tbuckley/cabot-search huggingface dataset:
EXTH-12. EFFECT OF THE PROTEIN ARGININE METHYLTRANSFERASE PRMT5 INHIBITION IN GLIOMA STEM-LIKE CELLS
Authors: Sandeep Mittal, Vikram Shaw, Yuji Piao, Soon Young Park, Sai Sriram, Jianwen Dong, Emmanuel Martinez-Ledesma, Verlene Henry, Ravesanker Ezhilarasan, Erik Sulman, Veerakumar Balasubramaniyan, John de Groot
Journal: Neuro-Oncology (2018)

Protein arginine methyltransferases (PRMTs) have gained significant scientific attention due to their ability to regulate various biological functions including epigenetic regulation, cell differentiation, signal transduction and most importantly their dysregulation in human disease including cancer. Among various cancers, Glioblastoma is the most aggressive primary malignant brain tumor with few effective therapies. Currently, in glioblastoma therapy, the high expression level of Protein arginine methyltransferase 5 (PRMT5) has been reported as a therapeutic target which represses the transcription of a target gene via forming symmetric dimethylarginine (SDMA) residues. By using a panel of molecularly distinct glioma stem like cells (GSCs) we investigated the effect of PRMT5 inhibitor GSK591 on cell viability. Furthermore, genomic, proteomic (reverse protein lysate array, RPPA), methylation status and GSC subtype were correlated with GSK591 IC50 to find predictors of drug sensitivity. Western blotting data showed high expression of PRMT5 and multiple bands of SDMAs in most GSCs tested (n=31) irrespective of molecular subtype, indicating PRMT5 enzymatic activity in GSC cell lines. However, there is only a small subset of 4 GSC lines (13%) as showed complete inhibition of SDMA expression at low doses (< 1.5 µM) in dose- and time-dependent fashion after GSK591 treatment. The sensitivity of GSK591 correlated with low methylation of multiple genes pre-treatment, including MAGI2, EGR2, and DUSP16. In addition, up-regulated genes in sensitive GSCs correlated with proliferation signatures using gene set enrichment analyses (GSEA). Including this, we also found the upregulation of senescence marker along with activation of autophagy genes (Beclin-1 and Akt) in GSCs sensitive to GSK591. Tight regulation of Akt-mTOR pathway enables cancer cells to survive in harsh conditions via activation of autophagy signaling. Currently, we are investigating the role of PRMT5 in tumor growth through the concomitant regulation of autophagy signaling in GSCs.
CADD-32. MECHANISMS OF ENHANCED DRUG DELIVERY IN BRAIN TUMORS WITH FOCUSED ULTRASOUND-INDUCED TRANSIENT BLOOD-TUMOR BARRIER DISRUPTION
Authors: Costas Arvanitis, Vasileios Askoxylakis, Yutong Guo, Meenal Datta, Jonas Kloepper, Gino Ferraro, Miguel Bernabeu, Dai Fukumura, Nathan McDannold, Rakesh Jain
Journal: Neuro-Oncology (2018)

Blood-brain/blood-tumor barriers (BBB and BTB) and interstitial transport may constitute major obstacles to the transport of therapeutics in brain tumors. In this study, we examined the impact of focused ultrasound (FUS) in combination with microbubbles on the transport of two relevant chemotherapy-based anticancer agents in HER2-positive breast cancer brain metastases at cellular resolution: doxorubicin, a non-targeted low molecular weight chemotherapeutic, and ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate. Using an orthotopic xenograft model of HER2-positive breast cancer brain metastasis and quantitative microscopy we demonstrate significant increases in the extravasation of both agents (7-fold and 2-fold for doxorubicin and T-DM1, respectively) and we provide evidence of increased drug penetration (>100µm vs. <20µm and 42 ± 7µm vs. 12 ± 4µm for doxorubicin and T-DM1, respectively) after application of FUS as compared to control (non-FUS). Integration of experimental data with physiologically based pharmacokinetic (PBPK) modeling of drug transport reveals that FUS in combination with microbubbles alleviates vascular barriers and enhances interstitial convective transport via an increase in hydraulic conductivity. Combination of experimental data and PBPK modeling suggests that FUS in combination with microbubbles increases the endothelial cell transmembrane transport and uptake. PBPK modeling indicates a selective increase in transvascular transport of doxorubicin through small vessel-wall pores size with a narrow range (Diameter: 10-50nm). Our work provides a quantitative framework for the optimization of FUS-drug combinations to maximize intratumoral drug delivery and facilitate the development of novel strategies to treat brain metastases.
Abstract 110: The Association Between the Timing of Epinephrine (Adrenalin) Administration and Survival from Out-of-Hospital Ventricular Fibrillation Arrest
Authors: Gordon A Ewy, Bentley J Bobrow, Vatsal Chikani, Arthur B Sanders, Charles W Otto, Mathias Zuercher, Daniel Spaite, Karl B Kern
Journal: Circulation (2014)

