.;Infectious and Tropical Diseases Department, Nantes University Hospital, Nantes, France.;GlaxoSmithKline, Research Triangle Park, NC, USA.",
"authors": "Curtis|L|L|;Nichols|G|G|;Stainsby|C|C|;Lim|J|J|;Aylott|A|A|;Wynne|B|B|;Clark|A|A|;Bloch|M|M|;Maechler|G|G|;Martin-Carpenter|L|L|;Raffi|F|F|;Min|S|S|",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D008055:Lipids; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir; D003402:Creatine Kinase",
"country": "England",
"delete": false,
"doi": "10.1310/hct1505-199",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1528-4336",
"issue": "15(5)",
"journal": "HIV clinical trials",
"keywords": "HIV-1; dolutegravir; integrase inhibitor; safety",
"medline_ta": "HIV Clin Trials",
"mesh_terms": "D019380:Anti-HIV Agents; D056486:Chemical and Drug Induced Liver Injury; D003402:Creatine Kinase; D015658:HIV Infections; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008055:Lipids; D010078:Oxazines; D010879:Piperazines; D011605:Psychoses, Substance-Induced; D011728:Pyridones; D018746:Systemic Inflammatory Response Syndrome",
"nlm_unique_id": "100936377",
"other_id": null,
"pages": "199-208",
"pmc": null,
"pmid": "25350958",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Dolutegravir: clinical and laboratory safety in integrase inhibitor-naive patients.",
"title_normalized": "dolutegravir clinical and laboratory safety in integrase inhibitor naive patients"
} | [
{
"companynumb": "GB-BMSGILMSD-2015-0170865",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EFAVIRENZ\\EMTRICITABINE\\TENOFOVIR DISOPROXIL FUMARATE"
... |
{
"abstract": "BACKGROUND\nPatients with peripartum cardiomyopathy (PPCM) present with low blood pressure (SBP) often preventing uptitration of heart failure medication. We aimed to study prediction of risk and the contribution of high resting heart rate (HR) and low SBP to risk in recent onset of PPCM.\n\n\nMETHODS\nClinical assessment with HR and SBP, echocardiography and laboratory results were obtained at baseline and at six months on 206 patients with recent onset PPCM enrolled at two tertiary care centers in South Africa. Poor outcome was defined as the combined endpoint of death, LVEF<35% or remaining in New York Heart Association (NYHA) functional class III/IV at six months. Complete LV recovery was defined as LVEF ≥ 55% at six months.\n\n\nRESULTS\nPoor outcome was observed in 110 of 220 patients (53%), with 26 patients dying at six months (12.6%). There were 98 (47.5%) patients with SBP ≤ 110 mmHg. Patients with high HR (HR ≥ 100) and low SBP (< 110 mmHg) tended to have worse outcomes than patients below the HR median and high SBP. PPCM patients with low SBP and high HR were less likely to be on ACE-inhibitors (n = 35, 69% versus n = 129, 84%, p = 0.024) and on the beta blocker carvedilol (n = 24, 47% versus n = 98, 64%, p = 0.047). Low SBP, high HR and left ventricular end diastolic diameter at baseline were predictors of poor outcome. Patients with low SBP and high HR had the highest mortality (p = 0.0023).\n\n\nCONCLUSIONS\nThese findings suggest increased risk in patients with PPCM presenting with low SBP and high HR on standard heart failure medication possibly having implications on HF management.",
"affiliations": "Soweto Cardiovascular Research Unit, University of the Witwatersrand, South Africa.;Soweto Cardiovascular Research Unit, University of the Witwatersrand, South Africa.;Universitätsklinikum des Saarlandes, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Kirrberger Str. 1, D 66424 Homburg, Saar, Germany.;Soweto Cardiovascular Research Unit, University of the Witwatersrand, South Africa.;Universitätsklinikum des Saarlandes, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Kirrberger Str. 1, D 66424 Homburg, Saar, Germany. Electronic address: michael.boehm@uks.eu.",
"authors": "Libhaber|Elena|E|;Sliwa|Karen|K|;Bachelier|Katrin|K|;Lamont|Kim|K|;Böhm|Michael|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-5273",
"issue": "190()",
"journal": "International journal of cardiology",
"keywords": "Cardiomyopathy; Heart rate; PPCM; Pregnancy",
"medline_ta": "Int J Cardiol",
"mesh_terms": "D000328:Adult; D001794:Blood Pressure; D002311:Cardiomyopathy, Dilated; D005260:Female; D005500:Follow-Up Studies; D006339:Heart Rate; D006801:Humans; D058725:Peripartum Period; D011237:Predictive Value of Tests; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D013019:South Africa; D015996:Survival Rate; D016896:Treatment Outcome; D014463:Ultrasonography; D055815:Young Adult",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "376-82",
"pmc": null,
"pmid": "25966297",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Low systolic blood pressure and high resting heart rate as predictors of outcome in patients with peripartum cardiomyopathy.",
"title_normalized": "low systolic blood pressure and high resting heart rate as predictors of outcome in patients with peripartum cardiomyopathy"
} | [
{
"companynumb": "DE-CIPLA LTD.-2015DE05683",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBurkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.\n\n\nMETHODS\nWe retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.\n\n\nRESULTS\nThe most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.\n\n\nCONCLUSIONS\nB. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.",
"affiliations": "Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan.;Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan.;Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan.;Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan.;Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan.;Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan.;Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan.;Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan. hsiao.chinghsi@gmail.com.",
"authors": "Ho|Ming-Chih|MC|;Kang|Eugene Yu-Chuan|EY|;Yeh|Lung-Kun|LK|;Ma|David H K|DHK|;Lin|Hsin-Chiung|HC|;Tan|Hsin-Yuan|HY|;Chen|Hung-Chi|HC|;Hsiao|Ching-Hsi|CH|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12941-020-00407-6",
"fulltext": "\n==== Front\nAnn Clin Microbiol Antimicrob\nAnn Clin Microbiol Antimicrob\nAnnals of Clinical Microbiology and Antimicrobials\n1476-0711 BioMed Central London \n\n407\n10.1186/s12941-020-00407-6\nResearch\nClinico-microbiological profile of Burkholderia cepacia keratitis: a case series\nHo Ming-Chih 1 Kang Eugene Yu-Chuan 1 Yeh Lung-Kun 12 Ma David H. K. 12 Lin Hsin-Chiung 12 Tan Hsin-Yuan 12 Chen Hung-Chi 12 Hsiao Ching-Hsi hsiao.chinghsi@gmail.com 12 1 grid.413801.f0000 0001 0711 0593Department of Ophthalmology, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Road, Linkou, Taipei, Taiwan \n2 grid.145695.aCollege of Medicine, Chang Gung University, Taoyuan, Taiwan \n7 1 2021 \n7 1 2021 \n2021 \n20 61 5 2020 3 12 2020 © The Author(s) 2021Open 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\nBurkholderia cepacia, an opportunistic pathogen mainly affecting patients with cystic fibrosis or immunocompromised, has rarely been documented as a cause of corneal infection. The clinical and microbiological profiles of B. cepacia keratitis are reported herein.\n\nMethods\nWe retrospectively reviewed the medical record of 17 patients with culture-proven B. cepacia keratitis, treated between 2000 and 2019 at Chang Gung Memorial Hospital, Taiwan. Our data included predisposing factors, clinical presentations, treatments, and visual outcomes of B. cepacia keratitis as well as the drug susceptibility of the causative agent.\n\nResults\nThe most common predisposing factor for B. cepacia keratitis was preexisting ocular disease (seven, 41.2%), particularly herpetic keratitis (five). Polymicrobial infection was detected in seven (41.2%) eyes. All B. cepacia isolates were susceptible to ceftazidime. Main medical treatments included levofloxacin or ceftazidime. Surgical treatment was required in five (29.4%) patients. Only four (23.5%) patients exhibited final visual acuity better than 20/200.\n\nConclusions\nB. cepacia keratitis primarily affects patients with preexisting ocular disease, particularly herpetic keratitis, and responds well to ceftazidime or fluoroquinolones. However, the visual outcomes are generally poor.\n\nKeywords\nBurkholderia cepaciakeratitiscorneal ulcerdrug susceptibilityissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nBurkholderia cepacia complex, formerly known as Pseudomonas cepacia, is a group of aerobic Gram-negative bacilli comprising more than 20 species [1, 2]. It can exist in various environments, such as soil or water, and can infect both humans and plants. In humans, B. cepacia is principally an opportunistic pathogen that causes various diseases, such as lung infections, in patients with cystic fibrosis or chronic granulomatous disease. Ocular manifestations caused by B. cepacia include endophthalmitis and keratitis, both of which are vision-threatening [3–9]. Several case series have reported on B. cepacia endophthalmitis, which occurs after ocular surgery or ocular trauma. Compared with endophthalmitis, B. cepacia keratitis has rarely been reported, with only eight sporadic cases being documented thus far [4, 5, 7, 9, 10]. Here, we report on 17 cases of B. cepacia keratitis. By reviewing patient demographics, risk factors, clinical presentations, treatment, and visual outcomes, we identified the characteristics of the disease, thus contributing additional knowledge on B. cepacia keratitis.\n\nMaterials and methods\nThis single-center retrospective study included data of 17 patients diagnosed as having B. cepacia keratitis at Chang Gung Memorial Hospital, Taiwan between December 2003 and August 2019. Corneal scrapings, obtained under topical anesthesia, were inoculated on blood and chocolate agar, thioglycolate broth, and Lowenstein–Jenson agar as well as subjected to Gram staining. The various media were routinely incubated for one week or longer, depending on the medium, before the final culture result was obtained. Isolates were identified, by using conventional biochemical tests; matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry was applied starting in 2013. Antimicrobial susceptibility was evaluated using the standard disk diffusion method and interpreted according to the guidelines established by the Clinical and Laboratory Standards Institute (CLSI). For B. cepacia isolates, ceftazidime, meropenem, and sulfamethoxazole–trimethoprim were tested. Each patient’s demographic data, risk factors, clinical presentations, treatments, and visual outcomes were reviewed. We provided a case report (patient 13) as a representative of B. cepacia keratitis in our study. We defined the location of an ulcer as central if it was located within 2 mm of fixation, periphery if it involved a zone within 2 mm from the limbus, and paracentral if it was in between. The ulcer size was defined as small (< 2 mm), medium (2–6 mm), or large (> 6 mm) on the basis of the longest diameter. Predisposing factors were classified into ocular trauma, contact lens wear, preexisting ocular disease, recent ocular surgery, and systemic disease. Prior steroid use was also recorded. Visual acuity was measured using Snellen charts.\n\nResults\nTable 1 lists the demographic and clinical data of the patients. The mean patient age was 62.4 ± 17.2 (range 24–88) years. A total of 17 eyes were involved, with nine right eyes and eight left eyes in eight male and nine female patients. Mean follow-up duration was 2.76 years (range 7 days to nine years).\n\n\nTable 1 The demographic and baseline characteristics of the patients with Burkholderia capecia keratitis\n\nNo.\tAge/\nsex\tYear\tRisk factors\tPrior use\nof cortico-\nsteroid\tLocation\n, size\tHypopyon\tCorneal perforation\tTreatment\tSurgery\tPresenting\nVA\tFinal\nVA\tOther isolates\t\n1\t71/f\t2003\tDiabetic mellitus\t−\tC, L\t+\t−\tCeftazidime, Vancomycin\t−\tNLP\tNLP\t\t\n2\t52/m\t2007\tOcular trauma\t+\tC, S\t+\t−\tCeftazidime, Sulfamethoxazole/Trimethoprim\tAMT\tCF\tCF\tCandida parapsilosis\t\n3\t64/f\t2010\tDiabetic mellitus, Recent ocular surgery (PKP)\t+\tC, L\t−\t−\tCeftazidime\tAMT, patch graft, evisceration\tNLP\tNLP\t\t\n4\t71/m\t2010\tHZV keratitis\t−\tC, L\t−\t+\tAmikacin, Vancomycin, Sulfamethoxazole/Trimethoprim\t−\tNLP\tNLP\tSerratia marcescens\t\n5\t24/m\t2010\tHSV keratitis\t+\tPC, L\t−\t−\tCeftazidime, acyclovir\t−\tCF\t20/200\t\t\n6\t57/f\t2014\tHSV keratitis\t−\tC, L\t−\t+\tLevofloxacin, acyclovir\tPatch graft, PKP\tHM\tLP\t\t\n7\t85/m\t2016\tUnknown\t−\tC, L\t+\t−\tAmikacin, voriconazole\t−\tHM\tHM\tFusarium solani\t\n8\t53/m\t2016\tOcular trauma\t+\tPC, M\t+\t+\tCeftazidime, Moxifloxacin (oral), Vancomycin\t\t20/200\t20/70\t\t\n9\t84/f\t2017\tOcular surface problem\t−\tPC, S\t−\t−\tLevofloxacin\t−\tCF\tCF\t\t\n10\t50/f\t2017\tContact lens wear\t−\tPC, S\t−\t−\tLevofloxacin\t−\t20/25\t20/50\t\t\n11\t88/f\t2017\tRecent ocular surgery (PKP, AMT)\t+\tC, M\t+\t−\tLevofloxacin\tAMT\tHM\t20/1000\tPseudomonas aeruginosa\t\n12\t60/m\t2017\tUnknown\t−\tC, L\t+\t−\tLevofloxacin\tAMT, keratectomy, tarsorrhaphy, patch graft\tCF\tNA\t\t\n13\t84/f\t2018\tHSV keratitis\t+\tPC, S\t+\t+\tCeftazidime\t−\tHM\tCF\t\t\n14\t65/f\t2018\tDiabetic mellitus, Recurrent ocular ulcer\t+\tPC, M\t+\t−\tLevofloxacin\t−\tHM\tNLP\tCorynebacterium propinquum, Corynebacterium species\t\n15\t48/m\t2018\tOcular trauma\t−\tPC, S\t−\t−\tLevofloxacin\t−\t20/50\t20/30\tBacillus megaterium,\n\nArthrobacter species\n\n\t\n16\t69/f\t2019\tUnknown\t−\tC, L\t−\t−\tLevofloxacin\t−\tNLP\tNLP\tPseudomonas aeruginosa\t\n17\t36/m\t2019\tHZV keratitis, Contact lens wear\t+\tC, M\t−\t−\tLevofloxacin\t−\tCF\t20/400\t\t\nAMT amniotic membrane transplantation, C central, CF counting fingers, f female, HM hand motion, HSV herpes simplex virus, HZV herpes zoster virus, L large, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, PKP penetrating keratoplasty, S small, VA visual acuity\n\n\n\nOf the 17 corneal ulcers, 10 (58.8%) were located in the central cornea. In terms of size, eight (47.1%), four (23.5%), and five (29.4%) corneal ulcers were defined as large, medium, and small, respectively. Hypopyon was present in eight (47.1%) patients. Corneal perforation was observed in four (23.5%) patients—in two at presentation and in two during treatment.