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"abstract": "Spontaneous Coronary Artery Dissection (SCAD) is an important cause of myocardial infarction that typically affects women without traditional cardiovascular risk factors. It is the most common cause of myocardial infarction in pregnant and postpartum women. SCAD is often underdiagnosed due to the lack of clinician familiarity, and patients with pregnancy-associated SCAD often have more severe clinical presentations than those without. We present a case of SCAD in a multiparous woman who presented with acute chest pain in the postpartum period.",
"affiliations": "Department of Medicine, University of California, San Francisco, CA, USA.;Department of Medicine, University of California, San Francisco, CA, USA.;Department of Medicine, University of California, San Francisco, CA, USA.;Department of Medicine, University of California, San Francisco, CA, USA.;Department of Medicine, University of California, San Francisco, CA, USA.",
"authors": "Yogeswaran|Vidhushei|V|https://orcid.org/0000-0001-6984-3602;Ramakrishna|Satvik|S|https://orcid.org/0000-0002-5143-6010;MacGregor|John S|JS|https://orcid.org/0000-0002-1331-1057;Zier|Lucas|L|https://orcid.org/0000-0002-3879-5529;Goldschlager|Nora|N|https://orcid.org/0000-0002-9273-8541",
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"doi": "10.1155/2021/4057182",
"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404 2090-6412 Hindawi \n\n10.1155/2021/4057182\nCase Report\nPregnancy-Associated Chest Pain: A Case of Spontaneous Coronary Artery Dissection\nhttps://orcid.org/0000-0001-6984-3602Yogeswaran Vidhushei vidhushei.yogeswaran@ucsf.edu\n1\n https://orcid.org/0000-0002-5143-6010Ramakrishna Satvik \n1\n\n2\n https://orcid.org/0000-0002-1331-1057MacGregor John S. \n1\n\n2\n https://orcid.org/0000-0002-3879-5529Zier Lucas \n1\n\n2\n https://orcid.org/0000-0002-9273-8541Goldschlager Nora \n1\n\n2\n \n1Department of Medicine, University of California, San Francisco, CA, USA\n\n2Division of Cardiology, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA\nAcademic Editor: Assad Movahed\n\n\n2021 \n15 1 2021 \n2021 405718215 3 2020 21 12 2020 6 1 2021 Copyright © 2021 Vidhushei Yogeswaran et al.2021This 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.Spontaneous Coronary Artery Dissection (SCAD) is an important cause of myocardial infarction that typically affects women without traditional cardiovascular risk factors. It is the most common cause of myocardial infarction in pregnant and postpartum women. SCAD is often underdiagnosed due to the lack of clinician familiarity, and patients with pregnancy-associated SCAD often have more severe clinical presentations than those without. We present a case of SCAD in a multiparous woman who presented with acute chest pain in the postpartum period.\n==== Body\n1. Introduction\nSCAD is a rare but important cause of myocardial infarction (MI) and sudden cardiac death. SCAD is defined as an epicardial coronary dissection not associated with atherosclerosis, trauma, or iatrogenic injury and is the most common cause of pregnancy-associated and postpartum MI [1]. SCAD typically occurs in women without traditional atherosclerotic cardiovascular risk factors, and the mechanism of injury is thought to be coronary artery obstruction from an intramural hematoma or intimal disruption [2]. Risk factors for SCAD are fibromuscular dysplasia, connective tissue disease, physical stress, emotional stress, pregnancy, and multiparity. It is hypothesized that hormonal changes during pregnancy weaken the coronary arterial vessel walls; multiparous women can accumulate these changes over several pregnancies [2].\n\nPatients with pregnancy-associated SCAD often have more acute presentations and high-risk features than patients with non-pregnancy-associated SCAD. Most cases of pregnancy-associated SCAD occur in the first month postpartum, with the majority in the first week following delivery [3]. It is important to recognize SCAD in clinical practice as the population affected, and management is different than other causes of MI.\n\n2. Case Report\nA 44-year-old gravida 6 para 4 postpartum woman presented to the emergency department (ED) complaining of substernal chest pain. That afternoon, she experienced sudden-onset severe left-sided chest pain radiating to her back and shoulder. She had been discharged four days prior after induction of labor for chronic hypertension with an uncomplicated vaginal birth. Her medical history was notable only for hypertension, for which she took metoprolol. She was maintained on metoprolol with good blood pressure control for the duration of her pregnancy and after induction. The day prior to admission she was under significant emotional distress after her infant was hospitalized with hyperbilirubinemia.\n\nIn the ED, the patient was afebrile, her blood pressure was 164/101 mm Hg, her heart rate was 60 beats per minute, and she was breathing 16 breaths per minute. Her cardiovascular examination was unremarkable with normal heart sounds with no murmurs, rubs, or gallops and no jugular venous distension. Her lungs were clear, her abdomen was soft, and she had no extremity edema. Her complete blood count and comprehensive metabolic panel results were within normal limits. Her initial troponin I was 0.41 ng/mL (reference range, <0.04 ng/mL), and her electrocardiogram (ECG) (Figure 1) was significant for ST elevation in leads V2-V5 consistent with an anterior ST-segment elevation myocardial infarction (STEMI). Her chest X-ray showed normal mediastinum, no signs of cardiomegaly, and clear lungs.\n\nGiven the concern for acute coronary syndrome (ACS), the patient was emergently taken to the cardiac catheterization lab. Her coronary angiogram showed haziness of the midleft anterior descending (LAD) artery followed by an abrupt change in arterial caliber extending to the distal LAD and diagonal branches (Figure 2(a)). There was no clear visualization of a dissection flap, but there was a visible long segment of diffuse vessel narrowing in the mid to distal LAD highly suspicious for coronary dissection. Contrast flow in the distal vessel was normal (TIMI 3), and there were no luminal changes with the administration of intracoronary nitroglycerin. There was no angiographic evidence of atherosclerotic disease in any of her coronary arteries, and no evidence of narrowing in the coronary arteries outside of the LAD. Her chest pain was resolved during the procedure, and her ECG showed normalization of her ST elevation. Given the patient's hemodynamic stability, normal blood flow in the distal LAD, resolution of chest pain, and suspicion for dissection, she was managed conservatively.\n\nShe was started on IV nitroglycerin for hypertension, metoprolol, and dual antiplatelet therapy with aspirin and clopidogrel and then transferred to the coronary care unit for close observation. Her transthoracic echocardiogram showed normal left ventricular function with an ejection fraction of 68% and hypokinetic septal and apical walls in the distribution of the LAD. Her repeat ECG (Figure 3) showed the expected evolution of her STEMI with QS waves and T-wave inversions seen in leads V2-V5. She was weaned off the nitroglycerin and transitioned to captopril and nifedipine for strict blood pressure control and safety with breastfeeding.\n\nShe remained chest-pain free during the course of the hospitalization and underwent a repeat angiogram to evaluate for the progression of disease given the diagnostic uncertainty. Her repeat angiogram on day 6 of hospitalization showed complete resolution of the LAD lesion (Figure 2(c)) consistent with dissection. Compared to the initial angiogram, the area of haziness was no longer present, and the vessel tapered appropriately towards the apical LAD. However, a new tubular narrowing with abrupt vessel caliber change (Figure 2(d)) was noted in the midposterior descending artery (PDA), compared to her initial angiogram (Figure 2(b)) with normal flow and no clear dissection flap. This event was concerning for a new dissection event. The patient was asymptomatic throughout her hospitalization and was discharged home with close obstetric, primary care, and cardiology outpatient follow-up.\n\n3. Discussion\nIn this postpartum woman presenting with a STEMI with angiographic findings suggestive of coronary dissection and no evidence of atherosclerotic disease, a diagnosis of SCAD was made. SCAD commonly presents as ACS with ST-segment changes, and early angiography should be performed to confirm the diagnosis, assess the coronary anatomy, and facilitate revascularization when necessary [2–4]. SCAD is often misdiagnosed and a research group recently published a flowchart to aid in the diagnosis [5]. Angiographically, SCAD has three main classifications: Type 1 is identified by contrast staining showing multiple lumens, Type 2 is an abrupt change in vessel caliber with diffuse tubular stenoses of varying length, and Type 3 is a focal stenosis that mimics atherosclerosis and intracoronary imaging using intravascular ultrasound or optical coherence tomography is often required to confirm the diagnosis. The angiographic appearance of Type 2 is often missed and shorter lengths, such as 20-30 mm, may require repeat angiography or intracoronary imaging to make the diagnosis [4, 6]. The patient in this case had a Type 2 SCAD lesion with suggestive features on the initial angiogram that was confirmed with a repeat angiogram showing healing of her lesion. The LAD is the most common artery affected in both pregnancy-associated and non-pregnancy-associated SCAD [2, 3]. Patients with pregnancy-associated SCAD often have more severe clinical presentations than non-pregnancy-related SCAD with multivessel dissections and acute heart failure [3].\n\nOnce a diagnosis is made, SCAD consensus guidelines recommend a conservative approach in patients who are hemodynamically stable and without active ischemia [2, 4, 6]. Invasive management in SCAD is associated with a high incidence of iatrogenic coronary dissection. Patients should be initiated on aspirin, beta-blockade, and additional antiplatelet therapy with clopidogrel for up to 12 months after the initial event. The role of antiplatelet therapy in SCAD is unclear but is extrapolated from its evidence in acute coronary syndrome and may be beneficial with prothrombotic intimal tears. Beta-blockade is thought to reduce arterial shear stress and may be beneficial through mechanisms similar to that of the treatment of aortic dissection [6]. The majority of SCAD patients (70-90%) managed conservatively have spontaneous healing of their dissection. However, patients with hemodynamic instability, electrical instability, ongoing/recurrent ischemia, abnormal blood flow (TIMI 0-1), and/or left-main coronary artery dissection should be considered for urgent revascularization [2].\n\nDue to the risk of early dissection recurrence or extension, SCAD patients should be observed inpatient for 2-4 days until asymptomatic and clinically stable [4, 6]. Patients with pregnancy-associated SCAD have been found to have a higher prevalence of multivessel dissection events [3]. The patient had a new dissection event on her repeat coronary angiogram but remained chest-pain free without any new evidence of ischemia. There is growing evidence into the role that pregnancy and future pregnancy play with SCAD recurrence and the rates of recurrence have been reported to be as high as 30 percent [7]. This creates a relevant ethical question, and a recent experience-based survey reported that the majority of responders discourage future pregnancy after SCAD [8]. Patients who decide to proceed with pregnancy should have dedicated care with cardiologists and obstetric specialists [7].\n\n4. Conclusion\nSCAD is an important and underdiagnosed cause of MI associated with pregnancy. Clinicians should maintain high suspicion in women presenting with chest pain in the postpartum period. The diagnosis of SCAD should be made with early angiography, and a conservative approach with medical management is recommended if possible. All patients with SCAD should be followed closely outpatient as researchers learn more information on the factors associated with recurrence.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\nAll authors had a role in writing and reviewing this case report.\n\nFigure 1 Patient's initial ECG showing ST-segment elevation in V2-V5, consistent with anterior STEMI.\n\nFigure 2 Frame A: initial angiogram showing Type 2 SCAD, with a long segment of diffuse vessel narrowing in the mid to distal LAD. Frame B: initial angiogram showing the PDA with no angiographic disease or narrowing. Frame C: repeat angiogram on hospital day 6 showing healing of initial SCAD lesion after medical therapy. Frame D: repeat angiogram showing new Type 2 SCAD lesion in the mid-PDA.\n\nFigure 3 Repeat ECG on day 2 of hospitalization showing the expected evolution of anterior STEMI with QS waves and T-wave inversions seen in V2-V5.\n==== Refs\n1 Elkayam U. Jalnapurkar S. Barakkat M. N. Pregnancy-associated acute myocardial infarction: a review of contemporary experience in 150 cases between 2006 and 2011 Circulation 2014 129 16 1695 1702 10.1161/CIRCULATIONAHA.113.002054 2-s2.0-84899049493 24753549 \n2 Hayes S. N. Kim E. S. H. Saw J. Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association Circulation 2018 137 19 e523 e557 10.1161/CIR.0000000000000564 2-s2.0-85043516435 29472380 \n3 Tweet M. S. Hayes S. N. Codsi E. Gulati R. Rose C. H. Best P. J. M. Spontaneous coronary artery dissection associated with pregnancy Journal of the American College of Cardiology 2017 70 4 426 435 10.1016/j.jacc.2017.05.055 2-s2.0-85027442767 28728686 \n4 Saw J. Aymong E. Sedlak T. Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes Circulation Cardiovascular Interventions 2014 7 5 645 655 10.1161/CIRCINTERVENTIONS.114.001760 2-s2.0-84925856162 25294399 \n5 Buccheri D. Piraino D. Andolina G. Sistema de puntuacion para el enfoque diagnostico y terapeutico de la diseccion coronaria espontanea Revista Espa de Cardiologia (English Edition) 2016 69 9 878 879 10.1016/j.rec.2016.05.007 \n6 Yip A. Saw J. Spontaneous coronary artery dissection—a review Cardiovascular Diagnosis and Therapy 2015 5 1 37 48 25774346 \n7 Tweet M. S. Hayes S. N. Gulati R. Rose C. H. Best P. J. Pregnancy after spontaneous coronary artery dissection: a case series Annals of Internal Medicine 2015 162 8 598 600 10.7326/l14-0446 2-s2.0-84928139337 25894037 \n8 Buccheri D. Zambelli G. Alfonso F. Cortese B. Pulse on spontaneous coronary artery dissections: experience-based survey JACC: Cardiovascular Interventions 2017 10 14 1469 1471 10.1016/j.jcin.2017.05.039 2-s2.0-85024389829 28728664\n\n",
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"title": "Pregnancy-Associated Chest Pain: A Case of Spontaneous Coronary Artery Dissection.",
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"abstract": "OBJECTIVE\nAn open-label, dose-escalating phase Ib/IIa trial was performed to establish a safety profile of ascending doses of cetuximab (IMC C225) in combination with doxorubicin administered weekly for 6 treatments in patients with metastatic castration-resistant prostate cancer. The secondary endpoint was to assess the efficacy of cetuximab in combination with doxorubicin as well as to determine the optimal biologic dose and the maximum tolerated dose.\n\n\nMETHODS\nPatients in 8 groups received escalating doses of cetuximab 20-300 mg/m(2) plus doxorubicin 15 or 20 mg/m(2) given intravenously weekly for 6 consecutive weeks, followed by a 1-week observation period. A treatment response was defined as a > 50% decline in prostate-specific antigen (PSA) or regression of radiographically measurable disease.\n\n\nRESULTS\nOf the 36 treated patients, 25% had grade 2 neutropenia, 39% had leukopenia, and 44% had stomatitis at doxorubicin 20 mg/m(2). Erythematous skin exanthema was seen in 38% of the patients. There was no significant regression of bone or soft tissue disease, but stable disease was observed in 20 (65%) of the 31 patients with bone disease and 14 (61%) of the 23 patients with lymph node disease. Declines in PSA were modest in the 36 patients, with 1 (2.7%) with an 80% decline from baseline, 2 (5.6%) with > 50% to < 80% declines, and 14 (39%) with progression. Median survival was approximately 18 months.\n\n\nCONCLUSIONS\nIn a heavily pretreated population of men with metastatic castration-resistant prostate cancer, this study of cetuximab/doxorubicin was associated with minimal PSA declines posttherapy, though median survival was longer compared to historical control groups. Further studies with cetuximab combined with more contemporary chemotherapy for castration-resistant prostate cancer might be warranted.",
"affiliations": "Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. slovins@mskcc.org",
"authors": "Slovin|Susan F|SF|;Kelly|W Kevin|WK|;Wilton|Andrew|A|;Kattan|Michael|M|;Myskowski|Patricia|P|;Mendelsohn|John|J|;Scher|Howard I|HI|",
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"title": "Anti-epidermal growth factor receptor monoclonal antibody cetuximab plus Doxorubicin in the treatment of metastatic castration-resistant prostate cancer.",
"title_normalized": "anti epidermal growth factor receptor monoclonal antibody cetuximab plus doxorubicin in the treatment of metastatic castration resistant prostate cancer"
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"abstract": "We describe a boy with Fanconi anemia (FA) who developed acute lymphoblastic leukemia (ALL) (FAB-LI) followed by acute myeloid leukemia (AML) (FAB-M5) at relapse. The patient was diagnosed with early pre-B-cell ALL without preceding aplastic anemia and was treated with ALL-oriented chemotherapy which included doxorubicin (a total dose of 140 mg/m(2) administered), which is a topoisomerase II inhibitor. Complete remission was obtained, but after 38 weeks AML developed. The karyotype of ALL cells at diagnosis showed 46,XY, and that of AML cells at relapse was 46,XY, t(11;16)(q23;p13). An MLL gene rearrangement and MLL-CBP chimeric mRNA were found in AML, but not in ALL. A diagnosis of FA was confirmed by an increased number of chromosomal breaks and rearrangements in peripheral blood lymphocytes cultured with mitogen in the presence of mitomycin C. We conclude that this FA patient developed ALL followed by a therapy-related t(11;16)-AML resulting in an MLL-CBP fusion. Further examination of such patients would shed light on leukemogenesis in FA patients. Genes Chromosomes Cancer 27:264-269, 2000.",
"affiliations": "Division of Hematology, Department of Pediatrics, Dokkyo University School of Medicine, Tochigi, Japan. fwiw4736@mb.infoweb.ne.jp",
"authors": "Sugita|K|K|;Taki|T|T|;Hayashi|Y|Y|;Shimaoka|H|H|;Kumazaki|H|H|;Inoue|H|H|;Konno|Y|Y|;Taniwaki|M|M|;Kurosawa|H|H|;Eguchi|M|M|",
"chemical_list": "D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D050882:CREB-Binding Protein; C494363:CREBBP protein, human",
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"mesh_terms": "D000595:Amino Acid Sequence; D001483:Base Sequence; D050882:CREB-Binding Protein; D002648:Child; D002880:Chromosomes, Human, Pair 11; D002885:Chromosomes, Human, Pair 16; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007621:Karyotyping; D007948:Leukemia, Monocytic, Acute; D008297:Male; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D016609:Neoplasms, Second Primary; D009687:Nuclear Proteins; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011519:Proto-Oncogenes; D015534:Trans-Activators; D014157:Transcription Factors; D014178:Translocation, Genetic",
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"title": "MLL-CBP fusion transcript in a therapy-related acute myeloid leukemia with the t(11;16)(q23;p13) which developed in an acute lymphoblastic leukemia patient with Fanconi anemia.",
"title_normalized": "mll cbp fusion transcript in a therapy related acute myeloid leukemia with the t 11 16 q23 p13 which developed in an acute lymphoblastic leukemia patient with fanconi anemia"
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"abstract": "Endocardial cushion defect (ECD) can be partial (with two distinct valves) or complete (only one atrioventricular valve), and surgical therapy is usually required. The optimal surgical technique is controversial but De Vega's annuloplasty is widely performed. Tricuspid valve thrombosis are rarely seen after surgery. We present a 39-year-old male patient with tricuspid valve thrombosis after De Vega's annuloplasty without the use of a ring.",
"affiliations": "Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.;Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.;Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.;Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.;Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.;Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.;Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.;Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.;Department of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey.",
"authors": "Efe|Süleyman Çağan|SÇ|;Unkun|Tuba|T|;Izci|Servet|S|;Cap|Murat|M|;Bakal|Ruken Bengi|RB|;Acar|Rezzan Deniz|RD|;Geçmen|Cetin|C|;Erdoğan|Emrah|E|;Ozdemir|Nihal|N|",
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"fulltext": "\n==== Front\nJ Cardiovasc Thorac ResJ Cardiovasc Thorac ResJ Cardiovasc Thorac ResJCVTRTBZMEDJournal of Cardiovascular and Thoracic Research2008-51172008-6830Tabriz University of Medical Sciences 10.15171/jcvtr.2014.012Case ReportThrombus Formation on the Tricuspid Valve After De Vega’s Annuloplasty and Repair of Endocardial Cushion Defect Efe Süleyman Çağan Unkun Tuba İzci Servet Çap Murat Bakal Ruken Bengi Acar Rezzan Deniz Geçmen Çetin Erdoğan Emrah Özdemir Nihal \nDepartment of Cardiology, Kosuyolu Kartal Heart Training and Research Hospital, Istanbul, Turkey\n* Corresponding author: Süleyman Çağan Efe, Email: scaganefe@gmail.com2014 30 9 2014 6 3 203 204 14 8 2014 17 9 2014 © 2014 The Author(s)2014\nThis is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nhttp://journals.tbzmed.ac.ir/JCVTREndocardial cushion defect (ECD) can be partial (with two distinct valves) or complete (only one atrioventricular valve), and surgical therapy is usually required. The optimal surgical technique is controversial but De Vega’s annuloplasty is widely performed. Tricuspid valve thrombosis are rarely seen after surgery. We present a 39-year-old male patient with tricuspid valve thrombosis after De Vega’s annuloplasty without the use of a ring.\n\nCongenital Heart DefectsTricuspid ValveMass\n==== Body\nCase report\n\nA 39-year-old male was referred to our hospital because of a cardiac murmur in his physical examination. Echocardiogram was performed and ostium primum atrial septum defect (ASD) and inlet type ventricular septum defect (VSD) were determined. On transesophageal echocardiography (TEE) , a cleft in posterior mitral leaflet was seen as well.\n\n\n\nThe patient was referred for surgery in our center. Repair of both ASD and VSD, mitral cleft repair, and De Vega’s annuloplasty was performed. The post-operative course was uneventful, and he was discharged on metoprolol and acetylsalicylic acid (ASA). On his 6-month follow-up echocardiogram, because of a 2 × 1.2 cm mass was found on his septal leaflet of tricuspid valve (Figure 1-A; Supplemantary video 1), TEE was performed . A mass of 2.1 × 1.5 cm with a smooth border originating from septal and anterior leaflets was seen (Figure 1B-C ) on TEE. There was no defect on atrial and ventricular septum.\n\n\nFigure 1\nA) Transthoracic echocardiographic image showing a 2 x 1.2 cm mass on septal leaflet of tricuspid valve (LV, left ventricle; RV, right ventricle; RA, right atrium). B) Transesophageal echocardiographic image showing a 2.1 x 1.5 cm mass with a smooth border originating from septal and anterior leaflets of tricuspid valve (LV, left ventricle; RV, right ventricle; RA, right atrium). C)On 3D Transesophageal echocardiography, the mass on septal leaflet of tricuspid valve was seen. D) Postoperative image of resected material.\n\nA B C D \nPotential causes for thrombosis were examined; blood analysis showed activated partial thromboplastin time of 24 s (normal range: 20-40 s), prothrombin time of 13 s (normal range: 10-14 s) and international normalized ratio (INR) of 1.2 Lupus anticoagulant was negative and anti-cardiolipin antibodies were low. He had no history of hypercoagulopathy or deep vein thrombosis.\n\n\n\nFor prevention of embolism and exclusion of tumor, surgical operation was performed. The excised specimen was reported as an organized thrombus (Figure 1-D), therefore, anticoagulation with warfarin was prescribed for 6 months after the operation.\n\n\nDiscussion\n\nThe common atrioventricular canal was divided into left and right by the fusion of superior and inferior endocardial cushions. A defect in this stage of development result in ostium primum ASD, inlet type VSD and structural defects in atrioventricular valves. Endocardial cushion defect (ECD) can be partial (with two distinct valves) or complete (only one atrioventricular valve), and surgical correction is almost always required. Tricuspid valve repair is indicated in patients who have moderate to severe tricuspid regurgitation and undergoing cardiac surgery. The optimal surgical technique is controversial but De Vega’s annuloplasty was widely performed. However, in patient with severe annular dilatation and pulmonary hypertension recurrence is common with De Vega’s procedure and ring annuloplasty is preferred.1\n\n\n\nTricuspid valve thrombosis are quite rare and can be examined in 3 groups; 1) Patients with antiphospholipid syndromes, 2) Patients with structural defects and 3) Idiopathic thrombus formation without any coagulopathy or structural defect. Tricuspid valve thrombus in patients with antiphospholipid syndrome can present with symptoms of tricuspid stenosis.2 Thrombus formation in patient with structural defect is rather rare. Konishi et al reported a case of organized thrombus of tricuspid valve in a patient with VSD and tricuspid pouch.\n\n\n\nStagnation of blood around the septal leaflet pouch was thought to be responsible for thrombus formation.3 Mario et al reported another case of tricuspid thrombus in a patient with mild hyperhomocysteinemia who underwent tricuspid ring annuloplasty and ASD repair.4 Moreover, tricuspid valve thrombosis was reported in two separate cases with no known cardiac anomaly or coagulopathy. But the origin of thrombus was found to be deep veins.5,6\n\n\n\nWe report a rare case with a tricuspid thrombus formation after De Vega’s annuloplasty without the use of a ring. Although right-sided prosthetic materials have a higher incidence of thrombotic complication, postoperative antithrombotic therapy is not advised after tricuspid valve repair in current practice guidelines. Therefore, the anticoagulant therapy was not administered to this patient. However, it has been reported that the continued use of anti-aggregant therapy should be considered in patients with tricuspid repair after surgery.7 Our patient had quitted ASA treatment 3 months after the operation, and the thrombus formation might be precipitated by the cessation of anti-aggregant therapy. In our case, the thrombus was larger than 10 mm and surgical treatment was preferred. In smaller thrombus, follow-up with anticoagulant or anti-aggregant medication may be considered.7 In literature, thrombus management was usually done by anticoagulant therapy, and no evidence was found for appropriate use of antithrombotic and anticoagulant regimes. The anticoagulation for at least 3 months is recommended for the patients with venous thromboembolism but, if irreversible risk factors exists, extended anticoagulant therapy should be recommended.8 We reevaluated our patient 6 months after surgery with TEE. There was no new thrombus formation, therefore we medicated our patient with ASA instead of warfarin as a long term treatment. The patient had no more events after one-year follow-up.\n\n\nEthical issues\n\nThe study was approval by the Local Ethics Committee.\n\n\nCompeting interests\n\nAuthors declare no conflict of interests in this study.\n\n\nSupplementary materials\nSupplementary video 1:\n Transthoracic subcostal view showing a mass on septal leaflet of tricuspid valve.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Kara I Koksal C Cakalagaoglu C Sahin M Yanartas M Ay Y Recurrent Tricuspid Insufficiency Is the Surgical Repair Technique a Risk Factor? Tex Heart Inst J 2013 40 34 41 23466680 \n2 Mukhopadhyay S Suryavanshi S Yusuf J Chandrashekhar Rastogi V Trehan V Isolated thrombus producing tricuspid stenosis: An unusual presentation in primary antiphospholipid syndrome Indian Heart J 2004 56 61 3 15129795 \n3 Konishi H Fukuda M Kato M Misawa Y Fuse K Organized thrombus of the tricuspid valve mimicking valvular tumor Ann Thorac Surg 2001 71 2022 4 11426791 \n4 Castaño M Gualis J Martín CE Early Thrombosis of a Tricuspid Annuloplasty Ring and Mild Hyperhomocysteinemia Ann Thorac Surg 2011 92 e125 6 22115269 \n5 Paolillo V Gastaldo D Barretta A Guerra F Idiopathic organized thrombus of the tricuspid valve mimicking valvular tumor Tex Heart Inst J 2004 31 192 3 15212138 \n6 Saxena P Mejia R Tam RK A rare presentation of tricuspid valve thrombus in a normal heart Ann Thorac Surg 2005 80 1498 500 16181900 \n7 Butchart EG Gohlke-Bärwolf C Antunes MJ Tornos P De Caterina R Cormier B Working Groups on Valvular Heart Disease, Thrombosis, and Cardiac Rehabilitation and Exercise Physiology, European Society of CardiologyRecommendations for the management of patients after heart valve surgery Eur Heart J 2005 26 2463 71 16103039 \n8 Guyatt GH Akl EA Crowther M Gutterman DD Schuünemann HJ American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel Executive Summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines Chest 2012 141 7S 47S 22315257\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2008-5117",
"issue": "6(3)",
"journal": "Journal of cardiovascular and thoracic research",
"keywords": "Congenital Heart Defects; Mass; Tricuspid Valve",
"medline_ta": "J Cardiovasc Thorac Res",
"mesh_terms": null,
"nlm_unique_id": "101528712",
"other_id": null,
"pages": "203-4",
"pmc": null,
"pmid": "25320670",
"pubdate": "2014",
"publication_types": "D002363:Case Reports",
"references": "15212138;15129795;23466680;22115269;16103039;22315257;11426791;16181900",
"title": "Thrombus Formation on the Tricuspid Valve After De Vega's Annuloplasty and Repair of Endocardial Cushion Defect.",
"title_normalized": "thrombus formation on the tricuspid valve after de vega s annuloplasty and repair of endocardial cushion defect"
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"abstract": "BACKGROUND\nCryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology.\n\n\nMETHODS\nWe describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology.\n\n\nRESULTS\nAll 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids.\n\n\nCONCLUSIONS\nThese data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.",
"affiliations": "Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda,Maryland; anil.panackal@nih.gov.;Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), NIH, Bethesda, Maryland.;Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), NIH, Bethesda, Maryland.;Neurology Consult Service, NINDS, NIH, Bethesda, Maryland.;Center for Infectious Disease Imaging, Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, Maryland.;Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda,Maryland.;Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda,Maryland.;Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), NIH, Bethesda, Maryland.;Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), NIH, Bethesda, Maryland.;Infectious Diseases, Kaiser San Jose Medical Center, San Jose, California.;Division of Infectious Diseases, Stony Brook University, Stony Brook, New York.;Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda,Maryland.;Neuroimmunological Diseases Unit, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke (NINDS), NIH, Bethesda, Maryland.;Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda,Maryland.",
"authors": "Panackal|Anil A|AA|;Komori|Mika|M|;Kosa|Peter|P|;Khan|Omar|O|;Hammoud|Dima A|DA|;Rosen|Lindsey B|LB|;Browne|Sarah K|SK|;Lin|Yen-Chih|YC|;Romm|Elena|E|;Ramaprasad|Charu|C|;Fries|Bettina C|BC|;Bennett|John E|JE|;Bielekova|Bibiana|B|;Williamson|Peter R|PR|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D007166:Immunosuppressive Agents; D016559:Tacrolimus; D008775:Methylprednisolone; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciw739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "64(3)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "\nCryptococcus\n; cauda equina/conus syndromes; meningoencephalitis; pulse corticosteroids.; spinal arachnoiditis",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D001100:Arachnoiditis; D015415:Biomarkers; D016516:CD4-CD8 Ratio; D003454:Cryptococcus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D000069544:Infectious Encephalitis; D018810:Magnetic Resonance Angiography; D008297:Male; D016919:Meningitis, Cryptococcal; D008590:Meningoencephalitis; D008727:Methotrexate; D008775:Methylprednisolone; D008875:Middle Aged; D009460:Neurologic Examination; D020551:Pulse Therapy, Drug; D016559:Tacrolimus; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "275-283",
"pmc": null,
"pmid": "28011613",
"pubdate": "2017-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18841709;25391338;20047480;15040176;22711298;26724637;24319084;19182676;23509356;21253011;7103428;731311;15181565;24963568;19230429;16798715;25808056;24510966;2360963;16257113;23874010;8815760;22670042;17945156;23242412;26863355;26814182;22937064;1686893;19589083;24643864;22421244;23457543;27042677;7935577;6541311;23555970;26020932;20722603",
"title": "Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults.",
"title_normalized": "spinal arachnoiditis as a complication of cryptococcal meningoencephalitis in non hiv previously healthy adults"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP013165",
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"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
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"abstract": "Objective: We performed a single-center retrospective study to determine the different efficacy of tocilizumab (TCZ) in the early and late stages and in three phenotypic subgroups (monocyclic, polycyclic, and persistent) of systemic juvenile idiopathic arthritis (sJIA). Methods: Clinical and serological parameters of 77 sJIA patients treated by TCZ were collected from November 1, 2013 to May 1, 2019. Patients were grouped based on the duration group A < 6 months (n = 41) and group B > 6 months (n = 36) and divided into three phenotypes: monocyclic (n = 12), polycyclic (n = 14), and persistent (n = 51) course. Results: At baseline, group A had pronounced ESR, fever less active arthritis than group B (p < 0.05). After 12 weeks of therapy, TCZ alleviated fever, ESR, CRP, and systemic-onset juvenile arthritis disease activity score-27 (sJADAS27) in both group A and group B (p>0.05), while the efficacy of TCZ in relieving active arthritis in group A was better than that in group B (p<0.05). After 1 year of TCZ therapy, it showed that patients with monocyclic phenotype had the highest clinical response rate (91.7%, odds ratio = 0, 95% CI: 24-24, p = 0.00), followed by the polycyclic (28.6%, odds ratio = 2.1, 95% CI: 10.5-18.8, p = 0.00) and the persistent course (9.8%, odds ratio = 1.2, 95% CI: 9.5-13.8, p = 0.00). Conclusion: TCZ can quickly relieve fever and inflammation, especially when patients have less active arthritis with shorter disease duration. The long-term efficacy of TCZ is related to the phenotypes, among which the monocyclic is the best, and the persistent is the worst.",
"affiliations": "Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.;Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.;Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.;Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.;Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.;Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.",
"authors": "Yan|Xin|X|;Tang|Wenjing|W|;Zhang|Zhiyong|Z|;Zhang|Yu|Y|;Luo|Chong|C|;Tang|Xuemei|X|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2021.735846",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.735846\nPediatrics\nOriginal Research\nTocilizumab in Systemic Juvenile Idiopathic Arthritis: Response Differs by Disease Duration at Medication Initiation and by Phenotype of Disease\nYan Xin 1 2 3\nTang Wenjing 1 2 3\nZhang Zhiyong 1 2 3\nZhang Yu 1 2 3\nLuo Chong 1 2 3\nTang Xuemei 1 2 3 *\n\n1Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China\n2Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China\n3Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China\nEdited by: Marco Cattalini, Asst of the Brescia Spedali Civili, Italy\n\nReviewed by: Oya Koker, Istanbul University, Turkey; Ezgi Deniz Batu, Hacettepe University, Turkey\n\n*Correspondence: Xuemei Tang tangxuemei2008@163.com\nThis article was submitted to Pediatric Rheumatology, a section of the journal Frontiers in Pediatrics\n\n08 11 2021\n2021\n9 73584603 7 2021\n01 10 2021\nCopyright © 2021 Yan, Tang, Zhang, Zhang, Luo and Tang.\n2021\nYan, Tang, Zhang, Zhang, Luo and Tang\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nObjective: We performed a single-center retrospective study to determine the different efficacy of tocilizumab (TCZ) in the early and late stages and in three phenotypic subgroups (monocyclic, polycyclic, and persistent) of systemic juvenile idiopathic arthritis (sJIA).\n\nMethods: Clinical and serological parameters of 77 sJIA patients treated by TCZ were collected from November 1, 2013 to May 1, 2019. Patients were grouped based on the duration group A < 6 months (n = 41) and group B > 6 months (n = 36) and divided into three phenotypes: monocyclic (n = 12), polycyclic (n = 14), and persistent (n = 51) course.\n\nResults: At baseline, group A had pronounced ESR, fever less active arthritis than group B (p < 0.05). After 12 weeks of therapy, TCZ alleviated fever, ESR, CRP, and systemic-onset juvenile arthritis disease activity score-27 (sJADAS27) in both group A and group B (p>0.05), while the efficacy of TCZ in relieving active arthritis in group A was better than that in group B (p<0.05). After 1 year of TCZ therapy, it showed that patients with monocyclic phenotype had the highest clinical response rate (91.7%, odds ratio = 0, 95% CI: 24–24, p = 0.00), followed by the polycyclic (28.6%, odds ratio = 2.1, 95% CI: 10.5–18.8, p = 0.00) and the persistent course (9.8%, odds ratio = 1.2, 95% CI: 9.5–13.8, p = 0.00).\n\nConclusion: TCZ can quickly relieve fever and inflammation, especially when patients have less active arthritis with shorter disease duration. The long-term efficacy of TCZ is related to the phenotypes, among which the monocyclic is the best, and the persistent is the worst.\n\nsystemic juvenile idiopathic arthritis\ntocilizumab\nclinical trial\npediatric\ntreatment\n==== Body\npmcIntroduction\n\nSystemic juvenile idiopathic arthritis (sJIA) is a systemic inflammatory disease clinically characterized by fever, lymphadenopathy, arthritis, rash, and serositis. sJIA is the most serious subtype of juvenile idiopathic arthritis (1) and accounts for 30% to 40% of all JIA in Asia (2). A significant number of patients develop severe disease and treatment-related complications such as persistent arthritis, growth delay, and osteoporosis. Serious complications which are potentially fatal including macrophage activation syndrome (MAS) occur in 10% to 15% of children with sJIA (3–5). sJIA is divided into three phenotypes: monocyclic, polycyclic, and persistent course (6, 7).\n\nThe etiology of sJIA is not fully understood; proinflammatory cytokines including interleukin (IL)-6, IL-1, and IL-18 play an important role in the pathogenesis of the disease. IL-6 mediates systemic inflammation in sJIA, leading to joint synovial hyperplasia and joint destruction (8–10). Blockade of IL-6 represents the main mechanism of sJIA treatment and prevention of potential complications (11).\n\nIn 2011, the United States and Europe successively approved tocilizumab, a humanized monoclonal antibody TCZ against the IL-6 receptor for treating children with sJIA. Due to the heterogeneity of sJIA, the clinical response of patients treated with TCZ is different; hence, it is needed to better characterize the profile of patients with sJIA who are more likely to respond to IL-6 blockade. Pacharapakornpong et al. (12) found that in the early TCZ treatment (<6 months), sJIA patients had a higher remission rate than late TCZ treatment (>6 months). In this study, we performed a single-center retrospective study to determine the different efficacy of TCZ in the early and late stages and in three phenotypic subgroups (monocyclic, polycyclic, and persistent) of sJIA. The safety profile and therapeutic effect of TCZ were observed and analyzed to provide a clinical basis for the treatment of children with sJIA.\n\nMaterials and Methods\n\nStudy Design and Population\n\nWe conducted a single-center retrospective study including patients with sJIA meeting the 2011 American College of Rheumatology designation criteria (13), who were starting TCZ in the Department of Rheumatology and Immunology, Chongqing Medical University, from November 1, 2013 to May 1, 2019. Patients with other rheumatic, infectious, neoplastic, and autoinflammatory diseases were excluded. Patients treated with other biological agents (e.g., infliximab and etanercept) in the previous 3 months were allowed. The enrolled patients who were in the active stage of the disease were allowed non-Steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) (e.g., MTX, thalidomide, hydroxychloroquine, and leflunomide), among which the glucocorticoid dose was standardized to ≤1 mg/kg/day.\n\nTCZ was given at a dosage of 8–12 mg/kg (12 mg/kg for body weight < 30 kg, 8 mg/kg for body weight ≥ 30 kg) with a slow intravenous infusion every 2 weeks. After 12 weeks, TCZ was given every 4 weeks and every 6 weeks after an initial 24 weeks of treatment. All children received TCZ at least six times. This study is in line with the ethical standards set by the Chinese Medical Ethics Committee, and the subject's guardians provided informed consent.\n\nAssessment and Outcomes\n\n(1) The temperature, the presence of skin rash, arthritis severity, and liver and spleen lymph nodes of sJIA patients were measured before TCZ treatment, and after 2, 12, 24, and 52 weeks.\n\n(2) Laboratory indexes of white blood cell, hemoglobin, platelet, alanine aminotransferase, aspartate aminotransferase, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were recorded during the TCZ treatment follow-up.\n\n(3) The systemic-onset juvenile arthritis disease activity score-27 (14) (sJADAS-27) scoring system was used to evaluate the efficacy of TCZ treatment during the follow-up. The sJADAS-27 score includes five aspects: a physician's assessment of disease activity, parent and child's assessment of disease activity, the number of active joints, ESR, and clinical manifestations. The sum of the following five scores determines the sJADAS27 score. Assessment of disease severity: doctors, parents, and children used a 10-cm intuitive visual analog scale to evaluate disease activity, with a total score of 10 points (0 points for disease-free activity and 10 points for maximum disease activity) for the doctor score and 10 points for the parent and children score. The number of active joints: each active joint scores 1 point. Arthritis activity refers to swelling joint and limitations of joint movement due to pain or tenderness. ESR: standardized to 0 to 10 points using the formula (ESR-20)/10 (if ESR < 20 mm/h, it is converted to 0, and if ESR ≥ 120 mm/h it is converted to 10). Clinical aspects: fever, 37–38°C scores 1 point, 38–39°C scores 2 points, 39–40°C scores 3 points, >40°C, 4 points; rash scores 1 point; lymphadenopathy, liver and/or spleen swelling, serositis, anemia, hemoglobin < 90 g/l, platelets > 600 × 109/l, and/or ferritin > 500 ng/ml score 1 point each. The evaluation of joints under the sJADAS27 score includes 27 joints: one cervical joint, two elbow joints, two wrist joints, six first to third metacarpophalangeal joints, 10 proximal interphalangeal joints, two hip joints, two knee joints, and two ankle joints.\n\n(4) Based on Wallace criteria (15), therefore, no clinical activity is defined as no joint with active disease, no fever, rash, serositis, hepatosplenomegaly, or systemic lymphadenopathy caused by sJIA, no active uveitis, normal ESR/CRP level (ESR < 20 mm/H, CRP < 8 mg/l, a high ESR/CRP level not caused by sJIA is acceptable); the best possible score of disease activity is reported by a physician global assessment (such as a score of 0 on the visual analog scale); and the duration of morning stiffness is < 15 min. Clinical remission is defined as no clinically active disease for ≥ 6 months. A period of active disease is defined as one or more of the following: >1 active joint; abnormal ESR/CRP levels; a score of 0–10 on the visual analog scale; overall disease activity defined by a physician global assessment score > 0; parent and child health overall status score ≥ 0.\n\n(5) Monocyclic: disease activity followed by a long period of remission lasting for 2 years. Polycyclic: alternating periods of disease activity and remission, manifesting as recurrent attacks. Persistent course: fever and active arthritis lasting for more than 3 months, accompanied by a significant increase in inflammatory indicators such as ESR and CRP (6, 7).\n\nStatistical Analysis\n\nStatistical analysis was conducted using SPSS23.0 statistical software. The Shapiro–Wilk's test was used for checking the normality in the distribution of numeric variables. The statistical description is presented as mean and standard deviation for quantitative data conforming to the normal distribution, medians and interquartile range (IQR) for continuous variables, and number and percentages for categorical variables. Comparison between groups was analyzed by χ2 test, repeated measurement analysis of variance (ANOVA), and rank-sum test. Comparison of prognosis among groups was analyzed by survival analysis. p-value < 0.05 was considered statistically significant.\n\nResults\n\nShort-Term Efficacy of TCZ\n\nA total of 77 sJIA patients (52 males and 25 females) with a median age of 6.3 years (2.5 ~ 12 years) and a median disease duration of 11 months (0 ~ 52 months) were enrolled at baseline. Patients were grouped based on the duration (before TCZ treatment): group A ≤ 6 months (n = 41) and group B > 6 months (n = 36) (Table 1).\n\nTable 1 Baseline characteristics of patients with systemic juvenile idiopathic arthritis.\n\n\tGroup A (n = 41)\tGroup B (n = 36)\tp -value\t\nMale (%)\t26 (63.4)\t26 (72.2)\t0.410\t\nAge at diagnosis (years)\t6.8(1.25–12)\t5.8(2.25–13.75)\t0.582\t\nDisease duration before tocilizumab treatment (months)\t0.8(0–6)\t24.2(6–84)\t0.000*\t\nNumber of patients who previously received DMARDs (%)\t22 (53.7)\t29 (80.6)\t0.013*\t\nNumber of patients who previously received glucocorticoids (%)\t27 (65.9)\t25 (69.4)\t0.737\t\nData are presented as median and IQR, and number and percentages. n, number of patients; DMARDs, disease-modifying antirheumatic drugs;\n\n* p < 0.05.\n\nAt baseline, group A had pronounced ESR, fever, and less active arthritis compared to group B (p < 0.05). There were 40 (40/41) patients with fever in group A, 29 (29/36) in group B (Table 2). Active arthritis was mainly in the knees, ankles, wrists, and hips in both groups A and B. After 2 weeks of TCZ treatment, fever, active arthritis, sJADAS-27 score, white blood cell counts, ESR, and CRP levels had significantly relieved (p < 0.05) in both group A and group B. After the 12 week treatment, the effect of TCZ in relieving active arthritis in group A was better than in group B (p < 0.05). There was no difference between group A and group B in relieving fever, sJADAS-27 score, white blood cell count, ESR, and CRP (each p > 0.05), as shown in Table 2.\n\nTable 2 Changes in clinical parameters after tocilizumab treatment in children with systemic juvenile idiopathic arthritis.\n\n\tGroup\tBaseline\tWeek 2\tWeek 4\tWeek 12\tF\tp -value\t\nFever\tA\t40/411\t2/41a\t4/41\t6/41\t0.759\t0.386\t\n\tB\t29/36\t9/36a\t5/36\t4/36\t\t\t\nNumber of active arthritis episodes\tA\t3.2 ± 3.01\t1.1 ± 1.9a\t0.5 ± 1.0b\t0.7 ± 1.6\t6.395\t0.014*\t\n\tB\t4.4 ± 3.7\t2.4 ± 2.4a\t1.7 ± 2.0b\t1.1 ± 1.9c\t\t\t\nsJADAS-27 score\tA\t21.7 ± 4.2\t6.0 ± 4.9a\t4.8 ± 5.3\t4.9 ± 6.1\t3.298\t0.73\t\n\tB\t21.8 ± 5.8\t10.4 ± 7.0a\t7.4 ± 6.4b\t5.2 ± 5.2c\t\t\t\nWBC (× 109/L)\tA\t19.9 ± 10.0\t14.6 ± 9.0a\t13.2 ± 9.1\t12.7 ± 10.5\t3.652\t0.06\t\n\tB\t15.6 ± 7.1\t11.8 ± 5.6a\t10.2 ± 4.2b\t10.7 ± 8.0\t\t\t\nESR (mm/H)\tA\t91.5 ± 30.61\t18.4 ± 20.1a\t22.3 ± 36.9\t26.2 ± 40.0\t2.652\t0.108\t\n\tB\t76.8 ± 28.0\t21.1 ± 21.8a\t15.4 ± 23.5\t13.3 ± 22.8\t\t\t\nCRP (mg/L)\tA\t78.4 ± 42.3\t13.1 ± 13.1a\t22.1 ± 32.5\t19.1 ± 24.3\t0.152\t0.698\t\n\tB\t89.7 ± 33.7\t17.8 ± 23.9a\t14.0 ± 17.6b\t17.8 ± 28.5\t\t\t\nData are presented as mean ± standard deviation, and number and percentages.\n\n1 Comparison between group A and group B at baseline, p < 0.05:\n\na compared with baseline, p < 0.05;\n\nb compared with 2 weeks of treatment, p < 0.05;\n\nc compared with 4 weeks of treatment, p < 0.05.\n\n* Comparison of the effect of tocilizumab (12 weeks of treatment) in group A and group B, p < 0. 05. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; WBC, white blood cell count.\n\nLong-Term Efficacy of TCZ\n\nThe treatment duration of TCZ in group A was 9.5 months (IQR 3–36) and 11.7 months (IQR 3–24) in group B. All patients were followed up for at least 24 months.\n\nAt the 1 year follow-up, there was no significant difference in the proportion of patients who achieved clinical remission, no clinical activity, and clinical activity period in both group A and group B (p > 0.05). Three clinical phenotypes were defined as follows: monocyclic (n = 12), polycyclic (n = 14), and persistent (n = 51) course. A comparison of the efficacy of TCZ in patients with three phenotypes revealed significant differences in the outcome; it showed that patients with monocyclic phenotype had the highest clinical response (with no clinical manifestation and normalized inflammation parameter) rate (91.7%, odds ratio = 0, 95% CI: 24–24, p = 0.00), followed by the polycyclic (28.6%, odds ratio =2.1, 95% CI: 10.5–18.8, p = 0.00) and the persistent course (9.8%, odds ratio =1.2, 95% CI: 9.5–13.8, p = 0.00) (Figure 1).\n\nFigure 1 Clinical response with 12 weeks of tocilizumab treatment in different phenotypes.\n\nA comparison of prognosis among groups was analyzed by survival analysis. All the patients were followed up for 24 months. In the initial stage of TCZ treatment, the three phenotypes of patients had good clinical responses. As time went by, the clinical response of a single course was better than polycyclic and persistent course.\n\nAdverse Events\n\nThis study represented 67.5 years of TCZ exposure in 77 sJIA patients; adverse events occurred in 21 patients (Table 3). Leukopenia was observed in seven patients, including one leukopenia induced by streptococcal infection, two infusion reactions characterized by fever and cold chills, and facial blushing, which occurred during the second infusion of TCZ. This was relieved by discontinuing the infusion and intravenous dexamethasone treatment and did not reoccur during later TCZ infusions. One infusion reaction occurred during the sixth TCZ infusion, presented as fever, chills, and cyanosis, and was also relieved by discontinuing the infusion and intravenous dexamethasone treatment. For this patient, TCZ treatment was terminated. Two patients experienced MAS, one at 3 months and the other at 6 months of tocilizumab treatment. Two patients had continuous active disease during tocilizumab treatment, and MAS was improved after comprehensive treatment instead of TCZ.\n\nTable 3 Adverse events in patients receiving tocilizumab.\n\nAdverse event\tNumber\t\nLeukopenia\t7\t\nElevated transaminases\t5\t\nInfusion reaction\t3\t\nPneumonia, pulmonary consolidation\t2\t\nSepticemia\t1\t\nStreptococcal infection\t1\t\nMacrophage activation syndrome\t2\t\n\nDiscussion\n\nThe treatment of sJIA usually requires NSAIDs, DMARDs, and glucocorticoids (6). It is necessary to use biological agents when it is refractory to glucocorticoids and DMARDs (10, 16). The pathophysiological basis of sJIA is the activation of pro-inflammatory cytokines, especially IL-1β and IL-6 (17, 18). Currently, there are two main biological treatment strategies for sJIA: IL-1 and IL-6 biologic blockade (19, 20). However, in China, IL-1 blockers are still unavailable so that IL-6 blockers are the main biologic treatment for sJIA.\n\nIn our study, we found that fever, active arthritis, sJADAS-27 score, white blood cell count, ESR, and CRP can be relieved after 2 weeks of TCZ treatment. TCZ has significant short-term efficacy for sJIA. Furthermore, we observed sJIA patients with TCZ administration in early stage and found that it had better remission of active arthritis than those administrated in the late stage after 12 weeks of treatment. TCZ can quickly relieve fever and inflammation (indicated by decreased CRP and ESR) (21–24), especially for patients showing less active arthritis in the early stage. Doaa et al. (25) identified that younger patients with shorter disease duration and greater systemic manifestations showed more favorable outcomes by TCZ therapy. These observations are consistent with the window of opportunity hypothesis, which suggests that IL-6 blockade may be more effective in early sJIA, when the disease is characterized by more prominent systemic presentation and less active arthritis (26). Likewise, Alexeeva et al. (27) found that only earlier age at initiation of TCZ therapy was a statistically significant factor associated with reaching the best response to therapy in polyarticular JIA.\n\nThe course of sJIA varies and is divided into three phenotypes (7). In this study, sJIA was classified as monocyclic (n = 12, 15.6%), polycyclic (n = 14, 18.2%), and persistent course (n = 51, 66.2%). Bielak et al. (28) defined three phenotypes of sJIA: monocyclic, polycyclic, and polyarticular disease, which occurs as arthritis flares in >4 joints. Systemic inflammation, such as fever, elevated CRP, and ESR, is not more prominent in patients with multi-joint sJIA than single-joint sJIA, and systemic inflammation gradually evolves into an autoimmune disease phenotype (24, 29). The heterogeneity of sJIA contributes to the differences. Bielak et al. found that polycyclic and monocyclic sJIA responded better to tocilizumab than polyarticular sJIA. In our study, the clinical response was worst in patients with persistent course and the best in monocyclic. A previous study indicated that IL-1 inhibitors may be useful if patients do not respond to TCZ. sJIA with persistent course often show polyarticular JIA, and in these patients, TCZ is effective for fever and inflammation, but not for polyarthritis. Therefore, sJIA with persistent course who do not respond to TCZ may need an IL-1 antagonist or a TNF-a monoclonal antibody (30). To obtain optimal therapeutic responses, it is necessary to predict the disease phenotype of sJIA at an early stage. Singh-Grewal et al. (7) proposed that the clinical features observed at 3 months (the presence of active arthritis and fever) and 6 months (elevated ESR > 26 mm/H requiring corticosteroid treatment) are accurate predictors of a patient's disease course. This information helps identify patient's risk of developing into persistent disease and having a higher likelihood of a poor functional outcome, which need timely therapeutic intervention to prevent from joint damage and disability. Therefore, early TCZ treatment is recommended for such patients with early predictions that may be persistent courses.\n\nThe most common adverse effect observed in our study was granulocytopenia, which was mild and not accompanied by severe infection. Clinical remission was achieved in six of the seven cases, suggesting that patients who develop granulocytopenia after TCZ treatment may have a greater chance to obtain clinical remission. Neutropenia associated with sJIA is dependent on IL-6 levels, and leukocytopenia and granulocytopenia may be used as biomarkers of susceptibility to treatment with IL-6 monoclonal antibodies (31). There were two cases of MAS, which was not unexpected given that previous studies report that 20% to 25% of patients with sJIA treated with biological agents develop MAS (32). Current research suggests that TCZ does not prevent the occurrence of MAS, and indeed in some patients, TCZ may even trigger this reaction. The specific cause and mechanism are unclear. It is possible that when a patient experiences an obvious episode of active sJIA, TCZ antagonizes IL-6 which could trigger a negative feedback loop, therefore causing amplified and excessive inflammation and inducing MAS. Therefore, the timing of TCZ treatment is a critical factor.\n\nLimitation Points in This Study\n\nIn this study, glucocorticoids were standardized to ≤1 mg/kg/day to avoid the effect of high doses, but almost 60%–70% patients enrolled were taken at baseline. In addition, we did not study the beneficial effects of TCZ on glucocorticoid reduction and catch-up growth. Moreover, due to economic conditions, TCZ was not added every 2 weeks strictly, which could have a partial impact on the research results. It was a single-center retrospective study with low number of patients enrolled, so prospective cohort studies and further multicenter clinical studies are needed to shed additional light on this matter and ultimately improve the care of patients with sJIA.\n\nConclusion\n\nWe demonstrated that TCZ can quickly relieve fever and inflammation, especially when patients have less active arthritis with shorter disease duration. The long-term efficacy of TCZ is related to the phenotype; therefore, it is necessary to predict the disease phenotype of sJIA at an early stage. These findings may help to define the profile of patients with sJIA who are more likely to benefit from TCZ.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nWritten informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nXY analyzed the data and wrote the paper. WT and ZZ collected and analyzed the data. YZ and CL collected the patients. XT ideated the study and revised the paper. All authors approved the final version of the manuscript.\n\nFunding\n\nThis work was supported by the Natural Science Foundation of China (Grant Number 82001655).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nThe authors would like to thank the parents and children who enrolled in the study and the health professionals from the department of laboratory medicine. Their outstanding support and contributions are gratefully appreciated.\n==== Refs\nReferences\n\n1. Cimaz R . Systemic-onset juvenile idiopathic arthritis. Autoimmun Rev. (2016) 15 :931–34. 10.1016/j.autrev.2016.07.004 27392503\n2. Thierry S Fautrel B Lemelle I Guillemin F . Prevalence and incidence of juvenile idiopathic arthritis: a systematic review. Joint Bone Spine. (2014) 81 :112–7. 10.1016/j.jbspin.2013.09.003 24210707\n3. Ravelli A Davì S Minoia F . Martini A, Cron RQ. Macrophage activation syndrome. Hematol Oncol Clin North Am. (2015) 29 :927–41. 10.1016/j.hoc.2015.06.010 26461152\n4. Behrens EM Beukelman T Paessler M Cron RQ . Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol. (2007) 34 :1133–8.17343315\n5. Bleesing J Prada A. Siegel DM Villanueva J Olson J Llowite NT . The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum. (2007) 56 :965–71. 10.1002/art.22416 17328073\n6. Li Cf . Pay attention to the diagnosis and treatment of systemic-onset juvenile idiopathic arthritis. Chinese Journal of Practical Pediatrics. (2018) 33 :1604–7. 10.3760/cma.j.issn.2095-428x.2018.21.002\n7. Singh-Grewal D Schneider R Bayer N Feldman BM . Predictors of disease course and remission in systemic juvenile idiopathic arthritis: significance of early clinical and laboratory features. Arthritis Rheum. (2006) 54 :1595–601. 10.1002/art.21774 16645998\n8. Lin YT Wang CT Gershwin ME Chiang BL . The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis. Autoimmun Rev. (2011) 10 :482–9. 10.1016/j.autrev.2011.02.001 21320644\n9. Kumar S . Systemic juvenile idiopathic arthritis: diagnosis and management. Indian J Pediatr.(2016) 83 :322–7. 10.1007/s12098-016-2060-z 26916892\n10. Martini A . Systemic juvenile idiopathic arthritis. Autoimmun Rev.(2012) 12 : 56–9. 10.1016/j.autrev.2012.07.022 22884552\n11. Horneff G Schulz AC Klotsche J Hospach A Minden K Foeldvari I . Experience with etanercept, tocilizumab and interleukin-1 inhibitors in systemic onset juvenile idiopathic arthritis patients from the BIKER registry. Arthritis Res Ther. (2017) 19 :256. 10.1186/s13075-017-1462-2 29166924\n12. Pacharapakornpong T Vallibhakara SA Lerkvaleekul B Vilaiyuk S . Comparisons of the outcomes between early and late tocilizumab treatment in systemic juvenile idiopathic arthritis. Rheumatol Int. (2017) 37 :251–5. 10.1007/s00296-016-3595-z 27798725\n13. Beukelman T Patkar NM Saag Kg Tolleson RS Cron RQ Dewitt EM . American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. (2011) 63 :465–82. 10.1002/acr.20460 21452260\n14. Jessica T Angela P Elena A Laura P Yasser EM Priyankar P . Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis. Rheumatology. (2019).32829413\n15. Wallace CA Ruperto N Giannini E . Preliminary criteria remission for select categories of juvenile idiopathic arthritis. J Rheumatol. (2004) 31 :2290–4.15517647\n16. Kenan B Amra A Sezgin S Gurkan T Gulberk T Oya K . Prognosis, complications and treatment response in systemic juvenile idiopathic arthritis patients: a single-center experience. Int J Rheum Dis. (2019) 22 :1661–9. 10.1111/1756-185X.13649 31273940\n17. Pascual V Allantaz F Arce E Punaro M Banchereau J . Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med. (2019) 210 :1479–86. 10.1084/jem.20050473 15851489\n18. Benedetti FD Massa M Pignatti P Albani S Novick D Martini A . Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest. (1994) 93 :2114–9. 10.1172/JCI117206 8182142\n19. Yokota S Imagawa T Mori M Miyamae T Aihara Y Takei S . Afficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebocontrolled, withdrawal phase III trial. Lancet. (2008) 371 :998–1006. 10.1016/S0140-6736(08)60454-7 18358927\n20. Quartier P Allantaz F Cimaz R Pillet P Messiaen C Bardin C . A multicentre, randomized, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. (2011) 70 :747–54. 10.1136/ard.2010.134254 21173013\n21. Geng LL Miao F Zhou Y Li XQ . Efficacy and safety of tocilizumab on refractory systemic onset juvenile idiopathic arthritis: observation on 16 cases. Chin J Pract Pediatr. (2019) 34 :37–40. 10.19538/j.ek2019010612\n22. Duan Z Lin ZP Xu K Deng YH Peng Y Li L . Efficacy of tocilizmnab in the treatment of systemic juvenile idiopathic arthritis. Chin J Pract Pediatr. (2017) 32 :1632–5. 10.3760/cma.j.issn.2095-428x.2017.21.008\n23. Lai JM Wu FQ Zhou ZX Kang M Huang XL Su GX . Tocilizumab for refractory systemic juvenile idiopathic arthritis. Chin J Pediatr. (2017) 55 :830–4. 10.3760/cma.j.issn.0578-1310.2017.11.008 32933962\n24. Yao W Sun L Liu HH Shi Y Li GM Zhou LJ . Long term effect of tocilizumab on refractory systemic juvenile idiopathic arthritis. J Clin Pediatr. (2017) 35 :454–7. 10.3969/j.issn.1000-3606.2017.06.014\n25. Nada DW Moghazy A Allam AE Alunno A Ibrahim AM . Short-term outcomes and predictors of effectiveness of tocilizumab in systemic juvenile idiopathic arthritis: a prospective cohort study. Med. (2021) 8 :665028. 10.3389/fmed.2021.665028 34041254\n26. Nigrovic PA . Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol. (2014) 66 :1405–13. 10.1002/art.38615 24623686\n27. Alexeeva E Dvoryakovskaya T Soloshenko M Denisova R Isaeva K Mamutova A . AB0431 earlier age at therapy initiation is associated with better response to tocilizumab therapy in patients with juvenile idiopathic polyarthritis. Ann. Rheum. Dis. (2018) 77 :1378. 10.1136/annrheumdis-2018-eular.6487\n28. Bielak M Husmann E Weyandt N Haas JP Hugle B Horneff G . IL-6 blockade in systemic juvenile idiopathic arthritis – achievement of inactive disease and remission (data from the German AID-registry). Bio Med Central. (2018) 16 . 10.1186/s12969-018-0236-y 29622022\n29. Hügle B Hinze C. Lainka E Fischer N Haas JP . Development of positive antinuclear antibodies and rheumatoid factor in systemic juvenile idiopathic arthritis points toward an autoimmune phenotype later in the disease course. Pediatr Rheumatol. (2014) 12 :28. 10.1186/1546-0096-12-28 25114627\n30. Hinze CH Holzinger D Lainka E Haas JP Speth F Kallinich T . Practice and consensus-based strategies in diagnosing and managing systemic juvenile idiopathic arthritis in Germany. Pediatr Rheumatol Online J. (2018) 16 :7. 10.1186/s12969-018-0224-2 29357887\n31. Kostik MM Isupova EA Chikova IA Dubko MF Masalova VV Snegireva LS . Reasons for inactive disease and flare in systemic onset juvenile idiopathic arthritis patients during tocilizumab treatment. Clin Exp Rheumatol. (2018) 36 :335–41.29303703\n32. Beukelman T . Treatment advances in systemic juvenile idiopathic arthritis. F1000Prime Rep. (2014) 6 :21. 10.12703/P6-21 24765526\n\n",
"fulltext_license": "CC BY",
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"issue": "9()",
"journal": "Frontiers in pediatrics",
"keywords": "clinical trial; pediatric; systemic juvenile idiopathic arthritis; tocilizumab; treatment",
"medline_ta": "Front Pediatr",
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"nlm_unique_id": "101615492",
"other_id": null,
"pages": "735846",
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"pmid": "34820342",
"pubdate": "2021",
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"references": "29303703;15851489;21452260;32829413;15517647;17328073;29166924;24623686;31273940;25114627;24765526;27392503;26916892;27798725;29141313;21320644;26461152;22884552;29357887;8182142;17343315;21173013;18358927;24210707;29622022;34041254;16645998",
"title": "Tocilizumab in Systemic Juvenile Idiopathic Arthritis: Response Differs by Disease Duration at Medication Initiation and by Phenotype of Disease.",
"title_normalized": "tocilizumab in systemic juvenile idiopathic arthritis response differs by disease duration at medication initiation and by phenotype of disease"
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"abstract": "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inherited disorder leading to severe organ-specific autoimmunity. IPEX is caused by hemizygous mutations in FOXP3, which codes for a master transcription factor of regulatory T (TReg) cell development and function. We describe a four-year-old boy with typical but slightly delayed-onset of IPEX with autoimmune diabetes mellitus, enteropathy, hepatitis and skin disease. We found the unreported FOXP3 splice site mutation c.816+2T>A that leads to the loss of leucine-zipper coding exon 7. RNA-Seq revealed that FOXP3Δ7 leads to differential expression of FOXP3 regulated genes. After myeloablative conditioning the patient underwent allogeneic HSCT from a matched unrelated donor. HSCT led to the resolution of all IPEX symptoms including insulin requirement despite persisting autoantibody levels. After initial full donor engraftment nearly complete autologous reconstitution was documented, but donor-derived TReg cells persisted with a lineage-specific chimerism of >70% and the patient remained in clinical remission.",
"affiliations": "Pediatric Hematology/Oncology/Immunology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.;Pediatric Hematology/Oncology/Immunology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.;Pediatric Hematology/Oncology/Immunology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.;Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-University Munich, Munich, Germany.;Department of Pediatric Gastroenterology, Children's Hospital, Klinikum Kassel, Kassel, Germany.;Pediatric Hematology/Oncology/Immunology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.;Pediatric Hematology/Oncology/Immunology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.;Pediatric Hematology/Oncology/Immunology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.;Pediatric Hematology/Oncology/Immunology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address: fabian.hauck@med.uni-muenchen.de.",
"authors": "Magg|Thomas|T|;Wiebking|Volker|V|;Conca|Raffaele|R|;Krebs|Stefan|S|;Arens|Stefan|S|;Schmid|Irene|I|;Klein|Christoph|C|;Albert|Michael H|MH|;Hauck|Fabian|F|",
"chemical_list": "C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clim.2018.03.008",
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"issn_linking": "1521-6616",
"issue": "191()",
"journal": "Clinical immunology (Orlando, Fla.)",
"keywords": "Autoimmune diabetes mellitus; FOXP3; HSCT; IPEX; Splice site mutation; T(Reg)",
"medline_ta": "Clin Immunol",
"mesh_terms": "D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1; D003967:Diarrhea; D005091:Exons; D051858:Forkhead Transcription Factors; D040181:Genetic Diseases, X-Linked; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007154:Immune System Diseases; D008213:Lymphocyte Activation; D008297:Male; D009154:Mutation; D050378:T-Lymphocytes, Regulatory",
"nlm_unique_id": "100883537",
"other_id": null,
"pages": "52-58",
"pmc": null,
"pmid": "29567430",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "IPEX due to an exon 7 skipping FOXP3 mutation with autoimmune diabetes mellitus cured by selective TReg cell engraftment.",
"title_normalized": "ipex due to an exon 7 skipping foxp3 mutation with autoimmune diabetes mellitus cured by selective treg cell engraftment"
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"companynumb": "DE-SA-2018SA130984",
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"abstract": "We report the case of a 39-year-old woman with acute myeloid leukemia (AML) with monocytic differentiation showing hemophagocytosis by leukemic blasts. This phenomenon is known to be associated with certain chromosomal changes, including t(8;16), der(8), inv(8), and t(16;21); however, in this case, the patient had a normal female karyotype. To our knowledge, this is the first published case of normal karyotype AML with hemophagocytosis by leukemic blasts.",
"affiliations": "Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee klsalazar@houstonmethodist.org.;Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.",
"authors": "Salazar|Katrina L|KL|;Mosse|Claudio|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1309/LMUDI1L6PU0MYHSL",
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"issn_linking": "0007-5027",
"issue": "46(1)",
"journal": "Laboratory medicine",
"keywords": "acute myeloid leukemia; erythrophagocytosis; hemophagocytosis; leukophagocytosis; monocytic differentiation; t(8;16)",
"medline_ta": "Lab Med",
"mesh_terms": "D000328:Adult; D002454:Cell Differentiation; D005260:Female; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute; D051359:Lymphohistiocytosis, Hemophagocytic; D009000:Monocytes",
"nlm_unique_id": "0250641",
"other_id": null,
"pages": "64-8",
"pmc": null,
"pmid": "25617396",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Normal karyotype in a case of acute myeloid leukemia with monocytic differentiation and hemophagocytosis by leukemic blasts.",
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"abstract": "Given the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study.\n\n\n\nA 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient's symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles.\n\n\n\nWe report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.",
"affiliations": "College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard St. S.E., Minneapolis, MN, 55455, USA.;College of Pharmacy, Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, 1110 Kirby Dr., Duluth, MN, 55812, USA.;College of Pharmacy, Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, 1110 Kirby Dr., Duluth, MN, 55812, USA.;College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard St. S.E., Minneapolis, MN, 55455, USA.;College of Pharmacy, Department of Experimental and Clinical Pharmacology and College of Medicine, Department of Psychiatry, University of Minnesota, 308 Harvard St. S.E., Minneapolis, MN, 55455, USA. jrbishop@umn.edu.",
"authors": "Eum|Seenae|S|;Schneiderhan|Mark E|ME|;Brown|Jacob T|JT|;Lee|Adam M|AM|;Bishop|Jeffrey R|JR|",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D000068180:Aripiprazole",
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"doi": "10.1186/s12888-017-1396-x",
"fulltext": "\n==== Front\nBMC PsychiatryBMC PsychiatryBMC Psychiatry1471-244XBioMed Central London 139610.1186/s12888-017-1396-xCase ReportPharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report Eum Seenae eumxx005@umn.edu 1Schneiderhan Mark E. meschnei@d.umn.edu 2Brown Jacob T. jtbrown@d.umn.edu 2Lee Adam M. leeam@umn.edu 1Bishop Jeffrey R. jrbishop@umn.edu 31 0000000419368657grid.17635.36College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard St. S.E., Minneapolis, MN 55455 USA 2 0000000419368657grid.17635.36College of Pharmacy, Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, 1110 Kirby Dr., Duluth, MN 55812 USA 3 0000000419368657grid.17635.36College of Pharmacy, Department of Experimental and Clinical Pharmacology and College of Medicine, Department of Psychiatry, University of Minnesota, 308 Harvard St. S.E., Minneapolis, MN 55455 USA 3 7 2017 3 7 2017 2017 17 23810 3 2017 22 6 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nGiven the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study.\n\nCase presentation\nA 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient’s symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles.\n\nConclusions\nWe report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.\n\nKeywords\nAripiprazole long-acting injectableWearing-off symptomsDRD2Clinical pharmacogenetic testingissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nApproximately one-third of patients with schizophrenia treated with antipsychotics continue to experience persistent psychotic symptoms [1]. Moreover, given the complex nature of symptom presentation and medication regimens in patients with psychotic disorders, outpatient psychiatric clinics are in need of ways to improve patient care. Although there are no simple tests to determine if a patient will have a response or remission of schizophrenia symptoms with a selected antipsychotic agent and dose, pharmacogenetic information along with other clinical information may offer great potential to optimize pharmacotherapy and improve the overall quality of life in psychiatric patients.\n\nPharmacogenetics is the study of how genetic variations influence drug therapy and focuses on the variants associated with pharmacokinetics and pharmacodynamics of medications. Over 160 medications, including antipsychotics such as aripiprazole, list pharmacogenetic information in the product labeling to date [2]. Neuropsychiatric medications account for about one-third of those, including many commonly used antidepressant, antipsychotic, and antiepileptic medications [3]. While research in psychiatric pharmacogenetics has significantly increased over the past 20 years, clinical application is just beginning with many emerging questions of how, when, and if to use this information.\n\nThe pharmacogenetic biomarker most commonly included in the product labeling for many antipsychotic medications is the cytochrome P450 2D6 (CYP2D6) gene related to drug metabolism and pharmacokinetic properties of drugs such as aripiprazole, risperidone, perphenazine, iloperidone, and others [2, 4, 5]. Genes thought to impact pharmacodynamics of antipsychotics (e.g. dopamine-D2, serotonin-5HT2A receptors, etc.) are not included in product labeling, but are often included in many available genetic testing panels for psychotropic medications. While there are studies published highlighting the mechanistic consequences of some polymorphisms in these genes as well as associations with some clinical outcomes, the clinical utility of pharmacodynamic gene variants in guiding antipsychotic pharmacotherapy is not as clear as variants which influence pharmacokinetics. Variation in the dopamine-D2 receptor gene (DRD2) is one example of a pharmacodynamic gene that has been extensively investigated in relation to treatment outcomes, as it is a primary target for all currently available antipsychotic agents. Although there are conflicting results, meta-analyses highlight that the rs1799732 -141C Ins/Del ‘deletion’ polymorphism may be associated with decreased responsiveness to antipsychotic medications [6, 7]. How to consider this information in the context of clinical care is unclear.\n\nAripiprazole (oral), one of the antipsychotic agents examined in the meta-analysis [6], was approved by the U.S. Food and Drug Administration (FDA) in late 2002 for the treatment of schizophrenia, and is a unique second generation antipsychotic with partial agonist activity at D2 and serotonin (5-hydroxytryptamine, 5-HT) 1A receptors, and antagonist activity at 5-HT2A receptors [8]. The first aripiprazole long-acting injectable (LAI) formulation, Abilify Maintena®, was approved in early 2013 at the recommended dose of 400 mg IM injection every 4 weeks [8]. Aripiprazole lauroxil (Aristada®) is a newer LAI aripiprazole formulation, which was FDA approved in October 2015 [8]. Aripiprazole lauroxil is an N-acyloxymethyl prodrug that undergoes a 2-step bioconversion in the plasma from the lauroxil to an intermediate, N-hydroxymethyl-aripiprazole via enzyme-mediated hydrolysis. The N-hydroxymethyl-aripiprazole then undergoes a hydrolysis reaction to aripiprazole [9]. Aripiprazole lauroxil is available at a dose of 441 mg (deltoid or gluteal), 662 mg and 882 mg (only gluteal) corresponding to aripiprazole LAI 300 mg, 450 mg and 600 mg (corresponding to oral aripiprazole 10 mg/day, 15 mg/day and 20 mg/day), respectively [8]. While these two formulations are similar with respect to dosing/administration intervals, they are different with regards to their formulations which influence some of their pharmacokinetic parameters including T1/2 and Tmax [8]. The clinical implications of these differences in the context of altered drug metabolism or target receptor sensitivities are unclear.\n\nThe dosing strategies for LAI antipsychotics include relatively standardized conversions from oral formulations to recommended administration intervals. The injection intervals for LAIs depend on the specific agent (e.g. every 4 weeks for aripiprazole, haloperidol, and paliperidone; every 2 weeks for risperidone, etc.) and are based on extensive pharmacokinetic studies of patients as well as computer simulations [10]. Although not extensively reported in the literature, there are clinical reports of some patients requiring shorter dosing intervals or higher than approved doses of LAI antipsychotics with unclear reasons.\n\nHere, we present a case of a patient with treatment-refractory schizoaffective disorder for whom pharmacogenetic testing was obtained in an attempt to explain his wearing-off symptoms with aripiprazole LAI 400 mg every 3 weeks combined with daily oral aripiprazole. Although there have been anecdotal clinical reports of symptom breakthrough at the end of a LAI antipsychotic dosing cycle, no published studies or cases have previously reported this phenomena with aripiprazole LAI. This case discussion focuses on pharmacogenetic testing as a proof of concept strategy to hypothesize a mechanism and management strategy for these breakthrough phenomena with aripiprazole LAI.\n\nCase presentation\nAB, a 51-year-old African American male [height 195.6 cm, weight 141 kg, body mass index 36.9 kg/m2] with chart diagnoses of schizoaffective disorder, depressive type and post-traumatic stress disorder, was referred to a community mental health center in March of 2014 to address medication non-adherence and lack of medication effectiveness. AB’s symptoms were first reported in 2006 and included depressed mood and persecutory auditory hallucinations with command hallucinations to either self-harm (e.g. insulin overdose) or stop his medications. His referral in 2014 included details of treatment and symptoms since 2008. The referral notes highlighted a complicated psychiatric history with approximately eight psychiatric hospitalizations over the previous five years, predominantly attributed to depressive episodes and suicide attempts. His other medical history includes uncontrolled type 2 diabetes with diabetic neuropathy, hypertension, asthma, obstructive sleep apnea, diverticulitis, chronic musculoskeletal pain, and chronic headaches. His medication list at the time of this report (February, 2017) is provided in Table 1.Table 1 Patient’s current medication list\n\nIndication\tMedication\tDose\tRoute of Administration\t\nMental Health\t\n Schizoaffective disorder\tAripiprazole lauroxil\t882 mg once a month\tIM\t\n Depression\tSertraline\t150 mg every morning\tPO\t\n Insomnia\tZolpidem CR\t12.5 mg at bedtime\tPO\t\n Smoking cessation\tVarenicline\t1 mg BID\tPO\t\nCardiovascular\t\n Hypertension\tAmlodipine\t10 mg once a day\tPO\t\nAtenolol\t50 mg once a day\tPO\t\nLosartan\t100 mg once a day\tPO\t\nSpironolactone\t100 mg once a day\tPO\t\n Prevention of CV disease\tAspirin\t81 mg once a day\tPO\t\nType 2 DM\t\n DM\tInsulin glargine\t120 units BID\tSC\t\nInsulin aspart\tAs directed\tSC\t\nMetformin\t1000 mg BID\tPO\t\n Diabetic neuropathy\tGabapentin\t1200 mg TID\tPO\t\nRespiratory\t\n Asthma\tIpratropium-albuterol\t18–103 mcg 2 puffs BID\tNasal\t\nAlbuterol nebulizer\tAs directed\tNasal\t\nBudesonide-formoterol\t160–4.5 mcg 2 puffs BID\tNasal\t\n Congestion\tFluticasone\t50 mcg 1 spray once a day\tNasal\t\nOxymetazoline\t0.05% 1 spray every night\tNasal\t\nPain\t\n Pain\tTramadol\t100 mg TID PRN\tPO\t\nGastrointestinal\t\n GERD\tOmeprazole\t20 mg BID\tPO\t\n\nIM intramuscular, PO by mouth, CR controlled release, BID twice a day, CV cardiovascular, DM diabetes mellitus, SC subcutaneous, TID three times a day, PRN as needed, GERD gastroesophageal reflux disease\n\n\n\n\nBetween 2008 and 2012, he was trialed on and off multiple antipsychotic agents including risperidone (titrated up to 6 mg/day), haloperidol (titrated up to 15 mg/day), quetiapine (titrated up to 800 mg/day), and ziprasidone (titrated up to 200 mg/day); all for a duration of at least 12 weeks without significant improvement. A trial of olanzapine (titrated up to 15 mg/day) resulted in slightly improved psychotic symptoms; however, was ultimately discontinued due to worsening diabetes control. At this time, oral aripiprazole 5 mg/day was started (April 2012).\n\nAt the time of his referral (March, 2014), the patient was on oral aripiprazole 15 mg/day, which was titrated up to 30 mg/day through March 2015, and the patient reported improvement in auditory hallucinations, mood, and suicidal ideations. In March 2015, AB agreed to start long-acting injectable (LAI) aripiprazole with the goal to eventually discontinue the oral aripiprazole to provide a safeguard for non-adherence if the command hallucinations returned. Subsequently, aripiprazole LAI, 400 mg intramuscularly (IM) was administered into the gluteal muscle every 4-weeks combined with oral aripiprazole 30 mg/day. The plan was to reduce the aripiprazole oral dose to 15 mg/day at 2-weeks post-injection. Eight weeks after initiating aripiprazole LAI, a marked improvement in psychiatric symptoms was noted. Over approximately 12-weeks, the oral aripiprazole supplementation was reduced to 5 mg/day (June 2015); however, within 4-weeks of oral aripiprazole dose reduction to 5 mg/day, his auditory hallucinations returned and worsened. The oral aripiprazole dose was then increased back to 7.5 mg/day with a noticeable positive response. At a 2-week follow-up appointment after this dose increase (July 2015), auditory hallucinations were reported to be “not as bad” but worse 1-week prior to his aripiprazole injection, resulting in a modification of aripiprazole LAI frequency from 400 mg IM every 4-weeks to every 3-weeks along with the 7.5 mg/day oral aripiprazole. In October 2015, since he complained of worsening auditory hallucinations approximately 3 days prior to his next injection, oral aripiprazole 2 mg/day as needed (up to 2 times/week) was added to his current regimen (aripiprazole LAI 400 mg every 3-week and oral aripiprazole 7.5 mg/day) for this wearing-off symptoms.\n\nThe continuing need for oral aripiprazole and symptom breakthrough prior to his every 3-week aripiprazole injection prompted further inquiry as to which variables might be contributing to this pattern of response/non-response. Considerations included medications/substances interactions, pharmacokinetic characteristics, and administration techniques (i.e. site of administration, syringe length and gauge, etc.), all of which were ruled out as contributing factors. No significant drug/substance interactions were noted (Table 1). Since adherence was not in question with an LAI medication, serum drug concentrations were not ordered. Pharmacogenetic variables influencing drug metabolism were then considered, and a commercially available psychiatry-focused pharmacogenetic testing panel was ordered in October 2015 (Table 2).Table 2 Patient’s pharmacogenetic test results\n\nGene\tGenotype\tPredicted Phenotype\t\n\nCYP2C19\n\t*1/*2\tIntermediate Metabolizer\t\n\nCYP2D6\n\t*1/*2\tExtensive (Normal) Metabolizer\t\n\nCYP3A4/CYP3A5\n\t*1/*1; *1/*1\tExtensive (Normal) Metabolizer\t\n\nUGT2B15\n\t*1/*1\tExtensive (Normal) Metabolizer\t\n\nDRD2\n\tINS/DEL\tReduced Responder\t\n\nHTR2C\n\tC/C\tNormal Expressor\t\n\nMTHFR\n\tC/C (C677T); A/A (A1298C)\tNormal Activity\t\n\nCYP cytochromes P450, UGT uridine 5′-diphospho-glucuronosyltransferase, DRD2 dopamine receptor D2 gene, HTR2C 5-hydroxytryptamine receptor 2C gene, MTHFR methylene tetrahydrofolate reductase gene\n\n\n\n\nPharmacogenetic test results for drug-metabolizing enzymes cytochrome P450 2D6 (CYP2D6) and CYP3A4 did not explain the patient’s need for high aripiprazole dose nor his breakthrough symptoms. However, the patient was found to carry a genetic variation in the dopamine receptor D2 gene (DRD2), −141C Ins/Del polymorphism (rs1799732). This polymorphism has been linked to variation in striatal dopamine receptor density [11, 12] and reduced response to some antipsychotics [6], which is consistent with AB’s reduced response to many antipsychotic agents.\n\nWith no clear pharmacogenetic influence on drug metabolism, yet a documented need for higher doses of aripiprazole, additional dosing strategies were explored. At this time, a new long-acting injectable formulation of aripiprazole, aripiprazole lauroxil, was considered due higher dosing options (aripiprazole lauroxil 882 mg every 4-weeks, equivalent to aripiprazole LAI 600 mg) [8, 13]. Therefore, in December 2015, the decision was made to switch to aripiprazole lauroxil 882 mg IM (gluteal) every 4-weeks. Although the plan was to continue the oral aripiprazole for 3 weeks, the patient discontinued the oral aripiprazole on his own after the first injection. The patient initially noted injection site pain with the lauroxil formulation after the first 2 administrations, but no other adverse reactions were reported. Due to the every 3-weeks (aripiprazole LAI) vs. every 4-weeks (aripiprazole lauroxil) dosing strategies, the approximate daily doses from two long acting formulations were similar (19 mg/day with aripiprazole LAI vs. 21 mg/day with aripiprazole lauroxil, respectively). As of February 2017, he continues to tolerate the aripiprazole lauroxil and reports not needing to use oral aripiprazole.\n\nDiscussion\nHere, we report a case of an African American male experiencing breakthrough symptoms towards the end of the LAI cycle at a high dose of aripiprazole LAI, even in combination with additional oral supplementation. This patient benefited from switching to the lauroxil formulation. Pharmacogenetic testing revealed that the patient is a CYP2D6 normal metabolizer but carries a -141C Ins/Del polymorphism in DRD2 gene.\n\nIn the present case, after multiple antipsychotic failures, aripiprazole therapy has been beneficial in reducing depression, psychotic symptoms, and self-injurious behaviors, but patterns of symptom re-emergence resulted in efforts to determine how best to optimize therapy. Several factors related to AB’s increased aripiprazole dose requirements and breakthrough symptoms were assessed, including medication/substance interactions, injection technique (i.e. length and gauge of the needle and site of administration), and pharmacokinetic characteristics (i.e. large volume of distribution and BMI). Although previous studies suggest that sites of injection as well as injection techniques may impact the pharmacokinetics of other LAI antipsychotics [14, 15], we confirmed that aripiprazole LAI was administered according to the FDA labeling recommendations [8] to rule out improper injection technique or location as a source of dosing/administration variability. In addition, no other factors were found to possibly contribute to his patterns of response.\n\nAripiprazole is primarily metabolized by CYP3A4 and CYP2D6. Diminished CYP2D6 activity due to reduced or non-functional alleles results in an 80% increase in aripiprazole AUC and 2-fold increase in the elimination half-life in CYP2D6 poor metabolizers (PMs) as compared to extensive metabolizers (EMs), leading to a recommendation to start at a lower dose in CYP2D6 PMs [8, 16]. CYP2D6 ultra-rapid metabolizers (UMs) have increased activity due to functional allele duplications as compared to those who are EMs, and although it is presumed these patients may experience lower levels of aripiprazole and increased concentrations of the CYP2D6 metabolite dehydroaripiprazole, there is a dearth of literature related to this topic. Initially, we hypothesized that this patient may be an UM for CYP2D6 due to his atypical dose requirements; however, this was ruled out with pharmacogenetic testing.\n\nInterestingly the pharmacogenetic test report noted that the patient carries a polymorphism in the DRD2 gene (−141C Ins/Del, rs1799732). This polymorphism is located in the promoter region of DRD2 and shown to influence D2 expression [11, 12]. A number of candidate gene studies have investigated the relationship between the -141C Ins/Del variant and susceptibility to schizophrenia, producing conflicting results [17, 18]. Other genetic studies have identified over 4000 variants in DRD2, some of which were shown to be related to risk for psychiatric disorders in genome-wide association studies (GWAS) [19]. A meta-analyses of 6 studies identified an association of the -141C Del polymorphism with poorer clinical response to antipsychotic agents (risperidone, olanzapine, chlorpromazine, clozapine, and aripiprazole) [6], which resulted in this particular variant being included in some clinically available pharmacogenetic testing panels. When information across all studies is taken into consideration, the composite odds ratio from meta-analysis is 0.65 (95% CI = 0.43 to 0.97), demonstrating the odds of response to antipsychotics are approximately 35% less in patients with the ‘risk’ variant (rs1799732). While research studies suggest that DRD2 genetic variants may contribute to differences in antipsychotic response, the clinical utility of this information is yet unclear.\n\nOur patient’s different response to two aripiprazole injection formulations with similar daily doses (from injection: approximately 19 mg/d vs. 21 mg/d) is intriguing. One possible explanation may involve differences in pharmacokinetic profiles between two aripiprazole injection formulations. The pharmacokinetic parameters for these two formulations are included in Table 3. At steady state, decline in drug plasma concentration starts approximately 7 days after injection (Tmax = 6.5 days, see reference [20]) with aripiprazole LAI, whereas the drop is delayed to approximately 21 days after injection (Tmax = 21.1 days) with aripiprazole lauroxil [8]. This is thought to be from more controlled release of the lauroxil formulation after injection via utilization of LinkeRx technology [21, 22]. Given the lack of head to head data, it is difficult to directly compare pharmacokinetics of the two products, although less fluctuation in aripiprazole and its active metabolite levels from slower dissolution rate of aripiprazole lauroxil may explain why our patient does not exhibit wearing-off symptoms anymore with this product.Table 3 Tmax and T1/2 (mean (SD)) of aripiprazole after administration of long acting injectable aripiprazole (Abilify Maintena®) and aripiprazole lauroxil (Aristada®)\n\n\tAfter single gluteal injection of aripiprazole 400 mg equivalents\tAfter 4th gluteal injection of aripiprazole 300 mg equivalentsa\n\t\nAripiprazole LAI\tAripiprazole lauroxil\tAripiprazole LAI\tAripiprazole lauroxil\t\nTmax (day)\t22 (4–22)b\n\t44.0 (11.7)\t6.5 (0.5–21.2)b\n\t21.1\t\nT1/2 (day)\t10.5 (3.9)\t18.0 (4.8)\t29.9 (8.0)\t29 (6)\t\n\naPharmacokinetic parameters at steady-state. Data for the 400 mg equivalents is not available for aripiprazole lauroxil. For the purpose of comparison between two agents, data for the 300 mg equivalents is included\n\n\nbReported as median (range)\n\n\n\n\nTo date only a few polymorphisms in DRD2 (i.e. rs1800497 and rs1799732) are currently available as clinical tests [5], and even for the variants that are included on commercially available pharmacogenetic panels, literature focusing on how best to use results from those variants (such as an association of the variants with need for altered dosing strategies) is lacking. One recently published study showed that antipsychotic dose requirement is more likely to be increased over time in schizophrenia patients with the -141C Del allele compared to the Del non-carriers. Although it was a preliminary study with a relatively small sample size, the findings suggested a relationship between the Del allele and need for higher antipsychotic doses in chronic schizophrenia patients [23]. In addition, the need for altered dosing strategies may be consistent with previous finding indicating that patients with schizophrenia who carry the -141C Del allele had significantly longer time to achieve sustained clinical response to antipsychotic medications compared to those with Ins/Ins homozygous [24]. In this study, authors suggested a possibility that lower brain D2 receptor density in patients having Ins/Ins genotype may make antipsychotic agents more efficient at reaching therapeutic levels of blockade compared to Del carriers.\n\nAn additional consideration is that the allele frequencies of variants in DRD2 differ across populations, with the -141C Del variant known to be more common in persons of African Ancestry (up to approximately 60%), such as our patient [25, 26]. While extensive differences in antipsychotic responsiveness are not usually observed across race groups, one previous study showed that the proportion of patients being prescribed antipsychotic dosages above the recommended range (300–1000 chlorpromazine equivalents) was 10% higher in African Americans compared to Caucasians (p-value = 0.003). However, the use of depot injections may confound the association between higher antipsychotic dosing and patient race in this study [27]. Two other studies have also reported that African Americans were more likely to be on a high dose (>1000 chlorpromazine equivalents) than Caucasians [28, 29], although Segal et al. concluded the results may be due to less treatment engagement with African American patients [29]. As confounding factors (i.e. use of LAI antipsychotics or treatment engagement) made it difficult to accurately assess this relationship, more research is needed to examine how race or ancestry may influence antipsychotic dosing patterns. One hypothesis for further investigation is that higher allele frequency of the -141C Del variant in persons of African Ancestry may, at least in part, explain higher antipsychotic doses in these patients.\n\nConclusions\nWe report an African American patient who exhibited wearing-off symptoms with aripiprazole LAI and then benefited from changing to the aripiprazole lauroxil formulation. Pharmacogenetic testing ruled out genetic alteration that may influence drug metabolism, but noted that the patient carries a DRD2 -141C Del polymorphism (rs1799732), which may alter D2 density in the brain. It is important to clarify that co-occurrence of this variant in an individual having a history of antipsychotic nonresponse and increased dosing requirements does not imply causation. However, previous meta-analyses have associated this polymorphism with reduced response, and it is included on some psychiatry focused pharmacogenomic panels for this reason, but without guidance or supporting evidence to suggest what to do for carriers. The importance of presenting this case is therefore two-fold. The first is that some patients with partial response or symptom recurrence towards the end of the usual dosing interval for aripiprazole LAI may benefit from switching to an alternative formulation. The reasons for this are unclear and warrant further investigation. Second, our case suggests that some individuals may be sensitive to the pharmacokinetic differences between the aripiprazole LAI and lauroxil formulations at similar overall exposures, but the biological reasons for this are unknown. One hypothesis for further exploration is that genetic variation resulting in altered D2 expression or function may result in altered sensitivity to antipsychotic medications, requiring different dosing or drug selection strategies.\n\nAbbreviations\nCYPCytochrome P450\n\nDRD2Dopamine-D2 receptor gene\n\nEMExtensive metabolizer\n\nFDAU.S. Food and Drug Administration\n\nGWASGenome-wide association studies\n\nIMIntramuscularly\n\nLAILong-acting injectable\n\nPMPoor metabolizer\n\nUMUltra-rapid metabolizer\n\nAcknowledgements\nWe express gratitude to the patient presented here.\n\nFunding\nThere was no funding source.\n\nAvailability of data and materials\nData sharing is not applicable to this article, as this is a single-patient case report. No datasets besides those reported in the article were generated during the current study.\n\nAuthors’ contributions\nSE, MES, JTB, AML, and JRB were all involved in the medication therapy management and pharmacogenetic assessment of the patient. SE wrote the first draft of the manuscript. All authors contributed in the preparation of the manuscript and have approved the final version of the manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication of this case report was obtained from the patient. A copy of the signed written consent to publish is available for review by the editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hasan A Falkai P Wobrock T Lieberman J Glenthoj B Gattaz WF World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance World J Biol Psychiatry 2012 13 318 378 10.3109/15622975.2012.696143 22834451 \n2. U.S. Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labeling. 2017. http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. Accessed 01 Feb 2017.\n3. Drozda K Müller DJ Bishop JR Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options Pharmacotherapy 2014 34 166 184 10.1002/phar.1398 24523097 \n4. Clinical Pharmacogenetics Implementation Consortium. CPIC Genes-Drugs Pairs. 2017. https://cpicpgx.org/genes-drugs/ Accessed 1 Feb 2017.\n5. Eum S, Lee AM, Bishop JR. Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations. Dialogues Clin Neurosci. 2016;18:323–37.\n6. Zhang J-P Lencz T Malhotra AK D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis Am J Psychiatry 2010 167 763 772 10.1176/appi.ajp.2009.09040598 20194480 \n7. Pouget JG Müller DJ Pharmacogenetics of antipsychotic treatment in schizophrenia Methods Mol Biol 2014 1175 557 587 10.1007/978-1-4939-0956-8_14 25150876 \n8. U.S. Food and Drug Administration. FDA Approved Drug Products. 2017. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed 01 Feb 2017.\n9. Rohde M M Rk N Håkansson AE Jensen KG Pedersen H Dige T Biological conversion of aripiprazole lauroxil - An N-acyloxymethyl aripiprazole prodrug Results Pharma Sci 2014 4 19 25 10.1016/j.rinphs.2014.04.002 25756003 \n10. Spanarello S La Ferla T The pharmacokinetics of long-acting antipsychotic medications Curr Clin Pharmacol 2014 9 310 317 10.2174/15748847113089990051 23343447 \n11. Jönsson EG Nöthen MM Grünhage F Farde L Nakashima Y Propping P Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers Mol Psychiatry 1999 4 290 296 10.1038/sj.mp.4000532 10395223 \n12. Arinami T Gao M Hamaguchi H Toru M A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia Hum Mol Genet 1997 6 577 582 10.1093/hmg/6.4.577 9097961 \n13. Meltzer HY Risinger R Nasrallah HA Du Y Zummo J Corey L A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia J Clin Psychiatry. 2015 76 1085 1090 10.4088/JCP.14m09741 26114240 \n14. Yin J Collier AC Barr AM Honer WG Procyshyn RM Paliperidone Palmitate Long-Acting Injectable Given Intramuscularly in the Deltoid Versus the Gluteal Muscle: Are They Therapeutically Equivalent? J Clin Psychopharmacol 2015 35 447 449 26061612 \n15. Procyshyn RM Banasch JL Barr AM Honer WG Breakthrough symptoms after switching long-acting injectable paliperidone palmitate from the gluteal to the deltoid site of administration J Psychiatry Neurosci 2016 41 E56 E57 10.1503/jpn.150206 27116902 \n16. Swen JJ Nijenhuis M de Boer A Grandia L Maitland-van der Zee AH Mulder H Pharmacogenetics: from bench to byte--an update of guidelines Clin Pharmacol Ther 2011 89 662 673 10.1038/clpt.2011.34 21412232 \n17. Sáiz PA García-Portilla MP Arango C Morales B Arias B Corcoran P Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: Data from an association study Prog Neuro-Psychopharmacol Biol Psychiatry 2010 34 26 31 10.1016/j.pnpbp.2009.09.008 \n18. Xiao L Shen T Peng D-H Shu C Jiang K Wang G-H Functional -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter and schizophrenia in a Chinese Han population J Int Med Res 2013 41 1171 1178 10.1177/0300060513483415 23816932 \n19. Schizophrenia Working Group of the Psychiatric Genomics Consortium Biological insights from 108 schizophrenia-associated genetic loci Nature 2014 511 421 427 10.1038/nature13595 25056061 \n20. Mallikaarjun S Kane JM Bricmont P McQuade R Carson W Sanchez R Pharmacokinetics, tolerability and safety of aripiprazole once-monthly in adult schizophrenia: an open-label, parallel-arm, multiple-dose study Schizophr Res 2013 150 281 288 10.1016/j.schres.2013.06.041 23890595 \n21. Remenar JF Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics Mol Pharm 2014 11 1739 1749 10.1021/mp500070m 24679167 \n22. Turncliff R Hard M Du Y Risinger R Ehrich EW Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia Schizophr Res 2014 159 404 410 10.1016/j.schres.2014.09.021 25266547 \n23. Takase M, Kanahara N, Oda Y, Niitsu T, Watanabe H, Iyo M. The impacts of dopamine D2 receptor polymorphism and antipsychotic dosage on dopamine supersensitivity psychosis in schizophrenia. Schizophr Res. 2017; doi:10.1016/j.schres.2017.03.014.\n24. Lencz T Robinson DG Xu K Ekholm J Sevy S Gunduz-Bruce H DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients Am J Psychiatry 2006 163 529 531 10.1176/appi.ajp.163.3.529 16513877 \n25. Mi H Thomas PD Ring HZ Jiang R Sangkuhl K Klein TE PharmGKB summary: dopamine receptor D2 Pharmacogenet Genomics 2011 21 350 356 10.1097/FPC.0b013e32833ee605 20736885 \n26. National Center for Biotechnology Information. Database of Single Nucleotide Polymorphisms (dbSNP). 2017. https://www.ncbi.nlm.nih.gov/projects/SNP/. Accessed 01 Feb 2017.\n27. Walkup JT McAlpine DD Olfson M Labay LE Boyer C Hansell S Patients with schizophrenia at risk for excessive antipsychotic dosing J Clin Psychiatry 2000 61 344 348 10.4088/JCP.v61n0504 10847308 \n28. Lehman AF Steinwachs DM Patterns of usual care for schizophrenia: initial results from the Schizophrenia Patient Outcomes Research Team (PORT) Client Survey Schizophr Bull 1998 24 11 20 10.1093/oxfordjournals.schbul.a033303 9502543 \n29. Segal SP Bola JR Watson MA Race, quality of care, and antipsychotic prescribing practices in psychiatric emergency services Psychiatr Serv 1996 47 282 286 10.1176/ps.47.3.282 8820552\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-244X",
"issue": "17(1)",
"journal": "BMC psychiatry",
"keywords": "Aripiprazole long-acting injectable; Clinical pharmacogenetic testing; DRD2; Wearing-off symptoms",
"medline_ta": "BMC Psychiatry",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011618:Psychotic Disorders; D012559:Schizophrenia",
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"title": "Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report.",
"title_normalized": "pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long acting injection a case report"
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"abstract": "Drug interaction is a frequent situation in pediatrics and child psychiatry. Carbamazepine (CBZ) is an antiepileptic drug used as a mood stabilizer in child psychiatry. CBZ is known to be a potent inducer of various CYP isoenzymes of cytochrome P450, which might result in a decrease in the plasma concentration of associated treatments. We describe two cases of CBZ overdosage in adolescent inpatients (14 and 16 years). The patients were treated with risperidone associated with fluoxetine in one and with loxapine in the other case, and CBZ was introduced as a mood stabilizer. Patients presented typical clinical symptoms (fatigue, dizziness, gastrointestinal signs, blurred vision). Overdosage was confirmed by an elevated CBZ plasma concentration (17 and 15.5 mg/L, therapeutic range 4-12 mg/L). We recommend introducing CBZ very progressively in patients treated with psychotropics, particularly when it is associated to several treatments. An intensification of clinical and biological follow-up with early plasma concentration testing should allow for better treatment adjustment.",
"affiliations": "Service universitaire de psychiatrie de l'enfant et de l'adolescent, hôpitaux pédiatriques de Nice CHU-Lenval, 57, avenue de la Californie, 06200 Nice, France.;Service universitaire de psychiatrie de l'enfant et de l'adolescent, hôpitaux pédiatriques de Nice CHU-Lenval, 57, avenue de la Californie, 06200 Nice, France.;Service universitaire de psychiatrie de l'enfant et de l'adolescent, hôpitaux pédiatriques de Nice CHU-Lenval, 57, avenue de la Californie, 06200 Nice, France.;Service universitaire de psychiatrie de l'enfant et de l'adolescent, hôpitaux pédiatriques de Nice CHU-Lenval, 57, avenue de la Californie, 06200 Nice, France.;Service universitaire de psychiatrie de l'enfant et de l'adolescent, hôpitaux pédiatriques de Nice CHU-Lenval, 57, avenue de la Californie, 06200 Nice, France. Electronic address: thummler.s@pediatrie-chulenval-nice.fr.",
"authors": "Fernandez|A|A|;Dor|E|E|;Menard|M-L|ML|;Askenazy|F|F|;Thümmler|S|S|",
"chemical_list": "D005473:Fluoxetine; D002220:Carbamazepine; D018967:Risperidone; D008152:Loxapine",
"country": "France",
"delete": false,
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"issue": "22(5)",
"journal": "Archives de pediatrie : organe officiel de la Societe francaise de pediatrie",
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"medline_ta": "Arch Pediatr",
"mesh_terms": "D000293:Adolescent; D002220:Carbamazepine; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D062787:Drug Overdose; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine; D006801:Humans; D008152:Loxapine; D001523:Mental Disorders; D018967:Risperidone",
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"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Carbamazepine and psychotropic treatment interaction: Two case studies of carbamazepine overdosage.",
"title_normalized": "carbamazepine and psychotropic treatment interaction two case studies of carbamazepine overdosage"
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"abstract": "Antibiotics are a significant cause of adverse events (AE), but few studies have focused on prescriptions in hospitalized patients. In infectious diseases departments, the high frequency and diversity of antibiotics prescribed makes AE post-marketing monitoring easier. The aim of our study was to assess the incidence and type of AE in the infectious diseases department of a French teaching tertiary-care hospital. The main characteristics of each hospitalization, including all antibiotics prescribed and any significant AE were recorded prospectively in the medical dashboard of the department. We included all patients having suffered an AE due to systemic antibiotics between January 2008 and March 2011. Among the 3963 hospitalized patients, 2682 (68%) received an antibiotic and 151/2682 (5.6%) suffered an AE. Fifty-two (34%) AE were gastrointestinal disorders, 32 (21%) dermatological, 20 (13%) hepatobiliary, 16 (11%) renal and urinary disorders, 13 (9%) neurological and 11 (7%) blood disorders. Rifampin, fosfomycin, cotrimoxazole and linezolid were the leading causes of AE. Sixty-two percent of the antibiotics causing an AE were stopped and 38% were continued (including 11% with a dose modification). Patients suffering from AE had an increased length of stay (18 vs 10 days, P < 0.001). Our data could help choosing the safest antibiotic when several options are possible.",
"affiliations": "Service d'Infectiologie, CHU de Nice, Nice, France, johan_courjon@hotmail.fr.",
"authors": "Courjon|J|J|;Pulcini|C|C|;Cua|E|E|;Risso|K|K|;Guillouet|F|F|;Bernard|E|E|;Roger|P-M|PM|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-013-1920-y",
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"issn_linking": "0934-9723",
"issue": "32(12)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": null,
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003141:Communicable Diseases; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005602:France; D006748:Hospital Departments; D006784:Hospitals, Teaching; D006801:Humans; D015994:Incidence; D055552:Infectious Disease Medicine; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "8804297",
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"references": "9425690;18707833;17047216;7791255;21911446;12419643;15661578;9146859;8909827;23362517;20177360;18694344;15844215;22111719;21586591;9002493;21885385;20307191;22351681;1453334;17944688;18473103;15544697",
"title": "Antibiotics-related adverse events in the infectious diseases department of a French teaching hospital: a prospective study.",
"title_normalized": "antibiotics related adverse events in the infectious diseases department of a french teaching hospital a prospective study"
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"abstract": "We describe a case of progressive disseminated histoplasmosis (PDH) and disseminated cytomegalovirus (CMV) with development of haemophagocytic lymphohistiocytosis in a 62-year-old man of Bangladeshi origin living in the UK.\nThe patient had a background of ulcerative colitis for which he took prednisolone and azathioprine. He presented with fever, lethargy, cough, weight loss and skin redness, and was initially treated for bacterial cellulitis and investigated for underlying malignancy. He developed multiple progressive erythematous skin lesions, sepsis and colitis requiring management on intensive care. A skin biopsy showed yeasts in the dermis and sub-cutaneous fat, which were confirmed as Histoplasma capsulatum by PCR. Disseminated CMV with evidence of end organ gastrointestinal disease was also diagnosed. Despite anti-viral and anti-fungal treatment, the patient deteriorated with evidence of bone marrow suppression and a diagnosis of haemophagocytic lymphohistiocytosis was made.\nPDH is classically seen in patients with significant immunosuppression, e.g. those with human immunodeficiency virus (HIV) or on anti-TNF therapy; however, we present a case of reactivation of Histoplasma in a non-HIV patient. We consider the importance of contemplating reactivation of endemic mycoses and CMV in critically unwell and deteriorating patients.",
"affiliations": "The Royal London Hospital, Whitechapel Road, Whitechapel, London E1 1BB, UK.;The Royal London Hospital, Whitechapel Road, Whitechapel, London E1 1BB, UK.;The Royal London Hospital, Whitechapel Road, Whitechapel, London E1 1BB, UK.;The Royal London Hospital, Whitechapel Road, Whitechapel, London E1 1BB, UK.",
"authors": "Lucey|Olivia|O|;Carroll|Iain|I|;Bjorn|Thomas|T|;Millar|Michael|M|",
"chemical_list": null,
"country": "England",
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"doi": "10.1099/jmmcr.0.005170",
"fulltext": "\n==== Front\nJMM Case RepJMM Case RepjmmcrjmmcrJMM Case Reports2053-3721Microbiology Society jmmcr00517010.1099/jmmcr.0.005170Case ReportGastrointestinalReactivation of latent Histoplasma and disseminated cytomegalovirus in a returning traveller with ulcerative colitis http://jmmcr.microbiologyresearch.orgLucey Olivia *Carroll Iain Bjorn Thomas Millar Michael The Royal London Hospital, Whitechapel Road, Whitechapel, London E1 1BB, UK*Correspondence: Olivia Lucey, olivialucey@doctors.org.uk12 2018 23 11 2018 23 11 2018 5 12 e00517016 8 2018 09 11 2018 © 2018 The Authors2018This 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.Introduction\nWe describe a case of progressive disseminated histoplasmosis (PDH) and disseminated cytomegalovirus (CMV) with development of haemophagocytic lymphohistiocytosis in a 62-year-old man of Bangladeshi origin living in the UK.\n\nCase presentation\nThe patient had a background of ulcerative colitis for which he took prednisolone and azathioprine. He presented with fever, lethargy, cough, weight loss and skin redness, and was initially treated for bacterial cellulitis and investigated for underlying malignancy. He developed multiple progressive erythematous skin lesions, sepsis and colitis requiring management on intensive care. A skin biopsy showed yeasts in the dermis and sub-cutaneous fat, which were confirmed as Histoplasma capsulatum by PCR. Disseminated CMV with evidence of end organ gastrointestinal disease was also diagnosed. Despite anti-viral and anti-fungal treatment, the patient deteriorated with evidence of bone marrow suppression and a diagnosis of haemophagocytic lymphohistiocytosis was made.\n\nConclusion\nPDH is classically seen in patients with significant immunosuppression, e.g. those with human immunodeficiency virus (HIV) or on anti-TNF therapy; however, we present a case of reactivation of Histoplasma in a non-HIV patient. We consider the importance of contemplating reactivation of endemic mycoses and CMV in critically unwell and deteriorating patients.\n\nprogressive disseminated histoplasmosiscytomegaloviruslymphohistiocytosishaemophagocyticreactivationimmunosuppressionliposomal amphotericin BOpenAccessEmbargo0\n==== Body\nIntroduction\nThis case highlights the importance of carefully considering infectious differentials in a rapidly deteriorating patient with sepsis; with specific focus on reactivation of latent infections acquired in endemic regions, either from recent travel or prior exposure at any time. Progressive disseminated histoplasmosis (PDH) is a rare disease that is usually associated with cellular immune dysfunction, particularly in hosts with human immunodeficiency virus (HIV) or on anti-TNF therapy, but should also be considered in patients on ‘lighter’ immunosuppression, such as low-dose prednisolone with a compatible clinical syndrome [1]. The case also demonstrates the usefulness of tissue biopsies in atypical skin lesions in unwell patients with emphasis on rapid diagnostics, e.g. PCR in diagnosing Histoplasma capsulatum. Once the diagnosis of haemophagocytic lymphohistiocytosis (HLH) is established, early identification of its driver(s) is crucial. This patient had both evidence of disseminated cytomegalovirus (CMV) infection and histoplasmosis; highlighting the need for clinicians to consider multiple infectious aetiologies in critically unwell patients.\n\nCase report\nA 62-year-old man of Bangladeshi origin was brought to the emergency department with lethargy and fever. Over the previous 2 weeks, he had developed a productive cough and weight loss. His past medical history included ulcerative colitis (diagnosed in 1999), which was quiescent on surveillance colonoscopy 2 days prior to admission. A suspicious rectal lesion was, however, biopsied. He had coronary artery bypass grafting in 1999, type 2 diabetes, hypertension, hyperlipidaemia and chronic hepatitis B. His medication included prednisolone, 10 mg daily (which he had been taking for 15 years), azathioprine 150 mg daily, Asacol (mesalazine) 2 mg daily, tenofovir and allopurinol 100 mg daily. His family acknowledged he had been taking prednisolone at greater than the prescribed dose for approximately 2 months prior to admission.\n\nThe patient was born in Sylhet, Bangladesh, and had moved to the UK aged 14. 6 months previous to the admission, he had travelled back to Sylhet for a 1 month family visit. He had not been unwell during the trip or until presentation. There was no unusual exposure history. There was no other significant or relevant travel history during his lifetime.\n\nOn examination he had a temperature of 34.8 °C, a non-tender erythematous left calf overlying a saphenous vein harvest site. His haemoglobin was 116 g l−1, white cell count 6.2x109 per litre and C-reactive protein 138 mg l−1. Initial management included empirical intravenous flucloxacillin 1 g four times daily for presumed cellulitis. A lower limb ultrasound excluded deep vein thromboses, and a computed tomography scan of chest, abdomen and pelvis demonstrated a rectal mass and a right basal pneumonia. Antibiotics were changed to intravenous benzylpenicillin 1.2 g four times daily and oral clarithromycin 500 mg twice daily.\n\nOver the initial week, his condition deteriorated with fever to 40 °C, rising C-reactive protein and erythema spreading up the left leg to the scrotum, abdomen, left flank and right leg. The skin became tender and warm to touch. Dermatologists reviewed the skin on day 6 (Fig. 1a). A differential diagnosis of multifocal cellulitis, panniculitis or migratory thrombophlebitis, in the context of possible malignancy was made. The patient developed a tender, swollen right testicle. An ultrasound showed epididymo-orchitis. Empirical treatment with oral ciprofloxacin 500 mg twice daily and oral doxycycline 100 mg twice daily was added.\n\nFig. 1. (a) Medial aspect of the left leg. (b) Grocott–Gomori stain of a skin biopsy.\n\nThe infectious diseases team suggested changing the benzylpenicillin to intravenous ceftriaxone 2 g daily, and adding oral linezolid 600 mg twice daily and intravenous amikacin 1.2 g once daily. Vasculitic, auto-immune and sexual health (HIV, chlamydia, gonorrhoea) screens and mycoplasma serology were negative. A trans-thoracic echocardiogram showed no signs of endocarditis. Blood cultures were negative.\n\nOn day 12, the patient was transferred to critical care for ventilation and noradrenaline (dose titrated to blood pressure within the standard critical care range of 6–13 µg min−1) for septic shock, considered secondary to cellulitis. He remained febrile at 40 °C and had developed a coagulopathy and bloody diarrhoea. His antibiotics were changed to meropenem 1 g three times daily and linezolid 600 mg twice daily. Plastic surgeons and urologists did not suspect necrotizing fasciitis.\n\nThe erythema spread to his flanks. No papules, nodules or umbilicated lesions were noted. In view of the diagnostic uncertainty, a skin biopsy was performed on day 15. A rectal biopsy showed CMV inclusion bodies and the plasma CMV DNA viral load was 15 304 copies ml−1. Intravenous ganciclovir 375 mg twice daily was initiated on day 19 to treat suspected disseminated CMV disease with evidence of colitis, epididymo-orchitis and panniculitis. CMV DNA was detected in skin, urine and throat samples.\n\nDue to worsening leucopenia and thrombocytopenia, the ganciclovir was changed to foscarnet 4.5 g three times daily. Fluconazole 400 mg daily was added empirically on day 27 given the lack of clinical improvement, due to the presence of Candida albicans in the urine on day 24. The skin biopsy was reported on day 28 as showing septal/lobar panniculitis. To exclude necrotizing fasciitis, a scrotal incision was performed, which was sterile. Examination of the rectum showed no inflammation.\n\nThe fluconazole was switched to micafungin 100 mg daily on day 31, due to the growth of Candida glabrata from urine culture on day 30. Following a methenamine silver stain, the histopathologists reported the first skin biopsy as showing small, round yeasts of 3–5 microns within well-circumscribed areas of inflammation in the dermis and subcutaneous fat (Fig. 1b). A skin biopsy was repeated the same day with samples sent for microbiological and fungal culture and molecular testing. On day 34, the pan-fungal PCR confirmed DNA from H. capsulatum. The micafungin was changed to AmBisome (amphotericin B) 320 mg daily.\n\nA bone marrow biopsy was performed on day 33, which showed pancytopenia with increased macrophage activity, without evidence of malignancy, acid-fast bacilli or fungi. Ferritin and triglyceride levels were raised (47 798 µg l−1 and 2.45 mmol l−1, respectively) supporting a diagnosis of HLH. Immunosuppression was considered, but due to the patient's extremely poor clinical condition was not given. The bone marrow culture subsequently grew H. capsulatum. The patient continued to deteriorate and died on day 36 of admission.\n\nDiscussion\nWe have described a case of PDH in a 62-year-old man living in a non-endemic area for histoplasmosis. This case demonstrates reactivation of latent histoplasmosis, presumably primarily acquired in Bangladesh. It is postulated that viable organisms persist in the tissues following the primary infection and subsequently reactivate [2]. Patients with cellular immune dysfunction, primary immune deficiency disorders, HIV and those on immunosuppressive therapy, e.g. anti TNF-α, are at particular risk of severe or disseminated forms [1]. In this case, the corticosteroids and azathioprine appear to have been the main risk factor for reactivation; however, it has been shown that although these drugs increase the odds of developing an opportunistic infection in inflammatory bowel disease patients (by a factor of 15), histoplasmosis is a rare infection to occur with these immunosuppressive drugs [3]. The fact that the patient had administered higher than prescribed doses of prednisolone prior to admission may have accelerated and contributed to the reactivation process. Culture of Histoplasma from extra-pulmonary sites, e.g. skin, bone marrow, is the gold standard for diagnosing PDH [4]. Previous descriptions of skin involvement have included nodules, abscesses, fistulae and cellulitis with plaques rather than a panniculitis [2]. Suspecting a fungal aetiology of atypical skin lesions and early skin biopsy in cases where there is progression, clinical deterioration or diagnostic difficulty is paramount. The in-house pan-fungal rRNA-PCR allowed a diagnosis to be made within 3 days of biopsy, highlighting the important role of PCR in achieving a timely diagnosis as the bone marrow culture was not available until 29 days after the patient's death. Histopathological examination of tissue (in this case, skin) can reveal the typical 2–4 micron yeast structures of Histoplasma; however, this lacks specificity, as these structures may be confused with other fungi [4]. Knowledge of the geographical distribution of H. capsulatum is incomplete [5]. Disseminated histoplasmosis has been described in Bangladesh [6]. It is plausible that endemic areas for histoplasmosis are more widespread than commonly documented.\n\nThe consequences of CMV reactivation in unwell patients are not well understood, and the subject of debate and research. In immunocompromised critically ill hosts, CMV has an immunomodulatory effect with mortality from secondary infections, malignancy and cardiovascular disease, and the evidence supports prophylaxis and treatment in these settings [7]. In immunocompetent patients, the evidence is less clear; whether CMV acts as a pathogen or a marker of disease severity remains uncertain. Some studies categorize recent corticosteroid use as significant immunosuppression; however, others do not [8]. The most frequent precipitant for reactivation is sepsis, with corticosteroids also recognized [9].\n\nThe clinical impact of the disseminated CMV infection in our case is unclear, but is likely to have contributed to the patient’s deterioration. Our patient received 17 days of anti-virals without improvement. It is important to consider the adverse effects of anti-virals; perhaps the bone marrow suppression was potentiated by the ganciclovir. The Histoplasma infection is likely to have been the more significant pathogen and precipitating factor for HLH.\n\nWe had not considered a fungal aetiology until late in the disease course. Initially a bacterial cellulitis was considered the main differential, despite an atypical distribution of erythema, poor response to empirical antibiotics and negative blood cultures. Subsequently, the disease was attributed to disseminated CMV, prior to the diagnosis of histoplasmosis. We discussed our propensity to biases as clinicians. Anchoring bias occurs when clinicians focus on one diagnosis despite evidence to the contrary, whilst confirmation bias acknowledges only information that confirms or refutes the suspected diagnosis [10]. On reflection, alternative diagnoses should have been considered earlier. The immunosuppressant properties of steroids are perhaps under-estimated in the presence of other factors such as age, co-morbidities and sepsis. This case highlights the potential for reactivation of latent infections in patients with a history of corticosteroid use, relevant travel or in those who are deteriorating or critically unwell.\n\nFunding information\nThe authors received no specific grant from any funding agency.\n\nConflicts of interest\nThe authors declare that there are no conflicts of interest.\n\nEthical statement\nFormal consent for publication was obtained from patient.\n\nAbbreviations: CMV, cytomegalovirus; HIV, human immunodeficiency virus; HLH, haemophagocytic lymphohistiocytosis; PDH, progressive disseminated histoplasmosis.\n==== Refs\nReferences\n1 Adenis AA Aznar C Couppié P Histoplasmosis in HIV-infected patients: a review of new developments and remaining gaps Curr Trop Med Rep 2014 1 119 128 10.1007/s40475-014-0017-8 24860719 \n2 Marques SA Hozumi S Camargo RM Carvalho MF Marques ME Histoplasmosis presenting as cellulitis 18 years after renal transplantation Med Mycol 2008 46 725 728 10.1080/13693780802247736 18671166 \n3 Toruner M Loftus EV Harmsen WS Zinsmeister AR Orenstein R Risk factors for opportunistic infections in patients with inflammatory bowel disease Gastroenterology 2008 134 929 936 10.1053/j.gastro.2008.01.012 18294633 \n4 Guimarães AJ Nosanchuk JD Zancopé-Oliveira RM Diagnosis of histoplasmosis Braz J Microbiol 2006 37 1 13 10.1590/S1517-83822006000100001 20445761 \n5 Antinori S Histoplasma capsulatum : more widespread than previously thought Am J Trop Med Hyg 2014 90 982 983 10.4269/ajtmh.14-0175 24778192 \n6 Gugnani HC Denning DW Rahim R Sadat A Belal M Burden of serious fungal infections in Bangladesh Eur J Clin Microbiol Infect Dis 2017 36 993 997 10.1007/s10096-017-2921-z 28161744 \n7 Nichols WG Corey L Gooley T Davis C Boeckh M High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection J Infect Dis 2002 185 273 282 10.1086/338624 11807708 \n8 Limaye AP Kirby KA Rubenfeld GD Leisenring WM Bulger EM Cytomegalovirus reactivation in critically ill immunocompetent patients JAMA 2008 300 413 422 10.1001/jama.300.4.413 18647984 \n9 Jaber S Chanques G Borry J Souche B Verdier R Cytomegalovirus infection in critically ill patients: associated factors and consequences Chest 2005 127 233 241 10.1378/chest.127.1.233 15653989 \n10 Stiegler MP Neelankavil JP Canales C Dhillon A Cognitive errors detected in anaesthesiology: a literature review and pilot study Br J Anaesth 2012 108 229 235 10.1093/bja/aer387 22157846\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2053-3721",
"issue": "5(12)",
"journal": "JMM case reports",
"keywords": "cytomegalovirus; haemophagocytic; immunosuppression; liposomal amphotericin B; lymphohistiocytosis; progressive disseminated histoplasmosis; reactivation",
"medline_ta": "JMM Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101639133",
"other_id": null,
"pages": "e005170",
"pmc": null,
"pmid": "30863547",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "11807708;15653989;18294633;18647984;18671166;20445761;22157846;24778192;24860719;28161744",
"title": "Reactivation of latent Histoplasma and disseminated cytomegalovirus in a returning traveller with ulcerative colitis.",
"title_normalized": "reactivation of latent histoplasma and disseminated cytomegalovirus in a returning traveller with ulcerative colitis"
} | [
{
"companynumb": "GB-TEVA-2019-GB-1156525",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Clubfoot, a common major structural malformation, develops early in gestation. Epidemiologic studies have identified higher risks among boys, first-born children, and babies with a family history of clubfoot, but studies of risks associated with maternal exposures are lacking. We conducted the first large-scale, population-based, case-control study of clubfoot with detailed information on maternal medication use in pregnancy. Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina during 2007-2011. Cases were 646 mothers of children with clubfoot without other major structural malformations (i.e., isolated clubfoot); controls were mothers of 2,037 children born without major malformations. Mothers were interviewed within 12 months of delivery about medication use, including product, timing, and frequency. Odds ratios were estimated for exposure to 27 medications in pregnancy months 2-4 after adjustment for study site, infant sex, first-born status, body mass index (weight (kg)/height (m)(2)), and smoking. Odds ratios were less than 1.20 for 14 of the medications; of the remainder, most odds ratios were only slightly elevated (range, 1.21-1.66), with wide confidence intervals. The use of antiviral drugs was more common in clubfoot cases than in controls (odds ratio = 4.22, 95% confidence interval: 1.52, 11.73). Most of these results are new findings and require confirmation in other studies.",
"affiliations": null,
"authors": "Werler|Martha M|MM|;Yazdy|Mahsa M|MM|;Kasser|James R|JR|;Mahan|Susan T|ST|;Meyer|Robert E|RE|;Anderka|Marlene|M|;Druschel|Charlotte M|CM|;Mitchell|Allen A|AA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/aje/kwu096",
"fulltext": null,
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"issn_linking": "0002-9262",
"issue": "180(1)",
"journal": "American journal of epidemiology",
"keywords": "clubfoot; malformation; medications; pregnancy",
"medline_ta": "Am J Epidemiol",
