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{
"abstract": "OBJECTIVE\nParaneoplastic encephalitides usually precede a diagnosis of cancer and are often refractory to immunosuppressive therapy. Conversely, autoimmune encephalitides are reversible conditions that can occur in the presence or absence of cancer.\n\n\nOBJECTIVE\nTo report the induction of autoimmune encephalitis in 2 patients after treatment of metastatic cancer with a combination of the immune checkpoint inhibitors nivolumab and ipilimumab.\n\n\nMETHODS\nA retrospective case study was conducted of the clinical and management course of 2 patients with progressive, treatment-refractory metastatic cancer who were treated with a single dose each (concomitantly) of the immune checkpoint inhibitors nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg.\n\n\nMETHODS\nNivolumab and ipilimumab.\n\n\nMETHODS\nThe clinical response to immunosuppressive therapy in suspected autoimmune encephalitis in the setting of immune checkpoint inhibitor use.\n\n\nRESULTS\nAutoantibody testing confirmed identification of anti-N-methyl-D-aspartate receptor antibodies in the cerebrospinal fluid of 1 patient. Withdrawal of immune checkpoint inhibitors and initiation of immunosuppressive therapy, consisting of intravenous methylprednisolone sodium succinate equivalent to 1000 mg of methylprednisolone for 5 days, 0.4 mg/kg/d of intravenous immunoglobulin for 5 days, and 2 doses of rituximab, 1000 mg, in 1 patient and oral prednisone, 60 mg/d, in the other patient, resulted in improved neurologic symptoms.\n\n\nCONCLUSIONS\nImmune checkpoint inhibition may favor the development of immune responses against neuronal antigens, leading to autoimmune encephalitis. Early recognition and treatment of autoimmune encephalitis in patients receiving immune checkpoint blockade therapy will likely be essential for maximizing clinical recovery and minimizing the effect of drug-related toxic effects. The mechanisms by which immune checkpoint inhibition may contribute to autoimmune encephalitis require further study.",
"affiliations": "Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurology, Hospital Clínic/Institut d'Investigació Biomèdica August Pi i Sunyer, University of Barcelona, Barcelona, Spain3Institució Catalana de Recerca i Estudis Avançats, University of Barcelona, Barcelona, Spain.;Bristol-Myers Squibb, Plainsboro, New Jersey.;Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.",
"authors": "Williams|Tanya J|TJ|;Benavides|David R|DR|;Patrice|Kelly-Ann|KA|;Dalmau|Josep O|JO|;de Ávila|Alexandre Leon Ribeiro|AL|;Le|Dung T|DT|;Lipson|Evan J|EJ|;Probasco|John C|JC|;Mowry|Ellen M|EM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D000074324:Ipilimumab; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaneurol.2016.1399",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6149",
"issue": "73(8)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D004359:Drug Therapy, Combination; D004660:Encephalitis; D005260:Female; D050031:Hashimoto Disease; D006801:Humans; D007155:Immunologic Factors; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D000077594:Nivolumab; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "928-33",
"pmc": null,
"pmid": "27271951",
"pubdate": "2016-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer.",
"title_normalized": "association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2015-017707",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHOLECALCIFEROL"
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{
"abstract": "To evaluate the incidence and outcome of secondary immune thrombocytopenia (ITP) in a large cohort of paediatric Spanish patients.\n\n\n\nA retrospective observational study was conducted in two paediatric University hospitals in Spain between 2009 and 2019, which included children from 4 months to 18 years old diagnosed with ITP. Data were recorded from clinical charts: gender, age at diagnosis, coexisting condition and associated characteristics, outcome and treatment.\n\n\n\nSecondary ITP was diagnosed in 87 out of 442 patients (19.6%). Post-immunisation ITP was seen in younger children. The onset of secondary ITP to autoimmune diseases (AD) and immunodeficiencies (ID) was at an older age and had more tendency to be insidious, and platelet level was higher than primary ITP. Mean time from ITP onset to AD diseases or ID diagnosis was 1.2 and 2.6 years, respectively. Whereas the cumulative incidence of remission was significantly higher in post-immunisation and post-viral infection (compared with primary ITP patients), it was worse in AD and ID patients.\n\n\n\nIdentification of secondary ITP is important as it predicts outcome. Most of them are diagnosed at ITP onset, but AD diseases and ID should be ruled out periodically as they are usually identified later.",
"affiliations": "Pediatric Hematology Department, Hospital Sant Joan de Déu Barcelona, Esplugues de Llobregat, Barcelona, Spain.;Hematology Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Pediatric Hematology Department, Hospital Sant Joan de Déu Barcelona, Esplugues de Llobregat, Barcelona, Spain.;Fundación Investigación Biomédica Hospital Infantil Niño Jesús (FIBHINJ), Madrid, Spain.;Pediatric Hematology Department, Hospital Sant Joan de Déu Barcelona, Esplugues de Llobregat, Barcelona, Spain.;Pediatric Hematology Department, Hospital Sant Joan de Déu Barcelona, Esplugues de Llobregat, Barcelona, Spain.;Hematology Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.;Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain.",
"authors": "Berrueco|Rubén|R|0000-0002-1068-7489;Sebastián|Elena|E|;Solsona|María|M|;González de Pablo|Jesús|J|;Ruiz-Llobet|Anna|A|;Mesegué|Montse|M|;Gálvez|Eva|E|;Sevilla|Julián|J|",
"chemical_list": null,
"country": "Norway",
"delete": false,
"doi": "10.1111/apa.15765",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0803-5253",
"issue": "110(6)",
"journal": "Acta paediatrica (Oslo, Norway : 1992)",
"keywords": "autoimmune diseases; children; immune thrombocytopenia; immunodeficiency; paediatric; vaccines",
"medline_ta": "Acta Paediatr",
"mesh_terms": "D000368:Aged; D002648:Child; D006801:Humans; D015994:Incidence; D016553:Purpura, Thrombocytopenic, Idiopathic; D012189:Retrospective Studies; D013030:Spain; D013921:Thrombocytopenia",
"nlm_unique_id": "9205968",
"other_id": null,
"pages": "1952-1958",
"pmc": null,
"pmid": "33460494",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Secondary immune thrombocytopenia in children: Characteristics and outcome of a large cohort from two Spanish centres.",
"title_normalized": "secondary immune thrombocytopenia in children characteristics and outcome of a large cohort from two spanish centres"
} | [
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"companynumb": "NVSC2021ES081980",
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"activesubstancename": "METHOTREXATE"
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"abstract": "BACKGROUND Retropharyngeal hematoma is a relatively rare diagnosis that requires a high clinical suspicion and stabilization of the airway to prevent rapid deterioration. We report a case of a spontaneous retropharyngeal hematoma in an elderly patient with myelodysplastic syndrome and associated thrombocytopenia. CASE REPORT A 90-year-old man with myelodysplastic syndrome was brought to the Emergency Department with complaints of difficulty swallowing and muffled voice for 24 hours. Upon arrival, his vital signs and physical exam were unremarkable, except that when he was asked to take a sip of water, he could not swallow it. Complete blood count was remarkable for leukocytosis of 14.3×10³/mcL, hemoglobin of 9.0 gm/dL, and platelet count of 26×10³/mcL. Chest X-ray and lateral soft-tissue neck X-rays were grossly unremarkable. The patient was admitted for further evaluation and was scheduled for esophagogastroduodenoscopy. During intubation for esophagogastroduodenoscopy, the patient was noted to have significant airway narrowing. A subsequent CT scan revealed a 3×2×2 cm supraglottic hypodensity, thought to represent a retropharyngeal hematoma. The patient was transferred to the Intensive Care Unit (ICU) and received platelet transfusions. The ICU course was complicated by anemia, which necessitated transfusion of packed red blood cells. On hospital day 7, the patient reported resolution of his symptoms and was discharged home. CONCLUSIONS This case adds to the growing body of literature on spontaneous retropharyngeal hematomas. High clinical suspicion is warranted in patients who present with acute dysphagia, odynophagia, and dysphonia. Prompt imaging and airway management are vital in managing patients with this condition.",
"affiliations": "Frank H. Netter MD School of Medicine, Quinnipiac University, Hamden, CT, USA.;Frank H. Netter MD School of Medicine, Quinnipiac University, Hamden, CT, USA.",
"authors": "Fox|Elliott C|EC|;Manchala|Venkata|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.909502",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3011590210.12659/AJCR.909502909502ArticlesRetropharyngeal Hematoma as an Unusual Presentation of Myelodysplastic Syndrome: A Case Report Fox Elliott C. ABCDEF1Manchala Venkata ABCDEF12\n1 Frank H. Netter MD School of Medicine, Quinnipiac University, Hamden, CT, U.S.A.\n2 Department of Medicine, St. Vincent’s Medical Center, Bridgeport, CT, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Elliott C. Fox, e-mail: elliott.fox@quinnipiac.edu2018 17 8 2018 19 969 972 14 2 2018 30 5 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 90\n\nFinal Diagnosis: Spontaneous retropharyngeal hematoma\n\nSymptoms: Dysphagia\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Hematology\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nRetropharyngeal hematoma is a relatively rare diagnosis that requires a high clinical suspicion and stabilization of the airway to prevent rapid deterioration. We report a case of a spontaneous retropharyngeal hematoma in an elderly patient with myelodysplastic syndrome and associated thrombocytopenia.\n\nCase Report:\nA 90-year-old man with myelodysplastic syndrome was brought to the Emergency Department with complaints of difficulty swallowing and muffled voice for 24 hours. Upon arrival, his vital signs and physical exam were unremarkable, except that when he was asked to take a sip of water, he could not swallow it. Complete blood count was remarkable for leukocytosis of 14.3×103/mcL, hemoglobin of 9.0 gm/dL, and platelet count of 26×103/mcL. Chest X-ray and lateral soft-tissue neck X-rays were grossly unremarkable. The patient was admitted for further evaluation and was scheduled for esophagogastroduodenoscopy. During intubation for esophagogastroduodenoscopy, the patient was noted to have significant airway narrowing. A subsequent CT scan revealed a 3×2×2 cm supraglottic hypodensity, thought to represent a retropharyngeal hematoma. The patient was transferred to the Intensive Care Unit (ICU) and received platelet transfusions. The ICU course was complicated by anemia, which necessitated transfusion of packed red blood cells. On hospital day 7, the patient reported resolution of his symptoms and was discharged home.\n\nConclusions:\nThis case adds to the growing body of literature on spontaneous retropharyngeal hematomas. High clinical suspicion is warranted in patients who present with acute dysphagia, odynophagia, and dysphonia. Prompt imaging and airway management are vital in managing patients with this condition.\n\nMeSH Keywords:\nHematomaLaryngoscopyMyelodysplastic-Myeloproliferative DiseasesThrombocytopenia\n==== Body\nBackground\nSpontaneous retropharyngeal hematoma is a rare diagnosis that has been linked to numerous coagulopathies [1]. Retropharyngeal hematomas can cause emergent airway compromise and are associated with a mortality rate of approximately 10% [2]. Intubation or cricothyrotomy is often necessary in patients with retropharyngeal hematoma due to rapid progression of the hematoma and blockage of the airway. Thus, initial physical exam and imaging studies are crucial for making a timely diagnosis. We describe a case that appears to be related to underlying myelodysplastic syndrome. Despite the patient’s known medical history and clear evidence of thrombocytopenia, the treatment team did not appreciate the hematoma until incidental visualization during intubation. Thus, spontaneous retropharyngeal hematoma should be included in the diagnosis when examining a patient with dysphagia or odynophagia, dysphonia, and dyspnea.\n\nCase Report\nA 90-year-old man was brought in to the Emergency Department (ED) from home with a chief concern of difficulty swallowing and a cough. He reported worsening dysphagia over the previous 24 h, with an inability to eat, take pills, or drink during that time. A home health aide noted that his voice had become muffled as well over this time. He had no history of similar symptoms and denied dyspnea and any sensation of throat or mouth swelling. Further review of systems was negative. Past medical history included hypertension, atrial fibrillation, myocardial infarction, prostate cancer, myelodysplastic syndrome, chronic obstructive pulmonary disease and peripheral artery disease. His surgical history included abdominal aortic aneurysm repair, two coronary artery stent placements, laparoscopic cholecystectomy, and tonsillectomy at age 5. Home medications at the time of presentation included metoprolol succinate (50 mg PO once daily), amlodipine (5 mg PO once daily), furosemide (40 mg PO once daily), and tamsulosin (0.4 mg PO once daily).\n\nUpon arrival to the ED, his vitals were as follows: temperature 36.4°C, heart rate 96 bpm, blood pressure 148/60 mmHg, and O2 saturation 99% on room air. He was not in apparent distress and the physical exam was unremarkable, except when he was asked to take a sip of water, he coughed, sputtered, and could not swallow it.\n\nComplete blood count was remarkable for leukocytosis of 14.3×103/mcL (reference range 4.8–10.8), hemoglobin of 9.0 gm/dL (reference range 14.0–18.0), mean corpuscular volume of 98.6 fL (reference range 80.0–94.0), red cell distribution width of 17.1% (reference range 11.5–14.5), and platelet count of 26×103/mcL (reference range 140–440). The basic metabolic panel was unremarkable. Coagulation labs showed an international normalized ratio of 1.07 (reference range 0.84–1.12). The chest X-ray was unremarkable and lateral soft tissue X-ray of the neck was read as equivocal, with possible thickening of aryepiglottic folds (Figure 1). The decision was made to admit the patient for esophagogastroduodenoscopy (EGD) and further medical management. During intubation for EGD, the patient was noted via laryngoscope to have a large hematoma posterior to the pharynx, as well as airway narrowing and deviation, so the procedure was aborted. The patient was transferred to the ICU at this time due to new-onset tachypnea and the possibility of airway compromise. A computed tomography (CT) scan was performed, showing an approximately 3×2×2 cm supraglottic hypodensity, thought to represent a spontaneous retropharyngeal hematoma (Figure 2). The patient received 3 units of platelets at this time, with the goal of raising his platelet count above 50×103/mcL.\n\nThe ICU course was complicated by episodes of atrial fibrillation and associated tachycardia, which were controlled initially with metoprolol (5 mg IV every 6 hours) and after three days with his home dose of metoprolol succinate (50 mg PO once daily). He continued to be NPO (nil per oris [nothing by mouth]) during the stay and intermittently coughed up bloody sputum. The patient’s hemoglobin slowly dropped over the ICU course to a nadir of 6.9 gm/dL on hospital day 6, which necessitated a transfusion of 1 unit of packed red blood cells. On hospital day 7, he reported that his swallowing had improved and his voice was sounding less muffled. He was discharged home with the hematoma improved at the time of discharge.\n\nDiscussion\nWhile there are sporadic case reports of retropharyngeal hematomas, this case is the first to our knowledge of a spontaneous retropharyngeal hematoma in a patient with myelodysplastic syndrome and thrombocytopenia [1–9]. Until the hematoma was incidentally visualized, neither history, physical exam, labs, nor initial imaging led anyone to suspect this pathology. Thus, this diagnosis requires a high clinical suspicion, particularly in the context of a coagulopathy such as myelodysplastic syndrome.\n\nMyelodysplastic syndrome has varying presentations. In this patient, thrombocytopenia was the dominant manifestation and likely was the main precipitating factor for the development of the hematoma. Other case reports have found spontaneous retropharyngeal hematomas in patients on anticoagulation with warfarin and novel oral anticoagulants, but thrombocytopenia appears to be an independent risk factor as well [1,2,7]. One previous report of spontaneous retropharyngeal hematoma in a patient with Epstein-Barr virus was attributed to a combination of acute tonsillitis, bone marrow suppression and altered clotting profile due to the virus [10]. Spontaneous retropharyngeal hematomas have occurred after minor trauma such as sneezing or coughing, but can also happen in the absence of such trauma [8]. The specific precipitating factor for this case remains a mystery, but it is likely that minor trauma in the setting of thrombocytopenia played a role in the development of the hematoma.\n\nThe main lesson that can be taken from this and similar cases is that airway management is the most important consideration. The decision not to intubate in this patient was in part due to the patient’s wishes. However, a tracheostomy kit was placed at the bedside and left there for the entire clinical course in anticipation of potentially rapid and devastating airway closure. It has been reported that 33% of patients require emergency surgical airway access within 2 hours of ED arrival and up to 10% of all cases end in death [3]. From the ED to the ICU, plans must be in place for a surgical airway, in addition to rapidly enlarging hematomas and other hematologic complications, in anticoagulated or coagulopathic patients.\n\nConclusions\nThis case emphasizes a rare but life-threatening condition that has the potential for rapid clinical deterioration. Clinicians should be aware of spontaneous retropharyngeal hematomas when examining patients with unexplained symptoms similar to those above.\n\nWe gratefully acknowledge the support for this project from St. Vincent’s Medical Center and Frank H. Netter MD School of Medicine at Quinnipiac University.\n\nConflict of interest\n\nNone.\n\nFigure 1. A lateral soft-tissue X-ray of the neck was obtained after initial chest X-ray was negative. The lateral film was read as equivocal, with possible thickening of the arylepiglottic folds (arrow).\n\nFigure 2. Sagittal CT obtained after abnormal findings noted on direct laryngoscopy showed a 3×2×2 cm supraglottic hypodensity (arrow), thought to represent a spontaneous retropharyngeal hematoma.\n==== Refs\nReferences:\n1. Naqvi A Hawwass D Seto A A tough pill to swallow-spontaneous retropharyngeal hematoma: a rare and unusual complication of rivaroxaban therapy Cardiology and Angiology: An International Journal 2015 4 4 156 59 \n2. Bloom DC Haegen T Keefe MA Anticoagulation and spontaneous retropharyngeal hematoma J Emerg Med 2003 24 4 389 94 12745040 \n3. Martí Gomar L Gomar LM Jiménez MG Garcerán RM Spontaneous retropharyngeal haematoma Acta Otorrinolaringologica (English Edition) 2012 63 1 77 78 \n4. Kang SS Jung SH Kim MS Spontaneous retropharyngeal hematoma – a case report Korean J Pain 2010 23 3 211 14 20830269 \n5. Findlay JM Belcher E Black E Sgromo B Tracheo-oesophageal compression due to massive spontaneous retropharyngeal haematoma Interact Cardiovasc Thorac Surg 2013 17 1 179 80 23518292 \n6. Ditkofsky N Hanna T Spontaneous retropharyngeal hematoma N Engl J Med 2016 374 3 e3 26789902 \n7. Sinert R Scalea T Retropharyngeal and bowel hematomas in an anticoagulated patient Acad Emerg Med 1994 1 1 67 72 7621156 \n8. Genovesi MG Simmons DH Airway obstruction due to spontaneous retropharyngeal hemorrhage Chest 1975 68 6 840 42 53128 \n9. Gurr DE Walls RM Anti-coagulation and spontaneous retropharyngeal hematoma J Emerg Med 2003 24 4 469 70 12745054 \n10. Jones TM Owen GO Morar P Spontaneous retropharyngeal haematoma attributable to Epstein-Barr virus infection J Laryngol Otol 1996 110 11 1075 77 8944887\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D000402:Airway Obstruction; D006406:Hematoma; D006801:Humans; D008297:Male; D009190:Myelodysplastic Syndromes; D010608:Pharyngeal Diseases; D010614:Pharynx; D013921:Thrombocytopenia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "969-972",
"pmc": null,
"pmid": "30115902",
"pubdate": "2018-08-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12745040;23518292;21122827;12745054;7621156;26789902;8944887;20830269;53128",
"title": "Retropharyngeal Hematoma as an Unusual Presentation of Myelodysplastic Syndrome: A Case Report.",
"title_normalized": "retropharyngeal hematoma as an unusual presentation of myelodysplastic syndrome a case report"
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"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-053549",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
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... |
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"abstract": "Drug-induced hepatotoxicity is a common cause of acute hepatitis, and the recognition of the responsible drug may be difficult. We describe a case of clopidogrel-related acute hepatitis. The diagnosis is strongly suggested by an accurate medical history and liver biopsy. Reports about cases of hepatotoxicity due to clopidogrel are increasing in the last few years, after the increased use of this drug. In conclusion, we believe that physicians should carefully consider the risk of drug-induced hepatic injury when clopidogrel is prescribed.",
"affiliations": "1Hepatology Unit; and 2Anatomopathology Unit, National Institute for Infectious Diseases \"L. Spallanzani,\" Rome, Italy.",
"authors": "Pisapia|Raffaella|R|;Abdeddaim|Amina|A|;Mariano|Andrea|A|;Rianda|Alessia|A|;Vincenzi|Laura|L|;Taibi|Chiara|C|;Baiocchini|Andrea|A|;Del Nonno|Franca|F|;DʼOffizi|Gianpiero|G|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e318293b0d6",
"fulltext": null,
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"issn_linking": "1075-2765",
"issue": "22(1)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000208:Acute Disease; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e8-e13",
"pmc": null,
"pmid": "23846525",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Acute hepatitis associated with clopidogrel: a case report and review of the literature.",
"title_normalized": "acute hepatitis associated with clopidogrel a case report and review of the literature"
} | [
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"companynumb": "IT-DRREDDYS-GER/ITL/13/0033901",
"fulfillexpeditecriteria": "2",
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"activesubstancename": "PANTOPRAZOLE"
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"abstract": "BACKGROUND\nCarbamazepine (CBZ) is a widely used anticonvulsant with a low molecular weight that allows for extracorporeal removal of free drug by both dialytic and hemoperfusion techniques, particularly in a massive overdose where serum protein binding is saturated. This report presents a case of CBZ intoxication where we were able to compare the mass removal of CBZ using hemoperfusion, with the mass removal of CBZ achieved with continuous renal replacement therapy (CRRT) during combined treatment.\n\n\nMETHODS\nThe Jafron HA230 resin hemoperfusion cartridge was applied in series with the continuous veno-venous hemofiltration (CVVH) circuit. Baseline and ongoing serum drug levels along with further samples from pre- and post-hemoperfusion cartridges and from CVVH effluent were collected.\n\n\nRESULTS\nCombined CVVH and resin hemoperfusion therapy in series was associated with a 50% reduction in the CBZ level from 16 mg/L to 8 mg/L over 3 h, far more rapid than that observed with CVVH alone or in the absence of extracorporeal drug clearance in the preceding hours. The combination therapy removed close to 35 mg/h of CBZ.\n\n\nCONCLUSIONS\nThe combination of CRRT and hemoperfusion can be easily deployed, appears safe, and is able to combine the CBZ mass removal achieved with each technique, thus to maximize CBZ extraction.",
"affiliations": "Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia.;Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia, rahulcp@hotmail.com.;Victorian Poisons Information Centre, Austin Hospital, Melbourne, Victoria, Australia.;Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia.;Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia.",
"authors": "Baylis|Simon|S|;Costa-Pinto|Rahul|R|;Hodgson|Sarah|S|;Bellomo|Rinaldo|R|;Baldwin|Ian|I|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000520520",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-5068",
"issue": null,
"journal": "Blood purification",
"keywords": "Carbamazepine; Case report; Hemofiltration; Hemoperfusion; Intoxication",
"medline_ta": "Blood Purif",
"mesh_terms": null,
"nlm_unique_id": "8402040",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "34879379",
"pubdate": "2021-12-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combined Hemoperfusion and Continuous Veno-Venous Hemofiltration for Carbamazepine Intoxication.",
"title_normalized": "combined hemoperfusion and continuous veno venous hemofiltration for carbamazepine intoxication"
} | [
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"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-324085",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
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"abstract": "A 35-year-old female presented with headache in the third week postpartum period following uneventful cesarean delivery. She had left sided ptosis, pain, and numbness over left face since third trimester. Post-delivery magnetic resonance imaging revealed invading left sphenoid sinus meningioma. She was planned for combined endonasal and pterional craniotomy. Her preoperative investigations including sodium, glucose, and liver functions were normal. Intraoperatively during endonasal phase a high urine output (UO) with rising sodium were noticed which continued with worsening sodium (156 mEq/L after 3 h). Desmopressin 1 mcg IV administered which normalized UO for the rest of surgical duration with trends of declining sodium (149 mEq/L at the end of procedure). Her postoperative MRI was normal however desmopressin could not be discontinued because of increasing sodium and UO without it. She was discharged on oral desmopressin, hydrocortisone and levothyroxine. On her follow-up 3.5 months later she had normal sodium and normal UO.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, King Fahad Medical City, Riyadh, KSA.;Department of Anesthesiology and Perioperative Medicine, King Fahad Medical City, Riyadh, KSA.;Department of Anesthesiology and Perioperative Medicine, King Fahad Medical City, Riyadh, KSA.;Department of Anesthesiology and Perioperative Medicine, King Fahad Medical City, Riyadh, KSA.",
"authors": "Bithal|Parmod K|PK|;Jan|Ravees|R|;Butt|Yasser Majid|YM|;Alshuaibi|Khalid|K|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/sja.SJA_885_20",
"fulltext": "\n==== Front\nSaudi J Anaesth\nSaudi J Anaesth\nSJA\nSaudi Journal of Anaesthesia\n1658-354X\n0975-3125\nWolters Kluwer - Medknow India\n\nSJA-15-204\n10.4103/sja.SJA_885_20\nCase Report\nIntraoperative central diabetes insipidus in a postpartum patient during decompression of base of brain lesion: Missing out the diagnosis of Sheehan's syndrome?\nBithal Parmod K.\nJan Ravees\nButt Yasser Majid\nAlshuaibi Khalid\nDepartment of Anesthesiology and Perioperative Medicine, King Fahad Medical City, Riyadh, KSA\nAddress for correspondence: Dr. Ravees Jan, Department of Anesthesiology and Perioperative Medicine, King Fahad Medical City, Riyadh 11525, KSA. E-mail: janravees@gmail.com\nApr-Jun 2021\n01 4 2021\n15 2 204206\n20 8 2019\n10 9 2020\n17 9 2020\nCopyright: © 2021 Saudi Journal of Anaesthesia\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This 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.\nA 35-year-old female presented with headache in the third week postpartum period following uneventful cesarean delivery. She had left sided ptosis, pain, and numbness over left face since third trimester. Post-delivery magnetic resonance imaging revealed invading left sphenoid sinus meningioma. She was planned for combined endonasal and pterional craniotomy. Her preoperative investigations including sodium, glucose, and liver functions were normal. Intraoperatively during endonasal phase a high urine output (UO) with rising sodium were noticed which continued with worsening sodium (156 mEq/L after 3 h). Desmopressin 1 mcg IV administered which normalized UO for the rest of surgical duration with trends of declining sodium (149 mEq/L at the end of procedure). Her postoperative MRI was normal however desmopressin could not be discontinued because of increasing sodium and UO without it. She was discharged on oral desmopressin, hydrocortisone and levothyroxine. On her follow-up 3.5 months later she had normal sodium and normal UO.\n\nKey words:\n\nCentral diabetes insipidus\ndesmopressin\npuerperium\nSheehan's syndrome\n==== Body\nIntroduction\n\nCentral diabetes insipidus (CDI) results from surgery involving hypothalamic–pituitary–axis (HPA) and can be transient or permanent. Transient condition resolves in vast majority of patients within first postoperative week and only 2.7% develop permanent CDI.[1] It almost always develops 24–48 h postoperatively.[2]\n\nSheehan's syndrome (SS), a known complication of pregnancy usually follows massive bleeding causing hypotension, however it may result after uncomplicated delivery and produces CDI in 5% of them.[3] Latter category of patients has mild unrecognized panhypopituitarism and when they receive glucocorticoids CDI becomes overt.[4]\n\nWe report a patient with presumably unrecognized mild SS with panhypopituitarism who presented with intracranial lesion, during postpartum period. Patient developed CDI during surgery likely from steroids administration.\n\nCase Report\n\nA 35-year-old, 79 kg female developed left sided ptosis with ipsilateral facial pain and numbness during third trimester of pregnancy but was not investigated. Following uneventful cesarean delivery in a peripheral hospital, her symptoms improved only to worsen subsequently. Her brain magnetic resonance imaging (MRI) revealed sphenoid sinus meningioma invading suprasellar, left cavernous sinus and left orbital areas. During the third postpartum week she presented to emergency department of our hospital with increasing headache. Neurosurgeon administered her dexamethasone and planned for combined endonasal and left pterional craniotomy in collaboration with ENT surgeon. Her investigations revealed normal liver functions and blood glucose, Na 140 mEq/L and K 3.6 mEq/L. Following anesthesia induction and tracheal intubation, 8 mg of dexamethasone was administered. Anesthesia was maintained with 50% oxygen and infusion of fentanyl and propofol. Intrarterial blood pressure, neurophysiology monitoring beside routine monitoring was instituted. Approximately 30 min into endonasal phase, her Na was 144 mEq/L and K was 3.7 mEq/L with normal glucose. Urine output (UO) at that time was 200 ml, which increased to 250 ml in the next hour. She was receiving 5 ml/kg/h of crystalloids. No diuretic or mannitol was administered during the procedure. Nearly 30 min before the completion of nasal procedure, Na was 146 mEq/L with 300 ml UO. ENT surgeon handed over the patient to neurosurgeon after 90 min. Serum Na kept on worsening and reached 156 mEq/L after 3 h with increasing UO. Therefore, a presumptive diagnosis of CDI was made in consultation with endocrinologist and 1 mcg of desmopressin was given IV. UO during the remaining surgical period got reduced to 70–100 ml/h with decline in Na to 149 mEq/L at the end of nine hours of procedure. Total UO was 3,000 cc (most of which was in pre-desmopressin phase). Owing to the stormy intraoperative course she was ventilated overnight in the neurocritical care unit (NCCU) and was extubated next day after her check MRI which was normal. In NCCU, discontinuation of desmopressin resulted in recurrence of polyuria, hypernatremia, and high serum osmolality (309 mOsm/kg). Desmopressin was restarted 1 mcg twice daily IV and later on changed to oral route 60 mcg morning and evening with 30 mcg in the afternoon. In addition, she was advised hydrocortisone and levothyroxine. She was discharged home after 2 weeks, with normal Na and normal UO. On her last visit to the clinic after 3.5 months, her Na and UO were controlled on desmopressin.\n\nDiscussion\n\nHigh UO with increasing Na raised suspicion of CDI which was established by robust response to desmopressin. Common surgical reason for its occurrence is HPA injury and it manifests postoperatively in most patients.[2] There are report of transient CDI developing during nasal sinus surgery and during dexmedetomidine infusion, from unknown etiology.[56]\n\nCDI during pregnancy and puerperium is extremely rare and can be difficult to recognize as polydipsia and polyuria are common in pregnancy. CDI can get exacerbated or become apparent during pregnancy from an accelerated catabolism of antidiuretic hormone (ADH) by placental vasopressinase enzyme. Most cases of gestational CDI are from conditions which impair the hepatic clearance of vasopressinase.[7] Even massive release of placental vasopressinase into circulation from placental abruption has also caused postpartum CDI.[8] However, CDI does not follow the placental manipulation during uncomplicated cesarean delivery. Furthermore, gestational CDI does not last beyond 6 weeks of puerperium.[9]\n\nAn uncommon complication of pregnancy is Sheehan's syndrome (SS), characterized by varying degree of anterior pituitary dysfunction. Most have mild disease which goes untreated. Though massive hemorrhage producing hypotension is the cause, it rarely presents even after uncomplicated delivery and produces CDI in 5% of them.[3] Many SS patients have impaired neurohypophyseal functions.[10] Thus, CDI may be a feature of postpartum panhypopituitarism which is infrequently recognized due to wide spectrum in severity of CDI in postpartum hypopituitarism, as well as its masking from concomitant glucocorticoids insufficiency.[11] ADH deficiency is unveiled by glucocorticoids administration from unknown mechanism.[4]\n\nOur patient was 3 weeks into postpartum and had none of the risk factors to suggest heightened vasopressinase activity. She had uncomplicated cesarean delivery and was not given dexmedetomidine during surgery. We speculate that she probably suffered a brief period of hypotension, either during cesarean or during postpartum period, which was dismissed as insignificant but caused mild posterior pituitary damage. Administration of dexamethasone before and during surgery unmasked neurohypophysis dysfunction with resultant CDI. Other possible reason is that endonasal phase of surgery triggered transient CDI from some obscure etiology which was superimposed by trauma to HPA, converting thereby, temporary condition into permanent.[5] However, this theory looks untenable because injury to HPA does not induce CDI intraoperatively.[2] Moreover, there was no intraoperative CSF leak and most significantly postoperative MRI was normal.12\n\nIn conclusion, one should suspect SS of some degree causing panhyopituitarism in a postpartum patient who develops CDI following administration of steroids during surgery and CDI in such patients is permanent.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nReferences\n\n1 Sigounas D Sharpless JL Cheng ML Johnson TG Senior BA Ewend MG Predictors and incidence of central diabetes insipidus after endoscopic pituitary syrgery Neurosurgery 2008 62 71 8 18300893\n2 Daly SC U HS Drummond JC Cottrell JE Patel P The pituitary gland and associated pathologic states Cottrell and Patel's Neuroanesthesia 2017 6th ed New York (USA) Elsevier 465\n3 Kelestimur F Sheehan's syndrome Pituitary 2003 6 181 8 15237929\n4 Chin XR Quek TP Leow MK Central diabetes insipidus unmasked by corticosteroid therapy for cerebral metastasis: Beware the case with pituitary involvement and hypopituitarism J R Coll Physicians Edinb 2017 47 247 9 29465100\n5 Ansar M Gard A Schwaje AT Owen SR Transient central diabetes insipidus during prolonged sinus surgery. Case report and literature review Otolaryngol Case Rep 2020 14 100139\n6 Charran O Lee YI A case of dexmedetomidine (precedex) induced diabetes insipidus in medical intensive care unit Am J Resp Crit Care Med 2019 199 A6634\n7 Kalelioglu I Uzum AK Yildirim A Ozkan T Gungor F Has R Transient gestational diabetes insipidus diagnosed in successive pregnancies: Review of pathophysiology, diagnosis, treatment, and management of delivery Pituitary 2007 10 87 93 17308961\n8 Walia A Bizhanova A Huang W Goldsmith SI Gossett DR Kopp P Acute diabetes insipidus mediated by vasopressinase after placental abruption J Clin Endocrinol Metab 2013 98 881 6 23393172\n9 Shrier RW Systemic arterial vasodilation, vasopressin and vasopressinase in pregnancy J Am Soc Nephrol 2010 21 570 2 19959721\n10 Atmaca H Tanriverdi F Gokce C Unluhizarci K Kelestimur F Posterior pituitary function in Sheehan's syndrome Eur J Endocrinol 2007 156 563 7 17468192\n11 Schwartz AR Leddy AL Recognition of diabetes insipidus in postpartum hypopituitarism Obstet Gynecol 1982 59 394 8 6804902\n12 Ajlan AM Abdulqader SB Achrol AJ Aljamaan Y Feroze AH Katznelson L Diabetes insipidus following endoscopic transsphenoidal surgery for pituitary adenoma J Neurol Surg B Skull Base 2018 79 117 22 29868315\n\n",
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"issue": "15(2)",
"journal": "Saudi journal of anaesthesia",
"keywords": "Central diabetes insipidus; Sheehan's syndrome; desmopressin; puerperium",
"medline_ta": "Saudi J Anaesth",
"mesh_terms": null,
"nlm_unique_id": "101500601",
"other_id": null,
"pages": "204-206",
"pmc": null,
"pmid": "34188642",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29465100;15237929;17468192;29868315;17308961;6804902;18300893;23393172;19959721",
"title": "Intraoperative central diabetes insipidus in a postpartum patient during decompression of base of brain lesion: Missing out the diagnosis of Sheehan's syndrome?",
"title_normalized": "intraoperative central diabetes insipidus in a postpartum patient during decompression of base of brain lesion missing out the diagnosis of sheehan s syndrome"
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"abstract": "Lanthanum carbonate is a phosphate binder that is used to reduce serum phosphate levels in patients with end-stage renal disease (ESRD). Lanthanum forms insoluble lanthanum phosphate complexes that are supposed to pass through the gastrointestinal (GI) tract unabsorbed. Phosphate binders have been reported to deposit in the GI tract and can cause mucosal injury. There are few case reports of GI bleeding associated with phosphate binder deposits. This case report presents a patient with iron deficiency anaemia secondary to biopsy-proven lanthanum deposits in the upper GI tract. There were no overt signs of active GI bleeding. Patient's anaemia improved with discontinuation of the phosphate binder. Lanthanum could be a hidden cause of resistant anaemia among patients with ESRD through asymptomatic GI blood loss.",
"affiliations": "Internal Medicine, US Air Force Hospital Lackland AFB, San Antonio, Texas, USA.;US Air Force Hospital Keesler AFB, Keesler AFB, Mississippi, USA.;US Air Force Hospital Keesler AFB, Keesler AFB, Mississippi, USA.",
"authors": "Awad|Christina|C|;Gilkison|Karin|K|;Shaw|Erwin|E|",
"chemical_list": "C119467:lanthanum carbonate; D007811:Lanthanum",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226157",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "12(3)",
"journal": "BMJ case reports",
"keywords": "Gi bleeding; drugs: gastrointestinal system; gastrointestinal system; oesophagus; ulcer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D018798:Anemia, Iron-Deficiency; D005753:Gastric Mucosa; D006801:Humans; D054559:Hyperphosphatemia; D007676:Kidney Failure, Chronic; D007811:Lanthanum; D008297:Male",
"nlm_unique_id": "101526291",
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"pages": null,
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"pmid": "30878952",
"pubdate": "2019-03-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27303074;28852493;29515344;25413959;28038714;28781325",
"title": "Lanthanum phosphate binder-induced iron deficiency anaemia.",
"title_normalized": "lanthanum phosphate binder induced iron deficiency anaemia"
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"activesubstancename": "DARBEPOETIN ALFA"
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"abstract": "Multiple myeloma is a B-cell neoplastic disorder and represents 1% of all cancers and 13% of hematological malignancies. It is predominantly a disease of elderly, and less than 3% of all cases are below the age of 40 years. We present the case of a 29-year-old lady with multiple myeloma who had spontaneous conception during maintenance therapy and subsequently a successful pregnancy outcome. She gave birth to a healthy female infant through normal vaginal delivery and subsequently could remain off therapy for 5 years. Since the patient had a history of abortions and stillbirth, it was a precious pregnancy and we could successfully salvage both the mother and the baby. Young female patients of myeloma who are in remission can be encouraged to start a family during their reproductive years with the support of a comprehensive care team of hematologists/oncologists and obstetricians.",
"affiliations": "Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014 India.;Department of Obstetrics and Gynaecology, Lady Hardinge Medical College, New Delhi, 110001 India.;Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014 India.",
"authors": "Garg|Akanksha|A|0000-0002-2020-7928;Aggarwal|Monika|M|;Kashyap|Rajesh|R|",
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"issue": "71(1)",
"journal": "Journal of obstetrics and gynaecology of India",
"keywords": "Bad obstetric history; Myeloma; Pregnancy",
"medline_ta": "J Obstet Gynaecol India",
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"nlm_unique_id": "0374763",
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"pages": "78-81",
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"references": "4417641;27283927;26847816;7847542;14715876;5944257;18291591;18637123;21064133;5742077;23964646;23488659",
"title": "Pregnancy and Its Successful Outcome in a Patient with Multiple Myeloma.",
"title_normalized": "pregnancy and its successful outcome in a patient with multiple myeloma"
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"abstract": "Blunt renal trauma is relatively common in children. Conservative management has become the mainstay of treatment. A 4-year-old boy presented following a fall onto his right abdomen resulting in renal trauma. Initial conservative management was followed by complete embolization of the kidney. The resulting continued hypertension, as well as endothelial disruption, resulted in PRES as manifested by a single instance of generalized seizure. The patient regained normal neurological function following nephrectomy. Better understanding of the potential for acute hypertensive crisis resulting in PRES in the urology community may result in more urgent and effective management in these scenarios.",
"affiliations": "Maine Medical Center Department of Urology, Tufts University School of Medicine. Electronic address: william_conor.daly@tufts.edu.;Maine Medical Center Department of Pediatric Neurology, Tufts University School of Medicine.;Maine Medical Center Department of Pediatric Nephrology, Tufts University School of Medicine.;Maine Medical Center Department of Urology, Tufts University School of Medicine.",
"authors": "Daly|William C|WC|;Reynolds|Thomas|T|;Tanzer|Marie|M|;Chalmers|David J|DJ|",
"chemical_list": null,
"country": "United States",
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"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
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"title": "Posterior Reversible Encephalopathy Syndrome Following Failure of Conservative Management in Renal Trauma: Case Report.",
"title_normalized": "posterior reversible encephalopathy syndrome following failure of conservative management in renal trauma case report"
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"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare idiosyncratic drug reaction with a mortality of up to 10%. As the name suggests, it is characterized by skin rash, eosinophilia, and systemic symptoms resulting from the involvement of visceral organs. We present a case of DRESS in a patient who was on both lamotrigine and levetiracetam, where levetiracetam turned out to be the inciting agent. The interesting features of the case include the onset of symptoms about 70 days after the initiation of levetiracetam, the lack of prominent eosinophilia and the involvement of the gall bladder, which was previously unknown with Levetiracetam. It also reinforces the importance of using the RegiSCAR score in the diagnosis of DRESS. The symptoms resolved over the next few months after drug withdrawal.",
"affiliations": "Internal Medicine, Bronx Lebanon Hospital Icahn School of Medicine at Mount Sinai, New York, USA.;Pathology, Bronx Lebanon, New York, USA.;Internal Medicine, University of Kentucky, Lexington, USA.;Dermatology, Bronx Lebanon, New York, USA.;Infectious Disease, Bronx Lebanon, New York, USA.",
"authors": "Singh|Tushi|T|;Niazi|Masooma|M|;Karri|Kishore|K|;Rudikoff|Donald|D|;Gonzalez|Efrain|E|",
"chemical_list": null,
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4245Internal MedicineMedical EducationGastroenterologyA Rare Case of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Syndrome with Cholecystitis in a Patient on Levetiracetam Muacevic Alexander Adler John R Singh Tushi 1Niazi Masooma 2Karri Kishore 3Rudikoff Donald 4Gonzalez Efrain 5\n1 \nInternal Medicine, Bronx Lebanon Hospital Icahn School of Medicine at Mount Sinai, New York, USA \n2 \nPathology, Bronx Lebanon, New York, USA \n3 \nInternal Medicine, University of Kentucky, Lexington, USA \n4 \nDermatology, Bronx Lebanon, New York, USA \n5 \nInfectious Disease, Bronx Lebanon, New York, USA \nTushi Singh drtushisingh@gmail.com13 3 2019 3 2019 11 3 e424525 2 2019 12 3 2019 Copyright © 2019, Singh et al.2019Singh et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/18265-a-rare-case-of-dress-drug-reaction-with-eosinophilia-and-systemic-symptoms-syndrome-with-cholecystitis-in-a-patient-on-levetiracetamDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare idiosyncratic drug reaction with a mortality of up to 10%. As the name suggests, it is characterized by skin rash, eosinophilia, and systemic symptoms resulting from the involvement of visceral organs. We present a case of DRESS in a patient who was on both lamotrigine and levetiracetam, where levetiracetam turned out to be the inciting agent. The interesting features of the case include the onset of symptoms about 70 days after the initiation of levetiracetam, the lack of prominent eosinophilia and the involvement of the gall bladder, which was previously unknown with Levetiracetam. It also reinforces the importance of using the RegiSCAR score in the diagnosis of DRESS. The symptoms resolved over the next few months after drug withdrawal.\n\nadverse reactioncholecystitisdrug rash with eosinophilia and systemic symptomsThe 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\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially life-threatening condition with a mortality rate of 10% [1]. Levetiracetam is a widely prescribed antiepileptic known for its favorable side-effect profile. While DRESS is more common with other anticonvulsants, levetiracetam is a rare cause of DRESS. Cholecystitis in levetiracetam-induced DRESS has not been reported yet, to the best of our knowledge. We present a case with a 70-day lag in the manifestation of DRESS after initiating levetiracetam. The diagnostic challenge was posed by the fact that the patient was on both levetiracetam as well as lamotrigine.\n\nCase presentation\nA 36-year-old female was discovered to have an astrocytoma after she presented with new onset seizures. She was started on levetiracetam to control the seizures. Seven weeks later, she presented with break-through seizures while the serum levetiracetam level was therapeutic. Lamotrigine was then added to her medications. Four weeks later, she presented with a rash, right upper quadrant abdominal pain, and fever for four days. She denied any nausea, vomiting, diarrhea, or joint pains. Her medical history was significant for allergies to nuts and pollen. The family history was not significant. She denied having traveled out of the city in the last 18 months. She was a stay-at-home mother of one child.\n\nOn physical examination, she was in mild distress due to abdominal pain, febrile to 38 degree Celsius, pulse of 110 per minute, respiratory rate of 18 breaths per min, blood pressure of 124/77 mm Hg in the right upper limb in the supine position, and oxygen saturation of 98% on room air. A reticulated macular erythematous rash was noted on the upper extremities (Figure 1) and trunk (Figure 2). The head and neck exam did not demonstrate any localized swelling, lymphadenopathy, or icterus. There was no oral ulceration or conjunctival injection. Cardiac and lung exam were within normal limits. The abdominal exam revealed right upper quadrant tenderness with Murphy’s sign. Initial lab data demonstrated an eosinophil count of 4 x 10^5/ml, elevated white cell count, alanine aminotransferase (ALT) of 1231 units/L, and aspartate aminotransferase (AST) of 1026 units/L. Alkaline phosphatase was 362 units/L. Lamotrigine was stopped as DRESS was considered. Over the next 48 hours. there was no improvement, against expectations. An ultrasound of the abdomen followed by magnetic resonance cholangiopancreatography confirmed the presence of acalculous cholecystitis. Antibiotics were administered for cholecystitis. Two days later, her abdominal pain subsided but she remained febrile (T-max of 39.3 Deg C). By now, the reticulated erythema spread to her face and lower extremities (Figure 3). Her face became edematous, and she developed enlarged salivary glands and lower lip edema (Figure 4). Her pharynx was noted to be erythematous and her tonsils were enlarged and covered with exudates. Cervical and submandibular lymphadenopathy developed as well. At this time, an alternate diagnosis was entertained while she did not improve over the next one week. She was immune to hepatitis A and B. Antibody to hepatitis C was negative. The antinuclear antibody, anti-smooth muscle antibody, antimitochondrial antibody, and liver-kidney microsomal assay were negative. Serum ceruloplasmin was within normal limits. Serum toxicology showed a salicylate and acetaminophen level within normal limits. Urine toxicology was negative for substances of abuse. Serum titers for rubella, rubeola, mumps, Epstein Barr virus, cytomegalovirus, varicella zoster, and human herpesvirus-6 were negative. Anti-streptococcal titers, throat culture for Streptococcus, and diphtheria culture were sent as well and reported no growth or negative growth. The cell count peripheral smear did not demonstrate mononucleosis or atypical lymphocytosis. A chest radiograph demonstrated a newly developed right-sided pleural effusion without evidence of consolidation. A skin biopsy was done, which confirmed perivascular dermatitis such as that seen in drug hypersensitivity (Figures 5-6).\n\nFigure 1 Reticulated erythematous rash on the upper limb on presentation\nFigure 2 Reticulated erythematous rash on the trunk on presentation \nFigure 3 Swelling and rash on the soles: Day 2\nFigure 4 Facial edema and lip swelling: Day 2\nFigure 5 Skin biopsy on low magnification\nBiopsy with epidermis, dermis, and subcutaneous tissue showing superficial and mid-dermal perivascular dermatitis consistent with a hypersensitivity reaction.\n\nFigure 6 Skin biopsy on high magnification (x100)\nBiopsy showing perivascular infiltrate consisting of lymphocytes, macrophages, and rare eosinophils.\n\nAbout 10 days after presentation, the levetiracetam was discontinued because of the lack of improvement in symptoms with the cessation of lamotrigine. With that, she began to improve gradually with the disappearance of the skin rash over the next few days, resolution of the facial and the lymph node swelling, as well as a return of transaminases to the baseline over the next few weeks.\n\nDiscussion\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening hypersensitivity reaction first described with phenytoin in the 1940s [2]. Anticonvulsants and sulfonamides are the most frequently implicated drugs [3]. DRESS usually occurs two to eight weeks after exposure to the trigger medication, and it is characterized by fever, rash, lymphadenopathy, and facial swelling. Cell counts usually demonstrate eosinophilia and leukocytosis. Inflammation of the visceral organs, namely, the liver, kidney, heart, and skin, is also a hallmark of the disease. [4] The pathogenesis is not completely understood, and a combination of genetic deficiencies in drug metabolizing enzymes [5] and the reactivation of the herpes virus due to interaction with the drug [6] has been implicated. The RegiSCAR score (Table 1) is a widely used scoring system that assists in the diagnosis of DRESS where a score of 5 and above confirms the diagnosis [7]. The scoring system uses the clinical, serological, as well as histological aspects of the condition to assign scores. It is broken down as shown below. Our patient met the criteria for DRESS with a score of 6. The scoring points included enlarged lymph nodes (cervical and submandibular) (+1) and skin rash covering over 50% of the body surface area (+1) with edema and scaling (+1), visceral organ involvement (lungs, liver, and gallbladder) (+2). Viral infections, including hepatitis A, B, C and measles, rubella, mumps, as well as ANA, mycoplasma, chlamydiae, and blood cultures were negative (+1). \n\nTable 1 RegiSCAR scoring system\nFinal score <2 - Not DRESS, 2-3 - Possible, 4-5 - Probable, >5 - Definite\n\nDRESS: drug reaction with eosinophilia and systemic symptom syndrome; BSA: body surface area\n\nFeatures\tNo\tYes\tUnknown\t\nFever, >38.5deg C\t-1\t0\t-1\t\nEnlarged lymph node, >1cm\t0\t1\t0\t\nEosinophilia >700 or >10% / >1500 or >20%\t0\t1 / 2\t0\t\nAtypical Lymphocytes\t0\t1\t0\t\nSkin Rash >50% BSA\t0\t1\t0\t\nAt least two of edema, infiltration, purpura or scaling\t-1\t1\t0\t\nBiopsy suggesting DRESS\t-1\t0\t0\t\nInternal organ involvement 1, 2 or more\t1\t2\t0\t\nResolution in over 15 days\t-1\t \t-1\t\nAt least three biological investigations done to rule out an alternative diagnosis\t0\t1\t0\t\nIt has been shown that DRESS may be associated with acalculous cholecystitis [8] but reports remain incidental and too few to arrive at a prediction. Only five cases of levetiracetam-induced DRESS have been reported so far [9-11]. Only three cases of cholecystitis associated with DRESS have been reported [12-13]. Allopurinol has been the implicated drug in these cases. To the best of our knowledge, this is the first reported case of levetiracetam-induced DRESS that is associated with cholecystitis. Our case stands out for the prolonged latency of over 70 days instead of the recorded average of one to eight weeks [14] from drug initiation to symptom onset. The lack of eosinophilia on presentation and the presence of lamotrigine in the medication list threw us off the mark but the gradual development of her symptoms even a week after withdrawal of lamotrigine helped us zero in on the inciting drug. This was further aided by the initiation of resolution within 24 hours of withdrawal of levetiracetam. Usually, the resolution occurs over about 6-9 weeks [15]. Our patient had a complete clinical recovery in about eight weeks but the liver functions took over 12 months to resolve. Steroids have been used for the treatment of DRESS in the past but its use remains controversial. As our patient improved in line with our expectations after cessation of levetiracetam, we decided to adopt a wait-and-watch policy in keeping with the patient's wishes. She was started on topiramate for seizure control and has remained well on it.\n\nConclusions\nAlthough rare, levetiracetam has been established to cause DRESS. It is important for physicians to entertain the diagnosis when the patient meets the criteria even if the clinical hallmarks (eosinophilia, for example) are absent. DRESS is also associated with acalculous cholecystitis. Early discontinuation of the offending medication leads to quicker recovery.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Drug reaction with eosinophilia and systemic symptoms. A retrospective study of 60 cases Arch Dermatol Chen YC Chiu HC Chu CY 1373 1379 A 146 2010 20713773 \n2 Phenytoin-induced DRESS: a case report J Allergy Clin Immunol Yazicioglu M Mentes DA Turgut B 106 115 2005 \n3 DRESS syndrome. Part 1. Clinical perspectives J Am Acad Dermatol Husain Z Reddy B Schwartz RA 706 708 68 2013 \n4 Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS) Semin Cutan Med Surg Bocquet H Bagot M Roujeau JC 250 257 15 1996 9069593 \n5 Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome Br J Dermatol Choquet-Kastylevsky G Intrator L Chenal C Bocquet H Revuz J Roujeau JC 1026 1032 139 1998 https://www.ncbi.nlm.nih.gov/pubmed/9990366 9990366 \n6 Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesviruses and antiviral and antidrug immune responses Allergol Int Shiohara T Inaoka M Kano Y 1 8 55 2006 17075280 \n7 Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure Arch Dermatol Eshki M Allanore L Musette P 67 72 145 2009 19153346 \n8 Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients Medicine (Baltimore) M’rad M’rad Leclerc-Mercier S Blanche P 131 140 88 2009 19440116 \n9 Levetiracetam-induced drug reaction with eosinophilia and systemic symptoms syndrome Ann Pharmacother Gómez-Zorrilla S Ferraz AV Pedrós C Lemus M Peña C 7 8 46 2012 \n10 Drug reaction with eosinophilia and systemic symptoms syndrome in a patient taking phenytoin and levetiracetam: a case report J Med Case Rep Hall DJ Fromm JS 2 7 2013 23286229 \n11 Dress syndrome induced by levetiracetam J Eur Acad Dermatol Venereol Eleni K 377 378 29 2015 24397826 \n12 Allopurinol-induced drug reaction with eosinophilia and systemic symptoms syndrome: a cause of acalculous cholecystitis Cureus Waseem H Inayat F Abduraimova M Kamholz S 1569 9 2017 \n13 Drug rash with eosinophilia and systemic symptoms syndrome following cholestatic hepatitis A: a case report Korean J Hepatol An J Lee JH Lee H 84 88 18 2012 https://www.ncbi.nlm.nih.gov/pubmed/22511907 22511907 \n14 The drug hypersensitivity syndrome: what is the pathogenesis? Arch Dermatol Sullivan JR Shear NH 357 364 137 2001 https://www.ncbi.nlm.nih.gov/pubmed/11255340 11255340 \n15 The DRESS syndrome: a literature review Am J Med Cacoub P Musette P Descamps V Meyer O Speirs C Finzi L Roujeau JC 588 597 124 2011 https://www.amjmed.com/article/S0002-9343(11)00258-0/fulltext 21592453\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(3)",
"journal": "Cureus",
"keywords": "adverse reaction; cholecystitis; drug rash with eosinophilia and systemic symptoms",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pages": "e4245",
"pmc": null,
"pmid": "31131168",
"pubdate": "2019-03-13",
"publication_types": "D002363:Case Reports",
"references": "11255340;17075280;19153346;19440116;20713773;21592453;22511907;22764327;23286229;23602182;24397826;29057181;9069593;9990366",
"title": "A Rare Case of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Syndrome with Cholecystitis in a Patient on Levetiracetam.",
"title_normalized": "a rare case of dress drug reaction with eosinophilia and systemic symptoms syndrome with cholecystitis in a patient on levetiracetam"
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"abstract": "To assess the safety of buprenorphine compared with methadone to treat pregnant women with opioid use disorder.\n\n\n\nWe searched PubMed, Embase and the Cochrane Library from inception to February 2015 for randomized controlled trials (RCT) and observational cohort studies (OBS) that compared buprenorphine with methadone for treating opioid-dependent pregnant women. Two reviewers assessed independently the titles and abstracts of all search results and full texts of potentially eligible studies reporting original data for maternal/fetal/infant death, preterm birth, fetal growth outcomes, fetal/congenital anomalies, fetal/child neurodevelopment and/or maternal adverse events. We ascertained each study's risk of bias using validated instruments and assessed the strength of evidence for each outcome using established methods. We computed effect sizes using random-effects models for each outcome with two or more studies.\n\n\n\nThree RCTs (n = 223) and 15 cohort OBSs (n = 1923) met inclusion criteria. In meta-analyses using unadjusted data and methadone as comparator, buprenorphine was associated with lower risk of preterm birth [RCT risk ratio (RR) = 0.40, 95% confidence interval (CI) = 0.18, 0.91; OBS RR = 0.67, 95% CI = 0.50, 0.90], greater birth weight [RCT weighted mean difference (WMD) = 277 g, 95% CI = 104, 450; OBS WMD = 265 g, 95% CI = 196, 335] and larger head circumference [RCT WMD = 0.90 cm, 95% CI = 0.14, 1.66; OBS WMD = 0.68 cm, 95% CI = 0.41, 0.94]. No treatment differences were observed for spontaneous fetal death, fetal/congenital anomalies and other fetal growth measures, although the power to detect such differences may be inadequate due to small sample sizes.\n\n\n\nModerately strong evidence indicates lower risk of preterm birth, greater birth weight and larger head circumference with buprenorphine treatment of maternal opioid use disorder during pregnancy compared with methadone treatment, and no greater harms.",
"affiliations": "Venebio Group, LLC, Richmond, Virginia, USA.;Venebio Group, LLC, Richmond, Virginia, USA.;Center for Biobehavioral Health Disparities Research, Division of Community Health, Duke University, Durham, NC, USA.;Venebio Group, LLC, Richmond, Virginia, USA.;Venebio Group, LLC, Richmond, Virginia, USA.;Venebio Group, LLC, Richmond, Virginia, USA.;UNC Horizons, Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.",
"authors": "Zedler|Barbara K|BK|;Mann|Ashley L|AL|;Kim|Mimi M|MM|;Amick|Halle R|HR|;Joyce|Andrew R|AR|;Murrelle|E Lenn|EL|;Jones|Hendrée E|HE|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1111/add.13462",
"fulltext": "\n==== Front\nAddictionAddiction10.1111/(ISSN)1360-0443ADDAddiction (Abingdon, England)0965-21401360-0443John Wiley and Sons Inc. Hoboken 10.1111/add.13462ADD13462ADD-15-1082.R2ReviewReviewsBuprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta‐analysis of safety in the mother, fetus and child Barbara K. Zedler et al.Buprenorphine safety during pregnancyZedler Barbara K. barb.zedler@venebio.com \n1\nMann Ashley L. \n1\nKim Mimi M. \n2\nAmick Halle R. \n1\nJoyce Andrew R. \n1\nMurrelle E. Lenn \n1\nJones Hendrée E. \n3\n\n4\n1 Venebio Group, LLCRichmondVirginiaUSA2 Center for Biobehavioral Health Disparities Research, Division of Community HealthDuke UniversityDurhamNCUSA3 UNC Horizons, Department of Obstetrics and Gynecology, School of MedicineUniversity of North Carolina at Chapel HillChapel HillNCUSA4 Departments of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology, School of MedicineJohns Hopkins UniversityBaltimoreMDUSA* Correspondence to: Barbara Zedler, Venebio Group, LLC, 7400 Beaufont Springs Drive, Suite 300, Richmond, VA 23225, USA. E‐mail: barb.zedler@venebio.com\n30 6 2016 12 2016 111 12 10.1111/add.v111.122115 2128 16 11 2015 16 2 2016 06 5 2016 © 2016 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.This 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.Abstract\nAims\nTo assess the safety of buprenorphine compared with methadone to treat pregnant women with opioid use disorder.\n\nMethods\nWe searched PubMed, Embase and the Cochrane Library from inception to February 2015 for randomized controlled trials (RCT) and observational cohort studies (OBS) that compared buprenorphine with methadone for treating opioid‐dependent pregnant women. Two reviewers assessed independently the titles and abstracts of all search results and full texts of potentially eligible studies reporting original data for maternal/fetal/infant death, preterm birth, fetal growth outcomes, fetal/congenital anomalies, fetal/child neurodevelopment and/or maternal adverse events. We ascertained each study's risk of bias using validated instruments and assessed the strength of evidence for each outcome using established methods. We computed effect sizes using random‐effects models for each outcome with two or more studies.\n\nResults\nThree RCTs (n = 223) and 15 cohort OBSs (n = 1923) met inclusion criteria. In meta‐analyses using unadjusted data and methadone as comparator, buprenorphine was associated with lower risk of preterm birth [RCT risk ratio (RR) = 0.40, 95% confidence interval (CI) = 0.18, 0.91; OBS RR = 0.67, 95% CI = 0.50, 0.90], greater birth weight [RCT weighted mean difference (WMD) = 277 g, 95% CI = 104, 450; OBS WMD = 265 g, 95% CI = 196, 335] and larger head circumference [RCT WMD = 0.90 cm, 95% CI = 0.14, 1.66; OBS WMD = 0.68 cm, 95% CI = 0.41, 0.94]. No treatment differences were observed for spontaneous fetal death, fetal/congenital anomalies and other fetal growth measures, although the power to detect such differences may be inadequate due to small sample sizes.\n\nConclusions\nModerately strong evidence indicates lower risk of preterm birth, greater birth weight and larger head circumference with buprenorphine treatment of maternal opioid use disorder during pregnancy compared with methadone treatment, and no greater harms.\n\nBuprenorphinedependencefetusharmmethadoneopioid use disorderpregnancy source-schema-version-number2.0component-idadd13462cover-dateDecember 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:24.11.2016\n\n\nZedler , B. K. \n, \nMann , A. L. \n, \nKim , M. M. \n, \nAmick , H. R. \n, \nJoyce , A. R. \n, \nMurrelle , E. L. \n, and \nJones , H. E. \n (2016 ) Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta‐analysis of safety in the mother, fetus and child . Addiction , 111 : 2115 –2128 . doi: 10.1111/add.13462.\n==== Body\nIntroduction\nThe incidence of prescription and illicit opioid use during pregnancy has increased substantially in the United States since 2000, paralleling a similar escalation in the general population 1. Moreover, the prevalence of opioid use disorder (OUD) during pregnancy more than doubled between 1998 and 2011, to four per 1000 deliveries 2.\n\nAll pregnancies have a background risk of adverse consequences. Pregnant women with OUD have a higher frequency of additional risk factors for adverse pregnancy outcomes than pregnant women who do not use opioids. These risk factors include chronic viral infections, psychiatric conditions, poor health behaviors, adverse social conditions and inadequate prenatal care 3, 4.\n\nComplete opioid abstinence throughout pregnancy is ideal for both mother and fetus, but acute withdrawal during pregnancy is not recommended 5, 6. Relapse rates are high and repeated cycles of intoxication and withdrawal are associated with significant fetal distress that can lead to placental insufficiency and consequent pregnancy loss, intrauterine growth restriction (IUGR) and preterm labor and birth 5, 7, 8, 9. The accepted treatment for OUD during pregnancy is long‐acting opioid agonist medication‐assisted treatment (OMAT), such as methadone (MET) or buprenorphine (BUP), within the context of a comprehensive program of obstetric care and psychosocial interventions 5, 8, 10, 11, 12, 13, 14. Adequate medication treatment maintains stable opioid blood levels that reduce maternal craving for and use of heroin or other opioids and improves prenatal care and fetal/infant outcomes compared with untreated opioid use or opioid withdrawal 11, 15, 16. MET maintenance treatment during pregnancy has been used widely since the early 1970s via daily visits to government‐regulated clinics 17. BUP maintenance treatment has been used increasingly since its approval in France in 1996 and the United States in 2002, partly because of its availability in the private practitioner setting and pharmacology that enables less than daily dosing, lower overdose risk and fewer drug interactions 11, 18. Three RCTs have been conducted comparing BUP and MET as OMAT in pregnancy, with a primary focus on multiple measures of neonatal abstinence syndrome (NAS) 19, 20, 21. Previous systematic reviews and meta‐analyses of these RCTs 5, 22 concluded that BUP and MET have similar efficacy for reducing pregnant women's opioid use but that neither opioid agonist was superior for all maternal, fetal and child outcomes 11. However, uncertainty was high regarding the conclusions due to the small body of evidence, particularly for outcomes other than NAS, due largely to their infrequency. For NAS, the meta‐analyses identified no difference between BUP and MET in the frequency of NAS requiring treatment, the amount of morphine or time required to treat or the length of hospitalization. However, the single, large RCT (n = 131) 19 observed significantly less severe NAS, based on 89% less morphine required to treat and 43% shorter hospitalization, compared with no difference in the two small RCTs (n = 14 20 and n = 21 21). No additional RCTs are available or likely to be performed, but the cumulative body of relevant observational studies has not been reviewed rigorously or synthesized quantitatively for any pregnancy outcomes.\n\nThe objectives of this review were to assess systematically all available evidence from clinical studies regarding the safety of buprenorphine compared with methadone treatment of opioid‐dependent pregnant women and provide quantitative treatment effect estimates for selected pregnancy outcomes, as feasible.\n\nMethods\nThe conduct and reporting of this review conform with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement (Supporting information, Figure S1) 23.\n\nSearch strategy and inclusion criteria\nWe searched the PubMed and Embase databases and the Cochrane Database of Systematic Reviews from their inception through February 2015 using the search strategy in Supporting information, Table S1 without language restrictions. We searched manually the reference lists of review papers and the included studies to identify additional papers.\n\nWe included studies if they: (1) were RCTs or observational (cohort or case–control) studies (OBSs); (2) enrolled opioid‐dependent pregnant women; (3) compared buprenorphine or buprenorphine–naloxone with methadone as OMAT; and (4) reported original data on one or more specified pregnancy‐related outcomes representing important potential pregnancy‐related harms (Table 1). This review focused on outcomes other than NAS for practical reasons. There are several pregnancy outcomes besides NAS which lack systematic review or meta‐analysis to date and, due to its numerous measures, NAS would benefit from a separate systematic review that includes eligible OBSs. Two researchers reviewed each title and abstract independently and then assessed the full texts of potentially eligible papers. Disagreements between reviewers regarding eligibility were resolved by consensus.\n\nTable 1 Inclusion criteria and outcome definitions.\n\n\nStudy component\n\t\nCriterion/definition\n\t\n\nPopulation\n\tOpioid‐dependent pregnant women\t\n\nIntervention\n\tBuprenorphine prescribed as opioid agonist medication‐assisted treatment for opioid use disordera\n\t\n\nComparator\n\tMethadone prescribed as opioid agonist medication‐assisted treatment for opioid use disorder\t\n\nOutcomes\n\t\t\nSpontaneous fetal death\t\nMiscarriage (death of a fetus or embryo at or before 20 completed weeks gestation)\n\nStillbirth (death of a fetus after 20 completed weeks gestation)\t\nAll fetal death\tSpontaneous fetal death plus induced fetal death (induced abortion)\t\nPreterm birth\tLive birth before 37 completed weeks gestationb\n\t\nFetal growth outcomes\t\t\n*Birth weight (g)\tConverted to grams as necessary\t\n*Low birth weight (LBW)\t< 2500 g regardless of gestational age\t\n*Small for gestational age (SGA)\tBirth weight below an established sex‐ and gestational week‐specific mean valuec\n\t\n*Intrauterine growth restriction (IUGR)\tDiminished growth velocity documented in two or more intrauterine growth assessments\t\n*Head circumference at birth (cm)\tConverted to centimeters as necessary\t\nFetal/congenital anomalies\tAn abnormality of structure (malformation), function or metabolism present at birth or identified at fetal death; birth defects\t\nSudden infant death syndrome (SIDS)\tUnanticipated and unexplained death of a live‐born infant before age 1 year\t\nFetal/child neurodevelopment\tCognitive, behavioral, sensory, motor or functional development. Abnormal is a delay or impairment\t\nMaternal adverse events during pregnancy\tCategorized by each study as serious (e.g. death) or non‐seriousd\n\t\n\nStudy designs\n\tRandomized controlled trials, observational (cohort or case–control) studies\t\nEGA = estimated gestational age.\n\na We included one study that treated women with an abuse‐deterrent combination buprenorphine (BUP)–naloxone formulation 44, but excluded it from quantitative analyses.\n\nb Preterm birth was defined as < 36 completed weeks gestation in Colombini 2008 37.\n\nc SGA was defined as birth weight below: (a) 2 standard deviations from the sex‐ and gestational‐week specific mean value (Jones 2010 19; Kakko 2008 39); (b) 10th percentile of the sex‐ and gestational‐week specific mean value (Siedentopf 2004 47); or (c) the 5th percentile of the sex‐ and gestational‐week specific mean value (Brulet 2007 36; Meyer 2015 43).\n\nd Maternal adverse events were defined as: (a) medical events (Lacroix 2011 41); (b) complications (Prasad 2013 44); or (c) any untoward medical occurrence (Jones 2010 19).\n\nData extraction and risk of bias assessment\nTwo researchers extracted data independently from each included paper into standardized tables and resolved discrepancies by consensus. A senior researcher confirmed the accuracy of entries. We contacted authors as feasible if additional information was needed. We categorized studies as RCT or OBS based on elements as reported. Two researchers assessed the risk of bias (ROB) independently for each outcome as high, medium or low, and a senior researcher resolved any conflicts. For RCTs, we assessed randomization adequacy, allocation concealment, missing outcome data, selective outcome reporting and blinding of participants, study personnel and assessors according to standards of the US Agency for Healthcare Research and Quality (AHRQ) 24. For OBSs, we evaluated the selection of participants, comparability of cohorts, exposure and outcome assessment and follow‐up adequacy using the Newcastle–Ottawa Scale as expanded by Guyatt 25, 26.\n\nData synthesis and statistical analyses\nThe unit of analysis was pregnancies or live births, depending on the outcome. We conducted meta‐analyses of the unadjusted study data using random effects models (DerSimonian & Laird method) 27 to account for heterogeneity among the studies and estimated unadjusted treatment effects as weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) for binary outcomes. Statistical significance was defined as a 95% confidence interval (CI) for the pooled effect that did not include zero for WMDs or 1.0 for RRs.\n\nWe anticipated a substantial amount of missing outcome data from attrition based upon the challenges of research with opioid‐dependent people, especially during pregnancy 19, 28, 29. We decided a priori to include only unadjusted outcome data as available from studies with low or medium ROB in our main analyses. To examine the stability of the main estimates, we conducted sensitivity analyses by including high ROB studies or imputing missing binary data under best‐ and worst‐case scenarios 28, 29. We combined OBSs with similar study methods and clinical variability 30 and calculated summary treatment effect estimates separately by study design 28, 29. We estimated inconsistency (heterogeneity) across studies using the I\n2 statistic 28 and investigated sources of clinical and/or methodological variation when we suspected heterogeneity that might affect the results 31. We synthesized outcome data qualitatively when studies were too heterogeneous to pool quantitatively or when only a single study reported an outcome. For comparisons with 10 or more studies we inspected funnel plots to assess potential publication bias 32. Analyses were conducted using Comprehensive Meta‐Analysis, version 3.2 (Biostat; Englewood, NJ, USA).\n\nRating strength of evidence (SOE)\nSOE is a summary of confidence in our findings. We evaluated the SOE for each outcome based on guidance established by AHRQ using five domains: study limitations, directness, consistency, precision and reporting bias 33. The assigned grade (high, moderate, low, insufficient) represents the degree of confidence in the effect estimates for an outcome. We graded SOE separately for the bodies of evidence from RCTs and OBSs.\n\nResults\nOf 1111 citations identified, 140 full‐text papers were assessed for eligibility, and 18 studies 18, 19, 20, 21, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 (reported in 23 papers 18, 19, 20, 21, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52) satisfied our inclusion criteria (Fig. 1). The only three RCTs 19, 20, 21 (six papers 19, 20, 21, 50, 51, 52) that have been conducted to date were included (223 participants; published 2005–10) (Supporting information, Table S2). Fifteen OBSs 18, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 48 (17 papers) 18, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 enrolled a total of 1923 participants in prospective 18, 34, 35, 36, 37, 38, 39, 41, 42, 45, 46, 47 (n = 12) or retrospective 43, 44, 48 (n = 3) cohort studies published 2001–15. No case–control studies were identified. The abuse‐deterrent combination BUP–naloxone formulation is prescribed increasingly as OMAT, particularly in the United States and Australia 53, 54. We included one study that treated women with BUP–naloxone 44, but considered it too clinically different from the other studies to include in quantitative analyses. However, sensitivity analyses indicated that effect estimates did not differ for any outcome, whether the BUP–naloxone study was included or excluded. Sample sizes were 15–609. Attrition ranged from 22% 20 to 33% 19 overall in the RCTs and was unbalanced between treatment groups in two RCTs 19, 20. The range of estimated gestational age at study enrollment was 6–37 weeks. The mother's average daily dose at delivery ranged from 5.1 to 18.7 mg for BUP and 35–99.4 mg for MET. Outcome definitions among the studies were generally consistent, except for maternal adverse events (AEs) and small for gestational age (SGA) (Table 1). Statistical heterogeneity was low among the main analyses except for growth outcomes [birth weight (two RCTs, I\n2 = 50%); LBW (two OBSs, I\n2 = 62%); and SGA (two OBSs, I\n2 = 50%)]. ROB was rated medium for each RCT (n = 3, Supporting information, Table S3) and medium (n = 9) 18, 38, 39, 40, 41, 42, 43, 48, 49 or high (n = 8) 34, 35, 36, 37, 44, 45, 46, 47 for all OBSs (Supporting information, Table S4). Twelve OBSs assessed the balance between treatment groups for various confounding factors at study enrollment (Supporting information, Table S2), but only two OBSs adjusted for confounding factors in estimating treatment effects 39, 48. If not provided through an integrated, comprehensive prenatal addiction treatment program, MET was generally administered by standalone clinics or pharmacies while BUP was provided by office‐based practitioners. Visual inspection of the funnel plot for preterm birth revealed no evidence of publication bias (Supporting information, Figure S2); no other outcomes had enough studies to yield a reliable funnel plot.\n\nFigure 1 Flow of paper disposition and study selection\n\nSpontaneous fetal death\nAmong the seven studies 19, 20, 21, 35, 38, 39, 41 that assessed spontaneous fetal death, five medium ROB studies reported at least one (Supporting information, Table S5). The difference in treatment effect between BUP and MET was not significant from two RCTs 19, 20 and three OBSs 38, 39, 41 (Table 2 and Fig. 2a), but the direction differed by study design. The risk estimate did not change in sensitivity analyses that included all fetal deaths (spontaneous deaths and elective terminations) or imputed missing pregnancy outcomes.\n\nFigure 2 (a) Spontaneous fetal death; (b) fetal/congenital anomalies associated with buprenorphine compared with methadone\n\nFetal/congenital anomalies\nNine studies 19, 21, 34, 38, 39, 41, 43, 46, 48 that evaluated malformations or other defects at birth or pregnancy loss identified chromosomal defects and cardiovascular, central nervous system, craniofacial and musculoskeletal malformations (Supporting information, Table S7). Only two studies treated essentially all women with MET from preconception to end of pregnancy 41, 48. Among the medium ROB RCT 19 and four OBSs 38, 41, 43, 48 that reported at least one defect, the treatment effect was not significantly different in magnitude or direction between BUP and MET (Table 2 and Fig. 2b).\n\nTable 2 Summary of findingsa and strength of evidence for buprenorphine compared with methadone treatment of opioid use disorder during pregnancy.\n\n\nOutcome\n\t\nNo. of studies\na\n(n pregnancies or live births)\n\t\nSummary effect size\na\n(95% CI)\n\t\nStrength of evidence grade\nb\n\t\nSpontaneous fetal death\t\t\t\t\nRCT\t2 (187)\tRR = 0.26 (0.03–2.31)\tLow\t\nObservational\t3 (271)\tRR = 1.17 (0.32–4.27)\tLow\t\nFetal/congenital anomalies\t\t\t\t\nRCT\t1 (131)\tRR = 0.42 (0.02–10.08)\tInsufficient\t\nObservational\t4 (933)\tRR = 1.18 (0.39–3.62)\tLow\t\nPreterm birth\t\t\t\t\nRCT\t3 (166)\tRR = 0.40 (0.18–0.91)c\n\tLow\t\nObservational\t7 (1343)\tRR = 0.67 (0.50–0.90)d\n\tModerate\t\nBirth weight, g\t\t\t\t\nRCT\t2 (150)\tWMD = 324 (32–617)\tLow\t\nObservational\t6 (1085)\tWMD = 265 (196–335)\tModerate\t\nLow birth weight\t\t\t\t\nObservational\t2 (222)\t0.51 (0.17–1.59)\tLow\t\nSmall for gestational age\t\t\t\t\nRCT\t1 (131)\tRR = 0.63 (0.06–6.77)\tInsufficient\t\nObservational\t2 (692)\tRR = 0.67 (0.34–1.31)\tLow\t\nIntrauterine growth restriction\t\t\t\t\nObservational\t2 (385)\tRR = 0.80 (0.57–1.12)\tLow\t\nHead circumference, cm\t\t\t\t\nRCT\t2 (150)\tWMD = 0.90 (0.14–1.66)\tLow\t\nObservational\t5 (960)\tWMD = 0.68 (0.41–0.94)\tModerate\t\nSudden infant death syndrome (SIDS)\t\t\t\t\nObservational\t1 (83)\t0% BUP versus 6% MET (P = 0.19)\tInsufficient\t\nNeurodevelopment (fetal and child)\t\t*Fetal heart rate and motor activity suppression (third trimester): BUP < MET (P < 0.05)e\n\t\t\nRCT\t1 (175)\t*Visual selective attention at 4 months of age: no significant difference BUP versus METe\n\tInsufficient\t\nObservational\t2 (198)\t*Visual latency at 52 months of age: BUP < MET (prolonged) (P = 0.02)e\n\tInsufficient\t\nNon‐serious maternal adverse events\t\t\t\t\nRCT\t1 (175)\t77% BUP versus 93% MET (P = 0.003)\tInsufficient\t\nSerious maternal adverse events\t\t\t\t\nRCT\t1 (175)\t9% BUP versus 16% MET (P = 0.19)\tInsufficient\t\nMaternal death\t0 (0)\tNA\tInsufficient\t\nBUP = buprenorphine; MET = methadone; NA = not applicable; WMD = weighted mean difference; RCT = randomized controlled trial; CI = confidence interval; RR = relative risk.\n\na Includes only studies with low or medium risk of bias and cases with an outcome available.\n\nb Based on assessment of five domains: study limitations (risk of bias), consistency, directness, precision and reporting bias (Berkman 2013 33). See Supporting information, Table S6 for definitions and the full findings.\n\nc A relative risk of 0.40 would result in 120 fewer premature infants per 1000 births in BUP‐treated pregnant women compared with MET‐treated women. See Fig. 3 for details.\n\nd A relative risk of 0.67 would result in 49 fewer premature infants per 1000 births in BUP‐treated pregnant women compared with MET‐treated women. See Fig. 3 for details.\n\ne Preliminary evidence: the clinical significance of these findings is unknown.\n\nPreterm birth\nSeventeen studies 18, 19, 20, 21, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 47, 48 reported preterm births. The effect estimate from three RCTs 19, 20, 21 indicated lower risk of preterm birth for BUP compared with MET. Similarly, the treatment effect among seven medium ROB OBSs 18, 38, 39, 41, 42, 43, 48 showed that BUP was associated with a decreased risk of preterm birth compared with MET (Table 2 and Fig. 3). The treatment effect was similar in sensitivity analyses that included six OBSs with high ROB 34, 35, 36, 37, 45, 47 (including one that defined preterm birth as before 36 weeks gestation) 37 or imputed missing data.\n\nFigure 3 Preterm birth associated with buprenorphine compared with methadone\n\nInfant growth outcomes\nEight of 14 studies 19, 21, 39, 41, 42, 43, 48, 49 reporting birth weight had medium ROB. In two RCTs 19, 21 BUP‐exposed neonates averaged 324 g heavier than MET‐exposed neonates. In six OBSs 39, 41, 42, 43, 48, 49 the mean difference was 265 g (Table 2 and Fig. 4a). Results were similar in sensitivity analyses that included four high ROB studies 35, 37, 45, 47. The treatment effect attenuated and was non‐significant in two OBS that adjusted for gestational age at birth 39 or maternal age, cigarette smoking, polysubstance use, OMAT dose and duration of dependence 48. Preterm births in the studies included in the birth weight meta‐analysis ranged from 0 to 19% in the two RCTs (0 and 7% for BUP; 9 and 19% for MET) and 4–19% among the five OBSs (4–19% for BUP; 8–17% for MET). One OBS excluded preterm births from the birth weight analysis 49.\n\nFigure 4 (a) Birth weight; (b) head circumference associated with buprenorphine compared with methadone\n\nHead circumference was similarly significantly larger in infants born to BUP‐treated than MET‐treated women among seven medium ROB studies 19, 21, 39, 42, 43, 48, 49. In two RCTs 19, 21, BUP‐exposed newborns' heads averaged 0.90 cm larger than MET‐exposed newborns. In five OBSs 39, 42, 43, 48, 49, mean head circumference was 0.68 cm larger in BUP‐ than MET‐exposed infants (Table 2 and Fig. 4b). The treatment effect did not differ after adjustment for a number of factors (excluding gestational age) in one OBS 48.\n\nConversely, the risk of low birth weight (< 2500 g) did not differ significantly between BUP and MET exposure in two medium ROB OBSs 39, 48 (Table 2 and Fig. 5a), nor did the risk of being SGA in two medium ROB OBSs 39, 43 (Table 2 and Fig. 5b). The effect estimate was similar when two high ROB studies 36, 47 were included. One RCT 19 observed SGA in 2% of BUP‐exposed and 3% of MET‐exposed infants, a non‐significant difference. The RR for IUGR from two medium ROB OBSs 18, 41 was 0.80 (Table 2 and Fig. 5c) and did not change appreciably when a high ROB cohort study 35 was included.\n\nFigure 5 (a) Low birth weight; (b) small for gestational age; (c) intrauterine growth restriction associated with buprenorphine compared with methadone\n\nSudden infant death syndrome\nOne medium ROB OBS (n = 83) 39 observed that no infants exposed to BUP in utero experienced sudden infant death syndrome (SIDS) within 4 months of birth compared with two of 36 exposed to MET (5.6%), a non‐significant difference (Table 2). One death occurred in a 5‐week old male born at 38 weeks and treated for NAS. The MET‐treated mother was HIV‐positive and smoked 10–15 cigarettes daily. The other death was an 8‐week old female delivered at 38 weeks via caesarean section for IUGR and treated for NAS. The effect estimate was similar when a high ROB OBS 46 was included.\n\nFetal/child neurodevelopment\nAs gestation progresses, coupling of fetal movement and heart rate increases, reflecting coordination of autonomical and somatic nervous systems and general fetal wellbeing 55. Neurobehavior can be monitored non‐invasively with non‐stress testing (NST) that assesses heart rate variability and associated fetal movement. A high ROB substudy of a RCT assessed maternal blood levels and NST after daily dosing of OMAT during the third trimester 51. Peak OMAT blood levels were associated with significantly less suppression of fetal heart rate variability and movement and more favorably reactive NSTs in BUP‐ versus MET‐treated women (Supporting information, Table S8). Another RCT substudy found similar differential treatment‐related effects on heart rate and movement in the early versus late third trimester 50.\n\nTwo medium ROB cohort studies assessed visual development in infants and children exposed prenatally to OMAT (Supporting information, Table S8). One found no significant difference in visual selective attention among 31 children of mothers treated with BUP versus MET 40. The second study found significantly prolonged visual latency in 22 infants of MET‐treated mothers compared with 30 infants of BUP‐treated mothers 49.\n\nAdverse effects\n\nThree included studies reported non‐fatal maternal AEs 19, 41, 44 (Supporting information, Table S9), while none reported any maternal deaths. One RCT (n = 175) 19 assessed AEs weekly and graded them as serious or non‐serious. The RCT observed a lower risk of non‐serious AEs in BUP‐treated women but no difference in the risk of serious AEs. Two high ROB OBSs that did not describe how AEs were collected or assessed had disparate findings. One study (n = 90) 44 reporting selected AEs that are typically considered serious found no significant treatment‐related difference for BUP–naloxone versus MET. The other study (n = 135) 41 reported all AEs and found an increased risk of AEs overall for BUP.\n\nDiscussion\nWe synthesized the evidence from three RCTs and 15 OBSs that compared buprenorphine and methadone treatment of pregnant women with OUD. We calculated treatment‐related risk estimates for eight pregnancy‐related outcomes, including four without previous published meta‐analysis. Our work confirms and extends previous treatment risk estimates from limited RCT evidence by also synthesizing the available, larger body of observational study evidence.\n\nConsistent with previous RCT‐based meta‐analyses 5, 22, we identified no statistically or clinically significant difference between BUP and MET in the risk estimates for spontaneous fetal death among the OBSs and across all studies. However, the paucity of events and small sample sizes limited the precision of estimates, ability to stratify by early versus late pregnancy losses and the confidence in our estimates of the relationship between fetal death and OMAT. The overall frequency of spontaneous fetal deaths in women with OUD among both study types was substantially lower than the estimated 15–20% in the general population. Further, most occurred after the first trimester, in contrast to three‐fourths of spontaneous losses during the first trimester in the general population 56, 57. This apparent underestimate is probably related to a delay by many opioid‐dependent pregnant women in seeking prenatal care until after completing the high‐risk first trimester 35, 58, 59 and insufficient reporting of time of enrollment in several studies 36, 37, 44, 45, 46. Our ability to assess the relationship between fetal death and OMAT was also limited substantially, given sparse and inconsistent patient‐level reporting of gestational timing (onset and duration) of BUP or MET treatment and important potential confounders 60, 61.\n\nWe found no difference in the risk of fetal/congenital anomalies by maternal treatment. The frequency and type of reported anomalies were broadly similar to what would be expected in the general population, with no particular patterns noted by treatment group. However, most studies characterized the reported defects poorly and failed to collect or describe relevant confounders adequately or even details of exposure to the opioid agonist, particularly during the critical first trimester. Moreover, no included study was powered to detect an increase in specific congenital anomalies, which occur rarely (≤ 1/1000 births), and sparse events and exposed pregnancies limited the precision of estimates. In addition, defects not readily apparent at birth may be under‐ascertained, as no studies evaluating congenital anomalies followed infants through the entire first year. Therefore, we have limited confidence in our effect estimates.\n\nThe risk of preterm birth was lower in BUP‐exposed infants compared with MET‐exposed infants. The risk reduction found was consistent between study types and with a previous meta‐analysis of the same RCTs examined in the present analysis 5. However, potentially confounding influences were not reported or adjusted for in any treatment effect estimates. Notwithstanding these limitations, we have moderate confidence in our findings.\n\nUnadjusted birth weight and head circumference were significantly greater in infants of BUP‐treated mothers compared with MET‐treated mothers. The findings were consistent between study designs and with previous meta‐analyses 5, 22. We have moderate confidence in these treatment estimates, but adequate adjustment of confounding factors, particularly gestational age, and larger sample sizes would probably provide more stable and valid estimates of treatment effect. A very small body of observational studies showed no association between prenatal BUP or MET and LBW, IUGR or SGA. The sparse body of evidence limits confidence in the LBW, SGA and IUGR findings.\n\nFetal growth and birth parameters are influenced by sex, gestational age, multi‐fetal pregnancy, maternal cigarette smoking and use of other substances, and placental and anatomical factors 62. Studies in this review were inconsistent in describing whether they included multi‐fetal pregnancies and preterm births (both tend to be smaller) in analyses of growth parameters. Multi‐fetal pregnancies were infrequent and unlikely to significantly impact effect estimates differentially. However, failure to adjust for gestational age or exclude preterm births from growth parameter analyses may overestimate the effects of maternal BUP treatment due to BUP's associated significantly lower risk of preterm birth. We were unable to explore fully this confounding effect without patient‐level data. Aggregated source data for birth weight and head circumference also limited the clinical interpretation of treatment effect estimates because established norms, and thus minimally important differences, are sex‐ and gestational age‐dependent 63.\n\nData from three small studies provided preliminary and insufficient evidence that maternal BUP treatment may be associated with more favorable fetal neurobehavior than MET treatment. The developing fetal nervous system appeared more vulnerable to opioid‐related suppression earlier versus later in pregnancy with significantly less suppression of fetal heart rate and movement by BUP compared with MET, at least transiently at peak maternal exposure associated with once‐daily dosing 64. Split‐dose administration of MET has been associated with less fetal suppression 65.\n\nOne medium ROB RCT that collected and analyzed maternal AEs systematically found significantly fewer non‐serious AEs but no difference in serious AEs among BUP‐treated women versus MET‐treated women. Differential cardiovascular effects are plausible due to the established risk of QT‐interval prolongation and serious arrhythmia associated with MET 66, 67. Two high ROB OBSs with poorly characterized methods of collecting and analyzing AEs had discordant findings. In one study, with significantly more AEs in BUP‐treated women, the cohorts were comparable for several confounders but the MET‐treated women had more frequent study visits (a confounding co‐intervention) 41. The evidence regarding AEs is insufficient to draw a clinically meaningful conclusion in either direction. Future studies should collect and analyze treatment‐associated AEs during pregnancy in a systematic and standardized fashion and use an established system to code and analyze AEs descriptively 68.\n\nA strength of this review is the inclusion of all available evidence regarding opioid agonist treatment during pregnancy, including data from well‐conducted observational cohort studies 69, 70, 71. Previous published systematic reviews and meta‐analyses included only three RCTs, with a total combined sample size of 223 drawn from seven university treatment centers in the United States and Austria. The addition of 1923 participants in 15 cohort studies conducted in six additional countries and among a wider range of clinical settings increased the precision, statistical power and generalizability of our findings. Furthermore, most outcomes examined were largely objective, documented routinely in clinical obstetric practice and thus less prone to detection bias from measurement error and lack of blinding. Concordance between the treatment‐related risk estimates from both the RCTs and OBSs bolstered confidence in the strength of the evidence for spontaneous fetal death, fetal/congenital anomalies, preterm birth, birth weight, head circumference and SGA.\n\nThe main limitations were the uneven quality of the studies and limited number of events and sample sizes, potentially providing low statistical power to detect between‐group differences. RCTs provide the most consistent and unbiased estimates of treatment effects, but high‐quality RCTs often are not available, particularly in vulnerable populations such as the one under study 68, 69. The complexities of both OUD and pregnancy present daunting challenges in the design, recruitment and conduct of rigorous clinical studies. Moreover, RCTs are generally not designed with sufficient sample size (especially for rare outcomes such as fetal death and congenital anomalies), follow‐up duration or population variability for results generalizable to the population at large. The RCTs included in this review were conducted rigorously, but suffered from relatively high levels of overall and differential attrition that increased the risk of selection bias and were not accounted for optimally in the published analyses 28, 70 Twelve of the 15 observational studies assessed baseline comparability of the cohorts for a few confounders or co‐interventions but did not adjust effect estimates for imbalances. For example, many studies did not assess, report or adjust for concomitant substance use during pregnancy as evaluated by urine toxicology or self‐report. Information on substance use would inform the interpretation of the OMAT‐related effects in terms of possible differences between the study participants.\n\nFinally, maternal AEs and fetal/congenital anomalies (and, to a lesser extent, SGA) were defined inconsistently or ascertained among the studies that reported them, increasing clinical heterogeneity and limiting the opportunity to pool results among studies. In clinical studies, AEs are often not collected, analyzed or reported in a standardized and systematic fashion 68.\n\nConclusion\nBUP treatment of maternal opioid use disorder during pregnancy was not associated with greater harms than MET treatment, and moderately strong evidence indicated lower risk of preterm birth, greater birth weight and larger head circumference with BUP. Our results confirm and extend previous RCT evidence and further inform benefit/risk assessment in clinical decision‐making regarding treatment of pregnant women with OUD, although evidence is currently insufficient to establish superior safety of either opioid agonist during pregnancy for all maternal, fetal and child outcomes examined.\n\nDeclaration of interests\nPartial funding for this review was provided by Indivior PLC (formerly Reckitt Benckiser Pharmaceuticals) to Venebio Group, LLC. The review was conceived, designed, executed and reported by the authors, who had sole control over the literature selected, data analysis, interpretation and manuscript preparation. Indivior PLC was asked to review the final manuscript for proprietary information. The opinions and conclusions of the authors are their own and do not necessarily reflect the position of Indivior. At the time the work was conducted, B.K.Z., A.L.M., M.M.K., H.R.A., A.R.J. and E.L.M. were paid consultants of Venebio Group, LLC, which has had research and consulting agreements with Indivior PLC. H.E.J. has no financial ties to either Indivior PLC or Venebio Group, LLC, and did not receive any form of remuneration in the preparation or writing of this paper. All authors report no other potential conflicts of interest with the gaming, pharmaceutical, alcohol or tobacco industries.\n\nSupporting information\n\nFigure S1 Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) checklist.\n\n\nFigure S2 Funnel plot for studies reporting preterm birth.\n\n\nTable S1 Literature search strategy.\n\n\nTable S2 Characteristics of included studies.\n\n\nTable S3 Risk of bias in included observational studies.\n\n\nTable S4 Risk of bias in included randomized controlled trials (RCTs).\n\n\nTable S5 Spontaneous fetal death associated with buprenorphine compared with methadone: individual studies.\n\n\nTable S6 Summary of findings and grading the strength of evidence for buprenorphine compared with methadone treatment of opioid use disorder during pregnancy.\n\n\nTable S7 Fetal/congenital anomalies associated with buprenorphine compared with methadone: individual studies.\n\n\nTable S8 Fetal and child neurodevelopment associated with buprenorphine compared with methadone: individual studies.\n\n\nTable S9 Maternal adverse events associated with buprenorphine compared with methadone: individual studies.\n\n Figure S1 Supporting info item\n\nClick here for additional data file.\n\n Acknowledgements\nThe authors wish to thank Drs Georgiy Bobashev, Dale Glasser, and Pradeep Rajan for helpful comments on drafts of the text, Dr Laura Morgan for contributions to the assessment of study quality and preparation of forest plots and Dr Pradeep Rajan and Molly Ronayne Sherwood for assistance in the literature search.\n==== Refs\nReferences\n1 \nSubstance Abuse and Mental Health Services Administration (SAMHSA) \n. 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"issn_linking": "0965-2140",
"issue": "111(12)",
"journal": "Addiction (Abingdon, England)",
"keywords": "Buprenorphine; dependence; fetus; harm; methadone; opioid use disorder; pregnancy",
"medline_ta": "Addiction",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000701:Analgesics, Opioid; D001724:Birth Weight; D002047:Buprenorphine; D005260:Female; D005313:Fetal Death; D047109:Fetal Development; D006801:Humans; D007231:Infant, Newborn; D008691:Methadone; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D061214:Patient Safety; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D047928:Premature Birth; D011295:Prenatal Care; D016032:Randomized Controlled Trials as Topic; D013398:Sudden Infant Death",
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"pages": "2115-2128",
"pmc": null,
"pmid": "27223595",
"pubdate": "2016-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D017418:Meta-Analysis; D016454:Review; D000078182:Systematic Review",
"references": "3802833;11064485;21538146;24366859;23324442;21142534;25405293;18355989;17889498;9794682;27223595;19392907;25622120;24461476;11745008;1868279;22525931;18783498;19621070;22640765;22841456;17305901;9022256;12867211;18008179;23161599;617308;21803546;23135165;15545678;1889920;20100760;21823171;21496917;20868741;19317968;20177760;16257138;19751825;9462324;23106925;22512363;23243466;25402596;18823754;21636246;15943939;23106930;19881889;21480011;18283247;9547764;19219093;7841636;11451790;16445556;1130446;25490943",
"title": "Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta-analysis of safety in the mother, fetus and child.",
"title_normalized": "buprenorphine compared with methadone to treat pregnant women with opioid use disorder a systematic review and meta analysis of safety in the mother fetus and child"
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"abstract": "Emerging evidence suggests aspirin may be an effective venous thromboembolism (VTE) prophylaxis for orthopaedic trauma patients, with fewer bleeding complications. We used a patient-centered weighted composite outcome to globally evaluate aspirin versus low-molecular-weight heparin (LMWH) for VTE prevention in fracture patients.\n\n\n\nWe conducted an open-label randomized clinical trial of adult patients admitted to an academic trauma center with an operative extremity fracture, or a pelvis or acetabular fracture. Patients were randomized to receive LMWH (enoxaparin 30-mg) twice daily (n = 164) or aspirin 81-mg twice daily (n = 165). The primary outcome was a composite endpoint of bleeding complications, deep surgical site infection, deep vein thrombosis, pulmonary embolism, and death within 90 days of injury. A Global Rank test and weighted time to event analysis were used to determine the probability of treatment superiority for LMWH, given a 9% patient preference margin for oral administration over skin injections.\n\n\n\nOverall, 18 different combinations of outcomes were experienced by patients in the study. Ninety-nine patients in the aspirin group (59.9%) and 98 patients in the LMWH group (59.4%) were event-free within 90 days of injury. Using a Global Rank test, the LMWH had a 50.4% (95% CI, 47.7-53.2%, p = 0.73) probability of treatment superiority over aspirin. In the time to event analysis, LMWH had a 60.5% probability of treatment superiority over aspirin with considerable uncertainty (95% CI, 24.3-88.0%, p = 0.59).\n\n\n\nThe findings of the Global Rank test suggest no evidence of superiority between LMWH or aspirin for VTE prevention in fracture patients. LMWH demonstrated a 60.5% VTE prevention benefit in the weighted time to event analysis. However, this difference did not reach statistical significance and was similar to the elicited patient preferences for aspirin.",
"affiliations": "Department of Surgery, R A Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.;Department of Orthopaedics, R A Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.;Department of Orthopaedics, R A Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.;Department of Orthopaedics, R A Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.;Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.;Department of Orthopaedics, R A Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.;Department of Surgery, R A Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.",
"authors": "Haac|Bryce E|BE|;O'Hara|Nathan N|NN|0000-0003-0537-3474;Manson|Theodore T|TT|;Slobogean|Gerard P|GP|0000-0002-9111-9239;Castillo|Renan C|RC|;O'Toole|Robert V|RV|;Stein|Deborah M|DM|;|||",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D005343:Fibrinolytic Agents; D001241:Aspirin",
"country": "United States",
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"doi": "10.1371/journal.pone.0235628",