\n\nPredisposing factors of keratitis were identified in 14 patients, with four patients demonstrating multifactorial causes of keratitis. Preexisting ocular diseases (seven eyes, 41.2%), particularly herpetic keratitis (five eyes), was the most common predisposing factor. Other risk factors, including trauma (three eyes), systemic disease (three eyes), contact lens wear (two eyes), and recent ocular surgery (two eyes), were relatively evenly distributed. Prior corticosteroid use was noted in eight (47.1%) patients.\n\nOf the 17 B. cepacia culture-positive scrapings, seven cases (41.2%) were polymicrobial (Table 1). All 17 B. cepacia isolates were susceptible to ceftazidime; all except for one (16/17, 94.1%) were susceptible to meropenem and sulfamethoxazole–trimethoprim.\n\nAll patients were treated with empiric topical antibiotics initially, and adjustments were made according to clinical response or culture results. Levofloxacin, ceftazidime, and amikacin, the main antibiotics for treating B. cepacia keratitis, were prescribed to nine (52.9%), six (35.3%), and two (11.7%) patients, respectively. In patients with polymicrobial keratitis, other antimicrobials were added. A total of 12 patients (70.6%) responded well to antimicrobials, whereas five patients (29.4%) required surgical interventions including amniotic graft transplantation, patch graft, tarsorrhaphy, and evisceration. Multiple surgeries were required in three patients.\n\nVisual acuity (VA) worse than 20/200 was noted in 14 patients (82.4%) at presentation; moreover, four patients (23.5%) had no light perception. After treatment, six eyes exhibited improved vision but only four patients (23.5%) had a final VA better than 20/200.\n\nCase report (Patient 13)\nAn 84-year-old female patient with herpes simplex virus disciform keratitis was undergoing treatment with topical prednisolone acetate (1%) and oral acyclovir and exhibited sudden onset of blurred vision in her right eye one month after discontinuing the antiviral medication. On examination, VA in the right eye was hand motions. Slit-lamp examination revealed corneal epithelial defect with infiltrate, thinning with a descematocele, and localized edema; strong anterior chamber reaction with hypopyon was also present (Fig. 1). Corneal scrapings were sent for cultures. She was administered on topical vancomycin (25 mg/mL) and ceftazidime (25 mg/mL) hourly and oral famciclovir three times a day. The corneal culture grew B. cepacia complex, susceptible to ceftazidime, meropenem, and sufamethoxazole-trimethoprim. She was maintained on topical ceftazidime, and when the infection was controlled, a topical corticosteroid was added. The ulceration resolved within 1 week. At 9-month follow-up, she had a corneal scar with VA of 20/400 in the right eye.\n\n\nFig. 1 The slit-lamp photograph revealed central corneal epithelial defect with infiltrate, thinning with a descemetocele, and hypopyon\n\n\n\nDiscussion\nB. cepacia is a rare causative agent of keratitis; only eight cases of B. cepacia keratitis have been reported in previous studies (Table 2). B. cepacia accounted for 0.51% (5/875) of microbial keratitis cases in our previous ten-year (2003–2012) study [11], but we identified 12 more cases in recent years. To our best knowledge, this study is by far the largest case series related to B. cepacia keratitis. In conjunction with previously reported cases, we provided a more detailed overview of the clinical characteristics of B. cepacia keratitis.\n\n\nTable 2 Clinical data of the patients with Burkholderia capecia keratitis\n\n\tAge/sex\tRisk factor\tPrior steroid use\tLocation, size\tHypopyon\tMedical treatment\tSurgery\tPresenting VA\tFinal VA\tOther isolates\\\t\nMatoba et al. [7]\t59/m\tHSV keratitis\t+\tC, M\t-\tLevofloxacin\t-\tCF\t20/200\tEnterococcus species, Staphylococcus aureus\t\nLin et al. [5]\t16/f\tOrtho-keratology lens\t–\tPC, S\t–\tCiprofloxacin\t–\t20/40\t20/20\tPseudomonas putida, Pseudomonas aeruginosa.\t\nOrnek et al. [18]a\t78/f\tCataract surgery\t+\tC, M\t–\tCiprofloxacin +IVI\n\nCeftazidime\n\n\t–\tNLP\tNA\t\t\nChaurasia et al. [4]\tNA\tUnknown\t+\tNA, M\t–\tCiprofloxacin\tTissue adhesive\tLP\tNA\t\t\n\tNA\tUnknown\t–\tNA, S\t+\tCiprofloxacin\t–\tNA\tNA\t\t\n\tNA\tTrauma\t–\tNA, L\t+\tCiprofloxacin\tTPK\tLP\tNA\t\t\n\tNA\tTPK\t+\tNA, S\t–\tCeftazidime\t–\tHM\tNA\t\t\nReddy et al. [9]\t27/m\tLASIK\t+\tC, multiple infiltrates\t+\tTobramycin and Gatifloxacin\t\tCF\t20/20\t\t\nC central, CF counting fingers, f female, HM hand motion, IVI intravitreal injection, L large, LASIK laser assisted in situ keratomileusis, LP light perception, m male, M medium, NA not available, NLP no light perception, PC paracentral, S small, TPK therapeutic penetrating keratoplasty\n\na A case of keratitis and endophthalmitis\n\n\n\nIn our study, the most common predisposing factor of B. cepacia keratitis was preexisting ocular disease, particularly herpetic keratitis. Matoba et al. also presented a patient with herpetic stroma keratitis, under oral acyclovir and topical prednisolone acetate treatment, who developed polymicrobial keratitis including B. ambifaria (belonging to the B. cepacia complex), Enterococcus spp., and Staphylococcus aureus [7]. Infection with herpes virus might cause sub-basal nerve damage of the cornea [12, 13]. The impaired corneal sensory innervation leads to a reduction of protective reflexes and trophic neuromodulators, which affect the wound-healing function of the cornea [14], making its surface an easy target for opportunistic bacteria such as B. cepacia. In addition, if the local immune response has been suppressed by topical steroids, a herpetic corneal ulcer can predispose microbial adherence, furthering the infection. Recent ocular surgery with simultaneous topical steroid use was noted in three of the previously reported eight patients with B. cepacia keratitis and two patients in our study (Tables 1 and 2), suggesting that local immunosuppression may play a role in such an opportunistic infection.\n\nIn our study, approximately 40% of B. cepacia culture-positive corneal scrapings were polymicrobial, as were two (25%) of the previously reported eight cases (Table 2). These mixed infections might be due to direct inoculation because of a corneal injury, contamination through the process of corneal scraping, or opportunistic transmission in these immunocompromised patients [15]. Tuft et al. proposed a synergy effect of interactions between organisms in polymicrobial infection [16] and speculated that the primary organism may create a niche, either by providing a sequestered environment or by supplying specific metabolic requirements for a second organism, that predisposes the host to further infection or turns a normally nonpathogenic organism into a pathogen. The mixed infections might modulate the clinical course of the disease, causing unexpected treatment effects.\n\nB. cepacia demonstrates multidrug resistance, including resistance to carboxypenicillins, polymyxins, and aminoglycosides. Nevertheless, sulfamethoxazole–trimethoprim, ceftazidime, and meropenem have been revealed to be the most effective agents on the basis of in vitro susceptibility data, which agrees with our drug susceptibility test results [17]. We did not test for susceptibility to fluoroquinolones, the most popular empiric antibiotic in the field of ophthalmology. Chaurasia et al. performed an antibiotic susceptibility test for four B. cepacia isolated from keratitis and reported 100% susceptibility to ceftazidime and 50% susceptibility to ciprofloxacin/norfloxacin [4]. In the case report by Reddy et al. the isolate from the patient with B. cepacia keratitis was resistant to moxifloxacin, gatifloxacin, tobramycin, and ceftazidime and susceptible only to sulfamethoxazole–trimethoprim in vitro; nevertheless, in vivo, the ulcer resolved completely after tobramycin and gatifloxacin treatment (Table 2) [9]. The other three isolates from previously reported B. cepacia keratitis cases were susceptible to ceftazidime and ciprofloxacin [5, 7, 18]. On the basis of the antibiotic susceptibility and clinical results of the patients with B. cepacia keratitis (Tables 1 and 2), fluoroquinolones could be initiated as empiric antibiotics. However, if fluoroquinolone use does not improve the clinical course, ceftazidime may be a suitable alternative. Even after aggressive medical treatment, about one-third of the patients in our study and two (25%) of the previously reported eight B. cepacia keratitis cases required surgical interventions (Tables 1 and 2).\n\nThe visual outcome of B. cepacia keratitis was generally poor both in our and previously reported cases (Tables 1 and 2). The unfavorable visual outcomes may be related to old age, poor vision at presentation, comorbidities, and mixed infections. The rather high surgical rates and perforation rates may also contribute to the poor prognosis of the disease.\n\nThe retrospective design and small sample size are the limitations of this study. In addition, elucidating the real pathogenic role of B. cepacia was difficult because polymicrobial infections were detected in approximately 40% of our patients. Nevertheless, as the largest case series reporting B. cepacia keratitis, this study provides more detailed information regarding the clinical and microbiological profiles of this infection.\n\nIn conclusion, although relatively uncommon, B. cepacia could be a causative agent of infectious keratitis. Our findings revealed that preexisting ocular disease, particularly herpetic keratitis, was the leading predisposing factor of B. cepacia keratitis. B. cepacia demonstrated clinical response to the treatment of ceftazidime and fluoroquinolone, but some patients required surgical intervention. However, the visual outcome was generally poor.\n\nAbbreviation\nVAVisual acuity\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthors’ contributions\nAll authors have participated directly in planning and execution of the work. MCH, EYCK: acquisition and analysis of data, drafting and writing the article;LKY, DHKM, HCL, HYT, HCC: acquisition and analysis of data; CHH: design of the study, acquisition of data, final approval. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe data analyzed during this study are available on request from the corresponding author, Ching-Hsi Hsiao. The data are not publicly available due to it containing information that could compromise the privacy of research participants.\n\nEthics approval and consent to participate\nThe study adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB number: 202000181B0), which granted a waiver of consent because patient anonymity was maintained by the data source.\n\nConsent for publication\nThe consent for publication of biometric data from Patient 13 was obtained.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Mahenthiralingam E Urban TA Goldberg JB The multifarious, multireplicon Burkholderia cepacia complex Nat Rev Microbiol 2005 3: 144 56 10.1038/nrmicro1085 15643431 \n2. LiPuma JJ Update on the Burkholderia cepacia complex Curr Opin Pul Medicine 2005 11 528 33 10.1097/01.mcp.0000181475.85187.ed \n3. Sachdeva V Joseph V Sharma S Das T Burkholderia cepacia Endophthalmitis Clinico-Microbiologic Profile Outcomes Retina 2011 31 1801 5 21478807 \n4. Chaurasia S Muralidhar R Das S Sangwan VS Reddy AK Gopinathan U Keratitis Caused by Burkholderia cepacia Br J Ophthalmol 2011 95: 746 7 10.1136/bjo.2010.187492 20940314 \n5. Lin YC Chen KH Hsu WM Daytime orthokeratology associated with infectious keratitis by multiple gram-negative bacilli: Burkholderia cepacia, Pseudomonas putida, and Pseudomonas aeruginosa Eye Contact Lens 2006 32 19 20 10.1097/01.icl.0000167714.53847.8c 16415688 \n6. Eser I Altan T Stahl J Aydin M Inan N Kapran Z Yilmaz O Two cases of Burkholderia cepacia endophthalmitis Br J Ophthalmol 2006 90 1211 10.1136/bjo.2006.097972 \n7. Matoba AY Polymicrobial keratitis secondary to Burkholderia ambifaria, enterococcus , and staphylococcus aureus in a patient with herpetic stromal keratitis Br J Ophthalmol 2003 136 748 9 \n8. Pathengay A Raju B Sharma S Das T Recurrent endophthalmitis caused by Burkholderia cepacia Eye 2005 19 358 10.1038/sj.eye.6701501 15286665 \n9. Reddy JC Tibbetts MD Hammersmith KM Nagra PK Rapuano CJ Successful management of Burkholderia cepacia keratitis after LASIK J Refract Surg 2013 29 8 9 10.3928/1081597X-20121228-02 \n10. Wright TM Afshari NA Microbial keratitis following corneal transplantation Am J Ophthalmol 2006 142 1061 2 10.1016/j.ajo.2006.06.051 17157593 \n11. Hsiao CH Sun CC Yeh LK Ma DH Chen PY Lin HC Tan HY Chen HC Chen SY Huang YC Shifting trends in bacterial keratitis in Taiwan: a 10-year review in a tertiary-care hospital Cornea 2016 35 313 7 10.1097/ICO.0000000000000734 26764878 \n12. Danileviciene V Zemaitiene R Gintauskiene VM Nedzelskiene I Zaliuniene D Corneal sub-basal nerve changes in patients with herpetic keratitis during acute phase and after 6 months Medicina 2019 55 214 10.3390/medicina55050214 \n13. Versura P Giannaccare G Pellegrini M Sebastiani S Campos EC Neurotrophic keratitis: current challenges and future prospects Eye Brain 2018 10 37 45 10.2147/EB.S117261 29988739 \n14. Sousa SA Ramos CG Leitao JH Burkholderia cepacia complex: emerging multihost pathogens equipped with a wide range of virulence factors and determinants Int J Microbiol 2011 607575 9 \n15. Ahn M Yoon KC Ryu SK Cho NC You IC Clinical aspects and prognosis of mixed microbial (bacterial and fungal) keratitis Cornea 2011 30 409 13 10.1097/ICO.0b013e3181f23704 21045645 \n16. Tuft S Polymicrobial infection and the eye Br J Ophthalmol 2006 90 257 8 10.1136/bjo.2005.084095 16488937 \n17. Sfeir MM Burkholderia cepacia complex infections: more complex than the bacterium name suggest J Infect 2018 77 166 70 10.1016/j.jinf.2018.07.006 30012345 \n18. Ornek K Ozdemir M Ergin A Burkholderia cepacia keratitis with endophthalmitis J Med Microbiol 2009 58 1517 8 10.1099/jmm.0.011197-0 19661206\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1476-0711",
