tbuckley/cabot-search huggingface dataset:
Comedications and potential drug-drug interactions with direct-acting antivirals in hepatitis C patients on hemodialysis
Authors: Po-Yao Hsu, Yu-Ju Wei, Jia-Jung Lee, Sheng-Wen Niu, Jiun-Chi Huang, Cheng-Ting Hsu, Tyng-Yuan Jang, Ming-Lun Yeh, Ching-I Huang, Po-Cheng Liang, Yi-Hung Lin, Ming-Yen Hsieh, Meng-Hsuan Hsieh, Szu-Chia Chen, Chia-Yen Dai, Zu-Yau Lin, Shinn-Cherng Chen, Jee-Fu Huang, Jer-Ming Chang, Shang-Jyh Hwang, Wan-Long Chuang, Chung-Feng Huang, Yi-Wen Chiu, Ming-Lung Yu
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: Direct‐acting antivirals (DAAs) have been approved for hepatitis C virus (HCV) treatment in patients with end-stage renal disease (ESRD) on hemodialysis. Nevertheless, the complicated comedications and their potential drug-drug interactions (DDIs) with DAAs might limit clinical practice in this special population.Methods: The number, class, and characteristics of comedications and their potential DDIs with five DAA regimens were analyzed among HCV-viremic patients from 23 hemodialysis centers in Taiwan.Results: Of 2,015 hemodialysis patients screened in 2019, 169 patients seropositive for HCV RNA were enrolled (mean age, 65.6 years; median duration of hemodialysis, 5.8 years). All patients received at least one comedication (median number, 6; mean class number, 3.4). The most common comedication classes were ESRD-associated medications (94.1%), cardiovascular drugs (69.8%) and antidiabetic drugs (43.2%). ESRD-associated medications were excluded from DDI analysis. Sofosbuvir/velpatasvir/voxilaprevir had the highest frequency of potential contraindicated DDIs (red, 5.6%), followed by glecaprevir/pibrentasvir (4.0%), sofosbuvir/ledipasvir (1.3%), sofosbuvir/velpatasvir (1.3%), and elbasvir/grazoprevir (0.3%). For potentially significant DDIs (orange, requiring close monitoring or dose adjustments), sofosbuvir/velpatasvir/voxilaprevir had the highest frequency (19.9%), followed by sofosbuvir/ledipasvir (18.2%), glecaprevir/pibrentasvir (12.6%), sofosbuvir/velpatasvir (12.6%), and elbasvir/grazoprevir (7.3%). Overall, lipid-lowering agents were the most common comedication class with red-category DDIs to all DAA regimens (n=62), followed by cardiovascular agents (n=15), and central nervous system agents (n=10).Conclusions: HCV-viremic patients on hemodialysis had a very high prevalence of comedications with a broad spectrum, which had varied DDIs with currently available DAA regimens. Elbasvir/grazoprevir had the fewest potential DDIs, and sofosbuvir/velpatasvir/voxilaprevir had the most potential DDIs.
EPCO-12. SINGLE CELL PROFILING OF LONG NON-CODING RNAS IN GLIOMA
Authors: Bharati Mehani, Hye-Jung Chung, Russell Bandle, Sarah Young, Michael Kelly, Kenneth Aldape
Journal: Neuro-Oncology (2020)

Abstract Non-coding RNAs have critical functions across biological processes that regulate glioma initiation and progression, and deregulated expression of long non-coding RNAs (lncRNAs) have been implicated in the onset and progression of malignancies. The majority of these transcripts exhibit tissue- and cancer-specific expression but little has been investigated at the single-cell level. We performed single cell RNA Sequencing (10x Genomics) for 9 IDH-wild-type glioblastomas from 7 patients. In total 66,825 cells dissociated from tumor tissues and not sorted were included in this analysis which encompassed 41,989 mean sequencing reads and 2,619 median coding genes per cell. Single cell analysis of lncRNAs in captured 190 median lncRNAs per cell and demonstrated a distinct lncRNA expression profile for glioma cells compared to the non-tumor cells with SOX2-OT significantly upregulated (2X) in glioma cells. Consistent with this finding, SOX2-OT is known to be overexpressed in a variety of cancers and has been previously implicated in glioma proliferation and migration. We then examined patterns of lncRNA expression in GBM expression subtypes. Subtype correlation indicated overexpression of RMST (classical subtype), PCED1B-AS1 (mesenchymal) and LINC00689 (proneural) lncRNAs in these expression subtypes. Consistent with these findings, upregulation of each of these 3 lncRNAs have previously been implicated on pro-tumorigenic effects, including in glioma. Examination of an independent published single cell GBM dataset also validated PCED1B-AS1 in the mesenchymal subtype. Comparison with bulk tumor GBM profiles (IDHwt TCGA GBM dataset) also showed correlations with the expression of RMST, PCED1B-AS1 and LINC00689 lncRNAs in the classical, mesenchymal and proneural subtypes respectively. Overall, these results indicate lncRNA expression can be determined in 10x-generated glioma single cell data and may reveal additional insights about cellular state and glioma biology.