"mesh_terms": "D000328:Adult; D016022:Case-Control Studies; D003025:Clubfoot; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008404:Massachusetts; D008423:Maternal Age; D009518:New York; D009657:North Carolina; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012042:Registries; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "7910653",
"other_id": null,
"pages": "86-93",
"pmc": null,
"pmid": "24824985",
"pubdate": "2014-07-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "10981930;15777434;16458650;7254912;16933214;11186881;3974658;15172848;2865223;9291904;17610748;10731504;5355276;15860081;11850551;21983213;7408309;11032161;7351421;18022868;12499950;9637807;20583169;25171134;15060180;17596601;14925320;15552558;23449641;23686911;22678995;12587918",
"title": "Medication use in pregnancy in relation to the risk of isolated clubfoot in offspring.",
"title_normalized": "medication use in pregnancy in relation to the risk of isolated clubfoot in offspring"
} | [
{
"companynumb": "US-JNJFOC-20140804386",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Topiramate is one of the newer generation antiepileptic drugs with a beneficial clinical effect on various seizure types. In this study, we present the clinical findings of hypohidrosis and hyperthermia with topiramate in pediatric patients. The data were collected retrospectively on 173 patients diagnosed as epilepsy on topiramate treatment, and hypohidrosis-related symptoms induced by topiramate were found in 22 patients. Their mean age was 64.45 +/- 56.63 months. The mean duration of topiramate treatment was 7.09 +/- 2.46 months, and the mean dose was 5.37 +/- 1.75 mg/kg/day. All of the patients complained of hypohidrosis and hyperthermia. Six (27.2%) of them had facial flushing, 4 (18.1%) had heat sensation and only 1 (4.5%) had lethargy. Hypohidrosis-related symptoms resolved after discontinuation of the medication. In conclusion, children treated with topiramate should be cautioned regarding these potential adverse effects and advised to avoid its use during the hot summer season.",
"affiliations": "Department of Pediatric Neurology, Cukurova University Faculty of Medicine, Adana, Turkey. fincecik@yahoo.com",
"authors": "Incecik|Faruk|F|;Hergüner|M Ozlem|MO|;Altunbaşak|Sakir|S|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "54(5)",
"journal": "The Turkish journal of pediatrics",
"keywords": null,
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005334:Fever; D005500:Follow-Up Studies; D005632:Fructose; D006801:Humans; D007007:Hypohidrosis; D015994:Incidence; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D012307:Risk Factors; D012640:Seizures; D000077236:Topiramate; D014421:Turkey",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "515-8",
"pmc": null,
"pmid": "23427516",
"pubdate": "2012",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Hypohidrosis and hyperthermia during topiramate treatment in children.",
"title_normalized": "hypohidrosis and hyperthermia during topiramate treatment in children"
} | [
{
"companynumb": "TR-CIPLA LTD.-2016TR08829",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
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"drugadditional": "3",
... |
{
"abstract": "Fracture liaison services (FLS) have been implemented worldwide, but we present one of the first reported experiences in China. Only 1 out of 226 patients had a secondary fracture within 1 year. This serves as a platform to improving solutions and decreasing imminent fractures for future use nationwide in China.\n\n\n\nFracture liaison services (FLS) have been implemented worldwide but we present one of the first reported experiences in China. Vertebral fragility fracture is one of the earliest fracture to occur. The objective of this study was to implement a dedicated fracture service to decrease imminent fractures for future use nationwide in China.\n\n\n\nPatients 50 years or older with a recent vertebral compression fracture were recruited. All patients were offered investigation with DXA scan and blood taking. Treatment was provided with calcium and vitamin D supplements and denosumab injections. The primary outcome was the imminent fracture rate or the re-fracture rate occurring within 2 years of the initial one. Secondary outcomes were bone mineral density (BMD), treatment initiation, adherence to drug, compliance to follow-up, falls, mortality, pain, quality of life, pain-related disability with Roland-Morris Disability Questionnaire (RMDQ), and Oswestry Disability Index (ODI).\n\n\n\nTwo hundred twenty-six patients (n = 226) were analyzed. 0.4% (n = 1) had an imminent fracture within 2 years. 11.1% (n = 25) had a fall within 2 years, in which 1 resulted in a major osteoporotic fracture. 7.1% died (n = 16) within the 2-year time period. 97.8% (n = 221) underwent BMD investigation with an initial DXA scan. One hundred percent (n = 226) had treatment initiation and were prescribed with Denosumab injections. 89.8% (n = 203) were compliant and showed complete adherence to drug therapy over the 2 years. Pain, quality of life, and disability were significantly improved.\n\n\n\nThis is the first reported fracture liaison service for vertebral fracture patients reported in China. Future FLS should incorporate muscle and sarcopenic assessments as a routine, and also research on novel interventions in this area would significantly improve patient outcomes.",
"affiliations": "Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.;Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.;Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.;Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.;Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.;Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China. louis@ort.cuhk.edu.hk.;Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.",
"authors": "Wong|Ronald Man Yeung|RMY|;Ko|Shaau Yiu|SY|;Chau|Wai-Wang|WW|;Lee|Linus Chee Yeen|LCY|;Chow|Simon Kwoon Ho|SKH|;Cheung|Wing Hoi|WH|;Law|Sheung Wai|SW|",
"chemical_list": "D050071:Bone Density Conservation Agents",
"country": "England",
"delete": false,
"doi": "10.1007/s11657-021-01036-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "16(1)",
"journal": "Archives of osteoporosis",
"keywords": "China; Fracture liaison Service; Muscle; Sarcopenia; Vertebral compression fractures",
"medline_ta": "Arch Osteoporos",
"mesh_terms": "D050071:Bone Density Conservation Agents; D002681:China; D050815:Fractures, Compression; D006801:Humans; D009132:Muscles; D010024:Osteoporosis; D058866:Osteoporotic Fractures; D011788:Quality of Life; D055502:Secondary Prevention; D016103:Spinal Fractures",
"nlm_unique_id": "101318988",
"other_id": null,
"pages": "168",
"pmc": null,
"pmid": "34743234",
"pubdate": "2021-11-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21450337;11535963;28560474;14593451;21211578;28451733;31659457;28138228;24553898;29460102;29555309;31182670;21368100;27386723;22012531;32427525;21927922;11470614;16320034;29439718;17377107;16340107;31714470;32202056;28919380;22829395;18594096;18202065;25888399;30610245;2886201;31081853;27239407;31696271;29436202;23535738;28236126;26333528;19967338;26308229;19760437;22128754",
"title": "The first reported fracture liaison service (FLS) for vertebral fractures in China: is muscle the missing gap?",
"title_normalized": "the first reported fracture liaison service fls for vertebral fractures in china is muscle the missing gap"
} | [
{
"companynumb": "CN-AMGEN-CHNSP2021181971",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nSepsis due to Clostridium perfringens, one of several clostridial species, is an important cause of massive intravascular hemolysis in patients with underlying malignancies. Chronic liver diseases, immunosuppression, and presence of malignancies were risk factors for Clostridium perfringens sepsis. Therefore, Clostridium perfringens sepsis should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. This case report focuses on findings characteristic of an intravascular hemolysis due to Clostridium perfringens after transhepatic arterial chemoembolization.\n\n\nMETHODS\nAn 83-year-old Japanese man presented to our hospital because of a third recurrence of hepatocellular carcinoma. He had nonalcoholic steatohepatitis-related cirrhosis, and underwent radiofrequency ablation and transhepatic arterial chemoembolization therapy for hepatocellular carcinoma of S4/S8 and S2. He had a medical history of pancreatic carcinoma and underwent pylorus-preserving pancreaticoduodenectomy approximately 5 years ago. Because follow-up computed tomography showed a recurrence of the hepatocellular carcinoma, he underwent transhepatic arterial chemoembolization with a hepatic arterial infusion of 20 mg epirubicin, followed by 4 mL Lipiodol (ethiodized oil). On the sixth day after the procedure, he complained of fever and hematuria with jaundice. Laboratory findings indicated hemolysis and increased inflammatory response. Although we initiated antibiotic therapy combined with surgical debridement for infection after transhepatic arterial chemoembolization, he died within 6 hours. The autopsy showed a 4-cm local necrotic hepatic tumor. The cut surface revealed a tumor with an internal spongiform appearance, which was a pseudocystic and partially necrotic lesion. In addition, a diffuse spread of Gram-positive rods in multiple organs including the heart was histologically confirmed. The culture obtained by fluid aspiration from the hepatic abscess revealed Clostridium perfringens. Although the role of Clostridium perfringens was never established during the life of this patient, based on the clinical course and the culture from the hepatic abscess at postmortem, intravascular hemolysis secondary to Clostridium perfringens sepsis was suspected.\n\n\nCONCLUSIONS\nIntravascular hemolysis secondary to Clostridium perfringens should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. Biliary reconstruction is an especially important risk factor for infection.",
"affiliations": "Department of Gastroenterology, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8533, Japan. kiruha@kitasato-u.ac.jp.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.",
"authors": "Uojima|Haruki|H|;Onoue|Mie|M|;Hidaka|Hisashi|H|;Wada|Naohisa|N|;Tanaka|Yoshiaki|Y|;Inoue|Tomoyoshi|T|;Kubota|Kousuke|K|;Nakazawa|Takahide|T|;Shibuya|Akitaka|A|;Koizumi|Wasaburo|W|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D015251:Epirubicin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2023-x",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 202310.1186/s13256-019-2023-xCase ReportA suspected case of Clostridium perfringens sepsis with intravascular hemolysis after transhepatic arterial chemoembolization: a case report Uojima Haruki +81-467-46-1717kiruha@kitasato-u.ac.jp 12Onoue Mie ono_mie_1212@yahoo.co.jp 2Hidaka Hisashi hisashi7@kitasato-u.ac.jp 2Wada Naohisa naow0829@kitasato-u.ac.jp 2Tanaka Yoshiaki tanakay@kitasato-u.ac.jp 2Inoue Tomoyoshi inoue.tm@kitasato-u.ac.jp 2Kubota Kousuke k.kubota@kitasato-u.ac.jp 2Nakazawa Takahide tnakazaw@kitasato-u.ac.jp 2Shibuya Akitaka ashibuya@kitasato-u.ac.jp 2Koizumi Wasaburo koizumi@med.kitasato-u.ac.jp 21 0000 0004 0377 3017grid.415816.fDepartment of Gastroenterology, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa 247-8533 Japan 2 0000 0000 9206 2938grid.410786.cDepartment of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0375 Japan 27 4 2019 27 4 2019 2019 13 1253 7 2018 20 2 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nSepsis due to Clostridium perfringens, one of several clostridial species, is an important cause of massive intravascular hemolysis in patients with underlying malignancies. Chronic liver diseases, immunosuppression, and presence of malignancies were risk factors for Clostridium perfringens sepsis. Therefore, Clostridium perfringens sepsis should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. This case report focuses on findings characteristic of an intravascular hemolysis due to Clostridium perfringens after transhepatic arterial chemoembolization.\n\nCase presentation\nAn 83-year-old Japanese man presented to our hospital because of a third recurrence of hepatocellular carcinoma. He had nonalcoholic steatohepatitis-related cirrhosis, and underwent radiofrequency ablation and transhepatic arterial chemoembolization therapy for hepatocellular carcinoma of S4/S8 and S2. He had a medical history of pancreatic carcinoma and underwent pylorus-preserving pancreaticoduodenectomy approximately 5 years ago. Because follow-up computed tomography showed a recurrence of the hepatocellular carcinoma, he underwent transhepatic arterial chemoembolization with a hepatic arterial infusion of 20 mg epirubicin, followed by 4 mL Lipiodol (ethiodized oil). On the sixth day after the procedure, he complained of fever and hematuria with jaundice. Laboratory findings indicated hemolysis and increased inflammatory response. Although we initiated antibiotic therapy combined with surgical debridement for infection after transhepatic arterial chemoembolization, he died within 6 hours. The autopsy showed a 4-cm local necrotic hepatic tumor. The cut surface revealed a tumor with an internal spongiform appearance, which was a pseudocystic and partially necrotic lesion. In addition, a diffuse spread of Gram-positive rods in multiple organs including the heart was histologically confirmed. The culture obtained by fluid aspiration from the hepatic abscess revealed Clostridium perfringens. Although the role of Clostridium perfringens was never established during the life of this patient, based on the clinical course and the culture from the hepatic abscess at postmortem, intravascular hemolysis secondary to Clostridium perfringens sepsis was suspected.\n\nConclusion\nIntravascular hemolysis secondary to Clostridium perfringens should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. Biliary reconstruction is an especially important risk factor for infection.\n\nKeywords\nIntravascular hemolysisClostridium perfringensTranshepatic arterial chemoembolizationissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nSepsis due to Clostridium perfringens, one of several clostridial species, is an important cause of massive intravascular hemolysis in patients with underlying malignancies [1, 2]. Although C. perfringens sepsis is rare, massive intravascular hemolysis due to C. perfringens sepsis can have a particularly rapid fatal clinical course [3]. A literature review showed that chronic liver diseases, immunosuppression, and presence of malignancies were risk factors for C. perfringens sepsis [4]. In particular, C. perfringens sepsis should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma (HCC). This case report focuses on findings characteristic of an intravascular hemolysis secondary to C. perfringens sepsis after transhepatic arterial chemoembolization (TACE).\n\nCase presentation\nAn 83-year-old Japanese man presented to our hospital because of a third recurrence of HCC. He had nonalcoholic steatohepatitis-related cirrhosis, and underwent radiofrequency ablation for a partial HCC of S4/S8 in his liver 3 years ago. Because abdominal computed tomography (CT) revealed multiple HCC of S4/S8 and S2 in his liver 1 year ago, he underwent TACE therapy with an emulsified mixture of Lipiodol (ethiodized oil) and Farmorubicin (epirubicin) together with gelatin sponge particles for multiple tumors. After the second TACE, abdominal CT revealed sufficient Lipiodol (ethiodized oil) retention and the inefficacy of this treatment. However, follow-up CT showed a HCC recurrence in the left lobe 2 months ago. His medical history included reflux esophagitis, hypertension, and pancreatic carcinoma and he underwent pylorus-preserving pancreaticoduodenectomy approximately 5 years ago. His medications included amlodipine 5 mg, candesartan 4 mg, and esomeprazole 20 mg, all once daily. He was nondiabetic, did not smoke tobacco or drink alcohol, and had no history of any drug or food allergies. His family and social history were unremarkable. He appeared well on presentation. His body mass index was 26.2 kg/m2, with no noticeable body weight changes. He had an axillary temperature of 36.0 °C, a heart rate of 70 beats/minute, and blood pressure of 118/52 mmHg, with an oxygen saturation of 98% on room air at admission. No conjunctival pallor, icterus, cyanosis, or spider nevi were detectable on physical examination. Cardiovascular and respiratory examinations indicated normal jugular venous pressure and heart sounds, with no detectable murmurs, and normal breath sounds, with no crackle or wheeze. There were no particular abnormal physical findings. Laboratory studies indicated elevated creatinine and α-fetoprotein levels (Table 1). Abdominal ultrasonography showed several hypoechoic masses in his liver; an abdominal plane CT showed multiple lesions with the greatest extent more than 40 mm in the left lobe of his liver (Fig. 1).Table 1 Summary of the laboratory data\n\n\tNormal range\tBefore procedure\tThe sixth day after the procedure\t\nComplete blood count\t\n White blood cells\t× 102/ μL\t30–97\t40\t291\t\n Neutrophils\t%\t36.6–79.9\t70.1\t92\t\n Hemoglobin\tg/dL\t13.1–17.6\t9.3\t5.1\t\n Platelet counts\t× 104/ μL\t12.4–30.5\t11.6\t11.4\t\nBiochemistry\t\n Total bilirubin\tmg/dL\t0.1–1.2\t0.7\t14\t\n Aspartate aminotransferase\tIU/L\t12–35\t33\t1300\t\n Alanine aminotransferase\tIU/L\t6–40\t76\t362\t\n Lactate dehydrogenase\tIU/L\t119–229\t235\t4523\t\n γ-glutamyl transpeptidase\tIU/L\t0–48\t82\t108\t\n Alkaline phosphatase\tIU/L\t115–359\t427\t751\t\n Blood-urea-nitrogen\tmg/dL\t7.4–19.5\t32.8\t45.9\t\n Creatinine\tmg/dL\t0.5–1.2\t1.35\t1.50\t\n Total protein\tg/dL\t6.4–8.3\t6.7\t6.0\t\n Albumin\tg/dL\t3.8–5.2\t3.2\t2.4\t\n Sodium\tmEq/L\t135–147\t140\t132\t\n Potassium\tmEq/L\t3.4–4.8\t4.1\t4.7\t\n Ammonia\tμg/dL\t12–66\t102\t145\t\n HbA1c\t%\t4.6–6.2\t5.5\t\t\nCoagulation\t\n PT-INR\t\t0.89–1.12\t1.04\t1.58\t\n APTT\tseconds\t23.6–31.3\t22.9\t44.1\t\nTumor marker\t\n Alpha-fetoprotein\tng/mL\t0–10\t36,690\t\t\n PIVKA-II\tmAU/mL\t0–39\t3743\t\t\nSerology\t\n Hepatitis B surface antigen\t\t\tnegative\t\t\n Hepatitis C virus antibody\t\t\tnegative\t\t\nAPTT activated partial thromboplastin time, HbA1c glycated hemoglobin, PIVKA-II protein induced by vitamin K absence-II, PT-INR prothrombin time-international normalized ratio\n\nFig. 1 Computed tomography images in the axial plane. A low-density nodule (white arrow) in the left lobe is shown. Dynamic computed tomography was difficult to perform in this patient because of decreased renal function\n\n\n\nOwing to our patient’s high risk of liver abscess after TACE because of his medical history of pancreaticoduodenectomy, the treatment course was carefully decided after consultation with our patient and his family. He underwent TACE with a hepatic arterial infusion of 20 mg epirubicin, followed by 4 mL Lipiodol (ethiodized oil) (Fig. 2). A few days after undergoing the procedure, he was generally well except for mild symptoms attributed to postembolization syndrome. Despite antibiotic therapy (cefmetazole 3 grams daily) to prevent infection, he complained of fever, nausea, and hematuria on the sixth day after the procedure. He appeared unwell, severely jaundiced, and extremely restless. When his condition deteriorated, he had an axillary temperature of 39.0 °C, a heart rate of 110 beats/minute, and blood pressure of 90/40 mmHg. He presented with deterioration in hemoglobin levels and renal function, anemia, and a coagulation dysfunction. Furthermore, total bilirubin and direct bilirubin levels increased. Because elevated bilirubin and lactate dehydrogenase due to destruction of red blood cells showed hemolytic anemia, we performed a Coombs test for autoimmune hemolytic anemia to detect the presence of antibodies against red blood cells. However, the results for both the direct and indirect Coombs tests were negative. Based on our patient’s severe clinical course and laboratory data suggestive of hemolysis, intravascular hemolysis secondary to C. perfringens sepsis was suspected.Fig. 2 Hepatic angiogram showing a large 40-mm hepatic tumor corresponding to the lesion on plane computed tomography. The hypervascular tumor in the left lobe is depicted as a round mass of contrast opacification (straight white arrow) and as being supplied by the left hepatic artery\n\n\n\nBecause the embolic and necrotic lesion after TACE was suspected to be the focus of infection, we initiated antibiotic therapy (piperacillin/tazobactam 4.5 grams and clindamycin 600 mg) combined with surgical debridement. However, he died within 6 hours following unsuccessful cardiopulmonary resuscitation. An autopsy showed a 4-cm local, necrotic, hepatic tumor. The cut surface revealed a tumor with an internal spongiform appearance, which was a pseudocystic and partially necrotic lesion (Fig. 3). In addition, a diffuse spread of Gram-positive rods in multiple organs including the heart was histologically confirmed (Fig. 4). The culture obtained by fluid aspiration from the hepatic abscess revealed C. perfringens.Fig. 3 Gross appearance of the liver at autopsy. The cut surface revealed a tumor with an internal spongiform appearance, that of a pseudocystic and partially necrotic lesion measuring 50 mm in the maximum dimension (white arrowhead)\n\nFig. 4 a Pathogenesis of multiple small abscesses. These abscesses contained a thin rim of epithelioid histiocytes and other inflammatory cells (Gram stain × 10). b Colonies of Gram-positive rods observed on Gram staining (arrows) in the heart (Gram stain × 550)\n\n\n\nDiscussion\nWe reported a suspected case of massive intravascular hemolysis due to C. perfringens after TACE. In the present case, the role of C. perfringens was never established during the life of the patient. However, based on the severe clinical course and the culture obtained by fluid aspiration from the hepatic abscess at postmortem, intravascular hemolysis secondary to C. perfringens sepsis was suspected.\n\nC. perfringens is an anaerobic Gram-positive rod that is naturally found in the intestines of humans and wild animals [4]. Although C. perfringens sepsis is rare, its association with massive hemolysis is well known, with death occurring within hours of presentation in patients similar to the present case [5–7]. The alpha toxin produced by C. perfringens is primarily responsible for the disease pathogenesis. This toxin, which possesses phospholipase C and sphingomyelinase activities, can damage the structural integrity of the red blood cell membrane, leading to spherocytosis and subsequent hemolysis [8, 9].\n\nA review of studies on hemolysis associated with C. perfringens in the literature showed that infection was attributed to immunosuppression related to ageing, chronic disease, and presence of malignancies [10]. As the infected focus was commonly the liver and gastrointestinal tract, suspecting C. perfringens sepsis after TACE for HCC in liver cirrhosis was reasonable. Therefore, C. perfringens sepsis should always be considered in the differential diagnosis of HCC in patients presenting with fever and hemolysis after the procedure.\n\nAccording to a search of reports in PubMed using the medical subject terms “TACE/transarterial embolization (TAE),” “clostridial sepsis,” and/or “hemolysis,” there were five cases of intravascular hemolysis secondary to C. perfringens sepsis after TACE/TAE [11–13] (Table 2). The median age of patients at presentation was 74 years (range, 70–83 years), with all five patients being male. Some patients had important risk factors for infection in the gastrointestinal tract, such as gastrectomy, or invasive endoscopic procedures, resulting in tissue damage. In particular, TACE for HCC after biliary reconstruction including pancreaticoduodenectomy should be avoided as much as possible because severe liver abscess could frequently occur. The median tumor diameter was 99 mm (range, 40–179 mm). In all cases of infection after TACE, epirubicin, doxorubicin, and oxaliplatin were administered, with epirubicin being the most frequently used.Table 2 Patients with intravascular hemolysis secondary to Clostridium perfringens sepsis after transhepatic arterial chemoembolization/transarterial embolization\n\nCase\tReference\tYear\tAge\tSex\tTumor\tDiameter\tLiver cirrhosis\tPOD\tRisk factor\tALT\tDrug\tTreatment\tOutcome\t\nPre TACE\tPost TACE\tHemolysis\t\n1\t[11]\t1992\t83\tMale\tHCC\t115 mm\t\t1\t\tNormal range\t\t\tDoxorubicin\tAntibiotic\tDead\t\n2\t[12]\t2010\t74\tMale\tHCC\t\t\t5\tGastrectomy\t\t\t\tEpirubicin\tAntibiotic\nDrainage\tSurvival\t\n3\t[12]\t2011\t70\tMale\tHCC\t83 mm\t\t2\tERBD\t316\t\t\tEpirubicin\tAntibiotic\nDrainage\tDead\t\n4\t[13]\t2014\t71\tMale\tHCC\t179 mm\t+\t2\t\t145\t1652\t2312\t5-fluorouracil\nOxaliplatin\tAntibiotic\tSurvival\t\n5\tOur case\t2017\t83\tMale\tHCC\t40 mm\t+\t6\tPPPD\t76\t120\t362\tEpirubicin\tAntibiotic\tDead\t\nALT alanine aminotransferase, ERBD endoscopic retrograde biliary drainage, HCC hepatocellular carcinoma, POD postoperative day, PPPD pancreaticoduodenectomy, TACE transhepatic arterial chemoembolization\n\n\n\nThe common symptoms of sepsis associated with hemolysis were hematuria, fever, and hypotension, which began within 1 week (range, 1–6 days) after the procedure. Although some reports did not mention laboratory data, the review showed a decrease in the median hemoglobin level from pre-procedure (11.6 mg/dL) to the occurrence of hemolysis (6.6 mg/dL). An increase in the median total bilirubin level from 1.15 mg/dL to 11.9 mg/dL, an increase in the median aspartate aminotransferase (AST) level from 73 to 1626 IU/L, and an increase in the alanine aminotransferase (ALT) level from 110.5 to 1337 IU/L was observed at hemolysis associated with C. perfringens. Of note, a few cases showed that liver function enzyme levels at post-procedure were elevated compared with those at pre-procedure. Liver damage after chemo-embolic therapy for HCC may be a high risk factor for C. perfringens infection.\n\nImaging studies, especially ultrasonography and CT, showed multiple hypovascular lesions, but it was difficult to distinguish hepatic abscesses from tumors because there were no diagnostic features of hepatic abscesses after TACE/TAE for HCC. Therefore, diagnosis was bacteriologically confirmed through identification of the presence of C. perfringens in the blood culture or the abscess.\n\nWith respect to treatment, all the patients received antibiotic therapy, and two patients underwent surgery. The mortality rate was 60.0%, with a median time to death of 9.7 hours (range, 0–96 hours). In all fatal cases, patients already went into shock or died before a diagnosis and decision to operate could be made. In one patient who survived, surgical drainage in combination with appropriate antibiotic therapy may have improved survival. If there was a perceived infected focus such as a hepatic abscess, the recommended treatment included aggressive surgical drainage together with high-dose antibiotic therapy.\n\nConclusion\nIntravascular hemolysis secondary to C. perfringens should always be considered in patients who present with liver damage after chemo-embolic therapy for HCC. Biliary reconstruction is an especially important risk factor for infection.\n\nAbbreviations\nCTComputed tomography\n\nHCCHepatocellular carcinoma\n\nTACETranshepatic arterial chemoembolization\n\nTAETransarterial embolization\n\nAcknowledgements\nWe thank Robert E. Brandt, founder, CEO, and CME of MedEd Japan, for editing the manuscript.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nMO, HU, HH, NW, YT, TI, KK, TN, AS, and WK contributed equally to this work. HU and MO collected and analyzed the data; MO drafted the manuscript; HH, NW, YT, TI, KK, TN, AS, and WK offered technical or material support. All authors have read and approved the final version of the manuscript to be published.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review from this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Martí Gelonch L Jiménez Agüero R Rodríguez Canas N Enríquez Navascués JM Massive haemolysis due to sepsis caused by Clostridium perfringens secondary to liver abscess. Presentation of two cases with a similar history Gastroenterol Hepatol 2018 41 9 562 563 10.1016/j.gastrohep.2017.11.012. 29455931 \n2. García Carretero R, Romero Brugera M, Vazquez-Gomez O, Rebollo-Aparicio N. Massive haemolysis, gas-forming liver abscess and sepsis due to Clostridium perfringens bacteraemia. BMJ Case Rep. 2016; 10.1136/bcr-2016-218014.\n3. Lim AG, Rudd KE, Halliday M, Hess JR. Hepatic abscess-associated Clostridial bacteraemia presenting with intravascular haemolysis and severe hypertension. BMJ Case Rep. 2016; 10.1136/bcr-2015-213253.\n4. Shindo Y Dobashi Y Sakai T Monma C Miyatani H Yoshida Y Epidemiological and pathobiological profiles of Clostridium perfringens infections: review of consecutive series of 33 cases over a 13-year period Int J Clin Exp Pathol 2015 8 569 577 25755747 \n5. Dutton D Gavrilova N Massive intravascular hemolysis with organ failure due to Clostridium perfringens : evidence of intracytoplasmic C. perfringens Blood 2013 122 310 10.1182/blood-2013-01-472407 24032126 \n6. Ingimarsdottir IJ Asmundsdottir LR Gottfredsson M Case of the month: patient with septic shock and massive intravascular haemolysis Laeknabladid 2012 98 289 290 22647407 \n7. Ng H Lam SM Shum HP Yan WW Clostridium perfringens liver abscess with massive haemolysis Hong Kong Med J 2010 16 310 312 20683077 \n8. Ochi S Oda M Nagahama M Sakurai J Clostridium perfringens alpha-toxin-induced hemolysis of horse erythrocytes is dependent on Ca2+ uptake Biochim Biophys Acta 2003 1613 79 86 10.1016/S0005-2736(03)00140-8 12832089 \n9. Sakurai J Nagahama M Oda M Clostridium perfringens alpha-toxin: characterization and mode of action J Biochem 2004 136 569 574 10.1093/jb/mvh161 15632295 \n10. van Bunderen CC Bomers MK Wesdorp E Peerbooms P Veenstra J Clostridium perfringens septicaemia with massive intravascular haemolysis: a case report and review of the literature Neth J Med 2010 68 343 346 20876913 \n11. Gerson LB Pont A Cummins RT Clostridial bacteremia and death following chemoembolization for hepatocellular carcinoma J Vasc Interv Radiol 1994 5 167 170 10.1016/S1051-0443(94)71477-9 8136598 \n12. Oshima S Takaishi K Tani N Hirano M Ikeda K Makari Y Two cases of liver abscess caused by Clostridium perfringens after transcatheter arterial chemoembolization Gan To Kagaku Ryoho 2013 40 1795 1797 24393925 \n13. Li JH Yao RR Shen HJ Zhang L Xie XY Chen RX Clostridium perfringens infection after transarterial chemoembolization for large hepatocellular carcinoma World J Gastroenterol 2015 21 4397 4401 10.3748/wjg.v21.i14.4397 25892893\n\n",
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"keywords": "Clostridium perfringens; Intravascular hemolysis; Transhepatic arterial chemoembolization",
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"mesh_terms": "D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic; D006528:Carcinoma, Hepatocellular; D003016:Clostridium perfringens; D004621:Embolization, Therapeutic; D015251:Epirubicin; D017809:Fatal Outcome; D006461:Hemolysis; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009364:Neoplasm Recurrence, Local; D018805:Sepsis",
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"title": "A suspected case of Clostridium perfringens sepsis with intravascular hemolysis after transhepatic arterial chemoembolization: a case report.",
"title_normalized": "a suspected case of clostridium perfringens sepsis with intravascular hemolysis after transhepatic arterial chemoembolization a case report"
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"abstract": "The COVID-19 pandemic and its impact on health systems had a significant effect on the management of inflammatory diseases in the long term and myopathies could be signs of COVID-19, making it difficult to diagnose the cause and effect relationship. An unvaccinated 62-year-old female patient followed for polymyositis was tested positive for COVID-19 on polymerase chain reaction (PCR) of nasopharyngeal swab revealed by dyspnea and rhinorrhea with fever and pulmonary involvement of 75%. She had an enlarged left ventricle with complete left branch block, inaugural diabetes mellitus with ketosis, kidney dysfunction, and inflammatory syndrome. Despite the early initiation of invasive ventilation in combination with the national protocol against covid-19, the patient died on day 4 of care. The best management should anticipate comorbidities and the evolutionary profile would guide the continuation of the treatment. Polymyositis like other rheumatic diseases was associated with a very high risk of developing a severe form of COVID-19. The combination of elder age and comorbidities led to a severe form of COVID-19 and therefore to a poor prognosis. The article aimed to show the severity of the association of covid-19 with polymyositis at the comorbid stage.",
"affiliations": "Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.;Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco.",
"authors": "Musoni|L|L|;Ezzouine|H|H|;Ettouki|O|O|;Mansour|A|A|;Nour|M|M|;Elkhaouri|I|I|;Darif|A|A|;Raid|M|M|;Elkasmi|M|M|;Charra|B|B|",
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"doi": "10.1016/j.amsu.2021.102598",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)00548-3\n10.1016/j.amsu.2021.102598\n102598\nCase Report\nPolymyositis and covid-19: A morbide association (a case report)\nMusoni L. musoniliberat@gmail.com\na∗\nEzzouine H. ab\nEttouki O. a\nMansour A. a\nNour M. a\nElkhaouri I. a\nDarif A. a\nRaid M. a\nElkasmi M. a\ncharra B. ab\na Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Morocco\nb Medical Intensive Care Unit, CHU Ibn Rochd, Casablanca, Morocco\n∗ Corresponding author. musoniliberat@gmail.com\n26 7 2021\n8 2021\n26 7 2021\n68 10259819 7 2021\n25 7 2021\n© 2021 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nThe COVID-19 pandemic and its impact on health systems had a significant effect on the management of inflammatory diseases in the long term and myopathies could be signs of COVID-19, making it difficult to diagnose the cause and effect relationship.\n\nAn unvaccinated 62-year-old female patient followed for polymyositis was tested positive for COVID-19 on polymerase chain reaction (PCR) of nasopharyngeal swab revealed by dyspnea and rhinorrhea with fever and pulmonary involvement of 75%. She had an enlarged left ventricle with complete left branch block, inaugural diabetes mellitus with ketosis, kidney dysfunction, and inflammatory syndrome. Despite the early initiation of invasive ventilation in combination with the national protocol against covid-19, the patient died on day 4 of care. The best management should anticipate comorbidities and the evolutionary profile would guide the continuation of the treatment. Polymyositis like other rheumatic diseases was associated with a very high risk of developing a severe form of COVID-19. The combination of elder age and comorbidities led to a severe form of COVID-19 and therefore to a poor prognosis. The article aimed to show the severity of the association of covid-19 with polymyositis at the comorbid stage.\n\nHighlights\n\n• The association of covid-19 and polymyositis is few or not frequent in the literature.\n\n• Myositis can be one of the symptoms of covid-19 with risk of a worsening of the pre-existing pathology: polymyositis.\n\n• The article shows the severity of the association of covid-19 with polymyositis.\n\n• Poorly controlled treatment of polymyositis leads to serious consequences with the severe form of covid-19.\n\n• Polymyositis is a risk factor for severe covid-19.\n\nKeywords\n\nSARS-Cov-2\nPolymyositis\nCOVID-19\nMorbid association\nCase report\n==== Body\nConflicts of interest\n\nNone.\n\n1 Introduction\n\nThe COVID-19 pandemic and its impact on health systems had a significant effect on the management of inflammatory diseases in the long term. Inflammatory myopathies, of which polymyositis is a part, could be signs of COVID-19, making it difficult to diagnose the cause and effect relationship. The long-term treatment given to these patients exposes them to side effects that are sometimes fatal or may induce them to develop the severe form of COVID-19 disease. Patients with autoimmune and inflammatory diseases have a higher incidence of co-morbidities such as metabolic syndrome and ischemic heart disease putting them at risk of developing severe COVID-19 infection. The aim of this work was to show the severity of the association of covid-19 with polymyositis at the comorbid stage.\n\nThis manuscript has been reported in line with SCARE's 2020 Criteria [1].\n\n2 Case report\n\nWe report a case of an unvaccinated 62-year-old female patient followed for polymyositis under corticosteroid therapy for seven years. Five days before admission the patient presented with dyspnea associated with rhinorrhea with uncalculated fever. When the respiratory symptoms worsened, the patient went to the emergency room with pulsed oxygen saturation at 40% in ambient air and 91% under a high-concentration mask. A chest CT scan with contrast injection showed multiple frosted glass foci of multilobar and bilateral pleural and central topography, some linear subpleural opacities without lymph node hypertrophy of the mediastinal and hilar chains, moderate cardiomegaly with the integrity of the pleura and the wall concluding to a COVID-19 viral pneumopathy with pulmonary involvement estimated at 75% (Fig. 1) which was confirmed with a polymerase chain reaction of the nasopharyngeal swab. On admission in the intensive care unit, she was conscious with a Glasgow coma scale of 15/15, reactive and symmetrical pupils, without sensory-motor deficit or cutaneous signs of dermatomyositis. Blood pressure at 140/70 mmHg, heart rate at 80 beats per minute, pulse oxygen saturation at 77% in ambient air and 93% under high concentration mask at 15L/min, and breathing rate at 22 cycles per minute (CPM). The electrocardiogram showed a regular sinus rhythm at 100 beats per minute, the PR space fixed at 0.16 sec; complete left branch block, QT corrected to 0.42sec. On transthoracic echocardiography, we noted an undilated left ventricle with minimal left ventricular hypertrophy, global contractility preserved with the ejection fraction estimated at 50%, minimal mitral insufficiency, complying with undilated inferior vena cava (17mm). Capillary blood glucose was at 27.5mmol/L, urinary labstix noted Ketone ++, glycosuria +++, glycated hemoglobin at 12.8%, which concluded to a diabetes mellitus with ketosis, probably induced by long-term corticosteroid therapy. Blood gases showed PH: 7.39; PaCO2: 44 mmHg; PaO2: 59.5 mmHg; HCO3-: 26.4mmol; TCO2: 27.8mmol; SaO 2: 90.5% under high concentration mask at 15L/minute; respiration rate 21 cpm with a ratio PaO2/FiO2 = 198.3. The biological tests show a blood count with white blood cells at 9840/mm3, neutrophil polynuclear cells at 7950/mm3, lymphocytes at 1130/mm3, blood platelets at 321000/mm3, hemoglobin at 12.2g/dl. In addition, C-reactive protein at 316 mg/L; blood urea at 14.65mmol/L; blood creatinine at 207.74μmolg/L; aspartate aminotransferase (ASAT) at 44UI/L; alanine aminotransferase (ALAT) at 22UI/L; Albumin at 36g/L. The patient received a nationally adopted treatment for SARS-CoV-2 made by hydroxychloroquine, azithromycin, vitamin C & D; zinc, ceftriaxone, low molecular weight heparin preventive dose, acetylsalicylic acid; methylprednisolone, insulin therapy, proton pump inhibitor as well as respiratory physiotherapy. The evolution was marked by the worsening on the respiratory level with Pulse Oxygen Saturation at 88% under high concentration mask at 15L/min, a polypnea at 30 cpm, and 97% under non-invasive ventilation with polypnea at 24 cpm. The patient was intubated on day 3 and died on day 4 of hospitalization due to severe refractory hypoxia.Image Chest CT scan showing multiple frosted glass foci of multilobar and bilateral pleural and central topography.\n\nImage\n\n3 Discussion\n\nPolymyositis is a rheumatic disease of inflammatory myopathies [2]. It is clinically characterized by proximal muscle weakness of the limbs with myalgia [3], and when it affects the respiratory system, it can manifest itself as cough, fever, and dyspnea. The biological inflammatory syndrome can vary, and the creatine kinase assay confirms the myogenic syndrome with a level greater than or equal to three times normal [4]. Treatment is mainly based on corticosteroids and immunosuppressants, and the choice of treatment is guided by the presentation of the disease [3,4]. In the absence of underlying tumor pathology, adult myositis has a relatively favorable prognostic condition, with current 5-year survival rates of about 90% [4]. Substantive treatment must be continued with an adaptation of corticoid doses, avoiding non-steroidal anti-inflammatory drugs, and favoring paracetamol for symptomatic treatment [5,6]. It should also be mentioned that patients with rheumatic diseases are more sensitive to COVID-19 either because of the rheumatological disease complication or because of the drugs used [6,7]. Patients with myositis, dermatomyositis, polymyositis have a very high risk of developing COVID-19 [5]. The immune response is compromised for patients under immunosuppressive therapies, and then are more exposed to infections [8]. Other Risk factors for developing severe COVID-19 infection in rheumatic patients are elder age, lung disease, diabetes mellitus, long-term corticosteroid therapy, sepsis, high activity of the underlying rheumatic disease [5],cardiac pathologies, pneumopathy [4,7], associated tumor pathology, black race, delay of inadequate initial therapy [4]. Our patient was being followed for polymyositis under long-term corticosteroid therapy. She presented a fever with dyspnea and rhinorrhea with a biological inflammatory syndrome made of a C-reactive protein at 316mg/L. The lung involvement was estimated at 75% on a chest CT scan. It concluded to SARS COV-2 on polymyositis with comorbidities. It has been described that polymyositis could be observed during infection with viruses, especially retroviruses [4] and more recently COVID-19 [9]. Comorbidities such as diabetes mellitus, heart disease, obesity, impaired renal function are risk factors for mortality [10,11], and when associated with an age greater than 59 years, are predictive factors for the development of rapidly progressive severe or fatal COVID-19 infection [[10], [11], [12], [13]].\n\n4 Conclusion\n\nPatients followed for polymyositis are exposed to a very high risk of developing a severe form of COVID-19. Therapeutic management of COVID-19 remains the same as for other patients. The treatment of the comorbidities is a cornerstone of a good prognosis. Despite the early diagnosis and treatment, the prognosis of these patients remains poor and putting polymyositis in the risk factors of severe forms of covid-19.\n\nEthical approval\n\nThe study is exempt from ethical approval in our institution.\n\nAuthor contribution\n\nLibérat Musoni: designed the study, wrote the protocol and the first draft of the manuscript Hanane Ezzouine: designed the study, wrote the protocol and the first draft of the manuscript Omar Ettouki: designed the study, wrote the protocol and the first draft of the manuscript Akram. Mansour: managed the analyses, and the correction of the manuscript Mariam Nour: managed the analyses, and the correction of the manuscript Imane Elkhaouri: managed the analyses, and the correction of the manuscript Aicha Darif: managed the analyses, and the correction of the manuscript Mehdi Raid: managed the analyses, and the correction of the manuscript Maroua Elkasmi: managed the analyses, and the correction of the manuscript Boubaker charra: reading and correction of the manuscriptAll authors read and approved the final manuscript.\n\nSources of funding\n\nNo funding for research.\n\nRegistration of research studies: not necessary it is not the first case\n\n• Clinicaltrials.gov – for all human studies – free.\n\n• Chinese Clinical Trial Registry chictr.org.cn – for all human studies - free.\n\n• Researchregistry.com – for all human studies – charge.\n\n• ISRCTN.com – for all human studies – charge.\n\n• There are many national registries approved by the UN that can be found here.\n\nGuarantor\n\nMUSONI Libérat.\n\nConsent\n\nWritten informed consent was obtained from the patient's family for publication of this case.\n\nDeclaration of competing interest\n\nNo conflicts of interest.\n\nAcknowledgements\n\nWe would like to thank the chief of the Intensive Care Unit and all the team who participated in the care of the patients for whom we owe all the data.\n==== Refs\nReferences\n\n1 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. Thoma A. The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358\n2 Bakkouri J.E. Les auto-anticorps associés aux myosites ou myopathies inflammatoires 9 2020 5\n3 Salort-Campana E. Comment j’explore une myopathie inflammatoire ? Pratique Neurologique - FMC avr 11 2 2020 113 121\n4 Cherin P. Polymyosites et dermatomyosites. EMC - appareil locomoteur janv 1 1 2006 1 10\n5 Ouali Z.E. Rhumatismes chroniques et covid-19: recommandations thérapeutiques des sociétés savantesChronic rheumatism and covid-19: therapeutic recommendations from learned societies 2020 [cité 23 mai 2021]; Disponible sur: https://rmr.smr.ma/371-rhumatismes-chroniques-et-covid-19-recommandations-therapeutiques-des-societes-savantes\n6 Arora G. Kassir M. Jafferany M. Galadari H. Lotti T. Satolli F. The COVID ‐19 outbreak and rheumatologic skin diseases. Dermatologic Therapy [Internet] 33 4 2020 [cité 23 mai 2021], Disponible sur:\n7 So H. Mak J.W.-Y. So J. Lui G. Lun F. Lee J. Incidence and clinical course of COVID-19 in patients with rheumatologic diseases: a population-based study Seminars in Arthritis and Rheumatism. oct 50 5 2020 885 889\n8 Talotta R. Robertson E. Autoimmunity as the comet tail of COVID-19 pandemic WJCC 8 17 6 sept 2020 3621 3644 32953841\n9 Beydon M. Chevalier K. Al Tabaa O. Hamroun S. Delettre A.-S. Thomas M. Myositis as a manifestation of SARS-CoV-2 Ann Rheum Dis. mars 80 3 2021 e42-e42\n10 Wan S.A. Teh C.L. Sachdev Manjit Singh B. Cheong Y.K. Chuah S.L. Jobli A.T. Clinical features of patients with rheumatic diseases and COVID-19 infection in Sarawak, Malaysia Ann. Rheum. Dis. 24 2020 annrheumdis-2020-218425\n11 Richardson S. Hirsch J.S. Narasimhan M. Crawford J.M. McGinn T. Davidson K.W. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area JAMA. 26 mai 323 20 2020 2052\n12 Druyan A. Lidar M. Brodavka M. Levy I. Barzilai A. Pavlotsky F. The risk for severe COVID 19 in patients with autoimmune and/or inflammatory diseases: first wave lessons. Dermatologic Therapy [Internet] [cité 11 juill 2021];34(1). Disponible sur: https://onlinelibrary.wiley.com/doi/10.1111/dth.14627 2021\n13 Recommandations d’experts portant sur la prise en charge en réanimation des.pdf.\n\n",
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"keywords": "COVID-19; Case report; Morbid association; Polymyositis; SARS-Cov-2",
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"title": "Polymyositis and covid-19: A morbide association (a case report).",
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"abstract": "Fulminant myocarditis has been reported in patients treated with immune checkpoint inhibitors. We present the first described case of acute immune-mediated myocarditis and myositis associated with durvalumab plus tremelimumab combination therapy. The patient was undergoing treatment for advanced endometrial cancer.\nA 75-year-old Caucasian female presented with difficulty ambulating due to neck protraction, imbalance, and increased shortness of breath with exertion 3 weeks after her first durvalumab and tremelimumab administration for advanced endometrial cancer. While the patient's initial laboratory data showed an acute transaminitis and elevated creatine phosphokinase (CPK), consistent with myositis, she developed complete heart block and ventricular dysfunction, with elevated troponins. Endomyocardial biopsy confirmed a diagnosis of immune-mediated myocarditis. She was treated with high-dose steroids and mycophenolate mofetil, which led to eventual native conduction and left ventricular ejection fraction recovery. Upon discharge, she was titrated off of steroids over 8 weeks and her mycophenolate was subsequently stopped. A follow-up computed tomography scan revealed progression of metastatic disease. The patient remains alive using supplemental oxygen 3 months after admission.\nDurvalumab plus tremelimumab combination therapy can lead to fulminant immune-mediated myocarditis. This patient's myocarditis was amenable to treatment with high-dose intravenous steroids and mycophenolate.",
"affiliations": "Cardiology Division, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United States.;Cardiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.;Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.;Cardiology Division, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United States.;Cardiology Division, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United States.;Department of Medicine, Weill Cornell Medical College, New York, NY, United States.",
"authors": "Mahmood|Syed S|SS|;Chen|Carol L|CL|;Shapnik|Natalie|N|;Krishnan|Udhay|U|;Singh|Harsimran S|HS|;Makker|Vicky|V|",
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"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(18)30050-X10.1016/j.gore.2018.05.014Case ReportMyocarditis with tremelimumab plus durvalumab combination therapy for endometrial cancer: A case report Mahmood Syed S. aChen Carol L. bcShapnik Natalie dKrishnan Udhay acSingh Harsimran S. acMakker Vicky makkerv@mskcc.orgcd⁎a Cardiology Division, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, United Statesb Cardiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United Statesc Department of Medicine, Weill Cornell Medical College, New York, NY, United Statesd Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States⁎ Corresponding author at: Gynecologic Medical Oncologic Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States. makkerv@mskcc.org01 6 2018 8 2018 01 6 2018 25 74 77 27 4 2018 29 5 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nFulminant myocarditis has been reported in patients treated with immune checkpoint inhibitors. We present the first described case of acute immune-mediated myocarditis and myositis associated with durvalumab plus tremelimumab combination therapy. The patient was undergoing treatment for advanced endometrial cancer.\n\nCase presentation\nA 75-year-old Caucasian female presented with difficulty ambulating due to neck protraction, imbalance, and increased shortness of breath with exertion 3 weeks after her first durvalumab and tremelimumab administration for advanced endometrial cancer. While the patient's initial laboratory data showed an acute transaminitis and elevated creatine phosphokinase (CPK), consistent with myositis, she developed complete heart block and ventricular dysfunction, with elevated troponins. Endomyocardial biopsy confirmed a diagnosis of immune-mediated myocarditis. She was treated with high-dose steroids and mycophenolate mofetil, which led to eventual native conduction and left ventricular ejection fraction recovery. Upon discharge, she was titrated off of steroids over 8 weeks and her mycophenolate was subsequently stopped. A follow-up computed tomography scan revealed progression of metastatic disease. The patient remains alive using supplemental oxygen 3 months after admission.\n\nConclusions\nDurvalumab plus tremelimumab combination therapy can lead to fulminant immune-mediated myocarditis. This patient's myocarditis was amenable to treatment with high-dose intravenous steroids and mycophenolate.\n\nHighlights\n• First description of myocarditis after durvalumab plus tremelimumab therapy\n\n• Myocarditis developed despite low-dose steroids.\n\n• Myocarditis responded to high-dose IV steroids (20 mg/Kg) and mycophenolate.\n\n\n\nKeywords\nEndometrial cancerDurvalumabTremelimumabImmune-mediated myocarditisCardio-oncologyMyositis\n==== Body\n1 Introduction\nEndometrial cancer is the most common gynecologic malignancy in the United States, with approximately 63,230 newly diagnosed cases and 11,350 associated deaths expected in 2018 (Siegel et al., 2018). From 1987 to 2008, there was a 50% increase in the incidence of endometrial cancer, with an approximate 300% increase in the number of associated deaths (Calle et al., 2003; National Cancer Institute, 2018). Although there are many chemotherapeutic and targeted therapies approved for ovarian, fallopian tube and primary peritoneal cancers, since the 1971 approval of megestrol acetate for the palliative treatment of advanced endometrial cancer, only pembrolizumab has been Food and Drug Administration approved for high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) endometrial cancer. As a result, there has been an ever-growing focus on the development of novel therapies to treat advanced endometrial cancer.\n\nImmune checkpoint inhibitors (i.e., monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 [CTLA-4], programmed cell death 1 [PD-1], and its ligand [PD-L1]) have revolutionized treatment in a myriad of malignancies previously associated with poor prognosis. Immunotherapy has been aggressively explored in endometrial cancer (NCT03367741, NCT02982486, NCT03241745, NCT02899793, NCT03310567, NCT02630823, and NCT02501096). Over the past several years, cases of myocarditis and fatal heart failure have been reported in patients with cancer treated with immune checkpoint inhibition (ICI), both as single agents and in combinations (Heinzerling et al., 2016; Johnson et al., 2016). Here, we present the first described case of acute immune-mediated myocarditis and myositis associated with durvalumab plus tremelimumab combination therapy. Of note, the patient was undergoing treatment for advanced endometrial cancer.\n\n2 Case presentation\nA 75-year-old Caucasian woman presented with vaginal spotting. An endometrial biopsy revealed serous carcinoma. She underwent a robotically assisted radical hysterectomy, bilateral pelvic and aortic lymph node dissection, and omentectomy. Pathology revealed a stage IIIC2 serous carcinoma of the endometrium with one positive right aortic lymph node. DNA mismatch repair proteins were retained on immunohistochemistry. She received intravaginal radiation therapy followed by carboplatin area under the curve (AUC) 5 and paclitaxel.\n\nAfter a 6-month remission, she was found to have newly metastatic disease, with bilateral pulmonary nodules, a hepatic lesion, and lymphadenopathy. She was enrolled on a randomized phase 2 trial comparing the PD-L1 inhibitor durvalumab alone versus durvalumab plus the CTLA-4 inhibitor tremelimumab for advanced endometrial cancer. She was randomized to the combination arm and received her first cycle of durvalumab 1500 mg flat dose and tremelimumab 75 mg flat dose. On Cycle 1 Day 1, she reported minimal side effects, only grade 1 skin pruritus.\n\nNearly 4 weeks after initiating immunotherapy, she presented with a 5-day history of difficulty ambulating due to neck weakness, imbalance, and progressive dyspnea on exertion. She was afebrile, with stable vital signs. She had no cardiac risk factors and denied any other cardiac symptoms. Her physical exam was normal; however, a chest radiograph demonstrated scattered interstitial opacities possibly due to pneumonitis and not an infectious or inflammatory process. Initial laboratory data were notable for newly developed transaminitis (aspartate transaminase [AST] 308/alanine transaminase [ALT] 252) and an elevated creatine phosphokinase (CPK) level to 5158 U/L (normal, <140). Intravenous methylprednisolone at 1 mg/kg was started immediately for suspected pneumonitis and myositis. A CT of her chest ruled out pneumonitis, instead confirming bi-basilar consolidations and numerous metastases to lungs, liver, and bone.\n\nThirty-six hours later, her dyspnea had worsened, now requiring 6 L of nasal cannula (NC). She was found to be newly bradycardic (40 bpm), and an electrocardiogram (ECG) showed new complete heart block (Fig. 1A) with junctional escape rhythm, and at other times, accelerated idioventricular escape rhythm. She was transferred to the intensive care unit (ICU), where a transvenous pacer (TVP) was placed. Her troponin I, checked for the first time at this point, was elevated to 5 ng/mL (normal, <0.02 ng/mL; Fig. 2). A bedside transthoracic echocardiogram (TTE) showed 54% left ventricular ejection fraction (EF), with regional areas of hypokinesis. Over the next 12 h, despite an escalated intravenous methylprednisolone dose to 10 mg/kg and the addition of mycophenolate mofetil 1000 mg oral twice daily, her troponin I rose to 6.7 ng/mL. She continued to alternate between intermittent intrinsic normal sinus rhythm at 80 bpm, and requiring pacing via TVP. The patient was then placed on 1000 mg (20 mg/kg) daily intravenous methylprednisolone (high dose) for presumed myocarditis secondary to ICI therapy, similar to the established treatment for acute rejection in orthotopic heart transplant patients. Emergent cardiac catheterization and endomyocardial biopsy were performed later that day and revealed non-obstructive coronary disease and lymphohistiocytic myocarditis (Fig. 3) with occasional eosinophils.Fig. 1 (A) Electrocardiogram (ECG) with complete heart block showing atrial activity dissociated from ventricular activity. (B) ECG with resolution of heart block with synchronized atrial and ventricular activity.\n\nFig. 1Fig. 2 Time course of complete heart block occurrence, troponin elevation, and initiation of mycophenolate mofetil and high-dose steroids.\n\nCHB, complete heart block; TVP, transvenous pacemaker.\n\nFig. 2Fig. 3 Hematoxylin and eosin stain of right ventricular endomyocardial biopsy showing lymphohistiocytic infiltration with occasional eosinophils.\n\nFig. 3\n\nTwelve hours after the initiation of 1000 mg intravenous methylprednisolone, her troponin I levels began to drop, steadily declining over the subsequent weeks (Fig. 2). She required intermittent pacing for 2 days while receiving high-dose methylprednisolone, after which she returned to sinus rhythm (Fig. 1B). High-dose methylprednisolone was discontinued after 3 days, and she was started on 1.5 mg/kg prednisone, with a plan for tapering by 10 mg (0.2 mg/Kg) per week, and weekly troponin measurements for myocarditis recurrence surveillance. She was continued on mycophenolate 1000 mg twice daily, with a plan to discontinue the medication after completing her prednisone taper. She had a persistent 2 L NC oxygen requirement, attributed to her increased metastatic pulmonary cancer burden, which did not improve with diuresis. A TTE after pacing discontinuation demonstrated an abnormally low EF of 35%; she was started on enalapril for heart failure, which had to be discontinued due to low blood pressure. A repeat TTE 2 months after her presentation showed an improved EF of 59%. Despite these improvements, she still requires oxygen by NC and is unable to independently perform daily activities.\n\n3 Discussion\nImmune checkpoint receptors on both T cells and non-immune–related cells such as those of the myocardium play a key role in the maintenance of self tolerance; their therapeutic blockade can alter immunological tolerance (Lichtman, 2013; Rodig et al., 2003), resulting in autoimmune or inflammatory immune-mediated adverse events (AEs). Non-cardiac side effects of ICI are typically limited to grade ≤ 3 AEs treatable with low-dose steroids (Postow et al., 2018). Myocarditis associated with ICI, however, can be fulminant (Mahmood et al., 2018). More data are needed to establish the incidence of ICI-associated myocarditis. In a multi-center registry of ICI-associated myocarditis, the prevalence at one institution was 1%, with half of these patients experiencing major adverse cardiovascular events (MACEs) of grade 4 or 5 severity (Boutros et al., 2016). In a Bristol-Myers Squibb safety database, 18 drug-related severe AEs of myocarditis (0.09% of the database) were noted (Eigentler et al., 2016; Costa et al., 2017), which is likely an underestimate, as myocarditis was not initially recognized as an AE of ICI. Combination therapy of an anti-CTLA-4 agent with either an anti-PD1 or anti-PD-L1 agent has been associated with an increased rate of myocarditis (Johnson et al., 2016), as well as non-cardiac immune-mediated AEs, resulting in discontinuation of treatment in almost 40% of treated patients (Mahmood et al., 2018).\n\nICI is an important advancement in the treatment of metastatic malignancies, and clinicians should have the ability to recognize and manage the AEs associated with this treatment approach, as well as with strategies to help patients tolerate cardiac AEs (Johnson et al., 2016). The median time to presentation of myocarditis is 34–65 days after initiation of treatment (Mahmood et al., 2018). Four of 5 cases of ICI-associated myocarditis occur within the first 3 months of starting therapy (Larkin et al., 2015; Postow et al., 2015) and a troponin T of ≥1.5 ng/mL is associated with a four-fold increase of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block (Brahmer et al., 2018). Although data are lacking, experience-based algorithms for myocarditis surveillance have proposed checking troponin with every infusion (if dosed every 3 weeks) or with every other infusion (if fortnightly dosed) for the first 3 months of treatment (Mahmood et al., 2018; Escudier et al., 2017). TTE does not appear to be an effective surveillance tool, as more than half of ICI-associated myocarditis cases present with a normal EF (Mahmood et al., 2018). Patients with suspected ICI-associated myocarditis (i.e., presenting with symptoms of shortness of breath, chest pain, orthopnea, paroxysmal nocturnal dyspnea or fatigue) should have troponin measured and promptly referred to cardio-oncology or cardiology if warranted. Current registry data have relied upon cardiac magnetic resonance imaging or endomyocardial biopsy to establish a myocarditis diagnosis (Mahmood et al., 2018). In the event of hemodynamic instability or conduction abnormality, patients should be transferred to a cardiac ICU (Mahmood et al., 2018; Brahmer et al., 2018).\n\nRecent data suggest ICI-associated myocarditis is amenable to treatment with immunosuppression (Mahmood et al., 2018). Higher mg/kg dosing of intravenous methylprednisolone is associated with a lower rate of major adverse cardiovascular events (2 mg/kg vs 0.8 mg/kg, p = 0.04 for non-MACE vs MACE, respectively). There was a non-significant trend towards less MACE when methylprednisolone is started promptly on admission for myocarditis (18 h vs 27 h, p = 0.12 for non-MACE vs MACE, respectively). Data on the use of other immunosuppressive agents such as mycophenolate, infliximab, and anti-thymoglobulin are lacking.\n\nThis is the first described case of durvalumab and tremelimumab–associated myocarditis and myositis. This AE occurred after the initial dose and progressed rapidly. Myocarditis was accompanied by other immune-related AEs and responded to high-dose steroids and mycophenolate. Left ventricular dysfunction was not the initial symptom, and cardiac symptoms were not prominent early on. Vigilance on the part of the treating oncologist and close monitoring for immune-related cardiac events is imperative, as the mortality associated with cardiac AEs is high. However, prompt initiation of high-dose intravenous methylprednisolone is associated with improved cardiac outcomes (Mahmood et al., 2018; Escudier et al., 2017).\n\n4 Conclusions\nAlthough myocarditis is a serious AE of ICI therapy, the cardiotoxicity is treatable with high-dose immunosuppression, as seen in our case report. ICI is an important advancement in cancer therapy, and this case report provides insight into the management of cardiac AEs associated with cancer therapy.\n\nConsent\nAccording to our institutional policies, this case report has obtained Institutional Review Board exemption.\n\nConflict of interest statement\nThe authors have no conflicts of interest to declare.\n\nFunding\nDrs. Chen and Makker are supported in part by the NIH/NCI MSK Cancer Center Support Grant P30CA008748.\n\nAuthor contributions\nManuscript writing: SS Mahmood, CL Chen, V Makker.\n\nAnalysis of data: SS Mahmood, CL Chen, V Makker.\n\nCreation/acquisition of figures: N Shapnik, U Krishnan, HS Singh.\n\nManuscript review and critique: SS Mahmood, CL Chen, N Shapnik, U Krishnan, HS Singh, V Makker.\n\nFinal approval of manuscript: SS Mahmood, CL Chen, N Shapnik, U Krishnan, HS Singh, V Makker.\n\nFunding\nDrs. Chen and Makker are supported in part by the NIH/NCI MSK Cancer Center Support Grant P30CA008748.\n==== Refs\nReferences\nBoutros C. Tarhini A. Routier E. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination Nat. Rev. Clin. Oncol. 13 2016 473 486 27141885 \nBrahmer J.R. Lacchetti C. Schneider B.J. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline J. Clin. Oncol. 2018 Feb 14 1714 1768 JCO2017776385 10.1200/JCO.2017.77.6385 29442540 \nCalle E.E. Rodriguez C. Walker-Thurmond K. Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults N. Engl. J. Med. 348 2003 1625 1638 12711737 \nCosta R. Carneiro B.A. Agulnik M. Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials Oncotarget 8 2017 8910 8920 27852042 \nEigentler T.K. Hassel J.C. Berking C. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy Cancer Treat. Rev. 45 2016 7 18 26922661 \nEscudier M. Cautela J. Malissen N. Clinical features, management, and outcomes of immune checkpoint inhibitor–related cardiotoxicity Circulation 136 2017 2085 2087 29158217 \nHeinzerling L. Ott P.A. Hodi F.S. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy J. Immunother. Cancer 4 2016 50 27532025 \nJohnson D.B. Balko J.M. Compton M.L. Fulminant myocarditis with combination immune checkpoint blockade New Engl. J. Med. 375 2016 1749 1755 27806233 \nLarkin J. Chiarion-Sileni V. Gonzalez R. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma New Engl. J. Med. 373 2015 23 34 26027431 \nLichtman A.H. The heart of the matter: protection of the myocardium from T cells J. Autoimmun. 45 2013 90 96 23810579 \nMahmood S.S. Fradley M.G. Cohen J.V. Myocarditis in patients treated with immune checkpoint inhibitors J. Am. Coll. Cardiol. 71 2018 1755 1764 29567210 \nNational Cancer Institute Drugs Approved for Endometrial Cancer 2018 American Cancer Society \nPostow M.A. Chesney J. Pavlick A.C. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma New Engl. J. Med. 372 2015 2006 2017 25891304 \nPostow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade New Engl J Med 378 2018 158 168 29320654 \nRodig N. Ryan T. Allen J.A. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis Eur. J. Immunol. 33 2003 3117 3126 14579280 \nSiegel R.L. Miller K.D. Jemal A. Cancer statistics, 2018 CA Cancer J. Clin. 68 2018 7 30 29313949\n\n",
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"journal": "Gynecologic oncology reports",
"keywords": "Cardio-oncology; Durvalumab; Endometrial cancer; Immune-mediated myocarditis; Myositis; Tremelimumab",
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"title": "Myocarditis with tremelimumab plus durvalumab combination therapy for endometrial cancer: A case report.",
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"abstract": "An 81-year-old immunocompetent patient with bronchiectasis and refractory Mycobacterium abscessus lung disease was treated for 6 months with a three-phage cocktail active against the strain. In this case study of phage to lower infectious burden, intravenous administration was safe and reduced the M. abscessus sputum load tenfold within one month. However, after two months, M. abscessus counts increased as the patient mounted a robust IgM- and IgG-mediated neutralizing antibody response to the phages, which was associated with limited therapeutic efficacy.",
"affiliations": "Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.;Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.;Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.;Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Investigational Pharmacy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA. gfh@pitt.edu.;Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. kcohen8@jhmi.edu.",
"authors": "Dedrick|Rebekah M|RM|http://orcid.org/0000-0002-3666-711X;Freeman|Krista G|KG|http://orcid.org/0000-0002-2944-5076;Nguyen|Jan A|JA|;Bahadirli-Talbott|Asli|A|;Smith|Bailey E|BE|;Wu|Andrew E|AE|;Ong|Aaron S|AS|;Lin|Cheng Ting|CT|http://orcid.org/0000-0003-0275-8037;Ruppel|Lisa C|LC|;Parrish|Nicole M|NM|;Hatfull|Graham F|GF|http://orcid.org/0000-0002-6705-6821;Cohen|Keira A|KA|http://orcid.org/0000-0002-4521-397X",
"chemical_list": "D057134:Antibodies, Neutralizing",
"country": "United States",
"delete": false,
"doi": "10.1038/s41591-021-01403-9",
"fulltext": null,
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"issn_linking": "1078-8956",
"issue": "27(8)",
"journal": "Nature medicine",
"keywords": null,
"medline_ta": "Nat Med",
"mesh_terms": "D000369:Aged, 80 and over; D057134:Antibodies, Neutralizing; D001435:Bacteriophages; D006801:Humans; D008297:Male; D008991:Monitoring, Physiologic; D009165:Mycobacterium Infections, Nontuberculous; D009500:Neutralization Tests",
"nlm_unique_id": "9502015",
"other_id": null,
"pages": "1357-1361",
"pmc": null,
"pmid": "34239133",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "33005701;28739795;17277290;4273800;30763536;26440922;24893003;33785625;32991269;26548913;30292481;31207123;13306955;22748808;30395179;27872066;32086501;28807909;31068712;28704651",
"title": "Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection.",
"title_normalized": "potent antibody mediated neutralization limits bacteriophage treatment of a pulmonary mycobacterium abscessus infection"
} | [
{
"companynumb": "US-009507513-2112USA008279",
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"abstract": "Despite conventional diuretic therapy, volume overload persists in many patients with decompensated heart failure. Adverse effects of diuretics are common, including worsening kidney function and electrolyte disturbance. Furthermore, decreased kidney function also affects the response to diuretics and is associated with an increased risk of mortality. A 10-year-old boy with congestive heart failure (CHF) complicated by advanced chronic kidney disease (CKD) presented with oliguria and generalized edema. He was being treated with furosemide and spironolactone, and these doses were increased to 3 mg/kg/day after admission. Although edema decreased temporarily, the symptoms worsened and furosemide resistance developed 2 months later. Tolvaptan (0.1 mg/kg/day) was started, resulting in a gradual increase in the plasma sodium level and adequate decongestion of the volume overload state. Cardiac function also improved. The use of tolvaptan should be considered in pediatric cases of conventional diuretic-resistant CHF, even when complicated by advanced CKD.",
"affiliations": "Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Hirano|Daishi|D|;Kakegawa|Daisuke|D|;Yamada|Akifumi|A|;Ito|Akira|A|;Miwa|Saori|S|;Ida|Hiroyuki|H|",
"chemical_list": "D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004232:Diuretics; D000077602:Tolvaptan",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.12590",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1328-8067",
"issue": "57(1)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "children; chronic kidney disease; congestive heart failure; furosemide; tolvaptan",
"medline_ta": "Pediatr Int",
"mesh_terms": "D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D002648:Child; D004232:Diuretics; D004351:Drug Resistance; D006333:Heart Failure; D006801:Humans; D008297:Male; D051437:Renal Insufficiency; D000077602:Tolvaptan",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "183-5",
"pmc": null,
"pmid": "25711263",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tolvaptan in a pediatric patient with diuretic-resistant heart and kidney failure.",
"title_normalized": "tolvaptan in a pediatric patient with diuretic resistant heart and kidney failure"
} | [
{
"companynumb": "JP-TEVA-552938ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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{
"abstract": "A large number of adults and children consume soy in various forms, but little information is available regarding potential neurological side effects. Prior work indicates an association between the consumption of soy-based diets and seizure prevalence in mouse models of neurological disease and in children with autism. Herein, we sought to evaluate potential associations between the consumption of soy-based formula during infancy and disease comorbidities in persons with fragile X syndrome (FXS), while controlling for potentially confounding issues, through a retrospective case-control survey study of participants with FXS enrolled in the Fragile X Online Registry with Accessible Research Database (FORWARD). There was a 25% usage rate of soy-based infant formula in the study population. We found significant associations between the consumption of soy-based infant formula and the comorbidity of autism, gastrointestinal problems (GI) and allergies. Specifically, there was a 1.5-fold higher prevalence of autism, 1.9-fold GI problems and 1.7-fold allergies in participants reporting the use of soy-based infant formula. The major reason for starting soy-based infant formula was GI problems. The average age of seizure and allergy onset occurred long after the use of soy-based infant formula. We conclude that early-life feeding with soy-based infant formula is associated with the development of several disease comorbidities in FXS.",
"affiliations": "Department of Neurology, University of Wisconsin, Madison, WI 53706, USA.;Survey Center, University of Wisconsin, Madison, WI 53706, USA.;Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI 53792, USA.;Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA.;National Fragile X Foundation, Folsom, CA 94596, USA.;Survey Center, University of Wisconsin, Madison, WI 53706, USA.;MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, CA 95817, USA.;Departments of Human Genetics and Pediatrics, Emory University, Atlanta, GA 30322, USA.;Boston Children's Hospital, Boston, MA 02115, USA.;Autism & Developmental Medicine Institute, Geisinger Lewisburg, Lewisburg, PA 17837, USA.;Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA.;Children's National Health System, Washington, DC 20010, USA.;Children's National Health System, Washington, DC 20010, USA.;Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.;Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.;Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA.;Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA.",
"authors": "Westmark|Cara J|CJ|;Kniss|Chad|C|;Sampene|Emmanuel|E|;Wang|Angel|A|;Milunovich|Amie|A|;Elver|Kelly|K|;Hessl|David|D|;Talboy|Amy|A|;Picker|Jonathon|J|;Haas-Givler|Barbara|B|;Esler|Amy|A|;Gropman|Andrea L|AL|;Uy|Ryan|R|;Erickson|Craig|C|;Velinov|Milen|M|;Tartaglia|Nicole|N|;Berry-Kravis|Elizabeth M|EM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/nu12103136",
"fulltext": "\n==== Front\nNutrients\nNutrients\nnutrients\nNutrients\n2072-6643 MDPI \n\n33066511\n10.3390/nu12103136\nnutrients-12-03136\nArticle\nSoy-Based Infant Formula is Associated with an Increased Prevalence of Comorbidities in Fragile X Syndrome\nhttps://orcid.org/0000-0003-3919-3279Westmark Cara J. 1* Kniss Chad 2 Sampene Emmanuel 3 Wang Angel 4 https://orcid.org/0000-0003-2784-1523Milunovich Amie 5 Elver Kelly 2 Hessl David 6 Talboy Amy 7 Picker Jonathon 8 Haas-Givler Barbara 9 Esler Amy 10 Gropman Andrea L. 11 Uy Ryan 11 Erickson Craig 12 Velinov Milen 13 Tartaglia Nicole 14 Berry-Kravis Elizabeth M. 4 1 Department of Neurology, University of Wisconsin, Madison, WI 53706, USA\n2 Survey Center, University of Wisconsin, Madison, WI 53706, USA; ckniss@ssc.wisc.edu (C.K.); kelver@ssc.wisc.edu (K.E.)\n3 Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI 53792, USA; sampene@biostat.wisc.edu\n4 Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA; angel_wang@rush.edu (A.W.); elizabeth_berry-kravis@rush.edu (E.M.B.-K.)\n5 National Fragile X Foundation, Folsom, CA 94596, USA; amie@fragileX.org\n6 MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California, Davis, CA 95817, USA; drhessl@ucdavis.edu\n7 Departments of Human Genetics and Pediatrics, Emory University, Atlanta, GA 30322, USA; amy.talboy@emory.edu\n8 Boston Children’s Hospital, Boston, MA 02115, USA; jonathon.picker@childrens.harvard.edu\n9 Autism & Developmental Medicine Institute, Geisinger Lewisburg, Lewisburg, PA 17837, USA; bahaasgivler@geisinger.edu\n10 Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA; else0007@umn.edu\n11 Children’s National Health System, Washington, DC 20010, USA; AGropman@childrensnational.org (A.L.G.); RSUY@childrensnational.org (R.U.)\n12 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; craig.erickson@cchmc.org\n13 Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA; milen.velinov@opwdd.ny.gov\n14 Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA; Nicole.tartaglia@childrenscolorado.org\n* Correspondence: westmark@wisc.edu; Tel.: +1-608-262-9730\n14 10 2020 \n10 2020 \n12 10 313607 9 2020 06 10 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).A large number of adults and children consume soy in various forms, but little information is available regarding potential neurological side effects. Prior work indicates an association between the consumption of soy-based diets and seizure prevalence in mouse models of neurological disease and in children with autism. Herein, we sought to evaluate potential associations between the consumption of soy-based formula during infancy and disease comorbidities in persons with fragile X syndrome (FXS), while controlling for potentially confounding issues, through a retrospective case-control survey study of participants with FXS enrolled in the Fragile X Online Registry with Accessible Research Database (FORWARD). There was a 25% usage rate of soy-based infant formula in the study population. We found significant associations between the consumption of soy-based infant formula and the comorbidity of autism, gastrointestinal problems (GI) and allergies. Specifically, there was a 1.5-fold higher prevalence of autism, 1.9-fold GI problems and 1.7-fold allergies in participants reporting the use of soy-based infant formula. The major reason for starting soy-based infant formula was GI problems. The average age of seizure and allergy onset occurred long after the use of soy-based infant formula. We conclude that early-life feeding with soy-based infant formula is associated with the development of several disease comorbidities in FXS.\n\nautismfragile X syndrome (FXS)infant formulaseizuressoy\n==== Body\n1. Introduction\nFragile X syndrome (FXS) is the most common form of inherited intellectual disability with a frequency of 1 in 5000 males and 1 in 4000–8000 females [1]. The disorder is clinically characterized by highly variable cognitive disability, autism, seizures, delays in language development, anxiety disorders, aggression and attention-deficit/hyperactivity disorder (ADHD) [1,2]. Seizures are the most substantial medical problem in children with FXS occurring in ~8–16% of males and ~3–7% of females, typically in the first 5 years of life [1]. Although FXS is not one of the 29 core conditions included in the newborn screening (NBS) guidelines developed by the American College of Medical Genetics, it is a high priority genetic disorder for which screening would be possible if there was an empirically-supported therapy [3]. Findings from our laboratory indicate that soy-based diets increase seizure prevalence in a mouse model of FXS (Fmr1KO mice) and are associated with increased febrile seizures, simple partial seizures, epilepsy comorbidity and autism phenotypes in a population of children with autism [4,5,6]. Thus, we hypothesized that consumption of soy-based formula during infancy exacerbates seizures in neurodevelopmental disorders such as FXS.\n\nThere is a dearth of studies regarding the effects of soy consumption on infant development [7,8,9,10,11,12,13]. Soy contains high levels of plant estrogens (phytoestrogens, isoflavones), which may mimic or antagonize natural estrogen activity. A substantial percentage (12%) of infant formulas are soy-based and have phytoestrogen levels in the range of 4.5–8 mg/kg/day [7,8,9,10,11]. Taking into consideration body weight, infants fed soy-based formulas consume 6–11 times the amount of phytoestrogens necessary to produce hormone-like effects in adults [14].\n\nCurrent public health policies regarding soy-based infant formulas include positions from the American Academy of Pediatrics, “There is no conclusive evidence from animal, adult human, or infant populations that dietary soy isoflavones may adversely affect human development, reproduction, or endocrine function,” and the National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR), “The overall evidence was considered insufficient to reach a conclusion on whether the use of soy infant formula produces or does not produce developmental toxicity with infant exposure in girls or boys at recommended intake levels” [15,16]. These policies are in place for the general population, albeit there have been no studies specifically testing the effects of soy-based infant formulas in neurodevelopmental disabilities. Vulnerable populations, such as FXS, are likely more susceptible to the potential neurotoxic effects of high doses of bioactive dietary components.\n\nIt is not possible, at this time, to conduct a prospective evaluation of infant diet on FXS phenotypes as the average age of diagnosis is 35–37 months in boys and 42 months in girls [17], which occurs long after children have transitioned from formula to solid food. If specific food products are determined to affect the prevalence or severity of seizures or other disease phenotypes in FXS, NBS could be employed to identify susceptible infants and inform decisions regarding infant feeding recommendations. We conducted a retrospective survey analysis to determine if there were associations between the consumption of soy-based infant formula and seizure history, cognitive ability and autistic behaviors in participants with FXS enrolled in the Fragile X Online Registry with Accessible Research Database (FORWARD), the largest registry of FXS participants [18]. Previous FORWARD studies had not examined the impact of infant diet on disease outcomes. This analysis specifically examines associations between caregiver-reported use of soy-based infant formula and comorbid disorders, while comparing findings to prior data attained from the Simons Foundation Autism Research Initiative (SFARI) medical record database. We find significantly increased comorbidity of autism, GI problems and allergies in the FORWARD population associated with the use of soy-based infant formula. We emphasize that this study shows associations between soy-based infant formula and FXS comorbidities and not cause and effect relationships.\n\n2. Materials and Methods\nEthics Approvals. Each participating clinic obtained institutional review board (IRB) approval from their institution before enrolling families in FORWARD. Those approvals provided that the clinics were allowed to contact families for participation in other research studies based on FORWARD consent form. Thus, this study did not need to be evaluated for IRB approval at the participating clinics as each clinic only provided packets to the families, who then contacted the University of Wisconsin Survey Center (UWSC) to participate. This study was reviewed by the UW Health Sciences IRB and determined to meet the criteria for exempt Human Subjects research in accordance with Category 2 defined under 45 CFR-46.\n\nStudy Design. We utilized a national registry of FXS families maintained by FORWARD to conduct the first case-control study evaluating associations between early childhood feeding practices and the severity of common FXS phenotypes (seizures, cognition and autistic behavior). The specific components of the study included the following: (1) design a questionnaire to assess demographics, infant feeding practices, frequency and severity of seizures, cognitive ability, autistic behaviors and comorbid diagnoses in a FXS population by parental survey; (2) recruit seizure (cases) and non-seizure (controls) full-mutation FXS participants to a retrospective case-control study examining associations between soy-based infant formula use and FXS phenotypes; and (3) examine associations between soy-based infant formula and clinical characteristics (i.e., frequency and severity of seizures, cognitive ability, autistic behaviors) while accounting for duration of use of soy-based infant formula and potentially confounding factors, such as food allergies. Hypotheses included the following: (1) soy-based infant formula will be associated with increased frequency and severity of seizures in FXS, (2) soy-based infant formula will be associated with decreased cognitive ability in FXS, and (3) soy-based infant formula will be associated with elevated autistic behaviors in FXS.\n\nQuestionnaire. A 55-point questionnaire was designed to assess demographics, infant feeding practices, frequency and severity of seizures, and comorbid diagnoses. Questions were adapted from the Center for Disease Control and Prevention (CDC) Infant Feeding Practices II, the Fragile X Clinical & Research Consortium (FXCRC) parent report form, and the SFARI medical records database questionnaires. In addition, cognitive ability and autistic behaviors were assessed by adapting questions from well-established tools into the questionnaire. Cognitive tools included the Ages and Stages Questionnaire (ASQ) for 36-months, and autistic tools included the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R), and the Social Responsiveness Scale (SRS) parental survey. The primary endpoint of interest examined was seizure history. The primary predictor variable was the type of infant milk (casein, soy, breast) consumed. Questions regarding variables of interest were embedded in the survey to discourage participant knowledge of the study hypothesis. Demographic information on gender, age, race/ethnicity was collected. Existing data in FORWARD could not be used in this study because their coordinating center is not allowed to provide data at an individual level to investigators due to the rarity of the disorder.\n\nStudy Population & Participant Recruitment. The FXCRC was established in 2006 with support from the National Fragile X Foundation (NFXF) and subsequently expanded in 2009 with support by a grant from the Centers for Disease Control and Prevention (CDC) and consists of 22 FXS clinics and research facilities across the United States. The FXCRC developed FORWARD in 2011 to facilitate multisite data collection on individuals with FXS and to assist researchers in identifying participants who may be interested in and meet the eligibility criteria for specific research projects [18]. More than 1350 of the registrants are full-mutation FXS, and 1102 have a completed Clinical Report Form with seizure history. The study population included full-mutation FXS individuals enrolled in FORWARD and whose parents/caregivers had previously agreed to be contacted for research studies. Per FORWARD internal review board (IRB) guidelines, participants must be contacted directly by clinic directors for participation in research studies. Thus, for recruitment, participants in FORWARD with a history of seizures were identified as well as 4-fold more control participants. Controls were FXS participants without a reported history of seizures. Cases and controls were reasonably balanced on age and sex. The Principal Investigator, at the UW-Madison, contacted the clinical directors at all FORWARD sites and invited them to participate in the study. Individual clinics that agreed to participate in the study were provided a list of eligible participants associated with their site by the staff at FORWARD. The clinics sent parents/guardians a letter that informed them of the proposed study, invited them to participate, and emphasized the voluntary and confidential nature of the research. The letter requested that the primary caregiver of the participant with FXS return an enclosed card with their contact information to the UWSC for participation in the project.\n\nRecruitment Sample Size Justification. During the study design phase, FORWARD had a total of 122 enrolled participants with a seizure history (cases). By recruiting all cases with a seizure history (n = 122) and 4-fold more non-seizure controls (n = 488) to the study, estimating a 50% response rate (n = 61 cases; n = 244 controls), and assuming that the non-seizure population had a 20% usage rate of soy-based infant formula similar to the SFARI population [5], the proposed sample size would be able to detect with 80% (90%) power a 16 (19) percentage point difference in the proportion of soy-based formula use among cases versus controls, with a one-sided test of type I error of 0.05. Based on prior recruiting studies through FORWARD, a 50% response rate was deemed very conservative. Parents of FXS individuals are a highly motivated group that enthusiastically volunteer to participate in research projects to further therapeutic interventions for their children. There is a long history of collaboration and trust between these families and the clinician members of FORWARD that sent out the initial invitations for study participation. An expectation of 36% (39%) soy use among cases was reasonable as previous analysis of autism participants in the SFARI database indicated a 44% rate of soy-based infant formula use in participants reporting simple partial seizures [5].\n\nData Collection. Data collection occurred in two phases because the identities of FORWARD participants were not directly available to the Principal Investigator and included a four-wave mail survey strategy to ensure maximum response rates. Phase 1 consisted of sending prepared sample collection packets to 10 FXS clinics across the United States. The packets were designed to only need a printed address label attached to each packet (postage was already provided for each packet) A copy of the packet that was used for Rush University Medical Center is provided in Appendix A. Phase 2 consisted of (1) mailing the questionnaire (Fragile X Syndrome Nutrition Study, Appendix B) with a cover letter from the Principal Investigator containing a $2 bill pre-incentive and a postage-paid return envelope; (2) mailing a thank you postcard reminder 5–7 days after the initial mailing; and (3) sending full mailings (same as the first, but without the $2 bill and a slightly differently worded cover letter) to non-responders from the first two mailings 3–4 weeks after the initial survey packets were sent. The UWSC mailed the questionnaires and incentives, tracked responses, and provided an electronic dataset to the Principal Investigator. The informed consent document was embedded in the questionnaire to ensure return of the signed documents.\n\nData Analysis. Data were analyzed in accordance with STROBE guidelines. Percentages, means, standard error of the means (SEM), odds ratios (OR), and 95% confidence intervals (CI) were computed to describe the population. Fisher exact test (if less than 5 outcomes per cell) or Pearson’s uncorrected chi-square tests were used to examine the null hypotheses that the prevalence of comorbidities in FXS are the same in infants fed soy-based infant formula or not. Student’s t-tests were used to compare the means of two populations. Statistical significance was defined as p < 0.05. A Bonferroni correction was not applied for multiple comparisons. The number of participants for each comparison is reported in the corresponding tables. This manuscript addresses the hypothesis that soy-based infant formula is associated with increased frequency and severity of seizures in FXS. Subsequent manuscripts will address the other study hypotheses regarding cognitive ability and specific autistic behaviors as well the association of comorbidities with breast milk.\n\n3. Results\n3.1. Response Rates\nBetween 27 August 2019 and 6 November 2019, the UWSC mailed out a total of 863 sample collection packets to the 10 participating FXS Clinics (Table 1). A total of 185 caregivers returned participation cards requesting a total of 241 questionnaires for persons with FXS (some families had multiple children with FXS). Thus, the overall phase 1 response rate for the study was 21%. Response rates for individual clinics varied between 0–54% (Table 1).\n\nPhase 2 of the data collection involved sending the 12-page questionnaire (Fragile X Syndrome Nutrition Study) to recruited participants. Between 19 December 2019 and 7 February 2020, the UWSC mailed out a total of 234 survey packets to the 180 respondents from phase 1. A copy of the questionnaire is provided in Appendix B. During phase 2, the UWSC learned that 11 of the 234 mailed survey packets were duplicates of other survey packets. At the end of the data collection period (28 February 2020), the UWSC estimated that they sent survey packets to a total of 223 non-duplicated parents or guardians resulting in 199 returned non-duplicated questionnaires. There were 9 pairs of participants with identical birth dates, but each pair differed on a defining characteristic such as sex, autism comorbidity, allergy comorbidity, or birth weight indicating a low likelihood of participant duplication in the dataset. The overall phase 2 response rate for the study was 89% (199 returned surveys per 223 non-duplicated cases) (Table 2). Seven of the 10 clinics had a 75% or greater response rate for phase 2, which is outstanding for a mail survey.\n\n3.2. Participant Demographics\nThe population for this study included full-mutation FXS registrants in FORWARD. Participants were invited based on a case-control study design, which included all registrants with a seizure history (cases) and 4-fold more participants without a seizure history (controls). At the end of the field period, there were 199 completed surveys. Based on caregiver-reported seizure history, the final dataset included 28 cases and 169 controls equating to 14% of participants reporting a seizure history. Demographics indicated 73% male participants, which coincides with the reported enrollment of 76% full mutation males in FORWARD [18]. The cases and controls had similar characteristics regarding ethnicity, birth weight and length, and current BMI (Table 3). Participant age at the time of the survey was significantly higher, 23 versus 17 years, for the cases; however, the average reported age of the first seizure was 7 years (SEM 0.97). Exclusion of participants under 7 years of age from the control cohort resulted in an average age of 19 years (SEM 0.78), which is not statistically different from the cases (p = 0.09). The prevalence of comorbidities, including autism, Down syndrome, food allergies, diabetes, and gastrointestinal (GI) problems, was not significantly different between cases and controls. Reported epilepsy comorbidity was inconsistent with reported and clinical seizure history and was not included in this analysis.\n\n3.3. Infant Feeding\nIn the study population, 142 out of 199 caregivers indicated that their child had been fed breastmilk, 52 respondents checked “No” to Q18, 2 respondents left the question blank, and 3 respondents checked “Don’t know”. This corresponds to a 73% rate of breastfeeding among Yes/No respondents, which aligns with CDC data indicating national averages from 76–84% between 2009–2016 in the general population [19]. In the study population, 96 out of 199 caregivers indicated that their child had been fed cow milk formula during their first year of life, 90 respondents checked “No” to Q23, 1 respondent left the question blank, and 12 respondents checked “Don’t know”. This corresponds to a 52% usage rate of cow milk formula among Yes/No respondents. In the study population, 45 out of 199 caregivers indicated that their child with FXS had been fed soy-based formula during their first year of life, 132 respondents checked “No” to Q28, 3 respondents left the question blank, and 19 respondents checked “Don’t know”. This corresponds to a 25% usage rate of soy-based infant formula among Yes/No respondents compared to 17% in the SFARI population [5] and 12% in the general population [5,6,7,8,9,10,11,12,13,14,15,16]. Binning the infant feeding data by cases and controls indicated no statistically significant differences dependent on infant diet (Table 4). The pre-study power calculation was based on recruitment of 305 participants and assumed a 16–19-percentage point difference in the use of soy-based infant formula between cases and controls. The study recruited at 65% (199 participants) of the anticipated level. The non-significant 1.7-fold increase in the use of soy-based infant formula in the cases was based on a 16-percentage point difference (p = 0.09).\n\n3.4. Comorbid Conditions as a Function of Infant Feeding with Soy-Based Formula\nThere was a 1.5-fold higher rate of comorbid autism in FXS participants who had been fed soy-based infant formula (64% autism with soy versus 44% no soy; p = 0.026) (Table 5). These findings are congruent with cited prevalence rates of 15–67% of comorbid autism in FXS [20,21]. The prevalence of food allergies was not statistically different between soy and no soy cohorts, albeit a larger study population may statistically support a 2-fold increase in food allergies associated with soy-based infant formula in FXS. The prevalence of diabetes was very low with only 2 participants out of 199 reporting diabetes. This was expected as diabetes is very rare in FXS [22]. There was a 1.9-fold higher rate of GI problems in FXS participants who had been fed soy-based infant formula (47% GI problems with soy versus 25% no soy; p < 0.01). The vast majority of respondents reported GI problems commencing before 3 years of age. GI problems are common in children and adults with FXS [23,24]. There was a 2.0-fold (not statistically significant) higher rate of reported seizures in the FXS participants who had been fed soy-based infant formula (p = 0.08). These data support findings from the SFARI autism population where there was a 2.1-fold higher rate of comorbid epilepsy in a high functioning autism population who had been fed soy-based infant formula (3.6% epilepsy with soy, N = 330, versus 1.7% no soy, N = 1563; p = 0.02) [5]. There was a 1.7-fold higher rate of reported allergies in FXS participants who had been fed soy-based infant formula (56% allergies with soy versus 33% no soy; p < 0.01). These data corroborate findings from the SFARI autism population where there was a 2.3-fold higher rate of allergies with soy-based infant formula (3.5% allergies with soy, N = 341, versus 1.5% no soy, N = 1608; p = 0.01), albeit the overall allergy prevalence was much higher in the FXS population [25]. Participants (8.3%) in the soy cohort reported no comorbid conditions compared to 33% in the no soy cohort (p = 0.004). Data binned as a function of sex indicate similar trends for males and females (Table S1). Overall, these data demonstrate that soy-based infant formula is associated with several disease comorbidities in FXS.\n\n3.5. Seizure Types and Timing in the Study Population\nThe primary hypothesis to be tested in this study was that the prevalence of seizures in FXS would be higher in infants fed soy-based versus non-soy-based formula or breast milk. Prior to commencing the study, FORWARD staff estimated that approximately 11% of registrants had a seizure history. The study design included recruitment at one case per 4 controls to increase participation by participants with a seizure history. Based on caregiver-reported seizure history, the dataset included 28 cases and 169 controls, or 14% of participants reporting a seizure history. Thus, the study did not succeed in enriching for participants with a seizure history. Regarding seizure type, 9 participants reported data regarding both seizure type and the use of soy-based infant formula and 16 participants for seizure type and no soy use (Table 6). Of note, no participants reported febrile seizures, which were reported in 2% of the SFARI population where they were 2.6-fold higher in participants fed soy-based infant formula (soy 4.2%, N = 333; no soy 1.6%, N = 1581) [5]. Based on concerns that seizures types reported by caregivers did not reflect prior literature on seizure types in FXS [1], 17 patients from Rush with seizures could be identified and compared with data regarding seizure type in the medical record. Only 4 families correctly identified the seizure type and thus data from the survey regarding seizure type cannot be considered accurate.\n\nData regarding the age at which participants with FXS had their first seizure was available for 26 participants (meaN = 7.5 years; SEM = 0.97) and was not statistically different between soy-based infant formula (meaN = 8.2 years; SEM = 2.2; N = 9) and no soy based-infant formula (meaN = 7.0 years; SEM = 1.0; N = 15; p = 0.58). Twenty-six caregivers answered the question, “Was your child given medication to treat the seizures?”, with 22 reporting “Yes”. The participants not receiving medications were fed breast milk and/or cow milk formula (3 reporting). The participants medicated for seizures were fed breast milk (68%, N = 22 reporting), cow milk formula (45%, N = 20 reporting) and soy-based formula (43%; N = 21 reporting). Although not statistically significant with the small sample size, these data suggest that that use of soy-based infant formula may be associated with increased use of medications to treat seizures in FXS.\n\n3.6. Caregiver-Reported Reasons for Starting and Stopping Soy-Based Infant Formula\nIn response to Q30, “Some examples of why people might choose to feed their child soy-based formulas include problems with other foods such as allergy, intolerance, constipation, diarrhea, too much mucus, gas, too much spit up, vomiting, or parental choice. Why was your child fed soy-based formula?”, the most common reasons included gastrointestinal issues (Table 7). The most common reasons for stopping soy-based infant formula were related to the child’s age and the transition from formula to whole cow milk and solid foods (Table 8).\n\n3.7. Gastrointestinal Problems in the Study Population\nRespondents (N = 57) provided data regarding the start of GI problems in their children with FXS. For 8 participants, data was not available regarding the use of soy-based infant formula. The remaining respondents reported use of soy-based infant formula (N = 18) or not (N = 31). All FXS participants reporting the use of soy-based infant formula and GI problems, with age data available for when GI problems started, commenced GI problems between birth and 3 years of age with 61% having GI problems within 2 weeks of age and 78% within the first year compared to only 9.7% within 2 weeks and 58% within the first year for participants not fed soy-based infant formula (Table 9). The average age of commencing GI problems was 7.8 months for the soy cohort compared to over 4 years for the no soy cohort. For all participants reporting GI problems within 2 weeks of age and the use of soy-based infant formula (N = 11), GI problems were reported before or at the same time as starting soy-based infant formula. These data suggest that soy-based infant formula is used at higher rates in FXS due to comorbid GI problems in newborns.\n\n3.8. Allergies in the Study Population\nRespondents (N = 73) reported data regarding the age of commencement and/or identification of allergies in their children with FXS. Allergies trended an average of 22 months earlier (p = 0.06) with a significant increase in prevalence within both 2 weeks and 1 year of age (p < 0.05) in FXS participants fed soy-based infant formula versus no soy (Table 10). In response to Q17, “Some examples of allergens include pollen, dust, pets, latex, eggs, fish, gluten or wheat, milk, nuts, medications, and many others. What are the allergens your child reacts to now or has in the past?”, the most prevalent allergens were seasonal related followed by food products and medications (Table 11). All participants reporting the timing of allergies exhibited symptoms by 13 years of age. Of note, all participants reporting allergies within 2 weeks of age included milk or lactose as an allergen. The percentage of participants with FXS reporting allergies (37%) is comparable to the general population in which 30% of adults and 40% of children have allergies. The percentage of participants with FXS reporting food allergies (16%) is higher than the general population, which reports 5.4–8% prevalence of food allergies in children [26,27]. Caregivers (N = 16, 8%) reported allergic reactions to Amoxicillin and/or cephalasporin antibiotics. These drugs are commonly prescribed for bacterial infections including otitis media (middle ear infections), which are common in FXS. About 10% of Americans report allergies to penicillin or related antibiotics [28]. Of 21 participants reporting use of soy-based infant formula, the prevalence of allergies and the timing of both, only 2 reported the prevalence of allergies before commencing soy-based infant formula and both of those reported milk allergies within 2 weeks of birth. The average age of allergy onset occurs long after discontinuation of infant formula.\n\n4. Discussion\nThere is little knowledge regarding how early life feeding is associated with neurological development, particularly in neurodevelopmental disorders. To fill this gap, we conducted the first study examining associations between infant feeding practices, specifically soy-based infant formula, and disease outcomes in children with FXS using FORWARD as a sampling frame to collect new data through parental surveys. This unique study population, with a high prevalence of seizures compared to the general population, allowed for a smaller cohort size. Published estimates of formula intolerance range from 2–7.5%; yet, 12% of infants are fed soy-based formula suggesting that nonstandard, soy-based formulas are used excessively [16]. Infants with FXS are often hypotonic and have initial poor latch and suck with breastfeeding, as well as frequent recurrent emesis because of reflux [1]. We found that 25% of FORWARD participants in this survey study reported use of soy-based infant formula. We also found associations between the consumption of soy-based infant formula and increased comorbidity of autism, GI problems and allergies. The data did not reach statistical significance to corroborate prior retrospective analysis of medical record data from the SFARI population where the prevalence of seizures in autistic children fed soy-based infant formula was higher [5]. However, line item analysis of the Aberrant Behavior Checklist (ABC) in the SFARI population indicated that several autistic behaviors were exacerbated in autistic children reported to have consumed soy-based infant formula [6], and analysis of comorbid conditions in the SFARI population indicated associations between soy-based formula and increased allergies, ADHD and bipolar disorder [25]. Overall, these findings from FORWARD FXS and SFARI autism populations strongly suggest that early-life feeding with soy-based infant formula is associated with adverse neurological outcomes in these developmental disabilities. It remains to be determined if babies destined to have more severe disability (autism, seizures, etc.) are harder to breastfeed (will not latch on, hyper, colic) and have more feeding intolerance and potentially more severe problems with gastroesophageal reflux (GERD) and bowel dysregulation, leading to the increased use of formula including soy formula.\n\nAn important goal of this project was to account for potentially confounding issues instigating the use of soy-based infant formula. The Infant Feeding and Early Development (IFED) Study found that the top-rated maternal reasons for use of soy-based formula include: “I fed my other child(ren) soy formula” (54%), “I think soy is healthier than other types of formula” (54%), “I suspect my baby had milk intolerance or my family has trouble digesting cow’s milk” (52%), “My family and friends recommended it” (27%), “I chose soy formula for religious reasons” (17%), “Health care provider recommended soy” (15%), “I prefer a dairy-free diet” (12%), “My child had colic or other digestive problem” (7%), “I suspected my baby had a food allergy or intolerance (other than milk)” (7%), and “Family follows a vegan diet” (1%) [12]. In the IFED population, 70% of mothers were Black, and 57% had a high school education or less. In contrast, in FORWARD, the highest ranked reasons for the use of soy-based infant formula were medical-related, particularly GI issues. In the soy cohort, 61% of infants exhibited GI problems within 2 weeks of age, and the initiation of soy-based formula started at the same time or after the GI problems. These data suggest that a high rate of GI problems in newborns with FXS necessitates alternate feeding strategies including the use of soy-based infant formula. Thus, early GI problems are a potentially confounding issue here. It is possible that the GI issues and resulting effects on nutritional intake produced the increased prevalence of autism, and that soy is simply a marker (correlate) of the underlying cause of the GI problems.\n\nThe strengths of this study design include: (1) this study is the first to link parent-reported data on infant feeding practices of children with FXS to disease phenotypes in those children; (2) FORWARD offers a unique study population with a high prevalence of seizures compared to the general population allowing for smaller cohort sizes; (3) the caregivers are a highly motivated group of parents eager to participate in research studies; and (4) FORWARD is an established FXS registry.\n\nThe limitations of this study include the following: (1) A limitation of all retrospective studies is the inability to fully evaluate the temporality of the relationships examined. Although a longitudinal approach would better enable evaluation of causality, it is currently impossible in this population because most participants are not diagnosed with FXS until three years of age after infant formula has been discontinued. (2) Another limitation is recall bias. Parents were asked to answer a series of questions regarding infant feeding and the frequency and severity of seizures, which may have occurred years earlier. The selection of questions was chosen with great care as to yield more accurate measures, and recall bias regarding infant formula usage was not expected to be a problem as parents typically switch formulas for specific reasons such as GI problems or allergies. (3) Another limitation is parental report of seizure type, which was not accurate as families are not trained in classifying seizures and doctors may not have told the parents which type(s) of seizures their child had. These data are best attained by review of the medical records. (4) Another limitation is response rates leading to concerns that that the case sample is not representative of the population of children with FXS experiencing seizures. We observed a low response rate (19%) at the phase 1 level and a high response rate (89%) at the phase 2 level. The majority (61%) of the completed questionnaires were from a single clinic (Rush University Medical Center). We could not address the Phase 1 response rate issue due to FORWARD IRB regulations that precluded our inability to contact participants until after they returned contact information to the UWSC. Moving forward, we plan to increase participant response by conducting the survey online through the NFXF whereby consent is attained through voluntary participation in an online survey. (5) Another limitation is potential selection bias. Many participants switch from breast milk to cow milk formula to soy-based formula, and the need for multiple dietary changes may be due to a more severe FXS phenotype.\n\nIn a clinical setting, parents seek medical attention for their infants with FXS at the onset of developmental delays. Population-wide NBS is not performed in the U.S. because there is no treatment. Hence, most children are three years or older before diagnosis. Considering the dearth of treatments for FXS and the high comorbidity of early-life GI problems, our findings warrant further investigation. There are alternatives to soy-based infant formula that could be implemented in the clinic for infants with FXS experiencing problems with breastfeeding and cow milk-based formulas. However, NBS for FXS would be required to enable an early diagnosis and choice of infant feeding.\n\n5. Conclusions\nIn conclusion, this case-control, retrospective survey study provides data regarding associations between the use of soy-based infant formula and comorbid conditions in participants with FXS recruited through FORWARD. Of importance, the data suggest that the usage rate of soy-based infant formula is twice as high in FXS compared to the general population and that the prevalence of autism, GI problems and allergies in FXS participants is statistically higher in soy-fed participants. It remains to be determined if soy-based infant formula causes increased comorbidities or serves as a correlate for underlying GI problems in FXS. The findings support further study examining the effects of infant nutrition on neurological development and consideration of the pros and cons of implementing NBS for FXS to identify individuals who may benefit from early nutritional management. Some mothers know that they are going to have a baby with FXS, and they could receive nutritional counseling now.\n\nAcknowledgments\nWe thank the research coordinators and administrative assistants at the participating clinics for assistance with participant recruitment: Keirsa Nimmons (Emory University), Kate Pawlowski (Boston Children’s Hospital), Lauren Kasparson (Geisinger), Olivia Walter (Cincinnati Children’s), Felicia Balsamo and Singh Shavana (NY Institute for Basic Research in Developmental Disabilities), and Karen Regan (Children’s Hospital of Colorado). We thank Michael Tranfaglia of FRAXA Research Foundation and members of the FORWARD Steering Committee (Stephanie Sherman, Howard Andrews, Walter Kaufman) and laboratory (Pamela Westmark, Alejandra Gutierrez, Laura Borth) for helpful discussions and/or critical review of the manuscript. We thank the families who participated in the study.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary Materials\nThe following are available online at https://www.mdpi.com/2072-6643/12/10/3136/s1, Table S1: Analysis of FXS comorbidities as a function of sex and soy-based infant formula.\n\nClick here for additional data file.\n\n Author Contributions\nConceptualization, C.J.W.; methodology, C.J.W.; formal analysis, C.J.W. and E.S.; investigation, C.J.W., A.W., A.M., D.H., A.T., J.P., B.H.-G., A.E., A.L.G., R.U., C.E., M.V., N.T., and E.M.B.-K.; data curation, C.K. and K.E.; writing—original draft preparation, C.J.W.; writing—review and editing, C.J.W., C.K., E.S., A.M., D.H., R.U., M.V., and E.M.B.-K.; visualization, C.J.W.; project administration, C.J.W.; funding acquisition, C.J.W. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), grant number HD097067. FORWARD was supported by cooperative agreements U01DD000231, U19DD000753 and U01DD001189, funded by the CDC. This article’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Department of Health and Human Services.\n\nConflicts of Interest\nThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nAppendix A\nCopy of 4-wave mail survey sent to participants.\n\nAppendix B\nCopy of the survey, Fragile X Syndrome Nutrition Study.\n\nnutrients-12-03136-t001_Table 1Table 1 Clinic Participation Phase 1.\n\nClinic\tSample Collection Packets\tResponse Rate (%) 1\t\nSent\tReturned\tDuplicates\t\nChildren’s Hospital Boston\t36\t3\t0\t8\t\nChildren’s Hospital Colorado\t111\t18\t0\t16\t\nChildren’s Nat Health System\t13\t3\t0\t23\t\nCincinnati Children’s\t78\t0\t0\t0\t\nEmory Univ School of Medicine\t44\t11\t0\t25\t\nGeisinger Medical Clinic\t21\t7\t0\t33\t\nNY State Institute for Basic Research\t50\t13\t1\t26\t\nRush Univ Medical Center\t375\t106\t14\t28\t\nUC Davis Health System\t122\t17\t1\t14\t\nUniversity of Minnesota\t13\t7\t0\t54\t\nTOTAL 2\t863\t185\t16\t21\t\n1 The response rate was calculated by dividing the number of returned sample collection cards by the number of sample collection packets sent out and multiplying by 100. 2 Five sample collection packets requesting questionnaires for 7 persons were returned too late (after 1 February 2020) to be included in the phase 2 mailing. The remaining 180 returned cards requesting questionnaires for 234 participants contained 16 duplicates whereby the same clinic sent multiple sample collection packets to the same parent/guardian (N = 14) or multiple clinics each sent a sample collection packet to the same parent/guardian (N = 2). To adhere to institutional review board (IRB) rules, the University of Wisconsin Survey Center (UWSC) did not see the list of 863 parents/guardians that received sample collection packets from the 10 fragile X syndrome (FXS) clinics. Thus, the total number of duplicates cannot be certain. Elimination of known duplicates and late returns gave a return rate of 19% (164/842*100).\n\nnutrients-12-03136-t002_Table 2Table 2 Subject Participation Phase 2.\n\nClinic\tQuestionnaires\tResponse Rate (%) 1\t\nRequested\tSent\tReturned\t\nChildren’s Hospital Boston 2\t3\t0\t0\t0\t\nChildren’s Hospital Colorado 2\t28\t26\t25\t96\t\nChildren’s Nat Health System\t4\t4\t4\t100\t\nCincinnati Children’s\t0\t0\t0\t0\t\nEmory Univ School of Medicine\t10\t10\t9\t90\t\nGeisinger Medical Clinic\t10\t10\t4\t40\t\nNY State Institute for Basic Research\t15\t15\t13\t87\t\nRush Univ Medical Center 3\t142\t142\t130\t92\t\nUC Davis Health System 2\t21\t19\t17\t89\t\nUniversity of Minnesota\t8\t8\t6\t75\t\nTOTAL 2\t241\t234\t208\t89\t\n1 The response rate was calculated by dividing the number of returned questionnaires by the number of sent questionnaires and multiplying by 100. 2 There were 5 sample collection cards, requesting questionnaires for 7 persons with FXS, that were returned too late to be included in the phase 2 mailing. These participants were not sent questionnaires as the field period was designed to end by the end of February 2020, and there was not enough time to mail survey packets out and expect to have them returned. 3 Eleven of the mailed survey packets were duplicates of other survey packets that were not removed between phases 1 and 2. The response rate for Rush is the same (92%) after elimination of the duplicates resulting in 131 sent packets and 121 returned packets. The overall response rate was unchanged at 89%.\n\nnutrients-12-03136-t003_Table 3Table 3 Characteristics of the FXS Population.\n\n\n\t\n\tCases (Seizures)\tControls (No Seizures)\t\nPopulation Size, % (N)\tMale\t16 (23)\t84 (121)\t\nFemale\t9.4 (5)\t91 (48)\t\nEthnicity, %\tAmerican Indian or Alaskan\t0\t0.59\t\nAsian\t3.6\t1.8\t\nBlack or African American\t0\t4.1\t\nHispanic or Latino\t3.6\t7.1\t\nNative Hawaiian 1\t0\t0\t\nWhite\t100\t91\t\nOther Race or Ethnicity 2\t0\t1.8\t\nAge at Survey, Years (SEM) 3\t\n\t23 (2.0)\t17 (0.78)\t\nBirth Weight, Pounds (SEM)\t\n\t7.8 (0.25)\t7.5 (0.10)\t\nBirth Length, Inches (SEM)\t\n\t21 (0.35)\t20 (0.15)\t\nCurrent BMI, Pounds (SEM)\t\n\t24 (1.1)\t23 (0.62)\t\nComorbidities, % (N)\tAutism\t64 (25)\t47 (157)\t\nDown Syndrome\t0 (28)\t0 (158)\t\nFood Allergies\t15 (26)\t9.9 (152)\t\nDiabetes\t3.6 (28)\t0.64 (157)\t\nGI Problems\t26 (27)\t32 (164)\t\nSEM: Standard error of the mean; GI: gastrointestinal; 1 Native Hawaiian or Other Pacific Islander. 2 Other Race or Ethnicity answers included 1 response “3/4 Eastern European Jew, ¼ Punjabi Indian”, 1 response “German and Scandinavian”, and 1 response “German and Norwegian”. 3 Student t-test, p = 0.007. The median age for cases was 20 and the median age for controls was 16.\n\nnutrients-12-03136-t004_Table 4Table 4 Infant Feeding in the FXS Population.\n\n\n\tCases 3 (Seizures)\tControls (No Seizures)\tChi Square p\t\nBreast milk, % (N)\t63 (27)\t74 (165)\t0.24\t\nCow milk formula, % (N) 1\t50 (24)\t50 (157)\t0.98\t\nSoy-based formula, % (N) 2\t38 (24)\t22 (148)\t0.09\t\n1 Participants (n = 1 case and n = 4 controls) were counted as “No” for cow milk formula because duration was 3 days or less. 2 Participants (n = 3 controls) were counted as “No” for soy-based infant formula because the duration was 3 days or less. 3 Participants (n = 1 case) was excluded because the seizure was due to sepsis at birth before feeding commenced.\n\nnutrients-12-03136-t005_Table 5Table 5 Analysis of FXS comorbidities as a function of soy-based infant formula.\n\nPhenotype\tSoy % (N)\tNo Soy % (N)\t\np\n1\n\tOdds Ratio\t95% CI\t\nnone\t8.3 (36)\t33 (105)\t0.0040 2\t5.5\t1.6–19\t\nautism\t64 (39)\t44 (126)\t0.026\t2.3\t1.1–4.8\t\nfood allergies\t18 (40)\t9.1 (121)\t0.14\t2.1\t0.76–5.9\t\ndiabetes\t0 (41)\t1.6 (126)\t1.0\t0.60\t0.028–13\t\nGI problems\t47 (43)\t25 (129)\t0.0073\t2.6\t1.3–5.4\t\nseizures\t22 (41)\t11 (134)\t0.08\t2.2\t0.90–5.6\t\nallergies\t56 (43)\t33 (132)\t0.0086\t2.5\t1.3–5.1\t\nCI: Confidence interval; 1 Chi-squared test was used unless any variable contained less than N = 5 in which case Fisher exact test was used. 2 Fisher exact test.\n\nnutrients-12-03136-t006_Table 6Table 6 Parent versus clinic-reported seizure types in study population.\n\nSeizure Type\tParent-Reported\tClinic Chart 5\t\nSoy % (N) 1,2\tNo Soy % (N) 3,4\tSoy % (N) 6\tNo Soy % (N) 7\t\nfebrile\t0 (6)\t0 (12)\t0 (3)\t0 (6)\t\natonic\t20 (5)\t0 (11)\t0 (3)\t0 (6)\t\ngeneralized\t75 (4)\t50 (12)\t67 (3)\t33 (6)\t\nabsence\t60 (5)\t70 (10)\t0 (3)\t0 (6)\t\nsimple partial\t50 (4)\t44 (9)\t0 (3)\t0 (6)\t\ncomplex partial\t50 (4)\t20 (10)\t67 (3)\t67 (6)\t\ninfantile spasms\t0 (5)\t13 (8)\t0 (3)\t0 (6)\t\n1 There was a total of 9 participants answering YES to use of soy formula and providing at least partial data for seizure type. The number of participants providing YES/NO data for each seizure type is provided in parentheses. Four participants reported multiple seizure types. 2 One participant reported “some other type of seizure”, which included “found in bed motionless and nonresponsive for 4–5 h twice”. 3 There was a total of 16 participants answering NO to use of soy formula and providing at least partial data for seizure type. The number of participants providing YES/NO data for each seizure type is provided in parentheses. Six participants reported multiple seizure types. 4 Three participants reported other seizure types, which were described as: “acting out”, “post birth due to sepsis (group B strep)”, and “one seizure followed by paralysis on one side”. The sepsis seizure was not included in the analysis as it occurred at birth before feeding commenced. 5 Clinical records from Rush University Medical Center were matched with 17 of 20 participants with a seizure history. Of the 17 chart reviews, parents correctly identified the seizure type in 4 surveys, identified a correct seizure type but either included additional seizure type(s) and/or missed a seizure type in 3 surveys, and wrongly identified the seizure type in 6 surveys. Caregiver-reported seizure data was missing for 4 participants. 6 There were 3 Rush participants answering YES, and 7 participants answering NO, to use of soy formula and having both parent- and clinic-reported seizure data. One participant reported both generalized tonic-clonic and complex seizures. 7 One participant reported another seizure type: “post birth due to sepsis (group B strep)”, and was not included in the analysis as the seizure occurred at birth before feeding commenced.\n\nnutrients-12-03136-t007_Table 7Table 7 Reasons children with FXS were fed soy-based formulas.\n\n\nN\n\tReasons 1\t\n12\tVomiting, reflux, gas, diarrhea, constipation, colic\t\n10\tSpitting up\t\n10\tAllergy or intolerance to cow milk, rash\t\n9\tDoctor recommended or started in hospital\t\n5\tParental choice; thought it was better, healthier, gentler on stomach\t\n4\tNot making enough breast milk, wouldn’t latch on\t\n3\tAvailable at the time, added food source\t\n3\tIrritable, fussy, ear infection\t\n1\tLiked soy more than others\t\n1 A total of 45 participants provided responses with many participants listing multiple reasons.\n\nnutrients-12-03136-t008_Table 8Table 8 Reasons children with FXS were stopped being fed soy-based formulas.\n\n\nN\n\tReasons 1\t\n21\tTransitioned to whole cow milk and/or baby food, child age, drinking from cup\t\n7\tDidn’t help with vomiting, acid reflux, fussiness or colic or caused spitting up, vomiting, stomach pain or colic\t\n5\tParental choice\t\n4\tTransitioned to soy milk\t\n3\tDoctor recommendation\t\n2\tDidn’t accept it\t\n1\tOutgrew reflux\t\n1\tLearned breast milk could be stored\t\n1 A total of 41 caregivers provided responses.\n\nnutrients-12-03136-t009_Table 9Table 9 Timeframe of GI problems in FXS study population as a function of soy-based diet.\n\nAge\tSoy % (N = 18)\tNo Soy % (N = 31)\t\np\n\tOdds Ratio\t95% CI\t\n0–2 weeks (%)\t61\t9.7\t0.0002 1\t15\t3.2–67\t\n0–12 months (%)\t78\t58\t0.22 1\t2.5\t0.67–9.5\t\n0–3 years (%)\t100\t77\t0.038 1\t11\t0.61–211\t\nMean age (mo) (SEM)\t7.8 (2.7)\t52 (15)\t0.031 2\tn/a\tn/a\t\n1 Fisher exact test. 2 Student t-test.\n\nnutrients-12-03136-t010_Table 10Table 10 Timeframe of allergies in FXS study population as a function of soy-based diet.\n\nAge\tSoy % (N = 22) \tNo Soy % (N = 40)\t\np\n\tOdds Ratio\t95% CI\t\n0–2 weeks (%)\t14\t0\t0.041 1\t15\t0.72–296\t\n0–12 months (%)\t45\t20\t0.035 2\t3.3\t1.1–10\t\n0–3 years (%)\t77\t60\t0.17 2\t2.3\t0.70–7.4\t\nMean age (mo) (SEM)\t28 (6.7)\t50 (7.2)\t0.06 3\tn/a\tn/a\t\n1 Fisher exact test. 2 Chi square test. 3 Student t-test.\n\nnutrients-12-03136-t011_Table 11Table 11 Allergens reported in FXS study population.\n\n\nN\n\tAllergen 1\t\n44\tSeasonal (dust, grass, hay, mold, pollen, trees, weeds)\t\n31\tFood products (corn, dairy, eggs, fish, food dyes/fillers, gluten, oats, oranges, peanut, rice, sesame, tree nuts, turkey, wheat)\t\n20\tMedications (Abilify, Amoxicillin, Brevital IV, cephalosporins, vaccines (Prevar, H1N1 flu), Risperdal, Ritalin, sulfa drug, Trileptal)\t\n11\tAnimals (cats, dogs, feathers, hair, mice, wood clothing)\t\n2\tInsects\t\n2\tChemicals (detergents, perfumes)\t\n1 A total of 74 caregivers provided responses with many listing multiple allergens.\n==== Refs\nReferences\n1. Hagerman R.J. Berry-Kravis E. Hazlett H.C. Bailey D.B. Jr. Moine H. Kooy R.F. Tassone F. Gantois I. Sonenberg N. Mandel J.L. Fragile X syndrome Nat. Rev. Dis. Primers 2017 3 17065 10.1038/nrdp.2017.65 28960184 \n2. Hagerman R.J. Hagerman P.J. Physical and Behavioral Phenotype John Hopkins University Press Baltimore, MD, USA 2002 3 109 \n3. Riley C. Wheeler A. Assessing the fragile X syndrome newborn screening landscape Pediatrics 2017 139 S207 S215 10.1542/peds.2016-1159G 28814541 \n4. Westmark C.J. Westmark P.R. Malter J.S. Soy-based diet exacerbates seizures in mouse models of neurological disease J. Alzheimers Dis. 2013 33 797 805 10.3233/JAD-2012-121426 23034522 \n5. Westmark C.J. Soy infant formula and seizures in children with autism: A retrospective study PLoS ONE 2014 9 e80488 10.1371/journal.pone.0080488 24622158 \n6. Westmark C.J. Soy infant formula may be associated with increased autistic behaviors Autism-Open Access 2013 3 20727 25401047 \n7. Jing H. Gilchrist J.M. Badger T.M. Pivik R.T. A longitudinal study of differences in electroencephalographic activity among breastfed, milk formula-fed, and soy formula-fed infants during the first year of life Early Hum. Dev. 2010 86 119 125 10.1016/j.earlhumdev.2010.02.001 20172664 \n8. Li J. Dykman R.A. Jing H. Gilchrist J.M. Badger T.M. Pivik R.T. Cortical responses to speech sounds in 3- and 6-month-old infants fed breast milk, milk formula, or soy formula Dev. Neuropsychol. 2010 35 762 784 10.1080/87565641.2010.508547 21038165 \n9. Adgent M.A. Daniels J.L. Edwards L.J. Siega-Riz A.M. Rogan W.J. Early-life soy exposure and gender-role play behavior in children Environ. Health Perspect. 2011 119 1811 1816 10.1289/ehp.1103579 21813368 \n10. Pivik R.T. Andres A. Bai S. Cleves M.A. Tennal K.B. Gu Y. Badger T.M. Infant diet-related changes in syllable processing between 4 and 5 months: Implications for developing native language sensitivity Dev. Neuropsychol. 2016 41 215 230 10.1080/87565641.2016.1236109 27759424 \n11. Harlid S. Adgent M. Jefferson W.N. Panduri V. Umbach D.M. Xu Z. Stallings V.A. Williams C.J. Rogan W.J. Taylor J.A. Soy formula and epigenetic modifications: Analysis of vaginal epithelial cells from infant girls in the IFED study Environ. Health Perspect. 2017 125 447 452 10.1289/EHP428 27539829 \n12. Adgent M.A. Umbach D.M. Zemel B.S. Kelly A. Schall J.I. Ford E.G. James K. Darge K. Botelho J.C. Vesper H.W. A longitudinal study of estrogen-responsive tissues and hormone concentrations in infants fed soy formula J. Clin. Endocrinol. Metab. 2018 103 1899 1909 10.1210/jc.2017-02249 29506126 \n13. Li T. Badger T.M. Bellando B.J. Sorensen S.T. Lou X. Ou X. Brain cortical structure and executive function in children may be influenced by parental choices of infant diets AJNR Am. J. Neuroradiol. 2020 41 1302 1308 10.3174/ajnr.A6601 32527846 \n14. Setchell K.D. Zimmer-Nechemias L. Cai J. Heubi J.E. Exposure of infants to phyto-oestrogens from soy-based infant formula Lancet 1997 350 23 27 10.1016/S0140-6736(96)09480-9 9217716 \n15. Bhatia J. Greer F. American Academy of Pediatrics Committee on Nutrition Use of soy protein-based formulas in infant feeding Pediatrics 2008 121 1062 1068 10.1542/peds.2008-0564 18450914 \n16. McCarver G. Bhatia J. Chambers C. Clarke R. Etzel R. Foster W. Hoyer P. Leeder J.S. Peters J.M. Rissman E. NTP-CERHR expert panel report on the developmental toxicity of soy infant formula Birth Defects Res. B Dev. Reprod. Toxicol. 2011 92 421 468 10.1002/bdrb.20314 21948615 \n17. Bailey D.B. Jr. Raspa M. Bishop E. Holiday D. No change in the age of diagnosis for fragile X syndrome: Findings from a national parent survey Pediatrics 2009 124 527 533 10.1542/peds.2008-2992 19581269 \n18. Sherman S.L. Kidd S.A. Riley C. Berry-Kravis E. Andrews H.F. Miller R.M. Lincoln S. Swanson M. Kaufmann W.E. Brown W.T. FORWARD: A registry and longitudinal clinical database to study fragile X syndrome Pediatrics 2017 139 S183 S193 10.1542/peds.2016-1159E 28814539 \n19. Centers for Disease Control and Prevention Available online: https://www.cdc.gov/breastfeeding/data/nis_data/results.html (accessed on 10 August 2020) \n20. Clifford S. Dissanayake C. Bui Q.M. Huggins R. Taylor A.K. Loesch D.Z. Autism spectrum phenotype in males and females with fragile x full mutation and premutation J. Autism Dev. Disord. 2007 37 738 747 10.1007/s10803-006-0205-z 17031449 \n21. Kaufmann W.E. Cortell R. Kau A.S. Bukelis I. Tierney E. Gray R.M. Cox C. Capone G.T. Stanard P. Autism spectrum disorder in fragile X syndrome: Communication, social interaction, and specific behaviors Am. J. Med. Genet. A 2004 129 225 234 10.1002/ajmg.a.30229 \n22. Dy A.B.C. Tassone F. Eldeeb M. Salcedo-Arellano M.J. Tartaglia N. Hagerman R. Metformin as targeted treatment in fragile X syndrome Clin. Genet. 2018 93 216 222 10.1111/cge.13039 28436599 \n23. Kidd S.A. Lachiewicz A. Barbouth D. Blitz R.K. Delahunty C. McBrien D. Visootsak J. Berry-Kravis E. Fragile X syndrome: A review of associated medical problems Pediatrics 2014 134 995 1005 10.1542/peds.2013-4301 25287458 \n24. Utari A. Adams E. Berry-Kravis E. Chavez A. Scaggs F. Ngotran L. Boyd A. Hessl D. Gane L.W. Tassone F. Aging in fragile X syndrome J. Neurodev. Disord. 2010 2 70 76 10.1007/s11689-010-9047-2 20585378 \n25. Westmark C.J. Soy-based therapeutic baby formulas: Testable hypotheses regarding the pros and cons Front. Nutr. 2017 3 59 10.3389/fnut.2016.00059 28149839 \n26. Asthma and Allergy Foundation of America Available online: https://www.aafa.org/allergy-facts/ (accessed on 10 August 2020) \n27. Gupta R.S. Springston E.E. Warrier M.R. Smith B. Kumar R. Pongracic J. Holl J.L. The prevalence, severity, and distribution of childhood food allergy in the United States Pediatrics 2011 128 9 17 10.1542/peds.2011-0204 \n28. Khan D.A. Solensky R. Drug allergy J. Allergy Clin. Immunol. 2010 125 S126 S137 10.1016/j.jaci.2009.10.028 20176256\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6643",