"fulltext": "\n==== Front\nPLoS One\nPLoS ONE\nplos\nplosone\nPLoS ONE\n1932-6203 Public Library of Science San Francisco, CA USA \n\n10.1371/journal.pone.0235628\nPONE-D-20-05342\nResearch Article\nMedicine and Health Sciences\nVascular Medicine\nThromboembolism\nVenous Thromboembolism\nMedicine and Health Sciences\nClinical Medicine\nSigns and Symptoms\nHemorrhage\nMedicine and Health Sciences\nVascular Medicine\nHemorrhage\nBiology and Life Sciences\nPhysiology\nPhysiological Parameters\nBody Weight\nMedicine and Health Sciences\nPublic and Occupational Health\nPreventive Medicine\nProphylaxis\nBiology and Life Sciences\nAnatomy\nBody Limbs\nArms\nMedicine and Health Sciences\nAnatomy\nBody Limbs\nArms\nMedicine and Health Sciences\nSurgical and Invasive Medical Procedures\nMedicine and Health Sciences\nVascular Medicine\nThromboembolism\nVenous Thromboembolism\nDeep Vein Thrombosis\nMedicine and Health Sciences\nClinical Medicine\nClinical Trials\nRandomized Controlled Trials\nMedicine and Health Sciences\nPharmacology\nDrug Research and Development\nClinical Trials\nRandomized Controlled Trials\nResearch and Analysis Methods\nClinical Trials\nRandomized Controlled Trials\nAspirin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in orthopaedic trauma patients: A patient-centered randomized controlled trial\nVTE prevention in fracture patientsHaac Bryce E. ConceptualizationData curationFormal analysisInvestigationMethodologyProject administrationResourcesSupervisionWriting – original draftWriting – review & editing1 http://orcid.org/0000-0003-0537-3474O'Hara Nathan N. ConceptualizationData curationFormal analysisInvestigationMethodologyProject administrationResourcesSupervisionWriting – original draftWriting – review & editing2* Manson Theodore T. ConceptualizationInvestigationProject administrationSupervisionWriting – review & editing2 http://orcid.org/0000-0002-9111-9239Slobogean Gerard P. ConceptualizationData curationInvestigationMethodologyProject administrationSupervisionWriting – review & editing2 Castillo Renan C. ConceptualizationData curationInvestigationMethodologyProject administrationWriting – review & editing3 O'Toole Robert V. ConceptualizationData curationInvestigationMethodologyProject administrationResourcesSupervisionWriting – review & editing2 Stein Deborah M. ConceptualizationData curationFormal analysisInvestigationMethodologyProject administrationResourcesSupervisionWriting – review & editing1 on behalf of the ADAPT Investigators ¶ 1 \nDepartment of Surgery, R A Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America\n2 \nDepartment of Orthopaedics, R A Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America\n3 \nDepartment of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America\nLeroyer Christophe Editor Universite de Bretagne Occidentale, FRANCE\nCompeting Interests: The authors have declared that no competing interests exist.\n\n¶ Membership of the ADAPT Investigators is provided in the Acknowledgments.\n\n* E-mail: nohara@som.umaryland.edu\n3 8 2020 \n2020 \n15 8 e023562826 2 2020 17 6 2020 © 2020 Haac et al2020Haac 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\nEmerging evidence suggests aspirin may be an effective venous thromboembolism (VTE) prophylaxis for orthopaedic trauma patients, with fewer bleeding complications. We used a patient-centered weighted composite outcome to globally evaluate aspirin versus low-molecular-weight heparin (LMWH) for VTE prevention in fracture patients.\n\nMethods\nWe conducted an open-label randomized clinical trial of adult patients admitted to an academic trauma center with an operative extremity fracture, or a pelvis or acetabular fracture. Patients were randomized to receive LMWH (enoxaparin 30-mg) twice daily (n = 164) or aspirin 81-mg twice daily (n = 165). The primary outcome was a composite endpoint of bleeding complications, deep surgical site infection, deep vein thrombosis, pulmonary embolism, and death within 90 days of injury. A Global Rank test and weighted time to event analysis were used to determine the probability of treatment superiority for LMWH, given a 9% patient preference margin for oral administration over skin injections.\n\nResults\nOverall, 18 different combinations of outcomes were experienced by patients in the study. Ninety-nine patients in the aspirin group (59.9%) and 98 patients in the LMWH group (59.4%) were event-free within 90 days of injury. Using a Global Rank test, the LMWH had a 50.4% (95% CI, 47.7–53.2%, p = 0.73) probability of treatment superiority over aspirin. In the time to event analysis, LMWH had a 60.5% probability of treatment superiority over aspirin with considerable uncertainty (95% CI, 24.3–88.0%, p = 0.59).\n\nConclusion\nThe findings of the Global Rank test suggest no evidence of superiority between LMWH or aspirin for VTE prevention in fracture patients. LMWH demonstrated a 60.5% VTE prevention benefit in the weighted time to event analysis. However, this difference did not reach statistical significance and was similar to the elicited patient preferences for aspirin.\n\nThe study was not funded, nor did any of the authors receive salary support from a funder for the research described in the manuscript. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.Data Availability\nAll relevant data are within the manuscript and its Supporting Information files.\n==== Body\nIntroduction\nTrauma is a well-described risk factor for venous thromboembolism (VTE) [1–8], but controversy exists regarding the optimal thromboprophylaxis regimen following orthopaedic trauma [9–11]. The Eastern Association for the Surgery of Trauma and the American College of Chest Physicians (ACCP) recommend low-molecular-weight heparin (LMWH) for VTE prophylaxis in trauma patients [11, 12]. However, many orthopaedic trauma surgeons prefer aspirin in light of recent studies suggesting aspirin may be an effective alternative in VTE prevention with a reduced likelihood of bleeding and wound complications [13–19]. As a result, the ACCP guidelines now include aspirin as an option for high-risk orthopaedic surgery patients [11]. To date, most randomized studies comparing these regimens have been conducted in the arthroplasty population. Considering that orthopaedic trauma patients often have multiple injuries that may increase VTE and bleeding risks, drawing inference from the arthroplasty literature is cautioned. Based on the lack of scientific support for various regimens in this population, the Orthopaedic Trauma Association Evidence-Based Quality Value and Safety Committee recently emphasized the need for standardized VTE prevention guidelines to improve care [20].\n\nLike many treatment decisions, determining the optimal thromboprophylaxis regimen for a given patient requires clinicians to weigh the benefits and risks of the available treatment options. Clinical trials traditionally have a separate comparison between the study groups for each study outcome. The analysis technique used in this trial was based on the foundational work by Evans and Follman [21], where the study patient’s experiences are compared between the two treatment groups, allowing multiple outcomes to be counted for a given patient.\n\nThe clinical relevance of this patient-centered approach can be improved further using composite outcomes that incorporate patient preferences to weigh or rank the plausible outcomes. Techniques, such as a Global Rank test or time to event analysis with weighted, repeated events, can determine the probability of treatment superiority among two or more treatment options [21, 22]. The elicited patient preferences can also be used to determine the preferred treatments under various patient-important thresholds for treatment superiority.\n\nWe performed a randomized controlled trial to globally evaluate aspirin versus LMWH for VTE prophylaxis after orthopaedic trauma. In this study, we incorporated several innovative techniques in patient-centered research. Patient preference data was used to weigh the relative importance of the outcomes included our composite endpoint [23], which included bleeding complications, deep surgical site infections, deep vein thrombosis, pulmonary embolism, and death. The patient preference data were also used to set our threshold for a significant difference between the prophylaxis options under the consideration that patients preferred the route of administration for aspirin over the LWMH injections.\n\nMaterials and methods\nTrial design\nThe A Different Approach to Preventing Thrombosis (ADAPT) trial was a single-center open-label prospective randomized controlled trial that compared the global benefit of aspirin versus LMWH for orthopaedic trauma patients within 90 days of injury. Global benefit being the synthesis of several patient-important outcomes. Patients were enrolled from January through November 2016 at an academic trauma center in Baltimore, Maryland. Patient follow-up was completed in April 2017. Ethics approval was obtained from the University of Maryland institutional review board (IRB) on September 12, 2015, and informed consent was obtained for all enrolled patients. The trial was registered in clinicaltrials.gov (NCT02774265) on May 17, 2016. Due to an administrative oversight, the trial was registered after patient enrolment was initiated, but prior to the completion of patient enrolment. The authors confirm that all ongoing and related trials for this drug have been registered.\n\nPatient selection\nAll adult trauma patients admitted with an operative extremity fracture proximal to the carpals or metatarsals, or any hip or acetabular fracture requiring VTE prophylaxis were included in the study. We excluded prisoners, pregnant patients, non-English-speaking patients, patients with an indication for therapeutic anticoagulation or high-dose aspirin (>81 mg daily), and patients receiving pre-existing VTE prophylaxis, therapeutic anticoagulation before admission, or patients that received more than two doses of VTE prophylaxis before consent. Patients with a VTE within the last six months, impaired creatinine clearance (≤30 mL/min), history of heparin-induced thrombocytopenia or aspirin or non-steroidal anti-inflammatory allergy, or another contraindication to receiving a study medication were also excluded. Eligible patients were approached by a member of the research team within 48 hours of admission to the study location and enrolled after obtaining written informed consent.\n\nRandomization\nPatients were randomly assigned in a 1:1 ratio to VTE prophylaxis by LMWH or aspirin. Randomization was performed with REDCap, using blocks of six, by research staff at the time of enrollment. The study group allocation was not concealed to the patients, surgeons, or research staff.\n\nStudy intervention and procedures\nPatients allocated to the LMWH group received 30-mg doses of enoxaparin twice daily with allowance for dose adjustment based on body mass index or anti-factor Xa levels. Patients allocated to the aspirin group received 81-mg doses twice daily. Administration of aspirin was oral, rectal, or via any other form of enteral access. The off-label use of 81-mg aspirin for the indication of VTE prophylaxis was approved by the IRB of record. The duration of prophylaxis was based on hospital guidelines and was dependent on fracture location and weightbearing status. Mechanical prophylaxis with intermittent pneumatic compression devices was ordered as part of the clinical protocol for all inpatients. Study follow-up was conducted 90 days after fracture either at the patient’s clinic appointment or by phone. A chart review was conducted at that time to ensure that no events were missed in the patient review.\n\nAll prophylaxis doses were monitored daily during the index admission by the study’s research staff. Additionally, medication adherence was assessed at all clinical follow-up visits. Aspirin use by patients for reasons other than VTE prophylaxis was also tracked. Medication contamination and unplanned crossover were recorded.\n\nStudy outcomes\nThe primary outcome was a composite that included bleeding complications, VTE, deep surgical site infections, and death occurring within 90 days after injury. Bleeding complications were defined as a ≥2 g/dL drop in hemoglobin within a 24-hour period after initiation of the study medication, blood transfusion, gastrointestinal bleeding, surgical site hematoma requiring reoperation, or other bleeding events requiring intervention or after initiation of the prophylaxis regimen. The administration of a blood transfusion was at the discretion of the treating clinician who ordered the transfusion. VTE events included pulmonary embolism (PE) defined as either massive, submassive, or clinically significant PE, and clinically significant deep vein thrombosis (DVT) occurring after initiation of the prophylaxis regimen. No screening of asymptomatic patients for VTE events was conducted. Massive and submassive PE were defined using the American Heart Association definitions [24]. Clinically significant PE was defined as symptomatic PE that did not fit massive or submassive criteria. Clinically significant DVT was defined as symptomatic acute thrombus in a deep vein. All VTE events were diagnosed using standard imaging techniques, including angiography, computed tomography angiography, ventilation-perfusion scan, or duplex ultrasonography. Deep surgical site infection (SSI) required a reoperation and was defined based on the Centers for Disease Control and Prevention criteria [25]. All study events were diagnosed and documented by the clinical treating team. All adverse events were reviewed by the Data and Safety Monitoring Board.\n\nWeighting of study outcomes\nOutcome weights were derived for the study outcomes based on the results of a discrete choice experiment [23]. The experiment surveyed 232 orthopaedic trauma patients to quantify the relative importance of the included endpoints. Using the methods described by Udogwu et al [26], the relative importance of the component outcomes was used to calculate the outcome weights (Table 1) and determined a hierarchy of severity for the observed combination of events experienced during the first 90 days from injury. The weights of the component outcomes are reported relative to death, which has been weighted as 1.00.\n\n10.1371/journal.pone.0235628.t001Table 1 Weights for component outcomes derived from previously published data.\nComponent Outcome\tWeight\t\nDeath\t1.000\t\nVTE Event (Pulmonary Embolism or Deep Vein Thrombosis)\t0.055\t\nDeep Surgical Site Infection\t0.015\t\nBleeding Complication\t0.010\t\nStatistical analysis\nPrevious research determined that patients preferred the oral administration of VTE prophylaxis over a subcutaneous injection, assuming the treatment benefits were similar [23]. We then compared the strength of the patients’ route preference with VTE outcome preferences relative to baseline risks. Based on the calculated margins, we determined that patients would be willing to accept a 9% increase in the probability of an adverse event to avoid VTE prophylaxis by skin injection. Therefore, a sample size of 160 patients in each treatment group would provide 80% power to detect a 59% treatment superiority, assuming a nonparametric distribution of the weighted outcome and a two-sided alpha of 0.05 [27].\n\nAll analyses followed the intention-to-treat principle. We used two techniques to compare the probability of treatment superiority of aspirin with LWMH—a Global Rank test and a weighted time to event analysis. For the Global Rank test, all study outcomes were multiplied by the calculated weight and summed for each patient [28]. Ranks were then assigned to patients so that an event free outcome receives a rank of one. All other combinations of outcomes experienced by patients in the study are ranked based on their cumulative weight. The ranks were compared using a Wilcoxon Rank Sums test. The treatment effect was reported as the Probability Index [29, 30], which is the probability that a randomly selected patient from the aspirin group has a superior outcome rank than a randomly selected patient from the LMWH group. A probability of 50% is considered a null effect.\n\nWe also analyzed the data using a time to event model that weighted each event and then adjusted the patient’s health state based on that event for their remaining person-time [26]. Each patient was able to incur an unlimited number of events prior to 90-days post-injury or death, at which point they were censored in the analysis. All patients entered into the study event free. After an event, the remaining person-time that they contributed to the analysis was discounted at one minus the cumulative weight of the events the patient had experienced to that point in time (Fig 1). The treatment effect was reported as the probability of treatment superiority calculated as 1/(1-hazard ratio) [21]. The time to event analysis had 50% power to detect a 59% probability of treatment superiority with a two-sided alpha of 0.05 and the assumption that one-third of the patients would experience at least one study event within 90-days of injury. For patients with incomplete follow-up, last observation carry-forward was used to impute missing outcome weights [31]. We also performed an unweighted analysis comparing the study outcomes between the treatment groups using chi-square tests. The results of the unweighted analyses are available in the supporting information. All analyses were performed using R Version 3.6.1 (Vienna, Austria).\n\n10.1371/journal.pone.0235628.g001Fig 1 Schematic demonstrating how event-free person-time is weight based on the events experienced by an individual patient.\nResults\nStudy population\nOf the 482 eligible patients, 329 were randomly assigned to receive VTE prophylaxis by LMWH or aspirin (LMWH, n = 164; aspirin, n = 165) (Fig 2). The mean age of the study participants was 47 years (SD, 20 years), and the majority (68%) were male. More than one-third of the participants had a recent history of tobacco use, 10% were diabetic, and 14% were taking daily aspirin before the fracture. Nearly 5% had a history of previous VTE. Most injuries were caused by blunt trauma (96%) to either the lower extremities or pelvis and acetabulum (92%). Nearly one-fourth of the fractures were open, and chest (25%) and head (22%) were common concomitant non-orthopaedic injuries. A full 90-day follow-up was achieved for 93% of the study population. Patient demographics by treatment arm are described in Table 2.\n\n10.1371/journal.pone.0235628.g002Fig 2 CONSORT diagram.\n10.1371/journal.pone.0235628.t002Table 2 Baseline patient characteristics (n = 329).\n\tLMWH (n = 164)\tAspirin (n = 165)\t\nAge, mean (SD), yr\t45.4 (20.4)\t48.0 (18.6)\t\nSex, n (%)\t\t\t\n Male\t119 (72.6)\t104 (63.0)\t\n Female\t45 (27.4)\t61 (37.0)\t\nRace, n (%)\t\t\t\n White\t97 (59.5)\t106 (64.2)\t\n Black\t53 (3.3)\t45 (27.3)\t\n Hispanic\t2 (1.2)\t5 (3.0)\t\n Mixed\t6 (3.7)\t3 (1.8)\t\n Other\t5 (3.1)\t6 (3.6)\t\nCurrent smoker, n (%)\t62 (38.3)\t65 (39.3)\t\nHistory of venous thromboembolism, n (%)\t7 (4.3)\t8 (4.8)\t\nComorbidities, n (%)\t\t\t\n Peptic ulcer\t3 (1.8)\t12 (7.2)\t\n Diabetes\t16 (9.8)\t17 (10.3)\t\n Active cancer\t2 (1.2)\t5 (3.0)\t\n Immunosuppression\t9 (5.5)\t8 (4.8)\t\nAdditional medications, n (%)\t\t\t\n Aspirin, daily pre-injury\t23 (14.0)\t22 (13.3)\t\n Plavix, pre-injury\t2 (1.2)\t1 (0.6)\t\n Oral contraceptive/estrogen\t3 (1.8)\t3 (1.8)\t\nBody mass index, n (%), kg/m2\t\t\t\n Underweight (<18.5)\t4 (2.5)\t6 (3.7)\t\n Normal weight (18.5–24.9)\t57 (35.0)\t57 (35.0)\t\n Overweight (25.0–29.9)\t53 (32.5)\t47 (28.8)\t\n Obese (≥30.0)\t49 (30.1)\t53 (32.5)\t\nInjury Severity Score, mean (SD)\t11.0 (5.7)\t11.0 (6.6)\t\nMechanism of injury, n (%)\t\t\t\n Blunt\t147 (94.2)\t148 (97.4)\t\n Penetrating\t7 (4.5)\t2 (1.3)\t\n Other\t2 (1.3)\t2 (1.3)\t\nOpen fracture, n (%)\t39 (23.4)\t37 (22.4)\t\nFracture location, n (%)\t\t\t\n Upper extremity\t41 (25.0)\t42 (25.5)\t\n Lower extremity and pelvis/acetabulum\t149 (90.9)\t154 (93.3)\t\n Multi-limb\t44 (27.0)\t43 (26.1)\t\nNon-orthopaedic injury (AIS ≥2), n (%)\t\t\t\n Abdomen\t14 (8.5)\t17 (10.3)\t\n Head\t36 (22.0)\t35 (21.2)\t\n Chest\t43 (26.2)\t39 (23.6)\t\nLMWH, low molecular weight heparin; AIS, Abbreviated Injury Scale.\n\nAdherence with assigned intervention\nThe median time from admission to the initiation of study medication was one day in both treatment arms (aspirin IQR: 0–2; LMWH IQR: 0–1). The medication adherence for patients allocated to the aspirin arm (94.0%) was not significantly different than patients allocated to LWMH (91.1%, p = 0.18). Patients randomized to aspirin maintained daily prophylaxis significantly longer than those randomized to LMWH (median, 41 versus 26 doses; p<0.01).\n\nTwenty-eight (17.0%) patients in the aspirin arm, and 57 (34.8%) patients in the LMWH arm, were administered prophylaxis only during their inpatient admission. Four (2.4%) patients in the aspirin arm and 3 (1.8%) patients in the LMWH arm were on prophylaxis for longer than 28 days.\n\nGlobal rank analysis\nOverall, 18 different combinations of outcomes were experienced by patients in the study (Table 3). Ninety-nine patients in the aspirin group (59.9%) and 98 patients in the LMWH group (59.4%) were event-free within 90 days of injury. The cumulative weight of the events was 3.7 in the aspirin group and 2.5 in the LMWH group. Using a Global Rank test, the LMWH had a 50.4% (95% CI, 47.7–53.2%, p = 0.73) probability of treatment superiority over aspirin (Fig 3). Given the patient preference for aspirin [23], the probability of treatment superiority does not meet the 59% LMWH benefit threshold required for patients to change their preference to LMWH.\n\n10.1371/journal.pone.0235628.g003Fig 3 Probability density of weighted outcomes between treatment groups.\n10.1371/journal.pone.0235628.t003Table 3 Outcomes experienced by patients in the study and their assigned weight.\nRank\tWeight\tOverall N (%)\tASA N (%)\tLMWH\tEvent Description\t\n1\t0\t197 (59.9)\t99 (60.3)\t98 (59.4)\tEvent free\t\n2\t0.0099\t61 (18.5)\t32 (19.5)\t29 (17.6)\tBleeding event\t\n3\t0.0153\t16 (4.9)\t7 (4.3)\t9 (5.5)\tDeep SSI\t\n4\t0.0198\t21 (6.4)\t10 (6.1)\t11 (6.7)\tTwo bleeding events\t\n5\t0.0252\t7 (2.1)\t3 (1.8)\t4 (2.4)\tDeep SSI, bleeding event\t\n6\t0.0351\t3 (0.9)\t2 (1.2)\t1 (0.6)\tDeep SSI, two bleeding events\t\n7\t0.0398\t1 (0.3)\t0 (0.0)\t1 (0.6)\tFour bleeding events\t\n8\t0.0548\t7 (2.1)\t5 (3.1)\t2 (1.2)\tVTE\t\n9\t0.0647\t5 (1.5)\t1 (0.6)\t4 (2.4)\tVTE, bleeding event\t\n10\t0.0746\t1 (0.3)\t1 (0.6)\t0 (0.0)\tVTE, two bleeding events\t\n11\t0.0845\t2 (0.6)\t2 (1.2)\t0 (0.0)\tVTE, three bleeding events\t\n12\t0.0899\t1 (0.3)\t0 (0.0)\t1 (0.6)\tVTE, deep SSI, two bleeding events\t\n13\t0.1096\t1 (0.3)\t0 (0.0)\t1 (0.6)\tTwo VTEs\t\n14\t0.1393\t1 (0.3)\t0 (0.0)\t1 (0.6)\tTwo VTEs, three bleeding events\t\n15\t0.1644\t1 (0.3)\t1 (0.6)\t0 (0.0)\tThree VTEs\t\n16\t0.1842\t1 (0.3)\t0 (0.0)\t1 (0.6)\tThree VTEs, two bleeding events\t\n17\t1.000\t2 (0.6)\t0 (0.0)\t2 (1.2)\tDeath\t\n18\t1.0198\t1 (0.3)\t1 (0.0)\t0 (0.0)\tDeath, two bleeding events\t\nTime to event analysis\nIn the time to event analysis, the cumulative weighted probability of being event-free at 90-days post-fracture was 97.8% (95% CI, 95.5–1.00%) in the aspirin group and 98.5% (95% CI, 96.6–1.00%) in the LMWH group (Fig 4). LMWH had a 60.5% probability of treatment superiority over aspirin in this analysis but with considerable uncertainty (95% CI, 22.5–88.5%, p = 0.63) given the limited statistical power for this analysis.\n\n10.1371/journal.pone.0235628.g004Fig 4 Weighted time to event analysis comparing the probability of being event-free within 90 days of injury.\nThis analysis allows for multiple events for a given patient.\n\nDiscussion\nIn our primary comparison of aspirin with LMWH, there was no evidence of a significant difference in the probability of VTE prophylaxis superiority for orthopaedic trauma patients. In our time to event analysis, the point estimate for the VTE prophylaxis superiority of LMWH exceeded the 59% patient-important threshold. However, this finding was not statistically significant, given the considerable uncertainty around this point estimate.\n\nThe ADAPT trial is the first prospective randomized controlled trial to compare the effect of aspirin versus LMWH for VTE prophylaxis in orthopaedic trauma patients. We utilized patient preference data to weight and rank patient-important outcomes to determine the global VTE prophylactic benefit between the two medications [23]. Further, we considered the route of administration for the two medications and calculated a minimal importance threshold based on patients’ preference for oral administration over skin injections [23].\n\nWe aimed to describe medication differences under the totality of evidence gained from the trial. Under the ordinal rankings of the Global Rank test, the two medications were nearly indistinguishable in their overall performance. When time from injury was accounted for in the analysis, the probability of VTE prophylaxis superiority for LMWH increased after 45 days from injury, when several patients in the aspirin arm sustained subsequent events. Considering the longer median duration of VTE prophylaxis in the aspirin arm, the probability of VTE prophylaxis superiority may have diverged further if the duration of prophylaxis was consistent between the two arms.\n\nOur analytic approach has several benefits. The composite outcome synthesizes the risk and benefits of VTE prophylaxis that clinicians and patients must consider when selecting a regimen. Further, the composite outcome included death, which then accounts for competing risks that often distort the interpretation of individual outcomes [21]. Allowing for multiple events for a given patients accounts for the correlation between events, and provides a more accurate representation of the patient experience.\n\nThis study had several limitations. The pragmatic nature resulted in some treatment contamination and a significant difference in the duration of prophylaxis. Study participants, clinicians, and research team members were not blinded to the treatment regimen. Lack of blinding and allocation concealment may have led to a treatment bias resulting in a differential threshold for diagnostic testing of study outcomes. However, we did not observe differential rates of diagnostic testing between the treatment groups. The study was a single-center study, which may limit its generalizability. The weights assigned to the study outcomes were derived from a VTE prophylaxis preference study. The bleeding complication weights did not account for the severity of bleeding events and more severe complications, such as intracranial bleeding or a retroperitoneal hematoma, that would likely have received a higher weight. The study had a broad eligibility criterion, and the VTE and bleeding risk may vary among this patient population. The study was adequately powered to detect a patient-important difference with the Global Rank test, but was limited in the time to event analysis. A larger prospective randomized study is needed to compare the VTE prophylactic effectiveness of these regimens for the specific outcomes included in our composite outcome and to determine the heterogeneity in treatment effect.\n\nThe findings of this randomized trial suggest that LMWH has a null to moderate global benefit for VTE prophylaxis in orthopaedic trauma patients. When considering patient preferences for an oral route of administration over a skin injection, aspirin is preferred based on the Global Rank analysis. The time to event framework suggests that the global VTE prevention benefits of LMWH may exceed the patient preference margin for aspirin. An evaluation of the effectiveness of these medications on specific clinical endpoints will require a considerably larger sample.\n\nSupporting information\nS1 File CONSORT checklist.\n(DOC)\n\nClick here for additional data file.\n\n S2 File Study data.\n(XLSX)\n\nClick here for additional data file.\n\n S3 File Approved study protocol.\n(PDF)\n\nClick here for additional data file.\n\n S4 File Unweighted results.\n90-day results using a intention to treat analysis.\n\n(DOCX)\n\nClick here for additional data file.\n\n The ADAPT Investigators includes the authors listed in the byline, along with Herman Johal (McMaster University), Richard Van Besien, Peter Z. Berger, George B. Reahl, Dimitrius Marinos, Yasmin Degani, Daniel Mascarenhas, Daniel Connelly, Thomas M. Scalea, who are all affiliated with the University of Maryland School of Medicine. Bryce Haac, MD (brycehaac@gmail.com) is the lead author for the study group.\n==== Refs\nReferences\n1 Shackford SR , Moser KM . 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Ann Intern Med . 2013 ;158 (11 ):800 −806\n. 10.7326/0003-4819-158-11-201306040-00004 \n23732713 \n14 [no authors listed]. Collaborative overview of randomised trials of antiplatelet therapy: III. reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients: antiplatelet trialists’ collaboration\n. BMJ . 1994 ;308 (6923 ):235 −246\n. 8054013 \n15 [no authors listed]. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial\n. Lancet . 2000 ;355 (9212 ):1295 −1302\n. 10776741 \n16 Bozic KJ , Vail TP , Pekow PS , Maselli JH , Lindenauer PK , Auerbach AD . Does aspirin have a role in venous thromboembolism prophylaxis in total knee arthroplasty patients?\n\nJ Arthroplasty . 2010 ;25 (7 ):1053 −1060\n. 10.1016/j.arth.2009.06.021 \n19679434 \n17 Vulcano E , Gesell M , Esposito A , Ma Y , Memtsoudis SG , Gonzalez Della Valle A . Aspirin for elective hip and knee arthroplasty: a multimodal thromboprophylaxis protocol\n. Int Orthop . 2012 ;36 (10 ):1995 −2002\n. 10.1007/s00264-012-1588-4 \n22684546 \n18 Raphael IJ , Tischler EH , Huang R , Rothman RH , Hozack WJ , Parvizi J . Aspirin: an alternative for pulmonary embolism prophylaxis after arthroplasty?\n\nClin Orthop Relat Res . 2014 ;472 (2 ):482 −488\n. 10.1007/s11999-013-3135-z \n23817755 \n19 Gehling H , Giannadakis K , Lefering R , Hessmann M , Achenbach S , Gotzen L . Prospective randomized pilot study of ambulatory prevention of thromboembolism: 2 times 500 mg aspirin (ASS) vs. clivarin 1750 (NMH) [in German]\n. Unfallchirurg . 1998 ;101 (1 ):42 −49\n. 10.1007/s001130050231 \n9522671 \n20 Sagi HC , Ahn J , Ciesla D , Collinge C , Molina C , Obremskey WT , et al\nOrthopaedic Trauma Association Evidence Based Quality Value and Safety Committee. Venous thromboembolism prophylaxis in orthopaedic trauma patients: a survey of OTA member practice patterns and OTA expert panel recommendations\n. J Orthop Trauma . 2015 ;29 (10 ):e355 −e362\n. 10.1097/BOT.0000000000000387 \n26402304 \n21 Evans SR , Follmann D . Using Outcomes to Analyze Patients Rather than Patients to Analyze Outcomes: A Step toward Pragmatism in Benefit:risk Evaluation\n. Stat Biopharm Res . 2016 ;8 (4 ):386 –393\n. 10.1080/19466315.2016.1207561 \n28435515 \n22 Evans SR , Rubin D , Follmann D , et al\nDesirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR)\n. Clin Infect Dis . 2015 ;61 (5 ):800 –806\n. 10.1093/cid/civ495 \n26113652 \n23 Haac BE , O'Hara NN , Mullins CD , et al\nPatient preferences for venous thromboembolism prophylaxis after injury: a discrete choice experiment\n [published correction appears in BMJ Open. 2017 Dec 22;7(12):e016676corr1]. BMJ Open . 2017 ;7 (8 ):e016676 \n10.1136/bmjopen-2017-016676 \n28801426 \n24 Jaff MR , McMurtry MS , Archer SL , Cushman M , Goldenberg N , et al\nAmerican Heart Association Council on Cardiopulmonary , Critical Care , Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis , Thrombosis and Vascular Biology . Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association\n. Circulation . 2011 ;123 (16 ):1788 –1830\n. 10.1161/CIR.0b013e318214914f \n21422387 \n25 Centers for Disease Control and Prevention. Surgical Site Infection Event—Procedure-Associated Module. January 2020. Available at: https://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf. Accessed February 9, 2020.\n26 Udogwu U , Howe A , Frey K , et al\nA Patient-Centered Composite Endpoint Weighting Technique for Orthopaedic Trauma Research\n. BMC Med Res Methodol . 2020 . Accepted. In Press.\n27 Noether GE . Sample-size determination for some common nonparametric tests\n. J Am Stat Assoc \n1987 ; 82 :645 –7\n.\n28 Ramchandani R , Schoenfeld DA , Finkelstein DM . Global rank tests for multiple, possibly censored, outcomes\n. Biometrics . 2016 ;72 (3 ):926 –935\n. 10.1111/biom.12475 \n26812695 \n29 Brown PM , Ezekowitz JA . Composite End Points in Clinical Trials of Heart Failure Therapy: How Do We Measure the Effect Size?\n. Circ Heart Fail . 2017 ;10 (1 ):e003222 \n10.1161/CIRCHEARTFAILURE.116.003222 \n28077429 \n30 Acion L , Peterson JJ , Temple S , Arndt S . Probabilistic index: an intuitive non-parametric approach to measuring the size of treatment effects\n. Stat Med . 2006 ; 25 :591 –602\n. 10.1002/sim.2256 \n16143965 \n31 Shao J , Zhong B . Last observation carry-forward and last observation analysis\n. Stat Med . 2003 ;22 (15 ):2429 –2441\n. 10.1002/sim.1519 \n12872300\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000925:Anticoagulants; D001241:Aspirin; D017984:Enoxaparin; D005260:Female; D005343:Fibrinolytic Agents; D050723:Fractures, Bone; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D054556:Venous Thromboembolism; D055815:Young Adult",
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"title": "Aspirin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in orthopaedic trauma patients: A patient-centered randomized controlled trial.",
"title_normalized": "aspirin versus low molecular weight heparin for venous thromboembolism prophylaxis in orthopaedic trauma patients a patient centered randomized controlled trial"
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"abstract": "Müllerianosis is a rare benign lesion of the urinary bladder, which is constituted by two or more of the Müllerian-duct-derived tissues. We report a 45-year-old perimenopausal multiparous woman presenting with occasional episodes of dysuria and lower abdominal discomfort of recent duration. Ultrasound examination revealed a well-defined lesion in urinary bladder and the absence of left kidney. Contrast-enhanced CT of the abdomen confirmed the findings. During diagnostic cystoscopy, haemorrhagic polypoidal lesions were noted in the left side of the posterolateral wall and dome of urinary bladder along with the absence of left ureteric orifice. Transurethral resection of the bladder lesions was done and histology examination confirmed the diagnosis of Müllerianosis. She was administered Luteinizing hormone-releasing hormone (LHRH) agonist monthly. At 1 year of follow-up, cystoscopy showed only scar tissue. The case was reported for the rarity of Müllerianosis noted in a patient with unilateral agenesis of kidney, a possible cause of delayed presentation.",
"affiliations": "Department of Urology, MIOT International, Chennai, India ssrl25@gmail.com.;Department of Urology, MIOT International, Chennai, India.;Department of Pathology, MIOT International, Chennai, India.;Department of Pathology, MIOT International, Chennai, India.",
"authors": "Rajaian|Shanmugasundaram|S|http://orcid.org/0000-0002-8132-348X;Murugasen|Lakshman|L|;Jain|Deepti|D|;Chakravarthy Narasimhachar|Srinivas|S|",
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"journal": "BMJ case reports",
"keywords": "pathology; urological cancer; urological surgery; urology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003558:Cystoscopy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009095:Mullerian Ducts; D000075529:Solitary Kidney; D001743:Urinary Bladder; D001749:Urinary Bladder Neoplasms",
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"pmid": "32675120",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Müllerianosis of the urinary bladder with unilateral complete renal agenesis: a rare coincidental finding causing delayed presentation.",
"title_normalized": "m llerianosis of the urinary bladder with unilateral complete renal agenesis a rare coincidental finding causing delayed presentation"
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"abstract": "Bortezomib is a proteasome inhibitor, approved for treating newly diagnosed and relapsed multiple myeloma (MM). This realworld, multicenter, observational, non-interventional study of bortezomib was designed to collect and analyze prospective data in Taiwanese patients with relapsed or refractory MM. The primary endpoints included clinical effectiveness outcomes (disease response, disease progression [PD], time-to-response, time-toprogression, response duration, and overall survival [OS]). Secondary endpoints were safety and healthcare resource utilization. Total 100 patients (median [range] age 64.9 [37.0-85.5] years) were enrolled; 47 patients completed the study. Of the withdrawn patients (n=53), there were 48 deaths (PD-related death: n=35, adverse events [AEs]-related: n=12, other reason: n=1), and 5 due to loss to follow-up. Four patients in Cycle 1, 6 patients each in Cycle 2 and 5, 7 in Cycle 3, 10 patients in Cycle 4, 5 patients in Cycle 6, and 3 patients each in Cycle 7 and 8 achieved overall response during the study. Time-to-response was 4.68 months (95%CI: 3.2, NE) and response duration was 10.08 months (95%CI: 2.3, 28.6). Median OS was 9.8 months (95%CI: 3.8, 13.7), and median time-to-progression was 11.3 months (95%CI: 6.2, 20.2). Most common non-hematological AEs were diarrhea (n=32) and hypoesthesia (n=25); most common hematological AE was thrombocytopenia (n=18). Efficacy and safety profile of bortezomib in Taiwanese patients with MM was similar to global and other Asian population. Study provides a critical insight on use of bortezomib in realworld clinical practice, which can be helpful for Taiwanese healthcare providers' decision-making processes.",
"affiliations": "National Taiwan University Hospital, Taiwan.;National Cheng Kung University Hospital, Taiwan.;Kaohsiung Chang Gung Memorial Hospital, Taiwan.;Tri-Service General Hospital, National Defense Medical Center, Taiwan.;Kaohsiung Medical University Memorial Hospital.;Mackay Memorial Hospital, Taiwan.;Johnson & Johnson Investment Ltd, Shanghai, P.R. China.;Janssen Medical Affairs, Taiwan.;Chang-Hua Christian Hospital, Taiwan.",
"authors": "Huang|Shang-Yi|SY|;Chen|Tsai-Yun|TY|;Kuo|Ching-Yuan|CY|;Chen|Yeu-Chin|YC|;Lin|Sheng-Fung|SF|;Chang|Ming-Chih|MC|;Lv|Xinzhu|X|;Yang|Betty|B|;Chang|Cheng-Shyong|CS|",
"chemical_list": null,
"country": "Italy",
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"doi": "10.4081/oncol.2019.377",
"fulltext": "\n==== Front\nOncol RevOncol RevONCOLOncology Reviews1970-55651970-5557PAGEPress Publications, Pavia, Italy 10.4081/oncol.2019.377ReviewBortezomib therapy in a real-world setting in patients with relapsed or refractory multiple myeloma Huang Shang-Yi 1Chen Tsai-Yun 2Kuo Ching-Yuan 3Chen Yeu-Chin 4Lin Sheng-Fung 5Chang Ming-Chih 6Lv Xinzhu 7Yang Betty 8Chang Cheng-Shyong 91 National Taiwan University Hospital, Taiwan2 National Cheng Kung University Hospital, Taiwan3 Kaohsiung Chang Gung Memorial Hospital, Taiwan4 Tri-Service General Hospital, National Defense Medical Center, Taiwan5 Kaohsiung Medical University Memorial Hospital6 Mackay Memorial Hospital, Taiwan7 Johnson & Johnson Investment Ltd, Shanghai, P.R. China8 Janssen Medical Affairs, Taiwan9 Chang-Hua Christian Hospital, TaiwanChanghua Christian Hospital, Changhua City, Changhua County, Taiwan. 886.47000626. cs4816@gmail.comContributions: all named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nConflict of interests: Dr Betty Yang is employee of Johnson & Johnson Taiwan Ltd.\n\nRegistration: VELCADE® Observational Study Protocol 26866138MMY4055\n\nCompliance with ethics guidelines: the study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent with Good Clinical Practices and applicable regulatory requirements. The study protocol and informed consent form were reviewed and approved by the Institutional Review Boards and/or Independent Ethics Committee at all sites. All enrolled patients provided written informed consent for their participation in the study.\n\n18 1 2019 14 1 2019 13 1 37712 6 2018 22 10 2018 ©Copyright S-Y. Huang et al., 20192019Licensee PAGEPress, ItalyThis work is licensed under a Creative Commons Attribution NonCommercial 4.0 License (CC BY-NC 4.0).Bortezomib is a proteasome inhibitor, approved for treating newly diagnosed and relapsed multiple myeloma (MM). This realworld, multicenter, observational, non-interventional study of bortezomib was designed to collect and analyze prospective data in Taiwanese patients with relapsed or refractory MM. The primary endpoints included clinical effectiveness outcomes (disease response, disease progression [PD], time-to-response, time-toprogression, response duration, and overall survival [OS]). Secondary endpoints were safety and healthcare resource utilization.\n\nTotal 100 patients (median [range] age 64.9 [37.0-85.5] years) were enrolled; 47 patients completed the study. Of the withdrawn patients (n=53), there were 48 deaths (PD-related death: n=35, adverse events [AEs]-related: n=12, other reason: n=1), and 5 due to loss to follow-up. Four patients in Cycle 1, 6 patients each in Cycle 2 and 5, 7 in Cycle 3, 10 patients in Cycle 4, 5 patients in Cycle 6, and 3 patients each in Cycle 7 and 8 achieved overall response during the study. Time-to-response was 4.68 months (95%CI: 3.2, NE) and response duration was 10.08 months (95%CI: 2.3, 28.6). Median OS was 9.8 months (95%CI: 3.8, 13.7), and median time-to-progression was 11.3 months (95%CI: 6.2, 20.2). Most common non-hematological AEs were diarrhea (n=32) and hypoesthesia (n=25); most common hematological AE was thrombocytopenia (n=18).\n\nEfficacy and safety profile of bortezomib in Taiwanese patients with MM was similar to global and other Asian population. Study provides a critical insight on use of bortezomib in realworld clinical practice, which can be helpful for Taiwanese healthcare providers’ decision-making processes.\n\nKey words\nBortezomibeffectivenessmultiple myelomaobservationalreal-worldFunding: this study was sponsored by Johnson & Johnson Taiwan Ltd.\n==== Body\nIntroduction\nIncidence of multiple myeloma (MM) is increasing in Asian countries (including Korea and Taiwan) owing to rapid industrialization and increased life span.1,2 In Taiwan, the incidence rate of MM is 0.75/100,000 individuals and mortality rate is 0.59/100,000 deaths.1\n\nThe introduction of novel therapeutic agents (proteasome inhibitors and immunomodulatory agents), and advances in supportive care have substantially increased response rates and patient survival in MM.3,4 Bortezomib, a proteasome inhibitor, is approved for treating patients with newly diagnosed and relapsed MM in the United States,5-7 and for treating MM in Europe and several other countries (including China).8,9 Bortezomib with dexamethasone exhibits a favorable safety profile and overall response rate (ORR) of up to 67% in patients with relapsed and refractory MM.10,11 Bortezomib is associated with low incidences of thromboembolic complications, and may provide a better safety profile than immunomodulatory agents like thalidomide and lenalidomide. 12 Bortezomib plus melphalan-prednisone has shown to significantly improve outcomes in patients newly diagnosed with MM and ineligible for high-dose therapy.13\n\nHowever, variability between results from clinical trials and those observed in routine healthcare are common in cancer treatment. We report results from an observational study conducted in Taiwan that was designed to evaluate safety and efficacy of bortezomib in patients with relapse or refractory MM, with ≥1 prior chemotherapy regimen, in a real-world practice scenario (VELCADE ® Observational Study Protocol 26866138MMY4055).\n\nMethods of research\nParticipants\nTaiwanese patients (of either sex) aged ≥18 years, with relapsed or refractory MM and ≥1 prior chemotherapy regimen were enrolled. All participating patients had already initiated bortezomib therapy within the approved indications. Patients having contraindications listed in package insert (VELCADE®, registered trademark of Millennium Pharmaceuticals, Inc., Cambridge, USA) and participating in another investigational study of bortezomib were excluded.\n\nPatients received the usual treatment and investigations for their condition and were not exposed to experimental investigations during the study. The prescription of bortezomib was not decided in advance by the VELCADE® Observational Study protocol, and separated from the decision to include the patient in the study. The de-identified patient data were encrypted as dictated by international data protection laws.\n\nThe study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent with Good Clinical Practices and applicable regulatory requirements. The study protocol and informed consent form were reviewed and approved by the Institutional Review Boards and/or Independent Ethics Committee at all sites. All enrolled patients provided written informed consent for their participation in the study.\n\nStudy design\nThis was an observational study conducted in Taiwan (7 sites) to document the use of bortezomib in patients who were initiating bortezomib therapy within the approved indication in a real-world setting. The study was conducted between 23 March 2011 and 24 September 2015.\n\nThe duration of the study was set prospectively for 4 years from the date the first patient initiated bortezomib. The patient recruitment period was two years. Data collection occurred at baseline and at the end of each cycle of bortezomib therapy via paper-based case report form (CRF), with the exception of SAEs, which were reported within 24 hours of knowledge of the event to the assigned local operating company designate. All patients were followed up to 2 years post treatment; subsequent therapies for MM were documented during the entire post-treatment survival follow-up period up to two years. For patients who discontinued bortezomib before disease progression (PD) and for those who progressed while on bortezomib treatment, post-treatment followup was continued every 12 weeks. For patients who reinitiated bortezomib, data collection was done as per the bortezomib treatment period documentation process. All concomitant treatments were recorded up to the conclusion of the last cycle.\n\nAll bortezomib dosages were eligible for the study. Bortezomib was administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with 9 mg/mL (0.9%) sodium chloride solution for injection.\n\nDose adjustments and cycle delays were at physician’s discretion. Bortezomib treatment was withheld at the onset of any Grade 3 non-hematological or any Grade 4 hematological toxicities, excluding neuropathy, and was re-initiated following resolution of toxicity symptoms, at 25% reduced dose (1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the toxicity was unresolved or in case of recurrence, bortezomib was discontinued unless the benefit of treatment clearly outweighed the risk. Management of bortezomib-related neuropathic pain and/or peripheral neuropathy is presented in Table S1. Patients with preexisting severe neuropathy were treated with bortezomib only after careful risk/benefit assessment.\n\nConcomitant medication\nExcept investigational compounds, all other concomitant medications (bisphosphonates, colony stimulating factors, erythropoietin, platelet and red cell transfusions, loperamide, prophylactic antiemetic, antineoplastic therapy, antibiotics, and non-steroidal anti-inflammatory agents), anti-MM agents (including systemic corticosteroids, clarithromycin, and thalidomide), and treatments consonant with real-world practice (orthopedic surgery, kyphoplasty, emergency local radiotherapy) were allowed during the study.\n\nEfficacy\nThe primary endpoint was to evaluate the clinical effectiveness outcomes associated with bortezomib (disease response, disease progression, time-to-response, time-to-progression, response duration, and overall survival [OS]). Disease response was classified as complete response (CR), near CR (nCR), very good partial response (VGPR), partial response (PR), and minimal response (MR), stable disease (SD) or PD. The ORR was defined as the proportion of patients with CR, nCR, VGPR, PR, and MR. The methods and criteria used to evaluate the disease responses were chosen and recorded by the physician. Commonly used response criteria included the EBMT criteria,14 Southwest Oncology Group criteria,15 and the M-protein criteria16 for disease response.\n\nDisease progression included PD and relapsed CR (RCR). Time-to-response (from first dose of bortezomib to first response [CR/nCR/PR/MR]); response duration (from first response to first documented PD [determined as the first indication of progression, e.g. sufficient elevation of M-protein, new skeletal event, etc.], RCR, or death); time-to-progression (from first dose of bortezomib to first documented PD or RCR); and OS (from first dose of bortezomib to death) were also assessed.\n\nSafety\nSafety assessments included monitoring of treatment-emergent adverse events (TEAEs), skeletal events (fractures, irradiation of bone, surgery on bone, spinal cord compression), clinical laboratory parameters, electrocardiograms, vital sign measurements, and physical examination. All AEs were assessed using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE v3.0) and were monitored through 30 days after the last bortezomib dose.\n\nHealth care resource utilization\nAssessments included number of bortezomib dosages (in mg per m2 of body surface area [BSA]) and duration of each cycle, emergency visits, number and duration of hospitalization, therapeutic procedures (e.g., surgery), diagnostic radiography and laboratory procedures, concomitant medications used (including overthe- counter and prescription medications).\n\nStatistical analysis\nSince this observational study was designed to generate data for informative purposes, it was descriptive than comparative, and no formal hypotheses were tested in this study. The sample size was mainly determined by pragmatic considerations. Total 100 patients who were initiating bortezomib therapy were to be enrolled. Analyses were carried out on all-patients analysis set (all patients enrolled and treated with bortezomib). Safety analyses were performed on patients who received ≥1 dose of bortezomib (safety population).\n\nAll statistical analyses were performed using SAS® version 9.4 (Cary, NC, USA). The continuous endpoints were summarized descriptively. The number and percentage of patients for the different response categories were tabulated and two-sided 95% confidence intervals (CI) presented. Estimates of the time-to-event endpoints (response duration, OS, and time-to-progression) were obtained using the Kaplan-Meier method. Safety and healthcare resource utilization parameters were summarized descriptively.\n\nResults\nDemographics and baseline characteristics\nTotal 47 of 100 enrolled patients completed the study and 53 were withdrawn from the study (including 48 deaths [PD-related deaths: n=35, AE-related deaths: n=12, death due to other reason: n=1, heart failure]), loss to follow-up: n=5). All enrolled patients received ≥1 dose of bortezomib. Of the 100 patients, 49 were men; the median age was 64.9 years (range 37.0-85.5), with 50 patients ≥18 to <65 years of age and 50 patients ≥65 years of age. Most patients had advanced disease (Stage IIIA as per Durie-Salmon criteria) at baseline (Table 1).\n\nPrior therapies and concomitant medications\nThe majority of patients received chemotherapy (n= 80) or hormone therapy (n=77) prior to study entry. The most frequently (≥50 patients) used prior chemotherapy medication was thalidomide (n=57) while the most frequently (≥40 patients) used prior hormonal medication were dexamethasone (n=49) and prednisone (n=43) (Table S2).\n\nThe most frequently (≥50 patients) used concomitant medications were dexamethasone (n=79), acetaminophen (n=60) and thalidomide (n=59). Subsequent to the last bortezomib cycle, 58 patients received chemotherapy (thalidomide: n=22, cyclophosphamide: n=9, melphalan and lenalidomide: n=5 each, bortezomib: n=4, other drugs: n=19), 47 patients received hormonal therapy, 9 patients received immunotherapy and 1 patient received radiotherapy for treating MM.\n\nTreatment compliance\nMajority of patients received bortezomib 1.3 mg/m2 dose during the study (Cycle 1: 87%, Cycle 2: 80%, Cycle 3: 84%, Cycle 4: 82%, Cycle 5: 84%, Cycle 6: 81%, Cycle 7: 82%, Cycle 8: 81%; Cycle 9-11: 100%) followed by 1.0 mg/m2 dose (Cycle 2: 5%, Cycle 3, 4 and 5: 3% each, Cycle 7 and 8: 1% each). Nine patients had one-dose adjustments during the study (Cycle 1: n=3, Cycle 2: n=2, Cycle 3: n=1, Cycle 4: n=2, Cycle 6: n=1) while one patient each in Cycle 2 and Cycle 3 had dose adjustments done thrice and twice respectively.\n\nEfficacy\nPatients had disease assessment done during Cycle 1 (7 patients) to Cycle 8 (3 patients). Four patients in Cycle 1, 6 patients each in Cycle 2 and 5, 7 in Cycle 3, 10 patients in Cycle 4, 5 patients in Cycle 6, and 3 patients each in Cycle 7 and 8 achieved OR (CR+ nCR + VGPR + PR + MR) during the study; of these, 1 patient each in Cycle 2, 4, 5 and 8 and 2 patients in Cycle 6 achieved CR and 2 patients each in Cycle 1, 4, and 5. One patient in Cycle 7 had PD. One patient each in follow-up visit 1, 2, 4, 6, and 8 achieved an nCR. One patient each in follow-up visit 2, 3 and 7, and 2 patients in follow-up 6 had PD (Table 2).\n\nAt the 25th percentile, the time-to-response was 4.68 months (95% CI: 3.2 months, not evaluable) (Table 3, Figure 1), while the response duration was 10.08 months (95% CI: 2.3, 28.6 months) (Table 3, Figure 2). Overall, 35 patients with response had PD (including death due to PD) or RCR and 65 patients maintained response during the study. At 25th percentile, the time-to-progression was 11.28 months (95% CI: 6.2, 20.2 months) (Table 3, Figure 3). Data from 54 patients were censored for the Kaplan-Meier estimates of death, and 46 patients died during the study or follow-up. At the 50th percentile, the median survival time was 30.72 months (95% CI: 18.2 months, not evaluable) (Table 3, Figure 4).\n\nTime-to-response was defined as the duration in days between the start date of bortezomib therapy and the date of first documented evidence of response including CR, nCR, VGPR, PR or MR. Median time-to-response could not be evaluated.\n\nDuration of response was defined as the duration from the date on which response documented until PD, RCR, and death due to PD among patients who had a response. Time to progression was defined as the duration in days between the start of bortezomib therapy and the date of first documented evidence of confirmed PD (including death due to PD) or RCR.\n\nSafety\nOverall, 99 patients experienced ≥1 AE; of these, 57 patients had TEAEs (possibly related [n=30], probably related [n=19], very likely related [n=8]). Total, 57 patients experienced ≥1 serious TEAE; 50 patients had severe/life-threatening/fatal TEAEs. There were 12 deaths during the study; 6 due to TEAEs (septic shock and sepsis [n=3], acute respiratory distress syndrome [n=2], and acute myocardial infarction, plasma cell myeloma, pyrexia, lacunar infarction, pneumonia and acute respiratory failure, and respiratory failure [n=1]), and 6 due to PD (Table 4). Total, 71 patients had TEAEs persisting while 14 patients had TEAEs resolved at the end of the study. Of the 99 patients, 19 patients received ≥1 concomitant medication for a TEAE during the study.\n\nThe most commonly reported (>30% patients) TEAEs was diarrhea (n=32). Total 14 patients reported peripheral neuropathy (Table 4). The most common treatment-emergent SAEs were pneumonia (n=17), sepsis (n=7), pyrexia and septic shock (n=6 each), and herpes zoster (n=5).\n\nMost patients (≥62 patients) received only 4 cycles of bortezomib therapy and had routine hematology and biochemistry laboratory evaluations from baseline through Cycle 4. The mean (SD) platelet count decreased from 188.7 (118.3)×103/μL (baseline, n=94) to 154.3 (108.4)×103/μL in Cycle 1 (n=96) and increased to 164.5 (105.9)×103/μL in Cycle 2 (n=86), 177.4 (109.8)×103/μL in Cycle 3 (n=71), and 176.2 (79.8)×103/μL in Cycle 4 (n=61). Mean changes from baseline were statistically significant (P<0.05) for decreases in eosinophils and basophils (Cycle 1), and lymphocytes (Cycles 1, 2, 4), increases in neutrophils, monocytes, hematocrit, hemoglobin levels and red blood cell counts (Cycles 1-4). Additionally, significant increases (P<0.05) from baseline were observed for white blood cell counts in Cycles 2 and 4. The mean serum lactate dehydrogenase levels were significantly (P<0.05) increased from baseline to Cycle 3, while the mean serum total protein levels were significantly (P<0.05) decreased from baseline to Cycle 4. There were no other clinically meaningful and significant mean changes from baseline in any of the chemistry parameters over time.\n\nThere were statistically significant decrease (P<0.05) in mean changes from baseline through Cycle 8 in IgG protein (n=8~33) and through Cycle 4 in IgA protein (n=14~17). There were no other statistically significant mean changes from baseline to Cycle 9 in any of the efficacy laboratory evaluations.\n\nAt baseline, the mean (SD) percentage of plasma cells in bone marrow of 72 patients was 42.3 (28.0)% and 19 patients had ≥3 bone lesions. For patients with available data (C1, n=1; C3, 2; C4, n=5; C6, n=3; C8, n=2) one patient in Cycle 1 had 43.2% plasma cells in bone marrow and 1 patient in Cycle 5 had 11.6% plasma cells in bone marrow while 2 patients each in Cycle 3 and 8, 5 in Cycle 4 and 3 in Cycle 6, the mean plasma cells in bone marrow was <7%.\n\nEight patients had extramedullary plasmacytoma at baseline. The most commonly (≥3 patients) used methods for evaluation were physical exam (n=3) and other methods (including echocardiogram and x-ray; 3 patients) while plasmacytoma biopsy was performed for 4 patients. Following bortezomib treatment, only 4 patients (Cycle 2: n=3; Cycle 4: n=1) had extramedullary plasmacytoma (confirmed by biopsy). Fewer patients (n=7) had ≥1 new skeletal event with spinal cord compression (Cycle 2 and 3: n=2 each) being the most common new skeletal event during the study.\n\nHealthcare resource utilization\nTotal 42 patients had emergency visits and 50 patients were hospitalized during the study; however, the number of patients with emergency visits decreased from Cycle 1 (n=25) to 8 (n=4) and further during follow-up 3 (n=1). Also, the number of patients who were hospitalized decreased from Cycle 1 (n=17) to 8 (n=4), and follow-up 1 (n=1). Most of these patients were hospitalized for infection (Cycle 1: n=6, Cycle 2: n=7, Cycle 3, Cycle 7, and follow- up 1: n=1 each). No patient was hospitalized for blood transfusion. The mean (SD) number of hospital days was 18.1 (19.2) days; the mean (SD) number of hospital days varied from 12.3 (9.1) to 25.0 (20.1) days (except in Cycle 8: 6.3 [4.7] days). Overall, 91 patients received ≥1 blood transfusion during the study. However, the number of patients receiving ≥1 blood transfusion decreased from Cycle 1 (n=27) to 9 (n=1), and follow-up 1 (n=1). The number of patients with diagnostic radiography did not vary greatly from Cycles 1 to 4 and ranged from 4 to 6. One patient in Cycle 8 had diagnostic radiography. No patients had diagnostic radiography in Cycles 5 to 7 and Cycles 9 to 11. Residual/recurrence disease was reported in 1 patient each in Cycle 1, 2 and 3, and 2 patients in Cycle 4.\n\nDiscussion\nProteasome inhibitors and immunomodulators have therapeutic advantages over conventional strategies, and hence have emerged as a more feasible treatment option for patients with relapsed/refractory MM, particularly those ineligible for high-dose chemotherapy.17,18 Several studies have established the efficacy and safety of bortezomib in the Caucasians,10,11,13,19-21 and Asians.22,23 However, as clinical trials are restrictive in their setup and design,24 the current observational study was designed to simulate the real-world practice scenario and help insight into the therapeutic feasibility of bortezomib in Taiwanese patients with relapsed or refractory MM.\n\nThe majority of patients received bortezomib 1.3 mg/m2 and did not require dose adjustment during the study. Literature suggests that maximum inhibition (73-83%) of 20S proteasome is observed at this dose.25 The response duration (10.08 months) is consistent with that observed in the Caucasian populations (12.7 months).20\n\nThis being a real-world study, investigators only reported results from assessments that they considered necessary at each visit, thus only a very small number of patients had any kind of assessment done at each cycle. Data was hence insufficient to derive the ORR for this population. Nevertheless, cycle-wise ORR was determined to evaluate the effectiveness of bortezomib in these patients.\n\nOf the evaluable Taiwanese patients with MM, the majority demonstrated PR; this is consistent with earlier studies in Asian population (25%-42%).22,23 Furthermore, although SD status was not achieved in most patients, those demonstrating PD were notably few. These findings are consistent with global and Asian studies,20,22,23 which supports the therapeutic advantage of bortezomib when introduced early as salvage treatment in the course of disease. It should be noted here that although studies have demonstrated that higher response quality is associated with longer response duration and survival,26-28 not all studies show an absolute benefit of achieving CR, and there may exist a subgroup of patients who may obtain prolonged survival often without ever achieving CR.29,30 For such a subgroup treatment emphasizing depth of response may be too toxic and less beneficial. In such cases the goal is to obtain the best possible response while managing toxicities. However, as most of the patients received only 4 cycles of treatment, the efficacy could not be assessed completely in the present study. Although agents including bortezomib show high anti-MM activity, most patients with MM eventually relapse, including those who achieved CR with the initial therapy. However, in the current study no patient had RCR during the study or follow-up. Thus, the efficacy results of this observational study in real-world setting demonstrates the utilization and feasibility of bortezomib, confirming its use in Taiwanese patients with relapse or refractory MM.\n\nThe safety profile of bortezomib was similar to that observed with other global studies and no unexpected safety findings were observed. Although thrombocytopenia and osteoporosis are the most common TEAEs reported, 6 both events were low in this study (thrombocytopenia: n=18; osteoporosis: n=1). There were very few clinically meaningful and significant (P<0.05) mean changes from baseline through Cycle 8 in the hematology laboratory parameters and most of them were related to MM. There were few emergency visits and hospitalizations during the study. Deaths due to TEAEs, SAEs and AEs leading to discontinuation were also low in this study. Thus, it indicates that bortezomib produces a manageable toxicity profile in the Taiwanese population.\n\nAccording to the rule of reimbursement by Taiwan national insurance, all the MM patients can use maximum 8 cycles of bortezomib before disease progression. Therefore, most of the patients in this study could use full dose bortezomib 1.3 mg/m2 before disease progression or withdrawal that demonstrates tolerability of bortezomib in RR MM patients. Study results suggest that approximately 40% patients require more than 4 cycles of bortezomib and approximately 25% patients need more than 8 cycles.\n\nOne limitation of this observational study was that the majority of patients (≥62 patients) received only 4 cycles of bortezomib therapy and hence the complete efficacy and safety profile of bortezomib could not be assessed. Being a non-interventional study, investigators were not obliged to perform every assessment at every visit listed in the protocol, thus the number of patients who had effectiveness or health care resource utilization assessment done was very low throughout the study.\n\nConclusions\nThe current observational study supports that the efficacy and drug toxicity profile of bortezomib in Taiwanese patients with MM is similar to global and Asian population in real-world practice. Also, study provides a critical insight on use of bortezomib in realworld clinical practice, which can be helpful for Taiwanese healthcare providers’ decision-making processes.\n\nAcknowledgments\nThe authors thank all the patients for their participation in this study, and acknowledge the collaboration and commitment of all investigators and their staff. The authors thank Dr. Rishabh Pandey (SIRO Clinpharm) for providing writing assistance and Dr. Namit Ghildyal (Janssen Research & Development, LLC.) for providing additional editorial support for this manuscript.\n\nFigure 1. Median time-to-response following bortezomib therapy in Taiwanese patients with MM (all patients analysis set).\n\nFigure 2. Median duration of response following bortezomib therapy in Taiwanese patients with MM (all patients analysis set).\n\nFigure 3. Median time-to-progression following bortezomib therapy in Taiwanese patients with MM (all patients analysis set).\n\nFigure 4. Overall survival following bortezomib therapy in Taiwanese patients with MM (all patients analysis set).\n\nTable 1. Demographics and baseline characteristics (all patients analysis set).\n\nCharacteristics\tAll-patient analysis set\t\nWomen, n (%)\t51(51)\t\nMen\t49(49)\t\nAge, years, median (range)\t64.9 (37.0-85.5)\t\nStage of myeloma at baseline\t\t\n(durie-salmon criteria), n (%)\t\t\n IA\t2(2)\t\n II\t1(1)\t\n IIA\t7(7)\t\n IIB\t1(1)\t\n IIIA\t32(32)\t\n IIIB\t11(11)\t\n Not available\t46(46)\t\nStage of myeloma at baseline (ISS Criteria), n (%)\t\t\n I\t13(13)\t\n II\t22(22)\t\n III\t35(35)\t\n Not available\t30(30)\t\nType of myeloma, n (%)\t\t\n Secretory\t95(95)\t\n Non-secretory\t5(5)\t\nNew bone lesions at baseline, n (%)\t\t\n 1\t4(4)\t\n 2\t5(5)\t\n ≥3\t19(19)\t\n Not available\t72(72)\t\nPlasma cells in bone marrow, n; median (range)\t72; 42.5 (0.2-98.0)\t\nExtramedullary plasmacytoma present, n (%)\t8(8)\t\nHemoglobin (gm/L), n; median (range)\t95; 9.3 (5.5-15.4)\t\nPlatelet count (×103/μL), n; median (range)\t94; 171.0 (23.0-610.0)\t\nSerum creatinine level, n (%)\t\t\n <2 mg/dL\t83(83)\t\n ≥2 mg/dL\t17(17)\t\nAlbumin, n (%)\t \t\n <3.5 g/dL\t83(83)\t\n ≥3.5 g/dL\t17(17)\t\nSerum β2-microglobulin, n (%)\t\t\n <2.5 mg/dL\t35(35)\t\n 2.5-5.5 mg/dL\t3(3)\t\n >5.5 mg/dL\t6(6)\t\nISS, International staging system; SD, standard deviation.\n\nTable 2. Disease response to bortezomib in individual cycles (all patients analysis set).\n\nCycle (number of patients)\tResponse, n (%)\t\n\tOR\tCR\tnCR\tVGPR\tPR\tMR\tSD\tPD\tRCR\t\n\tn (%)\tn (%)\tn (%)\tn (%)\tn (%)\tn (%)\tn (%)\tn (%)\tn (%)\t\n1 (n=100)\t4 (4.0)\t0\t0\t1 (1.0)\t3 (3.0)\t0\t1 (1.0)\t2 (2.0)\t0\t\n2 (n=88)\t6 (6.8)\t1 (1.1)\t0\t1 (1.1)\t1 (1.1)\t3 (3.4)\t0\t1 (1.1)\t0\t\n3 (n=76)\t7 (9.2)\t0\t0\t3 (3.9)\t1 (1.3)\t3 (3.9)\t0\t0\t0\t\n4 (n=62)\t10 (16.1)\t1(1.6)\t0\t1 (1.6)\t7 (11.3)\t1 (1.6)\t2 (3.2)\t2 (3.2)\t0\t\n5 (n=38)\t6 (15.8)\t1 (2.6)\t0\t1 (2.6)\t4 (10.5)\t0\t0\t2 (5.3)\t0\t\n6 (n=32)\t5 (15.6)\t2 (6.3)\t1 (3.1)\t0\t2 (6.3)\t0\t0\t0\t0\t\n7 (n=27)\t3 (11.1)\t0\t0\t0\t3 (11.1)\t0\t0\t1 (3.7)\t0\t\n8 (n=26)\t3 (11.5)\t1 (3.8)\t0\t1 (3.8)\t0\t1 (3.8)\t0\t0\t0\t\nCR, complete response; nCR, near complete response; MR, minimal response; OR, overall response; RCR, relapse from CR; PR, partial response; PD, disease progression; SD, stable disease; VGPR, very good partial response.\n\nTable 3. Summary of Kaplan-Meier estimates (all patients analysis set).\n\nNo. of patients\tEvent n (%)\tCensored n (%)\tPercentile\tMonths\t95% CI\t\nTime-to-responsea\t\n100\t22(22)\t78(78)\t75\tNE\tNE\t\n\t\t\t50\tNE\tNE\t\n\t\t\t25\t4.68\t(3.2, NE)\t\nDuration of responseb\t\n22\t9(41)\t13(59)\t75\tNE\t(28.6, NE)\t\n\t\t\t50\tNE\t(10,1, NE)\t\n\t\t\t25\t10.08\t(2.3, 28.6)\t\nTime-to-progressionc\t\n100\t35(35)\t65(65)\t75\tNE\tNE\t\n\t\t\t50\tNE\t(30.1, NE)\t\n\t\t\t25\t11.28\t(6.2, 20.2)\t\nOverall survival\t\n100\t46(46)\t54(54)\t75\tNE\tNE\t\n\t\t\t50\t30.72\t(18.2, NE)\t\n\t\t\t25\t9.84\t(3.8, 13.7)\t\naTime-to-response was defined as the duration in days between the start date of bortezomib therapy and the date of first documented evidence of response including CR, nCR, VGPR, PR or MR.\n\nbDuration of response was defined as the duration from the date on which response documented until PD, RCR, and death due to PD among patients who had a response\n\ncTime-to-progression was defined as the duration in days between the start of bortezomib therapy and the date of first documented evidence of confirmed PD (including death due to PD) or RCR; All percentages are calculated based on number of patients.\n\nTable 4. Safety profile of bortezomib in Taiwanese patients with MM (all patients analysis set).\n\nCharacteristics\tAll patients analysis set (N=100) n (%)\t\nTotal number of patients with ≥1 AE\t99(99)\t\nNumber of deaths\t18(18)\t\nTEAEs leading to death\t12(12)\t\nDisease progression\t6(6)\t\nAE relationship for TEAEs leading to death\t \t\nNot related\t6(6)\t\nPossibly related\t3(3)\t\nProbably related\t3(3)\t\nNumber of patients with SAEs\t12(12)\t\nMaximum severity of SAE\t \t\nGrade 3\t4(4)\t\nGrade 4\t5(5)\t\nGrade 5\t3(3)\t\nMost common TEAEs (>10% patients)\t \t\nDiarrhea\t32(32)\t\nHypoesthesia\t25(25)\t\nCough\t24(24)\t\nPyrexia\t23(23)\t\nInsomnia\t22(22)\t\nConstipation\t19(19)\t\nThrombocytopenia\t18(18)\t\nPneumonia\t18(18)\t\nDecreased appetite\t17(17)\t\nDizziness\t17(17)\t\nBack pain\t16(16)\t\nFatigue\t16(16)\t\nHerpes zoster\t15(15)\t\nNeuropathy peripheral\t14(14)\t\nVomiting\t13(13)\t\nMalaise\t13(13)\t\nUpper respiratory tract infection\t13(13)\t\nAbdominal pain\t12(12)\t\nAbdominal distension\t11(11)\t\nEdema peripheral\t11(11)\t\nHypokalemia\t11(11)\t\nRhinorrhoea\t11(11)\t\nRash\t11(11)\t\nTEAE, treatment-emergent adverse event.\n==== Refs\nReferences\n1. Lee JH Lee DS Lee JJ \nMultiple myeloma in Korea: past, present, and future perspectives. Experience of the Korean multiple myeloma working party . Int J Hematol \n2010 ;92 :52 -7 .20544403 \n2. Huang SY Yao M Tang JL \nEpidemiology of multiple myeloma in Taiwan: increasing incidence for the past 25 years and higher prevalence of extramedullary myeloma in patients younger than 55 years . Cancer \n2007 ;110 :896 -905 .17594697 \n3. Rollig C Knop S Bornhauser M. \nMultiple myeloma . Lancet \n2015 ;385 :2197 -208 .25540889 \n4. Bianchi G Anderson KC \nUnderstanding biology to tackle the disease: multiple myeloma from bench to bedside, and back . CA Cancer J Clin \n2014 ;64 :422 -44 .25266555 \n5. Food and Drug Administration . Velcade (bortezomib) I. Prescribing Information . Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021602s031s032lbl.pdf Accessed: October 2017 .\n6. Kane RC Bross PF Farrell AT Pazdur R. \nVelcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy . Oncologist \n2003 ;8 :508 -13 .14657528 \n7. Kane RC Dagher R Farrell A \nBortezomib for the treatment of mantle cell lymphoma . Clin Cancer Res \n2007 ;13 :5291 -4 .17875757 \n8. Myeloma Euronet . Treatment with bortezomib . Available from: http://www.myelomaeuronet.org/en/multiple-myeloma/treatment-withbortezomib.php Accessed: October 2017 .\n9. LoRusso PM Venkatakrishnan K Ramanathan RK \nPharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432 . Clin Cancer Res \n2012 ;18 :2954 -63 .22394984 \n10. Jagannath S Barlogie B Berenson J \nA phase 2 study of two doses of bortezomib in relapsed or refractory myeloma . Br J Haematol \n2004 ;127 :165 -72 .15461622 \n11. Richardson PG Barlogie B Berenson J \nExtended follow- up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial . Cancer \n2006 ;106 :1316 -9 .16470606 \n12. Lonial S Richardson PG San Miguel J \nCharacterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma . Br J Haematol \n2008 ;143 :222 -9 .18713253 \n13. San Miguel JF Schlag R Khuageva NK \nBortezomib plus melphalan and prednisone for initial treatment of multiple myeloma . N Engl J Med \n2008 ;359 :906 -17 .18753647 \n14. Blade J Samson D Reece D \nCriteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma subcommittee of the EBMT. European Group for Blood and Marrow Transplant . Br J Haematol \n1998 ;102 :1115 -23 .9753033 \n15. Thompson JL Hansen LA \nThalidomide dosing in patients with relapsed or refractory multiple myeloma . Ann Pharmacother \n2003 ;37 :571 -6 .12659617 \n16. Myeloma.org. Concise review of the disease and treatment options . Available from: https://www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf Accessed: October 2017 .\n17. Katzel JA Hari P Vesole DH \nMultiple myeloma: charging toward a bright future . CA Cancer J Clin \n2007 ;57 :301 -18 .17855486 \n18. Bae J Munshi NC Anderson KC \nImmunotherapy strategies in multiple myeloma . Hematol Oncol Clin North Am \n2014 ;28 :927 -43 .25212890 \n19. Richardson PG Barlogie B Berenson J \nA phase 2 study of bortezomib in relapsed, refractory myeloma . N Engl J Med \n2003 ;348 :2609 -17 .12826635 \n20. Richardson PG Sonneveld P Schuster M \nExtended follow- up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial . Blood \n2007 ;110 :3557 -60 .17690257 \n21. Richardson PG Sonneveld P Schuster MW \nBortezomib or high-dose dexamethasone for relapsed multiple myeloma . N Engl J Med \n2005 ;352 :2487 -98 .15958804 \n22. Lin M Hou J Chen W \nImproved response rates with bortezomib in relapsed or refractory multiple myeloma: an observational study in Chinese patients . Adv Ther \n2014 ;31 :1082 -94 .25331616 \n23. Igarashi N Chou T Hirose T \nBortezomib and dexamethasone for Japanese patients with relapsed and refractory multiple myeloma: a single center experience . Int J Hematol \n2010 ;92 :518 -23 .20886379 \n24. Singal AG Higgins PD Waljee AK \nA primer on effectiveness and efficacy trials . Clin Transl Gastroenterol \n2014 ;5 :e45 .24384867 \n25. Curran MP McKeage K. \nBortezomib: a review of its use in patients with multiple myeloma . Drugs \n2009 ;69 :859 -88 .19441872 \n26. Barlogie B Anaissie E Haessler J \nComplete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma . Cancer \n2008 ; 113 :355 -9 .18470907 \n27. Hoering A Crowley J Shaughnessy JD \nComplete remission in multiple myeloma examined as time-dependent variable in terms of both onset and duration in Total Therapy protocols . Blood \n2009 ;114 :1299 -305 .19515721 \n28. Niesvizky R Richardson PG Rajkumar SV \nThe relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma . Br J Haematol \n2008 ;143 :46 -53 .18673366 \n29. Rajkumar SV Fonseca R Dispenzieri A \nEffect of complete response on outcome following autologous stem cell transplantation for myeloma . Bone Marrow Transplant \n2000 ;26 :979 -83 .11100277 \n30. Pineda-Roman M Bolejack V Arzoumanian V \nComplete response in myeloma extends survival without, but not with history of prior monoclonal gammopathy of undetermined significance or smouldering disease . Br J Haematol \n2007 ;136 : 393 -9 .17156398\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1970-5557",
"issue": "13(1)",
"journal": "Oncology reviews",
"keywords": "Bortezomib; effectiveness; multiple myeloma; observational; real-world",
"medline_ta": "Oncol Rev",
"mesh_terms": null,
"nlm_unique_id": "101519906",
"other_id": null,
"pages": "377",
"pmc": null,
"pmid": "30858932",
"pubdate": "2019-01-14",
"publication_types": "D016428:Journal Article",
"references": "11100277;12659617;12826635;14657528;15461622;15958804;16470606;17156398;17594697;17690257;17855486;17875757;18470907;18673366;18713253;18753647;19441872;19515721;20544403;20886379;22394984;24384867;25212890;25266555;25331616;25540889;9753033",
"title": "Bortezomib therapy in a real-world setting in patients with relapsed or refractory multiple myeloma.",
"title_normalized": "bortezomib therapy in a real world setting in patients with relapsed or refractory multiple myeloma"
} | [
{
"companynumb": "TW-TAKEDA-2019TUS004375",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
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"drugadditional": "3",
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{
"abstract": "OBJECTIVE\nCertain antimicrobial drugs interact with sulfonylureas to increase the risk of hypoglycemia.\n\n\nOBJECTIVE\nTo determine the risk of hypoglycemia and associated costs in older patients prescribed glipizide or glyburide who fill a prescription for an antimicrobial drug.\n\n\nMETHODS\nThis was a retrospective cohort study of Texas Medicare claims from 2006 to 2009 for patients 66 years or older who were prescribed glipizide or glyburide and who also filled a prescription for 1 of the 16 antimicrobials most commonly prescribed for this population.\n\n\nMETHODS\nWe assessed hypoglycemia events and associated Medicare costs in patients prescribed 1 of 7 antimicrobial agents thought to interact with sulfonylureas, using noninteracting antimicrobials as a comparison. We used a repeated measure logistic regression, controlling for age, sex, ethnicity, Medicaid eligibility, comorbidity, prior emergency department visits for hypoglycemia, prior hospitalizations for any cause, nursing home residence, and indication for the antimicrobial. We estimated odds of hypoglycemia, number needed to harm, deaths during hospitalization for hypoglycemia, and Medicare costs for hypoglycemia treatment.\n\n\nMETHODS\nAny hospitalization or emergency department visit owing to hypoglycemia within 14 days of antimicrobial exposure.\n\n\nRESULTS\nIn multivariable analyses controlling for patient characteristics and indication for antimicrobial drug use, clarithromycin (odds ratio [OR], 3.96 [95% CI, 2.42-6.49]), levofloxacin (OR, 2.60 [95% CI, 2.18-3.10]), sulfamethoxazole-trimethoprim (OR, 2.56 [95% CI, 2.12-3.10]), metronidazole (OR, 2.11 [95% CI, 1.28-3.47]), and ciprofloxacin (OR, 1.62 [95% CI, 1.33-1.97]) were associated with higher rates of hypoglycemia compared with a panel of noninteracting antimicrobials. The number needed to harm ranged from 71 for clarithromycin to 334 for ciprofloxacin. Patient factors associated with hypoglycemia included older age, female sex, black or Hispanic race/ethnicity, higher comorbidity, and prior hypoglycemic episode. In 2009, 28.3% of patients prescribed a sulfonylurea filled a prescription for 1 of these 5 antimicrobials, which were associated with 13.2% of all hypoglycemia events in patients taking sulfonylureas. The treatment of subsequent hypoglycemia adds $30.54 in additional Medicare costs to each prescription of 1 of those 5 antimicrobials given to patients taking sulfonylureas.\n\n\nCONCLUSIONS\nPrescription of interacting antimicrobial drugs to patients on sulfonylureas is very common, and is associated with substantial morbidity and increased costs.",
"affiliations": "Sealy Center on Aging, University of Texas Medical Branch, Galveston2Department of Internal Medicine, University of Texas Medical Branch, Galveston3Department of Preventive Medicine, University of Texas Medical Branch, Galveston4Department of Community He.;Sealy Center on Aging, University of Texas Medical Branch, Galveston2Department of Internal Medicine, University of Texas Medical Branch, Galveston3Department of Preventive Medicine, University of Texas Medical Branch, Galveston4Department of Community He.;Sealy Center on Aging, University of Texas Medical Branch, Galveston2Department of Internal Medicine, University of Texas Medical Branch, Galveston3Department of Preventive Medicine, University of Texas Medical Branch, Galveston4Department of Community He.;Sealy Center on Aging, University of Texas Medical Branch, Galveston2Department of Internal Medicine, University of Texas Medical Branch, Galveston3Department of Preventive Medicine, University of Texas Medical Branch, Galveston4Department of Community He.;Sealy Center on Aging, University of Texas Medical Branch, Galveston2Department of Internal Medicine, University of Texas Medical Branch, Galveston3Department of Preventive Medicine, University of Texas Medical Branch, Galveston4Department of Community He.;Sealy Center on Aging, University of Texas Medical Branch, Galveston2Department of Internal Medicine, University of Texas Medical Branch, Galveston3Department of Preventive Medicine, University of Texas Medical Branch, Galveston4Department of Community He.",
"authors": "Parekh|Trisha M|TM|;Raji|Mukaila|M|;Lin|Yu-Li|YL|;Tan|Alai|A|;Kuo|Yong-Fang|YF|;Goodwin|James S|JS|",
"chemical_list": "D000890:Anti-Infective Agents; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D008795:Metronidazole; D002939:Ciprofloxacin; D064704:Levofloxacin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D017291:Clarithromycin; D005905:Glyburide; D005913:Glipizide",
"country": "United States",
"delete": false,
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"title": "Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas.",
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"abstract": "BACKGROUND\nIntracerebral hemorrhage is an infrequent but severe complication in pregnant women with hypertension.\n\n\nMETHODS\nWe describe an atypical case of a patient with no risk factors who developed sudden eclampsia and spontaneous intracerebral hemorrhage during the 34(th) week of pregnancy. She underwent successful emergent Cesarean section followed by craniotomy. Both intraoperative surveillance and postoperative magnetic resonance angiographic examination of the cerebral vessels failed to identify an aneurysm, arteriovenous malformation, tumor, or leptomeningeal disease.\n\n\nCONCLUSIONS\nWe discuss the management of this case and review the literature regarding the threshold for which initiation of antihypertensive treatment is indicated in pregnant patients.",
"affiliations": "Ghaly Neurosurgical Associates, Aurora, IL, USA.",
"authors": "Ghaly|Ramsis F|RF|;Candido|Kenneth D|KD|;Sauer|Ruben|R|;Knezevic|Nebojsa Nick|NN|",
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"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-3-6510.4103/2152-7806.97167Case ReportComplete recovery after antepartum massive intracerebral hemorrhage in an atypical case of sudden eclampsia Ghaly Ramsis F. rfghaly@aol.com1234*Candido Kenneth D. kdcandido@yahoo.com24Sauer Ruben rubenivansauer@gmail.com2Knezevic Nebojsa Nick nick.knezevic@gmail.com241 Ghaly Neurosurgical Associates, Aurora, IL, USA2 Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL, USA3 Department of Anesthesiology, John Stroger Cook County Hospital, Chicago, IL, USA4 Department of Anesthesiology, University of Illinois, Chicago, IL, USA* Corresponding author2012 19 6 2012 3 6505 2 2012 08 2 2012 Copyright: © 2012 Ghaly RF.2012This 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:\nIntracerebral hemorrhage is an infrequent but severe complication in pregnant women with hypertension.\n\nCase Description:\nWe describe an atypical case of a patient with no risk factors who developed sudden eclampsia and spontaneous intracerebral hemorrhage during the 34th week of pregnancy. She underwent successful emergent Cesarean section followed by craniotomy. Both intraoperative surveillance and postoperative magnetic resonance angiographic examination of the cerebral vessels failed to identify an aneurysm, arteriovenous malformation, tumor, or leptomeningeal disease.\n\nConclusion:\nWe discuss the management of this case and review the literature regarding the threshold for which initiation of antihypertensive treatment is indicated in pregnant patients.\n\nEclampsiaintracerebral hemorrhagepregnancy\n==== Body\nINTRODUCTION\nThe incidence of preeclampsia–eclampsia in the USA is 7–10%.[18] Preeclampsia is defined as the de novo appearance of hypertension (systolic BP of ≥140 mmHg or diastolic BP of ≥90 mmHg), accompanied by new-onset proteinuria (defined as ≥300 mg/day) developing after the 20th week of pregnancy.[22] The incidence of stroke in women who are younger than 50 years of age is <5%.[2] Stroke contributes to 12% of all maternal deaths,[16] and in patients with preeclampsia when the stroke is present, it accounts for 50% of all deaths related to cerebral complications in this group.[20]\n\nWe present a unique case of sudden eclampsia and intracerebral hemorrhage (ICH) during an otherwise normal pregnancy.\n\nCASE REPORT\nA-32-year-old female, G2P1 at 34 weeks of gestational age, with regular prenatal care, and with no history of headache, proteinuria, or hypertension on previous visits presented to the OB clinic for a routine follow-up visit. On the day of the visit, her BP was 150/90 mmHg, thought to be due to anxiety, and she was admitted to the OB ward for observation. Hypertension was considered borderline and was intermittently treated by IV labetalol, but without resolution. Approximately 10 h after admission, she started to complain of diffuse headache, nausea, vomiting, and epigastric pain. The work-up was negative for other findings of preeclampsia (liver function test, proteinuria, uric acid). During the course of the admission, the BP ranged between 150/90 and 180/110 mmHg, and her headache symptoms increased. The patient's condition progressed to a sudden onset of a focal seizure on the left side, which progressed to generalized tonic–clonic seizures, and she suddenly became unresponsive. At that point, magnesium sulfate was administered (4 g loading dose over 20–30 minutes) with a maintenance dose of 1 g/h. One gram of phenytoin was administered to control the seizure. Immediate blood analysis showed the following: a drop in platelets to 116,000/μl; elevated liver function tests alanine transaminase (ALT; 866 units/L) and aspartate transaminase (AST; 971 units/L); uric acid of 6.2 mg/dl; and alkaline phosphatase of 169 mg/dl. Arterial blood gases showed a metabolic acidosis (pH = 7.1, base deficit= -14). The diagnosis of eclampsia was made and the decision to deliver the fetus by an emergency Cesarean section was determined. The airway was secured using a rapid sequence technique, and a healthy infant was delivered under general anesthesia with Apgar scores of 8 and 10 at 1 and 5 minutes, respectively. Postoperatively, the patient remained comatose, and the Glasgow Coma Scale (GCS) revealed a score of 4 (1 + 2 + 1), 1 h after the Cesarean section. Ninety minutes later, she demonstrated a decerebrate posture with non-reactive pupils (3 mm diameter). At this point, the OB team considered it to be a structural brain injury. A non-contrast computed tomography (CT) scan revealed an intracerebral hematoma [Figure 1]. Emergency neurosurgery consultation was ordered. The patient was rushed to the operating room with mannitol 1 g/kg and furosemide 20 mg IV infusion, while maintaining a mean arterial BP of 80 mmHg and a PaCO2 of 30 mmHg. Disseminated intravascular coagulopathy (DIC) was treated by administering two packed RBC units to elevate the Hg to 10 g/dl. Twenty units of platelets and 4 units of fresh frozen plasma were given to correct the coagulopathy. Right frontotemporal craniotomy was performed, with evacuation of an intracerebral hematoma and insertion of right frontal external ventricular drain. Intraoperatively, there was no evidence of an aneurysm or any tumor-like tissue. A postoperative CT scan confirmed the resolution of the ICH [Figure 2]. Pathology report indicated no malignant cells, atypia, arteriovenous malformation, or leptomeningeal disease. The magnetic resonance imaging (MRI) and MRI-angiography revealed after surgery no gross anomaly other than postoperative changes [Figure 3].\n\nFigure 1 Pre-operative CT scans of the head (a) axial view showing dissecting intraparenhymal right frontal hematoma and absence of brain sulci indicating extensive brain swelling (b) axial view showing extensive intraventricular hemorrhage, 1 cm midline shift, subarachnoid hemorrhage and brain swelling (c) axial view showing 4th ventricular hemorrhage and prominence of temporal ventricular horns indicating obstruction\n\nFigure 2 Post-operative CT scans of the head (a) axial view showing resolution of ventricular and cerebral hemorrhage, placement of right intraventricular drain and resolution of midline shift (b) axial view represents successful resolution of dissecting evacuation of right frontal intracerebral hemorrhage\n\nFigure 3 Postoperative magnetic resonance angiography demonstrating no brain aneurysm and disruption of regional blood–brain barrier at the site of hematoma\n\nIn the ICU, the intracranial pressure (ICP) was normalized to less than 10 mmHg, and supported hemodynamic and ventilatory measures were weaned off over the next couple of days. The patient opened her eyes and started responding to commands by the third postoperative day. Liver function tests and the coagulopathy normalized by postoperative day 5. Postoperatively, the pupils were increasingly reactive over the next 7 days. The GCS was 9 (1 + 3 + 5), and platelet transfusions were required to maintain the platelet count to ≥100,000/μl. The trachea was extubated on postoperative day 7. In less than 3 weeks, the patient was transferred to rehabilitation services where physical, occupational, and speech therapies were conducted for 4 weeks. In the outpatient clinic, all antihypertensive medications (angiotensin-converting-enzyme [ACE] inhibitor, calcium channel blocker, and vasodilator) were weaned off within 2 months. The patient regained all her intellectual functions, personality, and various social activities within 6 months. She was also weaned off all seizure medication, and 3 years later she was deemed to have regained a full cognitive recovery.\n\nDISCUSSION\nThis case illustrates an atypical presentation of a patient with uneventful prenatal care for the first 34 weeks, who developed a sudden onset of hypertension and rapid progression within hours to seizure and ICH. Ideally, CT scan should have been ordered and concomitant Cesarean section and craniotomy performed. However, the differential diagnosis of ICH was not in the armamentarium of the OB team at that time. The elevation of BP was considered borderline by the OB team and the seizure was underplayed early, until the patient did not awaken from anesthesia and the anesthesia team examined the pupils and decided to get a CT scan. This case is unique because the patient had a complete recovery by employing aggressive medical and surgical intervention for the ICH, despite a poor preoperative neurological status (GCS 4) and a 7-h delay of definitive diagnosis and decompression.\n\nEclampsia is the most common cause of ICH associated with pregnancy,[121332] and it is responsible for 5–12% of maternal deaths during pregnancy.[6] Contrary to what is published, our patient did not have any of the known risk factors for ICH, such as maternal age >35, African American race, tobacco dependence, substance abuse, coagulopathy, or previous preeclampsia/eclampsia.[115] However, our patient was from India, and there are some reports indicating a higher incidence of hemorrhagic stroke in Asian women compared to Caucasian patients, most commonly occurring in the prepartum stage (58%).[14]\n\nCerebrovascular malformations are evident in 20–67% of patients with pregnancy-related ICH.[112732] In our case, no underlying vascular malformation or aneurysm was found by either intraoperative surveillance or postoperative MRI. The vascular tissue structure of the brain, the changing of coagulation status during pregnancy, and the pathological state of preeclampsia-eclampsia, such as endothelial dysfunction, could have contributed in our case to the ICH.[517]\n\nTo the best of our knowledge, ICH in this case was due to the escalation in the BP, with no other preeclampsia findings and normal prenatal care. The brief BP rise led the OB team to believe that the rise of BP was related to anxiety. The sequence of events began with hypertension, followed shortly thereafter by development of severe preeclampsia, eclampsia, and ICH. A sudden increase in BP can lead to hypertensive encephalopathy in pregnant women without a history of hypertension, even with a diastolic BP around 100 mmHg. Clinical manifestations of severe headache, visual disturbances, seizure, and coma may rapidly follow.[29] Eclampsia may be seen with BPs below the range that produces encephalopathy, and there is no correlation between BP and electroencephalographic abnormalities in preeclamptic–eclamptic patients. There are no findings that suggest any direct relation between the degree of hypertension and eclamptic convulsions.[24–25]\n\nAdditional studies in patients with preeclampsia/eclampsia found a moderate decrease in cerebrovascular resistance together with increased cerebral blood flow velocities, causing cerebral hyperperfusion,[34] losses of autoregulatory mechanisms, and eclampsia with ICH. Even though there are two reports in the literature, with similar clinical presentations, our case is unique because the patient developed ICH only a couple of hours after the first recordings of elevated BP.[423] In one case, the patient had preeclampsia superimposed on chronic hypertension, where at 34 weeks of pregnancy she presented with a BP of 165/100 mmHg. She received nifedipide and magnesium sulfate to control the event.[5] The second case is a patient at 36 weeks of pregnancy with 10 days of induced hypertension and 3 days of neurological symptoms. In this case, the authors did not use magnesium sulfate, which could have had a favorable effect on hemodynamic stability.[23] Our case is a prime example supporting early initiation of therapy with magnesium sulfate. It has been proposed that magnesium sulfate may prevent vasospasm by acting as a calcium antagonist.[33] Mg2+ is a bivalent ion resembling Ca2+ and is therefore a competitive antagonist of Ca2+, having opposing effects on vascular tone.[28] Increased Ca2+ concentration has been shown to induce vasospasm in isolated cerebral arteries.[24] The effect of vasospasm is amplified by lowering the concentration of Mg2+ and is alleviated by increasing the concentration of Mg2+.[24] Hypomagnesemia causes increased cerebral vascular tension, whereas hypermagnesemia reverses vasospasm induced by hallucinogens, alcohol, serotonin, and potassium chloride.[24] The vasospasm in eclampsia is assumed to be provoked by Ca2+ ion in the pathway of smooth muscle activation, with the final result being vasoconstriction. However, there is a differential sensitivity of cerebral and systemic arteries to calcium blocking agents, consistent with the levels of free Mg2+ threefold in cerebrospinal fluid and almost double the content of Mg2+ in the walls of cerebral arteries compared with systemic arteries.[24] During ischemia, the calcium influx is through ion channels linked to the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor.[24] The increase of Mg2+ concentration can block the effects on inward current flow through these channels. It has been suggested that a large part of the magnesium sulfate effect in eclampsia may be exerted by blocking NMDA receptors, especially since their involvement in epileptiform bursting has been demonstrated.[71921] In cases like ours, the rapid increase in the BP made it difficult to realize the benefits of initiating magnesium sulfate to prevent the complications of severe preeclampsia and to reduce the rate of eclampsia. Even in cases with mild preeclampsia, due to few studies and the limited enrolment of patients, it is difficult to draw conclusions.[24]\n\nEven though there are reports of simultaneous Cesarean section and craniotomy,[3] there are cases of differed intervention because either the patient needed to be transported to the facility with a neurosurgery team[9] or, in our case, due to delayed diagnosis. However, even with a delay of diagnosis, it is never too late to do neurosurgery and achieve complete brain recovery. Previous reports support our efforts. Witlin[31] has reported six patients with ICH with delayed diagnosis from 1 to 4 days. The mortality was 66%, but remarkably one patient with ICH in the right caudate nucleus survived. In our case, young age and hormonal changes of pregnancy with increased levels of estrogens may have played a neuroprotective role. Estradiol seems to protect the cerebral tissue, at least through three different mechanisms. The first mechanism is a non-estrogen receptor (ER)-mediated effect, which reduces the level of NMDA currents and the calcium influx that might decrease cell death during ischemia.[30] The second mechanism is through estrogens’ influence on the nitric oxide synthase family to induce vasodilation and improve the blood flow to compromised brain regions.[8] The third mechanism of estrogens is the role as antioxidants inhibiting lipid peroxidation via the C3 hydroxyl group located on the phenolic A-ring of steroids.[10] These findings may be the key to understanding the excellent outcome in our patient.[1026]\n\nThis case emphasizes that even short time hypertension should be treated aggressively to prevent ICH. Even though eclampsia can cause seizures with no ICH, OB and family practitioners should be suspicious about ICH. The prompt intervention of a multidisciplinary team (obstetric, neurosurgery, and anesthesiology) is required to ameliorate the devastating effects of eclampsia and ICH.\n\nAvailable FREE in open access from: http://www.surgicalneurologyint.com/text.asp?2012/3/1/65/97167\n==== Refs\nREFERENCES\n1 Bateman BT Schumacher HC Bushnell CD Pile-Spellman J Simpson LL Sacco RL Intracerebral hemorrhage in pregnancy: Frequency, risk factors, and outcome Neurology 2006 67 424 9 16894102 \n2 Bousser MG Stroke in women: The 1997 Paul Dudley White International Lecture Circulation 1999 99 463 7 9927389 \n3 Chang L Looi-Lyons L Bartosik L Tindal S Anesthesia for cesarean section in two patients with brain tumors Can J Anesth 1999 46 61 5 10078406 \n4 Dai X Diamond JA Intracerebral hemorrhage: A life-threatening complication of hypertension during pregnancy J Clin Hypertens (Greenwich) 2007 9 897 900 17978598 \n5 Davie CA O’Brien P Stroke and pregnancy J Neurol Neurosurg Psychiatry 2008 79 240 5 17986502 \n6 Dias MS Sekhar LN Intracranial hemorrhage from aneurysms and arteriovenous malformations during pregnancy and the puerperium Neurosurgery 1990 27 855 65 2274125 \n7 Dingledine R Hynes MA King GL Involvement of N-methyl-D-aspartate receptors in epileptiform bursting in the rat hippocampal slice J Physiol 1986 380 175 89 2886653 \n8 Dubal DB Wise PM Estrogen and neuroprotection: From clinical observations to molecular mechanisms Dialogues Clin Neurosci 2002 4 149 61 22034440 \n9 Goldschlager T Steyn M Loh V Selvanathan S Vonau M Campbell S Simultaneous craniotomy and caesarean section for trauma J Trauma 2009 66 E50 1 19088560 \n10 Green PS Gordon K Simpkins JW Phenolic A ring requirement for the neuroprotective effects of steroids J Steroid Biochem Mol Biol 1997 63 229 35 9459189 \n11 Horton JC Chambers WA Lyons SL Adams RD Kjellberg RN Pregnancy and the risk of hemorrhage from cerebral arteriovenous malformations Neurosurgery 1990 27 867 71 2274126 \n12 Jaigobin C Silver FL Stroke and pregnancy Stroke 2000 31 2948 51 11108754 \n13 Kittner SJ Stern BJ Feeser BR Hebel R Nagey DA Buchholz DW Pregnancy and the risk of stroke N Engl J Med 1996 335 768 74 8703181 \n14 Klatsky AL Friedman GD Sidney S Kipp H Kubo A Armstrong MA Risk of hemorrhagic stroke in Asian American ethnic groups Neuroepidemiology 2005 25 26 31 15855802 \n15 Kurth T Kase CS Berger K Gaziano JM Cook NR Buring JE Smoking and risk of hemorrhagic stroke in women Stroke 2003 4 2792 5 14615625 \n16 Lanska DJ Kryscio RJ Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis Stroke 2000 31 1274 82 10835444 \n17 Liang CC Chang SD Lai SL Hsieh CC Chueh HY Lee TH Stroke complicating pregnancy and the puerperium Eur J Neurol 2006 13 1256 60 17038042 \n18 MacKay AP Berg CJ Atrash HK Pregnancy-related mortality from preeclampsia and eclampsia Obstet Gynecol 2001 97 533 8 11275024 \n19 Mayer ML Westbrook GL Guthrie PB Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones Nature 1984 309 261 3 6325946 \n20 Moodley J Maternal deaths associated with hypertensive disorders of pregnancy: A population-based study Hypertens Pregnancy 2004 23 247 56 15617624 \n21 Nowak L Bregestovski P Ascher P Herbet A Prochiantz A Magnesium gates glutamate-activated channels in mouse central neurones Nature 1984 307 462 5 6320006 \n22 Roberts JM Pearson G Cutler J Lindheimer M NHLBI Working Group on Research on Hypertension During Pregnancy Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy Hypertension 2003 1 437 45 12623940 \n23 Roopa S Hegde HV Torgal SV Melkundi S Sunita TH Mudaraddi RR Anesthetic management of combined emergency cesarean section and craniotomy for intracerebral hemorrhage in a patient with severe pre-eclampsia Curr Anaesth Crit Care 2010 21 292 5 \n24 Sadeh M Action of magnesium sulfate in the treatment of preeclampsia-eclampsia Stroke 1989 20 1273 5 2672428 \n25 Sibai BM Spinnato JA Watson DL Lewis JA Anderson GD Effect of magnesium sulfate on electroencephalographic findings in preeclampsia-eclampsia Obstet Gynecol 1984 64 261 6 6738959 \n26 Subbiah MT Kessel B Agrawal M Rajan R Abplanalp W Rymaszewski Z Antioxidant potential of specific estrogens on lipid peroxidation J Clin Endocrinol Metab 1993 77 1095 7 8408459 \n27 Tang CH Wu CS Lee TH Hung ST Yang CY Lee CH Preeclampsia-eclampsia and the risk of stroke among peripartum in Taiwan Stroke 2009 40 1162 8 19228854 \n28 Uchida E Bohr DF Myogenic tone in isolated perfused resistance vessels from rats Am J Physiol 1969 216 1343 50 5786720 \n29 Varon J Marik PE The diagnosis and management of hypertensive crises Chest 2000 118 214 27 10893382 \n30 Weaver CE Jr Park-Chung M Gibbs TT Farb DH 17beta-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors Brain Res 1997 761 338 41 9252035 \n31 Witlin AG Friedman SA Egerman RS Frangieh AY Sibai BM Cerebrovascular disorders complicating pregnancy - beyond eclampsia Am J Obstet Gynecol 1997 176 1139 45 discussion 1145-8 9215166 \n32 Witlin AG Mattar F Sibai BM Postpartum stroke: A twenty-year experience Am J Obstet Gynecol 2000 183 83 8 10920313 \n33 Zaret GM Possible treatment of pre-eclampsia with calcium channel blocking agents Med Hypotheses 1983 12 303 19 6366485 \n34 Zunker P Happe S Georgiadis AL Louwen F Georgiadis D Ringelstein EB Maternal cerebral hemodynamics in pregnancy-related hypertension. A prospective transcranial Doppler study Ultrasound Obstet Gynecol 2000 16 179 87 11117090\n\n",
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"keywords": "Eclampsia; intracerebral hemorrhage; pregnancy",
"medline_ta": "Surg Neurol Int",
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"title": "Complete recovery after antepartum massive intracerebral hemorrhage in an atypical case of sudden eclampsia.",
"title_normalized": "complete recovery after antepartum massive intracerebral hemorrhage in an atypical case of sudden eclampsia"
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"abstract": "Organizing pneumonia (OP) is a poorly understood complication of hematopoietic stem cell transplant (HSCT). We identified 15 patients diagnosed with OP following HSCT and described their clinical course. CT chest findings were remarkable for multifocal infiltrates that were predominantly consolidating or ground glass opacities. Bronchoalveolar lavage (BAL) was performed on 14 patients with five having lymphocytosis (> 25% lymphocytes), three with eosinophilia (> 5% eosinophils), three with neutrophilia (> 30% neutrophils), and three with normal cell counts. Flow cytometry was analyzed on BAL fluid in 13 patients with 11 having a CD4/CD8 of < 0.9. Initial treatment with 0.3-1.0 mg/kg prednisone resulted in improvement in symptoms, in radiographic findings, and in pulmonary function testing for the majority of patients. Six patients had recurrence of OP after completing treatment. Eleven patients had evidence of extra-pulmonary graft-versus-host disease prior to diagnosis of OP, and seven patients were diagnosed with an upper respiratory tract infection (URI) within 8 weeks of OP diagnosis. Most patients respond well to prednisone with significant improvement in pulmonary function, but risk of recurrence is high after cessation of steroid treatment. Risk factors for the development of OP may include prior URI.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, University of Kansas School of Medicine, Kansas City, KS, USA. kbrownback@kumc.edu.;Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA.;Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas School of Medicine, Kansas City, KS, USA.",
"authors": "Brownback|Kyle R|KR|http://orcid.org/0000-0003-4320-8023;Frey|John W|JW|;Abhyankar|Sunil|S|",
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"issue": "98(9)",
"journal": "Annals of hematology",
"keywords": "Bronchiolitis obliterans; Organizing pneumonia; Pulmonary infiltrate; Stem cell transplant",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid; D004802:Eosinophilia; D004804:Eosinophils; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D011014:Pneumonia; D012129:Respiratory Function Tests; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9107334",
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"pages": "2187-2195",
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"pubdate": "2019-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "8980962;23933758;6647749;21126596;2805873;21105791;17580252;11593314;17618318;26228813;17488669;17671231;16338616;12869516;16012315;16880372;29037300;26045243;20663943;28894914;1499702;23001801;21441964;25398933;26527676;24460438;27590103;23305044;24977681;18757459;26031713;3409736;14644923;19684637;29058699",
"title": "Bronchoscopic features, associations, and outcomes of organizing pneumonia following allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "bronchoscopic features associations and outcomes of organizing pneumonia following allogeneic hematopoietic stem cell transplantation"
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"abstract": "BACKGROUND Psoriasis is known as the most frequent disease treated by long-term topical steroids. It is also known that patients with thick, chronic plaques require the highest potency topical steroids. However, the treatment is limited to up to four weeks due to risk of systemic absorption. CASE REPORT An 80-year-old man was diagnosed with type 2 diabetes 16 years before, and was being administered insulin combined with alpha glucosidase inhibitor. He was diagnosed with plaque psoriasis and his oral steroid treatment was switched to topical steroid treatment due to lack of improvement and poorly controlled blood glucose level. The hypoglycemic events improved after the psoriatic lesions improved. CONCLUSIONS Control of blood glucose level is difficult at the very beginning of topical steroid treatment for psoriasis especially if a patient is receiving insulin treatment. Intense monitoring of blood glucose level during initiation of topical steroid treatment is necessary to prevent unfavorable complications.",
"affiliations": "Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan.;Community Medical Support Institute, Saga University Faculty of Medicine, Saga City, Saga, Japan.;Health Care Center, Fukuoka University, Fukuoka City, Fukuoka, Japan.;Health Care Center, Fukuoka University, Fukuoka City, Fukuoka, Japan.;Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan.;Community Medical Support Institute, Saga University Faculty of Medicine, Saga City, Saga, Japan.;Japan Department of Pharmacy, Saga University Hospital Pharmacy, Saga University Hospital, Saga City, Saga, Japan.;Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan.;Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan.;Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan.;Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan.;Community Medical Support Institute, Saga University Faculty of Medicine, Saga City, Saga, Japan.;Community Medical Support Institute, Saga University Faculty of Medicine, Saga City, Saga, Japan.;Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan.;Community Medical Support Institute, Saga University Faculty of Medicine, Saga City, Saga, Japan.;Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan.",
"authors": "Hongo|Yui|Y|;Ashida|Kenji|K|;Ohe|Kenji|K|;Enjoji|Munechika|M|;Yamaguchi|Miyuki|M|;Kurata|Tsuyoshi|T|;Emoto|Akiko|A|;Yamanouchi|Hiroko|H|;Takagi|Satoko|S|;Mori|Hitoe|H|;Kawata|Nozomi|N|;Hisata|Yoshio|Y|;Sakanishi|Yuta|Y|;Izumi|Kenichi|K|;Sugioka|Takashi|T|;Anzai|Keizo|K|",
"chemical_list": "D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.905470",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2912990510.12659/AJCR.905470905470ArticlesChange of Oral to Topical Corticosteroid Therapy Exacerbated Glucose Tolerance in a Patient with Plaque Psoriasis Hongo Yui ABCDEF1Ashida Kenji ABCDEFG2Ohe Kenji DEF3Enjoji Munechika DE3Yamaguchi Miyuki BCDEF1Kurata Tsuyoshi BCDEF2Emoto Akiko BCDEF4Yamanouchi Hiroko BCDEF1Takagi Satoko BCDE1Mori Hitoe BDCEF1Kawata Nozomi BCDEF1Hisata Yoshio CDEF2Sakanishi Yuta BE2Izumi Kenichi BCDEF1Sugioka Takashi BCDEF2Anzai Keizo ADEFG1\n1 Department of Internal Medicine, Saga University Hospital, Saga City, Saga, Japan\n2 Community Medical Support Institute, Saga University Faculty of Medicine, Saga City, Saga, Japan\n3 Health Care Center, Fukuoka University, Fukuoka City, Fukuoka, Japan\n4 Japan Department of Pharmacy, Saga University Hospital Pharmacy, Saga University Hospital, Saga City, Saga, JapanAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Kenji Ashida, e-mail: ashida@intmed3.med.kyushu-u.ac.jp2017 13 11 2017 18 1198 1203 24 5 2017 08 8 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 80\n\nFinal Diagnosis: Plaque psoriasis• drug induced diabetes\n\nSymptoms: Hyperglycemia• adrenocortical dysfunction\n\nMedication: Oral steroid• Topical steroid• Insulin\n\nClinical Procedure: Changing route and strength of steroid administration\n\nSpecialty: Endocrinology• Dermatology\n\nObjective:\nRare disease\n\nBackground:\nPsoriasis is known as the most frequent disease treated by long-term topical steroids. It is also known that patients with thick, chronic plaques require the highest potency topical steroids. However, the treatment is limited to up to four weeks due to risk of systemic absorption.\n\nCase Report:\nAn 80-year-old man was diagnosed with type 2 diabetes 16 years before, and was being administered insulin combined with alpha glucosidase inhibitor. He was diagnosed with plaque psoriasis and his oral steroid treatment was switched to topical steroid treatment due to lack of improvement and poorly controlled blood glucose level. The hypoglycemic events improved after the psoriatic lesions improved.\n\nConclusions:\nControl of blood glucose level is difficult at the very beginning of topical steroid treatment for psoriasis especially if a patient is receiving insulin treatment. Intense monitoring of blood glucose level during initiation of topical steroid treatment is necessary to prevent unfavorable complications.\n\nMeSH Keywords:\nAdministration, TopicalDiabetes Mellitus, Type 2Psoriasis\n==== Body\nBackground\nSystemically administered steroids increase insulin resistance [1] along with impaired insulin excretion [2], and thus are well known for causing impaired glucose tolerance as well as attenuated control of blood glucose level in type 2 diabetes mellitus. In contrast, topical administration of strong steroids, at even high doses, are thought to rarely effect blood glucose level or cause side effects found in systemic administration of steroids [3]. Here, we report a case of severe plaque psoriasis of a diabetic patient treated by topical steroids resulting in difficult control of blood glucose level. With more severe psoriatic skin lesions, stronger and higher dose topical steroids are needed, which could result in increased absorption of the steroids with side effects comparable to systemically administered steroids. In this study, we proposed that intense monitoring of blood glucose levels should be performed during the initial period of topical steroid administration in diabetic cases with severe psoriasis.\n\nCase Report\nAn 80-year-old man was admitted to the dermatology department in our hospital for itchy systemic erythema. He received daily oral administration of two tablets of betamethasone dchlorophenylamine maleic acid (0.5 mg betamethasone per tablet) from a nearby dermatologist with no improvement of his erythema. He was treated for type 2 diabetes mellitus starting at 64 years of age and his mother and two brothers were also diabetic. Recently, he was treated with lispro-insulin at 42 units per day and voglibose at 0.9 mg per day, but his hemoglobin (Hb)A1c was poorly controlled (8–9%). Insulin excretion was normal with blood C-peptide level of 1.98 mg/dL (C-peptide index 0.98) when fasting blood glucose level was 202 mg/dL. The skin lesions (Figure 1A–1C) showed erythema accumulated in a cobble-stone manner with psoriatic lesions from abdomen to extremities covering 80% of his body. Many scratches due to itchiness were also observed. Purpura was also seen on his extremities. There was no systemic inflammation. The oral steroid treatment was switched to 10 g/day of an “upper mid-strength, class 3” topical steroid, mometasone furoate [4], combined with psoralen-ultraviolet A therapy (PUVA) on the psoriatic lesions. The patient’s blood glucose level was poorly controlled and it was necessary to increase his insulin administration to a final level of 36 units of neutral protamine hagedorn (NPH) and 38 units of lispro-insulin per day. We checked the systematic effect of the topical steroid by evaluating the patient’s adrenocortical function. His early morning ACTH level was less than 2.0 pg/mL with blood cortisol level less than 1.0 μg/dL, which showed secondary central suppression of adrenocortical function by the exogenous topical steroids. The skin lesions and blood glucose control improved and the patient was discharged from the hospital with follow-up as an outpatient. However, on the second day after discharge, he found painful erosions and pus lavers on his extremities and buttocks (Figure 2A, 2B). Antibiotic treatment by oral and skin administration route did not improve the lesions and thus he was readmitted to the hospital on the seventh day after discharge. His inflammation marker CRP was 7.85 mg/dL, and the skin biopsy (Figure 2C, 2D) of the pus lavers were diagnosed as impetigo. Methicillin-sensitive Staphylococcus aureus was identified from the pus, and the skin lesions were diagnosed as staphylococcus scalded skin syndrome. After he was discharged from the hospital, he stopped using the topical steroid on his own decision. On his second admission, his HbA1c was 7.6% and fasting blood glucose level was 130 mg/dL with lower doses of lispro-insulin than first admission, despite his infection. He experienced hypoglycemia and thus insulin administration needed to be further lowered. To our surprise, re-administration of topical steroids did not affect the blood glucose level, and the psoriatic skin lesions were improved. Since the skin lesions were improved, the topical steroid was substituted with mid-strength, class 4, beclomethasone dipropionate. Topical steroid treatment was continued, and skin lesions of redness and erosion almost completely improved (Figure 2E), and discharged from the hospital. The amount of insulin per day increased from 38 to 74 units during the first period of hospitalization, and lowered to 32 units at the day of discharge during the second period of hospitalization (Figure 3). The total amount of topical steroids until the second time he left the hospital was upper mid-strength, class 3: total 245 g (mometasone furoate), mid-strength, class 4: total 115 g (beclomethasone dipropionate), and lower mid-strength, class 5: total 15 g (hydrocortisone butyrate).\n\nDiscussion\nPsoriasis is a chronic inflammatory skin disease found in 2–3% of the population in western countries [5], but around 0.1% in Japan with a tendency for males. The red scalp-like erythema can occur in local regions or occur systemically, and is known for the inflammation it causes; it has also been associated with increasing the rate of diabetes as well as evoking diabetic complications [6]. Psoriasis is frequently encountered in clinic settings when treating patients with diabetes and is often requires long-term treatment with topical steroids [7]. Topical steroids are known to be effective for treating psoriasis; its application to skin lesions that are less than 10% of the whole skin area, is up to 30 g per week, with re-evaluation of the treatment every four weeks, has been suggested to prevent desultory treatment [8]. Topical steroids are categorized by their strength of effectiveness: super potent (class 1); potent (class 2); upper mid-strength (class 3); mid-strength (class 4); low mid-strength (class 5); mild (class 6); and least potent (class 7) [9]. Different absorption efficacies of topical steroids between skin regions must also be considered during treatment [10]. While steroids are very effective, they also have associated risks of local side effects, such as irreversible striae cutis. Skin atrophy is the most frequent and important of these side effects [11]. The strength and amount of topical steroid is also related to systemic side effects. The amount of topical steroid that may trigger suppression of adrenocortical function (shown as equivalent to betamethasone amount) is as follows: 10 g of 0.05% clobetasol propionate (class 1) is equivalent to 0.5 mg of betamethasone; and 40 g of it is equivalent to 1 mg of betamethasone [12]. It is known that 2 g per day of this cream can decrease morning cortisol level in a few days [13,14]. Thus, it has been suggested that less than 50 g per week of potent steroids should be used to prevent these systemic adverse effects [15]. However, many cases show a transient suppression of adrenocortical function at the start of topical steroid treatment and rarely show clinical problems [7]. Thus, the systemic adverse effects of topical steroids need more study, especially for patients receiving insulin therapy. For the case reported here, we used a two-rank lower topical steroid for the face, and 10 g per day of an “upper mid-strength, class 3” topical steroid. This cleared the alert level of “strength and amount” of topical steroid usage, but induced suppression of adrenocortical function and exacerbation of blood glucose level. This was interesting. Despite, 10 g of 0.05% clobetasol propionate being the equivalent to 0.5 mg of betamethasone [12], the systemic adverse effect of steroid exacerbated upon switching from oral betamethasone at 0.5 mg per day to 0.05% clobetasol propionate at 10 g per day. We speculated that the barrier function of the skin was destroyed by psoriasis and peeled off by scratching due to the itchiness, leading to higher absorption rate of the topical steroid. Generally, though there are differences between regions of the skin in abortion, simple applications to the skin have uptakes of 3%–5% of steroids, with a peak in blood cortisol concentration at 12–24 hours after administration. This peak slowly declines after five additional days [10]. However, if the skin is peeled off its stratum corneum, it is known that a tremendous rate (78–90%) of steroid uptake peeks at 4–6 hours after administration [12]. The skin barrier function at psoriatic lesions in our patient’s case was possibly abrogated, inducing an increase in topical steroid absorption, evoking higher blood cortisol concentration from external steroid administration to a wider portion of the skin, resulting in exacerbated blood glucose levels as well as suppressed adrenocortical function. This was confirmed when the amount of topical steroid was lowered due to impetigo. Improvement of the skin surface by topical steroid can restore skin barrier function as well as lower the absorption rate of the topical steroid. In most cases, the suppression of adrenocortical function is restored after the effect of the topical steroid has been attenuated [7,15]. The case presented here showed rapid improvement of blood glucose control after the skin surface was improved by topical steroid on readmission to our hospital, despite the presence of infection. In such situations, one must be careful that adrenocortical function is transiently suppressed; that improvement of inflammation improves insulin resistance; that improvement of blood glucose to normal levels relieves glucose toxicity, and necessary insulin doses are rapidly reduced with increased risks of hypoglycemia and for prolonged hypoglycemia. The rapid change in psoriatic skin condition by topical steroid treatment changes steroid uptake dramatically, and thus, delicate handling is required in severe cases of psoriasis.\n\nConclusions\nWe report here a case of psoriasis where blood glucose control was exacerbated when switching steroid treatment from oral treatment to topical treatment. Topical steroids are thought to have less systemic adverse effects than oral steroids, but it must be fully recognized that each treatment type has different strengths with different absorption rates depending on the region of the skin where it is administered; the amount and range of the administered area; and the condition of the skin surface. Unlike oral steroids where absorption rates do not change, topical steroids have differential absorption rates during different phases of skin disease where the skin condition changes dramatically with concurrent dramatic changes in blood glucose levels. Thus, topical steroids need delicate handling depending on the penetration of psoriasis (condition of the skin surface) and existence of impaired control of blood glucose levels.\n\nConflict of interest\n\nNone.\n\nFigure 1. Skin lesions at first admission. (A) Back. (B) Left side of the chest. (C) Appearance of the right knee. Cobblestone-like fused erythematous macules with scales were found on the trunk and extremities. Moreover, scattered purple spots were also seen on the extremities. (D, E) Biopsy specimens from sites of skin rash on the trunk: (D) low-power field, (E) high-power field. The stratified squamous epithelial cell layer showed mild parakeratosis and enlarged epidermal projection. The liquefaction degeneration of the epithelial basal cells was very mild, and the upper dermis showed edema and infiltration of lymphocytes and neutrophils around the dilated capillaries. The erythematous macules had nonspecific findings, with no obvious atypical cells.\n\nFigure 2. Skin lesions at the time of readmission and at second discharge. (A) Left forearm. (B) Left foot. Scattered erosive lesions and pus were observed on the extremities and buttocks. (C, D) Biopsy specimens from the erosive erythematous macules with pustule crusts on the extremities were compatible with impetigo: (C) low-power field, (D) high-power field. Cystic lesions were noted between the stratified squamous intraepithelial and subepithelial layers. The surface of the cyst showed collapse and necrosis, and fibrin formation and neutrophil infiltration were observed in the cyst. Moreover, spongiosis was seen in the surrounding stratified squamous epithelial cell layer. No club-like enlargement of the epidermal projection was seen but dilated capillaries were present in the upper layer of the dermis, which may indicate pustular psoriasis. (E) Back. An obvious improvement of the redness and erosion was observed.\n\nFigure 3. Clinical course. Upon switching from oral steroid treatment to external-use steroid preparation, blood glucose control worsened and the required insulin dose increased. The required insulin dose decreased with the improvement of inflammatory changes in the skin. Eventually, the patient continued the external steroid therapy but with the same insulin dose as before the start of treatment, which led to improved blood glucose control. Open circles indicate fasting blood glucose level in the morning, if available. Gray columns indicate standard deviations of the fasting blood glucose level before breakfast, before lunch, before dinner and at 21 o’clock with averages of them as a horizontal bar.\n==== Refs\nReferences:\n1. Andrews RC Walker BR Glucocorticoids and insulin resistance: Old hormones, new targets Clin Sci (Lond) 1999 96 513 23 10209084 \n2. Delaunay F Khan A Cintra A Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids J Clin Invest 1997 100 2094 98 9329975 \n3. Bewley A Expert consensus: time for a change in the way we advise our patients to use topical corticosteroids Br J Dermatol 2008 158 917 20 18294314 \n4. WHO collaborating centre for Drug Statistics methodology ATC/DDD Index (updated Dec 19, 2016) \n5. Chen J Kuai D Zhang L Psoriasis increased the risk of diabetes: A meta-analysis Arch Dermatol Res 2012 304 119 25 22210176 \n6. Azfar RS Seminara NM Shin DB Increased risk of diabetes mellitus and likelihood of receiving diabetes mellitus treatment in patients with psoriasis Arch Dermatol 2012 148 995 1000 22710320 \n7. Castela E Archier E Devaux S Topical corticosteroids in plaque psoriasis: A systematic review of risk of adrenal axis suppression and skin atrophy J Eur Acad Dermatol Venereol 2012 26 Suppl. 3 47 51 22512680 \n8. Paul C Gallini A Archier E Evidence-based recommendations on topical treatment and phototherapy of psoriasis: Systematic review and expert opinion of a panel of dermatologists J Eur Acad Dermatol Venereol 2012 26 Suppl. 3 1 10 \n9. Tadicherla S Ross K Shenefelt PD Fenske NA Topical corticosteroids in dermatology J Drugs Dermatol 2009 8 1093 105 20027937 \n10. Feldmann RJ Maibach HI Regional variation in percutaneous penetration of 14C cortisol in man J Invest Dermatol 1967 48 181 83 6020682 \n11. Furue M Terao H Rikihisa W Clinical dose and adverse effects of topical steroids in daily management of atopic dermatitis Br J Dermatol 2003 148 128 33 12534606 \n12. Takeda K Harada T Asato T Review on systemic effects of topical corticosteroids – with special reference to adrenocortical suppression following percutaneous absorption Igaku No Ayumi 1977 101 817 29 \n13. Olsen EA Cornell RC Topical clobetasol-17-propionate: Review of its clinical efficacy and safety J Am Acad Dermatol 1986 15 246 55 3528243 \n14. Ohman EM Rogers S Meenan FO McKenna TJ Adrenal suppression following low- dose topical clobetasol propionate J R Soc Med 1987 80 422 24 3656312 \n15. Hengge UR Ruzicka T Schwartz RA Cork MJ Adverse effects of topical glucocorticosteroids J Am Acad Dermatol 2006 54 1 15 quiz 16–18 16384751\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "18()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000284:Administration, Oral; D000287:Administration, Topical; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2; D005938:Glucocorticoids; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D007328:Insulin; D008297:Male; D011565:Psoriasis",
"nlm_unique_id": "101489566",
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"pages": "1198-1203",
"pmc": null,
"pmid": "29129905",
"pubdate": "2017-11-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18294314;16384751;9329975;22210176;6020682;10209084;22512680;3656312;20027937;22710320;3528243;12534606;22512675",
"title": "Change of Oral to Topical Corticosteroid Therapy Exacerbated Glucose Tolerance in a Patient with Plaque Psoriasis.",
"title_normalized": "change of oral to topical corticosteroid therapy exacerbated glucose tolerance in a patient with plaque psoriasis"
} | [
{
"companynumb": "JP-GLENMARK PHARMACEUTICALS-2017GMK030048",
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"activesubstancename": "HYDROCORTISONE BUTYRATE"
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"abstract": "Adhesions due to previous upper abdominal surgery may complicate later liver transplantation. Here we report successful living donor liver transplantation (LDLT) in a patient with a history of total gastrectomy. A 32-year-old Japanese woman developed end-stage liver failure due to alcoholic cirrhosis. She had undergone total gastrectomy, pancreato-splenectomy, and partial colectomy due to rupture of a pancreatic cyst. LDLT was performed using a right lobe graft from her sister. To minimize blood loss and injury to the jejunum, adhesions between the left lobe and nearby organs were dissected without blood flow in or out of the liver. The right liver graft was implanted uneventfully. She was extubated on postoperative day (POD) 1, but then developed septic shock due to aspiration pneumonia on POD 2. She was reintubated and antibiotics and antifungal agents were administered. Administration of tacrolimus was changed to an intravenous route on POD 3. Her condition improved and she was re-extubated on POD 9. On POD 14, tacrolimus was administered orally. She was discharged from our hospital on POD 30 without any other events and is doing well 6 months after LDLT. We believe that careful planning, such as mobilizing the left lobe with the blood flow blocked just before liver explantation, elevating the head of the bed during tube-feeding, and calculating the area under the curve after drug administration will enable liver transplantation for patients with a history of total gastrectomy.",
"affiliations": "Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.;Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.;Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.;Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.;Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.;Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.;Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.;Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.;Department of Transplantation and Pediatric Surgery, Kumamoto University Graduate School of Medical Sciences.",
"authors": "Shimata|Keita|K|;Irie|Tomoaki|T|;Kadohisa|Masashi|M|;Kawabata|Seiichi|S|;Ibuki|Sho|S|;Narita|Yasuko|Y|;Yamamoto|Hidekazu|H|;Sugawara|Yasuhiko|Y|;Hibi|Taizo|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5582/bst.2019.01037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1881-7815",
"issue": "13(2)",
"journal": "Bioscience trends",
"keywords": "LDLT; Total gastrectomy; adhesion; aspiration pneumonia; tacrolimus",
"medline_ta": "Biosci Trends",
"mesh_terms": "D000328:Adult; D000072226:Computed Tomography Angiography; D005260:Female; D005743:Gastrectomy; D006801:Humans; D008099:Liver; D016031:Liver Transplantation; D019520:Living Donors; D011182:Postoperative Care; D000267:Tissue Adhesions",
"nlm_unique_id": "101502754",
"other_id": null,
"pages": "212-215",
"pmc": null,
"pmid": "30982792",
"pubdate": "2019-05-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Living donor liver transplantation for a patient with a history of total gastrectomy.",
"title_normalized": "living donor liver transplantation for a patient with a history of total gastrectomy"
} | [
{
"companynumb": "JP-ASTELLAS-2019JP008742",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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"activesubstancename": "TACROLIMUS"
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{
"abstract": "Pulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare® network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS.\n\n\n\nPatients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare® database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients' data were compared.\n\n\n\nA total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 ± 3.27 years old for non-DS and 2.9 ± 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution.\n\n\n\nDS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease.",
