tbuckley/cabot-search huggingface dataset:
INNV-32. DETERMINATION OF INTERLEUKIN 10 IN THE DIAGNOSIS OF PCNSL
Authors: Gerardo Arellano-Flores, Enrique Gomez-Figueroa, Michele Breda-Yepes, Alberto Gonzalez-Aguilar
Journal: Neuro-Oncology (2018)

Primary central nervous system lymphoma (PCNSL) is an extranodal lymphoma and accounts for 5% of intracranial neoplasms. The diagnosis is made by biopsy, but false negative rates of 11–30% have been reported usually due to patients being previously treated with steroids or insufficient sample obtained. In addition the population in which it occurs are patients older than 50 years, which present comorbidities and sometimes the surgical procedure represents a high risk. Patients with a confirmatory histopathological study and who also had a lumbar puncture as part of their approach were included. IL-10 was determined by immunoassay technique (ELISA) and it was taken as normal range 2–4 pg/dl. 39 patients (16 women and 23 men) with confirmed diagnosis were included, with an average age of 50.1 years. The mean CSF proteins was 76.5 mg/dl, hypoglycorrhachia was present in 20.5%, the mean CSF cells were 15.9, mean IL-10 was 120 pg/dl with 94.8% higher than 4 pg/dl. Correlation coefficient between IL10 level and overall survival was performed without finding any significant results. The determination of IL-10 is a less invasive determination that can allow the diagnosis of PCNSL, it is an alternative where the diagnosis is not clear, the biopsy is risky or the result is not conclusive; however, it is necessary to determine its value in other pathologies to evaluate its sensitivity and specificity.
Abstract 10020: Impact of Race on Temporal Trends in Hospitalizations and Outcomes in New York State Among Patients With Valvular Heart Diseases
Authors: Phyllis G Supino, Ofek Y Hai, Usha S Govindarajulu, Jeffrey S Borer
Journal: Circulation (2015)

Introduction: Valvular heart diseases (VHD) are a growing public health problem but effect of race on temporal changes in VHD hospitalizations, valve surgeries and hospital mortality rates is undefined. Hypothesis: Non-White patients (pts) with VHD are at higher risk of hospital mortality vs White pts. Methods: We retrospectively analyzed all inpatient hospital records obtained between 1983-2012 from the New York State Statewide Planning and Research Cooperative System database with a primary or secondary ICD-9 code for VHD and racial self-classification (n=2,443,056). Linear regression was used to evaluate temporal changes in numbers of valve hospitalizations and valve surgeries performed among racial groups; ANOVA, χ 2 and t-tests were used, as appropriate, to compare subgroup differences on baseline clinical characteristics and lengths of stay; logistic regression (age, gender-adjusted) compared risk of hospital mortality by race. Results: During the 30-yr interval, proportions of non-White (predominantly Black) to White VHD pts increased by 65.9% (all VHD) and 72.1% (valve surgery). Though 12±1 yrs younger than White pts (p&lt;.001), Black pts had more concomitant hypertension, diabetes, heart failure and/or kidney disease and longer lengths of stay (p&lt;.001, all) vs White pts. Across all racial groups, hospital death risk was highest among Black pts (Figure), with men at greatest risk among all VHD cases (OR= 1.27, 95% CI=1.22-1.31, p&lt;.001) and women at highest risk after valve surgery (OR= 1.32, 95% CI=1.18-1.48, p&lt;.001). Conclusions: Pt demographics in New York hospitals are changing: pts from minority racial groups are proportionally increasing. The higher hospital mortality rates among Black pts with VHD is unexplained, though racial disparities in access to care and health risk factors may be involved. These disparities require evaluation as they will increasingly impact the health care system as the numbers of affected individuals continue to grow.
GENE-25. LOSS OF m6A RNA METHYLATION DURING GLIOMA STEM CELL DIFFERENTIATION IS REGULATED BY MIRNAS AND PROMOTES TRANSLATION EFFICIENCY
Authors: John Zepecki, Eduardo Fajardo, Kristin Snyder, Charlotte Guetta-Terrier, Oliver Tang, Atom Sarkar, Andras Fiser, Steven Toms
Journal: Neuro-Oncology (2018)