"issue": "12(10)",
"journal": "Nutrients",
"keywords": "autism; fragile X syndrome (FXS); infant formula; seizures; soy",
"medline_ta": "Nutrients",
"mesh_terms": "D001321:Autistic Disorder; D016022:Case-Control Studies; D015897:Comorbidity; D005260:Female; D005526:Food, Formulated; D005600:Fragile X Syndrome; D005767:Gastrointestinal Diseases; D006801:Humans; D006967:Hypersensitivity; D007223:Infant; D041943:Infant Formula; D007227:Infant Nutritional Physiological Phenomena; D008297:Male; D015995:Prevalence; D012042:Registries; D012189:Retrospective Studies; D012640:Seizures; D013025:Soybeans; D011795:Surveys and Questionnaires",
"nlm_unique_id": "101521595",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33066511",
"pubdate": "2020-10-14",
"publication_types": "D016428:Journal Article",
"references": "25287458;17031449;20176256;21948615;21813368;23034522;18450914;28960184;28814541;32527846;28814539;21038165;27759424;9217716;25401047;28436599;27539829;20172664;15326621;28149839;20585378;19581269;29506126;24622158;21690110",
"title": "Soy-Based Infant Formula is Associated with an Increased Prevalence of Comorbidities in Fragile X Syndrome.",
"title_normalized": "soy based infant formula is associated with an increased prevalence of comorbidities in fragile x syndrome"
} | [
{
"companynumb": "US-OTSUKA-2021_023667",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report a case of Aspergillus fumigatus endogenous endophthalmitis in an immunocompetent patient initially diagnosed as acute retinal necrosis.\n\n\nMETHODS\nCase report.\n\n\nMETHODS\nA 67-year-old woman with a remote history of treated pulmonary tuberculosis and no ocular history presented to an outside retina specialist with a sudden onset of floaters and blurred vision in one eye. Examination and fluorescein angiography at the time revealed findings suspicious for acute retinal necrosis, and the patient was started on oral valganciclovir and an intravitreal injection of ganciclovir. Despite treatment, the patient's vision and pain worsened. After evaluation at the University of Southern California Roski Eye Institute, she was diagnosed with a likely fungal endogenous endophthalmitis based on ultrasound findings and underwent emergent vitrectomy. A chest x-ray demonstrated partial collapse of the right upper lobe with hilar enlargement.\n\n\nRESULTS\nAspergillus fumigatus was cultured from vitreous, blood, and bronchoalveolar lavage samples, suggesting that the patient's infection had a pulmonary origin, most likely from the right upper lobe that had healed from previous tuberculosis infection.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first reported case of Aspergillus endogenous endophthalmitis in an immunocompetent patient secondary to pulmonary changes that occurred from previously treated tuberculosis.",
"affiliations": "University of Southern California Roski Eye Institute, Los Angeles, California.;University of Southern California Roski Eye Institute, Los Angeles, California.;University of Southern California Roski Eye Institute, Los Angeles, California.;University of Southern California Roski Eye Institute, Los Angeles, California.;University of Southern California Roski Eye Institute, Los Angeles, California.",
"authors": "Sastry|Ananth|A|;Kwon|Julie Y|JY|;Tan|Jeffrey J|JJ|;Rodger|Damien C|DC|;Rao|Narsing A|NA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000910",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": null,
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32004182",
"pubdate": "2020-01-29",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ENDOGENOUS ASPERGILLUS ENDOPHTHALMITIS IN AN IMMUNOCOMPETENT PATIENT WITH A REMOTE HISTORY OF PULMONARY TUBERCULOSIS.",
"title_normalized": "endogenous aspergillus endophthalmitis in an immunocompetent patient with a remote history of pulmonary tuberculosis"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2022-000863",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALGANCICLOVIR"
},
"drugadditional": "... |
{
"abstract": "This case report describes the clinical course of a young woman suffering from binge eating disorder (BED) associated with obesity. It illustrates the efficacy of different medications in the treatment of BED and related conditions and is followed by the comments and clinical observations of 2 practicing psychiatrists. The issues described in this paper have important clinical implications and are topical, given that BED is now recognized as a specific disorder in the new Diagnostic and Statistical Manual of Mental Disorders, fifth edition classification system, but neither the US Food and Drug Administration nor any other regulatory agency has yet approved a drug for treatment of this disease, despite its very prevalent and disabling nature. Growing evidence from the fields of psychopathology and neurobiology, including preclinical and clinical studies, converges to support the idea that \"overeating\" has much in common with other behavioral addictions, and substance abuse treatment agents may show promise for the treatment of BED.",
"affiliations": "From the Division of Psychiatry (AG, SdV, SB, AF), Department of Molecular Medicine, University of Siena School of Medicine, Siena, Italy; Department of Psychiatry, Neurobiology, Pharmacology and Bio-technologies (FC), University of Pisa, Pisa, Italy; Department of Psychiatry (NI), Massachusetts General Hospital, Boston, MA; and University of Washington School of Social work (JB), Seattle, WA.",
"authors": "Goracci|Arianna|A|;Casamassima|Francesco|F|;Iovieno|Nadia|N|;di Volo|Silvia|S|;Benbow|Jim|J|;Bolognesi|Simone|S|;Fagiolini|Andrea|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000085",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "9(1)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000328:Adult; D056912:Binge-Eating Disorder; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D006801:Humans; D009765:Obesity",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "20-4",
"pmc": null,
"pmid": "25629882",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Binge eating disorder: from clinical research to clinical practice.",
"title_normalized": "binge eating disorder from clinical research to clinical practice"
} | [
{
"companynumb": "IT-CIPLA LTD.-2015IT03616",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional":... |
{
"abstract": "Bupropion, an amphetamine-like dual mechanism drug, is approved and increasingly used for the treatment of major depression, and its use is associated with a dose-dependent risk of epileptic seizures. Suicide attempts are frequent in major depression and often an overdose of the drugs available is ingested. Therefore, it is important to be aware of the clinical course, including EEG and neurological symptoms, as well as treatment and prognosis of bupropion intoxication. We report on the clinical and EEG course of a women who ingested 27 g of bupropion in a suicide attempt. Myoclonic seizures were followed by generalized tonic-clonic seizures and coma associated with EEG burst-suppression and brief tonic seizures. Active carbon and neuro-intensive care treatment, including respiratory support, were given. Within three days, the patient returned to a stable clinical condition with a mildly encephalopathic EEG. In conclusion, bupropion intoxication requires acute intensive care treatment and usually has a good prognosis, however, misinterpretation of the clinical and EEG presentation may lead to errors in management.",
"affiliations": "Epilepsy Center Hessen - Marburg, Department of Neurology, University Hospital Marburg and Philipps-University Marburg, Marburg, Clinic for Psychiatry and Psychotherapy, Vitos Gießen-Marburg, Marburg.;Department of Psychiatry and Psychotherapy, University Hospital Marburg and Philipps -University Marburg, Marburg.;Department of Nephrology, University Hospital Marburg and Philipps-University Marburg, Marburg.;Epilepsy Center Hessen - Marburg, Department of Neurology, University Hospital Marburg and Philipps-University Marburg, Marburg.;Epilepsy Center Hessen - Marburg, Department of Neurology, University Hospital Marburg and Philipps-University Marburg, Marburg, Epilepsy Center Frankfurt Rhine-Main, Neurocenter, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt, Germany.",
"authors": "Noda|Anna Hiro|AH|;Schu|Ulrich|U|;Maier|Tanja|T|;Knake|Susanne|S|;Rosenow|Felix|F|",
"chemical_list": "D016642:Bupropion",
"country": "France",
"delete": false,
"doi": "10.1684/epd.2017.0896",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "19(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "bupropion intoxication; coma; seizure",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D016642:Bupropion; D003128:Coma; D003865:Depressive Disorder, Major; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006801:Humans; D008875:Middle Aged; D013406:Suicide, Attempted",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "109-113",
"pmc": null,
"pmid": "28246063",
"pubdate": "2017-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epileptic seizures, coma and EEG burst-suppression from suicidal bupropion intoxication.",
"title_normalized": "epileptic seizures coma and eeg burst suppression from suicidal bupropion intoxication"
} | [
{
"companynumb": "DE-PRINSTON PHARMACEUTICAL INC.-2017PRN00235",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPROPION HYDROCHLORIDE"
},
... |
{
"abstract": "Crystalline nephropathy can occur following treatment with multiple therapeutic agents. We describe a human immunodeficiency virus (HIV)-infected patient treated for 2 years with combination antiretroviral therapy including atazanavir (ATV). Kidney biopsy revealed a crystalline nephropathy associated with diffuse chronic and granulomatous interstitial inflammation. Following the biopsy, treatment with ATV was discontinued and kidney function returned to pretreatment baseline levels. ATV, which has a well-established association with nephrolithiasis, is a rare but important cause of crystalline nephropathy. Recognition of this association and prompt withdrawal of the offending agent are critical to optimize outcomes.",
"affiliations": "Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY. Electronic address: ds3356@cumc.columbia.edu.;Department of Medicine, Trinitas Regional Medical Center, Seton Hall University School of Health & Medical Science, Elizabeth, NJ.;Department of Medicine, Trinitas Regional Medical Center, Seton Hall University School of Health & Medical Science, Elizabeth, NJ.;Department of Medicine, Trinitas Regional Medical Center, Seton Hall University School of Health & Medical Science, Elizabeth, NJ.;Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY.;Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY.",
"authors": "Santoriello|Dominick|D|;Al-Nabulsi|Majdi|M|;Reddy|Aravinda|A|;Salamera|Julius|J|;D'Agati|Vivette D|VD|;Markowitz|Glen S|GS|",
"chemical_list": "D017320:HIV Protease Inhibitors; D000069446:Atazanavir Sulfate",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2017.02.376",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "70(4)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Atazanavir (ATV); HIV; acute renal failure; combined antiretroviral therapy (cART); crystalline nephropathy; granulomatous interstitial inflammation; kidney biopsy; kidney function",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000069446:Atazanavir Sulfate; D003460:Crystallization; D017320:HIV Protease Inhibitors; D006801:Humans; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "576-580",
"pmc": null,
"pmid": "28579422",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atazanavir-Associated Crystalline Nephropathy.",
"title_normalized": "atazanavir associated crystalline nephropathy"
} | [
{
"companynumb": "US-MYLANLABS-2017M1072148",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EMTRICITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Elderly patients are more prone to encounter some adverse factors when they receive chemotherapy compared to younger patients. Addition of rituximab to a reduced dose (RD) of cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy might improve patient outcomes with an improved toxicity profile when provided to elderly patients with diffuse large B-cell lymphoma.\n\n\n\nA total of 53 patients aged ≥ 65 years with diffuse large B-cell lymphoma diagnosed between August 2012 and December 2014 were enrolled onto this study. RD-R-CHOP regimen consisted of rituximab at 375 mg/m2, cyclophosphamide at 600 mg/m2, doxorubicin at 30 mg/m2, and vincristine at 1 mg on day 1 of each cycle and 40 mg of prednisone on days 1 to 5. Patients received granulocyte colony-stimulating factor if they experienced grade 3/4 neutropenia or febrile neutropenia during any cycle.\n\n\n\nThe median follow-up duration was 18 months (range, 1-44 months). Complete response and overall response rates were 64.1% and 81.1%, respectively. Three-year event-free and overall survival rates were 45.7% ± 8.4% and 62.7% ± 8.1%, respectively. Grade 3/4 neutropenia occurred in 20 patients (37.7%), while febrile neutropenia occurred in 7 patients (20.7%).\n\n\n\nOutcomes of RD-R-CHOP chemotherapy were comparable to those of standard-dose R-CHOP or previous dose-adjusted R-CHOP chemotherapy. In the future, strategies such as tailored therapy based on geriatric assessment results are needed to determine the chemotherapeutic dosage.",
"affiliations": "Division of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.;Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.;Division of Hematology-Oncology, Keimyung University, School of Medicine, Keimyung University Hospital, Daegu, Republic of Korea.;Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea.;Department of internal medicine, Inje university college of medicine, Haeundae Paik hospital, Busan, Republic of Korea.;Department of Internal Medicine, Division of Hemato-Oncology, Inje University Busan Paik Hospital, Busan, Republic of Korea.;Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Hematology-Oncology, Kosin University Gospel Hospital, Busan, South Korea.;Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea.;Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea.;Division of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea. Electronic address: hojinja@hanmail.net.",
"authors": "Park|Sungwoo|S|;Jo|Jae-Cheol|JC|;Do|Young Rok|YR|;Yang|Deok-Hwan|DH|;Lim|Sung-Nam|SN|;Lee|Won-Sik|WS|;Kim|Won Seog|WS|;Lee|Ho Sup|HS|;Hong|Dae-Sik|DS|;Kim|Hyo Jung|HJ|;Shin|Ho-Jin|HJ|",
"chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2018.11.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "19(3)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Chemotherapeutic dosage; Lymphoproliferative disorders; Older patients; Prognostic factors; Toxicity",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011241:Prednisone; D000069283:Rituximab; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "149-156",
"pmc": null,
"pmid": "30581162",
"pubdate": "2019-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Multicenter Phase 2 Study of Reduced-Dose CHOP Chemotherapy Combined With Rituximab for Elderly Patients With Diffuse Large B-Cell Lymphoma.",
"title_normalized": "multicenter phase 2 study of reduced dose chop chemotherapy combined with rituximab for elderly patients with diffuse large b cell lymphoma"
} | [
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"companynumb": "KR-PFIZER INC-2018530496",
"fulfillexpeditecriteria": "1",
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"abstract": "The aetiology of dilated cardiomyopathy (DCM) is highly heterogeneous including genetic and/or acquired (infective, toxic, immune, endocrine, and nutritional) factors. The major part of acquired DCM in developed countries is caused by either viral or autoimmune myocarditis. It is believed that the activation of the T-lymphocyte cell system is the major pathomechanism underlying autoimmune myocarditis and inflammatory DCM (DCMi). However, in the hearts of a subset of patients, a significant number of CD20+ B-lymphocytes can be detected too. Limited information exists on the role of B-cell-dependent mechanisms in the progression of DCMi. Particularly CD20+ B-lymphocytes, which can be targeted by anti-CD20+ B-lymphocytes antibodies or inhibitors, might contribute to the pathogenesis of myocardial damage beyond antibody production.\nHere, we present a case series of six patients with subacute and chronic endomyocardial biopsy-proven CD20+ B-lymphocyte-associated DCMi, where symptomatic heart failure therapy, with or without combined immunosuppressive therapy with steroid-based treatment regime, was insufficient to improve cardiac function. Five patients improved clinically several weeks after a standard infusion protocol with rituximab, a chimeric monoclonal antibody against the pan-B-cell surface molecule CD20.\nOur case series shows that CD20+ B-lymphocyte persistence can play a pathophysiologic role in a subset of DCMi patients and highlights the potential of targeting CD20+ B cells in patients with prominent CD20+ B-lymphocyte persistence.",
"affiliations": "Department of Cardiology, Charité, University Medicine Berlin, Humboldt-Universität zu Berlin, Campus Virchow, Berlin, Germany.;Department of Cardiology, Charité, University Medicine Berlin, Humboldt-Universität zu Berlin, Campus Virchow, Berlin, Germany.;Department of Cardiology, Charité, University Medicine Berlin, Humboldt-Universität zu Berlin, Campus Virchow, Berlin, Germany.;Charité Research Organisation, Charité, University Medicine Berlin, Campus Mitte, Berlin, Germany.;Experimental Immunocardiology, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Augustenburger Platz 1, Berlin, Germany.;Experimental Immunocardiology, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Augustenburger Platz 1, Berlin, Germany.;Department of Cardiology, Charité, University Medicine Berlin, Humboldt-Universität zu Berlin, Campus Virchow, Berlin, Germany.;Department of Cardiology, Charité, University Medicine Berlin, Humboldt-Universität zu Berlin, Campus Virchow, Berlin, Germany.",
"authors": "Tschöpe|Carsten|C|;Van Linthout|Sophie|S|;Spillmann|Frank|F|;Posch|Maximilian G|MG|;Reinke|Petra|P|;Volk|Hans-Dieter|HD|;Elsanhoury|Ahmed|A|;Kühl|Uwe|U|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytz131",
"fulltext": "\n==== Front\nEur Heart J Case RepEur Heart J Case RepehjcrEuropean Heart Journal: Case Reports2514-2119Oxford University Press 10.1093/ehjcr/ytz131ytz131Case SeriesTargeting CD20+ B-lymphocytes in inflammatory dilated cardiomyopathy with rituximab improves clinical course: a case series Tschöpe Carsten 123Van Linthout Sophie 123Spillmann Frank 1Posch Maximilian G 4Reinke Petra 25Volk Hans-Dieter 26http://orcid.org/0000-0002-4864-7685Elsanhoury Ahmed 12Kühl Uwe 121 \nDepartment of Cardiology, Charité, University Medicine Berlin, Humboldt-Universität zu Berlin, Campus Virchow, Berlin, Germany2 \nExperimental Immunocardiology, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Augustenburger Platz 1, Berlin, Germany3 \nDZHK (German Center for Cardiovascular Research), Partner Site Berlin, Oudenarder Str. 16, Berlin, Germany4 \nCharité Research Organisation, Charité, University Medicine Berlin, Campus Mitte, Berlin, Germany5 \nCharité, University Medicine Berlin, Berlin Center for Advanced Therapies (BECAT), Campus Virchow, Berlin, Germany6 \nDepartment of Immunology, Charité, University Medicine Berlin, Institute of Medical Immunology, Campus Virchow, Berlin, GermanyDinov Borislav Handling EditorDaniel Georgia EditorNyolczas Noémi EditorCassar Mark Philip EditorGreen Peregrine EditorAhmed Elsanhoury and Uwe Kühl authors contributed equally to this work.\n\n Corresponding author. Tel: +49 30 450 553711, Fax: +49 30 450 7553712, Email: carsten.tschoepe@charite.de9 2019 31 7 2019 31 7 2019 3 3 ytz13112 3 2019 16 4 2019 05 7 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 \nThe aetiology of dilated cardiomyopathy (DCM) is highly heterogeneous including genetic and/or acquired (infective, toxic, immune, endocrine, and nutritional) factors. The major part of acquired DCM in developed countries is caused by either viral or autoimmune myocarditis. It is believed that the activation of the T-lymphocyte cell system is the major pathomechanism underlying autoimmune myocarditis and inflammatory DCM (DCMi). However, in the hearts of a subset of patients, a significant number of CD20+ B-lymphocytes can be detected too. Limited information exists on the role of B-cell-dependent mechanisms in the progression of DCMi. Particularly CD20+ B-lymphocytes, which can be targeted by anti-CD20+ B-lymphocytes antibodies or inhibitors, might contribute to the pathogenesis of myocardial damage beyond antibody production.\n\nCase summary \nHere, we present a case series of six patients with subacute and chronic endomyocardial biopsy-proven CD20+ B-lymphocyte-associated DCMi, where symptomatic heart failure therapy, with or without combined immunosuppressive therapy with steroid-based treatment regime, was insufficient to improve cardiac function. Five patients improved clinically several weeks after a standard infusion protocol with rituximab, a chimeric monoclonal antibody against the pan-B-cell surface molecule CD20.\n\nDiscussion \nOur case series shows that CD20+ B-lymphocyte persistence can play a pathophysiologic role in a subset of DCMi patients and highlights the potential of targeting CD20+ B cells in patients with prominent CD20+ B-lymphocyte persistence.\n\nInflammatory dilated cardiomyopathyCD20+B-lymphocytesRituximabCase reportBerlin-Brandenburg Center for Regenerative TherapiesGerman Federal Ministry of Education and Research0313911\n==== Body\nLearning points\n\nMeasurement of CD20+ B-lymphocytes should be included in the routine endomyocardial biopsies diagnostics.\n\nCD20+ B-lymphocyte persistence can be the reason for steroid-refractory inflammatory dilated cardiomyopathy.\n\nCD20+ B-lymphocyte persistence can be targeted by CD20 inhibitors or antibodies like rituximab.\n\n\n\n\n\n\n\nIntroduction\nThe major part of acquired dilated cardiomyopathy (DCM) in developed countries is caused by either viral or autoimmune myocarditis.1–3 About 30% of myocarditis cases, myocardial inflammation does not resolve but progresses into chronic inflammatory DCM (DCMi).4,5 Particularly in patients with histologically confirmed ongoing inflammation in the absence of viral persistence, an abnormal myocardial immune response with or without autoantibodies are prone to progress to DCMi.4,6 It is believed that the major pathomechanisms in immune myocarditis and DCMi involve the activation of the T-lymphocyte system (like CD4+, CD8+, CD3+ cells) and macrophages (like CD86+ cells), which can be targeted by immunosuppressive interventions including steroid-based treatment regimens.4,7,8 With respect to CD20+ B-lymphocytes, we analysed a panel of 156 endomyocardial biopsies (EMB) from DCMi patients and found that 52.6% displayed in addition to T lymphocytes a presence of more than seven CD20+ cells/mm2 (42% >10 cells/mm2). Immunohistochemical examinations of the EMB were carried out at the Institute of Cardiac Diagnostics and Therapies ‘IKDT’ according to a standard procedure.9 In a subset of DCMi patients, a prominent presence of CD20+ B-lymphocytes was detected (28.5% >20 cells/mm2) (Figure 1A). Importantly, CD20+ staining was independent from the antibody-producing CD138+ plasma cells (Figure 2). Our patient registry shows that prednisolone/azathioprine therapy was ineffective in circa 33% of EMB-proven DCMi patients despite having no underlying viral cause. Looking at CD20+ B-lymphocytes, 63% of the non-responders had persistently high counts (average 20.8 cells/mm2), the other 37% had low counts in the follow-up biopsies only (average 12.50 cells/mm2) (Figure 1B). Limited information exists on the role of B-cell-dependent mechanisms in the progression of DCMi. However, there is accumulating evidence demonstrating that CD20+ B-lymphocytes contribute to the pathogenesis of myocardial damage directly by their own secretome and by aggravating the T-cell system.10–14 Recently, B-lymphocytes were shown to aggravate myocardial inflammation via suppressing the anti-inflammatory M2 macrophages.15 Therefore, we hypothesized that CD20+ B-lymphocytes can contribute independently of the T-cell system to the course of DCMi and may belong to a subclass of DCMi’s, which could benefit from an intervention with rituximab (RTX), a chimeric monoclonal antibody against the pan-B-cell surface molecule CD20.\n\n\nFigure 1 Pie graph representations of CD20+ B-lymphocytes-association with inflammatory dilated cardiomyopathy. (A) The pie chart represents 82 patients (red) with endomyocardial biopsies CD20+ B-lymphocytes infiltrates (>7 cells/mm2) out of 156 inflammatory dilated cardiomyopathy patients. (B) The main pie chart represents 24 endomyocardial biopsies-proven inflammatory dilated cardiomyopathy patients who were treated with prednisolone/azathioprine for 6 months, 16 patients (blue) were responders and eight patients (yellow) were non-responders. The pie-of-pie represents the steroid non-responders of which five patients (dark red) showed high-persistent endomyocardial biopsies CD20+ B-lymphocyte infiltrates (average 20.8 cells/mm2), and three patients (orange) with newly identified low-grade CD20+ B-lymphocytes in the follow-up biopsies (average 12.50 cells/mm2).\n\nFigure 2 Representative pictures of CD20+ B-lymphocytes (A, C) and CD138+ plasma cells (B, D) infiltrates in paraffin-embedded endomyocardial biopsies of two patients with CD20+ myocarditis, indicating that the CD20 staining pattern differs from that from CD138 staining. Magnification x 200; CD 138: Anti-CD20: monoclonal mouse antibody, clone 8J662 (Fa. Biomol, Hamburg, Germany); Anti-CD138; clone B-A38 (Roche Diagnostics, Mannheim, Germany).\n\nCase series\nHere, we detail our experience with six patients who received RTX in a single patient use approach. Their characteristics are summarized in the Table 1. A standard protocol efficient to deplete B cells in approved indications, consisting of two administrations of 375 mg/m2 RTX (MabThera® Roche Pharma AG) and 150 mg cortisone (to prevent infusion-related reactions) in a 4-week interval, was applied in addition to standard heart failure therapy. No other immunosuppressive agents were administered throughout the RTX treatment period, aiming to exclusively target CD20+ lymphocytes. All administrations were safe and well tolerated in these six patients. No unexpected infusion-related reactions or other treatment-emergent adverse drug reactions including infections occurred.\n\nTable 1 Baseline and post-treatment characteristics of the patients\n\nPatient\t1\t2\t3\t4\t5\t6\t\nAge at diagnosis (years)\t56\t68\t76\t70\t73\t47\t\nSex\tFemale\tFemale\tMale\tMale\tFemale\tMale\t\nNYHA class at diagnosis\tIV\tIII–IV\tIII\tIV\tIII\tII\t\nNYHA class 8 weeks after treatment\tII\tI–II\tII\tIII\tII\tII\t\nLVEF at diagnosis (%)\t29\t45\t19\t14\t24\t22\t\nLVEF 4 weeks after treatment (%)\t46\t53\t31\t23\t37\t25\t\nLVEDD at diagnosis (mm)\t57\t55\t70\t76\t72\t74\t\nLVEDD after treatment (mm)\t47\t44\t64\t65\t60\t72\t\nCD20+ count in diagnostic biopsy (cells/mm2)\t20.25\t633\t11\t>7\t>7\t10\t\nCD20+ count in follow-up biopsy (cells/mm2)\tND\tND\t6.52\tND\tND\t17.5\t\nCD3+ count in diagnostic biopsy (cells/mm2)\t7.4\t638\t8.5\t10.2\t3.1\t23\t\nCD3+ count in follow-up biopsy (cells/mm2)\t2.8\t6.3\t6.2\t6\t6.8\t82\t\nMac-1 count in diagnostic biopsy (cells/mm2)\t43\t230\t38.4\t60.7\t30.8\t48.57\t\nMac-1 count in follow-up biopsy (cells/mm2)\t16.3\t30\t43.3\t21.1\t52\t120\t\nNT-proBNP at diagnosis (pg/mL)\t2544\t3316\t15 318\t1555\t7800\t1329\t\nNT-proBNP after treatment (pg/mL)\t1293\t362\t11 814\t2197\t4230\t789\t\nLVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; ND, not detectable (below technical detection limit); NT-proBNP, N-terminal pro-B-type natriuretic peptide.\n\nPatient 1\nPatient 1 was a 56-year-old woman with newly diagnosed heart failure due to DCMi [New York Heart Association (NYHA) IV]. Coronary heart disease had been excluded by coronary angiography. One month later, transthorathic echocardiography (TTE) and angiography showed a mildly dilated left ventricle [left ventricular (LV) end-diastolic diameter (LVEDD) 57 mm] with a significantly reduced systolic function [ejection fraction (EF) 29%]. Cardiac function improved slightly after initiation of symptomatic heart failure therapy including a cardiac resynchronization therapy (CRT) system. Endomyocardial biopsies analyses showed a persistence of a significant number of CD20+ B-lymphocytes infiltrates slightly elevated macrophages and normal CD3+ T-lymphocytes without signs of viral genomes. Upon first and second RTX administration, LV function improved to EF 46% and 52%, respectively. CD3+ T-lymphocytes and macrophages (Mac-1) declined from 7.4 to 2.8 cells/mm2 and 43 to 16.3 cells/mm2, respectively, while CD20+ B-lymphocytes had resolved completely. Eight months after treatment, LVEDD had changed from 57 to 47 mm and a repeated stress TTE showed a further rise in EF from EF 52% (basal) to 63% after dobutamine. All parameters remained stable during the follow-up period of 12 months. NYHA status improved to Class II.\n\nPatient 2\nPatient 2 was a 68-year-old woman who had been treated with a Hodgkin-directed chemotherapy 9 years ago. During the last 9 years, cardiac function was documented as normal and stable. Shortly after pneumonia, she presented with a rapid onset of heart failure symptoms and TTE showed impaired systolic function (EF 25%; LVEDD 55 mm; NYHA III–IV). Endomyocardial biopsies were obtained to differentiate a chemotherapy induced-DCM from an inflammatory-driven cardiomyopathy after exclusion of coronary heart disease. Endomyocardial biopsies analyses revealed a massive CD3+ T-lymphocytes (376 cells/mm2) and CD20+ B-lymphocytes (780 cells/mm2) virus-negative acute myocarditis. An immunosuppressive therapy with steroids (prednisolone: initial dose 60 mg/day tapered by 10 mg bi-weekly for 6 months) and azathioprine (150 mg/day) led to an increase of EF up to 45%, whereas N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels decreased from 6621 to 3316 pg/mL. Two months later, the patient decompensated again, despite optimal medical treatment. A follow-up EMB still showed a persistent CD3+ T-lymphocytes- and CD20+ B-lymphocyte-inflammation (CD3: 638 cells/mm2 and CD20: 633 cells/mm2). Upon RTX, the EF improved from 45% to 53%. A control EMB showed normal CD3+ T-lymphocytes (6.3 cells/mm2), no CD20 infiltrates and a significantly reduced NT-proBNP of 362 pg/mL, respectively. The patient stayed stable (EF 57%, NYHA I–II) and NT-proBNP levels were nearly normal (282 pg/mL) 1 year later.\n\nPatient 3\nPatient 3 was a 76-year-old male with a 5-year history of DCM. Several EMBs analyses in the past 2 years excluded a significant existence of CD3+ T-lymphocyte infiltrates and macrophages. CD20+ B-lymphocytes had not been evaluated at that time. LV function declined over time from 28% to 19% (Supplementary material online, Video SA). The LV was dilated (LVEDD 70 mm). The next EMB, taken after a second cardiac decompensation despite optimal medical treatment, showed slightly elevated CD3+ T-lymphocytes and significantly elevated CD20+ B-lymphocyte infiltrates (11 cells/mm2), therefore, we initiated RTX therapy. Transthorathic echocardiography, before the second RTX-administration, revealed no changes in LV diastolic diameter but an increase in left ventricular ejection fraction (LVEF) compared with baseline from 19% to 31%. Yet, TTE at 6 and 12 months post the second dose of RTX showed an improved LV function and a smaller left ventricle (EF 36%; LVEDD 64 mm) (Supplementary material online, Video SB).\n\nPatient 4\nPatient 4 was a 70-year-old male patient with a 5-year history of EMB-proven DCMi who reported increased dyspnoea at exertion, despite standard heart failure therapy. The EF was initially 14% and a 76 mm LVEDD was recorded. A repeated EMB analysis showed classical CD20+ B-lymphocytes infiltrates. Whereas a 4-week post first dose examination showed no basal echocardiographic changes, an improvement of EF from 15 to 23% accompanied with a change in LVEDD (65 mm) was found at 6 months after the second RTX administration.\n\nPatient 5\nPatient 5 was a 73-year-old woman with a 4-year history of DCM. Initially, the EF was about 14%. Neither macrophages, T-lymphocytes, nor a significant persistence of cardiotropic viruses were detected in the first EMB. No specific treatment options could be offered. At that time, no investigation for CD20+ B-lymphocytes had been established. The EF improved up to 24% according to standard heart failure therapy, which included a CRT system. Over the years, she suffered more and more from heart failure symptoms, accompanied by a rise in NT-proBNP levels and a reduction in 6 min walking distance. The EF and LVEDD remained unchanged, but LV contractility reserve started to decline as documented by a stress TTE examination. Re-evaluation of her former taken EMBs showed a significant infiltration of CD20 B-lymphocytes, which were confirmed in a repeat EMB. At that time, RTX was initiated. We found a very rapid improvement of EF already after the first RTX infusion. A follow-up TTE prior to the second RTX administration showed a significantly smaller left ventricle (LVEDD: 72–60 mm) with an increased EF up to 37%, compared to baseline 4 weeks after treatment initiation. After the second dose administration, echocardiographic parameters remained stable. Without changes of the symptomatic heart failure therapy, NT-proBNP values decreased from 7800 to 4230 pg/mL, whereas NYHA functional class improved from III to II and the 6-min-walk test showed an improvement from 350 to 420 m.\n\nPatient 6\nPatient 6 was a 47-year-old man who suffered from a mild borderline myocarditis (EF 53%, LVEDD 63 mm) which had resolved spontaneously as documented by two follow-up biopsies 4 and 8 months after baseline EMB. LVEF remained mildly reduced (EF 49%, LVEDD 59 mm). An anti-inflammatory treatment and further biopsies were declined by the patient. Five years later, the patient presented with significant worsening of his cardiac function (EF 22%, LVEDD 72 mm) despite only mild heart failure symptoms (NYHA II). Endomyocardial biopsies revealed a pronounced virus-negative myocardial inflammation with elevated CD3 (107 cells/mm2) and CD20+ B-lymphocytes (9.2 cells/mm2). Upon a 6 months treatment with prednisolone and azathioprine systolic LV function did not improve (EF 22%, LVEDD 74 mm). CD3-positive-lymphocytes decreased moderately (23 cells/mm2), while CD20+ B cells remained unchanged (10 cells/mm2). Since B cells often decline when T cells are reduced spontaneously or upon treatment, we suggested a CD20+ B-lymphocyte-driven myocarditis and started a RTX intervention. The control EMB 4 months after treatment revealed a more focally clustered persistent inflammatory cardiomyopathy with increased T-lymphocytes (82 cells/mm2) and CD20+ B-lymphocytes (17.5 cells/mm2). Myocardial function remained severely restricted (EF 25%, LVEDD 72 mm).\n\nEndomyocardial biopsies material from Patients 1 and 2 further allowed extra experimental insights. RTX treatment led to a reduction in cardiac inflammation as seen by a drop in the EMB mRNA expression of adhesion molecules (VCAM-1 and ICAM-1) as well as of the proinflammatory cytokines TNF-α and IL-18. Furthermore, in Patient 1, RTX led to a reduction in the activation of the innate immunity, which follows from the 3.0-, 6.5-, 5.8-, 5.6-, 6.3-, and 22-fold reduction in the mRNA expression of triggers and components of the NLRP3 inflammasome NOD-2, S100A9, S100A8, NLRP3, caspase 1, and IL1β, respectively. Similar observations were seen in Patient 2.\n\nDiscussion\nOur case series describe for the first time the existence of a specific CD20+ B-lymphocyte-driven DCMi, which can profit from RTX. Recent experimental data foster the important role of B cells in myocardial remodelling.11,13,14,16 However, although CD20+ and CD138+ cells differed in their staining pattern, the reduction of CD20+ B-lymphocytes may indirectly limit the production of anti-myocardial antibodies and B-cell-mediated T-cell activation in the myocardium.11 Yet, the underlying mechanisms remain to be fully elucidated. It should be emphasized that individual outcomes are not representative, yet the pharmacodynamics of RTX in DCMi patients remains to be shown in a controlled clinical trial.\n\nPatient 1 and 2 experienced the most distinct improvement as seen in TTE accompanied by an improvement in haemodynamic parameters. Patient 1 was the youngest subject who received RTX and had a short medical history of heart failure. Both factors may have contributed to this favourable outcome. However, a spontaneous self-healing mechanism cannot be completely excluded in this case.5 Patient 2, who initially showed massive CD3+ and CD20+ lymphocyte infiltrates and did not respond after immunosuppressive therapy with steroids and azathioprine, healed after RTX. Nevertheless, the cases 3–5 showed a disease onset, years before RTX initiation. A spontaneous healing mechanism can be excluded, especially since we found a very fast long-acting improvement of cardiac function shortly after initiation of RTX intervention. RTX administrations favourably influenced the course of the disease as shown by angiography, TTE, and haemodynamics, except for Patient 6, which we cannot explain and probably just indicate that also under RTX non-responder exists.\n\nIn conclusion, patients with prominent CD20+ B-lymphocytes persistence can profit from RTX. In addition, we generally recommend to include the evaluation of CD20+ B-lymphocyte presence into the routine EMB diagnostics.\n\nLead author biography\nUniv. Prof. Dr. med. Carsten Tschöpe is the vise director of the Department of Cardiology, Charité, CVK and chair of the cardiology platform - Berlin Institute of Health Center for Regenerative Therapies. He is a Professor of medicine and cardiology. The main research areas of Prof. Tschöpe include inflammatory cardiomyopathy, immunocardiology and heart failure with preserved ejection fraction.\n\nSupplementary Material\nytz131_Supplementary_Data Click here for additional data file.\n\n Acknowledgements\nWe thank Monika Willner, Kerstin Puhl, and Marzena Sosnowski for excellent technical assistance. We are thankful to the members and co-workers of the ‘Institut Kardiale Diagnostik und Therapie’ (IKDT, CEO: Prof Heinz—Peter Schultheiss), who did the biopsy routine analysing.\n\nFunding\nThis work was supported by the Berlin-Brandenburg Center for Regenerative Therapies – (BCRT) sponsored by the German Federal Ministry of Education and Research (BMBF; 0313911) to C.T.\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. All patients have signed an informed consent according to the local ethics committee (application no. EA2/140/16).\n\n\nConflict of interest: An application patent has been filed for a CD20/CD19/CD21-directed therapy in DCMi (Europe: 10713861.2; USA: 13/264.090; registered applicant: Charité). All authors confirm that there is no conflict of interest to be declared.\n==== Refs\nReferences\n1 \nCharron P , Elliott PM , Gimeno JR , Caforio ALP , Kaski JP , Tavazzi L. \nThe Cardiomyopathy Registry of the EURObservational Research Programme of the European Society of Cardiology: baseline data and contemporary management of adult patients with cardiomyopathies . Eur Heart J 2018 ;39 :1784 –1793 .29378019 \n2 \nTrachtenberg BH , Hare JM. \nInflammatory cardiomyopathic syndromes . Circ Res 2017 ;121 :803 –818 .28912184 \n3 \nSeferovic PM , Polovina M , Bauersachs J , Arad M , Gal TB , Lund LH. \nHeart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology . Eur J Heart Fail 2019 ;21 :553 –576 .30989768 \n4 \nCaforio AL , Pankuweit S , Arbustini E , Basso C , Gimeno-Blanes J , Felix SB , Fu M , Heliö T , Heymans S , Jahns R , Klingel K , Linhart A , Maisch B , McKenna W , Mogensen J , Pinto YM , Ristic A , Schultheiss HP , Seggewiss H , Tavazzi L , Thiene G , Yilmaz A , Charron P , Elliott PM \nCurrent state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases . Eur Heart J 2013 ;34 :2636 –2648 , 2648a–2648d.23824828 \n5 \nD'Ambrosio A , Patti G , Manzoli A , Sinagra G , Di Lenarda A , Silvestri F , Di Sciascio G \nThe fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: a review . Heart 2001 ;85 :499 –504 .11302994 \n6 \nVan Linthout S , Tschöpe C. \nInflammation—cause or consequence of heart failure or both? \nCurr Heart Fail Rep \n2017 ;14 :251 –265 .28667492 \n7 \nDominguez F , Kühl U , Pieske B , Garcia-Pavia P , Tschöpe C. \nUpdate on myocarditis and inflammatory cardiomyopathy: reemergence of endomyocardial biopsy . Rev Esp Cardiol (Engl Ed) 2016 ;69 :178 –187 .26795929 \n8 \nMerken J , Hazebroek M , Van Paassen P , Verdonschot J , Van Empel V , Knackstedt C , Abdul Hamid M , Seiler M , Kolb J , Hoermann P , Ensinger C , Brunner-La Rocca H-P , Poelzl G , Heymans S. \nImmunosuppressive therapy improves both short- and long-term prognosis in patients with virus-negative nonfulminant inflammatory cardiomyopathy . Circ Heart Fail 2018 ;11 :e004228. 29449368 \n9 \nLeone O , Veinot JP , Angelini A , Baandrup UT , Basso C , Berry G , Bruneval P , Burke M , Butany J , Calabrese F , d'Amati G , Edwards WD , Fallon JT , Fishbein MC , Gallagher PJ , Halushka MK , McManus B , Pucci A , Rodriguez ER , Saffitz JE , Sheppard MN , Steenbergen C , Stone JR , Tan C , Thiene G , van der Wal AC , Winters GL. \n2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology . Cardiovasc Pathol 2012 ;21 :245 –274 .22137237 \n10 \nCordero-Reyes AM , Youker KA , Torre-Amione G. \nThe role of B-cells in heart failure . Methodist DeBakey Cardiovasc J 2013 ;9 :15 –19 .23519014 \n11 \nCordero-Reyes AM , Youker KA , Trevino AR , Celis R , Hamilton DJ , Flores-Arredondo JH. \nFull expression of cardiomyopathy is partly dependent on B-cells: a pathway that involves cytokine activation, immunoglobulin deposition, and activation of apoptosis . J Am Heart Assoc 2016 ;5 .\n12 \nWeber MS , Prod'homme T , Patarroyo JC , Molnarfi N , Karnezis T , Lehmann-Horn K , Danilenko DM , Eastham-Anderson J , Slavin AJ , Linington C , Bernard CCA , Martin F , Zamvil SS. \nB-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity . Ann Neurol 2010 ;68 :369 –383 .20641064 \n13 \nYu M , Wen S , Wang M , Liang W , Li H-H , Long Q , Guo H-P , Liao Y-H , Yuan J. \nTNF-alpha-secreting B cells contribute to myocardial fibrosis in dilated cardiomyopathy . J Clin Immunol 2013 ;33 :1002 –1008 .23558825 \n14 \nZouggari Y , Ait-Oufella H , Bonnin P , Simon T , Sage AP , Guérin C , Vilar J , Caligiuri G , Tsiantoulas D , Laurans L , Dumeau E , Kotti S , Bruneval P , Charo IF , Binder CJ , Danchin N , Tedgui A , Tedder TF , Silvestre J-S , Mallat Z. \nB lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction . Nat Med 2013 ;19 :1273 –1280 .24037091 \n15 \nLi Y , Huang Y , Wu W , Wei B , Qin L. \nB cells increase myocardial inflammation by suppressing M2 macrophage polarization in coxsackie virus B3-induced acute myocarditis . Inflammation 2019 ;42 :953. 30604194 \n16 \nMatsumoto Y , Park IK , Kohyama K. \nB-cell epitope spreading is a critical step for the switch from C-protein-induced myocarditis to dilated cardiomyopathy . Am J Pathol 2007 ;170 :43 –51 .17200181\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "3(3)",
"journal": "European heart journal. Case reports",
"keywords": "B-lymphocytes; CD20+; Case report; Inflammatory dilated cardiomyopathy; Rituximab",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31365055",
"pubdate": "2019-09-01",
"publication_types": "D016428:Journal Article",
"references": "20641064;11302994;26769625;30604194;26795929;28667492;30989768;22137237;24037091;29449368;29378019;23558825;28912184;23519014;17200181;23824828",
"title": "Targeting CD20+ B-lymphocytes in inflammatory dilated cardiomyopathy with rituximab improves clinical course: a case series.",
"title_normalized": "targeting cd20 b lymphocytes in inflammatory dilated cardiomyopathy with rituximab improves clinical course a case series"
} | [
{
"companynumb": "DE-MYLANLABS-2019M1132846",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Sixteen patients with advanced hematologic malignancies were transplanted with HLA-identical allogeneic peripheral blood stem cells (PBSCs) that were selected for CD34+ cells by an avidin-biotin immunoadsorption technique. The median age of patients was 48 years (range, 37 to 67). Patients received 12.0 or 13.2 Gy of total body irradiation followed by 120 mg/kg of cyclophosphamide. Normal donors received 16 mg/kg of granulocyte-colony stimulating factor on days 1 to 6 followed by PBSC harvests on days 4 to 7. PBSC harvests were processed each day on a single avidin-blotin column containing an antibody to the CD34 antigen and processed cells were infused without cryopreservation daily for 4 consecutive days. Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine alone for 5 patients and CSA plus methotrexate for 11 patients. A median of 18.64 (6.74 to 34.97) x 10(8) CD34+ cells/kg patient body weight were collected from each donor. A median of 8.96 (2.62 to 17.34) x 10(8) CD34+ cells/kg patient body weight were recovered after avidin-biotin adsorption which represented a median CD34+ cell yield of 53% (18% to 77%) with a median purity of 62% (34% to 82%). There was a reduction in CD3+ cells from a median of 557.26 (227.73 to 677.77) x 106/kg to 0.73 x 10(4)/kg (0.40 to 3.65), in CD4+ cells from 351.72 (194.47 to 520.11) x 10(6)/kg to 0.40 (0.15 to 1.03) x 10(4)/kg and in CD8+ cells from 169.74 (53.34 to 325.83) x 10(6)/ kg to 0.32 (0.12 to 2.71) x 10(4)/kg representing a median 2.8 (2.19 to 3.14) log reduction in T cells. One patient died of infection on day 3 posttransplant and was unevaluable for recovery of neutrophils. The median day to recovery of 500 neutrophils/mL was 15 (8 to 26) in the remaining 15 patients. Six of 16 patients falled to achieve a platelet count of 20,000/mL before death on days 3 to 97 of transplant-related complications. The median day to achieving platelets of 20,000 mL in the remaining 10 patients was 11 (7 to 31). Eight of 16 patients (50%) died between 3 and 97 days posttransplant, 7 of transplant-related causes, and 1 of progressive disease. Grade 2-4 acute GVHD occurred in 12 out of 14 (86%) and grades 3-4 in 6 out of 14 (43%) evaluable patients. Six of 8 evaluable patients developed clinical chronic GVHD and 1 developed subclinical chronic GVHD. Bone marrow and/or peripheral blood chimerism studies in 12 evaluable patients showed 97% to 100% donor type in 11 patients with 1 patient in relapse showing 40% donor cells 60 to 90 days posttransplant. Four of 16 patients (25%) are alive and disease-free 312 to 576 days after transplant. There were no episodes of graft failure or rejection. This study shows that allogeneic transplantation using CD34+ selected PBSC results in prompt and sustained engraftment. CD34+ selection, as employed in this preliminary study, however, resulted in an apparently higher rate of acute and chronic GVHD. However, The sample size is quite small and precludes a more definitive conclusion regarding GVHD.",
"affiliations": "Fred Hutchinson Cancer Research Center, Seattle, WA, USA.",
"authors": "Bensinger|W I|WI|;Buckner|C D|CD|;Shannon-Dorcy|K|K|;Rowley|S|S|;Appelbaum|F R|FR|;Benyunes|M|M|;Clift|R|R|;Martin|P|P|;Demirer|T|T|;Storb|R|R|;Lee|M|M|;Schiller|G|G|",
"chemical_list": "D018952:Antigens, CD34; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003520:Cyclophosphamide; D011241:Prednisone; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "88(11)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D001773:Blood Cells; D002452:Cell Count; D002469:Cell Separation; D003520:Cyclophosphamide; D016572:Cyclosporine; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007163:Immunosorbent Techniques; D007166:Immunosuppressive Agents; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011241:Prednisone; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014916:Whole-Body Irradiation",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "4132-8",
"pmc": null,
"pmid": "8943847",
"pubdate": "1996-12-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy.",
"title_normalized": "transplantation of allogeneic cd34 peripheral blood stem cells in patients with advanced hematologic malignancy"
} | [
{
"companynumb": "US-AMGEN-USASP2020132150",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "A 71-year-old female was diagnosed with localized renal cell carcinoma in July 2008 with subsequent metastasis in 2012 to the right adrenal gland, lungs, and brain. Due to disease progression, she was started on pazopanib 800 mg daily in October 2012. In November 2016, the patient developed an ill-defined, red, 10 × 15 cm indurated plaque on the left lateral upper thigh with a discrete 3 cm firm tender tumor without ulceration. An incisional biopsy was performed and showed panniculitis with features resembling sclerosing lipogranuloma. Alternative causes including rheumatologic disease and trauma were ruled out. We report the first case of pazopanib-induced panniculitis. Key clinical and histopathological features include tender subcutaneous nodules, exclusion of other causes, and fatty microcysts within a densely sclerotic background on pathology. As targeted therapies are becoming increasingly common in the field of oncology, prompt identification and reporting of adverse reactions is critical for proper management.",
"affiliations": "Divisions of Internal Medicine.;Oncology.;Dermatology.;Dermatopathology, Mayo Clinic Scottsdale, Arizona, USA.;Dermatology.",
"authors": "Nafissi|Nellie N|NN|;Karlin|Nina|N|;Pittelkow|Mark R|MR|;Dicaudo|David J|DJ|;Mangold|Aaron R|AR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000999",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "32(4)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": null,
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "474-475",
"pmc": null,
"pmid": "33290313",
"pubdate": "2021-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Panniculitis in a patient with metastatic renal cell carcinoma on a tyrosine kinase inhibitor.",
"title_normalized": "panniculitis in a patient with metastatic renal cell carcinoma on a tyrosine kinase inhibitor"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2021US297541",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAZOPANIB"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo explore the possibility of choriocarcinoma syndrome developing as a potentially fatal complication in patients with this pathology.\n\n\nMETHODS\nChoriocarcinoma syndrome consists of hemorrhagic manifestations of metastases in advanced germ cell cancer containing large elements of choriocarcinoma. It should be suspected in patients with high tumor mass, multiple metastases and elevated tumor markers characteristic of germ cell tumors. It usually occurs before and during the onset of systemic treatment with chemotherapy. Failure to diagnose it can lead to fatal consequences and may require aggressive diagnostic and therapeutic measures such as surgery. It can also be prevented by developing a good therapeutic strategy that includes an interdisciplinary team, raising the possibility of deferring testicular surgery and beginning chemotherapy beforehand.\n\n\nRESULTS\nWe report two cases of men with the diagnosis of choriocarcinoma syndrome on liver metastases. We provide ultrasound and CT images of the two cases of hemorrhage on liver metastases and radiological characteristics peculiar to each case that have never been published before.\n\n\nCONCLUSIONS\nThere should be a high index of suspicion of life-threatening complications in patients with germ cell tumors with a choriocarcinoma component, including the development of life-threatening choriocarcinoma syndrome.",
"affiliations": "Urology Department y Unidad de Enfermería. Hospital de Jerez de la Frontera. Cádiz. Spain.",
"authors": "Medina|Ana|A|;Ramos|Manuel|M|;Amenedo|Margarita|M|;París|Lorena|L|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-0614",
"issue": "67(8)",
"journal": "Archivos espanoles de urologia",
"keywords": null,
"medline_ta": "Arch Esp Urol",
"mesh_terms": "D002822:Choriocarcinoma; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D011247:Pregnancy; D013577:Syndrome",
"nlm_unique_id": "0064757",
"other_id": null,
"pages": "711-4",
"pmc": null,
"pmid": "25306991",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Choriocarcinoma syndrome.",
"title_normalized": "choriocarcinoma syndrome"
} | [
{
"companynumb": "US-ACCORD-065453",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
"druga... |
{
"abstract": "To assess prospectively luteinized unruptured follicle (LUF) syndrome in juvenile idiopathic arthritis (JIA) patients with and without non-steroidal anti-inflammatory drugs (NSAIDs) and healthy controls. Twenty-three adolescent and young adult female JIA patients (ILAR criteria) and 11 female healthy subjects were studied by pelvic ultrasound monitoring for follicular development and ovulation in one menstrual cycle. LUF syndrome was prospectively investigated by pelvic ultrasound with a dominant ovarian follicle without signs of follicular rupture, with elevation of serum progesterone in the luteal phase of the menstrual cycle and luteinizing hormone (LH) detected in the urine. Comparison between JIA patients with (n = 8) vs. without NSAIDs (n = 15) and healthy controls (n = 11) revealed that LUF syndrome was significantly higher in the former group (2 (25%) vs. 0% vs. 0%, p = 0.049). These two patients with LUF syndrome had normal menstrual cycles without reduced ovarian reserve, and they were under naproxen 500 mg bid during the menstrual cycle. Disease duration was comparable in JIA with and without NSAIDs [19.8 (4.4-25) vs. 13 (3.1-33) years, p = 0.232]. Further comparison between JIA patients with and without NSAIDs and healthy controls showed similar mean anti-Müllerian hormone levels (p = 0.909), estradiol (p = 0.436), FSH (p = 0.662), LH (p = 0.686), and mean antral follicle count (p = 0.240) and ovarian volume (p = 0.363). No differences were evidenced in three groups regarding Caucasian race, body mass index, duration, and length of menstrual cycles (p > 0.05). This is the first study to identify that JIA patients have a high frequency of LUF without impaired ovarian reserve. Future prospective studies are necessary to determine if chronic/continuous use of NSAIDs in JIA will have an impact in these patients' fertility.",
"affiliations": "Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP, 05403-000, Brazil.;Pediatric Rheumatology Unit, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.;Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP, 05403-000, Brazil.;Division of Gynecology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.;Division of Gynecology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.;Pediatric Rheumatology Unit, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.;Pediatric Rheumatology Unit, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.;Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP, 05403-000, Brazil.;Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP, 05403-000, Brazil.;Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP, 05403-000, Brazil. clovisaasilva@gmail.com.",
"authors": "Tomioka|Renato B|RB|;Ferreira|Gabriela R V|GRV|;Aikawa|Nadia E|NE|;Maciel|Gustavo A R|GAR|;Serafini|Paulo C|PC|;Sallum|Adriana M|AM|;Campos|Lucia M A|LMA|;Goldestein-Schainberg|Claudia|C|;Bonfá|Eloisa|E|;Silva|Clovis A|CA|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-018-4208-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "37(10)",
"journal": "Clinical rheumatology",
"keywords": "Fertility; Juvenile idiopathic arthritis; Luteinized unruptured follicle syndrome; Non-steroidal anti-inflammatory drugs",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001171:Arthritis, Juvenile; D005260:Female; D006801:Humans; D010049:Ovarian Diseases; D006080:Ovarian Follicle; D014463:Ultrasonography; D055815:Young Adult",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "2869-2873",
"pmc": null,
"pmid": "30003441",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "24909636;8646437;24881927;10952743;20799266;19074167;17239869;24418305;19136673;8624628;16855077;15705365;14760812;12195782;3817171;24878927;17711894;20598224;21618455;27586847",
"title": "Non-steroidal anti-inflammatory drug induces luteinized unruptured follicle syndrome in young female juvenile idiopathic arthritis patients.",
"title_normalized": "non steroidal anti inflammatory drug induces luteinized unruptured follicle syndrome in young female juvenile idiopathic arthritis patients"
} | [
{
"companynumb": "BR-BION-007327",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
"druga... |
{
"abstract": "METHODS\nA 85-year-old patient, initially treated for aspiration pneumonia on the intensive care unit acutely complained again of nausea which was immediately treated by an i. v. bolus of metoclopramide (MCP). Without another incident of aspiration she subsequently developed acutely massive dyspnoea, increasing cyanosis and somnolence.\n\n\nMETHODS\nOn physical exam the patient showed tachycardia, dyspnoea and progressive somnolence. Laboratory investigation showed no significant abnormalities other than improving inflammatory markers. Computer tomography of the chest as well as bronchoscopy also revealed no pathologies. Blood gas analysis (BGA) however showed a massive increase in methemoglobinemia from 0.5 % just prior to MCP injection to 53.1 % after MCP injection; simultaneously the pO2 decreased from 74 auf 54 mmHg and the pCO2 from 37.7 to 34.1 mmHg.\n\n\nMETHODS\nInstant therapy with toluidine blue led to a dramatic improvement of the patient's symptoms as well as a rapid normalisation of the pathological BGA. Soon after the patient could be dismissed.\n\n\nCONCLUSIONS\nThe development of a severe and acute methemoglobinemia following the administration of MCP is described in this case report. Rapidly evolving dyspnoea following administration of MCP should instantly lead to the consideration of acute methemoglobinemia as differential diagnosis. Rapid diagnosis by blood gas analysis and instant therapy by toloudine blue (TB) can effectively prevent a potentially lethal course. The pathogenesis, clinical presentation, diagnosis and therapy for methemoglobinemia are discussed.",
"affiliations": "Medizinische Klinik, Evangelisches Krankenhaus Bethesda, Mönchengladbach. grossmann@bethesda-mg.de",
"authors": "Grossmann|J|J|;Neuwald|S|S|;Wiese|B|B|",
"chemical_list": "D000932:Antiemetics; D014048:Tolonium Chloride; D008787:Metoclopramide",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0031-1299072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "50(6)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D000369:Aged, 80 and over; D000932:Antiemetics; D005260:Female; D006801:Humans; D008708:Methemoglobinemia; D008787:Metoclopramide; D009325:Nausea; D012128:Respiratory Distress Syndrome; D014048:Tolonium Chloride; D016896:Treatment Outcome",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "585-8",
"pmc": null,
"pmid": "22660993",
"pubdate": "2012-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute respiratory failure after metoclopramide for methemoglobinemia - a rare and potentially life-threatening side effect.",
"title_normalized": "acute respiratory failure after metoclopramide for methemoglobinemia a rare and potentially life threatening side effect"
} | [
{
"companynumb": "DE-VISTAPHARM, INC.-VER201709-000551",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugadditional... |
{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome can have insidious symptoms which may lead to acute liver failure and death. Prompt recognition, stopping offending drug, and initiating corticosteroid are the mainstay of treatment. Early involvement of a specialist liver unit is vital.",
"affiliations": "Liver Intensive Therapy Unit (LITU) King's College Hospital London UK.;Liver Intensive Therapy Unit (LITU) King's College Hospital London UK.;Department of Dermatology King's College Hospital London UK.;Department of Histopathology King's College Hospital London UK.;Liver Histopathology Laboratory King's College Hospital London UK.;Department of Dermatology King's College Hospital London UK.;Liver Intensive Therapy Unit (LITU) King's College Hospital London UK.",
"authors": "Subhani|Mohsan|M|https://orcid.org/0000-0001-8739-7263;Dong|Victor|V|https://orcid.org/0000-0002-6875-3768;Connolly|Aveen|A|https://orcid.org/0000-0002-3470-7405;Salisbury|Jonathan|J|https://orcid.org/0000-0002-5889-4276;Miquel|Rosa|R|https://orcid.org/0000-0001-7414-0186;Walsh|Sarah|S|https://orcid.org/0000-0001-7251-9547;Pirani|Tasneem|T|https://orcid.org/0000-0001-7357-7634",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3218",
"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/ccr3.3218\nCCR33218\nCase Report\nCase Reports\nTrimethoprim‐induced drug reaction with eosinophilia and systemic symptoms (DRESS) associated with reactivation of human herpes virus‐6 (HHV‐6) leading to acute liver failure\nSUBHANI et al.Subhani Mohsan https://orcid.org/0000-0001-8739-7263\n1\n\n2\nMohsan.subhani@nottingham.ac.uk Dong Victor https://orcid.org/0000-0002-6875-3768\n1\n Connolly Aveen https://orcid.org/0000-0002-3470-7405\n3\n Salisbury Jonathan https://orcid.org/0000-0002-5889-4276\n4\n Miquel Rosa https://orcid.org/0000-0001-7414-0186\n5\n Walsh Sarah https://orcid.org/0000-0001-7251-9547\n3\n Pirani Tasneem https://orcid.org/0000-0001-7357-7634\n1\n \n1 \nLiver Intensive Therapy Unit (LITU)\nKing's College Hospital\nLondon\nUK\n\n\n2 \nUniversity of Nottingham\nNottingham\nUK\n\n\n3 \nDepartment of Dermatology\nKing's College Hospital\nLondon\nUK\n\n\n4 \nDepartment of Histopathology\nKing's College Hospital\nLondon\nUK\n\n\n5 \nLiver Histopathology Laboratory\nKing's College Hospital\nLondon\nUK\n\n* Correspondence\n\nMohsan Subhani, Liver Intensive Therapy Unit (LITU), King's College Hospital, London SE5 9RS, UK.\n\nEmail: Mohsan.subhani@nottingham.ac.uk\n\n09 8 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.122568 2573\n28 5 2020 09 7 2020 10 7 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/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome can have insidious symptoms which may lead to acute liver failure and death. Prompt recognition, stopping offending drug, and initiating corticosteroid are the mainstay of treatment. Early involvement of a specialist liver unit is vital.\n\nDrug reaction with eosinophilia and systemic symptoms (DRESS) syndrome can have insidious symptoms which may lead to acute liver failure and death. Prompt recognition, stopping offending drug, and initiating corticosteroid are the mainstay of treatment. Early involvement of a specialist liver unit is vital.\n\n\nacute liver failuredrug reaction with eosinophilia and systemic symptomsdrug‐induced liver injuryhuman herpes virus‐6jaundiceliver transplant source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nSubhani \nM \n, \nDong \nV \n, \nConnolly \nA \n, et al. Trimethoprim‐induced drug reaction with eosinophilia and systemic symptoms (DRESS) associated with reactivation of human herpes virus‐6 (HHV‐6) leading to acute liver failure\n. Clin Case Rep . 2020 ;8 :2568 –2573\n. 10.1002/ccr3.3218\n==== Body\n1 INTRODUCTION\nWe present a case of acute liver failure requiring emergency liver transplant due to trimethoprim‐induced drug reaction with eosinophilia and systemic symptoms (DRESS) and associated reactivation of human herpesvirus 6. The case highlights the importance of early recognition, stopping offending drug, and initiating corticosteroids to prevent the poor outcome.\n\nDrug reaction with eosinophilia and systemic symptoms (DRESS) is a poorly recognized syndrome, which can lead to significant cutaneous, hematologic, and solid organ dysfunction. It may present with an insidious and nonspecific feature, leading to a delay in diagnosis. As this case illustrated, failure to recognize the condition in its earliest stages, stop the culprit drug, and initiate corticosteroid treatment may lead to a dramatically poor outcome for the patient. Our case outlines the clinical features of DRESS presenting to a physician, which can easily be mistaken for a viral illness. It highlights the role of acute liver failure units and emergency liver transplantation in severe cases progressing to liver failure. It also adds to the limited reports in the literature of positive outcomes following rescue liver transplantation in the context of severe DRESS.\n\n2 CASE HISTORY AND EXAMINATION\nA 22‐year‐old Caucasian woman had a 3‐week history of fluctuating fatigue, pyrexia, malaise, sweats, and myalgia presented to a local hospital with worsening symptoms, jaundice, and a macular rash starting on hands and feet that spread to rest of body. A week prior to hospitalization she also experienced nausea, vomiting, and diarrhea. She developed a diffused macular rash, marked liver function derangement, and significant coagulopathy. A presumptive diagnosis of acute liver failure secondary to viral infection or lymphoma was made, and the patient was transferred to the regional liver transplant unit for further management. On further evaluation by the receiving critical care team, it was established that the primary care physician had commenced her on trimethoprim for acne 6 weeks before the onset of symptoms. She had subsequently felt unwell within days of taking the medication and had discontinued it 2 weeks later. She had a history of Gilbert syndrome and well‐controlled asthma. She was a 3rd‐year medical student with no history of alcohol misuse, smoking, illicit drug use, foreign travel or other risk factors for liver disease. Her family history was insignificant. On physical examination, she was icteric, had a widespread macular rash affecting the trunk and limbs with marked facial and ear swelling. She had diffused axillary, cervical, and inguinal lymphadenopathy and hepatosplenomegaly. No genital, mucosal, or eye involvement was observed, though the patient was noted to have mild cheilitis. Her vital signs were stable; she was apyrexial with no overt signs of hepatic encephalopathy.\n\n3 DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS AND MANAGEMENT\nDay 1 of admission: In the context of the patient's history and presentation, the differential diagnoses of acute viral hepatitis, drug‐induced liver injury (DILI), drug rash with eosinophilia and systemic symptoms (DRESS), and lymphoproliferative disorder were considered. The results of admission investigations are given in Table 1, the full acute liver injury workup (Table 1) was initiated, and supportive management commenced as per the unit's set protocol. Day 2‐4 of admission: On the second day of admission to intensive care, she developed grade‐4‐hepatic encephalopathy along with hypotension, worsening renal dysfunction, hyperammonemia, and hyperlactatemia. Endotracheal intubation and mechanical ventilation for airway protection were required. She was deeply sedated for neurological protection, and vasopressor support was commenced. High volume continuous venovenous hemodiafiltration (CVVHDF) was initiated for ammonia clearance. Computer tomography (CT) of the liver (Figure 1), liver biopsy (Figure 2), skin, and lymph node biopsy was performed, the patient RegiSCAR score was calculated 7 (Table 1), and a diagnosis of DRESS syndrome was confirmed after early specialist input from dermatology, hepatology, and hematology. Under dermatology guidance, she was commenced on methylprednisolone 250 mg once a day, and although pulsed steroid therapy led to rapid resolution of the rash and pyrexia, and dramatic improvement transaminitis, her synthetic liver functions, jaundice, hepatic encephalopathy and physiology further deteriorated. She met poor prognostic criteria for spontaneous recovery without emergency liver transplantation. On the third day of admission, she was listed for super urgent liver transplantation with no contraindications. Although human herpes virus‐6 (HHV‐6) serology is not a routine screening test for transplant workup, a plasma sample had been requested due to its recognized association with DRESS. The results confirmed reactivation with a high viral load of >500 000 copies/mL. Antiviral treatment with intravenous acyclovir 10 mg/kg (IV) and intravenous foscarnet 15 mg/kg three times a day was subsequently commenced. Day 5 of admission: She received an orthotopic liver transplant. The explanted liver displayed histological features (Figure 2) most compatible with drug‐induced liver injury, hepatocellular type, consistent with the proposed diagnosis. However, as we could not demonstrate the presence or absence of the virus within the liver and there are no specific histological features for HHV6 infection, definitive exclusion of this virus as a direct cause of the hepatocellular damage is not possible. Immediate postoperatively she received a single 1 g dose of methylprednisolone followed by standard renal sparing immunosuppression with Prograf (tacrolimus) 2 mg twice a day together with a modified higher dose of methylprednisolone at 60 mg once a day as ongoing treatment for DRESS. Antiviral treatment was continued for HHV‐6 viremia. Day 1‐4 postoperative: After a transient rise in AST on postoperative day 2, her liver enzymes improved consistently. Day 5 postoperative: She was extubated. Day 7 postoperative: All organ support including renal replacement therapy was discontinued by, and she was discharged to the post‐transplant ward for further recovery and was eventually discharged home. Follow‐up: She continues to attend the post‐transplant follow‐up clinic and remains under dermatology follow‐up for management of acne with alternative agents and long‐term monitoring of DRESS.\n\nTABLE 1 Laboratory investigation (non‐invasive acute liver failure screen)\n\nTest\tResult (Ref Range\na\n)\tTest\tResult (Ref Range\na\n)\t\nDay 1 admission investigation\t\nHemoglobin\t127 (120‐160 g/L)\tTotal bilirubin\t121 (3‐22 μmol/L)\t\nNeutrophil\t11.4 (2‐7.5 × 109/L)\tConjugated bilirubin\t84 (0‐5 μmol/L)\t\nTotal WCC\t14.6 (4‐11 × 109/L)\tALT\t4143 (1‐50 IU/L)\t\nEosinophil\t0.13 (0.1‐0.4 × 109/L)\tAST\t5895 (1‐45 IU/L)\t\nPlatelets\t106 (150‐400 × 109/L)\tALP\t246 (30‐130 IU/L)\t\nINR\t4.45 (0.9‐1.1)\tGGT\t140 (1‐54 IU/L)\t\nAmmonia (NH4)\t126 (11.2‐34.5 μmol/L)\tArterial PH\t7.40 (7.35‐7.45)\t\nLDH\t2718 (<250 U/L)\tRandom glucose\t5.2 (<11.1 mmol/L)\t\nSerum Na\t134 (135‐145 mmol/L)\tHCO3\t19.2 (22‐29 mmol/L)\t\nUrea\t12.5 (2.9‐8.2 mmol/L)\tLactate\t8.2 (<2 mmol/L)\t\nSerum creatinine\t129 (50‐110 μmol/L)\t\t\t\nPeripheral blood film\tAtypical lymphocytes\nb\n, toxic granulation and left shift of neutrophils\t\t\t\nDay 2 investigations\t\nSkin biopsy\tLymph node and bone marrow biopsy\tLiver Biopsy (Figure 2)\t\nCT AP (Figure 1)\tEchocardiogram = normal\t\t\nInvestigations sent on day 1, results were available on days 2 and 3\t\t\t\t\nVirology/microbiology panel\t\t\t\t\nHepatitis A\tIgG positive\tMonospot\tNegative\t\nHepatitis E\tNegative\tHHV IgM & IgG\tNot done\t\nHepatitis BsAg & DNA\tNegative\tHHV‐6 DNA\t555 879 copies/mL\t\nHepatitis C Ab\tNegative\tHHV‐8 DNA\tNegative\t\nCMV\tIgG positive\tVZV\tIgG positive\t\nEBV\tIgG positive\tLeptospira\tNegative\t\nAdenovirus\tNegative\tToxoplasma\tNegative\t\nHIV\tNegative\tAtypical pneumonia\tNegative\t\nOther non‐invasive liver screens\t\nANA\tNegative\tIgG\t8.9 (6‐16 g/L)\t\nANCA\t1/320 speckled\tIgM\t2.85 (0.4‐2.5 g/L)\t\nDsDNA\tNegative\tIgA\t1.77 (0.8‐3 g/L)\t\nAnti‐GP Ab\tNegative\tHFE (H63D/C282Y)\tNegative\t\nAnti‐SM Ab\tNegative\tA1AT phenotype\tPIMM (normal)\t\nAnti‐LKM Ab\tNegative\tCeruloplasmin\t0.18 (0.2‐0.45 mg/dL)\t\nAnti‐mitochondrial Ab\tNegative\tFerritin\t28 898 (41‐400 μg/L)\t\nTSH\t0.19 (0.27‐4.2 mIU/L)\tBlood group\tO+ (positive)\n\t\nRegiSCAR score\t\n\nPatient RegiSCAR score = 7\n\n\nExtent of rash = 1, rash suggestive of drug reaction = 1, systemic features = 4 (eosinophilia, lymph nodes, solid organ involvement, and fever), relevant negative tests (eg, hepatitis A, B, C) = 1 (RegiSCAR classification for likelihood diagnosis of DRESS: possible case score = 2 to 3; probable case score = 4 to 5; definite case score = 6 to 7).\n\n\n\t\nAbbreviations: A1 AT, alpha 1 antitrypsin; Ab, antibody; Ag, antigen; ALT, alanine transaminase; ANA, antinuclear antibody; ANCA, antinuclear cytoplasmic antibody; anti‐LKM, anti–liver‐kidney microsomal antibody; anti‐sm, antismooth muscle antibody; AST, aspartate transaminase; CMV, cytomegalovirus; Ds DNA, double‐stranded DNA; EBV, Epstein‐Barr virus; GGT, gamma‐glutamyl transferase; HCO3, bicarbonate; HFE, gene for hereditary hemochromatosis; HHV, human herpes virus; Ig, immunoglobulin; INR, international normalized ratio; LDH, lactate dehydrogenase; Na, sodium; NH4, ammonia; TSH, thyroid‐stimulating hormone; WCC, white cell count.\n\na UK laboratory reference ranges for adult female.\n\nb Typical for DRESS.\n\nJohn Wiley & Sons, LtdFIGURE 1 CT Abdomen: Lymphadenopathy with marked hepatosplenomegaly\n\nFIGURE 2 Liver histology: Subacute liver failure secondary to submassive hepatocellular necrosis. Representative macroscopic and microscopic images: A, Representative macroscopic section of the explanted liver. The liver is collapsed (723 g) with a single small area of residual parenchyma (inset), cholestatic (marked with arrows). B, Low magnification microscopy of this area demonstrates centrilobular‐based hepatocellular loss with bridging hepatocyte loss and collapse (*), in contrast with the total absence of hepatocytes observed in most of the liver tissue. Hepatocyte specific antigen immunostaining highlights the map‐like appearance of the area, 20×. C, Higher magnification of a centrilobular area, with perivenular confluent hepatocyte loss (*). Portal tracts (PT) show overall mild inflammation, with predominantly lymphocytes and occasional plasma cells and eosinophils. Residual hepatocytes show acute bilirubinostasis (arrows), H&E, 200×. D, Sirius red stain shows, no evidence of significant fibrosis, only collapse 200×\n\n4 DISCUSSION\nDrug reaction with eosinophilia and systemic symptoms (DRESS) represents a severe idiosyncratic cutaneous response to medications that also have systemic involvement in the form of hematologic and solid organ dysfunction.\n1\n Most commonly involved solid organs include the lungs (5%‐25% of cases), the kidneys (10%‐30% of cases), and the liver (60%‐80% of cases).\n2\n Patients are often asymptomatic with deranged liver enzymes but may present with hepatomegaly and jaundice.\n3\n There is usually a latency period between 2 and 6 weeks from the time a medication is started to development of symptoms.\n4\n This long latency and the insidious and nonspecific symptoms in the early stages of DRESS lead to delays in diagnosis, and misattribution of symptoms to infection. Clinical features of DRESS itself include skin reactions and an inflammatory systemic involvement. DRESS generally begins with the eruption of a maculopapular skin rash symmetrically distributed over the body and extremities along with systemic symptoms including fevers, lymphadenopathy, and malaise.\n5\n\n\n\nA scoring system for DRESS has been described by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR).\n6\n The RegiSCAR DRESS scoring system allows assessment of the probability that a particular constellation of clinical symptoms represents DRESS, as opposed to an alternative diagnosis such as infection, from a possible total score of 7, scores equate to the following probabilities: score of 2—3: possible case; score 4—5: probable case; and score 6—7: definite case.\n6\n This scoring system includes acute rash, suspected drug‐related reaction, hospitalization, fever, laboratory abnormalities (lymphocyte count above or below normal, low platelet count, and/or eosinophilia), at least one internal organ involvement, and lymphadenopathy at more than two sites.\n5\n\n\n\nDrugs commonly associated with DRESS include anticonvulsants like carbamazepine, phenytoin, and lamotrigine as well as antibiotics such as dapsone, minocycline, and vancomycin.\n7\n There have also been cases of co‐trimoxazole as the causative agent in the development of DRESS.\n8\n There appears to be an association between human leukocyte antigen (HLA) haplotypes and susceptibility to different drug exposures resulting in DRESS.\n9\n Sukasem et al recently published a study suggesting that for the combination drug, co‐trimoxazole (CTX), which contains trimethoprim, there is an HLA susceptibility type for severe drug reactions—HLA‐B*15:02 and HLA‐C*08:01 alleles were significantly associated with CTX‐induced Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and HLA‐B*13:01 alleles were significantly associated with CTX‐induced DRESS. However, this association was observed only in HIV‐infected patients but not in non‐HIV‐infected patients. Our patient was HIV negative so while it would be interesting to know if she was positive for HLA‐B*13:01, no conclusions could be drawn from this.\n10\n\n\n\nLiver injury can be cholestatic, hepatocellular, or mixed and is defined by the RegiSCAR as serum alanine aminotransferase (ALT) levels more than two times the upper limit of normal and/or serum alkaline phosphatase (ALP) levels >1.5 times the upper limit of normal.\n6\n Hematologic abnormalities are often detected during laboratory investigations and include leukocytosis, lymphocytosis, and eosinophilia.\n2\n Although liver involvement is usually mild and transient, rarely, severe impairment progressing to acute liver failure (ALF) with jaundice, coagulopathy, and hepatic encephalopathy (HE) can occur.\n7\n Severe liver injury is a contributing factor for having a prolonged clinical course of DRESS.\n8\n In fact, severe hepatitis and liver failure accounts for most of the deaths associated with DRESS.\n9\n, \n10\n\n\n\nTohyama et al\n11\n looked at 100 patients with DRESS and found that patients with elevated HHV6 IgG antibodies suffered from severe organ involvement and a prolonged course compared with showing no reactivation of HHV‐6 and all patients with a fatal outcome were in the HHV‐6 reactivation group. A study by Harma et al\n12\n found the presence of HHV‐6 in 80% of explanted livers in patients undergoing liver transplantation for ALF of unknown etiology.\n\nHuman herpesvirus reactivation especially human herpesvirus‐6 (HHV‐6) is frequently encountered which may suggest prior HHV‐6 infection as a risk factor for the development of DRESS.\n4\n The immunological response against herpes viruses such as HHV‐6 by activated CD8+ T lymphocytes is implicated in the cause of the visceral and cutaneous manifestations, with higher cytokines levels in patients with the most severe visceral involvement. Severe manifestations of DRESS responsible for multiorgan failure or death have been seen in cases associated with an identification of HHV 6 reactivation. In the absence of DRESS, HHV‐6 alone as primary infection or reactivation has also been implicated in the cause of unexplained ALF in immunocompetent adults. Most cases of DRESS have been reported in adults with an incidence of 1 in 1000 to 1 in 10 000 drug exposures. The mortality rate is estimated to be between 5% to −10%.\n13\n, \n14\n The development of autoimmune conditions, particularly thyroid disease, but also diabetes mellitus, and alopecia areata following an episode of DRESS are well‐described. Patients should have thyroid function assessed 4‐6 weeks postrecovery, and at 6 months, or when symptoms suggestive of thyroid dysfunction present.\n15\n, \n16\n\n\n\nIn our case, the patient had insidious fluctuating symptoms for weeks, which delayed her presentation, diagnosis, and initiation of definitive treatment. She had classical signs for DRESS and a high HHV6 viral load (viral DNA = 555 879 copies), which is in keeping with previously reported literature, where DRESS is frequently associated with human herpesvirus reactivation, especially HHV‐6. This may play a role in the development of severe liver injury and liver failure.\n\n5 CONCLUSION\nOverall, DRESS is a rare idiosyncratic drug reaction. The liver is the most commonly affected internal organ. Management of DRESS no matter the severity or type of organ involvement typically requires withdrawal of the suspected offending medication, oral or intravenous corticosteroids, and supportive care. Although liver involvement is usually mild and transient, severe organ dysfunction and ALF can occur requiring intensive supportive management. Corticosteroids may not be beneficial once ALF ensues and urgent liver transplantation is the only lifesaving option. Given the rarity of such cases, it is currently difficult to predict the prognosis post–liver transplantation for these patients. The early transfer to the liver transplant center after index suspicion, prompt involvement of relative specialities, a multidisciplinary approach and timely completion of investigations added to a positive outcome in our case.\n\n6 LEARNING POINTS\nDrug reaction with eosinophilia and systemic symptoms (DRESS) represents a severe idiosyncratic cutaneous response to medications that also have systemic involvement in the form of hematologic and solid organ dysfunction.\n\nDRESS is often associated with human herpes virus‐6 (HHV‐6) reactivation.\n\nThe liver is the most common internal organ involved in DRESS. This is usually mild and transient but rarely can progress to severe impairment and acute liver failure (ALF).\n\nSystemic high‐dose corticosteroids are the main treatment option.\n\nIf liver involvement progresses to severe hepatic dysfunction and ALF, corticosteroids may be of limited benefit and ultimately, lifesaving urgent liver transplantation is required.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nMS: developed case report concept and design, consented, collected the data, performed literature search, performed critical analysis, drafted the manuscript, and revised and wrote the final manuscript. VD: performed literature search and revised the manuscript. TP: revised the manuscript, served as specialist input on hepatology and liver intensive care aspect of the case report, and supervised the study. JS and RM: revised the manuscript and served as critical specialist input on histopathology aspect of the case report. SW and AC: revised the manuscript and served as critical specialist input on dermatology aspect of the case report.\n\nACKNOWLEDGMENTS\nThe case report has been presented as ePoster in Critical Care Canada forum 2019.\n17\n Consent statement: The patient has given a valid written consent to publish the case and case‐related investigations. As this is a case report, it does not require a full ethical board approval.\n==== Refs\nREFERENCES\n1 \n\nWalsh \nSA \n, \nCreamer \nD \n. Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking\n. Clin Exp Dermatol . 2011 ;36 (1 ):6 ‐11\n.21143513 \n2 \n\nKardaun \nSH \n, \nSekula \nP \n, \nValeyrie‐Allanore \nL \n, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study\n. Br J Dermatol . 2013 ;169 (5 ):1071 ‐1080\n.23855313 \n3 \n\nLin \nIC \n, \nYang \nHC \n, \nStrong \nC \n, et al. Liver injury in patients with DRESS: a clinical study of 72 cases\n. J Am Acad Dermatol . 2015 ;72 (6 ):984 ‐991\n.25801338 \n4 \n\nWalsh \nS \n, \nDiaz‐Cano \nS \n, \nHiggins \nE \n, et al. Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases\n. Br J Dermatol . 2013 ;168 (2 ):391 ‐401\n.23034060 \n5 \n\nShiohara \nT \n, \nMizukawa \nY \n. Drug‐induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): an update in 2019\n. Allergol Int . 2019 ;68 (3 ):301 ‐308\n.31000444 \n6 \n\nKardaun \nSH \n, \nSidoroff \nA \n, \nValeyrie‐Allanore \nL \n, et al. Variability in the clinical pattern of cutaneous side‐effects of drugs with systemic symptoms: does a DRESS syndrome really exist?\n\nBr J Dermatol . 2007 ;156 (3 ):609 ‐611\n.17300272 \n7 \n\nMennicke \nM \n, \nZawodniak \nA \n, \nKeller \nM \n, et al. Fulminant liver failure after vancomycin in a sulfasalazine‐induced DRESS syndrome: fatal recurrence after liver transplantation\n. Am J Transplant . 2009 ;9 (9 ):2197 ‐2202\n.19706026 \n8 \n\nTetart \nF \n, \nPicard \nD \n, \nJanela \nB \n, \nJoly \nP \n, \nMusette \nP \n. Prolonged evolution of drug reaction with eosinophilia and systemic symptoms: clinical, virologic, and biological features\n. JAMA Dermatol . 2014 ;150 (2 ):206 ‐207\n.24369386 \n9 \n\nCriado \nPR \n, \nCriado \nRF \n, \nAvancini \nJM \n, \nSanti \nCG \n. Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) / Drug‐induced Hypersensitivity Syndrome (DIHS): a review of current concepts\n. An Bras Dermatol . 2012 ;87 (3 ):435 ‐449\n.22714760 \n10 \n\nChoudhary \nS \n, \nMcLeod \nM \n, \nTorchia \nD \n, \nRomanelli \nP \n. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome\n. J Clin Aesthet Dermatol . 2013 ;6 (6 ):31 ‐37\n.23882307 \n11 \n\nTohyama \nM \n, \nHashimoto \nK \n, \nYasukawa \nM \n, et al. Association of human herpesvirus 6 reactivation with the flaring and severity of drug‐induced hypersensitivity syndrome\n. Br J Dermatol . 2007 ;157 (5 ):934 ‐940\n.17854362 \n12 \n\nHarma \nM \n, \nHockerstedt \nK \n, \nLautenschlager \nI \n. Human herpesvirus‐6 and acute liver failure\n. Transplantation . 2003 ;76 (3 ):536 ‐539\n.12923440 \n13 \n\nMartinez‐Cabriales \nSA \n, \nShear \nNH \n, \nGonzalez‐Moreno \nEI \n. Liver involvement in the drug reaction, eosinophilia, and systemic symptoms syndrome\n. World J Clin Cases . 2019 ;7 (6 ):705 ‐716\n.30968035 \n14 \n\nChen \nYC \n, \nChiu \nHC \n, \nChu \nCY \n. Drug reaction with eosinophilia and systemic symptoms: a retrospective study of 60 cases\n. Arch Dermatol . 2010 ;146 (12 ):1373 ‐1379\n.20713773 \n15 \n\nKano \nY \n, \nTohyama \nM \n, \nAihara \nM \n, et al. Sequelae in 145 patients with drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR)\n. J Dermatol . 2015 ;42 (3 ):276 ‐282\n.25623158 \n16 \n\nKano \nY \n, \nShiohara \nT \n. Long‐term outcome of patients with severe cutaneous adverse reactions\n. Dermatol Sin . 2013 ;31 (4 ):211 ‐216\n.\n17 \n\nDong \nVS \n, \nSubhani \nM \n, \nPirani \nT \n. A rare case of trimethoprim induced drug reaction with eosinophilia and systemic symptoms (DRESS) leading to acute liver failure requiring liver transplantation\n. Critical Care Canada forum. 2019 \nhttps://cccf.multilearning.com/cccf/2019/eposters/283404/victor.dong.a.rare.case.of.trimethoprim.induced.drug.reaction.with.html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D1\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(12)",
"journal": "Clinical case reports",
"keywords": "acute liver failure; drug reaction with eosinophilia and systemic symptoms; drug‐induced liver injury; human herpes virus‐6; jaundice; liver transplant",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "2568-2573",
"pmc": null,
"pmid": "33363781",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "30968035;31000444;17300272;20713773;12923440;23882307;21143513;17854362;23855313;25623158;24369386;19706026;23034060;22714760;25801338",
"title": "Trimethoprim-induced drug reaction with eosinophilia and systemic symptoms (DRESS) associated with reactivation of human herpes virus-6 (HHV-6) leading to acute liver failure.",
"title_normalized": "trimethoprim induced drug reaction with eosinophilia and systemic symptoms dress associated with reactivation of human herpes virus 6 hhv 6 leading to acute liver failure"
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"abstract": "Frequently used in the management of hypertension and heart failure, hydralazine is associated with the development of adverse rheumatologic side effects. The authors highlight a unique case of drug-induced lupus and drug-induced anti-neutrophil cytoplasmic antibody (ANCA) vasculitis from hydralazine use in a 50-year-old man with sarcoidosis and hypertension.",
"affiliations": "School of Medicine, Baylor College of MedicineHoustonTexas.;School of Medicine, Baylor College of MedicineHoustonTexas.;Department of Medicine, Baylor College of MedicineHoustonTexas.;Department of Pathology and Immunology, Baylor College of MedicineHoustonTexas.;Department of Medicine, Baylor College of MedicineHoustonTexas.;Department of Medicine, Baylor College of MedicineHoustonTexas.",
"authors": "Espinosa|Maria Catalina|MC|0000-0002-4290-2470;Ding|Belicia|B|;Choi|Kati|K|;Cohen|Daniel N|DN|0000-0003-2561-2495;Marcelli|Marco|M|;Ifoeze|Onome Whiteru|OW|",
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"issn_linking": "0899-8280",
"issue": "32(2)",
"journal": "Proceedings (Baylor University. Medical Center)",
"keywords": "Drug-induced anti-neutrophil cytoplasmic antibody vasculitis; drug-induced lupus; hydralazine; leukocytoclastic vasculitis",
"medline_ta": "Proc (Bayl Univ Med Cent)",
"mesh_terms": null,
"nlm_unique_id": "9302033",
"other_id": null,
"pages": "231-234",
"pmc": null,
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"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": "1310098;19424772;21590349;23316942;26157889;27748260;28632810;29519741;30005854;6432120;6497533;6786464;7357301;7973636",
"title": "A simultaneous presentation of drug-induced lupus with drug-induced ANCA vasculitis secondary to hydralazine use in a patient with sarcoidosis.",
"title_normalized": "a simultaneous presentation of drug induced lupus with drug induced anca vasculitis secondary to hydralazine use in a patient with sarcoidosis"
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"abstract": "Radiotherapy (RT) and/or concurrent chemoradiation (CRT) is the mainstay for the treatment of locally advanced head-and-neck cancer (LAHNC). Sepsis remains a poorly understood and unrecognized event in head-and-neck cancer. The study aims to hypothesize a 'toxicity syndrome' leading to sepsis and subsequent sepsis-related deaths. A retrospective audit of all 125 LAHNC patients treated radically from January 2013 to June 2017 was conducted. A total of fifteen toxic deaths were reported. Thirteen deaths were attributed to sepsis. Individual toxicity for death was ascertained only for three cases. A toxicity syndrome namely 'mucositis-dysphagia-aspiration-sepsis (MDAS) complex' was proposed as the cause of death in the rest ten cases. The authors recommend the surveillance of the 'MDAS complex' for the prevention of early toxicity-related deaths in patients with LAHNC undergoing RT or CRT.",
"affiliations": "Department of Radiation Oncology, St John's Medical College and Hospital, Bengaluru, India. Electronic address: sandeepmuzumder@gmail.com.;Department of Radiation Oncology, St John's Medical College and Hospital, Bengaluru, India.",
"authors": "Muzumder|Sandeep|S|;Srikantia|Nirmala|N|",
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"keywords": "Chemoradiation; Head-and-neck cancer; Mortality; Radiation therapy; Sepsis; Toxicity syndrome",
"medline_ta": "Med Hypotheses",
"mesh_terms": "D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D006258:Head and Neck Neoplasms; D006801:Humans; D052016:Mucositis; D012189:Retrospective Studies",
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"title": "Toxicity syndrome and early competing deaths in head-and-neck cancer undergoing radiation therapy: Observation and hypothesis.",
"title_normalized": "toxicity syndrome and early competing deaths in head and neck cancer undergoing radiation therapy observation and hypothesis"
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"abstract": "We describe the case of an elderly woman with elderly-onset rheumatoid arthritis, where the use of 4 mg/kg/day of hydroxychloroquine (HCQ) was followed by the onset of psychomotor agitation with marked physical and verbal violence towards her partner, including throwing objects at her partner. No disturbance in sleep and no anxiety, nervousness, or irritability had emerged before the onset of her psychomotor agitation. The disappearance of agitation following targeted pharmacologic intervention and HCQ interruption, its re-onset after reintroduction of the drug, and the high score (9) of Naranjo's algorithm are surely linked to the existence of a causal relationship between HCQ and psychomotor agitation. HCQ may produce undesirable effects on the central nervous system, mainly irritability, nervousness, emotional changes, and nightmares. To the best of our knowledge, there are only a few case reports of psychosis due to HCQ. No favoring condition such as pharmacokinetic interactions or a personal and family psychiatric history was present in our patient. The neuropsychiatric manifestations we observed could be considered a bizarre-type adverse drug reaction linked to an individual's hypersensitivity.",
"affiliations": "Internal and geriatric department, Rheumatologic outpatient clinic and geronthorheumatologic service, Hospital \"Mariano Lauro\", viale dei Pini 1, 80065, Sant'Agnello, Naples, Italy. cirmanzo@libero.it.;Center for cognitive diseases and dementias, Catanzaro Lido, ASP Catanzaro, Catanzaro, Italy.;Center for cognitive diseases and dementias, Catanzaro Lido, ASP Catanzaro, Catanzaro, Italy.",
"authors": "Manzo|Ciro|C|;Gareri|Pietro|P|;Castagna|Alberto|A|",
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"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 282584764810.1007/s40800-017-0048-xCase ReportPsychomotor Agitation Following Treatment with Hydroxychloroquine Manzo Ciro cirmanzo@libero.it 1Gareri Pietro 2Castagna Alberto 21 Internal and geriatric department, Rheumatologic outpatient clinic and geronthorheumatologic service, Hospital “Mariano Lauro”, viale dei Pini 1, 80065 Sant’Agnello, Naples, Italy 2 Center for cognitive diseases and dementias, Catanzaro Lido, ASP Catanzaro, Catanzaro, Italy 4 3 2017 4 3 2017 12 2017 4 6© The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.We describe the case of an elderly woman with elderly-onset rheumatoid arthritis, where the use of 4 mg/kg/day of hydroxychloroquine (HCQ) was followed by the onset of psychomotor agitation with marked physical and verbal violence towards her partner, including throwing objects at her partner. No disturbance in sleep and no anxiety, nervousness, or irritability had emerged before the onset of her psychomotor agitation. The disappearance of agitation following targeted pharmacologic intervention and HCQ interruption, its re-onset after reintroduction of the drug, and the high score (9) of Naranjo’s algorithm are surely linked to the existence of a causal relationship between HCQ and psychomotor agitation. HCQ may produce undesirable effects on the central nervous system, mainly irritability, nervousness, emotional changes, and nightmares. To the best of our knowledge, there are only a few case reports of psychosis due to HCQ. No favoring condition such as pharmacokinetic interactions or a personal and family psychiatric history was present in our patient. The neuropsychiatric manifestations we observed could be considered a bizarre-type adverse drug reaction linked to an individual’s hypersensitivity.\n\nissue-copyright-statement© The Author(s) 2017\n==== Body\nKey Points\n\nHydroxychloroquine can induce adverse effects on the central nervous system, from irritability, nervousness, and emotional changes to true psychoses.\t\nDoses greater than 6 mg/kg/day, pharmacokinetic interactions, a personal or family psychiatric history and the disease per se for which HCQ is used can represent important favoring conditions.\t\nIn susceptible individuals, hydroxychloroquine can exert a stimulant effect on the central nervous system in the absence of these favoring conditions, probably as a consequence of an individual’s hypersensitivity.\t\n\n\n\nIntroduction\nHydroxychloroquine (HCQ) is a synthetic antimalarial drug derived from 4-aminoquinoline; it has been used for several decades for the treatment of some rheumatic diseases such as rheumatoid arthritis (RA). A dosage between 3 and 6 mg/bodyweight/day is considered therapeutic. In obese individuals, the dosage must be assessed considering the patient’s ideal bodyweight [1, 2]. Hydroxychloroquine may potentially result in adverse effects on the central nervous system, mainly irritability, nervousness, emotional changes, nightmares, and even true psychoses [3, 4]. We describe the case of an elderly person with elderly-onset rheumatoid arthritis (RA), where the use of therapeutic doses of HCQ was followed by the appearance of psychomotor agitation.\n\nCase Report\nEDC was an 80-year-old Caucasian woman affected with RA since 78 years of age. She was receiving pharmacologic treatment with methotrexate (MTX 10 mg weekly subcutaneously), oral folate supplementation (folic acid 5 mg, 24 h after MTX), and low doses of oral corticosteroids (6-methylprednisolone 8 mg/day in the first 2 weeks, then 4 mg/day for a further 2 weeks; and then administered during exacerbations only for a short time). Her comorbidities were: (1) familiar hypercholesterolemia (she used pravastatin 20 mg after dinner); (2) high blood pressure (she used amlodipine 5 mg daily); and (3) non-hemodynamically significant carotid atheromasia (she used acetylsalicylic acid 100 mg at lunchtime). She had no psychiatric history and no family history of psychiatric problems. After 2 years, RA was stable with an overall minimal disease activity, with a 28-item Disease Activity Score of 2.6 and a Clinical Disease Activity Index of 3.1 [5]. The patient asked the rheumatologist to stop MTX because she complained of general malaise and fatigue, which significantly affected her quality of life. These effects were not improved by switching to oral administration of MTX. It was proposed to take one tablet of HCQ/day (HCQ 200 mg; 4 mg/kg/day); her weight was 52 kg and her body mass index was 20.06 kg/m2. No over-the-counter or herbal supplements were used by the patient. Ten days later she developed, while she was healthy, significant psychomotor agitation [6] with marked physical and verbal violence towards her partner, including throwing objects at her partner. No disturbance in sleep and no anxiety, nervousness, or irritability had emerged prior to the onset of her psychomotor agitation. It was necessary to transport EDC to the hospital’s emergency room in her city, where she was administered half a vial of intramuscular promazine (equal to 25 mg). The agitation ceased in less than 1 h and there were no relapses or sequelae. Brain magnetic resonance imaging plus contrast medium was performed; it was negative for vascular lesions or neoplastic diseases and only a mild age-related atrophy was found. Laboratory tests were normal. Because no other potential triggers were identified, HCQ administration was interrupted. At a consultation 2 week later, we did not attribute the agitation to HCQ use and advised to introduce it again. However, following two tablets of HCQ, the agitation appeared again.\n\nThe patients was treated with promazine drops (15 drops equal to 30 mg) and HCQ was stopped again—the agitation disappeared. The administration of a placebo did not cause the onset of agitation to the patient. When we applied the Naranjo scale [7] to our patient, she had a score of 9 and this authorized the diagnosis of a defined (and not random) adverse drug reaction. One year later, the patient presented with neither cognitive impairment nor psychosis, with no further episodes of agitation. The patient’s cognition, in particular, was assessed using the Mini-Mental State Examination by Folstein et al. [8] in the Italian version validated by Magni et al. [9]; her score was equal to 26. At present, she is taking pravastatin, amlodipine, and acetylsalicylic acid with small doses of corticosteroids (4 mg of 6-methylprednisolone or 5 mg of prednisone) as needed. The RA is stable and well controlled (28-item Disease Activity Score of 2.8; Clinical Disease Activity Index score of 3.1).\n\nDiscussion\nHydroxychloroquine includes the vast majority of prescriptions for RA. It is an alkylated 4-aminoquinoline. It is more polar, less lipophilic, and has more difficulty in diffusing across cell membranes compared with chloroquine. Near-complete absorption following an oral dose occurs within 2–4 h and is relatively unaffected by concomitant ingestion of food [10]. Variability in the extent of absorption leads to differences in steady-state HCQ concentrations among patients, potentially contributing to the variability in response observed in clinical practice [11]. Hydroxychloroquine has a large volume of distribution owing to extensive sequestration of the drug by tissues. In particular, a plasma volume of distribution up to 44,257 L for HCQ has been reported [12, 13]. Drug disposition proceeds in three phases: distribution from blood to tissues, equilibration between blood and tissues, and release from tissues back into blood [11, 13, 14]. These phases have half-lives of 3–8, 40–216 h, and 30–60 days, respectively. The most commonly quoted median value for the terminal elimination half-life is 40 days [15]. Metabolism of HCQ occurs by dealkylation in the liver; the two most important metabolites are desethyl chloroquine and bisdesethyl chloroquine, both of which have pharmacologic activity and are thought to be approximately as toxic as the parent compounds [11]. Thirty to 79% of an oral dose of HCQ is metabolized and 21–70% is excreted without metabolism [15]. At steady state, the ratio of HCQ to desethyl hydroxychloroquine was 1.75 ± 0.37 [10]. Cytochrome P450 3A4 inhibitors such as ketoconazole, cimetidine, and ciprofloxacin may increase the half-lives of HCQ [16, 17, 18]. The possible HCQ-induced neuropsychiatric side effects depend on its ability to cross the blood–brain barrier. In the brain, HCQ can have a tissue concentration 10–20 times higher than a plasma concentration [2, 14].\n\nThere are several possible mechanisms hypothesized for the onset of HCQ-induced psychosis. For example, the induction of a cholinergic imbalance with acetylcholine reduction, probably mediated by prostaglandin E and interleukin-1; the accumulation of metabolic and toxic wastes as a result of lysosome dysfunction, where HCQ accumulates; the down-regulation of P-glycoprotein at the level of the blood–brain barrier. Drug interactions (as already mentioned) may represent an additional mechanism. Finally, the possibility that it may be an idiosyncratic or bizarre-type adverse drug reaction [19] must be considered. Other antimalarial drugs such as chloroquine and mefloquine can cause neuropsychiatric side effects [20–24]. There are only a few case reports of psychosis due to HCQ [3, 18, 25, 26]. Our patient used a dose of HCQ equal to 4 mg/bodyweight/day; this dosage is within the therapeutic range. None of the three molecules taken from our patient was within the categories of drugs causing interaction with HCQ. Psychomotor agitation cannot be considered a manifestation of elderly-onset RA; neurological and psychiatric manifestations in the course of RA mostly depend on vasculitis, opportunistic infections, and accelerated atherosclerosis [27], all conditions excluded in our patient. Therefore, the RA was (at the time of the introduction of HCQ) in a minimal activity and typically there is a close relationship between disease activity and RA extra-articular manifestations. Our patient was not receiving corticosteroid treatment and this aspect needs to be highlighted.\n\nIn other case reports regarding the relationship between neuropsychiatric manifestations and therapy with HCQ, some important biases were present, such as important pharmacokinetic interactions (18), a potential effect of the rheumatic disease on the neuropsychiatric manifestations (3), and a personal and/or family history of psychiatric disorders (25, 26). Furthermore, the bodyweight (real or ideal) of the patient was not always reported or properly assessed in other case reports.\n\nConclusions\nHydroxychloroquine may produce undesirable effects on the central nervous system. These side effects usually appear with high doses of the drug (>6 mg/bodyweight/day) or in the presence of favoring elements (pharmacokinetic interactions, personal and family psychiatric history, the disease for which HCQ is used). To our knowledge, the possibility that HCQ may cause psychomotor agitation in the absence of such favoring elements has not been reported. The disappearance of agitation after targeted pharmacologic intervention and HCQ interruption, its reonset following reintroduction of the drug and the score of Naranjo’s algorithm are surely linked to the existence of a causal relationship between HCQ and psychomotor agitation. Furthermore, 1 year after the discontinuation of HCQ, our patient presented with no further episodes of psychomotor agitation or other psychotic manifestations and she had good cognitive performance.\n\nWe can hypothesize that in susceptible people, for unknown reasons, HCQ might exert a stimulant effect on the central nervous system resulting in agitation onset that disappears on drug interruption and is responsive to sedative treatments. The neuropsychiatric manifestations described in our patient could be considered a bizarre-type adverse drug reaction linked to an individual’s hypersensitivity.\n\nCompliance with Ethical Standards\nFunding\nNo financial support was received for the conduct and preparation of this case report.\n\nConflict of interest\nCiro Manzo, Pietro Gareri, and Alberto Castagna declare they have no conflicts of interest directly relevant to the content of this case report.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent may be requested from the corresponding author.\n==== Refs\nReferences\n1. McKenzie AH Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials Am J Med. 1983 75 1A 40 45 10.1016/0002-9343(83)91269-X \n2. Rynes RI. Antimalarials. In: Kelley WN, Harris ED Jr, Ruddy S, Sledge CB, editors. Textbook of rheumatology. Philadelphia: Saunders Company; 2001. p. 864–5.\n3. Hsu WH Chiu NY Huang SS Hydroxychloroquine-induced acute psychosis in a systemic lupus erythematosus female Acta Neuropsychiatrica. 2011 23 318 319 10.1111/j.1601-5215.2011.00575.x 25380045 \n4. Drew JF Concerning the side effects of antimalarial drugs used in the extended treatment of rheumatic diseases Med J Aust. 1962 49 618 620 \n5. Tubach F Wells GA Ravaud P Dougados M Minimal clinically important difference, low disease activity state, and patient acceptable symptom state: methodological issues J Rheumatol. 2005 32 10 2025 2029 16206363 \n6. American Psychiatric Association Diagnostic and statistical manual of mental disorders 2013 5 Washington, DC American Psychiatric Association \n7. Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther. 1981 30 2 239 245 10.1038/clpt.1981.154 7249508 \n8. Folstein MF Robins LN Helzer JE The Mini-Mental State Examination Arch Gen Psychiatry. 1983 40 7 812 10.1001/archpsyc.1983.01790060110016 6860082 \n9. Magni E Binetti G Bianchetti A Mini-Mental State Examination: a normative study in Italian elderly population Eur J Neurol. 1996 3 3 198 202 10.1111/j.1468-1331.1996.tb00423.x 21284770 \n10. Bothwell B Furst DE Day RO Furst DE Hydroxychloroquine Antirheumatic therapy: actions and outcomes 2005 Basel Piet L.C.M. van Riel and Barry Bresnihan 81 92 \n11. McLachlan AJ Tett SE Cutler DJ Day RO Bioavaliability of hydroxychloroquine tablets in patients with rheumatoid arthritis Br J Rheumatol. 1994 33 3 235 239 10.1093/rheumatology/33.3.235 8156285 \n12. Tett S Cutler D Day R Antimalarials in rheumatic diseases Baillieres Clin Rheumatol. 1990 4 467 489 10.1016/S0950-3579(05)80004-4 2093438 \n13. Munster T Gibbs JP Shen D Hydroxychloroquine concentration response relationships in patients with rheumatoid arthritis Arthritis Rheum. 2002 46 1460 1469 10.1002/art.10307 12115175 \n14. Giacomello A. Antimalarici di sintesi derivati della 4-aminochinolina. In: D’Elia S, D’Erasmo E, Giacomello A, et al, editors. Farmacologia clinica reumatologica. Milan: Masson ed.; 1987. p. 98–9.\n15. Tett SE Cutler DJ Day RO Brown KF Bioavailability of hydroxychloroquine tablets in healthy volunteers Br J Clin Pharmacol. 1989 27 771 779 10.1111/j.1365-2125.1989.tb03439.x 2757893 \n16. Katz SJ Russell AS Re-evaluation of antimalarials in treating rheumatic diseases: reappreciation and insights into new mechanisms of action Curr Eye Res. 2011 23 278 281 \n17. Kim KA Park JY Lee SJ Lim S Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes Arch Pharm Res. 2003 26 631 637 10.1007/BF02976712 12967198 \n18. Das P Rai A Chopra A Philbrick K Psychosis likely induced by hydropxychloroquine in a patient with chronic Q fever: a case report and clinically relevant review of pharmacology Psychosomatics. 2014 55 409 413 10.1016/j.psym.2013.06.017 24268495 \n19. Rawlins MD Clinical pharmacology: adverse reactions to drugs BMJ. 1981 282 974 976 10.1136/bmj.282.6268.974 6781682 \n20. Kwak YT Yang Y Park SY Chloroquine-associated psychosis mimicking very late-onset schizophrenia: case report Geriatr Gerontol. 2015 15 1096 1097 10.1111/ggi.12490 \n21. Livezey J Oliver T Cantilena L Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine Drug Saf Case Rep. 2016 3 7 10.1007/s40800-016-0030-z 27747687 \n22. Tran TM Browning J Dell ML Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report Malaria J. 2006 5 74 10.1186/1475-2875-5-74 \n23. Good MI Shader RI Lethality and behavioral side effects of chloroquine J Clin Psychopharmacol. 1982 2 40 47 10.1097/00004714-198202000-00005 7040501 \n24. Maxwell NM Nevin RL Stahl S Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy Clin Case Rep. 2015 3 6 379 387 10.1002/ccr3.238 26185633 \n25. Ward WQ Walter-Ryan WG Shehi GM Toxic psychosis: a complication of antimalarial therapy J Am Acad Dermatol. 1985 12 5 863 865 10.1016/S0190-9622(85)70109-0 4008689 \n26. Gonzales-Nieto JA Costa-Juan E Psychiatric symptoms induced by hudroxychloroquine Lupus. 2015 24 339 340 10.1177/0961203314558863 25378239 \n27. Joaquim AF Appenzeller S Neuropsychiatric manifestations in rheumatoid arthritis Autoimmun Rev. 2015 14 12 1116 1122 10.1016/j.autrev.2015.07.015 26238502\n\n",
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"title": "Psychomotor Agitation Following Treatment with Hydroxychloroquine.",
"title_normalized": "psychomotor agitation following treatment with hydroxychloroquine"
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"abstract": "BACKGROUND\nIn Japan, a new anti-tuberculous drug, delamanid, was recognized as the drug of choice to treat multi-drug resistant pulmonary tuberculosis in July 2014.\n\n\nMETHODS\nWe treated 28 cases of multidrug-resistant tuberculosis (MDR-TB) and three cases of extensively drug-resistant tuberculosis (XDR-TB) with delamanid from July 2014 to June 2018 at our hospital.\n\n\nRESULTS\nThere were 21 men and 10 women, with the mean age of 48 and 37 years, respectively. We used an average of 4.4 sensitive anti-tuberculous drugs for the MDR-TB cases and 4.7 for the XDR-TB cases with delamanid. We used linezolid in 19 of 31 cases, although it has not been recognized as an anti-tuberculous drug in Japan. On electrocardiography, QTc prolongation of more than 450 ms was seen in two cases (6.4%), but they were asymptomatic, thus the treatment with delamanid could be continued. In 10 cases, surgical resection was performed. We completed the treatment in 20 cases and continued the treatment in seven cases; however, the treatment was discontinued in four cases because of side effects. In all cases, the sputum cultures were negative.\n\n\nCONCLUSIONS\nDelamanid is a relatively safe drug with few side effects. However, some patients could not continue it because of difficulty of use in combination, therefore delamanid should be prescribed considering the side effects of all therapies in the regimen.",
"affiliations": "Department of Respiratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan. Electronic address: okumuram@fukujuji.org.;Department of Respiratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan.;Department of Respiratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan.;Department of Respiratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan.;Department of Respiratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan.;Department of Respiratory Medicine, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan.;Japan Anti-Tuberculous Association, Japan.",
"authors": "Okumura|Masao|M|;Yoshiyama|Takashi|T|;Ogata|Hideo|H|;Kurashima|Atsuyuki|A|;Yoshimori|Kozo|K|;Ohta|Ken|K|;Kudoh|Shoji|S|",
"chemical_list": "D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles",
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"issue": "58(2)",
"journal": "Respiratory investigation",
"keywords": "Chemotherapy; Delamanid; MDR-TB; Surgical resection; XDR-TB",
"medline_ta": "Respir Investig",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles; D010080:Oxazoles; D017410:Practice Guidelines as Topic; D014397:Tuberculosis, Pulmonary",
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"title": "Treatment of multidrug-resistant pulmonary tuberculosis with delamanid based on Japanese guideline recommendations.",
"title_normalized": "treatment of multidrug resistant pulmonary tuberculosis with delamanid based on japanese guideline recommendations"
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"abstract": "Cosmetic or therapeutic use of botulinum toxin type A (BoNT-A) is usually safe but can rarely cause iatrogenic botulism. Iatrogenic botulism and myasthenia gravis (MG) share similar clinical features, because both BoNT-A and anti-acetylcholine receptorantibodies impair neuromuscular transmission. We report a patient who underwent cosmetic BoNT-A injection and later developed serious local and systemic adverse reactions. The peculiarity of this case is that a latent seropositive MG was eventually discovered, suggesting that both iatrogenic botulism and MG contributed to the clinical picture. This patient is one of the less than 10 reported cases worldwide in whom MG was unmasked by BoNT-A injection. He is the first to be assessed in detail by single-fiber electromyography. This case emphasizes the risk associated with BoNT-A injection in patients with subclinical impairment of neuromuscular transmission and prompts the search for MG in case of exaggerated response.",
"affiliations": "Department of Neurology, University of Liège, CHU Sart-Tilman, Liège, Belgium.;Department of Neurology, University of Liège, CHU Sart-Tilman, Liège, Belgium.;Department of Neurophysiology, University of Liège, CHU Sart-Tilman, Liège, Belgium.;Department of Neurology, University of Liège, CHU Sart-Tilman, Liège, Belgium.;Department of Neurology, University of Liège, CHU Sart-Tilman, Liège, Belgium.",
"authors": "Timmermans|Grégory|G|;Depierreux|Frédérique|F|;Wang|François|F|;Hansen|Isabelle|I|;Maquet|Pierre|P|",
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"country": "Switzerland",
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"doi": "10.1159/000502350",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000502350crn-0011-0244Case ReportCosmetic Injection of Botulinum Toxin Unmasking Subclinical Myasthenia Gravis: A Case Report and Literature Review Timmermans Grégory a*Depierreux Frédérique aWang François bHansen Isabelle aMaquet Pierre aaDepartment of Neurology, University of Liège, CHU Sart-Tilman, Liège, BelgiumbDepartment of Neurophysiology, University of Liège, CHU Sart-Tilman, Liège, Belgium*Grégory Timmermans, Department of Neurology, University of Liège/CHU Sart-Tilman, Rue des Deux Eglises 62, BE–4120 Neupré, Liège (Belgium), E-Mail gregorire14@hotmail.beMay-Aug 2019 16 8 2019 16 8 2019 11 2 244 251 26 7 2019 26 7 2019 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.Cosmetic or therapeutic use of botulinum toxin type A (BoNT-A) is usually safe but can rarely cause iatrogenic botulism. Iatrogenic botulism and myasthenia gravis (MG) share similar clinical features, because both BoNT-A and anti-acetylcholine receptorantibodies impair neuromuscular transmission. We report a patient who underwent cosmetic BoNT-A injection and later developed serious local and systemic adverse reactions. The peculiarity of this case is that a latent seropositive MG was eventually discovered, suggesting that both iatrogenic botulism and MG contributed to the clinical picture. This patient is one of the less than 10 reported cases worldwide in whom MG was unmasked by BoNT-A injection. He is the first to be assessed in detail by single-fiber electromyography. This case emphasizes the risk associated with BoNT-A injection in patients with subclinical impairment of neuromuscular transmission and prompts the search for MG in case of exaggerated response.\n\nKeywords\nBotulinum toxinMyasthenia gravisIatrogenic botulismSingle-fiber electromyography\n==== Body\nIntroduction\nLocal injection of botulinum toxin type A (BoNT-A) is frequently conducted for therapeutic or cosmetic purposes, and is most often safe. Possible complications are mainly related to local or systemic toxin diffusion. BoNT-A local spread to adjacent muscles is common and is generally transient. For instance, dysphagia is not rare after toxin injection for cervical dystonia, as well as eyelid ptosis after periocular injection. BoNT-A systemic diffusion can also occur but generally with no clinical consequences. Indeed, single-fiber electromyography studies have shown altered neuromuscular transmission in muscles distant from the injection site without any associated symptom [1, 2]. Nevertheless, in rare cases, systemic diffusion leads to clinical manifestations of variable severity (dysphagia, generalized muscular weakness, respiratory failure, …) [3, 4, 5]. This condition, referred to as iatrogenic botulism, remains exceptional in healthy subjects and often results, at least in cosmetic cases, from inappropriate injections of unlicensed toxins in beauty salons [6]. By contrast, in patients with an underlying neuromuscular disease such as myasthenia gravis (MG), the potency of BoNT-A is increased, even at low dose. This increased sensitivity can be explained by synergistic effects of BoNT-A and MG on neuromuscular blockade. Here, we highlight this phenomenon by reporting a patient in whom BoNT-A administration unmasked subclinical MG.\n\nCase Report\nA 43-year-old man with unremarkable medical history and no chronic medication was admitted to the emergency department for bilateral eyelid ptosis and binocular diplopia gradually worsening for 10 days (Fig. 1). Symptoms were initially mild but progressed in a few days to nearly complete eyelid closure and external ophthalmoplegia. Six weeks before symptom onset, the patient had received cosmetic injection of abobotulinum toxin A (Azzalure®; Galderma) to the glabellar, forehead, and lateral canthal rhytids (total of 84 U in one session). A similar injection had been performed 2 years earlier with no adverse effect. Neurological examination was entirely normal apart from ocular signs. Conventional blood tests, cerebrospinal fluid analysis, and brain magnetic resonance imaging were normal. A first electroneuromyography (ENMG) showed normal parameters: normal nerve conduction velocities and latencies(fibular and sural nerves), normal amplitudes of the compound muscle action potential (CMAP), decremental responses <10% during repetitive nerve stimulation (RNS) at 3 Hz of the facial nerves (nasalis, orbicularis oculi), right ulnar nerve (abductor digiti minimi), and radial nerve (anconeus). However, a single-fiber study (SFEMG) of the left orbicularis oculi showed major impairment of neuromuscular transmission (mean jitter of 112 µs with 50% blocking). Interestingly, in most neuromuscular junctions, jitter and blocking were greater with low discharge rates (5 Hz) than with high ones (40 Hz), suggesting a presynaptic disorder (Fig. 2). Based on these clinical and electrophysiological data, a local effect of BoNT-A was suspected. The patient was first treated with oral pyridostigmine 240 mg/day, based on the intuition that it would help neuromuscular transmission, but to no avail. By contrast, subcutaneous neostigmine 0.25 mg every 2 h was associated with a rapid but moderate clinical improvement. This treatment was nonetheless discontinued after a few days due significant bradycardia. Two weeks later, the patient experienced further clinical deterioration with worsening of the eyelid ptosis, dysphagia, and subjective generalized weakness. Repetitive nerve stimulation at 3 Hz revealed, this time, decremental responses in all muscles tested (decrement in percentages of area: right nasalis 35%, left nasalis 36%, right trapezius 26%, right anconeus 24%, right abductor digiti minimi 29%). Repair of decremental response was recorded in the right abductor digiti minimi (6 vs. 29%) after 1 min of voluntary contraction, followed by a worsening of decremental response (37 vs. 29%) 3 min after this effort, suggesting a postsynaptic disorder. Serum acetylcholine receptor antibodies (anti-AChR) were measured in the hypothesis of MG and went back strongly positive at 6.4 nmol/L (normal values <0.5), which was confirmed by a second test. Therefore, the simultaneous diagnosis of MG was established. Computed tomography of the chest showed no thymoma. Pyridostigmine treatment was gradually resumed (without significant bradycardia) in combination with oral methylprednisolone 1 mg/kg. Slowly progressive clinical improvement was then observed; dysphagia and generalized weakness completely resolved in 4 weeks, while moderate ptosis and ophthalmoparesis persisted for more than 6 months.\n\nDiscussion\nTo our knowledge, this patient is the 8th case reported in the literature of latent MG, revealed by BoNT-A injection [7, 8, 9, 10, 11, 12, 13, 14], and the most documented case from an electrophysiological point of view. These different cases are listed in Table 1. It should be noted that 7 other cases of BoNT-A injection have been reported in patients with already diagnosed myasthenia [15, 16, 17, 18, 19, 20, 21].\n\nBoNT-A inhibits presynaptic release of acetylcholine at the neuromuscular junction, whereas MG antibodies block acetylcholine receptors on the postsynaptic side. The combination of the two mechanisms has therefore synergistic detrimental effect on neuromuscular transmission. This phenomenon probably explains the clinical manifestations observed in our patient. In this case, the purely ocular and steady (i.e., nonfluctuating) nature of the initial symptoms as well as the history of recent periocular BoNT-A injection strongly suggested a local action of BoNT-A. However, the subsequent occurrence of clinical deterioration associated with dysphagia and generalized weakness could not be explained by the local effect of the toxin alone and suggested the existence of a systemic process related to the toxin itself (iatrogenic botulism) or to a neuromuscular disorder, or both. The presence of AChR antibodies, the partial response to neostigmine, and the highly suggestive electrophysiological picture eventually led to the diagnosis of MG. We surmise that MG was latent, and that BoNT-A injection brought it to the symptomatic threshold by its usually subclinical action on neuromuscular junction in both local and remote muscles. In other words, neuromuscular transmission, already jeopardized on its postsynaptic side by subclinical effects of anti-AChR antibodies, eventually failed when the toxin disturbed its presynaptic component.\n\nOur patient experienced an unusually long delay between BoNT-A injection and symptom onset (about 6 weeks). This contrasts with the other reported cases whose latency period ranged from 1 to 36 days [6]. We do not know the reason for this delayed course. Another interesting aspect is the history of a previous injection session, 2 years earlier, without adverse event. This feature is actually observed in other cases of iatrogenic botulism (with or without MG), where complications only occur after several injection sessions [5, 8, 13, 22]. One possible explanation might be that toxin spread is highly unpredictable and varies substantially from one injection to another. Finally, it should be stressed that our patient suffered from significant complications despite the use of usual BoNT-A doses. Similar findings have been observed in previously reported cases, with doses as low as 12 U sufficient to trigger symptoms [15]. This highlights the increased sensitivity of patients with neuromuscular disease to the effects of BoNT-A. It should be noted, however, that other patients with MG have been successfully treated with BoNT-A without complications [16, 17, 19].\n\nElectrophysiological assessment is of particular interest in this case because it combines signs of pre- and postsynaptic involvement. The expected electrophysiologic findings in human botulism are a reduction of CMAP amplitude, an incremental response of CMAP to high-rate RNS or voluntary contraction (postactivation facilitation), a moderate and inconstant decremental response to slow-rate RNS, the absence of postactivation exhaustion, and a “myogenic” pattern on needle-EMG [23, 24, 25]. It is worthy of note that these data come mainly from studies of foodborne and infant botulism rather than iatrogenic botulism. In MG, the classical electrical features are a decremental response of CMAP to slow-rate RNS, a repair of the decrement immediately after 1 min of voluntary exercise followed by a worsening of the decrement 3–4 min post exercise (postactivation exhaustion) [26]. Single-fiber EMG is virtually always abnormal in both botulism and MG (increased jitter with frequent impulse blocking) and is therefore not a discriminating test unless the discharge rate is modified [27] (see below). In this patient, the typical features of MG were found with RNS, but not those of botulism. Indeed, neither reduced CMAP amplitude nor increment have been observed (the latter may arise from the former). This does not rule out, however, the existence of botulism, since conventional EMG can remain normal in mild cases of botulism, especially in iatrogenic ones [5, 22, 28, 29]. In our patient, electrical evidence of a partly presynaptic involvement was provided only by SFEMG: jitter decreased with higher discharge rates, which is equivalent to postactivation facilitation during high-rate RNS. This effect of firing rate is suggestive of a presynaptic blockade and is usually not seen in isolated MG, where, on the contrary, jitter decreases with slower discharge rates [23, 24, 25, 27, 30]. Overall, the electrophysiological abnormalities encountered in our patient combined features of pre- and postsynaptic dysfunction of neuromuscular transmission.\n\nConclusion\nThe synergistic effects of MG and BoNT-A explain why patients with an underlying neuromuscular disease have an increased risk of adverse reaction after BoNT-A injection. In patients with known neuromuscular disease or obvious clinical signs (e.g., dysphagia), caution is advised and BoNT-A should be either avoided or used sparingly if there is no therapeutic alternative. By contrast, there is no practical way to identify patients with latent, subclinical neuromuscular junction abnormalities before BoNT-A administration. Indeed, screening for neuromuscular disorder through anti-AChR antibodies or EMG testing is not conceivable. Thus, a complete patient history and physical examination must be conducted before BoNT-A injection, seeking any clinical data suggestive of latent MG. If the patient presents an exaggerated response to BoNT-A, especially if he responds toacetylcholinesterase inhibitors, MG should be considered before any further injection. Finally, an uncomplicated prior injection does not guarantee the absence of side effects after subsequent injections, even at low doses.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose. Informed consent for patient information and images to be published was provided by the patient.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThe authors received no funding support for the publication of this case report.\n\nAuthor Contributions\nEach author contributed to the treatment of the patient and diagnosis of the disease.\n\nFig. 1 A 43-year-old man presenting with constant bilateral eyelid ptosis and external ophthalmoplegia gradually worsening for 10 days.\n\nFig. 2 SFEMG results of the left orbicularis oculi showing increased jitter with impulse blocking. In most neuromuscular junctions, mean jitter value and percentages of blocking decreases as the firing rate increases, which suggests presynaptic abnormalities.\n\nTable 1 Comparison of patients with latent (unknown) MG unmasked by BoNT-A injection\n\nFirst author, year [Ref. No.]\tIndication (age, sex)\tMuscles injected\tBoNT-A dose (type)\tPrior BoNT-A injections\tSymptoms (latency/duration)\tENMG findings\t\nBrunnschweiler, 1997 [7]\tTherapeutic: cervical dystonia (56, F)\tSplenius capitis\t12.5 ng(Dysport)\tUnspecified\tDysphagia, chewing muscles weakness, dyspnea (3 weeks/unspecified)\tDecrement (% unspecified) in left deltoideus and left “facial”\t\n\t\nBorodic, 1998 [9] then Tarsy, 2000 [8]\tTherapeutic: blepharospasm, oromandibular dyskinesia (80, F)\tOrbicularis oculi, lower facial\t120 U (Botox)\t18 injections (30–120 U) over the past 13 years with no complication\tPtosis, diplopia, dysarthria, dysphagia, generalized weakness (4 days/5 months)\tNormal RNS ↑ jitter in posterior cervical and upper extremity muscles\t\n\t\nIwase, 2006 [10]\tTherapeutic: blepharospasm (78, F)\tOrbicularis oculi\t40 U (unspecified)\t2 injections (80 U and 60 U) 1 month and 4 months earlier, with no complication\tDysphagia, dysarthria, generalized weakness (1 week/3 months)\tUnspecified\t\n\t\nDressier, 2010 [11]\tTherapeutic: cervical dystonia (66, F)\tSternocleido-mastoideus, splenius capitis, trapezius\t72 U (Botox)\t6 injection series (72–180 U) with unspecified timing\tDiplopia (1 month/unspecified)\tUnspecified (pathological serial stimulation)\t\n\t\nGlick, 2013 [12]\tCosmetic: glabellar and lateral cantal rhytids (64, F)\tPeriocular\t58 U (unspecified)\t1 injection 8 months earlier (25 U), with no complication\tDiplopia (1 week/unspecified)\tUnspecified\t\n\t\nDurmuş-Tekçe, 2016 [13]\tTherapeutic: oromandibular dystonia (80, F)\tHyoglossus\t10 MU (unspecified)\t8 injections (10 U), every 3 months before the occurrence, with no complication\tPtosis, diplopia, dysphagia, dyspnea, generalized weakness (10 days/6 months)\tRNS: dysfunction of neuromuscular junction\t\n\t\nChegini, 2017 [14]\tCosmetic: facial rhytids (30, F)\tUnspecified\tUnspecified\t2 injections during the preceding months, with no complication\tPtosis, diplopia, dysphagia, dysarthria, dyspnea, generalized weakness (the preceding months/unspecified)\tRNS: signs of pre- and para-synaptic myopathy\t\n\t\nTimmermans (this report)\tCosmetic: glabellar and lateral cantal rhytids (43, M)\tPeriocular\t84 U (Azzalure)\t1 injection 2 years earlier, with no complication\tPtosis, diplopia, dysphagia, generalized weakness (6 weeks/>6 months)\t↑ jitter (orbicularisoculi), decrement\n==== Refs\nReferences\n1 Singer C Weiner WJ Lange DJ Brain MF Greene P Lovelace RE Letters to the editor Muscle Nerve 1993 16 (6) 677 82 \n2 Garner CG Straube A Witt TN Gasser T Oertel WH Time course of distant effects of local injections of botulinum toxin Mov Disord 1993 8 (1) 33 7 8380486 \n3 Coban A Matur Z Hanagasi HA Parman Y Iatrogenic botulism after botulinum toxin type A injections Clin Neuropharmacol 2010 5 33 (3) 158 60 20150804 \n4 Ghasemi M Norouzi R Salari M Asadi B Iatrogenic botulism after the therapeutic use of botulinum toxin-A: a case report and review of the literature Clin Neuropharmacol 2012 Sep-Oct 35 (5) 254 7 22986799 \n5 Bhatia KP Münchau A Thompson PD Houser M Chauhan VS Hutchinson M Generalised muscular weakness after botulinum toxin injections for dystonia: a report of three cases J Neurol Neurosurg Psychiatry 1999 7 67 (1) 90 3 10369829 \n6 Bai L Peng X Liu Y Sun Y Wang X Wang X Clinical analysis of 86 botulism cases caused by cosmetic injection of botulinum toxin (BoNT) Medicine (Baltimore) 2018 8 97 (34) e10659 30142749 \n7 Brunnschweiler H Fuhr P Steck AJ P. Fuhr AJS. First clinical manifestation of myasthenia gravis after injection of botulinum toxin for cervical dystonia Electroencephalogr Clin Neurophysiol 1997 102 (3) 28 9 \n8 Tarsy D Bhattacharyya N Borodic G Myasthenia gravis after botulinum toxin A for Meige syndrome Mov Disord 2000 7 15 (4) 736 8 10928589 \n9 Borodic G Myasthenic crisis after botulinum toxin Lancet 1998 12 352 (9143) 1832 \n10 Iwase T Iwase C Systemic effect of local and small-dose botulinum toxin injection to unmask subclinical myasthenia gravis Graefes Arch Clin Exp Ophthalmol 2006 3 244 (3) 415 6 16175373 \n11 Dressler D Subclinical myasthenia gravis causing increased sensitivity to botulinum toxin therapy J Neural Transm (Vienna) 2010 11 117 (11) 1293 4 20953643 \n12 Glick ZR Vaphiades MS Northington ME OnabotulinumtoxinA unmasking myasthenia gravis Dermatol Surg 2013 3 39 (3 Pt 1) 472 3 23157683 \n13 Durmuş Tekçe H Deymeer F Oflazer Serdaroğlu P Parman Y Myasthenia Gravis after Botulinum Toxin Type A Injection Turkish J Neurol. 2016 22 (3) 143 4 \n14 Chegini A Therapeutic Plasma Exchange in a rare case myasthenic crisis after Botox injection Atheroscler Suppl 2017 11 30 283 5 29096852 \n15 Watts J Brew B Tisch S Myasthenia gravis exacerbation with low dose ocular botulinum toxin for epiphoria J Clin Neurosci 2015 12 22 (12) 1979 81 26188667 \n16 Hara K Matsuda A Kitsukawa Y Tanaka K Nishizawa M Tagawa A Botulinum toxin treatment for blepharospasm associated with myasthenia gravis Mov Disord 2007 7 22 (9) 1363 4 17486596 \n17 Fasano A Bentivoglio AR Ialongo T Soleti F Evoli A Treatment with botulinum toxin in a patient with myasthenia gravis and cervical dystonia Pontine / extrapontine myelinolysis occurring in the setting of an eating disorder 2005 \n18 Emmerson J Botulinum toxin for spasmodic torticollis in a patient with myasthenia gravis Mov Disord 1994 5 9 (3) 367 367 8041381 \n19 Gonçalves MRR Barbosa ER Zambon AA Marchiori PE Treatment of cervical dystonia with botulinum toxin in a patient with myasthenia gravis. Arq Neuropsiquiatr 1999 57 (3 A) 683 685 10667297 \n20 Patel V Elston J Malhotra R Prolonged Effect of Botulinum Toxin- A Treatment in Patients with Myasthenia Gravis J Clin Exp Ophthalmol 2011 02 (03) 2155 6 \n21 El-Heis S Burke G Gibb W Ardern-Jones MR Myaesthenia gravis exacerbation caused by axillary injection of botulinum toxin A for treatment of hyperhidrosis Clin Exp Dermatol 2017 4 42 (3) 357 9 28111784 \n22 Crowner BE Torres-Russotto D Carter AR Racette BA Systemic Weakness After Therapeutic Injections of Botulinum Toxin A Clin Neuropharmacol 2010 33 (5) 243 7 20852412 \n23 Cruz Martínez A Anciones B Ferrer MT Díez Tejedor E Pérez Conde MC Bescansa E Electrophysiologic study in benign human botulism type B Muscle Nerve 1985 9 8 (7) 580 5 2995805 \n24 Cherington M Electrophysiologic methods as an aid in diagnosis of botulism: a review Muscle Nerve 1982 5 9S S28 9 6763148 \n25 Cherington M Botulism: update and review Semin Neurol 2004 6 24 (2) 155 63 15257512 \n26 Howard JF Jr Electrodiagnosis of disorders of neuromuscular transmission Phys Med Rehabil Clin N Am 2013 2 24 (1) 169 92 23177038 \n27 Sanders DB Howard JF Jr AAEE minimonograph # 25: single-fiber electromyography in myasthenia gravis Muscle Nerve 1986 Nov-Dec 9 (9) 809 19 3785290 \n28 Lispi L Leonardi L Longitudinal neurophysiological assessment of intramuscular type-A botulin toxin in healthy humans. 2018 329 332 \n29 Leonardi L Haggiag S Petrucci A Lispi L Electrophysiological abnormalities in iatrogenic botulism: two case reports and review of the literature J Clin Neurosci 2019 2 60 (October) 138 41 30348587 \n30 Schiller HH Stålberg E Human botulism studied with single-fiber electromyography Arch Neurol 1978 6 35 (6) 346 9 655906\n\n",