"affiliations": "Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012, Paris, France.;Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012, Paris, France.;APHP, Pediatric Pulmonology department, RespiRare, Necker Enfants Malades Hospital , 75015, Paris, France.;APHP, Pediatric Pulmonology department, RespiRare, Faculty Paris Diderot VII, Inserm U1149, Robert Debré Hospital, Paris, France.;Pediatric department, Hospital Center, Inserm U646, 72037, Le Mans, France.;Pediatric Pulmonology department, University Hospital, Rouen, France.;Pediatric Pulmonology department, University Hospital, Inserm 1078, Brest, France.;Pediatric department, University Hospital, Tours, France.;Pediatric department, University Hospital, Nancy, France.;Pediatric Pulmonology department, University Hospital, UMR CNRS 8204 - Inserm U1019, Lille, France.;Pediatric Pulmonology department, University Hospital, UMR CNRS 8204 - Inserm U1019, Lille, France.;Pediatric Pulmonology department, RespiRare, Créteil University Hospital, Inserm U955, Créteil, France.;Pediatric Pulmonology department, University Hospital, UMR CNRS 5558, Lyon, France.;Pediatric Pulmonology department, University Hospital, U1219, Bordeaux, France.;Pediatric department, Hospital Centre, Angouleme, France.;Pediatric Pulmonology department, University Hospital, Inserm U892, Angers, France.;Pediatric Pulmonology department, University Hospital, Inserm U1046, Montpellier, France.;APHP, Pediatric Pulmonology department, RespiRare, Necker Enfants Malades Hospital , 75015, Paris, France.;Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012, Paris, France.;Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012, Paris, France.;Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012, Paris, France.;Institut Jérôme Lejeune, Paris, France.;Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012, Paris, France.;Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012, Paris, France.;Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012, Paris, France. nadia.nathan@aphp.fr.",
"authors": "Alimi|Aurelia|A|;Taytard|Jessica|J|;Abou Taam|Rola|R|;Houdouin|Véronique|V|;Forgeron|Aude|A|;Lubrano Lavadera|Marc|M|;Cros|Pierrick|P|;Gibertini|Isabelle|I|;Derelle|Jocelyne|J|;Deschildre|Antoine|A|;Thumerelle|Caroline|C|;Epaud|Ralph|R|;Reix|Philippe|P|;Fayon|Michael|M|;Roullaud|Sylvie|S|;Troussier|Françoise|F|;Renoux|Marie-Catherine|MC|;de Blic|Jacques|J|;Leyronnas|Sophie|S|;Thouvenin|Guillaume|G|;Perisson|Caroline|C|;Ravel|Aimé|A|;Clement|Annick|A|;Corvol|Harriet|H|;Nathan|Nadia|N|0000-0001-5149-7975;|||",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s13023-018-0806-6",
"fulltext": "\n==== Front\nOrphanet J Rare DisOrphanet J Rare DisOrphanet Journal of Rare Diseases1750-1172BioMed Central London 80610.1186/s13023-018-0806-6ResearchPulmonary hemosiderosis in children with Down syndrome: a national experience Alimi Aurelia aurelia_alimi@yahoo.fr 1Taytard Jessica jessica.taytard@aphp.fr 1Abou Taam Rola rola.aboutaam@aphp.fr 2Houdouin Véronique veronique.houdouin@aphp.fr 3Forgeron Aude aforgeron@ch-lemans.fr 4Lubrano Lavadera Marc Marc.Lubrano@chu-rouen.fr 5Cros Pierrick pierrick.cros@chu-brest.fr 6Gibertini Isabelle I.GIBERTINI@chu-tours.fr 7Derelle Jocelyne j.derelle@chru-nancy.fr 8Deschildre Antoine antoine.deschildre@chru-lille.fr 9Thumerelle Caroline caroline.thumerelle@chru-lille.fr 9Epaud Ralph ralph.epaud@chicreteil.fr 10Reix Philippe philippe.reix@chu-lyon.fr 11Fayon Michael michael.fayon@chu-bordeaux.fr 12Roullaud Sylvie sylvie.roullaud@ch-angouleme.fr 13Troussier Françoise FrTroussier@chu-angers.fr 14Renoux Marie-Catherine mc-renoux@chu-montpellier.fr 15de Blic Jacques j.deblic@aphp.fr 2Leyronnas Sophie sophie.leyronnas@aphp.fr 1Thouvenin Guillaume guillaume.thouvenin@aphp.fr 116Perisson Caroline caroline.perisson@aphp.fr 1Ravel Aimé Aime.Ravel@institutlejeune.org 17Clement Annick 118Corvol Harriet 116http://orcid.org/0000-0001-5149-7975Nathan Nadia nadia.nathan@aphp.fr 118for the French RespiRare® group 1 0000 0004 1765 1600grid.411167.4Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France 2 0000 0004 0593 9113grid.412134.1APHP, Pediatric Pulmonology department, RespiRare, Necker Enfants Malades Hospital , 75015 Paris, France 3 0000 0004 1937 0589grid.413235.2APHP, Pediatric Pulmonology department, RespiRare, Faculty Paris Diderot VII, Inserm U1149, Robert Debré Hospital, Paris, France 4 Pediatric department, Hospital Center, Inserm U646, 72037 Le Mans, France 5 grid.41724.34Pediatric Pulmonology department, University Hospital, Rouen, France 6 0000 0004 0472 3249grid.411766.3Pediatric Pulmonology department, University Hospital, Inserm 1078, Brest, France 7 0000 0004 1765 1600grid.411167.4Pediatric department, University Hospital, Tours, France 8 0000 0004 1765 1301grid.410527.5Pediatric department, University Hospital, Nancy, France 9 0000 0004 0471 8845grid.410463.4Pediatric Pulmonology department, University Hospital, UMR CNRS 8204 - Inserm U1019, Lille, France 10 0000 0004 0386 3258grid.462410.5Pediatric Pulmonology department, RespiRare, Créteil University Hospital, Inserm U955, Créteil, France 11 Pediatric Pulmonology department, University Hospital, UMR CNRS 5558, Lyon, France 12 0000 0004 0593 7118grid.42399.35Pediatric Pulmonology department, University Hospital, U1219, Bordeaux, France 13 Pediatric department, Hospital Centre, Angouleme, France 14 0000 0004 0472 0283grid.411147.6Pediatric Pulmonology department, University Hospital, Inserm U892, Angers, France 15 0000 0000 9961 060Xgrid.157868.5Pediatric Pulmonology department, University Hospital, Inserm U1046, Montpellier, France 16 0000 0001 2308 1657grid.462844.8Sorbonne Université, Inserm UMR-S938, Paris, France 17 grid.453925.cInstitut Jérôme Lejeune, Paris, France 18 0000 0001 2308 1657grid.462844.8Sorbonne Université, Inserm UMR-S933, Paris, France 20 4 2018 20 4 2018 2018 13 602 10 2017 12 4 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare® network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS.\n\nMethods\nPatients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare® database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients’ data were compared.\n\nResults\nA total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 ± 3.27 years old for non-DS and 2.9 ± 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution.\n\nConclusions\nDS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13023-018-0806-6) contains supplementary material, which is available to authorized users.\n\nKeywords\nPulmonary hemosiderosisDown syndromeChildrenAutoimmunityInterstitial lung diseaseCeliac diseaseVasculitisPulmonary hypertensionissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPulmonary hemosiderosis is a rare lung disease characterised by the triad hemoptysis, iron deficiency anaemia, alveolar and/or interstitial opacities on lung imaging. Bronchoalveolar lavage (BAL) and/or lung biopsy ascertain the diagnosis. The BAL fluid is bloody with a hemosiderin-laden macrophage ratio above 30% and/or a Golde score higher than 50 [1]. Its frequency is poorly documented, but some authors hypothesised an incidence of 0.24–1.23 per million [2]. In children, very few cases are described worldwide. An association with celiac disease (Lane-Hamilton syndrome) and cow milk protein intolerance (Heiner syndrome) has been reported [3–6]. However, apart from the disease-specific condition, the aetiology and the pathophysiology of pulmonary hemosiderosis remain unknown. It is a chronic disease that commonly evolves in successive relapses separated by periods of remission. The prognosis is highly variable from a unique exacerbation with a complete recovery to multiple relapses with a risk of evolution toward lung fibrosis and terminal respiratory insufficiency. Corticosteroids are the mainstay of the treatment, with some children receiving also immunosuppressive drugs [7]. The French reference centre for rare lung diseases network RespiRare® previously reported a paediatric study population of 25 children aged 0.8 to 14 years old at diagnosis [8]. Two important findings were observed: 5 (20%) children presented with both pulmonary hemosiderosis and Down syndrome (DS), a percentage higher than expected; and at least one tested autoantibody was found positive in 50%. The present study aimed to investigate the newly documented relationships between pulmonary hemosiderosis and DS in the RespiRare® network.\n\nMaterials and methods\nPatients\nPrevalent patients with pulmonary hemosiderosis were retrieved from the national RespiRare® database with a query on the words pulmonary hemosiderosis, alveolar hemorrhage, siderophage, Golde score and hemoptysis. The database and data collection have been approved by French national data protection authorities (CNIL n°908,324 and CCTIRS n°08.015bis). Each patient and/or his or her legal representatives were informed prior to entering their data in the database. The charts of all the patients meeting the keywords were reviewed. Patients with a proven pulmonary hemosiderosis on BAL and/or lung biopsy between 1997 and 2017 were selected. Patients older than 20 years old at the time of the study were excluded.\n\nData\nThe following data were collected from the RespiRare® database and analysed: age at diagnosis; gender; DS status; familial history of pulmonary hemosiderosis and/or autoimmune disease; initial symptoms; biological parameters, including hemoglobin (Hb), reticulocytes, autoantibodies (antinuclear antibodies [ANA], anti-cytoplasmic antibodies [ANCA], anti-smooth muscle, anti-cyclic citrullinated peptide [CCP], anti-proteinase-3 [PR-3], anti-myeloperoxidase [MPO], anti-DNA, anti-endomysium, anti-transglutaminase, anti-SSA, anti-cardiolipin) and rheumatoid factor (RF); lung imaging results, including chest X-ray and thoracic high-resolution computed tomography (HRCT); pulmonary function tests (PFT); BAL and histological results; type and durations of treatments; and evolution of the disease with a specific attention to the presence or absence of pulmonary arterial hypertension (PAH) and relapses. Relapses were defined by the presence of a hemoptysis and/or a respiratory exacerbation (defined according to the ChiLD criteria) [9] associated with either new radiological findings compatible with an alveolar bleeding or increased anaemia or deglobulisation.\n\nStatistics\nThe data from the pulmonary hemosiderosis patients with no DS, the non-DS group, were compared to those from the patients with both pulmonary hemosiderosis and DS, the DS group. Quantitative values were reported as median and range or mean and standard deviations. Qualitative data were reported as number (percentages). Comparisons between groups were established using a non-parametric t-test. P values less than 0.05 were considered statistically significant.\n\nResults\nPopulation clinical characteristics\nA total of 42 paediatric patients were followed for pulmonary hemosiderosis in the RespiRare network. Eight patients were excluded because they were older than 20 years. The main clinical characteristics of the 34 included patients are presented in Table 1 and Additional file 1: Table S1. The age at diagnosis ranged from 3 days to 11.5 years old (Fig. 1). Among the 34 included patients, 9 (26%) presented with DS genetically confirmed (DS group); 8 had a free and homogeneous trisomy, and one patient had a partial trisomy with unbalanced translocation inherited from a balanced translocation in her mother.Table 1 Main characteristics of the patients with pulmonary hemosiderosis\n\n\tAll patients n = 34\tNon-DS group n = 25\tDS group n = 9\tP-value\t\nn (%)\tn (%)\tn (%)\t\nGirls\t22 (65%)\t18 (72%)\t4 (44%)\t0.22\t\nBoys\t12 (35%)\t7 (28%)\t5 (56%)\t0.22\t\nMean age at the diagnosis\t3.80 ± 3.30\t4.15 ± 3.27\t2.92 ± 3.45\t0.47\t\nFamily history\t\n Pulmonary hemosiderosis\t3 (9%)\t3(12%)\t0 (0%)\t0.55\t\n Autoimmune disorder\t2 (6%)\t0 (0%)\t2 (22%)\t0.06\t\nPersonal history\t\n PAH\t3 (9%)\t0 (0%)\t3 (33%)\t0.01\t\n Cardiopathy\t4 (12%)\t0 (0%)\t4 (44%)\t0.003\t\nSymptoms at presentation\t\n Hemoptysis\t16 (47%)\t14 (56%)\t2 (22%)\t0.13\t\n Cough\t10 (29%)\t8 (32%)\t2 (22%)\t0.69\t\n Dyspnoea\t23 (68%)\t15 (60%)\t9 (100%)\t0.03\t\n Pneumonia\t9 (26%)\t6 (24%)\t3 (33%)\t0.67\t\nMinimal hemoglobin\t\n < 7 g/dl\t20 (62.5%)\t14* (61%)\t6 (56%)\t1\t\n ≥ 7 g/dl\t12 (37.5%)\t9* (39%)\t3 (44%)\t1\t\nAbbreviations: DS down syndrome, PAH pulmonary arterial hypertension\n\n*missing data for 2 patients\n\nFig. 1 Age at presentation of the 34 included patients. Black bars represent the ages at presentation of the non-DS patients, and white bars represent the ages at presentation of the DS patients\n\n\n\nIn the non-DS group (n = 25), the sex ratio was in favour of girls (72%). Three patients had a familial form of the disease (one had an uncle with pulmonary hemosiderosis and 2 were siblings), 2 had a biologically confirmed cow’s milk allergy (one diagnosed at the same time as the pulmonary hemosiderosis and the other 5 years before), and one patient was also diagnosed with type B Niemann Pick disease. In this group, none of the patients presented with cardiac comorbidities.\n\nIn the DS group (n = 9), the sex ratio was in favour of boys (56%). Two had a familial history of autoimmunity without pulmonary hemosiderosis, and 4 had a congenital cardiopathy. Two had identified PAH prior to the pulmonary hemosiderosis diagnosis. The other comorbidities are listed in Additional file 1: Table S1.\n\nAt diagnosis, dyspnoea was the most frequent symptom (n = 23, 68%). Hemoptysis was documented in only 16 (47%) of the patients (Table 1). The patients of the DS group presented with a higher frequency of dyspnoea (100% in the DS group vs. 60% in the non-DS group, P = 0.04) and less hemoptysis (22% vs. 56%, respectively; P = 0.1). Cough and pneumonia were also frequently reported at diagnosis in both groups.\n\nInvestigations at diagnosis\nIn both groups, most patients presented with a severe anaemia (Hb < 7 g/dl). All the patients presented with an alveolar and interstitial pattern with a diffuse distribution of the lesions on the chest radiography and/or the HRCT scan (available for 28 [82%] patients, Fig. 2). The main abnormalities were ground-glass opacities, nodules, and alveolar condensations. Lung fibrosis was already present at the first evaluation for 2 patients (one in each group).Fig. 2 Lung imaging of two patients in the DS group (patients 1 and 2), and two in the non-DS group (patients 12 and 15). Panels a and b Chest x-ray and thoracic HRCT-scan of patient 1 at diagnosis (8 months of age) show bilateral alveolar opacities with a posterior predominance and diffuse ground glass opacities. Panels c and d Chest x-ray and thoracic HRCT-scan of patient two at 1 month of age show bilateral diffuse ground glass opacities. Panels e and f Chest x-ray and thoracic HRCT-scan of patient 12 at 4.3 years old show bilateral alveolar condensations with a patchy repartition, central and peripheral, and surrounding ground glass opacifications. Panels g and h Chest x-ray and thoracic HRCT-scan of patient 15 at 5 years old show bilateral patchy ground glass opacifications and signs of lung fibrosis with reticulations and sub-pleural cysts\n\n\n\nAll BAL were consistent with the diagnosis of pulmonary hemosiderosis, with a median of 83% of hemosiderin-laden macrophages and/or a median Golde score of 168. Four patients (all in the non-DS group) underwent an open lung biopsy with a positive Perls’ staining for all.\n\nAt diagnosis, only 13 of the 34 patients were able to perform PFT because of their young age or their general or respiratory condition. PFT were normal in 7 (54%) patients and showed a restrictive, an obstructive, or a mixed syndrome in, respectively, 2 (15%), 1 (8%), and 2 (15%) patients. Diffusion capacity of the lung for carbon monoxide (DLCO) was measured in 4 patients and was below expected values (< 75%) for 3 of them, 2 and 1 in the non-DS group and the DS group, respectively.\n\nAs previously described, a large number of the patients presented with biological signs of autoimmunity (Table 2): 24 (75%) patients had at least one positive antibody, 18 (78%) in the non-DS group and 6 (67%) in the DS group. In both groups, ANA were the most frequently observed antibodies (n = 11, 32%); the other positive antibodies were ANCA, anti-smooth muscle, RF, anti-CCP, anti-PR-3, anti-MPO, anti-DNA, anti-endomysium, anti-transglutaminase, anti-SSA and anti-cardiolipin. Their repartition between both groups is listed in Fig. 3.Table 2 Positive antibodies at diagnosis in the pulmonary hemosiderosis cohort\n\nPositive antibodies\tTotal (32 patients)*\tnon-DS group (23 patients)*\tDS group (9 patients)\tP-value\t\n\tn (%)\tn (%)\tn (%)\t\n1\t12 (34%)\t9 (39%)\t3 (33%)\t0.78\t\n2\t7 (19%)\t6 (26%)\t1 (11%)\t0.64\t\n> 2\t5 (12%)\t3 (13%)\t2 (22%)\t0.60\t\nTotal\t24 (75%)\t18 (78%)\t6 (67%)\t0.04\t\nAbbreviations:\nDS down syndrome\n\n*Missing data for 2 patients in the non-DS group\n\nFig. 3 Number of patients with positive antibodies in each group. The black bars represent the number of non-DS patients with positive antibodies and the white bars represent the number of DS patients with positive antibodies. The % in each bar is the % of patients in each group with positive antibodies. Abbreviations: DS = Down syndrome, ANCA = anti-cytoplasmic antibodies; ANA = antinuclear antibodies; CCP = anti-cyclic citrullinated peptide; PR3 = anti-proteinase 3; MPO = anti-myeloperoxidase; TG = anti-transglutaminase; DS = Down syndrome\n\n\n\nTreatment\nTreatment information was available for 32 patients. All the patients received systemic corticosteroids as first-line treatment. Monthly intravenous pulses of methylprednisolone (300 mg/m2/day for 3 days) were used for four (12%) patients, oral corticosteroids (1 to 2 mg/kg/day) for 9 (28%) patients, and both for 19 (59%) patients. A long-term treatment was necessary for the majority of them, with 30% of the patients still receiving corticosteroids after 1 year of follow-up, and 25% after 5 years. Because the three deceased patients belonged to the DS group, the duration of the corticosteroid treatment could not be compared between both groups.\n\nMore than 25% of the patients were treated with second-line therapies. A total of ten patients received hydroxychloroquine (31%): nine patients in the non-DS group and one in the DS group. Immunosuppressive drugs (mycophenolate mofetil, cyclophosphamide and/or azathioprine) were used for nine patients (28%): six (26%) in the non-DS group and three (33%) in the DS group. Beside drugs, patients with cow’s milk protein allergies were treated with an exclusion diet [10].\n\nEvolution\nThe mean length of follow-up was 4.9 [0.8–18.3] years; most of the patients (n = 25, 73.5%) were followed for more than 3 years. For 13 (40.6%) patients, pulmonary hemosiderosis occurred only as a single event, with no relapse after treatment (Table 3). Nineteen patients (59.3%) experienced at least one relapse: 13 (56.5%) patients in the non-DS group and six (67%) in the DS group (P = 0.63). Five patients, all in the DS group, presented with a PAH. The PAH pre-existed the pulmonary hemosiderosis for two and was secondary for three patients. Three of them died after multiple relapses from acute PAH and/or massive pulmonary hemorrhage at age 0.7, 2 and 7 years old, respectively. For these three patients, the pulmonary hemosiderosis was diagnosed within the first months of life.Table 3 Evolution of the patients with pulmonary hemosiderosis\n\n\tTotal (32 patients)*\tnon-DS group (23 patients)*\tDS group (9 patients)\tP-value\t\nn (%)\tn (%)\tn (%)\t\nNo relapses\t13 (40.6%)\t10 (43.4%)\t3 (33.3%)\t0.7\t\nRelapses\t19 (59.3%)\t13 (56.5%)\t6 (67%)\t0.46\t\nPulmonary arterial hypertension\t5 (14.7%)\t0\t5 (55%)\t0.0003\t\nDeath\t3 (9%)\t0\t3 (33%)\t0.0003\t\nAbbreviations:\nDS down syndrome\n\n*Missing data for 2 patients in the non-DS group\n\n\n\nDiscussion\nPulmonary hemosiderosis is a very rare disease in children, and its pathophysiology remains unclear. We report here our national experience through the RespiRare® network. This study highlights the surprising over-representation of DS in pulmonary hemosiderosis paediatric patients. DS is the most common genetic disorder, with a prevalence reaching 140 per 100,000 children [11]. Therefore, in our pulmonary hemosiderosis cohort population of 34 patients, 0 to 1 patient with DS was expected. However, nine children, i.e., around a quarter of the pulmonary hemosiderosis population, presented with DS. Pulmonary hemosiderosis in DS patients has not been reported on so far, except through isolated case reports [12, 13]. Moreover, based on our national findings, the estimated prevalence of pulmonary hemosiderosis in children reaches 1.85 per 1,000,000 children, compared to 138.5 per 1,000,000 DS children.\n\nPatients with and without DS displayed remarkable differences. In the DS group, six patients out of 9 were younger than 3 years old at diagnosis, whereas in the non-DS patients, two-thirds of the patients were older than 3 years old [8, 14–16]. Although hemoptysis is a classic sign of the disease, it was present in fewer than half of the patients, whereas dyspnoea was the most frequent respiratory symptom. DS patients seemed to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more secondary PAH and a major risk of fatal evolution.\n\nIn this study, autoimmunity stigma was documented in a large majority of the patients in both groups (75%, n = 24). The link between pulmonary hemosiderosis and the presence of circulating autoantibodies is not clearly understood in patients with no valid diagnosis criteria for vasculitis [8]. DS, particularly in men, is known to be associated with a high incidence of autoimmune disorders such as thyroiditis, hypothyroidism, type 1 diabetes, Addison disease, celiac disease, and other, rarer, disorders, including primary sclerosing cholangitis [17]. Lungs are not considered a privileged target for DS autoimmunity, but autoantibodies are frequently found in DS patients even with no evidence of clinical autoimmune disease [18]. Recent studies reported the crucial role in DS autoimmune dysfunction of the autoimmune regulator protein (AIRE) located on chromosome 21. AIRE is selectively expressed in the thymus and is a transcription factor for many tissue-restricted antigens that enhance the generation of regulatory T-cells and consecutively induce a central tolerance. It is presumed to protect against autoimmune diseases. Bi-allelic mutations of AIRE are associated with an autoimmune disease that is similar to the spectrum of autoimmunity observed in DS [19]. In DS, despite three expressed copies of AIRE, the overall AIRE expression was shown to be reduced compared to controls. All together, these findings favour a central role of AIRE in DS autoimmune disorders [20, 21]. Autoimmunity could be one of the links between DS and pulmonary hemosiderosis. In our study, several antibodies were found exclusively in DS or non-DS patients, but the majority of the patients had positive circulating antibodies, with no significant differences between groups. Surprisingly, DS patients did not receive more immunosuppressive agents than those of the non-DS group (P = 0.41). The reasons for fewer prescriptions of immunosuppressive drugs in DS patients are unclear. A hypothesis could be that clinicians were avoiding the risk of major sensitivity to chemotherapy in DS patients [22–24].\n\nAnother hypothesis to explain the association between pulmonary hemosiderosis and DS could be an altered alveolar and vascular development of the lungs. It is known that children with DS have more microscopic pulmonary malformations and present an increased risk for PAH development, independently from cardiac malformations [25]. Histological descriptions have shown elements in favour of arrested lung development such as alveolar simplification, persistence of a double capillary network, prominence of a bronchial circulation or, more recently, intrapulmonary bronchopulmonary anastomoses [26]. Lung epithelial development is closely related to signalling from the vascular compartment: an inhibition of the vascular endothelial growth factor (VEGF) induces an altered angiogenesis and an abnormal alveolar structure development in the foetus [27]. Several anti-angiogenic factors are located on chromosome 21: endostatin (COL18A1), beta-amyloid protein (APP), and regulator of calcineurin 1 (RCAN1). These factors are overexpressed during the DS foetal period due to the three copies of the genes. It has recently been shown that their up-regulation in DS lung tissues was associated with a reduced vessel density and an increase of the vessel wall thickness compared to non-DS lung tissues [28]. The in-utero capillary development of the DS foetus is consistent with the hypothesis of an altered maturation of the capillary network of the alveoli and the absence of regression of the thick arterial musculature of the pulmonary vessels [29]. This impaired vascular development could be responsible for an altered alveolar maturation with simplified large alveoli. The reduced total alveolar surface associated with an abnormal capillary network could constitute a risk factor for hypoxemia, PAH and alveolar hemorrhage.\n\nPatients with DS have additional risk factors for PAH due to chronic hypoxia and recurrent hypoxic events such as frequent congenital heart diseases, lung infections, recurrent aspirations, and obstructive sleep apnea syndrome (OSAS) [30]. OSAS is observed in up to half of adult DS patients [31]. In children, extreme prevalence between 0 and 100% has been reported in small cohorts [30, 32, 33]. Multiple factors can explain OSAS in children with DS, but the main causes include hypotonia, facial dysmorphia with macroglossia and narrow upper airways. It has also been suggested that tonsillar growth in the first months of life could increase the airway collapse [34]. Central apnoea reported in DS patients can also increase the OSAS severity. Untreated OSAS increases chronic hypoxia and, subsequently, PAH development. Altogether, in DS patients, the severity of pulmonary hemosiderosis could be due to the combination of a higher susceptibility to autoimmune lesions of the alveolar capillary, an abnormal lung capillary bed and a higher PAH risk. These pathophysiologic hypotheses could shed further new light on possible abnormal lung maturation in non-DS patients with pulmonary hemosiderosis.\n\nConclusion\nThis study reports for the first time a higher risk of severe pulmonary hemosiderosis in DS paediatric patients. Because alveolar bleeding symptoms can be inconspicuous, it could be suggested to perform a chest X-ray in all DS patients with chronic unexplained anaemia and/or chronic, unexplained dyspnoea. At this stage, only hypotheses can be proposed on the links between DS and pulmonary hemosiderosis such as an increased risk of PAH. If such a hypothesis is confirmed by further studies, systematic sleep investigations in DS patients could be proposed to screen for OSAS and to prevent PAH. For all pulmonary hemosiderosis patients, with or without DS, autoimmune explorations are critical at diagnosis and may be repeated regularly. In the era of genomic research, DS patients’ aggregation in such a rare disease could be a real opportunity to link chromosome 21 genes to new pathophysiologic clues for pulmonary hemosiderosis.\n\nAdditional file\n\nAdditional file 1: Table S1. Detailed characteristics of the 34 included patients. (DOCX 24 kb)\n\n \n\n\nAbbreviations\nAIREAutoimmune regulator protein\n\nANAAntinuclear antibodies\n\nANCAAnti-cytoplasmic antibodies\n\nAPPBeta-amyloid protein\n\nBALBronchoalveolar lavage\n\nCCPCyclic citrullinated peptide\n\nCOL18A1Gene encoding the endostatin\n\nCSCorticosteroids\n\nDLCODiffusion capacity of the lung for carbon monoxide\n\nDSDown syndrome\n\nFFemale\n\nHbHemoglobin\n\nHCQHydroxychloroquine\n\nHRCTHigh-resolution computed tomography\n\nMMale\n\nMDMissing data\n\nMMFMycophenolate mofetil\n\nMPOMyeloperoxidase\n\nOSASObstructive sleep apnea syndrome\n\nPAHPulmonary arterial hypertension\n\nPFTPulmonary function tests\n\nPR3Proteinase 3\n\nRCAN1Regulator of calcineurin 1\n\nRFRheumatoid factor\n\nTGTransglutaminase\n\nVEGFVascular endothelial growth factor\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s13023-018-0806-6) contains supplementary material, which is available to authorized users.\n\nWe thank the Assistance Publique Hôpitaux de Paris, Sorbonne Université, Paris, France, and the national networks for rare lung diseases: Centre de référence des maladies respiratoires rares (RespiRare), Centre de référence des maladies pulmonaires rares (OphaLung) and Filière de soins pour les maladies respiratoires rares (RespiFIL). We also thank the Jerôme Lejeune Institute for Down syndrome. The ILD cohort is developed in collaboration with the Rare Cohort Disease (RaDiCo)-ILD project (ANR-10-COHO-0003), the FP7-305653-child-EU project and the COST Action European network for translational research in children’s and adult interstitial lung disease (COST-ILD) project (CA16125).\n\nAvailability of data and materials\nThe data supporting the results reported in this article are extracted from the national database RespiRare and can be available under request.\n\nAuthors’ contributions\nAA and NN collected the data and wrote the manuscript. NN, JT, HC, GT, CP, SL, AC reviewed the manuscript. RAT, VH, AF, ML, PC, IG, JD, AD, CT, RE, PR, MF, FT, MCR, JdB, AR provided patients data, and reviewed the manuscript. AR provided his expertise on Down syndrome. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe database and data collection have been approved by French national data protection authorities (CNIL n°908,324 and CCTIRS n°08.015bis). Each patient and/or his or her legal representatives were informed prior to entering their data in the database.\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. Drew WL Finley TN Golde DW Diagnostic lavage and occult pulmonary hemorrhage in thrombocytopenic immunocompromised patients Am Rev Respir Dis 1977 116 2 215 221 889174 \n2. Bakalli I Kota L Sala D Idiopathic pulmonary hemosiderosis - a diagnostic challenge Ital J Pediatr 2014 40 35 10.1186/1824-7288-40-35 24708654 \n3. Khemiri M Ouederni M Khaldi F Barsaoui S Screening for celiac disease in idiopathic pulmonary hemosiderosis Gastroenterol Clin Biol 2008 32 8–9 745 748 10.1016/j.gcb.2008.05.010 18603390 \n4. Lane DJ Hamilton WS Idiopathic steatorrhoea and idiopathic pulmonary haemosiderosis Br Med J 1971 2 5753 89 90 10.1136/bmj.2.5753.89 5551274 \n5. Moissidis I Chaidaroon D Vichyanond P Bahna SL Milk-induced pulmonary disease in infants (Heiner syndrome) Pediatr Allergy Immunol 2005 16 6 545 552 10.1111/j.1399-3038.2005.00291.x 16176405 \n6. Heiner DC Respiratory diseases and food allergy Ann Allergy 1984 53 6 Pt 2 657 664 6239577 \n7. Chin CIC Kohn SL Keens TG Margetis MF Kato RM A physician survey reveals differences in management of idiopathic pulmonary hemosiderosis Orphanet J Rare Dis 2015 10 98 10.1186/s13023-015-0319-5 26289251 \n8. Taytard J Nathan N de BJ New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare(®) cohort Orphanet J Rare Dis 2013 8 161 10.1186/1750-1172-8-161 24125570 \n9. Clement A de BJ Epaud R Management of children with interstitial lung diseases: the difficult issue of acute exacerbations Eur Respir J 2016 48 6 1559 1563 10.1183/13993003.01900-2016 27903688 \n10. Sethi GR Singhal KK Puri AS Mantan M Benefit of gluten-free diet in idiopathic pulmonary hemosiderosis in association with celiac disease Pediatr Pulmonol 2011 46 3 302 305 10.1002/ppul.21357 20967850 \n11. Mégarbané A Ravel A Mircher C The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and treatment of Down syndrome Genet Med 2009 11 9 611 616 10.1097/GIM.0b013e3181b2e34c 19636252 \n12. Tenenbaum A Malkiel S Wexler ID Levy-Khademi F Revel-Vilk S Stepensky P Anemia in children with Down syndrome Int J Pediatr 2011 2011 813541 10.1155/2011/813541 21941570 \n13. Watanabe H Ayusawa M Kato M Idiopathic pulmonary hemosiderosis complicated by Down syndrome Pediatr Int Off J Jpn Pediatr Soc 2015 57 5 1009 1012 10.1111/ped.12690 \n14. Mourad AA Parekh H Bahna SL A 17-month-old patient with severe anemia and respiratory distress Allergy Asthma Proc 2015 36 6 506 511 10.2500/aap.2015.36.3888 26534758 \n15. Kabra SK Bhargava S Lodha R Satyavani A Walia M Idiopathic pulmonary hemosiderosis: clinical profile and follow up of 26 children Indian Pediatr 2007 44 5 333 338 17536132 \n16. Nuesslein TG Teig N Rieger CH Pulmonary haemosiderosis in infants and children Paediatr Respir Rev 2006 7 1 45 48 10.1016/j.prrv.2005.11.003 16473816 \n17. Bull MJ Committee on genetics. Health supervision for children with Down syndrome Pediatrics 2011 128 2 393 406 10.1542/peds.2011-1605 21788214 \n18. Nisihara RM Skare TL Silva MBG High positivity of anti-CCP antibodies in patients with Down syndrome Clin Rheumatol 2007 26 12 2031 2035 10.1007/s10067-007-0606-1 17387532 \n19. Mathis D Benoist C Aire Annu Rev Immunol 2009 27 287 312 10.1146/annurev.immunol.25.022106.141532 19302042 \n20. Skogberg G Lundberg V Lindgren S Altered expression of autoimmune regulator in infant Down syndrome thymus, a possible contributor to an autoimmune phenotype J Immunol Baltim Md 1950 2014 193 5 2187 2195 \n21. Giménez-Barcons M Casteràs A Armengol M del P Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens J Immunol Baltim Md 1950 2014 193 8 3872 3879 \n22. Meyr F Escherich G Mann G Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome Br J Haematol 2013 162 1 98 106 10.1111/bjh.12348 23594030 \n23. Peeters M Poon A Down syndrome and leukemia: unusual clinical aspects and unexpected methotrexate sensitivity Eur J Pediatr 1987 146 4 416 422 10.1007/BF00444952 2958283 \n24. Taub JW Ge Y Down syndrome, drug metabolism and chromosome 21 Pediatr Blood Cancer 2005 44 1 33 39 10.1002/pbc.20092 15390307 \n25. Saji T Clinical characteristics of pulmonary arterial hypertension associated with Down syndrome Pediatr Int Off J Jpn Pediatr Soc 2014 56 3 297 303 10.1111/ped.12349 \n26. Bush D Abman SH Galambos C Prominent intrapulmonary bronchopulmonary anastomoses and abnormal lung development in infants and children with Down syndrome J Pediatr 2017 180 156 162.e1 10.1016/j.jpeds.2016.08.063 27666181 \n27. Le Cras TD Markham NE Tuder RM Voelkel NF Abman SH Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure Am J Physiol Lung Cell Mol Physiol 2002 283 3 L555 L562 10.1152/ajplung.00408.2001 12169575 \n28. Reynolds LE Watson AR Baker M Tumour angiogenesis is reduced in the Tc1 mouse model of Down’s syndrome Nature 2010 465 7299 813 817 10.1038/nature09106 20535211 \n29. Galambos C Minic AD Bush D Increased lung expression of anti-Angiogenic factors in Down syndrome: potential role in abnormal lung vascular growth and the risk for pulmonary hypertension PLoS One 2016 11 8 e0159005 10.1371/journal.pone.0159005 27487163 \n30. Konstantinopoulou S Tapia IE Kim JY Relationship between obstructive sleep apnea cardiac complications and sleepiness in children with Down syndrome Sleep Med 2016 17 18 24 10.1016/j.sleep.2015.09.014 26847969 \n31. Hill EA Obstructive sleep apnoea/hypopnoea syndrome in adults with Down syndrome Breathe Sheff Engl 2016 12 4 e91 e96 10.1183/20734735.012116 \n32. Levanon A Tarasiuk A Tal A Sleep characteristics in children with Down syndrome J Pediatr 1999 134 6 755 760 10.1016/S0022-3476(99)70293-3 10356146 \n33. Dyken ME Lin-Dyken DC Poulton S Zimmerman MB Sedars E Prospective polysomnographic analysis of obstructive sleep apnea in Down syndrome Arch Pediatr Adolesc Med 2003 157 7 655 660 10.1001/archpedi.157.7.655 12860786 \n34. Hill CM Evans HJ Elphick H Prevalence and predictors of obstructive sleep apnoea in young children with Down syndrome Sleep Med 2016 27–28 99 106 10.1016/j.sleep.2016.10.001 27938928\n\n",
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"abstract": "Recently, as the number of case reports of IgG4-related kidney disease (IgG4-RKD) has increased, the histopathological features and clinical approach have been clarified. IgG4-RKD generally has a benign prognosis due to the efficacy of steroid therapy and rarely requires dialysis. Herein, we report a case of IgG4-RKD that presented with a subacute onset, advanced to end-stage kidney disease, and finally required maintenance hemodialysis despite steroid therapy. A 75-year-old man was admitted to our hospital for further evaluation of subacute renal failure. Diffuse enlargement of the kidney on computed tomography and increased urinary N-acetyl-β-D-glucosaminidase and α1-microglobulin levels led us to suspect IgG4-RKD. Upon admission, the laboratory serological findings were as follows: creatinine 3.3 mg/dL, urea nitrogen 46.9 mg/dL, and IgG4 235 mg/dL. Urinalysis showed slight proteinuria without hematuria. Percutaneous renal needle biopsy showed diffuse infiltration of abundant lymphocytes and IgG4-positive plasma cells and storiform fibrosis, which is specific to IgG4-RKD, in the interstitium on light microscopy. Slight linear deposition of C3 was also observed in the tubules on immunofluorescence microscopy, with no electron-dense deposits. He was definitively diagnosed as having IgG4-RKD and started on prednisolone 0.6 mg/kg/day. However, the renal insufficiency continued to progress and hemodialysis was necessary. As the prednisolone was tapered, renal function did not improve and maintenance hemodialysis was started. In conclusion, this case indicates that the prognosis of IgG4-RKD is not necessarily benign and that further studies involving more patients are needed.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Juntendo Shizuoka Hospital, Izunokuni, Japan.;Division of Nephrology, Department of Internal Medicine, Juntendo Shizuoka Hospital, Izunokuni, Japan.;Division of Nephrology, Department of Internal Medicine, Juntendo Shizuoka Hospital, Izunokuni, Japan.;Division of Nephrology, Department of Internal Medicine, Juntendo Shizuoka Hospital, Izunokuni, Japan.;Division of Nephrology, Department of Internal Medicine, Juntendo Shizuoka Hospital, Izunokuni, Japan.;Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.;Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.",
"authors": "Wakabayashi|Keiichi|K|;Yanagawa|Hiroyuki|H|;Hayashi|Yoko|Y|;Aoyama|Rumi|R|;Shimizu|Yoshio|Y|;Tomino|Yasuhiko|Y|;Suzuki|Yusuke|Y|",
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"fulltext": "\n==== Front\nCase Rep Nephrol DialCase Rep Nephrol DialCNDCase Reports in Nephrology and Dialysis2296-9705S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com 10.1159/000496465cnd-0009-0001Case ReportProgressive Renal Dysfunction due to IgG4-Related Kidney Disease Refractory to Steroid Therapy: A Case Report Wakabayashi Keiichi aYanagawa Hiroyuki aHayashi Yoko aAoyama Rumi aShimizu Yoshio ac*Tomino Yasuhiko bSuzuki Yusuke b1Division of Nephrology, Department of Internal Medicine, Juntendo Shizuoka Hospital, Izunokuni, Japan2Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan3Shizuoka Medical Research Center for Disaster, Juntendo University, Izunokuni, Japan*Yoshio Shimizu, MD, Division of Nephrology, Department of Internal Medicine, Juntendo Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2211 (Japan), E-Mail yosimizu@juntendo.ac.jpJan-Apr 2019 8 2 2019 8 2 2019 9 1 1 7 10 9 2018 9 12 2018 2019 Copyright © 2019 by S. Karger AG, Basel2019This 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.Recently, as the number of case reports of IgG4-related kidney disease (IgG4-RKD) has increased, the histopathological features and clinical approach have been clarified. IgG4-RKD generally has a benign prognosis due to the efficacy of steroid therapy and rarely requires dialysis. Herein, we report a case of IgG4-RKD that presented with a subacute onset, advanced to end-stage kidney disease, and finally required maintenance hemodialysis despite steroid therapy. A 75-year-old man was admitted to our hospital for further evaluation of subacute renal failure. Diffuse enlargement of the kidney on computed tomography and increased urinary N-acetyl-β-D-glucosaminidase and α1-microglobulin levels led us to suspect IgG4-RKD. Upon admission, the laboratory serological findings were as follows: creatinine 3.3 mg/dL, urea nitrogen 46.9 mg/dL, and IgG4 235 mg/dL. Urinalysis showed slight proteinuria without hematuria. Percutaneous renal needle biopsy showed diffuse infiltration of abundant lymphocytes and IgG4-positive plasma cells and storiform fibrosis, which is specific to IgG4-RKD, in the interstitium on light microscopy. Slight linear deposition of C3 was also observed in the tubules on immunofluorescence microscopy, with no electron-dense deposits. He was definitively diagnosed as having IgG4-RKD and started on prednisolone 0.6 mg/kg/day. However, the renal insufficiency continued to progress and hemodialysis was necessary. As the prednisolone was tapered, renal function did not improve and maintenance hemodialysis was started. In conclusion, this case indicates that the prognosis of IgG4-RKD is not necessarily benign and that further studies involving more patients are needed.\n\nKeywords\nIgG4-related kidney diseaseSteroid therapyProgressive renal dysfunction\n==== Body\nIntroduction\nIgG4-related disease (IgG4-RD) is a systemic inflammatory disorder defined by the combined presence of a characteristic histopathological appearance (i.e., abundant infiltration of plasma cells with IgG4), interstitial fibrosis in the involved organs, i.e., the pancreas, gallbladder, salivary glands, retroperitoneum, lungs, prostate and kidney, and elevated serum levels of IgG4 [1].\n\nThe most common feature of the renal involvement in IgG4-RD is tubulointerstitial nephritis with abundant IgG4-positive plasma cells and storiform fibrosis, which are findings specific to IgG4-RD, in the interstitium. However, some cases with glomerular injury, i.e., membranous glomerulonephritis, IgA nephropathy, and membranoproliferative glomerulonephritis, have also been described [2]. Consequently, while increasing levels of N-acetyl-β-D-glucosaminidase (NAG) and α1-microglobulin (α1-MG) are the main findings of IgG4-related kidney disease (IgG4-RKD) on urinalysis, slight proteinuria and microhematuria may also appear. Computed tomography (CT) is the most recommended radiographic imaging method for IgG4-RKD. However, the use of contrast medium requires careful judgment in patients with impaired renal function. Diffuse enlargement of the kidney on noncontrast CT and multiple low-density lesions on enhanced CT are the most common findings. A hypovascular solitary nodule in the kidney and diffuse thickening of the renal pelvis wall are rarely observed on CT, and it is necessary to distinguish these findings from malignant tumors [2]. Moreover, IgG4-RKD an often be accompanied by autoimmune pancreatitis (AIP) and Mikulicz disease. However, several cases without these diseases have also been reported [2]. As such, the clinical course of IgG4-RKD is varied and it is sometimes difficult to diagnose.\n\nIgG4-RKD is thought to be responsive to steroid therapy, similar to AIP [1]. Saeki et al. [3] reported that decreased renal function, hypocomplementemia, or abnormal renal radiologic findings improved rapidly 1 month after the start of steroid therapy in 18 of 19 patients with IgG4-RKD. Moreover, maintenance therapy with low-dose prednisolone is recommended to prevent relapse [1].\n\nIgG4-RKD generally has a benign prognosis due to its responsiveness to steroid therapy and rarely requires dialysis. Recently, while the number of case reports associated with IgG4-RKD has been increasing and the histopathological feature and clinical approach have been clarified, it remains controversial. Herein, we report a case of IgG4-RKD who presented with subacute onset, advanced to end-stage kidney disease, and finally required maintenance hemodialysis despite the administration of glucocorticoid therapy.\n\nCase Report\nA 75-year-old man was admitted to our hospital for further evaluation of subacute renal failure. He had no past history associated with bronchial asthma or drug administration and no other medical problems, history of smoking, habitual drinking, or family history of renal disease. Upon admission, his body weight was 51.0 kg, height was 171.0 cm (body mass index 17.4), temperature was 36.8°C, and blood pressure was 125/74 mm Hg. The lymph nodes were not palpable, and there were no signs of leg edema. The peripheral white blood cell count was 4,600/mm3, with 3,450 neutrophils/mm3 and 92 eosinophils/mm3; the hematocrit was 27.1′; the red blood cell count was 2,710,000/mm3, hemoglobin was 8.9 g/dL, and the platelet count was 156,000/mm3. Laboratory serological findings were as follows: total protein 7.5 g/dL, albumin 4.4 g/dL, creatinine 3.3 mg/dL, urea nitrogen 46.9 mg/dL, and C-reactive protein 0.6 mg/dL. The serum IgG and IgG4 levels were 1,614.0 and 235.0 mg/dL, respectively. Serum protein electrophoresis showed no signs of gammopathy. Slight hypocomplementemia in C4 (C3 83 mg/dL, C4 21.7 mg/dL, CH50 49 U/mL) was also observed. Antinuclear and antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibody, SS-A and SS-B antibodies, as well as cryoglobulin were all negative. Serum angiotensin-converting enzyme, soluble interleukin-2 receptor, and tumor marker levels were within normal limits. Urinalysis showed proteinuria of 0.9 g/day without hematuria and increasing levels of NAG (22.8 IU/L) and α1-MG (85 mg/L). Whole-body CT and magnetic resonance imaging showed no pleural effusion, ascites, lymph node swelling, or enlargement of organs, except for diffuse enlargement of the kidneys (Fig. 1). The longest diameter of the kidneys was > 12 cm. A whole-body gallium scan showed no abnormal accumulation.\n\nPercutaneous renal needle biopsy showed diffuse infiltration of abundant lymphocytes and IgG4-positive plasma cells and storiform fibrosis, which is specific to IgG4-RKD, in the interstitium on light microscopy. There were no signs of injury of the glomeruli or basement membrane. No crescent forms were observed in glomeruli. Slight linear deposition of C3 was observed in the tubules on immunofluorescence microscopy, and no electron-dense deposits were observed (Fig. 2a, b). Immunohistochemically, IgG4-positive plasma cells were markedly observed in the interstitium (> 10 IgG4-positive plasma cells/high-power field), and the ratio of IgG4-positive plasma cells to IgG-positive plasma cells was > 90′ (Fig. 2c, d).\n\nThe diagnosis of IgG4-RKD was reached based upon the above-described findings, and the patient was started on prednisolone at a dose of 0.6 mg/kg/day (30 mg/day). Serum IgG4 and creatinine levels and urinary α1-MG level improved temporarily; however, renal insufficiency continued to advance as the prednisolone was tapered. It became necessary to decrease the dose of the steroid after the onset of severe steroid psychosis. He lost his appetite and became malnourished, and we abandoned the additional therapy because of the risk of infection. The renal function did not improve and maintenance dialysis was initiated. Serum creatinine as well as urinary NAG and α1-MG levels became exacerbated as the prednisolone was tapered. However, the serum IgG4 level continued to decline. Moreover, the diffuse enlargement of kidneys, which was detected by CT, did not improve from the initiation of steroid therapy to the initiation of hemodialysis.\n\nDiscussion and Conclusion\nHerein, we report a rare case of IgG4-RKD, which was limited to the kidneys and exhibited severe tubulointerstitial nephritis and required maintenance hemodialysis despite steroid therapy. This case exhibited increasing serum levels of IgG4 and a slight decrease in complement, diffuse enlargement of the kidneys on CT, storiform fibrosis and diffuse infiltration of abundant lymphocytes, and IgG4-positive plasma cells in the interstitium, in the absence of glomerulonephritis. While serum IgG4 levels tended to decrease after steroid therapy, serum levels of creatinine and markers of tubular damage became exacerbated and the kidney enlargement persisted. There have been a few reports describing cases of IgG4-RKD that required maintenance hemodialysis. Saida et al. [4] reported a Japanese case of IgG4-RKD who required maintenance dialysis despite steroid therapy. In that report, IgG4-RKD developed after withdrawal of steroid therapy for AIP. The authors concluded that the reasons for the relapse were the rapid discontinuation of steroid without maintenance therapy, the high serum creatinine level at onset, and the coexistence of membranous nephropathy.\n\nIn general, IgG4-RKD has a benign prognosis due to its responsiveness to steroid therapy, similar to AIP and Mikulicz disease [5, 6, 7]. According to the therapeutic plan for AIP in Japan, it is recommended to initiate treatment with prednisolone at 0.6 mg/kg/day and to taper the dose every several weeks to 2.5–10 mg/day as a maintenance dose. However, no consensus exists on the term for maintenance therapy. As with the recommended treatment course, prednisolone was initiated at 0.6 mg/kg/day and tapered every 4 weeks in the present case; however, this approach was not effective. Moreover, the prednisolone had to be discontinued rapidly due to the development of uremia during the tapering process.\n\nSaeki et al. [5] reported that early treatment for IgG4-RKD is important because steroid therapy had elicited rapid, but not complete, improvement of renal function in patients with an estimated glomerular filtration rate < 60 mL/min before therapy. The estimated glomerular filtration rate in the present case was 12.6 mL/min, which could be one of the reasons that the steroid therapy was insufficient. Kawano et al. [2] reported 41 cases of IgG4-RKD and described their characteristics. In that report, serum IgG levels were > 1,800 mg/dL in more than 90′ and > 3,000 mg/dL in more than 50′ of all patients. Moreover, the authors reported that only 2 cases exhibited IgG4-RD limited to the kidney and that it was common for IgG4-RD to develop simultaneously at three to four organs. In the present case, the serum IgG level was within normal limits and increased slowly, which could have delayed disease detection.\n\nMizushima et al. [8] reported that the findings of kidney enlargement on CT improved after steroid therapy. In this case, steroid therapy was ineffective and the enlargement of the kidney did not improve after the steroid therapy. Consequently, there was the potential to change the treatment to intravenous steroid pulse therapy or to increase the oral dose. Aoki et al. [9] reported a case of Mikulicz disease that was complicated by severe interstitial nephritis associated with IgG4 and successfully treated by methylprednisolone semipulse therapy. Moreover, some reports have shown that steroid pulse therapy is effective for the prevention of relapse in AIP patients [10] and that steroid pulse therapy is effective in reducing the maintenance dose in biliary stenosis caused by AIP [11].\n\nWith the exception of steroids, immunosuppressive agents are rarely used because steroids exhibit good efficacy against IgG4-RKD; thus, the efficacy and safety of immunosuppressives have not yet been established. However, there have been several reports using immunosuppressive agents in some refractory cases, recurrent cases, and a case of IgG4-RKD complicated by membranous glomerulonephritis. McMahon et al. [12] described the efficacy of rituximab as a steroid-sparing option for refractory IgG4-tubulointerstitial nephritis. Alexander et al. [13] stated that membranous glomerulonephritis should be included in the spectrum of IgG4-RD and should be suspected in proteinuric IgG4-RD patients. They further reported that mycophenolate mofetil and cyclophosphamide were effective in such patients. Moreover, several agents such as azathioprine, mycophenolate mofetil, and methotrexate have been attempted as steroid-sparing agents or maintenance drugs in some reports, but their effects were controversial because there were no clinical trials [11].\n\nIn conclusion, the clinical course of IgG4-RKD varies widely and it can sometimes be difficult to diagnosis. In particular, there are no reports on a case of rapidly progressive IgG4-RKD. Intravenous steroid pulse therapy and an increasing dose of oral steroid as well as other immunosuppressive agents should be considered in cases of rapidly progressing renal failure and pathologically severe cases, as the present case, as well as steroid-refractory and recurrent cases. This case indicates that the prognosis of IgG4-RKD is not necessarily benign and that further studies involving more patients are needed.\n\nStatement of Ethics\nThe authors have no ethical conflicts to declare.\n\nDisclosure Statement\nThe authors declare no conflict of interest. No funding was received for this case report.\n\nAcknowledgment\nThe authors are indebted to the nephrologists and patients at Juntendo Shizuoka Hospital for their collaboration in this study.\n\nFig. 1 Computed tomography kidney findings at onset. Diffuse enlargement of the kidneys was observed. The longest diameter of the kidneys was > 12 cm.\n\nFig. 2 Renal biopsy findings. a Normal glomeruli and storiform fibrosis, which is specific to IgG4-related kidney disease, were observed in the interstitium on light microscopy (Azan staining, ×100). b Diffuse infiltration of abundant mononuclear cells and plasma cells (marked by arrows) was observed in the interstitium (hematoxylin and eosin staining, ×200). c, d The immunohistochemical findings of IgG4 (c) and IgG (d) are shown. IgG4-positive plasma cells were markedly observed in the interstitium (> 10 IgG4-positive plasma cells/high-power field), and the ratio between IgG4-positive and IgG-positive plasma cells (marked by arrows) was > 90′. e Slight linear deposition of C3 was observed in the tubules on immunofluorescence microscopy.\n==== Refs\nReferences\n1 Stone JH Zen Y Deshpande V IgG4-related disease N Engl J Med 2012 2 366 (6) 539 51 22316447 \n2 Kawano M Saeki T Nakashima H Nishi S Yamaguchi Y Hisano S Proposal for diagnostic criteria for IgG4-related kidney disease Clin Exp Nephrol 2011 10 15 (5) 615 26 21898030 \n3 Saeki T Nishi S Imai N Ito T Yamazaki H Kawano M Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis Kidney Int 2010 11 78 (10) 1016 23 20720530 \n4 Saida Y Homma N Hama H Ueno M Imai N Nishi S [Case of IgG4-related tubulointerstitial nephritis showing the progression of renal dysfunction after a cure for autoimmune pancreatitis] Nihon Jinzo Gakkai Shi 2010 52 (1) 73 9 20166545 \n5 Saeki T Kawano M Mizushima I Yamamoto M Wada Y Nakashima H The clinical course of patients with IgG4-related kidney disease Kidney Int 2013 10 84 (4) 826 33 23698232 \n6 Raissian Y Nasr SH Larsen CP Colvin RB Smyrk TC Takahashi N Diagnosis of IgG4-related tubulointerstitial nephritis J Am Soc Nephrol 2011 7 22 (7) 1343 52 21719792 \n7 Deshpande V Zen Y Chan JK Yi EE Sato Y Yoshino T Consensus statement on the pathology of IgG4-related disease Mod Pathol 2012 9 25 (9) 1181 92 22596100 \n8 Mizushima I Yamada K Fujii H Inoue D Umehara H Yamagishi M Clinical and histological changes associated with corticosteroid therapy in IgG4-related tubulointerstitial nephritis Mod Rheumatol 2012 11 22 (6) 859 70 22262474 \n9 Aoki A Sato K Itabashi M Takei T Yoshida T Arai J A case of Mikulicz's disease complicated with severe interstitial nephritis associated with IgG4 Clin Exp Nephrol 2009 8 13 (4) 367 72 19142575 \n10 Sugimoto M Takagi T Suzuki R Konno N Watanabe K Nakamura J Efficacy of Steroid Pulse Therapy for Autoimmune Pancreatitis Type 1: A Retrospective Study PLoS One 2015 9 10 (9) e0138604 26381760 \n11 Matsushita M Yamashina M Ikeura T Shimatani M Uchida K Takaoka M Effective steroid pulse therapy for the biliary stenosis caused by autoimmune pancreatitis Am J Gastroenterol 2007 1 102 (1) 220 1 17278279 \n12 McMahon BA Novick T Scheel PJ Bagnasco S Atta MG Rituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis: Case Report and Review of the Literature Medicine (Baltimore) 2015 8 94 (32) e1366 26266393 \n13 Alexander MP Larsen CP Gibson IW Nasr SH Sethi S Fidler ME Membranous glomerulonephritis is a manifestation of IgG4-related disease Kidney Int 2013 3 83 (3) 455 62 23254897\n\n",
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"keywords": "IgG4-related kidney disease; Progressive renal dysfunction; Steroid therapy",
"medline_ta": "Case Rep Nephrol Dial",
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"title": "Progressive Renal Dysfunction due to IgG4-Related Kidney Disease Refractory to Steroid Therapy: A Case Report.",
"title_normalized": "progressive renal dysfunction due to igg4 related kidney disease refractory to steroid therapy a case report"
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"abstract": "Spinal subarachnoid hemorrhage is a life-threatening condition often associated with markedly high morbidity and mortality rates. However, diagnosis is difficult because of its atypical symptoms. We herein describe a 52-year-old Chinese man who had been receiving warfarin therapy since having undergone mechanical mitral valve replacement surgery 3 years previously. Two days before admission to our hospital, he suddenly developed low back pain, urinary incontinence, and paraplegia. He was diagnosed with acute myelitis at a local hospital, but he subsequently developed a slight headache and was transferred to our hospital 2 days later. The patient was suspected to have subarachnoid hemorrhage based on his computed tomography (CT) findings. On the third day after admission, a CT scan showed both subarachnoid and cerebral hemorrhage. Blood tests revealed an international normalized ratio ranging from 1.44 to 1.86 and a prothrombin time of 16.5 to 21.3 s. We performed a lumbar puncture and obtained bloody cerebrospinal fluid. The patient also underwent spinal CT and angiography, which confirmed the diagnosis of spontaneous spinal subarachnoid hemorrhage. Because his general condition was poor, he underwent conservative treatment, and his neurologic function slightly improved after discharge.",
"affiliations": "Department of Neurology, The First Hospital of Changsha, Changsha, China.;Department of Neurology, The First Hospital of Changsha, Changsha, China.;Department of Neurology, The First Hospital of Changsha, Changsha, China.",
"authors": "Li|Miao|M|https://orcid.org/0000-0001-5936-128X;Liu|Qingfang|Q|;Tang|Hongyu|H|",
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"fulltext": "\n==== Front\nJ Int Med Res\nJ Int Med Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n10.1177/0300060520961683\n10.1177_0300060520961683\nCase Report\nDelayed diagnosis of spinal subarachnoid hemorrhage in association with warfarin administration: a case report and literature review\nhttps://orcid.org/0000-0001-5936-128XLi Miao Liu Qingfang Tang Hongyu Department of Neurology, The First Hospital of Changsha, Changsha, China\nMiao Li, Department of Neurology, The First Hospital of Changsha, 311 Yingpan Road, Kaifu District, Changsha, Hunan Province 410005, P. R. China. Email: limiao666888@126.com\n12 10 2020 \n10 2020 \n48 10 030006052096168326 5 2020 4 9 2020 © The Author(s) 20202020SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Spinal subarachnoid hemorrhage is a life-threatening condition often associated with markedly high morbidity and mortality rates. However, diagnosis is difficult because of its atypical symptoms. We herein describe a 52-year-old Chinese man who had been receiving warfarin therapy since having undergone mechanical mitral valve replacement surgery 3 years previously. Two days before admission to our hospital, he suddenly developed low back pain, urinary incontinence, and paraplegia. He was diagnosed with acute myelitis at a local hospital, but he subsequently developed a slight headache and was transferred to our hospital 2 days later. The patient was suspected to have subarachnoid hemorrhage based on his computed tomography (CT) findings. On the third day after admission, a CT scan showed both subarachnoid and cerebral hemorrhage. Blood tests revealed an international normalized ratio ranging from 1.44 to 1.86 and a prothrombin time of 16.5 to 21.3 s. We performed a lumbar puncture and obtained bloody cerebrospinal fluid. The patient also underwent spinal CT and angiography, which confirmed the diagnosis of spontaneous spinal subarachnoid hemorrhage. Because his general condition was poor, he underwent conservative treatment, and his neurologic function slightly improved after discharge.\n\nMisdiagnosisspinal subarachnoid hemorrhagewarfarininternational normalized ratioprothrombin timeneurologic functiontypesetterts2\n==== Body\nIntroduction\nSpinal subarachnoid hemorrhage (SSH) is uncommon, occurring in <1% of all patients with subarachnoid hemorrhage (SAH).1,2 The causes of SSH include trauma (often by lumbar puncture), vascular lesions (arteriovenous malformation or fistula, aneurysm), coagulopathy, systemic lupus erythematosus, coarctation of the aorta, and Behçet’s disease.3–5 However, hemorrhage in association with anticoagulant therapy is rarely seen. Warfarin is one of the most frequently used anticoagulants to prevent atrial fibrillation as well as venous and arterial thromboembolism.6 Taking precautions against thromboembolism secondary to mechanical valve replacement is especially important when treating patients with rheumatic heart disease.7,8 Patients who have undergone implantation of a mechanical valve prosthesis are committed to lifelong anticoagulant therapy with warfarin.9 However, highly variable dose-related problems exist among patients undergoing warfarin treatment.7 We herein describe a patient who was initially misdiagnosed with acute myelitis and was subsequently confirmed to have spontaneous SSH based on his clinical symptoms and results of lumbar puncture, spinal angiography, and brain and spinal computed tomography (CT).\n\nCase report\nA 52-year-old Chinese man was admitted to the Department of Neurology at The First Hospital of Changsha on 1 August 2019. He had been continuously taking warfarin at a dosage of 3.125 mg/day since having undergone mechanical mitral valve replacement surgery 3 years previously. His most recent international normalized ratio (INR) had been measured 1 week before presentation, and the result was 2.2. Two days before admission, the patient suddenly developed low back pain with no obvious cause followed by nausea and vomiting. He was diagnosed with acute myelitis at a local hospital. The next morning, the patient developed a lack of bilateral leg strength, numbness spreading across his feet and chest, urinary incontinence, and a fever of 38.44°C. At the time of admission to our hospital, a CT scan showed no brain abnormalities. A urinary catheter was inserted, and the patient was transferred to the Department of Neurology at our hospital for further examination and diagnosis.\n\nUpon admission, the patient was conscious and alert with a good sense of direction. His back pain had become less severe than that experienced during the occurrence of paraplegia and numbness; however, he developed a mild headache. Physical examination showed flaccid paraparesis in both legs and an obviously rigid neck. His cranial nerves remained intact. Based on the patient’s history and neurological test results, we performed a lumbar puncture on the day of admission. The cerebrospinal fluid (CSF) was bloody at all three puncture sites; therefore, we concluded that the attempts had been unsuccessful because of puncture injury. The patient underwent a spinal CT scan, which revealed degenerative change in the lumbar spine and a Schmorl node at T9 (Figure 1(a)–(c)). However, no cauda equina or nerve root compression was observed. An urgent brain CT scan showed no abnormalities. Because the patient had a history of mechanical valve replacement surgery, magnetic resonance imaging was contraindicated. Examination of the peripheral blood showed that the INR was 1.95 and that the prothrombin time (PT) was 1.96 s. On the second day, the patient’s brain CT results suggested SAH (Figure 1(d)). We performed another lumbar puncture, and bloody CSF was retrieved again in three test tubes, thus confirming SSH (Figure 3(a)). On the third day, the patient experienced more frequent headaches, and the back of his neck grew increasingly more painful. A second brain CT scan showed a high-density area in the left posterior occipital region that was compatible with SAH (Figure 1(e)). Repeated blood tests revealed a PT of 21.3 s and INR of 1.86.\n\nFigure 1. Computed tomography (CT) findings. (a–c) Spinal CT showed no hemorrhage but revealed degenerative changes in the lumbar region and a Schmorl node of T9. (d) Brain CT results suggested subarachnoid hemorrhage (SAH). (e) A second brain CT examination revealed hyperdense areas in the left posterior occipital region compatible with SAH. (f) Follow-up brain CT conducted 12 days later no longer showed the previously detected hyperdense areas and SAH.\n\nIn view of the negative spinal CT results, we performed spinal angiography. Still, no arteriovenous malformation or other vascular abnormalities were found (Figure 2(a)–(e)). Considering the patient’s medical history and clinical manifestations, we temporarily stopped his anticoagulation treatment and administered vitamin K to reverse the anticoagulation, aminocaproic acid to induce hemostasis, and nimodipine to prevent vasospasm; we also performed CSF replacement. Continuous lumbar punctures produced fluid containing hemorrhage and yellow pigmentation (Figure 3(b)). The high-density area in the left posterior occipital region and the SAH markers were negative after 12 days of follow-up (Figure 1(f)). Therefore, the patient restarted his warfarin treatment at 1.25 mg/day. At this time point, his PT and INR were 16.5 s and 1.44, respectively. Three days later, we adjusted his warfarin dosage to 2.5 mg/day. Another 2 days later, the patient developed nasal hemorrhage with a PT of 17.3 s and INR of 1.52. Nasal endoscopy examination revealed chronic rhinitis with no other abnormalities. Therefore, we adjusted the warfarin dosage to 1.875 mg/day. Neither nasal bleeding nor cerebral or spinal hemorrhage occurred thereafter.\n\nFigure 2. Spinal angiography demonstrated no evidence of an arteriovenous malformation or other vascular abnormality.\n\nFigure 3. Lumbar puncture results. (a) Lumbar puncture yielded bloody cerebrospinal fluid and positivity on a three-tube test. (b) Two sequential lumbar puncture tests revealed hemorrhage and xanthochromia.\n\nThe SSH in this case was presumed to have developed as a result of the oral anticoagulant therapy based on the rise in the PT and INR. Therefore, the dosage was altered accordingly. Because the patient’s general condition was relatively weak and continuous anticoagulation treatment is more effective than sporadic treatment, we performed no surgical treatments. The patient was finally discharged 32 days after admission. Some functional improvements were observed after discharge; he became able to move himself with a standing turner and the assistance of another person instead of entirely depending on others.\n\nDiscussion\nSSH rarely occurs, accounting for <1% of all cases of SAH.10,11 It may be caused by trauma, arteriovenous malformation, arteriovenous fistulas, aneurysms, tumors, vasculitis (systemic lupus erythematosus, Behçet’s disease), bleeding diatheses, or anticoagulant therapy.10 However, the etiology of SSH is not entirely clear. It is generally believed that minor trauma can increase the intrathoracic, intraluminal, and intra-abdominal pressure among spinal vessels, especially the valveless radiculomedullary veins traversing the subarachnoid space, resulting in torn vessels.2,10 Lumbar puncture with CSF replacement can relieve symptoms of SAH. Defibrination caused by spinal cord pulsation can reduce the possibility of a subarachnoid hematoma. If bleeding becomes chronic; however, the CSF mechanism will fail to neutralize this force, resulting in potential clotting. Therefore, close attention to the use of anticoagulant drugs is required.\n\nAnticoagulant therapy is often complicated by hemorrhage.8 Our patient developed spontaneous SSH accompanied by cranial and nasal hemorrhage while receiving warfarin therapy, although his INR and PT were normal. Therefore, he required monitoring with coagulation studies to minimize the chance of complications during anticoagulant therapy as well as adjustments to his warfarin dosage.12 Insufficient or excessive use of anticoagulants can be life-threatening, and the risk of thromboembolism and bleeding depends largely on anticoagulation therapy. Both the British Society for Haematology and the American College of Chest Physicians suggest that the INR range for most warfarin indications is 2 to 3.13 In practice, however, it is challenging to keep the INR within that range.14,15 Ming and Klein16 reported that only 44% of patients achieved a satisfactory INR. The anticoagulation effect of warfarin is subject to individual variability, leading to possible hemorrhage or thrombosis despite careful dosage adjustments.8 Yuan7 reported that Chinese patients generally need a lower warfarin dose than Caucasians. You et al.14 conducted a retrospective study in Hong Kong showing that the best INR range was 1.8 to 2.4 in a group of Chinese patients; this range was associated with the lowest incidence of bleeding or thromboembolism.\n\nTypical symptoms of SSH include sudden back pain, severe headache, quadriplegia, paraplegia, numbness, sensory change, and urinary or fecal incontinence. The clinical manifestations are markedly diverse among different individuals. Physical examination generally shows different degrees of defects in motor, sensory, and sphincter functions that are correlated with the degree of pathological changes. Therefore, it is difficult for doctors to make a correct judgment in the beginning of the patient’s clinical course, leading to misdiagnosis as reported in the present case. Our patient developed no severe headache attacks and showed normal brain CT findings, and he was misdiagnosed with acute myelitis at a local hospital. Even with advanced neuroimaging techniques, the diagnosis of SSH is often challenging.3 Magnetic resonance imaging is an essential method with which to identify SSH because it can show the size and extension of the hemorrhage and its relationship with the spinal cord.8 However, the role of CT in the diagnosis of SSH is limited. As described in the present case, only spinal and head CT can be performed for patients who have undergone mechanical valve replacement surgery. No positive results were found in either examination, leading to difficulty observing the hemorrhagic lesion. If the presence of a vascular pathology is considered during the diagnostic procedures, selective spinal angiography should be performed to exclude an arteriovenous malformation or aneurysm. Similarly, acquisition of bloody CSF by lumbar puncture may help the clinician to diagnose SSH. However, SSH may exhibit more bleeding than SAH; the CSF may be bloodlike and considered to be a puncture injury, which will affect the diagnosis. In the present case, the first CSF examination revealed “bloody” fluid, but we considered this to be a consequence of puncture injury. Cihangiroglu et al.12 reported that the majority of SSH cases were diagnosed based on surgical or autopsy findings. Therefore, SSH should not be missed in patients with acute paraplegia, especially those with severe back pain and headache. When lumbar puncture shows “bloody” CSF, it should not be mistaken for puncture injury when performing subsequent punctures.\n\nMost researchers advocate treating SSH by emergency surgery.17 Such treatment can reduce compression, restore the free flow of CSF, and reduce mortality. Patient recovery after the operation depends on the nerve condition and onset time. In a literature review by Kreppel et al.,18 patients who received treatment within 12 hours after disease onset showed the highest recovery rate (65.9%), while patients who received treatment within 13 hours to 1 week after disease onset showed a recovery rate of only 29%. Surgical treatment is not suitable for patients with a relatively weak general condition. The postoperative recovery effect is reportedly poor in patients with complete paraplegia.19,20 In the present case, the patient was diagnosed with spontaneous SSH, and because he had been taking warfarin, surgery may have been associated with significant risks. Therefore, we chose conservative treatment for him.\n\nConclusion\nIn the present case, a patient with acute paraplegia accompanied by severe back pain and headache and whose lumbar puncture showed “bloody” CSF was easily considered to have sustained a puncture injury; he was misdiagnosed with acute myelitis, delaying the treatment of SSH. Patients who have undergone mechanical valve replacement require long-term oral anticoagulation therapy with warfarin. Even if their INR is lower than the standard of 2 to 3, they are at risk of bleeding and SSH.\n\nEthics statement\nWe have concealed the patient’s details in this pathological report to ensure that his identity is not revealed in any way. Thus, neither ethics committee nor institutional review committee approval was required. The patient described in this report provided oral informed consent.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iD\nMiao Li https://orcid.org/0000-0001-5936-128X\n==== Refs\nReferences\n1 Kappler SB Davis JE. \nAn uncommon cause of acute back pain: spinal subarachnoid hemorrhage progressing to spinal cord compression\n. J Emerg Med . 2014 ; \n48 : 432 –435\n.\n2 Oji Y Noda K Tokugawa J , et al\nSpontaneous spinal subarachnoid hemorrhage after severe coughing: a case report\n. J Med Case Rep . 2013 ; \n7 : 274 .24365331 \n3 Sato K Roccatagliata L Depuydt S , et al\nMultiple aneurysms of thoracic spinal cord arteries presenting with spinal infarction and subarachnoid hemorrhage: case report and literature review.\n\nNeurosurgery . 2012 ; \n71 : E1053 .23086108 \n4 Govindarajan R Salgado E. \nSpinal subarachnoid hemorrhage mimicking a carotid artery dissection\n. Neurosurgery . 2011 ; \n69 : E787 –E788\n.21623243 \n5 Chung J Park IS Hwang S-H , et al\nAcute spontaneous spinal subdural hematoma with vague symptoms.\n\nJ Korean Neurosurg Soc . 2014 ; \n56 : 269 .25368774 \n6 Bruce-Brand RA Colleran GC Broderick JM , et al\nAcute nontraumatic spinal intradural hematoma in a patient on warfarin.\n\nJ Emerg Med . 2013 ; \n45 : 695 –697\n.23988138 \n7 Yuan H.-Y. \nA novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity\n. Hum Mol Genet . 2005 ; \n14 : 1745 –1751\n.15888487 \n8 Krynetskiy E McDonnell P. \nBuilding individualized medicine: prevention of adverse reactions to warfarin therapy.\n\nJ Pharmacol Exp Ther . 2007 ; \n322 : 427 –434\n.17496169 \n9 Wang MS Lang X Cui S , et al\nClinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality after rheumatic valve replacement: a randomized and controlled trial\n. Int J Med Sci . 2012 ; \n9 : 472 –479\n.22927772 \n10 Kakitsubata Y Theodorou SJ Theodorou DJ , et al\nSpontaneous spinal subarachnoid hemorrhage associated with subdural hematoma at different spinal levels.\n\nEmerg Radiol . 2010 ; \n17 : 69 –72\n.19184145 \n11 Fatehi F Basiri K Ghorbani A. \nSpinal subarachnoid hemorrhage accompanied with intraventricular hemorrhage\n. J Res Med Sci . 2013 ; \n18 (Suppl 1 ): S86 –S88\n.23961296 \n12 Cihangiroglu M Bulut S Nayak S. \nSpinal subarachnoid hemorrhage complicating oral anticoagulant therapy\n. Eur J Radiol . 2001 ; \n39 : 176 –179\n.11566245 \n13 Lam MPS Cheung BMY. \nThe pharmacogenetics of the response to warfarin in Chinese\n. Br J Clin Pharmacol . 2011 ; \n73 : 340 –347\n.\n14 You JHS Chan FWH Wong RSM , et al\nIs INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation?\n\nBr J Clin Pharmacol . 2005 ; \n59 : 582 –587\n.15842557 \n15 Zhao L Chen C Li B , et al\nVerification of pharmacogenetics-based warfarin dosing algorithms in Han-Chinese patients undertaking mechanic heart valve replacement\n. Plos One . 2014 ; \n9 : e94573 .24728385 \n16 Ming TML Klein TE. \nPharmacogenetics of warfarin: challenges and opportunities.\n\nJ Hum Genet . 2013 ; \n58 : 334 –338\n.23657428 \n17 Moyer TP Kane DJ Baudhuin LM , et al\nWarfarin sensitivity genotyping: a review of the literature and summary of patient experience.\n\nMayo Clin Proce . 2009 ; \n84 : 1079 –1094\n.\n18 Kreppel D Antoniadis G Seeling W. \nSpinal hematoma: a literature survey with meta-analysis of 613 patients.\n\nNeurosurgery Rev . 2003 ; \n26 : 1 –49\n.\n19 Brilstra EH Rinkel GJ Algra A , et al\nRebleeding, secondary ischemia, and timing of operation in patients with subarachnoid hemorrhage.\n\nNeurology , 2000 ; \n55 : 1656 .11113219 \n20 Oz O Akgun H Yücel M , et al\nCerebral venous thrombosis presenting with subarachnoid hemorrhage after spinal anesthesia\n. Acta Neurologica Belgica . 2011 ; \n111 : 237 –240\n.22141292\n\n",
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"issue": "48(10)",
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"keywords": "Misdiagnosis; international normalized ratio; neurologic function; prothrombin time; spinal subarachnoid hemorrhage; warfarin",
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"mesh_terms": "D057210:Delayed Diagnosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D013129:Spinal Puncture; D013131:Spine; D013345:Subarachnoid Hemorrhage; D014859:Warfarin",
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"title": "Delayed diagnosis of spinal subarachnoid hemorrhage in association with warfarin administration: a case report and literature review.",
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"abstract": "Methotrexate is a widely used disease-modifying anti-rheumatic drug. Its effectiveness has been proven in placebo-controlled trials and in comparison with other disease-modifying anti-rheumatic drugs. The pharmacokinetics of methotrexate are highly variable and unpredictable. In patients with normal renal function, the recommended dose in rheumatoid arthritis ranges between 7.5 and 15 mg/week, but in recent years, even dosages up to 25 mg weekly are used. Toxicity includes myelosuppression, gastrointestinal adverse effects, hepatotoxicity and pneumonitis. Renal impairment and age are considered major risk factors for developing methotrexate toxicity, but studies show conflicting results. Whether methotrexate can be administered to patients with end-stage kidney disease has not been formally tested. The present case illustrates the severe side effects of low-dose methotrexate treatment in a patient with end-stage kidney disease. Seven other cases have reported similar and even more severe and irreversible consequences after low-dose regimen. In view of these side effects we strongly recommend to monitor toxicity rigorously in patients with stage 3 or stage 4 kidney disease and not to use methotrexate in patients with stage 5 kidney disease.",
"affiliations": "Department of Nephrology, University Hospital AZ-VULB, Laarbeeklaan 101, B-1090 Brussels, Belgium. olivier.boey@az.vub.ac.be",
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"abstract": "Background Lenvatinib treatment has shown a significant improvement in progression-free survival in patients with metastatic, progressive, radioiodine-refractory differentiated thyroid cancer, although its use is associated with considerable toxicity. Fatigue is one of the most frequent adverse events (AEs). It has been reported that adrenal insufficiency (AI) may be involved in lenvatinib-related fatigue. In our study, we assessed the pituitary/adrenal axis before and during treatment, and the possible involvement of AI in lenvatinib-related fatigue. This was done to clarify the incidence, development, and time course of AI during lenvatinib treatment. Methods We studied 13 patients who were selected for lenvatinib therapy. Adrenal function was evaluated by measuring cortisol and adrenocorticotropic hormone (ACTH) levels and through the ACTH (250 μg) stimulation test. Results During treatment, seven patients (54%) developed AI. High levels of ACTH were observed in accordance with the diagnosis of primary AI (PAI). By evaluating the first ACTH test, before starting lenvatinib treatment, we found that patients with <646,6 nmol/L cortisol peak had an increased risk of developing PAI during lenvatinib treatment. Fatigue was observed in 11 patients (84,6%) during lenvatinib treatment. Cortisone acetate treatment induced an improvement in fatigue in six of seven patients (85,7%) in the PAI group, without the need to change the lenvatinib dosage. Conclusions PAI may be considered one of the most common AEs associated with lenvatinib. Our data strongly suggest that PAI could be involved in lenvatinib-associated fatigue, particularly in patients with extreme fatigue. In this context, early diagnosis of PAI is essential, especially since glucocorticoid replacement therapy can induce a significant improvement in fatigue, without the need to reduce the dosage of lenvatinib. However, further studies are required to confirm these preliminary findings.",
"affiliations": "Azienda Ospedaliero-Universitaria Sant'Andrea Roma, Endocrinology Unit, via di Grottarossa 1039, Rome, Rome, Italy, 00189; montisg@yahoo.it.;Azienda ospedaliero-universitaria Sant'Andrea, Roma, Roma, Roma (RM), Italy; fpresciuttini90@gmail.com.;Azienda Ospedaliera Universitaria Sant'Andrea, Endocrinology Unit, Rome, Rome, Italy; mariagraziadeiana@hotmail.it.;Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Endocrinology Unit, Roma, Italy; dott.cecilia.motta@gmail.com.;Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Roma, Italy; fedramori@gmail.com.;Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Roma, Italy; valerio.renzelli@gmail.com.;Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Roma, Italy; antonio.stigliano@uniroma1.it.;Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Roma, Italy; vin.toscano@icloud.com.;Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Roma, Italy; giuseppe.pugliese@uniroma1.it.;Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Rome, Italy.",
"authors": "Monti|Salvatore|S|;Presciuttini|Federica|F|;Deiana|Maria Grazia|MG|;Motta|Cecilia|C|;Mori|Fedra|F|;Renzelli|Valerio|V|;Stigliano|Antonio|A|;Toscano|Vincenzo|V|;Pugliese|Giuseppe|G|;Poggi|Maurizio|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/thy.2021.0040",
"fulltext": "\n==== Front\nThyroid\nThyroid\nthy\nThyroid\n1050-7256\n1557-9077\nMary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA\n\n34663079\n10.1089/thy.2021.0040\n10.1089/thy.2021.0040\nThyroid Cancer and Nodules\nCortisol Deficiency in Lenvatinib Treatment of Thyroid Cancer: An Underestimated Common Adverse Event\nMONTI ET AL.\nADRENAL INSUFFICIENCY IN LENVATINIB TREATMENT\nMonti Salvatore *\nPresciuttini Federica *\nDeiana Maria Grazia\nMotta Cecilia\nMori Fedra\nRenzelli Valerio\nStigliano Antonio\nToscano Vincenzo\nPugliese Giuseppe\nPoggi Maurizio\nEndocrinology and Diabetes Unit, Azienda Ospedaliero-Universitaria Sant'Andrea, “Sapienza” University, Rome, Italy.\n* Both these authors should be considered joint first authors.\n\nAddress correspondence to: Salvatore Monti, MD, PhD, Endocrinology and Diabetes Unit, Azienda Ospedaliero-Universitaria Sant'Andrea, “Sapienza” University, via di Grottarossa 1035/1039, I-00189 Rome, Italy salvatore.monti@uniroma1.it\n01 1 2022 January 2022\n17 1 2022\n17 1 2022\n32 1 4653\n© Salvatore Monti et al., 2022; Published by Mary Ann Liebert, Inc.\n2022\nSalvatore Monti et al.\nhttps://creativecommons.org/licenses/by/4.0/ This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBackground: Lenvatinib treatment has shown a significant improvement in progression-free survival in patients with metastatic, progressive, radioiodine-refractory differentiated thyroid cancer, although its use is associated with considerable toxicity. Fatigue is one of the most frequent adverse events (AEs). It has been reported that adrenal insufficiency (AI) may be involved in lenvatinib-related fatigue. In our study, we assessed the pituitary/adrenal axis before and during treatment, and the possible involvement of AI in lenvatinib-related fatigue. This was done to clarify the incidence, development, and time course of AI during lenvatinib treatment.\n\nMethods: We studied 13 patients who were selected for lenvatinib therapy. Adrenal function was evaluated by measuring cortisol and adrenocorticotropic hormone (ACTH) levels and through the ACTH (250 μg) stimulation test.\n\nResults: During treatment, seven patients (54%) developed AI. High levels of ACTH were observed in accordance with the diagnosis of primary AI (PAI). By evaluating the first ACTH test, before starting lenvatinib treatment, we found that patients with <646.6 nmol/L cortisol peak had an increased risk of developing PAI during lenvatinib treatment. Fatigue was observed in 11 patients (84.6%) during lenvatinib treatment. Cortisone acetate treatment induced an improvement in fatigue in six of seven patients (85.7%) in the PAI group, without the need to change the lenvatinib dosage.\n\nConclusions: PAI may be considered one of the most common AEs associated with lenvatinib. Our data strongly suggest that PAI could be involved in lenvatinib-associated fatigue, particularly in patients with extreme fatigue. In this context, early diagnosis of PAI is essential, especially since glucocorticoid replacement therapy can induce a significant improvement in fatigue, without the need to reduce the dosage of lenvatinib. However, further studies are required to confirm these preliminary findings.\n\nfatigue\nlenvatinib\nprimary adrenal insufficiency\nthyroid cancer\n==== Body\npmcIntroduction\n\nLenvatinib is an oral, multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC) (1,2). In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, the median progression-free survival was 18.3 months using lenvatinib, and 3.6 months using placebo (3). However, adverse events (AEs) occurred in almost all patients (97.3%) treated with lenvatinib (3).\n\nAlthough supportive care may be an option for managing AEs, according to the severity of AEs, lenvatinib must be discontinued, interrupted, or administered at a reduced dosage (3), which decreases treatment efficacy. Fatigue is one of the most frequent AEs that lead to discontinuation of lenvatinib treatment.\n\nIn 2017, at our Endocrine Center, a patient with lenvatinib-related fatigue developed primary adrenal insufficiency (PAI); cortisone acetate (CA) therapy improved fatigue in the patient (unpublished observation). In 2019, Colombo et al. demonstrated PAI in four of the seven patients affected by RR-DTC during treatment with lenvatinib; CA relieved fatigue in them (4).\n\nPAI is a severe and potentially life-threatening condition (5–7). The majority of PAI symptoms are nonspecific, and diagnosis is frequently delayed (6). The simultaneous presence of undiagnosed PAI in patients with RR-DTC may have a strongly negative impact on the morbidity and mortality of patients treated with lenvatinib.\n\nWe evaluated the pituitary/adrenal axis before and during treatment to clarify the incidence, development, and time course of PAI during lenvatinib treatment. In addition, the possible impact of PAI on lenvatinib-related fatigue was evaluated.\n\nMaterials and Methods\n\nWe analyzed consecutive patients with RR-DTC who started lenvatinib treatment between June 2017 and November 2019 at our Endocrine Center. All patients showed progression according to RECIST 1.1 criteria (8). Eligible patients received no prior therapy with TKIs.\n\nPatients with a history of adrenal disease, adrenal metastases, nephrotic syndrome, and liver disease, or who had been or were being treated with steroids or any drug known to interfere with steroid hormone secretion and metabolism were considered noneligible.\n\nWe only included patients treated with lenvatinib for at least 6 months. Performance status was evaluated for each patient using the Eastern Cooperative Oncology Group (ECOG).\n\nAEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (9), and lenvatinib was discontinued, interrupted, or reduced according to the severity of AEs.\n\nAs this is a retrospective analysis of de-identified data collected as part of the routine clinical procedure, ethical review and approval was not required, but written informed consent was obtained from all patients. The study was conducted in accordance with the provisions of the Declaration of Helsinki, local legislation, and institutional requirements.\n\nAll patients were evaluated before and after starting lenvatinib treatment by performing medical history, physical examination, laboratory analysis, and hormonal evaluation. Patients underwent clinical examinations weekly for the first month, and monthly thereafter. Laboratory analysis was scheduled every month. Adrenal function was evaluated before and during lenvatinib treatment every 3 months by measuring cortisol and adrenocorticotropic hormone (ACTH) levels and using the ACTH (cosyntropin; 250 μg) stimulation test. Peak cortisol levels below 500 nmol/L, after ACTH injection, at 30 or 60 minutes, indicate adrenal insufficiency (AI), according to the most recent recommendations (5).\n\nIn patients with AI, CA was started at a dosage of 25–37.5 mg/day, according to the weight and clinical conditions (5). In all these patients, the ACTH-test was repeated after 3 months and, in patients with sufficient follow-up, after 6–9 months, after stopping CA for 48 hours.\n\nAll hormones were analyzed using a chemiluminescence immunoassay. The sensitivity of the assays was 1.13 pg/mL for ACTH and 0.5 nmol/L for cortisol; the intra-assay and interassay coefficients of variations were 4.9% and 8.9% for ACTH and 4.3% and 5.5% for cortisol (LIASON XL Analyzer). Normal values were 4.7–48.8 pg/mL for ACTH and 101–536 nmol/L for cortisol.\n\nStatistical analyses\n\nA descriptive analysis of all the sample parameters was carried out. The normality of the distribution of our continuous quantitative variables was demonstrated through the Shapiro–Wilk test and confirmed with the Kolmogorov–Smirnov and D'Agostino and Pearson tests. Continuous quantitative variables were reported as mean and standard deviation (SD). The qualitative variables were presented as absolute frequencies and percentages.\n\nStatistical differences between the two groups of continuous variables were assessed using paired or unpaired Student t test, when appropriate. The comparison of frequencies between the groups of qualitative variables was analyzed using the chi-square or Fisher test, when appropriate. The correlation between different variables was determined using the Spearman test. The cortisol peak performance after the ACTH test was evaluated using receiver operating characteristic (ROC) curve analysis and the most accurate cutoff calculated with sensitivity and specificity. Statistical significance was set at p < 0.05, and all tests were two sided. All statistical analyses were performed using GraphPad Prism 8 (Graph Pad Software, Inc.).\n\nResults\n\nFrom June 2017 to November 2019, 23 patients with progressive RR-DTC started lenvatinib. Ten patients were excluded from our study (five had a follow-up of less than 6 months; five were taking glucocorticoids for problems related to RR-DTC).\n\nThe characteristics of 13 patients enrolled are reported in Tables 1 and 2.\n\nTable 1. Clinical and Pathological Features of the Patients Treated with Lenvatinib\n\nPatient No., Sex\tTumor histotype, variant\tMetastasis\tECOG status\tAge at lenvatinib, start (years)\tLenvatinib starting dose (mg)\tFollow-up (months)\tPAI (yes/no)\tPAI diagnosis after lenvatinib started (months)\tAEs (Grade)a\t\n1, F\tPTC, classic\tLung, neck\t0\t63\t14\t6\tNo\t/\tHypertension (2), proteinuria (1), fatigue (2), palmar plantar erythrodysesthesia syndrome (1), arthralgia/myalgia (1)\t\n2, M\tHurthle cell\tLymph nodes, lung\t0\t44\t24\t28\tNo\t/\tHypertension (1), proteinuria (1)\t\n3, F\tPTC, solid\tLymph nodes, lung\t0\t40\t24\t9\tNo\t/\tHypertension (1), proteinuria (1), diarrhea (2)\t\n4, M\tFTC\tLung, neck, bone\t0\t77\t20\t6\tYes\t3\tHypertension (2), proteinuria (1), fatigue (2), diarrhea (2), stomatitis (1), palmar plantar erythrodysesthesia syndrome (1), dysphonia (1)\t\n5, M\tFTC\tLymph nodes, lung\t1\t79\t24\t29\tNo\t/\tHypertension (2), proteinuria (1), fatigue (3), diarrhea (2), weight loss (3) stomatitis (1), nausea/vomiting (1)\t\n6, F\tPTC, classic\tLung, bone\t1\t75\t14\t24\tYes\t3\tHypertension (2), proteinuria (2), fatigue (3), weight loss (2), stomatitis (1), nausea/vomiting (1), dysphonia (1)\t\n7, F\tPTC, classic\tLymph nodes, lung\t1\t82\t10\t6\tNo\t/\tHypertension (1), fatigue (1), diarrhea (1), weight loss (1), stomatitis (1)\t\n8, F\tPTC, tall cell\tLymph nodes, lung\t0\t67\t24\t15\tYes\t3\tHypertension (2), fatigue (2), stomatitis (2), palmar plantar erythrodysesthesia syndrome (3)\t\n9, M\tPTC, tall cell\tBone, neck\t0\t73\t24\t15\tYes\t9\tHypertension (2), fatigue (3), diarrhea (2), weight loss (2), stomatitis (1), palmar plantar erythrodysesthesia syndrome (1)\t\n10, F\tPTC, classic\tLung, bone\t0\t61\t24\t29\tYes\t18\tHypertension (2), fatigue (3), diarrhea (1), weight loss (3), stomatitis (1), palmar plantar erythrodysesthesia syndrome (2), nausea/vomiting (1), dysphonia (1), alopecia (1)\t\n11, F\tPTC, solid\tLymph nodes, lung, bone\t0\t68\t24\t29\tYes\t6\tHypertension (2), proteinuria (2), fatigue (2), diarrhea (2), weight loss (2)\t\n12, F\tPTC, follicular\tLymph nodes, lung\t1\t66\t24\t27\tYes\t12\tHypertension (2), proteinuria (1), fatigue (2), weight loss (3)\t\n13, M\tPTC, tall cell\tLymph nodes, lung, bone, brain\t0\t56\t20\t6\tNo\t/\tHypertension (2), fatigue (2), weight loss (2), nausea/vomiting (1)\t\nSome AEs of lenvatinib treatment may be symptoms related to PAI: fatigue, weight loss, diarrhea, nausea, and vomiting. In our study, only fatigue was associated with PAI (see the Results and Discussion sections); none of the other symptoms was significantly associated with PAI.\n\na AEs were assessed using the National Cancer Institute CTCAE version 4.03 (9).\n\nAEs, adverse events; CTCAE, Common Terminology Criteria for Adverse Events; ECOG, Eastern Cooperative Oncology Group; F, female; FTC, follicular thyroid cancer; M, male; PAI, primary adrenal insufficiency; PTC, papillary thyroid cancer.\n\nTable 2. Baseline Characteristics of Patients Treated with Lenvatinib\n\nCharacteristic\tAll patients\tPAI\tNo-PAI\t\nNo.\t13\t7\t6\t\nAge, years, mean ± SD\t65.46 ± 12.82\t69.57 ± 5.65\t60.67 ± 17.45a\t\n >60 Years, n (%)\t10 (77)\t7 (100)\t3 (50)\t\n ≤60 Years, n (%)\t3 (23)\t0 (0)\t3 (50)\t\nSex, n (%)\t\n Female\t8 (61.5)\t5 (71.4)\t3 (50)\t\n Male\t5 (38.5)\t2 (28.6)\t3 (50)\t\nWeight, kg, mean ± SD\t70.59 ± 13.64\t71 ± 13.2\t70.12 ± 15.39a\t\nPerformance status, n (%)\t\n ECOG 0\t9 (69.2)\t5 (71.4)\t4 (66.7)\t\n ECOG 1\t4 (30.8)\t2 (28.6)\t2 (33.3)\t\nStarting dose lenvima, mg, mean ± SD\t20.8 ± 4.93\t22 ± 3.83\t19.33 ± 6.02a\t\nFollow-up, months, mean ± SD\t17.62 ± 10.22\t20.71 ± 8.84\t14 ± 11.3a\t\nTSH, μIU/mL, mean ± SD\t0.095 ± 0.074\t0.078 ± 0.083\t0.115 ± 0.065a\t\nACTH, pg/mL, mean ± SD\t29.84 ± 9.4\t31.9 ± 5.64\t27.4 ± 12.7a\t\nCortisol, nmol/L, mean ± SD\t384.6 ± 73.86\t396.5 ± 60.33\t370.7 ± 91.08a\t\nPeak cortisol, nmol/L (ACTH test), mean ± SD\t644.5 ± 81.53\t600.9 ± 36.42\t695.4 ± 90.01b\t\n >646.6, n (%)\t \t1 (14.3)\t5 (83.3)\t\n ≤646.6, n (%)\t \t6 (85.7)\t1 (16.7)\t\na No significant difference with PAI group.\n\nb Significant difference between PAI groups.\n\nACTH, adrenocorticotropic hormone; no-PAI, without primary adrenal insufficiency; SD, standard deviation; TSH, thyrotropin.\n\nBefore and during lenvatinib treatment, all our patients had electrolytes, hemoglobin, albumin, and renal function in the normal range. Moreover, there were no significant alterations in glycemia or hepatic function.\n\nPrimary adrenal insufficiency\n\nNone of the 13 patients had PAI before starting treatment; in all the cases, the cortisol peak was higher than 500 nmol/L (Fig. 1 and Table 3). During lenvatinib treatment, 7 of the 13 patients (54%, CI 0.2249–0.852) had PAI (Fig. 1); the cortisol peak at PAI diagnosis was 392.7 ± 67.78 nmol/L (mean ± SD). The mean time for development of PAI was 7.71 ± 5.7 months. Six of the seven (86%) patients developed PAI within 12 months of starting lenvatinib treatment (Fig. 1 and Table 3).\n\nFIG. 1. ACTH (250 μg) stimulation test of all 13 patients treated with lenvatinib at baseline (0, before starting therapy) and during follow-up (3, 6, 9, 12, 15, 18, 21, 24, and 27 months). Seven patients (#4, #6, #8, #9, #10, #11, and #12) had an insufficient response (cortisol peak <500 nmol/L) indicating adrenal insufficiency. After 12 months of treatment, PAI patient #6 interrupted lenvatinib for 34 days and ACTH stimulation was normal; after lenvatinib restarted, a recurrence of PAI (cortisol peak <500) was demonstrated (see Results). ACTH, adrenocorticotropic hormone; PAI, primary adrenal insufficiency. Color images are available online.\n\nTable 3. Adrenal Function Before and During Lenvatinib Treatment\n\nPatient No./sex\tCortisol peak before lenvatinib (nmol/L)\tACTH before lenvatinib (pg/mL)\tPAI (yes/no)\tPAI diagnosis after lenvatinib started (months)\tCortisol peak at PAI diagnosis (nmol/L)\tACTH at PAI diagnosis (pg/mL)\t\n1/F\t661\t16.2\tNo\t/\t/\t/\t\n2/M\t765\t21.1\tNo\t/\t/\t/\t\n3/F\t670\t11.9\tNo\t/\t/\t/\t\n4/M\t540\t26.7\tYes\t3\t418\t56.8\t\n5/M\t575\t39.4\tNo\t/\t/\t/\t\n6/F\t598\t25.2\tYes\t3\t432\t70.2\t\n7/F\t669\t34\tNo\t/\t/\tNo\t\n8/F\t672\t26.4\tYes\t3\t421\t31.5\t\n9/M\t584\t39\tYes\t9\t268\t95.7\t\n10/F\t598\t36.5\tYes\t18\t452\t65.3\t\n11/F\t582\t34.2\tYes\t6\t328\t91\t\n12/F\t632\t35.3\tYes\t12\t430\t197.1\t\n13/M\t832\t42\tNo\t/\t/\t/\t\nACTH normal level: 6–48.8 pg/mL. None of the 13 patients had PAI before starting treatment; in all cases the cortisol peak was higher than 500 nmol/L. Seven of the 13 patients developed PAI during lenvatinib treatment; cortisol peak after ACTH stimulation and ACTH level were reported at the time of PAI diagnosis in the seven patients. Six of the seven patients with PAI had increased ACTH levels at the time of diagnosis. In one patient without an increase in ACTH levels (patient #8), we excluded a pituitary origin by evaluating other pituitary hormones using pituitary magnetic resonance. However, during follow-up, this patient manifested high levels of ACTH (maximum value 61.5 pg/mL, 9 months after the start of lenvatinib treatment).\n\nPatients with a subnormal response started the CA replacement treatment. The ACTH-test was repeated after 3 months, stopping CA for 48 hours. A further ACTH-test was repeated after 6–9 months in the patients with sufficient follow-up; in all cases AI diagnosis was confirmed.\n\nAfter 1 year of treatment, lenvatinib was interrupted for 34 days in a 76-year-old patient with PAI (Fig. 1, patient #6) because of surgical complications after cholecystectomy. In this patient, we repeated the ACTH-test after appropriate interruption of CA; the cortisol peak was normal. CA was stopped, and lenvatinib was restarted at the same dosage (14 mg) taken before cholecystectomy. However, after 3 months of lenvatinib treatment, two consecutive ACTH-tests demonstrated recurrence of PAI.\n\nThe mean cortisol peak after the first ACTH-test before starting lenvatinib treatment was significantly lower in the PAI group than in the no-PAI group (Table 2).\n\nWe assessed the presence of a possible cortisol peak cutoff to predict the development of PAI during lenvatinib. Using the ROC curve analysis, the most accurate cortisol peak threshold was <646.6 nmol/L with 85.71% sensitivity and 83.33% specificity (area under the curve 0.8333, CI 0.5685–1.098, p = 0.0452). Using this cutoff, only one of the six patients with cortisol peak >646.6 nmol/L developed PAI, whereas six of the seven patients with <646.6 nmol/L peak developed PAI (p = 0.0291; relative risk 5.143; sensitivity 85.71%, specificity 83.33%, positive predictive value 85.71%, and negative predictive value 83.33%).\n\nThe cortisol peak in the ACTH-test decreased significantly during lenvatinib treatment.\n\nBefore lenvatinib treatment, ACTH levels were normal in all patients. PAI diagnosis was associated with an increase in the ACTH levels (Fig. 2 and Table 3).\n\nFIG. 2. ACTH levels of seven patients that developed PAI, at baseline (0, before starting therapy) and during follow-up, until PAI diagnosis. The red line is the upper limit of the reference range 48.8 pg/mL. In six of seven PAI patients (#4, #6, #9, #10, #11, and #12), ACTH levels increased before diagnosis of PAI. Only #12 had very high ACTH levels (greater than twofold the upper limit of reference range) at the time of PAI diagnosis. In the only patient without an increase in ACTH levels (Fig. 3, patient #8), we excluded pituitary origin by evaluating other pituitary hormones and pituitary magnetic resonance. However, during follow-up, this patient manifested high levels of ACTH (maximum value 61.5 pg/mL). Color images are available online.\n\nSix of the seven patients (85.6%) with PAI had an increase in ACTH levels, 5 ± 2.68 months before PAI diagnosis. In one patient without an increase in ACTH levels (Fig. 2 and Table 3, patient #8), we excluded a pituitary origin by evaluating other pituitary hormones and pituitary magnetic resonance.\n\nPAI was diagnosed in 7 of the 10 patients aged >60 years and in none of the 3 patients aged ≤60 years (Table 2); however, the difference was not statistically significant (p = 0.0699).\n\nThe development of PAI was not associated with initial weight, follow-up duration, ECOG status, sex, or starting dose or dose intensity of lenvatinib.\n\nIn all the cases enrolled, adrenal metastases or other adrenal gland alterations were excluded by whole-body computed tomography scans and whole-body [18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography performed for tumor assessment.\n\nFatigue\n\nNone of our patients complained of fatigue before initiating lenvatinib therapy. During follow-up, fatigue was observed in 11 patients (84.6%, Table 1). The mean time of onset of fatigue was 6.64 ± 6.6 weeks (range 2–23) and the onset of fatigue was early, 2–4 weeks, in most cases (72.7%).\n\nFatigue was demonstrated in all 10 patients aged >60 years and in 1 of the 3 patients aged ≤60 years (p = 0.0330, relative risk 14.67; sensitivity 100%, specificity 91.67%, positive predictive value 66.67%, and negative predictive value 100%).\n\nSeven of 11 patients with fatigue developed PAI (63.4%); therefore, the prevalence of fatigue was 100% in the PAI group and 66.7% in the no-PAI group (p = 0.1923) (Fig. 3).\n\nFIG. 3. Fatigue in patients with PAI and without PAI (no-PAI). Fatigue was evaluated by the National Cancer Institute CTCAE version 4.03 (9). Fatigue is defined as a disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities. According to CTCAE, three grades of severity of fatigue were identified: Grade 1, fatigue relieved by rest; Grade 2, fatigue not relieved by rest, limiting activities of daily living, such as preparing meals, shopping for groceries or clothes, using the telephone, and managing money; Grade 3, fatigue not relieved by rest, limiting simple activities of daily living, such as bathing, dressing and undressing, feeding self, using the toilet, taking medications, and bedridden for much of the day. None of our patients at the onset of fatigue had tumor progression, increased TSH levels or alteration in hemoglobin levels, sodium levels, potassium levels, glycemia, albumin concentration, and abnormal hepatic and renal functions. Furthermore, there were no other known causes of fatigue in our patients. (a) Fatigue in PAI patients. All seven patients with PAI had fatigue (see Results). At the time of PAI diagnosis, three patients had grade 3 fatigue (#6, #9, and #10) and four patients had grade 2 fatigue (#4, #8, #11, and #12). After starting replacement CA therapy, six patients (#4, #6, #8, #9, #10, and #11), which constitutes 85.7%, had a significant improvement in fatigue that persisted during follow-up in five patients (#4, #6, #9, #10, and #11), without the need to change lenvatinib dosage. Two patients (#9 and #10) resolved fatigue with AC therapy. (b) Fatigue in patients with no-PAI. Four patients (#1, #5, #7, and #13) in the no-PAI group had fatigue. In two (#1 and #5) of the four patients, an improvement in fatigue was observed after reducing lenvatinib dosage: patient #1 reduced lenvatinib for other adverse events and patient #2 reduced lenvatinib due to the severity of fatigue (grade 3). CA, cortisone acetate; CTCAE, Common Terminology Criteria for Adverse Events; TSH, thyrotropin. Color images are available online.\n\nThe prevalence of severe fatigue (grade 3) was higher in the PAI group, 42.8% (3/7 patients), than in the no-PAI group, 16.7% (1/6 patients) (Fig. 3), but the difference was not statistically significant (p = 0.5594).\n\nCA significantly reduced fatigue in 85.7% of all PAI patients (p = 0.0152) (Fig. 3a), without changing lenvatinib dosage, also in severe fatigue; on the contrary, in the no-PAI group, a reduction of lenvatinib dosage was necessary in grade 3 fatigue (Fig. 3b).\n\nFatigue was not associated with initial weight, ECOG status, sex, follow-up duration, or starting dose or dose intensity of lenvatinib.\n\nAge correlated positively with development (p = 0.0007, r = 0.8124, CI 0.4733–0.9418) and with the severity of fatigue (p = 0.0166, r = 0.6482, CI 0.1513–0.8836). There was a tendency for a positive association between fatigue severity and PAI (p = 0.0527; r = 0.5476).\n\nDiscussion\n\nIn this study, PAI was observed in 54% of cases, often in the first 12 months of lenvatinib treatment. According to current guidelines, we used a high-dose ACTH test: the “gold standard” for the diagnosis of PAI (5). The association with increased ACTH levels is consistent with the diagnosis of PAI (5).\n\nOur results agree with those of Colombo et al.'s study, which demonstrated PAI in 57% of the seven patients treated with lenvatinib (4). However, these authors evaluated adrenal function only during lenvatinib treatment and not before therapy.\n\nThe strength of our study was the ability to evaluate adrenal function before lenvatinib treatment, demonstrating normal adrenal function in all cases.\n\nConsidering its prevalence, PAI may be defined as one of the most common, recently observed AEs of lenvatinib.\n\nThe negative adrenal effect of lenvatinib may be transient, and recovery of adrenal function may be obtained after lenvatinib interruption. In fact, in one of our patients with PAI, the interruption of lenvatinib was associated with a recovery of adrenal function.\n\nPAI is a severe and potentially life-threatening condition, and its early diagnosis is important (5–7). Interestingly, by evaluating the first ACTH-test, before starting lenvatinib treatment, we found, based on our analysis of only 13 patients, that patients with a <646.6 nmol/L cortisol peak had an increased risk of developing PAI during lenvatinib treatment. We suggest that baseline ACTH-testing and ACTH levels in patients selected for lenvatinib therapy might help inform the need for subsequent evaluation for PAI.\n\nAn apparent limitation of our study is that we did not evaluate levels of renin and aldosterone. We chose not to evaluate the levels of these hormones because they were altered by antihypertensive treatments. Hypertension was present in eight patients (61.5%) before starting lenvatinib treatment and in all patients during follow-up. However, sodium and potassium levels were always normal, indicating that mineralocorticoid function was preserved.\n\nWe did not evaluate levels of salivary cortisol or free urinary cortisol in our study. Plasma total cortisol levels can be affected by potential changes in cortisol-binding globulin. This may be a limitation of the present study. However, as reported, the limitations of the measurement of total cortisol are typically less important in the evaluation of PAI (high ACTH) than in the diagnosis of secondary or tertiary AI (low or inappropriately normal ACTH) (10).\n\nAnother potential limitation of our study may be that adrenal autoantibodies were not determined. However, all our patients had normal adrenal function before lenvatinib treatment, and when PAI developed, mineralocorticoid function was preserved, excluding autoimmune adrenalitis (11).\n\nIn almost all patients with PAI in our study, ACTH levels were not as high as those observed in the diagnosis of non-lenvatinib-related PAI (usually greater than twofold the upper limit of range) (5) (Fig. 2). This observation may be explained by the early diagnosis of PAI in our patients, according to our study design, or milder PAI associated with lenvatinib treatment, which prevented a significant increase in ACTH levels.\n\nThe mechanisms involved in the development of lenvatinib-induced PAI are unknown. Lenvatinib is a multitargeted TKI; in particular, two of its targets, the vascular endothelial growth factor (VEGF) receptors (VEGFRs) and platelet-derived growth factor receptor alpha (PDGFRα), may be implicated in adrenal control.\n\nAnti-VEGF action markedly reduces vascular density in the adrenal cortex in animal studies (12,13). Interestingly, VEGF expression is more marked in the fasciculata than in the zona glomerulosa in the bovine adrenal cortex (13). Therefore, the inhibition of the VEGF pathway by lenvatinib may reduce the production of glucocorticoids.\n\nFatigue is one of the most common treatment-related AEs. In the real-life studies, fatigue was observed in 39.1–100% of cases (14–21), in agreement with our work (84.6%).\n\nThe mean time for the first onset of fatigue in our patients was 6.64 ± 6.6 weeks, in agreement with Haddad et al. (6.1 weeks) (22).\n\nThe development and severity of fatigue were associated with age; in particular, in our study, age >60 years significantly increased the risk of fatigue during lenvatinib treatment. We found a similar situation for PAI, which was observed only in patients aged >60 years; however, for PAI the different prevalence was not statistically significant. It is known that older patients are more likely to experience AEs from lenvatinib treatment (23).\n\nFatigue management is a challenge for physicians, and many conditions may be involved, including anemia, stomatitis, decreased appetite, weight loss, diarrhea, nausea, vomiting, electrolyte disturbances, and increased levels of thyrotropin (TSH) (1,24,25). In many cases, as also in our study, a specific condition cannot be identified and lenvatinib must be discontinued, interrupted, or reduced in dosage, with a possible worsening of treatment efficacy (1).\n\nIn our study, severe fatigue (grade 3) was observed in 42.8% of patients and in 16.7% of patients without PAI. There was a tendency for a positive association between fatigue severity and PAI, but this did not reach statistical significance, probably due to the small number of cases.\n\nCA improved fatigue in 85.7% of patients with PAI, without having to reduce lenvatinib dosage. In contrast, in patients without PAI, grade 3 fatigue required a lenvatinib dosage reduction. It is important to underline how the advantages of glucocorticoid therapy were obtained with physiological doses of CA (25–37.5 mg/day), according to the current guidelines (5).\n\nThe combination of these observations shows that PAI may be one of the many causes of lenvatinib-related fatigue, in agreement with a previous study (4). However, the sample size of this study was small; as a result, the CIs were wide.\n\nIn conclusion, our study confirms that lenvatinib induces PAI, and strengthens the evidence by assessing adrenal function both before and during treatment. Moreover, through the first assessment of adrenal function, both before and during treatment, this is the first study that strongly suggests that lenvatinib induces PAI. PAI must be considered one of the most common AEs associated with lenvatinib. Our data also strongly suggest that PAI may be involved in lenvatinib-related fatigue, particularly in patients who experience extreme fatigue. However, further studies are required to confirm these findings. Underdiagnosis and undermanagement of PAI in patients with RR-DTC, both potentially life-threatening conditions, may have a negative impact on the morbidity and mortality of patients treated with lenvatinib. We propose evaluating adrenal function in all patients selected for lenvatinib treatment to potentially inform the risk of developing PAI. The majority of patients on lenvatinib experience fatigue and they should be assessed for PAI.\n\nAuthors' Contributions\n\nS.M. and F.P: study planning and coordination. S.M., F.P., V.T., G.P., and M.P.: investigation, methodology, and writing—original draft. S.M. and F.P.: data curation and statistical analysis. S.M., F.P, M.G.D., C.M., F.M., V.R., and A.S.: visiting clinicians.\n\nAuthor Disclosure Statement\n\nAll the authors have nothing to disclose.\n\nFunding Information\n\nNo funding was received for this article.\n==== Refs\nReferences\n\n1. Fugazzola L, Elisei R, Fuhrer D, et al. 2019 European Thyroid Association guidelines for the treatment and follow-up of advanced radioiodine-refractory thyroid cancer. Eur Thyroid J 8 :227–245.31768334\n2. Jin Y, Van Nostrand D, Cheng L, et al. 2018 Radioiodine refractory differentiated thyroid cancer. Crit Rev Oncol Hematol 125 :111–120.29650270\n3. Schlumberger M, Tahara M, Wirth LJ, et al. 2015 Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372 :621–630.25671254\n4. Colombo C, De Leo S, Di Stefano M, et al. 2019 Primary adrenal insufficiency during lenvatinib or vandetanib and improvement of fatigue after cortisone acetate therapy. J Clin Endocrinol Metab 104 :779–784.30383218\n5. Bornstein SR, Allolio B, Arlt W, et al. 2016 Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 101 :364–389.26760044\n6. Bleicken B, Hahner S, Ventz M, et al. 2010 Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. Am J Med Sci 339 :525–531.20400889\n7. Rushworth RL, Torpy DJ, Falhammar H 2019 Adrenal crisis. N Engl J Med 381 :852–861.31461595\n8. Eisenhauer EA, Therasse P, Bogaerts J, et al. 2009 New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45 :228–247.19097774\n9. National Cancer Institute 2010 Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Available at https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf (accessed April 14, 2020).\n10. Verbeeten KC, Ahmet AH 2018 The role of corticosteroid-binding globulin in the evaluation of adrenal insufficiency. J Pediatr Endocrinol Metab 31 :107–115.29194043\n11. Naletto L, Frigo A, Ceccato F, et al. 2019 The natural history of autoimmune addison's disease from the detection of autoantibodies to development of the disease: a long follow-up study on 143 patients. Eur J Endocrinol 180 :223–234.30608902\n12. Yang Y, Zhang Y, Cao Z, et al. 2013 Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. Proc Natl Acad Sci U S A 110 :12018–12023.23818623\n13. Gaillard I, Keramidas M, Liakos P, et al. 2000 ACTH-regulated expression of vascular endothelial growth factor in the adult bovine adrenal cortex: a possible role in the maintenance of the microvasculature. J Cell Physiol 185 :226–234.11025444\n14. Kim SY, Kim SM, Chang H, et al. 2019 Safety of tyrosine kinase inhibitors in patients with differentiated thyroid cancer: real-world use of lenvatinib and sorafenib in Korea. Front Endocrinol (Lausanne) 10 :384.31244783\n15. Balmelli C, Railic N, Siano M, et al. 2018 Lenvatinib in advanced radioiodine-refractory thyroid cancer—a retrospective analysis of the Swiss lenvatinib named patient program. J Cancer 9 :250–255.29344270\n16. Takahashi S, Kiyota N, Yamazaki T, et al. 2019 A Phase II study of the safety and efficacy of lenvatinib in patients with advanced thyroid cancer. Future Oncol 15 :717–726.30638399\n17. Locati LD, Piovesan A, Durante C, et al. 2019 Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy. Eur J Cancer 118 :35–40.31299580\n18. Aydemirli MD, Kapiteijn E, Ferrier KRM, et al. 2020 Effectiveness and toxicity of lenvatinib in refractory thyroid cancer: Dutch real-life data. Eur J Endocrinol 182 :131–138.31751307\n19. Berdelou A, Borget I, Godbert Y, et al. 2018 Lenvatinib for the treatment of radioiodine-refractory thyroid cancer in real-life practice. Thyroid 28 :72–78.29048237\n20. Molina-Vega M, García-Alemán J, Sebastián-Ochoa A, et al. 2018 Tyrosine kinase inhibitors in iodine-refractory differentiated thyroid cancer: experience in clinical practice. Endocrine 59 :395–401.29275532\n21. Giani C, Valerio L, Bongiovanni A, et al. 2021 Safety and quality-of-life data from an Italian expanded access program of lenvatinib for treatment of thyroid cancer. Thyroid 31 :224–232.32907501\n22. Haddad RI, Schlumberger M, Wirth LJ, et al. 2017 Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes. Endocrine 56 :121–128.28155175\n23. Brose MS, Worden FP, Newbold KL, et al. 2017 Effect of age on the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the phase III SELECT trial. J Clin Oncol 35 :2692–2699.28613956\n24. Resteghini C, Cavalieri S, Galbiati D, et al. 2017 Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients. Best Pract Res Clin Endocrinol Metab 31 :349–361.28911730\n25. Capdevila J, Newbold K, Licitra L, et al. 2018 Optimisation of treatment with lenvatinib in radioactive iodine-refractory differentiated thyroid cancer. Cancer Treat Rev 69 :164–176.30032061\n\n",
"fulltext_license": "CC BY",
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"journal": "Thyroid : official journal of the American Thyroid Association",
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"pmid": "34663079",
"pubdate": "2021-10-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cortisol deficiency in Lenvatinib treatment of thyroid cancer: an underestimated, common adverse event.",
"title_normalized": "cortisol deficiency in lenvatinib treatment of thyroid cancer an underestimated common adverse event"
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"companynumb": "IT-Eisai Medical Research-EC-2021-102255",
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"abstract": "Primary aldosteronism, eponymously known as Conn's syndrome, has recently gained recognition as the most common cause of endocrine hypertension. Unilateral subtypes, such as aldosterone secreting adenomas, are managed surgically and are potentially curable. The background of refractory hypertension and hypokalaemia in a forty-year-old man raised suspicions of Conn's syndrome which was localised to an aldosterone secreting adenoma in the right adrenal gland. The patient underwent a laparoscopic intraperitoneal right adrenalectomy which resulted in normalisation of his plasma aldosterone concentration as well as improved blood pressure control.",
"affiliations": "Medical Outpatient Department, Bertha Gxowa Hospital, South Africa.;Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital, South Africa.;Department of Surgery, Chris Hani Baragwanath Academic Hospital, South Africa.;Department of Surgery, Chris Hani Baragwanath Academic Hospital, South Africa.",
"authors": "Carides|M D|MD|;Sishuba|N T|NT|;Bombil|I|I|;Christofides|C|C|",
"chemical_list": "D000450:Aldosterone",
"country": "South Africa",
"delete": false,
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"issue": "59(3)",
