tbuckley/cabot-search huggingface dataset:
GENE-40. MEGF10, A GLIOMA SURVIVAL ASSOCIATED MOLECULAR SIGNATURE PREDICTS IDH MUTATION STATUS
Authors: Guanzhang Li, Zhiliang Wang, Wei Zhang, Zheng Wang, Tao Jiang
Journal: Neuro-Oncology (2018)

Glioma is the most common primary brain tumor with various genetic alterations, among which IDH mutation is the most common mutation and plays an important role in glioma early development, especially in lower grade glioma (WHO II-III). Previous studies have found that IDH mutation is tightly associated with extensive methylation across whole genome in glioma. To investigate the role of IDH, we obtained methylation data of 777 samples from CGGA (Chinese Glioma Genome Atlas) and TCGA (The Cancer Genome Atlas) with IDH mutation status available. A package compiled under R language called Tspair, was used as the main analytic tool to find potential probes that were significantly affected by IDH mutation. ROC analysis, Kaplan-Meier analysis, Gene ontology analysis and Gene Set Variation Analysis were further performed to explore the clinical values and biological functions of the candidate gene. We found one pair of probes, cg06940792 and cg26025891 was capable of predicting IDH mutation status precisely. The hyper-methylated probe was cg06940792, designed in the promoter region of MEGF10 while the hypo-methylated probe was cg26025891, designed in the promoter region of PSTPIP1. Survival analysis proved that hyper-methylation or low expression of MEGF10 indicated a favorable prognosis in 983 glioma samples. Moreover, gene ontology analysis demonstrated that MEGF10 was associated with cell migration, cell proliferation and regulation of apoptosis in glioma. All findings above can be validated in three other independent cohorts. In a word, our results suggested that methylation level and mRNA expression of MEGF10 in glioma was not only correlated with IDH mutation, but also associated with clinical outcome of patients, providing potential guide for future dissection of IDH role in glioma.
MNGI-22. A PROGNOSTIC INDEX TO PREDICT THE RISK OF ACTIVE MONITORING FAILURE FOR INCIDENTALLY-FOUND ASYMPTOMATIC MENINGIOMAS
Authors: Abdurrahman Islim, Midhun Mohan, Richard Moon, Nitika Rathi, Ruwanthi Kolamunnage-Dona, Andrew Brodbelt, Samantha Mills, Michael Jenkinson
Journal: Neuro-Oncology (2018)

30% of meningiomas are incidental findings. There is no consensus on the optimal management (active monitoring, surgery, radiosurgery). Develop a prognostic index to identify patients at risk of active monitoring failure. Active monitoring failure was defined as: new symptoms, MRI progression (absolute growth rate 2 cm3/year or absolute growth rate 1 cm3/year + relative growth rate 30%/year) or loss of treatment options. A prognostic model was developed using MRI and patient co-morbidity (Charlson-Index) in a retrospective cohort (2007–2015). 385 patients (403 meningiomas) were studied; mean age was 62.6 years (SD=12.0); 301 (78.2%) were female. Over a median of 36.0 months (range: 3–120), 1688 MRI were performed (mean=4 scans/patient). 44 (10.9%) meningiomas failed active monitoring. Median time to failure was 33.0 months (range: 5–102). Model parameters were based on statistical and clinical considerations and included: increasing tumour volume (HR=2.17 [95% CI=1.53–3.09], p<0.001), peritumoural signal change (HR=1.58 [95% CI=0.65–3.85], p=0.313), FLAIR/T2 hyperintense meningiomas (HR=10.6 [95% CI=5.39–21.0], p<0.001) and proximity to neurovascular structures (HR=1.38 [95% CI=0.74–2.56], p=0.314). Discriminatory power of the model was excellent (Harrells C statistic=0.89). Patients were stratified into low, medium and high-risk groups and rates of failed active monitoring at 5-years were 3%, 28% and 75% respectively. Low-risk patients had non-oedematous, small iso/hypointense meningiomas, distant from neurovascular structures. After 5-years of follow-up, the probability of failed active monitoring plateaued in all risk groups. Older patients with co-morbidities (Charlson-Index 6) were 15-times more likely to die than to receive intervention at 5-years following diagnosis, regardless of risk-group. Most meningiomas remain clinically and radiologically stable. Patients with Charlson-Index 6 do not require active monitoring. Low-risk patients require less frequent MRI monitoring. Follow-up beyond 5-years may not be required for all patients. Stratifying follow-up according to risk-group has the potential to reduce the cost of healthcare.