Introduction: The benefit of epinephrine administration by emergency medical services providers (EMS) during resuscitation of patients with out-of-hospital-cardiac arrest (OHCA) is controversial. To address the association of the timing of epinephrine administration and outcome, we accessed the Save Hearts in Arizona Register and Educational (SHARE) program registry, and analyzed the time between 9-1-1 dispatches, the first dose of epinephrine and survival to hospital discharge. Methods: A retrospective analysis of prospectively collected statewide OHCA data using the SHARE database between October 2004 and December 2013. Results: There were 2,213 OHCA with a shockable initial rhythm who received epinephrine by EMS. Logistic regression was performed adjusted for age, gender, witnessed, bystander CPR, arrival time (dispatch to scene), and dispatch to defibrillation time, year, and method of ventilation. Of these, 396 (17.8%) survived to discharge. The times from dispatch to first epinephrine administration were analyzed. Survival progressively decreased with longer time intervals of epinephrine administration: Survival, &lt; 9 min (99/398) 24.8%, 9-13 min (216/1,058) 20.4% and &gt;13 min (81/757) 10.7%. The Adjusted odds ratio for decreased survival for the group receiving epinephrine after 13 minutes was 2.32 (95% CI 1.5-3.4) (p&lt;0.0001). The neurological CPC Scores of the 242 survivors was also related to time delay of epinephrine administration: CPC 1 or 2 were; &lt; 9 min 69 (17.3%), 9-13 min 132 (12.4%), &gt;13 min 47 (6.2%). Survival was significantly less in those receiving epinephrine &gt;13 min after EMS arrival (Chi Square p&lt;0.0001). Conclusion: In this retrospective database analysis, epinephrine administered by EMS to patients with OHCA and a shockable rhythm in &lt;13 min from dispatch was associated with significant improvement in survival compared to epinephrine administered &gt;13 min after dispatch.
Abstract 15558: Impact of Temporal Changes in Body Fat Distribution on Blood Pressure and Hypertension: Observations From the Dallas Heart Study
Authors: Alvin Chandra, Colby Ayers, Ian Neeland
Journal: Circulation (2017)

Background: Increased visceral adiposity is associated with incident hypertension independent of other adiposity measures. The effects of changes in visceral adiposity over time on hypertension is ...
Hepatology Highlights
Authors: Omar Mousa, Harmeet Malhi, Robert E. Schwartz, Tasha B. Kulai, Hirsh D. Trivedi, Daryl T.Y. Lau, Nicole T. Shen, Robert S. Brown, Petra Hirsova, Xu Xu, Hayley T. Nicholls, Joseph F. Pisa, Zaid H. Tafesh, Brett E. Fortune, Vikas Gupta, Enis Kostallari, Nicholas Russo, Arun B. Jesudian
Journal: Hepatology (2019)

Mousa, Omar; Malhi, Harmeet; Schwartz, Robert E.; Kulai, Tasha B.; Trivedi, Hirsh D.; Lau, Daryl T.Y.; Shen, Nicole T.; Brown, Robert S. Jr.; Hirsova, Petra; Xu, Xu; Nicholls, Hayley T.; Pisa, Joseph F.; Tafesh, Zaid H.; Fortune, Brett E.; Gupta, Vikas; Kostallari, Enis; Russo, Nicholas; Jesudian, Arun B. Author Information
SURG-15. UPFRONT MRI-GUIDED STEREOTACTIC LASER-ABLATION IN NEWLY DIAGNOSED GLIOBLASTOMA: A MULTICENTER REVIEW OF SURVIVAL OUTCOMES COMPARED TO A MATCHED COHORT OF BIOPSY-ONLY PATIENTS
Authors: Alireza Mohammadi, Mayur Sharma, Thomas Beaumont, Kevin Juarez, Hanna Kemeny, Cosette Dechant, Andreas Seas, Nehaw Sarmey, Bryan Lee, Xuefie Jia, Peter Fecci, Joachim Baehring, Jennifer Moliterno, Veronica Chiang, Manmeet Ahluwalia, Albert Kim, Gene Barnett, Eric Leuthardt
Journal: Neuro-Oncology (2018)