"journal": "South African journal of surgery. Suid-Afrikaanse tydskrif vir chirurgie",
"keywords": null,
"medline_ta": "S Afr J Surg",
"mesh_terms": "D000236:Adenoma; D000315:Adrenalectomy; D000328:Adult; D000450:Aldosterone; D006801:Humans; D006929:Hyperaldosteronism; D006973:Hypertension; D008297:Male",
"nlm_unique_id": "2984854R",
"other_id": null,
"pages": "131a-131c",
"pmc": null,
"pmid": "34515436",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The role of surgery in Conn's syndrome - a case of refractory hypertension secondary to an aldosterone secreting adenoma.",
"title_normalized": "the role of surgery in conn s syndrome a case of refractory hypertension secondary to an aldosterone secreting adenoma"
} | [
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"activesubstancename": "AMLODIPINE BESYLATE"
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"abstract": "OBJECTIVE\nTo present the therapeutic management of severe complications related to postoperative mitomycin extravasation.\n\n\nMETHODS\nDescription of clinical cases, medical and surgical management and pathologic results of surgical specimens.\n\n\nRESULTS\nWe report two cases of patients with extravesical mitomycin leakage after postoperative instillation. No bladder perforation was evident during tumor surgery. In both cases radical cystectomy was required.\n\n\nCONCLUSIONS\nPostoperative mitomycin instillation may have undesirable consequences. The possible problems derived from its administration must be known, and each case must be individualized before administering this chemotherapy.",
"affiliations": "Urology Department. Hospital Clínico Universitario de Valencia. Valencia. Spain.;Urology Department. Hospital Universitario de la Ribera. Valencia. Spain.;Anatomo-Pathological Department. Hospital Clínico Universitario de Valencia. Valencia. Spain.;Urology Department. Hospital Clínico Universitario de Valencia. Valencia. Spain.",
"authors": "Panach-Navarrete|Jorge|J|;Ferrandis-Cortés|Cristina|C|;Sales-Maicas|María Ángeles|MÁ|;Martínez-Jabaloyas|José María|JM|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D016685:Mitomycin",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-0614",
"issue": "68(7)",
"journal": "Archivos espanoles de urologia",
"keywords": null,
"medline_ta": "Arch Esp Urol",
"mesh_terms": "D000283:Administration, Intravesical; D000368:Aged; D000903:Antibiotics, Antineoplastic; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006801:Humans; D008297:Male; D016685:Mitomycin; D011183:Postoperative Complications; D012422:Rupture, Spontaneous; D001745:Urinary Bladder Diseases",
"nlm_unique_id": "0064757",
"other_id": null,
"pages": "633-6",
"pmc": null,
"pmid": "26331401",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Mitomycin extravasation after postoperative instillation.",
"title_normalized": "mitomycin extravasation after postoperative instillation"
} | [
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"companynumb": "ES-ACCORD-034277",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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"actiondrug": "5",
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"activesubstancename": "MITOMYCIN"
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"abstract": "BACKGROUND\nNovel targeted agents and combinations have become available in multiple lines of treatment for human epidermal growth factor receptor 2-positive (HER2(+)) metastatic breast cancer (MBC). In this context, alternatives to the lapatinib (L) and capecitabine (C) regimen, evaluating L combined with other cytotoxic drugs, are warranted.\n\n\nMETHODS\nIn the present phase II, multicenter study, patients with HER2(+) MBC with progression after taxane were randomized between L, 1250 mg, combined with C, 2000 mg/m(2) on days 1 to 14 (LC), vinorelbine (V), 25 mg/m(2) on days 1 and 8 (LV), or gemcitabine (G), 1000 mg/m(2) on days 1 and 8 (LG), every 21 days. The primary endpoint was the overall response rate.\n\n\nRESULTS\nA total of 142 patients were included from 2009 to 2012. No differences were found in the patient baseline characteristics. The median age was 51 years, 69% were postmenopausal, 32% had liver metastasis, 57% were hormone receptor negative, and 48% had been previously treated with trastuzumab. The overall response rate was 49% (95% confidence interval [CI], 34.8%-63.4%), 56% (95% CI, 40%-70.4%), and 41% (95% CI, 27%-56.8%) in the LC, LV, and LG groups, respectively. The median progression-free survival was 9 months in the LC arm and 7 months in the other 2 arms (P = .28). The most common grade 3 and 4 adverse events were hand-foot syndrome (18%), diarrhea (6%), and increased alanine aminotransferase/aspartate aminotransferase (4%) in the LC arm; neutropenia (36%), diarrhea (9%), and febrile neutropenia (6%) in the LV arm; and neutropenia (47%), alanine aminotransferase/aspartate aminotransferase (13%), and rash (4%) in the LG arm.\n\n\nCONCLUSIONS\nLV and LG seem to be active combinations in patients with HER2(+) MBC after taxane failure. The overall toxicity was manageable in all regimens.",
"affiliations": "Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.;Instituto Brasileiro de Controle do Câncer, São Paulo, São Paulo, Brazil.;Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, São Paulo, Brazil.;Instituto Nacional de Câncer, Rio de Janeiro, Brazil.;Fundação Doutor Amaral Carvalho, Jaú, Brazil.;Instituto de Ensino e Pesquisa São Lucas, Santo André, Brazil.;Instituto de Ensino e Pesquisa São Lucas, Santo André, Brazil.;Centro de Pesquisas Oncológicas de Santa Catarina, Florianópolis, Brazil.;Hospital A.C. Camargo, São Paulo, Brazil.;Centro Oncológico de Rosário, Rosário, Argentina.;Clínica Amo, Salvador, Brazil.;Investigaciones Clínicas Ciudad de Buenos Aires, Buenos Aires, Argentina.;Fundación Centro Oncológico de Integración Regional, Mendoza, Argentina.;Centro San Roque, Tucumán, Argentina.;ISIS Clínica Especializada, Santa Fé, Argentina.;CER Instituto Médico, Buenos Aires, Argentina.;Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil.;Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil. Electronic address: gustavo.werutsky@lacog.org.br.;Pontifical Catholic University of Rio Grande do Sul School of Medicine, Hospital São Lucas, Porto Alegre, Brazil.",
"authors": "Gómez|Henry L|HL|;Neciosup|Silvia|S|;Tosello|Célia|C|;Mano|Max|M|;Bines|José|J|;Ismael|Gustavo|G|;Santi|Patrícia X|PX|;Pinczowski|Hélio|H|;Nerón|Yeni|Y|;Fanelli|Marcello|M|;Fein|Luis|L|;Sampaio|Carlos|C|;Lerzo|Guillermo|G|;Capó|Adolfo|A|;Zarba|Juan J|JJ|;Blajman|César|C|;Varela|Mirta S|MS|;Martínez-Mesa|Jeovany|J|;Werutsky|Gustavo|G|;Barrios|Carlos H|CH|",
"chemical_list": "D011799:Quinazolines; D043823:Taxoids; D000077341:Lapatinib; D003841:Deoxycytidine; D014747:Vinblastine; D000069287:Capecitabine; C056507:gemcitabine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000077235:Vinorelbine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "16(1)",
"journal": "Clinical breast cancer",
"keywords": "Chemotherapy; Human epidermal growth factor receptor 2-positive; Lapatinib; Metastatic breast cancer; Treatment outcome",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D003841:Deoxycytidine; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008875:Middle Aged; D011799:Quinazolines; D018719:Receptor, ErbB-2; D016879:Salvage Therapy; D043823:Taxoids; D014747:Vinblastine; D000077235:Vinorelbine; D055815:Young Adult",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "38-44",
"pmc": null,
"pmid": "26642810",
"pubdate": "2016-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Phase II Randomized Study of Lapatinib Combined With Capecitabine, Vinorelbine, or Gemcitabine in Patients With HER2-Positive Metastatic Breast Cancer With Progression After a Taxane (Latin American Cooperative Oncology Group 0801 Study).",
"title_normalized": "a phase ii randomized study of lapatinib combined with capecitabine vinorelbine or gemcitabine in patients with her2 positive metastatic breast cancer with progression after a taxane latin american cooperative oncology group 0801 study"
} | [
{
"companynumb": "BR-CIPLA LTD.-2016BR01164",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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{
"abstract": "To characterise the different types of pulmonary hypertension (PH) among idiopathic inflammatory myopathy (IIM). A retrospective case series with assessment of PH by right heart catheterisation, extent of interstitial lung disease (ILD) and outcome of vasoactive therapy.The group of patients with IIM with PH (n=9) showed a median age at PH diagnosis of 62 years (IQR 48-71 years; eight women), seven diagnosed with polymyositis and two with dermatomyositis; median disease duration of 5.7 years and five patients with a positive anti-Jo1 antibody. We found one patient to be classified in PH WHO group 2 (left heart disease), five patients in WHO group 3 (lung disease) and three patients in WHO group 1 (pulmonary arterial hypertension (PAH)). During median observed follow-up of 24 months, mortality for the total group was 44%. Surprisingly, we found a relevant group (33%) of patients with IIM who suffered from non-ILD-PH, which reflects the presence of PAH phenotype. This result should lead to more awareness among treating physicians that complaints of dyspnoea among patient with IIM could be related to PAH and not only ILD. The role of vasoactive therapy remains to be defined in patients with IIM suffering from PAH or PH-ILD.",
"affiliations": "Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.;Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.;Scientific Institute for Quality of Health Care, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.",
"authors": "Bhansing|Kavish J|KJ|0000-0003-4266-000X;Vonk-Noordegraaf|Anton|A|;Oosterveer|Frank Pt|FP|;van Riel|Piet Lcm|PL|;Vonk|Madelon C|MC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/rmdopen-2016-000331",
"fulltext": "\n==== Front\nRMD OpenRMD OpenrmdopenrmdopenRMD Open2056-5933BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 28879041rmdopen-2016-00033110.1136/rmdopen-2016-000331Connective Tissue Diseases1506Clinical casePulmonary arterial hypertension, a novelty in idiopathic inflammatory myopathies: insights and first experiences with vasoactive therapy http://orcid.org/0000-0003-4266-000XBhansing Kavish J 1Vonk-Noordegraaf Anton 2Oosterveer Frank PT 2van Riel Piet LCM 3Vonk Madelon C 1\n1 \nDepartment of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands\n\n2 \nDepartment of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands\n\n3 \nScientific Institute for Quality of Health Care, Radboud University Medical Center, Nijmegen, The Netherlands\nCorrespondence to MD Kavish J Bhansing; k.bhansing@reuma.umcn.nl2017 9 6 2017 3 1 e00033113 7 2016 05 1 2017 05 2 2017 © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2017This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/To characterise the different types of pulmonary hypertension (PH) among idiopathic inflammatory myopathy (IIM). A retrospective case series with assessment of PH by right heart catheterisation, extent of interstitial lung disease (ILD) and outcome of vasoactive therapy.The group of patients with IIM with PH (n=9) showed a median age at PH diagnosis of 62 years (IQR 48–71 years; eight women), seven diagnosed with polymyositis and two with dermatomyositis; median disease duration of 5.7 years and five patients with a positive anti-Jo1 antibody. We found one patient to be classified in PH WHO group 2 (left heart disease), five patients in WHO group 3 (lung disease) and three patients in WHO group 1 (pulmonary arterial hypertension (PAH)). During median observed follow-up of 24 months, mortality for the total group was 44%. Surprisingly, we found a relevant group (33%) of patients with IIM who suffered from non-ILD-PH, which reflects the presence of PAH phenotype. This result should lead to more awareness among treating physicians that complaints of dyspnoea among patient with IIM could be related to PAH and not only ILD. The role of vasoactive therapy remains to be defined in patients with IIM suffering from PAH or PH-ILD.\n\nPolymyositisDermatomyositisPulmonary FibrosisTreatmentspecial-featureunlocked\n==== Body\nKey messages\nWhat is already known about this subject?\nPulmonary hypertension (PH) is a life-threatening condition and is associated with patients with idiopathic inflammatory myopathy (IIM). Although interstitial lung disease (ILD) is frequently found among patients with IIM patients, the question is whether this lung disease explains the presence of PH in all patients with IIM.\n\nWhat does this study add?\nSurprisingly, we found a relevant group (33%) of patients with IIM who suffered from non-ILD-PH, which reflects the presence of pulmonary arterial hypertension (PAH) phenotype. The role of vasoactive therapy remains to be defined in patients with IIM suffering from PAH or PH-ILD.\n\nHow might this impact on clinical practice?\nThis result should lead to more awareness among treating physicians that complaints of dyspnoea among patients with IIM could be related to PAH and not only ILD.\n\nIntroduction\nPulmonary hypertension (PH) is a life-threatening condition presenting with symptoms like breathlessness, fatigue and syncope.1 PH can occur as a complication of systemic autoimmune diseases.2–4 The association with polymyositis (PM) and dermatomyositis (DM), together classified as idiopathic inflammatory myopathy (IIM), is not well known.5 So far, only a few cases reported on PH in patients with IIM.6–11 However, two recent cohort studies among antisynthetase patients revealed a prevalence of PH ranging from 7.9% to 14.8% with a worsened prognosis.12 13 These study results reflect the clinical relevance of PH as a complication of IIM.\n\nPatients with PH can be classified according to the WHO classification in pulmonary arterial hypertension (PAH) (group 1), PH associated to left heart disease (group 2), PH associated to lung disease (group 3), chronic thromboembolic PH (group 4) and PH with unclear mechanism (group 5).14 The cause of PH in patients with IIM is however still unclear. Although interstitial lung disease (ILD) is frequently found among patients with IIM, occurring in up to 65% of the patients,15 the question is whether this lung disease explains the presence of PH in all patients with IIM. In addition, data on long-term follow-up are scarce.\n\nFor this, we describe the clinical characteristics and follow-up of nine patients with IIM with PH and investigated the cause and effect of PH in these patients.\n\nMethods\nThis is a retrospective case series which consisted of patients with IIM (n=9) with PH of two Dutch university hospitals (Radboud University Medical Center, Nijmegen) (n=4) and (VU University Medical Center, Amsterdam) (n=5) which are both expert centres for PH. According to Dutch law and regulations, the study was exempted from approval of a medical ethical committee and no informed consent was required since this was an observational, non-interventional study.\n\nParticipants\nAll patients with IIM fulfilled at least the criteria for probable IIM according to the European Neuromuscular Centre (ENMC) classification criteria.16 PH was defined as an increase in mean pulmonary arterial pressure (mPAP) ≥25 mm Hg assessed with right heart catheterisation (RHC).14 All known patients with IIM and PH were included at both medical centres (VU University Medical Center, a registry of patients with PH; Radboud University Medical Center, Myositis Nijmegen cohort).\n\nInterstitial lung disease\nPresence of extensive ILD was defined as signs of pulmonary fibrosis on high-resolution computed tomography (HRCT) scan with >10% lung involvement. Limited ILD was defined as extent of lung parenchymal involvement ≤10% on HRCT which is a conservative cut-off in comparison with staging system of Goh et al (≤20%).17 In remaining cases with an indeterminate extent on HRCT, an abnormal pulmonary function test (total lung capacity (TLC) <70% predicted) was used to classify extensive ILD. A blinded pulmonologist (AV-N) retrospectively reviewed all available HRCT scans using the Wells method to score the presence and extent of ILD.18\n\n\nHaemodynamics RHC\nBased on pulmonary capillary wedge pressure (PCWP), PH can be divided into precapillary PH (PCWP ≤15 mm Hg) and postcapillary PH (PCWP >15 mm Hg), which can be related to different clinical causes.14 Patients with precapillary PH and limited ILD were defined as non-ILD-PH (reflecting PAH), whereas patients with precapillary PH and extensive ILD as ILD-PH. Other parameters which were assessed by RHC were PCWP, cardiac output and pulmonary vascular resistance (PVR). Outcome of vasoactive therapy in patients with PH-IIM was evaluated by available information on mortality, hospital admissions, therapy adjustments and alterations of 6 min walking test (6MWT) or WHO functional class (WHO-FC).19 The WHO-FC system grades severity of limitations due to PH on a scale of 1 (no limitations) to 4 (limitation of all exercise).\n\nCase report\nPatients\nOur cohort consists of nine patients, of which seven patients were diagnosed with polymyositis and two with dermatomyositis. The median age at diagnosis of PH was 62 years (IQR 48–68 years; eight women). The median disease duration of IIM at diagnosis of PH was 5.7 years (IQR 3–10.3 years). In five patients, anti-Jo1 autoantibody was present (table 1).\n\nTable 1 Clinical and haemodynamic characteristics of each patient at PH diagnosis\n\nCharacteristics\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\tPatient 7\tPatient 8\tPatient 9\t\nClinical characteristics\tPM\tPM\tPM\tPM overlap SLE\tDM\tDM\tPM\tPM\tPM\t\n ANA\t+\t+\t+\t+\t+\t−\t+\t+\t–\t\n Anti-Jo1\t+\t+\t–\t–\tNA\t+\t+\t–\t+\t\n Raynaud’s phenomenon\t+\t+\t–\t–\t–\t+\t+\t+\t–\t\n Arthritis (history)\t+\t+\t+\t–\t+\t+\t+\t+\t–\t\n Disease duration (years)\t20.4\t8.8\t5.1\t1.2\t5.8\t0.6\t10\t5.4\t10.7\t\n WHO functional class\t2\t3\t2\t4\t4\t3\t2\t3\t3\t\nWHO PH group\t3\t3\t1\t2\t1\t3\t3\t3\t1\t\nHRCT scan\t\t\t\t\t\t\t\t\t\t\n Lung fibrosis on HRCT\t+\t+\t+\tNA\t–\t+\t+\t+\t+\t\n Wells score\t2\t3\t2\tNA\t0\t2\t3\t1\t3\t\n Lung involvement (%)\t70\t70\t10\tNA\t0\t90\t30\t90\t10\t\nExtent of ILD\tExtensive\tExtensive\tLimited\tExtensive\tLimited\tExtensive\tExtensive\tExtensive\tLimited\t\nPulmonary function test\t\t\t\t\t\t\t\t\t\t\n TLC (% of predicted)\t66\t80\t64\t57\t51\t87\t65\t50\t105\t\n DLCO (% of predicted)\t66\t53\t68\tNA\t39\t67\t69\t62\t42\t\n6 Min walking test (m)\tNA\t143\t420\tNA\tNA\tNA\t308\t235\t307\t\nRHC\t\t\t\t\t\t\t\t\t\t\n Mean PAP (mm Hg)\t45\t40\t66\t41\t60\t32\t25\t33\t52\t\n PCWP (mm Hg)\t12\t5\t7\t35\t1\t14\t11\t14\t14\t\n Cardiac index (L/min/m2)\tNA\tNA\t2.3\t1.4\t2.2\t2.6\t2.5\tNA\t2.1\t\n Cardiac output (L/min)\tNA\t3.8\t5.1\t3.1\t2.7\t4.6\t4.6\t3.3\t3.3\t\n PVR (dynes/s/cm5)\tNA\t743\t928\t155\t1749\t315\t242\t461\t109\t\nANA, antinuclear antibody; DLCO, diffusing capacity for carbon monoxide; DM, dermatomyositis; ILD, interstitial lung disease; PAP, pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PM, polymyositis; PVR, pulmonary vascular resistance; RHC, right heart catheterisation; SLE, systemic lupus erythematosus; TLC, total lung capacity; NA, not available.\n\nInterstitial lung disease\nSigns of pulmonary fibrosis on HRCT scans were present in seven patients (88%), with scans performed in eight out of nine patients. All seven patients had a precapillary PH. A Wells score of 3, presenting dominance of a reticular pattern (ie, fibrosis) was present in three (38%) patients. The median lung involvement was 50% of the surface (range 0%–90%) with four patients ≥70% lung involvement on the scans. Three patients (37%) displayed none or limited lung involvement (surface ≤10%) (table 1, patients 3, 5 and 9).\n\nPH characterisation\nEight patients presented with precapillary PH. Chronic thromboembolic PH and multifactorial PH causes were excluded. One patient was diagnosed with postcapillary PH caused by severe aorta valve stenosis, PH WHO group 2 (table 1).\n\nCombining information on ILD with RHC data demonstrates that five out of eight precapillary patients with PH had a fair to severe lung fibrosis, while the other three patients had none to limited lung fibrosis. Those three patients were diagnosed with PAH associated to IIM, WHO group 1 (patients 3, 5 and 9). In these patients, pulmonary fibrosis was either absent or present in <10% of the pulmonary surface (table 1). The remaining five patients with fair to severe pulmonary fibrosis were classified as PH caused by ILD (PH-ILD), WHO group 3.14\n\n\nOutcome\nThe total group of patients with IIM and PH revealed a mortality of four patients (44%) during a median observed follow-up of 16 months. Within 5 months of diagnosis of PH, two patients died (patients 4 and 5), one due to heart failure complicated by severe aorta valve stenosis. The other patients died as a result of respiratory failure complicated with pneumonia before vasoactive therapy could be started.\n\nVasoactive therapy was initiated in seven patients with precapillary PH (table 2). Therapy included the use of prostanoids, endothelin receptors antagonists and phosphodiesterase type-5 inhibitors. Follow-up information was unavailable in one patient due to transfer to another hospital (patient 8). After the start of therapy, two patients revealed an increase of walking distance (18% and 9%) during 6 min walking test after 2 and 12 months (patients 2 and 3). However, after initial improvement, one patient died 3 years later due to heart failure (patient 3). Stabilisation of walking distance after 6 months was observed in one patient. After 2 years, the patient died due to respiratory failure (patient 7). In one patient, pulmonary haemodynamics returned to normal after 1 year of therapy with bosentan (patient 6). The remaining two patients on PH therapy suffered from a slow progression on the WHO-FC (patients 1 and 9).\n\nTable 2 Follow-up of vasoactive therapy effect\n\nPatient\tTherapy at diagnosis\tWHO-FC at PH diagnosis\tTherapy adjustments\tObserved follow-up (months)\tDescription outcome\tWHO-FC at end follow-up\tFinal outcome\t\n1\tS\t2\tS↑: 18 months \nS↑: 36 months\t36\tSlow progression to WHO-FC 3\t3\tAlive\t\n2\tS\t3\tS + I: 12 months\t16\tRemains at WHO-FC 3 after iloprost therapy\t3\tAlive\t\n3\tB\t2\tB + S: 7 months \nB + S + T: 24 months\t36\tSlow progression to WHO-FC 3 \n6-MWT at diagnosis 420 m, at 8 months 459 m, at 28 months 390m\t4\tDeath due to heart failure after 36 months\t\n6\tB\t3\tB↑: 48 months\t48\tWith bosentan no PH after 12 months, after 48 months progressive dyspnoea\tNA\tAlive\t\n7\tS\t2\tStop S: 8 months\t24\tExacerbation of PM after 8 months, ↑ prednisone and start tacrolimus\t4\tDeath due to respiratory failure after 24 months\t\n8\tS\t3\tNA\t0\tUnknown due to transfer to other hospital\tNA\tNA\t\n9\tA\t3\tDiuretics: 2 months\t12\tShort hospitalisation after 2 months due to heart failure, after 12 months stable in WHO-FC 3\t3\tAlive\t\nA, ambrisentan; B, bosentan; I, iloprost inhalation; S, sildenafil; T, treprostinil; ↑, increase of dose; WHO-FC, WHO functional class; 6-MWT, 6 min walking test; PM, polymyositis; NA, not available.\n\nDiscussion\nIn this clinical case series, we describe a group of nine patients with PH-IIM followed at two referral centres for PH. We found one patient to be classified as PH, WHO group 2 (left heart disease), five patients in WHO group 3 (lung disease) and three patients in WHO group 1 (PAH). Our study confirms previous results, indicating that the majority of the PH in IIM can be classified as PH-ILD, WHO group 3.6–12 However, PAH associated to IIM is a possibility, in this group occurring in 33% of the patients.\n\nThe pathogenesis of PAH in IIM is unknown; however, involvement of pulmonary vessels by diffuse infiltrative and inflammatory processes is likely to contribute.5 An autopsy study among patients with PM found suggestive changes for PAH by encroachment of the pulmonary blood vessel lumen with medial smooth muscle hyperplasia.20 More recently, a Swedish study demonstrated that sera of anti-Jo1-positive patients with PM could activate endothelial cells in healthy lung tissue.21 Altogether, these findings reinforce the hypothesis of specific pulmonary vascular involvement in the aetiology of PH among patients with IIM and the role of anti-tRNA synthetase autoantibodies such as anti-Jo1.5 12 20 21\n\n\nInterestingly, two out of the three patients with PAH revealed the lowest diffusing capacity for carbon monoxide (DLCO) values in our study. This observation tends to suggest, conversely to PAH among patients with systemic sclerosis, that patients with IIM with PAH are associated with low DLCO values in pulmonary function test.22 23\n\n\nAlthough small retrospective studies suggested that specific PAH therapy may be used in the presence of severe PH due to chronic lung disease, the benefit of this therapy still has to be demonstrated. In our cohort, initiation of PAH treatment was performed on the discretion of the treating doctor, including six patients with ILD and one patient without ILD. Although our observations suggest that some of our patients seem to benefit from such an approach, the uncontrolled nature of this observational study does not allow to draw any conclusions on the effectiveness of such an approach in PAH.\n\nA recent French observational study showed a 3-year survival of 58% in patients with PH antisynthetase.12 The overall mortality in our study was 44% which suggests that the presence of PH was associated with a worse survival.\n\nThe strength of our study is the novelty of reporting cases of PAH among patients with IIM with complete RHC data.\n\nA limitation of our study is that all patients were recruited from two tertiary referral PH expert centres, which could have led to a selection bias. However, to study an uncommon complication (PH) in a rare disease (IIM) inevitably leads to multicentre recruitment at tertiary centres. Furthermore, limited serology data were available by which proper classification of the presence of antisynthetase syndrome and further determination of antinuclear antibody positivity was not possible.\n\nIn conclusion, in this study, we found the presence of ILD-PH in the majority (55%) of the selected patients with IIM and PH. Surprisingly, a relevant group (33%) of patients with IIM suffered from non-ILD-PH, which reflects the presence of PAH phenotype on which connective tissue disease itself plays a role in the aetiology. Vasoactive therapy could play a role in the treatment of patients with IIM and PAH phenotype. Altogether, this result should lead to more awareness among treating physicians that complaints of dyspnoea among patients with IIM could be related to PAH and not only ILD. Given the rarity of PH-IIM, a joined international effort is required to obtain more insights in the different PH phenotypes and the optimal treatment strategy of this disease.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1. \nVonk MC , van Dijk AP , Heijdra YF , et al \nPulmonary hypertension: its diagnosis and management, a multidisciplinary approach . Neth J Med \n2005 ;63 :193 –8 .16011010 \n2. \nProudman SM , Stevens WM , Sahhar J , et al \nPulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment . Intern Med J \n2007 ;37 :485 –94 .10.1111/j.1445-5994.2007.01370.x \n17547726 \n3. \nBull TM , Fagan KA , Badesch DB \nPulmonary vascular manifestations of mixed connective tissue disease . Rheum Dis Clin North Am \n2005 ;31 :451 –64 .10.1016/j.rdc.2005.04.010 \n16084318 \n4. \nHeresi GA , Minai OA \nLupus-associated pulmonary hypertension: long-term response to vasoactive therapy . Respir Med \n2007 ;101 :2099 –107 .10.1016/j.rmed.2007.05.020 \n17618103 \n5. \nLega JC , Reynaud Q , Belot A , et al \nIdiopathic inflammatory myopathies and the lung . Eur Respir Rev \n2015 ;24 :216 –38 .10.1183/16000617.00002015 \n26028634 \n6. \nYaqub S , Moder KG , Lacy MQ \nSevere, reversible pulmonary hypertension in a patient with monoclonal gammopathy and features of dermatomyositis . Mayo Clin Proc \n2004 ;79 :687 –9 .10.4065/79.5.687 \n15132415 \n7. \nMinai OA \nPulmonary hypertension in polymyositis-dermatomyositis: clinical and hemodynamic characteristics and response to vasoactive therapy . Lupus \n2009 ;18 :1006 –10 .10.1177/0961203309102822 \n19762403 \n8. \nTaniguchi Y , Horino T , Kato T , et al \nAcute pulmonary arterial hypertension associated with anti-synthetase syndrome . Scand J Rheumatol \n2010 ;39 :179 –80 .10.3109/03009740903270615 \n20109080 \n9. \nChatterjee S , Farver C \nSevere pulmonary hypertension in Anti-Jo-1 syndrome . Arthritis Care Res \n2010 ;62 :425 –9 .10.1002/acr.20109 \n\n10. \nHanda T , Nagai S , Kawabata D , et al \nLong-term clinical course of a patient with anti PL-12 antibody accompanied by interstitial pneumonia and severe pulmonary hypertension . Intern Med \n2005 ;44 :319 –25 .10.2169/internalmedicine.44.319 \n15897644 \n11. \nCavagna L , Prisco E , Montecucco C , et al \nPulmonary arterial hypertension in antisynthetase syndrome: comment on the article by Chatterjee and Farver . Arthritis Care Res \n2011 ;63 :633 –4 .10.1002/acr.20392 \n\n12. \nHervier B , Meyer A , Dieval C , et al \nPulmonary hypertension in antisynthetase syndrome: prevalence, aetiology and survival . Eur Respir J \n2013 ;42 :1271 –82 .10.1183/09031936.00156312 \n23397301 \n13. \nAggarwal R , Cassidy E , Fertig N , et al \nPatients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients . Ann Rheum Dis \n2014 ;73 :227 –32 .10.1136/annrheumdis-2012-201800 \n23422076 \n14. \nGaliè N , Humbert M , Vachiery JL , et al \n2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) . Eur Respir J \n2015 \n2015 ;46 :903 –75 .10.1183/13993003.01032-2015 \n26318161 \n15. \nLabirua A , Lundberg IE \nInterstitial lung disease and idiopathic inflammatory myopathies: progress and pitfalls . Curr Opin Rheumatol \n2010 ;22 :633 –8 .10.1097/BOR.0b013e32833f1970 \n20827201 \n16. \nHoogendijk JE , Amato AA , Lecky BR , et al \n119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands . Neuromuscul Disord \n2004 ;14 :337 –45 .10.1016/j.nmd.2004.02.006 \n15099594 \n17. \nGoh NS , Desai SR , Veeraraghavan S , et al \nInterstitial lung disease in systemic sclerosis: a simple staging system . Am J Respir Crit Care Med \n2008 ;177 :1248 –54 .10.1164/rccm.200706-877OC \n18369202 \n18. \nWells AU , Hansell DM , Rubens MB , et al \nThe predictive value of appearances on thin-section computed tomography in fibrosing alveolitis . Am Rev Respir Dis \n1993 ;148 (4 Pt 1 ):1076 –82 .10.1164/ajrccm/148.4_Pt_1.1076 \n8214928 \n19. \nMcGoon M , Gutterman D , Steen V , et al \nScreening, early detection, and diagnosis of pulmonary arterial hypertension: accp evidence-based clinical practice guidelines . Chest \n2004 ;126 (1 Suppl ):14S –34 .10.1378/chest.126.1_suppl.14S \n15249493 \n20. \nDenbow CE , Lie JT , Tancredi RG , et al \nCardiac involvement in polymyositis: a clinicopathologic study of 20 autopsied patients . Arthritis Rheum \n1979 ;22 :1088 –92 .486220 \n21. \nBarbasso Helmers S , Englund P , Engström M , et al \nSera from anti-Jo-1-positive patients with polymyositis and interstitial lung disease induce expression of intercellular adhesion molecule 1 in human lung endothelial cells . Arthritis Rheum \n2009 ;60 :2524 –30 .10.1002/art.24683 \n19644880 \n22. \nHachulla E , Gressin V , Guillevin L , et al \nEarly detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study . Arthritis Rheum \n2005 ;52 :3792 –800 .10.1002/art.21433 \n16320330 \n23. \nMukerjee D , St George D , Knight C , et al \nEchocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis . Rheumatology \n2004 ;43 :461 –6 .10.1093/rheumatology/keh067 \n15024134\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2056-5933",
"issue": "3(1)",
"journal": "RMD open",
"keywords": "Dermatomyositis; Polymyositis; Pulmonary Fibrosis; Treatment",
"medline_ta": "RMD Open",
"mesh_terms": null,
"nlm_unique_id": "101662038",
"other_id": null,
"pages": "e000331",
"pmc": null,
"pmid": "28879041",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "8214928;15249493;15099594;16320330;17547726;17618103;20109080;26028634;486220;23422076;16084318;19644880;23397301;26318161;19762403;21452276;16011010;15024134;18369202;15132415;15897644;20827201;20391490",
"title": "Pulmonary arterial hypertension, a novelty in idiopathic inflammatory myopathies: insights and first experiences with vasoactive therapy.",
"title_normalized": "pulmonary arterial hypertension a novelty in idiopathic inflammatory myopathies insights and first experiences with vasoactive therapy"
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"abstract": "Multiple myeloma is a malignancy of plasma cell proliferation leading to production of monoclonal immunoglobins. Among the classic features of multiple myeloma are bone lesions, which typically manifest in the axial skeleton, vertebrae, pelvis, skull, ribs, and proximal extremities. The several types of multiple myeloma include symptomatic multiple myeloma, monoclonal gammopathy of undetermined significance, smoldering/indolent myeloma, and solitary plasmacytoma of bone. Although rare, plasmacytomas of the foot and ankle have been described in published studies. We present, to the best of our knowledge, the first description of classic diffuse myelomatosis lesions associated with symptomatic myeloma in the foot of a patient with advanced disease who was treated in the podiatric surgery clinic for pathologic fracture.",
"affiliations": "Resident, Department of Surgery, Steward St. Elizabeth's Medical Center, Brighton, MA. Electronic address: benjamin.saviet@my.rfums.org.;Podiatric Surgery Residency Director, Department of Surgery, Steward St. Elizabeth's Medical Center, Brighton, MA.;Attending Physician and Assistant Professor, Department of Hematology Oncology, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA.",
"authors": "Saviet|Benjamin M|BM|;Marcoux|John T|JT|;Narayanasami|Uma|U|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1053/j.jfas.2016.11.020",
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"issn_linking": "1067-2516",
"issue": "56(2)",
"journal": "The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons",
"keywords": "foot; lytic lesions; myelomatosis; pathologic fracture; toe",
"medline_ta": "J Foot Ankle Surg",
"mesh_terms": "D001859:Bone Neoplasms; D005598:Fractures, Spontaneous; D006801:Humans; D008297:Male; D008682:Metatarsal Bones; D008875:Middle Aged; D009101:Multiple Myeloma; D035583:Rare Diseases; D050277:Toe Phalanges",
"nlm_unique_id": "9308427",
"other_id": null,
"pages": "357-361",
"pmc": null,
"pmid": "28231967",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rare Pedal Manifestation of Diffuse Multiple Myeloma Lesions.",
"title_normalized": "rare pedal manifestation of diffuse multiple myeloma lesions"
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"companynumb": "US-CELGENEUS-USA-2017039542",
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{
"abstract": "BACKGROUND\nAnti-tumour necrosis factor [TNF] therapy in combination with thiopurine is the most effective strategy for Crohn's disease, but raises safety concerns.\n\n\nMETHODS\nIn a retrospective multicentre study, we investigated long-term outcome of patients starting anti-TNF monotherapy for Crohn's disease and investigated whether introducing an immunomodulator in patients losing response to anti-TNF monotherapy is effective for resetting immunogenicity.\n\n\nRESULTS\nA total of 350 adult patients with Crohn's disease received either infliximab [n = 178, 51%] or adalimumab [n = 172, 49%] monotherapy. Mean duration of follow-up was 42 months. An immunomodulator was initiated in 53 patients [15%]. At last follow-up, 73.1% [n = 38] were in clinical remission [one patient with missing data]. Multivariate analysis identified anti-TNF type [higher need for starting immunomodulator for infliximab than for adalimumab; p = 0.0058] and first- vs second-/third-/fourth-line anti-TNF therapy [p = 0.014] as predictors of immunomodulator initiation. Among the 18 patients with available data, introduction of an immunomodulator was able to restore infliximab trough level within the therapeutic range and to induce clinical remission in 10 patients [55%]. Cumulative probability of remaining on anti-TNF therapy was 57.9% at 5 years among the 297 patients not starting an immunomodulator during follow-up.\n\n\nCONCLUSIONS\nAn immunomodulator was initiated in 15% of patients with Crohn's disease starting anti-TNF monotherapy. Independent predictors of immunomodulator initiation were infliximab use and second-/third-/fourth-line anti-TNF therapy. Resetting immunogenicity with an immunomodulator was effective in half of patients in a sub-study. Persistence of anti-TNF treatment at 5 years was observed in half of the 297 patients not starting an immumodulator in a real-life setting.",
"affiliations": "Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, Nancy, France peyrinbiroulet@gmail.com.;Department of Biostatistics, Institut de Cancérologie de Lorraine, Vandoeuvre les Nancy, France.;Institute for Research on Cancer and Aging, Department of Gastroenterology & Nutrition, Hôpital de l'Archet, Nice, France.;Gastroenterology Department, University of Liège, Liège, Belgium.;Institute for Research on Cancer and Aging, Department of Gastroenterology & Nutrition, Hôpital de l'Archet, Nice, France.;Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, Nancy, France.;Gastroenterology Department, University of Liège, Liège, Belgium.;Institute for Research on Cancer and Aging, Department of Gastroenterology & Nutrition, Hôpital de l'Archet, Nice, France.;Gastroenterology Department, University Hospital of Saint-Etienne, Saint-Etienne, France.",
"authors": "Peyrin-Biroulet|Laurent|L|;Salleron|Julia|J|;Filippi|Jérôme|J|;Reenaers|Catherine|C|;Antunes|Ophélie|O|;Filipe|Virginie|V|;Louis|Edouard|E|;Hébuterne|Xavier|X|;Roblin|Xavier|X|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D000069285:Infliximab; D000068879:Adalimumab; D001379:Azathioprine; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjw008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "10(5)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Crohn’s disease; Infliximab; adalimumab; anti-TNF monotherapy",
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents; D001379:Azathioprine; D003424:Crohn Disease; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "516-24",
"pmc": null,
"pmid": "26802084",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "25863276;25067824;24809234;21646246;25110252;20393175;21407178;19861953;23103905;19174781;24013361;18832518;23662928;22139830;21228429;24970900",
"title": "Anti-TNF Monotherapy for Crohn's Disease: a 13-year Multicentre Experience.",
"title_normalized": "anti tnf monotherapy for crohn s disease a 13 year multicentre experience"
} | [
{
"companynumb": "FR-JNJFOC-20160505249",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
"drugadditional": null,
... |
{
"abstract": "Corticosteroids and immunosuppressive agents are considered mainstays of therapy for connective tissue disease-related interstitial lung disease (CTD-ILD); however, tacrolimus with corticosteroid therapy has not been fully investigated. Our objectives were to examine the multidimensional therapeutic benefit and tolerability of the combined therapy for the initial treatment of patients with CTD-ILD.\n\n\n\nIn this retrospective case series, we identified consecutive CTD-ILD patients treated with tacrolimus plus intravenous (i.v.) methylprednisolone (1000 mg i.v. 3 days a week for 2 weeks) followed by low-dose prednisolone (10 mg/day). We assessed the multidimensional therapeutic benefit and tolerability including lung physiology, exercise capacity, exercise oxygen desaturation, modified Medical Research Council (MMRC) and St George's Respiratory Questionnaire (SGRQ).\n\n\n\nA total of 26 ILD patients with the underlying CTD diagnoses included 11 with rheumatoid arthritis, 9 with dermatomyositis, 4 with Sjögren's syndrome and 2 others. From baseline to 12 months, the combined therapy significantly improved forced vital capacity (FVC; 77.8% to 94.6%, P < 0.001), diffusing capacity of the lung for carbon monoxide (DLCO ; 66.1% to 75.1%, P < 0.001), 6-min walk distance (6MWD; 530 to 568 m, P = 0.02), lowest oxygen saturation on pulse oximetry (SpO2 ; 85% to 89%, P = 0.01), MMRC (1.3 to 0.8, P = 0.01) and SGRQ (38 to 21, P < 0.001). During the study period, only one patient's therapy was discontinued due to an adverse event and none had a life-threatening adverse event attributed to the combined therapy.\n\n\n\nIn our cohort of CTD-ILD, two courses of pulse dose methylprednisolone therapy followed by prednisone and oral tacrolimus appeared to be well tolerated, and to have multidimensional efficacy.",
"affiliations": "Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan.;Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan.;Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan.;Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.;Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Radiology, Kinki Central Hospital of Mutual Aid Association of Public Health Teachers, Itami, Japan.;Department of Laboratory of Pathology, Nagasaki University Hospital, Nagasaki, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Yamano|Yasuhiko|Y|0000-0002-7779-9215;Taniguchi|Hiroyuki|H|;Kondoh|Yasuhiro|Y|0000-0001-7456-5459;Ando|Masahiko|M|;Kataoka|Kensuke|K|;Furukawa|Taiki|T|;Johkoh|Takeshi|T|;Fukuoka|Junya|J|;Sakamoto|Koji|K|;Hasegawa|Yoshinori|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D011241:Prednisone; D016559:Tacrolimus; D008775:Methylprednisolone",
"country": "Australia",
"delete": false,
"doi": "10.1111/resp.13365",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1323-7799",
"issue": "23(11)",
"journal": "Respirology (Carlton, Vic.)",
"keywords": "autoimmune disease; collagen vascular diseases; interstitial lung disease; quality of life; respiratory function test",
"medline_ta": "Respirology",
"mesh_terms": "D000368:Aged; D003240:Connective Tissue Diseases; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D008168:Lung; D017563:Lung Diseases, Interstitial; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D011241:Prednisone; D020551:Pulse Therapy, Drug; D012129:Respiratory Function Tests; D012189:Retrospective Studies; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "9616368",
"other_id": null,
"pages": "1041-1048",
"pmc": null,
"pmid": "30011421",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Multidimensional improvement in connective tissue disease-associated interstitial lung disease: Two courses of pulse dose methylprednisolone followed by low-dose prednisone and tacrolimus.",
"title_normalized": "multidimensional improvement in connective tissue disease associated interstitial lung disease two courses of pulse dose methylprednisolone followed by low dose prednisone and tacrolimus"
} | [
{
"companynumb": "JP-EDENBRIDGE PHARMACEUTICALS, LLC-JP-2018EDE000373",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "BACKGROUND\nHoarding behaviour, which is generally defined as collecting and keeping unnecessary, cheap objects or things that can not be used, is more common in elderly than young people. The prevelance of hoarding behaviour in dementia was reported as 22%. In this paper, three different types of dementia cases are presented in order to emphasize the clinical awareness for hoarding disorder, which is common in the elderly, especially those with dementia.\n\n\nMETHODS\nThe first case is a patient with a diagnosis of frontotemporal dementia who was collecting old things before the appearance of bahavioural changes like verbal and physical agitation. The second one is a patient who was admitted with complaints of forgetting, diagnosed as having Alzheimer's Disease and presented with paper hoarding behavior in his clinical follow-up. The last patient was presented with visual hallucinations, forgetting, collecting old things and depressive symptoms. He received a diagnosis of Lewy body dementia.\n\n\nCONCLUSIONS\nIt is prominent that all three different dementia cases hoarding behavior at early stages of dementia. It should be kept in mind that hoarding behavior which begins at late life might be a sign of dementia or it might appear in the dementia process.",
"affiliations": null,
"authors": "Biçer Kanat|Bilgen|B|;Altunöz|Umut|U|;Kırıcı|Sevinç|S|;Baştuğ|Gülbahar|G|;Özel Kızıl|Erguvan Tuğba|ET|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-2163",
"issue": "27(2)",
"journal": "Turk psikiyatri dergisi = Turkish journal of psychiatry",
"keywords": null,
"medline_ta": "Turk Psikiyatri Derg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D003704:Dementia; D003937:Diagnosis, Differential; D000067836:Hoarding Disorder; D006801:Humans; D008297:Male; D011594:Psychometrics",
"nlm_unique_id": "9425936",
"other_id": null,
"pages": "0",
"pmc": null,
"pmid": "27370065",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hoarding Behavıour in Three Different Types of Dementia Cases.",
"title_normalized": "hoarding behav our in three different types of dementia cases"
} | [
{
"companynumb": "PHHY2016TR092498",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RIVASTIGMINE"
},
"drugadditional": null,
"d... |
{
"abstract": "There are 20.8 million Americans with diabetes, and metformin is the most commonly prescribed oral diabetes agent. A review of our metformin experience highlights common pitfalls that lead to life-threatening or fatal poisonings. We describe 3 patients with metformin toxicity; 2 of 3 patients were prescribed metformin despite end-stage renal disease (ESRD). Case 1: a 40-year-old woman presented after a polysubstance overdose. Within 8 h, vomiting and lethargy developed; a profound acidosis, pH 6.95, pCO(2) 26, pO(2) 195, and elevated serum lactate 21 mmol/L (ref 0.5-1.6 mmol/L) were noted. Further inquiry revealed that the patient had ingested metformin. She was intubated; bicarbonate therapy and hemodialysis were initiated; however, she became hypotensive and died. A metformin level was 150 μg/mL (therapeutic 1-2 μg/mL). Case 2: a 69-year-old woman with non-insulin-dependent diabetes mellitus (NIDDM) and ESRD presented to the Emergency Department (ED), having missed dialysis. She was sluggish and complained of abdominal pain; an acidosis, pH 7.37, pCO(2) 20, pO(2) 171; anion gap 38, and elevated serum lactate 18.9 mmol/L were noted. Hemodialysis was initiated when it was revealed that she took metformin daily. She improved rapidly and a metformin level was 27.4 μg/mL. Case 3: a 57-year-old woman with a history of NIDDM and ESRD presented with dyspnea. Laboratory studies showed pH 7.03, pCO(2) 21, pO(2) 99; anion gap 36, and lactate 16 mmol/L. Bicarbonate therapy and hemodialysis were initiated after discovering that she had recently been prescribed metformin. She had a fatal cardiac arrest after dialysis was completed. We describe 3 ED patients with occult metformin toxicity diagnosed after laboratory results showed an anion gap metabolic acidosis and elevated lactate levels. All patients had lethargy, vomiting, or abdominal pain, also suggesting sepsis or mesenteric infarction. Despite sodium bicarbonate therapy and hemodialysis, metformin-associated lactic acidosis was fatal in 2 of 3 patients. Emergency Physicians must be vigilant to recognize metformin toxicity in patients at high risk for metformin-associated lactic acidosis.",
"affiliations": "Department of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.",
"authors": "Perrone|Jeanmarie|J|;Phillips|Carolyn|C|;Gaieski|David|D|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2007.11.055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "40(3)",
"journal": "The Journal of emergency medicine",
"keywords": null,
"medline_ta": "J Emerg Med",
"mesh_terms": "D000140:Acidosis, Lactic; D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D004636:Emergency Service, Hospital; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D008875:Middle Aged; D006435:Renal Dialysis; D018570:Risk Assessment; D012494:Sampling Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "271-5",
"pmc": null,
"pmid": "18571361",
"pubdate": "2011-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Occult metformin toxicity in three patients with profound lactic acidosis.",
"title_normalized": "occult metformin toxicity in three patients with profound lactic acidosis"
} | [
{
"companynumb": "US-Glenmark Generics Europe Ltd.-GGEL20110800780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Drug-induced liver injury (DILI) is the leading cause of liver failure in the United States and the most common cause of drug recall. As opposed to the recognized direct toxicity of super-therapeutic acetaminophen or chemotherapeutic agents in children, limited data exists for pediatric populations on the incidence of idiosyncratic DILI (iDILI) that may develop independently of drug dose or duration of administration. To improve the detection of adverse drug reactions at our hospital, we utilized electronic medical records-based automated trigger tools to alert providers of potential iDILI. Clinical criteria concerning for iDILI were defined as serum ALT > 5x or serum bilirubin > 1.5x upper limit of normal in the setting of medication exposure. Over a two year period, 12 patients were identified as having possible or probable iDILI. Out of the identified patients, three were males, and the mean age was 10.8 years. Implicated agents included eight antibiotics, two anti-epileptics, one anti-psychotic, and one anti-inflammatory medication. Roussel-Uclaf Causality Assessment Methods identified one \"possible\" case, 11 \"probable\" cases, and one \"highly probable\" case of iDILI. Improved awareness and more vigilant programming can generate better data on iDILI and improve our understanding of the condition and its incidence in children.",
"affiliations": "Children's Mercy Hospital, Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Kansas City, MO, USA.;Children's Mercy Hospital, Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Kansas City, MO, USA.;The University of Tennessee Health Science Center, Department of Pediatrics, Memphis, TN, USA.;Children's Mercy Hospital, Division of Gastroenterology, Kansas City, MO, USA.;Children's Mercy Hospital, Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Kansas City, MO, USA.;Children's Mercy Hospital, Division of Gastroenterology, Kansas City, MO, USA. rtfischer@cmh.edu.",
"authors": "Sandritter|Tracy L|TL|;Goldman|Jennifer L|JL|;Habiger|Clayton J|CJ|;Daniel|James F|JF|;Lowry|Jennifer|J|;Fischer|Ryan T|RT|http://orcid.org/0000-0002-2576-4694",
"chemical_list": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1038/s41598-019-54075-4",
"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 5407510.1038/s41598-019-54075-4ArticleAn electronic medical records-based approach to identify idiosyncratic drug-induced liver injury in children Sandritter Tracy L. 1Goldman Jennifer L. 12Habiger Clayton J. 3Daniel James F. 4Lowry Jennifer 1http://orcid.org/0000-0002-2576-4694Fischer Ryan T. rtfischer@cmh.edu 41 Children’s Mercy Hospital, Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Kansas City, MO USA 2 Children’s Mercy Hospital, Division of Infectious Disease, Kansas City, MO USA 3 0000 0004 0386 9246grid.267301.1The University of Tennessee Health Science Center, Department of Pediatrics, Memphis, TN USA 4 Children’s Mercy Hospital, Division of Gastroenterology, Kansas City, MO USA 2 12 2019 2 12 2019 2019 9 1809023 8 2019 30 10 2019 © The Author(s) 2019Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Drug-induced liver injury (DILI) is the leading cause of liver failure in the United States and the most common cause of drug recall. As opposed to the recognized direct toxicity of super-therapeutic acetaminophen or chemotherapeutic agents in children, limited data exists for pediatric populations on the incidence of idiosyncratic DILI (iDILI) that may develop independently of drug dose or duration of administration. To improve the detection of adverse drug reactions at our hospital, we utilized electronic medical records-based automated trigger tools to alert providers of potential iDILI. Clinical criteria concerning for iDILI were defined as serum ALT > 5x or serum bilirubin > 1.5x upper limit of normal in the setting of medication exposure. Over a two year period, 12 patients were identified as having possible or probable iDILI. Out of the identified patients, three were males, and the mean age was 10.8 years. Implicated agents included eight antibiotics, two anti-epileptics, one anti-psychotic, and one anti-inflammatory medication. Roussel-Uclaf Causality Assessment Methods identified one “possible” case, 11 “probable” cases, and one “highly probable” case of iDILI. Improved awareness and more vigilant programming can generate better data on iDILI and improve our understanding of the condition and its incidence in children.\n\nSubject terms\nAutoimmune hepatitisHepatotoxicityissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nDrug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States1 and the most common cause of drug recall from the market2. Recent data demonstrate that in adult patients with confirmed DILI, one in 10 will need to undergo transplantation and one in six will have evidence of long term liver injury six months after initial suspected damage3. In an analysis by Mindikoglu and colleagues of 73,977 patients (adults and children) that underwent transplant from October of 1987 to December of 2006, they identified 661 cases of drug-induced acute liver failure. Ninety-four of these were in children, with acetaminophen being responsible for the largest portion of cases (29%)4. The Pediatric Acute Liver Failure Study Group showed that DILI accounted for 16% of acute liver failure cases in the United States5. Again, the most common etiology was acetaminophen overdose (12% of all acute liver failure), and 4% were due to non-acetaminophen drug injury5.\n\nWhile the direct hepatotoxicity of super-therapeutic acetaminophen is well-described6, the less frequent, idiosyncratic causes of DILI (iDILI) in pediatric patients remain poorly understood. Exposure to antimicrobials, antiepileptics, antidepressants, and medications for attention deficit disorders represent most iDILI cases in children4,7,8. Active surveillance of pediatric iDILI is rare. The diagnosis and—as importantly—the determination of iDILI causality remains a significant obstacle in clinical practice. This difficulty can be attributed to several key factors. Clinically, biochemically, and histologically, iDILI can resemble many forms of both acute and chronic liver injury. Definitive laboratory studies are lacking, further complicating the diagnosis, and determination of drug causality is limited to scoring systems that were not designed for pediatric patients.\n\nChildren’s Mercy Hospital (CMH) is a 354-bed, tertiary care, free-standing children’s hospital in Kansas City, MO. To better characterize and detect possible adverse drug reactions (ADR) in children, our hospital developed a campus-wide pharmacovigilance service, the Drug Safety Service (DSS) in October 2010. The DSS is operated by a dedicated clinical pharmacist in the Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation with the support of the Pharmacy Department. A detailed description of the development and operation of the program has been previously described9. The goal of the program is to identify and improve documentation of potential adverse drug reaction cases, and in turn, better understand medications associated with toxicity and possible preventive strategies. To further enhance the identification of ADR, specifically related to DILI, EMR triggers were developed and implemented in 2012 to screen patients for potential DILI. Herein, we assess two years of cases associated with pediatric iDILI and report on the implicated agents as well as associated clinical and laboratory characteristics in our population.\n\nResults\nA total of 3,275 inpatient and outpatient lab values were assessed during the study period with 791 and 2,484 values triggering alanine aminotransferase (ALT) and bilirubin criteria, respectively (Fig. 1). Following the exclusion of redundant patients (triggers of the same type in the same patient that corresponded to an already assessed case) a total of 1,515 unique events remained with 453 ALT and 1,062 bilirubin triggers. Both values were triggered simultaneously in 90 patients. This represents a mean of 3.0 unique triggers to review per week day averaging five minutes per review. Of the unique ALT triggers, 2.6% (n = 12) were considered possible or probable iDILI (Table 1). However, 26% of these ALT triggers were associated with chemotherapy. When chemotherapy ALT triggers were excluded, possible or probable iDILI rose to 3.4%. Of the non-chemotherapy bilirubin triggers, only 0.5% (n = 5) were associated with iDILI. No cases of iDILI were associated with an isolated bilirubin trigger as all patients had an elevated ALT.Figure 1 Workflow for the identification of possible idiosyncratic drug-induced liver injury.\n\nTable 1 Percent of ALT elevations associated with underlying causes.\n\nProbable Etiologies of ALT Triggers\t\n\tNumber\tPercent of Total\t\nAll Events\t453\t100.0\t\nChemotherapy\t118\t26.0\t\nInfection\t68\t15.0\t\nTrauma\t29\t6.4\t\nCongenital Liver Disease\t23\t5.1\t\nCardiac Disease\t22\t4.8\t\nMusculoskeletal Disease\t15\t3.3\t\nSepsis\t15\t3.3\t\nCholelithiasis/Cholecystitis\t14\t3.1\t\nDILI\t12\t2.6\t\nParenteral Nutrition Use\t12\t2.6\t\nUnknown\t40\t8.8\t\nMiscellaneous*\t85\t18.7\t\n*Includes diagnoses with fewer than 10 cases (e.g., cystic fibrosis, liver transplant, etc.).\n\n\n\nOverall, 67,817 ALT values and 75,306 bilirubin levels were obtained across the inpatient and outpatient settings in our hospital system during the examined years. Focusing on ALT values, these were obtained from 27,130 unique patients in the two years studied. Thus, only 1.6% of the unique patients with ALT levels drawn had a triggering ALT (n = 453), and only 0.04% (n = 12) had iDILI. Interestingly, the inpatient setting accounted for only 8% (n = 2,182) of unique patient ALT levels, but 55% (n = 253) of the observed ALT triggers.\n\niDILI clinical characteristics\nTwelve possible or probable cases of iDILI were found in our assessment and their characteristics are listed in Table 2. Majority of patients were female (N = 9; 75%) and in early adolescence with an average age of 10.8 years. Symptoms at the time of presentation varied significantly; fever (n = 7), fatigue (n = 6), rash, abdominal pain, jaundice (n = 5 for each), arthralgia, nausea/vomiting, and pruritus (n = 4 for each) were experienced by patients (Table 3). The majority of patients displayed a hepatocellular injury pattern based on the application of the Roussel-Uclaf Causality Assessment Method (RUCAM)10,11. The RUCAM assessment first defines whether an injury is “hepatocellular,” “mixed,” or “cholestatic” based on the “R ratio.” Nine patients had hepatocellular injury with a minority presenting with a mixed pattern (n = 3). No patients presented with a cholestatic injury pattern alone, as defined by the R ratio (Table 2). Six patients were evaluated for iDILI in the inpatient setting, with five of those patient admissions being related to iDILI. Four hospitalized patients had iDILI with hypersensitivity features, including two with drug reaction with eosinophilia and systemic symptoms (DRESS) and one that developed hemophagocytic lymphohistiocytosis (HLH). The four patients with hypersensitivity reactions required steroids and hospitalization, while the HLH patient was the only one to develop an associated coagulopathy. No patient developed liver failure in our series, nor did any patient undergo liver biopsy.Table 2 Demographic and clinical features of iDILI patients.\n\niDILI Patient Characteristics\t\n\tHospitalized (n = 6)\tOutpatient (n = 6)\tp-value\t\nFemale gender\t5 (83%)\t4 (67%)\t\t\nMean age (years)\t10.2\t11.4\t0.74\t\nInjury type (based on R ratio*)\t\t\t\t\n Hepatitis\t5\t4\t\t\n Cholestatic\t0\t0\t\t\n Mixed\t1\t2\t\t\nMean peak ALT (U/L)\t1251.7\t898.5\t0.6\t\nMean peak bilirubin (gm/dL)\t4.6\t2.1\t0.23\t\nMean eosinophils (cells/mcL)\t0.36\t0.12\t0.27\t\nEtiology\t\nAntimicrobials\t3\t5\t\t\n Oxacillin\t1\t\t\t\n Minocycline\t\t2\t\t\n Doxycycline\t\t1\t\t\n Azithromycin\t1\t\t\t\n Trimethroprim\t\t1\t\t\n Trimethoprim- sulfamethoxazole\t1\t\t\t\n Amoxicillin\t\t1\t\t\nAntiepileptics\t2\t\t\t\n Lamotrigine\t1\t\t\t\n Carbamazepine\t1\t\t\t\nAntipsychotics\t\t1\t\t\n Aripiprazole\t\t1\t\t\nAnti-inflammatory\t1\t\t\t\n Sulfasalazine\t1\t\t\t\nSteroid treatment\t4 (67%)\t0 (0%)\t\t\nMean RUCAM\t7.5\t7.8\t0.65\t\n*R = (ALT value/ALT ULN)/(ALKP value/ALKP ULN).\n\nR > 5 = hepatocellular, R < 2 = cholestatic, R between 2 and 5 = mixed.\n\nTable 3 Reported signs and symptoms in children with iDILI.\n\nSymptoms associated with iDILI\t\nPatient No.\tJaundice\tJoint pain\tRash\tFever\tNaseua/vomiting\tAbdominal pain\tFatigue\tPruritus\t\n1\t\t\tX\t\t\t\t\tX\t\n2\t\tX\t\t\t\tX\tX\t\t\n3\tX\t\tX\tX\tX\tX\tX\tX\t\n4\t\tX\t\t\t\tX\tX\t\t\n5\tX\t\t\tX\t\tX\t\t\t\n6\tX\tX\t\tX\t\t\tX\t\t\n7\t\t\tX\tX\t\t\t\tX\t\n8\t\t\t\t\t\tX\tX\t\t\n9\t\tX\tX\tX\tX\t\t\tX\t\n10\t\t\t\t\t\t\t\t\t\n11\tX\t\tX\tX\tX\t\tX\t\t\n12\tX\t\t\tX\tX\t\t\t\t\n\n\nLaboratory values\nOf the 12 cases of iDILI described, all 12 triggered our DSS based on ALT and five triggered based on both ALT and bilirubin levels. No cases were identified using the bilirubin trigger alone. The mean initial ALT value was 840 U/L, with the mean peak being 1075 U/L for all iDILI cases. The mean initial total bilirubin level in iDILI patients was 2.7 mg/dL with an average peak value of 3.4 mg/dL. In the majority of cases, initial ALT and bilirubin values were the peak values, and they did not vary significantly between hospitalized and non-hospitalized patients. The mean peak ALT in iDILI-related hospitalized patients was 1251.7 U/L and the mean peak ALT in non-hospitalized patients was 898.5 U/L, with a p-value of 0.6. The mean peak bilirubin in hospitalized versus non-hospitalized patients was 4.6 and 2.1, respectively (p = 0.28). These data are detailed in Table 4.Table 4 Detailed clinical features of iDILI patients.\n\nPatient\tSuspected Agent\tAge at iDILI (years)\tSex\tType of Injury*\tTime to symptoms (days)\tTime from symptoms to trigger\tPeak ALT\tPeak ALP\tPeak GGT\tPeak Bili\tEosinophils (cells x 103/mcL)\tRUCAM\tHospitalization (days)\tType of Reaction\t\n1\tOxacillin\t6.3\tM\t1\t22\t3\t898\t222\tND\t0.4\t0.01\t7\t25 (unrelated)\tHepatitis\t\n2\tMinocycline\t15.3\tF\t1\t84\t0\t1131\t288\t105\t1\t0\t8\t0\tHepatitis\t\n3\tLamotrigine\t15.9\tF\t3\t75\t33\t470\t294\t1146\t8.5\t0.01\t8\t41\tDIHS-HLH\t\n4\tMinocycline\t16.8\tF\t1\t731\t15\t1763\t184\t157\t0.9\t0.24\t8\t0\tHepatitis\t\n5\tAzithromycin\t3.9\tF\t1\t3\t0\t4438\t546\t140\t10.1\t0.13\t7\t3\tHepatitis\t\n6\tDoxycyline\t16.8\tF\t3\t92\t6\t344\t214\t136\t3.4\t0.03\t8\t0\tHepatitis\t\n7\tSulfasalazine\t3.7\tF\t1\t21\t8\t463\t201\tND\t0.9\t1.2\t8\t13\tDIHS-DRESS\t\n8\tAripiprazole\t11.0\tM\t1\t32\t0\t206\t43\t31\t0.7\t0.12\t5\t0\tHepatitis\t\n9\tCarbamazepine\t16.9\tF\t1\t8\t3\t814\t69\t115\t0.4\t0.2\t7\t13\tDIHS\t\n10\tTrimethoprim\t1.2\tM\t1\t213\t0\t944\t292\tND\t0.3\t0.12\t10\t0\tHepatitis\t\n11\tTrimethoprim-sulfamethoxazole\t14.6\tF\t3\t25\t6\t427\t313\tND\t7.2\t0.6\t8\t8\tDIHS-DRESS\t\n12\tAmoxicillin\t7.3\tF\t3\t8\t0\t1003\t276\tND\t6.6\t0.2\t8\t0\tHepatitis\t\n*(1 = hepatocellular; 2 = cholestatic; 3 = mixed).\n\nDIHS = drug-induced hypersensitivity; HLH = hemophagocytic lymphohistiocytosis; DRESS = drug reaction with eosinophilia and systemic symptoms.\n\n\n\nNon-DILI ALT triggers\nFurther investigation revealed that ALT elevations attributed to infection (n = 68), trauma (n = 29), congenital cholestasis (biliary atresia, Alagille, etc.; n = 23), and congenital heart disease (n = 22) made up the largest proportions of patients with ALT triggers not associated with iDILI (Table 1). Investigation into the bilirubin triggers revealed that most of the non-iDILI cases were related to physiologic/human milk jaundice and hemoglobinopathies (e.g., sickle cell disease and thalassemias).\n\nSuspected drugs and causality assessment\nAntimicrobials (n = 8) were the most prevalent drug class associated with DILI. Additionally, anti-epileptics (n = 2), anti-psychotics (n = 1) and anti-inflammatory agents (n = 1) were identified. Minocycline (n = 2) and trimethoprim-sulfamethoxazole (n = 2) were the most commonly implicated single agents (Table 4). Acne and other bacterial infections were the most common indications for suspected medication use. The average RUCAM score for all groups was 7.7.\n\nTemporal relationship\nFollowing the first reported dose of a suspected medication, the median time to initial presentation of symptoms (or lab trigger if asymptomatic) was 28.5 days (range 3 to 731). The EMR trigger occurred a median of three days (range 0–33) following onset of reported symptoms. The majority of patients had a relatively benign clinical course, with no chronic liver disease identified in a median of 4.1 years of follow-up (range 1.8–5.0 years). Six patients were identified and managed in the outpatient setting and did not require hospitalization. The median number of hospital days for the six hospitalized patients was 13 (range 3–41). The median time to normalization of ALT following the recognized iDILI was 35 days, with there being no significant difference between patients managed in the inpatient setting and those seen as outpatients. Hospitalized patients normalized their ALT in an average of 19.2 days, while the ALT was noted to be in the normal range for outpatient iDILI patients after an average of 154.3 days (p = 0.15). Outpatients typically did not have the same frequency of lab draws as inpatients, and they did not receive steroids during recovery.\n\nDiscussion\nIn this study, we have examined the utility of a dedicated pharmacovigilance program in detecting iDILI. In two years, 12 cases of possible, probable, or highly probable cases of liver injury were identified at our single center, a rate of detection that compares favorably to the 66 possible or probable pediatric cases identified in a 13-year, six-center study7,8. This is important in a number of respects. First, our study shows that iDILI detection rates may increase with implementation of an inpatient and outpatient service dedicated to identification of potential iDILI cases, and that pediatric iDILI is likely under-recognized. Two, this study emphasizes the fact that medications prescribed for both serious and relatively benign indications can lead to significant liver injury.\n\nDetection and identification of iDILI is challenging for multiple reasons. As with other drug-induced diseases, the diagnosis of DILI is a diagnosis of exclusion or all other possible cause (e.g., Hep A, B, C infection, alpha-1-antitrypsin, Wilson’s disease). Drug exposure correlation is highly variable (days to months)12. The time of onset of liver dysfunction varies depending on the drug and the patient and can be long after the first ingestion of drug which might provide a false security that there is not a drug induced cause. For example minocycline and atomoxetine are both noted to have a prolonged latency (minocycline: median 569 days (range 196–647) and atomoxetine: median 510 days (range 117–699))7.\n\nAdditionally, unique diagnostic difficulties exist for determining iDILI in pediatrics. Specifically, the current laboratory assessment for DILI included the use of alkaline phosphate. Alkaline phosphatase is expressed in liver tissues and increases during cholestasis. However, increased serum alkaline phosphate can be a result of accelerated bone growth and excessive enzyme secretion by osteoblasts in children and therefore is a poor marker of DILI in children13. The RUCAM, the primary DILI causality assessment tool, requires the measurement of the alkaline phosphatase (ALKP) to ALT ratio to characterize injury. Substituting measurement of gamma-glutamyl transferase (GGT) for ALKP should be studied in iDILI causality assessments. We noted that the GGT, when measured, increased in conjunction with the transaminases and bilirubin. Some cases of cholestasis had higher GGT elevations than others. We would presume that GGT may more accurately correspond to a cholestatic iDILI response relative to alkaline phosphatase. Unfortunately, GGT is not part of the standard liver panel at many centers (including our own) and we have limited data on GGT significance in DILI. The necessary integration of an unreliable marker (alkaline phosphatase) in pediatric patients may confound the score and merits the development of a novel pediatric causality assessments.\n\nLiver biopsy may be helpful in identifying microscopic changes that differentiate DILI from liver injury of other origins, though it is not an obligatory part of the DILI workup14. DILI may present histologically in the form of a number of different liver diseases, and biopsies may be non-specific. As reviewed by Teschke and Frenzel15, anywhere from 13–65% of patients in DILI case series from the past two decades undergo biopsy. Interestingly, no patient in our series underwent liver biopsy. A rapid recovery in most patients was observed following withdrawal of the implicated drug, sometimes in combination with immunosuppressive therapy, thus eliminating the necessity of biopsy. While biopsy may indeed be important in assessing more chronic forms of liver injury (or in differentiating severe—and potentially treatable—autoimmune disease from other forms of injury) drug withdrawal and monitoring were sufficient in our group. We recommend approaching the need for biopsy on a case-by-case basis, as a lack of histologic specificity may not justify procedural risk15.\n\nOf note, chronic liver injury (defined as continued injury six months after initial diagnosis by the DILI Network16) did not develop in any of our patients to the best of our knowledge. One patient in the group died from complications of respiratory failure and sepsis in the setting of progressive dysautonomia associated with a previous traumatic brain injury. Hepatitis and liver dysfunction did not contribute to the death in that case. Overall, our patients would compare favorably to the 17% rate of chronic DILI reported in adults16, recognizing that older age is a recognized risk factor for the development of chronic DILI17. They would also compare favorably to Kumar and colleague’s report, where 11% of pediatric patients had a DILI-related death, and 14% went on to develop chronic disease. However, this report was notable in that three-fourths of cases were caused by complementary and alternative medicines and anti-tuberculosis agents18. These agents were not identified in our population. In contrast, in an updated report from the DILI Network that analyzed pediatric patients in the United States, liver failure was noted in 5% of iDILI patients, and chronic disease developed in 17% of patients7,8. We must acknowledge that our long-term assessment was based on up to five years of chart follow-up, and not on a repeat clinic visit, imaging or lab values after normalization of transaminases. Chronic injury can be asymptomatic, and specific screening for long-term complications (e.g., steatosis, peliosis hepatitis, nodular regenerative hyperplasia, etc.17) was not done.\n\nAs in other reports on pediatric DILI, antimicrobials were the most prevalent drug class associated with iDILI in our population7,8. Minocycline, used for the treatment of acne, was implicated twice in our identified cases of iDILI. All patients had a positive anti-nuclear antibody (ANA) screen, and symptoms suggesting an autoimmune presentation, including rash, athralgias, and fatigue. DILI attributed to minocycline is well recognized19–21 and continues to be a common example of drug-induced autoimmune hepatitis7,8,22,23. A Cochrane database study revealed that minocycline did not have a superior efficacy compared to other tetracyclines, however, and that the risk of autoimmune-type side effects of increased with duration of use24. Another review found doxycycline was efficacious as minocycline but with a smaller decreased risk of DILI25. We conclude that regular liver enzyme monitoring should be implemented with minocycline and—if possible—avoiding the medication altogether for the treatment of acne may be prudent.\n\nThis study is limited by its retrospective design and by the fact it represents cases at a single center. Also, our criteria for DILI were based on the work of Aithal and colleagues14, and do not necessarily reflect the same criteria set forth by other centers and consortia7,8,26. The lack of specific biomarkers makes the diagnosis of DILI dependent on the interpretation of laboratory, radiographic and/or histologic investigations to rule-out other causes of liver disease. Such interpretation might rely on expert consensus. For example, the DILI Network provided the following criteria for identifying iDILI in patients older than two years: clinical suspicion of hepatotoxicity combined with an aspartate aminotransferase (AST) or ALT of >5 times the ULN for the local center (or >5 times the pre-drug average) or ALKP > 2 times the ULN or pre-drug average, or serum bilirubin > 2.5 mg/dL along with any elevations in AST, ALT, or ALKP levels, or an internationalized normal ratio (INR) > 1.5 with any elevations in AST, ALT, or ALKP levels. And, ultimately, causality was determined by their own expert committee, with the DILIN Causality Committee using both RUCAM and the DILIN Causality Assessment score to determine the presence of DILI7,8,26.\n\nOther published methods of identifying iDILI in large electronic record datasets have been explored. Methods have included searching for iDILI using the International Classification of Diseases-9th edition or -10th edition (ICD-9 or ICD-10) codes that are widely used to classify patients’ principal diagnoses. However, the codes lack specificity in the ICD-9 and ICD-10 index for iDILI, and the system relies on the medical knowledge of the coding staff to correctly enter the diagnosis27,28. Text searching methods may be an additional tool to identify iDILI, but efforts require specific language in patient notes, and case detection sensitivity may be sacrificed with increased search term efficiency29. That said, the approach our center used in identifying iDILI may be useful in future multi-center studies—perhaps in combination with previously examined strategies—to better identify and collect data on patients.\n\nThe majority of pediatric DILI reports have focused on hospitalized cases of DILI7,8,30. Our ADR mechanisms were able to detect potential iDILI in affiliated outpatient settings in addition to hospitalized patients. Thus, less severe, but perhaps no less important cases of iDILI were identified. In two years of iDILI identification, half of all cases (including one patient that sustained liver injury without any symptoms) were managed solely in the outpatient setting. Drug discontinuation was the only treatment necessary for these patients. Understanding what factors play roles in preventing hospitalizations related to iDILI, and quickly predicting cases that may progress to more serious disease is an imperative area of further study.\n\nConclusion\nDILI represents a potentially life-threatening and preventable cause of liver injury. Better mechanisms for understanding and predicting injury are desperately needed to prevent harm to thousands of children annually. We reviewed our experience with a hospital-wide adverse drug reaction reporting system, and identified a number of cases of suspected iDILI, at a rate that is higher than previously reported from other multicenter trials. Such approaches applied across an institution or institutions could better identify and define iDILI and improve our understanding of this enigmatic condition.\n\nMaterials and Methods\nData from subjects was collected and reviewed as part of the CMH Institutional Review Board-approved DSS ADR-detection project from January 1, 2012 to December 31, 2013. All procedures performed in studies involving human participants were in accordance with the ethical standards of the CMH Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of retrospective study, written informed consent was waived by the CMH Institutional Review Board.\n\nAs part of the ADR-detection project, an automated daily report is generated using SAP BusinessObjects (Walldorf, Germany) which searches laboratory data in the electronic medical record (EMR; Cerner, Kansas City, MO) and sorts data based on the specific criteria defined by the user. Selected criteria to detect potential DILI included serum ALT > 5x ULN and/or total serum bilirubin > 1.5x ULN which were based on clinical chemistry criteria for DILI as established by Aithal et al.14. For reference, the upper limit of normal identified at CMH for ALT is 50 U/L for all ages and for total bilirubin is 1.2 mg/dL in children older than 6 months. A dedicated clinical pharmacist then reviews the medical history of all patients meeting trigger criteria (Fig. 1). Patients were excluded if a known underlying diagnosis was associated with abnormal liver enzyme elevation. Identification of possible contributing medications was based on the known side effect profile for the medications the child was receiving and the drug exposure timeline relative to the triggered laboratory result. When a possible iDILI was recognized, the clinical pharmacist would contact and discuss the case with the prescribing physician. The prescribing physician determined the course of action or possible referral for further evaluation. If the drug was implicated as a possible cause of the liver injury, the ADR profile was updated to recognize the iDILI side effect including the severity assessment.\n\nThe injury relationship was further defined by application of the RUCAM10,11. The RUCAM assessment first defines whether an injury is “hepatocellular,” “mixed,” or “cholestatic” based on the R ratio. This ratio is calculated by dividing the ALT by the ALKP using multiples of the local upper limit of normal for both values. As such, R = (ALT value/ALT ULN)/(ALKP value/ALKP ULN). R ratios of >5 define a hepatocellular injury, <2 a cholestatic injury, and between 2 and 5 a mixed injury. The RUCAM score then categorizes patients into “definite or highly probable” (score > 8), “probable” (score 6–8), “possible” (score 3–5), “unlikely” (score 1–2) and “excluded” (score </ = 0) cases of iDILI. All cases deemed possible, probably, or definite where included in the study. Patients receiving chemotherapy and patients with acetaminophen toxicity were excluded from further evaluation after identification.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor contributions\nAll authors are responsible for the reported research, and all authors have participated in the conceptualization, drafting, and/or revising of the manuscript. The data were collected by T.S., C.H. and R.F.; data were analyzed by C.H., R.F. and J.G. The paper was written by J.G., J.L., J.D. and R.F.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Bernal W Auzinger G Dhawan A Wendon J Acute liver failure Lancet 2010 376 190 201 10.1016/S0140-6736(10)60274-7 20638564 \n2. Chen M FDA-approved drug labeling for the study of drug-induced liver injury Drug Discov Today 2011 16 697 703 10.1016/j.drudis.2011.05.007 21624500 \n3. Fontana RJ Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives Gastroenterology 2014 146 914 928 10.1053/j.gastro.2013.12.032 24389305 \n4. Mindikoglu AL Magder LS Regev A Outcome of liver transplantation for drug-induced acute liver failure in the United States: analysis of the United Network for Organ Sharing database Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2009 15 719 729 10.1002/lt.21692 \n5. Lee WM Squires RH Jr. Nyberg SL Doo E Hoofnagle JH Acute liver failure: Summary of a workshop Hepatology 2008 47 1401 1415 10.1002/hep.22177 18318440 \n6. EASL Clinical Practice Guidelines: Drug-induced liver injury. Journal of hepatology (2019).\n7. Molleston JP Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study Journal of pediatric gastroenterology and nutrition 2011 53 182 189 10.1097/MPG.0b013e31821d6cfd 21788760 \n8. DiPaola F Antimicrobials and Antiepileptics Are the Leading Causes of Idiosyncratic Drug-induced Liver Injury in American Children Journal of pediatric gastroenterology and nutrition 2019 69 152 159 10.1097/MPG.0000000000002383 31169665 \n9. Goldman JL Sullins A Sandritter T Leeder JS Lowry J Pediatric Pharmacovigilance: Enhancing Adverse Drug Reaction Reporting in a Tertiary Care Children’s Hospital Ther Innov Regul Sci 2013 47 566 571 30235581 \n10. 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Aithal GP Case definition and phenotype standardization in drug-induced liver injury Clinical pharmacology and therapeutics 2011 89 806 815 10.1038/clpt.2011.58 21544079 \n15. Teschke R Frenzel C Drug induced liver injury: do we still need a routine liver biopsy for diagnosis today? Annals of hepatology 2013 13 121 126 10.1016/S1665-2681(19)30913-5 24378275 \n16. Chalasani N Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study Gastroenterology 2015 148 1340 1352 e1347 10.1053/j.gastro.2015.03.006 25754159 \n17. Stine JG Chalasani N Chronic liver injury induced by drugs: a systematic review Liver international: official journal of the International Association for the Study of the Liver 2015 35 2343 2353 10.1111/liv.12958 26346512 \n18. Kumar A Clinical Spectrum and Outcome of Pediatric Drug Induced Liver Injury Indian journal of pediatrics 2018 85 676 678 10.1007/s12098-017-2570-3 29247427 \n19. 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Kircik LH Doxycycline and minocycline for the management of acne: a review of efficacy and safety with emphasis on clinical implications J Drugs Dermatol 2010 9 1407 1411 21061764 \n26. Fontana RJ Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct Drug safety 2009 32 55 68 10.2165/00002018-200932010-00005 19132805 \n27. Jinjuvadia K Kwan W Fontana RJ Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury The American journal of gastroenterology 2007 102 2437 2443 10.1111/j.1572-0241.2007.01456.x 17662100 \n28. Sobhonslidsuk A Poovorawan K Soonthornworasiri N Pan-Ngum W Phaosawasdi K The incidence, presentation, outcomes, risk of mortality and economic data of drug-induced liver injury from a national database in Thailand: a population-base study BMC gastroenterology 2016 16 135 10.1186/s12876-016-0550-0 27793116 \n29. 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"fulltext_license": "CC BY",
"issn_linking": "2045-2322",
"issue": "9(1)",
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"medline_ta": "Sci Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D014150:Antipsychotic Agents; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D015994:Incidence; D008111:Liver Function Tests; D008297:Male; D014481:United States",
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"pubdate": "2019-12-02",
"publication_types": "D016428:Journal Article",
"references": "18318440;1532250;28005582;8229110;19132805;22895927;19562705;8229111;24378275;24389305;16481640;8470208;8618800;26346512;27793116;29247427;25754159;21788760;8074603;30926241;21061764;21544079;21624500;20638564;26597192;30235581;10685779;31169665;17404879;17662100",
"title": "An electronic medical records-based approach to identify idiosyncratic drug-induced liver injury in children.",
"title_normalized": "an electronic medical records based approach to identify idiosyncratic drug induced liver injury in children"
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"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3",
... |
{
"abstract": "A case of a 68-year-old male patient, who was admitted to our department with stomach pain, nausea, vomiting and diarrhea lasting for more than two weeks is presented. In addition, shortly before being admitted, the patient also complained of neurological symptoms, severe hypertension, rash and high fever. Laboratory tests revealed thrombocytopenia, hemolytic anemia and elevated creatinine. After receiving the information, that for the last three weeks the patient was taking ticlopidine, we started to suspect the Moschcowitz syndrome. For this reason the patient was transferred to a Hematological Institute, where the diagnosis was confirmed.",
"affiliations": "Katedra i Zakład Patologii Ogólnej i Doświadczalnej, Warszawski Uniwersytet Medyczny, ul. Krakowskie Przedmieście 26/28, 00-927 Warszawa, Poland. gosiawojciech@yahoo.com",
"authors": "Wojciechowska|Małgorzata|M|;Grzywanowska-Łaniewska|Iwona|I|;Załeska-Zydlewska|Izabela|I|;Dłuzniewski|Mirosław|M|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-9032",
"issue": "67(6)",
"journal": "Kardiologia polska",
"keywords": null,
"medline_ta": "Kardiol Pol",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D003937:Diagnosis, Differential; D005759:Gastroenteritis; D006801:Humans; D008297:Male; D010956:Plasmapheresis; D010975:Platelet Aggregation Inhibitors; D011697:Purpura, Thrombotic Thrombocytopenic; D013921:Thrombocytopenia; D013988:Ticlopidine",
"nlm_unique_id": "0376352",
"other_id": null,
"pages": "656-9",
"pmc": null,
"pmid": "19618322",
"pubdate": "2009-06",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "From gastroenteritis complicated by acute renal failure to... the Moschcowitz syndrome.",
"title_normalized": "from gastroenteritis complicated by acute renal failure to the moschcowitz syndrome"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213233",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TICLOPIDINE"
},
"dru... |
{
"abstract": "BACKGROUND\nRecently, a controversy has emerged: is the rate of recurrence of hepatocellular carcinoma (HCC) higher following treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapy? However, the risk of HCC recurrence has not been studied in liver transplant (LTx) recipients who received DAA therapy. The aim of the present study is to compare the rate of HCC recurrence in LTx recipients who did or did not receive DAA therapy.\n\n\nMETHODS\nSixty-three patients received LTx with HCC. Twenty-seven (42.9%) with HCV received DAA therapy (Group A), 20 (31.7%) with HCV did not receive DAA therapy (Group B), and 16 (25.4%) did not have HCV (Group C).\n\n\nRESULTS\nIn group A, three (11%), in group B, one (5%), and in group C, none had recurrence of HCC. Actuarial 4-year recurrence-free survival was 88.9, 95, and 100% in group A, B, and C, respectively (p = 0.37). Group A was subdivided into two groups for comparison with Group B: A1 included five patients who had end of treatment response (ETR) without sustained virological response (SVR), and A2 included 20 patients who achieved SVR. Three patients from A1 had HCC recurrence and no patients from A2 had HCC recurrence. (p = 0.0038; group A1, A2, and B).\n\n\nCONCLUSIONS\nThe rate of HCC recurrence in LTx patients with DAA therapy was significantly higher with ETR, without SVR, after DAA therapy compared to patients with SVR or patients who did not receive DAA therapy. LTx recipients with HCC receiving DAA therapy requires further studies.",
"affiliations": "Division of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University, Mail Code H062, 500 University Drive, PO Box 850, Hershey, PA, 17033-0850, USA. ajain1@pennstatehealth.psu.edu.;Division of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University, Mail Code H062, 500 University Drive, PO Box 850, Hershey, PA, 17033-0850, USA.;Division of Gastroenterology, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA.;Division of Gastroenterology, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA.;Division of Gastroenterology, Department of Medicine, College of Medicine, Pennsylvania State University, Hershey, PA, USA.;Division of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University, Mail Code H062, 500 University Drive, PO Box 850, Hershey, PA, 17033-0850, USA.;CSL Behring, 1020 First Ave, King of Prussia, PA, USA.;Division of Transplantation, Department of Surgery, College of Medicine, Pennsylvania State University, Mail Code H062, 500 University Drive, PO Box 850, Hershey, PA, 17033-0850, USA.",
"authors": "Jain|Ashokkumar|A|http://orcid.org/0000-0002-8475-973X;Miller|Danielle|D|;Schreibman|Ian|I|;Riley|Thomas R|TR|;Krok|Karen L|KL|;Dohi|Takehiko|T|;Sharma|Rajeev|R|;Kadry|Zakiyah|Z|",
"chemical_list": "D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; C586541:ledipasvir; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1007/s12072-019-09930-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1936-0533",
"issue": "13(2)",
"journal": "Hepatology international",
"keywords": "Chemoembolization; Hepatitis C; Immunosuppression; Metastatic disease",
"medline_ta": "Hepatol Int",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D001562:Benzimidazoles; D006528:Carcinoma, Hepatocellular; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes; D019698:Hepatitis C, Chronic; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response",
"nlm_unique_id": "101304009",
"other_id": null,
"pages": "190-198",
"pmc": null,
"pmid": "30680672",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": "10363896;11965579;14755775;15378504;15657158;18471511;18650514;19330875;23268517;23921081;25304641;25754160;25825070;27084592;27136189;27288051;27304548;27318327;27337961;27349488;27388925;27417216;27476763;27480589;28390144;7557855;8594428;9563957",
"title": "Is there increased risk of hepatocellular carcinoma recurrence in liver transplant patients with direct-acting antiviral therapy?",
"title_normalized": "is there increased risk of hepatocellular carcinoma recurrence in liver transplant patients with direct acting antiviral therapy"
} | [
{
"companynumb": "US-GILEAD-2019-0400576",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
"drugadditional": nul... |
{
"abstract": "While anaphylaxis can occur at any time during general anesthesia, 90% of cases occur at induction of anesthesia. As several drugs are administered simultaneously at this time, it is difficult to identify the causative agent. However, it has been found that rocuronium is the most common drug associated with perioperative anaphylaxis. We treated 2 cases of patients who were administered sugammadex for anaphylactic symptoms thought to be caused by rocuronium, after which the anaphylactic symptoms disappeared. One of the most important aspects of treating anaphylactic shock is improving hemodynamics. If signs indicating circulatory collapse are observed, epinephrine should be administered immediately. However, because rocuronium was suspected of being the causative agent, and taking the patients' clinical course over time into consideration, sugammadex was initially administered. As a result, symptoms improved. Therefore, we believe that the administration of sugammadex may be effective for treating anaphylaxis caused by rocuronium and also help in identifying the causative agent.",
"affiliations": "Department of Anesthesiology, Aichi Gakuin University School of Dentistry, Nagoya, Japan.;Department of Anesthesiology, Aichi Gakuin University School of Dentistry, Nagoya, Japan.;Department of Anesthesiology, Aichi Gakuin University School of Dentistry, Nagoya, Japan.;Department of Anesthesiology, Aichi Gakuin University School of Dentistry, Nagoya, Japan.;Department of Anesthesiology, Aichi Gakuin University School of Dentistry, Nagoya, Japan.;Department of Anesthesiology, Aichi Gakuin University School of Dentistry, Nagoya, Japan.;Department of Anesthesiology, Aichi Gakuin University School of Dentistry, Nagoya, Japan.",
"authors": "Hashimoto|Mayumi|M|;Sato Boku|Aiji|A|;Tachi|Naoko|N|;Okumura|Yoko|Y|;Kadoi|Kanenori|K|;Harada|Jun|J|;Okuda|Masahiro|M|",
"chemical_list": "D000732:Androstanols; D003473:Neuromuscular Nondepolarizing Agents; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D000077123:Rocuronium",
"country": "United States",
"delete": false,
"doi": "10.2344/anpr-66-01-07",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-3006",
"issue": "66(3)",
"journal": "Anesthesia progress",
"keywords": "Anaphylactic shock; Epinephrine; Rocuronium; Sugammadex",
"medline_ta": "Anesth Prog",
"mesh_terms": "D000707:Anaphylaxis; D000732:Androstanols; D006801:Humans; D003473:Neuromuscular Nondepolarizing Agents; D000077123:Rocuronium; D000077122:Sugammadex; D047408:gamma-Cyclodextrins",
"nlm_unique_id": "0043533",
"other_id": null,
"pages": "151-155",
"pmc": null,
"pmid": "31545668",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21945608;24286446;21149287;22154092;11387113;21348251;12074414;10823122;21757555;27885199;19178399;19858877;21904780;16461139",
"title": "Two Cases of Rocuronium-Induced Anaphylaxis/Anaphylactic Shock Successfully Treated With Sugammadex.",
"title_normalized": "two cases of rocuronium induced anaphylaxis anaphylactic shock successfully treated with sugammadex"
} | [
{
"companynumb": "JP-009507513-1309JPN013782",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROCURONIUM BROMIDE"
},
"drugadditional": "1"... |
{
"abstract": "Neuroleptic malignant syndrome is a rare but life-threatening idiosyncratic complication following the use of antipsychotic agents, anaesthesia and surgery. It is characterized by hyperthermia, muscle rigidity, autonomic disturbances and mental state alterations.\nA 31 year old female weighing 60kg received a depot preparation of Fluphenazine on account of depression with psychotic features observed two days prior to elective Cholecystectomy under general anaesthesia. Surgery and anaesthesia were essentially uneventful. Forty eight hours post-operatively, the patient developed features suggestive of neuroleptic malignant syndrome complicated by aspiration pneumonitis. This necessitated her admission into the intensive care unit. She had prolonged stay in the intensive care unit, where she was mechanically ventilated, developed deep venous thrombosis of the left upper limb and required tracheostomy on account of prolonged endotracheal intubation. Patient recovered fully following bromocriptine and dantrolene therapy. She was discharged home after 60 days on admission and has remained in good health.\nThough rare, neuroleptic malignant syndrome can occur in young adult females following use of antipsychotics, anaesthesia and surgery. Its clinical course can be prolonged and distressing with the use of depot preparations. Early diagnosis and prompt supportive measures are essential to reduce morbidity and mortality.",
"affiliations": "Department of Surgery, University of Benin Teaching Hospital, PMB 1111, Benin City, Nigeria. pagbonrofo@gmail.com; peter.agbonrofo@uniben.edu. Tel:+234 802-829-6343.;Department of Anaesthesiology, University of Benin Teaching Hospital, PMB 1111, Benin City, Nigeria. osakuejohn@yahoo.com. Tel:+234 806-036-2070, +234 809-111-4193.",
"authors": "Agbonrofo|Peter I|PI|;Osakue|John E|JE|",
"chemical_list": "D014150:Antipsychotic Agents; D005476:Fluphenazine",
"country": "Uganda",
"delete": false,
"doi": "10.4314/ahs.v18i3.37",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1680-6905",
"issue": "18(3)",
"journal": "African health sciences",
"keywords": "Neuroleptic malignant syndrome; University of Benin Teaching Hospital; adult female",
"medline_ta": "Afr Health Sci",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D005260:Female; D005476:Fluphenazine; D006801:Humans; D007362:Intensive Care Units; D009459:Neuroleptic Malignant Syndrome; D009549:Nigeria",
"nlm_unique_id": "101149451",
"other_id": null,
"pages": "786-789",
"pmc": null,
"pmid": "30603012",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10928001;11525080;12538292;12952806;15119907;23543750;25578944;28144147;2863986;3527659;3664920;6101595;7622829;7717493;8093494;8747565;9165568;9699705",
"title": "Neuroleptic malignant syndrome in a young adult female at the university of Benin Teaching Hospital: a case report.",
"title_normalized": "neuroleptic malignant syndrome in a young adult female at the university of benin teaching hospital a case report"
} | [
{
"companynumb": "NG-ACCORD-088911",
"fulfillexpeditecriteria": "1",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nFluocinolone acetonide (FAc) intravitreal implant (ILUVIEN(®); Alimera Sciences Limited, Aldershot, UK) has been approved in the UK for the treatment of chronic diabetic macula edema, insufficiently responsive to available therapies. It is inserted into the vitreous cavity through a 25-gauge needle. Migration of the implant to the anterior chamber (AC) can occur through gaps in the posterior capsule especially in vitrectomized eyes. Early removal of AC-dislocated FAc implant is essential to prevent corneal edema and damage from raised intraocular pressure.\n\n\nOBJECTIVE\nTo demonstrate a simple and novel technique, with a previous capsular tear, for removal of AC-migrated FAc implant and reinsertion into the vitreous cavity without compromising implant integrity.\n\n\nMETHODS\nA side port incision was created with a keratome and an anterior chamber maintainer introduced and secured. Subsequently, a corneal incision was created at 12 o'clock through which a 23-gauge backflush needle (flute needle) was advanced into the anterior chamber and passive suction used to secure the implant. The flute needle was then placed through the defect in the posterior capsule and the exit port blocked, causing loss of suction and allowing the implant to fall into the posterior segment. The sulcus intraocular lens (IOL) was centralized simply by manipulating it approximately 180 degrees to provide adequate anterior capsule support.\n\n\nRESULTS\nThe FAc implant was successfully removed from AC in two patients and reinserted into the vitreous cavity without damage or complications either for the eye or the implant. IOL in both patients were repositioned to close the gap in posterior capsule. After 2 months, the implant remains in the vitreous cavity. This paper presents data from one of these cases.\n\n\nCONCLUSIONS\nUsing 23-gauge flute needle to retrieve dislocated FAc implant is a safe and easy technique.\n\n\nBACKGROUND\nAlimera Sciences Ltd.",
"affiliations": "James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, UK. ibraheemelghrably@nhs.net.;James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, UK.;James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, UK.",
"authors": "El-Ghrably|Ibraheem A|IA|;Saad|Ahmed|A|;Dinah|Christiana|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1007/s40123-015-0035-1",
"fulltext": "\n==== Front\nOphthalmol Ther\nOphthalmol Ther\nOphthalmology and Therapy\n2193-8245\n2193-6528\nSpringer Healthcare Cheshire\n\n35\n10.1007/s40123-015-0035-1\nCase Report\nA Novel Technique for Repositioning of a Migrated ILUVIEN® (Fluocinolone Acetonide) Implant into the Anterior Chamber\nEl-Ghrably Ibraheem A. ibraheemelghrably@nhs.net\n\nSaad Ahmed\nDinah Christiana\nJames Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW UK\n22 7 2015\n22 7 2015\n12 2015\n4 2 129133\n8 5 2015\n© The Author(s) 2015\nIntroduction\n\nFluocinolone acetonide (FAc) intravitreal implant (ILUVIEN®; Alimera Sciences Limited, Aldershot, UK) has been approved in the UK for the treatment of chronic diabetic macula edema, insufficiently responsive to available therapies. It is inserted into the vitreous cavity through a 25-gauge needle. Migration of the implant to the anterior chamber (AC) can occur through gaps in the posterior capsule especially in vitrectomized eyes. Early removal of AC-dislocated FAc implant is essential to prevent corneal edema and damage from raised intraocular pressure.\n\nAim\n\nTo demonstrate a simple and novel technique, with a previous capsular tear, for removal of AC-migrated FAc implant and reinsertion into the vitreous cavity without compromising implant integrity.\n\nMethod\n\nA side port incision was created with a keratome and an anterior chamber maintainer introduced and secured. Subsequently, a corneal incision was created at 12 o’clock through which a 23-gauge backflush needle (flute needle) was advanced into the anterior chamber and passive suction used to secure the implant. The flute needle was then placed through the defect in the posterior capsule and the exit port blocked, causing loss of suction and allowing the implant to fall into the posterior segment. The sulcus intraocular lens (IOL) was centralized simply by manipulating it approximately 180 degrees to provide adequate anterior capsule support.\n\nResults\n\nThe FAc implant was successfully removed from AC in two patients and reinserted into the vitreous cavity without damage or complications either for the eye or the implant. IOL in both patients were repositioned to close the gap in posterior capsule. After 2 months, the implant remains in the vitreous cavity. This paper presents data from one of these cases.\n\nConclusion\n\nUsing 23-gauge flute needle to retrieve dislocated FAc implant is a safe and easy technique.\n\nFunding\n\nAlimera Sciences Ltd.\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1007/s40123-015-0035-1) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nChronic diabetic macular edema\nFluocinolone acetonide\nILUVIEN\nIntravitreal implant\nSteroid implant migration\nissue-copyright-statement© Springer Healthcare 2015\n==== Body\nIntroduction\n\nA 74-year-old male with a 24-year history of Type 2 diabetes developed chronic diabetic macula edema in his right eye. Previous therapies included macular grid laser and intravitreal avastin for diabetic macula edema. He had phacoemulsification complicated by posterior capsule rupture and loss of a nucleus fragment into the posterior segment. He subsequently underwent 23-gauge pars plana vitrectomy and removal of lens fragment, followed by sulcus placement of an intraocular lens.\n\nAt his 1-month post-operative visit, the right visual acuity was 6/60 and intraocular pressure was 22 mmHg. Slit lamp examination revealed a slightly inferiorly displaced intraocular lens and on optical coherence tomography (OCT); his central macula thickness was 619 µm. He underwent monthly intravitreal Lucentis injections over 4 months, but his macula edema persisted, with no improvement in visual acuity. At this time, the decision was made to proceed with insertion of the fluocinolone acetonide intravitreal (FAc) implant (ILUVIEN®; Alimera Sciences Limited, Aldershot, UK), which was performed without complication as an outpatient procedure.\n\nHe was reviewed in the clinic 13 days later and the right visual acuity was 6/36 and central macular thickness was 517 µm. However, slit lamp examination revealed the FAc implant lying horizontally in the inferior angle of the anterior chamber (Fig. 1). Intraocular pressure was 30 mmHg and there was no associated corneal edema.Fig. 1 Migrated ILUVIEN implant in the inferior angle of anterior chamber\n\nMethod Used to Reposition the Migrated Implant\n\nFive days later, the patient was taken to the operating room. (Please see the video for case 1 in the supplementary material.) A side port incision was created with a keratome and an anterior chamber maintainer introduced and secured (Fig. 2). Subsequently, a corneal incision was created at 12 o’clock through which a backflush needle (flute needle) was advanced into the anterior chamber and passive suction used to secure the intact implant (Fig. 3). The flute needle was then placed through the defect in the posterior capsule and the exit port blocked, causing loss of suction and allowing the implant to fall into the posterior segment. The sulcus intraocular lens (IOL) was centralized simply by rotating it approximately 180 degrees to provide adequate anterior capsule support (Fig. 4). Three weeks post-operatively, the patient’s visual acuity was 6/60, the IOL is centrally placed, intraocular pressure (IOP) is 17 mmHg, the cornea remains clear and the FAc implant remains in the posterior segment. This outcome remained stable after 1 year of follow-up.Fig. 2 Anterior chamber maintainer in the anterior chamber, superior gap in posterior capsule and inferior displacement of the intraocular lens\n\nFig. 3 ILUVIEN implant inside the tip of flute needle and redirected to vitreous cavity through the gap in posterior capsule\n\nFig. 4 Centralized intraocular lens after repositioning and covering posterior capsule\n\nInformed consent was obtained from the patient for being included in this study.\n\nDiscussion\n\nFAc implant is a non-biodegradable cylindrical tube (measuring 3.5 × 0.37 mm) of polyimide loaded with 190 micrograms of FAc that is inserted into the vitreous cavity through a 25-gauge needle in an outpatient setting [1]. The FAc implant has been approved by the United Kingdom National Institute for Health and Care Excellence (NICE technology appraisal TA301) for people with chronic diabetic macular edema (DMO) who have an artificial lens in their eye if: the implant is used in the eye with the artificial lens; and, their DMO has not responded sufficiently to other treatments [2].\n\nTo our knowledge, this is the first reported case of anterior chamber migration of the FAc implant. Multiple cases of anterior migration of the intravitreal dexamethasone implant (Ozurdex®; Allergan Pharmaceuticals Ireland, Westport, Ireland) have been reported in the literature [3–5]. The importance of prompt removal of the anteriorly migrated dexamethasone implants was emphasized by Khurana et al. [6] in their recently published series of 18 episodes (15 patients) with anterior migration of the dexamethasone implant. In their series, 89% of cases developed corneal edema, with keratoplasty recommended in 43% for non-resolving corneal edema after removal of the dexamethasone implant. They also identified previous vitrectomy and an absent or compromised posterior capsule (factors which are present in our case) as risk factors for anterior migration. Khurana et al. also described unsuccessful attempts to grasp the implant with tying forceps and intraocular forceps in some cases, resulting in disintegration of the implant into smaller pieces.\n\nIn our report, we describe a novel technique for surgical removal and repositioning. The flute needle devised by Dr. Steve Charles (Memphis, USA) is an invaluable tool used for various posterior segment procedures. This includes simultaneous exchange of intraocular fluid for air, a gas/air mixture or silicone oil, internal drainage of subretinal fluid through a hole in the retina and manipulation of a giant retinal tear. It consists simply of a blunt-ended needle (available in various gauge sizes) connected by a Luer fitting or Luer lock to a handle.\n\nWithin the handle, an internal channel connects the Luer terminal to an exit port in a depression on the side of the handle. When the needle is introduced into the vitreous cavity via a pars plana sclerotomy, closure of the exit port by the surgeon’s finger prevents flow of fluid or gas from the eye. Removal of the finger allows egress of fluid along the needle and through the exit hole, provided an infusion of gas or fluid maintains the intraocular pressure above atmospheric pressure. Using the same principles, the flute needle can be used in the anterior chamber, in our case as a suction/aspiration device to grasp and reposition the FAc implant.\n\nWe used a 23-gauge backflush/flute needle, which allowed easy grasp of the FAc implant. For a dexamethasone implant, a 20-gauge needle would be appropriate. This technique is quick, requires minimal manipulation or tissue disturbance and allows for easy repositioning of the implant, if desired. The non-biodegradable nature of the FAc implant allowed manipulation and repositioning without the implant breaking into pieces.\n\nWhile corneal decompensation has been described in association with anterior migration of the dexamethasone implant and Retisert® insert (containing 0.59 milligrams of FAc [7]; Bausch & Lomb, Rochester, NY, USA), this did not occur in our patient. We postulate that this is as a result of prompt repositioning of the implant, the smaller size of the FAc implant compared to the dexamethasone implant (which is 0.46 mm in diameter and 6 mm in length [8]) or a combination of both factors. However, there are reports of the drug-eluting portion of the Retisert insert (which is 1.5 mm) dislocating into the anterior chamber and causing corneal edema [9]. As non-resolving corneal edema is a potential risk [10], prompt removal is advocated in these cases.\n\nOf note, there was resolution of intraocular pressure back to normal limits after removal of the implant. Reports suggest that placement of steroid implants closer to the trabecular meshwork or ciliary body results in a higher incidence of raised intraocular pressure [7].\n\nConclusion\n\nIn conclusion, we describe a case of a FAc implant dislocation and a novel technique for ease of removal from the anterior chamber of the eye. Early removal is essential to prevent corneal edema and damage from raised intraocular pressure. Caution should be employed when deciding to inject the FAc implant in the eye with posterior capsule defects and when anterior migration occurs, we recommend repositioning into the vitreous cavity with a backflush/flute needle as a straightforward technique.\n\nElectronic supplementary material\n\nSupplementary material 1 (PDF 309 kb)\n\nSupplementary material 2 (MP4 25278 kb)\n\nAll named authors meet International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.\n\nArticle processing charges for this publication were funded by Alimera Sciences Ltd.\n\nConflict of interest\n\nI. A. El-Ghrably, A. Saad and C. Dinah have nothing to disclose.\n\nCompliance with ethics guidelines\n\nInformed consent was obtained from the patient for being included in this study.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\n==== Refs\nReferences\n\n1. Summary of product characteristics for ILUVIEN 190 micrograms intravitreal implant in applicator. https://www.medicines.org.uk/emc/medicine/27636. Accessed Apr 27, 2015.\n2. NICE technology appraisals [TA301]. Fluocinolone acetonide intravitreal implant for treating chronic diabetic macular oedema after an inadequate response to prior therapy (rapid review of technology appraisal guidance 271). 2013. https://www.nice.org.uk/guidance/ta301. Accessed Apr 27, 2015.\n3. Ragam AP, Kolomeyer AM, Nayak NV, Chu DS. The use of ozurdex (dexamethasone intravitreal implant) during anterior segment surgery in patients with chronic recurrent uveitis. J Ocul Pharmacol Ther. 2015. doi:10.1089/jop.2015.0009.\n4. Kocak N Ozturk T Karahan E Kaynak S Anterior migration of dexamethasone implant in a pseudophakic patient with intact posterior capsule Indian J Ophthalmol 2014 62 11 1086 1088 10.4103/0301-4738.146763 25494252\n5. Collet B Management of ozurdex in the anterior chamber JAMA Ophthalmol. 2013 131 12 1651 1652 10.1001/jamaophthalmol.2013.5610 24337563\n6. Khurana RN Appa SN McCannel CA Elman MJ Wittenberg SE Parks DJ Ahmad S Yeh S Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies Ophthalmology 2014 121 1 67 71 10.1016/j.ophtha.2013.06.033 23890421\n7. Campochiaro PA Nguyen QD Hafiz G Bloom S Brown DM Busquets M Ciulla T Feiner L Sabates N Billman K Kapik B Green K Kane FE FAMOUS Study Group Aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide inserts or fluocinolone acetonide implants Ophthalmology 2013 120 3 583 587 10.1016/j.ophtha.2012.09.014 23218184\n8. Summary of product characteristics for OZURDEX 700 micrograms intravitreal implant in applicator. https://www.medicines.org.uk/emc/medicine/23422. Accessed Apr 27, 2015.\n9. Almeida DR Chin EK Mears K Russell SR Mahajan VB Spontaneous dislocation of a fluocinolone acetonide implant (retisert) into the anterior chamber and its successful extraction in sympathetic ophthalmia Retin Cases Brief Rep. 2015 9 2 142 144 10.1097/ICB.0000000000000119 25411930\n10. Costagliola C Romano V Forbice E Angi M Pascotto A Boccia T Semeraro F Corneal oedema and its medical treatment Clin Exp Optom. 2013 96 6 529 535 10.1111/cxo.12060 23679934\n\n",
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"keywords": "Chronic diabetic macular edema; Fluocinolone acetonide; ILUVIEN; Intravitreal implant; Steroid implant migration",
"medline_ta": "Ophthalmol Ther",
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"title": "A Novel Technique for Repositioning of a Migrated ILUVIEN(®) (Fluocinolone Acetonide) Implant into the Anterior Chamber.",
"title_normalized": "a novel technique for repositioning of a migrated iluvien fluocinolone acetonide implant into the anterior chamber"
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"abstract": "We report a 12-year-old female patient with acute macular neuroretinopathy assessed with multimodal retinal exams. Initial fluorescein angiogram and optical coherence tomography angiography (OCT-A) were both normal, and after 4 months OCT-A showed abnormal vascular flow with normal flow in superficial retina layers, choroid, and choriocapillaris.",
"affiliations": "Physician Department of Ophthalmology, Universidade Federal de São Paulo - EPM, São Paulo, Brazil.;Physician Department of Ophthalmology, Universidade Federal de São Paulo - EPM, São Paulo, Brazil.;Physician Department of Ophthalmology, Universidade Federal de São Paulo - EPM, São Paulo, Brazil.;Physician Department of Ophthalmology, Universidade Federal de São Paulo - EPM, São Paulo, Brazil.",
"authors": "Nakayama|Luis Filipe|LF|;Kase|Camila|C|;Bergamo|Vinicius Campos|VC|;de Moraes|Nilva Simeren Bueno|NSB|",
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"fulltext": "\n==== Front\nCase Rep Ophthalmol\nCase Rep Ophthalmol\nCOP\nCase Reports in Ophthalmology\n1663-2699 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000509849\ncop-0011-0620\nCase Report\nTwelve-Year-Old Girl with Acute Macular Neuroretinopathy: A Multimodal Retinal Evaluation\nNakayama Luis Filipe * Kase Camila Bergamo Vinicius Campos de Moraes Nilva Simeren Bueno Physician Department of Ophthalmology, Universidade Federal de São Paulo − EPM, São Paulo, Brazil\n*Luis Filipe Nakayama, Physician Department of Ophthalmology, Universidade Federal de São Paulo − EPM, Botucatu St. 821, Vila Clementino, São Paulo, SP 04023-062 (Brazil), nakayama.luis@gmail.com\nSep-Dec 2020 \n13 11 2020 \n13 11 2020 \n11 3 620 625\n9 5 2020 2 7 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.We report a 12-year-old female patient with acute macular neuroretinopathy assessed with multimodal retinal exams. Initial fluorescein angiogram and optical coherence tomography angiography (OCT-A) were both normal, and after 4 months OCT-A showed abnormal vascular flow with normal flow in superficial retina layers, choroid, and choriocapillaris.\n\nKeywords\nRetinaMultimodal retinal examsOptical coherence tomography angiography\n==== Body\nBackground\nAcute macular neuroretinopathy (AMN) is a rare disease, more common in young female patients [1]. AMN was first described in 1975 by Bos and Deutman [2] as intraretinal dark reddish wedge-shaped lesions. The exact pathophysiology is yet unknown, and the proposed mechanism is ischemia in deep retinal capillary plexus or in choriocapillaris, but this does not fully explain optical coherence tomography (OCT) findings [3].\n\nOCT angiography (OCT-A) is a noninvasive exam that evaluates retinal and choroid vascular plexus through optic interferometry [4].\n\nWe describe a 12-year-old female patient with clinical and OCT compatible AMN findings, who presented an initial normal OCT-A, and after 4 months, showed a flow deficit in deep retinal vascular layers.\n\nCase Report\nA 12-year-old female patient with a chief complaint of sudden visual scotoma in right eye. She denied past ocular history or flu-like symptoms, and only reported use of combined oral contraceptive pill (drospirenone 3 mg and ethinyl estradiol 0.03 mg) due to polycystic ovary syndrome for 5 months.\n\nAt ophthalmological exam, she had a visual acuity of 20/20 (−1.0 spherical diopters) in both eyes. Normal anterior biomicroscopy intraocular pressure of 14 mm Hg in both eyes and the pupillary exam was normal. She presented abnormal retinal reflex in the macular area of the left eye.\n\nColor fundus retinography showed subtle abnormal retina in the macular area of the right eye, more visible on infra-red retinography. Red-free were normal, and autofluorescence imaging showed a subtle hypo-signal in the macular area (Fig. 1).\n\nFluorescein angiogram was normal in all phases in both eyes, without hyper- or hypofluorescence areas during the exam (Fig. 1).\n\nOCT showed areas of hyper-signal in deep retina, corresponding to areas from infra-red retinography (Fig. 2).\n\nInitial OCT-A did not show areas of flow deficit in the superficial retina, deep retina, choriocapillaris, and choroid (Fig. 3).\n\nFour months after onset of symptoms, the patient reported improvement of visual scotoma, the OCT showed thinning of retinal layers (Fig. 3), and OCT-A showed a decrease in vascular flow in an area corresponding to AMN. Vascular decrease flow was present in deep retinal vascular layer. Superficial retinal layer and choriocapillaris were both normal in the initial and the follow-up exam (Fig. 4).\n\nDiscussion\nWe report a case of acute macular neuroretinopathy in a 12-year-old female patient, one of the youngest AMN patients reported in the literature.\n\nThis patient did not have any past ocular history and started taking combined oral contraceptive pills 5 months ago. Although combined oral contraceptive pill use is associated with AMN, it is difficult to establish a direct correlation between its use and AMN [1].\n\nKrill disease is a possible differential diagnosis, but OCT lesion location does not correspond with that disease. White dots syndromes such as multiple evanescent white dot syndrome and acute posterior multifocal placoid pigment epitheliopathy and central serous chorioretinopathy are possible differential diagnoses, but ophthalmological findings and ancillary retinal exams favored the diagnosis of AMN.\n\nExact AMN pathophysiology is yet unknown, and previous reports with OCT-A speculated a choroidal disease with retinal involvement [3]. Our case reports an initial normal vasculature in all retinal and choroid layer in on OCT-A, with flow deficit mainly at the deep retinal plexus layer at the 4-month follow-up OCT-A. These findings contribute to the hypothesis that AMN is a deep vascular plexus disease. In OCT-A, shadowing artifacts may occur on images, but the fundus color retinography did not show any hemorrhage or opacity that could have prevented light from reaching the tissue. To avoid segmentation artifact, the exam was manually corrected for the previous automatic segmentation in all slabs.\n\nWith a normal retinal fundus exam, multimodal retinal exams helped to establish AMN diagnosis and follow-up, mainly infrared retinography, OCT, and OCT-A.\n\nIn this disease, OCT-A is a good option for diagnosis and follow-up, since capillary plexus ischemia usually is not significant enough to change fluorescein angiogram exam.\n\nConclusion\nAMN is a rare disorder, and multimodal exams help to better understand the characteristics of this disease. This is one of the youngest patients with an AMN reported to date.\n\nStatement of Ethics\nEthics approval is not applicable. Informed consent for publication of clinical details and images was obtained from the patient.\n\nConflict of Interest Statement\nNo competing interests to declare.\n\nFunding Sources\nNo funding to declare.\n\nAuthor Contributions\nL.F. Nakayama: project concept, examination, article writing, review. V.C. Bergamo: article writing, review. N.S.B. Moraes: project concept, review, project coordinator. All authors read and approved the final manuscript.\n\nAvailability of Data and Material\nThe datasets generated during the current study are available upon reasonable request from the corresponding author L.F. Nakayama.\n\nAcknowledgements\nWe would like to thank Ophthalmology sector from Escola Paulista de Medicina/São Paulo Federal University.\n\nFig. 1 Imaging on presentation. a Right eye fundus photography without visible changes. b Right eye near infrared fundus fluorescence with circular petaloid lesion nasal to the fovea. c Right eye normal fundus autofluorescence. d Right eye normal intravenous fluorescein angiography. e Left eye fundus photography without visible changes. f Left eye normal near infrared fundus fluorescence. g Left eye normal fundus autofluorescence. h Left eye normal intravenous fluorescein angiography.\n\nFig. 2 Swept source OCT. a Right eye horizontal slab with increased reflectiveness in intermediate layers nasal to the fovea. b Right eye vertical slab with increased reflectiveness in intermediate layers superior and inferior to the fovea. c Left eye horizontal slab with normal retinal layers on OCT.\n\nFig. 3 a Initial presentation. OCT with increased reflectiveness in intermediate layers nasal to the fovea. b Four months' follow-up. Increased retinal thickness and irregularity in intermediate retinal layers. Improvement of hyperreflectiveness in intermediate retinal layers.\n\nFig. 4 OCT-A of right eye. a Imaging on presentation. OCT-A in all layers with normal vasculature. Crescent-shape lesion visible in outer retina en-face exam. b Four months' follow-up. Decreased flow in deep retina plexus in corresponding area to near infra-red lesion. Normal superficial, outer retina and choriocapillaris plexus. Crescent-shape lesion visible in deep and outer retina en-face exam.\n==== Refs\nReferences\n1 Bhavsar KV Lin S Rahimy E Joseph A Freund KB Sarraf D Acute macular neuroretinopathy: A comprehensive review of the literature Surv Ophthalmol 2016 Sep-Oct 61 (5) 538 65 26973287 \n2 Bos PJ Deutman AF Acute macular neuroretinopathy Am J Ophthalmol 1975 10 80 (4) 573 84 1180301 \n3 Thanos A Faia LJ Yonekawa Y Randhawa S Optical Coherence Tomographic Angiography in Acute Macular Neuroretinopathy JAMA Ophthalmol 2016 11 134 (11) 1310 4 27685015 \n4 Kashani AH Chen CL Gahm JK Zheng F Richter GM Rosenfeld PJ Optical coherence tomography angiography: A comprehensive review of current methods and clinical applications Prog Retin Eye Res 2017 9 60 66 100 28760677\n\n",