Targeting an Autocrine Regulatory Loop in Cancer Stem-like Cells Impairs the Progression and Chemotherapy Resistance of Bladder Cancer
Authors: Kai-Jian Wang, Chao Wang, Li-He Dai, Jun Yang, Hai Huang, Xiao-Jing Ma, Zhe Zhou, Ze-Yu Yang, Wei-Dong Xu, Mei-Mian Hua, Xin Lu, Shu-Xiong Zeng, Hui-Qing Wang, Zhen-Sheng Zhang, Yan-Qiong Cheng, Dan Liu, Qin-Qin Tian, Ying-Hao Sun, Chuan-Liang Xu
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Cancer stem-like cells (CSCs) contribute to bladder cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder cancer. Experimental Design: The expression of the epithelial marker OV6 and other markers in human bladder cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6− bladder cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder cancer mouse model was established to evaluate the in vivo effects of a YAP inhibitor (verteporfin) and a PDGFR inhibitor (CP-673451) on the cis-platinum resistance of OV6+ CSCs in bladder cancer. Results: Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder cancer patients. Compared with OV6− cells, OV6+ bladder cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6+ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6+ bladder cancer CSCs in an orthotopic bladder cancer model. Conclusions: OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder cancer.
Abstract 18476: Ventricular Ectopy During Leadless Pacemaker Implantation is Associated With Favorable Stable Sensing and Capture Thresholds
Authors: Ivan Mendoza, Rachel Volke, Karina Gonzalez, Juan Pablo Zambrano
Journal: Circulation (2017)

Introduction: Leadless pacemaker implantations are increasingly common in the US and around the world. At the current moment, it remains unclear any potential early predictors or factors associated with a positive electrical outcomes such as improvement of sensing & ventricular capture thresholds. Minimizing the amount of time under fluoroscopy is beneficial for patients, practitioners and institutions. Obtaining favorable placement upon the first attempts at deployment allow shorter procedure and fluoroscopy times Hypothesis: We hypothesized that the presence of brief ventricular ectopy (VT) upon leadless pacemakers deployment is associated with optimal electrical outcomes such a improvement of sensing & ventricular capture thresholds Methods: A total of twelve (12) consecutive leadless pacemakers implantations were performed with the Medtronic Micra leadless pacemaker system .Patient demographics, cardiac history, left ventricular function (EF) & indications were obtained . VT while performing the “ pul...
NCMP-17. EVOLUTION OF CEREBRAL MICROBLEEDS AFTER PROTON IRRADIATION IN LOW-GRADE GLIOMA PATIENTS
Authors: Thanakit Pongpitakmetha, Michael Parsons, Marc R. Bussière, Anand Viswanathan, Helen Shih, Jorg Dietrich
Journal: Neuro-Oncology (2018)

Cranial irradiation is associated with neurovascular injury, such as cerebral microbleeds (CMBs). We have previously shown that CMBs progressively increase in number with each year after completion of photon-based radiation therapy (RT). We hypothesize that proton RT may be associated with reduced microvascular injury given its limitation of radiation exposure to the treatment field, To explore the temporal and spatial pattern of CMBs after proton RT, we followed a cohort of glioma patients using longitudinal imaging over a 10-year period. 20 patients with low-grade glioma were treated with proton RT (54 Gy, 1.8Gy/fx). The occurrence of CMBs was evaluated longitudinally using T2* gradient echo imaging and susceptibility-weighted imaging at baseline and up to 10 years post RT. The temporal and spatial distribution patterns of CMBs were characterized. The mean age at time of RT was 38.2 years (SD 8.8 yrs) in this cohort of 20 patients (13 male, 7 female). Patients were followed for a median time of 7.5 yrs (range 1.5–10). CMBs were detected with an incidence of 40% at 1 yr, 71% at 2 yrs, 94% at 5 yrs and 100% at 10yrs. The average cumulative number of CMBs per patient was 0.67 at 1 year, 2.5 at 2 yrs, 8.9 at 5 yrs and 12.5 at 10 yrs. CMBs occurred in lobar (83.4%), deep territory (11.5%) and infratentorial distribution (5%). One patient developed disseminated cortical superficial siderosis 3 years after RT and 3 patients developed intracerebral hemorrhage between 4 and 8 yrs after RT. CONCLUSIONS: In this cohort of low-grade glioma patients and similar to photon irradiated patients the prevalence of CMBs increases with each year following proton RT and mostly follows a lobar distribution pattern. CMBs are usually only detected within the main radiation field but can be associated with intracerebral hemorrhage.