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"journal": "Case reports in neurology",
"keywords": "Botulinum toxin; Iatrogenic botulism; Myasthenia gravis; Single-fiber electromyography",
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"pubdate": "2019",
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"references": "29096852;15257512;22986799;16175373;26188667;17486596;23177038;30348587;23157683;29128986;655906;9851395;8380486;2995805;20150804;10369829;20852412;28111784;3785290;20953643;10667297;30142749;15985599;8041381;6763148;10928589",
"title": "Cosmetic Injection of Botulinum Toxin Unmasking Subclinical Myasthenia Gravis: A Case Report and Literature Review.",
"title_normalized": "cosmetic injection of botulinum toxin unmasking subclinical myasthenia gravis a case report and literature review"
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"abstract": "Cortical tremor (CT) is a form of cortical reflex myoclonus that can mimic essential tremor (ET). Clinical features that are helpful in distinguishing CT from ET are the irregular and jerky appearance of the movements. We report two patients with CT with coexisting orthostatic movements, either orthostatic tremor (OT) or myoclonus, who experienced functional improvement in both cortical myoclonus and orthostatic movements when treated with levetiracetam.",
"affiliations": "Department of Neurology, Movement Disorder Division, 5 East 98th St, New York, NY 10029 USA ; Icahn School of Medicine at Mount Sinai, New York, NY USA.;Department of Neurology, Movement Disorder Division, 5 East 98th St, New York, NY 10029 USA ; Icahn School of Medicine at Mount Sinai, New York, NY USA.",
"authors": "Termsarasab|Pichet|P|;Frucht|Steven J|SJ|",
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"doi": "10.1186/s40734-014-0013-0",
"fulltext": "\n==== Front\nJ Clin Mov DisordJ Clin Mov DisordJournal of Clinical Movement Disorders2054-7072BioMed Central London 1310.1186/s40734-014-0013-0Case ReportCortical Tremor (CT) with coincident orthostatic movements Termsarasab Pichet Pichet.Termsarasab@mountsinai.org Frucht Steven J Steven.Frucht@mssm.edu Department of Neurology, Movement Disorder Division, 5 East 98th St, New York, NY 10029 USA Icahn School of Medicine at Mount Sinai, New York, NY USA 2 2 2015 2 2 2015 2015 2 731 8 2014 8 12 2014 © Termsarasab and Frucht; licensee BioMed Central Ltd. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Cortical tremor (CT) is a form of cortical reflex myoclonus that can mimic essential tremor (ET). Clinical features that are helpful in distinguishing CT from ET are the irregular and jerky appearance of the movements. We report two patients with CT with coexisting orthostatic movements, either orthostatic tremor (OT) or myoclonus, who experienced functional improvement in both cortical myoclonus and orthostatic movements when treated with levetiracetam.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s40734-014-0013-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nCortical tremorOrthostatic tremorLevetiracetamissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nCortical tremor (CT) is a syndrome described in the literature by multiple names, including familial cortical tremor, benign adult familial myoclonic epilepsy, familial adult myoclonic epilepsy, autosomal dominant cortical myoclonus and epilepsy, and familial cortical myoclonic tremor among others [1]. We will use the term CT in this paper for consistency. Clinically small-amplitude, irregular, jerky movements affect the distal limbs in posture and action. The disorder can mimic essential tremor (ET), and many patients are incorrectly diagnosed with ET [2]. Electrophysiologic studies however reveal features of cortical reflex myoclonus including cortical spikes prior to myoclonus on back-averaging, giant somatosensory-evoked potentials (SEPs), and enhanced C-reflex [3].\n\nAlthough tremulous movements in the legs have been described in some case reports of CT [4,5], to our knowledge coincident orthostatic movements, have not been reported in these patients. We present two patients with CT with coexisting orthostatic movements, either orthostatic tremor (OT) or myoclonus, both of whom enjoyed a favorable response to treatment of CT and orthostatic movements with levetiracetam.\n\nCase presentation\nPatient 1\nA 61-year-old woman was referred for evaluation of tremulous movements of her hands that had progressively worsened over the past five years. Movements could not be voluntarily suppressed and were severe enough to cause functional disability (Additional file 1: Video 1). In addition, she had instability when standing, and noticed that this feeling of instability instantly disappeared when she began to walk or if she held onto a wall. There was no history of epilepsy. Examination revealed frequent and moderate amplitude myoclonic jerks affecting both hands at rest. Myoclonus was worse with posture and action, such as when performing finger-to-nose testing. There was a superimposed, regular, oscillatory action tremor of both hands with approximately 6-Hz ET-like frequency (Additional file 1: Video 1). This tremor was also visible on Archimedes spiral (Figure 1A). The tremor occurred in the same pattern without inconsistency or incongruency. When she stood, there was a very low amplitude high frequency tremor of her legs that was visible and palpable. Leg tremor abated immediately when she put her hand on the wall, and disappeared when she walked. There were no signs of parkinsonism. MRI of the brain and routine EEG were unremarkable.Figure 1 \nPanel A, B and C demonstrate spirals and handwriting of patient 1 in January 2013, February 2013, and May 2013, respectively. She was on no medication in January 2013, levetiracetam 2,000 mg/day in February 2013, and levetiracetam 2,000 mg/day and primidone 100 mg/day in May 2013. Panels A1, B1 and C1 are spirals from the left hand, and panels A2, B2 and C2, are from the right. Panels B3 and C3 are handwriting from the right hand. There is improvement of her hand spirals and handwriting over time.\n\n\n\nA diagnosis of CT and coincident orthostatic movements (likely OT) was ascertained clinically. Physiologic confirmation was unfortunately not available. She was started on levetiracetam with a slow titration to 2,000 mg/day, with marked improvement of both her myoclonus, the ET-like movements of her hands (Figure 1B and C), and symptoms of OT (Additional file 2: Video 2). Primidone was added and titrated up slowly to 100 mg/day with more improvement in tremulous movements of her hands. However, she could not tolerate it due to sedation, and the dose was decreased to 50 mg/day. Clonazepam was ineffective.\n\nPatient 2\nAn 85-year-old woman presented with symptoms of unsteadiness when standing, leading to multiple falls. She had also noticed that on several occasions her left hand flung out uncontrollably. On examination, low amplitude myoclonic jerks of the left arm occurred with posture and action. Twenty seconds after standing up, she developed irregular jerky movements of the left leg which made her very unsteady. These movements disappeared when she reached out for the wall or when she began to walk, but recurred 20 seconds after she stopped walking (Additional file 3: Video 3). There were no signs of parkinsonism. A DAT scan obtained prior to evaluation by the referring neurologist was normal.\n\nA clinical diagnosis of CT with likely coincident OT was made; physiologic confirmation was not available. She was treated with levetiracetam with a slow titration up to 1,500 mg/day. Significant improvement in both cortical tremor and OT was noted, but she developed depression. The dose was decreased to 1,000 mg/day with resolution of depression, and symptoms of CT and OT remained well controlled (Additional file 4: Video 4).\n\nDiscussion\nWe present two patients whose histories and examinations support the diagnosis of CT. Both patients also had symptoms and signs of orthostatic movements, and both conditions responded to treatment with levetiracetam. OT is phenomenologically distinct from cortical myoclonus. Orthostatic myoclonus has been reported as a differential diagnosis of OT [6,7]; we recognize that electrophysiology would be required to distinguish these two. The pathophysiology of orthostatic myoclonus is still not well understood, and the link between cortical reflex myoclonus and orthostasis myoclonus remains unknown. In addition, the differential diagnosis in our second patient includes late-onset asymmetric myoclonus in which cortical myoclonus is an electrophysiologic hallmark [8]. However, due to lack of electrophysiology, we cannot confirm if the left leg movements were indeed compatible with orthostatic tremor or myoclonus. Late-onset asymmetric myoclonus is very rare, and the association between CT and this entity is unknown.\n\nAlthough postural hand tremor can be seen in OT, it is usually mild and present only when standing, unlike the myoclonic movements of the arms in our patients. The tremor of OT emerges after a latency with standing and markedly improves or immediately disappears with walking or touching a wall. OT is characterized by a 13–18 Hz tremor of both legs that may not be visible, and is considered to be one of the highest frequency tremors [9].\n\nCharacteristic clinical clues for the diagnosis of CT are tremulous small amplitude movements in the distal limbs that are jerky and arrhythmic. Although we did not have physiologic confirmation, the appearance of the movements and their dramatic response to levetiracetam supports the likelihood that they were indeed myoclonic. The distal predominance and triggering with action and intention are other clues to a likely cortical origin of the myoclonic jerks. Electrophysiologic testing would have been helpful in identifying characteristic features such as cortical spikes prior to myoclonus on back-averaging technique, giant SEPs, and enhanced C-reflex. Neither patient had a family history of a similarly affected relative, and neither one had a history of seizures, commonly seen in this condition [1].\n\nLevetiracetam is an antiepileptic medication that binds to synaptic vesicle glycoprotein 2A (SV2A) in the brain, which in turn inhibits presynaptic calcium channel and neuronal activities. Levetiracetam possesses efficacy in treating cortical myoclonus, and the response to levetiracetam in our patients supports the diagnosis of CT. Although some ET patients may experience improvement with levetiracetam, the degree of improvement in our patients was quite striking, and indeed two randomized studies failed to show improvement of tremor with the drug [10,11].\n\nInterestingly, patient 1 also has improvement in tremulous movements of her hands with primidone. This does not necessarily reflect the diagnosis of essential tremor. Primidone acts in the central nervous system, possibly affecting voltage-gated sodium channels, although the exact mechanism of action is unknown. It was originally used as an epileptic agent. Thus, we are not surprised that her cortical tremor was improved by primidone as well.\n\nThe coincident improvement of OT in our patients deserves comment. The pathophysiology of OT is incompletely understood. Abnormalities in central cerebello-thalamo-cortical oscillatory networks have been proposed [12]. The reduction of calcium currents by levetiracetam [13] may indirectly enhance GABA in this network, which may lead to reduction of OT. Although levetiracetam was found to be ineffective in one double-blind crossover study in OT [14], anecdotally some OT patients respond to levetiracetam therapy, as did both of our patients.\n\nEstablishing a correct diagnosis of both CT and OT is important for optimal treatment. Misinterpretation of tremulous movements as ET may lead to treatment with β-blockers which are typically ineffective in CT and OT [15]. Medications that are reported to be effective in OT include clonazepam and gabapentin. For CT, in addition to levetiracetam, clonazepam and valproic acid may also be effective.\n\nConclusion\nWe report the two cases of CT with co-existing orthostatic movements, possibly OT. Levetiracetam may be an effective treatment options in these patients. Further study in larger number of patients with CT, and electrophysiology studies may be utilized to confirm the diagnosis of OT, or increase sensivity in detecting OT in CT patients with unsteadiness.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAdditional files\nAdditional file 1: Video 1. Patient 1 had mild-to-moderate kinetic and postural greater than rest “tremor” of both hands. Her “tremor” was irregular and jerky, and in fact, it was cortical myoclonus. There was no stimulus sensitivity to somesthetic stimuli when examining with a pin. She felt imbalance when standing, and this feeling abated when walking. When she stopped walking and stood still, she felt unsteady again which was better when she touched the wall with her hand. When she wrote or drew a spiral, there was myoclonus visible in both hands.\n\nAdditional file 2: Video 2. Video demonstrates her examination when patient 1 was on levetiracetam 2,000 mg/day. There was improvement of myoclonus in both hands, at rest and with action. In addition, there was improvement of orthostatic tremor and she felt more steady when standing. Myoclonus in both hands when writing or drawing a spiral was also improved.\n\nAdditional file 3: Video 3. Patient 2 demonstrated mild postural and terminal kinetic “tremor” in both hands. The “tremor” was irregular and jerky, not typical for essential tremor. The phenomenology is indeed myoclonus. She felt unsteady when standing, and better when walking, touching the wall or holding the examiner’s hand or finger.\n\nAdditional file 4: Video 4. Video demonstrates the examination when patient 2 was on levetiracetam 1,000 mg/day. There was improvement in myoclonus of her hands, and orthostatic tremor. She felt more steady when walking.\n\n\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nPT participated in patient evaluation, drafting/revising the manuscript, video editing. SJF participated in patient evaluation, drafting/revising the manuscript, video editing and study concept. Both authors read and approved the final manuscript.\n==== Refs\nReferences\n1. van Rootselaar AF van Schaik IN van den Maagdenberg AM Koelman JH Callenbach PM Tijssen MA Familial cortical myoclonic tremor with epilepsy: a single syndromic classification for a group of pedigrees bearing common features Mov Disord 2005 20 665 673 10.1002/mds.20413 15747356 \n2. Bourdain F Apartis E Trocello JM Vidal JS Masnou P Vercueil L Vidailhet M Clinical analysis in familial cortical myoclonic tremor allows differential diagnosis with essential tremor Mov Disord 2006 21 599 608 10.1002/mds.20725 16281296 \n3. Terada K Ikeda A Mima T Kimura M Nagahama Y Kamioka Y Murone I Kimura J Shibasaki H Familial cortical myoclonic tremor as a unique form of cortical reflex myoclonus Mov Disord 1997 12 370 377 10.1002/mds.870120316 9159732 \n4. Labauge P Amer LO Simonetta-Moreau M Attane F Tannier C Clanet M Castelnovo G An-Gourfinkel I Agid Y Brice A Ducros A LeGuern E Absence of linkage to 8q24 in a European family with familial adult myoclonic epilepsy (FAME) Neurology 2002 58 941 944 10.1212/WNL.58.6.941 11914412 \n5. van Rootselaar F Callenbach PM Hottenga JJ Vermeulen FL Speelman HD Brouwer OF Tijssen MA A Dutch family with ‘familial cortical tremor with epilepsy’. Clinical characteristics and exclusion of linkage to chromosome 8q23.3-q24.1 J Neurol 2002 249 829 834 10.1007/s00415-002-0729-x 12140665 \n6. Glass GA Ahlskog JE Matsumoto JY Orthostatic myoclonus: a contributor to gait decline in selected elderly Neurology 2007 68 1826 1830 10.1212/01.wnl.0000260225.46732.af 17360964 \n7. van Gerpen JA A retrospective study of the clinical and electrophysiological characteristics of 32 patients with orthostatic myoclonus Parkinsonism Relat Disord 2014 20 889 893 10.1016/j.parkreldis.2014.05.006 24894119 \n8. Katschnig P Massano J Edwards MJ Schwingenschuh P Cordivari C Bhatia KP Late-onset asymmetric myoclonus: an emerging syndrome Mov Disord 2011 26 1744 1748 10.1002/mds.23676 21618610 \n9. Deuschl G Bain P Brin M Consensus statement of the Movement Disorder Society on Tremor Ad Hoc Scientific Committee Mov Disord 1998 13 Suppl 3 2 23 9827589 \n10. Elble RJ Lyons KE Pahwa R Levetiracetam is not effective for essential tremor Clin Neuropharmacol 2007 30 350 356 10.1097/WNF.0b013E31807A32C6 18090460 \n11. Handforth A Martin FC Pilot efficacy and tolerability: a randomized, placebo-controlled trial of levetiracetam for essential tremor Mov Disord 2004 19 1215 1221 10.1002/mds.20147 15390011 \n12. Muthuraman M Hellriegel H Paschen S Hofschulte F Reese R Volkmann J Witt K Deuschl G Raethjen J The central oscillatory network of orthostatic tremor Mov Disord 2013 28 1424 1430 23926026 \n13. Angehagen M Margineanu DG Ben-Menachem E Ronnback L Hansson E Klitgaard H Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons Neuroreport 2003 14 471 475 10.1097/00001756-200303030-00035 12634506 \n14. Hellriegel H Raethjen J Deuschl G Volkmann J Levetiracetam in primary orthostatic tremor: a double-blind placebo-controlled crossover study Mov Disord 2011 26 2431 2434 10.1002/mds.23881 21953629 \n15. Ikeda A Kakigi R Funai N Neshige R Kuroda Y Shibasaki H Cortical tremor: a variant of cortical reflex myoclonus Neurology 1990 40 1561 1565 10.1212/WNL.40.10.1561 2215948\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2054-7072",
"issue": "2()",
"journal": "Journal of clinical movement disorders",
"keywords": "Cortical tremor; Levetiracetam; Orthostatic tremor",
"medline_ta": "J Clin Mov Disord",
"mesh_terms": null,
"nlm_unique_id": "101662043",
"other_id": null,
"pages": "7",
"pmc": null,
"pmid": "26788343",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "18090460;21953629;12634506;11914412;24894119;21618610;16281296;17360964;15747356;12140665;15390011;9159732;23926026;9827589;2215948",
"title": "Cortical Tremor (CT) with coincident orthostatic movements.",
"title_normalized": "cortical tremor ct with coincident orthostatic movements"
} | [
{
"companynumb": "US-UCBSA-2016004687",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Although intrahepatic cholestasis of pregnancy (ICP) remains poorly understood, there are several perinatal complications associated with this condition. This study aimed to examine perinatal outcomes of women with ICP, evaluate outcomes according to severity of disease, and monitor time to symptom improvement following diagnosis.\n\n\n\nIt involves a prospective, observational study of women with ICP at a single institution. Women with new-onset pruritus without rash were referred to a high-risk obstetrics clinic and evaluated with fasting total bile acids (TBA). Laboratory-confirmed ICP was defined as fasting TBA ≥10 µmol/L. Following diagnosis, a standardized protocol was utilized, including treatment with ursodeoxycholic acid (UDCA). Perinatal outcomes were compared amongst those with and without ICP, and to the general population. Women with ICP were further analyzed based on maximum TBA: 10 to 39, 40 to 99, and ≥100 µmol/L. A Kaplan-Meier survival curve was used to analyze time to symptom improvement.\n\n\n\nA total of 404 patients were evaluated and 212 (52%) were diagnosed with ICP. The mean gestational age at diagnosis was 34.1 ± 3.3 weeks. When comparing those with ICP to those not confirmed, and to the general population, there were no differences in age, parity, mode of delivery, preeclampsia, or stillbirth (p > 0.05). Preterm birth was significantly associated with ICP (p < 0.01). This relationship was significant across increasing severity of TBA (p < 0.01) and persisted when examining rates of spontaneous preterm birth (p < 0.01). All women with fasting TBA ≥40 µmol/L delivered preterm due to premature rupture of membranes or spontaneous labor. Time to symptom improvement after diagnosis was over 2 weeks on average; however, this time increased with worsening severity of disease.\n\n\n\nDespite treatment with UDCA, women with ICP are at increased risk for spontaneous preterm birth, and this risk significantly increased with severity of disease. Although not significant, a trend exists between increasing time to symptom improvement and worsening severity of disease.\n\n\n\n· Preterm birth is significantly increased in patients diagnosed with intrahepatic cholestasis of pregnancy.. · The risk of preterm birth in women with ICP increases across increasing strata of disease.. · Following initiation of treatment in patients with ICP, symptom improvement takes more than 2 weeks..",
"affiliations": "Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.",
"authors": "Yule|Casey S|CS|0000-0002-9611-6248;Holcomb|Denisse S|DS|;Kraus|Alexandria C|AC|;Brown|Charles E L|CEL|;McIntire|Donald D|DD|;Nelson|David B|DB|",
"chemical_list": "D001647:Bile Acids and Salts",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0040-1717076",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1631",
"issue": "38(5)",
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001647:Bile Acids and Salts; D002780:Cholestasis, Intrahepatic; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D016015:Logistic Models; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D047928:Premature Birth; D011446:Prospective Studies; D050497:Stillbirth; D013781:Texas; D055815:Young Adult",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "414-420",
"pmc": null,
"pmid": "32971564",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Cholestasis: A Prospective Study of Perinatal Outcomes and Time to Symptom Improvement.",
"title_normalized": "cholestasis a prospective study of perinatal outcomes and time to symptom improvement"
} | [
{
"companynumb": "US-ALLERGAN-2038581US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": null,
"d... |
{
"abstract": "Limited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions.We prospectively followed patients admitted to 4 hospitals' medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission.There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34-65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (P ≤ 0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06-2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09-1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07-1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17-3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable.In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect South Africa's high HIV and tuberculosis burden. Identification and management of these ADRs should be considered in HIV and tuberculosis care and treatment programs and should be emphasized in health care worker training programmes.",
"affiliations": "From the Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Cape Town (JPM, CN, NK, AS, UM, MB, MFDS, RDW, GM, KC); Department of Medicine, East London Hospital Complex and Walter Sisulu University, East London (AGP); Department of Medicine, Edendale Hospital, Pietermaritzburg, South Africa (DPKW), US Centers for Disease Control and Prevention, Pretoria (EUI, GA); National Department of Health, Pretoria (MD); and Pharmaceutical Services, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa (MD).",
"authors": "Mouton|Johannes P|JP|;Njuguna|Christine|C|;Kramer|Nicole|N|;Stewart|Annemie|A|;Mehta|Ushma|U|;Blockman|Marc|M|;Fortuin-De Smidt|Melony|M|;De Waal|Reneé|R|;Parrish|Andy G|AG|;Wilson|Douglas P K|DPK|;Igumbor|Ehimario U|EU|;Aynalem|Getahun|G|;Dheda|Mukesh|M|;Maartens|Gary|G|;Cohen|Karen|K|",
"chemical_list": "D019380:Anti-HIV Agents; D000995:Antitubercular Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000003437",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7974",
"issue": "95(19)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D003430:Cross-Sectional Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections; D006760:Hospitalization; D006761:Hospitals; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011446:Prospective Studies; D012307:Risk Factors; D012737:Sex Factors; D013019:South Africa; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e3437",
"pmc": null,
"pmid": "27175644",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "12061133;19709728;12197196;15827761;837969;15073757;17879931;16224307;18070223;16912251;24047689;10118597;22563365;25595711;25475751;22438900;17689801;18594048;24052632;21407815;24714066;23588107;17620824;16180936;20635827;17711539;15350153;8364259;12569078;17662147;19709737;19709736;25083223;23201214;19709731;9555760;12792009;20673002;20384533;22506106;6781682;24585558;9797802",
"title": "Adverse Drug Reactions Causing Admission to Medical Wards: A Cross-Sectional Survey at 4 Hospitals in South Africa.",
"title_normalized": "adverse drug reactions causing admission to medical wards a cross sectional survey at 4 hospitals in south africa"
} | [
{
"companynumb": "PHHY2016ZA089541",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDual antiplatelet therapy (DAP) is necessary to prevent thromboembolic events during carotid stenting, stent-assisted coil embolization, and implant of flow diverters (FD). However, DAP in the acute phase may be challenging. An intravenous alternative, cangrelor, has rapid onset, short plasma half-life, and more reliable antiplatelet action for acute interventions. The study objective was to evaluate feasibility and safety of IV cangrelor during acute neuroendovascular surgery procedures.\n\n\nMETHODS\nWe performed a retrospective analysis of our database of patients treated with stent-assisted coil embolization, FD placement for aneurysmal subarachnoid hemorrhage (aSAH), or stenting for acute internal carotid artery (ICA) occlusion where IV cangrelor was used. Morbidity, mortality, incidence of thromboembolic events, hemorrhages, and 90-day outcomes were reported.\n\n\nRESULTS\nTen patients were found in our database from June 2018 through January 2019. Four patients had aSAH, four had middle cerebral artery strokes with tandem lesions, one had an ICA occlusion, and one had a vertebral artery aneurysm. One of the ten patients experienced a thrombotic event. One patient developed new post-procedural bleeding and two had worsening intracranial hemorrhage. Five patients were discharged home in stable condition, two to acute rehabilitation, one to a nursing facility, and two others expired (likely the result of the severe and evolving strokes). Of the eight who were discharged, six (75%) had a good 90-day functional outcome (modified Rankin Scale 0-2).\n\n\nCONCLUSIONS\nAcute administration of IV cangrelor with or without oral ticagrelor is a feasible antiplatelet treatment option for acute neuroendovascular procedures.",
"affiliations": "Miami Cardiac & Vascular Institute, Baptist Health South Florida, Miami, Florida, USA linfante.italo@gmail.com.;Translational Medicine, Florida International University Herbert Wertheim College of Medicine, Miami, Florida, USA.;Miami Neuroscience Institute, Baptist Health South Florida, Miami, Florida, USA.;Miami Cardiac & Vascular Institute, Baptist Health South Florida, Miami, Florida, USA.;Miami Cardiac & Vascular Institute, Baptist Health South Florida, Miami, Florida, USA.",
"authors": "Linfante|Italo|I|;Ravipati|Kaushik|K|;Starosciak|Amy Kathryn|AK|http://orcid.org/0000-0001-5647-3868;Reyes|Dennys|D|;Dabus|Guilherme|G|",
"chemical_list": "D058921:Purinergic P2Y Receptor Antagonists; D000249:Adenosine Monophosphate; C117446:cangrelor; D000077144:Clopidogrel; D000077486:Ticagrelor",
"country": "England",
"delete": false,
"doi": "10.1136/neurintsurg-2020-015841",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1759-8478",
"issue": "13(1)",
"journal": "Journal of neurointerventional surgery",
"keywords": "aneurysm; flow diverter; stent; stroke; thrombectomy",
"medline_ta": "J Neurointerv Surg",
"mesh_terms": "D000249:Adenosine Monophosphate; D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077144:Clopidogrel; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058921:Purinergic P2Y Receptor Antagonists; D012189:Retrospective Studies; D000069322:Self Expandable Metallic Stents; D020521:Stroke; D013345:Subarachnoid Hemorrhage; D000077486:Ticagrelor; D016896:Treatment Outcome",
"nlm_unique_id": "101517079",
"other_id": null,
"pages": "30-32",
"pmc": null,
"pmid": "32414891",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intravenous cangrelor and oral ticagrelor as an alternative to clopidogrel in acute intervention.",
"title_normalized": "intravenous cangrelor and oral ticagrelor as an alternative to clopidogrel in acute intervention"
} | [
{
"companynumb": "US-BAYER-2020-100502",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TICAGRELOR"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nOver the last decade, there has been a paradigm shift in the extracorporeal treatment of intoxications. The availability of new treatment options, especially new membranes has led to a decrease in the use of techniques like charcoal hemoperfusion, once considered the gold standard to eliminate highly protein bound substances.\nThe EXtracorporeal Treatments In Poisoning (EXTRIP) workgroup is a collaborative international effort of pharmacologists, toxicologists, critical care physicians, and nephrologists that is reviewing all available evidence in extracorporeal procedures for the treatment of poisonings in a standardized way to distill treatment recommendations for the physician at the bedside. One of the first available EXTRIP guidelines summarizes treatment recommendations for severe carbamazepine intoxications.\n\n\nMETHODS\nWe report the case of a 43-year-old Caucasian woman with who ingested about 21 g carbamazepine in a suicidal attempt together with alcohol. Combining gastroscopic removal of carbamazepine and multiple dose activated charcoal with intermittent high-flux hemodialysis lowered the initial carbamazepine level of 56.5 mg/l (47 mg/l before dialysis) to 25 mg/l. The patient, who initially required mechanical ventilation could be transferred to the psychiatric ward 24 h after ICU admission.",
"affiliations": "Zentrum Innere Medizin, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Deutschland.;Zentrum Innere Medizin, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Deutschland.;Zentrum Innere Medizin, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Deutschland.;Zentrum Innere Medizin, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Deutschland.;Zentrum Innere Medizin, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Deutschland.;Zentrum Innere Medizin, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Deutschland. kielstein@yahoo.com.",
"authors": "Drick|N|N|;Patecki|M|M|;Arelin|V|V|;Schmidt|J J|JJ|;Wahl|O|O|;Kielstein|J T|JT|",
"chemical_list": "D003692:Delayed-Action Preparations; D002220:Carbamazepine; D000431:Ethanol",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00063-015-0010-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2193-6218",
"issue": "110(7)",
"journal": "Medizinische Klinik, Intensivmedizin und Notfallmedizin",
"keywords": "Dibenzazepines; Hemodialysis; Poisoning; Renal replacement therapy; Therapeutic drug monitoring",
"medline_ta": "Med Klin Intensivmed Notfmed",
"mesh_terms": "D000328:Adult; D002220:Carbamazepine; D003131:Combined Modality Therapy; D003422:Critical Care; D003692:Delayed-Action Preparations; D062787:Drug Overdose; D000431:Ethanol; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D008657:Metabolic Clearance Rate; D011175:Positive-Pressure Respiration; D017410:Practice Guidelines as Topic; D006435:Renal Dialysis; D013406:Suicide, Attempted",
"nlm_unique_id": "101575086",
"other_id": null,
"pages": "551-4",
"pmc": null,
"pmid": "25801374",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9493333;23171639;16253717;23942786;24844159;24844155;22715378;25355482;21057310;12078955",
"title": "Successful hemodialysis for life-threatening carbamazepine drug overdose: Case-based introduction of new guidelines.",
"title_normalized": "successful hemodialysis for life threatening carbamazepine drug overdose case based introduction of new guidelines"
} | [
{
"companynumb": "DE-ACTAVIS-2015-23929",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALCOHOL"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nTramadol can cause life-threatening toxicity in overdose; however, data on its toxicity in children are lacking. This study investigates toxicity associated with tramadol ingestions in children. The hypothesis is that children will experience dose-related central nervous system and respiratory depression and seizures.\n\n\nMETHODS\nA retrospective evaluation of cases from the National Poison Center Data System between January 1, 2000, and December 31, 2013, was performed. Inclusion criteria were age below 6 years and single-substance acute tramadol ingestion. For dose-effect analysis, cases with sufficient dose quantity information were included.\n\n\nRESULTS\nThere were 7334 cases that met inclusion criteria. Outcomes were 84.8% no effect, 12.6% minor, 2.2% moderate, and 0.4% major effect. There was 1 fatality. Most of the children (36.4%) were treated/released from the emergency department; other management sites were home (36.4%), admission (5.9%), and others (3.2%). In the 1115 children with symptoms, drowsiness (N = 611) and vomiting (N = 178) occurred most frequently. More serious clinical effects included respiratory depression in 36 and seizures in 24 children. Of 2772 children with milligram dose recorded, there were 10 cases of respiratory depression and 6 of seizure. Median doses for respiratory depression and seizure were 225 (range, 50-600 mg) and 525 mg (range, 50-1050 mg), respectively. The minimum weight-based dose for respiratory depression/arrest was 7.9 mg/kg and for seizures, 4.8 mg/kg.\n\n\nCONCLUSIONS\nSeizure and respiratory depression are uncommon in pediatric tramadol ingestions. Given the small number of patients with dose data and lack of laboratory confirmation of dose, more studies are needed to determine the minimum dose at which medical management is recommended.",
"affiliations": "From the Maryland Poison Center, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, MD.",
"authors": "Stassinos|Gina L|GL|;Gonzales|Lawrence|L|;Klein-Schwartz|Wendy|W|",
"chemical_list": "D000701:Analgesics, Opioid; D014147:Tramadol",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "35(2)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000701:Analgesics, Opioid; D002675:Child, Preschool; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011039:Poison Control Centers; D012189:Retrospective Studies; D014147:Tramadol",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "117-120",
"pmc": null,
"pmid": "28225374",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Characterizing the Toxicity and Dose-Effect Profile of Tramadol Ingestions in Children.",
"title_normalized": "characterizing the toxicity and dose effect profile of tramadol ingestions in children"
} | [
{
"companynumb": "US-MYLANLABS-2015M1033279",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
... |
{
"abstract": "We present a case series of 5 patients with proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) of renal allografts to better define its natural history, presenting characteristics, pathological features and treatment outcome.\n\n\n\nThese 5 patients presented 5 to 19 months post-kidney transplantation for complaints of serum creatinine (Scr) elevation, proteinuria or hematuria. Membranoproliferative glomerulonephritis (MPGN) pattern was the most frequently observed histological manifestation. Immunofluorescence showed monoclonal IgG3κin 3 patients and IgG3λ in the other 2 cases. Immunofluorescence staining helped to establish PGNMID in the absence of conspicuous microscopic changes in one case. Rituximab and bortezomib were effective in alleviating proteinuria in all 4 treated patients and decreasing Scr in 2 cases. Plasmapheresis treatment in another patient was not effective in preventing Scr elevation. At last-follow-up, 2 patients were in dialysis and 2 had improved kidney function with almost normal Scr and no proteinuria. The remaining one patient died of pulmonary infections.\n\n\n\nWe conclude that PGNMID occurs early after kidney transplant. PGNMID should be included in the differential diagnoses of recurrent MPGN in renal allografts. Rituximab and bortezomib are helpful to decrease proteinuria and Scr in a subset of patients. Larger studies are needed to conclusively establish best treatment strategies for PGNMID in renal allografts.",
"affiliations": "National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000, China. wjqdoctor@163.com.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Medical University, Nanjing, 210000, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000, China.",
"authors": "Wen|Jiqiu|J|;Wang|Wei|W|;Xu|Feng|F|;Chen|Jinsong|J|;Zhang|Mingchao|M|;Cheng|Dongrui|D|;Ni|Xuefeng|X|;Li|Xue|X|;Liu|Zhihong|Z|",
"chemical_list": "D007074:Immunoglobulin G",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-018-0969-3",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 96910.1186/s12882-018-0969-3Research ArticleClinicopathological analysis of proliferative glomerulonephritis with monoclonal IgG deposits in 5 renal allografts Wen Jiqiu +86 13851767588wjqdoctor@163.comwjqkidney@hotmail.com 1Wang Wei wjqdoctor@163.com 2Xu Feng wjqdoctor@163.com 1Chen Jinsong wjqdoctor@163.com 1Zhang Mingchao wjqdoctor@163.com 1Cheng Dongrui wjqdoctor@163.com 1Ni Xuefeng wjqdoctor@163.com 1Li Xue wjqdoctor@163.com 1Liu Zhihong wjqdoctor@163.com 11 0000 0001 0115 7868grid.440259.eNational Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University Jinling School of Medicine, Nanjing, 210000 China 2 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Medical University, Nanjing, 210000 China 11 7 2018 11 7 2018 2018 19 17325 10 2017 26 6 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\nWe present a case series of 5 patients with proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) of renal allografts to better define its natural history, presenting characteristics, pathological features and treatment outcome.\n\nResults\nThese 5 patients presented 5 to 19 months post-kidney transplantation for complaints of serum creatinine (Scr) elevation, proteinuria or hematuria. Membranoproliferative glomerulonephritis (MPGN) pattern was the most frequently observed histological manifestation. Immunofluorescence showed monoclonal IgG3κin 3 patients and IgG3λ in the other 2 cases. Immunofluorescence staining helped to establish PGNMID in the absence of conspicuous microscopic changes in one case. Rituximab and bortezomib were effective in alleviating proteinuria in all 4 treated patients and decreasing Scr in 2 cases. Plasmapheresis treatment in another patient was not effective in preventing Scr elevation. At last-follow-up, 2 patients were in dialysis and 2 had improved kidney function with almost normal Scr and no proteinuria. The remaining one patient died of pulmonary infections.\n\nConclusions\nWe conclude that PGNMID occurs early after kidney transplant. PGNMID should be included in the differential diagnoses of recurrent MPGN in renal allografts. Rituximab and bortezomib are helpful to decrease proteinuria and Scr in a subset of patients. Larger studies are needed to conclusively establish best treatment strategies for PGNMID in renal allografts.\n\nKeywords\nBortezomibMonoclonalityKidney transplantationPGNMIDRituximabhttp://dx.doi.org/10.13039/501100001809National Natural Science Foundation of China81570681Wen Jiqiu issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nOne of the main conundrums complicating kidney transplantation (KT) is recurrence or de novo appearance of various glomerulonephritides. Lately a new distinct entity that recurs shortly after KT and microscopically predominantly manifests as membranoproliferative glomerulonephritis (MPGN) pattern and immunofluorescently defined as monoclonal IgG deposition in the mesangium and along the glomerular basement membrane (GBM) has been named proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) [1–3]. In fact, other light microscopic patterns, such as membranous features and endocapillary proliferative pattern have also been reported [1–3]. Although also caused by the deposition of monoclonal immunoglobulins, this entity is distinct from other common monoclonal immunoglobulin deposition disease, such as light- and/or heavy-chain deposition disease [4].\n\nSome PGNMIDs cases were probably underrecognized previously, which may partially be explained by its rarity. As far as we are aware, only scarce case reports or small case series of PGNMID containing no more than 16 cases in the renal allografts have been reported to date [3, 5, 6]. Herein, we reported another case series containing 5 PGNMIDs that were referred to our center. We aim to better define the natural history, presenting characteristics, pathological features and treatment outcome of this elusive entity.\n\nMethods\nFive patients with PGNMID were retrospectively identified after searching the electronic pathology report database at National Clinical Research Institute of Nephrology, Jingling Hospital (Nanjing, China) from January 2009 to April 2017. Pathological findings were carefully re-evaluated by two experienced renal pathologists (F.X, M.C.Z). Diagnostic criteria for PGNMID were in accordance with those described previously [1–3]. Briefly, immunofluorescence (IF) examination showed 1) positivity of IgG and negativity for IgA and IgM in only the glomeruli; 2) IgG heavy-chain subclass analysis must fulfill that only one subclass present; 3)predominantly one light-chain (kappa or lambda) positivity; 4)exclusion of cryoglobulinemia through clinical or laboratory workups. Additionally, light microscopic evidence of proliferative glomerulonephritis should also be present. All the 5 patients included were admitted for indication biopsies. Biopsy specimens were routinely processed by standard techniques for light microscopy (LM), IF and electron microscopy (EM) observations. Stains used for LM included HE, PAS, Masson and PASM stain. IF were performed with a panel of antibodies, including IgG, IgA, IgM, C1q, C4, kappa, lambda, C4d and IgG subclasses (IgG1, IgG2, IgG3 and IgG4).\n\nPatients’ medical records were also reviewed for clinical and laboratory workup information. This study was approved by the Clinical Research Ethic Committee of Jingling Hospital. Written informed consents to publish their medical details were obtained from all the patients.\n\nResults\nDemographics, clinical features and laboratory workups\nDemographics, clinical features and laboratory workups of 5 included cases were summarized in Table 1. Two patients have undergone native biopsy with an unequivocal diagnosis of MPGN while no clear diagnoses were made in the other 3 cases since no native biopsy have been performed. All renal allograft biopsies were indicative, including proteinuria (5 cases), elevated serum creatinine (Scr) (4 cases) and hematuria (5 cases). The time interval from transplant to PGNMID is generally short, ranging from 5 months to 19 months.Table 1 Summary of demographics, clinical features, laboratory workups in 5 included patients\n\nPatient\t1\t2\t3\t4\t5\t\n\tPre-KT\tPost-KT\t1st post-KT biopsy\t2nd post-KT biopsy\t3rd post-KT biopsy\tPost-KT\tPost-KT\t1st post-KT biopsy\t2nd post-KT biopsy\t\nSex/Age\tM/38\tM/41\tM/44\tM/45\tM/48\tF/30\tM/51\tM/51\tM/53\t\nCause of ERSD\tMPGN (PGNMID)\tMPGN\tUnknown\tUnknown\tMPGN\t\nTransplant type\t\tDCD\tDCD\tDCD\tLiving-related donor\tDCD\t\nImmunosuppression protocol\t\tPre + MMF + CsA\tPre + MMF + FK506\tPre + MMF + FK506\tPre + MMF + FK506\tPre + MMF + FK506\t\nPRA\t\tI-/II-\tI-/II-\tI-/II-\tI-/II-\tI+/II-\tI-/II+\tI-/II-\tI-/II-\t\nTime interval from KT to PGNMID\t\t19 months\t\t15 monthsa\t52 months\t10.5 months\t11 months\t5 months\t33 months\t\nScr at biopsy (mg/dL)\t9.2\t0.77\t1.26\t1.24\t3.05\t1.2\t1.67\t1.88\t1.33\t\nProteinuria at biopsy (g/24 h)\t4+\t2.21\t\t2+\t6.09\t0.66\t5.5\t1.3\t37.03\t\nHematuria at biopsy\t2+\t3+\tND\tND\t2+\t3+\t4+\t2+\t3+\t\nUrine C3 (mg/dL)\t32.0\t8.2\tND\tND\tND\tND\t3\tND\tND\t\nSerum C3/C4\tND\tNormal\tND\tND\tND\tNormal\tNormal\tNormal\tNormal\t\nSerum kappa/lambda\tND\tND\tND\tNormal\tNormal\t4.2/2.51 mg/L\t86.51/68.8 mg/L\tNormal\tND\t\nCryoglobulin\tNegative\tNegative\tND\tNegative\tNegative\tNegative\tNegative\tNegative\tND\t\nC3NeF\tNegative\tNegative\tND\tND\tND\tNegative\tNegative\tNegative\tND\t\nCFH\tND\tND\tND\tND\tND\tNormal\tNormal\tNegative\tND\t\nCFH antibody\tND\tNegative\tND\tND\tND\tNegative\tND\tNegative\tND\t\nHBV/HCV/HIV\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\tHCV+\tNegative\t\nSerum M spike\tND\tND\tND\tNegative\tNegative\tNegative\tNegative\tNegative\tNegative\t\nBone marrow aspirate\tND\tND\tND\tND\tND\tNegative\tNegative\tNegative\tNegative\t\nRange: urine C3 < 2.76 mg/dl; serum kappa: 7-23 mg/L; serum lambda: 6-20 mg/L\n\nAbbreviations: C3NeF C3 nephrotic factor, CFH complement factor H, CsA cyclosporin, KT kidney transplantation, MMF mycophenolate mofetil, MPGN membranoproliferative glomerulonephritis, ND not done or not available, PRA panel reactive antibody, Pre predisone, Scr serum creatinine\n\na: in the 2nd biopsy of case 2, PGNMID was retrospectively diagnosed. The diagnosis at that time was mild mesangial proliferation\n\n\n\nLaboratory work-ups indicated normal serum complement C3/C4 levels in all 4 cases tested. Nevertheless, urine C3 excretion was increased in all 2 cases measured. Serum light-chain levels varied in different patients. Laboratory testing for cryoglobulin, C3 nephritic factor, complement factor H, complement factor H antibody and HBV/HCV/HIV were all negative except in case 5 in which HCV was present. These tests help to exclude cryoglobulinemia, C3 glomerulopathy and immune-complex-mediated glomerulonephritis that commonly manifested as MPGN pattern histopathologically. Serum monoclonal protein spike as detected by electrophoresis was negative in all 4 cases tested and bone marrow aspirate examination was also negative for plasma cell dyscrasias in 3 performed cases.\n\nRenal biopsy findings\nRenal pathological findings of a total of 9 biopsies were summarized in Table 2.Table 2 Summary of renal pathology findings of 5 included patients\n\nPatient\t1\t2\t3\t4\t5\t\n\tPre-KT\tPost-KT\t1st post-KT biopsy\t2nd post-KT biopsy*\t3rd post-KT biopsy\tPost-KT\tPost-KT\t1st post-KT biopsy\t2nd post-KT biopsy\t\nMicroscopic pattern\tMPGN\tMPGN\tMild mesangial proliferation\tMild mesangial proliferation\tMPGN + Crescents\tModerate to severe mesangial proliferation\tDiffuse proliferation\tModerate mesangial proliferation\tMPGN\t\nGlomeruli sclerosed (%)\t24\t0\t7.6\t0\t26.7\t0\t27.8\t0\t5.3\t\nCrescents (%)\t23.8\t16.7\t0\t0\t53.3\t0\t0\t3\t10.5\t\nIF/TA\tModerate\tMild\tNo IF/TA\tNo IF/TA\tmoderate\tMild\tModerate\tMild\tModerate\t\nIgG isotype\tIgG3/kappa\tIgG3/kappa\tNone\tIgG3/kappa\tIgG3/kappa\tIgG3/Lambda\tIgG3/Lambda\tIgG3/kappa\tIgG3/kappa\t\nC3\t++\t++\t–\t++\t–\t+++\t++\t++\t++\t\nC1q\t++\t+\t–\t–\t+\t+++\t++\t+\t++\t\nElectron-dense deposits\tGBM + mesangial\tGBM + mesangial\tNegative\tMainly mesangial\tSubendothelial + mesangial\tSubendothelial + mesangial + subepithelial\tGBM\tGBM + mesangial\tGBM + mesangial\t\nAbbreviations: AAMR acute antibody-mediated rejection, GBM glomerular basement membrane, IF/TA interstitial fibrosis and tubular atrophy, KT kidney transplantation, MPGN membranoproliferative glomerulonephritis, PGNMID proliferative glomerulonephritis with monoclonal IgG deposits\n\n*: in the 2nd biopsy of case 2, PGNMID was retrospectively diagnosed. The diagnosis at that time was mild mesangial proliferation\n\n\n\nPatient 1: Microscopic observation of the native kidney biopsy showed a classic MPGN pattern with mesangial proliferation leading to hypercellularity and glomerular tuft lobulation. Mesangial interposition resulting in the so-called characteristic “tram tracks” or “double contours” could also be frequently observed and validated by silver stain. Masson trichrome stain revealed intense fuchsinophilic immune-complexes in the mesangium and along the GBM. IF indicated intense IgG, C3 and C1q positivity in the mesangium and along the GBM with granular texture. Heavy-chain subclass analysis showed only IgG3 positivity with negativity for IgG1, IgG2 and IgG4. Light-chain IF demonstrated kappa positivity and lambda negativity. EM findings were congruent with IF with electron-dense deposits along the GBM and in the mesangium. PGNMID recurrence was documented with the allograft biopsy showed similar LM (Fig. 1a, b) and IF features (Fig. 1c-h) with the native kidney biopsy, even though fuchsinophilic deposits observed by Masson trichrome stain and EM (Fig. 1i) were less conspicuous and widespread.Fig. 1 Renal biopsy findings in the renal allograft of Patient 1. a Classic MPGN-pattern is obvious in this allograft biopsy (PAS × 200). b Masson staining showed a few fuchsinophilic immune-complexes. c-h IF profiles: positive IgG (c), IgG3 (d), C3 (g), C1q (h), kappa (e) and negative lambda (f) staining that were similar to the native kidney biopsy IF results. i EM showed electron-dense deposits along the GBM\n\n\n\nPatient 2: Medical record documented the native kidney disease was MPGN, however, a detailed re-evaluation of the slides of the native kidney biopsy was unobtainable. In the 1st allograft biopsy, only mild mesangial proliferation were seen (Fig. 2a-b) with negative IF and EM (Fig. 2c). In the 2nd allograft biopsy that was performed 12 months later, LM also only revealed mild mesangial proliferation (Fig. 2d-e). Nevertheless, IF showed bright granular staining for IgG (subcalss IgG3) and kappa predominantly in the mesangium(Fig. 2f-h). IF staining for C3, C1q and IgA, IgM were all negative. EM revealed obviously electron-dense deposits mainly in the mesangium (Fig. 2i). A 3rd biopsy performed 36 months after the 2nd biopsy demonstrated MPGN pattern in LM (Fig. 2j-k). Crescents and moderate interstitial fibrosis and tubular atrophy were also seen. Fuchsinophilic immune-complex deposits can occasionally be seen in the mesangium. In addition to similar IF findings with the 2nd biopsy, positive staining for C1q was also present (Fig. 2l-o). EM (Fig. 2p) showed extensive electron-dense deposits in the subendothelium and mesangium.Fig. 2 Pathological findings of 3 consecutive renal allograft biopsies in Patient 2. In the 1st allograft biopsy, only mild mesangial proliferation were seen (a, PAS × 400). No fuchsinophilic immune-complexes were found (b, Masson× 400). EM was normal with no obvious electron-dense deposits noticed (c). In the 2nd allograft biopsy that was performed 12 months later, LM only revealed mild to moderate mesangial proliferation (d, PAS × 400). Still, no fuchsinophilic immune-complexes could be observed (e, Masson× 400). Nevertheless, IF showed bright granular staining for IgG (subcalss IgG3) and kappa predominantly in the mesangium (f-h). EM revealed obviously electron-dense deposits mainly in the mesangium (i). A 3rd biopsy performed 36 months after the 2nd biopsy demonstrated MPGN pattern and crescents (j, PAS × 400) and obvious fuchsinophilic immune-complexes (k, Masson× 400). In addition to similar IF findings with the 2nd biopsy, positive staining for C1q was also present (l-o). EM (p) showed extensive electron-dense deposits in the subendothelium and mesangium\n\n\n\nPatient 3: This patient was complicated by acute antibody-mediated rejection as indicated by extensive peritubular capillaritis and extensive peritubular capillary C4d positive staining. LM showed diffuse proliferative glomerulonephritis. IF were typical of PGNMID with monoclonal IgG3 and lambda positivity. C3 and C1q staining were also positive. EM demonstrated extensive electron-dense deposits in the mesangium and in the subendothelial spaces. Subepithelial electron-dense deposits were also occasionally observed.\n\nPatient 4: LM and IF features were similar to those found in patient 3. Nonetheless, EM showed diffuse electron-dense deposits along the GBM. Widespread foot process effacement was seen, which explained massive proteinuria in this patient.\n\nPatient 5: The 1st allograft biopsy was noticeable for obvious fuchsinophilic immune-complexes in the mesangium. IF indicated monoclonality of IgG3. Tubulitis was also present, which was consistent with acute cellular rejection. In the 2nd allograft biopsy 28 months later, extensive MPGN-pattern was observed in the majority of glomeruli. Histological deterioration as indicated by increasing interstitial fibrosis, glomerular lobulation and widespread foot process effacement were observed.\n\nTreatment response, adverse events and prognosis\nTreatment regimens, treatment-related adverse events and follow-up results were summarized in Table 3. PGNMID was treated with plasma exchange in 2 patient (patient 1 and 5), rituximab in 1 patient (patient 2) and bortezomib in 3 cases (patient 3, 4 and 5). Patient 3 was also treated with pulse steroid for concomitant antibody-mediated rejection. Patient 5 was first treated with sofosbuvir and daclatasvir for HCV infection, then with pulse steroid since acute rejection was considered to be the main cause for Scr elevation. No serious treatment-related complications were observed except varicella infection in patient 4. Long-term follow-up in patient 2 and 3 showed worsening Scr, resulting in dialysis. Scr and proteinuria in patient 4 and 5 decreased and then stabilized. Patient 1 died of pulmonary infections at 13 months follow-up. After treating with bortezomib and plasma exchange, patient 5 experienced dramatically decreased proteinuria.Table 3 Treatment protocols and follow-up in 5 included patients\n\nPatient\t1\t2\t3\t4\t5\t\n\tPost-KT\t1st post-KT biopsy\t2nd post-KT biopsy\t3rd post-KT biopsy\tPost-KT\tPost-KT\t1st post-KT biopsy\t2nd post-KT biopsy\t\nScr/proteinuria at biopsy\t0.77/2.21\t\t\t3.05/6.09\t1.2/0.66\t1.67/5.5\t\t1.33/37.03\t\nTreatment\tPlasma exchange\tNone\tNone\tRituximab\tPulse steroid + bortezomib\tBortezomib\tSofosbuvir + Daclatasvir + pulse steroid\tBortezomib + plasma exchange\t\nTreatment-related complication\tNone\t\t\tNone\tNone\tVaricella infection\tNone\tNone\t\nFollow-up timea\t13 months\t\t\t39 months\t7 months\t11 months\t\t1 months\t\nLast follow-up Scr(mg/dl)/Proteinuria(g/d)\tDeath due to pulmonary infections\t\t\tIn dialysis\tIn dialysis\t1.1/−\t\t1.25/14\t\na: follow-up time here denotes the time interval between treatment to last outpatient follow-up\n\n\n\nDiscussion\nPGNMID is a rare disease entity that was first reported by Nasr et al. [1] in the native kidneys mimicking kidney lesions caused by immune-complex-mediated glomerulonephritis. To the best of our knowledge, the largest series reported in the native kidneys contained 60 cases [7] and only 16 cases [5] of recurrent or de novo PGNMID have been reported in renal allografts. In this retrospective study, some observations that we have made regarding PGNMID are of important clinical significance. First, PGNMID generally occurs early after KT. The longest time interval from KT to PGNMID occurrence in our series is 19 months. Second, PGNMID is rare; however, its IF manifestation is stereotypical with solely positivity of one subclass of IgG, one subclass of light-chains and frequently positive C3 and C1q staining in only the glomeruli. Third, the gradual progression of PGNMID, as illustrated by case 2, is characterized by positive IF staining for IgG subclass and EM finding of electron-dense immune-complex which is unappreciable by LM then to apparent mesangial expansion and immune-complex deposition as detected by Masson staining. At last, rituximab and bortezomib, two drugs that function to eliminate B lymphocytes and plasma cells respectively, were effective in a subset of patients included in our study.\n\nThe clinical manifestations and laboratory workups of de novo or recurrent PGNMID are totally non-specific. Frequent presenting complaints included elevated Scr, proteinuria and hematuria. Nasr et al. [2] reported that 97.1 and 77.1% of patients had > 1 g/24 h proteinuria and hematuria respectively at the time of biopsy. Interestingly, PGNMID was incidentally found in case 3 and 5 when biopsied for suspicion of acute rejection. In fact, it has been reported that PGNMID was concomitantly found in biopsy specimens that were also present for other common conditions, such as BK-virus nephropathy and transplant glomerulopathy [6]. Laboratory workups for common etiologies of MPGN are frequently negative, including cryoglobulinemia, factors leading to complement alternative pathway dysregulation (C3 nephritic factor, complement factor H antibody) and infectious etiologies. Despite the glomerular deposits are monoclonal in nature, serum monoclonal protein (M spike) and bone marrow aspirate examination are all negative in cases tested. No serum or urine parapprotein were detected in all the patients tested in the renal allograft patients reported by Nasr et al. [3]. However, serum or urine parapprotein and plasma cell dyscrasia was detected in 29.7 and 9% of patients respectively in the largest cohort of native kidneys [7]. Due to potent immunosuppression, detecting an overt lymphoproliferative disorder is even more difficult in transplant patients. Nonetheless, overt plasma cell neoplasia has been reported in a patient with renal allograft [8]. Due to our limited follow-up time and incomplete work-up for lymphoproliferative disorders, it is prudent to follow-up these patients closely for early detection.\n\nThe microscopic manifestations of PGNMID in the renal allografts are almost the same as those in the native kidneys [2, 3]. MPGN-like pattern and diffuse proliferative glomerulonephritis-like pattern are predominantly seen in this series. The key distinguishing and diagnostic feature of PGNMID is by IF with demonstration of monoclonality of both heavy and light chain with both C3 and C1q frequently being positive. EM is not only helpful in corroborating IF findings, but also conducive for excluding other common mimickers, such as immunotactoid glomerulopathy, fibrillary glomerulonephritis and LHCDD. In the transplant biopsy specimens, transplant glomerulopathy should also be excluded since it may also show MPGN-like pattern. The mere diagnosis of MPGN or MPGN-like changes has now been strongly discouraged since this diagnosis provides little information regarding the underlying etiology and thus unhelpful to clinical management and recurrence risk assessment [9]. The proposed main diagnostic modality has now switched to IF [10]. A combined use of LM, IF and EM is strongly favored as long as the patient condition and specimen volume permits. It is obvious that PGNMID will be missed when IF is omitted with only LM performed as illustrated in case 2 of our series.\n\nGiven that PGNMID occurs shortly after KT, this risk should be discussed with patients before transplant. It is unequivocal that PGNMID was recurrent in patient 1. Recurrence was strongly favored in patient 2 even though no original native kidney biopsy material can be re-evaluated. Similarly, de novo appearance of PGNMID in case 3, case 4 and case 5 were highly unlikely given that these 3 patients presented shortly after KT. In a protocol biopsy study, Nasr and associates [3] demonstrated that PGNMID recurrence can be documented at biopsy as early as a mean of 3.8 months post-KT.\n\nThe exact etiology and pathogenesis of PGNMID remains largely unknown, rendering correspondingly etiology-based treatment unpractical to date. All the implicating IgG subtype in our series is IgG3, which is consistent with findings reported in both the native and transplanted kidneys [2, 3]. Many investigators attributed this finding to the speculation that IgG3 subtype has strong affinity to the glomeruli due to its propensity to self-aggregate and binds to the GBM which is negatively-charged and fixes complement, causing endothelial injury and ensuing endocapillary and mesangial proliferation [1–3]. Nevertheless, serum complement levels were normal in our series in most patients, as is often the case reported by others [1–3, 11]. Lately there were reports [12, 13] that PGNMID was a renal manifestation of monoclonal gammopathy of renal significance which is characterized by renal damage caused by the deposition of monoclonal immunoglobulins secreted by low-grade lymphoproliferative disorders. Thus a complete hematologic work-up including serum and urinary M protein detection, bone marrow aspirate and/or bone marrow biopsy, serum light-chain measurement or even fluorescence in situ hybridization for multiple myeloma should be performed to exclude underlying hematologic dyscrasias.\n\nTreatment strategy employing rituximab or bortezomib, though justified theoretically to reduce immunoglobulin levels and thus alleviate glomerular injury, failed to be demonstrated to be effective in decreasing Scr in 2 of the 4 treated patients. Nevertheless, rituximab and bortezomib are effective in alleviating proteinuria in all 4 patients. Plasmapheresis treatment alone failed to avert Scr elevation in patient 1. In the native kidneys, Nasr group [3] reported that among 4 patients treated with rituximab, 2 patients achieved partial remission as defined as 50% reduction of proteinuria. This group also found favorable effect of rituximab in alleviating proteinuria in allografts with PGNMID. The experience of bortezomib use in PGNMID is limited. It has been found to be ineffective in alleviating proteinuria or stabilizing renal function in a patient with PGNMID in the native kidneys [2]. In another report [5], carfilzomib, also a protease-inhibitor like bortezomib, is effective in reducing Scr in a renal allograft with PGNMID. There is a case report [14] observing that plasmapheresis combined with intravenous immunoglobulins and mycophenolate mofetil reduced Scr and proteinuria from 2 mg/dl and 3.3 g/24 h to 1.1 mg/dl and 0.2 g/24 h respectively. To date, there is no proven effective therapeutic approaches for PGNMID and the number of treated patients is small. Therefore, larger studies are needed to conclusively demonstrate the efficacy of various treatment strategies.\n\nConclusions\nIn conclusion, we reported 5 rare cases of PGNMID in the renal allografts that presented shortly after KT. The diagnosis of PGNMID relies heavily on IF, which could detect monoclonal IgG deposits even in the absence of obvious LM morphological changes. Rituximab and bortezomib are helpful for alleviating proteinuria and reducing Scr in a subset of patients. Due to limited case number and retrospective nature of our report, larger prospective studies are needed to conclusively provide evidence-based treatment strategies and prognosticators.\n\nAbbreviations\nEMElectron microscopy\n\nGBMGlomerular basement membrane\n\nIFImmunofluorescence\n\nKTKidney transplantation\n\nLMLight microscopy\n\nMPGNMembranoproliferative glomerulonephritis\n\nPGNMIDProliferative glomerulonephritis with monoclonal IgG deposits\n\nScrSerum creatinine\n\nFunding\nThis study is funded by the China Natural Science Foundation (grant number: 81570681).\n\nAvailability of data and materials\nThe data is available upon request to the corresponding author.\n\nAuthors’ contributions\nAll authors contributed to the conception of the study and WW, XF, CJS,CDR, LX,NXF contributed to data acquisition and data analysis. XF and ZMC contributed to pathologic interpretation. WJQ, WW and LZH drafted and all other authors critically revised the manuscript and all authors gave final gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.\n\nEthics approval and consent to participate\nAll patients provided written informed consent to take part in the study. The study was approved by the Clinical Research Ethic Committee of Jingling Hospital.\n\nConsent for publication\nAll patients provided written informed consent to publish their medical details and case descriptions.\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. Nasr SH Markowitz GS Stokes MB Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis Kidney Int 2004 65 85 96 10.1111/j.1523-1755.2004.00365.x 14675039 \n2. Nasr SH Satoskar A Markowitz GS Proliferative glomerulonephritis with monoclonal IgG deposits J Am Soc Nephrol 2009 20 2055 2064 10.1681/ASN.2009010110 19470674 \n3. Nasr SH Sethi S Cornell LD Proliferative glomerulonephritis with monoclonal IgG deposits recurs in the allograft Clin J Am Soc Nephrol 2011 6 122 132 10.2215/CJN.05750710 20876681 \n4. Motwani SS Herlitz L Monga D Paraprotein-related kidney disease: glomerular diseases associated with paraproteinemias Clin J Am Soc Nephrol 2016 11 2260 2272 10.2215/CJN.02980316 27526706 \n5. Al-Rabadi L Francis JM Henderson J Ghai S Proliferative glomerulonephritis with monoclonal immunoglobulin in renal allografts Clin Kidney J 2015 8 722 728 10.1093/ckj/sfv105 26613031 \n6. Albawardi A Satoskar A Von Visger J Brodsky S Nadasdy G Nadasdy T Proliferative glomerulonephritis with monoclonal IgG deposits recurs or may develop de novo in kidney allografts Am J Kidney Dis 2011 58 276 281 10.1053/j.ajkd.2011.05.003 21705124 \n7. Bhutani G Nasr SH Said SM Hematologic characteristics of proliferative glomerulonephritides with nonorganized monoclonal immunoglobulin deposits Mayo Clin Proc 2015 90 5 587 596 10.1016/j.mayocp.2015.01.024 25939936 \n8. Batal I Markowitz GS Wong W Filgrastim-induced crescentic transformation of recurrent IgG2λ GN J Am Soc Nephrol 2016 27 7 1911 1915 10.1681/ASN.2016010061 27147425 \n9. Sethi S Fervenza FC Membranoproliferative glomerulonephritis--a new look at an old entity N Engl J Med 2012 366 1119 1131 10.1056/NEJMra1108178 22435371 \n10. Sethi S Fervenza FC Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification Semin Nephrol 2011 31 341 348 10.1016/j.semnephrol.2011.06.005 21839367 \n11. Komatsuda A Ohtani H Sawada K Joh K Wakui H Proliferative glomerulonephritis with discrete deposition of monoclonal immunoglobulin κ1 CH 2 heavy chain and λ light chain: a new variant of monoclonal immunoglobulin deposition disease Pathol Int 2013 63 63 67 10.1111/pin.12024 23356227 \n12. Guiard E Karras A Plaisier E Patterns of noncryoglobulinemic glomerulonephritis with monoclonal Ig deposits: correlation with IgG subclass and response to rituximab Clin J Am Soc Nephrol 2011 6 1609 1616 10.2215/CJN.10611110 21700823 \n13. Sato K, Makabe S, Iwabuchi Y, et al. Successful treatment with steroid and cyclosporine A in a patient with immunoglobulin A proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Nephrology (Carlton) Doi: 10.1111/nep.13261. [Epub ahead of print].\n14. Ranghino A Tamagnone M Messina M A case of recurrent proliferative glomerulonephritis with monoclonal IgG deposits after kidney transplant treated with plasmapheresis Case Rep Urol 2012 2 45 52\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "19(1)",
"journal": "BMC nephrology",
"keywords": "Bortezomib; Kidney transplantation; Monoclonality; PGNMID; Rituximab",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000328:Adult; D064591:Allografts; D005260:Female; D005500:Follow-Up Studies; D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D007074:Immunoglobulin G; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012189:Retrospective Studies; D014184:Transplantation, Homologous",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "173",
"pmc": null,
"pmid": "29996809",
"pubdate": "2018-07-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22435371;25939936;23197955;19470674;26613031;23356227;20876681;27526706;27147425;21839367;14675039;21705124;21700823;29577510",
"title": "Clinicopathological analysis of proliferative glomerulonephritis with monoclonal IgG deposits in 5 renal allografts.",
"title_normalized": "clinicopathological analysis of proliferative glomerulonephritis with monoclonal igg deposits in 5 renal allografts"
} | [
{
"companynumb": "PHHY2019CN188088",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDuring a clinical trial of a novel hydrocodone/acetaminophen combination, a high incidence of serum alanine aminotransferase (ALT) elevations was observed.\n\n\nOBJECTIVE\nTo characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo.\n\n\nMETHODS\nA randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient, diet-controlled (meals provided), longitudinal study of 145 healthy adults in 2 US inpatient clinical pharmacology units.\n\n\nMETHODS\nEach participant received either placebo (n = 39), 1 of 3 acetaminophen/opioid combinations (n = 80), or acetaminophen alone (n = 26). Each active treatment included 4 g of acetaminophen daily, the maximum recommended daily dosage. The intended treatment duration was 14 days. Main Outcomes Serum liver chemistries and trough acetaminophen concentrations measured daily through 8 days, and at 1- or 2-day intervals thereafter.\n\n\nRESULTS\nNone of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09; P<.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved.\n\n\nCONCLUSIONS\nInitiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations.",
"affiliations": "Department of Medicine, University of North Carolina, Chapel Hill, USA. pbwatkins@med.unc.edu",
"authors": "Watkins|Paul B|PB|;Kaplowitz|Neil|N|;Slattery|John T|JT|;Colonese|Connie R|CR|;Colucci|Salvatore V|SV|;Stewart|Paul W|PW|;Harris|Stephen C|SC|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000082:Acetaminophen; D000410:Alanine Transaminase",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.296.1.87",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-7484",
"issue": "296(1)",
"journal": "JAMA",
"keywords": null,
"medline_ta": "JAMA",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D000410:Alanine Transaminase; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D016037:Single-Blind Method",
"nlm_unique_id": "7501160",
"other_id": null,
"pages": "87-93",
"pmc": null,
"pmid": "16820551",
"pubdate": "2006-07-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial.",
"title_normalized": "aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily a randomized controlled trial"
} | [
{
"companynumb": "US-JNJFOC-20060700392",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nA case of serotonin syndrome that developed during concurrent linezolid and fluoxetine is presented.\n\n\nCONCLUSIONS\nA 23-year-old white male patient was originally admitted to receive intravenous chemotherapy for acute myelogenous leukemia. He had a history of intravenous amphetamine abuse, hepatitis B virus infection, hepatitis C virus infection, depression, and bipolar disorder. The patient's routine medications before admission included methadone, fluoxetine, voriconazole, transdermal nicotine patch, lorazepam, and quetiapine. The patient developed persistent neutropenia and complications from chemotherapy, including mild mucositis. Despite treatment with levofloxacin, acyclovir, and voriconazole, the patient developed high fevers. Levofloxacin was discontinued and aztreonam and vancomycin were started. After a blood culture revealed that the bacteria were likely vancomycin resistant, vancomycin was discontinued and linezolid was initiated. Nine hours later, the patient began complaining of severe pain in his abdomen. After a total of four doses of linezolid, the patient reported further discomfort. Two days after linezolid initiation, a health care team member identified the interaction between fluoxetine and linezolid as the cause of the patient's symptoms, and linezolid was discontinued. All symptoms resolved within 48 hours. While resolution generally occurs within 24-48 hours after discontinuing the offending agent, the time to resolution may be delayed if the agent has a long half-life or active metabolites, in which case admission to an intensive care unit is recommended. Cyproheptadine and chlorpromazine may also be used to treat symptoms.\n\n\nCONCLUSIONS\nSerotonin syndrome developed in a patient taking concurrent linezolid and fluoxetine.",
"affiliations": "Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts 01608, USA. michael.steinberg@wor.mcphs.edu",
"authors": "Steinberg|Michael|M|;Morin|Anna K|AK|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D011743:Pyrimidines; D000069349:Linezolid; C001247:fluoxydine",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp060227",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "64(1)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000081:Acetamides; D000328:Adult; D000890:Anti-Infective Agents; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D000069349:Linezolid; D008297:Male; D023303:Oxazolidinones; D011743:Pyrimidines; D020230:Serotonin Syndrome; D014481:United States",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "59-62",
"pmc": null,
"pmid": "17189581",
"pubdate": "2007-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mild serotonin syndrome associated with concurrent linezolid and fluoxetine.",
"title_normalized": "mild serotonin syndrome associated with concurrent linezolid and fluoxetine"
} | [
{
"companynumb": "US-PFIZER INC-2018477125",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nDonor-derived carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has recently emerged as a critical early complication after renal transplantation. Although CRKP is usually sensitive to tigecycline, monotherapy with this drug is often less than effective. We investigated the efficacy of a combined regimen of tigecycline with high-dose, extended-infusion meropenem in the treatment of donor-derived CRKP infection after kidney transplantation.\n\n\nMETHODS\nFrom Jan. 2016 to Dec. 2017, a total of 12 CRKP isolates were detected from cultures of the organ preservation solution used for soaking the donor kidneys at our institute. Probable or possible donor-derived infection (DDI) was identified in 8 transplant recipients. Clinical data were retrospectively analyzed.\n\n\nRESULTS\nKlebsiella pneumoniae carbapenemase-2 (KPC-2)-producing CRKP was reported to be positive in organ preservation solution cultures at 3.5±0.9 days after transplantation, leading to surgical site (n=3), urinary tract (n=4), and/or bloodstream (n=2) infections in 8 recipients. The drug susceptibility tests showed that CRKP was sensitive to tigecycline, but resistant to meropenem. In 7 patients who received tigecycline combined with high-dose extended-infusion meropenem, DDIs were successfully cured. The length of hospital stay was 31 (18-129) days, and the serum creatinine at discharge was 105.8±16.7 µmol/L. The one remaining patient who received tigecycline combined with intravenous-drip meropenem died of septic shock. A median follow-up of 43 months (33-55) showed no recurrence of new CRKP infection in the 7 surviving recipients.\n\n\nCONCLUSIONS\nIt was suggested that a prompt and appropriate combination therapy using tigecycline with high-dose extended-infusion meropenem is effective in treating donor-derived KPC-2-producing CRKP infection after renal transplantation.",
"affiliations": "Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.;Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.;Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.;Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.;Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.;Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.;Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. zhulan@tjh.tjmu.edu.cn.;Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. gchen@tjh.tjmu.edu.cn.",
"authors": "Wang|Zhi-Qiang|ZQ|;Guo|Zhi-Liang|ZL|;Feng|Hao|H|;Fu|Cheng|C|;Zhao|Guang-Yuan|GY|;Ma|Ke|K|;Zhu|Lan|L|;Chen|Gang|G|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.1007/s11596-021-2397-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2523-899X",
"issue": "41(4)",
"journal": "Current medical science",
"keywords": "carbapenem-resistant Klebsiella pneumoniae; donor-derived infection; meropenem; renal transplantation; tigecycline",
"medline_ta": "Curr Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101729993",
"other_id": null,
"pages": "770-776",
"pmc": null,
"pmid": "34403102",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of Donor-derived Carbapenem-resistant Klebsiella pneumoniae Infection after Renal Transplantation with Tigecycline and Extended-infusion Meropenem.",
"title_normalized": "treatment of donor derived carbapenem resistant klebsiella pneumoniae infection after renal transplantation with tigecycline and extended infusion meropenem"
} | [
{
"companynumb": "CN-PFIZER INC-202101212059",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
},
"drugadditional": "1",
... |
{
"abstract": "To examine 3 legal cases in which physicians prescribed methotrexate to women with a viable intrauterine pregnancy, presumed to be ectopic, resulting in adverse fetal outcomes.\n\n\n\nWe conducted an electronic literature search for legal cases using the keywords “methotrexate” and “pregnancy” in the LexisNexis legal research engine as well as an Internet-wide search using the additional keyword “verdict.” We manually searched the resultant list of identified cases and categorized the studies identified in the search by verdict, award amount, and outcome of the embryo exposed to methotrexate.\n\n\n\nThe monetary awards are typically greater when the embryo exposed to methotrexate lives and requires continuous medical and custodial care as compared to when the fetus dies in utero or shortly after birth.\n\n\n\nPhysicians who, with all good intentions, prescribe methotrexate to women with a viable pregnancy, presumed to be ectopic, could find them-selves liable for an adverse fetal outcome. For the benefit of patients, their unborn offspring, and the liability exposure of the physician, it is important to be very cautious when prescribing methotrexate.",
"affiliations": null,
"authors": "Garcia-Jasso|Carlos A|CA|;Kilic|Gokhan S|GS|;Wen|Tony|T|;Snyder|Russell R|RR|;Jain|Sangeeta|S|;Phelps|John Y|JY|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0024-7758",
"issue": "62(3-4)",
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"title": "Medicolegal Review of Methotrexate Administration to Viable Intrauterine Pregnancies.",
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"abstract": "BACKGROUND\nThe use of monoclonal antibodies in various settings has been linked to the development of progressive multifocal leukoencephalopathy (PML). Whilst this association is well-described with agents such as rituximab and natalizumab, the literature describing the occurrence of PML with ofatumumab therapy (especially in a haematology setting) is sparse. This case aims to draw attention to the above association with a particular focus on the mechanisms by which B-cell-depleting therapy can precipitate PML during the treatment of haematological malignancy.\n\n\nMETHODS\nA 68-year-old Caucasian man presented with acute-on-subacute confusion and reduced mobility. He had a history of chronic lymphocytic leukaemia for which he had completed six cycles of ofatumumab and chlorambucil 2 months prior to presentation. Biochemistry, physical examination and imaging were unremarkable on admission. Subsequent neurological examination demonstrated diminished reflexes and an extensor right plantar, while magnetic resonance imaging (MRI) assessment revealed white matter hyperintensities in the frontal lobes with restricted diffusion surrounding these areas. Cerebrospinal fluid (CSF) analysis demonstrated normal cell counts and chemistry but detected John Cunningham virus (JCV) via polymerase chain reaction (PCR), with a quantitative value of 41,850 gEg/ml. CSF immunophenotyping excluded malignant processes. A diagnosis of PML was confirmed, and with the support of palliative care, the patient was discharged to a hospice for ongoing care with the family's agreement.\n\n\nCONCLUSIONS\nPML remains a rare complication of ofatumumab treatment. Nevertheless, clinicians should maintain a certain level of suspicion for this risk, especially in the context of patients presenting with clinical syndromes of encephalopathy and focal neurologic deficits. Furthermore, research to better our understanding of the manifold links between B-cell function and JCV regulation could provide valuable information for use in the future prevention and treatment of PML.",
"affiliations": "The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. james.forryan@me.com.;The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK.",
"authors": "Forryan|James|J|;Yong|Jun|J|",
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"doi": "10.1186/s13256-020-2360-9",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2360\n10.1186/s13256-020-2360-9\nCase Report\nRapid cognitive decline in a patient with chronic lymphocytic leukaemia: a case report\nForryan James james.forryan@me.com 12 Yong Jun 12 1 grid.269741.f0000 0004 0421 1585The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK \n2 Haematology Department, Duncan Building, Liverpool, UK \n3 3 2020 \n3 3 2020 \n2020 \n14 3917 8 2019 5 2 2020 © The Author(s). 2020Open 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\nThe use of monoclonal antibodies in various settings has been linked to the development of progressive multifocal leukoencephalopathy (PML). Whilst this association is well-described with agents such as rituximab and natalizumab, the literature describing the occurrence of PML with ofatumumab therapy (especially in a haematology setting) is sparse. This case aims to draw attention to the above association with a particular focus on the mechanisms by which B-cell-depleting therapy can precipitate PML during the treatment of haematological malignancy.\n\nCase presentation\nA 68-year-old Caucasian man presented with acute-on-subacute confusion and reduced mobility. He had a history of chronic lymphocytic leukaemia for which he had completed six cycles of ofatumumab and chlorambucil 2 months prior to presentation. Biochemistry, physical examination and imaging were unremarkable on admission. Subsequent neurological examination demonstrated diminished reflexes and an extensor right plantar, while magnetic resonance imaging (MRI) assessment revealed white matter hyperintensities in the frontal lobes with restricted diffusion surrounding these areas. Cerebrospinal fluid (CSF) analysis demonstrated normal cell counts and chemistry but detected John Cunningham virus (JCV) via polymerase chain reaction (PCR), with a quantitative value of 41,850 gEg/ml. CSF immunophenotyping excluded malignant processes. A diagnosis of PML was confirmed, and with the support of palliative care, the patient was discharged to a hospice for ongoing care with the family’s agreement.\n\nConclusion\nPML remains a rare complication of ofatumumab treatment. Nevertheless, clinicians should maintain a certain level of suspicion for this risk, especially in the context of patients presenting with clinical syndromes of encephalopathy and focal neurologic deficits. Furthermore, research to better our understanding of the manifold links between B-cell function and JCV regulation could provide valuable information for use in the future prevention and treatment of PML.\n\nKeywords\nProgressive multifocal leukoencephalopathy, Chronic lymphocytic leukaemia, Ofatumumab, Monoclonal antibodies, B-cell-depleting therapyissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nProgressive multifocal leukoencephalopathy (PML) is a rare but increasingly common demyelinating disease of the central nervous system (CNS) with a particularly poor prognosis, most conspicuously so among patients with haematological malignancy (typically having a 90% mortality rate within 2 months of diagnosis) [1, 2].\n\nThe aetiologic agent, the JC virus (JCV), was first culture-isolated in 1971 and posthumously named after an early subject with PML, John Cunningham. JCV is of the Polyomavirus genus and is pervasive in healthy human populations, although pertinently, the JCV archetype (found in the urine of approximately 1/3 of adults) is not pathogenic [3, 4]. Therefore, whilst the archetypal form of the virus is attributed to the primary infection (usually occurring in childhood), for pathogenicity, the JCV requires explicit conditions. Studies have demonstrated homogeneity of the non-coding regulatory region (RR) in archetypal JCV, whilst the RR seen in isolated JCV prototypes from PML patients differs, with unique (to each individual) repeats of a 98-bp element that shows variation from the norm [5]. Therefore, rearrangement of the RR in the context of immunosuppression, rather than transmission, likely allows activation of the JCV. Furthermore, it is the RR that contains determinants of neurotropism and neurovirulence, giving further credence to its rearranging serving as a catalyst for PML [6].\n\nThe three most common PML populations comprise those with human immunodeficiency virus positive (HIV+) disease, haematological malignancies and relapsing-remitting multiple sclerosis (RRMS) on natalizumab [7]. Indeed, as human immunodeficiency virus (HIV) infection has become more prevalent throughout the world, and with the advent of B-cell-depleting immunomodulatory therapy in malignancy and autoimmune conditions, the prevalence of PML has risen; as an example, a 2018 study from Sweden looking at the incidence of PML per 100,000 found an increase in the average incidence rate from 0.026 (between 1988 and 2010) to 0.11 (between 2011 and 2013) [8].\n\nHere we report a case of PML secondary to B-cell-depleting therapy with ofatumumab. Over the past decade, a new understanding of the role of B-cells in autoimmunity has begun to emerge. Whereas B-cells initially were thought to exert their effects predominately through antibody production, considerable evidence now exists to support their role in modifying T-cell function through cytokine production, co-stimulation and antigen presentation. Therefore, the wielding of B-cell depleting monoclonal antibodies in the treatment of autoimmune pathology and lymphoproliferative disorders should be appreciated for what it is—a double-edged sword with clear benefits of a more tolerable immune environment and suppression of uncontrolled lymphoproliferation—with the unwanted potential for previously suppressed viruses (i.e., JCV) to exploit the softening of immune regulation.\n\nCase presentation\nA Caucasian male in his late 60s with a background of TP53-negative chronic lymphocytic leukaemia (CLL) presented through the Emergency Department with reduced mobility and confusion of 2 weeks’ duration. The diagnosis of CLL had been made 4 years prior and was originally staged as Binet A (less than three areas of lymphadenopathy and with no anaemia or thrombocytopaenia); unfortunately, the profound progression of symptoms and lymphadenopathy in the preceding year had necessitated a progression from surveillance to active management. The patient had therefore been enrolled in the RIALTO trial and completed six cycles of ofatumumab and chlorambucil 2 months prior to this presentation. Notably, a subtler deterioration in memory had occurred in the 2 months prior to admission, but before this, the patient was fully independent with normal cognition.\n\nOther comorbidities included fatty liver changes, gout and recurrent respiratory tract infections associated with hypogammaglobulinaemia. A comprehensive medical history (including drug history) failed to explain his symptoms. No relevant family or travel history was present. On initial assessment in the Emergency Department, physical examination was unremarkable except for a Glasgow Coma Scale (GCS) score of 14/15 due to confusion. Neurological examination in the Emergency Department was documented as normal.\n\nRoutine bloodwork on admission (including full blood count, bone, renal and liver profile, thyroid function testing and vitamin assessments) was unrevealing. The white cell count was 6.6, with neutrophils of 4.8 and lymphocytes of 1.2. A chest X-ray and computed tomography (CT) brain demonstrated no acute lung or intracranial pathology, respectively. Microbiological sampling of the stool, urine and blood demonstrated no organisms on smear or culture. A CT neck/thorax/abdomen/pelvis showed interval improvement in the size of enlarged subcarinal, portocaval, right iliac and left iliac lymph nodes (compared to a previous CT of 8 months prior) and stable splenomegaly.\n\nEarly in the admission, concerns were raised by various members of the team about progressive cognitive impairment, loss of independence, inability to follow simple commands and a lack of insight. A further neurological examination was undertaken on admission to a medical ward which revealed diminished reflexes and an extensor right plantar response. A brain magnetic resonance imaging (MRI) (Fig. 1) then demonstrated white matter hyperintensities in the frontal lobes, with restricted diffusion in a flame front configuration surrounding the lesions. No abnormal enhancement was seen.\nFig. 1 (a) Axial T1-weighted magnetic resonance imaging (MRI) showing asymmetric hypointense areas in the bilateral frontal white matter (arrows). (b, c) They appear hyperintense on the corresponding T2-weighted and FLAIR sequences. (d) The lesions do not enhance following intravenous contrast administration. (e, f) A thin rim of diffusion restriction can be seen along the advancing edge of the lesion on the DWI images and the corresponding ADC maps (arrowheads)\n\n\n\nThe MRI appearances, in conjunction with the clinical syndrome presenting itself, were felt to be highly suggestive of progressive multifocal leukoencephalopathy (PML). Other differentials, such as secondary central nervous system (CNS) lymphoma and CNS CLL infiltration, were considered less likely due to an absence of the typical avid enhancement usually seen on MR imaging. To help confirm a diagnosis, CSF analysis was undertaken. No organisms were grown from the CSF, and the white cell count was 44 per c.mm (100% lymphocytes). CSF protein was raised at 0.68. The CSF virology and opportunistic infection screen (cryptococcal, toxoplasma and Mycobacterium tuberculosis) were negative apart from detection of John Cunningham virus (JCV) via polymerase chain reaction (PCR), with a quantitative value of 41,850 gEg/ml; the symptomatology, radiological findings and CSF analysis were considered confirmatory of PML. The CSF immunophenotyping and morphology demonstrated no features of CLL or lymphoma. Ultimately, a brain biopsy was not performed because this would not have influenced the management, and the invasive nature of the procedure would have carried considerable risk given the patient’s performance status. We involved our palliative care colleagues in the care of this gentleman and were able to facilitate discharge to a hospice for ongoing symptom control and care. The patient sadly passed away roughly 3 months after the diagnosis of PML.\n\nDiscussion\nWe report an adult patient with progressive cognitive decline and neurological dysfunction secondary to a diagnosis of PML. This occurred after B-cell-depleting therapy with ofatumumab in an attempt to treat his underlying CLL.\n\nA tug of war has occurred in recent years between those who believe B-cells partake in both humoral and cellular immunity and those who dispute the role of B-cells in the latter. One can find evidence in the literature to support both arguments: for example, mice studies indicate that B-cell depletion impairs CD4+ T-cell memory and cytokine production, thus reducing protection against viruses [9], whilst others would argue the opposite, showing that cytotoxic T-cell memory is maintained even in B-cell-deficient mice subjected to lymphocytic choriomeningitis virus [10]. Nevertheless, studies that refute a role for B-cells in cellular immune responses have typically been published around the turn of the millennium, whereas they are now dwarfed in number by those supporting a role for B-cells in both types of immune response. Given the weight of evidence to support a modulatory role for B-cells in CD4 and CD8 T-cell responses, it is hard to ignore the association. Indeed, in a perversion of their intended action, B-cell depleting therapies have provided the milieu for researchers to shed light on the multi-mechanistic role that B-cells have in immune responses.\n\nThe existence of distinct B-cell populations within the subsets ‘effector’ (memory) and ‘regulatory’, and the ability of both types to modulate T-cell activity through antigen-presentation, cytokine release and co-stimulation, have long been known. Several studies have demonstrated a role for antigen-presenting B cells in the proliferation and differentiation of T-cells [11–13]. Furthermore, co-stimulatory B-cell surface molecules have their own role to play in T-cell responses; for example, a study demonstrated that in mouse bone marrow chimeras with CD80/86 knockout B-cells (but with other APCs retaining these CD markers), resistance to the induction of proteoglycan-induced arthritis was present. This suggested that CD80/86 upregulation on B-cells was a prerequisite for autoreactive T-cell activation and induction of arthritis; interestingly, proteoglycan-specific autoantibody titres were comparable in CD80/86 wild-type and knockout populations, thus offering more credence to the antibody-independent action of B-cells in cellular immunity [14]. The dichotomy between ‘effector’ and ‘regulatory’ B-cell is most apparent when related to their profile of cytokine production. Two effector subgroups, Be1 and Be2, produce cytokines linked to Th1 and Th2 responses respectively and are known to enhance T-cell-mediated immune responses. Conversely, B regulatory cells (the term Bregs was first coined by Mizoguchi and Bhan in 2002) also exist that produce an IL-10 predominant cytokine profile with T regulatory-cell (Treg) action, ultimately suppressing the T-cell response and creating a more tolerogenic immune environment.\n\nRelevant to this particular case is the occurrence of PML in populations receiving B-cell-depleting therapy for lymphoproliferative disorders. The incidence of haematologic B-cell malignancies continues to rise in the Western world, but the advent of B-cell-depleting monoclonal antibody (mAb) therapy in the 1980s revolutionised treatment [15]. Identification of B-cell-restricted CD19 and CD20 antigens ushered in development of targeted mAb therapy, thereby leading to multi-mechanistic elimination of malignant B-cells [16]. Commonly used agents include rituximab, alemtuzumab and ofatumumab; the latter binds to a more proximal membrane epitope leading to improved complement-dependent cytotoxicity, with the potential caveat of increased susceptibility to the complications of B-cell depletion. As discussed, to say that decreased humoral activity explained the action of B-cell-depleting therapy would be an oversimplification; indeed, reviews and longitudinal case studies suggest a minimal role for specific antibody response as a regulatory factor in JCV infection [17, 18]. This supports suggestions that the role of B-cells in PML is multi-faceted, independent of antibody secretion and related to altered cell-mediated immunity; for example, B-cell-deficient IgM knockout mice lose their normal CD4 and CD8 response to a lymphocytic choriomeningitis virus (LCMV) variant, whilst non-IgM secretory B-cell-replete mice retained this function [19, 20]. Moving back toward the concept of Bregs, rituximab (an anti-CD20 monoclonal antibody) has repeatedly been shown to enrich the Breg pool, whilst depleting the Be1 levels and thus shifting the ratio of T- and B-cells in favour of the regulatory (Breg/Treg) phenotype [21]. Prior to B-cell-depleting therapy, the memory effector B- and T-cell activity predominates, and Be1/Th1 amplification loops are closely involved (when dysregulated) in the development of autoimmune disease [22]. This is where rituximab (and other B-cell depleting mAbs) come in—curtailing T-cell effector activity and depleting malignant B-cell clones in autoimmune and lymphoproliferative disease respectively. Nevertheless, where there is push, there is pull; shifting the immune environment to one of ‘tolerance’ and regulatory B- and T-cell activity removes the protection against JCV that the effector presence provided. One is left with the dilemma of how to retain the role of B-cells in JCV control—Th1-type cytokine release and propagation of Th1/CD8 activity—when treatment of these conditions necessitates B-cell depletion and leads to repopulation of the B-cell pool with naïve IL-10/35-producing Bregs.\n\nThe diagnosis of PML is contingent on the sum of clinical, radiological, virologic and histopathologic findings. The clinical signs are varied, the most common of which are motor impairment (typically hemiparesis), visual field defects, dysphasia and behavioural changes. MRI is the preferred imaging modality for detecting the changes synonymous with PML: multiple hyperintense (on T2-weighted and FLAIR images; hypointense on T1) white matter lesions within the affected lobes without oedema or mass effect, although a definitive diagnosis is only established by either virologic or histopathologic findings [23]. With well-established, evidence-based consensus guidelines recommending high-frequency MRI brain monitoring in high-risk natalizumab-treated multiple sclerosis patients, cases such as ours raise the question as to whether this practice should be extended to other at-risk groups [24]. Nevertheless, whilst studies in natalizumab-treated patients demonstrate improved survival and morbidity outcomes with early PML diagnosis [25, 26], similar results need to be demonstrated outside this group before sequential MR imaging is recommended more broadly.\n\nFor diagnosis, cerebrospinal fluid (CSF) examination for presence of the JCV is advised (ultrasensitive PCR techniques have a sensitivity > 95%), with several authorities accepting positive CSF JCV, clinical and radiological findings as confirmatory of PML [27]. Notably, a potential exists for both false-negative and false-positive CSF JCV DNA results (even with ultrasensitive PCR) [28]. In these instances, clinical assessment is paramount; proceeding to brain biopsy in high-suspicion patients with negative CSF tests is appropriate, while low CSF JCV titres in patients lacking clinical and imaging evidence of PML should be followed up with repeat testing and consideration of other pathology. Brain biopsy demonstrating asymmetric foci of demyelination and oligodendroglial cell intranuclear inclusions of JCV is an invasive, but extremely sensitive and specific, diagnostic tool.\n\nAs mentioned earlier, the prognosis of the disease is extremely poor. The incidence of PML is likely underestimated on account of its rapid progression and fickle presentation, thereby rendering diagnosis difficult. If confirmed, treatment options remain sparse (JCV is species-specific to humans, thus preventing animal model studies), with timely implementation of combination anti-retroviral treatment (cART) in HIV populations and cessation of immunomodulatory therapy being the only current options offering any survival benefit [29]. Currently, no specific prophylaxis for PML or effective anti-JCV treatment exists, and therefore, outcomes in PML are dependent on an individual’s ability to recover immune function [30]. Consequently, the poorest prognosis group is that of haematological malignancy; immune reconstitution is often not achievable in this group because of the innate bone marrow depression associated with the primary disease and long-term immune cell depletion that occurs secondary to treatment.\n\nMoving forwards, the focus should be on prevention, early diagnosis and expanding treatment options. The identification of immunisation options is an ongoing endeavour; passive and active vaccines are at various stages of drug development, but isolated case reports with the use of JCV-directed cytotoxic T lymphocytes (CTLs) show promise [31]. Regular imaging and stratification of high-risk patients using expert-developed algorithms and JC biomarkers (e.g., the JCV antibody index) already play a role in the timely diagnosis of PML in certain patient cohorts and could be used more widely if studies demonstrated evidence in their favour [32]. Pharmacological treatment of established PML with antiviral agents preventing JCV cell entry, retrograde transport and DNA replication is in its infancy and currently is based on theoretical and anecdotal evidence [30]. Furthermore, as alluded to earlier, the understanding of B-cell function in JCV behaviour and PML is still unclear, although many studies suggest a significant role for B-cells in modifying the T-cell-mediated control of JCV infection. Therefore, further endeavours to better classify the relationships that exist between JCV and B-cells is likely to have a significant impact within the field of PML prevention and management.\n\nConclusions\nIn conclusion, this case report aims to highlight the association between B-cell-depleting therapy and PML, particularly in the setting of haematological malignancy and with lesser used therapies such as ofatumumab. PML should take its place in any differential list for a patient receiving B-cell-depleting mAbs who presents with new neurology and cognitive defects as in our case. Additionally, we aim to bring attention to the mechanisms by which B-cell-depleting therapy can create an immune environment in which the JCV can become pathogenic; this raises the question as to how we can treat autoimmune and lymphoproliferative disease with B-cell-depleting therapy whilst mitigating the resultant increased risk of PML. Knowing the risk of PML with B-cell-depleting therapy, expediting research into JCV vaccination and pharmacological treatment, with concomitant development of evidence-based risk stratification algorithms and predictive biomarkers, seems the best way of reducing this risk at present. Finally, whilst rituximab’s effects on B-cell populations has been extensively studied (e.g., the shift from an effector B-cell pool to one made up of naïve B-cells and plasma cells), the same cannot be said of ofatumumab; clarification as to the phenotype of post-treatment B-cell populations with other B-cell-depleting mAbs could be revealing in terms of their risk-profile for PML compared to rituximab.\n\nAbbreviations\nBregB regulatory cells\n\ncARTcombination anti-retroviral treatment\n\nCLLchronic lymphocytic leukaemia\n\nCNScentral nervous system\n\nCSFcerebrospinal fluid\n\nCTcomputed tomography\n\nCTLscytotoxic T lymphocytes\n\nGCSGlasgow Coma Scale (GCS)\n\nJCVJohn Cunningham virus\n\nMRImagnetic resonance imaging\n\nPCRpolymerase chain reaction\n\nPMLprogressive multifocal leukoencephalopathy\n\nRRregulatory region\n\nRRMSrelapsing-remitting multiple sclerosis\n\nTregT regulatory-cell\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nMany thanks to the family of the described patient who kindly gave consent for this article to be written and sent for publication.\n\nThank you to Dr. Arvind Arumainathan (Consultant Haematologist in The Royal Liverpool University Hospital) for expert advice within the field of lymphoma and B-cell-depleting therapy.\n\nWe would like to also thank Dr. Ankur Arora (Consultant Radiologist in The Royal Liverpool University Hospital) for his expert advice within the field of neuroradiology and his selection of appropriate MR images and figure legend.\n\nAuthors’ contributions\nJF and JY were involved in writing, reading and editing the manuscript. Both authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. 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Weber T Weber F Petry H Luke W Immune response in progressive multifocal leukoencephalopathy: an overview J Neuro-Oncol. 2001 7 311 317 \n23. Berger JR Aksamit AJ Clifford DB PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section Neurology. 2013 80 15 1430 1438 10.1212/WNL.0b013e31828c2fa1 23568998 \n24. Wattjes MP Rovira A Miller D Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-establishing disease prognosis and monitoring patients Nat Rev Neurol. 2015 11 10 597 606 26369511 \n25. Dong-Si T Richman S Wattjes MP Outcome and survival of asymptomatic PML in natalizumab-treated MS patients Ann Clin Transl Neurol. 2014 1 10 755 764 10.1002/acn3.114 25493267 \n26. Dahlhaus S Hopener R Chan A Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients J Neurol Neurosurg Psychiatry. 2013 84 1068 1074 10.1136/jnnp-2013-304897 23606731 \n27. Cinque P Koralnik IJ Clifford DB The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: defining a consensus terminology J Neuro-Oncol. 2003 9 Suppl 1 88 92 \n28. Neil EC DeAngelis LM Progressive multifocal leukoencephalopathy and haematologic malignancies: a single cancer center retrospective review Blood Adv. 2017 1 23 2041 2045 10.1182/bloodadvances.2017008201 29296850 \n29. Clifford DB Progressive multifocal leukoencephalopathy therapy J Neuro-Oncol. 2015 21 6 632 636 \n30. Pavlovic D Patera AC Nyberg F Gerber M Liu M Progressive multifocal leukoencephalopathy: current treatment options and future perspectives Ther Adv Neurol Disord. 2015 8 6 255 273 10.1177/1756285615602832 26600871 \n31. Balduzzi A Lucchini G Hirsch H Basso S Cioni M Rovelli A Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient Bone Marrow Transplant. 2011 46 7 987 992 10.1038/bmt.2010.221 20921942 \n32. McGuigan C Craner M Guadagno J Kapoor R Mazibrada G Molyneux P Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group J Neurol Neurosurg Psychiatry. 2016 87 2 117 125 26492930\n\n",
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"keywords": "Progressive multifocal leukoencephalopathy, Chronic lymphocytic leukaemia, Ofatumumab, Monoclonal antibodies, B-cell-depleting therapy",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D001921:Brain; D002699:Chlorambucil; D060825:Cognitive Dysfunction; D017051:Hospice Care; D006801:Humans; D007577:JC Virus; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D010166:Palliative Care; D016133:Polymerase Chain Reaction",
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"title": "Rapid cognitive decline in a patient with chronic lymphocytic leukaemia: a case report.",
"title_normalized": "rapid cognitive decline in a patient with chronic lymphocytic leukaemia a case report"
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"abstract": "A combination of parenteral medications (often referred to as standard combination therapy) is frequently used in the treatment of acute migraine in the pediatric emergency department (PED). The primary aim of this study was to evaluate the two-hour, 24-hour, and seven-day impact of one such regimen on pain in children who present to the PED. Standard combination therapy for purposes of our study is defined as a bolus of intravenous saline, and a combination of intravenous ketorolac, prochlorperazine, and diphenhydramine.\n\n\n\nThis prospective observational study included 120 children between the ages seven and 18 years who presented to the PED with migraine, whose parents could read and understand the consent form in English, and who were treated with standard combination therapy. The primary outcome measure for this study was the change in severity of pain as noted by the child using the Faces Pain Scale-Revised. We analyzed normally distributed continuous variables by mean and standard deviation, whereas non-normally distributed continuous variables are reported by median and interquartile range.\n\n\n\nNonparametric Friedman testing on the entire cohort (n = 120) noted that there was a statistically significant change in the Faces pain scale from before administration of standard combination therapy to the two-hour, 24-hour, and one-week time point with a reduction in pain score of 87.5%, 100%, and 50%, respectively, at the three time points.\n\n\n\nThis study noted moderate relief of pain after administration of standard combination therapy, which persisted at one-week after administration.",
"affiliations": "Professor of Pediatrics and Emergency Medicine, Children's Hospital of Michigan/Central Michigan University, Detroit, Michigan.;Resident in Pediatrics, Children's Hospital of Michigan, Detroit, Michigan.;Biostatistician, Children's Hospital of Michigan, Detroit, Michigan.;Professor of Pediatrics and Neurology, Children's Hospital of Michigan/Central Michigan University, Detroit, Michigan. Electronic address: lsivaswamy@med.wayne.edu.",
"authors": "Kannikeswaran|Nirupama|N|;Desai|Lavina|L|;Farooqi|Ahmad|A|;Sivaswamy|Lalitha|L|",
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"title": "Effectiveness of Standard Combination Therapy in Pediatric Migraine.",
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"abstract": "Objective and Importance. Cyclic neutropenia (CyN) is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk of infection. Case. A 25-year-old male diagnosed with CyN, on G-CSF but worsening quality of life. Pretransplant investigations revealed ELANE mutation positive severe CyN along with familial Mediterranean fever (MEFV) mutation. Intervention. Bone marrow transplantation as treatment for dual mutation (ELANE and MEFV mutation) positive severe CyN. Conclusion. BMT may be considered as an alternative treatment for severe CyN in patients who are refractory to G-CSF. It is postulated that in our patient the combined mutations (CyN and MEFV) may have contributed to the severity of this individual's symptoms. We suggest CyN patients who present with severe symptoms have evaluation with ELANE mutation testing, Periodic Fever Syndromes Panel, and routine marrow assessment with FISH, conventional cytogenetics, and morphological evaluation for MDS/AML.",
"affiliations": "Department of Medicine, University of Arizona, Tucson, AZ, USA.;Department of Medicine, University of Arizona, Tucson, AZ, USA; Department of Pediatrics, University of Arizona, Tucson, AZ, USA; Division of Blood & Marrow Transplantation, University of Arizona, Tucson, AZ, USA; Department of Pathology, University of Arizona, Tucson, AZ, USA.;Department of Medicine, University of Arizona, Tucson, AZ, USA.;Department of Pathology, University of Arizona, Tucson, AZ, USA.;Department of Pediatrics, University of Arizona, Tucson, AZ, USA; Division of Hematology and Oncology, University of Arizona, Tucson, AZ, USA.",
"authors": "Okolo|Onyemaechi N|ON|0000-0001-5576-2924;Katsanis|Emmanuel|E|0000-0003-1466-6965;Yun|Seongseok|S|0000-0001-7343-1635;Reveles|Candace Y|CY|0000-0002-3759-5699;Anwer|Faiz|F|0000-0001-6914-7439",
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"doi": "10.1155/2017/5375793",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2017/5375793Case ReportAllogeneic Transplant in ELANE and MEFV Mutation Positive Severe Cyclic Neutropenia: Review of Prognostic Factors for Secondary Severe Events http://orcid.org/0000-0001-5576-2924Okolo Onyemaechi N. \n1\n\n*\nhttp://orcid.org/0000-0003-1466-6965Katsanis Emmanuel \n1\n\n2\n\n3\n\n4\nhttp://orcid.org/0000-0001-7343-1635Yun Seongseok \n1\nhttp://orcid.org/0000-0002-3759-5699Reveles Candace Y. \n4\nhttp://orcid.org/0000-0001-6914-7439Anwer Faiz \n2\n\n5\n1Department of Medicine, University of Arizona, Tucson, AZ, USA2Department of Pediatrics, University of Arizona, Tucson, AZ, USA3Division of Blood & Marrow Transplantation, University of Arizona, Tucson, AZ, USA4Department of Pathology, University of Arizona, Tucson, AZ, USA5Division of Hematology and Oncology, University of Arizona, Tucson, AZ, USA*Onyemaechi N. Okolo: ookolo@deptofmed.arizona.eduAcademic Editor: Kostas Konstantopoulos\n\n2017 18 1 2017 2017 537579321 9 2016 1 12 2016 7 12 2016 Copyright © 2017 Onyemaechi N. Okolo 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.\nObjective and Importance. Cyclic neutropenia (CyN) is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk of infection. Case. A 25-year-old male diagnosed with CyN, on G-CSF but worsening quality of life. Pretransplant investigations revealed ELANE mutation positive severe CyN along with familial Mediterranean fever (MEFV) mutation. Intervention. Bone marrow transplantation as treatment for dual mutation (ELANE and MEFV mutation) positive severe CyN. Conclusion. BMT may be considered as an alternative treatment for severe CyN in patients who are refractory to G-CSF. It is postulated that in our patient the combined mutations (CyN and MEFV) may have contributed to the severity of this individual's symptoms. We suggest CyN patients who present with severe symptoms have evaluation with ELANE mutation testing, Periodic Fever Syndromes Panel, and routine marrow assessment with FISH, conventional cytogenetics, and morphological evaluation for MDS/AML.\n\nNational Cancer InstituteP30 CA023074\n==== Body\n1. Introduction\nCyclic neutropenia (CyN) is a rare stem cell disorder with a prevalence of one to two per million [1]. It results from a heterozygous mutation in the ELANE (full length) gene that encodes neutrophil elastase on chromosome 19p13.3 [2]. Horwitz et al. hypothesized that the cellular mechanism in CyN is likely due to gain-of-function mutation and proteolysis [2]. The abnormal enzyme resulting from mutated ELANE gene damages hematopoietic cells as they differentiate to the neutrophil lineage [3]. The damage occurs through the initiation of the unfolded protein response, which accelerates apoptosis of developing myeloid cells [4].\n\nThree to five days of profound neutropenia (<0.2 × 109/L) recurs every 21 days in more than 90% of CyN patients, although the cycle can range from 2 to 4 weeks [5]. The manifestations may be variable and include fever, lymphadenopathy, mouth ulcers, and infections such as sinusitis, pharyngitis, cellulitis, pneumonia, and acute peritonitis. Symptoms are usually recurrent, and sometimes severe, having led to death [5]. The standard of care for CyN is the use of granulocyte colony stimulating factor (G-CSF), which leads to an increase in absolute neutrophils counts and reduces neutropenic periods and severe events [6]. Although not common in CyN, myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) transformation is a well-known complication observed in cases of severe congenital neutropenia (SCN), a similar but noncyclical neutropenia caused by mutation of the ELANE gene, and less frequently, the GFI1 gene [7]. Transformation has been shown to occur in SCN that has been treated with G-CSF (seen in 16% of patient studied by Makaryan et al.) [4]. There is limited literature on utilizing allogeneic bone marrow transplant (BMT) to treat SCN [6], as it is rarely used for treatment of only very severe conditions of neutropenia.\n\nFamilial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder caused by a mutation of the MEFV (Mediterranean fever) gene, which is responsible for making pyrin. A missense mutation or a deletion of the gene leads to dysfunction of pyrin [8]. This protein is present in neutrophils and we report the first case of cyclic neutropenia with ELANE mutation in combination with MEFV mutation resulting in severe symptoms. We hypothesize that this unique combination of mutations in our patient may have contributed to severe symptoms resulting in need for allogeneic stem cell transplantation.\n\n2. Case Presentation\nThe patient is a 25-year-old Caucasian male with CyN, who was diagnosed at age one. Since childhood he suffered through multiple hospitalizations for severe infections and required numerous surgeries related to his underlying neutropenia. He had an extensive history of oral mucosa lesions, throat, ear, fingernail and buttock infections, and bouts of bloody diarrhea with colitis. His surgeries included tonsillectomy, mastoidectomy, appendectomy, and cholecystectomy. His quality of life had been deteriorating, and the patient voiced unhappiness. His neutropenic cycles were initially every 25–28 days with 3–5 days of nadir, and he had temporary improvement in his cycles with filgrastim treatment. Neutropenic cycles shortened to 15–18 days but he remained vulnerable to infections during his nadirs and suffered opportunistic infections on a number of occasions despite G-CSF, which was more recently replaced with PEGylated G-CSF.\n\nFollowing evaluation of the patient at our institution, he underwent testing for ELANE mutation, which identified c.573_597 + 5del, heterozygous, frame-shift deletion mutation of neutrophil elastase, located in the neutrophils. Additionally, the Periodic Fever Syndromes Panel was performed (testing for LPIN2, MEFV, MVK, NLRP3, PSTPTP1, and TNFRSF1A) and returned positive for MEFV (Mediterranean fever) with nucleic acid change c. [1105C>T; 1223G>A] and amino acid alteration p. [Pro369Ser; Arg408Gln]. Bone marrow biopsy (core and aspirate; Figures 1(a), 1(b), 1(c), and 1(d)) showed myeloid hyperplasia with prominent toxic granulation and a shift with immaturity consistent with G-CSF effect, but with no overt dysplasia and only 1% blasts, and otherwise normal hematopoiesis with no evidence of malignancy.\n\nGiven the G-CSF refractory neutropenia and progressive symptomatic disease, the decision was made to proceed to off protocol, institutional standard allogeneic BMT. In the absence of matched sibling, patient received a 10 of 10 antigen matched unrelated bone marrow hematopoietic stem cell transplant. The patient was given conditioning chemotherapy using combination cyclophosphamide (Cy), fludarabine (FLU), anti-thymocyte globulin (ATG), and low dose total body irradiation (200 cGy). The patient was started on methotrexate (10 mg/m2 on days +1, +3, +6, and +11) and cyclosporine (120 to 150 mg BID dose and goal trough level 200–250) for GvHD prophylaxis. Posttransplant course was complicated by neutropenic fever and signs of engraftment syndrome with mild tachypnea and generalized rash; this responded to a short-term course of prednisone. By day +14, the patient engrafted for neutrophils and platelets (Table 1), and bone marrow biopsy (core and aspirate; Figures 2(a), 2(b), 2(c), and 2(d)) and DNA test at 2 months confirmed 100% donor chimerism. He was discharged from hospital on day +20 with no evidence of GvHD, feeling well and eating normally. He was seen in clinic initially weekly and then every two weeks for his normal follow-up appointments and he remained well and asymptomatic. He presented on day +53 after BMT with a 7-day history of severe diarrhea and was admitted to the hospital. Endoscopy showed granularity and cobble stone appearance in the small bowel, consistent with GI GvHD. Biopsy obtained from endoscopy revealed grade 4 of 4 GI GvHD, with extensive mucosal ulceration and development of pneumatosis cystoids intestinalis, acute serositis, and likely focal microperforation. Despite treatment with steroids, calcineurin inhibitors, cellcept, budesonide, and infliximab, the grade IV GI GvHD progressed and he developed perforation of the cecum requiring subtotal colectomy. After a prolonged hospital stay, patient died of respiratory failure and septic shock +128 days following BMT.\n\n3. Discussion\nCyclic neutropenia is a hematopoietic stem cell disorder, which was demonstrated by Krance et al. after the unintended transfer of the disorder from an affected (but generally asymptomatic) individual to her unaffected sister via bone marrow transplant in order to treat acute lymphoblastic leukemia (ALL) [18]. Phenotypic presentation of the disease is variable, but a correlation between mutation type and disease severity may exist, which may help predict the patient population that would benefit from more aggressive therapy. Lange and Jones compiled a list of deaths related to CyN, which showed that many patients died due to sepsis, colitis, pulmonary complication, lymphosarcoma, and massive gastrointestinal hemorrhage [19]. Few neutropenia patients who are refractory to routine therapy and have severe symptoms undergo treatment with allogenic stem cell transplantation [7], but there is paucity of published literature on this subject [8, 20, 21] (see Table 2 for summary).\n\nStem cell transplantation has been used to treat congenital neutropenia that is unresponsive or only partially responsive to G-CSF since the 1970s [20]. A report on 11 patients (age 6 months to 15.9 years) between 1976 and 1998 who underwent transplant is one of the first truly comprehensive works that provided information regarding long term outcomes—in fact one patient was followed up for 22 years after transplant at the time of publication [20]. The report showed that all patients who received HSCT from a sibling had survived, one patient had severe GvHD, and all but one patient continued to require G-CSF secondary to transplant rejection [20]. Other studies have shown that if a sibling donor is not available, an unrelated HLA-matched BMT can be successful even in situation of pretransplant infection [21]. A general study of patients with inherited immunodeficiency states was conducted by Amrolia et al. and they reported that nonmyeloablative SCT allowed for fast engraftment from both related (sibling) and unrelated matched donors with minimal toxicity (conditioning regimen: fludarabine-melphalan-antilymphocyte globulin) [22].\n\nOur patient had a history of multiple hospitalizations due to recurrent fevers and infections including perirectal abscess as well as intermittent bloody diarrhea from colitis, which were of major concern. His phenotypic presentation was high risk, though the risk associated with his specific ELANE mutation (c.573_597+5del, heterozygous, frame-shift deletion mutation) is unclear. According to Germeshausen et al., there is, as of yet, no clear genotype-phenotype correlation with ELANE mutations and predicted severity of disease, suggesting that a wide range of other mechanisms including epigenetic and environmental factors may play an important role as well [23]. In an attempt to assess the correlation of specific mutations and disease severity, Makaryan et al. showed that the cumulative incidence of a severe event (defined as MDS/AML transformation, transplant, or death) in SCN and CyN patients after 20 years of G-CSF treatment was over 70% if the mutation was located in exon 5, over 50% if the mutation was located from the 5′ UTR region through exon 2, and 35% for patients whose mutation was located in the interior of the gene from exon 3 through intron 4. Moreover, those with mutations G214R and C151Y all experienced a severe event, 10% with the S126L mutation had a severe event, and none with P139L or IVS4+5G>A had a severe event, and of the individuals studied, P139L, IVS4+5G>A, and S126L were seen in both SCN and CyN whereas C151Y and G214R were seen only in SCN [4]. The study showed that, after 20 years of G-CSF, the risk of a severe event in SCN was 46% and 7% in CyN. Further, they found that the ELANE genotype may influence the risk of severe bacterial infections and that the dose of G-CSF needed to treat neutropenia also correlated to mutation type [4]. Beekman and Touw state that secondary leukemia in SCN likely arises because of chronic genotoxic stress in the HSC compartment, which leads to acquisition of oncogenic mutations [24].\n\nG-CSF is considered standard treatment of CyN [6] and although our patient had initially benefitted from G-CSF, during later years he experienced multiple severe infections. Moreover, malignant transformation to MDS or AML has been reported as one of the most serious complications of prolonged G-CSF treatment [24]. One study with SCN patients by Beekman and Touw demonstrated MDS/AML risk to increase over time from 2.9% per year after 6 years to 8% after 12 years [24], and individuals that required more than the median dose (8 mcg/kg/day) were shown to have incidence up to 40% after 12 years compared to 11% in patients who responded to lower doses. MDS/AML transformation upon long term G-CFS use has not been reported in CyN patients [24], although it is also possible that these findings of transformation in SCN may be due to longer duration with disease that transforms to malignancy on its own.\n\nCurrently, no standard treatment algorithm exists to determine when a patient with CyN should be considered for allogeneic BMT when refractory to G-CSF. Allogeneic BMT is currently the only alternative therapy for those with SCN who are refractory to G-CSF [7, 10, 12] but there is limited data on outcomes. Fioredda et al. report outcomes on 136 SCN patients who underwent BMT. Their data showed a 3-year-overall survival posttransplant of 82% and transplant related mortality of 17% [10]. Younger patients (less than 10 years of age at time of transplant) did better overall [10]. There was a 21% cumulative incidence of GvHD at day +90 and 20% cumulative incidence at 1 year [10]. Another study by Oshima et al. reported a cumulative incidence of grade II-IV GvHD of 11% [12]. The difference between both studies may be due to median age of subjects (younger in the Oshima group) or type of conditioning regimen utilized. Due to the similarities between CyN and SCN, allogeneic BMT is a potentially curative treatment for individuals only with severe CyN. Transplant use may be considered as the last measure for patients due to its high risks associated with transplantation, including GvHD and transplant related mortality. In SCN, it is critical to quickly detect signs of malignant transformation in order to pursue alternatives treatment such as allogeneic BMT in a timely manner due to risk of transformation to MDS/leukemia [7]. Although watchful waiting is considered an acceptable option, it is important to keep in mind that, in cases of SCN, success rates of transplantation in more advanced stages of malignant transformation are less than earlier stage [23], and an earlier age of transplantation has been shown to lead to long term success [7], indicating the need for systematic approach to decide optimal time for transition to BMT from G-SCF.\n\nIn addition to ELANE mutation, our patient had positive finding of familial Mediterranean fever (MEFV). MEFV is an autosomal recessive disorder characterized by mutation of the gene MEFV that produces the protein pyrin found within cytoskeletons of certain WBCs including neutrophils [25]. Characteristics of this mutation include recurrent but self-limited episodes of fever, pleuritis, arthritis, and peritonitis [25]. This unique dual mutation finding in our patient may have contributed to his severe symptoms due to higher susceptibility to infections, although this cannot be confirmed because the specific amino acid alteration of MEFV found in our patient can present with typical familial Mediterranean fever which can have an asymptomatic presentation [26].\n\n4. Conclusion\nCyclic neutropenia has a wide range of phenotypic presentations. Treatment with G-CSF is adequate for many affected by CyN but few are refractory to treatment with G-CSF. Allogenic transplantation is option of last resort but it is potentially curative. Secondary severe event (MDS/AML transformation, transplant, or death) in SCN and CyN patients after 20 years of G-CSF treatment is seen over 70% if the ELANE mutation was located in exon 5, over 50% if the mutation was located from the 5′ UTR region through exon 2, and 35% for patients whose mutation was located in the interior of the gene from exon 3 through intron 4. Mutations G214R and C151Y are linked severe event. Only 10% with the S126L mutation had a severe event and P139L or IVS4+5G>A is not linked with severe event. After 20 years of G-CSF, the risk of a severe event in SCN is 46% and 7% in CyN. Other than factors described above, there is no other correlate for CyN genotype to phenotype in order to predict severity. We suggest patients who present to transplant physicians for evaluation need to have ELANE testing along with additional comprehensive testing like Periodic Fever Syndromes Panel testing for LPIN2, MEFV, MVK, NLRP3, PSTPTP1, and TNFRSF1A, in addition to routine marrow assessment with FISH and conventional cytogenetics and morphological evaluation for MDS/AML. This first report suggests that combined ELANE/MEFV mutations may have worse prognosis due to severe symptoms in CyN.\n\nAcknowledgments\nThis work was supported by the National Cancer Institute, National Institutes of Health, Bethesda, MD (Grant P30 CA023074).\n\nCompeting Interests\nAll authors declare no conflict of interests.\n\nAuthors' Contributions\nAll authors performed the study, contributed to data, analyzed and summarized the data, and wrote the paper.\n\nFigure 1 Myeloid hyperplasia with prominent granulation and a shift to immaturity consistent with growth factor (G-CSF) effect. (a) Bone marrow aspirate low power (20x), (b) bone marrow aspirate high power (100x), (c) bone marrow core biopsy (20x), and (d) bone marrow core biopsy (60x).\n\nFigure 2 Engrafting bone marrow with trilineage hematopoiesis and decreased cellularity compared to previous marrow (30% versus 80%). (a) Bone marrow aspirate low power (10x), (b) bone marrow aspirate high power (60x), (c) bone marrow core biopsy (40x), and (d) bone marrow core biopsy (100x).\n\nTable 1 Laboratory results before and after allogeneic BMT.\n\n \tDay −5 \tDay −2 \tDay +7 \tDay +27 \tDay +41 \tDay +78 \t\nWBC (1000/uL)\t18.5\t4.9\t<0.1\t2.9\t2.9\t5.7\t\nANC (1000/uL)\t16.3\t4.90\tToo few\t1.50\t1.80\t5.50\t\nHemoglobin (g/dL)\t11.7\t10.8\t6.5\t10.6\t7.5\t11.8\t\nPlatelet (1000/uL)\t140\t56\t31\t227\t164\t77\t\nTable 2 Summary of relevant literature of SCN and HSCT.\n\nArticle reference\tSubjects\tDemographics\tTreatment\tConclusion\t\n[9]\t1\t4 y/o male with SCN\tHSCT: matched unrelated donor (MUD)\t“HSCT is a useful treatment for SCN patients, especially those who are at high risk for leukemic transformation”\t\n\n\n\t\n[10]\t136\t0–43 y/o male and females with SCN\tHSCT\n(i) 61 HLA matched related donors\n(ii) 61 HLA-MUD\n(iii) 14 mismatched donors\t“3-year overall survival (OS) was 82%, and transplant-related mortality (TRM) was 17%… Cumulative incidence (1 year) of chronic GVHD was 20%”\t\n\n\n\t\n[11]\t7 (one subject transplanted twice)\t2.8–28 y/o males and females with SCN\tHSCT\n(i) 3 HLA matched siblings\n(ii) 3 HLA-MUD\n(iii) 2 cord blood\t“Two of seven (29%) patients died; both had MDS/L… one patient has chronic GVHD 2 years post-transplant”\t\n\n\n\t\n[12]\t18\t0.2–16.7 y/o males and females with SCN\tHSCT\n(i) 9 HLA matched siblings\n(ii) 9 HLA-MUD\t“Engraftment occurred at the first HSCT in 12 patients, four patients received a second HSCT for graft failure, and two patients died. The cause of death was renal failure and graft failure at the first and second HSCT, respectively. The cumulative incidence of grade II–IV acute GVHD and TRM at the first transplantation was 11% and 5.6%, respectively”\t\n\n\n\t\n[13]\tN/a. Review of guidelines and treatments\tMales and females with SCN, leukocyte adhesion deficiency, and chronic granulomatous disease\tHSCT with matched and medically unrelated donors\t“Allogeneic stem cell transplantation and, possibly, gene-replacement therapy are the only curative treatments available”\t\n\n\n\t\n[14]\tReview of 300 patients on Severe Chronic Neutropenia International Registry (SCNIR)\tMales and females with SCN\t(i) GCSF\n(ii) HSCT\t“More than 90% of patients respond to recombinant human (rHu) G-CSF with ANCs that can be maintained at approximately 1.0 × 10(9)/L… Hematopoietic stem cell transplantation (HSCT) is still the only available treatment for patients refractory to rHuG-CSF treatment”\t\n\n\n\t\n[15]\t600 patients with CN collected by the SCNIR\tMales and females with SCN\t(i) GCSF\n(ii) HSCT\t“In recent analyses the influence of the G-CSF dose required to achieve neutrophil response (ANC > 1,000/microL) in the risk of developing acute myeloid leukemia (AML) has been reported”\t\n\n\n\t\n[7]\t101 SCN, 9 of which received HSCT\tMales and females with SCN\tHSCT\n(i) 2 HLA matched related donors\n(ii) 7 HLA-MUD\t“HSCT is feasible for patients with SCN who do not respond to G-CSF, who have malignant transformation, or who are at a high risk of malignant transformation, even if an HLA-identical sibling donor is not available” \t\n\n\n\t\n[16]\t300 patients from SCNIR\tMales and females with SCN\t(i) GCSF\n(ii) HSCT\t“Adverse events documented in this group of patients include splenomegaly, thrombocytopenia, osteoporosis and malignant transformation into MDS/leukemia. If and how rHuG-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. For those patients who are refractory to rHuG-CSF treatment and continue to have severe and often life-threatening bacterial infections, hematopoietic stem cell transplantation (HSCT) is still the only currently available treatment”\t\n\n\n\t\n[17]\tN/a (review of characteristics, diagnosis, management, and genetic counseling)\tMales and females with SCN\tGCSF\n(i) HSCT\t“Treatment with granulocyte colony-stimulating factor (G-CSF) ameliorates symptoms and reduces infections in almost all affected individuals. For affected individuals with a well-matched donor, hematopoietic stem cell transplantation (HSCT) may be the preferred treatment option. HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation”\n==== Refs\n1 Bellanné-Chantelot C. Clauin S. Leblanc T. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register Blood 2004 103 11 4119 4125 10.1182/blood-2003-10-3518 2-s2.0-2542434031 14962902 \n2 Horwitz M. Benson K. F. Person R. E. Aprikyan A. G. Dale D. C. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis Nature Genetics 1999 23 4 433 436 10.1038/70544 2-s2.0-0032757863 10581030 \n3 Dale D. C. Cyclic and chronic neutropenia: an update on diagnosis and treatment Clinical Advances in Hematology & Oncology 2011 9 11 868 869 22252620 \n4 Makaryan V. Zeidler C. Bolyard A. A. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia Current Opinion in Hematology 2015 22 1 3 11 10.1097/MOH.0000000000000105 2-s2.0-84916933346 25427142 \n5 Dale D. C. Bolyard A. A. Aprikyan A. Cyclic neutropenia Seminars in Hematology 2002 39 2 89 94 10.1053/shem.2002.31917 2-s2.0-0036222065 11957190 \n6 Hammond W. P. Price T. H. Souza L. M. Dale D. C. Treatment of cyclic neutropenia with granulocyte colony-stimulating factor The New England Journal of Medicine 1989 320 20 1306 1311 10.1056/nejm198905183202003 2-s2.0-0024360994 2469956 \n7 Ferry C. Ouachée M. Leblanc T. Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register Bone Marrow Transplantation 2005 35 1 45 50 10.1038/sj.bmt.1704718 2-s2.0-19944427804 15489867 \n8 Livneh A. Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever Bailliere's Best Practice and Research in Clinical Rheumatology 2000 14 3 477 498 10.1053/berh.2000.0089 2-s2.0-0033797615 10985982 \n9 Kawaguch K. Matsubara K. Uchida Y. Successful treatment with allogenic hematopoietic stem cell transplantation of a severe congenital neutropenia patient harboring a novel ELANE mutation Rinsho Ketsueki 2014 55 11 2294 2299 10.11406/rinketsu.55.2294 25501410 \n10 Fioredda F. Iacobelli S. Van Biezen A. Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation Blood 2015 126 16 1885 1892 10.1182/blood-2015-02-628859 2-s2.0-84944233630 26185129 \n11 Carlsson G. Winiarski J. Ljungman P. Hematopoietic stem cell transplantation in severe congenital neutropenia Pediatric Blood & Cancer 2011 56 3 444 451 21072829 \n12 Oshima K. Hanada R. Kobayashi R. Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: an analysis of 18 Japanese cases Pediatric Transplantation 2010 14 5 657 663 10.1111/j.1399-3046.2010.01319.x 2-s2.0-77954514634 20331518 \n13 Elhasid R. Rowe J. M. Hematopoetic stem cell transplantation in neutrophil disorders: severe congenital neutropenia, leukocyte adhesion deficiency and chronic granulomatous disease Clinical Reviews in Allergy & Immunology 2010 38 1 61 67 10.1007/s12016-009-8129-y 19452286 \n14 Zeidler C. Welte K. Kostmann syndrome and severe congenital neutropenia Seminars in Hematology 2002 39 2 82 88 11957189 \n15 Welte K. Zeidler C. Dale D. C. Severe congenital neutropenia Seminars in Hematology 2006 43 3 189 195 16822461 \n16 Zeidler C. Schwinzer B. Welte K. Severe congenital neutropenia: trends in diagnosis and therapy Klinische Pädiatrie 2000 212 4 145 152 10994541 \n17 Dale D. C. Pagon R. A. Adam M. P. Ardinger H. H. ELANE-related neutropenia GeneReviews(R) 1993 Seattle, Wash, USA University of Washington \n18 Krance R. A. Spruce W. E. Forman S. J. Human cyclic neutropenia transferred by allogeneic bone marrow grafting Blood 1982 60 6 1263 1266 2-s2.0-0020360905 6753968 \n19 Lange R. D. Jones J. B. Cyclic neutropenia: review of clinical manifestations and management American Journal of Pediatric Hematology Oncology 1981 3 4 363 367 2-s2.0-0019854897 \n20 Zeidler C. Welte K. Barak Y. Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation Blood 2000 95 4 1195 1198 2-s2.0-0034651925 10666190 \n21 Toyoda H. Azuma E. Hori H. Successful unrelated BMT in a patient with Kostmann syndrome complicated by pre-transplant pulmonary ‘bacterial’ abscesses Bone Marrow Transplantation 2001 28 4 413 415 10.1038/sj.bmt.1703156 2-s2.0-0034837122 11571517 \n22 Amrolia P. Gaspar H. B. Hassan A. Nonmyeloablative stem cell transplantation for congenital immunodeficiencies Blood 2000 96 4 1239 1246 2-s2.0-0034663152 10942363 \n23 Germeshausen M. Deerberg S. Peter Y. Reimer C. Kratz C. P. Ballmaier M. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia Human Mutation 2013 34 6 905 914 10.1002/humu.22308 2-s2.0-84878151900 23463630 \n24 Beekman R. Touw I. P. G-CSF and its receptor in myeloid malignancy Blood 2010 115 25 5131 5136 10.1182/blood-2010-01-234120 2-s2.0-77954676938 20237318 \n25 Gershoni-Baruch R. Brik R. Shinawi M. Livneh A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever European Journal of Human Genetics 2002 10 2 145 149 10.1038/sj/ejhg/5200776 2-s2.0-0036224497 11938447 \n26 Ryan J. G. Masters S. L. Booty M. G. Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein Annals of the Rheumatic Diseases 2010 69 7 1383 1388 10.1136/ard.2009.113415 2-s2.0-77954999821 19934105\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2017()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