The dynamic and reversible N6-methyladenoside (m6A) affects eukaryotic mRNA localization, stability, splicing and translation. However, the role of m6A RNA methylation in the regulation of translation efficiency in human cancer cells is largely unknown. Here, using ribosome profiling, integrated transcriptome and m6A RNA sequencing analyses, we determined that as patient derived glioma cells transition from stem cells to differentiated cells, they exhibit loss of m6A RNA methylation and an increased rate of translation of the demethylated transcripts. We identified that the sequence motifs of the m6A peak regions of genes that lose m6A RNA during glioma stem cell differentiation, are complementary to the seed sequences of specific miRNAs. Expression of these target specific miRNAs results in loss of m6A RNA methylation without affecting transcript levels. Moreover, miRNAs induce cellular demethylase activity, increase the association of FTO with RNA in nuclear speckles and the binding of FTO to the miRNA-targeted and demethylated transcripts. This study highlights a critical role of m6A RNA methylation in regulation of translation in human cancer cells and identifies regulatory miRNAs that functionally influence the epitranscriptome during glioma stem cell differentiation.
TMOD-14. A PATIENT-DERIVED CANCER CELL LINE ATLAS OF PRIMARY AND METASTATIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Frederik De Smet, Yuen-Yi Tseng, Shakti Ramkissoon, Lori Ramkissoon, Kristine Pelton, Ruben Ferrer Luna, Dena Panovska, Kate Schoolcraft, Fiona Watkinson, Shawna Bilton, Victoria Hung, Kin-Hoe Chow, Jack Geduldig, Sarah Becker, Robert Jones, Paula Keskula, Sahar Alkhairy, Mimoun Delmar, Josh Arraya, Crystal Oh, Alexa Yeagley, Anneke Kramm, E Antonio Chiocca, Wenya (Linda) Bi, Mark Kieran, Brian Alexander, Ian Dunn, Rameen Beroukhim, Jesse Boehm, Keith Ligon
Journal: Neuro-Oncology (2018)

Tumors involving the central nervous system (CNS) include over 200 primary and metastatic subtypes with major clinical impact. Research on CNS neoplasms has been hampered by the lack of appropriate models for many subtypes. We established a robust workflow and systematic culturing approach to create cancer cell line models from all adult and pediatric CNS cancer patients and here report the results of these ongoing efforts. Tumor samples from consented patients with CNS cancers were systematically collected from 2008–18. Tumors were grown in different media and substrates and growth verified by >5 passages. Genomic verification was performed using NGS analysis (focused SNV and CNA) and expression profiling assays. We attempted to generate cell line models from >1500 consented brain tumor patients at the Brigham and Women’s and Boston Children’s Hospital (IRB-10–417) under the DFCI Living Tissue Bank Program as well as within the Broad Institute Cancer Cell Line Factory (CCLF) Project and the Leuven Living Tissue Bank (IRB-S59804, Belgium). 120 different tumor types, including high and low-grade brain tumors of both adult and pediatric origin, were evaluated for in vitro growth in >2000 culturing attempts. The success rate of growing high-grade tumors (i.e. glioma and of other origin) was robustly high (~50%), while the growth verification rate for low-grade tumors remained low (<1%). Overall, growth beyond passage 5 was achieved in ~30% of cases, and of the growth verified models, also ~30% were genomically verified to represent cancer, with the majority maintaining genomic and/or transcriptional features. In addition to primary CNS tumors, we were now also able to grow metastatic cultures, resulting in >150 novel model systems covering >20 primary and metastatic diagnoses. Patient-derived cell lines may be created at scale from primary and metastatic CNS tumors to support pre-clinical cancer research but technological improvements will be required to culture even more tumor types.
PATH-08. THE IVY GLIOBLASTOMA PATIENT ATLAS - A NOVEL CLINICAL AND RADIO-GENOMICS RESOURCE FOR EARLY PHASE CLINICAL TRIAL DESIGN AND INTERPRETATION
Authors: Keith Ligon, Janine Lupo, Annette Molinaro, Shannon Block, Sarah Charbonneau, Jack Geduldig, Anat Stemmer-Rachamimov, Lisa DeAngelis, William Yong, Nikolaus Schultz, Robert Young, Raymond Huang, Susan Chang, Isabel Arrillaga-Romany, Brian Alexander, David Reardon, Joanna J Phillips, John de Groot, Timothy Cloughesy, Howard Colman, Michael Prados, Patrick Wen, Nicholas Butowski, Ingo Mellinghoff, Benjamin Ellingson
Journal: Neuro-Oncology (2018)