"issue": "20(1)",
"journal": "Annals of clinical microbiology and antimicrobials",
"keywords": "Burkholderia cepacia; corneal ulcer; drug susceptibility; keratitis",
"medline_ta": "Ann Clin Microbiol Antimicrob",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019121:Burkholderia Infections; D016956:Burkholderia cepacia; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D007634:Keratitis; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014792:Visual Acuity",
"nlm_unique_id": "101152152",
"other_id": null,
"pages": "6",
"pmc": null,
"pmid": "33413453",
"pubdate": "2021-01-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26764878;16217180;20940314;17157593;29988739;16929075;23311735;19661206;16488937;15286665;14516823;16415688;21045645;31137905;21478807;20811541;30012345;15643431",
"title": "Clinico-microbiological profile of Burkholderia cepacia keratitis: a case series.",
"title_normalized": "clinico microbiological profile of burkholderia cepacia keratitis a case series"
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"abstract": "OBJECTIVE\nAcetaminophen-related acute liver injury and liver failure (ALF) result from ingestion of supratherapeutic quantities of this analgesic, frequently in association with other forms of substance abuse including alcohol, opioids, and cocaine. Thus, overdosing represents a unique high-risk behavior associated with other forms of drug use disorder.\n\n\nMETHODS\nWe examined a series of 21 single nucleotide polymorphisms (SNPs) in 9 genes related to impulsivity and/or stress responsivity that may modify response to stress. Study subjects were 229 white patients admitted to tertiary care liver centers for ALF that was determined to be due to acetaminophen toxicity after careful review of historical and biochemical data. Identification of relevant SNPs used Sanger sequencing, TaqMan, or custom microarray. Association tests were carried out to compare genotype frequencies between patients and healthy white controls.\n\n\nRESULTS\nThe mean age was 37 years, and 75.6% were female, with similar numbers classified as intentional overdose or unintentional (without suicidal intent, occurring for a period of several days, usually due to pain). There was concomitant alcohol abuse in 30%, opioid use in 33.6%, and use of other drugs of abuse in 30.6%. The genotype frequencies of 2 SNPs were found to be significantly different between the cases and controls, specifically SNP rs2282018 in the arginine vasopressin gene (AVP, odds ratio 1.64) and SNP rs11174811 in the AVP receptor 1A gene (AVPR1A, odds ratio 1.89), both of which have been previously linked to a drug use disorder diagnosis.\n\n\nCONCLUSIONS\nPatients who develop acetaminophen-related ALF have increased frequency of gene variants that may cause altered stress responsivity, which has been shown to be associated with other unrelated substance use disorders.",
"affiliations": "Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, New York.;Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, New York.;Center for Clinical and Translational Science, Rockefeller University, New York, New York.;Center for the Genetics of Host Defense, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas.;Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas.;Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, New York.;Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas.",
"authors": "Randesi|Matthew|M|;Levran|Orna|O|;Correa da Rosa|Joel|J|;Hankins|Julia|J|;Rule|Jody|J|;Kreek|Mary Jeanne|MJ|;Lee|William M|WM|;|||",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.jcmgh.2017.01.008",
"fulltext": "\n==== Front\nCell Mol Gastroenterol HepatolCell Mol Gastroenterol HepatolCellular and Molecular Gastroenterology and Hepatology2352-345XElsevier S2352-345X(17)30016-410.1016/j.jcmgh.2017.01.008Original ResearchAssociation of Variants of Arginine Vasopressin and Arginine Vasopressin Receptor 1A With Severe Acetaminophen Liver Injury Randesi Matthew 1Levran Orna 1Correa da Rosa Joel 2Hankins Julia 3Rule Jody 4Kreek Mary Jeanne 1bLee William M. william.lee@utsouthwestern.edu4∗bAcute Liver Failure Study GroupReuben Adrian Fontana Robert J. Davern Timothy McGuire Brendan Stravitz R. Todd Durkalski Valerie Liou Iris Fix Oren Schilsky Michael Ganger Daniel MDChung Raymond T. Koch David Reddy K. Rajender Rossaro Lorenzo 1 Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, New York2 Center for Clinical and Translational Science, Rockefeller University, New York, New York3 Center for the Genetics of Host Defense, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas4 Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas∗ Correspondence Address correspondence to: William M. Lee, MD, FACP, FAASLD, Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, Suite 420, Dallas, Texas 75390-8887. fax: (214) 645–6114.Division of Digestive and Liver DiseasesUT Southwestern Medical Center at Dallas5959 Harry Hines Boulevard, Suite 420DallasTexas 75390-8887 william.lee@utsouthwestern.edub Authors share co-senior authorship.\n\n5 2017 24 1 2017 3 3 500 505 30 11 2016 16 1 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background & Aims\nAcetaminophen-related acute liver injury and liver failure (ALF) result from ingestion of supratherapeutic quantities of this analgesic, frequently in association with other forms of substance abuse including alcohol, opioids, and cocaine. Thus, overdosing represents a unique high-risk behavior associated with other forms of drug use disorder.\n\nMethods\nWe examined a series of 21 single nucleotide polymorphisms (SNPs) in 9 genes related to impulsivity and/or stress responsivity that may modify response to stress. Study subjects were 229 white patients admitted to tertiary care liver centers for ALF that was determined to be due to acetaminophen toxicity after careful review of historical and biochemical data. Identification of relevant SNPs used Sanger sequencing, TaqMan, or custom microarray. Association tests were carried out to compare genotype frequencies between patients and healthy white controls.\n\nResults\nThe mean age was 37 years, and 75.6% were female, with similar numbers classified as intentional overdose or unintentional (without suicidal intent, occurring for a period of several days, usually due to pain). There was concomitant alcohol abuse in 30%, opioid use in 33.6%, and use of other drugs of abuse in 30.6%. The genotype frequencies of 2 SNPs were found to be significantly different between the cases and controls, specifically SNP rs2282018 in the arginine vasopressin gene (AVP, odds ratio 1.64) and SNP rs11174811 in the AVP receptor 1A gene (AVPR1A, odds ratio 1.89), both of which have been previously linked to a drug use disorder diagnosis.\n\nConclusions\nPatients who develop acetaminophen-related ALF have increased frequency of gene variants that may cause altered stress responsivity, which has been shown to be associated with other unrelated substance use disorders.\n\nKeywords\nImpulsivityStress ResponsivityPituitary-Adrenal AxisOverdoseAbbreviations used in this paper\nALF, acute liver failureALFSG, Acute Liver Failure Study GroupAPAP, acetaminophenSNP, single nucleotide polymorphism\n==== Body\nSummary\nAcetaminophen (APAP)-related acute liver injury/liver failure (ALF) often appears to occur in the setting of substance abuse. We identified two single nucleotide polymorphisms previously associated with drug use disorder in a carefully adjudicated group of APAP ALF patients.\n\n\n\nAcetaminophen (APAP)-induced liver injury is the most common cause of acute liver failure (ALF) in American adults,1 with nearly 500 deaths annually attributed to excessive dosing of this ubiquitous pain reliever. The safe upper limit for daily dosing has variably been thought to be 4000 mg/day or possibly less.2 Excessive APAP dosing can occur with intent of self-harm (suicide attempt) or unintentionally while seeking pain relief, typically for a period of several days by using increased amounts each day.3, 4 Early on, an association was made between alcohol abuse and APAP unintentional overdoses, referred to initially as therapeutic misadventure.5 Both intentional and unintentional APAP overdoses have been shown to be associated with substance abuse of both alcohol and opioids, particularly the opioid (hydrocodone/acetaminophen) combination products.6 In 1 study of 275 APAP-related ALF patients, 55% had a history of alcohol use and 35% a history of alcohol abuse, and 53% had taken an opioid-APAP combination product.4 In a follow-up study of a larger cohort of 306 APAP toxicity survivors, 55% had a history of psychiatric disease compared with only 27% of non-APAP survivors, 46% of APAP patients had a history of prior substance abuse vs 15% of non-APAP patients, and 14% had a specific history of injection drug use vs 8% for the non-APAP group.7 Understanding what determines these behaviors might lead to better identification of high-risk patients and development of prevention strategies.\n\nWith either intentional or unintentional etiologies, critical behavioral differences could lead to high-risk behaviors. Impulsivity is a character trait defined as “acting suddenly in an unplanned manner to satisfy a desire,” ie, not thinking things through to understand the potential impact of a decision. More recently, impulsivity has been recognized as a measurable trait that is correlated with a variety of addictive behaviors.8 We have recently shown that higher impulsivity scores on the Barratt impulsivity scale are detected in both intentional and unintentional APAP overdoses when compared with control populations (Sanders C, Lee WM, unpublished data, submitted for publication).\n\nDuring the last 15 years numerous single nucleotide polymorphisms (SNPs) have been found to be associated with addictive behavior, including impulsivity.8, 9, 10 Many of these SNPs are in genes associated with the stress response, including the genes involved in hormonal systems of the hypothalamic/pituitary/adrenal axis.11, 12, 13, 14, 15, 16, 17, 18 For example, the μ-opioid receptor gene, OPRM1, has polymorphisms, specifically A118G, that have been linked to increased vulnerability/susceptibility to alcohol and opioid addiction.11, 14, 15, 19 The μ-opioid receptor is used by both exogenous and endogenous opiates and can exert control over stress responsivity, addiction, and withdrawal. We hypothesized that this polymorphism or others that are related may have an impact in patients with APAP overdoses, especially in patients who have multiple substance dependencies. Furthermore, we speculated that the genetic association may be stronger or more apparent in subjects with intentional APAP overdose compared with those with nonintentional overdose. Thus, variations in several of these genes that alter the host’s ability to respond to stressful situations may indeed correlate with the observed tendency of addictive behavior.\n\nThe Acute Liver Failure Study Group (ALFSG) (ClinicalTrials.gov: NCT00518440) has been prospectively identifying and studying the etiologies, presenting features, and clinical outcomes of adults with ALF during the past 17 years while collecting biosamples—serum, plasma, and DNA. During this time period, ALFSG has enrolled more than 3000 subjects in its registry, 46% of whom suffered from severe or fatal APAP liver injury. Because stress and the response to stress are closely linked to addictive behavior and APAP toxicity patients have frequently been identified as substance abusers, we sought to determine whether specific variants in stress-related genes are over-represented in an APAP overdose cohort compared with population controls. By using DNA from 229 of these APAP subjects, we sought to identify whether selective variants in genes related to stress/impulsivity and addiction are associated with APAP overdose cases, because these findings might shed light on the patients’ tendency to abuse APAP products.\n\nMethods\nPatients\nAmong the 1669 subjects who were enrolled in the ALFSG registry database between January 1, 2002 and December 31, 2013 according to principles established in the initial ALFSG report,1 we selected a consecutive group of patients with unequivocal APAP in whom DNA had also been collected as part of enrollment. Subjects in the overall adult ALFSG registry were enrolled from 33 academic centers in the United States and met criteria for ALF, namely coagulopathy (international normalized ratio ≥ 1.5) and grade 1–4 of hepatic encephalopathy, within 26 weeks of the first symptoms, without overt underlying liver disease. Because patients enrolled are by definition encephalopathic, written informed consent was obtained from the legal next of kin in each case. Demographic, clinical, laboratory, radiologic, and outcomes data were recorded prospectively. For the purpose of the present study, we selected only patients who self-reported as white.