"mesh_terms": null,
"nlm_unique_id": "101576456",
"other_id": null,
"pages": "5375793",
"pmc": null,
"pmid": "28197346",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "11957190;23463630;10994541;15489867;21072829;14962902;11571517;11938447;10666190;10581030;20237318;11957189;6753968;25501410;10985982;20331518;26185129;19934105;2469956;7036779;16822461;19452286;25427142;22252620;10942363",
"title": "Allogeneic Transplant in ELANE and MEFV Mutation Positive Severe Cyclic Neutropenia: Review of Prognostic Factors for Secondary Severe Events.",
"title_normalized": "allogeneic transplant in elane and mefv mutation positive severe cyclic neutropenia review of prognostic factors for secondary severe events"
} | [
{
"companynumb": "US-ACCORD-048877",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Immune-related adverse events induced by immune checkpoint inhibitor (ICI) therapy may affect diverse organ systems, including skeletal and cardiac muscle. ICI-associated myositis may result in substantial morbidity and occasional mortality. We present a case of a patient with advanced non-small cell lung cancer who developed grade 4 myositis with concurrent myocarditis early after initiation of anti-programmed death ligand 1 therapy (durvalumab). Autoantibody analysis revealed marked increases in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody levels that preceded clinical toxicity, and further increased during toxicity. Notably, the patient had a history of intolerable statin myopathy, which had resolved clinically after statin discontinuation and prior to ICI initiation. This case demonstrates a potential association between statin exposure, autoantibodies, and ICI-associated myositis.",
"affiliations": "Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;School of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;School of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.",
"authors": "von Itzstein|Mitchell S|MS|0000-0003-0530-3169;Khan|Shaheen|S|;Popat|Vinita|V|;Lu|Rong|R|;Khan|Saad A|SA|;Fattah|Farjana J|FJ|;Park|Jason Y|JY|;Bermas|Bonnie L|BL|;Karp|David R|DR|;Ahmed|Murtaza|M|;Saltarski|Jessica M|JM|;Gloria-McCutchen|Yvonne|Y|;Xie|Yang|Y|;Li|Quan-Zhen|QZ|;Wakeland|Edward K|EK|;Gerber|David E|DE|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2019-0911",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "25(8)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000082082:Immune Checkpoint Inhibitors; D008175:Lung Neoplasms; D009220:Myositis",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "e1242-e1245",
"pmc": null,
"pmid": "32400023",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "26090508;23550685;24023601;26104017;29480216;29885538;17177964;30001928;30359135;21403872;30377338;27864576;29200081;25610638",
"title": "Statin Intolerance, Anti-HMGCR Antibodies, and Immune Checkpoint Inhibitor-Associated Myositis: A \"Two-Hit\" Autoimmune Toxicity or Clinical Predisposition?",
"title_normalized": "statin intolerance anti hmgcr antibodies and immune checkpoint inhibitor associated myositis a two hit autoimmune toxicity or clinical predisposition"
} | [
{
"companynumb": "US-CHANGZHOU PHARMACEUTICAL FACTORY-2107566",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DURVALUMAB"
},
"drugadditio... |
{
"abstract": "METHODS\nCardiotoxicity is a rare but serious side effect of clozapine. We present a case of a psychiatric patient on chronic clozapine 75 mg daily, who presented with congestive heart failure secondary to the cardiotoxic effects of the psychiatric medication.\nConventional heart failure treatment failed to improve symptoms.\n\n\nMETHODS\nA course of 40 mg of intravenous immunoglobulin and 125 mg of steroids was implemented, after which the patient made a full recovery. We hope to raise awareness of concurrent clozapine-induced pericarditis and myocarditis and propose a role of intravenous immunoglobulin and steroids in the treatment of drug-induced cardiomyopathy.",
"affiliations": "Wichita Falls Family Practice Residency Program, Wichita Falls, TX.",
"authors": "Cheng|Albert|A|;Ahmed|Mohanned|M|;Shuaib|Waqas|W|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D003024:Clozapine; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000751",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "26(4)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D066126:Cardiotoxicity; D003024:Clozapine; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008775:Methylprednisolone; D009205:Myocarditis; D009206:Myocardium; D010493:Pericarditis; D010496:Pericardium; D011618:Psychotic Disorders; D016896:Treatment Outcome",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e485-e486",
"pmc": null,
"pmid": "29659374",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravenous Immunoglobulin and Methylprednisolone for Clozapine-Associated Perimyocarditis.",
"title_normalized": "intravenous immunoglobulin and methylprednisolone for clozapine associated perimyocarditis"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2018091984",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAZODONE HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Clostridioides difficile infection is a relatively rare cause of diarrhoea in children, but there are frequent recurrences when it occurs, despite targeted antibiotic treatment.\n\n\n\nA 2-year-old boy with concomitant motility disorder and a 14-year-old girl with Down syndrome experienced several infections with C. difficile, respectively after the use of antibiotics for otitis media and extended use of antibiotics in addition to chemotherapy. Both were treated successfully with faecal transplants.\n\n\n\nClostridioides difficile infections occur in children, mainly after extended use of antibiotics or when the immune system is impaired. In case of recurring C. difficile infections, children can be treated safely and effectively with faecal transplants.",
"affiliations": "Amsterdam UMC, afd. Maag-, Darm-, en Leverziekten, Amsterdam.;Amsterdam UMC, afd. Medische Microbiologie en Infectiepreventie, Amsterdam.;Amsterdam UMC, afd. Medische Microbiologie en Infectiepreventie, Amsterdam.;Amsterdam UMC, afd. Medische Microbiologie en Infectiepreventie, Amsterdam.;Amsterdam UMC, Baarn.;Amsterdam UMC, afd. Kindergeneeskunde, Amsterdam.",
"authors": "Ooijevaar|Rogier E|RE|;van Rossen|Tessel M|TM|;Vandenbroucke-Grauls|Christina M J E|CMJE|;Budding|Andries E|AE|;Kneepkens|C M F|CMF|;de Meij|Tim G J|TGJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "163()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D002675:Child, Preschool; D016360:Clostridioides difficile; D003015:Clostridium Infections; D000069467:Fecal Microbiota Transplantation; D005260:Female; D006801:Humans; D008297:Male; D010033:Otitis Media; D012008:Recurrence",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31361420",
"pubdate": "2019-07-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Faecal transplants for children with recurrent infections.",
"title_normalized": "faecal transplants for children with recurrent infections"
} | [
{
"companynumb": "NL-FDC LIMITED-2089430",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "A young child being diagnosed with cancer naturally generates a pretty melancholy reaction. Each cancer can be managed with a vast array of treatment options that are available either individually or as a combination, the final goal of which is total eradication of the condition in the affected individual. Since, most of these treatments are administered during the age of tooth formation, they may affect stages of odontogenesis. Most common treatment of childhood cancers includes--chemotherapy and radiotherapy. With recent advancements in cancer therapy additional treatment options like laser therapy, radiation in the form of brachytherapy or teletherapy, cryotherapy, thermochemotherapy, etc. are available. As treatment of childhood cancers starts at a very young age coinciding with dental development, a number of dental malformations have been reported in childhood cancer survivors. The most common ocular cancer in children is retinoblastoma. This is the first such reported case and unique one where microdontia has affected all the first premolars.",
"affiliations": "Department of Pediatric and Preventive Dentistry, College of Dental Sciences and Research, Ahmedabad, Gujarat, India. veekart@yahoo.co.in",
"authors": "Venkataraghavan|Karthik|K|;Patil|Shankargouda|S|;Guvva|Sowjanya|S|;Karthik|Sandhya|S|;Bhandi|Shilpa|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.5005/jp-journals-10024-1328",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-3711",
"issue": "14(2)",
"journal": "The journal of contemporary dental practice",
"keywords": null,
"medline_ta": "J Contemp Dent Pract",
"mesh_terms": "D001641:Bicuspid; D017024:Chemotherapy, Adjuvant; D002648:Child; D015353:Eye Enucleation; D005260:Female; D006801:Humans; D008310:Malocclusion; D020360:Neoadjuvant Therapy; D009805:Odontogenesis; D010347:Patient Care Planning; D011859:Radiography; D018714:Radiotherapy, Adjuvant; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D014097:Tooth, Unerupted",
"nlm_unique_id": "101090552",
"other_id": null,
"pages": "360-4",
"pmc": null,
"pmid": "23811674",
"pubdate": "2013-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Abnormal odontogenesis following management of childhood cancer (retinoblastoma): review and a new variant.",
"title_normalized": "abnormal odontogenesis following management of childhood cancer retinoblastoma review and a new variant"
} | [
{
"companynumb": "PHHY2015IN102937",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "We report the case of a patient who had cerebral aspergillosis after otorhinolaryngologic surgery and who was successfully and safely treated with high-dose voriconazole (200 mg q6h) for more than 1 year thanks to a TDM-guided approach coupled with pharmacological review and with genotyping of CYP2C19 polymorphisms. The findings support the idea that personalized medicine based on TDM coupled with the need of avoiding drug-drug interactions may be helpful for maximizing the net benefit (probability of efficacy vs. probability of adverse events) of voriconazole in the management of long-term treatment of cerebral aspergillosis.",
"affiliations": "Department of Medicine, University of Udine, Udine, Italy.;Clinic of Infectious Diseases, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.;Department of Medicine, University of Udine, Udine, Italy.;Department of Medicine, University of Udine, Udine, Italy.;Department of Medicine, University of Udine, Udine, Italy.;Department of Medicine, University of Udine, Udine, Italy.",
"authors": "Cojutti|Pier Giorgio|PG|;Merelli|Maria|M|;Allegri|Lorenzo|L|;Damante|Giuseppe|G|;Bassetti|Matteo|M|;Pea|Federico|F|0000-0002-6966-7167",
"chemical_list": "D000935:Antifungal Agents; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13789",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "85(1)",
"journal": "British journal of clinical pharmacology",
"keywords": "clinical pharmacology; cytochrome P450; genetic polymorphism; infectious diseases; pharmacokinetics; therapeutic drug monitoring",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000935:Antifungal Agents; D001232:Aspergillus fumigatus; D001921:Brain; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D006801:Humans; D008134:Long-Term Care; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020953:Neuroaspergillosis; D013517:Otorhinolaryngologic Surgical Procedures; D000071185:Pharmacogenomic Testing; D011110:Polymorphism, Genetic; D011183:Postoperative Complications; D013997:Time Factors; D016896:Treatment Outcome; D065819:Voriconazole",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "266-269",
"pmc": null,
"pmid": "30414213",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports",
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"title": "Successful and safe long-term treatment of cerebral aspergillosis with high-dose voriconazole guided by therapeutic drug monitoring.",
"title_normalized": "successful and safe long term treatment of cerebral aspergillosis with high dose voriconazole guided by therapeutic drug monitoring"
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"abstract": "We are presenting a case of Listeria monocytogenes spontaneous bacterial peritonitis (SBP) monomicrobial non-neutrocytic bacterascites (MNS) in a patient with malignant ascites secondary to cholangiocarcinoma who underwent peritoneal catheter placement. Listeria peritonitis is uncommon, with cancer patients at a higher risk. Listeria infection should be suspected in susceptible patients once there is no response to empiric antibacterial or if the initial culture report shows gram positive bacilli, the antibacterial of choice is ampicillin.",
"affiliations": "Wellstar Atlanta Medical Center, United States.;Wellstar Atlanta Medical Center, United States.;Wellstar Atlanta Medical Center, United States.",
"authors": "Eisa|Mohamed|M|;Tefera|Kibrewessen|K|;Alvanpour|Anahita|A|",
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"doi": "10.1016/j.idcr.2018.e00430",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30113-610.1016/j.idcr.2018.e00430e00430ArticleListeria peritonitis and bacteremia in a patient with cholangiocarcinoma Eisa Mohamed dr.moe.eisa@gmail.com⁎Tefera Kibrewessen Alvanpour Anahita Wellstar Atlanta Medical Center, United States⁎ Corresponding author. dr.moe.eisa@gmail.com09 8 2018 2018 09 8 2018 14 e00430 e00430 31 5 2018 23 7 2018 24 7 2018 © 2018 Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We are presenting a case of Listeria monocytogenes spontaneous bacterial peritonitis (SBP) monomicrobial non-neutrocytic bacterascites (MNS) in a patient with malignant ascites secondary to cholangiocarcinoma who underwent peritoneal catheter placement. Listeria peritonitis is uncommon, with cancer patients at a higher risk. Listeria infection should be suspected in susceptible patients once there is no response to empiric antibacterial or if the initial culture report shows gram positive bacilli, the antibacterial of choice is ampicillin.\n==== Body\nIntroduction\nAmong patients with ascites in the United States, most (85%) have cirrhosis and portal hypertension [1]. Malignancy-related ascites is much less common, accounting for or contributing to ascites formation in approximately 7–10% of patients.\n\nSpontaneous bacterial peritonitis (SBP) is defined as an ascites fluid infection without an evident intra-abdominal surgically treatable source; it primarily occurs in patients with advanced cirrhosis [2]. Peritonitis also can occur in patients treated with continuous ambulatory peritoneal dialysis [3]. The diagnosis is established by a positive ascites fluid bacterial culture and an elevated ascites fluid absolute polymorphonuclear leukocyte (PMN) count (≥250 cells/mm3). There are three variants of SBP that are also “spontaneous” (i.e., there is no surgically treatable source for the infection) [4]: Culture-negative neutrocytic ascites, monomicrobial non-neutrocytic bacterascites and polymicrobial bacterascites.\n\nThe organisms most commonly involved in this infection are gram-negative bacilli like Escherichia coli and Klebsiella pneumoniae, and gram-positive bacteria like Streptococcus pneumoniae and Staphylococcus aureus. Listeria monocytogenes is an uncommon gram-positive bacillus implicated in infections in neonates, pregnant females, the elderly and immunocompromised patients. Listeria monocytogenes-induced SBP is rare with total of 110 cases reported in the literature (including foreign languages Spanish, German and French) from 1966 to 2017 according to Medline search. Monobacterial non-neutrocytic bacterascites (MNB) is a variant of SBP, where the ascites fluid culture is positive but the ascites neutrophil count is less than 250/mm3. Forty percent of these patients will subsequently have SBP [5].\n\nMonomicrobial non-neutrocytic bacterascites (MNB) usually represents the colonization phase of ascitic fluid infection [6]. The floras are similar to those of SBP [6]. MNB may progress to spontaneous bacterial peritonitis (SBP), or in 62–86% of cases, resolve spontaneously.\n\nListeria monocytogenes is an important bacterial pathogen in neonates, immunosuppressed patients, older adults, pregnant women, and occasionally, previously healthy individuals. The importance of underlying diseases was illustrated in a series of 165 adults with culture-proven Listeria infection: 69% of cases in non-pregnant adults occurred in patients with cancer, AIDS, organ transplant recipients, or corticosteroid therapy [7].\n\nCase report\nA 64 year old Asian male with the recent diagnosis of cholangiocarcinoma with peritoneal and mesenteric implants presented to our facility following a fall with altered mental status for 3 days. He had received his first course of chemotherapy before admission, consisting of gemcitabine/cisplatin on day 1 and day 8. His family reported multiple episodes of recorded fever, lethargy and loss of appetite. 2 days before his admission he had seen his oncologist and subsequently had a peritoneal catheter placed. EMS on arrival reported a temperature of 103, HR of 120 and BP of 110/70. Upon arrival to the hospital he was confused, disoriented to time/place and person. There was no asterixis and abdominal examination revealed distention with peritoneal catheter in place. His initial labs showed WBC 4500 (Absolute neutrophil count 4248), hemoglobin 11.1, platelets of 27,000 and ammonia level of 44. His liver enzymes were normal, Albumin 2.9, bilirubin 2.2 and alkaline phosphatase was normal. His thrombocytopenia was contributed to the recent history of chemotherapy. CT abdomen showed a percutaneous drainage catheter overlying the lower part of the abdomen, extensive ascites, likely malignant, and multiple poorly defined intrahepatic masses; the CT head was negative for acute changes. He received ceftriaxone and piperacillin/tazobactam, subsequently the ceftriaxone was changed to vancomycin when he was transferred to the ICU. Ascitic fluid analysis revealed absolute neutrophil count of 36 and blood culture grew gram positive bacilli later during the clinical course confirmed to be Listeria monocytogenes. A suspicion of Listeria meningitis was raised, however given the thrombocytopenia; the family refused lumbar puncture because of the bleeding risk, and also refused an MRI of the brain to exclude metastasis. At that point the ascites fluid culture grew Listeria monocytogenes, ampicillin was started. His temperature curve normalized dramatically after the first dose of ampicillin although he remained critically ill, and his hospital course was complicated with atrial arrhythmia and hypotension requiring high doses of pressers support. He continued to deteriorate despite the maximum supportive care in form of acute kidney injury and electrolytes disturbances; his family refused further vasopressers and made him DNR with discontinuation of the pressers support. He died a few hours following de-escalation of care.\n\nDiscussion\nListeria monocytogenes is the only Listeria species that regularly infects humans, although rare cases of human infections with Listeria ivanovii (a pathogen of ruminants) and Listeria grayi have been reported [8,9]. Listeria is an aerobic and facultatively anaerobic, beta-hemolytic, non–spore-forming, short gram-positive rod that exhibits characteristic tumbling motility by light microscopy [10,11]. Listeria occurs singly or in short chains. On Gram stain, Listeria may resemble Pneumococci (diplococci), Enterococci, or Diphtheroids (Corynebacteria) or be gram variable and be confused with Haemophilus species [10,11]. In particular, when a positive blood or cerebrospinal fluid culture is preliminarily identified as Diphtheroids, the clinician should consider the possibility that the isolate represents Listeria [10].\n\nListeria monocytogenes, although an uncommon cause of illness in the general population, is an important pathogen in pregnant patients, neonates, elderly individuals, and immunocompromised individuals. Patients with cancer, particularly those of blood, are also at high risk for Listeria infection [12]. It is typically a food-borne organism. Listeria is also a common veterinary pathogen, being associated with abortion and encephalitis in sheep and cattle. It can be isolated from soil, water, and decaying vegetation. The most common clinical manifestation is diarrhea. A mild presentation of fever, nausea, vomiting, and diarrhea may resemble a gastrointestinal illness. The microorganism has gained recognition because of its association with epidemic gastroenteritis. In 1997, an outbreak of noninvasive gastroenteritis occurred in 2 schools in northern Italy, involving more than 1500 children and adults [13]. Bacteremia and meningitis are more serious manifestations of disease that can affect individuals at high risk. Unless recognized and treated, Listeria infections can result in significant morbidity and mortality.\n\nMost cases of Listeria monocytogenes–induced SBP occur in patients with chronic liver disease. It has also been reported after bowel wall injury resulting from paracentesis, Esophagogastroduodenoscopy (EGD), malignancy, hepatic transplantation, and continuous ambulatory peritoneal dialysis [3]. Despite the worldwide prevalence of listeriosis, two thirds of the cases of SBP caused by Listeria monocytogenes have been reported from Spain. The exact reason for this regional predilection is not known, though dietary habits have been implicated in its pathogenesis [14].\n\nAlthough cirrhosis is the cause of ascites formation in most patients (approximately 85% of cases), 7%–10% of patients develop ascites secondary to a malignancy [15]. Approximately 50% of patients with malignant ascites have peritoneal carcinomatosis with an additional 13% of patients having extensive liver metastases resulting in portal hypertension [16]. Spontaneous bacterial peritonitis (SBP) occurs more often in ascitic fluid with low protein concentrations. Isner et al in 1977, reported one patient with gastric adenocarcinoma who developed SBP after chemotherapy. At autopsy, 75% of the patient's liver parenchyma was replaced by tumor [17]. After that, less than 10 cases of SBP in malignant ascites have been reported. Five of the cases had extensive metastasis to the liver [[17], [18], [19], [20]]. A case report of SBP in a patient with gastric carcinoma without liver metastasis, prompted the author to consider gastro-intestinal bleeding as a risk factor for SBP in malignant ascites [21]. Alfonso et al in 2005 believed that two of the cases which were reported earlier, should not be considered as SBP because they did not have more than 250 PMN/mm3 in the peritoneal fluid. These cases should be classified as “monomicrobial non-neutrocytic bacterascites” [22].\n\nIntravenous antibacterials must be started immediately when the diagnosis is suspected or confirmed. Diagnosis is established by culture of the organism from blood, CSF, or other sterile body fluid. Person-to-person transmission does not occur; therefore, isolation precautions are not necessary. Ampicillin is the drug of choice. It interferes with bacterial cell wall synthesis during active multiplication, causing bactericidal activity against susceptible organisms. Gentamicin is an adjunctive therapy that can be used in conjunction with ampicillin. Penicillin-allergic patients should be skin tested and desensitized if necessary or treated with trimethoprim-sulfamethoxazole, which inhibits bacterial synthesis of dihydrofolic acid by competing with paraaminobenzoic acid, which results in inhibition of bacterial growth.\n\nConclusion\nListeria monocytogenes peritonitis is rare with only few cases having been reported thus far. Listeria infection should be suspected once there is no response to the empirical antibacterial in 24–48 h or initial cultures report showing Gram positive rods or diphtheroids. It should be especially suspected in malignancy and immunosuppresed patients.\n\nAuthors contribution\nEisa, Mohamed: The first author, who wrote the case report, participated in the literature review and wrote the manuscript.\n\nKibrewessen, Tefera: The attending who was taking care of the case, revised the final draft of the case report.\n\nAlvanpour, Anahita: The resident who was taking care of the patient and participated in the literature review.\n==== Refs\nReferences\n1 Runyon B.A. Montano A.A. Akriviadis E.A. Antillon M.R. Irving M.A. McHutchison J.G. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites Ann Intern Med 117 3 1992 215 1616215 \n2 Akriviadis E.A. Runyon B.A. Utility of an algorithm in differentiating spontaneous from secondary bacterial peritonitis Gastroenterology 98 1 1990 127 2293571 \n3 Myers J.P. Peterson G. Rashid A.J. Peritonitis due to Listeria monocytogenes complicating continuous ambulatory peritoneal dialysis Infect Dis 148 6 1983 1130 \n4 Sheer T.A. Runyon B.A. Spontaneous bacterial peritonitis variants Dig Dis 23 1 2005 39 15920324 \n5 Jammula P, Listeria monocytogenes-induced monomicrobial non-neutrocytic bacterascites; Department of Internal Medicine, University of Texas Medical Branch, Galveston 77555-0570, USA. PMID: 12425510.\n6 Runyon B.A. Monomicrobial nonneutrocytic bacterascites: a variant of spontaneous bacterial peritonitis Hepatology 12 4 Pt 1 1990 710 2210672 \n7 Schuchat A. Deaver K.A. Wenger J.D. Plikaytis B.D. Mascola L. Pinner R.W. Role of foods in sporadic listeriosis. Case-control study of dietary risk factors. The Listeria Study Group JAMA 267 15 1992 2041 1552639 \n8 Guillet C. Join-Lambert O. Le Monnier A. Leclercq A. Mechaï F. Mamzer-Bruneel M.F. Human listeriosis caused by Listeria ivanovii Emerg Infect Dis. 16 1 2010 13 \n9 Salimnia H. Patel D. Lephart P.R. Fairfax M.R. Chandrasekar P.H. Listeria grayi: vancomycin-resistant, gram-positive rod causing bacteremia in a stem cell transplant recipient Transpl Infect Dis 12 6 2010 526 20626713 \n10 Lorber B. Listeria monocytogenes Mandell G.L. Bennett J.E. Dolin R. Principles and practice of infectious diseases 7th ed 2010 Churchill Livingstone Philadelphia p. 2707 \n11 Bille J. Listeria and Erysipelothrix Manual of clinical microbiology 9th ed 2007 ASM Press Washington, DC p. 474 \n12 Mook P. O’Brien S.J. Gillespie I.A. Concurrent conditions and human listeriosis, England, 1999–2009 Emerg Infect Dis 17 1 2011 38 43 21192852 \n13 Aureli P. Fiorucci G.C. Caroli D. Marchiaro G. Novara O. Leone L. An outbreak of febrile gastroenteritis associated with corn contaminated by Listeria monocytogenes N Engl J Med 342 17 2000 1236 1241 10781619 \n14 Polanco A. Gines C. Canton R. Spontaneous bacterial peritonitis caused by Listeria monocytogenes: two case reports and literature review Eur J Clin Microbiol Infect Dis 11 1992 346 349 1396755 \n15 Runyon B.A. Montano A.A. Akriviadis E.A. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites Ann Intern Med 117 3 1992 215 220 1616215 \n16 Runyon B.A. Hoefs J.C. Morgan T.R. Ascitic fluid analysis in malignancy-related ascites Hepatology 8 5 1988 1104 1109 3417231 \n17 Isner J. Macdonald J.S. Schein P.S. Spontaneous Streptococcus pneumonia peritonitis in a patient with metastatic gastric cancer Cancer 39 1977 2306 2309 870172 \n18 Bac D.V. de Marie S. van Blankenstein M. Spontaneous bacterial peritonitis complicating malignancy-related ascites Dig Dis Sci 41 1996 131 132 8565745 \n19 Gonciarz M. Petelenz M. Gonciarz Z. Spontaneous bacterial peritonitis associated with ascites due to malignant lymphoma Am J Gastroenterology 84 1989 988 \n20 Adeonigbagbe O. Khademi A. Karowe M. Gualtieri N. Robilotti J. Listeria monocytogenes peritonitis: an unusual presentation and review of the literature J Clin Gastroenterology 30 2000 436 437 \n21 Makharia G.K. Sharma B.C. Bhasin D.K. Singh K. Spontaneous bacterial peritonitis in a patient with gastric carcinoma J Clin Gastroenterol 27 1998 269 270 9802463 \n22 Tafur Alfonso Javier Quevedo Fernando Do we see spontaneous bacterial peritonitis in patients with malignant ascites? Acta Gastroenterológica Latinoamericana 35 septiembre (3) 2005 196 197 16333978\n\n",
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"title": "Listeria peritonitis and bacteremia in a patient with cholangiocarcinoma.",
"title_normalized": "listeria peritonitis and bacteremia in a patient with cholangiocarcinoma"
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"abstract": "Non-prescribed buprenorphine (NPB) use increased in the US. This study aims to characterize heterogeneity in patterns of NPB and other opioid use among individuals with current opioid use disorder.\n\n\n\nThe study recruited 356 participants in Dayton (Montgomery County), Ohio, area in 2017-2018 using targeted and Respondent Driven Sampling. Participants met the following criteria: 1) 18 years or older, 2) current moderate/severe opioid use disorder (DSM-5), 3) past 6-month NPB use. Latent class analysis (LCA) was conducted to identify subgroups based on past 6-month (days of NPB and heroin/fentanyl use; use of NPB to get high; use of non-prescribed and prescribed pharmaceutical opioids; participation in formal treatment) and lifetime (years since first NPB and other illicit opioid use) characteristics. Selected auxiliary variables were compared across classes using Asparouhov and Muthén's 3-step approach.\n\n\n\n49.7% were female, and 88.8% were non-Hispanic whites. 89% used NPB to self-treat withdrawal. LCA resulted in three classes: \"Heavy Heroin/Fentanyl Use\" (61%), \"More Formal Treatment Use\" (29%) and \"Intense NPB Use\" (10%). After adjusting for multiple testing, the following past 6-month variables differed significantly between classes: injection as a primary route of heroin/fentanyl administration (p < 0.001), cocaine use (p = 0.044), unintentional drug overdose (p = 0.023), and homelessness (p = 0.044), with the \"Intense NPB Use\" class having the lowest prevalences.\n\n\n\nPredominance of self-treatment goals and the association between more intense NPB use and lower risks of adverse consequences suggest potential harm minimization benefits of NPB use. More research is needed to understand consequences of NPB use over time.",
"affiliations": "Center for Interventions, Treatment, and Addictions Research, Department of Population and Public Health Sciences, Boonshoft School of Medicine, Wright State University, United States. Electronic address: raminta.daniulaityte@wright.edu.;Department of Population and Public Health Sciences, Boonshoft School of Medicine, Wright State University, Dayton, United States; Department of Psychiatry, Boonshoft School of Medicine, Wright State University, United States.;Center for Interventions, Treatment, and Addictions Research, Department of Population and Public Health Sciences, Boonshoft School of Medicine, Wright State University, United States.;Department of Epidemiology, Columbia University Mailman School of Public Health, United States.;Center for Interventions, Treatment, and Addictions Research, Department of Population and Public Health Sciences, Boonshoft School of Medicine, Wright State University, United States.;Center for Interventions, Treatment, and Addictions Research, Department of Population and Public Health Sciences, Boonshoft School of Medicine, Wright State University, United States.;Center for Interventions, Treatment, and Addictions Research, Department of Population and Public Health Sciences, Boonshoft School of Medicine, Wright State University, United States.",
"authors": "Daniulaityte|Raminta|R|;Nahhas|Ramzi W|RW|;Silverstein|Sydney|S|;Martins|Silvia|S|;Zaragoza|Angela|A|;Moeller|Avery|A|;Carlson|Robert G|RG|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.drugalcdep.2019.107574",
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"issn_linking": "0376-8716",
"issue": "204()",
"journal": "Drug and alcohol dependence",
"keywords": "Buprenorphine; Buprenorphine diversion; Heroin; Illicit opioids; Non-pharmaceutical fentanyl; Overdose; Self-treatment",
"medline_ta": "Drug Alcohol Depend",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D002047:Buprenorphine; D062787:Drug Overdose; D005260:Female; D006703:Homeless Persons; D006801:Humans; D000077272:Latent Class Analysis; D008297:Male; D009820:Ohio; D009293:Opioid-Related Disorders; D063487:Prescription Drug Misuse; D015995:Prevalence; D055815:Young Adult",
"nlm_unique_id": "7513587",
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"pages": "107574",
"pmc": null,
"pmid": "31568934",
"pubdate": "2019-11-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "18929686;28245872;30909018;22704124;22589497;27692193;21781202;28194688;9787998;26116543;27810654;25869542;24680219;15450648;23276315;28859050;10741575;22356664;7844656;19588330;30359928;31146200;21466501;15223087;29573649;22036303;24984689;17439869;24018232;29693427;26066931;25221984;23722632;19874152;18504513;31229187;16002026;28694272;23199896;21844833;17305687;26785634;15925268;20155591;20598829;20434868;30095563;30326396;28554597;25980599;25205666",
"title": "Patterns of non-prescribed buprenorphine and other opioid use among individuals with opioid use disorder: A latent class analysis.",
"title_normalized": "patterns of non prescribed buprenorphine and other opioid use among individuals with opioid use disorder a latent class analysis"
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"abstract": "Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global pandemic. Patients with myasthenia gravis (MG), often treated with immunosuppressants, might be at higher risk of developing COVID-19 and of demonstrating a severe disease course. We aimed to study prevalence and describe features of COVID-19 in MG patients.\n\n\n\nIn May 2020, we conducted telephonic interviews with MG patients followed at our referral center. We collected structured data regarding MG and COVID-19, which was diagnosed as probable or confirmed according to the European Centre for Disease Prevention and Control case definition. We compared confirmed-COVID-19 prevalence calculated from the beginning of the pandemic in MG patients with that of the overall Pavia district.\n\n\n\nWe interviewed 162 MG patients (median age, 66 y; interquartile range 41-77; males 59.9%), 88 from the Pavia district. Three patients had SARS-CoV-2-confirmed by polymerase chain reaction and eight had probable-COVID-19. In the Pavia district, the prevalence of confirmed-COVID-19 among MG patients (1/88, 1.14%) and overall population (4777/546 515, 0.87%) did not differ (P = .538). Higher Myasthenia Gravis Foundation of America clinicalclass and the need for recent rescue treatment, but not ongoing immunosuppressive treatments, were associated with COVID-19 risk. Of 11 MG patients with probable/confirmed-COVID-19, 3 required ventilator support, and 2 elderly patients died of COVID-19 respiratory insufficiency. Only 1 of11 patients experienced worsening MG symptoms, which improved after increasing their steroid dose.\n\n\n\nThe risk of COVID-19 in MG patients seems to be no higher than that of the general population, regardless of immunosuppressive therapies. In our cohort, COVID-19 barely affected MG course.",
"affiliations": "Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.;Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.;Neuroncology Unit, IRCCS Mondino Foundation, Pavia, Italy.;Neuroncology Unit, IRCCS Mondino Foundation, Pavia, Italy.;Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.;Neuroncology Unit, IRCCS Mondino Foundation, Pavia, Italy.;Multiple Sclerosis Research Center, IRCCS Mondino Foundation, Pavia, Italy.;Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.;Department of Neurophysiopathology, IRCCS Mondino Foundation, Pavia, Italy.;Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.;Emergency Neurology, IRCCS Mondino Foundation, Pavia, Italy.;Multiple Sclerosis Research Center, IRCCS Mondino Foundation, Pavia, Italy.;BioData Science Center, IRCCS Mondino Foundation, Pavia, Italy.;IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Neuroncology Unit, IRCCS Mondino Foundation, Pavia, Italy.",
"authors": "Businaro|Pietro|P|0000-0002-5990-4640;Vaghi|Gloria|G|;Marchioni|Enrico|E|;Diamanti|Luca|L|;Arceri|Sebastiano|S|;Bini|Paola|P|;Colombo|Elena|E|;Cosentino|Giuseppe|G|;Alfonsi|Enrico|E|;Costa|Alfredo|A|;Ravaglia|Sabrina|S|0000-0001-8749-3706;Mallucci|Giulia|G|;Ballante|Elena|E|;Franciotta|Diego|D|;Gastaldi|Matteo|M|0000-0003-2288-2000",
"chemical_list": "D007166:Immunosuppressive Agents",
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"delete": false,
"doi": "10.1002/mus.27324",
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"issn_linking": "0148-639X",
"issue": "64(2)",
"journal": "Muscle & nerve",
"keywords": "COVID-19; comorbidities; corticosteroids; epidemiology; immunosuppressive treatments; myasthenia gravis",
"medline_ta": "Muscle Nerve",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000086382:COVID-19; D000087123:COVID-19 Nucleic Acid Testing; D018450:Disease Progression; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis",
"nlm_unique_id": "7803146",
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"pages": "206-211",
"pmc": null,
"pmid": "34031902",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "COVID-19 in patients with myasthenia gravis: Epidemiology and disease course.",
"title_normalized": "covid 19 in patients with myasthenia gravis epidemiology and disease course"
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"activesubstancename": "AZITHROMYCIN"
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{
"abstract": "Although temozolomide has been extensively used to treat various tumors, there is a lack of large-cohort studies on temozolomide's toxicity profile. The toxicity profiles and associated factors in patients treated with temozolomide-containing regimens were analyzed.\nPatients treated with temozolomide-containing regimens in the Affiliated Union Hospital of Huazhong University of Science and Technology from January 2008 to December 2019 were included. A retrospective analysis of the clinical data of patients treated with temozolomide-containing regimens was performed. Univariate chi-square test and multivariate logistic regression analysis were employed to identify factors associated with the occurrence of toxicities.\nAmong the 1057 patients received temozolomide-containing regimens, 922 patients were included in our analyses. Of the 922 patients, 484 patients (52.5%) experienced toxicities. Univariate analysis revealed that radiotherapy, chemotherapy cycle, chemotherapy regimen, and clinical stage were significantly associated with the toxicity during temozolomide treatment (P < 0.05). The chemotherapy regimen, chemotherapy cycle, and clinical stage were significantly associated with the overall occurrence of toxicities (P < 0.05). A chemotherapy regimen, chemotherapy cycle, and clinical stage were associated with the hematological system's toxicities, whereas gender, age, clinical diagnosis, and clinical stage were related to gastrointestinal toxicities (P < 0.05). Clinical diagnosis, chemotherapy regimen, and age were associated with liver toxicity (P < 0.05).\nToxicities are common among patients receiving temozolomide-containing regimens. Clinicians should be aware of factors associated with toxicities to minimize the impact of the toxicity.",
"affiliations": "Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.;Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People's Republic of China.",
"authors": "Shi|Chen|C|;Wang|Xiong|X|;Diao|Changdong|C|;Zhu|Haixia|H|;Yuan|Qi|Q|;Liu|Jinmei|J|;Li|Shijun|S|;Gu|Ming|M|;Zhang|Yu|Y|",
"chemical_list": "D000077204:Temozolomide",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/DDDT.S305792",
"fulltext": "\n==== Front\nDrug Des Devel Ther\nDrug Des Devel Ther\ndddt\ndddt\nDrug Design, Development and Therapy\n1177-8881\nDove\n\n305792\n10.2147/DDDT.S305792\nOriginal Research\nToxicities and Associated Factors in Patients Receiving Temozolomide-Containing Regimens: A 12-Year Analysis of Hospital Data\nShi et al\nShi et al\nShi Chen 12\nWang Xiong 12\nDiao Changdong 12\nZhu Haixia 12\nYuan Qi 12\nLiu Jinmei 12\nLi Shijun 12\nGu Ming 12\nZhang Yu 12\n1 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People’s Republic of China\n2 Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, People’s Republic of China\nCorrespondence: Ming Gu; Yu Zhang Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST), Wuhan, People’s Republic of China Email gimyonline@163.com; whxhzy@163.com\n20 5 2021\n2021\n15 21512159\n07 2 2021\n03 5 2021\n© 2021 Shi et al.\n2021\nShi et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nObjective\n\nAlthough temozolomide has been extensively used to treat various tumors, there is a lack of large-cohort studies on temozolomide’s toxicity profile. The toxicity profiles and associated factors in patients treated with temozolomide-containing regimens were analyzed.\n\nPatients and Methods\n\nPatients treated with temozolomide-containing regimens in the Affiliated Union Hospital of Huazhong University of Science and Technology from January 2008 to December 2019 were included. A retrospective analysis of the clinical data of patients treated with temozolomide-containing regimens was performed. Univariate chi-square test and multivariate logistic regression analysis were employed to identify factors associated with the occurrence of toxicities.\n\nResults\n\nAmong the 1057 patients received temozolomide-containing regimens, 922 patients were included in our analyses. Of the 922 patients, 484 patients (52.5%) experienced toxicities. Univariate analysis revealed that radiotherapy, chemotherapy cycle, chemotherapy regimen, and clinical stage were significantly associated with the toxicity during temozolomide treatment (P < 0.05). The chemotherapy regimen, chemotherapy cycle, and clinical stage were significantly associated with the overall occurrence of toxicities (P < 0.05). A chemotherapy regimen, chemotherapy cycle, and clinical stage were associated with the hematological system’s toxicities, whereas gender, age, clinical diagnosis, and clinical stage were related to gastrointestinal toxicities (P < 0.05). Clinical diagnosis, chemotherapy regimen, and age were associated with liver toxicity (P < 0.05).\n\nConclusion\n\nToxicities are common among patients receiving temozolomide-containing regimens. Clinicians should be aware of factors associated with toxicities to minimize the impact of the toxicity.\n\nKeywords\n\ntemozolomide\ntoxicity\nhematological system\ngastrointestinal system\nliver toxicity\nthe National Natural Science Foundation of China National Key Research and Development Plan of China This study was supported by the National Natural Science Foundation of China (Grant No. 82073402) and National Key Research and Development Plan of China (2017YFC0909900).\n==== Body\nIntroduction\n\nTemozolomide is an imidazotetrazine derivative and a second-generation alkylating agent with antitumor effects. Orally administered temozolomide capsules are fully absorbed and well distributed in tissues; hence, the drug crosses the blood-brain barrier resulting in predictable adverse reactions.1 Temozolomide’s toxic profile and side effects are relatively mild and tolerable in patients receiving six or more cycles of treatment.2 Temozolomide has been associated with anemia, lymphopenia, neutropenia, and severe thrombocytopenia.2 In clinical practice, temozolomide has been extensively used to treat glioma, non-small cell lung cancer, leukemia, melanoma, lymphoma, and certain solid tumors. Among other chemotherapeutics, temozolomide provides the most potent antitumor effects in glioblastoma.3 In China, temozolomide has been on the market for nearly 20 years. Due to its sound curative effects in glioma patients, temozolomide has become the first-line treatment for malignant brain tumors.4,5\n\nTemozolomide’s efficacy and therapeutic regimen have been extensively studied in various tumors.6–11 However, there is a lack of large-cohort studies on the toxicity profile of temozolomide. In this study, we retrospectively analyzed clinical data in patients treated with temozolomide in our hospital during the past 12 years. The in-depth analysis of the temozolomide-related toxicities can guide the clinical use of temozolomide to prevent toxicities.\n\nMethods\n\nStudy Population\n\nThis study was approved by the Ethics Committee of Union Hospital of Tongji Medical College of Huazhong University of Science and Technology (reference number: 2019-S893). This retrospective study analyzed the toxicity profiles of cancer patients treated with temozolomide-containing regimens from January 1, 2008, to December 31, 2019, at the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology. The hospital is a 5000 - bed comprehensive university teaching hospital in Wuhan, a megacity in China. The exclusion criteria were 1) patients with poor treatment adherence (irregular use, discontinuation or change of medication), which might have affected the evaluation of temozolomide’s safety and efficacy, and 2) patients with incomplete data.\n\nStudy Design\n\nA “Temozolomide Safety Reassessment Research Card” was designed to collect demographic data, medication status, and toxicity occurrence. Additional information gathered included Karnofsky Performance Status Scale (KPS scale), body-mass index (BMI), drug manufacturer, radiotherapy, chemotherapy cycle, chemotherapy regimen, clinical diagnosis, and clinical tumor stage. Data were retrieved from the hospital electronic health records (EHR).\n\nChemotherapy regimens were divided into five categories: (1) concurrent chemoradiotherapy with adjuvant chemotherapy (usually six cycles of adjuvant chemotherapy with temozolomide alone); (2) mono-chemotherapy (only temozolomide); (3) combined chemotherapy with two drugs (temozolomide combined with capecitabine, cisplatin, irinotecan, apatinib, bevacizumab, recombinant human endostatin, gemcitabine, methotrexate, or rituximab); (4) complex chemotherapy regimen, including multidrug chemotherapy involving three or more drugs and concurrent chemoradiotherapy followed by combined chemotherapy; (5) adjuvant chemotherapy after radiotherapy. In this analysis, the chemotherapy cycle was regarded as the total cycle number with clear examination results during the patient’s hospitalization. Usually, temozolomide was used for five days in a cycle, and each cycle lasted for 28 days. However, in concurrent chemoradiotherapy, temozolomide was employed for 42 consecutive days, and this was regarded as one chemotherapy cycle due to the continuous use of temozolomide in concurrent chemoradiotherapy.\n\nThe severity of toxicities was assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.12 The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each adverse event. Grade 1- mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 - moderate: minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3 - severe or medically significant but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 - life-threatening consequences; urgent intervention indicated. Grade 5 - death related to an adverse event.\n\nStatistical Analysis\n\nData were recorded using Microsoft Excel®, and SPSS 25.0 was used for statistical analyses. Normally distributed data were expressed as means ± standard deviation (SD), whereas categorical data were expressed as percentages. The chi-square test was used to compare groups, and the influencing factors were analyzed by multivariate logistic regression analysis. Significant factors in univariate analysis were used in multivariate logistic regression analysis. P-values < 0.05 were considered statistically significant.\n\nResults\n\nCharacteristics of Patients and Analysis of Toxicities\n\nA total of 1057 patients were treated with temozolomide-containing regimens within the analysis period, and 922 met the inclusion and exclusion criteria. Among the 922 patients, 558 were males, and the average age was 45.25 years (ranged from 1 to 93 years). Toxicities were reported in 484 of the 922 patients, with an overall toxicity rate of 52.5% (Table 1).Table 1 Univariate Analysis of Factors Affecting the Overall Occurrence of Toxicities\n\nVariable\tWith Toxicities (n=484)\tWithout Toxicities (n=438)\tTotal (n=922)\tχ2 Value\tP-value\t\nN (Constituent Ratio)\tN (Constituent Ratio)\tN (Constituent Ratio)\t\nGender\t\t\t\t0.441\t0.507\t\n Male\t288 (59.5%)\t270 (61.6%)\t558 (60.5%)\t\t\t\n Female\t196 (40.5%)\t168 (38.4%)\t364 (39.5%)\t\t\t\nAge\t\t\t\t2.046\t0.563\t\n <18\t32 (6.6%)\t24 (5.5%)\t56 (6.1%)\t\t\t\n 18–39\t134 (27.7%)\t109 (24.9%)\t243 (26.4%)\t\t\t\n 40–59\t233 (48.1%)\t217 (49.5%)\t450 (48.8%)\t\t\t\n >59\t85 (17.6%)\t88 (20.1%)\t173 (18.8%)\t\t\t\nKPS score\t\t\t\t1.781\t0.776\t\n 100\t27 (5.6%)\t30 (6.8%)\t57 (6.2%)\t\t\t\n 90\t250 (51.7%)\t235 (53.7%)\t485 (52.6%)\t\t\t\n 80\t138 (28.5%)\t118 (26.9%)\t256 (27.7%)\t\t\t\n 70\t47 (9.7%)\t40 (9.1%)\t87 (9.4%)\t\t\t\n ≤60\t22 (4.5%)\t15 (3.4%)\t37 (4.0%)\t\t\t\nDrug manufacturer\t\t\t\t0.088\t0.766\t\n Domestic\t372 (76.9%)\t333 (76.0%)\t705 (76.5%)\t\t\t\n Import\t112 (23.1%)\t105 (24.0%)\t217 (23.5%)\t\t\t\nRadiotherapy\t\t\t\t9.117\t0.003*\t\n Yes\t323 (66.7%)\t250 (57.1%)\t573 (62.1%)\t\t\t\n No\t161 (33.3%)\t188 (42.9%)\t349 (37.9%)\t\t\t\nChemotherapy cycle\t\t\t\t39.599\t<0.001*\t\n 1\t210 (43.4%)\t268 (61.2%)\t478 (51.8%)\t\t\t\n 2\t81 (16.7%)\t69 (15.8%)\t150 (16.3%)\t\t\t\n 3\t48 (9.9%)\t31 (7.1%)\t79 (8.6%)\t\t\t\n 4\t39 (8.1%)\t24 (5.5%)\t63 (6.8%)\t\t\t\n 5\t27 (5.6%)\t11 (2.5%)\t38 (4.1%)\t\t\t\n 6\t35 (7.2%)\t22 (5.0%)\t57 (6.2%)\t\t\t\n 7\t21 (4.3%)\t6 (1.2%)\t27 (2.9%)\t\t\t\n 8 or more\t23 (4.8%)\t7 (1.6%)\t30 (3.3%)\t\t\t\nChemotherapy regimen\t\t\t\t32.858\t<0.001*\t\n Concurrent chemoradiotherapy with adjuvant chemotherapy\t284 (58.7%)\t226 (51.6%)\t510 (55.3%)\t\t\t\n Mono-chemotherapy\t73 (15.1%)\t118 (26.9%)\t191 (20.7%)\t\t\t\n Combined chemotherapy\t50 (10.3%)\t58 (13.2%)\t108 (11.7%)\t\t\t\n Complex chemotherapy regimen\t55 (11.4%)\t20 (4.6%)\t75 (8.1%)\t\t\t\n Only as adjuvant chemotherapy after radiotherapy\t22 (4.5%)\t16 (3.7%)\t38 (4.1%)\t\t\t\nClinical diagnosis\t\t\t\t8.652\t0.124\t\n Glioma\t304 (62.8%)\t256 (58.4%)\t560 (60.7%)\t\t\t\n Lung cancer\t39 (8.1%)\t38 (8.7%)\t77 (8.4%)\t\t\t\n Melanoma\t35 (7.2%)\t28 (6.4%)\t63 (6.8%)\t\t\t\n Lymphoma\t26 (5.4%)\t17 (3.9%)\t43 (4.7%)\t\t\t\n Neuroendocrine carcinoma\t13 (2.7%)\t25 (5.7%)\t38 (4.1%)\t\t\t\n Others\t67 (13.8%)\t74 (16.9%)\t141 (15.3%)\t\t\t\nClinical stage\t\t\t\t14.420\t<0.001*\t\n Stage 1–2\t123 (25.4%)\t162 (37.0%)\t285 (30.9%)\t\t\t\n Stage 3–4\t361 (74.6%)\t276 (63.0%)\t637 (69.1%)\t\t\t\nNote: *P<0.01 indicates statistically significant differences.\n\nAbbreviation: KPS, Karnofsky Performance Status.\n\nAs a retrospective study, we have observed differences in the dosage of temozolomide in different chemotherapy regimens. Concurrent chemoradiotherapy is 75mg/m2/d for 42 days (some patients do not use it for 42 days, and some patients only use temozolomide from Monday to Friday each week), and this was regarded as one chemotherapy cycle due to the continuous use of temozolomide in concurrent chemoradiotherapy. In the adjuvant treatment period or in combination with other chemotherapy regimens, the dosage of temozolomide is usually 150mg/m2/d or 200mg/m2/d for 5 days, and each cycle lasted for 28 days. Different temozolomide-containing regimens in our study were listed in Supplemental Table 1.\n\nA total of 787 toxic cases were recorded in patients treated with temozolomide-containing regimens. The most common cases involved the hematological system (34.9%, 275/787), followed by the gastrointestinal system (24.8%, 195/787) (Supplemental Table 2). When cases were analyzed based on chemotherapy regimens, the concurrent chemoradiotherapy with adjuvant chemotherapy accounted the most, 55.3% (435/787), followed by temozolomide mono-therapy (17%, 134/787) (Table 2).Table 2 Different Chemotherapy Regimens and the Associated Toxicities\n\nTemozolomide Regimen\tNumber of Patients (n=922)\tNumber of Patients with Toxicities (n=484)\tCase of Hematological System Toxicity (n=275)\tCase of Gastrointestinal System Toxicity (n=195)\tCase of Liver Function Toxicity (n=139)\tCase of Other Toxicity (n=178)\tTotal Toxicity Case (n=787)\t\nN (Constituent Ratio)\tN (Constituent Ratio)\tN (Constituent Ratio)\tN (Constituent Ratio)\tN (Constituent Ratio)\tN (Constituent Ratio)\tN (Constituent Ratio)\t\nConcurrent chemoradiotherapy with adjuvant chemotherapy\t510(55.3%)\t284(58.7%)\t174(63.3%)\t78(40.0%)\t98(70.5%)\t86(48.3%)\t435(55.3%)\t\nMono-chemotherapy\t191(20.7%)\t73(15.1%)\t28(10.2%)\t57(29.2%)\t8(5.8%)\t41(23.0%)\t134(17.0%)\t\nCombined chemotherapy\t108(11.7%)\t50(10.3%)\t25(9.1%)\t27(13.8%)\t13(9.4%)\t22(12.4%)\t87(11.1%)\t\nComplex chemotherapy regimen\t75(8.1%)\t55(11.4%)\t34(12.4%)\t22(11.3%)\t15(10.8%)\t17(9.6%)\t88(11.2%)\t\nAdjuvant chemotherapy after radiotherapy\t38(4.1%)\t22(4.5%)\t14(5.1%)\t11(5.6%)\t5(3.6%)\t12(6.7%)\t42(5.3%)\t\n\nAmong the 922 patients who were treated with temozolomide, 183 patients concurrently received other chemotherapeutic agents. The toxicity occurrence based on the concurrent drugs used in more than ten patients is listed in Table 3. The most common combination drug used was capecitabine (31.7%, 58/183), followed by cisplatin (23.5%, 43/183).Table 3 Occurrence of Toxicities in Combined Temozolomide Chemotherapy\n\nCombined Drug\tNumber of Patients\tNumber of Patients with Toxicities\tRate of Toxicity Occurrence (%)\t\nCapecitabine\t58\t15\t25.9\t\nCisplatin\t43\t30\t69.8\t\nBevacizumab\t28\t11\t39.3\t\nIrinotecan\t22\t17\t77.2\t\nRituximab\t20\t15\t75.0\t\nMethotrexate\t17\t12\t70.6\t\nRecombinant Human Endostatin\t17\t12\t70.6\t\nPemetrexed\t10\t8\t80.0\t\n\nAmong the 922 patients analyzed, 285 (30.9%) were classified as clinical stages 1–2, and 637 (69.1%) as stages 3–4. The occurrence of toxicities in patients with different clinical diagnoses and at different stages is listed in Table 4. In patients at clinical stages of 1 and 2, patients with glioma (n = 192) experienced the highest rate of toxicities (47.9%, 92/192), followed by patients with lymphoma (46.7%, 7/15). This pattern was also observed in patients at clinical stages 3 and 4, patients with glioma (n = 368) had the highest rate of toxicities (77.7%, 286/368), followed by patients with lymphoma (67.9%, 19/28). The rates of toxicity occurrence were higher in stages 3–4 than stages 1–2 regardless of cancer types. Due to the large gap in the number of toxicity occurrence of different severities, no statistically significant factors affecting toxicity severity are identified.Table 4 Occurrence of Toxicities at Different Clinical Tumor Stages\n\nClinical Diagnosis\tClinical Stage 1–2\tClinical Stage 3–4\t\nWith Toxicity\tWithout Toxicity\tRate of Toxicity (%)\tWith Toxicity\tWithout Toxicity\tRate of Toxicity (%)\t\nGlioma\t92\t100\t47.9\t286\t82\t77.7\t\nLung cancer\t1\t2\t33.3\t38\t36\t51.3\t\nMelanoma\t4\t9\t30.8\t31\t19\t62.0\t\nLymphoma\t7\t8\t46.7\t19\t9\t67.9\t\nNeuroendocrine carcinoma\t1\t2\t33.3\t12\t23\t34.3\t\nOther\t18\t41\t30.5\t49\t33\t59.8\t\n\nThe case toxicity severities were assessed using the CTCAE rating scale. A total of 726 cases (92.2%) were rated at grades 1–2, and 61 (7.8%) were rated grade 3 or above. Within the grades 1–2 categories, the hematological system accounted for 249 cases (34.3%, 249/726), followed by the gastrointestinal system (25.9%, 188/726). Within the grades 3 or above category, the hematological system accounted for the most, 26 cases (42.6%, 26/61), followed by the other type (37.7%, 23/61) (Table 5).Table 5 Severity of Toxicity\n\nTypes of Toxicity\tGrade 1–2 (n=726)\tGrade 3 and Above (n=61)\tTotal (n=787)\t\nN (Constituent Ratio)\tN (Constituent Ratio)\tN (Constituent Ratio)\t\nHematological system\t249(34.3%)\t26(42.6%)\t275(34.9%)\t\nGastrointestinal system\t188(25.9%)\t7(11.5%)\t195(24.8%)\t\nLiver function\t134(18.5%)\t5(8.2%)\t139(17.7%)\t\nOther\t155(21.3%)\t23(37.7%)\t178(22.6%)\t\n\nFactors Affecting the Toxicity Occurrence of Temozolomide-Containing Regimens\n\nUnivariate analysis indicates that radiotherapy, chemotherapy cycle, chemotherapy regimen, and clinical stage were significant factors affecting the toxicity occurrence (P < 0.05) (Table 1). Among the 922 patients, 616 had BMI recorded in EHR. Univariate analysis revealed that BMI was not associated with the overall toxicity occurrence (P = 0.082) (Supplemental Table 3).\n\nThe variables that showed statistical significance in univariate analysis were used as independent variables in logistic multivariate regression analysis. The overall toxicity and toxicities in the hematological system, gastrointestinal system, and liver were used as dependent variables. A chemotherapy regimen, chemotherapy cycle, and clinical stage were identified as factors significantly affecting the overall occurrence of toxicity (P<0.05) (Table 6).Table 6 Multivariate Analysis of Factors Affecting the Overall Occurrence of Toxicities\n\nVariable\tB\tStandard Error\tWald\tSignificance\tOR (95% CI)\t\nGender\t\t\t\t\t\t\n Female\t0.137\t0.144\t0.901\t0.343\t1.147 (0.864–1.521)\t\n Male\t\t\t\t\tRef (1.00)\t\nAge\t\t\t\t\t\t\n <18\t0.279\t0.338\t0.683\t0.409\t1.322 (0.682–2.563)\t\n 18–39\t0.275\t0.222\t1.544\t0.214\t1.317 (0.853–2.033)\t\n 40–59\t0.062\t0.191\t0.107\t0.744\t1.064 (0.732–1.549)\t\n >59\t\t\t\t\tRef (1.00)\t\nClinical diagnosis\t\t\t\t\t\t\n Lung cancer\t1.000\t0.459\t4.740\t0.029\t2.718 (1.105–6.688)\t\n Melanoma\t1.135\t0.469\t5.867\t0.015\t3.112 (1.242–7.800)\t\n Glioma\t0.799\t0.427\t3.508\t0.061\t2.224 (0.964–5.135)\t\n Lymphoma\t0.894\t0.529\t2.859\t0.091\t2.444 (0.867–6.886)\t\n Others\t0.789\t0.440\t3.216\t0.073\t2.201 (0.929–5.211)\t\n Neuroendocrine carcinoma\t\t\t\t\tRef (1.00)\t\nChemotherapy regimen\t\t\t\t\t\t\n Complex chemotherapy regimen\t1.400\t0.398\t12.388\t<0.001\t4.057 (1.860–8.849)\t\n Only as adjuvant chemotherapy after radiotherapy\t1.080\t0.677\t2.5441\t0.111\t2.944 (0.781–11.094)\t\n Combined chemotherapy\t0.423\t0.279\t2.301\t0.129\t1.526 (0.884–2.635)\t\n Concurrent chemoradiotherapy with adjuvant chemotherapy\t1.214\t0.596\t4.153\t0.042\t3.366 (1.047–10.818)\t\n Mono-chemotherapy\t\t\t\t\tRef (1.00)\t\nChemotherapy cycle\t\t\t\t\t\t\n 2\t0.407\t0.199\t4.160\t0.041\t1.502 (1.016–2.221)\t\n 3\t0.702\t0.259\t7.350\t0.007\t2.019 (1.215–3.354)\t\n 4\t0.605\t0.296\t4.177\t0.041\t1.831 (1.025–3.271)\t\n 5\t1.128\t0.387\t8.508\t0.004\t3.091 (1.448–6.597)\t\n 6\t0.582\t0.309\t3.557\t0.059\t1.790 (0.977–3.278)\t\n 7\t1.215\t0.483\t6.328\t0.012\t3.370 (1.308–8.685)\t\n 8 or more\t1.396\t0.465\t8.992\t0.002\t4.038 (1.622–10.055)\t\n 1\t\t\t\t\tRef (1.00)\t\nRadiotherapy\t\t\t\t\t\t\n Yes\t0.376\t0.568\t0.438\t0.508\t1.456 (0.478–4.432)\t\n No\t\t\t\t\tRef (1.00)\t\nClinical stage\t\t\t\t\t\t\n Stage 1–2\t−0.586\t0.157\t13.844\t<0.001\t0.557 (0.409–0.758)\t\n Stage 3–4\t\t\t\t\tRef (1.00)\t\nAbbreviations: OR, odds-ratio; CI, confidence-interval.\n\nA chemotherapy regimen, chemotherapy cycle, and clinical stage were identified as factors significantly affecting the occurrence of toxicities in the hematological system (P<0.05) (Supplemental Table 4). Gender, age, clinical diagnosis, and clinical stage were factors significantly associated with toxicity in the gastrointestinal system (P<0.05) (Supplemental Table 5). Clinical diagnosis, chemotherapy regimen, and age were factors significantly affecting the occurrence of toxicity in the liver (P<0.05) (Supplemental Table 6).\n\nAmong the 922 cases, 21 cases were observed to be active discontinuation of the drug, except for 3 cases due to economic reasons and 1 case due to switching chemotherapy regimens, the other 17 cases were reported in Supplemental Table 7. It can be observed that of the 17 cases of discontinuation, 16 cases of discontinuation occurred in the first cycle, and only 1 case occurred in the third cycle. 13 cases of drug discontinuation occurred during concurrent radiotherapy and chemotherapy. 7 cases continued to complete the treatment of temozolomide after the toxicity was reduced or disappeared. 5 cases of drug discontinuation indicated related hematological system toxicity, 5 cases of drug discontinuation indicated related gastrointestinal system toxicity, 4 cases of drug discontinuation accompanied with liver injury. Multiple toxicity were also observed in 7 cases occurred in the first chemotherapy cycle. Cases of multiple toxicity were analyzed based on chemotherapy regimens, the concurrent chemoradiotherapy with adjuvant chemotherapy accounted the most, 57.1% (4/7), followed by combined chemotherapy (28.6%, 2/7) and temozolomide mono-therapy (14.3%, 1/7).(Supplemental Table 7).\n\nDiscussion\n\nThis retrospective analysis reveals that in patients receiving temozolomide-containing regimens, the toxicity occurrence rate is high, around 50%. A chemotherapy regimen, chemotherapy cycle, and clinical stage are significant factors affecting the overall toxicity occurrence. Factors affecting the toxicity occurrence varies among organ systems.\n\nEvaluation of Toxicity Occurred in the Combination Therapy\n\nWhen combined with the orally-administered chemotherapeutic agent capecitabine, the toxicity rate in temozolomide-treated patients is 25.9% (15/58), lower than that of patients receiving temozolomide mono-chemotherapy (38.2%, 73/191). However, why the combination of temozolomide with capecitabine has a favorable safety profile remains unclear. The combination of temozolomide with injectable chemotherapeutics increases the toxicity rate occurrence except for the combination with bevacizumab, which exhibits a comparable rate to temozolomide mono-chemotherapy.\n\nEvaluation of Factors Associated with Temozolomide-Containing Therapies\n\nA chemotherapy regimen and chemotherapy cycle are significant factors affecting the overall toxicity occurrence. The risk of toxicity in complex chemotherapy regimens and concurrent chemoradiotherapy with adjuvant chemotherapy is 4.06 and 3.37 times higher than that of temozolomide mono-chemotherapy. Hematological toxicity incidence was 275/922 (29.8%) and only 26/922 (2.8%) for grade 3 or higher. Gastrointestinal system toxicity incidence was 195/922 (21.3%), and only 7/922 of grade 3 or higher. Abnormal liver function incidence was 139 of 922 (15.1%), and the incidence of grade 3 or higher toxicity was only 5 of 922 (0.5%). Results of retrospective analysis revealed that the chemotherapy regimen containing temozolomide was found to be safe with a low overall incidence of grade 3 or 4 toxicity.\n\nThe toxicity of different chemotherapy regimens containing temozolomide was also investigated in other studies. Brada reported that incidences of grade 3–4 hematological and grade 3–4 non-hematological toxicity in the temozolomide monotherapy for glioblastoma were the same as 25%.13 Chua reported a higher incidences of grade 3–4 hematological toxicity (36.4%) and grade 3–4 non-hematological toxicity (40.9%) in chemotherapy regimens containing temozolomide.14 However, a low incidence of toxicity in the temozolomide monotherapy for glioblastoma was also reported that the incidence of grade 3–4 hematological toxicity was 2.4% and no grade 3–4 non-hematological toxicity was observed.15 It should be noted that the toxicity evaluations were based on the specific chemotherapy regimens.\n\nNotably, patients receiving more treatment cycles exhibit a significantly higher rate of toxicity occurrence. In patients receiving temozolomide for eight cycles or above, the risk is 4.04 times higher than patients receiving one treatment cycle (P < 0.05). The risk of toxicity in patients at clinical stages 1–2 is only 0.56 times higher than that of patients at stages 3–4 (P < 0.001). Interestingly, the factors affecting the toxicity occurrence varies among different organ systems.\n\nA chemotherapy regimen, chemotherapy cycle, and clinical stage are significant factors affecting the hematological system’s toxicity. In patients undergoing concurrent chemoradiotherapy with adjuvant chemotherapy, adjuvant chemotherapy after radiotherapy, and complex chemotherapy, the risk of toxicity is 6.42, 5.31, and 4.79 times higher, respectively, than patients receiving mono-chemotherapy (P < 0.05). A study on the risks of toxicity in patients receiving temozolomide-containing regimens for glioma treatment also indicates a higher risk of concurrent chemoradiotherapy with adjuvant chemotherapy than mono-chemotherapy.16 The number of chemotherapy cycles is also associated with the risk of toxicity. Importantly, patients receiving temozolomide for eight cycles or above exhibit a six times higher toxicity rate than patients receiving one cycle (P < 0.05). Gender is not a significant factor associated with the risk of hematological toxicity occurrence in our analysis. This is different from a retrospective analysis of 680 patients with malignant glioma, which reveals that temozolomide’s hematological toxicity is higher in women than in men.14 This discrepancy could be attributed to the fact that we included all cancer patients treated with temozolomide, not just glioma patients. The risk of hematological toxicities in patients at clinical stages 1–2 is only 0.64 times higher than that in patients at stages 3–4 (P < 0.05).\n\nClinical diagnosis, clinical stage, gender, and age are significant factors affecting the gastrointestinal system’s toxicity occurrence. In lung cancer patients, the risk of the gastrointestinal system toxicity is 6.2 times higher than that in patients with neuroendocrine tumors (P < 0.01). The risk of gastrointestinal toxicity in patients at clinical stages 1–2 is only 0.59 times higher than that in patients at stages 3–4 (P < 0.05). Our analysis is consistent with another study, which indicates that the risk of gastrointestinal toxicity is 1.88 times higher in women than in men (P < 0.01).17\n\nClinical diagnosis, chemotherapy regimen, and age are significant factors contributing to treatment-related liver dysfunction. The risk of abnormal liver function in lymphoma patients is 6.01 times higher than that in patients with neuroendocrine tumors (P < 0.05). The risk of liver toxicity in patients undergoing concurrent chemoradiotherapy with adjuvant chemotherapy, complex chemotherapy, and combined chemotherapy is 6.75, 4.33, and 3.37 times higher, respectively, compared with the risk in patients receiving temozolomide mono-chemotherapy (P < 0.05). The risk of liver dysfunction in patients under 18 is only 0.09 times higher than that in patients aged over 59 (P < 0.05). Notably, out of 56 patients aged under 18, only one patient (1.79%) exhibited liver toxicity instead of the 15.1% overall incidence of treatment-related liver dysfunction.\n\nOur study analyzed patients who received temozolomide-containing regimens over 12 years using data from real-world clinical practice. The findings may help clinicians better design temozolomide-containing chemotherapies and monitor at-risk patients to develop treatment-related toxicities. The study has the following limitations 1) the analysis is a single-center study, and 2) the study is retrospective in nature. We did not assess the clinical outcome of the patients.\n\nConclusion\n\nIn patients treated with temozolomide-containing regimens, toxicities present commonly in the hematological and gastrointestinal systems and the liver. Clinicians should pay particular attention to the significant factors associated with the toxicity occurrence, such as the chemotherapy regimen, chemotherapy cycle, and the patient’s clinical stage.\n\nEthics Approval and Consent to Participate\n\nThis study was approved by the Ethics Committee of Union Hospital of Tongji Medical College of Huazhong University of Science and Technology (reference number: 2019-S893). The requirement for informed consent was waived by the ethics committee due to the retrospective nature of the study. The patient data that was collected will be treated with confidentiality and in compliance with Declaration of Helsinki.\n\nDisclosure\n\nAll authors declare that they have no conflicts of interest.\n==== Refs\nReferences\n\n1. Friedman HS, Kerby T, Calvert H. Temozolomide and treatment of malignant glioma. Clin Cancer Res. 2000;6 (7 ):2585–2597.10914698\n2. Grieco A, Tafuri MA, Biolato M, et al. Severe cholestatic hepatitis due to temozolomide: anadverse drug effect to keep in mind. Case report and review of literature. Medicine(Baltimore). 2015;94 (12 ):e476. doi:10.1097/MD.0000000000000476 25816026\n3. He J, Ch H. Research progress on resistance mechanism of temozolomide in treatment of glioblastoma(in Chinese). Chin J Mod Appl Pharm. 2019;36 (23 ):3001–3007. doi:10.13748/j.cnki.issn1007-7693.2019.23.024\n4. Niu XD, Ma DW, Tian HL, et al. Efficacy of temozolomide versus traditional Chemotherap- -eutic drugs in the treatment of glioma: a systematic review(in Chinese). J Int Neuro Neurosurg. 2014;41 (1 ):1–6.\n5. Bai Y, Chen Y, Hong X, et al. Newcastle disease virus enhances the growth-inhibiting and proapoptotic effects of temozolomide on glioblastoma cells in vitro and in vivo. Sci Rep. 2018;8 (1 ):11470. doi:10.1038/s41598-018-29929-y 30065314\n6. Roger S, Monika EH, Warren PM, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised Phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10 (5 ):459–466. doi:10.1016/S1470-2045(09)70025-7 19269895\n7. Sastre-Gallego S, Fernández-Lizarbe E, Martín-Sánchez M, et al. EP-1204: limited margin radiotherapy and temozolomide for glioblastoma multiforme: pattern of failure. Radiother Oncol. 2018;127 :S671. doi:10.1016/S0167-8140(18)31514-7\n8. Silke BN, Gabi S, Hendrik B, et al. Temozolomide during radiotherapy of glioblastoma Multiforme:Dailyadministration improves survival. Strahlenther Onkol. 2017;193 (11 ):890–896. doi:10.1007/s00066-017-1110-4 28197654\n9. Wee CW, Kim E, Kim TM, et al. Impact of interim progression during the surgery-to-radiotherapy interval and its predictors in glioblastoma treated with temozolomide-based radiochemotherapy. J Neurooncol. 2017;134 (1 ):169–175. doi:10.1007/s11060-017-2505-x 28547592\n10. Brachman DG, Wang M, Ashby LS, et al. Phase II Trial of Temozolomide (TMZ), Motexafin Gadolinium (MGd), and 60 Gy Fractionated Radiation (RT) for Newly Diagnosed Supratentorial Glioblastoma (GBM): results of RTOG 0513. Int J Radiat Oncol Bio Phys. 2011;81 (2 ):S129–S130. doi:10.1016/j.ijrobp.2011.06.267\n11. Brada M, Stenning S, Gabe R, et al. Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol. 2010;28 (30 ):4601–4608. doi:10.1200/JCO.2009.27.1932 20855843\n12. CTCAE v4.0, Common terminology criteria for adverse events [EB/OL]; 2011. Available from: http://www.calgb.org/Public/meetings/presentations/2009/summer_group/cra_cont_ed/06a_CTCAE-Setser_062009.pdf. Accessed 58, 2021.\n13. Brada M, Hoang-Xuan K, Rampling R, et al. Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol. 2001;12 (2 ):259–266. doi:10.1023/a:1008382516636 11300335\n14. Chua SL, Rosenthal MA, Wong SS, et al. Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme. Neuro Oncol. 2004;6 (1 ):38–43. doi:10.1215/S1152851703000188 14769139\n15. Brandes AA, Ermani M, Basso U, et al. Temozolomide in patients with glioblastoma at second relapse after fifirst line nitrosourea-procarbazine failure: a phase II study. Oncol. 2002;63 (1 ):38–41. doi:10.1159/000065718\n16. Zhou B, Mao Q, Wang P, et al. The Adverse Effects Analysis of Temozolomide in Glioma Chemotherapy(in Chinese). Chin J Neurooncol. 2012;10 (1 ):14–18.\n17. Armstrong TS, Cao Y, Scheurer ME, et al. Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro Oncol. 2009;11 (6 ):825–832. doi:10.1215/15228517-2008-120 19179423\n\n",
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"journal": "Drug design, development and therapy",
"keywords": "gastrointestinal system; hematological system; liver toxicity; temozolomide; toxicity",
"medline_ta": "Drug Des Devel Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006761:Hospitals; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D012189:Retrospective Studies; D000077204:Temozolomide; D055815:Young Adult",
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"title": "Toxicities and Associated Factors in Patients Receiving Temozolomide-Containing Regimens: A 12-Year Analysis of Hospital Data.",
"title_normalized": "toxicities and associated factors in patients receiving temozolomide containing regimens a 12 year analysis of hospital data"
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"abstract": "To improve the outcome of allogeneic stem cell transplantation in refractory acute myeloid leukemia (AML), we conducted a single-arm phase II clinical trial to evaluate the efficacy and feasibility of conditioning regimen following cytoreduction chemotherapy with 7-day interval. Adult patients with refractory AML were enrolled in the study and received fludarabine, cytarabine, and idarubicin (FLAG-IDA) as cytoreductive chemotherapy followed by busulfan and fludarabine (Flu-BU) conditioning regimen and transfusion of mobilized peripheral stem cells from human leukocyte antigen-matched sibling or unrelated donor. The primary endpoint of the study was 2-year leukemia-free survival (LFS) and secondary endpoints included complete-remission rate, 2-year overall survival (OS), nonrelapse mortality (NRM), and relapse rate. A total of 16 patients were enrolled with median age of 36 (16-60), which included 9 primary induction failure, 2 early relapse, and 5 with relapse/refractory disease. The median cycles of previous chemotherapy were 4 (3-10) with a median of 55% (1%-90%) blasts in bone marrow. Six patients received transplantation from matched sibling and 10 from matched unrelated donors. After transplantation, 15 patients achieved bone marrow remission (11 complete remissions [CRs] and 4 bone marrow remissions without platelet recovery) at day +28. A total of 8 patients remained alive in CR with median LFS of 29.5 months (9.5-40.5 months). Four patients relapsed and 3 of them died of disease and another 4 patients died because of transplantation-related toxicity. The 2-year NRM and relapse rates were 25.0% ± 10.8% and 33.4% ± 13.8%, respectively with 2-year OS at 53.5% ± 13.1% and LFS at 50.0% ± 12.5%. Based on the Simon 2-stage design, 5 out of first eligible 14 patients remained leukemia-free for more than 2 years after allogeneic hematopoietic stem cell transplantation; thus, the null hypothesis of the study will be rejected and the study protocol is accepted as being warranted for further study. Based on the above data, our phase II study demonstrated that the sequential FLAG-IDA cytoreduction chemotherapy followed by Flu-BU conditioning regimen given at the hematological nadir was feasible and has sufficient activity to warrant further investigation prospectively with a larger patient sample (clinicaltrials.gov identifier: NCT01496547).",
"affiliations": "From the Department of Hematology (WT, XF, LW, JH); and Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (LW, JH).",
"authors": "Tang|Wei|W|;Fan|Xing|X|;Wang|Ling|L|;Hu|Jiong|J|",
"chemical_list": "D003561:Cytarabine; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D015255:Idarubicin",
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"doi": "10.1097/MD.0000000000000706",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2588184710.1097/MD.0000000000000706007064800ArticleClinical Trial/Experimental StudyBusulfan and Fludarabine Conditioning Regimen Given at Hematological Nadir of Cytoreduction Fludarabine, Cytarabine, and Idarubicin Chemotherapy in Patients With Refractory Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation A Single Arm Pilot Consort StudyTang Wei MDFan Xing MDWang Ling MDHu Jiong MDAlkhiary. Wael From the Department of Hematology (WT, XF, LW, JH); and Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (LW, JH).Correspondence: Jiong Hu, Department of Hematology, Blood & Marrow Transplantation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 18F/OPD Bldg 197 Rui Jin Road II, Shanghai 200025, China (e-mail: hujiong@medmail.com.cn).4 2015 17 4 2015 94 15 e7068 12 2014 2 2 2015 6 3 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nTo improve the outcome of allogeneic stem cell transplantation in refractory acute myeloid leukemia (AML), we conducted a single-arm phase II clinical trial to evaluate the efficacy and feasibility of conditioning regimen following cytoreduction chemotherapy with 7-day interval.\n\nAdult patients with refractory AML were enrolled in the study and received fludarabine, cytarabine, and idarubicin (FLAG-IDA) as cytoreductive chemotherapy followed by busulfan and fludarabine (Flu-BU) conditioning regimen and transfusion of mobilized peripheral stem cells from human leukocyte antigen-matched sibling or unrelated donor. The primary endpoint of the study was 2-year leukemia-free survival (LFS) and secondary endpoints included complete-remission rate, 2-year overall survival (OS), nonrelapse mortality (NRM), and relapse rate.\n\nA total of 16 patients were enrolled with median age of 36 (16–60), which included 9 primary induction failure, 2 early relapse, and 5 with relapse/refractory disease. The median cycles of previous chemotherapy were 4 (3–10) with a median of 55% (1%–90%) blasts in bone marrow. Six patients received transplantation from matched sibling and 10 from matched unrelated donors. After transplantation, 15 patients achieved bone marrow remission (11 complete remissions [CRs] and 4 bone marrow remissions without platelet recovery) at day +28. A total of 8 patients remained alive in CR with median LFS of 29.5 months (9.5–40.5 months). Four patients relapsed and 3 of them died of disease and another 4 patients died because of transplantation-related toxicity. The 2-year NRM and relapse rates were 25.0% ± 10.8% and 33.4% ± 13.8%, respectively with 2-year OS at 53.5% ± 13.1% and LFS at 50.0% ± 12.5%. Based on the Simon 2-stage design, 5 out of first eligible 14 patients remained leukemia-free for more than 2 years after allogeneic hematopoietic stem cell transplantation; thus, the null hypothesis of the study will be rejected and the study protocol is accepted as being warranted for further study.\n\nBased on the above data, our phase II study demonstrated that the sequential FLAG-IDA cytoreduction chemotherapy followed by Flu-BU conditioning regimen given at the hematological nadir was feasible and has sufficient activity to warrant further investigation prospectively with a larger patient sample (clinicaltrials.gov identifier: NCT01496547).\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nRefractory acute myeloid leukemia (AML) remains as the most difficult clinical scenario. Though different therapeutic regimens were tested in clinical trials, the overall outcome remained poor.1–3 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for refractory AML.4,5 However, allogeneic transplantation with active leukemia failed to improve significantly the long-term outcome. Standard myeloablative conditioning regimen in these patients was associated with significant regimen-related mortality, whereas reduced intensity conditioning had less treatment-related complications, but was associated with extremely high relapse rates.6–8 The Center for International Blood and Marrow Transplant Research (CIMBTR) reported 3-year overall survival (OS) rates of 19% for AML patients with relapse disease or primary induction failure receiving myeloablative regimen.9 To further improve the outcome of allo-HSCT in such high-risk and refractory patients, sequential schedule of cytoreduction therapy followed by nonmyeloablative conditioning has been developed.10–14 Schmid et al had introduced a sequential conditioning regimen consisting of chemotherapy FLASMA followed by reduced-intensity conditioning (RIC) and prophylactic donor lymphocytes infusion (DLI) for patients with refractory AML. In their primary report, the 2-year OS and leukemia-free survival (LFS) were 40% and 37%, respectively and patients with only 2 cycles of previous chemotherapy might particularly benefit from the procedure.10 In another study using 5-day clofarabine as cytoreduction followed by initiation of conditioning during the nadir 14 days later for relapsed/refractory AML, 1-year progression-free survival (PFS), and OS were 25% and 38% respectively. Bone marrow biopsy 12 days after clofarabine treatment with effective cytoreduction was correlated with improved PFS.11\n\nTo further improve the outcome of patients with refractory leukemia, we developed a transplantation strategy consisting of sequential cytoreductive chemotherapy with fludarabine, cytarabine, and idarubicin (FLAG-IDA) followed by a reduced toxicity conditioning with busulfan and fludarabine (Flu-Bu) at the hematological nadir of chemotherapy-induced aplasia in refractory AML. The rationale is based on the significant anti-leukemia efficacy of FLAG-IDA regimen, which has been demonstrated in relapse or refractory AML, whereas the Flu-Bu regimen have been reported to be effective and less toxic as standard conditioning regimen in AML and myelodysplasia syndrome (MDS).15,16 In this study, we tested the hypothesis that maximizes the leukemia burden reduction by adding intensive chemotherapy regimen FLAG-IDA followed by the Flu-Bu conditioning given at the aplasia phase after cytoreduction chemotherapy may translate into better disease control after allo-HSCT.\n\nMETHODS\nStudy Design\nBetween June 15, 2011 and Jan 15, 2014, a total of 16 patients with refractory AML received allogeneic stem cell transplantation from HLA-matched donors in Blood & Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital. All these patients were enrolled in a prospective, single-arm phase II clinical trial to study the efficacy and feasibility of new transplantation protocol consisting of intensive cytoreductive chemotherapy followed by sequential conditioning regimen given with a 7-day interval. The study was performed in accordance with the Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice. The protocol was approved by the Ethics Committee of Rui Jin Hospital and was registered at www.clinicaltrials.gov (clinicaltrials.gov identifier: NCT01496547).\n\nEligibility Criteria\nPatients were included if they fulfilled the following criteria defining refractory AML10,17: primary induction failure (PIF) after 2 cycles of chemotherapy, first early relapse after a remission duration of <6 months, relapse disease refractory to salvage chemotherapy containing high-dose Ara-C. Further inclusion criteria were age between 16 and 60 years with available donor (HLA-matched family or unrelated stem cell donor with 8/8 or 10/10 HLA matching) and written informed consent. The exclusion criteria were creatinine clearance <50 mL/min, bilirubin or transaminases >3 times the upper limit of normal, cardiac shortening fraction <30% and pregnancy.\n\nTreatment Protocol\nBefore the treatment, bone marrow aspiration was performed to determine the disease status in all patients before a cytoreductive chemotherapy consisting of fludarabine (30 mg/m2), AraC (2 g/m2), and G-CSF 5 μg/kg from day −20 ∼ −16 and idarubicin 12 mg/m2 from day −16 ∼ day −14 (FLAG-IDA). A bone marrow aspiration was performed then on day −7 to access the marrow cellularity and residual blasts. A reduced toxicity conditioning regimen was consisted of fludarabine (30 mg/m2) from day −6 ∼ day −2 and busulfan 3.2 mg/kg from day −5 ∼ day −3 (Flu-Bu). G-CSF-mobilized peripheral stem cells were infused on day 0 in all patients (Figure 1). The graft-versus-host disease (GVHD) prophylaxis regimen included cyclosporine (CsA) 3 mg/kg from day −1 to day+60 with short methotraxate (MTX; 15 mg/m2 on day +1 and 10 mg/m2 day +3 and +6) and mycophenolate mofetil (MMF; 1000 mg/day) from day 0 to day +30 for all patients. Rabbit antithymocyte globulin (ATG, Thymoglobulin®, Sanofi/France) was given with a total dose of 6 mg/kg for unrelated donor from day −4 ∼ −1. The tapering of CsA started at Day +61 if no acute (GVHD) was documented. The prophylactic DLI was not eligible in the study. DLI was allowed only in case of documented loss of donor chimerism by polymerase chain reaction analysis of short-tandem repeat markers, increased minimal residual disease via flowcytometry or hematological relapse during follow-up.\n\nFIGURE 1 This figure illustrates the treatment scheme of the study protocol.\n\nToxicity Assessment\nThe electronic medical record was reviewed to grade toxicities according to NCI CTC Toxicity scale Version 2.0. aGVHD and chronic GVHD (cGVHD) were diagnosed and graded accordingly.18,19\n\nSample Size and Statistical Consideration\nThe primary endpoint of the study was 2-year LFS, whereas LFS was defined as being alive without relapse of leukemia. A 2-year LFS of 15% with the study protocol will be of no interest clinically because it is not superior to the conventional or standard transplantation protocol according to our own historical control data and available literature, whereas a 2-year LFS reaching 45% will be of interest for further study.9–11 All patients enrolled in the study must be followed-up to the occurrence of event (relapse of leukemia or death from any cause) or at least 2 years after allo-HSCT without any event defined above.\n\nThe sample size of 14 patients was determined based on Simon 2-stage minimax design with type one error rate α at 0.05 and power at 0.8.20 If no patient among the first 5 enrolled in the study maintained leukemia-free at 2 years after allo-HSCT, the trial will be stopped early for futility. At the end, if only ≤4 patients out of 14 enrolled patients in the study maintained leukemia-free at the landmark of 2 years after allo-HSCT, no further investigation of the study protocol is warranted. Otherwise, the FLAG-IDA/Flu-Bu protocol will be considered as being warranted for larger-scale clinical trial.\n\nThe secondary endpoints of study included complete remission rate (CR) on day 28 after allo-HSCT, 2-year nonrelapse mortality (NRM), 2-year relapse rate, and 2-year OS (the time from enrollment to death from any cause). The distribution of time-to-event endpoints such as LFS and OS was estimated using the Kaplan–Meier method. Probability of NRM and relapse rate was calculated using reciprocal cumulative incidence estimates. Additionally, we compared the overall outcome of the study with our historical control series in terms of OS, LFS, NRM, and relapse rate. Log-rank test was used for the analysis with P values reported as 2-sided and <0.05 as statistical significance.21 SPSS (SPSS Inc, Chicago, IL) software packages were used for data analysis.\n\nRESULTS\nPatients’ Characteristics\nBetween June 15, 2011 and Jan 15, 2014, a total of consecutive 20 patients with refractory AML were referred to Blood & Marrow Transplantation Center and received allo-HSCT as salvage therapy. Among them, 4 patients without HLA-matched donor sibling (MSD) and unrelated donor (MUD, not available in 3 and refusal from donor in 1) received allo-HSCT from related haploidentical donors were excluded from the analysis. The remaining 16 patients with MSD (n = 6) or MUD (n = 10) were enrolled in the study. For those patients enrolled for MSD transplantation, no salvage chemotherapy was given, whereas for those patients for MUD transplantation, salvage chemotherapy was allowed during the work-up phase to MUD transplantation based on the decision of their primary hematologists.\n\nInitially, 14 patients enrolled received cytoreductive chemotherapy and conditioning regimen on schedule except for 2 patients (UPN4 and 8) who experienced severe neutropenic fever with sepsis after FLAG-IDA chemotherapy, which lead to a 3-day delay of Flu-Bu conditioning delivery after successful antibiotics treatment and the day-7 bone marrow evaluation was not performed. Thus, 2 more patients were enrolled who received the FLAG-IDA chemotherapy, day-7 bone marrow assessment, and Flu-Bu conditioning on schedule. All these 16 patients completed the cytoreduction chemotherapy, conditioning regimen, and mobilized peripheral stem cells infusion sequentially. The data of first 14 patients enrolled were eligible for determination of either rejection or acceptance of the study null hypothesis in the statistical consideration, whereas data of all 16 patients were included for the analysis of overall transplantation outcome, toxicity, and comparison study to the historical control.\n\nThe patients’ characteristics of all 16 patients are summarized in Table 1. The median age of patients was 36 (16–60). Among 16 patients enrolled, 9 had PIF, 2 early relapse and 5 had relapse/refractory disease. All these patients received at least 3 cycles of chemotherapy (median 4, range 3–10). Fifteen patients had active disease and only 1 patient (UPN 8) who failed to obtained CR after first 2 cycles of induction chemotherapy (idarabicin + cytarabine) with a 9/10 matched MUD donor identified was enrolled in the study. During the work-up period for MUD transplantation with delay for almost 2 months, the very patient obtained CR with 2 additional cycles of salvage chemotherapy (Fludarabine + cytarabine + G-CSF, FLAG). Since the patient insisted to undergo the study protocol, the allo-HSCT was performed accordingly. Overall, the median percentage of blasts in bone marrow before the FLAG-IDA chemotherapy was 55% (1%–90%). The graft contained a median of 7.15 × 108/kg mononuclear cells (MNC, range 3.8–12.7) and 6.45 × 106 CD34+/kg (range 2.26–22.0).\n\nTABLE 1 Patients’ Characteristics\n\nTransplantation Outcome\nAs to the cytoreduction, the bone marrow analysis on day -7 was evaluable in a total of 14 patients (except for UPN 4 and 8) and all demonstrated an extremely hypocellularity without any blasts (n = 12) or only few blasts (<5 in per bone marrow smear, n = 2).\n\nAs to the engraftment, 1 patient (UPN 4) died before engraftment, whereas the remaining 15 patients achieved neutrophil engraftment (>0.5 × 109 cells/L) with median of 15 days (range 9–24). The engraftment of platelet (>20 × 109 cells /L) occurred in 12 patients with a median of 19.5 days (range 10–30), whereas remaining 3 patients had poor platelet recovery dependent on platelet transfusions for at least 3 months after transplantation (Figure 2).\n\nFIGURE 2 The probability of neutrophils and platelet engraftment after transplantation in 16 patients.\n\nAmong the 15 patients with evaluable chimerism data at day 28, all had complete donor chimersim (>99%) in unfractionated bone marrow nucleated cell compartments in which 11 patients achieved CR and 4 with bone marrow remission without platelet recovery (CRp, Table 2).\n\nTABLE 2 Clinical Outcome\n\nUp to the last follow-up at Nov 30, 2014, with a median follow-up of 10.5 months (0.5–40.5) for all patients, 4 patients died because of transplantation-related toxicity including infection before engraftment, post-transplant lymphoproliferative disorder (PTLD), sudden death, and pulmonary fungal infection respectively (as shown in Table 2). Accumulated 100-day NRM and 2-year NRM were 18.7% ± 9.8% and 25.0% ± 10.8%, respectively.\n\nA total of 4 patients relapsed 3.5, 4.5, 5.5, and 7 months, respectively after transplantation with 2-year accumulated relapse rate of 33.4% ± 13.8%. One patient (UPN3) declined any further treatment and 2 patients (UPN 7 and 9) failed to respond to rescue chemotherapy and all died of disease. Only 1 patient (UPN 14) achieved remission with salvage therapy with decitabine and low-dose chemotherapy followed by DLI and remained in remission up to last follow-up (as shown in Table 2).\n\nOverall, 8 patients remained alive without relapse for a median of 29.5(9.5–40.5) months and 6 of them already maintained leukemia-free for >2 years after allo-HSCT. Based on a median follow-up of 26.5 months for all alive patients, the estimated 2-year OS and LFS were 53.5% ± 13.1% and 50.0% ± 12.5%, respectively.\n\nTransplantation Toxicity\nThe toxicities of this transplantation protocol were mainly hematological toxicities and toxicity of gastric intestinal tract as shown in Tables 3 and 4. All patients developed grade IV neutropenia and thrombocytopenia. The median duration of neutropenia was 24 days (18–36). All these patients experienced at least 1 episode of neutropenic fever (14 grade III and 2 grade IV) and septic shock (grade IV) was documented in 2 patients after FLAG-IDA chemotherapy causing a 3-day delay of conditioning regimen given. The gastric intestine (GI) toxicity such as anorexia, mucositis, and diarrhea occurred almost in all patients and total parenteral nutrition (TPN) support had to be given in 12 of 16 patients. Grade III GI bleeding was documented in 1 patient after conditioning regimen and recovered well after intensive supportive care. The liver toxicity was mild to moderate and only 1 veno-occlusion disease was documented (as shown in Tables 3 and 4).\n\nTABLE 3 Major Toxicities\n\nTABLE 4 Overall Toxicity Grading\n\nAs to the aGVHD, in 15 evaluable patients, 8 developed aGVHD in which grade II in 6 and no grade III-IV aGVHD occurred. For 12 evaluable patients for cGVHD, 3 patients had limited cGVHD and another 3 had experienced extensive cGVHD (as shown in Table 2).\n\nComparison with Historical Control\nIn the next analysis, we compared the transplantation outcome of patients enrolled in the clinical trial with our historical control series of 26 patients with refractory AML received allogeneic transplantation from Jan 1st, 2000 to May 30, 2011 in our Blood and Marrow Transplantation Center (patient's characteristics as show in Table 5). When compared to the study group, the historical control group had significant lower bone marrow blasts before transplantation and all other clinical features were not significantly different between 2 groups. As to the transplantation outcome, most patients in the historical control group relapsed or died of transplantation toxicity within 6 months with only 3 patients remained disease-free 6 months after transplantation and 2 remained alive in continuous remission for >3 years up to the last follow-up. When compared with the historical control group, the outcome of patients enrolled in the study group was significantly improved in relapse rate (vs 81.2% ± 9.1%, P = 0.002), LFS (vs 11.1% ± 6.0%, median 3.7 months, P = 0.01), and OS (vs. 11.19% ± 6.0%, median 4.5 months, P = 0.002), whereas the NRM was not significantly different (vs 41.9% ± 14.8%, P = 0.5) as shown in Figure 3.\n\nTABLE 5 Patients’ Characteristics for Patients in Historical Control Group Compared With Study Group\n\nFIGURE 3 (A) The 2-year overall survival of patients in study group (53.5% ± 13.1%) compared with historical control (11.1% ± 6.0%, P = 0.002). (B) The 2-year leukemia-free survival of patients in study group (50.0% ± 12.5%) compared with historical control (11.1% ± 6.0%, P = 0.01). (C) The 2-year relapse rate of patients in study group (33.4% ± 13.8%) compared with historical control (81.2% ± 9.1%, P = 0.002). (D) The 2-year nonrelapse mortality in study group (25.0% ± 10.8%) compared with historical control (40.9% ± 14.8%, P = 0.50).\n\nLandmark Analysis\nAccordingly to the statistic consideration, patient (UPN 8) was excluded from analysis for statistical hypothesis rejection or acceptance because a bone marrow remission was documented before the FLAG-IDA chemotherapy. Among first 14 patients (UPN 1–15, UPN 8 excluded) enrolled in the study, 8 patients relapsed or died from either relapse or transplantation-related toxicity within 2 years after allo-HSCT. One patient (UPN 13) remained leukemia-free up to the last follow-up but did not complete the 2-year landmark. Importantly, the remaining 5 patients completed the designed follow-up for at least 2 years after allo-HSCT without relapse or other lethal event, thus based on the statistical analysis, the null hypothesis of the trial is rejected and the FLAG-IDA/Flu-Bu transplantation protocol is considered being possible to result a potential 2-year LFS around 45%, which is of clinical interest and required confirmation in further large-scale clinical trial.\n\nDISCUSSION\nTreatment options for adult patients with refractory AML are extremely limited.1,2,22 Although HSCT is generally the only curative option, active disease before HSCT leads to limited survival.4–8 The reported long-term survival in young patients undergoing fully myeloablative regimens approaches 25% at 3 years and <10% with RIC regimens at 5 years.23,24 One strategy to improve the outcomes is to give preconditioning cytoreduction therapy with active chemotherapy regimen and the feasibility of this strategy has been shown prospectively in refractory AML patients with active disease.10–13\n\nSeveral lines of evidence demonstrated that lower leukemia burden before transplantation was prognostic factor for achievement of CR and improvement of long-term outcomes after allo-HSCT. In an EBMT Registry, analysis of 168 primary refractory AML underwent unrelated donor transplantation, a lower percentage of bone marrow blasts at transplant was associated with improved survival.25 In a retrospective study, 17 patients with active refractory AML and extensive previous therapy received clofarabine as cytoreduction chemotherapy followed by 14–21 days conditioning regimen with fludarabine, alemtuzumab, and melphalan (Flu/Mel/Alem) or busulfan (Flu/BU/Alem). The effective cytoreduction after clofarabine at the hematological nadir in terms of blast clearance (blasts <10% in bone marrow) was important prognostic factor. The PFS was 6.4 months for patients who achieved cytoreduction after initial induction, compared with 3.8 months (P = .035) for those who did not. OS was 16.6 months for patients who achieved cytoreduction compared with 5.1 months (P = 0.053) for patients who did not.11\n\nIn our historical control series with conventional conditioning regimen such as Bu-Cy ± Vp16 or Cy-TBI ± Vp16, although remission can be achieved after allo-HSCT in these patients with refractory AML with median LFS of 3.7 months and OS of 4.5 months which was comparable to the group without success cytoreduction by clofarabine in the study reported by Locke et al.11 Most patients relapsed rapidly within 6 months (70.0% ± 10.2% as shown in Figure 3C) after transplantation, which was before the development of potential allogeneic graft-versus leukemia (GVL) effect, which is more likely associated with cGVHD and believed to have greater impact on the long-term disease control.10,26–28\n\nIn this prospective study, the goal was to evaluate whether the new strategy to give conditioning regimen at the nadir of cytoreductive chemotherapy could result in significantly better disease control after transplantation in refractory AML. The enrolled patients with primary or relapsed/refractory AML were heavily pre-treated with extreme high risk because of a median marrow blast of 55%. Of note, 7 days after FLAG-IDA chemotherapy, almost all evaluable patients achieved an extreme hypocellular bone marrow with significant clearance of blasts. Moreover, 8 of 16 patients remained in CR at last follow-up with a median follow-up of 29.5 months (9.5–40.5) without prophylactic DLI. Actually 5 of them remained leukemia-free for >2 years (including 2 for >3 years). Interestingly, 7 of 8 patients who remained alive in remission had either aGVHD or cGVHD. Based on these observations, we speculated that for refractory AML the sequential administration of Flu-Bu conditioning at the aplasia phase of intensive FLAG-IDA cytoreductive chemotherapy, which significantly depleted the leukemia burden, may lead to improved early disease control (7 of 15 evaluable patients remained in CR at the first 6 months after allo-HSCT). This benefit can be possibly enhanced or maintained by the subsequent GVL effect associated with aGVHD or cGVHD and eventually translates into better long-term disease control.10\n\nThe major challenge of this protocol was the toxicity such as prolonged myelo-suppression and GI toxicity associated with intensive chemotherapy and conditioning regimen given with a short interval. Indeed, we observed significant myelosuppression, which leads to prolonged neutropenia and increased risk of infection in which all patients had at least 1 episode of neutropenic fever, including 2 patients with septic shock. Aggressive supportive care such as transfusion blood products and TPN were required in most patients. Fortunately, the overall accumulated NRM of patients following HCT was comparable to the historical control.\n\nOverall, we present the results of phase II trial of conditioning regimen Flu-Bu sequentially given at the hematological nadir of previous cytoreductive chemotherapy. FLAG-IDA was feasible and can be considered as effective salvage treatment for patients with refractory AML. The small number of patients studied in the trial precludes any definitive conclusions, but this strategy has sufficient activity to warrant further investigation prospectively with a larger patient sample.\n\nUncited reference\n20.\n\nAcknowledgments\nThe authors thank Dr Ming Wan and Dr Jun-Cai Xu from Shanghai Clinical Research Center (SCRC) for assistance in the sample size estimation and statistics analysis.\n\nAbbreviations: aGVHD = acute GVHD, allo-HSCT = allogeneic hematopoietic stem cell transplantation, AML = acute myeloid leukemia, ATG = antithymocyte globulin, cGVHD = chronic GVHD, CIMBTR = Center for International Blood and Marrow Transplant Research, CR = complete remission, Crp = bone marrow remission without platelet recovery, CsA = cyclosporine, DLI = donor lymphocytes infusion, FLAG-IDA = fludarabine, cytarabine and idarubicin, Flu-Bu = busulfan and fludarabine, GI = gastric-intestine, GVHD = graft-versus-host disease, GVL = graft-versus leukaemia, LFS = leukemia-free survival, MDS = myelodysplasia syndrome, MMF = mycophenolate mofetil, MNC = mononuclear cells, MSD = HLA-matched sibling donor, MTX = methotraxate, MUD = HLA-matched unrelated donor, NRM = nonrelapse mortality, OS = overall survival, PFS = progression-free survival, PIF = primary induction failure, PTLD = post-transplant lymphoproliferative disorder, RIC = reduced-intensity conditioning, TPN = total parenteral nutrition.\n\nWT and XF contributed equally to the manuscript.\n\nThe authors declare no conflict of interest.\n==== Refs\nREFERENCES\n1. Craddock C Tauro S Moss P \nBiology and management of relapsed acute myeloid leukaemia . Br J Haematol \n2005 ; 129 :18 –34 .15801952 \n2. Mato AR Morgans A Luger SM \nNovel strategies for relapsed and refractory acute myeloid leukemia . Curr Opin Hematol \n2008 ; 15 :108 –114 .18300756 \n3. Revesz D Chelghoum Y Le QH \nSalvage by timed sequential chemotherapy in primary resistant acute myeloid leukemia: analysis of prognostic factors . Ann Hematol \n2003 ; 11 :684 –690 .12928754 \n4. Fung HC Stein A Slovak M \nA long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantation outcome . Biol Blood Marrow Transplant \n2003 ; 12 :766 –771 .14677116 \n5. Michallet M Thomas X Vernant JP \nLong-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Societe Francaise de Greffe de Moelle (SFGM) . Bone Marrow Transplant \n2000 ; 26 :1157 –1163 .11149725 \n6. Biggs JC Horowitz MM Gale RP \nBone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy . Blood \n1992 ; 4 :1090 –1093 .1498326 \n7. Mehta J Powles R Horton C \nBone marrow transplantation for primary refractory acute leukaemia . Bone Marrow Transplant \n1994 ; 3 :415 –418 .7994265 \n8. Sierra J Storer B Hansen JA \nTransplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA matching, and marrow cell dose . Blood \n1997 ; 89 :4226 –4235 .9166868 \n9. Duval M Klein JP He WS \nHematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure . J Clin Oncol \n2010 ; 28 :3730 –3738 .20625136 \n10. Schmid C Schleuning M Schwerdtfeger R \nLong-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation . Blood \n2006 ; 108 :1092 –1099 .16551971 \n11. Locke FL Artz A Rich E \nFeasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML . Bone Marrow Transplant \n2010 ; 45 :1692 –1698 .20208570 \n12. Platzbecker U Thiede C Fussel M \nReduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia . Leukemia \n2006 ; 20 :707 –714 .16482208 \n13. Buchholz S Dammann E Stadler M \nCytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome . Eur J Haematol \n2012 ; 88 :52 –60 .21883483 \n14. Liu QF Fan ZP Zhang Y \nSequential intensified conditioning and tapering of prophylactic immunosuppressants for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation for refractory leukemia . Biol Blood Marrow Transplant \n2009 ; 15 :1376 –1385 .19822296 \n15. Martin MG Augustin KM Uy GL \nSalvage therapy for acute myeloid leukemia with fludarabine, cytarabine, and idarubicin with or without gemtuzumab ozogamicin and with concurrent or sequential G-CSF . Am J Hematol \n2009 ; 84 :733 –737 .19806665 \n16. Russell JA Tran HT Quinlan D \nOnce-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: Study of pharmacokinetics and early clinical outcomes . Biol Blood Marrow Transplant \n2002 ; 8 :468 –476 .12374451 \n17. Estey E \nTreatment of refractory AML . Leukemia \n1996 ; 10 :932 –936 .8667647 \n18. Glucksberg H Storb R Fefer A \nClinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors . Transplantation \n1974 ; 18 :295 –304 .4153799 \n19. Filipovich AH Weisdorf D Pavletic S \nNational Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease, I: diagnosis and staging working group report . Biol Blood Marrow Transplant \n2005 ; 11 :945 –956 .16338616 \n20. Jung SH Lee TY Kim KM \nAdmissible two-stage designs for phase II cancer clinical trials . Stat Med \n2004 ; 23 :561 –569 .14755389 \n21. Lee ET , editor. Statistical Methods for Survival Data Analysis . Belmont, CA : Lifetime Learning ; 1980 p. 355 .\n22. Ofran Y Rowe JM \nTreatment for relapsed acute myeloid leukemia: what is new? \nCurr Opin Hematol \n2012 ; 19 :89 –94 .22227525 \n23. Horowitz MM Rowlings PA \nAn update from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry on current activity in hematopoietic stem cell transplantation . Curr Opin Hematol \n1997 ; 4 :395 –400 .9358995 \n24. Sierra J Storer B Hansen JA \nUnrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience . Bone Marrow Transplant \n2000 ; 26 :397 –404 .10982286 \n25. Craddock C Labopin M Pillai S \nFactors predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukaemia . Leukemia \n2011 ; 25 :808 –813 .21339758 \n26. Schmid C Schleuning M Ledderose G \nSequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome . J Clin Oncol \n2005 ; 23 :5675 –5687 .16110027 \n27. Weisdorf D Zhang MJ Arora M \nGraft-versus-host disease induced graft-versus-leukemia effect: greater impact on relapse and disease-free survival after reduced intensity conditioning . Biol Blood Marrow Transplant \n2012 ; 18 :1727 –1733 .22766220 \n28. Kataoka I Kami M Takahashi S \nClinical impact of graft-versus-host disease against leukemias not in remission at the time of allogeneic hematopoietic stem cell transplantation from related donors. The Japan Society for Hematopoietic Cell Transplantation Working Party . Bone Marrow Transplant \n2004 ; 34 :711 –719 .15361916\n\n",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002066:Busulfan; D003561:Cytarabine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015255:Idarubicin; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D033581:Stem Cell Transplantation; D019172:Transplantation Conditioning; D014740:Vidarabine; D055815:Young Adult",
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"title": "Busulfan and fludarabine conditioning regimen given at hematological nadir of cytoreduction fludarabine, cytarabine, and idarubicin chemotherapy in patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation: a single arm pilot consort study.",
"title_normalized": "busulfan and fludarabine conditioning regimen given at hematological nadir of cytoreduction fludarabine cytarabine and idarubicin chemotherapy in patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation a single arm pilot consort study"
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"abstract": "We describe the first reported case, to our knowledge, of disseminated pneumococcal infection involving a left ventricular assist device (LVAD). The management of this infection was extremely challenging, requiring multiple surgical debridements, LVAD removal, and prolonged courses of antibiotics. The Streptococcus pneumoniae isolate was found to be serotype 19F, which is included in both the pneumococcal polysaccharide and conjugate vaccines. This report highlights the importance of routine screening for up-to-date vaccination in patients who undergo LVAD implantation.",
"affiliations": "Division of Infectious Diseases, University of Kentucky College of Medicine, Lexington, Kentucky, USA.;Division of Cardiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.;Division of Infectious Diseases, University of Kentucky College of Medicine, Lexington, Kentucky, USA.",
"authors": "Reeves|J S|JS|;Rajagopalan|N|N|;Huaman|M A|MA|",
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"country": "Denmark",
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"doi": "10.1111/tid.12413",
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"issue": "17(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Streptococcus pneumoniae; device-related infection; left ventricular assist device; transplant; vaccine",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D011008:Pneumococcal Infections; D011183:Postoperative Complications",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "613-6",
"pmc": null,
"pmid": "26073334",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
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"title": "Disseminated Streptococcus pneumoniae infection involving a ventricular assist device.",
"title_normalized": "disseminated streptococcus pneumoniae infection involving a ventricular assist device"
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"abstract": "Polymyxin B (PMB), which is regarded as the ultimate antibacterial treatment against some intractable gram-negative bacteria with its outstanding anti-bacterial activities, inflicts several adverse effects on patients. However, skin hyperpigmentaion (SH) induced by PMB is very rare. Here, we report a case of polymyxin B-induced skin hyperpigmentation (PMB-iSH) in a 21-year-old female. To the best of our knowledge, this is the first case of PMB-iSH in China.\n\n\n\nA 21-year-old female patient with sepsis received the administration of PMB by intravenous injection for the treatment of multi-drug resistant Klebsiella pneumoniae (MDR-KP) infection. She later suffered from a rare adverse drug reaction (ADR), namely PMB-iSH, after 5-day PMB administration during her treatment. There were multiple red rashes spread on the whole body skin at first. With the rashes fading away, SH with dark round spots appeared, associated with no pain or pruritus. The skin of the head and neck was darkened evidently, and dark brown spots were spread on the skin of trunk and limbs. About a month after her admission, urged by the relatives, the patient was transferred back to the local hospital for further treatment in the end, and her skin color didn't recover to the previous state at that time.\n\n\n\nBoth our case and the literature review highlight that PMB can give rise to SH indeed. Clinicians and pharmacists should attach great importance to this rare pigmentary disorder and further investigation is warranted.",
"affiliations": "Department of Pharmacy, Xiaolan Hospital Affiliated to Southern Medical University, Zhongshan, China.;Department of Pharmacy, Zhongshan People's Hospital, Zhongshan, China.;Department of Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China.;Department of Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China.;Department of Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine, EICU 3 Floor, 5 Building, 197 Ruijin No. 2 Road, Huangpu District, Shanghai, China. chenerzhen@hotmail.com.;Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine, 202 Room, 12 Building, 197 Ruijin No. 2 Road, Huangpu District, Shanghai, China. hejuanwin@126.com.",