Newly diagnosed GBM represents a population of increased focus in early phase clinical trials. However, a key limitation of current genomic databases of GBM, such as TCGA, is that patient populations eligible for inclusion in these databases exhibit inherent biases and exhibit limitations on the quality of clinical and imaging data available for integration with genomics. To address these limitations and to better represent the genomics of patient populations commonly enrolled to early phase clinical trials, we prospectively consented and enrolled GBM patients to the Ivy Foundation Glioblastoma Patient Atlas Project. A total of 1591 patients from 7 participating sites of the Ben and Catherine Ivy Foundation Consortium for Early Phase Clinical Trials were consented to the project and clinical data was entered into a centrally managed clinical trials database. Overall 658 subjects had pre- and post-surgical imaging centrally reviewed and recorded and 387 subjects had sufficient tissue for completion of targeted exome sequencing of approximately 500 cancer causing genes (Oncopanel or Impact). More than 308 subjects had a complete set of genomics, imaging, and clinical data, including TMZ/RT use, KPS, progression, and steroid use. Histopathological features, MGMT, and IDH mutation status were also annotated. Of the subjects with full clinical data, 171 had expired by the time of last analysis of the cohort. Genomic and clinical characteristics unique to the early phase clinical trial population compared to TCGA and other cohorts of GBM were identified and radio-genomic and other advanced population-based analyses were performed. All clinical, genomic and imaging data are being utilized to create an Ivy cBio Portal for sharing of this rich dataset within the neurooncology community.
Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production
Authors: Jakob G. Knudsen, Alexander Hamilton, Reshma Ramracheya, Andrei I. Tarasov, Melissa Brereton, Elizabeth Haythorne, Margarita V. Chibalina, Peter Spégel, Hindrik Mulder, Quan Zhang, Frances M. Ashcroft, Julie Adam, Patrik Rorsman
Journal: Cell Metabolism (2018)
Cholangioscopic diagnostic classification of bile duct lesions: a worthwhile task, not an easy one
Authors: Frederic Prat, Bertrand Napoleon
Journal: Endoscopy (2018)

Bile duct lesions are revealed by signs and symptoms that result from an obstructive process. The obstruction may be intraluminal, arising from the biliary epithelium (cholangitic or neoplastic), or extraluminal, as a result of compression by a malignancy or a regional inflammatory process such as pancreatitis. The list of diseases – benign and malignant – that can produce a biliary stenosis is pretty long, although 80 % are malignant, with pancreatic carcinoma being the most common [1]. Diagnosis is often straightforward, for example when a mass is amenable to endoscopic ultrasound-guided fine-needle aspiration [2], or when the patient’s history suggests a definite etiology (e. g. postoperative); however, some lesions are much more difficult to determine by standard means such as magnetic resonance imaging and endoscopic retrograde cholangiopancreatography with brushing or fluoroscopically guided biopsies [3].
Evaluation of Fowler–Stephens orchiopexy for high-level intra-abdominal cryptorchidism: A systematic review and meta-analysis
Authors: Chengjun Yu, Chunlan Long, Yi Wei, Xiangliang Tang, Bin Liu, Lianju Shen, Xueyi Dong, Tao Lin, Dawei He, Shengde Wu, Guanghui Wei
Journal: International Journal of Surgery (2018)
Abstract 18552: Impact of Revascularization on Fractional Flow Reserve and Absolute Myocardial Blood Flow as Assessed by Serial [15O]H2O PET Imaging
Authors: Roel Driessen, Ibrahim Danad, Wijnand Stuijfzand, Stefan Schumacher, Adriaan Lammertsma, Albert van Rossum, Niels van Royen, Pieter Raijmakers, Paul Knaapen
Journal: Circulation (2017)

