tbuckley/cabot-search huggingface dataset:
PS1054 INTENSIFIED CONDITIONING WITH FLUDARABINE/MELPHALAN PLUS TOTAL BODY IRRADIATION VERSUS FLUDARABINE/MELPHALAN ALONE FOR ACUTE MYELOID LEUKEMIA
Authors: S. Lindner, F. Lang, T. Berg, J. Riemann, S. Ajib, Z. Jedlickova, S. Gueller, R. Toenges, J. Steinmann, H. Martin, H. Serve, G. Bug
Journal: HemaSphere (2019)

Background: Cytomegalovirus (CMV) infection is a major complication after allogeneic stem cell transplantation (ASCT). Aims: The aim of the study was to evaluate the impact of CMV reactivation on the relapse rate after ASCT in patients with acute myeloid leukemia (AML). Methods: Retrospective study conducted in patients with AML who underwent ASCT from HLA identical sibling donor between January 2011 and December 2018. Conditioning regimen consisted of Busulfex and Cyclophosphamide (Bu/Cy) or Fludarabine and Busulfex (F/Bu). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and a short course of methotrexate. Antiviral prophylaxis for CMV infection was assured by Acyclovir from day +1 to day +180. CMV detection was carried out once-a-week from engraftment to day +100 by either pp 65 antigenemia test or real-time quantitative PCR. Results: Ninety-three patients were enrolled (55 men and 38 women). Median age was 33 years (range, 5 - 49 y). At the time of transplant, 73 patients (78.5%) were in CR1, 16 patients (17.2%) were in CR2 and 4 patients (4.3%) were in response failure. CMV serostatus for donor (D) and recipient (R) was available for 44 cases (47.3%). Serostatus of R+/D+ and R+/D− was observed in 38 patients (86.4%). Stem cell source were BM in 49 cases (52.7%) and PBSC in 44 cases (47.3%). No graft failure was observed. Acute GVHD grade II-IV occurred in 19 patients (20.4%). Chronic GVHD was observed in 40 patients (45.4%). Twenty-nine patients (31.2%) developed CMV reactivation. With a median follow-up of 2 years (range 49 days – 7 years), the overall survival (OS) and the non-relapse mortality (NRM) were not statistically significant between patients with CMV reactivation and those without CMV reactivation (74% vs 63%, p = 0.3 and 20.7% vs 7.8%, p = 0.08, respectively). Twenty-four patients (25.8%) relapsed at a median of 6 months (range 2 - 67 months). the rate of relapse among patients with CMV reactivation was significantly lower than in those without CMV reactivation (10.3% vs 32.8%, p = 0.02). In univariate analysis, the CMV reactivation was the only factor associated with a decreased risk of relapse (OR = 0.23, 95% CI: 0.06–0.87, p = 0.02). Summary/Conclusion: CMV reactivation was associated with decreased relapse risk after ASCT for patients with AML without a benefit in OS.
PB2034 INVASIVE ASPERGILLOSIS IN PEDIATRIC PATIENTS WITH MALIGNANCIES
Authors: Y. Dinikina, O. Shadrivova, M. Belogurova, S. Ignatyeva, T. Bogomolova, E. Boichenko, N. Klimko
Journal: HemaSphere (2019)