"authors": "Zheng|Guanhao|G|;Cao|Li|L|;Che|Zaiqian|Z|;Mao|Enqiang|E|;Chen|Erzhen|E|;He|Juan|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D011112:Polymyxin B",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-018-0226-1",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 22610.1186/s40360-018-0226-1Case ReportPolymyxin B-induced skin hyperpigmentation: a rare case report and literature review Zheng Guanhao ken521540@gmail.com 1Cao Li lily726531797@foxmail.com 2Che Zaiqian chezaiqian@163.com 3Mao Enqiang maoeq@yeah.net 3Chen Erzhen chenerzhen@hotmail.com 4He Juan hejuanwin@126.com 51 0000 0000 8877 7471grid.284723.8Department of Pharmacy, Xiaolan Hospital Affiliated to Southern Medical University, Zhongshan, China 2 grid.476868.3Department of Pharmacy, Zhongshan People’s Hospital, Zhongshan, China 3 0000 0004 1760 6738grid.412277.5Department of Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China 4 0000 0004 1760 6738grid.412277.5Department of Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine, EICU 3 Floor, 5 Building, 197 Ruijin No. 2 Road, Huangpu District, Shanghai, China 5 0000 0004 1760 6738grid.412277.5Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai JiaoTong University School of Medicine, 202 Room, 12 Building, 197 Ruijin No. 2 Road, Huangpu District, Shanghai, China 4 7 2018 4 7 2018 2018 19 4127 2 2018 20 6 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\nPolymyxin B (PMB), which is regarded as the ultimate antibacterial treatment against some intractable gram-negative bacteria with its outstanding anti-bacterial activities, inflicts several adverse effects on patients. However, skin hyperpigmentaion (SH) induced by PMB is very rare. Here, we report a case of polymyxin B-induced skin hyperpigmentation (PMB-iSH) in a 21-year-old female. To the best of our knowledge, this is the first case of PMB-iSH in China.\n\nCase presentation\nA 21-year-old female patient with sepsis received the administration of PMB by intravenous injection for the treatment of multi-drug resistant Klebsiella pneumoniae (MDR-KP) infection. She later suffered from a rare adverse drug reaction (ADR), namely PMB-iSH, after 5-day PMB administration during her treatment. There were multiple red rashes spread on the whole body skin at first. With the rashes fading away, SH with dark round spots appeared, associated with no pain or pruritus. The skin of the head and neck was darkened evidently, and dark brown spots were spread on the skin of trunk and limbs. About a month after her admission, urged by the relatives, the patient was transferred back to the local hospital for further treatment in the end, and her skin color didn’t recover to the previous state at that time.\n\nConclusion\nBoth our case and the literature review highlight that PMB can give rise to SH indeed. Clinicians and pharmacists should attach great importance to this rare pigmentary disorder and further investigation is warranted.\n\nKeywords\nPolymyxin BSkin hyperpigmentationSepsisCase reportShanghai Municipal Science and Technology Commission of biological medicineNo.12411950500Chen Erzhen http://dx.doi.org/10.13039/501100001809National Natural Science Foundation of ChinaNo. 81772107No. 81571931Chen Erzhen Shanghai Shen Kang Hospital Development Center Clinical Science and technology innovation project SHDC12017116Chen Erzhen Important and weak discipline construction plan for health and family planning system of Shanghai2016ZB0206Chen Erzhen Program for Outstanding Medical Academic Leader of Shanghai2018ChenErzhenChen Erzhen issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nSkin hyperpigmentation (SH) is a common type of skin disease with various inducing factors. Drug-induced skin hyperpigmentation (DiSH) is an important part of SH, accounting for 10 to 20% of all acquired SH cases [1]. A variety of drugs can trigger DiSH, such as tetracycline, NSAIDs, anti-malarial agents, anti-psychotic agents, cytotoxic agents, amiodarone, etc. [1]. Minocycline is the most common trigger among the aforementioned drugs [2]. Recently, SH has been observed in several patients who received the treatment of intravenous polymyxin B (PMB). Here we discuss a patient with sepsis who was treated by intravenous PMB and suffered from a rare adverse drug reaction (ADR) afterward, namely polymyxin B-induced skin hyperpigmentation (PMB-iSH), on the basis of a literature review of its epidemiology, pathological mechanism, treatment options and prognosis.\n\nCase presentation\nHistory and previous admissions\nThis was a rare case of PMB-iSH in a 21-year-old female in China. In her postpartum period, the patient suffered from chest pain, fever and even coma for a fortnight. She was sent to the local hospital due to cardiac arrest by 4 times on 27th January 2017. After CPR, she regained consciousness gradually but still was in a continuous febrile state. Klebsiella pneumoniae was isolated from the samples of blood and sputum cultures. Besides, anti-microbial therapy hadn’t worked effectively since she was treated with cefepime, imipenem and tigecycline.\n\nEICU admission\nThe patient was soon admitted to the emergency intensive care unit (EICU) of Ruijin Hospital affiliated to Shanghai Jiao Tong University on 26th April. Upon admissionto our hospital, she was still in fever, unconscious in a dyspneic state, and mechanical ventilation was initiated after tracheotomy with metal tracheal tube.\n\nExamination in EICU & adjustment for anti-infectious therapy\nA full-body computed tomography (CT) scan identified thickened pericardium, bilateral pleural effusion with multiple exudative focuses, hepatosplenomegaly and pelvic effusion in this patient. Empiric antibiotic treatment was started for Klebsiella pneumoniae infection with piperacillin-tazobactam (4.5 g, intravenously, q.8 h). The sample of microbial sputum culture on 29th April revealed that a large amount of multi-drug resistant Klebsiella pneumoniae (MDR-KP) grew, which was merely susceptible to tigecycline, sulfamethoxazole (SMZ) and PMB. The infection parameters from laboratory examination increased remarkably: hypersensitive C-reactive protein 37.0 mg/L [0~ 3 mg/L] and procalcitonin 3.37 ng/mL [< 0.50 ng/mL]. In light of the above-mentioned examination results, we replaced piperacillin-tazobactam with meropenem (2 g, intravenously, q.8 h) and tigecycline (100 mg intravenously q.12 h) with the addition of colistin (1-million unit by aerosol inhalation q.8 h) on 4th May.\n\nOccurrence of PMB-iSH\nAfter the adjustment for the treatment, her body temperature dropped to normal and remained stable. During this period, repeated cultures of blood, sputum, vaginal secretion and fluid drained from the hip joint were carried out. MDR-KP, susceptible to tigecycline, SMZ and PMB was detected in all the samples. On 18th May, multiple exudations were aggravated in bilateral lungs compared to that upon admission, according to a chest CT scan. As a result, PMB (500,000 units, intravenously, q.12 h) was administered at once. Four days later, there were multiple red rashes spread on the whole body skin. With the rashes fading away, SH with dark round spots was seen on 23rd May (5 days after intravenous PMB) without pain or pruritus. More dark brown spots were spread on the skin of trunk and limbs, especially on that of lower abdomen, right hand and right foot as depicted in Figs. 1, 2, 3 and 4, although the skin of the head and neck was also darkened evidently. Despite this adverse event, the therapeutic regimen was still applied in consideration of MDR-KP infection of multiple organs. PMB was utilized in the same dosage until the patient was transferred back to the local hospital, and skin biopsy wasn’t performed.Fig. 1 Hyperpigmentation in the head and face\n\nFig. 2 Hyperpigmentation in the lower abdomen\n\nFig. 3 Hyperpigmentation in the right hand\n\nFig. 4 Hyperpigmentation in the right foot\n\n\n\nPost-treatment course\nOn 21st May, she suffered from diarrhea suddenly with intra-abdominal pressure (IAP) increasing to 19 cm H2O. About 500 ml black stool was found in the patient’ s excrement. Her serum creatinine was elevated dramatically to 430 μmol/L [53~ 97 μmol/L], and anuria occurred. The laboratory examinations revealed the following results: the level of hemoglobin was significantly reduced to 57 g/L [113~ 151 g/L] and platelet counts 63 × 109/L [101~ 320 × 109/L]. Her liver function was impaired moderately: total bilirubin was 43.6 μmol/L [4.7~ 24 μmol/L], direct bilirubin was 26.0 μmol/L [0~ 6.8 μmol/L], and γ-GT went up to 103 IU/L [7~ 64 IU/L]. The results of coagulation test were as follows: APTT 50.1 s [22.3~ 38.7 s], PT 12.9 s [10.0~ 16.0 s], TT 24.80s [14.00~ 21.00s], Fg 1.5 g/L [1.8~ 3.5 g/L], FDP 12.5 mg/L [0~ 5 mg/L] and D-Dimer 2.66 mg/L [< 0.55 mg/L]. They indicated that the patient suffered from coagulation abnormality and hyperfibrinolysis, hence disseminated intravascular coagulation (DIC). After phlebotomy, the transfusion of cryoprecipitate prepared from plasma frozen within 24 Hours (PF24) started immediately. Meanwhile, low-dose heparin (3 U/kg/h) was administered prudently for anticoagulation therapy. 2 days later, bleeding disappeared. On 25th May, urged by the relatives, the patient was transferred back to the local hospital for further treatment. At that time, her skin color didn’t recover to the previous state. Owing to her relatives’ will, we failed to make a follow-up visit. The treatment timeline is shown in Fig. 5.Fig. 5 Treatment timeline of this patient\n\n\n\nDiscussion & conclusion\nOf polymyxins and lipopeptide antibiotics, colistin and PMB were isolated from Paenibacillus ploymyxa and has been available in clinical use since 1959. They have excellent anti-microbial activity against a variety of gram-negative bacteria. Unfortunately, the polymyxins were once replaced by those more effective and safer antibiotics like aminoglycosides on account of their severe nephrotoxicity and neurotoxicity. But in the last few decades, great importance was attached to the polymyxins again by clinicians due to the inevitable appearance of multi-drug resistant (MDR) bacteria. They were even regarded as the ultimate antibacterial treatment against some intractable gram-negative bacteria with their outstanding anti-bacterial activity as well, such as Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, carbapenem-resistant Enterobacteriaceae, etc. [3–5].\n\nWhen it comes to the polymyxins, their chemical structure, antimicrobial spectrum and mechanism are extremely similar, although colisitin is a pro-drug for clinical use [4]. The most common ADR of the polymyins is nephrotoxicity, while neurotoxicity and hypersensitivity are also other main ADRs [6]. It is a nonnegligible fact that SH is proved as a significant side effect induced by PMB, and no SH cases induced by colistin have been reported.\n\nOnly a few case reports on PMB-iSH have been found so far. Knueppel R.C. et al. reported two suspected cases in 2007 for the first time [7]. A patient who suffered from MDR-KP infection was found with SH after treated by intravenous PMB for 4 days, according to the description by Lahiry S. et al. [8]. Besides, there were several cases in neonates and infants as well. Gothwal S. et al. reported 3 babies who had progressive SH after intravenous PMB. They maintained that the cumulative effect of PMB might be a possible reason for darkened skin, which was likely to cause the immaturity of kidney functions of neonates, since PMB was excreted through the kidney mainly [9]. Interestingly, Shih L K et al. used Felix von Luschan Skin Color Chart to classify the color of skin tone into 36 different scales. 16 infants were recruited in this study, treated by 15,000 units/kg intravenous PMB every 12 h for 14 days. Based on the average change of skin tone, the skin tone of all the subjects were progressively darkened during the treatment period and reached the peak at the end of the treatment of intravenous PMB (on the 14th day) [10].\n\nIn 2016, Mattos K.P. et al. carried out a cohort study on PMB-iSH, which included 60 patients with gram-negative infection who received a 14-day PMB treatment. PMB-iSH was found in 15% of the subjects usually on the 3rd day of the treatment period. Their skin color were darkened to various shades of brown, particularly in the neck and face [11]. It was reported in another study that this pigmentary disorder was found in 8% of 249 patients who used PMB [12].\n\nTo the best of our knowledge, the case previously presented is the first case of PMB-iSH in China. On the basis of Naranjo Adverse Drug Reaction Probability Scale, PMB was probably associated with SH (+ 1 for conclusive reports on this reaction, + 2 for adverse events occurring after PMB administration, + 1 for confirmed by objective evidences, + 2 for the absence of possible alternative causes = 6 points) [13, 14].\n\nBesides PMB, the patient received omeprazole, meropenem, SMZ, colistin, tigecycline and heparin during her treatment period. Among these drugs, tigecycline and omeprazole could cause DiSH. It was reported that tigecycline could induce SH, similar to minocycline [15]. However, SH occurred after the use of PMB for a few days, and their temporal correlation was found in this case. Hence, we considered PMB was the trigger of SH rather than tigecycline and omeprazole. In addition, drug-drug interaction should not be ignored. The combination of colistin and PMB may increase the risk of nephrotoxicity, which may cause the cumulation of PMB in vivo. Due to the limited medical resources and the critical condition of this patient, no further treatment was carried out for this issue.\n\nHowever, it must be pointed out that acute renal insufficiency may be an important factor for PMB-iSH. Since up to 60% of PMB is excreted unchanged with urine and strongly associated with nephrotoxicity, its elimination half-life increases with reduced renal function. For individuals with renal impairment, reduced dose of PMB is required because of lower clearance rate. Back to this patient, her glomerular filtration rate (GFR) was almost 14.44 mL/min, indicating she suffered from severe acute kidney injury (AKI) during her treatment period. This could give rise to PMB accumulation so that the blood concentration would significantly increase. Although there is no direct evidence to prove that PMB-iSH is a dose-dependent ADR, higher drug level in the body can be a related factor for skin darkening in some studies [9, 10].\n\nThe pathological mechanism of PMBiSH is still unclear. Overall, there are 4 possible basic pathological mechanisms of DiSH: (1) the most common drug-induced mechanism is the production and accumulation of melanin within cutaneous cells,, especially in dermal macrophages; (2) the druge accumulation, associated with no melanin, usually exists within extracellular matrix or within dermal macrophages; (3) a specific drug plays a key role in the synthesis of other special pigments like lipofuscin; (4) drug-associated injury to dermal vessels usually results in the leakage of many red blood cells and the deposition of iron [1]. Most of relevant researches maintain that DiSH is attributed to an extensive inflammation, induced by inflammatory factors and producing allergic or toxic effects.\n\nOne probable mechanism of PMB-iSH is that PMB induces the release of histamine and the synthesis of melanin [11, 16, 17]. Histamine is released by basophils, mast cells and neurons in skin tissues, which can activate the inflammatory reaction by acting on 4 receptors (H1 to H4) [18]. Yoshida M. et al. described the melanogenic effect of histamine: it could activate the H2 receptor of melanocytes, then up-regulate the activities of both tyrosinase and protein kinase A with the latter acting as a key role in melanogenesis [19]. Furthermore, it is proved that pigmented skin is more common in the head and neck since there are more melanocytes distributed in them [12].\n\nAnother presumed mechanism is related to epidermal langerhans cells. The research by Miori L. et al. revealed that the occurrence of SH meant the patient was at the stage of the post-inflammatory pathological progress, and the langerhans cells played a crucial role in chronic inflammatory skin diseases [20]. According to the histopathological results of a PMB-iSH patient’s skin biopsy, Mattos K. P. H. et al. found that the greater proliferation of epidermal langerhans cells and dermal dendritic cells occurred indeed [12]. Based on the information above, it is presumed that PMB is an initiating factor of the pathological progress.\n\nLast but not least, it was described by Choi H. et al. that IL-6 could inhibit the proliferation of melanocytes and the generation of melanin [21]. Mattos K. P. H et al. found the expression of IL-6 was lower in several patients who suffered from the pigmented skin with PMB [12]. These research results may link the level of IL-6 to PMB-iSH. Further investigations should be carried out for verification.\n\nThe treatment of DiSH has already been challenging, let alone that of PMB-iSH. No specific treatment has been reported in literature up to now. This may be attributed to the fact that the illness is chronic and continuous progression that can easily relapse. For the patients whose symptoms can be relieved by lowering dosage, it is of great importance to find the balance between DiSH and therapeutic effects. What’s more, it is necessary to find suitable alternative drugs and adjust the dosage in accordance with the patient’ s physiological conditions and other clinical parameters. Another intervention is to avoid the exposure to sunlight, particularly ultraviolet ray, as much as possible so as to reduce the synthesis and accumulation of melanin. Topical or laser therapy through skin whitening agent may also be alternative ways to help the patients whose melanin concentrate within epidermal cells get rid of DiSH [1, 2].\n\nNowadays, it is still controversial on whether ceasing PMB can reverse the pathological change to pigmented skin and restore the original color. Zavascki A. P. et al. treated a 55-year-old male patient with hospital acquired pneumonia (HAP) by 14-day intravenous PMB treatment. His skin of the head and neck was evidently darkened during the treatment period. His skin tone was not restored to normal 3 months after PMB was withdrawn. On the basis of the Naranjo Adverse Drug Reaction probability scale, PMB was probably associated with hyperpigmentation (+ 2 for adverse events occurring after drug administration, + 1 for confirmed by objective evidences, + 2 for the absence of possible alternative cause = 5 points) [22]. A 14-year-old female patient with aplastic anaemia who experienced an allogenic haematopoietic stem cell transplantation also suffered from PMB-iSH. On the 5th day of PMB treatment to treat postoperative infection, there was diffused SH and dark round spots on her upper body. Skin biopsy displayed that the patient underwent interface dermatitis with vacuolar damage. There were lots of melanophages and melanin pariticles within epidermal and dermal cells. Unlike the former patient, this patient was found with gradual recovery at the 3-month follow-up visit. Her skin color was restored to normal and the dark spots got shallow. And the spots almost disappeared at the 6-month follow-up visit [23].\n\nThere are some novel findings from our case. First of all, for the first time, it is observed that the appearance of red rashes is prior to the occurrence of PMB-iSH. We may infer that PMB-iSH is possibly related to drug-induced hypersensitivity reaction, which is caused by the release of histamine and characterized as a symptom of rash and erythra. Secondly, based on our literature review, PMB-iSH mostly occurs on the skin of the head, neck and upper body. But in our case, not only did SH occur in the aforesaid locations, but also more serious symptoms were seen on the skin of the lower body and limbs.\n\nIn conclusion, PMB can give rise to SH indeed. Both clinicians and pharmacists should attach great importance to it. With the pathological mechanism still unclear, one of its probable reasons is associated with the release of histamine. Once PMB-iSH was observed, we should weigh the advantages and disadvantages of using PMB, and keep balance between curative effects and adverse event by such measures as dosage adjustment, cessation of drug administration and change to alternative antibiotics. Additionally, topical therapy and laser therapy can be treatments for PMB-iSH. Overall, further investigation is warranted.\n\nAbbreviations\nADRAdverse drug reaction\n\nAKIAcute kidney failure\n\nCPRCardiopulmonary resuscitation\n\nCTComputed tomography\n\nDiSHDrug-induced skin hyperpigmentation\n\nEICUEmergency intensive care unit\n\nGIBGastrointestinal bleeding\n\nHAPHospital acquired pneumonia\n\nIAPIntra-abdominal pressure\n\nIL-6Interleukin-6\n\nMDRMulti-drug resistance\n\nMDR-KPMulti-drug resistant Klebsiella pneumoniae\n\nPMBPolymyxin B\n\nPMB-iSHPolymyxin B-induced skin hyperpigmentation\n\nSHSkin hyperpigmentaion\n\nSMZSulfamethoxazole\n\nAcknowledgements\nThe authors thank the staff of the EICU Department of Ruijin Hospital affiliated to Shanghai JiaoTong University School of Medicine for their facilities and collaboration.\n\nFunding\nThis study was supported by Program for Outstanding Medical Academic Leader of Shanghai. This study was also funded by Shanghai Shen Kang Hospital Development Center Clinical Science and technology innovation project (No.SHDC12017116) and Important and weak discipline construction plan for health and family planning system of Shanghai (No.2016ZB0206), the biological medicine research program of Shanghai Municipal Science and Technology Commission (No.12411950500), and the National Natural Science Foundation of China (No. 81772107 and 81571931).\n\nAuthors’ contributions\nGHZ and JH conceived and designed this study. GHZ, LC, and ZQC performed the study. ZQC and EQM made substantial contributions to acquisition of data, and involved in drafting the manuscript. GHZ and LC wrote the paper. ZQC and EQM made substantial contributions to general supervision of the research group. EZC made substantial contributions to acquisition, analysis and interpretation of the data, supported the present study with national fundings, and provided the analysis tools. JH and EZC reviewed and revised the manuscript critically for important intellectual content, and approved the final version. All authors read and approved the manuscript.\n\nEthics approval and consent to participate\nThis study was approved by Ruijin Hospital Institutional Review Board and has been performed in accordance with the ethical standards laid down in “Declaration of Helsinki 1964” and its later amendments or comparable ethical standards. One patient was enrolled in the study and informed consent forms were signed by this patient.\n\nConsent for publication\nWritten informed consent was obtained from the patient to the publication of this case report. A copy of the written informed consent is available for the review by the editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Dereure O Drug-induced skin pigmentation. Epidemiology, diagnosis and treatment Am J Clin Dermatol 2001 2 4 253 10.2165/00128071-200102040-00006 11705252 \n2. Krause W Drug-induced hperpigemntation: a systematic review J Dtsch Dermatol Ges 2013 11 7 644 651 23650908 \n3. Nation RL Li J Cars O Couet W Dudley MN Kaye KS Mouton JW Paterson DL Tam VH Theuretzbacher U Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus Lancet Infect Dis 2015 15 2 225 10.1016/S1473-3099(14)70850-3 25459221 \n4. Tran TB Velkov T Nation RL Forrest A Tsuji BT Bergen PJ Li J Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet? Int J Antimicrob Agents 2016 48 6 592 597 10.1016/j.ijantimicag.2016.09.010 27793510 \n5. Velkov T, Dai C, Ciccotosto GD, Cappai R, Hoyer D, Li J. Polymyxins for CNS infections: pharmacology and neurotoxicity. Pharmacol Ther. 2017;\n6. Kelesidis T Falagas ME The safety of polymyxin antibiotics Expert Opin Drug Saf 2015 14 11 1687 1701 10.1517/14740338.2015.1088520 26365594 \n7. Knueppel RC Rahimian J Diffuse cutaneous hyperpigmentation due to tigecycline or polymyxin B Clin Infect Dis 2007 45 1 136 10.1086/518706 17554719 \n8. Lahiry S Choudhury S Mukherjee A Bhunya PK Bala M Polymyxin B-induced diffuse cutaneous hyperpigmentation J Clin Diagn Res 2017 11 2 FD01 FD02 28384882 \n9. Gothwal S Meena K Sharma SD Polymyxin B Induced generalized hyperpigmentation in neonates Indian J Pediatr 2016 83 2 179 180 10.1007/s12098-015-1798-z 26088547 \n10. Shih LK, Gaik CL. Polymyxin B induced generalized skin hyperpigmentation in infants. J Pediatr Scis. 2014;6:e215.\n11. Mattos KP Lloret GR Cintra ML Gouvea IR Betoni TR Mazzola PG Moriel P Acquired skin hyperpigmentation following intravenous polymyxin B treatment: a cohort study Pigment Cell Melanoma Res 2016 29 3 388 390 10.1111/pcmr.12468 26909746 \n12. Mattos KPH Cintra ML Gouvea IR Ferreira LA Velho P Moriel P Skin hyperpigmentation following intravenous polymyxin B treatment associated with melanocyte activation and inflammatory process J Clin Pharm Ther 2017 42 5 573 578 10.1111/jcpt.12543 28497462 \n13. Naranjo CA FRCPC DNHSM Lanctôt MKL Advances in the diagnosis of adverse drug reactions J Clin Pharmacol 1992 32 10 897 904 10.1002/j.1552-4604.1992.tb04635.x 1447396 \n14. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 10.1038/clpt.1981.154 7249508 \n15. Vandecasteele SJ De Ceulaer J Wittouck E Tigecycline induced hyperpigmentation of the skin Open Forum Infect Dis 2016 3 1 ofw033 10.1093/ofid/ofw033 27011952 \n16. Fechner GA Jacobs JJ Parsons PG Inhibition of melanogenesis in human melanoma cells by novel analogues of the partial histamine (H2) agonist nordimaprit Biochem Pharmacol 1993 46 1 47 10.1016/0006-2952(93)90346-X 8347136 \n17. Voitenko VG Bayramashvili DI Zebrev AI Zinchenko AA Relationship between structure and histamine releasing action of polymyxin B and its analogues Agents Actions 1990 30 1-2 153 10.1007/BF01969025 1695439 \n18. Marone G Granata F Spadaro G Genovese A Triggiani M The histamine-cytokine network in allergic inflammation J Allergy Clin Immunol 2003 112 4 Suppl 83 88 10.1016/S0091-6749(03)01881-5 \n19. Yoshida M Takahashi Y Inoue S Histamine induces Melanogenesis and morphologic changes by protein kinase a activation via H2 receptors in human normal melanocytes J Investig Dermatol 2000 114 2 334 342 10.1046/j.1523-1747.2000.00874.x 10651995 \n20. Miori L Vignini M Rabbiosi G Flagellate dermatitis after bleomycin. A histological and immunohistochemical study Am J Dermatopathol 1990 12 6 598 602 10.1097/00000372-199012000-00011 1702587 \n21. Choi H Kim K Han J Choi H Jin SH Lee EK Shin DW Lee TR Lee AY Noh M Kojic acid-induced IL-6 production in human keratinocytes plays a role in its anti-melanogenic activity in skin J Dermatol Sci 2012 66 3 207 215 10.1016/j.jdermsci.2012.03.002 22464230 \n22. Zavascki AP Manfro RC Maciel RA Falci DR Head and neck hyperpigmentation probably associated with Polymyxin B therapy Ann Pharmacother 2015 49 10 1171 1172 10.1177/1060028015595643 26187742 \n23. Zavascki AP Schuster LF Duquia RP Histopathological findings of pigmented lesion and recovery of natural skin colour in a patient with polymyxin B-associated diffuse hyperpigmentation Int J Antimicrob Agents 2016 48 5 579 580 10.1016/j.ijantimicag.2016.08.010 27720305\n\n",
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"issue": "19(1)",
"journal": "BMC pharmacology & toxicology",
"keywords": "Case report; Polymyxin B; Sepsis; Skin hyperpigmentation",
"medline_ta": "BMC Pharmacol Toxicol",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D017495:Hyperpigmentation; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D011112:Polymyxin B; D055815:Young Adult",
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"title": "Polymyxin B-induced skin hyperpigmentation: a rare case report and literature review.",
"title_normalized": "polymyxin b induced skin hyperpigmentation a rare case report and literature review"
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"abstract": "To determine the safety of tipifarnib in combination with escalating doses of bortezomib and to determine the maximum tolerated dose in patients with untreated high-risk MDS and oligoblastic acute myeloid leukemia, who were not eligible for intensive therapy.\n\n\n\nIn a \"3 + 3″ design, patients received fixed doses of tipifarnib 200 mg bid (days 1-21) and escalating doses of bortezomib (days 8, 15, 22) every 4 weeks in 4-6 cycles.\n\n\n\nThe combination was tolerated well by the 11 patients in this study without reaching the maximum tolerated dose. Myelosuppression was the most frequent side effect, but usually of short duration. Interestingly a complete response with or without complete count recovery was observed in three patients and three additional patients had stable disease. The median duration of overall survival was 449 days. Two patients were still alive at 4.0 and 4.3 years, including one patient in continuing CR.\n\n\n\nThe combination of tipifarnib and bortezomib was tolerated well and appeared to have clinical activity in patients with high-risk MDS and AML with low counts of marrow blasts. Our results warrant further evaluation in a phase II study.",
"affiliations": "Dept. of Hematology, Radboudumc, Nijmegen, the Netherlands; Dept. of Haematology, Leeds Teaching Hospitals, St James Institute of Oncology, Leeds, UK. Electronic address: P.Muus@KPNplanet.nl.;Dept. of Hematology, Radboudumc, Nijmegen, the Netherlands.;Dept. of Hematology, Radboudumc, Nijmegen, the Netherlands; Dept. Rheumatology, Elisabeth-TweeSteden Ziekenhuis, Tilburg, the Netherlands.;Dept. of Hematology, Radboudumc, Nijmegen, the Netherlands.;Dept. of Hematology, Radboudumc, Nijmegen, the Netherlands; Dept. of Tumor Immunology, Radboudumc, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.",
"authors": "Muus|Petra|P|;Langemeijer|Saskia|S|;van Bijnen|Sandra|S|;Blijlevens|Nicole|N|;de Witte|Theo|T|",
"chemical_list": "D015363:Quinolones; D000069286:Bortezomib; C402769:tipifarnib",
"country": "England",
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"doi": "10.1016/j.leukres.2021.106573",
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"issn_linking": "0145-2126",
"issue": "105()",
"journal": "Leukemia research",
"keywords": "Acute myeloid leukemia; Bortezomib; Farnesyltransferase inhibitor; Hypomethylating agents; Myelodysplastic syndromes; Phase I; Proteasome inhibitor; Tipifarnib",
"medline_ta": "Leuk Res",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D015363:Quinolones; D016896:Treatment Outcome",
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"pubdate": "2021-06",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase I clinical trial to study the safety of treatment with tipifarnib combined with bortezomib in patients with advanced stages of myelodysplastic syndrome and oligoblastic acute myeloid leukemia.",
"title_normalized": "a phase i clinical trial to study the safety of treatment with tipifarnib combined with bortezomib in patients with advanced stages of myelodysplastic syndrome and oligoblastic acute myeloid leukemia"
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"abstract": "Therapy-related myeloid neoplasms are secondary malignancies that are often fatal, but their risk factors are not well understood. Evidence suggests that individuals with clonal haemopoiesis have increased risk of developing haematological malignancies. We aimed to identify whether patients with cancer who have clonal haemopoiesis are at an increased risk of developing therapy-related myeloid neoplasms.\n\n\n\nWe did this retrospective case-control study to compare the prevalence of clonal haemopoiesis between patients treated for cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). All patients in both case and control groups were treated at MD Anderson Cancer Center (Houston, TX, USA) from 1997 to 2015. We used the institutional medical database to locate these patients. Patients were included as cases if they were treated for a primary cancer, subsequently developed therapy-related myeloid neoplasms, and had available paired samples of bone marrow from the time of therapy-related myeloid neoplasm diagnosis and peripheral blood from the time of primary cancer diagnosis. Patients were eligible for inclusion as age-matched controls if they were treated for lymphoma, received combination chemotherapy, and did not develop therapy-related myeloid neoplasms after at least 5 years of follow-up. We used molecular barcode sequencing of 32 genes on the pretreatment peripheral blood samples to detect clonal haemopoiesis. For cases, we also used targeted gene sequencing on bone marrow samples and investigated clonal evolution from clonal haemopoiesis to the development of therapy-related myeloid neoplasms. To further clarify the association between clonal haemopoiesis and therapy-related myeloid neoplasm development, we also analysed the prevalence of clonal haemopoiesis in an external cohort of patients with lymphoma who were treated in a randomised trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin. This trial was done at MD Anderson Cancer Center between 1999 and 2001 (protocol number 98-009).\n\n\n\nWe identified 14 cases and 54 controls. Of the 14 cases, we detected clonal haemopoiesis in the peripheral blood samples of ten (71%) patients. We detected clonal haemopoiesis in 17 (31%) of the 54 controls. The cumulative incidence of therapy-related myeloid neoplasms in both cases and controls at 5 years was significantly higher in patients with clonal haemopoiesis (30%, 95% CI 16-51) than in those without (7%, 2-21; p=0·016). In the external cohort, five (7%) of 74 patients developed therapy-related myeloid neoplasms, of whom four (80%) had clonal haemopoiesis; 11 (16%) of 69 patients who did not develop therapy-related myeloid neoplasms had clonal haemopoiesis. In the external cohort, the cumulative incidence of therapy-related myeloid neoplasms at 10 years was significantly higher in patients with clonal haemopoiesis (29%, 95% CI 8-53) than in those without (0%, 0-0; p=0·0009). In a multivariate Fine and Gray model based on the external cohort, the presence of clonal haemopoiesis significantly increased the risk of therapy-related myeloid neoplasm development (hazard ratio 13·7, 95% CI 1·7-108·7; p=0·013).\n\n\n\nPreleukaemic clonal haemopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal haemopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms. A prospective trial to validate this concept is warranted.\n\n\n\nCancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, NIH through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program.",
"affiliations": "Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Institute of Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: afutreal@mdanderson.org.",
"authors": "Takahashi|Koichi|K|;Wang|Feng|F|;Kantarjian|Hagop|H|;Doss|Denaha|D|;Khanna|Kanhav|K|;Thompson|Erika|E|;Zhao|Li|L|;Patel|Keyur|K|;Neelapu|Sattva|S|;Gumbs|Curtis|C|;Bueso-Ramos|Carlos|C|;DiNardo|Courtney D|CD|;Colla|Simona|S|;Ravandi|Farhad|F|;Zhang|Jianhua|J|;Huang|Xuelin|X|;Wu|Xifeng|X|;Samaniego|Felipe|F|;Garcia-Manero|Guillermo|G|;Futreal|P Andrew|PA|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(16)30626-X",
"fulltext": "\n==== Front\n10095724627004Lancet OncolLancet Oncol.The Lancet. Oncology1470-20451474-54882792355210.1016/S1470-2045(16)30626-Xnihpa859966ArticlePre-leukemic clonal hematopoiesis and the risk of therapy-related\nmyeloid neoplasms: a case-control study Takahashi Koichi M.D.129*Wang Feng Ph.D.2*Kantarjian Hagop ProfM.D.1Doss Denaha M.S.3Khanna Kanhav M.S.3Thompson Erika M.S.3Zhao Li Ph.D.2Patel Keyur M.D., Ph.D.4Neelapu Sattva M.D.5Gumbs Curtis B.S.2Bueso-Ramos Carlos ProfM.D., Ph.D.4DiNardo Courtney D M.D.1Colla Simona Ph.D.1Ravandi Farhad ProfM.D.1Zhang Jianhua Ph.D.28Huang Xuelin Ph.D.6Wu Xifeng ProfM.D., Ph.D.7Samaniego Felipe M.D.5Garcia-Manero Guillermo ProfM.D.1Andrew Futreal P. ProfPh.D.2†1 Department of Leukemia, The University of Texas MD Anderson Cancer\nCenter, Houston, Texas2 Department of Genomic Medicine, The University of Texas MD Anderson\nCancer Center, Houston, Texas3 Department of Genetics, The University of Texas MD Anderson Cancer\nCenter, Houston, Texas4 Department of Hematopathology, The University of Texas MD Anderson\nCancer Center, Houston, Texas5 Department of Lymphoma and Myeloma, The University of Texas MD\nAnderson Cancer Center, Houston, Texas6 Department of Biostatistics, The University of Texas MD Anderson\nCancer Center, Houston, Texas7 Department of Epidemiology, The University of Texas MD Anderson\nCancer Center, Houston, Texas8 Institute of Applied Cancer Science, The University of Texas MD\nAnderson Cancer Center, Houston, Texas9 Department of Hematology and Oncology, Graduate School of Medicine,\nKyoto University, Kyoto, Japan† Correspondence to: P. Andrew Futreal, Ph.D., Department\nof Genomic Medicine, Unit 1954 The University of Texas MD Anderson Cancer, 1515\nHolcombe Boulevard, Houston, TX 77030;\nafutreal@mdanderson.org* These authors contributed equally to this project.\n\n18 3 2017 03 12 2016 1 2017 01 1 2018 18 1 100 111 This manuscript version is made available under the CC BY-NC-ND 4.0\nlicense.Background\nTherapy-related myeloid neoplasms (t-MNs) are often fatal secondary\nmalignancies. Risk factors for t-MNs are not well understood. Recent studies\nsuggested that individuals with clonal hematopoiesis have higher risk of\ndeveloping hematological malignancies. We hypothesized that cancer patients\nwith clonal hematopoiesis have increased risk of developing t-MNs.\n\nMethods\nWe conducted a retrospective case-control study to compare the\nprevalence of clonal hematopoiesis between patients who developed t-MNs\n(cases) and who did not develop t-MNs (control). For cases, we studied14\npatients with various types of cancers who developed t-MNs and whose paired\nsamples of t-MN bone marrow (BM) and peripheral blood (PB) that were\npreviously obtained at the time of primary cancer diagnosis were available.\nFifty four patients with lymphoma who received combination chemotherapy and\ndid not develop t-MNs after at least 5 years of follow up were studied as a\ncontrol. We performed molecular barcode sequencing of 32 genes on the\npre-treatment PB samples to detect clonal hematopoiesis. For the t-MN cases,\nwe also performed targeted gene sequencing on t-MN BM samples and\ninvestigated clonal evolution from clonal hematopoiesis to t-MNs. To confirm\nassociation between clonal hematopoiesis and t-MN development, we also\nanalyzed prevalence of clonal hematopoiesis in a separate cohort of 74\npatients with lymphoma. All of these patients were treated under the\nprospective randomized trial of frontline chemotherapy with\ncyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or\nwithout melatonin and 5 (7%) of them had developed t-MNs.\n\nFindings\nIn 14 patients with t-MNs, we detected pre-leukemic mutations in 10\nof their prior PB samples (71%). In control, clonal hematopoiesis\nwas detected in 17 patients (31%), and the cumulative incidence of\nt-MNs at 5 years was significantly higher in patients with clonal\nhematopoiesis (30% [95% CI: 16% –\n51%] vs. 7% [95% CI: 2%\n– 21%], P = 0.016). In the separate cohort,\n5 patients (7%) developed t-MNs and 4 (80%) of them had\nclonal hematopoiesis. The cumulative incidence of t-MNs at 10 years was\nsignificantly higher in patients with clonal hematopoiesis (29%\n[95% CI: 8%–53%] vs.\n0% [95% CI: 0%–0%],\nP = 0.0009). Multivariate Fine and Gray model showed that having\nclonal hematopoiesis significantly increased the risk of t-MN development\n(HR = 13.7, P = 0.013).\n\nInterpretation\nPre-leukemic clonal hematopoiesis is frequently detected in patients\nwith t-MNs at the time of their primary cancer diagnosis and before patients\nwere exposed to chemotherapy/radiation therapy. Detection of clonal\nhematopoiesis significantly increased the risk of t-MN development in\npatients with lymphoma. These data suggest potential approaches of screening\nclonal hematopoiesis in cancer patients to identify patients at risk of\nt-MNs and warrants a validation in prospective trial investigating a role of\nclonal hematopoiesis as a predictive marker for t-MNs.\n==== Body\nIntroduction\nTherapy-related myeloid neoplasms (t-MNs) are secondary malignancies that\ndevelop in patients who have received cytotoxic chemotherapy and/or ionizing\nradiation therapy.(1, 2) The cumulative incidence of t-MNs is approximately\n1–10% of patients at risk, with an incidence that varies\nsignificantly among different cancer types and treatment regimens.(3–5) t-MNs\nusually develop 3–8 years after exposure to chemotherapy and/or radiation\ntherapy, are frequently associated with poor prognostic features, such as complex\ncytogenetics and TP53 mutations, and respond poorly to conventional\nchemotherapies.(6) Patients with t-MNs\nhave poor outcomes, with an estimated median overall survival of 8–10 months\nand a 5-year overall survival rate of 10–20%.(6–9)\n\nExposure to certain types of chemotherapy is a known treatment-related risk\nfactor for t-MNs. For example, t-MNs occur more frequently in patients who receive\nalkylating agents and topoisomerase II inhibitors than in patients who receive\nantimetabolites or taxanes.(4, 10, 11) Use of a\ngranulocyte colony-stimulating factor (G-CSF) in cancer patients is associated with\nthe risk of t-MNs.(12, 13) High-dose chemotherapy followed by autologous stem\ncell transplant (auto-SCT) has also been shown to increase the risk of t-MNs in\nlymphoma patients.(14) Furthermore, there is\na dose-dependent relationship between the risk of t-MNs and cumulative dose of\nplatinum exposure in patients with ovarian cancer.(15) In contrast, little is known about patient-related risk factors for\nt-MN susceptibility. Older age has been shown to increase the risk of t-MNs, and\nalthough there have been several reports of germline polymorphisms associated with\nrisk, none have been validated.(6, 14, 16–21) In patients with\nlymphoma who underwent auto-SCT, gene expression signature of 38 genes in pre-SCT\nsamples or accelerated shortening of telomere length in post-SCT myeloid cells were\nshown to be associated with t-MNs.(22, 23) Despite these efforts, currently, there is\nno predictive biomarker or risk-stratified approach for early detection or\nprevention of t-MNs.\n\nRecent studies have reported that pre-leukemic mutations, such as mutations\nin DNMT3A, TET2, and ASXL1, can be detected in peripheral blood\n(PB) samples from healthy individuals, a phenomenon referred to as clonal\nhematopoiesis of indeterminate potential (CHIP).(24–28) Compared to\nindividuals without CHIP, those with CHIP were found to have an increased risk of\ndeveloping hematological neoplasms. CHIP was also identified in approximately\n2% of patients with solid tumors analyzed as part of The Cancer Genome Atlas\n(TCGA).(29) Furthermore, pre-leukemic\nTP53 mutations were detectable in peripheral blood (PB) samples\nthat were obtained years before patients developed t-MNs.(30)\n\nThese data collectively suggest that t-MNs arise from antecedent clonal\nhematopoiesis and detection of clonal hematopoiesis at the time of cancer diagnosis\ncould aid in identifying cancer patients at increased risk of developing subsequent\nt-MNs. We addressed these hypotheses by first studying patients with t-MNs with\npaired samples of diagnostic BM at the time of t-MN diagnosis and PB that were\npreviously obtained at the time of primary cancer diagnosis. We then compared the\nprevalence of clonal hematopoiesis between patients who did and did not develop\nt-MNs and confirmed the association between clonal hematopoiesis and t-MN risk in a\nseparate cohort.\n\nMethods\nStudy design and participants\nWe designed a case-control study to compare prevalence of clonal\nhematopoiesis between patients who developed t-MNs (cases) and who did not\ndevelop t-MNs (control). The flow chart summarizes the study design (Figure 1). For cases, we searched our\nclinical database for the patients with diagnosis of t-MNs between 2003 and 2015\nand identified 169 patients with t-MNs. Of those, 14 patients were found to have\nBM samples obtained at the time of t-MN diagnosis and PB samples that were\npreviously obtained at the time of primary cancer diagnosis and before they were\nexposed to chemotherapy and/or radiation therapy. Other 155 t-MN patients did\nnot have prior PB samples available, therefore were not eligible for analysis.\nThe clinical history of these 14 patients is described in the Supplemental Appendix (page\n2–3). To create a control group, we searched 300 patients with lymphoma\nwhose pre-treatment PB samples were available for analysis. We first selected\nthe patients who met the following criteria: 1) received combination\nchemotherapy regimen including alkylating agent, 2) had at least 5 years of\nfollow up and no clinical evidence of t-MN development, and 3) no bone marrow\nmetastasis of lymphoma by bilateral bone marrow biopsy. Seventy seven of 300\npatients (26%) met these criteria. After matching the age with cases in\n1:3 or grater ratio, 54 patients were matched as a control. We chose lymphoma\npatients as a control because they are reported to have the highest risk of\ndeveloping t-MNs(11), they almost always\nreceive alkylating agents with or without topoisomerase II inhibitor containing\nregimens, and they occasionally undergo auto-SCT, thus have sufficient exposures\nto treatment-related risk factors. Next, to confirm the association between\nclonal hematopoiesis and t-MN risk, as a separate cohort, we studied 74 patients\nwith lymphoma who were treated with a frontline randomized trial of\ncyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or\nwithout melatonin (hereafter called external cohort).(31) Pre-treatment PB samples from these patients were\navailable for analysis under an ongoing tissue banking protocol at The\nUniversity of Texas MD Anderson Cancer Center. Written informed consent for\nsample collection and analysis was obtained from all patients. All study\nprotocols adhered to the Declaration of Helsinki and were approved by the\nInstitutional Review Board at MD Anderson (PA15-0400).\n\nProcedures\nTargeted gene sequencing of t-MN BM samples\nWe used a SureSelect custom panel of 295 genes (Agilent Technologies,\nSanta Clara, CA) that are recurrently mutated in hematologic malignancies (Supplemental Appendix,\npage 5). Full details of sequencing and bioinformatics analyses to detect\nhigh-confidence driver mutations are described in the Supplemental Appendix (page 4).\n\nMolecular barcode sequencing of PB samples and detection of clonal\nhematopoiesis\nBecause we expected low variant allele frequency (VAF) for mutations in\nthese samples, we used Haloplex High Sensitivity (HS) technology (Agilent\nTechnologies, Santa Clara, CA), an amplicon-based targeted deep sequencing\nmethod that incorporates more than 1 million unique molecular barcodes and\nallows for consensus calls of low frequency alleles. To avoid bias in calling\nlow-VAF variants, we called variants blindly without any bias for driver\nmutations detected in t-MN BM or clinical outcome of the patients. We applied\nthe same variant calling criteria in all 3 cohorts and bioinformatician who\nperformed variant calling was blinded for clinical outcome. We targeted 32 genes\nthat covered driver mutations detected in t-MN as well as mutations reported as\nclonal hematopoiesis in previous studies (Supplemental Appendix, page\n6).(25, 26, 29) Full\ndetails of the sequencing and bioinformatics algorithms are described in Supplemental Appendix\n(page 4).\n\nStatistical analysis\nThe chi-square or Fisher exact test was used to assess differences in\ncategorical variables, and the Mann-Whitney U test was used to analyze\ncontinuous variables difference after testing normal distribution by\nShapiro-Wilk test. Specifically, distribution of VAF did not follow normal\ndistribution (P = 0.001). Cumulative incidence rate of t-MN development\nover time was compared by Gray test while considering non-t-MN death as a\ncompeting event. Fine and Gray proportional hazard regression model was used to\nevaluate association between t-MN development and other multiple variables.\n\nSince this study was retrospective design and sample size was limited\ndue to the availability of samples, we estimated the power of our study. We\nexpected detection rate of clonal hematopoiesis as 70% for patients who\ndeveloped t-MNs (cases) and 20% for patients who did not develop t-MNs\n(control). The first assumption is based on the result of 14 t-MN paired sample\nanalysis. The second assumption is based on the previous study that analyzed\nTCGA’s data where it reported the prevalence of clonal hematopoiesis in\ngeneral cancer population to be 2%.(29) Since our molecular barcode sequencing had higher sensitivity\nthan whole exome sequencing used in the TCGA study, we assumed that detection\nrate of clonal hematopoiesis in control can be up to 20%. Based on this\nassumption, in case-control study of 68 patients, with 8 years of follow up,\nhazard function was estimated at 0.082 and 0.012 for patients with clonal\nhematopoiesis and for patients without, respectively, which yielded 97%\npower with α error of 0.05. In an external cohort of 74 patients, with\n17 years of follow up, hazard function was estimated at 0.015 and 0.001 for\npatients with clonal hematopoiesis and for patients without, respectively, which\nyielded 86% power with alpha error of 0.05. All statistical analyses\nwere performed using SPSS (version 22; IBM Corporation, Armonk NY) and R (ver.\n3.1.3). The study followed the recommendation by Strengthening The Reporting of\nObservational Studies in Epidemiology (STROBE) Statement checklist.\n\nRole of the funding sources\nThe funders of this study had no role in the study design, data\ncollection, data analysis, data interpretation, and manuscript writing. K.T.,\nF.W., and P.A.F. had access to the raw data. The corresponding author had full\naccess to all of the data and the final responsibility to submit for\npublication.\n\nResults\nClinical characteristics and driver mutations of 14 patients with\nt-MNs\nWe first studied 14 patients with t-MNs for whom paired BM and prior PB\nsamples were available. The clinical characteristics of these patients are shown\nin Table 1. Of the 14 patients, 5\n(31%) had therapy-related acute myeloid leukemia (t-AML) and 9\n(69%) had therapy-related myelodysplastic syndromes (t-MDS). The median\nlatency period from primary cancer diagnosis to t-MN diagnosis was 3 years (IQR:\n2–4 years).\n\nChemotherapy for primary cancers included alkylating agent-containing\nregimens in 10 of 14 patients (71%) and topoisomerase II\ninhibitor-containing regimens in 6 of 14 patients (43%). A high\nproportion of the patients had high-risk cytogenetic abnormalities such as del\n5q/−5 in 4 of 14 patients (29%), del 7q/−7 in 6 of 14\npatients (43%), or complex karyotype in 5 of 14 patients\n(36%).\n\nTargeted gene sequencing of 295 genes of the t-MN BM samples (median\n383x coverage, IQR: 224–584x coverage) revealed 29 driver mutations in\n16 genes in 13 patients (Figure 2). We did\nnot detect any driver point mutations in patient UID984. Consistent with the\nprior data, the most frequently detected driver mutation in t-MN BM was\nTP53 mutation in 5 of 14 patients (36%).(30) The median VAF of driver mutations\ndetected in t-MN BM samples was 26.2% (IQR: 18–41%).\n\nPre-leukemic driver mutations are detectable at the time of cancer diagnosis\nand before therapy\nWe next studied whether t-MN driver mutations could be detected in the\nPB samples that were previously obtained at the time of primary cancer\ndiagnosis. PB samples obtained at the time of primary cancer diagnosis were\nsequenced using molecular barcode deep sequencing of 32 genes (median coverage\n1,446x, IQR: 315–3,138x coverage). Among 29 driver mutations detected in\n13 t-MN BM samples, 21 mutations (72%) were detectable as pre-leukemic\nclonal hematopoiesis in 10 patients’ prior PB samples (77%,\nTable 2). The median VAF of driver\nmutations detected in prior PB samples was 8.5% (IQR:\n3.9–19.9%). Patient UID31000 had two TP53\nmutations with stable VAF around 50% in both samples, and these were\nalso detected in skin fibroblasts, which confirmed a germline origin (this case\nwas confirmed as Li-Fraumeni Syndrome and is described elsewhere(32)). Therefore, these 2 TP53\nmutations were removed from further analysis. Of note, this patient also had a\nsomatic TET2 mutation as clonal hematopoiesis, and it later\nbecame a driver in the t-MN BM.\n\nWe also expanded our analysis to other mutations including non-drivers\nand mutations that were lost from prior PB samples (Supplemental Appendix, page 14). We\ndetected 12 mutations in prior PB samples that were not detected in t-MN BM\nsamples. There were also 8 other mutations in prior PB samples that were\ndetected in t-MN BM but with small VAF and not designated as drivers. The VAF\nwas significantly higher in the mutations that became drivers than in the\nmutations that did not become drivers (8.5% [IQR:\n3.9–19.9%] vs. 1.2% [IQR:\n0.6–1.2%], P < 0.0001; Supplemental Appendix, page 15).\nThese results implicate the clonal selection process under the selective\npressure of chemotherapy with or without radiation therapy.\n\nAll 14 patients had normal blood counts and no clinical evidence of\nleukemia at the time of primary cancer diagnosis. Of note, 3 patients (UID17285,\nUID19684, and UID12484) had bilateral bone marrow biopsies as part of their\nlymphoma staging work-up, and none of them showed morphological evidence of\nleukemia at the time of their lymphoma diagnosis, despite the presence of clonal\nhematopoiesis with relatively high VAF in UID17285 and UID19684.\n\nPrevalence of clonal hematopoiesis in the control cohort\nA high prevalence of pre-leukemic driver mutations in patients who\ndeveloped t-MNs (10 of 14, 71%) suggests that detection of clonal\nhematopoiesis at the time of primary cancer diagnosis may be useful in\nidentifying patients at increased risk of t-MNs. To further explore this, we\nexamined the prevalence of clonal hematopoiesis in pre-treatment PB samples from\nage-matched control cohort of patients with lymphoma who did not develop t-MNs\nafter therapy. The clinical characteristics of the 54 patients in the control\ncohort are described in Supplemental Appendix (page 7) and are compared with those of 14\nt-MN cases. The median age was 58 years (IQR: 49–63 years) and was\nsimilar to that of the 14 t-MN cases (median 62 years [IQR:\n46–65 years], P = 0.62). Because control cohort is\ncomprised of patients with lymphoma, there were some obvious differences in\nclinical characteristics including the difference in primary cancer diagnosis,\nproportion of patients who received alkylating agents or topoisomerase II\ninhibitors, and radiation therapy. Follow up duration was also shorter in\ncontrol cohort (cases vs. control, median 8.9 years [95% CI:\n6.3–11.5 years, IQR: 7.2–9.1 years] vs. 6.1 years\n[95% CI: 6.0–6.3 years, IQR: 5.8–6.2\nyears], P = 0.001). Although there were significant difference\nin each of the clinical characteristics, overall, this control cohort had\nsufficient treatment-related risk factors for t-MNs, because all the patients\nreceived multiple cycles of alkylating agents, 14 of 54 (26%) patients\nreceived radiation therapy, and 6 of 53 (11%) patients underwent for\nauto-SCT.\n\nUsing the same molecular barcode sequencing, we detected 22 mutations in\n17 of 54 (31%) patients’ pre-treatment PB samples (Supplemental Appendix,\npage 8). Overall, patients who developed t-MNs had significantly higher\nincidence of clonal hematopoiesis at the time of cancer diagnosis (71%\nvs. 31%, P = 0.008). The cumulative incidence of t-MNs at 5\nyears was significantly higher in patients with clonal hematopoiesis than in\npatients without (30% [95% CI:\n16–51%] vs. 7% [95% CI:\n2–21%], P = 0.016; Figure 3A). The median VAF of the mutations detected as clonal\nhematopoiesis was significantly higher in the t-MN cases than in the control\n(t-MN cases vs. control, median 2.4% [IQR:\n1%–8.5%] vs. 0.8% [IQR:\n0.5%–1.3%], P = 0.001; Figure 3B).\n\nClonal hematopoiesis increases the risk of t-MNs\nTo confirm the association between clonal hematopoiesis and t-MN\ndevelopment, we sequenced the mononuclear cells of pre-treatment PB (PBMC)\nsamples from 74 patients with lymphoma who received frontline CHOP-based\nchemotherapy as part of a clinical trial (external cohort). The clinical\ncharacteristics of these patients are summarized in Supplemental Appendix (page 9). The\nmedian age of this group was 56 years (IQR: 44–64 years). All patients\nreceived CHOP with or without melatonin as a frontline therapy, and 35 of 74\n(47%) and 16 of 74 (22%) patients received radiation therapy and\nhigh-dose chemotherapy followed by autologous SCT, respectively. The median\nfollow-up duration for this cohort was 14.8 years (95% CI:\n14.5–15.1 years, IQR: 12.2–15.2 years), and 5 of 74 patients\n(7%) developed t-MNs (clinical characteristics are summarized in Supplemental Appendix,\npage 10) with a median latency period of 5.4 years (IQR: 3.3–8.3\nyears).\n\nMolecular barcode sequencing of pre-treatment PBMC samples detected a\ntotal of 17 mutations as clonal hematopoiesis in 15 of 74 patients (23%;\nSupplemental\nAppendix, page 11). Clonal hematopoiesis was detected in 4 of 5\npatients (80%) who developed t-MNs, whereas it was detected in only 11\nof 69 patients (16%) who did not develop t-MNs (P = 0.005). Of\nnote, one patient (UID800699) who developed t-MDS but did not have clonal\nhematopoiesis had an unusually long latency period (12.8 years), raising the\npossibility of a de novo MDS. Nonetheless, the positive predictive value (PPV)\nand negative predictive value (NPV) of clonal hematopoiesis in t-MN development\nwere 26.7% (95% CI: 7.8–55.1%) and 98.3%\n(95% CI: 90.9–99.9%), respectively. The cumulative\nincidence of t-MN development at 10 years was significantly higher in patients\nwith clonal hematopoiesis than in patients without (29%\n[95% CI: 8–53%] vs. 0%\n[95% CI: 0–0%], P = 0.0009;\nFigure 4). Consistent with prior\nstudies, patients who underwent auto-SCT had higher rates of t-MNs at 10 years\nthan patients who did not (19% [95% CI:\n4–41%] vs. 2% [95% CI:\n1–9%], P = 0.003; Supplemental Appendix, page 16).\nAge at the time of lymphoma diagnosis (60 years or older vs. younger) and\nradiation treatment (yes vs. no) did not affect the rate of t-MNs at 10 years\n(Supplemental\nAppendix, page 17–18). In a Fine and Gray model for t-MN\ndevelopment considering clonal hematopoiesis and auto-SCT, both variables\nsignificantly increased the risk of t-MNs (clonal hematopoiesis: HR 13.7\n[95% CI: 1.7–108.7], P = 0.013;\nauto-SCT: HR 10.8 [95% CI: 1.1–107.9], P\n= 0.043; Table 3). There was no\ncorrelation between the two variables (P = 0.29, Supplemental Appendix, page 12). In\nthe external cohort, there was no difference in VAF of clonal hematopoiesis\nbetween patients who developed t-MNs and those who did not (median VAF\n0.4% [IQR: 0.3–1.1%] vs. 0.9%\n[IQR: 0.2–1.9%], P = 0.56).\n\nOverall, in the entire cohort including patients from the case-control\nand external cohort (N = 142), patients with clonal hematopoiesis were\nolder than patients without (median 60 years [IQR: 50–66\nyears] vs. 56 years [IQR: 45–62 years], P\n= 0.028; Supplemental\nAppendix, page 19). Furthermore, RUNX1,\nTP53, SRSF2 and TET2 were\nmore frequently mutated as clonal hematopoiesis in patients who developed t-MNs\ncompared to the patients who did not develop t-MNs (Supplemental Appendix, page\n20).\n\nDiscussion\nIn this study, we have demonstrated that in 10 of 14 patients (71%)\nwith t-MNs, pre-leukemic driver mutations were detectable as clonal hematopoiesis at\nthe time of primary cancer diagnosis. Although clonal hematopoiesis was detected in\nthe control patients who did not develop t-MNs, the prevalence was significantly\nlower (26%). This finding was also confirmed in an external cohort, in which\nthe presence of clonal hematopoiesis significantly increased the risk of t-MNs in a\nmultivariate model, which suggests the potential usefulness of clonal hematopoiesis\nas a clinical biomarker for risk prediction, surveillance, and early detection of\nt-MNs.\n\nEarly detection of myeloid neoplasms has been a challenging task due to the\nlack of a clearly identifiable pre-malignant state. However, the recent discovery of\nCHIP in healthy individuals suggested that myeloid neoplasms have a pre-malignant\ncondition characterized by clonal hematopoiesis and its detection may help identify\nindividuals at risk of developing myeloid neoplasms.(25–27, 29) We explored this hypothesis in the context of t-MNs\nbecause exposures to chemotherapy may further increase the risk of developing t-MNs\nin patients with antecedent clonal hematopoiesis, which could allow us to identify a\npopulation at significant risk of myeloid neoplasms.\n\nIn a case-control study, we found that the VAF of the detected mutations was\nsignificantly higher in patients who went on to develop t-MNs compared to patients\nin the control, which is consistent with the findings in healthy individuals.(25) Similarly, the mutations detected as clonal\nhematopoiesis that became drivers in t-MN BM had higher VAF than the mutations that\ndid not become drivers. These findings were not supported in an external cohort,\nwhich may be a result of the sampling strategy (PBMC) enriching for non-myeloid\ncells (the presumptive lineage of origin for clonal hematopoiesis) as opposed to\nbuffy coats in the first two cohorts. Although, the recent study that compared VAF\nof clonal hematopoiesis in different cellular compartments (myeloid and lymphoid)\nsuggested that clonal hematopoiesis originates from a long term hematopoietic stem\nand progenitor cells and VAF was similar between myeloid and lymphoid cells.(33)\n\nNonetheless, these results suggest that each instance of clonal\nhematopoiesis possesses a different degree of risk for the development of t-MNs, and\nthe risk is influenced by both the mutation and its VAF. In fact, genes such as\nRUNX1 and TP53 were more frequently mutated as\nclonal hematopoiesis in patients who developed t-MNs than in patients who did not.\nClonal hematopoiesis characterized by the above mutations and high VAF may carry\nhigher risk of developing into t-MNs. Further study will be required to better\nunderstand the risk stratification of clonal hematopoiesis. In our study, the PPV of\nclonal hematopoiesis was 26.7% (95% CI: 7.8–55.1%),\nwhereas the NPV was 98.3% (95% CI: 90.9–99.9%). The\nlow PPV of clonal hematopoiesis in this study currently limits its clinical utility\nas a predictive marker. This is likely because we included all detected mutations as\nclonal hematopoiesis. Future studies that define the best predictive VAF cut-off and\nhigh-risk mutations may improve the predictive value of clonal hematopoiesis.\n\nThe prevalence of clonal hematopoiesis in our series was much higher than\nwhat was reported in TCGA patients (approximately 2%).(29) This is likely attributed to the higher sensitivity\nof the molecular barcode deep sequencing method used in our study compared to the\nwhole exome sequencing used in the TCGA data set. It highlights not only how\nfrequent clonal hematopoiesis is when sensitive sequencing methods are used(30, 33)\nbut also the importance of defining clinically relevant clonal hematopoiesis (i.e.,\nhigh-risk clonal hematopoiesis).\n\nNot surprisingly, patients with clonal hematopoiesis in our series were\nsignificantly older than those without. Prior studies have indicated that older age\nis a risk factor for t-MNs.(6, 14, 16) However,\nin our study, age did not affect risk of t-MNs but clonal hematopoiesis did. It is\ncurrently unclear whether age itself or the increased risk of clonal hematopoiesis\nin the elderly plays a larger role in the development of t-MNs.\n\nPreviously, Wong et al. analyzed 7 patients with t-MNs with\nTP53 mutations and found that 4 of them had had identical\nTP53 mutations years before t-MN development.(30) In particular, 2 patients had evidence of\nTP53 mutations prior to therapy. The results presented here\nconfirm and expand upon these data. A substantial fraction of t-MN patients had\nevidence of driver mutations as clonal hematopoiesis before they were treated with\nchemotherapy. These mutations included TP53 as well as other driver\ngenes. Our results raise fundamental questions about the role of chemotherapy and\nradiation therapy in t-MN development. The prevailing hypothesis has been that\ngenotoxic insult from chemotherapy and radiation therapy induces mutations in\nhematopoietic cells, and accumulation of these mutations leads to t-MNs.(34) However, these data from our group and\nothers suggest that ancestral driver mutations pre-exist as clonal hematopoiesis\nbefore exposure to therapy. In the mice model of chimeric bone marrow\ntransplantation, Bondar et al. and Marusyk et al. previously showed that\nTp53+/− hematopoietic cells had\nselective advantage over wild type cells in response to irradiation, which appeared\nto be mediated by decreased radiation induced cellular senescence in the\nTp53+/− cells.(35, 36) Similarly,\nWong et al. showed that\nTp53+/− hematopoietic\ncells had competitive expansion over wild type cells after exposure to\nN-ethyl-N-nitrosourea.(30) In the absence\nof irradiation or chemotherapy, the competitive advantage of mutant cells over wild\ntype cells was minimal. It is likely that clonal hematopoiesis with pre-leukemic\ndriver mutations has clonal advantage over wild type cells but in non-stress\nphysiological state, such advantage is marginal. However, upon exposure to\nchemotherapy and/or radiation therapy, mutated clone demonstrates grater clonal\nadvantage over wild type cells which leads to clonal expansion of mutant cells. In\naddition to the clonal expansion, secondary acquisition of other driver mutations or\nchromosomal aberrations likely contributes to t-MN transformation. In the current\nstudy, we could not identify longitudinal samples between the time from primary\ncancer and t-MN development. Future work in a prospective trial monitoring clonal\ntrajectory over time may provide further insight into the role of chemo-radiation\ntherapy exposure in instigating clonal expansion and secondary alterations that\nfurther drive clonal hematopoiesis to full transformation and ultimately to\nt-MNs.\n\nOur study has several limitations. First, both control and an external\ncohorts are comprised of patients with lymphoma and the prevalence of clonal\nhematopoiesis in these cohorts may not accurately reflect that of patients with\nother cancers. Based on the analysis of TCGA’s data, Xie et al. reported\nthat prevalence of clonal hematopoiesis was not significantly different among\npatients with different cancer types.(29)\nAlthough this study did not include patients with lymphoma, we assume that the\nprevalence of clonal hematopoiesis in our patients with lymphoma is not\nsignificantly different from that of patients with other cancer types. Second,\ncase-control study lacked formal matching procedure and control cohort had\nrelatively short follow up duration. As stated above, difference in primary cancer\ntypes would likely not affect the prevalence of clonal hematopoiesis as long as the\nage is matched. Furthermore, overall treatment-related risk factor should be\nequivalent or even higher in the control cohort because lymphoma patients almost\nuniformly receive alkylating agents and some will even undergo auto-SCT,\nAdditionally, longer follow up of the control cohort would likely not yield\ndifferent conclusion, as the difference in prevalence of clonal hematopoiesis is\nsubstantial (70% vs. 26%) and additional follow up would likely add\nonly 1–2 t-MN development, if it occurs. From these reasons, we believe that\nthe current control cohort can function as a reasonable control. Plus, we believe\nthat the confirmation of the findings in an external cohort which has much longer\nfollow up duration and homogeneous clinical courses would complement these\nlimitations. Third, t-MN sequencing was conducted on whole bone marrow aspirate. Due\nto the inevitable contamination of normal cells, VAF of driver mutations may not\naccurately reflect actual clonality of the mutation. This may explain why some of\nthe driver mutations detected in t-MN samples had less than 50% VAF. Fourth,\nwe could not analyze association between G-CSF use and t-MNs risk in this study. Use\nof G-CSF in cancer patients has been shown as an important risk factor for\nt-MNs.(12,13) We attempted to retrospectively collect data on G-CSF use in the\nsecond cohort. However, because the trial was conducted 17 years ago and did not\nprospectively collect the data on G-CSF use and many patients received chemotherapy\nat outside institution, we could not capture all the data of G-CSF use in this\nstudy. It is of interest to analyze interaction between clonal hematopoiesis and\nG-CSF use and its effect on t-MN risk.\n\nIn summary, pre-leukemic clonal hematopoiesis was frequently detected in\npatients with t-MNs at the time of primary cancer diagnosis and before exposure to\ntherapy. Detection of clonal hematopoiesis significantly increased the risk of t-MN\ndevelopment. These data suggest potential approaches of screening for clonal\nhematopoiesis in cancer patients to identify patients at risk of t-MN development\nand warrants validation in a prospective trial investigating a role of clonal\nhematopoiesis as a risk factor for t-MNs.\n\nSupplementary Material\nsupplement Funding: Cancer Prevention Research Institute of Texas, Welch\nFoundation, UT System STARS Award, Edward P. Evans Foundation, Fundacion Ramon\nAreces, Red and Charline McCombs Institute for the Early Detection and Treatment of\nCancer, Institutional Research Grant at the MD Anderson Cancer Center, NCI Leukemia\nSPORE, Khalifa Scholar Award, NIH through MD Anderson Cancer Center Support Grant,\nand MD Anderson’s MDS/AML Moon Shot Program.\n\nThis study was supported by the Cancer Prevention Research Institute of Texas\n(R120501: PAF and RP100202 GGM), the Welch Foundation (G-0040, PAF), the UT System\nSTARS Award (PS100149: PAF), the Edward P. Evans Foundation (GGM), the Fundacion\nRamon Areces (GGM), the Red and Charline McCombs Institute for the Early Detection\nand Treatment of Cancer Award (KT), an Institutional Research Grant at the MD\nAnderson Cancer Center (KT), NCI Leukemia SPORE Career Development Grant (KT),\nKhalifa Scholar Award (KT), National Institute of Health (NIH) through the MD\nAnderson Cancer Center Support Grant P30 CA016672, and by generous philanthropic\ncontributions to MD Anderson’s MDS/AML Moon Shot Program (KT, HK, GGM, and\nPAF). We would like to thank Zachary Bohannan and Joseph Munch for their\nprofessional input on the manuscript.\n\nConflict of interest disclosures\n\nAuthors have no conflicts of interest to declare.\n\nAuthor contributions\n\nKT, GGM, and AF designed the study, analyzed data, and wrote the manuscript. FW\nand JZ performed bioinformatics analysis and wrote the manuscript. LZ and XH\nassisted statistical analysis. KT, CDD, FR, HK, FS and GGM treated patients and\ncollected patients’ sample. DD, KK, ET and CG performed sequencing. CBR\nand KPT performed pathological diagnosis. KP, SP, YW, FS and XW provided\nsamples. SC analyzed data and wrote manuscript. HK, GGM and AF provided\nleadership and managed the study team. All authors read and approved the\nmanuscript.\n\nThis is a PDF file of an unedited manuscript\nthat has been accepted for publication. As a service to our customers we are\nproviding this early version of the manuscript. The manuscript will undergo\ncopyediting, typesetting, and review of the resulting proof before it is\npublished in its final citable form. Please note that during the production\nprocess errors may be discovered which could affect the content, and all legal\ndisclaimers that apply to the journal pertain.\n\nFigure 1 Flow chart summarizing the sample selection process.\n\nFigure 2 Landscape of high-confidence driver mutations detected in diagnostic BM samples\nfrom patients with t-MNs. Only 13 cases are shown because UID984 did not have\nany detectable driver mutations. Asterix indicates double mutations in one\ngene.\n\nFigure 3 (A) Cumulative incidence of t-MN development between patients with\nor without clonal hematopoiesis in a case-control study. (B) Box\nplot comparing the VAF of mutations detected as clonal hematopoiesis between\npatients who developed t-MNs and those who did not (control) (median\n2.4% [IQR: 1%–8.5%] vs.\n0.8% [IQR: 0.5%–1.3%], P\n= 0.001).\n\nFigure 4 Cumulative incidence of t-MN development between patients with or without clonal\nhematopoiesis in an external cohort.\n\nTable 1 Clinical characteristics of the 14 patients with therapy-related myeloid\nneoplasms (t-MNs). UID indicates de-identified unique patient identification\nnumber.\n\nUID\tAge at primary cancer\tGender\tPrimary Cancer\tChemotherapy\tRadiation therapy\tLatency to t-MN (years)\tAge at t-MN\tt-MN diagnosis\tCytogenetics in t-MN bone marrow\t\nUID12766\t55\tMale\tColon adenocarcinoma\t5-FU, Oxaliplatin\t-\t4\t59\tt-AML\tNormal\t\nUID984\t63\tMale\tEsophageal adenocarcinoma\t5-FU, Docetaxel\t50 Gy\t7\t70\tt-MDS\t46~47,XY,+X,del(7)(\nq11.2),r(7),add(9)(q12)\t\nUID10164\t50\tFemale\tMalignant peripheral nerve sheath\ntumor\tDoxorubicin, Ifosphamide\t-\t1\t51\tt-MDS\t46,XX,+1,der(1;7)(q10;p10)\t\nUID6982\t70\tMale\tSmall Cell Lung Cancer\tCisplatin, Etoposide\t70 Gy\t3\t73\tt-AML\t46,XY,del(5)(q15q33)\t\nUID488\t47\tFemale\tNSCLC\tCarboplatin, Paclitaxel, Gemcitabine,\nVinorelbine\t50 Gy\t8\t55\tt-MDS\tNormal\t\nUID36491\t62\tMale\tSmall cell lung and NSCLC\tCisplatin, Etoposide, Carboplatin,\nPaclitaxel\t70 Gy\t4\t66\tt-MDS\t42,X,-Y,del(1)(q21),del(7)(q\n22q34),del(14)(q12q21),−16,−18,−21,−22,−\n22,\t\nUID4473\t44\tMale\tRectal adenocarcinoma\tCapecitabine\t50 Gy\t6\t50\tt-MDS\tNormal\t\nUID17285\t69\tMale\tHodgkin lymphoma\tDoxorubicin, Bleomycin, Vinblastine,\nDacarbazine\t-\t2\t71\tt-MDS\t45,XY,add(2)(p12),−5,−7,t(11;17)(q13;p11.2),+mar\t\nUID19684\t63\tMale\tFollicular lymphoma\tRituximab, Cyclophosphamide, Doxorubicin,\nVincristine, Prednisone\t-\t3\t66\tt-MDS\t46,XY,−7,+22\t\nUID7394\t74\tMale\tPenile Squamous cell cancer\tPaclitaxel, Ifosphamide, Cisplatin,\nCapecitabine\t65 Gy\t3\t77\tt-MDS\t46,XY,del(5)(q13q33),\n46,XY,der(3;5)(q10;p10),+8\t\nUID49278\t63\tMale\tLung adenocarcinoma\tCarboplatin, pemetrexed\t66 Gy\t1\t64\tt-AML\t45,X,-Y\t\nUID12484\t64\tMale\tMantle Cell Lymphoma\tBortezomib, Rituximab, Cyclophosphamide,\nVincristine, Doxorubicin, Cytarabine, Methotrexate, Ibrutinib\t-\t2\t66\tt-AML\t45,XY,der(7;17)(p10; q10)\t\nUID19304\t25\tFemale\tGliobastoma multiforme\tTemozolamide\t60 Gy\t3\t28\tt-MDS\t46,XX,inv(3)(q21q26.2)\t\nUID31000**\t40\tMale\tRhabdomyos arcoma\tIfosphamide, Adriamycin\t50 Gy\t3\t43\tt-AML\t44,XY,del(5)(q13),add(7)(q11.2),−11,−12,−17,−17,+r,+mar\t\n* UID: Unique patient ID,\n\nNSCLC: Non small cell lung cancer, t-MN: therapy-related myeloid\nneoplasms.\n\n** The case was later confirmed to have Li-Fraumeni Syndrome\n\nTable 2 Summary of the changes of variant allele frequency (VAF) of driver mutations from\nthe time of primary cancer diagnosis to the time of of t-MN diagnosis. Only 13\ncases are shown because UID984 did not have any driver mutations detected.\nEleven of 13 patients (85%) had evidence of detectable driver mutations\nin PB samples obtained at the time of primary cancer diagnosis. Variants that\nwere not detected in prior PB samples are indicated as ND (not detected). For\neach variant detected in the prior PB samples, depth of sequencing at the given\nallele and binomial P value of the variant are listed.\n\nPatient ID\tGene\tAA Change\tVAF Primary Cacner (%)\tVAF t-MNs (%)\tDepth Primary Cancer (x)\tBinomial P value\t\nUID12766\tWT1\tp.S381X\tND\t14.75\t2197\tNA\t\nUID10164\tRUNX1\tp.L98fs\t3.69\t23.27\t1463\t2.20E-16\t\nUID6982\tIDH2\tp.R140Q\t15.83\t45.51\t2502\t2.20E-16\t\n\tSRSF2\tp.P95delinsRP\t13.76\t25.32\t872\t2.20E-16\t\nUID488\tDNMT3A\tp.R882P\t19.93\t33.14\t1612\t2.20E-16\t\nUID36491\tIDH2\tp.R172K\tND\t15.46\t2300\tNA\t\n\tTP53\tp.H193R\t22.31\t73.09\t2627\t2.20E-16\t\nUID4473\tTET2\tp.L1212X\t5.29\t45.34\t1286\t2.20E-16\t\nUID17285\tTET2\tp.Y1255X\t8.45\t18.06\t568\t2.20E-16\t\n\tTP53\tp.Y205C\t8.57\t22.31\t2008\t2.20E-16\t\n\tU2AF1\tp.Q157P\t3.92\t11.73\t2578\t2.20E-16\t\nUID19684\tDNMT3A\tp.R882C\t18.85\t47.06\t1920\t2.20E-16\t\n\tNRAS\tp.G13V\t7.65\t8.82\t1424\t2.20E-16\t\n\tPTPN11\tp.G60V\t4.31\t14.81\t881\t2.20E-16\t\nUID7393\tKRAS\tp.G12A\tND\t10.28\t389\tNA\t\n\tNRAS\tp.G13R\tND\t17.1\t1715\tNA\t\n\tTP53\tp.Y107X\t0.92\t97.16\t3058\t2.20E-16\t\nUID49278\tFLT3\tp.D593delinsEAPGEVD\t0.98\t22.45\t1636\t2.20E-16\t\n\tGNB1\tp.K57E\t28.53\t37.79\t1623\t2.20E-16\t\n\tKDM6A\tp.R658X\t1.19\t72.12\t672\t6.36E-12\t\n\tRAD21\tp.E553X\tND\t41.2\t198\tNA\t\n\tRUNX1\tp.G165fs\tND\t20.66\t939\tNA\t\n\tRUNX1\tp.R204X\t0.68\t30.67\t1629\t1.23E-12\t\n\tSRSF2\tp.P85H\t36.92\t33.58\t1154\t2.20E-16\t\nUID12484\tTP53\tp.L194H\tND\t41.97\t1723\tNA\t\nUID19304\tGATA2\tp.Y322_M325de linsW\tND\t33.7\t3172\tNA\t\nUID31000\tTET2\tp.H1380Y\t8.74\t21.21\t2093\t2.20E-16\t\n\tTP53\tp.R156H\t54.14\t58.64\t1620\t2.20E-16\t\n\tTP53\tp.R267Q\t42.11\t52.46\t1850\t2.20E-16\t\nTable 3 Fine-Gray proportional hazard regression model for t-MN development.\n\nFull model\tHR (95% CI)\tP – value\tReduced model\tHR (95% CI)\tP-value\t\nClonal hematopoiesis (vs.\nno)\t14.0 (1.4 – 136.4)\t0.023\tClonal hematopoiesis (vs.\nno)\t13.7 (1.7– 108.7)\t0.013\t\nAuto-SCT (vs. no)\t9.2 (0.6–150.5)\t0.12\tAuto-SCT (vs. no)\t10.8 (1.1– 107.9)\t0.043\t\nXRT (vs. no)\t0.6 (0.08–4.0)\t0.56\t\t\t\t\nAge ≥ 60 years (vs. < 60\nyears)\t0.7 (0.07–6.3)\t0.73\t\t\t\t\n* HR: Hazard ratio, CI: Confidence interval, SCT: Stem cell transplant, XRT:\nRadiation therapy\n\nResearch in context\nEvidence before this study\nWe searched PubMed for reviews and research articles published in\nEnglish before June, 2016, about therapy-related myeloid neoplasms (t-MNs) and\ntheir risk factors. We used the following keywords: “therapy-related\nmyeloid neoplasms”, “t-MNs”, “t-MDS”,\n“t-AML”, and “risk factors”. There are several\nknown treatment-related risk factors for t-MNs, including exposures to\nalkylating agents, topoisomerase 2 inhibitors, and high dose chemotherapy with\nautologous stem cell transplant. In contrast, little is known about host\nsusceptibility. Older age was shown to increase the risk of t-MNs. Several\ngermline polymorphisms have also been associated with the risk, but none of them\nwere validated. As such, there is no predictive biomarker for t-MNs.\n\nAdded value of this study\nPre-leukemic clonal hematopoiesis was frequently detected in cancer\npatients who subsequently developed t-MNs, and it was detected at the time of\ntheir primary cancer diagnosis and before any therapy was given. Patients with\npre-leukemic clonal hematopoiesis had significantly higher risk of developing\nt-MNs than patients without clonal hematopoiesis.\n\nImplications of all the available evidence\nCancer patients with pre-leukemic clonal hematopoiesis have increased\nrisk of developing t-MNs. 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2012 44 11 1179 81 23001125 \n25 Jaiswal S Fontanillas P Flannick J Age-related clonal hematopoiesis associated with adverse\noutcomes The New England journal of medicine 2014 371 26 2488 98 25426837 \n26 Genovese G Kahler AK Handsaker RE Clonal hematopoiesis and blood-cancer risk inferred from blood\nDNA sequence The New England journal of medicine 2014 371 26 2477 87 25426838 \n27 Steensma DP Bejar R Jaiswal S Clonal hematopoiesis of indeterminate potential and its\ndistinction from myelodysplastic syndromes Blood 2015 126 1 9 16 25931582 \n28 McKerrell T Park N Moreno T Leukemia-associated somatic mutations drive distinct patterns of\nage-related clonal hemopoiesis Cell Rep 2015 10 8 1239 45 25732814 \n29 Xie M Lu C Wang J Age-related mutations associated with clonal hematopoietic\nexpansion and malignancies Nature medicine 2014 20 12 1472 8 \n30 Wong TN Ramsingh G Young AL Role of TP53 mutations in the origin and evolution of\ntherapy-related acute myeloid leukaemia Nature 2015 518 7540 552 5 25487151 \n31 Sarma A Rodriguez MA Cabanillas F A randomized trial of CHOP chemotherapy with or without melatonin\nin patients with favorable prognosis large B-cell lymphoma Journal of Clinical Oncology 2004 22 14 745s-s \n32 DiNardo CD Bannon SA Routbort M Evaluation of patients and families with concern for\npredispositions to hematologic malignancies within the Hereditary\nHematologic Malignancy Clinic (HHMC) Clinical Lymphoma Myeloma and Leukemia 2016 16 7 417 28 \n33 Young AL Challen GA Birmann BM Druley TE Clonal haematopoiesis harbouring AML-associated mutations is\nubiquitous in healthy adults Nat Commun 2016 7 12484 27546487 \n34 Bhatia S Therapy-related myelodysplasia and acute myeloid\nleukemia Semin Oncol 2013 40 6 666 75 24331189 \n35 Bondar T Medzhitov R p53-mediated hematopoietic stem and progenitor cell\ncompetition Cell Stem Cell 2010 6 4 309 22 20362536 \n36 Marusyk A Porter CC Zaberezhnyy V DeGregori J Irradiation selects for p53-deficient hematopoietic\nprogenitors PLoS Biol 2010 8 3 e1000324 20208998\n\n",
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"issue": "18(1)",
"journal": "The Lancet. Oncology",
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"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D002999:Clone Cells; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006410:Hematopoiesis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015994:Incidence; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes; D009367:Neoplasm Staging; D009369:Neoplasms; D016609:Neoplasms, Second Primary; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate; D013781:Texas",
"nlm_unique_id": "100957246",
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"pmid": "27923552",
"pubdate": "2017-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
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"title": "Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study.",
"title_normalized": "preleukaemic clonal haemopoiesis and risk of therapy related myeloid neoplasms a case control study"
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"abstract": "OBJECTIVE\nThe COSMOS study was a phase 2a clinical trial that showed high cure rates of genotype 1 chronic hepatitis C (CHC) and a favorable side effect profile using a 12-week regimen of simeprevir + sofosbuvir (SIM + SOF). Given the small number of patients treated with the SIM + SOF regimen in the COSMOS trial, there is uncertainty regarding the efficacy and safety of this combination therapy. We now report our experience with the COSMOS regimen in the multiethnic population of Hawaii, including patients of East Asian ancestry and with decompensated cirrhosis.\n\n\nMETHODS\nThis study is a retrospective review of 138 patients treated with a fixed dose regimen of SIM 150 mg and SOF 400 mg daily at a single referral center. We collected data on demographics, side effects, laboratory studies and sustained virological response (SVR). Statistical analysis was performed with Stata v8.2 software.\n\n\nRESULTS\nBaseline characteristics of the 138 patients initiated with SIM + SOF therapy were: 68.8 % cirrhotic (22.1 % of those Child-Pugh Class B), 37 % Asian, 11.6 % Pacific Islander, 63 % male, mean age 61.3 ± 7.8 years, mean BMI 27.8 ± 6.1 kg/m(2), 26.8 % diabetic, 63.8 % genotype 1a, 44.9 % previously treatment experienced. A total of 100 % of patients that completed therapy (n = 137) had undetectable viral loads at end of treatment (EOT). Twelve patients relapsed post-treatment resulting in an overall 12 week SVR (SVR12) rate of 89.1 %. 95 % of decompensated cirrhotic patients achieved SVR12, compared to 85.3 % of compensated cirrhotic patients and 93 % of non-cirrhotic patients. 92 % of Asian patients achieved SVR12 compared to 87.5 % in non-Asian patients. There were no statistically significant differences in SVR12 between treatment naive and treatment experienced patients (86.8 vs 91.9 %). 87.5 % of post-transplant patients achieved SVR12. The main side effects were headache 16.2 %, fatigue 24.2 %, pruritis 14.1 %; none were >grade 2 in severity. There were no differences in side effect profiles of patients with decompensated cirrhosis. Pruritis only was statistically significant between Asians and non-Asians (22 vs 5.7 %). Trends toward improvement in platelet counts and total bilirubin were noted at 12-weeks post treatment, while improvement in albumin in cirrhotic patients reached statistical significance (3.77-4.01 mg/dL, p = 0.0108).\n\n\nCONCLUSIONS\nThe 12-week fixed dose course of SIM + SOF was well tolerated in a multiethnic population of primarily cirrhotic patients, including those with decompensated disease. This real world trial achieved SVR12 rates comparable to the COSMOS data. Higher incidence of adverse side effects was not observed with an exception of higher rate of pruritis in Asians. The increase in albumin in cirrhotic patients was statistically significant and suggested early improvement in synthetic function following viral eradication. Higher BMI (≥30 kg/m(2)) was the only factor that correlated with post-treatment relapse by multivariate analysis.",
"affiliations": "Liver Center, Queen's Medical Center, Honolulu, HI, USA.;Department of Medicine, John A. Burns School of Medicine, Honolulu, HI, USA. resham@hawaii.edu.;Department of Medicine, John A. Burns School of Medicine, Honolulu, HI, USA.;Liver Center, Queen's Medical Center, Honolulu, HI, USA.;Liver Center, Queen's Medical Center, Honolulu, HI, USA.;Liver Center, Queen's Medical Center, Honolulu, HI, USA.;Liver Center, Queen's Medical Center, Honolulu, HI, USA.;Liver Center, Queen's Medical Center, Honolulu, HI, USA.;Liver Center, Queen's Medical Center, Honolulu, HI, USA.;Liver Center, Queen's Medical Center, Honolulu, HI, USA.",
"authors": "Roytman|Marina|M|;Ramkissoon|Resham|R|;Wu|Christina|C|;Hong|Leena|L|;Trujillo|Ruby|R|;Huddleston|Leslie|L|;Poerzgen|Peter|P|;Seto|Todd|T|;Wong|Linda|L|;Tsai|Naoky|N|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D000069616:Simeprevir",
"country": "United States",
"delete": false,
"doi": "10.1007/s12072-016-9719-4",
"fulltext": null,
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"issn_linking": "1936-0533",
"issue": "10(4)",
"journal": "Hepatology international",
"keywords": "Decompensated cirrhosis; East-Asian; Hepatitis C; Simeprevir + sofosbuvir; Treatment",
"medline_ta": "Hepatol Int",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D044466:Asians; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004333:Drug Administration Routes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012254:Ribavirin; D000069616:Simeprevir; D016896:Treatment Outcome",
"nlm_unique_id": "101304009",
"other_id": null,
"pages": "616-23",
"pmc": null,
"pmid": "27026431",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article",
"references": "23470616;25078309;21745274;19814621;20069649;24928290;25821099;21319189;16702586",
"title": "Examining the clinical course of genotype 1 chronic hepatitis C patients treated with the cosmos regimen: including patients with advanced liver disease and East Asian ancestry.",
"title_normalized": "examining the clinical course of genotype 1 chronic hepatitis c patients treated with the cosmos regimen including patients with advanced liver disease and east asian ancestry"
} | [
{
"companynumb": "US-JNJFOC-20160720449",
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"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
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{
"abstract": "BACKGROUND\nHepatitis B and C coinfection is commonly seen in clinical practice. In coinfected individuals, high levels of hepatitis C viremia are often associated with low levels of serum hepatitis B DNA. Hepatitis B reactivation in hepatitis C-infected patients treated with pegylated interferon and ribavirin has been reported, but severe or fulminant reactivation is uncommon. Hepatitis C treatment-associated hepatitis B reactivation in patients with chronic hepatitis C and isolated core antibody has not been reported previously.\n\n\nMETHODS\nA 59-year-old white woman with chronic hepatitis C genotype 1B and isolated hepatitis B core antibody initiated treatment with simeprevir, sofosbuvir, and ribavirin for treatment of chronic hepatitis C. She responded very well to treatment initially with near normalization of aminotransferases and hepatitis C viral load suppressed to below the level of quantification after 4 weeks of treatment. At week 11 of a planned 12-week course, she developed fulminant hepatic failure due to hepatitis B reactivation and ultimately required liver transplantation. Fortunately, her posttransplant clinical course was unremarkable.\n\n\nCONCLUSIONS\nThis is the first report of hepatitis B reactivation in a patient with isolated hepatitis B core antibody leading to fulminant hepatic failure and liver transplantation after initiation of treatment with sofosbuvir, simeprevir, and ribavirin for hepatitis C. This case raises the concern for the risk of severe hepatitis B reactivation in hepatitis B and C-coinfected patients or chronic hepatitis C-infected patients with isolated hepatitis B core antibody treated with direct-acting antiviral drugs for hepatitis C.",
"affiliations": "Department of Medicine, Division of Gastroenterology and Hepatology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA, 98195, USA. aende@medicine.washington.edu.;Department of Medicine, Division of Infectious Disease, University of Washington, 1959 Northeast Pacific Street, Seattle, WA, 98195, USA. hyangkim@uw.edu.;Department of Pathology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA, 98195, USA. myeh@u.washington.edu.;Department of Medicine, Division of Gastroenterology and Hepatology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA, 98195, USA. JHarper@medicine.washington.edu.;Department of Medicine, Division of Gastroenterology and Hepatology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA, 98195, USA. clandis@medicine.washington.edu.",
"authors": "Ende|Alexander R|AR|;Kim|Nina H|NH|;Yeh|Matthew M|MM|;Harper|Jason|J|;Landis|Charles S|CS|",
"chemical_list": "D000998:Antiviral Agents; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-015-0630-8",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 63010.1186/s13256-015-0630-8Case ReportFulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report Ende Alexander R. aende@medicine.washington.edu Kim Nina H. hyangkim@uw.edu Yeh Matthew M. myeh@u.washington.edu Harper Jason JHarper@medicine.washington.edu Landis Charles S. clandis@medicine.washington.edu Department of Medicine, Division of Gastroenterology and Hepatology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195 USA Department of Medicine, Division of Infectious Disease, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195 USA Department of Pathology, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195 USA 28 7 2015 28 7 2015 2015 9 16416 12 2014 29 5 2015 © Ende et al. 2015\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nHepatitis B and C coinfection is commonly seen in clinical practice. In coinfected individuals, high levels of hepatitis C viremia are often associated with low levels of serum hepatitis B DNA. Hepatitis B reactivation in hepatitis C-infected patients treated with pegylated interferon and ribavirin has been reported, but severe or fulminant reactivation is uncommon. Hepatitis C treatment-associated hepatitis B reactivation in patients with chronic hepatitis C and isolated core antibody has not been reported previously.\n\nCase presentation\nA 59-year-old white woman with chronic hepatitis C genotype 1B and isolated hepatitis B core antibody initiated treatment with simeprevir, sofosbuvir, and ribavirin for treatment of chronic hepatitis C. She responded very well to treatment initially with near normalization of aminotransferases and hepatitis C viral load suppressed to below the level of quantification after 4 weeks of treatment. At week 11 of a planned 12-week course, she developed fulminant hepatic failure due to hepatitis B reactivation and ultimately required liver transplantation. Fortunately, her posttransplant clinical course was unremarkable.\n\nConclusions\nThis is the first report of hepatitis B reactivation in a patient with isolated hepatitis B core antibody leading to fulminant hepatic failure and liver transplantation after initiation of treatment with sofosbuvir, simeprevir, and ribavirin for hepatitis C. This case raises the concern for the risk of severe hepatitis B reactivation in hepatitis B and C-coinfected patients or chronic hepatitis C-infected patients with isolated hepatitis B core antibody treated with direct-acting antiviral drugs for hepatitis C.\n\nKeywords\nHepatitis BHepatitis CSimeprevirSofosbuvirFulminant liver failureLiver transplantHepatitis B reactivationissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nSofosbuvir and simeprevir were approved by the Food and Drug Administration (FDA) for treatment of chronic hepatitis C virus (HCV) in 2013. Sofosbuvir is a novel nucleotide analogue inhibitor of the hepatitis C virus NS5B polymerase with potent antiviral activity. Simeprevir is a second-generation inhibitor of the hepatitis C NS3/4A protease. The combination of these agents for treatment of chronic hepatitis was rapidly adopted because of improved safety, tolerability and efficacy compared with prior pegylated interferon (Peg-IFN)-based treatments [1].\n\nA large proportion of HCV-infected patients, as high as 61.5% in one study [2], have evidence of prior exposure to hepatitis B virus (HBV) with the profile of an isolated core antibody [2–6]. Here we report the first case of HBV reactivation in a patient with isolated HBV core antibody (HBcAb) leading to fulminant hepatic failure and liver transplantation following treatment with simeprevir, sofosbuvir, and ribavirin for HCV.\n\nCase presentation\nA 59-year-old white woman with chronic HCV genotype 1B had initiated treatment with simeprevir, sofosbuvir, and ribavirin. She had been treated with standard interferon and ribavirin in the remote past with no response. She also had a history of Burkitt’s lymphoma in remission for 2 years. Her pretreatment laboratory test results were remarkable for aspartate aminotransferase (AST) 235 and alanine transaminase (ALT) 168U/L. She had a liver biopsy 8 months prior to presentation showing grade 1 inflammation and stage 2/4 fibrosis with histopathologic features of both chronic HCV and nonalcoholic steatohepatitis (Fig. 1a, b). Immunohistochemistry for HBV surface and core antigens in her liver biopsy specimen were negative. Her serum HBV surface antigen (HBsAg) was nonreactive at that time with reactive core antibody but absent surface antibody. A HBV deoxyribonucleic acid (DNA) level measured 2 years prior to this presentation was undetectable. Her 4-week HCV level was less than 12IU/mL with AST and ALT approaching normal at 38 and 31U/L, respectively. Her ribavirin was discontinued at that time because of anemia.Fig. 1 \na Low-power magnification of a biopsy specimen from 8 months prior to presentation shows chronic hepatitis with mild steatosis, and mild portal and lobular inflammation. b High-power magnification of specimen in (a) demonstrates the component of steatohepatitis, composed of areas of steatosis, ballooned hepatocytes, and lobular inflammation. c and d Diagnostic core needle biopsy performed one week before liver transplantation shows hepatocytes with positive immunohistochemical nuclear staining for hepatitis B virus core antigen (c) and positive immunohistochemical cytoplasmic staining for hepatitis B virus surface antigen (d). Arrows in (c) and (d) indicate examples of positive immunohistochemical staining. Immunohistochemistry for hepatitis B virus surface antigen was negative on a liver biopsy specimen obtained 8 months prior to presentation (not shown). e Core needle biopsy performed 1 week before liver transplantation shows severe hepatitis with bridging and confluent necrosis, marked inflammation, and ductular reaction. f High-magnification view of liver explant specimen shows confluent necrosis and bridging necrosis with bile ductular reaction and cholestasis\n\n\n\nAt week 11 of a planned 12-week course, she was found to have ALT 2263U/L, AST 2870U/L, total bilirubin of 9.1mg/dL and an international normalized ratio (INR) of 1.9. Repeat HBV serologies revealed a positive HBsAg and a viral load of 29,000,000IU/mL. Her HCV viral load was undetectable. A transjugular liver biopsy revealed severe hepatitis with confluent necrosis, marked portal and lobular inflammation, many apoptotic bodies, and extensive periportal and pericellular fibrosis (Fig. 1e). HBV surface and core antigens were identified on immunohistochemistry (Fig. 1c, d).\n\nTenofovir was started on day 3 of presentation for treatment of HBV. Despite treatment, she became increasingly encephalopathic with a rising INR and was transferred to the intensive care unit. She underwent liver transplantation 10 days into her hospital admission. Her posttransplant course was unremarkable and she was discharged home 1 week posttransplant. The liver explant pathology showed an area of confluent necrosis with extensive reticular collapse with no diagnostic evidence of lymphoma (Fig. 1f). Her HCV viral load was tested at 12 and 24 weeks posttransplant and has remained undetectable. HBV remains suppressed with ongoing tenofovir therapy.\n\nDiscussion\nApproximately 350 million people are infected with HBV and 170 million people are infected with HCV worldwide. The exact number of patients infected with both HCV and HBV is unknown, but estimates of the rates of HCV coinfection in individuals with HBV (HBsAg positive) vary from 9 to 30 %, depending on geographic region [7]. The incidence of isolated HBcAb in HCV-infected individuals is likely even higher because screening programs often only test for HBsAg [2, 3].\n\nSeveral studies have shown that the HBV and HCV interact with each other and HCV infection can suppress HBV replication [2]. Coinfected patients commonly have lower HBV DNA levels, and decreased hepatic expression of HBsAg and HBV core antigen compared to HBV monoinfected patients [2–7]. In addition, in vitro studies have also shown evidence that HCV can suppress HBV replication [2]. This has led to the hypothesis of reciprocal interaction between viruses where HBV replication is inhibited by HCV. Hence, the potential for reactivation of HBV following HCV treatment has long been a concern.\n\nWe are not aware of any data or reports of HBV reactivation with the recently approved direct-acting antivirals for HCV. However, HBV reactivation with Peg-IFN and ribavirin treatment has been reported in patients chronically coinfected with HBV and HCV. One report documented the reappearance of HBV DNA in 38% of HBV/HCV-coinfected patients during Peg-IFN/ribavirin treatment [8]. However, no clinical hepatitis developed and HBsAg seroconversion occurred in 30% of patients, suggesting that interferon-based therapy suppresses both viruses. We are not aware of any studies describing treatment-associated HBV reactivation in patients with chronic HCV and isolated HBcAb.\n\nBoth Peg-IFN and ribavirin have been shown to be effective treatments for chronic HBV infection [8–10] and Peg-IFN is currently an approved treatment for chronic active HBV infection [9]. Until recently, standard of care for HCV treatment included both Peg-IFN and ribavirin. However, newly approved direct-acting antivirals, such as simeprevir and sofosbuvir are specifically directed to inhibit HCV replication and can be used in combination without Peg-IFN [1]. These new agents, unlike Peg-IFN and ribavirin, should not have any inhibitory effect on HBV. Therefore, using these agents in the absence of Peg-IFN may bring about increased risk for HBV reactivation in HCV/HBV-coinfected patients. Furthermore, we reason that this case represents evidence to support the theory of reciprocal HCV/HBV interaction most frequently characterized by an inhibition of HBV replication by HCV. With the potential inhibitory effect of chronic HCV on HBV eliminated with oral antiviral treatment in our patient, HBV replication was no longer restricted leading to fulminant HBV reactivation necessitating liver transplantation.\n\nConclusions\nThis case raises concern for the safety of new direct-acting antiviral drugs in patients coinfected with HBV and HCV, or in those who have chronic HCV infection and isolated HBcAb. It remains unclear whether HBV booster immunization may have prevented this episode [11]. Close monitoring of aminotransferases and/or HBsAg or HBV DNA levels may be warranted in such patients during oral interferon-free direct-acting antiviral therapy.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nALTAlanine transaminase\n\nASTAspartate aminotransferase\n\nDNADeoxyribonucleic acid\n\nFDAFood and Drug Administration\n\nHbHemoglobin\n\nHBcAbHBV core antibody\n\nHBsAbHBV surface antibody\n\nHBsAgHBV surface antigen\n\nHBVHepatitis B virus\n\nHCVHepatitis C virus\n\nINRInternational normalized ratio\n\nPeg-IFNPegylated interferon\n\nRNARibonucleic acid\n\nCompeting interests\n\nDr. Charles Landis currently receives grant/research funding from Gilead, the manufacturer of sofosbuvir.\n\nAuthors’ contributions\n\nAE and CL drafted the manuscript, analyzed data and gave final approval. NHK and JH analyzed and interpreted data, provided critical revision and final approval. MY provided histopathology images. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe express our special thanks to Ramasamy Bakthavatsalam M.B.B.S. for helpful discussions and performing the transplant surgery.\n==== Refs\nReferences\n1. Lawitz E Sulkowski MS Ghalib R Rodriguez-Torres M Younossi ZM Corregidor A Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study Lancet. 2014 384 1756 65 10.1016/S0140-6736(14)61036-9 25078309 \n2. Bini EJ Perumalswami PV Hepatitis B virus infection among American patients with chronic hepatitis C virus infection: prevalence, racial/ethnic differences, and viral interactions Hepatology. 2010 51 759 66 20140950 \n3. Chu CJ Lee SD Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment J Gastroenterol Hepatol. 2008 23 512 20 10.1111/j.1440-1746.2008.05384.x 18397482 \n4. Saravanan S Velu V Nandakumar S Madhavan V Shanmugasundaram U Murugavel KG Hepatitis B virus and hepatitis C virus dual infection among patients with chronic liver disease J Microbiol Immunol Infect. 2009 42 122 8 19597643 \n5. Tyson GL Kramer JR Duan Z Davila JA Richardson PA El-Serag HB Prevalence and predictors of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients Hepatology. 2013 58 538 45 10.1002/hep.26400 23505059 \n6. Amin J Law MG Bartlett M Kaldor JM Dore GJ Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study Lancet. 2006 368 938 45 10.1016/S0140-6736(06)69374-4 16962883 \n7. Crockett SD Keeffe EB Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection Ann Clin Microbiol Antimicrob. 2005 4 13 10.1186/1476-0711-4-13 16159399 \n8. Yu ML Lee CM Chen CL Chuang WL Lu SN Liu CH Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up Hepatology. 2013 57 2135 42 10.1002/hep.26266 23322699 \n9. Lok AS McMahon BJ Chronic hepatitis B: update 2009 Hepatology. 2009 50 661 2 10.1002/hep.23190 19714720 \n10. Galban-García E1 Vega-Sanchez H Gra-Oramas B Jorge-Riaño JL Soneiras-Perez M Haedo-Castro D Efficacy of ribavirin in patients with chronic hepatitis B J Gastroenterol 2000 35 347 52 10.1007/s005350050359 10832669 \n11. Siddiqui F Mutchnick M Kinzie J Peleman R Naylor P Ehrinpreis M Prevalence of hepatitis A virus and hepatitis B virus immunity in patients with polymerase chain reaction-confirmed hepatitis C: implications for vaccination strategy Am J Gastroenterol. 2001 96 858 63 10.1111/j.1572-0241.2001.03633.x 11280565\n\n",
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"issn_linking": "1752-1947",
"issue": "9()",
"journal": "Journal of medical case reports",
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"medline_ta": "J Med Case Rep",
"mesh_terms": "D000998:Antiviral Agents; D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D006509:Hepatitis B; D019698:Hepatitis C, Chronic; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008875:Middle Aged; D012008:Recurrence; D000069616:Simeprevir; D000069474:Sofosbuvir",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "164",
"pmc": null,
"pmid": "26215390",
"pubdate": "2015-07-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16962883;18397482;19597643;19714720;16159399;20140950;23505059;25078309;10832669;11280565;23322699",
"title": "Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report.",
"title_normalized": "fulminant hepatitis b reactivation leading to liver transplantation in a patient with chronic hepatitis c treated with simeprevir and sofosbuvir a case report"
} | [
{
"companynumb": "US-JNJFOC-20150813567",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
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"activesubstancename": "SIMEPREVIR"
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{
"abstract": "Primary carcinomas of the urethra differ by location and histologic subtype. Primary urethral cancer of the proximal urethra is rare and aggressive tumor with a high propensity for regional and distant metastases.\nIn this case report, we present primary urothelial carcinoma of the prostatic urethra, diagnosed by transrectal ultrasound-guided biopsy of the prostate and having multiple metastases at the time of diagnosis. Metastatic patients were initiated chemotherapy according to the histological type of urethral cancer.\nUrothelial carcinomas of the urethra are rarely seen, and therefore there is no standard treatment regimen for early-stage or metastatic disease. Gemcitabine-, platinum-, and taxane-based treatments are used in the metastatic stage.",
"affiliations": "Tepecik Training and Research Hospital, İzmir, Turkey.;Tepecik Training and Research Hospital, İzmir, Turkey.;Tepecik Training and Research Hospital, İzmir, Turkey.;Tepecik Training and Research Hospital, İzmir, Turkey.",
"authors": "Kisa|Erdem|E|;Semiz|Hüseyin Salih|HS|;Küçük|Ülkü|Ü|;İlbey|Yusuf Özlem|YÖ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0391560318808631",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-5603",
"issue": "86(3)",
"journal": "Urologia",
"keywords": "Urethral cancer; chemotherapy; multimodal therapy; urethral carcinoma; urothelial carcinoma",
"medline_ta": "Urologia",
"mesh_terms": "D002295:Carcinoma, Transitional Cell; D006801:Humans; D008297:Male; D008875:Middle Aged; D011467:Prostate; D014523:Urethral Neoplasms",
"nlm_unique_id": "0417372",
"other_id": null,
"pages": "161-164",
"pmc": null,
"pmid": "30373476",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metastatic primary urothelial carcinoma of the prostatic urethra: A case report.",
"title_normalized": "metastatic primary urothelial carcinoma of the prostatic urethra a case report"
} | [
{
"companynumb": "TR-FRESENIUS KABI-FK201912058",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
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"drugadditional": "3",
... |
{
"abstract": "Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have transformed the management of many malignancies. Although rare, immune-mediated myocarditis presents unique clinical challenges due to heterogenous presentation, potential life-threatening consequences, and the time-critical need to differentiate it from other causes of cardiac dysfunction. Increasingly, TKI are being combined with ICI to promote immune modulation and improve efficacy. However, these combinations are associated with more toxicities. This series describes six patients with advanced melanoma who developed immune-mediated myocarditis while receiving an anti-PD-1 antibody or an anti-PD-L1 antibody plus a mitogen-activated protein kinase inhibitor. It provides a review of their heterogenous clinical presentations, investigational findings and treatment outcomes. Presentations ranged from asymptomatic cardiac enzyme elevation to death due to heart failure. We highlight the role of cardiac MRI (CMRI), a sensitive and non-invasive tool for the early detection and subsequent monitoring of myocardial inflammation. Five of the six patients exhibited CMRI changes characteristic of myocarditis, including mid-wall myocardial oedema and late gadolinium enhancement in a non-coronary distribution. Critically, two of these patients had normal findings on echocardiogram. Of the five patients who received immunosuppression, four recovered from myocarditis and one died of cardiac failure. The sixth patient improved with cardiac failure management alone. Three of the four patients responding to ICI derived long-term benefit. Clinical vigilance, prompt multimodal diagnosis and multidisciplinary management are paramount for the treatment of immune-mediated myocarditis.",
"affiliations": "The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Grattan Street, Parkville, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Grattan Street, Parkville, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia.;The Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia.;The Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Grattan Street, Parkville, Australia. Electronic address: shahneen.sandhu@petermac.org.",
"authors": "Guo|Christina W|CW|;Alexander|Marliese|M|;Dib|Youseph|Y|;Lau|Peter K H|PKH|;Weppler|Alison M|AM|;Au-Yeung|George|G|;Lee|Belinda|B|;Khoo|Chloe|C|;Mooney|Don|D|;Joshi|Subodh B|SB|;Creati|Louise|L|;Sandhu|Shahneen|S|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D020107:Troponin T; D020929:Mitogen-Activated Protein Kinase Kinases; D003402:Creatine Kinase",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2019.09.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "124()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Drug-related side effects and adverse events; Immunotherapy; Magnetic resonance imaging; Melanoma; Myocarditis",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D003402:Creatine Kinase; D003937:Diagnosis, Differential; D004452:Echocardiography; D005260:Female; D006321:Heart; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases; D009205:Myocarditis; D009206:Myocardium; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D012878:Skin Neoplasms; D020107:Troponin T",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "15-24",
"pmc": null,
"pmid": "31707280",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A closer look at immune-mediated myocarditis in the era of combined checkpoint blockade and targeted therapies.",
"title_normalized": "a closer look at immune mediated myocarditis in the era of combined checkpoint blockade and targeted therapies"
} | [
{
"companynumb": "AU-ROCHE-2482625",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COBIMETINIB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Context. Many phosphoinositide-3-kinase (PI3K) inhibitors are under trial for cancer treatment. We present a patient taking taselisib who developed ketoacidosis within 1 week of starting canagliflozin. Case Description. A 69-year-old female patient with no previous history of diabetes mellitus was enrolled in a clinical trial for taselisib therapy in stage IV breast cancer. Hyperglycemia treatment with metformin was insufficient and not tolerated. The addition of canagliflozin daily resulted in ketoacidosis and hospitalization within 1 week. Conclusions. This case report brings together 2 poorly understood and relatively understudied disorders of glucose homeostasis: hyperglycemia due to PI3K inhibition and euglycemic ketoacidosis due to dehydration/SGLT2 inhibition. It demonstrates the complexities of glucose management in the setting of PI3K inhibition. PI3K stimulation (via insulin) in this setting is counterintuitive; therefore, non-insulin-mediated therapies (eg, metformin, thiazolidinediones) might be favored over insulin-mediated therapies.",
"affiliations": "Vanderbilt University Medical Center, Nashville, TN, USA.;Vanderbilt University Medical Center, Nashville, TN, USA.;Vanderbilt University Medical Center, Nashville, TN, USA.",
"authors": "Bowman|Christopher|C|;Abramson|Vandana|V|;Wellons|Melissa|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2324709617725351",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961772535110.1177_2324709617725351Case ReportKetoacidosis With Canagliflozin Prescribed for Phosphoinositide 3-Kinase Inhibitor–Induced Hyperglycemia: A Case Report Bowman Christopher MD1Abramson Vandana MD1Wellons Melissa MD11 Vanderbilt University Medical Center, Nashville, TN, USAMelissa Wellons, MD, Division of Endocrinology, Diabetes, and Metabolism, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37232, USA. Email: melissa.wellons@Vanderbilt.Edu23 8 2017 Jul-Sep 2017 5 3 232470961772535127 3 2017 22 6 2017 26 6 2017 © 2017 American Federation for Medical Research2017American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Context. Many phosphoinositide-3-kinase (PI3K) inhibitors are under trial for cancer treatment. We present a patient taking taselisib who developed ketoacidosis within 1 week of starting canagliflozin. Case Description. A 69-year-old female patient with no previous history of diabetes mellitus was enrolled in a clinical trial for taselisib therapy in stage IV breast cancer. Hyperglycemia treatment with metformin was insufficient and not tolerated. The addition of canagliflozin daily resulted in ketoacidosis and hospitalization within 1 week. Conclusions. This case report brings together 2 poorly understood and relatively understudied disorders of glucose homeostasis: hyperglycemia due to PI3K inhibition and euglycemic ketoacidosis due to dehydration/SGLT2 inhibition. It demonstrates the complexities of glucose management in the setting of PI3K inhibition. PI3K stimulation (via insulin) in this setting is counterintuitive; therefore, non–insulin-mediated therapies (eg, metformin, thiazolidinediones) might be favored over insulin-mediated therapies.\n\nketoacidosisdrug-induced hyperglycemiaphosphoinositide 3-kinase inhibitorcanagliflozincover-dateJuly-September 2017\n==== Body\nContext\nBreast cancer is estimated to be the third leading cause of cancer-related death in women.1 A commonly mutated pathway in breast cancer (~25%) is the phosphoinositide-3-kinase (PI3K) pathway.2 Many PI3K inhibitors are under trial for breast, brain, and lung cancers, as well as hematologic malignancies.3 One such agent is taselisib, which is under study for postmenopausal breast cancer. We present a patient taking taselisib who developed ketoacidosis within 1 week of starting canagliflozin.\n\nCase Presentation\nA 69-year-old woman was referred to the endocrine clinic for hyperglycemia. Six weeks prior to her visit, she enrolled in a taselisib (GDC-0032, Genentech) clinical trial that included weekly paclitaxel and dexamethasone 8 mg PO (premedication for paclitaxel), as well as daily taselisib for stage IV breast cancer. Her hemoglobin A1C was 5.4% 9 months prior to her trial start. After trial initiation, her serum glucoses increased from <100 mg/dL (nonfasting, pretrial) to values >270 mg/dL (nonfasting, 17 days after trial initiation). She was prescribed metformin 500 mg twice a day, which was increased to 1000 mg twice a day. However, the patient developed persistent diarrhea not resolved by over-the-counter medicines, and glucoses remained elevated (fasting >150 mg/dL, random >300 mg/dL).\n\nA criterion for taselisib clinical trial continued eligibility was maintenance of blood sugars <200 mg/dL. After discussion with the patient, metformin was stopped due to nausea and diarrhea, and canagliflozin 100 mg daily was prescribed (Figure 1). Five days after canagliflozin initiation, the patient presented to oncology for follow-up. At this visit, she reported persistent nausea and diarrhea. Labs at her oncology visit (Table 1; hospital day [HD] −3) included normal electrolytes, creatinine, and CO2 (25 mmol/L). The following day she presented to a local emergency room with worsening nausea and vomiting. An abdominal X-ray showed no evidence of bowel obstruction. Her blood urea nitrogen had increased from 11 to 26 mg/dL, and CO2 decreased from 25 to 18 mmol/L (Table 1). She received supportive treatment (intravenous fluids, anti-emetics) and was discharged. The following day she returned to the emergency room with nausea, vomiting, and lightheadedness. Her labs were notable for CO2 14, glucose 143, anion gap 21, with normal lactate, moderate acetone (detectable by olfaction by admitting physician when he walked in the room), and arterial blood glass with pH 7.27, pCO2 24 mm Hg, and pO2 105 mm Hg. Urine ketones were positive at 80. Lipase, lactate, aspartate transaminase, alanine transaminase, alkaline phosphatase, and white blood cell count were all within normal limits.\n\nFigure 1. Medication adjustments during taselisib treatment.\n\nTable 1. Laboratory Values and Medicines During Clinic Visits and Hospitalization.\n\n\tHD −10\tHD −3\tHD −1\tHD #1\tHD #2\tHD #4\t\nNa (mmol/L)\t136\t139\t137\t139\t139\t138\t\nK (mmol/L)\t3.9\t3.7\t4.0\t4.2\t3.0\t3.3\t\nCl (mmol/L)\t97\t97\t101\t104\t108\t105\t\nCO2 (mmol/L)\t27\t25\t18\t14\t21\t24\t\nBUN (mg/dL)\t12\t11\t26\t28\t13\t5\t\nCr (mg/dL)\t0.68\t0.73\t0.79\t0.72\t0.40\t0.39\t\nGlu (mg/dL)\t176\t151\t153\t143\t105\t110\t\nAnion gap\t12\t17\t18\t21\t10\t9\t\nUrine SG\t\t1.028\t\t1.018\t\t\t\nUrine Glu (mg/dL)\t\t>1000\t\t>500\t\t\t\nUrine ketone (mg/dL)\t\t40\t\t80\t\t\t\nUrine blood\t\tNegative\t\tNegative\t\t\t\nUrine LE\t\tNegative\t\tNegative\t\t\t\nUrine nitrite\t\tNegative\t\tNegative\t\t\t\nPertinent medications\tDex\tDex/Cana\t\t\t\t\t\nStopped medications\tMet\t\t\tCana; taselisib\t\t\t\nAbbreviations: HD, hospital day (HD #1 = date of admission); Na, sodium; K, potassium; Cl, chloride; CO2, carbon dioxide; BUN, blood urea nitrogen; Cr, creatinine; Glu, glucose; SG, specific gravity; LE, leukocyte esterase; Met, metformin; Cana, canagliflozin 100 mg; Dex, dexamethasone 8 mg.\n\nThe patient was treated over the next 4 days with intravenous fluids and anti-emetics, while stopping the canagliflozin and taselisib. Her fasting blood glucoses ranged between 75 and 110 mg/dL. Since that hospitalization, the patient has remained off of canagliflozin and has not had any further acidosis.\n\nDiscussion\nThis case report brings together 2 poorly understood and relatively understudied disorders of glucose homeostasis: (1) hyperglycemia due to PI3K inhibition and (2) euglycemic ketoacidosis due to dehydration/SGLT2 inhibition. The first disorder is a likely common manifestation of a newly emerging class of targeted cancer therapy (ie, hyperglycemia associated with PI3K inhibitors), while the second disorder is an uncommon manifestation of a frequently used oral hypoglycemic medication (ie, euglycemic ketoacidosis with SGLT2 inhibition). This case is thus a good example of the modern complexities of managing the side effects of novel cancer therapies.\n\nThe precise mechanism through which PI3K inhibitors cause hyperglycemia is unknown. In healthy individuals, insulin signaling occurs via binding of insulin to an insulin receptor or insulin-like growth factor 1 (IGF-1) receptor, activating insulin receptor substrate proteins, which then bind to PI3K. This binding of PI3K has a variety of downstream effects leading to glucose uptake and glycogen synthesis. Class I PI3K is composed of a heterodimer: p110 (catalytic subunit, consisting of p110α, β, δ, or γ), as well as a p85 regulatory subunit.4 This is further divided into IA and IB based on sequence similarity. Inhibition of class IA PI3K via knockout of pik3r1 and pik3r2 genes in mice led to a decrease in insulin secretion and increased glucose intolerance, suggesting that class IA PI3K in β-cells is important for maintaining intracellular Ca2+ levels and cell-cell synchronization.4\n\nOne of the on-target toxicities of taselisib inhibition of class IA PI3K p110α subunit in β-cells is hyperglycemia. In the liver of mice, deletion of p110α reduces insulin sensitivity, impairs glucose tolerance, and increases gluconeogenesis.4 In 8-week-old mice, p110α partial inactivation (heterozygous p110α D933A/WT) causes hyperinsulinemia and glucose intolerance.5 However, in older mice (66 weeks) with chronic partial p110α inactivation, it was shown that p110α inactivation protects from glucose intolerance, fat accumulation, and age-related reduction in insulin sensitivity compared to control aged mice, suggesting that prolonged PI3K inhibition might not negatively affect organismal metabolism.6 In phase I human clinical trials of taselisib, hyperglycemia occurred in up to 38% of patients, with a more common incidence and severity at higher doses.7 In phase I trials of alpelisib, another p110α inhibitor, hyperglycemia incidence was 62%.8 Hyperglycemia incidence was 30% and 48%, respectively, in phase I trials of the pan-PI3K inhibitors buparlisib and pictilisib.9 Hyperglycemia incidence was estimated at 80% in a retrospective study of 4 phase I PI3K inhibitors, specifically 2 targeting pan-PI3K, 1 targeting PIK3α subunit, and 1 targeting PIK3β subunit. These estimates were obtained from clinical trials data from a single cancer hospital (The Royal Marsden Hospital and Institute of Cancer Research, London, UK).10\n\nSGLT2 inhibitors appear to cause euglycemic diabetic ketoacidosis (DKA) and ketosis in some patients. A recent case series (9 patients) and an US Food and Drug Administration advisory (73 cases, 44 type 2 diabetes [T2D] cases, 15 type 1 diabetes [T1D] cases) have described euglycemic DKA and ketoacidosis with SGLT2 inhibitors.11,12 A phase II double-blinded study of canagliflozin added to insulin therapy in T1D diabetics found that canagliflozin 100 mg and 300 mg was associated with an increased risk of DKA requiring hospitalization as compared with placebo (4.3%, 6%, and 0%, respectively).13\n\nMultiple mechanisms for the increased risk for acidosis in patients taking SGLT2 inhibitors are proposed. In T1D, increasing urine glucose excretion with SGLT2 inhibitors results in lower glucose levels. In turn, patients may reflexively lower their insulin dose to prevent hypoglycemia. Less insulin results in a decreased amount of suppression of lipolysis from adipose tissue and more hepatic ketogenesis.14 In T2D, SGLT2 inhibitors increase plasma glucagon levels. Elevated glucagon and low relative endogenous insulin production increases lipolysis, releasing free fatty acids from adipose tissue, which are converted to ketone bodies.15 Hypovolemia (via osmotic diuresis) also leads to increased cortisol/epinephrine/glucagon, further amplifying insulin resistance, ketogenesis, and lipolysis. This patient had clinical factors that increased her risk of ketoacidosis, specifically hypovolemia and nausea with vomiting. Stopping the canagliflozin at her office visit (HD −3) when her urine showed 40 mg/dL ketones may have prevented her significant ketoacidosis.\n\nOur case demonstrates the complexities of managing the undesired, yet on-target, hyperglycemic effect of acute PI3K inhibition. If PI3K inhibition is the goal, then glucose controlling agents with mechanistic action outside of the PI3K pathway may be preferred. These glucose controlling agents include metformin, thiazolidinediones, acarbose, pramlintide, colesevelam, and SGLT2 inhibitors. However, as our case demonstrates, SGLT2 inhibitors may not be a good therapeutic choice for patients on PI3K inhibitors. It is important to monitor closely for euglycemic ketoacidosis in patients taking SGLT2 inhibitors, especially when nausea, vomiting, or dehydration are suspected. Patients with end-stage cancers may be at increased risk of hypovolemia, making the risk-benefit ratio of SGLT2 inhibitors unsatisfactory. In addition, the use of steroids (eg, dexamethasone, in the case of our patient) may exacerbate hyperglycemia to a degree that an SGLT2 may not be effective. Management of steroid-induced hyperglycemia in combination with PI3K-induced hyperglycemia may be especially difficult. Determining whether this hyperglycemia can be managed without elimination of one or both of these cancer therapies is an area in need of more research. Whether PI3K-stimulating hypoglycemic agents (such as insulin, sulfonylureas, DPP4-inhibitors/GLP-1 agonist, or meglitinides) can be used without risk of tumor growth is another area in need of more research.\n\nConclusions\nFuture studies are needed to establish the prevalence and incidence of drug-induced hyperglycemia in patients administered PI3K inhibitors, as well as the best management approach to ensuing hyperglycemia. Effective hyperglycemia management strategies for patients on PI3K inhibitors might provide the opportunity for patients with known diabetes mellitus to be included in clinical trials of PI3K therapy, and receive a beneficial cancer therapy.\n\nDeclaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CB and VA have no conflicts of interest to disclose. MW has served on an Advisory Board for Novartis Oncology.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Vanderbilt does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Informed consent for patient information to be published in this article was not obtained because the patient has passed away.\n==== Refs\nReferences\n1 \nHowlader N Noone A Krapcho M et al \nSEER Cancer Statistics Review, 1975-2013 . Bethesda, MD : National Cancer Institute \nhttp://seer.cancer.gov/csr/1975_2013/. Published 4 \n2016 \nAccessed July 27, 2017 .\n2 \nBaselga J \nTargeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer . Oncologist . 2011 ;16 (suppl 1 ):12 -19 .\n3 \nLiu P Cheng H Roberts TM Zhao JJ \nTargeting the phosphoinositide 3-kinase pathway in cancer . Nat Rev Drug Discov . 2009 ;8 :627 -644 .19644473 \n4 \nKaneko K Ueki K Takahashi N et al \nClass IA phosphatidylinositol 3-kinase in pancreatic beta cells controls insulin secretion by multiple mechanisms . Cell Metab . 2010 ;12 :619 -632 .21109194 \n5 \nFoukas LC Claret M Pearce W et al \nCritical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation . Nature . 2006 ;441 :366 -370 .16625210 \n6 \nFoukas LC Bilanges B Bettedi L et al \nLong-term p110a PI3K inactivation exerts a beneficial effect on metabolism . EMBO Mol Med . 2013 ;5 :563 -571 .23483710 \n7 \nJuric D Krop I Ramanathan RK et al \nPhase I dose-escalation study of taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors . Cancer Discov . 2017 ;7 :704 -715 .28331003 \n8 \nMayer IA Abramson VG Formisano L et al \nA phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2− metastatic breast cancer . Clin Cancer Res . 2017 ;23 :26 -34 .27126994 \n9 \nBusaidy NL Farooki A Dowlati A et al \nManagement of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway . J Clin Oncol . 2012 ;30 :2919 -2928 .22778315 \n10 \nGuena E Roda D Rafii S et al \nComplications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on phase I clinical trials . Br J Cancer . 2015 ;113 :1541 -1547 .26554652 \n11 \nPeters AL Buschur EO Buse JB Cohan P Diner JC Hirsch IB \nEuglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition . Diabetes Care . 2015 ;38 :1687 -1693 .26078479 \n12 \nFood and Drug Administration. FDA drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood . http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Published 5 \n15 , 2015 \nAccessed July 27, 2017 .\n13 \nPeters AL Henry RR Thakkar P Tong C Alba M \nDiabetic ketoacidosis with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 1 diabetes . Diabetes Care . 2016 ;39 :532 -538 .26989182 \n14 \nTaylor SI Blau JE Rother KI \nSGLT2 inhibitors may predispose to ketoacidosis . J Clin Endocrinol Metab . 2015 ;100 :2849 -2852 .26086329 \n15 \nUnger RH Cherrington AD \nGlucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover . J Clin Invest . 2012 ;122 :4 -12 .22214853\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "5(3)",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "canagliflozin; drug-induced hyperglycemia; ketoacidosis; phosphoinositide 3-kinase inhibitor",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709617725351",
"pmc": null,
"pmid": "28856166",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "23483710;21109194;28331003;21278436;19644473;16625210;27126994;26989182;22214853;26554652;26078479;22778315;26086329",
"title": "Ketoacidosis With Canagliflozin Prescribed for Phosphoinositide 3-Kinase Inhibitor-Induced Hyperglycemia: A Case Report.",
"title_normalized": "ketoacidosis with canagliflozin prescribed for phosphoinositide 3 kinase inhibitor induced hyperglycemia a case report"
} | [
{
"companynumb": "US-TEVA-2019-US-1017208",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TASELISIB"
},
"drugadditional": "3",
... |
{
"abstract": "Sarcoidosis is a multisystem disease characterized histologically by noncaseating granulomas. Localization of sarcoidosis to the CNS is termed neurosarcoidosis, a complex and rare neuroinflammatory form of sarcoidosis. When the spinal cord is involved, lesions are often intradural. Here, we present a rare case of progressive myelopathy secondary to multifocal spinal extradural neurosarcoidosis with spinal cord compression and without pulmonary involvement.\n\n\n\nA 29-year-old African American female presented to the emergency department with numbness and paresthesia of 2-month duration in her left lower extremity and 2-week duration in her right lower extremity. The patient reported difficulty ambulating, paresthesia below the umbilicus, and back pain radiating to bilateral lower extremities. She endorsed 9-month history of cough, subjective fevers, night sweats, and unintentional 15 kg weight loss. Examination revealed 4/5 strength in the left lower extremity. MRI of the brain and spinal cord revealed enhancing extradural lesions, with spinal cord compression at T8 measuring 1.3 × 1.9 cm. Lumbar puncture demonstrated oligoclonal bands and increased CSF neutrophils, lymphocytes, monocytes, and protein. T8 laminectomy with resection of the epidural lesion was performed. Histology showed granulomas, consistent with neurosarcoidosis. At follow-up, repeat spinal MRI revealed disease progression with intramedullary involvement. Long-term immunosuppressive treatment was eventually initiated with satisfactory response.\n\n\n\nThis is a rare case of myelopathy secondary to spinal extradural neurosarcoidosis. Spinal neurosarcoidosis is predominantly an intradural process. Our review of the literature identified only seven cases of extradural neurosarcoidosis presenting with compressive myelopathy. Additional insight into management and rehabilitation following pathological diagnosis is of clinical significance.",
"affiliations": "College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, USA. ryan.shields@rockets.utoledo.edu.;College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, USA.;College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, USA.;College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, USA.;College of Medicine and Life Sciences, The University of Toledo, Toledo, OH, USA.;Department of Pathology, The University of Toledo, Toledo, OH, USA.;Department of Pathology, The University of Toledo, Toledo, OH, USA.;Department of Neurology, The University of Toledo, Toledo, OH, USA.",
"authors": "Shields|Ryan|R|0000-0001-7177-3316;Sagan|Olivia|O|0000-0001-5340-5544;Roebke|Logan|L|;Vander Maten|Josh|J|;Shah|Shailen|S|;Chang|George|G|;Ibrahim|Dalia|D|;Naz|Sumayya|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41394-021-00450-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2058-6124",
"issue": "7(1)",
"journal": "Spinal cord series and cases",
"keywords": null,
"medline_ta": "Spinal Cord Ser Cases",
"mesh_terms": "D000328:Adult; D002493:Central Nervous System Diseases; D005260:Female; D006801:Humans; D012507:Sarcoidosis; D013117:Spinal Cord Compression; D013118:Spinal Cord Diseases",
"nlm_unique_id": "101680856",
"other_id": null,
"pages": "89",
"pmc": null,
"pmid": "34584071",
"pubdate": "2021-09-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "32547820;18661424;29325956;16775923;16401897;8805157;31297669;31093476;25779004;14589469;26593139;23364469",
"title": "Rare case of multifocal extradural and intramedullary neurosarcoidosis without pulmonary involvement: a case report and literature review.",
"title_normalized": "rare case of multifocal extradural and intramedullary neurosarcoidosis without pulmonary involvement a case report and literature review"
} | [
{
"companynumb": "US-AMGEN-USASP2021179703",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe colon shows frequent eosinophilic infiltration in allergic proctocolitis of infants, whereas in adults, eosinophilic infiltration of the colon is less defined and may be found in different conditions including drug-induced colitis, even though the pathological findings are often inconsistent.\n\n\nOBJECTIVE\nTo quantify eosinophils in the mucosa of normal controls and to compare them with those of patients with abdominal symptoms related to 'drug colitis'.\n\n\nMETHODS\nMucosal biopsies were obtained during colonoscopy in 15 controls and in 27 patients with abdominal symptoms, a history of probable 'drug-related colitis' and without obvious causes of eosinophilia.\n\n\nRESULTS\nThe drugs related to the patient symptoms were nonsteroidal anti-inflammatory drugs (70%), antiplatelet agents (19%) and oestroprogestinic agents (11%). Colonoscopy was normal in 30% of patients and abnormal in 70%. Histology showed low content of inflammatory cells and normal crypt architecture in-patients with endoscopy similar to inflammatory bowel diseases. The eosinophil score was significantly higher in the left side of the colon in the patient group compared with controls.\n\n\nCONCLUSIONS\nThe finding of an increased eosinophil count limited to the left (descending and sigmoid) colon is an important clue towards a diagnosis of drug-related colitis.",
"affiliations": "Division of Internal Medicine, Desio General Hospital, Desio, Italy.",
"authors": "Casella|G|G|;Villanacci|V|V|;Fisogni|S|S|;Cambareri|A R|AR|;Di Bella|C|C|;Corazzi|N|N|;Gorla|S|S|;Baldini|V|V|;Bassotti|G|G|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D010975:Platelet Aggregation Inhibitors; D011372:Progestins",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2036.2008.03913.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "29(5)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001706:Biopsy; D016022:Case-Control Studies; D003092:Colitis; D003106:Colon; D004804:Eosinophils; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011372:Progestins; D012189:Retrospective Studies; D013223:Statistics as Topic",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "535-41",
"pmc": null,
"pmid": "19077107",
"pubdate": "2009-03-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Colonic left-side increase of eosinophils: a clue to drug-related colitis in adults.",
"title_normalized": "colonic left side increase of eosinophils a clue to drug related colitis in adults"
} | [
{
"companynumb": "IT-JNJFOC-20171121782",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nCorticosteroids generally result in short-lasting neuropsychiatric symptoms following cessation, but the following case highlights an unusually long-lasting course of symptoms in a patient following near immediate cessation of medication, despite medication management and electroconvulsive therapy. The case presentation will be followed by a discussion of the presentation, treatment, and management of steroid-induced neuropsychiatric symptoms.\n\n\nMETHODS\nThe patient was followed from symptom onset to resolution.\n\n\nRESULTS\nThe patient's symptom course was unusually long and required a long course of multimodal therapy.\n\n\nCONCLUSIONS\nCorticosteroids are commonly used medications both in a wide variety of medical settings, and despite this, their neuropsychiatric effects are poorly understood. The affective and behavioral symptoms, in particular mania and psychosis, can be unpredictable and challenging to treat as in our patient, who developed a long-lasting psychotic episode on high-dose steroids despite discontinuation and treatment of nearly six months. This was despite having tolerated steroids multiple times in the past.",
"affiliations": "Psychiatry Department, UCSF Fresno, Fresno, CA, USA Mgable@fresno.ucsf.edu.;VA Central California, CA, USA.",
"authors": "Gable|Mary|M|;Depry|Dwayne|D|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000069348:Quetiapine Fumarate; D003907:Dexamethasone; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1177/0091217415612735",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2174",
"issue": "50(4)",
"journal": "International journal of psychiatry in medicine",
"keywords": "Corticosteroids; neuropsychiatric symptoms; psychosis",
"medline_ta": "Int J Psychiatry Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D001714:Bipolar Disorder; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004565:Electroconvulsive Therapy; D006760:Hospitalization; D006801:Humans; D008134:Long-Term Care; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011605:Psychoses, Substance-Induced; D011696:Purpura, Thrombocytopenic; D000069348:Quetiapine Fumarate; D019233:Retreatment; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "0365646",
"other_id": null,
"pages": "398-404",
"pmc": null,
"pmid": "26644319",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Sustained corticosteroid- induced mania and psychosis despite cessation: A case study and brief literature review.",
"title_normalized": "sustained corticosteroid induced mania and psychosis despite cessation a case study and brief literature review"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201601323",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,... |
{
"abstract": "Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.",
"affiliations": "Internal Medicine, Jersey Shore University Medical Center, Neptune City, USA.;Internal Medicine, Jersey Shore University Medical Center, Neptune City, USA.;Internal Medicine, Jersey Shore University Medical Center, Neptune City, USA.;Pulmonary and Critical Care Medicine, Jersey Shore University Medical Center, Neptune City, USA.;Pulmonary and Critical Care Medicine, Jersey Shore University Medical Center, Neptune City, USA.",
