tbuckley/cabot-search huggingface dataset:
Tissue 2-Hydroxyglutarate as a Biomarker for <i>Isocitrate Dehydrogenase</i> Mutations in Gliomas
Authors: Hao-Wen Sim, Romina Nejad, Wenjiang Zhang, Farshad Nassiri, Warren Mason, Kenneth D. Aldape, Gelareh Zadeh, Eric X. Chen
Journal: Clinical Cancer Research (2019)

Isocitrate dehydrogenase (IDH) mutations are common in low-grade gliomas and the IDH mutation status is now integrated into the WHO classification of gliomas. IDH mutations lead to preferential accumulation of the R- relative to the S-enantiomer of 2-hydroxyglutarate (2-HG). We investigated the utility of tissue total 2-HG, R-2-HG, and the R-2-HG/S-2-HG ratio (rRS) as diagnostic and prognostic biomarkers for IDH mutations in gliomas.Experimental Design: Glioma tissue and blood samples from 87 patients were analyzed with HPLC-MS/MS coupled with a CHIROBIOTIC column to quantify both enantiomers of 2-HG. ROC analysis was conducted to evaluate the sensitivity and specificity of 2-HG, R-2-HG, and rRS. The feasibility of real-time determination of IDH status was evaluated in 11 patients intraoperatively. The prognostic value of rRS was evaluated using the Kaplan-Meier method.The rRS in glioma tissues clearly distinguished patients with IDH-mutant versus wild-type tumors (P < 0.001). Sensitivity and specificity using an rRS cut-off value of 32.26 were 97% and 100%, respectively. None of total 2-HG, R-2-HG, or rRS was elevated in serum samples. Among patients with IDH-mutant tumors, tissue rRS stratifies overall survival. The duration of tissue analysis is approximately 60 minutes.Our study demonstrates that rRS is a reliable biomarker of IDH mutation status. This technique can be used to determine IDH mutation status intraoperatively, and to guide treatment decisions based on IDH mutation status in real time. Finally, rRS values may provide additional prognostic information and further validation is required.
Abstract MP29: Factors Associated With Stability of Metabolically Healthy Obesity: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Sarah M Camhi, Aviva Must, Philimon N Gona, Arlene Hankinson, Andrew Odegaard, Jared P Reis, Erica P Gunderson, David R Jacobs, Mercedes Carnethon
Journal: Circulation (2018)