Background: Invasive aspergillosis (IA) is an important cause of infectious morbidity and mortality in immunocompromised pediatric patients. Early recognition and initiation of antifungal treatment are key to the infection control and possibility to continue anticancer treatment. Aims: To evaluate risk factors and treatment results of IA in children with malignancies. Methods: Retrospective analysis of the pediatric register of IA in malignancies from 1997 to January 2019. For the probable and proven IA diagnosis EORTC / MSG, 2008 criteria were used. Results: 46 pediatric patients with malignancies were included, median age ‐ 8 years, males – 69,5%. IA was diagnosed after cytostatic chemotherapy in 42 patients (91,3%), in debut of cancer prior to chemotherapy – 4 (8,7%). Hematological malignancies were underlying diseases in 39 patients (84,7%), solid tumors – 7 (15,2%). Most frequent hematological diagnoses were myeloid leukemia (34,7%) and acute lymphoblastic leukemia (34,7%). Among solid malignancies – central nervous system tumors (42,8%). Risk factors of IA were prolonged ≥10 days neutropenia – 82,6%, steroid therapy – 50%, long‐term lymphocytopenia – 45,6%, severe bacterial infections (30,4%), and cytomegalovirus infection (8,8%). Main site of IA were lungs (89,1%), clinical signs were non‐specific. Typical imaging findings included the halo sign – 32,6% and air crescent sign – 4,3%. Galactomannan test in bronchoalveolar lavage fluid was positive in 83 %, in serum and cerebrospinal fluid – 37%. Mycological examination of specimen was attempted in 25% of patients. Among them septated hyphae by microscopy was diagnosed in 20%. Aspergillus spp . were isolated in culture in 28%. The etiology agents were A.fumigatus – 57%, A.niger – 29%, and A.ustus – 14%. Antifungal treatment received 100% of patients, with voriconazole only – 54,3%. 12‐week survival was 81%. In all cases of IA before chemotherapy after infection control anticancer therapy was continued. 63% of patients continued antifungal therapy concomitantly chemotherapy, voriconazole was canceled during vincristine use. Summary/Conclusion: Cases of IA in children with hematological malignancies were registered more frequently compared to solid tumors (84,7% vs 15,2%). The main risk factors of IA were prolonged neutropenia (82,6%), steroid therapy (50%), lymphocytopenia (45,6%). 12‐weeks overall survival was 81%. There were no contraindications for anticancer therapy to continue after infection control. In cases of continuation of antifungal treatment drug‐drug interactions should be considered.
LncRNA DCRF regulates cardiomyocyte autophagy by targeting miR-551b-5p in diabetic cardiomyopathy
Authors: Yu Feng, Weiting Xu, Wei Zhang, Wenjing Wang, Tong Liu, Xiang Zhou
Journal: Theranostics (2019)

Background: We generated a rat model of diabetic cardiomyopathy (DCM) and reported significant upregulation of the long non-coding RNA DCRF. This study was designed to determine the molecular mechanisms of DCRF in the development of DCM. Methods: Real-time PCR and RNA fluorescent in situ hybridization were conducted to detect the expression pattern of DCRF in cardiomyocytes. Histological and echocardiographic analyses were used to assess the effect of DCRF knockdown on cardiac structure and function in diabetic rats. mRFP-GFP-LC3 fluorescence microscopy, transmission electron microscopy, and Western blotting were carried out to determine cardiomyocyte autophagy. RNA immunoprecipitation and luciferase reporter assays were performed to elucidate the regulatory role of DCRF/miR-551b-5p/PCDH17 pathway in cardiomyocyte autophagy. Results: Our findings showed that DCRF knockdown reduced cardiomyocyte autophagy, attenuated myocardial fibrosis, and improved cardiac function in diabetic rats. High glucose increased DCRF expression and induced autophagy in cardiomyocytes. RNA immunoprecipitation and luciferase reporter assays indicated that DCRF was targeted by miR-551b-5p in an AGO2-dependent manner and PCDH17 was the direct target of miR-551b-5p. Forced expression of DCRF was found to attenuate the inhibitory effect of miR-551b-5p on PCDH17. Furthermore, DCRF knockdown decreased PCDH17 expression and suppressed autophagy in cardiomyocytes treated with high glucose. Conclusion: Our study suggests that DCRF can act as a competing endogenous RNA to increase PCDH17 expression by sponging miR-551b-5p, thus contributing to increased cardiomyocyte autophagy in DCM.
Shared dysregulation of long non-coding RNA and developmental gene networks in histone H3 K27M gliomas and PF-A ependymomas.
Authors: Lauren Sanders, Allison Cheney, Holly Beale, Ellen Kephart, Isabel Bjork, Jacob Joseph Pfeil, Sofie R. Salama, David Haussler, Olena Morozova
Journal: Journal of Clinical Oncology (2019)