DIPG-75. PRECISION MEDICINE FOR PAEDIATRIC HIGH-GRADE DIFFUSE MIDLINE GLIOMAS - RESULTS FROM THE ZERO CHILDHOOD CANCER COMPREHENSIVE PRECISION MEDICINE PROGRAM
Authors: Dong-Anh Khuong-Quang, Sumanth Nagabushan, Neevika Manoharan, Greg Arndt, Paulette Barahona, Mark J Cowley, Paul G Ekert, Tim Failes, Noemi Fuentes Bolanos, Maely Gauthier, Andrew J Gifford, Michelle Haber, Amit Kumar, Richard B Lock, Glenn M Marshall, Chelsea Mayoh, Emily Mould, Murray D Norris, Anjana Gopalakrishnan, Natacha Omer, Peter Trebilcock, Toby N Trahair, Maria Tsoli, Katherine Tucker, Marie Wong, Vanessa Tyrrell, Loretta Lau, David S, Ziegler
Journal: Neuro-Oncology (2020)

Abstract The Australian Zero Childhood Cancer (ZERO) program aims to assess the feasibility of a comprehensive precision medicine approach to improve outcomes for patients with an expected survival &amp;lt;30%. ZERO combines molecular profiling (whole genome sequencing, whole transcriptome sequencing, DNA methylation profiling) with in vitro high-throughput drug screening (HTS) and patient-derived xenograft drug efficacy testing. We report on the cohort of patients with midline high-grade glioma (HGG), including H3-K27M DMG, enrolled on the pilot study (TARGET) and on the ongoing ZERO clinical trial (PRISM). We identified 48 patients with midline HGG. Fresh or cryopreserved samples were submitted in 37 cases and cell culture was attempted in 30/37 cases with 45% success rate. The most commonly mutated genes/pathways identified by molecular profiling include H3-K27M mutations, DNA repair pathway, and PI3K/mTOR pathway. Two targetable fusions (NTRK and FGFR1) were reported. Five patients with germline alterations were identified. Thirty-five (72%) patients received a therapeutic recommendation from the ZERO molecular tumour board and the main recommended therapies were mTOR inhibitors, PARP inhibitors or tyrosine kinase inhibitors. HTS added evidence for the recommended therapy (n=3) or identified novel potential therapy (n=1). Out of the 35 patients, 16 received a recommended drug. Response to treatment was complete response for five months (n=1), partial response for nine months (n=1), stable disease (n=4), and progressive disease (n=10). These results highlight the feasibility of the ZERO platform and the value of fresh biopsy, necessary for pre-clinical drug testing. Targetable alterations were identified leading to clinical benefit in six patients.
RTID-12. PHASE 2 TRIAL OF TUMOR TREATING FIELDS (TTFIELDS) PLUS RADIATION THERAPY (RT) PLUS TEMOZOLAMIDE (TMZ) COMPARED TO RT PLUS TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA (ndGBM)
Authors: Rachel Grossman, Dror Limon, Felix Bokstein, Carmit Ben Harosh, Deborah Blumenthal, Zvi Ram
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE In the EF-14 phase 3 trial, TTFields 9200 kHz) added to maintenance TMZ increased median OS to 20.9 months versus 16.0 months with maintenance TMZ (p&amp;lt; 0.001) in ndGBM. Preclinical investigations showed that TTFields/RT have a synergistic effect. A pilot study (N=10) in ndGBM demonstrated the feasibility and safety of TTFields combined with RT/TMZ (Grossman Front Onc 2020). The only TTFields-related adverse event was array-associated skin toxicity. Median PFS was 8.9 months. Based on these encouraging results, this prospective, randomized phase 2 study [NCT03869242] in 60 patients further investigates if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression. METHODS Following debulking surgery or biopsy, 60 patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy &amp;gt;3 months will be randomized 1:1 to: i) RT with concomitant TMZ/TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ combined with TTFields (experimental arm) up to 24 months; or ii) RT with concomitant TMZ alone followed by maintenance TMZ combined with TTFields (control arm). Patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or with implanted electronic devices will be excluded. The primary endpoint is the rate of progression free survival at 12 months (PFS12). Treatment with TTF will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. All adverse events will graded per CTCAE V5.0. The sample size of 60 patients provides 80% power with two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). Follow-up will continue for &amp;gt;12 months from recruitment of the last patient.