Background: The demographic, behavioral or lifestyle factors associated with transitioning from metabolically healthy (MHO) to metabolically unhealthy obesity (MUO) are unknown. Methods: CARDIA participants (n=735) were included if they were not obese (BMI &lt;30 kg/m 2 ) at baseline and developed obesity at exams 7, 10, 15, 20, or 25 years. MHO was defined as the presence of obesity and 0-1 risk factor: SBP/DBP ≥130/85mmHg; glucose ≥100mg/dL; triglycerides (≥150mg/dL); and HDL-C (men &lt;40, women &lt;50mg/dL) or on relevant medication. MUO was defined as obesity and 2+ risk factors. Duration of MHO and obesity were estimated (yrs). Phenotypes were categorized by MHO duration (%; MHO duration÷obesity duration): stable MHO (100%); transient MHO (1-99%); MUO (0%). Factors were compared between phenotypes using linear or logistic regression (adjusted for sex, race, baseline BMI, age). Multinomial logistic regression analysis was used to determine which factors [obesity duration, BMI change (ΔBMI), obesity onset age, physical activity (PA), alcohol intake, smoking] associated with transient MHO and MUO, relative to stable MHO. Results: Participants were 55% black and 72% women. Relative to transient MHO (n=184, 25%), stable MHO (n=347, 47%) had 5.4±0.5 yrs later obesity onset, 3.4±0.4 kg/m 2 smaller ΔBMI, 5.6±0.5 yrs shorter obesity duration, and 2.4±0.5 yrs longer MHO duration (all p&lt;0.0001), with no significant differences for PA (moderate, vigorous or total), alcohol or smoking. Relative to stable MHO, transient MHO were less likely to be female, but more likely to smoke, have increased obesity duration and ΔBMI. Relative to stable MHO, MUO (n=204, 28%) were less likely to be female or black, more likely to smoke, have lower total PA, lower alcohol, and increased ΔBMI (Table 1). Conclusion: Obesity duration, ΔBMI and smoking were the strongest correlates of transition from MHO to MUO. MUO were more likely to have adverse health factors. Additional research should explore the cardiovascular consequences of the transition of MHO to MUO.
Timing and Intensity of Early Intervention Service Use and Outcomes Among a Safety-Net Population of Children
Authors: Beth M. McManus, Zachary Richardson, Margaret Schenkman, Natalie Murphy, Elaine H. Morrato
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Federal per-child early intervention (EI) appropriations have declined, while accountability for improving children's development and function has increased. It is critical to understand high-value EI services and systems. <h3>Objective</h3> To examine EI service timeliness and intensity, and the association between service intensity and outcomes. <h3>Design, Setting, and Participants</h3> This secondary data analysis cohort study linked pediatric primary care electronic health records and EI program records from October 1, 2014, to September 30, 2016. Sample children from a large, urban safety-net health system and EI program who were younger than 35 months with a developmental disability or delay were examined. Data analysis was conducted from December 15, 2017, to May 15, 2018. <h3>Exposures</h3> The study included measures of condition type and severity, race and ethnicity, family income, insurance type, sex, birth weight, and language. <h3>Main Outcomes and Measures</h3> The timeliness of EI (days from referral to EI care plan), service intensity (hours per month) overall and for core EI services (physical, occupational, speech therapy, and developmental intervention), and change in function (measured on a 13-point scale). Adjusted quantile median regression estimated timeliness and intensity. Adjusted linear regression estimated change in function. <h3>Results</h3> Of the 722 children who received an EI care plan (median [interquartile range] time to receive EI care plan, 56.0 [1.0-111.0] days) 457 (63.3%) were male, 447 (62.0%) were younger than 12 months, 207 (28.7%) were 12 to 24 months, and 68 (9.3%) were 25 to 35 months. A total of 663 children (91.8%) had a household income of less than $20 000 annually; 305 (43%) of the sample children received an EI care plan within the 45-day deadline. Median (interquartile range) for EI intensity was 2.7 (2.3-3.6) hours per month. Children living above the federal poverty threshold received greater occupational therapy intensity (b, 1.9; 95% CI, 0.9-3.0). Greater clinical severity was associated with more timely receipt of an EI care plan. Compared with infants, 2-year-old children received a care plan almost 2 months sooner (b, −52.0; 95% CI, −79.7 to −24.3). An additional hour per month of EI service was associated with a 3-point functional gain (b, 3.0; 95% CI, 1.5-5.9) among children with complete outcomes information (n = 448). <h3>Conclusions and Relevance</h3> In this study, greater EI service intensity was associated with better functional gains, yet most children in the study received delayed care and/or low service intensity. Clinical and EI record linkages could serve as a framework for improving EI processes.
OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer
Authors: M.E. Robson, N. Tung, P. Conte, S.-A. Im, E. Senkus, B. Xu, N. Masuda, S. Delaloge, W. Li, A. Armstrong, W. Wu, C. Goessl, S. Runswick, S.M. Domchek
Journal: Annals of Oncology (2019)

In the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation (BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population.
Abstract 17967: Remote Ischemic Preconditioning Preceding Coronary Artery Bypass Grafting Reduces the Volume of Ischemic Brain Lesions
Authors: Hrvoje Gasparovic, Tomislav Kopjar, Milan Rados, Alan Anticevic, Marko Rados, Branko Malojcic, Visnja Ivancan, Tea Fabijanic, Maja Cikes, Davor Milicic, Vladimir Gasparovic, Bojan Biocina
Journal: Circulation (2017)