\n\nEtiologic diagnoses were made by each study site’s primary investigator on the basis of the history and clinical presentation and laboratory, radiographic, and, when available, liver biopsy results. Further adjudication was provided by using an algorithm for confirmation of APAP overdoses developed by the ALFSG causality subcommittee. The algorithm includes the following specific criteria: a history of APAP ingestion, detection of APAP in plasma, biochemical pattern that is consistent with APAP toxicity with high serum aminotransferase levels (≥1000 IU/L) along with total bilirubin <10.0 mg/dL at presentation, and, if available, presence of APAP-Cys adducts. These criteria have been validated previously in the ALFSG cohort.4 All subjects were considered to fit the patient phenotype as highly likely/definite APAP toxicity if they met the criteria for history of ingestion and/or parent compound detectable, with appropriate biochemistries as outlined.\n\nIntentionality (intentional/suicidal/single time point vs unintentional [typically for pain relief, suicide denied]) was determined by the site investigator on the basis of findings outlined in Schiødt et al.3 The control subjects (n = 208) were healthy volunteers ascertained by the Laboratory of the Biology of Addictive Diseases at the Rockefeller University who were previously genotyped on a custom Illumina addiction array for other studies.13, 17\n\nGenotyping\nGenes/single nucleotide polymorphism selection\nNine genes were selected on the basis of their known involvement with impulsivity and/or stress responsivity. A total of 21 SNPs from these 9 genes were selected on the basis of previous reports of potential functionality and/or association with impulsivity and stress responsivity (Table 1). These SNPs were chosen because they were previously found to be associated with heroin and/or cocaine dependence or show changes in their gene expression when exposed to the drug. The μ-opioid receptor (OPRM1) variants, rs1799971 (A118G) and rs1799972 (C17T), have previously been linked to both alcohol and heroin addiction.14, 15, 19, 20 We have previously shown the catechol-O-methyltransferase (COMT) variants, rs4680 and rs4818, to be associated with opioid dependence.21 The variants in FK506 binding protein 5 (FKBP5), galanin (GAL), arginine vasopressin (AVP), arginine vasopressin receptor 1A (AVPR1A), corticotropin releasing factor (CRH), and CRH receptors 1 and 2 (CRHR1 and CRHR2) were chosen for study because they have been found to be associated with a greater vulnerability for dependence, or they are in high-linkage disequilibrium with an SNP that was found to be associated with addiction.22\n\nGenotyping\nThe OPRM1 SNPs, both located in exon 1, were genotyped by Sanger sequencing a 300–base pair region of the DNA that was first amplified by polymerase chain reaction. Each sequence was manually evaluated for determination of the genotype at the 2 OPRM1 variants. Genotyping of the remaining variants for the case samples was performed by using TaqMan SNP genotyping assays (Life Technologies, Carlsbad, CA) following the manufacturer’s recommended protocol. The end-point reactions were scanned and then analyzed on an ABI Prism 7900HT Sequence Detection System (Life Technologies). All TaqMan genotype data were visually inspected for quality. The control samples were genotyped by using a custom Illumina array as described.17\n\nStatistical Analysis\nAssociation tests were carried out between the following groups: intentional vs unintentional overdoses, unintentional vs controls, and all overdose cases (intentional, unintentional, and unknown) vs controls with PLINK v 1.9. Deviations from Hardy-Weinberg equilibrium were checked by χ2 test with a critical limit of significance of P values <.001 (taking into account Bonferroni correction for multiple SNPs). In addition, SNPs with a minor allele frequency of less than 0.05 were excluded from further analysis. Association analysis was carried out by logistic regression that considered 3 models of inheritance: recessive, dominant, and additive. The nominal significance level was computed according to 2 different methods within each association model: first, from logistic regression (p0) based on the asymptotic distribution of the test statistic (t from Wald test); second, by permutation analysis (EMP1) that compares the observed statistic with 100,000 statistics obtained in permutations in the correspondent SNP. To control the family-wise error rate when testing multiple SNPs, the observed statistic was compared with the maximum of permuted statistics over all SNPs (EMP2).\n\nResults\nThe study group met stringent criteria for APAP diagnosis to be included (Table 2). In addition to clinical criteria, all 43 that were tested were positive for the presence of APAP-Cys adducts, confirming a toxic ingestion.23, 24 Selected clinical data are shown in Tables 2 and 3, divided by intentional, unintentional, and unknown overdose type as described above. The proportion giving a history of alcohol and/or drug abuse or having positive toxicology screening was similar to prior studies. Overall, recorded evidence for abuse of alcohol, opiates, or other drugs of abuse (principally cocaine) was greater than 30%. Among intentional cases, 34 of 99 were believed to have used only 1 of the 3 categories of drugs of abuse listed, 18 took 2, and 3 were positive in all 3 categories. Likewise, among the unintentional group, 45 were found to have used only 1 drug of abuse, 23 had taken 2 classes, and 5 were found to have used 3 types of abuse agents.\n\nThe SNPs genotyped are listed in Table 1. Of these, one SNP, OPRM1 rs1799972 (C17T), was excluded on the basis of minor allele frequency <.05. None of the SNPs in the study significantly violated Hardy-Weinberg equilibrium. Two SNPs, rs2282018 in AVP and rs11174811 in AVPR1A, showed significant association of genotype with APAP overdose when all overdose cases were compared with controls (Table 1, bold highlight). The SNPs are in an intron and the 3' untranslated region, respectively, on chromosome 12. The common alleles, T for AVP SNP rs2282018 (frequency, 0.58) and C for AVPR1A SNP rs11174811 (frequency, 0.72), are the risk alleles. The significant associations were detected under dominant model of inheritance with odds ratios of 1.89 and 1.64, respectively. No other significant associations were detected, and there were no differences observed when the unintentional group was considered separately and compared with the intentional overdose or control groups (data not shown).\n\nDiscussion\nIn the present study, we analyzed genotypes of carefully characterized APAP overdose subjects who had experienced severe liver injury, because both unintentional and intentional overdosing appears to represent high-risk behaviors. The 2 SNPs we identified in the AVP gene and the gene of one of its receptors, AVPR1A, have previously been associated with drug use disorders.16, 17 One of these studies17 used the same control sample that was used in the current study but a different case sample. We did not observe differences in the gene frequency between the intentional and unintentional groups. This could relate to the relatively small sample sizes, or that both groups, as noted, are associated with drug use disorders and impulsivity.4, 6, 7\n\nAnalysis of a limited and select group of candidate systems of genes that are associated with drug use behavior allowed us to narrow our focus, providing a wider approach than specific targeted SNPs but a narrower one than conventional genome-wide association studies. AVPR1A receptors are located throughout the brain and may serve several functions, but they specifically are associated with stress responsivity, how the pituitary-adrenal axis responds to stress. AVPR1A variants have been studied extensively and show strong associations with several social behaviors including sibling conflict and autism.16, 25, 26, 27, 28, 29 The AVPR1A SNP rs11174811 identified in the current study is specifically thought to be associated with potential seed recognition sites for microRNAs miR-526b and miR-578 and has been shown to be functional in vitro.28 Disruption of microRNA binding by the AVPR1A rs11174811 risk allele appears to confer poorer response to stress as shown in a variety of settings.16 The functionality of AVP SNP rs2282018 is unknown; however, arginine vasopressin ligands and receptors compose the pituitary axis for at least some forms of stress responses.29\n\nAlthough highly popular, APAP is a dose-related toxin with a relatively narrow therapeutic window, resulting in frequent overdosing in certain settings such as unrelieved pain and where the perception is of its great safety. The tendency to display impulsive behavior and to use 1 or more additional substances including alcohol and the combination opioid/acetaminophen products has been well-recognized, conferring increased risk associated with both suicidal and unintentional overdoses.4, 6, 7 Subjects in the present study were selected for the specific phenotype of APAP ALF by using a detailed algorithm developed by the ALFSG, supplemented by the APAP adduct assay, to provide a high degree of certainty that APAP toxicity was present and caused the liver failure in the patients studied.23, 24 It is noteworthy that most of the SNPs examined encode for stress responsivity and the tendency to addictive behaviors across the drug use disorder spectrum: alcohol, opiates, and cocaine.16\n\nSeveral unrelated SNPs have been identified that encode for increased sensitivity to APAP toxicity, involving polymorphisms in either the cytochrome P450 or UDP-glucuronosyltransferase genes.30, 31 These SNPs were not examined here. They might be important in certain patients who are susceptible to liver injury after ingesting less than 4 g/day, the maximum accepted level for safe APAP ingestion; however, this remains controversial. Such patients are infrequent and unlikely to account for the relatively common occurrence of ALF that is in association, for the most part, with documented overdoses of significant proportion.5\n\nWe conclude that APAP ALF patients, who are known to have a propensity for impulsivity and high-risk behavior, have higher frequency of certain genetic variants associated with drug use disorders. These variants have been previously shown to relate in part to altered stress responsivity. This clinical association in our population is largely confined to the AVP and AVPR1A gene loci.16, 17, 29 These initial observations should now be confirmed in a larger study of carefully selected APAP overdose patients.\n\nAcknowledgments\nThe Acute Liver Failure Study Group investigators during the period the patient data and DNA were collected included Adrian Reuben, Robert J. Fontana, Timothy Davern, Brendan McGuire, R. Todd Stravitz, Valerie Durkalski, Iris Liou, Oren Fix, Michael Schilsky, Daniel Ganger, MD, Raymond T. Chung, David Koch, K. Rajender Reddy, and Lorenzo Rossaro.\n\nConflicts of interest The authors disclose no conflicts.\n\nFunding Supported by NIDDK U-01-DK58369, W.M.L., principal investigator, and a grant to M.J.K. from the Dr. Miriam & Sheldon G. Adelson Medical Research Foundation. The testing for acetaminophen adducts was performed in the laboratory of Dr Laura James, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital Research Institute, Little Rock, AR.\n\nTable 1 List of SNPs Evaluated\n\nGene\tSNP\tCHR\tPosition\tLocation\tAlleles\tMAF\tModel\tp0\tEMP1\tEMP2\tOR (95% CI)\t\nAVP\trs2282018\t20\t3064949\tIntronic\tT/C\t0.42\tDom\t.028\t0.030\t0.258\t1.89 (1.07–3.34)\t\n\trs2740204\t20\t3062467\tIntronic\tC/A\t0.40\tDom\t.104\t0.099\t0.832\t\t\nAVPR1A\trs11174811\t12\t63540476\t3′ UTR\tC/A\t0.18\tDom\t.018\t0.015\t0.252\t1.64 (1.08–2.50)\t\n\trs3021529\t12\t63545680\t5′ UTR\tC/T\t0.15\tDom\t.053\t0.044\t0.589\t\t\nCOMT\trs4818\t22\t19951207\tIntronic\tC/G\t0.41\tRec\t.383\t0.357\t0.999\t\t\n\trs4680\t22\t19951271\tIntronic\tG/A\t0.49\tRec\t.829\t0.821\t1\t\t\nCRH\trs6996265\t8\t67086350\t3′UTR\tG/A\t0.11\tRec\t.181\t0.141\t0.948\t\t\n\trs3176921\t8\t67091379\tPromoter\tT/C\t0.11\tRec\t.115\t0.102\t0.727\t\t\n\trs6472257\t8\t67092180\tPromoter\tG/A\t0.10\tRec\t.181\t0.141\t0.948\t\t\nCRHR1\trs81189\t17\t43894798\tIntronic\tG/C\t0.22\tDom\t.554\t0.566\t1\t\t\n\trs242939\t17\t43895579\tIntronic\tT/C\t0.49\tDom\t.989\t0.999\t1\t\t\n\trs8072451\t17\t44282654\tIntronic\tC/T\t0.07\tDom\t.543\t0.522\t1\t\t\nCRHR2\trs2284217\t7\t30713608\tIntronic\tC/T\t0.22\tDom\t.106\t0.112\t0.842\t\t\nFKBP5\trs3800373\t6\t35542476\t3′ UTR\tA/C\t0.31\tDom\t.366\t0.364\t0.999\t\t\n\trs7757037\t6\t35548236\tIntronic\tG/A\t0.45\tDom\t.580\t0.595\t1\t\t\n\trs1360780\t6\t35607571\tIntronic\tC/T\t0.32\tDom\t.358\t0.356\t0.999\t\t\n\trs9470080\t6\t35646435\tIntronic\tC/T\t0.33\tDom\t.265\t0.293\t0.993\t\t\nGAL\trs694066\t11\t68452985\tIntronic\tC/T\t0.06\tDom\t.405\t0.390\t1.000\t\t\n\trs3136541\t11\t68457943\tIntronic\tT/C\t0.33\tDom\t.138\t0.119\t0.909\t\t\nOPRM1\trs1799971\t6\t154360797\tIntronic\tA/G\t0.13\tRec\t.418\t0.479\t1.000\t\t\nNOTE. The two po values in bold are the only associations found to be nominally significant. OR above 1 represents risk effect of the major allele. Alleles are listed as major/minor.\n\nChr, chromosome; CI, confidence interval; DOM, dominant; EMP1, point-wise empirical P value obtained by permutation; EMP2, empirical P value that controls for multiple SNPs; MAF, minor allele frequency; OR, odds ratio; po, technical P value obtained from logistic regression; REC, recessive.\n\nTable 2 Age, Gender, and History of Opioid Use, Other Drug Abuse, and Alcohol Use or Abuse for the Overall APAP Group and Subgroups\n\n\tAll (N = 229)\tIntentional (N = 99)\tUnintentional (N = 98)\tUnknown (N = 32)\t\nAge, y (median)\t37\t34\t38\t50\t\n\tN\t%\tN\t%\tN\t%\tN\t%\t\nGender (female)\t173\t75.6\t73\t73.7\t77\t78.6\t23\t71.8\t\nOpioid use\t77\t33.6\t19\t19.2\t45\t45.9\t13\t59.4\t\nOther drug abuse\t70\t30.6\t33\t33.3\t28\t28.6\t9\t28.1\t\nEtOH use\t84\t36.7\t33\t33.3\t40\t40.8\t11\t34.4\t\nEtOH abuse\t69\t30.1\t27\t27.3\t33\t33.7\t9\t28.1\t\nNOTE. Of the 229 APAP subjects, 197 were classifiable as intentional or unintentional, with 32 remaining as unknown type.