"authors": "Al-Taei|Mustafa H|MH|;AlAzzawi|Mohammed|M|;Albustani|Safa|S|;Alsaoudi|Ghadier|G|;Costanzo|Eric|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.13055",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13055\nAnesthesiology\nEmergency Medicine\nInternal Medicine\nIncorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection\nMuacevic Alexander\nAdler John R\nAL-Taei Mustafa H 1\nAlAzzawi Mohammed 1\nAlbustani Safa 1\nAlsaoudi Ghadier 2\nCostanzo Eric 2\n1 Internal Medicine, Jersey Shore University Medical Center, Neptune City, USA\n2 Pulmonary and Critical Care Medicine, Jersey Shore University Medical Center, Neptune City, USA\nMustafa H. AL-Taei mustafa.altaei@hmhn.org\n1 2 2021\n2 2021\n13 2 e1305531 1 2021\nCopyright © 2021, AL-Taei et al.\n2021\nAL-Taei et al.\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/50591-incorrect-route-for-injection-inadvertent-tranexamic-acid-intrathecal-injection\nTranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.\n\ntranexamic acid\nspinal anasthesia\nintrathecal complication\nrisk of seizure\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nTranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.\n\nCase presentation\n\nA 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.\n\nDiscussion\n\nTXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].\n\nIn another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].\n\nIn our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.\n\nIn conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].\n\nConclusions\n\nIn conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Tranexamic acid: a clinical review Anaesthesiol Intensive Ther Ng WCK Jerath A Wąsowicz M 339 350 47 2015 https://pubmed.ncbi.nlm.nih.gov/25797505/ 25797505\n2 Intrathecal tranexamic acid - an accident waiting to happen? Int J Obstet Anesth Al-Kadhimi S Patel AD Plaat F 116 117 34 2018 29343416\n3 Spinal tranexamic acid - a new killer in town Anaesthesia Palanisamy A Kinsella SM 831 833 74 2019 30985919\n4 Accidental intrathecal injection of tranexamic acid Case Rep Anesthesiol Mahmoud K Ammar A 646028 2012 2012 22606407\n5 Studies on the mechanisms of action of aprotinin and tranexamic acid as plasmin inhibitors and antifibrinolytic agents Blood Coagul Fibrinolysis Longstaff C 537 542 5 1994 https://pubmed.ncbi.nlm.nih.gov/7531000/ 7531000\n6 Inadvertent intrathecal injection of tranexamic acid Saudi J Anaesth Kaabachi O Eddhif M Rais K Zaabar MA 90 92 5 2011 21655027\n7 [Accidental injection of tranexamic acid (Transamin) during spinal anaesthesia] Ma Zui Xue Za Zhi Wong JO Yang SF Tsai MH 249 252 26 1988 http://www.ncbi.nlm.nih.gov/pubmed/3185176 3185176\n8 Convulsions and refractory ventricular fibrillation after intrathecal injection of a massive dose of tranexamic acid Anesthesiology Yeh HM Lau HP Lin PL Sun WZ Mok MS 270 272 98 2003 https://pubmed.ncbi.nlm.nih.gov/12503009/ 12503009\n9 Cerebral complication of antifibrinolytic therapy in the treatment of ruptured intracranial aneurysm. Animal experiment and a review of literature Eur Neurol Yamaura A Nakamura T Makino H Hagihara Y 77 84 19 1980 6893025\n10 Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a γ-aminobutyric acid A receptor antagonistic effect J Pharmacol Exp Ther Furtmüller R Schlag MG Berger M 168 173 301 2002 11907171\n11 Tranexamic acid concentrations associated with human seizures inhibit glycine receptors J Clin Invest Lecker I Wang DS Romaschin AD Peterson M Mazer CD Orser BA 4654 4666 122 2012 23187124\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(2)",
"journal": "Cureus",
"keywords": "intrathecal complication; risk of seizure; spinal anasthesia; tranexamic acid",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e13055",
"pmc": null,
"pmid": "33680597",
"pubdate": "2021-02-01",
"publication_types": "D002363:Case Reports",
"references": "23187124;6893025;21655027;30985919;7531000;11907171;22606407;25797505;3185176;29343416;12503009",
"title": "Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.",
"title_normalized": "incorrect route for injection inadvertent tranexamic acid intrathecal injection"
} | [
{
"companynumb": "US-TILLOMEDPR-2021-EPL-000882",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRANEXAMIC ACID"
},
"drugadditional": nul... |
{
"abstract": "Genomic medicine provides opportunities to personalize cancer therapy for an individual patient. Although novel targeted therapies prolong survival, most patients with cancer continue to suffer from burdensome symptoms including pain, depression, neuropathy, nausea and vomiting, and infections, which significantly impair quality of life. Suboptimal management of these symptoms can negatively affect response to cancer treatment and overall prognosis. The effect of genetic variation on drug response-otherwise known as pharmacogenomics-is well documented and directly influences an individual patient's response to antiemetics, opioids, neuromodulators, antidepressants, antifungals, and more. The growing body of pharmacogenomic data can now guide clinicians to select the safest and most effective supportive medications for an individual patient with cancer from the very first prescription. This review outlines a theoretical patient case and the implications of using pharmacogenetic test results to personalize supportive care throughout the cancer care continuum.\n\n\n\nIntegration of palliative medicine into the cancer care continuum has resulted in increased quality of life and survival for patients with many cancer types. However, suboptimal management of symptoms such as pain, neuropathy, depression, and nausea and vomiting continues to place a heavy burden on patients with cancer. As demonstrated in this theoretical case, pharmacogenomics can have a major effect on clinical response to medications used to treat these conditions. Recognizing the value of supportive care pharmacogenomics in oncology and application into routine practice offers an objective choice for the safest and most effective treatment compared with the traditional trial and error method.",
"affiliations": "Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA Jai.Patel@carolinashealthcare.org.;NorthShore University Health System, Evanston, Illinois, USA.;NorthShore University Health System, Evanston, Illinois, USA.;The DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida, USA.",
"authors": "Patel|Jai N|JN|0000-0001-9845-3697;Wiebe|Lauren A|LA|;Dunnenberger|Henry M|HM|;McLeod|Howard L|HL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2017-0599",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "23(8)",
"journal": "The oncologist",
"keywords": "Cancer; Oncology; Pharmacogenetics; Pharmacogenomics; Supportive care; Symptom management",
"medline_ta": "Oncologist",
"mesh_terms": "D005260:Female; D023281:Genomics; D006801:Humans; D008495:Medical Oncology; D008875:Middle Aged; D009369:Neoplasms; D010166:Palliative Care; D010597:Pharmacogenetics",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "956-964",
"pmc": null,
"pmid": "29622698",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "28745577;28306618;11452243;24510446;19692698;24479687;23665933;25239082;16205777;23803057;21192313;21768513;25558980;16879459;21128110;22796890;27471406;19018716;21270786;21926427;22231601;19783098;26871520;20739920;15927391;15625333;26775563;16633156;27606312;17541852;19845698;25974703;26233624;25292429;23512709;17351937;12065557;24858822;24458010;22761409;18253134;24259697;15115912;17564651;17156920;23555934;25012726;27893130;25239277;24733808;24366929;24269714;28029308;28705252;25800768;20818875;11230034;28699646;14499440;19094200;26616742;7703232;28002639;23444277;26721535;22508819;18713907;25084200;28480783;25800762;24914145;27997040;22733128;26489070;18070221;24733793;21241245;21735164;12204664;21692616;16476833;17361124;18443637;18781855;22406651;15504181",
"title": "Value of Supportive Care Pharmacogenomics in Oncology Practice.",
"title_normalized": "value of supportive care pharmacogenomics in oncology practice"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0104057",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "It is well known that calcium channel blockers (CCBs) are the first line of therapy for vasospastic angina (VSA). Here, we report two cases of VSA with an increase in the frequency of angina attacks after switching from a brand-name to a generic CCB. In both cases, angina recurred upon switching from a brand-name CCB to a generic CCB during follow-up. The patients' condition improved upon switching back to the original CCB. Both cases involved a high severity of VSA, based on the results of spasm provocation testing. These findings suggest that, in some patients with severe VSA, the frequency of angina attacks increases when switching from a brand-name CCB to a generic CCB. Cardiologists should consider this factor when prescribing drugs for angina.",
"affiliations": "Department of Education and Training, JR Hiroshima Hospital, Hiroshima 732-0057, Japan.;Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima 732-0057, Japan.;Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima 732-0057, Japan.;Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima 732-0057, Japan.;Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima 732-0057, Japan. hiroteraga71@gmail.com.",
"authors": "Goto-Semba|Remi|R|;Fujii|Yuichi|Y|;Ueda|Tomohiro|T|;Oshita|Chikage|C|;Teragawa|Hiroki|H|",
"chemical_list": null,
"country": "United States",
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"doi": "10.4330/wjc.v10.i3.15",
"fulltext": "\n==== Front\nWorld J CardiolWJCWorld Journal of Cardiology1949-8462Baishideng Publishing Group Inc jWJC.v10.i3.pg1510.4330/wjc.v10.i3.15Case ReportIncreased frequency of angina attacks caused by switching a brand-name vasodilator to a generic vasodilator in patients with vasospastic angina: Two case reports Goto-Semba Remi Department of Education and Training, JR Hiroshima Hospital, Hiroshima 732-0057, JapanFujii Yuichi Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima 732-0057, JapanUeda Tomohiro Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima 732-0057, JapanOshita Chikage Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima 732-0057, JapanTeragawa Hiroki Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima 732-0057, Japan. hiroteraga71@gmail.comAuthor contributions: Goto-Semba R, Fujii Y, Ueda T and Oshita C contributed to the acquisition of data; Goto-Semba R and Teragawa H contributed to writing; Teragawa H revised the manuscript.\n\nCorrespondence to: Hiroki Teragawa, FACC, FACP, FAHA, MD, PhD, Chief Doctor, Department of Cardiovascular Medicine, JR Hiroshima Hospital, 3-1-36 Futabanosato, Higashi-ku, Hiroshima 732-0057, Japan. hiroteraga71@gmail.com\n\nTelephone: +81-82-2621171 Fax: +81-82-2621499\n\n26 3 2018 26 3 2018 10 3 15 20 24 11 2017 12 1 2018 6 2 2018 ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.2018This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.It is well known that calcium channel blockers (CCBs) are the first line of therapy for vasospastic angina (VSA). Here, we report two cases of VSA with an increase in the frequency of angina attacks after switching from a brand-name to a generic CCB. In both cases, angina recurred upon switching from a brand-name CCB to a generic CCB during follow-up. The patients’ condition improved upon switching back to the original CCB. Both cases involved a high severity of VSA, based on the results of spasm provocation testing. These findings suggest that, in some patients with severe VSA, the frequency of angina attacks increases when switching from a brand-name CCB to a generic CCB. Cardiologists should consider this factor when prescribing drugs for angina.\n\nVasospastic anginaAcetylcholineBrand-name drugsGeneric drugsRefractory chest pain\n==== Body\nCore tip: Calcium-channel blockers (CCBs) are the first line of therapy for vasospastic angina (VSA). Here, we report two cases of VSA with an increase in the frequency of angina attacks after switching from a brand-name to a generic CCB. Switching back to the original CCB improved the patients’ condition in both cases. Both cases involved highly severe VSA. It is important for cardiologists to check whether VSA patients who have refractory angina attacks while taking a CCB are taking a brand-name or generic CCB.\n\nINTRODUCTION\nVasospastic angina (VSA) is caused by myocardial ischemia due to sudden excessive vasoconstriction of the epicardial coronary arteries[1,2]. It has been demonstrated that coronary spasm causes not only unstable angina but also exertional angina, acute coronary syndrome, and acute sudden death[1,2]. In every patient, it is important to assess whether coronary spasm is associated with the patients’ symptoms or with their pathology. VSA is generally diagnosed on the basis of a combination of characteristic chest symptoms and transient ST-T segment changes on the electrocardiogram (ECG)[3]. However, our personal experience is that in many patients, the diagnosis of VSA cannot be made based on these findings. In such cases, the spasm provocation test (SPT) has been very effective in making a correct diagnosis of VSA[4,5]. The treatment for VSA is based on life-style management and drug therapy. The use of calcium-channel blockers (CCBs) to prevent VSA is recommended as the first line of therapy[3].\n\nGeneric drugs are identical to, but substantially less expensive than their brand-name counterparts with respect to the dosage, strength, route of administration, quality, performance characteristics, and intended use[6]. Thus, the use of generic drugs can help reduce overall medical expenses, and their market share is expanding even in Japan. In general, the effects of brand-name and generic drugs are identical[6,7]. However, the effects may not be applicable for all patients and may differ according to the patients’ disease severity and/or subtype.\n\nHere, we present two cases of VSA with increase in the frequency of angina attacks after switching from a brand-name CCB to a generic CCB.\n\nCASE REPORT\nCase 1\nA 70-year-old woman experienced chest pain at rest. She was admitted to our institution to undergo coronary angiography (CAG) because her cardiac CT scan indicated coronary artery stenosis. On admission, her vitals were stable. Blood testing revealed hyperlipidemia. ECG, echocardiography, and chest radiography showed no specific findings. CAG showed no significant coronary stenosis, and subsequent SPT using acetylcholine (ACh) revealed bilateral spasm at the distal segment of the right coronary artery (RCA) at a dose of 50 µg of ACh, and a focal spasm at the mid-segment of the left anterior descending (LAD) coronary artery at a dose of 30 µg of ACh. Intracoronary infusions of nitroglycerin relieved the bilateral coronary spasms (Figure 1). She was diagnosed with VSA and was prescribed diltiazem hydrochloride (100 mg capsule, BID) and pitavastatin calcium hydrate (2 mg tablet, QD). After 10 mo, isosorbide dinitrate patches (40 mg patch, QD) were added because her chest pain recurred four times a month. After that, however, she felt discomfort due to dermal isosorbide dinitrate, so the patches were discontinued and she was switched from diltiazem hydrochloride to benidipine hydrochloride (4 mg tablet, BID), which improved her anginal symptoms. After 4 mo, she switched from benidipine hydrochloride to a generic CCB. At that time, she began to have angina attacks four to five times a month. Therefore, we switched her back to the brand-name CCB, and she has not experienced chest pain since (Table 1).\n\nTable 1 Time course of frequency of chest pain and cardiovascular drug regimen in Case 1\n\nTime course\tFrequency of chest pain\tCardiovascular drug regimen\t\nDischarge\tNone\tDiltiazem hydrochloride (brand-name) 100 mg capsule, BID\t\nPitavastatin calcium (brand-name) 2 mg tablet, QD\t\n10 mo later\t4/mo\tDiltiazem hydrochloride (brand-name) 100 mg capsule, BID\t\nPitavastatin calcium (brand-name) 2 mg tablet, QD\t\nIsosorbide dinitrate (brand-name) 40 mg tape, QD\t\n11 mo later\tNone, but nausea (+)\tBenidipine hydrochloride (brand-name) 4 mg tablet, QD\t\nPitavastatin calcium (brand-name) 2mg tablet, QD\t\n12 mo later\tNone\tBenidipine hydrochloride (brand-name) 4 mg tablet, QD\t\nPitavastatin calcium (brand-name) 2 mg tablet, QD\t\n14 mo later\tNone\tBenidipine hydrochloride (generic) 4 mg tablet, QD\t\nPitavastatin calcium (brand-name) 2 mg tablet, QD\t\n15 mo later\t4-5/mo\tBenidipine hydrochloride (brand-name) 4 mg tablet, QD\t\nPitavastatin calcium (brand-name) 2 mg tablet, QD\t\nThereafter\tNone\tBenidipine hydrochloride (brand-name) 4 mg tablet, QD\t\nPitavastatin calcium (brand-name) 2 mg tablet, QD\t\nFigure 1 Coronary angiography and spasm provocation test (SPT) for Case 1. Coronary angiograms show angiographically normal coronary arteries (left upper and lower panels). During the SPT, coronary spasms occurred at the distal segment of the right coronary artery (RCA) at 50 μg of ACh (middle upper panel) and at the mid-segment of the left anterior descending coronary artery (LAD) at 30 μg of ACh (middle lower panel). These coronary spasms resolved after an injection of nitroglycerin (right upper and lower panels). Spastic segments are indicated by arrows.\n\nCase 2\nA 50-year-old man, who had previously undergone percutaneous coronary artery stenting for unstable angina and was also diagnosed as having VSA, was treated with many kinds of vasodilators. He was admitted to our institution to undergo CAG due to increased frequency of chest pain at night and during early mornings, with an overall frequency of three or four times per week over several months. His coronary risk factors included smoking (40/d × 30 years) and hypercholesterolemia. On admission, his vitals were stable. ECG, chest radiography, and echocardiography showed no specific findings. CAG showed no significant coronary stenosis, including stented segments. SPT, performed when taking vasodilators, revealed diffuse spasms in the three major coronary arteries (at doses of 30 µg of ACh for the RCA and 50 µg of ACh for the left coronary artery). Intracoronary infusions of nitroglycerin relieved the bilateral coronary spasms (Figure 2). We questioned him in detail about his past medications to determine treatment options. He had been on medication [isosorbide dinitrate (20 mg tablet, BID and 40 mg patch, QD), diltiazem hydrochloride (100 mg tablet, BID), verapamil hydrochloride (80 mg tablet, at bedtime), sarpogrelate hydrochloride (100 mg tablet, BID), ezetimibe (10 mg tablet, QD), aspirin (100 mg tablet, QD), rosuvastatin calcium (20 mg tablet, QD), ethyl icosapentate (900 mg capsule, BID), and nitroglycerin (0.3 mg tablet, prn)] before admission, but the frequency of angina attacks had been increasing ever since he switched from a brand-name CCB to a generic CCB several months earlier. After we switched back from the generic CCB to the brand-name CCB, the frequency of angina attacks decreased to once per week (Table 2).\n\nTable 2 Time course of frequency of chest pain and cardiovascular drug regimen in Case 2\n\nTime course\tFrequency of chest pain\tCardiovascular drug regimen\t\nSeveral months ago\t\tDiltiazem hydrochloride (brand-name) 100 mg capsule, BID\t\n\tIsosorbide dinitrate (brand-name) 20 mg capsule, BID\t\n\tIsosorbide dinitrate (brand-name) 40 mg tape, QD\t\n\tVerapamil hydrochloride (brand-name) 80 mg tablet, at bedtime\t\n\tSarpogrelate hydrochloride (generic) 100mg tablet, BID\t\n1/wk\tRousvastatin calcium (brand-name) 20 mg tablet, QD\t\n\tEzetimibe (brand-name) 10 mg tablet, QD\t\n\tEthil isosapentate (generic) 900 mg capsule, QD\t\nSeveral months ago, admission\t\tDiltiazem hydrochloride (generic) 100 mg capsule, BID\t\n\tIsosorbide dinitrate (brand-name) 20 mg capsule, BID\t\n\tIsosorbide dinitrate (brand-name) 40 mg tape, QD\t\n\tVerapamil hydrochloride (brand-name) 80 mg tablet, at bedtime\t\n\tSarpogrelate hydrochloride (generic) 100 mg tablet, BID\t\n\tRousvastatin calcium (brand-name) 20 mg tablet, QD\t\n\tEzetimibe (brand-name) 10 mg tablet, QD\t\n\tEthil isosapentate (generic) 900 mg capsule, QD\t\n3-4/wk\t\t\nThereafter\t\tDiltiazem hydrochloride (brand-name) 100 mg capsule, BID\t\n\tIsosorbide dinitrate (brand-name) 20 mg capsule, BID\t\n\tIsosorbide dinitrate (brand-name) 40 mg tape, QD\t\n\tVerapamil hydrochloride (brand-name) 80 mg tablet, at bedtime\t\n\tSarpogrelate hydrochloride (generic) 100 mg tablet, BID\t\n\tRousvastatin calcium (brand-name) 20 mg tablet, QD\t\n\tEzetimibe (brand-name) 10 mg tablet, QD\t\n1/wk\tEthil isosapentate (generic) 900 mg capsule, QD\t\nFigure 2 Coronary angiography and SPT for Case 2. Coronary angiograms show no significant coronary stenosis of either the RCA (left upper panel) or the left circumflex artery (LCA, left lower panel). The SPT performed during treatment with several vasodilator showed coronary spasms at the distal segments of the RCA at a dose of 30 μg ACh (middle upper panel), distal to the stented segment of the LAD and at the diffuse segment of the LCA (middle lower panel). These coronary spasms resolved immediately after an injection of nitroglycerin (right upper and lower panels). Spastic segments are indicated by arrows.\n\nDISCUSSION\nWe describe two cases of VSA with an increase in the frequency of angina attacks after switching from a brand-name CCB to a generic CCB. In both cases of VSA, chest pain was under control to some extent while taking the brand-name CCB. However, switching to a generic CCB increased the frequency of angina attacks. Switching back to the brand-name CCB regimen reduced the frequency of angina attacks. These cases suggest that switching of coronary vasodilators from a brand-name drug to a generic drug has could worsen anginal symptoms in some patients with VSA.\n\nOne advantage of using generic drugs is the reduction in medical expenditure because of their low cost. However, brand-name drugs and generic drugs differ in terms of their dosage, additives, and production methods. A comparative study of the amount of CCB-related substances identified in a purity test reported that a generic CCB contains twice as much analog of the active ingredient than a brand-name CCB[8]. On the other hand, according to meta-analyses, generic and brand-name drugs used in cardiovascular disease are clinically equivalent: there is no evidence supporting the superiority of brand-name drugs over generic drugs[6,7]. Specifically, the difference in the effects of brand-name and generic vasodilators used for cardiovascular diseases, especially for VAS, is not known.\n\nVariation in the severity of VSA is seasonal, and it cannot be denied that the worsening and improvement of angina attacks in these two cases may be because of the natural course of VSA symptoms. However, we think that the dramatic changes in the frequency of angina attacks immediately after switching of CCBs-between generic and brand-name drugs-was because of the lower efficacy of the generic CCBs used. Although similar effects can be expected in the majority of patients treated for VSA with either generic or brand-name drugs, it is possible that the effects of these two drugs differ based on patients’ disease severity and/or the nature of their disease. Our two cases of VSA demonstrated a positive SPT including multi-vessel spasms and spasm provocation induced by low doses of ACh, which is characteristic of intractable VSA[9]. In addition, the patient described in case 2 had a positive SPT even while on a treatment regimen that included several vasodilators, demonstrating highly severe VSA. Accordingly, even a minor change in the effect of CCBs when switching between brand-name drugs and generic drugs may influence the VSA attack threshold. Thus, switching from a brand-name drug to a generic drug may worsen angina attacks in patients with highly severe VSA.\n\nCCBs are generally recommended as the first line of therapy to prevent angina attacks in VSA patients, and some patients have angina attacks even while taking CCB medications[3]. In such cases, we follow several courses of action. First, we must consider the type of CCB, because CCBs may differ in their ability to prevent angina attacks[10,11]. Second, we must consider the dosing regimen, such as whether a submaximal or maximal dose or medication once or twice a day would be appropriate. We sometimes encounter patients on a once-a-day CCB regimen who have angina attacks just before they are due to take their medication. Third, we must consider the medication timing. In general, angina attacks often occur between midnight and the early morning[1,2]. Thus, taking a CCB at bedtime is usually recommended. However, for some VSA patients, taking a CCB at the time of rising may be effective. In addition, we may add another vasodilator such as long-acting nitrates, nicorandil and other types of CCBs (dihydropyridine CCB vs non-dihydropyridine CCB)[12]. Finally, as shown in the present case reports, we must check whether the prescribed vasodilators are brand-name vasodilators or not. This may also prevent a redundant increase in the numbers of vasodilators prescribed to such patients.\n\nThere were several limitations in the present case reports. We did not observe any ST-T changes on ECG during anginal attacks. Furthermore, we did not perform a repeat coronary angiography and spasm provocation test to confirm the effect of brand-name vs generic coronary vasodilators. Thus, the severity of anginal symptoms was based only on self-assessment.\n\nIn conclusion, switching of CCBs from brand-name drugs to generic ones may worsen angina attacks in some patients with VSA. Therefore, when treating VSA patients with medication-refractory anginal symptoms, it is important that cardiologists confirm the type (brand-name or generic) of vasodilator drugs used.\n\nARTICLE HIGHLIGHTS\nCase characteristics\nThe frequency of angina attacks increased after switching a brand-name vasodilator to a generic vasodilator in two patients with vasospastic angina (VSA).\n\nClinical diagnosis\nVSA.\n\nDifferential diagnosis\nOrganic coronary stenosis, microvascular angina, chest pain syndrome and gastroesophageal reflux disease.\n\nLaboratory diagnosis\nBoth patients had dyslipidemia, but the laboratory tests for lipid levels were within normal limits because they were being treated for dyslipidemia.\n\nImaging diagnosis\nCoronary angiography and the spasm provocation test showed bilateral coronary spasm in both cases. These findings are indicative of severe VSA.\n\nTreatment\nAfter switching back from the generic vasodilators to the brand-name vasodilators, the frequency of angina attacks decreased to baseline in both patients.\n\nRelated reports\nAccording to meta-analyses, the clinical effects of generic and brand-name drugs used in cardiovascular disease are similar, but it is unclear whether this is the case for patients with higher severity of VSA.\n\nTerm explanation\nVSA is characterized by the transient vasoconstriction of the epicardial coronary artery, leading to myocardial ischemia. VSA causes not only rest angina but also exertional angina, acute coronary syndrome and ischemic cardiac arrest.\n\nExperience and lessons\nGeneric vasodilators may not sufficiently prevent angina attacks in patients with a high severity of VSA. Thus, when treating VSA patients with medication-refractory anginal symptoms, it is important that cardiologists confirm the type (brand-name or generic) of vasodilator drugs used.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Cardiac and cardiovascular systems\n\nCountry of origin: Japan\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInformed consent statement: The patients involved in this study gave their written informed consent authorizing use and disclosure of their protected health information.\n\nConflict-of-interest statement: None of the authors have any conflict of interest to declare.\n\nPeer-review started: November 24, 2017\n\nFirst decision: December 27, 2017\n\nArticle in press: February 6, 2018\n\nP- Reviewer: Avanzas P S- Editor: Cui LJ L- Editor: A E- Editor: Li RF\n==== Refs\n1 Yasue H Kugiyama K Coronary spasm: clinical features and pathogenesis Intern Med 1997 36 760 765 9392345 \n2 Yasue H Nakagawa H Itoh T Harada E Mizuno Y Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment J Cardiol 2008 51 2 17 18522770 \n3 JCS Joint Working Group Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013) Circ J 2014 78 2779 2801 25273915 \n4 Sueda S Kohno H Ochi T Uraoka T Tsunemitsu K Overview of the pharmacological spasm provocation test: Comparisons between acetylcholine and ergonovine J Cardiol 2017 69 57 65 27856130 \n5 Sueda S Miyoshi T Sasaki Y Sakaue T Habara H Kohno H Safety and optimal protocol of provocation test for diagnosis of multivessel coronary spasm Heart Vessels 2016 31 137 142 25366987 \n6 Manzoli L Flacco ME Boccia S D’Andrea E Panic N Marzuillo C Siliquini R Ricciardi W Villari P Ioannidis JP Generic versus brand-name drugs used in cardiovascular diseases Eur J Epidemiol 2016 31 351 368 26620809 \n7 Kesselheim AS Misono AS Lee JL Stedman MR Brookhart MA Choudhry NK Shrank WH Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis JAMA 2008 300 2514 2526 19050195 \n8 Ichihara E Okumra M Yoshida F Kawano Y Ookura K Iwakiri T Yasuda K Shiotsuki S Matsuda M MIzumoto K Generics should be evaluated form an overall perspective -characteristics of benidipine hydrochroride tablets whose dosage form has been changed and comparison of branded and generic products regarding drug information supplied Jpn J Pharm Health Care Sci 2008 34 366 373 \n9 Teragawa H Fujii Y Oshita C Ueda T Importance of the spasm provocation test in diagnosing and clarifying the activity of vasospastic angina Interv Cardiol J 2017 3 58 \n10 Nishigaki K Inoue Y Yamanouchi Y Fukumoto Y Yasuda S Sueda S Urata H Shimokawa H Minatoguchi S Prognostic effects of calcium channel blockers in patients with vasospastic angina--a meta-analysis Circ J 2010 74 1943 1950 20668353 \n11 Oikawa Y Matsuno S Yajima J Nakamura M Ono T Ishiwata S Fujimoto Y Aizawa T Effects of treatment with once-daily nifedipine CR and twice-daily benidipine on prevention of symptomatic attacks in patients with coronary spastic angina pectoris-Adalat Trial vs Coniel in Tokyo against Coronary Spastic Angina (ATTACK CSA) J Cardiol 2010 55 238 247 20206078 \n12 Rodríguez-Mañero M Oloriz T le Polain de Waroux JB Burri H Kreidieh B de Asmundis C Arias MA Arbelo E Díaz Fernández B Fernández-Armenta J Long-term prognosis of patients with life-threatening ventricular arrhythmias induced by coronary artery spasm Europace 2017 Epub ahead of print\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "10(3)",
"journal": "World journal of cardiology",
"keywords": "Acetylcholine; Brand-name drugs; Generic drugs; Refractory chest pain; Vasospastic angina",
"medline_ta": "World J Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101537090",
"other_id": null,
"pages": "15-20",
"pmc": null,
"pmid": "29588810",
"pubdate": "2018-03-26",
"publication_types": "D002363:Case Reports",
"references": "27856130;28387796;25366987;20668353;26620809;25273915;20206078;18522770;9392345;19050195",
"title": "Increased frequency of angina attacks caused by switching a brand-name vasodilator to a generic vasodilator in patients with vasospastic angina: Two case reports.",
"title_normalized": "increased frequency of angina attacks caused by switching a brand name vasodilator to a generic vasodilator in patients with vasospastic angina two case reports"
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"abstract": "Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recently approved drug class for the treatment of type 2 diabetes mellitus (T2D). Although they are largely well-tolerated, their intake has been associated with euglycemic diabetic ketoacidosis (DKA) in some rare cases. We report the case of a 70-year-old male with type 2 diabetes and no history of DKA, who started therapy with empagliflozin one day before presenting with acute pancreatitis and laboratory findings consistent with euglycemic DKA. SGLT2i can induce euglycemic DKA from the first dose. Given the atypical presentation, a high degree of clinical suspicion is required to recognize this complication.",
"affiliations": "Internal Medicine Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal.;Internal Medicine Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal.;Internal Medicine Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal.;Internal Medicine Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal.;Internal Medicine Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal.;Surgery Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal.;Internal Medicine Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal.",
"authors": "Calçada|Marta Brandão|MB|;Fernandes|Luís|L|;Soares Costa|Rita|R|;Montezinho|Sara|S|;Martins Duarte|Filipa|F|;Frutuoso|Luísa|L|;Freitas|Ana Raquel|AR|",
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"doi": "10.3390/clinpract11020031",
"fulltext": "\n==== Front\nClin Pract\nClin Pract\nclinpract\nClinics and Practice\n2039-7275\n2039-7283\nMDPI\n\n33917274\n10.3390/clinpract11020031\nclinpract-11-00031\nCase Report\nEuglycemic Diabetic Ketoacidosis after a Single Dose of Empagliflozin in a Patient with Pancreatitis\nCalçada Marta Brandão 1*\nFernandes Luís 1\nSoares Costa Rita 1\nMontezinho Sara 1\nMartins Duarte Filipa 1\nFrutuoso Luísa 2\nFreitas Ana Raquel 1\nVenketaraman Vishwanath Academic Editor\n1 Internal Medicine Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal; luisp.fernandes@outlook.com (L.F.); ritafscosta@gmail.com (R.S.C.); saramontezinho@gmail.com (S.M.); filipamartinsduarte@hotmail.com (F.M.D.); rakel.freitas@hotmail.com (A.R.F.)\n2 Surgery Department, Centro Hospitalar de Entre o Douro e Vouga, 4520-211 Santa Maria da Feira, Portugal; luisafrutuoso04@gmail.com\n* Correspondence: martabcalcada@hotmail.com\n06 4 2021\n6 2021\n11 2 216218\n09 2 2021\n29 3 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recently approved drug class for the treatment of type 2 diabetes mellitus (T2D). Although they are largely well-tolerated, their intake has been associated with euglycemic diabetic ketoacidosis (DKA) in some rare cases. We report the case of a 70-year-old male with type 2 diabetes and no history of DKA, who started therapy with empagliflozin one day before presenting with acute pancreatitis and laboratory findings consistent with euglycemic DKA. SGLT2i can induce euglycemic DKA from the first dose. Given the atypical presentation, a high degree of clinical suspicion is required to recognize this complication.\n\ndiabetic ketoacidosis\nsodium-glucose cotransporter 2 inhibitors\ndiabetes\nempagliflozin\n==== Body\n1. Introduction\n\nSodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recently approved drug class for type 2 diabetes mellitus treatment (T2D). This group of oral glucose-lowering drugs acts on the kidney by inhibiting glucose reabsorption to the blood in the proximal tubule, consequently leading to glucosuria [1].\n\nOn 1st August 2014, empagliflozin, a SGLT2i, was approved by the US Food and Drug Administration (FDA) as an adjunctive therapy to diet and exercise to improve glycemic control in adults with TD2 [2]. On 2nd December, 2016, a new indication for empagliflozin was FDA approved: to reduce the risk of cardiovascular death in adult patients with T2D and cardiovascular disease [3].\n\nAlthough this drug class is generally well-tolerated, in May 2015 the FDA emitted a warning on the potential risk of diabetic ketoacidosis (DKA) with unusually low-to-moderately elevated levels of serum glucose (Euglycemic DKA), following the use of SGLT2i [4]. The proposed mechanisms of Euglycemic DKA induced by SGLT2i are as follows: by reducing blood glucose levels, SGLT2i decrease the secretion of endogenous insulin by pancreatic b-cells. This in turn stimulates pancreatic a-cells, leading to increased glucagon secretion. SGLT2i also directly stimulate a-cells, thereby increasing plasma glucagon concentration and also promoting hepatic ketogenesis [5] In addition, SGLT2i increase the reabsorption of acetoacetate in the renal tubules, which raises ketonemia [5].\n\nThe rare presentation of Euglycemic DKA may lead to a delay in diagnosis and treatment with serious and potentially fatal consequences.\n\nIn this article, we describe an uncommon presentation of empagliflozin-associated euglycemic DKA in a patient with T2D, only one day after empagliflozin introduction.\n\n2. Case Report\n\nSeventy-year-old man with a past medical history of alcoholism, overweight (Body Mass Index of 28.9 kg/m2) and T2D for more than 10 years, well-controlled with a combination of dipeptidyl peptidase-4 inhibitor, biguanide and sulfonylurea (last known HbA1c 7.8%; average blood glucose levels of 162 mg/dL), with no previous episodes of DKA.\n\nHe presented to the emergency department with epigastric pain and vomiting for 3 days. The day before, he had been prescribed empagliflozin for hyperglycemia. At admission, he was alert and oriented, with dehydrated skin and mucous membranes. The blood pressure was 136/90 mmHg with a pulse of 116 bpm. He was febrile (tympanic temperature −38 °C) and had tachypnea. Cardiac and pulmonary auscultation was clear. There was diffuse abdominal tenderness but with no signs of peritoneal irritation. Urinary output was >0.5 mL/kg/h.\n\nLabs showed normal renal function and no electrolyte abnormalities. Amylase (253 U/L) and lipase (493 U/L) were elevated. There was also hyperglycemia (188 mg/dL), ketonemia (6.6 mmol/L) and metabolic acidemia with an increased anion gap (AG)—pH 7.28; pCO2 22 mmHg; HCO3− 10.3 mEq/L; lactate 2.0 mmol/L; AG 26 mmol/L—which worsened despite aggressive intravenous fluid replacement. Other causes of metabolic acidosis with an increased AG were excluded (renal insufficiency lactic acidosis and intoxication either by methanol, ethylene glycol or salicylates) and the diagnosis of SGLT2 Inhibitor-Associated Euglycemic DKA was assumed, aggravated in the context of an acute pancreatitis and decreased carbohydrate intake. Normal saline with dextrose and intravenous continuous insulin perfusion were started, alongside vital signs, hourly blood glucose, serum ketones and potassium were monitored. Afterwards, he was admitted to the surgical ward, with daily Internal Medicine evaluation, under a basal-bolus insulin regimen, with a favorable clinical evolution. After hospital discharge, the patient remained on basal-bolus insulin therapy, and was also referred to a specialized diabetes mellitus consultation for follow-up.\n\n3. Discussion\n\nDKA is a serious and potentially fatal T2D complication, occurring because of a profound insulin deficit. Euglycemic DKA is an unusual subset, characterized by metabolic acidosis with a pH < 7.3 and serum bicarbonate <18 mEq/L, ketosis, and serum glucose >200 mg/dL [6,7].\n\nDKA incidence in T2D is 1.34/million people per year [8]. In opposition, the incidence rate of euglycemic DKA is uncertain. Insulin dose reduction or cessation, severe acute illness, dehydration, surgery, low-carbohydrate diet, or excessive alcohol intake are among the risk factors [9,10].\n\nIn the present case, acute pancreatitis was considered the main trigger for DKA development. Acute pancreatitis is associated with decreased oral intake, possibly leading to a catabolic state with subsequent ketone bodies formation in the context of SGLT2i use. Excessive alcohol consumption may have also favored DKA appearance. However, it is unexpected that a single drug dose administration could have caused such a significant impact, since the average reported time from SGLT2i start or dose increasement to euglycemic DKA onset is 43 days (range 1 to 365 days) [4].\n\nFurthermore, the development of acute pancreatitis was related to incretin-based therapeutics in varied randomized controlled trials [11]. In our patient, dipeptidyl peptidase-4 inhibitor features as a potential cause of acute pancreatitis; however, there is no established causality [12]. Nonetheless, drug discontinuation is recommended after an episode of acute pancreatitis [12], which was done.\n\nTreatment for SGLT2i-associated euglycemic DKA is identical to conventional DKA, besides immediate drug withdrawal. Fortunately, in our case, the identification of the predisposing factors allowed for a rapid recognition of this entity and led to a timely treatment.\n\n4. Conclusions\n\nAlthough euglycemic DKA is a known SGLT2i adverse effect, its rarity and atypical presentation requires a high degree of clinical suspicion. Furthermore, as our case highlights, this diagnosis should be kept in mind as a possible complication since SGLT2i first administration. This is a potentially fatal condition in which early diagnosis and treatment allow for a complete clinical recovery.\n\nAuthor Contributions\n\nM.B.C.—manuscript preparation and review of the literature; A.R.F.—manuscript preparation and review of the literature; L.F. (Luis Fernandes)—review of the manuscript; R.S.C.—review of the manuscript; S.M.—review of the manuscript; F.M.D.—review of the manuscript; L.F. (Luisa Frutuoso)—review of the manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nInformed consent was obtained from the patient.\n\nData Availability Statement\n\nNo new data were created or analyzed in this study. Data sharing is not applicable to this article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest. The authors have no financial disclosures.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Bakris G.L. Fonseca V.A. Sharma K. Wright E.M. Renal sodium-glucose transport: Role in diabetes mellitus and potential clinical implications Kidney Int. 2009 75 1272 1277 10.1038/ki.2009.87 19357717\n2. US Food and Drug Administration FDA Approves Jardiance to Treat Type 2 Diabetes 2014 Available online: https://www.drugs.com/newdrugs/fda-approves-jardiance-empagliflozin-type-2-diabetes-4064.html (accessed on 15 March 2021)\n3. US Food and Drug Administration FDA Approves Jardiance (Empagliflozin) to Reduce Cardiovascular Death in Adults with Type 2 Diabetes 2016 Available online: https://www.drugs.com/newdrugs/fda-approves-jardiance-empagliflozin-reduce-cardiovascular-death-adults-type-2-diabetes-4462.html (accessed on 15 March 2021)\n4. US Food and Drug Administration Drug Safety and Availability. FDA Drug Safety Communication: FDA Revises Labels of SGLT2 Inhibitors for Diabetes to Include Warnings about Too Much Acid in the Blood and Serious Urinary Tract Infections 2020 Available online: https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm (accessed on 22 January 2021)\n5. Taylor S.I. Blau J.E. Rother K.I. SGLT2 inhibitors may predispose to ketoacidosis J. Clin. Endocrinol. Metab. 2015 100 2849 2852 10.1210/jc.2015-1884 26086329\n6. Modi A. Agrawal A. Morgan F. Euglycemic diabetic ketoacidosis: A review Curr. Diabetes Rev. 2017 13 315 321 10.2174/1573399812666160421121307 27097605\n7. Rosenstock J. Ferrannini E. Euglycemic diabetic ketoacidosis: A predictable, detectable, and preventable safety concern with SGLT2 inhibitors Diabetes Care 2015 38 1638 1642 10.2337/dc15-1380 26294774\n8. Jensen M.L. Persson F. Andersen G.S. Ridderstråle M. Nolan J.J. Casrtensen B. Jørgensen M.E. Incidence of ketoacidosis in the Danish type 2 diabetes population before and after introduction of sodium–glucose cotransporter 2 inhibitors—A nationwide, retrospective cohort study 1995–2014 Diabetes Care 2017 40 e57 e58 10.2337/dc16-2793 28283564\n9. Goldenberg R.M. Berard L.D. Cheng A.Y. Gilbert G.D. Verma S. Woo V.C. Yale J.-F. SGLT2 inhibitor-associated diabetic ketoacidosis: Clinical review and recommendations for prevention and diagnosis Clin. Ther. 2016 38 2654 2664 10.1016/j.clinthera.2016.11.002 28003053\n10. Hayami T. Kato Y. Kamiya H. Kondo M. Naito E. Sugiura Y. Kojima C. Sato S. Yamada Y. Kasagi R. Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet J. Diabetes Investig. 2015 6 587 590 10.1111/jdi.12330\n11. Meier J.J. Nauck M.A. Risk of pancreatitis in patients treated with incretin-based therapies Diabetologia 2014 57 1320 1324 10.1007/s00125-014-3231-y 24723174\n12. American Diabetes Association 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021 Diabetes Care 2021 44 Suppl. 1 S111 S124 10.2337/dc21-S009 33298420\n\n",
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"keywords": "diabetes; diabetic ketoacidosis; empagliflozin; sodium-glucose cotransporter 2 inhibitors",
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"title": "Euglycemic Diabetic Ketoacidosis after a Single Dose of Empagliflozin in a Patient with Pancreatitis.",
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"abstract": "The development of new targeted therapies has considerably changed the therapeutic paradigm of melanoma, significantly increasing overall survival (OS) and progression-free survival (PFS). However, skin-related adverse sequelae might occur and impact on patients' quality of life.\nIn this article we will cover the most important dermatological toxicities related to BRAF and MEK-inhibitors, along with updated management strategies.\nBRAF inhibitors have represented a revolution in the treatment of melanoma. They have improved the outcome of the disease and therefore represent an important option in the management and care of patients with advanced melanoma. Skin toxicity (especially the onset of squamous skin carcinomas) has been considered a major cutaneous side effect and, although the addition of MEK inhibitors in combination has significantly reduced the incidence of skin sequelae, serious skin adverse events might develop anyway and impact significantly on patients'quality of life and on national health system budget. The introduction of BRAF and MEK inhibitors as a new effective adjuvant treatment option for stage III and ulcerated melanoma has proved a significant impact on the risk of recurrence, and may have interesting developments in the near future as a further therapeutic tool.",
"affiliations": "Department of Skin Cancers, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.;Department of Skin Cancers, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.;Department of Skin Cancers, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.;Department of Skin Cancers, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.;Department of Otolaryngology Surgery and Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.;Department of Skin Cancers, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.;Department of Skin Cancers, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy.",
"authors": "Scarpato|Luigi|L|0000-0003-2748-786X;Festino|Lucia|L|0000-0002-3035-266X;Vanella|Vito|V|0000-0002-1276-5516;Madonna|Gabriele|G|0000-0001-9395-3190;Mastroianni|Massimo|M|;Palla|Marco|M|0000-0001-8901-0974;Ascierto|Paolo Antonio|PA|0000-0002-8322-475X",
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"title": "Dermatologic adverse events associated with targeted therapies for melanoma.",
"title_normalized": "dermatologic adverse events associated with targeted therapies for melanoma"
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"abstract": "In an attempt to abrogate the deleterious effects of graft-versus-host disease (GVHD), allogeneic transplantation for nonmalignant diseases was performed using high-dose CD34-cell infusion, partial T cell depletion, and no posttransplantation GVHD prophylaxis. Between 1998 and 2004, 16 patients with matched related donors were treated. Median age was 1.5 years (range, 5 months-18 years). The conditioning regimen consisted of busulphan 16 mg/kg, cyclophosphamide 200 mg/kg, antithymocyte globulin (ATG) 25 mg/kg, and fludarabine 200 mg/m(2). No GVHD prophylaxis was given. High doses of CD34 cells, positively selected by immunomagnetic beads, were infused at a median dose of 10.7 x 10(6) CD34/kg (range, 7.4-50 x 10(6)). A total of 1 x 10(5)/kg T cells were given. All patients engrafted, with no graft rejections. All were alive and well at a median of 37 months posttransplantation (range, 18-89 months). Only 1 patient developed chronic GVHD. No episodes of severe infection occurred during or after transplantation. Immunologic reconstitution with CD3/CD4 T cells > 200/microL was observed at a median of 117 days and that with naive T cells (CD4/CD45RA) at a median of 188 days posttransplantation. Our findings suggest that allogeneic transplantation from a matched family donor for nonmalignant disorders can be successfully performed using high doses of CD34 cells, moderate T cell depletion, and no posttransplantation immunosuppression.",
"affiliations": "Department of Pediatric Hemato-Oncology, Meyer Children Hospital, Haifa, Israel. r_elhasid@rambam.health.gov.il <r_elhasid@rambam.health.gov.il>",
"authors": "Elhasid|Ronit|R|;Arush|Myriam Ben|MB|;Zaidman|Irena|I|;Leiba|Ronit|R|;Barak|Ayelet Ben|AB|;Postovsky|Sergey|S|;Haddad|Nuhad|N|;Katz|Tami|T|;Pollack|Shimon|S|;Sami|Ivanka|I|;Gidoni|Osnat|O|;Rubin|Dina|D|;Mandel|Hanna|H|;Attias|Dina|D|;Reisner|Yair|Y|;Etzioni|Amos|A|;Rowe|Jacob M|JM|",
"chemical_list": "D018952:Antigens, CD34",
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"mesh_terms": "D000293:Adolescent; D018952:Antigens, CD34; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D006801:Humans; D007107:Immune System; D007223:Infant; D008212:Lymphocyte Depletion; D008297:Male; D012189:Retrospective Studies; D015996:Survival Rate; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
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"title": "Safe and efficacious allogeneic bone marrow transplantation for nonmalignant disorders using partial T cell depletion and no posttransplantation graft-versus-host-disease prophylaxis.",
"title_normalized": "safe and efficacious allogeneic bone marrow transplantation for nonmalignant disorders using partial t cell depletion and no posttransplantation graft versus host disease prophylaxis"
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"abstract": "Bidirectional ventricular tachycardia (BDVT), a rare ventricular arrhythmia, is commonly caused by digitalis toxicity or channelopathies and is rarely caused by aconite toxicity, myocarditis, infarction, or sarcoidosis. This paper describes a patient with BDVT, recurrent syncope, myocardial disarray, and interstitial fibrosis on histology but normal results on echocardiography with variants in the TTN, KCNH2, and GATA4 genes. (Level of Difficulty: Advanced.).",
"affiliations": "Department of Cardiac Electrophysiology, Toronto General Hospital, Toronto, Ontario, Canada.;Department of Cardiology, Vardhman Mahavir Medical College and Safdarjung Hospital, Delhi, India.;Department of Pathology, All India Institute of Medical Science, New Delhi, India.;Department of Radiology and Imaging, Fortis Escorts Heart Institute, New Delhi, India.;Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Aurora Center for Advanced Atrial Fibrillation Therapies, Aurora Cardiovascular Services, Aurora Health Care, Milwaukee, Wisconsin.",
"authors": "Chakraborty|Praloy|P|;Isser|Hermohander Singh|HS|;Arava|Sudheer|S|;Bhatia|Mona|M|;Mandal|Kausik|K|;Jahangir|Arshad|A|",
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"doi": "10.1016/j.jaccas.2019.05.018",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(19)30031-2\n10.1016/j.jaccas.2019.05.018\nCase Report\nClinical Case\nUnusual Cause of Bidirectional Ventricular Rhythm\nChakraborty Praloy DM praloyc@hotmail.com\na∗\nIsser Hermohander Singh DM b\nArava Sudheer MD c\nBhatia Mona MD d\nMandal Kausik DM e\nJahangir Arshad MD f\na Department of Cardiac Electrophysiology, Toronto General Hospital, Toronto, Ontario, Canada\nb Department of Cardiology, Vardhman Mahavir Medical College and Safdarjung Hospital, Delhi, India\nc Department of Pathology, All India Institute of Medical Science, New Delhi, India\nd Department of Radiology and Imaging, Fortis Escorts Heart Institute, New Delhi, India\ne Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India\nf Aurora Center for Advanced Atrial Fibrillation Therapies, Aurora Cardiovascular Services, Aurora Health Care, Milwaukee, Wisconsin\n∗ Address for correspondence: Dr. Praloy Chakraborty, Department of Cardiac Electrophysiology, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. praloyc@hotmail.com\n19 6 2019\n6 2019\n19 6 2019\n1 1 2126\n4 4 2019\n1 5 2019\n2 5 2019\n© 2019 The Authors\n2019\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBidirectional ventricular tachycardia (BDVT), a rare ventricular arrhythmia, is commonly caused by digitalis toxicity or channelopathies and is rarely…\n\nBidirectional ventricular tachycardia (BDVT), a rare ventricular arrhythmia, is commonly caused by digitalis toxicity or channelopathies and is rarely caused by aconite toxicity, myocarditis, infarction, or sarcoidosis. This paper describes a patient with BDVT, recurrent syncope, myocardial disarray, and interstitial fibrosis on histology but normal results on echocardiography with variants in the TTN, KCNH2, and GATA4 genes. (Level of Difficulty: Advanced.)\n\nGraphical abstract\n\nKey Words\n\nbidirectional ventricular tachycardia\nsarcoidosis\nventricular arrhythmia\nventricular bigeminy\nventricular tachycardia\n==== Body\nPresentation\n\nAn 11-year-old male patient presented with recurrent history of syncope during exercise for the previous 5 years. There were no prodromal symptoms associated with loss of consciousness or symptoms after recovery within 1 min. The patient was not taking medications or dietary or herbal supplements. Physical examination was unremarkable except for the presence of regularly irregular pulse. Resting electrocardiography (ECG) results showed premature ventricular complexes (PVC) of the left bundle branch block (LBBB) shape in lead V1 in the form of ventricular bigeminy (Figure 1A). Blood chemistry test results were normal. Twenty-four-hour ambulatory Holter monitor traces showed multiple PVCs (n = 24,957 in 24 h) of LBBB (Figure 1A), and right bundle branch block (RBBB) (Figure 1B), and several short runs of nonsustained ventricular rhythm, the longest of which was of RBBB morphology shapes in V1 with alternating left and right frontal axes (Figure 1B).Learning Objectives\n\n• Work-up of patients with bidirectional VT to narrow the differential diagnosis by stepwise use of ECG, exercise stress test, imaging, biopsy, and genetic testing.\n\n• Importance of histology and genetic testing to assess for early manifestation of concealed form of a disease, for example, hypertrophic cardiomyopathy in this case.\n\n• Management of bidirectional VT with beta-blockers and flecainide as recommended for CPVT, with monitoring for potential adverse effects, use of ICD for secondary prevention of sudden death, and use of uncommon antiarrhythmic agent that effectively suppressed refractory VT in this patient in the acute setting and over the long term.\n\nFigure 1 Ventricular Premature Complexes and Slow Bidirectional Ventricular Rhythm\n\n(A) Resting electrocardiogram of premature ventricular complexes in the form of ventricular bigeminy. (B) 24-h Holter monitor traces demonstrating a run of nonsustained slow ventricular rhythm with right bundle branch block morphology in V1 but alternating left and right frontal axis. (C) ECG in sinus rhythm with sinus arrhythmia, a QTc complex of 0.39 s, and a large U-wave in the precordial lead with a QTU interval of 0.51 s.\n\nMedical History\n\nNo significant illnesses. No family history of cardiac disorder or sudden death.\n\nDifferential Diagnosis\n\nBidirectional ventricular rhythm or tachycardia: catecholaminergic polymorphic ventricular tachycardia (CPVT); Andersen-Tawil syndrome (ATS); digoxin toxicity; aconitine toxicity; myocarditis; myocardial ischemia; familial hypokalemic periodic paralysis; sarcoidosis; tumor of the ventricle.\n\nInvestigations\n\nEchocardiography demonstrated normal biventricular function, wall thickness, and chamber dimensions (Figure 2A). Exercise ECG failed to demonstrate any signs of myocardial ischemia, sustained arrhythmias, or VT. The PVC frequency, however, increased with exercise. With the clinical history of exertional syncope and documented nonsustained slow bidirectional ventricular rhythm with structurally normal heart by echocardiography, cardiac channelopathy (CPVT vs. ATS) was believed to be the most probable diagnosis with history negative for digoxin or aconitine use and normal imaging study results. Neuroelectrophysiological testing was negative for ATS.Figure 2 Echocardiographic and CMR Images of the Proband Heart\n\n(A) Apical 4-chamber view of 2-dimensional echocardiogram showing normal wall thickness and chamber dimensions. (B) CMR image of 4-chamber phase sensitive inversion recovery view demonstrating a linear myocardial crypt (arrow) seen on 3D balanced turbo field-echo sequence images enhancing post-contrast on delayed images. There was no evidence of ventricular septal defect or ventricular hypertrophy. CMR = cardiac magnetic resonance.\n\nManagement\n\nTreatment with a beta-adrenergic antagonist (metoprolol tartrate, 25 mg twice daily) was started. When the dose of beta-blocker was increased over the next week (metoprolol tartrate, 3 times a day), the patient developed bradycardia without any decrease in PVC load. Hence, a combined therapy of reduced dose beta-blocker (metoprolol tartrate, 25 mg twice daily) and flecainide (50 mg twice daily) was started under continuous cardiac monitoring. Twenty-four hours after the initiation of flecainide, while in his hospital bed and not asleep, the patient went into cardiac arrest due to fast VT degenerating to ventricular fibrillation. The arrhythmia episode was detected immediately on the monitor and was cardioverted. The first biphasic 100-J shock failed, but successful cardioversion to sinus rhythm was achieved with the second, 200-J shock. After direct current cardioversion, ECG recoding showed frequent multifocal PVCs. Considering the possibility of flecainide toxicity, the drug was stopped, and the patient was treated with intravenous sodium bicarbonate. Sodium bicarbonate and conventional antiarrhythmic agents including amiodarone failed to control the ectopy, but the patients responded dramatically to intravenous phenytoin. ECG in showed sinus rhythm with marked sinus arrhythmia, QTc of 0.39 s, and prominent U-wave in the precordial lead with prolonged Q-U interval (0.51 s) (Figure 1C). Cardiac magnetic resonance tomography with gadolinium showed the presence of a deep crypt at the left ventricular aspect of the septal myocardium with associated discrete delayed post-contrast hyperenhancement (Figure 2B). Endomyocardial biopsy from the interventricular septum demonstrated myocyte disarray, increased interstitial fibrosis, and myocyte hypertrophy (Figure 3). The same histological changes were seen in all 4 biopsy samples from different areas of the interventricular septum (2 from the mid septum and 2 from the apical septum).Figure 3 Histological Changes on Endomyocardial Septal Biopsy Samples of the Proband Heart\n\n(A) Endomyocardial biopsy fragment (arrows) showed mild hypertrophy with nucleomegaly, myocyte disarray (hematoxylin and eosin [H&E] stain; original magnification ×10]). (B) Intermyofiber fibrosis (blue arrow) (Masson trichrome [MT] stain; original magnification ×40). Inflammatory cell infiltrate was absent.\n\nWith the histological changes suggestive of hypertrophic cardiomyopathy (HCM) in the absence of imaging evidence of ventricular hypertrophy, a diagnosis of phenotype-negative HCM (nonhypertrophic hypertrophic cardiomyopathy) was considered, and genetic analysis using next generation sequencing targeting the panel of 195 genes associated with cardiomyopathies and channelopathies obtained (Strand Centre for Genomics and Personalized Medicine, Bangalore, India). Three variants were found to be significant. A heterozygous nonsense variation in TTN (p.Ala6612LeufsTer6) was classified as pathogenic and 2 heterozygous missense variations, one at KCNH2 (p.Val535Met) and the other at GATA4 (p.Pro407Gln) were classified as variants of unclear significance. Both of the patient’s parents were asymptomatic and had normal baseline ECG, echocardiography, 24-h Holter monitoring, and exercise ECG results. Genetic analysis showed that the patient’s father harbored the same variation in the TTN and KCNH2 genes, whereas the mother carried the variation in the GATA4 gene.\n\nWith the clinical, electrocardiographic, imaging, histological, and genetic data, the patient’s condition was diagnosed as dual HCM and long QTU phenotype due to variation in TTN and KCNH2. An insertable cardioverter-defibrillator was implanted. Treatment with beta-blocker and phenytoin was continued.\n\nDiscussion\n\nThe expressed phenotype of this patient is a variable combination of heart muscle disease and channelopathy. In 1990, autopsy studies reported that sudden cardiac death patients with a family history of HCM may demonstrate widespread interstitial fibrosis with myocardial disarray in the absence of ventricular hypertrophy 1, 2. The increased availability of genetic analysis in HCM patients documented the fact that a subset of individuals in the family of classical HCM patients carry the causative gene mutation in the absence of classical ventricular hypertrophy (3). This subset of individuals was categorized as a genotype positive/phenotype negative (G+P−) or a nonhypertrophic hypertrophic cardiomyopathy phenotype. Detection of myocardial crypts in cardiac magnetic resonance imaging has been suggested as a marker of G+P− HCM (4); however, this is not specific for HCM and can be observed in patients with left ventricular hypertrophy or ischemic heart disease (5). Although the natural history of G+P− subsets is reported to be mostly benign (6), there are reports of sudden cardiac arrest in G+ family members of HCM patients in the absence of left ventricular hypertrophy (7). Endomyocardial biopsy in this patient demonstrated myocardial disarray, myocyte hypertrophy, and nucleomegaly suggestive of HCM. Autopsy studies have reported that myocardial disarray may be found in some areas of normal heart (8). In the present patient, however, widespread disarray was documented in all biopsy samples obtained from the apical and mid septum and was associated with increased interstitial fibrosis, and pathological changes in cardiomyocytes reduce the possibility of “physiological disarray.” The patient had a history of recurrent exertional syncope with spontaneous recovery over the previous 5 years and developed cardiac arrest only after initiation of flecainide therapy. There is the possibility that flecainide sustained VT due to a re-entrant mechanism with slowing of conduction within the myocardium along the fibrotic area, thus creating a proarrhythmic milieu within the microscopic structural abnormality in an otherwise grossly normal heart. Alternatively, flecainide could have exerted proarrhythmic effects due to its mild potassium channel blocking properties, predisposing to prolongation of repolarization and triggered activity, particularly if the repolarization reserve was already reduced, which is a possibility due to reduction in the rapid component of the delayed rectifier current (IKr) that may result from the KCNH2 variant. Bradycardia with flecainide has been described with sinoatrial conduction delays but seems unlikely in this patient.\n\nThe genetic test revealed a variation in the TTN gene, which encodes Titin, a sarcomeric protein. TTN mutations have been reported in HCM as well as in dilated cardiomyopathy. The variation identified (c.19831delC) is predicted to cause a frame shift and consequently premature termination of the protein (p.Ala6612LeufsTer6), which could result in a loss-of-function. Although the identified variant seems to be a novel mutation, a variation immediately proximal to the site described in this patient has been reported as “disease causing” in a patient with dilated cardiomyopathy (9). Whether the novel variant identified in the TTN gene in this patient with a structurally normal heart, according to echocardiography, but with histological characteristics of HCM (myocyte disarray, interstitial fibrosis, and myocyte hypertrophy), is an early manifestation of concealed HCM or of dilated cardiomyopathy is not known. This can only be determined by long-term follow-up that may reveal time-dependent expression of the phenotype.\n\nIn this patient, features such as episodes of nonsustained slow, bidirectional ventricular rhythm, PVCs of 2 different patterns, unique response of the arrhythmia to phenytoin and prominent U-wave in sinus rhythm ECG are interesting characteristics. BDVT and characteristic U-wave abnormality is a feature of ATS that presents with modest prolongation of QT and prominent U-wave and prolong QU interval, as was observed in the patient. A range of 10% to 15% of patients with genetically defined LQTS may present with baseline normal QTc (10). Phenytoin, a Class Ib antiarrhythmic agent, can reduce the duration of the action potential by inhibiting the slow sodium current and the inward calcium current in the plateau phase of action potential in Purkinje fibers (11), and clinical reports of phenytoin effectiveness in torsades de pointes, even in refractory cases, has been published (12). The unique response of arrhythmia to phenytoin may be a phenotypical expression of the complex electrophysiological milieu in the patient with myocardial disarray, fibrosis, and mutations in the TTN and KCNH2 genes.\n\nThe patient harbors a variation in KCNH2 gene that encodes the potassium voltage-gated channel subfamily H member 2 protein, which plays a role in the transport of potassium ions across the cell membrane during repolarization through the rapid component of the delayed rectifier Kþ channels IKr. Pathogenic variations in the KCNH2 gene have been shown to be associated with the autosomal dominant Romano-Ward long QT syndrome (loss of function) and short QT syndrome (gain of function). The identified variant in the present patient has been previously reported in a proband and his mother with LQTS2 (13), both with normal QT intervals (QTc <450 ms), but with a prominent U-wave, such as in the patient, suggesting contributory role of the variation in the expressed phenotype.\n\nThe association between HCM and QTc prolongation has been reported with prolongation of repolarization attributed to the sheer mass of ventricular myocardium 14, 15 and electrical remodelling with down-regulation of repolarizing K+ channels. Recent studies, however, reported concomitant LQT-related gene mutations associated with QT interval prolongation in HCM patients (16) in whom the ECG changes may appear earlier than those with ventricular hypertrophy alone (17).\n\nIn the present study, both the child and his father harbored the same variation in TTN and KCNH2 gene, but the father lacked the variation in the GATA4 gene, which could have influenced the selective expression of disease phenotype in the proband. Thus, the GATA4 variation could be acting as a genetic modifier in the patient, as previously reported for patients with HCM (18).\n\nFollow-up\n\nDuring 3 years’ follow-up, this patient has been asymptomatic, without any clinical VT or any significant ventricular arrhythmia, documented on 24 h ambulatory ECG monitoring. Follow-up echocardiography has so far failed to demonstrate any ventricular hypertrophy or dilatation.\n\nConclusions\n\nBDVT with structurally normal heart has been described in at least 2 channelopathies, CPVT and ATS. To the best of the present authors’ knowledge, BDVT has not been reported with any spectra of HCM. This study reports a rare case of BDVT in a patient with combined phenotype of nonhypertrophic hypertrophic cardiomyopathy with prominent U wave and a prolonged QTU interval. Under autosomal dominant conditions, the absence of a family history can be explained by variable penetrance or expression of the abnormal genes; in the present case, it is proposed that GATA4 could have acted as a genetic modifier for TTN and KCNH2 in the proband, giving rise to a complex phenotype of variable combination of heart muscle and electrical disease not observed in the parents.\n\nAcknowledgments\n\nThe authors thank Jennifer Pfaff and Susan Nord, Aurora Cardiovascular and Thoracic Service Line, Aurora Health Care, Milwaukee, Wisconsin, for their editorial assistance, and Brian Miller and Brian Schurrer for help with the figures.\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n==== Refs\nReferences\n\n1 McKenna W.J. Stewart J.T. Nihoyannopoulos P. McGinty F. Davies M.J. Hypertrophic cardiomyopathy without hypertrophy: two families with myocardial disarray in the absence of increased myocardial mass Br Heart J 63 1990 287 290 2278798\n2 Maron B.J. Kragel A.H. Roberts W.C. Sudden death in hypertrophic cardiomyopathy with normal left ventricular mass Br Heart J 63 1990 308 310 2278803\n3 Maron B.J. Semsarian C. Emergence of gene mutation carriers and the expanding disease spectrum of hypertrophic cardiomyopathy Eur Heart J 31 2010 1551 1553 20439260\n4 Maron M.S. Rowin E.J. Lin D. Prevalence and clinical profile of myocardial crypts in hypertrophic cardiomyopathy Circ Cardiovasc Imaging 5 2012 441 447 22563033\n5 Child N. Muhr T. Sammut E. Prevalence of myocardial crypts in a large retrospective cohort study by cardiovascular magnetic resonance J Cardiovasc Magn Reson 16 2014 66 25231729\n6 Gray B. Ingles J. Semsarian C. Natural history of genotype positive-phenotype negative patients with hypertrophic cardiomyopathy Int J Cardiol 152 2011 258 259 21862152\n7 Christiaans I. Lekanne dit Deprez R.H. van Langen I.M. Wilde A.A. Ventricular fibrillation in MYH7-related hypertrophic cardiomyopathy before onset of ventricular hypertrophy Heart Rhythm 6 2009 1366 1369 19539541\n8 Becker A.E. Caruso G. Myocardial disarray. A critical review Br Heart J 47 1982 527 538 7044398\n9 Jansweijer J.A. Nieuwhof K. Russo F. Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy Eur J Heart Fail 19 2017 512 521 27813223\n10 Moric-Janiszewska E. Markiewicz-Łoskot G. Łoskot M. Weglarz L. Hollek A. Szydłowski L. Challenges of diagnosis of long-QT syndrome in children Pacing Clin Electrophysiol 30 2007 1168 1170 17725765\n11 Scheuer T. Kass R.S. Phenytoin reduces calcium current in the cardiac Purkinje fiber Circ Res 53 1983 16 23 6861294\n12 Yager N. Wang K. Keshwani N. Torosoff M. Phenytoin as an effective treatment for polymorphic ventricular tachycardia due to QT prolongation in a patient with multiple drug intolerances BMJ Case Rep 2015 2015 pii: bcr2015209521\n13 Shao C. Lu Y. Liu M. Electrophysiological study of V535M hERG mutation of LQT2 J Huazhong Univ Sci Technolog Med Sci 31 2011 741 748 22173492\n14 Martin A.B. Garson A. Jr. Perry J.C. Prolonged QT interval in hypertrophic and dilated cardiomyopathy in children Am Heart J 127 1994 64 70 8273757\n15 Johnson J.N. Grifoni C. Bos J.M. Prevalence and clinical correlates of QT prolongation in patients with hypertrophic cardiomyopathy Eur Heart J 32 2011 1114 1120 21345853\n16 Wang L. Zuo L. Hu J. Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family Europace 18 2016 602 609 25825456\n17 Shao H. Zhang Y. Liu L. [Relationship between electrocardiographic and genetic mutation (MYH7-H1717Q, MYLK2-K324E and KCNQ1-R190W) phenotype in patients with hypertrophic cardiomyopathy] Zhonghua Xin Xue Guan Bing Za Zhi 44 2016 50 54 26813553\n18 Alonso-Montes C. Rodríguez-Reguero J. Martín M. Rare genetic variants in GATA transcription factors in patients with hypertrophic cardiomyopathy J Investig Med 65 2017 926 934\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "1(1)",
"journal": "JACC. Case reports",
"keywords": "bidirectional ventricular tachycardia; sarcoidosis; ventricular arrhythmia; ventricular tachycardia; ventricular bigeminy",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "21-26",
"pmc": null,
"pmid": "34316734",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "21862152;22563033;17725765;8273757;2278798;25231729;26071440;7044398;20439260;19539541;28381408;26813553;6861294;25825456;21345853;22173492;27813223;2278803",
"title": "Unusual Cause of Bidirectional Ventricular Rhythm.",
"title_normalized": "unusual cause of bidirectional ventricular rhythm"
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"companynumb": "CA-MYLANLABS-2020M1020776",
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"abstract": "In the present study, we aimed to evaluate temporal changes in heart-type fatty acid-binding protein (h-FABP) and myocardial performance index (Tei index) following administration of 5-fluorouracil (5-FU), a chemotherapeutic agent associated with myocardial ischemia induced by coronary vasospasm. Thirty-two patients with cancer receiving their first 5-FU-based chemotherapy were included in the study. Prior to chemotherapy and 24 hours after the initiation of chemotherapy, all patients underwent a comprehensive echocardiographic examination. Blood samples were taken for h-FABP and troponin I (TnI) measurements at different time points during the first 24 hours of 5-FU administration. Postinfusion echocardiography revealed worsening in Tei index (0.37 ± 0.08 vs 0.43 ± 0.07, P < .001). Clinically overt cardiotoxicity was evident in 4 (12.5%) of our patient population. Heart-type fatty acid binding protein and TnI levels were within normal ranges at all time points. Our results suggest that ischemia coronary vasospasm due to 5-FU cardiotoxicity should be reviewed. Furthermore, Tei index might be a sensitive indicator of occult 5-FU cardiotoxicity.",
"affiliations": "Department of Cardiology, Ahi Evren Training and Research Hospital, Trabzon, Turkey drtt61@gmail.com.;Department of Cardiology, Sakarya University Training and Research Hospital, Sakarya, Turkey.;Department of Cardiology, Ahi Evren Training and Research Hospital, Trabzon, Turkey.;Department of Cardiology, Ahi Evren Training and Research Hospital, Trabzon, Turkey.;Department of Cardiology, Ahi Evren Training and Research Hospital, Trabzon, Turkey.;Department of Cardiology, Kafkas University Hospital, Kars, Turkey.;Department of Cardiology, Izmir Sifa University Hospital, Izmir, Turkey.;Department of Clinical Oncology, Kanuni Education and Research Hospital, Trabzon, Turkey.;Department of Cardiology, Samsun Education and Research Hospital, Samsun, Turkey.;Department of Cardiology, Ahi Evren Training and Research Hospital, Trabzon, Turkey.;Department of Cardiology, Sakarya University Training and Research Hospital, Sakarya, Turkey.;Department of Cardiology, Ahi Evren Training and Research Hospital, Trabzon, Turkey.",
"authors": "Turan|Turhan|T|;Agac|Mustafa Tarik|MT|;Aykan|Ahmet Çağrı|AÇ|;Kul|Selim|S|;Akyüz|Ali Rıza|AR|;Gökdeniz|Tayyar|T|;Gül|İlker|İ|;Cengiz|Ercüment|E|;Boyacı|Faruk|F|;Erkan|Hakan|H|;Akdemir|Ramazan|R|;Celik|Sukru|S|",
"chemical_list": "D015415:Biomarkers; D050556:Fatty Acid-Binding Proteins; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1177/0003319716637516",
"fulltext": null,
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"issn_linking": "0003-3197",
"issue": "68(1)",
"journal": "Angiology",
"keywords": "5-fluorouracil; cardiotoxicity; echocardiography; heart-type fatty acid-binding protein",
"medline_ta": "Angiology",
"mesh_terms": "D000368:Aged; D015415:Biomarkers; D066126:Cardiotoxicity; D042241:Early Diagnosis; D004452:Echocardiography; D050556:Fatty Acid-Binding Proteins; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia",
"nlm_unique_id": "0203706",
"other_id": null,
"pages": "52-58",
"pmc": null,
"pmid": "26980771",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Usefulness of Heart-Type Fatty Acid-Binding Protein and Myocardial Performance Index for Early Detection of 5-Fluorouracil Cardiotoxicity.",
"title_normalized": "usefulness of heart type fatty acid binding protein and myocardial performance index for early detection of 5 fluorouracil cardiotoxicity"
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{
"companynumb": "TR-ACCORD-098773",
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"activesubstancename": "FLUOROURACIL"
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"abstract": "The COVID-19 pandemic has dramatically challenged the national health systems worldwide in the last months. Dalbavancin is a novel antibiotic with a long plasmatic half-life and simplified weekly administration regimens, thus representing a promising option for the outpatient treatment of Gram-positive infections and the early discharge of hospitalized patients. Dalbavancin is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Many preliminary data seem to support its use in other indications, such as osteomyelitis, prosthetic joint infections, and infective endocarditis.\n\n\n\nA search in the literature using validated keywords (dalbavancin, Gram-positive infections, Gram-positive cocci, ABSSSI, intravenous treatment, and long-acting antibiotics) was conducted on biomedical bibliographic databases (PubMed and Embase) from 2004 to 30 September 2020. Results were analyzed during two consensus conferences with the aim to review the current evidence on dalbavancin in Gram-positive infections, mainly ABSSSI, osteomyelitis, and infective endocarditis, highlight the main limitations of available studies and suggest possible advantages of the molecule.\n\n\n\nThe board identifies some specific subgroups of patients with ABSSSIs who could mostly benefit from a treatment with dalbavancin and agrees that the design of homogenous and robust studies would allow a broader use of dalbavancin even in other clinical settings.",
"affiliations": "Department of Systems Medicine, University of Rome \"Tor Vergata\", Rome, Italy; Infectious Diseases Clinic, University Hospital \"Tor Vergata\", Rome, Italy.;Infectious Diseases Clinic, Policlinico San Martino Hospital and Department of Health Sciences, University of Genoa, Genoa, Italy.;ARNAS Civico Di Cristina Benfratelli Hospital Trust, Palermo; PROMISE Department, University of Palermo School of Medicine, Palermo, Italy.;Department of Medical Sciences, University of Turin, Turin, Italy.;Department of Infectious Diseases and Infectious Emergencies, Immunodeficiences and Gender Related Infectious Diseases, Cotugno Hospital A.O. Dei Colli, Napoli, Italy.;Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.;Infectious and Tropical Diseases Unit, Department of Medicine and Surgery, University of Insubria and ASST-Sette Laghi, Varese, Italy.;Department of Medical and Surgical Sciences, University of Bologna - IRRCS Policlinico St Orsola, Bologna, Italy.;Clinical and Research Department, National Institute for Infectious Diseases Lazzaro Spallanzani, Rome, Italy.;Department of Medicine, University of Udine, Udine, Italy.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.;Department of Medical and Surgical Sciences, University of Bologna - IRRCS Policlinico St Orsola, Bologna, Italy.",
"authors": "Andreoni|Massimo|M|0000-0002-3205-9758;Bassetti|Matteo|M|0000-0002-0145-9740;Corrao|Salvatore|S|0000-0001-5621-1374;De Rosa|Francesco Giuseppe|FG|0000-0001-8338-0130;Esposito|Vincenzo|V|;Falcone|Marco|M|0000-0003-3813-8796;Grossi|Paolo|P|0000-0003-2883-5061;Pea|Federico|F|0000-0002-6966-7167;Petrosillo|Nicola|N|0000-0002-2585-7567;Tascini|Carlo|C|0000-0001-9625-6024;Venditti|Mario|M|0000-0003-2639-0281;Viale|Pierluigi|P|0000-0003-1264-0008",
"chemical_list": "D000900:Anti-Bacterial Agents; D017334:Teicoplanin; C469289:dalbavancin",
"country": "England",
"delete": false,
"doi": "10.1080/14787210.2021.1894130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-7210",
"issue": "19(9)",
"journal": "Expert review of anti-infective therapy",
"keywords": "ABSSSIs; COVID-19; Gram-positive; dalbavancin; endocarditis; long-acting; osteomyelitis",
"medline_ta": "Expert Rev Anti Infect Ther",
"mesh_terms": "D000553:Ambulatory Care; D000818:Animals; D000900:Anti-Bacterial Agents; D000086382:COVID-19; D004334:Drug Administration Schedule; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D017192:Skin Diseases, Bacterial; D017334:Teicoplanin",
"nlm_unique_id": "101181284",
"other_id": null,
"pages": "1125-1134",
"pmc": null,
"pmid": "33682593",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "The role of dalbavancin for Gram positive infections in the COVID-19 era: state of the art and future perspectives.",
"title_normalized": "the role of dalbavancin for gram positive infections in the covid 19 era state of the art and future perspectives"
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"companynumb": "AT-ALLERGAN-1909516US",
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"activesubstancename": "DALBAVANCIN HYDROCHLORIDE"
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{
"abstract": "Hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease caused by dysregulated activation of macrophages against one's blood cells. Major pathologic feature of HLH is hemophagocytosis. We present a case of HLH complicating methotrexate toxicity in a 65-year-old psoriatic patient with history of renal disease. Diagnosis of HLH was established as he fulfilled five out of eight HLH diagnostic criteria. This case report is presented to enlighten clinicians about the clinical entity of HLH and to suspect and recognize this rare and generally fatal disease at the earliest.",
"affiliations": "Department of Dermatology, PSG Institute of Medical Science and Research, Coimbatore, Tamil Nadu, India.;Department of Dermatology, PSG Institute of Medical Science and Research, Coimbatore, Tamil Nadu, India.;Department of Pathology, PSG Institute of Medical Science and Research, Coimbatore, Tamil Nadu, India.;Department of Pathology, PSG Institute of Medical Science and Research, Coimbatore, Tamil Nadu, India.",
"authors": "Anjali|V T|VT|;Rai|Reena|R|;Maheswari|G Uma|GU|;Kumar|Prasanna N|PN|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/idoj.IDOJ_299_19",
"fulltext": "\n==== Front\nIndian Dermatol Online J\nIndian Dermatol Online J\nIDOJ\nIndian Dermatology Online Journal\n2229-5178 2249-5673 Wolters Kluwer - Medknow India \n\nIDOJ-11-219\n10.4103/idoj.IDOJ_299_19\nCase Report\nHemophagocytic Lymphohistiocytosis Complicating Methotrexate Toxicity\nAnjali V. T. Rai Reena Maheswari G. Uma 1 Kumar Prasanna N. 1 Department of Dermatology, PSG Institute of Medical Science and Research, Coimbatore, Tamil Nadu, India\n1 Department of Pathology, PSG Institute of Medical Science and Research, Coimbatore, Tamil Nadu, India\nAddress for correspondence: Dr. Reena Rai, Department of Dermatology, PSG Institute of Medical Science and Research, Peelamedu, Coimbatore - 641 004, Tamil Nadu, India. E-mail: drreena_rai@yahoo.co.in\nMar-Apr 2020 \n09 3 2020 \n11 2 219 221\n6 2019 11 2019 Copyright: © 2020 Indian Dermatology Online Journal2020This 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.Hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease caused by dysregulated activation of macrophages against one's blood cells. Major pathologic feature of HLH is hemophagocytosis. We present a case of HLH complicating methotrexate toxicity in a 65-year-old psoriatic patient with history of renal disease. Diagnosis of HLH was established as he fulfilled five out of eight HLH diagnostic criteria. This case report is presented to enlighten clinicians about the clinical entity of HLH and to suspect and recognize this rare and generally fatal disease at the earliest.\n\nCytopeniashemophagocytic lymphohistiocytosishemophagocytic syndrome\n==== Body\nIntroduction\nHemophagocytic syndrome or hemophagocytic lymphohistiocytosis is a clinical syndrome of hyperinflammation resulting in uncontrolled and ineffective immune response.[12] It may be primary or secondary. Primary HLH is a genetic entity. Secondary HLH is associated with infections, malignancies, immune disorders, or drugs.[2345] In both types, activated macrophages engulf erythrocytes, leukocytes, platelets, and precursor cells in bone marrow, liver, and lymph nodes.[6] Most severe forms of the disease lead to a sepsis like picture and multiorgan dysfunction. HLH is a disease of rapid progression and has high mortality despite treatment.[3789] We report a case of secondary HLH complicating methotrexate toxicity and sepsis.\n\nCase History\nA 65-year-old male, a case of chronic plaque psoriasis on intermittent therapy with methotrexate since 15 years and chronic kidney disease since 5 years presented with fever, severe body ache, and ulcerative lesions over lips and trunk. He developed these symptoms 5 days after inadvertent intake of tablet methotrexate 5 mg for 5 consecutive days. Examination showed tender inguinal and axillary lymphadenopathy, hemorrhagic crusting of lips, and necrotic ulcers over psoriatic plaques and as well as normal skin with severe skin tenderness and positive Nikolsky's sign. Since ulcers were present over psoriatic plaques, methotrexate-induced skin necrosis was suspected. Histopathology findings were skin with detached stratum corneum, large subcorneal pustule [Figure 1a], mild spongiosis, marked regenerative atypia, basal vacuolar degeneration, pigment incontinence, and apoptotic keratinocytes [Figure 1b]. Routine investigations showed bicytopenia with hemoglobin of 9.6 g/dl, WBC of 600 cells/mm3 with normal platelet count of 120,000 cells/mm3. His renal function tests were altered with elevated urea (106 mg/dl) and creatinine levels (3.16 mg/dl). The patient was started on antibiotics, leucovorin rescue therapy (folinic acid 10 mg every 6th hourly), and injection Filgrastim (Granulocyte colony-stimulating factor) 300 mg subcutaneously daily. There was worsening pancytopenia and renal function and further developed splenomegaly, features of sepsis. Blood culture was positive for Group B streptococci and methicillin sensitive staphylococcus aureus and procalcitonin levels were elevated (24.5 ng/ml). His antibiotics were upgraded and platelet transfusion given in spite of which patient developed fever, tachycardia, hypotension with further decrease in platelet count to 6,000 cells/mm3 on 5th day. Secondary HLH was suspected and a workup was rapidly initiated based on HLH 2004 diagnostic criteria. Peripheral smear revealed pancytopenia [Figure 2]. Bone marrow aspiration was done which showed megaloblastic erythroid maturation, maturation arrest in the myeloid series, and hemophagocytosis [Figure 3a and b]. Patient had hyperferritinemia (>500 mcg/L) with normal fibrinogen (522 mg/dl) and triglycerides (50 mg/dl) levels. He thus fulfilled 5 out of 8 diagnostic criteria of HLH and was treated as per HLH 2004 protocol with systemic antifungals and injection dexamethasone 10 mg/m2. Despite all supportive measures, patient developed multiorgan dysfunction and succumbed.\n\nFigure 1 (a) Skin with detached stratum corneum, large subcorneal pustule (H and E, ×4). (b) Mild spongiosis, marked regenerative atypia, basal vacuolar degeneration, pigment incontinence and apoptotic keratinocytes (H and E, ×40)\n\nFigure 2 Peripheral smear showing pancytopenia (Giemsa ×40)\n\nFigure 3 Bone marrow showing hemophagocytosis. (a) Giemsa ×40. (b) Oil immersion ×100)\n\nDiscussion\nHLH is a rare disease characterized by cytokine overproduction and tissue infiltration with cytotoxic lymphocytes and activated macrophages resulting in fever, hepatosplenomegaly, and cytopenias.[129] A strict diagnostic criteria of HLH was given in 2004 by Histiocyte Society and is as follows.[910] Molecular diagnosis consistent with HLH that is the identification of mutations of PRF1, UNC13D, or STX11 or patient should fulfill five out of the eight criteria: fever (>100.4°F), splenomegaly, cytopenia affecting at least two of three lineages: Hb <9 g/dl (in infants <4 weeks: Hb <10 g/100 ml, platelets <100 × 109/L, Neutrophils <1 × 109/L), hypertriglyceridemia (fasting >265 mg/dl) and or hypofibrinogenemia (≤150 mg/dl), ferritin >500 ng/ml, hemophagocytosis in bone marrow, spleen, or lymph nodes, low or absent NK cell activity, soluble CD25 (soluble IL-2 receptor) >2400 U/ml and in the case of familial HLH there should be no evidence of malignancy.\n\nThis patient presented with features of methotrexate toxicity with skin necrosis, bone marrow suppression, and renal failure. His progressive pancytopenia was initially thought to be due to high dose methotrexate. He did not respond to leucovorin rescue therapy or injection Filgrastim and worsened clinically with features suggestive of sepsis due to which antibiotics were upgraded. He was evaluated for HLH as he had progressive pancytopenia unresponsive to treatment and decreased counts in spite of platelet transfusions. The major pathologic feature of HLH is hemophagocytosis as seen in our patient. It is also seen in conditions like sepsis and multiorgan failure.[3] There is considerable clinical and laboratory overlap between sepsis and HLH.[89] Diagnosis of HLH was established in our patient as he fulfilled five out of eight diagnostic criteria of HLH. This is a rare presentation of HLH complicating methotrexate toxicity. This case report is presented to enlighten clinicians about HLH inorder to reduce the mortality associated with the disease.\n\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Janka G Hemophagocytic lymphohistiocytosis: When the immune system runs amok Klin Padiatr 2009 221 278 85 19707989 \n2 Rosado FG Kim AS Hemophagocytic lymphocytosis: An update on diagnosis and pathogenesis Am J Clin Pathol 2013 139 713 27 23690113 \n3 Gupta S Weitzman S Primary and secondary hemophagocytic lymphohistiocytosis: Clinical features, pathogenesis and therapy Expert Rev Clin Immunol 2010 6 137 54 20383897 \n4 Mehta RS Smith RE Hemophagocytic lymphohistiocytosis (HLH): A review of literature Med Oncol 2013 30 740 24105023 \n5 Freeman HR Ramanan AV Review of haemophagocytic lymphohistiocytosis Arch Dis Child 2011 96 688 93 20584844 \n6 Favara BE Hemophagocytic lymphohistiocytosis: A hemophagocytic syndrome Semin Diagn Pathol 1992 9 63 74 1561489 \n7 Rouphael NG Talati NJ Vaughan C Cunningham K Moreira R Gould C Infections associated with haemophagocytic syndrome Lancet Infect Dis 2007 7 814 22 18045564 \n8 Price B Lines J Lewis D Holland N Haemophagocytic lymphohistiocytosis: A fulminant syndrome associated with multiorgan failure and high mortality that frequently masquerades as sepsis and shock S Afr Med J 2014 104 401 6 25214245 \n9 Henter JI Horne A Arico M Egeler RM Filipovich AH Imashuku S HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer 2007 48 124 31 16937360 \n10 Henter JI Tondini C Pritchard J Histiocyte disorders Crit Rev Oncol Hematol 2004 50 157 74 15157664\n\n",
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"issn_linking": "2229-5178",
"issue": "11(2)",
"journal": "Indian dermatology online journal",
"keywords": "Cytopenias; hemophagocytic lymphohistiocytosis; hemophagocytic syndrome",
"medline_ta": "Indian Dermatol Online J",
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"pages": "219-221",
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"pmid": "32477983",
"pubdate": "2020",
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"references": "15157664;24105023;16937360;23690113;1561489;19707989;20584844;25214245;20383897;18045564",
"title": "Hemophagocytic Lymphohistiocytosis Complicating Methotrexate Toxicity.",
"title_normalized": "hemophagocytic lymphohistiocytosis complicating methotrexate toxicity"
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"abstract": "The long duration of 4 months of postoperative adjuvant chemotherapy is currently recommended for locally advanced rectal cancer after preoperative chemoradiation and surgery. Whether a short duration could be applied in these patients is unknown. So, the purpose of this study is to evaluate the effects on prognosis based on different durations of adjuvant chemotherapy for rectal cancer. We performed a retrospective study of 200 rectal cancer patients who were treated with preoperative chemoradiation and were pathologically graded as ypII and ypIII stages between March 2003 and May 2012. All patients were divided into 2 groups according to the median duration of adjuvant chemotherapy of 2 months. Overall survival (OS) and disease-free survival (DFS) were compared between patients with duration shorter and longer than 2 months in the whole group and subgroups of ypII and ypIII. Recurrence patterns were also analyzed in all subgroups. Multivariate analysis was performed to explore clinical factors that were significantly associated with DFS, local recurrence-free survival, and distant metastasis-free survival. In subgroup of ypII stage, the 5-year OS and DFS were similar between patients in long and short durations of adjuvant chemotherapy. For patients of ypIII stage, although no significant difference was found in OS between patients in short and long durations, DFS was showed to be higher in the group of long duration. Further analysis showed that longer duration of adjuvant chemotherapy could lead to improved control of distant metastasis and no impact on local control. Multivariable analysis indicated that long duration of adjuvant chemotherapy is significantly associated with longer distant metastasis-free survival in patients with ypIII stage, but not in those with ypII stage. A long duration of at least 2 months of postoperative adjuvant chemotherapy is necessary for patients with ypIII stage, whereas it may not be absolutely appropriate for those with ypII stage. Therefore, we suggest a tailored selection of durations of adjuvant chemotherapy for locally advanced rectal cancer.",
"affiliations": "From the Department of Radiation Oncology (K-YY, Y-ML), SunYat-Sen Memorial Hospital, SunYat-Sen University; and Department of Radiation Oncology (RH, XY, Y-HG), State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.",
"authors": "You|Kai-Yun|KY|;Huang|Rong|R|;Yu|Xin|X|;Liu|Yi-Min|YM|;Gao|Yuan-Hong|YH|",
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"doi": "10.1097/MD.0000000000003427",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2710043610.1097/MD.0000000000003427034273700Research ArticleObservational StudyIs It Possible to Shorten the Duration of Adjuvant Chemotherapy for Locally Advanced Rectal Cancer? You Kai-Yun MDHuang Rong MDYu Xin MDLiu Yi-Min MDGao Yuan-Hong MDLi. Jianfeng From the Department of Radiation Oncology (K-YY, Y-ML), SunYat-Sen Memorial Hospital, SunYat-Sen University; and Department of Radiation Oncology (RH, XY, Y-HG), State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.Correspondence: Yi-Min Liu, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (e-mail: liuyiminsys@sina.cn).Co-correspondence: Yuan-Hong Gao, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China (e-mail: gaoyh69@sina.cn).4 2016 22 4 2016 95 16 e342716 11 2015 6 3 2016 28 3 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nThe long duration of 4 months of postoperative adjuvant chemotherapy is currently recommended for locally advanced rectal cancer after preoperative chemoradiation and surgery. Whether a short duration could be applied in these patients is unknown. So, the purpose of this study is to evaluate the effects on prognosis based on different durations of adjuvant chemotherapy for rectal cancer.\n\nWe performed a retrospective study of 200 rectal cancer patients who were treated with preoperative chemoradiation and were pathologically graded as ypII and ypIII stages between March 2003 and May 2012. All patients were divided into 2 groups according to the median duration of adjuvant chemotherapy of 2 months. Overall survival (OS) and disease-free survival (DFS) were compared between patients with duration shorter and longer than 2 months in the whole group and subgroups of ypII and ypIII. Recurrence patterns were also analyzed in all subgroups. Multivariate analysis was performed to explore clinical factors that were significantly associated with DFS, local recurrence-free survival, and distant metastasis-free survival.\n\nIn subgroup of ypII stage, the 5-year OS and DFS were similar between patients in long and short durations of adjuvant chemotherapy. For patients of ypIII stage, although no significant difference was found in OS between patients in short and long durations, DFS was showed to be higher in the group of long duration. Further analysis showed that longer duration of adjuvant chemotherapy could lead to improved control of distant metastasis and no impact on local control. Multivariable analysis indicated that long duration of adjuvant chemotherapy is significantly associated with longer distant metastasis-free survival in patients with ypIII stage, but not in those with ypII stage.\n\nA long duration of at least 2 months of postoperative adjuvant chemotherapy is necessary for patients with ypIII stage, whereas it may not be absolutely appropriate for those with ypII stage. Therefore, we suggest a tailored selection of durations of adjuvant chemotherapy for locally advanced rectal cancer.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nCurrently, the standard care for locally advanced rectal cancer is preoperative chemoradiotherapy followed by surgery. Irrespective of the final pathology, approximately 4 months of postoperative adjuvant chemotherapy (total 6 months of perioperative chemotherapy) is typically recommended.1 However, the evidence supporting this recommendation is limited.2 Several studies have questioned the need of adjuvant chemotherapy for locally advanced rectal patients, especially for those with ypT0–2,3–6 a subset of patients who exhibited favorable response and were reported to achieve excellent survival regardless of receiving adjuvant chemotherapy or not.7–9\n\nMeanwhile, the recent clinical trial of ADORE has well established the significant value of FOLFOX adjuvant chemotherapy for rectal cancer with ypII-III.10 However, the percentage of patients who could fulfill the full courses of adjuvant chemotherapy is less than 50% and many of the patients are unable to complete all the planned courses due to the side effects or other reasons during the long time of adjuvant chemotherapy.3,11,12 Thus, some patients received just inadequate durations of postoperative adjuvant chemotherapy. But, whether a shorter duration of adjuvant chemotherapy is suitable for rectal cancer patients is still unknown. Previous work has proved that adjuvant chemotherapy may not be need for ypT0–2N0 patients, whereas there were still some controversies regarding patients with ypT3–4N0.4,10 And our present study is to further explore whether a shorter duration of adjuvant chemotherapy should be adopted for the patients with ypT3–4N0, and also for those with ypTanyN+.\n\nMETHODS\nEthics Statement\nThis research was approved by the Ethics Committee of Sun Yat-sen University Cancer Center, and written informed consent was obtained from every patients included in the study.\n\nPatients\nThe data were extracted from a prospective database that enrolled all patients who underwent surgical treatment at Sun Yat-sen University Cancer Center from 2004 to 2012. The patient characteristics, operative findings, pathologic reports, adjuvant treatment, and follow-up data were included in the database. The selection criteria for the study were as follows: locally advanced rectal cancer, staged based on a clinical examination, such as endorectal ultrasound, pelvic computed tomography, and magnetic resonance imaging; received preoperative chemoradiation followed by total mesorectal excision (TME) surgery; pathologically staged as ypII and ypIII; underwent at least 1 course of postoperative adjuvant chemotherapy; no evidence of distant metastasis during the treatment and no concurrent malignancy or prior history of radiotherapy to the pelvis. Two hundred cases were included after reviewing the clinical data.\n\nTreatment\nAll the patients were prescribed to receive a standard protocol of neoadjuvant chemoradiotherapy, including 2 courses of concurrent chemotherapy. The prescribed dose for the entire pelvis was 46 Gy in 23 fractions for the pelvic with an additional 4 Gy divided into 2 fractions injected into the primary tumor. The radiotherapy technique was based on a 3-dimensional conformal radiotherapy treatment planning system (PINNACLE 8) using a 3-field irradiation plan (8-MV photon posterior–anterior field and 15-MV photon opposed lateral beams). The clinical target volume (CTV) has included the region of primary rectal tumor, perirectal tissues, the presacral lymph nodes, the internal iliac lymph nodes, and the obturator lymph nodes. The superior border of the CTV was at the bottom of L5, and the inferior border was 3 cm distal to the tumor. The anterior border was the posterior margin of the bladder or uterus, and the posterior border was the anterior margin of the sacrum. Planned target volume was defined as CTV+ 8 to 10 mm.\n\nThe regimens of the concurrent chemotherapy were FOLFOX6 and Xelox. A total of 41 patients were treated with chemotherapy using FOLFOX6 (85 mg/m2 oxaliplatin, 400 mg/m2 leucovorin, and 400 mg/m2 5-FU iv d1 followed by 2400 mg/m2 civ 46–48 hours), and the other 159 patients received Xelox (100 mg/m2 oxaliplatin d1 and 1000 mg/m2 capecitabine bid, po, d1–14).\n\nAt an interval of 5 to 12 weeks after the completion of chemoradiotherapy, radical surgery for rectal cancer was conducted. All operations were performed by colorectal surgeons according to the principles and methods of TME, including low anterior resection, abdominoperineal resection, and Hartmann.\n\nAdjuvant chemotherapy was administered to the patients according to the regimens of FOLFOX6 (85 mg/m2 oxaliplatin, 400 mg/m2 leucovorin, and 400 mg/m2 5-FU iv d1 followed by 2400 mg/m2 civ 46–48 hours), Xelox (130 mg/m2 oxaliplatin d1 and 1000 mg/m2 capecitabine bid, po, d1–14), or the single agent capecitabine (1250 mg/m2 bid, po, d1–14). The median duration of adjuvant chemotherapy was 2 months (range 0.7–4.2 months). Thus, all the patients included in our study were dichotomized into 2 groups according to the median duration: short-duration group and long-duration group.\n\nPathologic Classification\nPathologic tumor staging of the resected specimen was performed by experienced pathologists. The operative specimens of 200 patients were restaged according to the American Joint Committee on Cancer (AJCC) 7th Edition staging system. All of the specimens were carefully dissected to evaluate all potentially involved lymph nodes, and the median number of retrieved lymph nodes was 6 (range 2–37 nodes). Additionally, circumferential resection margin (CRM) involvement was defined as the maximum distance between the tumor and the proper rectal fascia of less than 1 mm. Negative CRM, as demonstrated by pathology, was achieved for all patients in this study.\n\nToxicity Assessment for Adjuvant Chemotherapy\nThe therapy-related adverse events were defined as complications that occurred during adjuvant treatment, which were graded based on Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Severe adverse events were defined as any grade ≥3 toxicity. Adverse events were recorded for each patient and were documented in our colorectal database.\n\nFollow-up\nThe follow-up policy was every 3 months for the first 2 years after surgery and every 6 months thereafter. The evaluations were done based on the complete blood count, liver function test, carcinoembryonic antigen (CEA), carbohydrate antigen 19–9 (CA19–9), and physical examination during each visit. Chest radiography, computed tomography scanning of the abdomen and pelvis, and colonoscopy were conducted every 6 months. The follow-ups for each patient were recorded in our database. In this study, the median follow-up period for all patients was 46 (range 10–107) months.\n\nStatistical Analysis\nAll statistical analyses were performed by SPSS software, version 18.0. Categorical variables were analyzed by using the chi-square test or Fisher exact test. Continuous variables were analyzed by the Student t test or Mann–Whitney U test. The Kaplan–Meier method was employed to compare disease-free survival (DFS) rates and overall survival (OS) rates. Multivariate analysis of DFS, local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) was performed by Cox proportional-hazards regression, and Cox proportional-hazards model was performed using a forward conditional selection of variables. Variables with P value <0.2 were entered into a Cox model. P < 0.05 was considered to be statistically significant.\n\nRESULTS\nClinical Characteristics\nIn all, 200 patients who underwent chemo-radiotherapy treatment and radical resection were included in our study. Among these patients, 120 patients were administered with 2 to 4.2 months of adjuvant chemotherapy, and the remaining 80 patients underwent it for a shorter duration of 0.7 to 2 months. Comparing with the patients who have received a longer duration of adjuvant chemotherapy, those who have received a shorter duration of it exhibited an older appearance, lower level of pretreatment CEA, and more percentage of clinical II stage. No significant difference in sex, hemoglobin (Hb), tumor location, clinical T stage, clinical N stage, tumor grade, concurrent chemotherapy, type of surgery, number of retrieved lymph nodes, ypN stage, ypT stage, regimens of adjuvant chemotherapy, and follow-ups were showed between the 2 groups (Table 1).\n\nTABLE 1 Patient Demographics, Baseline Tumor Characteristics, Type of Surgery, and Pathologic Outcome\n\nSurvival Analysis for the Entire Group\nFor the entire group, 40 patients died during the follow-ups. The 5-year OS rates in the long-duration and short-duration groups were 78.5% and 73.5%, respectively (Figure 1, Table 2), which was not significantly different between the 2 groups (P = 0.129). Sixty patients with tumor recurred. Among them, local recurrence was found in 18 patients, distant metastasis was detected in 32 patients, and both local and distant recurrences were found in 10 patients. Furthermore, the 5-year DFS rates were also comparable between the long-duration and short-duration groups (71.0% vs 58.5%; P = 0.145) (Figure 2, Table 2). We also performed the analysis based on ypTNM stage, and it was found that patients with ypIII stage acquired worse survival than those with ypII stage (Table 3).\n\nFIGURE 1 Overall survival (OS) for the whole group stratified by duration of adjuvant chemotherapy. No significant difference was found in OS between patients with long and short durations for the whole group (P = 0.129).\n\nTABLE 2 Survival for the Whole Group Patients\n\nFIGURE 2 Disease-free survival (DFS) for the whole group stratified by duration of adjuvant chemotherapy. No significant difference was found in DFS between patients with long and short durations for the whole group (P = 0.145).\n\nTABLE 3 The Comparison of the OS and DFS between ypII Stage and ypIII Stage\n\nSurvival Analysis for the Subgroup of ypII Stage\nIn the subgroup of ypII stage, 29 patients experienced recurrence; among these 17 patients died of tumor recurrence. There were 9 patients who displayed local recurrence and 16 patients who only exhibited distant metastasis. The remaining 4 patients developed both local and distant recurrence. In the long-duration and short-duration groups, the 5-year OS rates were 81.6% and 84.1%, respectively, and the 5-year DFS rates were 75.0% and 71.8%, respectively (Figures 3 and 4, Table 4). No significant difference was detected in either OS (P = 0.409) or DFS (P = 0.803). Further analysis of the recurrence pattern revealed that there were no differences in both the local recurrence and distant metastasis rates between groups of longer duration and shorter duration (P > 0.05) (Table 5).\n\nFIGURE 3 Overall survival (OS) for the subgroup of ypII stage stratified by duration of adjuvant chemotherapy. No significant difference was found in OS between patients with long and short durations for subgroup of ypII stage (P = 0.449).\n\nFIGURE 4 Disease-free survival (DFS) for the subgroup of ypII stage stratified by duration of adjuvant chemotherapy. No significant difference was found in DFS between patients with long and short durations for subgroup of ypII stage (P = 0.803).\n\nTABLE 4 Survival for Subgroup of ypII Stage\n\nTABLE 5 Recurrence Patterns for Patients with ypII Stage\n\nSurvival Analysis for the Subgroup of ypIII Stage\nFor the patients with ypIII stage, those who were undergoing long duration of adjuvant chemotherapy exhibited longer DFS than those who were undergoing short duration of it (P = 0.027) (Figure 5, Table 6). However, there was no significant difference in OS between the 2 groups (P = 0.086) (Figure 6, Table 6). Additionally, based on analysis of distant metastasis, the patients in the long-duration adjuvant-chemo group displayed a lower rate of distant metastasis than those in the short-duration adjuvant-chemo group (P = 0.041). Meanwhile, the rate of local recurrence between the 2 groups was similar (P = 0.364) (Table 7).\n\nFIGURE 5 Disease-free survival (DFS) for the subgroup of ypIII stage stratified by duration of adjuvant chemotherapy. Significant difference was found in DFS between patients with long and short durations for subgroup of ypIII stage (P = 0.027).\n\nTABLE 6 Survival for Subgroup of ypIII Stage\n\nFIGURE 6 Overall survival (OS) for the subgroup of ypIII stage stratified by duration of adjuvant chemotherapy. No significant difference was found in OS between patients with long and short durations for subgroup of ypIII stage (P = 0.086).\n\nTABLE 7 Recurrence Patterns for Patients with ypIII Stage\n\nClinical Predictors of DFS, LRFS, and DMFS\nFor patients with ypIII stage, multivariate analysis indicates that the factors of adjuvant chemotherapy and retrieved lymph nodes were the independent predictors of DFS. And the retrieved lymph nodes were found to be specifically associated with LRFS. Furthermore, short-duration adjuvant chemotherapy was also found to be significantly associated with lower DMFS, with patients who have received short-duration adjuvant chemotherapy having a 2.4-fold increased risk of distant metastasis in relation to those who received long duration of it (Table 8). However, in patients with ypII stage, the duration of adjuvant chemotherapy was not significantly associated with the survival. The location of the tumor was found to be the only factor to predict DMFS, and no other factors were detected to be associated with DFS or LRFS (Table 9).\n\nTABLE 8 Multivariate Analyses of DFS, LRFS, and DMFS for ypIII Stage Patients\n\nTABLE 9 Multivariate Analyses of DFS, LRFS, and DMFS for ypII Stage Patients\n\nToxicity of Adjuvant Chemotherapy\nThe most common toxicity types for adjuvant chemotherapy were diarrhea, hand-foot syndrome, and neutropenia. Severe adverse events during the adjuvant chemotherapy were observed mostly in the toxicity types of diarrhea, hand-foot syndrome, and nausea. It was further found that severe adverse events of toxicity types of diarrhea and hand-foot syndrome occurred more likely in the group receiving long-duration therapy than in the group receiving short-duration therapy. Whereas, other toxicity types with severe grade (grade ≥3) were similar between the 2 groups (Table 10).\n\nTABLE 10 Toxicity of Adjuvant Chemotherapy\n\nDISCUSSION\nAlthough a full course of adjuvant chemotherapy is still highly recommended for locally advanced rectal cancer after long-course chemoradiotherapy followed by radical resection, our current study has proposed certain challenges to this process of care. We found out that there were no significant differences in both OS and DFS among the patients who received long and short duration of adjuvant chemotherapy for the whole group of patients in our study. However, further subgroup analysis showed that, in patients with ypIII stage, those who were in the long-duration adjuvant-chemo group acquired longer DFS than those who were in the short-duration adjuvant-chemo group. But, in the subgroup of ypII stage, better survival has not been detected in patients who have received longer duration of adjuvant chemotherapy compared with those who have received shorter duration of it. Furthermore, we explored the pattern of recurrence for different subgroups. In the subgroup of ypIII stage, the results indicated similar local recurrence rates between patients who received long and short duration of adjuvant chemotherapy, but the rate of distant metastasis was found to be higher in the short-duration adjuvant-chemo group than that in the long-duration adjuvant-chemo group. Most importantly, this decreased rate of distant metastasis brought by longer duration of adjuvant chemotherapy was not shown in patients with ypII stage, revealing that the benefit of the long-duration postoperative adjuvant chemotherapy was focused on reducing the risk of distant metastasis only for those with ypIII stage. The value for patients with ypII stage was not fully supported. Multivariate analysis was performed using Cox proportional-hazards regression to ensure that the results are presented in a more constructed manner, The results showed that adjuvant chemotherapy was an independent predictor of DMFS for patients with ypIII stage, with patients who have received shorter duration of adjuvant chemotherapy having a 2.4-fold increased risk of distant metastasis compared with those who have received a longer duration of it. However, for patients with ypII stage, adjuvant chemotherapy was not significantly associated with the survival.\n\nThe benefit of adjuvant chemotherapy after neoadjuvant chemoradiotherapy and surgery in locally advanced rectal cancer is controversial and therefore, may be a reason for the wide variability in applications of adjuvant chemotherapy among institutions.2,13 There is also no conclusive evidence to define the optimal duration and regimen of adjuvant chemotherapy, which may lead to variability in physician recommendations and the patients’ decisions from different trials.10–12,14–16 As we know, 4 randomized clinical trials have specifically evaluated the value of adjuvant chemotherapy for locally advanced rectal cancer receiving neoadjuvant chemoradiotherpy. And they are EORTC22921, CHRONICLE, I-CNR-RT, and PROCTOR-SCRIPT trials.11,14–16 None of the 4 trials showed significant differences of OS and DFS between the patients who did and did not receive postoperative adjuvant chemotherapy. However, before we may accept the conclusion, we should also notice that the compliance to adjuvant chemotherapy was poor in those trials. Less than 50% of the patients in the EORTC22921 trial and CHRONICLE trial completed all cycles of chemotherapy. Thus, we could not exclude the possibility that it was due to the inadequate duration of adjuvant chemotherapy in the experimental group that lead to no improvement in survival by the adjuvant treatment. This hypothesis may be supported by the trial of ADORE, in which nearly all the patients completed the long-duration adjuvant chemotherapy and FOLFOX adjuvant chemotherapy was found to be effective. In the trial of ADORE, Hong et al randomly assigned 321 patients to use fluorouracil + leucovorin and FOLFOX. After a median follow-up of 38.2 months, the 3-year DFS was shown to be significantly higher in the FOLFOX group compared with that in fluorouracil + leucovorin group. And this difference was proved to be more obvious in patients with pathological stage III.10 The ADORE trial just indicated that adjuvant chemotherapy of FOLFOX was effective in rectal cancer patients with ypII and ypIII, and the regimen of adjuvant chemotherapy added with oxaliplatin tend to bring better survival than that containing only fluorouracil and leucovorin. Besides, Hong and Ryan mentioned that the reduced-dose bolus fashion of postoperative chemotherapy in the EORTC22921 trial, the small numbers of patients and poor accrual in CHRONICLE trial, and the underpower to detect a small survival benefit in the PROCTOR-SCRIPT trial may also affect the true results of the trials which were designed to explore the need of adjuvant chemotherapy for locally advanced rectal cancer.17 Furthermore, some studies still supported the routine use of postoperative adjuvant chemotherpay in some subsets of rectal cancer patients, especially in patients with ypII and ypIII stage.18,19 However, whether a short-duration adjuvant therapy could be applied is still unknown. Our present work further addresses this problem, showing that a short duration of fewer than 2 months of adjuvant therapy did not lead to impaired survival for patients with ypII stage, and long-duration adjuvant chemotherapy may still be needed for patients with ypIII stage.\n\nThe clinical dilemma of low compliance to the long duration of 4 months of postoperative adjuvant chemotherapy is often faced by the patients and physicians. Many patients failed to complete the long-duration adjuvant chemotherapy and some patients did not even receive it at all. As is reported by Haynes et al, significant variation exists in the receipt of postoperative chemotherapy after resection and it was shown that pathologic stage was the strongest determinant of which patients received postoperative chemotherapy with stage I are less likely to receive it than stage III.20 Other factors, such as age, Eastern Cooperative Oncology Group performance status ≥1, on Medicaid or indigent compared with private insurance, presence of reoperation/wound infection, and no closure of ileostomy/colostomy, were also found to be significantly associated with not receiving adjuvant chemotherapy.21 The reasons accounted for not completing all courses of the adjuvant chemotherapy in our study were mainly the toxicity caused by chemotherapy, poor performance status, the economic ability, and refusal. Whether shortening the adjuvant treatment time would be possible for these patients was clinically meaningful. As far as we know, we are the first to hypothesize and suggest that a short duration of adjuvant chemotherapy may be applied in patients with ypII stage. Whereas, for patients with ypIII stage, long duration of adjuvant chemotherapy seems to play a vital role in decreasing the rate of distant metastasis and should still be administered among these patients. Although our study was retrospective, there was no randomized trial that would specifically address this problem. The value was that many more patients with ypII stage would only undergo shorter duration of postoperative adjuvant chemotherapy, which can save a lot of time and alleviate the severity of toxicity caused by the chemotherapy.\n\nThere were several limitations in our present study. One of which was a retrospective analysis of a small sample size of rectal cancer patients with a short follow-up. Although we have supported that, in patients with ypII stage, long time of more than 2 months of adjuvant chemotherapy did not lead to better survival than that of fewer than 2 months, the exact duration has not yet been clearly outlined and it would only be fully answered by large randomized controlled clinical trials. Furthermore, patients with ypIII stage were more likely to develop distant failure rather than local recurrence in the long-term follow-up. Thus, whether the intensity of 4 months of postoperative adjuvant chemotherapy recommended by National Comprehensive Cancer Network guidelines could actually eradicate the potential of micro-distant metastasis is still unknown. Another major problem was due to the limited cases for patients receiving different regimens in the adjuvant chemotherapy, it prevented us from doing further analyses in deciding whether regimen added with oxaplatin would bring improved survival, as was found in the trial of ADORE.\n\nIn conclusion, the current study performed by us does not suggest more than 2 months of adjuvant chemotherapy for rectal cancer patients with ypII stage. However, for patients with ypIII stage, adjuvant chemotherapy of fewer than 2 months showed limited power to control the rate of distant metastasis. Thus, at least 2 months of adjuvant chemotherapy is highly recommended for these patients. Furthermore, distant failure was a major problem in locally advanced rectal cancer after preoperative chemoradiotherapy, and systemic therapy seems to be the main treatment to control it. So, identifying the optimum duration and regimen of adjuvant chemotherapy is imperative and need further investigation.\n\nAbbreviations: CA19-9 = carbohydrate antigen 19-9, CEA = carcinoembryonic antigen, CRM = circumferential resection margin, CTV = clinical target volume, DFS = disease-free survival, DMFS = distant metastasis-free survival, Hb = hemoglobin, LRFS = local recurrence-free survival, OS = overall survival, TME = total mesorectal excision.\n\nConflict of interest statement: The authors have declared no conflicts of interest.\n==== Refs\nREFERENCES\n1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: rectal cancer , 2015 \nhttp://www.nccn.org/ .\n2. Bujko K Glynne-Jones R Bujko M \nDoes adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials . Ann Oncol \n2010 ; 21 :1743 –1750 .20231300 \n3. Bosset JF Collette L Calais G \nChemotherapy with preoperative radiotherapy in rectal cancer . N Engl J Med \n2006 ; 355 :1114 –1123 .16971718 \n4. Govindarajan A Reidy D Weiser MR \nRecurrence rates and prognostic factors in ypN0 rectal cancer after neoadjuvant chemoradiation and total mesorectal excision . Ann Surg Oncol \n2011 ; 18 :3666 –3672 .21590450 \n5. Huh JW Kim HR \nPostoperative chemotherapy after neo-adjuvant chemoradiation and surgery for rectal cancer: Is it essential for patients with ypT0–2N0? \nJ Surg Oncol \n2009 ; 100 :387 –391 .19582821 \n6. Kiran RP Kirat HT Burgess AN \nIs adjuvant chemotherapy really needed after curative surgery for rectal cancer patients who are node-negative after neoadjuvant chemoradiotherapy? \nAnn Surg Oncol \n2012 ; 19 :1206 –1212 .21935748 \n7. Capirci C Valentini V Cionini L \nPrognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients . Int J Radiat Oncol Biol Phys \n2008 ; 72 :99 –107 .18407433 \n8. de Campos-Lobato LF Stocchi L Da LMA \nPathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence . Ann Surg Oncol \n2011 ; 18 :1590 –1598 .21207164 \n9. Park IJ You YN Agarwal A \nNeoadjuvant treatment response as an early response indicator for patients with rectal cancer . J Clin Oncol \n2012 ; 30 :1770 –1776 .22493423 \n10. Hong YS Nam BH Kim KP \nOxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial . Lancet Oncol \n2014 ; 15 :1245 –1253 .25201358 \n11. Glynne-Jones R Counsell N Quirke P \nChronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control . Ann Oncol \n2014 ; 25 :1356 –1362 .24718885 \n12. Rödel C Liersch T Becker H \nPreoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial . Lancet Oncol \n2012 ; 13 :679 –687 .22627104 \n13. Beets GL Glimelius BL \nAdjuvant chemotherapy for rectal cancer still controversial . Lancet Oncol \n2014 ; 15 :130 –131 .24440476 \n14. Bosset JF Calais G Mineur L \nFluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study . Lancet Oncol \n2014 ; 15 :184 –190 .24440473 \n15. Sainato A Cernusco Luna Nunzia V Valentini V \nNo benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT) . Radiother Oncol \n2014 ; 113 :223 –229 .25454175 \n16. Breugom AJ van Gijn W Muller EW \nAdjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial . Ann Oncol \n2015 ; 26 :696 –701 .25480874 \n17. Hong TS Ryan DP \nAdjuvant chemotherapy for locally advanced rectal cancer: is it a given? \nJ Clin Oncol \n2015 ; 33 :1878 –1880 .25940719 \n18. Geva R Itzkovich E Shamai S \nIs there a role for adjuvant chemotherapy in pathological complete response rectal cancer tumors following neoadjuvant chemoradiotherapy? \nJ Cancer Res Clin Oncol \n2014 ; 140 :1489 –1494 .24849731 \n19. Maas M Nelemans PJ Valentini V \nAdjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients . Int J Cancer \n2015 ; 137 :212 –220 .25418551 \n20. Haynes AB You YN Hu CY \nPostoperative chemotherapy use after neoadjuvant chemoradiotherapy for rectal cancer: Analysis of Surveillance, Epidemiology, and End Results-Medicare data, 1998–2007 . Cancer \n2014 ; 120 :1162 –1170 .24474245 \n21. Khrizman P Niland JC ter Veer A \nPostoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: a national comprehensive cancer network analysis . J Clin Oncol \n2013 ; 31 :30 –38 .23169502\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "95(16)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000970:Antineoplastic Agents; D017024:Chemotherapy, Adjuvant; D002681:China; D003082:Colectomy; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D018714:Radiotherapy, Adjuvant; D012004:Rectal Neoplasms; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e3427",
"pmc": null,
"pmid": "27100436",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "23169502;21207164;24849731;22627104;16971718;25201358;25418551;25480874;18407433;25940719;22493423;20231300;19755047;21935748;24440473;21590450;19582821;24718885;25454175;24474245;24440476",
"title": "Is It Possible to Shorten the Duration of Adjuvant Chemotherapy for Locally Advanced Rectal Cancer?",
"title_normalized": "is it possible to shorten the duration of adjuvant chemotherapy for locally advanced rectal cancer"
} | [
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"companynumb": "CN-ROCHE-1390141",
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"abstract": "A 37-year-old man suffered irreversible profound symptomatic bradycardia requiring a pacemaker 3 days after beginning tizanidine/loxoprofen combination therapy for neck pain. This combination therapy is prescribed frequently for joint pain; however, combining loxoprofen with tizanidine could increase the risk of symptomatic bradycardia that is both permanent and severe. Similar cases have not been reported. This case suggests that tizanidine should be used cautiously when combined with loxoprofen, and drug interaction screening should be performed.",
"affiliations": "1 Division of Nutrition, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, People's Republic of China.;2 Division of Cardiology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, People's Republic of China.",
"authors": "Li|Xiaolin|X|;Jin|Yunpeng|Y|http://orcid.org/0000-0003-4242-7072",
"chemical_list": "D000700:Analgesics; D010666:Phenylpropionates; C040656:loxoprofen; C023754:tizanidine; D003000:Clonidine",
"country": "England",
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"doi": "10.1177/0300060518765009",
"fulltext": "\n==== Front\nJ Int Med ResJ. Int. Med. ResIMRspimrThe Journal of International Medical Research0300-06051473-2300SAGE Publications Sage UK: London, England 2958755410.1177/030006051876500910.1177_0300060518765009Case ReportsIrreversible profound symptomatic bradycardia requiring pacemaker after tizanidine/loxoprofen combination therapy: a case report Li Xiaolin 1http://orcid.org/0000-0003-4242-7072Jin Yunpeng 2\n1 Division of Nutrition, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, People’s Republic of China\n2 Division of Cardiology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, People’s Republic of ChinaYunpeng Jin, Division of Cardiology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, N1 Shangcheng Road, Yiwu 322000, Zhejiang, People’s Republic of China. Email: 8013013@zju.edu.cn27 3 2018 6 2018 46 6 2466 2469 14 1 2018 22 2 2018 © The Author(s) 20182018SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).A 37-year-old man suffered irreversible profound symptomatic bradycardia requiring a pacemaker 3 days after beginning tizanidine/loxoprofen combination therapy for neck pain. This combination therapy is prescribed frequently for joint pain; however, combining loxoprofen with tizanidine could increase the risk of symptomatic bradycardia that is both permanent and severe. Similar cases have not been reported. This case suggests that tizanidine should be used cautiously when combined with loxoprofen, and drug interaction screening should be performed.\n\nCase reporttizanidineloxoprofenbradycardiaside effectpacemaker\n==== Body\nIntroduction\nTizanidine, an α2-adrenergic receptor agonist, is a widely used medication for the treatment of muscle spasticity and pain.1 However, adverse events have been reported with its use, including somnolence, dry mouth, asthenia, and dizziness.2–4 Bradycardia is among the reported events following tizanidine overdose.5\n\nThere are only rare reports of bradycardia as a side effect of tizanidine at conventional doses.6,7 In those cases, the heart rate improved after tizanidine was stopped. Another report describes a 93-year-old woman with irreversible profound symptomatic bradycardia from tizanidine.8 Here we report the case of a man who experienced irreversible profound symptomatic bradycardia requiring pacemaker placement after tizanidine/loxoprofen combination therapy.\n\nCase report\nA 37-year-old man with the chief complaints of profound dyspnea and dizziness for 3 days was admitted to the hospital with blood pressure 130/66 mmHg and heart rate 42 beats per minute. He was previously healthy and had been taking no other medications. His personal history and family history were unremarkable; specifically, he had no family history of heart disease. Three days before hospital admission, he had been seen at a pain clinic and was started on tizanidine and loxoprofen for neck pain. After taking an 18-mg total dose of tizanidine and 300 mg of loxoprofen, the patient developed severe symptomatic bradycardia. At admission, his oxygen saturation was normal, and an electrocardiogram revealed third-degree atrioventricular block with a heart rate of 42 beats per minute (Figure 1). His echocardiogram was normal. Laboratory testing revealed elevated triglycerides at 2.72 mmol/L. Troponin T and CK-MB were negative both at admission and 6 hours later. Tizanidine and loxoprofen were withheld, and IV fluids were administered upon admission. Cardiac catheterization was performed with no abnormal finding, and a transvenous pacer was placed immediately. During the next few days, his heart rate improved only slightly. Before discharge, the patient received a dual-chamber pacemaker for continued severe symptomatic bradycardia. After receiving the pacemaker, an electrocardiogram (Figure 2) and Holter electrocardiogram (Figure 3) revealed continuous paced rhythm.\n\nFigure 1. Electrocardiogram before pacemaker.\n\nFigure 2. Electrocardiogram after pacemaker.\n\nFigure 3. Holter electrocardiogram after pacemaker.\n\nThe study protocol was approved by the Ethics Committee of The Fourth Affiliated Hospital of Zhejiang University School of Medicine. The patient provided written informed consent for this case report.\n\nDiscussion\nThe usual causes of bradycardia such as electrolyte disorders, intracranial pressure elevation, hypothyroidism, infection, hypothermia, hyperactive carotid sinus reflex, organic heart disease, and pharmacotherapy with digitalis, beta-blockers and antiarrhythmics were excluded in this case.\n\nBradycardia as a side effect of tizanidine has been reported.5–7 In such cases, the heart rate improved after tizanidine was stopped. The heart rate of this adult patient barely improved despite cessation of tizanidine. It is possible that the severe permanent bradycardia experienced by this patient resulted solely from tizanidine; however, tizanidine/loxoprofen combination therapy could be the cause. A case involving the interaction of tizanidine combined with rofecoxib has been reported.7 Tizanidine is mainly metabolized by cytochrome P450;9 loxoprofen inhibits this enzyme,10 so an interaction between these drugs is possible.\n\nIrreversible profound symptomatic bradycardia has never been reported as a side effect of loxoprofen; however, palpitations may occur with oral loxoprofen.11 The cardiac electrophysiological properties of tizanidine and loxoprofen have yet to be clarified. Thus, it should be considered that the combined use of tizanidine and loxoprofen increases the risk of tizanidine-associated irreversible profound symptomatic bradycardia.\n\nIrreversible profound symptomatic bradycardia requiring pacemaker placement after using tizanidine/loxoprofen combination therapy has not been reported. Through this case, we believe that tizanidine should be used cautiously when combined with loxoprofen and drug interaction screening should be performed.\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==== Refs\nReferences\n1 Milanov I Georgiev D. \nMechanisms of tizanidine action on spasticity. \nActa Neurol Scand \n1994 ; \n89 : 274 –279 .8042446 \n2 Wagstaff AJ Bryson HM. \nTizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders. \nDrugs \n1997 ; \n53 : 435 –452 .9074844 \n3 Nance PW Sheremata WA Lynch SG et al \nRelationship of the antispasticity effect of tizanidine to plasma concentration in patients with multiple sclerosis. \nArch Neurol \n1997 ; \n54 : 731 –736 .9193208 \n4 \nA double-blind, placebo-controlled trial of tizanidine in the treatment of spasticity caused by multiple sclerosis. United Kingdom Tizanidine Trial Group . Neurology \n1994 ; \n44 (11 Suppl 9 ): S70 –S78 .7970014 \n5 Spiller HA Bosse GM Adamson LA. \nRetrospective review of Tizanidine (Zanaflex) overdose. \nJ Toxicol Clin Toxicol \n2004 ; \n42 : 593 –596 .15462150 \n6 Publow SW Branam DL. \nHypotension and bradycardia associated with concomitant tizanidine and lisinopril therapy. \nAm J Health Syst Pharm \n2010 ; \n67 : 1606 –1610 .20852161 \n7 Kick A Bertoli R Moschovitis G et al \n[Extreme sinus bradycardia (30/min) with acute right heart failure under tizanidine (Sirdalud). Possible pharmacological interaction with rofecoxib (Vioxx)]. \nMed Klin (Munich) \n2005 ; \n100 : 213 –216 [in German, English Abstract].15834531 \n8 Cortes J Hall B Redden D. \nProfound symptomatic bradycardia requiring transvenous pacing after a single dose of tizanidine. \nJ Emerg Med \n2015 ; \n48 : 458 –460 .25456780 \n9 Granfors MT Backman JT Laitila J et al \nTizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. \nBr J Clin Pharmacol \n2004 ; \n57 : 349 –353 .14998432 \n10 Iwasaki K Matsuda H Nagase K et al \nEffects of twenty-three drugs on the metabolism of FK506 by human liver microsomes . Res Commun Chem Pathol Pharmacol \n1993 ; \n82 : 209 –216 .7508138 \n11 Greig SL Garnock-Jones KP. \nLoxoprofen: a review in pain and inflammation . Clin Drug Investig \n2016 ; \n36 : 771 –781 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "46(6)",