Introduction: In case of ischemia causing coronary artery disease (CAD), the main goal of myocardial revascularization is to restore myocardial perfusion. Yet, little is known on the effect of reva...
NIMG-06. KINETICS-BASED RESPONSE METRIC DISCRIMINATE IMPROVED OUTCOMES FOR PATIENTS RECEIVING BEVACIZUMAB-BASED THERAPIES
Authors: Kyle Singleton, Destiney Kirby, Sandra Johnston, Cassandra Rickertsen, Gustavo De Leon, Scott Whitmire, Kamala Clark-Swanson, Yvette Morris, Bernard Bendok, Maciej Mrugala, Alyx Porter, Kristin Swanson
Journal: Neuro-Oncology (2018)

Evaluating treatment response in glioblastoma is a difficult task for clinicians, particularly in recurrent disease. Current response metrics focus on changes in imageable tumor burden which can be ambiguously affected by anti-angiogenic therapy. In previous work, we reported the ability of the Days Gained (DG) response metric to discriminate patients receiving bevacizumab into long and short-term survival groups. In this work, we investigate how the DG metric performs for patients who received bevacizumab with a concurrent cytotoxic agent (e.g. CCNU) compared to patients who received bevacizumab alone. We identified a set of 38 patients with recurrent glioblastoma who received bevacizumab therapy (21 patients) or bevacizumab with concurrent CCNU (17 patients). Each case had tumor volumes segmented on two dates prior and one day post therapy on T1GD and FLAIR MR imaging. DG scores were calculated using tumor growth characteristics and were used to evaluate discrimination of patient survival and time to progression (TTP) using Kaplan-Meier curves and logistic regression. An optimal threshold of 162 DG (p= 0.0393, log rank) on T1GD imaging was discriminative for TTP in bevacizumab cases. Combination therapy with CCNU showed a similar trend for the correlation between DG and TTP outcomes as for bevacizumab alone. Patients receiving bevacizumab alone had significant DG thresholds for survival following treatment (T1GD: 162 DG, p=0.01857; FLAIR: 216 DG, p=0.0387). Although predictive of TTP, combination therapy was not significantly associated with increased overall survival from time of treatment. DISCUSSION: Days gained was able to discriminate survival and TTP for patients receiving bevacizumab therapy alone. Discriminative power for combination therapy with CCNU demonstrated the same trend for TTP outcomes. Growing evidence supports DG as a clinically meaningful metric of treatment response even in the context of anti-angiogenic therapies that are known to ambiguously modulate imaging features on MRI.
Abstract 034: Tracking Lifestyle Behaviors, Healthcare Access, and Healthcare Quality for Cardiometabolic Diseases at the State-Level From 1990-2016
Authors: Marissa B Reitsma, Ryan M Barber, Gregory A Roth, Ashkan Afshin
Journal: Circulation (2018)