Laser ablation (LA) is used as an upfront treatment in patients with deep seated newly diagnosed Glioblastoma (nGBM). We evaluated the outcomes of LA in patients with nGBM and compared them with a matched biopsy-only cohort. 24 nGBM patients underwent upfront LA at Cleveland Clinic, Washington University in St. Louis and Yale University (6/2011–12/2014) followed by chemo/radiotherapy (CRT). Also, 24 out of 171 nGBM patients with biopsy from Duke and Yale Universities who followed by CRT were matched with our LA cohort based on age (<70 vs 70), gender, tumor location (deep vs lobar) and volume (<11 cc vs 11 cc). Progression-free survival (PFS), overall survival (OS), disease-specific PFS and OS ((DS-PFS, DS-OS) were our endpoints. Three prognostic groups were identified based on extent of tumor ablation by thermal-damage-threshold (TDT)-lines. The median tumor volume in LA (n=24) and biopsy only (n=24) groups was 9.3 cm3 and 8.2 cm3 respectively. Overall, median estimate of OS and PFS in LA cohort was 14.4 and 4.3 months compared to 15.8 months and 5.9 months for biopsy only cohort. On multivariate analysis, favorable TDT-line prognostic groups were associated with lower incidence of disease specific death (p=0.03) and progression (p=0.05) compared to other groups including biopsy only cohort. Only age (<70 years, p=0.02) and tumor volume (<11 cc, p=0.03) were favorable prognostic factors for OS. CONCLUSIONS: The maximum tumor coverage by laser ablation followed by radiation/chemotherapy is an effective treatment modality in patients with newly diagnosed GBM who are not a candidate for standard craniotomy, compared to biopsy only cohort. The TDT-line prognostic groups were independent predictor of disease specific death and progression after laser ablation.
SURG-20. LASER-INTERSTITIAL THERMAL THERAPY VERSUS CRANIOTOMY FOR TREATMENT OF RADIATION NECROSIS OR RECURRENT TUMOR IN BRAIN METASTASES FAILING RADIOSURGERY
Authors: Christopher Hong, Judy Deng, Alberto Vera, Veronica Chiang
Journal: Neuro-Oncology (2018)

Laser-interstitial thermal therapy (LITT) and craniotomy are both options for treatment of radiation necrosis (RN) and re-growing tumor (RT) occurring after radiosurgery for brain metastases. No studies to-date have compared the two options. We performed a single institution, single surgeon retrospective study of previously irradiated brain metastases treated by LITT or craniotomy between February 2007 and September 2016. Data collected included demographics, steroid dosing, neurological outcomes, local progression-free survival (PFS), and overall survival from surgery date. Categorical variables and outcomes were analyzed with Fishers exact and log-rank tests, respectively. Of 75 patients, 42 had RT (56%) and 33 (44%) purely RN. Of patients with RT, 26 underwent craniotomy and 16 LITT. For RN, 15 had craniotomy and 18 LITT. No significant difference was found between LITT and craniotomy in ability to taper off steroids (p=0.53), including ability to initiate or resume immunotherapy post-operatively in melanoma patients (craniotomy: 10/16, 62.5% versus LITT: 8/11, 72.7%; p=0.69). PFS and OS were similar for LITT versus craniotomy, respectively: %PFS at 1-year = 72.2% versus 61.1%, %PFS at 2-years = 60.0% versus 61.1%, p=0.72; %OS at 1-year = 69.0% versus 69.3%, %OS at 2-years = 56.6% versus 49.5%, p=0.90. Craniotomy resulted in higher rates of pre-operative deficit improvement than LITT (p<0.01). On subgroup analysis, patients undergoing craniotomy for RN trended towards improved PFS compared with those undergoing LITT for RN or those with tumor (regardless of local treatment option). LITT appears to be as efficacious as craniotomy in achieving local control of recurrent irradiated brain metastases and facilitating steroid taper, regardless of pathology, including post-operative initiation or resumption of immunotherapy in melanoma patients. Craniotomy, however, is more advantageous in relieving those with pre-operative symptoms and may provide a survival advantage in those with radiation necrosis.
PDCT-11. SURVEILLANCE DATA DEMONSTRATES THE TOLERABILITY OF TUMOR TREATING FIELDS IN PEDIATRIC GLIOMA PATIENTS
Authors: Derek Hanson
Journal: Neuro-Oncology (2018)