e21523 Background: Diffuse pediatric gliomas harboring a Histone-H3 K27M mutation are more aggressive than H3-wild type gliomas and demonstrate global hypomethylation at the K27 residue 1 . As a result, these tumors show global aberrant gene expression, resulting in a stem-like proliferative cell population 2 . Posterior fossa (PF) ependymomas, on the other hand, harbor few significantly recurrent somatic mutations, but PF-A and PF-B subgroups have been defined on the basis of epigenetic differences 3 . Compared to PF-B, the PF-A subgroup demonstrates H3K27 hypomethylation, aberrant gene expression and aggressive tumor growth 4,5 . Methods: We recently identified a set of long non-coding RNA (lncRNA) that are transiently expressed in early brain development 6 , and hypothesized that H3K27M gliomas and PF-A ependymomas may share methylation-related dysregulation of lncRNA networks responsible for maintaining normal differentiation programs. Results: Here we describe a network of regulatory lncRNA with increased expression in both H3K27M gliomas and PF-A ependymomas, as compared to H3-WT gliomas and PF-B ependymomas. We demonstrate that increased expression of this lncRNA network correlates with the over-expression of signaling pathways involved in maintaining a non-differentiated, proliferative phenotype and driving tumorigenesis. Conclusions: We hypothesize that in both H3K27M gliomas and PF-A ependymomas, aberrant global methylation may be driving lncRNA to activate and maintain stem-like states in early neural development, suggesting similarities in epigenetically driven, developmental origins for both tumor types. References: 1. Chan KM, Fang D, Gan H, et al. Genes Dev. 2013;27(9):985-90; 2. Filbin MG, Tirosh I, Hovestadt V, et al. Science. 2018;360(6386):331-5; 3. Witt H, Mack SC, Ryzhova M, et al. Cancer cell. 2011;20(2):143-57; 4. Bayliss J, Mukherjee P, Lu C, et al. Sci. Transl. Med. 2016;8(366):366ra161; 5. Mack SC, Witt H, Piro RM, et al. Nature. 2014;506(7489):445; 6. Field AR, Jacobs FM, Fiddes IT, et al. bioRxiv. 2017:232553.
MET IHC Is a Poor Screen for MET Amplification or MET Exon 14 Mutations in Lung Adenocarcinomas: Data from a Tri-Institutional Cohort of the Lung Cancer Mutation Consortium
Authors: Robin Guo, Lynne D. Berry, Dara L. Aisner, Jamie Sheren, Theresa Boyle, Paul A. Bunn, Bruce E. Johnson, David J. Kwiatkowski, Alexander Drilon, Lynette M. Sholl, Mark G. Kris
Journal: Journal of Thoracic Oncology (2019)
Abstract 049: Promoter Methylation of Glucocorticoid Receptor Gene Is Associated with Subclinical Cardiovascular Disease: a Monozygotic Twin Study
Authors: Jinying Zhao, Jack Goldberg, Arshed A Quyyumi, Uphoff Irina, Viola Vaccarino
Journal: Circulation (2012)

Background: Epigenetic mechanisms are increasingly being recognized as a key factor in the pathogenesis of cardiovascular disease (CVD). Endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is a marker for early atherosclerotic CVD, a predictor of future cardiovascular events. The glucocorticoid receptor gene (NR3C1) regulates a variety of biological processes including cardiovascular, metabolic, immunologic, and homeostatic functions. Genetic polymorphisms in NR3C1 have been associated with atherosclerosis and several cardiometabolic risk factors. However, no study has yet investigated the potential role of NR3C1 promoter methylation in atherosclerosis. Objective: To examine the potential association between NR3C1 promoter methylation and FMD in a monozygotic (MZ) twin sample. Method: We studied 84 male-male monozygotic twin pairs drawn from the Vietnam Era Twin Registry. These twin pairs were recruited by the Emory Twins Heart Study, which investigates psychological, behavioral and biological risk factors for subclinical cardiovascular disease using a twin design. The twins were free of a self-reported previous diagnosis of cardiovascular disease at the time of enrollment. Brachial artery FMD was measured by ultrasound. The methylation levels of 25 CpG residues in the NR3C1 promoter region in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between DNA methylation variation and FMD was examined using nonparametric regression by regressing the intra-pair difference in FMD on the intra-pair difference in DNA methylation level at each CpG site, separately, adjusting for potential confounders including age, smoking, body mass index (BMI), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), blood glucose level and systolic blood pressure. Multiple testing was controlled by the false discovery rate. Results: Mean methylation level of the 25 CpG sites encompassing the NR3C1 promoter region was 2.1%. Methylation levels at 7 of the 25 CpG residues were significantly associated with FMD. On average, a 10% increase in mean methylation was associated with a 0.13 increase in FMD (95% CI: 0.09–0.17; p &lt;0.0001) after controlling for confounding factors. Conclusion: Increased promoter methylation of NR3C1 is significantly associated with decreased risk for subclinical atherosclerosis assessed by FMD. Given the critical role of this gene in regulating hypothalamic-pituitary-adrenal axis (HPA) function, it is possible that aberrant promoter methylation of this gene may affect atherogenesis through its influence on the HPA system, a mechanism known to be involved in cardiovascular disease.
Abstract P319: Prospective Association Between Beta-2 Microglobulin and the Risk of Ischemic Stroke in Women
Authors: Pamela M Rist, Monik C Jiménez, Kathryn M Rexrode
Journal: Circulation (2016)