Introduction: While a range of population-level and clinical interventions have been implemented to improve cardiometabolic (CM) health in the US, little is known about their different effects at the state-level. Objective: To develop a novel index to evaluate the performance of the healthcare system and population-level interventions to improve CM health at the state-level from 1990 to 2016. Methods: To evaluate healthcare access and quality, we estimated risk-standardized age-standardized mortality rates for six CM diseases that are amenable to healthcare. Risk-standardization removed geographic variation in all risk factors not directly amenable to medical intervention. To evaluate the effect of population-level interventions, we estimated the risk-weighted exposure to lifestyle risk factors including smoking, alcohol, diet, body mass index, and physical activity. We averaged the healthcare index with the risk factor index to create a single composite index. Data sources included mortality and risk factor estimates from the Global Burden of Disease 2016 Study. Results: Between 1990 and 2016, healthcare access and quality for CM diseases significantly improved in 38 states. These increases were mainly driven by significant improvements nationwide in healthcare for ischemic heart disease, ischemic stroke, and rheumatic heart disease. Notably, healthcare for diabetes significantly worsened in 16 states. There were no significant changes in the lifestyle risk factor index since 1990. Stability was driven by diverging trends, with smoking and diet quality significantly improving and BMI significantly worsening in all states. Importantly, the gap between the best and worst performing states across all indices increased between 1990 and 2016, indicating greater health disparities. Conclusions: This study has quantified the separate and combined effects of healthcare access, quality, and risk factors on CM health, with implications on priority setting for both population-level and clinical interventions.
CMET-04. METASTATIC GASTROINTESTINAL CANCER TO THE SKULL BASE MIMICKING NF2
Authors: Phioanh Nghiemphu, Richard Everson, Marco Giovannini, Melissa Reider-Demer, Zev Wainberg, Akira Ishiyama
Journal: Neuro-Oncology (2018)

Cancers of gastrointestinal (GI) origin rarely metastasize to the brain and is present in less than 1% of patients at diagnosis. We present a case of GI cancer presenting with bilateral cerebellopontine angle masses resembling bilateral vestibular schwannomas (VS) seen in Neurofibromatosis type 2 (NF2). A 40 year-old woman presented to our NF2 multidisciplinary clinic after 4 months of vertigo, unilateral hearing loss and facial paralysis. Brain MRI was consistent with bilateral vestibular schwannomas with no other findings. Her symptoms then progressed over 2 months with bilateral hearing loss and facial paralysis despite two treatments with bevacizumab, and repeated imaging revealed tumor enlargement bilaterally. The patient underwent a resection of the larger, right-sided skull base mass, and pathology revealed an adenocarcinoma of gastrointestinal origin. FDG-PET and CT of the chest, abdomen, and pelvis revealed diffused lymphadenopathy in the abdomen. The patient also had an elevated CA 19-9 level. Next generation sequencing of the resected skull base mass was most consistent with a tumor of GI origin. This is the first known case of metastatic GI cancer to the skull base resembling the bilateral VS seen in NF2.
Transformation of normal NIH-3T3 cells into highly oncogenic and invasive cancer cells by MBD2 overexpression
Authors: Stephen Andrews, Bushra Ateeq, Jerome Torrisani, Ana D'Alessio, Alexander Unterberger, Jing-Ni Ou, Marilene Paquet, Shafaat Rabbani, Moshe Szyf
Journal: Cancer Research (2007)