PDTM-28. THE CONTRIBUTION OF PAX GENES AS NOVEL TUMOR SUPPRESSORS IN GROUP 3 MEDULLOBLASTOMA
Authors: Jamie Zagozewski, Ludivine Morrison, Margaret Stromecki, Gareth Palidwor, Vijay Ramaswamy, Tamra Werbowetski-Ogilvie
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. Of the four distinct molecular MB subgroups, Group 3 MB has the worst prognosis, is highly metastatic, and is poorly defined with regard to the pathways that contribute to tumor progression. OTX2 is overexpressed/amplified in 80% of Group 3 MB, where it contributes to increased self-renewal and reduced neuronal differentiation. In order to identify genes associated with an OTX2 gene regulatory network in Group 3 MB cells, we mapped changes in active (H3K4me3) and repressive (H3K27me3) histone modifications following OTX2 silencing in Group 3 MB tumorspheres by ChIP-sequencing. Genes with significant changes in H3K27me3 profiles were associated with neuronal differentiation while genes that had significant changes in H3K4me3 profiles were associated with cell cycle progression. Interestingly, significant loss of H3K27me3 was observed for 114 transcription factors, indicating an overall de-repression of transcription factor expression following OTX2 silencing. Members of the PAX gene family were among the transcription factors de-repressed upon OTX2 silencing, and their role in MB progression has not been explored. Expression analysis in a cohort of 763 patient samples demonstrated that PAX3 and PAX6 expression is significantly lower in Group 3 MB. Reduced expression of PAX3 and PAX6 in Group 3 MB correlated with a significant reduction in overall patient survival. Following OTX2 knockdown in established and newly derived Group 3 MB cell lines, significant increases in PAX3 and PAX6 expression were observed providing further support for our ChIP-sequencing data. Finally, silencing of PAX6 expression resulted in an increase in cell growth suggesting a putative tumor suppressor role in Group 3 MB. Our ongoing and future studies include the further evaluation of putative divergent regulatory roles of OTX2 and PAX6 controlling neuronal differentiation in Group 3 MB.