Introduction: Elevated beta-2 microglobulin (B2M) is associated with total stroke. Previous studies have not examined the association between B2M and ischemic stroke risk or ischemic stroke subtypes. We hypothesized that women with higher B2M levels would be at increased risk of experiencing ischemic stroke events. Methods: We performed a nested case-control study among women enrolled in the Nurses’ Health Study who provided blood samples at baseline (1989-1990) and were free of cardiovascular disease and cancer. We measured B2M levels in 460 ischemic strokes cases which occurred between 1989-2008 confirmed by medical record review and classified as thrombotic or embolic, and in 460 controls matched 1:1 to the cases on age, race, date of blood collection, menopausal status, postmenopausal hormone use, and smoking status. We analyzed the association between B2M and ischemic stroke using multivariable conditional logistic regression conditional on the matching factors and adjusted for physical activity, body mass index, aspirin use, alcohol consumption, log transformed total cholesterol to HDL cholesterol ratio, and history of diabetes, high blood pressure, and coronary heart disease or revascularization. Results: The mean age at baseline was 60.5 years with a median of 9.0 years to stroke event. Median levels of B2M were higher among cases (1.86 mg/L) than controls (1.80 mg/L; p-value for Wilcoxon rank sum test=0.009). Those in the highest B2M quartile had a multivariable adjusted increased risk of ischemic stroke compared to those in the lowest quartile (OR=1.68; 95% CI: 1.08, 2.62) (Table). Other quartiles were not associated with an increased risk of ischemic stroke compared to those in the lowest quartile. The association between B2M and thrombotic ischemic stroke was similar to the overall ischemic stroke results. However, we observed no association between B2M and embolic ischemic stroke risk. Conclusion: High levels of B2M were associated with an increased risk of ischemic strokes of thrombotic origin among women.
Abstract 19897: Preclinical Evaluation of Proangiogenic Gene Therapy by Ultrasound Targeted Microbubble Destruction of Vascular Endothelial Growth Factor Minicircle DNA in a Model of Severe Peripheral Arterial Disease in Watanabe Heritable Hyperlipidemic Rabbits
Authors: Hao H Chen, Michael A Kuliszeski, Dmitriy Rudenko, Howard Leong-Poi
Journal: Circulation (2017)

Background: Ultrasound targeted microbubble destruction (UTMD) is a non-invasive technique for gene delivery. We have previously shown that UTMD of vascular endothelial growth factor (VEGF) plasmid...
US suicide rates in young people are highest since 2000
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Suicide rates among young people in the US have increased to their highest since 2000, new figures show.1

Researchers from Harvard Medical School analysed data from the Centers for Disease Control and Prevention’s Underlying Cause of Death database and found that the suicide rate in people aged 15 to 19 increased from eight per 100 000 in 2000 to 11.8 per 100 000 in 2017.

Meanwhile, in young adults aged 20 to 24 the overall suicide rate …
PB1939 ACCURACY AND SPEED OF REPORTING MOLECULAR RESPONSE IN PATIENTS ON TYROSINE KINASE INHIBITORS THERAPY WITH GENEXPERT CARTRIDGE‐BASED BCR‐ABL1 QUANTITATION
Authors: M. Dreisinger, Š. Stangler Herodež
Journal: HemaSphere (2019)