\n\nEtOH abuse, >4 drinks daily or >14 drinks per week; EtOH (alcohol) use, 1–4 drinks daily or <14 per week (16 mg/drink); other drug abuse, history or toxicology screen positive for cocaine, benzodiazepines, other non-specified polysubstances.\n\nTable 3 Laboratory Data for the Same APAP Groups\n\n\tAll\tIntentional\tUnintentional\tUnknown\t\nN\tMedian\tMean\tN\tMedian\tMean\tN\tMedian\tMean\tN\tMedian\tMean\t\nAST (IU/L)\t229\t5734\t6933\t99\t6333\t7670\t98\t5423\t6441\t32\t4123\t6158\t\nALT (IU/L)\t229\t4867\t5779\t99\t5864\t6573\t98\t4538\t5424\t32\t3810\t4412\t\nT Bili (mg/dL)\t229\t3.9\t4.5\t99\t3.9\t4.1\t98\t3.9\t4.0\t32\t6.4\t7.1\t\nAPAP level (mg/L)\t217\t32.0\t79.6\t96\t69.3\t119.4\t91\t24.0\t44.1\t30\t42.0\t59.7\t\nAdducta (nmol/mL)\t43\t9.9\t13.0\t21\t11.0\t15.9\t19\t7.4\t9.7\t3\t17.1\t14.5\t\nNOTE. Values >1 nmol APAP-Cys/mL are considered significant and specific for APAP hepatotoxicity.20\n\nALT, alanine aminotransferase; AST, aspartate aminotransferase; T Bili, total bilirubin.\n\na Adduct levels are measured by high-pressure chromatography with electrochemical detection.\n==== Refs\nReferences\n1 Ostapowicz G. Fontana R.J. Schiodt F.V. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States Ann Intern Med 137 2002 947 954 12484709 \n2 Acetaminophen: background and overview. Meeting material from the June 29, 2009 joint meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Advisory Committee and Nonprescription Drug Advisory Committee 2009 Food and Drug Administration Silver Spring, MD Available at: http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm Accessed January 19, 2016 \n3 Schiødt F.V. Rochling F.J. Casey D.L. Acetaminophen toxicity in an urban county hospital N Engl J Med 337 1997 1112 1117 9329933 \n4 Larson A.M. Fontana R.J. Davern T.J. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study Hepatology 42 2005 1364 1372 16317692 \n5 Seeff L. Cuccerini B.A. Zimmerman H.J. Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure Ann Intern Med 104 1986 399 404 3511825 \n6 Lee W.M. Acetaminophen hepatotoxicity: changing perceptions of a social/medical issue Hepatology 46 2007 966 970 17894320 \n7 Fontana R.J. Ellerbe C. Durkalski V.E. Two-year outcomes in initial survivors with acute liver failure: results from a prospective, multicenter study Liver Int 35 2015 370 380 25039930 \n8 Kreek M.J. Nielsen D.A. Butelman E.R. Genetic influences on impulsivity, risk-taking, stress responsivity, and vulnerability to drug abuse and addiction Nat Neurosci 8 2006 1450 1457 \n9 Kreek M.J. Levran O. Reed B. Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics J Clin Invest 122 2012 3387 3393 23023708 \n10 Reed B. Butelman E. Yuferov V. Genetics of opiate addiction Curr Psychiatry Rep 16 2014 504 25209027 \n11 Bond C. LaForge K.S. Tian M. Single-nucleotide polymorphism in the human Mu opioid receptor gene alters β-endorphin binding and activity: possible implications for opiate addiction Proc Natl Acad Sci 95 1998 9608 9613 9689128 \n12 Kreek M.J. Role of a functional human gene polymorphism in stress responsivity and addictions Clin Pharmacol Ther 83 2008 615 618 18323858 \n13 Levran O. London O. O’Hara K. Genetic susceptibility to heroin addiction: a candidate gene association study Genes Brain Behavior 7 2008 720 729 \n14 Bart G. Kreek M.J. LaForge S. Increased attributable risk related to a functional m-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden Neuropsycho-pharmacology 30 2005 417 422 \n15 Bart G. Heilig M. LaForge S. Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden Molecular Psychiatry 9 2004 547 549 15037869 \n16 Maher B.S. Vladimirov V.I. Latendresse S.J. The AVPR1A gene and substance abuse disorders: association, replication and functional evidence Biol Psychiatry 70 2011 519 527 21514569 \n17 Levran O. Peles E. Randesi M. Stress-related genes and heroin addiction: a role for a functional FKBP5 haplotype Psychoneuroendocrinology 45 2014 67 76 24845178 \n18 Levran O. Peles E. Randesi M. Dopaminergic pathway polymorphisms and heroin addiction: further support for association of casein kinase 1ε variants Pharmacogenomics 16 2014 2001 2009 \n19 Kroslak T. LaForge S. Gianotti R.J. The single nucleotide receptor polymorphism A118G alters functional properties of the mu opioid receptor J Neurochem 103 2007 77 87 17877633 \n20 Crystal H.A. Hamon S. Randesi M. A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African American women Addict Biol 17 2012 181 191 21070507 \n21 Levran O. Randesi M. da Rosa J.C. Overlapping dopaminergic pathway genetic susceptibility to heroin and cocaine addictions in African Americans Ann Hum Genet 79 2015 188 198 25875614 \n22 Reed B. Butelman H.R. Yuferov V. Genetics of opiate addiction Curr Psychiatry Rep 16 2014 504 510 25209027 \n23 Davern T.J. II James L.P. Hinson J.A. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure Gastroenterology 130 2006 687 694 16530510 \n24 Khandelwal N. James L.P. Sanders C. Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure Hepatology 53 2011 567 576 21274877 \n25 Meyer-Lindenberg A. Kolachana B. Gold B. Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans Mol Psychiatry 14 2009 968 975 18490926 \n26 Bachner-Melman R. Zohar A.H. Bacon-Shnoor N. Link between vasopressin receptor (AVPR1A) promoter region microsatellites and measures of social behavior J Individ Differ 6 2005 2 10 \n27 Walum H. Westberg L. Henningsson S. Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans Proc Natl Acad Sci U S A 105 2008 14153 14156 18765804 \n28 Nossent A.Y. Hansen J.L. Doggen C. SNPs in microRNA binding sites in 3′-UTRs of RAAS genes influence arterial blood pressure and risk of myocardial infarction Am J Hypertension 24 2011 999 1006 \n29 Kreek M.J. Zhou Y. Levran O. Functions of arginine vasopressin and its receptors: importance of molecular genetic studies in bidirectional translational research Biol Psychiatry 70 2011 502 503 21864735 \n30 Court M.H. Freytsis M. Wang X. The UDP-glucuronosyltransferase (UGT) 1A polymorphism c.2042C>G (rs 8330) is associated with increased human liver acetaminophen glucuronidation, increased UGT1A Exon 5a/5b splice variant mRNA ratio, and decreased risk of unintentional acetaminophen-induced acute liver failure J Pharmacol Exp Ther 345 2013 297 307 23408116 \n31 Court M.H. Peter I. Hazarika S. Candidate gene polymorphisms in patients with acetaminophen-induced acute liver failure Drug Metab Dispos 42 2014 28 32 24104197\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-345X",
"issue": "3(3)",
"journal": "Cellular and molecular gastroenterology and hepatology",
"keywords": "ALF, acute liver failure; ALFSG, Acute Liver Failure Study Group; APAP, acetaminophen; Impulsivity; Overdose; Pituitary-Adrenal Axis; SNP, single nucleotide polymorphism; Stress Responsivity",
"medline_ta": "Cell Mol Gastroenterol Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101648302",
"other_id": null,
"pages": "500-505",
"pmc": null,
"pmid": "28462386",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": "17894320;9689128;24845178;25039930;23023708;25875614;17877633;16317692;18765804;3511825;18518925;16251987;21677697;24104197;25521358;16530510;21274877;15525999;15037869;18323858;12484709;21864735;25209027;9329933;21070507;23408116;21514569;18490926",
"title": "Association of Variants of Arginine Vasopressin and Arginine Vasopressin Receptor 1A With Severe Acetaminophen Liver Injury.",
"title_normalized": "association of variants of arginine vasopressin and arginine vasopressin receptor 1a with severe acetaminophen liver injury"
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... |
{
"abstract": "Two patients developed kidney failure due to oxalate deposition in the kidney while taking orlistat. Cessation of orlistat was followed by partial recovery of kidney function. The mechanism by which orlistat causes hyperoxaluria and the management of orlistat-induced oxalate nephropathy is reviewed. We suggest that all patients taking orlistat are at risk of this condition, which may develop insidiously and is easily overlooked. Monitoring of kidney function of patients taking orlistat is warranted.",
"affiliations": "Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.;Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.;Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.;Department of Histopathology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.",
"authors": "Solomon|Laurence Richard|LR|;Nixon|Andrew Christopher|AC|;Ogden|Leanne|L|;Nair|Beena|B|",
"chemical_list": "D019440:Anti-Obesity Agents; D007783:Lactones; D002129:Calcium Oxalate; D000077403:Orlistat",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Acute Renal Failure; Contraindications And Precautions; Metabolic Disorders; Obesity (nutrition); Renal System",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D019440:Anti-Obesity Agents; D002129:Calcium Oxalate; D005260:Female; D006801:Humans; D006959:Hyperoxaluria; D007683:Kidney Tubular Necrosis, Acute; D007783:Lactones; D008297:Male; D008853:Microscopy; D009765:Obesity; D000077403:Orlistat; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29133578",
"pubdate": "2017-11-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24350530;10730683;17121780;25383321;24049105;24527242;15253722;28236885;23432752;25701816;26645872;15671430;15266516;12010224;9225172;14693982;23342420;27152294;18095746;21482850;23221343;17377509;18272781;15027893;18059457;17185156;24115475;18451780;351269;23739234",
"title": "Orlistat-induced oxalate nephropathy: an under-recognised cause of chronic kidney disease.",
"title_normalized": "orlistat induced oxalate nephropathy an under recognised cause of chronic kidney disease"
} | [
{
"companynumb": "GB-GLAXOSMITHKLINE-GB2017183146",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GLICLAZIDE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of a 41-year-old woman, wearer of contact lenses who was presented to the emergency room with a 2-month history of pain and red eye. She presented with a severe keratitis refractory to quinolones, fortified antibiotics and clotrimazole. Due to the risk of perforation, a tectonic penetrating keratoplasty (PK) was performed. Clinical signs of keratitis recurrence were observed and cultures were positive for Purpureocillium lilacinum (former Paecilomyces lilacinus) The patient did not improve on topical amphotericin B and intracameral voriconazole. Worsening of clinical condition required a new PK. Oral posaconazole was initiated postoperatively and suspended at the fourth postoperative month. The cornea remains clear until the last follow-up visit, 12 months after the second graft. To our knowledge, this is the second case report that documents the effectiveness of oral posaconazole in a refractory P. lilacinus keratitis, resistant to other second-generation triazoles and conventional antifungals.",
"affiliations": "Department of Ophthalmology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.;Clinical Pathology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.;Department of Ophthalmology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.;Department of Ophthalmology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.",
"authors": "Almeida Oliveira|Mariana|M|;Carmo|Analia|A|;Rosa|Andreia|A|;Murta|Joaquim|J|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228645",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(4)",
"journal": "BMJ case reports",
"keywords": "anterior chamber; drugs: infectious diseases; eye; transplantation; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents; D003937:Diagnosis, Differential; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D007634:Keratitis; D015948:Keratoplasty, Penetrating; D010143:Paecilomyces; D012008:Recurrence; D014230:Triazoles",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30975779",
"pubdate": "2019-04-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26135494;21631575;17721308;19054804;16961630;14761725;22002343;24974133;17172900;24858020;19195638;18577634;19284327;26490029;16310149;22925066;18190324;26521140",
"title": "Posaconazole in the treatment of refractory Purpureocillium lilacinum (former Paecilomyces lilacinus) keratitis: the salvation when nothing works.",
"title_normalized": "posaconazole in the treatment of refractory purpureocillium lilacinum former paecilomyces lilacinus keratitis the salvation when nothing works"
} | [
{
"companynumb": "PT-MYLANLABS-2019M1046481",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "OFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "Good outcomes with kidney and liver transplantation in HIV-positive patients have led clinicians to recommend lung transplantation in HIV-positive patients based on extrapolated data. Pre-transplant mycobacterial infection is associated with an increased risk of developing new infection or aggravating existing infection, though it does not contraindicate transplantation in non-HIV-infected patients. However, no data exists regarding the outcome of HIV-positive patients with pre-transplant mycobacterial infection. We report a case of double lung transplantation in a 50-year-old HIV-positive patient with alpha-1 antitrypsin deficiency. Prior to transplantation, Mycobacterium kansasii was isolated in one sputum culture and the patient was considered merely colonized as no clinical evidence of pulmonary or disseminated disease was present. The patient successfully underwent a double lung transplantation. Nontuberculous mycobacterial infection was diagnosed histologically on examination of native lungs. Surveillance and watchful waiting were chosen over treatment of the infection. HIV remained under control post-transplantation with no AIDS-defining illnesses throughout the follow-up. A minimal acute rejection that responded to increased corticosteroids was reported. At 12 months post-transplant, a bronchiolitis obliterans syndrome was diagnosed after a drop in FEV1. No evidence of isolation nor recurrence of nontuberculous mycobacteria was reported post-transplantation. At 15 months post-transplant, the patient remained stable with an FEV1 of 30%. The presence of pre-transplant nontuberculous mycobacterial infection did not translate into recurrence of nontuberculous mycobacterial infection post-transplant. Whether it contributed to bronchiolitis obliterans syndrome remains unknown.",