3925  Introduction: Cancer cells are hallmarked by global DNA hypomethylation and regional hypermethylation of tumor suppressor genes. The latter has been extensively studied while not much attention has been given to global DNA hypomethylation. MBD2 is the only protein that has been shown to directly remove the methyl group from CG di-nucleotides; though, it has also been reported to be a transcriptional repressor. Inhibition of MBD2 attenuates tumorigenesis, metastasis, and reverses the hypomethylation of metastatic genes in cell culture and in vivo. Additionally, germ line deletion of the mbd2 gene protects mice from intestinal tumors. Therefore, we tested the hypothesis that MBD2 causes oncogenic and metastatic transformation of cells by triggering global hypomethylation.  Results: MBD2 and a mutant MBD2 lacking the MBD domain were stably and transiently expressed in mouse fibroblast NIH-3T3 cells. We determined that MBD2 induces global hypomethylation and histone H3 lysine 9 acetylation in an MBD domain dependent manner. Several assays revealed that the MBD2 cell lines, but not the mutant nor the control cell lines, were transformed and highly invasive in cell culture. Only the MBD2 cell lines were highly tumorigenic and invasive when injected into Nude mice while also showing a remarkable ability to invade and degrade bone tissue when injected into the tibia of SCID mice. We also determined that MBD2 is required for maintaining a transformed state triggered by activated HA-RAS in NIH-3T3 cells. MBD2 knockdown in these cells attenuated transformation and increased DNA methylation supporting our hypothesis. To delineate the effects of MBD2 overexpression on specific gene expression, a genomic approach using affymetrix expression arrays was employed. Four hundred and forty four genes were identified to have their mRNA expression altered by MBD2 expression. Genes involved in tumorgenesis, bone degradation, or with no known function that were induced in both MBD2 and HA-Ras expressing cell lines were chosen for further study. Knocking down selected candidate genes9 mRNA in MBD2 overexpressing NIH-3T3 cells resulted in attenuated tumorigenesis while knocking down MBD2 in HA-RAS cells significantly reduced these genes9 expression levels. CHIP assay of the promoter and bisulfite sequencing of the same regions for the candidate genes revealed that MBD2 binds only to regions associated with demethylated DNA and that these regions are associated with H3 lysine 9 acetylation.  Summary: Our results support the hypothesis that MBD2, through activation of global cancer pathways, transforms normal fibroblast cells into highly oncogenic, invasive, and metastatic cancer cells; therefore, MBD2 is a novel cancer therapeutic candidate.  Supported by a grant from the National Cancer Institute of Canada to MS.
HOUT-19. TREATMENT PATTERNS, OUTCOMES, AND PROGNOSTIC INDICATORS IN ELDERLY PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE SINGLE INSTITUTION ANALYSIS
Authors: Margaret Johnson, John Kirkpatrick, Mallika Weant, Zachary Vaslow, Eric Lipp, James Herndon, Frances McSherry, Annick Desjardins, Dina Randazzo, Henry Friedman, David Ashley, Katherine Peters
Journal: Neuro-Oncology (2018)

There are limited evidence-based guidelines for treatment of elderly glioblastoma (GBM) patients. This analysis explores prognostic indicators that may help guide treatment in this population. This retrospective analysis includes 106 patients 75 years old seen at the Preston Robert Tisch Brain Tumor Center between 2004–2016. Kaplan-Meier methods estimated overall survival (OS). Time to OS was censored at last follow-up for patients still alive. Univariate Cox proportional hazards models assessed predictors of OS. Median age at diagnosis was 79 years (range: 75–93). Median follow-up was 68.8 months. Median survival was 8.1 months (95% CI: 6.5, 9.3). Patients with biopsy-only had significantly worse OS than patients with gross total resection (GTR) (Hazard Ratio (HR)=2.64 (95% CI: 1.69, 4.12); p<0.001) or subtotal resection (STR) (HR=2.54 (95% CI: 1.33, 4.85); p=0.005; OS=5.0 vs 9.8 vs 12.7 months, respectively). Of 84 patients with data available regarding radiotherapy (RT), there was no significant difference in OS between patients receiving 3 weeks of RT versus 6 weeks. Patients not receiving RT had significantly worse OS than patients with 3-week (HR=7.66 (95% CI: 3.25, 18.03); p<0.001) or 6-week courses (HR=8.95 (95% CI: 4.16, 19.27); p<0.001; OS=4.5 vs 9.2 vs 11.2 months, respectively). Patients with biopsy-only tended to have lower KPS and were less likely to receive RT. In the subset of 66 patients with known methylation status, unmethylated patients showed a trend towards worse OS than methylated patients (OS=7.5 vs 11.5 months, respectively; HR=1.65 (95% CI: 0.987, 2.759); p=0.056). A post-op KPS80 was predictive of better OS (9.3 vs 5.4 months; HR=0.976 (95% CI: 0.954, 0.999); p=0.043). Biopsy-only, no RT, lower KPS and absence of MGMT methylation were associated with worse OS. Extent of resection (STR vs GTR) and duration of radiation (3 weeks vs 6 weeks) did not influence OS.