QOL-49. THE IMPACT OF OTOTOXICITY AND VISUAL IMPAIRMENT ON EDUCATION IN CHILDREN TREATED FOR CNS TUMOURS
Authors: Harriet Dulson, Rachel McAndrew, Mark Brougham
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Children treated for CNS tumours experience a very high burden of adverse effects. Platinum-based chemotherapy and cranial radiotherapy can cause ototoxicity, which may be particularly problematic in patients who have impaired vision and cognition as a result of their tumour and associated treatment. This study assessed the prevalence of impaired hearing and vision and how this may impact upon education. METHODS 53 patients diagnosed with solid tumours in Edinburgh, UK between August 2013–2018 were included in the study. Patients were split into three groups according to treatment received: Group 1 – cisplatin-based chemotherapy and cranial radiotherapy; Group 2 - platinum-based chemotherapy, no cranial radiotherapy; Group 3 – benign brain tumours treated with surgery only. Data was collected retrospectively from patient notes. RESULTS Overall 69.5% of those treated with platinum-based chemotherapy experienced ototoxicity as assessed by Brock grading and 5.9% of patients had reduced visual acuity. Patients in Group 1 had the highest prevalence of both. 44.4% of patients in Group 1 needed increased educational support following treatment, either with extra support in the classroom or being unable to continue in mainstream school. 12.5% of Group 2 patients required such support and 31.3% in Group 3. CONCLUSIONS Children with CNS tumours frequently require support for future education but those treated with both platinum-based chemotherapy and cranial radiotherapy are at particular risk, which may be compounded by co-existent ototoxicity and visual impairment. It is essential to provide appropriate support for this patient cohort in order to maximise their educational potential.
MODL-04. MODELING CNS HGNET-BCOR PATHOGENESIS USING NEURAL STEM CELLS
Authors: Satoshi Nakata, Ming Yuan, Eric Raabe, Charles Eberhart
Journal: Neuro-Oncology (2020)

Abstract Central nervous system high-grade neuroepithelial tumor with BCL6-corepressor alteration (CNS HGNET-BCOR) is a recently identified entity characterized by internal tandem duplication (ITD) of BCOR, a core component of polycomb repressive complex (PRC) 1.1. BCOR-ITD exclusively occurs within an essential binding domain, suggesting aberrant epigenetic activities as a possible mechanism of gliomagenesis; however, the effect of this alteration on the transcriptome and DNA methylation are poorly understood. We have generated new CNS HGNET-BCOR models by lentiviral transduction of the BCOR-ITD into human and murine neural stem cells. In the human model, qRT-PCR and subsequent RNA-seq identified a transient derepression of PRC2-target genes comparing to an isogenic model with overexpression of wildtype-BCOR. A similar effect was found in clinical specimens from previous studies. In the murine-cell model, we confirmed increased clonogenicity in soft-agar assays, and tumors developed in mice flanks. Global DNA methylation levels evaluated by ELISA were significantly lower than those of parent cells, and 177 genes were differentially expressed on RNA-seq analysis comparing to BCOR-overexpressing control cells, including upregulation of known oncogenes. These results suggest that BCOR-ITD and associated alterations in the function of PRC1.1 affect methylation patterns in neural stem cells, driving transcriptional changes and oncogenic transformation into CNS HGNET-BCOR. More detailed analyses, including methylation arrays comparisons with clinical samples and in-silico drug sensitivity testing, are being performed.