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"issue": "11(3)",
"journal": "Case reports in ophthalmology",
"keywords": "Multimodal retinal exams; Optical coherence tomography angiography; Retina",
"medline_ta": "Case Rep Ophthalmol",
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"title": "Twelve-Year-Old Girl with Acute Macular Neuroretinopathy: A Multimodal Retinal Evaluation.",
"title_normalized": "twelve year old girl with acute macular neuroretinopathy a multimodal retinal evaluation"
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"abstract": "A 63-year-old woman presented to our hospital for cough, sputum, and abnormal shadows on chest X-ray. Schizophyllum commune was isolated from mucous plugs. Positive specific IgE and IgG against the fungi, elevated serum IgE, and mucous plugs with typical histologic findings of allergic bronchopulmonary mycosis (ABPM) led to the diagnosis of ABPM due to S. commune. We initially administered itraconazole unsuccessfully. Changing the antifungal agent to voriconazole resulted in improvement of the symptoms and chest imaging findings. Her ABPM has not relapsed for two years since the cessation of voriconazole, which was administered for one year.",
"affiliations": "Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.;Department of Pathology, Saitama Cardiovascular and Respiratory Center, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.;Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan.",
"authors": "Ishiguro|Takashi|T|;Kagiyama|Naho|N|;Kojima|Ayako|A|;Yamada|Masami|M|;Nakamoto|Yasuo|Y|;Takaku|Yotaro|Y|;Shimizu|Yoshihiko|Y|;Kurashima|Kazuyoshi|K|;Takayanagi|Noboru|N|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2960796610.2169/internalmedicine.0668-17Case ReportAllergic Bronchopulmonary Mycosis Due to Schizophyllum commune Treated Effectively with Voriconazole Ishiguro Takashi 1Kagiyama Naho 1Kojima Ayako 12Yamada Masami 12Nakamoto Yasuo 13Takaku Yotaro 1Shimizu Yoshihiko 4Kurashima Kazuyoshi 1Takayanagi Noboru 1\n1 Department of Respiratory Medicine, Saitama Cardiovascular and Respiratory Center, Japan\n2 Department of Respiratory Medicine, Tokyo Jikei University, Japan\n3 Department of Respiratory Medicine, Kyorin University Hospital, Japan\n4 Department of Pathology, Saitama Cardiovascular and Respiratory Center, JapanCorrespondence to Dr. Takashi Ishiguro, ishiguro.takashi@pref.saitama.lg.jp\n\n30 3 2018 1 9 2018 57 17 2553 2557 15 12 2017 24 1 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 63-year-old woman presented to our hospital for cough, sputum, and abnormal shadows on chest X-ray. Schizophyllum commune was isolated from mucous plugs. Positive specific IgE and IgG against the fungi, elevated serum IgE, and mucous plugs with typical histologic findings of allergic bronchopulmonary mycosis (ABPM) led to the diagnosis of ABPM due to S. commune. We initially administered itraconazole unsuccessfully. Changing the antifungal agent to voriconazole resulted in improvement of the symptoms and chest imaging findings. Her ABPM has not relapsed for two years since the cessation of voriconazole, which was administered for one year. \n\nallergic bronchopulmonary mycosisSchizophyllum communevoriconazoleitraconazole\n==== Body\nIntroduction\nAllergic bronchopulmonary mycosis (ABPM) is an immunologic disorder caused by a hyperimmune response to the endobronchial growth of certain fungi. ABPM due to Aspergillus sp. (ABPA) was first reported in 1952 by Hinson et al (1). Cases of ABPM due to non-Aspergillus fungi have been increasing in number. Schizophyllum commune, which is a basidiomycetes fungus found throughout Japan, was found to be the most frequent causative fungus of non-Aspergillus ABPM in Japan (2). However, definitive treatment of ABPM due to S. commune has not been established.\n\nWe experienced a case of ABPM due to S. commune in which itraconazole (ITCZ) failed but voriconazole (VRCZ) was effective. We report this case and review previous reports of ABPM due to S. commune.\n\nCase Report\nA 63-year-old woman presented to our hospital for cough, sputum, and abnormal shadows on chest X-ray. She had developed a cough since December 2012. She presented to a local physician who prescribed dextromethorphan, which was ineffective. She presented to another hospital where chest X-ray showed consolidation in the left middle lung field (Fig. 1a). Chest computed tomography (CT) showed mucoid impaction of the lingual bronchus (Fig. 1b) but did not show highly attenuated mucus, which is a CT finding highly specific for ABPM. She was therefore referred to our hospital for a further evaluation in April 2013. The patient had never smoked or been exposed to dust, nor had she ever worked in a garden or on a farm, which would suggest exposure to dense soil or water. She had never experienced periodic paroxysms of dyspnea interspersed with intervals of complete or nearly complete remission, which would suggest asthma.\n\nFigure 1. Chest imaging findings on admission. Chest X-ray showed band-like shadows and consolidation in the left middle lung field (a). Chest computed tomography showed mucous plugs in the lingual bronchi (b). Bronchoscopy showed a mucous plug at the lingual bronchus (c).\n\nLaboratory tests did not show eosinophilia (300/mm3), but her serum IgE value was elevated to 1,363 IU/mL. Specific IgE against Aspergillus species was positive, but antibodies against Aspergillus species measured by complement fixation test were negative. Pulmonary function testing (% predicted) showed a vital capacity of 2.89 L (101.4%), forced vital capacity (FVC) of 2.93 L (102.8%), forced expiratory volume in 1 second (FEV1) of 2.52 L (137.0%), and an FEV1/FVC ratio of 86.0%, and an airway response to a beta-stimulant could not be induced. Sputum did not yield significant positive cultures, including for fungi. Lymphadenopathy and pleural effusion were not observed. We performed bronchoscopy and found mucous plugs in the lingual bronchus (Fig. 1c). Complete removal of the mucous plugs by bronchoscopy was attempted unsuccessfully. However, culture of one mucous plug that was obtained yielded a colony with a fluffy-like appearance, which was identified as S. commune at Chiba University Research Center for Pathogenic Fungi and Microbial Toxicoses. Serum values of IgE and IgG against S. commune measured at this same research center also were positive. The mucous plugs included eosinophils and Charcot-Leyden crystals, and fungal hyphae were also found in the plugs (Fig. 2). Although a clinical diagnosis of bronchial asthma was not established, we diagnosed her as having ABPM due to S. commune on the basis of histologic findings (3), culture results, and serum specific antibodies against S. commune.\n\nFigure 2. Histologic findings. A biopsy specimen of a mucus plug obtained via bronchoscopy showed fungal hyphae, eosinophils, and Charcot-Leyden crystals. a. Hematoxylin and Eosin staining (×200), b. Grocott stain (×200).\n\nDespite carefully rechecking her social history, we could find no clue as to the route of infection. We started ITCZ 200 mg daily from May 2013 for 16 weeks, but her symptoms did not improve, and mucoid impaction increased in the lingual bronchus. Peripheral eosinophils increased to 500/mm3, and her serum IgE value rose to 1,439 IU/mL. We then changed the antifungal agent from ITCZ to VRCZ from August 2013, which improved her symptoms and decreased the number of mucous plugs. No mucous plugs were found on a chest CT scan obtained in August 2014 (Fig. 3), and the VRCZ was stopped. Since then, she has been followed up on an outpatient basis, and ABPM has not recurred through her most recent follow-up in November 2017. Throughout the clinical course, the level of peripheral eosinophils did not increase further, and her serum IgE value gradually decreased to 547 IU/mL at the most recent follow-up.\n\nFigure 3. Chest computed tomography at the final follow-up examination. Chest computed tomography showed the area of central bronchiectasis that the mucous plugs had impacted.\n\nDiscussion\nWe herein report a case of ABPM due to S. commune in which ITCZ was ineffective. VRCZ cleared the mucous plugs, and the patient was followed up with no relapse of the ABPM for two years after one year of treatment with VRCZ.\n\nReports of ABPM due to S. commune have been increasing but are still relatively few, with only 25 found in the literature (4). Definitive treatment strategies have not been established, and ABPM due to S. commune has been managed with reference to the strategies of ABPA. Corticosteroid therapy is the mainstay of therapy for ABPA (5), and the guidelines recommend a combination of systemic corticosteroids and antifungal agents for ABPA (5). However, the long-term adverse effects of corticosteroid therapy may result in profound immunosuppression and debilitating metabolic abnormalities. It has been reported that pulmonary infection is not rare in ABPM patients due to the underlying impaired immune status (6). Furthermore, corticosteroid-induced immunosuppression may induce or very rarely result in progression of ABPA to invasive pulmonary aspergillosis (5). Therefore, we hesitated to start systemic corticosteroid as a first-line therapy in our patient.\n\nTreatments of ABPM patients in previous reports include bronchial toilet, inhaled corticosteroid, systemic corticosteroid therapy, expectorant, and antifungal agents. Antifungal agents spare the effects of corticosteroids by diminishing the antigenic stimulus for bronchial inflammation, and ITCZ is administered most frequently, followed by amphotericin-B (intravenously, via inhalation, or via intrabronchial administration with a bronchoscope). There have been several reports of patients with ABPM due to S. commune successfully treated by antifungal agent alone (7,8) (Table). We therefore initially administered ITCZ alone for 16 weeks, but the serum IgE value and mucous plugs on the chest CT increased. We assumed that single ITCZ therapy was ineffective and that other treatment modalities were required. The successful treatment with VRCZ in several patients with ABPA and one with ABPM due to S. commune has been reported (9-11), and VRCZ has a low minimum inhibitory concentration (12,13) against S. commune. Therefore, we administered VRCZ alone, which decreased our patient's serum IgE value and improved the findings on chest imaging. Serum concentrations of ITCZ and VRCZ were not measured in the present case, nor was susceptibility testing of these agents performed. We were unable to clarify the exact mechanism behind the effectiveness of VRCZ in our case nor why the ITCZ was ineffective. Future studies should discuss the effectiveness of antifungals on ABPM based on the absorption, serum and tissue concentration, and susceptibility against the causative fungi.\n\nTable. Treatment Duration and Effects of Antifungals in Previous Reports of ABPM/MIB Caused by Schizophyllum commune.\n\nAge/Sex\t\tAntifungals\t\tDuration\t\tEffect\t\tReference\t\n54/F\t\tITCZ\t\t10 months\t\tIneffective\t\t18\t\n72/F\t\tITCZ and inhalation of amphotericin-B\t\t1 year\t\tEffective\t\t19\t\n44/F\t\tInhalation of amphotericin-B plus ICS plus oral PSL\t\tUnknown\t\tEffective\t\t20\t\n51/F\t\tIntravenous amphotericin-B\t\t1 month\t\tEffective\t\t21\t\n51/F\t\tITCZ\t\t4 months\t\tEffective\t\t22\t\n54/F\t\tITCZ\t\t3 months\t\tEffective\t\t23\t\n75/F\t\tITCZ\t\t4 months\t\tEffective\t\t24\t\n55/M\t\tOral PSL plus ITCZ\t\t134 days\t\tEffective\t\t25\t\n64/F\t\tITCZ plus oral PSL\t\t3 months\t\tEffective\t\t26\t\n63/F\t\tInhalation and intrabronchial administration of amphotericin-B\t\t2 months\t\tEffective\t\t27\t\n53/F\t\tFluconazole \nInhalation and intrabronchial administration of amphotericin-B\t\tUnknown \nUnknown\t\tIneffective \nEffective\t\t27\t\n82/F\t\tOral PSL plus ITCZ plus inhalation of ICS\t\tUnknown\t\tEffective\t\t27\t\n53/F\t\tITCZ plus ICS and SM combination\t\tUnknown\t\tEffective\t\t28\t\n70/F\t\tITCZ\t\t3 months\t\tEffective\t\t29\t\n61/F\t\tOral ITCZ and PSL\t\tUnknown\t\tEffective\t\t30\t\n59/F\t\tVRCZ plus ICS\t\tUnknown\t\tEffective\t\t31\t\nABPM: allergic bronchopulmonary mycosis, MIB: mucoid impaction of the bronchi, S. commune: Schizophyllum commune, ITCZ: itraconazole, VRCZ: voriconazole, SM: salmeterol, PSL: prednisolone, ICS: inhaled corticosteroid\n\nAlthough reports of VRCZ use for ABPM due to S. commune are limited, the present report suggests that the administration of VRCZ may be effective for patients with ABPM due to S. commune when ITCZ is ineffective.\n\nThe recommended duration of ITCZ therapy for ABPA is 16 weeks (14), but the adequate treatment period of ITCZ and other antifungal agents for ABPM due to S. commune remains unclear. Treatment periods with antifungal agents differ among reports (Table). Most patients who received antifungals are treated for three to four months. We previously reported a patient with ABPM due to S. commune who has not relapsed for seven years after the three-month administration of ITCZ (8). However, we also experienced a patient who relapsed after ITCZ therapy for four months (7). There is one report of a patient who relapsed 4 months after 10-month treatment with ITCZ (15), but ITCZ and inhalation of amphotericin-B administered for 1 year improved another patient's condition (16). Only one case of ABPM due to S. commune treated with VRCZ has been reported, and the recommended treatment period of VRCZ is unclear. However, by referring to these experiences and previous reports, we administered VRCZ for one year, and our patient has not relapsed in the two years since the cessation of the VRCZ. Further accumulation of cases is needed to clarify the appropriate length of treatment.\n\nOur report has several limitations. First, our and other previous reports include limited information on the patients' long-term prognosis. Most reports of patients with ABPM due to S. commune have focused on a short clinical course after the initiation of treatment. Long-term problems of ABPA include irreversible pulmonary and bronchial destruction. These same problems may be present in ABPM due to S. commune, and thus treatment strategies need to be discussed from a long-term perspective. Second, we did not conduct a sensitivity test of VRCZ against S. commune, which is suggested when using antifungal agents (17).\n\nIn conclusion, we suggest that VRCZ may be an effective treatment option for ABPM due to S. commune, but further studies are needed to confirm the benefits of VRCZ for this condition.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe thank Katsuhiko Kamei at Chiba University Research Center for Pathogenic Fungi and Microbial Toxicoses for the identification of S. commune and measurement of serum-specific IgE and IgG against S. commune.\n==== Refs\n1. \nHinson KF , Moon AJ , Plummer NS \nBroncho-pulmonary aspergillosis; a review and a report of eight new cases . Thorax \n7 : 317 -333 , 1952 .13015523 \n2. \nChowdhary A , Agarwal K , Kathuria S , Gaur SN , Randhawa HS , Meis JF \nAllergic bronchopulmonary mycosis due to fungi other than Aspergillus: a global overview . Crit Rev Microbiol \n40 : 30 -48 , 2014 .23383677 \n3. \nBosken CH , Myers JL , Greenberger Katzenstein AL \nPathologic features of allergic bronchopulmonary aspergillosis . Am J Surg Pathol \n12 : 216 -222 , 1988 .3344888 \n4. \nIshiguro T , Takayanagi N , Kagiyama N , Shimizu Y , Yanagisawa T , Sugita Y \nClinical characteristics of biopsy-proven allergic bronchopulmonary mycosis: varieties in causative fungi and laboratory findings . Intern Med \n53 : 1407 -1411 , 2014 .24990332 \n5. \nWalsh TJ , Anaissie EJ , Denning DW , et al; Infectious Diseases Society of America . \nTreatment of aspergillosis; clinical practice guidelines of the Infectious Diseases Society of America . Clin Infect Dis \n46 : 327 -360 , 2008 .18177225 \n6. \nIshiguro T , Takayanagi N , Baba Y , Takaku Y , Kagiyama N , Sugita Y \nPulmonary nontuberculous mycobacteriosis and chronic lower respiratory tract infections in patients with allergic bronchopulmonary mycosis without cystic fibrosis . Intern Med \n55 : 1067 -1070 , 2016 .27150856 \n7. \nIshiguro T , Takayanagi N , Harasawa K , et al \nMucoid impaction of the bronchi caused by Schizophyllum commune which developed after discontinuation of itraconazole administration . Nihon Kokyuki Gakkai Zasshi \n47 : 296 -303 , 2009 (in Japanese, Abstract in English).19455959 \n8. \nIshiguro T , Takayanagi N , Tokunaga D , et al \nPulmonary Schizophyllum Commune infection developing mucoid impaction of the bronchi . Yale J Biol Med \n80 : 105 -111 , 2007 .18299722 \n9. \nErwin GE , Fitzgerald JE \nCase report: allergic bronchopulmonary aspergillosis and allergic fungal sinusitis successfully treated with voriconazole . J Asthma \n44 : 891 -895 , 2007 .18097869 \n10. \nGlackin L , Leen G , Elnavir B , Greally P \nVoriconazole in the treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis . Ir Med J \n102 : 29 , 2009 .19284017 \n11. \nShen Q , Yao YK , Yang Q , Zhou JY \nSchizophyllum commune-induced pulmonary mycosis . Chin Med J \n129 : 2141 -2142 , 2016 .27569249 \n12. \nGonzález GM , Sutton DA , Thompson E , Tijerina R , Rinaldi MG \nIn vitro activities of approved and investigational antifungal agents against 44 clinical isolated of basidiomycetous fungi . Antimicrob Agents Chemother \n45 : 633 -635 , 2001 .11158771 \n13. \nChowdhary A , Kathuria S , Singh PK , et al \nMolecular characterization and in vitro antifungal susceptibility profile of Schizophyllum commune, an emerging basidiomycete in bronchopulmonary mycoses . Antimicrob Agents Chemother \n57 : 2845 -2848 , 2013 .23507274 \n14. \nGuidelines Committee for Deep-seated Mycoses . \nGuidelines for management of deep-seated mycoses 2014 . Kyowa-Kikaku , Tokyo , 2014 (in Japanese).\n15. \nKamei K , Unno H , Nagao K , Kuriyama T , Nishimura K , Miyaji M \nAllergic bronchopulmonary mycosis caused by the basidiomycetous fungus Schizophyllum commune . Clin Infect Dis \n18 : 305 -309 , 1994 .8011808 \n16. \nTomita K , Hashizume I , Kasamatsu N , et al \nAllergic bronchopulmonary mycosis caused by Schizophyllum commune . Nihon Kyobu Shikkan Gakkai Zasshi \n34 : 804 -809 , 1996 (in Japanese).8810763 \n17. \nChowdhary A , Kathuria S , Agarwal K , Meis JF \nReply to “implications of high antifungal susceptibility on Schizophyllum commune-associated allergy in clinical practice” . Antimicrob Agents Chemother \n57 : 5784 , 2013 .24123345 \n18. \nKamei K , Unno H , Nagao K , et al \nAllergic bronchopulmonary mycosis caused by the basidiomycetous fungus Shizophyllum commune . Clin Infect Dis \n18 : 305 -309 , 1994 .8011808 \n19. \nTomita K , Hashizume I , Kasamatsu N , et al \nAllergic bronchopulmonary mycosis caused by Schizophyllum commune . Nihon Kyobu Shikkan Gakkai Zasshi \n34 : 804 -809 , 1996 (in Japanese).8810763 \n20. \nYamashina S \nABPM due to Shizophyllum commune . Jpn J Antibiotics \n50 : 51 -54 , 1997 (in Japanese).9139133 \n21. \nYamazaki Y , Sakashita H , Tanaka T , Kamei K , Nishimura K , Yoshizawa Y \nMucoid impaction caused by monokaryotic mycelium of Shizophyllum commune in association with bronchiectasis . Intern Med \n39 : 160 -162 , 2000 .10732837 \n22. \nIto Y , Sasaki S , Watanabe S , et al \nA case of mucoid impaction of bronchi (MIB) due to Shizophyllum commune . Nihon Kokyuki Gakkai Zasshi \n39 : 266 -270 , 2001 (in Japanese).11481826 \n23. \nIshiguro T , Takayanagi N , Tokunaga D , et al \nPulmonary Shizophyllum commune infection developing mucoid impaction of the bronchi . Yale J Biol Med \n80 : 105 -111 , 2007 .18299722 \n24. \nIshiguro T , Takayanagi N , Harasawa K , et al \nMucoid impaction of the bronchi caused by Shizophyllum commune which developed after discontinuation of Itraconazole administration . Nihon Kokyuki Gakkai Zasshi \n47 : 296 -303 , 2009 (in Japanese).19455959 \n25. \nAmemiya Y , Shirai R , Tokimatsu I , et al \nAllergic bronchopulmonary mycosis induced by Schizophyllum commune: case report and review of the literature . Nihon Kokyuki Gakkai Zasshi \n47 : 692 -697 , 2009 (in Japanese, Abstract in English).19764511 \n26. \nUruga H , Imafuku A , Hanada S , et al \nA case of allergic bronchopulmonary mycosis caused by Shizophyllum commune presenting with hyperattenuated mucoid impaction . Nihon Kokyuki Gakkai Zasshi \n48 : 749 -754 , 2010 (in Japanese).21066863 \n27. \nMasunaga A , Morimoto K , Ando T , Ikushima S , Takemura T , Oritsu M \nNihon Kokyuki Gakkai Zasshi \n48 : 912 -917 , 2010 (in Japanese).21226297 \n28. \nIshiguro T , Takayanagi N , Saito A , et al \nAllergic bronchopulmonary mycosis due to Shizophyllum commune and Aspergillus fumigatus . Nihon Kokyuki Gakkai Zasshi \n49 : 612 -618 , 2011 (in Japanese).21894779 \n29. \nOgawa H , Fujimura M , Takeuchi Y , Makimura K , Satoh K \nThe definitive diagnostic process and successful treatment for ABPM caused by Shizophyllum commune: a report of two cases . Allergol Intern \n61 : 163 -169 , 2012 .\n30. \nSeki M , Ohno H , Hotoh K , et al \nAllergic bronchopulmonary mycosis due to co-infection with Aspergillus fumigatus and Shizophyllum commune . IDCases \n1 : 5 -8 , 2014 .26839766 \n31. \nShen Q , Yao YK , Yang Q , Zhou JY \nSchizophyllum commune-induced Pulmonary Mycosis . Chin Med J \n129 : 2141 -2142 , 2016 .27569249\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(17)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Schizophyllum commune; allergic bronchopulmonary mycosis; itraconazole; voriconazole",
"medline_ta": "Intern Med",
"mesh_terms": "D000935:Antifungal Agents; D005260:Female; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D008875:Middle Aged; D012567:Schizophyllum; D013183:Sputum; D065819:Voriconazole",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2553-2557",
"pmc": null,
"pmid": "29607966",
"pubdate": "2018-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8011808;18097869;27569249;18177225;10732837;26839766;24990332;22377527;19455959;21066863;3344888;21894779;19764511;24123345;18299722;19284017;11481826;21226297;9139133;8810763;27150856;11158771;13015523;23383677;23507274",
"title": "Allergic Bronchopulmonary Mycosis Due to Schizophyllum commune Treated Effectively with Voriconazole.",
"title_normalized": "allergic bronchopulmonary mycosis due to schizophyllum commune treated effectively with voriconazole"
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"companynumb": "JP-MYLANLABS-2018M1075266",
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"activesubstancename": "ITRACONAZOLE"
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"abstract": "Vasculitis may accompany neoplasias and be of paraneoplastic type or associated with drugs used in patient treatment. We evaluated skin biopsies of twenty-eight cases with vasculitis accompanying leukemias reviewed and clinical outcome was evaluated. Eleven of the 28 cases had paraneoplastic vasculitis and 17 had vasculitis associated with various drugs including chemotherapy, cytokines and antibacterial agents. Paraneoplastic vasculitis was seen in 3 cases with chronic myelocytic leukemia in blastic phase, 5 patients with acute myeloblastic leukemia, and 3 with myelodysplastic syndrome. Drugs responsible for the 17 cases of vasculitis included hydroxyurea, vincristine, cytosine-arabinoside, methotrexate, all-trans retinoic acid, granulocyte-colony stimulating factor, interferon and antibiotics. Paraneoplastic vasculitis is not rare in leukemias and may be a manifestation of the blastic phase of chronic myeloid leukemia. Furthermore paraneoplastic vasculitis can be fatal in myelodysplastic syndromes and may be present clinically before the specific diagnosis is made. Drugs used in routine therapy may be the cause of the vasculitis, thus skin biopsy should be performed in all cutaneous lesions in patients with hemopoietic neoplasias.",
"affiliations": "Faculty of Medicine, Department of Oncology, Cukurova University, Balcali, Adana, Turkey. sepay@mail.cu.edu.tr",
"authors": "Paydaş|S|S|;Zorludemir|S|S|;Sahin|B|B|",
"chemical_list": "D000890:Anti-Infective Agents; D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.3109/10428190009054886",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "40(1-2)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D001706:Biopsy; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007938:Leukemia; D017254:Leukemic Infiltration; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012871:Skin Diseases; D014657:Vasculitis",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "105-12",
"pmc": null,
"pmid": "11426610",
"pubdate": "2000-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Vasculitis and leukemia.",
"title_normalized": "vasculitis and leukemia"
} | [
{
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"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
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{
"abstract": "Toxic epidermal necrolysis (TEN) is a rare and life-threatening allergic drug reaction. We report a 26-year-old young female with end-stage renal disease on maintenance hemodialysis developing TEN while on filgrastim and phenytoin. It was successfully treated with intravenous immunoglobulins and steroids.",
"affiliations": "Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India.;Department of Nephrology, Kasturba Medical College, Kasturba Hospital, Manipal University, Manipal, Karnataka, India.;Department of Nephrology, Kasturba Medical College, Kasturba Hospital, Manipal University, Manipal, Karnataka, India.;Department of Nephrology, Kasturba Medical College, Kasturba Hospital, Manipal University, Manipal, Karnataka, India.;Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India.;Department of Pathology, Kasturba Medical College, Kasturba Hospital, Manipal University, Manipal, Karnataka, India.",
"authors": "Mateti|Uday Venkat|UV|;Nagaraju|Shankar Prasad|SP|;Bairy|Manohar|M|;Attur|Ravindra Prabhu|RP|;Nagappa|Anantha Naik|AN|;Rao|Anuradha Calicut Kini|AC|",
"chemical_list": null,
"country": "India",
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"doi": "10.4103/2277-9175.152119",
"fulltext": "\n==== Front\nAdv Biomed ResAdv Biomed ResABRAdvanced Biomedical Research2277-9175Medknow Publications & Media Pvt Ltd India ABR-4-6310.4103/2277-9175.152119Case ReportToxic epidermal necrolysis in hemodialysis patient Mateti Uday Venkat Nagaraju Shankar Prasad 1Bairy Manohar 1Attur Ravindra Prabhu 1Nagappa Anantha Naik Rao Anuradha Calicut Kini 2Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India1 Department of Nephrology, Kasturba Medical College, Kasturba Hospital, Manipal University, Manipal, Karnataka, India2 Department of Pathology, Kasturba Medical College, Kasturba Hospital, Manipal University, Manipal, Karnataka, IndiaAddress for correspondence: Dr. Anantha Naik Nagappa, Professor, Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal - 576 104, Karnataka, India. E-mail: anantha1232000@gmail.com2015 27 2 2015 4 6324 10 2013 07 5 2014 Copyright: © 2015 Mateti.2015This 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.Toxic epidermal necrolysis (TEN) is a rare and life-threatening allergic drug reaction. We report a 26-year-old young female with end-stage renal disease on maintenance hemodialysis developing TEN while on filgrastim and phenytoin. It was successfully treated with intravenous immunoglobulins and steroids.\n\nEnd stage renal diseasefilgrastimhemodialysisphenytointoxic epidermal necrolysis\n==== Body\nINTRODUCTION\nToxic epidermal necrolysis (TEN) is a rare and life-threatening allergic drug reaction. Skin blistering with epidermal and mucosal necrolysis with subsequent detachment from an inflamed underlying dermis is a hallmark of the condition.[1] The major causative drugs for TEN have been found to be antimicrobials, NSAIDs, and anti-epileptics such as phenytoin, lamotrigine, carbamazepine, and phenobarbital.[2] We report a case of TEN in an end-stage renal disease patient who was on Phenytoin as an antiepileptic and developed TEN after starting Filgrastim for her leukopenia.\n\nCASE REPORT\nA 26-year-old young female with end-stage renal disease due to focal segmental glomerulosclerosis on maintenance hemodialysis was admitted for malignant hypertension to our Nephrology department. She was known to have tuberculous lymphadenitis and was on antituberculosis therapy for the preceding 4 months. On the day of admission, she had an episode of generalized tonic clonic seizures for which she was given 1 gram of phenytoin intravenously as loading dose and was continued on 300 mg PO daily. After 2 weeks, she was noted to have neutropenia (Absolute neutrophil count- <1000/mm3). She was evaluated for neutropenia and filgrastim 300 mcg was injected subcutaneously. Within a few hours of injection she reported itching around the site of injection and swelling of eyes, facial swelling, and itchy red rashes over the lips, face, upper and lower back [Figure 1]. Erythematous papules over legs, hands and several bullae and purpuric lesions over the palm, sole and feet were observed [Figure 2]. She developed desquamation of skin involving >80% of the skin surface and mucosa. There was no involvement of the eyes. So both phenytoin and filgrastim were withdrawn immediately. A skin biopsy was performed, which showed ulcerated epidermis with necrotic keratinocytes with acrosyringeal extension and few eosinophils overlying focally necrotic and edematous papillary dermis with neutrophil and lymphocytic infiltrate, melanin drop out along with perivascular lymphocytosis and adnexal structures. Subepidermal bulla was seen with focal in growth of epidermis [Figure 3]. It was suggestive of TEN.\n\nFigure 1 Skin lesions on the trunk\n\nFigure 2 Lesions on the upper limb\n\nFigure 3 Photomicrograph depicting toxic epidermal necrolysis; H and E stain. (×5)\n\nFigure 4 Improvement in the lesions of skin after treatment\n\nThe patient was shifted to ICU and was treated with intravenous immunoglobulin (IVIG) 2 g/kg over 5 days and steroids with prophylactic antibiotics. Daily dressing was performed. She was continued on hemodialysis during the hospital stay and gradually her skin lesions improved significantly [Figure 4]. Presently she is doing well and is on maintenance hemodialysis.\n\nDISCUSSION\nTEN has been reported with antiepileptics especially with carbamazepine (18.25%) and phenytoin (13.37%) which are usually used in the management of generalized tonic clonic seizures.[34] Most patients who develop TEN on anti-epileptic drugs do so within 8 weeks of starting the drug (85-100%).[5] Though TEN is a known adverse effect of phenytoin, in our case the patient developed TEN within 4-6 hours after the injection of filgrastim after having been on phenytoin for 2 weeks. So whether the reaction was due to phenytoin or filgrastim or an unknown interaction between the two drugs is unclear. As there was a temporal association with filgrastim, both the drugs were withdrawn. The patient was treated with intravenous immunoglobulins and steroids with complete recovery.\n\nThere is a need for continuous reporting of such a rare life-threatening adverse effect of drugs in order to increase awareness and to prevent serious reactions like TEN. This can be confirmed by further detailed assessment of adverse drug reactions which can be performed by using the World Health Organization's (WHO) causality, Naranjo's algorithm and Hartwig scale.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Endorf FW Cancio LC Gibran NS Toxic epidermal necrolysis clinical guidelines J Burn Care Res 2008 29 706 12 18695603 \n2 Fernández FA Pintor E Quesada R Garcés FJ Toxic epidermal necrolysis induced by phenytoin and whole brain radiotherapy Actas Dermosifiliogr 2007 98 483 5 17669303 \n3 Radhakrishnan K Nayak SD Kumar SP Sarma PS Profile of antiepileptic pharmacotherapy in a tertiary referral center in South India: A pharmacoepidemiologic and pharmacoeconomic study Epilepsia 1999 40 179 85 9952264 \n4 Mathur S Sen S Ramesh L M-Kumar S Utilization pattern of antiepileptic drugs and their adverse effects, in a teaching hospital Asian J Pharm Clin Res 2010 3 55 9 \n5 Mockenhaupt M Viboud C Dunant A Naldi L Halevy S Bouwes Bavinck JN Stevens-Johnson syndrome and toxic epidermal necrolysis: Assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study J Invest Dermatol 2008 128 35 44 17805350\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2277-9175",
"issue": "4()",
"journal": "Advanced biomedical research",
"keywords": "End stage renal disease; filgrastim; hemodialysis; phenytoin; toxic epidermal necrolysis",
"medline_ta": "Adv Biomed Res",
"mesh_terms": null,
"nlm_unique_id": "101586897",
"other_id": null,
"pages": "63",
"pmc": null,
"pmid": "25821763",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "17669303;17805350;18695603;9952264",
"title": "Toxic epidermal necrolysis in hemodialysis patient.",
"title_normalized": "toxic epidermal necrolysis in hemodialysis patient"
} | [
{
"companynumb": "IN-AMGEN-INDSP2015033774",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PHENYTOIN"
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"drugadditional": null,
... |
{
"abstract": "To report the incidence, predictors, and outcome of rituximab (RTX)-associated autoimmune disease flare.\n\n\n\nWe conducted a retrospective study in a tertiary referral center from 2005 to 2015. Disease flare was defined as the onset of a new organ involvement or worsening of autoimmune disease within 4 weeks following RTX.\n\n\n\nAmong the 185 patients, we identified 7 disease flares (3.4%). All were due to type II mixed cryoglobulinemia vasculitis. Vasculitis flare occurred after a median time of 8 days (range 2-16) following RTX infusion and included acute kidney insufficiency (n = 7), purpura with cutaneous (n = 7), gastrointestinal (GI) tract involvement (n = 4), and myocarditis (n = 1). Patients with RTX-associated cryoglobulinemia vasculitis flare had these conditions more frequently: renal involvement (p = 0.0008), B cell lymphoproliferation (p = 0.015), higher level of cryoglobulin (2.1 vs 0.4 g/l, p = 0.0004), and lower level of C4 (0.02 vs 0.05, p = 0.023) compared to patients without flare after RTX (n = 43). Four patients (57%) died after a median time of 3.3 months. The 1-year survival rate was poorer in patients with vasculitis flare after RTX compared to their negative counterpart [43% (95% CI 18-100) vs 97% (95% CI 92-100), p < 0.001]. Immunofluorescence analysis of kidney biopsy in patients with worsening RTX-associated vasculitis highlighted the presence of RTX-, IgM-, and IgG1-positive staining of endomembranous deposits and thrombi within kidney lesions.\n\n\n\nRTX-associated cryoglobulinemia vasculitis flare is associated with high mortality rate. We provided evidence that kidney lesions are due to immune complex deposition and to glomerular obstruction by cryoglobulinemia and RTX.",
"affiliations": "From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France.;From the Départements Hospitalo-Universitaires (DHU) Inflammation, Immunopathologie, Biothérapie, Université Pierre et Marie Curie; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Department of Pathology, Laboratory of Immunology, and Pharmacy Department; Département de Biostatistiques, Hôpital Saint-Louis; AP-HP, Groupe Hospitalier Lariboisière, Department of Internal Medicine, Paris; Hôpital Bretonneau, Centre Hospitalier de Tours, Department of Internal Medicine, Tours; Hôpital Necker, Laboratory of Immunology, Paris; Centre Hospitalier de Valence, Department of Internal Medicine, Valence, France. david.saadoun@aphp.fr.",
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"abstract": "Although most women with type 1 diabetes experience the normal transition to menopause, there is little information about the impact of hormone replacement therapy on their glycemic profiles. A 54-year-old postmenopausal woman with fulminant type 1 diabetes was admitted to our hospital due to diabetic ketoacidosis. She was treated with fluid replacement and a continuous insulin infusion. Thereafter, her glycemic profile was well maintained by daily multiple insulin injections. However, her glycemic profiles immediately deteriorated following the administration of progesterone in hormone replacement therapy. This transient deterioration implies that external progesterone can lead to the deterioration of glycemic profiles in postmenopausal women with type 1 diabetes.",
"affiliations": "Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Japan.",
"authors": "Tanaka|Sho|S|;Hishiki|Mikano|M|;Ogasawara|Junko|J|;Sorimachi|Erisa|E|;Nakayama|Mari|M|",
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"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.56.7663Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 28250300Case ReportThe Deterioration of the Glycemic Profile during Hormone Replacement Therapy in a Patient with Fulminant Type 1 Diabetes Tanaka Sho 1Hishiki Mikano 2Ogasawara Junko 2Sorimachi Erisa 2Nakayama Mari 21 Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Japan2 Department of Diabetology and Endocrinology, Tokyo Metropolitan Hiroo Hospital, JapanCorrespondence to Dr. Sho Tanaka, tanakasho13@gmail.com\n\n1 3 2017 56 5 531 534 30 4 2016 27 6 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Although most women with type 1 diabetes experience the normal transition to menopause, there is little information about the impact of hormone replacement therapy on their glycemic profiles. A 54-year-old postmenopausal woman with fulminant type 1 diabetes was admitted to our hospital due to diabetic ketoacidosis. She was treated with fluid replacement and a continuous insulin infusion. Thereafter, her glycemic profile was well maintained by daily multiple insulin injections. However, her glycemic profiles immediately deteriorated following the administration of progesterone in hormone replacement therapy. This transient deterioration implies that external progesterone can lead to the deterioration of glycemic profiles in postmenopausal women with type 1 diabetes. \n\ndiabetes mellitus, type 1hormone replacement therapyprogesterone\n==== Body\nIntroduction\nFulminant type 1 diabetes is a metabolic disease that is characterized by the rapidly progressive impairment of insulin secretion, which leads to diabetic ketoacidosis (1). While there is no sex-specific prevalence, women develop type 1 diabetes at a younger age (35.1±15.8 years) than men with or without an association with pregnancy or delivery (2). Thus, most women with fulminant type 1 diabetes experience a transition to menopause.\n\nHormone replacement therapy (HRT) is frequently administered to women with postmenopausal syndrome. The HRT regimens can be roughly classified into the 2 following types: estrogen only and estrogen plus progesterone. Although each regimen is associated with both risks and benefits, the estrogen plus progesterone regimen is preferably administered to women with an intact uterus to avoid estrogen-induced endometrial cancer (3). Furthermore, previous research has revealed that both HRT regimens improved the glycemic profiles of women with type 2 diabetes (4). In contrast, while glycemic fluctuations have been observed in parallel with the estrous cycles in women with type 1 diabetes (which would imply that HRT would alter the glycemic profile of such women (either positively or negatively), there is little detailed information on this matter (5-7).\n\nWe herein report a case of fulminant type 1 diabetes in a patient whose glycemic profile deteriorated during HRT using estradiol and medroxyprogesterone.\n\nCase Report\nA 54-year-old Japanese woman was admitted to hospital because of disturbance of consciousness, which followed 1 week of progressive appetite loss and nausea accompanied by vomiting. Her significant medical history included vasomotor symptoms associated with postmenopausal syndrome, which had been diagnosed when the patient was 50 years of age. She had been treated with an HRT regimen that consisted of estrogen plus medroxyprogesterone. With the exception of the patient's postmenopausal syndrome, her medical history, including the results of her previous check-ups and her family and travel history, was unremarkable. She had never used tobacco and did not drink alcohol.\n\nOn physical examination, the patient's Glasgow Coma Scale (GCS) value was 13: E4 V3 M6, her body temperature was 34.3℃, her blood pressure was 82/46 mmHg, her pulse was regular at 104 beats/min, and her respiratory rate was 24 breaths/min. Body measurements could not be made on admission due to the patient's acute distress. After her recovery, her height (149.5 cm) and weight (39.3 kg) were measured. She had dry mucous membranes and decreased skin turgor. There was no sign of skin rash, lymph node swelling, thyroid enlargement, pathological rales/murmurs, remarkable abdominal findings, or pretibial edema.\n\nThe laboratory data on arrival revealed severe hyperglycemia and metabolic acidosis with ketone bodies. The patient's glycated hemoglobin level (6.9%) was still mild considering her plasma glucose value. Her serum levels of urea nitrogen, creatinine, transaminase, creatine kinase, amylase, and lipase were remarkably elevated. Her serum electrolyte levels were imbalanced. A urinalysis revealed proteinuria, glucosuria, ketonuria, and occult hematuria. Detailed data are shown in Table 1. Although computed tomography revealed mild pancreatomegaly, there was no evidence of effusion around the pancreas or abnormal findings in relation to the chest, liver, adrenal gland, kidney, spleen, uterus, or ovaries were evident.\n\nTable 1. Laboratory Findings on Admission.\n\nHematological examination\t\nWhite blood cell\t8,700\t/μL\t(3,500-9,500)\t\nHemoglobin\t13.3\tg/dL\t(12.0-15.0)\t\nPlatelets\t13.7 × 104\t/μL\t(14.0-38.0)\t\nTotal protein\t7.2\tg/dL\t(6.3-8.5)\t\nUrea nitrogen\t97.9\tmg/dL\t(7.0-22.0)\t\nCreatinine\t4.1\tmg/dL\t(0.4-0.9)\t\nSodium\t128\tmEq/L\t(136-146)\t\nPotassium\t6.2\tmEq/L\t(3.3-5.0)\t\nChloride\t82\tmEq/L\t(95-110)\t\nTotal bilirubin\t0.4\tmg/dL\t(0.3-1.0)\t\nAspartate aminotransferase\t43\tU/L\t(8-37)\t\nAlanine aminotransferase\t62\tU/L\t(5-35)\t\nLactate dehydrogenase\t168\tU/L\t(110-255)\t\nCreatine kinase\t2,242\tU/L\t18-150)\t\nAlkaline phosphatase\t659\tU/L\t(120-385)\t\nAmylase\t4,221\tU/L\t(40-180)\t\nLipase\t1,046\tU/L\t(17-57)\t\nHDL cholesterol\t53\tmg/dL\t(35-90)\t\nLDL cholesterol\t111\tmg/dL\t(70-139)\t\nTriglyceride\t73\tmg/dL\t(50-180)\t\nC-reactive protein\t2.7\tmg/dL\t(0.0-0.3)\t\nCasual plasma lucose\t75.4\tmmol/L\t(4-6)\t\nGlycated emoglobin\t6.9\t%\t(4.6-6.2)\t\nC-peptide\t0.1\tng/mL\t(0.8-2.5)\t\nAcetoacetic acid\t5,440\tμmol/L\t(0-55)\t\n3-Hydroxybutanoic acid\t21,280\tμmol/L\t(0-85)\t\nUrinary examination\t\nProtein\t(±)\t\t\t\nGlucose\t(4+)\t\t\t\nKetone body\t(2+)\t\t\t\nOccult blood\t(2+)\t\t\t\nAtrial blood gas analysis under reservoir mask at O2 10L/min\t\npH\t7.040\t\t(7.350-7.450)\t\nPaCO2\t11.6\tmmHg\t(35.0-45.0)\t\nPaO2\t322.3\tmmHg\t(75.0-100.0)\t\nHCO3-\t3.1\tmmol/L\t(20.0-26.0)\t\nBase excess\t-25.5\tmmol/L\t(-3.0-3.0)\t\nThe patient was diagnosed with diabetic ketoacidosis due to fulminant type 1 diabetes. She was simultaneously treated with fluid replacement and continuous insulin infusion to maintain her vital signs and her plasma glucose and electrolyte levels. On day 3, the patient's ketonuria, kidney function, electrolytes and vital signs had normalized. On day 4, the continuous infusion of insulin was withdrawn and daily multiple insulin injection therapy was administered with blood glucose monitoring. On day 5, the patient's liver function spontaneously normalized. The insulin dose was titrated and the mean preprandial blood glucose was maintained. On day 11, HRT was restarted; initially, only percutaneous estradiol gel (1 mg/day) was administered. Her glycemic profiles showed unremarkable changes during this period. On day 21, oral medroxyprogesterone (2.5 mg/day) was administered in addition to percutaneous estradiol gel. Subsequently, her glycemic profiles showed an immediate deterioration, despite a stable carbohydrate intake, suitable injection technique and a good physical condition. No factors that might have exacerbated the patient's glycemic control (such as fever, electrolytic imbalance, liver dysfunction, kidney dysfunction or heart failure) were observed. The mean preprandial blood glucose level was elevated to a maximum of 22.1 mmol/L on the day after the administration of medroxyprogesterone. HRT was discontinued, and her glycemic profile immediately improved. The average pre-prandial blood glucose level during administration of medroxyprogesterone was significantly higher than it was before (p=0.0017) and after (p<0.001) the administration (Table 2). The patient's glycemic profile from the day of admission until discharge are shown in Figure. The clinical course after this transient deterioration was uneventful. The patient was discharged on day 45.\n\nTable 2. Preprandial Blood Glucose around Medroxyprogesterone Administration.\n\n\tPreceding 5 days\tDuring 5 days\tFollowing 5 days\t\nAverage (±SD) mmol/L\t10.8 (±3.1)\t16.2 (±6.7)\t9.5 (±3.4)\t\nFigure. The clinical course of this case. The horizontal axis indicates the clinical time course. The solid line indicates the mean preprandial blood glucose values; the left vertical axis shows the units of glucose. The vertical gray bars indicate the total daily dose from multiple daily insulin injections; the left vertical axis shows the total daily dose units. The horizontal gray bars show continuous insulin infusion, estradiol, and medroxyprogesterone, respectively.\n\nThe results of the serological findings and the patient's insulin secretory capacity, which were obtained subsequent to her recovery, are shown in Table 3. The patient was negative for autoantibodies and her insulin secretion were completely impaired. These findings were compatible with fulminant type 1 diabetes.\n\nTable 3. Serological Findings and Insulin Secretory Capacity Subsequently Obtained after Patient’s Recovery.\n\nSerological examination\t\nAnti GAD antibody\t1.8\tU/mL\t(0.0-1.4)\t\nAnti IA2 antibody\t<0.4\tU/mL\t(0.0-0.3)\t\nAnti IAA antibody\t0.7\t%\t(<0.3)\t\nAnti TPO antibody\t<5.0\tU/mL\t(<15.9)\t\nAnti Tg antibody\t<10\tU/mL\t(<27.9)\t\nInsulin secretory capacity\t\nFasting C-peptide\t0.1\tng/mL\t\t\nGlucagon stimulated C-peptide\t0.1\tng/mL\t\t\nUrine C-peptide\t1.6\tμg/day\t(22.8-155.2)\t\nDiscussion\nPrevious studies have revealed that HRT improves the glycemic profiles of women with type 2 diabetes (4). Conversely, the deterioration of the glycemic profile after the administration of medroxyprogesterone that was observed in the present case implied that the external application of progesterone can alter the glycemic profile of postmenopausal women with type 1 diabetes.\n\nThere are few reports on the impact of HRT on the glycemic profiles of women with type 1 diabetes. A meta-analysis pointed out that the previous randomized controlled trials were underpowered and concluded that there is little evidence about the impact of HRT on the glycemic profiles in women with type 1 diabetes (6). Moreover, our literature search revealed no detailed information about the impact of progesterone in HRT in women with type 1 diabetes.\n\nSeveral investigators have reported a relationship between the glycemic profile and the estrous cycle. For instance, a mild upward trend in the postprandial plasma glucose values in the luteal phase was observed, even in young women without diabetes (8). Furthermore, the glycemic fluctuations that were observed in women with type 1 diabetes were more prominent; it was reported (and clinically experienced) that the glycemic profile deteriorated in the luteal phase and improved in the follicular phase (5). The cause of this fluctuation was presumed to be due to the increased level of progesterone in the luteal phase. Medroxyprogesterone worsened the insulin sensitivity of macaques. Furthermore, fundamental studies reported that the administration of estrogen and progesterone lowered and raised the plasma glucose levels, respectively, in an alloxan-induced type 1 diabetes mouse model (9,10). Moreover in humans, the administration of medroxyprogesterone raised fasting glucose and insulin levels (11). Given this information, the glycemic profiles in type 1 diabetes seem to be fragile in the presence of sex steroid fluctuations and it was implied that HRT, especially medroxyprogesterone, can lead to a deterioration in the insulin sensitivity and thereby lead to a high glucose level.\n\nAlthough there is a previously reported case of a pregnant woman with type 1 diabetes whose glycemic profile deteriorated following an intramuscular injection of hydroxyprogesterone, the extent of her deterioration was milder than that which was observed in the present case (12). Certainly this patient's small build, her race, drug-specific effects, and the route of administration were candidate etiologies for this drastic glycemic fluctuation. However, it is very difficult to make a fair judgment due to the extreme scarcity of information about HRT in type 1 diabetes. The present study is associated with some limitations: we could not confirm whether the repeated oral administration of medroxyprogesterone would cause another episode of glucose deterioration. Because, the patient did not suffer from vasomotor symptoms, that is, hot flushes and night sweats despite the discontinuance of HRT, we did not approve the re-administration of medroxyprogesterone. Thus, there is a need for further studies about the impact of HRT, including progesterone, on large numbers of postmenopausal women with type 1 diabetes.\n\nOpinions are divided among investigators as to whether women with type 1 diabetes have an earlier menopause than individuals without type 1 diabetes. However, if it is assumed that most patients with type 1 diabetes will experience a transition to menopause, an appropriate and safe HRT regimen should to be established. In summary, this case implies that the external administration of progesterone might deteriorate the glycemic profiles of postmenopausal women with type 1 diabetes and should alert physicians to the necessity of further investigation to establish a safe regimen of HRT for these women.\n\nThe authors state that they have no Conflict of Interest (COI).\nAcknowledgement\nWe thank Dr. Masayoshi Soma, Professor of Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, for his help in providing clinical advice for this case.\n==== Refs\n1. \nImagawa A , Hanafusa T , Miyagawa J , Matsuzawa Y \nA novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group . N Engl J Med \n342 : 301 -307 , 2000 .10655528 \n2. \nImagawa A , Hanafusa T , Uchigata Y , et al \nFulminant type 1 diabetes: a nationwide survey in Japan . Diabetes Care \n26 : 2345 -2352 , 2003 .12882860 \n3. \nManson JE , Chlebowski RT , Stefanick ML , et al \nMenopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials . JAMA \n310 : 1353 -1368 , 2013 .24084921 \n4. \nFerrara A , Karter AJ , Ackerson LM , et al \nHormone replacement therapy is associated with better glycemic control in women with type 2 diabetes: The Northern California Kaiser Permanente Diabetes Registry . Diabetes Care \n24 : 1144 -1150 , 2001 .11423493 \n5. \nBarata DS , Adan LF , Netto EM , Ramalho AC \nThe effect of the menstrual cycle on glucose control in women with type 1 diabetes evaluated using a continuous glucose monitoring system . Diabetes Care \n36 : e70 , 2013 .23613610 \n6. \nMackay L , Kilbride L , Adamson KA , Chisholm J \nHormone replacement therapy for women with type 1 diabetes mellitus . Cochrane Database Syst Rev \n6 : CD008613 , 2013 .\n7. \nScott AR , Dhindsa P , Forsyth J , Mansell P \nEffect of hormone replacement therapy on cardiovascular risk factors in postmenopausal women with diabetes . Diabetes Obes Metab \n6 : 16 -22 , 2004 .14686958 \n8. \nBennal AS , Kerure SB \nGlucose handling during menstrual cycle . Int J Reprod Contracept Obstet Gynecol \n2 : 284 -287 , 2013 .\n9. \nCruzen CL , Baum ST , Colman RJ \nGlucoregulatory function in adult rhesus macaques (Macaca mulatta) undergoing treatment with medroxyprogesterone acetate for endometriosis . J Am Assoc Lab Anim Sci \n50 : 921 -925 , 2011 .22330788 \n10. \nBhattacharya S , Bank S , Maiti S , K Sinha A \nThe control of hyperglycemia by estriol and progesterone in alloxan induced type I diabetes mellitus mice model through hepatic insulin synthesis . Int J Biomed Sci \n10 : 8 -15 , 2014 .24711743 \n11. \nBerenson AB , van den Berg P , Williams KJ , Rahman M \nEffect of injectable and oral contraceptives on glucose and insulin levels . Obstet Gynecol \n117 : 41 -47 , 2011 .21173642 \n12. \nSasaki S , Yasuda T , Kaneto H , Kuroda A , Fujita Y \nBasal insulin requirements after progesterone treatment in a type 1 diabetic pregnant woman . Intern Med \n52 : 259 -262 , 2013 .23318859\n\n",
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"mesh_terms": "D001786:Blood Glucose; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D007328:Insulin; D008525:Medroxyprogesterone; D008875:Middle Aged",
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"title": "The Deterioration of the Glycemic Profile during Hormone Replacement Therapy in a Patient with Fulminant Type 1 Diabetes.",
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"abstract": "BACKGROUND\nMultimodal pain management is an integral part of enhanced recovery pathways. The most effective pain management strategies have not been determined.\n\n\nOBJECTIVE\nThe purpose of this study was to compare liposomal bupivacaine transversus abdominis plane block with epidural analgesia in patients undergoing colorectal surgery.\n\n\nMETHODS\nThis is a single-institution, open-label randomized (1:1) trial.\n\n\nMETHODS\nThis study compared liposomal bupivacaine transversus abdominis plane block with epidural analgesia in patients undergoing elective open and minimally invasive colorectal surgery in an enhanced recovery pathway.\n\n\nMETHODS\nTwo hundred were enrolled. Following randomization, allocation, and follow-up, there were 92 patients with transversus abdominis plane block and 87 patients with epidural analgesia available for analysis.\n\n\nMETHODS\nThe interventions comprised liposomal bupivacaine transversus abdominis plane block versus epidural analgesia.\n\n\nMETHODS\nThe primary outcomes measured were numeric pain scores and the overall benefit of analgesia scores.\n\n\nRESULTS\nThere were no significant differences in the Numeric Pain Scale and Overall Benefit of Analgesia Score between groups. Time trend analysis revealed that patients with transversus abdominis plane block had higher numeric pain scores on the day of surgery, but that the relationship was reversed later in the postoperative period. Opioid use was significantly less in the transversus abdominis plane block group (206.84 mg vs 98.29 mg, p < 0.001). There were no significant differences in time to GI recovery, hospital length of stay, and postoperative complications. Cost was considerably more for the epidural analgesia group.\n\n\nCONCLUSIONS\nThis study was conducted at a single institution.\n\n\nCONCLUSIONS\nThis randomized trial shows that perioperative pain management with liposomal bupivacaine transversus abdominis plane block is as effective as epidural analgesia and is associated with less opioid use and less cost. These data and the more favorable risk profile suggest that liposomal bupivacaine transversus abdominis plane block is a viable multimodal perioperative pain management option for this patient population in an established enhanced recovery pathway.\n\n\nBACKGROUND\nhttp://www.clinicaltrials.gov (NCT02591407). See Video Abstract at http://links.lww.com/DCR/A737.",
"affiliations": "Department of Surgery, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Department of Surgery, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Department of Academic Research, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Biostatistics and Epidemiology Methods Consulting, BEMC, LLC, Ann Arbor, Michigan.;Biostatistics and Epidemiology Methods Consulting, BEMC, LLC, Ann Arbor, Michigan.;Department of Academic Research, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Department of Pharmacy, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Department of Pharmacy, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Department of Anesthesiology, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Division of Colon and Rectal Surgery, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Division of Colon and Rectal Surgery, St Joseph Mercy Hospital, Ann Arbor, Michigan.;Division of Colon and Rectal Surgery, St Joseph Mercy Hospital, Ann Arbor, Michigan.",
"authors": "Felling|Daniel R|DR|;Jackson|Miles W|MW|;Ferraro|Jane|J|;Battaglia|Michael A|MA|;Albright|Jeremy J|JJ|;Wu|Juan|J|;Genord|Cheryl K|CK|;Brockhaus|Kara K|KK|;Bhave|Rohit A|RA|;McClure|Amanda M|AM|;Shanker|Beth-Ann|BA|;Cleary|Robert K|RK|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1097/DCR.0000000000001211",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3706",
"issue": "61(10)",
"journal": "Diseases of the colon and rectum",
"keywords": null,
"medline_ta": "Dis Colon Rectum",
"mesh_terms": "D000009:Abdominal Muscles; D000328:Adult; D015360:Analgesia, Epidural; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D002045:Bupivacaine; D003106:Colon; D003107:Colorectal Surgery; D013505:Digestive System Surgical Procedures; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009407:Nerve Block; D017063:Outcome Assessment, Health Care; D059408:Pain Management; D010147:Pain Measurement; D010149:Pain, Postoperative; D019990:Perioperative Care; D011184:Postoperative Period",
"nlm_unique_id": "0372764",
"other_id": null,
"pages": "1196-1204",
"pmc": null,
"pmid": "30192328",
"pubdate": "2018-10",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Liposomal Bupivacaine Transversus Abdominis Plane Block Versus Epidural Analgesia in a Colon and Rectal Surgery Enhanced Recovery Pathway: A Randomized Clinical Trial.",
"title_normalized": "liposomal bupivacaine transversus abdominis plane block versus epidural analgesia in a colon and rectal surgery enhanced recovery pathway a randomized clinical trial"
} | [
{
"companynumb": "US-PACIRA PHARMACEUTICALS, INC.-2019EXPUS00732",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ONDANSETRON"
},
"drugad... |
{
"abstract": "Transplant associated thrombotic microangiopathy is a severe complication of Hematopoeitic stem cell transplantation. Although there is agreement in terms of diagnostic criteria, treatment options are not clarified yet. We present a patient aged 2.6 years who developed transplant associated thrombotic microangiopathy after allogeneic bone marrow transplantation and to discuss both risk factors and possible spontaneous remission of transplant associated thrombotic microangiopathy.",
"affiliations": "South East Asia Institute for Thalassemia, Prem Niketan Hospital, Ashram Marg, Near Durgapura Byepass, Jaipur, 302016 India.;South East Asia Institute for Thalassemia, Prem Niketan Hospital, Ashram Marg, Near Durgapura Byepass, Jaipur, 302016 India.;Cure two Children Foundation, Florence, Italy.;Cure two Children Foundation, Florence, Italy.;Cure two Children Foundation, Florence, Italy.",
"authors": "Marwah|Priya|P|;Soni|Rajpreet|R|;Faulkner|Lawrence|L|;Missiry|Mohammed El|ME|;Uderzo|Cornelio|C|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-014-0404-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0971-4502",
"issue": "30(Suppl 1)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "CMV infection; Cyclosporine; Microangiopathy; Transplantation",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "356-8",
"pmc": null,
"pmid": "25332618",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports",
"references": "16041306;17683362;11960280;20717073;17525895;15205669;8362266;16786586;17433026;16969286;7670410;21776339;11399602;16951692;21596850;11100281;15983555",
"title": "Remission of microangiopathy in transplanted thalassemic child.",
"title_normalized": "remission of microangiopathy in transplanted thalassemic child"
} | [
{
"companynumb": "PHHY2015IN169058",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "Coronavirus disease 2019 (COVID-19) has been shown to be associated with a lot of neurological complications, of whom Guillain-Barre syndrome (GBS) is an important post-infectious consequentiality. More than 220 patients with GBS have been reported thus far. We intend to share our experience with five patients of GBS where one of them had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the cerebrospinal fluid (CSF). This is the first-ever report demonstrating the presence of SARS-CoV-2 in the CSF of an adult patient; a similar occurrence has recently been described in a pediatric patient. We wish to emphasize the fact that commonly GBS occurs as a result of a post-infectious process but in a few cases where the symptoms of COVID-19 and GBS occur concurrently, corresponding to the viremic phase, separate pathogenesis needs to be thought of. This para-infectious nature is exemplified by the presence of virus in the cerebrospinal fluid of one of our patients. We review the neuroinvasive potential of SARS-Cov-2 in this regard and draw parallels with Cytomegalovirus, Zika virus, and Human Immunodeficiency virus-associated occurrences of GBS.",
"affiliations": "Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Microbiology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Infectious Diseases, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Microbiology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India.;Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India.",
"authors": "Khan|Farman|F|;Sharma|Praveen|P|;Pandey|Saurabh|S|;Sharma|Deepak|D|;V|Vijayavarman|V|;Kumar|Neeraj|N|;Shukla|Suruchi|S|;Dandu|Himanshu|H|;Jain|Amita|A|;Garg|Ravindra K|RK|;Malhotra|Hardeep S|HS|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": "10.1002/jmv.27159",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-6615",
"issue": "93(10)",
"journal": "Journal of medical virology",
"keywords": "COVID-19; Guillain-Barre syndrome; cerebrospinal fluid; reverse-transcriptase polymerase chain reaction",
"medline_ta": "J Med Virol",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D002555:Cerebrospinal Fluid; D005260:Female; D020275:Guillain-Barre Syndrome; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D000086402:SARS-CoV-2; D016896:Treatment Outcome",
"nlm_unique_id": "7705876",
"other_id": null,
"pages": "6045-6049",
"pmc": null,
"pmid": "34170552",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29267923;27857121;33610751;33990525;32840686;24163275;32203186;33967575;29348962;27705091;33039230;2194422;32346093;34170552;34119673;12639723",
"title": "COVID-19-associated Guillain-Barre syndrome: Postinfectious alone or neuroinvasive too?",
"title_normalized": "covid 19 associated guillain barre syndrome postinfectious alone or neuroinvasive too"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2021-21770",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "An optimal pretransplant conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in older adults has not been established. Three prospective multicenter phase II studies were conducted, in which 142 patients older than 54 years (median age, 61 years; range 55-70 years) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) received a myeloablative dose of intravenous busulfan (ivBu, 12.8 mg/kg) along with fludarabine (180 mg/m2) ± low dose total body irradiation for allo-HSCT between September 2009 and February 2013. A total of 103 AML and 39 MDS patients including 21 related bone marrow (BM) or peripheral blood (PB), 50 unrelated BM, and 71 unrelated cord blood (UCB) transplantation were enrolled. Grade 3 or greater toxicities were observed in 105 patients. Neutrophil engraftment was achieved in 70 out of the 71 related PB/BM or unrelated BM recipients, and 61 out of the 71 UCB recipients. The cumulative incidence rates of relapse and non-relapse mortality after 2 years were 24.0 and 24.1%, respectively. The overall and event-free survival rates at 2 years were 53.3 and 47.4%, respectively. The myeloablative dose of ivBu was well tolerated without increased toxicity-related mortality in older adults who underwent allo-HSCT with any donor source.",
"affiliations": "Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan. nuchida@toranomon.gr.jp.;Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyoto, Japan.;Department of Hematology, Saiseikai Maebashi Hospital, Gunma, Japan.;Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.;Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.;Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan.;Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.;Department of Hematology, Hyogo Cancer Center, Hyogo, Japan.;Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.;Department of Hematology, National Kyushu Medical Center, Fukuoka, Japan.;Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kyoto, Japan.;Department of Research and Development of Next Generation Medicine, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.;Department of Hematology, Faculty of Medicine, Hokkaido University, Hokkaido, Japan.;Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan.;Division of Hematology and Oncology, St. Luke's International Hospital, Tokyo, Japan.;Division of Hematology and Oncology, St. Luke's International Hospital, Tokyo, Japan.;Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.;Department of Hematology, Karatsu Higashimatsuura Medical Association, Saga, Japan.",
"authors": "Uchida|Naoyuki|N|http://orcid.org/0000-0001-5952-5926;Matsumoto|Kana|K|;Sakura|Toru|T|;Hidaka|Michihiro|M|;Miyamoto|Toshihiro|T|;Eto|Tetsuya|T|;Maeda|Yoshinobu|Y|;Murayama|Tohru|T|;Fujishima|Naohito|N|;Yoshimoto|Goichi|G|;Morita|Kunihiko|K|;Kishimoto|Junji|J|;Teshima|Takanori|T|;Taniguchi|Shuichi|S|;Yamashita|Takuya|T|;Mori|Shin-Ichiro|SI|;Akashi|Koichi|K|;Harada|Mine|M|;|||",
"chemical_list": "D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-020-02941-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "112(4)",
"journal": "International journal of hematology",
"keywords": "Allogeneic hematopoietic stem cell transplantation; Intravenous busulfan; Myeloablative conditioning; Older adults",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D002066:Busulfan; D017322:Clinical Trials, Phase II as Topic; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D011446:Prospective Studies; D011829:Radiation Dosage; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine; D014916:Whole-Body Irradiation",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "510-523",
"pmc": null,
"pmid": "32656637",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Myeloablative intravenous busulfan-containing regimens for allo-HSCT in AML or MDS patients over 54 years old: combined results of three phase II studies.",
"title_normalized": "myeloablative intravenous busulfan containing regimens for allo hsct in aml or mds patients over 54 years old combined results of three phase ii studies"
} | [
{
"companynumb": "JP-OTSUKA-2020_017668",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nTo report a case of rhabdomyolysis after concomitant use of simvastatin, a commonly used hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and fluconazole, an azole antifungal agent.\n\n\nMETHODS\nAn 83-year-old white man with a history of congestive heart failure and hyperlipidemia presented to the hospital 1 week following the addition of fluconazole to a medication regimen that included simvastatin 40 mg once daily. The patient had severe muscle weakness and a markedly elevated serum creatine kinase activity, which resolved following discontinuation of simvastatin and fluconazole.\n\n\nCONCLUSIONS\nRhabdomyolysis is a recognized adverse effect of HMG-CoA reductase inhibitors (statins), commonly caused by their interaction with other drugs, such as azole antifungals, that inhibit the cytochrome P450 isoenzyme family. An objective causality assessment revealed that the adverse drug event was probable. Although drug interactions have been described for combinations of other HMG-CoA reductase inhibitors and azole antifungals, rhabdomyolysis likely caused by the interaction between simvastatin and fluconazole has not yet been reported. This case reinforces the importance of being vigilant for drug interactions, particularly in connection with commonly prescribed medications such as statins.\n\n\nCONCLUSIONS\nPatients receiving statins who have cancer may receive azole antifungals and other drugs that inhibit CYP3A4 during treatment, predisposing them to toxicity. These patients should therefore be monitored closely for drug interactions.",
"affiliations": "School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA. medasha@acsu.buffalo.edu",
"authors": "Shaukat|Aasma|A|;Benekli|Mustafa|M|;Vladutiu|Georgirene D|GD|;Slack|James L|JL|;Wetzler|Meir|M|;Baer|Maria R|MR|",
"chemical_list": "D000935:Antifungal Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015725:Fluconazole; D019821:Simvastatin; D003402:Creatine Kinase",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1C467",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "37(7-8)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents; D003402:Creatine Kinase; D015725:Fluconazole; D006333:Heart Failure; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006949:Hyperlipidemias; D008297:Male; D012206:Rhabdomyolysis; D019821:Simvastatin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1032-5",
"pmc": null,
"pmid": "12841814",
"pubdate": "2003",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Simvastatin-fluconazole causing rhabdomyolysis.",
"title_normalized": "simvastatin fluconazole causing rhabdomyolysis"
} | [
{
"companynumb": "US-PFIZER INC-2003025271",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Timed sequential chemotherapy (TSC) combining mitoxantrone on days 1-3, etoposide on days 8-10 and cytarabine on days 1-3 and 8-10, was administered to 240 patients with advanced acute myelogenous leukemia (AML). Sixty one percent of patients, with a 95% confidence interval (CI) ranging from 54 to 67%, achieved complete remission (CR), including 47% (CI: 38-55%) of refractory patients and 78% (CI: 70-86%) of late first relapse patients (p < 0.0001). Thirty percent of patients did not respond to therapy and 9% died from toxicity. Median duration of neutropenia was 32 days and of thrombocytopenia 29 days. Severe non hematologic toxicity included sepsis in 45% of patients and mucositis in 27%. Post-remission therapy varied but included maintenance chemotherapy in most patients, a second course of TSC in 27, autologous stem cell transplantation in 17 and allogeneic transplantation in 20. Median survival of patients who were not transplanted was 7 months with 13% (CI: 7-19%) survival at 5 years. Median disease-free survival (DFS) was 9 months with 13% (CI: 6-20%) DFS at 5 years. Previous refractoriness was the main factor associated with poor prognosis for achieving CR, DFS and survival in a multivariate analysis. There was no difference in DFS between patients receiving the different modalities of intensive post-remission therapy. These results confirm initial reports on TSC and show that some patients with first relapse off therapy can enjoy prolonged DFS using chemotherapy only.",
"affiliations": "Service d'Hématologie, Hôpital Edouard Herriot, Lyon, France.",
"authors": "Archimbaud|E|E|;Leblond|V|V|;Fenaux|P|P|;Dombret|H|H|;Cordonnier|C|C|;Dreyfus|F|F|;Cony-Makhoul|P|P|;Tilly|H|H|;Troussard|X|X|;Auzanneau|G|G|;Thomas|X|X|;Ffrench|M|M|;Marie|J P|JP|",
"chemical_list": "D003561:Cytarabine; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008942:Mitoxantrone; D003630:Daunorubicin",
"country": "France",
"delete": false,
"doi": "10.1007/s00282-996-0161-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1269-3286",
"issue": "38(2)",
"journal": "Hematology and cell therapy",
"keywords": null,
"medline_ta": "Hematol Cell Ther",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D003630:Daunorubicin; D005047:Etoposide; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D007951:Leukemia, Myeloid; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone",
"nlm_unique_id": "9613253",
"other_id": null,
"pages": "161-7",
"pmc": null,
"pmid": "8931997",
"pubdate": "1996-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Timed sequential chemotherapy for advanced acute myeloid leukemia.",
"title_normalized": "timed sequential chemotherapy for advanced acute myeloid leukemia"
} | [
{
"companynumb": "FR-PFIZER INC-2020380659",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nTo determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2).\n\n\nMETHODS\nIn this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks.\n\n\nRESULTS\nTwo grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg.\n\n\nCONCLUSIONS\nBased on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.",
"affiliations": "Digestive Oncology Unit, University Hospital Gasthuisberg, 3000 Leuven, Belgium. Eric.VanCutsem@uz.kuleuven.ac.be",
"authors": "Van Cutsem|Eric|E|;Khayat|David|D|;Verslype|Chris|C|;Billemont|Bertrand|B|;Tejpar|Sabine|S|;Meric|Jean-Baptiste|JB|;Soussan-Lazard|Karen|K|;Assadourian|Sylvie|S|;Cartot-Cotton|Sylvaine|S|;Rixe|Olivier|O|",
"chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000077146:Irinotecan; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "49(1)",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": null,
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D055815:Young Adult",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "17-24",
"pmc": null,
"pmid": "22921183",
"pubdate": "2013-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours.",
"title_normalized": "phase i dose escalation study of intravenous aflibercept administered in combination with irinotecan 5 fluorouracil and leucovorin in patients with advanced solid tumours"
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"abstract": "BACKGROUND\nHepatitis E virus (HEV) infections in immunosuppressed patients can result in chronic hepatitis that rapidly progresses to cirrhosis (1, 2). When immunosuppressed transplant recipients are treated with pegylated -interferon and ribavirin, HEV clears and liver histology improves (2). However, we are not aware of reports about how this therapy works in patients with HIV infection.\n\n\nOBJECTIVE\nTo describe the clinical and laboratory response to antiviral therapy for chronic HEV infection in a patient also infected with HIV.\n\n\nMETHODS\nWe studied a 48-year-old bisexual male with HIV- 1 infection who was chronically infected with HEV genotype 3a and had several years of painful sensory neuropathy of uncertain cause in the lower limbs (3). He had malaise, persistently abnormal liver function tests, and active inflammation and cirrhosis on liver biopsy (Figure).Before beginning anti-HEV therapy, the patient had an undetectable HIV viral load and a CD4 cell count between 30 and 150 cells/mL for the previous 2 years while receiving combination antiretroviral therapy (abacavir–lamivudine once daily and lopinavir–ritonavir twice daily).",
"affiliations": null,
"authors": "Dalton|Harry R|HR|;Keane|Frances E|FE|;Bendall|Richard|R|;Mathew|Joe|J|;Ijaz|Samreen|S|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; D012254:Ribavirin",
"country": "United States",
"delete": false,
"doi": "10.7326/0003-4819-155-7-201110040-00017",
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"issn_linking": "0003-4819",
"issue": "155(7)",
"journal": "Annals of internal medicine",
"keywords": null,
"medline_ta": "Ann Intern Med",
"mesh_terms": "D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D015658:HIV Infections; D016751:Hepatitis E; D006801:Humans; D016867:Immunocompromised Host; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D012254:Ribavirin",
"nlm_unique_id": "0372351",
"other_id": null,
"pages": "479-80",
"pmc": null,
"pmid": "21969351",
"pubdate": "2011-10-04",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Treatment of chronic hepatitis E in a patient with HIV infection.",
"title_normalized": "treatment of chronic hepatitis e in a patient with hiv infection"
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"companynumb": "GB-KADMON PHARMACEUTICALS, LLC-KAD201311-001538",
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"abstract": "To explore the influence of pretreatment lymphopenia on the toxicity and efficacy of first-line chemotherapy in patients with metastatic esophagus squamous cell carcinoma (ESCC). In total, 215 patients were included in this retrospective study. Correlations between pretreatment lymphopenia (lymphocyte count <1 × 10(9) /L) and the occurrence of toxicity and the efficacy of first-line palliative chemotherapy were investigated. Pretreatment lymphopenia was found in 19.1% of the patients. The overall response rate (ORR) was 35.5% (65 of 183 patients). Patients with pretreatment lymphopenia had a lower ORR to chemotherapy compared with those without lymphopenia (22.2% vs. 38.8%, respectively; P = 0.045). Furthermore, the patients with pretreatment lymphopenia have higher grade 3-4 hematological toxicity than that of patients without pretreatment lymphopenia (19 of 41 patients, 46.3% vs. 54 of 174 patients, 31.0%; P = 0.048). Pretreatment lymphopenia was not correlated with grade 3-4 nonhematological toxicity. Multivariate analysis showed that pretreatment lymphopenia is an independent prognostic factor. Patients with pretreatment lymphopenia had a significantly shorter overall survival time than those without lymphopenia (8.2 months vs. 12.7 months; P = 0.020). This study shows that pretreatment lymphopenia is a good prognostic factor as well as a predictive factor for tumor response and chemotherapy-related hematological toxicity in metastatic ESCC.",
"affiliations": "Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.;Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, China.",
"authors": "Kou|Furong|F|;Lu|Zhihao|Z|;Li|Jian|J|;Zhang|Xiaotian|X|;Lu|Ming|M|;Zhou|Jun|J|;Wang|Xicheng|X|;Gong|Jifang|J|;Gao|Jing|J|;Li|Jie|J|;Li|Yan|Y|;Shen|Lin|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.638",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.638CAM4638Original ResearchClinical Cancer ResearchOriginal ResearchPretreatment lymphopenia is an easily detectable predictive and prognostic marker in patients with metastatic esophagus squamous cell carcinoma receiving first‐line chemotherapy Kou Furong \n1\nLu Zhihao \n1\nLi Jian \n1\nZhang Xiaotian \n1\nLu Ming \n1\nZhou Jun \n1\nWang Xicheng \n1\nGong Jifang \n1\nGao Jing \n1\nLi Jie \n1\nLi Yan \n1\nShen Lin \n1\n1 Key laboratory of Carcinogenesis and Translational Research (Ministry of Education)Department of GI OncologyPeking University School of OncologyBeijing Cancer Hospital & InstituteBeijing100142China* Correspondence\n\nLin Shen, Research Building 602, 52 Fucheng Road, Haidian District, Beijing, China 100142. Tel: 86‐10‐88196561; Fax: 86‐10‐88196561; E‐mail: lin100@medmail.com.cn\n26 1 2016 5 2016 5 5 10.1002/cam4.2016.5.issue-5778 786 03 9 2015 22 11 2015 16 12 2015 © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nTo explore the influence of pretreatment lymphopenia on the toxicity and efficacy of first‐line chemotherapy in patients with metastatic esophagus squamous cell carcinoma (ESCC). In total, 215 patients were included in this retrospective study. Correlations between pretreatment lymphopenia (lymphocyte count <1 × 109/L) and the occurrence of toxicity and the efficacy of first‐line palliative chemotherapy were investigated. Pretreatment lymphopenia was found in 19.1% of the patients. The overall response rate (ORR) was 35.5% (65 of 183 patients). Patients with pretreatment lymphopenia had a lower ORR to chemotherapy compared with those without lymphopenia (22.2% vs. 38.8%, respectively; P = 0.045). Furthermore, the patients with pretreatment lymphopenia have higher grade 3–4 hematological toxicity than that of patients without pretreatment lymphopenia (19 of 41 patients, 46.3% vs. 54 of 174 patients, 31.0%; P = 0.048). Pretreatment lymphopenia was not correlated with grade 3–4 nonhematological toxicity. Multivariate analysis showed that pretreatment lymphopenia is an independent prognostic factor. Patients with pretreatment lymphopenia had a significantly shorter overall survival time than those without lymphopenia (8.2 months vs. 12.7 months; P = 0.020). This study shows that pretreatment lymphopenia is a good prognostic factor as well as a predictive factor for tumor response and chemotherapy‐related hematological toxicity in metastatic ESCC.\n\nChemotherapyefficacyesophageal squamous cell carcinomalymphopeniaprognosistoxicity source-schema-version-number2.0component-idcam4638cover-dateMay 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.8.9 mode:remove_FC converted:12.05.2016\n\nCancer Medicine \n2016 ; 5 (5 ): 778 –786 \n\n\n\nFurong Kou and Zhihao Lu contributed equally to this work\n==== Body\nIntroduction\nEsophageal carcinoma is one of the most common cancers in the world, with an incidence that ranks eighth among all of the malignant cancers 1. In contrast with the predominant adenocarcinoma in western countries, ~95% of esophageal carcinoma in China can be classified as esophagus squamous cell carcinoma (ESCC). Most patients were diagnosed at the advanced stage, yet, treatment is mainly palliative and based on systemic chemotherapy.\n\nThe combination of cisplatin and 5‐fluorouracil was considered the standard regimen, with an efficacy of 33–35% 2, 3. Unfortunately, new cytotoxic drugs (paclitaxel, docetaxel, irinotecan, etc.) 4, 5, 6 and targeted drugs (cetuximab 7, gefitinib 8, etc.) did not make a breakthrough with regard to efficacy and improving survival of patients with ESCC. Moreover, chemotherapy‐related toxicities, especially hematological toxicities such as leukopenia, neutropenia, and febrile neutropenia were common. The rate of grade 3–4 hematological toxicity was 14–34.1% when treated with cisplatin, 5‐fluorouracil, docetaxel, or paclitaxel 2, 3, 5, 6. In one study, febrile neutropenia was also found in 6.1% patients 5.\n\nIt is necessary to screen patients who are most likely to benefit from chemotherapy with high efficacy and low toxicity, which may lead to a good prognosis. Previously, too much attention was focused on the tumor itself. Cancer is a systemic disease, and the immune system of the host is thought to play a central role in cancer suppression 9. Lymphocytes are crucial components of the immune system that may affect tumor growth and the survival of patients. Recently, pretreatment lymphopenia has been shown to be a poor prognostic factor for various cancers 10, 11, 12, 13, 14, 15. Furthermore, lymphopenia has been shown to be a powerful predictor of chemotherapy‐induced toxicity, as well as of the efficacy of chemotherapy in colorectal cancer, breast cancer, lung cancer, etc. 10, 16, 17, 18. The overall response rate (ORR) in patients with pretreatment lymphopenia was significantly lower than in patients with normal lymphocyte counts 10, 16, 17, 18. However, no studies focused on metastatic ESCC patients receiving first‐line chemotherapy.\n\nTherefore, the purpose of this retrospective study was to examine the impact of pretreatment lymphocyte counts on survival, tumor response, and treatment‐related toxicity in metastatic ESCC patients receiving first‐line chemotherapy.\n\nPatients and Methods\nPatients\nThis study is a retrospective analysis of a cohort of patients with esophageal cancer at the Peking University Cancer Hospital Gastrointestinal Medical Oncology Department between January 2005 and January 2013. Detailed clinical data for patients were recorded in a regularly updated electronic database. Eligibility criteria included the following: (1) all pathologically confirmed ESCC with metastatic diseases (the 7th edition of the American Joint Committee on Cancer Staging); (2) patients receiving first‐line chemotherapy; (3) life expectancy ≥3 months; and (4) pretreatment and follow‐up laboratory values measured at our institution are available in the electronic medical record. Patients were excluded if they fulfilled the following criteria: (1) they experienced recurrence within 6 months after adjuvant chemotherapy or chemoradiation therapy; or (2) they had pathologically confirmed esophageal adenocarcinoma, small cell carcinoma, lymphoma, or adenosquamous cell carcinoma. The study was approved by the Research Ethics Committee of Peking University Cancer Hospital.\n\nData collection\nDemographic, treatment, and laboratory‐based characteristics were obtained from the electronic medical records of each patient. Patient‐specific variables included age, sex, Karnofsky Performance Status (KPS), height, weight, and weight loss before chemotherapy. Tumor‐specific variables included primary tumor location, histologic grade, and sites of metastasis. Treatment parameters consisted of regimens of first‐line chemotherapy, second‐line therapy, radiation, and whether or not patients received surgery. Pretreatment laboratory values, including complete blood counts (white blood cell, neutrophil, lymphocyte, platelet values), albumin, and tumor makers (CEA, CYFRA2‐11 and SCC), were recorded before first‐line chemotherapy was administered. The dichotomization of these variables was based on the upper (white blood cells, neutrophils, platelet, and tumor markers) and lower (albumin and lymphocytes) ranges of the normal measurements for these markers. Neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) were also calculated and defined as variables for analysis. We used the medians of NLR and PLR as cutoff points for dichotomization.\n\nAssessment of toxicity, response and survival\nHematological toxicity and nonhematological toxicity were recorded according to the National Cancer Institute Common Toxicity Criteria Version 3.0 (NCI‐CTC.V3.0) based on direct questioning, physical examination, and laboratory tests. All patients who had received at least one course of chemotherapy were evaluated for toxicity. Tumor assessment was performed every 6 weeks or earlier in cases of clinical suspicion of progression using computed tomography scanning. The objective response to treatment was classified using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0). For this analysis, patients with complete or partial response were classified as responders, and those with stable or progressive disease were classified as nonresponders. ORR was the percentage of responders of the total patients. Overall survival (OS) was calculated from the first day of chemotherapy to death from any cause or last follow‐up, at which time data were censored. Survival data were available for all patients.\n\nStatistical analysis\nDifferent potential predictive variables for OS were considered to be dichotomous. Accordingly, pretreatment lymphocyte count was considered to be <1 × 109/L (defined as lymphopenia) or ≥1 × 109/L (Fig. 1). The chi‐squared test was used to compare proportions between groups. Univariate survival analysis was performed using the Kaplan–Meier method with the log‐rank test. Multivariate survival analysis was performed using a Cox regression model including those factors that were significant (P < 0.1) on univariate analysis. SPSS (version 17.0, Inc., Chicago, IL) statistical software was used for the statistical analysis. All P‐values were two sided, and P < 0.05 was considered statistically significant.\n\nFigure 1 Kaplan–Meier curves of overall survival (OS) according to pretreatment lymphocyte counts. Patients with pretreatment lymphocyte counts <1 × 109/L had shorter OS (median 12.7 months, n = 41) than patients with lymphocyte counts ≥1 × 109/L (median 8.2 months, n = 174; P = 0.020).\n\nResults\nPatient characteristics\nFrom January 2005 to January 2013, 215 patients were eligible for this retrospective analysis. The last follow‐up time was April 1, 2015. Demographic, treatment and pretreatment laboratory characteristics of these patients are summarized in Table 1.\n\nTable 1 Patient characteristics (N = 215)\n\nClincopathological characteristics\t\nN (%)\t\nMedian age (years) [range]\t58 [42–82]\t\nGender: male vs. female\t184 (85.6) vs. 31 (14.4)\t\nKPS: >80 vs. ≤80\t151 (70.2) vs. 64 (29.8)\t\nWeight loss: ≤5% vs. >5%\t132 (61.4) vs. 83 (38.6)\t\nGrade: well or moderately vs. poorly or undifferentiated\t112 (52.1) vs. 103 (47.9)\t\nPrimary tumor location: cervical or upper vs. middle or lower\t36 (16.7) vs. 179 (83.3)\t\nLiver metastasis\t61 (28.4)\t\nLung metastasis\t74 (34.4)\t\nBone metastasis\t20 (9.3)\t\nDistant lymph node metastasis\t171 (79.5)\t\nNumber of metastatic sites: <3 vs. ≥3\t175 (81.4) vs. 40 (18.6)\t\nFirst‐line chemotherapy: PTX‐based regimen vs. non‐PTX‐based regimensa\n\t160 (74.4) vs. 55 (25.6)\t\nTherapy after first‐line chemotherapy\t137 (63.7)\t\nSecond‐line chemotherapy\t47 (21.9)\t\nPTX‐based chemotherapy\t18 (8.3)\t\nIrinotecan‐based chemotherapy\t24 (11.2)\t\nOther chemotherapy regimensb\n\t5 (2.3)\t\nPalliative radiotherapy\t120 (55.8)\t\nOther treatmentsb\n\t5 (2.3)\t\nSurgery history\t76 (35.3)\t\nRadiation: radical vs. palliativeb\n\t10 (4.7) vs. 125 (58.1)\t\nWhite blood cell count:>10 × 109/L [range]\t19 (8.8) [2.91–18 × 109/L]\t\nNeutrophil count: >8 × 109/L [range]\t14 (6.5) [0.84–14.73 × 109/L]\t\nLymphocyte count: <1 × 109/L [range]\t41 (19.1) [0.3–5.14 × 109/L]\t\nPlatelet count: >300 × 109/L [range]\t35 (16.3) [81–615 × 109/L]\t\nNLR: median [range]\t3.0 [0.47–12.79]\t\nPLR: median [range]\t153.0 [19.64–723.33]\t\nAlbumin: ≤40 g/L [range]\t42 (19.5) [18.1–51.5 g/L]\t\nCEA: >5 ng/mL [range]\t45 (20.9) [0.2–994.2 ng/mL]\t\nCYFRA2‐11: >3.3 ng/mL [range]\t102 (47.4) [0.8–237.3 ng/mL]\t\nSCC: >1.5 ng/mL [range]\t91 (42.3) [0–96 ng/mL]\t\nKPS, Karnofsky Performance Status; PTX, Paclitaxel; NLR, neutrophil‐lymphocyte ratio; PLR, platelet‐lymphocyte ratio.\n\na Non‐PTX‐based regimens: fluorouracil‐based, irinotecan‐based, cisplatin‐based, gemcitabine‐based, capecitabine‐based, S‐1‐based and etoposide‐based.\n\nb Other chemotherapy regimens: fluorouracil‐based, cisplatin‐based, gemcitabine‐based, etoposide‐based, oxaliplatine‐based and S‐1‐based. Other treatments: third‐line chemotherapy, transarterial chemoembolization, radiofrequency ablation. Palliative radiation fields: brain, bone, lung, liver, lymph node, and anastomotic stoma.\n\nJohn Wiley & Sons, LtdThe median age was 58 years with a range of 42–82. The majority of patients were male (85.6%). All patients presented with metastases, while 61 (28.4%) patients were afflicted with liver, 74 (34.4%) with lung, and 20 (9.3%) with bone metastasis. Other metastatic sites, such as brain, adrenal glands, kidney, and pleura, were rare. All patients received first‐line chemotherapy, with 74.4% of the patients receiving a paclitaxel‐based regimen. Other drugs in non‐paclitaxel‐based regimens included fluorouracil, irinotecan, and cisplatin etc. A small proportion of patients (24.2%) used nimotuzumab‐targeted therapy during chemotherapy. Ten (4.7%) patients received radical esophagus radiation, while palliative radiation was applied in 125 (58.1%) patients. The targets of palliative radiotherapy included the primary tumor or the sites of metastasis (brain, bone, lung, liver, lymph node, etc.). After first‐line chemotherapy, 137 (63.7%) patients received subsequent therapy, including second‐line chemotherapy (47 patients), palliative radiotherapy (120 patients), and other treatments (5 patients). Most patients had normal pretreatment complete blood count values, while 19.1% of the patients had pretreatment lymphopenia. The median values of NLR and PLR were 3.0 and 153.0.\n\nUnivariate and multivariate analyses of prognostic factors for OS\nThe median OS for the entire cohort (N = 215) was 11.1 months (95% CI, 8.982–13.218). Among the 26 variables in the univariate analysis, 15 variables were identified to be statistically significantly prognostic factors (gender, weight loss, liver metastasis, bone metastasis, number of metastatic sites, first‐line chemotherapy, second‐line chemotherapy, palliative radiation history, white blood cell count, neutrophil count, lymphocyte count, NLR, PLR, CYFRA2‐11, SCC; P < 0.05).\n\nThe 17 factors identified in the above‐described univariate analysis (P < 0.1) were used to construct the multivariate cox proportional hazards model for survival. The following eight factors remaining in the model were considered independent prognostic factors: gender (P = 0.000), weight loss (P = 0.000), liver metastasis (P = 0.026), first‐line chemotherapy (P = 0.000), second‐line chemotherapy (P = 0.000), surgery history (P = 0.000), palliative radiation history (P = 0.000), and pretreatment lymphopenia (P = 0.021). The results of univariate and multivariate analyses are shown in Table 2.\n\nTable 2 Univariate and multivariate analysis of the characteristics associated with the overall survival\n\nCharacteristics\tmOS (month)\tUnivariate analysis\tMultivariate analysis\t\nChi‐square\t\nP value\tHR (95% CI)\t\nP value\t\nClinicopathological characteristics\t\nAge (≤65/>65)\t11.1/12.0\t0.001\t0.970\t\t\t\nGender (Male/Female)\t10.3/28.9\t10.651\t\n0.001\n\t0.298 (0.162–0.549)\t\n0.000\n\t\nKPS (>80/≤80)\t11.1/11.2\t0.229\t0.632\t\t\t\nWeight loss (≤5%/>5%)\t13.5/9.0\t16.641\t\n0.000\n\t1.991 (1.363–2.909)\t\n0.000\n\t\nGrade (well or moderately/poorly or undifferentiated)\t12.0/11.1\t0.206\t0.650\t\t\t\nPrimary tumor location (Cervical or upper/Middle or lower)\t13.5/10.7\t0.937\t0.333\t\t\t\nLiver metastasis (Yes/No)\t8.7/12.9\t14.178\t\n0.000\n\t1.559 (1.053–2.307)\t\n0.026\n\t\nLung metastasis (Yes/No)\t10.6/13.0\t0.021\t0.886\t\t\t\nBone metastasis (Yes/No)\t9.0/11.3\t4.123\t\n0.042\n\t\t\t\nDistant lymph node metastasis (Yes/No)\t10.5/13.1\t0.086\t0.770\t\t\t\nNumber of metastatic sites (<3/≥3)\t12.0/8.7\t6.745\t\n0.009\n\t\t\t\nTreatment characteristics\t\nFirst‐line chemotherapy (PTX‐based regimen/non‐PTX‐based regimens)\t13.0/8.1\t20.616\t\n0.000\n\t0.366 (0.244–0.549)\t\n0.000\n\t\nSecond‐line chemotherapy (Yes/No)\t15.8/9.5\t5.416\t\n0.020\n\t0.474 (0.315–0.713)\t\n0.000\n\t\nSurgery history (Yes/No)\t13.5/10.6\t3.185\t\n0.074\n\t0.486 (0.330–0.717)\t\n0.000\n\t\nRadical radiation history (Yes/No)\t12.0/11.1\t0.322\t0.571\t\t\t\nPalliative radiation history (Yes/No)\t13.9/8.6\t13.264\t\n0.000\n\t0.475 (0.332–0.680)\t\n0.000\n\t\nPretreatment laboratory characteristics\t\nWhite blood cell count (≤10/>10)×109/L\t11.3/8.7\t6.374\t\n0.012\n\t1.711 (0.934–3.134)\t0.082\t\nNeutrophil count (≤8/>8)×109/L\t11.3/5.2\t8.281\t\n0.004\n\t\t\t\nLymphocyte count (<1/≥1)×109/L\t12.7/8.2\t5.435\t\n0.020\n\t0.586 (0.373–0.922)\t\n0.021\n\t\nPlatelet count (≤300/>300)×109/L\t11.2/8.7\t3.186\t\n0.074\n\t\t\t\nNLR (≤3.0/>3.0)\t13.5/8.7\t13.337\t\n0.000\n\t\t\t\nPLR (≤153.0/>153.0)\t13.6/9.5\t7.879\t\n0.005\n\t\t\t\nAlbumin (≤40/>40) g/L\t11.3/11.1\t0.641\t0.423\t\t\t\nCEA (≤5/>5) ng/mL\t11.3/10.5\t0.400\t0.527\t\t\t\nCYFRA2‐11 (≤3.3/>3.3) ng/mL\t13.7/9.8\t8.946\t\n0.003\n\t\t\t\nSCC (≤1.5/>1.5) ng/mL\t13.7/9.8\t13.705\t\n0.000\n\t1.422 (0.972–2.081)\t0.069\t\nmOS, median overall survival; HR, hazard ratio; KPS, Karnofsky Performance Status; PTX, Paclitaxel; NLR, neutrophil‐lymphocyte ratio; PLR, platelet‐lymphocyte ratio. Bold values indicate a statistically difference in univariate analysis (P< 0.1) and statistically significant difference in multivariate analysis (P<0.05).\n\nJohn Wiley & Sons, LtdRelationship between pretreatment lymphopenia and patient characteristics\nPretreatment lymphopenia was significantly correlated with liver metastasis (P = 0.005), bone metastasis (P = 0.019), and number of metastatic sites (P = 0.000). As for the other clinicopathological data (age, sex, KPS, weight loss, primary tumor location, lung metastasis, and distant lymph node metastasis), no significant differences were detected between the groups. Moreover, pretreatment lymphopenia was also significantly correlated with some laboratory data, including white blood cell count, neutrophil count, NLR, and PLR. There were no significant differences in treatment‐related data between the groups except for surgery history (P = 0.001). The relationships between the pretreatment lymphocyte counts and patients characteristics are shown in Table 3.\n\nTable 3 Comparison of the characteristics and treatment efficacy of patients with or without pretreatment lymphopenia\n\n\tPatients with lymphocyte count\tChi‐square\t\nP value\t\n<1 × 109/L (n = 41)\t≥1 × 109/L (n = 174)\t\nClinicopathological characteristics\t\nAge (≤65/>65)\t28/13\t133/41\t1.170\t0.188\t\nGender (Male/Female)\t38/3\t146/28\t2.070\t0.133\t\nKPS (>80/≤80)\t29/12\t122/52\t0.006\t0.551\t\nWeight loss (≤5%/>5%)\t25/16\t107/67\t0.004\t0.543\t\nGrade (well or moderately/poorly or undifferentiated)\t23/16\t89/77\t0.366\t0.366\t\nPrimary tumor location (cervical or upper/middle or lower)\t7/34\t29/145\t0.004\t0.555\t\nLiver metastasis (Yes/No)\t19/22\t42/132\t8.049\t\n0.005\n\t\nLung metastasis (Yes/No)\t16/25\t58/116\t0.476\t0.303\t\nBone metastasis (Yes/No)\t8/33\t12/162\t6.259\t\n0.019\n\t\nDistant lymph node metastasis (Yes/No)\t31/10\t140/34\t0.480\t0.31\t\nNumber of metastatic sites (<3/≥3)\t24/17\t151/23\t17.481\t\n0.000\n\t\nTreatment characteristics\t\nFirst‐line chemotherapy (PTX‐based regime/non‐PTX‐based regimes)\t27/14\t133/41\t1.952\t0.117\t\nSecond‐line chemotherapy (Yes/No)\t7/35\t41/133\t0.931\t0.227\t\nSurgery history (Yes/No)\t24/17\t52/122\t11.919\t\n0.001\n\t\nRadical radiation history (Yes/No)\t4/37\t6/168\t2.977\t0.100\t\nPalliative radiation history (Yes/No)\t23/18\t72/102\t2.915\t0.063\t\nPretreatment laboratory characteristics\t\nWhite blood cell count (≤10/>10) ×109/L\t41/0\t155/19\t4.793\t\n0.016\n\t\nNeutrophil count (≤8/>8)×109/L\t41/0\t160/14\t3.444\t\n0.050\n\t\nPlatelet count (≤300/>300)×109/L\t35/6\t146/28\t0.053\t0.517\t\nNLR (≤3.0/>3.0)\t3/38\t104/70\t36.518\t\n0.000\n\t\nPLR (≤153.0/>153.0)\t2/39\t105/69\t40.835\t\n0.000\n\t\nAlbumin (≤40/>40) g/L\t10/31\t32/142\t0.760\t0.252\t\nCEA (≤5/>5) ng/mL\t29/12\t139/33\t2.020\t0.115\t\nCYFRA2‐11 (≤3.3/>3.3) ng/mL\t14/22\t72/80\t0.843\t0.233\t\nSCC (≤1.5/>1.5) ng/mL\t24/15\t89/76\t0.737\t0.249\t\nTreatment efficacy\t\nCR + PR/SD + PD\t8/28\t57/90\t3.460\t\n0.045\n\t\nORR[(CR + PR)%]\t22.2%\t38.8%\t\nKPS, Karnofsky Performance Status; PTX, Paclitaxel; NLR, neutrophil‐lymphocyte ratio; PLR, platelet‐lymphocyte ratio; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, overall response rate. Bold values indicate statistically significant difference (P≤0.05) in chi‐square test.\n\nJohn Wiley & Sons, LtdTumor response and pretreatment lymphocyte counts\nOf the total 215 patients, 183 patients were evaluated for response to first‐line chemotherapy. The ORR was 35.5% (65 of 183 patients). Pretreatment lymphopenia was significantly associated with lower ORR to chemotherapy. Eight of the 36 patients with pretreatment lymphopenia responded to chemotherapy versus 57 of the 147 patients without pretreatment lymphopenia (22.2% vs. 38.8%, respectively; P = 0.045). The details are summarized in Table 3.\n\nTreatment‐related toxicities and pretreatment lymphocyte counts\nThe most common hematological toxicities were leukopenia (67.4%) and neutropenia (61.9%). Similarly, leukopenia and neutropenia were also the most common grade 1–2 and grade 3–4 toxicities (45.6% and 30.2%, respectively). Moreover, the total hematological toxicity for all patients was 22.3% (48 patients) for grade 3 and 11.6% (25 patients) for grade 4. The most prevalent nonhematological toxicity was nausea (67.0%), with 62.3% of cases being grade 1–2 and 4.7% being grade 3–4.\n\nThe relationship between pretreatment lymphopenia and grade 3–4 toxicity was assessed in 215 patients (Table 4). Grade 3–4 hematological toxicity was observed in 19 of 41 patients with pretreatment lymphopenia (46.3%), and in 54 of 174 patients (31.0%) with lymphocyte count ≥1 × 109/L (P = 0.048). Pretreatment lymphopenia was not correlated with grade 3–4 nonhematological toxicity (including fatigue, nausea, vomiting, diarrhea, hair loss, muscle/joint pain, and liver damage).\n\nTable 4 Comparison of the grade 3–4 hematological and nonhematological toxicities of patients with or without pretreatment lymphopenia (N = 215)\n\nGrade 3–4 toxicity\tPatients with lymphocyte count, n (%)\tChi‐square\t\nP value\t\n<1 × 109/L (n = 41)\t≥1 × 109/L (n = 174)\t\nHematological toxicity\t19 (46.3)\t54 (31.0)\t3.467\t\n0.048\n\t\nFatigue\t1 (2.4)\t5 (2.9)\t0.023\t0.687\t\nNausea\t1 (2.4)\t9 (5.2)\t0.559\t0.399\t\nVomiting\t1 (2.4)\t8 (4.6)\t0.386\t0.461\t\nDiarrhea\t0\t2 (1.1)\t0.476\t0.654\t\nHair loss\t0\t10 (5.7)\t2.471\t0.115\t\nMuscle/joint pain\t0\t1 (0.6)\t0.237\t0.809\t\nLiver damage\t1 (2.4)\t6 (3.4)\t0.107\t0.602\t\nBold values indicate statistically significant difference (P≤0.05) in chi‐square test.\n\nJohn Wiley & Sons, LtdDiscussion\nIn this study, we established a prognostic model for metastatic ESCC patients receiving first‐line chemotherapy consisting of eight factors: pretreatment lymphopenia, gender, weight loss, liver metastasis, first‐line chemotherapy regimens, second‐line chemotherapy, primary tumor surgery, and palliative radiation. Furthermore, pretreatment lymphopenia was shown to be not only as a prognostic factor for short‐term survival but also as a predictive factor for tumor response and treatment‐related hematological toxicity in these patients.\n\nTo the best of our knowledge, the host immune system plays a central role in cancer suppression 9. Various factors are related to the body's immune status, such as lymphocytes in the peripheral blood, tumor‐infiltrating lymphocytes (TILs) 19, 20, 21, and treatment‐related lymphopenia 12, 22, 23. Lymphocytes in the peripheral blood are considered to be crucial components of the immune system and to reflect immune responsiveness. Lymphopenia, which was associated with an immunosuppressed state, was common in patients with solid tumors 10, 11, 12, 24. Previous studies have demonstrated that lymphopenia is related to the short‐term survival of various cancers, such as lung cancer, glioma, colorectal cancer, pancreatic cancer, and nasopharyngeal cancer 10, 11, 12, 13, 14, 18. Feng et al. 15 also found that preoperative lymphopenia is an independent poor prognostic factor in ESCC patients who had undergone esophagectomy without preoperative neoadjuvant chemotherapy and/or radiotherapy. Similarly, our study showed that patients with metastatic ESCC and pretreatment lymphopenia had a shorter survival time than those without lymphopenia (8.2 months vs. 12.7 months; P = 0.020).\n\nWe also analyzed the relationship between lymphopenia and tumor response to first‐line chemotherapy. The result showed that lymphopenia was significantly associated with lower ORR to chemotherapy (22.2% vs. 38.8%; P = 0.045). The same result was found in several other tumors. Lissoni et al. 18 conducted a study that included 183 patients (lung cancer: 89 cases; colorectal cancer: 63 cases; breast cancer: 31 cases) and found that the ORR in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (10% vs. 43%, P < 0.001). Ceze et al. 10 also found that the objective response rate was significantly lower in lymphopenic patients than in other colorectal cancer patients receiving chemotherapy (12.5% vs. 40.2%; P = 0.004).\n\nThere are several distinct mechanisms that chemotherapeutic agents can modify the interactions between tumor cells and host immune system 25. Chemotherapy succeeds in triggering tumor cell death, which restore or enhance the expression of tumor antigens and increase their susceptibility to immune attack 25, 26. In some cases, the immune system may contribute to make chemotherapy optimally efficient. Total lymphocyte counts play a key role in immune response. Lymphopenia might reflect a state of immune depression, which decreased the effect of immune attack causing the lower effect of therapy 18. However, the underlying mechanism between lymphopenia and decreased tumor response in ESCC patients is complicated and not fully revealed. Future studies need to be done to clarified the mechanisms in patients with metastatic ESCC.\n\nChemotherapy‐related toxicity was impacted by many factors, such as KPS, nutritional status, genetic polymorphism, and drug administration schedule. Our study showed that pretreatment lymphopenia was also related to increased risk of grade 3–4 hematological toxicity in ESCC patients. Several studies had demonstrated that in many tumors lymphopenia was associated with febrile neutropenia 17, platelet transfusion 27, and severe anemia 28. It was also found that early lymphopenia (day 5 after chemotherapy) was also a risk factor for chemotherapy‐induced febrile neutropenia 29. Furthermore, the subset of pretreatment lymphocytes, such as CD4+T cells, was considered to be an independent risk factor for febrile neutropenia 30.\n\nBecause pretreatment lymphocytes play a role in treatment‐related toxicity, as well as ORR and OS after first‐line chemotherapy, it was necessary to consider the influence of lymphocytes when selecting a treatment plan. For the patients with pretreatment lymphopenia, which indicated a low ORR and a high toxicity for chemotherapy, it was necessary to determine whether we could decrease the ration of chemotherapy and increase the ration of immunotherapy or targeted therapy.\n\nThe cause of pretreatment lymphopenia has not been fully clarified, and the explanations are likely to be multifactorial. Some studies demonstrated that tumors could directly induce T lymphocyte apoptosis using the Fas/FasL pathway 31. Overexpressed tumor‐derived antigens could cause the persistent polyclonal activation of lymphocytes, leading to their apoptosis 32. In addition to tumor‐related lymphopenia, host‐related factors could also lead to the decrease in lymphocytes. Altered lymphocyte homeostasis 33, such as a progressive decline of IL‐2 34 in the blood concentrations, appears to be associated with lymphopenia. Cachexia syndrome could exhibit lymphopenia, which might be due to the effect of cytokines, such as TNF‐α 35.\n\nPrevious studies 36, 37, 38 have demonstrated that surgery could induce immune suppression, by causing changes of lymphocyte numbers and subtypes. It was found that surgery and the associated neuroendocrine and paracrine responses could increase the secretion of immune suppressing hormones, which decreased numbers and activity of natural killer cells, Th1 and cytotoxic T lymphocyte cells and increased regulatory T cells, so as to reduce interleukin‐12 and interferon‐γ expression 37. However, those studies only focus on the immune response a short period of time after the surgery, the long‐term effects of surgery on host immune response in cancer patients are still uncertain. In our study, people who underwent primary tumor surgery had a higher proportion of lymphopenia than patients who did not undergo surgery (31.5% vs. 12.2%, P = 0.001). Due to the small numbers of patients with primary tumor surgery history in this retrospective study, we could not draw any definite conclusion; however, it is not possible to exclude that surgery can induce long‐term immune suppression and lymphopenia in some patients. Further prospective studies in metastatic ESCC patients are required to verify the results. Our results also showed that live metastasis, bone metastasis, and inflammatory factors (white blood cells, neutrophils, NLR, and PLR) were likely to be contributing factors because they were correlated with lymphopenia. These findings also indicated that lymphopenia was related to both tumor factors and host factors.\n\nBased on these theories, some studies put forward the ideas of reversing lymphopenia or increasing the lymphocyte counts, expecting to improve survival and tumor response. Interventions in cancer patients, such as using hematopoietic stimulating factors, Toll‐like receptor (TLR) agonists, nutritional support, have showed promising results 39, 40, 41.\n\nOur study also has several limitations. The retrospective approach may lead to inherent biases. Only those patients with collected pretreatment lymphocyte counts receiving first‐line chemotherapy at our institution were eligible for inclusion, possibly causing a selection bias. In the future, we will observe both the total and subset of peripheral blood lymphocyte counts, and the TILs can be evaluated in future studies.\n\nIn conclusion, pretreatment blood lymphocyte count was an easily detectable predictive factor for stage IV ESCC patients receiving first‐line chemotherapy. Pretreatment lymphopenia indicated short‐term survival, as well as a low tumor response and high treatment‐induced toxicity. Our results, combined with future analyses of subtype and the dynamic change in lymphocyte counts, may lead to individualized treatment and provide evidence for future immunotherapy of ESCC.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nJemal , A. \n, \nF. \nBray \n, \nM. M. \nCenter \n, \nJ. \nFerlay \n, \nE. \nWard \n, and \nD. \nForman \n. 2011 \nGlobal cancer statistics . CA Cancer J. Clin. \n61 :69 –90 .21296855 \n2 \n\nBleiberg , H. \n, \nT. \nConroy \n, \nB. \nPaillot \n, \nA. J. \nLacave \n, \nG. \nBlijham \n, \nJ. 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Blood \n92 :405 –410 .9657738 \n28 \n\nMarec‐Berard , P. \n, \nJ. Y. \nBlay \n, \nM. \nSchell \n, \nM. \nBuclon \n, \nC. \nDemaret \n, and \nI. \nRay‐Coquard \n. 2003 \nRisk model predictive of severe anemia requiring RBC transfusion after chemotherapy in pediatric solid tumor patients . J. Clin. Oncol. \n21 :4235 –4238 .14615453 \n29 \n\nChoi , C. W. \n, \nH. J. \nSung \n, \nK. H. \nPark \n, \nS. Y. \nYoon \n, \nS. J. \nKim \n, \nS. C. \nOh \n, et al. 2003 \nEarly lymphopenia as a risk factor for chemotherapy‐induced febrile neutropenia . Am. J. Hematol. \n73 :263 –266 .12879430 \n30 \n\nBorg , C. \n, \nI. \nRay‐Coquard \n, \nI. \nPhilip \n, \nG. \nClapisson \n, \nN. \nBendriss‐Vermare \n, \nC. \nMenetrier‐Caux \n, et al. 2004 \nCD4 lymphopenia as a risk factor for febrile neutropenia and early death after cytotoxic chemotherapy in adult patients with cancer . Cancer \n101 :2675 –2680 .15503313 \n31 \n\nHoffmann , T. K. \n, \nG. \nDworacki \n, \nT. \nTsukihiro \n, \nN. \nMeidenbauer \n, \nW. \nGooding \n, \nJ. T. \nJohnson \n, et al. 2002 \nSpontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance . Clin. Cancer Res. \n8 :2553 –2562 .12171883 \n32 \n\nLenardo , M. \n, \nK. M. \nChan \n, \nF. \nHornung \n, \nH. \nMcFarland \n, \nR. \nSiegel \n, \nJ. \nWang \n, et al. 1999 \nMature T lymphocyte apoptosis–immune regulation in a dynamic and unpredictable antigenic environment . Annu. Rev. Immunol. \n17 :221 –253 .10358758 \n33 \n\nDworacki , G. \n, \nN. \nMeidenbauer \n, \nI. \nKuss \n, \nT. K. \nHoffmann \n, \nW. \nGooding \n, \nM. \nLotze \n, et al. 2001 \nDecreased zeta chain expression and apoptosis in CD3+ peripheral blood T lymphocytes of patients with melanoma . Clin. Cancer Res. \n7 (3 Suppl ):947s –957s .11300496 \n34 \n\nLissoni , P. \n, \nS. \nBarni \n, \nF. \nRovelli \n, and \nG. \nTancini \n. 1991 \nLower survival in metastatic cancer patients with reduced interleukin‐2 blood concentrations. Preliminary report . Oncology \n48 :125 –127 .1997935 \n35 \n\nAggarwal , S. \n, \nS. \nGollapudi \n, and \nS. \nGupta \n. 1999 \nIncreased TNF‐alpha‐induced apoptosis in lymphocytes from aged humans: changes in TNF‐alpha receptor expression and activation of caspases . J. Immunol. \n162 :2154 –2161 .9973490 \n36 \n\nBartal , I. \n, \nR. \nMelamed \n, \nK. \nGreenfeld \n, \nS. \nAtzil \n, \nA. \nGlasner \n, \nV. \nDomankevich \n, et al. 2010 \nImmune perturbations in patients along the perioperative period: alterations in cell surface markers and leukocyte subtypes before and after surgery . Brain Behav. Immun. \n24 :376 –386 .19254757 \n37 \n\nKadosawa , T. \n, and \nA. \nWatabe \n. 2015 \nThe effects of surgery‐induced immunosuppression and angiogenesis on tumour growth . Vet. J. \n205 :175 –179 .25956342 \n38 \n\nGreenfeld , K. \n, \nR. \nAvraham \n, \nM. \nBenish \n, \nY. \nGoldfarb \n, \nE. \nRosenne \n, \nY. \nShapira \n, et al. 2007 \nImmune suppression while awaiting surgery and following it: dissociations between plasma cytokine levels, their induced production, and NK cell cytotoxicity . Brain Behav. Immun. \n21 :503 –513 .17293081 \n39 \n\nFumagalli , L. A. \n, \nJ. \nVinke \n, \nW. \nHoff \n, \nE. \nYpma \n, \nF. \nBrivio \n, and \nA. \nNespoli \n. 2003 \nLymphocyte counts independently predict overall survival in advanced cancer patients: a biomarker for IL‐2 immunotherapy . J. Immunother. \n26 :394 –402 .12973028 \n40 \n\nLissoni , P. \n, \nF. \nBrivio \n, \nL. \nFumagalli \n, \nG. \nDi Fede \n, and \nG. \nBrera \n. 2005 \nEnhancement of the efficacy of chemotherapy with oxaliplatin plus 5‐fluorouracil by pretreatment with IL‐2 subcutaneous immunotherapy in metastatic colorectal cancer patients with lymphocytopenia prior to therapy . In Vivo \n19 :1077 –1080 .16277025 \n41 \n\nVoo , K. S. \n, \nL. \nBover \n, \nM. L. \nHarline \n, \nJ. \nWeng \n, \nN. \nSugimoto \n, and \nY. J. \nLiu \n. 2014 \nTargeting of TLRs inhibits CD4+ regulatory T cell function and activates lymphocytes in human peripheral blood mononuclear cells . J. Immunol. \n193 :627 –634 .24928999\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "5(5)",
"journal": "Cancer medicine",
"keywords": "Chemotherapy; efficacy; esophageal squamous cell carcinoma; lymphopenia; prognosis; toxicity",
"medline_ta": "Cancer Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D008231:Lymphopenia; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "778-86",
"pmc": null,
"pmid": "26814381",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article",
"references": "21448592;12171883;12407406;17135638;23623280;17293081;16277025;15503313;11300496;11689594;11556830;24495699;19254757;26814381;25956342;21737504;10358758;12610500;23432821;21436444;8712798;15255546;24928999;19102357;25501097;25267597;24174270;21296855;12879430;22318781;1997935;9301445;14615453;21764477;25342911;23264913;12973028;21364688;9657738;22812722;24950987;9973490",
"title": "Pretreatment lymphopenia is an easily detectable predictive and prognostic marker in patients with metastatic esophagus squamous cell carcinoma receiving first-line chemotherapy.",
"title_normalized": "pretreatment lymphopenia is an easily detectable predictive and prognostic marker in patients with metastatic esophagus squamous cell carcinoma receiving first line chemotherapy"
} | [
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"companynumb": "CN-ROCHE-1767251",
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"abstract": "Minocycline is an antibiotic widely used in the treatment of acne. Among the induced auto-immune disorders, cutaneous polyarteritis nodosa (PAN) is very rare. A new case is reported below. A 23-year-old female patient treated with minocycline for acne for 24 months developed sub-cutaneous nodules, livedo reticularis and pigmented lesions of the lower limbs. Antineutrophil cytoplasmic antibodies (ANCA) were positive at 1/320. Skin biopsy showed vasculitis of a medium-sized artery. The role of minocycline was suspected using the imputability criteria. The diagnosis of minocycline-induced cutaneous PAN with ANCA was sustained. After withdrawal of the treatment, the nodular lesions decreased spontaneously, whereas livedo disappeared and inflammatory parameters were normalized after oral corticosteroid therapy. Minocycline is a tetracycline which is efficient for treating acne. Auto-immune disorders are frequently observed. Among them, it is very rare to observe cutaneous PAN associated with positive ANCA. The pathophysiological mechanisms are discussed.",
"affiliations": "Department of Dermatology, University Hospital, 2 Place Saint-Jacques, 25030 Besançon, France.",
"authors": "Pelletier|Fabien|F|;Puzenat|Eve|E|;Blanc|Dominique|D|;Faivre|Brigitte|B|;Humbert|Philippe|P|;Aubin|François|F|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019268:Antibodies, Antineutrophil Cytoplasmic; D008911:Minocycline",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1167-1122",
"issue": "13(4)",
"journal": "European journal of dermatology : EJD",
"keywords": null,
"medline_ta": "Eur J Dermatol",
"mesh_terms": "D000152:Acne Vulgaris; D000328:Adult; D000900:Anti-Bacterial Agents; D019268:Antibodies, Antineutrophil Cytoplasmic; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D007868:Leg Dermatoses; D008911:Minocycline; D010488:Polyarteritis Nodosa",
"nlm_unique_id": "9206420",
"other_id": null,
"pages": "396-8",
"pmc": null,
"pmid": "12948923",
"pubdate": "2003",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minocycline-induced cutaneous polyarteritis nodosa with antineutrophil cytoplasmic antibodies.",
"title_normalized": "minocycline induced cutaneous polyarteritis nodosa with antineutrophil cytoplasmic antibodies"
} | [
{
"companynumb": "FR-IMPAX LABORATORIES, INC-2015-IPXL-00908",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
... |
{