Abstract 035: Prevalence and Predictors of Cholesterol Screening, Awareness, and Statin Treatment Among Individuals With Familial Hypercholesterolemia in the U.S. (1999-2014)
Authors: Emily M Bucholz, Angie M Rodday, Katherine Kolor, Muin Khoury, Sarah D deFerranti
Journal: Circulation (2018)

Background: Familial hypercholesterolemia (FH) significantly increases the risk of atherosclerotic cardiovascular disease (ASCVD); however, recent data from ambulatory care centers suggests that prescription rates for statins remain low in patients with severe dyslipidemia or diagnosed FH. National rates of screening, awareness, and treatment with statins among individuals with FH or severe dyslipidemia are unknown. Methods: Data from the 1999 to 2014 National Health and Nutrition Examination Survey (NHANES) were used to estimate prevalence rates of self-reported screening, awareness, and statin therapy among U.S. adults ≥20 years of age (n=42,471 weighted to represent 212 million U.S. adults) with FH (defined using the Dutch Lipid Clinic criteria) and with severe dyslipidemia (defined as low-density lipoprotein cholesterol (LDL-C) levels ≥190mg/dL). Logistic regression was used to identify sociodemographic and clinical correlates of hypercholesterolemia awareness and statin therapy. Results were extrapolated to the U.S. adult population. Results: The US prevalence of definite/probable FH was 0.47% (standard error 0.03%) and of severe dyslipidemia was 6.59% (SE 0.17%). Rates of cholesterol screening and awareness were high (&gt;80%) among adults with definite/probable FH or severe dyslipidemia; however, statin use was uniformly low (52.3% (SE 8.2%) of adults with definite/probable FH and 37.6% (SE 1.2%) of adults with severe dyslipidemia). Less than half of those on statins were prescribed a high-intensity statin. The prevalence of statin use in adults with definite/probable FH and severe dyslipidemia increased slightly over time but not faster than trends in the general population. Older age, insurance, having a usual source of care, diabetes, hypertension, and having a personal history of early ASCVD were associated with statin use. The discrepancy between cholesterol screening and treatment rates was most pronounced in younger patients, uninsured patients, and patients without a usual source of care. Conclusions: Despite high rates of cholesterol screening and awareness, only about half of U.S adults with FH are on statin therapy and even fewer are prescribed a high-intensity statin; young and uninsured patients are at the highest risk for under treatment. A low rate of statin use in young adults is of particular relevance given the early onset of ASCVD in adults with FH. This study highlights an opportunity and an imperative to improve statin treatment rates in this high-risk population. Additional studies are needed to better understand how to close the gap between screening and treatment among adults with FH and improve treatment rates among those with limited access to care.
ATIM-34. TARGETING THE CD200 CHECKPOINT FOR THE FIGHT AGAINST CENTRAL NERVOUS SYSTEM TUMORS
Authors: Michael Olin, Zhengming Xiong, Elisabeth Pluhar, and Christopher Moertel
Journal: Neuro-Oncology (2018)

Numerous ongoing clinical trials targeting immune checkpoints have failed to enhance survival in patients with CNS tumors. We are targeting a unique checkpoint, CD200, which controls the immune system through paired inhibitory and activation receptors. The CD200 checkpoint interferes with tumor-immune interactions through multiple mechanisms: i) CD200 is secreted from tumors inducing an immunosuppressive environment, ii) CD200 is upregulated in tumor-associated vascular endothelial cells, creating an immunological barricade around the tumor microenvironment. We are targeting the activation receptor with a peptide ligand (CD200AR-L) activates antigen-presenting cells, enhancing dendritic cell maturation, cytokine production and antigen specific T cell activation. Treatment with CD200AR-L significantly extends survival in two murine glioma models. Directing the immune system to fight the tumor, requires introduction of an antigen such as autologous or allogeneic tumor lysate for non-immunogenic tumors such as CNS tumors. In an ongoing pilot study treating companion dogs with high-grade glioma, patients receiving a canine specific CD200 peptide inhibitor in combination with the autologous tumor lysate vaccine increased median survival to 330 days, compared to 194 with lysate alone. Currently, 41% of the dogs are alive; the longest living dog is now 810 days post-surgery. 28% of dogs died of non-tumor related deaths. In contrast, 100% of the dogs in the tumor lysate-only group died of tumor recurrence. Furthermore, serum chemistry profiles and physical examinations showed that the peptide did not induce any systemic toxicity. Importantly, we have developed human CD200 peptide ligands that enhance cytokine secretion, dendritic cell maturation, and antigen-specific immune response. This innovative research may provide a significant breakthrough for the field of cancer immunotherapy. We have also demonstrated that the use of a CD200AR-L in a murine breast carcinoma model resulted in a significant survival benefit. In this light, CD200AR-L may be a powerful immunotherapy platform for other solid tumors.