There are few treatment options for pediatric patients with high grade gliomas Adult patients with newly diagnosed or recurrent glioblastoma multiforme have the option of treatment with tumor treating fields (TTFields), which have shown efficacy and safety in Phase 3 randomized trials. TTFields are a noninvasive anti-mitotic therapy administered via transducer arrays strategically arranged on the shaved scalp. TTFields are not approved for the treatment of high grade glioma in pediatric patients. Post-marketing surveillance data were collected for pediatric glioma patients receiving TTFields. Compiled safety data are presented for patients <18 years receiving TTFields for the treatment of glioma. A review of the clinical information for pediatric patients (<18 years of age) treated with TTFields in the United States and Europe identified 30 patients. The safety data obtained from post-market surveillance in all 30 patients were analyzed to identify adverse events (AEs) based on the MedDRA body system (system organ class) preferred terms. Sixteen (53%) pediatric patients experienced at least 1 AE while receiving TTFields treatment. Patients reported general AEs include: electric sensations in 10% (3/30); fatigue in 10% (3/30), heat sensation in 10% (3/30) and 17% reported pain (5/30) in any location. Nervous system AEs included headache (10%), seizure (7%) and balance disorder (7%). The most common AE were skin reactions that were reported by 7 patients (23%). One patient reported hyperhidrosis (3%). CONCLUSIONS: There were no unexpected AEs associated with TTFields in pediatric patients. The most frequently reported AEs were skin reactions likely related to the placement of TTFields transducers on the scalp; incidence was comparable to the rate of skin reactions reported in adult GBM patients. The tolerability of TTFields in pediatric patients from this post-marketing surveillance data support further investigations to assess efficacy and safety of TTFields in pediatric glioma patients.
CMET-41. LIFETIME LUNG, BREAST, AND SKIN CANCER BRAIN METASTASES INCIDENCE: A REPRODUCIBLE SEER-MEDICARE STUDY
Authors: Mustafa Ascha, Quinn Ostrom, Jeremy Bordeaux, Andrew Sloan, Frederick Schumacher, Carol Kruchko, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2018)

With improvements in cancer detection and primary cancer control, brain metastases (BM) become a greater concern. The Surveillance, Epidemiology, and End-Results (SEER) program recently released data on BM diagnosed at the same time as primary cancer, referred to as synchronous BM (SBM). Tentative evidence of lifetime BM (LBM) is present in Medicare claims, expanding the utility of these new SBM data. This is a reproducible SEER-Medicare study estimating synchronous versus lifetime frequencies of BM for primary lung, breast, and skin cancers. MATERIALS AND SEER data were linked to Medicare claims from 2007–2014 to identify incidence proportions (IP) and average annual age-adjusted incidence rates of SBM and LBM. SEER SBM data were linked to Medicare claims and used as a gold standard to evaluate Medicare BM algorithms, the classification performance of which informed similar estimates of LBM incidence. The IP of SEER SBM in lung, breast, and skin cancers was 9.6%, 0.3%, and 1.1%, respectively. The greatest SBM IP among lung cancer patients was 13.4% for non-small cell lung cancer, and among breast cancer patients was 0.7% for triple-negative breast cancer. The greatest LBM IP among lung cancers was 21.7% in small-cell lung cancer, 4.0% in triple negative cases for breast cancer, and 1.7% in nevi and melanomas. Concordance between Medicare claims and SEER regarding SBM was 0.61 (95% CI: 0.60 - 0.62) for lung cancer, 0.45 (95% CI: 0.39 - 0.51) for breast cancers, and 0.65 (95% CI: 0.59 - 0.70) for melanoma. Fewer SBM cases were found in Medicare claims than in SEER. CONCLUSIONS: These analyses provide a population-level glimpse into the natural history of BM, estimating both synchronous and lifetime incidence in lung, breast, and skin cancers using a large dataset that is representative of the US.
INNV-06. FACTORS INFLUENCING RECEPTIVITY TO CLINICAL RESEARCH IN AN URBAN NEURO-ONCOLOGY PRACTICE
Authors: Mary Welch, Grant Conway, Grace Hillyer, Leslie Segall, Dan Otap, Laura Donovan, Teri Kreisl, Fabio Iwamoto, Andrew B Lassman
Journal: Neuro-Oncology (2018)