"abstract": "Sulfamethoxazole/Trimethoprim (SMX/TMP) is a commonly used antibiotic, its' known adverse reaction of hepatotoxicity leading to acute liver failure is considered rare. We present a case of a 22 year old female who developed jaundice and acute liver failure one week after taking SMX/TMP for a UTI. After an extensive work up, a clinical diagnosis of SMX/TMP induced liver failure was reached. Over the course of several weeks she made a good clinical and biochemical recovery with supportive care. In this case report we describe her clinical presentation and course, and present a brief review of the literature.",
"affiliations": "Department of Medicine, Stroger Hospital of Cook County, 1901 W Harrison St, Chicago, IL, 60612, USA. sayabusin@hotmail.com.",
"authors": "Abusin|Salaheldin|S|;Johnson|Swapna|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1757-1626-1-44",
"fulltext": "\n==== Front\nCases JCases Journal1757-1626BioMed Central 1757-1626-1-441863720410.1186/1757-1626-1-44Case ReportSulfamethoxazole/Trimethoprim induced liver failure: a case report Abusin Salaheldin 1sayabusin@hotmail.comJohnson Swapna 1swapna419@yahoo.com1 Department of Medicine, Stroger Hospital of Cook County, 1901 W Harrison St, Chicago, IL, 60612, USA2008 18 7 2008 1 44 44 18 6 2008 18 7 2008 Copyright © 2008 Abusin and Johnson; licensee BioMed Central Ltd.2008Abusin and Johnson; licensee BioMed Central Ltd.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.\n\nSulfamethoxazole/Trimethoprim (SMX/TMP) is a commonly used antibiotic, its' known adverse reaction of hepatotoxicity leading to acute liver failure is considered rare. We present a case of a 22 year old female who developed jaundice and acute liver failure one week after taking SMX/TMP for a UTI. After an extensive work up, a clinical diagnosis of SMX/TMP induced liver failure was reached. Over the course of several weeks she made a good clinical and biochemical recovery with supportive care. In this case report we describe her clinical presentation and course, and present a brief review of the literature.\n==== Body\nIntroduction\nSulfamethoxazole/Trimethoprim (SMX/TMP) is a commonly used antibiotic for respiratory, gastrointestinal and urinary tract infections caused by a range of aerobic gram-positive and gram-negative bacteria. It also has activity against Listeria monocytogenes, Nocardia and Pneuomcystis jiroveci.\n\nSMX/TMP is generally well tolerated in non-HIV-infected patients in whom adverse reactions occur in approximately 6 to 8 percent of individuals. In comparison, the adverse reaction rate is as high as 25 to 50 percent in HIV-infected patients, with many of the reactions being severe.\n\nThe most common adverse reactions include nausea, vomiting, anorexia, dermatological reactions such as pruritis, urticaria and less commonly Steven Johnson Syndrome. Life-threatening adverse reactions include neutropenia, exfoliative dermatitis (a severe skin disorder with generalized erythema and scaling) and toxic epidermal necrolysis (an acute severe reaction with widespread erythema and detachment of the epidermis). Acute liver failure has only been reported in a few cases worldwide, and has been attributed to the sulphonamide component of the drug.\n\nCase presentation\nA previously healthy 22 year old female presented to our institution with nausea, vomiting and general malaise which started 2 days after taking SMX/TMP for a presumed urinary tract infection. Though feeling ill she continued her antibiotic course. On day 6 of SMX/TMP, her family noticed yellow discoloration of the sclera and urged her to go to the hospital. SMX/TMP was stopped on admission. On examination her only positive finding was generalized icterus most notably in the sclera, she had no signs of hepatic encephalopathy, or hepatomegaly. Her initial laboratory investigations showed an AST of 3077, ALT 4067, Alkaline Phosphatase 128, total bilirubin 5.1, INR 1.8, and albumin of 3.6. Over the course of her hospital stay her liver enzymes showed a downward trend, her total bilirubin peaked at 24.4, with direct bilirubin of 17.5, and INR at 2.16, after which they all gradually dropped. Ultrasound Liver with Doppler Flow showed normal liver size and echogenicity, with no obstruction of the biliary tree and normal blood flow. She was found to be negative for Hepatitis A, B, and C viruses, HIV, HSV and EBV. RPR, autoimmune panel, thyroid function, serum copper and ceruloplasmin were all within normal limits. Acetominophen was not detected in her blood. Based on the timing of jaundice in relation to SMX/TMP exposure, and the absence of any other identifiable cause, she was diagnosed with SMX/TMP induced acute liver failure. Her liver function improved with no intervention, and she made an uneventful recovery. At 2 months, she was asymptomatic, and her liver function tests including coagulation profile were back to normal.\n\nDiscussion\nThe sulfamethoxazole component of SMX/TMP is responsible for most of its' side effects including liver failure. Although Trimethoprim alone can be used for treatment of uncomplicated UTI[1], SMX/TMP is commonly used for that purpose in the United States for unclear reasons.\n\nThree forms of SMX/TMP induced liver damage have been described; hepatocellular[2], mixed hepatocellular cholestatic[3], and (more recently) bile duct injury with ductopenia or Vanishing Bile duct syndrome[4,5]. The onset of symptoms usually occurs within a few days of exposure as did in our patient, but can take up to a 1–2 months[6,7]. Patients usually present with jaundice, nausea, vomiting, and pruritis (if cholestatic). LFTs may show a hepatocellular or cholestatic pattern depending on the type of injury, coagulopathy is also seen. Patients might have other feature of an allergic reaction such as skin rash, eosinophilia[7,8]. Extrahepatic manifestations include pancytopenia[8], pancreatitis[9,10], and acute renal failure[7,8].\n\nDiagnosis is suspected from the clinical presentation, and absence of other causes, in addition to suggestive changes on liver biopsy. Invitro tests such as lymphocyte transformation test have been reported to aid in the diagnosis[11]. Rechallenge with SMX/TMP as a method for diagnosis has been reported in the literature in the 1960s[12,13]. However, rechallenge even at small doses can lead to terminal hepatic failure[2], and it has fallen out of favor and only reported inadvertently since[14].\n\nThe severity of SMX/TMP induced liver injury can range from mild symptoms with elevated liver enzymes to fulminant hepatic failure with hepatic encephalopathy and coagulopathy. Outcome can be favorable with spontaneous resolution, as in our patient, or unfavorable leading to death reported in both HIV[15], (in this case it was associated with a delayed diagnosis) and non HIV infected patients[2,16].\n\nTreatment is generally supportive, liver transplantation has been successful for both fulminant hepatic failure[17] and vanishing bile duct syndrome[4].\n\nConclusion\nThis case illustrates a rare but clinically important side effect of a commonly used antibiotic. It alerts the physician to suspect drugs as a cause in any patient presenting with jaundice and/or acute liver failure. Failure to do so has been associated with a fatal outcome. It also shows that in the right clinical context, the diagnosis can be established without the need for an invasive liver biopsy in a patient with coagulopathy.\n\nAbbreviations\nAST: Aspartate aminotransferase; ALT: Alanine aminotransferase; INR: International Normalized Ratio; HIV: Human Immunodeficiency virus; RPR: Rapid plasma reagin test for syphilis; HSV: Herpes Simplex Virus; EBV: Epstein Barr virus.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nSA and SJ were involved in the care of the patient during her hospital stay, and both analyzed and interpreted the patient data, and contributed to writing the manuscript. All authors read and approved the final manuscript.\n==== Refs\nHooton TM Besser R Foxman B Fritsche TR Nicolle LE Acute uncomplicated cystitis in an era of increasing antibiotic resistance: a proposed approach to empirical therapy Clin Infect Dis 39 75 80 2004 Jul 1 15206056 10.1086/422145 \nRansohoff DF Jacobs G Terminal hepatic failure following a small dose of sulfamethoxazole-trimethoprim Gastroenterology 1981 80 816 819 7202951 \nAbi Mansur P Ardiaca MC Allam C Shammaia M Trimethoprim-sulfamethoxazole induced cholestasis Am J Gastroenterol 1981 76 356 359 7325149 \nYao F Behling CA Saab S Li S Hart M Lyche KD trimethoprim-sulfamethoxazole induced vanishing bile duct syndrome Am J Gastroenterology 1997 92 167 169 \nAltraif I Lilly L Wanless IR Heathcote J Cholestatic liver disease with ductopenia (vanishing bile duct syndrome) after administration of clindamycin and trimethoprim-sulfamethoxazole Am J Gastroenterol 1994 89 1230 4 8053440 \nMair SS Kaplan JM Levine LH Geraci K Trimethoprim sulfamethoxazole induced cholestasis Am J Gastroentertol 1981 76 511 512 \nKraemer MJ Kendall R Hickman RO Hass JE Bierman CW a generalized allergic reaction with acute interstiial nephritis following trimethoprim-sulfamethoxazole use Ann Allergy 1982 49 323 325 7149348 \nWindecker R Steffen Cascorbi I Thurmann PA cotrimoxazole induced liver and renal failure Eur J Clin Pharmacol 2000 56 191 3 10877016 10.1007/s002280050740 \nBrett AS Shaw SV Simultaneous pancreatitis and hepatitis associated with trimethoprim-sulfamethoxazole Am J Gastroenterol 1999 94 267 8 9934769 10.1111/j.1572-0241.1999.00812.x \nAlberti-Flor JJ Hernandez ME Ferrer JP Howell S Jeffers L Fulminant liver failure and pancreatitis associated with the use of sulfamethoxazole-trimethoprim Am J Gastroenterol 1989 84 1577 9 2596461 \nHofer T Becker EW Weigand K Berg PA Demonstration of sensitized lymphocytes to trimethoprim/sulfamethoxazole and ofloxacin in a patient with cholestatic hepatitis J Hepatol 1992 15 262 3 1506646 10.1016/0168-8278(92)90045-Q \nFries J Siraganian R Sulfonamide hepatitis. Report of a case due to sulfamethoxazole and sulfisoxazole New Engl J Med 1966 274 95 97 5901208 \nDujovne CA Chan CH Zimmerman HJ Sulfonamide hepatic injury. Review of the litertature and report of a case due to sulfamethoxazole New Engl J Med 1967 277 785 788 6046676 \nThies PW Dull WL Trimethoprim-sulfamethoxazole induced cholestatic hepatitis Arch Intern Med 1984 144 1691 1692 6331808 10.1001/archinte.144.8.1691 \nKreisberg R Clinical problem-solving. We blew it N Engl J Med 332 945 9 1995 Apr 6; 7661934 10.1056/NEJM199504063321409 \nIlario MJ Ruiz JE Axiotis CA Acute fulminant hepatic failure in a woman treated with phenytoin and trimethoprim-sulfamethoxazole Arch Pathol Lab Med 2000 124 1800 3 11100060 \nZaman F Ye G Abreo KD Latif S Zibari GB Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure Clin Transplant 2003 17 461 4 14703931 10.1034/j.1399-0012.2003.00040.x\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1757-1626",
"issue": "1(1)",
"journal": "Cases journal",
"keywords": null,
"medline_ta": "Cases J",
"mesh_terms": null,
"nlm_unique_id": "101474272",
"other_id": null,
"pages": "44",
"pmc": null,
"pmid": "18637204",
"pubdate": "2008-07-18",
"publication_types": "D016428:Journal Article",
"references": "7149348;14703931;1506646;8995964;7325149;6046676;10877016;8053440;9934769;7661934;5901208;15206056;2596461;11100060;7202951;6331808",
"title": "Sulfamethoxazole/Trimethoprim induced liver failure: a case report.",
"title_normalized": "sulfamethoxazole trimethoprim induced liver failure a case report"
} | [
{
"companynumb": "US-EMCURE PHARMACEUTICALS LTD-2019-EPL-0635",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "Several epidemiological and pathological findings suggest that the female sex hormones may influence the development of meningiomas. However, the role of pregnancy, oral contraceptives, and fertilization therapies is still controversial.\nFrom the surgical series of 354 patients with meningiomas operated between 2006 and 2019, the group of 72 premenopausal women was separately considered. The tumor location, WHO grade, Ki67-labeling index (LI), progesterone receptor (PR) expression, and histological types were studied in premenopausal women with and without hormone-related conditions were compared.\nIn this premenopausal group, 24 patients had hormone-related conditions, including use of oral contraceptives in 16, intrauterine fertilization in one, pregnancy in three, and tumors of the female reproductive system in four. The group of patients with hormone-related conditions, as compared to that with no hormone related conditions, showed slightly lower median age (38 versus 43 years) and no significant difference of meningioma location WHO grade, Ki 67-Li, PR expression and histological type. The clinical onset during pregnancy in three patients and tumor growth during contraceptive progesterone therapy in two others were evidenced.\nThe biological behavior of meningiomas and their pathological findings, including PR expression, are not correlated with the different hormone related conditions in premenopausal female patients. Contraceptives and fertilization therapies, mainly with progesterone, should be avoided in patients with meningiomas.",
"affiliations": "Neurosurgical Clinic, Department of Neurosciences and Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;Neurosurgical Clinic, Department of Neurosciences and Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;Neurosurgical Clinic, Department of Neurosciences and Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;Section of Pathology, Department of Advanced Biomorphological Sciences, University \"Federico II\", Naples, Italy.;Neurosurgical Clinic, Department of Neurosciences and Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;Neurosurgical Clinic, Department of Neurosciences and Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;Neurosurgical Clinic, Department of Neurosciences and Reproductive and Odontostomatological Sciences, University \"Federico II\", Naples, Italy.;Section of Pathology, Department of Advanced Biomorphological Sciences, University \"Federico II\", Naples, Italy.",
"authors": "Maiuri|Francesco|F|;Mariniello|Giuseppe|G|;Somma|Teresa|T|;Guadagno|Elia|E|;Corvino|Sergio|S|;Pagano|Serena|S|;Orlando|Valentina|V|;Del Basso De Caro|Marialaura|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.556701",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.556701\nOncology\nOriginal Research\nMeningiomas in Premenopausal Women: Role of the Hormone Related Conditions\nMaiuri Francesco \n1\n\n*\n Mariniello Giuseppe \n1\n Somma Teresa \n1\n Guadagno Elia \n2\n Corvino Sergio \n1\n Pagano Serena \n1\n Orlando Valentina \n1\n Del Basso De Caro Marialaura \n2\n \n1\nNeurosurgical Clinic, Department of Neurosciences and Reproductive and Odontostomatological Sciences, University “Federico II”, Naples, Italy\n\n\n2\nSection of Pathology, Department of Advanced Biomorphological Sciences, University “Federico II”, Naples, Italy\n\nEdited by: Hailiang Tang, Huashan Hospital Affiliated to Fudan University, China\n\nReviewed by: Christoph Straube, Technical University of Munich, Germany; Emanuele La Corte, University of Bologna, Italy\n\n*Correspondence: Francesco Maiuri, frmaiuri@unina.it\nThis article was submitted to Neuro-Oncology and Neurosurgical Oncology, a section of the journal Frontiers in Oncology\n\n\n11 12 2020 \n2020 \n10 55670128 4 2020 09 11 2020 Copyright © 2020 Maiuri, Mariniello, Somma, Guadagno, Corvino, Pagano, Orlando and Del Basso De Caro2020Maiuri, Mariniello, Somma, Guadagno, Corvino, Pagano, Orlando and Del Basso De CaroThis 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.Background\nSeveral epidemiological and pathological findings suggest that the female sex hormones may influence the development of meningiomas. However, the role of pregnancy, oral contraceptives, and fertilization therapies is still controversial.\n\nMethods\nFrom the surgical series of 354 patients with meningiomas operated between 2006 and 2019, the group of 72 premenopausal women was separately considered. The tumor location, WHO grade, Ki67-labeling index (LI), progesterone receptor (PR) expression, and histological types were studied in premenopausal women with and without hormone-related conditions were compared.\n\nResults\nIn this premenopausal group, 24 patients had hormone-related conditions, including use of oral contraceptives in 16, intrauterine fertilization in one, pregnancy in three, and tumors of the female reproductive system in four. The group of patients with hormone-related conditions, as compared to that with no hormone related conditions, showed slightly lower median age (38 versus 43 years) and no significant difference of meningioma location WHO grade, Ki 67-Li, PR expression and histological type. The clinical onset during pregnancy in three patients and tumor growth during contraceptive progesterone therapy in two others were evidenced.\n\nConclusion\nThe biological behavior of meningiomas and their pathological findings, including PR expression, are not correlated with the different hormone related conditions in premenopausal female patients. Contraceptives and fertilization therapies, mainly with progesterone, should be avoided in patients with meningiomas.\n\nmeningiomaprogesterone receptor expressionpregnancyoral contraceptivesfertilization therapies\n==== Body\nIntroduction\nMeningiomas are mostly benign tumors which arise from meningothelial cells of the arachnoid membrane; their incidence is about two fold higher in women than in men (1).\n\nSeveral epidemiological and pathological findings other than the higher female incidence may suggest that sex hormones may play a role in the development of these tumors. These include the frequent presence of progesterone and estrogen receptors in the meningioma tissue (2–7), the possible association with tumors of the female system (8–10), the documented changes of the meningioma biology during the menstrual cycle and pregnancy (11–13), the sometimes reported regression after delivery (14), the in vitro proliferation of meningioma cell lines in culture after exposure of estrogen and progesterone (15, 16). Besides, the incidence and risk of meningioma in patients with sex hormone-related conditions and during the exogenous use of sex hormones for contraceptive therapies have been investigated in several studies (16–22).\n\nIn this monoinstitutional study we have investigated the epidemiological and pathological findings of premenopausal women with meningioma and the effects of the sex hormone-related conditions in this age group.\n\nMaterials and Methods\nPatient Population and Study Design\nThree hundred fifty-four patients with primary intracranial and spinal meningiomas who underwent surgery at the neurosurgical clinic of the “Federico II” University of Naples between January 2006 and April 2019 were retrospectively reviewed. Cases of recurrent meningiomas and those with insufficient data were excluded. From the overall series, 72 female patients where the diagnosis of meningioma was made in the premenopausal age period were selected for the study. These 72 patients were classified in two groups: group A with sex hormone-related conditions at the meningioma diagnosis and group B with no hormone-related conditions.\n\nEthical approval for this human study was not required according to local and or national legislation.\n\nAnalyzed Factors\nThe factors analyzed in the study include meningioma location, WHO grade, progesterone receptor (PR) expression, Ki67-MIB1, recurrence rate. The sex hormone-related conditions, which were analyzed in the premenopausal group, include exogenous hormone contraceptive therapies, pregnancy at the meningioma diagnosis, hormone-related extraneural tumors, and fertilization therapies.\n\nThe tumor location was defined from the review of the MR images and the surgical descriptions. Four groups were identified: group 1 or medial skull base including olfactory groove, ethmoidal–sphenoidal planum, tuberculum sellae, parasellar, clival-petroclival, and foramen magnum meningiomas; group 2 or lateral skull base, including the middle and lateral sphenoid wing and temporal fossa meningiomas and those of the petrous bone and occipital fossa; group 3 or non-skull base, including convexity, parasagittal or falx meningiomas, those of the tentorium, cerebellar convexity, and pineal region, and those of the lateral ventricles; group 4, including spinal meningiomas.\n\nThe surgical specimens were reviewed independently by two pathologists (MC and EG). The WHO grade was defined according to the 2007 WHO classification (23). The immunohistochemical studies were performed to evaluate the Ki67-MIB1 and the PR expression. The specimens were fixed in neutral buffered 10% formalin, embedded in paraffin and cut into sections of 5 mm thickness.\n\nThe expression of PR was determined in all specimens with monoclonal antibody against the progesterone (DAKO 1:400, overnight incubation). The quantitative evaluation was expressed as percentage for positive nuclei among 100 cells, for a total of 500 cells. The following score was used: 1. absent or low (L) (<15%); 2. moderately low (ML) (16–50%); 3. moderately high (MH) (51–79%); 4. high (H) (≥80%) (\nFigure 1\n).\n\nFigure 1 Immunohistochemical evaluation of progesterone receptor antibody expression: nuclear signal respectively in less than 1% (A), in 15% (B) and in 95% (C) of neoplastic cells (200× magnification).\n\nThe expression of Ki67-MIB1 was evaluated in all specimens by using the monoclonal antibody MIB1 Immunotech® (DAKO system, dilution 1:1,000, overnight incubation). The streptavidin–biotin system and the diaminobenzidine (DAB) were used for antigen detection and visualization. A specimen of breast carcinoma was used as a positive control. Ki67-LI count was performed by eye counting, taking the average on five adjacent representative fields of neoplastic cells in a hot spot area. The values of Ki67-LI were classified into two groups: group I ≤4%; group II >4%.\n\nThe histological types of WHO grade I meningiomas were classified as: meningothelial, transitional, fibroblastic, psammomatous, microcystic, secretory, chordoid.\n\nStatistical Analysis\nThe meningioma location, WHO grade, Ki67-MIB1, PR expression and histological subtype were analyzed in all patients and stratified in the two groups, of patients with and without sex hormone-related conditions.\n\nThe data were analyzed by one-way ANOVA test or Fisher’s exact test, and p-value was correlated. A p value ≤0.05 was considered statistically significant. All tests were two-sided and carried out with Graph Prism 5 software (Graph Pad Software, La Jalla. CA. USA).\n\nResults\nEpidemiological and Pathological Data\nThe 72 female patients where the meningioma was diagnosed in the premenopausal age period account for 20% of the overall series of 354 meningiomas and 27.5% of the 262 female patients at all ages. Twenty-four patients (39.3%) were in group A with sex hormone-related conditions at the meningioma diagnosis and 48 (66.7%) in group B with no hormone-related conditions. The epidemiological and pathological data are summarized in \nTable 1\n. The patient age ranged from 19 to 52 years (median age 42 years), with no significant difference between groups A and B (38 vs 43 years, p = 0.81). According to the location (\nTable 1\n) 18 meningiomas (25%) were medial skull base, 11 (15%) lateral skull base, 40 (56%) non-skull base and three (4%) spinal. Fifty-five tumors (77%) were WHO grade I and 17 (23%) WHO grade II. The Ki-67Li was ≤4% in 43 patients (60%) and >4% in 29 (40%). The PR expression was <15% of the tumor cells in 10 cases (14%), between 16 and 50% in 17 (28%), between 51 and 79% in nine (13%) and ≥80% in 36 (50%). The more frequent histological subtypes of WHO I meningiomas were transitional (49%), fibroblastic (27%), and meningothelial (11%), whereas others were infrequent. The differences of tumor location, WHO grade, Ki67Li, PR expression, and histological subtype between group A and group B were not statistically significant (\nTable 1\n).\n\nTable 1 Epidemiological and pathological data on premenopausal women with and without hormone-related conditions.\n\nCovariates\tOverall premenopausal A + B (72 pts)\tGroup A (24 pts)\tGroup B (48 pts)\tStatistical significance P value\t\nMedian age\t42 y\t38 y\t43 y\t0.081\t\nMeningioma location\n- Median skull base\n- Lateral skull base\n- Non-skull base\n- Spinal\t\n\n18 (25%)\n11 (15%)\n40 (56%)\n3 (4%)\t\n\n8 (33%)\n4 (17%)\n12 (50%)\n-\t\n\n10 (21%)\n7 (15%)\n28 (58%)\n3 (6%)\t\t\nWHO grade\n- I\n- II\t\n\n55 (77%)\n17 (23%)\t\n\n17 (70%)\n7 (30%)\t\n\n38 (79%)\n10 (21%)\t\t\nKi67Li\n- ≤4%\n- >4%\t\n\n43 (60%)\n29 (40%)\t\n\n16 (67%)\n8 (33%)\t\n\n27 (56%)\n21 (44%)\t\t\nProgesterone receptor expression\n- <15%\n- 16–15%\n- 51–79%\n- ≥80%\t\n\n10 (14%)\n17 (23%)\n9 (13%)\n36 (50%)\t\n\n5 (21%)\n6 (25%)\n2 (8%)\n11 (46%)\t\n\n5 (10%)\n11 (23%)\n7 (15%)\n25 (52%)\t\t\nHistological type (WHO I)\n- Meningothelial\n- Transitional\n- Fibroblastic\n- Psammomatosus\n- Microcystic\n- Secretory\n- Chordoid\t\n\n6 (11%)\n27 (49%)\n15 (27%)\n4 (7%)\n1 (2%)\n1 (2%)\n1 (2%)\t\n\n2 (12%)\n10 (58%)\n4 (24%)\n1 (6%)\n-\n-\n-\t\n\n4 (10.5%)\n17 (45%)\n11 (29%)\n3 (8%)\n1 (2.5%)\n1 (2.5%)\n1 (2.5%)\t\t\nSex Hormone-Related Conditions\nTwenty-four premenopausal women had associated sex hormone-related conditions at meningioma diagnosis. These include use of oral contraceptives in 16, assisted fertilization in one, pregnancy in three and hormone-related tumors of the sex female system in four (\nTable 2\n). Among the 16 patients with oral contraceptives (progesterone–estrogen), nine currently use the therapy at the meningioma diagnosis, and seven had used it up to 1 to 2 years before the diagnosis. Another patient, a 35-year-old woman with tuberculum sellae meningioma (\nFigure 2\n), presented visual deficit during the treatment of artificial in vitro fertilization and with human chorionic gonadotropin.\n\nTable 2 Sex hormone-related conditions at meningioma diagnosis (24 patients).\n\n•oral contraceptives\n •current use\n •previous use (1 to 2 years previously)\t16 (67%)\n9\n7\t\n•pregnancy\t3 (12.5%)\t\n•hormone-related tumors\n •breast cancer\n •ovarian cyst\n •ovarian adenoma\t4 (16.5%)\n2\n1\n1\t\n•artificial fertilization\t1 (4%)\t\nFigure 2 Post-contrast cranial MRI of 35-year-old female with tuberculum sellae meningioma presenting sudden onset of visual deficit during artificial in vitro fertilization treatment on the therapy with human chorionic gonadotrophin.\n\nFour patients had an associated tumor of the female system diagnosed and treated within 3 years before the meningioma diagnosis; these included ovarian cyst in one case, ovarian adenoma in another, and breast carcinoma in two.\n\nThirty-nine (54%) among the 72 patients (14 in group A and 25 in group B) experienced one or more previous pregnancies 3 or more years before the meningioma diagnosis. In these patients the previous pregnancy was not considered as hormone-related condition because the pregnancy-related hormonal effects were not present at the meningioma diagnosis. Thus, the correlation between pregnancy and meningioma occurrence and growth was difficult to be defined.\n\nIn three women, the onset of the clinical symptoms occurred during pregnancy, between the 26th and 30th gestational weeks (\nTable 3\n). The tumor location was in all three cases on the midline skull base (ethmoidal–sphenoidal planum in two and tuberculum sellae in one); the tumor size was very large in two cases (6.5 and 7 cm) (\nFigures 3\n, \n4\n). A rapid decrease of the visual function was the presenting symptom in all three cases, with intracranial hypertension in one. Surgery for meningioma resection was performed 2 and 7 days after the delivery in two patients, whereas another decided to delay the operation. The tumor resection was complete (Simpson 2) (24). All three meningiomas were WHO grade I with high PR expression (≥80%) and Ki67-LI ≤4%. All three patients were symptom-free with no recurrence 18 months to 3 years after surgery.\n\nTable 3 Data of three patients with meningiomas presenting during pregnancy.\n\nN. of cases\tA ge\tGestational age at onset (weeks)\tNeurological symptoms\tDelivery\tInterval time between delivery and craniotomy\tMeningioma location and size\tEntity of resection\tPathology\tOutcome\t\n1.\t37 y\t26\tintracranial\nhypertension sopor\nvisual loss\tcesarian delivery\n(32 wks)\t2 days\tethmoidal–sphenoidal planum\n(6.5 cm)\tcomplete\n(Simpson\n2)\tWHO I, transitional\nKi67 3%\nPR 90%\tcured at 6 y\t\n2.\t30 y\t30\tbilateral visual loss\tspontaneous delivery\n(at term)\t6 months\tethmoidal–sphenoidal planum\n(7 cm)\tcomplete\n(Simpson\n2) two stages\tWHO I, transitional\nKi67 3% PR 90%\tcured at 26 mos\t\n3.\t2\n8\ny\t28\tbilateral visual loss\tspontaneous delivery\n(at term)\t7 days\ttuberculum sellae\n(3 cm)\tcomplete\n(Simpson\n2)\tWHO I, transitional\nKi67 3%\nPR 80%\tcured at 8 y\t\nFigure 3 Preoperative post contrast MRI, axial (A), coronal (B) and sagittal (C) sequences of 37-year-old female with large ethmoidal–sphenoidal planum meningioma presenting with visual loss and intracranial hypertension syndrome at 26th week of pregnancy; postoperative post-contrast axial (D) and coronal (E) sequences.\n\nFigure 4 Preoperative post-contrast MRI, axial (A), coronal (B) and sagittal (C) sequences of 30- year-old female with giant meningioma of spheno-ethmoidal planum presenting with bilateral visual deficit at 30th week of pregnancy; postoperative postcontrast axial (D) and coronal (E) sequences: complete tumor removal.\n\nTwo patients with known meningioma experienced tumor growth during contraceptive therapy with progesterone alone in a close MRI follow-up before surgery. The tumor location was parasagittal in one and tentorial in another; both had low PR values (30 and 1%).\n\nEight patients of the group of 72 premenopausal women experienced tumor recurrence (11%). It occurred in four cases (one WHO II and three WHO I) among 24 of group 1A with sex hormone-related conditions (16%) and in four cases (three WHO grade II and one WHO I) among 48 of group 1B with no hormone-related conditions (8%).\n\nDiscussion\nMeningiomas occur more frequently in postmenopausal women than in premenopausal ones, with a ratio of about 3:1 in our series. This difference is likely due to hormonal differences between the two age groups.\n\nThe role of the menopause as a risk factor for meningioma is cited in several studies, which provide controversial results. Some of them report a two to fivefolds higher risk (18, 25–28) or a moderately higher risk (29, 30) in postmenopausal women, whereas no association was found in others (31, 32). The occurrence of meningiomas in premenopausal women may involve some epidemiological and pathological aspects and may be influenced by coexisting hormone-related conditions, such as pregnancy and contraceptive and fertilization therapies.\n\nWe will discuss these conditions and the clinical significance of the correlated basic research studies.\n\nMeningioma Location and Pathological Findings\nThis study first discusses the location and pathological and immunohistochemical findings of meningiomas in premenopausal women.\n\nNo significant difference of tumor location was evidenced between premenopausal patients with and without hormone-related conditions. Although we have demonstrated in a previous study that medial skull base meningiomas have higher PR expression than lateral skull base and non-skull base ones (33), this finding is not correlated with the hormonal status.\n\nWe did not find significant differences for WHO grade, Ki 67-MIB1, and PR expression in premenopausal women, according to the presence of hormone-related conditions.\n\nThese data confirm that the biological behavior of meningiomas and their PR expression are not correlated with the different hormonal status of the female patients.\n\nPregnancy\nThe relationship between pregnancy and meningiomas is a discussed problem in the neurosurgical practice. The risk of meningioma in female patients with one or more previous pregnancies does not seem to be increased (25–27, 30, 32, 34–37).\n\nThe onset of neurological symptoms of a known or a still undiagnosed meningioma during pregnancy (more often at the second or third trimester) or at delivery is a rare event which has been reported in 150 cases, as confirmed by several literature reviews (13, 38, 39).\n\nPregnancy-related meningiomas, when compared to those in the general population, are more frequently supratentorial (95%) and located in the medial skull base (68%); they are more often large (40% >5cm) and present in more than half of the cases with often rapid decrease of the visual function. Most reported cases are WHO grade I (75%), with mean Ki67-LI <4% and mean PR expression of 90%. The three cases of our series agree with these features.\n\nThus, pregnancy-related meningiomas exhibit more favorable pathological findings suggesting a better prognosis. The often reported sudden onset and rapid progression of clinical symptoms at the second or third trimester may depend on several factors, including increase of size, peritumoral edema, increase of the vascular supply to the tumor and probably pituitary-related hormone changes (13).\n\nThe rapid visual deterioration and sudden intracranial hypertension from a large meningioma, as in case one of our series, is a dangerous event at risk of visual deficit. The meningioma resection sudden after delivery is the best option, if possible. However, if necessary, an urgent craniotomy may be decided after the 27th week, or the delivery may be anticipated to allow the craniotomy.\n\nOral Contraceptives\nThe use of hormone-based contraceptives is widely diffuse in young women. The risk of meningioma correlated to contraceptive use has been discussed in several studies of the last 20 years (16–18, 20, 22, 26–28, 30, 32, 36, 37, 39). These provide controversial results, depending on several factors, such as type of contraceptive drugs, current or past use, and duration of the treatment.\n\nThe studies including patients using progesterone-only contraceptives (17, 18, 22) have shown increased risk of meningioma in those taking therapy for more than 5 years (17) and in those with PR positive meningiomas (18), and increased risk of recurrence and decrease of the progression free-survival (22). Two patients of our series who currently used progesterone-based contraceptives experienced tumor progression before surgical resection.\n\nIn the studies including patients who used estrogen-only or estrogen–progesterone contraceptives, those who currently used them showed increased risk of meningioma than those who had used them in the past (26, 27, 36, 39); besides, an increased meningioma risk was also evidenced for contraceptive use for more than 5 years (26, 27, 31).\n\nThe relationship between oral contraceptive use and hormone status of meningiomas is still unclear. Among the 16 patients of our series who used contraceptive therapy the PR expression of the meningioma was ≥80% in eight and <50% in eight, with no statistically significant difference. Korhonen et al. (18) report slightly higher risk for tumors expressing ER than for PR; on the other hand, Horland et al. (22) did not find significant differences. Custer et al. (26) showed increased risk of meningioma with low PR expression during contraceptive therapy. The two patients of our series showing increased tumor growth before surgery had low PR expression (30 and 1%). This agrees with the known more aggressive tumor biology in cases with low PR expression (40).\n\nThe experiences of our and other studies suggest avoiding contraceptive therapy, mainly with progesterone, in patients with meningioma.\n\nFertility Therapies\nThe fertility treatments include a variety of methods: pharmacological ovarian stimulation, intrauterine insemination, in vitro fertilization, injection of human chorionic gonadotropin. One patient of our series with tuberculum sellae meningioma developed visual symptoms during the artificial insemination and treatment with chorionic gonadotropin.\n\nThe relationship between fertility treatment and meningiomas has scarcely been discussed. In the study of Korhonen et al. (18) the fertility treatments did not influence the risk of meningioma. Three single case reports describe meningiomas diagnosed in women with history of fertilization (41–43). In the study of Shahin et al. (44), the group of female patients with meningioma and history of fertility treatment had significantly younger age and higher rate of multiple non-skull base meningiomas as compared to the group with no fertility treatment. The development of meningiomas, even multiple, was reported in patients exposed to high-dose progesterone therapy (45, 46). All these data suggest that fertility treatments may influence the meningioma tumorigenesis. However, further studies are needed to better define this relationship.\n\nConclusion\nThe pathological findings, biological behavior, and PR expression of meningiomas are not correlated with the hormone status and hormone-related conditions of the female patients. Pregnancy may be responsible for the sudden clinical onset of intracranial meningiomas because of the hormone-related tumor changes. Contraceptive and fertilization therapies, mainly with progesterone, should be avoided in patients with known meningiomas because of the risk of symptom occurrence and tumor progression.\n\nCharacteristics of the Study\nStrengths\nThis study discusses a scarcely focused aspect of meningiomas concerning their occurrence in premenopausal women and the differences between those with and without hormone-related conditions.\n\nLimitations\nThis study is retrospective. Data on the hormonal substitution among postmenopausal women are lacking.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nAuthor Contributions\nAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.\n\nConflict of Interest\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\nAbbreviation\nKi67-LI, Ki67 Labelling Index; PR, Progesterone Receptor; ER, Estrogen Receptor; MRI, Magnetic Resonance Images.\n==== Refs\nReferences\n1 \nWiemels J Wrensch M Claus EB \nEpidemiology and etiology of meningioma\n. J Neurooncol (2010 ) 99 (3 ):307–14. 10.1007/s11060-010-0386-3 \n\n2 \nMartuza RL MacLaughlin DT Ojemann RG \nSpecific estradiol binding in schwannomas, meningiomas, and neurofibromas\n. 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Cancer Causes Control (2011 ) 22 (5 ):697 –714\n. 10.1007/s10552-011-9742-7 \n21359526 \n20 \nCea-Soriano L Blenk T Wallander MA Rodríguez LA \nHormonal therapies and meningioma: is there a link\n? Cancer Epidemiol (2012 ) 36 (2 ):198 –205\n. 10.1016/j.canep.2011.08.003 \n21943794 \n21 \nBenson VS Kirichek O Beral V Green J \nMenopausal hormone therapy and central nervous system tumor risk: large UK prospective study and meta-analysis\n. Int J Cancer (2015 ) 136 (10 ):2369–77. 10.1002/ijc.29274 \n\n22 \nHarland TA Freeman JL Davern M McCracken DJ Celano EC Lillehei K \nProgesterone-only contraception is associated with a shorter progression-free survival in premenopausal women with WHO Grade I meningioma\n. J Neurooncol (2018 ) 136 (2 ):327–33. 10.1007/s11060-017-2656-9 \n\n23 \nLouis DN Ohgaki H Wiestler OD Cavenee WK Burger PC Jouvet A \nThe 2007 WHO classification of tumours of the central nervous system\n. Acta Neuropathol (2007 ) 114 (2 ):97 –109\n. 10.1007/s00401-007-0243-4 \n17618441 \n24 \nSimpson D \nThe recurrence of intracranial meningiomas after surgical treatment\n. J Neurol Neurosurg Psychiatry (1957 ) 20 (1 ):22 –39\n. 10.1136/jnnp.20.1.22 \n13406590 \n25 \nPreston-Martin S Monroe K Lee PJ Bernstein L Kelsey J Henderson S \nSpinal meningiomas in women in Los Angeles County: investigation of an etiological hypothesis\n. Cancer Epidemiol Biomarkers Prev (1995 ) 4 (4 ):333–9.\n26 \nCuster B Longstreth WT Phillips LE Koepsell TD Van Belle G \nHormonal exposures and the risk of intracranial meningioma in women: a population-based case-control study\n. BMC Cancer (2006 ) 6 :152. 10.1186/1471-2407-6-152 \n16759391 \n27 \nLee E Grutsch J Persky V Glick R Mendes J Davis F \nAssociation of meningioma with reproductive factors\n. Int J Cancer (2006 ) 119 (5 ):1152–7. 10.1002/ijc.21950 \n\n28 \nQi ZY Shao C Huang YL Hui GZ Zhou YX Wang Z \nReproductive and exogenous hormone factors in relation to risk of meningioma in women: a meta-analysis\n. PLoS One (2013 ) 8 (12 ):e83261 . 10.1371/journal.pone.0083261 \n24386167 \n29 \nSchlehofer B Blettner M Preston-Martin S Niehoff D Wahrendorf J Arslan A \nRole of medical history in brain tumour development. Results from the international adult brain tumour study\n. Int J Cancer (1999 ) 82 (2 ):155–60. 10.1002/(sici)1097-0215(19990719)82:23.0.co;2-p \n\n30 \nHatch EE Linet MS Zhang J Fine HA Shapiro WR Selker RG \nReproductive and hormonal factors and risk of brain tumors in adult females\n. Int J Cancer (2005 ) 114 (5 ):797 –805\n. 10.1002/ijc.20776 \n15609304 \n31 \nMichaud DS Gallo V Schlehofer B Tjønneland A Olsen A Overvad K \nReproductive factors and exogenous hormone use in relation to risk of glioma and meningioma in a large European cohort study\n. Cancer Epidemiol Biomarkers Prev (2010 ) 19 (10 ):2562–9. 10.1158/1055-9965.EPI-10-0447 \n\n32 \nJohnson DR Olson JE Vierkant RA Hammack JE Wang AH Folsom AR \nRisk factors for meningioma in postmenopausal women: results from the Iowa Women’s Health Study\n. Neuro Oncol (2011 ) 13 (9 ):1011–9. 10.1093/neuonc/nor081 \n\n33 \nMaiuri F Mariniello G Guadagno E Barbato M Corvino S Del Basso De Caro M \nWHO grade, proliferation index, and progesterone receptor expression are different according to the location of meningioma\n. Acta Neurochir (Wien) (2019 ) 161 (12 ):2553–61. 10.1007/s00701-019-04084-z \n\n34 \nSchlehofer B Blettner M Wahrendorf J \nAssociation between brain tumors and menopausal status\n. J Natl Cancer Inst (1992 ) 84 (17 ):1346–9. 10.1093/jnci/84.17.1346 \n\n35 \nLambe M Coogan P Baron J \nReproductive factors and the risk of brain tumors: a population-based study in Sweden\n. Int J Cancer (1997 ) 72 (3 ):389–93. 10.1002/(sici)1097-0215(19970729)72:33.0.co;2-l \n\n36 \nJhawar BS Fuchs CS Colditz GA Stampfer MJ \nSex steroid hormone exposures and risk for meningioma\n. J Neurosurg (2003 ) 99 (5 ):848–53. 10.3171/jns.2003.99.5.0848 \n\n37 \nBenson VS Pirie K Green J Casabonne D Beral V Collaborators MWS \nLifestyle factors and primary glioma and meningioma tumours in the Million Women Study cohort\n. Br J Cancer (2008 ) 99 (1 ):185–90. 10.1038/sj.bjc.6604445 \n\n38 \nChakravarthy V Kaplan B Gospodarev V Myers H De Los Reyes K Achiriloaie A \nHoudini Tumor: Case Report and Literature Review of Pregnancy-Associated Meningioma\n. World Neurosurg (2018 ) 114 :e1261–5. 10.1016/j.wneu.2018.03.187 \n\n39 \nClaus EB Black PM Bondy ML Calvocoressi L Schildkraut JM Wiemels JL \nExogenous hormone use and meningioma risk: what do we tell our patients\n? Cancer (2007 ) 110 (3 ):471–6. 10.1002/cncr.22783 \n\n40 \nMaiuri F De Caro MB Esposito F Cappabianca P Strazzullo V Pettinato G \nRecurrences of meningiomas: predictive value of pathological features and hormonal and growth factors\n. J Neurooncol (2007 ) 82 (1 ):63–8. 10.1007/s11060-005-9078-9 \n\n41 \nFrassanito P De Bonis P Mattogno PP Novello M Anile C \nHormonal therapy for fertility and huge meningioma: a purely random association\n? Acta Neurol Belg (2012 ) 112 (3 ):299 –301\n. 10.1007/s13760-012-0046-9 \n22426675 \n42 \nMotegi H Kobayashi H Terasaka S Ishii N Ito M Shimbo D \nHemorrhagic onset of rhabdoid meningioma after initiating treatment for infertility\n. Brain Tumor Pathol (2012 ) 29 (4 ):240–4. 10.1007/s10014-012-0088-y \n\n43 \nPatterson A Elashaal A \nFast-Growing Meningioma in a Woman Undergoing Fertility Treatments\n. Case Rep Neurol Med (2016 ) 2016 :3287381. 10.1155/2016/3287381 \n28116188 \n44 \nShahin MN Magill ST Dalle Ore CL Viner JA Peters PN Solomon DA \nFertility treatment is associated with multiple meningiomas and younger age at diagnosis\n. J Neurooncol (2019 ) 143 (1 ):137–44. 10.1007/s11060-019-03147-6 \n\n45 \nTer Wengel PV Martin E Gooren L Den Heijer M Peerdeman SM \nMeningiomas in three male-to-female transgender subjects using oestrogens/progestogens and review of the literature\n. Andrologia (2016 ) 48 (10 ):1130–7. 10.1111/and.12550 \n\n46 \nPeyre M Gaillard S de Marcellus C Giry M Bielle F Villa C \nProgestin-associated shift of meningioma mutational landscape\n. Ann Oncol (2018 ) 29 (3 ):681–6. 10.1093/annonc/mdx763\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "fertilization therapies; meningioma; oral contraceptives; pregnancy; progesterone receptor expression",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "556701",
"pmc": null,
"pmid": "33363003",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "29206892;28116188;15609304;3764648;31637512;8738495;14609164;17618441;28326464;21943794;16759391;29626688;7198726;22843130;21359526;13406590;18560401;29081037;16835295;24386167;6867927;25335165;21780859;1495104;21750006;30868355;26162042;26888610;16570277;20730482;8367042;22350616;20821343;17580362;23101448;2565555;10389745;20802020;11920521;22426675;2751899;6716168;9247278;15006250;17225937;7655327",
"title": "Meningiomas in Premenopausal Women: Role of the Hormone Related Conditions.",
"title_normalized": "meningiomas in premenopausal women role of the hormone related conditions"
} | [
{
"companynumb": "IT-BION-009380",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROGESTERONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "A breast cancer patient developed an atypical femoral fracture after 9 years of bisphosphonate therapy for the treatment of multiple bone metastases. We histopathologically analyzed the femoral cortical bone at the fracture site and the iliac cancellous bone. Four months prior to the fracture, the patient had experienced pain in the right femur and underwent plain radiography and bone scintigraphy which revealed cortical thickening and radioisotope accumulation at each site, respectively. The patient had also experienced a non-traumatic fracture at the same site on the contralateral side 2 years earlier. Based on these findings, atypical femoral fracture was diagnosed and intramedullary nailing performed. A cortical bone specimen taken from near the fracture site during surgery showed marked microdamages, and analysis of the iliac cancellous bone specimen revealed severely suppressed bone turnover. These findings suggest that microdamage and severely suppressed bone turnover are associated with atypical femoral fracture reported in this patient with long-term bisphosphonate therapy.",
"affiliations": "Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, 1750-1 Ikenobe Mikicho, Kitagun, Kagawa 761-0793, Japan. Electronic address: kiwata@med.kagawa-u.ac.jp.;Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, 1750-1 Ikenobe Mikicho, Kitagun, Kagawa 761-0793, Japan. Electronic address: task@med.kagawa-u.ac.jp.;Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, 1750-1 Ikenobe Mikicho, Kitagun, Kagawa 761-0793, Japan. Electronic address: thitora@med.kagawa-u.ac.jp.;Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, 1750-1 Ikenobe Mikicho, Kitagun, Kagawa 761-0793, Japan. Electronic address: yokkun@med.kagawa-u.ac.jp.;Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, 1750-1 Ikenobe Mikicho, Kitagun, Kagawa 761-0793, Japan. Electronic address: sanutetu@med.kagawa-u.ac.jp.",
"authors": "Iwata|Ken|K|;Mashiba|Tasuku|T|;Hitora|Toshiaki|T|;Yamagami|Yoshiki|Y|;Yamamoto|Tetsuji|T|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-2763",
"issue": "64()",
"journal": "Bone",
"keywords": "Atypical femoral fracture; Bisphosphonate; Bone turnover; Microdamage",
"medline_ta": "Bone",
"mesh_terms": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D005269:Femur; D006801:Humans; D008875:Middle Aged; D011859:Radiography",
"nlm_unique_id": "8504048",
"other_id": null,
"pages": "183-6",
"pmc": null,
"pmid": "24747352",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A large amount of microdamages in the cortical bone around fracture site in a patient of atypical femoral fracture after long-term bisphosphonate therapy.",
"title_normalized": "a large amount of microdamages in the cortical bone around fracture site in a patient of atypical femoral fracture after long term bisphosphonate therapy"
} | [
{
"companynumb": "PHHY2013JP006218",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "1",
"... |
{
"abstract": "OBJECTIVE\nThis case series highlights the novel use of intravitreal melphalan for nonvitreous retinoblastoma. It assesses the efficacy and toxicity of intravitreal melphalan for nonvitreous retinoblastoma.\n\n\nMETHODS\nThis observational small case series investigates three patients treated with intravitreal melphalan for nonvitreous retinoblastoma that was refractory to multiple-course ophthalmic artery chemosurgery. Patients' demographics, response to treatment, and toxicity of treatment as clinically evaluated are measured by electroretinogram.\n\n\nMETHODS\nThree eyes of three patients received a median of 7 weekly intravitreal melphalan injections (30 μg/0.07 cc) for persistent retinal or subretinal tumors refractory to treatment with multiple-course ophthalmic artery chemosurgery.\n\n\nRESULTS\nEyes remain tumor free at a median of 14-month follow-up. One eye was enucleated because of a vitreous hemorrhage that obscured fundus details. One eye had extinguished electroretinogram recordings before injections and two eyes had a decrease in electroretinogram responses over the intravitreal treatment course. The eye with subretinal seeding demonstrated marked retinopathy by ophthalmoscopy and fluorescein angiography and one eye was enucleated because of the development of a vitreous hemorrhage.\n\n\nCONCLUSIONS\nThis small case series highlights that nonvitreous disease that is, refractory or persistent despite previous ophthalmic artery chemosurgery can regress with intravitreal melphalan. However, this treatment may result in retinal toxicity.",
"affiliations": "*Memorial Sloan Kettering Cancer Center, New York, New York; †Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York; and ‡Icahn School of Medicine at Mount Sinai, New York, New York.",
"authors": "Francis|Jasmine H|JH|;Marr|Brian P|BP|;Brodie|Scott E|SE|;Gobin|Pierre|P|;Dunkel|Ira J|IJ|;Abramson|David H|DH|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000262",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "10(4)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D008297:Male; D008558:Melphalan; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D016879:Salvage Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "357-60",
"pmc": null,
"pmid": "26630243",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study",
"references": "24734170;24407202;25321846;24227979;24789622;25124953;25078631;24187047;23044940;22053101",
"title": "INTRAVITREAL MELPHALAN AS SALVAGE THERAPY FOR REFRACTORY RETINAL AND SUBRETINAL RETINOBLASTOMA.",
"title_normalized": "intravitreal melphalan as salvage therapy for refractory retinal and subretinal retinoblastoma"
} | [
{
"companynumb": "US-APOPHARMA USA, INC.-2015AP015637",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TOPOTECAN\\TOPOTECAN HYDROCHLORIDE"
},
... |
{
"abstract": "To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil.\n\n\n\nA retrospective cohort study of children with pulmonary hypertension (PH) treated with sildenafil at a single institution between 2004 and 2015. Baseline and follow-up data collected by chart review.\n\n\n\nThere were 269 children included in this study: 47 with idiopathic pulmonary arterial hypertension, 53 with congenital heart disease, 135 with bronchopulmonary dysplasia, 24 with congenital diaphragmatic hernia, and 7 with other causes. Sildenafil was initial monotherapy in 84.8% and add-on therapy in 15.2%. Median follow-up time was 3.1 years (2 weeks-12.4 years). On follow-up, 99 (37%) remained on sildenafil or transitioned to tadalafil, 93 (35%) stopped sildenafil for improvement in PH, 54 (20%) died, and 20 (7%) were lost to follow-up. PH was most likely to improve in those with bronchopulmonary dysplasia, allowing for the discontinuation of sildenafil in 45%. Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation. Overall survival was significantly lower in World Health Organization group 3 PH (bronchopulmonary dysplasia and congenital diaphragmatic hernia) vs group 1 (idiopathic pulmonary arterial hypertension and congenital heart disease), P = .02.\n\n\n\nIn this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving.",
"affiliations": "Division of Pediatric Cardiology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY.;Division of Pediatric Cardiology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY.;Division of Pediatric Cardiology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY.;Division of Pediatric Cardiology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY.;Division of Pediatric Cardiology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY. Electronic address: usk1@cumc.columbia.edu.",
"authors": "Cohen|Jennifer L|JL|;Nees|Shannon N|SN|;Valencia|Gerson A|GA|;Rosenzweig|Erika B|EB|;Krishnan|Usha S|US|",
"chemical_list": "D014665:Vasodilator Agents; D000068581:Tadalafil; D000068677:Sildenafil Citrate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2018.09.067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "205()",
"journal": "The Journal of pediatrics",
"keywords": "Sildenafil; bronchopulmonary dysplasia; congenital diaphragmatic hernia; congenital heart disease",
"medline_ta": "J Pediatr",
"mesh_terms": "D000293:Adolescent; D001997:Bronchopulmonary Dysplasia; D002648:Child; D002675:Child, Preschool; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006330:Heart Defects, Congenital; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D000068677:Sildenafil Citrate; D000068581:Tadalafil; D016896:Treatment Outcome; D014665:Vasodilator Agents",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "29-34.e1",
"pmc": null,
"pmid": "30396684",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "15823634;24976012;20339498;21311503;15956137;17344658;22240409;20359596;20451700;21357924;9815111;18952635;28079864;22311993;18055675;18950791;22128226;20585012;10052821;10908271;23375362;15017543;24637559;28676038;23220921;16291984;8550830;22086881",
"title": "Sildenafil Use in Children with Pulmonary Hypertension.",
"title_normalized": "sildenafil use in children with pulmonary hypertension"
} | [
{
"companynumb": "US-MYLANLABS-2019M1012370",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SILDENAFIL"
},
"drugadditional": null,
... |
{
"abstract": "The novel oral anticoagulants (NOACs) are indicated for stroke and systemic embolism prophylaxis in patients with nonvalvular atrial fibrillation (AF). Very few cases of intravenous recombinant tissue plasminogen activator (IV rt-PA) in patients under treatment with NOACs have been described. The decision to thrombolyze patients under NOACs is complex and requires a balance between the benefits of treatment and the risk of symptomatic hemorrhagic complications.We describe an unusual case of treatment IV rt-PA for acute ischemic stroke in a patient receiving dabigatran for AF. The decision to treat the patient with IV rt-PA was based on the combination of normal coagulation times with the long time elapsed after the last dose of dabigatran, when the drug effect was predictably residual.",
"affiliations": "Department of Internal Medicine, Unidade Local de Saúde do Litoral Alentejano (ULSLA).;Department of Internal Medicine, Unidade Local de Saúde do Litoral Alentejano (ULSLA).;Department of Internal Medicine, Unidade Local de Saúde do Litoral Alentejano (ULSLA).;Department of Internal Medicine, Unidade Local de Saúde do Litoral Alentejano (ULSLA); National Institute of Medical Emergency (INEM).;National Institute of Medical Emergency (INEM); Department of Neurology, Centro Hospitalar do Algarve (CHA). Electronic address: nzwalo@gmail.com.;Department of Internal Medicine, Unidade Local de Saúde do Litoral Alentejano (ULSLA); National Institute of Medical Emergency (INEM).;Department of Internal Medicine, Unidade Local de Saúde do Litoral Alentejano (ULSLA).",
"authors": "Diogo|Cátia|C|;Duarte|Josiana|J|;Sobral|Sofia|S|;Pestana|Paula|P|;Nzwalo|Hipólito|H|;Rita|Henrique|H|;Sousa E Costa|José|J|",
"chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D005343:Fibrinolytic Agents; D015091:beta-Alanine; D010959:Tissue Plasminogen Activator; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "32(11)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000991:Antithrombins; D001281:Atrial Fibrillation; D001562:Benzimidazoles; D000069604:Dabigatran; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D020521:Stroke; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D015091:beta-Alanine",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1435.e1-2",
"pmc": null,
"pmid": "24881517",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran.",
"title_normalized": "good outcome after intravenous thrombolysis for acute stroke in a patient under treatment with dabigatran"
} | [
{
"companynumb": "PT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-46697GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Carbapenem-resistant Acinetobacter baumannii (CR-Ab) has become a worrying health care problem, mainly in developing countries, such as Brazil. The objective was to investigate the prevalence and prognostic factors for CR-Ab infections at a Brazilian university hospital and examine the impact of inappropriate antimicrobial therapy on patient outcome.\n\n\n\nA retrospective study on hospitalized patients with CR-Ab infections was carried out from January 2013 to December 2017. An epidemiologic analysis was carried out to determine the frequency of infections, the epidemiologic indicators by year, the risk factors for 30-day mortality, and the impact of inappropriate therapy.\n\n\n\nA total of 489 patients were included in the study. A rate of 0.7 per 1,000 patient-day CR-Ab infections was observed, mostly in the lungs (54.7%), and predominantly in the adult intensive care unit. The occurrence of infections by CR-Ab per 1,000 patient-days in November 2014 exceeded the established control limit, confirming an outbreak.\n\n\n\nThe prevalence of CR-Ab increased in the investigated hospital, passing to an endemic pathogen with a direct impact on mortality and the control of these strains.",
"affiliations": "Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil. Electronic address: iararossi@ufu.br.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil; School of Medicine, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Hospital Infection Control Committee, Hospital das Clínicas, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.;Laboratory of Molecular Microbiology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil; Hospital Infection Control Committee, Hospital das Clínicas, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.",
"authors": "Rossi|Iara|I|;Royer|Sabrina|S|;Ferreira|Melina Lorraine|ML|;Campos|Paola Amaral|PA|;Fuga|Bruna|B|;Melo|Gabriel Nogueira|GN|;Machado|Luiz Gustavo|LG|;Resende|Daiane Silva|DS|;Batistão|Deivid|D|;Urzedo|Jane Eire|JE|;Gontijo-Filho|Paulo P|PP|;Ribas|Rosineide Marques|RM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015780:Carbapenems",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajic.2019.07.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-6553",
"issue": "47(12)",
"journal": "American journal of infection control",
"keywords": "Carbapenem-resistance; Outbreak",
"medline_ta": "Am J Infect Control",
"mesh_terms": "D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001938:Brazil; D015780:Carbapenems; D003428:Cross Infection; D005260:Female; D006785:Hospitals, University; D006801:Humans; D015994:Incidence; D007297:Inpatients; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D055815:Young Adult; D018440:beta-Lactam Resistance",
"nlm_unique_id": "8004854",
"other_id": null,
"pages": "1431-1435",
"pmc": null,
"pmid": "31399285",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Incidence of infections caused by carbapenem-resistant Acinetobacter baumannii.",
"title_normalized": "incidence of infections caused by carbapenem resistant acinetobacter baumannii"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-289218",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
... |
{
"abstract": "This is the first study to report changes in BMD and related risk factors among Chinese patients with HIV after initiation of tenofovir disoproxil fumarate (TDF)-containing antiretroviral therapy. Greater bone mineral density (BMD) loss was observed in patients treated with TDF, compared to those on non-TDF-containing regimens. Our findings provide important knowledge regarding the risk factors in the long-term clinical management of patients with HIV in China.\n\n\nBACKGROUND\nPersons living with HIV (PLWH) are at increased risk for osteoporosis and fracture. Tenofovir disoproxil fumarate (TDF) has been associated with higher rates of bone mineral density (BMD) loss, osteoporosis, and fracture. Few studies have studied the impact among PLWH in Asia.\n\n\nMETHODS\nWe analyzed retrospectively patients from the outpatient HIV clinic of a large tertiary hospital in Beijing, China, from March 2007 to May 2016. Patients who had dual-energy X-ray absorptiometry testing prior to antiretroviral initiation and at 48 and/or 96 weeks after initiation were included in this analysis.\n\n\nRESULTS\nA total of 136 patients were included (mean age 36.0 ± 10.6 years) and over 90% participants were male and Han Chinese ethnicity. We observed greater declines in BMD at the spine from baseline to week 48 (-2.94% vs. -0.74%) and at the hip from baseline to week 96 (-4.37% vs. -2.34%) in the TDF group compared with the non-TDF group. With regard to HIV-specific parameters, longer duration since HIV diagnosis and undetectable viral load over time were associated with lower BMD at the hip [relative risk (RR) 0.97, 95% confidence index (CI) (0.95, 0.99) per 1 year increase and RR 0.96, 95%CI (0.94, 0.99), respectively] and femoral neck [RR 0.97, 95%CI (0.95, 0.99) per 1 year increase and RR 0.97, 95%CI (0.95, 0.998), respectively] over 96 weeks.\n\n\nCONCLUSIONS\nThis is the first study to report changes in BMD among PLWH after initiation of TDF-based antiretroviral therapy in China. Our findings provide important knowledge for the long-term clinical management of PLWH from this region.",
"affiliations": "Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.;Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.;Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.;Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.;Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.;Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China. litsh@263.net.;Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China. evelyn.hsieh@yale.edu.",
"authors": "Guo|F|F|;Song|X|X|;Li|Y|Y|;Guan|W|W|;Pan|W|W|;Yu|W|W|;Li|T|T|;Hsieh|E|E|http://orcid.org/0000-0001-5018-8409",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-020-05584-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "32(2)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": "Bone mineral density; Fracture; Human immunodeficiency virus; Protease inhibitors; Tenofovir disoproxil fumarate",
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D001208:Asia; D015519:Bone Density; D002681:China; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "321-332",
"pmc": null,
"pmid": "32803316",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "26070969;28413362;29709013;28418990;22301411;26919733;25224293;27124896;29363823;19890183;26760232;26392000;23943825;21606537;25867913;24872136;29368537;26060295;23044316;23899016;18025112;22454762;28480762;31939111;25182228;25948863;28650589;28060010;28574962;25711332;29736771;25265073;25609682;30603840;26842728;28531309;28689877;29623648;29762165;29927785;27193748;25487753",
"title": "Longitudinal change in bone mineral density among Chinese individuals with HIV after initiation of antiretroviral therapy.",
"title_normalized": "longitudinal change in bone mineral density among chinese individuals with hiv after initiation of antiretroviral therapy"
} | [
{
"companynumb": "CN-GILEAD-2020-0492178",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
"drugadditiona... |
{
"abstract": "Rare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD.\n\n\n\nA medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student's t-test and Fisher's exact test.\n\n\n\nThe eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3+ CD8+ T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to <1% in CeD and normal duodenum; average PD-1 percentage was very low to absent in all cases (<3%). On follow-up, five patients with ICI-CeD improved on a gluten-free diet (GFD) as the sole therapeutic intervention (with down-trending tTG-IgA) while the other three required immunosuppression. All patients who developed ICI-Duo received immunosuppression with variable improvement in symptoms.\n\n\n\nICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression.",
"affiliations": "Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.;Harvard Medical School, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Department of Medicine, Columbia University, New York, New York, USA.;Harvard Medical School, Boston, MA, USA.;Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA.;Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.;Harvard Medical School, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA.;Harvard Medical School, Boston, MA, USA mldougan@partners.org.",
"authors": "Badran|Yousef R|YR|;Shih|Angela|A|;Leet|Donna|D|;Mooradian|Meghan J|MJ|0000-0002-8289-8015;Coromilas|Alexandra|A|;Chen|Jonathan|J|;Kem|Marina|M|;Zheng|Hui|H|;Borowsky|Jennifer|J|;Misdraji|Joseph|J|;Mino-Kenudson|Mari|M|0000-0002-9092-2265;Dougan|Michael|M|0000-0001-9266-2009",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2020-000958",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32581063\njitc-2020-000958\n10.1136/jitc-2020-000958\nClinical/Translational Cancer Immunotherapy\n1506\n2435\n2445\nOriginal researchImmune checkpoint inhibitor-associated celiac disease\nBadran Yousef R 12 Shih Angela 23 Leet Donna 2 http://orcid.org/0000-0002-8289-8015Mooradian Meghan J 24 Coromilas Alexandra 5 Chen Jonathan 23 Kem Marina 3 Zheng Hui 6 Borowsky Jennifer 3 Misdraji Joseph 23 http://orcid.org/0000-0002-9092-2265Mino-Kenudson Mari 23 http://orcid.org/0000-0001-9266-2009Dougan Michael 27 \n1 \nDepartment of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA\n\n\n2 \nHarvard Medical School, Boston, MA, USA\n\n\n3 \nDepartment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA\n\n\n4 \nDivision of Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA\n\n\n5 \nDepartment of Medicine, Columbia University, New York, New York, USA\n\n\n6 \nBiostatistics Center, Massachusetts General Hospital, Boston, MA, USA\n\n\n7 \nDivision of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA\n\nCorrespondence to Dr Michael Dougan; mldougan@partners.org\n2020 \n24 6 2020 \n8 1 e00095823 5 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.2020https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.Background\nRare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD.\n\nMethods\nA medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student’s t-test and Fisher’s exact test.\n\nResults\nThe eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3+ CD8+ T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to <1% in CeD and normal duodenum; average PD-1 percentage was very low to absent in all cases (<3%). On follow-up, five patients with ICI-CeD improved on a gluten-free diet (GFD) as the sole therapeutic intervention (with down-trending tTG-IgA) while the other three required immunosuppression. All patients who developed ICI-Duo received immunosuppression with variable improvement in symptoms.\n\nConclusions\nICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression.\n\ncostimulatory and inhibitory T-cell receptorsimmunotherapyinflammationhttp://dx.doi.org/10.13039/100009560American Gastroenterological AssociationResearch Scholar Awardhttp://dx.doi.org/10.13039/100000062National Institute of Diabetes and Digestive and Kidney Diseases1K08DK114563–01special-featureunlocked\n==== Body\nBackground\nCeliac disease (CeD) is a systemic autoimmune disease characterized by small intestinal enteropathy precipitated and propagated by dietary gluten in genetically susceptible individuals.1–3 When immunogenic gluten peptides traverse the intestinal lumen, they can elicit both an innate and an adaptive immune response, leading to the clinical and histological manifestations of CeD.4 Patients often present with a constellation of intestinal and/or extraintestinal manifestations, although some may be asymptomatic at diagnosis, and histological confirmation by the presence of intraepithelial lymphocytes (IELs) and villous atrophy is often necessary.3 5 Measurement of serum IgA antibodies to tissue transglutaminase (tTG-IgA; or IgG class in patients with IgA deficiency) is the first recommended screening test for patients with suspected CeD.1 2\n\n\nThe immune regulatory proteins cytotoxic T lymphocyte antigen (CTLA)-4 as well as programmed death (PD)−1 and its ligand PD-L1 are important immune regulatory proteins collectively referred to as immune checkpoints receptors. Studies have shown that these pathways can be appropriated by malignant tumors as a mechanism to circumvent antitumoral immune responses.6 Underscoring the importance of these pathways, immune checkpoint inhibitors (ICIs) have demonstrated impressive clinical activity, with monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1 now approved for the treatment of diverse cancers.7 8\n\n\nAlthough ICIs demonstrate remarkable efficacy against advanced cancers by enhancing antitumor effector functions of T cells,9 inhibition of these regulatory receptors leads to loss of tolerance and a wide spectrum of inflammatory toxicities known as immune-related adverse events (irAEs). When severe, irAEs can necessitate ICI therapy interruption, discontinuation, and treatment escalation with powerful immunosuppressive agents.10–13 Isolated ICI-associated duodenitis (ICI-Duo) has been reported after treatment with different immunotherapies,14 15 often with non-specific histological features.14–16 Interestingly, rare cases of patients with de novo elevation of serum tTG antibodies in the setting of treatment with ICIs have been reported.17–19\n\n\nThe nature of the relationship between serum tTG antibodies and ICI-Duo is currently unclear, but it has been hypothesized to reflect treatment-emergent CeD.17 20 Whether ICI-associated celiac disease (ICI-CeD) reflects new onset gluten sensitivity or is the first manifestation of previously asymptomatic CeD remains an open question. As the clinical and histological manifestations of gastrointestinal (GI) irAE are broad and may mimic other primary diseases (including CeD), this study aims to elucidate the clinicopathological and immunophenotypic characterizations of patients with ICI-CeD in comparison to ICI-Duo and conventional CeD.\n\nPatients and methods\nPatients\nA comprehensive search of the clinical and pathology records at the Massachusetts General Hospital (MGH) between the years 2015 and 2019 identified eight patients with ICI-CeD (confirmed by serological testing for tTG-IgA), along with nine patients with ICI-Duo defined as pathologically confirmed duodenal inflammation while on ICI therapy per routine standard of care or clinical trial protocol. Patients with concurrent colitis were excluded from the ICI-Duo cohort. All patients had been referred to the gastroenterology service for new GI problems after receiving ICIs. Positive infectious disease testing was an exclusion criteria, and included Clostridium difficile testing by toxin A/B immunoassay, stool ova and parasites examination, stool culture, and serum cytomegalovirus viral titers. This search was inclusive of a well-defined cohort of 376 patients with melanoma treated with ICI at the MGH Cancer Center between 2013 and 2017, which was used to calculate approximate frequencies of specific luminal toxicities (Melanoma Cohort). Additionally, a search of the pathology records identified age-matched, otherwise healthy patient controls with typical CeD (modified Marsh 3b) as well as non-CeD controls with normal duodenum.\n\nICI-CeD and ICI-Duo definitions\nICI-CeD was defined as clinical evidence of duodenitis with tTG antibody positivity that developed after ICI administration, with histopathological confirmation when available. ICI-Duo was defined as clinical and histological evidence of duodenitis with a negative tTG antibody. Patients with duodenitis who did not have tTG antibody measured and were treated with standard management for immune-related enterocolitis with appropriate response were included in the ICI-Duo group. Active colitis was ruled out in patients presenting with diarrhea through lower GI endoscopic evaluation.\n\nData collection\nDetails of the medical and oncological histories were reviewed in the electronic medical record. Data pertaining to ICI-Duo and ICI-CeD development and management include: presenting symptoms, laboratory workup, corticosteroid dose and number of steroid taper attempts, and infliximab use. Laboratory parameters including transferrin saturation, vitamin D, vitamin B12, and transaminases were captured between 2 weeks prior and 1 year after diagnosis of GI toxicity. Antitumor outcomes including overall survival (OS) and progression-free survival (PFS) were calculated and reviewed by a medical oncologist (MJM).\n\nHistology and immunohistochemistry\nDuodenal biopsies were reviewed by two GI pathologists (AS and MM-K) and assessed for villous blunting, neutrophilic duodenitis, expansion of the lamina propria, intraepithelial lymphocytosis, and surface erosion or ulceration. An immunohistochemical panel was performed on a representative slide of duodenum for each selected case and control case, consisting of the following markers and staining conditions: CD3 (Leica; RTU; ER2, 15 min), CD8 (Leica; RTU; ER1, 20 min), T-cell receptor δ (Santa Cruz Biotech; 1:200; ER2, 40 min), PD-L1 (Cell Signaling; 1:200; ER2, 20 min), PD-1 (Cell Marque; 1:200; ER2, 30 min), and CD68 (Biocare; RTU; ER1, 20 min).\n\nQuantification of the IELs is reported as an average number of CD3, CD8, and δγ positive cells per 100 enterocytes in three well-oriented villi. Quantification of lamina propria lymphocytes is reported as an average number of CD3 and CD8 cells per high power field (HPF; 400×) in three HPFs. Assessment of CD68, PD-L1, and PD-1 is reported as a percentage of lamina propria surface area infiltrated by positive cells in the biopsy.\n\nStatistical analysis\nPatients were grouped in two primary groups for analysis: ICI-Duo and ICI-CeD. Statistical analysis, including Fisher’s exact test, analysis of variance, and Student’s t-test, was performed using GraphPad Prism V.8 (GraphPad Software, La Jolla, California, USA) or Python SciPy V.1.4.1. Data are expressed as “mean±SD,” “mean±SE,” or “median (range)” where appropriate.\n\nResults\nDemographics and baseline characteristics\nWe identified nine patients who developed ICI-Duo (median age at presentation: 60 years; F:M=5:4) and eight patients who developed ICI-CeD (median age at presentation: 55 years; F:M=1:3; table 1). The majority (71%) of patients received ICI for treatment of metastatic melanoma. In the entire cohort, eight patients received single-agent PD-(L)1 inhibition, five received single-agent CTLA-4 inhibition, and four received combination anti-PD-(L)1/CTLA-4 inhibition. Prior to developing GI symptoms on the current ICI regimen, only one patient had received a different ICI regimen in the ICI-CeD group (n=1/8), compared with five patients in the ICI-Duo group (n=5/9). Among the patients who developed ICI-CeD, two had non-small cell lung cancer, one had extraskeletal myxoid chondrosarcoma and one had tonsillar squamous cell carcinoma. No patients had known metastasis to the GI tract on initiation of immunotherapy (table 1).\n\nTable 1 Demographics and baseline characteristics\n\nCharacteristics\tICI-duodenitis (n=9)\tICI-celiac disease (n=8)\tP value\t\nMedian age at presentation, years (range)\t60 (29–71)\t55 (44–73)\t0.804\t\nSex (F:M)\t5:4\t2:6\t0.334\t\nMalignancy type, N (%)\t\t\t\t\n Melanoma\t8/9 (89)\t4/8 (50)\t0.131\t\n Lung\t0/9 (0)\t2/8 (25)\t0.205\t\n Other\t1/9 (11)\t2/8 (25)\t0.576\t\nStage at initiation of ICI\t\t\t\t\n III\t3/9 (33)\t3/8 (37.5)\t>0.999\t\n IV\t6/9 (67)\t5/8 (62.5)\t\t\nMetastatic sites at ICI initiation\t\t\t\t\n Lung\t3/9 (33)\t3/8 (37.5)\t>0.999\t\n Liver\t2/9 (22)\t2/8 (25)\t\t\n Brain\t2/9 (22)\t1/8 (12.5)\t\t\n Other\t4/9 (44)\t0/8 (0)\t\t\n None\t3/9 (33)\t3/8 (37.5)\t\t\nHistory of prior immunotherapy use\t5/9 (56)\t1/8 (12.5)\t0.132\t\nImmunotherapy at time of symptom onset, N (%)\t\t\t\t\n α-CTLA-4\t4/9 (44)\t1/8 (12.5)\t0.294\t\n α-PD-(L)1\t3/9 (33)\t5/8 (62.5)\t0.346\t\n Combined therapy\t2/9 (22)\t2/8 (25)\t0.999\t\nAutoimmune disease history, N (%)\t0/9 (0)\t0/8 (0)\t>0.999\t\nLuminal GI disease history\t\t\t\t\n GERD\t4/9 (44)\t3/8 (37.5)\t>0.999\t\n H.pylori PUD\t0/9 (0)\t0/8 (0)\t>0.999\t\n IBD\t0/9 (0)\t0/8 (0)\t>0.999\t\n Celiac disease\t0/9 (0)\t1/8 (12.5)\t0.47\t\nFamily history of CeD\t0/9 (0)\t2/8 (25)\t0.205\t\nThe p value was calculated by Student’s t-test and analysis of variance method for numerical covariates and Fisher’s exact for categorical covariates where appropriate. Other malignancy types for immune checkpoint inhibitor-associated duodenitis (ICI-Duo): Hodgkin lymphoma (n=1). Other malignancy types for ICI-CeD: extraskeletal myxoid chondrosarcoma (n=1) and tonsillar squamous cell carcinoma (n=1). Patients with (none) listed for metastatic sites at therapy initiation had stage III disease. Other metastatic sites for ICI-Duo: adrenal gland (n=1), bone (n=2), and peritoneum (n=1). History of prior immunotherapy use was identified as any ICI used prior to the current regimen. Combined therapy denotes that patients recieved ipilimumab and a programmed cell death receptor (ligand)-1 (PD-(L)1) inhibitor as standard of care or on an investigational protocol. Family history of celiac disease denotes CeD in first or second degree relative.\n\nCTLA-4, cytotoxic T cell associated antigen 4; GERD, gastroesophageal reflux disease; GI, gastrointestinal; H.pylori, Helicobacter pylori; IBD, inflammatory bowel disease; PUD, peptic ulcer disease.\n\nThe two groups had comparable histories of extraintestinal autoimmune disease and luminal GI disease, and no patients had a history of liver disease. One patient who developed ICI-CeD was known to have clinically asymptomatic CeD that flared after ICI therapy. Of the eight patients who developed ICI-CeD, two had a family history of CeD in a first degree relative.\n\nTo determine an approximate frequency of ICI-CeD and ICI-Duo, the Melanoma Cohort was used as a defined population. Of the 376 patients in this cohort, 123 patients were sent to endoscopy and 96 of these patients had symptoms of possible ICI toxicity. Most patients with suspected toxicity were found to have mucosal inflammation on biopsy (63, 65.6% of total). Of these 63 patients with inflammation, 49 had colitis or enterocolitis (77.8%), 8 had enteritis or gastroenteritis (12.7%), 3 had isolated gastritis (4.8%), 1 had esophagitis (1.6%), 1 patient had new onset CeD (1.6%), and 1 patient had unclassified inflammation (1.6%). The patient with ICI-CeD represented 0.3% of the total Melanoma Cohort exposed to ICIs.\n\nClinical presentation\nThe most common presenting symptoms for both ICI-CeD and ICI-Duo were diarrhea and abdominal pain. The median time to symptom onset after ICI initiation was 48 days (range 20–409 days) in patients with ICI-Duo, compared with 82.5 days (range 18–679 days) in patients with ICI-CeD. Monotherapy with PD-(L)1 blockade led to a later onset of symptoms (median 159.5 days, range 19–679 days) compared with monotherapy with CTLA-4 or combined therapy with CTLA-4 and PD-(L)1 blockade (median 35 days, range 18–144 days; table 2). Extraintestinal manifestations including vitamin deficiencies, dermatitis herpitiformis, transaminase elevations, and constitutional symptoms, which were present between 2 weeks prior to diagnosis to 1 year after diagnosis, are reported in table 2.\n\nTable 2 Immune checkpoint inhibitor-associated duodenitis (ICI-Duo) and ICI-associated celiac disease (ICI-CeD) clinical course\n\nCharacteristics\tICI-Duo (n=9)\tICI-CeD (n=8)\tP value\t\nTime to symptoms onset (median, days)\t\t\n α-CTLA-4\t41.5 (n=4)\t31.0 (n=1)\t0.616\t\n α-PD-(L)1\t221 (n=3)\t119 (n=5)\t0.79\t\n Combined therapy\t27.5 (n=2)\t81 (n=2)\t0.487\t\n Overall\t48\t82.5\t0.623\t\nSymptoms at diagnosis\t\t\n Abdominal pain\t6/9 (67%)\t5/8 (62.5%)\t>0.999\t\n Diarrhea\t7/9 (78%)\t6/8 (75%)\t>0.999\t\n Nausea/vomiting\t5/9 (56%)\t2/8 (25%)\t0.314\t\n Weight loss\t0/9 (0%)\t0/8 (0%)\t>0.999\t\n BRBPR\t1/9 (11%)\t0/8 (0%)\t>0.999\t\nExtraintestinal manifestations\t\t\n Head fog/headaches\t1/9 (11%)\t1/8 (12.5%)\t>0.999\t\n Fatigue\t5/9 (56%)\t2/8 (25%)\t0.334\t\n Dermatitis herpitiformis\t0/9 (0%)\t0/8 (0%)\t>0.999\t\n B12 deficiency*\t0/2 (0%)\t1/6 (17%)\t>0.999\t\n Vitamin D deficiency\t0/0 (0%)\t2/4 (50%)\t>0.999\t\n Iron deficiency\t1/3 (33%)\t2/4 (50%)\t>0.999\t\n Folate deficiency\t0/2 (0%)\t0/4 (0%)\t>0.999\t\n Transaminase elevation\t2/9 (22%)\t1/8 (12.5%)\t>0.999\t\nTTG IgA\t\t\n Mean±SD\t1.3±0.23 (n=6)\t121.21±80.29 (n=8)\t0.003\t\n Median\t1.23\t105.3\t\t\nIgA\t\t\t\t\n Mean±SD\t144.75±41.67\t255.5±117.86\t0.113\t\n Median\t152\t233.5\t\t\nUpper endoscopy features\t\t\n Inflammation\t6/9 (67%)\t2/6 (33%)\t0.153\t\n Mucosal atrophy\t1/9 (11%)\t2/6 (33%)\t0.523\t\n Mucosal ulcers/erosions\t1/9 (11%)\t2/6 (33%)\t0.523\t\n Scalloping\t1/9 (11%)\t0/6 (0%)\t>0.999\t\n Normal duodenum\t0/9 (10%)\t1/6 (17%)\t>0.999\t\nHistological features at diagnosis\t\t\n Moderate-to-severe villous blunting\t9/9 (100%)\t5/6 (83%)\t0.4\t\n Increased IELs\t2/9 (22%)\t4/6 (67%)\t0.135\t\n Increased LP cellularity\t9/9 (100%)\t6/6 (83%)\t>0.999\t\n Neutrophilic duodenitis\t9/9 (100%)\t5/6 (83%)\t0.4\t\n Surface erosion/ulceration\t5/9 (56%)\t5/6 (83%)\t0.58\t\n*The p value was calculated by Student’s t-test and analysis of variance method for numerical covariates and Fisher’s exact for categorical covariates where appropriate. Time to symptoms onset is defined as time between the first dose of ICI and the development of symptoms. Combined therapy denotes that patients recieved ipilimumab and a programmed cell death receptor (ligand)-1 (PD-(L)1) inhibitor as standard of care or on an investigational protocol. All laboratory testings listed under ‘extraintestinal manifestations’ were performed between 2 weeks prior to establishing the diagnosis and 1 year after. Vitamin B-12 deficiency was defined as a vitamin B-12 level less than 200 ng/mL. Vitamin D deficiency was defined as a 25-OH vitamin D level less than 20 ng/mL. Iron deficiency was defined as a ferritin level less than 15 ng/mL at any hemoglobin level or a transferrin saturation less than 16%. Folate deficiency was defined as a serum folate concerntration of less than 2 ng/mL. Transaminase elevation were defined as alanine aminotransferase level higher than 33 units/L for males and 29 units/L for females. For patients with a tTG IgA level below the lower limit of the assay (less than 1.2 IU/mL), a level of 1.2 IU/mL was used for statistical calculations. Endoscopic features were all assessed on the first endoscopic evaluation of the patient at presentation. Features of inflammation included erythema, congestion, and granularity. Mucosal atrophy includes features of atrophy and loss of mucosal folds. No pathological change denotes a normal duodenum. All of the boldfaced numbers should be statistically significant and statistical significance is at p value of less than 0.05.\n\nBRBPR, bright red blood per rectum; CTLA-4, cytotoxic T cell associated antigen 4; IEL, intraepithelial lymphocytes; IgA, immunoglobulin A level at diagnosis; LP, lamina propria; tTG IgA, IgA antitissue transglutaminase antibodies at diagnosis.\n\nThe diagnosis of ICI-CeD was first established by measurement of tTG IgA (mean: 121.21±80.29 IU/mL). tTG IgA levels were higher in patients with ICI-CeD compared with an in-house cohort of patients with CeD (mean: 82.22±102.48 IU/mL) (table 2 and online supplementary table S1). Patients in the ICI-Duo cohort were defined as having a tTG-IgA within normal limits, or did not have a tTG-IgA drawn and were treated with immunosuppression. IgA levels were normal in all reported patients.\n\n10.1136/jitc-2020-000958.supp1Supplementary data \n\n\n\n A subset of patients who developed ICI-CeD had vitamin D deficiency (n=2/4) and iron deficiency (n=2/4), while one out of six tested had vitamin B12 deficiency (table 2). Additionally, the frequency of other irAEs in both patient cohorts was variable (online supplementary table S2) but notably, immune-related hepatitis was more commonly seen in patients with ICI-CeD than in patients with ICI-Duo.\n\nEndoscopic findings\nPatients presenting with upper GI symptoms (nausea, vomiting, or epigastric pain) without diarrhea underwent an initial upper endoscopy. Patients presenting with diarrhea underwent upper and lower GI endoscopy. Duodenal congestion, nodularity, or erythema were seen on endoscopy in 67% of patients with ICI-Duo, compared with 33% of patients with ICI-CeD (table 2 and figure 1). One patient with ICI-CeD had a grossly normal duodenum on endoscopic examination (table 2). Another patient had a history of asymptomatic CeD and developed a flare after ICI therapy; endoscopic evaluation was not performed in this case, and the patient was managed empirically through dietary modification.\n\nFigure 1 In a patient with immune checkpoint inhibitor (ICI)-associated duodenitis, an endoscopic image of the duodenum reveals diffuse inflammation characterized by congestion, erosions, erythema, and granularity (A). On biopsy, routine H&E showed a markedly active neutrophilic duodenitis with mild-to-moderate villous blunting, marked expansion of the lamina propria, and only mildly increased intraepithelial lymphocytes (B, C). A patient with ICI-celiac disease (CeD) showed endoscopic findings of diffuse inflammation characterized by congestion, erythema, and friability (D). Biopsy of the duodenum showed a mildly active neutrophilic duodenitis with marked villous blunting and increased intraepithelial lymphocytes (E). Intraepithelial lymphocytosis, however, was not present in all ICI-CeD biopsies (F).\n\nHistological and immunohistochemical findings\nDuodenal biopsies were performed in nine of nine patients with ICI-Duo, and in six of eight patients with ICI-CeD. Histological findings in patients with ICI-Duo universally included moderate-to-severe villous blunting (n=9/9), increased cellularity of the lamina propria (n=9/9), and active neutrophilic duodenitis (n=9/9); surface erosion and ulceration were seen in a slight majority (n=5/9), and intraepithelial lymphocytosis was seen occasionally (n=2/9). Histological findings in the duodenum of patients with ICI-CeD were similar, including moderate-to-severe villous blunting (n=5/6), increased cellularity of the lamina propria (n=6/6), active neutrophilic duodenitis (n=5/6), surface erosion or ulceration (n=5/6), and increased IELs (n=4/6; figure 1 and table 2). The absence of active colitis was confirmed on the colon biopsies from patients who underwent lower GI endoscopy.\n\nThe immunophenotypic characteristics of ICI-Duo and ICI-CeD were further assessed and quantified in comparison to CeD and normal duodenum (figures 2–4). In ICI-Duo, the average number of IELs per 100 enterocytes was 24 CD3+ T cells (± 10 cells); 20 CD8+ T cells (± 11 cells); and 1.3 γδ T cells (±2 cells). ICI-CeD had comparable numbers of average IELs per 100 enterocytes, with 25 CD3+ T cells (± 11 cells); 20 CD8+ T cells (± 19 cells); and 0.2 γδ T cells (±0.6 cells). There was no statistical significance in any of these measures between ICI-Duo and ICI-CeD (p=0.22 to 0.97). However, in comparison to ICI-Duo and ICI-CeD, usual CeD had increased numbers of average IELs per 100 enterocytes, with 48 CD3+ T cells (± 19 cells; p=0.0036 and 0.017, respectively); 33 CD8+ T cells (± 7 cells; p=0.0058 and 0.067, respectively); and 16 γδ T cells (±11 cells; p=0.00093 and 0.0036, respectively). Normal duodenum had significantly fewer CD3+ and CD8+ T cells and similar numbers of γδ T cells compared with ICI-Duo and ICI-CeD, with 8 CD3+ T cells (±4 cells; p=0.0046 and 0.0093, respectively); 6 CD8+ T cells (±3 cells; p=0.013 and 0.12, respectively); and 0.5 γδ T cells (±0.5 cells; p=0.36 and 0.55, respectively; figures 2 and 3).\n\nFigure 2 The immunophenotypic characteristics of immune checkpoint inhibitor-associated duodenitis (ICI-Duo) and ICI-celiac disease (CeD) were assessed and quantified in comparison to CeD and normal duodenum. (A) Number of intraepithelial lymphocytes expressed as an average number of CD3, CD8, and δγ positive cells per 100 enterocytes in three well-oriented villi. (B) Number of lamina propria lymphocytes reported as an average number of CD3 and CD8 cells per high power field (HPF; 400×) in three HPFs. (C) Percentage of lamina propria surface area infiltrated by positive cells in the biopsy stained for CD68, programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1). The p value was calculated by the Student t-test and the Welch’s t test for unequal variance, as appropriate. *P<0.05. **P<0.01. ***P<0.001.\n\nFigure 3 Representative images for (A–D) immune checkpoint inhibitor-associated duodenitis (ICI-Duo), (E–H) ICI-celiac disease (CeD), (I–L) CeD, and (M–P) normal duodenum are shown for routine H&E and immunostains for CD3, CD8, and T-cell receptor (TCR) γδ, respectively. In comparison to normal duodenum, ICI-Duo, ICI-CeD, and CeD show marked villous blunting, with a variably increased intraepithelial CD3+ CD8+ T cells. However, CeD is further characterized by a marked increase in intraepithelial γδ T cells compared with the other groups.\n\nFigure 4 Representative images for (A–D) immune checkpoint inhibitor-associated duodenitis (ICI-Duo), (E–H) ICI-celiac disease (CeD), (I–L) CeD, and (M–P) normal duodenum are shown for routine H&E and immunostains for CD68, programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1), respectively. In comparison to normal duodenum and CeD, patients treated with ICI (ICI-Duo and ICI-CeD) show increased CD68+ macrophages and PD-L1+ cells in the lamina propria. Immunohistochemical evidence of PD-1 expression was uniformly low to absent across all groups.\n\nQuantification of the inflammatory cells of the lamina propria showed that ICI-Duo had an average of 203 CD3+ T cells/HPF (±70 cells) and 112 CD8+ T cells/HPF (±50 cells), which were similar to ICI-CeD with 189 CD3+ T cells/HPF (±84 cells; p=0.72) and 113 CD8+ T cells/HPF (±68 cells; p=0.72). Compared with ICI-Duo and ICI-CeD, usual CeD showed similar numbers of CD3+ T cells at 169 CD3+ T cells/HPF (±51 cells; p=0.24 and 0.57, respectively), but fewer CD8+ T cells at 61 CD8+ T cells/HPF (±34 cells; p=0.017 and 0.057, respectively). Normal duodenum showed fewer lamina propria T cells compared with ICI-Duo and ICI-CeD, with 109 CD3+ T cells/HPF (±37 cells; p=0.016 and 0.08, respectively) and 39 CD8+ T cells/HPF (±14 cells; p=0.00085 and 0.04, respectively; figure 2).\n\nAssessment of CD68, PD-L1, and PD-1 was done through an estimate of percent cellularity in the lamina propria (percent lamina propria surface area infiltrated by positive cells; figures 2 and 4). ICI-Duo had an average CD68 percent cellularity of 39% (±22%); PD-L1 percent cellularity of 18% (±19%); and PD-1 percent cellularity of 3% (±7%). ICI-CeD had an average of CD68 percent cellularity of 18% (±14%); PD-L1 percent cellularity of 9% (±8%); and PD-1 percent cellularity of 0.3% (±0.5%), which are not statistically significant compared with ICI-Duo across the board (p=0.27 to 0.054). However, patients with ICI-Duo and ICI-CeD had increased CD68 and PD-L1 populations with similar PD-1 populations compared with CeD, which had an average CD68 percent cellularity of 12% (±6%; p=0.0010 and 0.18, respectively); PD-L1 percent cellularity of 0.8% (±2%; p=0.011 and 0.0068, respectively); and PD-1 percent cellularity of 0.7% (±2%; p=0.40 and 0.59, respectively). Normal duodenum showed smaller CD68, PDL1, and PD1 populations compared with ICI-Duo and ICI-CeD, with an average CD68 percent cellularity of 4.4% (±4%; p=0.06 and 0.035, respectively); PD-L1 percent cellularity of 0% (±0%; p=0.06 and 0.035, respectively); and PD-1 percent cellularity of 0% (±0%; p=0.41 and 0.19, respectively; figure 2).\n\nTreatment and clinical follow-up\nAmong patients with ICI-CeD, a gluten-free diet (GFD) was recommended to seven of eight patients (88%). Of these seven patients, five patients were started on a GFD on presentation with clinical remission of disease; in these cases, follow-up endoscopies were not pursued (table 3). The other two patients were administered steroids on presentation, with clarification of diagnosis with subsequent biopsy and tTG-IgA testing. On confirmation of an ICI-CeD diagnosis, these patients were transitioned to GFD alone, resulting in disease remission. In patients with ICI-CeD, tTG-IgA levels down trended (and in one patient decreased to undetectable levels) in response to a GFD (table 3). The single patient who was not trialed on GFD required steroids in addition to infliximab (antitumor necrosis factor (TNF)) for symptom control. A follow-up endoscopy in this patient showed duodenal erosions, and ICI therapy was subsequently terminated.\n\nTable 3 Immune checkpoint inhibitor-associated duodenitis (ICI-Duo) and ICI-celiac disease (CeD) treatment and survival\n\nCharacteristics\tICI-Duo (n=9)\tICI-CeD (n=8)\tP value\t\nRemission-inducing therapy\t\t\t\t\n GFD\t0/9 (0%)\t5/8 (62.5%)\t0.009\t\n Immunosuppression\t9/9 (100%)\t1/8 (12.5%)\t0.0004\t\n GFD + immunosuppression\t0/9 (0%)\t2/8 (25%)\t0.205\t\nTotal duration on steroids if used (weeks)\t\t\t\t\n Mean±SD\t9.50±3.26 (n=8)\t32.19±25.36 (n=3)\t0.261\t\nNumber of steroid tapering attempts\t\t\t\t\n 0\t1/9 (11%)\t5/8 (62.5%)\t0.049\t\n 1\t5/9 (56%)\t1/8 (12.5%)\t0.131\t\n 2\t2/9 (22%)\t0/8 (0%)\t0.47\t\n >2\t1/9 (11%)\t2/8 (25%)\t0.576\t\nDoses of infliximab to remission (mean)\t3 (n=4)\t1 (n=1)\tN/A\t\nRemission TTG IgA\t\t\t\t\n Mean±SD\tN/A\t37.9±57.87 (n=5)\tN/A\t\n Median\t\t5.5\t\t\nRemission IgA\t\t\t\t\n Mean±SD\tN/A\t155.0±57.17 (n=3)\tN/A\t\n Median\t\t173\t\t\nNeed to discontinue immunotherapy, N (%)\t6/9 (67)\t2/8 (25)\t0.153\t\nNumber of additional ICI doses received after onset of symptoms\t\t\t\n Mean±SD\t0.44±0.73\t1.38±1.69\t0.151\t\n Median (range)\t0 (0–2)\t1 (0–5)\t\t\nMalignancy restaging (best response)\t\t\t\t\n Complete response/relapse-free\t4/9 (44%)\t3/8 (37.5%)\t>0.999\t\n Objective response/partial response\t1/9 (11%)\t2/8 (25%)\t0.576\t\n Stable disease\t0/9 (0%)\t0/8 (0%)\t>0.999\t\n Progressive disease/relapsed\t4/9 (44%)\t3/8 (37.5%)\t>0.999\t\nProgression-free survival (months)\n \tMean: 11±11.29;\tMean: 13.75±16.39;\t0.689\t\nMedian: 7; range: 1–29\tMedian: 7; range: 1–47\t\t\nOverall survival (months)\n \tMean: 22.44±9.70;\tMean: 29.13±15.92\t0.306\t\nMedian: 20; range: 13–41\tMedian: 28; range: 8–52\t\t\nThe p-value was calculated by Student’s t-test and analysis of variance method for numerical covariates and χ2 test or Fisher’s exact for categorical covariates where appropriate. Immunosuppression denotes the use of either corticosteroids or antitumor necrosis factor medications. Remission tissue transglutaminase (tTG) IgA was defined as tTG IgA measured at the time of clinical symptomatic remission or endoscopic remission. Need to discontinue immunotherapy: restricted to complications of ICI-CeD or ICI-Duo and not due to loss of therapeutic effect or disease progression. Malignancy restaging after ICI was determined by the best response per Response Evaluation Criteria In Solid Tumors.\n\nGFD, gluten-free diet; N/A, not applicable.\n\nOnly two out of the eight patients who developed ICI-CeD and subsequently received steroids and GFD (n=1) or steroids and infliximab (n=1) were compelled to cease ICI therapy due to the severity of intestinal symptoms. The remaining six patients were able to continue ICI therapy on a GFD. Of these six patients, four patients ultimately discontinued ICI therapy due to disease progression.\n\nIn patients who developed ICI-Duo, eight out of nine patients required corticosteroids for symptom control. Four patients needed multiple doses of infliximab to control their disease (median three doses). In six out of nine patients who developed ICI-Duo, the ICI regimen had to be stopped or changed due to the severity of symptoms. Five patients underwent repeat esophagogastroduodenoscopy (EGD) and only two of those patients had endoscopic remission.\n\nPatients who developed ICI-CeD received a higher median number of additional ICI doses administered after development of symptoms compared with patients with ICI-Duo (1 vs 0). One patient with ICI-CeD remained controlled only with GFD and received five additional doses of ICI with good tumor response and no symptom recurrence. Median PFS was 7 months for both ICI-Duo and ICI-CeD. Median OS was 20 months in ICI-Duo compared with 28 months in ICI-CeD (table 3).\n\nDiscussion\nCurrent ICIs induce a wide spectrum of GI toxicities affecting the entire GI tract.21 Colitis or enterocolitis are the most frequent GI irAEs, affecting 15%–20% of patients who undergo endoscopic evaluation.22 ICI-CeD is less commonly appreciated but has been previously reported.17 18 20 Whether ICI-CeD represents de novo disease, or an exacerbation of underlying inflammation as can occur with inflammatory bowel disease, is unclear.23\n\n\nIn this study, we provide a clinical and pathological comparison between ICI-CeD and ICI-Duo, finding that the clinical presentation of ICI-CeD and ICI-Duo is very similar, with both pathologies presenting predominantly with abdominal pain and diarrhea. Although ICI-CeD does not appear to have the female predominance that usual CeD has, 25% of patients with ICI-CeD had a family history of CeD.24 A personal history of autoimmune disease was not predictive of the development of ICI-CeD, although the size of this study precludes definitive assessment. Similar to findings in published literature, prior exposure to immunotherapy was associated with a higher likelihood of developing ICI-Duo.16 25\n\n\nThe histological findings between ICI-Duo and ICI-CeD were similar in the upper GI tract, and in fact closely mimic those of typical CeD with villous blunting, active duodenitis, and patchy increased IELs.26 Immunophenotypic characterization showed that ICI-Duo and ICI-CeD have similar quantities of intraepithelial and lamina propria T cells, CD68+ macrophages, and PD-(L)1 populations. As expected, typical CeD also showed increased intraepithelial CD3+ and CD8+ T cells, though with a marked increase in intraepithelial γδ T cells compared with both ICI-Duo and ICI-CeD. Intraepithelial γδ T cells are known to be highly characteristic of conventional CeD and have been proposed as a diagnostic marker.27–29 Although the exact role of these lymphocytes in pathogenesis is not completely understood, the difference suggests that ICI-CeD may have a distinct immune etiology, or may represent a distinct phase of CeD that is not typically captured clinically. The pathological similarity between ICI-CeD and ICI-Duo suggest a common immunological mechanism, though likely with distinct antigenic targets.\n\nPatients with ICI toxicities showed a statistically significant increase in the presence of CD68+ and PD-L1+ macrophages in the lamina propria, compared with both CeD and normal duodenum. These quantitative findings did not appear to correlate with any specific type of ICI therapy, but are consistent with ongoing activation of interferon secreting T cells. The findings of varying populations of immune cells compared with CeD, in addition to the upregulation of PD-L1, also suggest that ICI-CeD and ICI-Duo are mechanistically distinct from conventional CeD. Alternatively, patients who develop ICI-CeD may have a variant of CeD that is controlled by immune checkpoint receptors and evolves to symptomatic disease only in the setting of ICI therapy.\n\nThe role of immune checkpoints in CeD pathogenesis has not been specifically studied. Nonetheless, murine models have been used to understand the importance of CTLA-4 and PD-1/PD-L1 in maintaining peripheral tolerance. The impact of PD-1 blockade on CD4 +T cells was studied through adoptively transferring CD4 +T cells harboring an ovalbumin (OVA) restricted T-cell receptor into wild-type mice.30 These mice were challenged with OVA peptide to induce tolerance, or with OVA peptide with lipopolysaccharide to induce an immune response while simultaneously blocking PD-1. In these mice, blockade of PD-1 did not prevent establishment of tolerance, nor did it overcome tolerance once it was established. However, in mice that were challenged with OVA and LPS, PD-1 blockade led to enhanced immunity, characterized by increased CD4+ T cell proliferative responses and interleukin 2 and interferon (IFN)-γ production.30\n\n\nIn a model in which OVA was expressed as a self-antigen in the small intestine, adoptively transferred naive OVA-specific CD8+ T cells in the setting of a PD-(L)1 blockade led to a breach of self-tolerance. In this setting, OVA-specific CD8+ T cells significantly expanded and produced a proinflammatory signal that led to a histological appearance similar to CeD in humans.31 Based on these studies, PD-1/PD-L1 appears to be important in limiting T cell activity in the gut. On the other hand, CTLA-4 is known to be crucial for tolerance induction in the early stages of the immune response as T cells are first presented with antigens by antigen presenting cells (APCs).32\n\n\nWe hypothesize that the immune cell activation in the setting of ICIs results in unmasking of gluten sensitivity in genetically susceptible people, leading to expansion of previously self-reactive CD4+ T cells and subsequent CD8+ T cell-induced tissue destruction. Our data suggest a role for both CTLA-4 and PD-1/PD-L1 in the immune regulation of CeD, though the relative importance of each regulatory pathways cannot be determined without a larger cohort, which would likely require a multicenter collaboration.\n\nIn the absence of pretreatment tTG-IgA titers, pretreatment histological confirmation, and HLA genotyping, we cannot definitively discern whether the patients in this study had de novo CeD (asymptomatic or subclinical) that progressed to symptomatic CeD in the setting of ICIs.3 Additionally, T-cell receptor sequencing to assess for clonal expansion will be crucial in expanding our understanding of ICI-CeD compared with usual CeD and ICI-Duo.\n\nThe onset of autoimmune diseases like CeD after therapy with immunomodulatory medications has been previously described.33 Some patients with hepatitis C that were treated with IFN-α-based regimens similarly developed CeD, with symptomatic improvement with GFD and cessation of IFN therapy.34 Additionally, Gentile et al demonstrated the development of ipilimumab-associated CeD in a patient with castration-resistant metastatic prostate cancer, who presented with refractory diarrhea after 3 doses of a CTLA-4 antagonist.20 The patient was treated with GFD and immunosuppression with budesonide and prednisone. He was successfully tapered off corticosteroids, and the serum tTG-IgA down trended appropriately. Another group reported the development of ICI-CeD in a patient who received pembrolizumab for locally recurrent melanoma.17 The patient developed symptoms within a week of the first infusion of pembrolizumab, and ICI-CeD was confirmed by histology and serum tTG-IgA. ICI therapy was discontinued due to persistence of symptoms, as the patient was unable to adhere to a GFD. Ultimately, the patient’s symptoms resolved with glucocorticoids administered for postural hypotension management.17\n\n\nThe responsiveness of ICI-CeD to GFD alone in five out of the eight cases (62%) indicates that gluten is an important antigen driving ICI-CeD, similar to standard CeD, despite the noted phenotypic differences in the immune infiltrate. Intriguingly, the similarities between ICI-CeD and ICI-Duo suggest that duodenitis may result from as of yet unidentified dietary triggers. A management strategy that relies on gluten restriction with monitoring of tTG-IgA and clinical symptoms may be sufficient for patients with ICI-CeD in the absence of gastric or colonic inflammation. Escalation to steroids and anti-TNF therapy can be used as second-line options if GFD fails to control disease activity.\n\nThe comparable clinical manifestations, time to symptom onset, and pace of disease progression of the different etiologies of ICI-induced GI toxicities support rigorous diagnostic evaluation in these patients, as clinical differences alone do not seem to be sufficient to determine etiology. The high sensitivity and specificity of tTG-IgA for CeD provide a compelling rationale for testing in all patients with suspected GI toxicities from ICIs early after symptom onset in order to exclude new onset CeD.\n\nWe have found that severity of diarrhea assessed by the Common Terminology Criteria for Adverse Events is unable to distinguish the various etiologies of ICI-induced GI toxicities from each other. For this reason, endoscopic biopsies play an integral role in the diagnostic workup of patients with suspected ICI GI toxicities; although most GI toxicities from ICIs occur in the colon, the frequency of upper GI toxicities justifies consideration of esophagogastroduodenocopy alongside a flexible sigmoidoscopy or colonoscopy.22 In addition to (entero)colitis and CeD, patients receiving ICI are at risk for pancreatic insufficiency and complications from GI mucosal metastases.35 36\n\n\nThe identification of ICI-CeD early in presentation could have substantial clinical implications. A GFD is a reasonable treatment strategy for patients with ICI-CeD (either alone or in combination with immunosuppression), and in many cases may be sufficient as monotherapy. Thus, tailoring therapy can enable patients to limit or avoid systemic immune suppression, and prevent unnecessary premature discontinuation of ICI treatment. Whether identification and treatment of ICI-CeD will have an effect on tumor outcomes is presently unclear, and will require establishing larger, preferably prospective cohorts.\n\nTwitter: @YRBadran\n\nYRB and AS contributed equally.\n\nMM-K and MD contributed equally.\n\nCorrection notice: Since the online publication of this article, the authors have noticed that the middle initial for author Yousef R Badran was missing. This has been corrected.\n\nContributors: YB, AS, DL, AC and MM-K compiled and reviewed all of the data. MJM assessed and confirmed the accuracy of the details relating to the patients’ oncological history and treatment. AS and MM-K performed the histopathological and immunohistochemical analysis of the patients’ samples. AS, JC, MK, JB, JM, and MM-K collected patient samples and identified the appropriate immunohistochemical panel. MD assessed and confirmed the accuracy of the patients’ gastroenterological history, treatment, and endoscopy results. YB, AS, and MD wrote the manuscript with contributions from all of the authors.\n\nFunding: Funding was provided by National Institutes of Health Mentored Clinical Scientist Development Award 1K08DK114563-01 and the American Gastroenterological Association Research Scholars Award (MD).\n\nCompeting interests: MD is a consultant for Genentech-Roche, Tillotts Pharma, and Partner Therapeutics. He received research funding from Novartis. He is on the scientific advisory board for Neoleukin Therapeutics.\n\nPatient consent for publication: Not required.\n\nEthics approval: This retrospective analysis was approved by the Partners Human Research Committee and the Institutional Review Board of the Massachusetts General Hospital (MGH).\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: Data sharing not applicable as no datasets generated and/or analyzed for this study.\n==== Refs\nReferences\n1 \nCaio G , Volta U , Sapone A , et al \nCeliac disease: a comprehensive current review\n. BMC Med \n2019 ;17 :142. 10.1186/s12916-019-1380-z \n31331324 \n2 \nLeonard MM , Sapone A , Catassi C , et al \nCeliac disease and Nonceliac gluten sensitivity: a review\n. JAMA \n2017 ;318 :647 –56\n. 10.1001/jama.2017.9730 \n28810029 \n3 \nLudvigsson JF , Leffler DA , Bai JC , et al \nThe Oslo definitions for coeliac disease and related terms\n. Gut \n2013 ;62 :43 –52\n. 10.1136/gutjnl-2011-301346 \n22345659 \n4 \nPagliari D , Urgesi R , Frosali S , et al \nThe interaction among microbiota, immunity, and genetic and dietary factors is the Condicio sine qua non celiac disease can develop\n. J Immunol Res \n2015 ;2015 :1 –10\n. 10.1155/2015/123653 \n\n5 \nFasano A , Catassi C \nClinical practice. celiac disease\n. N Engl J Med \n2012 ;367 :2419 –26\n. 10.1056/NEJMcp1113994 \n23252527 \n6 \nRegulation and Function of the PD-L1 Checkpoint - PubMed\n. Available: https://pubmed.ncbi.nlm.nih.gov/29562194-regulation-and-function-of-the-pd-l1-checkpoint/?from_single_result=29562194 [Accessed 3 Mar 2020 ].\n7 \nRibas A , Wolchok JD \nCancer immunotherapy using checkpoint blockade\n. Science \n2018 ;359 :1350 –5\n. 10.1126/science.aar4060 \n29567705 \n8 \nKruger S , Ilmer M , Kobold S , et al \nAdvances in cancer immunotherapy 2019 - latest trends\n. J Exp Clin Cancer Res \n2019 ;38 :268 . 10.1186/s13046-019-1266-0 \n31217020 \n9 \nWei SC , Duffy CR , Allison JP \nFundamental mechanisms of immune checkpoint blockade therapy\n. Cancer Discov \n2018 ;8 :1069 –86\n. 10.1158/2159-8290.CD-18-0367 \n30115704 \n10 \nPauken KE , Dougan M , Rose NR , et al \nAdverse events following cancer immunotherapy: obstacles and opportunities\n. Trends Immunol \n2019 ;40 :511 –23\n. 10.1016/j.it.2019.04.002 \n31053497 \n11 \nPostow MA , Sidlow R , Hellmann MD \nImmune-Related adverse events associated with immune checkpoint blockade\n. N Engl J Med \n2018 ;378 :158 –68\n. 10.1056/NEJMra1703481 \n29320654 \n12 \nBrahmer JR , Lacchetti C , Thompson JA \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline summary\n. J Oncol Pract \n2018 ;14 :247 –9\n. 10.1200/JOP.18.00005 \n29517954 \n13 \nAbu-Sbeih H , Ali FS , Alsaadi D , et al \nOutcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study\n. J Immunother Cancer \n2018 ;6 :142 . 10.1186/s40425-018-0461-4 \n30518410 \n14 \nMarthey L , Mateus C , Mussini C , et al \nCancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease\n. J Crohns Colitis \n2016 ;10 :395 –401\n. 10.1093/ecco-jcc/jjv227 \n26783344 \n15 \nCollins M , Michot JM , Danlos FX , et al \nInflammatory gastrointestinal diseases associated with PD-1 blockade antibodies\n. Ann Oncol \n2017 ;28 :2860 –5\n. 10.1093/annonc/mdx403 \n29045560 \n16 \nSoularue E , Lepage P , Colombel JF , et al \nEnterocolitis due to immune checkpoint inhibitors: a systematic review\n. Gut \n2018 ;67 :2056 –67\n. 10.1136/gutjnl-2018-316948 \n30131322 \n17 \nArnouk J , Mathew D , Nulton E , et al \nA celiac disease phenotype after checkpoint inhibitor exposure: an example of immune dysregulation after immunotherapy\n. ACG Case Rep J \n2019 ;6 :e00158. 10.14309/crj.0000000000000158 \n31737699 \n18 \nAlsaadi D , Shah NJ , Charabaty A , et al \nA case of checkpoint inhibitor-induced celiac disease\n. J Immunother Cancer \n2019 ;7 :203 . 10.1186/s40425-019-0694-x \n31383006 \n19 \nSchoenfeld SR , Aronow ME , Leaf RK , et al \nDiagnosis and management of rare immune-related adverse events\n. Oncologist \n2020 ;25 :6 –14\n. 10.1634/theoncologist.2019-0083 \n31694890 \n20 \nGentile NM , D'Souza A , Fujii LL , et al \nAssociation between ipilimumab and celiac disease\n. Mayo Clin Proc \n2013 ;88 :414 –7\n. 10.1016/j.mayocp.2013.01.015 \n23541015 \n21 \nDougan M , Pietropaolo M \nTime to dissect the autoimmune etiology of cancer antibody immunotherapy\n. J Clin Invest \n2020 ;130 :51 –61\n. 10.1172/JCI131194 \n31895048 \n22 \nHughes MS , Molina GE , Chen ST , et al \nBudesonide treatment for microscopic colitis from immune checkpoint inhibitors\n. J Immunother Cancer \n2019 ;7 :292 . 10.1186/s40425-019-0756-0 \n31699151 \n23 \nAbu-Sbeih H , Faleck DM , Ricciuti B , et al \nImmune checkpoint inhibitor therapy in patients with preexisting inflammatory bowel disease\n. J Clin Oncol \n2020 ;38 :576 –83\n. 10.1200/JCO.19.01674 \n31800340 \n24 \nTye-Din JA , Galipeau HJ , Agardh D \nCeliac disease: a review of current concepts in pathogenesis, prevention, and novel therapies\n. Front Pediatr \n2018 ;6 :350 . 10.3389/fped.2018.00350 \n30519552 \n25 \nGeukes Foppen MH , Rozeman EA , van Wilpe S , et al \nImmune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management\n. ESMO Open \n2018 ;3 :e000278. 10.1136/esmoopen-2017-000278 \n29387476 \n26 \nPubMed \nImmune-Related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies\n. Available: https://pubmed.ncbi.nlm.nih.gov/31361907-immune-related-adverse-events-in-the-gastrointestinal-tract-diagnostic-utility-of-upper-gastrointestinal-biopsies/?from_single_result=31361907 [Accessed 3 Mar 2020 ].\n27 \nRust C , Kooy Y , Peña S , et al \nPhenotypical and functional characterization of small intestinal TcR gamma delta + T cells in coeliac disease\n. Scand J Immunol \n1992 ;35 :459 –68\n. 10.1111/j.1365-3083.1992.tb02881.x \n1532668 \n28 \nDunne MR , Elliott L , Hussey S , et al \nPersistent changes in circulating and intestinal γδ T cell subsets, invariant natural killer T cells and mucosal-associated invariant T cells in children and adults with coeliac disease\n. PLoS One \n2013 ;8 :e76008. 10.1371/journal.pone.0076008 \n24124528 \n29 \nNijeboer P , van Gils T , Reijm M , et al \nGamma-Delta T lymphocytes in the diagnostic approach of coeliac disease\n. J Clin Gastroenterol \n2019 ;53 :e208 –13\n. 10.1097/MCG.0000000000001060 \n29782465 \n30 \nKonkel JE , Frommer F , Leech MD , et al \nPD-1 signalling in CD4(+) T cells restrains their clonal expansion to an immunogenic stimulus, but is not critically required for peptide-induced tolerance\n. Immunology \n2010 ;130 :92 –102\n. 10.1111/j.1365-2567.2009.03216.x \n20113370 \n31 \nReynoso ED , Elpek KG , Francisco L , et al \nIntestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade\n. J Immunol \n2009 ;182 :2102 –12\n. 10.4049/jimmunol.0802769 \n19201863 \n32 \nFife BT , Bluestone JA \nControl of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways\n. Immunol Rev \n2008 ;224 :166 –82\n. 10.1111/j.1600-065X.2008.00662.x \n18759926 \n33 \nDumoulin FL , Leifeld L , Sauerbruch T , et al \nAutoimmunity induced by interferon-alpha therapy for chronic viral hepatitis\n. Biomed Pharmacother \n1999 ;53 :242 –54\n. 10.1016/S0753-3322(99)80095-X \n10424246 \n34 \nCammarota G , Cuoco L , Cianci R , et al \nOnset of coeliac disease during treatment with interferon for chronic hepatitis C\n. Lancet \n2000 ;356 :1494 –5\n. 10.1016/S0140-6736(00)02880-4 \n11081540 \n35 \nBlecker D , Abraham S , Furth EE , et al \nMelanoma in the gastrointestinal tract\n. Am J Gastroenterol \n1999 ;94 :3427 –33\n. 10.1111/j.1572-0241.1999.01604.x \n10606298 \n36 \nEshet Y , Baruch EN , Shapira-Frommer R , et al \nClinical significance of pancreatic atrophy induced by Immune-Checkpoint inhibitors: a case-control study\n. Cancer Immunol Res \n2018 ;6 :1453 –8\n. 10.1158/2326-6066.CIR-17-0659 \n30275274\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "8(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "costimulatory and inhibitory T-cell receptors; immunotherapy; inflammation",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D000368:Aged; D001706:Biopsy; D002446:Celiac Disease; D003937:Diagnosis, Differential; D003967:Diarrhea; D004382:Duodenitis; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007108:Immune Tolerance; D007413:Intestinal Mucosa; D007421:Intestine, Small; D008297:Male; D008871:Microvilli; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32581063",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24124528;31383006;30518410;18759926;30519552;19201863;30115704;29045560;29320654;29387476;20113370;1532668;26783344;31217020;31331324;29517954;10606298;23541015;31053497;29782465;10424246;31694890;22345659;23252527;31895048;30131322;28810029;11081540;31361907;31800340;31699151;31737699;29567705;30275274;26090475",
"title": "Immune checkpoint inhibitor-associated celiac disease.",
"title_normalized": "immune checkpoint inhibitor associated celiac disease"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-060350",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "BACKGROUND\nEncapsulating peritoneal sclerosis (EPS) is the most severe complication of peritoneal dialysis (PD). Several retrospective reports published between 2007 and 2009 have suggested an increasing incidence of EPS occurring after kidney transplantation. We conducted a prospective observational study to determine the incidence of post-transplantation EPS and identify possible risk factors.\n\n\nMETHODS\nConsecutive PD patients undergoing kidney transplantation between 2009 and 2013 were included. Encapsulating peritoneal sclerosis was defined as gastrointestinal obstruction combined with radiological evidence of EPS. Gastrointestinal symptoms were assessed using a self-administered Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. Abdominal computed tomography (CT) was performed prospectively at 6 and 18 months post-transplantation. The primary end point was EPS during follow-up.\n\n\nRESULTS\nFifty-three PD patients were included (age 51 ± 14 years). Mean PD duration was 31.3 months. Peritoneal dialysis solutions low in glucose degradation products and icodextrin were used by 86.8% of patients. A fast or average-fast transport status was documented in 83.0%. After a median follow-up of 19 months, complete data of 47 patients were available for analysis. None of the patients developed clinical or radiological signs of EPS. The GSRS score improved from 1.87 to 1.55 (p = 0.024) and body weight increased from 75.9 to 78.3 kg (p = 0.003). Only 1 patient had new onset localized (< 20%) peritoneal thickening on CT 22 months post-transplantation.\n\n\nCONCLUSIONS\nPost-transplantation EPS did not develop in this cohort of patients with a relatively short time of PD exposure. This suggests that these patients can be transplanted safely without concern for the development of EPS, at least within the follow-up period of 19 months.",
"affiliations": "Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands A.C.Abrahams@umcutrecht.nl.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.",
"authors": "Abrahams|Alferso C|AC|;van Gelder|Maaike K|MK|;van der Veer|Jan Willem|JW|;de Jong|Pim A|PA|;van Leeuwen|Maarten S|MS|;Boer|Walther H|WH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3747/pdi.2016.00238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8608",
"issue": "37(4)",
"journal": "Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis",
"keywords": "Encapsulating peritoneal sclerosis; abdominal CT scan; gastrointestinal symptom rating scale; kidney transplantation; peritoneal dialysis",
"medline_ta": "Perit Dial Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010530:Peritoneal Dialysis; D056627:Peritoneal Fibrosis; D011183:Postoperative Complications; D011446:Prospective Studies; D012307:Risk Factors",
"nlm_unique_id": "8904033",
"other_id": null,
"pages": "443-450",
"pmc": null,