NIMG-37. DELAYED PSEUDOPROGRESSION IN TWO PATIENTS UNDERGOING TTFIELDS TREATMENT FOR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Allison Lowman, Sarah Hurrell, Samuel Bobholz, Jennifer Connelly, Elizabeth Cochran, Wade Mueller, Sean McGarry, Michael Brehler, Peter LaViolette
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Tumor treatment fields (TTFields) are approved by the FDA for newly diagnosed as well as recurrent glioblastoma (GBM). TTFields have been shown to extend survival by 4.9 months in newly diagnosed GBM, and a landmark overall survival rate of 13% at 5 years. However, the specific effects remain widely unknown, which has prevented widespread clinical use of this treatment. METHODS This case study examines two glioblastoma patients, IDH-1 wildtype, MGMT unmethylated, that received TTFields (Optune) in addition to maintenance temozolomide (TMZ) following radiation (RT). Both cases were followed using standard MR imaging. Second resections were performed due to radiographic progression of contrast enhancement. RESULTS Although imaging was concerning for tumor progression, pathology showed only treatment effect, ultimately leading to the diagnosis of pseudoprogression. Both patients fell outside the normal expected timeline for chemo-radiation induced pseudoprogression. Based on the pathology, both patients resumed treatment with TMZ/TTFields. One patient expired at 25 months and one is still alive. CONCLUSIONS Pathologic confirmation was essential for guiding further treatment and allowed patients to continue treatment that was effective despite contrary indications on imaging. These findings suggest that pathological confirmation should be strongly considered in patients receiving TMZ/TTFields who develop radiographic progression, potentially with a less invasive biopsy procedure. Future studies should look to characterize the underlying mechanism of interaction between TTFields/TMZ and quantify the prevalence, associated risk factors and whether there is a genotype more susceptible. Both patients reported here had O(6)-methylguanine-DNA methyltransferase (MGMT) unmethylated GBM, and while about 60% of glioblastomas are diagnosed likewise, it is possible that MGMT methylation status plays a role in TTFields response. Better characterization of this phenomenon will improve treatment guidance, potentially reducing unnecessary surgeries and the discontinuance of successful therapies.
Abstract 15733: The Left Ventricular Inflow Velocity Pattern in Patient With Symptomatic Premature Ventricular Contraction
Authors: Satoshi Takahashi, Takanao Mine, Kenki Ashida, Hideyuki Kishima, Masaharu Ishihara, Tohru Masuyama
Journal: Circulation (2017)

Background: Premature ventricular contraction (PVC) is one of the most common arrhythmias and only some patients complain of PVC-related symptoms. However the mechanisms which cause the symptoms re...
Erratum. Profibrotic Circulating Proteins and Risk of Early Progressive Renal Decline in Patients With Type 2 Diabetes With and Without Albuminuria. Diabetes Care 2020;43:2760–2767
Authors: Katsuhito Ihara, Jan Skupien, Hiroki Kobayashi, Zaipul I. Md Dom, Jonathan M. Wilson, Kristina O’Neil, Hannah S. Badger, Lenden M. Bowsman, Eiichiro Satake, Matthew D. Breyer, Kevin L. Duffin, Andrzej S. Krolewski
Journal: Diabetes Care (2020)

In Table 1 of the above-referenced article, the unit for serum matrix metalloproteinase 7 (MMP-7) …
Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study
Authors: Sarah Floud, Angela Balkwill, Siân Sweetland, Anna Brown, Elsa Mauricio Reus, Albert Hofman, Deborah Blacker, Mika Kivimaki, Jane Green, Richard Peto, Gillian K Reeves, Valerie Beral
Journal: The Lancet Public Health (2021)

Although dementia is associated with non-participation in cognitive and social activities, this association might merely reflect the consequences of dementia, rather than any direct effect of non-participation on the subsequent incidence of dementia. Because of the slowness with which dementia can develop, unbiased assessment of any such direct effects must relate non-participation in such activities to dementia detection rates many years later. Prospective studies with long-term follow-up can help achieve this by analysing separately the first and second decade of follow-up. We report such analyses of a large, 20-year study.
Rivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial
Authors: Tomasz J. Guzik, Chinthanie Ramasundarahettige, Nana Pogosova, Patricio Lopez-Jaramillo, Leanne Dyal, Scott D. Berkowitz, Eva Muehlhofer, Deepak L. Bhatt, Keith A.A. Fox, Salim Yusuf, John W. Eikelboom
Journal: Journal of the American College of Cardiology (2021)
NCMP-10. IDH MUTATION STATUS AND THE DEVELOPMENT OF VENOUS THROMBOEMBOLISM IN ASTROCYTOMA PATIENTS
Authors: Jacob Mandel, Michael Youssef, Shlomit Yust-Katz, Akash Patel, Ali Jalali, Ethan Ludmir, Jimin Wu, John de Groot
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Examine whether the status of the isocitrate dehydrogenase (IDH) gene is a risk factor for the development of venous thromboembolism (VTE) in astrocytoma patients. BACKGROUND The risk of venous thromboembolism (VTE) is high for patients with gliomas (10–30%). Unfortunately, biomarkers and predictive models for development of a VTE in brain cancer have not been validated. Prior research has suggested that IDH wildtype gliomas are at higher risk for development of VTE compared to IDH mutant tumors. DESIGN/METHODS We conducted a retrospective chart review of glioma patients enrolled in the PROACTIVE (Prospective Assessment of Correlative Biomarker) study at MD Anderson Cancer Center (MDACC). We obtained demographics, date of tumor diagnosis, initial pathology, IDH status (mutated or wildtype), extent of initial resection, KPS at time of initial resection, history of VTE, development of VTE, type of VTE (PE/DVT), KPS at time of VTE, treatment for VTE, bleeding complications, glioma treatments, date of last follow up and/or death. RESULTS We identified 282 astrocytoma patients consisting of 49 IDH mutant and 233 IDH wildtype astrocytomas. Glioblastoma was the histopathologic diagnosis in 30 (61.2%) of the IDH mutated astrocytomas compared to 227(97.4%) of the IDH wild type astrocytomas. VTE was identified in 52 (18.4%) of patients. VTE was diagnosed in 7 (14.3%) of the IDH mutated astrocytomas compared to 45 (19.3%) of the IDH wild type astrocytomas (p = 0.4094). Median time to VTE from diagnosis was 2.71 months. Median time to VTE from diagnosis was 2.6 months for IDH mutated astrocytomas compared to 3.06 months for the IDH wild type astrocytomas (p =0.8663). CONCLUSIONS IDH gene status did not appear as a significant risk factor for the development of venous thromboembolism (VTE) in our cohort of astrocytoma patients. Further research into potential biomarkers for VTE may be warranted.
Abstract P423: Lactation Duration is Associated With Favorable Cognitive Function in Women During Midlife: The 30-year Cardia Study
Authors: Erica P Gunderson, Cora E Lewis, Jennifer Lui, Kristine Yaffe, Stephen Sidney
Journal: Circulation (2020)

Introduction: Lactation has been associated with lower incidence of the metabolic syndrome, type 2 diabetes, hypertension, and early atherosclerosis in women across the childbearing years. The lower risk of cardiometabolic diseases related to higher lifetime lactation may also extend to levels of cognitive function during midlife. Hypothesis: We tested the hypothesis that lactation duration is associated with better cognitive function in women during midlife independent of antecedent risk factors, as well as obesity, diabetes, and hypertension. Methods: We included 904 women aged 18-30 years at baseline (1985-86) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study without no diabetes before ≥1 birth(s) after baseline, reported lactation duration for each post-baseline birth, and had 6 measures of cognitive function assessed at Year 30 (2015-16) including the Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), Stroop Test, Montreal Cognitive Assessment (MoCA), Letter Fluency Test, and Category Fluency Test. Linear regression models estimated mean (95%CI) cognition scores by lactation duration (none, &gt;0 to 6 mos, &gt; 6 to &lt;12 mos, ≥12 mos) adjusted for race, age, BMI, blood pressure, parity, and follow up covariates (Table 1). Results: Among parous women (46% black, 54% white) at 30-year follow up, average age was 54 yrs and 47% had obesity, 61% delivered ≥2 births since baseline, 29% used anti-hypertensive medications and 16% developed overt diabetes. Black women were less likely to report &gt;6 mos of total lactation for all births than white women (23% vs. 58%). Unadjusted and fully adjusted mean scores for 3 cognitive function measures had graded direct associations with increasing lactation duration; specifically, the RAVLT, MoCA and Category Fluency Test scores (all p-trend &lt; 0.01). Conclusions: In this prospective study, longer lactation duration was associated with more favorable cognition scores among women during midlife.