ATIM-15. A PHASE 1 STUDY OF Ad-RTS-hIL-12 + VELEDIMEX IN ADULTS WITH RECURRENT GLIOBLASTOMA: DOSE DETERMINATION WITH UPDATED OVERALL SURVIVAL
Authors: E Antonio Chiocca, Rimas Lukas, John Yu, Nancy Ann Oberheim Bush, Jill Buck, Nathan Demars, John Barrett, Arnold Gelb, Yunxia Wang, Laurence Cooper, Francois Lebel
Journal: Neuro-Oncology (2018)

Ad-RTS-hIL-12 (Ad) is a novel gene therapy expressing IL-12 via the RheoSwitch Therapeutic System® gene switch under control of an oral activator ligand, veledimex (V). We previously reported on an open label Phase I trial describing biological activity of recombinant IL-12 with downstream IFN-γ and activation of the immune system. We provide an update on the intratumoral injections of Ad (2x1011virus-particles) + V for patients with recurrent GBM (rGBM) in Group 1 (G1) (craniotomy, n=31) and initial results for Group 2 (G2) (stereotactic administration n=7). In G1, the V 20-mg cohort mOS increased to 12.7 months with mean follow-up of 12.9 months. 20-mg V in G1 showed fewer toxicities and higher V compliance (84%) compared with higher-doses of V (30 and 40-mg) with 75% and 67%, respectively. These data are encouraging compared to historical data that predict mOS of 5 to 8 months. An additional cohort at V 10-mg (n=6) was well tolerated, but subtherapeutic, with a mOS of 7.6 months (mean follow-up 6.7 months). There was an association between V dose level, blood-brain-barrier penetration, and drug-related adverse events (AEs) with increased TEAEs observed above V 20-mg. Subgroup analyses across all cohorts did not detect statistically significant differences including extent of resection or IDH mutation status. Subjects (20-mg V) who received a cumulative dose of ≤10mg of dexamethasone during the first 15 days of treatment showed improved OS versus >100mg of dexamethasone, suggesting corticosteroid-mediated blunting of the IL-12 dependent immune-mediated therapeutic effect. In the G2 20-mg V cohort, similar cytokine levels and reversible AEs were observed compared to G1; follow up is ongoing and mOS will be presented. Based on these results and the best risk-benefit profile, the 20-mg V dose level was chosen for further investigation. Combination with an immune checkpoint inhibitor in rGBM is underway.
INNV-09. PILOT STUDY OF A SMARTPHONE-BASED SYMPTOM ASSESSMENT (OURBRAINBANK) FOR SUBJECTS WITH GLIOBLASTOMAS
Authors: Jessica Morris, Kelli Duprey, Bruce Hellman, Ceci Zak, Lakshmi Nayak, Fabio Iwamoto
Journal: Neuro-Oncology (2018)

Self-reports from patients done monthly or every few months in the doctor’s office have several limitations, including poor recall, under- or over-reporting of events, among other biases. We developed a glioblastoma specific app (OurBrainBank) using a platform designed by uMotif, which was previously used in other conditions but has been customized for glioblastoma. All data are sent to a HIPPA compliant database. The subject can view or export their own data as well. Inclusion criteria included age 18 years or older, diagnosis of glioblastoma, English-speaking subject, and availability of a smartphone or tablet. After electronic informed consent, patients completed baseline questionnaires about their treatment and validated surveys (EORTC-QLQ, EORTC-BN20). Certain parameters such as sleep quality, exercise, mood, and fatigue were captured for all patients. In addition, patients picked 6 additional symptoms most relevant to their clinical condition. Over a 2-month period, since the study was IRB-approved and the app made available free of charge on app stores, there have been 591 individual patients downloads (167 on Android and 424 on iOS). Recruitment has relied heavily on social media and patient run online support groups. We will present the data on compliance, patient characteristics and symptoms tracking at the meeting. At this initial stage, OurBrainBank’s focus is on capturing patients’ symptoms. In the next steps, we plan to collect passive data from smartphones and other device trackers. Additionally, OurBrainBank will enable patients to donate their medical records to the database. The goal over the next few years is to create an unprecedented database of high quality and granularity with tens of thousands of de-identified glioblastoma patients, with open-access to qualified academic researchers. In addition, this powerful ‘real world experience’ database will be useful for pharma/biotech companies, and may also facilitate FDA drug approvals for glioblastoma.