"pmid": "28676511",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Absence of Post-Transplantation Encapsulating Peritoneal Sclerosis after Relatively Short Exposure to Peritoneal Dialysis: Prospective Analysis Using Repeated Abdominal CT Scanning.",
"title_normalized": "absence of post transplantation encapsulating peritoneal sclerosis after relatively short exposure to peritoneal dialysis prospective analysis using repeated abdominal ct scanning"
} | [
{
"companynumb": "NL-ASTELLAS-2017US037681",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Acquired factor V deficiency is a rare condition associated with a wide variety of causes. We herein report the case of a 75-year-old man who developed acquired factor V deficiency associated with gastrointestinal bleeding after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma. Laboratory data revealed prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) and a significant reduction in the factor V (FV) activity. Infusion of fresh-frozen plasma (FFP) was unable to correct the prolonged PT and APTT. Four weeks after onset, his coagulation parameters improved spontaneously with no particular treatment. The patient developed acquired FV deficiency after TACE treatment using cisplatin, and thus, cisplatin was suspected as the cause of this coagulopathy. If coagulopathy that is not corrected by FFP transfusion after TACE is observed, acquired factor V deficiency, although extremely rare, should be considered.",
"affiliations": "1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;2Division of Infection Diseases, Department of Hematology, Rheumatology and Clinical Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.;1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556 Japan.",
"authors": "Yamane|Taishi|T|;Imai|Katsunori|K|;Uchiba|Mitsuhiro|M|;Umezaki|Naoki|N|;Yamao|Takanobu|T|;Kaida|Takayoshi|T|;Nakagawa|Shigeki|S|;Hashimoto|Daisuke|D|;Yamashita|Yo-Ichi|YI|;Chikamoto|Akira|A|;Yoshida|Naoya|N|;Baba|Hideo|H|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-017-0290-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "6(3)",
"journal": "International cancer conference journal",
"keywords": "Acquired factor V deficiency; Hepatocellular carcinoma; Transcatheter arterial chemoembolization",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "126-130",
"pmc": null,
"pmid": "31149486",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports",
"references": "10097809;10218762;11896308;16138334;19404538;21052780;27428013;7082847",
"title": "Acquired factor V deficiency following transcatheter arterial chemoembolization for hepatocellular carcinoma: a case report.",
"title_normalized": "acquired factor v deficiency following transcatheter arterial chemoembolization for hepatocellular carcinoma a case report"
} | [
{
"companynumb": "JP-ACCORD-057137",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Caffeine is the most commonly used central nervous system stimulant. While it has a high LD50 (150-200 mg/kg), when ingested in significant quantity, caffeine can lead to severe and even lethal side effects. Manifestation of toxicity include tachyarrhythmias, seizures, and metabolic derangements which can eventually lead to cardiovascular collapse and death. Studies have shown that lethal doses of caffeine (80-100 μg/mL) can be seen with the ingestion of approximately 10 g of caffeine. Due to the low number of reported cases, there is no consensus on the standard of care for treatment of suspected caffeine overdose. This case details a 39-year-old male who presented to the emergency department (ED) after having ingested 50 g of caffeine. Despite a high dose esmolol infusion, the patient exhibited worsening tachyarrhythmias. Hemodialysis was started empirically given the known amount ingested and ongoing hemodynamic perturbations. Initial pre-dialysis caffeine level was found to be 254 μg/ml. After treatment with two sessions of hemodialysis the patient's caffeine level decreased dramatically. We believe this is the first case report to demonstrate the success of preemptive hemodialysis, prior to cardiovascular collapse and/or renal failure, in a case of caffeine overdose and should be considered very early in patients presenting with recent toxic ingestion.",
"affiliations": "Division of Critical Care Medicine, Jefferson Northeast Hospital, United States. Electronic address: Benjamin.kohl@jefferson.edu.;Department of Emergency Medicine, Jefferson Northeast Hospital, United States. Electronic address: kuljit.kaur@jefferson.edu.;Division of Critical Care Medicine, Jefferson Northeast Hospital, United States.;Department of Emergency Medicine, Jefferson Northeast Hospital, United States.;Department of Emergency Medicine, Jefferson Northeast Hospital, United States.;Department of Emergency Medicine, Jefferson Northeast Hospital, United States.",
"authors": "Kohl|Benjamin A|BA|;Kaur|Kuljit|K|;Dincher|Nathan|N|;Schumann|Jessica|J|;Carachilo|Tara|T|;Komurek|Christopher|C|",
"chemical_list": "D000697:Central Nervous System Stimulants; D002110:Caffeine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.09.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "38(3)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D002110:Caffeine; D000697:Central Nervous System Stimulants; D062787:Drug Overdose; D006801:Humans; D008297:Male; D006435:Renal Dialysis; D013406:Suicide, Attempted",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "692.e1-692.e3",
"pmc": null,
"pmid": "31785982",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute intentional caffeine overdose treated preemptively with hemodialysis.",
"title_normalized": "acute intentional caffeine overdose treated preemptively with hemodialysis"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-232312",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAFFEINE"
},
"drugad... |
{
"abstract": "Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndromes and sudden cardiac death. The epidemiology, pathogenesis, and optimal approaches to diagnosis and management are poorly understood. Additionally, SCAD as a syndrome is commonly under-recognized and its prognosis is not well studied. Guidelines on management of SCAD have not yet been established. We present three cases of SCAD that varied in their clinical presentation and describe the different management strategies utilized. This is followed by a review of the clinical features, epidemiology, prognosis, and potential treatment strategies for patients presenting with SCAD.",
"affiliations": "Baylor University Medical Center, Division of Cardiology, Dallas, TX; Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX.;Baylor University Medical Center, Division of Cardiology, Dallas, TX.;Baylor University Medical Center, Division of Cardiology, Dallas, TX; Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX; Texas A&M College of Medicine, Bryan, TX.;Baylor University Medical Center, Division of Cardiology, Dallas, TX; Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX; Texas A&M College of Medicine, Bryan, TX; The Heart Hospital, Plano, TX.;Baylor University Medical Center, Division of Cardiology, Dallas, TX; Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX; Texas A&M College of Medicine, Bryan, TX.",
"authors": "Afzal|Aasim|A|;Sarmast|Syed|S|;Choi|James W|JW|;McCullough|Peter A|PA|;Schussler|Jeffrey M|JM|",
"chemical_list": "D002317:Cardiovascular Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-6550",
"issue": "18(1)",
"journal": "Reviews in cardiovascular medicine",
"keywords": null,
"medline_ta": "Rev Cardiovasc Med",
"mesh_terms": "D000328:Adult; D002317:Cardiovascular Agents; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D003330:Coronary Vessel Anomalies; D054855:Drug-Eluting Stents; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D062645:Percutaneous Coronary Intervention; D012307:Risk Factors; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional; D014652:Vascular Diseases; D055815:Young Adult",
"nlm_unique_id": "100960007",
"other_id": null,
"pages": "29-36",
"pmc": null,
"pmid": "28509891",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Spontaneous Coronary Artery Dissection: A Review of Pathogenesis, Presentations, Treatment, and Outcomes.",
"title_normalized": "spontaneous coronary artery dissection a review of pathogenesis presentations treatment and outcomes"
} | [
{
"companynumb": "US-SHIRE-US201830685",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LISDEXAMFETAMINE DIMESYLATE"
},
"drugadditional": ... |
{
"abstract": "Several chemotherapy regimens have been used as second-line therapies for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). None have emerged as a preferred regimen. This retrospective study aimed to identify a regimen with high efficacy and low toxicity for patients with relapsed and refractory DLBCL. Fifty-eight patients diagnosed with relapsed or refractory DLBCL were included in the study. Patients were treated with cyclophosphamide, vindesine, cytarabine, dexamethasone and bleomycin (COAD-B). The overall response rate (ORR) was 70.7%, and the median remission duration was 13 months (3-48 months). The 1-, 2- and 4-year overall survival rates were 62.4%, 45.7% and 34.6%, respectively. The 1-, 2- and 4-year progression-free survival rates were 50.0%, 36.7% and 20.7%, respectively. The responses of patients with relapsed DLBCL to COAD-B were significantly better than those of patients with refractory DLBCL (p = 0.005). The main adverse reaction of patients was myelosuppression. Our data indicate that COAD-B should be used in treatment of patients with relapsed DLBCL.",
"affiliations": "Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , China.",
"authors": "Li|Minghui|M|;Li|Yufu|Y|;Yin|Qingsong|Q|;Mi|Ruihua|R|;Chen|Lin|L|;Du|Jianwei|J|;Wei|Xudong|X|",
"chemical_list": "D003561:Cytarabine; D001761:Bleomycin; D003907:Dexamethasone; D003520:Cyclophosphamide; D014751:Vindesine",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2013.848984",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "55(7)",
"journal": "Leukemia & lymphoma",
"keywords": "COAD-B regimen; Diffuse large B-cell lymphoma; chemotherapy; survival rate",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003520:Cyclophosphamide; D003561:Cytarabine; D003907:Dexamethasone; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome; D014751:Vindesine; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1578-83",
"pmc": null,
"pmid": "24070424",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment with cyclophosphamide, vindesine, cytarabine, dexamethasone and bleomycin in patients with relapsed/refractory diffuse large B-cell lymphoma.",
"title_normalized": "treatment with cyclophosphamide vindesine cytarabine dexamethasone and bleomycin in patients with relapsed refractory diffuse large b cell lymphoma"
} | [
{
"companynumb": "CN-BAXTER-2014BAX042937",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINDESINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nClinical features of systemic lupus erythematosus (SLE) have been described from different geographical regions in the world. The aim of this study was to obtain local and contemporary data on all-cause hospitalizations of SLE patients in an Israeli Medical Center.\n\n\nMETHODS\nThis is a retrospective observational single-center study. Revision of medical records of hospitalized lupus patients during 5-year period (January 2012-December 2016) was performed.\n\n\nRESULTS\nA total of 61 lupus patients and 138 hospitalizations were identified. Female-to-male ratio was 9:1. Average age was 42.5 years. Average disease duration was 14.58 years. Mean SLICC/ACR damage index was 0.75. The majority of patients were treated with lupus medications (47, 77%). The most common lupus medications were hydroxychloroquine (40, 65.5%), prednisone (25, 40.9%), and azathioprine (9, 14.75%). The most common reasons for hospitalization were disease flare (28, 20.3%), pregnancy and labor (26, 18.9%), and infection (19, 13.8%). The average length of hospitalization for all patients was 6.65 days. No fetal morbidity was recorded, and there was one event of maternal morbidity. There were no cases of acute coronary events. There were six ICU admissions (4.35%). Two admissions (1.45%) were complicated by hospital-acquired infection. Three patients died (2.17%) during hospital stay.\n\n\nCONCLUSIONS\nThis survey from a single Israeli medical center revealed low rates of pregnancy complications, coronary events, and nosocomial infections in hospitalized lupus patients. Further studies are required to determine whether these findings reflect local disease expression or it may remark global trend of decrease in lupus complications.",
"affiliations": "Internal Medicine B, Rheumatology Unit, Assaf Harofeh Medical Center, Be'er Ya'akov, Israel. oferl@asaf.health.gov.il.;Internal Medicine B, Rheumatology Unit, Assaf Harofeh Medical Center, Be'er Ya'akov, Israel.;Internal Medicine B, Rheumatology Unit, Assaf Harofeh Medical Center, Be'er Ya'akov, Israel.;Internal Medicine B, Rheumatology Unit, Assaf Harofeh Medical Center, Be'er Ya'akov, Israel.;Internal Medicine B, Rheumatology Unit, Assaf Harofeh Medical Center, Be'er Ya'akov, Israel.;Internal Medicine B, Rheumatology Unit, Assaf Harofeh Medical Center, Be'er Ya'akov, Israel.",
"authors": "Levy|Ofer|O|http://orcid.org/0000-0003-2606-7484;Markov|Andrey|A|http://orcid.org/0000-0002-0397-9918;Drob|Yulia|Y|http://orcid.org/0000-0002-3008-9806;Maslakov|Ilia|I|http://orcid.org/0000-0002-0558-2463;Tishler|Moshe|M|http://orcid.org/0000-0002-9570-7986;Amit-Vazina|Mirit|M|http://orcid.org/0000-0002-9654-4429",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-018-4147-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "38(10)",
"journal": "Rheumatology international",
"keywords": "Acute coronary syndrome; Hospitalization; Nosocomial infection; Pregnancy; Systemic lupus erythematosus",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000328:Adult; D005260:Female; D017052:Hospital Mortality; D006760:Hospitalization; D006801:Humans; D007557:Israel; D007902:Length of Stay; D008180:Lupus Erythematosus, Systemic; D008297:Male; D012017:Referral and Consultation; D012189:Retrospective Studies",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1841-1846",
"pmc": null,
"pmid": "30151719",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "1442853;26087254;23307831;26043954;27000153;24048215;25396063;26731012;2585886;25535200;1464868;29224680;29050537;25110993;26784479;19103632;9048514;25182206;19884213;1941820;16142865;28620060",
"title": "All-cause hospitalizations in systemic lupus erythematosus from a single medical center in Israel.",
"title_normalized": "all cause hospitalizations in systemic lupus erythematosus from a single medical center in israel"
} | [
{
"companynumb": "IL-ROCHE-2189019",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "The relative efficacy and safety of first-line metastatic colorectal cancer (mCRC) treatment regimens, capecitabine with irinotecan (CAPIRI) and 5-fluorouracil/leucovorin plus irinotecan (FOLFIRI), are not well defined. We identified and subsequently examined seven independent, randomized controlled clinical trials, performing a meta-analysis to compare these two treatment regimens. Using Medline, EMBASE, Cochrane Library (CENTRAL), and the American Society of Clinical Oncology Annual Meeting to search available literature until February 2014, we identified seven studies comparing safety and efficacy of CAPIRI and FOLFIRI in mCRC patients. These studies were pooled and evaluated for rates of progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and diarrhea. CAPIRI and FOLFIRI demonstrated similar efficacy outcomes, though CAPIRI was associated with a higher incidence of diarrhea. CAPIRI and FOLFIRI are equally effective options for first-line treatment of mCRC.",
"affiliations": "Department of Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai, 200080, People's Republic of China.",
"authors": "Ding|Hong-hua|HH|;Wu|Wei-dong|WD|;Jiang|Tao|T|;Cao|Jun|J|;Ji|Zheng-yi|ZY|;Jin|Jia-hua|JH|;Wang|Jing-jue|JJ|;Song|Wei-feng|WF|;Wang|Li-wei|LW|",
"chemical_list": "D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s13277-014-2970-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-4283",
"issue": "36(5)",
"journal": "Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine",
"keywords": null,
"medline_ta": "Tumour Biol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D003841:Deoxycytidine; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D009362:Neoplasm Metastasis; D017594:Publication Bias",
"nlm_unique_id": "8409922",
"other_id": null,
"pages": "3361-9",
"pmc": null,
"pmid": "25534239",
"pubdate": "2015-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't",
"references": "9440757;18065406;11689577;22748098;22240792;23463625;23352604;19386096;24574764;11304782;15763604;22349811;19622512;22237781;19955859;23725128;10744089;20920997;23413162;17947725;17630036",
"title": "Meta-analysis comparing the safety and efficacy of metastatic colorectal cancer treatment regimens, capecitabine plus irinotecan (CAPIRI) and 5-fluorouracil/leucovorin plus irinotecan (FOLFIRI).",
"title_normalized": "meta analysis comparing the safety and efficacy of metastatic colorectal cancer treatment regimens capecitabine plus irinotecan capiri and 5 fluorouracil leucovorin plus irinotecan folfiri"
} | [
{
"companynumb": "GR-CIPLA LTD.-2015GR00271",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo assess spontaneous reports of suspected adverse drug reactions in children aged 0-12 years from the Brazilian Health Regulatory Agency between 2008 and 2013.\n\n\nMETHODS\nA cross-sectional study on suspected adverse drug reactions reports related to medicines and health products in children was carried out for a six-year period (2008-2013). Year of report, origin of report by Brazilian state, gender, age, suspected drug, adverse reaction description and seriousness were included in the analysis. The data obtained was compared to the number of pediatric beds in health services and to global data from the VigiBase (World Health Organization).\n\n\nRESULTS\nA total of 3330 adverse drug reactions were reported in children in Brazil in the investigated period (54% were in boys). About 28% of suspected adverse drug reactions reports involved 0 to 1-year-old children. Almost 40% of reports came from the Southeast region. Approximately 60% were classified as serious events. There was death in 75 cases. Nearly 30% of deaths involved off-label use; 3875 medicines (465 active substances) were considered suspected drugs. Anti-infective (vancomycin, ceftriaxone, oxacillin, and amphotericin), nervous system (metamizole) and alimentary tract and metabolism medicines were more frequent in reports.\n\n\nCONCLUSIONS\nThe distribution of suspected adverse drug reactions reports by sex and age group corresponded to the profile of children hospitalized in Brazil. Data about seriousness and medicines reported may be useful to encourage regulatory actions and improve the safe use of medicines in children.",
"affiliations": "Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Observatório de Vigilância e Uso de Medicamentos, Rio de Janeiro, RJ, Brazil. Electronic address: elisangela@pharma.ufrj.br.;Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Observatório de Vigilância e Uso de Medicamentos, Rio de Janeiro, RJ, Brazil.;Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Programa de Pós Graduação em Ciência e Tecnologia Farmacêutica, Rio de Janeiro, RJ, Brazil.;Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Programa de Pós Graduação em Ciência e Tecnologia Farmacêutica, Rio de Janeiro, RJ, Brazil.;Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Observatório de Vigilância e Uso de Medicamentos, Rio de Janeiro, RJ, Brazil.;University of Liverpool, Institute of Translational Medicine, Department of Women's & Children's Health, Liverpool, United Kingdom.",
"authors": "Lima|Elisangela da Costa|EDC|;Matos|Guacira Corrêa de|GC|;Vieira|Jean M de L|JML|;Gonçalves|Ivana C da C R|ICDCR|;Cabral|Lucio M|LM|;Turner|Mark A|MA|",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "Brazil",
"delete": false,
"doi": "10.1016/j.jped.2018.05.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-7557",
"issue": "95(6)",
"journal": "Jornal de pediatria",
"keywords": "Adverse reactions; Children; Crianças; Database study reporting; Drug monitoring; Farmacoepidemiologia; Monitoramento de medicamentos; Pediatria; Pediatrics; Pharmacoepidemiology; Reações adversas; Relato de estudo de banco de dados",
"medline_ta": "J Pediatr (Rio J)",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D017677:Age Distribution; D000367:Age Factors; D001938:Brazil; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D004364:Pharmaceutical Preparations; D012737:Sex Factors",
"nlm_unique_id": "2985188R",
"other_id": null,
"pages": "682-688",
"pmc": null,
"pmid": "30030984",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Suspected adverse drug reactions reported for Brazilian children: cross-sectional study.",
"title_normalized": "suspected adverse drug reactions reported for brazilian children cross sectional study"
} | [
{
"companynumb": "BR-JNJFOC-20191245249",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Acute promyelocytic leukemia (APL) accounts for 8% to 10% of cases of acute myeloid leukemia (AML). Remission in cases of high-risk APL is still difficult to achieve, and relapses occur readily.\nHere, we describe a case of APL with high white blood cell counts in blood tests and hypogranular variant morphology in bone marrow, together with fms-like tyrosine kinase-3 with internal tandem duplication mutations (FLT3-ITD), and bcr-3 isoform of PML-RARα. Most importantly, we detected high level of Wilms' tumor gene (WT1) in marrow blasts, through the reverse transcription polymerase chain reaction (RT-PCR). To date, no clear conclusions about an association between WT1 expression levels and APL have been reached. This patient successively received a combined treatment regimen consisting of hydroxycarbamide, arsenic trioxide and idarubicin plus cytarabine, which ultimately enabled complete remission. Unfortunately, he subsequently died of sudden massive hemoptysis because of pulmonary infection.\nBased on our findings and a review of the literature, abnormal functioning of WT1 may be a high-risk factor in cases of APL. Further studies aimed towards evaluating the impact of WT1 expression on the prognosis for APL patients are of interest.",
"affiliations": "MD, PhD. Professor, Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.;MD. Attending Physician, Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.;MD. Affiliated Professor, Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.;MD, PhD. Full Professor, Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.;MD, PhD. Assistant Professor, Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.",
"authors": "Zhang|Xi|X|;Yang|Cheng|C|;Peng|Xiangui|X|;Chen|Xinghua|X|;Feng|Yimei|Y|",
"chemical_list": "D051941:fms-Like Tyrosine Kinase 3; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1516-3180.2016.020104102016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1516-3180",
"issue": "135(2)",
"journal": "Sao Paulo medical journal = Revista paulista de medicina",
"keywords": null,
"medline_ta": "Sao Paulo Med J",
"mesh_terms": "D000328:Adult; D016162:Genes, Wilms Tumor; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D051562:Proto-Oncogene Proteins c-bcr; D012307:Risk Factors; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "100897261",
"other_id": null,
"pages": "179-184",
"pmc": null,
"pmid": "28125133",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute WT1-positive promyelocytic leukemia with hypogranular variant morphology, bcr-3 isoform of PML-RARα and Flt3-ITD mutation: a rare case report.",
"title_normalized": "acute wt1 positive promyelocytic leukemia with hypogranular variant morphology bcr 3 isoform of pml rar and flt3 itd mutation a rare case report"
} | [
{
"companynumb": "BR-TEVA-769497ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARSENIC TRIOXIDE"
},
"drugadditional": "3",
... |
{
"abstract": "A 24-year-old woman with 21-hydroxylase deficient classic congenital adrenal hyperplasia, simple virilising form presented with secondary infertility. One year ago she had a spontaneous miscarriage in the second trimester of pregnancy. This time she conceived with prednisolone 5 mg and clomiphene citrate 100 mg. She was then continued with prednisolone during pregnancy. She had a spontaneous preterm delivery at 33 weeks. There was a marginal increase in the dose of prednisolone during pregnancy. There was no worsening of insulin resistance during pregnancy despite prednisolone administration. A normal healthy female infant was born and is being followed up on for ill-effects, if any, of maternal glucocorticoid administration during pregnancy. The baby girl has normal female external genitalia.",
"affiliations": "Department of Gynaecology, Chotu Ram Hospital, Rohtak, Haryana, India.",
"authors": "Jain|Deepti|D|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000312:Adrenal Hyperplasia, Congenital; D005260:Female; D005298:Fertility; D005938:Glucocorticoids; D006801:Humans; D050498:Live Birth; D011239:Prednisolone; D011247:Pregnancy; D011248:Pregnancy Complications; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24252839",
"pubdate": "2013-11-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23391953;11678836;10084573;16279367;18420648",
"title": "Fertility and pregnancy outcome in a woman with classic congenital adrenal hyperplasia.",
"title_normalized": "fertility and pregnancy outcome in a woman with classic congenital adrenal hyperplasia"
} | [
{
"companynumb": "IN-MYLANLABS-2016M1017476",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Mucormycosis has emerged as an important cause of invasive fungal infection in patients with hematologic malignancies. Gastrointestinal mucormycosis is an unusual presentation of this invasive fungal infection, and it causes considerable morbidity and mortality. Such outcomes are due in part to a nonspecific presentation that results in delays in diagnosis and treatment. Successful treatment of gastrointestinal mucormycosis involves surgical debridement and appropriate antifungal therapy.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, and.;Medical Oncology, Leukemia Service, Princess Margaret Cancer Centre, University Health Network; and.;Medical Oncology, Leukemia Service, Princess Margaret Cancer Centre, University Health Network; and.;Division of Infectious Diseases, Department of Medicine, and; Multi-Organ Transplant Program, University of Toronto, Toronto, ON.",
"authors": "Alghamdi|A|A|;Lutynski|A|A|;Minden|M|M|;Rotstein|C|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3747/co.24.3522",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-0052",
"issue": "24(1)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Mucormycosis, gastrointestinal; hemicolectomy",
"medline_ta": "Curr Oncol",
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"nlm_unique_id": "9502503",
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"pages": "e61-e64",
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"pubdate": "2017-02",
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"title": "Successful treatment of gastrointestinal mucormycosis in an adult with acute leukemia: case report and literature review.",
"title_normalized": "successful treatment of gastrointestinal mucormycosis in an adult with acute leukemia case report and literature review"
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"abstract": "Rivaroxaban is an oral anticoagulant approved for prevention of stroke, as well as for the treatment and prevention of venous thromboembolic disease. Hemopericardium is a serious complication of anticoagulant use, which has been reported with oral vitamin-K antagonists and newer oral anticoagulants. At the time of this report, to my knowledge, there are no published reports of hemorrhagic effusion leading to tamponade associated with a Factor Xa Inhibitor. I report a case of hemopericardium with associated tamponade in a patient who developed pericarditis while being treated with Rivaroxaban. The case highlights an important adverse effect of a newer anticoagulant, as well as the particular dangers of medication co-administration in the elderly.",
"affiliations": null,
"authors": "Boone|Stephen|S|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban",
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"issn_linking": "0011-7781",
"issue": "87(7)",
"journal": "Delaware medical journal",
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"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D002305:Cardiac Tamponade; D065427:Factor Xa Inhibitors; D006801:Humans; D008297:Male; D009025:Morpholines; D010493:Pericarditis; D000069552:Rivaroxaban; D013876:Thiophenes",
"nlm_unique_id": "0370077",
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"pages": "206-7",
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"pmid": "26285318",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cardiac Tamponade Associated with Rivaroxaban.",
"title_normalized": "cardiac tamponade associated with rivaroxaban"
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"abstract": "Gender dysphoria can present as a positive symptom of schizophrenia. Completion of gender affirmation surgeries should not occur as a result of male genital self-mutilation via a deferral of emergent surgical reconstruction. Instead, gender affirmation should be considered after a full workup and assessment for resolution of any acute psychosis.",
"affiliations": "Department of Urology New York Presbyterian Hospital Weill Cornell Medical College New York NY USA.;Department of Urology New York Presbyterian Hospital Weill Cornell Medical College New York NY USA.;Arthur Smith Institute for Urology Northwell Health Great Neck NY USA.",
"authors": "Wilcox Vanden Berg|Rand N|RN|https://orcid.org/0000-0002-5972-9897;Gaffney|Christopher D|CD|;Paduch|Darius A|DA|",
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"doi": "10.1002/ccr3.2935",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2935\nCCR32935\nCase Report\nCase Reports\nPresentation and resolution of gender dysphoria as a positive symptom in a young schizophrenic man who presented with self‐emasculation: Frontiers of bioethics, psychiatry, and microsurgical genital reconstruction\nWILCOX VANDEN BERG et al.Wilcox Vanden Berg Rand N. https://orcid.org/0000-0002-5972-9897\n1\n Gaffney Christopher D. \n1\n Paduch Darius A. dpaduch@northwell.edu \n2\n\n3\n \n1 \nDepartment of Urology\nNew York Presbyterian Hospital\nWeill Cornell Medical College\nNew York\nNY\nUSA\n\n\n2 \nArthur Smith Institute for Urology\nNorthwell Health\nGreat Neck\nNY\nUSA\n\n\n3 \nConsulting Research Services, Inc\nNorth Bergen\nNJ\nUSA\n\nCorrespondence\n\nDarius A. Paduch, Arthur Smith Institute for Urology, Northwell Health, 1000 Northern Boulevard, Suite 120, Great neck, NY 11021, USA.\n\nEmail: dpaduch@northwell.edu\n\n28 7 2020 \n9 2020 \n8 9 10.1002/ccr3.v8.91735 1740\n28 8 2019 24 2 2020 24 4 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nGender dysphoria can present as a positive symptom of schizophrenia. Completion of gender affirmation surgeries should not occur as a result of male genital self‐mutilation via a deferral of emergent surgical reconstruction. Instead, gender affirmation should be considered after a full workup and assessment for resolution of any acute psychosis.\n\nGender dysphoria can present as a positive symptom of schizophrenia. Completion of gender affirmation surgeries should not occur as a result of male genital self‐mutilation via a deferral of emergent surgical reconstruction. Instead, gender affirmation should be considered after a full workup and assessment for resolution of any acute psychosis.\n\n\ngender dysphoriapenisschizophreniaself‐amputationself‐castration source-schema-version-number2.0cover-dateSeptember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.1 mode:remove_FC converted:17.09.2020\n\n\nWilcox Vanden Berg \nRN \n, \nGaffney \nCD \n, \nPaduch \nDA \n. Presentation and resolution of gender dysphoria as a positive symptom in a young schizophrenic man who presented with self‐emasculation: Frontiers of bioethics, psychiatry, and microsurgical genital reconstruction\n. Clin Case Rep . 2020 ;8 :1735 –1740\n. 10.1002/ccr3.2935\n==== Body\n1 INTRODUCTION\nMale genital mutilations and modifications (MGMM) have been documented since antiquity and are still practiced globally.\n1\n In our practice, we classify MGMM as circumcision, amputation of the glans penis, amputation of the penile shaft (ie, penectomy), castration (ie, orchiectomy), removal of the skin of the scrotum (ie, scrotectomy), complete emasculation (ie, removal of the scrotal skin, penis, and testes), and other (eg. penile and scrotal piercing, subdermal foreign bodies, incisions of the urethra). Anthropologically, MGMM are often described as a rite of passage from boyhood to adulthood (eg, circumcision in adolescent boys in Africa), or as a sign of belonging to specific group (eg, Hijra and Skoptsy), and are either performed willingly or by the will of the parents/tribe.\n2\n In this paper, we will focus self‐performed MGMM as they present a multidisciplinary challenge.\n\nPenile amputation is most commonly due to accidental trauma, but it can also be a result of assault, iatrogenic causes such as during circumcision, or rarely as a form of self‐mutilation for religious reasons.\n3\n, \n4\n Due to the low incidence of traumatic penile amputation (TPA), most of our knowledge is derived from case reports with the largest series reported in Thailand during a string of domestic violence toward unfaithful husbands.\n5\n When not occurring for religious reasons, penile amputation is a surgical emergency requiring reattachment of the phallus with water tight urethroplasty to allow for voiding while standing and preservation of penile tissue for penetrative sexual intercourse.\n6\n\n\n\nSelf‐penile amputation and other forms of genital self‐mutilation (GSM) performed outside of religious reasons typically happen in the setting of mental illness, and in the third decade of life, more specifically, they often occur during an initial psychotic state or when a patient is not taking their medications.\n4\n, \n7\n, \n8\n For example, simultaneous self‐amputation and self‐castration is most often performed in the setting of schizophrenia.\n4\n\n\n\nGSM may be result of gender dysphoria in a patient unable to afford or qualify for gender affirmation surgery.\n9\n In the case of schizophrenia, convictions about belonging to the opposite sex may coexist with olfactory as well as sensory hallucinations within the genitals and are experienced by up to 20% of men with untreated schizophrenia. The patient experiences this as a sense of sexual abuse and believes that removing his own genitalia will relieve the unpleasant sensory input.\n10\n It is critical to make an appropriate decision before taking patient to the operating theater as the wrong surgical decision may have catastrophic consequences for the patient.\n\nWhen presented with GSM in the emergent setting in a patient with an acute psychosis, one must parse out the true underlying psychiatric disease or lack thereof. Such patients can present with gender dysphoria in conjunction with an acute psychosis or gender dysphoria as a positive sign of psychosis. As there are no established clinical pathways and consensus recommendations, such GSM presents logistic, bioethical, mental health, and legal challenges.\n\nWhen presented with GSM in a conscious patient claiming to be transgender and refusing organ reattachment, the treating team has a medico‐legal dilemma in assessing his mental disposition and legal competence. The patient's stated preference must be judged in the context of his psychiatric situation and consequences of refusing organ preservation.\n11\n\n\n\nUnfortunately, as the male genitalia are well perfused, bleed profusely, and thus require prompt intervention for organ preservation, this generally does not leave the requisite time to evaluate for true versus psychosis‐generated gender dysphoria. As a result, it is our opinion that in such cases, regardless of the patient's verbalized preference, the genitalia should be reattached as soon as possible.\n\nIn this report, we present a case of penile and testicular replantation in a patient with schizophrenia and auditory command hallucinations and gender dysphoria as a positive symptom of psychosis on presentation to the ED, which subsequently resolved completely with antipsychotics.\n\n2 CASE REPORT\nA 23‐year‐old male with a past medical history of Celiac disease, hypothyroidism, homelessness, and prior in‐patient treatments for schizophrenia presented to our institution after having amputated his penis, testicles, and most of his scrotum with a serrated knife. This was done in a public area, 20 minutes prior to arrival after taking two ibuprofens. The penile shaft, both testes, and scrotal skin were brought on ice with the patient by the EMT (Figure 1).\n\nFigure 1 Amputated penis, testicles, and scrotum. Distal penile stump was approximately 5 cm in length. Bilateral testes were amputated near the epididymides with approximately 3‐4 mm of spermatic cord stump remaining on the testicular side\n\nUpon arrival, the massive bleeding from the penile stump/groin was controlled by applying pressure with epinephrine‐socked gauze and the patient was stabilized according to trauma protocol. He denied hallucinations and suicidal ideations. He was withdrawn, had affective flattening, disorganized speech, and difficulties organizing his thoughts. He stated that he was homeless and was undergoing gender affirmation surgery but did not supply details. He did not want his penis to be re‐implanted nor his family to be informed. He had dramatically diminished sensation of pain given his injury. His toxicology screen was negative. On examination, his penis was amputated at the base. He was given a third‐generation cephalosporin and tetanus‐diphtheria‐acel pertussis vaccine. The prior psychiatric history of the patient could not be obtained at this time and was later hindered by the family's denial that he suffered from schizophrenia. The ED psychiatrist, the attending trauma surgeon, the reconstructive urologist (DAP), and the administrator‐on‐call all agreed that the patient was in an acute psychosis and lacked legal capacity to refuse emergent medical treatment. He was taken emergently to the operating room for microsurgical replantation. Aspirin therapy was started, and subcutaneous heparin (SQH) 5000 units TID was initiated. Prior to induction, he again stated that he was a transgender woman, refused reattachment, however, did desire for us to control the bleeding. Surgical details are described in the Appendix S1.\n\nAfter the index surgery, the patient was transferred to the surgical intensive care unit for graft perfusion monitoring. To increase penile perfusion, he was started on tadalafil 5 mg daily. Of note, the patient started to experience morning erections of the proximal and partial erections of the distal shaft within 2 weeks from reconstruction.\n\nPostoperative testosterone was 67 ng/dL, and he was started on replacement with testosterone enanthate IM 200 mg every 10 days. Given the contaminated nature of the wound, he was continued on IV antibiotics (switched to oral after 5 days and then continued for 6 days).\n\nGiven prior history of hypothyroidism, his thyroid function was evaluated; his thyroid‐stimulating hormone (TSH) was >150 uIU/mL and free T4 was 0.3 ng/dL. Levothyroxine was continued and increased to an appropriate dose.\n\nFive days after the index surgery, the patient developed classic venous skin congestion (Figure 2A) and twice‐daily medical leech therapy was initiated (one placed ventrally and once dorsally and allowed to imbibe until they fell off). This initially helped reduced the ecchymosis and hematoma (Figure 2B); however, it was stopped after 1 week when skin necrosis developed (Figure 2C). The SPY Fluorescence Imaging System (Stryker) confirmed no perfusion. As the penile skin started to form an eschar, wound care consisted of twice‐daily application of MediHoney gel (Derma Sciences) to eschar and Aquacel strips (ConvaTec) to exposed tissues. Daily bedside wound debridement was performed to remove necrotic skin and eschar.\n\nFigure 2 Medical leech therapy. A, Ecchymosis and hematoma as seen before initiation of therapy. B, Initial response to therapy. C, Development of necrosis with bullae\n\nTwo weeks after the index surgery, the patient underwent a retrograde urethrogram (RUG) showing no stricture nor extravasation (Figure 3); the Foley catheter was removed. He had no postvoid residual and voided without difficulty. Two weeks later, he was transferred to the psychiatric unit with continued local wound care awaiting eventual skin grafting. Prior to transfer to a psychiatric unit, the SQH and aspirin were discontinued and patient was started on pentoxifylline 400 mg TID to improve perfusion to penis.\n\nFigure 3 Retrograde Urethrogram. No evidence of stricture or extravasation\n\nApproximately 10 weeks after index injury, plastic surgery performed a 0.012”‐split‐thickness skin graft to the shaft using 110 cm2 from the lateral thigh, sutured in place with 4‐0 chromic interrupted sutures. The graft healed without any complications. Once the graft was fully epithelialized, the patient started using a penile pump daily to prevent the loss of penile length.\n\nFrom arrival in our ED, the psychiatry team was involved. He had been diagnosed with schizophrenia approximately 1 year prior but had not been compliant with his home antipsychotics (risperidone, later switched to paliperidone, and then long‐acting injectable paliperidone). He had a family history significant for suicide by multiple paternal relatives and father with bipolar disorder. Before his self‐mutilation, he had been a missing person while living undomiciled. He had a history of paranoid and persecutory delusions and suicidal ideations; there was no record of prior gender dysphoria. Daily assessment was performed by psychiatry and urology, and he was told that with improvement, he could be enrolled in a transgender program. After the index surgery, the patient initially stated that he had wanted gender affirmation surgery but had disorganized thoughts and poor understanding of his condition. Initially, he continued to endorse auditory hallucinations commanding him to amputate his genitalia; however, after the psychosis had resolved, he denied gender dysphoria. His antipsychotics were initially risperidone 1 mg twice daily and over the next 2 months up‐titrating to 8 mg twice daily and then cross‐tapered to clozapine 425 mg daily augmented with lithium 1200 mg daily until therapeutic levels met. He was discharged to a long‐term psychiatric facility on lithium 600 mg twice daily, clozapine 150 mg q‐AM and 275 mg QHS, and sertraline 150 mg q‐AM.\n\nThe patient presented for follow‐up at 12 months after the index surgery. He was still under psychiatric treatment. He denied being able to ejaculate; however, he was not self‐stimulating and denied sexual activity. The patient did endorse tumescence although it was not yet adequate for penetration. Penile sensation was present although reduced. The skin graft was well‐healed, the testis was palpable albeit atrophic, and the urethral meatus was patent (Figure 4). He was continued on testosterone replacement therapy (testosterone 339.7 ng/dL) and penile vacuum therapy. He was advised to use penile vibratory stimulation to help him reach orgasm if needed. He denied any gender dysphoria nor desire for gender affirmation surgery and identified himself as a heterosexual male.\n\nFigure 4 Penis at 1‐y follow up visit. A, Dorsal view, (B) left lateral view, (C) ventral view with patent meatus and scrotum\n\n3 DISCUSSION\nGSM involving removal of the penile shaft, both testes, and entire scrotal skin is extremely rare and most reported cases have been in the setting of psychosis.\n4\n Having first been reported by Krafft‐Ebing and Freud, patients with schizophrenia and delusions or desires of changing their sex or confusion about their sexual identity remain rare; such gender dysphoria as a positive symptom of schizophrenia is estimated at around 30%.\n12\n, \n13\n Interestingly, in patients who present with gender dysphoria as a positive symptom of schizophrenia, it dissipates with appropriate treatment as opposed to men with gender dysphoria and schizophrenia where it persists despite appropriate antipsychotics.\n10\n Awareness that acute gender dysphoria may be a sign of schizophrenia in patients presenting with GSM is critical for management. Only adequate control of schizophrenia, which can take months, and repeated evaluation of sexual identity over time can distinguish between “reactive” gender dysphoria or “true” gender dysphoria in a patient with mental illness. Thus, in an emergent situation, one must assume that the gender dysphoria is a positive symptom of the acute mental disorder. However, such approach is not without bioethical concerns.\n\nPatient autonomy to make medical decisions must be respected in patients with capacity. Legal competence is an integral part of patient autonomy; it requires mental capacity to reason and deliberate, hold appropriate values and goals, appreciate one's circumstances, understand the information given, and communicate the final decision. The principal of gravity of consequences justifies the escalating threshold for capacity required for legal competence in men with GSM.\n11\n In this case, the morbidity of following the patient's verbalized wishes (to complete the gender affirmation) would have been catastrophic, resulting in the irreversible loss of the genital function. While schizophrenia is associated with impaired decision‐making, the presence of mental illness does not always render the patient incapable of making their health care decisions; the provider use tools which have been developed to obtain consent in this vulnerable group such as MacArthur Competence Assessment Tool for Clinical Research.\n14\n This patient, however, lacked the ability to reason and appreciate consequences of his actions and therefore was unable to demonstrate that he had legal capacity. Therefore, despite his stated wish for gender affirmation surgery, the standards of transgender medicine dictate that physicians are to proceed with gender affirmation surgery only after the patient is free of psychiatric disorders such as psychosis or schizophrenia.\n15\n After proper psychiatric management, this patient's gender dysphoria resolved and further justified the replantation of the penis and testis.\n\nThe type of GSM can help elucidate the underlying psychiatric diagnosis. In a systematic review, Veeder and Leo found that while the severity of psychosis did not correlate with the degree of self‐injury, the diagnosis held by the patient did correlate with the type of injury. They found that in cases of self‐amputation, 58% had schizophrenia spectrum disorders (SSDs); in cases of self‐amputation and self‐castration, 52.9% had SSDs. Of note, this same group found that self‐castration alone was the most common form of GSM among truly transgender individuals with only 14.7% performing both castration and amputation.\n4\n Such complexity highlights the importance of close collaboration between the psychiatric service and reconstructive surgeon both the stabilization of the acute psychosis and the long‐term treatment.\n\nPrompt microsurgical replantation of the genitalia is crucial to meeting the goal of a functional, both for voiding and sexuality, and esthetic outcome.\n16\n, \n17\n While most literature focusing on small case series, small meta‐analyses have suggested that the best outcomes are achieved with decreased ischemia time and a microsurgical approach.\n18\n Ischemia time should be <16 hours, replantation should focus on a watertight urethral anastomosis, and the neurovascular anastomosis should preferably be done with a microsurgical approach.\n16\n, \n18\n, \n19\n In the presented case, the surgery was completed <12 hours after the injury.\n\nIn cases of successful penile replantation, complications are not rare. The case presented was complicated by testicular atrophy and venous congestion with superficial skin necrosis. Given the similarity in size between nonperfused testicular arteries and veins, and the loss of arterial flow to allow detection by microdoppler, testicular replantation remains technically difficult. This was further complicated by the location of the cut just proximal to the epididymis where the main testicular artery divides into sub‐millimeter branches. However, we attempted testicular replantation based on prior successful experience with replantation after traumatic orchiectomy.\n\nSkin venous congestion leading to necrosis occurs in over half of all penile replantations and is the most common complication.\n3\n, \n6\n, \n20\n The reason for such a high complication rate lays in the high variability of venous and arterial supply to the skin; arterial blood flow is provided by the external pudendal arteries, which branch early into smaller vessels, before the penis, making arterial re‐anastomosis of the skin's arterial supply difficult if not impossible.\n21\n Medical leach therapy was attempted given the prior success reported by others to treat venous congestion after penile replantation. The primary goal was to prevent arterial thrombosis and complete distal shaft necrosis with a secondary goal of preserving the integrity of the skin.\n22\n Medical leech therapy decreases the venous congestion of free flaps, which in turn decreases the back pressure on the arterial blood supply; to be fully successful in preserving skin integrity, venous drainage of the skin and adequate arterial supply have to be present.\n23\n In the present case, the superficial penile veins were very small (1‐2 mm) and the proximal veins could not be identified. We believe that if anatomically possible, every effort should be made to re‐anastomose veins to bridge the incision and allow for adequate drainage from the skin.\n\nOne novel approach that we suggest is the use of the SPY Fluorescence Imaging System to assess, or in our case confirm, the lack of skin perfusion to help counsel the patient on the likely need of a skin graft. However, while this can give insight into perfusion of the skin, one has to be careful not to draw conclusions about cavernosal arterial blood perfusion.\n\nUsing a microsurgical technique, we avoided the commonly reported complications of a urethral stricture or fistula at the urethral anastomosis. Prior groups have reported that with a microsurgical approach, the rate of urethral stricture is decreased, likely secondary to the possibility of identifying and re‐anastomosing the dorsal artery, which supplies the corpus spongiosum.\n17\n, \n21\n RUG in our patient confirmed this to be true and at 12‐month follow up was suggested by normal uroflowmetry and residual.\n\nThis case highlights the importance of prompt action and cooperation between acute care psychiatrists, trauma surgeons, reconstructive urologists, and administration to treat patients presenting with GSM. We hope that this case, the review of relevant literature, and our own experience will prompt major trauma centers to develop a multidisciplinary approach and standard operating procedures to address these emergent cases in which wrong assumptions about the nature of gender dysphoria can have catastrophic and irreversible consequences for the rest of the patient's life.\n\n4 CONCLUSION\nOur case highlights the importance of a multidisciplinary protocol for managing patients with GSM and psychosis. Furthermore, it supports the use of a microsurgical replantation for the self‐amputated penis and self‐castration. The complications present are consistent with those described in the literature. We also propose the use of fluorescence imaging to evaluate for skin perfusion of the penis after replantation.\n\nCONFLICT OF INTEREST\nThe authors report no competing interests.\n\nAUTHOR CONTRIBUTIONS\nRNWVB: involved in drafting of manuscript, study concept and design. CDG: involved in data acquisition, critical revision. DAP: served as senior/supervising author, involved in critical revision.\n\nSupporting information\nAppendix S1\n\nClick here for additional data file.\n==== Refs\nREFERENCES\n1 \n\nDoyle \nD \n. Ritual male circumcision: a brief history\n. J R Coll Physicians Edinb . 2005 ;35 :279 –285\n.16402509 \n2 \n\nZislin \nJ \n, \nKatz \nG \n, \nRaskin \nS \n, \nStrauss \nZ \n, \nTeitelbaum \nA \n, \nDurst \nR \n. Male genital self‐mutilation in the context of religious belief: the Jerusalem syndrome\n. Transcult Psychiatry . 2002 ;39 (2 ):257 ‐264\n.\n3 \n\nJezior \nJR \n, \nBrady \nJD \n, \nSchlossberg \nSM \n. Management of penile amputation injuries\n. World J Surg . 2001 ;25 (12 ):1602 ‐1609\n.11775199 \n4 \n\nVeeder \nTA \n, \nLeo \nRJ \n. Male genital self‐mutilation: a systematic review of psychiatric disorders and psychosocial factors\n. 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Mental capacity, legal competence and consent to treatment\n. Xxxx . 2004 ;97 :6 .\n12 \n\nKrafft‐Ebing \nRV \n. Psychopathia Sexualis: A Medico‐Forensic Study . Butterworth‐Heinemann ; 2013 .\n13 \n\nFreud \nS \n. The Schreber Case . London, UK : Penguin Classics Psychology ; 2003 .\n14 \n\nHostiuc \nS \n, \nRusu \nMC \n, \nNegoi \nI \n, \nDrima \nE \n. Testing decision‐making competency of schizophrenia participants in clinical trials. A meta‐analysis and meta‐regression\n. BMC Psychiatry . 2018 ;18 (1 ).\n15 \n\nColeman \nE \n, \nBockting \nW \n, \nBotzer \nM \n. The World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People (7th ed ). [Internet]. Minneapolis, MN : WPATH ; 2012 [cited 2012 Sep 20]. http://www.wpath.org/site_page.cfmpk_association_webpage_menu=1351&pk_association_webpage\n\n16 \n\nCaygill \nPL \n, \nFloyd \nMS \nJr\n, \nNew \nFJ \n, \nDavies \nMC \n. A successful microsurgical approach to treating penile amputation following genital self mutilation\n. J Surg Case Rep . 2018 ;2018 (10 ):rjy271 .30323918 \n17 \n\nVirasoro \nR \n, \nTonkin \nJB \n, \nMcCammon \nKA \n, \nJordan \nGH \n. Penile amputation: cosmetic and functional results\n. Sex Med Rev . 2015 ;3 (3 ):214 ‐222\n.27784611 \n18 \n\nRaheem \nOA \n, \nMirheydar \nHS \n, \nPatel \nND \n, \nPatel \nSH \n, \nSuliman \nA \n, \nBuckley \nJC \n. Surgical management of traumatic penile amputation: a case report and review of the world literature\n. Sex Med . 2015 ;3 (1 ):49 ‐53\n.25844175 \n19 \n\nGurunluoglu \nR \n, \nShah \nM \n, \nKim \nF \n. Microsurgical penile replantation after self‐inflicted amputation in a schizophrenic patient\n. Plast Reconstr Surg ‐ Glob Open . 2015 ;3 (3 ):e319 .25878930 \n20 \n\nFacio \nFN \n, \nSpessoto \nLC \n, \nArruda \nP \n, \nPaiva \nCS \n, \nArruda \nJG \n, \nFacio \nMF \n. Penile replantation after five hours of warm ischemia\n. Urol Case Rep . 2015 ;3 (3 ):77 ‐79\n.26793508 \n21 \n\nTuffaha \nSH \n, \nBudihardjo \nJD \n, \nSarhane \nKA \n, \nAzoury \nSC \n, \nRedett \nRJ \n. Expect skin necrosis following penile replantation\n. Plast Reconstr Surg . 2014 ;134 (6 ):1000e ‐1004e\n.\n22 \n\nBanihani \nOI \n, \nFox \nJA \n, \nGander \nBH \n, \nGrunwaldt \nLJ \n, \nCannon \nGM \n. Complete penile amputation during ritual neonatal circumcision and successful replantation using postoperative leech therapy\n. Urology . 2014 ;84 (2 ):472 ‐474\n.24928459 \n23 \n\nWhitaker \nIS \n, \nOboumarzouk \nO \n, \nRozen \nWM \n, et al, The efficacy of medicinal leeches in plastic and reconstructive surgery: a systematic review of 277 reported clinical cases\n. Microsurgery . 2012 ;32 (3 ):240 ‐250\n.22407551\n\n",
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"issn_linking": "2050-0904",
"issue": "8(9)",
"journal": "Clinical case reports",
"keywords": "gender dysphoria; penis; schizophrenia; self‐amputation; self‐castration",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
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"pages": "1735-1740",
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"pubdate": "2020-09",
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"title": "Presentation and resolution of gender dysphoria as a positive symptom in a young schizophrenic man who presented with self-emasculation: Frontiers of bioethics, psychiatry, and microsurgical genital reconstruction.",
"title_normalized": "presentation and resolution of gender dysphoria as a positive symptom in a young schizophrenic man who presented with self emasculation frontiers of bioethics psychiatry and microsurgical genital reconstruction"
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"abstract": "The standard of care for the first-line treatment of advanced gastrointestinal stromal tumor (GIST) is represented by imatinib, which is given daily at a standard dosage until tumor progression. Resistance to imatinib commonly occurs through the clonal selection of genetic mutations in the tumor DNA, and an increase in imatinib dosage was demonstrated to be efficacious to overcome imatinib resistance. Wild-type GISTs, which do not display KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations, are usually primarily insensitive to imatinib and tend to rapidly relapse in course of treatment. Here we report the case of a 53-year-old male patient with gastric GIST who primarily did not respond to imatinib and that, despite the administration of an increased imatinib dose, led to patient death. By using a deep next-generation sequencing barcode-aware approach, we analyzed a panel of actionable cancer-related genes in the patient cfDNA to investigate somatic changes responsible for imatinib resistance. We identified, in two serial circulating tumor DNA (ctDNA) samples, a sharp increase in the allele frequency of a never described TP53 mutation (c.560-7_560-2delCTCTTAinsT) located in a splice acceptor site and responsible for a protein loss of function. The same TP53 mutation was retrospectively identified in the primary tumor by digital droplet PCR at a subclonal frequency (0.1%). The mutation was detected at a very high allelic frequency (99%) in the metastatic hepatic lesion, suggesting a rapid clonal selection of the mutation during tumor progression. Imatinib plasma concentration at steady state was above the threshold of 760 ng/ml reported in the literature for the minimum efficacious concentration. The de novo TP53 (c.560-7_560-2delCTCTTAinsT) mutation was in silico predicted to be associated with an aberrant RNA splicing and with an aggressive phenotype which might have contributed to a rapid disease spread despite the administration of an increased imatinib dosage. This result underlies the need of a better investigation upon the role of TP53 in the pathogenesis of GISTs and sustains the use of next-generation sequencing (NGS) in cfDNA for the identification of novel genetic markers in wild-type GISTs.",
"affiliations": "Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Nuclear Medicine Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Pathology Unit, ULSS 17 Este-Monselice, Este, Italy.;Pathology Unit, ULSS 17 Este-Monselice, Este, Italy.;Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Medical Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.",
"authors": "Dalle Fratte|Chiara|C|;Guardascione|Michela|M|;De Mattia|Elena|E|;Borsatti|Eugenio|E|;Boschetto|Roberta|R|;Farruggio|Angelo|A|;Canzonieri|Vincenzo|V|;Romanato|Loredana|L|;Borsatti|Rachele|R|;Gagno|Sara|S|;Marangon|Elena|E|;Polano|Maurizio|M|;Buonadonna|Angela|A|;Toffoli|Giuseppe|G|;Cecchin|Erika|E|",
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"doi": "10.3389/fphar.2020.00036",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2020.00036PharmacologyCase ReportClonal Selection of a Novel Deleterious TP53 Somatic Mutation Discovered in ctDNA of a KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumor Resistant to Imatinib Dalle Fratte Chiara 1Guardascione Michela 1De Mattia Elena 1Borsatti Eugenio 2Boschetto Roberta 3Farruggio Angelo 3Canzonieri Vincenzo 45Romanato Loredana 1Borsatti Rachele 1Gagno Sara 1Marangon Elena 1Polano Maurizio 1Buonadonna Angela 6Toffoli Giuseppe 1*Cecchin Erika 11Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy2Nuclear Medicine Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy3Pathology Unit, ULSS 17 Este-Monselice, Este, Italy4Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy5Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy6Medical Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, ItalyEdited by: Gloria Ravegnini, University of Bologna, Italy\n\nReviewed by: Hirotoshi Kikuchi, Hamamatsu University School of Medicine, Japan; Lucia Taja-Chayeb, National Institute of Cancerology (INCan), Mexico\n\n*Correspondence: Giuseppe Toffoli, gtoffoli@cro.itThis article was submitted to Pharmacogenetics and Pharmacogenomics, a section of the journal Frontiers in Pharmacology\n\n07 2 2020 2020 11 3611 10 2019 14 1 2020 Copyright © 2020 Dalle Fratte, Guardascione, De Mattia, Borsatti, Boschetto, Farruggio, Canzonieri, Romanato, Borsatti, Gagno, Marangon, Polano, Buonadonna, Toffoli and Cecchin2020Dalle Fratte, Guardascione, De Mattia, Borsatti, Boschetto, Farruggio, Canzonieri, Romanato, Borsatti, Gagno, Marangon, Polano, Buonadonna, Toffoli and CecchinThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The standard of care for the first-line treatment of advanced gastrointestinal stromal tumor (GIST) is represented by imatinib, which is given daily at a standard dosage until tumor progression. Resistance to imatinib commonly occurs through the clonal selection of genetic mutations in the tumor DNA, and an increase in imatinib dosage was demonstrated to be efficacious to overcome imatinib resistance. Wild-type GISTs, which do not display KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations, are usually primarily insensitive to imatinib and tend to rapidly relapse in course of treatment. Here we report the case of a 53-year-old male patient with gastric GIST who primarily did not respond to imatinib and that, despite the administration of an increased imatinib dose, led to patient death. By using a deep next-generation sequencing barcode-aware approach, we analyzed a panel of actionable cancer-related genes in the patient cfDNA to investigate somatic changes responsible for imatinib resistance. We identified, in two serial circulating tumor DNA (ctDNA) samples, a sharp increase in the allele frequency of a never described TP53 mutation (c.560-7_560-2delCTCTTAinsT) located in a splice acceptor site and responsible for a protein loss of function. The same TP53 mutation was retrospectively identified in the primary tumor by digital droplet PCR at a subclonal frequency (0.1%). The mutation was detected at a very high allelic frequency (99%) in the metastatic hepatic lesion, suggesting a rapid clonal selection of the mutation during tumor progression. Imatinib plasma concentration at steady state was above the threshold of 760 ng/ml reported in the literature for the minimum efficacious concentration. The de novo TP53 (c.560-7_560-2delCTCTTAinsT) mutation was in silico predicted to be associated with an aberrant RNA splicing and with an aggressive phenotype which might have contributed to a rapid disease spread despite the administration of an increased imatinib dosage. This result underlies the need of a better investigation upon the role of TP53 in the pathogenesis of GISTs and sustains the use of next-generation sequencing (NGS) in cfDNA for the identification of novel genetic markers in wild-type GISTs.\n\ncirculating tumor DNATP53gastrointestinal stromal tumorimatinibliquid biopsy\n==== Body\nBackground\nGastrointestinal stromal tumors (GISTs) are the most common soft tissue tumors arising in the gastrointestinal tract. Common sites of GIST in the gastrointestinal tract include stomach (50%), small intestine (25%), rectum (5%), esophagus (< 5%), while extra-intestinal localizations are rare (< 5%). (DeMatteo et al., 2000; Casali et al., 2018) The diagnosis of GIST commonly relies on immunohistochemical (IHC) analysis of tumor tissue and is based on the assessment of KIT and DOG1 positivity. Based on histopathological features including mitotic index, tumor size, and primary site, risk-stratification schemes have been formulated. (Fletcher et al., 2002; Miettinen and Lasota, 2006).\n\nBy a molecular point of view, GISTs are characterized by gain-of-function mutations in KIT (70%–75% of cases) or PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) genes (5%–10% of cases). (Corless et al., 2004) The mutational status of KIT/PDGFRA represents a significant predictive factor for response to the targeted drug imatinib mesylate. In particular, patients displaying KIT exon 11 mutations are usually sensitive toward imatinib, whereas patients bearing KIT exon 9 mutations are less sensitive and benefit from a higher drug's starting dosage. (Debiec-Rychter et al., 2006) On the other hand, KIT exon 13 and 17 mutations are usually insensitive to imatinib and commonly arise later during treatment, leading to secondary acquired resistance. (Lasota et al., 2008) Concerning the less common PDGFRA mutations, the p.D842V substitution is associated to primary insensitivity to imatinib, thus suggesting an alternative drug, i.e., sunitinib. (Heinrich et al., 2003) The subpopulation of GIST patients who do not show KIT or PDGFRA mutations has been historically classified as “wild-type” and only in the last years the contribution of other genes, such as BRAF, SDH, and NF1, has emerged to play a role in the pathogenesis of GIST (Boikos et al., 2016).\n\nOnly a narrow panel of mutations is known to be directly associated with the primary or secondary resistance to imatinib. Indeed, so far, imatinib resistance is mainly attributed to mutations located in KIT, PDGFRA, BRAF, and SDH genes, and thus other “noncanonical” genes remain less investigated. The inclusion of other oncogenes into the panels which are routinely screened for imatinib treatment monitoring could lead to the identification of novel biomarkers for the early diagnosis of treatment failure. Moreover, the use of wider panels of genes could be of particular interest in wild-type GIST, for which the dynamic tracking of driver known mutations is not feasible.\n\nThe strategy of tumor mutations dynamic monitoring for early detection of imatinib resistant clones is of special worth, as alternative therapeutic approaches, after imatinib failure, are available in the clinical care, such as sunitinib and regorafenib. A suitable method for the dynamic monitoring of tumor behavior is offered by the circulating tumor DNA (ctDNA) analysis. In the framework of liquid biopsies, ctDNA represents a specific biomarker which displays the same molecular characteristics (i.e., mutations) of the tissue of origin thus representing a real-time source of tumor-derived DNA. In the clinical setting, ctDNA analysis has shown to be of prognostic significance in predicting the targeted therapy's response, as well as in the early identification of disease relapse and/or progression (Tie et al., 2016; Coombes et al., 2019; Siravegna et al., 2019).\n\nWith the aim of developing an innovative approach for the dynamic monitoring of imatinib in GIST patients, we set up a joint research project for the ctDNA analysis and for the monitoring of imatinib plasma Cmin in blood samples collected during patients' follow-up. The ctDNA analysis, by means of targeted deep sequencing, is focused on detecting tumor-related mutations which could be informative about disease status and treatment response.\n\nCase Presentation\nA 53-year-old male patient was diagnosed with gastric GIST in May 2015 at Azienda Ospedaliera ULSS 9 of Monselice (PD) for which he underwent a total gastrectomy with no evidence of residual disease. The tumor tissue examination revealed the characteristic spindle cell morphology of GIST and displayed a low mitotic index (< 1/50 HPF). Immunohistochemical stain revealed positivity for Ki67 and CD117 (c-KIT) antigens, confirming the diagnosis of GIST, whereas stains for smooth muscle alpha-actin, desmin, CD34, and S-100 were negative. A post hoc molecular analysis did not highlight any somatic mutation in KIT or PDGFRA, allowing to define it as a wild-type tumor. The patient was classified as a low risk of recurrence, and the wait-and-see approach was preferred to adjuvant treatment with imatinib. In November 2015, magnetic resonance showed the presence of six hepatic nodules with maximum diameter of 2.5 cm consistent with metastatic GIST lesions, so imatinib first-line therapy was started at the standard dosage of 400 mg/day. In March 2016, the patient accessed medical care in our hospital in which a magnetic resonance showed hepatic disease progression. The GIST derivation of hepatic lesions was confirmed through a tissue biopsy staining positively for c-KIT antigen (Figure 1A); therefore, imatinib dosage was increased to 800 mg/day. In October 2017, PET imaging revealed further hepatic disease progression in addition to bone and intra-abdominal metastatic spread, so the patient was switched to sunitinib. During the overall course of therapy, the patient displayed a primary resistance against imatinib since he never experienced a clinical benefit from treatment. The patient died because of disease progression in March 2018.\n\nFigure 1 (A) Immunhistochemical staining for CD117 (c-KIT) and (B) tumor composition of spindle cells and eosinophilic cytoplasm (hematoxylin and eosin) on the metastatic hepatic tissue.\n\nMethods\n(For a detailed description of Methods, see Supplementary Methods).\n\nBiological Sample Collection and Ethics Approval\nThe patient provided a signed informed consent at the time of enrollment. Blood samples were collected in January 2017 (sample IM_21.1) and in July 2017 (sample IM_21.2). A diagnostic residue of the formalin-fixed paraffin-embedded (FFPE) bioptic tissue derived from the hepatic lesion was provided by the Pathological Anatomy Division of IRCCS CRO, whereas primary FFPE surgical tissue was kindly provided by Azienda Ospedaliera ULSS 9 of Monselice (PD).\n\nDNA Extraction and Quality Control (QC)\nCell-free DNA (cfDNA) was extracted from 4 ml of plasma using the QIAamp MinElute ccfDNA Kit (Qiagen) and quantified with Quantus Fluorometer (Promega). Fragment size distribution was assessed by High Sensitivity TapeStation (Applied Biosystems). Germline DNA was extracted from 200 μl of buffy-coat using the automated BioRobot EZ1 (Qiagen). DNA from FFPE tissue (both primary tumor and hepatic metastasis) was extracted using the GeneRead DNA FFPE Kit (Qiagen) according to the manufacturer's instructions. The median tumor cell content was 80%, as established by a trained expert pathologist (Figure 1B).\n\nLibrary Preparation, Sequencing, and Data Analysis\nGenomic libraries were prepared using QiaSeq Human Actionable Solid Tumor Panel DNA (Qiagen). Regions covered by the panel are listed in Supplementary Table S1. Pooled libraries were paired-end (151 × 2) sequenced in an Illumina platform (MiSeq). Bioinformatic analysis was performed on a workstation with a 30-core Intel Core i7 and 64 GB of memory running Centos 7.5. Raw reads after trimming for quality were aligned against the reference genome hg19 (UCSC) using bwa aligner. (Li and Durbin, 2009) Variants were called using smCounter v 2 with default parameters. (Xu et al., 2019) Identified variants were manually verified using Integrative Genomics Viewer (IGV, https://www.broadinstitute.org/igv).\n\nddPCR Assay\ncfDNA, DNA from primary tumor, and DNA from metastatic tissue were interrogated for the presence of TP53 indel (c.560-7_560-2delCTCTTAinsT) by a ddPCR custom assay developed from BioRad (Bio-Rad Laboratories, Hercules, CA, USA). ddPCR was performed using primers and specific TaqMan probes targeting the wild-type TP53 sequence and the aberrant TP53 sequence bearing the indel c.560-7_560-2delCTCTTAinsT. As reference mutated control, a synthetic oligonucleotide bearing the TP53 indel c.560-7_560-2delCTCTTAinsT was used (Sigma Aldrich, St. Louis, MO, USA). As a reference wild-type control, a germline DNA in which the presence of the TP53 indel (c.560-7_560-2delCTCTTAinsT) was excluded through next-generation sequencing (NGS) was used. Droplet generation was performed using QX200™ Droplet Generator™ (Bio-Rad Laboratories, Hercules, CA, USA), and fluorescence emitted from droplets was measured using QX200™ Droplet Reader (Bio-Rad Laboratories, Hercules, CA, USA). Sample analysis was performed using QuantaSoft v1.7.4.0917 software (Bio-Rad Laboratories, Hercules, CA, USA). Details concerning ddPCR conditions and data analysis are reported in Supplementary Methods.\n\nComputational Prediction of Splicing Alteration\nSix freely available in silico tools were used to predict the impact of the splice-site mutation in TP53 gene on pre-mRNA splicing. Tools used are SpliceView (http://bioinfo.itb.cnr.it/~webgene/wwwspliceview.html), GENSCAN (http://hollywood.mit.edu/GENSCAN.html), NetGene2 (http://www.cbs.dtu.dk/services/NetGene2/), MaxEntScan (http://hollywood.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq.html), and Human Splicing Finder (HSF, http://www.umd.be/HSF/HSF.shtml) (Shapiro and Senapathy, 1987; Brunak et al., 1991; Hebsgaard et al., 1996; Burge and Karlin, 1997; Reese et al., 1997; Yeo and Burge, 2004; Houdayer et al., 2008; Desmet et al., 2009). To facilitate the output interpretation, we compared the score of the mutant with the score of the reference sequence.\n\nLiquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) Quantification of Imatinib Plasma Concentrations\nThe quantification of imatinib was obtained using an LC-MS/MS apparatus consisting of a Prominence UFLC XR (Shimadzu) coupled with an API 4000 QTrap mass spectrometer (SCIEX). Details concerning sample processing and experimental conditions are reported in Supplementary Methods.\n\nResults\nNext-Generation Sequencing of DNA Derived From Plasma (cfDNA), Primary Tumor Tissue, and Metastatic Tissue\nAfter variants calling by smCounter v2, genetic variants were filtered per the following criteria: passing filter (PASS), quality score ≥100, frequency of mutated allele ≥0.5%, and total number of reads mapping the chromosomal location (reads depth) ≥2,500 X. All the genetic variants were compared to those obtained by matched germline DNA sequencing to exclude from the analysis nonsomatic variants.\n\nIn the two serial cfDNA samples, one somatic indel affecting the exon 6 flanking site of TP53 gene indel (c.560-7_560-2delCTCTTAinsT) at nucleotide position c.560-2_c.560-7 was identified at a minor allele frequency (MAF) of 2.7% in the first plasma sample (IM_21.1) and of 9.7% in the second plasma sample (IM_21.2). No other somatic mutation was detected in cfDNA. The same TP53 indel was detected through NGS in the DNA from the metastatic tissue with a MAF of 99%. The mutation identified is an intronic indel that affects the canonical AG/GT splice site motif by the deletion of the nucleotide in position –2 upstream exon 6.\n\nThe identified variant was automatically annotated against the human TP53 genomic sequence NC_000017.10 (chr 17:7,571,720-7,590,868) corresponding to isoform NM_00546.5. The latest release of the International Agency for Research on Cancer (IARC) TP53 Mutation Database (Database R19, released on August 2018) (http://p53.iarc.fr/TP53GeneVariations.aspx) was used to check the de novo TP53 variant, confirming our novel finding. (Bouaoun et al., 2016) The characteristics of TP53 mutation are listed in Table 1.\n\nTable 1 TP53 somatic mutation identified by next-generation sequencing (NGS). Genomic coordinates of the mutation and the read depth in that chromosomal location are reported.\n\nSample ID\tGenomic coordinates\tRead depth\tUMT\tVMF\tMutation frequency (%)\tcDNA change\tType of mutation\t\nIM_21.1\t17:7,578,291\t6,672\t1,023\t28\t2.7\tc.560-7_560-2delCTCTTAinsT\tIndel\t\nIM_21.2\t17:7,578,291\t5,868\t876\t85\t9.7\tc.560-7_560-2delCTCTTAinsT\tIndel\t\nThe total number of reads bearing the same Unique Molecular Target (UMT) and those reporting the mutation [Variant Mutational Fraction (VMF)] was used to calculate the mutation frequency in each sample.\n\nDNA derived from the primary tumor tissue at surgery resulted wild-type for the regions analyzed, as no somatic mutation was detected.\n\nddPCR Analysis on Plasma, Primary Tumor Tissue, and Metastatic Tissue-Derived DNA\nThe custom ddPCR assay was harnessed to validate the presence of TP53 indel (c.560-7_560-2delCTCTTAinsT) in cfDNA and metastatic tissue. Primary tumor tissue was interrogated as well to perform a cross-platform comparison and increase the sensitivity in mutation detection.\n\nSince cfDNA IM_21.1 was completely depleted to perform NGS, only cfDNA IM_21.2 was analyzed through ddPCR. In cfDNA IM_21.2, the presence of the TP53 indels was confirmed by ddPCR, which revealed 16 mutated copies/µl, corresponding to 277 mutated copies/ml of plasma. So, in cfDNA, the MAF estimated by ddPCR was 17%, superior to that reported by NGS (9.7%). The MAF revealed in the metastatic tissue-derived DNA by ddPCR was comparable to that obtained by NGS analysis, confirming a complete selection of the mutated clone in the metastatic lesion (MAF ~100%). Notably, the use of ddPCR allowed the identification of TP53 indel also in the DNA derived from the primary tumor tissue with a mutated allele frequency of 0.1% that was not detectable by means of NGS (Figure 2).\n\nFigure 2 (A) Course of disease from the time of diagnosis, treatment administered, PET/CT images, and allele frequency of TP53 indel are shown. The mutated allele frequency in tumor tissue (black columns) is reported for the primary tumor [minor allele frequency (MAF) 0.1%, ddPCR] and for the metastatic lesion (MAF 99%, ddPCR) at the time of surgery and biopsic sampling, respectively. The ctDNA fraction (gray columns) is reported for the sample IM_21.1 [MAF 2.7%, next-generation sequencing (NGS)] and sample IM_21.2 (MAF 9.7%, NGS). PET/CT scans reporting the diameter of target lesions and performed in concomitance to blood sampling are shown as well. On the bottom of the plot, the imatinib dosage administered is indicated. (B) ddPCR plots reporting the signal generated from the wild-type (green dots) and the mutated (blue dots) sequence are shown. In chronological order are reported the primary tumor DNA, the metastatic DNA, and the IM_21.1 cfDNA.\n\nComputational Prediction of TP53c.560-7_560-2delCTCTTAinsT\nTools used to predict the effect of the TP53 indel at mRNA and the respective scores generated are listed in Table 2. All but one tool agree in identifying the canonical splice site in the wild-type TP53 sequence, and all of them predicted the splice site destruction in the mutated sequence. Consequently, the effect of the mutation was supposed to be deleterious by five out of six predictive tools, not being evaluable by means of NetGene2, which did not detect the wild-type splice site. The activation of an alternative splice site was predicted by HSF that identified a likely new splicing acceptor site located 30 nucleotides downstream from the canonical site. The new splice site was scored 50.40 by HSF (Table 2), and it is weaker than the canonical ones, which was scored 80.49. The activation of the new cryptic splice site would lead to an in-frame deletion of 10 amino acids from the position 187 to 196 in the mature protein. The description of the TP53 indel and its predicted effect on mRNA strand are depicted in Figure 3.\n\nTable 2 Computational prediction of the effect of the mutation on the TP53 splice site by the use of six different bioinformatic tools.\n\nTool\tOutput\tReference score\tMutated score\tPredicted effect\t\nSpliceView\tScore (0–100)\t83\tNot detected\tDeleterious\t\nGENSCAN\tProbability score (0–1)\t0.120\tNot detected\tDeleterious\t\nNetGene2\tConfidence score\t0.00\tNot detected\tNot evaluable\t\nNNSplice 0.9\tScore (0–1)\t0.94\tNot detected\tDeleterious\t\nHuman Splicing Finder (HSF)\tScore (0–100)\t80.49\tNot detected\tDeleterious\t\nMaxEntScan\tMaximum entropy score\t1.08\t–2.91\tDeleterious\t\nThe wild-type DNA sequence was compared with the mutated one, and the effect was predicted by comparing the two generated scores.\n\nFigure 3 In the figure are reported (A) the normal sequence and exon splicing of TP53 pre-mRNA (exons 5–6) and (B) aberrant splicing caused by the c.560-7_560-2delCTCTTAinsT (red) likely to generate an in-frame deletion of 30 nucleotides from mRNA due to the activation of a cryptic splice site (blu).\n\nMolecular biology analyses to confirm the mutation's impact on TP53 mRNA splicing were attempted but not feasible due to the very poor quality of FFPE RNA (data not shown).\n\nImatinib Plasma Levels\nThe sample IM_21.1 for Cmin analysis was collected 17.5 h after the previous imatinib; drug plasma concentration was determined as 987 ng/ml. The sample IM_21.2 was collected a week after the last intake of the drug. Therefore, this last sample was not suitable for Cmin determination given that the possible plasma imatinib concentration was not associated with steady state kinetics.\n\nDiscussion\nThe use of imatinib has favorably rewritten the natural history of GIST, improving the patients' outcome in terms of survival. However, primary and secondary resistance is the main weakness of imatinib and represents the leading cause of progression.\n\nThe primary resistance is related to tumor's molecular features at baseline and is assessed on tumor at the time of diagnosis, as recommended by clinical guidelines. (Casali et al., 2018) Wild-type GISTs, characterized by the absence of KIT/PDGFRA activating mutations, are a heterogeneous class of tumors showing multiple genetic and morphological features. Therapeutic strategies for the treatment of these tumor subtypes are not defined yet.\n\nSecondary imatinib resistance is commonly observed after 2 years of treatment in half of primarily responder patients as a consequence of the selective pressure exerted by the drug. In KIT/PDGFRA-mutated GISTs, the development of acquired resistance is commonly restricted to secondary mutations in these genes, enabling a more handling monitoring of disease progression by the detection of target mutations. In wild-type GISTs, which do not display a shared evolutionary path, the identification of genetic markers to assess tumor's evolution is urgently needed (Wei et al., 2018).\n\nThe possibility of interrogating ctDNA as a surrogate of tumor tissue by massive parallel sequencing has enabled the real-time detection of emergent resistance clones in several kinds of malignancies in a less invasive manner (Russo et al., 2016).\n\nIn this study, using a targeted NGS panel of hotspot regions of 23 cancer-related genes, we assessed the molecular evolution of a wild-type GIST by analyzing two serial cfDNA samples collected 6 months apart, the primary tumor tissue and the hepatic metastasis tissue. We found that a novel TP53 indel (c.560-7_560-2delCTCTTAinsT) was detected in cfDNA samples with an allele frequency of 2.7% (IM_21.1) and 9.7% (IM_21.2). The primary and relapsed tumors did not show KIT/PDGFRA mutations, but they harbored the same TP53 indel with an allele frequency of 0.1% and ~100%, respectively.\n\nThe functional impact of TP53 indel (c.560-7_560-2delCTCTTAinsT) was postulated on the basis of its localization in a highly conserved region. We hypothesized a misrecognition of the canonical splice site from the splicing machinery, which would result in the translation of a truncated or nonfunctional protein. Our hypothesis was sustained by five different in vitro algorithms that predicted the canonical splice site destruction and the likely activation of noncanonical ones, located 30 base pairs downstream of the canonical one in the intron 5/exon 6 boundary. At the protein level, the TP53 region excised from canonical mRNA transcription, both in the case of a complete or a partial loss of exon 6, is of pivotal relevance for the interaction with other proteins involved in the cell cycle regulation, such as AXIN1, HIPK1, and ZNF385A and is located in the DNA-binding domain. (Das et al., 2007; Sun et al., 2009) The production of an aberrant TP53 transcript leads to the transduction of a truncated and nonfunctional TP53 protein but could also drive the reduction of the TP53 expression as a consequence of a nonsense-mediated mRNA decay.\n\nTP53 is a tumor suppressor gene well known to play a pivotal role in the DNA repair process and in the apoptosis initiation. Its inactivation is a frequent event in cancer and is commonly associated with a worst prognosis (Basu and Murphy, 2016).\n\nAlthough only few studies have investigated the role of TP53 mutations in GIST, a consensus upon their association with imatinib resistance has been achieved. The first evidence demonstrating the correlation between TP53 mutations and imatinib insensitivity was described by Wendel et al. (2006) in BCR-ABL-positive leukemic cells. They observed that the mechanism of imatinib resistance was independent of the chemical inhibition of BCR-ABL kinase by imatinib, suggesting a downstream involvement of TP53 mutations in leading the drug's resistance. Further studies confirmed the loss of TP53 in chronic myeloid leukemia as a molecular feature associated with imatinib resistance (Al-achkar et al., 2012).\n\nRecently, in a study aimed at identifying genes involved in imatinib resistance in GIST-T1 cells through a CRISP-Cas9 knockout genome-wide screening, Cao et al. (2018) identified TP53 as one of the main genes associated to imatinib resistance. These evidences suggest that genomic alterations in genes related to the apoptosis pathway might represent an escape route exploited by tumor cells to evade imatinib therapy.\n\nIn KIT/PDGFRA mutant GISTs, there is no doubt upon the origin of the oncogenic signaling, and the development of imatinib resistance is mainly restricted to the acquisition of secondary KIT/PDGFRA mutant clones bearing novel mutations. In these groups of GISTs, the overall TP53 mutation rate was reported as low, emphasizing the oncogenic reliance on kinase-mediated signaling. However, a straightforward association between presence of TP53 aberrations and GIST malignancy has been observed, with a significant increase of TP53 aberrations in high-risk rather than in low-risk tumors. (Merten et al., 2016; Ihle et al., 2018; Heinrich et al., 2019) On the other hand, TP53 has emerged as one of the main mutated genes in wild-type GISTs, supporting its likely role in the pathogenesis of these tumor subtypes (Pantaleo et al., 2017).\n\nIn this clinical case study, the rapid metastatic evolution is consistent with the TP53 mutant clonal selection from the primary to the relapsed tumor. The homozygous presence of TP53 indel (c.560-7_560-2delCTCTTAinsT) in fundamentally all hepatic relapsed cells suggests once again an indisputable association between TP53 deleterious mutations in GIST and the establishment of an aggressive phenotype insensitive to imatinib.\n\nMoreover, the observation of no clinically actionable mutations, which might represent a molecular target for currently available therapeutic options, corroborates the lack of sensitivity toward imatinib reported here and implies the impossibility of prescribing further targeted drugs. Indeed, the administration of targeted therapies is limited to the presence of specific overexpressed or mutated molecular targets in tumor cells, thus making the management of wild-type tumors a challenging task.\n\nIn this case, the clinical tumor progression was well recapitulated by the longitudinal sequencing of ctDNA, which revealed the presence of TP53 c.560-7_560-2delCTCTTAinsT at increasing allele frequency over 6 months. This finding is significant since it sustains the feasibility of relying on information obtained by liquid rather than tissue biopsies for the assessment of genetic features in metastatic GISTs. A good concordance between mutated cfDNA and tumor tissue in GIST patients was reported by previous studies, which observed a higher detection rate of ctDNA in patients with active disease and high tumor burden, rather than in patients with complete response or localized disease. (Maier et al., 2013; Xu et al., 2018) In this frame, the allele frequency of mutated cfDNA was shown to increase or decrease according to disease progression or tumor shrinkage, respectively, allowing the dynamic monitoring of tumor changes in advance GIST.\n\nIn sample IM_21.1, Cmin resulted equal to 987 ng/ml (higher than the recommended threshold of 760 ng/ml); therefore, we reasonably consider adequate the imatinib level in patient's plasma and assume that his lack of response to therapy was not due to a concentration issue but more probably to the biological aggressiveness of the disease (Bouchet et al., 2016).\n\nIn summary, our work sustains the applicability of NGS of cfDNA for the monitoring of GIST patients on treatment with imatinib, and for the characterization of the mutational pattern of GISTs, especially in those classified as wild-type, for whom the identification of genetic markers is even more urgent due to the lack of targetable mutations. The screening of a panel of actionable genes offers the possibility of identifying new tumor markers, which may be relevant for the surveillance of tumor's evolution and for the development of new drugs. In the era of precision oncology, the baseline profiling of tumor is an imperative need for choosing the best therapeutic option and for avoiding the prolonged administration of ineffective drugs. Moreover, this procedure should be accompanied by the longitudinal follow-up of tumor genetics for the early identification of tumor changes and the emergence of resistance subclones. In this field, the use of liquid biopsy coupled with NGS represents a valuable tool to explore in parallel a wide range of genomic regions and to broader horizons upon tumor's evolutionary process. In the case here reported, the identification of a novel and deleterious TP53 indel (c.560-7_560-2delCTCTTAinsT), compatible with an aggressive and drug resistance phenotype, remarks the need for further investigations upon the role of TP53 in wild-type GISTs as well as on its involvement in the development of acquired resistance toward tyrosine kinase inhibitors. The clinical management of wild-type GIST remains a subject of open debate, and effective therapeutic strategies are still lacking. Even though this class of tumors usually displays an indolent course, the development of unpredicted outcomes such as the evolution into a more aggressive form must be considered. An accurate noninvasive molecular monitoring by the use of the liquid biopsy is of primary relevance to identify effective therapeutic strategies and to personalize the therapeutic strategies.\n\nData Availability Statement\nThe data cannot be made publicly available because the consent was not acquired from the patient to publish his genetic profile. Reasonable requests for data should be directed to: ececchin@cro.it.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Comitato Etico Indipendente-Centro di Riferimento Oncologico di Aviano. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nCDF, EC, EDM, MG, and GT were involved in designing the study, critically revising the results, and preparing the manuscript, CDF, RBR, LR, MP, EM, and SG were involved in the molecular, bioinformatic and biochemical analyses. MG, AB, RBS and AF collected samples and clinical data, EB provided the PET/CT scans and VC did the histopathological analysis. All authors discussed the results and contributed to the final manuscript.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgment\nThe authors acknowledge funding from \"Ministero della Salute Ricerca Corrente\".\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2020.00036/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\nAl-achkar W. Wafa A. Moassass F. Othman M. A. K. (2012 ). A novel dic (17;18) (p13.1;q11.2) with loss of TP53 and BCR/ABL rearrangement in an Imatinib resistant chronic myeloid leukemia . Mol. Cytogenet. \n5 , 36. 10.1186/1755-8166-5-36 \n22901309 \n\nBasu S. Murphy M. E. (2016 ). Genetic modifiers of the p53 pathway . Cold Spring Harb. Perspect. 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"fulltext_license": "CC BY",
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"issue": "11()",
"journal": "Frontiers in pharmacology",
"keywords": "TP53; circulating tumor DNA; gastrointestinal stromal tumor; imatinib; liquid biopsy",
"medline_ta": "Front Pharmacol",
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"nlm_unique_id": "101548923",
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"pages": "36",
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"pmid": "32116712",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "Clonal Selection of a Novel Deleterious TP53 Somatic Mutation Discovered in ctDNA of a KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumor Resistant to Imatinib.",
"title_normalized": "clonal selection of a novel deleterious tp53 somatic mutation discovered in ctdna of a kit pdgfra wild type gastrointestinal stromal tumor resistant to imatinib"
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"abstract": "HLA antigens, including HLA-A, B, C, DR and DQ have long been known to have an effect on transplant outcome. Presence of antibodies to these antigens is detrimental to transplant outcome as it ends up to either acute or chronic humoral rejection depending on the titer of the antibodies to these antigens. However, the role of HLA-DP is not fully clear, predominantly due to lack of adequate publications and the fact that DP antigen and antibody detection became possible with the advent of new beads technology. As a results, allocation system has not yet included HA-DP antibodies in virtual crossmatching. This report presents two novel cases with strong HLA-DP antibodies which resulted in acute humoral rejection (AMR).",
"affiliations": "Texas Medical Specialty, Inc., Dallas, TX, United States. Electronic address: Afzal.nikaein@hcahealthcare.com.;Medical City Dallas, Dallas, TX, United States. Electronic address: mark.lerman@hcahealthcare.com.;Medical City Fort Worth, Fort Worth, TX, United States; Univ. Utah School of Medicine, Salt Lake City, UT, United States. Electronic address: george.rofaiel@hsc.utah.edu.;Medical City Fort Worth, Fort Worth, TX, United States. Electronic address: sallam@tarrantnephrology.com.",
"authors": "Nikaein|A|A|;Lerman|M|M|;Rofaiel|G|G|;Allam|S R|SR|",
"chemical_list": "D006682:HLA-DP Antigens; D007518:Isoantibodies",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.trim.2018.09.002",
"fulltext": null,
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"issn_linking": "0966-3274",
"issue": "51()",
"journal": "Transplant immunology",
"keywords": null,
"medline_ta": "Transpl Immunol",
"mesh_terms": "D000368:Aged; D001788:Blood Grouping and Crossmatching; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006682:HLA-DP Antigens; D006650:Histocompatibility Testing; D006801:Humans; D056724:Immunity, Humoral; D018189:Immunomagnetic Separation; D007518:Isoantibodies; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous",
"nlm_unique_id": "9309923",
"other_id": null,
"pages": "58-61",
"pmc": null,
"pmid": "30237092",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Single center observation of the role of pre-existing HLA-DP antibodies in humoral rejection following renal transplantation.",
"title_normalized": "single center observation of the role of pre existing hla dp antibodies in humoral rejection following renal transplantation"
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"companynumb": "US-DRREDDYS-USA/USA/18/0106169",
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... |
{
"abstract": "Alopecia areata is a common type of non-scarring alo¬pecia. Although the exact pathogenesis remains elusive, alopecia areata is thought to have a multifactorial etiology described as an interplay of genetic predisposition and environmental exposures. In patients with genetic susceptibility, stress, infection, and microtrauma have been documented to decrease immunosuppressive cytokines that generally maintain the hair follicle's immune privilege. There is currently no curative therapy for alopecia areata, although some treatments can induce hair growth in a percentage of patients. It has been postulated that simvastatin reestablishes the immune privilege, and ezetimibe would provide an immunomodulatory and anti-inflammatory effect. We report a case of a 23 years-old woman with alopecia areata successfully treated with simvastatin/ezetimibe.",
"affiliations": "Servicio de Dermatología Hospital Clínico San Borja Arriarán. Santiago, Chile; Departamento de Dermatología, Facultad de Medicina, Universidad de Chile, Santiago, Chile. ORCID: 0000-0002-3718-120X.;Departamento de Dermatología, Facultad de Medicina, Universidad de Chile, Santiago, Chile. Dirección: Santos Dumont 999, Independencia, Santiago, Chile. Email: carolinac86@gmail.com. ORCID: 0000-0003-1227-8811.;Departamento de Dermatología, Facultad de Medicina, Universidad de Chile, Santiago, Chile. ORCID: 0000-0002-1536-1162.",
"authors": "Arellano|Javier|J|;Carrasco|Carolina|C|;García|Carolina|C|",
"chemical_list": "D007166:Immunosuppressive Agents; D019821:Simvastatin; D000069438:Ezetimibe",
"country": "Chile",
"delete": false,
"doi": "10.5867/medwave.2020.10.8053",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0717-6384",
"issue": "20(9)",
"journal": "Medwave",
"keywords": " Dermatology; Hair diseases; Alopecia areata",
"medline_ta": "Medwave",
"mesh_terms": "D000328:Adult; D000506:Alopecia Areata; D000069438:Ezetimibe; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007166:Immunosuppressive Agents; D019821:Simvastatin; D055815:Young Adult",
"nlm_unique_id": "101581949",
"other_id": null,
"pages": "e8053",
"pmc": null,
"pmid": "33231574",
"pubdate": "2020-11-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A report of successful management with simvastatin plus ezetimibe in alopecia areata.",
"title_normalized": "a report of successful management with simvastatin plus ezetimibe in alopecia areata"
} | [
{
"companynumb": "CL-LUPIN PHARMACEUTICALS INC.-2022-01759",
"fulfillexpeditecriteria": "2",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditiona... |
{
"abstract": "Autoimmune factor V deficiency (AiF5D) is caused by autoantibodies to coagulation factor V (FV); its clinical manifestations range from asymptomatic to fatal hemorrhage. Herein, we report the case of a 68-year-old man who was diagnosed with end-stage renal disease at the time of a femoral fracture and developed AiF5D after initiating hemodialysis. A wound infection that occurred after joint replacement was treated with antibiotics; however, it was poorly controlled. One month after the procedure, his coagulation time prolonged. The infection was improved by debridement and antibiotics; however, the coagulation time was not decreased and poor hemostasis at the shunt was still persistent. Because ELISA detected anti-FV-binding IgG with FV activity of <2.8% and FV inhibitor levels were 11.8 BU/ml, AiF5D was diagnosed. Oral prednisolone (PSL) was started. Dialysis was initially performed without anticoagulants, but blood clots were not found in the circuit. Anticoagulants were resumed when the coagulation time decreased. After achieving complete remission, PSL dose was tapered and finally discontinued. Few reports have described the management of AiF5D via dialysis. We consider that our report would be useful for the management of patients with similar manifestations.",
"affiliations": "Department of Hematology, Gunma University Graduate School of Medicine.;Department of Hematology, Gunma University Graduate School of Medicine.;The Japanese Collaborative Research Group (JCRG) on Acquired Coagulopathies supported by the Japanese Ministry of Health, Labor, and Welfare.;The Japanese Collaborative Research Group (JCRG) on Acquired Coagulopathies supported by the Japanese Ministry of Health, Labor, and Welfare.;Department of Hematology, Gunma University Graduate School of Medicine.;Department of Hematology, Gunma University Graduate School of Medicine.;Department of Hematology, Gunma University Graduate School of Medicine.;Department of Hematology, Gunma University Graduate School of Medicine.;Department of Hematology, Gunma University Graduate School of Medicine.;Department of Hematology, Gunma University Graduate School of Medicine.;Clinical Laboratory Center, Gunma University Hospital.;Clinical Laboratory Center, Gunma University Hospital.;Clinical Laboratory Center, Gunma University Hospital.;The Japanese Collaborative Research Group (JCRG) on Acquired Coagulopathies supported by the Japanese Ministry of Health, Labor, and Welfare.;Department of Hematology, Gunma University Graduate School of Medicine.",
"authors": "Matsumoto|Akira|A|;Ogawa|Yoshiyuki|Y|;Osaki|Tsukasa|T|;Souri|Masayoshi|M|;Yanagisawa|Kunio|K|;Ishizaki|Takuma|T|;Naito|Chiaki|C|;Ishikawa|Tetsuya|T|;Miyazawa|Yuri|Y|;Shimizu|Hiroaki|H|;Inoue|Madoka|M|;Hayakawa|Masaki|M|;Murakami|Masami|M|;Ichinose|Akitada|A|;Handa|Hiroshi|H|",
"chemical_list": "D005165:Factor V",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.61.445",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "61(5)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Acquired factor V inhibitor; Autoimmune factor V deficiency; Coagulation factor V; Hemodialysis",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D001780:Blood Coagulation Tests; D005165:Factor V; D005166:Factor V Deficiency; D006470:Hemorrhage; D006801:Humans; D008297:Male; D006435:Renal Dialysis",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "445-450",
"pmc": null,
"pmid": "32507806",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful management of acquired factor V deficiency developing shortly after induction of hemodialysis.",
"title_normalized": "successful management of acquired factor v deficiency developing shortly after induction of hemodialysis"
} | [
{
"companynumb": "NVSJ2020JP006813",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "The role of histone deacetylase inhibitors in the treatment of acute myeloid leukemia (AML) is not well characterized. The current study evaluated the safety and efficacy of panobinostat in combination with idarubicin and cytarabine in newly diagnosed patients aged ≤65 years with primary or secondary high-risk AML based on cytogenetic classification. Treatment included fixed dose idarubicin (12 mg/m2/d, IV; day 1-3) and cytarabine (100 mg/m2/d, continuous IV infusion; day 1-7) and escalating oral doses of panobinostat at 15 mg, 20 mg, and 25 mg, thrice weekly starting at week 2 of a 28-day cycle. Forty-six patients were enrolled (primary AML [n = 36], secondary AML [n = 10]). The median age was 55 years. The most common all-grade AEs were diarrhea (54.3%), nausea (39.1%), vomiting, and decreased appetite (each, 21.7%), stomatitis (19.6%), and fatigue (17.4%). The overall response rate was 60.9%, 43.5% achieved a complete remission (CR), and 17.4% achieved CR with incomplete count recovery. The event-free survival at 1-year was 78.3%. Panobinostat in combination with idarubicin and cytarabine demonstrated tolerable safety and efficacy in younger patients with high-risk AML. The recommended phase 2 dose of panobinostat in this combination was 20 mg. ClinicalTrials.gov registry no: NCT01242774, and European Trial Registry EudraCT no: 2009-016809-42.",
"affiliations": "Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Electronic address: Daniel_Deangelo@dfci.harvard.edu.;The Ohio State University Comprehensive Cancer Center, James Cancer Hospital, Columbus, Ohio, USA.;NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany.;Hospital de la Santa Creu i Sant Pau, IIB Sant Pau and José Carreras Institute, Autonomous University of Barcelona, Spain.;Stanford University School of Medicine, Stanford, California, USA.;Hospital Universitario de Salamanca, Salamanca (IBSAL) y Centro de Investigación del Cáncer (IBMCC-CSIC), Salamanca, Spain.;Universitätsklinikum Carl Gustav Carvus, Dresden, Germany.;Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.;Kliniken der Med. Hochschule Hannover, Hannover, Germany.;Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.;Novartis Healthcare Pvt. Ltd., Hyderabad, India.;Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.;Medical University of South Carolina, Hollings Cancer Center, Charleston, South Carolina, USA.",
"authors": "DeAngelo|Daniel J|DJ|;Walker|Alison R|AR|;Schlenk|Richard F|RF|;Sierra|Jorge|J|;Medeiros|Bruno C|BC|;Ocio|Enrique M|EM|;Röllig|Christoph|C|;Strickland|Stephen A|SA|;Thol|Felicitas|F|;Valera|Sue-Zette|SZ|;Dasgupta|Kohinoor|K|;Berkowitz|Noah|N|;Stuart|Robert K|RK|",
"chemical_list": "D000970:Antineoplastic Agents; D000077767:Panobinostat",
"country": "England",
"delete": false,
"doi": "10.1016/j.leukres.2019.106197",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "85()",
"journal": "Leukemia research",
"keywords": "AML; Acute myeloid leukemia; Cytarabine; Idarubicin; Panobinostat",
"medline_ta": "Leuk Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D000077767:Panobinostat; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "106197",
"pmc": null,
"pmid": "31541945",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26586702;19880497;17126723;28096533;15909291;14673054;26376137;24522247;28030834;18495956;12903007;28644114;28138160;4586956;28546581;1782481;22585696;26160880;23385375;29051280;16455952;19812608;9618772;23634996;12587104;16270213",
"title": "Safety and efficacy of oral panobinostat plus chemotherapy in patients aged 65 years or younger with high-risk acute myeloid leukemia.",
"title_normalized": "safety and efficacy of oral panobinostat plus chemotherapy in patients aged 65 years or younger with high risk acute myeloid leukemia"
} | [
{
"companynumb": "NVSC2019US002993",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PANOBINOSTAT"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nTemporary fecal diversion has been used to allow severe perianal Crohn's disease (CD) to heal. Most data on intestinal reconnection rates precede the biological era with limited patient follow-up after reconnection. We, therefore, sought to evaluate the natural history of perianal CD after fecal diversion.\n\n\nMETHODS\nWe identified 49 patients with CD and perianal involvement who underwent fecal diversion between 1991 and 2011 at a tertiary referral care center. Demographics, medication use, onset and extent of disease, and surgical interventions were abstracted. We determined the percentage of patients who were able to restore intestinal continuity and assessed the sustainability of this reversal. Time to intestinal reconnection and subsequent procedures were determined. We also examined temporal trends in the proportion of patients with perianal CD undergoing diversion or management with seton/EUA/fistulotomy between 2000 and 2011.\n\n\nRESULTS\nFifteen of 49 patients (31%) reestablished intestinal continuity during the study follow-up period. Ten of 15 patients (67%) who had reestablished intestinal continuity required an additional procedure to divert the fecal stream. Of the 5 patients who remained reconnected, 3 patients required further procedures to control sepsis. The proportion of patients with CD requiring perianal surgical interventions declined between 2000 and 2011.\n\n\nCONCLUSIONS\nSevere perianal CD remains a challenging problem. In patients with CD with perianal disease requiring fecal diversion, the likelihood of sustained intestinal continuity remains low, despite greater biological use. However, there has been a temporal decline in the rate of surgical interventions required for perianal CD from 2000 to 2011.",
"affiliations": "*Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; †Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; and ‡Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts.",
"authors": "Sauk|Jenny|J|;Nguyen|Deanna|D|;Yajnik|Vijay|V|;Khalili|Hamed|H|;Konijeti|Gauree|G|;Hodin|Richard|R|;Bordeianou|Liliana|L|;Shellito|Paul|P|;Sylla|Patricia|P|;Korzenik|Joshua|J|;Friedman|Sonia|S|;Ananthakrishnan|Ashwin N|AN|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/MIB.0000000000000216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "20(12)",
"journal": "Inflammatory bowel diseases",
"keywords": null,
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001004:Anus Diseases; D002648:Child; D003424:Crohn Disease; D005243:Feces; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010030:Ostomy; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D055815:Young Adult",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "2260-5",
"pmc": null,
"pmid": "25230164",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Natural history of perianal Crohn's disease after fecal diversion.",
"title_normalized": "natural history of perianal crohn s disease after fecal diversion"
} | [
{
"companynumb": "US-JNJFOC-20150414936",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHepatic hemangioendothelioma is a rare benign tumor in children, which frequently occurs in the first year of life. The clinical presentation is variable and the diagnosis is based on clinical suspicion, and laboratory and imaging studies. The objective was to describe a case of multifocal hepa tic hemangioendothelioma.\n\n\nMETHODS\n3-month-old girl who presented hepatomegaly without elements of hepatic or heart failure. Abdominal ultrasound and CT scan were used to diagnose hepatic hemangioendothelioma, which was confirmed by CT abdominal angiography. The patient received glucocorticoid treatment at high doses for a prolonged period. A year and a half after treatment, there was evidence of tumor remission. She had side effects from the established treatment.\n\n\nCONCLUSIONS\nIn asymptomatic patients with isolated hepatomegaly, it should be considered a probable tumor patho logy, considering the clinic and imaging studies. Possible complications and treatments risks must always be assessed. In this case, the tumor extension and its probable complications justified the use of prolonged corticosteroid therapy at high doses despite its adverse effects.",
"affiliations": "Departamento de Pediatría, Facultad de Medicina, Universidad de la República, Uruguay.;Hospital de Tacuarembó, Administración de los Servicios de Salud del Estado, Uruguay.;Departamento de Pediatría, Facultad de Medicina, Universidad de la República, Uruguay.",
"authors": "Zunino|Carlos|C|;Delgado|Maira|M|;Giachetto|Gustavo|G|",
"chemical_list": "D005938:Glucocorticoids",
"country": "Chile",
"delete": false,
"doi": "10.32641/rchped.v90i3.856",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0370-4106",
"issue": "90(3)",
"journal": "Revista chilena de pediatria",
"keywords": null,
"medline_ta": "Rev Chil Pediatr",
"mesh_terms": "D000072226:Computed Tomography Angiography; D005260:Female; D005938:Glucocorticoids; D006390:Hemangioendothelioma; D006529:Hepatomegaly; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "0404261",
"other_id": null,
"pages": "316-320",
"pmc": null,
"pmid": "31344192",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multifocal hepatic hemangioendothelioma.",
"title_normalized": "multifocal hepatic hemangioendothelioma"
} | [
{
"companynumb": "PHHY2019UY198616",
"fulfillexpeditecriteria": "1",
"occurcountry": "UY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Left bundle branch block (LBBB) usually occurs as a postoperative complication from surgical correction of congenital heart disease and can be associated with hypertensive heart disease, coronary artery disease, myocarditis, and aortic valvular disease. Although isolated LBBB is a conduction abnormality found in some healthy adults, it has not been reported in pediatric population. We report a 2-year-old, healthy African American female who was incidentally discovered to have isolated LBBB that has persisted in a follow-up of 3 years.",
"affiliations": "Division of Pediatrics, Department of Pediatrics, John H. Stroger Jr. Hospital of Cook County, 1900 W. Polk Street, Room 1134, Chicago, IL 60612, USA.;Electrophysiology, Advocate Children's Hospital, 440 W. 95th Street, Oak Lawn, IL 60453, USA.;Division of Pediatric Cardiology, John H. Stroger Jr. Hospital of Cook County, 1900 W. Polk Street, Room 1123, Chicago, IL 60612, USA.",
"authors": "Agrawal|Hitesh|H|0000-0001-9272-6949;Zimmerman|Frank|F|;Naheed|Zahra|Z|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/464579",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2014/464579Case ReportIsolated Left Bundle Branch Block in a Toddler http://orcid.org/0000-0001-9272-6949Agrawal Hitesh \n1\n*Zimmerman Frank \n2\nNaheed Zahra \n3\n1Division of Pediatrics, Department of Pediatrics, John H. Stroger Jr. Hospital of Cook County, 1900 W. Polk Street, Room 1134, Chicago, IL 60612, USA2Electrophysiology, Advocate Children's Hospital, 440 W. 95th Street, Oak Lawn, IL 60453, USA3Division of Pediatric Cardiology, John H. Stroger Jr. Hospital of Cook County, 1900 W. Polk Street, Room 1123, Chicago, IL 60612, USA*Hitesh Agrawal: hiteshdos@hotmail.comAcademic Editor: Tayfun Sahin\n\n2014 18 5 2014 2014 46457917 2 2014 29 4 2014 1 5 2014 Copyright © 2014 Hitesh Agrawal et al.2014This 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.Left bundle branch block (LBBB) usually occurs as a postoperative complication from surgical correction of congenital heart disease and can be associated with hypertensive heart disease, coronary artery disease, myocarditis, and aortic valvular disease. Although isolated LBBB is a conduction abnormality found in some healthy adults, it has not been reported in pediatric population. We report a 2-year-old, healthy African American female who was incidentally discovered to have isolated LBBB that has persisted in a follow-up of 3 years.\n==== Body\n1. Introduction\nIsolated LBBB has been widely described in adult literature [1–5]. Previous studies have postulated that it is an independent predictor of mortality and confers a risk similar to that of conventional cardiac risk factors [4, 5]. However, electrocardiographic (EKG) analysis of large cohorts of healthy children has failed to identify this entity [6–8]. This discrepancy may be due to the fact that adults are predisposed to age related degeneration of the conduction system or may have undetected ischemic or valvular heart disease or cardiomyopathy [1], which is uncommon in children. Chiu et al. studied cardiac conduction disturbances in 432,166 children (age group 6–20 years) and mentioned 1 case with isolated LBBB. However no further description or follow-up of this case is mentioned in the article [8].\n\n2. Case Report\nA 27-month-old African American female was brought to the emergency room within an hour of a questionable exposure to 1-2 pills of sustained release Nifedipine 30 mg tablets. Two tablets of Nifedipine were found missing in the grandmother's medication bottle following which she performed blind finger sweeps and retrieved some partially dissolved pill fragments from the patient's mouth. The child was alert and in no distress. Vitals' signs were stable: temperature: 98.1°F, heart rate: 109/minute, respiratory rate: 26/minute, and blood pressure: 116/69 mmHg. Cardiac exam revealed normal S1 and S2 with no murmurs. Initial laboratory studies including complete blood count, basic metabolic profile, and urinalysis were normal. No toxins were detected on urine toxicology screen. Activated charcoal of 1 gm/kg without sorbitol was given orally. Electrocardiography (EKG) demonstrated LBBB (Figure 1) with heart rate of 108/minute, PR interval of 148 milliseconds, QRS duration of 124 milliseconds, and QTc of 413 milliseconds. An echocardiogram demonstrated normal structural anatomy but M-mode showed asynchronous motion of the interventricular septum (Figure 2).\n\nThe child was admitted to pediatric intensive care unit for overnight observation. She remained hemodynamically stable and was discharged from the hospital the next day. Electrophysiology study done a year later showed a mildly prolonged H-V interval of 52 milliseconds (normal <50 milliseconds) and normal A-H interval of 54 milliseconds with otherwise normal AV conduction. No accessory pathways or dual AV nodal physiology was identified. No arrhythmias occurred with the induction protocols during the study. A 3-year follow-up with repeated EKGs (Figure 3) and echocardiograms showed that the LBBB persisted with preserved cardiac function. The ejection fraction has remained unchanged at approximately 60% (calculated via Simpson's method and M-mode), and E-point septal separation (EPSS) is <4.6 mm. The patient has remained asymptomatic since the initial diagnosis.\n\n3. Discussion\nAlthough Nifedipine poisoning causing bundle branch block and third degree heart block has been reported in children [9, 10], these are transient and occur at much higher doses—approximately 70 mg/kg [9]. Since the maximum possible dose of ingested Nifedipine was minimal in our patient and is much lower than the recommended therapeutic dose range of 0.5–3 mg/kg/day for management of pediatric hypertension [11], it was an unlikely etiology for the isolated LBBB.\n\nFurther testing with M-mode echocardiography showed asynchronous motion of the interventricular septum concurrent with the literature in adults with isolated LBBB. Grines et al. [12] postulated that LBBB causes a delay in the left ventricular depolarization resulting in delayed left ventricular contraction and relaxation compared with the right ventricle. This in turn can lead to diminished contribution of septal contraction towards ejection fraction and eventually result in systolic and diastolic dysfunction. However, this may not be prominent in childhood and may manifest later with age related degeneration of the conduction system.\n\n4. Conclusion\nA follow-up of 3 years has shown that patient has been asymptomatic and no progressive changes in the EKGs and echocardiograms have occurred. Hence, LBBB may be found as an isolated lesion in apparently healthy children even as young as 2 years of age. However, long term follow-up of cardiac conduction and ventricular function with serial EKGs and echocardiograms is required.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 EKG tracing at presentation showing left bundle branch block with heart rate of 108/minute, PR interval of 148 milliseconds, QRS duration of 124 milliseconds, and QTc of 413 milliseconds.\n\nFigure 2 M-mode echocardiographic image, at 1-year follow-up, showing asynchronous motion of the interventricular septum during diastole, marked by arrows.\n\nFigure 3 EKG tracing at 3-year follow-up showing persistence of left bundle branch block with heart rate of 84/minute, PR interval of 142 milliseconds, QRS duration of 126 milliseconds, and QTc of 377 milliseconds.\n==== Refs\n1 Fahey GJ Pinski SL Miller DP Natural history of isolated bundle branch block The American Journal of Cardiology 1996 77 1185 1190 8651093 \n2 Hardarson T Arnason A Eliasson GJ Palsson K Eyjolfsson K Sigfusson N Left bundle branch block: prevalence, incidence, follow-up and outcome European Heart Journal 1987 8 10 1075 1079 2-s2.0-0023230622 3678236 \n3 Mahmod M Karamitsos TD Suttie JJ Myerson SG Neubauer S Francis JM Prevalence of cardiomyopathy in asymptomatic patients with left bundle branch block referred for cardiovascular magnetic resonance imaging The International Journal of Cardiovascular Imaging 2012 28 5 1133 1140 21805313 \n4 Miller WL Ballman KV Hodge DO Rodeheffer RJ Hammill SC Risk factor implications of incidentally discovered uncomplicated bundle branch block Mayo Clinic Proceedings 2005 80 12 1585 1590 2-s2.0-28544442572 16342651 \n5 Rabkin SW Mathewson FA Tate RB Natural history of left bundle-branch block The British Heart Journal 1980 43 2 164 169 2-s2.0-0018882276 6444828 \n6 Niwa K Warita N Sunami Y Shimura A Tateno S Sugita K Prevalence of arrhythmias and conduction disturbances in large population-based samples of children Cardiology in the Young 2004 14 1 68 74 2-s2.0-5444263291 15237674 \n7 Hiss RG Lamb LE Electrocardiographic findings in 122,043 individuals Circulation 1962 25 947 961 13907778 \n8 Chiu SN Wang JK Wu MH Cardiac conduction disturbance detected in a pediatric population Journal of Pediatrics 2008 152 1 85 89 2-s2.0-37249087842 18154906 \n9 Wells TG Graham CJ Moss MM Kearns GL Nifedipine poisoning in a child Pediatrics 1990 86 1 91 94 2-s2.0-0025370443 2359687 \n10 Ramoska EA Spiller HA Myers A Calcium channel blocker toxicity Annals of Emergency Medicine 1990 19 6 649 653 2-s2.0-0025443092 2344082 \n11 Flynn JT Pasko DA Calcium channel blockers: pharmacology and place in therapy of pediatric hypertension Pediatric Nephrology 2000 15 3-4 302 316 2-s2.0-0033638940 11149130 \n12 Grines CL Bashore TM Boudoulas H Olson S Shafer P Wooley CF Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony Circulation 1989 79 4 845 853 2-s2.0-0024517171 2924415\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2014()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "464579",