Introduction: Neurological sequelae following cardiac surgery impact quality of life, mortality and health resource utilization. We hypothesized that remote ischemic preconditioning (RIPC) prior to CABG harbors a neuroprotective effect. Methods: In this randomized trial 70 CABG patients were assigned to undergo RIPC or a sham procedure. Structural brain MRI was complemented with resting state functional MRI to gain a whole-brain data-driven global connectivity analysis. A postoperative decrease of one standard deviation in neurocognitive tests was considered abnormal. Paired neurocognitive and MRI data were acquired pre- and postoperatively. Results: Two patients in each group didn’t have postoperative MRIs and were excluded. There were a total of 11 new brain ischemic lesions in 8 patients in the RIPC group, and 25 new lesions in 7 patients in the control group (8/33 (24%) vs. 7/33 (21%) P=1.0, mean ischemic volume 191±92 vs. 2588±5105 mm3, P=0.004). A total of 99 individual neurocognitive tests were per...
Abstract A029: Targeting neural transcription factor BRN2 in neuroendocrine prostate tumors
Authors: Ravi Shashi Nayana Munuganti, Daksh Thaper, Amina Zoubeidi
Journal: Cancer Research (2018)

Abstract Introduction: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as enzalutamide (ENZ), rapidly emerges and patients generally die within two years. In particular, a subset of patients who relapse following ARPI therapy exhibit lineage switching whereby tumors shed their dependence on AR signaling and emerge with neuroendocrine features. These tumors, termed treatment-induced neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and to date treatment remains decades-old cytotoxic chemotherapy, which carries a short-lived response at the cost of significant toxicity. Thus, the need to develop targeted treatments for this devastating disease is of paramount importance. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of NEPC and aggressive tumor growth, both in vitro and in vivo, suggesting that targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC. Methods: Using the integrated power of computational drug discovery platform and biologic testing we identified first-in-field inhibitors for BRN2. Results: One of the most potent inhibitors identified, Cpd 18, binds to BRN2 using a Drug Affinity Responsive Target Stability (DARTS) assay, decreases the expression of the neuroendocrine genes SOX2, NCAM1, CGA, NSE, PEG10, and N-Myc in BRN2Hi NCI-H660 cells with similar effect in 42DENZR cells. Moreover, Cpd18 displays pronounced antiproliferative activity in NCI-H660 and 42DENZR without any effect on BRN2 low/neg 16DCRPC and LNCaP cells. Combination treatment of Cpd 18 with ENZ prevents the trans-differentiation of 16DCRPC cells into NEPC-like morphology and downregulates the expression of NEPC markers. These outcomes confirmed that the BRN2 is a novel drug target that can help address the problem of ENZ-resistant form of NEPC. Conclusion: No therapies exist for highly lethal NEPC. Hence, the described work will identify first-in-field inhibitors for BRN2, a central driver of NEPC, and lay the preclinical foundation for the integration of such drugs into the treatment landscape to improve survival and quality of life for patients suffering from deadly form of prostate cancer. Citation Format: Ravi Shashi Nayana Munuganti, Daksh Thaper, Amina Zoubeidi. Targeting neural transcription factor BRN2 in neuroendocrine prostate tumors [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A029.
Handgrip strength is inversely associated with metabolic syndrome and its separate components in middle aged and older adults: a large-scale population-based study
Authors: Hongmei Wu, Mingyue Liu, Vu Thi Quynh Chi, Jing Wang, Qing Zhang, Li Liu, Ge Meng, Zhanxin Yao, Xue Bao, Yeqing Gu, Shunming Zhang, Shaomei Sun, Ming Zhou, Qiyu Jia, Kun Song, Jian Huang, Junsheng Huo, Bing Zhang, Gangqiang Ding, Kaijun Niu
Journal: Metabolism (2019)
Identifying the Best Approach to Patient-Centered Decisions About Serious Illness Care
Authors: Nancy Lau, J. Randall Curtis
Journal: JAMA Network Open (2019)