"journal": "The Journal of international medical research",
"keywords": "Case report; bradycardia; loxoprofen; pacemaker; side effect; tizanidine",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000328:Adult; D000700:Analgesics; D054537:Atrioventricular Block; D001919:Bradycardia; D002304:Cardiac Pacing, Artificial; D003000:Clonidine; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D019547:Neck Pain; D010666:Phenylpropionates",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "2466-2469",
"pmc": null,
"pmid": "29587554",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27444038;8042446;15462150;15834531;20852161;7508138;25456780;9074844;7970014;14998432;9193208",
"title": "Irreversible profound symptomatic bradycardia requiring pacemaker after tizanidine/loxoprofen combination therapy: a case report.",
"title_normalized": "irreversible profound symptomatic bradycardia requiring pacemaker after tizanidine loxoprofen combination therapy a case report"
} | [
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"companynumb": "CN-UNICHEM PHARMACEUTICALS (USA) INC-UCM201807-000161",
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"occurcountry": "CN",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIZANIDINE"
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"abstract": "OBJECTIVE\nAmong patients with upper abdominal malignancies, intensity-modulated radiation therapy (IMRT) can improve dose distributions to critical dose-limiting structures near the target. Whether these improved dose distributions are associated with decreased toxicity when compared with conventional three-dimensional treatment remains a subject of investigation.\n\n\nMETHODS\n46 patients with pancreatic/ampullary cancer were treated with concurrent chemoradiation (CRT) using inverse-planned IMRT. All patients received CRT based on 5-fluorouracil in a schema similar to Radiation Therapy Oncology Group (RTOG) 97-04. Rates of acute gastrointestinal (GI) toxicity for this series of IMRT-treated patients were compared with those from RTOG 97-04, where all patients were treated with three-dimensional conformal techniques. Chi-square analysis was used to determine if there was a statistically different incidence in acute GI toxicity between these two groups of patients.\n\n\nRESULTS\nThe overall incidence of Grade 3-4 acute GI toxicity was low in patients receiving IMRT-based CRT. When compared with patients who had three-dimensional treatment planning (RTOG 97-04), IMRT significantly reduced the incidence of Grade 3-4 nausea and vomiting (0% vs. 11%, p = 0.024) and diarrhea (3% vs. 18%, p = 0.017). There was no significant difference in the incidence of Grade 3-4 weight loss between the two groups of patients.\n\n\nCONCLUSIONS\nIMRT is associated with a statistically significant decrease in acute upper and lower GI toxicity among patients treated with CRT for pancreatic/ampullary cancers. Future clinical trials plan to incorporate the use of IMRT, given that it remains a subject of active investigation.",
"affiliations": "Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.",
"authors": "Yovino|Susannah|S|;Poppe|Matthew|M|;Jabbour|Salma|S|;David|Vera|V|;Garofalo|Michael|M|;Pandya|Naimesh|N|;Alexander|Richard|R|;Hanna|Nader|N|;Regine|William F|WF|",
"chemical_list": "D003841:Deoxycytidine; D000069287:Capecitabine; C056507:gemcitabine; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2009.10.043",
"fulltext": null,
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"issn_linking": "0360-3016",
"issue": "79(1)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014670:Ampulla of Vater; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D016009:Chi-Square Distribution; D003138:Common Bile Duct Neoplasms; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D041981:Gastrointestinal Tract; D006801:Humans; D008297:Male; D008875:Middle Aged; D058958:Organs at Risk; D010190:Pancreatic Neoplasms; D050397:Radiotherapy, Intensity-Modulated; D012189:Retrospective Studies",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "158-62",
"pmc": null,
"pmid": "20399035",
"pubdate": "2011-01-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers.",
"title_normalized": "intensity modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers"
} | [
{
"companynumb": "US-ROCHE-1915487",
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"drug": [
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"actiondrug": "5",
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"activesubstancename": "FLUOROURACIL"
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"drugadditional": "3",
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{
"abstract": "OBJECTIVE\nCardiotoxicity is an important limiting factor in the use of antineoplastic agents. The risk of arrhythmia and the electrophysiological effects of these agents are poorly characterized though increasing evidence suggests a high prevalence of complications.\n\n\nMETHODS\nPatients with substantial cardiovascular risk factors are often excluded from clinical trials, while the aging population of patients actually receiving therapies may have an underlying arrhythmogenic substrate due to comorbidities. Risk stratification of patients before the selection of a therapeutic regimen is essential. Given the regular use of combination therapies, the potential for arrhythmia of each agent must be fully understood. Despite limited data and understanding in clinical practice, decisions on whether to initiate specific therapies in high-risk patients and how to manage the associated complications are made regularly.\n\n\nCONCLUSIONS\nThis review describes the observed arrhythmias and proposed mechanisms for several major classes of antineoplastic agents. It also provides recommendations for risk stratification, monitoring, prophylaxis, and therapy, emphasizing the need for a collaborative relationship between oncologists and cardiologists and areas for future research.",
"affiliations": "Department of Medicine, The Johns Hopkins University, Baltimore, Md., USA.",
"authors": "Markman|Timothy M|TM|;Nazarian|Saman|S|",
"chemical_list": "D018943:Anthracyclines; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001152:Arsenicals; D010087:Oxides; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D000077237:Arsenic Trioxide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000446374",
"fulltext": null,
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"issn_linking": "0030-2414",
"issue": "91(2)",
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"keywords": null,
"medline_ta": "Oncology",
"mesh_terms": "D018943:Anthracyclines; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001145:Arrhythmias, Cardiac; D000077237:Arsenic Trioxide; D001152:Arsenicals; D066126:Cardiotoxicity; D006801:Humans; D010087:Oxides; D047428:Protein Kinase Inhibitors; D018570:Risk Assessment; D043823:Taxoids",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "61-8",
"pmc": null,
"pmid": "27256307",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Arrhythmia and Electrophysiological Effects of Chemotherapy: A Review.",
"title_normalized": "arrhythmia and electrophysiological effects of chemotherapy a review"
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"activesubstancename": "ARSENIC TRIOXIDE"
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{
"abstract": "We report of a 26-year-old female patient who was referred to our centre with congestive heart failure (CHF). Acute myocarditis with a high Parvovirus B19 virus load was diagnosed by myocardial biopsy. CHF improved after start of ramipril 5 mg/d, metoprolol, diuretics, immunoglobins, and a 24-hour infusion of levosimendan. Soon after initiation of medical therapy, the patient started to expectorate bronchial casts with varying frequencies (three times per week to five times daily). Thorough pneumological workup, including histology of the casts, microbiology, and a CT scan of the lungs, did not reveal any cause for bronchial cast formation. Inhalative corticoids were started without any benefit. Two years later, cardiac catheterisation demonstrated normalised left ventricular function. LV end-diastolic pressure, however, was still elevated at 14 mmHg. Endomyocardial biopsies at this time were negative for virus genome. Finally, we changed afterload reduction therapy from ramipril to candesartan. Within 24 hours, expectoration of bronchial casts terminated. Four weeks later, re-exposition to ramipril prompted immediate re-appearance of cast formation, which again stopped with switching back to candesartan. Finally, we were to prove that treatment with ramipril resulted in bronchial cast formation in this patient.",
"affiliations": "Pediatric Cardiology and Intensive Care Medicine, Georg-August-University, D-37075 Göttingen, Germany.;Pediatric Cardiology and Intensive Care Medicine, Georg-August-University, D-37075 Göttingen, Germany.;Pediatric Cardiology and Intensive Care Medicine, Georg-August-University, D-37075 Göttingen, Germany.",
"authors": "Plümacher|Kim Sarah|KS|https://orcid.org/0000-0002-7090-8490;Paul|Thomas|T|;Sigler|Matthias|M|",
"chemical_list": "D058671:Adrenergic beta-1 Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D008790:Metoprolol; D017257:Ramipril",
"country": "England",
"delete": false,
"doi": "10.1017/S1047951119002294",
"fulltext": null,
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"issn_linking": "1047-9511",
"issue": "29(12)",
"journal": "Cardiology in the young",
"keywords": "ACE inhibitors; Bronchial casts; Fontan circulation; bradykinin; plastic bronchitis",
"medline_ta": "Cardiol Young",
"mesh_terms": "D058671:Adrenergic beta-1 Receptor Antagonists; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors; D001980:Bronchi; D005260:Female; D006333:Heart Failure; D006801:Humans; D008790:Metoprolol; D009205:Myocarditis; D010322:Parvoviridae Infections; D016732:Parvovirus B19, Human; D017257:Ramipril",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "1565-1566",
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"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Expectoration of bronchial casts in association with Ramipril treatment.",
"title_normalized": "expectoration of bronchial casts in association with ramipril treatment"
} | [
{
"companynumb": "DE-PFIZER INC-2019293415",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": nul... |
{
"abstract": "Cocaine use accounts for 40% of the annual drug use related emergency department visits in the United States. Cocaine use is hence recognized as a major health problem. Cocaine blocks the presynaptic reuptake of norepinephrine and dopamine. The resulting increased adrenergic activity leads to vasoconstriction. Additionally, via various mechanisms, cocaine leads to a prothrombotic state and increases myocardial demand. Cocaine can cause coronary vasospasm and is therefore, associated with acute myocardial injury even in the absence of pre-existing atherosclerotic coronary artery disease. Nitroglycerin has a class 1C indication by the ACCF/AHA guidelines for patients with ST-segment elevation or depression that accompanies ischemic chest discomfort in the setting of cocaine use. It has been shown to reverse cocaine-induced coronary vasospasm and chest pain. In this case report, for the first time, we discuss how intravenous administration of high dose nitroglycerin to a patient in pulseless ventricular tachycardia with angiographically confirmed vasospasm induced by cocaine resulted in return of spontaneous circulation.",
"affiliations": "Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA. Babapoos@einstein.edu.;Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA.;Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.;Department of Medicine, Einstein Medical Center, Philadelphia, PA, 19141, USA.;Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA.;Division of Cardiology, Department of Medicine, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA, 19141, USA.",
"authors": "Babapoor-Farrokhran|Savalan|S|0000-0002-9898-2895;Kalla|Aditi|A|;Gill|Deanna|D|;Gulab|Asma|A|;Banka|Sahil|S|;Kalra|Sanjog|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-021-09635-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "21(6)",
"journal": "Cardiovascular toxicology",
"keywords": "Cocaine-induced coronary vasospasm; Coronary vasospasm; Nitroglycerin; ST elevation myocardial infarction",
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": null,
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "490-493",
"pmc": null,
"pmid": "33534027",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "10351966;1543310;1906905;3195611;20223096;14606991",
"title": "Peripheral Administration of Nitroglycerin in Pulseless Ventricular Tachycardia due to Cocaine-Induced Coronary Vasospasm.",
"title_normalized": "peripheral administration of nitroglycerin in pulseless ventricular tachycardia due to cocaine induced coronary vasospasm"
} | [
{
"companynumb": "US-MYLANLABS-2021M1036647",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": "3",
... |
{
"abstract": "Haploidentical transplantation with PTCY following marrow or PBSC graft has been associated with low incidence of GVHD in adults with similar data lacking in children. We report on the outcome of 25 patients <20 yr of age (median age 12 yr), undergoing a haploidentical PBSC transplantation for both malignant and non-malignant disorders. Engraftment was prompt and sustained. Cumulative incidences of acute GVHD and chronic GVHD were 40.3% and 16.7%, respectively. On subgroup analysis, it was evident that acute GVHD developed in 80% of patients <10 yr compared to only 13.3% in those between 10 and 20 yr [log-rank p = 0.001], despite similar graft composition with significantly higher NRM (60% vs. 0%; p = 0.001). The FFS was 63.5%; (79% in >10 yr and 40% in <10 yr, p = 0.01). Our data suggest that PTCY-based haploidentical PBSC transplantation is feasible in older children, but results in early and severe alloreactivity in younger children. These findings, despite being counterintuitive, could be explained by the variable metabolism of CY and oral mycophenolate in younger children indicating that PTCY-based approach as used in adults might not be adequate for younger children.",
"affiliations": "Department of Blood and Marrow Transplantation, Dharamshila Hospital and Research Centre, New Delhi, India.;Manashi Chakrabarti Foundation, Kolkata, India.;Manashi Chakrabarti Foundation, Kolkata, India.;CSIR-Indian Institute of Chemical Biology, Kolkata, India.;Department of Blood and Marrow Transplantation, Dharamshila Hospital and Research Centre, New Delhi, India.",
"authors": "Jaiswal|Sarita Rani|SR|0000-0002-9988-3514;Chakrabarti|Aditi|A|;Chatterjee|Sumita|S|;Ray|Kunal|K|;Chakrabarti|Suparno|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12724",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "20(5)",
"journal": "Pediatric transplantation",
"keywords": "graft-versus-host disease; haploidentical; pediatric; peripheral blood stem cell; post-transplantation cyclophosphamide",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D003520:Cyclophosphamide; D046148:Donor Selection; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D010865:Pilot Projects; D014019:Tissue Donors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "675-82",
"pmc": null,
"pmid": "27217372",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children.",
"title_normalized": "haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft the need to look beyond post transplantation cyclophosphamide in younger children"
} | [
{
"companynumb": "PHHY2016IN072424",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"d... |
{
"abstract": "Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma and four cases of PCNSL have previously been described in association with mycophenolate mofetil. We report the fifth case of PCNSL in a patient with lupus nephropathy while on mycophenolate mofetil treatment.",
"affiliations": "1 Department of Rheumatology, Trakya University Medical Faculty, Edirne, Turkey.;2 Department of Hematology, Trakya University Medical Faculty, Edirne, Turkey.;3 Department of Radiology, Trakya University Medical Faculty, Edirne, Turkey.;4 Department of Pathology, Trakya University Medical Faculty, Edirne, Turkey.;1 Department of Rheumatology, Trakya University Medical Faculty, Edirne, Turkey.",
"authors": "Balci|M A|MA|;Pamuk|G E|GE|;Unlu|E|E|;Usta|U|U|;Pamuk|O N|ON|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1177/0961203317691370",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "26(11)",
"journal": "Lupus",
"keywords": "Systemic lupus erythematosus; haematological changes; nephritis",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D016543:Central Nervous System Neoplasms; D038524:Diffusion Magnetic Resonance Imaging; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D009173:Mycophenolic Acid; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "1224-1227",
"pmc": null,
"pmid": "28152659",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Development of primary central nervous system lymphoma in a systemic lupus erythematosus patient after treatment with mycophenolate mofetil and review of the literature.",
"title_normalized": "development of primary central nervous system lymphoma in a systemic lupus erythematosus patient after treatment with mycophenolate mofetil and review of the literature"
} | [
{
"companynumb": "TR-ACCORD-048537",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Persistent pain after vaginal mesh surgery is a rare and agonizing entity that has devastating consequences for the patient's quality of life. Many etiologies have been blamed including nerve injuries and entrapments. Pudendal neuralgia is a rare chronic neuropathic pain syndrome in the anatomical territory of the pudendal nerve. Various treatment options, such as medication management, physiotherapy, nerve blocks, decompression surgery and neuromodulation, have been used, but the most appropriate treatment for pudendal neuralgia has not yet been determined. In this article, we present two cases of postoperative pelvic pain thought to be secondary to injury or mechanical distortion of the pudendal nerve after rectocele repair using mesh and tension-free vaginal tape sling. In cases of failed conservative treatment and of mesh removal surgery, laparoscopic pudendal nerve decompression and omental flap wrapping operation can be a treatment option for pudendal neuralgia.",
"affiliations": "Department of Urology, Faculty of Medicine, Canakkale Onsekiz Mart University, Canakkale, Turkey.;Department of Urology, Memorial Atasehir Hospital, Istanbul, Turkey.;Department of Urology, Memorial Atasehir Hospital, Istanbul, Turkey.",
"authors": "Sancak|Eyup Burak|EB|;Avci|Egemen|E|;Erdogru|Tibet|T|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/iju.13136",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-8172",
"issue": "23(9)",
"journal": "International journal of urology : official journal of the Japanese Urological Association",
"keywords": "laparoscopic pudendal nerve decompression; omental flap wrapping; pudendal neuralgia; rectocele repair; tension-free vaginal tape",
"medline_ta": "Int J Urol",
"mesh_terms": "D019299:Decompression, Surgical; D005260:Female; D006801:Humans; D010535:Laparoscopy; D017699:Pelvic Pain; D060525:Pudendal Nerve; D060545:Pudendal Neuralgia; D011788:Quality of Life; D013526:Surgical Mesh",
"nlm_unique_id": "9440237",
"other_id": null,
"pages": "797-800",
"pmc": null,
"pmid": "27250921",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pudendal neuralgia after pelvic surgery using mesh: Case reports and laparoscopic pudendal nerve decompression.",
"title_normalized": "pudendal neuralgia after pelvic surgery using mesh case reports and laparoscopic pudendal nerve decompression"
} | [
{
"companynumb": "TR-TEVA-2019-TR-1061108",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe pharmacological treatment for autism spectrum disorders is often poorly tolerated and has traditionally targeted associated conditions, with limited benefit for the core social deficits. We describe the novel use of a cannabidiol-based extract that incidentally improved core social deficits and overall functioning in a patient with autism spectrum disorder, at a lower dose than has been previously reported in autism spectrum disorder.\n\n\nMETHODS\nThe parents of a 15-year-old boy, of South African descent, with autism spectrum disorder, selective mutism, anxiety, and controlled epilepsy, consulted a medical cannabis physician to trial cannabis extract to replace seizure medications. Incidentally, at a very low cannabidiol-based extract dose, he experienced unanticipated positive effects on behavioral symptoms and core social deficits.\n\n\nCONCLUSIONS\nThis case report provides evidence that a lower than previously reported dose of a phytocannabinoid in the form of a cannabidiol-based extract may be capable of aiding in autism spectrum disorder-related behavioral symptoms, core social communication abilities, and comorbid anxiety, sleep difficulties, and weight control. Further research is needed to elucidate the clinical role and underlying biological mechanisms of action of cannabidiol-based extract in patients with autism spectrum disorder.",
"affiliations": "Caleo Health, Suite 200, 1402 8th Ave N.W., Calgary, AB, T2N 1B9, Canada. julianaponton@caleohealth.ca.;Alberta Children's Hospital, 2888 Shaganappi Trail N.W., Calgary, AB, Canada.;Caleo Health, Suite 200, 1402 8th Ave N.W., Calgary, AB, T2N 1B9, Canada.;Caleo Health, Suite 200, 1402 8th Ave N.W., Calgary, AB, T2N 1B9, Canada.;Caleo Health, Suite 200, 1402 8th Ave N.W., Calgary, AB, T2N 1B9, Canada.;Caleo Health, Suite 200, 1402 8th Ave N.W., Calgary, AB, T2N 1B9, Canada.;Caleo Health, Suite 200, 1402 8th Ave N.W., Calgary, AB, T2N 1B9, Canada.",
"authors": "Ponton|Juliana Andrea|JA|http://orcid.org/0000-0002-7405-1797;Smyth|Kim|K|;Soumbasis|Elias|E|;Llanos|Sergio Andres|SA|;Lewis|Mark|M|;Meerholz|Wilhelm August|WA|;Tanguay|Robert Lawrence|RL|",
"chemical_list": "D002186:Cannabinoids; D010936:Plant Extracts",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02478-7",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2478\n10.1186/s13256-020-02478-7\nCase Report\nA pediatric patient with autism spectrum disorder and epilepsy using cannabinoid extracts as complementary therapy: a case report\nhttp://orcid.org/0000-0002-7405-1797Ponton Juliana Andrea julianaponton@caleohealth.ca 1 Smyth Kim 2 Soumbasis Elias 1 Llanos Sergio Andres 1 Lewis Mark 1 Meerholz Wilhelm August 1 Tanguay Robert Lawrence 1 1 Caleo Health, Suite 200, 1402 8th Ave N.W., Calgary, AB T2N 1B9 Canada \n2 grid.454131.6Alberta Children’s Hospital, 2888 Shaganappi Trail N.W., Calgary, AB Canada \n22 9 2020 \n22 9 2020 \n2020 \n14 1625 4 2020 30 7 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThe pharmacological treatment for autism spectrum disorders is often poorly tolerated and has traditionally targeted associated conditions, with limited benefit for the core social deficits. We describe the novel use of a cannabidiol-based extract that incidentally improved core social deficits and overall functioning in a patient with autism spectrum disorder, at a lower dose than has been previously reported in autism spectrum disorder.\n\nCase presentation\nThe parents of a 15-year-old boy, of South African descent, with autism spectrum disorder, selective mutism, anxiety, and controlled epilepsy, consulted a medical cannabis physician to trial cannabis extract to replace seizure medications. Incidentally, at a very low cannabidiol-based extract dose, he experienced unanticipated positive effects on behavioral symptoms and core social deficits.\n\nConclusion\nThis case report provides evidence that a lower than previously reported dose of a phytocannabinoid in the form of a cannabidiol-based extract may be capable of aiding in autism spectrum disorder-related behavioral symptoms, core social communication abilities, and comorbid anxiety, sleep difficulties, and weight control. Further research is needed to elucidate the clinical role and underlying biological mechanisms of action of cannabidiol-based extract in patients with autism spectrum disorder.\n\nKeywords\nAutismCannabidiol extractPhytocannabinoidsComplementary treatmentissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAutism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by deficits in two major domains: restrictive, repetitive patterns of behavior, interests, or activities; and deficits in social communication and interaction [1, 2]. ASD is associated with a higher incidence of comorbid conditions including attention deficit hyperactivity disorder, anxiety, gastrointestinal disturbances, motor impairments, and epilepsy. Symptoms appear in early childhood and vary in severity leading to a broad range of clinical manifestations [2].\n\nThe pathogenesis of ASD is not completely understood [3]. Given its complexity and diverse clinical manifestations, it is believed that the etiopathogenesis of ASD is a combination of genetic, epigenetic, neurobiological, diet, and other environmental factors [4]. Hundreds of genes (NLGN, SHANK3, ZNF8034A, and UNC13A) [5, 6] have been linked to ASD, most of which are closely related to the development of the nervous system [1].\n\nThere is a myriad of theories that attempt to explain the occurrence of ASD [1, 3, 7], although the two most accepted are impaired synaptic transmission and disruption of neural connectivity. The endocannabinoid system (ECS) has attracted considerable attention as a potential contributor to ASD, as the development of the ECS is essential for regulating synaptic function by inhibiting the release of neurotransmitters from presynaptic neurons [1].\n\nThe management of ASD requires individualized, comprehensive treatment. Non-psychopharmacologic interventions (for example, cognitive behavioral therapy) modify disruptive behaviors and improve social communication skills with varying degrees of success. Traditional psychopharmacologic medications target specific ASD core behaviors (for example, repetitive behaviors) and associated behaviors (for example, hyperactivity, aggression, anxiety, and sleep disturbances), but do not treat core social communication deficits [8, 9]. These medications are well known for their substantial side effects. For example, aripiprazole and risperidone, the only two medications approved by the US Food and Drug Administration (FDA) to treat irritability and agitation in ASD, frequently cause somnolence, increased appetite, and weight gain [10]. No other medication has been approved for management of behavioral and/or core ASD symptoms. Challenges with these traditional treatment approaches include barriers to access (economical, geographic), lack of efficacy, and undesirable side effects, which have led many families to seek complementary and alternative medicine (CAM) to augment or replace standard therapy [8]. One of the newest CAM options now being explored in ASD (and, in fact, the wider medical community) is cannabinoids: for example, cannabidiol-based extract (CBE), which is an extract from the cannabis plant, rich in cannabidiol (CBD) [11].\n\nFollow-up of these patients must also be individualized as presentation of the disorder is highly variable. There are no validated questionnaires to accurately assess clinical progress, therefore, conducting an objective clinical assessment of related behavioral and core symptoms is challenging. Despite this, there are tools available for characterizing the overall functionality of patients with ASD, for example, Autism Spectrum Quotient (AQ) adults version [3].\n\nThe World Health Organization stated that CBD should not be scheduled with the International Drug Control Conventions because of growing evidence of its medicinal applications [12, 13]. It is imperative for health care providers to understand the minutiae of how cannabinoids interact with the human body and the different forms of cannabinoids that are available for medical use (for example, synthetocannabinoids, phytocannabinoids) [1]. Delta-9-tetrahydrocannabinol (THC) and CBD are the most well-known and studied phytocannabinoids. THC is associated with the impairing psychoactive effects of cannabis, resulting in potentially undesirable side effects (dizziness, anxiety, paranoia, dependency, cognitive impairment, and so on). In contrast, CBD is only minimally psychoactive and not impairing or intoxicating at typically used doses (for example, ≥ 20 mg/kg of CBD referred in the majority of intractable seizures studies) [1, 8, 10, 11].\n\nA multitude of studies have analyzed the use of high-dose CBD extract (~ 20 mg/kg of weight per dose) in the context of intractable seizure treatment [14, 15]. It has been reported that CBD effects are dose-dependent (for example, > 160 mg/day elicits a sedating effect and lower doses have been associated with increased wakefulness) [16]. A few case reports and observational studies have suggested the safety and efficacy of lower dose CBD, for treating behavioral symptoms in ASD [11, 17, 18]. In a prospective study, 188 patients with ASD were treated with lower to medium doses of phytocannabinoids (from 15 mg of CBD three times a day to 300 mg of CBD three times a day), the majority taking 1:20 CBE: 30% CBD to 1.5% THC [19]. This study found that cannabis was well tolerated, safe, and effective in relieving certain ASD symptoms. More research is needed to assess the long-term effects of CBD, as well as optimal dosing, formulation, delivery method, and so on to maximize both safety and efficacy.\n\nThis case report describes the clinical presentation of a pediatric, overweight patient with ASD, epilepsy, anxiety, insomnia, and social deficits who benefited clinically with even lower doses of CBE (4 mg of CBD and 0.2 mg of THC twice a day) compared to the ones already studied [19].\n\nCase presentation\nA 15-year-old boy, of South African descent, is presented with a long-standing history of social and communicative challenges dating back to early childhood, including difficulties in appropriate use of facial expressions, eye contact, and gestures to regulate social interaction (see Fig. 1 for patient’s timeline). He has a history of difficulty in establishing and maintaining relationships, although he has been able to establish some friendships. His mother notes a history of selective mutism dating back to age 3. He has areas of fixated interests and some ritualized behaviors that on assessment were below the threshold for a diagnosis of obsessive-compulsive disorder. In 2016, he was formally diagnosed as having ASD by a specialized organization in British Columbia (BC), the Interior Health Children’s Assessment Network (IHCAN), with supporting evidence from Autism Diagnostic Interview – Revised (ADI-R) and the Autism Diagnostic Observation Schedule 2 (ADOS-2). He does well academically and there are no cognitive concerns. Sometimes he shows aggressive behaviors towards his mother and other relatives.\nFig. 1 Patient’s timeline depicting important dates and events. ACH Alberta Children’s Hospital, ADI-R Autism Diagnostic Interview – Revised, ADOS-2 Autism Diagnostic Observation Schedule 2, ASD autism spectrum disorder, AQ Autism Spectrum Quotient (Adult), BC British Columbia, BMI body mass index (calculated by Du Bois method), CBD cannabidiol, CBE cannabidiol-based extract, CSHQ Children’s Sleep Habits Questionnaire (Abbreviated), CYMH Child and Youth Mental Health, IHCAN Interior Health Children’s Assessment Network, OCD obsessive-compulsive disorder, THC delta-9-tetrahydrocannabinol, upset stomach gastrointestinal side effects, VAS visual analog scale, VPA valproic acid. VAS severity for overall anxiety, social anxiety, aggressiveness and irritability, 0 = least severe, 10 = most severe. VAS for talkativeness, 0 = quiet, 10 = very talkative. VAS for focus, 0 = unfocused, 10 = focused\n\n\n\nHe was diagnosed as having epilepsy characterized by focal seizures at age 7 at an emergency department service in BC and was subsequently treated by his pediatrician and a pediatric neurologist at the Alberta Children’s Hospital (ACH). He was initially prescribed carbamazepine for seizures which was stopped in 2015 due to side effects (upset stomach), followed by clobazam (stopped in 2016 due to suicidal ideation) and valproic acid (VPA) (stopped in 2017 due to alopecia, tremor, and reflux). The latter also caused a significant weight gain of approximately 13 kg in 1 year, resulting in a calculated body mass index (BMI) with the Du Bois method of 25.5 kg/m2. He is currently on lamotrigine for seizures, lorazepam for breakthrough seizures, melatonin for insomnia, riboflavin, ranitidine, magnesium, and orally administered CBE 0.2 mL (4 mg of CBD and 0.1 mg twice a day). No therapy had been tried for behavioral symptoms, although his mother mentioned that VPA and lamotrigine were also prescribed for their effect on mood.\n\nHe is currently in psychotherapy at the Child and Youth Mental Health (CYMH) clinic in BC for his selective mutism and anxiety disorder diagnosed by psychiatrists in the same province. He has also had sleep difficulties since 2016. His perinatal history is unremarkable. His birth followed a full-term pregnancy and was uncomplicated except for a required caesarean section due to macrosomia (> 4000 g) and macrocephaly (his mother does not remember the measurement), and subsequent hospitalization for neonatal jaundice. No genetic syndrome was suspected; no genetic testing was ever done. He met expected neurodevelopmental milestones for his age. His mother and grandmother have a history of depression and anxiety. There is other familial history of eating disorders and alcoholism, but no history of genetic syndromes.\n\nIn mid-2017, his parents consulted a medical cannabis physician from Caleo Health to assess the suitability of cannabis-based medicines as adjunctive or replacement therapy for seizures. At the time, a physical examination and laboratory findings were normal. A neurologic examination was unremarkable; mental status – awake, alert, cooperative; cranial nerves – normal; motor – normal tone, bulk, strength, and reflexes in upper and lower extremities, proximal and distal, deep tendon reflexes 2+ symmetric. A skin examination was unremarkable, there were no hypopigmented macules, café-au-lait macules, neurofibromas, or axillae ephelides. A long-term (48-hour) electroencephalogram done in 2016 did not record any epileptogenic potentials; magnetic resonance imaging (MRI) showed no intracranial abnormalities and a computed tomography (CT) scan of his head was normal (2015). Laboratory results done mid-2017 were normal: complete blood count and differential, vitamin B12, creatinine, sodium, potassium, calcium, magnesium, total bilirubin, albumin, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, alanine aminotransferase, and triacylglycerol lipase. He had low ferritin (11 μg/L) but normal hemoglobin (159 g/L), due to starting a vegetarian diet, which was followed up by the family physician.\n\nHe had not had a clinical seizure in 6 months (last seizure in March 2017). Medications at the time of initiation of CBE were: lamotrigine 200 mg twice a day for seizures, lorazepam 1 mg sublingual (SL)/buccal as necessary, infrequently used for seizures, melatonin 6 mg for sleep initiation, riboflavin 400 mg administered orally once daily, magnesium 1 tablet administered orally once daily, and ranitidine 150 mg twice a day. When asked for symptom severity on a visual analog scale (VAS) (0 = least severe, 10 = most severe), his mother reported overall anxiety, social anxiety, aggressiveness, and irritability severity, at 10/10, 10/10, 6/10, and 9/10, respectively. On VAS to assess for talkativeness (0 = quiet, 10 = very talkative) in social situations, the mother reported 0/10. On VAS for concentration (0 = unfocused, 10 = very focused), 4/10 was reported. In regards to sleep, the mother stated he was sleeping approximately 5 to 6 hours, and was having trouble falling asleep. After the initial assessment, his parents gave consent to start therapy and CBE was prescribed (60 mL bottle of 1:20 CBE – 0.001% THC and 0.02% CBD), from CanniMed, with an olive oil carrier. His parents were instructed to administer 0.1 mL twice a day (2 mg CBD and 0.1 mg THC) and increase by 0.1 mL (2 mg CBD and 0.1 mg THC) per dose if no effects were shown to a maximum of 0.5 mL (10 mg CBD and 0.5 mg THC) per dose.\n\nIn December 2017, after 3 months of the CBE prescription, his mother increased the dose to 0.2 mL twice a day (4 mg CBD and 0.2 mg THC) as the family noted only mild improvements in anxiety symptoms. In August 2018, a medical cannabis follow-up was conducted. At 0.2 mL twice a day for almost 9 months, our patient’s family reported an improvement of 7 points for overall and social anxiety and irritability, and 6 points on aggressiveness on their respective VAS. Talkativeness improved by 4 points and focus by 2 points. In February 2020, another medical cannabis follow-up was conducted and positive effects were still evident at the same dose. When the mother was asked to complete the Children’s Sleep Habits Questionnaire (CSHQ) Abbreviated, she stated that he slept 7 hours and only had trouble falling asleep in his own bed as he resists going to bed. No side effects were reported (nausea/vomiting, diarrhea, headaches, euphoria, feeling high, anxiety, panic attacks, palpitations, somnolence during the day or drowsiness). Laboratory results remained normal and low ferritin was corrected. He began to initiate and reciprocate conversations with acquaintances he had previously been unable to speak to (for example, doctors, community members). He became more motivated and energetic, starting his own vegetarian diet and exercise programs, ultimately losing 6.4 kg after starting CBE for a calculated BMI of 21.33 kg/m2. He was able to start his first part-time job helping customers and interacting with them. He was instructed to fill out the self-administered Adult AQ which resulted in a normal score of 10 as shown in Table 1. His mother stated he now also has a girlfriend. Recently, his mother started weaning him off CBE to go on a trip and noted an immediate change. He became more irritable and aggressive.\nTable 1 Adult Autism Spectrum Quotient score\n\nItem\tPatient’s score\tMaximum score\t\nSocial skills\t2\t10\t\nAttention switching\t2\t10\t\nAttention to detail\t3\t10\t\nCommunication\t1\t10\t\nImagination\t2\t10\t\nTotal\t10\t50\t\nIn a study by Baron-Cohen et al. [20], control individuals showed a mean score of 16.5 while individuals with Asperger syndrome and high-functioning autism showed a mean score of 35\n\n\n\nIn discussion with their neurologist, the family decided to wean lamotrigine while remaining on CBE (0.2 mL twice a day – 4 mg CBD and 0.2 mg THC). Unfortunately, there was a recurrence of seizures and lamotrigine was titrated back to the full 200 mg twice a day dose.\n\nCurrently, our patient remains on the same medication as mentioned above, as well as low dose of CBE. He has maintained the positive effect on his behavioral symptoms, anxiety, sleep, and social deficits on CBE 1:20 ratio, 0.2 mL twice a day (4 mg CBD and 0.2 mg THC) and no side effects have been reported.\n\nDiscussion\nThis case demonstrates the benefit of a lower than previously studied CBE dose for core social communicative and behavioral ASD symptoms, as well as improvements in co-occurring anxiety, sleep dysregulation, and weight, which led to substantial improvements in both our patient’s and his family’s quality of life and daily functioning. There was partial response at the initial dose of 0.1 mL twice a day (2 mg CBD and 0.1 mg THC) and a dramatic response at 0.2 mL twice a day (4 mg CBD and 0.2 mg THC). Seizures recurred when conventional anti-epileptic medication (lamotrigine) was weaned while on the CBE at the 0.1 mL twice a day dose (low doses), reiterating CBE at this dose did not have any significant anti-epileptic effect; lamotrigine has not been weaned while on the 0.2 mL twice a day (4 mg CBD and 0.2 mg THC) dose of CBE. Typically, significant higher CBD doses are needed for seizure control (> 20 mg/kg per day) [14, 15].\n\nThe symptom improvement occurred within a 6-month period following the initiation of CBE treatment, during which time there were no new additions or significant alterations of/to any concurrent medications or therapies that could otherwise explain the improvements in symptomatology. It remains unclear whether the CBE directly modified the core ASD symptoms in some way, or whether the impact of CBE was secondary to its positive effects on comorbid conditions, namely anxiety and/or sleep dysregulation, which were producing or exacerbating underlying ASD behaviors. We must also consider there are limitations inherent in the method used to assess his clinical improvement, as the VAS and the AQ are not yet validated. These measures were chosen by default, as no scale is currently validated to assess clinical progress [3]. Seizures recurred at the initial 0.1 mL twice a day (2 mg CBD and 0.1 mg THC) dose of CBE. In addition to the fact that seizures were well controlled prior to starting CBE, the recurrence of seizures on the initial 0.1 mL twice a day dose of CBE, a dose at which symptoms were already starting to improve, suggests that improvements in ASD symptoms were not related to improvements in epilepsy control; the anti-seizure properties of CBD alone are unlikely to be the predominant mechanism responsible for the improvements in this patient’s ASD symptoms.\n\nThe ECS is a unique biological system that is present in the majority of body tissues. It plays an important role in cellular processes at the early stages of development [21]. The ECS is an essential regulatory system of the central nervous system that modulates both neurotransmission and synaptic plasticity. It is also involved in emotional and social functioning, and cognition [1, 21]. There is evidence that the ECS is underdeveloped in ASD [1, 22]. CBD may be treating core symptoms in ASD by interacting with the ECS to boost function in one way. CBD may increase the availability of the endogenous cannabinoids, anandamide (AEA), by directly inhibiting one of its degrading enzymes, that is, fatty amide acid hydrolase (FAAH) [1, 23, 24]. Wei et al. demonstrated that selective inhibition of FAAH in BTBR animals, increased AEA activity [25]. Further to this, a case–control study by Karhson et al. assessed AEA concentrations in ASD (n = 59) versus controls, and found lower AEA concentrations associated with ASD [26].\n\nHigh-dose CBD has been studied for seizures and has been approved by the FDA (Epidiolex) for the treatment of intractable epilepsy [14, 15, 27, 28], but there remains a lack of evidence for the use of phytocannabinoids in ASD [11]. Only a few low-powered studies address the clinical efficacy of cannabinoids for such symptoms, and there are no established recommendations for its use in ASD treatment [5, 6]. The majority of published studies for ASD either involve synthetic cannabinoids [11, 17, 18] or synthetic enzyme-inhibitors [25, 29]. Only a few studies offer evidence for the use of phytocannabinoids in ASD. An observational study by Bar-Lev Schleider et al. provided valuable information on safety and efficacy, but the study design was insufficient to draw strong conclusions on standard clinical care [19]. Clinicaltrials.gov lists an ongoing randomized trial comparing different phytocannabinoid extracts in the setting of behavioral symptoms, but results are not yet available [30]. Therefore, this case report is rare as it documents observed effects of CBE in ASD-related symptoms as opposed to other forms of cannabinoids (for example, nabilone, dronabinol, and nabiximols).\n\nFrom a clinical perspective, the use of CBD-based products to treat neuropsychiatric symptoms must be done only after appropriate education and informed discussion with families, including consideration of risks and benefits of CBD compared to other available treatment options, and with vigilant monitoring.\n\nResearch into the role of cannabinoids in treating ASD symptoms and associated behaviors is in its infancy. Although there is an increasing amount of evidence providing biological plausibility for the use of CBD in treating ASD [1, 5, 25, 26, 31], further research is essential to better understand the effects of phytocannabinoids on neurobiological pathways and their impact on behavior and brain function. Rigorous, controlled clinical trials are needed to further establish safety, especially long-term safety, optimal dosing, and efficacy, including further delineation of the effect of CBE on core versus associated ASD symptoms. Until sufficient, supportive evidence is found, CBE remains an unproven alternative treatment and should not replace conventional evidence-based treatments for children with autism. However, the unexpected and significant benefits of CBE in this case report highlight the urgent need and potential benefits of continuing to pursue research in this area.\n\nConclusion\nWhile there is a lack of strong evidence to support the use of CBE in ASD, this case report provides the first insight about lower than previously reported doses of phytocannabinoids in the form of CBE, which may benefit ASD-related behavioral and core social symptoms, as well as anxiety, sleep disturbances, and weight. We encourage scientists and clinicians to pioneer placebo-controlled studies to validate the clinical efficacy of very low doses of CBE in a larger cohort.\n\nAbbreviations\nAEAAnandamide\n\nASDAutism spectrum disorder\n\nECSEndocannabinoid system\n\nFDAFood and Drug Administration\n\nCAMComplementary and alternative medicine\n\nCBDCannabidiol\n\nCTComputed tomography\n\nCYMHChild and Youth Mental Health\n\nFAAHFatty amide acid hydrolase\n\nTHCDelta-9-tetrahydrocannabinol\n\nCBECannabidiol-based extract\n\nIHCANInterior Health Children’s Assessment Network\n\nMRIMagnetic resonance imaging\n\nSLSublingual\n\nADI-RAutism Diagnostic Interview – Revised\n\nADOS-2Autism Diagnostic Observation Schedule 2\n\nACHAlberta Children’s Hospital\n\nVPAValproic acid\n\nBMIBody mass index\n\nBCBritish Columbia\n\nVASVisual analog scale\n\nCSHQChildren’s Sleep Habits Questionnaire\n\nAQAutism Spectrum Quotient\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe want to thank Caleo Health and all the administrative staff. Special thanks to Michelle Andoy for supporting us.\n\nAuthors’ contributions\nJAP conceptualization, writing – draft and final manuscript, and analyzed information. WAM and ES made substantial contributions to acquisition of data. KS contributed with analysis as well as acquisition of the data. RLT investigated, conceived, and supervised the project. KS, RLT, and ES provided critical feedback and helped shaped the analysis of the case. JAP, WAM, and SAL assisted with acquisition of data. KS, ES, ML, and RLT participated in manuscript editing. WAM and RLT participated in funding acquisition. JAP and SAL coordinated and designed graphics. All authors discussed and contributed to the final manuscript. The authors read and approved the final manuscript.\n\nFunding\nWAM provided all the funding.\n\nAvailability of data and materials\nThe dataset generated and analyzed during this case report are available in Netcare (Alberta’s public Electronic Health Record used to store patient information).\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s legal guardian for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Zou M Li D Li L Wu L Sun C Role of the endocannabinoid system in neurological disorders Int J Dev Neurosci 2019 76 95 102 30858029 \n2. American Psychiatric Association. DSM-5 Diagnostic Classification. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; 2013 [cited 2019 Nov 6]. Available from: https://psychiatryonline.org/doi/10.1176/appi.books.9780890425596.x00DiagnosticClassification.\n3. Lai MC Lombardo MV Baron-Cohen S Autism Lancet. 2014 383 9920 896 910 24074734 \n4. Geschwind DH Genetics of autism spectrum disorders Trends Cogn Sci 2011 15 9 409 416 21855394 \n5. Jamain S Quach H Betancur C Råstam M Colineaux C Gillberg IC Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism Nat Genet 2003 34 1 27 29 12669065 \n6. Nguyen QA Horn ME Nicoll RA Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses Elife. 2016 5 e19236 27805570 \n7. Yenkoyan K Grigoryan A Fereshetyan K Yepremyan D Advances in understanding the pathophysiology of autism spectrum disorders Behav Brain Res 2017 331 92 101 28499914 \n8. Weissman L. Autism spectrum disorder in children and adolescents: Overview of management. In: Augustyn M, Patterson MC, Torchia MM, editors. UpToDate [Internet]. Waltham (MA): UpToDate Inc.; 2019 [updated 2019 Dec 19; cited 2019 Sep 19]. Available from: https://www.uptodate.com/contents/autism-spectrum-disorder-in-children-and-adolescents-overview-of-management?search=autismspectrumdisorder&source=search_result&selectedTitle=1~146&usage_type=default&display_rank=1.\n9. Posey DJ McDougle CJ Pharmacotherapeutic management of autism Expert Opin Pharmacother 2001 2 4 587 600 11336609 \n10. Goel R Hong JS Findling RL Ji NY An update on pharmacotherapy of autism spectrum disorder in children and adolescents Int Rev Psychiatry 2018 30 1 78 95 29693461 \n11. Weissman L, Hodges HK. Autism spectrum disorder in children and adolescents: Complementary and alternative therapies. In: Augustyn M, Patterson MC, Torchia MM, editors. Waltham (MA): UpToDate Inc.; 2019 [updated 2020 Feb 05; cited 2019 Sep 19]. Available from: https://www.uptodate.com/contents/autism-spectrum-disorder-in-children-andadolescents-complementary-and-alternative-therapies?search=Autism spectrum disorder in children and adolescents: Complementary and alternative therapies&source=.\n12. Whiting PF Wolff RF Deshpande S Di Nisio M Duffy S Hernandez AV Cannabinoids for Medical Use: A Systematic Review and Meta-analysis JAMA. 2015 313 24 2456 2473 26103030 \n13. World Health Organization. WHO Expert Committee on Drug Dependence: Fortieth Report [Internet]. 2018 [cited 2020 Jan 29]. Available from: https://apps.who.int/iris/bitstream/handle/10665/279948/9789241210225-eng.pdf?ua=1#:~:text=The fortieth meeting of the WHO, cannabis and its component substances.\n14. Devinsky O Cross JH Laux L Marsh E Miller I Nabbout R Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome N Engl J Med 2017 376 21 2011 2020 28538134 \n15. Devinsky O Patel AD Cross JH Villanueva V Wirrell EC Privitera M Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome N Engl J Med 2018 378 20 1888 1897 29768152 \n16. Babson KA, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep. 2017;19(4):23.\n17. Kurz R Blaas K Use of dronabinol ( delta-9-THC ) in autism: A prospective single-case-study with an early infantile autistic child Cannabinoids. 2010 5 4 4 6 \n18. Kruger T Christophersen E An Open Label Study of the Use of Dronabinol (Marinol) in the Management of Treatment-Resistant Self-Injurious Behavior in 10 Retarded Adolescent Patients J Dev Behav Pediatr 2006 27 5 441 \n19. Bar-Lev Schleider L Mechoulam R Saban N Meiri G Novack V Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy Sci Rep 2019 9 1 200 30655581 \n20. Baron-Cohen S Wheelwright S Skinner R Martin J Clubley E The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians J Autism Dev Disord 2001 31 1 5 17 11439754 \n21. Richardson KA Hester AK McLemore GL Prenatal cannabis exposure - The “first hit” to the endocannabinoid system Neurotoxicol Teratol 2016 58 5 14 27567698 \n22. Lafourcade M Larrieu T Mato S Duffaud A Sepers M Matias I Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions Nat Neurosci 2011 14 3 345 350 21278728 \n23. Schwarz R Ramer R Hinz B Targeting the endocannabinoid system as a potential anticancer approach Drug Metab Rev 2018 50 1 26 53 29390896 \n24. Philpott HT O’Brien M McDougall JJ Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis Pain. 2017 158 12 2442 2451 28885454 \n25. Wei D Dinh D Lee D Li D Anguren A Moreno-Sanz G Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment Cannabis Cannabinoid Res 2016 1 1 81 89 28861483 \n26. Karhson DS Krasinska KM Dallaire JA Libove RA Phillips JM Chien AS Plasma anandamide concentrations are lower in children with autism spectrum disorder Mol Autism 2018 9 1 1 6 29321841 \n27. Food and Drug Administration. Medication Guide - Epidiolex. In Carlsbad (CA): Greenwich Biosciences Inc.; 2018 [cited 2019 Nov 23]. p. 30. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.\n28. Thiele EA Marsh ED French JA Mazurkiewicz MB Benbadis SR Joshi C Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial Lancet. 2018 391 10125 1085 1096 29395273 \n29. Gould GG Seillier A Weiss G Giuffrida A Burke TF Hensler JG Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice Prog Neuro-Psychopharmacology Biol Psychiatry 2012 38 2 260 269 \n30. ClinicalTrials.gov [internet]. United States: Bethesda (MA): US National Library of Medicine; 2000 - . Identifier NCT02956226, Cannabinoids for Behavioral Problems in Autism Spectrum Disorder: A Double Blind, Randomized, Placebo-Controlled Trial with Crossover; 2016 Nov 6 [cited 2019 Sep 19]. Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT02956226?show_desc=Y#desc.\n31. Mazahery H Stonehouse W Delshad M Kruger MC Conlon CA Beck KL Relationship between long chain n-3 polyunsaturated fatty acids and autism spectrum disorder: Systematic review and meta-analysis of case-control and randomised controlled trials Nutrients. 2017 9 2 1 32\n\n",
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"mesh_terms": "D000293:Adolescent; D000067877:Autism Spectrum Disorder; D002186:Cannabinoids; D002648:Child; D000529:Complementary Therapies; D004827:Epilepsy; D006801:Humans; D008297:Male; D010936:Plant Extracts",
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"title": "A pediatric patient with autism spectrum disorder and epilepsy using cannabinoid extracts as complementary therapy: a case report.",
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"abstract": "Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.",
"affiliations": "Department of Medicine 1, University Hospital, J.W. Goethe University, Frankfurt am Main, Germany.;Gastroenterology-Hepatology Center Kiel, Kiel, Germany.;Department of Medicine 1, University Hospital, J.W. Goethe University, Frankfurt am Main, Germany.;Liver Unit, Asklepios Clinic St. Georg, IFI-Institute, Hamburg, Germany.;Center for Infectiology Berlin, Berlin, Germany.;Center for Interdisciplinary Medicine (CIM), Münster, Germany.;Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.;Center for HIV and Hepatogastroenterology, Düsseldorf, Germany.;Private Practice, Frankfurt am Main, Germany.;Hepatologie - Magdeburg, Magdeburg, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany.;Leberzentrum am Checkpoint Berlin, Berlin, Germany.;Private Practice for Internal Medicine, Berlin, Germany.;Department of Medicine I, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.;Infektiologikum, Frankfurt am Main, Germany.;Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.;AbbVie Deutschland GmbH & Co KG, Wiesbaden, Germany.;AbbVie Deutschland GmbH & Co KG, Wiesbaden, Germany.;AbbVie Deutschland GmbH & Co KG, Wiesbaden, Germany.;Center for Gastroenterology and Hepatology, Herne.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.",
"authors": "Welzel|T M|TM|;Hinrichsen|H|H|;Sarrazin|C|C|;Buggisch|P|P|;Baumgarten|A|A|;Christensen|S|S|;Berg|T|T|;Mauss|S|S|;Teuber|G|G|;Stein|K|K|;Deterding|K|K|;van Bömmel|F|F|;Heyne|R|R|;John|C|C|;Zimmermann|T|T|;Lutz|T|T|;Schott|E|E|;Hettinger|J|J|0000-0002-1024-0732;Kleine|H|H|;König|B|B|;Hüppe|D|D|;Wedemeyer|H|H|",
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"mesh_terms": "D015081:2-Naphthylamine; D000328:Adult; D000368:Aged; D000813:Anilides; D002219:Carbamates; D015331:Cohort Studies; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D005858:Germany; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D019438:Ritonavir; D012720:Severity of Illness Index; D013449:Sulfonamides; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine; D019562:Viral Load",
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"title": "Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry.",
"title_normalized": "real world experience with the all oral interferon free regimen of ombitasvir paritaprevir ritonavir and dasabuvir for the treatment of chronic hepatitis c virus infection in the german hepatitis c registry"
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"abstract": "Capecitabine, a prodrug of fluorouracil, is a component of many chemotherapy regimens used to treat a wide variety of malignancies. One of the most common adverse reactions experienced by those who have been exposed to capecitabine is palmar-plantar erythrodysesthesia (PPE). PPE is a cutaneous manifestation of chemotherapy-related drug toxicity that has signs and symptoms of erythema, edema, pain, ulceration, or desquamation of the palms of the hands and soles of the feet. The signs and symptoms occur with varying severity. There are few reports of the genitalia being similarly affected. The following case describes a patient with locally advanced rectal cancer who experienced erythrodysesthesia secondary to a capecitabine-containing neoadjuvant chemoradiation regimen that primarily and most significantly involved the genitalia.",
"affiliations": "Colon and Rectal Clinic, Swedish Cancer Institute, Seattle, USA.;Colon and Rectal Clinic, Swedish Cancer Institute, Seattle, USA.;Colon and Rectal Clinic, Swedish Cancer Institute, Seattle, USA.;Department of Oncology and Hematology, Polyclinic, Seattle, USA.;Department of Radiation Oncology, Swedish Cancer Institute, Seattle, USA.",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.7724\nDermatology\nRadiation Oncology\nOncology\nScrotal and Penile Erythrodysesthesia Associated with Neoadjuvant Capecitabine Chemoradiation\nMuacevic Alexander Adler John R Dricken Julie 1 Pettke Erica 1 Griffin John A 1 Li Henry Y 2 Mehta Vivek 3 \n1 \nColon and Rectal Clinic, Swedish Cancer Institute, Seattle, USA \n\n2 \nDepartment of Oncology and Hematology, Polyclinic, Seattle, USA \n\n3 \nDepartment of Radiation Oncology, Swedish Cancer Institute, Seattle, USA \n\nErica Pettke epettke@gmail.com\n18 4 2020 \n4 2020 \n12 4 e772429 10 2019 18 4 2020 Copyright © 2020, Dricken et al.2020Dricken 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/23743-scrotal-and-penile-erythrodysesthesia-associated-with-neoadjuvant-capecitabine-chemoradiationCapecitabine, a prodrug of fluorouracil, is a component of many chemotherapy regimens used to treat a wide variety of malignancies. One of the most common adverse reactions experienced by those who have been exposed to capecitabine is palmar-plantar erythrodysesthesia (PPE). PPE is a cutaneous manifestation of chemotherapy-related drug toxicity that has signs and symptoms of erythema, edema, pain, ulceration, or desquamation of the palms of the hands and soles of the feet. The signs and symptoms occur with varying severity. There are few reports of the genitalia being similarly affected. The following case describes a patient with locally advanced rectal cancer who experienced erythrodysesthesia secondary to a capecitabine-containing neoadjuvant chemoradiation regimen that primarily and most significantly involved the genitalia. \n\ncapecitabinescrotal erythrodysesthesianeoadjuvant chemoradiationThe 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\nPalmar-plantar erythrodysesthesia (PPE), also known as hand-foot syndrome, acral erythema, or Burgdorf’s reaction, is a cutaneous side effect associated with some cytotoxic agents used to treat many of the most common malignancies. Some of the available literature makes a distinction between PPE and hand-foot syndrome, with some using the terms interchangeably. For the purposes of this paper, the two terms will be considered to be synonymous. The syndrome is associated with prolonged administration of the systemic agent and appears to be dose-dependent. The onset and severity of the disease can be affected by peak plasma concentrations, total cumulative dose, and administration schedule. It was first described in 1984 when an association with protracted infusion of 5-fluorouracil (5-FU) was noted, but there was no association with bolus 5-FU [1].\n\nAlthough the present case involves a capecitabine-containing regimen, there are reported associations of PPE with all of the following: doxorubicin (particularly pegylated liposomal doxorubicin), cytarabine (particularly in combination with an anthracycline for treatment of acute leukemia), docetaxel, 5-FU, bleomycin, cisplatin, cyclophosphamide, daunorubicin, doxifluridine, etoposide, fludarabine, gemcitabine, hydroxyurea, idarubicin, ixabepilone, methotrexate, mitotane, paclitaxel, tegafur, thiotepa, vinorelbine. \n\nPossibly more significant than the agent itself is the drug formulation and administration schedule. The fact that the pegylated liposomal doxorubicin, liposomal daunorubicin, infusional 5-FU, and capecitabine have a stronger association with toxicities, of which PPE is included, than other drug formulations and administration schedules that do not result in such a sustained and prolonged tissue exposure would support this [2].\n\nVarious treatments for PPE have been proposed, all with varying and usually disappointing success. The most common and most successful intervention leading to the resolution of PPE is an interruption of therapy [3].\n\nCase presentation\nAn 87-year-old man presented with a history of intermittent bleeding per rectum for the last several months. He underwent a colonoscopy and was diagnosed with a moderately differentiated rectal adenocarcinoma with intact mismatch repair protein expression based on biopsy results. Magnetic resonance imaging revealed a T3N0 rectal cancer with extensive involvement of the sphincters, extending from the anorectal junction to 1 cm from the anal verge (Figure 1). Computed tomography images found no evidence of metastatic disease and the carcinoembryonic antigen level was 1.9.\n\nFigure 1 Pelvic MRI showing rectal mass\nHe was described as youthful and had relatively few comorbidities. He had a history of prostate cancer, for which he underwent brachytherapy eight years prior. Genetic polymorphism testing was not done.\n\nThe plan for neoadjuvant chemoradiation therapy consisted of capecitabine 825 mg/m2 twice daily (1500 mg twice daily) Monday through Friday, skipping non-radiation days, for six weeks; and 5040 cGy of radiation delivered over 28 fractions.\n\nAfter receiving 11 fractions of radiation therapy, the patient started to experience left groin pain that resolved without intervention. Three days later, he developed numbness of the hands and feet without erythema nor skin changes. Four days later, he again complained of scrotal discomfort. The dose of capecitabine was decreased to 1000 mg every AM and 1500 mg every PM, skipping non-radiation days, for the remaining weeks to complete a total course of six weeks. The patient stopped taking capecitabine, and the decision was made to stop radiation as well. At that point, he had received three weeks of capecitabine, and 14 of 28 fractions (2520 cGy of 5040 cGy) radiation.\n\nOne day later, he started to have significant diarrhea and hematuria. Over the next few days, he became dehydrated due to persistent diarrhea and was admitted to the hospital for treatment of dehydration and electrolyte derangements. Physical examination revealed severe scrotal and penile desquamation (Figures 2 and 3). He was seen and evaluated by the wound care team, and empiric treatment was started with silver sulfadiazine cream and antifungal cream. No skin nor wound cultures were obtained. The length of stay was nine days. By 30 days after discharge from the hospital, the pain had completely resolved, erythema nearly resolved, and desquamation significantly improved. \n\nFigure 2 Scrotal erythema and desquamation\nFigure 3 Inguinal and scrotal erythema\nIn order to evaluate the possibility of radiation-induced dermatitis, the radiation plan and delivery data were reviewed. The radiation fields were designed to intentionally avoid and limit the radiation dose to the patient’s genitalia and inguinal region. The initial plan had documented verification by a medical dosimetrist and a medical physicist. On the first day of treatment, a radiation output measurement was performed for each beam to further ensure that the beams were being delivered safely and accurately. These diode measurements were also all within 1.5% of the expected value and normal tolerances. Upon further investigation, no errors in the planning or delivery were identified. The patient's alignment, based on cone-beam CT data, was reviewed and found to have a close agreement between the expected and the acquired image sets. Finally, the alignment data for the C-RAD Catalyst™ system, the system that captures a 3D surface map of the patient, was reviewed and showed accurate alignment. \n\nOn follow up with his colorectal surgeon, the rectal mass was noted to be nodular, mobile, less bulky, and to involve the anal sphincters on the digital rectal exam. Re-staging MRI showed the rectal mass was no longer visible and only fibrosis was noted at its previous location. A flexible sigmoidoscopy demonstrated an ulcerated mass. The mass was biopsied and pathology resulted as moderately differentiated adenocarcinoma. After extensive multi-disciplinary discussions and obtaining a second opinion, he elected to forego further chemoradiation, and also decided against surgery.\n\nDiscussion\nPPE is a common side effect of capecitabine with a reported incidence of between 28-58% [4]. As of the time of this case report, there have been eight reported cases of PPE with the involvement of the scrotum and genitalia, including this one [5-8]. Despite the fact that PPE is seen in association with many other drugs used to treat malignancies, it appears as though the involvement of the genitals has been reported more commonly to the administration of capecitabine. Erythrodysesthesia may be seen in other areas of the body that experience increased pressure or temperature, such as the buttocks, under the breasts, in the axillae, and labial area.\n\nCapecitabine, a prodrug of fluorouracil, is a component of many chemotherapy regimens used to treat a wide variety of malignancies. It may be found to be more appealing than 5-FU because it is administered orally. Once swallowed, it is readily absorbed from the gastrointestinal tract. In the liver, a carboxylesterase hydrolyzes much of the compound to 5’-deoxy-5-fluorocytidine (5’-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, then converts the 5’-DFCR to 5’-deoxy-5-fluorouridine (5’-DFUR). Subsequently, the enzyme thymidine phosphorylase hydrolyzes the 5’-DFUR to the active drug 5-FU.\n\nFluorouracil is a fluorinated pyrimidine antimetabolite. It inhibits thymidylate synthetase, which ultimately interferes with DNA, and to a lesser degree, RNA synthesis. Fluorouracil appears to preferentially affect the G1 and S phases of the cell cycle.\n\nPathophysiology of PPE\n\nAs previously described, the conversion of capecitabine to 5-FU requires a series of enzymatic reactions. Genetic polymorphisms may play a role in increasing a person’s susceptibility to exhibiting signs and symptoms of toxicity. Although there are about 25 candidate genes identified in which variation may affect the efficacy and toxicity of capecitabine therapy, two specific genes are most commonly mentioned. Polymorphisms involving the genes that encode thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPD) have been mentioned as possibly contributing to the development of toxicity with capecitabine therapy. While genetic tests do exist to detect such polymorphisms, it is not standard of care to conduct testing prior to initiating fluoropyrimidine therapy.\n\nOf all of the genetic polymorphisms thought to be related to fluoropyrimidine intolerance, the gene that encodes DPD has been most studied. About 3-5% of Caucasians have a partial DPD deficiency, and 0.2% have a complete deficiency. All patients who are found to have less than 70% DPD activity are considered to be at risk for the development of severe drug-related toxicities [10]. In the literature review, no case of PPE with genital involvement mentioned testing for genetic polymorphisms, except for one. The one patient that was tested was found to have no mutation [5].\n\nThe pathophysiology of PPE is not well understood. Those without a genetic polymorphism still can experience signs and symptoms of toxicity, specifically PPE. One proposed mechanism is trauma to the palms and soles from normal daily activities leading to the rupture of small dermal capillaries. This allows the release of the drug into the surrounding tissues, causing an inflammatory response. The scrotum and genitalia could possibly be considered to sustain a fair amount of trauma during daily activities, but not nearly to the extent of the palms of the hands and soles of the feet [11].\n\nAnother mechanism that has been described focuses on the eccrine sweat glands. The palms, soles, scalp, and genitals contain the highest concentrations of eccrine sweat glands on the body. There are two different theories that involve the eccrine sweat glands.\n\nOne theory is that noninflammatory metaplasia of cuboidal epithelial cells of the eccrine sweat ducts occurs as a result of the direct toxic effects of the drug, known as eccrine squamous syringometaplasia (ESS). ESS appears from two to 39 days after initiation of chemotherapy and is reported as resolving spontaneously in 7-10 days. It has been suggested that histologic analysis may assist in differentiating ESS from other possible diagnoses [12]. \n\nA second theory that involves the eccrine sweat glands describes the accumulation of the drug on the skin surface, allowing it to penetrate the upper epidermis. Here, it shows cumulative toxic effects by forming free radicals that damage cellular structures. The same mechanism was implicated in the cutaneous signs and symptoms associated with pegylated liposomal doxorubicin therapy, and subsequently successfully targeted in preventing and treating the condition.\n\nTreatment and prevention of PPE\n\nVarious treatments for PPE have been suggested, all with varying degrees of efficacy. Ultimately, what is required in most cases is either interruption or discontinuation of the treatment. Out of eight cases of PPE with genito-scrotal involvement reported in the literature, including this case, seven required discontinuation of chemotherapy.\n\nAs with the appearance of any sign or symptom of toxicity, dose reduction may be a reasonable course of action. Lengthening the intervals of the drug administration schedule alone, or in addition to dose reduction, may be effective [1, 13].\n\nProphylactic measures may be taken in an attempt to prevent PPE from occurring. One systemic medication that has been frequently discussed is celecoxib. Celecoxib is a cyclooxygenase-2 (COX-2) inhibitor. Because some of the theories about the pathophysiology of PPE revolve around a local inflammatory tissue reaction after extravasation of the drug allowing it to penetrate the stratum corneum likely mediated by COX-2, it was thought that treatment with celecoxib may decrease the likelihood of development of PPE. In a meta-analysis, celecoxib was found to be associated with a statistically significant reduction of moderate to severe PPE. The authors claim that it is the “most promising” agent for the prevention of PPE. Some of the well-known potential side effects of celecoxib, however, have led some to not be in support of its use for this purpose [14].\n\nPyridoxine (vitamin B6) is an agent that is commonly administered to patients undergoing chemotherapy, with the intention of preventing PPE. It has been suggested that the use of pyridoxine to either prevent or treat PPE is based on poor evidence. The use of pyridoxine arose when similarities between PPE and acrodynia from pyridoxine deficiency was noted in rats. Two separate studies, one randomized clinical trial, and one meta-analysis both came to the same conclusion [14, 15]. There is no clinical evidence to support the use of pyridoxine to prevent or ameliorate PPE.\n\nTopical urea is a cream that is applied to the hands and feet. At low concentrations, it acts to retain moisture. This occurs because topically, urea promotes the uptake of water by the stratum corneum by allowing it to have a high water-binding capacity. In a meta-analysis, urea cream failed to demonstrate an advantage in the prevention of all-grades of PPE (Table 1) [16].\n\nTable 1 PPE common terminology of adverse events\nAdopted from [9].\n\nPPE - palmar-plantar erythrodysesthesia; ADL - activities of daily living\n\n\nGrade\n\t\nExplanation\n\t\n\nGrade 1\n\t\nMinimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain\n\t\n\nGrade 2\n\t\nSkin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting ADL\n\t\n\nGrade 3\n\t\nSevere skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting self-care ADL\n\t\nSystemic and topical steroids have been used to prevent and/or treat PPE. Their use has been poorly studied, especially in regard to capecitabine-associated PPE. Most of the literature regarding the use of steroids to treat and/or prevent PPE is in relation to pegylated liposomal doxorubicin. Even then, the literature is quite sparse. A study by Drake et al. used dexamethasone to treat those who experienced PPE after receiving pegylated liposomal doxorubicin for various gynecologic malignancies. In that study, nine patients developed PPE. Six received a dexamethasone taper. All six demonstrated a complete or near-complete resolution of PPE and required no dose modification. All three who did not receive steroids required treatment delays and dose reductions [16].\n\nApplication of topical antiperspirant has been hypothesized to be a potentially beneficial measure in preventing PPE given the idea that accumulation of the drug on the surface of the skin may occur via the eccrine sweat glands. One study suggests that the application of topical aluminum chlorohydrate is well-tolerated and may reduce the incidence of grade 2 or 3 PPE (Table 1) [17].\n\nWith fairly new technology allowing for the detection and measurement of concentrations of capecitabine on the surface of the skin, some parallels may be drawn between pegylated liposomal doxorubicin-associated PPE and capecitabine-associated PPE. Pegylated liposomal doxorubicin spreads evenly on the skin surface, penetrating into the superficial epidermis. There it shows cumulative toxic effect by forming free radicals that injure cellular structures. The topical application of an antioxidant ointment was found to be effective in preventing and treating PPE [18]. This theory was tested in patients who developed PPE secondary to capecitabine. Topical Mapisal®, an ointment that contains several antioxidants and has a high radical protection factor, was studied in comparison to topical 10% urea cream. The urea cream was found to be superior [19]. The topical application of silymarin, another agent rich in antioxidants, has been studied and found to potentially be useful in delaying the onset of PPE [19]. Given that one of the theories regarding the etiology of PPE is the accumulation of the drug on the skin surface due to sweating, it would be reasonable to attempt to mitigate the effects by controlling sweating. Regional cooling has been suggested as an intervention to prevent PPE. One study described placing ice packs around the wrists and ankles of patients receiving pegylated liposomal doxorubicin therapy for gynecologic malignancies. The authors indicated that the study demonstrated the intervention was an efficacious prevention strategy [20].\n\nConclusions\nPPE is a common adverse reaction to capecitabine, as well as many other drugs used to treat malignancies. Involvement of the genitals is rare but seems to be associated with increased severity of the adverse reaction. Although genital involvement has been reported with a few other drugs, it could potentially occur with the administration of any drug associated with the development of PPE. The symptoms can be debilitating, so early detection is prudent. This may mean that patients receiving capecitabine therapy need to be specifically asked about skin changes or pain in the genitals, or even have regular genital examinations.\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 Chemotherapy-associated palmar-plantar erythrodysesthesia syndrome Ann Intern Med Lokich JJ Moore C 798 800 101 1984 6497196 \n2 Multicentric survey on dose reduction/interruption of cancer drug therapy in 12.472 patients: indicators of suspected adverse reactions Oncotarget Casadei Gardini AC Tenti E Masini C 40719 40724 7 2016 27119511 \n3 Pegylated liposomal doxorubicin-associated hand-foot syndrome: recommendations of an international panel of experts Eur J Cancer van Moos R Thuerlimann BJ Aapro M 781 790 44 2008 18331788 \n4 Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study J Clin Oncol Hoff PM Ansari R Batist G 2282 2292 19 2001 11304782 \n5 Palmar-plantar erythrodysesthesia with genital involvement secondary to capecitabine chemoradiotherapy: a case report Cureus Hu H Corkum MT Perera F 0 10 2018 \n6 Unusual scrotal and penile ulceration together with palmar-plantar erythrodysesthesia syndrome in a patient with metastatic colon carcinoma treated with capecitabine J Eur Acad Dermatology Venereol Hadzavdic SL Buzina DS Murtezani I Skerlev M 304 306 31 2017 \n7 Genital erythrodysesthesia as a severe manifestation of capecitabine therapy: a report of 3 cases Arch Dermatol Fleta-Asin B Alcantara-Gonzalez J Alonso-Castro L Truchuelo-Diez M Jaen-Olasolo P 1123 1124 147 2011 21931065 \n8 Palmar-plantar erythrodysesthesia associated with scrotal and penile involvement with capecitabine Clin Colorectal Cancer Sapp CM DeSimone P 382 385 6 2007 17311704 \n9 Common terminology criteria for adverse events v4.0 (CTACE) National Institutes of Health / National Cancer Institute USA U.S. Department of Health and Human Services 2009 https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf \n10 Capecitabine therapy and DPYD genotype Medical Genomics Summaries Dean L USA National Center for Biotechnology Information 2016 https://www.ncbi.nlm.nih.gov/books/NBK385155/ \n11 Management of hand-foot syndrome induced by capecitabine J Oncol Pharm Pract Gressett SM Stanford BL Hardwicke F 131 141 12 2006 17022868 \n12 Eccrine squamous syringometaplasia Holland-Frei Cancer Medicine Apisarnthanarax N Duvic MM Hamilton BC Decker Inc. 6th 2003 http://www.ncbi.nlm.nih.gov \n13 Palmar-plantar erythrodysesthesia associated with chemotherapy and its treatment Case Rep Oncol Farr KP Safwat A 229 235 4 2011 21537373 \n14 Prevention strategies for chemotherapy-induced hand-foot syndrome: a systematic review and meta-analysis of prospective randomized trials Support Care Cancer Macedo LT Lima JPN dos Santos LV Sasse AD 1585 1593 22 2014 24463616 \n15 Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome a randomized clinical trial JAMA Oncol Yap YS Kwok LL Syn N 1538 1545 3 2017 28715540 \n16 Oral dexamethasone attenuates Doxil®-induced palmar-plantar erythrodysesthesias in patients with recurrent gynecologic malignancies Gynecol Oncol Drake RD Lin WM King M Farrar D Miller DS Coleman RL 320 324 94 2004 15297168 \n17 Prevention of palmar-plantar erythrodysesthesia with an antiperspirant in breast cancer patients treated with pegylated liposomal doxorubicin (SAKK 92/08) Breast Templeton AJ Ribi K Surber C 244 249 23 2014 24656636 \n18 Mapisal versus urea cream as prophylaxis for capecitabine-associated hand-foot syndrome: a randomized phase III trial of the AIO quality of life working group J Clin Oncol Hofheinz RD Gencer D Schulz H 2444 2449 33 2015 26124485 \n19 Topical silymarin administration for prevention of capecitabine-induced hand-foot syndrome: a randomized, double-blinded, placebo-controlled clinical trial Phytother Res Elyasi S Shojaee FSR Allahyari A Karimi G 1323 1329 31 2017 28635153 \n20 Prevention strategies in palmar-plantar erythrodysesthesia onset: the role of regional cooling Gynecologic Oncol Mangili G Petrone M Gentile C De Marzi P Vigano R Rabaiotti E 332 335 108 2008\n\n",
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"issue": "12(4)",
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"keywords": "capecitabine; neoadjuvant chemoradiation; scrotal erythrodysesthesia",
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"pubdate": "2020-04-18",
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"title": "Scrotal and Penile Erythrodysesthesia Associated with Neoadjuvant Capecitabine Chemoradiation.",
"title_normalized": "scrotal and penile erythrodysesthesia associated with neoadjuvant capecitabine chemoradiation"
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"abstract": "Dermatomyositis is an inflammatory disorder involving muscle and skin. Similar to many other autoimmune diseases, environmental factors appear to trigger the onset of disease in some cases. Many drugs have been reported to be associated with dermatomyositis, and rarely infections have been described as potential triggering agents. Here we are describing a case of dermatomyositis that developed after doxycycline and levofloxacin use, who also had recent Epstein-Barr virus infection. Dermatomyositis associated with doxycycline or levofloxacin use has not yet been described in the literature, while reports of dermatomyositis after Epstein-Barr virus infection have been rare and limited to juvenile dermatomyositis or in association with cancer. It is important for clinicians to be aware of this rare association so that the diagnosis and treatment can be exercised promptly.",
"affiliations": "University of Tennessee Medical School, Memphis, Tennessee.;Division of Rheumatology, University of Tennessee Health Science Center, Memphis, Tennessee. Electronic address: acharyasaurav@yahoo.com.;Division of Rheumatology, University of Tennessee Health Science Center, Memphis, Tennessee.;Division of Rheumatology, University of Tennessee Health Science Center, Memphis, Tennessee.;Department of Dermatology, University of Tennessee Health Science Center, Memphis, Tennessee.",
"authors": "Peravali|Rahul|R|;Acharya|Saurav|S|;Raza|Syed Hasan|SH|;Pattanaik|Debendra|D|;Randall|Milton Barry|MB|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000956:Antigens, Viral; D036022:Capsid Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; C041788:Epstein-Barr viral capsid antigen; D064704:Levofloxacin; D004318:Doxycycline",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2020.05.011",
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"issn_linking": "0002-9629",
"issue": "360(4)",
"journal": "The American journal of the medical sciences",
"keywords": "Antibiotics associated dermatomyositis; Dermatomyositis; EBV associated dermatomyositis",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000956:Antigens, Viral; D036022:Capsid Proteins; D003882:Dermatomyositis; D004318:Doxycycline; D020031:Epstein-Barr Virus Infections; D019309:Epstein-Barr Virus Nuclear Antigens; D006801:Humans; D064704:Levofloxacin; D016896:Treatment Outcome",
"nlm_unique_id": "0370506",
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"pages": "402-405",
"pmc": null,
"pmid": "32591093",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "11249823;21333952;24688790;11891205;18625537;23342374;25337792;16702496;19086074;29480216;31459613;11352244;30169847;24909624;29147464;22811739;31549298",
"title": "Dermatomyositis Developed After Exposure to Epstein-Barr Virus Infection and Antibiotics Use.",
"title_normalized": "dermatomyositis developed after exposure to epstein barr virus infection and antibiotics use"
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"abstract": "This study aims to describe the frequency and characteristics of anticonvulsant medication treatments initiated in the neonatal period.\n\n\n\nWe analyzed a cohort of neonates with a seizure diagnosis who were discharged from institutions in the Pediatric Health Information System between 2007 and 2016. Adjusted risk ratios and 95% confidence intervals for characteristics associated with neonatal (≤ 28 days postnatal) anticonvulsant initiation were calculated via modified Poisson regression.\n\n\n\nA total of 6,245 infants from 47 institutions were included. There was a decrease in both phenobarbital initiation within the neonatal period (96.9 to 91.3%, p = 0.015) and continuation at discharge (90.6 to 68.6%, p <0.001). Levetiracetam (7.9 to 39.6%, p < 0.001) initiation within the neonatal period and continuation at discharge (9.4 to 49.8%, p < 0.001) increased. Neonates born at ≥ 37 weeks' gestation and those diagnosed with intraventricular hemorrhage, ischemic/thrombotic stroke, other hemorrhagic stroke, and hypoxic ischemic encephalopathy (HIE) had a higher probability of anticonvulsant administration. The most prevalent diagnosis was HIE (n = 2,223, 44.4%).\n\n\n\nPhenobarbital remains the most widely used neonatal seizure treatment. Levetiracetam is increasingly used as a second line therapy. Increasing levetiracetam use indicates a need for additional study to determine its effectiveness in reducing seizure burden and improving long-term outcomes.",
"affiliations": "Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.;Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.;Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.;Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.;Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.;Department of Pediatrics, The Ohio State University, Columbus, Ohio.;Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio.;Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.",
"authors": "Le|Vi T|VT|;Abdi|Hibo H|HH|;Sánchez|Pablo J|PJ|;Yossef|Lina|L|;Reagan|Patricia B|PB|;Slaughter|Laurel A|LA|;Firestine|Angela|A|;Slaughter|Jonathan L|JL|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010634:Phenobarbital",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0039-1698457",
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"issue": "38(5)",
"journal": "American journal of perinatology",
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"mesh_terms": "D000927:Anticonvulsants; D000074042:Cerebral Intraventricular Hemorrhage; D016208:Databases, Factual; D005260:Female; D005865:Gestational Age; D006801:Humans; D020925:Hypoxia-Ischemia, Brain; D007231:Infant, Newborn; D000077287:Levetiracetam; D008297:Male; D010634:Phenobarbital; D012189:Retrospective Studies; D012640:Seizures; D020521:Stroke; D014481:United States",
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"pubdate": "2021-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
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"title": "Neonatal Antiepileptic Medication Treatment Patterns: A Decade of Change.",
"title_normalized": "neonatal antiepileptic medication treatment patterns a decade of change"
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"abstract": "AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC).\n\n\n\nAZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival.\n\n\n\nDuring escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III-IV AEs. Six-month PFS was 85% (90% CI: 66%-94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024).\n\n\n\nXelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791).",
"affiliations": "University of Leicester, Leicester, UK. Electronic address: at107@le.ac.uk.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Belfast City Hospital, Belfast, UK.;University of Oxford, Oxford, UK.;Bristol Haematology & Oncology Centre, Bristol, UK.;St. James University Hospital, Leeds, UK.;Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.;Oncology Clinical Trials Office, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Oncology Clinical Trials Office, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, UK.",
"authors": "Thomas|Anne|A|;Virdee|Pradeep S|PS|;Eatock|Martin|M|;Lord|Simon R|SR|;Falk|Stephen|S|;Anthoney|D Alan|DA|;Turkington|Richard C|RC|;Goff|Matthew|M|;Elhussein|Leena|L|;Collins|Linda|L|;Love|Sharon|S|;Moschandreas|Joanna|J|;Middleton|Mark R|MR|",
"chemical_list": "C548875:AZD 8931; D010071:Oxaloacetates; D011799:Quinazolines; D000077150:Oxaliplatin; D000069287:Capecitabine; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; D018719:Receptor, ErbB-2; D020893:Receptor, ErbB-3",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2019.10.010",
"fulltext": "\n==== Front\nEur J CancerEur. J. CancerEuropean Journal of Cancer0959-80491879-0852Elsevier Science Ltd S0959-8049(19)30773-710.1016/j.ejca.2019.10.010ArticleDual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma Thomas Anne at107@le.ac.uka∗Virdee Pradeep S. bEatock Martin cLord Simon R. dFalk Stephen eAnthoney D. Alan fTurkington Richard C. gGoff Matthew hElhussein Leena bCollins Linda hLove Sharon bMoschandreas Joanna bMiddleton Mark R. dia University of Leicester, Leicester, UKb Centre for Statistics in Medicine, University of Oxford, Oxford, UKc Belfast City Hospital, Belfast, UKd University of Oxford, Oxford, UKe Bristol Haematology & Oncology Centre, Bristol, UKf St. James University Hospital, Leeds, UKg Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UKh Oncology Clinical Trials Office, University of Oxford, Oxford, UKi NIHR Oxford Biomedical Research Centre, UK∗ Corresponding author: Leicester Cancer Research Centre, University of Leicester, Osborne Building, Leicester Royal Infirmary, Leicester, LE1 5WW, UK. at107@le.ac.uk1 1 2020 1 2020 124 131 141 22 8 2019 7 10 2019 13 10 2019 © 2019 The Authors2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Background\nAZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC).\n\nMethods\nAZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival.\n\nResults\nDuring escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III–IV AEs. Six-month PFS was 85% (90% CI: 66%–94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024).\n\nConclusion\nXelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791).\n\nHighlights\n• First study to assess safety and tolerability of the novel pan erbB inhibitor AZD8931 in oesophagogastric cancer (OGC).\n\n• Recommended phase II dose schedule determined to be 20-mg bd for 4 days on/3 days off, per cycle.\n\n• Feasibility of adding novel targeted therapies to standard-of-care for oesophago-gastric cancer is confirmed.\n\n\n\nKeywords\nOesophagogastric cancerDual erbB inhibitorAZD8931\n==== Body\n1 Introduction\nIn the UK, gastric and oesophageal cancers account for approximately 16,000 cases per annum with mortality approaching 13,000 cases per annum [1]. In the western world, oesophageal adenocarcinoma incidence rates have increased markedly over the last 30 years [2] with the majority of patients presenting with advanced disease [3]. The UK national oesophagogastric cancer (OGC) audit (2018) determined that only 38.6% of patients were treated with curative intent, with a 5-year overall survival (OS) of 15% for oesophageal and 19% for gastric cancers [4]. There is, therefore, an urgent need to develop more effective therapies.\n\nPatients with operable OGC may be treated with neoadjuvant chemotherapy [5], perioperative chemotherapy [[6], [7], [8]], or preoperative chemoradiotherapy [9]. The choice of therapy depends on the location of the tumour, the histology (squamous versus adenocarcinoma), the patient's performance status, and their comorbidity. Several other strategies, including treatment intensification [10] and anti-angiogenic therapies [11], have failed to demonstrate additional benefit in operable patients. Trastuzumab has demonstrated activity in patients with advanced human epidermal growth factor receptor-2 (EGFR) (HER2/erbB2) positive OGC [12,13], and results from neoadjuvant studies using this in addition to chemotherapy are awaited [14,15].\n\nWhilst HER2 is an established target in OGC, further molecular subclassifications include overexpression of EGFR (HER1/erbB1) and heterodimeric activation of HER2 via erbB3 (HER3) [16,17], advocating extension of therapeutic targeting encompassing the wider EGFR family. AZD8931 is a novel small-molecule inhibitor, which has equipotent activity against signalling by EGFR, erbB2, and erbB3. In preclinical models, AZD8931 has greater anti-cancer activity than other EGFR inhibitors, such as gefitinib and lapatinib, which have narrower spectrums of erbB receptor inhibition [18]. AZD8931 combined with chemotherapy may, therefore, have activity in a wider group of patients with OGC (and other solid tumour) than for those just exhibiting highly HER2 amplified disease.\n\nThe Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) study sought to establish the maximum tolerated dose (MTD) of AZD8931 in combination with oxaliplatin and capecitabine (Xelox) in patients with OGC (dose escalation phase). After establishment of the recommended phase II dose (RP2D), the dose expansion phase aimed to give preliminary efficacy assessments and further investigate the safety and tolerability of AZD8931 in combination with Xelox.\n\n2 Materials and methods\nThe DEBIOC study was conducted in accordance with the International Conference of Harmonisation of Good Clinical Practice and the Declaration of Helsinki. Ethical approval was provided by a research ethics committee (12/SC/0090).\n\n2.1 Patients\nFor dose escalation, eligible participants were chemonaive with inoperable metastatic OGC (measurable by RECIST 1.1), aged ≥18 years, had World Health Organisation performance status of 0 or 1 and adequate haematological, renal, hepatic, respiratory, and cardiac function. For dose expansion, eligible patients had histologically confirmed operable adenocarcinoma of the oesophagus or gastrooesophageal junction, including Siewert type I and II gastrooesophageal junction cancers, and were deemed suitable for neoadjuvant chemotherapy. Patients who had received prior chemotherapy for OGC were excluded. The full inclusion and exclusion criteria are detailed in Supplementary Appendix A. All participants provided written informed consent.\n\n2.2 Study design and treatment\nFor dose escalation, a rolling-six design [19] was used, with three oral AZD8931 dose levels: 20 mg bd, 40 mg bd, and 60 mg bd. Two intermittent schedules of AZD8931 were investigated once recruitment to the 20 mg bd group was complete: 14 days on/7 days off (schedule 1) and 4 days on/3 days off every week in a cycle (schedule 2). Patients would receive oral AZD8931 monotherapy twice daily for three days, then together with Xelox chemotherapy from day 4 for eight 21-day cycles (Xelox: oxaliplatin at 130 mg/m2 IV over 2 h on day one of every cycle; capecitabine 1250 mg/m2 bd for cycle duration). AZD8931 could continue after cessation of Xelox providing there was no evidence of tumour progression and treatment was tolerated.\n\nThe dose expansion phase was an open-label study, with patients randomised 2:1 to receive either Xelox + AZD8931 at AZD8931 RP2D for two 21-day cycles, or Xelox alone as neoadjuvant treatment. Patients without disease progression (as per RECIST 1.1) would undergo radical oesophagogastric surgical resection with extended lymph node dissection 4-6 weeks after completing neoadjuvant chemotherapy. Those who received AZD8931 in the expansion phase could commence maintenance AZD8931 at the same dose, 6–12 weeks after successful surgical resection (complete [R0]/marginal [R1]) for up to 12 months (if no evidence of recurrent disease). Safety follow-up was scheduled for four weeks after AZD8931 treatment ended. Tumour response assessment was performed via CT scan at 43 days from commencing neoadjuvant treatment to determine eligibility for surgery and at six months after surgery for analysis of outcomes.\n\n2.3 Sample size\nThe maximum number of participants for dose escalation was 42: six patients taking one of three dose levels for two intermittent schedules, plus up to six patients recruited before implementation of the intermittent schedules.\n\nSample size for the expansion phase was based on observing outcomes that would render the AZD8931 regimen worthy of further investigation: with 20 patients receiving AZD8931, 78% progression-free survival (PFS) at 6 months from surgery corresponds to a lower one-sided 95% confidence limit for true 6-month PFS of 54%. In addition, an 80% R0 resection rate among 20 patients corresponds to a lower one-sided 80% confidence limit of 64%. Patients were randomised 2:1 with the majority receiving the treatment combination. One reason for this was to ensure sufficient numbers to evaluate feasibility of maintenance treatment, as drop-out after surgery was envisaged. The Xelox alone (reference) arm size was 10, giving a total of 30 patients to be randomised in the expansion phase.\n\n2.4 Statistical analysis\nThe primary objective of the study was to determine the MTD of AZD8931 in combination with Xelox, defined as the highest dose level at which fewer than 2 of 6 patients experienced a dose limiting toxicity (DLT). DLTs were based on clinical and laboratory toxicity assessments (defined by National Cancer Institute-Common Toxicity Criteria, version 4.0, with the full definition provided in Supplementary Appendix B). Patients were evaluable for dose escalation analysis if they completed cycle 1 of AZD8931 treatment or withdrew from cycle 1 because of a DLT.\n\nSecondary outcomes (dose expansion phase only) were PFS, PFS at 6 months, R0 rate at surgery, OS, OS at 12 months and safety. PFS was defined as time (days) from randomisation to progression (determined by RECIST 1.1) or death from any cause. Patients without disease progression and alive at the end of the study were censored at the date they were last known to be alive and progression-free. R0 rate was defined as the proportion of patients achieving a complete surgical resection divided by the total number of patients randomised in the respective arm. OS was defined as the time (days) from randomisation to death (any cause). Patients who were alive at the end of the study were censored at the date they were last known to be alive. Adverse events (AEs) were defined using the Common Terminology Criteria for Adverse Events, v4.03, and collected from the first day of treatment up to 30 days after ending treatment. Safety analyses were performed on an as-treated basis in both phases of the study. There were two safety populations in the expansion phase: patients who received at least one dose during the neoadjuvant period and patients who received at least one dose of maintenance AZD8931 postoperatively. Escalation phase safety data were summarised descriptively for each dose cohort separately and overall, with the number and percentage of patients experiencing each type of AE reported. Expansion phase safety data were summarised in accordance with the type and grade of AE, with number and percentage of patients experiencing the AE reported. Efficacy analyses (expansion phase only) were performed on an intention-to-treat basis. In the expansion phase, median follow-up time was calculated using the reverse Kaplan-Meier method [20]. The six-month PFS (90% CI), 12-month OS (90% CI) and 24-month OS (90% CI) estimates were taken from Kaplan-Meier survival curves. R0 rate was compared between groups using Fisher's exact test. Analyses were undertaken using Stata, version 15.1 (StataCorp, College Station, TX, USA) and R, version 3.4.2. A (two-sided) 10% significance level was used.\n\n3 Results\n3.1 Patients\nTwenty-four patients were recruited to the escalation phase between June 2012 and October 2014 in three ECMC UK centres (Oxford, Leicester and Belfast). Thirty patients were randomised to the expansion phase between March 2015 and May 2016 in five ECMC UK centres (Oxford, Leicester, Belfast, Bristol and Leeds) and follow-up ended in November 2017. Consolidated Standards of Reporting Trials (CONSORT) diagrams are shown for escalation and expansion phases (Fig. 1 and Fig. 2, respectively). Baseline demographics for escalation and expansion phases are summarised in Table 1, Table 2, respectively. The number of patients by HER2 status in addition to sample discordance between those collected at baseline (biopsy) and at surgery is described in Table 3.Fig. 1 CONSORT diagram showing patient flow for the phase I dose escalating study component for AZD8931 in combination with oxaliplatin and capecitabine (Xelox) chemotherapy in patients with oesophago-gastric adenocarcinoma. BD, bi-daily.\n\nFig. 1Fig. 2 CONSORT diagram showing patient flow for the randomised phase II dose expansion study component for AZD8931 in combination with oxaliplatin and capecitabine (Xelox) chemotherapy in patients with oesophagogastric adenocarcinoma vs Xelox alone. ITT, intention to treat.\n\nFig. 2Table 1 Baseline demographics for patients in the dose escalation phase (n = 24).\n\nTable 1Variable\t20 mg BD Cont. (n = 6)\t20 mg BD 14on 7 off (n = 7)\t20 mg BD 4on 3 off (n = 7)\t40 mg BD 4on 3 off (n = 4)\tTotal (n = 24)\t\nAge, in years, median (range)\t63 (35–72)\t74 (52–78)\t60 (43–69)\t54 (39–69)\t62 (35–78)\t\nGender male, n (%)\t5 (83%)\t6 (86%)\t4 (57%)\t3 (75%)\t18 (75%)\t\nWHO PS 0, n (%)\t5 (83%)\t5 (71%)\t6 (86%)\t3 (75%)\t19 (79%)\t\nWHO PS 1, n (%)\t1 (17%)\t2 (29%)\t1 (14%)\t1 (25%)\t5 (21%)\t\nHER2 status positive, n (%)\t3 (50%)\t2 (29%)\t2 (29%)\t1 (25%)\t8 (33%)\t\nHER2 status negative, n (%)\t3 (50%)\t5 (71%)\t4 (57%)\t3 (75%)\t15 (63%)\t\nHER2 status unknown, n (%)\t0\t0\t1 (14%)\t0\t1 (4%)\t\nLocally advanced disease, n (%)\t0\t0\t2 (29%)\t0\t2 (8%)\t\nMetastatic disease, n (%)\t6 (100%)\t7 (100%)\t5 (71%)\t4 (100%)\t22 (92%)\t\nPrior radiotherapy, n (%)\t0\t1 (14%)\t0\t0\t1 (4%)\t\nBD, bi-daily; WHO PS, World Health Organisation performance status; HER2, human epidermal growth factor receptor-2.\n\nTable 2 Baseline demographics for the expansion phase by treatment group (n = 30).\n\nTable 2Variable\tAZD893 + XELOX (n = 20)\tXELOX (n = 10)\tTotal (n = 30)\t\nAge, years, median (range)\t63 (50–78)\t66 (25–75)\t64 (25–78)\t\nGender male, n (%)\t17 (85%)\t10 (100%)\t27 (90%)\t\nWHO PS 0, n (%)\t17 (85%)\t7 (70%)\t24 (80%)\t\nWHO PS 1, n (%)\t3 (15%)\t3 (30%)\t6 (20%)\t\nHER2 status, positive, n (%)\t1 (5%)\t0\t1 (3%)\t\nHER2 status, negative, n (%)\t15 (75%)\t8 (80%)\t23 (77%)\t\nHER2 status, unknowna, n (%)\t4 (20%)\t2 (20%)\t6 (20%)\t\nEGFR status, positive, n (%)\t6 (30%)\t4 (40%)\t10 (33%)\t\nEGFR status, negative, n (%)\t10 (50%)\t4 (40%)\t14 (47%)\t\nEGFR status, unknowna, n (%)\t4 (20%)\t2 (20%)\t6 (20%)\t\nSiewert type I, n (%)\t4 (20%)\t1 (10%)\t5 (17%)\t\nSiewert type II, n (%)\t7 (35%)\t2 (20%)\t9 (30%)\t\nSiewert type Oesophagus, n (%)\t9 (45%)\t7 (70%)\t16 (53%)\t\nEGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor-2; WHO PS, World Health Organisation performance status.\n\na Status unknown at biopsy because of block being unavailable (5); did not consent for use (1).\n\nTable 3 Number of patients by HER2 status. Discordance in HER2 status is shown between diagnostic biopsy and resection specimens.\n\nTable 3Diagnostic Biopsy\tResection specimens\t\nXelox + AZD8931 (n = 20)\tXelox (n = 10)\t\nHER2 status\tPositive\tNegative\tUnknown\tPositive\tNegative\tUnknown\t\nPositive\t0\t1\t0\t0\t0\t0\t\nNegative\t2\t9\t4\t0\t6\t2\t\nUnknown\t0\t1\t3\t1\t0\t1\t\n\n\n3.2 Treatment compliance\nIn the escalation phase, all patients received AZD8931 monotherapy in the 3-day run in period without missed or reduced doses. In cycle 1 of AZD combined with Xelox, five patients missed AZD8931 doses because of AEs (fatigue, diarrhoea, poor oral, vomiting and coronary spasm), by own choice, or in error. Three patients did not complete cycle 1 of Xelox: one withdrew consent, one because of experiencing a rash, and one because of experiencing a coronary spasm. Over all cycles, patients stopped AZD8931 because of toxicity (n = 7, 29%), disease progression (n = 16, 67%) or consent withdrawal (n = 1, 4%).\n\nIn the expansion phase, 14 of 20 patients (70%) completed two cycles of neoadjuvant AZD8931 treatment in the Xelox + AZD8931 group. Three (15%) did not complete two cycles: one due to an AE (out of range liver function test) and two due to a serious adverse event (SAE) (diarrhoea). AZD8931 diary cards for the other three patients were unavailable, so it could not be confirmed that they completed the two cycles of AZD8931. Seventeen patients (85%) completed two cycles of neoadjuvant Xelox treatment; all patients received their allocated oxaliplatin, but two patients did not complete capecitabine treatment due to a SAE (diarrhoea). The diary card for one patient was unavailable, so it could not be confirmed whether the two cycles of capecitabine were completed.\n\nOf the 10 patients in the Xelox-alone group, six (60%) completed two cycles of neoadjuvant Xelox. Two patients (20%) did not complete two cycles because of a SAE (diarrhoea) and AE (atrial fibrillation). Diary cards for the remaining two patients were unavailable, so it could not be confirmed whether they completed the two cycles of AZD8931.\n\nIn the Xelox+AZD8931 group, 17 of 20 patients had surgery, compared with 10 of 10 patients in the Xelox-alone group. Of the 17 patients in the Xelox + AZD8931 group who had surgery, 11 continued to AZD8931 maintenance, with six completing 12 months of treatment. Three patients stopped treatment because of disease progression, one as per the decision of the treating clinician and one in error after taking approximately 11 months of maintenance AZ8931.\n\n3.3 Adverse events\nDuring dose escalation, there were 428 grade I–IV AEs: 77 occurred during cycle 1 and 351 after cycle 1. All but one patient experienced at least four AEs during the escalation phase. There were 62 grade III–IV AEs: six during cycle 1 and 56 after cycle 1. AEs at grade III were experienced by 20 (83%) patients, with the most common grade III–IV AEs being diarrhoea (n = 7, 29%) and vomiting (n = 4, 17%) (Table 4). Thirty-three SAEs in fifteen (63%) patients were reported during dose escalation: four during cycle 1 and 29 after cycle 1. Of these SAEs, 39% (13/33) were deemed related to AZD8931. Common SAEs were diarrhoea (n = 9, 38%) and vomiting (n = 4, 17%). There were six suspected unexpected serious adverse reactions (SUSARs) among four patients, none of which were deemed definitely related to AZD8931: three (13%) patients experienced vomiting (one at grade II; two at grade III; all SAEs were possibly related to AZD8931) and two (8%) experienced diarrhoea (all at grade III and possibly or probably related to AZD8931). Note: one patient had both diarrhoea (on two separate occasions) and vomiting.Table 4 Number (%) of patients with grade III–IV AEs of each type during the escalation phasea.\n\nTable 4n (%)\t20 mg Continuous (n = 6)\t20 mg 14ON 7OFF (n = 7)\t20 mg 4ON 3OFF (n = 7)\t40 mg 4ON 3OFF (n = 4)\tTotal (n = 24)\t\nDiarrhoea\t3 (50%)\t1 (14%)\t1 (14%)\t2 (50%)\t7 (29%)\t\nVomiting\t–\t3 (43%)\t1 (14%)\t–\t4 (17%)\t\nNausea\t1 (17%)\t–\t1 (14%)\t–\t2 (8%)\t\nGastrointestinal haemorrhage\t2 (33%)\t–\t–\t–\t2 (8%)\t\nNeutropenia\t–\t2 (29%)\t–\t–\t2 (8%)\t\nPyrexia\t–\t1 (14%)\t–\t1 (25%)\t2 (8%)\t\nFatigue\t2 (33%)\t–\t–\t–\t2 (8%)\t\nDehydration\t1 (17%)\t–\t1 (14%)\t–\t2 (8%)\t\nPulmonary embolism\t1 (17%)\t1 (14%)\t–\t–\t2 (8%)\t\na Only AEs occurring in ≥5% of patients are reported in this table.\n\n\n\nDuring neoadjuvant treatment in the expansion phase, 144 AEs were reported in total. In the Xelox-alone group, 90% (9/10) of patients had an AE, compared with 80% (16/20) in the Xelox + AZD8931 group. The most common AEs were diarrhoea (9/20, 45% Xelox + AZD8931; 4/10, 40% Xelox alone), nausea (8/20, 40% Xelox + AZD8931; 2/10, 20% Xelox alone) and fatigue (7/20, 35% Xelox + AZD8931; 5/10, 50% Xelox alone). AEs by system organ are reported in Fig. 3. Grade III–IV AEs were reported in 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5 of 10 (50%) patients in the Xelox-alone group, with the most common being diarrhoea and vomiting (Table 5). Grade III–IV diarrhoea was deemed related to Xelox treatment for both patients in the Xelox + AZD8931 group and related to AZD8931 for one of them. In the Xelox only group, grade III–IV diarrhoea was related to the Xelox treatment for one patient. There were 13 SAEs during the neoadjuvant treatment period, with 43% (3/7) reported among the Xelox + AZD8931 group deemed related to AZD8931. The most common SAE was diarrhoea, of which there were four occurrences (Table 6).Fig. 3 Percentage of patients with AEs in each system organ during neoadjuvant treatment in the expansion phase.\n\nFig. 3Table 5 Number (%) of patients with grade III-IV adverse events (AE) of each type during neoadjuvant treatment for the randomised expansion phase.\n\nTable 5AE term\tXelox + AZD8931 (n = 20)\tXELOX (n = 10)\t\nDiarrhoeaa\t2 (10%)\t2 (20%)\t\nVomitinga,b\t1 (5%)\t1 (10%)\t\nHypophosphataemia\t–\t1 (10%)\t\nLiver function test abnormalb\t–\t1 (10%)\t\nPulmonary embolisma\t1 (5%)\t1 (10%)\t\nSepsis\t–\t1 (5%)\t\na One patient in the AZD893 + XELOX group had three grade III–IV AEs: diarrhoea, vomiting and pulmonary embolism.\n\nb One patient in the XELOX-alone group had two grade III–IV AEs: vomiting and liver test function abnormal.\n\nTable 6 Serious adverse events (SAEs) that occurred during neoadjuvant treatment for the expansion phase, by treatment group.\n\nTable 6Treatment group\tSAE\tGrade\tRelated to\t\nAZD8931\tCapecitabine\tOxaliplatin\t\nXelox + AZD8931\tDiarrhoea\tII\tProbably\tProbably\tProbably\t\nXelox + AZD8931\tDiarrhoea\t111\tPossibly\tPossibly\tProbably not\t\nXelox + AZD8931\tDiarrhoea\t111\tPossibly\tDefinitely\tPossibly\t\nXelox + AZD8931\tHaematuria\tI\tProbably not\tDefinitely not\tDefinitely not\t\nXelox + AZD8931\tHaematuria\tI\tProbably not\tDefinitely not\tDefinitely not\t\nXelox + AZD8931\tPain\tI\tProbably not\tProbably not\tProbably not\t\nXelox + AZD8931\tVomiting\tIII\tDefinitely not\tProbably\tPossibly\t\nXelox\tDiarrhoea\tIII\tNA\tDefinitely\tPossibly\t\nXelox\tDyspepsia\tII\tNA\tPossibly\tProbably\t\nXelox\tHypophosphatemiaa\tIV\tNA\tProbably not\tProbably\t\nXelox\tOut of range LFTs\tIII\tNA\tProbably\tPossibly\t\nXelox\tSepsis\tIII\tNA\tDefinitely\tDefinitely\t\nXelox\tVomiting\tIII\tNA\tProbably\tPossibly\t\nLFT, liver function test; NA, not applicable.\n\na SUSAR.\n\n\n\nAll 11 patients experienced an AE during AZD8931 postoperative maintenance. In total, there were 33 AEs (n = 19, 58% related to AZD8931), with the most common grade I–IV AE being skin rash, experienced by four patients (36%) on AZD8931 maintenance (related to AZD8931 in three patients). There were two grade III AEs: metastases to central nervous system and arthritis, both considered not to be related to AZD8931. One SAE reported during maintenance (grade III brain metastasis) was considered related to the underlying disease.\n\nTwo SUSARs were reported during the expansion phase: thoracotomy wound dehiscence (Xelox + AZD893) and hypophosphataemia (Xelox-only), both of which were grade IV.\n\n3.4 Maximum tolerated dose\nIn total, 22 of 24 patients were evaluable for the dose escalation analysis. Four DLTs were observed amongst 22 patients: (1) failure to deliver 100% of the planned dose of Xelox because of grade III fatigue attributable to AZD8931 with or without Xelox; (2) failure to deliver 100% of the planned dose of Xelox because of grade III diarrhoea and vomiting attributable to AZD8931 with or without Xelox; (3) failure to deliver 100% of the planned dose of Xelox because of grade III vomiting attributable to AZD8931 with or without Xelox; (4) grade III rash which persisted for at least 5 days despite optimal treatment. No DLTs were observed in the 20-mg bd 14d on/3d off schedule, which was declared as the RP2D.\n\n3.5 Survival and resection rates\nIn the dose expansion phase, median follow-up was 26.8 months. Ten patients (33%) progressed or died during the course of the expansion phase: 9 (45%) patients in the Xelox + AZD8931 group and 1 (10%) in the Xelox-alone group. Median PFS could not be estimated in either groups (Fig. 4A). The lower 90% confidence limit for median PFS in the Xelox + AZD8931 group was estimated as 9.1 months. PFS at six months was 85% (90% CI: 66%, 94%) in the Xelox + AZD8931 group and 100% in the Xelox-alone group.Fig. 4 Kaplan-Meier plots showing progression-free survival as per RECIST 1.1 (A) and overall survival (B) for participants receiving AZD8931 + Xelox vs Xelox alone in the expansion phase.\n\nFig. 4\n\nEight deaths (all disease-related) occurred during the expansion phase; 7 (35%) deaths in the Xelox + AZD8931 group and 1 (10%) in the Xelox-alone group. OS at 12 months was 87% (90% CI: 72%, 94%) overall: 80% (90% CI: 60%, 91%) in the Xelox + AZD8931 group and 100% in the Xelox alone group (Fig. 4B). OS at 24 months was 72% (90% CI: 56%, 84%) overall: 64% (90% CI: 43%, 79%) in the Xelox + AZD8931 group and 90% (90% CI: 58%, 98%) in the Xelox-alone group. Median OS time could not be estimated for either group. The lower 90% confidence limit for median OS time in the Xelox + AZD8931 group was estimated as 17.9 months.\n\nThe proportion of patients achieving R0 resection at surgery was 45% (n = 9) in the Xelox + AZD8931 group and 90% (n = 9) in the Xelox-alone group (P = 0.024). All patients who underwent surgery achieved either R0 or R1 resection.\n\n4 Discussion\nDefining new treatment options in OGC is critical for improving outcomes. Approximately 30% of patients with OGC have disease characterised by HER2 amplification [21] and benefit from treatment with the anti-HER2 monoclonal antibody, trastuzumab. However, benefit may also be realised in HER2-low or HER2-negative tumours by targeting the wider EGFR family. ErbB3 expression, for example, has been increasingly characterised in oesophageal cancers [22,23] and is associated with poor prognosis [24]. Furthermore, erbB3 plays a central role in signal transduction via the phosphatidylinositol-3-kinase pathway, activating both EGFR and HER2 to further deregulate pro-proliferative signalling networks. AZD8931 is an equipotent reversible inhibitor of EGFR, erbB2, and erbB3 [25] which may therefore offer added therapeutic benefit across a wider range of OGC molecular subtypes.\n\nThe primary end-point for DEBIOC was to determine the MTD for AZD8931 in combination with Xelox chemotherapy in patients with OGC. The four DLTs observed in the escalation phase included the AEs diarrhoea and vomiting, reflecting the most commonly reported AEs across all dose levels. A dose finding study of AZD8931 in patients with advanced solid tumours by Tjulandin et al. [26], gave bi-daily single-agent dosing from 40 to 300 mg. Here, diarrhoea was also the most common AE across all doses and contributed to two DLTs in the 300-mg cohort. However, in FOCUS-4, a molecularly stratified randomised trial in patients with colorectal cancer, a 40 mg–20 mg dose reduction in AZD8931 was mandated primarily because of skin rash in 20% of patients [27]. The multi-institutional, neoadjuvant therapy (MINT) study assessed the combination of AZD8931 with anastrozole in breast cancer patients, revealing an increased incidence of diarrhoea, rash, and acneform dermatitis compared with placebo [28]. In addition, discontinuation of anastrozole was reported at greater rates for those receiving AZD8931 than placebo. In contrast, during the expansion phase of DEBIOC, diarrhoea was reported at similar rates for both arms whereas overall grade III–IV AEs were reported in 10% patients in the Xelox + AZD8931 group compared with 50% patients receiving Xelox alone, suggesting that this combination is both safe and tolerable. DEBIOC is also the first study to consider AZD8931 in long-term postsurgical maintenance therapy, during which time 58% patients experienced AZD8931-related AEs, the most common being skin rash. Although skin rash is a common grade III–IV toxicity typically occurring in 10–20% of patients receiving tyrosine kinase inhibitors [29], no events of this nature ≥ grade III were observed with AZD8931 in the expansion phase.\n\nThe discordance between the diagnostic biopsy and resection specimens for both HER2 and EGFR status, demonstrates potential heterogeneity of expression in these cancers or indeed a neoadjuvant treatment effect. There is clear evidence to support molecular stratification to identify those patients who will gain clinical benefit from being exposed to targeted agents [13,30]. Eliminating this discordance is essential if we are going to accurately stratify patients to receive targeted agents.\n\nNeoadjuvant chemotherapy offers significant survival benefit (equating to approximately 7% at 2 years) in OGC compared with surgery alone [31,32]. Previous studies specifically assessing neoadjuvant Xelox in oesophageal cancer estimated a 2-year OS to be 42% and PFS to be 32.5% [33]. In the UK MRC OE05 study, OS at two years was approximately 50% (taken from their Kaplan-Meier curve [10]. In DEBIOC, OS at two years was 72% (90% CI: 56%, 84%). In DEBIOC, median PFS in both arms was not established because of the small proportion of events per group. R0 resection rates of 90% in the Xelox-only group were significantly better than for the AZD8931 arm but were also much higher than would be expected for Xelox alone, with R0 resection following neoadjuvant chemotherapy typically ranging from approximately 59%–82% [5,10,34,35]. The small size of this study is likely a major contributing factor to these disparities.\n\n5 Conclusions\nThe RP2D of the equipotent inhibitor of EGFR, erbB2, and erbB3, AZD8931, in combination with standard-of-care neoadjuvant Xelox chemotherapy in resectable patients with OGC is 20-mg bd (4 days on/3 off every week). Although the sample size was too small to draw conclusions regarding efficacy, this study shows that expansion of triplet neoadjuvant therapy to include a pan-erbB inhibitor, where specific HER2-targeting therapies may not be appropriate, appears both safe and tolerable.\n\nFunding\nThis work was supported by AstraZeneca, Cancer Research UK [C10604/A14112] the Experimental Cancer Medicine Centre (ECMC) and NIHR Clinical Research Network [UKCRN ID 11855]. Additional NHS clinical service support costs for patient care while on study were met by the hosting sites. This study was part of the NIHR portfolio.\n\nConflict of interest statement\nA.T., M.E., S.R.L., S.F., D.A.A., R.C.T., M.G., L.E., and S.L. declare no conflict of interest. During the conduct of the study, P.S.V. and L.C. report receiving grants from AstraZeneca. J.M. reports grants from AstraZeneca and Cancer Research UK. M.R.M. reports grants from Roche, AstraZeneca and GSK; received personal fees from Amgen, Roche, GSK, Novartis, Immunocore, BMS, Eisai, Merck, Rigontec, BiolineRx and Array Biopharma; received non-financial support from Immunocore and Merck; has been a member of the Advisory Board/and has also received study fees (institution only) from Novartis,\nMillennium, Immunocore, BMS, Vertex, Eisai, Pfizer, Merck, Rigontec, Regeneron, TCBiopharma, Array Biopharma and Replimune; and also having IDSMC membership with Eisai.\n\nAppendix A Supplementary data\nThe following is/are the Supplementary data to this article:Supplementary Appendix A\nFull study inclusion and exclusion criteria\n\nSupplementary Appendix A Supplementary Appendix B\nDose Limiting Toxicity Criteria for the escalation phase\n\nSupplementary Appendix B \n\nAcknowledgements\nThis study was sponsored by the University of Oxford, with trial management provided by the Oncology Clinical Trials Office. Statistical expertise was provided by the Centre for Statistics in Medicine, Oxford, UK, supported by Cancer Research UK (grant C5529/A16895). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and the Leicester ECMC Grant number C10604/A25151. The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. Support for manuscript writing was provided by Lynne Howells (Leicester Cancer Research Centre, Leicester, UK).\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejca.2019.10.010.\n==== Refs\nReferences\n1 CRUK. Cancer Statistics. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/: [CRUK] .\n2 Offman J. Pesola F. Sasieni P. Trends and projections in adenocarcinoma and squamous cell carcinoma of the oesophagus in England from 1971 to 2037 Br J Canc 118 2018 1391 1398 \n3 Berry M.F. Esophageal cancer: staging system and guidelines for staging and treatment J Thorac Dis 6 Suppl 3 2014 S289 S297 24876933 \n4 HQIP National Oesophago-gastric cancer audit 2018 Healthcare Quality Improvement Partnership https://www.nogca.org.uk/content/uploads/2018/09/NOGCA-2018-Annual-Report-1.pdf \n5 Allum W.H. Stenning S.P. Bancewicz J. Clark P.I. Langley R.E. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer J Clin Oncol 27 2009 5062 5067 19770374 \n6 Al-Batran S.-E. Homann N. Schmalenberg H. Kopp H.-G. Haag G.M. Luley K.B. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): a multicenter, randomized phase 3 trial J Clin Oncol 35 2017 4004 \n7 Ychou M. Boige V. Pignon J.P. Conroy T. Bouche O. Lebreton G. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial J Clin Oncol 29 2011 1715 1721 21444866 \n8 Cunningham D. Allum W.H. Stenning S.P. Thompson J.N. Van de Velde C.J. Nicolson M. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N Engl J Med 355 2006 11 20 16822992 \n9 Noordman B.J. Verdam M.G.E. Lagarde S.M. Hulshof M. van Hagen P. van Berge Henegouwen M.I. Effect of neoadjuvant chemoradiotherapy on health-related quality of life in esophageal or junctional cancer: results from the randomized CROSS trial J Clin Oncol 36 2018 268 275 29161204 \n10 Alderson D. Cunningham D. Nankivell M. Blazeby J.M. Griffin S.M. Crellin A. Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial Lancet Oncol 18 2017 1249 1260 28784312 \n11 Cunningham D. Stenning S.P. Smyth E.C. Okines A.F. Allum W.H. Rowley S. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial Lancet Oncol 18 2017 357 370 28163000 \n12 Okines A. Cunningham D. Chau I. Targeting the human EGFR family in esophagogastric cancer Nat Rev Clin Oncol 8 2011 492 21468131 \n13 Bang Y.J. Van Cutsem E. Feyereislova A. Chung H.C. Shen L. Sawaki A. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial Lancet 376 2010 687 697 20728210 \n14 Rivera F. Jiménez P. Garcia Alfonso P. Lopez C. Gallego J. Limon M.L. NeoHx study: perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma—R0 resection, pCR, and toxicity analysis J Clin Oncol 31 2013 1 23129739 \n15 Hofheinz R. Hegewisch-Becker S. Thuss-Patience P.C. Kunzmann V. Fuchs M. Graeven U. HER-FLOT: trastuzumab in combination with FLOT as perioperative treatment for patients with HER2-positive locally advanced esophagogastric adenocarcinoma: a phase II trial of the AIO Gastric Cancer Study Group J Clin Oncol 32 2014 1 24276780 \n16 Fichter C.D. Timme S. Braun J.A. Gudernatsch V. Schopflin A. Bogatyreva L. EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer Int J Cancer 135 2014 1517 1530 24510732 \n17 Yoon H.H. Sukov W.R. Shi Q. Sattler C.A. Wiktor A.E. Diasio R.B. HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma Cancer 120 2014 415 424 24151090 \n18 Hickinson D.M. Klinowska T. Speake G. Vincent J. Trigwell C. Anderton J. AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer Clin Cancer Res 16 2010 1159 1169 20145185 \n19 Skolnik J.M. Barrett J.S. Jayaraman B. Patel D. Adamson P.C. Shortening the timeline of pediatric phase I trials: the rolling six design J Clin Oncol 26 2008 190 195 18182661 \n20 Shuster J.J. Median follow-up in clinical trials J Clin Oncol 9 1991 191 192 1985169 \n21 Cancer Genome Atlas Research N. Analysis Working Group: asan U, Agency BCC, Brigham, Women's H, Broad I, et al. Integrated genomic characterization of oesophageal carcinoma Nature 541 2017 169 175 28052061 \n22 Wei Q. Chen L. Sheng L. Nordgren H. Wester K. Carlsson J. EGFR, HER2 and HER3 expression in esophageal primary tumours and corresponding metastases Int J Oncol 31 2007 493 499 17671674 \n23 Ecker B.L. Taylor L. Zhang P.J. Furth E.E. Ginsberg G.G. McMillan M.T. HER3 expression is a marker of tumor progression in premalignant lesions of the gastroesophageal junction PLoS One 11 2016 e0161781 \n24 Kol A. Terwisscha van Scheltinga A.G. Timmer-Bosscha H. Lamberts L.E. Bensch F. de Vries E.G. HER3, serious partner in crime: therapeutic approaches and potential biomarkers for effect of HER3-targeting Pharmacol Ther 143 2014 1 11 24513440 \n25 Barlaam B. Anderton J. Ballard P. Bradbury R.H. Hennequin L.F. Hickinson D.M. Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors ACS Med Chem Lett 4 2013 742 746 24900741 \n26 Tjulandin S. Moiseyenko V. Semiglazov V. Manikhas G. Learoyd M. Saunders A. Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors Investig New Drugs 32 2014 145 153 23589215 \n27 Adams R. Brown E. Brown L. Butler R. Falk S. Fisher D. Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2-3 randomised trial Lancet Gastroenterol Hepatol 3 2018 162 171 29254887 \n28 Johnston S. Basik M. Hegg R. Lausoontornsiri W. Grzeda L. Clemons M. Inhibition of EGFR, HER2, and HER3 signaling with AZD8931 in combination with anastrozole as an anticancer approach: phase II randomized study in women with endocrine-therapy-naive advanced breast cancer Breast Canc Res Treat 160 2016 91 99 \n29 Lacouture M.E. Anadkat M. Jatoi A. Garawin T. Bohac C. Mitchell E. Dermatologic toxicity occurring during anti-EGFR monoclonal inhibitor therapy in patients with metastatic colorectal cancer: a systematic review Clin Colorectal Cancer 17 2018 85 96 29576427 \n30 Petty R.D. Dahle-Smith A. Stevenson D.A.J. Osborne A. Massie D. Clark C. Gefitinib and EGFR gene copy number aberrations in esophageal cancer J Clin Oncol 35 2017 2279 2287 28537764 \n31 Gebski V. Burmeister B. Smithers B.M. Foo K. Zalcberg J. Simes J. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis Lancet Oncol 8 2007 226 234 17329193 \n32 Medical Research Council Oesophageal Cancer Working G. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial Lancet 359 2002 1727 1733 12049861 \n33 Wahba H.A. El-Hadaad H.A. Abd-Ellatif E.A. Neoadjuvant concurrent chemoradiotherapy with capecitabine and oxaliplatin in patients with locally advanced esophegeal cancer Med Oncol 29 2012 1693 1698 21706368 \n34 Schuhmacher C. Gretschel S. Lordick F. Reichardt P. Hohenberger W. Eisenberger C.F. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954 J Clin Oncol 28 2010 5210 5218 21060024 \n35 van den Ende T. Smyth E. Hulshof M. van Laarhoven H.W.M. Chemotherapy and novel targeted therapies for operable esophageal and gastroesophageal junctional cancer Best Pract Res Clin Gastroenterol 36–37 2018 45 52\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0959-8049",
"issue": "124()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "AZD8931; Dual erbB inhibitor; Oesophagogastric cancer",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D003967:Diarrhea; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005076:Exanthema; D005221:Fatigue; D005260:Female; D006801:Humans; D008297:Male; D000072662:Margins of Excision; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D000077150:Oxaliplatin; D010071:Oxaloacetates; D000077982:Progression-Free Survival; D011799:Quinazolines; D018719:Receptor, ErbB-2; D020893:Receptor, ErbB-3; D013274:Stomach Neoplasms; D014839:Vomiting",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "131-141",
"pmc": null,
"pmid": "31765988",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20728210;29563637;27654971;20145185;28052061;19770374;24151090;21444866;21468131;24876933;24900741;29576427;27559738;29254887;16822992;28784312;12049861;24510732;21706368;28163000;21060024;1985169;18182661;23589215;24513440;29161204;17671674;30551856;28537764;17329193",
"title": "Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma.",
"title_normalized": "dual erb b inhibition in oesophago gastric cancer debioc a phase i dose escalating safety study and randomised dose expansion of azd8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma"
} | [
{
"companynumb": "GB-PFIZER INC-2018494262",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nPaget disease is commonly asymptomatic and discovered when an imaging test is performed for another clinical indication or when elevated serum alkaline phosphatase is found. Bone pain usually appears late in the disease process and is only present in a minority of patients. For diagnosis, X-ray and bone scan are the most recommended imaging methods; radionuclide imaging of the skeleton has become the standard, since it is the most sensitive test for detecting increased bone activity. For treatment, either bisphosphonates or calcitonin are recommended.\n\n\nMETHODS\nWe present a 74-year-old patient diagnosed with prostate cancer in 2001 who developed bone metastases concomitant with a Paget bone disease.\n\n\nRESULTS\nThis patient received treatment with Ra-223, having stable disease in bone scan and no relevant toxicities.\n\n\nCONCLUSIONS\nThere is no clinical experience with Ra-223 and Paget disease, since it is characterized classically as a high bone turnover disease and therefore there is no rationale to administer a drug that has a high bone affinity. Nevertheless, Ra-223 is not contraindicated.",
"affiliations": " Department of Nuclear Medicine, Centro Integral Oncológico Clara Campal (CIOCC), Hospital de Madrid Sanchinarro, Grupo HM Hospitales, Madrid - Spain.; Department of Nuclear Medicine, Centro Integral Oncológico Clara Campal (CIOCC), Hospital de Madrid Sanchinarro, Grupo HM Hospitales, Madrid - Spain.; Departament of Rheumatology, Centro Integral Oncológico Clara Campal (CIOCC), Hospital de Madrid Sanchinarro, Grupo HM Hospitales, Madrid - Spain.",
"authors": "García Cañamaque|Lina|L|;Rioja Parada|Cristina|C|;García De la Peña|Paloma|P|",
"chemical_list": "D011868:Radioisotopes; D019275:Radiopharmaceuticals; C581106:radium Ra 223 dichloride; D011883:Radium",
"country": "United States",
"delete": false,
"doi": "10.5301/tj.5000641",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "103(Suppl. 1)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000368:Aged; D001859:Bone Neoplasms; D006801:Humans; D008297:Male; D010001:Osteitis Deformans; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D011883:Radium",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "e53-e55",
"pmc": null,
"pmid": "28525684",
"pubdate": "2017-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "223Ra-dichloride response in a patient with Paget disease and bone metastases secondary to castration-resistant prostate cancer.",
"title_normalized": "223ra dichloride response in a patient with paget disease and bone metastases secondary to castration resistant prostate cancer"
} | [
{
"companynumb": "ES-ASTELLAS-2018US004965",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENZALUTAMIDE"
},
"drugadditional": "3",
... |
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