Background: Monitoring of minimal residual disease (MRD) in chronic myeloid leukemia (CML) patients who are on tyrosine kinase inhibitors (TKI) is one of the best standardized molecular methods. Guidelines for treating these patients include the evaluation of molecular response (MR) based on % BCR‐ABL1 on the International Scale (IS) in defined time points. Achieving timely MR is necessary for determining the status of the disease and the use of appropriate therapy. Aims: The aim of this study was to introduce the GeneXpert cartridge‐based BCR‐ABL1 detection into routine molecular monitoring of CML Slovenian patients from north‐eastern region and compare the MR results with those obtained from a standard laboratory method. Methods: BCR‐ABL1 transcript quantification was performed in 40 peripheral blood samples from CML patients at different stages of the disease in two different laboratories. First one used automated GeneXpert BCR‐ABL Ultra Assay (Cepheid, USA) and the second one used standardized laboratory protocol. The results for both analyzes were expressed as % IS and were estimated by MR according to Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Results: The analysis of the results showed that there were no statistically significant differences in the results expressed in % IS (p = 0, 272). Samples according to the estimated MR were divided into 3 groups (8 MR3 samples, 3 MR4 samples and 27 ≥ MR4.5 samples). 27/40 samples had a completely identical MR with both methods. Furthermore, 11/40 samples had higher MR obtained with GeneXpert, while 0/40 samples had lower MR compared to SP. In 2/40 cases, GeneXpert gave MR5 for sample with SP MR3 and MR4 for sample with SP MR3. None of the results obtained with GeneXpert had any effect on a different clinical decision on treatment with TKI as obtained under the SP. When the major molecular response (MMR) was analyzed, 78% agreement was achieved. Summary/Conclusion: GeneXpert BCR‐ABL Ultra Assay provides reproducible results and doesn’t show significant differences compared with the standardized laboratory protocol. From clinical aspect, GeneXpert BCR‐ABL Ultra Assay correctly classified the patients in MR and can be considered as a useful and very fast clinical tool for the molecular follow up of patients on tyrosine kinase inhibitors.
PS1492 ASSESSING TREATMENT RESPONSE IN CONGENITAL THROMBOTIC THROMBOCYTOPENIC PURPURA WITH AN INNOVATIVE SHEAR FLOW-BASED ASSAY
Authors: C. Vendramin, F. Alwan, M. Thomas, M. Scully
Journal: HemaSphere (2019)

Background: Congenital Thrombotic Thrombocytopenic Purpura (TTP) is defined by severe ADAMTS13 activity (<10%) and absence of anti-ADAMTS13 antibodies, confirmed by mutational analysis. ADAMTS13 deficiency results in increased ultra large Von Willebrand Factor (VWF) multimers and disseminated microvascular ischemia. Current replacement therapy is primarily using plasma infusion (PI). Dose and PI interval are selected empirically for each patient. At present there is no method to assess disease and treatment response in patients with cTTP. Aims: We developed an innovative shear flow-based assay to assess cTTP, with normal platelet counts, receiving plasma infusion (PI) or intermediate purity factor VIII concentrate (BPL-8Y). Methods: A VenaFlux semi-automated microfluidic system provides high shear flow. Citrated whole blood was treated with DiOC6 for platelet fluorescence. Thrombus formation on collagen-coated microchannels was analysed by an epifluorescence microscope and an automated calculation of total surface coverage was developed. Surface coverage represented increasing thrombus formation (VWF-platelets). Total surface coverage within 180 seconds equalled 100% coverage. Normal range for surface coverage, using 50 normal controls, was 6–39%. cTTP samples were taken 30 minutes before and after prophylaxis (PI or BPL-8Y) and surface coverage determined. Further re-measurement was undertaken after initiation of antiplatelet therapy. Results: 21 confirmed cTTP patients: 18 female and 3 male, median age: 33 years (range 16–69). Median pre-treatment surface coverage was 89% (range 47–100%), with no significant difference considering mutation type (homozygous 98%, heterozygous 83%, p = 0.097) or age of presentation (childhood onset 73%, adult onset 90%, p = 0.19). PI improved surface coverage results (post PI coverage 44%, p = 0.0005). Antiplatelet therapy further improved median surface coverage, pre and post prophylaxis. Median pre-treatment surface coverage for patients receiving PI and antiplatelet therapy was 50% (p < 0.0001). This improvement was confirmed by the median post-treatment coverage (19% for patients on antiplatelets vs. 44% for patients not on antiplatelets, p = 0.0011). Post-treatment surface coverage returned to normal range in 100% patients who received PI and antiplatelet therapy compared to 50% in patients who received PI alone (p = 0.04). Summary/Conclusion: This advanced shear flow-based assay showed increased thrombi formation in cTTP patients, despite ‘remission’, confirming severe ADAMTS13 deficiency is associated with increased circulating ultra large VWF multimers and platelet thrombi. This assay provides additional information on treatment assessment in cTTP patients, optimised with regular PI and antiplatelet therapy, and it guides treatment.
Paying for Cancer Care
Authors: Robert Steinbrook
Journal: JAMA Internal Medicine (2019)

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