Emily B. Rubin, MD, JD; Anna E. Buehler, BA; Elizabeth Cooney, MPH; Nicole B. Gabler, PhD; Adjoa A. Mante, BA; Scott D. Halpern, MD, PhD
Brentuximab Vedotin Alone and in Combination with Bendamustine As Salvage Therapy for Primary Refractory or Relapsed Hodgkin Lymphoma: Multicentre Experience of the Polish Lymphoma Research Group (PLRG)
Authors: Anna Czyz, Anna Lojko-Dankowska, Monika Joks, Mieczyslaw Komarnicki, Monika Dlugosz-Danecka, Wojciech Jurczak, Justyna Rybka, Tomasz Wrobel, Ewa Paszkiewicz, Jan Walewski, Dorota Hawrylecka, Joanna Drozd-Sokolowska, Edyta Subocz, Szymanska Agata, Magdalena Witkowska, Piotr Smolewski, Agnieszka Kolkowska, Ewa Lech Maranda, Wanda Knopinska-Posluszny, Sebastian Giebel, Jan Zaucha
Journal: Blood (2018)
Durable Remissions after Discontinuation of Combined Targeted Treatment in Patients with Chronic Lymphocytic Leukemia (CLL) Harbouring a High-Risk Genetic Lesion (del(17p)/TP53 Mutation)
Authors: Paula Cramer, Julia von Tresckow, Jasmin Bahlo, Sandra Robrecht, Eugen Tausch, Moritz Fürstenau, Petra Langerbeins, Othman Al-Sawaf, Anna-Maria Fink, Kirsten Fischer, Clemens-Martin Wendtner, Barbara Eichhorst, Michael Kneba, Stephan Stilgenbauer, Michael Hallek
Journal: Blood (2018)
Abstract 17240: Differences in Longitudinal Trends in Skeletal Thigh Muscle Area Assessed With Magnetic Resonance Imaging Among Diabetic and Non-Diabetic Peripheral Artery Disease Patients
Authors: Carlos B Ortiz, Eric Y Yang, Changyi Chen, Salim S Virani, Panos Kougias, Alan B Lumsden, Joel D Morrisett, Christie M Ballantyne, Vijay Nambi, Gerd Brunner
Journal: Circulation (2017)

Introduction: Peripheral artery disease (PAD) is associated with impaired leg function and with leg muscle atrophy, highlighting the importance of muscle size. The understanding of longitudinal cha...
Association analysis of the major histocompatibility complex region in psoriasis vulgaris
Authors: D. Ran, M. Cai, H. Huang, Y. Zhou, X. Zheng, L. Tang, L. Wen, Z. Zhu, Y. Zhang, W. Li, D. Qian, L. Jin, Q. Zhang, Q. Xu, X. Zhang, Y. Sheng, S. Yang
Journal: British Journal of Dermatology (2019)
Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial
Authors: Patrick Y. Wen, Mehdi Touat, Brian M. Alexander, Ingo K. Mellinghoff, Shakti Ramkissoon, Christine S. McCluskey, Kristine Pelton, Sam Haidar, Sankha S. Basu, Sarah C. Gaffey, Loreal E. Brown, Juan Emmanuel Martinez-Ledesma, Shaofang Wu, Jungwoo Kim, Wei Wei, Mi-Ae Park, Jason T. Huse, John G. Kuhn, Mikael L. Rinne, Howard Colman, Nathalie Y.R. Agar, Antonio M. Omuro, Lisa M. DeAngelis, Mark R. Gilbert, John F. de Groot, Timothy F. Cloughesy, Andrew S. Chi, Thomas M. Roberts, Jean J. Zhao, Eudocia Q. Lee, Lakshmi Nayak, James R. Heath, Laura L. Horky, Tracy T. Batchelor, Rameen Beroukhim, Susan M. Chang, Azra H. Ligon, Ian F. Dunn, Dimpy Koul, Geoffrey S. Young, Michael D. Prados, David A. Reardon, W.K. Alfred Yung, Keith L. Ligon
Journal: Journal of Clinical Oncology (2019)

Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation.This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]).Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
Comparison of clinical and pathologic staging in esophageal cancer.
Authors: Anthony Joseph Scholer, Abhineet Uppal, Debopriya Ghosh, Mary Kledzik, Juan Santamaria-Barria, Adam Khader, Trevan D Fischer, Melanie Goldfarb
Journal: Journal of Clinical Oncology (2019)