"affiliations": "Département de Microbiologie médicale et Infectiologie, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.;Service de Chirurgie Thoracique, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.;Service de Pneumologie, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.;Département de Microbiologie médicale et Infectiologie, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.;Département de Microbiologie médicale et Infectiologie, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.",
"authors": "Ambaraghassi|Georges|G|http://orcid.org/0000-0002-2054-5644;Ferraro|Pasquale|P|;Poirier|Charles|C|;Rouleau|Danielle|D|;Fortin|Claude|C|",
"chemical_list": "D000900:Anti-Bacterial Agents; D044966:Anti-Retroviral Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12999",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": null,
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D044966:Anti-Retroviral Agents; D015897:Comorbidity; D006678:HIV; D015658:HIV Infections; D006801:Humans; D008168:Lung; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D019909:Mycobacterium kansasii; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D019562:Viral Load; D019896:alpha 1-Antitrypsin Deficiency",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12999",
"pmc": null,
"pmid": "30203904",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Double lung transplantation in an HIV-positive patient with Mycobacterium kansasii infection.",
"title_normalized": "double lung transplantation in an hiv positive patient with mycobacterium kansasii infection"
} | [
{
"companynumb": "CA-ASTELLAS-2019US007366",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHypersecretion of PTHrP is a relatively common cause of malignancy-related hypercalcemia but has only been described in a few cases of neuroendocrine tumors (NET).\n\n\nOBJECTIVE\nThe aim of this case report is to describe the clinical syndrome, complex therapeutic interventions, and unusual complications caused by persistent PTHrP hypersecretion in a patient with a pancreatic NET.\n\n\nMETHODS\nA 58-yr-old male patient presented with nonspecific abdominal pain and was found to have severe hypercalcemia secondary to a well-differentiated NET of the pancreas associated with extensive liver metastases. Elevated ionized calcium levels accompanied by low serum PTH and remarkably elevated PTHrP concentrations were consistent with PTHrP-related hypercalcemia that proved to be resistant to various chemotherapeutic regimens and supportive therapy. Partial control of the humoral syndrome was obtained only after the application of cytoreductive interventions and the introduction of various molecular targeted therapies. Due to persistent PTHrP action, bone disease emerged in the form of brown tumors.\n\n\nCONCLUSIONS\nThe manifestation of paraneoplastic syndrome due to PTHrP hypersecretion, despite its rareness in NET, should be considered in the differential diagnosis of hypercalcemia in such tumors. Moreover, the appearance of bone lesions in this setting may be in the context of metabolic bone disease and could be misdiagnosed as bone metastases.",
"affiliations": "Department of Pathophysiology (Endocrine Unit), University of Athens Medical School, Mikras Asias 75, 11527, Athens, Greece. geokan@endo.gr",
"authors": "Kanakis|G|G|;Kaltsas|G|G|;Granberg|D|D|;Grimelius|L|L|;Papaioannou|D|D|;Tsolakis|A V|AV|;Öberg|K|K|",
"chemical_list": "D044162:Parathyroid Hormone-Related Protein",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2011-2592",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "97(4)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D015746:Abdominal Pain; D006801:Humans; D006934:Hypercalcemia; D006961:Hyperparathyroidism; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D010002:Osteitis Fibrosa Cystica; D010190:Pancreatic Neoplasms; D044162:Parathyroid Hormone-Related Protein; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "E627-31",
"pmc": null,
"pmid": "22319031",
"pubdate": "2012-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Unusual complication of a pancreatic neuroendocrine tumor presenting with malignant hypercalcemia.",
"title_normalized": "unusual complication of a pancreatic neuroendocrine tumor presenting with malignant hypercalcemia"
} | [
{
"companynumb": "PHHY2012GR037431",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Checkpoint inhibition has emerged as a promising therapeutic strategy for several types of cancer. Immune-related adverse effects (irAEs) commonly involve the endocrine system. Distinguishing endocrine side effect-related symptoms from disease progression or treatment-related toxicity can be challenging. If not recognized in time, endocrine irAEs may be life-threatening. As the use of checkpoint inhibitors is expected to increase, there is a need for more awareness of endocrine irAEs amongst health care professionals. We describe three cases that illustrate the importance of timely recognition, patient education and the management of endocrinopathies. Two patients who were treated with the checkpoint inhibitor ipilimumab developed hypophysitis and subsequent episodes of hypocortisolism. These cases underline both the frequency of diagnostic delay and the importance of patient education with regard to glucocorticoid stress dosage. The third patient presented with diabetes mellitus after administration of nivolumab. A multidisciplinary approach is warranted to ensure optimal care for patients with endocrine irAEs.",
"affiliations": "Amsterdam UMC, locatie VUmc, Afd. Interne Geneeskunde, sectie Endocrinologie, Amsterdam.;Amsterdam UMC, locatie VUmc, Afd. Interne Geneeskunde, sectie Endocrinologie, Amsterdam.;Amsterdam UMC, locatie VUmc, Afd. Medische Oncologie, Amsterdam.;Amsterdam UMC, locatie VUmc, Afd. Medische Oncologie, Amsterdam.;Amsterdam UMC, locatie VUmc, Afd. Medische Oncologie, Amsterdam.;Amsterdam UMC, locatie VUmc, Afd. Interne Geneeskunde, sectie Endocrinologie, Amsterdam.",
"authors": "Chen|Weena J Y|WJY|;Krul-Poel|Yvonne H M|YHM|;Roth|Chantal|C|;Labots|Mariette|M|;van den Eertwegh|Alfons J M|AJM|;Dreijerink|Koen M A|KMA|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab; D000077594:Nivolumab",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "163()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000224:Addison Disease; D000074322:Antineoplastic Agents, Immunological; D003920:Diabetes Mellitus; D006801:Humans; D000072659:Hypophysitis; D000074324:Ipilimumab; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D000077594:Nivolumab",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31714042",
"pubdate": "2019-10-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Endocrine side effects of checkpoint inhibitors.",
"title_normalized": "endocrine side effects of checkpoint inhibitors"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-126259",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Severe haemolytic anaemia is a rare complication of prosthetic valve thrombosis (PVT). Emergent surgical replacement of the affected valve is normally the treatment of choice unless contraindicated, such as in high surgical risk patients. Systemic thrombolysis is the alternative to surgical valve replacement. The purpose of this report is to highlight the unique case of an elderly man with New York Heart Association class IV heart failure, history of extensive cardiopulmonary surgeries and haemorrhagic stroke, who presented with severe haemolytic anaemia secondary to prosthetic mitral valve thrombosis. After weighing the risks and benefits, our decision was to use systemic thrombolytic therapy, even in light of the patient's previous intracranial haemorrhage. Pretreatment and post-treatment Doppler echocardiography showed markedly reduced regurgitant jetting that ultimately resolved completely, thereby eliminating the underlying cause of haemolysis and achieving symptom resolution.",
"affiliations": "Hackensack University Medical Center, Hackensack, New Jersey, USA.;Department of Cardiology, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Hackensack University Medical Center, Hackensack, New Jersey, USA.;Department of Cardiology, Hackensack University Medical Center, Hackensack, New Jersey, USA.",
"authors": "Beckord|Brian|B|;Berkowitz|Robert|R|;Espinoza|Cholene|C|;Anand|Neil|N|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D005343:Fibrinolytic Agents; D006350:Heart Valve Prosthesis; D006801:Humans; D008297:Male; D008943:Mitral Valve; D015912:Thrombolytic Therapy; D013927:Thrombosis; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24879723",
"pubdate": "2014-05-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24062899;1993782;9809956;17170355;9870192;15446502;12598078;18574274;17670514;9362411;8746900",
"title": "Systemic thrombolysis: cure for prosthetic mitral valve thrombosis in the comorbid, non-surgical candidate.",
"title_normalized": "systemic thrombolysis cure for prosthetic mitral valve thrombosis in the comorbid non surgical candidate"
} | [
{
"companynumb": "US-ROCHE-1432192",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nSmoking during pregnancy causes many adverse pregnancy and birth outcomes. Nicotine replacement therapy (NRT) is effective for cessation outside pregnancy but efficacy and safety in pregnancy are unknown. We hypothesised that NRT would increase smoking cessation in pregnancy without adversely affecting infants.\n\n\nOBJECTIVE\nTo compare (1) at delivery, the clinical effectiveness and cost-effectiveness for achieving biochemically validated smoking cessation of NRT patches with placebo patches in pregnancy and (2) in infants at 2 years of age, the effects of maternal NRT patch use with placebo patch use in pregnancy on behaviour, development and disability.\n\n\nMETHODS\nRandomised, placebo-controlled, parallel-group trial and economic evaluation with follow-up at 4 weeks after randomisation, delivery and until infants were 2 years old. Randomisation was stratified by centre and a computer-generated sequence was used to allocate participants using a 1 : 1 ratio. Participants, site pharmacies and all study staff were blind to treatment allocation.\n\n\nMETHODS\nSeven antenatal hospitals in the Midlands and north-west England.\n\n\nMETHODS\nWomen between 12 and 24 weeks' gestation who smoked ≥ 10 cigarettes a day before and ≥ 5 during pregnancy, with an exhaled carbon monoxide (CO) reading of ≥ 8 parts per million (p.p.m.).\n\n\nMETHODS\nNRT patches (15 mg per 16 hours) or matched placebo as an 8-week course issued in two equal batches. A second batch was dispensed at 4 weeks to those abstinent from smoking.\n\n\nMETHODS\n\n\n\nMETHODS\nself-reported, prolonged abstinence from smoking between a quit date and childbirth, validated at delivery by CO measurement and/or salivary cotinine (COT) (primary outcome). Infants, at 2 years: absence of impairment, defined as no disability or problems with behaviour and development. Economic: cost per 'quitter'.\n\n\nRESULTS\nOne thousand and fifty women enrolled (521 NRT, 529 placebo). There were 1010 live singleton births and 12 participants had live twins, while there were 14 fetal deaths and no birth data for 14 participants. Numbers of adverse pregnancy and birth outcomes were similar in trial groups, except for a greater number of caesarean deliveries in the NRT group. Smoking: all participants were included in the intention-to-treat (ITT) analyses; those lost to follow-up (7% for primary outcome) were assumed to be smoking. At 1 month after randomisation, the validated cessation rate was higher in the NRT group {21.3% vs. 11.7%, odds ratio [OR], [95% confidence interval (CI)] for cessation with NRT, 2.05 [1.46 to 2.88]}. At delivery, there was no difference between groups' smoking cessation rates: 9.4% in the NRT and 7.6% in the placebo group [OR (95% CI), 1.26 (0.82 to 1.96)]. Infants: at 2 years, analyses were based on data from 888 out of 1010 (87.9%) singleton infants (including four postnatal infant deaths) [445/503 (88.5%) NRT, 443/507 (87.4%) placebo] and used multiple imputation. In the NRT group, 72.6% (323/445) had no impairment compared with 65.5% (290/443) in placebo (OR 1.40, 95% CI 1.05 to 1.86). The incremental cost-effectiveness ratio for NRT use was £4156 per quitter (£4926 including twins), but there was substantial uncertainty around these estimates.\n\n\nCONCLUSIONS\nNicotine replacement therapy patches had no enduring, significant effect on smoking in pregnancy; however, 2-year-olds born to women who used NRT were more likely to have survived without any developmental impairment. Further studies should investigate the clinical effectiveness and safety of higher doses of NRT.\n\n\nBACKGROUND\nCurrent Controlled Trials ISRCTN07249128.\n\n\nBACKGROUND\nThis project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 54. See the NIHR Journals Library programme website for further project information.",