"pmc": null,
"pmid": "24963416",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "18154906;21805313;15237674;16342651;2924415;2359687;3678236;11149130;2344082;8651093;13907778;6444828",
"title": "Isolated left bundle branch block in a toddler.",
"title_normalized": "isolated left bundle branch block in a toddler"
} | [
{
"companynumb": "US-BAYER-2014-100169",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIFEDIPINE"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nTo evaluate the clinical outcomes of percutaneous sclerotherapy for congenital head and neck lymphatic malformations in our institution.\n\n\nMETHODS\nOver a 7-year period, 17 children (10 M, 7 F) mean age 5.8 months (5 days to 13 months) underwent 49 sclerotherapy procedures for congenital head and neck malformations. The imaging and clinical records were reviewed for each patient. Ten of 17 had macrocystic disease; 7 of 17 had microcystic disease. Imaging response was categorized by volume reductions of 0% to 25%, 25% to 50%, 50% to 75%, or 75% to 100%. A concentration of 10 mg/mL doxycycline was used routinely via catheter in 3 instillations with a dose range of 50 to 500 mg per session as per our standard protocol in 17 of 17 patients. In more recent patients, systemic doxycycline levels were obtained after instillations. Additional treatments included direct injection doxycycline (10/17), instillation of absolute ethanol (7/17) or sodium tetradecyl sulfate (4/17), or a combination of these methods.\n\n\nRESULTS\nImaging improvement of ≥ 76% was noted in 11 of 17. Of these, 8 of 11 had macrocystic disease. Four of 17 had 51% to 75% resolution, of which 3/4 were mixed. Two of 17 children had 25% to 50% resolution with a mixed lesion. Seven of 49 peri-procedural complications: hemolytic anemia in 2 infants, hypoglycemic and metabolic acidosis in 3 neonates aged 7 to 10 days, transient hypotension during absolute alcohol instillation in 1 neonate, and self-limiting skin excoriation secondary to peri-catheter leakage of doxycycline in one neonate. Neonates prone to these systemic complications had doxycycline doses of greater than 250 mg and resulted in serum levels of >5 μg/mL but as high as 21 μg/mL. Delayed neural complications occurred in 7 of 49 procedures, Horner's syndromes in 4 of 49 procedures, transient left lip weakness in 1 of 49 procedures, right facial nerve palsy in 1 of 49 procedures, and transient left hemidiaphragm paralysis in 1/49 procedures.\n\n\nCONCLUSIONS\nOur experience with catheter directed doxycycline sclerotherapy provides excellent results for large macrocystic head and neck lymphatic malformations. Microcystic and mixed lesions continue to provide a therapeutic challenge.",
"affiliations": "Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.",
"authors": "Cahill|Anne Marie|AM|;Nijs|Els|E|;Ballah|Deddeh|D|;Rabinowitz|Deborah|D|;Thompson|Lynn|L|;Rintoul|Natalie|N|;Hedrick|Holly|H|;Jacobs|Ian|I|;Low|David|D|",
"chemical_list": "D012597:Sclerosing Solutions; D000431:Ethanol; D004318:Doxycycline; D012981:Sodium Tetradecyl Sulfate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpedsurg.2011.07.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3468",
"issue": "46(11)",
"journal": "Journal of pediatric surgery",
"keywords": null,
"medline_ta": "J Pediatr Surg",
"mesh_terms": "D000402:Airway Obstruction; D000743:Anemia, Hemolytic; D004318:Doxycycline; D000431:Ethanol; D005260:Female; D006258:Head and Neck Neoplasms; D006732:Horner Syndrome; D006801:Humans; D007003:Hypoglycemia; D007223:Infant; D007231:Infant, Newborn; D007267:Injections; D007322:Instillation, Drug; D018191:Lymphangioma, Cystic; D044148:Lymphatic Abnormalities; D008279:Magnetic Resonance Imaging; D008297:Male; D015641:Radiography, Interventional; D012189:Retrospective Studies; D012597:Sclerosing Solutions; D015911:Sclerotherapy; D012981:Sodium Tetradecyl Sulfate; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014463:Ultrasonography",
"nlm_unique_id": "0052631",
"other_id": null,
"pages": "2083-95",
"pmc": null,
"pmid": "22075337",
"pubdate": "2011-11",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations: a single center experience.",
"title_normalized": "percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations a single center experience"
} | [
{
"companynumb": "US-PFIZER INC-2019460702",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE HYCLATE"
},
"drugadditional": "3",... |
{
"abstract": "High-dose chemotherapy and hematopoietic stem cell support remains a curative treatment option for relapsed or nonresponsive germ cell tumors, and has been applied experimentally to control severe autoimmune diseases. In the present study, we report on a patient with systemic lupus erythematosus nephritis who developed a nonseminomatous germ cell tumor that relapsed after standard chemotherapy and surgery. The patient received high-dose chemotherapy supported by autologous hematopoietic cell transplantation based on its indication for relapsed germ cell tumors. Prolonged control of his relapsed germ cell tumor and systemic lupus erythematosus was attained with high-dose chemotherapy and hematopoietic stem cell support. An extensive literature review is provided alongside a detailed discussion of the aforementioned case.",
"affiliations": "Department of Medicine, 2nd Division of Medical Oncology & Hematopoietic Cell Transplantation Program, Metaxa Cancer Hospital, 51 Botassi Street, Piraeus, Greece. ckosmas1@hotmail.com",
"authors": "Kosmas|Christos|C|;Papachrysanthou|Theodora|T|;Daladimos|Theodoros|T|;Athanasopoulos|Aggelos|A|;Tsavaris|Nicolas|N|;Vlachoyiannopoulos|Panayiotis G|PG|",
"chemical_list": "D005047:Etoposide; D003520:Cyclophosphamide; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.2217/fon.13.70",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "9(9)",
"journal": "Future oncology (London, England)",
"keywords": null,
"medline_ta": "Future Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D005047:Etoposide; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008297:Male; D009364:Neoplasm Recurrence, Local; D009373:Neoplasms, Germ Cell and Embryonal; D011379:Prognosis; D016879:Salvage Therapy; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "101256629",
"other_id": null,
"pages": "1401-6",
"pmc": null,
"pmid": "23980687",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Control of relapsed germ cell tumor and SLE nephritis by high-dose chemotherapy and autologous hematopoietic cell transplantation.",
"title_normalized": "control of relapsed germ cell tumor and sle nephritis by high dose chemotherapy and autologous hematopoietic cell transplantation"
} | [
{
"companynumb": "PHHY2013GR107848",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
"druga... |
{
"abstract": "This study reports a case of human immunodeficiency virus (HIV)-related natural killer/T-cell lymphoma with an unexpected clinical course. The lymphoma cells were positive for Epstein-Barr virus and the primary nodal lesions regressed after chemotherapy and combined antiretroviral therapy (c-ART); however, brain metastasis progressed along with a reduction in the CD8+ T-cell count. Chemotherapy was discontinued and the patient was treated with c-ART alone, resulting in regression of the brain lesions and recovery of the CD8+ T-cell count. This case highlights the importance of maintaining anti-tumor immunity in patients with HIV-related lymphoma.",
"affiliations": "Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-Machi Minatojima, Chuo-Ku, Kobe, 650-047, Japan, yosuke.nagahata@gmail.com.",
"authors": "Nagahata|Yosuke|Y|;Kato|Aiko|A|;Imai|Yukihiro|Y|;Ishikawa|Takayuki|T|",
"chemical_list": "D044966:Anti-Retroviral Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-014-1610-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "100(4)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D001932:Brain Neoplasms; D018414:CD8-Positive T-Lymphocytes; D015658:HIV Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D007111:Immunity, Cellular; D018655:Lymphocyte Count; D016399:Lymphoma, T-Cell",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "402-6",
"pmc": null,
"pmid": "24938379",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": "15239400;21328430;20562330;8392401;8656264;12429802;18370955;16254143;8065017;12517536;11300939;23073619;11308402;22355047;11296137;22244256;19805668;18172004;20032536;19561234;9042803;24014242;16427492;21557043;1328576;17117491;21990393;10524519;10950375;8541390;6142304;12239141;15790718;8099121;23593987;9631151;18154487;17509986",
"title": "HIV-related NK/T-cell lymphoma in the brain relapsed during intensive chemotherapy but regressed after chemotherapy discontinuation: the importance of maintaining cellular immunity.",
"title_normalized": "hiv related nk t cell lymphoma in the brain relapsed during intensive chemotherapy but regressed after chemotherapy discontinuation the importance of maintaining cellular immunity"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1008776",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Background. Cytomegalovirus (CMV) antiviral drug resistance constitutes an increasing challenge in transplantation. Foscarnet is usually proposed when resistance for ganciclovir is suspected, but its use is limited by its nephrotoxicity. Case Presentation. We report a case of multiresistant CMV disease in a kidney transplant recipient. Foscarnet was prescribed after ganciclovir treatment failure in a patient with two mutations in the UL97 viral gene. Foscarnet induced biopsy-proven kidney crystal precipitation that resulted in severe acute transplant failure and nephrotic syndrome. Despite a large decrease in immunosuppression, CMV disease was not controlled and a salvage therapy with Brincidofovir (BCV), which is an oral lipid conjugate of cidofovir with limited nephrotoxicity, was attempted. Clinical and virological remission was observed after a 21-day course of BCV, despite mild and reversible liver toxicity. However, a new relapse could not be effectively cured by BCV due to a new mutation in the UL54 gene, which is known to confer resistance to cidofovir. A new course of foscarnet finally resulted in prolonged CMV remission. Herein, we present a review of foscarnet nephropathy cases in solid-organ transplanted patients. Conclusions. This unique case highlights the potential benefit of BCV use during resistant CMV infection, although mutations in the UL54 gene may limit its therapeutic efficacy. These findings need to be confirmed in clinical trials.",
"affiliations": "Centre de Néphrologie et Transplantation Rénale, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix-Marseille University, Marseille, France.;Fédération de Bactériologie-Virologie-Hygiène, Hôpital Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Laboratoire de Bactériologie-Virologie-Hygiène, Centre Hospitalier Universitaire, Limoges, France.;Centre de Néphrologie et Transplantation Rénale, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix-Marseille University, Marseille, France.;Centre de Néphrologie et Transplantation Rénale, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix-Marseille University, Marseille, France.;Centre de Néphrologie et Transplantation Rénale, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Pharmacie Hospitalière, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Aix-Marseille University, Marseille, France; Laboratoire d'Anatomie Pathologique, Hôpital Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Centre de Néphrologie et Transplantation Rénale, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix-Marseille University, Marseille, France.;Centre de Néphrologie et Transplantation Rénale, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.",
"authors": "Vial|Romain|R|;Zandotti|Christine|C|;Alain|Sophie|S|;Decourt|Alexandre|A|;Jourde-Chiche|Noémie|N|0000-0001-9315-1577;Purgus|Raj|R|;Bornet|Charleric|C|;Daniel|Laurent|L|;Moal|Valérie|V|;Legris|Tristan|T|0000-0002-5156-1444",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/3624146",
"fulltext": "\n==== Front\nCase Rep TransplantCase Rep TransplantCRITCase Reports in Transplantation2090-69432090-6951Hindawi Publishing Corporation 10.1155/2017/3624146Case ReportBrincidofovir Use after Foscarnet Crystal Nephropathy in a Kidney Transplant Recipient with Multiresistant Cytomegalovirus Infection Vial Romain \n1\n\n2\nZandotti Christine \n3\nAlain Sophie \n4\nDecourt Alexandre \n1\n\n2\nhttp://orcid.org/0000-0001-9315-1577Jourde-Chiche Noémie \n1\n\n2\nPurgus Raj \n1\nBornet Charleric \n5\nDaniel Laurent \n2\n\n6\nMoal Valérie \n1\n\n2\nhttp://orcid.org/0000-0002-5156-1444Legris Tristan \n1\n\n*\n1Centre de Néphrologie et Transplantation Rénale, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France2Aix-Marseille University, Marseille, France3Fédération de Bactériologie-Virologie-Hygiène, Hôpital Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France4Laboratoire de Bactériologie-Virologie-Hygiène, Centre Hospitalier Universitaire, Limoges, France5Pharmacie Hospitalière, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France6Laboratoire d'Anatomie Pathologique, Hôpital Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France*Tristan Legris: tristan.legris@ap-hm.frAcademic Editor: Frieder Keller\n\n2017 27 2 2017 2017 362414626 12 2016 12 2 2017 Copyright © 2017 Romain Vial et al.2017This 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.\nBackground. Cytomegalovirus (CMV) antiviral drug resistance constitutes an increasing challenge in transplantation. Foscarnet is usually proposed when resistance for ganciclovir is suspected, but its use is limited by its nephrotoxicity. Case Presentation. We report a case of multiresistant CMV disease in a kidney transplant recipient. Foscarnet was prescribed after ganciclovir treatment failure in a patient with two mutations in the UL97 viral gene. Foscarnet induced biopsy-proven kidney crystal precipitation that resulted in severe acute transplant failure and nephrotic syndrome. Despite a large decrease in immunosuppression, CMV disease was not controlled and a salvage therapy with Brincidofovir (BCV), which is an oral lipid conjugate of cidofovir with limited nephrotoxicity, was attempted. Clinical and virological remission was observed after a 21-day course of BCV, despite mild and reversible liver toxicity. However, a new relapse could not be effectively cured by BCV due to a new mutation in the UL54 gene, which is known to confer resistance to cidofovir. A new course of foscarnet finally resulted in prolonged CMV remission. Herein, we present a review of foscarnet nephropathy cases in solid-organ transplanted patients. Conclusions. This unique case highlights the potential benefit of BCV use during resistant CMV infection, although mutations in the UL54 gene may limit its therapeutic efficacy. These findings need to be confirmed in clinical trials.\n==== Body\n1. Introduction\nHuman cytomegalovirus (CMV) infections represent a major clinical issue after solid-organ transplantation, especially when the donor's serological status is positive and the recipient is seronegative (D+/R−) [1]. Despite improvement in diagnosis, prevention, and treatment strategies [2–4], concerns related to antiviral drug resistance (ADR) constitute an increasing challenge for the transplant physician. ADR was tested in a retrospective French cohort study of D+/R− kidney transplant recipients up to one year after transplant if the viremia increased during antiviral therapy. ADR was observed in 16% of the 80 patients who were treated preemptively versus 3% of the 32 patients who received 3 months of valganciclovir-based prophylaxis (p = 0.05) [5]. Other risk factors for ADR include the type of transplant (highest risk for lung and kidney-pancreas recipients), D+/R− serostatus, delay in commencement of prophylaxis, high peak blood viral load (>105 copies/ml), increased duration of antiviral exposure, and suboptimal drug concentration [6]. Intravenous ganciclovir (GCV) or oral valganciclovir (vGCV) is recommended as the first-line treatments for CMV disease within the transplant population [2]. Other drugs, such as foscarnet (FOS) and cidofovir (CDV), are typically proposed as second-line therapies when ADR is suspected. However, FOS and CDV cause significant nephrotoxicity, and FOS also induces electrolyte abnormalities. Brincidofovir (BCV), which is a new orally bioavailable lipid acyclic nucleoside phosphonate that is converted intracellularly into CDV diphosphate, has limited renal toxicity [7]. Here, we report a case of BCV use in the setting of FOS nephrotoxicity in a transplant recipient with CMV ADR.\n\n2. Case Presentation\nA 42-year-old woman with stage 5D chronic kidney disease related to MYH9-related disease received her first kidney transplant from a familial living donor. Repeated anti-HLA antibody blood testing was negative, despite previous blood transfusions and pregnancies. The A, B, DR, and DQ HLA mismatches were 0/1/1/1, respectively. The CMV serostatus was D+/R−. Her immunosuppressive regimen consisted of an induction with antithymocyte globulins and a maintenance regimen with ciclosporin A, azathioprine, and steroids. She also received cotrimoxazole and vGCV prophylaxis for 6 months (900 mg/d). With the exception of two deep venous thrombosis episodes, the first seven months after transplantation was unremarkable with good transplant function (serum creatinine level = 100 μmol/L). One month after vGCV discontinuation on day (D) 222 after graft, she was admitted for a fever of 38.2°C and epigastric pain without diarrhea. Her biological tests revealed a severe lymphocytopenia (150/mm3). Her serum creatinine level was 122 μmol/L. The blood and urine cultures and liver and pancreatic tests were unremarkable, whereas her pp65 antigenemia was strongly positive (600 positive cells/200000 polymorphonuclear leukocytes (PC)). The chest X-ray and fundus examination did not suggest pulmonary or retinal CMV involvement. An upper gastrointestinal endoscopy revealed gastritis with a positive CMV polymerase chain reaction (PCR). Due to the diagnosis of possible CMV gastrointestinal disease [4], a first intravenous GCV treatment (10 mg/kg/d) was started together with a decrease in immunosuppression (half azathioprine dose), resulting in a slow but sustained decrease in the CMV antigenemia. Two months of GCV was needed to obtain viral clearance defined by two consecutive weekly negative antigenemia results.\n\nOne week after GCV discontinuation on D288, she was readmitted for fever recurrence and abdominal pain and a relapse of CMV disease was observed (antigenemia = 20 PC). No retinitis was found again. As digestive symptoms were similar to recent primary CMV infection, no new upper endoscopy was performed. A new GCV-based treatment (10 mg/kg/day) was started. No clinical or biological improvement was noted after two weeks of treatment (antigenemia = 115 PC) despite azathioprine withdrawal. Genotypic testing for ADR in the UL97 kinase gene revealed two common mutations (A594V and L595S) associated with moderate viral resistance for GCV [13] and no mutation in the UL54 DNA polymerase gene. The kidney graft function was stable (serum creatinine level = 100 μmol/L). Thus, a second-line treatment with intravenous FOS (180 mg/kg/d) was initiated at D306. A fast decrease in the CMV viral load was observed that allowed FOS weaning at D320. A second relapse of CMV infection (same symptoms, antigenemia = 25 PC, blood quantitative CMV PCR = 351000 DNA copies/mL) at D329 led us to restart FOS at the same dose. Unfortunately, 6 days after this new FOS course a severe acute graft failure was noted (serum creatinine level = 450 μmol/L, blood ciclosporin trough level = 200 ng/mL) that was associated with an acute nephrotic syndrome (urinary protein creatinine ratio = 4.5 g/g and serum albumin = 2.6 g/dL). A transplant biopsy showed diffuse tubular necrosis and tubular and intraglomerular crystal deposits that obstructed capillaries and were suggestive of FOS nephropathy. No sign of acute rejection or CMV transplant infection was noted on the biopsy (Figure 1). At that time, the CMV antigenemia had become negative, blood CMV PCR was weak (1381 copies/mL), and FOS was stopped, which allowed a partial reversal of the glomerulopathy and transplant failure (serum creatinine level = 150 μmol/L and proteinuria = 1 g/d).\n\nHowever, at D341 a third CMV relapse occurred (antigenemia = 78 PC, PCR = 141000 copies/mL). Because the FOS toxicity was recent, we decided to begin a double-dose of GCV therapy [14] together with intravenous immunoglobulins (2 infusions of 0.3 g/kg/d at a 10-day interval) and a decrease in the ciclosporin target trough level (100 ng/mL). One month later, persistent low-grade symptoms and mild but positive CMV antigenemia (5–15 PC) reflected the failure of this regimen. A second genotypic testing for ADR revealed the same L595S mutation in the UL97 gene without mutation in the UL54 gene. To avoid new FOS toxicity, oral BCV was introduced (100 mg orally twice a week) at D376 for 21 days with good results on clinical and viral parameters (negative antigenemia and blood PCR after 17 days). A mild isolated cytolysis (alanine and aspartate aminotransferase (ALT and AST) = 137 and 104 IU/L, respectively) and moderate epigastric pain were observed during therapy. Liver ultrasonography was normal. The liver enzymes returned to normal levels and the abdominal pain disappeared after BCV discontinuation. Nevertheless, at D412 a 4th relapse was observed (antigenemia = 16 PC, blood PCR = 95700 copies/mL) and was again treated with BCV for 15 days (200 mg/week). After 15 days of BCV, persistent diarrhea and abdominal pain indicated a new upper gastrointestinal endoscopy together with a colonoscopy. CMV PCR biopsies of stomach and large bowel were positive (3380 and 3020 copies/mL, respectively). Blood CMV antigenemia and PCR were 9 PC and 38200 copies/mL, respectively, after 15 days of BCV. A new mild and isolated cytolysis (ALT = 143, ASAT = 155 IU/L) appearing at the same time led us to definitely stop BCV. Liver enzymes returned to normal levels after BCV discontinuation. No liver biopsy was performed. A third genotypic ADR test, performed at the end of the second course of BCV, revealed a novel F412L mutation in the UL54 DNA polymerase gene that was associated with moderate resistance for GCV and CDV but not FOS [15]. Before reinitiating FOS, a new transplant biopsy was performed at D441 (serum creatinine = 150 μmol/L and proteinuria = 1 g/g). Seven of the 25 glomeruli were sclerotic. Interstitial fibrosis and tubular atrophy were mild without crystals, rejection, or CMV signs. A new two-month course of intravenous FOS (50 mg/kg/d, dose tailored to decreased glomerular filtration rate) was necessary to achieve a complete resolution of CMV infection (negative antigenemia and PCR) without any new FOS nephropathy. Figure 2 describes the course of the CMV disease together with the course of immunosuppression and blood lymphocyte counts.\n\nCurrently, the patient's overall condition is normal 6 months after the final treatment, without secondary CMV prophylaxis. Repeated CMV antigenemia tests have been negative, and the graft function remains stable (mean creatinine = 130 μmol/L, proteinuria = 0.6 g/g, without anti-HLA antibodies).\n\n3. Discussion\nTo our knowledge, we report the first published case of refractory CMV infection treated with BCV in a kidney transplant recipient. BCV (formerly CMX001) is a lipid conjugate of CDV and is highly active in vitro against various double-stranded DNA viruses, such as adenoviruses, herpesviruses, human papillomaviruses, polyomaviruses (including BK virus), and orthopoxviruses [7]. BCV can inhibit the UL54 CMV DNA polymerase when it is converted intracellularly into CDV. Interestingly, BCV's in vitro activity is increased by 422-fold compared to CDV [16], probably due to its more efficient cellular uptake facilitated by the lipid chain. In contrast to CDV, which is actively secreted from the blood into kidney proximal tubule cells by organic anion transporters (OAT), BCV is not a substrate of OAT1 and thus has a lower risk of nephrotoxicity.\n\nA phase 2 study of BCV involved 230 CMV-seropositive allogeneic hematopoietic cell transplant (HCT) recipients who were randomized to receive BCV or a placebo to prevent CMV events. The incidence of CMV events was significantly lower among patients who received BCV at a dose of 100 mg twice weekly than among those who received the placebo. Diarrhea, vomiting, and abdominal pain were the most common adverse effects in the group that received this dose. No increased risk of nephrotoxicity was observed [17]. However, in the recent phase 3 SUPPRESS trial, despite an antiviral effect seen at the end of the on-treatment period at week 14 following HCT (with patients who received BCV experiencing fewer clinically significant CMV infections than patients in the placebo group (24 percent versus 38 percent, p = 0.002)), the primary endpoint of prevention of significant CMV infection at week 24 was not reached (data reported at the 2016 BMT Tandem Meetings). These clinical results in a population at risk for kidney injuries together with the in vitro findings mentioned above prompted us to try BCV in our difficult case of GCV resistance and previous FOS nephrotoxicity. Since our personal experience, BCV use has been recently reported in other case studies as a potential curative treatment involving severe resistant dsDNA viral infections (CMV, HSV, and VZV) in HCT recipients and immunocompromised cancer patients [18–21].\n\nIn our report, BCV treatment resulted initially in a remission of CMV disease but was marked by abdominal pain, diarrhea, and ALT elevation. Liver metabolism has been proposed to be the most likely major route of elimination for BCV [7]. Mild dose-dependent ALT elevations were observed in 10 to 40% of stem-cell recipients [17]. The known metabolic pathway of BCV, the course of our clinical case, the typical damage, and the rechallenging situation are clearly enough to confirm a BCV induced liver damage, even if mild and likely dose-dependent. However, it was difficult to distinguish between side effect of BCV and gastrointestinal CMV infection itself, regarding abdominal pain and diarrhea.\n\nSimilar to CDV, CMV resistance to BCV only involves UL54 DNA polymerase mutations and not UL97 mutations [15]. In the phase 2 trial mentioned above, no known resistance-associated mutations were detected in the BCV arms. Two mutations (M827I and R1052C) in the UL54 gene were found in a small number of subjects without decreased susceptibility to BCV, CDV, GCV, or FOS [22]. Our case and another case in a lung transplant recipient treated with BCV [23] illustrated that BCV could be associated with the A987G and F412L UL94 mutations known to confer ADR to CDV.\n\nThus, BCV could constitute an antiviral alternative in cases with UL97 mutations when FOS is contraindicated or in cases of FOS nephrotoxicity. Foscarnet nephropathy was initially described in the 1980s as a frequent complication in AIDS patients undergoing treatment for CMV infection [24]. In vivo trisodium foscarnet crystals mixed with sodium calcium salt were first identified by infrared microscopy in the glomerular capillary lumens and tubules of AIDS patients [25]. Importantly, isotonic saline infusion of 1.5 to 2.5 liters per day was demonstrated to reduce this renal toxicity by increasing FOS clearance and constituted the best preventive strategy [24]. Nonetheless, renal failure is possible with FOS despite appropriate hydration. Cases of biopsy-proven FOS crystal precipitation in the transplantation field are relatively scarce and are summarized in Table 1. With the exception of one lung recipient, all patients were kidney transplant recipients. FOS nephropathy does not seem to appear during the first days of therapy but rather after several weeks of treatment. Glomerular crystallization seems to be associated with worse acute kidney injury than isolated tubular crystallization [12]. At worst, FOS nephropathy led to kidney graft loss. Interestingly, FOS precipitation was also observed in the lungs, heart, pancreas, and gastrointestinal tract in two patients with severe systemic crystal dissemination [10, 11].\n\nIn conclusion, BCV appeared to be useful in this complicated case of CMV resistance. Although CMV became also resistant to BCV and some mild toxicity occurred, the length of BCV course allowed FOS nephropathy to recover, which facilitated repeated use of FOS, ultimate clearance of the virus, and preserved transplant function. A clinical trial of BCV to manage resistant CMV disease is needed.\n\nAcknowledgments\nThe authors thank Chimerix Inc. (Durham, NC, USA) for the generous delivery of Brincidofovir for compassionate use. Brincidofovir was delivered after temporary permission (Autorisation Temporaire d'Utilisation, ATU) was received from the French Agence Nationale de Securité du Médicament et des Produits de Santé (ANSM).\n\nConsent\nThe patient provided written informed consent before use of Brincidofovir.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Foscarnet nephropathy in the kidney transplant. (a) Masson's trichrome staining (×200) showed intraglomerular crystalline precipitation obstructing the capillaries and crushing the mesangium together with fibrinoid thrombi. (b) Jones methenamine silver staining (×400) also revealed FOS crystals within the glomerular capillaries. (c) Masson's trichrome staining (×200) showed crystals that resembled short sticks with angular edges in the tubular lumen. (d) Jones methenamine silver staining (×400) also revealed FOS crystals within the tubular lumen.\n\nFigure 2 Course of multiresistant CMV disease. (a) Evolution of CMV antigenemia (red line) and kidney transplant function (serum creatinine level, blue line) together with antiviral therapies and genotypic mutations. PC: positive cells/200000 polymorphonuclear leukocytes. GCV: ganciclovir. CDV: cidofovir. (b) Evolution of blood ciclosporin levels (black line) and lymphocytes counts (blue line).\n\nTable 1 Summary of cases of biopsy-proven foscarnet nephropathy during CMV infection in solid organ transplantation.\n\nReference\tType of transplant\tIndication of FOS\tTime to nephropathy after FOS initiation\tPeak serum creatinine\tProteinuria\tBiopsy results\tOutcome\t\n[8, 9]\tKidney\nD+/R−\tCMV syndrome\nPersistent high CMV viremia after 65 days of GCV\t30 days (single treatment)\t387 μmol/L\t7 g/d\tBirefringent crystal precipitation surrounded by macrophages in glomeruli and tubules. Fibrinoid thrombi.\nBlack crystals with Von Kossa's reaction.\tFOS withdrawn after 27 days.\nSeven months after FOS nephropathy: creatinine level at 158 μmol/L, proteinuria at 2 g/d.\nSecond transplant biopsy: moderate interstitial fibrosis and tubular atrophy with sclerosis of half glomeruli, no crystal, and positive in situ CMV PCR.\t\n\n\n\t\n[10]\tLung\nD−/R+\tCMV bronchiolitis\nM460I mutation in the UL97 gene\t35 days (second treatment; first treatment of 4 weeks)\t475 μmol/L\tNR\tAutopsy: birefringent short crystals with angular edges in glomeruli (with rupture of capillaries and Bowman's capsule) and in tubules with tubular necrosis and granulomas.\tNo FOS withdrawal.\nDeath 5.5 months after CMV disease (mild acute rejection, chronic lung rejection).\nCrystals found in lungs, esophagus, kidney, epicardium, pericardium, and tricuspid valve at autopsy.\t\n\n\n\t\n[11]\tKidney\nD−/R+\tAsymptomatic reactivation of GCV resistant strain despite prophylactic valganciclovir\t21 days (single treatment)\tAnuria, hemodialysis\tNR\tCrystals in tubules and in one-third of glomeruli with rupture of the basement membrane, tubular necrosis, and macrophages.\tMultiorgan (kidney, pancreas, and myocardium) damage due to FOS crystal precipitation.\nPancreatitis and myocarditis resolved.\nGraft loss and dialysis therapy continued.\t\n\n\n\t\n[12]\tKidney\nD+/R−\tCMV hepatitis and retinitis\nA594V mutation in the UL97 gene\tAfter 14 days (single treatment)\t157 μmol/L\tNR\tBirefringent crystals in the tubular lumens.\nBlack crystals with Von Kossa's reaction.\tFOS withdrawal.\nTen months after FOS nephropathy: creatinine level at 112 μmol/L.\nSecond transplant biopsy: disappearance of crystal deposition.\t\n\n\n\t\nPR\tKidney\nD+/R−\tCMV gastritis\nA594V and L595S mutations in the UL97 gene\t6 days (second treatment; first treatment of 14 days)\t450 μmol/L\t4.5 g/g of creatininuria\tCrystals in glomeruli and tubules.\tFOS withdrawal followed by Brincidofovir.\nSecond biopsy: disappearance of crystals, sclerosis of one-third glomeruli, mild interstitial fibrosis, and tubular atrophy.\nThird treatment with FOS: resolution of CMV disease.\nOne year after FOS nephropathy: creatinine level at 130 μmol/L, proteinuria at 0.6 g/g.\t\nCMV, cytomegalovirus; FOS, foscarnet; GCV, ganciclovir; NR, not reported; PCR, polymerase chain reaction; PR, present report.\n==== Refs\n1 Beam E. Razonable R. R. Cytomegalovirus in solid organ transplantation: epidemiology, prevention, and treatment Current Infectious Disease Reports 2012 14 6 633 641 10.1007/s11908-012-0292-2 2-s2.0-84870501968 22992839 \n2 Kotton C. N. Kumar D. Caliendo A. M. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation Transplantation 2013 96 4 333 360 10.1097/TP.0b013e31829df29d 2-s2.0-84883455574 23896556 \n3 Razonable R. R. Humar A. Cytomegalovirus in solid organ transplantation American Journal of Transplantation 2013 13 s4 93 106 10.1111/ajt.12103 2-s2.0-84874828991 23465003 \n4 Ljungman P. Boeckh M. Hirsch H. H. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials Clinical Infectious Diseases 2017 64 1 87 91 10.1093/cid/ciw668 27682069 \n5 Couzi L. Helou S. Bachelet T. High incidence of anticytomegalovirus drug resistance among D+R− kidney transplant recipients receiving preemptive therapy American Journal of Transplantation 2012 12 1 202 209 10.1111/j.1600-6143.2011.03766.x 2-s2.0-84855959376 21967659 \n6 Le Page A. K. Jager M. M. Iwasenko J. M. Scott G. M. Alain S. Rawlinson W. D. Clinical aspects of cytomegalovirus antiviral resistance in solid organ transplant recipients Clinical Infectious Diseases 2013 56 7 1018 1029 10.1093/cid/cis1035 2-s2.0-84875010780 23243176 \n7 Lanier R. Trost L. Tippin T. Development of CMX001 for the treatment of poxvirus infections Viruses 2010 2 12 2740 2762 10.3390/v2122740 2-s2.0-79952136133 21499452 \n8 Justrabo E. Zanetta G. Martin L. Irreversible glomerular lesions induced by crystal precipitation in a renal transplant after foscarnet therapy for cytomegalovirus infection Histopathology 1999 34 4 365 369 10.1046/j.1365-2559.1999.00642.x 2-s2.0-0032893278 10231404 \n9 Zanetta G. Maurice-Estepa L. Mousson C. Foscarnet-induced crystalline glomerulonephritis with nephrotic syndrome and acute renal failure after kidney transplantation Transplantation 1999 67 10 1376 1378 10.1097/00007890-199905270-00016 2-s2.0-0033609380 10360595 \n10 Tischler V. Schuurmans M. M. Boehler A. Gaspert A. Crystal precipitation and granulomatous inflammation in multiple organs after foscarnet therapy in a lung transplant recipient The Journal of Heart and Lung Transplantation 2012 31 9 1037 1040 10.1016/j.healun.2012.05.008 2-s2.0-84864918311 22766024 \n11 Philipponnet C. Michel P.-A. Daudon M. Brocheriou I. Boffa J.-J. Intravascular foscarnet crystal precipitation causing multiorgan failure American Journal of Kidney Diseases 2014 65 1 152 155 10.1053/j.ajkd.2014.07.024 2-s2.0-84922371002 25301103 \n12 Iwami D. Ogawa Y. Fujita H. Successful treatment with foscarnet for ganciclovir-resistant cytomegalovirus infection in a kidney transplant recipient: a case report Nephrology 2016 21 S1 63 66 10.1111/nep.12767 2-s2.0-84976541153 26970406 \n13 Lurain N. S. Chou S. Antiviral drug resistance of human cytomegalovirus Clinical Microbiology Reviews 2010 23 4 689 712 10.1128/CMR.00009-10 2-s2.0-78049355534 20930070 \n14 West P. Schmiedeskamp M. Neeley H. Oberholzer J. Benedetti E. Kaplan B. Use of high-dose ganciclovir for a resistant cytomegalovirus infection due to UL97 mutation Transplant Infectious Disease 2008 10 2 129 132 10.1111/j.1399-3062.2007.00249.x 2-s2.0-40849098571 17605740 \n15 Chou S. Phenotypic diversity of cytomegalovirus DNA polymerase gene variants observed after antiviral therapy Journal of Clinical Virology 2011 50 4 287 291 10.1016/j.jcv.2011.01.004 2-s2.0-79952618827 21295516 \n16 Williams-Aziz S. L. Hartline C. B. Harden E. A. Comparative activities of lipid esters of cidofovir and cyclic cidofovir against replication of herpesviruses in vitro Antimicrobial Agents and Chemotherapy 2005 49 9 3724 3733 10.1128/AAC.49.9.3724-3733.2005 2-s2.0-24144458260 16127046 \n17 Marty F. M. Winston D. J. Rowley S. D. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation New England Journal of Medicine 2013 369 13 1227 1236 10.1056/NEJMoa1303688 2-s2.0-84884528238 24066743 \n18 El-Haddad D. El Chaer F. Vanichanan J. Brincidofovir (CMX-001) for refractory and resistant CMV and HSV infections in immunocompromised cancer patients: a single-center experience Antiviral Research 2016 134 58 62 10.1016/j.antiviral.2016.08.024 27582067 \n19 Camargo J. F. Morris M. I. Abbo L. M. The use of brincidofovir for the treatment of mixed dsDNA viral infection Journal of Clinical Virology 2016 83 1 4 10.1016/j.jcv.2016.07.021 2-s2.0-84982803413 27513204 \n20 Mullane K. M. Nuss C. Ridgeway J. Brincidofovir treatment of acyclovir-resistant disseminated varicella zoster virus infection in an immunocompromised host Transplant Infectious Disease 2016 18 5 785 790 10.1111/tid.12583 27481400 \n21 Voigt S. Hofmann J. Edelmann A. Sauerbrei A. Kühl J. Brincidofovir clearance of acyclovir-resistant herpes simplex virus-1 and adenovirus infection after stem cell transplantation Transplant Infectious Disease 2016 18 5 791 794 10.1111/tid.12582 27482652 \n22 Randall Lanier E. Foster S. Brundage T. Analysis of mutations in the gene encoding cytomegalovirus DNA polymerase in a phase 2 clinical trial of brincidofovir prophylaxis Journal of Infectious Diseases 2016 214 1 32 35 10.1093/infdis/jiw073 2-s2.0-84979266779 26941282 \n23 Kaul D. R. Stoelben S. Cober E. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246 American Journal of Transplantation 2011 11 5 1079 1084 10.1111/j.1600-6143.2011.03530.x 2-s2.0-79955544310 21521474 \n24 Deray G. Martinez F. Katlama C. Foscarnet nephrotoxicity: mechanism, incidence and prevention American Journal of Nephrology 1989 9 4 316 321 10.1159/000167987 2-s2.0-0024328491 2554731 \n25 Maurice-Estepa L. Daudon M. Katlama C. Identification of crystals in kidneys of AIDS patients treated with foscarnet American Journal of Kidney Diseases 1998 32 3 392 400 10.1053/ajkd.1998.v32.pm9740154 2-s2.0-0031657564 9740154\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6951",
"issue": "2017()",
"journal": "Case reports in transplantation",
"keywords": null,
"medline_ta": "Case Rep Transplant",
"mesh_terms": null,
"nlm_unique_id": "101591863",
"other_id": null,
"pages": "3624146",
"pmc": null,
"pmid": "28348914",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "24066743;23465003;20930070;27582067;9740154;17605740;27482652;26970406;21521474;2554731;21967659;22766024;25301103;23243176;26941282;16127046;23896556;22992839;10231404;27513204;10360595;27481400;21295516;27682069;21499452",
"title": "Brincidofovir Use after Foscarnet Crystal Nephropathy in a Kidney Transplant Recipient with Multiresistant Cytomegalovirus Infection.",
"title_normalized": "brincidofovir use after foscarnet crystal nephropathy in a kidney transplant recipient with multiresistant cytomegalovirus infection"
} | [
{
"companynumb": "FR-CLINIGEN GROUP PLC/ CLINIGEN HEALTHCARE LTD-FR-CLGN-17-00123",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FOSCARNET SODIUM"
... |
{
"abstract": "The CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) is a genetic mutation-targeted treatment in cystic fibrosis that results in profound improvements in clinical outcomes. Each of the compounds are substrates of CYP3A4/5, the cytochrome P450 enzyme family for which tacrolimus is also a substrate. The use of these compounds in an individual with a solid organ transplant has not been previously studied and there is potential for a drug interaction. In this report, we describe a pediatric liver transplant recipient with clinical decline related to cystic fibrosis who improved substantially with ETI, without significant impact on the systemic exposure of either ETI or tacrolimus.",
"affiliations": "McWhorter School of Pharmacy, Samford University, Birmingham, AL.;Department of Pharmacology and Toxicology, UAB, Birmingham, AL.;Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL; Department of Pediatrics, Division of Pulmonary and Sleep Medicine, UAB, Birmingham, AL.;Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, UAB, Birmingham, AL.;Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of South Carolina, Charleston, SC.;Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL; Department of Pharmacology and Toxicology, UAB, Birmingham, AL.;McWhorter School of Pharmacy, Samford University, Birmingham, AL.;Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL; Department of Pediatrics, Division of Pulmonary and Sleep Medicine, UAB, Birmingham, AL. Electronic address: jguimbellot@peds.uab.edu.",
"authors": "Smith|Megan|M|;Ryan|Kevin J|KJ|;Gutierrez|Hector|H|;Sanchez|Luz Helena Gutierrez|LHG|;Anderson|Janaina Nogueira|JN|;Acosta|Edward P|EP|;Benner|Kim W|KW|;Guimbellot|Jennifer S|JS|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jcf.2021.05.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1569-1993",
"issue": null,
"journal": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society",
"keywords": "CFTR; Cytochrome p450; Drug interaction; Elexacaftor; Ivacaftor; Liver transplantation; Tacrolimus; Tezacaftor",
"medline_ta": "J Cyst Fibros",
"mesh_terms": null,
"nlm_unique_id": "101128966",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34130909",
"pubdate": "2021-06-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ivacaftor-elexacaftor-tezacaftor and tacrolimus combination in cystic fibrosis.",
"title_normalized": "ivacaftor elexacaftor tezacaftor and tacrolimus combination in cystic fibrosis"
} | [
{
"companynumb": "US-VERTEX PHARMACEUTICALS-2020-009342",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ELEXACAFTOR\\IVACAFTOR\\TEZACAFTOR"
},
... |
{
"abstract": "Intraarticular corticosteroid (IAC) injections are often used to treat temporomandibular joint (TMJ) arthritis associated with juvenile idiopathic arthritis (JIA). One potential complication of IA therapy is heterotopic bone formation (HBF). The purpose of our study was to evaluate risk factors for HBF development in children with JIA who received IA therapy for TMJ arthritis.\n\n\n\nThis was a retrospective study of children with JIA who had received ≥ 1 IAC injection into the TMJ. Survival regression analysis was performed to identify risk factors for the development of HBF.\n\n\n\nThere were 238 children included, of whom 33 (14%) developed HBF. No cases of HBF were diagnosed prior to the initial injection. Univariate analysis revealed that the risk factors for development of HBF were the total number of injections received into the TMJ and age at diagnosis of JIA, while the length of time from diagnosis of JIA to the first injection was inversely associated with the risk of HBF formation. The total number of injections was no longer significant following adjusted survival models. Children with HBF had increased physical examination evidence of acute or chronic changes, namely decreased maximal incisal opening and increased likelihood of jaw deviation.\n\n\n\nHBF within the TMJ is relatively common in patients with JIA receiving IAC injections for TMJ arthritis. Future prospective studies are required to delineate the risks posed by the injections themselves as opposed to the underlying disease activity, as well as to evaluate alternative forms of local therapy to the TMJ.",
"affiliations": "From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA. MStoll@peds.uab.edu.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.;From the Department of Pediatrics at the University of Alabama at Birmingham, Birmingham, Alabama, USA.",
"authors": "Stoll|Matthew L|ML|;Amin|Dina|D|;Powell|Kathlyn K|KK|;Poholek|Catherine H|CH|;Strait|Rachel H|RH|;Aban|Inmaculada|I|;Beukelman|Timothy|T|;Young|Daniel W|DW|;Cron|Randy Q|RQ|;Waite|Peter D|PD|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.171306",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "45(9)",
"journal": "The Journal of rheumatology",
"keywords": "HETEROTOPIC OSSIFICATION; INTRAARTICULAR INJECTIONS; JUVENILE ARTHRITIS; TEMPOROMANDIBULAR JOINT",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D001171:Arthritis, Juvenile; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007270:Injections, Intra-Articular; D008279:Magnetic Resonance Imaging; D008297:Male; D009999:Ossification, Heterotopic; D012189:Retrospective Studies; D012307:Risk Factors; D013704:Temporomandibular Joint",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "1301-1307",
"pmc": null,
"pmid": "29764966",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk Factors for Intraarticular Heterotopic Bone Formation in the Temporomandibular Joint in Juvenile Idiopathic Arthritis.",
"title_normalized": "risk factors for intraarticular heterotopic bone formation in the temporomandibular joint in juvenile idiopathic arthritis"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-230271",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"d... |
{
"abstract": "OBJECTIVE\nBacterial colonization is considered a major risk factor for necrotizing enterocolitis (NEC). The objective of the present study was to test the hypothesis that histamine-2 receptor (H2-) blockers alter colonic bacterial colonization by analyzing and comparing the fecal microbiota in premature infants with and without H2-blocker therapy using sensitive molecular biological techniques.\n\n\nMETHODS\nSeventy-six premature infants ≤1500 g or <34 weeks gestation were enrolled in this case-controlled, cross-sectional study. Stool samples were collected from 25 infants receiving H2-blockers and 51 babies who had never received them. Following DNA extraction and PCR amplification of 16S rRNA, 454 pyrosequencing was undertaken and the resulting sequences were subjected to comparison with published sequence libraries.\n\n\nRESULTS\nProteobacteria and Firmicutes were the major phyla contributing to fecal microbial communities. Microbial diversity was lower, relative abundance of Proteobacteria (primarily of the family Enterobacteriaceae) was increased, whereas that of Firmicutes was decreased in the stools of infants receiving H2-blockers compared with those who had never received them.\n\n\nCONCLUSIONS\nAlthough not designed to look specifically at the effect of H2-blockers on the incidence of NEC, our study suggests that their use lowers fecal microbial diversity and shifts the microfloral pattern toward Proteobacteria. These alterations in fecal microbiota may predispose the vulnerable immature gut to necrotizing enterocolitis and suggest prudence in the use of H2-blockers in the premature infant.",
"affiliations": "Department of Pediatrics, Division of Neonatology, Louisiana State University Health Sciences Center, New Orleans, LA 70118, USA. rwetze@lsuhsc.edu",
"authors": "Gupta|Raegan W|RW|;Tran|Lynn|L|;Norori|Johana|J|;Ferris|Michael J|MJ|;Eren|A Murat|AM|;Taylor|Christopher M|CM|;Dowd|Scot E|SE|;Penn|Duna|D|",
"chemical_list": "D006635:Histamine H2 Antagonists",
"country": "United States",
"delete": false,
"doi": "10.1097/MPG.0b013e318282a8c2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-2116",
"issue": "56(4)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D016022:Case-Control Studies; D002657:Child Development; D003430:Cross-Sectional Studies; D020345:Enterocolitis, Necrotizing; D005243:Feces; D005260:Female; D006090:Gram-Negative Bacteria; D006094:Gram-Positive Bacteria; D006635:Histamine H2 Antagonists; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D007413:Intestinal Mucosa; D007422:Intestines; D008137:Longitudinal Studies; D008145:Louisiana; D008297:Male; D020560:Proteobacteria; D012307:Risk Factors",
"nlm_unique_id": "8211545",
"other_id": null,
"pages": "397-400",
"pmc": null,
"pmid": "23254444",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Histamine-2 receptor blockers alter the fecal microbiota in premature infants.",
"title_normalized": "histamine 2 receptor blockers alter the fecal microbiota in premature infants"
} | [
{
"companynumb": "US-SA-2019SA248480",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANITIDINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "The Jarisch-Herxheimer reaction (JHR) is a transient inflammatory syndrome triggered hours after the start of antibiotic treatment of spirochete infections, namely syphilis. Clinically, JHR manifests as an abrupt onset of constitutional symptoms and exacerbation of cutaneous lesions that resolve without intervention. JHR's pathogenesis is unclear and it is histopathologically rarely reported. Herein, the authors report a 47-year-old woman, with solitary erythema migrans and positive Lyme disease serology, who presented for medical care 14 days after commencement of doxycycline therapy. She complained of malaise, facial flushing, gingival erythema, and acquisition of additional plaques characterized by swelling, increased erythema, pruritus, and exfoliative scale. Punch biopsies demonstrated subacute to chronic spongiotic psoriasiform reaction patterns with a superficial lymphocytic infiltrate. By Borrelia-specific immunohistochemistry, spirochetes were found in the deep dermis, unassociated with inflammation, and focally in the upper spinous layer, associated with spongiosis. Borrelia burgdorferi DNA was detected by nested polymerase chain reaction. Doxycycline was discontinued, and symptoms and signs resolved within a few days. Liberation of endotoxin-like materials (eg, lipoproteins) from degenerating spirochetes and concomitant cytokine production is the suspected cause of JHR and supported by the finding of lesional spirochetes. Alternatively, a reversal reaction with a delayed-type hypersensitivity reaction is also a plausible cause based on spirochetes found in the lymphocytic spongiotic dermatitis.",
"affiliations": "*Department of Pathology, Divisions of Dermatology and Dermatopathology, Albany Medical College, Albany, NY; †Upper Hudson Valley Dermatology, Castleton, NY; and ‡Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.",
"authors": "Kadam|Pooja|P|;Gregory|Neal A|NA|;Zelger|Bernhard|B|;Carlson|J Andrew|JA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000000093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "37(6)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D004318:Doxycycline; D003875:Drug Eruptions; D015787:Erythema Chronicum Migrans; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "e68-74",
"pmc": null,
"pmid": "25033009",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Delayed onset of the Jarisch-Herxheimer reaction in doxycycline-treated disease: a case report and review of its histopathology and implications for pathogenesis.",
"title_normalized": "delayed onset of the jarisch herxheimer reaction in doxycycline treated disease a case report and review of its histopathology and implications for pathogenesis"
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"abstract": "Women with Turner syndrome (TS) are subfertile due to premature ovarian insufficiency. Most women require hormone replacement therapy for attaining menarche and assisted reproductive technology (ART) using donor oocytes, autologous oocytes or in-vitro fertilisation for conception. Irrespective of the karyotype, monosomy X (45, X) or mosaic pattern, women with TS hold a very high risk for pregnancy due to high mortality rate secondary to aortic dissection and severe pre-eclampsia. Such high-risk pregnancies mandate extensive prepregnancy counselling, the need for multidisciplinary teams, close surveillance and follow-up to attain a successful outcome. In this article, we report one such case of pregnancy in a woman with TS carrying a twin gestation following ART with donor oocyte.",
"affiliations": "Obstetrics and Gynecology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India drrmonishaa@gmail.com.;Obstetrics and Gynecology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India.",
"authors": "Rajsekher|Monishaa|M|;Narayanan|Palaniappan|P|",
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"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "endocrinology; gynaecology and fertility; hypertension; obstetrics; pregnancy; reproductive medicine",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D009035:Mothers; D011247:Pregnancy; D016649:Primary Ovarian Insufficiency; D027724:Reproductive Techniques, Assisted; D014424:Turner Syndrome",
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"pmid": "34116994",
"pubdate": "2021-06-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Turning a Turner to a twin mother.",
"title_normalized": "turning a turner to a twin mother"
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"abstract": "We are reporting on a case of a 41-year-old woman who presented with metastatic gastroesophageal junction cancer and who achieved prolonged survival with a multimodal treatment approach. After initially experiencing robust response to chemotherapy, she was treated for distant recurrence with palliative radiation to the gastrohepatic and supraclavicular lymph nodes and subsequently, given her unusual near-complete response, with reirradiation to the abdomen with curative intent for residual disease. The case presented is unique due to the patient's atypical treatment course, including technically difficult reirradiation to the abdomen, and the resulting prolonged survival despite metastatic presentation.",
"affiliations": "Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.;Department of Medical Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.;Department of Gastroenterology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.;Department of Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.;Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.;Department of Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.;Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.;Department of Medical Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.;Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.",
"authors": "Smith|William H|WH|;Pintova|Sofya|S|;DiMaio|Christopher J|CJ|;Manolas|Panagiotis|P|;Lee|Dong-Seok|DS|;Hiotis|Spiros P|SP|;Kartsonis|Maria|M|;Holcombe|Randall F|RF|;Dharmarajan|Kavita V|KV|",
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"doi": "10.1155/2015/941508",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2015/941508Case ReportAn Unusual Course of Metastatic Gastroesophageal Cancer Smith William H. \n1\n\n*\nPintova Sofya \n2\nDiMaio Christopher J. \n3\nManolas Panagiotis \n4\nLee Dong-Seok \n5\nHiotis Spiros P. \n4\nKartsonis Maria \n6\nHolcombe Randall F. \n2\nDharmarajan Kavita V. \n6\n1Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA2Department of Medical Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA3Department of Gastroenterology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA4Department of Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA5Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA6Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA*William H. Smith: william.smith@icahn.mssm.eduAcademic Editor: Ming-Hsui Tsai\n\n2015 3 12 2015 2015 9415084 8 2015 19 11 2015 Copyright © 2015 William H. Smith 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.We are reporting on a case of a 41-year-old woman who presented with metastatic gastroesophageal junction cancer and who achieved prolonged survival with a multimodal treatment approach. After initially experiencing robust response to chemotherapy, she was treated for distant recurrence with palliative radiation to the gastrohepatic and supraclavicular lymph nodes and subsequently, given her unusual near-complete response, with reirradiation to the abdomen with curative intent for residual disease. The case presented is unique due to the patient's atypical treatment course, including technically difficult reirradiation to the abdomen, and the resulting prolonged survival despite metastatic presentation.\n==== Body\n1. Introduction\nCancers of the esophagus and gastroesophageal junction (GEJ) represent one of the most rapidly increasing types of tumor in many Western countries [1, 2]. In particular, the incidence of adenocarcinoma of the lower esophagus has risen dramatically in correlation to increases in the prevalence of known risk factors [1].\n\nIn localized or locally advanced disease resection has historically been considered the primary curative modality. Surgery alone has resulted in unsatisfactory survival outcomes, providing motivation for investigation of multimodal treatment approaches. Large randomized trials have demonstrated significantly improved survival with the addition of chemotherapy or chemoradiotherapy compared to surgery alone in early stage gastric and esophageal tumors [3–6].\n\nLimited reports in the literature suggest that multimodality therapy may improve outcomes for some patients with advanced gastroesophageal malignancies [7]. Here, we report a case of GEJ adenocarcinoma that despite widespread disease at diagnosis achieved prolonged progression-free survival with minimal morbidity through an atypical combination of chemoradiation followed by reirradiation to the abdomen.\n\n2. A Case Report\nIn October 2012, a 41-year-old woman in otherwise excellent health presented with new onset abdominal and back pain to the emergency department at our institution where imaging revealed a solid gastrohepatic mass and associated left para-aortic lymphadenopathy. Endoscopic biopsy revealed invasive poorly differentiated HER2-negative adenocarcinoma of the GEJ. Histology demonstrated signet ring cells. Positron emission tomography (PET) demonstrated right axillary lymph node avidity (SUV (standardized uptake value) 10.8) and left para-aortic adenopathy (SUV 11.8) (Figure 1). Subsequent biopsy of the enlarged axillary lymph node confirmed the presence of stage IV adenocarcinoma of gastroesophageal origin. Peritoneal washings cytology was negative for malignant cells.\n\nThe patient began FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy. Restaging after 12 cycles of FOLFOX (oxaliplatin discontinued after cycle 10 secondary to neuropathy) demonstrated a near-complete response to therapy on PET scan. Patient continued on infusional 5-FU/LV. However, after additional 6 cycles of infusional 5-FU/LV surveillance, PET scan revealed recurrent disease in the left supraclavicular fossa (SUV 23.3) and gastrohepatic nodal region (SUV 2.6). The patient underwent a course of palliative radiotherapy to the two sites of recurrence at a dose of 30 Gy in ten once-daily fractions with concurrent 5-fluorouracil (FU) and leucovorin chemotherapy. The patient continued the infusional 5-FU/LV every 2 weeks after the completion of radiation for an additional 4 months. Follow-up PET 2 months following radiotherapy demonstrated resolution of avidity in both nodal regions and at the site of the primary tumor. However, endoscopy showed persistent, biopsy proven adenocarcinoma at the GEJ.\n\nThe case was then presented in our multidisciplinary tumor board. Given the patient's robust initial treatment response and excellent performance status, and in consideration of her prolonged survival up to this point despite metastatic presentation, we hoped that definitive treatment to the primary site would produce a favorable outcome.\n\nManagement options considered included palliative chemotherapy alone, surgical resection of residual disease, additional radiation to the GEJ with or without chemotherapy [5], or additional radiation to the GEJ with/without chemo followed by surgical resection [4]. After several conversations regarding the risks and benefits of the different treatment options, the patient elected to proceed with neoadjuvant chemoradiation (CRT) to the GEJ despite the potentially increased risks of acute and late toxicity associated with reirradiation to the abdomen.\n\nThe patient thus completed a course of CRT to the GEJ primary to a dose of 41.4 Gy in 23 fractions with concurrent carboplatin (AUC = 2 × 5 weeks) and paclitaxel (50 mg/m2) per the CROSS regimen [4]. To increase the precision of the reirradiation treatment the patient underwent endoscopic ultrasound guided fiducial marker placement prior to simulation. The patient was placed in supine position and immobilized with a custom alpha cradle and compression belt and underwent CT simulation with 4D CT to document respiratory motion. The previously treated target volume was reproduced on the current planning scan to determine areas of overlap. A region of overlap including portions of the small bowel and stomach was limited to a cumulative dose constraint of 85 Gy in 2 Gy equivalents (Figure 2). Treatment was delivered with a 5-field IMRT plan to a planning target volume (PTV) that included the distal esophagus and proximal stomach up to the level of the fiducial markers. Daily cone beam CT imaging was used to minimize inaccuracies in setup and allow for a smaller than traditional margin around the PTV.\n\nThe patient tolerated treatment well with the exception of grade 3 nausea/vomiting, controlled with an escalated antiemetic regimen which included aprepitant, grade 2 neuropathy and grade 2 gastritis managed with sucralfate and proton-pump inhibitors. At follow-up visit she endorsed only mild treatment related grade 2 fatigue and grade 1 esophagitis. The patient decided to forego post-CRT resection for concern regarding the morbidity of the surgery and was instead continued on maintenance 5-FU/Leucovorin. PET at 2 months following completion of CRT showed no evidence of disease.\n\nSurveillance EGD at 4 months following completion of definitive CRT showed persistence of adenocarcinoma at the GEJ primary. PET demonstrated mildly increased uptake at the primary site (SUV 3.2), suggestive of recurrence of local disease. The patient subsequently initiated treatment with ramucirumab. At 7 months following completion of CRT and 30 months following diagnosis, the patient was found to have progression of disease with interval development of peritoneal carcinomatosis. She developed complications of carcinomatosis with deterioration of her performance status. She was no longer a candidate for further anticancer treatment and enrolled in hospice. The patient passed away approximately 32 months after her initial presentation.\n\n3. Discussion\nGEJ cancer is a devastating disease that bears a dismal prognosis and commonly presents at an advanced stage, especially among younger patients such as the case presented in this report [8]. In metastatic cases, median survival is 6 months and 5-year survival is only 4% [8, 9]. Our patient lived 32 months after initial diagnosis of metastatic disease, much exceeding the median. We speculate that it may be in part due to the biology of her disease, site of her metastases (lymph node only at presentation), and multimodality therapy she received [10].\n\nManagement of patients with advanced, unresectable GEJ cancer represents a challenging scenario of continued uncertainty. External beam radiation therapy with concurrent chemotherapy is the standard approach for patients with locally advanced, unresectable disease. While this may provide sustained survival benefit in select locally advanced cases [11, 12], in metastatic disease such as in our patient the goal of care is most often palliative.\n\nTreatment with fluoropyrimidine- or taxane-based chemotherapy is recommended in addition to supportive measures as first-line therapy in cases of metastatic GEJ cancer [13]. The role of FOLFOX chemotherapy in such cancers has been supported by multiple studies [14–17]. Nevertheless, no consensus yet exists regarding first-line chemotherapy regimen for metastatic disease. Our patient achieved an excellent response to FOLFOX and palliative CRT and was left without evidence of residual metastatic disease for 9 months.\n\nWhen two surveillance studies suggested no other disease outside the primary site, the question became how to continue treating the patient. The patient was clear that she did not want to continue chemotherapy indefinitely due to the negative impact on her quality of life. We therefore hoped that treatment to the primary site with curative intent would be able to maximize her time off therapy. After an extensive discussion of the patient's case at the GI multidisciplinary tumor board, the management options under consideration included palliative chemotherapy alone, surgical resection of residual disease, additional radiation to the GEJ with or without chemotherapy [5], or additional radiation to the GEJ with/without chemo followed by surgical resection [4]. In locally advanced resectable disease, neoadjuvant CRT is the preferred treatment paradigm with definitive CRT reserved only for those patients who decline or are otherwise not fit to undergo surgery [13].\n\nSurgery alone was not recommended in this patient, given the unacceptable risks of substantial morbidity and possible mortality in a patient who presented with metastatic disease. Moreover, even with pathologically complete resection, locoregional and distant failures are common. Several trials have demonstrated the benefit of neoadjuvant CRT versus surgery alone in GEJ cancer (Table 1) [3–5, 18–22]. However, radiation therapy would involve reirradiation of previously treated bowel, stomach, and esophageal tissues putting the patient at risk of perforation or fistula formation as some of these tissues had already received life-time tolerance doses of radiation.\n\nThe CALGB 9781/RTOG97-16 trial compared neoadjuvant CRT to surgery alone in patients with surgically resectable esophageal or GEJ cancer [5]. Median survival increased from 1.79 years in the surgery group to 4.48 years in the trimodality group (p = 0.002) [5]. In the setting of previous irradiation, dose used in the CALGB trial would not have been physically possible to achieve while maintaining dosing constraints.\n\nThe CROSS trial randomized patients with resectable esophageal or GEJ cancer to CRT (radiation to 41.4 Gy with concurrent carboplatin/paclitaxel) followed by surgery versus surgery alone [4]. An R0 resection was achieved in 92% of patients in the CRT arm compared to 69% in the control arm (p < 0.001), with 29% of adenocarcinomas showing a pathological complete response in the CRT arm [4]. Median overall survival was 49.4 months in the CRT arm compared to 24.0 months in the control arm (p = 0.003) [4]. This trial helped to establish the standard for treatment of locally advanced, resectable esophageal, and GEJ cancer [13]. While being technically difficult, reirradiation of the GE junctional region to a dose of 41.4 Gy would be feasible if carefully performed.\n\nThe literature on reirradiation to the abdomen is limited. Haque et al. first reported on a series of 13 patients who underwent reirradiation to the abdomen for gastrointestinal malignancies, finding that such treatment was generally well tolerated and provided a limited but clinically noteworthy duration of local control [23]. In this study, patients with a prior history of radiotherapy (median dose 45 Gy) were treated with a hyperfractionated course of 1.5 Gy fractions twice daily to a median dose of 30 Gy (range 24–48 Gy). Two patients terminated reirradiation early due to toxicity: one due to grade 3 abdominal pain and gastrojejunal anastomosis bleeding requiring hospitalization and one due to grade 2 duodenal ulceration and stricture [23]. Patients had limited overall survival (median survival 14 months), reflecting the poor prognosis of those with recurrent or metastatic abdominal malignancies included in this study [23]. However, only one patient in this cohort had gastric cancer (none had esophageal or GEJ cancer) and most received a lower retreatment dose following a longer retreatment interval than our patient [23].\n\nA recent retrospective study of 10 patients who underwent reirradiation to the esophagus for recurrent esophageal squamous cell carcinoma demonstrated that such treatment is associated with a high risk for severe toxicity [24]. In this study, most patients (70%) experienced at least grade 2 toxicity (esophagitis in 4, dysphagia in 3, anemia in 1, and anorexia in 1) and 3 patients (30%) experienced esophageal perforation and tracheoesophageal fistula formation [24]. Those patients experiencing esophageal perforation and fistula formation received 50.4 Gy primary treatment followed by reirradiation to 45.0–50.4 Gy after an interval of 4.8–15 months [24]. Thus, while reirradiation was associated with a high risk for severe toxicity, relatively high cumulative doses were administered in these cases with a short interval between initial and retreatment.\n\nAfter much consideration it was felt that for our patient the risks of surgery alone outweighed the potential benefits given the high likelihood of recurrence. Due to the patient's prior palliative radiation to the gastrohepatic nodal region we could not safely deliver the standard curative dose per CALGB 9781/RTOG97-16 (50.4 Gy) without overdosing the nearby bowel [5] and risking potentially unacceptable acute and late toxicities including fistulas and bowel obstructions. The patient thus underwent neoadjuvant CRT per the CROSS regimen because the lower radiation dose (41.4 Gy) would allow us to meet our dosing constraints for normal tissues while still treating with curative intent [4, 5]. This was contingent upon the patient planning for post-CRT resection to remove the primary tumor site and also the reirradiated tissues, thereby minimizing radiation-related toxicities.\n\nThe patient's PET showed no evidence of disease at 2 month following completion of CRT. In the CROSS trial, 29% of patients showed complete pathological response on resection [4]. Thus, despite this patient's ensuing locoregional failure, her initial response gave reason to suspect that CRT alone with 41.4 Gy dose of radiotherapy might be sufficient for cure. While cure was not achieved, this patient tolerated treatment relatively well and was still alive without progression of disease until 7 months following reirradiation.\n\nThere is no consensus treatment for recurrent GEJ adenocarcinoma. Our patient's case demonstrates that reirradiation to the abdomen may be safe and beneficial in select individuals. As the CROSS trial has helped define initial management of locally advanced resectable GEJ adenocarcinoma, most patients presenting with recurrence will have already undergone initial radiation to 41.4 Gy. In such cases, reirradiation to 30 Gy with concurrent chemotherapy would result in the same cumulative dose as in our patient and appears to be reasonable in select patients with good performance status. Advancing technological capabilities to provide more precise radiation delivery fields may improve our ability to treat recurrent GEJ cancers with reirradiation in the future. As such, we propose that while each patient must be considered in the context of his or her particular circumstances, reirradiation with concurrent chemotherapy should represent a preferred option for salvage therapy. Given the complexities of such treatment, a better understanding of the factors determining who would benefit most from this therapy and who is at greatest risk of toxicity is needed.\n\nSurvival of 32 months after diagnosis of metastatic GEJ adenocarcinoma in our patient suggests that multidisciplinary discussion and multimodality therapy in appropriately selected cases may result in longer survival.\n\nConflict of Interests\nThe authors have no actual or potential conflict of interests.\n\nFigure 1 Selected PET/CT scans. (a) Initial PET/CT at the time of diagnosis showing uptake in GEJ, left para-aortic lymph nodes (SUV 11.8), and right axillary lymph nodes (SUV 10.8). (b) Surveillance PET/CT showing recurrence in the left supraclavicular fossa (SUV 23.3) and gastrohepatic nodal region (SUV 2.6). (c) PET/CT prior to second course of radiotherapy showing no residual metabolic uptake outside of the primary. (d) PET/CT post-reirradiation to the GEJ primary. (e) Shallow ulceration of GEJ with pathology demonstrating persistent adenocarcinoma. (f) Red circles highlight areas of increased uptake. Corresponding dates are shown.\n\nFigure 2 Palliative and reirradiation treatment to the abdomen. (a) Initial palliative radiation treatment to the gastrohepatic nodal region with corresponding isodose lines. (b) Reirradiation to the abdomen including the GEJ primary showing cumulative dose with corresponding isodose lines.\n\nTable 1 Summary of the literature reviewed on neoadjuvant chemoradiotherapy in GEJ cancer.\n\n \tMedian F/U (years)\tPopulation (% of patients)\tRandomization (patients)\tOverall survival\tProgression-free survival\t\nMedian (years)\t3–5 years (%)\tMedian (years)\t3–5 years (%)\t\n\nVan Hagen et al. (2012) [4] \nCROSS trial\t3.8\tResectable esophageal (73%) or GEJ (24%) CA\tCarboplatin + paclitaxel/41.4 Gy + surgery (178)\t4.1∗\n\t47%∗ (5 yr)\t—\t—\t\nSurgery alone (188)\t2.0∗\n\t34%∗ (5 yr)\t—\t—\t\n\n\n\t\n\nTepper et al. (2008) [5] \nCALGB 9781 trial\t6.0\t\nStages I–III of CA of esophagus or GEJ\tCisplatin + 5-FU/50.4 Gy + surgery (30)\t4.5∗\n\t39% (5 yr)\t3.5∗\n\t28% (5 yr)\t\nSurgery alone (26)\t1.8∗\n\t16% (5 yr)\t1.0∗\n\t15% (5 yr)\t\n\n\n\t\n\nStahl et al. (2009) [18] \nPOET trial\t3.8\t\nLocally advanced adenocarcinoma of GEJ\tCisplatin + 5-FU + leucovorin/30 Gy + surgery (60)\t2.8\t47.4% (3 yr)\t—\t76.5% (3 yr)\t\nCisplatin + 5-FU + leucovorin + surgery (59)\t1.8\t27.7% (3 yr)\t—\t59.0% (3 yr)\t\n\n\n\t\n\nBurmeister et al. (2005) [19]\t5.4\tEsophageal CA including lower third/gastric cardia (79%)\tCisplatin + 5-FU/35 Gy + surgery (128)\t1.9\t11.7% (5 yr)\t1.3\t10.2% (5 yr)\t\nSurgery alone (128)\t1.6\t7.8% (5 yr)\t1.0\t7.0% (5 yr)\t\n\n\n\t\n\nWalsh et al. (1996) [20]\t0.8\tEsophageal CA including lower third/cardia (85%)\tCisplatin + 5-FU/40 Gy + surgery (58)\t1.3∗\n\t32% (3 yr)∗\n\t—\t—\t\nSurgery alone (55)\t0.9∗\n\t6% (3 yr)∗\n\t—\t—\t\n\n\n\t\n\nUrba et al. (2001) [21]\t8.2\t\nStages I–III of CA of esophagus or GEJ \tCisplatin + 5-FU + vinblastine/45 Gy + surgery (50) \t1.4\t30% (3 yr)\t—\t28% (3 yr)\t\nSurgery alone (50)\t1.5\t16% (3 yr)\t—\t16% (3 yr)\t\n(i) ∗Statistically significant value.\n\n(ii) F/U: follow-up, CA: cancer, 5-FU: 5-fluorouracil, and yr: years.\n\n(iii) —: not reported.\n==== Refs\n1 Jemal A. Bray F. Center M. M. Ferlay J. Ward E. Forman D. Global cancer statistics CA Cancer Journal for Clinicians 2011 61 2 69 90 10.3322/caac.20107 2-s2.0-79952232216 \n2 Vial M. Grande L. Pera M. Epidemiology of adenocarcinoma of the esophagus, gastric cardia, and upper gastric third Adenocarcinoma of the Esophagogastric Junction 2010 182 Berlin, Germany Springer 1 17 Recent Results in Cancer Research 10.1007/978-3-540-70579-6_1 \n3 Tepper J. E. O'Neil B. Transition in biology and philosophy in the treatment of gastroesophageal junction adenocarcinoma Journal of Clinical Oncology 2009 27 6 836 837 10.1200/JCO.2008.19.5982 2-s2.0-60849094487 19139425 \n4 Van Hagen P. Hulshof M. C. C. M. van Lanschot J. J. B. Preoperative chemoradiotherapy for esophageal or junctional cancer The New England Journal of Medicine 2012 366 22 2074 2084 10.1056/nejmoa1112088 2-s2.0-84861679981 22646630 \n5 Tepper J. Krasna M. J. Niedzwiecki D. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781 Journal of Clinical Oncology 2008 26 7 1086 1092 10.1200/JCO.2007.12.9593 2-s2.0-41949119177 18309943 \n6 Cunningham D. Allum W. H. Stenning S. P. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer The New England Journal of Medicine 2006 355 1 11 20 10.1056/nejmoa055531 2-s2.0-33745726677 16822992 \n7 Kim K. H. Lee K.-W. Baek S. K. Survival benefit of gastrectomy ± metastasectomy in patients with metastatic gastric cancer receiving chemotherapy Gastric Cancer 2011 14 2 130 138 10.1007/s10120-011-0015-7 2-s2.0-79959378068 21373855 \n8 Wang Z. Goodman M. Saba N. El-Rayes B. F. Incidence and prognosis of gastroesophageal cancer in rural, urban, and metropolitan areas of the United States Cancer 2013 119 22 4020 4027 10.1002/cncr.28313 2-s2.0-84887042505 23963864 \n9 Siegel R. Ma J. Zou Z. Jemal A. Cancer statistics, 2014 CA: A Cancer Journal for Clinicians 2014 64 1 9 29 10.3322/caac.21208 2-s2.0-84892805731 24399786 \n10 Gandaglia G. Karakiewicz P. I. Briganti A. Impact of the site of metastases on survival in patients with metastatic prostate cancer European Urology 2015 68 2 325 334 10.1016/j.eururo.2014.07.020 25108577 \n11 Herskovic A. Martz K. Al-Sarraf M. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus The New England Journal of Medicine 1992 326 24 1593 1598 10.1056/nejm199206113262403 2-s2.0-0026769381 1584260 \n12 Al-Sarraf M. Martz K. Herskovic A. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study Journal of Clinical Oncology 1997 15 1 277 284 2-s2.0-0031022804 8996153 \n13 Ajani J. A. D'Amico T. A. Almhanna K. Esophageal and esophagogastric junction cancers, version 1.2015 Journal of the National Comprehensive Cancer Network 2015 13 2 194 227 25691612 \n14 Al-Batran S.-E. Hartmann J. T. Probst S. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie Journal of Clinical Oncology 2008 26 9 1435 1442 10.1200/jco.2007.13.9378 2-s2.0-41149154862 18349393 \n15 Chiarion-Sileni V. Innocente R. Cavina R. Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer Cancer Chemotherapy and Pharmacology 2009 63 6 1111 1119 10.1007/s00280-008-0834-3 2-s2.0-63949084961 18825381 \n16 Conroy T. Galais M.-P. Raoul J.-L. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial The Lancet Oncology 2014 15 3 305 314 10.1016/s1470-2045(14)70028-2 2-s2.0-84896710018 24556041 \n17 Pernot S. Mitry E. Samalin E. Biweekly docetaxel, fluorouracil, leucovorin, oxaliplatin (TEF) as first-line treatment for advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: safety and efficacy in a multicenter cohort Gastric Cancer 2014 17 2 341 347 10.1007/s10120-013-0266-6 2-s2.0-84898794565 23739764 \n18 Stahl M. Walz M. K. Stuschke M. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction Journal of Clinical Oncology 2009 27 6 851 856 10.1200/jco.2008.17.0506 2-s2.0-60849118127 19139439 \n19 Burmeister B. H. Smithers B. M. Gebski V. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial The Lancet Oncology 2005 6 9 659 668 10.1016/s1470-2045(05)70288-6 16129366 \n20 Walsh T. N. Noonan N. Hollywood D. Kelly A. Keeling N. Hennessy T. P. J. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma The New England Journal of Medicine 1996 335 7 462 467 10.1056/nejm199608153350702 2-s2.0-0029737381 8672151 \n21 Urba S. G. Orringer M. B. Turrisi A. Iannettoni M. Forastiere A. Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma Journal of Clinical Oncology 2001 19 2 305 313 2-s2.0-0035863382 11208820 \n22 Ronellenfitsch U. Schwarzback M. Hofheinz R. Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus Cochrane Database of Systematic Reviews 2013 5 CD008107 10.1002/14651858.CD008107.pub2 \n23 Haque W. Crane C. H. Krishnan S. Reirradiation to the abdomen for gastrointestinal malignancies Radiation Oncology 2009 4 1, article 55 10.1186/1748-717x-4-55 2-s2.0-71549138681 \n24 Kim Y. S. Lee C. G. Kim K. H. Re-irradiation of recurrent esophageal cancer after primary definitive radiotherapy Radiation Oncology Journal 2012 30 4 182 188 10.3857/roj.2012.30.4.182 2-s2.0-84872459232 23346537\n\n",
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"title": "An Unusual Course of Metastatic Gastroesophageal Cancer.",
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"abstract": "BACKGROUND\nDipyridamole stress is commonly used for myocardial perfusion imaging and is generally safe. Myocardial ischaemia can occasionally occur and is classically thought to be due to coronary steal as a result of redistribution of flow away from collateral dependent myocardium. Although ischaemia more commonly presents as electrocardiographic (ECG) ST depression and angina, ST-elevation myocardial infarction may occur as a very rare complication.\n\n\nMETHODS\nWe report a case of a patient who developed chest pain and ST depression during dipyridamole infusion. The pain persisted despite intravenous aminophylline with new inferior ST elevation soon after. Coronary angiography showed subtotal right coronary artery occlusion with no collateral supply. The symptoms and ECG changes resolved after percutaneous coronary intervention.\n\n\nCONCLUSIONS\nCoronary steal may not fully account for our patient's presentation given the failure of aminophylline and absent angiographic collaterals. Vasospasm may be triggered by dipyridamole and can directly cause ischaemia or provoke rupture of an unstable plaque. Augmentation of cardiac energetics during vasodilator stress may also play a role.",
"affiliations": "Department of Cardiology, Tan Tock Seng Hospital, 11 Jln Tan Tock Seng, Singapore, Singapore.;Department of Cardiology, Tan Tock Seng Hospital, 11 Jln Tan Tock Seng, Singapore, Singapore.;Department of Cardiology, Tan Tock Seng Hospital, 11 Jln Tan Tock Seng, Singapore, Singapore.",
"authors": "Li|Ki Fung Cliff|KFC|;Ho|Hee Hwa|HH|;Yew|Min Sen|MS|",
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"fulltext": "\n==== Front\nEur Heart J Case RepEur Heart J Case RepehjcrEuropean Heart Journal: Case Reports2514-2119Oxford University Press 3144960610.1093/ehjcr/ytz054ytz054Case ReportsA case report of dipyridamole stress-induced ST depression progressing to ST-elevation myocardial infarction despite intravenous aminophylline: steal, spasm, or something else? http://orcid.org/0000-0001-9433-0139Li Ki Fung Cliff Ho Hee Hwa http://orcid.org/0000-0002-1491-5864Yew Min Sen Department of Cardiology, Tan Tock Seng Hospital, 11 Jln Tan Tock Seng, Singapore, SingaporeToth Gabor G Handling EditorVidal-Perez Rafael EditorMoutiris Joseph EditorMilasinovic Dejan EditorXaplanteris Panagiotis EditorBaghdarrasian Lilit EditorAkhtar Mohammed Majid EditorGreen Peregrine Editor Corresponding author. Tel: +6562566011, Fax: +6563526682, Email: Min_sen_yew@ttsh.com.sg6 2019 26 4 2019 26 4 2019 3 2 ytz05405 9 2018 05 4 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.2019 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.comAbstract\nBackground\nDipyridamole stress is commonly used for myocardial perfusion imaging and is generally safe. Myocardial ischaemia can occasionally occur and is classically thought to be due to coronary steal as a result of redistribution of flow away from collateral dependent myocardium. Although ischaemia more commonly presents as electrocardiographic (ECG) ST depression and angina, ST-elevation myocardial infarction may occur as a very rare complication.\n\nCase summary\nWe report a case of a patient who developed chest pain and ST depression during dipyridamole infusion. The pain persisted despite intravenous aminophylline with new inferior ST elevation soon after. Coronary angiography showed subtotal right coronary artery occlusion with no collateral supply. The symptoms and ECG changes resolved after percutaneous coronary intervention.\n\nDiscussion\nCoronary steal may not fully account for our patient’s presentation given the failure of aminophylline and absent angiographic collaterals. Vasospasm may be triggered by dipyridamole and can directly cause ischaemia or provoke rupture of an unstable plaque. Augmentation of cardiac energetics during vasodilator stress may also play a role.\n\nCase reportIschaemiaInfarctionDipyridamoleCoronary stealVasospasm\n==== Body\nIntroduction\nDipyridamole stress myocardial perfusion imaging (MPI) is generally safe although myocardial ischaemia manifesting as electrocardiographic (ECG) ST depression and angina can occur.1 ST-elevation myocardial infarction (STEMI) is a rare complication.1 Coronary steal refers to the shunting of blood flow away from collateral dependent myocardium after vasodilation and is generally believed to be the main mechanism for dipyridamole-induced myocardial ischaemia.2 As such, presence of angiographic collaterals is a pre-requisite for steal to occur2–4 and symptoms should reverse with aminophylline use.5,6 We report a case of post-dipyridamole myocardial ischaemia with initial ST depression progressing to STEMI despite intravenous (IV) aminophylline. Coronary angiography revealed a severe stenosis with no collaterals. A literature review and brief discussion on possible alternative mechanisms for this occurrence is also presented.\n\n\nLearning points\n\nMyocardial ischaemia can occur during dipyridamole stress testing although myocardial infarction is a rare occurrence.\n\nAlthough coronary steal is thought to be the most likely cause for vasodilator-induced myocardial ischaemia, other mechanisms such as coronary vasospasm or spontaneous plaque rupture may play a role.\n\n\n\n\n\n\n\nTimeline\n29 July 2011\tDeveloped non-ST-elevation myocardial infarction (NSTEMI). Culprit lesion was a 95% stenosis in the mid-right coronary artery (RCA). Percutaneous coronary intervention (PCI) performed with drug eluting stent (Taxus Element, Boston Scientific). Residual 80% proximal to mid-left anterior descending (LAD) artery disease.\t\n1 August 2011\tStaged PCI to LAD with drug-eluting stent (Xience V, Abbott).\t\n21 June 2018\tSeen in outpatient clinic for exertional dyspnoea without chest pain. Dipyridamole stress myocardial perfusion imaging (MPI) was ordered.\t\n23 July 2018\tPresents for 1 day rest-dipyridamole stress MPI.\t\n 09:30 h\tRest component of MPI performed uneventfully.\t\n 11:30 h\tInitiation of dipyridamole infusion as stress portion of non-invasive MPI (0.56 mg/kg intravenously over 4 min).\t\n 11:34 h\tDevelopment of chest pain with inferior and lateral ST-segment depression.\t\n 11:35 h\tDipyridamole infusion stopped and intravenous aminophylline 250 mg given with no relief.\t\n 11:43 h\tDevelopment of inferior ST elevation.\t\n 12:26 h\tUrgent coronary angiogram showed a right dominant circulation, patent LAD and RCA stents with a subtotally occluded distal RCA. PCI to the RCA using a drug-coated balloon (Magic Touch 2.0 × 15 mm, Concept Medicals) resulted in resolution of angina and ST elevations.\t\n26 July 2018\tDischarged from hospital.\t\n13 December 2018\tReviewed in clinic. Improvement in exertional dyspnoea. No chest pain.\t\nCase presentation\nA 67-year-old lady with hypertension and dyslipidaemia presented in mid 2018 with a 6 month history of New York Heart Association (NYHA) functional Class II exertional dyspnoea with no chest pain. She was on daily Aspirin 100 mg after a non-ST-elevation myocardial infarction in 2011 requiring left anterior descending and right coronary artery (LAD and RCA) percutaneous coronary intervention (PCI) with drug-eluting stents. A 1-day rest-dipyridamole stress MPI was ordered, with the rest MPI completed uneventfully with no perfusion defects seen (Figure 1). She was asymptomatic with a normal baseline ECG (Figure 2) before 0.56 mg/kg of IV dipyridamole was infused over 4 min for stress. During the final minute of the infusion, she developed angina and her ECG showed sinus tachycardia with ST depression (Figure 3). Dipyridamole infusion was stopped and IV aminophylline 250 mg was given with no relief. At 9 min post-dipyridamole, new inferior ST elevation with reciprocal ST depression in I, aVL was noted (Figure 4). The rhythm remained in sinus tachycardia with no atrioventricular block. She did not receive any medications before her urgent transfer to the cardiac catheterization laboratory where oral Ticagrelor 180 mg and intra-arterial (through radial arterial sheath) Glyceryl trinitrate 200 mcg were given on table. Coronary angiography showed a right dominant circulation, patent LAD, and RCA stents with a subtotally occluded distal RCA (Figure 5 and Supplementary material online, Videos S1–S4). There was no significant disease in the rest of the LAD and circumflex vessel. No collaterals supplying the RCA could be visualized angiographically. In view of the small vessel size, the procedurist performed PCI to the RCA using a drug-coated balloon (Magic Touch 2.0 × 15 mm, Concept Medicals) rather than a stent. Percutaneous coronary intervention resulted in resolution of angina and ST elevation. The post-PCI serum troponin I was 1575 ng/L. A transthoracic echocardiogram showed left ventricular ejection fraction of 50% with RCA territory hypokinesia. The patient was discharged well after 4 days.\n\n\nFigure 1 Normal rest myocardial perfusion performed prior to stress testing.\n\nFigure 2 Patient’s baseline resting electrocardiogram showing no significant abnormalities.\n\nFigure 3 Electrocardiogram performed when patient developed angina during the final minute of dipyridamole infusion, showing new ST depression in inferior and lateral leads.\n\nFigure 4 Electrocardiogram 9 min post-dipyridamole infusion, showing new ST elevation in the inferior leads with reciprocal ST depression in I, aVL.\n\nFigure 5 (Top left and top right) Coronary angiogram of the left system showing non-obstructed coronaries (see Supplementary material online, Videos S1 and S2). (Bottom left) Coronary angiogram showing subtotal occlusion in distal right coronary artery (see Supplementary material online, Video S3). (Bottom right) Angiographic results post-drug coated balloon angioplasty to the lesion (see Supplementary material online, Video S4).\n\nDiscussion\nMyocardial ischaemia with angina and ECG changes after vasodilator stress is uncommon.1,7 ST depression is observed more frequently whereas occurrences of ST elevation are limited to isolated case reports.5–10 To our knowledge, this is the first reported case of dipyridamole-induced ECG ST depression progressing to ST elevation despite the use of aminophylline. The elevated serum troponin and inferior wall motion abnormalities seen on the echocardiogram despite an earlier normal rest MPI indicates that myocardial infarction did occur post-dipyridamole stress. However, the mechanism of STEMI in this case may not be related to the classical ‘coronary steal’, in which ischaemia occurs when dipyridamole-induced coronary vasodilation results in redistribution of flow away from collateral dependent myocardium.8 The presence of angiographic collaterals, which was not seen in our patient, appears to be a pre-requisite for coronary steal to occur.2–4,11 Moreover, as seen in previous case reports, the ischaemic signs and symptoms are expected to improve with IV aminophylline should steal phenomenon be present.5,6 Instead, our patient had persistent chest pain with evolution of ST depression to ST-segment elevation after IV aminophylline, which is not consistent with the pathophysiology of coronary steal.\n\nApart from steal, coronary spasm has also been implicated in vasodilator-induced myocardial ischaemia. ST-segment elevation post-adenosine stress has been reported to occur in the presence of normal coronaries and is attributed to coronary vasospasm secondary to activation of adenosine A1 receptors.9 Qamruddin also reported a case of ST elevation occurring 13 min after regadenoson injection. Angiography revealed a non-occlusive but functionally significant LAD stenosis. Interestingly, the post-stress myocardial perfusion images were normal, illustrating that ischaemia did not occur at the time of vasodilator stress and that coronary vasospasm occurred after cessation of the pharmacological effects of the vasodilator.12 Our patient, however, did not exhibit angiographic evidence of coronary vasospasm despite having ongoing chest discomfort and ST elevation. This makes vasospasm a less likely possibility although it cannot be completely excluded given that intracoronary nitroglycerine was not administered prior to PCI.\n\nSpontaneous fissuring or rupture of an unstable plaque is the typical mechanism for myocardial infarction. This can occur post-exercise stress and has been attributed to repeated vasospasm from circulating catecholamines resulting in plaque rupture and subtotal coronary occlusion.13 Increased flexing of atherosclerotic coronary arteries during exertion may also play a role.14 Although these mechanisms have not been conclusively demonstrated in the setting of vasodilator stress, Kwai et al.10 reported a case of ST-segment elevation post-oral dipyridamole that persisted despite aminophylline but resolved only after IV streptokinase. This case highlights the possibility of dipyridamole-induced coronary thrombosis as the cause of STEMI. Although coronary vasospasm may have been the inciting event resulting in plaque rupture, we postulate that augmentation of cardiac energetics post-dipyridamole15 may possibly result in a hyperdynamic state similar to exercise that can provoke rupture of an unstable plaque.\n\nIn summary, our patient developed myocardial ischaemia with ST-segment depression soon after dipyridamole infusion that progressed to inferior ST-segment elevation myocardial infarction. Steal phenomenon is unlikely to be the cause in view of the failure of IV aminophylline and absent angiographic collaterals. Coronary vasospasm was not angiographically evident but may have been present initially which resulted in the preceding ST-segment depression. The subsequent ST-segment elevation with subtotal coronary occlusion is likely due to unstable plaque rupture secondary to coronary vasospasm and/or increased cardiac work from dipyridamole stress. Apart from being a valuable addition to the limited existing literature on post-vasodilator myocardial infarction, this case also illustrates the importance of warning patients of the possibility of myocardial infarction when taking consent for pharmacological stress. Continuous procedural cardiac monitoring is recommended for all patients even if the indication is not for typical chest pain, as seen in our patient who had exertional dyspnoea as an angina equivalent. Further work, especially in the field of intracoronary imaging, is needed to better understand the pathophysiology of this rare but clinically significant entity.\n\nLead author biography\nDr Min Sen Yew is a consultant cardiologist in Tan Tock Seng Hospital, Singapore. He underwent fellowship training in nuclear cardiology and cardiovascular computed tomography at the Royal Brompton Hospital, London. His clinical interest is in multimodality cardiac imaging, including nuclear cardiology, cardiac computed tomography, as well as cardiac magnetic resonance imaging\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance. \n\n\nConflict of interest: none declared.\n\nSupplementary Material\nytz054_Supplementary_Video Click here for additional data file.\n==== Refs\nReferences\n1 \nHenzlova MJ , Duvall WL , Einstein AJ , Travin MI , Verberne HJ \nASNC imaging guidelines for SPECT nuclear cardiology procedures: stress, protocols, and tracers . J Nucl Cardiol 2016 ;23 :606 –639 .26914678 \n2 \nAkinboboye OO , Idris O , Chou RL , Sciacca RR , Cannon PJ , Bergmann SR. \nAbsolute quantitation of coronary steal induced by intravenous dipyridamole . J Am Coll Cardiol 2001 ;37 :109 –116 .11153724 \n3 \nRosseel M , Dendale P , De Sadeleer C , Schoors D , Block P , Franken PR. \nDipyridamole-induced angina pectoris during sestamibi stress test in patients with significant coronary artery disease: clinical, angiographic, and nuclear determinants . Angiology 1997 ;48 :301 –307 .9112878 \n4 \nGliozheni E , Picano E , Bernardino L , Pingitore A , Sicari R , Marzilli M. \nAngiographically assessed coronary collateral circulation increases vulnerability to myocardial ischemia during vasodilator stress testing . Am J Cardiol 1996 ;78 :1419 –1424 .8970418 \n5 \nHansen CL , Williams E. \nSevere transmural myocardial ischemia after dipyridamole administration implicating coronary steal . Clin Cardiol 1998 ;21 :293 –296 .9562942 \n6 \nMutlu H , Leppo J. \nCoronary steal and ST elevation during dipyridamole stress testing leading to coronary artery bypass grafting . J Nucl Cardiol 2007 ;14 :892 –897 .18022117 \n7 \nBeinart R , Matetzky S , Shechter M , Fefer P , Rozen E , Beinart T , Hod H , Chouraqui P. \nStress-induced ST-segment elevation in patients without prior Q-wave myocardial infarction . J Electrocardiol 2008 ;41 :312 –317 .18490025 \n8 \nSafi AM , Pillai N , Rachko M , Chaudhry K , Stein RA. \nDipyridamole-induced ST-segment elevation indicative of transmural myocardial ischemia—a case report . Angiology 2001 ;52 :553 –557 .11512695 \n9 \nGolzar J , Mustafa SJ , Movahed A. \nChest pain and ST-segment elevation 3 minutes after completion of adenosine pharmacologic stress testing . J Nucl Cardiol 2004 ;11 :744 –746 .15592198 \n10 \nKwai AH , Jacobson AF , McIntyre KM , Williams WH , Tow DE. \nPersistent chest pain following oral dipyridamole for thallium 201 myocardial imaging . Eur J Nucl Med 1990 ;16 :745 –746 .2384110 \n11 \nBecker LC. \nConditions for vasodilator-induced coronary steal in experimental myocardial ischemia . Circulation 1978 ;57 :1103 –1110 .416923 \n12 \nQamruddin S , Huang HW , Mehra A , Bonyadlou S , Yoon AJ. \nST segment elevation ECG changes during pharmacologic stress with regadenoson . Clin Nucl Med 2016 ;41 :62 –64 .26447370 \n13 \nCiampricotti R , el Gamal MI. \nUnstable angina, myocardial infarction and sudden death after an exercise stress test . Int J Cardiol 1989 ;24 :211 –218 .2504674 \n14 \nAlbano AJ , Thompson PD , Kapur NK. \nAcute coronary thrombosis in Boston marathon runners . N Engl J Med 2012 ;366 :184 –185 .22236231 \n15 \nBarletta G , Del Bene MR. \nEffects of dipyridamole on cardiac and systemic haemodynamics: real-time three-dimensional stress echo beyond regional wall motion . J Cardiovasc Med Hagerstown Md 2011 ;12 :455 –459 .\n\n",
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"journal": "European heart journal. Case reports",
"keywords": "Case report; Coronary steal; Dipyridamole; Infarction; Ischaemia; Vasospasm",
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"title": "A case report of dipyridamole stress-induced ST depression progressing to ST-elevation myocardial infarction despite intravenous aminophylline: steal, spasm, or something else?",
"title_normalized": "a case report of dipyridamole stress induced st depression progressing to st elevation myocardial infarction despite intravenous aminophylline steal spasm or something else"
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"abstract": "OBJECTIVE\nMethotrexate is an immunosuppressant that is used to treat patients with Crohn's disease (CD). However, there are few data on the long-term effects of methotrexate maintenance therapy for these patients. We assessed the sustained clinical benefits and tolerability of methotrexate monotherapy after thiopurine therapy in patients with CD.\n\n\nMETHODS\nWe analyzed data from 3 hospitals on 174 consecutive patients with CD (age, 35 ± 12 y) who received methotrexate monotherapy after thiopurine therapy (23% also did not respond to anti-tumor necrosis factor therapy) from 2000 to 2010. We assessed patient characteristics and the tolerability and sustained clinical benefits of the treatment. Sustained clinical benefit was defined as ongoing use of methotrexate or intentional discontinuation of successful therapy before the end-of-study point.\n\n\nRESULTS\nThe number of patients with sustained clinical benefits from methotrexate monotherapy were 98 (86%), 50 (63%), 27 (47%), and 3 (20%), at 6, 12, 24, and 60 months, respectively. Forty-five patients (26%) discontinued methotrexate because of intolerance, particularly within 6 months after therapy began. Adverse responses generally were mild; only 1 patient required admission to the hospital for infection with cytomegalovirus, and no drug-related deaths were reported. Intolerance of the preceding thiopurine therapy was associated with adverse events during methotrexate therapy.\n\n\nCONCLUSIONS\nIn a large cohort study of patients who received methotrexate monotherapy after thiopurine therapy for CD, 47% continued to receive the therapy or intentionally discontinued successful therapy within 2 years, and 20% did so within 5 years. Long-term use of methotrexate was well tolerated and relatively safe.",
"affiliations": "Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands. ml.seinen@vumc.nl",
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"abstract": "Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.",
"affiliations": "National Patient Advocate Foundation, Arizona State University, Phoenix, AZ, USA.;Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.;Division of Pediatric Gastroenterology, Hepatology and Nutrition, Stanford University, Palo Alto, CA, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA.;Miami Transplant Institute, 1801 NW 9th Avenue, Miami, FL, USA.;Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA. klcdoc127@gmail.com.",
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"keywords": "Bioequivalence; Microbiome; Primary sclerosing cholangitis; Ulcerative colitis; Vancomycin",
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"mesh_terms": "D000293:Adolescent; D015209:Cholangitis, Sclerosing; D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa; D014640:Vancomycin; D055815:Young Adult",
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"title": "Successful response of primary sclerosing cholangitis and associated ulcerative colitis to oral vancomycin may depend on brand and personalized dose: report in an adolescent.",
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"abstract": "Takayasu's arteritis (TA) is a rare chronic inflammatory disease affecting mainly the aorta and its main branches. We report a case of a 24-year-old primigravida, an African patient, with TA planned for caesarean section at 37 weeks of gestation. Clinically, she has involvement of aortic arch and its branches and abdominal aorta. She underwent caesarean section and delivered an alive baby boy under successful spinal anaesthesia with insignificant complications. Although it is rare in the African continent, anesthesiologists should be up-to-date with the knowledge of perioperative anesthetic management of TA in pregnant cases requiring operative delivery.",
"affiliations": "Department of Anaesthesia and Critical Care, University of Botswana, Botswana.;Department of Obstetrics and Gynaecology, University of Botswana, Botswana.;Department of Surgery, University of Botswana, Botswana.",
"authors": "Kassa|Mamo Woldu|MW|;Benti|Tadele Melese|TM|;Bedada|Alemayehu Ginbo|AG|",
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"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-30-28110.11604/pamj.2018.30.281.16182Case ReportSuccessful spinal anaesthesia for caesarean section in an African patient with Takayasu’s arteritis Kassa Mamo Woldu 1&Benti Tadele Melese 2Bedada Alemayehu Ginbo 31 Department of Anaesthesia and Critical Care, University of Botswana, Botswana2 Department of Obstetrics and Gynaecology, University of Botswana, Botswana3 Department of Surgery, University of Botswana, Botswana& Corresponding author: Mamo Woldu Kassa, Department of Anaesthesia and Critical Care, University of Botswana, Botswana20 8 2018 2018 30 28128 5 2018 06 8 2018 © Mamo Woldu Kassa et al.2018The 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.Takayasu's arteritis (TA) is a rare chronic inflammatory disease affecting mainly the aorta and its main branches. We report a case of a 24-year-old primigravida, an African patient, with TA planned for caesarean section at 37 weeks of gestation. Clinically, she has involvement of aortic arch and its branches and abdominal aorta. She underwent caesarean section and delivered an alive baby boy under successful spinal anaesthesia with insignificant complications. Although it is rare in the African continent, anesthesiologists should be up-to-date with the knowledge of perioperative anesthetic management of TA in pregnant cases requiring operative delivery.\n\nAfrican patientcaesarean sectionspinal anaesthesiaTakayasu´s arteritis\n==== Body\nIntroduction\nTakayasu's arteritis (TA) is a rare chronic progressive inflammatory disease of uncertain aetiology, but suspected to have multiple causes [1-11]. Takayasu first described the disease in 1908 [1-8]. TA usually affects aorta and its main branches commonly: carotid, subclavian and renal arteries [1-10]. TA affects more women than men with a ratio ranging from 4:1to 8:1[2-4, 10, 11]. The peak incidence is in the 2nd-3rd decades [5]. It is common in Japan [1], Asia and South America, and less common in Europe and North America [4-6, 10]. Intimal infiltration by lymphocytes and other inflammatory cells results in the replacement of vessel wall elastic tissue by fibrous tissue with subsequent formation of stenosis, occlusion and aneurysm [1, 5]. The major cause of hypertension in TA is renovascular but it can result from an abnormal function of the carotid and aortic sinus baroreceptors and/or reduced elasticity and a marked narrowing of the aorta and major arteries [8]. Clinical symptoms depend on the distribution of the involved vasculature and ischemic disturbance of the organs affected. This may result in claudication, ischemic pain and fatigue of the limbs, and carotid arteries may give headache, vertigo, syncope, convulsions, transient hemiplegia, aphasia, and visual disturbance; renal artery involvement may cause hypertension and some patients may progress to aortic insufficiency and congestive heart failure [1, 2, 5, 9]. Physical findings depends on the affected artery and include high blood pressure and reduction or loss of palpable pulses in the neck and limbs [7, 9]. Pulmonary involvement leads to pulmonary hypertension [9]. Management of TA involves corticosteroid and other immunosuppressive agents [1, 5, 10, 11]. Some cases of TA may require further treatment in the form of angioplasty or surgical correction [4, 5, 7, 10]. The commonest cause of death in TA are heart failure, myocardial infarction (MI) and stroke [5, 11]. Fatal complications during pregnancy include aortic aneurysm rupture and cerebral haemorrhage [10]. Anaesthesia in TA is complicated by uncontrolled hypertension leading to end organ dysfunction, stenosis of major blood vessels affecting regional circulation, and difficulties in the monitoring of arterial blood pressure [8]. The initial manifestation of TA may occur during pregnancy [4]. The effect of pregnancy on TA is unclear [1, 5, 7, 9]. But in 60-90% of cases hypertensive complications including preeclampsia, exacerbated chronic hypertension, miscarriage or fetal loss are reported [5-7]. Reports on spinal anaesthesia for caesarean section for the management of patients with TA in African continent is almost non-existent. We are presenting a case of TA pregnant patient who successfully delivered by caesarean section using spinal anaesthesia.\n\nPatient and observation\nWe are presenting a 24-year-old African premegravida who was diagnosed with Takayasu's arteritis and underwent caesarean section under spinal anesthesia at Princess Marina Hospital, the largest tertiary teaching hospital in Gaborone, Botswana. She is 37 weeks pregnant weighing 65kg and 160cm of height. She was diagnosed with TA 5 years ago fulfilling four of the American college of rheumatology diagnostic criteria: age < 40 years, blood pressure difference of more than 10mmHg in right and left arm, claudication and bruit in the abdominal aorta. She was scheduled for elective caesarean section for severe oligohydramnios with intrauterine growth restriction (IUGR). She was under treatment for her TA and hypertension taking amlodipine 10mg peros per day, methyldopa 500mg twice peros per day and prednisolone 5mg peros per day. Except for occasional headache the hypertension and TA were well controlled. On examination she looks healthy, with BP 140/80mmHg on her right arm and 190/101mmHg on her left arm with pulse rate of 96 per minute. All pulses in both lower limb are present. She has no features of cardiac failure. Laboratory tests such as: full blood count, serum electrolyte, and renal function tests were normal. Echocardiogram showed 60% left ventricular ejection fraction and mild left ventricular hypertrophy and normal right ventricle. Preoperative anaesthetic evaluation showed oxygen saturation of 98% on room air, Mallampatti airway and ASA each class 2. Peripheral venous excess was secured on the left forearm and 500ml of lactated ringer was infused to overcome acute reduction of blood pressure following spinal anaesthesia. She was given amoxicillin 2gm Peros, ranitidine 50mg Intravenous, metoclopramide injection 10mg Intravenous, and hydrocortisone 100mg Intravenous to prevent Addison's crisis.\n\nShe was positioned in sitting position and a 25G quinicke's spinal needle is used to administer 1.5ml of 0.5% hyperbaric bupivacaine combined with 20μg fentanyl at L3-L4 space under aseptic condition. Sensory block was achieved at T4 level. A pillow was placed under her neck to prevent stretching of the carotid arteries with further compromise in blood flow, tilted to the left lateral to prevent aorto-caval compression. She was monitored with three lead electrocardiogram, pulse oximeter on her left index finger, and non-invasive blood pressure. Following administration of the spinal anaesthesia there was a drop of BP in the right arm from 140/80mmHg to 120/60mmHg which was corrected back to base line by 1l of lactated ringer. No vasopressor was used as the blood pressure remained in the range of 140/80mmHg to 135/78mmHg. Lower segment caesarean section was performed and a baby boy with APGAR score of 9 and 10 at 5th and 10th minute weighing 2.2kg was delivered. Then 10 IU of oxytocin in 500ml of lactated ringer was infused post-delivery. The operation took 25 minutes and the estimated blood loss was 500ml. Patient was admitted to post-natal high dependency ward. Postoperatively her blood pressure remained around preoperative levels. She was discharged home on fifth postoperative day on her regular PO medications and advised to follow at postnatal and cardiology clinic.\n\nDiscussion\nTakayasu's arteritis is a rare disease usually affecting aorta and its main branches [1-10]. Majority are women [2-4, 10, 11], with pick incidence in second and third decades [5] as the case in our patient. It is common in Japan, [1] Asia and South America, and less common in Europe and North America [4-6, 10]. Although TA is reported in Africa, reports in association with pregnancy and spinal anesthesia is limited. American college of Rheumatology diagnostic criteria for TA: age of onset 40 or less, claudication, aortic or subclavian bruits, decreases brachial pulses, difference more than 10mmHg between right and left arm systolic pressure and angiographic findings (irregular intimal surface, stenosis of the aorta or its branches, poststenotic dilatations, secular aneurysms or the typical narrowed \"rat tail\" appearance) [1] of hemodynamically significant lesions in the aorta or its major branches [3, 4, 7, 10], the presence of at least three of the above criteria confirms the diagnosis with 97% specificity and 92% sensitivity [1, 4]. Our patient is less than 40 years, has carotid bruit and a difference of more than 10mmHg in systolic blood pressure between right and left arm. Ishikawa et al, classified TA in pregnancy depending on the severity of retinopathy, secondary hypertension, aortic regurgitation and arterial aneurysm with particular indicators of maternal outcome: group I patients are with no complications, group IIa have one mild complication, group IIb have one severe complication and group III have several mild complications [2, 5-7]. Our patient having hypertension will be in group IIb. For group IIb and III, operative delivery is preferred with the aim of avoiding increased blood volume and hence arterial pressure which can occur during uterine contraction [5, 7] . Our patient being IIb and having oligohydramnios and IUGR operative delivery was planned. Preoperative evaluation involves identifying the distribution of affected arteries, degree of organ involvement with special attention to cardiac, pulmonary, renal and cerebral function in addition to drugs used for the treatment of TA [2]. Chronic use of corticosteroids could lead to suppression of endogenous corticosteroids release [7], hence our patient was given 100mg of hydrocortisone preoperatively. Invasive BP monitoring is advised in patients with BP measurement difficulty to obtain in any extremity and if rapid fluctuation in BP is anticipated [5-7, 10], which is not the case in our patient.\n\nIn addition to pregnancy induced physiological changes anaesthetic management in TA takes compromised regional circulation into consideration [8, 10, 11]. The anaesthetic goal in a patient with TA is the maintenance of blood pressure during perioperative period [11, 12]. Low dose regional anaesthesia (RA) combined with opioid causes less hemodynamic instability and allows easy monitoring of cerebral circulation [2, 10, 11]. Unlike general anaesthesia RA is associated with less risk of aspiration, pressure response during intubation and extubation which may aggravate hypertension and tachycardia leading to MI, Congestive heart failure (ccf) and intracranial hemorrhage [5, 7, 8, 11]. RA may cause hypotension inducing cerebral, renal, intestinal or uterine ischemia, [2, 6, 8, 10] but can be minimized by pre-anaesthetic volume expansion. Spinal anaesthesia hypotension can be corrected by generous IV fluid and by placing the patient in reverse Trendelenburg position [2]. Different doses of bupivacaine and fentanyl combination were reported with successful including 6.5 mg hyperbaric bupivacaine and 25 μg fentanyl [8]. We used 7.5mg of 0.5% hyperbaric bupivacaine combined with 20μg fentanyl successfully. Most TA patients need monitoring particularly for the first 24 hours following operative delivery under spinal anesthesia as about 60% of patients develop postoperative problems following inadequate control of arterial pressure including heart failure or fatal stroke in a small group of patients [5, 10]. Our patient's condition was optimal in recovery and she was transferred to the post-natal ward for regular BP monitoring.\n\nConclusion\nBlood pressure control during pregnancy, delivery and immediate post delivery period is an important step in reducing obstetric morbidity in this group of patients. Spinal anesthesia allows easy monitoring of cerebral perfusion. Although TA is very rare on the Africa continent, anesthesiologists should be up-to-date on the perioperative anesthetic management of TA.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors’ contributions\nMamo Woldu Kassa did pre-anesthetic evaluation and administered the spinal anesthesia, conceived the idea of reporting, did literature review and reviewed the manuscript; Tadele Melese Benti prepared the patient, performed the operation, and reviewed the manuscript; Alemayehu Ginbo Bedada did literature review and prepared the manuscript. The authors read and approved the final version of the manuscript.\n==== Refs\nReferences\n1 Dey M Kapur A Goyal S Wadhwa RD Srivastava A Agarwal R Takayasu arteritis in pregnancy Med J Armed Forces India 2015 71 Suppl 1 S227 S229 26265841 \n2 Hampl KF Schneider MC Skarvan K Bitzer J Graber J Spinal anaesthesia in a patient with Takayasu's disease Br J Anaesth 1994 72 1 129 32 7906534 \n3 Isobe M Takayasu arteritis revisited: current diagnosis and treatment Int J Cardiol 2013 168 1 3 10 23415176 \n4 Strider D Robinson T Guarini J Ivey J Challenges with Takayasu's arteritis: a case study J Vasc Nurs 1996 14 1 12 7 8703796 \n5 Henderson K Fludder P Epidural anaesthesia for caesarean section in a patient with severe Takayasu's disease Br J Anaesth 1999 83 6 956 9 10700801 \n6 Tiwari AK Tomar GS Chadha M Kapoor MC Takayasu's arteritis: anesthetic significance and management of a patient for cesarean section using the epidural volume extension technique Anesth Essays Res 2011 5 1 98 101 25885310 \n7 Leal Pda C Silveira FF Sadatsune EJ Clivatti J Yamashita AM Takayasus's arteritis in pregnancy: case report and literature review Rev Bras Anestesiol 2011 61 4 479 85 21724011 \n8 Dutta B Pandey R Darlong V Garg R Low-dose spinal anaesthesia for a parturient with Takayasu's arteritis undergoing emergency caesarean section Singapore Med J 2010 51 6 e111 3 20658099 \n9 Grewal K Samsoon G Combined spinal-epidural anaesthesia for caesarean section in a patient with Takayasu's disease Int J Obstet Anesth 2003 12 3 234 5 \n10 Ioscovich A Gislason R Fadeev A Grisaru-Granovsky S Halpern S Peripartum anesthetic management of patients with Takayasu's arteritis: case series and review Int J Obstet Anesth 2008 17 4 358 64 18691876 \n11 Gautam S Srivastava VK Kumar S Wahal R Successful low-dose spinal anaesthesia for lower segment caesarean section in a patient with Takayasu arteritis BMJ Case Rep 2013 2013 \n12 Sharma BK Jain S Vasishta K Outcome of pregnancy in Takayasu arteritis Int J Cardiol 2000 75 Suppl 1 S159 62 10980356\n\n",
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"issue": "30()",
"journal": "The Pan African medical journal",
"keywords": "African patient; Takayasu´s arteritis; caesarean section; spinal anaesthesia",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000773:Anesthesia, Obstetrical; D000775:Anesthesia, Spinal; D002585:Cesarean Section; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D013625:Takayasu Arteritis; D055815:Young Adult",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Successful spinal anaesthesia for caesarean section in an African patient with Takayasu's arteritis.",
"title_normalized": "successful spinal anaesthesia for caesarean section in an african patient with takayasu s arteritis"
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