Fewer than 3% of cancer patients participate in clinical trials. Nervous system involvement creates additional challenges to accrual including reduced capacity for informed decision-making and increased reliance on caregivers. To better identify barriers to enrollment, we designed and tested surveys to elicit patient perceptions about research and collect data on potential factors influencing receptivity to involvement. A 20-item survey, later expanded to 44, was provided to patients at the time of their first outpatient visit. The survey was voluntary and administered as part of a QI initiative conducted by Columbia’s Division of Neuro-oncology over the course of 54 clinical practice days. Questions assessed demographics (race/ethnicity, education, language, employment, marital status); social support; travel burden; medical information and decision-making preferences; receptivity to participation in research and rationales for refusal. Approximately 200 patients received the questionnaire; 139 (70%) responded. Median age was 55 (range: 17–85). There were 70 (50%) men; 55 (40%) self-identified as non-Hispanic White; 20 (14%) were non-fluent in English. Diagnoses included high grade glioma (29%), CNS metastases (24%), meningioma (13%), primary CNS lymphoma (3%) and low-grade glioma (5%). Of 121 responders, 37 (31%) were unwilling to participate in research a priori. The percentage increased to 42% if randomization was involved, 61% if placebo-controlled. Logistic regression was performed to assess the impact of factors on respondents’ willingness to participate in clinical research. Disease severity was the strongest predictor of receptivity (OR: 3.4; CI 1.3–8.8), but full-time employment (OR: 3.2; CI 1.2–8.5) and the presence of caregiver support (OR: 5.4; CI: 1.2–24.4) were also significant. While further research is needed to better understand barriers to trial enrollment, caregiver influence remains largely unexplored. To that end, Columbia is undertaking a pilot to assess the short and long-term impacts of high grade glioma on caregivers and their role in clinical decision making.
The Reciprocity between Radiotherapy and Cancer Immunotherapy
Authors: Yifan Wang, Zhi-Gang Liu, Hengfeng Yuan, Weiye Deng, Jing Li, Yuhui Huang, Betty Y.S. Kim, Michael D. Story, Wen Jiang
Journal: Clinical Cancer Research (2018)

The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in treating locally advanced diseases, thus requiring them to be combined with standard treatments in the hope of producing synergistic antitumor responses. Radiotherapy, in particular, has long been hypothesized to have actions complementary to those of immune checkpoint blockade, and a growing body of evidence indicates that cancer immunotherapy may also have radiosensitizing effects, which would provide unique benefit for locoregional treatments. Recent studies have demonstrated that when immune cells are activated by immunotherapeutics, they can reprogram the tumor microenvironment in ways that may potentially increase the radiosensitivity of the tumor. In this review, we highlight the evidence that supports reciprocal interactions between cancer immunotherapy and radiotherapy, where in addition to the traditional notion that radiation serves to enhance the activation of antitumor immunity, an alternative scenario also exists in which T-cell activation by cancer immunotherapy may sensitize tumors to radiation treatment through mechanisms that include normalization of the tumor vasculature and tissue hypoxia. We describe the empirical observations from preclinical models that support such effects and discuss their implications for future research and trial design.
PRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival
Authors: Xiaoqing Lu, Tharu M. Fernando, Chen Lossos, Nevin Yusufova, Fan Liu, Lorena Fontán, Matthew Durant, Huimin Geng, Jacob Melnick, Yuan Luo, Francisco Vega, Vincent Moy, Giorgio Inghirami, Stephen Nimer, Ari M. Melnick, Izidore S. Lossos
Journal: Blood (2018)
Updates in prognostic markers for gliomas
Authors: Elisa Aquilanti, Julie Miller, Sandro Santagata, Daniel P Cahill, Priscilla K Brastianos
Journal: Neuro-Oncology (2018)

Gliomas are the most common primary malignant brain tumor in adults. The traditional classification of gliomas has been based on histologic features and tumor grade. The advent of sophisticated molecular diagnostic techniques has led to a deeper understanding of genomic drivers implicated in gliomagenesis, some of which have important prognostic implications. These advances have led to an extensive revision of the World Health Organization classification of diffuse gliomas to include molecular markers such as isocitrate dehydrogenase mutation, 1p/19q codeletion, and histone mutations as integral components of brain tumor classification. Here, we report a comprehensive analysis of molecular prognostic factors for patients with gliomas, including those mentioned above, but also extending to others such as telomerase reverse transcriptase promoter mutations, O6-methylguanine-DNA methyltransferase promoter methylation, glioma cytosine-phosphate-guanine island methylator phenotype DNA methylation, and epidermal growth factor receptor alterations.