"affiliations": "Division of Primary Care, University of Nottingham, Nottingham, UK.;Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.;Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK.;Institute for Women's Health, University College London, London, UK.;Academic Division of Midwifery, University of Nottingham, Nottingham, UK.;Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.;Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK.;Division of Primary Care, University of Nottingham, Nottingham, UK.;Department of Health Sciences, University of York, York, UK.;Department of Health Sciences, University of York, York, UK.;Division of Primary Care, University of Nottingham, Nottingham, UK.;Division of Primary Care, University of Nottingham, Nottingham, UK.;Division of Primary Care, University of Nottingham, Nottingham, UK.",
"authors": "Cooper|Sue|S|;Lewis|Sarah|S|;Thornton|James G|JG|;Marlow|Neil|N|;Watts|Kim|K|;Britton|John|J|;Grainge|Matthew J|MJ|;Taggar|Jaspal|J|;Essex|Holly|H|;Parrott|Steve|S|;Dickinson|Anne|A|;Whitemore|Rachel|R|;Coleman|Tim|T|;|||",
"chemical_list": "D009538:Nicotine",
"country": "England",
"delete": false,
"doi": "10.3310/hta18540",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1366-5278",
"issue": "18(54)",
"journal": "Health technology assessment (Winchester, England)",
"keywords": null,
"medline_ta": "Health Technol Assess",
"mesh_terms": "D000279:Administration, Cutaneous; D000328:Adult; D002675:Child, Preschool; D003362:Cost-Benefit Analysis; D004311:Double-Blind Method; D004739:England; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009538:Nicotine; D017063:Outcome Assessment, Health Care; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012907:Smoking; D016540:Smoking Cessation; D000074606:Smoking Prevention; D013995:Time; D061485:Tobacco Use Cessation Devices",
"nlm_unique_id": "9706284",
"other_id": null,
"pages": "1-128",
"pmc": null,
"pmid": "25158081",
"pubdate": "2014-08",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The SNAP trial: a randomised placebo-controlled trial of nicotine replacement therapy in pregnancy--clinical effectiveness and safety until 2 years after delivery, with economic evaluation.",
"title_normalized": "the snap trial a randomised placebo controlled trial of nicotine replacement therapy in pregnancy clinical effectiveness and safety until 2 years after delivery with economic evaluation"
} | [
{
"companynumb": "GB-JNJFOC-20140906856",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NICOTINE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nImmune hemolytic anemia is a well-known complication after allogeneic hematopoietic stem cell transplantation (HSCT). Posttransplant hemolytic anemia results in increased red blood cell transfusions and medical sequelae including iron overload.\n\n\nMETHODS\nWe present a case report of immune hemolytic anemia that occurred after allogeneic HSCT from an ABO major-mismatched, HLA-matched unrelated donor. The patient had high anti-donor A type antibodies that were unresponsive to treatment with steroids and rituximab, resulting in persistent transfusion dependence. A detailed time course of anti-A titers, plasma cell content of the marrow, and B-cell content of the blood is presented. Treatment with bortezomib, a protease inhibitor, eliminated residual host-type plasma cells secreting anti-A and restored normal donor-derived erythropoiesis.\n\n\nCONCLUSIONS\nThis report, and a review of literature for treatment of immune hemolytic anemia after allogeneic HSCT, supports the utility of bortezomib as plasma cell-targeted therapy in this setting.",
"affiliations": "Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.",
"authors": "Hosoba|Sakura|S|;Jaye|David L|DL|;Cohen|Cynthia|C|;Roback|John D|JD|;Waller|Edmund K|EK|",
"chemical_list": "D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib",
"country": "United States",
"delete": false,
"doi": "10.1111/trf.12815",
"fulltext": "\n==== Front\nTransfusionTransfusiontrfTransfusion0041-11321537-2995Blackwell Publishing Ltd Oxford, UK 10.1111/trf.12815Transplantation and Cellular EngineeringSuccessful treatment of severe immune hemolytic anemia after allogeneic stem cell transplantation with bortezomib: report of a case and review of literature Hosoba Sakura 1Jaye David L 2Cohen Cynthia 2Roback John D 3Waller Edmund K 131 Winship Cancer Institute, Emory University School of MedicineAtlanta, Georgia2 Department of Pathology and Laboratory Medicine, Emory University School of MedicineAtlanta, Georgia3 Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, Emory University School of MedicineAtlanta, GeorgiaAddress reprint requests to: Edmund K. Waller, MD, PhD, FACP, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA 30322; e-mail: ewaller@emory.edu.2 2015 25 8 2014 55 2 259 264 21 4 2014 22 6 2014 26 6 2014 © 2014 The Authors. Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.2014This 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.Background\nImmune hemolytic anemia is a well-known complication after allogeneic hematopoietic stem cell transplantation (HSCT). Posttransplant hemolytic anemia results in increased red blood cell transfusions and medical sequelae including iron overload.\n\nCase Report\nWe present a case report of immune hemolytic anemia that occurred after allogeneic HSCT from an ABO major–mismatched, HLA-matched unrelated donor. The patient had high anti-donor A type antibodies that were unresponsive to treatment with steroids and rituximab, resulting in persistent transfusion dependence. A detailed time course of anti-A titers, plasma cell content of the marrow, and B-cell content of the blood is presented. Treatment with bortezomib, a protease inhibitor, eliminated residual host-type plasma cells secreting anti-A and restored normal donor-derived erythropoiesis.\n\nConclusion\nThis report, and a review of literature for treatment of immune hemolytic anemia after allogeneic HSCT, supports the utility of bortezomib as plasma cell–targeted therapy in this setting.\n==== Body\nImmune hemolytic anemia is a well-known complication of allogeneic hematopoietic stem cell transplantation (HSCT).1 Hemolysis typically occurs from 2 to 25 months after HSCT2,3 with an incidence of 3.1% to 6%.2,4 For the purpose of relative comparison to the incidence of hemolytic anemia observed outside of the transplant setting, this is much higher than the incidence of immune hemolytic anemia in the general population (incidence rates per year, 0.0008%; prevalence, 0.17%).5,6\n\nSevere immune hemolytic anemia alone rarely causes death in adults4 but is often associated with other complications and significant morbidity.4,7 Thus, early effective treatment can prevent transfusion-related complications. Conventional options to treat immune hemolytic anemia after allogeneic HSCT include corticosteroids, intravenous immunoglobulin (IVIG), splenectomy, donor lymphocyte infusion, plasma exchange, erythropoietin, rituximab, and other immunosuppressing agents such as cyclosporine.3,8 Bortezomib is an inhibitor of the 26S proteasome and approved for the treatment of multiple myeloma and mantle cell lymphoma in the United States; it has recently been reported as treatment for immune hemolytic anemia,9,10 but the efficacy and safety of bortezomib on secondary immune disorders in allogeneic HSCT recipients has not been extensively described. In this case report, we describe the successful use of bortezomib as treatment of persistent immune hemolytic anemia after allogeneic HSCT and review published articles related to management of immune hemolytic anemia in this setting.\n\nCase Report\nA 57-year-old man presented with pancytopenia and a marrow examination that showed International Prognostic Scoring System intermediate-2 myelodysplastic syndrome, with deletion of 3q26 on cytogenetic analysis. He developed secondary acute myeloid leukemia after three cycles of treatment with decitabine and achieved a complete remission (CR) after 7 + 3 induction therapy and two cycles of high-dose cytarabine consolidation.\n\nHe received an allogeneic granulocyte–colony-stimulating factor–mobilized peripheral blood stem cell transplantation from a male HLA-matched unrelated donor in first CR. The donor's blood group was A+ D+ and the recipient's was O D+. The allogeneic blood stem cell graft contained 9.8 × 106 CD34+ cells/kg and 114.4 × 106 CD19+ cells/kg. The patient received a reduced-intensity conditioning regimen consisting of 5 days of 25 mg/m2/day fludarabine and 2 days of 70 mg/m2/day melphalan. Prograf and methotrexate (15 mg/m2 on Day 1 and 10 mg/m2 on Days 3, 6, and 11) were given for prophylaxis of graft-versus-host disease (GVHD). He developed Grade I acute GVHD of skin on Day 34 after transplantation that responded well to topical steroids and resolved within a week. The remainder of his immediate posttransplant course was uncomplicated.\n\nHe remained red blood cell (RBC) transfusion dependent after achieving neutrophil and platelet engraftment on Day 17. A marrow aspiration on Day 97 showed decreased erythroblasts and excess plasma cells along with reduced reticulocytes in the blood (Figs. 1B and 2). Plasma cells in the marrow were stained in marrow sections with anti-CD138 monoclonal antibody (MoAb; Fig. 2) and estimated CD138 immunohistochemical score blinded to case identical number and date (Fig. 1D). Anti-A IgG and IgM antibody titers were elevated consistent with persistence of host-type plasma cells (Fig. 1C).\n\nFig 1 Clinical course of the reported patient with immune hemolytic anemia. (A) Treatment course of steroids (black bars), rituximab (black arrows), and bortezomib (orange arrows). The height of the black bars shows the relative dose of steroids. (B) Graph of Hb (black dashed line) and reticulocyte percentage (red solid line) with timing of RBC transfusions (black arrows). (C) Graph of total IgG (black solid line with diamonds) and IgM (black dashed line with triangles) and anti-A IgG titers (green solid line with diamonds) and anti-A IgM titers (green dashed line with triangles). Semiquantitative titration of anti-A of both the IgM and the IgG subclasses were performed using standard methods. Briefly, 2% suspensions of A1 reagent RBCs were mixed with patient plasma in test tubes. For IgM detection, after 15 minutes of incubation at room temperature the samples were centrifuged and macroscopic agglutination was quantified; for IgG, samples were incubated for 60 minutes at 37°C, washed to remove unbound antibody, incubated with anti-human IgG, and then centrifuged to score agglutination.13 (D) Numbers of CD19+ cells in blood (black dashed line) were assessed by flow cytometry, and plasma cells percentage score for nucleated cells in bone marrow (blue solid line) were estimated blinded to case identical number and date.\n\nFig 2 Histologic sections of marrow from the patient with immune hemolytic anemia. Tissue sections were immune stained with anti-CD138 MoAb, and CD138+ cells were visualized after secondary staining with a horseradish peroxidase–labeled secondary antibody. Immunohistochemical analysis for CD138+ plasma cells present in marrow biopsies obtained on Day –22 (A), Day +97 (B), Day +160 (C), and Day +249 (D) with respect to the day of transplant are shown. Overall cellularities of the marrow at the times represented in A, B, C, and D were 40, 60, 50, and 15%.\n\nOn Day 118, the patient's hemolytic anemia was treated with 1 mg/kg/day methylprednisolone without a change in the anti-A titer or improved erythropoiesis (Figs. 1B and 1C). He then received 375 mg/m2 rituximab weekly × 4 doses starting on Day 132 posttransplant with residual anti-A IgG and IgM antibodies and continued reliance on RBC transfusions every 10 days (Figs. 1B and 1C). CD19+ cells were eliminated from the blood after rituximab administration (Fig. 1D) although anti-A IgG and IgM antibodies in the blood and plasma cells in the marrow persisted (Figs. 1C and 2). As a third-line therapy, he received weekly subcutaneous injections of 1.3 mg/m2 bortezomib starting on Day 175 (Fig. 1A).\n\nAfter four doses of bortezomib, serum anti-A levels decreased and then disappeared (Fig. 1C). Likewise, reticulocytes started to increase in the blood from Day 342 (Fig. 1B) and hemoglobin (Hb) increased with resolution of his transfusion-dependent hemolysis. In aggregate, he had received a total of 30 RBC units before erythropoiesis recovered.\n\nImmunohistochemical analysis of CD138+ cells in serial histologic sections of marrow obtained before transplant (Day −22, Fig. 2A) and after transplant on Days +97 (Fig. 2B), +160 (Fig. 2C), and +249 (Fig. 2D) showed an increased frequency of plasma cells (relative to marrow from healthy controls) present before transplantation (Fig. 2A) and persistence of CD138+ plasma cells during the first 3 months after transplantation (Fig. 2B). Treatment with steroids and rituximab decreased the numbers of plasma cells in the marrow (Fig. 2C), and subsequent treatment with bortezomib further reduced the relative frequency of plasma cells in the marrow (Fig. 2D). While rituximab treatment may have contributed to mild impairment of hematopoiesis and reduced overall cellularity of the marrow, bortezomib treatment was associated with a further reduction in the frequency of CD138+ plasma cells in the marrow relative to nucleated cells from approximately 1.8% (Fig. 2C) to 0.6% (Fig. 2D).\n\nDiscussion\nThere are three possible mechanisms for immune hemolytic anemia after allogeneic HSCT.11 The first mechanism is that the antibodies against donor ABO type RBCs derived from recipient lymphocytes persist or recur after allogeneic SCT causing hemolysis. This can be seen in ABO major–mismatched allogeneic HSCT. The second mechanism is that the antibodies derived from donor lymphocytes attack recipient ABO type RBCs. This is called passenger lymphocyte syndrome and can be seen in ABO minor–mismatched allogeneic HSCT. The third is that donor plasma cells produce immune antibodies that cause hemolysis of donor ABO RBCs after engraftment. The hemolysis caused by this mechanism can be seen in any type of allogeneic HSCT even in ABO-matched transplantation. With all three mechanisms, successful treatment requires suppression of the plasma cells secreting antibodies to RBCs or erythroid progenitors.