31 Background: Randomized trials have demonstrated improved disease-free survival for more advanced esophageal cancer treated with neoadjuvant chemo radiation (NCXRT). However, accurately treating a patient relies on the accuracy of pre-treatment T and N staging with endoscopy ultrasound and cross-sectional imaging, which is unknown, and can lead to over or under-treatment. Therefore, the objective of this study is to compare the clinical and pathologic staging in patients with early esophageal cancer that would be impacted by inaccurate clinical staging. Methods: Primary, non-metastatic esophageal cancer patients who had upfront esophagectomy without neoadjuvant CXRT between 2004 and 2013 were identified in the National Cancer database. The Kappa index was used to determine patient and tumor characteristics that effected concordance between clinical and pathologic T and N staging (p &gt; 0.05 shows discordance). Results: Of 1810, 43 % of clinical T2 tumors were upstaged compared to 38% of T1 and 13% of clinical T2 were downstaged. Clinically positive N1 disease had the greatest concordance (91%) between clinical and pathologically staging, compared to clinical N0, where 57% were upstaged. Some patient groups significantly impacted the concordance rates of staging. T-Stage was less accurate (more discordant) in females (68%, kappa 0.41, p = 0.057) and Blacks (59%, kappa 0.023, p = 0.069) whereas overall N-stage was more discordant in Hispanics (83%, kappa, 0.67, p = 0.165). Conclusions: Accurate staging for esophageal adenocarcinoma can significantly impact the course of treatment. Upfront surgical resection of clinical T1 lesions and node negative tumors are at risk for under-treatment due to poor concordance with pathological stage, which may lead to decreased survival compared to a regimen of NCXRT. Clinicians should be aware of patient and tumor characteristics that increase the likelihood of discordance between clinical and pathologic staging when discussing treatment options for patients with esophageal cancer.
Abstract 14680: Effect of Patiromer in Hyperkalemic Patients With or Without RAASi
Authors: Robert A Kloner, Coleman Gross, Jinwei Yuan, Ansgar Conrad, Pablo E Pergola
Journal: Circulation (2017)

Introduction: Hyperkalemia (HK) affects HF patients (pts) with renal disease even if not on RAASi. Prior studies of patiromer, a nonabsorbed K+-binder approved for HK, involved pts with HK while on...
PTH-010 Cecal withdrawal time: assessing standards of colonoscopy in district general hospital
Authors: Usama Aslam, Mehreen Mudassar, Syed Anjum Gardezi
Journal: Endoscopy (2018)

<h3>Introduction</h3> The British Society of Gastroenterology, the UK Joint Advisory Group on GI Endoscopy, and the Association of Coloproctology of Great Britain and Ireland have developed quality assurance measures and key performance indicators for the delivery of colonoscopy within the UK. However, studies have suggested that high variations in the quality of colonoscopy among different endoscopists are reflected in surrogate measures such as adenoma detection, cecal intubation rates, withdrawal times, and incidence of complications. This documents identifies the unacceptable variation in practice and measures adopted to improve quality of care. <h3>Method</h3> A prospective, observational colonoscopy practice audit was conducted of cecal withdrawal time at Glangwili General Hospital, Carmarthem for patients who presented for colonoscopy between August 2017 to January 2018. Diagnostic procedures were included in the study comprising two cycles 8 months apart. Patients with history of colonic surgery were eliminated. Same endoscopy nurse manually collected the data from 5 different endoscopist using stopwatch without them knowing. Both the cycles were 3 months apart during which different measures were taken to improve withdrawal time including sending individual feedback to endoscopists, one to one discussions between endoscopy consultant lead and involved endoscopist and keeping a timer in endoscopy room to keep tract of time. <h3>Results</h3> We reviewed 10 colonoscopies performed by each endoscopist in each cycle of audit and mean cecal withdrawal time is shown below. After taking appropriate measure to improve quality of care following results were obtained. Following graph shows variation in mean withdrawal time between two cycles compared against set standards. Below shows the comparison of 1 st and 2nd cycle showing rectal retroflexion performed and imaging of cecal landmarks recording done by each endoscopist <h3>Conclusion</h3> Practice among endoscopists varied with majority providing good standard of care. Weak points identified during 1 st stem of audit cycle and changes implemented lead to improvement in quality of care but still there is further room for improvement. Regular audits are important to make sure that colonoscopy practice meets key performance indicators outlined by JAG and BSG in order to increase polyp detection rate. <h3>References</h3> 1. UK key performance indicators and quality assurance standards for colonoscopy -the British Society of Gastroenterology, the Joint Advisory Group on GI Endoscopy, the Association of Coloproctology of Great Britain and Ireland. 2. Point-of-care, peer-comparator colonoscopy practice audit: The Canadian Association of Gastroenterology Quality Program – Endoscopy.