\n\nA review of the literature found 18 reports of treatment of immune hemolytic anemia that developed after allogeneic HSCT in patients with hematologic disease (Table 1). Clinical outcomes on a total of 92 patients were reported, with 39 deaths and 33 survivors. Treatment with oral prednisone or IV methylprednisolone, with an initial dose of 1 mg/kg/day, was administrated as first-line treatment in almost all cases. Hemolytic anemia resolved with steroids alone in 12 of 92 cases, with at least another 60 cases remaining transfusion dependent. Reported second-line therapy of post–allogeneic HSCT immune hemolytic anemia included IVIG and, after Food and Drug Administration (FDA) approval, expansion to bulky non-Hodgkin's lymphoma in 2001,23 rituximab, a MoAb against the CD20 protein.4,9 Although rituximab has been reported as effective treatment for immune hemolytic anemia in the nontransplant setting,24 13 of 32 patients treated with rituximab for hemolytic anemia after allogeneic transplant did not achieve CR from RBC transfusion dependence. For patients with immune hemolytic anemia that persists after administration of steroids, IVIG, and rituximab, less immunosuppressive treatment that is more specifically targeted to plasma cells is needed, as many patients with immune hemolytic anemia die from opportunistic infections during immunosuppressive drug therapy.3,7\n\nTABLE 1 Published data about immune hemolytic anemia after allogeneic HSCT for hematologic malignancies\n\nPublication\tNumber of patients\tPrimary disease\tStem cell source\tFirst line\tSecond or more line\tClinical course\tReference\t\n1990\t1\tCML\tBMT\tSteroids\t\t1 alive\t14\t\n1994\t1\tCML\tBMT\tSteroids\t\t1 alive\t15\t\n1996\t1\tAA\tBMT\tSteroids\tAZA, VCR, IVIG, SPLX, TLI, 2nd HSCT\t1 dead\t16\t\n1996\t7\t\tTCD-BMT\tSteroids\tIVIG, PE, EPO\t3 alive, 4 dead\t3\t\n1997\t5\t3 ALL, 1 CML, 1 MDS\tBMT\tSteroids\tIVIG\t5 alive\t17\t\n2001\t9\tCML\tTCD-BMT\tSteroids\tSPLX, DLI, IVIG\t7 alive, 2 dead\t8\t\n2001\t1\tALL\tBMT\tSteroids\tCsA, CY, THAL, IVIG, ALG\t1 alive\t7\t\n2001\t1\tLymphoma\tPBSCT\tSteroids\t\t1 dead\t18\t\n2005\t4\tHD, NHL, ALL, AML\tPBSCT\tSteroids\tIVIG, Ritux\t4 alive\t19\t\n2007\t9\tCML, AA, MPD\tBMT\tSteroids\tIVIG, AZA, SPLX, VCR, TLI\t5 alive, 4 dead\t2\t\n2007\t1\tHemophagocytic lymphohistiocytosis\tCBT\tSteroids\tIVIG, Ritux\t1 alive\t20\t\n2007\t12\tLeukemia, MDS, lymphoma, AA, MM, others\tBMT\tSteroids\tRitux\t2 alive, 10 dead\t4\t\n2009\t1\tCML\tCBT\tSteroids\tIVIG, Ritux, MMF, CY, PE, SPLX\t1 dead\t21\t\n2011\t1\tAML\tBMT\tSteroids\t\t1 alive\t22\t\n2012\t1\tAML\tPBSCT\tRitux\tDLI, BTZ\t1 alive\t9\t\n2013\t20\tMalignancies and nonmalignancies\tCBT\tSteroids\tRitux, CsA, IVIG\t\t33\t\n2013\t2\tAML\tCBT\tSteroids\tIVIG, Ritux, CsA, SPLX, BTZ, Eculiz, PE\t2 dead\t10\t\n2014\t15\tLeukemia, AA, FA, MPS, others\t9 BMT, 2 PBSCT, 4 CBT\tSteroids\tIVIG, Ritux\t1 dead, 14 alive\t34\t\nSummary\t92 patients\t\t\t\t\t32 alive, 38 dead\t\t\nAA = aplastic anemia; ALG = antilymphocyte globulin; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AZA = azathioprine; BMT = bone marrow transplantation; BTZ = bortezomib; CBT = cord blood cell transplantation; CML = chronic myeloid leukemia; CsA = cyclosporine; CY = cyclophosphamide; DLI = donor lymphocyte infusion; Eculiz = eculizumab; EPO = erythropoietin; FA = Fanconi anemia; HD = Hodgkin's lymphoma; MDS = myelodysplastic syndrome; MM = multiple myeloma; MMF = mycophenolate mofetil; MPD = myeloproliferative disorder; MPS = mucopolysaccaridosis; NHL = non-Hodgkin's lymphoma; PBSCT = peripheral blood stem cell transplantation; PE = plasma exchange; Ritux = rituximab; SPLX = splenectomy; TCD = T-cell depleted; THAL = thalidomide; TLI = total lymph node irradiation; VCR = vincristine.\n\nBortezomib is a dipeptide boronate proteasome inhibitor, which reversibly inhibits the 26S proteasome function and leads to the accumulation of polyubiquitinated proteins, inducing the death of both short- and long-lived plasma cells by activation of the terminal unfolded protein response.25–27 The US FDA approved bortezomib to treat multiple myeloma and mantle cell lymphoma patients. In view of its effect on malignant B cells and plasma cells, bortezomib has been used to treat other plasma disorders, with case reports of successful treatment of immune hemolytic anemia related to cryoglobulinemia, systemic lupus erythematosus, and myasthenia gravis.28–30 In addition, bortezomib can deplete alloreactive T cells in allo-HSCT recipients, decrease T-helper Type 1 cells that secrete interferon-γ and interleukin-2,31 and impair activation of monocyte-derived dendritic cells.32 Koreth and colleagues12 have recently demonstrated that bortezomib is efficacious as part of GVHD prophylaxis for patients who received HLA-mismatched allogeneic HSCT after reduced-intensity conditioning regimens. The literature on post–allo-HSCT hemolytic anemia reports the use of bortezomib as third-line therapy in only three patients, with one surviving responder (Table 1).\n\nWe report successful treatment with bortezomib of a case of immune hemolytic anemia after allogeneic HSCT that was resistant to steroids and rituximab. For our patient, rituximab depleted CD19+ cells in the blood, but marrow plasma cells were resistant to steroids and rituximab, with persistence of anti-A. After bortezomib administration, anti-A titers decreased and marrow plasma cells were eliminated with a concomitant increase in reticulocytes in the blood and RBC transfusion independence. This case supports the utility of bortezomib treatment to specifically target the residual host-type plasma cells responsible for production of anti-A.\n\nIn conclusion, immune hemolytic anemia after allogeneic HSCT for hematologic malignancy is a well-recognized complication that occurs rarely but is responsible for considerable morbidity and reported mortality of more than 50%. Although many cases with hemolytic anemia respond to standard treatment including steroids, IVIG, and rituximab, effective third-line therapy has not been established. We describe successful treatment of immune hemolytic anemia resistant to steroids and rituximab with bortezomib. Disappearance of anti-A was concomitant with elimination of CD138+ plasma cells from the marrow.\n\nConflict of Interest\nThe authors have disclosed no conflicts of interest.\n\nCRcomplete remission\n\nHSCThematopoietic stem cell transplantation\n==== Refs\nReferences\n1 Petz LD Hemolysis associated with transplantation Transfusion 1998 38 224 228 9563400 \n2 Chen FE Owen I Savage D Late onset haemolysis and red cell autoimmunisation after allogeneic bone marrow transplant Bone Marrow Transplant 1997 19 491 495 9052917 \n3 Drobyski WR Potluri J Sauer D Autoimmune hemolytic anemia following T cell-depleted allogeneic bone marrow transplantation Bone Marrow Transplant 1996 17 1093 1099 8807120 \n4 Sanz J Arriaga F Montesinos P Autoimmune hemolytic anemia following allogeneic hematopoietic stem cell transplantation in adult patients Bone Marrow Transplant 2007 39 555 561 17351645 \n5 Klein NP Ray P Carpenter D Rates of autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety studies Vaccine 2010 28 1062 1068 19896453 \n6 Eaton WW Rose NR Kalaydjian A Epidemiology of autoimmune diseases in Denmark J Autoimmun 2007 29 1 9 17582741 \n7 Pratt G Kinsey SE Remission of severe, intractable autoimmune haemolytic anaemia following matched unrelated donor transplantation Bone Marrow Transplant 2001 28 791 793 11781633 \n8 Cwynarski K Goulding R Pocock C Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia: association with leukaemic relapse and treatment with donor lymphocyte infusions Bone Marrow Transplant 2001 28 581 586 11607771 \n9 Poon LM Koh LP Successful treatment of isohemagglutinin-mediated pure red cell aplasia after ABO-mismatched allogeneic hematopoietic cell transplant using bortezomib Bone Marrow Transplant 2012 47 870 871 21874058 \n10 Rovira J Cid J Gutierrez-Garcia G Fatal immune hemolytic anemia following allogeneic stem cell transplantation: report of 2 cases and review of literature Transfus Med Rev 2013 27 166 170 23562007 \n11 Watz E Remberger M Ringden O Analysis of donor and recipient ABO incompatibility and antibody-associated complications after allogeneic stem cell transplantation with reduced-intensity conditioning Biol Blood Marrow Transplant 2014 20 264 271 24274982 \n12 Koreth J Stevenson KE Kim HT Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation J Clin Oncol 2012 30 3202 3208 22869883 \n13 AABB Technical methods and procedures 2011 17th ed Bethesda, MD American Association of Blood Banks \n14 Klumpp TR Caligiuri MA Rabinowe SN Autoimmune pancytopenia following allogeneic bone marrow transplantation Bone Marrow Transplant 1990 6 445 447 1965793 \n15 Tamura T Kanamori H Yamazaki E Cold agglutinin disease following allogeneic bone marrow transplantation Bone Marrow Transplant 1994 13 321 323 8199573 \n16 De Lord C Marsh JC Smith JG Fatal autoimmune pancytopenia following bone marrow transplantation for aplastic anaemia Bone Marrow Transplant 1996 18 237 239 8832026 \n17 Godder K Pati AR Abhyankar SH De novo chronic graft-versus-host disease presenting as hemolytic anemia following partially mismatched related donor bone marrow transplant Bone Marrow Transplant 1997 19 813 817 9134174 \n18 Tiplady CW Fitzgerald JM Jackson GH Massive haemolysis in a group A recipient of a group O peripheral blood stem cell allogeneic transplant Transfus Med 2001 11 455 458 11851944 \n19 Raj K Narayanan S Augustson B Rituximab is effective in the management of refractory autoimmune cytopenias occurring after allogeneic stem cell transplantation Bone Marrow Transplant 2005 35 299 301 15568036 \n20 Radhi M Rumelhart S Tatman D Severe autoimmune hemolytic anemia after unrelated umbilical cord blood transplant for familial hemophagocytic lymphohistiocytosis: significant improvement after treatment with rituximab J Pediatr Hematol Oncol 2007 29 125 127 17279011 \n21 Rokicka M Styczynski J Michalewska B Fatal combined immune hemolytic anemia after double cord blood transplantation in imatinib-resistant CML Bone Marrow Transplant 2009 44 383 385 19219078 \n22 Nakata J Tamaki H Ikegame K Direct antiglobulin test-negative autoimmune hemolytic anemia associated with HLA-haploidentical stem cell transplantation Int J Hematol 2011 93 558 560 21472396 \n23 Rastetter W Molina A White CA Rituximab: expanding role in therapy for lymphomas and autoimmune diseases Annu Rev Med 2004 55 477 503 14746532 \n24 Rigal D Meyer F [Autoimmune haemolytic anemia: diagnosis strategy and new treatments] Transfus Clin Biol 2011 18 277 285 21474357 \n25 Dasanu CA Bortezomib: friend or foe of hemolytic anemia? J Oncol Pharm Pract 2011 17 233 235 20562167 \n26 Meister S Schubert U Neubert K Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition Cancer Res 2007 67 1783 1792 17308121 \n27 Neubert K Meister S Moser K The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis Nat Med 2008 14 748 755 18542049 \n28 Frohlich K Holle JU Aries PM Successful use of bortezomib in a patient with systemic lupus erythematosus and multiple myeloma Ann Rheum Dis 2011 70 1344 1345 21173019 \n29 Carson KR Beckwith LG Mehta J Successful treatment of IgM-mediated autoimmune hemolytic anemia with bortezomib Blood 2010 115 915 20110437 \n30 Gomez AM Vrolix K Martinez-Martinez P Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis J Immunol 2011 186 2503 2513 21239719 \n31 Blanco B Perez-Simon JA Sanchez-Abarca LI Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines Blood 2006 107 3575 3583 16282346 \n32 Nencioni A Schwarzenberg K Brauer KM Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation Blood 2006 108 551 558 16537813 \n33 Daikeler T Labopin M Ruggeri A New autoimmune diseases after cord blood transplantation: a retrospective study of EUROCORD and the Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation Blood 2013 121 1059 1064 23247725 \n34 Faraci M Zecca M Pillon M Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience Biol Blood Marrow Transplant 2014 20 272 278 24274983\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0041-1132",
"issue": "55(2)",
"journal": "Transfusion",
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"medline_ta": "Transfusion",
"mesh_terms": "D064591:Allografts; D000744:Anemia, Hemolytic, Autoimmune; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D004920:Erythropoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells; D011719:Pyrazines; D020127:Recovery of Function",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "259-64",
"pmc": null,
"pmid": "25156334",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "9052917;16537813;23247725;20562167;21874058;14746532;21472396;22869883;20110437;21173019;11851944;1965793;17351645;19896453;21239719;21474357;11607771;19219078;8199573;18542049;9134174;8832026;24274983;23562007;17308121;24274982;16282346;8807120;11781633;15568036;9563400;17582741;17279011",
"title": "Successful treatment of severe immune hemolytic anemia after allogeneic stem cell transplantation with bortezomib: report of a case and review of literature.",
"title_normalized": "successful treatment of severe immune hemolytic anemia after allogeneic stem cell transplantation with bortezomib report of a case and review of literature"
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